Method for manufacturing α-bromoacetophenone compound

Abstract

A method for manufacturing an -bromoacetophenone compound includes brominating a specific phenyl compound by reacting the specific phenyl compound with bromine in a solvent including at least one organic acid ester compound so as to obtain the -bromoacetophenone compound that is a liquid at 5 C. to 30 C.

Claims

1. A method for manufacturing an -bromoacetophenone compound of Formula (2) below, comprising: brominating a phenyl compound of Formula (1) below by reacting the phenyl compound with bromine in a solvent including at least one organic acid ester compound to produce the -bromoacetophenone compound of Formula (2), wherein the -bromoacetophenone compound is a liquid at 5 C. to 30 C., and a total content of the organic acid ester compound is 50 to 100 mass % of a total amount of the solvent used in the bromination, ##STR00018## in Formula (1), R.sup.1 and R.sup.2 each independently represent an alkyl group, R.sup.3 to R.sup.6 each independently represent a hydrogen atom or a substituent, at least one of R.sup.3, R.sup.4, R.sup.5, or R.sup.6 is a hydrogen atom, Y.sup.1 and Y.sup.2 each independently represent an oxygen atom or a sulfur atom, n represents 2 to 3, and R.sup.7 represents a hydrogen atom, an alkyl group, an acyl group, or a trialkylsilyl group, and ##STR00019## in Formula (2), R.sup.1 to R.sup.7, Y.sup.1, Y.sup.2, and n each have the same meaning as R.sup.1 to R.sup.7, Y.sup.1, Y.sup.2, and n in Formula (1) above.

2. The method for manufacturing an -bromoacetophenone compound according to claim 1, wherein a reaction temperature of the bromination is 20 C. or greater.

3. The method for manufacturing an -bromoacetophenone compound according to claim 1, wherein the solvent including at least one organic acid ester compound is selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, propyl acetate, isopropyl acetate, and a combination thereof.

4. The method for manufacturing an -bromoacetophenone compound according to claim 1, wherein a reaction temperature of the bromination is 40 C. or greater.

5. The method for manufacturing an -bromoacetophenone compound according to claim 3, wherein a reaction temperature of the bromination is 40 C. or greater.

6. The method for manufacturing an -bromoacetophenone compound according to claim 1, wherein an amount of the solvent including at least one organic acid ester compound is 0.5 to 60 mL per 1 g of the phenyl compound in a reaction liquid which is all of the solvent, bromine, and the phenyl compound.

7. The method for manufacturing an -bromoacetophenone compound according to claim 1, wherein the solvent including at least one organic acid ester compound is a liquid and the bromination is performed by adding the bromine or a mixture comprising bromine and the liquid solvent including at least one organic acid ester compound dropwise into a mixture comprising the phenyl compound and the liquid solvent including at least one organic acid ester compound, or the bromination is performed by adding a mixture comprising the bromine and the liquid solvent including at least one organic acid ester compound dropwise into the phenyl compound or a mixture comprising the phenyl compound and the liquid solvent including at least one organic acid ester compound.

8. The method for manufacturing an -bromoacetophenone compound according to claim 7, wherein the bromination is performed by adding the mixture comprising the bromine and the liquid solvent including at least one organic acid ester compound dropwise into the mixture comprising the phenyl compound and the liquid solvent including at least one organic acid ester compound.

9. The method for manufacturing an -bromoacetophenone compound according to claim 8, wherein a ratio of an amount A of the solvent including at least one organic acid ester compound in the mixture comprising the bromine and the liquid solvent including at least one organic acid ester compound and an amount B of the liquid solvent including at least one organic acid ester compound in the mixture comprising the phenyl compound and the liquid solvent including at least one organic acid ester compound satisfies B:A=90:10 to 30:70 in a volume ratio.

10. The method for manufacturing an -bromoacetophenone compound according to claim 1, wherein a total content of the organic acid ester compound is 70 to 100 mass % of a total amount of the solvent used in the bromination.

11. The method for manufacturing an -bromoacetophenone compound according to claim 3, wherein a total content of the organic acid ester compound is 70 to 100 mass % of a total amount of the solvent used in the bromination.

12. The method for manufacturing an -bromoacetophenone compound according to claim 4, wherein a total content of the organic acid ester compound is 70 to 100 mass % of a total amount of the solvent used in the bromination.

13. The method for manufacturing an -bromoacetophenone compound according to claim 5, wherein a total content of the organic acid ester compound is 70 to 100 mass % of a total amount of the solvent used in the bromination.

14. The method for manufacturing an -bromoacetophenone compound according to claim 1, wherein the solvent including at least one organic acid ester compound is selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, butyl propionate, and a combination thereof.

Description

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) The method for manufacturing an -bromoacetophenone compound according to the invention (hereinafter, simply referred to as a manufacturing method according to the invention) is described in detail.

(2) The manufacturing method according to the invention uses a phenyl compound represented by Formula (1) below, as a starting material.

(3) ##STR00003##

(4) In Formula (1), R.sup.1 and R.sup.2 each independently represent an alkyl group. This alkyl group may be linear or branched. R.sup.1 and R.sup.2 are alkyl groups preferably having 1 to 10 carbon atoms, more preferably having 1 to 5 carbon atoms, even more preferably having 1 to 3 carbon atoms, are even more preferably methyl or ethyl, and most preferably methyl.

(5) R.sup.1 and R.sup.2 may be linked to each other to form a ring. A group in a ring structure formed by linking R.sup.1 and R.sup.2 is preferably a cycloalkyl group. This cycloalkyl group is a cycloalkyl group more preferably having 3 to 10 carbon atoms, and even more preferably having 4 to 8 carbon atoms, and specifically, R.sup.1 and R.sup.2 are preferably cyclopropyl, cyclobutyl, cycloheptyl, or cyclohexyl.

