WO2000075094A2 - Method for producing a halogenated acetophenone - Google Patents

Method for producing a halogenated acetophenone Download PDF

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WO2000075094A2
WO2000075094A2 PCT/JP2000/003605 JP0003605W WO0075094A2 WO 2000075094 A2 WO2000075094 A2 WO 2000075094A2 JP 0003605 W JP0003605 W JP 0003605W WO 0075094 A2 WO0075094 A2 WO 0075094A2
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gas
acetophenone
formula
reaction
chlorine gas
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PCT/JP2000/003605
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French (fr)
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WO2000075094A3 (en
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Hisayoshi Jonishi
Akihiro Kotani
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Ishihara Sangyo Kaisha, Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms

Definitions

  • the present invention relates to an industrial method for producing a specific halogenated acetophenone which is useful as an intermediate for pharmaceuticals, agricultural chemicals, etc.
  • a method for producing a dichloroacetophenone as one of halogenated acetophenones by chlorination of an acetophenone is disclosed, for example, in ORGANIC SYNTHESES COLLECTIVE VOLUME 3(1955) p.538-541, (2) J.Org. Che . ,Vol.45,No.l5,1980 p.2976-2984, (3) Bull.Chem.Soc. Jpn. , 65 (1992) p.2549-2551, or ⁇ JP-A-8- 283243.
  • References ⁇ and (2) disclose a method of reacting an acetophenone with a chlorine gas in the presence of acetic acid to obtain a dichloroacetophenone.
  • Reference (3) discloses a method of reacting an acetophenone with benzyltrimethylammonium tetrachloroiodate as a chlorinating agent to obtain a desired product.
  • reference ® discloses a method of reacting an acetophenone with a chlorine gas to obtain a dichloroacetophenone, whereby the reaction can be carried out in the absence of a solvent when the melting points of the starting material and the product are not higher than 80°C.
  • a hydrogen chloride gas produced by a side reaction new side reactions will be induced, whereby the purity and the yield of the desired product will be substantially lowered. Therefore, it has been difficult to produce a halogenated acetophenone on an industrial scale.
  • the present invention provides a method for producing a halogenated acetophenone, which comprises reacting an acetophenone of the formula (I) :
  • A is a halogen atom, an alkyl group which may be substituted, an alkoxy group which may be substituted, or a nitro group
  • R is a hydrogen atom or an alkyl group
  • n is an integer of from 0 to 2 , with a halogen, to obtain a halogenated acetophenone of the formula (II) :
  • a and n are as defined above, and B is a haloalkyl group, wherein an inert gas is supplied together with the halogen.
  • a chlorinated acetophenone is a typical compound.
  • Such a chlorinated acetophenone can be produced by reacting the acetophenone of the formula (I) with a chlorine gas, wherein an inert gas is supplied together with the chlorine gas .
  • A, R and n are as defined above, is the most typical compound.
  • substituent for the alkyl group which may be substituted and the alkoxy group which may be substituted in the definition of A in the formulae (I), (II) and (II'), a halogen atom such as fluorine, chlorine or iodine; a phenyl group; or a C ⁇ _ alkoxy group such as methoxy group, an ethoxy group or a propoxy group, may, for example, be mentioned.
  • the number of substituents may be one or more, and in a case where two or more substituents are present, they may be the same or different.
  • the halogen atom in the definition of A may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the haloalkyl group which may be substituted, in the definition of B in the formula (II) may be one having at least one of hydrogen atoms of an alkyl group substituted by a halogen atom. However, it is preferably one having at least one of hydrogen atoms of an alkyl group substituted by a chlorine atom. Most preferred is a - CC1 2 R group, wherein R is as defined above.
  • the compound of the formula (I) may be one available as a commercial product. Otherwise, it can be prepared by a method disclosed in a published literature such as JP-A-6-279346 or JP-A-10-182544.
  • the compound of the formula (I) is an acetophenone, such as, acetophenone; a chloroacetophenone such as 2 ' -chloroacetophenone, 3 ' -chloroacetophenone or 4 ' -chloroacetophenone; a dichloroacetophenone such as 2 ' , 3 ' -dichloroacetophenone, 2 ' , 4 ' -dichloroacetophenone, 2 ', 5 ' -dichloroacetophenone, 3 ', 4 ' -dichloroacetophenone or 3 ', 5 ' -dichloroacetophenone; or a bromoacetophenone such as 2 ' -bromoacetophenone, 3 ' -bromoacetophenone or 4'- bromoacetophenone; a dibromoacetophenone such as 2'3'- dibromoacetophenone
  • acetophenone a chloroacetophenone such as 2 ' -chloroacetophenone, 3'- chloroacetophenone or 4 ' -chloroacetophenone; a bromoacetophenone such as 2 ' -bromoacetophenone, 3'- bromoacetophenone or 4 ' -bromoacetophenone; a methoxyacetophenone such as 2 ' -methoxyacetophenone, 3'- methoxyacetophenone or 4 ' -methoxyacetophenone; a methylacetophenone such as 2 ' -methylacetophenone, 3'- methylacetophenone or 4 ' -methylacetophenone; an ethylacetophenone such as 2 ' -ethylacetophenone, 3'- ethylacetophenone or 4 ' -ethylacetophenone; propylacetophenone; butylace
  • acetophenone 3 ' -chloroacetophenone, 4'- chloroacetophenone, 3 ' -bromoacetophenone, 4'- bromoacetophenon, 3 ' -methylacetophenone, 4'- methylacetophenone, 3 ' -ethylacetophenone or 4 ' - ethylacetophenone .
