JP2008297247A - Method for producing diaryl ether compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a commercially suitable method for producing a diaryl ether compound producing the compound under a mild condition without using a complicate operation. <P>SOLUTION: The problem of the invention can be solved by producing the diaryl ether compound under a mild condition without using a complicate operation by reacting an aryl halide, a metal alkoxide and a phosphazene compound in the absence of a silylation agent and a hydroxy compound. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention relates to a method for producing a diaryl ether compound by reacting an aryl halide, a metal alkoxide and a phosphazene compound.
A diaryl ether compound is a compound used in many fields such as physiologically active substances such as pharmaceuticals and agricultural chemicals, and other synthetic raw materials (see, for example, Non-Patent Document 1).

Bioorganic & Medicinal Chemistry Letters, 16, 2163-2169 (2006)

  Conventionally, as a method for obtaining a diaryl ether compound, a reaction in which an aryl halide and a hydroxyaryl compound are used using, for example, sodium hydride and a copper bromide / dimethyl sulfide complex (see, for example, Non-Patent Document 2) or palladium Reaction (for example, refer nonpatent literature 3) performed using metal catalysts, such as these is known. However, some of the hydroxyaryl compounds are highly corrosive, such as phenol, and have disadvantages in terms of safety.

  In recent years, a reaction for obtaining a diaryl ether compound using a phosphazene compound in the presence of a silylating agent has also been reported. However, in this method, in order to obtain the desired product in good yield, aryl fluoride or a halogenated aryl compound having an electron withdrawing group at the 2-position or 4-position is used as a starting material. The silylating agent had to be added in order to cause the reaction after the silylation of the compound, which was industrially disadvantageous as a method for producing the diaryl ether compound (see, for example, Non-Patent Document 4).

R.C.Larock, Comprehensive Organic Transformations.Second edition, 1999, John Wiley & Sons, Inc. J. Org. Chem., 67 (16), 5553-5556 (2002) Eur.J.Org.Chem., 1965-1968 (2005)

  An object of the present invention is to solve the above-mentioned problems, and in the absence of a silylating agent and a hydroxyaryl compound, under mild conditions and without requiring complicated operation, aryl halides, metal alkoxides and phosphazenes. An object of the present invention is to provide an industrially suitable method for producing a diaryl ether compound that can be reacted with a compound to produce a diaryl ether compound.

  In the absence of silylating agent and hydroxyaryl compound, general formula (1)

(In the formula, Ar represents an aryl group which may have a substituent, and X represents a halogen atom.)
An aryl halide, a metal alkoxide, and a phosphazene compound which may have a substituent represented by:
General formula (2)

(In the formula, Ar has the same meaning as described above.)
It solves by the manufacturing method of the diaryl ether compound shown by these.

  According to the present invention, an aryl halide, a metal alkoxide, and a phosphazene compound are reacted with each other in the absence of a silylating agent and a hydroxy compound and under a mild condition without requiring a complicated operation. An industrially suitable production method that can be produced can be provided.

  The aryl halide used in the reaction of the present invention is represented by the general formula (1). In the general formula (1), Ar represents an aryl group which may have a substituent, for example, an aromatic hydrocarbon group such as a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group; a quinolyl group, a pyridyl group An aromatic heterocyclic group such as a group is shown. X is a halogen atom, and represents, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

  The aryl 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, and a substituent formed through a sulfur 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, (may be acetalized) acyl groups such as toluoyl group; a methoxycarbonyl group, an alkoxycarbonyl group such as methoxycarbonyl group and ethoxycarbonyl group; a cyano group; an aryloxycarbonyl group such as phenoxycarbonyl group. These groups include various isomers.

  Examples of the substituent formed through the oxygen atom include 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; a phenoxyl group And aryloxyl groups such as toluyloxyl group and naphthyloxyl group. These groups include various isomers.

  Examples of the substituent formed through the nitrogen atom include dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group, methylethylamino group, methylpropylamino group, methylbutylamino group, diphenylamino group, N -Secondary amino group such as methyl-N-methanesulfonylamino group; heterocyclic amino group such as morpholino group, piperidino group, piperazinyl group, pyrazolidinyl group, pyrrolidino group, indolyl group; imino group. These groups include various isomers.

  Examples of the substituent formed through the sulfur atom include alkylthio groups such as methylthio group, ethylthio group, and propylthio group; arylthio groups such as phenylthio group, toluoylthio group, and naphthylthio group. These groups include various isomers.

  Examples of the metal alkoxide used in the reaction of the present invention include alkali metal alkoxides such as potassium alkoxide, sodium alkoxide and lithium alkoxide. Examples of the alkoxide include alkyl such as methoxide, ethoxide, propoxide, butoxide, and pentoxide. Oxides; metal alkoxides having hydrocarbon groups such as aralkyl oxides such as phenethyl oxide. These alkoxides include various isomers. Preferably, sodium alkoxide, potassium alkoxide, more preferably sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, and potassium t-butoxide are used. In addition, you may use these metal alkoxides individually or in mixture of 2 or more types. Moreover, you may use it as it is, or you may use what is melt | dissolved in the organic solvent.

The amount of the metal alkoxide to be used is preferably 1 mol to 100 mol, more preferably 1 mol to 10 mol, per 1 mol of aryl halide.

