WO2006051723A1

WO2006051723A1 - Method for producing 1-halo-3-aryl-2-propanone

Info

Publication number: WO2006051723A1
Application number: PCT/JP2005/020070
Authority: WO
Inventors: Akira Nishiyama; Nobuo Nagashima
Original assignee: Kaneka Corporation
Priority date: 2004-11-09
Filing date: 2005-11-01
Publication date: 2006-05-18

Abstract

1-halo-3-aryl-2-propanone can be produced with ease and with good efficiency without the use of a reagent being difficult to handle or the equipment for a super low temperature reaction, by using a method comprising reacting an enolate prepared from an arylacetic acid or an arylacetic acid derivative, which is inexpensive and easily available, and a base, with a haloacetic acid derivative, which is inexpensive and easily available, followed by the treatment with an acid. 1-halo-3-aryl-2-propanone is useful as a pharmaceutical intermediate or the like.

Description

1 _Hello 3 _Areal _ 2 _Propanone production method

Technical field

[0001] The present invention relates to a process for producing 1halo3arylo-2propanones useful as pharmaceutical intermediates.

Background art

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

[0003] (1) A method for producing 1-claw-mouth 3 phenyl 2-propanone by reacting phenylacetyl chloride with diazomethane and treating the resulting a-diazoketone with hydrochloric acid (Non-patent Document 1).

[0004] (2) A method for producing 1 chloro-3 phenyl 2 propanone by reacting chloroacetyl chloride and benzylmagnesium chloride at 60 ° C. or lower (Patent Document 1).

[0005] (3) A method in which 1-chloro-3-phenyl-2-propanol produced by reacting epicchlorohydrin and phenylmagnesium chloride is acidified with sodium dichromate (Non-patent Document 2).

[0006] (4) Reacting ethyl acetate with chloromethyllithium at 115 ° C,

3 Method for producing phenyl 2 propanone (Non-patent Document 3).

[0007] (5) By reacting ferrocetyl chloride with meldrum acid and treating with tert-butanol, tert-butyl ferroacetoacetate is produced and further chlorinated with sulfuryl chloride. A process for producing 1 chloro-3 ferrue 2 propanone by decomposing (Patent Document 2).

[0008] However, the method (1) uses explosive and difficult-to-use diazomethane, and the production methods (2) and (4) require an ultra-low temperature reaction facility. In the method of 3), it is a problem that a highly toxic chromium compound is used. In the method of (5), the number of steps is long and inefficient. Have issues in implementation Patent Document 2: JP 05-286902 A

Non-Patent Document 1: Organic Synthesis, 1946, 26, 13-15.

Non-Patent Document 2: Eur. J. Med. Chem., 1979, 14 (2), 165-170.

Non-Patent Document 3: Tetrahedron Lett., 1984, 25 (8), 835-838.

Disclosure of the invention

Problems to be solved by the invention

[0009] In view of the above situation, the present invention provides a process for producing 1-halo-3-aryl-propanones that can be easily and efficiently carried out on a commercial scale at low cost and easily available raw materials. For the purpose.

Means for solving the problem

As a result of intensive studies, the present inventors have reacted enolate prepared from allylacetic acid or allylacetic acid derivative with haloacetic acid derivative, followed by treatment with acid, thereby producing 1 The inventors have found that 2-propanones can be easily produced, and have completed the present invention.

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

[0012] [Chemical 4]

(In the formula, Ar represents an aryl group having 6 to 20 carbon atoms which may have a substituent, or a heteroaryl group having 3 to 15 carbon atoms which may have a substituent.) And the general formula (2)

[0014] [Chemical 5]

[0015] (wherein X ¹ represents a halogen atom and L represents a leaving group) is reacted with a haloacetic acid derivative, followed by treatment with an acid, 3):

[0016] [Chemical 6]

[0017] (In the formula, Ar and X ¹ are the same as described above).

The invention's effect

[0018] According to the present invention, 1 halo 3 aryl 2 propanones can be easily and efficiently produced on a commercial scale from inexpensive and readily available phenylacetic acid derivatives and haloacetic acid derivatives.

BEST MODE FOR CARRYING OUT THE INVENTION

[0019] First, the raw materials and products used in the present invention will be described.