  • Specific examples for the compound of the formula (II) as the desired product of the method of the present invention may be halogenated acetophenones corresponding to the above specific examples for the compound of the formula (I) .
  • the alkyl group represented by -CHR in the acetophenone of the formula (I) will be halogenated preferentially from a hydrogen atom located close to the carbonyl group.
  • a 2-haloacetophenone such as 2-chloro- 4 ' -methyacetophenone; a 2 , 2-dihaloacetophenone such as 2 , 2-dichloro-4 ' -methylacetophenone; and a 2,2,2- trihaloacetophenone such as 2 , 2 , 2-trichloro-4 ' - methylacetophenone, may, for example, be mentioned.
  • dichloroacetophenones of the above formula (II') are most typical compounds.
  • halogen to be used in the method of the present invention it is preferred to employ a chlorine gas.
  • the chlorine gas is not particularly limited so long as it is industrially available, but it is preferably dried.
  • the chlorine gas is usually used as bubbled in the solution for reaction.
  • the chlorine gas is used usually in an amount of from 0.8 to 4.0 mol per mol of the compound of the formula (I) .
  • the inert gas to be used for the reaction may be any gas so long as it is inert to the halogenation reaction, such as nitrogen, air, argon or helium.
  • the inert gas may be supplied into the reaction system as mixed with the chlorine gas or independently from the chlorine gas .
  • both gases may be supplied into the reaction system simultaneously or suitably alternatively so that both gases will be supplied.
  • the reaction can be carried out by a suitable combination of the method of supplying a mixed gas of the inert gas and the chlorine gas into the reaction system and a method of supplying the inert gas and the chlorine gas independently into the reaction system.
  • the amount of the inert gas to be supplied is from 0.1 to 50 mol times the amount of the chlorine gas to be supplied.
  • a dichloroacetophenone of the formula (II') is to be produced, it is supplied in an amount of from 0.1 to 10 mol times, preferably from 0.5 to 5.0 mol times, the amount of the chlorine gas to be supplied.
  • the reaction temperature for the method of the present invention is from 20 to 100°C in a case where a chlorine gas is employed as the halogen. Further, during the reaction, it is necessary to maintain a predetermined reaction temperature. Particularly when a dichloroacetophenone of the formula (II') is to be produced, the reaction temperature is from 20 to 80°C, preferably from 40 to 70°C.
  • the reaction time in such a case can not generally be defined, since it is affected by the supply rate of the chlorine gas, but it is usually from 2 to 30 hours.
  • the formed hydrogen chloride gas can be removed from the system, and it is possible to prevent side reactions of the hydrogen chloride gas with the starting material, with an intermediate product or with the desired product. Accordingly, it is possible to produce a dichloroacetophenone of high purity in good yield and in a large amount.
  • the reaction in the method of the present invention can be carried out in the absence of a solvent or by means of a solvent inert to the halogenation. It is preferred to carry out the reaction in the absence of a solvent.
  • an alcohol such as methanol, ethanol or propanol
  • an organic acid such as formic acid or acetic acid
  • a halogenated alkylene such as methylene dichloride or ethylene dichloride
  • the compound of the formula (II) as the desired compound may be used as it is without isolation for a reaction to produce a pharmaceutical, an agricultural chemical or an intermediate thereof.
  • a necessary compound e.g. a dichloroacetophenone may be isolated by a usual method from the reaction system containing the compound of the formula (II) and, if necessary, may be purified by distillation or recrystallization. In either case, the interior of the system after completion of the reaction may be substituted by an inert gas, as the case requires.
  • a method for producing a chlorinated acetophenone of the formula (II) which comprises reacting an acetophenone of the formula (I) with a chlorine gas, wherein an inert gas is supplied together with the chlorine gas.
  • the amount of the reaction product thereby obtained was 3035 g.
  • This product was analyzed, whereby the purity of 2 , 2-dichloro- 4 ' -methylacetophenone was 91.6%, and the yield of 2,2- dichloro-4 ' -methylacetophenone to the starting material was 91.4%.
