Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~L268~51~
QUINOLIZINONE COMPOUND, PROCESSES FOR
PREPARATION THEREOF AND PHARMACEUTICAL
COMPOSITION COMPRISING THE SAIYE
. - .
; This invention relates to quinolizinone compound
and a salt thereof. More particularly, it relates to
a new quinolizinone compound and a pharmaceutically
acceptable salt thereof which have inhibitory activities
on allergy and ulcer,;to processes for preparation
thereof, and to a pharmaceutical composition comprising
the same.
Accordingly, one object of this invention is to
provide the new and useful quinolizinone compound and
a pharmaceutically acceptable salt thereof.
Another object of this invention is to provide
processes for preparation of said quinolizinone
compound and the salt thereof. ~ ;
.
A further object of this invention is to provide
:~ :
~.
. -
- : :
:~
- ~ :,,:
lZ68~58
a pharmaceutical composition comprising, as an active
ingredient, said quinolizinone compound o~ the
pharmaceutically acceptable salt thereof.
Still further object of this invention is to
provide a therapeutical method for treatment of allergic
disease and ulcer in human be:ing and animals.
The quinolizinone compound of this invention can
be represented by the following formula (I) :
O (I)
wherein Rl is carboxy! amidated carboxy, cyano,
thiocarbamoyl or tetrazolyl group;
R7 is hydrogen or aryl;
R2 is hydrogen, hydro~y, lower alkyl or lower
alkoxy;
R3 is hydrogen, hydroxy, lower alkyl, lower
alkoxy, carboxy, protected carboxy, lower
alkenyloxy, aryl which may have suitable
substituent(s), arylthio, aroyl, ar(lower)-
alkyl, arenesulfonyl, arylamino which may
ha~e a suitable substituent or aryloxy; and
;~ R2 and R3 can be located at any place on the
3`~` quinolizinone ring and can be linked
together to form -CH2CH2CH2-, -C~=CH- or
-CH=CH-CH=CH-.
According to this invention, the object compound
(I) can be prepared by the processes as illustrated by
the following schemes.
6~
Process 1 :
,
7 Elimination of
R2 R R3 the carboxy 2 7 3
\ \ / protective R R R
4 sroup ~
R ~ ~ N ~ COOH
O O
(II) (Ia)
or a salt thereof or a salt thereof
Process 2 :
R2 R7 R3 R2 R7 R3
~ COOH ,~ ~1
(Ia) (Ib)
or its reactive derivative or a salt thereof
at the carboxy group or a
salt thereof
: ` :
Process 3 :
:, :
; R2 R7 R3 R2 R7 R3
~ ~ CONH .- ~ ~ C~N
: ~
(Ic) (Id)
~ or a salt thereof or a salt thereof
: 3:5
. .
..
-
.
- . :
- 4
Process 4 :
R2 7 R3 R2 R7 R3
~ ~ C=N Hydrogen s~lfide ~ C-NH
5~ N ~ ~ . ~ ~ N~ ~ 11 2
O O
(Id) (Ie)
or a salt thereof or a salt thereof
10Process 5 ~
__
R R R R2 R7 R3
C-N ~ t ~ ~ - N
O - O
(Id) (If)
: or a salt thereof or a salt thereof
Process 6 :
, .
2 7 3 Elimlnation of
R R /Ra the carboxyR2 R7 COOH
1 protectiva gro~p :
` (Ig) (Ih)
.`~. 25 or a salt thereof or a salt thereof
~ whexein R2, R3 and R7 are each as defined above,
:~ Ra is amidated carboxy, and
~. 3U~ R4 and R3~are each protected carboxy.
:: Among the starting compounds~n the present
~ invention, the compound (II) can be prepared by the
: processes which are illustrated:in the following
~ 35 schemes. :
: .
:.. .;~.. :.: - ~
Process A ~
R4 H
2 - 4 ~ 5
10(III)
(V)
or a salt thereof
or a salt thereof
Process A - (2) :
: 15 2 R
R ~ Ring closure R ~
N ~ R6 reaction~ N ~ R4
- R4 ~ R5 O
R4 (IIa)
(V) or a salt thereof
or a salt thereof
: Process B - (1) :
~ .
:~
R4 H
3~ CH ~ ~ H
(IIIc) (~c)
~5 or a sa7t: theFeof or a salt thereof
': ~
: - . .
~: , , ~ ~ .. ..
-- 6 --
~Z63~4S8
Process B - ~2) :
-
C CH~ ~
/ H~Ring closure
\\ ~ R6reaction CH ~ ~ ~
~ ~ ~ R4 J
R4 ~ R5
R4 (IIh)
~c) or a salt thereof
or a salt thereof
Process C ~
R4 H
R R
- ~ CH ) (IV) ~ (CH )
:~ N 2 n . __~N ~ 2 n
R ~ R5
(IIIa) ~4
or- a salt thereof (Va)
or a salt thereof
Process C - (2) :
: ~ (CH2)n
,G~ Ring closure ~
(CH2)n r = ~ ~ R4
R4 ~ 5 O
R
R (IIb):
or a salt thereof
: (Va)
or a salt thereof
..
Process D - tl) :
4/~==~ 5 ~ R4
(Iva) N ~
2 ~ R5
R4
(IIIb) (Vb)
10or a salt thereof or a salt thereof
Process D - t2) :
R4
~ 4 Ring closure
~N ~ R reactiOn ~ N
R4 ~ R5 O
(IIc)
H
or a salt thereof
(Vb)
or a salt thereof
.:
Process E :
~ :;
R6 Introduction of R~
- :the hydroxy ~
prote-c~iv~gro:up Rg ~ ~ ~ :
30HO ~N ~ R4 ~ ' ~N ~ R4
~ O
(XId) (IIe)
or a salt thereof or a salt thereof
:' :
':
- ~ - . ' . : , , . :
.. . ...
:
:...: -
s~
Process F :
.
~ F~
~ ~ ~ Oxidation
R4 ~ ~ ~ R4
. O
(IIf) (IIg)
or a salt thereo or a salt thereof
Process G :
,
Introduction of
the hydroxy
~ protective group
~N~cH2oH ~:H20R8
` 20 (IIId) (IIIe)
: or a salt thereof or a salt thereof
, .
Process H : ~ ~
: :;
: 25
Elimination of
8 the hydroxy
OR :: pro~ective ~ :~OH
~ ; group
~N~ R ~ ~R4 ~ ~
~ ~: :
, :
:~ or a salt thereof : or a salt thereof
~ 35
i : ~
~ :: :
,.: : : :
. .
. :: ., : . . - : :. , , ~ -. .
- 7-2 -
Processl
S Oxidation SO2
. ~ ~ ~ R4
O O
(IIj) (IIk) -- ,
or a salt thereof or a salt thereof
(to be continued to the next page.)
~;
: :
3~ :
: :
: : :
_.
'
:.~
,
. .
~Ei8~
wherein R2, R- and R are each as defined above,
R is lower al~oxy,
R6 is hydrogen, protected hydroxy, lower alkyl,
lower alkoxy, carboxy, protected carboxy,
lower alkenyloxy, aryl which may have suitable
substituent(s), arylthio, aroyl, ar(lower)-
alkyl, arenesulfonyl, arylamino which may have
a suitable substituent or aryloxy,
R8 is hydroxy protective group,
R9 is protected hydroxy and
n is 1 or 2.
Suitable pharmaceutically acceptable salts of
the object compounds (I) are conventional non-toxic
salt and include an acid addition salt such as an
organic acid salt (e.g. acetate, trifluoroacetate,
maleate, tartrate, methanesulfonate, benzenesulfonate,
formate, toluenasulfonate, etc.), an inorganic acid
salt (e.g. hydrochloride, hydrobromide, hydriodide,
sulfate, nitrate, phosphate, ~tc.),~or a salt with
an amino acid (e.g. arginine, aspartic acid, glutamic
~; acid, etc.), or a metal salt such as an alkali metal
salt (e.g. sodium salt, potassium salt, etc.) and
an alkaline earth metal salt (e.g. calcium salt,
; 25 magnesium salt, etc.?, an ammonium salt, an organic
base salt (e.g. trimethylamine salt, triethylamine ~ -
salt, pyridine salt, picoline saltj dicyclohexylamine
salt, N,N'-dibenzylethylenediamine salt, etc.),
or the like.
3~
In the above and subsequent descriptions of the
present speci~ication, suitable examples and illustrations
of the various definitions which the present invention
include within the scope thereof are explained in
detail as follows.
.: :
:
"., , '
~: ., ., : : ,, , -. - : .:
9 ~ 34S~
The term "lower" is intended to mean 1 to 6 carbon
atoms, unless otherwise indicated.
Suitable "lower alkyl" and "lower alkyl" moiety in
"ar(lower)alkyl" may include straight or branched one,
having 1 to 6 carbon atom(s), such as methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or ~he
like.
Suitable "lower alkoxy" may include methoxy,
~0 ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
tert-butoxy, pentyloxy, tert-pen~yloxy, hexyloxy, and
the like, preferably one having 1 to 4 carbon atom(s).
Suitable "lower alkenyloxy" may include vinyloxy,
l-propenyloxy, allyloxy, l-butenyloxy, 2-butenyloxy,
2-pentenyloxy, and the like, preferably ones having 2
to 4 carbon atoms.
Suitable-"protected carboxy" may include esterified
carboxy
wherein "esterified carboxy" can be referred to the
ones as mentioned below.
Suitable examples of the ester moiety of an
esterified carboxy may be the ones such as lower alkyl
ester (e.g. methyl ester, ethyl ester, propyl ester,
isopropyl ester, butyl ester, isobutyl ester, tert-butyl
ester, pentyl ester, hexyl ester, l-cyclopropylethyl
ester, etc.) which may have at least one suitable
substituent(s), for example, lower alkanoyloxy(lower)-
~0; alkyl ester [e.g~ acetoxymethyl es~er, propionyloxy-
~ methyl ester, butyryIoxymethyl ester, valer~loxymethyl
;~ ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester,
l(or 2)-~cetoxyethyl ester, l(or Z or 3)-acetoxypropyl
ester, l(or 2 or 3 or 4)-acetoxybutyl ester, l(or 2)-
propionyloxyethyl ester, I(or 2 or 3)-propionyloxypropyl
-- 10 --
8~
ester, l(or 2)-butyryloxyethyl ester, l(or 2)-
isobutyryloxyethyl ester, l(or 2)-pivaloyloxyethyl
ester, l(or 2)-hexanoyloxyethyl ester, isobutyryloxy-
methyl ester, 2-ethylbutyryloxymethyl ester, 3,3-
dimethylbutyryloxymethyl ester, l(or 2)-pentanoyloxyethyl
ester, etc.] lower alkanesulfonyl(lower)alkyl ester (e.g.
2-mesylethyl ester, etc.),
mono(or di or tri)-halo(lower)alkyl ester (e.g.
2- odoethyl ester, 2,2,2-trichloroethyl ester, etc.),
lower alkoxycarbonyloxy(lower)alkyl ester (e.g.
methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl
ester, 2-methoxycarbonyloxyethyl ester, l-ethoxycarbonyl-
oxyethyl ester, l-isopropoxycarbonyloxyethyl ester, etc.),
phthalidylidene(lower)alkyl ester, or
- 15 (5-lo~er alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester
[e.g. (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester,
(S-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,
(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.];
lower alkenyl ester (e.g. vinyl ester, allyl ester,
etc.);
lower alkynyl ester (e.g. ethynyl ester, propynyl
ester, etc.);
ar(lower)alkyl ester which may have at least one
suitable substituent(s) (e.g. benzyl ester, 4-
; 25 methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl
ester, trityl ester, benzhydryl ester,
bis(methoxyphenyl)methyl ester, 3,4-dimethoxyben~yl
ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.);
aryl ester which may have at least one suitable
substituent(s) (e.g. phenyl ester, 4-chlorophenyl ester,
tolyl ester, tert-butylphenyl ester, xylyl ester,
; mesityl ester, cumenyl ester, etc.);
phthalidyl ester; and the like.
:,
Preferable examples of the esteri~ied caxboxy
.. ..
, .
: .:
. .. . ..
:, :
.
. .:: .: . .
z~s~
as mentioned above may include lower alkoxycarbonyl
(e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarb~nyl, isobutoxycarbonyl,
tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxy-
carbonyl, hexyloxycarbonyl, l-cyclopropylethoxycarbonyl,
etc.).
Suitable "amidated carboxy" may include amide (-CONH2)
which may have suitable substituent(s) on the nitrogen
atom, wherein said substituent(s) may in~lude
heterocyclic group which may have suitable substituent(s),
aryl which may have suitable substituent(s) as mentioned
below, and the like.
"Heterocyclic group" as mentioned above means, in
detail, saturated or unsaturated, monocyclic or
polycyclic heterocyclic group containing at least one
hetero-atom such as an oxygen, sulfur, nitrogen atom
and the like.
And, especially preferably heterocyclic group may be
heterocyclic group such as
unsaturated 3 to 8-membered more preferably 5 or
6-membered heteromonocyclic group containing l to
4-nitrogen atom(s), for example, pyrrolyl, pyrrolinyl,
imidazolyl, pyrazolyl, pyrid~l and its N-oxide,
dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
triazolyl (e.g. 4H-l,Z,4-triazolyl, lH-1,2,3-triazolyl,
2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. lH-
tetrazolyl, 2H-tetrazolyl, etc.), triazinyl (e.g.
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-
membered)heteromonocyclic group containing l to 4
` nitrogen atom(s), for example, pyrrolidinyl,
imidazolidinyl, piperidino, piperazinyl, etc.;
::
- 12 -
:~68~S8
unsaturated condensed heterocyclic group containing
1 to 4 nitrogen atom(s), for example, indolyl,
isoindolyl, indolizinyl, benzimidazolyl, quinolyl,
isoquinolyl, indazolyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-
membered) heteromonocyclic group containing 1 to 2
oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,
oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.;
saturated 3 to 8-membered (more preferably 5 or 6-
membered) heteromonocyclic group containing 1 to 2
oxygen atom(s) and 1 to 3 nitrogen atom(s), for
example, morpholinyl, syndonyl, etc.;
unsaturated condensed heterocyclic group containing
1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s),
for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or
6-membered)heteromonocyclic group containing 1 to 2
sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,
thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1,2,3-
thiadia~olyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-
membered) heteromonocyclic group containing 1 to ~
sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,
thiazolidinyl, etc.;
; unsaturated 3 to 8-membered (more preferably 5 or 6-
membered) heteromonocyclic group containing 1 to 2
sulfur atom(s), for example, thienyl, dihydrodithiinyl,~ 30 dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing
: 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s),
for e~ample, benzothiazolyl, benzothiadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 to 6-
mem~ered) heteromonocyclic group containing an oxygen
. .
. :: ' :.: :
: -. . .
.:
~ :
~:61~4S8
atom, for example, furyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-
meFmbered) heteromonocyclic group containing an oxygen
atom and 1 to 2 sulfur atom(s), for example,
dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing
1 to 2 sulfur atom(s), for example, benzothienyl,
benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing
an oxygen atom and 1 to 2 sulfur atom(s), for example,
benzoxathiinyl, etc. and the like, wherein said
"heterocyclic group" may have one or more suitable
substituent(s) such as halogen (e.g., chlorine, bromine,
iodine or fluorine), lower alkyl (e.g., methyl, ethyl,
propyl, etc.) as stated above, amino, or the like.
Suitable "protected hydroxy" may include a
hydroxy group protected by a conventional hydroxy-
protectiva group, for example, lower alkyl (e.g. methyl,
ethyl, propyl, n-butyl, etc.), lower alkenyl (a.g. vinyl,
allyl, etc.), ar(lower)alkyl such as mono- or di- or
triphenyl(lower)alkyl (e.g. benzyl, benzhydryl, trityl,
etc.), etc., trisubstituted silyl such as tri(lower)-
alkylsilyl (e.g. trimethylsilyl, triethylsilyl,
isopropyldimethylsilyl, tert-butyldimethylsilyl,
diisopropylmethylsilyl, etc ), triarylsilyl (e.g.
triphenylsilyl, etc.), triar(lower)alkylsilyl (e.g.
tribenzylsilyl, etc.), etc., and the like.
~:;
Suitable "aryl" may include phenyl, tolyl, xylyl,
cumenyl, naphthyl, biphenylyl, and the like, which may
have one or more suitable substituent(s) such as amino,
nitro, halogen (e.g. fluorine, chlorine, bromine, iodine,
etc.), lower alkoxy as exemplified above, carboxy, a
protected carboxy group as exemplified above, hydroxy,
and the like.
';
13 1 126Ei~58
Suitable "aryl" moiety in the terms "arylthio",
"ar(lower)alkyl" and "arylamino" can be referred to the
ones as exemplified above.
Suitable "aroyl" may include benzoyl, toluoyl,
naphthoyl, and the like.
Suitable "arenesulfonyl" may include benzenesulfonyl,
p-toluenesulfonyl, and the like.
The aforesaid "arylamino" may have a suitable
substituent such as lower alkyl (e.g. methyl, ethyl,
etc.) on the nitrogen atom, and the like.
Suitable "aryloxy" may include phenoxy, tolyloxy,
and the like.
Suitable "hydroxy protective group" can be
referred to the ones as exemplified above.
2Q
Preferable "amidated carboxy" may be carbamoyl,
pyridylamido, pyrimidinylamido which may have lower
alkyl, pyrazinylamido, phenylamido which may have
~ hydroxy, thiazolylamido, triazinylamido, triazolylamido
`~ 25 which may have amino, pyridazinylamido which may have
halogen, or tetrazolylamido, or the like.
The processes for preparing the object compounds
(I) of the present invention are ~xplained in detail
in the following.
Process 1 :
-- .. _ . .
The object compound (Ia) or a salt thereof can be
~;
- :
.~.,., ' ~ ~
`' , ~,
', '~ '
~2~
prepared by subjecting the compound (II) or a salt
thereof to elimination reaction of the carboxy
protective group.
Suitable salt of the compound (II) can be referred
to the acid addition salt exemplified for the compound
(I) and suitable salt of the compound (Ia) can be
referred to the ones as exemplified for the compound (I).
In the present elimination reaction, all conventional
methods used in the elimination reaction of the carboxy
protective group, for example, hydrolysis, reduction,
elimination using Lewis acid, etc. are applicable.
When the carboxy protective group is an ester, it can be
eliminated by hydrolysis or elimination using Lewis acid.
The hydrolysis is preferably carried out in the presence
of a base or an acid.
Suitable base may include, for example, an inorganic
base such as alkali metal hydroxide (e~g. sodium
hydroxide, potassium hydroxide, etc.), alkaline earth
metal hydroxide (e.y. magnesium hydroxide, calcium
hydroxide, etc.), alkali metal carbonate (e.g. sodium
carbonate, potassium carbonate, etc.), alkaline earth
metal carbonate (e.g. magnesium carbonate, calcium
carbonate, etc.), alkali metal bicarbonate (e.g. sodium
bicarbonate, potassium bicarbonate, etc.), alkali metal
acetate (e.g. sodium acetate, potassium acetate, etc.),
alkaline earth metal phosphate (e.g. magnesium phosphate,
calcium phosphate, etc.), alkali metal hydrogen phosphate
(e.g. disodium hydrogen phosphate, dipotassium
hydrogen phosphate, etc.), or the like, and an organic
base such as trialkylamine (e.g. trimethylamine,
triethylamine~ etc.), picoline, N-methylpyrrolidine,
N-methylmorpholine, I,5-diazabicyclo[4,3,0]non-5-one,
,
: : . ~,:, .
~ 15 -
~8~S8
1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo-
[5,4,0]undecene-5 or the like. The hydrolysis using
a base is often carried out in water or a hydrophilic
organic solvent or a mixed solvent thereof.
Suitable acid may include an organic acid (e.g.
formic acid, acetic acid, propionic acid, etc.) and
an inorganic acid (e.g. hydrochloric acid,
hydrobromic acid, sulfuric acid, etc.).
The presPnt hydrolysis is usually carried out in
an organic solvent, water or a mixed solvent thereof.
The reaction temperature is not critical, and it
may suitable be selected in accordance with the kind of
the carboxy protectiva group and the elimination method.