The enolate which is the raw material of the present invention has the general formula (1):

[0020] [Chemical 7]

[0021] Here, Ar is an aryl group having 6 to 20 carbon atoms which may have a substituent, or The C3-C15 heteroaryl group which may have a substituent is represented. Examples of the aryl group include a phenyl group, a naphthyl group, and a biphenyl group, and examples of the heteroaryl group include a pyridyl group, a furanyl group, a cheenyl group, a pyrrolyl group, an oxazolyl group, and an isoxazolyl group. , Pyrazolyl group, benzofuranyl group, benzothiazolyl group, or indolyl group.

[0022] Examples of the substituent for 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; —Alkylamino groups having 1 to 12 carbon atoms such as butylamino groups; Dialkylamino groups having 1 to 12 carbon atoms such as dimethylamino groups and di nbutylamino groups; Aralkylamino groups having 7 to 12 carbon atoms such as benzylamino groups; Dibenzylamino groups and the like A dialkylamino group having 7 to 12 carbon atoms; an alkylsulfolumino group having 1 to 12 carbon atoms such as a methanesulfo-lamino group; a sulfonic acid group; a sulfonamide group; an azido group; a trifluoromethyl group; a carboxyl group; A C1-12 acyl group such as a group; a 7-12 carbon atom group such as a benzoyl group; a hydroxyl group; a methoxy group, a n-butoxy group, etc. An alkyloxy group having 1 to 12 carbon atoms; a aralkyloxy group having 7 to 12 carbon atoms such as a benzyloxy group; an aralkyloxy group having 6 to 12 carbon atoms such as a phenoxy group; an asiloxy group having 1 to 12 carbon atoms such as an acetyloxy group; C 7-12 allylooxy group such as benzoyloxy; C 3-12 silyloxy group such as trimethylsilyloxy group; C 1-12 alkylsulfo-loxy group such as methanesulfo-loxy group; Carbon such as methylthio group Examples thereof include alkylthio groups of 1 to 12. Among them, preferred is a halogen atom, and more preferred is a chlorine atom. A preferred example of the number of substituents is 0 to 3.

[0023] Ar is preferably a phenyl group substituted by a halogen atom !, a aryl group having 6 to 20 carbon atoms, or a four-hole phenyl group.

[0024] Aryl acetic acid used to prepare the enolate is represented by the general formula (4):

ArCH CO H (4)

twenty two

It is represented by Here, Ar is the same as described in the general formula (1).

[0025] Further, the allyl acetic acid derivative used to prepare the enolate is represented by the general formula ( (ArCH CO) M ¹ (5)

2 2 n

It is represented by Here, Ar is the same as described in the general formula (1). M ¹ represents a metal, a trialkylsilyl group, or ammonium, and n represents an integer of 1 to 3. Specific examples of M ¹ include, for example, alkali metals such as lithium, sodium, potassium, or cesium; alkaline earth metals such as magnesium or calcium; metals such as aluminum, zinc, or copper; trimethylsilyl groups, and triethylsilyl groups. Or a trialkylsilyl group such as tert-butyldimethylsilyl group; an ammonia such as tetramethylammonium, tetran-butylammonium, or benzyltrimethylammonium.

[0026] Further, as n, for example, M ¹ is ^{1 in the case} of the above alkali metal; copper; trialkylsilyl group; ammonium; M ¹ is 2 in the case of the above alkaline earth metal; copper or zinc. When M ¹ is aluminum, it becomes 3. Preferably, M ¹ is an alkali metal such as lithium, sodium, potassium, or cesium, n is a force of 1, or M ¹ is an alkaline earth metal such as magnesium or calcium, and n is 2. is there. More preferably, M ¹ is lithium, sodium or potassium, and n is 1.

[0027] Regarding the acquisition of the compound (5), for example, the compound (4) and an alkali metal hydroxide, an alkali metal hydrogen carbonate, an alkali metal carbonate, an alkaline earth metal hydroxide, an alkali It can be easily prepared by reacting an earth metal carbonate, copper hydroxide, zinc hydroxide, or hydroxyaluminum hydroxide.

[0028] Another allyl acetic acid derivative used for preparing the enolate is represented by the general formula (6):

ArCH CO M ² X ² (6)

twenty two

It is represented by Here, Ar is the same as described in the general formula (1). M ² represents a metal, and X 2 represents a halogen atom. Specifically, M ² is, for example, an alkaline earth metal such as magnesium or calcium, or zinc, and is preferably magnesium. X ² is specifically a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and preferably a chlorine atom.

