1,4-DIHYDROPYRIDINE DERIVATIVES, PROCESS FOR PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION OF THE SAME

DERIVES DE LA 1,4-DIHYDROPYRIDINE; LEUR PREPARATION ET LES PRODUITS PHARMACEUTIQUES QUI EN DERIVENT

English Abstract

ABSTRACT OF THE DISCLOSURE
New 1,4-dihydropyridine derivatives and their process
of preparation are provided of the formula:-
<IMG>
wherein R1 is aryl which may have one or more suitable substit-
uent(s) or
a heterocyclic group,
R2 and R3 are each, same or different, esterified
carboxy, and
R4 and R5 are each hydrogen; cyano; lower alkyl; or
substituted lower alkyl in which the substituent
is cyano, hydroxy, acyloxy, hydroxyimino, hydra-
zono, lower alkoxyimino, hydroxy(lower)-alkylimino,
N'-or N', N'-di-(lower)alkylamino-(lower)alkylimino,
hydrazino, hydroxy(lower)-alkylamino, N'-or N', N'-
di(lower)alkylamino-(lower)alkylamino, a 5 or 6-
membered saturated N-containing heterocyclic-1-yl
which may have hydroxy, lower alkyl or hydroxy
(lower)alkyl, or oxo wherein thus formed carbonyl
may be protected with suitable protecting group;
provided that, when one of R4 and R5 is hydrogen
or lower alkyl, the other is always cyano or said
substituted lower alkyl, and when R4 and R5 are not
hydrogen or lower alkyl, both of them are a group
selected from cyano and said substituted lower alkyl,
or R4 is hydrogen or lower alkyl and R3 and R5 are combined
to form a group of the formula:

<IMG> , <IMG> , <IMG> or <IMG>
wherein R6 is hydrogen or methyl and R7 is 2-(N,N-
diethylamino)ethyl or 2-hydroxyethyl; the compounds
have vasodilating and anti-hypertensive activity,
and are useful for therapeutical treatment in cardio-
vascular diseases and hypertension in human beings.

Claims

The embodiments of the invention in which an exclu-
sive property or privilege is claimed are defined as follows:
1. A process for preparation of a 1,4-dihydropyridine
derivative of the formula:
<IMG> (I)
wherein R1 is phenyl which is unsubstituted or substituted by
one or more substituents selected from the group con-
sisting of halogen, nitro, trihalo(lower)alkyl, lower
alkoxy, hydroxy and lower alkenyloxy; thienyl; or
furyl;
R2 and R3 which may be the same or different are each
lower alkoxycarbonyl, halo(lower)alkoxycarbonyl,
hydroxy(lower)alkoxycarbonyl, lower alkoxy(lower)-
alkoxycarbonyl, phenyl(lower)alkoxycarbonyl, phenyl-
(lower)alkoxy(lower)alkoxycarbonyl, phenoxy(lower)-
alkoxycarbonyl, N,N-di(lower)alkylamino(lower)alkoxy-
carbonyl or N-lower alkyl-N-phenyl(lower)alkylamino-
(lower)alkoxycarbonyl; and
R4 and R5, which may be the same or different, are
each hydrogen; cyano; lower alkyl; or substituted lower
alkyl in which the substituent is selected from the
group consisting of cyano, hydroxy, lower alkanoyloxy,
carboxy(lower)alkanoyloxy, lower alkoxycarbonyl-
(lower)alkanoyloxy, N-lower alkyl-N-phenyl(lower)-
alkylamino(lower)alkanoyloxy, benzoyloxy, 4-chloro-
148

phenoxyacetoxy, hydroxyimino, hydrazono, lower
alkoxyimino, hydroxy(lower)alkylimino, N', N'-di-
(lower)alkylamino(lower)alkylimino, hydroxy(lower)-
alkylamino, N' , N'-di(lower)alkylamino(lower)-
alkylamino, piperazin-1-yl substituted by lower
alkyl or hydroxy(lower)alkyl, oxo, gem-di(lower)
alkoxy, and gem-lower alkylenedioxy, provided that,
when one of R4 and R5 is hydrogen or lower alkyl, the
other is cyano or said substituted lower alkyl, and
when R4 and R5 are not hydrogen or lower alkyl, R4
and R5 are both the same group, which is selected
from cyano and said substituted lower alkyl or
R4 is hydrogen or lower alkyl and R3 and R5 are com-
bined to form a group of the formula:
<IMG> or <IMG>
wherein R6 is hydrogen or methyl and R7 is 2-(N,N-diethylamino)-
ethyl or 2-hydroxyethyl, which comprises
(a)-(i) reacting a compound of the formula:
<IMG> (II)
wherein R1, R3 and R5a are each as defined below, with an amino
compound of the formula:
<IMG> (III)
wherein R2 and R4a are each as defined below,
(ii) subjecting a mixture of an aldehyde compound of the
formula:
149

R1 -CHO (II')
wherein R1 is as defined below,
an ester of .beta.-ketonic acid of the formula:
R5a - COCH2 - R3 (II")
wherein R3 and R5a are each as defined below,
and an amino compound of formula (III) as defined above, to
reaction, or
(iii) reacting an acetylene compound of the formula:
R2 - C?C -R4a (III')
wherein R2 and R4a are each as defined below,
with ammonia or an ammonium salt and a compound of formula (II)
as defined above to give a compound of the formula:
<IMG> (I-1)
wherein R1, R2 and R3 are each as defined above and R4a and R5a
are each hydrogen, lower alkyl or lower alkyl substituted with
gem-di(lower)alkoxy or gem-lower alkylenedioxy, provided that at
least one of R4a and R5a is lower alkyl substituted with gem-di-
(lower)alkoxy or lower alkylenedioxy, and when neither R4a nor
R5a is hydrogen or lower alkyl, R4a and R5a are both the same, or
(b) hydrolysing a compound of the formula:
<IMG> (I-1)
wherein R1, R2, R3, R4a and R5a are each as defined above, to
give a compound of the formula:
150

<IMG> (I-2)
wherein R1, R2 and R3 are each as defined above and R4b and R5b
are each hydrogen, lower alkyl or lower alkyl substituted with
oxo, provided that at least one of R4b and R5b is lower alkyl
substituted with oxo, and when neither R4b nor R5b is hydrogen
or lower alkyl, R4b and R5b are both the same, or
(c) reacting a compound of the formula:
<IMG> (I-2)
wherein R1, R2, R3, R4b and R5b are each as defined above, with
an amine of the formula:
R8 - NH2 (IV)
wherein R8 is hydroxy, amino, lower alkoxy, hydroxy(lower)alkyl
or N' ,N'-di(lower)alkylamino(lower)alkyl, to give a compound
of the formula:
<IMG> (I-3)
wherein R1, R2 and R3 are each as defined above and R4c and R5c
which may be the same or different, are each. hydrogen, lower
alkyl or substituted lower alkyl in which the substituent is
selected from the group consisting of hydroxyimino, hydrazono,
lower alkoxyimino, hydroxy(lower)alkylimino and N' ,N'-di(lower)-
151

alkylamino(lower)alkylimino, provided that at least one of R4c
and R5c is said substituted lower alkyl, and when neither R4c
nor R5c is hydrogen or lower alkyl, R4c and R5c are both the
same, or
(d) treating a compound of the formula:
<IMG> (I-3')
wherein R1, R2 and R3 are each as defined above and R'4c and
R'5c, which may be the same or different, are each hydrogen,
lower alkyl or .omega.-hydroxyimino(lower)alkyl, provided that at
least one of R'4c and R'5c is .omega. -hydroxyimino(lower)alkyI, and
when neither R'4c nor R'5c is hydrogen or lower alkyl, R'4c and
R'5c are both the same, with a dehydrating agent to give a com-
pound of the formula:
<IMG> (I-4)
wherein R1, R2 and R3 are each as defined above and R4d and R5d
which may be the same or different, are each hydrogen, lower
alkyl, cyano or .omega.-cyano(lower)alkyl, provided that, when one of
R4d and R5d is hydrogen or lower alkyl, the other is cyano or
.omega. -cyano(lower)alkyl, and when R5d and R4d are not hydrogen
or lower alkyl, R5d and R4d are both the same group, which is
selected from cyano or .omega.-cyano(lower)alkyl, or R4d is hydrogen
or lower alkyl and R3 and R5d are combined together to form a
group of the formula:
<IMG>
or
(e) reducing a compound of the formula:
152

<IMG> (I-2')
wherein R1, R2 and R3 are each as defined above and R'4b and
R'5b, which may be the same or different, are each hydrogen,
lower alkyl or substituted lower alkyl in which the substituent
is oxo, hydroxy(lower)alkylimino or N' ,N'-di(lower)alkylamino-
(lower)alkylimino, provided that at least one of R'4b and R'5b
is said substituted lower alkyl and when neither R'4b nor R'5b
is hydrogen or lower alkyl, R'4b and R'5b are both the same,
to give a compound of the formula:
<IMG> (I-5)
wherein R1, R2 and R3 are each as defined above and R4e and R5e,
which may be the same or different, are each hydrogen, lower
alkyl or substituted lower alkyl in which the substituent is
hydroxy, hydroxy(lower)alkylamino or N' ,N'-di(lower)alkylamino-
(lower)alkylamino, provided that at least one of R4e and R5e is
said substituted lower alkyl, and when neither R4e nor R5e is
hydrogen or lower alkyl, R4e and R5e are both the same; or R4e
is hydrogen or lower alkyl and R3 and R5e are combined together
to form
<IMG> or <IMG>
wherein R6 and R7 are each as defined above, or
(f) reacting a compound of the formula
153

<IMG> (I-5')
wherein R1, R2 and R3 are each as defined above and R'4e and
R'5e, which may be the same or different, are each hydrogen,
lower alkyl or hydroxy(lower)alkyl, provided that at least one
of R'4e and R'5e is hydroxy(lower)alkyl, and when neither R'4e
nor R'5e is hydrogen and lower alkyl, R'4e and R'5e are both
the same, with an acylating agent of the formula:
R9 - OH (V)
wherein R9 is lower alkanoyl, carboxy(lower)alkanoyl, lower
alkoxycarbonyl(lower)alkanoyl, N-lower alkyl-N-phenyl(lower)-
alkylamino(lower)alkanoyl, benzoyl or 4-chlorophenoxyacetyl, or
a reactive derivative thereof, to give a compound of the formula:
<IMG> (I-6)
wherein R1, R2 and R3 are each as defined above and R4f and R5f,
which may be the same or different, are each hydrogen, lower
alkyl and acyloxy(lower)alkyl, in which the acyl moiety is se-
lected from the group consisting of lower alkanoyl, carboxy-
(lower)alkanoyl, lower alkoxycarbonyl(lower)alkanoyl, N-lower
alkyl-N-phenyl(lower)alkylamino(lower)alkanoyl, benzoyl and 4-
chlorophenoxyacetyl, provided that at least one of R4f and R5f
is said acyloxy(lower)alkyl, and when neither R4f nor R5f is
hydrogen or lower alkyl, R4f and R5f are both the same, or
(g) oxidizing a compound of the formula:
154

<IMG> (I-5")
wherein R1, R2 and R3 are each as defined above and R"4e and
R"5e, which may be the same or different, are each hydrogen,
lower alkyl, or .omega.-hydroxy(lower)alkyl, provided that at least
one of R"4e and R"5e is .omega.-hydroxy(lower)alkyl, and when neither
R"4e nor R"5e is hydrogen or lower alkyl, both R"4e and R"5e
are the same, to give a compound of the formula:
<IMG> (I-7)
wherein R1, R2 and R3 are each as defined above and R4g and R5g,
which may be the same or different, are each hydrogen, lower
alkyl, formyl or .omega. -formyl(lower)alkyl, provided that, when one
of R4g and R5g is hydrogen or lower alkyl, the other is always
formyl or .omega. -formyl(lower)alkyl, and when R4g and R5g are not
hydrogen or lower alkyl, both of them are the same group select-
ed from formyl and .omega.-formyl(lower)alkyl, or
(h) heating a compound of formula (I-5), as defined above,
wherein R4e is hydrogen or lower alkyl and R5e is hydroxy-
methyl, or a compound of formula (I-3), as defined above, where-
in R4c is hydrogen or lower alkyl and R5c is hydrazonomethyl,
to give a compound of the formula:
<IMG> (I-8)
155

wherein R1 and R2 are each as defined above, R4h is hydrogen
or lower alkyl, and R3 and R5h are combined together to form a
group of the formula:
<IMG> or <IMG>
in which R6 is as defined above, or
(i) subjecting a compound of formula (I-5'), as defined
above, to halogenation to give a halo-compound, followed by a
substitution reaction of the thus obtained halo-compound with
piperazine substituted by lower alkyl or hydroxy(lower)alkyl, to
give the compound (I) wherein R1, R2 and R3 are each as defined
above and R4 and R5, which may be the same or different, are
each hydrogen, lower alkyl or lower alkyl substituted with
piperazin-1-yl substituted by lower alkyl or hydroxy(lower)-
alkyl, provided that at least one of R4 and R5 is said substi-
tuted lower alkyl, and when neither R4 nor R5 is hydrogen or
lower alkyl, R4 and R5 are both the same, or,
(j) reacting the compound (I) wherein R1, R2, R3, R4 and
R5 are each as defined above and at least one of R2 and R3 is
halo(lower)alkoxycarbonyl with N,N-di(lower)alkyl- or N-lower
alkyl-N-phenyl(lower)alkyl-amine to give the compound (I) where-
in R1, R2, R3, R4 and R5 are each as defined above and at least
one of R2 and R3 is N,N-di(lower)alkylamino(lower)alkoxycarbonyl
or N-lower alkyl-N-phenyl(lower)alkylamino(lower)alkoxycarbonyl,
or
(k) subjecting the compound (I) wherein R1, R2, R3, R4 and
R5 are each as defined above and at least one of R2 and R3 is
halo(lower)alkoxycarbonyl to hydrolysis to give the compound (I)
wherein R1, R2, R3, R4 and R5 are each as defined above and at
least one of R2 and R3 is hydroxy(lower)alkoxycarbonyl, or
(1) reacting the compound of formula (I-2) as defined
156

above, with a lower alkanediol to give the compound (I) wherein
R1, R2 and R3 are each as defined above and R4 and R5, which may
be the same or different, are each hydrogen, lower alkyl or gem-
lower alkylenedioxy(lower)alkyl, provided that at least one of
R4 and R5 is said gem-lower alkylenedioxy(lower)alkyl, or
(m) halogenating a compound of formula (I-5'), as defined
above, and reacting the thus obtained halo-compound with a com-
pound of formula:
R10-CN
wherein R10 is hydrogen or a metal to give the compound (I)
wherein R1, R2 and R3 are each as defined above and R4 and R5,
which may be the same or different, are each hydrogen, lower
alkyl or cyano(lower)alkyl, provided that at least one of R4
and R5 is cyano(lower)alkyl, and when neither R4 nor R5 is
hydrogen or lower alkyl, R4 and R5 are both the same.
2. A process for preparation of a 1,4-dihydropyridine
derivative of the formula:
<IMG>
wherein R1 is phenyl, substituted by one or more substituents
selected from the group consisting of halogen, nitro, trihalo-
(lower)alkyl, lower alkoxy, hydroxy and lower alkenyloxy;
thienyl, or furyl;
one of R2 and R3 is lower alkoxy carbonyl and the other is lower
halo(lower)alkoxycarbonyl, lower alkoxy(lower)alkoxycarbonyl,
hydroxy(lower)alkoxycarbonyl, phenyl(lower)alkoxycarbonyl,
phenoxy(lower)alkoxycarbonyl, phenyl(lower)alkoxy(lower)alkoxy-
carbonyl, N,N-di(lower)alkylamino(lower)alkoxycarbonyl or N-
lower alkyl-N-phenyl(lower)alkylamino(lower)alkoxycarbonyl; and
157

one of R4a and R5a is lower alkyl and the other is gem-di-
(lower)alkoxy(lower)alkyl or gem-lower alkylenedioxy(lower)-
alkyl, or R4a and R5a are both the same gem-di(lower)alkoxy-
(lower)alkyl, which comprises reacting a compound of the
formula:
<IMG> (II)
wherein R1, R3 and R5a are each as defined above, with an amino
compound of the formula:
<IMG> (III)
wherein R2 and R4a are each as defined above.
3. A process according to claim 2, wherein Rl is 2-
halophenyl, 2- or 3-nitrophenyl, 2-trihalo(lower)alkylphenyl,
2-lower alkoxyphenyl, 3-hydroxyphenyl, 2-halo-5-nitrophenyl,
2-lower alkenyloxyphenyl, thienyl or furyl, one of R4a and R5a
is lower alkyl and the other is 1,1-di(lower)alkoxy(lower)-
alkyl or 1,1-lower alkylenedioxy(lower)alkyl, or R4a and R5a
are both the same 1,1-di(lower)alkoxy(lower)alkyl.
4. A process according to claim 3, wherein R1 is 3-
nitrophenyl, R2 and R3 are each lower alkoxycarbonyl, R4a is
lower alkyl and R5a is 1,1-di(lower)alkoxy(lower)alkyl.
5. A process according to claim 4, wherein R1 is 3-
nitrophenyl, R2 and R3 are each ethoxycarbonyl, R4a is methyl
and R5a is diethoxymethyl.
6. A process according to claim 3, wherein R1 is 3-
nitrophenyl, R3 is 2-chloroethoxycarbonyl, 2-hydroxyethoxy-
carbonyl, 2-ethoxyethoxycarbonyl, 2-(N,N-diethylamino)ethoxy-
carbonyl or 2-(N-methyl-N-benzylamino)ethoxycarbonyl, R2 is
158

ethoxycarbonyl, R4a is diethoxymethyl and R5a is methyl.
7. A process according to claim 3, wherein Rl is 2-
chlorophenyl, 2-nitrophenyl, 2-trifluoromethylphenyl, 2-methoxy-
phenyl, 2-chloro-5-nitrophenyl, 2-allyloxyphenyl, 2-thienyl or
2-furyl, R2 and R3 are each methoxycarbonyl or ethoxycarbonyl,
R4a is methyl and R5a is diethoxymethyl, 1,1-dimethoxyethyl or
ethylenedioxymethyl or R4a and R5a are both diethoxymethyl.
8. A process according to claim 3, wherein R1 is 2-
chlorophenyl, 2-nitrophenyl or 3-hydroxyphenyl, R2 is ethoxy-
carbonyl, R3 is ethoxycarbonyl, 2-chloroethoxycarbonyl, 2-
ethoxyethoxycarbonyl, benzyloxycarbonyl, 2-phenoxyethoxy-
carbonyl or 2-benzyloxyethoxycarbonyl, R4a is diethoxymethyl
and R5a is methyl.
9. A process for preparing a 1,4-dihydropyridine de-
rivative of the formula:
<IMG>
wherein R1 is halophenyl, R2 and R3 are each lower alkoxy-
carbonyl, R4a is lower alkyl and R5a is 1,1-di(lower)alkoxy-
(lower)alkyl, which comprises subjecting a mixture of an
aldehyde compound of the formula
R1-CHO
wherein R1 is as defined above, an ester of a .beta. -ketonic acid
of the formula:
R5a - COCH2 - R3
wherein R3 and R5a are each as defined above, and an amino
159

compound of the formula:
<IMG>
wherein R2 and R4a are each as defined above, to reaction.
10. A process according to claim 9, wherein R1 is 2-
chlorophenyl, R2 and R3 are each ethoxycarbonyl, R4a is methyl
and R5a is diethoxymethyl.
11. A process for preparing a 1,4-dihydropyridine de-
rivative of the formula:
<IMG>
wherein R1 is halophenyl, R2 and R3 are each lower alkoxy-
carbonyl, and R5a is 1,1-di(lower)alkoxy(lower)alkyl, which
comprises reacting an acetylene compound of the formula:
R2-C ? CH
wherein R2 is as defined above, with ammonia or an ammonium
salt and a compound of the formula:
<IMG>
wherein R1, R3 and R5a are each as defined above.
12. A process according to claim 11, wherein R1 is 2-
chlorophenyl, R2 is methoxycarbonyl, R3 is ethoxycarbonyl and
R5a is diethylmethyl.
13. A process for preparing a 1,4-dihydropyridine
derivative of the formula:
160

<IMG>
wherein R1 is phenyl substituted by one or more substituents
selected from halogen, nitro, trihalo(lower)alkyl, lower alkoxy,
hydroxy and lower alkenyloxy; thienyl, or furyl;
R2 is lower alkoxycarbonyl, hydroxy(lower)alkoxy-
carbonyl, lower alkoxy(lower)alkoxycarbonyl, phenyl(lower)-
alkoxycarbonyl, phenoxy(lower)alkoxycarbonyl, phenyl(lower)-
alkoxy(lower)alkoxycarbonyl, N,N-di(lower)alkylamino(lower)-
alkoxycarbonyl or N-lower alkyl-N-phenyl(lower)alkylamino(lower)-
alkoxycarbonyl,
R3 is lower alkoxycarbonyl,
R4b is hydrogen, lower alkyl or lower alkyl substituted
with oxo, and
R5b is lower alkyl substituted with oxo, provided that
when R4b is lower alkyl substituted with oxo, R5b is the same
as R4b which comprises hydrolyzing a compound of the formula:
<IMG>
wherein R1, R2 and R3 are each as defined above,
R4a is hydrogen, lower alkyl or lower alkyl substituted
with gem-di(lower)alkoxy, and R5a is lower alkyl substituted
with gem-di(lower)alkoxyh provided that when R4a is lower alkyl
substituted with gem-di(lower)alkoxy, R5a is the same as R4a.
14. A process according to claim 13, wherein
R1 is 2-halophenyl, 2- or 3-nitrophenyl, 2-trihalo-
161

(lower)alkylphenyl, 2-lower alkoxyphenyl, 3-hydroxyphenyl, 2-
halo-5-nitroohenyl, 2-lower alkenyloxyphenyl, thienyl or furyl,
R4a is hydrogen, lower alkyl or 1,l-di(lower)alkoxy-
(lower)alkyl,
R5a is 1,1-di(lower)alkoxy(lower)alkyl,
R4b is hydrogen, lower alkyl or lower alkanoyl, and
R5b is lower alkanoyl, provided that when R4a is 1,1-
di(lower)alkoxy(lower)alkyl, R5a is the same as R4a; and when
R4b is lower alkanoyl, R5b is the same as R5a.
15. A process according to claim 14, wherein
R1 is 3-nitrophenyl, R2 and R3 are each lower alkoxy-
carbonyl, R4a and R4b are each lower alkyl, R5a is 1,1-di(lower)-
alkoxy(lower)alkyl and R5b is lower alkanoyl.
16. A process according to claim 15, wherein
R1 is 3-nitrophenyl, R2 and R3 are each ethoxycarbonyl,
R4a and R4b are each methyl, R5a is diethoxymethyl and R5b is
formyl.
17. A process according to claim 14, wherein
R1 is 3-nitrophenyl, R2 is 2-ethoxyethoxycarbonyl, 2-
(N,N-diethylamino)ethoxycarbonyl or 2-(N-methyl-N-benzylamino)-
ethoxycarbonyl, R3 is ethoxycarbonyl, R4a and R4b are each
methyl, R5a is diethoxymethyl and R5b is formyl.
18. A process according to claim 14, wherein
R1 is 2-chlorophenyl, 2-nitrophenyl, 2-trifluoromethyl-
phenyl, 2-methoxyphenyl, 3-hydroxyphenyl, 2-chloro-5-nitro-
phenyl, 2-allyloxyphenyl, 2-thienyl or 2-furyl
R2 is methoxycarbonyl, ethoxycarbonyl, 2-hydroxyethoxy-
carbonyl, 2-ethoxyethoxycarbonyl, benzyloxycarbonyl, 2-phenoxy-
ethoxycarbonyl, 2-benzyloxyethoxycarbonyl,
R3 is methoxycarbonyl or ethoxycarbonyl,
R4a is hydrogen, methyl or 1,1-diethoxymethyl,
162

R5a is 1,1-diethoxymethyl or 1,1-dimethoxyethyl
R4b is hydrogen, methyl or formyl, and
R5b is formyl or acetyl, provided that when R4a is
1,1-diethoxymethyl, R5a is 1,1-diethoxylmethyl, and when R4b is
formyl, R5b is formyl.
19. A process for preparing a 1,4-dihydropyridine de-
rivative of the formula:
<IMG>
wherein R1 is phenyl substituted by one or more substituents
selected from halogen, nitro, trihalo(lower)alkyl and lower
alkenyl; or furyl,
R2 is lower alkoxycarbonyl, lower alkoxy(lower)-
alkoxycarbonyl, phenoxy(lower)alkoxycarbonyl, phenyl(lower)-
alkoxy(lower)alkoxycarbonyl, N,N-di(lower)alkylamino(lower)
alkoxycarbonyl or N-lower alkyl-N-phenyl(lower)alkylamino-
(lower)alkoxycarbonyl,
R3 is lower alkoxycarbonyl, R4c is lower alkyl and R5c
is substituted lower alkyl, in which the substituent is hydroxy-
imino, hydrazono, lower alkoxyimino, hydroxy(lower)alkylimino
or N',N'-di(lower)alkylamino(lower)alkylimino, which comprises
reacting a compound of the formula:
<IMG>
wherein R1, R2 and R3 are each as defined above,
R4b is lower alkyl, and R5b is lower alkyl substituted
with oxo, with an amine of the formula:
163

R8-NH2
wherein R8 is hydroxy, amino, lower alkoxy, hydroxy(lower)-
alkyl or N,N-di(lower)alkylamino(lower)alkyl.
20. A process according to claim 19, wherein
R1 is 2-halophenyl, 2- or 3-nitrophenyl, 2-trihalo-
(lower)alkylphenyl, 2-halo-5-nitrophenyl, 2-lower alkenyloxy-
phenyl or furyl
R5b is lower alkanoyl, and R5c is 1-hydroxyimino(lower)-
alkyl, 1-hydrazono(lower)alkyl, 1-lower alkoxyimino(lower)-
alkyl, 1-[hydroxy(lower)alkylimino](lower)alkyl or 1-[N',N'-di-
(lower)alkylamino(lower)alkylimino](lower)alkyl.
21. A process according to claim 20, wherein
R1 is 3-nitrophenyl, R2 and R3 are each lower alkoxy-
carbonyl, R5c is 1-hydroxyimino(lower)alkyl, and R8 is hydroxy.
22. A process according to claim 21, wherein
R1 is 3-nitrophenyl, R2 and R3 are each ethoxycarbonyl,
R4b and R4c are each methyl, R5b is formyl, R5c is hydroxyimino-
methyl and R8 is hydroxy.
23. A process according to claim 20, wherein
R1 is 3-nitrophenyl, R2 is 2-ethoxyethoxycarbonyl,
2-(N,N-diethylamino)ethoxycarbonyl or 2-(N-methyl-N-benzyl-
amino)ethoxycarbonyl, R3 is ethoxycarbonyl, R4b and R4c are each
methyl, R5b is formyl, R5c is hydroxyiminomethyl and R8 is
hydroxy.
24. A process according to claim 20, wherein
R1 is 2-chlorophenyl, 2-nitrophenyl 2-trifluoromethyl-
phenyl, 2-chloro-5-nitrophenyl, 2-allyloxyphenyl or 2-furyl;
R2 is ethoxycarbonyl, 2-ethoxyethoxycarbonyl, 2-phenoxyethoxy-
carbonyl, 2-benzyloxyethoxycarbonyl or 2-(N-methyl-N-benzyl-
164

amino)ethoxycarbonyl; R3 is ethoxycarbonyl; R4b and R4c are each
methyl; R5b is formyl; R5c is hydroxyiminomethyl, hydrazono-
methyl, methoxyiminomethyl, 3-(N,N-dimethylamino)propylimino-
methyl, 2-(N,N-diethylamino)ethyliminomethyl or 2-hydroxyethyl-
iminomethyl, and R8 is hydroxy, amino, methoxy, 3-(N,N-dimethyl-
aminopropyl, 2-(N,N-dimethylamino)ethyl or 2-hydroxyethyl.
25. A process for preparation of a 1,4-dihydropyri-
dine derivative of the formula:
<IMG>
wherein R1 is phenyl substituted by one or more substituents
selected from halogen, nitro, trihalo(lower)alkyl
and lower alkenyloxy; or furyl;
R2 is lower alkoxycarbonyl, lower alkoxy(lower)alkoxy-
carbonyl, phenoxy(lower)alkoxycarbonyl, phenyl(lower)-
alkoxy(lower)alkoxycarbonyl, N,N-di(lower)alkylamino-
(lower)alkoxycarbonyl or N-lower alkyl-N-phenyl(lower)-
alkylamino(lower)alkoxycarbonyl;
R3 is lower alkoxycarbonyl;
R4d is lower alkyl and
R5d is cyano or .omega.-cyano(lower)alkyl; or
R1, R2 and R4d are each as defined above, and
R3 and R5d are combined together to form a group of the
formula:
165

<IMG>
which comprises treating a compound of the formula:
<IMG>
wherein R1 and R2 are each as defined above,
R'3 is lower alkoxycarbonyl,
R'4c is lower alkyl and
R'5c is .omega.-hydroxyimino(lower)alkyl,
with a dehydrating agent.
26. A process according to claim 25, wherein
R1 is 2-halophenyl, 2- or 3-nitrophenyl, 2-trihalo-
(lower)alkylphenyl, 2-halo-5-nitrophenyl, 2-lower alkenyloxy-
phenyl or 2-furyl.
27. A process according to claim 26, wherein
R1 is 3-nitrophenyl, R2 and R3 are each lower alkoxy-
carbonyl, R'4c and R4d are each lower alkyl, R'5C is hydroxy-
iminomethyl and R5d is cyano.
28. A process according to claim 27, wherein
R1 is 3-nitrophenyl, R2 and R3 are each ethoxycarbonyl,
R'4c and R4d are each methyl, R'5c is hydroxyiminomethyl and
R5d is cyano.
29. A process according to claim 26, wherein
R1 is 3-nitrophenyl, R2 is 2-ethoxyethoxycarbonyl, 2-
(N,N-diethylamino)ethoxycarbonyl or 2-(N-methyl-N-benzylamino)-
166

ethoxycarbonyl, R3 is ethoxycarbonyl, R'4c and R4d are each
methyl, R'5c is hydroxyiminomethyl and R5d is cyano.
30. A process according to claim 26, wherein
R1 is 2-chlorophenyl, 2-nitrophenyl, 2-trifluoromethyl-
phenyl, 2-chloro-5-nitrophenyl, 2-allyloxyphenyl or 2-furyl, R2
is ethoxycarbonyl, 2-ethoxyethoxycarbonyl, 2-phenoxyethoxy-
carbonyl or 2-benzyloxyethoxycarbonyl, R3 and R'3 are each
ethoxycarbonyl, R'4c and R4d are each methyl, R'5c is hydroxy-
iminomethyl or 2-hydroxyiminoethyl and R5d is cyano or cyano-
methyl.
31. A process according to claim 26, wherein
R1 is 2-halophenyl, R2 is ethoxycarbonyl, R'4c and R4d
are each methyl, R'3 is ethoxycarbonyl, R5c is hydroxyimino-
methyl and R3 and R5d are combined together to form a group of
the formula:
<IMG>
32. A process for preparation of a 1,4-dihydro-
pyridine derivative of the formula:
<IMG>
wherein R1 is phenyl, substituted by one or more substituents
selected from halogen, nitro, trihalo(lower)alkyl, lower
alkoxy, hydroxy and lower alkenyloxy or thienyl;
167

R2 is lower alkoxycarbonyl, hydroxy(lower)alkoxy-
carbonyl, phenyl(lower)alkoxycarbonyl, lower alkoxy-
(lower)alkoxycarbonyl or N-lower alkyl-N-phenyl(lower)-
alkylamino(lower)alkoxycarbonyl; R3 is lower alkoxy-
carbonyl; R4e is hydrogen, lower alkyl or hydroxy(lower)-
alkyl, and R5e is hydroxy(lower)alkyl, hydroxy(lower)-
alkylamino(lower)alkyl or N' ,N'-di(lower)alkylamino-
(lower)alkylamino(lower)alkyl, provided that when R4e
is hydroxy(lower)alkyl, R5e is the same as R4e, or
R1, R2 and R4e are each as defined above, and
R3 and R5e are combined together to form a group of the
formula:
<IMG> or <IMG>
in which R6 is hydrogen or methyl and R7 is 2-hydroxyethyl or
2-(N,N-diethylamino)ethyl, which comprises reducing a compound
of the formula:
<IMG>
wherein R1 and R2 are each as defined above,
R'3 is lower alkoxycarbonyl;
R'4b is hydrogen, lower alkyl or lower alkyl substituted
with oxo,
R'5b is lower alkyl substituted with oxo; hydroxy(lower)
alkylimino or N',N'-di(lower)alkylamino(lower)alkyl-
imino, provided that when R'4b is lower alkyl substituted
with oxo, R'5b is the same as R'4b
168

33. A process according to claim 32, wherein
R1 is 2-halophenyl, 2- or 3-nitrophenyl, 2-trihalo-
(lower)alkylphenyl, 2-lower alkoxyphenyl, 3-hydroxyphenyl, 2-
halo-5-nitrophenyl, 2-2-lower alkenyloxyphenyl or 2-thienyl;
R'5b is lower alkanoyl and R5e is 1-hydroxy(lower)alkyl.
34. A process according to claim 33, wherein
R1 is 3-nitrophenyl; R2, R3 and R'3 are each lower
alkoxycarbonyl; R'4b and R4e are each lower alkyl; R'5b is
lower alkanoyl and R5e is 1-hydroxy(lower)alkyl.
35. A process according to claim 34, wherein
R1 is 3-nitrophenyl; R2, R3 and R'3 are each ethoxy-
carbonyl; R'4b and R4e are each methyl; R'5b is formyl and R5e
is hydroxymethyl.
36. A process according to claim 33, wherein
R1 is 3-nitrophenyl; R2 is 2-ethoxyethoxycarbonyl or
2-(N-methyl-N-benzylamino)ethoxycarbonyl; R3 and R'3 are each
ethoxycarbonyl; R'4b and R4e are each methyl; R'5b is formyl
and R5e is hydroxymethyl.
37. A process according to claim 33, wherein
R1 is 2-chlorophenyl; 2-nitrophenyl, 2-trifluoro-
methylphenyl, 2-methoxyphenyl, 3-hydroxyphenyl, 2-chloro-5-
nitrophenyl, 2-allyloxyphenyl or 2-thienyl; R2 is methoxy-
carbonyl, ethoxycarbonyl, 2-hydroxyethoxycarbonyl or benzyl-
oxycarbonyl; R3 and R'3 are each ethoxycarbonyl; R'4b is
hydrogen, methyl or formyl; R4e is hydrogen, methyl or hydroxy-
methyl; R'5b is formyl, acetyl, 2-hydroxyethyliminomethyl or
2-(N,N-diethylamino)ethyliminomethyl and R5e is hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethylaminomethyl or 2-(N,N-diethyl-
amino)ethylaminomethyl; provided that when R'4b is formyl, R'5b
is formyl, and when R4e is hydroxymethyl, R5e is hydroxymethyl.
169

38. A process according to claim 33, wherein
R1 is 2-chlorophenyl, 2-nitrophenyl, 2-methoxyphenyl
or 2- thienyl, R2 and R'3 are each ethoxycarbonyl, R'4b and R4e
are each methyl, R'5b is formyl, 2-hydroxyethyliminomethyl or
2-(N,N-diethylamino)ethyliminomethyl and R5e is a group of the
formula:
<IMG> or <IMG>
in which R7 is 2-hydroxyethyl or 2-(N,N-diethylamino)ethyl.
39. A process for preparation of a 1,4-dihydro-
pyridine derivative of the formula:
<IMG>
wherein R1 is halophenyl or nitrophenyl;
R2 is lower alkoxycarbonyl or N-lower alkyl-N-phenyl-
(lower)alkylamino(lower)alkoxycarbonyl;
R3 is lower alkoxycarbonyl;
R4f is lower alkyl;
R5f is acyloxy(lower)alkyl in which the acyl moiety is
selected from lower alkanoyl, carboxy(lower)alkanoyl, lower
alkoxycarbonyl(lower)alkanoyl, N-lower alkyl-N-phenyl(lower)
alkylamino(lower)alkanoyl, benzoyl and 4-chlorophenoxyacetyl,
which comprises reacting a compound of the formula:
170

<IMG>
wherein R1, R2 and R3 are each as defined above, R'4e is lower
alkyl and R'5e is hydroxy(lower)alkyl, with an acylating agent
of the formula:
R9 - OH
wherein R9 is lower alkanoyl, carboxy(lower)alkanoyl, lower
alkoxycarbonyl(lower)alkanoyl, N-lower alkyl-N-phenyl(lower)_
alkylamino(lower)alkanoyl, benzoyl or 4-chlorophenoxyacetyl,
or a reactive derivative thereof.
40. A procecs according to claim 39, wherein
R1 is 2-chlorophenyl, or 2- or 3-nitrophenyl:
R2 is ethoxycarbonyl or 2-(N-methyl-N-benzylamino)-
ethoxycarbonyl;
R3 is ethoxycarbonyl, R'4e and R4f are methyl; R'5e is
hydroxymethyl:
R5f is acetoxymethyl, 3-carboxypropionyioxymethyl, 5-
ethoxycarbonylvaleryloxymethyl, 3-(N-methyl-N-benzylamino)-
propionyloxymethyl; benzoyloxymethyl or 4-chlorophenoxyacetoxy-
methyl, and R9 is acetyl, 3-carboxypropionyl, 5-ethoxycarbonyl-
valeryl, 3-(N-methyl-N-benzylamino)propionyl, benzoyl or 4-
chlorophenoxyacetyl.
41. A process for the preparation of a 1,4-dihydro-
pyridine derivative of the formula:
171

<IMG>
wherein R1 is halophenyl, R2 and R3 are each lower alkoxycarbonyl,
R4g is lower alkyl, and R5g is formyl, which comprises
oxidizing a compound of the formula:
<IMG>
wherein R1, R2 and R3 are each as defined above, R"4e is lower
alkyl; and R"5e is hydroxymethyl.
42. A process according to claim 41, wherein
R1 is 2-chlorophenyl; R2 and R3 are each ethoxy-
carbonyl: R"4e and R4g are each methyl; R"5e is hydroxymethyl
and R5g is formyl.
43. A process for preparation of a 1,4-dihycro-
pyridine derivative of the formula:
<IMG>
wherein R1 is halophenyl, nitrophenyl or thienyl;
R2 is lower alkoxycarbonyl;
R4h is lower alkyl; and
R'3 and R5h are combined together to form a group of
172

the formula:
<IMG>
which comprises heating a compound of the formula:
<IMG>
wherein R1 and R2 are each as defined above;
R3 is lower alkoxycarbonyl;
R4 is lower alkyl and
R5 is hydroxymethyl or hydrazonomethyl.
44. A process according to claim 43, wherein
R1 is 2-chlorophenyl, 2-nitrophenyl or 2-thienyl,
R2 and R3 are each ethoxycarbonyl; R4 and R4h are
each methyl; and R5 is hydroxymethyl or hydrazonomethyl.
45. A process for preparation of a 1,4-dihydro-
pyridine derivative of the formula:
<IMG>
wherein R1 is halophenyl; R2 and R3 are each lower alkoxycar-
bonyl, R4 is lower alkyl and R5 is lower alkyl substituted with
piperazin-1-yl substituted by lower alkyl or hydroxy(lower)-
alkyl, which comprises subjecting a compound of the formula:
173

