JP2805114B2 - α, β-unsaturated ketoester derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel α, β-unsaturated ketoester derivatives. The compound of the present invention is a compound of the general formula [IV] useful as a biodegradation enzyme inhibitor of the antineoplastic 5-fluorouracil

[0002]

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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 Related Art 2,4-Dihydroxypyridine derivatives inhibit the biodegradation enzyme of 5-fluorouracil, an antineoplastic agent (Japanese Patent Laid-Open No. 62-155215). 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]

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

[0008]

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[0009] However, these methods have problems such as the necessity of employing extreme reaction conditions of 200 ° C in an autoclave under acidic conditions, or the necessity of a very large number of steps. Is not a satisfactory manufacturing method.

[0010]

SUMMARY OF THE INVENTION An object of the present invention is to produce a 2,4-dihydroxypyridine derivative which is an inhibitor of the antineoplastic 5-fluorouracil biodegradation enzyme under mild conditions and in a short process. To provide an intermediate for

[0011]

Means for Solving the Problems The present inventors have proposed 2,4-
In the course of studying a method for producing a dihydroxypyridine derivative under mild conditions and in a short process, an α, β-unsaturated ketoester derivative represented by the following general formula [I] is a novel compound not described in the literature, The present inventors have found that they are useful as intermediates for producing 2,4-dihydroxypyridine derivatives, and have completed the present invention.

That is, the present invention relates to a compound represented by the general formula [I]:

[0013]

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[Wherein, R and R ′ are the same or different and each have 1 carbon atom as a lower alkyl group or a substituent.
An alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms
And X represents a halogen atom], and X represents a halogen atom].

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

[0016]

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

The compound of the general formula [I] of the present invention is synthesized by performing 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 described above.

[0019]

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Each step of the acylation reaction and the esterification reaction in the above reaction scheme is carried out in more detail as follows.

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

[0022]

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The acylation reaction between malonyl dichloride and the compound of the formula [II] is carried out without a 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, and diethyl ether, tetrahydrofuran,
Examples thereof include ethers such as dioxane, aromatic hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as dichloromethane and chloroform.

The compound of the formula [II] is preferably used in an amount of about 1 to 20 equivalents, more preferably about 3 to 10 equivalents, based on malonyl dichloride. The reaction temperature is about −78 ° C. to about the boiling point of the solvent, preferably about −78 ° C. to about 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 acylation reaction. The compound of the general formula [III] and the base are added without a solvent or as a solution. Solvents that can be used when added as a solution are not particularly limited as long as they do not participate in the reaction, and ethers such as diethyl ether, tetrahydrofuran and dioxane, benzene, aromatic hydrocarbons such as toluene, Examples thereof include halogenated hydrocarbons such as dichloromethane and chloroform. The base is not particularly limited, for example, pyridine,
Examples thereof include organic amines such as triethylamine, alkoxides such as sodium methoxide and sodium ethoxide, and phenoxides such as sodium phenoxide.

The reactant is used in an amount of about 2 to 20 equivalents of the compound of the formula [III] to malonyl dichloride. The base is used in an amount of 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 about room temperature, preferably about -20 ° C to 0 ° C. Reaction time is 0.5-6
About 0.5 hours, more preferably about 0.5 to 2 hours.

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

Further, in order to derive the compound of the general formula [I] of the present invention into a 2,4-dihydroxypyridine derivative represented by the general formula [IV], the compound of the general formula [I] obtained by the above esterification reaction is obtained. One step of subjecting the compound to a ring-closing reaction with ammonia in the absence or in a solvent is sufficient. Solvents that can be used when performing this reaction in a solvent are not particularly limited as long as they do not participate in the reaction, and include alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran, and 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.

As the ammonia used for the ring closure reaction, liquid ammonia, gaseous ammonia or a solution dissolved in a solvent may be introduced into the reaction system, or may be introduced in situ in the reaction system.
u. The solvent used when ammonia is dissolved in a solvent is not particularly limited as long as it does not participate in the reaction.Methanol, alcohols such as ethanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, acetonitrile , N,
Examples include aprotic polar solvents such as N-dimethylformamide and dimethyl sulfoxide, and water. in s
In order to generate ammonia in itu, a conventionally known method may be employed. In this case, typical examples of the reagent include, but are not limited to, a combination of ammonium salts such as ammonium chloride and a base such as sodium hydroxide and potassium hydroxide. When liquid ammonia is used, it may be used in excess and used as a reactant / solvent.

The reactant is used in an amount of about 2 to 30 equivalents of ammonia based on the compound of the formula [I].
As the reaction temperature, a wide range of temperatures can be used.
Although a temperature of about 8 to 300 ° C. can be adopted, in the present invention,
Usually, the temperature is preferably from about -20 ° C to room temperature, 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 closure reaction can be carried out continuously after the completion of the esterification reaction without isolating and purifying the compound of the formula [I]. That is, there is an advantage that a continuous acylation reaction, esterification reaction and ring closure reaction can be performed in one pot. The conditions of each reaction at this time are the same as the conditions of 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, for example, recrystallization, column chromatography, extraction and the like.

[0033]

As described above, the compound of the general formula [I] of the present invention is a 2,4-dihydroxypyridine of the general formula [IV] which is an inhibitor of the antineoplastic 5-fluorouracil biodegradation enzyme. They are very useful as intermediates for preparing derivatives under mild conditions and in short steps.

[0034]

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]

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Ethyl-β-chlorovinyl ether5.
3 g (50 mmol) of anhydrous diethyl ether (5 m
l) 1.4 g of malonyl dichloride (10
mmol) was added dropwise. After stirring this reaction solution at room temperature for 24 hours, 2.02 g (20 mmol) of triethylamine was added.
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 obtained residue, and the crystallized product was separated by filtration. The filtrate is concentrated under reduced pressure, and the resulting residue is distilled under reduced pressure to a boiling point of 1
1.58 g of the title compound at 32-135 ° C./1 mmHg
(72% yield).

NMR (CDCl ₃ ) δ: 1.28 (3
H, t, J = 7 Hz), 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]

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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% aqueous ammonia at 0 ° C., followed by stirring for 3 hours. After allowing the reaction solution to stand at 0 ° C. for 24 hours, the crystallized 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 (decomposed). . The filtrate was concentrated under reduced pressure, and washed with a mixed solvent of ethanol and water to obtain 123 mg (yield: 8%) of the title compound.

[0042]

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 69/738 Z C07D 213/69 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula [1] [Wherein, R and R ′ are the same or different and are each a lower alkyl group or an alkyl having 1 to 6 carbon atoms as a substituent.
Group or an alkoxy group having 1 to 6 carbon atoms
And X represents a halogen atom. An α, β-unsaturated ketoester derivative represented by the formula: