JP2006143606A - Method for preparing 1-halo-3-aryl-2-propanones - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method capable of simply and efficiently preparing 1-halo-3-aryl-2-propanones useful as intermediates of drugs on a commercial scale from inexpensive and easily available raw materials. <P>SOLUTION: The 1-halo-3-aryl-2-propanones can be prepared in a good yield by reacting an inexpensive and easily available arylacetic ester derivative and a β-ketosulfoxonium ylide compound produced from a trimethylsulfoxonium ylide with a hydrogen halide in the presence of a halide to inhibit by-products to a minimum. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a process for producing 1-halo-3-aryl-2-propanones useful as pharmaceutical intermediates.

  The following methods are known as methods for producing 1-halo-3-aryl-2-propanones.

  (1) A method for producing 1-chloro-3-phenyl-2-propanone by reacting phenylacetyl chloride with diazomethane and treating the α-diazoketone produced with hydrochloric acid (Non-patent Document 1).

  (2) A method for producing 1-chloro-3-phenyl-2-propanone by reacting chloroacetyl chloride and benzylmagnesium chloride at −60 ° C. or less (Patent Document 1).

  (3) A method in which epichlorohydrin and phenylmagnesium chloride are reacted and the resulting 1-chloro-3-phenyl-2-propanol is oxidized with sodium dichromate (Non-patent Document 2).

  (4) A method of producing 1-chloro-3-phenyl-2-propanone by reacting ethyl phenylacetate and chloromethyllithium at −115 ° C. (Non-patent Document 3).

  (5) By reacting phenylacetyl chloride with meldrum acid and treating with tert-butanol, tert-butyl phenylacetoacetate is produced, and further chlorinated with sulfuryl chloride, followed by acid hydrolysis to give 1- A method for producing chloro-3-phenyl-2-propanone (Patent Document 2).

  However, the method (1) uses diazomethane which is explosive and difficult to handle, and the production methods (2) and (4) require an ultra-low temperature reaction facility. The method (3) is extremely toxic. It is a problem that a chromium compound is used, and the method (5) has problems in implementation on a commercial scale, such as the number of steps and inefficiency in the conventional technology. It was.

  Moreover, the following method is known as a general method for producing 1-halo-2-propanones from a β-ketosulfoxonium ylide compound.

  (6) A method in which a β-ketosulfoxonium ylide compound and hydrogen chloride are reacted in a methylene chloride, acetonitrile, or chloroform solvent (Non-Patent Document 4).

  (7) A method of reacting a β-ketosulfoxonium ylide compound with hydrogen chloride or hydrogen bromide in an acetic acid solvent (Non-patent Document 5).

(8) A method of reacting a β-ketosulfoxonium ylide compound and methanesulfonic acid in a tetrahydrofuran solvent in the presence of lithium chloride (Non-patent Document 6).
WO01 / 23383 JP 05-286902 A Organic Synthesis, 1946, 26, 13-15. Eur. J. et al. Med. Chem. 1979, 14 (2), 165-170. Tetrahedron Lett. 1984, 25 (8), 835-838. Bulletin de la Society Chimique de France, 1987, (5), 861-866. Synlett, 1993, (1), 51-53. J. et al. Org. Chem. 2004, 69, 1629-1633.

  However, when the present inventors applied the conventional methods described in (6) to (8) in the production of the desired 1-halo-3-aryl-2-propanones, a plurality of unexpected side reactions were observed. It was found that the yield of the target product was remarkably lowered. That is, the present invention is a method for producing 1-halo-3-aryl-2-propanones in high yield, which can be carried out easily and efficiently on a commercial scale, from inexpensive and readily available raw materials in view of the above-mentioned present situation. Is the purpose.

  As a result of intensive studies, the present inventors have reacted a by-product by reacting a β-ketosulfoxonium ylide compound produced from an aryl acetate derivative and a trimethylsulfoxonium ylide with a hydrogen halide in the presence of a halide. As a result, it was found that 1-halo-3-aryl-2-propanones can be produced with good yield, and the present invention has been completed.

  That is, the present invention relates to the general formula (1);

（式中、Ａｒは置換基を有してもよい炭素数６〜１５のアリール基、又は置換基を有してもよい炭素数３〜１５のヘテロアリール基を表す。）で表されるβ−ケトスルホキソニウムイリド化合物を、ハロゲン化物存在下にハロゲン化水素と反応させることを特徴とする、一般式（２）；

(In the formula, Ar represents an aryl group having 6 to 15 carbon atoms which may have a substituent, or a heteroaryl group having 3 to 15 carbon atoms which may have a substituent). A general formula (2), characterized in that a ketosulfoxonium ylide compound is reacted with a hydrogen halide in the presence of a halide;

（式中、Ａｒは前記に同じ。Ｘはハロゲン原子を表す。）で表される１−ハロ−３−アリール−２−プロパノンの製造法である。

(In the formula, Ar is the same as described above. X represents a halogen atom.) A method for producing 1-halo-3-aryl-2-propanone represented by:

  The present invention also provides a compound represented by the general formula (1)

（式中、Ａｒは置換基を有してもよい炭素数６〜１５のアリール基、又は置換基を有してもよい炭素数３〜１５のヘテロアリール基を表す。）で表されるβ−ケトスルホキソニウムイリド化合物でもある。

(In the formula, Ar represents an aryl group having 6 to 15 carbon atoms which may have a substituent, or a heteroaryl group having 3 to 15 carbon atoms which may have a substituent). -Ketosulfoxonium ylide compounds.

  The present invention is to produce 1-halo-3-aryl-2-propanones easily and efficiently from inexpensive and readily available starting materials, and with high yields while minimizing by-products. Can be implemented on a commercial scale.

  First, the raw materials, products, and by-products used in the present invention will be described.

  The aryl acetate derivative which is a starting material of the present invention has the general formula (3);

で表される。ここで、Ａｒは置換基を有してもよい炭素数６〜１５のアリール基、又は置換基を有してもよい炭素数３〜１５のヘテロアリール基を表す。アリール基としては例えば、フェニル基、ナフチル基、又はビフェニル基等が挙げられ、ヘテロアリール基としては例えば、ピリジル基、フラニル基、チエニル基、ピローリル基、オキサゾリル基、イソオキサゾリル基、ピラゾリル基、ベンゾフラニル基、ベンゾチアゾリル基、又はインドリル基等が挙げられる。その中でも好ましくはフェニル基である。前記Ａｒの置換基としては、例えばフッ素原子、塩素原子、臭素原子、ヨウ素原子等のハロゲン原子；ニトロ基；ニトロソ基；シアノ基；アミノ基；ヒドロキシアミノ基；メチルアミノ基、ｎ−ブチルアミノ基等の炭素数１〜１２のアルキルアミノ基；ジメチルアミノ基、ジｎ−ブチルアミノ基等の炭素数１〜１２のジアルキルアミノ基；ベンジルアミノ基等の炭素数７〜１２のアラルキルアミノ基；ジベンジルアミノ基等の炭素数７〜１２のジアラルキルアミノ基；メタンスルホニルアミノ基等の炭素数１〜１２のアルキルスルホニルアミノ基；スルホン酸基；スルホンアミド基；アジド基；トリフルオロメチル基；カルボキシル基；アセチル基等の炭素数１〜１２のアシル基；ベンゾイル基等の炭素数７〜１２のアロイル基；水酸基；メトキシ基、ｎ−ブトキシ基等の炭素数１〜１２のアルキルオキシ基；ベンジルオキシ基等の炭素数７〜１２のアラルキルオキシ基；フェノキシ基等の炭素数６〜１２のアリールオキシ基；アセチルオキシ基等の炭素数１〜１２のアシルオキシ基；ベンゾイルオキシ等の炭素数７〜１２のアロイルオキシ基；トリメチルシリルオキシ基等の炭素数３〜１２のシリルオキシ基；メタンスルホニルオキシ基等の炭素数１〜１２のアルキルスルホニルオキシ基；メチルチオ基等の炭素数１〜１２のアルキルチオ基等が挙げられ、その中でも好ましくは塩素原子である。また、置換基の数は０〜３個が好ましい例として挙げられる。Ａｒとして具体的には、４−クロロフェニル基が好ましい。

It is represented by Here, Ar represents a C6-C15 aryl group which may have a substituent, or a C3-C15 heteroaryl group which may have a substituent. Examples of the aryl group include a phenyl group, a naphthyl group, and a biphenyl group. Examples of the heteroaryl group include a pyridyl group, a furanyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a pyrazolyl group, and a benzofuranyl group. , A benzothiazolyl group, an indolyl group, and the like. Of these, a phenyl group is preferred. Examples of the substituent of Ar include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; nitro group; nitroso group; cyano group; amino group; hydroxyamino group; methylamino group, n-butylamino group An alkylamino group having 1 to 12 carbon atoms such as dimethylamino group, a dialkylamino group having 1 to 12 carbon atoms such as di-n-butylamino group; an aralkylamino group having 7 to 12 carbon atoms such as benzylamino group; Diaralkylamino group having 7 to 12 carbon atoms such as benzylamino group; Alkylsulfonylamino group having 1 to 12 carbon atoms such as methanesulfonylamino group; Sulfonic acid group; Sulfonamide group; Azido group; Trifluoromethyl group; An acyl group having 1 to 12 carbon atoms such as an acetyl group; an aroyl group having 7 to 12 carbon atoms such as a benzoyl group; a hydroxyl group; An alkyloxy group having 1 to 12 carbon atoms such as xy group and n-butoxy group; an aralkyloxy group having 7 to 12 carbon atoms such as benzyloxy group; an aryloxy group having 6 to 12 carbon atoms such as phenoxy group; acetyloxy A C1-C12 acyloxy group such as a group; a C7-C12 aroyloxy group such as benzoyloxy; a C3-C12 silyloxy group such as a trimethylsilyloxy group; a C1-C12 such as a methanesulfonyloxy group An alkylthio group having 1 to 12 carbon atoms such as a methylthio group, among which a chlorine atom is preferable. Moreover, 0-3 are mentioned as a preferable example of the number of substituents. Specifically, 4-chlorophenyl group is preferable as Ar.

  R represents an alkyl group having 1 to 5 carbon atoms, specifically a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, or the like. Can be mentioned. Among these, a methyl group or an ethyl group is preferable.

  Another starting material of the present invention, trimethylsulfoxonium ylide, has the formula (4):

で表される。

It is represented by

  The β-ketosulfoxonium ylide compound which is an intermediate product of the present invention has the general formula (1);

で表される。ここで、Ａｒは一般式（３）における説明と同じである。なお、一般式（１）で表されるβ−ケトスルホキソニウムイリド化合物は文献に未記載の新規化合物である。

It is represented by Here, Ar is the same as described in the general formula (3). In addition, the β-ketosulfoxonium ylide compound represented by the general formula (1) is a novel compound not described in the literature.

  1-halo-3-aryl-2-propanones, which are end products of the present invention, are represented by the general formula (2);

で表される。ここで、Ａｒは一般式（３）における説明と同じである。Ｘはハロゲン原子を表し、具体的には例えば、フッ素原子、塩素原子、臭素原子、又はヨウ素原子であり、好ましくは塩素原子である。

It is represented by Here, Ar is the same as described in the general formula (3). X represents a halogen atom, specifically, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and preferably a chlorine atom.

  Next, in the present invention, 1-halo-1-aryl-2-propanone which is one of the by-products in question is represented by the general formula (5);

で表される。ここで、Ａｒ、Ｘは一般式（２）における説明と同じである。また、別の副生物である１−ヒドロキシ−３−アリール−２−プロパノン類は一般式（６）；

It is represented by Here, Ar and X are the same as in the general formula (2). Another by-product, 1-hydroxy-3-aryl-2-propanone, is represented by the general formula (6);

で表される。ここで、Ａｒは一般式（２）における説明と同じである。さらにもう一つの副生物である１−ヒドロキシ−１−アリール−２−プロパノン類は一般式（７）；

It is represented by Here, Ar is the same as described in the general formula (2). Still another by-product, 1-hydroxy-1-aryl-2-propanone, is represented by the general formula (7);

で表される。ここで、Ａｒは一般式（２）における説明と同じである。

It is represented by Here, Ar is the same as described in the general formula (2).

  Next, the manufacturing method of this invention is demonstrated.

  First, a method for producing the β-ketosulfoxonium ylide compound represented by the general formula (1) will be described.

  The β-ketosulfoxonium ylide compound represented by the general formula (1) is obtained by reacting the aryl acetate derivative represented by the general formula (3) with the trimethylsulfoxonium ylide represented by the formula (4). Can be manufactured. Here, the trimethylsulfoxonium ylide represented by the formula (4) is prepared from a trimethylsulfoxonium halide such as trimethylsulfoxonium chloride, trimethylsulfoxonium bromide, or trimethylsulfoxonium iodide and a base. Is possible. The trimethylsulfoxonium halide is preferably trimethylsulfoxonium bromide. Examples of the base include, but are not limited to, organic lithium reagents such as methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, and phenyl lithium; sodium amide, potassium amide, lithium diisopropylamide, lithium Alkali metal amides such as hexamethyldisilazide, sodium diisopropylamide, sodium hexamethyldisilazide, or potassium hexamethyldisilazide; n-butylmagnesium chloride, tert-butylmagnesium chloride, n-butylmagnesium bromide, odor Grignard reagents such as tert-butylmagnesium bromide, phenylmagnesium bromide, or tert-butylmagnesium iodide; magnesium chloride diisopropylamide, magnesium bromide diisopropyl Halomagnesium amides such as pyramide; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkalis such as sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide Metal alkoxides; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. Among them, preferred are alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide and potassium tert-butoxide. More preferably sodium hydride. The amount of the base used is preferably 1 to 5 times the molar amount, more preferably 1 to 2 times the molar amount relative to the trimethylsulfoxonium halide. The reaction temperature for preparing trimethylsulfoxonium ylide is preferably 0 to 120 ° C, more preferably 40 to 80 ° C, from the viewpoint of yield improvement.

  Examples of the reaction solvent for preparing trimethylsulfoxonium ylide include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; pentane, Aliphatic hydrocarbon solvents such as hexane, heptane and methylcyclohexane; Halogen solvents such as methylene chloride, 1,2-dichloroethane and chlorobenzene; Amides solvents such as N, N-dimethylformamide and N, N-dimethylacetamide; Urea solvents such as dimethylpropylene urea; phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide can be used. Of these, tetrahydrofuran, toluene, N, N-dimethylformamide, dimethyl sulfoxide and the like are preferable. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.

  Next, the trimethylsulfoxonium ylide thus obtained is reacted with an arylacetic acid ester derivative represented by the general formula (3), and the β-ketosulfoxonium ylide represented by the general formula (1) is reacted. A compound is obtained. Here, the method and the order of addition of the reagents are not particularly limited, but preferably, the trimethylsulfoxo represented by the formula (4) is added by adding the trimethylsulfoxonium halide to the solution of the base. A solution of nium ylide is prepared, and the aryl acetate ester derivative represented by the general formula (3) is added thereto, or the above prepared formula is added to the solution of the aryl acetate ester derivative represented by the general formula (3). It may be performed by adding a solution of trimethylsulfoxonium ylide represented by (4). At this time, with respect to the aryl acetate derivative represented by the general formula (3), the amount of trimethylsulfoxonium halide used is preferably 1 to 10 times mol, more preferably 1 to 3 times mol. Amount.

