JPWO2016190280A1 - Process for producing O- [1- (2-hydroxypropyl)] oxime compound - Google Patents

Abstract

The present invention provides an inexpensive and efficient method for producing an extremely high purity O- [1- (2-hydroxypropyl)] oxime compound suitable as an intermediate for pharmaceuticals, agricultural chemicals, electronic materials and the like. An extremely high purity formula (1) including the following steps (a) to (c): wherein R 1 and R 2 each independently represents a C 1 -C 6 alkyl group or the like. ] The industrially useful manufacturing method regarding the O- [1- (2-hydroxypropyl)] oxime compound represented by this. [Chemical 1] [Selected figure] None

Description

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

Conventionally, O- [1- (2-hydroxypropyl)] oxime compounds are known as compounds useful as intermediates for pharmaceuticals, agricultural chemicals, electronic materials and the like.
As its production method, 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). Further, a method for producing O- [1- (2-hydroxypropyl)] acetone oxime by reacting acetone oxime and propylene oxide in the presence of triethylamine is known (see Patent Document 2). Further, 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 is known (Patent Document 3). reference).
Some methods for producing O- [1- (2-hydroxyalkyl)] oxime compounds are also known (see Patent Documents 1 and 4 and Non-Patent Document 1).

US 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, 81, 4223

  Regarding the method for producing an O- [1- (2-hydroxypropyl)] oxime compound, Patent Documents 1, 2, 3 and Non-patent Document 1 describe a process 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 formula (1) and the compound represented by formula (3) is obtained as a product. The production ratio of the compound represented by Formula (1) and the compound represented by Formula (3) at that time is usually 85/15 to 96/4.

Since the compound represented by the formula (1) and the compound represented by the formula (3) are very close to each other, they are represented by the formula (1) by a normal 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 pharmaceuticals, agricultural chemicals, electronic materials, etc., the compound represented by the formula (3) is mixed into the product as an impurity. It will cause adverse effects on performance.
Therefore, a novel process for producing an O- [1- (2-hydroxypropyl)] oxime compound that is suitable as an intermediate for pharmaceuticals, agricultural chemicals, electronic materials, etc. and contains as little of the compound represented by formula (3) as possible. Development is desired.

  As a result of intensive studies to solve the above problems, the present inventors have reacted an isomer mixture of an O- [1- (2-hydroxypropyl)] oxime compound with a cyclic acid anhydride available as an industrial raw material. It was found that an extremely high purity O- [1- (2-hydroxypropyl)] oxime compound was obtained by mixing with an aqueous solution of a basic compound, and the present invention was completed.

［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, this invention relates to the manufacturing method as described in the following [1]-[76].
[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, Forms a 7-membered carbocycle. ] The manufacturing method of the O- [1- (2-hydroxypropyl)] oxime compound represented by this.
Step (a): Formula (2):

(Wherein R ¹ and R ² represent the same meaning as defined above), a step of reacting oxime compound with propylene oxide in the presence of a basic compound Step (b): Step ( The step of reacting the mixture obtained in a) with a cyclic acid anhydride in the presence of a basic compound Step (c): The mixture obtained in step (b) is mixed with an aqueous solution of a basic compound. And a step of obtaining an O- [1- (2-hydroxypropyl)] oxime compound represented by the formula (1)

[2]
The amount of cyclic acid anhydride used is 0.04 to 1.0 equivalent relative to 1 equivalent of the compound represented by formula (1) in the mixture obtained in 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. )] A method for producing an 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 ) ₃ or a phenyl group, or R ¹ and R ² together with the carbon atom to which they are attached. The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of [1] to [3] above, wherein a 6-membered carbocyclic ring is formed.

[5]
Each of R ¹ and R ² independently represents —CH ₃ , —CH ₂ CH ₃ , —CH ₂ CH ₂ CH ₃ , —CH (CH ₃ ) ₂ , —C (CH ₃ ) ₃ or a phenyl group; Or the production of an O- [1- (2-hydroxypropyl)] oxime compound according to the above [4], wherein R ¹ and R ² together with the carbon atom to which they are bonded form a 6-membered carbocyclic ring. 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 process for producing an O- [1- (2-hydroxypropyl)] oxime compound according to the above [5], which forms a 6-membered carbocycle together with the carbon atom to which they are bonded.

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

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

[9]
In the step (c), the basic compound is O- [1- (2-hydroxy) according to any one of the above [1] to [8], wherein the basic compound is sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate. Propyl)] an 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- in any one of said [1] thru | or [9] which is alkaline-earth metal bicarbonate, alkaline-earth metal phosphate, alkaline-earth metal hydrogenphosphate, or an organic base. (2-Hydroxypropyl)] Method for producing oxime compound.
[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, 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]
The production of the O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [9], wherein the basic compound is an alkali metal hydroxide in the step (a). 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- The O- [1- (2- (dimethylamino) pyridine, imidazole, or 1,8-diazabicyclo [5,4,0] -7-undecene) according to any one of the above [1] to [9]. Hydroxypropyl)] oxime compound Method.
[14]
In the step (a), the basic compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, any one of the above [1] to [9] A method for producing an O- [1- (2-hydroxypropyl)] oxime compound.
[15]
[1] In the step (a), the basic compound is triethylamine, tributylamine, pyridine, 4- (dimethylamino) pyridine, imidazole or 1,8-diazabicyclo [5,4,0] -7-undecene. The manufacturing method of the O- [1- (2-hydroxypropyl)] oxime compound of any one of thru | or [9].
[16]
The O- [1- (2-hydroxypropyl)] oxime compound according to any one of [1] to [9], wherein the basic compound is sodium hydroxide or potassium hydroxide in the step (a). Manufacturing method.
[17]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [9], wherein in the step (a), the basic compound is sodium hydroxide.
[18]
The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [9], wherein in the step (a), the basic compound is potassium hydroxide.

