JPH0649701B2 - Quinolidinone compounds and their preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to quinolidinone compounds and salts thereof.
More particularly, this invention relates to novel quinolidinone compounds and salts thereof which have inhibitory activity against allergies and ulcers.

That is, an object of the present invention is to provide novel and useful quinolidinone compounds and salts thereof.

The quinolidinone compounds of the present invention can be represented by the following formula (I):

(wherein ^R2 represents hydrogen, a lower alkyl group, or a lower alkoxy group; ^R3 represents a lower alkyl group, a lower alkoxy group, a lower alkenyloxy group, a naphthyl group, a biphenyl group, a phenyl group having a lower alkyl group, a phenyl group having a halogen atom, a phenyl group having a lower alkoxy group, an arylthio group, an aroyl group, an aryl(lower)alkyl group, an arenesulfonyl group, an arylamino group or an aryloxy group which may have a lower alkyl group on the nitrogen atom; and ^R2 and ^R3 are located at the 1- and 9-positions of the quinolidinone ring and are bonded to each other to _{form -CH2CH2CH2-} or _-CH =C
H− can be formed).

According to the present invention, the object compound (I) can be prepared by the process shown in the following reaction scheme.

Manufacturing method 1 (wherein ^R2 and ^R3 have the same meanings as above, and ^R4 represents a protected carboxy group).

Among the starting compounds of the present invention, compound (II) can be produced by the production method shown in the following reaction scheme.

Manufacturing method A-(1) Manufacturing method A-(2) Manufacturing method B-(1) Manufacturing method B-(2) Manufacturing method C Manufacturing method D Manufacturing method E (wherein ^R2 and ^R4 have the same meaning as above, ^R5 is a lower alkoxy group, ^R6 is hydrogen, a lower alkyl group, a lower alkoxy group, a lower alkenyloxy group, a naphthyl group, a biphenyl group, a phenyl group having a lower alkyl group, a phenyl group having a halogen atom, a phenyl group having a lower alkoxy group, an arylthio group, an aroyl group, an aryl(lower)alkyl group, an arenesulfonyl group, an arylamino group or an aryloxy group which may have a lower alkyl group on the nitrogen atom, ^R9 is a protected hydroxy group, and n is 1 or 2.)

Suitable salts of the object compound (I) are conventional non-toxic salts, such as organic acid salts such as acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.; inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.; or acid addition salts such as salts with amino acids such as arginine, aspartic acid, glutamic acid, etc.; or metal salts such as alkali metal salts such as sodium salt, potassium salt, etc. and alkaline earth metal salts such as calcium salt, magnesium salt, etc.; ammonium salts, such as trimethylamine salt, triethylamine salt,
Pyridine salt, picoline salt, dicyclohexylamine salt,
Examples include organic base salts such as N,N'-dibenzylethylenediamine salts.

In the above and following descriptions of this specification, preferred examples and explanations of various definitions encompassed within the scope of this invention are set forth in detail below.

"Lower" shall mean 1 to 6 carbon atoms, unless otherwise indicated.

Suitable "lower alkyl" and suitable "lower alkyl" portions of "aryl(lower)alkyl" include methyl,
Included are straight or branched chain alkyl groups having 1 to 6 carbon atoms such as ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl, and the like.

Suitable "lower alkoxy groups" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, tertiary pentyloxy, hexyloxy, and the like, preferably those having 1 carbon atom.
Examples include those having 1 to 4.

Suitable "lower alkenyloxy groups" include vinyloxy, 1-propenyloxy, allyloxy, 1-butenyloxy, 2-butenyloxy, 2-pentenyloxy, and the like, preferably those having 2 to 4 carbon atoms.

Suitable "protected carboxy groups" include "esterified carboxy groups" as described below.

Suitable examples of the ester moiety of the esterified carboxy group include, for example, methyl ester, ethyl ester,
lower alkyl esters which may have at least one suitable substituent, such as propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, and the like; examples thereof include acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester,
Valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1
(or 2)-acetoxyethyl ester, 1 (or 2 or 3)-acetoxypropyl ester, 1 (or 2 or 3 or 4)-acetoxybutyl ester,
1(or 2)-propionyloxyethyl ester,
lower alkanoyloxy(lower)alkyl esters such as 1(or 2 or 3)-propionyloxypropyl ester, 1(or 2)-butyryloxyethyl ester, 1(or 2)-isobutyryloxyethyl ester, 1(or 2)-pivaloyloxyethyl ester, 1(or 2)-hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester and 1(or 2)-pentanoyloxyethyl ester; lower alkanesulfonyl(lower)alkyl esters such as 2-mesylethyl ester;
mono- (or di- or tri-)-halo(lower) alkyl esters such as trichloroethyl ester, lower alkoxycarbonyloxy(lower) alkyl esters such as methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, phthalidylidene(lower) alkyl esters, or, for example, (5-methyl-2-oxo-
1,3-dioxol-4-yl)methyl ester,
(5-ethyl-2-oxo-1,3-dioxole-4
(5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower) alkyl esters such as (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester; lower alkenyl esters such as vinyl esters and allyl esters; lower alkynyl esters such as ethynyl esters and propynyl esters;
aryl(lower)alkyl esters which may have at least one suitable substituent, such as tert-butylbenzyl ester; for example, phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester;
Examples include aryl esters which may have at least one suitable substituent, such as xylyl ester, mesityl ester, cumenyl ester, etc.; phthalidyl ester, etc.

Preferred examples of the esterified carboxy group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,
Examples include lower alkoxycarbonyl groups such as tertiary pentyloxycarbonyl, hexyloxycarbonyl, 1-cyclopropylethoxycarbonyl, and the like.

Suitable "hydroxy group-protecting groups" include conventional hydroxy protecting groups, examples of which include alk(lower) groups such as lower alkyl groups such as methyl, ethyl, propyl, tertiary butyl, etc.; lower alkenyl groups such as vinyl, allyl, etc.; and mono-, di-, or triphenyl(lower) alkyl groups such as benzyl, benzhydryl, trityl, etc.
Examples include hydroxy groups protected by alkyl groups, for example, tri-substituted silyl groups such as tri(lower)alkylsilyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tertiary butyldimethylsilyl, and diisopropylmethylsilyl, triarylsilyl groups such as triphenylsilyl, and tri(lower)alkylsilyl groups such as tribenzylsilyl.

Suitable "aryl groups" of the "arylthio group", "(lower) arylalkyl group" and "arylamino group" include phenyl, tolyl, xylyl, cumenyl, naphthyl, biphenylyl and the like.

Suitable "aroyl groups" include benzoyl, trioyl, naphthoyl, and the like.

Suitable "arenesulfonyl groups" include benzenesulfonyl, p-toluenesulfonyl, and the like.

Suitable "aryloxy groups" include phenoxy, tolyloxy, and the like.

The process for producing the object compound (I) of the present invention will be explained in detail below.

Process 1 The object compound (I) or a salt thereof can be prepared by subjecting compound (II) or a salt thereof to elimination reaction of the carboxy-protecting group.

Suitable salts of compound (II) include the acid addition salts exemplified for compound (I).

In this elimination reaction, any conventional method used in the elimination reaction of a carboxy-protecting group, such as hydrolysis, reduction, elimination using Lewis acid, etc., can be applied. When the carboxy-protecting group is an ester, the protecting group can be eliminated by hydrolysis or elimination using Lewis acid. Hydrolysis is preferably carried out in the presence of a base or acid.

Suitable bases include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate,
Examples include inorganic bases such as alkali metal acetates such as sodium acetate and potassium acetate, alkaline earth metal phosphates such as magnesium phosphate and calcium phosphate, alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, and organic bases such as trialkylamines such as trimethylamine and triethylamine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-one, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[5.4.0]undecene-5, etc. Hydrolysis using a base is often carried out in water or a hydrophilic organic solvent, or a mixture thereof.

Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, etc., and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc.

This hydrolysis is usually carried out in an organic solvent, water or a mixture thereof.

The reaction temperature is not particularly limited and may be appropriately selected depending on the type of carboxy protecting group and the type of removal method.

Elimination using a Lewis acid is preferably applied to the elimination of substituted or unsubstituted alk(lower)alkyl esters, and is carried out by reacting compound (II) or a salt thereof with a Lewis acid such as a boron trihalide such as boron trichloride or boron trifluoride, a titanium tetrahalide such as titanium tetrachloride or titanium tetrabromide, a tin tetrahalide such as tin tetrachloride or tin tetrabromide, an aluminum halide such as aluminum chloride or aluminum bromide, or a trihaloacetic acid such as trichloroacetic acid or trifluoroacetic acid. This elimination reaction is preferably carried out in the presence of a cation scavenger such as anisole or phenol, and is usually carried out in the presence of a nitroalkane such as nitromethane or nitroethane, an alkylene halide such as methylene chloride or ethylene chloride, diethyl ether,
The reaction is carried out in a solvent such as carbon disulfide, but can also be carried out in any other solvent that does not adversely affect the reaction. These solvents may also be used in mixtures thereof.