The elimination using Lewis acid is preferable
to eliminate substituted or unsubstituted ar(lower)-
alkyl ester and carried out by reacting the compound
(II) or a salt thereof with Lewis acid such as boron
trihalide te.g. boron trichloride, boron trifluoride,
etc.), titanium tetrahalide (e.g. titanium tetra-
chloride, titanium tetrabromide, etc.), tin tetrahalide
(e.g. tin tetrachloride, tin tetrabromide etc.),
aluminum halide (e.g. aluminum chloride, aluminum
bromide, etc.), trihaloacetic acid (e.g. trichloro-
acetic acid, trifluoroacetic acid, etc.) or the like.This elimination reaction is preferably carried out
in the presence of cation trapping agents (e.g.
anisole, phenol, etc.) and is usually carried out in
a solvent such as nitroalkane (e.g. nitromethane,
3~ nitroethane, etc.), alkylene halide (e.g. methylene
chloride, ethylene chloride, e~c.), diethyl ether,
carbon disulfide or any other solvent which does not
adversely affect the reaction. These solvents may be
used as a mixture thereof.
:
~- . : ~ ,
. : .. ,, ~ ,. . : . . . .. ..
- ' ~
` ,. ' ;:, ~' ~ ' ,' : -
.; :: .. ~,. :
- 16 ~ 84S~
The reduction elimination can be applied preferably
for elimination of the protective group such as halo(lower)-
alkyl (e.g. 2-iodoethyl, 2,2,2-trichloroethyl, etc.) ester,
ar(lower)alkyl (e.g. benzyl, etc.) ester or the like.
The reduction method applicable for the elimination
reaction may include, for example, reduction by using a
combination of a metal (e.g. zinc, zinc amal~am, etc.)
or a salt of chromium compound (e.g. chromous chloride,
chromous acetate, etc.) and an organic or an inorganic
acid (e.g. acetic acid, propionic acid, hydrochloric
acid, etc.); and conventional catalytic reduction in the
presence of a conventional metallic catalyst (e.g.
palladium carbon, Raney nickel, etc.).
The reaction temperature is not critical, and the
reaction is usually carried out under cooling, at
ambient temperature or under warming.
The present elimination reaction of the carboxy
protective group includes, within its scope, the case
that another protected carboxy are converted into free
carboxy during the reaction or the post-treating step of
- the present process.
;:
; Process 2 :
The object compound (Ib) or a salt thereof can be
prepared by subjecting the compound (Ia) or its reactive
derivative at the carboxy group or a salt thereof to
amidation reaction.
Suitable salt of the compound (Ib) can be referred
to the salt exemplified for the compound (I).
The amidating agent to be used in the present
amidation reaction may include amine which may have
suitable substituent(s) such as heterocyclic group
which may have suitable substituent(s) or aryl which
may have su:Ltable substituent(s) on the nitrogen atom.
,.
..:
- ~ : ,
. . .
' '~
: . . .
. : ,. ~
Suitable reactive derivative at the carboxy group
of the compound (Ia) may include an acid halide, an
acid anhydride, an activated ester, and the like.
The suitable example ma~ be an acid chloride, an acid
azide; a mixed acid anhydride with an acid such as
substituted phosphoric acid (e.g. dialkylphosphoric
acid, phenylphosphoric acid, diphenylphosphoric acid,
dibenzylphosphoric acid, halogenated phosphoric acid,
etc.), dialkylphosphorous acid, sulforous acid, thio-
sulfuric acid, sulfuric acid, alkylcarbonic acid,aliphatic carboxylic acid (e~g. pivalic acid, pentanoic
acid, isopentanoic acid, 2-ethylbutyric acid or
trichloroacetic acid, etc.) or aromatic carboxylic acid
(e.g. benzoic acid, etc.); a symmetrical acid anhydride;
or an acitvated ester (e.g. cyanomethyl ester, methoxy-
methyl ester, dimethyliminomethyl [(CH3)2~=CH-] ester,
vinyl ester, propargyl ester, p-nitrophenyl ester,
2,4-dinitrophenyl ester, trichlorophenyl ester,
pentachlorophenyl ester, mesylphenyl ester,
phenylazophenyl ester, phenyl thioester, p-nitrophenyl
thioester, p-cresyl thioester, carboxymethyl thioester,
; pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl
thioester, etc.), or an ester with a N-hydroxy compound
(e.g. N,N-dimethylhydroxylamine, l-hydroxy-2-( lH)-pyridone,
N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-
6-chloro-lH-benzotriazole, etc.), and the like.
When the compound (Ia) is used in a free acid form
or its salt form in the reaction, the reaction is
preferably carried out in the presence of a conventional
condensing agent such as N,N'-dicyclohexylcarbodiimide,
N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-ethyl-N'-
(3-dimethylaminopropyl)carbodiimide, l,l'-carbonyldi-
imidazole, thionyl chloride, oxalyl chloride, lower
alkoxycarbonyl halide [e.g. ethyl chloroformate, isobutyl
:,
,
: ` . -
- 18 ~ 1 Z ~ 8 ~ 8
chloro~ormate, etc.], l-(p-chlorobenzenesulfonyloxy)-6-
chloro-lH-benzotriazole, or the like.
The reaction is usually carried out in a conventional
solvent such as water, acetone, dio~ane, chloroform,
methylene chloride,ethylene chloride, tetrahydrofuran,
ethyl acetate, N,N-dimethylformamide, pyridine or any
other organic solvent which does not adversely influence
the reaction. Among these solvents, hydrophilic solvents
may be used in a mixture with water.
The reaction in the presence of a condensing agent
is usually carried out in an anhydrous, but not critical
conditions.
The reaction may be carried out in the presence
of an inorganic or an organic base such as an alkali
metal hydroxide (e.g. sodium hydroxide, potassium
hydroxide, etc.), an alkali metal carbonate (e.g. sodium
carbonate, potassium carbonate, etc.), an alkali metal
bicarbonate (e.g. sodium bicarbonate, potassium
bicarbonate, etc.), tri(lower)alkylamine (e.g.
trimethylamine, triethylamine etc.), pyridine or its
derivative (e.g. picoline, lutidine, 4-dimethylaminopyridine,
etc.), or the like. In case that the base or the
condensing agent to be used is in liquid t it can be used
also as a solvent.
The reaction temperature is not critical, and the
reaction is usually carried out under heating or under
warming, preferably under heating.
Process 3 :
The object compound (Id) or a salt thereof can be
prepared by subjecting the compound (Ic) or a salt thereof
.
.. . ~ : ~ . .,
:
,. . :
-: .
' ' ' ,,,~ ~ ,- '. ' `' :' . -
.
~68q~S~
-- 19 --
to dehydration reaction.
The dehydrating agent to be used in this dehvdration
; reaction may include phosphory] chloride, thionyl
chloride, phosphorus pentoxide, phosphorus pentachloride,phosphorus pentabromide and the like.
The present reaction is usually carried out in a
solvent such as dioxane, chloroform, methylene chloride,
1,2-dichloroethane, tetrahydro-furan, pyridine, aceto-
nitrile, dimethylfoxmamide or any other solvent which
does not adversely affect the reaction.
The reaction temperature is not critical and the
reaction is usually carried out at ambient temperature,
under warming or heating.
Process 4 :
The object compound (Ie) or a salt thereof can be
~0 prepared by reacting the compound (Id) or a salt thereof
with hydrogen sulfide.
The present reaction is usually carried out in a
solvent such as dioxane, chloroform, methylene chloride,
1,2-dichloroethane, tetrahydrouran, pyridine, aceto-
nitrile, dimethylformamide or any other solvent which
does not adversely affect the reaction.
The reaction temperature is not critical and the
reaction is usually carried out at ambient temperature,
under warming or heating.
Process 5 :
The object compound (If~ or a salt thereof can be
prepared by subjecting the compound (Id~ or a salt thereof
~`
- 20 - ~ ~68~
to the formation reaction of a tetrazole group.
Suitable salt of the compound ~If) and (Id) can be
referred to the acid addition salt exemplified for the
compound (I)
The agent to be used in the pres~nt reaction may
include conventional ones such as combination of alkali
metal azide (e.g., potassium azide, sodium azide etc.) and
ammonium halide (e.g. ammoni~ chloride), or the like.
The present reaction is usually carried out in a
solvent such as dioxane, chloroform, methylene chloride,
1,2-dichloroethane, tetrahydrofuran, pyridine, acetonitrile,
dimethylformamide or any other solvent which does not
adversely affect the reaction.
The reaction temperature is not critical and the
reaction is usually carried out under warming or heating.
Process 6 :
The compound ~Ih) or a salt thereof can be prepared by
subjecting the compound (Ig) or a salt thereof to
elimination reaction of the carboxy protective group.
Suitable salts of the compounds (Ig) and (Ih) can be
referred to the salts exemplified for the compound (I).
The present reaction can be carried out in a similar
manner to that of Process 1 as mentioned above, and therefore
the reaction modes and conditions (e.g. reaction temperature,
solvent, etc.) are referred to those of Process 1.
Process A ~
~ , .
The compound (V) or a salt thereof can be prepared by
reacting the compound (III) or a salt thereof with the
compound (IV).
Suitable salts of the compounds(III) and (V) can be
referred to the acid addition salts exemplified for the
compound (I).
The present reaction can be preferably carried out
in the presence of alkyl lithium (e.g., n-butyl lithium),
~5 lithium dii.sopropylamide, alkalimetal aIkoxide (e.g.,
sodium methoxide, sodium ethoxide etc.) and the like.
-.:, ., , , : - .,
:; : . ,
- -: - . .. .
:., .. ... :. .. :
, ,
: ~ :
The present reaction is usually carried out in a
solvent such as acetone, dioxane, acetonitrile,
dimethylformamide, benzene, hexane, chloroform,
methylene chloride, ethylene chloride, ~etrahydrofuran,
ethyl acetate, or any other so:Lvent which does not
adversely affect the reaction.
The reaction temperature ls not critical and the
reaction is usually carried out: under cooling, at
ambient temperature or under heating.
Process A - (2) :
The compound (IIa) or a salt thereof can be
prepared by subjecting the compound (V) or a salt
thereof to ring closure reaction.
Suitable salt of the compound (V) can be referred
to the acid addition salt exemplified for the compound (I).
The present reaction may preferably be carried out
in the presence of a suitable agent such as the mixture
of diphenyl and diphenylether, which is used as heating
medium.
The reaction temperature is not critical and the
reaction is usually carried out under heating.
Process B ~
The compound (Vc) or a salt thereof can be prepared
by reacting the compound (IIIc) or a salt thereof with
the compound (IV).
Suitable salts of the compounds (Vc) and (IIIc)
can be referred to the acid addition salts exemplified
for the compound (I~.
::~
:, ~..., ~ -
,~
- 22 ~ ~2684S~
The present reaction can be carried out in a similax
manner to that of Process A ~ as mentioned above.
Process B - (2) :
_ _ _
The compound (IIh) or a salt thereof can be
prepared by subjecting the compound (Vc) or a salt thereof
to ring closure reaction.
Suitable salts of the compound (IIh) and (Vc) can
be referred to the acid addition salts exemplified for
the compound (I).
The present reaction can be carried out in a similar
manner to that of Process A - (2) as mentioned above.
Process C - (1) :
The compound (Va) or a salt thereof can be prepared
by reacting the compound (IIIa) or a salt thereof with
the compound (IV).
Suitable salts of the compound (IIIa) and (Va) can
be referred to the acid addition salts exemplified for the
compound (I).
The present reaction can be carried out in a similar
manner to that of Process A - (1) as mentioned above.
Process C - (2) :
; .
The compound (IIb) or a salt thereof can be prepared
~0~ by subjecting the compound (Va) or a salt thereof to ring
closure reaction.
Suitable salts of the compound (IIb) and (Va) can be
referred to t:he acid addition salts exemplifed for the
~5~ compound (I).
:.~
:' . ' ~ ,
:. -~ . : ,., :
.
~68~S~i3
The present reaction can be carried out in a similar
manner to that of Process A - (2) as mentioned above.
Process D ~
The compound (Vb) or a salt thereof can be prepared
by reacting the compound (IIIb) or a salt thereof with
the compound (IVa).
Suitable salts of the compounds (IIIb~ and (Vb) can
be referred to the acid addition salts exemplified for
the compound (I).
The present reaction can be carried out in a similar
manner to that of Process A - (1) as mentioned above.
Process D - (2) :
.
- 15 The compound (IIc) or a salt thereof can be prepared
by subjecting the compound (Vb) or a salt thereof to ring
closure reaction.
Suitable salts o the compounds (IIc) and (Vb) can
be referred to the acid addition salts exemplified for
the compound (I).
The present reaction can be carried out in a simllar
manner to that of Process A - (2) as mentioned above.
Process E :
The object compound (IIe) or a salt thereof can be
prepared by subjecting the compound (IId) or a salt
thereof to introduction reaction of the hydroxy
protective group.
Suitable salt of the compounds (IId) and (IIe)
3~ can be referred to the acid addition salts as exemplified
for the compound (I).
In case that the protective group to be introduced
are lower alkyl or lower alkenyl, the reaction can be
carried out by reacting the compound (IId) with lower
3S alkylating agent or lower alkylating agent.
'
~ .
' .
: ,.'-: : . -
..
- 24 ~ ~Z68~
The lower alkylating agent or lower alkenylating
agent to be used in the present reaction may include
conventional one such as mono(or di)lower alkyl sulfate
(e.g. dimethyl sulfate, etc.), lower alkyl(lower)-
alkanesulfonate (e.g. methyl methanesulfonate, etc.),
halo(lower)alkane (e.g. bromomethane, iodomethane,
iodoethane,iodobutane etc.), halo(lower)alk.ene (e.g.
iodopropene etc.) or the like.
When lower alkyl ester of an acid is used as a
lower alkylating agent, the reaction is usually carried
out in a solvent such as water, acetone, tetrahydrofuran,
ethanol, ether, dimethylformamide or any other solvent
which does not adversely influence the reaction.
The present reaction is preferably carried out in
the present of a conventional base such as an inorganic
base or an organic base.
The reaction temperature is not critical and the
reaction is usually carried out under cooling to heating
around boiling point of the solvent.
ZO
Process F :
The compound (IIg) or a salt thereof can be prepared
by subjecting the compound (IIf) or a salt thereof to
oxidation reaction.
Z5 Suitable salt of the compound (IIf) can be referred
to the acid addition salt exempli~ied for the compound (I).
~uitable oxidizing agent to be used in this
oxidation reaction may include conventional ones such
as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone ~DDQ),
: ~a and the like.
The present o~idation is carried out with solvent
such as benzene, toluene, chloroform, methylene chloride,
carbon tetrachloride, diethyl ether, dimethylformamide
or any other solvent which does not adversely affect
~5~ the reaction, and the solvent is optionally selected
.
- -~.: - - . ~ -
:,. : - ~ : . :
.: ~: ~. -
, :,.. i. , .
: -, :
.. .. - ~,
- 25 - ~ ~6~5~
according to a kind of oxidizing a~ent to be used.
The reaction temperature of the oxidation reaction
oftthis process is not critical, and the reaction is
carried out under coolin~, at ambient temperature, under
warming or under heating. The reaction temperature is
optionally selected according to a kind of oxidizing
agent to be used.
Process G :
The compound (IIIe) or a salt thereof can be
prepared by subjecting the compound (IIId) or a salt
thereof to introduction reaction of the hydroxy
protective group.
The present reaction can be carried out in a
conventional manner.
In case that the protective group to be introduced
is a silyl group, the present reaction is carried out
by reacting the compound (IIId) or a salt thereof with
the compound of the formula :
Ra - X (VI)
wherein Ra is a trisubstituted silyl and
X is an acid residue.
.
Suitable acid residue may include halogen (e.g.,
chlorine, bromine; etc.) or the like.
The present reaction is preferably carried out in
the presence or imidazole, 4-substituted imidazole,
dimethylpyrazole, triazole or tetrazole.
~o The reaction is usually carried out in a conventional~
solvent such as water, acetone, dioxane, acetonitrile,
chloroform, methylene chloride, ethylene chloride,
tetrahydrofuran, ethyl acetatP, N,N-dimethylformamide,
pyridine or any other organic solvent which does not
adversely influence the reaction.
. .
.
.,..: .
.: ;~
:
' ~ , .
:
. .
:. ,
- ~ . ~ , ~, ,,...... , .. :
- ,
25 1 ~ 2 6~ ~ S ~
The reaction temperature is not critical and the
reaction is usually carried out under cooling, at
ambient temperature or under warminy.
Process H :
The compound (IIi) or a salt thereof can be
prepared ~y subjecting the compound (IIh) or a salt
thereof to elimination reaction of the hydroxy protective
group.
The present elimination reaction is carried out
in accordance with a conventional method such as
Process 1.
The present reactlon is preferably carried out
in the presence of a mild reagent such as
tetra-n-butylammonium fluoride.
The reac~ion is usually carried out in a con-
ventional solvent such as water, acetone, dioxane,
acetonitrile, chloroform, methylene chloride, ethylene
chloride, tetrahydrofuran, ethyl acetate,
N,N-dimethylformamide, pyridine or any other organic
solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the
reaction is usually carried out under cooling, at
ambient temperature or under warming.
- (to be continued to the next page.)
:
:`
3~
: :
:'
.. . : .
:- , -
- 25-2 -
~2~ 58
~roceSs I
The object compound (IIk) or a salt thereof can
be prepared by oxidizing the compound (IIj) or a salt
- thereof.
The oxidizing agent to be used in this reaction
may include an inorganic peracid or a salt thereof
(e.g. periodic acid, persulfuric acid, or sodium or
potassium salt thereof, etc.), an organic peracid or
a salt thereof (e.g. perbenzoic acid, m chloro-
perbenzoic acid, performic acid, peracetic acid,
chloroperacetic acid, trifluoroperacetic acid, or
sodium or potassium salt thereof, etc.), ozone,
hydrogen peroxide, urea-hydrogen peroxide, N-
halosuccinimide (e.g. N-bromosuccinimide, N-chloro-
succinimide, etc.), hypochlorite compound (e.g.
tert-butyl hypochlorite, etc.), permanganate (e.g.
potassium permanganate, etc.), or any other conventional
oxidizing agent which can oxidide a sulfinyl group
to a sulfonyl group.
The present reaction can also be carried out in
the presence of a compound comprising Group Vb or VIb
metal in the Periodic Table of elements, for example,
tungstic acid, molybdic acid, vanadic acid, etc., or
an alkali or an alkaline earth metal salt thereof.
The present oxidation reaction is usually carried
out in a conventional solvent which does not adversely
influence the reaction such as water, acetic acid,
chloroform, methylene chloride, acetone, methanol,
ethanol or a mixture thereof.
The reaction temperature is not critical and the
reaction is preferably carried out under cooling to
at ambient temperature.
. .
.
:
, :
'; ' ; : ': . : ' :
~ , " ,
;8~
- 25-3 -
Particularly, the compounds (I) possessing the
most potent antimicrobial activity can be represented
by the following formula:
Ri R3
R2f~N ~1
wherein Rl, R2, R3 and R7 are each as defined above,
and more particularly, Rl is tetrazolylamido,
R2 and R7 are each hydrogen, and
R3 is aryloxy or aroyl.
(to be continued to the next page.)
,
~ ~ ,
.:
. 30
:
,~
:
:~
~: .. : ::. .: .
. . ~ : : :: . .
' 1'.', . . . .. , - . .
- 25-4 -
lZ684~
For the purpose of showing pharmaceutical utility
of the quinolizinone compound (I), pharmaceutical test
data thereof are illustrated in the following.
S [1] Test compound :
N-[5-(lH-Tetrazolyl)l-4H-quinolizin-4-one-3-
carboxamide (hereinafter referred to as compound
~ ) ..
N-[5-(lH-Tetrazolyl)]-l-phenyl-4H-quinolizin-
4-one-3-carboxamide (here:inafter referred to as
compound ~ )
[2] Test :
(A) Inhibition on stress ulcer
Test Method :
Sprague-Dawley rats weighing about 200 g were used.
Each animal was immobilized in a small cage and put in
- a water bath allowing to respire. The temperature
of the water bath kept at 22C. The test compound ~ and
X were administered orally just before the immobilization.
Seven hours la~er, the animals were sacrificed ~nd
their stomachs were removed. The stomach was then
; fixed with 2% formalin. The area of ulcers was measured
for each animal. The mean area (mm2) in the test
animals was compared with that in the control animals. ;
~ ~a
:
`: :
.
.
.