[19]
In 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] above, which is an anhydride, hexahydrophthalic anhydride, tetrachlorophthalic anhydride, cis-4-cyclohexene-1,2-dicarboxylic anhydride or isododecenyl succinic anhydride The manufacturing method of the O- [1- (2-hydroxypropyl)] oxime compound of any one of these.
[20]
In the step (b), the cyclic acid anhydride is maleic anhydride, succinic anhydride, phthalic anhydride, itaconic anhydride, glutaric anhydride, adipic anhydride or citraconic anhydride. [1] A method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of [18].
[21]
In 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 isododece. The method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [18], which is a succinic anhydride.
[22]
The 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]
The production of the O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [18], wherein the cyclic acid anhydride is succinic acid anhydride in the step (b). Method.
[24]
The 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 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- in any one of said [1] thru | or [24] which is alkaline-earth metal bicarbonate, alkaline-earth metal phosphate, alkaline-earth metal hydrogen phosphate, or an organic base. (2-Hydroxypropyl)] Method for producing oxime compound.
[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 alkaline earth metal bicarbonate, alkaline earth metal phosphate, or 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 the basic compound is an organic base in the step (b).
[28]
In 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- The O- [1- (2- (2-methylamino) pyridine), imidazole, or 1,8-diazabicyclo [5,4,0] -7-undecene according to any one of the above [1] to [24]. Hydroxypropyl)] oxime compound Production method.
[29]
In the step (b), the basic compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, any one of the above [1] to [24] A method for producing an O- [1- (2-hydroxypropyl)] oxime compound.
[30]
[1] In the step (b), the basic compound is triethylamine, tributylamine, pyridine, 4- (dimethylamino) pyridine, imidazole or 1,8-diazabicyclo [5,4,0] -7-undecene. Thru | or the manufacturing method of the O- [1- (2-hydroxypropyl)] oxime compound of any one of [24].
[31]
In the step (b), the basic compound is triethylamine, tributylamine, or pyridine, the O- [1- (2-hydroxypropyl)] oxime compound according to any one of [1] to [24] above. Production method.
[32]
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 triethylamine.
[33]
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 tributylamine.
[34]
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 pyridine.

[35]
In step (c), the organic solvent containing the mixture obtained in step (b) is a hydrocarbon solvent, aromatic hydrocarbon solvent, halogenated hydrocarbon solvent, alcohol solvent, ketone solvent, nitrile solvent, carboxylic acid ester solvent. Or the manufacturing method of the O- [1- (2-hydroxypropyl)] oxime compound of any one of said [1] thru | or [34] which is a nitrogen-containing aprotic polar solvent.
[36]
[1] 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. Thru | or the manufacturing method of the O- [1- (2-hydroxypropyl)] oxime compound of any one of [34].
[37]
In the step (c), any one of the above [1] to [34], wherein the organic solvent containing the mixture obtained in the step (b) is a hydrocarbon solvent, an aromatic hydrocarbon solvent or a halogenated hydrocarbon solvent. A method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to Item.
[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 step (c), the organic solvent containing the mixture obtained in step (b) is an aromatic hydrocarbon solvent described in any one of [1] to [34] above. 2-hydroxypropyl)] oxime compound.
[40]
In the step (c), the organic solvent containing the mixture obtained in the step (b) is O- [1- (1-) described in any one of the above [1] to [34], which is a halogenated hydrocarbon solvent. 2-hydroxypropyl)] oxime compound.
[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 -O- of any one of [1] to [34] above, which is dichloroethane, chlorobenzene, trifluoromethylbenzene, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate or ethyl propionate 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 The 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 the step (c), the organic solvent containing the mixture obtained in the step (b) is benzene, xylene or toluene, and the O- [1- (1- 2-hydroxypropyl)] oxime compound.
[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. ] The manufacturing method of the O- [1- (2-hydroxypropyl)] oxime compound of any one of.
[45]
O- [1- (2-hydroxypropyl) according to any one of [1] to [34] above, wherein in the step (c), the organic solvent containing the mixture obtained in the step (b) is toluene. )] A method for producing an oxime compound.
[46]
O- [1- (2-hydroxypropyl) according to any one of [1] to [34] above, wherein in the step (c), the organic solvent containing the mixture obtained in the step (b) is dichloromethane. )] A method for producing an oxime compound.
[47]
In the step (c), the organic solvent containing the mixture obtained in the step (b) is 1,2-dichloroethane, the O- [1- (1) described in any one of the above [1] to [34]. 2-hydroxypropyl)] oxime compound.

[48]
In step (c), the basic compound is an alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal phosphate, alkali metal hydrogen phosphate, alkaline earth metal hydroxide, alkali Any one of [1] to [47], which is an earth metal carbonate, an alkaline earth metal bicarbonate, an alkaline earth metal phosphate, an alkaline earth metal hydrogen phosphate, or an organic base. Of producing an O- [1- (2-hydroxypropyl)] oxime compound.
[49]
In step (c), the basic compound is an alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal phosphate, alkali metal hydrogen phosphate, alkaline earth metal hydroxide, alkali O- of any one of [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 [1] to [47] above, wherein in the step (c), the basic compound is an alkali metal carbonate or an alkali metal bicarbonate. ] The manufacturing method of 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 the basic compound is an alkali metal carbonate in the step (c). .
[52]
In the step (c), the production of the O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [47], wherein the basic compound is an alkali metal bicarbonate. Method.
[53]
In 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- O- [1- (2- (dimethylamino) pyridine, imidazole, or 1,8-diazabicyclo [5,4,0] -7-undecene) according to any one of [1] to [47] above. 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, any one of the above [1] to [47] A method for producing an O- [1- (2-hydroxypropyl)] oxime compound.
[55]
The O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [47], wherein the basic compound is sodium hydroxide or potassium hydroxide in the step (c). Manufacturing method.
[56]
In the step (c), the production of the O- [1- (2-hydroxypropyl)] oxime compound according to any one of [1] to [47] above, wherein the basic compound is sodium carbonate or potassium carbonate. Method.
[57]
The O- [1- (2-hydroxypropyl)] oxime compound according to any one of the above [1] to [47], wherein the basic compound is sodium hydrogencarbonate or potassium hydrogencarbonate in the step (c) Manufacturing method.
[58]
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 in the step (c).
[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]
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 hydrogen carbonate in the step (c).
[61]
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 in the step (c).

[62]
O- [1- (2-hydroxypropyl)] consisting of continuously performing the steps (a) to (c) specified in any one of the above [1] to [61], respectively. A method for producing an oxime compound.
[63]
O described in [62] above, wherein the organic solvent is a hydrocarbon solvent, aromatic hydrocarbon solvent, halogenated hydrocarbon solvent, alcohol solvent, ketone solvent, nitrile solvent, carboxylic acid ester solvent or 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 [62] above, 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]
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, propionitrile, ethyl acetate or ethyl propionate.
[70]
The above [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, there is provided an inexpensive and efficient method for producing an extremely high purity O- [1- (2-hydroxypropyl)] oxime compound useful as an intermediate for pharmaceuticals, agricultural chemicals, electronic materials and the like. be able to.

  In the compounds encompassed by the present invention, there exist E- and Z-isomers, but the compounds according to the present invention include these E-isomers, Z-isomers, or E-isomers and Z-isomers. Are included in any proportion.

  In addition, in the compound (1) included in the present invention, an optically active substance resulting from the presence of one or two or more asymmetric carbon atoms may exist depending on the substituent. Such compounds include all optically active or racemic forms.