The reductive elimination method can be carried out by, for example, 2-iodoethyl ester, 2,
It is preferably applied to the removal of protecting groups such as halo(lower)alkyl esters such as 2,2-trichloroethyl ester, and alk(lower)alkyl esters such as benzyl ester, etc. Examples of reduction methods applicable to this removal reaction include a combination of a metal such as zinc or zinc amalgam, or a chromium compound salt such as chromium chloride or chromium acetate, with an organic or inorganic acid such as acetic acid, propionic acid, or hydrochloric acid; and conventional catalytic reduction methods in the presence of a conventional metal catalyst such as palladium-carbon or Raney nickel.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature or under heating.

Process A-(1) Compound (V) or a salt thereof can be prepared by reacting compound (III) or a salt thereof with compound (IV).

Suitable salts of compounds (III) and (V) include the acid addition salts exemplified for compound (I).

This reaction is preferably carried out in the presence of an alkyllithium such as n-butyllithium, lithium diisopropylamide, or an alkali metal alkoxide such as sodium methoxide or sodium ethoxide.

This reaction is usually carried out in a solvent such as acetone, dioxane, acetonitrile, dimethylformamide, benzene, hexane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, or ethyl acetate, but the reaction can also be carried out in any other solvent that does not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room 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 a ring-closure reaction.

Suitable salts of compound (V) include the acid addition salts exemplified for compound (I).

The reaction is preferably carried out in the presence of a suitable reagent such as a mixture of diphenyl and diphenyl ether used as the heating medium.

The reaction temperature is not particularly limited, but the reaction is usually carried out under heating.

Process B-(1) Compound (Va) or a salt thereof can be prepared by reacting compound (IIIa) or a salt thereof with compound (IV).

Suitable salts of compounds (IIIa) and (Va) include the acid addition salts exemplified for compound (I).

This reaction can be carried out in the same manner as in the above-mentioned Production Method A-(1).

Process B-(2) The compound (IIb) or a salt thereof can be prepared by subjecting the compound (Va) or a salt thereof to a ring-closure reaction.

Suitable salts of compounds (IIb) and (Va) include:
Examples of the acid addition salts include those exemplified for compound (I).

This reaction can be carried out in the same manner as in the above-mentioned Production Method A-(2).

Process C The compound (IIe) or a salt thereof can be prepared by subjecting the compound (IId) or a salt thereof to a reaction for introducing a hydroxy-protecting group.

Suitable salts of compounds (IId) and (IIe) include the acid addition salts exemplified for compound (I).

When the protecting group to be introduced is a lower alkyl or lower alkenyl group, the reaction is carried out by reacting compound (IId) or a salt thereof with a lower alkylating agent or a lower alkenylating agent.

The lower alkylating agent or lower alkenylating agent used in this reaction includes conventional lower alkylating agents or lower alkenylating agents such as mono(or di)-lower alkyl sulfates such as dimethyl sulfate, lower alkyl esters of lower alkanesulfonic acids such as methyl methanesulfonate, halo(lower)alkanes such as bromomethane, iodomethane, iodoethane, iodobutane, halo(lower)alkene such as iodopropene, and the like.

When a lower alkyl ester of an acid is used as the lower alkylating agent, the reaction is usually carried out in a solvent such as water, acetone, tetrahydrofuran, ethanol, ether, or dimethylformamide, but the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction.

The reaction is preferably carried out in the presence of a conventional base, such as an inorganic or organic base.

The reaction temperature is not particularly limited, and the reaction is usually carried out within a temperature range from cooling to heating up to near the boiling point of the solvent.

Process D The compound (IIg) or a salt thereof can be prepared by subjecting the compound (IIf) or a salt thereof to an oxidation reaction.

Suitable salts of compound (IIf) include the acid addition salts exemplified for compound (I).

Suitable oxidizing agents for use in this oxidation reaction include 2,
Examples of the oxidizing agent include conventional oxidizing agents such as 3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

This oxidation reaction is carried out in a solvent such as benzene, toluene, chloroform, methylene chloride, carbon tetrachloride, diethyl ether, or dimethylformamide, but the reaction can also be carried out in any other solvent as long as it does not adversely affect the reaction, and the solvent is selected arbitrarily depending on the type of oxidizing agent used.

The reaction temperature for the oxidation reaction in this production method is not particularly limited, and the reaction can be carried out under cooling, at room temperature, under warming, or under heating. The reaction temperature is selected arbitrarily depending on the type of oxidizing agent used.

Process E The compound (IIk) or a salt thereof can be prepared by subjecting the compound (IIj) or a salt thereof to an oxidation reaction.

Suitable oxidizing agents for use in this oxidation reaction include inorganic peracids or salts thereof, such as periodic acid, persulfuric acid or its sodium salt or potassium salt; organic peracids or salts thereof, such as perbenzoic acid, m-chlorobenzoic acid, performic acid, peracetic acid, chloroperacetic acid, trifluoroperacetic acid or its sodium salt or potassium salt; ozone, hydrogen peroxide, hydrogen peroxide urea; N-halosuccinimides, such as N-bromosuccinimide, N-chlorosuccinimide; hypochlorites, such as tert-butyl ester of hypochlorous acid; permanganates, such as potassium permanganate; or other conventional oxidizing agents capable of oxidizing a sulfinyl group to a sulfonyl group.

This reaction can be carried out in the presence of a compound of a metal of Group Vb or VIb of the periodic table, such as tungstic acid, molybdic acid, vanadic acid, or the alkali metal or alkaline earth metal salts thereof.

This oxidation reaction is usually carried out in water, acetic acid, chloroform, methylene chloride, acetone, methanol, ethanol, or a mixture thereof, but the reaction can also be carried out in any other solvent that does not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to room temperature.

The pharmaceutical compositions of this invention can be used in the form of pharmaceutical preparations, e.g., solid, semi-solid, or liquid preparations containing the active substance of this invention in admixture with organic or inorganic carriers or excipients suitable for topical, oral, or parenteral application. The active ingredient may be mixed with conventional non-toxic pharmaceutically acceptable carriers for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and other forms suitable for use. Carriers that can be used include water, glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, and other carriers suitable for use in the manufacture of solid, semi-solid, or liquid preparations. Additionally, auxiliary substances, stabilizers, thickeners, colorants, and flavoring agents may also be used. Pharmaceutical compositions can also be used in the form of pharmaceutical preparations containing a soluble or soluble ...
A preservative or bacteriostatic agent may also be included.The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired therapeutic effect depending upon the process and condition of diseases.

When this composition is administered to humans, it is preferably administered intravenously, intramuscularly, or orally. The dosage or therapeutically effective amount of the compound of the present invention varies depending on the age and condition of each patient to be treated, but the daily dosage for treating diseases in humans or animals is usually about 0.05 to 5 mg/kg of the active ingredient, and generally, an average of about 100 mg/kg is administered once.
2.5mg, 25mg, and 250mg are administered.

The present invention will be described below with reference to Production Examples and Examples.

Preparation Example 1: 2-methylpyridine (7m) in tetrahydrofuran (1
To the solution (40 ml) of 1.59 mol n-butyllithium in hexane (49 ml) was added dropwise with ice cooling. The temperature of the resulting dark red solution was allowed to rise to room temperature and stirred for 1 hour.
After cooling to −78°C, a solution of diethyl ethoxymethylenemalonate (15.68 m) in tetrahydrofuran (50 m) was added to 30
The reaction mixture was allowed to warm to -20°C and stirred at -20°C for 30 minutes. Acetic acid (4.48 ml) was added. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with 10% aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and the solvent was evaporated to give an oil (27%).
The residue was purified by silica gel (Merck, 70-230
ethyl 3-ethoxy-2-ethoxycarbonyl-4-(2-pyridyl)butyrate (19%) was obtained by chromatography on a column of 1000 ml of 1,000 sachets ...
g) is obtained as an oil.