(6) In Formula (1), R.sup.3 to R.sup.6 each independently represent a hydrogen atom or a substituent. However, at least one of R.sup.3, R.sup.4, R.sup.5, or R.sup.6 is a hydrogen atom. It is preferable that two or more of R.sup.3 to R.sup.6 (preferably, two or more including R.sup.4 and R.sup.6) are hydrogen atoms, it is more preferable that three or more thereof (preferably, three or more including R.sup.4 and R.sup.6) are hydrogen atoms, and it is even more preferable that all of R.sup.3 to R.sup.6 are hydrogen atoms.

(7) In a case where R.sup.3 to R.sup.6 are substituents, examples of these substituent include an alkyl group (an alkyl group preferably having 1 to 5 carbon atoms, more preferably having 1 to 3 carbon atoms, and even more preferably having 1 or 2 carbon atoms), a halogen atom (specifically, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a sulfo group, a sulfonyl group, a phosphonyl group, a boric acid group, an alkoxy group, and an amido group. Among these, methyl, ethyl, or a halogen atom is preferable.

(8) In Formula (1), R.sup.7 represents a hydrogen atom, an alkyl group, an acyl group, or a trialkylsilyl group. R.sup.7 is more preferably an acyl group.

(9) In a case where R.sup.7 is an alkyl group, the alkyl group may be linear or branched and may have a substituent. This alkyl group preferably has 1 to 10 carbon atoms, more preferably has 1 to 6 carbon atoms, and even more preferably has 1 to 5 carbon atoms. In a case where R.sup.7 is an alkyl group, the substituent that this alkyl group has may be linked to form a ring structure. Examples of the alkyl group that forms a ring structure in this manner include 2-tetrahydropyranyl. In a case where R.sup.7 is an alkyl group, the alkyl group is preferably an alkoxymethyl group (an alkoxymethyl group preferably having 1 to 10 carbon atoms and more preferably having 1 to 5 carbon atoms). Preferable examples in a case where R.sup.7 is an alkyl group include methyl, ethyl, propyl, isopropyl, t-butyl, methoxymethyl, ethoxymethyl, benzyl, p-methoxybenzyl, phenethyl, and 2-tetrahydropyranyl, and more preferable examples include methyl, methoxymethyl, benzyl, or 2-tetrahydropyranyl.

(10) In a case where R.sup.7 is an acyl group, the number of carbon atoms thereof is preferably 2 to 12, more preferably 2 to 10, and even more preferably 2 to 6. R.sup.7 is more preferably acetyl, pivaloyl, acryloyl, or benzoyl and even more preferably acetyl.

(11) In a case where R.sup.7 is a trialkylsilyl group, an alkyl group of a trialkylsilyl group may be linear or branched. This alkyl group preferably has 1 to 10 carbon atoms, more preferably has 1 to 6 carbon atoms, and even more preferably has 1 to 4 carbon atoms. Specifically, examples thereof include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, and triisopropylsilyl. R.sup.7 is preferably trimethylsilyl.

(12) In Formula (1), Y.sup.1 and Y.sup.2 each independently represent an oxygen atom or a sulfur atom, and it is more preferable that Y.sup.1 and Y.sup.2 are oxygen atoms.

(13) In Formula (1), n represents 2 to 3 and preferably represents 2. If n represents 2 or 3, the compound of Formula (2) which is a reaction product of the bromination (bromination reaction) is generally a liquid at 5 C. to 30 C. If n represents 0 to 1, regioselectivity of a bromination in the bromination reaction decreases. It is difficult to cause physical properties of the compound of Formula (2) which is a reaction product to be in the range determined in the invention.

(14) A method for synthesizing the phenyl compound represented by Formula (1) is not particularly limited and can be obtained in a common method. For example, the phenyl compound can be obtained by causing an acylating agent represented by Formula (1-b) below to react with a compound represented by Formula (1-a) below in the presence of Lewis acid of aluminium (III) chloride or the like.

(15) ##STR00004##

(16) In Formulae (1-a) and (1-b), R.sup.1 to R.sup.7, Y.sup.1, Y.sup.2, and n each have the same meaning as R.sup.1 to R.sup.7, Y.sup.1, Y.sup.2, and n in Formula (1), and preferable embodiments are also the same. X represents a halogen atom, and preferably a chlorine atom or a bromine atom.

(17) The phenyl compound represented by Formula (1) above is as described above and is generally a liquid at 5 C. to 30 C. If the compound of Formula (1) above is a liquid at 5 C. to 30 C., it is possible to cause the compound of Formula (2) below obtained by acylating the phenyl compound of Formula (1) above to be a liquid at 5 C. to 30 C. The expression a compound is a liquid at 5 C. to 30 C. according to the invention means that a crystal is not precipitated even if the compound is left for one week in an atmosphere of 5 C. to 30 C. under normal pressure.

(18) Specific examples of the phenyl compound represented by Formula (1) above are provided below, but the invention is not limited thereto.

(19) ##STR00005## ##STR00006##

(20) In the manufacturing method according to the invention, the phenyl compound represented by Formula (1) above and bromine are caused to react with each other in a specific reaction temperature by using a specific solvent. Accordingly, the -bromoacetophenone compound that is represented by Formula (2) below and is a liquid at 5 C. to 30 C. can be generally obtained with high purity in about 95% to 100% without a specific purification process.

(21) Since the -bromoacetophenone compound represented by Formula (2) below that can be obtained by the manufacturing method according to the invention is a liquid at a low temperature of 30 C. or lower, the -bromoacetophenone compound is a compound that is difficult for purification by a general recrystallization method. However, by the manufacturing method according to the invention, in the bromination reaction of the phenyl compound of Formula (1), bromination reaction of a ring constituting carbon atom of a benzene ring can be greatly suppressed. Accordingly, it is possible to obtain the -bromoacetophenone compound of Formula (2) below with high purity without providing a reaction product obtainable by the bromination reaction above to the purification process such as recrystallization.

(22) ##STR00007##

(23) In Formula (2) above, R.sup.1 to R.sup.7, Y.sup.1, Y.sup.2, and n each have the same meaning as R.sup.1 to R.sup.7, Y.sup.1, Y.sup.2, and n in Formula (1), and preferable embodiments are also the same.