  The reaction solvent for reacting the aryl acetate derivative represented by the general formula (3) with the trimethylsulfoxonium ylide represented by the formula (4) is the reaction used when preparing the trimethylsulfoxonium ylide. The same solvent can be used as it is, or a different one can be used. Specific examples and preferred examples thereof are the same as those described for the reaction solvent for preparing the trimethylsulfoxonium ylide. The amount of the solvent used in this reaction is not particularly limited, but is preferably 50 times or less, more preferably 5 to 20 times the weight of the aryl acetate derivative represented by the general formula (3).

  The reaction temperature for reacting the aryl acetate derivative represented by the general formula (3) with the trimethylsulfoxonium ylide represented by the formula (4) is preferably -30 to 50 from the viewpoint of improving the yield. ° C, more preferably -10 to 30 ° C.

  The reaction time for this reaction is preferably 5 minutes to 24 hours, more preferably 30 minutes to 5 hours, from the viewpoint of yield improvement.

  What is necessary is just to perform the general process for acquiring a product from a reaction liquid as a process after the said reaction. For example, water is added to the reaction solution after completion of the reaction, and a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like is added for extraction. Further, if necessary, the extract is washed with water or an alkaline aqueous solution such as an aqueous sodium hydroxide solution or an aqueous sodium hydrogen carbonate solution, and then the reaction solvent and the extraction solvent are distilled off by an operation such as heating under reduced pressure to obtain the desired product. can get. The target product thus obtained has sufficient purity that can be used in the subsequent step, but for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step, crystallization, The purity may be further increased by a general purification method such as fractional distillation or column chromatography. In the case of crystallization, the obtained β-ketosulfoxonium ylide compound represented by the general formula (1) is dissolved in a solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, and hexane. Crystallization can be performed by adding a poor solvent such as heptane. Further, cooling or concentration may be performed for the purpose of increasing the yield. Crystal separation may be performed by vacuum filtration, pressure filtration, centrifugation, or the like, and may be washed with a poor solvent such as hexane or heptane for the purpose of further improving the quality. Subsequently, the wet crystal can be dried under reduced pressure to obtain the β-ketosulfoxonium ylide compound represented by the general formula (1) as a high-purity crystal.

Finally, by reacting a β-ketosulfoxonium ylide compound represented by the general formula (1) with a hydrogen halide in the presence of a halide, 1-halo-3 represented by the general formula (2) A method for producing an aryl-2-propanone will be described.
Here, examples of the hydrogen halide include hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, and the like, and preferably hydrogen chloride. These hydrogen halides may be hydrofluoric acid, hydrochloric acid, hydrobromic acid, or hydroiodic acid which are aqueous solutions from the viewpoint of easy storage and handling, and hydrochloric acid is particularly preferable. The amount of the hydrogen halide used is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount relative to the β-ketosulfoxonium ylide compound represented by the general formula (1). It is.

  The halide used in the present invention includes lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, lithium chloride, sodium chloride, potassium chloride, cesium chloride, lithium bromide, sodium bromide, potassium bromide. Alkali metal halides such as cesium bromide, lithium iodide, sodium iodide, potassium iodide, cesium iodide; alkaline earth metal halides such as magnesium chloride, calcium chloride, magnesium bromide, calcium bromide; And ammonium halides such as ammonium chloride, ammonium chloride, ammonium bromide, and ammonium iodide. Preferred is lithium chloride, sodium chloride, potassium chloride, cesium chloride, magnesium chloride, calcium chloride, or ammonium chloride, and more preferred is sodium chloride or ammonium chloride. The amount of the halide used is preferably 1 to 200 times by mole, more preferably 10 to 100 times by mole, relative to the β-ketosulfoxonium ylide compound represented by the general formula (1). is there.