IR (film): 1730, 1590, 1470, 1440, 1370 cm ^-1 NMR (CDCl ₃ ) δ: 0.97 (t, 3H, J = 8 Hz), 1.26 (t, 6H, J = 8H
z), 3.12(d,1H,J=8Hz), 3.2−3.6(m,2H), 3.62(d,1H,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, 1H) Preparation Example 2 Ethyl 3-ethoxy-2-ethoxycarbonyl-4-(2-pyridyl)butyrate (18.9 g), diphenyl (48.85
A mixture of 200 ml of 100 ml of 100 ml of 100 ml of diphenyl ether (135.8 g) and 135.8 g of diphenyl ether was added to 200 ml of 1 ... diphenyl ether.
The reaction mixture was heated to 50° C. 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). The crude oil obtained was eluted with a mixture of ether and hexane (1:49).
1) to give 3-ethoxycarbonyl-4H
-quinolizin-4-one (11.48 g) is obtained as yellow crystals.

IR (nujol): 1670, 1625, 1490 cm ^-1 NMR (CDCl ₃ ) δ: 1.42 (t, 3H, J = 7Hz), 4.42 (q, 2H, J = 7H
z)、6.62(d,1H,J=8Hz)、7.02−7.38(m,1H)、7.53−7.6
8 (m, 2H), 8.33 (d, 1H, J=8 Hz), 9.23-9.47 (m, 1H) Preparation 3 The following compound is obtained in the same manner as in Preparation 1.

(1) 3-ethoxy-2-ethoxycarbonyl-4-[2
-(5-ethylpyridyl)]butyrate ethyl.

IR (film): 1750, 1730 cm ⁻¹ (2) 3-ethoxy-2-ethoxycarbonyl-3-[8
-(5,6,7,8-tetrahydroquinolyl)]ethyl propionate.

IR (film): 1750, 1730 cm ⁻¹ (3) 3-ethoxy-2-ethoxycarbonyl-4-[2
-(3-methylpyridyl)]butyrate ethyl.

IR (Nujol): 1750, 1735, 1575, 1440, 860, 790 cm ^-1 NMR (CDCl ₃ ) δ: 0.92 (t, 3H, J=5 Hz), 1.27 (t, 6H, J=5H
z)、2.37(s,3H)、3.08−3.60(m,4H)、3.70(d,1H,J=5H
z)、4.18(q,2H,J=5Hz)、4.22(q,2H,J=5Hz)、4.52(m,1
H), 7.05 (dd, 1H, J = 6Hz and 3Hz), 7.45 (d, 1H, J = 6H
z), 8.42 (d, 1H, J = 3 Hz), (4) 3-ethoxy-2-carbethoxy-4-[2-
(4-methylpyridyl)]butyrate ethyl.

IR (film): 1750, 1730, 1600, 1240, 1150, 1020 cm ^-1 NMR (CDCl ₃ ) δ: 0.97 (t, 3H, J = 7 Hz), 1.27 (t, 6H, J = 7H
z), 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=7Hz),6.87−
7.13 (m, 2H), 8.40 (d, 1H, J = 6 Hz), (5) 3-ethoxy-2-ethoxycarbonyl-4-[2
-(6-methylpyridyl)]butyrate ethyl.

IR (film): 1650, 1630, 1590, 1580, 1270, 1150, 1090
cm ^-1 NMR(CDCl ₃ )δ: 0.97(t,3H,J=7Hz), 1.25(t,6H,J=7H
z), 2.48(s,3H), 3.07(d,2H,J=5.5Hz), 3.60(q,2H,J=
7Hz), 3.23−3.57(m,1H), 4.18(q,4H,J=7Hz), 4.33−
4.67 (m, 1H), 6.85-7.15 (m, 2H), 7.33-7.66 (m, 1H) (6) 3-Ethoxy-2-ethoxycarbonyl-4-(2
-pyridyl)pentanoic acid ethyl ester.

IR (film): 1750, 1730, 1590, 1300, 1090, 1020 cm ^-1 NMR (CDCl ₃ ) δ: 1.00 (t, 3H, J = 7H), [1.35 (t, J = 7Hz),
1.25(t,J=7Hz), 1.25(s)9H], 3.00−3.75(m,4H), 3.9
3−4.58(m,5H), 6.98−7.60(m,2H), 7.65(m,1H), 8.58
(m,1H) (7) 3-ethoxy-2-ethoxycarbonyl-4-[2
-(5-methylpyridyl)]butyrate ethyl.

IR (film): 1740, 1730, 1600, 1480, 1150, 1090, 1025
cm ^-1 NMR(CDCl ₃ )δ: 1.00(t,3H,J=7Hz), 1.27(t,6H,J=7H
z)、2.32(s,3H)、3.00−3.77(m,4H)、4.22(q,3H,J=7H
z)、4.25(q,3H,J=7Hz)、7.03−7.50(m,2H)、8.37(m,1
H) (8) 3-ethoxy-2-ethoxycarbonyl-3-[7
Ethyl-(6,7-dihydro-5H-cyclopenta[6]pyridyl)]propionate.

IR (film): 1750 (sh), 1730, 1590, 1580 cm ^-1 NMR (CDCl ₃ ) δ: 0.80 (t, 3H, J = 7Hz), 1.30 (t, 6H, J = 7H
z), 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, 1H, J = 8Hz and
2Hz), 7.00-7.60(m,2H), 8.3-8.50(m,1H) (9) Ethyl 3-ethoxy-4-methoxy-4-(2-pyridyl)-2-ethoxycarbonylbutyrate.

IR (film): 1750, 1730, 1590, 1365, 1090, 1025, 760c
m ^-1 NMR(CDCl ₃ )δ: 0.78(t,3H,J=7Hz), 1.25(t,3H,J=7H
z), 1.28(t,3H,J=7Hz), 3.33(d,2H,J=4Hz), 3.60−4.
60 (m, 9H), 7.07-7.90 (m, 3H), 8.62 (m, 1H) Preparation 4 The following compound is obtained in the same manner as in Preparation 2.

(1) 7-ethyl-3-ethoxycarbonyl-4H-quinolizin-4-one.

Melting point 81-83℃ IR (nujol): 1720, 1630cm ^-1 NMR (CDCl ₃ ) δ: 1.32 (t, 3H, J = 7Hz), 1.44 (t, 3H, J = 7H
z)、2.76(q,2H,J=7Hz)、4.40(q,2H,J=7Hz)、6.60(d,1
H,J=8Hz), 7.52(s,2H), 8.32(d,1H,J=8Hz), 9.20(s,1
H) (2) 9-methyl-3-ethoxycarbonyl-4H-quinolizin-4-one.

Melting point 125-126℃ IR (nujol): 3090, 1725, 1645, 1590, 1125, 1100cm ^-1 NMR (CDCl ₃ ) δ: 1.40 (t, 3H, J = 7Hz), 2.50 (s, 3H), 4.42
(q,2H,J=7Hz)、6.63(d,1H,J=9Hz)、7.07(t,1H,J=7H
z)、7.47(d,1H,J=7Hz)、8.35(d,1H,J=9Hz)、9.32(d,J
= 7 Hz, 1H) Analysis: Calculated for _C13H13NO3 : C _67.52 , H _5.67 Found: C 67.51, H 5.83 (3) 8-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-one.

Melting point: 146-148°C IR (Nujol): 3060, 1720, 1660, 1640, 1245, 1155, 790
cm ^-1 NMR(CDCl ₃ )δ: 1.40(t,3H,J=7Hz), 2.50(s,3H), 4.38
(q,2H,J=7Hz)、6.50(d,1H,J=9Hz)、7.00(dd,1H,J=7H
z, 2Hz), 7.30 (d, 1H, J = 2Hz), 8.32 (d, 1H, J = 9Hz), 9.28
(d, 1H, J = 7Hz) Elemental analysis calculated for _C13H13NO3 : C _67.52 , H 5.67 Found: C 67.38, H 5.65 (4 ₎ 3-Ethoxycarbonyl-6-methyl-4H-quinolizin-4-one.

Melting point 90-93℃ IR (Nujol): 1720, 1650, 1620, 1590, 1265, 1120, 110
0,795cm ^-1 NMR(CDCl ₃ )δ: 1.35(t,3H,J=7Hz), 3.05(s,3H), 4.38
(q,2H,J=7Hz)、6.38(d,1H,J=8Hz)、6.67(m,1H)、7.25
(d, 1H, J = 4.5 Hz), 8.18 (d, _1H , J = ₈ Hz). Analysis: Calculated for _C13H13NO3 : C 67.52, H 5.67, N 6.07. Found: C 67.28, H 5.63, N 6.03. (5) 1-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-one.

Melting point 142-143℃ IR (Nujol): 1720, 1650, 1620, 1595, 1300, 1230, 116
0, 1120, 775 cm ^-1 NMR (CDCl ₃ ) δ: 1.42 (t, 3H, J = 7Hz), 2.40 (s, 3H), 4.43
(q,2H,J=7Hz), 7.20(m,1H), 7.62−7.80(m,2H), 8.25
(s, 1H), 9.47 (m, 1H). Elemental analysis: Calculated for _C13H13NO3 : C _67.52 , H 5.67, N _6.06 . Found: C 67.49, H 5.94, N 6.06. (6) 7-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-one.