<IMG>
wherein R1, R2, R3 and R4 are each as defined above, and
R5e is hydroxy(lower)alkyl, to halogenation to give
a halo-compound, followed by a substitution reaction of the
thus obtained halo-compound with lower alkyl piperazine or
hydroxy(lower)alkyl piperazine.
46. A process according to claim 45, wherein
R1 is 2-chlorophenyl, R2 and R3 are each ethoxycar-
bonyl, R4 is methyl: R5 is 4-methylpiperazin-1-ylmethyl or 4-
(2-hydroxyethyl)-piperazin-1-ylmethyl and R5e is hydroxymethyl.
47. A process for preparing a 1,4-dihydropyridine
derivative of the formula:
<IMG>
wherein R1 is nitrophenyl, R2 is N,N-di(lower)alkylamino(lower)-
alkoxycarbonyl or N-lower alkyl-N-phenyl(lower)alkylamino(lower)-
alkoxycarbonyl, R3 is lower alkoxycarbonyl, R4 is lower alkyl
and R5 is gem-di(lower)alkoxy(lower)alkyl, which comprises
reacting a compound of the formula:
<IMG>
174

wherein R1, R3, R4 and R5 are each as defined above, and
R'2 is halo(lower)alkoxycarbonyl, with N,N-di(lower)-
alkyl- or N-lower alkyl-N-phenyl(lower)alkyl-amine.
48. A process according to claim 47, wherein
R1 is 3-nitrophenyl; R2 is 2-(N,N-diethylamino)ethoxy-
carbonyl or 2-(N-methyl-N-benzylamino)ethoxycarbonyl; R'2 is
2-chloroethoxycarbonyl; R3 is ethoxycarbonyl; R4 is methyl and
R5 is diethoxymethyl.
49. A process for preparation of a 1,4-dihydro-
pyridine derivative of the formula:
<IMG>
wherein R1 is nitrophenyl: R2 is hydroxy(lower)alkoxycarbonyl,
R3 is lower alkoxycarbonyl R4 is lower alkyl and R5 is
gem-di(lower)alkoxy(lower)alkyl, which comprises subjecting a
compound of the formula:
<IMG>
wherein R1, R3, R4 and R5 are each as defined above, and
R'2 is halo(lower)alkoxycarbonyl, to hydrolysis.
50. A process according to claim 49, wherein
R1 is 2- or 3-nitrophenyl; R2 is 2-hydroxyethoxy-
carbonyl: R'2 is 2-chloroethoxycarbonyl, R3 is ethoxycarbonyl;
175

R4 is methyl and R5 is diethoxymethyl.
51. A process for preparation of a 1,4-dihydro-
pyridine derivative of the formula:
<IMG>
wherein R1 is nitrophenyl, R2 and R3 are each lower alkoxy-
carbonyl, R4 is lower alkyl and R5 is gem-lower alkylenedioxy-
(lower)alkyl, which comprises reacting a compound of the formula:
<IMG>
wherein R1, R2, R3 and R4 are each as defined above, and
R5b is lower alkyl substituted with oxo, with a lower
alkane diol.
52. A process according to claim 51, wherein
R1 is 2-nitrophenyl; R2 and R3 are each ethoxycarbo-
nyl: R4 is methyl, R5 is ethylenedioxymethyl and R5b is formyl.
53. A process for the preparation of a 1,4-dihydro-
pyridine derivative of the formula:
<IMG>
176

wherein R1 is nitrophenyl, R2 and R3 are each lower alkoxy-
carbonyl,
R4 is lower alkyl and R5 is cyano(lower)alkyl, which
comprises reacting a compound of the formula:
<IMG>
wherein R1, R2, R3 and R4 are each as defined above, and R'5 is
halo(lower)alkyl, with a compound of the formula
R10 - CN
wherein R10 is hydrogen or a metal.
54. A process according to claim 53, wherein
R1 is 2-nitrophenyl; R2 and R3 are each ethoxycarbonyl;
R4 is methyl; R5 is cyanomethyl; R'5 is chloromethyl and R10 is
sodium.
55. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 1, whenever prepared by the process of claim
1, or by an obvious chemical equivalent.
56. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 2, whenever prepared by the process of claim
2, or by an obvious chemical equivalent.
57. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 3, whenever prepared by the process of claim
3, or by an obvious chemical equivalent.
58. A 1,4-dihydropyridine derivative of formula (I),
177

as defined in claim 4, whenever prepared by the process of claim
4, or by an obvious chemical equivalent.
59. A 1,4-dihydropyridine derivative of formula (I), as
defined in claim 5, whenever prepared by the process of claim 5,
or by an obvious chemical equivalent.
60. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 6, whenever prepared by the process of claim
6, or by an obvious chemical equivalent.
61. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 7, whenever prepared by the process of claim
7, or by an obvious chemical equivalent.
62. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 8, whenever prepared by the process of claim
8, or by an obvious chemical equivalent.
63. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 9, whenever prepared by the process of claim
9, or by an obvious chemical equivalent.
64. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 10, whenever prepared by the process of
claim 10, or by an obvious chemical equivalent.
65. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 11, whenever prepared by the process of
claim 11, or by an obvious chemical equivalent.
66. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 12, whenever prepared by the process of
claim 12, or by an obvious chemical equivalent.
178

67. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 13, whenever prepared by the process of
claim 13, or by an obvious chemical equivalent.
68. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 14, whenever prepared by the process of
claim 14, or by an obvious chemical equivalent.
69. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 15, whenever prepared by the process of
claim 15, or by an obvious chemical equivalent.
70. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 16, whenever prepared by the process of
claim 16, or by an obvious chemical equivalent.
71. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 17, whenever prepared by the process of
claim 17, or by an obvious chemical equivalent.
72. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 18, whenever prepared by the process of
claim 18, or by an obvious chemical equivalent.
73. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 19, whenever prepared by the process of
claim 19, or by an obvious chemical equivalent.
74. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 20, whenever prepared by the process of
claim 20, or by an obvious chemical equivalent.
75. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 21, whenever prepared by the process of
claim 21, or by an obvious chemical equivalent.
179

76. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 22, whenever prepared by the process of
claim 22, or by an obvious chemical equivalent.
77. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 23, whenever prepared by the process of
claim 23, or by an obvious chemical equivalent.
78. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 24, whenever prepared by the process of
claim 24, or by an obvious chemical equivalent.
79. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 25, whenever prepared by the process of
claim 25, or by an obvious chemical equivalent.
80. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 26, whenever prepared by the process of
claim 26, or by an obvious chemical equivalent.
81. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 27, whenever prepared by the process of
claim 27, or by an obvious chemical equivalent.
82. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 28, whenever prepared by the process of
claim 28, or by an obvious chemical equivalent.
83. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 29, whenever prepared by the process of
claim 29, or by an obvious chemical equivalent.
84. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 30, whenever prepared by the process of
claim 30, or by an obvious chemical equivalent.
180

85. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 31, whenever prepared by the process of
claim 31, or by an obvious chemical equivalent.
86. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 32, whenever prepared by the process of
claim 32, or by an obvious chemical equivalent.
87. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 33, whenever prepared by the process of
claim 33, or by an obvious chemical equivalent.
88. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 34, whenever prepared by the process of
claim 34, or by an obvious chemical equivalent.
89. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 35, whenever prepared by the process of
claim 35, or by an obvious chemical equivalent.
90. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 36, whenever prepared by the process of
claim 36, or by an obvious chemical equivalent.
91. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 37, whenever prepared by the process of
claim 37, or by an obvious chemical equivalent
92. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 38, whenever prepared by the process of
claim 38, or by an obvious chemical equivalent.
93. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 39, whenever prepared by the process of
claim 39, or by an obvious chemical equivalent.
181

94. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 40, whenever prepared by the process of
claim 40, or by an obvious chemical equivalent.
95. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 41, whenever prepared by the process of
claim 41, or by an obvious chemical equivalent
96. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 42, whenever prepared by the process of
claim 42, or by an obvious chemical equivalent.
97. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 43, whenever prepared by the process of
claim 43, or by an obvious chemical equivalent.
98. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 44, whenever prepared by the process of
claim 44, or by an obvious chemical equivalent.
99. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 45, whenever prepared by the process of
claim 45, or by an obvious chemical equivalent.
100. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 46, whenever prepared by the process of
claim 46, or by an obvious chemical equivalent.
101. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 47, whenever prepared by the process of
claim 47, or by an obvious chemical equivalent.
102. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 48, whenever prepared by the process of
claim 48, or by an obvious chemical equivalent.
182

103. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 49, whenever prepared by the process of
claim 49, or by an obvious chemical equivalent.
104. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 50, whenever prepared by the process of
claim 50, or by an obvious chemical equivalent.
105. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 51, whenever prepared by the process of
claim 51, or by an obvious chemical equivalent.
106. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 52, whenever prepared by the process of
claim 52, or by an obvious chemical equivalent.
107. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 53, whenever prepared by the process of
claim 53, or by an obvious chemical equivalent.
108. A 1,4-dihydropyridine derivative of formula (I),
as defined in claim 54, whenever prepared by the process of
claim 54, or by an obvious chemical equivalent.
183

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE:
109, A process according to claim 3, wherein
R1 is 2-nitrophenyl, R2 is methoxycarbonyl, ethoxycarbonyl or
isopropoxycarbonyl, R3 is methoxycarbonyl, R4a is methyl and
R5a is dimethoxymethyl.
110. A process according to claim 3, wherein
R1 is 3-nitrophenyl; R2 is ethoxycarbonyl, R3 is 2-benzyloxy-
ethoxycarbonyl, R4a is diethoxymethyl and R5a is methyl.
111. A process according to claim 4, wherein
184

R1 is 3-nitrophenyl, R2 and R3 are each methoxycarbonyl, R4a is
methyl and R5a is dimethoxymethyl.
112. A process according to claim 14, wherein
R1 is 2-nitrophenyl, R2 is methoxycarbonyl or isopropoxycarbonyl,
R3 is methoxycarbonyl, R4a and R4b are each methyl, R5a is
dimethoxymethyl and R5b is formyl.
113. A process according to claim 14, wherein
R1 is 3-nitrophenyl, R2 is 2-benzyloxyethoxycarbonyl, R3 is
ethoxycarbonyl, R4a and R4b are each methyl, R5a is diethyl-
methyl and R5b is formyl.
114. A process according to claim 15, wherein
R1 is 3-nitrophenyl, R2 and R3 are each methoxycarbonyl, R4a
and R4b are each methyl, R5a is dimethoxymethyl, and R5b is
formyl.
115. A process according to claim 20, wherein
R1 is 2-nitrophenyl, R2 is methoxycarbonyl or isopropoxycar-
bonyl, R3 is methoxycarbonyl, R4b and R4c are each methyl, R5b
is formyl, R5c is hydroxyiminomethyl, and R8 is hydroxy.
116. A process according to claim 20, wherein
R1 is 3-nitrophenyl, R2 is 2-benzyloxyethoxycarbonyl, R3 is
ethoxycarbonyl, R4b and R4c are each methyl; R5b is formyl,
R5C i5 hydroxyiminomethyl, and R8 is hydroxy.
117. A process according to claim 21, wherein
R1 is 3-nitrophenyl, R2 and R3 are each methoxycarbonyl; R4b
and R4c are each methyl, R5b is formyl, R5c is hydroxyimino,
and R8 is hydroxy.
185

118. A process according to claim 26, wherein
1 is 2-nitrophenyl, R2 is methoxycarbonyl or isopropoxy-
carbonyl, R3 is methoxycarbonyl, R'4c and R4d are each methyl;
R'5c is hydroxyiminomethyl, and R5d is cyano.
119. A process according to claim 26, wherein
R1 is 3-nitrophenyl, R2 is 2-benzyloxyethoxycarbonyl; R3 is
ethoxycarbonyl; R'4c and R4d are each methyl; R'5c is hydroxy-
iminomethyl, and R5d is cyano.
120. A process according to claim 27, wherein
R1 is 3-nitrophenyl, R2 and R3 are each methoxycarbonyl; R'4c
and R4d are each methyl; R'5c is hydroxyiminomethyl, and R5d
is cyano.
121. A process according to claim 33, whereln
R1 is 2-nitrophenyl; R2 is methoxycarbonyl or isopropoxy-
carbonyl; R3 is methoxycarbonyl; R'4b and R4e are each methyl;
R'5b is formyl and R5e is hydroxymethyl.
122. A process according to claim 33, wherein
R1 is 2- or 3-nitrophenyl; R2 is 2-benzyloxyethoxycarbonyl,
R3 is ethoxycarbonyl; R'4b and R4e are each methyl; R'5b is
formyl, and R5e is hydroxymethyl.
123. A process according to claim 34, wherein
R1 is 3-nitrophenyl, R2 and R3 are each methoxycarbonyl, R'4b
and R4e are each methyl; R'5b is formyl, and R5e is hydroxy-
methyl.
124. A 1,4-dihydropyridine derivative as defined in
claim 109, whenever prepared by the process of claim 109, or
by an obvious chemical equivalent.
186

125. A 1,4-dihydropyridine derivative as defined in
claim 110, whenever prepared by the process of claim 110, or
by an obvious chemical equivalent.
126. A 1,4-dihydropyridine derivative as defined in
claim 111, whenever prepared by the process of claim 111, or
by an obvious chemical equivalent.
127. A 1,4-dihydropyridine derivative as defined in
claim 112, whenever prepared by the process of claim 112, or
by an obvious chemical equivalent.
128. A 1,4-dihydropyridine derivative as defined in
claim 113, whenever prepared by the process of claim 113, or
by an obvious chemical equivalent.
129. A 1,4-dihydropyridine derivative as defined in
claim 114, whenever prepared by the process of claim 114, or
by an obvious chemical equivalent.
130. A 1,4-dihydropyridine derivative as defined in
claim 115, whenever prepared by the process of claim 115, or
by an obvious chemical equivalent.
131. A 1,4-dihydropyridine derivative as defined in
claim 116, whenever prepared by the process of claim 116, or
by an obvious chemical equivalent.
132. A 1,4-dihydropyridine derivative as defined in
claim 117, whenever prepared by the process of claim 117, or
by an obvious chemical equivalent.
133. A 1,4-dihydropyridine derivative as defined in
claim 118, whenever prepared by the process of claim 118, or
by an obvious chemical equivalent.
187

134. A 1,4-dihydropyridine derivative as defined in
claim 119, whenever prepared by the process of claim 119, or
by an obvious chemical equivalent.
135. A 1, 4-dihydropyridine derivative as defined in
claim 120, whenever prepared by the process of claim 120, or
by an obvious chemical equivalent.
136. A 1,4-dihydropyridine derivative as defined in
claim 121, whenever prepared by the process of claim 121, or
by an obvious chemical equivalent.
137. A 1,4-dihydropyridine derivative as defined in
claim 122, whenever prepared by the process of claim 122, or
by an obvious chemical equivalent.
138. A 1,4-dihydropyridine derivative as defined in
claim 123, whenever prepared by the process of claim 123, or
by an obvious chemical equivalent.
188

139. A process for preparation of a 1,4-dihydropyridine
derivative of the formula:
<IMG> (I)
wherein R1 is phenyl which is unsubstituted or substituted by
one or more substituents selected from the group con-
sisting of halogen, nitro, cyano, lower alkoxy carbonyl,
lower alkyl sulfamoyl, trihalo(lower)alkyl, lower
alkoxy, hydroxy and lower alkenyloxy; thienyl; or furyl;
R2 and R3 which may be the same or different are each
lower alkoxycarbonyl, halo(lower)alkoxycarbonyl,
hydroxy(lower)alkoxycarbonyl, lower alkoxy(lower)-
alkoxycarbonyl, phenyl(lower)alkoxycarbonyl, phenyl-
(lower)alkoxy(lower)alkoxycarbonyl, phenoxy(lowerj-
alkoxycarbonyl, N,N-di(lower)alkylamino(lower)alkoxy-
carbonyl or N-lower alXyl-N-phenyl(lower)alkylamino-
(lower)alkoxycarbonyl; and
R4 and R5, which may be the same or different, are
each hydrogen; cyano; lower alkyl; or substituted lower
alkyl in which the substituent is selected from the
group consisting of cyano, hydroxy, lower alkanoyloxy,
carboxy(lower)alkanoyloxy, lower alkoxycarbonyl-
(lower)alkanoyloxy, N-lower alkyl-N-phenyl(lower)-
alkylamino(lower)alkanoyloxy, benzoyloxy, 4-chloro-
189

phenoxyacetoxy, hydroxyimino, hydrazono, lower
alkoxyimino, hydroxy(lower)alkylimino, N', N'-di-
(lower)alkylamino(lower)alkylimino, hydroxy(lower)-
alkylamino, N' , N'-di(lower)alkylamino(lower)-
alkylamino, piperazin-1-yl substituted by lower
alkyl or hydroxy(lower)alkyl, oxo, gem-di(lower)
alkoxy, and gem-lower alkylenedioxy, provided that,
when one of R4 and R5 is hydrogen or lower alkyl, the
other is cyano or said substituted lower alkyl, and
when R4 and R5 are not hydrogen or lower alkyl, both
of them are a group selected from cyano and said
substituted lower alkyl, or
R4 is hydrogen or lower alkyl and R3 and R5 are com-
bined to form a group of the formula:
<IMG> or <IMG>
wherein R6 is hydrogen or methyl and R7 is 2-(N,N-diethylamino)-
ethyl or 2-hydroxyethyl, which comprises
(a)-(i) reacting a compound of the formula:
<IMG> (II)
wherein R1, R3 and R5a are each as defined below, with an amino
compound of the formula:
<IMG> (III)
wherein R2 and R4a are each as defined below,
(ii) subjecting a mixture of an aldehyde compound of the
formula:
190

R1 -CHO (II')
wherein R1 is as defined below,
an ester of .beta.-ketonic acid of the formula:
R5a - COCH2 - R3 (II")
wherein R3 and R5a are each as defined below,
and an amino compound of formula (III) as define above, to
reaction, or
(iii) reacting an acetylene compound of the formula:
R2 - C?C -R4a (III')
wherein R2 and R4a are each as defined below,
with ammonia or an ammonium salt and a compound of formula (II)
as defined above to give a compound of the formula:
<IMG> (I-1)
wherein R1, R2 and R3 are each as defined above and R4a and R5a
are each hydrogen, lower alkyl or lower alkyl substituted with
gem-di(lower)alkoxy or gem-lower alkylenedioxy, provided that at
least one of R4a and R5a is lower alkyl substituted with gem-di-
(lower)alkoxy or lower alkylenedioxy, or
(b) hydrolysing a compound of the formula:
<IMG> (I-1)
wherein R1, R2, R3, R4a and R5a are each as defined above, to
give a compound of the formula:
191

<IMG> (I-2)
wherein R1, R2 and R3 are each as defined above and R4b and R5b
are each hydrogen, lower alkyl or lower alkyl substituted with
oxo, provided that at least one of R4b and R5b is lower alkyl
substituted with oxo, or
(c) reacting a compound of the formula:
<IMG> (I-2)
wherein R1, R2, R3, R4b and R5b are each as defined above, with
an amine of the formula:
R8 - NH2 (IV)
wherein R8 is hydroxy, amino, lower alkoxy, hydroxy(lower)alkyl
or N' ,N'-di(lower)alkylamino(lower)alkyl or a salt thereof to
give à compound of the formula:
<IMG> (I-3)
wherein R1, R2 and R3 are each as defined above and R4c and R5c
which may be the same or different, are each hydrogen, lower
alkyl or substituted lower alkyl in which the substituent is
selected from the group consisting of hydroxyimino, hydrazono,
lower alkoxyimino, hydroxy(lower)alkylimino and N' ,N'-di(lower)-
192

alkylamino(lower)alkylimino, provided that at least one of R4c
and R5c is said substituted lower alkyl, or
(d) treating a compound of the formula:
<IMG> (I-3')
wherein R1, R2 and R3 are each as defined above and R'4c and
R'5c, which may be the same or different, are each hydrogen,
lower alkyl or .omega.-hydroxyimino(lower)alkyl, provided that at
least one of R'4c and R'5c is .omega. -hydroxyimino(lower)alkyl, with
a dehydrating agent to give a compound of the formula:
<IMG> (I-4)
wherein R1, R2 and R3 are each as defined above and R4d andiR5d
which may be the same or different, are each hydrogen, lower
alkyl, cyano or .omega.-cyano(lower)alkyl, provided that, when one of
R4d and R5d is hydrogen or lower alkyl, the other is cyano or
.omega. -cyano(lower)alkyl, and when R5d and R4d are not hydrogen
or lower alkyl both of them are a group selected from cyano or
.omega.-cyano(lower)alkyl, or R4d is hydrogen or lower alkyl and R3
and R5d are combined together to form a group of the formula
<IMG>
or
(e) reducing a compound of the formula:
193

<IMG> (I-2')
wherein R1, R2 and R3 are each as defined above and R'4b and
R'5b, which may be the same or different, are each hydrogen,
lower alkyl or substituted lower alkyl in which the substituent
is oxo, hydroxy(lower)alkylimino or N' ,N'-di(lower)alkylamino-
(lower)alkylimino, provided that at least one of R'4b and R'5b
is said substituted lower alkyl, to give a compound of the
formula:
<IMG> (I-5)
wherein R1, R2 and R3 are each as defined above and R4e and R5e,
which may be the same or different, are each hydrogen, lower
alkyl or substituted lower alkyl in which the substituent is
hydroxy, hydroxy(lower)alkylamino or N' ,N'-di(lower)alkylamino-
(lower)alkylamino, provided that at least one of R4e and R5e is
said substituted lower alkyl, or R4e is hydrogen or lower alkyl
and R3 and R5e are combined together to form
<IMG> or <IMG>
wherein R6 and R7 are each as defined above, or
(f) reacting a compound of the formula
194

(I-5')
<IMG>
wherein R1, R2 and R3 are each as defined above and R'4e and
R'5e' which may be the same or different, are each hydrogen,
lower alkyl or hydroxy(lower)alkyl, provided that at least one
of R'4e and R'5e is hydroxy(lower)alkyl, with an acylating agent
of the formula:
R9 - OH (V)
wherein R9 is lower alkanoyl, carboxy(lower)alkanoyl, lower
alkoxycarbonyl(lower)alkanoyl, N-lower alkyl-N-phenyl(lower)-
alkylamino(lower)alkanoyl, benzoyl or 4-chlorophenoxyacetyl, or
a reactive derivative thereof, to give a compound of the formula:
(I-6)
<IMG>
wherein R1, R2 and R3 are each as defined above and R4f and R5f,
which may be the same or different, are each hydrogen, lower
alkyl and acyloxy(lower)alkyl, in which the acyl moiety is se-
lected from the group consisting of lower alkanoyl, carboxy-
(lower)alkanoyl, lower alkoxycarbonyl(lower)alkanoyl, N-lower
alkyl-N-phenyl(lower)alkylamino(lower)alkanoyl, benzoyl and 4-
chlorophenoxyacetyl, provided that at least one of R4f and R5f
is said acyloxy(lower)alkyl, or
(g) oxidizing a compound of the formula:
195

<IMG> (I-5")
wherein R1, R2 and R3 are each as defined above and R"4e and
R"5e, which may be the same or different, are each hydrogen,
lower alkyl, or .omega.-hydroxy(lower)alkyl, provided that at least
one of R"4e and R"5e is .omega.-hydroxy(lower)alkyl, to give a com-
pound of the formula:
(I-7)
<IMG>
wherein R1, R2 and R3 are each as defined above and R4g and R5g,
which may be the same or different, are each hydrogen, lower
alkyl, formyl or .omega.-formyl(lower)alkyl, provided that, when one
of R4g and R5g is hydrogen or lower alkyl, the other is always
formyl or .omega.-formyl(lower)alkyl, and R4g and R5g are not hydrogen
or lower alkyl, both of them are a group selected from formyl
and .omega.-formyl(lower)alkyl, or
(h) heating a compound of formula (I-5), as defined above,
wherein R4e is hydrogen or lower alkyl and R5e is hydroxy-
methyl, or a compound of formula (I-3), as defined above, where-
in R4c is hydrogen or lower alkyl and R5c is hydrazonomethyl,
to give a compound of the formula:
(I-8)
<IMG>
196

wherein R1 and R2 are each as defined above, R4h is hydrogen
or lower alkyl, and R3 and R5h are combined together to form a
group of the formula:
<IMG> or <IMG>
in which R6 is as defined above, or
(i) subjecting a compound of formula (I-5'), as defined
above, to halogenation to give a halo-compound, followed by a
substitution reaction of the thus obtained halo-compound with
piperazine substituted by lower alkyl or hydroxy(lower)alkyl, to
give the compound (I) wherein R1, R2 and R3 are each as defined
above and R4 and R5, which may be the same or different, are
each hydrogen, lower alkyl or lower alkyl substituted with
piperazin-1-yl cubstituted by lower alkyl or hydroxy(lower)-
alkyl, provided that at least one of R4 and R5 is said substi-
tuted lower alkyl, or
(j) reacting the compound (I) wherein R1, R2, R3, R4 and
R5 are each as defined ahove and at least one of R2 and R3 is
halo(lower)alkoxycarbonyl with N,N-di(lower)alkyl- or N-lower
alkyl-N-phenyl(lower)alkyl-amine to give the compound (I) where-
in R1, R2. R3, R4 and R5 are each as defined above and at least
one of R2 and R3 is N,N-di(lower)alkylamino(lower)alkoxycarbonyl
or N-lower alkyl-N-phenyl(lower)alkylamino(lower)alkoxycarbonyl,
or
(k) subjecting the compound (I) wherein R1, R2, R3, R4 and
R5 are each as defined above and at least one of R2 and R3 is
halo(lower)alkoxycarbonyl to hydrolysis to give the compound (I)
wherein R1, R2, R3, R4 and R5 are each as defined above and at
least one of R2 and R3 is hydroxy(lower)alkoxycarbonyl, or
(1) reacting the compound of formula (I-2) as defined
197

above, with a lower alkanediol to give the compound (I) wherein
R1, R2 and R3 are each as defined above and R4 and R5, which may
be the same or different, are each hydrogen, lower alkyl or gem-
lower alkylenedioxy(lower)alkyl, provided that at least one of
R4 and R5 is said gem-lower alkylenedioxy(lower)alkyl, or
(m) halogenating a compound of formula (I-5'), as defined
above, and reacting the thus obtained halo-compound with a com-
pound of formula:
R10-CN
wherein R10 is hydrogen or a metal to give the compound (I)
wherein R1, R2 and R3 are each as defined above and R4 and R5,
which may be the same or different, are each hydrogen, lower
alkyl or cyano(lower)alkyl, provided that at least one of R4
and R5 is cyano(lower)alkyl.
140. A process for preparation of a compound of the
formula:
<IMG> (I)
wherein R10 is cyano, lower alkoxycarbonyl or lower alkylsulfa-
moyl,
R2 and R3 are each lower alkoxycarbonyl,
one of R4 and R5 is lower alkyl and
the other is cyano or substituted lower alkyl in which the subs-
tituent is cyano, hydroxy, hydroxyimino, oxo or gem-di(lower)-
alkoxy, which comprises
198

(a)-(l) reacting a compound of the formula:
(II)
<IMG>
wherein R10 and R3 are each as defined above, and R5a is as
defined below, with an amino compound of the formula:
(III)
<IMG>
wherein R2 is as defined above, and R4a is as defined below, to
give a compound of the formula:
<IMG> (I-l)
wherein R10, R2 and R3 are each as defined above,
one of R4a and R5a is lower alkyl and
the other is lower alkyl substituted with gem-di(lower)-
alkoxy(lower)alkyl; or
(b) hydrolyzing a compound of formula (I-l), as defined
above to give a compound of the formula:
(I-2)
<IMG>
wherein R10, R2 and R3 are each as defined above,
one of R4b and R5b is lower alkyl and
the other is lower alkyl substituted with oxo, or
199

(c) reacting a compound of formula (I-2) as defined
above with hydroxylamine or a salt thereof to give a compound
of the formula:
<IMG>
(I-3)
wherein R10, R2 and R3 are each as defined above,
one of R4c and R5c is lower alkyl and
the other is hydroxyimino(lower)alkyl, or
(d) treating a compound of the formula:
<IMG> (I-3')
wherein R10, R2 and R3 are each as defined above,
one or R'4c and R'5c is lower alkyl and
the other is .omega.-hydroxyimino(lower)alkyl, with a
dehydrating agent to give a compound of the formula:
<IMG> (I-4)
wherein R10, R2 and R3 are each as defined above,
one of R4d and R5d is lower alkyl and
the other is cyano or .omega.-cyano(lower)alkyl, or
200

(e) reducing a compound of formula (I-2) as defined
above to give a compound of the formula:
<IMG> (I-5)
wherein R10, R2 and R3 are each as defined above,
Definition (i) and
one of R4e and R5e is lower alkyl and the other is
hydroxy(lower)alkyl.
141. A process for preparation of a 1,4-dihydropyridine
derivative of the formula:
<IMG>
wherein R10 is cyano, lower alkoxycarbonyl or lower alkyl-
sulfamoyl;
R2 and R3 are each lower alkoxycarbonyl; R4a is lower
alkyl and R5a is lower alkyl substituted with gem-di-
(lower)alkoxy(lower)alkyl, which comprises reacting a
compound of the formula:
<IMG>
wherein R10, R3 and R5a are each as defined above, with an
amino compound of the formula:
<IMG>
201

wherein R2 and R4a are each as defined above.
142. A process according to claim 141, wherein
R10 is 2-cyano; 2-lower alkoxycarbonyl or 2-lower alkylsulfamoyl
and R5a is 1,1-di(lower)alkoxy(lower)alkyl.
143. A process according to claim 142, wherein
R10 is 2-cyano; 2-methoxycarbonyl or 2-methylsulfamoyl; R2 and
R3 are each methoxycarbonyl or ethoxycarbonyl; R4a is methyl and
R5a is dimethoxymethyl or diethoxymethyl.
144. A process for preparing a 1,4-dihydropyridine
derivative of the formula:
<IMG>
wherein R10 is cyano, lower alkoxycarbonyl or lower alkyl-
sulfamoyl,
R2 and R3 are each lower alkoxycarbonyl,
R4b is lower alkyl, R5b is lower alkyl substituted with
oxo, which comprises hydrolyzing a compound of the
formula:
<IMG>
wherein R10, R2 and R3 are each as defined above,
R4a is lower alkyl and R5a is lower alkyl substituted
with oxo.
202

145. A process according to claim 144, wherein R10 is
2-cyano, 2-lower alkoxycarbonyl or 2-lower alkylsulfamoyl; R5a
is 1,1-di(lower)alkoxy(lower)alkyl and R5b is lower alkanoyl.
146. A process according to claim 145, wherein R10 is
2-cyano, 2-methoxycarbonyl or 2-methylsulfamoyl; R2 and R3 are
each methoxycarbonyl or ethoxycarbonyl; R4a and R4b are each
methyl, R5a is dimethoxymethyl or diethoxymethyl, and R5b is
formyl.
147. A process for preparing a 1,4-dihydropyridine
derivative of the formula:
<IMG>
wherein R10 is cyano or lower alkoxycarbonyl; R2 and R3 are
each lower alkoxycarbonyl; R4c is lower alkyl and R5c is
hydroxyimino(lower)alkyl, which comprises reacting a compound
of the formula:
<IMG>
wherein R10, R2 and R3 are each as defined above,
R4b is lower alkyl and R5b is lower alkyl substituted
with oxo, with hydroxylamine or a salt thereof.
148. A process according to claim 147, wherein
R10 is 2-cyano or 2-lower alkoxycarbonyl; R5b is lower alkanoyl
and R5c is 1-hydroxyimino(lower)alkyl.
203

149. A process according to claim 148, wherein
R10 is 2-cyano or 2-methoxycarbonyl; R2 and R3 are each methoxy-
carbonyl or ethoxycarbonyl; R4b and R4c are each methyl; R5b is
formyl and R5c is hydroxyiminomethyl.
150. A process for preparation of a 1,4-dihydropyri-
dine derivative of the formula:
<IMG>
wherein R10 is cyano or lower alkoxycarbonyl;
R2 and R3 are each lower alkoxycarbonyl;
R4d is lower alkyl and
R5d is cyano, which comprises treating a compound of the
formula:
<IMG>
wherein R10, R2 and R3 are each as defined above,
R'4c is lower alkyl and R'5c is hydroxyiminomethyl,
with a dehydrating agent.
151. A process according to claim 150, wherein R10 is
2-cyano or 2-lower alkoxycarbonyl.
152. A process according to claim 151, wherein R10 is
2-cyano or 2-methoxycarbonyl; R2 and R3 are each methoxy-
carbonyl or ethoxycarbonyl; R'4c and R4d are each methyl; R'5c
204

is hydroxyiminomethyl and R5d is cyano.
153. A process for preparation of a 1,4-dihydro-
pyridine derivative of the formula:
<IMG>
wherein R10 is cyano, lower alkoxycarbonyl or alkylsulfamoyl;
R2 and R3 are each lower alkoxycarbonyl; R4e is lower
alkyl and R5e is hydroxy(lower)alkyl, which comprises
reducing a compound of the formula:
<IMG>
wherein R10, R2 and R3 are each as defined above,
R4b is lower alkyl and R5b is lower alkyl substituted
with oxo.
154. A process according to claim 153, wherein R10 is
2-cyano, 2-lower alkoxycarbonyl or 2-lower alkylsulfamoyl; R5b
is lower alkanoyl and R5e is 1-hydroxy(lower)alkyl.
155. A process according to claim 154, wherein R10 is
2-cyano, 2-methoxycarbonyl or 2-methylsulfamoyl; R2 and R3
are each methoxycarbonyl or ethoxycarbonyl; R4b and R4e are
each methyl; R5b is formyl, and R5e is hydroxymethyl.
205

156. A 1,4-dihydropyridine derivative as defined in
claim 140, whenever prepared by the process of claim 140 or
by an obvious chemical equivalent.
157. A 1,4-dihydropyridine derivative as defined in
claim 141, whenever prepared by the process of claim 141 or
by an obvious chemical equivalent.
158. A 1,4-dihydropyridine derivative as defined in
claim 142, whenever prepared by the process of claim 142 or
by an obvious chemical equivalent.
159. A 1,4-dihydropyridine derivative as defined in
claim 143, whenever prepared by the process of claim 143 or
by an obvious chemical equivalent.
160. A 1,4-dihydropyridine derivative as defined in
claim 144, whenever prepared by the process of claim 144 or
by an obvious chemical equivalent.
161. A 1,4-dihydropyridine derivative as defined in
claim 145, whenever prepared by the process of claim 145 or
by an obvious chemical equivalent.
162. A 1,4-dihydropyridine derivative as defined in
claim 146, whenever prepared by the process of claim 146 or
by an obvious chemical equivalent.
163. A 1,4-dihydropyridine derivative as defined in
claim 147, whenever prepared by the process of claim 147 or
by an obvious chemical equivalent.
164. A 1,4-dihydropyridine derivative as defined in
claim 148, whenever prepared by the process of claim 148 or
by an obvious chemical equivalent.
206

165. A 1,4-dihydropyridine derivative as defined in
claim 149, whenever prepared by the process of claim 149 or
by an obvious chemical equivalent.
166. A 1,4-dihydropyridine derivative as defined in
claim 150, whenever prepared by the process of claim 150 or
by an obvious chemical equivalent.
167. A 1,4-dihydropyridine derivative as defined in
claim 151, whenever prepared by the process of claim 151 or
by an obvious chemical equivalent.
168. A 1,4-dihydropyridine derivative as defined in
claim 152, whenever prepared by the process of claim 152 or
by an obvious chemical equivalent.
169. A 1,4-dihydropyridine derivative as defined in
claim 153, whenever prepared by the process of claim 153 or
by an obvious chemical equivalent.
170. A 1,4-dihydropyridine derivative as defined in
claim 154, whenever prepared by the process of claim 154 or
by an obvious chemical equivalent.
171. A 1,4-dihydropyridine derivative as defined in
claim 155, whenever prepared by the process of claim 155 or
by an obvious chemical equivalent.
172. A 1,4-dihydropyridine derivative as defined in
claim 139, whenever prepared by the process of claim 139 or
by an obvious chemical equivalent.
207

Description

1080Z~;~
1,4-DIHYDROPYRIDINE DERIVATIVES, PROCESS
FOR PREPARATION THEREOF AND PHARMACEUTICAL
COMPOSITION OF THE SAME
This invention relates to 1,4-dihydropyridine
derivatives. More particularly, it relates to new 1,4-
dihydropyridine derivatives thereof which have vasodilating
and anti-hypertensive activity,to processes for the preparat-
ion thereof, snd to pharmaceutical composition comprising the
same for therapeutical treatment in cardiovascular deseases and
hypertension in human being.
Accordingly, one object of this invention is to
provide new and useful 1,4-dihydropyridine derivatives.
Another object of this invention is to pTovide
processes for the preparation of l,4-dihydropyridine derivatives.
A further object of this invention is to provide
useful pharmaceutical composition comprising said 1,4-
dihydropyridine derivatives as a vasodilator and anti-hypertensive.
Still further object of the present invention is to
provide a therapeutical method of treating cardiovascular
diseases such as coronary insufficiency, angina pectoris or
myocardial infarction and hypertension.
The 1,4-dihydropyridine derivatives of this invention
may be represented by the general formula:
R2 ~ R3 tl)
D
- 1 -
~p

1084)2~3
wherein Rl is phenyl which i8 unsubstituted or substituted by
one or more substituents selected from the group consisting of
halogen, nitro, trihalo(lower)alkyl, lower alkoxy, hydroxy and
lower alkenyloxy, thienyl or furyl, R2 and R3 which may be the
same or different are each lower alkoxycarbonyl, halo(lower)-
alkoxycarbonyl, hydroxy(lower)alkoxycarbonyl, lower alkoxy(lower)-
alkoxycarbonyl, phenyl(lower)alkoxycarbonyl, phenyl(lower)-
alkoxy(lower)alkoxycarbonyl, phenoxy(lower)alkoxycarbonyl,
~,N-di(lower)alkylamino(lower)alkoxycarbonyl or N-lower alkyl-
N-phenyl(lower)alkylamino(lower)alkoxycarbonyl~ and R4 and R5
which may be the same or different, are each hydrogen, cyano,
lower alkyl, or substituted lower alkyl in which the sub-
stituent is selected from the group consisting of cyano,
hydroxy, lower alkanoyloxy, carboxy(lower)alkanoyloxy, lower.
alkoxycarbonyl(lower)alkanoyloxy, N-lower alkyl-~-phenyl(lower)-
alkylamino(lower)alkanoyloxy, benzoyloxy, 4-chlorophenoxy-
acetoxy, hydroxyimino, hydra~ono, lower alkoxyimino, hydroxy-
(lower)alkylimino, N', N'-di(lower)alkylamino(lower)alkyl-
imino, hydroxy(lower)alkylamino, ~ '-di(lower)alkylamino-
(lower)alkylamino, piperazin-l-yl substituted by lower alkyl
or hydroxy(lower)alkyl, oxo, gem-di(lower)alkoxy, and gem-
lower alkylenedioxy, provided that, when one of R4 and R5 is
hydrogen or lower alkyl, the other is cyano or said substituted
lower alkyl, and when R4 and R5 are not hydrogen or lower
alkyl R4 and R5 are both the same group, which is selected
from cyano and said substituted lower alkyl, or R4 is hydrogen
or lower alkyl and R3 and R5 are combined to form a group of
the formula: .
O o o O
O ~H
-R7 or
Ll~ - 2 -
~ . .
.