Solvent

(24) In the manufacturing method according to the invention, the phenyl compound represented by Formula (1) above and bromine are reacted in the solvent including at least one organic acid ester compound. If at least one organic acid ester compound is used as a solvent, the solvent used in this bromination reaction may include a compound other than the organic acid ester compound in the solvent. The solvent may include an ether compound without a hydroxyl group.

(25) If a solvent including at least one organic acid ester compound is used, bromination reaction (side reaction) of a benzene ring that the phenyl compound of Formula (1) has is greatly suppressed, and thus a desired compound can be obtained with excellent purity. The reason thereof is not clear, but is assumed as follows.

(26) In the bromination reaction of the phenyl compound of Formula (1), it is assumed that bromination of the benzene ring which is side reaction occurs due to reaction between .sup.+ of bromine (corresponding to bromocation) and a benzene ring. However, according to the invention, in a case where an organic acid ester compound or an ether compound without a hydroxyl group is used as the solvent in the bromination reaction, it is assumed that .sup.+ is trapped in a solvent, the solvent coordinates with .sup.+ of bromine via an oxygen atom constituting an ester bond or an ether bond, such that bromination reaction of the benzene ring hardly occurs. Even if a solvent has an oxygen atom in a molecule structure, in a case where the solvent is a protonic solvent such as alcohol or acetic acid, the side reaction above cannot be effectively suppressed. It is assumed that this is because, if the solvent coordinates with a proton generated from the solvent via an oxygen atom itself, it becomes difficult for the solvent to coordinate with .sup.+ of bromine.

(27) The organic acid ester compound that is used as a solvent in the manufacturing method according to the invention is not particularly limited, and examples thereof include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, hexyl acetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, butyl propionate, hexyl propionate, methyl butyrate, ethyl butyrate, propyl butyrate, methyl isobutyrate, ethyl isobutyrate, propyl isobutyrate, -butyrolactone, -caprolactone, ethylene carbonate, propylene carbonate, 2-acetoxy-1-methoxypropane, methyl-3-methoxypropionate, cellosolve acetate, carbitol acetate, triethylene glycol diacetate, and dimethyl adipate, and one or two or more of these can be used. Among these, it is preferable to use one or two or more selected from methyl acetate, ethyl acetate, butyl acetate, propyl acetate, and isopropyl acetate.

(28) The organic acid ester compound used as a solvent according to the invention includes an ether bond in this molecule structure in some cases. That is, a solvent having both of the ester bond of the organic acid and the ether bond in the molecule structure is included in an organic acid ester compound. That is, the ether compound according to the invention is a solvent including an ether bond and not including an ester bond of an organic acid.

(29) In the manufacturing method according to the invention, the ether compound without a hydroxyl group that can be used as a solvent is not particularly limited, and examples thereof include diethyl ether, diethylene glycol dimethyl ether, dipropyl ether, dibutyl ether, dihexyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, isoamyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, diethylene glycol methylethyl ether, methyl tertiary butyl ether, diethylene glycol dibutyl ether, 1,4-dioxane, and tetrahydrofuran, and one or two or more of these can be used. Among these, one or two or more selected from diethylene glycol methyl ether, dipropyl ether, dibutyl ether, dihexyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, isoamyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, diethylene glycol methylethyl ether, diethylene glycol dibutyl ether, and 1,4-dioxane are preferably used, and 1,4-dioxane is more preferably used.

(30) In view of workability such as volatility and liquid separability, the solvent used in the bromination reaction according to the invention is preferably one or two or more selected from methyl acetate, ethyl acetate, butyl acetate, propyl acetate, isopropyl acetate, methyl propionate, and ethyl propionate, and more preferably one or two or more selected from methyl acetate, ethyl acetate, butyl acetate, propyl acetate, and isopropyl acetate.

(31) As described above, as long as the solvent used at the time of bromination reaction according to the invention includes a solvent selected from an organic acid ester compound and an ether compound without a hydroxyl group, the solvent may include a solvent other than an organic acid ester compound and an ether compound without a hydroxyl group. The solvent other than the organic acid ester compound and the ether compound without a hydroxyl group is not particularly limited. For example, a solvent selected from ketone, alcohol, dialkylformamide, N-alkylpyrrolidone, and toluene can be used, but the invention is not limited to these aspects, and a solvent that is generally used in the bromination reaction can be widely used. According to the invention, in the total amount of the solvent used at the time of the bromination reaction, a total content of the solvent including at least one organic acid ester compound is preferably 50 to 100 mass %, more preferably 70 to 100 mass %, and even more preferably 80 to 100 mass %.

(32) In the manufacturing method according to the invention, the phenyl compound represented by Formula (1) above is provided in the bromination reaction in a coexistence state with the specific solvent above. In the reaction liquid of the bromination reaction (that is, in the reaction liquid in which all of the solvent, bromine, and the phenyl compound which is a reactant are mixed), an amount of the solvent including at least one organic acid ester compound is preferably 0.1 mL or greater, more preferably 0.3 to 120 mL, also preferably 0.5 to 60 mL, also preferably 0.5 to 10 mL, and also preferably 0.5 to 5 mL per 1 g of the phenyl compound mixed into the reaction liquid of the bromination reaction. If a ratio of the solvent above and the phenyl compound above is caused to be in the preferable ratio above, the bromination reaction (side reaction) of the phenyl compound represented by Formula (1) above to the benzene ring can be more effectively suppressed, and bromination reaction to a desired site (an carbon of acyl group) more effectively proceeds.

(33) In the manufacturing method according to the invention, a ratio of the phenyl compound represented by Formula (1) above used in the bromination reaction and bromine is determined by a stoichiometric ratio. However, [bromine]/[phenyl compound of Formula (1)] is preferably 0.95 to 1.3, more preferably 1.0 to 1.2, and even more preferably 1.0 to 1.1 in a molar ratio.