- 26 -
:126~5~
Test Result :
" Ulcer index .
. Treatment No. -'2 . Inh.
1 19 Mean + S.E. .
2 26
~ ~ 19.2 + ~.8
Compound ~ 2 5
L~ 6.~ + 3.0 67
.7
_ _ . ~ ~ _ .
: Ulcer index
: Treatment No. 2 . . Inh. %
mm Mean~+ S.E.
Control ~ ~ 48.4 + 3~3
~ 1 10 . ~ . _
`~: Compound ~ : 2 ll :
3 3 8.4 ~ 1.9 83.7
3s ~ ~
~ r:
' ~
~ ' ` ' ,' '~ . . ..
. . ',1 : .
` . .
,~ . , ': '.
~Z~i8458
(B) Effect on passive cutaneous anaphylaxis (PCA).
~ Test Method
Recipient animals for PCA reactions were female
Sprague-Dawley rats, 7 weeks old, 180g-200g (Nihon Kurea).
Each experiment included 5 observations.
Five times crystallized ovalbumin (OVA) (Sigma Lot,
31F-8061) was used as antigen.
Female BDFl mice, 7 weeks old (Nihon Kurea~, were
- given a primary injection (lefl foot pad, s.c.) of
100 mcg OVA in 0.05ml saline and after 20 days a booster
injection by the same route. Blood was collected 28
- days after the primary injection and the sera were
stored at -80C.
The animals were shared with an electric clipper in
advance and prepared for Passive Cutaneous Anaphylaxis
- (PCA) by injecting 0.05ml of mouse antiserum dilutions
(1/16, 1/32) in each side of the dorsal skin.
They were then challenged 48 hours later with an
intravenous injection of 1 ml of 0.5% Evans Blue containing
5 mg OVA. Fifty minutes later, they were killed and the
lesions (diameter) mFasured.
A minimal skin response was one with a 5 mm or
greater diameter blue spot measured on the dermal side
of reflected skin. Drug activity was estimated using
3~ the following formula;
inhibition = (1 ~ ) x 100
Drugs were suspended in 0.1% methyl cellulose/saline
and yiven intravenously with the antigen.
. .
~: :::
: . : ~
';
.:, .: ~ .
; ~. . .~
.. ~
- 28 -
~:6Ei ~5~
Test Result :
. _ . .. .. ._
. Dose Inhibition (%)
S rng/kg Antiserum concentration
.. ._ 1/16 1/3
1 97.2 100
Compound ~ . - . .
94.5 100
1 0 . . .. .. _
The pharmaceutical composition of this invention
can be used in the form of a pharmaceutical preparation,
for example, in solid, semisolid or liquid form, which
contains an active substance of this invention in
admixture with an organic or inorganic carrier or
excipient suitable for external, oral or parenteral
applications. The active ingredient may be compounded,
for example, with the usual non-toxic, pharmaceutically
acceptable carriers for tablets, pellets, capsules,
; suppositories/ solutions, emulsions, suspensions, and
any other form suitable for use. The carriers which
can be used are water, glucose, lactose, gum acacia,
gelatin, mannitol, starch paste, magnesium trisilicate,
talc, corn starch, keratin, collidal ilica, potato ~ ::
starch, urea and other carriers suitable for use in
manufacturing preparations, in solid, semisolid, or ::~
liquid form, and in addition auxiliary, stabilizing,
thickening and coloring agents and perfumes~may be
~:; 30 used. The pharmaceutical compositions can also contain ::
- preservative or bacteriostatic agents to keep the
active ingredient in the desired preparations stable ~ ~:
: in acti~ity. The active object compound is included
~: in the pharmaceutical:composition in an amount sufficient
:~ 35 to produce the desired therapeutic effect upon the
'
.
' . '~ ' :
. :
:
~, : : -
..
. :. . ::
- 29 -
lZ~i84S8
process or condition of diseases.
For applying this composition to humans, it is
preferably to apply it by intravenous, intramuscular
S or oral administration. ~hile the dosage or thera-
peutically effective amount of the object compound
of this invention varies from and also depends upon
the age and condition of each individual patient to
be treated, a daily doses of about 0.05-5 mg of the
active ingredien~kg of a human being or an animal
in generally give for treating diseases, and an average,
single dose of about 2.5 mg, 25 mg and 250 mg in generally
administered.
The following preparations and examples are given
for purpose of illustrating this invention.
Preparation 1
To a solution of 2-methylpyridine (7 ml) in tetra-
~0 hydrofuran (140 ml) was added dropwise a solution of
n-butyl lithium (49 ml of 1.59 mol solution in hexane)
with ice-cooling. The resulting dark red solution was
allowed to warm to ambient temperature and stirred for
an hour. After cooling to -78C, a solution of diethyl
ethoxymethylenemalonate (15.68 ml) in tetrahydrofuran
(50 ml) was added over a period of 30 minutes. The
reaction mixture was allowed to warm to -20C and
stirred for 30 minutes at -20C. Acetic acid (4.48 ml)
was added. The solvent was distilled off, the residue
3~ wa~ dissolved in ethyl acetate and washed with 10%
aqueous solution of sodium bicarbonate, water and
saturated aqueous sodium chloride~ After drying over
magnesium sulfate, the ethyl acetate extract was filtered
and evaporated to give an oil (27 g). The residue was
~5 chromatographed on silica gel (Merck 70 - 230 mesh, 270 g)
, ,~"
.
' ~
` ~
.~ :
~ 30 - ~ z
eluting with chloroform to give ethyl 3-ethoxy-2-
ethoxycarbonyl-4-(2 pyridyl)butyrate (19 g) as an oil.
IR (film) : 1730, 1590, 1470, 1440, 1370 cm 1
NMR (CDC13) ~ : 0.97 tt, 3H, ~=8Hz), 1.26 tt, 6H,
J=8Hz), 3.12 (d, lH, J=8Hz), 3.2-3.6 (m, 2H),
3.~2 (d, lH, J=8Hz), 4.21 (q, 4H, J=8Hz),
4.47 (q, 2H, J=8Hz), 6.97-7.80 (m, 3H),
8.42-8.67 (m, 1~)
Preparation 2
A mixture of ethyl 3-ethoxy-2-ethoxycarbonyl 4-
(2-pyridyl)butyrate (18.9 g), diphenyl (48.85 g) and
diphenyl ether (135.8 g) was heated to 250C for 40
minutes. The reaction mixture was cooled to ambient
temperature and chromatographed on silica gel (Merck
70-230 mesh, 620 g) eluting with hexane and then a
mixture of ethanol and chloroform (1:49~ to give a
crude oil, which was crystallized from a mixture of
ether and haxane (1:1) to give 3-ethoxycarbonyl-4X-
quinolizin-4-one (11.48 g) as yellow crystal.
IR (Nujol) : 1670, 1625, 1490 cm 1
NMR (CDC13) ~ : 1.42 (t, 3H, J=7Hz)/ 4.42 (q, 2H,
J=7Hz), 6.62 (d, lH, J=8Hz), 7.02-7.38 (m, lH),
; 7.53 7.68 (m, 2H), 8.33 (d, lH, J=8Hz~,
9.23-9.47 (m, lH)
Preparation 3
The following compounds were obtained according to
a similar manner to that of Pre~a a lon 1.
~1) Ethyl 3-ethoxy-2-ethoxycarbonyl-4-[2-~5-
ethylpyridyl)]butyrate.
; IR (film) : 1750, 1730 cm
,:~
.:
(2) Ethvl 3-ethoxy-2-ethoxycarbonyl-4-(2-~uinolyl)-
butyrate.
;.~ :
;
- . . -
, ,,.. , - ,
.
- 31 -
~684S15
IR (film) : 1750 (sh), 1730 cm 1
(3) Ethyl 4-phenyl-3-ethoxy-2-ethoxycarbonyl-4-
(2-pyridyl)butyrate.
IR (film) : 1750 (sh), 1730 cm 1
(4) Ethyl 3-e~hoxy-2-ethoxycarbonyl-4-[2-(5-
hydroxypyridyl)]butyrate.
IR (fi~m) : 2550, 1730, 1490, 1270, 1160, 1090,
1025 cm 1
NMR (CDC13) ~ : 0.97 (t, 3H, J=7Hz), 1.25 (t, 6H,
J=7Hz), 3.07 (d, 2H, J=5Hz), 3.20-4.77 (m, 8H),
6.47 (m, lH), 7.07-7.37 (m, 2H), 8.17 (m, lH)
(5) Ethyl 3-ethoxy-2-ethoxycarbonyl-4-(1-isoquinolyl)-
butyrate.
IR (film) : 1750, 1730 cm 1
(6) Ethyl 3-ethoxy-2-ethoxycarbonyl-3-[8-(5,6,7,8-
tetrahydroquinolyl)]propionate.
IR (film) : 1750, 1730 cm 1
(7) Ethyl 3-ethoxy-2-ethoxycarbonyl-4-~2-(3-
methylpyridyl)]butyrate.
IR (Nujol~ : 1750, 1735, 1575, 1440, 860, 790 cm 1 ~ ;
N~R (CDC13) ~ : 0.92 (t, 3H, J=5Hz), 1.27 (t, 6H,
J=5Hz), 2.37 (s, 3H), 3.08-3.60 (m, 4H),
3.70 (d, lH~, ~=SHz), 4.~18 (q, 2H, J=5Hz),
4.22 (q, 2H; J=SHz), 4.52 (m, lH), 7.05 (dd, ;
3~ lH,-J=6Hz and 3~z), 7.45 (d, lH, J=6Hz),
8.42 (d, lH, J=3Hz)
(8) Ethyl 3-ethoxy-2-carboethoxy-4-[2-(4-
methylpyridyl)]butyrate.
- 35 IR (film) : 1750, 1730, 1600, 1240, 1150, 1020 cm 1
, :
:;: :
~.:
~ ..... .
,.
- : .
' ~, .: ~ : , . : ' '
- 32 - ~ ~6~45~
.
NMR (CDC13) ~ : 0.97 (t~ 3H, J=7Hz), 1.27 (t, 6H,
J-7Hz), 2.32 (s, 3H), 3.10 (d, 2H, J=5.5Hz),
3.28-3.58 (m, 2H), 4.20 (q, 3H, J=7Hz),
4.23 (q, 3H, J-7Xz), 6.87-7.13 (m, 2H),
8.40 (d, lH, J=6Hz)
(9) Ethyl 3-ethoxy-2-ethoxycarbonyl-4-[2-(6-
methylpyridyl~]butyrate.
IR (film) o 1650, 1630, 1590, 1580, 1270, 1150,
1090 cm
NMR (CDC13) ~ : 0.97 (t, 3H, J=7Hz), 1.25 (t, 6H,
J=7Hz), 2.48 (s, 3H), 3.07 (d, 2H, J=5.5Hz),
3.60 (q, 2H, J=7Hz), 3.23-3.57 (m, lH),
4.18 (q, 4H, J=7Hz), 4.33-4.67 (m, lH),
6.85-7.15 (m, 2H), 7.33-7.66 (m, lH)
(10) Ethyl 3-ethoxy-2-ethoxycarbonyl-4-(2-pyridyl)-
pentanoate.
IR (film) : 1750, 1730, 1590, 1300, 1090, 1020 cm
NMR (CDC13) ~ : 1.00 (t, 3~, J=7Hz), ~1.35 (t~ J=7Hz),
; 1.25 (t, J=7Hz), 1.25 (s) 9H], 3.00-3.75 (m, 4H),
3.93-4.58 (m, 5H), 6.98-7.60 (m, 2H), 7.65
(m, lH), 8.58 (m, lH)
(11) Ethyl 3-ethoxy-2-ethoxycarbonyl-4-~2-(5- ;
methylpyridyl)]butyrate.
;~ IR (film) : 1740, 1730, 1600, 1480, 1150, 1090,
1025 cm 1
; NMR (CDC13) ~ : 1.00 (t, 3H, J=7Hz), 1.27 (t, 6H,
3a J=7Hz), 2.32 (s, 3H), 3.00-3.77 (m, 4H),
4.22 (q, 3H, J=7Hz), 4.25 (q, 3H, J=7Hz),
7.03-7.50 (m, 2H), 8.37 (m, lH)
,~
(12) Ethyl 3-ethoxy-2-ethoxycaxbonyl-3-~7-(6,7-
~ 35 dihydro-5H-cyclopenta [b] pyridyl~]pxopionate.
:1 :
:
- 33 -
lZG84~ii8
IR (film) : 1750 (sh), 1730, 1590, 1580 cm 1
NMR (CDC13) ~ : 0.80 (t, 3H, J=7Hz), 1.30 (t, 6H,
~=7Hz), 2.00-2.40 (m, 2H), 2.80-3.70 (m, 4H),
4.0 (q, 2H, J=7Hz), 4.20 (q, 4H, J=7Hz),
4.80 (dd, lH, J=8Hz and 2Hz), 7.00-7.60 (m, 2H),
- 8.3-8.50 (m, lH)
(13) Ethyl 3-ethoxy-4-methoxy-4-(2-pyridyl)-2-
ethoxycarbonylbutyrate.
IR (~ilm) : 1750, 1730, 1590, 1365, 1090, 1025,
760 cm 1
NMR (CDC13) ~ : 0.78 (t, 3H, J=7Hz), 1.25 (t, 3H,
J=7Hz), 1.28 (t, 3H, J=7Hz), 3.33 (d, 2H,
J=4Hz), 3.60-4.60 (m, ~H ), 7.07-7.90 (m, 3H),
8.62 (m, lH)
(14) Ethyl 3-ethoxy-4-ethoxycarbonyl-4-(2-pyridyl)-
butyrate.
.; ~ :
20 Prepa_ation 4
:
The following compounds wexe obtained according to
a similar manner to that of Preparation 2.
~;~ (1) 2-Ethoxycarbonyl-lH-pyrido[1,2-a]quinolin-1-one.
mp. 104-105C. : ~ :
IR (Nujol) : 1730, 1660, 1530 cm 1
;~ NMR (CDC13) ~ : ~ 1.43 (t, 3H, J=7Hz), 4.43 (q, 2H,
J=7Hz), 6.40 (d, lH, J=8Hz)~, 7.0 and 7.45
; (ABq, 2H, J=lOHz), 7.50-7.70 (m, 4H), 8.20
: ~30 (d, lH, J=8Hz~, 9.70-10.0 (m, IH) ~;
~ (2) 7-Ethyl-3-athoxycarbonyl-4H-~uinolizin-4-one.
- mp. 81-83C.
IR (Nujol) : 1720, 1630 cm 1
;35 NMR (CDC13) ~ : 1.32 (t, 3H, J=7Hz), 1.44 (t, 3H,
.
' ,::: - ' ~ -
- 34 ~ iLZ ~ 845 8
J=7Hz), 2.76 (q, 2EI, J=7Hz), 4.40 tq, 2H,
J=7Hz), 6u60 (d, lH, J=8Hz), 7.52 (s, 2H),
8.32 (d, lH, J=8Hz), 9.20 (s, lH)
(3) 1-Phenyl-3-ethoxycar~onyl-4H-quinolizin-4-one.
mp. 120-123C.
IR (Nujol) : 1730, 1620 cm 1
NMR (CDC13) ~ : 1.36 (t, 3H, J=7Hz), 4.38 (q, 2H,
J=7Hz), 7.04-7.76 (m, 7H), 8.32 (s, lH),
9.48 (d, lH, J=8Hz)
(4) 8-Hydroxy-3-ethoxycarbonyl-4H-quinolizin-4-one.
mp. 242C. ~dec.)
IR (Nujol) : 3300, 3200, 1680, 1660, 1620, 1300,
;; 15 1140, 960, 900 cm 1
` NMR (DMSO-d6) ~: 2~27 (t, 3H, J=7Hz), 4.23 (q, 2H,
J=8Hz), 6.13 (d, lH, J=8Hz), 7.58 (dd, lH,
J=2Hz, 8Hz), 7.90 (d, lH, J=8Hz),
8.07 (d, lH, J=8Hz), 8.82 (d, lH, J=2Hz)
Anal. Calcd for C12HllNO4 : C, 61~80; H~ 4-75
Found : C, 62.18; H, 5.05
`l (5) 3-E~hoxycarbonyl-4H-pyrido~2,1-a~isoquinolin-4-
`~' one. mp. 155C.
IR (Nujol) : 3100, 1740, 1650, 1640 cm 1
NMR (CDC13) ~ :~ 1.46 (t, 3H, J=7Hz), 4.46 (q, 2H,~
J=7Hz), 7.23 (d, lH, J=8Hz), 7.35 (d, lH,
J=8Hz), 7.50-7.83 (m, 3H), 8.20-8.50 (m, lH),
8.46 (d, lH, J=8Hz), 9.10~(d, lH, J=8Hz),
` ~ 30 Anal. Cal~d for C16H13NO3 :
C; 71.90, H; 4.90, N; 5.24
Found : C; 71.40, H; 5.06, N; 5.17
::` ` : : :
(6) 9-Nethyl-3-ethoxycarbonyl-4H-quinoLizin-4-one.
mp. 125-126C.
: ~
:~
- 35 - ~Z6~4s~
IR (Nujol) : 3090, 1725, 1645, 1590, 1125,
1100 cm 1
NMR (CDC13) ~ : 1.40 (t, 3H, J=7Hz~, 2.50 (s, 3H),
4.42 (q, 2H, J=7Hz), 6.63 (d, lH, J=9Hz),
7.07 (t, lH, J=7Hz), 7.47 (d, lH, J=7Hz),
8.35 (d, lH, J=9Hz), 9.32 (d, J=7Hz, lH)
13 13 3 C; 67.52, H; 5.67
Found : C; 67.51, H; 5.83
_ (7) 8-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-
one. mp. 146-148C.
IR (Nujol) : 3060, 1720, 1660, 1640, 1245, 1155,
790 cm~l
NMR (CDC13) ~ : 1.40 (t, 3H, J=7Hz), 2.50 (s, 3H),
4.38 (q, 2H, J=7Hz), 6.50 (d, lE, J=9Hz),
7.00 (dd, lH, J=7Hz, 2Hz), 7.30 (d, lH,
J=2Hz), 8.32 (d, lH, J=9Hz), 9.28 (d, lH,
J=7Hz)
r C13H13NO3 : C; 67.52, H; 5.67
Found : C; 67.38, H; 5.65
(8) 3-Ethoxycarbonyl-6-methyl-4H-quinolizin-4-
one. mp. 90-93C.
IR (Nujol) : 1720, 1650, 1620, 1590, 1265, 1120,
~ 1100, 795 cm 1
NMR (CDC13) ~ : 1.35 (t, 3H, J=7Hz), 3.05 (s, 3H),
4.38 (q, 2H, J=7Hæ), 6.38 (d, lH, J=8Hz),
6.67 (m, lH), 7.25 (d, lH, J=4.5Hz),
8.18 (d, lH, J=8Hz)
Anal. Calcd for C13H13NO3 :
C; 67.52, H; 5.67, N; 6.07
Found : C; 67.28, H; 5.63, N; 6.03
(9) 1-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-
one. mp. 142-143C.
, . ~ . .
. ~.
.
~ . :
- 36 - ~Z~5~
IR (Nujol) : 1720, 1650, 1620, 1595, 1300, 1230,
1160, 1120, 775 cm 1
NMR (CDC13) ~ : 1.42 (t, 3H, J=7Hz), 2.40 (s, 3H),
4.43 (q, 2H, J=7Hz), 7.20 (m, lH), 7.62-7.80
; 5 (m, 2H), 8.25 (s, lH), 9.47 (m, 1~)
Anal. Calcd for C13H13NO3 :
C; 67.52, H; 5.67, N; 6.06
Found : C; 67.49, H; 5.94, N; 6.06
(10) 7-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-
one. mp. 146-149C.
IR (Nujol) : 1720, 1620, 1145, lIlD cm 1
NMR (CDC13) ~ : 1.42 (t, 3H, J=7Hz), 2.45 (s, 3H),
4.43 (q, 2H, J=7Hz), 6.62 (d, lH, J=8Hæ),
7.47-7.57 (m, 2H), 8.33 (d, lH, J=8Hz),
9.23 (m, lH)
Anal. Calcd for C13H13NO3
C; 67.52, H; 5.62, N; 6.06
Found : C; 67.44, H; 5.85j N; 6.00
(11) 2-Ethoxycarbonyl-8,9-dihydrocyclopenta[ij¦-3H-
quinolizin-3-one. mp. 149C.