' lO~OZ~3
wherein R6 is hydrogen or methyl and R7 is 2-(N,N-diethylamino)-
ethyl or 2-hydroxyethyl.
The terms used in the definitions of the symbols of
the general formulae given in this specification and claims are
explained as follows: the expression "such as" employed in this
specification is intended to identify convenient and suitable
examples; it is not intended to restrict the meaning of the
terms which it qualifies. The term "lower" used in connection
with an alkylene, alkyl and alkenyl is intended to mean the one
having 1 to 8 carbon atoms.
When the phenyl moiety ~n Rl i9 substituted with
halogen, the halogen or halo moiety is fluorine, chlorine,
bromine or iodine.
Lower alkylene may be one having a straight or
branched and saturated bivalent hydrocarbon chain such as
methylene, ethylene, methylmethylene, trimethylene, propylene
or tetramethylene.
Lower alkyl and lower alkyl moiety may be ones having
a straight or branched and saturated hydrocarbon chain such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,
pentyl, neo-pentyl, hexyl, heptyl or octyl.
Lower alkoxy and lower alkoxy moiety may suitably
be methoxy, ethoxy, propoxy, isopropoxy, butyoxy, t-butoxy
ane pentyloxy.
Halo(lower)alkyl or halo(lower)alkyl moiety may suit-
ably be mono-halo(lower)alkyl such as chloromethyl, bromomethyl
or chloropropyl; di-halo(lower)alkyl such as l,2-dichloroethyl,
1,2-dibromoethyl or 2,2-dichloroethyl; and tri-halo(lower)-
alkyl such as trifluoromethyl or 1,2,2-trichloroethyl.
Lower alkenyl and lower alkenyl moiety may be ones
having a straight or branched hydrocarbon chain which contains
one or more double bond(s), such as vinyl, allyl, butenyl,
butanedienyl or penta-2,4-dienyl.
j; - 3 -
~ ...................................... . . - .

108()2Z3
Acyl and acyl moiety may be lower alkanoyl such as
formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, iso-
valeryl, pivaloyl, ~ub~tituted lower alkanoyl, for example,
carboxy(lower)alkanoyl, e~terified carboxy(lower)alkanoyl such
as lower alkoxycarbonyl(lower)alkanoyl, N- or ~,N-di-substituted
amino(lower)alkanoyl such as N- or N,N-di-(lower)alkylamino-
(lower)alkanoyl (e.g. N-methyl (or N,N-dimethyl) aminoacetyl,
l(or 2)-[N-ethyl(or N,N-diethyl)amino]propionyl or l(or 2)-
[N-methyl-N-ethylamino]propionyl) or N-lower alkyl-N-ar(lower)-
alkylamino(lower)alkanoyl (e.g. l-(or 2)-[N-methyl-N-benzyl-
amino]propionyl) or aryloxy(lower)alkanoyl such as phenoxy-
acetyl, tolyloxyacetyl, 2(or 3 or 4)-chlorophenoxyacetyl, 2-
[2-(or 3 or 4)-chlorophenoxy]-propionyl, 2(or 3 or 4)-nitro-
phenoxyacetyl or 2(or 3 or 4)-methoxyphenoxyacetyl); aroyl such
as benzoyl, naphthoyl or toluoyl and the like.
The heterocyclic group for Rl is suitably thienyl or
furyl.
The esterified carboxy radicals in the definition of
R2 and R3 may be lower alkoxycarbonyl such as methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxy-
carbonyl; halo(lower)alkoxycarbonyl such as the halo-analogues
of the above-mentioned lower alkoxycarbonyl (e.g,, 2-bromo-
ethoxycarbonyl, 2-chloroethoxycarbonyl, 2 (or 3)-chloropropoxy-
carbonyl, 2 (or 3)-bromopropoxycarbonyl, 2,2-dichloroethoxy-
carbonyl or 2,2,2-trichloroethoxycarbonyl); hydroxy(lower)-
alkoxycarbonyl such as 2-hydroxyethoxycarbonyl or 2(or 3)-
hydroxypropoxycarbonyl; lower alkoxy(lower)alkoxycarbonyl such
as 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl or 2(or 3)-
methoxy(or ethoxy)propoxycarbonyl; aryloxycarbonyl such as
phenoxycarbonyl, tolyloxycarbonyl, xylyloxycarbonyl or p-chloro-
phenoxycarbonyl; ar(lower)alkoxycarbonyl such as benzyloxy-
carbonyl, p-bromobenzyloxycarbonyl, o-methoxybenzyloxycarbonyl
or phenethyloxycarbonyl, ar(lower)alkoxy(lower)alkoxycarbonyl
~ _ 4 _
`J
`:

`` 108V;~3
such as 2-(benzyloxyl)ethoxycarbonyl or 2(or 3)-(benzyloxy)-
propoxycarbonyl, aryloxy(lower)alkoxycarbonyl such as 2-
(phenoxy)ethoxycarbonyl or 2(or 3)-(phenoxy)propoxycarbonyl
N- or N,N-(di)-substituted amino(lower)alkoxycarbonyl such as
N- or N,N-(di)-(lower)alkylamino(lower)alkoxycarbonyl (e.g. 1-
(or 2)-[N-methyl(or N,N-dimethyl)amino]ethoxycarbonyl, l(or 2)-
[N-ethyl(or N,N-diethyl)amino]ethoxycarbonyl, or l(or 2)-(N-
methyl-N-ethylaminoethoxycarbonyl) or N-lower alkyl-N-ar(lower)-
alkylamino(lower)alkoxycarbonyl (e.g. 2-(N-methyl-N-benzyl-
amino)-ethoxycarbonyl) and the like, and further R2 and R3 may
be same or different.
Lower alkyl substituted with oxo includes lower
alkanoyl such as formyl, acetyl, propionyl, butyryl, iso-
butyryl, valeryl, isovaleryl or pivaloyl and lower alkanoyl-
(lower)alkyl such as formylmethyl, acetonyl, 2-formylethyl, 3-
formylpropyl or butyrylmethyl. The carbonyl group thereof may
be protected with suitable protecting group, and thus pro-
tected carbonyl group in this invention means a group given
by protecting the carbonyl with conventionally employed pro-
tecting group for a carbonyl. Suitable examples of such pro-
tected carbonyl group are acetal, cyclic-acetal, thioacetal,
cyclic-thioacetal, cyclicmonothioacetal or acylal types of
group. Examples of these lower alkyl containing such pro-
tected carbonyl group are gem-di(lower)alkoxy(lower)alkyl (e.g.
dimethoxymethyl, l,l-dimethoxyethyl, diethoxymethyl, dipro-
poxymethyl, 2,2-diethoxyethyl or 2,2-diethoxypropyl), gem-
lower alkylenedioxy(lower)alkyl (e.g. 1,3-dioxolan-2-yl,
2-methyl-1,3-dioxolan-2-yl, 4-methyl-1,3-dioxolan-2-yl, 4,5-
dimethyl-1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 2-methyl-1,3-
dioxan-2-yl, 1,3-dioxolan-2-ylmethyl,2-methyl-1,3-dioxolan-2-
ylmethyl or 3-(1,3-dioxolan-2-yl)propyl), gem-di(lower)alkyl-
thio(lower)-alkyl (e.g. dimethylthiomethyl, l,l-dimethylthio-
ethyl, diethylthiomethyl or 2,2-diethylthioethyl),
~ ~ - 5 _
~, ,,~. ....
~ .

108V2Z3
gem-lower alkylenedithio(lower)alkyl (e.g. 1,3-dithiolan-2-
yl, 2-methyl-1,3-dithiolan-2~yl, 4-methyl-1,3-dithiolan-2-
yl, 4,5-dimethyl-1,3-dithiolan-2-yl, 1,3-dithian-2-yl, 2-
methyl-1,3-dithian-2-yl, 1,3-dithiolan-2-ylmethyl, 2-methyl-1,3-
dithiolan-2-ylmethyl or 3-(1,3-dithiolan-2-yl)propyl), and
gem-di(lower)alkanoyloxy(lower)alkyl (e.g. diacetoxymethyl,
l,l-diacetoxyethyl, dipropionyloxymethyl or 2,2-dipropionyloxy-
ethyl), S or 6-membered saturated 1-oxa-3-thioheterocyclic-1-
yl(lower)alkyl (e.g. 1,3-oxathiolan-2-yl, 2-methyl-1,3-
oxathiolan-2-yl, 4-methyl-1,3-oxathiolan-2-yl, 4,5-
dimethyl-1,3-oxathiolan-2-yl, 1,3-oxothian-2-yl, 2-methyl-
1,3-oxothian-2-yl, 1,3-oxathiolan-2-ylmethyl, 2-methyl-
1,3-oxathiolan-2-ylmethyl or 3-(1,3-oxathiolan-2-yl)propyl).
nl
~ ~ - 5a -

- `-` lO~ Z;~
A 5 or 6-membered saturated N-contianing hetero-
cyclic-l-yl group may be one which may contain additional one
or more he~ero atom(s) selected from nitrogen, sulfur and
oxygen atoms such as pyrrolidin-l-yl, piperidino, imidazolidin-
l-yl, morpholino or thiomorpholino, and it may be optionally
substituted with hydroxy, lower alkyl or hydroxy(lower)alkyl
such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-
hydroxypropyl .
The other terms of each lower alkoxyimino, N'- or N',
N'-di-(lower)alkylamino(lower)alkylimino, hydroxy(lower)alkyli-
mino, N'- or N',N'-di-(lower)alkylamino(lower)alkylamino and
hydroxy(lower)alkylamino will be clearly defined by applying
optionally the above given exemplifications of the terms to them.
According to the present invention, 1,4-dihydropy-
ridine derivatives (I) can be produced by various processes,
which fall into the following classification:
(I Construction of fundamental structure)
1. Ring formation of 1,4-dihydropyridine nucleus.
(II Transformations of functions)
2. Hydrolysis for removal of protecting group of
protected carbonyl group
3. Condensation to form imino-function.
4. Dehydration
S. Reduction of oxo- or imino-function.
i 6. Acylation of hydroxy-function.
7. Oxidation of alcohol to carbonyl compound.
8. Pyrolytic ring closure.
9. Other transformations.
Each of these processes will be hereinafter illustrated.
, ~ :

108V223
1. Ring formation of 1,4-dihydropyridine nucleus.
Some of the compound (I) representable by the
following formula: Rl
R~5a ( I -1)
wherein Rl, R2 and R3 are each as defined above and R4a and
a are each hydrogen, lower alkyl or lower alkyl substituted with
oxo wherein thus formed carbonyl group is protected with
suitable protecting group, provided that at least one of R4a ~ ?
and R5a is iower alkyl substituted with oxo wherein thus formed
carbonyl group is protected with suitable protecting group,
can be prepared by carrying out one of the reactions of the
processes, which comprises
(1) reacting a compund of the formula:
Rl - CH - C - CO - R5a ~II)
R3
wherein Rl, R3 and R5a are each as defined above, with an amino ~-
compound of the formula:
R4a ~ C = CH - R2 (III)
N~2
wherein R2 and R4a are each as defined above,
(2) subjecting a mixture of an aldehyde compound of the formula:
Rl - CHO (II')
wherein Rl is as defined above,
an ester of ~ketonic acid of the formula:
R5a ~ COCH2 - R3 (II")
wherein R3 and R5a are each as defined above,
and an amino compound (III) to reaction, or
~ .
-- 7 -
~ ~' '" ' ' . ' .

~3) reacting an acetylene compound of the formula:
R2 ~ C = C - R4a (III')
wherein R2 and R4a are each as defined above, with ammonia or
an ammonium salt and a compound (II).
The s~arting compound ~II) used in the reactions (1)
and (3) may be novel and prepared by reacting the aldehyde
(II') with the ~-ketoacid ester (II") in a conventional manner,
and the ammonium salt used in the reaction (3) includes an
inorganic ammonium salt such as ammonium chloride or ammonium
sulfate,-or an organic ammonium salt such as ammonium acetate.
In the above reactions (1), (2) and (3), there can be
employed the starting compounds (II), (II"), (III) and (III')
wherein the symbols R4a and R5a are occasionally exchanged
into each other, even when both symbols are not the same groups,
and, in such case, the substantially same object compound (I-l)
may be; obtained not only when R4a and R5a are ~he same groups,
irrespective of R2 and R3 being the same groups or not, but also
when R4a and R5a are not the same groups and R2 and R3 are the
same groups.
Regarding the reactions(l) and (3), the starting compound
(II) may include geometric isomers such as cis-trans isomers
due to the double bond in its molecule. Such cis-trans isomers
may be equilibrated and, therefore, each or a mixture of
the isomers of (II) may be applied as the starting materials
to provide the same object compound (I-l).
The reactions ~1), (~) and (3) can be carried out
at ambient temperature or under warming or heating with or
without a suitable solvent such as benzene, toluene, xylene,
chloroform~ carbon tetrachloride, methylene chloride, ethylene
chloride, methanol, propanol, butanol, water or other conventional
- 8 --

1 0~V~ ~ 3
solvents. The reactions can be usually promoted in the presence
of an agent such as an acid (e.g. acetic acid), a base (e.g.
pyridine or picoline) or in a conventional buffer solution.
These agents may act as a reaction promotor and also used as
a solvent when they are in liquid. The reactions can be also
atcelerated by heating. The reaction condition may vary accord-
ing to the kind of the reactants to be used.
2. Hydrolysis for removal of protecting group of
protected carbonyl group.
The compound of the formula:
Rl
R2 ~ ~ ~ - R3 (I-2)
R4b N ` R5b
wherein Rl, R2 and R3 are each as defined above and R4b and
Rsb are each hydrogen, lower alkyl or lower alkyl substituted
with oxo, provided that at least one of R4b and R5b is lower
alkyl substituted with oxo, can be prepared by hydrolyzing
the compound (I-l~ which can be obtained in the above-mentioned
ring formation process. In this process, the protecting group(s)
of the carbonyl group on the alkyl group for R4a and/or R5a f
the compound (I-l) is removed by hydrolysis.
Hydrolysis may be carried out in a conventional manner
and, for example, the removal of the protecting groups of
acetal-type and cyclic acetal-type is preferably carried out
by an acidic hydrolysis, i.e. in the presence of an acid such
as an inorganic acid (e.g. hydrochloric acid or sulfuric acid)
or an organic acid ~e.g. formic acid, acetic acid, trifluoro-
acetic acid or p-toluenesulfonic aci~; the removal of the
protecting groups of thioacetal-type, cyclic thioacetal-type
.
. . . . . .

`~
8~ 22 3
~,ld cyclic monothioacetal type is preerably carried out by
hydrolysis in the presence of a heavy metal salt such as
mercuric chloride or copper chloride; and the removal of the
protecting group of acylal-type is preferably carried out by the
above mentioned acidic hydrolysis or a basic hydrolysis, i.e.
in the presence of a base such as an inorganic base (e.g.
sodium hydroxide, potassium hydroxide, sodium carbonate or
potassium carbonate) OT an organic base (e.g. sodium methoxide,
sodium e~hoxide, potassium methoxide, potassium ethoxide, pyri-
~i~e or picoline). These reactions of hydrolysis may be
carried out in a suitable conventional solvent such as water,
acetone, methyl ethyl ketone, dioxane, ethanol, methanol,
N,N~dimethylformamide, N-methylmorpholine or dimethylsulfoxide,
an optional mixture with water or a buffer solution thereof.
The reaction temperature is not restrictive, and the reaction
is usually conduc~ed under cooling, at room temperature or
under somewhat elevated temperature.
3. Condensation to form imino function
The compound of the formula: R
Rz ~ R3 (I-3)
4c H 5c
wherein Rl, R2 and R3 are each as defined above and R4c and R5c
are each hydrogen, lower alkyl or substituted lower alkyl in
which the subsituent is hydroxyimino, hydrazono, lower
alkoxyimino, hydroxy(lower)alkylimino or N'-or N, N-di-
~lower)alkylamino(lower)alkylimino, provided that at least
one of R4c and R5c is said substituted lower alkyl, may be
prepared by reacting a compound of the formula:
- 10 -

1081~Z23
R2~ 3
~ 2)
R
wherein Rl, R2, R3, R4b and R5b are each as defined above, with
an amine of the formula:
R8 ~ NH2 (I~)
wherein R8 is hydroxy, amino, lower alkoxy, hydroxy(lower)alkyl
or N - or N , N -di(lower)alkylamino(lower)alkyl.
According to this process the oxo group in R4b and/or
Rsb of the starting compound (I-2) is replaced by the imino
group of =N-R8 (wherein R8 is as defined above).
The starting compound (I-2) can be obtained by the
above-mentioned hydrolysis process.
The reaction is carried out in a usual manner, ~or
example, in the presence of a catalyst, such as an acid (e.g.
hydrochloric acid, hydrobromic acid, sulfuric acid, formic
acid, acetic acid, p-toluenesulfornic acid, boron trifluoride,
silicon tetrachloride or titanium tetrachloride); in a basic
condition realized by using the ~ree amino-compound (IV); or -
an acidic or basic conventional buffer solution, and usually
in a suitable conventional solvent such as water, dioxane,
ethanol, methanol or dimethylformamide or an optional mixture
with water thereof.
The reaction temperature is not restrictive, and the
reaction is usually carried out under cooling, at room tempera-
ture or under somewhat elevated temperature. The amine (IV),
which is used as a reactant, includes an N'- or N',N'Ydi-(lower)-
alkylamino(lower)alkylamine such as
N'-methyl or N~,N~-dimethylamino-ethylenediamine,
- 11 - ,

10~3it)~Z3
N'-ethyl or N',N'-diethylethylenediamine, N'-methyl or N',N'-di-
methylaminotrimethylenediamine or N'-ethyl or N',N'~iethyl-
aminotrimeth~lenediamine; hydroxy(lower)alkylamine such as
ethanolamine or propanolamine; hydroxylaminej hydrazine and
ilower alkoxyamine such as O-methyl-, O-ethyl-, O-propyl-,
or O-isopropyl-hydroxyamine. And these amines may be used
in the form of salt with an acid such as an inorganic acid
(e.g. hydrochloric acid or sulfuric acid) or an organic acid
(e.g. acetic acid).
4. Dehydration
The compound of the formula:
Rl
R2_- ~ R3 (I-4)
R4d N - R5d
~.
wherein Rl, R2 and R3 are each as defined above and R4d and
R5d are each hydrogen, lower alkyl, cyano or ~-cyano(lower)alkyl,
provided that, when one of R4d and R5d is hydrogen or lower
alkyl, the other is always cyano or ~-cyano(lower)alkyl, and
Iwhen R4d and R5d are not hydrogen or lower alkyl, both of them
are a group selected from cyano or ~-cyano(lower)alkyl, or
R4d is hydrogen or lower alkyl and R3 and R5d are combined
together to form a group of the formula:
~ .
may be prepared by treating the compound of the formula:
R ~ tI-3')
R 4c N R'5c
- 12 -

108VZ23
wherein Rl, R2 and R3 are each as defined above and R'4c and
R'sC are each hydrogen, lower alkyl or ~-hydroxyimino(lower)alkyl,
provided that at least one of R'4c and R'5c is ~-hydroxyimino-
(lower)alkyl, with a dehydrating agent.
i The starting compound (I-3') can be obtained by the
above-mentioned condensation process.
Suitable example of the dehydrating agent may be
organic or inorganic conventional ones such as an acid (e.g.
sulfuric acid, phosphoric acid, polyphosphoric acid, formic
acid, acetic acid, ethane sulfonic acid or p-tolene sulfonic
acid), an acid anhydride (e.g. acetic anhydride, benzoic
anhydride or phthalic anhydride), an acid halide (e.g. acetyl
chloride, benzoyl chloride, trichloroacetylchloride, mesyl
chloride, tosylchloride, ethyl chloroformate or phenylchloro-
formate), an inorganic halogen compound (e.g. thionylchloride,
~hosphorus pentachloride, phosphorus oxychioride, phosphorus
tribromide, stannic chloride or titanium tetrachloride), a
carbodiimIde ~e.g. N,N'-dicyclohexylcarbodiimide or N-
cyclohexyl-N'-morpholinoethylcarbodiimide), N,N'-carbonyldi^
imidazole, pentamethyleneketene-N-cyclohexylimine, ethoxyacety-
lene, 2-ethyl-7-hydroxyisoxazolium salt, another phosphorus
compound (e.g. phosphorus pentoxide, polyphosphoric acid
ethylester, triethylphosphate or phenylphsphate) or the like.
When an acid is used as the dehydrating agent, the reaction
may be conveniently conducted in the presence of its alkali
metal salt (e.g. sodium salt or potassium salt), or the like.
This reaction is usually carried out in a conventional
solvent such as diethyl ether, dimethylformamide, pyridine,
acetic acid, formic acid, benzene, carbon tetrachloride, chloro-
D form, methylene chloride, tetrahydrofuran, dioxane, and the
- 13 -

~0802Z3
like, and usually carried out at room temperature or under
heating, and the reaction temperature is not restrictive to
the above.
According to this process, the terminal -CH=N-OH function
in R'4c and/or R'5c of the starting compound (I-3~) is trans-
formed into cyano function in the resultant compound (I-4),
and further there tends to produce the compound of the formula:

Rz- ~ ~ (I-4~)
R ~ ~ N~ N
wherein Rl and R2 are each as defined above and R"4c is hydrogen
or lower alkyl when the starting compound (I-3') wherein R'5c is
hydroxyiminomethyl is treated, for example, in rather highly
j acidic condition. The compound (I-4') and the process for . ..
preparation thereof are also included in the scope of this
invention.
This dehydration process can be also carried out
successively to the foregoing condensation process without any -
isolation of the compound ~I-3'). This case is also included
in the scope of this. invention.
5. Reduction of oxo- or imino- function
The compound of the formula:
~ 5)
wherein Rl, R2 and R3 are each as defined above and R4e and R5e
are each hydrogen,-lower alkyl or substituted lower alkyl in
O which the substituent is hydroxy, hydrazino, hydroxy(lower)-a ~ lammo
- 14 -
::

`` 1(~802~3
~'- or N',N'-di(lower)alkylamino(lower)-
alkylamino, provided that at least one of R4e and R5e is
said substituted lower alkyl or R4e is hydrogen or lower
alkyl ~nd R3 and R5e are combined together to form ~3
or ~ R7 (wherein R6 and R7 are each as deflned above),
can be prepared by reducing the compound of the formula: :
R
R 4 ~ R35b (I-2')
) whe~ein Rl, R2 and R3 are each as defined above and R'4b and
R'5b are each hydrogen, lower alkyl or substituted lower
alkyl in which the substituent i-s oxo, hydrazono, hydraxy(lower)-
alkylimino or N'- or N',N'-di(lower)alkylamino(low.er)alkylimino,
provided that at least one Of R'4b and R'5b is said substituted
i lower alkyl.
The starting compound (I-2') can'be prepared by either
of the above-mentioned process hy.drolysis or condensation.
The reduction can be carried out by a conventional
manner for reduction of oxo or imino to hydroxy or amino,
3 respectively,for example, reduction with a reducing agent such as an
alkali metal hydride (e.g. lithium borohydride, sodium borohydride, ,
' potassium borohydr.ide'or sodium cyanoborohydride) or catalytic
reduction for which catalyst may be palladium carbon, palladium
chloride or rhodium carbon and the like in a suitable
` conventional solven~. Examples of such solvents are water,
methanol, ethanol, isopropanol, dimethylformamide, and the
like. The reaction temperature is not restrictive, and the
reaction is usually carried out under cooling, at room tempera-
ture or at somewhat elevated temperature. And, the method of
3 reduction may be optionally selected according to the kind of the
.

~` iO 8~ 2~ 3
starting compound (I-2').
According to this process, each oxo- or imino-
function in the starting compound (I-2') is transformed into
the hydroxy- or amino-function, respectively, in the resultant
compound (I-5), and further, the compound of the formula:
Rl O
R
o (I-5-1
N '
H R6
wherein R6 is as defined above and R4e is hydrogen or lower
alkyl, and the compound of the formula:
Rl O
R2 ~ N-R7 (I-5-2)
R4e H
wherein R7 is as defined above and R4e is hydrogen or lower
alkyl, can be produced simultaneously via the compound (I-5)
wherein R5e is hydroxymethyl (when R6 is hydrogen), l-hydro-
xyethyl (when R6 is methyl), 2-(N',N'-diethylamino)e`thylamino-
methyl (when R7 is 2-(N ,N -diethylamino)ethyl) or 2-hydroxy-
ethylaminomethyl (when R7 is 2-hydroxyethyl), respectively.
These cases are also included in the scope of this
invention.
6. Acylation of hydroxy function
The compound of the formula:
Rl
R ~ R3 (I-6)
R4f H R5f .
wherein Rl, R2 and R3 are each as defined above and R4f and R5f
- 16 -
~9 .

1080Z23
are e~ch hydrogen, lower alkyl or cyloxy~lower)alkyl,
provided that at least one of R4f and R5f is acyloxy(lower)-
alkyl, can be prepared by reacting the compound of the formula~
Rl :
; 2 ~ b 3 (I-5~)
R'4e N ' R~5
wherein Rl, ~2 and R3 are each as defined above and R'~e and
R'5e are each hydrogen, lower alkyl or hydroxy(lower)alkyl,
J provided that at least one of Rl4e and R~5e is hydroxy(lower)-
alkyl, with an acylating agent of the formula:
Rg - OH (V)
wherein Rg is acyl, or its reactive derivative.
The starting compound (I-5') can be prepared in the
; above-men~ioned reduction process.
Suitable examples of acyl for Rg are lower alkanoyl
which may be substituted with carboxy, esteri~ied carboxy,
N- or N,N-di-substituted amino or arylc~y, aroyl and the
like.
) Suitable acylating agent (V) includes lower alkanoic
acid such as formic acid, acetic acid, propionic acid, butyric
acid, isobutyric acid, valeric acid, isovaleric acid or
pivalic acid; carboxy(lower)alkanoic acid, i.e. di- or poly-
basic carboxylic acid such as malonic acid, succinic acid,
~, adipic acid, glutaric acid, adipic acid, pimeric acid or suberic
acid; esteriied carboxy(lower)alkanoic acid, i.e. a half ester
of the preceding di- or poly-basic carboxylic acid such as
a respective half lower alkyl ester (e.g. me-thyl ester, ethyl
ester or propyl ester); N- or N,N-di-substituted amino(lower)-
) alkanoiG acid such as N- or N,N-di-(lower)alkylamino(lower)-
- 17 -
.. . .

108~3
alksnoic acid te.g. N-methyl(or N, N-dimethyl)amino-acetic
acid, l(or 2)-~N-ethyl(or N,N-diethyl)amino]propionic acid
or l(or 2)-[N-methyl-N-ethylamino]propionic acid) or N-lower
alkyl-N-ar(lower)alkylamino(lower)alkanoic acid (e.g. 1-
(or 2)-[N-methyl-N-benzylamino] propionic acid~, aryl-
oxy tlower)alkanoic acid such as phenoxyacetic acid,
tolyloxyacetic acid, 2(or 3 or 4)-chlorophenoxyacetic acid,
2-~2(or 3 or 4)-chlorophenoxy]propionic acid, 2(or 3 or 4)-
nitrophenoxyacetic acid or 2(or 3 or 4)-methoxy-phenoxyacetic
acid); and aromatic carboxylic acid such as benzoic acid,
naphthoic acid, toluic acid; and the like.
The reactive derivative at the carboxy group of the
compound (V) may be its acid halide such as acid chloride, acid
anhydride; active amide; azide; or reactive ester such as methyl
ester, ethyl ester, cyanomethyl ester, p-nitrophenyl ester or
pyranyl ester.
The reaction can be preferably carried out in the
presence of a base such as an inorganic base (e.g. sodium
hydroxide, potassium hydroxide, sodium bicarbonate, potassium
bicarbonate, sodium carbonate or potassium carbonate) or
an organic base (e.g. N-methylpiperidine, triethylamine, pyridine,
N-methylmorphorine or N,N~dimethylaniline), and a suitable
conventional solventsuch as pyridine, ether, dioxane, acetone,
chloroform, me~hylene chloride, tetrahydrofuran, dimethyl-
formamide, benzene or water. The reaction temperature is not
restrictive, and the reaction is usually carried out under
cooling, at room temperature or under somewhat elevated tem-
perature. If necessary, there may be used a conventional
condensing agent such as phosphorus oxychloride, thionylchloride,
N~N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morphorino-
- 18 -

1(3t~Z23
thylcarbodiimide~ pentamethyleneketene-N-cyclohexylimine,
alkoxyacetylene, 2-ethyl-7-hydroxyisoxazolium salt, 2-ethyl-S-
(m-sulophenyl)isoxazolium hydroxide or 6-chloro-1-
tosyloxybenzotriazole.
7. Oxidation of alcohol to aldehyde
The compound of the formula:
Rl
~",~ R3
~ N~l (I-7)
O
wherein Rl, R2 and R3 are each as defined above and R4g and
R5g are each hydrogen, lower alkyl, formyl or ~-formyl(lower)alkyl,
provided that, when one of R4g and R5g is hydrogen or lower alkyl,
the other is always formyl or ~-formyl(low~r)alkyl, and R4g and R5g
are not hydrogen or lower alkyl, both of them are a group selected
from formyl and ~-formyl(lower)alkyl, may be also prepared by oxidiz-
ing the compound of the formula:
Rl
R2~ ~ R3
~ 1~ (I-5")
R" N ~ R"
4e H 5e
wherein Rl, R2 and R3 are each as defined above and Rl'4e and
R1l5e are each hydrogen, lower alkyl, or ~-hydroxy(lower)alkyl,
provided that at least one of R1l4e and R1l5e is ~-hydroxy(lower)- .
alkyl.
The starting compound (I-5") can be prepared in the
above-mentioned reduction process.
The oxidation can be carried out by any conventional
method which selectively oxidize an primary alcohol function
to the corresponding formyl function without any adverse
influence on the other parts of the compound (I-5").
A suitable oxidation is carried out by reacting the
-- 19 --

10~02;~3
starting compound (I-5'`) with an organic sul~onic acid or
its reactive derivative, pre~erably under warming and in the
presence of a base, with or without a solvent. This reaction
may be proceeded via the organic sulfonic acid ester of the
compound (I-5") as an intermediate which may be produced in
the course of the reaction.
Suitable organic sulfonic acid may be methanesulfonic
acid, p-toluenesulfonic acid, p-nitrophenylsulfonic acid and
the like, and its reactive derivative and the base can be
referred to those of the compound (V) as mentioned in the
preceding acylation process.
8. Pyrolytic ring closure
The compound of the formula:
Rl
R2~ ~ R3 (I-7)
R4'h N Rsh
wherein Rl and R2 are each as deined above, R4h is hydrogen
or lower alkyl, and R3 and R5h are combined together to form
a group of the formula: ~ ~ H
,~ :
in which R6 is as defined above, may be prepared by heating in
neat or in a conventional solvent the compound (I-5~ wherein
R4e is hydrogen or lower alkyl and R5e is hydroxymethyl, or
the compound (I-3) wherein R4c is hydrogen or lower alkyl and
RsC is hydrazonomethyl, respectively.
A suitable conventional solvent includes water,
methanol, ethanol, isopropanol, butanol, dioxane, benzene,
toluene, dimethylformamide, tetrahydrofuran, or a conventional
- 20 -
`,
:' . .

108(12~3
buffer solution and the like. The reaction can be accelerated
by the addition of a catalytic or more amount of an organic
or inorganic base such as trialkylamine (e.g. trimethylamine or
tri~thyla~ine), pyridine, alkali metal compound (e.g.
sodium hydroxide, potassium hydroxide, sodium bicarbonate or
potassium bicarbonate) and the like, or an organic or
inorganic acid such as acetic acid, p-toluensulfonic acid,
hydrochloric acid, sulfuric acid, boron trifluoride, silicon
tetrachloride, titanium tetrachloride an~ the like. The
reaction temperature is not so much restrictive, and the
reaction is preferably carried out under warming or heating.
9. Other transformations
1) The compound (I) wherein Rl, R2 and R3 are as defined above and R4
and R5 are each hydrogen, lower alkyl or lower alkyl substituted with
a 5 or 6-membered saturated N-containing heterocyclic-l-yl
which may have hydroxy, lower alkyl or hydroxy(lower)alkyl,
provided that at least one of R4 and R5 is
said substituted lower alkyi, can be prepared by
subjecting the compound (I-5') to halogenation of the hydroxy
function, whereby a halo-compound is provided, followed by
substitution reaction with a S or 6-membered saturated imino-
containing heterocyclic compound.
The first halogenation reaction can be carried out
by reacting halogenating agent such as conventional one (e.g.
thionyl chloride, phosphorus tribromide, phosphorus pentachloride
or phosgene) and other one which comprises a combination of
phosphorus compound such as triphenyl phspine or tri(lower)-
alkyl phosphite (e.g. trimethyl phosphite or triethyl phosphite)
and a polyhalo(lower)alkane such as carbon tetrachloride or
carbon tetrabTomide in a suitable solvent. Examples of the

1080Z~3
s~l~ents may be carbon tetrachloride, chloroform, methylene
chloride, benzene and the like. This reaction is preferably
carried out in around neutral conditions, therefore, the
latter combination agent is the most preferable one. Gn the
contrary, in case of the former conventional agent, it may be
usually carried out on maintianing ne~trality of the reaction
medium, for example, by neutralizing with a base~or scavenging
the resulting acidic substances from the halogenating agent
in the course of reaction performed. The reaction temperature
is usually varied in accordance with the kind of halogenating
agent, and therefore, the reaction is preferably carried out
at somewhat elevated temperature (e.g. under warming or heating)
in case of the latter combination agent, and at much more
milder temperature (e.g. under cooling or warming) in case of
the former conventional agent, and preferably under anhydrous
conditions.
The second substitution reaction is carried out in a
substantially similar manner to that of aforementioned acylation
process in the presence or absence of a base. The reaction can
be carried out in a suitable solvent such as chloroform, methy-
lene chloride, benzene, acetone, ether, tetrahydrofuran,
dimethylformamide, methanol, ethanol or propanol. The reaction
temperature is not restrictive, and the reaction is usually
carried out at room temperature or at an elevated temperature
(e.g. under warming or heating). According to this method,
the hydroxy~lower)alkyl group for R~4e and/or R15e of the
compound (I-5') is transformed at first into the halo~lower)alkyl
~roup and then inbo the lower alkyl substituted with S cr 6-m0~æ~ed saturated
N-containing heterocyclic-l-yl group for R4 and/or R5 of the compound
(I).
(2) The compound (I) wherein at least one of R2 and R3 is
- 22 -

iO 8~ Z Z 3
N- or N,N-di-substituted amino(lower)alkoxycarbonyl can be
prepared by reacting the corresponding compound (I) wherein
at least one of R2 and R3 is halo(lower)alkoxycarbonyl with a
N- or N,N-di-substituted amine in accordance with the
substantially same manner as that of the above-mentioned
substitution reaction in 1).
3) The compound (I) wherein at least one of R2 and R3 lS
hydroxy(lower)alkoxycarbonyl can be prepared by subjecting
the corresponding compound (I) wherein at least one of R2 and
R3 is halo(lower)alkoxycarbonyl to hydrolysis substantially
in the same method as that of the afore-mentioned hydrolysis
process.
4) The compou~d (I) wherein Rl, R2 and R3 are each as defined
above and R4 and R5 are each hydrogen, lower alkyl or substi-
tuted lower alkyl selected from gem-di-~lower)alkoxy(lower)-
alkyl; gem-lower alkylenedioxy(lower)alkyl; gem-di-(lower)-
alkylthio(lower)alkyl or gemr(lower)alkylene-dithio(l~wer)
alkyl, provided that at least one
of R4 and R5 is said substituted lower alkyl can be also
prepared by reacting the corresponding compound (I-2) with
a hydroxy compound such as lower alkanol (e.g. methanol, ethanol
or propanol) or lower alkane diol ~e.g. ethylene glycol,
propylene glycol, 2,3-butane diol or 1,3-propane diol); a
thiol compound such as lower alkanethiol (e.g. methanethiol
or ethanethiol) or lower alkane dithiol (e.g. ethanedithiol,
1,2-propanedithiol, 2,3-butanedithiol or 1,3-propanedithiol).
This reaction preferably carried out in the presence
of catalytic amount of an organic or inorganic acid such as
hydrochloric acid, sulfuric acid, acetic acid, boron trifluo-
- 23 -
.
'

iO 80 Z ~ 3
ride, zinc chloride or p-toluenesulfonic acid.
5) The compound (I) wherein Rl, R2 and R3 are each as defined
above and R4 and R5 are each hydrogen, lower alkyl or cyano-
~lower)alkyl, provided that at least one of R4 and R5 is
cyano(lower)alkyl can be prepared by reacting the halo-compound
obtained in the above transformation 1) with a compound of
the formula: Rlo~CN wherein ~10 is hydrogen or a metal.
Suitable metals for Rlo are alkali metal such as
sodium or potassium, alkaline earth metal such as magnesium
or calcium, heavy metal such as mercury or silver and the
like.
The reaction is usually carried out at room tempera-
ture or under heating in a suitable solvent such as water,
methanol, ethanol, butanol chloroform, benzene, toluene,
N,N-dimethylformamide, dimethylsulfoxide, N-methylmorpholine,
pyridine or other conventional solvent.
In accordance with the present invention, the
product which is given during the reaction is separated and
isolsted from the reaction mixture by methods commonly used
for this prupose, and may be subjected to routinely used
purification procedures, for instance, to recrystallization
from an appropriate solvent or a mixture of such solvents.
The compound (I) thus obtained wherein at least R2
and R3 or R4 and R5 are not just same each other, includes
stereoisomers due to the presence of at least one asymmetric
carbon atom at the fourth position of the 1,4-dihydropyridine
nucleus and can exist as each optical isomer or a racemic
mixture. And further some of the compound (I) which has not
less than two asymmetric carbon atoms in its molecule may
exist as each diastereomer(s~ or the mixture thereo. The
- 24 -
., .
.

' ~080~Z3
mixture of the diastereomers can be resolved into each racemic
compound by conventional resolution methods such as chromato-
graphy or fractional recrystallization and the like and the
racemic compound can be resolved into each optical isomer by
a conventional method for racemic resolution such as a
resolution by fractional recrystallization of a salt of the
racemic compound with an optically active acid (e.g.
tartaric acid or camphor sulfonic acid.
The compound (I)ispossessed of vasodilating activity
and useful for therapeutical treatment in hypertension and
cardiovascular diseases such as coronary insufficiency, angina
pectoris or myocardial infarction.
The compositions of this invention comprises, as an
active ingredient, the 1>4-dihydropyridine derivatives ~I) in
an amount of about S mg. to about 500 mg., preferably about
25 mg. to about 250 mg. per dosage unit.
~ ne skilled in the art will recognize that in
determining the amounts of the active ingredient in the
claimed dosage unit form, the activity of the ingredient as
well as the size of the host animal must be considered.
That is, on mg./kg. basis, the amount of the active ingredient
in the compositions will be about 1 ~g/kg. to about 10 mg./kg.
and more, preferably about 0.5 mg./kg. to about 5 mg./kg. For
administration purpose of this pharmaceutical composition, the
active ingredients may be usually formed as tablet, granule,
pow~er, capsule, suppository, suspensions, solutions and the
like. A pharmaceutical carrier or diluent includes solid or
liquid non-toxic pharmaceutically acceptable substances.
Bxemplar of solid or liquid carriers or diluents are lactose,
magnesium stearate, terra alba, sucrose, corn starch, talc,
- 25 -
., .

