PREPARATION D'ESTERS 1,4- DIHYDROPYRIDINEDICARBOXYLIQUES SYMETRIQUES

PROCESS FOR THE PREPARATION OF SYMMETRICAL 1,4- DIHYDROPYRIDINEDICARBOXYLIC ESTERS

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
In the preparation of a 1,4-dihydropyridine of
the formula
<IMG>
in which
R is a phenyl radical which is optionally sub-
stituted once or twice by nitro and/or chlorine,
R1 is a C1-C1-alkyl radical which is optionally
substituted by a C1-C4-alkoxy group
by preparing an ylidene compound of the formula
<IMG>
and reacting such ylidene compound with an enamine compound
of the formula
<IMG>
the improvement which comprises preparing the ylidene compound
by reaction of a ketocarboxylic ester of the formula
<IMG>
with an aldehyde of the formula RCHO, in a solvent in the presence
of a catalyst amount of any acetate salt of an amine at a tem-
perature from about -10°C up to 100°C.
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Revendications

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Patent claims
1. Process for the preparation of symmetrical 1,4-di-
hydorpyridines of the formula I
<IMG> (I)
in which
R represents a phenyl radical which is optionally
substituted once or twice by nitro and/or chlorine,
and
R1 represents a C1-C4-alkyl radical which is option-
ally substituted by a C1-C4-alkoxy group,
by reaction of an ylidene compound of the formula II
<IMG> (II)
with an enamine compound of the formula III
<IMG> (III)
characterised in that the ylidene compound of the formula
II is prepared by reaction of a ketocarboxylic ester of
the formula IV
<IMG> (IV)
with an aldehyde of the formula RCHO in a solvent, in the
presence of catalytic amounts of acetate salts of amines,
at temperatures from -10°C and up to 100°C.
Z. Process according to Claim 1, characterised in that
the reaction is carried out at 20-60°C.
3. Process according to Claim 1, characterised in that
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0.01 to 0.7 mol of catalyst is employed per mol of ylidene
compound.
4. Process according to Claim 1, characterised in that
0.02 to 0.2 mol of catalyst is employed per mol of ylidene
compound.
5. Process according to Claim 1, characterised in that
0.04 to 0.2 mol of catalyst is employed per mol of ylidene
compound.
6. Process according to Claim 1, characterised in that
1 to 2 mol of aldehyde is employed per mol of ketocarboxylic
ester.
7. Process according to Claim 1, characterised in that
1 mol of aldehyde is employed per mol of ketocarboxylic
ester.
Le A 22 066

