JP6687914B2 - Method for producing O- [1- (2-hydroxypropyl)] oxime compound - Google Patents

Description

  The present invention relates to a method for producing an O- [1- (2-hydroxypropyl)] oxime compound which is useful as an intermediate for medicines, agricultural chemicals, electronic materials and the like.

Conventionally, O- [1- (2-hydroxypropyl)] oxime compounds have been known as compounds useful as intermediates for medicines, agricultural chemicals, electronic materials and the like.
As a manufacturing method thereof, a method of reacting an oxime compound with propylene oxide or propylene carbamate is generally known. For example, a method for producing O- [1- (2-hydroxypropyl)] acetone oxime by reacting acetone oxime and propylene oxide in the presence of lithium ethoxide is known (Patent Document 1 and Non-Patent Document 1). 1). Further, there is known a method for producing O- [1- (2-hydroxypropyl)] acetone oxime by reacting acetone oxime and propylene oxide in the presence of triethylamine (see Patent Document 2). Further, there is known a method for producing O- [1- (2-hydroxypropyl)] acetophenone oxime by reacting acetophenone oxime and propylene oxide in the presence of potassium carbonate or sodium hydride (Patent Document 3). reference).
Also, some methods for producing O- [1- (2-hydroxyalkyl)] oxime compounds are known (see Patent Documents 1 and 4 and Non-Patent Document 1).

U.S. Patent Application Publication No. 3040097 International Publication No. 96/04238 JP, 2009-155327, A International Publication No. 2008/061616

Journal of the American Chemical Society, 1959, Vol. 81, p. 4223.

  Regarding the method for producing an O- [1- (2-hydroxypropyl)] oxime compound, in Patent Documents 1, 2, and 3 and Non-Patent Document 1, a production method in which an oxime compound and propylene oxide are reacted in the presence of a basic compound. A method is disclosed. Since propylene oxide has two reaction points, when propylene oxide is used, an isomer mixture of the compound represented by the formula (1) and the compound represented by the formula (3) is obtained as a product. In that case, the production ratio of the compound represented by the formula (1) and the compound represented by the formula (3) is usually 85/15 to 96/4.

Since the compound represented by the formula (1) and the compound represented by the formula (3) have structures very close to each other, they are represented by the formula (1) by an ordinary purification operation such as distillation purification. It is very difficult to selectively reduce only the compound represented by the formula (3) from the mixture of the compound and the compound represented by the formula (3). In addition, when the compound represented by the formula (1) is used as an intermediate for medicines, agricultural chemicals, electronic materials, etc., the compound represented by the formula (3) is mixed as an impurity in the product, and the product quality and It may cause a negative effect on performance.
Therefore, a novel method for producing an O- [1- (2-hydroxypropyl)] oxime compound, which is suitable as an intermediate for pharmaceuticals, agricultural chemicals, electronic materials, etc., and contains the compound represented by the formula (3) as little as possible, Development is desired.

  The present inventor has conducted extensive studies to solve the above problems, and as a result, after reacting an isomer mixture of O- [1- (2-hydroxypropyl)] oxime compounds with a cyclic acid anhydride available as an industrial raw material. It was found that an O- [1- (2-hydroxypropyl)] oxime compound having an extremely high purity can be obtained by mixing it with an aqueous solution of a basic compound, and completed the present invention.

［式中、Ｒ¹及びＲ²は、各々独立してＣ₁〜Ｃ₆アルキル基又はフェニル基を表すか、若しくは、Ｒ¹及びＲ²はそれらが結合する炭素原子と一緒になって５〜７員の炭素環を形成する。］で表されるＯ−［１−（２−ヒドロキシプロピル）］オキシム化合物の製造方法。
工程（ａ）：式（２）：

（式中、Ｒ¹及びＲ²は、上記の定義と同じ意味を表す。）で表されるオキシム化合物を、プロピレンオキサイドと、塩基性化合物の存在下で反応させる工程
工程（ｂ）：工程（ａ）で得られた混合物を、環状酸無水物と、塩基性化合物の存在下で反応させる工程
工程（ｃ）：工程（ｂ）で得られた混合物を、塩基性化合物の水溶液と混合して、式（１）で表されるＯ−［１−（２−ヒドロキシプロピル）］オキシム化合物を得る工程That is, the present invention relates to the production methods described in [1] to [76] below.
[1]
Formula (1) including the following steps (a) to (c):

[Wherein R ¹ and R ² each independently represent a C ₁ -C ₆ alkyl group or a phenyl group, or R ¹ and R ² together with the carbon atom to which they are bonded are 5 to 5 Form a 7-membered carbocycle. ] The manufacturing method of the O- [1- (2-hydroxypropyl)] oxime compound represented by these.
Step (a): Formula (2):

(In the formula, R ¹ and R ² have the same meanings as defined above.) A step of reacting an oxime compound with propylene oxide in the presence of a basic compound Step (b): Step ( Step of reacting the mixture obtained in a) with a cyclic acid anhydride in the presence of a basic compound Step (c): Mixing the mixture obtained in step (b) with an aqueous solution of a basic compound A step of obtaining an O- [1- (2-hydroxypropyl)] oxime compound represented by the formula (1)

[2]
The amount of the cyclic acid anhydride used is 0.04 to 1.0 equivalent to 1 equivalent of the compound represented by the formula (1) in the mixture obtained in the step (a). -A method for producing a [1- (2-hydroxypropyl)] oxime compound.

[3]
The O- [1- (2-hydroxypropyl) according to the above [1] or [2], wherein the cyclic acid anhydride is at least one selected from the group consisting of maleic anhydride, succinic anhydride and phthalic anhydride. )] Method for producing oxime compound.

[4]
R ¹ and R ² are each independently -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ( _{CH 3) (CH 2 CH 3} ), - CH 2 CH (CH 3) 2, -C (CH 3) or represents ₃ or a phenyl group, or, together with R ¹ and R ² are carbon atoms to which they are attached The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above items [1] to [3], which forms a 6-membered carbon ring.

[5]
R ¹ and R ^2, -CH ₃ each _{independently, -CH 2 CH 3, -CH 2} CH 2 CH 3, or represents _{-CH (CH 3) 2, -C} (CH 3) 3 or a phenyl group Alternatively, R ¹ and R ² together with the carbon atom to which they are attached form a 6-membered carbocycle, the production of the O- [1- (2-hydroxypropyl)] oxime compound according to the above [4]. Method.

[6]
R ¹ and R ² each independently represent —CH ₃ , —CH ₂ CH ₃ , —CH (CH ₃ ) ₂ , —C (CH ₃ ) ₃ or a phenyl group, or R ¹ and R ² Is a method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [5], which forms a 6-membered carbon ring together with the carbon atom to which they are bonded.

[7]
In the step (c), the organic solvent containing the mixture obtained in the step (b) is mixed with an aqueous solution of a basic compound, and the O- [1-] described in any one of the above [1] to [6]. (2-Hydroxypropyl)] oxime compound production method.

[8]
In step (c), the organic solvent containing the mixture obtained in step (b) is dichloromethane, 1,2-dichloroethane or toluene, O- [1- (2-hydroxypropyl)] according to the above [7]. Method for producing oxime compound.

[9]
In the step (c), the basic compound is sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate or potassium carbonate, and the O- [1- (2-hydroxy is described in any one of the above [1] to [8]. Propyl)] Method for producing oxime compound.

[10]
In the step (a), the basic compound is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal phosphate, an alkali metal hydrogen phosphate, an alkaline earth metal hydroxide, an alkaline earth metal carbonate, O- [1-] according to any one of [1] to [9] above, which is an alkaline earth metal bicarbonate, an alkaline earth metal phosphate, an alkaline earth metal hydrogen phosphate or an organic base. (2-Hydroxypropyl)] oxime compound production method.
[11]
In the step (a), the basic compound is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal phosphate, an alkali metal hydrogen phosphate, an alkaline earth metal hydroxide, an alkaline earth metal carbonate, The O- [1- (2-) described in any one of [1] to [9] above, which is an alkaline earth metal bicarbonate, an alkaline earth metal phosphate or an alkaline earth metal hydrogen phosphate. Hydroxypropyl)] oxime compound production method.
[12]
Production of the O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [9], wherein the basic compound in step (a) is an alkali metal hydroxide. Method.
[13]
In step (a), the basic compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, hydrogen phosphate. Dipotassium, magnesium hydroxide, calcium hydroxide, magnesium carbonate, calcium carbonate, magnesium hydrogen carbonate, calcium hydrogen carbonate, magnesium phosphate, calcium phosphate, magnesium hydrogen phosphate, calcium hydrogen phosphate, triethylamine, tributylamine, pyridine, 4- (Dimethylamino) pyridine, imidazole, or 1,8-diazabicyclo [5,4,0] -7-undecene O- [1- (2- Hydroxypropyl)] oxime compound Method.
[14]
In the step (a), the basic compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, according to any one of the above [1] to [9]. A method for producing an O- [1- (2-hydroxypropyl)] oxime compound.
[15]
In the step (a), the basic compound is triethylamine, tributylamine, pyridine, 4- (dimethylamino) pyridine, imidazole or 1,8-diazabicyclo [5,4,0] -7-undecene [1]. A method for producing the O- [1- (2-hydroxypropyl)] oxime compound according to any one of [1] to [9].
[16]
In the step (a), the basic compound is sodium hydroxide or potassium hydroxide, and the O- [1- (2-hydroxypropyl)] oxime compound according to any one of [1] to [9] above. Manufacturing method.
[17]
In the step (a), the method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [9], wherein the basic compound is sodium hydroxide.
[18]
In the step (a), the method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [9], wherein the basic compound is potassium hydroxide.

[19]
In the step (b), the cyclic acid anhydride is maleic acid anhydride, succinic acid anhydride, phthalic acid anhydride, itaconic acid anhydride, glutaric acid anhydride, adipic acid anhydride, citraconic acid anhydride, trimellitic acid. [1] to [18], which is an anhydride, hexahydrophthalic anhydride, tetrachlorophthalic anhydride, cis-4-cyclohexene-1,2-dicarboxylic acid anhydride or isododecenylsuccinic anhydride. The method for producing the O- [1- (2-hydroxypropyl)] oxime compound according to any one of 1.
[20]
In the step (b), the cyclic acid anhydride is maleic acid anhydride, succinic acid anhydride, phthalic acid anhydride, itaconic acid anhydride, glutaric acid anhydride, adipic acid anhydride or citraconic acid anhydride. 1] to the production method of the O- [1- (2-hydroxypropyl)] oxime compound according to any one of [18].
[21]
In the step (b), the cyclic acid anhydride is trimellitic acid anhydride, hexahydrophthalic acid anhydride, tetrachlorophthalic acid anhydride, cis-4-cyclohexene-1,2-dicarboxylic acid anhydride or isododecese. The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [18], which is nilcuccinic anhydride.
[22]
Production of the O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [18], wherein in step (b), the cyclic acid anhydride is maleic anhydride. Method.
[23]
Production of the O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [18], wherein in step (b), the cyclic acid anhydride is succinic anhydride. Method.
[24]
Production of the O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [18], wherein in the step (b), the cyclic acid anhydride is phthalic anhydride. Method.