  In this reaction, by performing the reaction in the presence of the above-mentioned halide, by-products other than the 1-halo-3-aryl-2-propanones represented by the general formula (2), which is the target product, are generated. Can be suppressed. At this time, as a by-product which becomes a problem, mainly 1-halo-1-aryl-2-propanones represented by the general formula (5), 1-hydroxy-3-aryl represented by the general formula (6) -2-propanone or 1-hydroxy-1-aryl-2-propanone represented by the general formula (7) can be mentioned. The generation of these by-products not only reduces the yield of 1-halo-3-aryl-2-propanones represented by the general formula (2) of the target compound, but also by-products with similar structures. It is necessary to repeat a complicated purification step for the separation, and this is not preferable in that the isolation yield of the target compound is greatly reduced. In the present invention, the production rate of 1-halo-3-aryl-2-propanone represented by the general formula (2) with respect to the by-product is preferably 0.4 or more, more preferably 1 That's it. Here, the production rate is the yield of 1-halo-3-aryl-2-propanones represented by the general formula (2) / [1-halo-1-aryl- represented by the general formula (5). Yield of 2-propanone + 1-hydroxy-3-aryl-2-propanone represented by general formula (6) + 1-hydroxy-1-aryl- represented by general formula (7) 2-propanone yield].

  The reaction solvent for this reaction is not particularly limited. For example, water; ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; pentane, hexane, Aliphatic hydrocarbon solvents such as heptane and methylcyclohexane; Halogen solvents such as methylene chloride, 1,2-dichloroethane and chlorobenzene; Amides solvents such as N, N-dimethylacetamide; Urea solvents such as dimethylpropylene urea; A phosphonic acid triamide solvent such as hexamethylphosphonic acid triamide can be used. Preferably, water is used from the viewpoint of dissolving the halide. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. The amount of the reaction solvent to be used is preferably 100 times or less, more preferably 5 to 20 times the weight of the β-ketosulfoxonium ylide compound represented by the general formula (1).

  The reaction temperature for this reaction is preferably 20 to 120 ° C., more preferably 50 to 90 ° C., from the viewpoint of yield improvement.

  The reaction time for this reaction is preferably 5 minutes to 24 hours, more preferably 30 minutes to 5 hours, from the viewpoint of yield improvement.

  The order of addition of the β-ketosulfoxonium ylide compound represented by the general formula (1), hydrogen halide, halide, and reaction solvent in the present reaction is not particularly limited.

  What is necessary is just to perform the general process for acquiring a product from a reaction liquid as a process after reaction. For example, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like is added to the reaction solution after completion of the reaction to perform the extraction operation. Further, if necessary, the extract is washed with water or an alkaline aqueous solution such as an aqueous sodium hydroxide solution or an aqueous sodium hydrogen carbonate solution, and then the reaction solvent and the extraction solvent are distilled off by an operation such as heating under reduced pressure to obtain the desired product. can get. The target product thus obtained has sufficient purity that can be used in the subsequent step, but for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step, crystallization, The purity may be further increased by a general purification method such as fractional distillation or column chromatography.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited only to these examples.

Example 1 Preparation of 2-oxo-3- (4-chlorophenyl) propylidodimethylsulfoxonium A suspension of 60% sodium hydride in 6.00 g (150 mmol) in tetrahydrofuran (100 mL) was heated to 60 ° C. to give an odor. 27.68 g (160 mmol) of trimethylsulfoxonium bromide was added over 1 hour. The mixture was further stirred for 2 hours under reflux conditions, and then cooled to 5 ° C. To this, 19.67 g (100 mmol) of methyl 4-chlorophenylacetate was added dropwise over 30 minutes and stirred at the same temperature for 2 hours. The reaction mixture was hydrolyzed by adding 50 mL of water, and extracted three times with ethyl acetate (100 mL). The extracts were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a white slurry solution (44.4 g). Ethyl acetate (75 mL) and hexane (150 mL) were added, and the mixture was stirred at 5 ° C. for 30 min. The crystals were filtered off under reduced pressure and further dried under vacuum to give the title compound as pale yellow crystals (22.42 g, yield: 92%). ).

