JP2006347889A - Method for producing 2-alkylmalonic acid compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an industrially suitable 2-alkylmalonic acid compound in which 2-alkylmalonic acid compound can be produced in high yield from 2-alkylidene malonic acid compound by a simple method. <P>SOLUTION: The method for producing 2-alkylmalonic acid compound comprises carrying out reduction reaction of 2-alkylidene malonic acid compound in at least one kind of solvent selected from a group consisting of aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, amides and ethers. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing a 2-alkylmalonic acid compound by reducing a 2-alkylidenemalonic acid compound. A 2-alkylmalonic acid compound is a useful compound as a raw material for pharmaceuticals and agricultural chemicals and a synthetic intermediate.

Conventionally, as a method for producing a 2-aralkyl or heteroaralkylmalonic acid compound by reducing a 2-alkylmalonic acid compound, for example, methyl 2-carbomethoxy-4,4-dimethylpentenoate and sodium borohydride are used. Is disclosed in which dimethyl 2- (2,2-dimethylmalonate) is produced in a yield of 62% (see, for example, Non-Patent Document 1). 2-alkylmalonic acid compound, which requires complicated post-treatment with a saturated aqueous solution of ammonium chloride and the use of methylene chloride as an extraction solvent, which complicates the isolation procedure. It was disadvantageous as an industrial production method.
Tetrahedron Asymmetry, 4 (9), 2025 (1993)

  The object of the present invention is to solve the above-mentioned problems and to produce a 2-alkylmalonic acid compound in a high yield from a 2-alkylidenemalonic acid compound by a simple method. -To provide a process for producing an alkylmalonic acid compound.

  An object of the present invention is to provide at least one solvent selected from the group consisting of aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, amides and ethers. In general formula (1)

(In the formula, R is an alkyl group which may have a substituent, and R ¹ and R ² may be the same or different and represent a hydrogen atom or a hydrocarbon group.)
A 2-alkylidenemalonic acid compound represented by the general formula (2):

（式中、Ｒ、Ｒ^１及びＲ^２は、前記と同義である。）

(In the formula, R, R ¹ and R ² are as defined above.)

This can be solved by a method for producing a 2-alkylmalonic acid compound represented by the following formula.

  According to the present invention, a 2-alkylmalonic acid compound can be produced in a high yield from a 2-alkylidenemalonic acid compound without requiring a complicated operation under mild conditions. A method for producing an alkylmalonic acid compound can be provided.

  The 2-alkylidenemalonic acid compound used in the reduction reaction of the present invention is represented by the above general formula (1). In the general formula (1), R is an alkyl group which may have a substituent. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, Examples include heptyl group, octyl group, nonyl group, decyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctyl group. These groups include various isomers.

  The alkyl group may have a substituent. Examples of the substituent include a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, a substituent formed through a sulfur atom, and a halogen atom.

  Examples of the substituent formed through the carbon atom include alkyl groups such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group; a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclo group. Cycloalkyl groups such as heptyl group; Alkenyl groups such as vinyl group, allyl group, propenyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group; quinolyl group, pyridyl group, pyrrolidyl group, pyrrolyl group, furyl group, thienyl group, etc. An aryl group such as phenyl group, tolyl group, fluorophenyl group, xylyl group, biphenylyl group, naphthyl group, anthryl group, phenanthryl group; acetyl group, propionyl group, acryloyl group, pivaloyl group, cyclohexylcarbonyl group, Benzoyl group, naphthoyl Group, acyl group such as toluoyl group (may be acetalized); carboxyl group; alkoxycarbonyl group such as methoxycarbonyl group and ethoxycarbonyl group; aryloxycarbonyl group such as phenoxycarbonyl group; trifluoromethyl group and the like A halogenated alkyl group; and a cyano group. These groups include various isomers.

  Examples of the substituent formed through the oxygen atom include a hydroxyl group; an alkoxyl group such as a methoxyl group, an ethoxyl group, a propoxyl group, a butoxyl group, a pentyloxyl group, a hexyloxyl group, a heptyloxyl group, and a benzyloxyl group; Aryloxyl groups such as phenoxyl group, toluyloxyl group, naphthyloxyl group and the like can be mentioned. These groups include various isomers.

  Examples of the substituent formed through the nitrogen atom include a primary amino group such as a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a cyclohexylamino group, a phenylamino group, and a naphthylamino group; Secondary amino groups such as amino group, diethylamino group, dipropylamino group, dibutylamino group, methylethylamino group, methylpropylamino group, methylbutylamino group, diphenylamino group, N-methyl-N-methanesulfonylamino group A morpholino group, a piperidino group, a piperazinyl group, a pyrazolidinyl group, a pyrrolidino group, an indolyl group or the like; an imino group; These groups include various isomers.