(34) In the manufacturing method according to the invention, the reaction temperature of the bromination reaction is not limited. However, the reaction temperature is preferably 10 C. or higher, more preferably 20 C. or higher, even more preferably 30 C. or higher, even more preferably 35 C. or higher, and most preferably 40 C. or higher. The reaction temperature of the bromination reaction is preferably a temperature close to a boiling point of bromine and a temperature of the boiling point or lower. Specifically, the reaction temperature is preferably 60 C. or lower and more preferably 55 C. or lower. Accordingly, selectivity of a bromination increases, and thus purity of the obtained compound of Formula (2) greatly increases.

(35) Desired reaction of an acyl group at an position is promoted by increasing the reaction temperature, and thus excess bromine in a reaction system is small. Therefore, it is assumed that side reaction with a benzene ring becomes difficult to proceed, and selectivity of the desired reaction of the acyl group at an position is improved.

(36) In the manufacturing method according to the invention, a reaction time of the bromination reaction is not particularly limited. However, the reaction time is preferably 15 minutes or longer from the start of the reaction (that is, from the start of the mixing of bromine and the phenyl compound of Formula (1)) and more preferably 30 minutes or longer. The reaction time of the bromination reaction is generally within five hours and preferably within three hours.

(37) The bromination is preferably performed in the dropwise addition reaction. This dropwise addition reaction is described below.

(38) In a case where the bromination reaction in the manufacturing method according to the invention is performed by dropwise addition reaction, the preferable aspects include aspects as follows.

(39) (I) An aspect of performing bromination reaction by feeding bromine into a dropwise addition funnel and adding this bromine dropwise to a mixed liquid (preferably a liquid obtained by dissolving the phenyl compound represented by Formula (1) above in a solvent including an organic acid ester compound, the same applies hereinafter) including the phenyl compound represented by Formula (1) above and a solvent selected from an organic acid ester compound and an ether compound without a hydroxyl group

(40) (II) An aspect of performing bromination reaction by feeding a mixed liquid including bromine and a solvent selected from an organic acid ester compound and an ether compound without a hydroxyl group (preferably a liquid obtained by dissolving bromine in a solvent including a solvent selected from an organic acid ester compound and an ether compound without a hydroxyl group, the same applies hereinafter) to a dropwise addition funnel and adding this mixed liquid dropwise into a phenyl compound (liquid) represented by Formula (1) above

(41) (III) An aspect of performing bromination reaction by feeding a mixed liquid including bromine and a solvent selected from an organic acid ester compound and an ether compound without a hydroxyl group into a dropwise addition funnel and adding this mixed liquid dropwise into a mixed liquid including the phenyl compound represented by Formula (1) above and a solvent selected from an organic acid ester compound and an ether compound without a hydroxyl group

(42) Among these, Aspect (I) or (III) above is preferable, and Aspect (III) is more preferable. In Aspect (III) above, a solvent mixed with bromine and a solvent mixed with the compound represented by Formula (1) above may be identical to or different from each other.

(43) In the dropwise addition reaction above, the aforementioned reaction temperature of the bromination reaction according to the invention is set to be a temperature of a liquid (liquid including the compound represented by Formula (1)) on a dropwise added side. For example, in a reaction system in which the compound represented by Formula (1) or a mixed liquid of this compound and a solvent are fed into a reaction container such as a flask or a reaction tank, a dropwise addition funnel is provided, and bromine or a mixed liquid of bromine and a solvent is added dropwise, a temperature of the liquid in the reaction container is the reaction temperature of the bromination reaction according to the invention.

(44) In the dropwise addition reaction above, dropwise addition time is not particularly limited and is appropriately adjusted according to consumption of dropwise added bromine. In view of further increasing selectivity of a bromination, the dropwise addition time is preferably one minute or longer, more preferably 15 minutes or longer, and even more preferably 30 minutes or longer. In the same point of view, the dropwise addition time is preferably within 180 minutes, more preferably within 120 minutes, even more preferably within 90 minutes, and even more preferably within 60 minutes. The dropwise addition is preferably performed during stirring the reaction liquid.

(45) Even after the dropwise addition is completed, stirring is generally continued for about 30 minutes to 5 hours, so as to age the reaction. The stirring time after dropwise addition is completed is more preferably caused to be 1 hour to 3 hours.

(46) With respect to starting time of dropwise addition of the dropwise addition reaction above, a ratio between the amount A of the solvent including at least one organic acid ester compound in the dropwise addition liquid including bromine and the amount B of the solvent including at least one organic acid ester compound in the liquid including the phenyl compound of Formula (1) is not particularly limited, but B:A (volume ratio) is preferably 100:0 to 10:90, more preferably 100:0 to 20:80, even more preferably 90:10 to 30:70, even more preferably 80:20 to 40:60, and even more preferably 70:30 to 50:50.

(47) A total solvent amount with respect to 1 g of the reactant (phenyl compound) of Formula (1) used in the dropwise addition reaction above is not particularly limited, but if the total solvent amount with respect to the reactant is small, the side reaction easily occurs. There is no problem in the reaction regarding to the fact that the total solvent amount becomes great. However, in view of manufacturing cost, a total solvent amount that is too great is not preferable. The total solvent amount with respect to 1 g of the reactant of Formula (1) is preferably 0.7 ml, to 120 mL, more preferably 1.0 mL to 120 mL, even more preferably 1.5 mL to 120 mL, and most preferably 2 mL to 120 mL.

(48) Specific examples of the compound represented by Formula (2) above which is a liquid at 5 C. to 30 C. are provided below, but the invention is not limited thereto.

(49) ##STR00008## ##STR00009##

(50) The -bromoacetophenone compound represented by Formula (2) is particularly suitable as a synthesis intermediate of a photopolymerization initiator.

(51) That is, if the -bromoacetophenone compound represented by Formula (2) and a base are reacted to each other, it is possible to obtain a compound represented by Formula (3) below. It is preferable that this reaction is performed by adding water. This compound represented by Formula (3) can be suitably used as a photopolymerization initiator, particularly, a radical polymerization initiator, or a precursor thereof.

