JP2006342102A - Method for preparing aryl or heteroaryl compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for preparing an industrially suitable aryl or heteroaryl compound which enables a high yield production of an aryl compound from a 2-aryl or heteroaryl malonic acid compound under mild conditions without requiring complicated operations. <P>SOLUTION: The method for preparing the aryl or heteroaryl compound comprises subjecting the 2-aryl or heteroaryl malonic acid compound to decarboxylation reaction in the presence of a base. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing an aryl compound from a 2-aryl or heteroaryl malonic acid compound. An aryl or heteroaryl compound is a compound useful as a raw material for pharmaceuticals and agricultural chemicals, or a synthetic intermediate.

Conventionally, as a method for producing an aryl or heteroaryl compound from a 2-aryl or heteroaryl malonic acid compound, for example, 2- (2-chloro-4-nitrophenyl) -2-methylmalonic acid in the presence of magnesium chloride A method in which diethyl is decarboxylated in N, N-dimethylacetamide at 140 to 150 ° C. to obtain 2-chloro-4-nitroethylbenzene in a yield of 72% (for example, see Non-Patent Document 1), sodium chloride 2- (2-chloro-4-nitrophenyl) -2-benzylmalonate was decarboxylated in a mixed solvent of dimethyl sulfoxide and water at 155 ° C. to give 2-chloro-4-nitro A method for obtaining bibenzyl in a yield of 85% (for example, see Non-Patent Document 2) is disclosed. However, in this method, a chlorine compound having a high reaction temperature and high corrosiveness to the reaction apparatus must be used, which is disadvantageous as an industrial method for producing an aryl or heteroaryl compound.
Synthesis, 12, 1659 (2000) Tetrahedron Lett., 42,8395 (2001)

  The object of the present invention is to solve the above-mentioned problems, and to produce an aryl compound from 2-aryl or heteroaryl malonic acid compound in high yield without requiring complicated operation under mild conditions. It is an object to provide an industrially suitable process for producing an aryl or heteroaryl compound.

  In the presence of a base, general formula (1)

(In the formula, Ar is an aryl group or heteroaryl group which may have a substituent, R ¹ is a hydrogen atom or a hydrocarbon group which may have a substituent, R ² and R ³ are (It may be the same or different and represents a hydrogen atom or a hydrocarbon group.)
A 2-aryl or heteroaryl malonic acid compound represented by the general formula (2)

(In the formula, Ar and R ¹ are as defined above.)
It is solved by the process for producing an aryl or heteroaryl compound represented by

  According to the present invention, an aryl or heteroaryl compound can be produced in a high yield from a 2-aryl or heteroaryl malonic acid compound without requiring a complicated operation under mild conditions. A process for producing an aryl or heteroaryl compound can be provided.

  The 2-aryl or heteroaryl malonic acid compound used in the decarboxylation 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, an acyl group such as toluoyl group (may be acetalized); a carboxyl group; an alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group (the alkoxycarbonyl group is added during the decarboxylation reaction of the present invention). An aryloxycarbonyl group such as a phenoxycarbonyl group (note that an aryloxycarbonyl group may be hydrolyzed to a carboxyl group during the decarboxylation reaction of the present invention). A halogenated alkyl group such as a trifluoromethyl group; 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 represents a hydrogen atom or a hydrocarbon group which may have a substituent. Examples of the hydrocarbon group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and a heptyl group. Group, octyl group, nonyl group, decyl group and other alkyl groups; cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and other cycloalkyl groups; benzyl group, phenethyl group, phenylpropyl group An aryl group such as a phenyl group, a p-tolyl group, a naphthyl group, and an anthryl group, and a benzyl group is preferable. These groups include various isomers. Further, the substituent on the hydrocarbon has the same definition as that defined for Ar.

R ² and R ³ may be the same or different and each represents a hydrogen atom or a hydrocarbon group, and the hydrocarbon group has the same definition as that defined for R ¹ .

  Examples of the base used in the reaction of the present invention include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkalis such as sodium hydrogen carbonate and potassium hydrogen carbonate Metal hydrogen carbonate; alkali metal alkoxides such as alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide and the like. These bases may be used alone or in combination of two or more.

  The amount of the base used is preferably 0.1 to 20 mol, more preferably 0.5 to 10 mol, per 1 mol of the 2-aryl or heteroaryl malonic acid compound.

  The decarboxylation reaction of the present invention is preferably carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol, isopropyl alcohol, t- Alcohols such as butyl alcohol; Ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone; N, N′-dimethylimidazolide Ureas such as non; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; benzene, toluene, xylene and the like Aromatic hydrocarbons . In addition, you may use these organic solvents individually or in mixture of 2 or more types.

  The amount of the solvent to be used is preferably 0.5 to 100 ml, more preferably 1 to 50 ml, with respect to 1 g of the 2-aryl or heteroaryl malonic acid compound.

  The decarboxylation reaction of the present invention is carried out, for example, by a method of mixing a 2-aryl or heteroaryl malonic acid compound, a base and a solvent and reacting them with stirring. The reaction temperature at that time is preferably 10 to 200 ° C., more preferably 20 to 120 ° C., and the reaction pressure is not particularly limited.

  An aryl or heteroaryl compound is obtained by the decarboxylation reaction of the present invention, and this is generally performed after completion of the reaction, for example, neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography, etc. It is isolated and purified by a simple manufacturing method.

  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 4-nitrobibenzyl)
In a glass container having an internal volume of 20 ml equipped with a stirrer, a thermometer and a reflux condenser, 1.0 g (2.69 mmol) of diethyl 2-benzyl-2- (4-nitrophenyl) malonate, 4 mol / l sodium hydroxide aqueous solution 2.36 ml (9.44 mmol) and 5 ml of dimethyl sulfoxide were added and reacted at 80 ° C. for 2 hours with stirring. After completion of the reaction, 6.14 ml (18.9 mmol) of 6 mol / l hydrochloric acid was added, followed by extraction with ethyl acetate, and the extract was concentrated. Subsequently, the concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 9/1) to obtain 0.28 g of 4-nitrobibenzyl as yellow crystals (isolated yield; 46%).
The physical properties of 4-nitrobibenzyl were as follows.

CI-MS; 228 (M + 1)
¹ H-NMR (CDCl ₃ , δ (ppm)); 2.91 to 3.06 (4H, m), 7.11 to 7.14 (2H, m), 7.18 to 7.30 (5H, m), 8.09 to 8.14 (2H, m)

  The present invention relates to a method for producing an aryl compound from a 2-aryl or heteroaryl malonic acid compound. An aryl or heteroaryl compound is a compound useful as a raw material for pharmaceuticals and agricultural chemicals, or a synthetic intermediate.

Claims (4)

In the presence of a base, general formula (1)

(In the formula, Ar is an aryl group or heteroaryl group which may have a substituent, R ¹ is a hydrogen atom or a hydrocarbon group which may have a substituent, R ² and R ³ are (It may be the same or different and represents a hydrogen atom or a hydrocarbon group.)
A 2-aryl or heteroaryl malonic acid compound represented by the general formula (2)

(In the formula, Ar and R ¹ are as defined above.)
The manufacturing method of the aryl or heteroaryl compound shown by these.   The process for producing an aryl or heteroaryl compound according to claim 1, wherein the decarboxylation reaction is carried out in a solvent.   The process for producing an aryl or heteroaryl compound according to claim 1, wherein the reaction temperature is 20 to 120 ° C. The method for producing an aryl or heteroaryl compound according to claim 1, wherein R ¹ is a benzyl group which may have a substituent.