[25]
In the step (b), the basic compound is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal phosphate, an alkali metal hydrogen phosphate, an alkaline earth metal hydroxide, an alkaline earth metal carbonate, O- [1-] according to any one of [1] to [24] above, which is an alkaline earth metal bicarbonate, an alkaline earth metal phosphate, an alkaline earth metal hydrogen phosphate or an organic base. (2-Hydroxypropyl)] oxime compound production method.
[26]
In the step (b), the basic compound is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal phosphate, an alkali metal hydrogen phosphate, an alkaline earth metal hydroxide, an alkaline earth metal carbonate, O- [1- (2-) described in any one of [1] to [24] above, which is an alkaline earth metal bicarbonate, an alkaline earth metal phosphate or an alkaline earth metal hydrogen phosphate. Hydroxypropyl)] oxime compound production method.
[27]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [24], wherein in the step (b), the basic compound is an organic base.
[28]
In the step (b), the basic compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, hydrogen phosphate. Dipotassium, magnesium hydroxide, calcium hydroxide, magnesium carbonate, calcium carbonate, magnesium hydrogen carbonate, calcium hydrogen carbonate, magnesium phosphate, calcium phosphate, magnesium hydrogen phosphate, calcium hydrogen phosphate, triethylamine, tributylamine, pyridine, 4- (Dimethylamino) pyridine, imidazole, or 1,8-diazabicyclo [5,4,0] -7-undecene, O- [1- (2- Hydroxypropyl)] oxime compound Production method.
[29]
In the step (b), the basic compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, according to any one of the above [1] to [24]. A method for producing an O- [1- (2-hydroxypropyl)] oxime compound.
[30]
In the step (b), the basic compound is triethylamine, tributylamine, pyridine, 4- (dimethylamino) pyridine, imidazole or 1,8-diazabicyclo [5,4,0] -7-undecene [1]. To [24], a method for producing the O- [1- (2-hydroxypropyl)] oxime compound.
[31]
In the step (b), the basic compound is O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [24], which is triethylamine, tributylamine or pyridine. Production method.
[32]
In the step (b), the method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [24], wherein the basic compound is triethylamine.
[33]
In the step (b), the method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [24], wherein the basic compound is tributylamine.
[34]
In the step (b), the method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [24], wherein the basic compound is pyridine.

[35]
In the step (c), the organic solvent containing the mixture obtained in the step (b) is a hydrocarbon solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an alcohol solvent, a ketone solvent, a nitrile solvent, a carboxylic acid ester solvent. Alternatively, the method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [34], which is a nitrogen-containing aprotic polar solvent.
[36]
In the step (c), the organic solvent containing the mixture obtained in the step (b) is a hydrocarbon solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a ketone solvent or a carboxylic acid ester solvent [1]. A method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of [1] to [34].
[37]
Any one of the above-mentioned [1] to [34], wherein in the step (c), the organic solvent containing the mixture obtained in the step (b) is a hydrocarbon solvent, an aromatic hydrocarbon solvent or a halogen-based hydrocarbon solvent. The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to item 1.
[38]
In the step (c), the organic solvent containing the mixture obtained in the step (b) is a hydrocarbon solvent, and the O- [1- (2- Hydroxypropyl)] oxime compound production method.
[39]
In the step (c), the organic solvent containing the mixture obtained in the step (b) is an aromatic hydrocarbon solvent, and the O- [1-(- 2-Hydroxypropyl)] oxime compound production method.
[40]
In the step (c), the organic solvent containing the mixture obtained in the step (b) is a halogenated hydrocarbon solvent, O- [1-(- 2-Hydroxypropyl)] oxime compound production method.
[41]
In the step (c), the organic solvent containing the mixture obtained in the step (b) is hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, heptane, benzene, xylene, toluene, dichloromethane, carbon tetrachloride, chloroform, 1,2. -Dichloroethane, chlorobenzene, trifluoromethylbenzene, acetone, methylethylketone, methylisobutylketone, acetonitrile, propionitrile, ethyl acetate or ethyl propionate O- according to any one of the above [1] to [34] A method for producing a [1- (2-hydroxypropyl)] oxime compound.
[42]
In the step (c), the organic solvent containing the mixture obtained in the step (b) is hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, heptane, benzene, xylene, toluene, dichloromethane, carbon tetrachloride, chloroform, 1,2. -A method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [34], which is dichloroethane, chlorobenzene or trifluoromethylbenzene.
[43]
In step (c), the organic solvent containing the mixture obtained in step (b) is benzene, xylene, or toluene, and the O- [1-(- 2-Hydroxypropyl)] oxime compound production method.
[44]
In the step (c), the organic solvent containing the mixture obtained in the step (b) is dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene or trifluoromethylbenzene [1] to [34]. ] The manufacturing method of O- [1- (2-hydroxypropyl)] oxime compound as described in any one of these.
[45]
In the step (c), the O- [1- (2-hydroxypropyl) according to any one of the above [1] to [34], wherein the organic solvent containing the mixture obtained in the step (b) is toluene. )] Method for producing oxime compound.
[46]
In the step (c), the O- [1- (2-hydroxypropyl) according to any one of the above [1] to [34], wherein the organic solvent containing the mixture obtained in the step (b) is dichloromethane. )] Method for producing oxime compound.
[47]
In the step (c), the organic solvent containing the mixture obtained in the step (b) is 1,2-dichloroethane, and the O- [1-(- 2-Hydroxypropyl)] oxime compound production method.

[48]
In the step (c), the basic compound is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal phosphate, an alkali metal hydrogen phosphate, an alkaline earth metal hydroxide or an alkali. The earth metal carbonate, alkaline earth metal bicarbonate, alkaline earth metal phosphate, alkaline earth metal hydrogen phosphate or organic base according to any one of the above [1] to [47]. And a method for producing an O- [1- (2-hydroxypropyl)] oxime compound.
[49]
In the step (c), the basic compound is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal phosphate, an alkali metal hydrogen phosphate, an alkaline earth metal hydroxide or an alkali. O- according to any one of the above [1] to [47], which is an earth metal carbonate, an alkaline earth metal bicarbonate, an alkaline earth metal phosphate or an alkaline earth metal hydrogen phosphate. A method for producing a [1- (2-hydroxypropyl)] oxime compound.
[50]
O- [1- (2-hydroxypropyl) according to any one of the above [1] to [47], wherein in the step (c), the basic compound is an alkali metal carbonate or an alkali metal bicarbonate. ] A method for producing an oxime compound.
[51]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [47], wherein in the step (c), the basic compound is an alkali metal carbonate. .
[52]
Production of the O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [47], wherein in the step (c), the basic compound is an alkali metal bicarbonate. Method.
[53]
In the step (c), the basic compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, hydrogen phosphate. Dipotassium, magnesium hydroxide, calcium hydroxide, magnesium carbonate, calcium carbonate, magnesium hydrogen carbonate, calcium hydrogen carbonate, magnesium phosphate, calcium phosphate, magnesium hydrogen phosphate, calcium hydrogen phosphate, triethylamine, tributylamine, pyridine, 4- (Dimethylamino) pyridine, imidazole, or 1,8-diazabicyclo [5,4,0] -7-undecene, O- [1- (2- Hydroxypropyl)] oxime compound Production method.
[54]
In the step (c), the basic compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, according to any one of [1] to [47] above. A method for producing an O- [1- (2-hydroxypropyl)] oxime compound.
[55]
In the step (c), the basic compound is sodium hydroxide or potassium hydroxide, and the O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [47]. Manufacturing method.
[56]
In the step (c), the basic compound is sodium carbonate or potassium carbonate, and the production of the O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [47]. Method.
[57]
In the step (c), the basic compound is sodium hydrogen carbonate or potassium hydrogen carbonate, and the O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [47]. Manufacturing method.
[58]
In the step (c), the method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [47], wherein the basic compound is sodium carbonate.
[59]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [47], wherein in the step (c), the basic compound is potassium carbonate.
[60]
In the step (c), the method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of [1] to [47], wherein the basic compound is sodium hydrogen carbonate.
[61]
In the step (c), the method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [47], wherein the basic compound is potassium hydrogen carbonate.

[62]
O- [1- (2-hydroxypropyl)], which comprises continuously performing steps (a) to (c) specified in any one of the above [1] to [61], respectively. Method for producing oxime compound.
[63]
O according to the above [62], wherein the organic solvent is a hydrocarbon solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an alcohol solvent, a ketone solvent, a nitrile solvent, a carboxylic acid ester solvent or a nitrogen-containing aprotic polar solvent. -A method for producing a [1- (2-hydroxypropyl)] oxime compound.
[64]
The O- [1- (2-hydroxypropyl)] oxime compound according to the above [62], wherein the organic solvent is a hydrocarbon solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a ketone solvent or a carboxylic acid ester solvent. Production method.
[65]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [62], wherein the organic solvent is a hydrocarbon solvent, an aromatic hydrocarbon solvent or a halogenated hydrocarbon solvent.
[66]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [62], wherein the organic solvent is a hydrocarbon solvent.
[67]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [62], wherein the organic solvent is an aromatic hydrocarbon solvent.
[68]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [62], wherein the organic solvent is a halogenated hydrocarbon solvent.
[69]
The organic solvent is hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, heptane, benzene, xylene, toluene, dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene, trifluoromethylbenzene, acetone, methyl ethyl ketone, methyl isobutyl ketone. The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [62], which is acetonitrile, acetonitrile, propionitrile, ethyl acetate or ethyl propionate.
[70]
The above-mentioned [62], wherein the organic solvent is hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, heptane, benzene, xylene, toluene, dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene or trifluoromethylbenzene. A method for producing an O- [1- (2-hydroxypropyl)] oxime compound.
[71]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [62], wherein the organic solvent is benzene, xylene or toluene.
[72]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [62], wherein the organic solvent is dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene or trifluoromethylbenzene.
[73]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [62], wherein the organic solvent is dichloromethane, 1,2-dichloroethane or toluene.
[74]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [62], wherein the organic solvent is toluene.
[75]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [62], wherein the organic solvent is dichloromethane.
[76]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [62], wherein the organic solvent is 1,2-dichloroethane.

  According to the present invention, an inexpensive and efficient process for producing an extremely high-purity O- [1- (2-hydroxypropyl)] oxime compound, which is useful as an intermediate for pharmaceuticals, agricultural chemicals, electronic materials, etc., is provided. be able to.

  The compounds included in the present invention include geometrical isomers of E-form and Z-form, but the compounds according to the present invention include these E-forms, Z-forms, or E-forms and Z-forms. It is intended to include a mixture containing at an arbitrary ratio.

  In the compound (1) included in the present invention, an optically active substance due to the presence of one or two or more asymmetric carbon atoms may exist depending on the substituents. Such compounds include all optically active isomers or racemates.

  Among the compounds included in the present invention, those which can be converted into salts by a conventional method include, for example, hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide and other hydrogen halide salts, nitric acid, sulfuric acid. Inorganic acid salts such as phosphoric acid, chloric acid, perchloric acid, sulfonic acid salts such as methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, tartaric acid , Oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid, carboxylic acid salts such as citric acid, amino acid salts such as glutamic acid and aspartic acid, lithium, sodium, potassium Alkali metal salts such as, alkaline earth metal salts such as calcium, barium and magnesium, aluminum salts, tetramethyl Moniumu salts, tetrabutylammonium salts, may be quaternary ammonium salts such as benzyltrimethylammonium salts.

