JPH0539241A - Alpha,beta-unsaturated ketoester derivative - Google Patents

Abstract

PURPOSE:To obtain a new alpha,beta-unsaturated ketoester derivative useful as an intermediate for producing, under mild conditions in a short process, a 2,4- dihydroxypyridine derivative as an inhibitor of an in vivo decomposing enzyme of 5-fluorouracyl which is an anti-malignant tumor agent. CONSTITUTION:An alpha,beta-unsaturated ketoester derivative expressed by formula I (R and R' are lower alkyl or phenyl capable of having substituent group; X is halogen) e.g. 4-chloro-5-ethoxy-3-oxo-4-pentenoic acid ethyl ester. This objective compound can be synthesized by subjecting malonydichloride expressed by formula IV to acylation reaction with a compound expressed by formula II and then adding a compound expressed by formula III and a base to the reaction mixture to subject the mixture to esterification reaction. Further, when the objective compound is subjected to a ring-closing reaction with ammonia under solvent-free conditions or in a solvent, the above-mentioned inhibitor expressed by formula V can be produced under mild conditions, preferably at -20 deg.C to ambient temperature in one process.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel α, β-unsaturated ketoester derivative. INDUSTRIAL APPLICABILITY The compound of the present invention is useful as an inhibitor of in vivo degrading enzyme of 5-fluorouracil, an antineoplastic agent.

[0002]

[Chemical 2]

It is useful as an intermediate for producing a 2,4-dihydroxypyridine derivative represented by the formula [wherein X represents a halogen atom].

[0004]

2. Description of the Prior Art 2,4-Dihydroxypyridine derivatives inhibit the in vivo degrading enzyme of 5-fluorouracil, which is an antineoplastic agent (Japanese Patent Laid-Open No. 62-155215), and the following reports have been made on its production method. In the following description,
"Ac" represents an acetyl group and "Et" represents an ethyl group.

(A) Recueil Des Travaux Chimiques
Des Pays-Bas), 73 , 704 (1954)

[0006]

[Chemical 3]

(B) Recueil Des Travaux Chimiques
Des Pays-Bas), 72 , 285 (1953)

[0008]

[Chemical 4]

[0009] However, these methods have the problems that they have to employ a radical reaction condition of 200 ° C in an autoclave under acidic conditions, or require a very large number of steps, and are industrial methods. However, this is not a satisfactory manufacturing method.

[0010]

The object of the present invention is to produce a 2,4-dihydroxypyridine derivative which is an in vivo inhibitor of the antineoplastic agent 5-fluorouracil in vivo under mild conditions and in a short process. Is to provide an intermediate for

[0011]

The present inventors have found that 2,4-
In the course of studying a method for producing a dihydroxypyridine derivative under mild conditions in a short process, an α, β-unsaturated ketoester derivative represented by the following general formula [I] is a novel compound not listed in the literature, The present invention has been completed by finding that it is useful as an intermediate for producing a 2,4-dihydroxypyridine derivative.

That is, the present invention has the general formula [I]

[0013]

[Chemical 5]

[Wherein R and R'are the same or different and each represents a lower alkyl group or an optionally substituted phenyl group, and X represents a halogen atom], α, β-unsaturated Related to ketoester derivatives.

In the present invention, the compound represented by the general formula [I] is E-form or Z-form with respect to the geometrical isomerism of the olefin bond.
Isomer or a mixture of E isomer and Z isomer in any ratio, and the following tautomers [I '] and [I "] exist. In the formula, R, R'and X are as described above. Is the same.

[0016]

[Chemical 6]

In the present invention, the lower alkyl group represented by R and R'is an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl and n-.
Examples thereof include butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl groups. R and R '
As the optionally substituted phenyl group represented by,
An alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl group or the like or alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-.
Butoxy, isobutoxy, sec-butoxy, tert
Examples thereof include a phenyl group which may have 1 to 3 substituents such as butoxy, pentyloxy and hexyloxy groups. The halogen atom represented by X is fluorine, chlorine,
Examples are bromine and iodine atoms.