  Among the compounds included in the present invention, those that can be converted into a salt according to a conventional method are, for example, salts of hydrogen halides such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, 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 Succinic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, carboxylic acid salt such as lactic acid, gluconic acid, citric acid, amino acid salt such as glutamic acid, aspartic acid, lithium, sodium, potassium Alkali metal salts such as alkaline earth metal salts such as calcium, barium and magnesium, aluminum salts, tetramethyla 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.

  As a halogen atom in this invention, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are mentioned. In the present specification, the notation “halo” also represents these halogen atoms.

In the present specification, the C ₁ -C ₆ alkyl group 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, 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 Group, 3, Specific examples include 3-dimethylbutyl group, 1,1,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, and the like. The range is selected.

Notation "R ¹ and R ² form a carbon ring of 5- to 7-membered together with the carbon atoms to which they are attached" herein, C ₄ R ¹ together with R ² It represents that a 5- to 7-membered ring is formed together with the carbon atom to which R ¹ and R ² are bonded by forming an alkylene chain of ˜C ₆ , and examples thereof include a cyclopentane ring and a cyclohexane ring. .
Next, O- [1- (2-hydroxypropyl)] oxime compound represented by formula (1) [hereinafter abbreviated as compound (1). The process (a) to the process (c) in the manufacturing method will be described in detail below.

[Step (a)]

Formula (2) [wherein R ¹ and R ² have the same meaning as defined above. ] [Hereinafter abbreviated as compound (2). Can be reacted with propylene oxide in the presence of a basic compound to produce compound (1).

Moreover, as a product of this step, the compound (1) is an isomer of the compound (1), which is the formula (3) [wherein R ¹ and R ² have the same meaning as defined above. ] [Hereinafter abbreviated as compound (3). ] As a mixture. The production ratio of compound (1) to 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, 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 bicarbonate and calcium bicarbonate, alkaline earth metals such as magnesium phosphate and calcium phosphate Al, such as phosphate, magnesium hydrogen phosphate, calcium hydrogen phosphate 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.

  As a usage-amount of a basic compound, 0.01-5 equivalent with respect to 1 equivalent of compound (2), Preferably 0.05-2 equivalent can be used.

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

  The step (a) can be performed under an atmospheric pressure, but in some cases, it can be performed in a pressure range of 0.001 to 100 MPa, preferably 0.1 to 10 MPa.

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

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

  The amount of the compound (1) obtained in the step (a) can be calculated by quantitative analysis by an 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 poured into water, separated, concentrated as necessary, or poured into water. The reaction mixture can be obtained by carrying out usual post-treatments such as extraction and, if necessary, concentration. Further, the reaction mixture can be used in the next step as it is without concentrating the solution of the reaction mixture obtained after the post-treatment. Moreover, the reaction mixture after completion | finish of reaction can also be used for next process as it is, without post-processing. When the need for purification arises, it can be separated and purified by any purification method such as distillation, recrystallization, column chromatograph, thin layer chromatograph, liquid chromatographic fractionation and the like.

[Step (b)]

A mixture of the compound (1) and the compound (3) is converted to a cyclic acid anhydride, for example, the formula (4) [wherein A represents —CH ₂ CH ₂ —, —CH═CH— or a 1,2-phenylene group, etc. Represent. In the presence of a basic compound, compound (1), formula (5) [wherein R ¹ and R ² represent the same meaning as defined above, A represents —CH ₂ CH ₂ —, —CH═CH—, a 1,2-phenylene group or the like. ] [Hereinafter abbreviated as compound (5). ] And formula (6) [wherein R ¹ and R ² have the same meaning as defined above, and A represents —CH ₂ CH ₂ —, —CH═CH—, a 1,2-phenylene group, or the like. ] [Hereinafter abbreviated as compound (6). ] Can be produced.

  In the present specification, the step (b) and the step (c) will be described using the acid anhydride represented by the formula (4) as the cyclic acid anhydride, but the cyclic acid anhydride used in the present invention will be described. The product is not limited to the acid anhydride represented by the formula (4).

  Since compound (3) is a primary alcohol compound, it reacts preferentially with compound (4) compared to 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 is reduced. Specifically, the abundance ratio of the compound (1) and the compound (3) is usually 99/1 to 100 / It becomes about 0.

  The cyclic acid anhydride used in the step (b) is not particularly limited as long as it is a compound that can react with the compound (3) to produce a ring-opened compound such as the compound (6). , Maleic anhydride, succinic anhydride, phthalic anhydride, itaconic anhydride, glutaric anhydride, adipic anhydride, citraconic anhydride, trimellitic anhydride, hexahydrophthalic anhydride, tetra Examples include chlorophthalic anhydride, cis-4-cyclohexene-1,2-dicarboxylic anhydride, and isododecenyl succinic anhydride. Among these, 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.

  The cyclic acid anhydride used in the step (b) is preferably 0.04 to 1.0 equivalent based on 1 equivalent of the compound (1), and the presence of the compound (3) in the reaction solution after completion of the 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, and particularly preferably 0.3 to 0.8 equivalent. , Most preferably 0.5 to 0.7 equivalent.

  Further, the cyclic acid anhydride in the step (b) may be used in two 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, 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 bicarbonate and calcium bicarbonate, alkaline earth metals such as magnesium phosphate and calcium phosphate Al, such as phosphate, magnesium hydrogen phosphate, calcium hydrogen phosphate Examples thereof include organic bases such as alkaline earth metal hydrogen phosphate, triethylamine, tributylamine, pyridine, 4- (dimethylamino) pyridine, imidazole, and 1,8-diazabicyclo [5,4,0] -7-undecene. . These basic compounds can be used alone or in combination of two or more.

  Moreover, regarding the usage-amount of a basic compound, 0.04-1.0 equivalent with respect to a compound (1), Preferably 0.1-1.0 equivalent can be used.

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

  The step (b) can be performed under an atmospheric pressure, but in some cases, it can be performed in a pressure range of 0.001 to 100 MPa, preferably 0.1 to 10 MPa.

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

  While the reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, it can be set in the range of usually 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 poured into water, separated, concentrated as necessary, or poured into water. The reaction mixture can be obtained by carrying out usual post-treatments such as extraction and, if necessary, concentration. Further, the reaction mixture can be used in the next step as it is without concentrating the solution of the reaction mixture obtained after the post-treatment. Moreover, the reaction mixture after completion | finish of reaction can also be used for next process as it is, without post-processing. When the need for purification arises, it can be separated and purified by any purification method such as distillation, recrystallization, column chromatograph, thin layer chromatograph, liquid chromatographic fractionation and the like.

[Step (c)]

  Since the organic solvent containing the mixture of the compound (1), the compound (5) and the compound (6) is mixed with the aqueous solution of the basic compound, the compound (5) and the 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, and hydrogen carbonate. Alkali metal bicarbonates such as sodium and potassium bicarbonate, alkali metal phosphates such as sodium phosphate and potassium phosphate, alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, hydroxylation 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.