  Next, specific examples of each substituent shown in the present specification are shown below. Here, n- means normal, i- means iso, s- means secondary, and t- means tertiary.

  Examples of the halogen atom in the present invention include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. In addition, the notation of “halo” in the present specification also represents these halogen atoms.

The notation of a C ₁ -C ₆ alkyl group in the present specification represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, n- Propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, s-butyl group, n-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1- Ethylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, neopentyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group Group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group Base, 3, Specific examples include 3-dimethylbutyl group, 1,1,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, etc. The range is selected.

In the present specification, the expression “R ¹ and R ² together with the carbon atom to which they are bonded to form a 5- to 7-membered carbocycle” means that R ¹ together with R ² is C ₄ To form a 5- to 7-membered ring together with the carbon atom to which R ¹ and R ² are bonded by forming an alkylene chain of C ₆ to C ₆ , and examples thereof include a cyclopentane ring and a cyclohexane ring. .
Next, an O- [1- (2-hydroxypropyl)] oxime compound represented by the formula (1) [hereinafter, abbreviated as compound (1). ] The steps (a) to (c) in the manufacturing method will be described in detail below.

[Step (a)]

Formula (2) [In the formula, R ¹ and R ² have the same meanings as defined above. ] An oxime compound represented by the following [abbreviated as compound (2) hereinafter. ] With propylene oxide in the presence of a basic compound, compound (1) can be produced.

In addition, as the product of this step, the compound (1) is an isomer of the compound (1), which is represented by the formula (3) [wherein, R ¹ and R ² have the same meanings as defined above. ] A compound represented by the following [hereinafter, abbreviated as compound (3)]. ] As a mixture with. The production ratio of the compound (1) and the compound (3) is usually 85/15 to 96/4.

  The propylene oxide used in step (a) can be used in an amount of 0.5 to 5 equivalents, preferably 0.9 to 1.5 equivalents, relative to 1 equivalent of compound (2).

  Examples of the basic compound used in the step (a) include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Alkali metal bicarbonates, alkali metal phosphates such as sodium phosphate, potassium phosphate, etc., alkali metal hydrogen phosphates such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, magnesium hydroxide, calcium hydroxide, etc. Alkaline earth metal hydroxides, alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate, alkaline earth metal bicarbonates such as magnesium hydrogen carbonate and calcium hydrogen carbonate, alkaline earth metal salts such as magnesium phosphate and calcium phosphate Alcohols such as phosphates, magnesium hydrogen phosphate, calcium hydrogen phosphate, etc. Li earth metal hydrogen phosphate salt, triethylamine, tributylamine, pyridine, 4- (dimethylamino) pyridine, imidazole, 1,8-diazabicyclo [5,4,0] -7-undecene and an organic base such as. These basic compounds can be used alone or in combination of two or more kinds.

  The amount of the basic compound used can be 0.01 to 5 equivalents, preferably 0.05 to 2 equivalents, relative to 1 equivalent of the compound (2).

  When using a solvent, the solvent used is not particularly limited as long as it does not inhibit the progress of the reaction, for example, hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, a hydrocarbon solvent such as heptane, benzene, xylene, toluene. Aromatic hydrocarbon solvent such as, dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene, halogenated hydrocarbon solvent such as trifluoromethylbenzene, alcohol solvent such as methanol, ethanol, 2-propanol, acetone, Ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, nitrile solvents such as acetonitrile and propionitrile, carboxylic ester solvents such as ethyl acetate and ethyl propionate, N, N-dimethylformamide, N, N-dimethyl Examples include nitrogen-containing aprotic polar solvents such as cetoamide, N-methylpyrrolidone, and 1,3-dimethyl-2-imidazolidinone, water, and the like, and preferably xylene, aromatic hydrocarbon solvents such as toluene, dichloromethane, and the like. A halogen-based hydrocarbon solvent such as 1,2-dichloroethane or water can be used. These solvents may be used as a mixture of two or more kinds.

  Step (a) can be carried out in an atmosphere of normal pressure, but in some cases, it can be carried out in a pressure range of 0.001 to 100 MPa, preferably 0.1 to 10 MPa.

  The reaction temperature can usually be set arbitrarily within the range of -90 to 200 ° C, but preferably within the range of -20 to 100 ° C.

  The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but can be set usually in the range of 10 minutes to 100 hours, preferably 10 minutes to 24 hours.

  The amount of compound (1) obtained in step (a) can be calculated by quantitative analysis by the internal standard method using high performance liquid chromatography (HPLC).

  The treatment method after the reaction is not particularly limited, but the reaction mixture after completion of the reaction is directly concentrated, or dissolved in an organic solvent, and then charged with water, separated, concentrated if necessary, or added to water, an organic solvent. The reaction mixture can be obtained by performing ordinary post-treatments such as extraction and concentration if necessary. Further, the reaction mixture can be used as it is in the next step without concentrating the solution of the reaction mixture obtained after the post-treatment. Further, the reaction mixture after completion of the reaction can be used as it is in the next step without post-treatment. When the need for purification arises, it can be separated and purified by any purification method such as distillation, recrystallization, column chromatography, thin layer chromatography and liquid chromatography fractionation.

[Step (b)]

A mixture of the compound (1) and the compound (3) is converted into a cyclic acid anhydride, for example, a compound represented by the formula (4) [wherein A is —CH ₂ CH ₂ —, —CH═CH—, or 1,2-phenylene group and the like. Represent ] By reacting with an acid anhydride represented by the formula (1), a compound (1), formula (5) [wherein R ¹ and R ² have the same meanings as defined above, a is -CH ₂ CH ₂ -, - it represents a CH = CH- or 1,2-phenylene group. ] A compound represented by the following [abbreviated as compound (5) hereinafter. ] And the formula (6) wherein, R ¹ and R ² have the same meanings as defined above, A is -CH ₂ CH ₂ -, - represents a CH = CH- or 1,2-phenylene group. ] A compound represented by the following [hereinafter, abbreviated as compound (6). ] It is possible to produce a mixture with

  In this specification, the step (b) and the step (c) are described using the acid anhydride represented by the formula (4) as the cyclic acid anhydride. However, the cyclic acid anhydride used in the present invention is described. The substance is not limited to the acid anhydride represented by the formula (4).

  Since compound (3) is a primary alcohol compound, it preferentially reacts with compound (4) as compared with compound (1) to form compound (6). As a result, at the end of the step (b), the abundance ratio of the compound (3) in the reaction solution decreases, and specifically, the abundance ratio of the compound (1) and the compound (3) is usually 99/1 to 100 /. It will be about 0.

  The cyclic acid anhydride used in step (b) is not particularly limited as long as it is a compound capable of reacting with compound (3) to form a ring-opened compound such as compound (6). , Maleic anhydride, succinic anhydride, phthalic anhydride, itaconic anhydride, glutaric anhydride, adipic anhydride, citraconic anhydride, trimellitic anhydride, hexahydrophthalic anhydride, tetra Examples thereof include chlorophthalic anhydride, cis-4-cyclohexene-1,2-dicarboxylic acid anhydride and isododecenyl succinic anhydride. Among them, maleic anhydride, succinic anhydride and phthalic anhydride are preferable from the viewpoint of easy availability. These cyclic acid anhydrides can be used alone or in combination of two or more kinds.

  The cyclic acid anhydride used in step (b) is preferably 0.04 to 1.0 equivalent with respect to 1 equivalent of compound (1), and the presence of compound (3) in the reaction solution after completion of step (b). From the viewpoint of further reducing the ratio, it is more preferably 0.1 to 1.0 equivalent, further preferably 0.2 to 0.9 equivalent, particularly preferably 0.3 to 0.8 equivalent. , And most preferably 0.5 to 0.7 equivalent.

  The cyclic acid anhydride in step (b) may be used twice or more times.

  Examples of the basic compound used in the step (b) include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Alkali metal bicarbonates, alkali metal phosphates such as sodium phosphate, potassium phosphate, etc., alkali metal hydrogen phosphates such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, magnesium hydroxide, calcium hydroxide, etc. Alkaline earth metal hydroxides, alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate, alkaline earth metal bicarbonates such as magnesium hydrogen carbonate and calcium hydrogen carbonate, alkaline earth metal salts such as magnesium phosphate and calcium phosphate Alcohols such as phosphates, magnesium hydrogen phosphate, calcium hydrogen phosphate, etc. Organic earth bases such as a lithium earth metal hydrogen phosphate, triethylamine, tributylamine, pyridine, 4- (dimethylamino) pyridine, imidazole, 1,8-diazabicyclo [5,4,0] -7-undecene, and the like. . These basic compounds can be used alone or in combination of two or more kinds.

  The basic compound can be used in an amount of 0.04 to 1.0 equivalents, preferably 0.1 to 1.0 equivalents, relative to compound (1).

  When using a solvent, the solvent used is not particularly limited as long as it does not inhibit the progress of the reaction, for example, hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, a hydrocarbon solvent such as heptane, benzene, xylene, toluene. Aromatic hydrocarbon solvent such as, dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene, halogenated hydrocarbon solvent such as trifluoromethylbenzene, alcohol solvent such as methanol, ethanol, 2-propanol, acetone, Ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, nitrile solvents such as acetonitrile and propionitrile, carboxylic ester solvents such as ethyl acetate and ethyl propionate, N, N-dimethylformamide, N, N-dimethyl Examples include nitrogen-containing aprotic polar solvents such as cetoamide, N-methylpyrrolidone, and 1,3-dimethyl-2-imidazolidinone, water, and the like, and preferably xylene, aromatic hydrocarbon solvents such as toluene, dichloromethane, and the like. A halogen-based hydrocarbon solvent such as 1,2-dichloroethane or water can be used. These solvents may be used as a mixture of two or more kinds.

  Step (b) can be performed under an atmosphere of normal pressure, but in some cases, it can be performed within a pressure range of 0.001 to 100 MPa, preferably 0.1 to 10 MPa.

  The reaction temperature can usually be set arbitrarily within the range of -90 to 200 ° C, but preferably within the range of -20 to 100 ° C.

  The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but can be set usually in the range of 10 minutes to 100 hours, preferably 10 minutes to 24 hours.

  The treatment method after the reaction is not particularly limited, but the reaction mixture after completion of the reaction is directly concentrated, or dissolved in an organic solvent, and then charged with water, separated, concentrated if necessary, or added to water, an organic solvent. The reaction mixture can be obtained by performing ordinary post-treatments such as extraction and concentration if necessary. Further, the reaction mixture can be used as it is in the next step without concentrating the solution of the reaction mixture obtained after the post-treatment. Further, the reaction mixture after completion of the reaction can be used as it is in the next step without post-treatment. When the need for purification arises, it can be separated and purified by any purification method such as distillation, recrystallization, column chromatography, thin layer chromatography and liquid chromatography fractionation.

[Step (c)]

  By mixing an organic solvent containing a mixture of compound (1), compound (5) and compound (6) with an aqueous solution of a basic compound, compound (5) and compound (6) move to the aqueous layer, Only the compound (1) can remain in the organic solvent.