The compound of the general formula [I] of the present invention is synthesized by carrying out 1) an acylation reaction and then 2) an esterification reaction according to the following reaction scheme. In the following formula, R,
R'and X are the same as above.

[0019]

[Chemical 7]

More specifically, each step of the acylation reaction and the esterification reaction in the above reaction process formula is carried out as follows.

1) Acylation Reaction The vinyl ether derivative of the general formula [II] as a raw material is
For example, according to the following reaction formula, it is easily synthesized from haloacetal such as chloroacetal [Recueil Des Trava
ux Chimiques Des Pays-Bas), 77 , 753 (1)
958)]. In the following formula, R and X are the same as above.
The above haloacetals are all known compounds or can be easily synthesized according to known methods.

[0022]

[Chemical 8]

The acylation reaction of malonyl dichloride with the compound of the general formula [II] is carried out without solvent or in a solvent. The solvent that can be used when performing this reaction in a solvent is not particularly limited as long as it does not participate in the reaction, diethyl ether, tetrahydrofuran,
Examples include ethers such as dioxane, aromatic hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as dichloromethane and chloroform.

The ratio of the reaction product to be used is preferably about 1 to 20 equivalents, more preferably about 3 to 10 equivalents of the compound of the general formula [II] with respect to malonyl dichloride. The reaction temperature is about -78 ° C to the boiling point of the solvent, preferably about -78 ° C to room temperature. The reaction time is about 1 to 96 hours, more preferably about 3 to 24 hours.

2) Esterification Reaction Next, the esterification reaction proceeds by adding an alcohol or phenol derivative of the general formula [III] and a base to the reaction mixture of the above-mentioned acylation reaction. The compound of the general formula [III] and the base are added without a solvent or as a solution. The solvent that can be used when added as a solution is not particularly limited as long as it does not participate in the reaction, diethyl ether, tetrahydrofuran, ethers such as dioxane, benzene, aromatic hydrocarbons such as toluene, Halogenated hydrocarbons such as dichloromethane and chloroform can be exemplified. The base is not particularly limited, for example, pyridine,
Examples include organic amines such as triethylamine, alkoxides such as sodium methoxide and sodium ethoxide, and phenoxides such as sodium phenoxide.

The proportion of the reaction product used is about 2 to 20 equivalents of the compound of the general formula [III] with respect to malonyl dichloride. The base is used preferably about 1 to 5 equivalents, more preferably about 2 to 3 equivalents, based on malonyl dichloride. The reaction temperature is about -78 ° C to room temperature, preferably about -20 ° C to 0 ° C. Reaction time is 0.5-6
It is about time, and more preferably about 0.5 to 2 hours.

The α, β-unsaturated ketoester derivative represented by the general formula [I] of the present invention thus obtained can be easily isolated by a conventional separation and purification method such as column chromatography, distillation and extraction. Can be purified separately.

Further, in order to derive the compound of the general formula [I] of the present invention into the 2,4-dihydroxypyridine derivative represented by the general formula [IV], the compound of the general formula [I] obtained by the above-mentioned esterification reaction is used. One step is sufficient, in which the compound is subjected to a ring-closing reaction with ammonia in the absence of solvent or in a solvent. The solvent that can be used when performing this reaction in the solvent is not particularly limited as long as it does not participate in the reaction, alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran, ethers such as dioxane, Aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, acetonitrile, N, N-dimethylformamide,
Examples include aprotic polar solvents such as dimethyl sulfoxide, water and the like.

Ammonia used in the ring-closing reaction is introduced into the reaction system by liquid ammonia, gaseous ammonia or a solvent dissolved in a solvent, or in situ in the reaction system.
generate in u. The solvent used when dissolving ammonia in the solvent is not particularly limited as long as it does not participate in the reaction, alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran, ethers such as dioxane, and acetonitrile. , N,
Examples thereof include aprotic polar solvents such as N-dimethylformamide and dimethyl sulfoxide, water and the like. in s
A conventionally known method may be adopted to generate ammonia in itu. In that case, a typical reagent can be exemplified by a combination of ammonium salts such as ammonium chloride and a base such as sodium hydroxide and potassium hydroxide, but is not limited thereto. When liquid ammonia is used, it may be used in excess and used as a reactant / solvent.