  • reaction product was analyzed by liquid chromatography and found to be a HPLC composition comprising 92.9% of 2 , 2-dichloro- ' -methylacetophenone, 0.6% of 2-chloro-4' -methylacetophenone, 2.0% of 2,2,2- trichloro-4 ' -methylacetophenone and 0.5% of 2 , 2-dichloro- 4 ' -chloromethylacetophenone .
  • EXAMPLE 2 Into a 5 liter four necked flask equipped with two gas supplying tubes, a reflux condenser, a thermometer and a stirrer, 2010 g of ' -methylacetophenone was charged, and heating was carried out so that the reaction temperature in the system was maintained to be from 45 to 55°C. From one gas supplying tube, a nitrogen gas (0.107 mol/min) was supplied, and 30 minutes later, from another gas supplying tube, a chlorine gas (0.0674 mol/min) was supplied over a period of 10 hours, while maintaining the above mentioned reaction temperature (provided that the nitrogen gas was stopped upon expiration of 7 hours) . Then, supply of the chlorine was stopped, and nitrogen bubbling was carried out for one hour.
  • a nitrogen gas (0.107 mol/min) was supplied, and 30 minutes later, from another gas supplying tube, a chlorine gas (0.0674 mol/min) was supplied over a period of 10 hours, while maintaining the above mentioned reaction temperature (provided that the nitrogen
  • the amount of the reaction product thereby obtained was 3064 g.
  • This product was analyzed, whereby the purity of 2 , 2-dichloro- 4 ' -methylacetophenone was 91.5%, and the yield of 2,2- dichloro-4 ' -methylacetophenone to the starting material was 92.1%.
  • reaction product was analyzed by liquid chromatography and found to have a HPLC composition comprising 94.3% of 2 , 2-dichloro-4 ' - methylacetophenone, 0.1% of 2-chloro-4'- methylacetophenone, 1.7% of 2 , 2 , 2-trichloro-4 ' - methylacetophenone and 0.5% of 2 , 2-dichloro-4 ' - chloromethylacetophenone .
  • HPLC composition comprising 94.3% of 2 , 2-dichloro-4 ' - methylacetophenone, 0.1% of 2-chloro-4'- methylacetophenone, 1.7% of 2 , 2 , 2-trichloro-4 ' - methylacetophenone and 0.5% of 2 , 2-dichloro-4 ' - chloromethylacetophenone .
  • the amount of the reaction product thereby obtained was 811 g.
  • This product was analyzed, whereby the purity of 2 , 2-dichloro-4 ' -methylacetophenone was 92.0%, and the yield of 2 , 2-dichloro-4 ' - methylacetophenone to the starting material was 91.8%.
  • the reaction product was analyzed by liquid chromatography and found to have a HPLC composition comprising 92.0% of 2 , 2-dichloro-4 ' -methylacetophenone, 2.8% of 2-chloro-4' -methylacetophenone, 2.6% of 2,2,2- trichloro-4 ' -methylacetophenone and 0.1% of 2 , 2-dichloro- 4 ' -chloromethylacetophenone .

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides a method for producing a specific acetophenone which is useful as an intermediate for pharmaceuticals or agricultural chemicals, i.e. a method for producing a halogenated acetophenone, which comprises reacting an acetophenone with a halogen, wherein an inert gas is supplied together with the halogen.

Description

DESCRIPTION METHOD FOR PRODUCING A HALOGENATED ACETOPHENONE TECHNICAL FIELD
The present invention relates to an industrial method for producing a specific halogenated acetophenone which is useful as an intermediate for pharmaceuticals, agricultural chemicals, etc. BACKGROUND ART
A method for producing a dichloroacetophenone as one of halogenated acetophenones by chlorination of an acetophenone, is disclosed, for example, in ORGANIC SYNTHESES COLLECTIVE VOLUME 3(1955) p.538-541, (2) J.Org. Che . ,Vol.45,No.l5,1980 p.2976-2984, (3) Bull.Chem.Soc. Jpn. , 65 (1992) p.2549-2551, or © JP-A-8- 283243. References φ and (2) disclose a method of reacting an acetophenone with a chlorine gas in the presence of acetic acid to obtain a dichloroacetophenone. Reference (3) discloses a method of reacting an acetophenone with benzyltrimethylammonium tetrachloroiodate as a chlorinating agent to obtain a desired product. Further, reference ® discloses a method of reacting an acetophenone with a chlorine gas to obtain a dichloroacetophenone, whereby the reaction can be carried out in the absence of a solvent when the melting points of the starting material and the product are not higher than 80°C. However, if a large amount of an acetophenone is chlorinated over a long period of time by these methods, by a hydrogen chloride gas produced by a side reaction, new side reactions will be induced, whereby the purity and the yield of the desired product will be substantially lowered. Therefore, it has been difficult to produce a halogenated acetophenone on an industrial scale. DISCLOSURE OF THE INVENTION
It is an object of the present invention to provide a method for producing a specific halogenated acetophenone efficiently on an industrial scale.