  Examples of the basic compound in the aqueous solution of the basic compound used in the step (c) include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, hydrogen carbonate. Alkali metal bicarbonate such as sodium and potassium hydrogen carbonate, alkali metal phosphate such as sodium phosphate and potassium phosphate, alkali metal hydrogen phosphate such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, and hydroxide Alkaline earth metal hydroxides such as magnesium and calcium hydroxide, alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate, alkaline earth metal bicarbonates such as magnesium hydrogen carbonate and calcium hydrogen carbonate, magnesium phosphate, Alkaline earth metal phosphates such as calcium phosphate, magnesium hydrogen phosphate, phosphorus Organic bases such as alkaline earth metal hydrogen phosphates such as calcium hydrogen, triethylamine, tributylamine, pyridine, 4- (dimethylamino) pyridine, imidazole, 1,8-diazabicyclo [5,4,0] -7-undecene Etc. These basic compounds can be used alone or in combination of two or more kinds.

  The amount of the basic compound used can be 0.02 to 10 equivalents relative to compound (1).

  Examples of the organic solvent used in the step (c) include hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane and heptane, aromatic hydrocarbon solvents such as benzene, xylene and toluene, dichloromethane and carbon tetrachloride. , Halogen-based hydrocarbon solvents such as chloroform, 1,2-dichloroethane, chlorobenzene and trifluoromethylbenzene, alcohol solvents such as methanol, ethanol and 2-propanol, ketone solvents such as acetone, methylethylketone and methylisobutylketone, acetonitrile and propylene. Nitrile solvents such as pionitrile, carboxylic ester solvents such as ethyl acetate and ethyl propionate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl Nitrogen-containing aprotic polar solvents such as 2-imidazolidinone, and the like, preferably aromatic hydrocarbon solvents such as xylene and toluene, and halogen-based hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane. Further preferably, toluene, dichloromethane and 1,2-dichloroethane can be used. These solvents may be used as a mixture of two or more kinds.

  Step (c) can be carried out in an atmosphere of normal pressure, but in some cases, it can be carried out in a pressure range of 0.001 to 100 MPa, preferably 0.1 to 10 MPa.

  The reaction temperature can be optionally set in the range of usually -15 to 200 ° C, preferably -5 to 50 ° C.

  The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but can be set usually in the range of 10 minutes to 100 hours, preferably 10 minutes to 24 hours.

The steps (a) to (c) can be continuously performed.
Performing the steps (a) to (c) continuously means that the product obtained in the previous step is used as it is in a crude product without isolation and purification in the next step. What is to do is to carry out step (b) using the product produced in step (a) as it is without isolation and purification, and to isolate the product produced in step (b). It is to carry out step (c) as it is without purification. The reaction vessels in which the steps (a), (b) and (c) are performed may be the same or different.

  Examples of the organic solvent used when the steps (a) to (c) are continuously performed include hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane and heptane, benzene, xylene, toluene and the like. Aromatic hydrocarbon solvents, dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene, halogenated hydrocarbon solvents such as trifluoromethylbenzene, alcohol solvents such as methanol, ethanol, 2-propanol, acetone, methyl ethyl ketone, Ketone solvents such as methyl isobutyl ketone, nitrile solvents such as acetonitrile and propionitrile, carboxylic ester solvents such as ethyl acetate and ethyl propionate, N, N-dimethylformamide, N, N-dimethylacetamide, N-medium Examples include nitrogen-containing aprotic polar solvents such as rupyrrolidone and 1,3-dimethyl-2-imidazolidinone, and preferably aromatic hydrocarbon solvents such as xylene and toluene, dichloromethane, 1,2-dichloroethane and the like. The halogen-based hydrocarbon solvent described in (3) above can be used, and more preferably, toluene, dichloromethane, or 1,2-dichloroethane can be used. These solvents may be used as a mixture of two or more kinds.

  The compound (1) obtained by the above steps (a) to (c) has extremely high purity. For example, the abundance ratio of the compound (1) and the compound (3) is 98/2 to 100/0, and preferably 99 / from the viewpoint of further enhancing the quality and performance of the product using the compound (1). It is 1 to 100/0, more preferably 99.5 / 0.5 to 100/0, and further preferably 99.9 / 0.1 to 100/0.

Hereinafter, the present invention will be described in more detail with reference to synthetic examples, but the present invention is not limited to these examples.
In addition, ¹ H-NMR was measured at 300 MHz or 600 MHz, and HPLC, LC / MS and GC, GC / MS were measured under the following conditions.
Further, NMR represents nuclear magnetic resonance spectrum, HPLC represents high performance liquid chromatography, LC / MS represents liquid chromatography mass measurement analysis method, GC represents gas chromatography, and GC / MS represents gas chromatography mass measurement analysis method.
Further, Rt represents a holding time.

[Example 1] Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (a): Butanone oxime 10.0 g (115 mmol) was suspended in water 50 g, and 48 mass% potassium hydroxide aqueous solution 1. 41 g (12.0 mmol) was added. After heating the reaction solution to 40 ° C., 8.05 g (139 mmol) of propylene oxide was added. After the addition was completed, the reaction solution was stirred at the same temperature for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and then partitioned with dichloromethane (100 mL, 20 mL). The obtained organic layer was washed with water (20 mL) and concentrated under reduced pressure. 15.8 g of the target crude product was obtained as a pale yellow oil.
As a result of qualitative analysis using HPLC, the target compound represented by the formula (7) described below [hereinafter, abbreviated as target product (7). ], And O- [2- (1-hydroxypropyl)] butanone oxime represented by the formula (8) which is an isomer [hereinafter, abbreviated as isomer (8). ] Area ratio of 94.3 / 5.7 (Rt = 11.4 minutes / 11.8 minutes) was confirmed. Further, as a result of analysis using GC / MS (CI +), two peaks (Rt = 5.67 min / 5.71 min) were observed, and MS of the two peaks were both m / z: 146 (MH +). Was confirmed.

Step (b): 0.58 g of the obtained crude product of the desired product [containing 2.5 mmol of the desired product (7)] was dissolved in 2.7 g of dichloromethane and cooled to 5 ° C. To the reaction solution, 0.073 g (0.72 mmol) of triethylamine and 0.082 g (0.82 mmol) of succinic anhydride were added. After the addition was completed, the reaction solution was stirred at the same temperature for 19 hours.
As a result of qualitative analysis of the reaction solution using HPLC, it was found that the area ratio of the target substance (7) to the isomer (8) was 100/0 (Rt = 11.4 min / 11.8 min). confirmed.
On the other hand, a compound represented by the following formula (9), which is a product obtained by reacting the target product (7) with succinic anhydride [hereinafter, abbreviated as compound (9). ] Rt = 13.3 min-13.4 min peak, the compound represented by the formula (10) in which the isomer (8) is reacted with succinic anhydride [hereinafter, abbreviated as compound (10). ] Was estimated to be a peak at Rt = 13.6 minutes to 13.7 minutes. That is, the area ratio of the target product (7), the isomer (8), the compound (9) and the compound (10) was 84.0 / 0 / 10.3. / 5.7.

As a result of analyzing the reaction solution using GC / MS (CI +), two peaks were observed. The MS of one peak was m / z: 146 (MH +) (Rt = 5.6 min) and the MS of the other peak was m / z: 246 (MH +) (Rt = 10.2 min). confirmed. It was estimated that the compound (9) and the compound (10) were detected by overlapping at Rt = 10.2 minutes.
In addition, as a result of analyzing the reaction solution using LC / MS (ESI +), two peaks were observed. The MS of one peak was m / z: 146 (MH +) (Rt = 2.3 min), and the MS of the other peak was m / z: 246 (MH +) (Rt = 3.5 min). confirmed. It was estimated that the compound (9) and the compound (10) were detected by overlapping at Rt = 3.5 minutes.

  Step (c): The reaction solution obtained in step (b) was washed with a 5 mass% sodium hydrogen carbonate aqueous solution (5 g × 2) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (7) was obtained in a yield of 35% (calculated from butanone oxime). It was also confirmed that the area ratio between the target product (7) and the isomer (8) was 100/0 (Rt = 11.4 minutes / 11.8 minutes).

The conditions for qualitative and quantitative analysis by high performance liquid chromatography are described below.
Column: Waters XBridge C18 3.5 μm, 4.6 mm × 150 mm,
Eluent: acetonitrile / water = 10/90 (5 minutes)-(10 minutes) -60/40 (2 minutes)-(3 minutes) -10/90 (10 minutes) (volume ratio),
Flow rate: 1 mL / min,
Column temperature: 40 ° C
Internal standard substance: None (1 point absolute quantification)
The conditions for analysis by GC / MS are described below.
Column: HP-5 manufactured by Agilent Technologies 0.32 mm ID × 30 m × 0.25 μm,
Temperature rising time and temperature rising rate: 40 ° C (2 minutes)-(20 ° C / minute) -300 ° C (7 minutes)
The conditions for analysis by LC / MS are described below.
Column: Waters XBridge C18 5 μm, 2.1 mm × 150 mm,
Eluent: acetonitrile / water = 40/60 (volume ratio)
Flow rate: 0.2 mL / min Column temperature: 40 ° C

[Examples 2 to 5] Synthesis of O- [1- (2-hydroxypropyl)] oxime compound According to the steps (a) to (c) described in Example 1, the starting material oxime compound ( The reaction was carried out by appropriately changing the acid anhydride used in 2) and step (b).
The yield of the O- [1- (2-hydroxypropyl)] oxime compound obtained in step (c) and the target product (7) and isomers calculated by qualitative analysis using HPLC or GC in each step The area ratio of the peak of (8) is shown in Table 1 below.

The conditions for qualitative and quantitative analysis by HPLC and GC are described below.
HPLC analysis conditions (Example 2)
Column: Waters XBridge C18 3.5 μm, 4.6 mm × 150 mm,
Eluent: methanol / water / 85 mass% phosphoric acid = 35/65 / 0.1 (volume ratio),
Flow rate: 0.8 mL / min,
Column temperature: 40 ° C
Internal standard substance: 4-methoxytoluene GC analysis conditions (Examples 3, 4, and 5)
Column: Agilent Technology CP-WAX 52 CB 0.25 mm ID × 25 m × 0.20 μm,
Temperature rising time and temperature rising rate: 40 ° C (0 minutes)-(5 ° C / minute) -90 ° C (0 minutes)-(10 ° C / minute) -250 ° C (10 minutes)
Internal standard substance: Diethylene glycol dimethyl ether

[Example 6] Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (a): Butanone oxime 10.0 g (115 mmol) was suspended in water 30 g, and 40 mass% sodium hydroxide aqueous solution 1. 15 g (11.5 mmol) was added. After heating the reaction solution to 40 ° C., 10.0 g (172 mmol) of propylene oxide was added. After the addition was completed, the reaction solution was stirred at the same temperature for 4 hours. After the reaction was completed, the reaction solution was cooled to 10 ° C., and then 95% by mass sulfuric acid 5.93 g (57.4 mmol) was added. After the addition was completed, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was partitioned with 1,2-dichloroethane (30 g × 2) at the same temperature. 71.8 g of a target 1,2-dichloroethane solution was obtained.
As a result of qualitative analysis using HPLC, it was confirmed that the area ratio of the target substance (7) and the isomer (8) was 94.4 / 5.6 (Rt = 6.6 min / 7.1 min). did.