1080;~23
stearic acid, gelatin, agar, pectin, acacia, peanut oil, olive
oil or sesame oil, cacao butter or the like. Similarly, the
carrier or diluent may include a time delay material such as
glyceryl monostearate or glyceryl distearate alone or with
a wax.
A wide variety of pharmaceutical forms can be
employed. Thus, if a solid carrier is used, the preparation
can be tabletted, placed in a hard gelatin capsule or in the
form of a troche or lozenge.
The pharmacological activity of the 1,4-dihydropyridines
of the formula (I) is demonstrated by standard procedures,
that is, by administering intravenously the following test
1,4-dihydropyridines to dogs anesthetized with pentobarbital
and recording the coronary blood flow. The test results are
given below:
[~L N02, (~3-- N02
3C H H5C200C ~ COOC2H5
[A] [B]
I ~ N02 ~ Cl
H5C200C ~ COOC~H5 H5C2ooC ~ COOC2H5
3 H 2 H3C N CH2H
[C] [D]
~ N02
H5C200C ~ COOCH CH N ~ 3
NC H CH3 . HCl
~]
-26-

1080223
Table. Increase of coronary blood 10w (%)
The values indicate percentages compared tO
control [29.5+5.5 ml/mln.].
~`~_ Dose ~g/kg
\ 64 250 1000
Compound ~
A 169 118 dead
B 190 174 155
C 214 168 175
D 171 l9S 179
E 185 215 144
Compound A is known as the generic name "Nifedipine"
and already marketed as a coronary vasodilator.
The following Examples are given merely for the
purpose of illustrating the syntheses of some specific object
compounds of the present invention, but not of limiting the
same thereto.
- 27 -
,

1080ZZ3
Example 1
l) A solution of 2-chlorobenzaldehyde (1.0543 g), ethyl
4,4-diethoxyacetoacetate (1.6477 g) and piperidine (1 to
2 drop(s)) in benzene (30 ml) was refluxed under azeotropic
dehydration for 4.5 hours. After cooling, the resultant
solution was washed with water and dried. The solvent
was removed from the solution to give orange oil (2.7196 g)
of ethyl 2-(2-chlorobenzylidene)-4,4-diethoxyacetoacetate.
The mixture of the compound obtained above and ethyl 3-
amino-4,4-diethoxycrotonate (1.6580 g) was heated with
stirring at about 100C for 1.5 hours and about 120C for
8 hours. After cooling, the reaction mixture was dis-
solved in ethyl acetate. The solution was washed wi~h
water and dried, and then the solvent was removed from the
solution to give orange oil (4.21 g) of diethyl 2,6-
bis(diethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydropyridine-
3,5-dicarboxylate. The product was purified by a column
chromatography on silica gel with an eluent (benzene :
ethyl acetate = 10 : 1) to give pure product.
I.R. Spectrum (Film)
v (cm~l) : 3430, 1695, 1610, 1487, 1472, 1368,
1273, 1200, 1093, 1059, 755
N.M.R. Spectrum (~, CDC13)
ppm : 1.22 (18H, t, J=7Hz), 3.3 to 3.9 (8H, m),
4.08 (4H, q, Jz7Hz), 5.55 (lH, s), 6.14
(2H, s), 6.9 to 7.5 (4H, m), 7.90 (lH,
broad s)
2)-(1) A solution of 2-chlorobenzaldehyde (14.0570 g),
ethyl 4,4-diethoxyacetoacetate (21.8240 g) and piperidine
(1 ml) in benzene (100 ml) was refluxed under azeotropic
- 28 -
-
.. . .. . .

1080223
dehydration for 4 hours. The resultant solution was
washed with water, dried and concentrated to give oily
ethyl 2-(2-chlorobenzylidene)-4,4-diethoxyacetoacetate.
The mixture of the compound obtained above and ethyl 3-
aminocrotonate (12.92 g) was heated in an oil bath
(about 100C) for 8 hours. The reaction mixture was
dissolved in ethyl acetate, washed with water~ dried and
then the solvent was removed to give crude oil (52.4 g).
The oil was purified by column chromatography on
silica gel with an eluent tbenzene : ethyl acetate =
20 : 1) to give diethyl 2-methyl-4-t2-chlorophenyl)-6-
diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,
which was recrystallized from n-hexane to give the pure
crystals (20.2445 g), m.p. 75 to 77C.
2)-t2) A solution of 2-chlorobenzaldehyde tl.4057 g),
ethyl acetate tl.3014 g) and piperidine (5 drops) in
benzene (10 ml) was refluxed under azeotropic dehydration
for 5 hours. After cooling, to the resultant solution
was added benzene, and the solution was washed with water
twice and dried. The solvent was removed from the
resultant solution to give yellowish oil of ethyl 2-t2-
chlorobenzylidene)acetoacetate (2.7351 g). The mixture
of the compound obtained above and ethyl 3-amino-4,4-
diethoxycrotonate (2.17 g) was heated at about 120C with
stirring for 4 hours. After cooling, the resultant oil
was dissolved in diethyl ether, washed with water and
saturated aqueous solution of sodium chloride in turn and
then dried. The solution was concentrated under reduced
pressure to give a reddish oil (4.5133 g). The pToduct
was purified by column chromatography on silica gel with
- 29 -

108~ 3
S an eluent (benzene:ethyl acetate = 20 : 1) to give yellowish
oil of diethyl 2-methyl-4-(2-chlorophenyl)-6-diethoxymethyl-
i' 1,4-dihydropyridine-3,5-dicarboxylate (2.25 g). The product
was crystallized in n-hexane and the crystals were collected
by filtration, which were identified with the authentic sample.
s~ 3) A mixture of 2-chlorobenzaldehyde (2.81 g), methyl
4,4-dimethoxy-3-oxovalerate (3.81 g) and piperidine (0.2 ml)
in benzene (20 ml) was refluxed under azeotropic dehydrat-
, ion for 7.5 hours. A small amount of benzene was added to
the reaction mixture and the resultant solution was washed
, with water and dried over magnesium sulfate. The solvent
was removed from the solution to give a reddish oil (7.04 g)
of methyl 2-(2-chlorobenzylidene)-4,4-dimethoxy-3-oxovalerate.
~, The mixture of the oily product ~6.39 g) obtained above and
methyl 3-aminocrotonate (2.33 g) was heated at 132C for
3.5 hours, allowed to stand and then dissolved in ethyl acetate.
i The resultant solution was washed with water and an aqueous
sodium chloride solution, and dried over magnesium sulfate.
, The solvent was removed from the solution under reduced
jl 20 pressure to give a viscous and brown oil (8.28 g).
This oil was subjected to column chromatography on silica
) gel with an eluent (a mixture of 20 parts of benzene and
one part of ethyl acetate by volume ) to give an oily
substance (5.26 g).
~25 This substance was dissolved in a mixture of ethyl acetate
and diethyl ether and the solvent was removed under reduced
pressure to give colorless powder (1.0625 g~. This powder
was recrystallized from a mixture of n-hexane and ethyl
acetate to give faint yellow granules of dimethyl 2-
' 30 methyl-4-~2-chlorophenyl)-6-~,l-dimethoxyethyl)1,4-
.
. ^r~ -- 3 0
,.' ~'~), '' '
: .

:~ 1080Z23
'~'
dihydropyridine-3,5-dicarboxylate, m.p. 145 to 146C.
4)-tl) A solution of 2-nitrobenzaldehyde ~9.0672 g),
, ethyl 4,4-diethoxyacetoacetate (13.0944 g) and piperidine
~- (1 ml) in benzene (45 ml) was refluxed under azeotropic
dehydration for 3 hours. To the resultant solution
was added water, and the solution was extracted with
diethyl ether. The extract was washed three times with
water, dried and then the solvent was removed under
reduced pressure to give ethyl 2-(2-nitrobenzylidene)-4,
¦ 10 4-diethoxyacetoacetate. The mixture of the compound
;~ obtained above and ethyl 3-aminocrotonate (7.7496 g) was
heated in an oil bath (9S to 100C) for 8 hours. The
i
resultant mixture was extracted with diethyl ether, and
the extract was washed with water and dried. The sol-
vent was removed from the extract. The residue was
$ purified by column chromatography on silica gel with an
eluent (benzene : ethyl acetate = 20 : 1) to give oily
~":
diethyl 2-methyl-4-(2-nitrophenyl)-6-diethoxymethyl-1,4-
~; dihydropyridine-3,5-dicarboxylate (19.3 g). The product
`~ 20 was crystallized in n-hexane and the crystals were col-
lected by filtration and then recrystallized from a mix-
ture of n-hexane and diethyl ether to give the pure
compound, m.p. 80 to 81.5C.
N.M.R. Spectrum (~, CDC13)
ppm : 1.16 (3H, t, J=7Hz), 1.18 (3H, t, J=7Hz),
~, 1.25 (6H, t, J=7Hz), 2.37 (3H, s),
3.4 to 4.4 (8H, m), 5.92 (lH, s), 6.20 (lH,s),
6.67 (lH, broad s), 7.0 to 7.8 (4H, m)
(2) A solution of 2-nitrobenzaldehyde (3.02Z4 g),
ethyl 4,4-diethoxyacetoacetate (4.3650 g) and piperidine
.~
'
- 31 -
.:., - .
~ ,. ' :.: ' ~ '

~ 08V;~;~3
r
~ (240mg) in benzene (12 ~1) was refluxed under azeotropic
`~ dehydration for 80 minutes. The reaction mixture was
allowed to stand to cool, and ethyl acetate was added
thereto. The mixture was washed with water twice and
, 5 dried. The solvent was removed to give an orange-
yellow oil (6.88 g). The oil was kept in a refrigerator
overnight to give crystals. The crystals were collected
by filtra~ion to give faint yellow crystals t3.3690 g),
which ~ere recrystallized from diisopropyl ether to give
0 colorless granules (2.2479 g) of ethyl 2-t2-nitrobenzyli-
~, dene)-4,4-diethoxyacetoacetate, m.p. 66 to 67.5C.
This product is one of the two isomers of ethyl 2-(2-
nitrobenzylidene)-4,4-diethoxyacetoacetate and shows
signal at 5.23 ppm(methine proton)and 8.31 ppm (olefinic
~; S proton) on N.M.R. spectrum (~, CDC13). The filtrate
;~ was condensed and the resultant brown oil, which comprises
the two isomers of ethyl 2-(2-nitrobenzylidene)-4,4-
diethoxyacetoacetate in the ratio approximately 1 : 1 and
shows signals of 4.93 and 5.23 ppm (methine proton ) and
8.17 and 8.31 ppm (olefinic proton ) on N.M.R. spectrum
(~, CDC13).
i! A mixture of the above obtained crystals (2.4497 g)
;j~ and ethyl 3-aminocrotonate (1.3508 g) was heated at 75 to
82C with stirring under slightly reduced pressure for
four hours and further heated at 105 to 108C for five
hours. The reaction mixture was cooled and crystallized.
' The resultant crystals were recrystallized from a mixture
, of diisopropyl ether and n-hexane to give crystals
:; (0.5128 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-
i
diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
.
- 32 -
, . . . . . . .

10802Z3
.,.
j
which was identified with the product of the above
Example 1-4)-(1).
~; 5) A solution of 3-nitrobenzaldehyde (2.27 g),
t ethyl 4,4-diethoxyacetoacetate ~3.28 g) and piperidine
t0.2 ml) in benzene (15 ml) was refluxed under azeotropic
dehydration for 3 hours. The resultant solution was
washed three times with water and dried over magnesium
- sulfate. The solvent was removed from the reaction
.~ ~
solution to give oily ethyl 2-(3-nitrobenzylidene)-4,4-
~L0 diethoxyacetoacetate (6.0 g). The mixture of the
compound obtained above and ethyl 3-aminocrotonate (1.94 g)
was heated at about 95 to 100C for 7 hours and then at
about 120C for 1.5 hours with stirring. After cooling,
~ the resultant oil was extracted with ethyl acetate and
the extract was washed with water and dried. The
solvent was removed from the resultant solution to give an
oil (7.8 g). The product was purified by column
.
; chromatography on silica gel with an eluent (benzene :
ethyl acetate = 20 : 1) to give the pure product of
Z0 diethyl 2-methyl-4-(3-nitrophenyl)-6-diethoxymethyl-1,4-
dihydropyridine-3,5-dicarboxylate (4.65 g).
I.R. Spectrum (Film)
¦ ~ (cm~l) : 3400, 1690, 1615, 1530, 1480,
1350, 1280, 1200, 1090, 920, 765
Z5 N.M.R. Spectrum (~, CDC13)
ppm : 1.23, 1.26 (12H, t, t, J=7Hz)
2.4 (3H, s), 3.5 to 3.86 (4H, m),
4.11 (4H, q, J=7Hz),
5.16 (lH, s), 6.82 (lH, broad),
7.25 to 8.16 (4H, m)
, . .
~ v - 33 -
,

1080ZZ3
6) A mixture of ethyl 2-(2-trifluoromethylbenzylidene)-
4,4-diethoxyacetoacetate (7.48 g) and ethyl 3-
aminocrotonate (2.582 g) was heated at 130C for 5
hours. The resultant mixture was dissolved in ethyl
S acetate and solution was washed with water twice,
dried over magnesium sulfate and concentrated under
reduced pressure to give a red oil (9.8 g). The oil
was subjected to column chromatography on silica gel
with an eluent (a mixture of 20 parts of benzene and
,; one part of diethyl ether by volume) to give an oily
substance. This substance turned into crystals, which
' were recrystallized from a mixture of n-hexane and
diethyl ether to give crystals of diethyl 2-methyl-4-
, (2-trifluoromethylphenyl)-6-diethoxymethyl~ 1,4-
dihydropyridine-3,5-dicarboxylate, m.p. 82 to 83C.
7) A solucion of 2-methoxybenzaldehyde (2.7228 g),
ethyl 4,4-diethoxyacetoacetate (4.3648 g) and piperidine
;~ ~ (4 or S drops) in benzene (20 ml) was refluxed under
azeotropic dehydration for 3 hours. The resultant
solution was washed with water and dried. The solvent .
was removed from the extract to give oily ethyl 2-(2-
; methoxybenzylidene)-4,4-diethoxyacetoacetate. The
mixture of the compound obtained above and ethyl 3-
aminocrotonate (2.5832 g) was heated in an oil bath
(about 100C) for 7 hours. After cooling,the reaction
mixture was extracted with diethyl ether, and the
extract was washed with water twice and dri~d over
magnesium sulfate. The solvent was removed to give a
red oil. The oil was purified by a column chromato-
, graphy on silica gel with an eluent (benzene: ethyl
acetate = 20 : 1) to give diethyl 2-methyl-4-(2-
."
~ - 34 -

108t)2Z3
methoxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-
3,5-dicarboxylate (5.0779 g). The product was re-
crystallized from n-hexane to give pale yellowish
prisms, m.p. 105 to 107C.
8) A mixture of 2-chloro-5-nitrobenzaldehyde (3.73 g),
ethyl 4,4-diethoxyacetoacetate (4.365 g) and piperidine
~272.5 mg) in benzene (10 ml) was refluxed under
azeotropic dehydration for 1.5 hours. To the mixture
was added ethyl acetate, and the resultant mixture was
washed three times with water and then with an aqueous
solution of sodium chloride, and dried over magnesium
sulfate. The solvent was removed under reduced pressure
to give a reddish brown oil (7.87 g) of ethyl 2-(2-
chloro-5-nitrobenzylidene)-4,4-diethoxyacetoacetate.
The mixture of thus obtained reddish brown oil and ethyl
3-aminocrotonate (3.48 g) was heated with stirring at
105 to 107C in an oil bath for 4.5 hours. The resultant
mixture was extracted with ethyl acetate, and the extract
was washed with water three times and then with an
aqueous solution of sodium chloride, and dried over
magnesium sulfate. After removal of the solvent from
the extract, the obtained residue (10.87 g) was subjected
to column chromatography on silica gel with an eluent
(a mixture of 20 parts of chloroform and one part of ethyl
acetate by volume). The fractions were checked with
thin-layer chromatography and crystals ~6.02 g) were
obtained by removing the solvent from the fraction con-
taining the designated substance. The crystals were
; recrystallized from a mixture of diethyl ether and n-
hexane to give crystals of diethyl 2-methyl-4-(2-chloro-
- 35 -

108VZZ3
S-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-
3,5-dicarboxylate, m.p. 117 to 118C.
9) A solution of thiophene-2-carbaldehyde (2.2430 g),
ethyl 4,4-diethoxyacetoacetate t4.3648 g) and piperidine
(4 drops) in benzene (20 ml) was refluxed under
azeotropic dehydration for 4.5 hours. After cooling,
to the resultant solution was added diethyl ether, and
the solution was washed with water and dried. The
solvent was removed from the reaction mixture to give
oily ethyl 2-(2-thenylidene)-4,4-diethoxyacetoacetate.
The mixture of the compound obtained above and ethyl 3-
aminocrotonate (2.6 g) was heated in an oil bath (about
100C) for 7.5 hours. The resultant mixture was dis-
solved in diethyl ether, washed with water and dried.
The solvent was removed to give brown oil (9.0 g~.
The oil was purified by column chromatography on silica
gel with an eluent (benzene : ethyl acetate = 20 : 1) to
give diethyl 2-methyl-4-(2-thienyl)-6-diethoxymethyl-1,
4-dihydropyridine-3,5-dicarboxylate. The product was
recrystallized from n-hexane to give yellowish crystals
(2.2056 g), m.p. 77 to 77.5C.
; 10) To a mixture of 2-furaldehyde (2.88 g) and
ethyl 4,4-diethoxyacetoacetate (6.55 g) in benzene (15 ml)
was added each one fourth portion of piperidine (408 mg)
with an interval of 15 minutes under refluxing with
azeotropic dehydration. Thus obtained mixture was re-
fluxed for another 30 minutes. To the reaction mixture
was added ethyl acetate, and the resultant mixture was
washed with water three times and then with an aqùeous
~ 30 solution of sodium chloride and dried over magnesium
:.
. . .
- 36 -
. .
. ~ ~

1080ZZ3
sulfate. The solvent was removed to give a reddish
brown oil t9.47 g) of ethyl 2-(2-furfurylidene)-4,4-
diethoxyacetoacetate. Then the mixture of the oil
gained above and ethyl 3-aminocrotonate (5.sg) was heated at
S 105C under stirring for 7 hours. The resultant
mixture was extracted with ethyl acetate, and the
extract was washed with water and an aqueous solution
of sodium chloride and then dried over magnesium sulfate.
- After removal of the solvent, the resultant oil was
purified by column chromatography on silica-gel with
an eluent (a mixture of 20 parts of chloroform and one
part of ethyl acetate by volume) and crystallized from
n-hexane t3 ml). The obtained crystals were washed
with n-hexane to result crystals (7.05 g). The resultant
lS crystals (S00 mg) were recrystallized from n-hexane to
give crystals (450 mg) of diethyl 2-methyl-4-~2-furyl)-
6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,
m.p. 59 to 60C.
11) A mixture of 2-nitrobenzaldehyde (3.02 g), 2-
ethoxyethyl acetoacetate (3.48 g) and piperidine (272.5 mg)
in benzene (10 ml) was refluxed under azeotropic
dehydration for 1.5 hours. The mixture was washed with
water three times and with an aqueous solution of sodium
chloride, dried over magnesium sulfate and concentrated.
To the resultant oil of 2-ethoxyethyl 2-(2-nitrobenzyli-
t '
dene)acetoacetate was added ethyl 3-amino-4,4-
diethoxycrotonate (4.77 g) and the mixture was heated
at 110C under stirring for 5 hours. The reaction
mixture was extracted with ethyl acetate and the extract
was washed with water three times and dried over magnes~um
,
- 37 -
,

1080223
sulfate. After removal of the solvent, the resultant
brown oil was purified by column chromatography with
an eluent ~a mixture of ten parts of benzene and one
part of ethyl acetate by volume) to give an oil (3.18 g)
of 2-ethoxyethyl 2-methyl-4-(2-nitrophenyl)-5-
ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-
carboxylate .
I.R. Spectrum (film)
v (cm~l) : 3420, 1730, 1695, 1650,
0 1610, 1530, 1480, 1355,
1275, 1210, 1100, 860,
830, 785, 752, 715
N.M.R. Spectrum (~, CDCQ3)
ppm : 1 to 1.37 (12H, m),
2.37 (3H, s),
3.28 to 4.3 (12H, m),
5.93 (lH, s),
6.2 ~lH, s),
6.78 tlH, m),
0 7.23 to 7.83 (4H, m)
12) A mixture of 2-nitrobenzaldehyde (4.536 g), 2-
chloroethyl acetoacetate (4.94 g) and piperidine (110 mg)
in benzene (18 ml) and acetic acid (360 mg) was refluxed
for an hour under azeotropic dehydration. The reaction
mixture was washed with water and dried. The solvent
` was distilled off to give an reddish oil of 2-chloroethyl
2-(2-nitrobenzylidene)acetoacetate, and thus obtained
- oil was treated with ethyl 3-amino-4,4-diethoxycrotonate
(7.1 g3 to give yellow granules of 2-chloroethyl 2-
;0 methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-
- 38 -

1080Z~3
1,4-dihydropyridine-3-sarboxylate, m.p. 82 to 84C
(recrystallized from diisopropyl ether).
'' S
13) A mixture of 2-nitrobenzaldehyde ~3.023 g),
benzyl acetoacetate (3.802 g) and piperidine (272.5 mg)
in benzene (10 ml), was treated in a substantially
similar manner that of Example 1-11) to give a brown
oil (6.94 g) of benzyl 2-(2-nitrobenzylidene)acetoacetate,
which was further treated with ethyl 3-amino-4,4-
diethoxycrotonate (4.34 B) to give a dark brown oil
(10.3 g). This oil was purified by column chromatography
~15 on silica-gel and the resultant oil (3.8 g) was crystal-
lized to give crystals (1.65 g) of benzyl 2-methyl-4-
(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-
dihydropyridine-3-carboxylate, m.p. 103 to 103.5C
(recrystallized from a mixture of diisopropyl ether and
~20 n-hexane).
14) In an essentially similar manner to that of
Example 1-11) given in the above, the following compounds
were obtained:-
Starting from a mixture of 2-nitrobenzaldehyde (3.02 g),
2-benzyloxyethyl acetoacetate (4.72 g), piperidine
(272.5 mg) in benzene (10.8 ml) was obtained 2-benzyloxy-
ethyl 2-(2-nitrobenzylidene)acetoacetate, which was
further treated with ethyl 3-amino-4,4-diethoxycrotonate
to give an oil (4.80 g) of 2-benzyloxyethyl 2-methyl-4-
(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-
- 39 -
' ~ ' ' '

1080;ZZ3
dihydropyridine-3-carboxylate.
I.R. Spectrum (film)
-1
v (cm ) : 3400, 1700, 1650, 1610, 1530, 1480
1355, 1273, 1205, 1090, 1055, 750, 700
N.M.R. Spectrum (~, CDCQ3)
ppm : 1.1 to 1.3 (9H, m),
2.32 (3H, s),
3.45 to 4.32 (lOH, m),
4.46 (2H, s),
5.94 (lH, s),
; 6.2 (lH, s),
6.82 (lH, s),
7.16 to 7.74 (9H, m)
15) In an essentially similar manner to that of
Example 1-11) given in the above, the following compounds
were obtained:-
Starting from a mixture of 2-nitrobenzaldehyde (3.02 g),
2-phenoxyethyl acetoacetate (4.44 g), piperidine (272.5 mg)
in benzene (10.8 ml) was obtained an oil (8.0 g) of 2-
~20 phenoxyethyl 2-(2-nitrobenzylidene)acetoacetate. Thus
obtained oil was treated with ethyl 3-amino-4,4-diethoxy-
crotonate (4.34 g) to give an oil of 2-phenoxyethyl 2-
methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-
1,4-dihydropyridine-3-carboxylate.
I.R. Spectrum (film)
v (cm~l) : 3410, 1700, 1602, 1535, 1480, 1356,
1277, 1250, 1210, 1100, 1060, 755, 695
N.M.R. Spectrum (~, CDCQ3)
.,
ppm : 1.13 (3H, t, J=7Hz),
1.23 (6H, t, J=7Hz)
:
- 40 -
: , -

1080Z23
ç
2.33 (3H, s),
3.41 to 4.47 (lOH, m),
; 5.91 (lH, s),
'~ 6.17 tlH, s),
6.71 to 7.71 (9H, m)
16) A mixture of 3-nitrobenzaldehyde (4.54 g), 2-
ethoxyethyl acetoacetate (5.23 g) and piperidine
5.2 mg) in benzene (15 ml) was refluxed under
azeotropic dehydration for 3 hours. The resultant
mixture was washed with water, an aqueous solution
saturated with sodium chloride and water in turn, dried
and concentrated to give an oil of 2-ethoxyethyl 2-
, (3-nitrobenzylidene)acetoacetate. To this oily product
was added ethyl 3-amino-4,4-diethoxycrotonate (6.5 g).
The mixture was heated at 110C for about 3 hours. The
reaction mixture was dissolved in ethyl acetate and
,, ,~
washed with water twice and dried. The solvent was
removed from the mixture to give an oil (15.58 g). This
oil was subjected to column chromatography on silica gel
' 20 with an eluent (a mixture of 10 parts of benzene and one
~; part of ethyl acetate by volume) to give an oily sub-
, . .
stance (8.09 g). This oily substance (0.93 g) was
treated with a mixture of n-hexane and diethyl ether to
give crystals, which were further recrystallized from a
ç, 25 mixture of n-hexane and diethyl ether to give yellow
~ granules (565.2 mg) of 2-ethoxyethyl 2-methyl-4-(3-
i nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-
' dihydropyridine-3-carboxylate, m.p. 99 to 100C.
17) A mixture of 2-chloroethyl 2-(3-nitrobenxylidene)-
acetoacetate (16 g) and ethyl 3-amino-4,4-diethoxycrotonate
,'':
7,~
- 41 -
-
,

~ 1080Z23
; .
~t (10. 85 g) was heated at 100C for 3 hours and allowed to
stand overnight at room temperature. Appearing crystals
were collected by filtration to give yellow crystals
t7.02 g), and then the filtrate was subjected to column
chromatography on silica gel with an eluent [a mixture
of 20 parts of benzene and one part of ethyl acetate by
volume] to give an oil (7.4 g). The oil was allowed to
~ ~ stand to give crystals (3.6 g) and put together with the
above obtained crystals (7.02 g). These crystals were
recrystallized from a mixture of n-hexane and diethyl
ether to give 2-chloroethyl 2-methyl-4-(3-nitrophenyl)-
5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-
3-carboxylate, m.p. 96 to 97C.
18) A mixture of ethyl 2-t3-hydroxybenzylidene)-
acetoacetate (2.1 g) and ethyl 3-amino-4,4-diethoxy-
crotonate (1.95 g) in n-propyl alcohol (1.5 ml) was heated
t ~ ' at 105C for 4.5 hours. After removal of the solvent
' from the reaction mixture under reduced pressure, ethyl
~ acetate was added to the residue. The resultant solution
-~ 20 was washed with water twice and an aqueous sodiumchloride solution in turn, and then dried over magnesium
sulfàte. The solvent was removed from the solution to
give red oil (4.2 g). The oil was subjected to column
jl chromatography on silica gel with an eluent [a mixture
of 10 parts of benzene and one part of diethyl ether by
volume] to give an oily substance, which was crystallized
from n-hexane to give crystals (1.5 g) ! These crystals
~` (280 mg) were recrystallized from a mixture of n-hexane
.:
and diethyl ether to give crystals of diethyl 2-methyl-
4-(3-hydroxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-
;
~,...
42 -
.. .

10802Z3
3,5-dicarboxylate (106.2 mg), m.p. 107 to 108C.
~; 19) A solution of 2-chlorobenzaldehyde (351.4 mg),
~- ethyl 4,4-diethoxyacetoacetate (s45.6 mg) and ethyl 3-
aminocrotonate (322.9 mg) in n-propanol ~2 ml) was
refluxed for 10 hours. The resultant solution was con-
centrated, and the residue was dissolved in ether, and
tr then washed twice with water. After drying the extract
over magnesium sulfate, the solvent was removed from the
ex~ract to give orange oil (1.1765 g). The oil was
~, 10 purified by a column chromatography on silica gel with
an eluent tbenzene : ethyl acetate = 20 : 1) to give
oily diethyl 2-methyl-4-(2-chlorophenyl)-6-diethoxymethyl-
1,4-dihydropyridine-3,5-dicarboxylate (374.6 mg). The
product was dissolved in n-hexane and allowed to stand
,; lS in a refrigerator, and the precipitated crystals were
collected by filtration and washed with n-hexane to give
pure crystals, m.p. 75 to 77C.
20) A mixture of ethyl 2-(2-chlorobenzylidene)-4,4-diethoxy-
acetoacetate (2.42 g), ammonium acetate (1 g) and methyl
propiolate (1 ml) in acetic acid (1 ml) was refluxed for
minutes. The reaction mixture was poured into an aqueous
solution of sodium bicarbonate and extracted twice with
~; ethyl acetate. The ethyl acetate layer was washed with
water and then with a saturated aqueous solution of sodium
chloride, dried, and further concentrated. The resultant
,
7 red oil was dissol~ed in diethyl ether and appeared
crystals were filtered off. The filtrate was concentrated
to give a brown oil (2.57 g). This oil was purified by
colomn chromatography on silica-gel with an eluent (a
' 30 mixture of ten parts of benzene and one part of ethyl
:''
~ 43 -
:~ :

~0802Z3
acetate by volume). The fraction containing the
designated substance was concentrated to give a yellow
oil (1.03 g) of methyl 4-(2-chlorophenyl}5-ethoxycarbonyl-
6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate.
I.R. Spectrum (film)
~ tcm 1) : 3350, 1700, 1590, 760
N.M.R. Spectrum (~, CDCQ3)
ppm : 5.45 (lH, s),
6.20 (lH, s)
0 21) Similarly, the following compounds were obtained:-
(1) 2-(N-Benzyl-N-methylamino)ethyl 2-methyl-4-
(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-
1,4-dihydropyridine-3-carboxylate.
I.R. Spectrum (film)
~ (cm~l) : 3400, 1700, 1690, 1610, 1523,
1475, 1350, 1275, 1197, 1092,
1055, 755, 698
N.M.R. Spectrum (~: CDCQ3 + D2O)
ppm : 1.21 (9H, t, J=7Hz), 2.21 (3H, s),
o 2.36 (3H, s), 2.63 (2H, t, J=6Hz),
3.5 (2H, s), 3.65 (2H, q, J=7Hz),
3.66 (2H, q, J=7Hz), 4.1 (2H, q),
4.18 (2H, t, J=6Hz), 5.18 (lH, s),
6.2 (lH, s), 6.86 (lH, s), 7.16 to 8.16
(4H, m)
~) 2-(N,N-Diethylamino)ethyl 2-methyl-4-(3-
nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-
1,4-dihydropyridine-3-carboxylate (a brown oil).
(3) 2-Hydroxyethyl 2-methyl-4-(3-nitrophenyl)-
0 5-ethoxycarbonyl-6-diethoxymethyl-1,4-
- 44 -

108(~223
dihydropyridine-3-carboxylate, m.p. 98 to 100C.
(4) 2-hydroxyethyl 2-methyl-4-(2-nitrophenyl)-5-
ethoxycarbonyl-6-diethoxymethyl-1,-4-dihydropyri-
dine-3-carboxylate.
I.R. Spectrum (film)
v (cm ~ : 3530, 3410, 3360 (shoulder),
1706 (shoulder), 1697, 1690
(shoulder), 1532, 1480, 1356,
1275, 1208, 1100, ~05, 860,
832, 785
N.M.R. Spectrum (~, CDCQ3)
ppm : 1.0 to 1.45 (9H, m),
2.39 (3H, s),
2.2 to 2.73 (lH, broad),
3.4 to 4.5 (lOH, m),
5) Diethyl 2-methyl-4-(2-nitrophenyl)-6-
ethylenedioxymethyl-1,4-dihydropyridine-3,5-
dicarboxylate, m.p. 152 to 153.5C.
Example 2
1) To a solution of diethyl 2,6-bis(diethoxymethyl)-4-
t2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
, (1.7 g) in acetone (17 ml) was added 6N-hydrochloric acid
(1.5 ml) and stirred at room temperature for 3 hours.
After removing the solvent, the residue was extracted
with diethyl ether and the extract was washed with water
and dried. The solvent was removed from the extract to
give diethyl 2,6-diformyl-4-(2-chlorophenyl)-1,4-dihydro-
pyridine-3,5-dicarboxylate (1.35 g). The product was
recrystallized fTom diethyl ether to give pure yellowish granules,
m.p. 85 to 86C.
,~
- 45 -
', :

~O~D~ Z 3
2) To a solution of diethyl 2-methyl-4-t2-chlorophenyl)-
6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(452mg) in acetone (5 ml) was added 6N-hydrochloric acid
(0.2 to 0.3 ml) and stirred at room temperature for an
hour. After removing acetone, the residue was extracted
with ethyl acetate twice and the extract was washed with
water and dried. The solvent was removed from the extract
to give diethyl 2-methyl-~-(2-chlorophenyl)-6-formyl-1,4-
dihydropyridine-3,5-dicarboxylate. The product was
recrystallized from a mixture of n-hexane and diethyl ether
to give the pure product, m.p. 87 to 88C.
3) To a solution of dimethyl 2-methyl-4-(2-chlorophenyl)-
6-(~l-dimethoxyethyl)-1,4-dihydropyridine-3,5-dicarboxylate
~409.9 mg) in acetone (5 ml) wasadded 6N hydrochloric acid (0.5 ml) and
stirred at room temperature for 17 minutes. The reaction
mixture was neutralized with an aqueous solution saturated
with sodium bicarbonate and the solvent was distilled off
under reduced pressure. Water was added to the residue
and the mixture was allowed to stand to give crystals,
which were collected by filtration and dried to give
crystals (350.2 mg). These crystals were recrystallized
from a mixture of n-hexane and ethyl acetate to give yellow
granules of dimethyl 2-methyl-4-(2-chlorophenyl)-6-acetyl-
1,4-dihydropyridine-3,5-dicarboxylate, m.p. 161 to 162C.
4) To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-
6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1563 g)
in acetone (10 ml) was added 6N-hydrochloric acid (2.5 ml)
and stirred at room temperature for 30 minutes. After
removing acetone, water was added to the residue and
neutralized with aqueous solution of sodium bicarbonate.
- 46 -
.

1080Z23
The precipitated solid was collected by filtration,
washed with water and then dried to give yellowish
powder of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-
1,4-dihydropyridine-3,5-dicarboxylate (0.9407 g).
The product was recrystallized from a mixture of ethanol
and n-hexane to give the pure product, m.p. 101 to 103C.
S) To a solution of diethyl 2-methyl-4-(3-
nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-
dicarboxylate ~462.5 mg) in acetone (4 ml) was added
6N-hydrochloric acid (0.4 ml) and stirred at room tem-
perature for an hour. After the reaction, the solvent
was removed from the resultant solution. To the
residue was added water, and the residue was pulverized.
The powder was collected by filtration, washed with water
and dried to give diethyl 2-methyl-4-t3-nitrophenyl)-6-
formyl-1,4-dihydropyridine-3,5-dicarboxylate (360 mg),
m.p. 130 to 133C.
; 6) To a solution of diethyl 2-methyl-4-(2-
trifluoromethylphenyl)-6-diethoxymethyl-1,4-dihydropyridine-
; 3,5-dicarboxylate (5.2 g) in acetone ( 5 ml ) was added
; 6N-hydrochloric acid (5 ml) and stirred at room temperature
for about 1.5 hours. After removal of the acetone, water
was added to the residue and the resultant aqueous
solution was extracted with ethyl acetate twice. The ex-
tract was washed with water and dried and the solvent was
removed therefrom to give a reddish oil (4.2 g) of diethyl
2-methyl-4-~2-trifluoromethylphenyl)-6-formyl-1,4-
dihydropyridine-3,5-dicarboxylate.
I.R. Spectrum (Nujol)
v (cm~l) : 3350, 1700, 1640, 1605, 1480, 1370,
- 47 -
:- . . . - .
., , - . .
, .

~080223
1308, 1200, 1100, 1035, 9S0, 763
N.M.R. Spectrum (~ : CDCQ3 + D2O)
ppm : 1.2 (6H, t, Js7Hz), 2.4 (3H, s),
; 3.92 to 4.38 (4H, m), 5.72 (lH, s),
S 7.06 (lH, s), 7.24 to 7.62 t4H, m~
7) To a solution of diethyl 2-methyl-4-(2-methoxy-
phenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-
dicarboxylate ~447.5 mg) in acetone (7.5 ml) was added
6N-hydrochloric acid (0.2 ml) and stirred at room
0 temperature for an hour. The resultant mixture was
treated in a similar manner to Example 2-4), to give
reddish yellow crystals of diethyl 2-methyl-4-(2-
methoxypheny)-6-formyl-1,4-dihydropyridine-3,5-
dicarboxylate (373.2 mg). The product was recrystal-
lS lized from a mixture of diethyl ether and n-hexane to
give the pure product, m.p. 111 to 112C.
8) To a solution of diethyl 2-methyl-4-(2-chloro-
5-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,
5-dicarboxylate (5.45 g) in acetone (54.5 ml) was added
6N hydrochloric acid ~5 ml) and the resultant mixture
was stirred at room temperature for l.S houTs. After
removal of the acetone from the reaction mixture, water
was added tothe residue and the mixture was allowed
to stand foT 15 minutes. The ~ecipitated crystals were
collected by filtration, washed with water and dried to
give crystals (4.2 g). Thus obtained crystals (500 mg)
were recrystallized from a mixture of n-hexane and ethyl
acetate to give crystals t347 mg) of diethyl 2-methyl-
4-(2-chloro-5-nitrophenyl)-6-formyl-1,4-dihydropyridine-
3,5-dicarboxylate, m.p. 172 to 173C.
- 48 -
, : ~

1~ 8~ 3
9) To a solution of diethyl 2-methyl-4-(2-thienyl)-
6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(424 mg) in acetone tlS ml) was added 6N-hydrochloric
acid t0.2 ml) and this solution was stirred at room
temperature for an hour. The resultant solution was
concentrated and the residue was extracted with diethyl
ether. The extract was washed with water and drie~ and
then the solvent was removed to give yellowish oil of
diethyl 2-methyl-4-(2-thienyl)-6-formyl-1,4-dihydro-
.o pyridine-3,5-dicarboxylate, which was soon crystallized.
The product was recrystallized from a mixture of n-hexane
and diethyl ether to give the pure product (247.7 mg),
m.p. 67 to 68.5C.
10) To a solution of diethyl 2-methyl-4-(2-furyl)-
L5 6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(6.6 g) in acetone t66 ml) was added 6N hydrochloric
acid (6.6 ml) and the resultant mixture was stirred for
one and three - fourth hour at room temperature. After
removal of the acetone from the reaction mixture, the
residue was extracted with ethyl acetate. The extract
was washed with water, dried and concentrated. The
resultant oil (6.1 g) was subjected to column chromato-
graphy on silica-gel with an eluent (a mixture of 20
parts of chloroform and one part of ethyl acetate by volume).
The concentrate (oil, 2.4 g) of the fraction of the
eluate which showed one spot on thin-layer chromatography
gave~crystals (1.79 g) and the concentrate (700 mg) of the
fraction of the eluent which showed plural spots on thin-
layer chromatography gave crystals (410 mg). These
crystals were combined together and recrystallized from
- 49 -
.
. ~ . -~ .,.