The present invention provides a method for producing a halogenated acetophenone, which comprises reacting an acetophenone of the formula (I) :
Figure imgf000003_0001
wherein A is a halogen atom, an alkyl group which may be substituted, an alkoxy group which may be substituted, or a nitro group, R is a hydrogen atom or an alkyl group, and n is an integer of from 0 to 2 , with a halogen, to obtain a halogenated acetophenone of the formula (II) :
Figure imgf000003_0002
wherein A and n are as defined above, and B is a haloalkyl group, wherein an inert gas is supplied together with the halogen. Among halogenated acetophenones of the formula (II), a chlorinated acetophenone is a typical compound. Such a chlorinated acetophenone can be produced by reacting the acetophenone of the formula (I) with a chlorine gas, wherein an inert gas is supplied together with the chlorine gas .
Among such chlorinated acetophenones, a dichloroacetophenone of the formula (II'):
Figure imgf000004_0001
wherein A, R and n are as defined above, is the most typical compound. As the substituent for the alkyl group which may be substituted and the alkoxy group which may be substituted, in the definition of A in the formulae (I), (II) and (II'), a halogen atom such as fluorine, chlorine or iodine; a phenyl group; or a Cι_ alkoxy group such as methoxy group, an ethoxy group or a propoxy group, may, for example, be mentioned. The number of substituents may be one or more, and in a case where two or more substituents are present, they may be the same or different. The halogen atom in the definition of A may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The haloalkyl group which may be substituted, in the definition of B in the formula (II) , may be one having at least one of hydrogen atoms of an alkyl group substituted by a halogen atom. However, it is preferably one having at least one of hydrogen atoms of an alkyl group substituted by a chlorine atom. Most preferred is a - CC12R group, wherein R is as defined above. The compound of the formula (I) may be one available as a commercial product. Otherwise, it can be prepared by a method disclosed in a published literature such as JP-A-6-279346 or JP-A-10-182544.
Specifically, the compound of the formula (I) is an acetophenone, such as, acetophenone; a chloroacetophenone such as 2 ' -chloroacetophenone, 3 ' -chloroacetophenone or 4 ' -chloroacetophenone; a dichloroacetophenone such as 2 ' , 3 ' -dichloroacetophenone, 2 ' , 4 ' -dichloroacetophenone, 2 ', 5 ' -dichloroacetophenone, 3 ', 4 ' -dichloroacetophenone or 3 ', 5 ' -dichloroacetophenone; or a bromoacetophenone such as 2 ' -bromoacetophenone, 3 ' -bromoacetophenone or 4'- bromoacetophenone; a dibromoacetophenone such as 2'3'- dibromoacetophenone , 2 ' 4 ' -dibromoacetophenone, 2 ' 5 ' - dibromoacetophenone, 3 ' 4 ' -dibromoacetophenone or 3'5'- dibromoacetophenone; a methylacetophenone such as 2'- ethy1acetophenone, 3 ' -methylacetophenone or 4'- methylacetophenone; a dimethylacetophenone such as 2 ',3'- dimethylacetophenone, 2 ', 4 ' -dimethylacetophenone, 2 ',5'- dimethylacetophenone, 3 ', 4 ' -dimethylacetophenone or 3 ', 5 ' -dimethylacetophenone; an ethylacetophenone such as 2 ' -ethylacetophenone, 3 ' -ethylacetophenone or 4'- ethylacetophenone; a diethylacetophenone such as 2 ',3'- diethylacetophenone, 2 ' , 4 ' -diethylacetophenone, 2',5'- diethylacetophenone, 3 ', 4 ' -diethylacetophenone or 3 ',5'- diethylacetophenone; a methoxyacetophenone such as 2'- methoxyacetophenone, 3 ' -methoxyacetophenone or 4'- methoxyacetophenone; a dimethoxyacetophenone such as
2 ' , 3 ' -dimethoxyacetophenone, 2 ' , 4 ' -dimethoxyacetophenone, 2 ' , 5 ' -dimethoxyacetophenone, 3 ' , 4 ' -dimethoxyacetophenone or 3 ', 5 ' -dimethoxyacetophenone; a chlorophenylethylketone such as 2 ' -chlorophenylethylketone, 3'- chlorophenylethylketone or 4 ' -chlorophenylethylketone; a dichlorophenylethylketone such as 2 ' , 3 ' - dichlorophenylethylketone, 2 ' , 4 ' - dichlorophenylethylketone, 2 ' , 5 ' - dichlorophenylethylketone , 3 ' , 4 ' - dichlorophenylethylketone or 3 ' , 5 ' - dichlorophenylethylketone; a chlorophenyl-i-propylketone such as 2 ' -chlorophenyl-i-propylketone, 3 ' -chlorophenyl- i-propylketone or 4 ' -chlorophenyl-i-propylketone; a dichlorophenyl-i-propylketone such as 2 ',3'- dichlorophenyl-i-propylketone, 2 ', 4 ' -dichlorophenyl-i- propylketone, 2 ', 5 ' -dichlorophenyl-i-propylketone, 3 ',4'- dichlorophenyl-i-propylketone or 3 ' , 5 ' -dichlorophenyl-i- propylketone; a chlorophenyl-n-propylketone such as 2 ' - chlorophenyl-n-propylketone, 3 ' -chlorophenyl-n- propylketone or 4 ' -chlorophenyl-n-propylketone; a dichlorophenyl-n-propylketone such as 2 ',3'- dichlorophenyl-n-propylketone, 2 ' , 4 ' -dichlorophenyl-n- propylketone, 2 ' , 5 ' -dichlorophenyl-n-propylketone, 3',4'- dichlorophenyl-n-propylketone or 3 ' , 5 ' -dichlorophenyl-n- propylketone; a chlorophenylpentylketone such as 2'- chlorophenylpentylketone, 3 ' -chlorophenylpentylketone or 4 ' -chlorophenylpentylketone; a dichlorophenylpentylketone such as 2 ', 3 ' -dichlorophenylpentylketone, 2 ',4'- dichlorophenylpentylketone, 2 ' , 5 ' - dichlorophenylpentylketone , 3 ' , 4 ' - dichlorophenylpentylketone or 3 ' , 5 ' - dichlorophenylpentylketone; a nitroacetophenone such as 2 ' -nitroacetophenone or a 3 ' -nitroacetophenone; propylacetophenone ; butylacetophenone ; pentylacetophenone; hexylacetophenone; propiophenone; methylpropiophenone ; ethylpropiophenone ; propylpropiophenone; butylpropiophenone ; pentylpropiophenone; hexylpropiophenone; butyrophenone or valerophenone . Among them, preferred is acetophenone, a chloroacetophenone such as 2 ' -chloroacetophenone, 3'- chloroacetophenone or 4 ' -chloroacetophenone; a bromoacetophenone such as 2 ' -bromoacetophenone, 3'- bromoacetophenone or 4 ' -bromoacetophenone; a methoxyacetophenone such as 2 ' -methoxyacetophenone, 3'- methoxyacetophenone or 4 ' -methoxyacetophenone; a methylacetophenone such as 2 ' -methylacetophenone, 3'- methylacetophenone or 4 ' -methylacetophenone; an ethylacetophenone such as 2 ' -ethylacetophenone, 3'- ethylacetophenone or 4 ' -ethylacetophenone; propylacetophenone; butylacetophenone; pentylacetophenone; hexylacetophenone; propiophenone; butyrophenone or valerophenone . Among them, more preferred is acetophenone, 3 ' -chloroacetophenone, 4'- chloroacetophenone, 3 ' -bromoacetophenone, 4'- bromoacetophenon, 3 ' -methylacetophenone, 4'- methylacetophenone, 3 ' -ethylacetophenone or 4 ' - ethylacetophenone .
Specific examples for the compound of the formula (II) as the desired product of the method of the present invention may be halogenated acetophenones corresponding to the above specific examples for the compound of the formula (I) . The alkyl group represented by -CHR in the acetophenone of the formula (I) will be halogenated preferentially from a hydrogen atom located close to the carbonyl group. As typical examples for the compound of the formula (II), a 2-haloacetophenone such as 2-chloro- 4 ' -methyacetophenone; a 2 , 2-dihaloacetophenone such as 2 , 2-dichloro-4 ' -methylacetophenone; and a 2,2,2- trihaloacetophenone such as 2 , 2 , 2-trichloro-4 ' - methylacetophenone, may, for example, be mentioned. Among compounds of the formula (II), dichloroacetophenones of the above formula (II') are most typical compounds. Further, as typical compounds among dichloroacetophenones of the formula (II'), 2,2- dichloroacetophenone and 2 , 2-dichloro-4 ' - methylacetophenone may, for example, be mentioned. As the halogen to be used in the method of the present invention, it is preferred to employ a chlorine gas. The chlorine gas is not particularly limited so long as it is industrially available, but it is preferably dried. The chlorine gas is usually used as bubbled in the solution for reaction. The chlorine gas is used usually in an amount of from 0.8 to 4.0 mol per mol of the compound of the formula (I) . When a dichloroacetophenone of the formula (II') is to be produced, it is particularly preferred to use the chlorine gas in an amount of from 2.0 to 3.5 mol . The inert gas to be used for the reaction may be any gas so long as it is inert to the halogenation reaction, such as nitrogen, air, argon or helium. When a chlorine gas is used as the halogen, the inert gas may be supplied into the reaction system as mixed with the chlorine gas or independently from the chlorine gas . In a case where the inert gas is supplied into the reaction system independently from the chlorine gas, both gases may be supplied into the reaction system simultaneously or suitably alternatively so that both gases will be supplied. Otherwise, the reaction can be carried out by a suitable combination of the method of supplying a mixed gas of the inert gas and the chlorine gas into the reaction system and a method of supplying the inert gas and the chlorine gas independently into the reaction system. The amount of the inert gas to be supplied, is from 0.1 to 50 mol times the amount of the chlorine gas to be supplied. Particularly when a dichloroacetophenone of the formula (II') is to be produced, it is supplied in an amount of from 0.1 to 10 mol times, preferably from 0.5 to 5.0 mol times, the amount of the chlorine gas to be supplied.