Step (b): 71.1 g of the obtained 1,2-dichloroethane solution of the target product [containing 60.5 mmol of the target product (7)] was cooled to 10 ° C. 0.73 g (7.26 mmol) of triethylamine and 0.59 g (6.05 mmol) of maleic anhydride were added to the reaction solution. After the addition was completed, the reaction solution was stirred at the same temperature for 3 hours. 0.73 g (7.26 mmol) of triethylamine and 0.59 g (6.05 mmol) of maleic anhydride were added to the reaction solution. After the addition was completed, the reaction solution was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction solution was qualitatively analyzed using HPLC.
Of the two newly detected peaks, the peak at Rt = 11.9 minutes is a compound represented by the following formula (11), which is a product obtained by reacting the target compound (7) with maleic anhydride. [Hereinafter, abbreviated as compound (11). ], The peak at Rt = 13.4 minutes is a compound represented by the formula (12) in which the isomer (8) is reacted with maleic anhydride [hereinafter, abbreviated as compound (12). ]] Was estimated. As a result of qualitative analysis, the area ratio of the target product (7), isomer (8), compound (11) and compound (12) was 77.4 / 0.7 / 12.2 / 9.7.
That is, it was confirmed that the area ratio between the target product (7) and the isomer (8) was 99.2 / 0.8 (Rt = 6.6 min / 7.1 min).

  Step (c): The reaction solution obtained in step (b) was washed with a 5% by mass aqueous sodium hydrogen carbonate solution (18 g × 3) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (7) was obtained in a yield of 44% (calculated from butanone oxime). It was also confirmed that the area ratio between the target product (7) and the isomer (8) was 99.2 / 0.8 (Rt = 6.6 min / 7.1 min).

The conditions for qualitative and quantitative analysis by HPLC are described below.
Column: Waters XBridge C18 3.5 μm, 4.6 mm × 150 mm
Eluent: methanol / water / 85 mass% phosphoric acid = 35/65 / 0.1 (volume ratio)
Flow rate: 0.8 mL / min Column temperature: 40 ° C
Internal standard substance: 4-methoxytoluene

[Example 7] Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (a): 25.0 g (287 mmol) of butanone oxime was suspended in 38 g of water to prepare a 40 mass% sodium hydroxide aqueous solution 2. 87 g (28.7 mmol) was added. After heating the reaction solution to 30 ° C., 21.7 g (373 mmol) of propylene oxide was added. After the addition was completed, the reaction solution was stirred at the same temperature for 4 hours. After completion of the reaction, the reaction solution was cooled to 10 ° C., and 8.89 g (86.1 mmol) of 95 mass% sulfuric acid was added. After the addition was completed, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated at the same temperature with toluene (25 g × 2). 83.6 g of a target toluene solution was obtained.
As a result of qualitative analysis using HPLC, it was confirmed that the area ratio of the target substance (7) and the isomer (8) was 94.9 / 5.1 (Rt = 6.7 min / 7.2 min). did.

Step (b): 83.1 g of the obtained toluene solution of the target substance [containing 155 mmol of the target substance (7)] was cooled to 10 ° C. To the reaction solution was added triethylamine (5.63 g, 55.6 mmol). At the same temperature, a mixed solution of 4.55 g (46.4 mmol) of maleic anhydride and 23 g of toluene was added to the reaction solution. After the addition was completed, the reaction solution was stirred at the same temperature for 1 hour.
As a result of qualitative analysis of the reaction solution using HPLC, the area ratio of the target compound (7), isomer (8), compound (11) and compound (12) was 71.2 / 0.3 / 19.0. It was /9.5 (Rt = 6.7 minutes / 7.2 minutes / 12.2 minutes / 13.8 minutes).
That is, it was confirmed that the area ratio between the target product (7) and the isomer (8) was 99.7 / 0.3 (Rt = 6.7 min / 7.2 min).
The reaction solution was analyzed by LC / MS (ESI ±) (analysis conditions described in Example 1), and as a result, two peaks were observed. MS of one peak is m / z: 146 (MH +) (Rt = 3.2 min), MS of another peak is m / z: 242 (MH-) (Rt = 2.5 min) It was confirmed. It was estimated that the compound (9) and the compound (10) were detected with overlapping at Rt = 2.5 minutes.

  Step (c): The reaction solution obtained in the step (b) was washed with a 15 mass% potassium carbonate aqueous solution (22 g × 2) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (7) was obtained in a yield of 46% (calculated from butanone oxime). It was also confirmed that the area ratio between the target product (7) and the isomer (8) was 99.7 / 0.3 (Rt = 6.7 min / 7.2 min).

  The qualitative and quantitative analyzes by HPLC used the conditions described in Example 6, and ethoxybenzene was used as the internal standard substance used in the quantitative analysis.

[Example 8] Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (a): Butanone oxime 85.0 g (976 mmol) was suspended in 170 g of water, and 40 mass% sodium hydroxide aqueous solution 1. 56 g (39.0 mmol) was added. After heating the reaction solution to 30 ° C., 73.7 g (1.27 mol) of propylene oxide was added. After the addition was completed, the reaction solution was stirred at the same temperature for 14 hours. After completion of the reaction, the reaction solution was cooled to 10 ° C., and 30.2 g (293 mmol) of 95 mass% sulfuric acid was added. After the addition was completed, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated with toluene (85 g × 2) at the same temperature. 282 g of a target toluene solution was obtained.
As a result of qualitative analysis using HPLC, it was confirmed that the area ratio of the target substance (7) and the isomer (8) was 94.7 / 5.3 (Rt = 7.2 min / 7.8 min). did.

Step (b): 10.4 g of the obtained toluene solution of the target substance [containing 20.3 mmol of the target substance (7)] was cooled to 10 ° C. 0.74 g (7.30 mmol) of triethylamine and 0.60 g (6.08 mmol) of maleic anhydride were added to the reaction solution. After the addition was completed, the reaction solution was stirred at the same temperature for 3 hours.
As a result of qualitative analysis of the reaction solution using HPLC, the area ratio of the target product (7), isomer (8), compound (11) and compound (12) was 67.8 / 0.5 / 22.0. It was /9.6 (Rt = 7.2 minutes / 7.8 minutes / 13.9 minutes / 15.7 minutes).
That is, it was confirmed that the area ratio between the target product (7) and the isomer (8) was 99.3 / 0.7 (Rt = 7.2 min / 7.8 min).

  Step (c): The reaction solution obtained in the step (b) was washed with a 5 mass% sodium hydrogen carbonate aqueous solution (5.9 g × 3) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (7) was obtained in a yield of 35% (calculated from butanone oxime). It was also confirmed that the area ratio of the target product (7) to the isomer (8) was 99.4 / 0.6 (Rt = 7.2 min / 7.8 min).

  The qualitative and quantitative analyzes by HPLC used the conditions described in Example 6, and ethoxybenzene was used as the internal standard substance used in the quantitative analysis.

[Example 9] Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (b): 15.1 g of a toluene solution of the target product obtained in the step (a) of Example 8 [target ( 7) in 29.3 mmol] was cooled to 5 ° C. To the reaction solution, 1.07 g (10.6 mmol) of triethylamine and 0.86 g (8.79 mmol) of maleic anhydride were added. After the addition was completed, the reaction solution was stirred at the same temperature for 3 hours.
As a result of qualitative analysis of the reaction solution using HPLC, the area ratio of the target compound (7), isomer (8), compound (11) and compound (12) was 67.8 / 0.2 / 22.5. /9.4 (Rt = 7.3 minutes / 7.9 minutes / 14.1 minutes / 15.9 minutes).
That is, it was confirmed that the area ratio between the target product (7) and the isomer (8) was 99.7 / 0.3 (Rt = 7.3 min / 7.9 min).

  Step (c): The reaction solution obtained in the step (b) was washed with a 5 mass% sodium carbonate aqueous solution (4.3 g × 2) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (7) was obtained in a yield of 41% (calculated from butanone oxime). It was also confirmed that the area ratio between the target product (7) and the isomer (8) was 99.8 / 0.2 (Rt = 7.3 min / 7.9 min).

  The qualitative and quantitative analyzes by HPLC used the conditions described in Example 6, and ethoxybenzene was used as the internal standard substance used in the quantitative analysis.

Example 10 Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (b): 13.9 g of a toluene solution of the target compound obtained in the step (a) of Example 8 [target ( 7) in 27.0 mmol] was cooled to 0 ° C. 0.98 g (9.72 mmol) of triethylamine was added to the reaction solution. At the same temperature, a mixed solution of maleic anhydride 0.78 g (8.10 mmol) and toluene 3.9 g was added to the reaction solution. After the addition was completed, the reaction solution was stirred at the same temperature for 2 hours.
As a result of qualitative analysis of the reaction solution using HPLC, the area ratio of the target compound (7), isomer (8), compound (11) and compound (12) was 68.0 / 0.3 / 22.3. /9.4 (Rt = 7.3 minutes / 7.9 minutes / 14.1 minutes / 15.9 minutes).
That is, it was confirmed that the area ratio between the target product (7) and the isomer (8) was 99.6 / 0.4 (Rt = 7.3 min / 7.9 min).

  Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous potassium hydrogen carbonate solution (3.9 g × 2) at 10 ° C. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (7) was obtained in a yield of 44% (calculated from butanone oxime). It was also confirmed that the area ratio between the target product (7) and the isomer (8) was 99.4 / 0.6 (Rt = 7.3 min / 7.9 min).

  The qualitative and quantitative analyzes by HPLC used the conditions described in Example 6, and ethoxybenzene was used as the internal standard substance used in the quantitative analysis.

[Example 11] Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (a): 100 g (1.15 mol) of butanone oxime was suspended in 300 g of water to prepare a 40 mass% sodium hydroxide aqueous solution. 5 g (115 mmol) was added. After heating the reaction solution to 30 ° C., 87.1 g (1.50 mol) of propylene oxide was added. After the addition was completed, the reaction solution was stirred at the same temperature for 4 hours. After the reaction was completed, the reaction solution was cooled to 10 ° C., and then 33.8 g (327 mmol) of 95 mass% sulfuric acid was added. After the addition was completed, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was partitioned at the same temperature with dichloromethane (300 g × 2). 729 g of a dichloromethane solution of the target substance was obtained.
As a result of qualitative analysis using HPLC, it was confirmed that the area ratio of the target substance (7) and the isomer (8) was 94.8 / 5.2 (Rt = 6.7 min / 7.2 min). did.

Step (b): 23.5 g of the obtained dichloromethane solution of the desired product [containing 22.2 mmol of the desired product (7)] was cooled to 10 ° C. 0.76 g (7.5 mmol) of triethylamine and 0.94 g (6.3 mmol) of phthalic anhydride were added to the reaction solution. After the addition was completed, the reaction solution was stirred at the same temperature for 23 hours. After completion of the reaction, the reaction solution was qualitatively analyzed using HPLC.
Of the two newly detected peaks, the peak at Rt = 47.9 minutes is a product obtained by reacting the target compound (7) with phthalic anhydride, and is a compound represented by the following formula (13). [Hereinafter, abbreviated as compound (13). ], The peak at Rt = 55.7 minutes is a compound represented by the formula (14) in which the isomer (8) is reacted with phthalic anhydride [hereinafter, abbreviated as compound (14). ]] Was estimated. As a result of qualitative analysis, the area ratio of the target substance (7), the isomer (8), the compound (13) and the compound (14) was 64.0 / 0.1 / 22.1 / 13.8.
That is, it was confirmed that the area ratio between the target product (7) and the isomer (8) was 99.8 / 0.2 (Rt = 6.7 min / 7.2 min).