`l IR (Nujol) : 3100, 1720, 1640, 1620, 1600, 1550,
1210, 1150 cm 1
; 25 NMR (CDC13) ~ : 1.43~(t, 3H, J-7Hz), 3.30 (broad s,
4H), 4.30 (q, 2H, J=7Hz),~ 7.0-7.30 ~m, 2H),
8.30 (s, lH), 8.86 (d, lH, J=6Hz)
Anal. Calcd for C14H13NO3 :
C; 69.12, H; 5.39, N; 5.76
Found : C; 68.16, H; 5.47, N; 5.69
:~ :
~12) 2-Ethoxycarbonyl-9,10-dihydro-8H-benzo[ij]-3H-
quinoli2in-3-one. mp. 118C.
IR (Nujol) ~: 1680, 1620, 1600, 1220 cm
NMR (CDC13) ~ : 1.40 (t, 3~, J=7Hz), 1.85-2.20 (m, 2H),
:: :
::
, . , ... ... ~ . .
- 37 -
~Z16~5~
2.80-3.20 (m, 4H), 4.40 (q, 2H, J=7Hz),
6.85-7.30 (m, 2H), 8.13 (s, lH), 9.20 (d, lE,
J=7Hz)
Anal. Calcd for C15H15NO3 :
C; 70.02, ~; 5.88, N; 5.44
Found : C; 69.78, ~; 5.95, N; 5.38
(13) 1-Methoxy-3-ethoxycarbonyl-4H quinolizin-4-
one. mp. 132-133C.
IR (Nujol) : 1680, 1670, 1620, 1595, 1360, 1120,
1020, 770 cm
NMR (CDC13) ~ : 1.43 (t, 3H, J=7Hz), 3.93 (s,
3H), 4.45 (q, 2H, J=7Hz), 7.25 (m, lH),
7.67 (m, lH), 7.97-8.20 (m, 2H), 9.47 (d,
lH, J=7.5Hz)
Anal. Calcd for C13H13NO4 :
C; 63.15, H; 5.30, N; 5.66
Found : C; 62.80, H; 5.33, N; 5.63
(143 1-Ethoxycarbonyl-4H-quinolizin-4-one.
mp. 114C.
IR (Nujol) : 1725, 1680, 1630 c~ 1
Anal. Calcd for C12HllNO3 :
~ C; 66.35, H; 5.10, N; 10.45
-~ 25 Found : C; 66.19, H; 4.81, N; 6.42
-~ Preparation 5
A solution of 2-ethoxycarbonyl-8,~-dihydrocyclopenta-
[ij]-3H-quinolizin-3-one (2.2 g)~and~dich}orodicyano-
benzoquinone (2~26 g) in benzene (110 ml) was refluxed
for two hours. The reaction mixture was cooled to 0C
and the precipitates were filter~ed The filtrate was
concentrated and the residue was chromatographed on
silica gel column (44 g) eluting with chloroform-methanol
(100:1 - 10:1). Evaporation of corresponding fractions
:
: ` :
~: :
- 38 -
~Z~8~
gave crude crystals which was washed with a mixture of
ether and hexane to afford 2-ethoxycarbonylcyclopenta-
[ij]-3H-quinolizin-3-one (1.82 g), mp. 127C.
IR (Nujol) : 3100, 1680-1700 (broad), 1620, 1570,
S 1230, 1210 cm 1
NMR (CDC13)~ : 1.46 (t/ 3H, J=7Hz), 4.46 (q, 2H,
J=7Hz), 6.80-7.60 (m, 3X), 8.13 (d, lH, ~=8Hz),
8.70 (s, lH), 9.20 (d, lH, J=8Hz)
Anal. Calcd for C14HllNO3 :
C; 69.70/ H; 4.60, N; 5.81
Found : C; 69.34, H; 4.80, N; 5.78
Preparation 6 :
To a stirred solution of 3-ethoxycarbonyl-7-hydroxy-
4H-quinolizin-4-one (4.5 g) in dry N,N-dimethylformamide
(90 ml) was added sodium hydride (60% in mineral oil,
0.93 g) at room temperature an~ the resulting solution
was kept for 30 minutes at 50C. The rcac~tion mixture
was treated with methyl iodide (4.13 g) and stirred for
30 minute at the same temperature. The reaction mixture
` was poured into dilute hydrochloric acid solution and
extracted with chloroform. The organic layer was washed
` with water, dried over anhydrous magnesium sulfate and
evaporated to give an oil (12.3 g) which was applied to
a silica gel column. Elution with chloroform-methanol
(99:1) ga~e 3-ethoxycarbonyl-7-methoxy-4H-quinolizin-
4-one (3.75 g), mp, 156-158C.
IR (Nujol) : 1720, 1620, lS00, 1140, 1100 cm 1
NMR (CDC13) ~ : 1.43 (t, 3H,~J=7Hz), 3.93 (s, 3H),
4.43 (q, 2H, J=7Hz), 6.63 (d, lH, ~=8.5Hz),
7.23-7.70 (m, 2H), 7.28 (d, lH, ~=8.5Hz),
9.00 (m, lH)
; Anal. Calcd for C13H13NO4 : C; 63.15, H; 5.30
Found : C; 62.62, H; 5.52
. .
,..
.
- 3~ -
45~
Preparation 7
The following compounds were obtained according
to a similar manner to that of Preparatlon 6.
S (1) 3-Ethoxycarbonyl-7-n-butoxy-4H-quinolizin-4-one.
mp. 132-133C.
IR (Nujol) : 1710, 1620, 1540, 1280, 1240, 1140,
845, 780 cm 1
NMR (CDC13) ~ : 1.00 (t, 3H, J=6Hz), 1.43 (t, 3H,
J=7.5Hz), 1.50-2.33 (m, 4H), 4.10 (t, 2H,
J=6Hz), 4.43 (q, 2H, J=7.5Hz), 6.63 (d, lH,
J=8Hz), 7.23-7.67 (m, 2H), 8.28 (d, lH,
J=8Hz), 8.97 (d, lH, J=2Hz)
Anal. Calcd for C16H19NO4 :
C; 66.42, H; 6.62, N; 4.84
Found : C; 66.54, H; 6.52, N; 4.82
(2) 3-Ethoxycarbonyl-7-isopropoxy-4H-quinolizin-
4-one. mp. 132-134C
IR (Nujol) : 1725, 1625, 1240, 1140, 1100, 970,
840 cm~l
NMR (CDC13) ~ : 1.42 (d, 6H, J=6Hz), 1.43 (t, 3H,
J=7.5Hz), 4.43 (q, lH, J=7.5Hz), 4.65 (m, 2H),
6.62 (d, lH, J=8.5Hz), 7.20-7.68 (m, 2H),
8.27 (d, lH, J=8.5Hz) t 9.00 (d, lH, J=2Hz)
Anal. Calcd for C15H17NO4 :
C; 65.44, H; 6.22, N; 5.09
Found : C; 65.66, H; 6.15, N; 5.10
Preparation 8
A solution of ethyl 2-pyridyl acetate (6.10 ml) in
ethanol (120 ml) containing sodium ethoxide (3.25 g)
was refluxed for one hour. The resulting reaction mixture
was treated with ethyl ethoxyacrylate (7.06 ml) and then
; 35 refluxed for three days. Acetic acid (4.6 ml) was added
.
: . :
. ~ .. - . . - .: . : - - :
.: : ~ , , :
:
; ~. :. .
- ~o -
~Z6~51~
to the reaction mixture and the solvent was evaporated
to dryness. The oily residue was dissolved in ethyl
acetate and washed with water, aqueous sodium bicarbonate
solution. The organic layer was dried over magnesium
S sulfate and then evaporated to give an oily residue
which was chromatographed on silica gel column.
Elution with benzene-ethyl acetate (lO:l) gave ethyl
3-ethoxy-4-ethoxycarbonyl-4-(2-pyridyl)butyrate (9.80 g)
as an oil.
---
(to be continued to the next page.)
::~
..
... . .. ..
~: ,
.
.: ,...... .
~: --,: ,,, , :
- 41 -
~Z~
Preparation 9
The following compounds were obtained according
to a similar manner to that of Preparation l.
(1) Ethyl 4-phenyl-4-(2-quinolyl)-3-ethoxy-2-
ethoxycarbonylbutyrate.
IR (Film) : 1750, 1730, 1590, 1500, 1150, 1090,
1030 cm 1
NMR (CDC13, ~) : 0.82 (3H, t, J=7Hz), 1.20 (3H, t,
J=7Hz), 1.28 (3H, t, J=7Hz), 3.12 (lH, m),
3.42-4.47 (6H, m), 4.67 (lH, m), 5.25 (lH, m),
7.12-8.27 (llH, m)
(2) Ethyl 4-(2-pyridyl)-4-(1-naphthyl)-3-ethoxy-
2-ethoxycarbonylbutyrate.
IR (Film) : 1750, 1720, 1580, 780, 750 cm 1
NMR (CDC13, ~) : 0.60 (3H, t, J=7Hz), 1.20 (6H,
t, J=7Hz), 2.20-4.53 (8H, m), 5.33 (lH, m),
6.95-8010 (lOH, m), 8.58 (lH, m)
(3) Ethyl 4-(2-pyridyl)-4-(4-biphenylyl~-3-
ethoxy-2-ethoxycarbonylbutyrate.
IR (Film) : 1750, 1730, 1590, 1485, 1300, 1150,
760 -1
NMR (CDC13, ~) : 0.83 (3~, t, J=7Hz), 1.33 (6H,
t, J-7Hz), 3.28 (lH, m~, 3.63 (2H, q, J=7Hz),
4.25 (4H, q, J-7Hz), 4.50-5~30 (2H, m),
- 7.02-7.83 (2H, m), 8.65 (lH, m)
(4) Ethyl 4-phenoxy-4-(2-pyridyl)-3-ethoxy-2-
ethoxycarbonylbutyrate.
IR (Film) : 1750, 1730, lS90, 1490, 1220, 1060,
750 cm 1
N~ (CDC13, ~) : 0.80 (3H, t, J=7Hz), 1.03 (3H,
t, J-7Hz), 1.28 (3~, t, J=7Hz), 2.73 (lH, m),
- . - :: , . . ,,
- . :: : ~ ,.,: . ::: .: - ,
- 42 -
~2ti~5~
3.17-3.70 (2H, m~, 3.80-4.40 (4H, m),
4.60 (lH, m), 5.55 (lH, m), 6.80-7.03 (3H, m),
7.10-7.40 (3H, m), 7.42-7.80 (2H, m),
8.65 (lH, m)
(5) Ethyl 4-(3-tolyl)-4-(2-pyridyl~-3-ethoxy-2-
ethoxycarbonylbutyrate.
IR (Film) : 1750, 1730, 1600, 1590, 1100,
700 cm
-- NMR (CC14, ~) : 0.72 (3H, t, J=7Hz), 1.07-1.45
(6H, m), 2.33 (3H, s), 3.12-3.73 (3H, m~,
3.87-4.48 (5H, m~, 4.95 (lH, m~, 6.85-7.72
(7H, m), 8.58 (lH, m~
(6) Ethyl 4-(2-pyridyl~-4-(4-chlorophenyl)-3-
ethoxy-2-ethoxycarbonylbutyrate.
IR (Film) : 1750, 1730, 1590, 1490, 1090,
750 cm 1
NMR (CDC13, ~) : 0.63-0.97 (3H, m), 1.05-1.50
(6H, m), 3.03-3.82 (3H, m), 3.93-4.58 (5H,
m), 4.93 (lH, m), 6.90-7.72 (7H, m), 8.53
(lH, m)
(7) Ethyl-4-(2-pyridyl)-4-(3-methoxyphenyl)-3-
ethoxy-2-ethoxycarbonylbutyrate.
IR (Film) : I750, 1730, 1590, 1470, 1440, 1370,
1160, 1100, 1040, 760, 700 cm 1
NMR (CC14, ~) : 0.73 (3H, t, J-7Hz), 1.07-1.48
(6H, m~, 2.85-4.53 (8H, m), 3.72 (3H, s),
4.93 (lH, m), 6.50 7.70 (7H, m~, 8.60 (lH,
m)
(8) Ethyl 4-(2-tolyl) 4-(2-pyridyl)-3-ethoxy-2-
ethoxycarbonylbutyrate.
IR (Film) : 3060, 1740, 1720, 1590, 1440, 1090,
860, 750 cm 1
,. , . - . . ~ - . .
~, ;- ,;...; ~ : -
- , - :. .
- 43 -
~LZ6~
NMR (CC14, ~) : 0.70 (3H, t, J=7Hz), 1.03-1.48
(6H, m), 2.4 (3H, m), 2.80-4.93 (9H, m),
6.80-7.60 (7H, m), 8.47 (lH, m)
(9) Ethyl 4-(2-pyridyl)-4-t-butyldimethylsiloxy-
3-ethoxy-2-ethoxycarbonylbutyrate.
IR (Film) : 1750, 1730, 1590, 1580 cm
Preparation 10
The following compounds were obtained according
to a similar manner to that of Preparation 2.
(1) 2-E~hoxycaxbonyl-4-phenyl-lH-pyrido~1,2-a]-
quinolin-l-one.
mp : 1;8-159C
IR (Nujol) : 1690, 1670, 1625, 1580, 1230, 1130,
1000 cm
NMR (CDC13, ~) : 1.40 (3H, t, J=7Hz), 4.42 (2H,
q, J=7Hz), 7.10-7.70 (lOH, m), 8.23 (lH, s),
9.68 (}H, m)
Anal. Calcd for C22H17N03 :
C; 76.95, H; 4.99, N; 4.08
Found : C; 76.76, H; 5.05, N; 4.00
(2) 1-(l Naphthyl)-3-ethoxycarbonyl-4H-quinolizin-
4-one.
mp : 161-163C
IR (Nujol) : 1690, 1665, 1590, 1270, 1240, 780,
770 cm 1
3~ NMR (CDCl3, ~) o 1.38 (3H, t, J=7Hz), 4.43 (2H,
q, J=7Hz), 7.05-7.77 (8H, m), 7.80-8.10 (2E,
m), 8.43 (lH, s), 9.58 (lH, m)
Anal. Calcd for C22~17N03 :
C; 76.95, H; 4.39, N; 4.08
Found : C; 77.14~ H; 5.27, N; 3.89
- . ~. . ~ :
: .: :
- . . ,: . : ~ .
-:, , ', :;''' :" :: ; : ' :
~ 44 ~ ~Z~845~
(3) 1-(4-Biphenylyl)-3-ethoxycarbonyl-4H-
quinolizin-4-one.
mp : 183-184.5C
IR (Nujol) : 1690, 1680, 1625, 1590, 1260, 770,
740 cm
NMR (CDC13, ~) : 1.40 (3~i, t, J=7Hz), 4.50 (2H,
q, J=7Hz), 7.08-8.02 (12H, m), 8.43 (lH, s),
9.55 (lH, m),
Anal. Calcd for C24HlgNO3-1/4H2O :
C; 77.09, H; 5.27, N; 3.75
Found : C; 77.04, H; 5.49, N; 3.60
~4) 1-Phenoxy-3-ethoxycarbonyl-4H-quinolizin-4-
one.
mp : 108-109C
IR (Nujol) : 1680, 1670, 1620, lS90, 1225, 1200,
1000 cm
NMR (CDC13, ~) : 1.40 (3H, t, J=7Hz), 4.42 (2H,
q, J=7Hz), 6.78-7.48 (6H, m), 7.57-7.98 (2H,
m), 8.23 (lH, s), 9O45 (lH, m)
Anal. Calcd for C18H15NO4 :
C; 69.89, H; 4.89, N; 4.53
Found : C; 70.18, H; 5.03, N; 4.51
(5) 1-(3-Tolyl)-3-ethoxycarbonyl-4H-quinolizin-
4-one.
mp : 109-111C
IR (Nujol) : 1725, 1645, 1620, 1595, 1240, 770 cm 1
NMR (CDC13, ~) : 1.42 (3H, t, J=7Hz), 2.45 (3H, s),
~0: 4.45 (2H, q, J=7Hz), 7.08-7.48 (5H, m),
7.53-7.95 (2H, m), 8.42 (lHi, s), 9.55 (lH, m)
Anal. Calcd for ClgH17NO3 1/SH2O :
C; 73.39, H; 5.64, N; 4.50
Found : C; 73.58, H; 5.62, N; 4.49
~5
.
- 45 -
~Z68458
(6) 1-(4-Chlorophenyl)-3-ethoxycarbonyl-4H-
- quinolizin-4-one.
mp : 159-160C
IR (Nujol) : 1680, 1670, 1490, 1295, 1260, 1240,
1130r 1020, 765 cm
NMR (CDC13, ~) : 1.40 (3H, t, J=7Hz), 4.43 (2H,
q, J=7Hz),6.97-7.87 (7H, m), 8.32 (lH, s),
9.48 (lH, m)
Anal. Calcd for C18H14ClNO3 :
C~ 65.96, H; 4.31, N; 4.27
Found : C; 65.81, H; 4.49, N; 4.19
(7) 1-(3-Methoxyphenyl)-3-ethoxycarbonyl-4H-
quinolizin-4-one.
mp : 155-157C
IR (Nujol) : 3070, 1730, 1650, 1625, 1595, 1130,
1100, 780 cm 1
NMR (CDC13, ~) : 1.42 (3H, t, J=7Hz), 3.80 (3H, s), `-
4.40 (2~, q, J=7Hz), 6.85-7.93 (7H, m),
8.35 (lH, s), 9.47 (lH, m)
Anal. Calcd for ClgH17NO4-1/4H2O :
C; 69.61, H; 5.38, N; 4.27
Found : C; 69.62, H; 5.29, N; 4~19
(8) 1-(2-Tolyl)-3-e~hoxycarbonyl-4H-quinolizin-
4-one.
mp : 97-98C
IR (Nujol) : 1730, 1680, 1620j 1480, 1230,
1100, 785 cm 1
a~ NMR (CDC13, ~) : 1.45 (3H, t, J=7Hz), 2.10 (3H,
s), 4.48 (2H, q, J=7Hz), 7.18-7.83 (7H, m),
8.42 (lH, s)~ 9.68 (lH, m)
Anal. Calcd for ClgH17NO3 :
C; 74.25, H; 5.57, N; 4.56
~5~ Found : C; 74.50, H;~5.66, N; 4.50
:..,
- ~6 -
iZ6~3~5~
(9) 1-t-Butyldimethylsiloxy-3-ethoxycaxbonyl-
4H-quinolizin-4-one.
mp : 80C
IR (Nujol) : 1695, 1675, 1620, 1590 cm
NL~R (CDC13~ ~) o 0.2 (6H" s), l.lO (9H, s),
1.45 (3H, t, J=7Hz), 4.45 (2H, q, J=7Hz),
7.10-8.0 (3H, m), 8.10 (lH, s), 9.15 ~lH, d,
J=8Hz)
Anal. Calcd for Cl8H25NO4Si
C; 62.22, H; 7.25, N; 4.03
Found : C; 61.97, H; 7.04, N; 4.08
Preparation ll
A mixture of 2-hydroxymethylpyridine (19.3 ml),
t-butyldimethylsilyl chloride (36.2 g) and imidazole
t27.2 g) in dLmethylformamide (190 ml~ was stirred
for two hours at room temperature. Water was added
to th~ reaction mixture a~d extracted with n-hexane.
The organi~ layer was washed with water, dried over
magnesium sulfate and then evaporated. The residue
was distilled to give 2-t-~utyldimethylsiloxymethyl-
pyridine ~42.30 g).
IR (Film) : 1595, 1585, 1260, 1160, 1140 cm 1
NMR tCDCl3, ~ : l.0 (6~, s),~1.83 (9H, s~,
4.70 (2H, s), 6.85-7.20 (}Hj m), 7.25-7.70
(2H, m), 8.20-8.30 (lH, m)
: ~ :
Preparation 12
To a solution of l-t-butyldimethylsiloxy-3-
3Q ethoxycarbonyl-4H-quinolizin-4-one (3.32 g) in
tetrahydrofuran (lO0 ml) was added a solution of tetra- ;
n-butylammonium fluoride (lM, 11.47 m}) at 0C.
The mixture was stirred ~or one hour and the solvent
was distilled off. The residue was dissolved in
~5 ethyl acetate, washed with wa~er and saturated sodium
: :
. . .