The reaction temperature for the method of the present invention is from 20 to 100°C in a case where a chlorine gas is employed as the halogen. Further, during the reaction, it is necessary to maintain a predetermined reaction temperature. Particularly when a dichloroacetophenone of the formula (II') is to be produced, the reaction temperature is from 20 to 80°C, preferably from 40 to 70°C. The reaction time in such a case can not generally be defined, since it is affected by the supply rate of the chlorine gas, but it is usually from 2 to 30 hours. As is evident from the following Examples and Comparative Examples, when an acetophenone and a chlorine gas are reacted while supplying an inert gas in accordance with the method of the present invention, the formed hydrogen chloride gas can be removed from the system, and it is possible to prevent side reactions of the hydrogen chloride gas with the starting material, with an intermediate product or with the desired product. Accordingly, it is possible to produce a dichloroacetophenone of high purity in good yield and in a large amount. The reaction in the method of the present invention can be carried out in the absence of a solvent or by means of a solvent inert to the halogenation. It is preferred to carry out the reaction in the absence of a solvent. Further, if a large amount of a solvent is employed, the production efficiency will decrease. As the solvent, an alcohol such as methanol, ethanol or propanol, an organic acid such as formic acid or acetic acid, or a halogenated alkylene such as methylene dichloride or ethylene dichloride, may be used.
To set various conditions in the method of the present invention as described in the forgoing, such as the types and amounts of the compound of the formula (I) and the desired compound of the formula (II), the type and the amount of the inert gas, the method of supplying the halogen and the inert gas, use or non-use of the solvent, and various reaction conditions, the reaction temperature and the reaction time varied depending upon the types of the compound of the formula (I) and the inert gas, it is possible to suitably select and combine them from the numerical values within usual ranges and from the numerical values within the preferred ranges, as shown above for the respective conditions.
After completion of the reaction in the method of the present invention, the compound of the formula (II) as the desired compound, may be used as it is without isolation for a reaction to produce a pharmaceutical, an agricultural chemical or an intermediate thereof. Otherwise, a necessary compound e.g. a dichloroacetophenone may be isolated by a usual method from the reaction system containing the compound of the formula (II) and, if necessary, may be purified by distillation or recrystallization. In either case, the interior of the system after completion of the reaction may be substituted by an inert gas, as the case requires. BEST MODE FOR CARRYING OUT THE INVENTION As practical embodiments of the present invention, various suitable combinations of the above mentioned various reaction conditions, such as, © the type and/or the amount of the compound of the formula (I), (D the type of the desired compound of the formula (II) , ® the amount of the halogen, © the type and/or the amount of the inert gas, © the method of supplying the halogen and the inert gas, © use or non-use of the solvent, © the reaction temperature, and ® the reaction time, may be mentioned. Some of preferred practical embodiments of the present invention will be shown below.
(1) A method for producing a chlorinated acetophenone of the formula (II) , which comprises reacting an acetophenone of the formula (I) with a chlorine gas, wherein an inert gas is supplied together with the chlorine gas.
(2) The above method for producing a chlorinated acetophenone, wherein the reaction is carried out by using the chlorine gas in an amount of from 0.8 to 4.0 mol per mol of the compound of the formula (I) .
(3) The above method for producing a chlorinated acetophenone, wherein the inert gas is supplied in an amount of from 0.1 to 50 mol times the amount of the chlorine gas .
(4) The above method for producing a chlorinated acetophenone, wherein the reaction is carried out at a reaction temperature of from 20 to 100°C. (5) The above method for producing a chlorinated acetophenone, wherein a mixed gas of the inert gas and the chlorine gas is supplied.
(6) The above method for producing a chlorinated acetophenone, wherein the inert gas is supplied independently from the chlorine gas.
(7) The above method for producing a chlorinated acetophenone, wherein the inert gas is nitrogen or dry air .
(8) The above method for producing a chlorinated acetophenone, wherein the reaction is carried out in the absence of a solvent.
(9) A method for producing a dichloroacetophenone of the formula (II'), which comprises reacting an acetophenone of the formula (I) with a chlorine gas, wherein an inert gas is supplied together with the chlorine gas.
(10) The above method for producing a dichloroacetophenone, wherein the reaction is carried out by using the chlorine gas in an amount of from 2.0 to 3.5 mol per mol of the compound of the formula (I) .