  As a result of analyzing the reaction solution using LC / MS (ESI ±), two peaks were observed. MS of one peak is m / z: 146 (MH +) (Rt = 3.3 min), MS of another peak is m / z: 294 (MH-) (Rt = 2.1 min) It was confirmed. It was estimated that Compound (13) and Compound (14) were detected with Rt = 2.1 min.

  Step (c): The reaction solution obtained in the step (b) was washed with a 5 mass% sodium hydrogen carbonate aqueous solution (6 g × 7) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (7) was obtained in a yield of 44% (calculated from butanone oxime). It was also confirmed that the area ratio between the target product (7) and the isomer (8) was 99.7 / 0.3 (Rt = 6.7 min / 7.2 min).

  The qualitative and quantitative analysis by HPLC used the conditions described in Example 6, and 4-methoxytoluene was used as the internal standard substance used in the quantitative analysis. The conditions described in Example 1 were used for the analysis by LC / MS.

Example 12 Synthesis of O- [1- (2-hydroxypropyl)]-3-methyl-2-butanone oxime Step (a): 15.3 g (149 mmol) of 3-methyl-2-butanone oxime and 23 g of water The suspension was added to 1.51 g (15.1 mmol) of 40 mass% sodium hydroxide aqueous solution. After heating the reaction solution to 30 ° C., 11.3 g (194 mmol) of propylene oxide was added. After the addition was completed, the reaction solution was stirred at the same temperature for 7 hours. 0.87 g (15 mmol) of propylene oxide was added to the reaction solution at the same temperature. After the addition was complete, the reaction solution was stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was cooled to 10 ° C., and then 4.39 g (42.5 mmol) of 95 mass% sulfuric acid was added. After the addition was completed, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was partitioned with toluene (15 g × 2) at the same temperature. 49.6 g of a target toluene solution was obtained.
As a result of qualitative analysis using HPLC, the target compound represented by the formula (15) described below [hereinafter, abbreviated as target product (15). ] And O- [2- (1-hydroxypropyl)]-3-methyl-2-butanone oxime represented by the formula (16) which is an isomer [hereinafter, abbreviated as isomer (16). ] The area ratio was 94.7 / 5.3 (Rt = 12.3 and 13.0 minutes / 13.6 and 14.5 minutes). As a result of analysis using GC / MS (CI +), one peak (Rt = 6.1 minutes) was observed, and it was confirmed that the MS of the peak was m / z: 160 (MH +).

Step (b): 23.0 g of the obtained toluene solution of the target product (containing 39.5 mmol of the target product (15)) was cooled to 10 ° C. To the reaction solution were added 1.45 g (14.3 mmol) of triethylamine and 1.16 g (11.8 mmol) of maleic anhydride. After the addition was completed, the reaction solution was stirred at the same temperature for 4 hours. After completion of the reaction, the reaction solution was qualitatively analyzed using HPLC.
Of the two newly detected peaks, the peaks at Rt = 24.1 and 25.2 minutes are represented by the following formula (17), which is a product of the reaction between the target compound (15) and maleic anhydride. Compound represented [hereinafter, abbreviated as compound (17). ], Rt = 27.7 and 29.4 min peaks are the compounds represented by the formula (18) in which the isomer (16) reacts with maleic anhydride [hereinafter, abbreviated as compound (18). ]] Was estimated. As a result of qualitative analysis, the area ratio of the target substance (15), isomer (16), compound (17) and compound (18) was 71.9 / 0.2 / 18.0 / 9.9.
That is, the area ratio of the target substance (15) and the isomer (16) is 99.7 / 0.3 (Rt = 12.5 and 13.3 min / 13.9 and 14.7 min). confirmed.

  As a result of analyzing the reaction solution using LC / MS (ESI ±), two peaks were observed. MS of one peak is m / z: 160 (MH +) (Rt = 4.4 min), MS of another peak is m / z: 256 (MH-) (Rt = 3.1 min) It was confirmed. It was estimated that the compound (17) and the compound (18) were detected overlapping at Rt = 3.1 minutes.

  Step (c): The reaction solution obtained in the step (b) was washed with a 15 mass% potassium carbonate aqueous solution (6 g × 2) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (15) was obtained in a yield of 47% (calculated from 3-methyl-2-butanone oxime). did. Also, the area ratio of the target substance (15) to the isomer (16) may be 99.7 / 0.3 (Rt = 12.5 and 13.3 min / 13.9 and 14.7 min). confirmed.

  The qualitative and quantitative analyzes by HPLC used the conditions described in Example 6, and 2-nitrotoluene was used as the internal standard substance used in the quantitative analysis. The conditions described in Example 1 were used for the analysis by GC / MS and LC / MS.

[Example 13] Synthesis of O- [1- (2-hydroxypropyl)]-3,3-dimethyl-2-butanone oxime Step (a): 12.9 g (112 mmol) of 3,3-dimethyl-2-butanone oxime ) Was suspended in 20 g of water, and 1.11 g (11.1 mmol) of 40 mass% sodium hydroxide aqueous solution was added. After heating the reaction solution to 30 ° C., 8.49 g (146 mmol) of propylene oxide was added. After the addition was completed, the reaction solution was stirred at the same temperature for 50 hours. After completion of the reaction, the reaction solution was cooled to 10 ° C., and then 3.33 g (32.2 mmol) of 95 mass% sulfuric acid was added. After the addition was completed, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated with toluene (13 g × 2) at the same temperature. 43.7 g of the target toluene solution was obtained.
As a result of qualitative analysis using HPLC, the object represented by the formula (19) described below [hereinafter, abbreviated as the object (19). ], And O- [2- (1-hydroxypropyl)]-3,3-dimethyl-2-butanone oxime represented by the formula (20) which is an isomer [hereinafter, abbreviated as isomer (20). ]] Was 95.0 / 5.0 (Rt = 35.4 min / 41.8 min). Further, as a result of analysis using GC / MS (CI +), one peak (Rt = 6.5 minutes) was observed, and it was confirmed that the MS of the peak was m / z: 174 (MH +).

Step (b): 19.4 g of the obtained toluene solution of the desired product [containing 34.9 mmol of the desired product (19)] was cooled to 10 ° C. To the reaction solution were added 1.28 g (12.6 mmol) of triethylamine and 1.05 g (10.7 mmol) of maleic anhydride. After the addition was completed, the reaction solution was stirred at the same temperature for 5 hours. To the reaction solution, 0.64 g (6.3 mmol) of triethylamine and 0.51 g (5.2 mmol) of maleic anhydride were added. After the addition was completed, the reaction solution was stirred at the same temperature for 18 hours. To the reaction solution were added 0.43 g (4.2 mmol) of triethylamine and 0.37 g (3.8 mmol) of maleic anhydride. After the addition was completed, the reaction solution was stirred at the same temperature for 2 hours. After completion of the reaction, the reaction solution was qualitatively analyzed using HPLC.
Of the two newly detected peaks, the peak at Rt = 65.6 minutes is a compound represented by the following formula (21), which is a product obtained by reacting the target compound (19) with maleic anhydride. [Hereinafter, abbreviated as compound (21). ], Rt = 81.5 min peak is a compound represented by the formula (22) in which the isomer (20) is reacted with maleic anhydride [hereinafter, abbreviated as compound (22). ]] Was estimated. As a result of qualitative analysis, the area ratio of the target substance (19), isomer (20), compound (21) and compound (22) was 61.8 / 0.3 / 28.3 / 9.6.
That is, it was confirmed that the area ratio of the target substance (19) to the isomer (20) was 99.6 / 0.4 (Rt = 35.1 min / 41.6 min).

  As a result of analyzing the reaction solution using LC / MS (ESI ±), two peaks were observed. MS of one peak is m / z: 174 (MH +) (Rt = 7.3 min), MS of another peak is m / z: 270 (MH-) (Rt = 2.5 min) It was confirmed. It was estimated that the compound (21) and the compound (22) were detected by overlapping with Rt = 2.5 minutes.

  Step (c): The reaction solution obtained in the step (b) was washed with a 15 mass% potassium carbonate aqueous solution (6 g × 2) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, the target product (19) was obtained in a yield of 45% (calculated from 3,3-dimethyl-2-butanone oxime). It was confirmed. It was also confirmed that the area ratio of the target substance (19) to the isomer (20) was 99.6 / 0.4 (Rt = 35.1 min / 41.6 min).

  The qualitative and quantitative analyzes by HPLC used the conditions described in Example 6, and ethoxybenzene was used as the internal standard substance used in the quantitative analysis. The conditions described in Example 1 were used for the analysis by GC / MS and LC / MS.

[Example 14] Synthesis of O- [1- (2-hydroxypropyl)] cyclohexanone oxime Step (a): 15.0 g (133 mmol) of cyclohexanone oxime was suspended in 23 g of water to prepare a 40 mass% sodium hydroxide aqueous solution 1. 34 g (13.4 mmol) was added. After heating the reaction solution to 30 ° C., 10.2 g (175 mmol) of propylene oxide was added. After the addition was completed, the reaction solution was stirred at the same temperature for 4 hours, further cooled to 10 ° C., and then stirred for 21 hours. After the reaction was completed, 95% by mass sulfuric acid (3.96 g, 38.4 mmol) was added to the reaction solution at the same temperature. After the addition was completed, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was partitioned with toluene (15 g × 2) at the same temperature. 49.0 g of a toluene solution of the target substance was obtained.
As a result of qualitative analysis using HPLC, the target compound represented by the formula (23) described below [hereinafter, abbreviated as target product (23). ] And O- [2- (1-hydroxypropyl)] cyclohexanone oxime represented by the formula (24) which is an isomer [hereinafter, abbreviated as isomer (24). ]] Was 94.5 / 5.5 (Rt = 12.0 min / 12.8 min). As a result of analysis using GC / MS (CI +), one peak (Rt = 8.0 minutes) was observed, and it was confirmed that the MS of the peak was m / z: 172 (MH +).

Step (b): 20.8 g of the obtained toluene solution of the desired product [containing 34.9 mmol of the desired product (23)] was cooled to 10 ° C. To the reaction solution, 1.27 g (12.6 mmol) of triethylamine and 1.00 g (10.2 mmol) of maleic anhydride were added. After the addition was completed, the reaction solution was stirred at the same temperature for 5 hours. After completion of the reaction, the reaction solution was qualitatively analyzed using HPLC.
Of the two newly detected peaks, the peak at Rt = 22.8 is a compound represented by the following formula (25), which is a product of the reaction of the target compound (23) and maleic anhydride. [Hereinafter, abbreviated as compound (25). ], Rt = 25.3 min peak is a compound represented by the formula (26) in which the isomer (24) is reacted with maleic anhydride [hereinafter, abbreviated as compound (26). ]] Was estimated. As a result of qualitative analysis, the area ratio of the target substance (23), the isomer (24), the compound (25) and the compound (26) was 70.0 / 0.2 / 20.7 / 9.2.
That is, it was confirmed that the area ratio between the target product (23) and the isomer (24) was 99.8 / 0.2 (Rt = 12.1 min / 13.0 min).