Melting point 146-149℃ IR (nujol): 1720, 1620, 1145, 1110 cm ^-1 NMR (CDCl ₃ ) δ: 1.42 (t, 3H, J = 7Hz), 2.45 (s, 3H), 4.43
(q,2H,J=7Hz), 6.62(d,1H,J=8Hz), 7.47−7.57(m,2
H), 8.33 (d, 1H, J = 8 Hz), 9.23 (m, 1H) _. Analysis: Calculated for _C13H13NO3 : C; _67.52 , H; 5.62, N; 6.06. Found: C; 67.44, H; 5.85, N; 6.00. (7) 2-Ethoxycarbonyl-8,9-dihydrocyclopenta[ij]-3H-quinolizin-3-one.

Melting point 149℃ IR (Nujol): 3100, 1720, 1640, 1620, 1600, 1550, 121
0, 1150cm ^-1 NMR (CDCl ₃ ) δ: 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,1H), 8.
86 (d, 1H, J = 6 Hz) Elemental analysis: _C14H13NO3 Calculated: C _69.12 , H 5.39, N _5.76 Found: C 68.16, H 5.47, N 5.69 (8) 2-Ethoxycarbonyl, 9,10-dihydro-8H
-benzo[ij]-3H-quinolizin-3-one.

Melting point 118℃ IR (nujol): 1680, 1620, 1600, 1220cm ^-1 NMR (CDCl ₃ ) δ: 1.40 (t,3H,J=7Hz), 1.85−2.20 (m,2
H), 2.80-3.20(m,4H), 4.40(q,2H,J=7Hz), 6.85-7.3
0 (m, 2H), 8.13 (s, 1H), 9.20 (d, _1H , J = 7 Hz ₎ . Analysis: Calculated for _C15H15NO3 : C 70.02, H 5.88, N 5.44. Found: C 69.78, H 5.95, N 5.38. (9) 1-Methoxy-3-ethoxycarbonyl-4H-quinolizin-4-one.

Melting point 132-133℃ IR (Nujol): 1680, 1670, 1620, 1595, 1360, 1120, 102
0,770cm ^-1 NMR(CDCl ₃ )δ: 1.43(t,3H,J=7Hz), 3.93(s,3H), 4.45
(q,2H,J=7Hz), 7.25(m,1H), 7.67(m,1H), 7.97−8.20
(m, 2H), 9.47 (d, _1H , J = 7.5 Hz). Elemental analysis: Calculated for _C13H13NO4 : C; 63.15, H; 5.30, N; 5.66. Found: C; 62.80, H; 5.33, N; 5.63. Preparation ₅ : A solution of 2-ethoxycarbonyl-8,9-dihydrocyclopenta[ij]-3H-quinolizin-3-one (2.2 g) and dichlorodicyanobenzoquinone (2.26 g) in benzene (110 ml) was refluxed for 2 hours. The reaction mixture was cooled to 0°C and filtered to remove precipitate. The solution was concentrated and the residue was subjected to column chromatography using silica gel (44 g) and purified by elution with a mixture of chloroform and methanol (100:1 to 100:1).
The crude crystals obtained by distilling off the solvent from the corresponding fractions were washed with a mixture of ether and hexane to give 2-
Ethoxycarbonylcyclopenta[ij]-3H-quinolizin-3-one (1.82 g) is obtained.

Melting point: 127°C IR (Nujol): 3100, 1680-1700 (Broad), 1620, 1570, 123
0, 1210cm ^-1 NMR (CDCl ₃ ) δ: 1.46 (t, 3H, J = 7Hz), 4.46 (q, 2H, J = 7H
z), 6.80−7.60(m,3H), 8.13(d,1H,J=8Hz), 8.70(s,1
H), 9.20 (d, 1H, J = 8 Hz). Elemental analysis: _C14H11NO3 , calculated: 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, and the mixture was stirred.
The solution is maintained at 50°C for 30 minutes. The reaction mixture is treated with methyl iodide (4.13 g) and stirred at the same temperature for 30 minutes. The reaction mixture is poured into dilute hydrochloric acid and extracted with chloroform. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated to give an oil (12.3 g), which is subjected to silica gel column chromatography. A chloroform-methanol (9
Elution with 100% hexanes (9:1) gave 3-ethoxycarbonyl-7-methoxy-4H-quinolizin-4-one (3.75 g).

Melting point 156-158℃ IR (nujol): 1720, 1620, 1500, 1140, 1100cm ^-1 NMR (CDCl ₃ ) δ: 1.43 (t, 3H, J = 7Hz), 3.93 (s, 3H), 4.43
(q,2H,J=7H), 6.63(d,1H,J=8.5Hz), 7.23−7.70(m,2
Elemental analysis for _C13H13NO4 : Calculated: C _; 63.15, H; 5.30; Found: C; 62.62, H; 5.52. Preparation Example ₇ The following compound is obtained in the same manner as in Preparation Example 6.

(1) 3-ethoxycarbonyl-7-n-butoxy-4H
-quinolizin-4-one.

Melting point 132-133℃ IR (Nujol): 1710, 1620, 1540, 1280, 1240, 1140, 84
5,780cm ^-1 NMR(CDCl ₃ )δ: 1.00(t,3H,J=6Hz), 1.43(t,3H,J=7.5H
z), 1.50−2.33(m,4H), 4.10(t,2H,J=6Hz), 4.43(q,2
H,J=7.5Hz), 6.63(d,1H,J=8Hz), 7.23−7.67(m,2H),
8.28 (d, 1H, J = 8H), 8.97 (d, 1H, J = _2Hz ) Elemental analysis: _C16H19NO4 Calculated: C; _66.42 , H; 6.62, N; 4.84 Found: C; 66.54, H; 6.52, N; 4.82 (2) 3-Ethoxycarbonyl-7-isopropoxy-4
H-Quinolizin-4-one.

Melting point: 132-134°C IR (Nujol): 1725, 1625, 1240, 1140, 1100, 970, 840°C
m ^-1 NMR(CDCl ₃ )δ: 1.42(d,6H,J=6Hz), 1.43(t,3H,J=7.5H
z)、4.43(q,1H,J=7.5Hz)、4.65(m,2H)、6.62(d,1H,J=
8.5Hz), 7.20−7.68(m,2H), 8.27(d,1H,J=8.5Hz), 9.0
0 (d, 1H, J = 2 Hz) Elemental analysis: _C15H17NO4 Calculated: C; 65.44, H; 6.22, N; 5.09 Found: C; 65.66, _{H ;} 6.15, N; 5.10 Preparation Example 8 The following compound is obtained in the same manner as in Preparation Example 1.

(1) 4-(2-pyridyl)-4-(1-naphthyl)-3-
Ethoxy-2-ethoxycarbonylbutyrate ethyl.

IR (film): 1750, 1720, 1580, 780, 750 cm ^-1 NMR (CDCl ₃ , δ): 0.60 (3H, t, J = 7 Hz), 1.20 (6H, t, J = 7
Hz)、2.20−4.53(8H,m)、5.33(1H,m)、6.95−8.10(10H,
m), 8.58(1H,m) (2) 4-(2-pyridyl)-4-(4-biphenylyl)
-Ethyl 3-ethoxy-2-ethoxycarbonylbutyrate.

IR (film): 1750, 1730, 1590, 1485, 1300, 1150, 760c
m ^-1 NMR (CDCl ₃ , δ): 0.83 (3H,t,J=7Hz), 1.33(6H,t,J=7
Hz), 3.28(1H,m), 3.63(2H,q,J=7Hz), 4.25(4H,q,J=7
Hz), 4.50-5.30(2H,m), 7.02-7.38(2H,m), 8.65(1H,m) (3) Ethyl 4-phenoxy-4-(2-pyridyl)-3-ethoxy-2-ethoxycarbonylbutyrate.

IR (film): 1750, 1730, 1590, 1490, 1220, 1060, 750c
m ^-1 NMR (CDCl ₃ , δ): 0.80 (3H,t,J=7Hz), 1.03(3H,t,J=7
Hz), 1.28(3H,t,J=7Hz), 2.73(1H,m), 3.17−3.70(2H,
m), 3.80−4.40(4H,m), 4.60(1H,m), 5.55(1H,m), 6.80
−7.03(3H,m), 7.10−7.40(3H,m), 7.42−7.80(2H,m),
8.65(1H,m) (4) 4-(3-tolyl)-4-(2-pyridyl)-3-
Ethoxy-2-ethoxycarbonylbutyrate ethyl.