  Moreover, as the usage-amount of a basic compound, 0.02-10 equivalent can be used with respect to a 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. Halogenated 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, methyl ethyl ketone and methyl isobutyl ketone, acetonitrile, Nitrile solvents such as pionitrile, carboxylic acid ester solvents such as ethyl acetate and ethyl propionate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl Examples thereof include nitrogen-containing aprotic polar solvents such as 2-imidazolidinone, preferably aromatic hydrocarbon solvents such as xylene and toluene, and halogen-based hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane. More preferably, toluene, dichloromethane, or 1,2-dichloroethane can be used. These solvents can be used by mixing two or more kinds.

  The step (c) can be performed under an atmospheric pressure, but in some cases, it can be performed in a pressure range of 0.001 to 100 MPa, preferably 0.1 to 10 MPa.

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

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

Process (a) thru | or process (c) can be performed continuously.
Performing step (a) to step (c) continuously means that the product obtained in the previous step is used in the next step as a crude product without isolation and purification, and the next step is performed. Carrying out step (b) using the product produced in step (a) as it is without isolation and purification, and isolating the product produced in step (b) It is to carry out step (c) using as it is without purification. In addition, the reaction container which performs a process (a), a process (b), and a process (c) may respectively be the same, or may differ.

  Examples of the organic solvent used when the steps (a) to (c) are continuously performed include hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, heptane, benzene, xylene, toluene and the like. Aromatic hydrocarbon solvents, halogenated hydrocarbon solvents such as dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene, 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 acid ester solvents such as ethyl acetate and ethyl propionate, N, N-dimethylformamide, N, N-dimethylacetamide, N-me Examples include nitrogen-containing aprotic polar solvents such as lupyrrolidone and 1,3-dimethyl-2-imidazolidinone, preferably aromatic hydrocarbon solvents such as xylene and toluene, dichloromethane, 1,2-dichloroethane and the like And, more preferably, toluene, dichloromethane and 1,2-dichloroethane can be used. These solvents can be used by mixing two or more kinds.

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

Synthesis examples are shown below to describe the present invention in more detail, but the present invention is not limited to these examples.
¹ H-NMR was measured at 300 MHz or 600 MHz, and HPLC, LC / MS, GC, and GC / MS were measured under the following conditions.
In addition, NMR represents nuclear magnetic resonance spectrum, HPLC represents high performance liquid chromatography, LC / MS represents liquid chromatography mass spectrometry, GC represents gas chromatography, and GC / MS represents gas chromatography mass measurement analysis.
Rt represents the holding time.

[Example 1] Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (a): 10.0 g (115 mmol) of butanone oxime was suspended in 50 g of water. 41 g (12.0 mmol) was added. After the reaction solution was heated to 40 ° C., 8.05 g (139 mmol) of propylene oxide was added. After completion of the addition, 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 separated 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, a target product represented by the following formula (7) [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). It was confirmed that the area ratio was 94.3 / 5.7 (Rt = 11.4 minutes / 11.8 minutes). Further, as a result of analysis using GC / MS (CI +), two peaks (Rt = 5.67 min / 5.71 min) were observed, and both MSs of the two peaks were m / z: 146 (MH +). It was confirmed that.

Step (b): 0.58 g of the obtained crude product (containing 2.5 mmol of the 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 completion of the addition, the reaction solution was stirred at the same temperature for 19 hours.
As a result of qualitative analysis of the reaction solution using HPLC, the area ratio of the target product (7) to the isomer (8) is 100/0 (Rt = 11.4 minutes / 11.8 minutes). 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). ] Is a peak of Rt = 13.3 minutes to 13.4 minutes, a compound represented by formula (10) in which isomer (8) has 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), isomer (8), compound (9) and 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 is m / z: 146 (MH +) (Rt = 5.6 min) and the MS of the other peak is m / z: 246 (MH +) (Rt = 10.2 min). confirmed. It was estimated that compound (9) and compound (10) were detected overlapping Rt = 10.2 minutes.
Moreover, as a result of analyzing this reaction solution using LC / MS (ESI +), two peaks were observed. The MS of one peak is m / z: 146 (MH +) (Rt = 2.3 min) and the MS of the other peak is m / z: 246 (MH +) (Rt = 3.5 min). confirmed. It was estimated that compound (9) and compound (10) were detected overlapping Rt = 3.5 minutes.

  Step (c): The reaction solution obtained in step (b) was washed with a 5% by mass aqueous sodium hydrogen carbonate solution (5 g × 2) at the same temperature. After completion of the washing, the obtained organic layer was quantitatively analyzed using HPLC. 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 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: XBridge C18 3.5 μm, 4.6 mm × 150 mm manufactured by Waters,
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: None (1 point absolute quantification)
The conditions for analysis by GC / MS are described below.
Column: HP-5 manufactured by Agilent Technologies, Inc. 0.32 mm ID × 30 m × 0.25 μm,
Temperature increase time and temperature increase rate: 40 ° C (2 minutes)-(20 ° C / minute)-300 ° C (7 minutes)
The conditions for analysis by LC / MS are described below.
Column: XBridge C18 5 μm, 2.1 mm × 150 mm, manufactured by Waters
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 oxime compound ( The reaction was performed by appropriately changing the acid anhydride used in 2) and step (b).
Yield of O- [1- (2-hydroxypropyl)] oxime compound obtained in step (c) and target product (7) and isomer calculated by qualitative analysis using HPLC or GC in each step The peak area ratio 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: XBridge C18 3.5 μm, 4.6 mm × 150 mm manufactured by Waters,
Eluent: methanol / water / 85% by 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: CP-WAX 52 CB 0.25 mm ID × 25 m × 0.20 μm manufactured by Agilent Technologies,
Temperature increase time and temperature increase rate: 40 ° C (0 minutes)-(5 ° C / minute)-90 ° C (0 minutes)-(10 ° C / minute)-250 ° C (10 minutes)
Internal standard: Diethylene glycol dimethyl ether

[Example 6] Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (a): 10.0 g (115 mmol) of butanone oxime was suspended in 30 g of water. 15 g (11.5 mmol) was added. After warming the reaction solution to 40 ° C., 10.0 g (172 mmol) of propylene oxide was added. After completion of the addition, 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 5.93 g (57.4 mmol) of 95 mass% sulfuric acid was added. After completion of the addition, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated with 1,2-dichloroethane (30 g × 2) at the same temperature. 71.8 g of a 1,2-dichloroethane solution of the target product was obtained.
As a result of qualitative analysis using HPLC, it was confirmed that the area ratio of the target compound (7) to the isomer (8) was 94.4 / 5.6 (Rt = 6.6 minutes / 7.1 minutes). did.