[0029] For obtaining the compound (6), for example, the compound (4) is reacted with an alkaline earth metal halide by the method described in WO2003Z054034. Can be easily prepared.

[0030] Next, the haloacetic acid derivative as the other starting material is represented by the general formula (2):

[0031] [Chemical 8]

[0032] Here, X ¹ represents a halogen atom, and specific examples include a fluorine atom, a chlorine atom, an odor atom, and an iodine atom. Preferably it is a chlorine atom.

[0033] L represents a leaving group and is not particularly limited. Specifically, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; a methanesulfonyloxy group, a p-toluenesulfo group. Sulfoxy groups such as -loxy group, trifluoromethanesulfo-roxy group; methoxycarbonyloxy group, ethoxycarbonyloxy group, isopropoxy group, carbon atoms such as l-loxy group, tert-butoxycarboloxy group Alkoxycarbonyloxy group of -5; benzyloxycarboxoxy group; phenoxycarboxoxy group; 1 imidazolyl group; methoxy group, ethoxy group, n propoxy group, isopropoxy group, n-butoxy group, sec butoxy group, tert alkoxy group having 1 to 5 carbon atoms such as butoxy group; buroxy group; phenoxy group; chloroacetoxy group; Roiruokishi group; Mechiruchi O radical, n Puchiruchio group alkylthio group of 1 to 5 carbon atoms; carbon number 6 to such phenylene Lucio group: Ariruchio group LO like. Preferred are alkoxy groups having 1 to 5 carbon atoms such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n butoxy group, sec butoxy group, and tert butoxy group; vinyloxy group; phenoxy group, and more preferable. Or an alkoxy group having 1 to 5 carbon atoms such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec butoxy group, and a tert butoxy group.

[0034] Next, the product of the present invention, 1 halo 3 aryl 2 propanone, has the general formula

(3):

[0035] [Chemical 9]

[0036] Here, Ar is the same as the description in the general formula (1), and X ¹ is the same as the description in the general formula (2).

[0037] Next, the production method of the present invention will be described.

In the present invention, the general formula (1):

[0038] [Chemical 10]

[0039] ヱ nolate represented by the general formula (2)

[0040] [Chemical 11]

[0041] By reacting the haloacetic acid derivative represented by the following formula, followed by treatment with an acid, the compound represented by the above formula (3) can be produced.

Here, the enolate represented by the general formula (1) is prepared by a known method, for example, by reacting an α-roaryl acetic acid derivative with a zero-valent metal such as lithium, sodium, magnesium, or zinc. In the present invention, the general formula (4):

ArCH CO H (4)

twenty two

Aryl acetic acid represented by the general formula (5): (ArCH CO) M ¹ (5)

2 2 n

Aryl acetic acid derivatives represented by the general formula (6):

ArCH CO M ² X ² (6)

twenty two

It can be prepared from an aryl acetate derivative represented by

[0043] Here, the base to be used is not particularly limited. For example, an organic lithium reagent such as methyl lithium, n-butyl lithium, sec butyl lithium, tert butyl lithium, or phenol lithium; sodium amide, potassium amide, Alkali metal amides such as lithium diisopropylamide, lithium hexamethyldisilazide, sodium diisopropylamide, sodium hexamethyldisilazide, or potassium hexamethyldisilazide; n-butylmagnesium chloride, tert-butylmagnesium chloride, n-butyl bromide Grignard reagents such as magnesium, tert-butylmagnesium bromide, phenolmagnesium bromide, or tert-butylmagnesium iodide; magnesium chloride diisopropylamide, magnesium diisopropylamide bromide, etc. Halomagnesium amides; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide Etc. Preferred is lithium diisopropylamide, n-butyllithium, magnesium diisopropylamide, tertbutylmagnesium chloride, or sodium hydride, and more preferred is tert-butylmagnesium chloride. These may be used alone or in combination of two or more.

[0044] The amount of the base used is preferably 1 to 10 times the molar amount of the allylic acetic acid or allylic acetic acid derivative represented by the general formula (4), (5), or (6), More preferably, the molar amount is 1 to 3 times.