  As a result of analyzing the reaction solution using LC / MS (ESI ±), two peaks were observed. MS of one peak is m / z: 172 (MH +) (Rt = 3.8 minutes), MS of another peak is m / z: 268 (MH-) (Rt = 2.1 minutes). It was confirmed. It was estimated that the compound (25) and the compound (26) were detected with an overlap of Rt = 2.1 minutes.

  Step (c): The reaction solution obtained in the step (b) was washed with a 15 mass% potassium carbonate aqueous solution (6 g × 2) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (23) was obtained in a yield of 49% (calculated from cyclohexanone oxime). It was also confirmed that the area ratio between the target product (23) and the isomer (24) was 99.7 / 0.3 (Rt = 12.1 min / 13.0 min).

  The qualitative and quantitative analyzes by HPLC used the conditions described in Example 6, and ethoxybenzene was used as the internal standard substance used in the quantitative analysis. The conditions described in Example 1 were used for the analysis by GC / MS and LC / MS.

[Example 15] Synthesis of O- [1- (2-hydroxypropyl)] acetophenone oxime Step (a): 15.1 g (112 mmol) of acetophenone oxime was suspended in 23 g of water to prepare a 40 mass% sodium hydroxide aqueous solution 1. 12 g (11.2 mmol) was added. After heating the reaction solution to 30 ° C., 8.50 g (146 mmol) of propylene oxide was added. After the addition was completed, the reaction solution was stirred at the same temperature for 6 hours, further cooled to 10 ° C., and then stirred for 16 hours. After the reaction was completed, 3.31 g (32.0 mmol) of 95 mass% sulfuric acid was added to the reaction solution at the same temperature. After the addition was completed, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was partitioned with toluene (15 g × 2) at the same temperature. 49.0 g of a toluene solution of the target substance was obtained.
As a result of qualitative analysis using HPLC, the target compound represented by the formula (27) described below [hereinafter, abbreviated as target product (27). ], And O- [2- (1-hydroxypropyl)] acetophenone oxime represented by the formula (28) which is an isomer [hereinafter, abbreviated as isomer (28). ] Area ratio of 94.2 / 5.8 (Rt = 27.1 minutes / 29.9 minutes) was confirmed. Moreover, as a result of analysis using GC / MS (CI +), one peak (Rt = 9.3 minutes) was observed, and it was confirmed that the MS of the peak was m / z: 194 (MH +).

Step (b): 20.1 g of the obtained target product in toluene solution [containing 25.6 mmol of the target product (27)] was cooled to 10 ° C. 0.93 g (9.2 mmol) of triethylamine and 0.78 g (8.0 mmol) of maleic anhydride were added to the reaction solution. After the addition was completed, the reaction solution was stirred at the same temperature for 24 hours. After completion of the reaction, the reaction solution was qualitatively analyzed using HPLC.
Of the two newly detected peaks, the peak at Rt = 54.2 minutes is a product obtained by reacting the target compound (27) with maleic anhydride, and is a compound represented by the following formula (29). [Hereinafter, abbreviated as compound (29). ], The peak at Rt = 63.5 minutes is a compound represented by the formula (30) in which the isomer (28) is reacted with maleic anhydride [hereinafter, abbreviated as compound (30). ]] Was estimated. As a result of qualitative analysis, the area ratio of the target substance (27), the isomer (28), the compound (29) and the compound (30) was 76.0 / 0.1 / 16.6 / 7.3.
That is, it was confirmed that the area ratio between the target product (27) and the isomer (28) was 99.8 / 0.2 (Rt = 27.3 min / 30.1 min).

  As a result of analyzing the reaction solution using LC / MS (ESI ±), two peaks were observed. MS of one peak is m / z: 194 (MH +) (Rt = 6.0 min), MS of another peak is m / z: 290 (MH-) (Rt = 2.3 min). It was confirmed. It was estimated that the compound (27) and the compound (28) were detected with overlapping at Rt = 2.3 minutes.

  Step (c): The reaction solution obtained in the step (b) was washed with a 15 mass% potassium carbonate aqueous solution (6 g × 2) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed using HPLC. As a result, it was confirmed that the target product (27) was obtained in a yield of 39% (calculated from acetophenone oxime). It was also confirmed that the area ratio of the target product (27) to the isomer (28) was 99.8 / 0.2 (Rt = 27.3 min / 30.1 min).

  The qualitative and quantitative analyzes by HPLC used the conditions described in Example 6, and 2-nitrotoluene was used as the internal standard substance used in the quantitative analysis. The conditions described in Example 1 were used for the analysis by GC / MS and LC / MS.

[Example 16] Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (a): 20.0 g (230 mmol) of butanone oxime was suspended in 30 g of water to prepare a 40 mass% sodium hydroxide aqueous solution 2. 31 g (23.1 mmol) was added. After heating the reaction solution to 30 ° C., 17.4 g (300 mmol) of propylene oxide was added. After the addition was completed, the reaction solution was stirred at the same temperature for 5 hours. After completion of the reaction, the reaction solution was cooled to 10 ° C., and 6.76 g (65.5 mmol) of 95 mass% sulfuric acid was added. After the addition was completed, the reaction solution was stirred at the same temperature for 17 hours. The reaction solution was separated with toluene (20 g × 2) at the same temperature. 65.8 g of a target toluene solution was obtained.
As a result of qualitative analysis using HPLC, it was confirmed that the area ratio of the target substance (7) and the isomer (8) was 94.8 / 5.2 (Rt = 6.7 min / 7.2 min). did.

Step (b): 20.0 g of the obtained toluene solution of the target substance [containing 39.5 mmol of the target substance (7)] was cooled to 10 ° C. 2.40 g (23.7 mmol) of triethylamine and 1.95 g (19.9 mmol) of maleic anhydride were added to the reaction solution. After the addition was completed, the reaction solution was stirred at the same temperature for 21 hours. To the reaction solution, 0.41 g (4.1 mmol) of triethylamine and 0.38 g (3.9 mmol) of maleic anhydride were added. After the addition was completed, the reaction solution was stirred at the same temperature for 74 hours.
As a result of qualitative analysis of the reaction solution using HPLC, the area ratio of the target compound (7), isomer (8), compound (11) and compound (12) was 44.5 / 0 / 47.9 / 7. It was 6.6 (Rt = 6.9 minutes / 7.4 minutes / 12.6 minutes / 14.2 minutes).
That is, it was confirmed that the area ratio between the target product (7) and the isomer (8) was 100/0 (Rt = 6.9 min / 7.4 min).

  Step (c): The reaction solution obtained in step (b) was washed with a 15 mass% potassium carbonate aqueous solution (6 g × 3) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (7) was obtained in a yield of 23% (calculated from butanone oxime). It was also confirmed that the area ratio between the target product (7) and the isomer (8) was 100/0 (Rt = 6.9 min / 7.4 min).

  The qualitative and quantitative analysis by HPLC used the conditions described in Example 6, and 4-methoxytoluene was used as the internal standard substance used in the quantitative analysis.

[Example 17] Synthesis of O- [1- (2-hydroxypropyl)] cyclohexanone oxime Step (b): Toluene solution 20.3 g of the target product obtained in the step (a) of Example 14 [target ( 23) in 34.1 mmol] was cooled to 10 ° C. To the reaction solution, 2.08 g (20.6 mmol) of triethylamine and 1.68 g (17.1 mmol) of maleic anhydride were added. After the addition was completed, the reaction solution was stirred at the same temperature for 1 hour.
As a result of qualitative analysis of the reaction solution using HPLC, the area ratio of the desired product (23), isomer (24), compound (25) and compound (26) was 52.2 / 0 / 39.6 / 8. 1 (Rt = 12.9 minutes / 13.7 minutes / 24.8 minutes / 27.6 minutes).
That is, it was confirmed that the area ratio between the target product (23) and the isomer (24) was 100/0 (Rt = 12.9 min / 13.7 min).

  Step (c): The reaction solution obtained in the step (b) was washed with a 15 mass% potassium carbonate aqueous solution (6 g × 2) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (23) was obtained in a yield of 30% (calculated from cyclohexanone oxime). It was also confirmed that the area ratio of the target product (23) to the isomer (24) was 100/0 (Rt = 12.9 min / 13.7 min).

  The qualitative and quantitative analyzes by HPLC used the conditions described in Example 6, and ethoxybenzene was used as the internal standard substance used in the quantitative analysis.

Example 18 Synthesis of O- [1- (2-hydroxypropyl)]-3-methyl-2-butanone oxime Step (b): Toluene solution of target compound obtained in step (a) of Example 12 23.0 g [containing 39.5 mmol of the desired product (15)] was cooled to 10 ° C. 2.44 g (24.1 mmol) of triethylamine and 1.95 g (19.9 mmol) of maleic anhydride were added to the reaction solution. After the addition was completed, the reaction solution was stirred at the same temperature for 3 hours.
As a result of qualitative analysis of the reaction solution using HPLC, the area ratio of the target substance (15), the isomer (16), the compound (17) and the compound (18) was 57.2 / 0 / 33.2 / 9. 0.7 (Rt = 12.9 and 13.7 min / 14.3 and 15.2 min / 25.3 and 26.4 min / 29.0 and 30.8 min).
That is, it was confirmed that the area ratio of the target substance (15) to the isomer (16) was 100/0 (Rt = 12.9 and 13.7 min / 14.3 and 15.2 min).

  Step (c): The reaction solution obtained in the step (b) was washed with a 15 mass% potassium carbonate aqueous solution (6 g × 2) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed using HPLC, and as a result, it was confirmed that the target substance (15) was obtained in a yield of 31% (calculated from 3-methyl-2-butanone oxime). did. It was also confirmed that the area ratio of the target substance (15) to the isomer (16) was 100/0 (Rt = 12.9 and 13.7 min / 14.3 and 15.2 min).

  The qualitative and quantitative analyzes by HPLC used the conditions described in Example 6, and 2-nitrotoluene was used as the internal standard substance used in the quantitative analysis.

Example 19 Synthesis of O- [1- (2-hydroxypropyl)] acetophenone oxime Step (b): 20.1 g of a toluene solution of the target compound obtained in the step (a) of Example 15 [target ( 25.7 mmol of 27)] was cooled to 10 ° C. 1.56 g (15.4 mmol) of triethylamine and 1.26 g (12.8 mmol) of maleic anhydride were added to the reaction solution. After the addition was completed, the reaction solution was stirred at the same temperature for 18 hours.
As a result of qualitative analysis of the reaction solution using HPLC, the area ratio of the target compound (27), isomer (28), compound (29) and compound (30) was 59.8 / 0 / 33.2 / 7. It was 0.0 (Rt = 29.6 minutes / 32.6 minutes / 60.3 minutes / 71.0 minutes).
That is, it was confirmed that the area ratio between the target product (27) and the isomer (28) was 100/0 (Rt = 29.6 min / 32.6 min).

  Step (c): The reaction solution obtained in step (b) was washed with a 15 mass% potassium carbonate aqueous solution (5 g × 3) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (27) was obtained in a yield of 29% (calculated from acetophenone oxime). It was also confirmed that the area ratio between the target product (27) and the isomer (28) was 100/0 (Rt = 29.6 min / 32.6 min).

  The qualitative and quantitative analyzes by HPLC used the conditions described in Example 6, and 2-nitrotoluene was used as the internal standard substance used in the quantitative analysis.