Step (b): 71.1 g of a 1,2-dichloroethane solution of the obtained target product (containing 60.5 mmol of the target product (7)) was cooled to 10 ° C. To the reaction solution, 0.73 g (7.26 mmol) of triethylamine and 0.59 g (6.05 mmol) of maleic anhydride were added. After completion of the addition, the reaction solution was stirred at the same temperature for 3 hours. To the reaction solution, 0.73 g (7.26 mmol) of triethylamine and 0.59 g (6.05 mmol) of maleic anhydride were added. After completion of the addition, 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.
Among the two newly detected peaks, the peak at Rt = 11.9 min is a product of the reaction of the target product (7) and maleic anhydride, and is represented by the following formula (11) [Hereinafter abbreviated as compound (11). ], Rt = 13.4 min peak is a compound represented by formula (12) in which isomer (8) is reacted with maleic anhydride [hereinafter abbreviated as compound (12). ]. 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 of the target product (7) to the isomer (8) was 99.2 / 0.8 (Rt = 6.6 minutes / 7.1 minutes).

  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 completion of the washing, the obtained organic layer was quantitatively analyzed using HPLC. As a result, it was confirmed that the target product (7) was obtained with a yield of 44% (calculated from butanone oxime). It was also confirmed that the area ratio of the target product (7) to the isomer (8) was 99.2 / 0.8 (Rt = 6.6 minutes / 7.1 minutes).

The conditions for qualitative and quantitative analysis by HPLC are described below.
Column: XBridge C18 3.5 μm, 4.6 mm × 150 mm manufactured by Waters
Eluent: methanol / water / 85% by mass phosphoric acid = 35/65 / 0.1 (volume ratio)
Flow rate: 0.8 mL / min Column temperature: 40 ° C
Internal standard: 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, and a 40% by mass aqueous sodium hydroxide solution. 87 g (28.7 mmol) was added. After warming the reaction solution to 30 ° C., 21.7 g (373 mmol) of propylene oxide was added. After completion of the addition, 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 completion of the addition, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated with toluene (25 g × 2) at the same temperature. 83.6 g of the target toluene solution was obtained.
As a result of qualitative analysis using HPLC, it was confirmed that the area ratio of the target product (7) and isomer (8) was 94.9 / 5.1 (Rt = 6.7 minutes / 7.2 minutes). did.

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

  Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous potassium carbonate solution (22 g × 2) at the same temperature. After completion of washing, the obtained organic layer was quantitatively analyzed using HPLC. 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 of the target product (7) to the isomer (8) was 99.7 / 0.3 (Rt = 6.7 minutes / 7.2 minutes).

  For qualitative and quantitative analysis by HPLC, the conditions described in Example 6 were used, and ethoxybenzene was used as an internal standard substance used for quantitative analysis.

[Example 8] Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (a): 85.0 g (976 mmol) of butanone oxime was suspended in 170 g of water. 56 g (39.0 mmol) was added. After the reaction solution was heated to 30 ° C., 73.7 g (1.27 mol) of propylene oxide was added. After completion of the addition, 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 completion of the addition, 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 the target toluene solution was obtained.
As a result of qualitative analysis using HPLC, it was confirmed that the area ratio of the target product (7) to the isomer (8) was 94.7 / 5.3 (Rt = 7.2 minutes / 7.8 minutes). did.

Step (b): 10.4 g of a toluene solution of the obtained target product (containing 20.3 mmol of the target product (7)) was cooled to 10 ° C. To the reaction solution, 0.74 g (7.30 mmol) of triethylamine and 0.60 g (6.08 mmol) of maleic anhydride were added. After completion of the addition, 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. /9.6 (Rt = 7.2 minutes / 7.8 minutes / 13.9 minutes / 15.7 minutes).
That is, it was confirmed that the area ratio of the target product (7) to the isomer (8) was 99.3 / 0.7 (Rt = 7.2 minutes / 7.8 minutes).

  Step (c): The reaction solution obtained in step (b) was washed with a 5% by mass aqueous sodium hydrogen carbonate solution (5.9 g × 3) at the same temperature. After completion of the washing, the obtained organic layer was quantitatively analyzed using HPLC. 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 minutes / 7.8 minutes).

  For qualitative and quantitative analysis by HPLC, the conditions described in Example 6 were used, and ethoxybenzene was used as an internal standard substance used for quantitative analysis.

[Example 9] Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (b): 15.1 g of toluene solution of the target product obtained in Step (a) of Example 8 [Target product ( 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 completion of the addition, 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 / 0.2 / 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 of the target product (7) to the isomer (8) was 99.7 / 0.3 (Rt = 7.3 minutes / 7.9 minutes).

  Step (c): The reaction solution obtained in step (b) was washed with a 5% by mass aqueous sodium carbonate solution (4.3 g × 2) at the same temperature. After completion of the washing, the obtained organic layer was quantitatively analyzed using HPLC. 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 of the target product (7) to the isomer (8) was 99.8 / 0.2 (Rt = 7.3 minutes / 7.9 minutes).

  For qualitative and quantitative analysis by HPLC, the conditions described in Example 6 were used, and ethoxybenzene was used as an internal standard substance used for quantitative analysis.

[Example 10] Synthesis of O- [1- (2-hydroxypropyl)] butanone oxime Step (b): 13.9 g of a toluene solution of the target product obtained in Step (a) of Example 8 [Target product ( 7) in 27.0 mmol] was cooled to 0 ° C. To the reaction solution, 0.98 g (9.72 mmol) of triethylamine was added. 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 completion of the addition, 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 product (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 of the target product (7) to the isomer (8) was 99.6 / 0.4 (Rt = 7.3 minutes / 7.9 minutes).

  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 completion of the washing, the obtained organic layer was quantitatively analyzed using HPLC. As a result, it was confirmed that the target product (7) was obtained with a yield of 44% (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 = 7.3 minutes / 7.9 minutes).

  For qualitative and quantitative analysis by HPLC, the conditions described in Example 6 were used, and ethoxybenzene was used as an internal standard substance used for 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, and 40% by mass of sodium hydroxide aqueous solution 11. 5 g (115 mmol) was added. The reaction solution was warmed to 30 ° C., and 87.1 g (1.50 mol) of propylene oxide was added. After completion of the addition, 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 33.8 g (327 mmol) of 95 mass% sulfuric acid was added. After completion of the addition, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated with dichloromethane (300 g × 2) at the same temperature. 729 g of the target dichloromethane solution was obtained.
As a result of qualitative analysis using HPLC, it was confirmed that the area ratio of the target product (7) to the isomer (8) was 94.8 / 5.2 (Rt = 6.7 minutes / 7.2 minutes). did.