[0045] The order of addition in this reaction is preferably such that the base can be held in the solution of allylic acetic acid or allylic acetic acid derivative represented by the general formula (4), (5), or (6), or The enolate solution represented by the general formula (1) can be prepared by adding the allylic acetic acid or the allylic acetic acid derivative represented by the general formula (4), (5), or (6) to the above solution.

[0046] Solvents used at this time are, for example, tetrahydrofuran, jetyl ether, 1, 4- Ether solvents such as dioxane and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; aliphatic hydrocarbon solvents such as pentane, hexane, heptane and methylcyclohexane; methylene chloride, 1, 2- Halogen solvents such as dichloroethane and black benzene; Amide solvents such as N, N-dimethylacetamide; Urea solvents such as dimethylpropylene urea; Phosphonic acid triamide solvents such as hexamethinorephosphonic acid triamide Can be used. Preferably, tetrahydrofuran, toluene, hexane and the like are used. These may be used alone or in combination of two or more. When two or more kinds are used in combination, the mixing ratio is not particularly limited. The amount of the reaction solvent to be used is preferably 50 times or less, more preferably 5 to 20 times the weight of the enolate (4), (5) or (6).

[0047] Preferably, the reaction temperature for preparing the enolate is also from the viewpoint of yield improvement-70 ° C ~: LOO ° C, more preferably no ultra-low temperature reaction equipment-20 ° C-50 ° C range.

[0048] The reaction time for preparing the enolate is preferably from 5 minutes to 2 minutes from the viewpoint of yield improvement.

4 hours, more preferably 30 minutes to 5 hours.

[0049] Next, an enolate represented by the above general formula (1) and a haloacetic acid derivative represented by the above general formula (2) obtained as described above or by other known methods are used. React. In that case, the reaction may be carried out by adding the haloacetic acid derivative to the enolate solution or by adding the enolate solution to the haloacetic acid derivative solution.

[0050] The amount of the haloacetic acid derivative used in this reaction is preferably relative to the enolate.

0.5 to 10 times the molar amount, more preferably 1 to 3 times the molar amount.

[0051] The reaction solvent for this reaction may be the same as or different from the solvent used at the time of forming the enolate, but the reaction solvent at the time of forming the enolate is generally used as it is. .

[0052] Examples of the reaction solvent for this reaction include ether solvents such as tetrahydrofuran, jetyl ether, 1,4-dioxane, and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; Aliphatic hydrocarbon solvents such as xane, heptane, methylcyclohexane; methylene chloride, 1,2-dichloroethane, black benzene Halogen solvents such as N; N amide solvents such as dimethylacetamide; urea solvents such as dimethylpropylene urea; phosphonic acid triamide solvents such as hexamethinorephosphonic acid triamide.

[0053] Preferably, tetrahydrofuran, toluene, hexane and the like can be mentioned. 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 use amount of the reaction solvent is preferably 50 times or less, more preferably 5 to 20 times the weight of the enolate represented by the general formula (1).

[0054] This reaction is characterized in that it can be carried out at a reaction temperature of 20 ° C or higher, and does not require an ultra-low temperature reaction facility. From the viewpoint of improving yield, it is more preferable to carry out at 20 ° C to 50 ° C.

[0055] The reaction time of this reaction is preferably 5 minutes to 24 hours, and more preferably 30 minutes to 5 hours, from the viewpoint of improving the yield.

[0056] Next, by treating the reaction mixture with an acid, 1 halo represented by the general formula (3)

It can be 3 reels or 2 propanones. At this time, the following formula (7):

[0057] [Chemical 12]

[0058] (wherein Ar and X ¹ are the same as defined above) are formed, and this is further decarboxylated to represent the target product represented by the general formula (3) 1 Halo 3 Areal 2 — Propanones are thought to be produced.

Here, examples of the acid used include mineral acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid; carboxylic acids such as formic acid, acetic acid, propionic acid, oxalic acid, and citrate; methanesulfonate Examples thereof include sulfonic acids such as acid and p-toluenesulfonic acid, preferably hydrogen chloride, sulfuric acid, and acetic acid. More preferably, it is salty hydrogen, and hydrochloric acid which is an aqueous solution thereof is more preferable in terms of handling. The amount of the acid used is in contrast to the enolate represented by the general formula (1). The molar amount is preferably 1 to 100 times, and more preferably 1 to 10 times the molar amount.