IR (film): 1750, 1730, 1600, 1590, 1100, 700 cm ^-1 NMR (CCl ₄ , δ): 0.72 (3H, t, J = 7 Hz), 1.07-1.45 (6H,
m)、2.33(3H,s)、3.12−3.73(3H,m)、3.87−4.48(5H,
m), 4.95(1H,m), 6.85-7.72(7H,m), 8.58(1H,m) (5) Ethyl 4-(2-pyridyl)-4-(4-chlorophenyl)-3-ethoxy-2-ethoxycarbonylbutyrate.

IR (film): 1750, 1730, 1590, 1490, 1090, 750 cm ^-1 NMR (CDCl ₃ , δ): 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(1H,
m), 6.90-7.72(7H,m), 8.53(1H,m) (6) Ethyl 4-(2-pyridyl)-4-(3-methoxyphenyl)-3-ethoxy-2-ethoxycarbonylbutyrate.

IR (film): 1750, 1730, 1590, 1470, 1440, 1370, 116
0, 1100, 1040, 760, 700 cm ^-1 NMR (CCl ₄ , δ): 0.73 (3H, t, J = 7Hz), 1.07−1.48 (6H,
m), 2.85−4.53(8H,m), 3.72(3H,s), 4.93(1H,m), 6.50
−7.70(7H,m), 8.60(1H,m) (7) 4-(2-tolyl)-4-(2-pyridyl)-3-
Ethoxy-2-ethoxycarbonylbutyrate ethyl.

IR (film): 3060, 1740, 1720, 1590, 1440, 1090, 86
0,750cm ^-1 NMR (CCl ₄ , δ): 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(1H,m) Preparation Example 9 The following compound is obtained in the same manner as in Preparation Example 2.

(1) 1-(1-naphthyl)-3-ethoxycarbonyl-
4H-Quinolizin-4-one.

Melting point 161-163°C IR (Nujol): 1690, 1665, 1590, 1270, 1240, 780, 770°C
m ^-1 NMR(CDCl ₃ ,δ): 1.38(3H,t,J=7Hz), 4.43(2H,q,J=7H
z)、7.05−7.77(8H,m)、7.80−8.10(2H,m)、8.43(1H,
s), 9.58 (1H, m) Elemental analysis _{for C22H17NO3} : Calculated: C; 76.95, H; 4.99, N; 4.08 Found: C; 77.14, _H ; 5.27, N; 3.89 (2) 1-(4-Biphenylyl)-3-ethoxycarbonyl-4H-quinolizin-4-one.

Melting point: 183-184.5°C IR (Nujol): 1690, 1680, 1625, 1590, 1260, 770, 740°C
m ^-1 NMR(CDCl ₃ ,δ): 1.40(3H,t,J=7Hz), 4.50(2H,q,J=7H
z), 7.08-8.02 (12H,m), 8.43 (1H,s), 9.55 (1H,m). Elemental analysis: _C24H19NO3.1 / _{4H2O .} Calculated: C; 77.09, H; 5.27, N; 3.75. Found: C; 77.04, H; 5.49, N; 3.60 _. (3) 1-Phenoxy-3-ethoxycarbonyl-4H-
Quinolizin-4-one.

Melting point 108-109℃ IR (Nujol): 1680, 1670, 1620, 1590, 1225, 1200, 100
0cm ^-1 NMR(CDCl ₃ ,δ): 1.40(3H,t,J=7Hz), 4.42(2H,q,J=7H
z)、6.78−7.48(6H,m)、7.57−7.98(2H,m)、8.23(1H,
s), 9.45 (1H,m) Elemental analysis: C ₁₈ H ₁₅ NO ₄ Calculated: C; 69.89, H; 4.89, N; 4.53 Found: C; 70.18, H; 5.03, N; 4.51 (4) 1-(3-Tolyl)-3-ethoxycarbonyl-4
H-Quinolizin-4-one.

Melting point 109-111℃ IR (nujol): 1725, 1645, 1620, 1595, 1240, 770cm ^-1 NMR (CDCl ₃ , δ): 1.42 (3H,t,J=7Hz), 2.45 (3H,s), 4.4
5(2H,q,J=7Hz), 7.08−7.48(5H,m), 7.53−7.95(2H,
m), 8.42 (1H,s), 9.55 (1H,m). Analysis: Calculated for _C19H17NO3.1 / _5H2O : C; _73.39 , H; _5.64 , N; 4.50. Found: C; 73.58, H; 5.62, N; 4.49. (5) 1-(4-Chlorophenyl)-3-ethoxycarbonyl-4H-quinolizin-4-one.

Melting point 159-160℃ IR (Nujol): 1680, 1670, 1490, 1295, 1260, 1240, 113
0, 1020, 765 cm ^-1 NMR (CDCl ₃ , δ): 1.40 (3H, t, J = 7Hz), 4.43 (2H, q, J = 7H
z), 6.97-7.87 (7H,m), 8.32 (1H,s), 9.48 ( _1H ,m) _{. Analysis: Calculated for C18H14ClNO3 :} C 65.96, H 4.31, N 4.27. Found: C 65.81, H 4.49, N 4.19. (6) 1-(3-Methoxyphenyl)-3-ethoxycarbonyl-4H-quinolizin-4-one.

Melting point 155-157℃ IR (Nujol): 3070, 1730, 1650, 1625, 1595, 1130, 110
0,780cm ^-1 NMR( _CDCl3 ,δ): 1.42(3H,t,J=7Hz), 3.80(3H,s), 4.4
0(2H,q,J=7Hz), 6.85−7.93(7H,m), 8.35(1H,s), 9.47
(1H,m) Elemental analysis _{: C19H17NO4.1 / 4H2O} Calculated: C; 69.61, H; 5.38, N; 4.27 Found: C; 69.62, H; 5.29, N; 4.19 (7) 1-(2-Tolyl)-3-ethoxycarbonyl-4
H-Quinolizin-4-one.

Melting point: 97-98℃ IR (Nujol): 1730, 1680, 1620, 1480, 1230, 1100, 785
cm ^-1 NMR(CDCl ₃ ,δ): 1.45(3H,t,J=7Hz), 2.10(3H,s), 4.4
8(2H,q,J=7Hz), 7.18−7.83(7H,m), 8.42(1H,s), 9.68
(1H, m) Elemental analysis: C ₁₉ H ₁₇ NO ₃ Calculated: C 74.25, H 5.57, N 4.56 Found: C 74.50, H 5.66, N 4.50 Preparation 10 The following compound is obtained in the same manner as in Preparation 1.

(1) 3-ethoxy-2-ethoxycarbonyl-4-(N
-methylanilino)-4-(2-pyridyl)butyric acid ethyl ester.

NMR(CDCl ₃ ,δ): 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), 3.20−4.5
0(7H,m), 5.00−5.60(2H,m), 6.50−7.80(8H,m), 8.57
(1H, d, J = 4.4 Hz) (2) Ethyl 3-ethoxy-2-ethoxycarbonyl-4-benzoyl-4-(2-pyridyl)butyrate.

(3) 3-ethoxy-2-ethoxycarbonyl-4-(2
-pyridyl)-4-benzylbutyric acid ethyl ester.

IR (film): 1750, 1730, 1635, 1585, 1365, 1290, 124
5, 1185, 1140, 1090, 1025, 745, 700cm ^-1 NMR (CDCl ₃ , δ): 0.98−1.50 (9H, m), 2.93−4.67 (11H,
m), 6.73-7.63 (8H,m), 8.48-8.63 (1H,m) (4) 3-ethoxy-2-ethoxycarbonyl-4-(2
-pyridyl)-4-phenylthiobutyric acid ethyl ester.

IR (film): 1750, 1730, 1590, 1440, 1300, 1150, 109
0, 1025, 760 cm ^-1 NMR (CDCl ₃ , δ): 0.83−1.40 (9H, m), 3.07−4.43 (7H,
Preparation Example 11 The following compound is obtained in the same manner as in Preparation Example 2.

(1) 3-ethoxycarbonyl-1-(N-methylanilino)-4H-quinolizin-4-one.

IR (Nujol): 1690, 1680, 1600, 1510, 1380, 1235 cm ^-1 NMR (DMSO-d ₆ , δ): 1.30 (3H, t, J = 7 Hz), 3.30 (3H,
s), 4.28(2H,q,J=7Hz), 6.50−8.10(8H,m), 8.15(1H,
s), 9.40 (1H, d, J = _{7 Hz} ) Elemental analysis: _C19H18N2O3 Calculated: C; 70.79, H; 5.63, N _; 8.69 Found: C; 71.00, H; 5.40, N; 8.56 Melting point: 129-132°C (2) 3-Ethoxycarbonyl-1-benzoyl-4H-
Quinolizin-4-one.