Step (b): 23.5 g of a dichloromethane solution of the obtained target product (containing 22.2 mmol of the target product (7)) was cooled to 10 ° C. To the reaction solution, 0.76 g (7.5 mmol) of triethylamine and 0.94 g (6.3 mmol) of phthalic anhydride were added. After completion of the addition, 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 of the reaction of the target product (7) and phthalic anhydride, and is a compound represented by the following formula (13) [Hereinafter, abbreviated as compound (13). ], Rt = 55.7 min peak is a compound represented by formula (14) in which isomer (8) is reacted with phthalic anhydride [hereinafter abbreviated as compound (14). ]. As a result of qualitative analysis, the area ratio of the target product (7), isomer (8), compound (13) and compound (14) was 64.0 / 0.1 / 22.1 / 13.8.
That is, it was confirmed that the area ratio of the target product (7) to the isomer (8) was 99.8 / 0.2 (Rt = 6.7 minutes / 7.2 minutes).

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

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

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

[Example 12] Synthesis of O- [1- (2-hydroxypropyl)]-3-methyl-2-butanone oxime Step (a): 15.1 g (149 mmol) of 3-methyl-2-butanone oxime was added to 23 g of water. And 1.51 g (15.1 mmol) of 40% by mass aqueous sodium hydroxide solution was added. After the reaction solution was heated to 30 ° C., 11.3 g (194 mmol) of propylene oxide was added. After completion of the addition, the reaction solution was stirred at the same temperature for 7 hours. To the reaction solution, 0.87 g (15 mmol) of propylene oxide was added at the same temperature. After completion of the addition, 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 4.39 g (42.5 mmol) of 95 mass% sulfuric acid was added. After completion of the addition, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated with toluene (15 g × 2) at the same temperature. 49.6 g of the target toluene solution was obtained.
As a result of qualitative analysis using HPLC, a target product represented by the following formula (15) [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). ] Was confirmed to be 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 a toluene solution of the obtained target product (containing 39.5 mmol of the target product (15)) was cooled to 10 ° C. To the reaction solution, 1.45 g (14.3 mmol) of triethylamine and 1.16 g (11.8 mmol) of maleic anhydride were added. After completion of the addition, 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.
Among the two newly detected peaks, the peaks at Rt = 24.1 and 25.2 minutes are the products obtained by reacting the target product (15) with maleic anhydride in the formula (17) described below. Represented compound [hereinafter abbreviated as compound (17). ], Rt = 27.7 and 29.4 min peaks are compounds represented by formula (18) in which isomer (16) is reacted with maleic anhydride [hereinafter abbreviated as compound (18). ]. As a result of qualitative analysis, the area ratio of the target product (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 product (15) to the isomer (16) is 99.7 / 0.3 (Rt = 12.5 and 13.3 minutes / 13.9 and 14.7 minutes). confirmed.

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

  Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous potassium carbonate solution (6 g × 2) at the same temperature. After completion of washing, the obtained organic layer was quantitatively analyzed using HPLC. 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. Moreover, the area ratio of the target product (15) to the isomer (16) may be 99.7 / 0.3 (Rt = 12.5 and 13.3 minutes / 13.9 and 14.7 minutes). confirmed.

  For qualitative and quantitative analysis by HPLC, the conditions described in Example 6 were used, and 2-nitrotoluene was used as an internal standard substance used for quantitative analysis. The conditions described in Example 1 were used for 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 a 40 mass% aqueous sodium hydroxide solution was added. The reaction solution was heated to 30 ° C., and 8.49 g (146 mmol) of propylene oxide was added. After completion of the addition, 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 3.33 g (32.2 mmol) of 95 mass% sulfuric acid was added. After completion of the addition, 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. 43.7g of the target toluene solution was obtained.
As a result of qualitative analysis using HPLC, a target product represented by the following formula (19) [hereinafter abbreviated as target product (19)]. And O- [2- (1-hydroxypropyl)]-3,3-dimethyl-2-butanone oxime represented by the isomer (20) [hereinafter abbreviated as isomer (20)]. It was confirmed that the area ratio was 95.0 / 5.0 (Rt = 35.4 minutes / 41.8 minutes). 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 a toluene solution of the obtained target product (containing 34.9 mmol of the target product (19)) was cooled to 10 ° C. To the reaction solution, 1.28 g (12.6 mmol) of triethylamine and 1.05 g (10.7 mmol) of maleic anhydride were added. After completion of the addition, 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 completion of the addition, the reaction solution was stirred at the same temperature for 18 hours. To the reaction solution, 0.43 g (4.2 mmol) of triethylamine and 0.37 g (3.8 mmol) of maleic anhydride were added. After completion of the addition, 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.
Among the two newly detected peaks, the peak at Rt = 65.6 minutes is a product obtained by reacting the target product (19) with maleic anhydride, and is represented by the following formula (21) [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). ]. As a result of qualitative analysis, the area ratio of the target product (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 product (19) to the isomer (20) was 99.6 / 0.4 (Rt = 35.1 minutes / 41.6 minutes).

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

  Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous potassium carbonate solution (6 g × 2) at the same temperature. After completion of washing, the obtained organic layer was quantitatively analyzed using HPLC. 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 product (19) to the isomer (20) was 99.6 / 0.4 (Rt = 35.1 minutes / 41.6 minutes).

  For qualitative and quantitative analysis by HPLC, the conditions described in Example 6 were used, and ethoxybenzene was used as an internal standard substance used for quantitative analysis. The conditions described in Example 1 were used for 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, and a 40 mass% aqueous sodium hydroxide solution. 34 g (13.4 mmol) was added. After warming the reaction solution to 30 ° C., 10.2 g (175 mmol) of propylene oxide was added. After completion of the addition, the reaction solution was stirred at the same temperature for 4 hours, further cooled to 10 ° C., and then stirred for 21 hours. After completion of the reaction, 3.96 g (38.4 mmol) of 95 mass% sulfuric acid was added to the reaction solution at the same temperature. After completion of the addition, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated with toluene (15 g × 2) at the same temperature. 49.0 g of the target toluene solution was obtained.
As a result of qualitative analysis using HPLC, the target product represented by the following formula (23) [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 an isomer (24). ] Was confirmed to be 94.5 / 5.5 (Rt = 12.0 minutes / 12.8 minutes). 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 a toluene solution of the obtained target product (containing 34.9 mmol of the target 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 completion of the addition, 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 minutes is a product obtained by reacting the target compound (23) with maleic anhydride, and is represented by the following formula (25) [Hereinafter abbreviated as compound (25). ], The peak of Rt = 25.3 minutes is a compound represented by the formula (26) in which the isomer (24) is reacted with maleic anhydride [hereinafter abbreviated as compound (26). ]. As a result of qualitative analysis, the area ratio of the target product (23), isomer (24), compound (25) and compound (26) was 70.0 / 0.2 / 20.7 / 9.2.
That is, it was confirmed that the area ratio of the target product (23) to the isomer (24) was 99.8 / 0.2 (Rt = 12.1 minutes / 13.0 minutes).