~O~DZZ 3
n-hexane to give needles (400 mg) of diethyl 2-methyl-
4-t2-furyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate,
m.p. 78 to 79.5C.
11) Starting from a mixture of 2-ethoxyethyl 2-methyl-
4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-
dihydropyridine-3-carboxylate (1.9 g) in acetone (19 ml)
and 6N hydrochloric acid (1.9 ml), was obtained, b~ applying
an essentially similar manner to that of Example 2-(1),
crystals of 2-ethoxyethyl 2-methyl-4-(2-nitrophenyl)-5-
~lO ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate,
m.p. 107 to 108C. (recrystallized from diisopropyl ether).
.~
12) To a solution of 2-hydroxyethyl 2-methyl-4-(2-
nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-
dihydropyridine-3-carboxylate (2.5 g) in acetone (30 ml)
was added 6N hydrochloric acid (1 ml) and treated in a sub-
, ,..;
i stantially similar manner to those of Example 2-(6) to
~; give a viscous oil (2.10 g) of 2-hydroxyethyl 2-methyl-4-
~2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-
3-carboxylate.
N.M.R. Spectrum (~, CDCQ3)
ppm : 6.07 (lH, s),
10.43 (lH, s)
13) In a substantially similar manner to that of
Example 2-6), was treated a mixture of benzyl 2-methyl-4-
(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-
dihydropyridine-3-carboxylate (1.5 g) in acetone (15 ml)
and 6N hydrochloric acid (1.5 ml) to give a reddish brown
oil which was crystallized and washed with n-hexane to
give crystals (1.30 g) of benzyl 2-methyl-4-(2-nitrophenyl)-
5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.
~ 50 ~
r.
i, :l,,,
;''., - - . ~
r ~ ~

1080Z23
.
I.R. Spectrum tNUjol)
v (cm~l) : 3400, 1699, 1673, 1608, 1530, 1490,
1380, 1355, 1220, 1110, 1030, 835,
795
j N.M.R. Spectrum (~, CDCQ3)
; ppm : 1.21 (3H, t, J=7Hz),
2.38 (3H, s),
4 to 4.4 (2H, m),
5 07 (2H, s),
6.01 (lH, s),
6.9 (lH, broad s),
7.25 to 7.8 (9H, m),
10.33 (lH, s)
14) Starting from a mixture of an oil (2.5 g) of
2-benzyloxyethyl 2-methyl-4-(2-nitrophenyl)-5-
ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-
carboxylate in acetone (25 ml) and 6N hydrochloric acid
(2 ml) was obtained a reddish oil (2.05 g) of 2-
benxyloxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-
6-formyl-1,4-dihydropyridine-3-carboxylate, in a
substantially similar manner to that of Fxample 2-6).
I.R. Spectrum (film)
v (cm l) : 3380, 1695, 1532, 1485, 1277, 1210,
llO0, 1040, 860, 750
.
; N.M.R. Spectrum (~, CDCQ3)
ppm : 2.40 (3H, s),
4.48 (2H, s),
6.08 (lH, s),
~ 10.40 (lH, s)
) 15) Starting from a mixture of 2-phenoxyethyl 2-methyl-
'
:

108V'~'~3
4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,
4-dihydropyridine-3-carboxylate (1.24 g) in acetone
(12 ml) and 6N hydrochloric acid (1.2 ml) was obtained
an oil (1.1 g) of 2-phenoxyethyl 2-methyl-4-(2-
; nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-
3-carboxylate, in a substantially similar manner to that
of Example 2-6).
I.R. Spectrum (film)
v (cm~l) : 3400, 1700, 1640, 1600, 1530, 1480,
o 1350, 1240, 1200, 1100, 860, 785
755, 692
N.M.R. Spectrum (~, CDCQ3)
ppm : 1.2 (3H, t, J=7Hz),
2.4 (3H, s),
3.98 to 4.46 (6H, m),
6.03 (lH, s),
6.71 to 7.76 (9H, m),
10.4 (lH, s)
16) To a solution of 2-ethoxyethyl 2-methyl-4-
0 (3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-
dihydropyridine-3-carboxylate (5.85 g) in acetone (60 ml)
was added 6N hydrochloric acid (3 ml) and the resultant
mixture was stirred at room temperature for about 2
hours. The solvent was distilled off under reduced
~5 pressure and water added to the residue. The mixture
was extracted with ethyl acetate twice and the extract
was washed with an a~ueous sodium chloride solution and
dried. The solvent was distilled off to give a reddish
~ oil (5.7 g), which was turned into crystals. These
crystals were pulverized with a mixture of n-hexane and
"
- 52 -

1080Z23
diethyl ether and the resultant powder (4.81 g) was
collected by filtration. The powder (1.81 g) was
recrystallized from a mixture of diethyl ether and
ethyl acetate to give orange-yellow granules
tl.2 g) of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-
S-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-
carboxylate, m.p. 100 to 101C.
17) To a solution of 2-(N-methyl-N-benzylamino)-
ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-
diethoxymethyl-1,4-dihydropyridine-3-carboxylate t7.25 g)
in acetone ~70 ml) was added 6N-hydrochloric acid (7 ml)
and the resultant mixture was stirred at room temperature
for 3 hours. The solvent was distilled off under re-
duced pressure. Water was added to the residue,
where an oily substance appeared. The aqueous mixture
was adjusted to an alkaline medium by addition of power
of sodium bicarbonate, and then extracted with ethyl
acetate. The extract was washed with water and dried,
and the solvent was distilled off under reduced pressure
to give a reddish oil (5.8 g) of 2-(N-methyl-N-benzylamino)-
ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-
1,4-dihydropyridine-3-carboxylate.
N.M.R. Spectrum (~ : CDCQ3+D20)
ppm : 1.29 (3H, t, J=7Hz), 2.21 (3H, s)
; 2.45 (3H, s), 2.63 (2H, t, J=6Hz),
3.51 (2H, s), 3.95 to 4.42 (2H, t),
3.95 to 4.42 (2H, q), 5.28 (lH, s),
7.08 (lH, s), 7.28 to 8.12 (4H, m),
10.54 (lH, s)
) I.R. Spectrum (Film)
- 53 -
.

1 0~UD2 2 3
v (cm~l) : 3350, 1735, 1700, 1690, 1635, 1600,
1525, 1480, 1350, 1279, 1215, 1100,
1030, 73s
18) To a mixture of a brown oil (2.46 g) of 2-
(N,N-diethylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-
ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-
3-carboxylate in acetone t24.6 ml) was added 6N hydro-
chloric acid (2.46 ml) and this mixture was stirred
for two hours at room temperature. The reaction
D mixture was adjusted to pH 7 with an aqueous solution
of sodium bicarbonate and the acetone was distilled off.
The residue was extracted with ethyl acetate, and the
extract was washed with water, dried, and concentrated
to give an oil (1.81 g) of 2-(N,N-diethylamino)ethyl
2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-
1,4-dihydropyridine-3-carboxylate.
N.M.R. Spectrum (~, CDCQ3)
ppm : 2.03 (3H, s),
5.3 (lH, s),
0 10.47 (lH, s)
19) To a mixture of diethyl 2-methyl-4-~3-hydroxy-
phenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-di-
czrboxi-late (1.16 g) in acetone (10 ml) was added 6N
hydrochloric acid (1 ml) and t~is mixture was stirred
at room temperature for 1.5 hours. The solvent was
distilled off under reduced pressure. The residue
was added with water and pulverized. The resultant
suspension was extracted with ethyl acetate and the
extract was washed with water and dried over magnesium
~0 sulfate. The solvent was distilled off under reduced
- 54 -
.

108V223
pressure and the residue was treated with diethyl
e~her to give crystals t0.8 g). The crystals
(200 mg) was recrystallized from a mixture of n-
hexane and diethyl ether to give pure crystals
tl30 mg) of diethyl 2-methyl-4-t3-hydroxyphenyl)-6-
formyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p.
141.5 to 142.SC.
20) To a mixture of a yellow oil (360 mg) of
methyl 4-(2-chlorophenyl)-5-ethoxycarbonyl-6-
0 diethoxymethyl-1,4-dihydropyridine-3-carboxylate in
acetone tlO ml) was added 6N hydrochloric acid tO.3 ml)
and the resultant mixture was stirred for 1.5 hours
at room temperature, and the acetone was removed.
Water was added to the residue and the mixture was
S extracted with ethyl acetate. The ethyl acetate layer
was washed with water, dried and concentrated. The
resultant orange oil t0.26 g) was crystallized and
the crystals were washed with n-hexane to give yellowish-
orange powder (80.7 mg) of methyl 4-(2-chlorophenyl)-
0 5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-
carboxylate.
~ I.R. Spectrum tNujol)
; v (cm~l) : 3300, 1690, 1675, 1491, 1442, 1376,
1303, 1221, 1186, 1090, 1060, 831, 757
!5 N.M.R. Spectrum t~, CDCQ3)
ppm : 1.0 (3H, t, J=7Hz),
' 3.68 (3H, s),
- 4.18 (2H, q, J=7Hz),
5.56 (lH, s),
;30 7 to 7.6 (6H, m),
, .
:
- 55 -
,- ~ . . .
. . , . ~ ~ . ,

1080Z23
10.44 (lH, s)
Example 3
1) The solution of diethyl 2-methyl-4-(2-
chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate
(377.8 mg), hydroxylamine hydrochloride (83.4 mg) and
sodium carbonate (63.6 mg) in ethanol (1 ml) was stirred
at room temperature for 30 minutes. After concentrating
the resultant solution, to the residue was added water.
After the mixture was extracted with ethyl acetate, the
extract was washed with water, and dried. The dried
extract was concentrated to give yellowish oil (476 mg).
The oil was crystallized with n-hexane to give diethyl
2-methyl-4-(2-chlorophenyl)-6-hydroxyiminomethyl-1,4-
dihydropyridine-3,5-dicarboxylate (318.8 mg), which was
~i identified by converting to the corresponding 6-cyano
compound, m.p. 136 to 137C.
2) A mixture of diethyl 2-methyl-4-(2-chlorophenyl)-
i; 6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (756 mg)
in ethanol (2 ml) and 85% hydrazine hydrate (141 mg) in
) water (1 ml) was stirred at room temperature for an hour.
The ethanol was distilled off under reduced pressuTe
and the residue was extracted with ethyl acetate. The
extract was washed with water, dried over magnesium
sulfate and concentrated under reduced pressure to give
an oil (960 mg). The oil was subjected to a column
chromatography on silica gel with an eluent [a mixture
of one part of benzene and one part of diethyl ether by
volume] to give an oily substance (720 mg), which was
allowed to stand for 14 days in a refrigerator to give
0 needles (120 mg) of diethyl 2-methyl-4-(2-chlorophenyl)-
- 56 -
~ ~ '

1080Z'~3
6-hydrazonomethyl-1,4-dihydropyridine-3,5-dicarboxylate,
m.p. 107 to 110C.
3) To a mixture of diethyl 2-methyl-4-(2-chlorophenyl)-
6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (525.3 mg)
and O-methylhydroxyamine hydrochloride (139.34 mg) in 99%
; ethanol (6 ml) was dropwise added a solution of sodium
carbonate (88.5 mg) in water (1 ml) over the period of
20 minutes under stirring at room temperature. The mixture
was stirred for another 10 minutes. The ethanol was
~0 distilled off under reduced pressure, and water was added
to the residue. The aqueous mixture was extracted with
diethyl ether and the extract was washed with water twice
and a saturated aqueous solution of sodium chloride, dried
and then concentrated under reduced pressure to give a
yellow oil. The oil turned into crystals, and these
crystals were washed with n-hexane to give yellow powder
(504.6 mg). This powder was recrystallized from a mixture
of 10 parts of n-hexane and one part of diethyl ether by
volume to give yellow glanules (301.5 mg) of diethyl 2-
~'0 methyl-4-(2-chlorophenyl)-6-methoxyiminomethyl-1,4-
dihydropyridine-3,5-dicarboxylate, m.p. 110 to 112C.
4) A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-
formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1651 g),
N,N-dimethyltrimethylenediamine (306.6 mg) and p-
!5 toluenesulfonic acid (catalytic amount) in dried benzene
~l (20 ml) was refluxed under azeotropic dehydration for
`~ 4.5 hours. The resultant solution was washed with
~ . :
water and dried. The solvent was removed from the solu- ~
tion to give brown oil (1.4748 g) of diethyl 2-methyl- ~ -
4-(2-nitrophenyl)-6-~3-(N,N-dimethylamino)propyl]imino-
- 57 -
: ;
- . ~

1080ZZ3
methyl-1,4-dihydropyridine-3,5-dicarboxylate.
I.R. Spectrum (Film)
v (cm ) : 3350, 1710, 1695, 1534, 1487,
1280, 1200, 1100, 1043, 860, 828, 785,
753, 715, 680
N.M.R. Spectrum (~, CDCQ3)
ppm : 1.18 ~3H, t), 1.2 (3H, t), 2.25 (6H, s),
2.41 (3H, s), 3.67 (2H, broad t),
3.8 to 4.3 (8H, m), 5.97 (lH, s), 7.2 to
0 7.8 (4H, m), 7.8 (lH, broad s), 8.97 (lH,
; t, J=lHz)
5) A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-
6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (970.9 mg),
N,N-diethylethylenediamine (290.5 mg) and p-toluenesulfonic
~5 acid (catalytic amount) in dried benzene (20 ml) was
.
refluxed under azeotropic dehydration for 4 hours. To
the resultant solution was added diethyl ether and the
solution was washed with water and dried. The solvent
was removed to give red oil (1.1711 g) of diethyl 2-
o methyl-4-(2-nitrophenyl)-6-[2-~N,N-diethylamino)ethyl]imino-
methyl-1,4-dihydropyridine-3,5-dicarboxylate.
I.R. Spectrum (Film)
(cm 1) : 3350, 1700, 1685, 1528, 1475, 1351,
1273, 1090, 852, 821, 788, 746, 708
N.M.R. Spectrum (~, CDCQ3)
ppm : 2.48 (3H, s), 5.99 (lH, s), 8.96 (lH, t,
J=IHz)
6) A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-
6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1651 g),
~o 2-aminoethanol (185 mg) and p-toluenesulfonic acid
:
- 58 -
-
'- ' ' ' ' . . '
.-

~ O~VZ ~ 3
(catalytic amount) in dried benzene (20 ml) was refluxed
under azeotropic dehydration for 1.5 hours. After
cooling to room temperature, water was added to the
resultant solution. The mixture was washed twice with
water. The aqueous layer was extracted with diethyl
ether and the extract was combined with the ben2ene
solution. The mixed solution was dried over magnesium
sulfate and then the solvent was removed from the
solutDn to give viscous oil (1.2397 g) of diethyl 2-
~0 methyl-4-(2-nitrophenyl)-6-(2-hydroxyethyl)iminomethyl-
1,4-dihydropyridine-3,5-dicarboxylate.
I.R. Spectrum (Film)
(cm 1) : 3500, 3360, 1694, 1536, 1484, 1280,
1220, 1101, 762, 753
N.M.R. Spectrum (~, CDCQ3)
ppm : 1.13 (3H, t, J=7Hz), 1.20 (3H, t, J=7Hz),
2 (lH, broad s), 2.38 (3H, s), 3.8 to 4.3
(4H, m), 3.87 (4H, broad s), 5.96 (lH, s),
7.2 to 7.8 (4H, m), 7.8 (lH, broad s),
o 9.0 (lH, broad s)
7)-~1) A mixture of diethyl 2-methyl-4-(2-trifluoro-
methylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxy-
late (870 mg), sodium carbonate (112.1 mg) and hydroxy-
lamine hydrochloride (147 mg) in ethanol (S ml) was
'5 stirred at room temperature for 30 minutes. After
removal of the ethanol, water was added to residue and
the solution was extracted with ethyl acetate. The
extract was washed with a saturated aqueous solution
- of sodium chloride, dried over magnesium sulfate and
O concentrated under reduced pressure to give pasty oil
- 59 -

1080ZZ3
(0.992 g). The oil was purified by column
chromatography on silica gel with an eluent [benzene
~ (10) + ethyl acetate (1)~ to give yellow powder (0.52 g)
! of diethyl 2-methyl-4-(2-trifluoromethylphenyl)-6-
, S hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.
I.R. Spectrum (Nujol)
~ ,, -1 .
-~ v (cm ) : 3410, 1695, 1680, 1655, 1483,
, 1445, 1370, 1309, 1221, 1106,
1090, 1057, 1034, 1010, 985, 772
0 N.M.R. Spectrum (~: CDCQ3)
ppm : 1.17 (3H, t, J=7Hz), 1.20 (3H, t,
J=7Hz), 2.35 (3H, s), 3.8 to 4.4
(4H, m), 5.64 (lH, broad s), 6.91
(lH, broad s), 7.2 to 7.7 (4H, m),
8.4 (1~, broad s), 8.8 (lH, s)
7)-(2) To a solution of diethyl 2-methyl-4-(2-
trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-
; 3,5-dicarboxylate (1.23 g) and hydroxylamine hydrochloride
(250.2 mg) in ethanol (5 ml) was added a solution of
'0 sodium carbonate (190.3 mg) in water (1.5 ml).
' The mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. To the residue
, was added water and the mixture was extracted with ethyl
acetate. The extract was washed with a saturated
!S aqueous solution of sodium chloride, dried over magnesium
sulfate and concentrated under reduced pressure to give an
~i oil. The oil was crystallized with n-hexane to give
~-
t~ crude crystals (1.09 g) of diethyl 2-methyl-4-(2-
I trifluoromethylphenyl)-6-hydroxyiminomethyl-1,4-
f ~0 dihydropyridine-3,5-dicarboxylate. -~
}
- 60 -
.:
, ~

1080Z23
8) To a mixture of 2-(N-methyl-N-benzylamino)-
ethyl 2-methyl 4-(3-nitrophenyl)-S-ethoxycarbonyl-6-
formyl-l,~-dihydropyridine-3-carboxylate (1.015 g)
and hydroxylamine hydrochloride ~116.8 mg) in ethanol
; (3 ml) was dropwise added slowly a solution of sodium
carbonate (127.2 mg) in water (1 ml~ and the resultant
mixture was stirred at room temperature for 50 minutes. 7The ethanol was distilled off under reduced pressure
and to the residue was added water and the mixture was
extracted with ethyl acetate. The extract was washed
with aqueous sodium chloride solution, dried and then
concentrated under reduced pressure to give a yellow
oil (1.01 g) of 2-(N-methyl-N-benzylamino)ethyl 2-
methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxy-
~5 iminomethyl-1,4-dihydropyridine-3-carboxylate.
I.R. Spectrum (film)
(cm~ ) : 3350, 1690, 1460, 1375, 1348,
1205, 1098, 1044, 738, 720, 700
N.M.R. Spectrum (~: CDCQ3)
O ppm : 1.22 (3H, t, J=7Hz), 2.26 (3H, s),
` 2.36 (3H, s), 2.70 t2H, t, J=6Hz),
3.58 (2H, s), 4.09 (2H, q, J=7Hz),
4.18 (2H, t, J=6Hz), 5.14 (lH, s),
; 7.1 to 8.1 (lOH, m), 8.97 (lH, s)
'5 9) According to a similar manner to those of
the above Example 3-(1) to - (8), the following
compounds were obtained :-
(1) Diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxy-
iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.
(2) Diethyl 2-methyl-4-(2-chloro-5-nitrophenyl)-
- 61 -
'

1080ZZ3
6-hydroxyiminomethyl-1,4-dihydropyridine-3,~-
dicarboxylate.
(3) Diethyl 2-methyl-4-(2-furyl)-6-hydroxyimino-
methyl-1,4-dihydropyridine-3,5-dicarboxylate.
S (4) 2-ethoxyethyl 2-~ethyl-4-~3-nitrophenyl)-5-
ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-
3-carboxylate.
(5) 2-(N,N-Diethylamino)ethyl 2-methyl-4-(3-
nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-
1,4-dihydropyridine-3-carboxylate.
Those compounds were prepared from the correspond-
ing 6-formyl compounds in a similar manner to those
of Examples 3-(1) to -(8) and were identified by
convertingthem to the corresponding 6-cyano compounds
Example 4
1)-(1) A mixture of diethyl 2-methyl-4-(2-
chlorophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-
3,5-dicarboxylate (0.6135 g) and N,N'-dicyclohexyl-
carbodiimide (804.6 mg) in pyridine (3 ml) was heated
under reflux for 6 hours. The resultant solution was
acidified with dilute hydrochloric acid and extracted
with ethyl acetate. The insoluble product was
filtered off and the filtrate was washed with water,
dried over magnesium sulfate and evaporated under
~25 reduced pressure. To the residue was added diethyl
ether and the mixture was filtered. The filtrate was
concentrated under reduced pressure to give red oil
(703.7 mg). The oil was purified by column chro-
matography on silica gel [eluent : benzene (10) +
ethyl acetate (1)] and crystallized with n-hexane.
; - 62 -
:' :

10802Z3
The crystals were recrystallized from a mixture of n-
hexane and diethyl ether to give yellow crystals
t417.1 ms) of diethyl 2-methyl-4-(2-chlorophenyl)-6-
cyano-1,4-dihydropyridine-3,5-dicarboxylate, m.p.
136 to 137C.
1)-(2) A mixture of diethyl 2-methyl-4-t2-
chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-
dicarboxylate (377.8 mg), sodium formate (125 mg) and
hydroxylamine hydrochloride (79.93 mg) in formic acid
(1.5 ml) was heated under reflux for an hour. Water was
added to the reaction mixture and the mixture was extracted
with ethyl acetate. The extract was filtered and the
filtrate was washed with water, an aqueous sodium bi-
carbonate solution, water and a saturated aqueous solution
of sodium chloride in turn and dried over magnesium
sulfate. After the solvent was distilled from the
solution, ether was added to the residue. The solution
was filtered and the filtrate was concentrated under
reduced pressure to give oil (210 mg). The oil was
crystallized from a mixture of n-hexane and diethyl ether
to give crystals (154.1 mg) of diethyl 2-methyl-4-(2-
chlorophenyl)-6-cyano-1,4-dihydropyridine-3,5-
dicarboxylate, which was identified with the authentic
sample. The insoluble yellow powder (110 mg) which was
collected by filtration in the above was theproduct of
ethyl l-oxo-6-methyl-8-(2-chlorophenyl)-5,8-dihydro-lH-
::j
pyrido[2,3-d][1,2]oxazine-7-carboxylate.
.i I.R. Spectrum (Nujol)
; v (cm 1) : 3340, 3250, 1730, 1693, 1686
3 (shoulder), 1670, 1504, 1374,
''''
, ~
-; - 63 -
' ~ ~ : ' , ,.'
, . . .

10802~3
1235, 1169, 1094, 972, 834, 778,
755
N.M.R. Spectrum (~: DMSO-d6)
ppm : 0.98 (3H, t, J=7Hz), 2.37 (3H, s),
; 3.90 (2H, q, J=7Hz), 5.35 (lH, s),
7.1 to 7.5 (4H, m), 10.02 (lH, s),
10.35 (lH, s)
1)-(3) A mixture of diethyl 2-methyl-4-(2-
chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxy-
) late (377.8 mg), sodium formate (125 mg), hydroxylamine
hydrochloride (79.93 mg) in formic acid (1.5 ml) was
stirred at room temperature for 5 minutes and acetic
anhydride (0.2 ml) was added to the solution. The
mixture was stirred at room temperature for 20 minutes
; and heated under reflux for an hour. After adding
water to the resultant solution, the solution was extracted
with ethyl acetate. The extract was washed with an
aqueous sodium bicarbonate solution, water and a
saturated aqueous sodium chloride solution in turn, dried
over magnesium sulfate and concentrated under reduced
pressure to give brown oil (0.41 g). The oil was crys-
tallized from a mixture of diethyl ether and n-hexane to
give yellow powder (207 mg) of diethyl 2-methyl-4-(2-
chlorophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate,
which was identified with the authentic sample.
1)-(4) A mixture of diethyl 2-methyl-4-(2-chloro-
phenyl}6-formyl-1,4-dihydropyridine-3,5-dicarboxylate
~377.8 mg), sodium acetate (164 mg) and hydroxylamine
hydrochloride (80 mg) in acetic acid (1.5 ml) was stirred
0 at room temperature for 30 minutes. After acetic
- 64 -

~080Z'~3
anhydride (0.2 ml) was added to the solution, the
solution was stirred at room temperature for an hour
and then heated under reflux for an hour. Water was
added to the reaction mixture, the solution was extracted
with diethyl ether. The extract was washed with water,
an aqueous sodium bicarbonate solution and water in turn
and dried over magnesium sulfate. The solution was con-
centrated under reduced pressure to give yellow oil
(410 mg). The oil was crystallized with n-hexane to give
crystals (342.4 mg) of diethyl 2-methyl-4-(2-chlorophenyl)-
6-cyano-1,4-dihydropyridine-3,5-dicarboxylate, which was
identified with the authentic sample.
2) A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-
6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.03 g),
hydroxylamine hydrochloride (417 mg), sodium acetate
(861.4 mg) in acetic acid (15 ml) was stirred at room
temperature for 30 minutes. Acetic anhydride (1 ml) was
added to the reaction mixture, and the mixture was stirred
at room temperature for 90 minutes and further refluxed
for an hour. The acetic acid was distilled off under
reduced pressure, and to the resultant residue was added
water, and the aqueous mixture was adjusted to pH 7 to 8
with sodium bicarbonate and extracted with diethyl ether.
., .
The extract was washed with water, dried over magnesium
sulfate and then concentrated under reduced pressure to
give an oil. This oil was subjected to column chromato-
graphy on silica gel with an eluent [a mixture of 4 parts
of benzene and one part of ethyl acetate by volume].
;- The resultant oily substance (1.7 g) was crystallized by
treating with a mixture of diethyl ether and n-hexane
- 65 _
.

- 1 0 80 2 2 3
m.p. 86 to 88C (recrystallized from a mixture of diisopropyl-
ether and ethanol).
These crystals were recrystallized from a mixture of
diethyl ether and n-hexane to give pure crystals
(1.23 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-cyano-
`~ 1,4-dihydropyridine-3,5-dicarbonate, m.p. 126 to 127.5C.
3)-(1) A solution of the powder (0.49 g) of diethyl
2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxyiminomethyl-
1,4-dihydropyridine-3,5-dicarboxylate and thionyl chloride
(1.5 ml) in dry diethyl ether (1.5 ml) was stirred at
room temperature for 30 minutes. After the resultant
solution was evaporated to dryness, water was added to
the residue and the mixture was extracted with ethyl acetate.
i- The extract was washed with water, dried over magnesium
sulfate and concentrated under reduced pressure to give a
brown oil (0.39 g). The oil was purified by a column
~; chromatography on silica gel with an eluent [benzene (5)
ethyl acetate (1)] and crystallized by treating with n-
, hexane to give yellow powder (50 mg). The powder was
;; recrystallized from a mixture of diethyl ether and n-hexane
to give crystals of diethyl 2-methyl-4-(2-trifluoromethyl-
~ phenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate, m.p.
- 140 to 143C.
' 3)-(2) A mixture of the crystals ~1.09 g) of diethyl
2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxyiminomethyl-
1,4-dihydropyridine-3,5-dicarboxylate and N,N'-
; dicyclohexylcarbodiimide (1.319 g) in pyridine ( 5 ml) was
heated under reflux for 6.5 hours. After removing pyridine,
:
dilute hydrochloric acid was added to the residue and the
~` mixture was stirred for 10 minutes. The mixture was
extracted with ethyl acetate and the insoluble product
) was filtered off. The filtrate was washed with water,
.
- 66 -

1080ZZ3
dried over magnesium sulfate and concentrated under
reduced pressure to give brown oil (1.09 g). The oil
was purified by column chromatography on silica gel with
an eluent [benzene (lO) ~ ethyl acetate (1)] to give oil
(720 mg). The oil was crystallized by treating with
n-he~ane and the precipitates were collected by filtration
and washed with n-hexane to give yellow powder (610 mg).
The powder was recrystallized from a mixture of ether and
n-hexane to give pure diethyl 2-methyl-4-(2-trifluoro-
L0 methylphenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate,
which was identified with the authentic sample, m.p. 140
to 143C.
3)-(3) A mixture of diethyl 2-methyl-4-(2-trifluoro-
methylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate
L5 (205.7 mg), sodium acetate (82 mg) and hydroxylamine
hydrochloride (40 mg) in acetic acid ~1.5 ml) was stirred
at room temperature for 30 minutes. After acetic anhydride
f' ~ (0.1 ml) was added,the solution was stirred at room tem-
~;: perature for 1.5 hours and then heated under reflux for an
;~0 hour. To the resultant solution was added water and the
solution was extracted with diethyl ether. The extract
was washed with water, an aqueous sodium bicarbonate solut-
ion and water in turn, dried over magnesium sulfate and con-
centrated under reduced pressure to give oil (201 mg).
-25 The oil was purified by column chromatography on silica gel
with an eluent [benzene ~5) + ethyl acetate (1)] to give
pure oil ~172.4 mg). The oil was crystallized by treating
with n-hexane to give powder (118 mg) of diethyl 2-methyl-
4-(2-trifluoromethylphenyl)-6-cyano-1,4-dihydropyridine-3,
5-dicarboxylate.
.
- 67 -
,

~ 10t302Z3
4) A mixture of diethyl 2-methyl-4-(2-chloro-5-
nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate
~; (3.70 g), hydroxylamine hydrochlorîde (695 mg)~ sodium
acetate (1.436 g) in acetic acid (36 ml) was stirred at
room temperature for 2.5 hours, and then acetic anhydride
7,, (2 ml) was added thereto. The resultant mixture was
stirred for 30 minutes and refluxed for 1.5 hours. After
removal of the acetic acid, water and ethyl acetate were
added to the reaction mixture and the resultant mixture
~ o was washed twice with dilute sodium bicarbonate aqueous
i solution and then with an aqueous sodium chloride, and
dried over magnesium sulfate. After removal of the sol-
vent the residue was washed with diethyl ether to give
; powder (2.5 g). The powder was subjected to column chro-
.5 matography on silica-gel with an eluent (a mixture of 10
parts of benzene and one part of ethyl acetate by volume).
The fraction of the eluate which showed only one spot on
~'i thin-layer chromatography was concentrated to give crude
crystals (450 mg) and the fraction of the eluate which
s ~o showed plural spots on thin-layer chromatography was also
concentrated to give crude crystals (1.0 g). Thus
obtained crude crystals were combined together and re-
crystallized from a mixture of benzene and ethyl acetate
to give pure crystals (657 mg) of diethyl 2-methyl-4-(2-
chloro-5-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-
dicarboxylate, m.p. 204.5 to 205.5C.
5) A mixture of diethyl 2-methyl-4-(2-furyl)-6-formyl-
1,4-dihydropyridine-3,5-dicarboxylate (1.6 g), hydroxy-
lamine hydrochloride (383.6 mg) and sodium acetate (787.6 mg)
in acetic acid (14 ml) was stirred for 30 minutes at room
~'
- 68 -
,.'.
.~ ~
~, . . .

108VZZ3
temperature. To the mixture, acetic anhydride tl ml)
; was added and stirred for 1.5 hours at room temperature
and further stirred for an hour under reflux. After
removal of the acetic acid from the reaction mixture,
water was added to the residue and the mixture was
sxtracted with ethyl acetate. The extract was washed
with saturated sodium bicarbonate solution and water and
dried, and then the solvent was distilled off under re-
duced pressure. The resultant brown oil ~1.8 g) was
purified by column chromatography on silica gel by an
eluent (a mixture of 15 parts of chloroform and one part
of ethyl acetate by volume). The concentrate t920 mg)
of the fraction of the eluate which showed one spot on
;: thin-layer chromatography and the concentrate of one
(450 mg) which showed plural spots respectively gave
crystals (totally 875 mg) and these were recrystallized
from a mixture of diethyl ether and n-hexane to give pure
crystals ~818 mg) of diethyl 2-methyl-4-(2-furyl)-6-cyano-
1,4-dihydropyridine-3,5-dicarboxylate, m.p. 139 to 141C.
6)-(1) A mixture of 2-(N-benzyl-N-methylamino)ethyl
2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyimino-
methyl-1,4-dihydropyridine-3-carboxylate (0.91 g) and N,N'-
dicyclohexylcarbodiimide (0.987 g) in pyridine ~ 5 ml)
was heated under reflux for 3 hours. After removal of the
pyridine under reduced pressure, water was added to the
residue. The mixture was extracted with ethyl acetate.
The insoluble product was filtered off and the filtrate
was washed with water, dried over magnesium sulfate and
concentrated under reduced pressure to give red oil (1.6 g).
The oil was purified by column chromatography on silica gel
; - 69 -

10~UV~ ~3
with an eluent [benzene (2) ~ ethyl acetate (1)] to give a
reddish oil (0.68 g) of 2-`~N-benzyl-N-methylamino)ethyl
2-methyl-4-~3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-
1,4-dihydropyridine-3-carboxylate.
i I.R. Spectrum ~Nujol)
v (cm 1) : 3320, 3250 (shoulder), 2240, 1708,
; 1685, 1525, 1500, 1345, 1293, 1210,
1100, 1030, 780, 735, 700
N.M.R. Spectrum (~: CDC~3)
) ppm : 1.25 (3H, t, J=7Hz), 2.15 (3H, s),
2.39 (3H, s), 2.62 (2H, t, J=7Hz),
; 3.48 (2H, s), 3.9 to 4.3 (4H, q (CH2CH3),
t ~COOCH2CH2N)), 5.26 (lH, s), 7.1 to
8.2 (lOH, m)
.3 The product obtained above was dissolved in diethyl ether
After adding ethanolic hydrochloric acid to the solution,
the solution was evaporated to dryness. The residue was
pulverized with n-hexane and the precipitating powder was
collected by filtration. The powder was recrystallized
D from an aqueous ethanol to give yellow pure crystals
~ (460.8 mg) of the object compound hydrochloride, m.p. 228
o
to 229 C.
6-(2) A mixture of 2-(N-benzyl-N-methylamino)ethyl
2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-
. ' .
6 dihydropyridine-3-carboxylate (253.8 mg), sodium acetate
(82 mg) and hydroxylamine hydrochloride (40 mg) in acetic
acid (1 ml) was stirred at room temperature for 30 minute$.
After acetic anhydride (0.1 ml) was added, the solution
was stirred at room temperature for an hour and then heated
O under reflux foT an hour. Water was added to the reaction
- 70 -

1080Z~3
mixture and the solution was neutralized with sodium
bicarbonate and then extracted with ethyl acetate.
The extract was washed with an aqueous sodium bicarbonate
solution and water in turn, dried over magnesium sulfate
and then concentrated under reduced pressure to give an
oil (250 mg) (quantitatively) of 2-tN-benzyl-N-methylamino)-
ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-
cyano-1,4-dihydropyridine-3-carboxylate, which was
identified with the authentic sample.
L0 7) Starting fTom a mixture of an oil (1.66 g) of
2-(N,N-diethylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-
ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate,
; hydroxylamine hydrochloride (0.302 g) and sodium acetate
tO.593 g) in acetic acid (12 ml) and acetic anhydride
L5 (1.8 ml) was obtained crystals (700 mg) according to a
similar manner to that of Example 4-2). These crystals
were recrystallized from ethanol to give pure crystals
(420 mg) of 2~N,N-diethylamino)ethyl 2-methyl-4-(8-
nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-
3-carboxylate, m.p. 150 to 152C.
R) A mixture of 2-ethoxyethyl 2-methyl-4-(3-
nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-
3-carboxylate (3.00 g), hydroxylamine hydrochloride
tO.5547 g), sodium acetate tl.l382 g) in acetic acid tlO
ml) was stirred for 30 minutes at room temperature. To
this mixture was added acetic anhydride tl.4 ml) and the
`' ! .
resultant mixture was stirred for an hour at room tem-
perature and refluxed for an hour. The acetic acid was
distilled off under reduced pressure, and to the residue
was added water. The resultant mixture was neutrallized

10~U02 2 3
with an aqueous solution of sodium bicarbonate and extracted
with ethyl acetat~ twice. The extract was washed with
water and an aqueous solutiDn saturated with sodium
chloride and dried. The solvent was distilled off and
i
thus obtained viscous oily substance (3.19 g) was subjected
to column chromatography on silica gel with an eluent ~a
mixture of 5 parts of benzene and one part of ethyl acetate
by volume] and a yellow oil (1.74 g) was obtained from
the fTaction which contained the designated product. The
) oil turned into crystals (1.56 g). These crystals were
recrystallized from benzene to give yellow powder (l.S g)
of 2-ethoxyethyl 2-methyl-4-~3-nitrophenyl)-5-ethoxycarbonyl-
;l 6-cyano-1,4-dihydropyridine-3-carboxylate-l/3 benzene, m.p.
89 to 91C. Thus obtained yellow powder was further re-
; crystallized from a mixture of diethyl ether and n-hexane
to give crystals of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-
5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate,
m.p. 115 to 116C.
9) A mixture of diethyl 2-methyl-4-(3-nitrophenyl)-6-
~0 formyl-l~4-dihydropyridine-3~5-dicarboxylate (I.9418 g),
hydroxylamine hydrochloride (399.6 mg), sodium acetate
t820 mg) in acetic acid (7.5 ml) was stirred at room tem-
perature for 30 minutes. After addition of acetic
anhydride (1 ml), the resultant mixture was stirred for an
hour at room temperature and further refluxed for an hour.
The acetic acid was distilled off, and water was added to
the residue. The resultant aqueous mixture was neutralized
by an aqueous solution saturated with sodium bicarbonate. A
Precipitating oily substance was extracted with ethyl
iO acetate twice. The extract was washed with an aqueous
.~
~ - 72 -
. ~. .

108()ZZ3
solution of sodium chloride and dried. The solvent
was distilled off under reduced pressure to give a
orange-yellow oil (2.0103 g). This oil
turned into crystals and these crystals were recrystal-
lized from a mixture of diethyl ether, ethyl acetate
and n-hexa~e to give yellow powder (0.9119 g). This
powder was dissolved into a mixture of 5 parts of
benzene and one part of ethyl acetate by volume and
filtered on silica gel to give crystals (1.02 g).
These crystals were recrystallized from a mixture of
benzene and diethyl ether to give yellow granules
(0.8479 g) of diethyl 2-methyl-4-(3-nitrophenyl)-6-cyano-
1,4-dihydropyridine-3,5-dicarboxylate, m.p. 174 to 177C.
10) Starting from a mixture of a reddish oil (2.0 g)
of 2-benzyloxyethyl 2-methyl-4-(2-nitrophenyl)-5-
ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate,
hydroxylamine hydrochloride (336.9 mg), sodium acetate
(662.9 mg) in acetic acid (15 ml) and acetic anhydride
~1.5 ml) was obtained crystals (767 m~) according to
a similar manner to that of Example 4-2). These crystals
were recrystallized from a mixture of benzene and diethyl
:, .
ether to give faint yellow crystals (450 mg) of 2-
benzyloxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-
6-cyano-1,4-dihydropyridine-3-carboxylate, m.p. 139 to
140C ~urther recrystallized from a mixture of diethyl
ether and n-hexane).
11) Starting from a mixture of 2-phenoxyethyl 2-
methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-
dihydTopyridine-3-carboxylate (1.03 g), hydroxylamine
hydrochloride (178.6 mg~ and sodium acetate (352 mg) in

1080ZZ3
acetic acid (8 ml) and acetic anhydride tl ml), there
was obtained in a similar manner to that of Example 4-2)
an oil (420 mg) of 2-phenoxyethyl 2-methyl-4-(2-
nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-
3-carboxylate.
I.R. Spectrum ~KBr)
(cm 1) ; 3330, 2250, 1710, 1600, 1530,
1500, 1300, 1216, 1110, 757
N.M.R. Spectrum (~, CDCQ3)
o ppm : 1.2 (3H, t, J=7Hz),
2.36 (3H, s),
4 to 4.4 (6H, m),
6.05 (lH, s),
6.73 (lH, m),
6.83 to 7.66 (9H, m)
12) Starting from a mixture of 2-ethoxyethyl 2-
methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-
dihydropyridine-3-carboxylate (900 mg), hydroxylamine
hydrochloride (167 mg) and sodium acetate (341 mg)
in acetic acid ( 7 ml) and acetic anhydride (1 ml) was
obtained by applying an essentially similar manner to that
of Example 4-2), crystals (420 mg) of 2-ethoxyethyl 2-
methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-
dihydropyridine-3-carboxylate, m.p. 129 to 130.5C
-25 (recrystallized from a mixture of diethyl ether and n-
hexane).
'.
:
~'~
- 74 -

10802Z3
13) Starting from a mixture of diethyl 2-methyl-
4-(2-nitrophenyl)-6-formylmethyl-~4-dihydropyridine-3,5-
dicarboxylate, hydroxylamine hydrochloride and sodium
acetate in acetic acid and acetic anhydride, was
obtained an oil of diethyl 2-methyl-4-(2-nitrophenyl)-
6-cyanomethyl--1,4-dihydropyridine-3,5-dicarboxylate,by
applying an essentially similar manner to that of
Example 4-2).
I.R. Spectrum (Liquid)
~ (cm 1) : 2210
.,
N.M.R. Spectrum (~ ,CDC13)
ppm: 1.17 (6H, t, J=7Hz), 2.32 (3H, s),
3.9 to 4.3 (4H, m), 4.78 (2H, s),
5.89 (lH, s), 7.14 (lH, broad s) `
l15 7.2 to 7.85 (4H, m)
; Example 5
1) To a solution of diethyl 2,6-diformyl-4-(2-
chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
(272.7 mg) in 99/O ethanol (7 ml) was added sodium
,' .
.
~'
, .
r
~ 75 ~
.-
,
, ~ ~, . . ....... .