[0060] This reaction is preferably carried out in the presence of force water that can be carried out in various solutions. The amount of water used is preferably 1 to: LOO times the weight, more preferably 5 to 30 times the weight of the acid.

[0061] Regarding the addition order of this reaction, the reaction mixture may be added to the acid or the acid aqueous solution, or the acid or the acid aqueous solution may be added to the reaction mixture. Alternatively, a method of adding an acid after first mixing the reaction mixture and water may be used.

[0062] From the viewpoint of shortening the reaction time and improving the yield, this reaction is preferably carried out at -20 ° C or higher, more preferably carried out at -20 ° C to 50 ° C.

[0063] The reaction time of this reaction is preferably 5 minutes to 24 hours, and more preferably 30 minutes to 5 hours, from the viewpoint of yield improvement.

[0064] As the treatment after the reaction, a general treatment for obtaining a reaction fluid product may be performed. For example, an extraction operation is performed by adding a general extraction solvent, for example, ethyl acetate, dimethyl ether, methylene chloride, toluene, hexane, or the like, to the reaction solution after completion of the reaction. Further, 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, or an aqueous acid solution such as an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution, and then heated under reduced pressure. The target product is obtained by distilling off the reaction solvent and the extraction solvent. The target product thus obtained has a 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.

Example

[0065] The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples.

[0066] (Example 1) 1 Chloro 3— (4 black mouth phenyl) 2 Propanone production

n-Butyllithium Z-hexane solution (1.54 mol / l) 14. 29 mL (22 mmol) was cooled to 5 ° C, and diisopropylamine 2.429 g (24 mmol) in tetrahydrofuran (10 mL) was added in 10 minutes. A solution of lithium diisopropylamide was prepared by dropwise addition. Five After stirring at ° C for 20 minutes, a tetrahydrofuran solution (20 mL) of 1.705 g (10 mmol) of 4-chloroacetic acid acetate was added dropwise thereto in 10 minutes. Further, after stirring at 5 ° C. for 20 minutes, 1.225 g (10 mmol) of chloroethyl acetate was added dropwise over 5 minutes, and further reacted at 5 ° C. for 1 hour. Subsequently, 5 mL of 35 wt% hydrochloric acid was added and stirred for 16 hours while allowing the temperature to rise naturally to room temperature. Extract 20 mL of toluene and 10 mL of water, and wash the organic layer successively with 20 mL of saturated sodium bicarbonate solution and 2 OmL of water, and then evaporate the solvent under reduced pressure to obtain 2.39 g of an orange oil. Obtained . When 10 mL of hexane is added, crystals are precipitated. After stirring at 5 ° C for 30 minutes, the crystals are filtered off under reduced pressure and dried under vacuum to give 1 Chloro-3- (4 black mouth phenol) -2 Propanone was obtained as white crystals (yield: 26%).

— NMR (CDC1, 400MHz / ppm): δ 3. 88 (2Η, s), 4.11 (2H, s), 7. 15 (

Three

2H, d), 7.32 (2H, d)

[0067] (Example 2) 1—Black mouth 3— (4 Black mouth phenyl) 2 Propanone steelmaking

4 A solution of 705 g (10 mmol) in tetrahydrofuran (20 mL) was cooled to 5 ° C, and then n-butyllithium Z-hexane solution (1.54 mol / l) 14. 29 mL (22 mmol) was added dropwise in 10 minutes. Further, after stirring at 5 ° C for 20 minutes, 1.225 g (10 mmol) of black ethyl acetate was added dropwise over 5 minutes, and further reacted at 5 ° C for 1 hour. To this, 5 mL of 35 wt% hydrochloric acid was added, and the mixture was naturally warmed to room temperature and stirred for 1 hour. Extraction was performed by adding 20 mL of toluene and 10 mL of water, and the organic layer was further washed successively with 20 mL of saturated sodium bicarbonate solution and 20 mL of water, and the solvent was distilled off under reduced pressure to obtain 1.4655 g of a red oily substance. . This was analyzed by high performance liquid chromatography (column: Shiseido CAPCELLPAK C18 4.6 X 250 mm, eluent: acetonitrile / phosphate buffer = 1/1, flow rate: 1. OmL / min., Column temperature: 40 ° C As a result of quantitative analysis using a detector (UV210 nm), the yield of the target 1-clog 3-(4 -black-foul) 1 -2 propanone was 28%.