¹ H-NMR (CDCl ₃ , 400 MHz / ppm): δ 3.36 (6H, s), 3.44 (2H, s), 4.26 (1H, s), 7.20 (2H, d), 7 .26 (2H, d)

Comparative Example 1 Production of 1-chloro-3- (4-chlorophenyl) -2-propanone 2-Oxo-3- (4-chlorophenyl) propylidodimethylsulfoxonium 260.7 mg (1 mmol) produced in Example 1 A solution consisting of 10 mL of water and 156.4 mg (1.5 mmol) of concentrated hydrochloric acid was stirred at 70 ° C. for 30 minutes. The crude product was obtained by adding and extracting 10 mL of ethyl acetate here, and concentrating under reduced pressure. This was subjected to high performance liquid chromatography (column: Shiseido CAPCELLPAK C18 4.6 × 250 mm, eluent: acetonitrile / phosphate buffer = 1/1, flow rate: 1.0 mL / min, column temperature: 40 ° C., detector. The yield of the title compound was 23%. Further, this was purified by silica gel column chromatography to obtain the title compound as a white solid (40.6 mg, yield: 20%).

¹ H-NMR (CDCl ₃ , 400 MHz / ppm): δ 3.88 (2H, s), 4.11 (2H, s), 7.15 (2H, d), 7.32 (2H, d)

Comparative Example 2 Production of 1-chloro-3- (4-chlorophenyl) -2-propanone 2-oxo-3- (4-chlorophenyl) propylidodimethylsulfoxonium 32.2 mg produced in Example 1 (0. 123 mmol), 19 mg (0.2 mmol) of methanesulfonic acid, 42 mg (1 mmol) of lithium chloride, and 2 mL of tetrahydrofuran were stirred at 70 ° C. for 30 minutes. The crude product was obtained by adding and extracting 10 mL of ethyl acetate here, and concentrating under reduced pressure. As a result of quantitative analysis of the product by the method described in Comparative Example 1, the yield of the title compound was 27%.

Examples 2 to 8 Production of 1-chloro-3- (4-chlorophenyl) -2-propanone 260.7 mg of 2-oxo-3- (4-chlorophenyl) propylidodimethylsulfoxonium prepared in Example 1 1 mmol), a halide described in Table 1, 10 mL of water, and 156.4 mg (1.5 mmol) of concentrated hydrochloric acid were stirred at 70 ° C. for 30 minutes. Table 1 below shows the results of quantitative analysis of the reaction solution after the reaction by the method described in Comparative Example 1 and obtaining the yield of each compound produced. Compound (2) in the table is the title compound 1-chloro-3- (4-chlorophenyl) -2-propanone, and compounds (5), (6) and (7) are by-products of this reaction, respectively. Compound (5) is 1-chloro-1- (4-chlorophenyl) -2-propanone, Compound (6) is 1-hydroxy-3- (4-chlorophenyl) -2-propanone, Compound (7) is 1- Hydroxy-1- (4-chlorophenyl) -2-propanone is shown.

実施例９ １−クロロ−３−（４−クロロフェニル）−２−プロパノンの製造
実施例１にて製造した２−オキソ−３−（４−クロロフェニル）プロピリドジメチルスルホキソニウム２．６０７ｇ（１０ｍｍｏｌ）、水１０ｍＬ、塩化アンモニウム１６．０５ｇ（３００ｍｍｏｌ）、濃塩酸１．５６４ｇ（１５ｍｍｏｌ）からなる溶液を７０℃、１．５時間攪拌した。トルエン２０ｍＬ、水１０ｍＬを加えて抽出し、有機層を水１０ｍＬで２回洗浄後、減圧濃縮することにより、赤色油状物２．２２６１ｇを得た（収率：６６％）。ここに、酢酸エチル２ｍＬ、ヘキサン８ｍＬ、シリカゲル１．０ｇを加えて２５℃、１０分攪拌し、シリカゲルを減圧濾別した。濾液を減圧濃縮し、酢酸エチル１ｍＬ、ヘキサン１０ｍＬを加えると結晶が析出し、５℃、３０分攪拌後、結晶を減圧濾別した。ヘキサン１０ｍＬで洗浄後、真空乾燥することにより、標題化合物を淡黄色結晶として得た（９４１．４ｍｇ、純度：１００重量％、収率：４６％）。