. ;-~ , , ,
: . .. ,:
., . :: , -
- 47 -
lZ6~SE~
chloride solution. After drying over magnesium
sulfate, the solvent was filtered and evaporated. The
residue was chromatographed on silica gel eluting with
chloroform to give l-hydroxy-3-~ethoxycarbonyl-4H-
quinolizin-4-one (1.13 g)O
mp : > 250C -
IR (Nujol) : 3 100, 1690, 1650, 1620 cm
NMR (D~O-d6, ~) : 1.30 ~3H, t, J=7Hz),
4.25 (2H, q, J=7Hz), 7.20-7.60 (lH, m),
7.90-8.10 (2H, m), 9.20-9.30 (lH, m),
9.60 (lH, s)
Anal. Calcd for C12HllNO4 :
C; 61.80, H; 4.75~ N; 6.01
Found : C; 61.11, H; 4.58, N; 5.91
( to be continued to the next page.)
2~
~` :
.
, . : .' ' : ,~
. ,. ~
.. : ,, .. :, .,
~.' . :. :'~,- - ..
- 48 -
~Z68~
Freparation 13
_
The following compounds were obtained according
- to a simllar manner to that of Preparation 1.
(1) Ethyl 4-phenyl-3-ethoxy-2-ethoxycarbonyl-4-(5-
hydroxy-2-pyridyl)butyrate.
(2) Ethyl 3-ethoxy-2-ethoxycar~onyl-4-(N-methylanilino)-
4-(2-pyridyl)butyrate.
NMR (CDC13, ~) : 0.90 (3H, t, J=7.2Hz), 1.14
(3H, t, J=7.2Hz), 1.30 (3H, t, J=7.2Hz),
3.03 (3H, s), 3.20-4.50 (7H, m),
5.00-5.60 (2H, m), 6.50-7.80 (8H, m),
8.57 (lH, d, J=4.4Hz)
(3) Ethyl 3-ethoxy-2-ethoxycarbonyl-4~benzoyl-4-
(2-pyridyl)butyrate.
(4) Ethyl 3-ethoxy-2-ethoxy~arbonyl-4-(2-pyridyl)-4-
~enzylbutyrate.
IR (film) : 1750, 1730, 1635, 1585, 1365, 1290,
1245, 1185, 1140, 1090, 1025, 7a5,
700 cm
NMR (CDC13, ~) 0 0.98-1.50 (9H, m), 2.93-4.67
(llH, m), 6.73-7.63 (8H, m), 8.48-8.63 (lH, m)
(5) Ethyl 3-ethoxy-2-ethoxycarbonyl-4-(2-pyridyl)-4-
phenylthiobutyrate.
IR (film) : 1750, 1730, 159Q, 1440, 1300, 1150,
1090, 1025, 760 cm 1
~MR (CDC13, ~j : 0.83-1.40 (9H, m), 3.07-4.43
(7H, m), 4.53-4.92 (2H, m), 7.0-7.73 (8H, m),
8.53 (lH, m)
,.. .
.;, , ."
;, ''- ,~ - .: .
- 49 -
gLZ6~58
Preparation 14
The following compounds were obtained according
to a similar manner to that of Preparation 2.
(1) 3-Ethoxycarbonyl-7-hydrox~ phenyl-4H-quinolizin-
4-one.
IR (Nujol) : 1720, 1620, 1490, 1450 cm
NMR (DMSO-d6, ~) : 1.30 (3H, t, J=7Hz),
4.26 (2H, q, J=7Hz) " .46 (5H, m),
7.60-7.70 (2H, m), 7.97 (lH, s),
8.98 (lH, d, J=2Hz)
Anal. Calcd for C18H15NO4 :
C, 69.89; H, 4.89; N, 4.53
Found : C, 69.20; H, 5.30; N, 4.14
(2) 3-Ethoxycarbonyl-l-(N-methylanilino)-4H-quinolizin-
4-one.
IR (Nujol) : 1690, 1680, 1600, 1510, 1380,
1235 cm
NMR (DMSO-d6, ~) : 1.30 (3H, t, J=7Hz),
3.30 (3H, s), 4.28 (2H, q, Ja7Hz), 6.50-8.10
(8H, m), 8.15 (lH, s), 9.40 (lH, d, J=7Hz)
Anal. Calcd for ClgH18N~O3
C, 70.79; H, 5.63; N, 8.69
Found : C, 71.~0; H, 5.40; M, 8.56
mp : 129-132C
(3) 3-Ethoxycarbonyl-l-benzoyl-4H-quinolizin-4-one.
mp : 176-178C
IR (Nujol) : 1750, 1630, 1580, 1485, 1220, 1110,
785 cm 1
NMR (CDC13, ~) : 1.37 (3H, t, J=7Hz), 4.38 (2H,
q, J=7Hz), 7.20-8.07 (7H, m), 8.62 (lH, s),
8.82-9.10 (lH, m), 9.42-9.67 (lH, m)
~, .
. .
: ~ ' , . ". .
.~ .
- ~ ~
:. , : , . . ..
..~
, ,~
,~ .
~ 50 ~ 1~684~
Anal. Calcd for C19H15NO4 :
C, 71.02; H, 4.70; N, 4.36
Found : C, 70.76; H, 4.96; N, 4.33
(4) 3-Ethoxycarbon~ benzyl-4H-quinolizin-4-one.
mp : 102-105C
IR (Nujol) : 1690, 1670, :L625, 1595, 1320, 1235,
765, 725 cm 1
NMR (CDC13, ~ 43 (3H, t, J=7Hz), 4.23 (2~,
s), 4.48 (2H, q, J=7H;~), 7.02-7.42 (6H, m),
7.52-7.78 (2H, m), 8.28 (lH, s), 9.45 (lH, m)
Anal. Calcd for C19H17NO3 :
C, 74.25; H, 5.57; N, 4.56
Found : C, 73.97; H, 5.72; N, 4.42
(5) 3-Ethoxycarbonyl-l-phenylthio-4H-quinolizin-4-one.
mp : 171-173C
IR (Nujol) : 1740, 1660, 1625, 1575, 1280, 1220,
1140, 1120, 780, 750 cm }
NMR ~CDC13, ~ : 1.40 (3H, t, J=7Hz), 4.42 (2H,
q, J=7Hz), 6.68-7.47 (5Hj m), 7.73 (lH, m),
8.33 (lH, m), 8.72 (lH, s), 9.52 (lH, m)
Anal. Calcd for C18H15NO3S~
C, 66.44; H, 4.65; N, 4.30
Found : C, 66.17; H, 4.69; N, 4.28
Preparat1on 15
A mixture of 2-chloromethylpyridine (50 g),
N-methylaniline (42 g), and potassium carbonate tl20 g)
in N,N-dimethylformamide (200 ml) was stirred for
4 hours at 120C. The reaction mixture was cooled to
room temperature, added to water (1 Q), and extracted
with ether. The ether extract was washed with water
and then treated with actlvated carbon. After dr~ying
over magnesium sulfate, the~ether extract was filtered
:
~z~ s~
and concentrated. The residue was crystallized from
isopropyl alcohol to give N-methyl-N-(2-pyridylmethyl)-
aniline (39 g).
mp : 60C
IR (Nujol) : 1610, 1590, 1570, 1510, 1470,
1440, 1360 cm 1
Preparat1on 16
To a solution of 2-methylpyridine (9.31 g) in
tetrahydrofuran (200 ml) was added a 1.5M hexane solution
of n-butyllithium (73.3 ml) at -20C. The resulting
solution was stirred for 30 minutes at room temperature
and added to a solution of ethyl benzoate (15.02 g) in
tetrahydrofuran (100 ml) at -60C. After stirring for
2 hours at -60C, acetic acid (15 ml) was added and
the resulting mixture was allowed to warm to room
temperature and concentrated in vacuo. The residue
was dissolved in ethyl acetate and washed with water.
The aqueous layer was reextracted with ethyl acetate
and the combined extracts were washed with water, 10
aqueous solution of sodium hydrogen carbonate, and
saturated a~ueous sodium chloride. After drying over
magnesium sulfate, thè ethyl acetate extracts were
filtered and evaporated. The residue ~20.5 g) was
chromatographed on silica gel (Merck 70-230 mesh,
308 g) eluting with chloroform to give 2-pyridylmethyl
phenyl ketone (10.86 g~ as an oil.
IR (Nuiol) : 1680, 1630, 1600, 1545, 1270,
1200, 1145, 1060, 800, 775, 690 cm 1
NMR (CDC13, ~) : 4.43 (1.5H, s), 6.02 (0.5~, s),
6.83-8.65 (9H, m)
Preparation 17
(1) To a solution of 5-hydroxy-2-methylpyridine
(10.66 g) in tetrahydrofuran (426 mI) was added
. .
. :: : ,. . :.
,. . : .
: . . , - : .
'' '., .~., '". ' ''' ,~ '
lZ61~5~
a solution of n-butyllithium (l.SM in hexane, 143 ml)
at -30~ -10C. The reaction mixture was allowed to
warm to room temperature and stirred for 1 hour at
room temperature. After cooling to -78C, cyclohexane
(11.14 ml) was added dropwise and allowed to warm to
0C and stirred for 30 minutes at 0C. After addition
of acetic acid (24.6 ml), the solvent was distilled
off and the residue was diluted with ethyl acetate,
and washed successively with water, 10~ aqueous sodium
hydrogen carbonate and aqueous saturated sodium
chloride. After drying over magnesium sulfate, the
ethyl acetate extract was filtered and evaporated.
The residue was washed with ethyl acetate to give
5-hydroxy-2-~(1-hydroxycyclohexyl)methyl]pyridine
(11.96 g).
IR (Nujol) : 1615, 1575, 1500, 1460 cm
NMR (CD30D, ~) : 1.20-2.00 (lOH, m),
2.90 (lH, s), 4.95 (2H, s), 7.20 (2H, m),
8.05 (lH, d, J=2.0Hz)
(2) A solution of S-hydroxy-2~ hydroxycyclohex-
yl)methyl~pyridine (1 g) in acetic acid (15 ml)
containing sulfuric acid (5 ml) was heated to reflux
for 1 hour. After cooling to room temperature, the
reaction mixture was poured on an ice, basified with
10~ a~ueous sodium hydrogen carbonate, and extracted
with ether. The combined ether extracts were washed
with aqueous saturated sodium chloride, dried over
magnesium sulfate, filtered, and concentrated. The
3Q residue was washed with isopropylalcohol to give 2-
benzyl-5-hydroxypyridine (409 mg).
IR (Nujol) : 1560, 1450, 1370, 1280 cm 1
NMR (CDC13, ~) : 4.07 (2H, s), 6.85-7.43 (7H, m),
8.08 (lH, d, J=3.0Hz), 10.30 (lH, broad s)
~ , .~ , .
,'' -' :; :: - : :' . . `'
.: -.. : ::: : .
- 53 -
~268~5~
Preparation 18
To a solution of l-phenylthio-3-ethoxycarbonyl-4H-
quinolizin-4-one (1.0 g) in acetic acid (20 ml) and
chloroform (7.5 ml), was added potassium permanganate
(583 mg) at 0C. After stirring for two hours at the
same temperature, the reaction mixture was allowed to
warm to room temperature and stirred further for one
hour. Potassium permanganate (194 mg) was added and
stirred overnight. To the resulting reaction mixture
wasadded. Saturated aqueous soclium thiosulfate solution
with ice-cooling and the mixture was extracted with
chloroform. After drying over magnesium sulfate, the
chloroform extract was filtered and evaporated. The
residue was washed with diisopropyl ether to gi~e
1-phenylsulfonyl-3-ethoxycarbo~yl-4H-quinolizin-4-one
(583 mg), mp 182C.
IR (Nujol) : 1710, 1680, 1640, 1580, 1200,
1150 cm 1
NMR (CDC13, ~) : 1.45 (3H~ t~ J=7Hz), 4-45
(2H, q, J=7Hz), 7.20-8.10 (7H, m), 8.60
(lH, d, J=8Hz), 9.18 (lH, s), 9.50 (lH, d,
J=8Hz)
Anal. Calcd for C18H15NO5S
C, 60.50; H, 4.23; N, 3.gZ
Found : C, 60.44; H, 4.51; N, 3.88
Preparation 19
To a solution of 3-ethoxycarbonyl-7-hydroxy-1-
phenyl-4H-quinolizin-4-one (5 g) in N,N-dimethyl-
formamide (100 ml) was added sodium hydxide (63.6~ in
mineral oil, 732 mg) at 50C. After stirring for
30 minutes at 50C, n-butyliodide (2.77 ml) was added.
After stirring for 1 hour at 50C, the mixture was
cooled to room temperature and added to a mixture of
aqueous hydrogen chloride and an ice.
. ...
- : . --
- ~
. .: -. . ,
- S4 ~ ~Z6~4~
The mixture was extracted with chloroform and the
chloroform extract was washed with 10% aqueous sodium
hydrogen carbonate and aqueous saturated sodium
chloride. After drying over magnesium sulfate, the
chloroform extract was filterecl and concentrated in
vacuo. The residue was chromatographed on silica gel
(Merck 70-230 mesh, 100 g), eluting with chloroform
and then 10% methanol in chloroform to give 3~ethoxy-
carbonyl-7-(n-butoxy)-1-phenyl-4H-quinolizin-4-one
(2.37 g).
mp : 94-95C
IR (Nujol) : 1730, 1690, 1655, 1630, 1480 cm
NMR (CDC13, ~) : 0.95 (3H, t, J=5Hz), 1.4~
(3E, t, J=5Hz), 1.30-2.10 (4H, m), 4.13 (2H,
t, J=5Hz), 4.45 (2H, q, J=5Hz), 7.30 (lH,
d, J=7Hz), 7.42 (5H, m), 7.67 (lH, d, J=7Hz),
8.27 (lH, s), 9.08 (lH, d, J=2Hz)
Anal. Calcd for C22H23NO4
C, 72.31; H, 6.34; N, 3.~83
Found : C, 71.74; H, 6.39; N, 3.80
Preparation 20
The following compound was obtained according to
a similar manner to ~hat of Preparation 6.
1-Allyloxy-3-ethoxycarbonyl-4H-quinolizin-4-one.
mp : 82-84C
IR (Nujol) : 1690, 1680, 1660, 1620, 1580, 1320,
1235, 1100, 1015, 770 cm 1
NMR (CDC13, ~) : 1.43 (3H, t, J=7Hz), 4.42 (2H,
a q, J=7Hz), 4.50-4.75 (2H, m), 5.15-5.67
(2H, m), 5.78-6.47 (lH, m), 6.97-8.32
(4H, m), 9.47 (lH, d, J=7.5Hz)
Anal. Calcd for C15H15NO4 :
C, 65.93i H, 5.53; N, 5.13
~`5 Found : C, 66.11; H, 5.36; N, 4.94
- '' "
lZ61~S8
Preparation 21
The following compound was obtained according to a
similar manner to that of Preparation 16.
(5-Hydroxypyridin-2-yl)methyl phenyl ketone
NMR ~CDC13, ~) : 4.44 (2H~ broad s), 6.85-7.70
(5~, m), 7.70-8.30 (3H, m), 9.34 (2H, s)
Preparation 22
The following compound was obtained according to
a similar manner to that of Preparation l.
Ethyl 4-benzoyl-3-ethoxy-2-ethoxycarbonyl-4-(5-
hydroxypyridin-2-yl)butyrate
IR (Nujol) : 1730, 1720, 1675, 1595 cm l
Preparation 23
The followi~g compound was obtained according to
a similar manner to that of Preparation 2
l-Benzoyl-3-ethoxycarbonyl-7-hydroxy-4H-quinolizin-
4-one.
IR (Nujol) : 1740, 1630, 1570, 1490 cm 1
NMR tDMSO-d6, ~) : 1.22 (3H, t, J=7Hz), 4.27 (2H,
q, J=7Hz), 7.~3-7.97 (6H, m), 8.22 (lH, s),
8.87 (lH, dl J=lOHz), 8.95 (lH, d, J=2Hz)
Preparation_24
The following compound was obtained according to
a similar manner to that of P ~ .
l-Benzoyl-3-ethoxycarbonyl-7-n-butoxy-4H-
quinolizin-4-one.
mp : 158-159C
IR (NujoL) : 1740, 1680, 1630, 1580, 1510 cm
" , ~
- , "
, .. . .. .
- 54-2 -
~z68~as~
NMR (CDC13, ~) : 0.98 (3H, t, J=5Hz), 1.23 (3H, t,
J=7Hz), 1.30-2.10 (4H, m), 4.02-4.48 (4H, m),
7.37-8.18 (6H, m), 8.33 (lH, s), 8.88 (lH, d,
J=lOHz), 9.03 (lH, cL, J=2Hz)
Preparation 25
To a solution of sodium ethoxide (sodium, 151 mg)
in ethanol (20 ml) was added ethyl pyrid-2-ylacetate
(1 ml) at room temperature and the mixture was stirred
for 1 hour at the same temperature. To the mixture
was added diethyl ethoxymethylenemalonate (1.33 ml) at
room temperature and the mixture was stirred at room
temperature overnight. To the mixture was added acetic
acid (0.75 ml) at room temperature and the precipitate
was filtered and washed with water to give 1,3-
diethoxycarbonyl-4H-quinolizin-4-one (896 mg).
mp : 130-131C
IR (Nujol) : 1680, 1625, 1585 cm 1
NMR (CDC13, ~) : 1.40 (6H, t), 4.20-4.55 (4H, m),
7.20-7.46 (lH, m), 7.72-8.00 (lH, m),
9.15 (lH, s), 9.27-9.64 (2H, m).
~: ,
:~
., : ~
: . .
. . .
- 55
~2~5~
Example 1
To a solution of 3-ethoxycarbonyl-4H-quinolizin-4-
one (~.17 g) in methanol (65.2 ml) was added dropwise
6N aqueous sodium hydroxide (6.5 ml) at room temperature.
After stirring for 20 minutes, water (10 ml) was added.
After stirring for 20 minutes, water (30 ml) was also
added. After stirring for an hour, the reaction
mixture was acidified to pH 3 with 4M aqueous hydrochloric
acid. The precipitate was filtered and washed with
water to give 4H-quinolizin-4-one-3-carboxylic acid
(1.75 g) as pale yellow crystal. mp 233C.
IR (Nujol) : 1730, 1610, 1585, 1320 cm 1
~IMR (DMSO-d6) ~ : 7.26 (d, lHI J=9Hz), 7.50-7.95
(m, lH), 8.00-8.20 (m, 2H), a.41 (d, lH,
lS J=9H2), 9.20-9.40 (m, lH)
Example 2
To a suspension of 4H-quinolizin-4-one-3-
carboxylic acid (1.69 g) in N,N-dimethylformamide
~16.9 ml) was added 1,1'-carbonyldiimidazole (2.-17 g)
at ambient temperature. The resulting suspension was
heated to 100C for 30 minutes and 5-amino-lI~-tetrazole
(1.06 g) was added at 100C. After stirring for
20 minutes at 100C, the reaction mixture was cooled to
0C. The precipitate was filtered and washed with
( to be continued to the next page.)
~5
.
i: :.~ ' .. , '
: .. , : . - -
~:
. . : ,: : : :
:. . : . .
~ 56 ~ ~26~S~
pre-cooled N,N-dimethylformamide and then ~ther to give
N-~5-(lH-tetrazolyl)]-4H-quinolizin-4-one-3-carboxamide
(2.0 g) as yellow solid. mp > 260C.
IR (Nujol) : 3200, 1660, 1620, 1500, 1310 cm
NMR (CF3COOH) ~ : 7.42 (d, lH, J=8Hz),
7.68-7.88 (m, lH), 7.98-8.29 (m, 2H),
8.72 (d, lH, J=8Hz), 9.48 (d, lH, J=8Hz)
Analysis Calcd. or CllH8O2N6 :
C; 51.56, H; 3.15, N; 32.80
Found : C; 51.70, H; 3.22, N; 32.99
Example 3
The following compounds were obtained according to
a similar manner to that of Exam~le 1.
(1) 7-Ethyl-4H-quinolizin-4-one-3-carboxylic acid.
mp. 193-195C.
IR (Nujol) : 3100, 1725, 1700, 1605 cm 1
NMR (CF3COOH) ~ : 1.52 (t, 3H, J=8Hz), 3.12 (q, 2H,
J=8Hz), 7.92 (d, lH, J=9Hz), 8.32 (s, 2H),
8~73 (d, lH, J=9Hz), 9.30 (m. lH).
