JP2006347888A - Method for producing 2-aralkyl- or heteroaralkyl-malonic acid compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially suitably producing a 2-aralkyl- or heteroaralkyl-malonic acid compound in which the 2-aralkyl- or heteroaralkyl-malonic acid compound can be produced in high yield from a 2-aralkylidene or heteroaralkylidene malonic acid compound by a simple method. <P>SOLUTION: The method for producing the 2-aralkyl- or heteroaralkyl-malonic acid compound comprises carrying out reduction reaction of the 2-aralkylidene or heteroaralkylidene 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-aralkyl or heteroaralkylmalonic acid compound by reducing a 2-aralkylidene or heteroaralkylidenemalonic acid compound. A 2-aralkyl or heteroaralkylmalonic 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-aralkylidene or heteroaralkylidenemalonic acid compound, for example, [(2-bromophenyl) methylene] propanediacid diethyl And a method of reacting sodium borohydride in ethanol is disclosed (for example, see Non-Patent Document 1). However, this method has a problem that the isolation operation becomes complicated because sodium borohydride must be added in portions and aftertreatment with glacial acetic acid must be performed carefully. Also disclosed is a method of reacting 1,1-diethoxycarbonyl-2-phenylethylene and sodium borohydride in acetonitrile in the presence of anhydrous indium chloride (see, for example, Non-Patent Document 2). However, this method has a problem that expensive indium chloride must be used. As described above, any of the methods is disadvantageous as an industrial method for producing a 2-aralkyl or heteroaralkylmalonic acid compound.
J. Med. Chem, 40 (4), 495 (1997) Tetrahedron, 59 (40), 7901 (2003)

  The object of the present invention is to solve the above-mentioned problems and to produce 2-aralkyl or heteroaralkylmalonic acid compound from 2-aralkylidene or heteroaralkylidenemalonic acid compound in high yield by a simple method. An object of the present invention is to provide a process for producing an industrially suitable 2-aralkyl or heteroaralkylmalonic 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, Ar represents an aryl group or heteroaryl 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-aralkylidene or heteroaralkylidenemalonic acid compound represented by the formula (2):

（式中、Ａｒ、Ｒ^１及びＲ^２は、前記と同義である。）

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

This can be solved by a method for producing a 2-aralkyl or heteroaralkylmalonic acid compound represented by the formula:

  According to the present invention, a 2-aralkyl or heteroaralkylmalonic acid compound can be produced in high yield from a 2-aralkylidene or heteroaralkylidenemalonic acid compound under mild conditions and without requiring complicated operation. In addition, an industrially suitable method for producing a 2-aralkyl or heteroaralkylmalonic acid compound can be provided.

  The 2-aralkylidene or heteroaralkylidene malonic acid compound used in the reduction reaction of the present invention is represented by the general formula (1). In the general formula (1), Ar is an aryl group or heteroaryl group which may have a substituent, and examples of the aryl group include a phenyl group, a p-tolyl group, a naphthyl group, and an anthryl group. The heteroaryl group includes, for example, a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, a pyridyl group, a quinolinyl group, and a carbazolyl group. These groups include various isomers.

  The aryl group or heteroaryl 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, decyl group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group; benzyl group, phenethyl group, phenylpropylene An aralkyl group such as a sulfur 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 used is preferably 0.5 to 50 g, more preferably 2 to 20 g, relative to 1 g of the 2-aralkylidene or heteroaralkylidene 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, per 1 mol of the 2-aralkylidene or heteroaralkylidene malonic acid compound.

  The reduction reaction of the present invention includes, for example, 2-aralkylidene or heteroaralkylidene malonic acid compounds, reducing agents and aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons. At least one solvent selected from the group consisting of amides, amides and 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.

  By the decarboxylation reaction of the present invention, a 2-aralkyl or heteroaralkylmalonic acid compound is obtained. After the reaction is completed, for example, neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography It is isolated and purified by a general production method such as

  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 dimethyl 2- (4-fluorobenzyl) malonate)
To a glass reaction vessel having an internal volume of 100 ml equipped with a stirrer, 10.0 g (37.3 mmol) of dimethyl 2- (4-fluorobenzylidene) malonate and 40 ml of tetrahydrofuran were added, and while cooling in an ice bath, sodium borohydride 1.53 g (37.3 mmol) was slowly added and allowed to react at room temperature for 2 hours 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 8.93 g of dimethyl 2- (4-fluorobenzyl) malonate as a colorless oil (isolated yield: 89.3%).
The physical properties of dimethyl 2- (4-fluorobenzyl) malonate were as follows.

CI-MS; 269 (M + 1)
¹ H-NMR (CDCl ₃ , δ (ppm)); 1.21 (6H, t, J = 6.9 Hz), 3.18 (2H, d, J = 7.8 Hz), 3.60 (1H, t, J = 8.1 Hz), 4.15 (4H, m), 6.93-6.99 (2H, m), 7.15-7.28 (2H, m)

  The present invention relates to a method for producing a 2-aralkyl or heteroaralkylmalonic acid compound by reducing a 2-aralkylidene or heteroaralkylidenemalonic acid compound. A 2-aralkyl or heteroaralkylmalonic 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, Ar represents an aryl group or heteroaryl 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-aralkylidene or heteroaralkylidenemalonic acid compound represented by the formula (2):

(In the formula, Ar, R ¹ and R ² are as defined above.)
A process for producing a 2-aralkyl or heteroaralkylmalonic acid compound represented by the formula:   The method for producing a 2-aralkyl or heteroaralkylmalonic acid compound according to claim 1, wherein the reduction reaction is carried out using a reducing agent.   The method for producing a 2-aralkyl or heteroaralkylmalonic acid compound according to claim 1, wherein the reducing agent is an alkali metal borohydride.