Melting point 176-178℃ IR (Nujol): 1750, 1630, 1580, 1485, 1220, 1110, 785
cm ^-1 NMR (CDCl ₃ , δ): 1.37 (3H,t,J=7Hz), 4.38(2H,q,J=7
Hz), 7.20−8.07(7H,m), 8.62(1H,s), 8.82−9.10(1H,
m), 9.42-9.67 ( _{1H, m). Elemental analysis for C19H15NO4 : Calculated} : C; 71.02, H; 4.70, N; 4.36. Found: C; 70.76, H; 4.96, N; 4.33. (3) 3-Ethoxycarbonyl-1-benzyl-4H-quinolizin-4-one.

Melting point 102-105℃ IR (Nujol): 1690, 1670, 1625, 1595, 1320, 1235, 76
5,725cm ^-1 NMR (CDCl ₃ , δ): 1.43 (3H,t,J=7Hz), 4.23 (2H,s), 4.
48(2H,q,J=7Hz), 7.02−7.42(6H,m), 7.52−7.78(2H,
m), 8.28 (1H, s), 9.45 (1H, m). Elemental analysis: C ₁₉ H ₁₇ NO ₃ Calculated: C 74.25, H 5.57, N 4.56 Found: C 73.97, H 5.72, N 4.42 (4) 3-Ethoxycarbonyl-1-phenylthio-4H
-quinolizin-4-one.

Melting point 171-173℃ IR (Nujol): 1740, 1660, 1625, 1575, 1280, 1220, 114
0, 1120, 780, 750 cm ^-1 NMR (CDCl ₃ , δ): 1.40 (3H, t, J = 7 Hz), 4.42 (2H, q, J = 7
Hz), 6.68−7.47(5H,m), 7.73(1H,m), 8.33(1H,m), 8.7
2 (1H, s), 9.52 (1H, m) Elemental analysis: Calculated for _C18H15NO3S : C 66.44, H _4.65 , N _4.30 Found: C 66.17, H 4.69, N 4.28 Preparation 12: A mixture of 2-chloromethylpyridine (50 g), N-methylaniline (42 g), and potassium carbonate (120 g) in N,N-dimethylformamide (200 ml) was stirred at 120°C for 4 hours. The reaction mixture was cooled to room temperature, added to water (1 g), and extracted with ether. The ether extract was washed with water and treated with activated charcoal. After drying over magnesium sulfate, the ether extract was filtered and concentrated. The residue was crystallized from isopropyl alcohol to give N-methyl-N-(2-pyridylmethyl)aniline (39 g).

Melting point 60℃ IR (Nujol): 1610, 1590, 1570, 1510, 1470, 1440, 136
Preparation ¹³ : To a solution of 2-methylpyridine (9.31 g) in tetrahydrofuran (200 m) is added a 1.5 molar hexane solution of n-butyllithium (73.3 m) at -20°C. The resulting solution is stirred at room temperature for 30 minutes and added to a solution of ethyl benzoate (15.02 g) in tetrahydrofuran (100 m) at -60°C.
After stirring at -60°C for 2 hours, acetic acid (15 ml) was added, the reaction mixture was allowed to warm to room temperature, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The aqueous layer was re-extracted with ethyl acetate, and the extracts were washed with water, 10% aqueous sodium bicarbonate, and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and the solvent was evaporated. The residue (20.5 g) was chromatographed on silica gel (Merck, 70-230 mesh, 308 g) eluting with chloroform to give 20% methyl 2-hydroxybenzoate.
- Pyridylmethylphenylketone (10.86 g) is obtained as an oil.

IR (Nujol): 1680, 1630, 1600, 1545, 1270, 1200, 114
5, 1060, 800, 775, 690cm ^-1 NMR (CDCl ₃ , δ): 4.43 (1.5H,s), 6.02 (0.5H,s), 6.83
-8.65(9H,m) Preparation 14: To a solution of 1-phenylthio-3-ethoxycarbonyl-4H-quinolizin-4-one (1.0 g) in acetic acid (20 ml) and chloroform (7.5 ml) was added potassium permanganate (58
To the mixture was added 3 mg of ethanol at 0° C. After stirring at the same temperature for 2 hours, the reaction mixture was allowed to warm to room temperature and stirred for an additional hour.
Potassium permanganate (194 mg) was added and the mixture was stirred overnight. Saturated aqueous sodium thiosulfate was added to the resulting reaction mixture under 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 give 1-phenylsulfonyl-3-ethoxycarbonyl-4H-quinolizin-4-one (583 mg).

Melting point 182℃ IR (nujol): 1710, 1680, 1640, 1580, 1200, 1150cm ^-1 NMR (CDCl ₃ , δ): 1.45 (3H,t,J=7Hz), 4.45 (2H,q,J=7
Hz), 7.20−8.10(7H,m), 8.60(1H,d,J=8Hz), 9.18(1H,
s), 9.50 (1H, d, J = 8 Hz) _. Elemental analysis: _{C18H15NO5S .} Calculated: C; 60.50, H; 4.23, N; 3.92. Found: C; 60.44, H; 4.51, N; 3.88. Preparation 15: To a solution of 3-ethoxycarbonyl-7-hydroxy-1-phenyl-4H-quinolizin-4-one (5 g) in N,N-dimethylformamide (100 ml) was added sodium hydride (63.6% in mineral oil, 732 mg) at 50°C. After stirring at 50°C for 30 minutes, n-butyl iodide (2.77 ml) was added.
After stirring at °C for 1 hour, the mixture is cooled to room temperature and added to a mixture of hydrochloric acid and ice. The mixture is extracted with chloroform.
The chloroform extract was washed with 10% aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over magnesium sulfate, the chloroform extract was filtered and distilled under reduced pressure. The residue was chromatographed on silica gel (Merck, 70-230 mesh, 100 g) eluting with chloroform and then with 10% chloroform in methanol to give 3-ethoxycarbonyl-7-methyl-2-propanol.
2.37 g of 1-(n-butoxy)-1-phenyl-4H-quinolizin-4-one are obtained.

Melting point 94-95℃ IR (nujol): 1730, 1690, 1655, 1630, 1480cm ^-1 NMR (CDCl ₃ , δ): 0.95 (3H,t,J=5Hz), 1.42 (3H,t,J=5
Hz)、1.30−2.10(4H,m)4.13(2H,t,J＝5Hz)、4.45(2H,q,
J=5Hz), 7.30(1H,t,J=7Hz), 7.42(5H,m), 7.67(1H,d,
1H,s), 8.27 (1H,s), 9.08 (1H,d,J=7 Hz). _Elemental analysis: Calculated for _C22H23NO4 : C; _72.31 , H; 6.34, N; 3.83. Found: C; 71.74, H; 6.39, N; 3.80. Preparation 16: The following compound is obtained in the same manner as in Preparation 6.

1-Allyloxy-3-ethoxycarbonyl-4H-quinolizin-4-one.

Melting point: 82-84℃ IR (Nujol): 1690, 1680, 1660, 1620, 1580, 1320, 123
5, 1100, 1015, 770 cm ^-1 NMR (CDCl ₃ , δ): 1.43 (3H, t, J = 7 Hz), 4.42 (2H, q, J = 7
Hz)、4.50−4.75(2H,m)、5.15−5.67(2H,m)、5.78−6.4
7 (1H, m), 6.97-8.32 (4H, m), 9.47 ( _1H , d, J = 7.5 Hz). Elemental analysis: Calculated for _C15H15NO4 : C; 65.93, H; 5.53, N; 5.13 _. Found: C; 66.11, H; 5.36, N; 4.94. Preparation 17: To a solution of 3-ethoxycarbonyl-4H-quinolizin-4-one (2.17 g) in methanol (65.2 m), 6N sodium hydroxide (6.5 m) was added dropwise at room temperature. After stirring for 20 minutes, water (10 m) was added. After stirring for 20 minutes, water (3 m) was added.
After stirring for 1 hour, the reaction mixture is acidified with 4N hydrochloric acid to pH 3. The precipitate is collected, washed with water, and
-quinolizin-4-one-3-carboxylic acid (1.75 g) is obtained as pale yellow crystals.

Melting point: 233°C IR (Nujol): 1730, 1610, 1585, 1320 cm ^-1 NMR (DMSO-d ₆ ) δ: 7.26 (d, 1H, J = 9 Hz), 7.50-7.95 (m, 1
H), 8.00−8.20(m,2H), 8.41(d,1H,J=9Hz), 9.20−9.4
0(m,1H) Example 1 The following compound is obtained in the same manner as in Preparation Example 17.