[Example 20] Synthesis of O- [1- (2-hydroxypropyl)] acetone oxime Step (a): 35.1 g (480 mmol) of acetone oxime was suspended in 54 g of water, and a 40 mass% sodium hydroxide aqueous solution was prepared. 88 g (48.8 mmol) was added. After heating the reaction solution to 30 ° C., 36.4 g (627 mmol) of propylene oxide was added. After the addition was completed, the reaction solution was stirred at the same temperature for 3 hours. After the reaction was completed, the reaction solution was cooled to 10 ° C., and then 14.2 g (138 mmol) of 95 mass% sulfuric acid was added. After the addition was completed, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was partitioned with toluene (36 g × 2) at the same temperature. 113 g of a target toluene solution was obtained.
As a result of qualitative analysis using HPLC, the target compound represented by the following formula (31) [hereinafter, abbreviated as target product (31). ], And O- [2- (1-hydroxypropyl)] acetone oxime represented by the formula (32) which is an isomer [hereinafter, abbreviated as isomer (32). ]] Was 94.4 / 5.6 (Rt = 3.9 min / 4.2 min). Moreover, as a result of analysis using GC / MS (CI +), one peak (Rt = 4.9 minutes) was observed, and it was confirmed that the MS of the peak was m / z: 132 (MH +).

Step (b): 21.5 g of the obtained toluene solution of the target substance [containing 43.3 mmol of the target substance (31)] was cooled to 10 ° C. 2.63 g (26.0 mmol) of triethylamine and 2.13 g (21.7 mmol) of maleic anhydride were added to the reaction solution. After the addition was completed, the reaction solution was stirred at the same temperature for 4 hours. After completion of the reaction, the reaction solution was qualitatively analyzed using HPLC.
Of the two newly detected peaks, the peak at Rt = 6.7 minutes is a compound represented by the following formula (33), which is a product obtained by reacting the target compound (31) with maleic anhydride. [Hereinafter, abbreviated as compound (33). ], The peak at Rt = 7.2 minutes is a compound represented by the formula (34) in which the isomer (32) is reacted with maleic anhydride [hereinafter, abbreviated as compound (34). ]] Was estimated. As a result of qualitative analysis, the area ratio of the target substance (31), isomer (32), compound (33) and compound (34) was 55.1 / 0 / 36.0 / 8.8.
That is, it was confirmed that the area ratio of the target substance (31) to the isomer (32) was 100/0 (Rt = 3.9 min / 4.3 min).

  As a result of analyzing the reaction solution using LC / MS (ESI ±), two peaks were observed. The MS of one peak is m / z: 132 (MH +) (Rt = 2.5 minutes), and the MS of the other peak is m / z: 228 (MH-) (Rt = 2.1 minutes). It was confirmed. It was estimated that the compound (33) and the compound (34) were detected with an overlap of Rt = 2.1 minutes.

  Step (c): The reaction solution obtained in the step (b) was washed with a 15 mass% potassium carbonate aqueous solution (6 g × 2) at the same temperature. After the completion of washing, the obtained organic layer was quantitatively analyzed by HPLC, and as a result, it was confirmed that the target product (31) was obtained in a yield of 27% (calculated from acetone oxime). It was also confirmed that the area ratio of the target substance (31) to the isomer (32) was 100/0 (Rt = 3.9 min / 4.3 min).

  The qualitative and quantitative analyzes by HPLC used the conditions described in Example 6, and ethoxybenzene was used as the internal standard substance used in the quantitative analysis. The conditions described in Example 1 were used for the analysis by GC / MS and LC / MS.

[Reference Example 1] Synthesis of O- [1- (2-hydroxypropyl)]-2-hydroxy-1-propylaldoxime O- [1- (2-hydroxypropyl)] butanone oxime 1.34 g (9.21 mmol) Was suspended in 13.4 g of water and cooled to 0 ° C. in a reactor equipped with a Dean-Stark tube. After completion of cooling, 5.13 g (49.2 mmol) of 35 mass% hydrochloric acid aqueous solution was added to the reaction solution. After completion of the addition, the mixture was stirred at the same temperature for 2 hours while blowing nitrogen gas, further stirred at 10 ° C for 2 hours, further stirred at 20 ° C for 1 hour, further stirred at 30 ° C for 2 hours and further 40 The mixture was stirred at 0 ° C for 4 hours, further at 50 ° C for 4 hours, and further at 40 ° C for 9 hours. After completion of the reaction, the reaction solution was cooled to room temperature and washed with dichloromethane (20 g × 2). After adding 9 g of butanone to the obtained aqueous layer, it was washed with dichloromethane (20 g × 3). After adding 30 g of saturated sodium hydrogencarbonate aqueous solution to the obtained water layer, it was concentrated. 50 g of ethanol was added to the concentrated residue, the precipitated insoluble matter was filtered, and the filtrate was concentrated. Further, 10 g of methanol was added to the concentrated residue, the precipitated insoluble matter was filtered, and 1 part of the filtrate was concentrated to obtain 0.03 g of the desired product as a pale yellow oil.
¹ H-NMR (600 MHz, ppm in CDCl ₃ ): δ1.18 (d, 3H), 1.35 (d, 3H), 3.00 (brs, 2H), 3.89 (m, 1H), 4 0.03 (m, 1H), 4.10 (m, 1H), 4.43 (m, 1H), 7.45 (d, 1H)
LC / MS (ESI +) m / z: 148 (MH +)
GC / MS (CI +) m / z: 148 (MH +)

The analytical conditions of GC / MS are described below.
Column: HP-5 manufactured by Agilent Technologies 0.32 mm ID × 30 m × 0.25 μm,
Temperature rising time and temperature rising rate: 40 ° C (2 minutes)-(20 ° C / minute) -300 ° C (7 minutes)
The LC / MS analysis conditions are described below.
Column: GL Science Inersil ODS-3, 3 μm, 2.1 mm × 50 mm,
Eluent: methanol / 0.1% by volume aqueous formic acid = 5/95 (volume ratio)
Flow rate: 0.45 mL / min Column temperature: 40 ° C

Reference Example 2 Synthesis of 3- [1- (2-butylideneaminooxy) -2-propyloxycarbonyl] -2- (Z) -propenoic acid O- [1- (2-hydroxypropyl)] butanone oxime 1.53 g (10.5 mmol) was dissolved in 19.9 g of dichloromethane and cooled to 0 ° C. After the cooling was completed, 1.59 g (16.2 mmol) of maleic anhydride and 1.59 g (15.7 mmol) of triethylamine were added to the reaction solution. After the addition was completed, the mixture was stirred at the same temperature for 53 hours. After completion of the reaction, 20 mL of saturated aqueous sodium hydrogen carbonate solution and 100 mL of ethyl acetate were added to separate the layers. 100 mL of ethyl acetate and a 1 mol / L aqueous hydrochloric acid solution were added to the aqueous layer until pH 3 was reached, and the layers were separated. Furthermore, the aqueous layer was extracted with ethyl acetate (200 mL × 3). The obtained organic layer was washed with 20 mL of saturated saline, and then the organic layer was concentrated and dried to obtain 2.19 g of the title compound as a pale yellow oil.
¹ H-NMR (300 MHz, ppm in CDCl ₃ ): δ1.07 (t, 3H), 1.33 (d, 3H), 1.79 (s, 3H), 2.17 (q, 2H), 4 .11 (m, 2H), 5.39 (m, 1H), 6.36 (d, 1H), 6.45 (d, 1H), 9.30 (brs, 1H)
LC / MS (ESI +) m / z: 244 (MH +)
GC / MS (CI +) m / z: 244 (MH +)

The analytical conditions of GC / MS are described below.
Column: HP-5 manufactured by Agilent Technologies 0.32 mm ID × 30 m × 0.25 μm,
Temperature rising time and temperature rising rate: 40 ° C (2 minutes)-(20 ° C / minute) -300 ° C (7 minutes)
The LC / MS analysis conditions are described below.
Column: Waters XBridge C18, 5 μm, 2.1 mm × 150 mm,
Eluent: acetonitrile / 0.2 volume% formic acid aqueous solution = 40/60 (volume ratio)
Flow rate: 0.2 mL / min Column temperature: 40 ° C

  INDUSTRIAL APPLICABILITY The present invention is useful as a method for producing an O- [1- (2-hydroxypropyl)] oxime compound which is useful as an intermediate for medicines, agricultural chemicals, electronic materials and the like.

Claims (9)

Formula (1) including the following steps (a) to (c):

[Wherein R ¹ and R ² each independently represent a C ₁ -C ₆ alkyl group or a phenyl group, or R ¹ and R ² together with the carbon atom to which they are bonded are 5 to 5 Form a 7-membered carbocycle. ] The manufacturing method of the O- [1- (2-hydroxypropyl)] oxime compound represented by these.
Step (a): Formula (2):

(In the formula, R ¹ and R ² have the same meanings as defined above.) A step of reacting an oxime compound with propylene oxide in the presence of a basic compound Step (b): Step ( Step of reacting the mixture obtained in a) with a cyclic acid anhydride in the presence of a basic compound Step (c): Mixing the mixture obtained in step (b) with an aqueous solution of a basic compound A step of obtaining an O- [1- (2-hydroxypropyl)] oxime compound represented by the formula (1)   The amount of the cyclic acid anhydride used is 0.04 to 1.0 equivalent to 1 equivalent of the compound represented by the formula (1) in the mixture obtained in the step (a). A method for producing a [1- (2-hydroxypropyl)] oxime compound.   The O- [1- (2-hydroxypropyl) according to claim 1 or 2, wherein the cyclic acid anhydride is at least one selected from the group consisting of maleic anhydride, succinic anhydride and phthalic anhydride. ] A method for producing an oxime compound. R ¹ and R ² are each independently -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ( _{CH 3) (CH 2 CH 3} ), - CH 2 CH (CH 3) 2, -C (CH 3) or represents ₃ or a phenyl group, or, together with R ¹ and R ² are carbon atoms to which they are attached The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of claims 1 to 3, which forms a 6-membered carbocycle. R ¹ and R ^2, -CH ₃ each _{independently, -CH 2 CH 3, -CH 2} CH 2 CH 3, or represents _{-CH (CH 3) 2, -C} (CH 3) 3 or a phenyl group Alternatively, R ¹ and R ² together with the carbon atom to which they are attached form a 6-membered carbocycle, wherein the O- [1- (2-hydroxypropyl)] oxime compound is prepared. . R ¹ and R ² each independently represent —CH ₃ , —CH ₂ CH ₃ , —CH (CH ₃ ) ₂ , —C (CH ₃ ) ₃ or a phenyl group, or R ¹ and R ² 6. The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to claim 5, wherein is combined with the carbon atom to which they are bonded to form a 6-membered carbocycle.   In the step (c), the organic solvent containing the mixture obtained in the step (b) is mixed with an aqueous solution of a basic compound, and the O- [1- ( 2-Hydroxypropyl)] oxime compound production method.   The O- [1- (2-hydroxypropyl)] oxime according to claim 7, wherein in the step (c), the organic solvent containing the mixture obtained in the step (b) is dichloromethane, 1,2-dichloroethane or toluene. Method for producing compound.   In the step (c), the basic compound is sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate, and the O- [1- (2-hydroxypropyl) according to any one of claims 1 to 8. )] Method for producing oxime compound.