(52) ##STR00010##

(53) In Formula (3), R.sup.1 to R.sup.6, Y.sup.1, Y.sup.2, and n each have the same meaning as R.sup.1 to R.sup.6, Y.sup.1, Y.sup.2, and in Formula (1) above, and preferable embodiments are also the same. R.sup.9 represents a hydrogen atom, an alkyl group (an alkyl group preferably having 1 to 10 carbon atoms, more preferably having 1 to 5 carbon atoms, and even more preferably having 1 to 3 carbon atoms), an acyl group (an acyl group preferably having 2 to 10 carbon atoms, more preferably having 2 to 6 carbon atoms, and even more preferably having 2 to 4 carbon atoms), or a trialkylsilyl group (a trialkylsilyl group preferably having 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms, and even more preferably 1 or 2 carbon atoms, with respect to one alkyl group of the trialkylsilyl group). Z represents a hydroxyl group, an alkoxy group (an alkoxy group preferably having 1 to 10 carbon atoms, more preferably having 1 to 5 carbon atoms, and even more preferably having 1 to 3 carbon atoms), or an alkylamino group (including a dialkylamino group. An alkylamino group preferably has 1 to 10 carbon atoms, more preferably has 1 to 5 carbon atoms, and even more preferably has 1 to 3 carbon atoms, with respect to one alkyl group of an alkylamino group).

(54) Examples of the base above include sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, cesium hydroxide, rubidium hydroxide, sodium alkoxide (for example, sodium methoxide and sodium ethoxide), and alkyl amine.

(55) If reaction with the -bromoacetophenone compound is performed, for example, by using sodium hydroxide as a base and adding a sodium hydroxide aqueous solution, Z in Formula (3) can be caused to be a hydroxyl group. In this case, if R.sup.7 of Formula (2) is an acyl group, the acyl group is hydrolyzed, and thus R.sup.9 of Formula (3) becomes a hydrogen atom.

(56) If sodium oxide is used as a base, Z in Formula (3) can be caused to be an alkoxy group.

(57) If alkylamine is used as a base, Z in Formula (3) can be caused to be an alkylamino group.

(58) The use amount of the base is preferably 1 to 50 and more preferably 5 to 20 by a molar ratio, with respect to one -bromoacetophenone compound.

(59) In the reaction between the -bromoacetophenone compound represented by Formula (2) and the base, it is preferable to use a mixed solvent of water and a water soluble organic solvent. Examples of this water soluble organic solvent include glycerin, alkane diol (polyhydric alcohols) such as 1,2,6-hexanetriol, trimethylolpropane, ethylene glycol, and propylene glycol; sugar alcohols; alkylalcohols having 1 to 4 carbon atoms such as ethanol, methanol, butanol, propanol, and isopropanol; glycol ethers such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol monomethyl ether acetate, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-propyl ether, ethylene glycol mono-isopropyl ether, diethylene glycol mono-isopropyl ether, ethylene glycol mono-n-butyl ether, ethylene glycol mono-t-butyl ether, diethylene glycol mono-t-butyl ether, triethylene glycol monoethyl ether, 1-methyl-1-methoxybutanol, propylene glycol mono methyl ether, propylene glycol monoethyl ether, propylene glycol mono-t-butyl ether, propylene glycol mono-n-propyl ether, propylene glycol mono-isopropyl ether, dipropylene glycol, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, dipropylene glycol mono-n-propyl ether, dipropylene glycol mono-isopropyl ether, and tripropylene glycol monomethyl ether. Among these, in view of volatilization removability, it is preferable to use alcohol having 1 to 4 carbon atoms (for example, one or two or more selected from ethanol, methanol, butanol, propanol, and isopropanol).

(60) The reaction between the -bromoacetophenone compound represented by Formula (2) and the base is preferably performed at 10 C. to 40 C. The reaction time of this reaction is preferably 0.5 to 5 hours.

(61) Hereinafter, the invention is described in detail with reference to examples, but the invention is not limited to the examples.

EXAMPLES

Reference Example 1

(62) As the compound represented by Formula (1), a compound 1a below was synthesized by a scheme 1 below.

(63) ##STR00011##

Synthesis of Compound a

(64) 97.2 g of acetic anhydride (0.95 mol) was added dropwise to 170.0 g of phenyl diglycol (PhDG, manufactured by Nippon Nyukazai Co, Ltd.) (0.93 mol) heated to 90 C. and was heated and stirred for six hours at 120 C. Thereafter, concentration was performed under reduced pressure, so as to obtain 204.4 g of a compound a (yield: 98%).

(65) .sup.1H-NMR (CDCl.sub.3)

(66) : 2.10 (3H, s), 3.78 (2H, m), 3.87 (2H, m), 4.15 (2H, m), 4.26 (2H, m), 6.90-6.98 (3H, m), 7.25-7.32 (2H, m)

Synthesis of Compound 1a

(67) 10.0 g of the compound a (44.59 mmol) was dissolved in 40 mL of chlorobenzene, was cooled to 5 C. in an ice bath, and 17.84 g of aluminum (III) chloride (133.78 mmol) was added. Thereafter, 5.59 mL of isobutyryl chloride (53.51 mmol) was added dropwise and was stirred for one hour. Subsequently, a reaction liquid was poured to 80 g of ice, a product was extracted with 40 mL of ethyl acetate, and an organic layer was sequentially washed with 80 mL of sodium bicarbonate water and 40 mL of salt water and was dried by using 10 g of magnesium sulfate. After this was filtrated, the filtrate was concentrated under reduced pressure, so as to obtain 11.87 g of the compound 1a (yield: 90%). The compound 1a was a liquid at 30 C.