Analysis Calcd. for C12HllNO3
C; 66.35, H; 5.10, N; 6.45
Found : C; 66.40, H; 5.14, N; 6.46
(2) 1-Pheryl-4H-quinolizin-4-one-3-carboxylic acid.
mp. 198C.
IR (Nujol) : 3315, 1740, 1620 cm 1
NMR (CF3COOH) ~ : 7.32-7.82 ~m, 5H), 7.92-8.23
(m, lH), 8.25-8.52 (m, 2H), 8.70 (s, lH),
9.48-9.72 (m, lH),
Analysis Calcd. for C16HllNO3 5/4H2O :
C; 66.78, H; 4.64, N; 4.87
Found : C; 66.89, H; 4.22, N; 4.59
-.
.. . ,
.;. . .
,. , ,, , ~, .
_ 57 _ ~2~845~
(3) lH-Pyrido~1,2-a]quinolin-1-one-2-carboxylic acid.
mp. 258-260C.
IR (Nujol~ : 2500, 1720 cm 1
NMR (CF3COOH) ~ : 7.75-8.33 (m, 5H), 8.43 (d, lH,
J=9Hz), 8.92 (d, lH, J-=8.5Hz), 9.73 (m, lH)
~nal. Calcd for C14HgMO3-1/10H2O :
C; 69.76, H; 3.85, N; 5.81
Found : C; 69.87, H; 4.13, N; 5.94
(4) 7-Hydroxy-4H-quinolizin-4-one-3-carboxylic
acid. mp. > 270C
IR (Nujol) : 3120, 2690, 1690, 1590 cm 1
NMR (CF3COOH) ~ : 7.87 (d, lH, J=8.5Hz),
8.07-8.42 (m, 2H), 8.58 (d, lH, J=8.5Hz),
9.07 (m, lH)
Anal. Calcd for CloH7NO4 1/4H2O :
C; 57.28, H; 3.61, N; 6.68
Found : C; 57.51, H; 3.60, N; 6.75
(5) 4H-P~rido[2,1-a3isoquinolin-4-one-3-carboxylic
acid. mp. > 250C.
IR (Nujol) : 3100, 1730, 1640, 1620 cm 1
NMR (CF3COOH) ~ : 8.0-8.40 (m, 4H), 8.80-9.30
(m~ 4H)
Anal. Calcd for C14HgMO3 :
C; 70.29, H; 3.79, N; 5~85
Fourd : C; 70.43, H; 4.15, N; 5.89
(6) 9,10-Dihydro-8H-benzo[ij]-3H-quinolizin-3-one-
2-carboxylic acid. mp. 254C.
IR ~Nujol) : 3200, 1710i 1610, 1590 cm
NMR (DM~O-d6) ~ : 1.80-2.30 (m, 2H), 2.70-3.20
(m, 6H), 7.30-7.85 (m, 2H), 8.10 (s, lHj,
9.10 ~d, lH, J=7Hz), 14~30 (s, lH)
-.
58
~684~5~
Anal. Calcd for C13HllNO3 :
C; 68.11, H; 4.84, N; 6.11
Found : C; 68.21, H; 5.12, N; 6.07
(7) 7-Methoxy-4H-quinolizin-4-one-3-carboxylic acid.
mp. 215-216C.
IR (Nujol) : 3150, 3100, 1700, 1610, 1590 cm 1
NMR (CF3COOH) ~ : 4.18 (s, 3H), 7.88 (d, lH, J=8.5Hz),
8.10-8.47 (m, 2H), 8.67 (d, lH, J=8.5Hz),
8.88 (m, lH)
Anal. Calcd for CllHgNO4 :
C; 60.27, H; 4.14, N; 6.39
Found : C; 59.90, H; 4.38, N; 6.48
(8) 9-Methyl-4H -quinolizin-4-one-3-carboxylic acid.
mp. 259-260C.
IR (NU3O1) : 3100, 3020, 1740, 1610, 1590, 1120,
780 cm 1
NMR (DMSO-d6) ~ : 2.92 (Sr 3H), 7.90 (d, lH,
J=7.5Hz), 8.07 (d, lH, J=9.5Hz), 8,05-8.38
(m, lH), 8.82 (d, lH, J=9.5Hz),
9.42 (d, lH, J=7.5Hz)
Anal. Calcd for Cl1HgNO3 :
C; 65.02, H; 4.46, N; 6.89
Found : C; 64.92, H; 4.76~ N; 6.89
(9) 8-Methyl-4H-quinolizin-4-one-3-carboxylic
acid. mp. 228-230C
IR (Nujol) : 3090, 3030, 2700, 1630, 1620, 1580,
785 cm 1
NMR (CF3COOH) ~ : 2.82 (s, 3H), 7.82 (d, lH, J--9Hz),
7.92 (dd, lH, J=7Hz, 2Hz), 8.17 (d, lH, J=2Hz),
8.68 (d, lH, J-9Hz), 9.37 (d, lH, J=7Hz)
Anal. Calcd for CllHgNO3 : C; 65.02, H; 4.46, N;6.89
Found : C; 64.88, H; 4.79, N; 6.85
,
:
~ 59 126~4S8
(10) 6-Methyl-4H-quinolizin-4-one-3-carboxylic acid.
mp. 185-187C.
IR (Nujol) : 3100, 2700, 1720, 1615, 1595, 1295,
1040, 800 c~ 1
S NMR (CF3COOH) ~ : 3.45 (s, 3H), 7.82 (d, lH, J=9Hz),
7.58-7.97 (m, lH), 8.10-8.30 (m, 2H),
8.68 (d, lH, J=9Hz)
Anal. Calcd for CllHgNO3 : C; 65.02, H; 4.46, N; 6.89
Found : C; 64.60, H; 4.52, N; 6.91
(11) 1-Methyl-4H-quinolizin-4-one-3-carboxylic acid.
mp. 258-260C.
IR (Nujol) : 1740, 1610, 1450, 780 cm 1
NMR (CF3COOH) ~ : 2.87 (s, 3H), 8.15 (m, lH),
~5 8.35-8.77 (m, 3H), 9.66 (m, lH~
Anal. Calcd for CllHgNO3 : C; 65.02, H 4.46, N; 6.89
Found : C; 64.70, H; 4.56, N; 6.86
(12) Cyclopenta[ij]-3H-quinolizin-3-one-2-carboxylic
2Q acid. mp > 250C
IR (Nujol) : 1730, 1620, 1590 cm 1
Anal. Calcd for C12H7NO3: C; 67-61, H; 3-31, N; 6.57
Found : C; 67.72, H; 3.37, N; 6.59
(13) 7-Methyl-4H-quinolizin-4-one-3-carboxylic
acid . mp. 222-224C
IR (Nujol) : 1720, 1600, 1590, 1320, 1125, 1110,
840 cm 1
NMR (CF3COOH) ~ : 2.77 (s, 3H), 7.93 (d, lH, J=9Hz),~
~a, 3~22-8.38 (m, 2H), 8.73 (d, lH, J=9Hz),
9.32 (s, 1~)
Anal. Calcd for CllHgNO3: C; 65.02, H; 4.46, N; 6.89
Found : C; 65.04, H; 4.31, N~ 6.91
(14) 4H-Quinolizin-4-one-1-carboxylic acid.
. ,.: :. -, ::-
.
,
i2~ 5~
mp. > 250C
IR (Nujol) : 1695, 1650 cm
NMR (DMSO-d6) ~ : 6.46 (d, lH, J=lOHz), 7.30-8.20
(m, 2H), 8.41 (d, lH, J=lOHz), 9.20-9.40
(m, 2H)
Anal. Calcd for CloH7NO3: C; 63,49, H; 3.73, N; 7.40
Found : C; 63.50, H; 3.81, N; 7.53
~15) 1-Methoxy-4H-quinolizin-4-one-3-carboxylic acid.
mp. 259-261C.
IR (Nujol) : 3100, 1630-, 1620, 1580, 1100, 1070,
780 cm 1
NMR (CF3COOH) ~ : 4.27 (s, 3H), 8.00-8.67 (m, 3H),
8.90 (m, lH), 9.52 (d, lH, J=7.5Hz)
Anal. Calcd for CllHgNO4: C; 60.28, H; 4 14, N; 6.39
Found : C; 59.64, H; 4.15, N; 6:30
(16) 7-n-Butoxy-4H-quinolizin-4-one-3-carboxylic
acid. mp. 120-122C.
IR (Nujol) : 1725, 1600, 1590, 1320, 1070, 1000 cm 1
NMR (CF3COOH~ ~ : 1.07 (t, 3H, J=6H ), 1.30-2.20
(m, 4H), 4.40 (t, 2H, J=6HZ), 7~90 (d, lH,
J=9.5Hz), 8.13-8.43 (m, 2H), 8.67 (d, lH,
J=9.5H2), 8.93 (d, lH, J=2Hz)
Anal- Calcd for C14H15~O4: C; 64.36, H; 5.79, N; 5.36
Found : C; 64.46, H; 5.80, N; 5.31
:
(17) 7-Isopropoxy-4H-quinolizin-4-one-3-carboxylic
acid. mp. 218-219C.
IR (Nujol) : 3140, 3090, 1720, 1620, 1120, 1060,
1000, 780 cm~l ;
NMR (CF3COOH) ~ : 1.67 (d, 6H, J=6Hz), 4.97 (lH,
J=6Hz), 7.88 (d, lH, J=9Hz), 8.10-8.43 (m, 4H),
8.63 ~d, lH, J=9Hz), 8.90~(d, lH, J=2Hz)
-.:
:
, . ..
- .~ . : :
-61 -
458
Anal. Calcd for C13H13NO4: C; 63.15, H; 5.30, N; 5.66
Found : C; 63.28, H; 5.18, N; 5.65
Example 4
The following compounds were o~tained according to
a similar manner to that of Example 2.
(1) N-[3-(4H-1,2,4-Triazol~1)]-4H-quinoliæin-4-one
3-carboxamide. mp. > 250C.
IR (Nujol) : 3400, 3300, 1700, 1660, 1650, 1620 cm 1
NMR (CF3COOH) ~ : 7.90-9.60 (m, 7H)
Anal. Calcd for C12HgN5O2 :
C; 56.47, H; 3.55, N; 27.44
- Found : C; 56.83, H; 3.79, N; 27.50
(2) N-[5-(lH-Tetrazolyl)]-9-methyl-4H-quinolizin-4-
one-3-carboxamide. mp. > 270C.
IR (Nujol) : 3200, 3100, 3080, 1660, 1620, 1590,
790 cm~l
NMR (CF3COOH) ~ : 2.80 (s, 3H), 7.50-7.87 (m, 2H),
8.08 (d, lH, J=7Hz), 8.78 (d, lH, J=9Hz),
- 9.43 (d, lH, J=7Hz)
Anal. Calcd for C12HloN6O2 :
C; 53.33, H; 3 73, N; 35.10
Found : C; 55.28, H; 3.88, N; 31.35
(3) N-[5-~lH-Tetrazolyl)]-7-ethyl-4H-quinolizin-
4-one~3-carboxamide. mp. > 250C. ~
IR (Nujol) : 3200, 1660, 1640, 162~0, 1590,
1490 cm~l
NMR (CF3COOH) ~ : 1.50 (t, 3H, J-7Hz),
3.05 (q, 2H, J=7.5Hz), 7.45 (d, lH, J=9Hz),
8.08 (s, 2H), 8.68 (d, lH, J=9Hz), 9.33 (m, lH)
Anal. Calccl for C13H12N6O2 : C; 5~.93, H; 4.25, N; 29.~56
Found : C; 55.32; H; 4.32, N; 29.72
:
:, ....
- 62 _ lZ6~458
(4) N-[5-(lH-Tetrazolyl)]-l-phenyl-4H-quinolizin-4-
one-3-carboxamide. mp. ~ 270C.
IR (Nujol) : 3180, 3100, 1680, 1620, 1490 cm 1
NMR (CF3COOH) ~ : 7.27-8.02 (m, 6H), 8.05-8.35
(m, 2H), 8.70 (s, lH), 9.48-9.75 (m, lH)
Anal. Calcd for C17H12N6O2 :
C; 61.44, H; 3.64, N; 25.29
Found : C; 61.21, H; 3.80, N; 24.83
t5) N-[5-(lH-Tetrazolyl)]-lH-pyrido[1,2-a]-
quinolin-l-one-2-carboxamide. mp. > 270C.
IR (Nujol) : 3200, 1670, 1610, 1580, 1530,
1480 cm 1
NMR (CF3COOH) ~ : 7.32 (d, lH, J=9Hz~, 7.48-8.33
(m, SH), 8.83 (dt lH, J=8Hz), 9.63 (m, lH)
Anal. Calcd for C15HloN6O2 :
C; 58.82, H; 3.29, N, 27.44
Found : C; 59.16, H; 3.42, N; 27.29
~6) N-~5-(lH-Tetrazolyl)]-7-hydroxy-4H-quinolizin-
4-one-3-carboxamide. mp. > 270C.
IR (Nujol) : 3120, 3090, 2530, 1670, 1640, 1540,
980 cm~l
NMR (CF3COOH) ~ : 7.73-7.70 (m, 2H), 8.03 (m, lH),
8.67 (m, lH), 9.15 (m, lH)
Anal. Calcd for CllH8N6O3 :
C; 49.06, H; 3.32, N; 32.11
Found : C; 48.56, H; 3.47, N; 32.66
(7) N-[5-(lH-Tetrazolyl)]-4H-pyrido[2,1-a]-
isoquinolin-4-one-3-carboxamide. mp. ~ 250C
IR (Nujol) : 3200, 1660, 1640, 1620 cm 1
Anal. Calcd for C15HloN6O2 :
C; 58.82, H; 3.29, N; 27.44
Found : C; 59.12, H; 3.57, N; 27.86
`
" : . . .
.. ....
. . .
63
1268~
(8) N-[5-(lH-Tetrazolyl)]-9,10-dihydro-8H-benzo-
[ij]-3H-quinolizin-3-one-2-carboxamide. mp. > 250C.
IR (Nujol) : 3200, 1660, 1640, 1620, 1600 cm 1
NMR tCF3CooH) ~ : 2.00-2.50 (m, 2H), 3.00-3.60
(m, 4H), 7.70-8.20 (m, 2H), 8.55 (s, lH),
9.40 (d, lH, J=7Hz)
Anal. Calcd for C14H12N6O2 :
C; 56.75, H; 4.08, N; 28.36
Found : C; 56.86, H; 4.27, N; 28.58
(9) N-[5-(lH-Tetrazolyl)]-7-methoxy-4H-quinolizin-
4-one-3-carboxamide. mp. >270C.
IR (Nujol) : 3200, 3100, 1680, 1650, 1610 cm 1
NMR (CF3COOH) ~ : 4.13 (s, 3H), 7.42 (d, lH,
J=9Hz), 7.73-8.17 (m, 2H), 8.5a (d, lH,
J=9Hz), 8.92 (m, lH)
Anal. Calcd for C12HloN6O3 :
C; 50.35, H; 3.52, N; 29.36
Found : C; 50.54, H; 3.55, N; 29.63
(10) N-(2-Thiazolyl)-4H-quinoIizin-4-one-3-
carboxamide. mp. 240C.
IR (Nujol) : 3100, 1665, 1620, 1490, 1320 cm 1
NMR (CF3COOH) ~ : 7.30-7.90 (m,~4H), 8.03-8.47
(m, 2H), 8.75 (d, lH, J=9Hz), 9.42 (d, lH,
J=7Hz)
Anal. Calcd for C13HgN3OS ~
C; 57.56, H; 3.34, N; 15.49
Found : C; 57.25, H; 3.77, N; 15.24
(11) N-(2-Hydroxyphenyl)-4H-quinolizin-4-one-3-
car~oxamide. mp. 247C.
IR (Nujol) : 1650, 1630, 1600 cm
NMR (CDC13) ~ : 6.ao-7.50 (m, SH), 7.70 (d, 2H,
; 35 J-7Hz)~ 8.76 (d, lH, J=8Hz), 9.40 (d, lH, ~;
J=8Hz), 10.10 (s, lH)
:
,.
,, :. ~ " . ~ ~ :
" . : ,
.. . . .
- ~4 -
~Z6~58
Anal. Calcd for C16H12N2O3 :
C; 68.57, H; 4.32, N; 9.99
Found : C; 68.04, H; 4.48, N; 10.11
(12) N-(2-Pyrimidinyl)-4H-quinolizin-4-one-3-
carboxamide. mp. 218C.
IR (Nujol) : 1690, 1650, 1620 cm
NMR (DMSO-d6) ~ : 7.10-8.20 (m, 5H), 8.50-8 80
(m, 3H), 9.20-9.40 (m, lH)
Anal. Calcd for C14HloN4O2 :
C; 63.15, H; 3.79, N; 21.04
Found : C; 61.20, H; 4.19, N; 20.76
(13) N-[5-(lH-Tetrazolyl)]-8-methyl-4H-quinolizin-
4-one-3-car~oxamide~ mp. > 270C
IR (Nujol) : 3200, 3150, 1660, 1635, 1590, 780 cm 1
N~ (CF3COOH) ~ : 2.73 (~, 3H), 7.35 (d, lH,
J=9Hz), 7.65 (dd, lH, J=7Hz, 2Hz), 7.83 (d,
lH, J=2Hz), 8.65 (d, lH, J=9Hz), 9.38 (d, lH,
J=7Hz)
Anal. Calcd for C12HloN6O2 :
C; 53.33, H; 3.73, N; 31.10
Found : C; 54.03, H; 3.84; N; 30.38
(14) N-~5-(lH-Tetrazolyl)]-6-methyl-4H-quinolizin-
4-one-3-carboxamide. mp. > 270C.
IR (Nujol) : 3200, 1660, 1620, 1590, 1030, 820
790 cm 1
NMR (CF3COOH) ~ : 3.33 (s, 3H), 7.37 (d, lH,
J=9Hz), 7.37-7.62 (m, lH), 7.87-8.07 (m, 2H),
8.60 (d, lH, J=9Hz)
Anal. Calcd for Cl~HloN6O2 :
C; 53.33, H; 3.73, N; 31.10
Found : C; 53.63, H; 3.92, N; 31.42
~ ,
. , . :
- - .
.. ~ :
.. .
- : : ,;'
:
- 65 - 1~6~4~
(15) N-[5-(lH-Tetrazolyl)]-l-methyl-4H-quinolizin-4-
one-3-carboxamide mp. > 270C.
IR (Nujol) : 3180, 1665, 1640, 1620, 1595, 1500,
1040, 1020, 770 cm 1
NMR (CF3COOH) ~ : 2.77 (s, 3H), 7.83-8.10 (m, lH),
8.38 (d, 2H, J=3Hz), 8.72 (s, lH), 9.65 (d,
lH, J=6Hz)
Anal. Calcd for C12HloN6O2 :
C; 53.55, H; 3.73, N; 31.10
Found : C; 53.71, H; 4.04, N; 31.03
(16) N-[5-(lH-Tetrazolyl)]-7-methyl-4H-quinolizin-
4-one-3-carboxamide. mp. > 270C.
IR (Nujol) : 3200, 1670, 1610, 1580, 1500, 1310,
1060, 1040, 849 cm 1
NMR (CF3COOH) ~ : 2.73 (s, 3H), 7.47 (d, lH,
J=9Hz), 8.03-8.50 (m, 2H), 8.70 (d, lH, J=9Hz),
9.33 (s, lH)
Anal. Calcd for C12HloN6O2
C; 53.33, H; 3.73, N; 31.10
Found : C; 53.61, H; 3.69, N; 31.34
(17) N-~6-(1,2,4-Triazinyl)]-4H-quinolizin-4-one-3-
car~oxamide. mp. 263C (dec.)
IR (Nujol) : 3100, 1690, 1620, 1580, 1520, 1500,
1040 cm
NMR (CF3COOH) ~ : 7.33 (d, lH~ J=9Hz), 7.60-8.23
(m, 3H), 8.72 (d, lH, J=9Hz), 9.10-9.17 (m! lH),
9.27-9.68 (m, 2H)
Anal. Calcd for C13HgN5O2-1/4H2O :
C; 57.51, H; 3.59, N; 25.97
Found : C; 57.51, H; 3.52, N; 25.77
(18) N-pyrazinyl-4H-quinolizin-4-one-3-carboxamide.
mp~ > 250C.