[Example 3] 1 Chloro-3- (4-chlorophenyl) 2 Production of propanone

60 weight ^_0/0 tetrahydrofuran suspension of sodium hydride 400 mg (10 mmol) of (10 m L) was cooled to 5 ° C, where the 4 black port Hue - added Caro Le acetate 1. 705 g of (10 mmol) in 10 min did. Further, n-butyllithium Z-hexane solution (1.54 mol / l) 7. 14 mL (l lmmol) was added dropwise over 5 minutes, and the mixture was stirred at 5 ° C for 20 minutes, followed by 1.225 g (10 mmol) In 5 minutes The reaction was carried out dropwise and further after 5 hours at 5 ° C. To this, 5 mL of 35% by weight hydrochloric acid was added, and the mixture was naturally warmed to room temperature and stirred for 1 hour. Extracted with 20 mL of toluene and 10 mL of water, and the organic layer was further washed successively with 20 mL of saturated sodium bicarbonate solution and 20 mL of water, and the solvent was distilled off under reduced pressure to obtain 1.4622 g of a yellow oil. It was. As a result of quantitative analysis of this product by the method described in Example 2, the yield of the target 1-black mouth 3- (4-black mouth fiber) -2 propanone was 20%.

[Example 4] 1—Black mouth 3— (4 Black mouth phenyl) 2 Production of propanone

4 A solution of 705g (10mmol) in tetrahydrofuran (20mL) was cooled to 5 ° C, and tert-butylmagnesium chloride / toluene / tetrahydrofuran solution (1.6mol / kg) 13.8g (22 mmol) was added dropwise over 5 minutes. After further stirring at 5 ° C. for 30 minutes, 1.225 g (10 mmol) of chloroethyl acetate was added dropwise over 5 minutes, and the reaction was further carried out at 5 ° C. for 1 hour. Here, 5 mL of 35 wt% hydrochloric acid was added, and the mixture was naturally warmed to room temperature and stirred for 1 hour. Extracted with 20 mL of toluene and 10 mL of water, and the organic layer was further washed successively with 20 mL of saturated sodium bicarbonate solution and 20 mL of water, and the solvent was distilled off under reduced pressure to obtain a colorless oily substance. Got. This was quantitatively analyzed by the method described in Example 2, and as a result, the yield of the target 1-black mouth 1- (4-black mouth phenol) 2 propanone was 57%.

[Example 5] 1—Black mouth 3— (4 Black mouth phenyl) 2 Propanone steelmaking

4 A solution of 705 g (10 mmol) in tetrahydrofuran (20 mL) was cooled to 5 ° C, and tert-butylmagnesium chloride / toluene / tetrahydrofuran solution (1.6 mol / kg) 13. 8 g (22 mmol) was added dropwise over 5 minutes. After further stirring at 5 ° C. for 30 minutes, 85 g (10 mmol) of methyl acetate 1.O was added dropwise over 5 minutes, and the reaction was further carried out after 5 hours at 5 ° C. To this was added 5 mL of 35 wt% hydrochloric acid, and the mixture was allowed to warm to room temperature and stirred for 1 hour. Extract with 20 mL of toluene and 10 mL of water, and wash the organic layer successively with 20 mL of saturated sodium bicarbonate solution and 20 mL of water, and evaporate the solvent under reduced pressure to give 1. 2609 g of colorless oil. It was. The product was quantitatively analyzed by the method described in Example 2. As a result, the yield of the target 1-black mouth 1- (4 black mouth) 2 propanone was 35%.