1080Z23
borohydride (52.7 mg) under stirring at about 5C and the
resultant mixture was further stirred at 5C for lO
minutes. The resultant solution was neutralized with
dilute hydrochloric acid and ethanol was removed at room
! 5 temperature under reduced pressure. To the residue was
added water and the precipitates were collected by filt-
ration, and then dried to give crude pale yellow crystals
(261.0 mg) of diethyl 2,6-dihydroxymethyl-4-t2-chloro-
phenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
~0 The crude crystals were recrystallized from a mixture of
ethanol and diethyl ether to give pure pale yellow needles,
m.p. l90 to 191C.
; 2) To a solution of diethyl 2-methyl-4-(2-chlorophenyl)-
6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.5 g)
L5 in ethanol (30 ml) was added sodium borohydride (155 mg)
under stirring and this mixture was further stirred at
room temperature for 2 hours. The resultant mixture was
acidified with dilute hydrochloric acid and the solvent
was removed. Water was added to the residue and the mix-
'O ture was extracted twice with ethyl acetate. After the
;~ extract was washed with water and dried, the solvent was
; removed under reduced pressure from the extract to give a
.
red oil (1.3525 g). The oil was dissolved in diethyl
ether and allowed to stand at room temperature. After
~,!5 the insoluble product was removed by filtration, the
filtrate was allowed to stand. The slowly precipitated
crystals were collected by filtration and recrystallized
from a mixture of diethyl ether and n-hexane to give pure
, crystals (92.0 mg) of diethyl 2-methyl-4-(2-chlorophenyl)-
--50 6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,
.
,, '
- 76 -
.
- . .

1080223
m.p. 143C. The insoluble product obtained above was
collected by filtration and recrystallized from ethyl
acetate to give colorless prisms (241.5 mg) of ethyl 2-
methyl-4-~2-chlorophenyl)-5-oxo-1,4,5,7-tetrahydrofuro-
[3,4 b]pyridine-3-carboxylate, m.p. 211 to 212C.
3) To a mixture of dimethyl 2-methyl-4-[2-
chlorophenyl)-6-acetyl-1,4-dihydropyridine-3,5-dicarboxy-
late ~450 mg) in methanol ~15 ml) was added gradually
~odium borohydride ~46.8 mg) under ice-cooling with
o stirring. The mixture was further stirred for 35 minutes
under ice-cooling. The solution was neutralized with
2N-hydrochloric acid under ice-cooling and the solvent
was distilled off under reduced pressure at a lower tem-
perature than 30C on a water-bath. To the residue was
~j 5 added water and a small amount of an aqueous sodium
! bicarbonate to adjust the medium to pH 7 to 8. The
resultant m1xture was allowed to stand to give white powder,
which was collected by filtration and dried to give powder
(395.0 mg). To this powder was added diethyl ether (20
ml) and the mixture was stirred for about 30 minutes at
room temperature. Insoluble white powder was collected
by filtration and washed with diethyl ether. The filtrate
and the washings were combined together and the solvent
was distilled off at relatively low temperature to give
~`5 crude crystals (100.5 g) of dimethyl 2-methyl-4-(2-
, chlorophenyl)-6-(1-hydroxyethyl)-1,4-dihydropyridine-3,5 di-
carboxylate, m.p. 145 to 147C.
The insoluble white powder obtained above uas collected by
~: filtration and washed with diethyl ether to give crude white powder
~S0 (264.2 mg) of methyl 2-methyl-4-(2-chlorophenyl-~-5-oxo-7-methyl-~,4j5j7-
tetrahydrofuro[3,4-b]pyridine-3-carboxylate, m.p. 228 to 233C.
! .
- 77 -

1080Z~3
4) To a solution of diethyl 2-methyl-4-(2-nitrophenyl~-
6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.0881 g)
in ethanol (20 ml) was gradually added sodium borohydride
(0.1892 g) under stirring and the resultant mixture was
further stirred at room temperature for an hour. The
solution was acidified with dilute hydrochloric acid
and stirred at room temperature for 30 minutes. After
the resultant solution was filtered, the filtrate was
concentrated under reduced pressure and extracted with
ethyl acetate. The extract was washed with water an~ ~ried
and then the solvent was removed to give orange oil
(1.8596 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-
hydroxymethyl-l~4-dihydropyridine-3~5-dicarboxylate. After the crude,
product was dissolved in ethanol, the solution was filtered.
The filtrate was concentrated under reduced pressure and
the oily residue was allowed to stand for 3 days. Thus
obtained crystals were recrystallized from ether to give
pure product, m.p. 112 to 113C.
The insoluble product obtained by filtration of the
resultant solution in the above was recrystallized from
ethanol to give pale yellow flakes (455.1 mg) of ethyl
2-methyl-4-(2-nitrophenyl)-5-oxo-1,4,5,7-tetrahydrofuro-
[3,4-b]pyridine-3-carboxylate, m.p. 220 to 222C. The
product was further recrystallized from ethyl acetate
to give pure product, m.p. 221 to 223C.
5) To a suspended solution of diethyl 2-methyl-4-
(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-
dicarboxylate ~233 mg) in ethanol ~10 ml) was added sodium
borohydride (22.7 mg) at 0 to 5C under stirring and
this mixture was further stirred at about 5~C for an hour
:
- 78 -

1~80ZZ3
and 10 minutes. After the reaction, the mixture was
adjusted to pH 4 to 5 with O.lN-hydrochloric acid, and
then the solvent was removed under reduced pressure.
The residue was extracted with ethyl acetate and the
extract was washed with water and dried over magnesium
sulfate. The extract was concentrated under reduced
pressure and the residue was crystallized by treating
with a mixture of diethyl ether and n-hexane. The
precipitated crystals were collected by filtration, dried
and recrystallized from a mixture of diethyl ether and
n-hexane to give crystals of diethyl 2-methyl-4-(3-
nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-
dicarboxylate (152 mg), m.p. 141 to 142.5C.
6) To a solution of diethyl 2-methyl-4-(2-
trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-3,5-
dicarboxylate (1.0 g) in ~thanol (20 ml) was gradually
added sodium borohydride (92 mg) under stirring and ice-
cooling and the resultant mixture was further stirred for
25 minutes. The resultant mixture was adjusted with
0.1 N hydrochloric acid to pH 4 to 5. The ethanol was
removed under reduced pressure without heating so much,
~ !.
and water was added to the residue to give crystals. The
, crystals were collected by filtration to give crude
crystals (1.2 g). These were recrystallized from a mixture
~ .
~;; of diethyl ether and n-hexane to give pure crystals of
diethyl 2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxy-
~- methyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 147 to
.5C.
7) To a solution of diethyl 2-methyl-4-(2-methoxy-
0 phenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate
:
- 79 -
''' ~ ` '' ' ' ~
.

1080223
(1.1320 g) in ethanol (30 ml) was gradually added sodium
borohydride (114 mg) under stirring and the resultant
mixture was further stirred at room temperature for an
hour. The resultant mixture was acidified with dilute
hydrochloric acid. After removing ethanol from the
mixture, water was added to ~he residue to solidify.
The solid was collected by filtration, dried and washed
with diethyl ether. The diethyl ether washings were
concentrated to the volume of about 10 ml and stood at
room temperature to give pale yellowish granules
(372.5 mg) of diethyl 2-methyl-4-(2-methoxyphenyl)-6-
hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,
m.p. 125 to 126C.
On the other hand, the solid obtained above, which was
collected by filtration and washed with diethyl ether,
was added to a mixed solution of p-toluenesulfonic acid
(catalytic amount) in ethanol (5 ml) and the mixture
was refluxed for one hour. After removal of ethanol,
the residue was pulverized with diethyl ether and
collected by filtration. The powder was recrystallized
from a mixture of acetone and ethyl acetate to give
colorless granules (114.8 mg) of ethyl 2-methyl-4-(2-
methoxyphenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]-
pyridine-3-carboxylate, m.p. 219 to 220C.
8) To a suspension of diethyl 2-methyl-4-(3-
hydroxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxy-
late (600 mg) in ethanol (15 ml), was added sodium
borohydride (63.5 mg) at 0C under stirring and the
- resultant mixture was further stirred for an hour.
The resultant mixture was adjusted with 0.1N hydrochloric
' .
- 80 -
- ,
.
.

108V223
acid to pH 3 to 4 under ice-cooling. The ethanol was
distilled off under reduced pressure and the residue was
extracted with ethyl acetate. The extract was washed
with water twice and an aqueous sodium chloride solution
in turn, dried over magnesium sulfate and then concentrated
under reduced pressure to give crystals (600 mg). These
were recrystallized from a mixture of ethyl acetate and
diethyl ether to give pure crystals (350 mg) of diethyl
2-methyl-4-(3-hydroxyphenyl)-6-hydroxymethyl-1,4-
dihydropyridine-3,5-dicarboxylate, m.p. 161.5 to 163C.
9) To a solution of diethyl 2-methyl-4-(2-thienyl)-
6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (940.68 mg)
in 99% ethanol (30 ml) was gradually added sodium boro-
hydride (113.5 mg) under stirring and this was further
, 15 stirred at room temperature for 2 hours. After removal
of ethanol, the residue was extracted with ethyl acetate
and the extract was washed twice with water and then
dried. The solvent was removed from the extract to give a
pale yellow oil. The oil was pulverized with n-hexane.
The powder was dissolved in ethyl acetate. After collect-
ing by filtration of the insoluble product, to the filtrate
; was added n-hexane and the mixture was allowed to stand in
,. .
refrigerator. The appearring crystals were collected by
filtration to give pale yellow granules (857.2 mg) of
diethyl 2-methyl-4-(2-thienyl)-6-hydroxymethyl-1,4-
dihydropyridine-3,5-dicarboxylate, m.p. 125 to 126C.
The insoluble product obtained above was collected by
filtration to give powder (33.3 mg) of ethyl 2-methyl-4-
~2-thienyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-
3-carboxylate, m.p. 232C.
- 81 -
~ : '

` 1080ZZ3
10) To a solution of 2-hydroxyethyl 2-methyl-4-(2-
nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-
3-carboxylate (2.0 g) in ethanol (40 ml) was added bit-by-
bit sodium borohydride (113.5 mg) at 5C under stirring.
S The mixture was further stirred at 5C for 30 minutes and
,:
acidified weakly with S0~ acetic acid. After removal of
the ethanol, to the residue was added water, and the
mixture was made slightly alkaline with an aqueous solution
of sodium bicarbonate, allowed to stand and then filtered,
when it became clear. The precipitate (1.58 g) was collected
by filtration ana recrystallized from a mixture of
ethanol and diisopropyl ether to give yellowish-orange
granules (0.99 g) of 2-hydroxyethyl 2-methyl-4-(2-
nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-
lS dihydropyridine-3-car~oxylate, m.p. 167 to 169C.
11) To a suspended solution of benzyl 2-methyl-4-
(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-
3-carboxylate (1.2 g) in ethanol (20 ml) was added sodium
I borohydride (60.6 mg) under ice-cooling and stirred, and
further stirred for an hour at 0C and another an hour at
3C. The reaction mixture was added with water and the
resultant mixture was adjusted to pH 6 to 7 with 2N
` hydrochloric acid, and the solvent was distilled off. The
residue was extracted with ethyl acetate and washed with
, . . .
water and dried. After removal of the solvent, the resul-
` tant oil (1.3 g) was purified by column chromatography on
silica gel with an eluent (a mixture of ten parts of benzene
and one part of ethyl acetate by volume) to give an oil
¢~ which was immediately crystallized. The resultant crystals
were recrystallized from a mixture of diethyl ether and
. .
- 82 -

~O ~ Z Z 3
n-hexane and dissolved in benzene. The benzene solution
was subjected to azeotropic process fi~e times to give
pure crystals of benzyl 2-methyl-4-(2-nitrophenyl)-5-
ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-
carboxylate, m.p. 51 to 57C.
12) To a suspension of 2-ethoxyethyl 2-methyl-4-(3-
nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-
3-carboxylate tl.13 g) in ethanol ~15 ml) was added sodium
borohydride (80 mg) with stirring under ice-cooling, and
.o this mixture was further stirred for an hour at the same
temperature. The reaction mixture was adjusted with
dilute hydrochloric acid to pH 6 under ice-cooling and then
the solvent was distilled off. To the residue was added
water and the aqueous mixture was extracted with diethyl
ether. The extract was washed with water and dried over
magnesium sulfate. Removal of the sol~ent gave an oil,
which was crystallized by treating with n-hexane.
These were recrystallized from a mixture of diethyl ether
and n-hexane to give pure crystals ~900 mg) of 2-ethoxyethyl
2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-
1,4-dihydropyridine-3-carboxylate, m.p. 99 to 100C.
13) To a solution of 2-(N-methyl-N-benzylamino)ethyl
2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-
dihydropyridine-3-carboxylate (1.5 g) in ethanol (15 ml)
was added sodium borohydride (112 mg) under stirring and
ice-cooling,and this mixture was further stirred for 20
minutes at the same temperature. The reaction mixture was
adjusted with 0.1 N hydrochloric acid to pH 6 to 7 under
ice-cooling, and concentrated under reduced pressure. To
the residue was added ethyl acetate and water, and the
'''
- 83 -

1080~23
aqueous layer was further washed with ethyl acetate twice.
The extract obtained above and the washings were put
together, washed with water, dried over magnesium sulfate,
and concentrated under reduced pressure to give an oil
(1.48 g) of 2-(N-methyl-N-benzylamino)ethyl 2-methyl-4-
(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-
dihydropyridine-3-carboxylate.
, ',
I.R. Spectrum (film)
v (cm 1) : 3390, 1730, 1680, 1650, 1600,
1520, 1460, 1345, 1200, 1100, 1025,
` 900, 780, 740, 700
N.M.R. Spectrum (~: CDCQ3 + D20)
ppm : 1.2 t3H, t, J=7Hz), 2.2 (3H, s),
2.38 (3H, s), 2.66 (2H, t, J~6Hz),
3.53 (2H, s), 3.97 to 4.26 (4H, m),
5.14 (lH, s), 7.28 to 8.15 (lOH, m)
; :
Thus obtained oil was dissolved into diethyl ether,
and 21% ethanolic hydrochloric acid (225 mg) was added
to the solution. A ~recipitating oil substance was
washed with diethyl ether several times by decantation
and pulverized to give powder (540 mg) of 2-(N-methyl-
N-benzylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-
ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-
carboxylate hydroch~oride which began to decompose at
89C with turning to brown.
r , .
'.' .50
'
~ ' .
"
- 84 -
:, . . ~, :
. .

1080Z~3
I. R. Spectrum (Nujol)
(cm 1) : 3300, 2600, 1680, 1525, 1375,
1350, 1200, 1095, 740, 700
14) To a mixture of powder (329 mg) of methyl 4-
(2-chlorophenyl)-5-ethoxycarbonyl-6-formyl-1,4-di-
hydropyridine-3-carboxylate in ethanol (lO ml) was added
sodium borohydride (25.11 mg) under ice-cooling.
After further stirring for 50 minutes, the mixture was
adjusted to pH 4 to 5 with dilute hydrochloric acid.
After removal of the ethanol, water was added to the
residue, which was extracted with thyl acetate.
The ethyl acetate layer was washed wi~h water and dried
and the residual crystals (about 280 mg) were dissolved
:,
in a mixture of diethyl ether and n-hexane and kept in
a refrigerator to give pure crystals (184 mg) of methyl
4-(2-chlorophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-
1,4-dihydropyridine-3-carboxylate, m.p. 187 to 188C.
,
,
' ~ .
'
`
,~,
' 25
:",~
:-``
~ 30
':
- 85 -
, . ' ` ' :

10~UV~ ~ 3
15) To a solution of diethyl 2-methyl-4-(2-
nitrophenyl)-6-[2-~,N-diethylamino)ethyl]iminomethyl-l,
4-dihydropyridine-3,5-dicarboxylate (l.l g) in 99% ethanol
(20 ml) was added sodium borohydTide (115 mg) under stirr-
ing and the mixture was further stirred at room temperature
for 5 hours. The resultant mixture was acidified with
dilute hydrochloric acid. After removing ethanol, water
was added to the residue and the mixture was washed with
diethyl ether. The aqueous layer was basified with an
aqueous solution of sodium bicarbonate and extracted with
ethyl acetate. The extract was washed with water and
dried. The solvent was removed from the extract to give
greenish brown oil (0.8087 g) of a mixture including
diethyl 2-methyl-4-(2-nitrophenyl)-6-[2-~,N-diethylamino)-
ethyl]aminomethyl-1,4-dihydropyridine-3,5-dicarboxylate
(one part) and ethyl 2-methyl-4-(2-nitrophenyl)-5-oxo-6-
[2-(N,N-diethylamino)ethyl]-1,4,5,7-tetrahydropyrrolo[3,
4-b]pyridine-3-carboxylate (one part). After dissolving
the mixture in ethanol, the solution was refluxed for
. .
5 hours. The removal of the solvent gave crystals.
These were recrystallized from ethanol to give yellow
needles (729.9 mg) of ethyl 2-methyl-4-(2-nitrophenyl)-5-
oxo-6-[2-(N,N-diethylamino)ethyl]-1,4,5,7-tetrahydropyrrolo-
[3,4-b]pyridine-3-carboxylate, m.p. 187 to 188C.
16) To a solution of diethyl 2-methyl-4-(2-nitrophenyl~-
6-(2-hydroxyethyl)iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate
-~ (1.2 g) in 95~ ethanol (lS ml) was added sodium borohydride (llS mg) and
- 86 -
. ' .

10~30ZZ3
stirred overnight at room temperature. The resultant
mixture was weakly acidified with dilute hydrochloric acid
and the ethanol was removed from the mixture. The
residue was basified with an aqueous solution of sodium
bicarbonate and then extracted with ethyl acetate.
The extract was washed with water and dried over magnesium
sulfate. The solvent was distilled off to give ~n oil of
diethyl 2-methyl-4-(2-nitrophenyl)-6-(2-hydroxyethyl)-
aminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. This
oil was dissolved in 95% ethanol tl5 ml) and the solution
was refluxed for 3 hours. Ethanol was removed from the
solution to give a red oil. The oil was pulverized and
recrystallized from a mixture of ethanol and diethyl ether
~ to give an orange crystals (0.5998 g) of ethyl 2-methyl-
i5 4-~2-nitrophenyl)-5-oxo-6-(2-hydroxyethyl)-1,4,5,7-
tetrahydropyrrolo-[3,4-b]pyridine-3-carboxylate. The
product was further recrystallized from a mixture of ethanol
and diethyl ether to give puTe pale orange granules, m.p.
210 to 211C.
Example 6
1) To a solution of diethyl 2-methyl-4-(2-chlorophenyl)-
6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(759.7 mg) in dried pyridine was dropwise added a solution
of acetyl chloride ~313.5 mg) in methylene chloride under
cooling and stirring. The mixture was stirred overnight
at room temperature. After removing the solvent, water
was added to the residue, and the mixture was weakly
acidified with dilute hydrochloric acid, and then extract-
; ed with diethyl ether. The extract was washed with an
aqueous saturated sodium chloride solution and water in turn,
- 87 -
' ,

1080ZZ3
and dried. The solvent was removed from the extract to
give viscous oil tO.99 g). The oil was allowed to stand
to pulverize and the crystals were washed with n-hexane
and collected by filtration to give crude product (0.6931 g)
i of diethyl 2-methyl-4-(2-chlorophenyl)-6-acetoxymethyl-1,4-
dihydropyridine-3,5-dicarboxylate. The crude product was
recrystallized from a mixture of diethyl ether and n-hexane to
give the pure product, m.p. 98C.
2) A mixed solution of diethyl 2-methyl-4-(2-
) chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-
dicarboxylate (0.3798 g~, pyridine (0.791 g) and succinic
anhydride (0.1501 g) in dioxane (S ml) was refluxed for 4.5
hours. The resultant solution was concentrated, acidified
with dilute hydrochloric acid and extracted with diethyl
i ether. The extract was washed with dilute hydrochloric
acid and water in turn. The diethyl ether extract was
back-extracted with an aqueous saturated sodium bicarbonate
solution and the aqueous solution was washed with diethyl
ether. The aqueous solution was acidified with dilute
0 hydrochloric acid to precipitate crystals. The crystals
were collected by filtration, washed with water and then
dried to give diethyl 2-methyl-4-(2-chlorophenyl)-6-
t3-carboxypropionyl)oxymethyl-1,4-dihydropyridine-3,5-
dicarboxylate (419.3 mg), m.p. 130 to 131C.
~5 3) To a solution of diethyl 2-methyl-4-(2-chlorophenyl)-
6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(0.7050 g) in pyridine (15 ml) was dropwise added a solution
of ethyl 5-chloroformylpentanoate (0.7706 g) in methylene
chloride under ice-cooling and the mixture was stirred at
iO room temperature for 2.5 hours. After removing the pyridine
. . .
- 88 -

1080Z~3
water was added to residue and the mixture was extracted
twice with ethyl acetate. The extract was washed with
dilute hydrochloric acid, an aqueous sodium bicarbonate
solution and water in turn, and then dried. The solvent
was removed from the extract to give a yellow oii ~1.0996 g)
The oil was pulverized and recrystallized from a mixed
solution of diethyl ether and n-hexane to give coloTless
flakes (0.7311 g) of diethyl 2-methyl-4-(2-chlorophenyl)-
6-~5-ethoxycarbonylvaleryl)oxymethyl-1,4-dihydropyridine-
0 3,5-dicar~oxylate, m.p. 91 to 92C.
4) To a mixture of sodium 3-tN-methyl-N-benzylamino)-
propionate (2.0 g) in diethyl ether (40 ml) was added thionyl
chloride (10 ml) with stirring under ice-cooling. The
resultant mixture was stirred at room temperature for 3
hours,heated under reflux for 2 hours and concentrated under
reduced pressure to give a solid containing 3-(N-methyl-
N-benzylamino)propionyl chloride. A suspension of thus
obtained solid in methylene chloride (5 ml) was added to
a solution of diethyl 2-methyl-4-(2-chlorophenyl)-6-
~0 hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.76 g)
in pyridine (5 ml) with stirring under ice-cooling. The
mixture was stirred for an hour under ice-cooling and con-
centrated under reduced pressure, and water was added to
the residue. The aqueous mixture was extracted with ethyl
Z5 acetate and the extract was washed with water, dried and
concentrated under reduced pressure to give a brown oil
(1.55 g). The oil was subjected to column chromatography
on silica gel with an eluent ~a mixture of 2 parts of
benzene and one part of ethyl acetate by volume] to give ~n
; 30 oily substance. The oily substance was allowed to stand
:,,
- 8~ -

1080223
overnight to give crystals. These crystals were washed
with n-hexane and recrystallized from a mixture of diethyl
ether and n-hexane to give pure crystals of diethyl 2-
methyl-4-(2-chlorophenyl)-6-{3-(N-methyl-N-benzylamino)-
propionyloxy}methyl-1,4-dihydropyridine-3,5-dicarboxylate,
m.p. 86 to 87C.
S) To a mixture of diethyl 2-methyl-4-(2-nitrophenyl)-
6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(2.35 g) in pyridine (30 ml), was dropwise added a solution
o of acetyl chloride (942 mg) in methylene chloride (5 ml)
,
under stirring and ice-cooling over the period of 7
minutes. The mixture was further stirred for 70 minutes
at room temperature. The pyridine was distilled ~ff under
reduced pressure and ethyl acetate was added to the residue.
;l5 The resultant mixture was washed twice with waterand adjusted
to pH 4 with hydrochloric acid and then an aqueous solution
of sodium chloride, dried and concentrated under reduced
pressure to give an oily substance. This oily substance
was crystallized by treating with a mixture of diethyl
; 20 ether and a small amount of n-hexane, and collected crude
crystals (2.5 g) were washed with n-hexane and thus obtained
crystals were recrystallized from diethyl ether to give
pure crystals (1.78 g) of diethyl 2-methyl-4-(2-nitrophenyl)-
6-acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p.
89 to 90C.
6) To a solution of diethyl 2-methyl-4-~3-nitrophenyl)-
,:
6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(l.9S g) in dried pyridine (25 ml) was dropwise added a
solution of acetyl chloride (785 mg) in methylene chloride
(5 ml) under ice-cooling and stirring over the period of
-- 90 --
.'
~'

10802~3
10 minutes. The mix~ure was further stirred for 50
minutes at room temperature. After removing the solvent,
the residue was dissolved in ethyl acetate. The extract
was washed with water five times and an aqueous solution
of sodium chloride in turn, and dried over magnesium
sulfate. The solvent was removed from the extract to
give a red oil (2.47 g). The oil was crystallized by
treating with diethyl ether, and the crystals were washed
with n-hexane and collected by filtration to give crude
crystals (2 g). These crystals were dissolved in diethyl
ether and the mixture was filtered on silica gel. The
filtrate was concentrated under reduced pressure and the
crystalline residue was recrystallized from a mixture of
diethyl ether and n-hexane to give pure crystals (1.45 g)
of diethyl 2-methyl-4-(3-nitrophenyl)-6-acetoxymethyl-
1,4-dihydropyridine-3,5-dicarboxylate, m.p. 133 to 135C.
7) To a mixture of 2-(N-methyl-N-benzylamino)ethyl 2-
methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-
1,4-dihydropyridine-3-carboxylate (630 mg) in pyridine
(lO ml) was added a solution of acetyl chloride (146 mg)
in methylene chloride (3 ml) under stirring and ice-cooling.
The resultant mixture was further stirred at 50 to 60C
for 2 hours. After removing the pyridine, water and
ethyl acetate were added to theresidue and the aqueous
layer was adjusted to pH 4. The organic layer was separated,
dried over magnesium sulfate and concentrated under reduced
pressure to give an oily substance (800 mg). This oily
substance was subjected to column chromatography on silic~
gel with an eluent [a mixture of 2 parts of benzene and 1
part of ethyl acetate by volume] to give an oil (620 mg) of
:
-- 91 --
~ , . .

108V2Z3
2-(N-methyl-N-benzylamino)ethyl 2-methyl-4-(3-nitrophenyl)-
5-ethoxycarbonyl-6-acetoxymethyl-1,4-dihydTopyridine-3-
carboxylate.
I.R. Spectrum ~film)
v (cm 1) : 3370, 1747, 1690, 1650~ 1615, 1530,
1480, 1350, 1210, 1100, 1045, 740,
700
N.M.R. Spectrum (~: CDCQ3+D2O)
ppm : 1.18 (3H, t, J=7Hz), 2.18 (6H, s),
.o 2.36 (3H, s), 2.6 (2H, t, J=6Hz),
3.5 (2H, s), 4.06 (2H, q, J-7Hz),
i 4.15 (2H, t, J=6Hz), 5.13 (lH, s),
5.31 (2H, s), 6.7 (lH, m),
7.23 to 8.08 (9H, m).
L5 Thus obtained oil (580 mg) was dissolved in diethyl
ether, and to the resultant solution was bit by bit added
a diethyl ether solutio~ of maleic acid to give a precipitat-
ing oil. This oil was washed with diethyl ether twice by
decantation and pulverized by n-hexane to give powder
!0 (405 mg) of 2-(N-methyl-N-benzylamino)ethyl 2-methyl-4-
(3-nitrophenyl)-5-ethoxycarbonyl-6-acetoxymethyl-1,4-
dihydropyridine-3-carboxylate maleate) m.p. 58 to 65C.
8) To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-
6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
'5 (1.95 g) in pyridine (25 ml) was dropwise added a solution
of benzoyl chloride (2.0 g) in methylene chloride (5 ml)
over 5 minutes at 5 to 6C with stirring. The resultant
mixture was stirred for 15 minutes at the same temperature
and then at room temperature for 2 hours, and followed by
stirring at 50C for an hour and a half.
:'
- 92
.

1080;~;~3
After the reaction was over, the pyridine was distilled
off and to the residue was added ethyl acetate and water.
The ethyl acetate layer was separated, washed with
dil. hy~rochloric acid twice and then aqueous solution of
sodium bicarbonate, and dried over magnesium sulfate.
The solvent was removed and the residue was soon crystallized
by treating with diethyl ether and collected by filtration.
These crude crystals were washed with a mixture of diethyl
ether and a small amount of ethyl acetate to give crystals,
which was recrystallized from ethyl acetate (25 ml) to
give powders of diethyl 2-methyl-4-(2-nitrophenyl)-6-
benzoyloxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,
m.p. 156 to 157C.
9) To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-
6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(1.95 g) in pyridine (25 ml) was dropwise added over
5 minutes a solution of p-chlorophenoxyacetyl chloride
(3.07 g) in methylene chloride under stirring and ice-cooling.
; The resultant mixture was stirred
overnight under cooling with water at 20C. After removal of
th~ pyridine, water was added to the residue. The precipitated
oily substance was extracted with ethyl acetate. The
extract was adjusted to pH 4 to 5 with dil. hydrochloric
acid, washed each three times with water and then an
aqueous solution of sodium bicarbonate and dried over
magnesium sulfate. The solvent was distilled off and the
residual oil (4.75 g) was subjected to column chromatography
-j on silica-gel using an eluent (benzene : ethyl acetate =
10 : 1) to give an oil (2.65 g) of diethyl 2-methyl-4-(2-
nitrophenyl)-6-(4-chlorophenoxy)acetoxymethyl-1,4-
.. ~
.
- 93 _
,~
- ~ :
- ~ ,

1080223
dihydropyridine-3,5-dicarboxylate, m.p. 86-~8C. (recrystallized
; from a mixture of diisopropylether and ethanol).
N.M.R. Spectrum (CDC13 + D20)
ppm : 1.13 (6H, t, J=7Hz), 2.2 (3H, s),
4.03, 4.08 (4H, q, J=7Hz), 4.73 (2H, s),
5.43 (2H, s), 5.88 (lH, s),
6.53 (lH, broad s), 6.76 to 7.83 (8H, m)
.''
Example 7
Stirring a solution of diethyl 2-methyl-4-(2-
chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-
dicarboxylate (1.1395 g) in dried pyridine (10 ml) at
room temperature, a solution of p-toluenesulfonyl
chloride (629.1 mg) in dried pyridine (10 ml) was dropwise
" 15 added gradually thereto. The resultant mixture was
stirred at room temperature for 1.5 hours and then heated
at 80C for 4.5 hours with stirring. After removal of
the pyridine, water was added to the residue and the
resultant aqueous mixture was acidified with dil.
hydrochloric acid and extracted twice with ethyl acetate.
The extract was washed with dil. hydrochloric acid and
then water, and dried. The resultant brown viscous oil
was purified by column chromatography on silica-gel
using an eluent (benzene : diethyl ether = 1 : 1) to give
an orange oil, which was crystallized by treating with
diethyl ether. The resultant crystals were collected ~y
filtration and recrystallized from a mixture of diethyl ether
and n-hexane to give orange-yellowish prisms (0.1926 g) of
diethyl 2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-
~3d dihydropyridine-3,5-dicarboxylate, m.p. 87 to 88C, which
was identified with an authentic sample.
:
.
- 94 -

1080Z23
Example 8
1) A solution of diethyl 2-methyl-4-(2-nitrophenyl)-
6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (0.9709 g)
and hydrazine hydrate (0.1252 g) in n-propyl alcohol
tlO ml) was stirred at room temperature for 30 minutes.
The resultant mixture contained mainly diethyl 2-methyl-
4-(2-nitrophenyl~-6-hydrazonomethyl-1,4-dihydropyridine-
3,5-dicarboxylate. Then the mixture was refluxed for
6 hours. After allowing to stand the resultant solution
in a refrigerator overnight, the precipitating crystals
were collected by filtration to give ethyl 2-methyl-4-
(2-nitrophenyl)-5-oxo-1,4,5,6-tetrahydro-3-pyrido[2,3-d]-
pyridazine-3-carboxylate (263.9 mg). The product was
recrystallized from a mixture of ethanol and N,N-dimethyl-
formamide to give the pure product, m.p. 279 to 281C.
2) A solution of diethyl 2-methyl-4-(2-chlorophenyl)-
6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(592.5 mg) and p-toluenesulfonic acid (catalytic amount)
in ethanol (6 ml) was refluxed for 4 hours. After the
resultant solution was concentrated, diethyl ether was -~
added to the residue. The precipitating crystals were
collected by filtration to give ethyl 2-methyl-4-(2-
chlorophenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-
3-carboxylate (317.5 mg). The crude product was re-
.. ~. . .
, ~5 crystallized from ethyl acetate to give colorless granules
(210.3 mg), m.p. 211 to 212C.
3) A solution of diethyl 2-methyl-4-(2-thienyl)-6-
hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (400 mg)
and p-~oluenesulfonic acid (catalytic amount) in 99%
ethanol (10 ml) was refluxed with stirring for 2 hours.
. I ,
- 95 -
,

2 ~ ~
After the resultant solution was concentrated, the
residue was pulverized. The powder was recrystallized
from ethyl acetate to give colorless prisms (203.2 mg)
of ethyl 2-methyl-4-~2-thienyl)-5-oxo-1,4,5,7-
tetrahydrofuro[3,4-b]pyridine-3-carboxylate, m.p. 232C.
Example 9
.~ .
1) A mixture of diethyl 2-methyl-4-(2-chlorophenyl)-
6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(379.8 mg) and triphenylphosphine (314.7 mg) in carbon
tetrachloride (5 ml) was refluxed for 3.5 hours. After
the solvent was removed, the residue was dried under
reduced pressure to give diethyl 2-methyl-4-(2-
chlorophenyl~6-ch~oromethyl-1,4-dihydropyridine-3,5-
dicarboxylate. To this residue in 99% ethanol (10 ml)
was added N-methylpiperazine (200 mg) and the solution
was stirred at room temperature for 50 hours. Ethanol
was removed from the reaction mixture and to the
residue was added water. The mixture was extracted
with ethyl acetate. After washing the extract with
water, the extract was back-extracted with dilute hydro-
chloric acid. The aqueous layer was washed with diethyl
ether, basified with an aqueous solution of sodium
bicarbonate, and then extracted with ethyl acetate.
The extract was washed with water, dried and then con-
centrated to give crude crystals (115.2 mg) of diethyl
2-methyl~4-(2-chlorophenyl)-6-(N-methylpiperazin~
methyl-1,4-dihydropyridine-3,5-dicarboxylate. The crude
crystals were recrystallized from a mixture of ethanol
and diethyl ether to give colorless needles, m.p. 179
to 180C.
- 96 -

10802~3
2) A mixture of diethyl 2-methyl-4-(2-chloro~henyl)-
6-hydroxymethyl-1,4-dihytropyridine-3,5-dicarboxylate
(1.1395 g) and triphenylphosphine (1.1803 g) in carbon
tetrachloride (10 ml) was heated under reflux for 2 hours.
~ 5 After removing the solvent under reduced pressure, the
- residue was dissolved in 99% ethanol (20 ml). To the
solution was added N-(2-hydroxyethyl)piperazine (859 mg)
and the mixture was heated at 70 to 75C for 8 hours.
The resultant mixture was concentrated under reduced
pressure and the residue was dissolved in ethyl acetate.
The solution was washed with water and then back-extracted
with an aqueous dilute hydrochloric acid. The aqueous
layer was washed with diethyl ether, alkalized with sodium
bicarbonate and then extracted with ethyl ~etate. The
lS extract was washed with water, dried over magnesium sulfate
and concentrated under reduced pressure to give crude
crystals (560 mg). These were recrystallized from a
mixture of ethanol and diethyl ether to give pure crystals
(80 mg) of diethyl 2-methyl-4-(2-chlorophenyl)-6-[N-
, 20 (2-hydroxyethyl)piperazin-1-yl]methyl-1,4-dihydropyridine--3,
S-dicarboxylate, m.p. 145 to 147C.
3) A mixture of 2-chloroethyl 2-methyl-4-(3-nitrophenyl)-
5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-
carboxylate (8.5 g), N-methylbenzylamine (2.70 g) and
triethylamine (2.6 g) in ethanol (40 ml) was heated under
reflux for 56 hours. After removing the ethanol, the
residue was dissolved in a mixture of ethyl acetate and water.
1 The organic layer was separated and washed with water,
"~,! dried over magnesium sulfate and concentrated under reduced
pressure to give an oil (11 g). The oil was subjected to
'
-- 97 --
. .. .
'''"

108VZZ3
column chromatography on silica gel with an eluent
[a mixture of 10 parts of benzene and one part of
diethyl ether by volume] to give an oil (7.35 g) of
2-(N-benzyl-N-methylamino)ethyl 2-methyl-4-(3-
nitrophenyl)_5-ethoxycarbonyl-6-diethoxymethyl-1,4-
dihydropyridine-3-carboxylate.
I.R. Spectrum (film)
(cm 1) : 3400, 1700, 1690, 1610, 1523,
1475, 1350, 1275, 1197, 1092,
lOS5, 755, 698
N.M.R. Spectrum (~: CDC13 + D20)
ppm : 1.21 (9H, t, J=7Hz), 2.21 (3H, s),
2.36 (3H, s), 2.63 (2H, t, J=6Hz),
3.5 (2H, s), 3.65 (2H, q, J=7Hz),
3.66 (2H, q, J=7Hz), 4.1 (2H, q),
4.18 (2H, t, J=6Hz), 5.18 (lH, s),
6.2 (lH, s), 6.86 (lH, s), 7.16 to 8.16
(4H, m)
4) A miXture of 2-chloroethyl 2-methyl-4-(3-
nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-
dihydropyridine-3-carboxylate (2.0 g), diethylamine (1.75
g) and sodium iodide t60.3 mg) in n-propylalcohol (4 ml)
was refluxed for 17 hours. After removal of the solvent
;', .
from the reaction mixture, water and ethyl acetate were
added to the residue. The ethyl acetate layer was washed
twice with water, dried over magnesium sulfate, and
concentrated to give a brown oil (2.46 g) of 2-(N,N-
diethylamino)ethyl 2-methy~-4-(3-nitrophenyl)-5-
ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-
carboxylate, which was identified by converting to the
-98-
.. ..... , ................. ~
:

108V2Z3
corresponding 6-formyl compound (oil) and then to the
corresponding 6-cyano compound, m.p. 150 to 152C.
5) A mixture of 2-chloroethyl 2-methyl-4-(3-
nitrophenyl)-S-ethoxycarbonyl-6-diethoxymethyl-1,4-
dihydropyridine-3-carboxylate ~1.491 g) and potassium
carbonate (456.1 mg) in ethanol (30 ml) was refluxed
for 6.5 hours. After removal of the ethanol, the
residue was extracted with ethyl acetate. The ethyl
acetate layer was washed twice with water and dried, and
the solvent was distilled off to give a viscous oil
(1.47 g). This oil was purified by column chromatography
and the resultant oil (0.82 g) was crystallized and
recrystallized from diisopropyl ether to give yellow
granules (0.60 g) of 2-hydroxyethyl 2-methyl-4-(3-
nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-
dihydropyridine-3-carboxylate, m.p. 98 to 100C.
A mixture of the granules (1.46 g) obtained in Example 1-12
and potassium carbonate (0.41 g) in 80% ethanol (20 ml)
was refluxed for 6.5 hours. After removal of the ethanol,
water was added to the residue, and t~e mixture was acidified
with dilute hydrochloric acld and extracted with ethyl
acetate. The extract was washed three times with water,
dried, and concentrated to give a brown oil tl.54 g).
Thus obtained oil was subjected to column chromatography
on silica gel with an eluent (a mixture of five parts
of benzene and two part of ethyl acetate by volume), and
the fraction containing the designated substance was con-
centrated to give a reddish oil (1.31 g) of 2-hydroxyethyl
2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-
1, 4-dihydropyridine-3-carboxylate.
_ 99 _
. . ~

1080ZZ3
I.R. Spectrum (film)
v (cm 1) : 3530, 3410, 3360 (shoulder),
1706 (shoulder), 1697, 1690 (shoulder),
1532, 1480, 1356, 1275, 1208, 1100,
~05, 860, 832, 785
N.M.R. Spectrum (~, CDCQ3)
ppm : 1.0 to 1.45 (9H, m),
2.39 ~3H, s),
2.2 to 2.73 (lH, broad),
3.4 to 4.5 (lOH, m)
~; ~) A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-
6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (388.37 mg),
ethylene glycol (186.21mg) and p-toluenesulfonic acid
(catalytic amount) in absolute benzene (5 ml) was refluxed
for 45 minutes under azeotropic dehydration. The reaction
mixture was allowed to stand and washed twice with an
aqueous solution of sodium bicarbonate. After removal of
l the solvent, the residue immediately turned into crystals.
;, Thus obtained crystals were recrystallized from a mixture
~20 ~f ethanol and diisopropyl ether to give yellow pure
crystals (0.32 g) of diethyl 2-methyl-4-(2-nitrophenyl)-
6-ethylenedioxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,
m.p. 152 to 153.5C.
, I
.
3o
..
:;,.' . - ' ~ ' .: . .