~ `
, . . . .
.. ~ :
... . . .
~ 66 - ~268~S~
IR (Nujol) : 3400, 1675, 1620, 1580, 1520, 1500,
1400, 1320, 780 cm 1
NMR (CF3COOH) ~ : 7.43 (d, lH, J=9.5Hz), 7.78 (m,
lH), 8.00-8.23 (m, 2H), 8.77 (d, 9.5Hz),
8.83 (d, J=7.5Hz), 8.78-8.98 (m, 3H),
9.55 (d, lH, J=7.5Hz), 9.82 (s, lH)
Anal- Calcd for C14H10N42 H2
C; 59.15, H; 4.25, N; 19.71
Found : C; 59.58, H; 4.03, N; 19.99
(19) N-~5-(lH-Tetrazolyl)]-cyclopenta[ij]-3H-
quinolizin-3-one-2-carboxamide. mp. > 250C
IR (Nujol) : 3200, 3100, 1660, 1620, 1600 cm
NMR (CF3COOH) ~ : 7.10-9.50 (m, 6H)
lS Anal. Calcd for C13H8N6O2 :
C; 55072, H; 2.88, N; 29.99
Found : C; 55.95, H; 3.01, N; 29.64
. .
(20) N-(2-Pyridyl)-4H-quinolizin-4-one-3-
2~ carboxamide. mp. 228-230C.
(21) N-~5-(lH-Tetrazolyl)]-4H-quinolizin-4-one-1-
carboxamide. mp. > 250c.
IR (Nujol) : 1690 (sh), 1660, 1620 cm
NMR (CF3COOH) ~ : 7.40-9.80 (m, 6H)
Anal. Calcd for CllH8N6O2 :
C; 51.56, H; 3.15, N; 32.80
Found : C; 51.71, H; 3.43, N; 32.41
3Qi (22) N-~6-(3-Chloropyridazinyl)]-4H-quinolizin-
4-one-3-carboxamide. mp. > 250C.
IR (Nujol) : 3100, 1680, 1620j 1580, 1510, 1070,
780 cm~l
NMR (CF3COO~) ~ : 7.38 (d, lH,~=9Hz) r 7.63-8.50
-~l5~ (m, 5H), 8.77 (d, lH, J=9Hz), 9.48 (m, lH).
.. :
,
..
~7 ~ Z ~ ~ 4 5
Anal. Calcd for C14H9ClN4O2 :
C; 55.92, H; 3.02, N; 18.63
Found : C; 55.65, H; 3.15, N; 19.14
(23) N-[5-(lH-Tetrazolyl)]-l-methoxy-4H-quinolizin-
54-one-3-carboxamide. mp. > 270C.
IR (Nujol) : 3200, 1660, 1650, 1620, 1290, 1015,
775 cm~l
NMR (CF3COOH) ~ : 4.33 (s, 3H), 8.13 (m, lH),
8.33 (s, lH), 8.43-9.02 (m, 2H), 9.62 (d,
10lH, J=7.5Hz)
Anal. Calcd for C12HloN6O3 :
C; 50.35, H; 3.52, N; 29.36
Found : C; 50.46, H; 3.45, N; 29.39
15(24) N-~2-(4,6-Dimethylpyrimidinyl)]-4H-quinolizin-
4-one-3-carboxamide. mpO 217-218C.
IR (Nujol) : 3460, 3120, 1690, 1650, 1620, 1060,
790 cm 1
NMR (CF3COOH)~ : 2.87 (s, 6H), 7.38 (d, lH,
20J=9Hz), 7.47-8.32 (m, 4H), 8.75 (d, }H, ~=9Hz),
9.63 (d, lH, J=7O5Hz)
Anal- Calcd for C16H14N42 1/3H2
C; 63.99, H; 4.92, N; 19.04
Found : C; 63.99, H; 4.92, N; 18.6
(25) N-[5-(lH-Tetrazolyl)~-7-n-butoxy-4E-q~inolizin-
4-one~3-carboxamide. mp. > 210C.
IR (Nujol) : 3200, 1665, 1640, 1625, 1590, 1000,
850, 780 cm-
lU~NMR (CF3COOH) ~ : 1.10 (t, 3H, J=5.5Hz), }.37-2.3
(m, 4H), 4.38 ~t, 2H, J=6~5Hz), 7.53 (d, lH,
J=8.5Hz), 7.97-8.28 (m, 2H), 8.67 (d, lH,
J=8.5Hz), 9.03 (sj lH)
Anal- Calcd for C15H16N63 C; 54-88~ H; 4-91~ N; 26-00
35~Found : C 55.14, H; 4.89, N; 25.83
.~
:
- 68 - ~Z~8~5~
(~6) N-[5-(lH-Tetrazolyl)]-7-isopropoxy-4H-quinolizin-
4-one-3-carboxamide. mp. > 270C.
IR (Nu~ol) : 3200, 1680, 1650, 1620, 1500, 1310,
780 cm 1
S NMR (CF3COOH) ~ : 1.77 (d, 6H, J=6Hz), 5.12 (sept,
lH, J=6Hz), 7.67 (d, lH, J=8.5Hz), 8.02-8.37
(m, 2H), 8.80 (d, lH, J=8.5Hz), 9.20 (s, lH)
Anal. Calcd for C14H14N6O3 :
C; 53.50, H; 4.49, N; 26.74
Found : C; 53.73, H; 4.41, N; 27.04 _
Example 5
(1) To a suspension of 4H-quinolizin-4-one-3-
carboxylic acid (2.27 g) in dry N,N-dimethylformamide
(22.7 ml) was added l,l'-carbonyldiimidazole (2~92 g).
The resulting suspension was heated to 100C and kept for
30 minutes. After cooling to room temperature the
resulting solution was treated with dry ammonia and
stirred for 20 minutes. The crystals separated was
collected by filtration and washed with water to give
4H-quinolizin-4-one-3-carboxamide (1.94 g).
mp. 230-232C.
IR (Nujol) : 3350, 3120, 1660, 1630 cm 1
NMR (CF3COOH) ~ : 7.58 (d, lH, J=9Hz), 7.75-8.07
(m, lH), 8.12 (m, 2H), 8.60 (d, lH, J=9Hz)
and 9.52 (d, lH, J=7Hz).
Anal. Calcd for CloH8N2O2 :
C; 63.83, H; 4.28, N; 14.89
Found : C; 63.96, H, 4.43, N; 14.90
~0
(2) A mixture of 4H-quinolizin-4-one-3-carboxamide
(1.0 g) and phosphorus oxychloride (50 ml) was refluxed
for one hour. The reaction mixture was concentrated
under reduced pressure and the residue was dissolved in
aqueous sodium bicarbonate soLution and chloroform.
.
.
- , : :. ,
~9 1;2684SE~
The chloroform extract was washed with water, dried over
anhydrous magnesium sulfate and then evaporated. The
residue was chromatographed on silica gel (30 g) eluting
with chloroform-methanol (50:1) to give 3-cyano-4H-
quinolizin-4-one, which on recrystallization from ether
gave crystals (800 mg), mp. 198-200C.
IR (Nujol) : 2420, 1680, 1620 cm
NMR (DMSO-d6) ~ : 6.93 (d, lH, J=8Hz), 7.30-7.60
(m,lH), 7.85-8.20 (m, 3H), 9.13 (d, lH,
J=8Hz)
(3) To a solution of 3-cyano-4H-quinolizin-4-one
(1.20 g) in a mixture of pyridine (50 ml) and triethylamine
(30 ml) was bubbled hydrogen sulfide gas ovex a period
of 30 minutes at room temperature. The resulting mixture
was allowed to stand at ambient temperature for 3 days.
The solvent was distilled off and the residue was washed
with a hot mixture of chloroform and methanol (1: 1)
and filtered. The filtrate was concentrated and the
residue was washed again wi~h a hot mixture of
chloroform and methanol (9 1) and filtered. The filtered
cake was washed well with a mixture of chloroform and
methanol (9:1) to give 4H-quinolizin-4-one-3-
thiocarboxamide (0.76 g).
mp. 220-230C.
IR (Nujol) : 3300, 3100, 1650, 1620, 1500 cm 1
NMR (DMSO-d6) ~ : 7.07 (d, lH, J=8Hz), 7.36-7.67
(m, lH), 7.80-8.10 (m, 2H), 9.13 (d, lH,
J=8Hz), 9.26 (d, lH, J=8Hz), 9.80 (broad s, lH)
(4) 3-Cyano-4H-quinolizin-4-one (4.21 g), sodium
azide (1.77 g), and ammonium chloride (1.45 g) was dissolved
in N,N-dimethyl-formamide (42 ml) and the resulting
mixture was heated at 1~0C for two days. The reaction
mixture was evaporated and the residue was dissolved in
- - . . : .
: - : - , .,: :
:..... ., . :.. - ~
~`7Q ~ ~2~4~5~
aqueous sodium bicarbonate solution and filtered.
The filtrate was acidified with dilute hydrochloric acid
to pH 1-2. The precipitates were filtered, washed with
water and then cold N,N-dimethylformamide. The filtered
solid was dissolved in hot N,N-dimethylformamide and
filtered. The filtrate was treated with ether and
kept at 0C. The crystals separated were filtered and
recrystallized from a mixture of ether and N,N-dimethyl
formamide to give 3-[5-(lH-tetrazolyl)]-4H-quinolizin-4-
one (1.1 g).mp. > 250C.
IR (Nujol) : 3200, 3100, 3050, 1660, 1620, 1590 cm 1
NMR (CF3COOH) ~ : 7.40 (d, lH, J=8Hz), 7.60-8.30
(m, 3H), 8.60 (d, lH, J=8Hz), 8.90 ts, lH),
9.40-9.60 (m, lH)
Anal. Calcd for CloH7ON5 :
C; 56.34~ H; 3.31, N; 32.85
Found : C; 56.55, H, 3.87, N; 33.0
Z0 Example 6
(1) A suspension of 4H-quinolizin-4-one-3-carboxylic
acid ~196.7 mg) in 0.lN-aqueous sodium hydroxide solution
(9.9 ml) was stirred for one hour at room temperature.
The resulting reaction mixtuxe was filtered and then the
filtrate was lyophilized to give sodium 4H-quinolizin-4-
one-3-carboxylate (201 mg).
IR (Nujol) : 1660 cm 1
NMR (D2O) ~ : 6.80 (d, lH, J=8Hz), 7.00-7.3C (m, lH),
7.40-7.60 (m, 2H), 8.05 (d, lH, J=8Hz),
3a 8.96 (d, lH, J=8Hz)
(2) The following compound was obtained according
to a similar manner to that of Example 6 - (1).
N-~5-(lH-Tetrazolyl)]-4H-quinolizin-4-one-3-
`:
,:. ., - ~ ., . , :
~ -
': -' -.. ,: , ' ~ . :
~ 71 ~ 1 2l6~ 45
carboxamide sodium salt.
IR (Nujol) : 1670 cm
NMR (D2O-DMSO-d6) ~ : 6.80 (d, lH, J=8Hz),
7.20-7.40 (m, lH), 7.40-7.60 (m, 2H),
8.10 (d, lH, J=8Hz), 8.88 (d, lH, J=8Hz)
(to be continued to the next page~)
~,
30`
~5
~ 72 ~ ~ ~ ~8~S~
Example 7
The following compounds were obtained according
to a similar manner to that of Example 1.
(1) 4-Phenyl-lH-pyrido[1,2-a]quinolin-1-one-2-
carboxylic acid.-
mp : 194-195C
IR (Nujol) : 3150, 2650, 1740, 1725, 1590, 1440,
1115, 825 cm 1
NMR (CF3COOH, ~) : 7.48-7.82 (5H, m), 7.93-8.48
(5H, m), 8.95 (lH, s), 9.70 (lH, m)
Anal. Calcd for C20H13NO3 :
C; 76.18, H; 4.16, N; 4.44
Found : C; 76.32, H; 4.56, N; 4.32
(2) 1-(1-Naphthyl)-4H-quinolizin-4-one~3-
carboxylic acid.
mp : >270C
IR (Nujol) : 1730, 1720, 1610, 770 cm 1
NMR (CF3COOH, ~ : 7.10-8.37 (lOH, m), 8.82 (lH,
s), 9.62 (lH, m)
Anal- Calcd ~or C20H13N3-1/2H~
C; 74.07, H; 4.35, N; 4.32
Found : C; 74.12, ~; 4.13, N; 4.22
`
~5 (3) 1-(4-Bipheny}yl)-4H-quinolizin-4-one-3-
carboxylic acid.
mp : 261-263C
IR (Nujol) : 3100, 1720, 1660, 1610, 1580, 1290,
890, 775 cm 1
3`~ NMR (CF3COOH, ~) : 7.20-8.47 (12H, m), 8.70
(lH, s), 9.53 (lH, m) --
Anal. Calcd for C22~15NO3-1/4H2O :
C; 76.40, H; 4.52, N; 4.05
Found : C; 76.41, H; 4.57, N; 3.93
.,
:.;... .. ...
.~ ., .: ,, :: , ,
.
~ 73 ~ ~Z6~45~
(4) 1-Phenoxy-4H-quinolizin-4-one-3-carboxylic
acid.
mp : 224-226C
IR (Nujol) : 3100, 2650, 1725, 1640, 1620, 1580,
1210, 910 cm 1
N~ (CF3COOH, ~ : 7.20-7.37 ~2H, m), 7,43-7.73
~3H, m), 8r78 (lH, s), 8.27 (lH, d, J=7.5Hz),
8.60 (lH, t, J=7.5Hz), 9.05 (lH, d, J=8.5Hz),
9.63 (lH, d, J=7.5Hz)
Anal. Calcd for C16HllNO4 :
C; 68.33, H 3.94, N; 4.98
Found : C; 68.45, H; 3.96, N; 4.96
(5) 1-(3-Tolyl)-4H-quinolizin-4-one-3-carboxylic
15acid.
mp : 176-178C
IR (Nujol) : 3130, 1740, 1620, 1590, 1220,
770, 705 cm~l
NMR (CF3COOH, ~) : 2.52 (3H, s), 7.17-7.67 (4H,
m), 7.90-8.50 (3H, m), 8.70 (lH, s),
9.58 (lH, m)
Anal. Calcd for C17H13NO3 :
C; 73.11, H; 4.69, N; 5.02
Found : C; 73.11, H; 4~85, N; 5.13
(6) 1-(4-Chlorophenyl)-4H-quinolizin-4-one-3-
carboxylic acid.
mp : 269-271C
IR (Nujol) : 3140, 1740, 1620, 1490, 1320, 1290,
1~ 1090, 890, 825, 775 cm 1
NMR (CF3COO~ 7.35-7.78 (4~, m), 7.92-8.47
(3H, m), 8.73 (lH, s), 9.62 (lH, m)
Anal. Calcd for C16HloClNO3 ;
C; 64.12, H; 3.36, N; 4.67
3~5 Found : C; 63.95, 3 3.33, N; 4.5
~,
. ,, :; .- ,. .: . ~
.. . .::..,: ,,,, . :.: " .
:: . . :,. ~ :
74
~26~345~
(7) 1-(2-Tolyl~-4H-quinolizin-4-one-3-carboxylic
acid.
mp : 168-170C
IR (Nujol) : 3400, 1720, 1610, 1290, 1070,
780 cm 1
NMR (CF3COOH, ~) : 2.17 (3H, s), 7.25-7.75 (4H,
m), 7.98-8.63 (3H, m), 8.80 (lH, s),
9.72 (lH, m)
Anal. Calcd for C17H13NO3 :
C; 73.11, H; 4.69, N; 5~02
Found : C; 72.95, H; 4.91, N; 5.01
(8) 1-(3-Methoxyphenyl~-4H-quinolizin-4 one-3-
carboxylic acid.
mp : 222-224C
IR (Nujol) : 3100, 1725, 1600, 1490, 1220, 1030,
780 cm~l
NMR (CF3COOHj ~) ; 4.10 (3H, s), 7.15-8.62 (7H,
m), 8.77 (lH, s), 9.62 (lH, m)
Anal. Calcd for C17H13NO4
~; 69.15, H; 4.44, N; 4 74
Found : C) 69.67, H; 4.70, N; 4.67
(9) 1-Hydroxy-4H-quinolizin-4-one-3-carboxylic
acid. ~ ~
IR (Nujol) : 3200, 3100, 1690, 1620 cm 1
N~ (CF3COOH, ~) : 8.00-9.50 (SH, m),
; - Anal. Calcd for C~loH7NO4
C; 58.54, ~; 3.44, N; 6.83
Found : C; 57.93, H; 3.56, N; 6.77
:: :
Example 3
The ~ollowing compounds were obtained according
to a similar manner to that of E ample 2.
:
:: : :
. .
_ 75 _ 1 Z ~ ~ ~ 5 8
(1) N-[5-(lH-Tetrazolyl)]-4-phenyl-lH-pyrido[1,2-a]-
quinolin-l-one-2-carboxamide.
mp : ~270C
IR (Nujol) : 3250, 3150, 1675, 1640, 1610, 1580,
1115 cm 1
Anal. Calcd for C21H14N5O2 :
C; 65.96, H; 3.69, N; 21.98
Found : C; 66.43, H; 3.99, N; 22.15
(2) N-~5-(lH-Tetrazolyl)]-(l-naphthyl) 4H-
quinolizin-4-one-3-carboxamide.
mp : ~ 270C
IR (Nu]ol) : 3280, 1665, 1640, 1620, 1290,
780, 770 cm
NMR (CF3COO~, ~) : 7.27-8.25 (lOH, m), 8.77
(lH, s), 9.68 (lH, m)
Anal. Calcd for C21H14N6O2 :
C; 65.96, H; 3.69, N; 21.98
Found : C; 60.51, H; 3.75, N; 21.91
(3) N-[5-(lH-Tetrazolyl)]-1-(4-biphenylyl)-4H-
quinolizin-4-one-3-carboxamide.
mp : ~ 270C
IR (Nujol) : 3180, 1670, 1625, 1590, 1100, 1035
780, 730 cm 1
Anal. Calcd for C23H16N6O2 :
C; 67.64, H; 3.95, N; 20.58
- Found : C; 68.04, H; 4.31, N; 20.39
(4) N-[5-(lH-~etrazolyl)]-l-phenoxy-4H-quinolizin-
4-one-3-carboxamide.
mp : ~ 270C
IR (Nujol) : 3200, 3150, 1660, 1620, 1590, 1010,
780, 750 cm 1
NMR (CF3COOH, ~) : 7.08 7.67 (5H, m), 7.97 (lH, m),
: : .. : :
. - : :
~Z6~S~
76
8.22-8.47 (2H, m~, 8.70 (lH, m), 9.67 (lH, m)
Anal. Calcd for C17H12N6O3 :
C; 58.6~, H; 3.47, N; 24.13
Found : C; 59.39, H; 3.54, N; 24.06
(5) N-[5-(lH-Tetrazolyl)]-1-(3-tolyl)-4H-
quinolizin-4-one-3-carboxamide.
mp : ~ 270C
IR (Nujol) : 3160, 1670, 1640, 1620, 1600,
1585 -1
N~R (CF3COOH, ~) : 2.-52 (2H, s), 7.17-7.62 (m, 4H),
7.70-8.40 (3H, m), 8.73 ~lH, s), 9.63 (lH, m)
Anal. Calcd for C18H14N6O2 :
C; 62.42, H; 4.07, N; 24 26
Found : C; 63.03, H; 4.16r N; 24.56
tS) N-[5-(lH-Tetrazolyl)]-1-(4-chlorophenyl) -4H-
quinolizin-4-one-3-carboxamide.
mp : ~ 270C
IR (Nu~ol) : 3220, 1675, 1640 ~ 1600, 1480, 1290,
1040, 770 cm 1
Anal. Calcd for C17HllClN6O2 :
C; 55.67, H; 3.02, N; 22.91
Found : C; 57.45, H; 3.26, N; 21.47
~
(7) N-(2-Pyridyl)-l-phenyl-4H-quinolizin-4-one-
3-carboxamide.
mp : 227-229C
IR (Nujol) : 1680, 1620, 1550, 1480, 1300, 780,
770 cm
NMR (CF3COOH, ~) : 7.35-8.18 (lOH, m), 8.35-8.77 ~
(2H, m), 9.60 (lH, m~ ;
Anal. Calcd for C21H15N32
C; 73.89, H; 4.43, N; 12.31
Found : C; 74.17, H; 4.61, N~ 12.Z6
:
- - . . .: .