Description

2L23a~ 3
The present 1nvent;on relates ~o a chemically
or;g;nal process for the preparat;on of known symmetrical
1,4 d;hydropyridinedicarboxylic esters.
Several processes.for ~heir preparation haYe al-
ready been d;sclosed. . .
Kirchner, Ber. 25,-2786 t1892) describes the reac-
t;on of aldehydes ~ith 3-ketocarboxyl;c esters and ammonia
in accordance with the react;on d;agram belo~:
. R
RC~O ~ 2 Rl--CO~C~2-COOR2 ~ N~3 ~_~ R2oo~ ~ QoR2
~ R
R1 ~ 1
Fox et al. J. Org. Chem~ 16, 1259 (1951~ mentions the
reaction of aldehydes with 3-ketocarboxylis esters and
enaminocarboxylic esters in accordance w~th the reaction
diagram belo~:
R \ / H
R20Oc` ~ COOR
RC~O ~ Rl-CO`C~2-COOR2 + R~-C-;C~-CR2 ~ ~ `~ 2
/ N ~R
Knoevenagel, Ber. 31, 743 (1898~ describes the
reaction of yl;dene-3-ketocarboxylic est~rs ~ith enamino~
carboxylic esters in accordance with the reaction diagram
belo~: . R H
. \/
. R200C ~ ~ COOR~
R-C~-C 1 + R1-C-C~-C00~2 ~~~~~ R ~ ~R
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S;n~e both aldehydes and ammon;a r~ac~ w;th keto-
carboxyl;c esters, it may be assumed that the yl;dene com-
pound and the enam;ne compound are aLso ini~ially formed
in the two processes mentioned f;rst.
. The d;sadvantages of the descr;bed pPOcesSeS are
regarded as being that the ylidene compounds can be ;so-
lated in the pure form only w;th d;ff;culty, and that
therefore the 1,4-dihydropyr;d;nedicarboxylic esters still
contain impur;ties which can be removed by pur;f;cat;on
processes only w;th great difficulty~
Ha~ing regard to the use of the 1,4~dihydropyridines
as medicaments~ there ;s a need to make these compounds
available in a high degree of purity. Thus, for exampleD
seven by products were demonstrated by thin-layer chroma-
tography in the preparation of 4 (2~-n;trophenyl)-2,6-di-
methyl-3,5 dicarboethoxy-1,4-dihydropyridine according-to
U.S. Patent 3,485,847.
Thus the invention relates to a process for the
preparat;on of symmetrical 1,4-dihydropyridines of the
formula I
R10OC ~ COOR1 -
C~/ N C~
;n wh;ch
R represents a phenyl radical which is optionally
subs~;tuted once or twice by nitro and/or chlorine9
25 ` and
R1 represents a C1-C4-alkyl radical which is option-
ally subst;tuted by a C1-C4-alkoxy group,
by reaction of an yl;dene compound of the formula II
/ C~C~3
R-CH=C (II~
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~

3 ~23~
with an enamine co~pound of the formula III
CH3-C~C~-CCOR1
NH2 ~III),
which is charac~erised in that the ylidene csnpound of the
formula II is prepared by reaction of a ketocarboxylic
es~er of the formula IV
C~3-C-C~2-CooR1 (IV)
O
~ith an aldehyde of the formula RCH0 in a solvent, in the
presence of cataly~;c amounts of acetate salts of amines,
at temperatures fro0 -10C to 100Cn
Acetate salts of a~ines which may be mentioned as
preferred are: piperidine or alkylpiperidine ace~ate,
morpholine or alkylmorpholine acetate, piperazine or atkYl-
piperazine __ acetate, pyrrolidine and
a~kylpyrrolidine acetate. Piper;d;ne --
acetate may be particularly mentioned. The alkyl radicals
in the catalysts preferably have 1-4 C atoms.
The solvents which are preferably used are aliphatic
alcohols, such as methanol, ethanol and/or isopropanol.
Tie preferred reaction temperatures are 20 60C~
The catalyst is preferably added in amsunts from
0.01 to 0O7 mol, particularly preferably 0.02 - 0~2 mol,
especially 0.04 - 0.2 mol, per mol of ylidene compound.
Preferably 1 to 2 mol, especially 1 mol, of alde-
hyde can be employed per mol of ketocarboxyllc ester ~f the
formula I`l.
In ~he formula I,
R preferably denotes a 2- or 3-nitrophenyl rad;cal,
a 2- or 3~chlorophenyl radical or a 2,3-dichloro-
phenyl radical, and
R1 preferably denotes methyl, ethyl, propyl, iso~
propyl, isobutyl or a propoxiethyl rad1cal.
The reaction of the ylidene compound of the formula
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,
:: .
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~ 3
4 --
II with the enamine compound of the formula ~ 5 carr1ed
out at temperatures from -10 to 130C, preferably from 50
to 100C.
Preferably 1 to 1.5 mol, part;cularly preferably
1 to 1~3, especially 1 to 1.Z, mol of the enam;ne compound
can be employed per mol of ylidene compound.
According to a particular embodiment, the crystal-
line ylidene compound rema;ns in according to ~he reaction
and is reacted directly ~ith the enamine compound.
1û It has to be denoted extremely surprising that the
ylidene-3-ketocarboxylic esters are produced in high purity
and excellent yield and can be very readily isolated using
the reaction accord;ng to the invention in the presence
of the catalysts mentioned.
Furthermore, i~ has to be deno~ed surprising that
the 1,4 dihydropyridine compounds are produced in such
high purity and can be isolated in the manner describedO
W;thout further purification processes, they contain no
by-products.
The process according to the invention has a number
of advantages.
Thus9 the yield is higher than according to the
known processes, and the isolated product does not need
to be subjected to further pur;fication stepsO
When o-nitrobenzaldehyde, methyl acetoacetate and
methyl 3-aminocrotonate are used as the starting mater;als,
then the course of the reaction can be represented by the
diagram belo~:
A) ~ 0 ~ 0 2
Le A Z2 066 ~ EsO ~ ~ C0-OCE~
:. - :
~:
:

~23~5~
~,
~2
B ) ~ ~CO~ + E~ ~E CO~ 5
GO--C~CE3 .
o2
C~32C ~ C02CH3
C~I3 ~:E13
.~
Th~ invention may be illustrated by the examples
~hich follo~:
a) Ylidenecarboxylic ester
116 9 tl mol) of methyl acetoacetate, 151 9 51 mol)
of 2-n;trobenzaldehyde, 2~4 9 ~0.04 mol) of glacial acetic
ac;d and 3.4 9 tO.04 mol) of piperidine are added in that
sequence, w;th st;rring, to 650 ml of- ;sopropanol at room
temperature.
The mixture ;s warmed to 40C and kept at this
temperature for 15 minutes a
It is then cooled to Z0C and stirr`ed for 16 hoursa
Subsequently ;t ;s cooled to 0C and st;rred at th;s tempera-
ture for 1 hour~ The supernatant solut;on ;s then removed
by suct;on, and the crystals are cent-rifuged with 130 ml
of ;ce-cold ;sopropanol and removed by suct;on.
The resulting~methyt 2-~2~'-nitrobenzyl;dene)aceto-
ace~ate ;s ;mmed;ately re~acted ;n the same vessel as des-
cr;4ed ;n b).
2U ~ ~ When the meehyl 2-~Z'-n~it~robenzyl;dene~acetoacetate
;s ;solated~and dr;;ed, then 241.7~g of~yellow crystals ~97%
of the theoret;cal;yield) of melting point ~9-101C are
obta;n'ed.~
Wh~en other~amo~unts~ of c~alyst are empLoyed ;n
place~of 0.04 mol of piperidi~ne acet~ate, then ehe follow-
;ng~y~i~eld~s~ar~e;~obtained.
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Amount Y;eld ~X)
0~08 mol 96.5
0.16 mol 97~6
0.5 mol 99.9
b) 750 ml of me~hanol and 111~5 9 tO~97 ~ol) of me~hyl
30aminocrotonate are added to ~he methyl 2-~2'-n;troben2-
ylidene)acetoacetate ~hich has been prepared according to
a) and is moist ~ith isopropanol. The mixture ;s heated
to reflux ~about 65C) and kept at this temperature for
36 hours.
After cooling to 0C, the result;ng crystals are
isolated and ~ashed ~ith 130 ml of methanol and 500 ml of
water and sucked dry.
302 9 (0.87 mol) of ~-~2-nitrophenyl)-2,6-dimethyl~
3,5-dicarbomethoxy-1,4-dihydropyridine of melting point
171-175C ~87X o~ the theore~ical yield) are obtainedD~
Thin-layer chromatography on Merck sil;ca gel ready-
coated p~ates tmobile phase: chloroform : acetone : petro-
leum ether = 3 : 2 : 5) show no visible by-products.
Comparison_experiment
Example 1 in U.S. Patent Specification 3,485,847
~as repeated and 4-t2-nitrophenyl~2,6-dimethyl-3,5-di-
carboethoxy-1,4-dihydropyridine was obta;ned as follows:
Yield ~X) 80
8y-products ~number~ 7
Colour red-bro~n
The same compound was prepared according to the
above processes a and b according to the inven~ion. The
follow;ng corresponding figures were obtained:
Yield S%) 85
3y-producSs ~number) none
Colour yellow
.
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