(1) 7-ethyl-4H-quinolizin-4-one-3-carboxylic acid.

Melting point 193-195℃ Melting point 233℃ IR (nujol): 3100, 1725, 1700, 1605cm ^-1 NMR (CF ₃ COOH) δ: 1.52 (t, 3H, J = 8Hz), 3.12 (q, 2H, J = 8H
z)、7.92(d,1H,J=9Hz)、8.32(s,2H)、8.73(d,1H,J=9H
z), 9.30 (m, 1H). Analysis for _C12H11NO3 : Calculated: C _66.35 , H 5.10, N 6.45 _. Found: C 66.40, H 5.14, N 6.46. (2) 9,10-Dihydro-8H-benzo[ij]-3H-quinolizin-3-one-2-carboxylic acid.

Melting point: 254°C IR (Nujol): 3200, 1710, 1610, 1590 cm ^-1 NMR (DMSO-d ₆ ) δ: 1.80-2.30 (m, 2H), 2.70-3.20 (m, 6
H), 7.30−7.85(m,2H), 8.10(s,1H), 9.10(d,1H,J=7H
z), 14.30 (s, 1H) Elemental analysis: Calculated for _C13H11NO3 : C 68.11, H _4.84 , N _6.11 Found: C 68.21, H 5.12, N 6.07 (3) 7-Methoxy-4H-quinolizin-4-one-3-
Carboxylic acid.

Melting point: 215-216°C IR (Nujol): 3150, 3100, 1700, 1610, 1590 cm ^-1 NMR (CF ₃ COOH) δ: 4.18 (s, 3H), 7.88 (d, 1H, J = 8.5 Hz),
8.10-8.47 (m, 2H), 8.67 (d, 1H, J = 8.5 Hz), _8.88 (m, 1H) _{. Analysis for C11H9NO4 :} Calculated: C; 60.27, H; 4.14, N; 6.39. Found: C; 59.90, H; 4.38, N; 6.48. (4) 9-Methyl-4H-quinolizin-4-one-3-carboxylic acid.

Melting point 259-260℃ IR (Nujol): 3100, 3020, 1740, 1610, 1590, 1120, 780
cm ^-1 NMR (DMSO−d ₆ ) δ: 2.92 (s, 3H), 7.90 (d, 1H, J = 7.5Hz),
8.07(d,1H,J=9.5Hz), 8.05−8.38(m,1H), 8.82(d,1H,J
= 9.5 Hz), 9.42 (d, _1H , J = 7.5 Hz) _. Elemental analysis for _C11H9NO3 : Calculated: C; 65.02, H; 4.46, N; 6.89. Found: C; 64.92, H; 4.76, N; 6.89. (5) 8-Methyl-4H-quinolizin-4-one-3-carboxylic acid.

Melting point 228-230℃ IR (Nujol): 3090, 3030, 2700, 1630, 1620, 1580, 785
cm ^-1 NMR (CF ₃ COOH) δ: 2.82 (s, 3H), 7.82 (d, 1H, J = 9Hz), 7.9
2(dd,1H,J=7Hz, 2Hz), 8.17(d,1H,J=2Hz), 8.68(d,1
1H, J = 9 Hz), 9.37 (d, _1H , J = ₇ Hz). Analysis for _C11H9NO3 : Calculated: C; 65.02, H; 4.46, N; 6.89. Found: C; 64.88, H; 4.79, N; 6.85. (6) 6-Methyl-4H-quinolizin-4-one-3-carboxylic acid.

Melting point: 185-187°C IR (Nujol): 3100, 2700, 1720, 1615, 1595, 1295, 104
0, 800cm ^-1 NMR (CF ₃ COOH) δ: 3.45 (s, 3H), 7.82 (d, 1H, J = 9Hz), 7.5
8-7.97 (m, 1H), 8.10-8.30 (m, 2H), 8.68 (d, _1H , J = ₉ Hz). Analysis for _C11H9NO3 : Calculated: C; 65.02, H; 4.46, N; 6.89. Found: C; 64.60, H; 4.52, N; 6.91. (7) 1-Methyl-4H-quinolizin-4-one-3-carboxylic acid.

Melting point: 258-260°C IR (Nujol): 1740, 1610, 1450, 780 cm ^-1 NMR (CF ₃ COOH) δ: 2.87 (s, 3H), 8.15 (m, 1H), 8.35-8.77
(m, 3H), 9.66 (m, 1H) _{. Elemental analysis for C11H9NO3 : Calculated} : C; 65.02, H; 4.46, N; 6.89. Found: C; 64.70, H; 4.56, N; 6.86. (8) Cyclopenta[ij]-3H-quinolizin-3-one-2-carboxylic acid.

Melting point >250°C. IR (Nujol): 1730, 1620, 1590 ^{cm -1.} Elemental analysis: Calculated for C ₁₂ H ₇ NO ₃ : C 67.61, H 3.31, N 6.57. Found: C 67.72, H 3.37, N 6.59. (9) 7-Methyl-4H-quinolizin-4-one-3-carboxylic acid.

Melting point 222-224℃ IR (Nujol): 1720, 1600, 1590, 1320, 1125, 1110, 840
cm ^-1 NMR (CF ₃ COOH) δ: 2.77 (s, 3H), 7.93 (d, 1H, J = 9Hz), 8.2
2-8.38 (m, 2H), 8.73 (d, 1H, J=9 Hz), 9.32 (s, 1H) _Elemental analysis: _C11H9NO3 Calculated: C; 65.02, H; 4.46, N; 6.89 Found: C; 65.04, H; 4.31, _N ; 6.91 (10) 1-Methoxy-4H-quinolizin-4-one-3-
Carboxylic acid.

Melting point 259-261℃ IR (Nujol): 3100, 1630, 1620, 1580, 1100, 1070, 780
cm ^-1 NMR(CF ₃ COOH) δ: 4.27(s,3H), 8.00−8.67(m,3H), 8.90
(m, 1H), 9.52 (d, 1H, J = _7.5 Hz) Elemental analysis: _C11H9NO4 Calculated: C; 60.28, H; 4.14, N; 6.39 Found: C; 59.64, H; _4.15 , N; 6.30 (11) 7-n-Butoxy-4H-quinolizin-4-one-
3-Carboxylic acid.

Melting point: 120-122°C IR (Nujol): 1725, 1600, 1590, 1320, 1070, 1000 cm ^-1 NMR (CF ₃ COOH) δ: 1.07 (t, 3H, J = 6 Hz), 1.30-2.20 (m, 4
H), 4.40(t,2H,J=6Hz),7.90(d,1H,J=9.5Hz),8.13−
8.43 (m, 2H), 8.67 (d, 1H, J = 9.5 Hz), 8.93 (d, _1H , J = ₂ Hz). Analysis: Calculated for _C14H15NO4 : C; 64.36, H; 5.79, N; 5.36. Found: C; 64.46, H; 5.80, N; 5.31. (12) 7-Isopropoxy-4H-quinolizin-4-one-3-carboxylic acid.

Melting point 218-219℃ IR (Nujol): 3140, 3090, 1720, 1620, 1120, 1060, 100
0,780cm ^-1 NMR (CF ₃ COOH) δ: 1.67 (d, 6H, J = 6Hz), 4.97 (1H, J = 6H
z), 7.88(d,1H,J=9Hz), 8.10−8.43(m,4H), 8.63(d,1
1H,J=9 Hz), 8.90 (d, 1H,J=2 Hz) Elemental analysis: Calculated _{for C13H13NO4} : C; _63.15 , H; 5.30, N; 5.66 Found: C; 63.28, H; 5.18, N; 5.65 Example 2 The following compound is obtained in the same manner as in Preparation 17.

(1) 1-(1-naphthyl)-4H-quinolizin-4-one-3-carboxylic acid.

Melting point >270°C IR (Nujol): 1730, 1720, 1610, 770cm ^-1 NMR ( _CF3COOH , δ): 7.10-8.37 (10H, m), 8.82 (1H, s),
9.62 (1H, m) Elemental analysis: _{C20H13NO3.1 / 2H2O} Calculated: C; _74.07 , H; 4.35, N; 4.32 Found: C; 74.12, H; 4.13, N; 4.22 (2) 1-(4-biphenylyl)-4H-quinolizine-4
-one-3-carboxylic acid.

Melting point 261-263℃ IR (Nujol): 3100, 1720, 1660, 1610, 1580, 1290, 89
0,775cm ^-1 NMR (CF ₃ COOH, δ): 7.20−8.47(12H,m), 8.70(1H,s),
9.53 (1H, m) Elemental analysis: _{C22H15NO3.1 / 4H2O} Calculated: C; 76.40, H; 4.52, N _; 4.05 Found: C; 76.41, H; 4.57, N; 3.93 (3) 1-phenoxy-4H-quinolizin-4-one-3
- Carboxylic acids.