(Example 6) 1 Chloro-3- (4-chlorophenyl) 2 Production of propanone

4 Black-mouthed phenylacetic acid 1. Add 705 g (10 mmol) in tetrahydrofuran (20 mL) at 5 ° C. Then, 13.8 g (22 mmol) of a tert-butylmagnesium chloride / toluene / tetrahydrofuran solution (1.6 mol / kg) was added dropwise over 5 minutes. After further stirring at 5 ° C for 30 minutes, 1.215 g (10 mmol) of black acetate butyl acetate was added dropwise over 5 minutes, and the reaction was further carried out after 5 hours at 5 ° C. Here, 5 mL of 35 wt% hydrochloric acid was added, and the mixture was naturally warmed to room temperature and stirred for 1 hour. Extract 20 mL toluene and 10 mL water, wash the organic layer successively with 20 mL saturated sodium bicarbonate solution and 20 mL water, and evaporate the solvent under reduced pressure. Obtained. As a result of quantitative analysis of this product by the method described in Example 2, the yield of the target 1-black mouth 1- (4-black mouth phenol) 2 propanone was 16%.

(Example 7) 1 Chloro 3— (4 black mouth phenyl) 2 Production of propanone

4 Sodium chloroacetate 1.926 g (10 mmol), tetrahydrofuran (10 mL), toluene (10 mL) slurry solution is cooled to 5 ° C, and then tert-butylmagnesium chloride Z toluene Z tetrahydrofuran solution ( 1. 6 mol / kg) 7.3 g (12 mmol) was added dropwise over 5 minutes. After further stirring at 5 ° C. for 30 minutes, 1.225 g (10 mmol) of chloroethyl acetate was added dropwise over 5 minutes, and the reaction was further carried out at 5 ° C. for 1 hour. To this, 5 mL of 35 wt% hydrochloric acid was added, and the mixture was naturally warmed to room temperature and stirred for 1 hour. Toluene 10mL and water 10mL were extracted, and the organic layer was further washed successively with saturated sodium bicarbonate solution 20mL and water 20mL, and the solvent was distilled off under reduced pressure to obtain 1.6611g of colorless oil. . The product was quantitatively analyzed by the method described in Example 2. As a result, the yield of the target 1-chloro-3- (4-chlorophenol) 2-propanone was 10%.

Claims

Claim General formula (1)

[Chemical 1]

[Chemical 2]

(Wherein X ¹ represents a halogen atom, and L represents a leaving group). A haloacetic acid derivative represented by the general formula (3):

[Chemical 3]

(In the formula, Ar and X ¹ are the same as above.) 1 Halo 3 Carry 2 Propanone production method.

[2] The enolate represented by the formula (1) is represented by the general formula (4):

ArCH CO H (4) (Wherein Ar is the same as above), allylic acetic acid represented by the general formula (5):

(ArCH CO) M ¹ (5)

2 2 n

(Wherein Ar is the same as above, M ¹ represents a metal, a trialkylsilyl group, or ammonia, and n is an integer of 1 to 3), or general Formula (6): ArCH CO M ² X ² (6)

twenty two

(In the formula, Ar is the same as above. M ² represents a metal and X ² represents a halogen atom.) Claim

The production method according to 1.

[3] The base used for the preparation of the enolate is at least one selected from the group consisting of lithium diisopropylamide, n-butyllithium, magnesium chloride diisopropylamide, tert butylmagnesium chloride and sodium hydride. Item 3. The manufacturing method according to Item 2.

[4] The process according to claim 2, wherein the basic force used for the preparation of the enolate is tert-butylmagnesium chloride.

[5] The production method according to any one of [2] to [4], wherein allylic acetic acid represented by the formula (4) is used for the preparation of the enolate.

[6] the preparation of the enolate, the formula (5) M ¹ is Ri lithium, sodium, or potassium der in, which comprises using the Ariru acid derivatives n is 1, one of the claims 2 to 4 The manufacturing method of crab.

[7] the preparation of the enolate, the formula (6) in a M ² is magnesium, which comprises using the Ariru acid derivative X ² is a chlorine atom, according to claim 2 Manufacturing method.

[8] The production method according to any one of [1] to [7], wherein the acid used in the treatment with the acid is hydrochloric acid.

[9] The reaction temperature according to any one of claims 1 to 8, wherein the reaction temperature when the enolate represented by the general formula (1) and the haloacetic acid derivative represented by the general formula (2) are reacted is 20 ° C or higher. The manufacturing method of crab.

[10] The production method according to any one of claims 1 to 9, wherein X ¹ is a chlorine atom, and L is an alkoxy group having 1 to 5 carbon atoms. [11] The production method according to any one of claims 1 to 10, wherein Ar is a phenol group or a 4-chlorophenol group.