(68) .sup.1H-NMR (CDCl.sub.3)

(69) : 1.20 (3H, s), 1.21 (3H, s), 2.10 (3H, s), 3.52 (1H, m), 3.78 (2H, m), 3.89 (2H, m), 4.20 (2H, m), 4.27 (2H, m), 6.97 (2H, d), 7.95 (2H, d)

Example 1

Synthesis of Compound 2a

(70) ##STR00012##

(71) 10.0 g of the compound 1a (0.034 mol) and 12.5 mL of ethyl acetate were added to a three-neck flask having capacity of 100 mL provided with a dropwise addition funnel and a thermometer, a liquid temperature in a three-neck flask was adjusted to 45 C., and stirring was performed. 12.5 mL of ethyl acetate and 5.7 g of bromine (0.036 mol) were mixed, and the mixed liquid was added to the dropwise addition funnel, was added dropwise for 30 minutes, and was stirred for two hours. Meanwhile, temperature of the reaction liquid in the three-neck flask was continuously maintained at 45 C. Subsequently, 7 mL of a 3 wt % aqueous solution of sodium hydrogen sulfite was added dropwise into the solution after stirring, and the organic layer was sequentially washed with an aqueous solution of sodium hydrogen carbonate and saturated saline solution and was dried by using magnesium sulfate. After this was filtrated, the filtrate was concentrated under reduced pressure, so as to obtain 11.6 g of a compound 2a (reaction product) (yield: 91%). Both of the compounds 1a and 2a were liquids at 5 C. to 30 C.

(72) .sup.1H-NMR (CDCl.sub.3)

(73) : 2.04 (6H, s), 2.08 (3H, s), 3.79 (2H, m), 3.85 (2H, m), 4.21 (2H, m), 4.26 (2H, m), 6.94 (2H, d), 8.21 (2H, d)

(74) In order to examine purity of the compound 2a obtained above, mol % of the compound 1a (reactant), the compound 2a (desired product), and a compound 3a (byproduct) that exist in the reaction product were calculated by expressions below, respectively based on peak areas at 7.95 ppm, 8.21 ppm, and 8.41 ppm of .sup.1H-NMR (CDCl.sub.3).
[mol % of reactant]=100[peak area at 7.95 ppm]/{[peak area at 7.95 ppm]+[peak area at 8.21 ppm]+[peak area at 8.41 ppm]}
[mol % of desired product]=1.00[peak area at 8.21 ppm]/{[peak area at 7.95 ppm]+[peak area at 8.21 ppm]+[peak area at 8.41 ppm]}
[mol % of byproduct]=100[peak area at 8.41 ppm]/{[peak area at 7.95 ppm]+[peak area at 8.21 ppm]+[peak area at 8.41 ppm]}

(75) Results are provided in a table below.

Examples 2 to 38, and 43 to 45

(76) In the synthesis of the compound 2a in Example 1, the compounds 2a in Examples 2 to 38 and 43 to 45 were obtained in the same manner as in the synthesis of the compound 2a of Example 1, except for changing the reaction condition to reaction conditions provided in the table below. The purity of the obtained compounds 2a was measured in the same manner as in Example 1. Results thereof are provided in the table below.

Example 39

(77) ##STR00013##

(78) In the synthesis of the compound 2a in Example 1, a compound 2d was obtained in the same manner as in the synthesis of the compound 2a in Example 1 except for using a compound 1d instead of the compound 1a and changing the reaction condition to a reaction condition provided in the table below. In Reference Example 1 above, the compound 1d was synthesized in the same manner as in Reference Example 1 except for using phenyl triglycol (synthesized in a method disclosed in Tetrahedron 1988, 44, 5, pages 1553 to 1558) instead of PhDG. Both of the compounds 1d and 2d were liquids at 5 C. to 30 C.

(79) Purity of the obtained compound 2d was calculated based on a peak ratio of .sup.1H-NMR (CDCl.sub.3) in the same manner as in Example 1. Results thereof are provided in the table below.

Example 40

(80) ##STR00014##

(81) In the synthesis of the compound 2a in Example 1, a compound 2e was obtained in the same manner as in the synthesis of the compound 2a in Example 1 except for using a compound 1e instead of the compound 1a and changing the reaction condition to a reaction condition provided in the table below. In Reference Example 1 above, the compound 1e was synthesized in the same manner as in Reference Example 1, except for using cyclopropanecarbonyl chloride instead of isobutyryl chloride. Both of the compounds 1e and 2e were liquids at 5 C. to 30 C.

(82) Purity of the obtained compound 2e was calculated based on a peak ratio of .sup.1H-NMR (CDCl.sub.3) in the same manner as in Example 1. Results thereof are provided in the table below.

Example 41

(83) ##STR00015##

(84) In the synthesis of the compound 2a in Example 1, a compound 2f was obtained in the same manner as in Example 1, except for using a compound 1f instead of the compound 1a and changing the reaction condition to a reaction condition provided in the table below. In Reference Example 1 above, the compound 1f was synthesized in the same manner as in Reference Example 1, except for using 2-ethythexanoyl chloride instead of isobutyryl chloride. Both of the compounds 1f and 2f were liquids 5 C. to 30 C.

(85) Purity of the obtained compound 2f was calculated based on the peak ratio of .sup.1H-NMR (CDCl.sub.3) in the same manner as in Example 1. The results are provided in the table below.

Example 42

(86) ##STR00016##

(87) In the synthesis of the compound 2a in Example 1, a compound 2g was obtained in the same manner as in the synthesis of the compound 2a in Example 1, except for using a compound 1g instead of the compound 1a and changing the reaction condition to the reaction condition provided in the table below. In Reference Example 1 above, the compound 1g was synthesized in the same manner as in Reference Example 1, except for using cyclohexanecarbonyl chloride instead of isobutyryl chloride. Both of the compounds 1g and 2g were liquids at 5 C. to 30 C.

(88) Purity of the obtained compound 2g was calculated based on a peak ratio of .sup.1H-NMR (CDCl.sub.3) in the same manner as in Example 1. The results are provided in the table below.