The ratio of the reactant used is about 2 to 30 equivalents of ammonia with respect to the compound of the general formula [I].
A wide range of reaction temperatures can be used, for example, -7
Although a temperature of about 8 to 300 ° C. can be adopted, in the present invention,
Usually, about −20 ° C. to room temperature is preferable, which is advantageous because the reaction can be carried out under mild conditions. If necessary, the reaction can be carried out using a sealed tube system. The reaction time is generally about 0.5 to 48 hours, preferably about 1 to 24 hours.

This ring-closing reaction can also be carried out continuously after the completion of the esterification reaction without isolating and purifying the compound of the general formula [I]. That is, there is an advantage that the continuous acylation reaction, esterification reaction and ring-closing reaction can be carried out in one pot. The conditions for each reaction at this time are the same as the conditions for each reaction step described above.

The 2,4-dihydroxypyridine derivative of the general formula [IV] obtained as described above can be easily isolated and purified by a usual separation and purification method such as recrystallization, column chromatography, extraction and the like.

[0033]

INDUSTRIAL APPLICABILITY As described above, the compound of the general formula [I] of the present invention is 2,4-dihydroxypyridine of the general formula [IV] which is an inhibitor of biodegradation enzyme of 5-fluorouracil, an antineoplastic agent. It is extremely useful as an intermediate for producing the derivative under mild conditions and in a short process.

[0034]

EXAMPLES The present invention will be specifically described below with reference to examples and reference examples.

Example 1 Synthesis of ethyl 4-chloro-5-ethoxy-3-oxo-4-pentenoate

[0036]

[Chemical 9]

Ethyl-β-chlorovinyl ether 5.
3 g (50 mmol) of anhydrous diethyl ether (5 m
l) To the solution, under ice cooling, malonyl dichloride 1.4 g (10
mmol) was added dropwise. After stirring the reaction solution at room temperature for 24 hours, 2.02 g of triethylamine (20 mmo)
l), a solution of 3 ml (50 mmol) of ethanol in diethyl ether (5 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 20 ml of diethyl ether was added to the resulting residue, and the crystallized product was filtered off. The filtrate is concentrated under reduced pressure, and the resulting residue is distilled under reduced pressure to give a boiling point of 1
1.58 g of the title compound at 32-135 ° C / 1 mmHg
(Yield 72%) was obtained.

NMR (CDCl ₃ ) δ: 1.28 (3
H, t, J = 7Hz), 1.42 (3H, t, J = 7H)
z), 3.71 (2H, s), 4.24 (4H, m),
7.75 (1H, s).

Reference Example 1 Synthesis of 5-chloro-2,4-dihydroxypyridine

[0040]

[Chemical 10]

4-chloro-5-ethoxy-3-oxo-
To an ethanol solution (10 ml) of 2.2 g (10 mmol) of ethyl 4-pentenoate was added 5 ml (82 mmol) of 28% ammonia water at 0 ° C., and the mixture was stirred for 3 hours. This reaction solution was allowed to stand at 0 ° C. for 24 hours, then the crystallization product was collected by filtration and recrystallized from ethanol-water to obtain 754 mg (yield 52%) of the title compound having a melting point of 265 ° C. or higher (decomposition). .. The filtrate was concentrated under reduced pressure and washed with a mixed solvent of ethanol-water to obtain 123 mg (yield 8%) of the title compound.

[0042]

Claims (1)

[Claims] 1. A compound represented by the general formula [I]: [In the formula, R and R ′ are the same or different and each represents a lower alkyl group or an optionally substituted phenyl group,
X represents a halogen atom. ] The alpha, beta-unsaturated ketoester derivative represented by these.