(11) The above method for producing a dichloroacetophenone, wherein the inert gas is supplied in an amount of from 0.1 to 10 mol times the amount of the chlorine gas .
(12) The above method for producing a dichloroacetophenone, wherein the inert gas is supplied in an amount of from 0.5 to 5.0 mol times the amount of the chlorine gas .
(13) The above method for producing a dichloroacetophenone, wherein the reaction is carried out at a reaction temperature of from 20 to 100°C.
(14) The above method for producing a dichloroacetophenone, wherein a mixed gas of the inert gas and the chlorine gas is supplied.
(15) The above method for producing a dichloroacetophenone, wherein the inert gas is supplied independently from the chlorine gas . (16) The above method for producing a dichloroacetophenone, wherein the inert gas is nitrogen or dry air.
(17) The above method for producing a dichloroacetophenone, wherein the reaction is carried out in the absence of a solvent.
Now, the present invention will be described in further detail with reference to Examples. However, it should be understood that the present invention is by no means restricted to such specific Examples. EXAMPLE 1
Into a 5 liter four necked flask equipped with two gas supplying tubes, a reflux condenser, a thermometer and a stirrer, 2010 g of 4 ' -methylacetophenone was charged, and heating was carried out so that the reaction temperature in the system was maintained to be from 45 to 55°C. From one gas blowing tube, a nitrogen gas (0.0719 mol/min) was supplied, and 30 minutes later, from another gas supplying tube, a chlorine gas (0.0674 mol/min) was supplied over a period of 10 hours, while maintaining the above mentioned reaction temperature (provided that the nitrogen gas was stopped upon expiration of 7 hours) . Then, supply of the chlorine was stopped, and nitrogen bubbling was carried out for one hour. The amount of the reaction product thereby obtained was 3035 g. This product was analyzed, whereby the purity of 2 , 2-dichloro- 4 ' -methylacetophenone was 91.6%, and the yield of 2,2- dichloro-4 ' -methylacetophenone to the starting material was 91.4%. Further, the reaction product was analyzed by liquid chromatography and found to be a HPLC composition comprising 92.9% of 2 , 2-dichloro- ' -methylacetophenone, 0.6% of 2-chloro-4' -methylacetophenone, 2.0% of 2,2,2- trichloro-4 ' -methylacetophenone and 0.5% of 2 , 2-dichloro- 4 ' -chloromethylacetophenone . EXAMPLE 2 Into a 5 liter four necked flask equipped with two gas supplying tubes, a reflux condenser, a thermometer and a stirrer, 2010 g of ' -methylacetophenone was charged, and heating was carried out so that the reaction temperature in the system was maintained to be from 45 to 55°C. From one gas supplying tube, a nitrogen gas (0.107 mol/min) was supplied, and 30 minutes later, from another gas supplying tube, a chlorine gas (0.0674 mol/min) was supplied over a period of 10 hours, while maintaining the above mentioned reaction temperature (provided that the nitrogen gas was stopped upon expiration of 7 hours) . Then, supply of the chlorine was stopped, and nitrogen bubbling was carried out for one hour. The amount of the reaction product thereby obtained was 3064 g. This product was analyzed, whereby the purity of 2 , 2-dichloro- 4 ' -methylacetophenone was 91.5%, and the yield of 2,2- dichloro-4 ' -methylacetophenone to the starting material was 92.1%. Further, the reaction product was analyzed by liquid chromatography and found to have a HPLC composition comprising 94.3% of 2 , 2-dichloro-4 ' - methylacetophenone, 0.1% of 2-chloro-4'- methylacetophenone, 1.7% of 2 , 2 , 2-trichloro-4 ' - methylacetophenone and 0.5% of 2 , 2-dichloro-4 ' - chloromethylacetophenone . EXAMPLE 3
Into a 1 liter four necked flask equipped with two gas supplying tubes, a reflux condenser, a thermometer and a stirrer, 536 g of 4 ' -methylacetophenone was charged, and heating was carried out so that the reaction temperature in the system was maintained to be from 60 to 70°C. From one gas supplying tube, dry air (1.08 1/min) was supplied, and 30 minutes later, from another gas supplying tube, a chlorine gas (0.0301 mol/min) was supplied over a period of 6 hours, while maintaining the above temperature (provided that the dry air was stopped upon expiration of 5 hours) . Then, supply of the chlorine was stopped, and dry air bubbling was carried out for one hour. The amount of the reaction product thereby obtained was 811 g. This product was analyzed, whereby the purity of 2 , 2-dichloro-4 ' -methylacetophenone was 92.0%, and the yield of 2 , 2-dichloro-4 ' - methylacetophenone to the starting material was 91.8%. The reaction product was analyzed by liquid chromatography and found to have a HPLC composition comprising 92.0% of 2 , 2-dichloro-4 ' -methylacetophenone, 2.8% of 2-chloro-4' -methylacetophenone, 2.6% of 2,2,2- trichloro-4 ' -methylacetophenone and 0.1% of 2 , 2-dichloro- 4 ' -chloromethylacetophenone . COMPARATIVE EXAMPLE