Comparative Example 1

(89) ##STR00017##

(90) In the synthesis of the compound 2a in Example 1, a compound 2x was obtained in the same manner as in the synthesis of the compound 2a in Example 1, except for using a compound 1x instead of the compound 1a and changing the reaction condition to a reaction condition provided in the table below. The compound 1x was synthesized in the same manner as in the method disclosed in EP1073702B. Both of the compounds 1x and 2x were solids at 5 C. to 30 C. A melting point of the compound 2x was 56 C.

(91) Purity of the obtained compound 2x was calculated based on a peak ratio of .sup.1H-NMR (CDCl.sub.3) in the same manner as in Example 1. Results thereof are provided in the table below.

Comparative Examples 2 to 15

(92) In the synthesis of the compound 2a in Example 1, the compound 2a was obtained in the same manner as in the synthesis of the compound 2a in Example 1, except for changing the reaction condition to a reaction condition provided in the table below. Purity of the obtained compound 2a was measured in the same manner as in Example 1. Results thereof are provided in the table below.

(93) TABLE-US-00001 TABLE 1 Examples Reaction temperature [ C.] (Reaction Reactant (Formula (1)) Bromine liquid Dropwise Mixed solvent Mixed solvent temperature in addition Example (Use amount (Use amount three-neck time No. Type Vessel [mL]) Vessel [mL]) flask) [min] 1 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (12.5) addition (12.5) funnel 2 1a Three-neck Ethyl acetate Dropwise 45 30 flask (25) addition funnel 3 1a Three-neck Ethyl acetate Dropwise 1,4-dioxane 45 30 flask (12.5) addition (12.5) funnel 4 1a Three-neck 1,4-dioxane Dropwise Ethyl acetate 45 30 flask (12.5) addition (12.5) funnel 5 1a Dropwise Ethyl acetate Three-neck Ethyl acetate 45 30 addition (12.5) flask (12.5) funnel 6 1a Three-neck Ethyl acetate Dropwise 1,4-dioxane 45 30 flask (12.5) addition (12.5) funnel 7 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (5) addition (20) funnel 8 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (10) addition (15) funnel 9 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 20 30 flask (12.5) addition (12.5) funnel 10 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 50 30 flask (12.5) addition (12.5) funnel 11 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 55 30 flask (12.5) addition (12.5) funnel 12 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 58 30 flask (12.5) addition (12.5) funnel 13 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 30 30 flask (12.5) addition (12.5) funnel 14 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 5 flask (12.5) addition (12.5) funnel 15 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 20 flask (12.5) addition (12.5) funnel 16 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 60 flask (12.5) addition (12.5) funnel 17 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 120 flask (12.5) addition (12.5) funnel 18 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 180 flask (12.5) addition (12.5) funnel 19 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (12.5) addition (20) funnel 20 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (12.5) addition (15) funnel 21 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (12.5) addition (12.5) funnel 22 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (12.5) addition (12.5) funnel 23 1a Three-neck Ethyl acetate Dropwise Ethyl 45 30 flask (12.5) addition acetate/dibutyl funnel ether = 8/2 (volume ratio) (12.5) 24 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (3.5) addition (3.5) funnel 25 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (5.0) addition (5.0) funnel 26 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (7.5) addition (7.5) funnel 27 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (50) addition (50) funnel 28 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (600) addition (600) funnel 29 1a Three-neck Methyl acetate Dropwise Methyl acetate 45 30 flask (12.5) addition (12.5) funnel 30 1a Three-neck Methyl acetate Dropwise Methyl acetate 20 30 flask (12.5) addition (12.5) funnel 31 1a Three-neck Butyl acetate Dropwise Butyl acetate 45 30 flask (12.5) addition (12.5) funnel 32 1a Three-neck Butyl acetate Dropwise Butyl acetate 20 30 flask (12.5) addition (12.5) funnel 33 1a Three-neck Propyl acetate Dropwise Propyl acetate 45 30 flask (12.5) addition (12.5) funnel 34 1a Three-neck Propyl acetate Dropwise Propyl acetate 20 30 flask (12.5) addition (12.5) funnel 35 1a Three-neck Isopropyl Dropwise Isopropyl 45 30 flask acetate addition acetate (12.5) funnel (12.5) 36 1a Three-neck Isopropyl Dropwise Isopropyl 20 30 flask acetate addition acetate (12.5) funnel (12.5) 37 1a Three-neck Methyl Dropwise Methyl 45 30 flask propionate addition propionate (12.5) funnel (12.5) 38 1a Three-neck Methyl Dropwise Methyl 20 30 flask propionate addition propionate (12.5) funnel (12.5) 39 1d Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (12.5) addition (12.5) funnel 40 1e Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (12.5) addition (12.5) funnel 41 1f Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (12.5) addition (12.5) funnel 42 1g Three-neck Ethyl acetate Dropwise Ethyl acetate 45 30 flask (12.5) addition (12.5) funnel 43 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 10 30 flask (12.5) addition (12.5) funnel 44 1a Three-neck Ethyl acetale Dropwise Ethyl acetate 5 30 flask (12.5) addition (12.5) funnel 45 1a Three-neck Ethyl acetate Dropwise Ethyl acetate 5 30 flask (12.5) addition (12.5) funnel Examples Use amount of Composition of reaction product solvent with (mol %) respect to 1 g of Desired Desired reactant Bromine/reactant product product Reactant Byproduct Example (Formula (1)) (Formula (1)) (Formula (Formula (Formula (Benzene ring No. [mL] [molar ratio] (2)) (2)) (1)) bromination) 1 2.5 1.05 2a 100 0 0 2 2.5 1.05 2a 100 0 0 3 2.5 1.05 2a 100 0 0 4 2.5 1.05 2a 100 0 0 5 2.5 1.05 2a 98.5 0 1.5 6 2.5 1.05 2a 100 0 0 7 2.5 1.05 2a 98.6 0 1.4 8 2.5 1.05 2a 99.0 0 1.0 9 2.5 1.05 2a 99.2 0 0.8 10 2.5 1.05 2a 100 0 0 11 2.5 1.05 2a 100 0 0 12 2.5 1.05 2a 99.9 0.1 0 13 2.5 1.05 2a 99.9 0 0.1 14 2.5 1.05 2a 97.6 0 2.4 15 2.5 1.05 2a 100 0 0 16 2.5 1.05 2a 100 0 0 17 2.5 1.05 2a 100 0 0 18 2.5 1.05 2a 100 0 0 19 2.5 1.1 2a 100 0 0 20 2.5 1.3 2a 97.2 0 2.8 21 2.5 1.00 2a 100 0 0 22 2.5 0.95 2a 95.5 4.5 0 23 2.5 1.05 2a 100 0 0 24 0.7 1.05 2a 94.5 0 5.5 25 1.0 1.05 2a 96.5 0 3.5 26 1.5 1.05 2a 99.5 0 0.5 27 10 1.05 2a 100 0 0 28 120 1.05 2a 100 0 0 29 2.5 1.05 2a 100 0 0 30 2.5 1.05 2a 98.1 0 1.9 31 2.5 1.05 2a 100 0 0 32 2.5 1.05 2a 97.9 0 2.1 33 2.5 1.05 2a 100 0 0 34 2.5 1.05 2a 98.2 0 1.8 35 2.5 1.05 2a 100 0 0 36 2.5 1.05 2a 98.3 0 1.7 37 2.5 1.05 2a 100 0 0 38 2.5 1.05 2a 98.2 0 1.8 39 2.5 1.05 2d 99.4 0 0.6 40 2.5 1.05 2e 99.5 0 0.5 41 2.5 1.05 2f 98.0 0 2.0 42 2.5 1.05 2g 97.9 0 2.1 43 2.5 1.05 2a 98.3 0 1.7 44 2.5 1.05 2a 96.7 0 3.3 45 2.5 1.05 2a 95.4 0 4.6