The phosphazene compound is a compound having a phosphorus-nitrogen bond, and examples thereof include a commercially available phosphazene compound synthesized by Schwesinger et al. And a proazaphosphatran compound synthesized by Verkade et al. The phosphazene compound used in the reaction of the present invention is preferably a tetrameric phosphazene compound of Schwesinger et al., More preferably 1-tert-butyl-4,4,4-tris (dimethylamino) -2,2′-. Bis [tris (dimethylamino) phosphoranylideneamino] -2Λ ⁵ , 4Λ ⁵ -catenadi (phosphazene) (hereinafter referred to as t-butyl-P4 phosphazene) (for example, see Non-Patent Document 5).

Sigma Aldrich Reagent Catalog Strong and Hindered Bases in Organic Synthesis, Chemfiles, Vol. 3, No. 1.

  In addition, you may use these phosphazene compounds individually or in mixture of 2 or more types. Moreover, you may use it as it is, or you may use what is melt | dissolved in water or an organic solvent.

  The phosphazene compound is preferably 0.01 to 10 mol, more preferably 1 to 5 mol, per 1 mol of the aryl halide.

  The reaction of the present invention can be carried out in the presence or absence of a solvent, but is preferably carried out in the presence of a solvent. Examples of the organic solvent used include aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; ethers such as tetrahydrofuran, tetrahydropyran, and 1,4-dioxane; ethyl acetate, Esters such as butyl acetate; Sulfoxides such as dimethyl sulfoxide; Sulfones such as sulfolane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; 1,3-dimethyl-2 -Ureas such as imidazolidinone. In addition, you may use these organic solvents individually or in mixture of 2 or more types.

  The amount of the organic solvent used is preferably 0 to 100 ml, more preferably 0 to 50 ml, with respect to 1 g of aryl halide.

  The reaction of the present invention is performed, for example, by a method of mixing an aryl halide, a metal alkoxide, and a phosphazene compound in an organic solvent and reacting them with stirring. The reaction temperature at that time is preferably -20 to 300 ° C, more preferably 0 to 150 ° C, and the reaction pressure is not particularly limited.

  A diaryl ether compound is obtained by the reaction of the present invention, and this can be obtained by a general production method such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography after completion of the reaction. Separated and purified.

  Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto. In addition, the analysis conditions by the high performance liquid chromatography used in each Example are as follows. Moreover, the product in each Example was confirmed by the coincidence of retention times by high performance liquid chromatography using the commercially available product as a standard.

Column: CAPCELL PAK C18 MGII, 5 μm,
4.6I. D * 250mm
Eluent: Water / methanol = 3/7 (volume ratio)
pH: Not prepared Flow rate: 1.0 ml / min
Column oven temperature: 40 ° C
Detection wavelength: 210 nm

Example 1 (Synthesis of diphenyl ether)
In a glass container having an internal volume of 20 ml equipped with a stirrer, a thermometer and a condenser tube, 0.134 ml (1.27 mmol) of bromobenzene, 89.9 mg (1.28 mmol) of potassium methoxide, 1 mol / ml under an argon gas atmosphere. An n-hexane solution of L t-butyl-P4 phosphazene (manufactured by Fluka) (1.27 ml, 1.27 mmol) and xylene (0.8 ml) were mixed and reacted at 100 ° C. for 5 hours with stirring. After completion of the reaction, methanol and 6 mol / L hydrochloric acid were added to the reaction solution, and then analyzed by high performance liquid chromatography (absolute calibration method). As a result, 21.6 mg of diphenyl ether was produced at a retention time of 17.0 minutes. (Reaction yield; 20%).
(Retention time of commercially available diphenyl ether (manufactured by Tokyo Chemical Industry): 17.0 minutes)

  The present invention relates to a method for producing a diaryl ether compound by reacting an aryl halide, a metal alkoxide and a phosphazene compound. A diaryl ether compound is a useful compound as a raw material for pharmaceuticals, agricultural chemicals, and synthetic intermediates, for example.

Claims (6)

In the absence of silylating agent and hydroxyaryl compound, general formula (1)

(In the formula, Ar represents an aryl group which may have a substituent, and X represents a halogen atom.)
An aryl halide, a metal alkoxide, and a phosphazene compound which may have a substituent represented by:
General formula (2)

(In the formula, Ar has the same meaning as described above.)
The manufacturing method of the diaryl ether compound shown by these.   The method for producing a diaryl ether compound according to claim 1, wherein the phosphazene compound is a tetrameric phosphazene compound. The tetrameric phosphazene compound is synthesized from 1-tert-butyl-4,4,4-tris (dimethylamino) -2,2′-bis [tris (dimethylamino) phosphoranylideneamino] -2Λ ⁵ , 4Λ ⁵ -catenadi ( The manufacturing method of the diaryl ether compound of Claim 1 or Claim 2 which is a phosphazene).   The method for producing a diaryl ether compound according to claim 1, wherein the alkyl group of the metal alkoxide is a metal alkoxide having a hydrocarbon group such as an alkyl group which may be substituted with an aryl group.   The method for producing a diaryl ether compound according to claim 1 or 4, wherein the metal of the metal alkoxide is an alkali metal metal alkoxide.   The diaryl ether according to claim 1, 4 or 5, wherein the metal alkoxide is selected from sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, and potassium t-butoxide. Compound production method.