1080ZZ3
7) A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-
hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(1.9518 g) and triphenylphosphine (1.4425 g) in carbon
; tetrachloride 120 ml) was refluxed for 5 hours. After
removal of the solvent, the residue was added to water and
extracted with ethyl acetate. The extract was washed with
water and dried. Removal of the solvent gave an orange-yellow
oil (3.63 g). This oil was subjected to column chromatography
on silica gel with an eluent (benzene : ethyl acetate = 5 : 2)
to give an oil (517 mg) of diethyl 2-methyl-4-(2-nitrophenyl)-
6-chloromethyl-1,4-dihydropyridine-3,5-dicarboxylate.
8) To a solution of an oil (517 mg) of diethyl 2-methyl-
;~ 4-(2-nitrophenyl)-6-chloromethyl-1,4-dihydropyridine-3,5-
dicarboxylate in 95% ethanol (1 ml) was added sodium
cyanide (93 mg), and the resultant mixture was stirred at
room temperature for 2 hours. Addition of water to the
reaction mixture precipitated an oil. The oil was extracted
twice with ethyl acetate, and the organic layer was washed
with water twice and with a saturated solution of sodium
~, 20 chloride and dried. Removal of the solvent gave a foamy oil
(0.42 g), which was subjected to column chromatography on '
silica gel with an eluent (benzene : ethyl acetate = 5 : 2)
to give a reddish orange oil (0.2783 g) of diethyl 2-methyl-
4-(2-nitrophenyl)-6-cyanomethyl-1,4-dihydropyridine-3,5-
dicarboxylate.
:,:
I.R. Spectrum (liquid)
~ (cm 1) : 2210
Example 10
. 1) To a mixture of 2-allyloxybenzaldehyde (8.11 g) and
ethyl 4~4-diethoxyacetoacetate (12.00 g) in benzene (about 31 ml)
'
, :
,
-- 101 --
- .
. ~ ~ : .-

1080ZZ3
was added acetic acid (0.36 g) and to the resultant mixture
was added each one third portion of piperidine (0.51 g) in
benzene (about 4 ml) with an interval of 20 minutes. After
refluxing for 2.5 hours the mixture was cooled to room
temperature and benzene (50 ml) was added thereto. The
resultant mixture was washed three times with water and
- dried over magnesium sulfate. Removing of the solvent,
a red oil was gained and to this oil was added ethyl 3-
`~ aminocrotonate (8.56 g). The resultant mixture was warmed
~0 at 55 to 60C for 6.5 hours under stirring and further for
2 hours at 72 to 75C and finally for 2.5 hour at 105 to
107C. The reaction mixture was subjected to column
chromatography on silica gel with an eluent to give an oil
(19.38 g) from the eluate. The oil (3.0 g) was further
, 15 purified on silica gel column chromatography with an eluent
, (benzene : ethyl acetate = 20 : 1) to give an oil (1.77 g)
~,, of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-diethoxymethyl-
1,4-dihydropyridine-3,5-dicarboxylate
I.R. Spectrum (liquid)
~20 ~ (cm 1) : 3430, 1695, 1650, 1618, 1490, 1371,
;i~ 1280, 1095, 930, 760
N.M.R. Spectrum (~ , CDC13)
ppm : 1.0 - 1.5 (12H, m), 2.28 (3H, s), 3.4 - 4.3 (8H, m),
5.35 (lH, s), 6.17 (lH, s), ca 4.5, ca 5-5.6,
ca 5.7-6.4 (5H, m), 6.5 - 7.4 (5H, m)
`~ 2) To a solution of diethyl 2-methyl-4-(2-allyloxyphenyl)-
6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.5 g)
in acetone (15 ml) was added 6N-hydrochloric acid (15 ml)
with stirring and the resultant mixture was further stirred
for an hour and 45 minutes at room temperature. The solvent
.
~'
- 102 -
'' , : ..
. . .

1080Z~3
was removed, and addition of water to ~he reqidue resulted
a yellowish suspension with precipitation of an oil, which
was immediately solidified. After being allowed to stand
for about 10 minutes, the precipitated solids were collected
~ 5 by filteration and washed with water and dried. Thus obtained
Y crude crystals were recrystallized from a mixture of
diisopropyl ether and acetone to give orange-yellow granules
` of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-formyl-1,4-
dihydropyridine-3,5-dicarboxylate, m.p. 129 to 131C.
~ ~ 10 3) A mixture of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-
r formyl-1,4-dihydropyridine-3,5-dicarboxylate (4.53 g),
hydroxylamine hydrochloride (866.9 mg), sodium acetate
~r (1. 2093 g) in acetic acid was stirred at room temperature
for an hour. Acetic anhydride (3.5 ml) was added to the
r~ 15 mixture and the resultant mixture was stirred at 93 to 98C
~ ~ for 3 hours. The acetic acid was distilled off under reduced
¦ pressure, and the residue was neutralized with a saturated
aqueous solution of sodium bicarbonate and extracted twice
with methylene chloride. The extract was washed with water
twice and dried. Removal of the solvent gave a brown oil
(6.42 g), which was immediately crystallized. The crystals
~:
were pulverized with diisopropyl ether to give yellow powder
(3.21 g), which was recrystallized from 90~ methanol to give
orange-yellow crystals of diethyl 2-methyl-4-(2-allyloxyphenyl)-
6-cyano-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 143 to
145C-
4) To a solution of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-
formyl-1,4-dihydropyridine-3,5-dicarboxylate (4.70 g) in
ethanol (100 ml) was gradually added at 4C sodium borohydride
(445.2 mg) and the resultant mixture was stirred at 4C
~r ;`
r ~ 10 3
,,~

` 1080223
for 1.5 hours under ice-cooling. The reaction mixture was
acidified with 50% acetic acid and ethanol was removed. To
the residue was added water and the aqueous mixture was
stirred for 10 minutes. The powder was collected by filtration
and washed with water to give crude crystals (4.49 g), which
were recrystallized from methanol to give yellow crystals
of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-hydroxymethyl-1,4-
dihydropiridine-3,5-dicarboxylate, m.p. 124 to 126C.
' 10
'
~ .
~:~ 30
:
~ - 104 -
~ .
. ' .

`-" 1080'~3
SUPPLEMENTARY DISCLOSURE
This disclosure and the principal disclosure relate
to new 1,4-dihydropyridine derivatives and their preparation
This disclosure is especially concerned with a sub-
group of 1,4-dihydropyridine derivatives within the scope of
the principal disclosure.
AS described in the principal disclosure the new 1,4-
dihydropyridine derivatives have vasodilating and anti-
hypertensive activity and pharmaceutical compositions con-
taining them can be used for therapeutical treatment in cardio-
vascular diseases and hypertension in human being.
. . .
Accordingly, one object of this invention is to
provide~ne~l and useful 1,4-dihydropyridine derivatives.
Another object of this invention is to provide
orocesses or the preparation of 1,4-dihydropyridine
derivatives.
A further object of this invention is to orovide
useful pharmaceutical composition comprising said 1,4-
dihydropyridine derivatives as a vasodilator and anti-
; 20 hypertensive.
Still further object of the present invention is
to provide a therapeutical method for treating cardiovascu-
lar diseases such as coronary insufficiency, angina pectoris
or myocardial infarction and hypertension.
The 1,4-dihydropyridine derivatives of this dis-
closure may be represented by the formula:
R2 ~ R3 (I)
H
- 105 _
: '

- 11)80~,Z3
wherein
Definition (i);
Rl is cyano, lower alkoxycarbonyl or lower alkylsulfamoyl,
R2 and R3 are each, same or different, esterified carboxy,
and
one of R4 and R5 is lo~er alkyl and
the other is cyano or substituted lower alkyl in ~hich
the substituent is cyano, hydroxy, hydroxyimino or oxo
wherein thus formed carbonyl may be protected ~ith
suitable protecting group,
or
Definition (ii);
. Rl is 2-nitro,
R2 is methoxycarbonyl, ethox~tcarbonyl or isopropxycarbonyl,
R3 is methoxycarbonyl,
R4 is methyl and
R5 is dimethoxymethyl, for~yl, hydroxyiminomethyl, cyano
or hydroxymethyl,
or
Definition (iii)
Rl is 3-nitro,
R~ and R3 are each methoxycarbonyl or
R2 is 2-ben~yloxyethoxycarbonyl and P~3 is ~thoxycarbonyl,
R~ is methyl and
25 R5 is dimethoxymethyl, formyl, hydroxyim nomethyl, cyano
or hydroxymethy.l,
or
Definition (iv);
Rl is 2-nitro,
R2 is 2-benzyloxyethoxycarbonyl,
. - 106 -

108V2;~3
R3 is ethoxycarbonyl,
R4 is meth~l and
R5 is hydroxymethyl.
The terms used in the definitions of the symbols
of the formulae given in this specification and claims are
explained as follows:
The term "lower" used in connection with an
alkane moiety such as alkyl is intended to mean the one
having 1 to 8 carbon atoms:-
Accordingly, (1) lower alkyl group and lower
alkyl moiety may be the ones having a straight or branched
and saturated hydrocarbon chain such as methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neo-
pentyl, hexyl, heptyl , octyl and the like;
(2) lower alkoxycarbonyl may be methoxycarbonyl, ethoxy-
carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbo-
nyl, t-butoxycarbonyl and the like; and
(3) lower alkylsulfamoyl may be methylsulfamoyl, ethylsul-
famoyl, propylsulfamoyl, isopropylsulfamoyl, butylsulfamoyl,
pentylsulfamoyl and the like.
Esterified carboxy for R2 and R3 includes prefer-
ably lower alkoxycarbonyl as mentioned above; halo(lower)
alkoxycarbonyl such as the halogenated analogues of above-
mentioned lower alkoxycarbonyl (e.g., 2-bromoethoxycarbonyl,
~25 2-chloroethoxycarbonyl, 2 (or 3)-chloropropoxycàrbonyl,
2 (or 3)-bromopropoxycarbonyl, 2,2-dichloroethoxycarbonyl
or 2,2,2-trichroloethoxycarbonyl); hydroxy(lower)alkoxy-
carbonyl such as 2-hydroxyethoxycarbonyl or 2(or 3)-
hydroxypropoxycarbonyl; lower alkoxy(lower)alkoxycarbonyl
such as 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl or
---107 _
':,

)
lV802;~3
2(or 3)-methoxy(or ethoxy)propoxycarbonyl; substituted-
or unsubstituted aryloxycarhonyl such as ~henoxycarbonyl,
tolyloxycarbonyl, xylyloxycarbonyl or p-chlorophenoxy-
: carbonyl; substituted- or unsubstituted ar(lower)alkoxy-
; 5 carbonyl such as benzyloxycarbonyl, p-bromobenzyloxycarbo-
nyl, o-methoxybenzyloxycarbonyl or phenethyloxycarbonyl;
ar(lower)alkoxy(lower)alkoxycarbonyl such as 2-~benzyloxy)-
ethoxycarbonyl or 2(or 3)-(benzyloxy)propoxycarbonyl;
aryloxy(lower)alkoxycarbonyl such as 2-(phenoxy)ethoxy-
carbonyl or 2(or 3)-(phenoxy)propoxycarbonyl; N- or N,N-
(di)substituted amino(lower)alkoxycarbonyl such as N- or
N,N-(di)-(lower)alkylamino(lower)alkoxycarbonyl (e.g.
l(or 2)-lN-methyl(or N, N-dimethyl)amino]ethoxycarbonyl,
3(or 2)-(N,N-dimethylaminopropoxycarbonyl), l(or 2)-
l 15 [N-ethyl(or N,N-diethyl)amino]ethoxycarbonyl, or l(or 2)-
i,~ (N-methyl-N-ethylamino)ethoxycarbon~l or N-lower alkyl-
~ N-ar(lower)alkylamino(lower)alkoxycarbonyl (e.g. N-methyl-
;, N-benzylaminoethXYcarbnyl ) and the like, and further
R2 and R3 may be same or different.
Lower alkyl substituted with oxo includes lower
alkanoyl such as formyl, acetyl, propionyl, butyryl, iso-
butyryl, valeryl, isovaleryl or pivaloyl and lower alkanoyl-
; (lower)alkyl such as formylmethyl, acetonyl, 2-formylethyl,
3-formylpropyl or butyrylmethyl. The carbonyl function
of said lower alkyl substituted with oxo may be protected
with suitable protecting group conventionally employed for
protecting carbonyl, and thus protected carbonyl group in
this invention means a protected carbonyl group such as
acetal, cyclic-acetal, thioacetal, cyclic-thioacetal,
` 30 cyclic-monothioacetal or acylal. Examples of these lower
.'~
, ,
~ - 108 -
.

108VZ;~3
alkyl containing such protected carbonyl group are gem-
(lower)alkoxy(lower)alkyl (e.g. dimethoxymethyl, 1,1- .
- dimethoxyethyl, diethoxymethyl, dipropoxymethyl, 2,2-
diethoxyethyl or 2,2-diethoxypropyl); gem-lower alkylenedi-
oxy(lower)alkyl (e.g. 1,3-dioxolan-2-yl, 2-methyl-1,3-
dioxolan-2-yl, 4-methyl-1,3-dioxolan-2-yl, 4,5-dimethyl-1,
3-dioxolan-2-yl, 1,3-dioxan-2-yl, 2-methyl-1,3-dioxan-2-yl,
1,3-dioxolan-2-ylmethyl, 2-methyl-1,3-dioxolan-2-ylmethyl
or 3-(1,3-dioxolan-2-yl)propyl); gem-di(lower)alkylthio-
(lower)-alkyl (e.g. dimethylthiomethyl, l,l-dimethylthio-
ethyl, diethylthiomethyl or 2,2-diethylthioethyl); gem-
lower alkylenedithio(lower)alkyl (e.g. 1,3-dithiolan-2-yl,
2-methyl-1,3-dithiolan-2-yl, 4-methyl-1,3-dithiolan-2-yl,
4,5-dimethyl-1,3-dithiolan-2-yl, 1,3-dithian-2-yl, 2-
methyl-1,3-dithian-2-yl, 1,3-dithiolan-2-ylmethyl, 2-
methyl-1,3-dithiolan-2-ylmethyl or 3-(1~-dithiolan-2-yl)-
propyl); and gem-di(lower)alkanoyloxy(lower)alkyl (e.g.
diacetoxymethyl, l,l-diacetoxyethyl, dipropionyloxymethyl
or 2,2-dipropionyloxyethyl); 5 or 6-membered saturated
1-oxa-3-thioheterocyclic-1-yl(lower)alkyl (e.g. 1,3-oxa-
thiolan-2-yl, 2-methyl-1,3-oxathiolan-2-yl, 4-methyl-1,3-
oxathiolan-2-yl, 4,5-dimethyl-1,3-oxathiolan-2-yl, 1,3-
oxothian-2-yl, 2-methyl-1,3-oxothian-2-yl, 1,3-oxathiolan-
2-ylmethyl, 2-methyl-1,3-oxathiolan-2-ylmethyl or 3-(1,3-
oxathiolan-2-yl)propyl).
According to the present invention, 1,4-dihydro-
pyridine derivatives (I) can be prepared by the following
processes :
(I Construction of fundamental structure)
1. Ring formation of 1,4-dihydropyridine nucleus.
,'~ .
-- 109 -
': '

10~302;~3
(II Transformations of functional group)
: 2. Hydrolysis for removal of protecting group
of protected carbonyl group
3. Condensation to form imino-function
4. Dehydration
. 5. Reduction of oxo-function
Each of these processes will be hereinfafter illustrated.
1. Ring formation of 1,4-dihydropyridine nucleus.
Some of the object compound (I) represented by
the following formula:
R2 ~ R3 (I-l)
R4 N R5a
wherein,
~ Definition (i)-l;
:~ Rl, R2 and R3 are each as defined in the above Definition
~i), and
: one of R4a and R5a is lower alkyl and
. 20 the other is lower alkyl substituted with oxo
wherein thus formed carbonyl is protected with suitable
protecting group, or
Definition (ii)-l or (iii)-l;
Rl R2 and R3 are each as defined in the above Definition
(ii) or (iii) and
R4a is methyl and
R5a is dimethoxymethyl,
can be prepared by carrying out one of the reactions of the
processes, which comprises
(1) reacting a compund of the formula:
-- 110 --
" ' " ' '

1080~3
~ - CH = C - CO - R5 (II)
i 1 R3
with an amino
compound of the formula:
R4a - f = CH R2 (III)
NH2
(2) subjecting a mixture of an aldehyde comuound of the
formula:
CHO
Rl (II'~
. an ester of ~-ketonic acid of the formula:
Rsa ~ COCH2 - R3 (II ")
and an amino compound (III) to reaction, or
. (3) reacting an acetylene compound of the formula:
, R2 ~ C - C - R4a (III')
w~th~ammonia or an ammonium salt and a compound (II~.
n Rl~ R2~ R3, R4a and R5a are each as defined
' 20 in the above Definition (i)-l, (ii)-l or (iii)-l.
~; . The starting compound (II) used in the reactions
(1) and (3) is novel and can be prepared by reacting the
aldehyde (II') with the ~-ketonic acid ester (II'') in a
conventional manner, and the ammonium salt used in the
s 25 reaction (3) includes an inorganic ammonium salt such as
ammonium chloride or ammonium sulfate, or an organic
ammonium salt such as ammonium acetate.
~,
Regarding the reactions (1) and (3), the starting
compound (II) may include geometric isomers such as cis-
, 30 trans isomers due to the double bond in its molecule.
, ~ .
--111 --
-

108()2Z3
Such cis-trans isomers may be equilibrated and, therefore,
each or a mixture of the isomers of (II) may be applied
as the starting materials to provide the same object
compound (I-l).
S The reactions (1), (2) and ~3) can be carried
out at ambient temperature or under warming or heating with
or without a suitable solvent such as benzene, toluene,
xylene, chloroform, carbon tetrachloride, methylene chlo-
ride, ethylene chloride, methanol, propanol, butanol,
water or other conventional solvents. The reactions can
be usually accelarated in the presence of an agent such as
an acid (e.g. acetic acid), a base (e.g. pyridine or pico-
line) or in a conventional buffer solution. These agents
act as a reaction accelarator and may be used as a solvent
when they are in liquid. The reactions can be also
accelerated by heating. The reaction condition may vary
according to the kind of the reactants to be used.
2. Hydrolysis for removal of protecting group
of protected carbonyl group.
The compound of the formula:
' , ~1'
~ 2)
2 ~ 3
R4b-- N 5b
wherein
Definition (i)-2;
Rl, R2 and R3 are each as defined in the above Definition
(i) and
one of R4b and Rsb is lower alk~l and
~30 the other is lower alkyl substituted with oxo, or
- 112 -

1080223
Definition (ii)-2 or (iii)-2;
Rl, R2 and R3 are each as defined in the above Definition
(ii) or (iii) and
R4b is methyl and
25b is formYl~
can be prepared by hydrolyzing the compound (I-l).
The starting compound (I-l) can be obtained by
the above-mentioned ring-formation process.
In this process, the protecting group(s) of the
carbonyl function on the lower alkyl group for R4a or R5a
of the compound (I-l) is removed off by hydrolysis to
generate the carbonyl function.
Hydrolysis may be carried out in a conventional
manner and, for example, removal of the acetal-type and
cyclic acetal-type protecting groups is preferably carried
out by an acidic hydrolysis, i.e. in the presence of an
.
acid such as an inorganic acid (e.g. hydrochloric acid or
; sulfuric acid) or an organic acid (e.g. formic acid, acetic
acid, trifluoroacetic acid or p-toluenesulfonic acid;
:: 1
removal of the protecting groups of thioacetal-type,
cyclic thioacetal-type and cyclic monothioacetal type is
....
', preferably carried out by hydrolysis in the presence of a
heavy metal salt such as mercuric chloride or copper
chloride; and removal of the acylal-type protecting group
.,
is preferably carried out by the above mentioned acidic
hydrolysis or a basic hydrolysis, i.e. in the presence of
":,
a base such as an inorganic base (e.g. sodium hydroxide,
potassium hydroxide, sodium carbonate or potassium carbon-
'- ate) or an organic base (e.g. sodium methoxide, sodium etho-
xide, potassium methoxide, potassium ethoxide, pyridine or
.,`
- 113 -
.. :; , . ~ , : .'

108()2Z3
picoline). These hydrolysis may be carried out in a suitable
conventional solvent such as water, acetone, methyl ethyl
ketone, dioxane, ethanol, methanol, ~,N-dimethylformamide,
N-methylmorpholine or dimethylsulfoxide, an optional mixture
with water or a buffer solution thereof. The reaction
temperature is not restrictive, and the reaction is usually
conducted under cooling, at room temperature or under some-
what elevated temperature.
3. Condensation to form imino function
The compound of the formula:
~ Rl
~ 3)
R4 ~ 5c
wherein
: Definition (i)-3;
Rl, R2 and R3 are each as defined in the above Definition
(i) and
one of R4c and RsC is lower alkyl and
the other is hydroxyimino(lower)alkyl, or
Definition (ii)-3 or (iii)-3;
Rl, R2 and R3 are each as defined in the above Definition
(ii) or (iii) and
R4c is methyl and R5c is hydroxyiminomethyl,
. 25 can be prepared by reacting the compound (I-2) with
hydroxylamine or a salt thereof.
. According to this process the oxo group (=O) in
R4b or R5b of the starting compound (I-2) is replaced by
the hydroxyimino group (=N-OH).
~ 30 The starting compound (I-2) can be obtained by
:
,i~ -- 11~ --
..~, . . .
~.

10~(~2~3 .
the above-mentioned hydrolvsis ~rocess.
Preferable salt of hydroxylamine may be a
salt with an acid such as an inorganic acid (e.g. hydro-
chloric acid or sulfuric acid) or an organic acid (e.g.
acetic acid).
The reaction is carried out in a usual manner,
for example, in the presence of a catalyst such as an
acid (e.~. hydrochloric acid, hydrobro~ic acid, sulfuric
acid, formic acid, acetic acid, p-toluenesulfornic acid,
boron trifluoride, silicon tetrachloride or titanium
tetrachloride); in a basic condition realized by using
the free hydroxylamine; or an acidic or basic conventional
buffer solution, and usually in a suitable conventional
solvent such as water, dioxane, ethanol, methanol or
dimethylformamide or an optional mixture with water thereof.
The reaction temperature is not restrictive, and
the reaction is usually carried out under cooling, at room
temperature or under somewhat elevated temperature.
4. Dehydration
The compound of the formula:
R4d ~ 5d (I-4)
H
wherein
Definition (i)-4;
Rl, R2 and R3 are each as defined in the above Definition
(i) and
one of R4d and R5d is lower alkyl and
the other is cyano or ~-cyano(lower)alkyl, or
- 115 -
. ~

~08()223
Definition (ii)-4 or (iii)-4
Rl, R2 and R3 are each as defined in the above Definition
(ii) or (iii) and
R4d is methyl and R5d is cyano,
can be prepared by treating the compound of the formula:
R 4c ~ R'5c (I-3~)
H
wherein
Definition (i)-3';
Rl, R2 and R3 are each as defined in the above Definition
(i) and
one f R'4c and R'sc is lower alkyl and
the other is ~-hydroxyimino(lower)alkyl, or
Definition (ii)-3' or (iii)-3';
Rl, R2 and R3 are each as defined in the above Definition
(ii) or (iii) and
R'4c is methyl and
R'5c is hydroxyiminomethyl,
with a dehydrating agent.
The starting compound (I-3') can be obtained by
the above-mentioned condensation process.
Suitable example of the dehydrating agent includes
-i 25 organic or inorganic conventional ones such as an acid (e.g.
sulfuric acid, phosphoric acid, polyphosphoric acid, formic
acid, acetic acid, ethane sulfonic acid or p-toluene sulfonic
acid), an acid anhydride (e.g. acetic anhydride, benzoic
anhydride or phthalic anhydride), an acid halide (e.g.
acetyl chloride, benzoyl chloride, trichloroacetyl chloride,
. ~ .
~ - - 116 -
: .
.

~0802Z3
mesyl chloride,tosyl chloride, ethyl chloroformate or
phenylchloroformate), an inorganic halogen compound (e.g.
thionylchloride, phosphorus pentachloride, phosphorus
oxychloride, phosphorus tribromide, stannic chloride or
titanium tetrachloride), a carbodiimide (e.g. N,N'-dicyclo-
hexylcarbodiimide or N-cyclohexyl-N'-morpholinoethylcarbo-
diimide), N,N'-carbonyldiimidazole, pentamethyleneketene-
N-cyclohexylimine, ethoxyacetylene, 2-ethyl-7~hydroxyisoxa-
zolium salt, another phosphorus compound (e.g. phosphorus
pentoxide, polyphosphoric acid ethylester, triethylphosph-
ate or phenylphcsphate) and the like. When an acid is used
as the dehydrating agent, the reaction may be conveniently
`' conducted in the presence of its alkali metal salt (e.g.
sodium salt or potassium salt), or the like.
This reaction is usually carried out in a
~` conventional solvent such as diethyl ether, dimethylform-
amide, pyridine, acetic acid~ formic acid, benzene, carbon
tetrachloride, chloroform, methylene chloride, tetrahydro-
furan, dioxane, and the like, and usually carried out at
room temperature or under heating, and the reaction
temperature is not restrictive to the above.
This dehydration process can be also carried out
successively to the foregoing condensation process without
any isolation of the compound (I-3'). This case is also
included in the scope of this invention.
5. Reduction of oxo-function
The compound of the formula:
[~3 R
30R4e_ ~ R5e (I-5)
H
~ .
~ - 117 -
,

108V223
wherein
Definition (i)-5;
Rl, R2 and R3 are each as defined in the above Definition (i) and
one of R4e and R5e is lower alkyl and
the other is hydroxy(lower)alkyl, or
Definition tii)-5, (iii)-5 or ~iv)-5;
Rl, R2 and R3 are each as defined in the above Definition
tli) (iii~ or (iy) and
e ~s methyl and
Rse is hydroxymethyl, ~ ~ ~ ~
LO can be prepared by reducing the compound (1-2).
The starting compound (I-2 ) can be prepared by
the above-mentioned hydrolysis process.
The reduction can be carried out by a convention-
al manner for reduction of oxo function to hydroxy, for
S example, reduction with a reducing agent such as an alkali
; 1 metal borohydride (e.g. lithium borohydride, sodium boro-
~1 hydride, potassium borohydride or sodium cyanoborohydride)
.
.. . .. . .. _, ~.. . _ ,__ . ... ..... _ _ _.. .. _ . _ _ , . _ . _ , , ,. _ .. . . . . _ . ....
i.:
. .
. ... .
!, ,
1 .
.: .
.. .. . . . . . . .
'':: . . . :
., :~ , ~ . , -
:, . . ' , ~ ' ' ;
, . . :'
::

10~0~3
or catalytic reduction for which catalyst may be palladium
carbon, palladium chloride or rhodium carbon and the like
in a suitable conventional solvent. Examples of such
solvents are water, methanol, ethanol, isopropanol, di-
S methylformamide, and the like. The reaction temperature
is not restrictive, and the reaction is usually carried
out under cooling, at room temperature or at somewhat
elevated temperature. And, the method of reduction may
be optionally selected according to the kind of the start-
ing compound (I-2 ).
In accordance with the present invention, the
product which is given during the reaction can be separat-
` ed and isolated from the reaction mixture by methods
;~ commonly used for this purpose, and may be subjected to
routinely used purification procedures, for instance, to
recrystallization from an appropriate solvent or a mixture
of such solvents.
The compound (I) thus obtained wherein R2 and
R3 are not just same each other, includes stereoisomers
due to the presence of at least one asymmetric carbon atom
at the fourth position of the 1,4-dihydropyridine nucleus
and can exist as each optical isomer or a racemic mixture.
The racemic compound can be resolved into each optical
isomer by a conventional method for racemic resolution
such as a resolution by fractional recrystallization of a
salt of the racemic compound with a conventional optically
active acid (e.g. tartaric acid or camphor sulfonic acid,
etc.)~
The compound (I) is possessed of vasodilating
activity and useful for therapeutical treatment in
- 119 -
. .~' . . .
, i .

~0802~3
hypertension and cardiovascular diseases such as coronary
insufficiency, angina pectoris or myocardial infarction.
For therapeutical purpose, the 1,4-dihydropyrid-
ine (I) is administered in oral daily dose o~ 0.1 to 500
mg, preferably 1 to 50 mg.
The compositions of this invention comprise ,
as an active ingredient, the 1,4-dihydropyridine derivati-
ves (I) in an amount of about 0.01 mg. to about 500 mg.,
preferably about 0.1 mg. to about 250 mg. per dosage unit
1 10 for oral and parenteral use.
i One skilled in the art will recognize that in
determining the amounts of the active ingredient in the
dosage unit form, the activity of the ingredient as well
~ l as the size of the host animal must be considered. For
; ~ 15 administration purpose of this pharmaceutical composition,
the active ingredients may be usually formed as tablet,
granule, powder, capsule, suppository, suspension ,
¦ solution and the like. A pharmaceutical carrier or dilu-
ent includes solid or liquid non-toxic pharmaceutically
acceptable substances. Exemplar of solid or liquid carri-
I ers or diluents are lactose, magnesium stearate, terra
alba, sucrose, corn starch, talc, stearic acid, gelatin,
agar, pectin, acacia, peanut oil, oilve oil or sesame oil,
;~ cacao butter or the like. Similarly, the carrier or dilu-
ent may include a time delay material such as glyceryl
monostearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be
employed. Thus, if a solid carrier is used, the preparat-
ion can be tabletted, placed in a hard gelatin capsule or
in the form of a troche or lozenge.
- 120 -
~ .
, . . .

1080ZZ3
- The pharmacological activity of the 1,4-dihydro-
pyridines of the formula (I) is demonstrated by standard
procedures, that is, by administering intravenously the
following test 1,4-dihydropyridines to dogs anesthetized
with pentobarbital and recording the coronary blood flow.
The test results are given below: .
~ NO2 . ~ CN
H3COOe-- ~ COOCH3 H3COOC ~ COOCH3
H3C CH3 H3C N CN
H H
: [A] [B]
,
,, ~L N02 , [~
H3COO ~ OOCH3 H3COOC ~ ~ OOCH3
H3 ~ H2OH H3C H N
lC] [D]
. I , .
': .
.
-,
~.
. .
. r~
;"''' ' '
"'' ~
'
' ' ,

108~223
Table. Increase of coranary blood flow l%)
The values indicate percentages compared to
control [29.5+5.5 ml/min.].
5 ~ se ~g/kg __
64 250 1000
Compound _ __
: . A 169 118 dead
B 885~1633 >1077
. C 8i3>1107 >2007
_ 344 688 >1491
Compound A is known as the generic name
~, nNifedipine" and already marketed as a coronary vasodilator.
;~ .
l~ . . The following Examples are given merely for the
: . j 15 purpose of illustrating the syntheses of some specific
~ . object compounds of the present invention, but not of
l,~ ~............................................ .
~..........
'~ limiting the same thereto.
~' :1 - -
;!
...
~ ~ ,
-- .
,. ~
.
~ :., . `
~; ,
.. .. . .
F'- -i ` ~ - . - .
.., ' : ~ , ~ . !
`~ . - " ' ' ' ' ~ :
. :, - : ,
. ' ' ' . ~ .
:` , ~: ,
` . . ' :
:, . .
' ': ' :
':.' . ' ' ' ' ' ':.': ` ,'' ' ' :
, ,. : . . , :' ' : '
' '. ': ' '
':;.'' ' ~ .

10802Z3
.~ .
Example 1
l-i) To a mixture of 2-cyanobenzaldehyde (5.0 g), methyl 4,
: 4-dimethoxyacetoacetate (7.39 g) and acetic acid (0.458 g)
in benzene (15 ml) was added portionwise each one third of
a solution of piperidine (390 mg) in benzene (5 ml) for each
20 minutes' interval . The mixture was heated to reflux for
2 hours and the resulting water was removed off azeotropica-
:
lly during the reaction course. After cooling, the reaction
mixture was shaken with a mixture of benzene (50 ml) and
water (30 ml), and the organic layer was separated and wash-
ed with diluted aqueous sodium bicarbonate solution and
water. The aqueous washings were extracted with benzene
(30 ml). The benzene extract was combined with the above
organic layer, washed with water, dried over magnesium sul-
fate and evaporated to dryness under reduced pressure. The
oily residue (14.8 g) was chromatographed ona -olumn of
silica-gel (200 g) and eluted with a mixture of benzene and
ethyl acetate (25:1, v/v) to give an oily methyl 2-(2-cyano-
, benzylidene)-4,4-dimethoxyacetoacetate (6.90 g). The thin
layer chromatogram and r~.M.R~ spectrum of this product show that
~; it consisted of a mixture of two stereoisomers.
. . ~ .
N.M.R. ~ ppm. (CDCl3) -~
3.4 (s, 3H);3.48 (s, 3H);3.78 and 3.90 (3H, each
, s );4.83 and 5.09 (lH, each s );7.43-7.8 (m, 4H);
i
~ 25 8.0 and 8.15 (lH, each s )
. , ' .
~ l-ii) A mixture of above obtained methyl 2-(2-cyanobenzyl-
: idene)-4,4-dimethoxyacetoacetate (6.8 g) and methyl 3-
'~ aminocrotonate (2.98 g) was heated under stirring at around
60C for 2 hours, and then the temperature was gradually
.:,.
~ ~ -123_

10802~3
raised and kept at 100 to 103C for 10 hours. During the
reaction course, n-propylalcohol (3 ml) was added into the
reaction mixture for dissolving the resulting crystalline
mass. The reaction mixture was dissloved in a mixture of
diisopropyl ether (9 ml) and methanol (3 ml) and allowed
to stand for a while to give pale brown fine crystals of
dimethyl 2-methyl-4-(2-cyanophenyl)-6-dimethoxymethyl-1,4-
dihydropyridine-3,5-dicarboxylate (6.39 g), an aliquot of
which was recrystallized fro~ a mixture of diisopropyl
ether and methanol (1:1, v/v) to give the pure crystals
mp. 133-134.5C
N.M.R. ~ ppm. (CDCl3)
; 3.4 (3H, s), 3.48 (3H, s), 3.78 and 3.9 (3H, s),
4.83 and 5.09 (lH, s), 7.43 to 7.8 (4H, m),
",
lS 8.0 and 8.15 (lH, s)
`l
2-i) To a mixture of methyl 2-formylbenzoate (4.92 g),
ethyl 4,4-diethoxyacetoacetate (7.2 g) and acetic acid
(0.36 g) in benzene (15 ml) was added porticnwise each one
third portion of a solution of piperidine (306 mg) in
benzene (5 ml) for each 20 minutes'interval , and the mix-
ture was heated to reflux for 3 hours under removing off
azeotropically the resulting water. After cooling, the
;~; reaction mixture was diluted with additional benzene (25
ml), washed three times with water and successively with
diluted aqueous sodium bicarbonate solution, water and
; saturated aqueous sodium chloride solution and dried over
magnesium sulfate. The solvent was distilled off under
reduced pressure to give reddish oil (12.7 g) of crude
-~ 30 ethyl 2-(2-methoxycarbonylbenzylide~-4,4-diethoxyaceto-
:.:
~,~ -12-4-
, ;,, ~
,

10802;~3
acetate which was used in the following reaction without
any further purification.
2-ii) A mixture of ethyl 2-~2-methoxycarbonylbenzyl-
idene)-4,4-diethoxyacetoacetate (12.7 g) and ethyl 3-
aminocrotonate (5.03 g) was heated under stirring at around
60 to 70C for 1.5 hours and then the temperature was raised
gradually, to keep at 90C for 3.5 hours and finally at 110
C for 4.5 hours. After cooling, the reaction mixture was
dissolved in ethyl acetate (50 ml), washed twice with water,
dried over magnesium sulfate and evaporated to driness
under reduced pressure to give reddish brown oily residue
~12.8 g). The oil was treated with a mixture of diisooro-
pyl ether and n-hexane (1:10, v/v) to give light brown
crystalline powder of diethyl 2-methyl-4-(2-methoxycarbonyl-
phenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxyl-
; ate (3.5 g). An additional crop (0.33 g) was recovered
from the mother liquor, and further crop (1.6 g) was recov-
ered from the whole mother liquor by subjecting the residu-
al oil (8.0 g) to column chromatography on silica-gel
(240 g), and eluted with a mixture of benzene and ethyl
acetate (15:1 and 10:1, v/v), (total yield 5.43 g). A
300 mg portion of the first crop was recrystallized from
3 ml of n-hexane to give 290 mg of the pure crystals,
mp 94-95C.
N.M.R. ~ ppm (CDC13)
1.25 (6H, t, J-7Hz), 1.15 (6H, t, J=7Hz), 2.33 (3H, s),
3.92 (3H, s), 3.42-4.23 (8H, m), 6.04 (lH, s), 6.11
(lH, s), 6.6 (lH, broad s), 7.0-7.8 (4H, m)
-125-
.
' :
.