(94) TABLE-US-00002 TABLE 2 Comparative Examples Reaction temperature [ C.] (Reaction Reactant Bromine liquid Dropwise Mixed solvent Mixed solvent temperature in addition Comparative (Use amount (Use amount three-neck time Example No. Type Vessel [mL]) Vessel [mL]) flask) [min] 1 1x Three-neck Butyl acetate Dropwise Butyl acetate 20 30 flask (12.5) addition (12.5) funnel 2 1a Three-neck Glacial acetic Dropwise Glacial acetic 45 30 flask acid addition acid (12.5) funnel (12.5) 3 1a Three-neck Glacial acetic Dropwise Glacial acetic 20 30 flask acid addition acid (12.5) funnel (12.5) 4 1a Three-neck Glacial acetic Dropwise Glacial acetic 20 30 flask acid addition acid (12.5) funnel (12.5) 5 1a Three-neck Dichloromethane Dropwise Dichloromethane 45 30 flask (12.5) addition (12.5) funnel 6 1a Three-neck Dichloromethane Dropwise Dichloromethane 20 30 flask (12.5) addition (12.5) funnel 7 1a Three-neck Dichloromethane Dropwise Dichloromethane 20 30 flask (12.5) addition (12.5) funnel 8 1a Three-neck Methanol Dropwise Methanol 45 30 flask (12.5) addition (12.5) funnel 9 1a Three-neck Methanol Dropwise Methanol 20 30 flask (12.5) addition (12.5) funnel 10 1a Three-neck Carbon Dropwise Carbon 45 30 flask tetrachloride addition tetrachloride (12.5) funnel (12.5) 11 1a Three-neck Carbon Dropwise Carbon 20 30 flask tetrachloride addition tetrachloride (12.5) funnel (12.5) 12 1a Three-neck Acetic acid Dropwise Acetic acid 45 30 flask (12.5) addition (12.5) funnel 13 1a Three-neck Acetic acid Dropwise Acetic acid 20 30 flask (12.5) addition (12.5) funnel 14 1a Three-neck Chlorobenzene Dropwise Chlorobenzene 45 30 flask (12.5) addition (12.5) funnel 15 1a Three-neck Chlorobenzene Dropwise Chlorobenzene 20 30 flask (12.5) addition (12.5) funnel Comparative Exmaples Use amount of Composition of reaction product solvent with (mol %) respect to 1 g of Desired Desired reactant Bromine/reactant product product Reactant Byproduct Comparative (Formula (1)) (Formula (1)) (Formula (Formula (Formula (Benzene ring Example No. [mL] [molar ratio] (2)) (2)) (1)) bromination) 1 2.5 1.05 2x 88.5 0 11.5 2 2.5 1.05 2a 89.5 0 10.5 3 2.5 1.05 2a 89.3 0.5 10.2 4 0.8 1.05 2a 84.2 0.6 15.2 5 2.5 1.05 2a 86.8 0 13.2 6 2.5 1.05 2a 88.2 1.5 10.3 7 0.8 1.05 2a 83.4 1.2 15.4 8 2.5 1.05 2a 70.7 13.2 16.1 9 2.5 1.05 2a 73 12.2 14.8 10 2.5 1.05 2a 83.7 1.5 14.8 11 2.5 1.05 2a 84.6 2.3 13.1 12 2.5 1.05 2a 87.6 0.7 11.7 13 2.5 1.05 2a 87.9 0.9 11.2 14 2.5 1.05 2a 61.7 22.1 16.2 15 2.5 1.05 2a 60.6 28.9 10.5

(95) From the results in Comparative Example 1 above, in a case where a compound in which n in Formula (1) was smaller than that of the invention was used as a reactant, even if the solvent regulated in the invention was used, it was resulted that selectivity of the bromination was low and purity of the obtained desired -bromoacetophenone compound was low.

(96) From the results of Comparative Examples 2 to 15 above, if the used solvent didn't include at least one organic acid ester compound, it was also resulted that selectivity of the bromination was low and purity of the obtained desired -bromoacetophenone compound was low.

(97) In contrast, in Examples 1 to 45 in which all of the requirements regulated in the invention are satisfied, it was understood that selectivity of the bromination was greatly increased and the -bromoacetophenone compound in which recrystallization was difficult was able to be obtained with high reaction purity.