Melting point 224-226℃ IR (Nujol): 3100, 2650, 1725, 1640, 1620, 1580, 121
0,910cm ^-1 NMR (CF ₃ COOH, δ): 7.20−7.37(2H,m), 7.43−7.73(3H,
m), 8.73(1H,s), 8.27(1H,d,J=7.5Hz), 8.60(1H,t,J=
7.5 Hz), 9.05 (1H, d, J = 8.5 Hz), 9.63 ( _{1H, d, J = 7.5 Hz). Analysis: Calculated for C16H11NO4 : C} ; 68.33, H; 3.94, N; 4.98. Found: C; 68.45, H; 3.96, N; 4.96. (4) 1-(3-Tolyl)-4H-quinolizin-4-one-3-carboxylic acid.

Melting point 176-178°C IR (Nujol): 3130, 1740, 1620, 1590, 1220, 770, 705°C
m ^-1 NMR(CF ₃ COOH,δ): 2.52(3H,s), 7.17−7.67(4H,m), 7.
90-8.50 (3H,m), 8.70 (1H,s), 9.58 (1H,m) Elemental analysis: _Calculated for _C17H13NO3 : C; _73.11 , H; 4.69, N; 5.02 Found: C; 73.11, H; 4.85, N; 5.13 (5) 1-(4-chlorophenyl)-4H-quinolizine-
4-one-3-carboxylic acid.

Melting point 269-271℃ IR (Nujol): 3140, 1740, 1620, 1490, 1320, 1290, 109
0,890,825,825cm ^-1 NMR (CF ₃ COOH, δ): 7.35−7.78(4H,m), 7.92−8.47(3H,
m), 8.73 (1H, s), _9.62 (1H, m) _. Analysis: _C16H10ClNO3 , calculated: C 64.12, H 3.36, N 4.67. Found: C 63.95, H 3.33, N 4.58. (6) 1-(2-Tolyl)-4H-quinolizin-4-one-3-carboxylic acid.

Melting point 168-170℃ IR (nujol): 3400, 1720, 1610, 1290, 1070, 780cm ^-1 NMR (CF ₃ COOH, δ): 2.17 (3H,s), 7.25-7.75 (4H,m), 7.
98-8.63 (3H,m), 8.80 (1H,s), 9.72 (1H,m) Elemental analysis: _Calculated for _C17H13NO3 : C; _73.11 , H; 4.69, N; 5.02 Found: C; 72.95, H; 4.91, N; 5.01 (7) 1-(3-Methoxyphenyl)-4H-quinolizin-4-one-3-carboxylic acid.

Melting point 222-224℃ IR (Nujol): 3100, 1725, 1600, 1490, 1220, 1030, 780
cm ^-1 NMR(CF ₃ COOH, δ): 4.10(3H,s), 7.15−8.62(7H,m), 8.
77 (1H, s), 9.62 (1H, m) Elemental analysis: Calculated _{for C17H13NO4} : C; _69.15 , H; 4.44, N; 4.74 Found: C; 69.67, H; 4.70, N; 4.67 Example 3 The following compound is obtained in the same manner as in Preparation 17.

(1) 7-(n-butoxy)-1-phenyl-4H-quinolizin-4-one-3-carboxylic acid.

Melting point 155-157℃ IR (nujol): 1720, 1610, 1495, 1425 cm ^-1 NMR (DMSO-d ₆ , δ): 0.95 (3H,t,J=5Hz), 1.3-2.0(4
H,m), 4.20(2H,t,J=5Hz), 7.3−7.7(5H,m), 7.80(2H,
s), 8.10(1H,s), 8.80(1H,s), 14.1(1H,broad s) (2) 1-Allyloxy-4H-quinolizin-4-one-
3-Carboxylic acid.

Melting point: 140-143°C IR (Nujol): 3100, 1730, 1720, 1610, 1580, 1420, 109
5, 1065, 770cm ^-1 NMR (CF ₃ CO ₂ H, δ): 4.90−5.13(2H,m), 5.35−5.78(2
H,m), 5.90−6.57(1H,m), 7.97−8.67(3H,m), 8.77−9.
03(1H,m), 9.39-9.67(1H,m) (3) 1-(N-methylanilino)-4H-quinolizine-
4-one-3-carboxylic acid.

Melting point: 185°C (decomposition) IR (Nujol): 1720, 1700 (sh), 1620 cm ^-1 NMR (CF ₃ COOH, δ): 3.58 (3H, s), 6.60-7.50 (5H, m), 7.
80-8.60 (3H, m), 8.64 (1H, s), 9.50 (1H, d, J = ₇ Hz) _Elemental analysis: Calculated 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.

Melting point 221-223℃ IR (Nujol): 3380, 1720, 1620, 1410, 1320, 1070, 102
Elemental analysis at 0,780 cm ^-1 : Calculated for C ₁₇ H ₁₃ NO ₃ : C 73.11, H 4.69, N 5.02 Found: C 73.72, H 4.92, N 5.04 (5) 1-Phenylthio-4H-quinolizin-4-one
3-Carboxylic acid.

Melting point 195-197℃ IR (Nujol): 3350, 1720, 1620, 1400, 1285, 1065, 88
5,780,740 cm ^-1 Elemental analysis: Calculated for C ₁₆ H ₁₁ NO ₃ S: C 64.63, H 3.73, N 4.71 Found: C 65.04, H 3.90, N 4.73 (6) 1-Phenylsulfonyl-4H-quinolizine-4-
one-3-carboxylic acid.

Melting point >250°C IR (Nujol): 1730, 1640, 1620, 1580, 1160, 1140 cm ^-1 NMR (DMSO-d ₆ , δ): 7.30-8.50 (7H, m), 8.60 (1H, d, J)
= 8 Hz), 9.00 (1H, s), 9.50 ( _{1H, d, J = 8 Hz). Elemental analysis: Calculated for C16H11NO5S : C} ; 58.35, H; 3.37. Found: C; 58.62, H; 3.31. Example 4: Dissolution of 3-ethoxycarbonyl-1-benzoyl-4H-quinolizin-4-one (2.14 g) in chloroform (65 ml).
Trimethylsilyl iodide (1.04 m) is added dropwise to the solution at 0° C. After stirring for 30 minutes at 0° C., trimethylsilyl iodide (1.04 m) is added. After stirring for 1 hour at room temperature, trimethylsilyl iodide (1.04 m) is added.
After stirring at room temperature for 2 hours, the reaction mixture was extracted with chloroform and washed with water. After drying over magnesium sulfate, the chloroform extract was collected and concentrated. The precipitate was washed with cold chloroform to give 1-benzoyl-4H-quinolizin-4-one-3-carboxylic acid (1.252 g) as yellow crystals.

IR (Nujol): 1735, 1630, 1610, 1455, 1440, 1370 cm ^-1 NMR (CDCl ₃ , δ): 6.70-8.30 (9H, m), 8.42-8.68 (1H,
d, J = 3 Hz) Elemental analysis: Calculated for _C17H11NO4 : C; _69.62 , H; _3.78 , N; 4.78 Found: C; 62.89, H; 3.54, N; 3.70 Mass: m/e 293 (M ⁺ )

──────────────────────────────────────────────────── Continued from the front page (56) References J. Chem. Soc., 1965, pp. 2633-2636 Z. Naturforsch., B:A Org. Chem., Org. Chem., 34B[5], (1979), pp. 716-719 J. Heterocycl. Chem., 10[2], (1973), pp. 139 Monatsh. Chem., 98[3], (1967), pp. 874−886 Tetrahedron, 23 [9], (1967), pp. 3851−3858 J. Org. Chem. ,43［18］, (1978), pp. 3536−3539

Claims (1)

[Claims] [Claim 1] General formula: (wherein ^R2 represents hydrogen, a lower alkyl group, or a lower alkoxy group; ^R3 represents a lower alkyl group, a lower alkoxy group, a lower alkenyloxy group, a naphthyl group, a biphenyl group, a phenyl group having a lower alkyl group, a phenyl group having a halogen atom, a phenyl group having a lower alkoxy group, an arylthio group, an aroyl group, an aryl(lower)alkyl group, an arenesulfonyl group, an arylamino group or an aryloxy group which may have a lower alkyl group on the nitrogen atom; and ^R2 and ^R3 are located at the 1- and 9-positions of the quinolidinone ring and are bonded to each other to _{form -CH2CH2CH2-} or _-CH =C
and salts thereof.