108(~'~Z3
3) To a solution of 2-N-methylsulfamoylbenzaldehyde
(1.75 g), methyl 4~4-dimethoXyacetoacetate (1.70 g), and
acetic acid (0.1 g) in benzene (5 ml) was added a solution
; of piperidine (90 mg) in benzene (3 ml) in a similar manner
S to the aforementioned Examples l-i) and 2-i), and the mix-
ture was heated to reflux for 2 hours.~uring the reaction
course,the resulting water was removed off azeotropically.
After cooling, the reaction mixture was diluted with
benzene (15 ml), washed twice with diluted aqueous sodium
bicarbonate solution and in turn with water and saturated
aqueous sodium chloride solution, dried over magnesium
sulfate and then evaporated to dryness under reduced pres-
sure to give reddish yellow oil (3.46 g). The oil was
~ chromatographed on a column of silica-gel (69 g) and elut-
; 15 ed with a mixture of benzene and ethyl acetate (3.5:1, v/v)
to give an oily methyl 2-(2-N-methylsulfamoylbenzylidene)-
4,4-dimethoxyacetoacetate (1.12 g). A mixture of thus
obtained oily methyl-2-(2-N-methylsulfamoylbenzylidene)-4,
; 4-dimethoxyacetoacetate (l.0 g) and methyl 3-aminocrotonate
(355 mg) was heated at 60C for 3 hours, and the tempera-
ture was raised gradually to 100C during 1.5 hours and
kept at 100C for 5.5 hours. The reaction mixture was
chromatographed on a column of silica-gel (33 g) and eluted
with mixture of benzene and ethyl acetate (5:1, v/v) to
give an oily dimethyl 2-methyl-4-(2-N-methylsulfamoylphenyl)
-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(840 mg).
N.M.R. ~ ppm (CDC13)
2.37 (3H, s), 2.65 (3H, d, J=3Hz), 3.40 (3H, s), 3.45
(3H, s), 3.63 (3H, s) 3.65 (3H, s), 4.77 (lH, q, J=3Hz),
-126-
. ~ .

1080ZZ3
5.11 (1~l, s), 6.01 (lH, s~, 6.88 (lH, broad s),
7.35-7.75 (4H, m)
4) A mixture of methy] 2-(2-nitrobenzylidene)-4,4-dimetho-
xyacetoacetate (15.19 g) and methyl 3-aminocrotonate (6.50
g) was heated at 60 to 63C for 6 hours and at 100 to 105C
for 4 hours and 45 minutes. The resulting crystalline
mass was triturated with methanol and collected by filtrat-
ion to give crystals of dimethyl 2-methyl-4-(2-nitrophenyl)
-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(12.04 g3. Thus obtained crystals (1.07 g) were recrys-
tallized from methanol (5 ml) to ~ive pure crystals (0.93
g), m.p. 132 to 133C.
N.M.R. ~ ppm (CDC13)
2.36 (3H, s), 3.40 (3H, s), 3.44 (3H, s),
3.56 (3H, s), 3.66 (3H, s), 5.76 (lH, s),
5.99 (lH, s), 6.85 (lH, broad s),
7.1 to 7.8 (4H, m)
5) A mixture of 2-nitrobenzaldehyde (6.8009 g), methyl
4,4-dimethoxyacetoacetate (8.7204 g), acetic acid (0.5405
g) and piperidine (0.4598 g) in benzene (30 ml) was heated
to reflux for 2 hours under azeptropic dehydration. The
reaction mixture was diluted with benzene (100 ml), washed
twice with water, and in turn with diluted a~ueous sodium
bicarbonate solution and water, dried over magnesium sulfa-
te and evaporated to dryness under reduced pressure to
give crude oily methyl 2-(2-nitrobenzylidene)-4,4-dimethox-
yacetoacetate (15.23 g).
A mixture of thus obtained crude oil (15.23 g) ard et~lyl
. .
~ ~ -127 _

108V2Z3
3-aminocrotonate (6.6840 g) was heated at around 65C ~or
6 hours and then at 98 to lOO~C for 5 hours. The resultant
viscous brown oil was dissolved in ethyl acetate, washed
;- three times with water, dried over magnesium sulfate and
evaporated to dryness under reduced pressure to give brown
oil (19.40 g). The residual oil was crystallized by tritu
ration with methanol (10 ml) to give yellowish crystalline
powder (12.77 g) of ethyl 2-methyl-4-(2-nitrophenyl)-5-
methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3-
carboxylate. An additional 0.53 g of crystals was recover-
ed from the mother liquor. Recrystallization from methanol
gave yellowish granules, m.p. 122-124C.
N.M.R. ~ ppm (CDC13)
l.lS (3H, t, J=7.5Hz), 2.38 (3H, s), 3.40 (3H, s),
3.45 (3H, s), 3.60 (3H, s), 4.04 (2H, q, J=7.5Hz),
4.08 (2H, q, J=7.5Hz), 5.83 (lH, s), 5.98 (lH, s),
~; 6.77 (lH, broad s), 7.1 to 7.85 (4H, m)
: ' ' '
6) To a solution of 2-nitrobenzaldehyde (6.80 g), methyl
4,4-dimethoxyacetoacetate (8.72 g) and acetic acid (0.54 g)
in benzene (30 ml), was added piperidine (0.46 g), in a
similar manner to aforementioned examples l-i) and 2-i),
; and the mixture was heated to reflux for 2 hours under
azeotropic dehydration. The reaction mixture, after cool-
ing, was diluted with benzene (100 ml), washed three times
with water, and in turn with diluted aqueous sodium bicarb-
onate solution and water, dried over magnesium sulfated
and evaporated to dryness under reduce pressure to give
oily methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoaceta-
te (14.73 g).
-128 -
" '

10802Z3
A mixture of the above obtained oil (14.70 g) and isopropyl
3-aminocrotonate (7.09 g) was heated at 60 to 63C for 2
hours and at 85 to 90C for about 10 hours. The reaction
mixture was treated with ethyl acetate to sive yellowish
crystals which were collected by filtration and washed with
methanol. The filtrate was concentrated and the residue
was treated with methanol to give additional crystals.
The combined crystals (11.10 g) were recrystallized from
methanol to give ~ure crystals of isopropyl ?.-methyl-4-(2-
nitrophenyl)-S-methoxycarbonyl-6-dimethoxymethyl-1,4-dihyd-
ropyridine-3-carboxylate, m.p. 143 - 145C.
N.M.R. ~ ppm (CDC13)
0.99 (3H, d, J=6Hz), 1.24 (3H, d, J=6Hz), 2.39 (3H, s),
3.37 (3H, s), 3.45 (3H, s), 3.60 (3H, s), 4.96 (lH,
hept., J=6Hz), 5.88 (lH, s), 5.96 (lH, s), 6.82 (lH,
s), 7.1 to 7.8 (4H, m)
.
7) To a mixture of 3-nitrobenzaldehyde(7.56 g), methyl 4,
4-dimethoxyacetoacetate (9,69 g) and acetic acid (600 mg)
in benzene (25 ml~ was added portionwise each one fifth
portion of piperidine (851 mg) in benzene (5 ml) for each
20 minutes'interval and the mixture was heated to reflux
for 4 hours under azeotropic dehydration. After cooling,
the reaction mixture was diluted with benzene (50 ml),
washed twice with diluted aqueous sodium bicarbonate solut-
ion, and in turn, with water and saturated aqueous solution
of sodium chloride, dried over magnesium sulfate and evapo-
rated to dryness under reduced pressure to give crude redd-
ish brown oily methyl (3-nîtrobenzylidene)-4,4-dimethyl-
acetoacetate (17.82 g) which was used in the following
-129_
' ~

108VZZ3
reaction without any further purification. A mixture of
above oil (17.82 g) and methyl 3-aminocrotonate (6.33 g)
was heated at 60 to 65C for 4.5 hours, at 100 to 105C
for 8 hours and 45 minutes. The reaction mixture was
chromatographed on a column of silica-gel (440 g) and
eluted with a mixture of benzene and ethyl acetate (10:1,
v/v) to give crystalline product (10.46 g) of dimethyl 2-
methyl-4-(3-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyri-
dine-3,5-dicarboxylate. T~.us obtained crystals
10 (720 mg)~2re recrystallized from diisopropyl ether (10 ml)
to give pure specimen (560 mg), mp 99 to 100C.
N.M.R. ~ ppm (CDC13)
2.47 (3H, s), 3.52 (3H, s), 3.57 (3H, s), 3.77 (3H, s),
5.25 (lH, s), 6.1 (lH, s), 6.98 (lH, broad s),
7.38 to 8.17 (4H, m)
. ' .
8) To a solution of 3-nitrobenzaldehyde (4.53 g), 2-benzy-
loxyethyl acetoacetate (7.79 g) and acetic acid (360 mg)
in benzene (15 ml), was added a solution of piperidine
(306 mg) in benzene (5 ml), in a similar manner to the
aforementioned Example l-i), and the mixture was heated
to reflux for 2.5 hours under azeotropic dehydration. The
reaction mixture was left to cool and diluted with benzene
(50 ml), washed with water, diluted aqueous sodium bicarbo-
nate solution and water, dried over magnesium sulfate and
then evaporated to dryness under reduced pressure to give
brown oily 2-benzyloxyethyl 2-(3-nitrobenzylidene)-
` acetoacetate (12.58 g). The mixture of
the above obtained oil (12.58 g) and ethyl 3-amino-4,4-
diethoxycrotonate (8.47 g) was heated at 100 to 102C for
-130-
.~''. , ' .

108V223
4 hours and at llo to llS~c for 6.5 hours. After cooling,
the reaction mixture was dissolved in ethyl acetate, washed
twice with water and saturated aqueous sodium chloride
solution, dried over magnesium sulfate and evaporated to
dryness under reduced pressure. The residual brown oil
(19.04 g) was chromatographed on a column of silica-gel
~` (570 g) and eluted with a mixture of benzene and ethyl
acetate (13:1, v/v) to give oily 2-benzyloxyethyl 2-methyl-
4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-
dihydropyridine-3-carboxylate (9.64 g).
N.~ pp. (CDC13)
1.17 (6H, t, J=7Hz), 1.23 (3H, t, J=7Hz), 2.35 (3H, s),
3.43 to 4.4 (lOH, m), 4.5 (2H, s), 5.18 (lH, s),
6.86 (lH, broad s), 7.33 to 8.13 (9H, m)
Example 2
1) To a solution of dimethyl 2-methyl-4-(2-cyanophenyl)-
6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(6.0 g) in acetone (60 mg) was added 6N hydrochloric acid
(6 ml), and the resultant mixture was stirred for 3 hours
at room temperature. The reaction mixture was diluted with
water (30 ml), and adjusted to pH 7.5 with an aqueous
sodium bicarbonate solution, and acetone was distilled
off under reduced pressure. The resultant crystalline
mass was crushed as finely as possible with a glass rod~
washed with an additional water (100 ml), collected by
filtration, further washed thoroughly with water, and
air-dried to give crystalline powder of dimethyl 2-methyl-
4-(2-cyanophenyl)-6-formyl-1,4-dihydro yridine-3,5-dicarbo-
xylate (5.19 g).
-131-

1080ZZ3
N.M.R. ~ ppm (CDC13)
2.41 (3H, 5), 3.65 t3EI, s), 3.75 (3H, s), 5.5 (lH, s),
7.0 (lH, s), 7.25 to 7.66 (4~1, m), 10.53 (lH, s)
2) To a solution of diethyl 2-methyl-4-(2-methoxycarbonyl-
phenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxy-
late (5.03 g) in acetone ~50 ml) was added 6N-hydrochloric
acid (5 ml), and the mixture was stirred for 2 hours at
room temperature. After adding water (30 ml), the reaction
mixture was neutralized with an aqueous sodium bicarbonate
solution and acetone was distilled off under reduced press-
ure. The resultant oily precipitates were extracted with
ethyl acetate. The ethyl acetate extracts were washed
with water, saturated aqueous sodium chloride solution,
dried over magnesium sulfate and evaporated to dryness
under reduced pressure to give reddish oil of crude dieth-
yl 2-methvl-4-(2-methoxvcarbonvl~henvl)-6-form~1-1,4-dihydro-
pvridine-3,5-dicarboxvlate (4.2~ g), which was used in a
succeeding reaction without further purific~tion.
N.M.R. ~ ppm (CDC13)
1.1 (3H, t, J=7Hz), 1.8 (3H, t, J=7Hz), 2.37 (3H, s),
3.93 (3H, s), 3.9 to 4.28 (4H, m), 6.2 (lH, s),
6.98 (lH, s), 7.1 to 7.8 (4H, m), 10.2 (lH, s)
3) A mixture of a solution of dimethyl 2-methyl-4-(2-N-
methylsulfamoylphenyl)-6-dimethoxymethyl-1,4-dihydropyridi-
- ne-3,5-dicarboxylate (600 mg) in acetone (6 ml) and 6N
hydrochloric acid (0.6 ml) was stirred for 2.5 hours at
room temperature and adjusted to pH 7 to 8 with a diluted
30- a~ueous sodium bicarbonate solution, and then acetone was
-132-
, ^
.

10802
distilled off under reduced pressure. The resultant oily
precipitate was triturated with additional water to
give crystalline powder of dimethyl 2-methyl-4-(2-N-methyl-
sulfamoylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarbox-
ylate (380 m~).
N.M.R. ~ ppm (CDC13)
2.45 (3H, s), 2.65 (3H, d, J=3Hz), 3.65 (3H, s),
3.76 (3H, s), 4.6 (lH, q, J=3Hz), 5.22 (lH, s)
7.09 (lH, broad s), 7.35 to 7.85 (4H, m), 10.49 (lH, s)
4) A mixture of a solution of dimethyl 2-methyl-4-(2-
nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-
dicarboxylate (10.68 g) in acetone (110 ml) and 6N hydro-
chloric acid (10 ml) was stirred at 25C for 3 hours, which
was neutrallized with an aqueous sodium bicarbonate soluti-
on and acetone was distilled off under reduced pressure.
The resultant reddish yellow oily precipitates were solidi-
fied,which were cracked finely, collected by iltration,
washed with water and air dried over-night to give crude
crystals of dimethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-
1,4-dihydropyridine-3,5-dicarboxylate (9.33 g).
N.M.R. ~ ppm (CDC13)
.~
2.41 (3H, s), 3.58 (3H, s), 3.71 (3H, s), 5.88 (lH, s),
7.10 (lH, broad s), 7.2 to 7.9 (4H, m), 10.43 (lH, s)
- 5) To a solution of isopropyl 2-methyl-4-(2-nitrophenyl)-
5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3,
- 5-carboxylate (10.5 g) in acetone (105 ml) was added 6-N
hydrochloric acid (15.5 ml) and the mixture was stirred at
25C for 2 hours. After removal of acetone, the resultant
`
.~ . .
-133-
:
,

1080Z23
solu~ion was diluted with water (50 ml), made alkaline
with saturated aqueous sodium bicarbonate solution, and
then extracted with ethyl acetate. The ethyl acetate
extract was washed twice with saturated aqueous sodium
chloride solution, dried over magnesium sulfate and evapor-
ated to dryness under reduced pressure. The reddish-yellow
oily residue (11.08 g) was triturated with a mixture of
diethyl ether and n-hexane to give yellowish crystalline
powder of isopropyl 2-methyl~4-(2-nitrophenyl)-5-methoxy-
carbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (8.94
g) -
N.M.R. ~ ppm (CDC13)
0.97 (3H, d, J=6Hz), 1.21 (3H, d, J=6Hz), 2.43 (3H, s),
- 3.70 (3H, s), 4.97 (lH, hept., J=6Hz), 6.00 (lH, s),
6.95 (lH, broad s), 7.2 to 7.9 (4H, m), 10.38 (lH, s)
6) To a solution of dimethyl 2-methyl-4-(3-nitrophenyl)-6-
dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (7.5
g) in acetone (75 ml) was added 6N hydrochlo ic acid (7.5
~` 20 ml) and the mixture was stirred at room temperature for 6
hours. The pricipitates which were separated out during
the reaction course were collected by filtration to give
yellowish crystals of dimethyl 2-methyl-4-(3-nitrophenyl)-
6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.26 g),
and the filtrate was adjusted to pH 7.5 to 8 with an aque-
ous sodium bicarbonate solution,and the acetone was distil-
. ; .
led off under reduced pressure to give additional crops of
orange-yellow crystals (3.84 g) of the same product
, (total yield, 6.1 g). A small portion of the first
crop was recrystallized from methanol to give pure crystals,
.''"'~ .
~'
-134-
.

108V2Z3
m.p. 157-157.5C.
N.M.R. ~ ppm tCDC13)
2.48 (3H, s), 3.7 (3H, s), 3.81 (3H, s), 5.3 (lH, s),
7.13 to 8.17 (5H, m), 10.5 (lH, s)
7) To a solution of 2-benzyloxyethyl 2-methyl-4-(3-nitro-
-phenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyrid-
ine-3-carboxylate (6.0 g) in acetone (60 ml) was added 6N
hydrochloric acid (6 ml) and the mixture was stirred at
room temperature for 2 hours. The reaction mixture was
adjusted to pH 7.5 to 8 with an aqueous sodium bicarbonate
solution, and acetone was distilled off under reduced pre-
ssure. The resultant solution was diluted with water (lSO
ml) to separate out oily precipitates, which were extracted
twice with ethyl acetate (100 ml and 50 ml, respectively).
The organic layer was washed with water, dried over magnes-
ium sulfate and evaporated to dryness under reduced pressu-
re to give oily 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)
-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxyla-
te (5.02 g).
N.M.R. ~ ppm (CDC13)
1.25 (3H, t, J=7Hz), 2.41 (3H, s), 4.5 (4H, s),
3.5 to 4.4 (6H, m), 5.29 (lH, s), 7.3 to 8.15
(lOH, m), 10.45 (lH, s)
Example 3
; 1) A mixture of dimethyl 2-methyl-4-(2-cyanophenyl~-6-
formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.4 g),
hydroxylamine hydrochloride (539.3 mg) and sodium acetate
(752.3 mg) in acetic acid (15 ml) was stirred at room
-135-
~ '
i
,

1080ZZ3
temperature for 55 minutes to form dimethyl 2-methyl-4-(2-
cyanophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-
dicarboxylate. To the reaction mixture was added acetic
anhydride (2.375 g), and the mixture was heated at 110C
for 4 hours with stirring. The reaction mixture was conce-
ntrated and treated with water (30 ml). The resultant
acidic solution was adjusted to pH 7.5 to 8 with an aqueous
sodium bicarbonate solution, and extracted twice with ethyl
acetate. The organic layer was washed with water, saturat-
ed aqueous sodium chloride solution, and evaporated to dry-
ness under reduced pressure. The residue was kept over-
night in a refrigerator for crystallization. The resultant
crystals were collected by filtration and washed with small
portion of cold methanol to give crystals of dimethyl 2-
methyl-4-(2-cyanophenyl)-6-cyano-1,4-dihydropyridine-3,5-
~ dicarboxylate (1.71 g). Additional crop (0.9 g) was recov-
; ered from the mother liquor. The combined crystals (2.61
g) were recrystallized from methanol to give pure crystals
~1.2 g), m.p. 166-166.5C.
N.M.R. ~ ppm (CDC13)
2.4 (3H, s), 3.67 (3H, s), 3.75 (3H, s), 5.42 (lH, s),
7.2 to 7.62 (4H, m), 7.9 (lH, s)
1:
2) A mixture of diethyl 2-methyl-4-(2-methoxycarbonylphen-
. '
~; 25 yl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.6 g),hydroxylamine hydrochloride (495 mg) and sodium acetate
(691 mg) in acetic acid (20 ml) was stirred at room temper-
ature for an hour to form diethyl 2-methyl-4-(2-methoxycar-
bonylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-
, . ,
dicarboxylate. To the reaction mixture was added acetic
I
i' .
- ~ -136-
..
'

1080223
..
anhydride (2.18 g) and the mixture was heated at 110C for
3.5 hours with stirring. .~cetic acid was distilled off
undex reduced pressure from the reaction mixture and the
resultant residue was adjusted to pH 8 with an aqueous
sodium bicarbonate solution and extracted with ethyl aceta-
te. The ethyl acetate extracts were washed with water,
and saturated aqueous sodium chloride solution, dried over
magnesium sulfate and then evaporated to dryness. The
resultant oil (2.88 g) was chromatographed on a column of
silica-gel (72 g), and eluted with a mixture of benzene
and ethyl acetate (10:1, v/v) to give an oil (1.6 g),
which was triturated with diisopropyl ether (3 ml) to give
crystalline powder (1.3 g). Recrystallization from a mix-
ture (20 ml) of diisopropyl ether and ethanol (15:1, v/v)
gave pure crystals of diethyl 2-methyl-4-(2-~ethoxycarbon-
ylphenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate
(1.03 g), mp 126 to 127C.
N.M.R. ~ ppm (CDC13)
1.15 (3H, t, J=7Hz), 1.24 (3H, t, J=7Hz), 2.33 (3H, s),
3.98 (3H, s), 3.90 to 4.38 (4H, q, J=7Hz), 6.22
(lH, s)/ 7.2 to 7.88 (4H, m)
'
3) A mixture of dimethyl 2-methyl-4-(2-nitrophenyl)-6-
formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.6 g),
hydroxylamine hydrochloride (764 mg) and sodium acetate
(1.06 g) in acetic acid (20 ml) was stirred at room temper-
ature for 45 minutes to form dimethyl 2-methyl-4-(2-nitro-
phenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicar-
boxylate. To the reaction mixture was added acetic anhydr-
ide (3.37 g) and the mixture was stirred at room temperature
.
-137-

1080Z23
for 15 minutes and then heated at 100C for 3 hours with
stirring. After removal of the acetic acid, the residue
was adjusted to pH 7.5 with an aqueous sodium bicarbonate
solution and extracted with ethyl acetate. The extract
was washed twice with water and saturated aqueous sodium
chloride solution, dried over magnesium sulfate and evapor-
ated to dryness under reduced pressure. The resultant oil
~3.80 g) was chromatographed on a column of silica-gel
(110 g) and eluted with a mixture of benzene and ethyl ace-
tate (9:1, v/v) to give crystals (2.05 g), which were recr-
ystallized from a mixture of ethyl acetate (12 ml) and n-
hexane (6 ml) to give yellow granules of dimethyl 2-methyl-
4-(2-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarbox-
ylate (1.19 g), mp 170.5 to 171.5C.
N.M.R. ~ ppm (CDC13)
2.37 (3H, s), 3.6 (3H, s), 3.7 (3H, s), 5.9 (lH, s),
7.34 to 7.83 (4H, m)
4) A mixture of isopropyl 2-methyl-4-(2-nitrophenyl)-5-
methoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate
(3.88 g), hydroxylamine hydrochloride (0.7644 g) and sodium
` acetate (1.0664 g) in acetic acid (20 ml) was stirred at
. ~ . .
room temperature for an hour to form isopropyl 2-methyl-4-
(2-nitrophenyl)-5-methoxycarbonyl-6-hydroxyiminomethyl-1,4-
dihydropyridine-3-carboxylate. To the reaction mixture was
added acetic anhydride (3.37 g) and the mixture was heated
-- at 95 to 100C for 6 hours. After removal of the acetic
; acid, water was added to the residue and the mixture was
- extracted with ethyl acetate. The extract was washed with
water, an aqueous sodium bicarbonate solution and water
: .
~ -138-
', ' ~ -

1080Z23
in turn, dried over magnesium sulfate and ~vapora-
ted to dryness under reduced pressure. The residual oil
(3.69 g) was chromatograohed on a column of silica-gel
(100 g), and eluted with a mixture of benzene and ethyl
S acetate (5:1, v/v) to give an oil of isopropyl 2-methyl-4-
(2-nitrophenyl)-5-methoxycarbonyl-6-cyano-1,4-dihydropyri-
dine-3-carboxylate (2.0 g), which was left in a refrigerat-
or for several days to crystallize. Recrystallization
from methanol gave pure crystals, m.p. 175.S-176.5C.
N.M.R. ~ ppm (CDC13)
0.91 (3H, d, J=6Hz), 1.17 (3H, d, J=6Hz), 2.33 (3H, s),
3.65 (3H, s), 4.9 (lH, hept., J=6Hz), 5.95 (lH, s),
6.8 (lH, broad s), 7.23 to 7.85 (4H, m)
5) A mixture of dimethyl 2-methyl-4-(3-nitrophenyl)-6-
formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.0 g),
hydroxylamine hydrochloride (424.3 mg) and sodium acetate
(591.8 mg) in acetic acid (12 ml) was stirred at room
temperature for 80 minutes to form dimethyl 2-methyl-4-(3-
- 20 nitrophenyl)-6-hydroxy-iminomethyl-1,4-dihydropyridine-3,
5-dicarboxylate. To the reaction mixture was added acetic
anhydride (1.87 g) and the mixture was heated at 110C for
3.5 hours with stirring. The reaction mixture was evapora-
ted to form crystalline mass which was neutralized by trea-
ting with diluted aqueous sodium bicarbonate solution and
the crystalline mass were pulverized, collected by filtrat-
ion and washed thoroughly with water to give crystals
(1.92 g). Recrystallization from a mixture of methanol
and ethyl acetate gave pure crystals of dimethyl 2-
methyl-4-(3-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-
-13g--
.
.

~080223
dicarboxylate (1.04 g), mp 206 to 207C. An addition~l
crop was recovered from the mother liquor of above recryst-
allization (0.6 g).
N.M.R. ~ ppm (CDC13)
2.4 (3~1, s), 3.65 (3H, s), 3.78 (3Y., s), 5.12 (lH, s),
6.76 (lH, broad s), 7.36 to 8.1 (4H, m)
6) A mixture of 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)
-5-ethoxycarbonyl-6~formyl-1,4-dihydropyridine-3-carboxy-
late (2.44 g), hydroxylamine hydrochloride (377 mg) and
sodium acetate (526 mg) in acetic acid (15 ml) was stirred
at room temperature for an hour to form 2-benzyloxyethyl
2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyimino-
methyl-1,4-dihydropyridine-3-carboxylate. To the reaction
mixture was added acetic anhydride (1.66 g) and the mixtu-
re was stirred at room temperature for an hour and then
heated at 100C for 3 hours with stirring. After removal
of the acetic acid, the residue was adjusted to pH 7.5
with aqueous sodium bicarbonate solution and extraced twice
with ethyl acetate. The extracts were washed twice with
water, and saturated aqueous sodium chloride solution,
dried over magnesium sulfate and evaporated to dryness in
vacuo. The residual brown oil (2.6 g) was chromatographed
; on a column of silica-gel (78 g) and eluted with a mixture
of benzene and ethyl acetate (12:1, v/v) to give an oil
(1.45 g). The oil was crystallized by triturating with a
small amount of mixture of diisopropyl ehter and diethyl
ether, and recrystallized from a mixture of diisopropyl
ether (9 ml) and ethanol (1 ml) to give pure crystals of
2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-S- ethoxycarbo-
-140-
: , . .

- 10~02;~3
nyl-6-cyano-1,4-dihydropyridine-3-carboxylate (840 mg),
mp 114 to 115C. An additional crop (560 mg) was recovered
from the filtrate by concentrating the filtrate and allow-
ing to stand the residue in a refrigerator.
N.M.R. ~ ppm (CDC13)
1.27 (3H, t, J=7Hz), 2.37 (3H, s), 3.65 (2H, t),
4.13 to 4.35 (4H, m), 4.5 (2H, s), 5.21 (lH, s),
7.2 to 8.1 (9H, m)
Example 4
1) To a cold solution of dimethyl 2-methyl-4-(2-cyanophe-
nyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.3 g)
in methanol (46 ml) at -5C was added portionwise sodium
borohydride (140.7 mg) for 10 minutes, during which
the temperature was kept at -4 to -5C with stirring.
The mixture was stirred for additional 15 minutes at
- -6C. The reaction mixture was diluted with water (20 ml)and
aeidified to about pH 5 with 50 ~ actic acid, and then
eondenSed under reduced pressure to separate out crystalli-
ne product. After adding water (30 ml), the erysta~s
were eollected by filtration, washed thoroughly with water
and dried. Thus obtained erystals (2.05 g) were recrystal-
lized from methanol (15 ml) to give pure crystals of di-
methyl 2-methyl-4-(2-cyanophenyl)-6-hydroxymethyl-1,4-
dihydropyridine-3,5-dicarboxylate (1.67 g), mp 177 to 178C.
N.M.R~ ~ ppm ~CDC13)
2.4 (3H, s), 3.63 (3H, s), 3.66 (3H, s),
4.8 (2H, broad s), 3.52 (lH, m), 5.35 (lH, s),
7.1 to 7.63 (4H, m)
-141-
; - ~. ~ . .
.. .

1080ZZ3
2) To a solution of diethyl 2-methyl-4-(2-methoxycarbonyl-
phenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate
(1.2 g) in ethanol (15 ml) was added portionwise sodium
borohydride (62.3 mg) at 0C over 30 minutes with stirring.
The mixture was stiired for further 20 minutes at 0C.
The reaction mixture was adjusted to pH 6 with 50 ~ acetic
acid and ethanol was distilled off under reduced pressure.
The residual solution was shaken with a mixture of water
and ethyl acetate, and the organic layer was separated,
washed wlth water, aqueous sodium bicarbonate solution and
water, dried over magnesium sulfate and evaporated to dry-
ness under reduced pressure. The residual oil (1.0 g) was
triturated in diethyl ether (2 ml) to give crude crystals.
Any recrystallization of the crude crystals were resulted
in insufficient purification. The recovered product
(0.9 g) was chromatographed on a column of silica-gel (27
g) and eluted with a mixture of benzene and ethyl acetate
(7:1, v/v) to give purified oil of diethyl 2-methyl-4-(2-
methoxycarbonylphenyl)-6-hydroxymethyl-1,4-dihydropyridine-
3,5-dicarboxylate (800 mg), which was crystallized and
recrystallized from a mixture of diethyl ether and n-hexane
to give pure crystals (500 mg), mp 106 to 108C.
N.~l.R. ~ ppm (CDC13)
1.05 (3H, t, J=7Hz), 1.1 (3H, t, J=7Hz), 2.25 (3H, s),
3.90 (3H, s), 3.85 to 4.13 (2H, m), 4.71 (2H, broad s),
5.98 (lH, s), 7 to 7.6 (5H, m)
3) To a cold suspension(-2C) ofdimethyl 2~methyl-4-(2-N-methyl-
sulfamoylpheny~r6-formyl-1,4-dihydropyridine-3,5-dicarboxy-
late (350 mg) in methanol (7 ml) was added each one
142-
.~. . .
:-.

1080223
third portion of sodium borohvdride(l7.85 mg) over 2 minutes
with stirring. Stirring was continued for additional an
hour and 40 minutes at -5 to -4C, during
which , the reaction mixture was diluted twice with methan-
ol; i.e. with 3 ml, after 30 minutes and with 4 ml after
1 hour; and a small portion of sodium borohydride (9 mg)
was added to the reaction mixture after 1 hour and 20
minutes. Water (30 ml) was added to the reaction mixture
and the resultant mixture was left to cool for 1 hour to
form crystalline precipitates. The resulting crystals
(260 mg) were collected by filtration and recrystallized
from methanol (3 ml) to give dimethyl 2-methyl-4-(2-N-methyl-
sulfamoylphenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-
dicarboxylate, m.p. 210 to 212C.
N.M.R. ~ ppm (DMSO-d6)
2.39 (3H, s), 3.33 (3H, s), 3.59 (6H, s),
4.66 (2H, broad d, J=5Hz), 5.03 (lH, s),
5.59 (lH, broad t, J=5Hz), 7.3-7.78 (5H, m),
7.34 (lH, s), 8.6 (lH, broad s)
4) A solution of dimethyl 2-methyl-4-(2-nitrophenyl)-6-
formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.60 g) in
methanol (72 ml) was cooled at 0C, and sodium borohydride
(0.2271 g) was added bit by bit thereto under cooling with
stirring. The mixture was stirred at the same temperature
for 15 minutes. The reaction mixture was adjusted to about
pH 6 with 50 ~ acetic acid and the methanol was distilled
off under reduced pressure below 30C. The residual solut-
ion was diluted with water (100 ml) and extracted with
ethyl acetate. The extract was washed with water, an
~, ~ -143-
:.. ' ' ' , ' ,
.: ' ' . . . .

1080~3
aqueous sodium bicarbonate solution and water in turn,
dried over magnesium sulfate and then evaporated to dryness.
The residual oil (3.70 g) was crystallized by triturating
with diisopropyl ether to give crude crystals (2.74 g),
which were recrystallized in first frcm methanol (8 ml) and
then from ethyl acetate (10 ml) to give pure crystals of
dimethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-
dihydropyridine-3,5-dicarboxylate (770 mg), mp 164.5 to
165C. The whole mother liquor of above recrystallizations
were combined together and concentrated. The crystalline
residue was collected by filtration and washed with metha-
nol (5 ml) to give additional crystals (1.72 g), which
were recrystallized from ethyl acetate to give additional
pure specimen of the same product obtained above, (840 mg)
m.p. 164.5 to 165C. Total yield, 1.61 g.
N.M.R. ~ ppm (CDC13)
2.33 (3H, s), 3.56 (3H, s)j 3.58 (3H, s),
4.76 (2H, s), 5.75 (lH, s), 7.25 to 7.75 (4H, m)
5) A solution of isopropyl 2-methyl-4-~2-nitrophenyl)-5-
methoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate
(3.88 g) in methanol (70 ml) was cooled below -3C, and
sodium borohydride (0.2082 g) was bit by bit added thereto
with stirring. After stirring for further 30 minutes at
-2C, the mixture was acidified with 50 ~ acetic acid, and
methanol was removed off under reduced pressure. The
resultant mixture was diluted with water and extraced with
`~ ethyl acetate. The extract was washed with water, a dilute
aqueous sodium bicarbonate solution and water in turn,
dried over magnesium sulfate and evaporated dryness under
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. j

108VZ23
- reduced pressure to give a reddish viscous oil (4.37 g),
which was triturated with a mixture of diethyl ehter and
n-hexane to give yellowish crystalline powder (3.75 g).
Recrystallization form methanol (10 ml) gave yellowish
granules of isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxy-
carbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate
(2.38 g), m.p. 135 to 137C, which were further recrystall-
ized from ethyl acetate (5 ml) to give the pure specimen
(1.08 g), m.p. 136.5 to 138C.
N.M.R. ~ ppm (CDC13)
0.96 (3H, d, J=6Hz), 1.22 (3H, d, J=6Hz), 2.38 (3H, s),
3.53 (3H, s), 4.70 (2H, s), 4.94 (lH, hept., J=6Hz),
5.83 (lH, s), ca 7.0 to 8.0 (5H, m)
:'
6) To a cold mixture of 2-benzyloxyethyl 2-methyl-4-(2-
nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-
3-carboxylate (1.8 g) in ethanol (36 ml) was added sodium
borohydride (75.5 mg) below -3C and the resultant mixture
was stirred at -3 to -5C for 40 minutes. The reaction
mixture was adjusted to pH 5 to 6 with 50 % acetic acid
.
and the ethanol was distilled off under reduced pressure.
The residue was diluted with water (100 ml) to separate
out crystalline mass, which were pluverized and collected
~ ! by filtration. The crystals (1.57 g) were recrystallized
; 25 from a mixture of diethyl ether and n-hexane. The obtain-
` ed crystals (910 mg? were not pure enough to analyze, then
these were combined again with filtrate and purified
through column chromatography on silica-gel column and
~: eluted with a mixture of benzene and ethyl acetate (10:1,
v/v) to give an oil (1 g), which was crystallized and
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! ~
.
.. . . .

108V223
recrystallized from a mixture of diisoprooyl ether and
ethanol to give pure crystals of 2-benzyloxyethyl 2-methyl-
4-(2-nitrophenyl)-5- ethoxycarbonyl-6-hydroxymethyl-1,4-
dihydropyridine-3-carboxylate 153D mg), m,p, 96 to 97C,
' 5 N.M.R. ~ ppm (CDC13)
~ ' 1. 10 (3H, t, J=7Hz), 2. 30 (3H, s), 4 . 47 (2H, s),
3.50-4.33 (6H~ m)~ 4.73 (2HI d~ J=5Hz)~
7 . 05-7. 75 (9H, m)
7) To a cold suspension of dimethyl 2-methyl-4-(3-nitro-
~henyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate
3.84 g) in methanol (76 ml) was added portionwiSe sodium
borohydride (221.8 mg) at -7C over 7 minutes with stirr-
~ ing. Stirring was continued for further 5.5 hours during
; 15 the course additional portion of sodium borohydride (40 mg)
{ was added to the reaction mixture. The resultant mixture
was diluted with water (50 ml), adjusted to pH 5 to 6 with
~i 50 % aqueous acetic acid, and a small amount of insoluble
substance was filtered off. The filtrate was evaporated
~; 20 and the residual mixture of solids and oils was washed
with diisopropyl ether (10 ml) to give solid product (2.7
g). The solid product was recrystallized once from a
mixture (20 ml) of methanol and diisopropyl ether (yield
1.78 g) and then recrystallization from methanol (6 ml) to
give pure crystals of dimethyl 2-methyl-4-(3-nitrophenyl)-
6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate
(1.48 g), m.p. 145 to 146C. An additional crop was reco-
vered from the mother liquor of the first recrystallization
by evaporating the solvent and triturating with methanol
- 30 as crystalline powder (330 mg).
-1~6-
!i

1080Z;~3
N.M.R. ~ ppm (CDC13)
2.40 (3H, s), 3.65 (6H, s), 4.81 (2H, d, J=5Hz)
5.11 (lH, s), 7.25-8.13 (6H, m)
8) To a cold mixture of 2-benzyloxyethyl 2-methyl-4-(3-
nitrophenyl)-5-ethoxycarboxyl-6-formyl-1,4-dihydropyridine-
3-carboxylate (2.0 g) in ethanol (40 ml) was added portion-
wise sodium borohydride (84.1 g) at -5C over 3 minutes
with stirring. After 35 minutes, additional sodium borohy-
ride (8.4 mg) was added and the mixture was stirred for
further 10 minutes at -2C. The reaction mixture was adju-
sted to pH 5 to 6 with 50 ~ aqueous acetic acid and ethanol
was distilled off under reduced pressure. The residual
mixture was diluted with water (100 ml) and extracted with
ethyl acetate. The extract was washed with water, dried
over magnesium sulfate, and evaporated to dryness under
reduced pressure to give an oil which was crystallized by
keeping in a refrigerator overnight. The crystals were
washed with n-hexane to give crystals (1.6 g) which were
; 20 recrystallized from a mixture (12 ml) of diisopropyl
ether and ethanol (1:1, v/v) to give pure crystals of 2-
benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-
- 6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate (860 mg),
m.p. 114.5 to 115.5C. A second crop was recovered from
the mother liquor in a usual manner to yield 220 mg,
m.p. 112 to 114C.
N.M.R. ~ ppm (CDC13)
1.20 (3H, t, J=7Hz), 2.75 (3H, s), 3.65 (2H, t, J=3Hz),
4.15 (2H, q, J=7Hz), 4.24 (2H, t, J=3Hz), 4.51 (2H, s),
4.78 (2H, broad s), 5.13 (lH, s), 7.20-8.13 (9H, m)
., .
.' :
-147-
.,' ~ .