, .'; ~ " ~ ' .,, :'
~ 77 ~ ~ 2l~8 4 5 8
(8) N-[5-(lH-Tetrazolyl)¦-l-hydroxy-gH-
quinolizin-4-one-3-carboxamide.
mp : ~ 250C
IR (Nujol) : 3200 (sh), 1660, 1620, 1580 cm 1
Anal. Calcd for CllH$N6O3-1/2H2O :
C; 46.97, H; 3.22, N; 29.85
Found : C; 46.48, H; 3.31, N; 29.57
(9) N-~5-(lH-Tetrazolyl)]-1-(3-methoxyphenyl)-4H-
quinolizin-4-one-3-carboxamide.
mp : ~ 270C ~-
IR (Nujol) : 3150, 1630, 1640, 1620, 1590, 1490,
1300, 1210, 1030, 790, 780 cm 1
NMR (CF3COOH, ~) : 4.13 (3H, s), 7.17-7.52 (3H,
m), 7.55-8.15 (2H, m), 8.18-8.43 (2H, m~,
8.80 (lH, s), 9.67 (lH, m)
Anal. Calcd for C18H14N6O3 :
C; 59.67, H; 3.89, N; 23.19
Found : C; 59.81, H; 4.19, N; 23.35
(10) N-~5-(lH-Tetrazolyl)]-1-(2-tolyl)-4H-quinolizin-
4-one-3-carboxamide.
mp : ~ 270C
IR (Nujol) : 3200, 3120, 1680, 1620, 1490, 1290,
1030, 780 cm
NMR (CF3COOH, ~) : 2.15 (3H, s), 7.25-7.70 (4H,
m), 7.77-8.43 (3H, m), 8.77 ~(lH, s),
9.77 (lH, s)
- :~
Anal. Calcd for ~18H14N6O2 :
C; 62.42, H; 4.07, N; 24.26
Found : C; 62.75, H; 4.06, N; 24.35
:
- : :
~ ~w
: `
. ~,
. :
--. , :
- 78 - 1~6~5~
Example 9
The following compounds were obtained according
to a similar manner to that of Exam ~e 1.
(1) 7-(n-Butoxy)-l-phenyl-4H-quinolizin-4-one-3-
carboxylic acid.
mp : 155-157C
IR (Nujol) : 1720, 1610, 1495, 1425 cm
NMR (DMSO-d6, ~) : 0.95 (3H, t, J=5Hz),
1.3-2.0 (4H, m), 4.20 (2H, t, J=SHz),
7.3-7.7 (5H, m), 7.80 (2H, s), 8.10 (lH, s),
8.80 (lH, s), 14.1 (lH, broad s)
(Z) l-Allyloxy-4H-quinolizin-4-one-3-carboxylic acid.
mp : 140-143C
IR (Nujol) : 3100, 1730, 1720, 1610, 1580, 1420,
1095, 1065, 770 cm 1
N~R (CF3CO2H, ~) : 4.90-5.13 (2H, m), 5.35-5.78
(2H, m), 5.90-6.57 (1~, m), 7.97-8.67 (3H, m),
8.77-9.03 (lH, m), 9.39-9.67 (lX, m)
(3) 1-(N-Methylanilino)-4H-quinolizin-4-one-3-
carboxylic acid.
mp : 185C (dec.)
IR (Nujol) : 1720, 1700 (sh), 1620 cm
NMR (CF3COOH/ ~) : 3.53 (3H, s), 6.60-7.50
(5H, m), 7.80-8.60 ~3X, m), 8.64 (lH, s),
9.50 (lH, d, J=7Hz)
Anal. Calcd for C17H14N2O3 :
C, 69.38; H, 4.79; N, 9.52
Found : C, 69.03; H, 4.76; N, 9.31
(4) 1-Benzyl-4H-quinolizin-4-one-3-carboxylic acid.
mp : 221-223C
IR (Nujol) : 3380, 1720, 1620, 1410, 1320, 1070,
1020, 780 cm 1
"" ~ ,",
,,: : ,
_ 79 _ ~Z6~4s~
Anal. Calcd for C17H13NO3 :
C, 73.11; H, 4.69; N, 5 02
Found : C, 73.72; H, 4.92; N, 5.04
(5) 1-Phenylthio-4~-quinolizin-4-one-3-carboxylic acid.
mp : 195-197C
IR (Nujol) : 3350, 1720, 1620, 1400, 1285, 1065,
885, 780, 740 cm 1
Anal. Calcd for C16HllNO3S' :
~ C, 64.63; H, 3.73; N, 4.71
Found : C, 65.04; H, 3.90; N, 4.73
(6) 1-Phenylsulfonyl-4H-quinolizin-4-one-3-carboxylic
acid.
mp : >250C
IR (Nujol) : 1730, 1640, 1620, 1580, 1160,
1140 cm 1
NMR (DMSO-d6, ~) : 7O30-8.50 (7H, m), 8.60 (lH,
d, J=8Hz), 9.00 (lH, s), 9.50 (lH, d, J=8Hz)
Anal. Calcd for C16HllNO5S' :
C, 58.35; H, 3.37
Found : C, 58.62; H, 3.31
.
Example 10
To a solution of 3-ethoxycarbonyl-1-benzoyl-4H-
quinolizin-4-one (2.14 g) in chloroform (65 ml) was
added dropwise trimethylsilyliodide (1.04 ml) at 0C.
After stirring for 30 minutes at 0C, trimethyl-
silyliodide (1.04 ml) was added. After stirring for
1 hour at room temperature, trimethylsilyliodide (1.04
ml) was added. After stirring for 2 hours at room
temperature, the reaction mixture was diluted with
chloroform and washed with water. After drying over
magnesium sulfate, the chloroform extract was filtered
~5 and concentrated. The precipitate was washed wi~h a
t ~
~ ,
,. ' ..... ' :,
.~
..
, ~ ~...... .
. ~ ..
:lZ~34~
- 80 -
cold chloroform to give l-ben2Oyl-4H-quinolizin-4-one-
3-carboxylic acid (1.252 g) as yellow crystals.
IR (Nujol) : 1735, 1630, 1610, 1455, 1440,
1370 cm 1
N~ (CDC13, ~) : 6.70-8.30 (9H, m), 8.42-8.68
(lH, d, J=3Hz)
Anal. Calcd for C17HllNO4 :
C, 69.62; H, 3.78; N, 4.78
Found : C, 62.89; H, 3.54; N, 3.70
Mass : m/e 293 (M )
Example_ll
The following compounds were obtained according
to a similar manner to that of Example 2.
(1) 7-(n-Butoxy)-l-phenyl-N-~5-(lH-tetrazolyl)]-4H-
quinolizin-4-one-3-carboxamide.
mp : >205C (dec.~
IR (Nujol) : 1670, 1635, 1580, 1370 cm
NMR (DMSO-d6, ~) : 1.00 (3H, t, J=5.6Hz),
1.02-2.10 (4H, m), 4.18-(2H, t, J=6Hz),
6.80-7.25 (2H, m), 7.30-7.65 (3H, m),
7.68-8.00 (2H, m), 8.20 (lH, s),
8.87 (lH, broad s)
(2) N-~5-(lH-Tetrazolyl)]-l-phenylthio-4H-quinolizin-
4-one-3-carboxamlde.
mp : >270C
IR (Nujol) : 3180, 1660, 1640, 1620, 1285, 1035,
3a 780, 730 cm
Anal. Calcd for C17H12N6O2S :
Cj 56.04; ~, 3.32; N, 23.06
Found ~ C, 56.61; H, 3.53; N, 23.48
~-5 (3) 1-(N-MethylanIllno)-N-~5-(lH-tetrazolyl)]-4H-
,
.
~, : :
: - :. , ,. . :
. :. ~. . . -
: . .-. ,.. . . :, : ,. ,
-- . ~ -:: .
- 81 - ~Z6~45~
quinolizin-4-one-3-carboxamide.
mp : >230C
IR (Nujol) : 3200, 1660, 1640, 1620, 1290,
1030 cm 1
NMR (CF3COOH, ~) : 3.74 (3H, s), 6.80-7.60 (5H,
m), 7.62-8.08 (lH, m), 8.15-8.40 (2H, m),
8.85 (lH, s), 9 65 (lH, d, J=7Hz)
(4) N-[5-(lH-Tetrazolyl)]-l-allyloxy-4H-quinolizin-4
one-3-carboxamide.
mp : >270C (dec.)
IR (Nujol) : 3200, 1660, 1620, 1580, 1500, 1220,
1100, 1040, 1020, 955, 770 cm 1
NMR (CF3COOH, ~) : 4.90-5.17 (2H, m), 5.37-5.80
(2H, m), 5.90-6.55 (lH, m), 8.93-9.02 (4H, m),
9.50-9.73 (lH, m)
Anal. Calcd ~or C14H12N6O3 :
C, 53.85; H, 3.87; N, 26.91
Found : C, 54.20; H, 3.81; N, 26.93
(5) N-[5-(lH-Tetrazolyl)]-l-benzyl-4H-quinolizin-4-
one-3-carboxamide.
mp : >270C.
IR (Nujol) : 3140, 1660, 1620, 1595, 1490, 1295,
1040, 1005, 775, 720, 690 cm 1
Anal. Calcd for ClgH14N62
C, 62.42; H, 4.07; N, 24.26
Found : C, 62.88; H, 4.54; ~, 24.52
(6) N-[5-(lH-Tetrazolyl)]-l-phe~ylsulfonyl-4H-quinolizin-
4-one-3-carboxamide.
mp : >250C
IR (Nujol) : 1680, 1640, 1620, 1590 cm 1
Anal. Calcd for Cl7H12N6O4S :
C, 51.51; H, 3.05; N, 21.20
Found : C, 51.71; H, 2.93; N, 21.83
, :
- . . . .
~26!345~
- 82 -
(7) 1-Benzoyl-N-~5-(lH-tetrazolyl)]-4H-quinolizin-
4-one-3-carboxamide.
mp : >250C
IR (Nujol) : 1690, 1630, 1380, 1240, 1120 cm 1
NMR (CF3COOH, ~ : 7.40-8.25 (5H, m),
8.22-8.51 (lH, m), 8.70 (lH, broad s),
8.93 (lH, s), 9.12 (lH, d, J=9Hz),
9.73 (lH, d, J=7Hz)
Anal Calcd for C18H12N6O3 :
C, 60.00; H/ 3.36; N, 23.32
Found : C, 56.90; H, 3.80; N, 24,97
Example 12
The following compounds were obtained according
to a similar manner to that of Example 6-(1).
(1) 1-8enzoyl-N-~5-(lH-tetrazolyl~]-4H-quinolizin-4-
one-3-carboxamide sodium salt.
mp : 248-250C (dec.)
IR (Nujol~ : 1670, 1610, 1550, 1480, 1450 cm 1
(2) N-~5-(lH-Tetrazolyl)]-l-phenyl-4H-quinolizin-4-
one-3-carboxamide sodium salt.
mp : >250C
IR (Nujol) : 3150 (broad), 1660 (sh), 1650,
1640, 1620 cm 1
NMR (DMSO-d6, ~ .40-8.00 (9H, m), 8.50 (lH,
- s~, 9.30-9.60 (lH, m)
:
(3) N-[5-(lH-Tetrazolyl~]-l-phenoxy-4H-quinoliz1n-4-
one-3-carboxamide sodium salt.
mp : >250C
IR (Nujol~ : 166Q cm I
NMR (DMSO-d6, ~) : 6.9-7~8 (6H, m), 8.01 (2~, d,
~5 J=4Hz~, 8.32 (lH, s), 9.42 (lH, d, J=7Hz~,
12.30 (lH,; s)
... . . ..
,,: :. - : ~ - ;:
,, . : ~ - . ..
: ~ ... ...
.
-: . . .
- 83 - ~26
Anal. Calcd for C17Hl1N6NaO3 :
C, 55.14; EI, 2.99; N, 22.70
Found : C, 54.78; H, 3.63; N, 20.44
(to be continued to the next page.)
:
;
~30
,
:
~.~
- 84 -
~26~4~
Example 13
The following compound was obtained according to
a similar manner to that of Example 1.
1-Benzoyl-7-n-butoxy-4H-quinolizin-4-one-3-
carboxylic acid
mp : 155-156C
IR (Nujol) : 1720, 1620, 1580, 1495 cm
NMR (CDC13, ~) : 1.03 (3H, t, J=6Hz), 1.30-2.17
(4H, m), 4.23 (2H, t, J=6Hz), 7.17-7.93 -r~
(6H, m), 8.70 (lH, s), 8 88 (lH, d, J=lOHz),
9.02 (lH, d, J=2Hz), 13.60 (lH, broad s)
Exa~le 14
The following compounds were obtained according
to a similar manner to that of Example 2.
(1) 1-Benzoyl-7-n-butoxy-N-(lH-tetrazol-5-yl)-4H-
quinolizin-4-one-3-carboxamide
mp : 227C
IR (Nujol) 1680, 1660, 1625, 1585, 1550, 1495 cm 1
NMR (DMSO-d6, ~) : 1.2-2.0 (4Hj m), 4~23 (2H, t,
J=6Hz), 7.08 (2H, broad s), 7.37-8.17 (6H, m),
8.43 (lH, s), 8.75 (lH, d, J=lOHz),
8.93 (lH, d, J=2Hz)
(2) N-(4H-5-Amino-1,2,4-triazol-3-yl)-7-n-butoxy-1-
phenyl-4H-quinolizin-4-one-3-carboxamide
mp : 220C
IR (Nujol) : 1690, 1650, 1490, 1465, 1450 cm 1
NMR (DMSO-~6, ~) : 0.80-1.10 (3H, t), 1.30-2.10
(4H, m), 4.18 (2H, t), 7.03 (lH, s),
7.40-7.65 (5H, m), 7.70 (lH, d, J=7Hz),
7.83 (lH, d, J=7Hæ), 8.26 (lH, s), 8.87 (lH, s)
Mass : m/e 387 (M+)
.. ..
:, : . . , . ,:
:,,: . : .
: .. :: - :.:. :
, :" ~' ~,. ' ., '- ' :.
- 85 - ~Z6~4S~
(3) 1-Ethoxycarbonyl-N-(lH-tetrazol-S-yl)-4H-
quinolizin-4-one-3-carboxamide
mp : >250C
IR (Nujol) : 1665, 1640, 1610, 1595~ 1580 cm
S Mass : m/e 328 (M )
Example 15
The following compounds wPre obtained according to
a similar manner to that of Example 6-(1).
(1) 1-Benzoyl-7-n-butoxy-N-(lH-tetrazol-5-yl)-4H-
quinoli2in-4-one-3-carboxamide sodium salt
mp : 200-203C
NMR (DMSO-d6, ~) : 0.98 (3H, t, J=6Hz), 1.20-2.0
(4H, m), 4.25 (2H, t, J=6Hz), 7.32-8.17
(6H, m), 8e57 (lH, s), ~.75 (lH, d, J=lOHz),
9.02 (lH, d, J=2Hz), 11.87 (lH, broad s)
(2) 7-n-Butoxy-l-phenyl-N-(lH-tetrazol-S-yl)-4H-
quinolizin-4~one-3-carboxamide sodium salt
IR (Nujol) : 1680, 1640, 1620, 1585 cm 1
NMR (DMSO-d6, ~) : 0.80-1.20 (3H, m), I.30-2.10
(4H~ m), 4.00-4.48 (2H, m), 7.43-7.68 (5H,
m), 7.70-7.90 (2H, m), 8~40 (1~, s),
9.00 (lH, d, J=2Hz)
Example 16
To a solution of 1,3-diethoxycarbonyl-4H-
quinolizin-4-one (l g) in chloroform (20 ml) was added
trimethylsilyl iodide (0.49 ml) at room temperature
and the mixture was stirred for 4 hours and heated with
re~lux for 4 hours. After cooling to room temperature,
the mixture was washed with water, aqueous sodium
thiosulfate, and brine. Drying over magnesium sulfate
and evaporation gave a crystalline residue, which was
- 86 -
~268~
washed with isopropyl alcohol to give l-ethoxycarbony -
4H-quinolizin-4-one 3-carboxylic acid (794 mg).
mp : 189C
IR (Nujol) : 1735, 1710, 1635, 1620 cm
NMR (DMSO-d6, ~) : 1.34 (3H, t, J=7Hz), 4.33
(2H, q, ~=7Hz), 7.45-7.95 (lH, m), 8.00-8.45
(lH, m), 8.90 (lH, ~;), 9.05-9.60 (2H, m),
Mass : m/e 261 (M )
Anal. Calcd. for Cl3HllN05 :
C, 59.77; H, 4.24; N, 5.36
Found : C, 59.12; H, 4.59; N, 5.33
Example 17
To a solution of 1,3-diethoxycarbonyl-4H-quinolizin-
4 one (896 mg) in methanol (9 ml) was added 6N aqueous
sodium hydroxide (2.58 ml) at room temperature and the
mixture was heated with reflux for an hour. After
cooling to 0C, the reaction mixture was acidified to
pH 2 with 6N hydrochloric acid and the precipitate
was filtered and washed with water to give 4H-
quinolizin-4-one~1,3-dicarboxylic acid (202 mg).
mp : >250C
IR (Nujol) : 1675, 1655, 1635 cm
NMR (D2O, NaOD, 3) : 7.30-8.10
8.65 (lH, s), 8.70-9.00 (lH, m), 9.30 (lH, d,
J=7Hz)
Example 18
To a solution of l-ethoxycarbonyl-N-(lH-tetrazol- ~`
5-yl)-4H-quinolizin-4-one-3-carboxamide (500 mg) in
N,N-dimethylformamide (5 ml) was added lN aqueous sodium
hydroxide (6 ml) at room temperature and the mixture
was heated at 100C for an hour. After cooling to 0C,
the mixture was acidified to pH 2 with 6N hydrochloric
acid and the precipitate was filtered and washed with
~,
-. "-
..:. ~ : .. .... - ,
. . .
- .: : ; . ,: ~ : , : .:;: . " ~
- 87 - ~26~4~
~ater to give l-carboxy-N-(lH-tetrazol-5-yl)-4H-
quinolizin-4-one-3-carboxamide (280 mg).
mp : >250C
IR (Nujol) : 1670, 1640, 1615, 1590 cm 1
NMR (D2O-NaOD, ~) : 7.24-7.60 (lH, m),
7.60-8.07 (lH, m), 8.68-9.05 (lH, m),
8.84 (lH, s), 9.30 (lH, d, J=8Hz)
Mass : m/e 272 (M+)
Anal. Calcd. for C12H8N6O4.H2O :
C, 45.29; H, 3.16; Nt 26.41
Found : C, 45.29; H, 3.62; N, 26.56
Example 19
To a solution of pyridin-2-ylacetic acid
hydrochloride (1 g) in N,N-dimethylformamide (10 ml)
was added N,N'-carbonyldiimidazole (934 mg) at room
temperature and the mixture was heated at 60C for
20 minutes. To the mixture was added 2,2-dimethyl-1,3-
dioxane-4,6-dione(830 mg) at 60C and the mixture was
stirred for 1 hour at the same temperature. The solvent
was distilled off and the residue was diluted with
chloroform and washed with water. The chloroform
layer was extracted with aqueous sodium hydrogen
carbonate and the aqueous layer was washed with chloroform
and acidified to pH 2 with 6N hydrochloric acid at 0C
and extracted with chloroform. The chloroform layer
was washed with brine, dried over magnesium sulfate, and
evaporated to give 2-hydroxy-4H-quinolizin-4-one-3-
carboxylic acid (220 mg).
3~ mp : 194-195C
IR (Nujol) : 1690, 1605, 1370, 1300 cm 1
NMR (DMSO-d6, ~) : 6.75 (lH, s), 7.15-7.45 (lH, m),
7.76 (2H, d), 8.90 ~lH, d, J=6Hz)
Mass : m/e 205 (M )
35~ Anal.Calcd. for CloH7NO4 : C, 58,S4; H, 3.44; N, 6.83
Found : C; 58.49; H, 3.17; N, 6.86
:,
:: : ~
:' . : ' : .
~Z61~LS~
- 88 -
In this specification, the expression "such as" means "for
example" and is not intended to be construed as limiting the values
hich it qualifies.