Into a 1 liter four necked flask equipped with a gas supplying tube, a reflux condenser, a thermometer and a stirrer, 603 g of 4 ' -methylacetophenone was charged, and heating was carried out so that the temperature in the system was maintained to be from 50 to 60°C. From the gas supplying tube, a chlorine gas (0.0197 mol/min) was supplied over a period of 10 hours. Then, supply of the chlorine was stopped, and nitrogen bubbling was carried out for one hour. The amount of the reaction product thereby obtained was 915 g. This product was analyzed, whereby the purity of 2 , 2-dichloro-4 ' -methylacetophenone was 83.4%, and the yield of 2 , 2-dichloro-4 ' - methylacetophenone to the starting material, was 83.5%. The reaction product was analyzed by liquid chromatography and found to have a HPLC composition comprising 86.4% of 2 , 2-dichloro-4 ' -methylacetophenone, 0% of 2-chloro-4 ' -methylacetophenone, 2.2% of 2,2,2- trichloro-4 ' -methylacetophenone, and 1.6% of 2,2- dichloro-4 ' -chloromethylacetophenone . INDUSTRIAL APPLICABILITY
By the present invention, a specific halogenated acetophenone which used to be difficult to produce on an industrial scale by a conventional method, can be produced efficiently.

Claims

CLAIMS 1. A method for producing a halogenated acetophenone, which comprises reacting an acetophenone of the formula
(I) :
Figure imgf000019_0001
wherein A is a halogen atom, an alkyl group which may be substituted, an alkoxy group which may be substituted, or a nitro group, R is a hydrogen atom or an alkyl group, and n is an integer of from 0 to 2 , with a halogen, to obtain a halogenated acetophenone of the formula (II) :
Figure imgf000019_0002
wherein A and n are as defined above, and B is a haloalkyl group, wherein an inert gas is supplied together with the halogen.
2. The method according to Claim 1, which comprises reacting an acetophenone of the formula (I):
Figure imgf000019_0003
wherein A is a halogen atom, an alkyl group which may be substituted, an alkoxy group which may be substituted, or a nitro group, R is a hydrogen atom or an alkyl group, and n is an integer of from 0 to 2 , with a chlorine gas, to obtain a chlorinated acetophenone of the formula (II) :
Figure imgf000020_0001
wherein A and n are as defined above, and B is a chlorine-substituted alkyl group, wherein an inert gas is supplied together with the chlorine gas.
3. The method according to Claim 2, which comprises reacting an acetophenone of the formula (I) :
Figure imgf000020_0002
wherein A is a halogen atom, an alkyl group which may be substituted, an alkoxy group which may be substituted, or a nitro group, R is a hydrogen atom or an alkyl group, and n is an integer of from 0 to 2 , with a chlorine gas, to obtain a dichloroacetophenone of the formula (II'):
Figure imgf000020_0003
wherein A, R and n are as defined above, wherein an inert gas is supplied together with the chlorine gas.
4. The method according to Claim 3, wherein the reaction is carried out by using the chlorine gas in an amount of from 2.0 to 3.5 mol per mol of the compound of the formula (I) .
5. The method according to Claim 3, wherein the inert gas is supplied in an amount of from 0.1 to 10 mol times the amount of the chlorine gas .
6. The method according to Claim 3, wherein the reaction is carried out at a reaction temperature of from 20 to 100°C.
7. The method according to Claim 3 , wherein a mixed gas of the inert gas and the chlorine gas is supplied.
8. The method according to Claim 3 , wherein the inert gas is supplied independently from the chlorine gas.
9. The method according to Claim 3 , wherein the inert gas is nitrogen or dry air.
10. The method according to Claim 3, wherein the reaction is carried out in the absence of a solvent.
PCT/JP2000/003605 1999-06-03 2000-06-02 Method for producing a halogenated acetophenone WO2000075094A2 (en)

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WO2003055479A1 (en) * 2001-12-21 2003-07-10 Consejo Superior De Investigaciones Cientificas Compounds and their therapeutic use related to the phosphorylating activity of the enzyme gsk-3
CN109593030A (en) * 2018-11-20 2019-04-09 西安近代化学研究所 A kind of α, the preparation method of alpha-single chloro acetophenone compounds

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* Cited by examiner, † Cited by third party
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WO2003055479A1 (en) * 2001-12-21 2003-07-10 Consejo Superior De Investigaciones Cientificas Compounds and their therapeutic use related to the phosphorylating activity of the enzyme gsk-3
CN109593030A (en) * 2018-11-20 2019-04-09 西安近代化学研究所 A kind of α, the preparation method of alpha-single chloro acetophenone compounds

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