Example 9 Production of 1-chloro-3- (4-chlorophenyl) -2-propanone 2.607 g (10 mmol) of 2-oxo-3- (4-chlorophenyl) propylidenedimethylsulfoxonium prepared in Example 1 A solution consisting of 10 mL of water, 16.05 g (300 mmol) of ammonium chloride and 1.564 g (15 mmol) of concentrated hydrochloric acid was stirred at 70 ° C. for 1.5 hours. Extraction was performed by adding 20 mL of toluene and 10 mL of water, and the organic layer was washed twice with 10 mL of water and then concentrated under reduced pressure to obtain 2.2261 g of a red oily substance (yield: 66%). To this, 2 mL of ethyl acetate, 8 mL of hexane, and 1.0 g of silica gel were added and stirred at 25 ° C. for 10 minutes, and the silica gel was filtered off under reduced pressure. The filtrate was concentrated under reduced pressure, and 1 mL of ethyl acetate and 10 mL of hexane were added to precipitate crystals. After stirring at 5 ° C. for 30 minutes, the crystals were filtered off under reduced pressure. After washing with 10 mL of hexane and vacuum drying, the title compound was obtained as pale yellow crystals (941.4 mg, purity: 100% by weight, yield: 46%).

Claims (10)

General formula (1);

(In the formula, Ar represents an aryl group having 6 to 15 carbon atoms which may have a substituent, or a heteroaryl group having 3 to 15 carbon atoms which may have a substituent). A general formula (2), characterized in that a ketosulfoxonium ylide compound is reacted with a hydrogen halide in the presence of a halide;

(In the formula, Ar is the same as above. X represents a halogen atom.) A process for producing 1-halo-3-aryl-2-propanones represented by:   The process according to claim 1, wherein the hydrogen halide is hydrogen chloride and X is a chlorine atom.   The production method according to claim 1 or 2, wherein the halide is sodium chloride or ammonium chloride.   The manufacturing method in any one of Claims 1-3 whose Ar is 4-chlorophenyl group. At least one reaction by-product is represented by the general formula (5);

(Wherein Ar and X are the same as defined above) 1-halo-1-aryl-2-propanones represented by the general formula (6);

(Wherein Ar is the same as defined above), or 1-hydroxy-3-aryl-2-propanone represented by the general formula (7);

(Wherein Ar is the same as defined above) 1-hydroxy-1-aryl-2-propanones represented by the general formula (2) for these by-products The production method according to claim 1, wherein the production rate of -2-propanone is 1 or more.
Here, the production rate is the yield of 1-halo-3-aryl-2-propanones represented by the general formula (2) / [1-hydroxy-3-aryl- represented by the general formula (5) Yield of 2-propanone + 1-hydroxy-3-aryl-2-propanone represented by general formula (6) + 1-hydroxy-1-aryl- represented by general formula (7) 2-propanone yield]. The β-ketosulfoxonium ylide compound represented by the general formula (1) is represented by the general formula (3);

(Wherein Ar is the same as defined above, R represents an alkyl group having 1 to 5 carbon atoms) and the formula (4);

It manufactures from the trimethylsulfoxonium ylide represented by these. The manufacturing method in any one of Claims 1-5 characterized by the above-mentioned.   The method according to claim 6, wherein the trimethylsulfoxonium ylide represented by the formula (4) is prepared from trimethylsulfoxonium bromide and sodium hydride.   The manufacturing method of Claim 6 or 7 whose R is a methyl group or an ethyl group. General formula (1);

(In the formula, Ar represents an aryl group having 6 to 15 carbon atoms which may have a substituent, or a heteroaryl group having 3 to 15 carbon atoms which may have a substituent). A ketosulfoxonium ylide compound.   The compound according to claim 9, wherein Ar is a 4-chlorophenyl group.