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

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

  For qualitative and quantitative analysis by HPLC, the conditions described in Example 6 were used, and ethoxybenzene was used as an internal standard substance used for quantitative analysis. The conditions described in Example 1 were used for 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, and 40% by mass aqueous sodium hydroxide solution 1. 12 g (11.2 mmol) was added. After the reaction solution was heated to 30 ° C., 8.50 g (146 mmol) of propylene oxide was added. After completion of the addition, the reaction solution was stirred at the same temperature for 6 hours, further cooled to 10 ° C., and then stirred for 16 hours. After completion of the reaction, 3.31 g (32.0 mmol) of 95 mass% sulfuric acid was added to the reaction solution at the same temperature. After completion of the addition, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated with toluene (15 g × 2) at the same temperature. 49.0 g of the target toluene solution was obtained.
As a result of qualitative analysis using HPLC, the target product represented by the following formula (27) [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 an isomer (28). ] Was confirmed to be 94.2 / 5.8 (Rt = 27.1 minutes / 29.9 minutes). Further, 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 a toluene solution of the obtained target product (containing 25.6 mmol of the target product (27)) was cooled to 10 ° C. To the reaction solution, 0.93 g (9.2 mmol) of triethylamine and 0.78 g (8.0 mmol) of maleic anhydride were added. After completion of the addition, 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.
Among the two newly detected peaks, the peak at Rt = 54.2 minutes is a product of the reaction of the target product (27) and maleic anhydride, and is represented by the following formula (29) [Hereinafter abbreviated as compound (29). ], The peak of 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). ]. As a result of qualitative analysis, the area ratio of the target product (27), isomer (28), compound (29) and compound (30) was 76.0 / 0.1 / 16.6 / 7.3.
That is, it was confirmed that the area ratio of the target product (27) to the isomer (28) was 99.8 / 0.2 (Rt = 27.3 minutes / 30.1 minutes).

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

  Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous potassium carbonate solution (6 g × 2) at the same temperature. After completion of the 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 minutes / 30.1 minutes).

  For qualitative and quantitative analysis by HPLC, the conditions described in Example 6 were used, and 2-nitrotoluene was used as an internal standard substance used for quantitative analysis. The conditions described in Example 1 were used for 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, and 40% by mass aqueous sodium hydroxide solution. 31 g (23.1 mmol) was added. After the reaction solution was heated to 30 ° C., 17.4 g (300 mmol) of propylene oxide was added. After completion of the addition, 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 completion of the addition, 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 the target toluene solution was obtained.
As a result of qualitative analysis using HPLC, it was confirmed that the area ratio of the target product (7) to the isomer (8) was 94.8 / 5.2 (Rt = 6.7 minutes / 7.2 minutes). did.

Step (b): 20.0 g of a toluene solution of the obtained target product (containing 39.5 mmol of the target product (7)) was cooled to 10 ° C. To the reaction solution, 2.40 g (23.7 mmol) of triethylamine and 1.95 g (19.9 mmol) of maleic anhydride were added. After completion of the addition, 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 completion of the addition, 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 product (7), isomer (8), compound (11) and compound (12) was 44.5 / 0 / 47.9 / 7. (Rt = 6.9 minutes / 7.4 minutes / 12.6 minutes / 14.2 minutes).
That is, it was confirmed that the area ratio of the target product (7) to the isomer (8) was 100/0 (Rt = 6.9 minutes / 7.4 minutes).

  Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous potassium carbonate solution (6 g × 3) at the same temperature. After completion of washing, the obtained organic layer was quantitatively analyzed using HPLC. 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 of the target product (7) to the isomer (8) was 100/0 (Rt = 6.9 minutes / 7.4 minutes).

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

[Example 17] Synthesis of O- [1- (2-hydroxypropyl)] cyclohexanone oxime Step (b): 20.3 g of a toluene solution of the target product obtained in Step (a) of Example 14 [Target product ( 23) 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 completion of the addition, 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 product (23), isomer (24), compound (25) and compound (26) was 52.2 / 0 / 39.6 / 8. (Rt = 12.9 minutes / 13.7 minutes / 24.8 minutes / 27.6 minutes).
That is, it was confirmed that the area ratio of the target product (23) to the isomer (24) was 100/0 (Rt = 12.9 minutes / 13.7 minutes).

  Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous potassium carbonate solution (6 g × 2) at the same temperature. After completion of the washing, the obtained organic layer was quantitatively analyzed using HPLC. As a result, it was confirmed that the target product (23) was obtained with 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 minutes / 13.7 minutes).

  For qualitative and quantitative analysis by HPLC, the conditions described in Example 6 were used, and ethoxybenzene was used as an internal standard substance used for quantitative analysis.

Example 18 Synthesis of O- [1- (2-hydroxypropyl)]-3-methyl-2-butanone oxime Step (b): Toluene solution of the target product obtained in Step (a) of Example 12 23.0 g [containing 39.5 mmol of the target product (15)] was cooled to 10 ° C. To the reaction solution, 2.44 g (24.1 mmol) of triethylamine and 1.95 g (19.9 mmol) of maleic anhydride were added. After completion of the addition, 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 (15), isomer (16), compound (17) and compound (18) was 57.2 / 0 / 33.2 / 9. (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 product (15) to the isomer (16) was 100/0 (Rt = 12.9 and 13.7 minutes / 14.3 and 15.2 minutes).

  Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous potassium carbonate solution (6 g × 2) at the same temperature. After completion of washing, the obtained organic layer was quantitatively analyzed using HPLC. As a result, it was confirmed that the target product (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 product (15) to the isomer (16) was 100/0 (Rt = 12.9 and 13.7 minutes / 14.3 and 15.2 minutes).

  For qualitative and quantitative analysis by HPLC, the conditions described in Example 6 were used, and 2-nitrotoluene was used as an internal standard substance used for quantitative analysis.

[Example 19] Synthesis of O- [1- (2-hydroxypropyl)] acetophenone oxime Step (b): 20.1 g of toluene solution of the target product obtained in Step (a) of Example 15 [Target product ( 27) in 25.7 mmol] was cooled to 10 ° C. To the reaction solution, 1.56 g (15.4 mmol) of triethylamine and 1.26 g (12.8 mmol) of maleic anhydride were added. After completion of the addition, 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 product (27), isomer (28), compound (29) and compound (30) was 59.8 / 0 / 33.2 / 7. 0.0 (Rt = 29.6 minutes / 32.6 minutes / 60.3 minutes / 71.0 minutes).
That is, it was confirmed that the area ratio of the target product (27) to the isomer (28) was 100/0 (Rt = 29.6 minutes / 32.6 minutes).

  Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous potassium carbonate solution (5 g × 3) at the same temperature. After completion of the 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 29% (calculated from acetophenone oxime). It was also confirmed that the area ratio of the target product (27) to the isomer (28) was 100/0 (Rt = 29.6 minutes / 32.6 minutes).

  For qualitative and quantitative analysis by HPLC, the conditions described in Example 6 were used, and 2-nitrotoluene was used as an internal standard substance used for 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 40% by mass aqueous sodium hydroxide solution. 88 g (48.8 mmol) was added. After the reaction solution was warmed to 30 ° C., 36.4 g (627 mmol) of propylene oxide was added. After completion of the addition, the reaction solution was stirred at the same temperature for 3 hours. After completion of the reaction, the reaction solution was cooled to 10 ° C., and then 14.2 g (138 mmol) of 95% by mass sulfuric acid was added. After completion of the addition, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated with toluene (36 g × 2) at the same temperature. 113 g of the target toluene solution was obtained.
As a result of qualitative analysis using HPLC, the target product 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 an isomer (32). ] Was confirmed to be 94.4 / 5.6 (Rt = 3.9 minutes / 4.2 minutes). 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 a toluene solution of the obtained target product (containing 43.3 mmol of the target product (31)) was cooled to 10 ° C. To the reaction solution, 2.63 g (26.0 mmol) of triethylamine and 2.13 g (21.7 mmol) of maleic anhydride were added. After completion of the addition, 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 product obtained by reacting the target compound (31) with maleic anhydride, and is represented by the following formula (33) [Hereinafter abbreviated as compound (33). ], The peak of Rt = 7.2 is a compound represented by the formula (34) in which the isomer (32) is reacted with maleic anhydride [hereinafter abbreviated as compound (34). ]. As a result of qualitative analysis, the area ratio of the target product (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 product (31) to the isomer (32) was 100/0 (Rt = 3.9 minutes / 4.3 minutes).

  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 compound (33) and compound (34) were detected overlapping Rt = 2.1 minutes.

  Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous potassium carbonate solution (6 g × 2) at the same temperature. After completion of washing, the obtained organic layer was quantitatively analyzed using HPLC. 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 product (31) to the isomer (32) was 100/0 (Rt = 3.9 minutes / 4.3 minutes).

  For qualitative and quantitative analysis by HPLC, the conditions described in Example 6 were used, and ethoxybenzene was used as an internal standard substance used for quantitative analysis. The conditions described in Example 1 were used for 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 connected to a Dean-Stark tube. After 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 4 ° C for 4 hours, further stirred at 50 ° C for 4 hours, and further stirred 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). To the obtained aqueous layer, 30 g of a saturated aqueous sodium hydrogen carbonate solution was added and then 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 target product as a pale yellow oil.
¹ H-NMR (600 MHz, ppm in CDCl ₃ ): δ 1.18 (d, 3H), 1.35 (d, 3H), 3.00 (brs, 2H), 3.89 (m, 1H), 4 .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 GC / MS analysis conditions are described below.
Column: HP-5 manufactured by Agilent Technologies, Inc. 0.32 mm ID × 30 m × 0.25 μm,
Temperature increase time and temperature increase rate: 40 ° C (2 minutes)-(20 ° C / minute)-300 ° C (7 minutes)
In addition, LC / MS analysis conditions are described below.
Column: Inersil ODS-3, 3 μm, 2.1 mm × 50 mm, manufactured by GL Sciences Inc.
Eluent: Methanol / 0.1% by volume aqueous formic acid solution = 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 completion of cooling, 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 completion of the addition, the mixture was stirred at the same temperature for 53 hours. After completion of the reaction, 20 mL of a saturated aqueous sodium hydrogen carbonate solution and 100 mL of ethyl acetate were added and separated. To the aqueous layer, 100 mL of ethyl acetate and a 1 mol / L hydrochloric acid aqueous solution were added until the pH reached 3, followed by liquid separation. Further, the aqueous layer was extracted with ethyl acetate (200 mL × 3). The obtained organic layer was washed with 20 mL of saturated brine, and the organic layer was concentrated and dried to give 2.19 g of the title compound as a pale yellow oil.
¹ H-NMR (300 MHz, ppm in CDCl ₃ ): δ 1.07 (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 GC / MS analysis conditions are described below.
Column: HP-5 manufactured by Agilent Technologies, Inc. 0.32 mm ID × 30 m × 0.25 μm,
Temperature increase time and temperature increase rate: 40 ° C (2 minutes)-(20 ° C / minute)-300 ° C (7 minutes)
The LC / MS analysis conditions are described below.
Column: XBridge C18 manufactured by Waters, 5 μm, 2.1 mm × 150 mm,
Eluent: acetonitrile / 0.2% by volume aqueous formic acid solution = 40/60 (volume ratio)
Flow rate: 0.2 mL / min Column temperature: 40 ° C

  The present invention is useful as a method for producing an O- [1- (2-hydroxypropyl)] oxime compound that is useful as an intermediate for pharmaceuticals, 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, Forms a 7-membered carbocycle. ] The manufacturing method of the O- [1- (2-hydroxypropyl)] oxime compound represented by this.
Step (a): Formula (2):

(Wherein R ¹ and R ² represent the same meaning as defined above), a step of reacting oxime compound with propylene oxide in the presence of a basic compound Step (b): Step ( The step of reacting the mixture obtained in a) with a cyclic acid anhydride in the presence of a basic compound Step (c): The mixture obtained in step (b) is mixed with an aqueous solution of a basic compound. And 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 relative 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. ] The manufacturing method of 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 ) ₃ or a phenyl group, or R ¹ and R ² together with the carbon atom 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 carbocyclic ring. Each of R ¹ and R ² independently represents —CH ₃ , —CH ₂ CH ₃ , —CH ₂ CH ₂ CH ₃ , —CH (CH ₃ ) ₂ , —C (CH ₃ ) ₃ or a phenyl group; Or a method for producing an O- [1- (2-hydroxypropyl)] oxime compound according to claim 4, wherein R ¹ and R ² together with the carbon atom to which they are bonded form a 6-membered carbocycle. . 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 together with the carbon atom to which they are bonded, forms a 6-membered carbocycle.   In step (c), the organic solvent containing the mixture obtained in step (b) is mixed with an aqueous solution of a basic compound, O- [1- (1- 2-hydroxypropyl)] oxime compound.   The O- [1- (2-hydroxypropyl)] oxime according to claim 7, wherein the organic solvent containing the mixture obtained in step (b) is dichloromethane, 1,2-dichloroethane or toluene in step (c). Compound production method.   The O- [1- (2-hydroxypropyl) according to any one of claims 1 to 8, wherein in the step (c), the basic compound is sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate. )] A method for producing an oxime compound.