  Examples of the substituent formed through the sulfur atom include a mercapto group; a thioalkoxyl group such as a thiomethoxyl group, a thioethoxyl group, and a thiopropoxyl group; a thiophenoxyl group, a thiotoluyloxyl group, and a thionaphthyloxyl group. Thioaryloxyl group and the like. These groups include various isomers.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

R ¹ and R ² may be the same or different and each represents a hydrogen atom or a hydrocarbon group. Examples of the hydrocarbon group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. Alkyl groups such as heptyl group, octyl group, nonyl group and decyl group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and cyclooctyl group; benzyl group, phenethyl group, phenylpropylene An aralkyl group such as a phenyl group; and an aryl group such as a phenyl group, a p-tolyl group, a naphthyl group, and an anthryl group. These groups include various isomers.

  The reduction reaction of the present invention comprises at least one selected from the group consisting of aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, amides and ethers. For example, aliphatic hydrocarbons such as pentane, hexane, heptane, 2-methylbutane, 2-methylpentane, 2-methylhexane, cyclopentane, cyclohexane, cycloheptane; methylene chloride, chloroform, Halogenated aliphatic hydrocarbons such as dichloroethane; Aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; Halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene; N, N-dimethylformamide, N, N Amides such as -dimethylacetamide and N-methylpyrrolidone; diisopropyl ether, tetrahydroph Ethers such as lan, dimethoxyethane, dioxane and the like can be mentioned, and ethers are preferably used. In addition, you may use these solvents individually or in mixture of 2 or more types.

  The amount of the solvent to be used is preferably 0.5 to 50 g, more preferably 2 to 20 g, with respect to 1 g of the 2-alkylidene malonic acid compound.

  In the reduction reaction of the present invention, it is desirable to use a reducing agent. Examples of the reducing agent used include alkali metal borohydrides such as lithium borohydride, sodium borohydride, and potassium borohydride; Examples thereof include alkali metal cyanoborohydrides such as sodium and potassium cyanoborohydride, preferably alkali metal borohydrides, more preferably sodium borohydride. In addition, you may use these reducing agents individually or in mixture of 2 or more types.

  The amount of the reducing agent used in the present invention is preferably 0.25 to 10 mol, more preferably 0.9 to 5 mol, relative to 1 mol of the 2-alkylidene malonic acid compound.

  The reduction reaction of the present invention includes, for example, a 2-alkylidene malonic acid compound, a reducing agent and aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, amides and It is carried out by a method of mixing at least one solvent selected from the group consisting of ethers and reacting with stirring. The reaction temperature at that time is preferably −20 to 200 ° C., more preferably 0 to 120 ° C., and the reaction pressure is not particularly limited.

  A 2-alkylmalonic acid compound is obtained by the decarboxylation reaction of the present invention, and this is generally performed after the reaction, for example, neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography, etc. Isolated and purified by conventional methods.

  Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.

Example 1 (Synthesis of diethyl 2-cyclohexylmethylmalonate)
To a glass reaction vessel having an internal volume of 100 ml equipped with a stirrer, 10.0 g (37.3 mmol) of diethyl 2-cyclohexylmethylidenemalonate and 25 ml of tetrahydrofuran were added and 0.79 g of sodium borohydride while being cooled in an ice bath ( 19.7 mmol) was slowly added and allowed to react for 1 hour at room temperature with stirring. After completion of the reaction, the reaction solution was concentrated, and then ethyl acetate and water were added for liquid separation. The obtained organic layer was concentrated under reduced pressure to obtain 4.29 g of diethyl 2-cyclohexylmethylmalonate as an colorless oil (isolation yield; 85.1%).
The physical properties of diethyl 2-cyclohexylmethylmalonate were as follows.

CI-MS; 257 (M + 1)
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.85 to 0.96 (2H, m), 1.11 to 1.24 (4H, m), 1.27 (6H, t, J = 7.2 Hz), 1.68 to 1.73 (5H, m), 1.77 to 1.82 (2H, m), 3.44 (1H, t, J = 7.5Hz), 4.19 (4H, q, J = 7.2Hz)

  The present invention relates to a method for producing a 2-alkylmalonic acid compound by reducing a 2-alkylidenemalonic acid compound. A 2-alkylmalonic acid compound is a useful compound as a raw material for pharmaceuticals and agricultural chemicals and a synthetic intermediate.

Claims (3)

In at least one solvent selected from the group consisting of aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, amides and ethers, the general formula (1 )

(In the formula, R is an alkyl group which may have a substituent, and R ¹ and R ² may be the same or different and represent a hydrogen atom or a hydrocarbon group.)
A 2-alkylidenemalonic acid compound represented by the general formula (2):

(In the formula, R, R ¹ and R ² are as defined above.)
The manufacturing method of 2-alkylmalonic acid compound shown by these.   The method for producing a 2-alkylmalonic acid compound according to claim 1, wherein the reduction reaction is performed using a reducing agent.   The process for producing a 2-alkylmalonic acid compound according to claim 1, wherein the reducing agent is an alkali metal borohydride.