[0001]The present invention relates to a method for producing an 0-[l-(2-hydroxypropyl)]oxime compound, which is useful as an intermediate for pharmaceuticals, agrochemicals, or electronic materials, for example.
BACKGROUND ART
[0002] Conventionally, 0-[l-(2-hydroxypropyl)]oxime compounds are known to be useful as intermediates for pharmaceuticals, agrochemicals, and electronic materials, for example.
A process for producing such a compound is generally known in which an oxime compound is reacted with propylene oxide or propylene carbamate. For example, processes are known in which 0-[l-(2-hydroxypropyl)]acetone oxime is produced by reacting acetone oxime and propylene oxide in the presence of lithium ethoxide (see Patent Document 1 and Non-Patent Document 1). Additionally, a process is known in which 0-[l-(2-hydroxypropyl)]acetone oxime is produced by reacting acetone oxime and propylene oxide in the presence of triethylamine (see Patent Document 2). Furthermore, a process is known in which 0-[l-(2-hydroxypropyl)]acetophenone oxime is produced by reacting acetophenone oxime and propylene oxide in the presence of potassium carbonate or sodium hydride (see Patent Document 3).
Several processes for producing 0-[l-(2-hydroxyalkyl)]oxime compounds are also known (see Patent Documents 1,4 and Non-Patent Document 1).

Prior Art Documents Patent Documents
[0003] Patent Document 1: specification of US Patent Application Publication No. 3,040,097
Patent Document 2: WO 96/04238 Al
Patent Document 3: Japanese Patent Application Publication No. 2009-155327 (JP 2009-155327 A)
Patent Document 4: WO 2008/061616 Al Non-Patent Document
[0004] Non-Patent Document 1: Journal of the American Chemical Society, 1959, vol. 81, p. 4223
SUMMARY OF THE INVENTION
Problem to be Solved by the Invention
[0005] Patent Documents 1,2,3 and Non-Patent Document 1 disclose processes for producing 0-[l-(2-hydroxypropyI)]oxime compounds by reacting oxime compounds and propylene oxide in the presence of basic compounds. Propylene oxide has two reaction sites; thus, when propylene oxide is used, an isomeric mixture of a compound of formula (1) and a compound of formula (3) is obtained as a product. The ratio of the compound of formula (1) to the compound of formula (3) produced in that case is typically 85/15 to 96/4.
[0006]

R2 R2 CH

O

(2) (1)
R1^^N^ Y 0H CH3
(3)
[0007] The compound of formula (1) and the compound of formula (3) are very similar in structure to each other; therefore, it is very difficult to selectively reduce only the compound of formula (3) from the mixture of the compound of formula (1) and the compound of formula (3) by means of a general purification procedure such as purification by distillation, for example. Furthermore, when the compound of formula (1) is used as an intermediate for a pharmaceutical, an agrochemical, or an electronic material, for example, the compound of formula (3) is included in the product as an impurity, which causes adverse effects on the product quality and performance.
Accordingly, there is a desire for the development of a novel process for producing an 0-[l-(2-hydroxypropyI)]oxime compound in which the inclusion of the compound of formula (3) has been minimized, which is suitable as an intermediate for pharmaceuticals, agrochemicals, or electronic materials, for example.
Means for Solving the Problem
[0008] As a result of extensive research to solve the above-described problem, the present inventors found that an 0-[l-(2-hydroxypropyl)]oxime compound with an extremely high purity can be obtained by reacting an isomeric mixture of the 0-[l-(2-hydroxypropyl)]oxime compound with a cyclic acid anhydride that is commercially available as an industrial raw material, and then mixing the mixture with an aqueous solution of a basic compound, thereby completing the present invention.
[0009] In summary, the present invention relates to processes as set forth in [1] to [76] below:

A method for producing an 0-[l-(2-hydroxypropyl)]oxime compound of formula
(1):
R2 CH3
RAN-°vA0H (1)
[wherein R and R are each independently a C\^ alkyl group or a phenyl group, or R and R2 taken together with the carbon atoms to which they are attached form a 5- to 7-membered carbocyclic ring],
the method comprising steps (a) to (c):
step (a): reacting an oxime compound of formula (2):
(wherein R and R are defined as above) with propylene oxide in the presence of a basic compound;
step (b): reacting the mixture obtained in step (a) with a cyclic acid anhydride in the presence of a basic compound; and
step (c): mixing the mixture obtained in step (b) with an aqueous solution of a basic compound to obtain the 0-[l-(2-hydroxypropyl)]oxime compound of formula (1).
[0010] [2]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to [1] above, wherein the cyclic acid anhydride is used in an amount of 0.04 to 1.0 equivalent per equivalent of the compound of formula (1) in the mixture obtained in step
(a)-
[0011] [3]
The method for producing an 0-[l-(2~hydroxypropyl)]oxime compound according to [1] or [2] above, wherein the cyclic acid anhydride is at least one selected from the group consisting of maleic anhydride, succinic anhydride, and phthalic anhydride.
[0012] [4]
The method for producing an 0-[l-(2-hydroxypropyl)] oxime compound according

to any one of [1] to [3] above, wherein R1 and R2 are each independently -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)(CH2CH3), -CH2CH(CH3)2, -C(CH3)33 or a phenyl group, or R1 and R2 taken together with the carbon atoms to which they are attached form a 6-membered carbocyclic ring.
[0013] [5]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to [4] above, wherein R1 and R2 are each independently -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, or a phenyl group, or R1 and R2 taken together with the carbon atoms to which they are attached form a 6-membered carbocyclic ring.
[0014] [6]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to [5] above, wherein R1 and R2 are each independently -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, or a phenyl group, or R1 and R2 taken together with the carbon atoms to which they are attached form a 6-membered carbocyclic ring.
[0015] [7]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [6] above, wherein in step (c), an organic solvent containing the mixture obtained in step (b) is mixed with the aqueous solution of the basic compound.
[0016] [8]
The method for producing an 0-[l-(2-hydroxypropyI)]oxime compound according to [7] above, wherein in step (c), the organic solvent containing the mixture obtained in step (b) is dichloromethane, 1,2-dichloroethane, or toluene.
[0017] [9]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [8] above, wherein in step (c), the basic compound is sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, or potassium carbonate.
[0018] [10]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according

6
to any one of [1] to [9] above, wherein in 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, an alkaline earth metal bicarbonate, an alkaline earth metal phosphate, an alkaline earth 5 metal hydrogen phosphate, or an organic base.
[11]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [9] above, wherein in step (a), the basic compound is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal phosphate, an alkali metal hydrogen 10 phosphate, an alkaline earth metal hydroxide, an alkaline earth metal carbonate, an alkaline earth metal bicarbonate, an alkaline earth metal phosphate, or an alkaline earth metal hydrogen phosphate.
[12]
The method for producing an 0-[l-(2-hydroxypropyI)]oxime compound according 15 to any one of [1] to [9] above, wherein in step (a), the basic compound is an alkali metal hydroxide.
[13]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [9] above, wherein in step (a), the basic compound is sodium 20 hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, magnesium hydroxide, calcium hydroxide, magnesium carbonate, calcium carbonate, magnesium hydrogen carbonate, calcium hydrogen carbonate, magnesium phosphate, calcium 25 phosphate, magnesium hydrogen phosphate, calcium hydrogen phosphate, triethylamine, tributylamine, pyridine, 4-(dimethylamino)pyridine, imidazole, or l,8-diazabicyclo[5,4,0]-7-undecene.
[14]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according

7 to any one of [1] to [9] above, wherein in step (a), the basic compound is sodium
hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium
hydrogen carbonate, or potassium hydrogen carbonate.
[15]
5 The method for producing an 0-[l-(2-hydroxypropyI)]oxime compound according
to any one of [1] to [9] above, wherein in step (a), the basic compound is triethylamine, tributylamine, pyridine, 4-(dimethylamino)pyridine, imidazole, or l,8-diazabicycIo[5,4,0]-7-undecene.
[16]
10 The method for producing an 0-[l-(2-hydroxypropyI)]oxirne compound according
to any one of [1] to [9] above, wherein in step (a), the basic compound is sodium hydroxide or potassium hydroxide.
[17]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according 15 to any one of [1] to [9] above, wherein in step (a), the basic compound is sodium hydroxide.
[18]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [9] above, wherein in step (a), the basic compound is potassium 20 hydroxide.
[0019] [19]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [18] above, wherein in step (b), the cyclic acid anhydride is maleic anhydride, succinic anhydride, phthalic anhydride, itaconic anhydride, glutaric anhydride, 25 adipic anhydride, citraconic anhydride, trimellitic anhydride, hexahydrophthalic
anhydride, tetrachlorophthalic anhydride, cis-4-cyclohexene-l,2-dicarboxylic anhydride, or isododecenylsuccinic anhydride.
[20]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according

8 to any one of [1] to [18] above, wherein in step (b), the cyclic acid anhydride is maleic
anhydride, succinic anhydride, phthalic anhydride, itaconic anhydride, glutaric anhydride,
adipic anhydride, or citraconic anhydride.
[21]
5 The method for producing an 0-[ 1 -(2-hydroxypropyI)]oxime compound according
to any one of [1] to [18] above, wherein in step (b), the cyclic acid anhydride is triraellitic anhydride, hexahydrophthalic anhydride, tetrachlorophthalic anhydride, cis-4~cyclohexene-l,2-dicarboxylic anhydride, or isododecenylsuccinic anhydride.
[22]
10 The method for producing an 0-[l-(2-hydroxypropyi)]oxime compound according
to any one of [1] to [18] above, wherein in step (b), the cyclic acid anhydride is maleic anhydride.
[23]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according 15 to any one of [1] to [18] above, wherein in step (b), the cyclic acid anhydride is succinic anhydride.
[24]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [18] above, wherein in step (b), the cyclic acid anhydride is phthalic 20 anhydride.
[0020] [25]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [ 1 ] to [24] above, wherein in step (b), the basic compound is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal phosphate, an alkali metal hydrogen 25 phosphate, an alkaline earth metal hydroxide, an alkaline earth metal carbonate, an alkaline earth metal bicarbonate, an alkaline earth metal phosphate, an alkaline earth metal hydrogen phosphate, or an organic base.
[26]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according

9
to any one of [1] to [24] above, wherein in 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, an alkaline earth metal bicarbonate, an alkaline earth metal phosphate, or an alkaline earth 5 metal hydrogen phosphate.
[27]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to any one of [1] to [24] above, wherein in step (b), the basic compound is an organic
base.
10 [28]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [24] above, wherein in step (b), the basic compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium 15 phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, magnesium hydroxide, calcium hydroxide, magnesium carbonate, calcium carbonate, magnesium hydrogen carbonate, calcium hydrogen carbonate, magnesium phosphate, calcium phosphate, magnesium hydrogen phosphate, calcium hydrogen phosphate, triethylamine, tributylamine, pyridine, 4-(dimethylamino)pyridine, imidazole, or 20 1,8-diazabicyclo[5,4,0]-7-undecene.
[29]
The method for producing an 0-[l-(2-hydroxypropyi)]oxime compound according to any one of [1] to [24] above, wherein in step (b), the basic compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium 25 hydrogen carbonate, or potassium hydrogen carbonate.
[30]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [24] above, wherein in step (b), the basic compound is triethylamine, tributylamine, pyridine, 4-(dimethylamino)pyridine, imidazole, or

10 l,8-diazabicyclo[5,4,0]-7-undecene.
[31]
The method for producing an 0-[l-(2-hydroxypropyI)]oxime compound according
to any one of [1] to [24] above, wherein in step (b), the basic compound is triethylamine,
5 tributylamine, or pyridine.
[32]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [24] above, wherein in step (b), the basic compound is triethylamine.
[33]
10 The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to any one of [1] to [24] above, wherein in step (b), the basic compound is tributylamine.
[34]
The method for producing an 0-[l-(2-hydroxypropyI)]oxime compound according
to any one of [1] to [24] above, wherein in step (b), the basic compound is pyridine.
15 [0021] [35]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [34] above, wherein in step (c), the organic solvent containing the mixture obtained in step (b) is a hydrocarbon solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an alcohol solvent, a ketone solvent, a nitrile solvent, a 20 carboxylate solvent, or a nitrogen-containing aprotic polar solvent.
[36]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [34] above, wherein in step (c), the organic solvent containing the mixture obtained in step (b) is a hydrocarbon solvent, an aromatic hydrocarbon solvent, a 25 halogenated hydrocarbon solvent, a ketone solvent, or a carboxylate solvent.
[37]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [34] above, wherein in step (c), the organic solvent containing the mixture obtained in step (b) is a hydrocarbon solvent, an aromatic hydrocarbon solvent,

11
or a halogenated hydrocarbon solvent.
[38]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [34] above, wherein in step (c), the organic solvent containing the 5 mixture obtained in step (b) is a hydrocarbon solvent.
[39]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to anyone of [1] to [34] above, wherein in step (c), the organic solvent containing the
mixture obtained in step (b) is an aromatic hydrocarbon solvent.
10 [40]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [34] above, wherein in step (c), the organic solvent containing the mixture obtained in step (b) is a halogenated hydrocarbon solvent.
[41]
15 The method for producing an 0-[l-(2-hydroxypropyl)]oxirne compound according
to any one of [1] to [34] above, wherein in step (c), the organic solvent containing the mixture obtained in step (b) is hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, heptane, benzene, xylene, toluene, dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene, trifluororaethyl benzene, 20 acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, or ethyl propionate.
[42]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [34] above, wherein in step (c), the organic solvent containing the 25 mixture obtained in step (b) is hexane, cyclohexane, methylcyclohexane,
ethylcyclohexane, heptane, benzene, xylene, toluene, dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene, or trifluoromethyl benzene.
[43]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according

12 to any one of [1] to [34] above, wherein in step (c), the organic solvent containing the
mixture obtained in step (b) is benzene, xylene, or toluene.
[44]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
5 to any one of [1] to [34] above, wherein in step (c), the organic solvent containing the
mixture obtained in step (b) is dichloromethane, carbon tetrachloride, chloroform,
1,2-dichloroethane, chlorobenzene, or trifluoromethyl benzene.
[45]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
10 to any one of [1] to [34] above, wherein in step (c), the organic solvent containing the
mixture obtained in step (b) is toluene.
[46]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to any one of [1] to [34] above, wherein in step (c), the organic solvent containing the
15 mixture obtained in step (b) is dichloromethane.
[47]
The method for producing an 0~[l-(2-hydroxypropyl)]oxime compound according
to any one of [1] to [34] above, wherein in step (c), the organic solvent containing the
mixture obtained in step (b) is 1,2-dichloroethane.
20 [0022] [48]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to any one of [l] to [47] above, wherein in step (c), the basic compound is an alkali metal
hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal
phosphate, an alkali metal hydrogen phosphate, an alkaline earth metal hydroxide, an
25 alkaline earth metal carbonate, an alkaline earth metal bicarbonate, an alkaline earth
metal phosphate, an alkaline earth metal hydrogen phosphate, or an organic base.
[49]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to any one of [1] to [47] above, wherein in step (c), the basic compound is an alkali metal

13
hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal
phosphate, an alkali metal hydrogen phosphate, an alkaline earth metal hydroxide, an
alkaline earth metal carbonate, an alkaline earth metal bicarbonate, an alkaline earth
metal phosphate, or an alkaline earth metal hydrogen phosphate.
5 [50]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [47] above, wherein in step (c), the basic compound is an alkali metal carbonate or an alkali metal bicarbonate.
[51]
10 The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to any one of [1] to [47] above, wherein in step (c), the basic compound is an alkali metal carbonate. [52]
The method for producing an 0-[l-(2-hydroxypropyl)3oxime compound according 15 to any one of [1] to [47] above, wherein in step (c), the basic compound is an alkali metal bicarbonate.
[53]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [47] above, wherein in step (c), the basic compound is sodium 20 hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, magnesium hydroxide, calcium hydroxide, magnesium carbonate, calcium carbonate, magnesium hydrogen carbonate, calcmm hydrogen carbonate, magnesium phosphate, calcium 25 phosphate, magnesium hydrogen phosphate, calcmm hydrogen phosphate, triethylamine, tributylamine, pyridine, 4-(dimethylamino)pyridine, imidazole, or l,8-diazabicyclo[5s4,0]-7-undecene. [54] The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according

14 to any one of [1] to [47] above, wherein in step (c), the basic compound is sodium
hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium
hydrogen carbonate, or potassium hydrogen carbonate.
[55]
5 The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to any one of [1] to [47] above, wherein in step (c), the basic compound is sodium hydroxide or potassium hydroxide.
[56]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according 10 to any one of [1] to [47] above, wherein in step (c), the basic compound is sodium carbonate or potassium carbonate.
[57]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [47] above, wherein in step (c), the basic compound is sodium 15 hydrogen carbonate or potassium hydrogen carbonate.
[58]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to any one of [1] to [47] above, wherein in step (c), the basic compound is sodium
carbonate.
20 [59]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of [1] to [47] above, wherein in step (c), the basic compound is potassium carbonate.
[60]
25 The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to any one of [1] to [47] above, wherein in step (c), the basic compound is sodium hydrogen carbonate.
[61]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according

15
to any one of [1] to [47] above, wherein in step (c), the basic compound is potassium
hydrogen carbonate.
[0023] [62]
A method for producing an 0-[l-(2-hydroxypropyl)]oxime compound comprising 5 successively performing steps (a) to (c) each specified in any one of [ 1 ] to [61 ] above.
[63]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to [62] above, wherein the organic solvent is a hydrocarbon solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an alcohol solvent, a ketone 10 solventj a nitrile solvent, a carboxylate solvent, or a nitrogen-containing aprotic polar solvent.
[64]
The method for producing an 0-[l-(2-hydroxypropyl)]oxirne compound according to [62] above, wherein the organic solvent is a hydrocarbon solvent, an aromatic 15 hydrocarbon solvent, a halogenated hydrocarbon solvent, a ketone solvent, or a carboxylate solvent.
[65]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to [62] above, wherein the organic solvent is a hydrocarbon solvent, an aromatic 20 hydrocarbon solvent, or a halogenated hydrocarbon solvent.
[66]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to [62] above, wherein the organic solvent is a hydrocarbon solvent.
[67]
25 The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to [62] above, wherein the organic solvent is an aromatic hydrocarbon solvent.
[68]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to [62] above, wherein the organic solvent is a halogenated hydrocarbon solvent.

16
[69]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to [62] above, wherein the organic solvent is hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, heptane, benzene, xylene, toluene, dichloromethane, carbon 5 tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene, trifluoromethyl benzene, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, or ethyl propionate.
[70]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according 10 to [62] above, wherein the organic solvent is hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, heptane, benzene, xylene, toluene, dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene, or trifluoromethyl benzene,
[71]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according 15 to [62] above, wherein the organic solvent is benzene, xylene, or toluene,
[72]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to [62] above, wherein the organic solvent is dichloromethane, carbon tetrachloride,
chloroform, 1,2-dichloroethane, chlorobenzene, or trifluoromethyl benzene.
20 [73]
The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to [62] above, wherein the organic solvent is dichloromethane, 1,2-dichloroethane, or toluene.
[74]
25 The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according
to [62] above, wherein the organic solvent is toluene.
[75]
The method for producing an 0-[l-(2-hydroxypropyI)]oxime compound according to [62] above, wherein the organic solvent is dichloromethane.

17 [76]
The method for producing an 0-[l-(2-hydroxypropyI)]oxime compound according
to [62] above, wherein the organic solvent is 1,2-dichloroethane.
5 Effects of the Invention
[0024] According to the present invention, an inexpensive and efficient process for producing an 0-[l-(2-hydroxypropyI)]oxime compound with an extremely high purity can be provided, the 0-[l-(2-hydroxypropyl)]oxime compound being useful as an intermediate for pharmaceuticals, agrochemicals, or electronic materials, for example.
10
MODES FOR CARRYING OUT THE INVENTION
[0025] The compounds included in the present invention contain E- and Z-forms of geometric isomers. The compounds according to the present invention include these E-form, Z-form and mixtures containing E- and Z-forms in any ratio.
15 [0026] The compound (1) included in the present invention may contain,
depending on the substituents, an optically active substance due to the presence of one or more asymmetric carbon atoms. The compounds according to the present invention include all optically active substances or racemates.
[0027] Among the compounds included in the present invention, examples of
20 salts that can be formed in accordance with a conventional method include salts of
hydrogen halides such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, and hydrogen iodide; salts of inorganic acids such as nitric acid, sulfuric acid, phosphoric acid, chloric acid, and perchloric acid; salts of sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and trifluoromethanesulfonic acid; salts of carboxylic acids such as
25 formic acid, acetic acid, propionic acid, trifluoroacetic acid, fiimaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid, and citric acid; salts of amino acids such as glutamic acid and aspartic acid; salts of alkali metals such as lithium, sodium, and potassium; salts of alkaline earth metals such as calcium, barium, and magnesium; salts of aluminum; and

18
quarternary ammonium salts such as tetramethylammonium salts, tetrabutylammonium
salts, and benzyltrimethylammonium salts.
[0028] Specific examples of the substituents shown herein will be described hereinafter. As used herein, the symbols n-, i-, s-, and t- mean normal, iso, secondary, 5 and tertiary, respectively.
[0029] Examples of halogen atoms in the present invention include fluorine, chlorine, bromine, and iodine atoms. The term "halo" as used herein also denotes these halogen atoms.
[0030] As used herein, the term "Ci.g alkyl group" denotes a linear or branched 10 hydrocarbon group having a carbon atom number of 1 to 6. Specific examples of Ci.g alkyl groups include methyl group, 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, 15 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, l-ethylbutyl group, 2-ethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyI group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1,1,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, and l-ethyl-2-methylpropyl group. An alkyl group whose carbon atom number is in each designated range is 20 selected.
[0031 ] As used herein, the recitation "R1 and R2 taken together with the carbon atoms to which they are attached form a 5- to 7-membered carbocyclic ring" means that R taken together with R forms a C^ alkylene chain, thereby forming a 5- to 7-membered ring together with the carbon atoms to which R1 and R2 are attached. 25 Specific examples of 5- to 7-membered carbocyclic rings include a cyclopentane ring and a cyclohexane ring.
Steps (a) to (c) of the process for producing an 0-[I-(2-hydroxypropyl)]oxime compound of formula (1) (hereinafter abbreviated as the "compound (1)") will be described in detail hereinafter.

19
[0032] [Step (a)]

?N"-~'" + ^^CH3 (a) " R1^N^
(2) (1)

R1' "N^ ^T "OH
CH3
(3)
[0033] The compound (1) can be produced by reacting an oxime compound of formula (2) [wherein R and R are as defined above] [hereinafter abbreviated as the 5 "compound (2)"] with propylene oxide in the presence of a basic compound.
[0034] As a product in this step, the compound (1) is obtained as a mixture of the compound (1) and a compound of formula (3) [wherein R1 and R2 are as defined above] [hereinafter abbreviated as the "compound (3)"], which is an isomer of the compound (1). The ratio of the compound (1) to the compound (3) produced is typically 85/15 to 96/4.
10 [0035] Propylene oxide used in step (a) can be used in an amount of 0.5 to 5
equivalents, and preferably 0.9 to 1.5 equivalents, per equivalent of the compound (2).
[0036] Examples of the basic compound used in step (a) include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal bicarbonates such as
15 sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal phosphates such as sodium phosphate and potassium phosphate; alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate; alkaline
20 earth metal bicarbonates such as magnesium hydrogen carbonate and calcium hydrogen carbonate; alkaline earth metal phosphates such as magnesium phosphate and calcium phosphate; alkaline earth metal hydrogen phosphates such as magnesium hydrogen phosphate and calcium hydrogen phosphate; and organic bases such as triethylamine,

20 tributylamine, pyridine, 4-(dimethylamino)pyridine, imidazole, and
l,8-diazabicyclo[5,4,0]-7-undecene. These basic compounds can be used alone or in
combination of two or more.
[0037] The basic compound can be used in an amount of 0.01 to 5 equivalents,
5 and preferably 0.05 to 2 equivalents, per equivalent of the compound (2).
[0038] When a solvent is used, the solvent to be used is not particularly limited as
long as it does not inhibit the reaction from proceeding. Examples of the solvent
include hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane,
ethylcyclohexane, and heptane; aromatic hydrocarbon solvents such as benzene, xylene,
10 and toluene; halogenated hydrocarbon solvents such as dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene, and trifluoromethyl benzene; alcohol solvents such as methanol, ethanol, and 2-propanol; ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; nitrile solvents such as acetonitrile and propionitrile; carboxylate solvents such as ethyl acetate and ethyl
15 propionate; nitrogen-containing aprotic polar solvents such as N,N-dimetbylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and 1 ,3-dimethyl-2-imidazoIidinone; and water. Preferably, aromatic hydrocarbon solvents such as xylene and toluene; halogenated hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane; and water can be used. These solvents can also be used as a mixture of two or more.
20 [0039] Step (a) can be performed in a normal-pressure atmosphere; in some cases,
step (a) can be performed at a pressure in the range of 0.001 to 100 MPa, preferably 0.1 to 10 MPa.
[0040] The reaction temperature can be typically adjusted to any temperature in the range of-90 to 200°C, and can be preferably adjusted in the range of-20 to 100°C.
25 [0041 ] Although the reaction time varies depending on the reactant concentration
or the reaction temperature, it can be typically adjusted in the range of 10 minutes to 100 hours, preferably 10 minutes to 24 hours.
[0042] The amount of the compound (1) obtained by means of step (a) can be calculated by quantitative analysis based on an internal standard method using high

21
performance liquid chromatography (HPLC).
[0043] Although the treatment method after the reaction is not particularly limited, the reaction mixture after the completion of the reaction may be subjected to a general post-treatment in which, for example, the mixture is directly concentrated, or the mixture 5 is dissolved in an organic solvent, and then water is added to the solution, the solution is separated, and the mixture is concentrated as required, or the mixture is added to water, subjected to organic solvent extraction, and concentrated as required, to obtain the reaction mixture. The reaction mixture may be directly used in the subsequent step, without concentrating the solution of the reaction mixture obtained after the
10 post-treatment. The reaction mixture after the completion of the reaction may also be directly used in the subsequent step, without any post-treatment. When purification is required, the reaction mixture can be separated and purified using any purification method such as distillation, recrystallization, column chromatography, thin layer chromatography, or preparative liquid chromatography.
15
[0044] [Step (b)]
R2 CH3 O
(I)
+
f o
(4)
CH3
(3)

(b)

-*>

3
R2 CH, R2 CH, O O

AA
RI-S^XZ-SJH + Ri-Nl^°^ -O' -A" -OH
(1) (5)
Rz OO
X.X.
CH3
(6)
R1-%,^°Y -o- -A- ^0H

22 [0045] The mixture of the compounds (1) and (3) is reacted with a cyclic acid
anhydride, which is, for example, an acid anhydride of formula (4) [wherein A is
-CH2CH2-, -CH=CH-, or 1,2-phenylene group, for example], in the presence of a basic
compound. As a result, a mixture of the compound (1), a compound of formula (5)
5 [wherein R1 and R2 are as defined above, and A is -CH2CH2-, -CH=CH-, or
1,2-phenylene group] [hereinafter abbreviated as the "compound (5)"], and a compound
of formula (6) [wherein R1 and R2 are as defined above, and A is -CH2CH2-, -CH=CH-,
or 1,2-phenylene group] [hereinafter abbreviated as the "compound (6)"] can be
produced.
10 [0046] Although steps (b) and (c) are described herein using the acid anhydride of
formula (4) as the cyclic acid anhydride, the cyclic acid anhydride used in the present invention is not limited to the acid anhydride of formula (4).
[0047] Because the compound (3) is a primary alcohol compound, it reacts with the compound (4) preferentially over the compound (1) to form the compound (6). As a
15 result, at the completion of step (b), the ratio of the compound (3) present in the reaction solution is reduced; specifically, the compound (1) and the compound (3) are typically present in a ratio of about 99/1 to 100/0.
[0048] The cyclic acid anhydride used in 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
20 compound like the compound (6). Examples of the cyclic acid anhydride include maleic anhydride, succinic anhydride, phthalic anhydride, itaconic anhydride, glutaric anhydride, adipic anhydride, citraconic anhydride, trimellitic anhydride, hexahydrophthalic anhydride, tetrachiorophthalic anhydride, cis-4~cyclohexene~l,2-dicarboxyiic anhydride, and isododecenylsuccinic anhydride. In particular, maleic anhydride, succinic
25 anhydride, and phthalic anhydride are preferred from the viewpoint of availability. These cyclic acid anhydrides can be used alone or in combination of two or more.
[0049] The amount of the cyclic acid anhydride used in step (b) is preferably 0.04 to 1.0 equivalent per equivalent of the compound (1); from the viewpoint of further reducing the ratio of the compound (3) present in the reaction solution after the

23 completion of step (b), the amount of the cyclic acid anhydride used in step (b) is more
preferably 0.1 to 1.0 equivalent, still more preferably 0.2 to 0.9 equivalent, particularly
preferably 0.3 to 0.8 equivalent, and most preferably 0.5 to 0.7 equivalent, per equivalent
of the compound (1).
5 [0050] The cyclic acid anhydride in step (b) may also be used in two or more
divided portions.
[0051] Examples of the basic compound used in step (b) include alkali metal
hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates
such as sodium carbonate and potassium carbonate; alkali metal bicarbonates such as
10 sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal phosphates such as sodium phosphate and potassium phosphate; alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate; alkaline
15 earth metal bicarbonates such as magnesium hydrogen carbonate and calcium hydrogen carbonate; alkaline earth metal phosphates such as magnesium phosphate and calcium phosphate; alkaline earth metal hydrogen phosphates such as magnesium hydrogen phosphate and calcium hydrogen phosphate; and organic bases such as triethylamine, tributylamine, pyridine, 4-(dimethylamino)pyridine, imidazole, and
20 l,8-diazabicyc!o[5,4,0]-7-undecene. These basic compounds can be used alone or in combination of two or more.
[0052] The basic compound can be used in an amount of 0.04 to 1.0 equivalent, and preferably 0.1 to 1.0 equivalent, per equivalent of the compound (1).
[0053] When a solvent is used, the solvent to be used is not particularly limited as
25 long as it does not inhibit the reaction from proceeding. Examples of the solvent include hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, and heptane; aromatic hydrocarbon solvents such as benzene, xylene, and toluene; halogenated hydrocarbon solvents such as dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene, and trifluoromethyl

24 benzene; alcohol solvents such as methanol, ethanol, and 2-propanol; ketone solvents
such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; nitrile solvents such as
acetonitrile and propionitrile; carboxylate solvents such as ethyl acetate and ethyl
propionate; nitrogen-containing aprotic polar solvents such as N,N-dimethylformamide,
5 N,N-dimethylacetamide, N-methylpyrrolidone, and l,3-dimethyl-2-imidazolidinone; and
water. Preferably, aromatic hydrocarbon solvents such as xylene and toluene;
halogenated hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane; and
water can be used. These solvents can also be used as a mixture of two or more.
[0054] Step (b) can be performed in a normal-pressure atmosphere; in some cases, 10 step (b) can be performed at a pressure in the range of 0.001 to 100 MPa, preferably 0.1 to 10 MPa.
[0055] The reaction temperature can be typically adjusted to any temperature in the range of-90 to 200°C, and can be preferably adjusted in the range of-20 to 100°C.
[0056] Although the reaction time varies depending on the reactant concentration 15 or the reaction temperature, it can be typically adjusted in the range of 10 minutes to 100 hours, preferably 10 minutes to 24 hours.
[0057] Although the treatment method after the reaction is not particularly limited, the reaction mixture after the completion of the reaction may be subjected to a general post-treatment in which, for example, the mixture is directly concentrated, or the mixture 20 is dissolved in an organic solvent, and then water is added to the solution, the solution is separated, and the mixture is concentrated as required, or the mixture is added to water, subjected to organic solvent extraction, and concentrated as required, to obtain the reaction mixture. The reaction mixture may be directly used in the subsequent step, without concentrating the solution of the reaction mixture obtained after the 25 post-treatment. The reaction mixture after the completion of the reaction may also be directly used in the subsequent step, without any post-treatment. When purification is required, the reaction mixture can be separated and purified using any purification method such as distillation, recrystallization, column chromatography, thin layer chromatography, or preparative liquid chromatography.

25

[0058] [Step (c)]
R2 CH3
RiAN^o^AoH R2 CH3 0 0
(5) +
R2 O 0
(1) RiAN^oN^oAAAOH
CH3
(6)

R2 CH
3
(C)
R1^SJ^0X^ ^OH
(1) [0059] An organic solvent containing the mixture of the compounds (1), (5), and
(6) is mixed with an aqueous solution of a basic compound. This causes the compounds
5 (5) and (6) to be transferred to the aqueous layer, which allows the compound (1) only to
remain in the organic solvent.
[0060] Examples of the basic compound in the aqueous solution of the basic
compound used in step (c) include alkali metal hydroxides such as sodium hydroxide and
potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium
10 carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal phosphates such as sodium phosphate and potassium phosphate; alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; alkaline earth metal carbonates such as magnesium
15 carbonate and calcium carbonate; alkaline earth metal bicarbonates such as magnesium hydrogen carbonate and calcium hydrogen carbonate; alkaline earth metal phosphates such as magnesium phosphate and calcium phosphate; alkaline earth metal hydrogen phosphates such as magnesium hydrogen phosphate and calcium hydrogen phosphate;

26 and organic bases such as triethylamine, tributylamine, pyridine,
4-(dimethylamino)pyridine) imidazole, and l,8-diazabicyelo[5,4,0]-7-undecene. These
basic compounds can be used alone or in combination of two or more.
[0061] The basic compound can be used in an amount of 0.02 to 10 equivalents 5 per equivalent of the compound (1).
[0062] Examples of the organic solvent used in step (c) include hydrocarbon
solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, and
heptane; aromatic hydrocarbon solvents such as benzene, xylene, and toluene;
halogenated hydrocarbon solvents such as dichloromethane, carbon tetrachloride,
10 chloroform, 1,2-dichloroethane, chlorobenzene, and trifmoromethyl benzene; alcohol
solvents such as methanol, ethanol, and 2-propanol; ketone solvents such as acetone,
methyl ethyl ketone, and methyl isobutyl ketone; nitrile solvents such as acetonitrile and
propionitrile; carboxylate solvents such as ethyl acetate and ethyl propionate; and
nitrogen-containing aprotic polar solvents such as N,N-dimethylformamide,
15 N,N-dimethylacetamide, N-methylpyrrolidone, and l,3-dimethyl-2~imidazolidinone.
Preferably, for example, aromatic hydrocarbon solvents such as xylene and toluene; and
halogenated hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane can
be used. More preferably, toluene, dichloromethane, and 1,2-dichloroethane can be
used. These solvents can also be used as a mixture of two or more.
20 [0063] Step (c) can be performed in a normal-pressure atmosphere; in some cases,
step (c) can be performed at a pressure in the range of 0.001 to 100 MPa, preferably 0.1 tolOMPa.
[0064] The reaction temperature can be typically adjusted to any temperature in
the range of-15 to 20G°C, and can be preferably adjusted in the range of-5 to 50°C.
25 [0065] Although the reaction time varies depending on the reactant concentration
or the reaction temperature, it can be typically adjusted in the range of 10 minutes to 100 hours, preferably 10 minutes to 24 hours.
[0066] Steps (a) to (c) can be successively performed.
Successively performing steps (a) to (c) means that the product obtained in the

27 preceding step is directly used in a crude form without isolation and purification in the
subsequent step to perform the subsequent step. That is, step (b) is performed directly
using the product formed in step (a) without isolation and purification, and then step (c) is
performed directly using the product formed in step (b) without isolation and purification.
5 The reactor for performing each of steps (a), (b), and (c) may be the same or different.
[0067] Examples of the organic solvent used in successively performing steps (a)
to (c) include hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane,
ethylcyclohexane, and heptane; aromatic hydrocarbon solvents such as benzene, xylene,
and toluene; halogenated hydrocarbon solvents such as dichloromethane, carbon
10 tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene, and trifluoromethyl benzene; alcohol solvents such as methanol, ethanol, and 2-propanol; ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; nitrile solvents such as acetonitrile and propionitrile; carboxylate solvents such as ethyl acetate and ethyl propionate; and nitrogen-containing aprotic polar solvents such as
15 N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and
l,3-dimethyl-2-imidazolidinone. Preferably, for example, aromatic hydrocarbon solvents such as xylene and toluene; and halogenated hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane can be used. More preferably, toluene, dichloromethane, and 1,2-dichloroethane can be used. These solvents can also be used
20 as a mixture of two or more.
[0068] The compound (1) obtained by steps (a) to (c) described above has an extremely high purity. For example, the compound (1) and the compound (3) are present in a ratio of 98/2 to 100/0; from the viewpoint of further enhancing the quality and performance of the product obtained using the compound (1), the compound (1) and
25 the compound (3) are preferably present in a ratio of 99/1 to 100/0, more preferably 99.5/0.5 to 100/0, and still more preferably 99.9/0.1 to 100/0.
Examples
[0069] The present invention will be described in more detail hereinafter with

28 reference to synthesis examples; however, the present invention is not limited to these
examples.
'H-NMR was measured at 300 or 600 MHz, and HPLC or LC/MS and GC or
GC/MS were measured under the below-described conditions.
5 NMR denotes a nuclear magnetic resonance spectrum, HPLC denotes high
performance liquid chromatography, LC/MS denotes liquid chromatography-mass
spectrometry, GC denotes gas chromatography, and GC/MS denotes gas
chromatography-mass spectrometry.
Rt denotes the retention time.
10 [0070] [Example 1] Synthesis of 0-[l-(2-hydroxypropyl)]butanone oxime
Step (a): 10.0 g (115 mmol) of butanone oxime was suspended in 50 g of water, and 1.41 g (12.0 mmol) of a 48% by mass aqueous solution of potassium hydroxide was added thereto. The reaction solution was heated to 40°C, and then 8.05 g (139 mmol) of propylene oxide was added thereto. After the completion of the addition, the reaction
15 solution was stirred at the same temperature for 5 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, and then separated using dichloromethane (100 mL, 20 mL). The resulting organic phase was washed with water (20 mL) and concentrated under reduced pressure. As a result, 15.8 g of a target product in a crude form was obtained as a pale yellow oil.
20 As a result of qualitative analysis of the target product using HPLC, the area ratio of
the target product of formula (7) below [hereinafter abbreviated as the "target product (7)"] to its isomer 0-[2-(l-hydroxypropyl)]butanone oxime of formula (8) below [hereinafter abbreviated as the "isomer (8)"] was determined to be 94.3/5.7 (Rt = 11.4 min/11.8 min). Moreover, as a result of analysis using GC/MS (CI+), two peaks (Rt =
25 5.67 min/5.71 min) were observed, and MS determined that both peaks were at m/z 146 (MH+).


H3C- A^°^N)H "Z°^"Ni^N" -OH
C7) (8)

CH3
CHa CH3 9H3

29 [0071] Step (b): 0.58 gof the obtained target product in a crude form [containing
2.5 mmol of the target product (7)] was dissolved in 2.7 g of dichloromethane, and the
solution was cooled to 5°C. To the reaction solution, 0.073 g (0.72 mmol) of
triethylamine and 0.082 g (0.82 mmol) of succinic anhydride were added. After the
5 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) was determined to be 100/0 (Rt = 11.4 min/11.8
min).
10 On the other hand, a compound of formula (9) below [hereinafter abbreviated as the
"compound (9)"], which is a product formed by the reaction of the target product (7) and succinic anhydride, was estimated to have a peak at Rt = 13.3 to 13.4 min, and a compound of formula (10) below [hereinafter abbreviated as the "compound (10)"], which is a product formed by the reaction of the isomer (8) and succinic anhydride, was
15 estimated to have a peak at Rt = 13.6 to 13.7 min. That is, the area ratio of the target product (7), the isomer (8), the compound (9), and the compound (10) was 84.0/0/10.3/5.7.

H*C.
H3a

CH3 CH3 CH3 CH3 O
H3c^AN-°^0A^ 0
(7) (9)

CH3
CH3 CH3 O
H3cA-°v^o^
CH3 O
(8) (10)

[0072] As a result of analysis of the reaction solution using GC/MS (CI+), two 20 peaks were observed. MS determined that one peak was at m/z 146 (MH+) (Rt = 5.6 min), and the other peak was at m/z 246 (MH+) (Rt = 10.2 min). The compounds (9) and (10) were estimated to be detected at Rt = 10.2 min in an overlapping manner.

30 Moreover, as a result of analysis of the reaction solution using LC/MS (ESI+), two
peaks were observed. MS determined that one peak was at m/z 146 (MH+) (Rt - 2.3
min), and the other peak was at m/z 246 (MH+) (Rt - 3.5 min). The compounds (9) and
(10) were estimated to be detected at Rt = 3.5 min in an overlapping manner.
5 [0073] Step (c): The reaction solution obtained in step (b) was washed with a 5%
by mass aqueous solution of sodium hydrogen carbonate (5 g x 2) at the same
temperature. After the completion of washing, quantitative analysis of the resulting
organic phase was performed using HPLC, which determined that the target product (7)
was obtained at a yield of 35% (calculated based on butanone oxime). The area ratio of
10 the target product (7) to the isomer (8) was determined to be 100/0 (Rt = 11.4 min/11.8
min).
[0074] The conditions for qualitative and quantitative analysis using high performance liquid chromatography were as follows: Column: Waters XBridge CI 8,3.5 jam, 4.6 mm x 150 mm 15 Eluent: acetonitrile/water = 10/90 (5 min)-(10 min)-60/40 (2 min)-(3 min)-10/90 (10 min) (volume ratio) Flow rate: 1 mL/min Column temperature: 40°C
Internal standard substance: none (single-point absolute quantification)
20 The conditions for GC/MS analysis were as follows:
Column: Agilent Technologies HP-5, 0.32 mm ID x 30 m x 0.25 um Temperature elevation time and rate: 40°C (2 mm)-(20oC/rnin)-300°C (7 min)
The conditions for LC/MS analysis were as follows: Column: Waters XBridge C18, 5 jam, 2.1 mm x 150 mm 25 Eluent: acetonitrile/water = 40/60 (volume ratio) Flow rate: 0.2 mL/min Column temperature: 40°C
[0075] [Examples 2 to 5] Synthesis of 0-[l-(2-hydroxypropyl)]oxime compounds
Reactions were performed in accordance with steps (a) to (c) described in Example

31
1, except that the oxime compound (2) as a starting material and the acid anhydride used
in step (b) were changed as appropriate.
Table 1 below shows the yields of the 0-[l-(2-hydroxypropyl)]oxime compounds obtained in step (c), as well as the area ratios of the peaks of the target product (7) and the 5 isomer (8), calculated by qualitative analysis using HPLC or GC in each of the steps.
[0076] Table 1

Example Oxime
Compound (2) Acid Anhydride Target Product (1) Yield (%) Target
Product/Isomer
Area Ratio

after
Step
(a) after
Step
(c)
1 Butanone Succinic Acid CHs CHJ 35 94.3/ 5.7 100/ 0
2 Butanone Maleic Acid 49 95.2/ 4.8 99.3
/0.7
3 Acetone Succinic Acid CH3 CHg 48 93.9/ 6.1 99.6/ 0,4
4 3,3-Dimethyl -2-Butanone Succinic Acid CH3 CH3 H3C OH3 - 95.6 /4.4 99.9/ 0.1*
5 3,3-Dimethyl -2-Butanone Maleic Acid CH3 CH3
"'V ^°^OH H3C bH, - 95.6/ 4.4 99.4/ 0.6*
* after step (b)
[0077] The conditions for qualitative and quantitative analysis using HPLC and
GC were as follows:
10 Conditions for HPLC analysis (Example 2)
Column: Waters XBridge C18, 3.5 um, 4.6 mm x 150 mm
Eluent: metbanol/water/85% by mass phosphoric acid = 35/65/0.1 (volume ratio)
Flow rate: 0.8 mL/min
Column temperature: 40°C 15 Internal standard substance: 4-methoxytoluene
Conditions for GC analysis (Examples 3,4 and 5)
Column: Agilent Technologies CP-WAX 52 CB, 0.25 mm ID x 25 m x 0.20 pxn

32 Temperature elevation time and rate: 40°C (0 min)-(5°C/min)-90°C (0
min)-(10°C/min)-250°C (10 min)
Internal standard substance: diethylene glycol dimethyl ether
[0078] [Example 6] Synthesis of 0-[l-(2-hydroxypropyl)]butanone oxime
5 Step (a): 10.0 g (115 mmol) of butanone oxime was suspended in 30 g of water, and
1.15 g (11.5 mmol) of a 40% by mass aqueous solution of sodium hydroxide was added
thereto. The reaction solution was heated to 40°C, and then 10.0 g (172 mmol) of
propylene oxide was added thereto. After the completion of the addition, the reaction
solution was stirred at the same temperature for 4 hours. After the completion of the
10 reaction, the reaction solution was cooled to 10°C, and then 5.93 g (57.4 mmol) of 95% by mass sulfuric acid was added thereto. After the completion of the addition, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated at the same temperature using 1,2-dichIoroethane (30 g x 2). As a result, 71.8 g of the 1,2-dichloroethane solution of a target product was obtained.
15 As a result of qualitative analysis of the target product using HPLC, the area ratio of
the target product (7) to the isomer (8) was determined to be 94.4/5.6 (Rt = 6.6 min/7.1 min).
[0079] Step (b): 71.1 g of the obtained 1,2-dichloroethane solution of the target product [containing 60.5 mmol of the target product (7)] was cooled to 10°C. To the
20 reaction solution, 0.73 g (7.26 mmol) of triethylamine and 0.59 g (6.05 mmol) of maleic anhydride were added. After the 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 the completion of the addition, the reaction solution was stirred at the same temperature for 1
25 hour. After the completion of the reaction, the reaction solution was qualitatively analyzed using HPLC.
Of the two peaks newly detected, a peak at Rt = 11.9 min was estimated to be from a compound of formula (11) below [hereinafter abbreviated as the "compound (11)"], which is a product formed by the reaction of the target product (7) and maleic anhydride,

33 and a peak at Rt - 13.4 min was estimated to be from a compound of formula (12) below
[hereinafter abbreviated as the "compound (12)"], which is a product formed by the
reaction of the isomer (8) and maleic anhydride. As a result of qualitative analysis, the
area ratio of the target product (7), the isomer (8), the compound (11), and the compound
(12) was 77.4/0.7/12.2/9.7.
That is, the area ratio of the target product (7) to the isomer (8) was determined to
be 99.2/0.8 (Rt = 6.6 min/7.1 min).

H,C.
H3CV

CH3 CH3 0 Y
H3CvAr0xA0V
(7) (11)
CH3
CH3 CH3 0 °Y°H
H3C^AN^O^XOA^)
CH3
(8) (12)
[0080] Step (c): The reaction solution obtained in step (b) was washed with a 5% 10 by mass aqueous solution of sodium hydrogen carbonate (18 g x 3) at the same
temperature. After the completion of washing, quantitative analysis of the resulting organic phase was performed using HPLC, which determined that the target product (7) was obtained at a yield of 44% (calculated based on butanone oxime). The area ratio of the target product (7) to the isomer (8) was determined to be 99.2/0.8 (Rt - 6.6 min/7.1 15 min).
[0081] The conditions for qualitative and quantitative analysis using HPLC were as follows:
Column: Waters XBridge C18,3.5 \im 4.6 mm x 150 mm Ement: methanol/water/85% by mass phosphoric acid - 35/65/0.1 (volume ratio) 20 Flow rate: 0.8 mL/min
Column temperature: 40°C
Internal standard substance: 4-methoxytoluene
[0082] [Example 7] Synthesis of 0-[l-(2-hydroxypropyl)]butanone oxime

34 Step (a): 25.0 g (287 mmol) of butanone oxime was suspended in 38 g of water, and
2.87 g (28.7 mmol) of a 40% by mass aqueous solution of sodium hydroxide was added
thereto. The reaction solution was heated to 30°C, and then 21.7 g (373 mmol) of
propylene oxide was added thereto. After the completion of the addition, the reaction
5 solution was stirred at the same temperature for 4 hours. After the completion of the
reaction, the reaction solution was cooled to 10°C, and then 8.89 g (86.1 mmol) of 95%
by mass sulfuric acid was added thereto. After the completion of the addition, the
reaction solution was stirred at the same temperature for 1 hour. The reaction solution
was separated at the same temperature using toluene (25 g x 2). As a result, 83.6 g of
10 the toluene solution of a target product was obtained.
As a result of qualitative analysis of the target product using HPLC, the area ratio of the target product (7) to the isomer (8) was determined to be 94.9/5.1 (Rt = 6.7 min/7.2 min).
[0083] Step(b): 83.1 gofthe obtained toluene solution ofthe target product
15 [containing 155 mmol ofthe target product (7)] was cooled to 10°C. To the reaction solution was added 5.63 g (55.6 mmol) of triethylamine. To the reaction solution, a mixed solution of 4.55 g (46.4 mmol) of maleic anhydride and 23 g of toluene was added at the same temperature. After the completion ofthe addition, the reaction solution was stirred at the same temperature for 1 hour.
20 As a result of qualitative analysis ofthe reaction solution using HPLC, the area ratio
ofthe target product (7), the isomer (8), the compound (11), and the compound (12) was 71.2/0.3/19.0/9.5 (Rt = 6.7 min/7.2 min/12.2 min/13.8 min).
That is, the area ratio ofthe target product (7) to the isomer (8) was determined to be 99.7/0.3 (Rt = 6.7 min/7.2 min).
25 As a result of analysis ofthe reaction solution using LC/MS (ESI±) (analytical
conditions described in Example 1), two peaks were observed. MS determined that one peak was at m/z 146 (MH+) (Rt = 3.2 min), and the other peak was at m/z 242 (MH-) (Rt = 2.5 min). The compounds (9) and (10) were estimated to be detected at Rt = 2.5 min in an overlapping manner.

35 [0084] Step (c): The reaction solution obtained in step (b) was washed with a 15%
by mass aqueous solution of potassium carbonate (22 g x 2) at the same temperature.
After the completion of washing, quantitative analysis of the resulting organic phase was
performed using HPLC, which determined that the target product (7) was obtained at a
5 yield of 46% (calculated based on butanone oxime). The area ratio of the target product
(7) to the isomer (8) was determined to be 99.7/0.3 (Rt = 6.7 min/7.2 min).
[0085] The conditions described in Example 6 were used for the qualitative and
quantitative analysis using HPLC, and ethoxybenzene was used as the internal standard
substance used for the quantitative analysis.
10 [0086] [Example 8] Synthesis of 0-[l-(2-hydroxypropyl)]butanone oxime
Step (a): 85.0 g (976 mmol) of butanone oxime was suspended in 170 g of water,
and 1.56 g (39.0 mmol) of a 40% by mass aqueous solution of sodium hydroxide was
added thereto. The reaction solution was heated to 30°C, and then 73.7 g (1.27 mol) of
propylene oxide was added thereto. After the completion of the addition, the reaction
15 solution was stirred at the same temperature for 14 hours. After the completion of the
reaction, the reaction solution was cooled to 10°C, and then 30.2 g (293 mmol) of 95%
by mass sulfuric acid was added thereto. After the completion of the addition, the
reaction solution was stirred at the same temperature for 1 hour. The reaction solution
was separated at the same temperature using toluene (85 g x 2). As a result, 282 g of the
20 toluene solution of a target product was obtained.
As a result of qualitative analysis of the target product using HPLC, the area ratio of
the target product (7) to the isomer (8) was determined to be 94.7/5.3 (Rt = 7.2 min/7.8
min).
[0087] Step (b): 10.4 g of the obtained toluene solution of the target product
25 [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 the 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

36 of the target product (7), the isomer (8), the compound (11), and the compound (12) was
67.8/0.5/22.0/9.6 (Rt - 7.2 min/7.8 min/13.9 min/15.7 min).
That is, the area ratio of the target product (7) to the isomer (8) was determined to
be 99.3/0.7 (Rt = 7.2 min/7.8 min).
5 [0088] Step (c): The reaction solution obtained in step (b) was washed with a 5%
by mass aqueous solution of sodium hydrogen carbonate (5.9 g x 3) at the same
temperature. After the completion of washing, quantitative analysis of the resulting
organic phase was performed using HPLC, which determined that the target product (7)
was obtained at a yield of 35% (calculated based on butanone oxime). The area ratio of
10 the target product (7) to the isomer (8) was determined to be 99.4/0.6 (Rt = 7.2 min/7.8
min).
[0089] The conditions described in Example 6 were used for the qualitative and
quantitative analysis using HPLC, and ethoxybenzene was used as the internal standard
substance used for the quantitative analysis.
15 [0090] [Example 9] Synthesis of 0-[l-(2-hydroxypropyl)]butanone oxime
Step (b): 15.1 g of the toluene solution of the target product [containing 29.3 mmol
of the target product (7)] obtained in step (a) of Example 8 was cooled to 5°C. To the
reaction solution, 1.07 g (10.6 mmol) of triethyiamine and 0.86 g (8.79 mmol) of maleic
anhydride were added. After the completion of the addition, the reaction solution was
20 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), the isomer (8), the compound (11), and the compound (12) was
67.8/0.2/22.5/9.4 (Rt = 7.3 min/7.9 min/14.1 min/15.9 min).
That is, the area ratio of the target product (7) to the isomer (8) was determined to
25 be 99.7/0.3 (Rt = 7.3 min/7.9 min).
[0091] Step (c): The reaction solution obtained in step (b) was washed with a 5%
by mass aqueous solution of sodium carbonate (4.3 g x 2) at the same temperature.
After the completion of washing, quantitative analysis of the resulting organic phase was
performed using HPLC, which determined that the target product (7) was obtained at a

37 yield of 41% (calculated based on butanone oxime). The area ratio of the target product
(7) to the isomer (8) was determined to be 99.8/0.2 (Rt = 7.3 min/7.9 min).
[0092] The conditions described in Example 6 were used for the qualitative and quantitative analysis using HPLC, and ethoxybenzene was used as the internal standard 5 substance used for the quantitative analysis.
[0093] [Example 10] Synthesis of 0-[l-(2-hydroxypropyl)]butanone oxime
Step (b): 13.9 g of the toluene solution of the target product [containing 27.0 mmol of the target product (7)] obtained in step (a) of Example 8 was cooled to 0°C. To the reaction solution was added 0.98 g (9.72 mmol) of triethylamine. To the reaction 10 solution, a mixed solution of 0.78 g (8.10 mmol) of maleic anhydride and 3.9 g of toluene was added at the same temperature. After the 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), the isomer (8), the compound (11), and the compound (12) was 15 68.0/0.3/22.3/9.4 (Rt = 7.3 min/7.9 min/14.1 min/15.9 min).
That is, the area ratio of the target product (7) to the isomer (8) was determined to be 99.6/0.4 (Rt = 7.3 min/7.9 min).
[0094] Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous solution of potassium hydrogen carbonate (3.9 g x 2) at 10°C. After 20 the completion of washing, quantitative analysis of the resulting organic phase was
performed using HPLC, which determined that the target product (7) was obtained at a yield of 44% (calculated based on butanone oxime). The area ratio of the target product (7) to the isomer (8) was determined to be 99.4/0.6 (Rt = 7.3 min/7.9 min).
[0095] The conditions described in Example 6 were used for the qualitative and 25 quantitative analysis using HPLC, and ethoxybenzene was used as the internal standard substance used for the quantitative analysis.
[0096] [Example 11] Synthesis of 0-[l-(2-hydroxypropyl)]butanone oxime
Step (a): 100 g (1.15 mol) of butanone oxime was suspended in 300 g of water, and 11.5 g (115 mmol) of a 40% by mass aqueous solution of sodium hydroxide was added

38 thereto. The reaction solution was heated to 30°C, and then 87.1 g (1.50 mol) of
propylene oxide was added thereto. After the completion of the addition, the reaction
solution was stirred at the same temperature for 4 hours. After the completion of the
reaction, the reaction solution was cooled to 10°C, and then 33.8 g (327 mmol) of 95%
5 by mass sulfuric acid was added thereto. After the completion of the addition, the
reaction solution was stirred at the same temperature for 1 hour. The reaction solution
was separated at the same temperature using dichloromethane (300 g x 2). As a result,
729 g of the dichloromethane solution of a target product was obtained.
As a result of qualitative analysis of the target product using HPLC, the area ratio of 10 the target product (7) to the isomer (8) was determined to be 94.8/5.2 (Rt = 6.7 min/7.2 min).
[0097] Step (b): 23.5 g of the obtained dichloromethane solution of the 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 15 anhydride were added. After the completion of the addition, the reaction solution was stirred at the same temperature for 23 hours. After the completion of the reaction, the reaction solution was qualitatively analyzed using HPLC.
Of the two peaks newly detected, a peak at Rt = 47.9 min was estimated to be from a compound of formula (13) below [hereinafter abbreviated as the "compound (13)"], 20 which is a product formed by the reaction of the target product (7) and phthalic anhydride, and a peak at Rt = 55.7 min was estimated to be from a compound of formula (14) below [hereinafter abbreviated as the "compound (14)"], which is a product formed by the reaction of the isomer (8) and phthalic anhydride. As a result of qualitative analysis, the area ratio of the target product (7), the isomer (8), the compound (13), and the compound 25 (14) was 64.0/0.1/22.1/13.8.
That is, the area ratio of the target product (7) to the isomer (8) was determined to be 99.8/0.2 (Rt = 6.7 rnin/7.2 min).

39

CH3 CH3 CH3 CH3 O *Y"
H3C^ /^N^°-^\OH H3C
(T) (13) I^J
O^ .OH
CH3 CH3 O ^V^

N^ Y "OH
CH3 CH3 ^^
(8) (14)
[0098] As a result of analysis of the reaction solution using LC/MS (ESI±), two peaks were observed. MS determined that one peak was at m/z 146 (MH+) (Rt = 3.3 min), and the other peak was at m/z 294 (MH-) (Rt = 2.1 min). The compounds (13) 5 and (14) were estimated to be detected at Rt = 2.1 min in an overlapping manner.
[0099] Step (c): The reaction solution obtained in step (b) was washed with a 5% by mass aqueous solution of sodium hydrogen carbonate (6 g x 7) at the same temperature. After the completion of washing, quantitative analysis of the resulting organic phase was performed using HPLC, which determined that the target product (7) 10 was obtained at a yield of 44% (calculated based on butanone oxime). The area ratio of the target product (7) to the isomer (8) was determined to be 99.7/0.3 (Rt = 6.7 min/7.2 min).
[0100] The conditions described in Example 6 were used for the qualitative and quantitative analysis using HPLC, and 4-methoxytoIuene was used as the internal 15 standard substance used for the quantitative analysis. The conditions described in Example 1 were used for the analysis using LC/MS.
[0101] [Example 12] Synthesis of 0-[l-(2-hydroxypropyl)]-3-methyl-2-butanone oxime
Step (a): 15.1 g (149 mmol) of 3-methyl-2-butanone oxime was suspended in 23 g 20 of water, and 1.51 g (15.1 mmol) of a 40% by mass aqueous solution of sodium
hydroxide was added thereto. The reaction solution was heated to 30°C, and then 11.3 g (L94 mmol) of propylene oxide was added thereto. After the completion of the addition, the reaction solution was stirred at the same temperature for 7 hours. To the reaction

40
solution, 0.87 g (15 mmol) of propylene oxide was added at the same temperature.
After the completion of the addition, the reaction solution was stirred at room temperature for 15 hours. After the completion of the reaction, the reaction solution was cooled to 10°C, and then 4.39 g (42.5 mmol) of 95% by mass sulfuric acid was added 5 thereto. After the completion of the addition, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated at the same temperature using toluene (15 g x 2). As a result, 49.6 g of the toluene solution of a target product was obtained.
As a result of qualitative analysis of the target product using HPLC, the area ratio of 10 the target product of formula (15) below [hereinafter abbreviated as the "target product (15)"] to its isomer 0-[2-(i-hydroxypropyl)]-3-methyl-2-butanone oxime of formula (16) below [hereinafter abbreviated as the "isomer (16)"] was determined to be 94.7/5.3 (Rt = 12.3 and 13.0 min/13.6 and 14.5 min). Moreover, as a result of analysis using GC/MS (CI+), one peak (Rt = 6.1 min) was observed, and MS determined that the peak was at 15 m/zl60(MH+).
CH3 CH3 9H3

N-°^OH H3°Y^N-°Y^OH
CH3 (15) CH3 (16)CH3
[0102] Step (b): 23.0 g of the obtained toluene solution of the target product [containing 39.5 mmol of the target product (15)] was cooled to 10°C. To the reaction solution, 1.45 g (14.3 mmol) of triethylamine and 1.16 g (11.8 mmol) of maleic 20 anhydride were added. After the completion of the addition, the reaction solution was stirred at the same temperature for 4 hours. After the completion of the reaction, the reaction solution was qualitatively analyzed using HPLC.
Of the two peaks newly detected, a peak at Rt = 24.1 and 25.2 min was estimated to be from a compound of formula (17) below [hereinafter abbreviated as the "compound 25 (17)"], which is a product formed by the reaction of the target product (15) and maleic anhydride, and a peak at Rt = 27.7 and 29.4 min was estimated to be from a compound of formula (18) below [hereinafter abbreviated as the "compound (18)"], which is a product

41 formed by the reaction of the isomer (16) and maleic anhydride. As a result of
qualitative analysis, the area ratio of the target product (15), the isomer (16), the
compound (17), and the 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) was determined to
be 99.7/0.3 (Rt = 12.5 and 13.3 min/13.9 and 14.7 min).
CH3 CH3 H3C. J^ ^O. J\ CH3
CH3 (15) CH3
CH3
1 J CH3
CH3 CH3 CH3
(16)
0^ .OH
(17)
O^ .OH
o ^r
CH3
(18)
[0103] As a result of analysis of the reaction solution using LC/MS (ESI±), two peaks were observed. MS determined that one peak was at m/z 160 (MH+) (Rt = 4.4 min), and the other peak was at m/z 256 (MH-) (Rt = 3.1 min). The compounds (17) 10 and (18) were estimated to be detected at Rt ~ 3.1 min in an overlapping manner.
[0104] Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous solution of potassium carbonate (6 g x 2) at the same temperature. After the completion of washing, quantitative analysis of the resulting organic phase was performed using HPLC, which determined that the target product (15) was obtained at a 15 yield of 47% (calculated based on 3-methyl-2-butanone oxime). The area ratio of the target product (15) to the isomer (16) was determined to be 99.7/0.3 (Rt = 12.5 and 13.3 min/13.9 and 14.7 min).
[0105] The conditions described in Example 6 were used for the qualitative and quantitative analysis using HPLC, and 2-nitrotoluene was used as the internal standard 20 substance used for the quantitative analysis. The conditions described in Example 1 were used for the analysis using GC/MS and LC/MS.
[0106] [Example 13] Synthesis of 0-[l-(2-hydroxypropyl)]-3,3-dimethyl-2-butanone oxime

42 Step (a): 12.9 g (112 mmol) of 3,3-dimethyl-2-butanone oxime was suspended in 20
gof water, and 1.11 g (11,1 mmol) of a 40% by mass aqueous solution of sodium
hydroxide was added thereto. The reaction solution was heated to 30°C, and then 8.49 g
(146 mmol) of propylene oxide was added thereto. After the completion of the addition,
5 the reaction solution was stirred at the same temperature for 50 hours. After the
completion of the reaction, the reaction solution was cooled to 10°C, and then 3.33 g
(32.2 mmol) of 95% by mass sulfuric acid was added thereto. After the completion of
the addition, the reaction solution was stirred at the same temperature for 1 hour. The
reaction solution was separated at the same temperature using toluene (13 g x 2). As a
10 result, 43.7 g of the toluene solution of a target product was obtained.
As a result of qualitative analysis of the target product using HPLC, the area ratio of the target product of formula (19) below [hereinafter abbreviated as the "target product (19)"] to its isomer 0-[2-(I-hydroxypropyl)]-3,3-dimethyl-2-butanone oxime of formula (20) below [hereinafter abbreviated as the "isomer (20)"] was determined to be 95.0/5.0
15 (Rt = 35.4 min/41.8 min). Moreover, as a result of analysis using GC/MS (Cl-f), one peak (Rt - 6.5 min) was observed, and MS determined that the peak was at m/z 174 (MH+).
CH3 CH3 ^3
H3C CH3 (19) H*C CH3 (20)CH3
[0107] Step (b): 19.4 g of the obtained toluene solution of the target product
20 [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 the 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 the
25 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 the completion of the addition, the

43 reaction solution was stirred at the same temperature for 2 hours. After the completion
of the reaction, the reaction solution was qualitatively analyzed using HPLC.
Of the two peaks newly detected, a peak at Rt = 65.6 min was estimated to be from a compound of formula (21) below [hereinafter abbreviated as the "compound (21)"], 5 which is a product formed by the reaction of the target product (19) and maleic anhydride, and a peak at Rt = 81.5 min was estimated to be from a compound of formula (22) below [hereinafter abbreviated as the "compound (22)"], which is a product formed by the reaction of the isomer (20) and maleic anhydride. As a result of qualitative analysis, the area ratio of the target product (19), the isomer (20), the compound (21), and the 10 compound (22) was 61.8/0.3/28.3/9.6.
That is, the area ratio of the target product (19) to the isomer (20) was determined to be 99.6/0.4 (Rt = 35.1 min/41.6 min).

H3C CH3 CH3 H3C CH3 CH3 O ^r •"
H3C CH3 (19) H3C CH3 (21)
H3C>^ H3C CH3
CH3 CH3
(20) H3CV H3C CH3 O ***
CH3 CH3
(22) .OH
[0108] As a result of analysis of the reaction solution using LC/MS (ESI±), two 15 peaks were observed. MS determined that one peak was at m/z 174 (MH-i-) (Rt = 7.3 min), and the other peak was at m/z 270 (MH-) (Rt - 2.5 min). The compounds (21) and (22) were estimated to be detected at Rt = 2.5 min in an overlapping manner.
[0109] Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous solution of potassium carbonate (6 g x 2) at the same temperature. 20 After the completion of washing, quantitative analysis of the resulting organic phase was performed using HPLC, which determined that the target product (19) was obtained at a yield of 45% (calculated based on 3,3-dimethyl-2-butanone oxime). The area ratio of the target product (19) to the isomer (20) was determined to be 99.6/0.4 (Rt = 35.1

44 min/41.6min).
[0110] The conditions described in Example 6 were used for the qualitative and
quantitative analysis using HPLC, and ethoxybenzene was used as the internal standard
substance used for the quantitative analysis. The conditions described in Example 1
5 were used for the analysis using GC/MS and LC/MS.
[0111] [Example 14] Synthesis of 0-[l-(2-hydroxypropyl)]cyclohexanone oxime
Step (a): 15.0 g (133 mmol) of cyclohexanone oxime was suspended in 23 g of
water, and 1.34 g (13.4 mmol) of a40%bymass aqueous solution of sodium hydroxide
was added thereto. The reaction solution was heated to 30°C, and then 10.2 g (175
10 mmol) of propylene oxide was added thereto. After the completion of the addition, the
reaction solution was stirred at the same temperature for 4 hours, cooled to 10°C, and
then stirred for 21 hours. After the completion of the reaction, 3.96 g (38.4 mmol) of
95% by mass sulfuric acid was added to the reaction solution at the same temperature.
After the completion of the addition, the reaction solution was stirred at the same
15 temperature for 1 hour. The reaction solution was separated at the same temperature
using toluene (15 g x 2). As a result, 49.0 g of the toluene solution of a target product
was obtained.
As a result of qualitative analysis of the target product using HPLC, the area ratio of
the target product of formula (23) below [hereinafter abbreviated as the "target product
20 (23)"] to its isomer 0-[2-(l-hydroxypropyl)]cyclohexanone oxime of formula (24) below
[hereinafter abbreviated as the "isomer (24)"] was determined to be 94.5/5.5 (Rt = 12.0
min/12.8 min). Moreover, as a result of analysis using GC/MS (CI+), one peak (Rt -
8.0 min) was observed, and MS determined that the peak was at m/z 172 (MH+).



(23)
25 [0H2] Step (b): 20.8 g of the obtained toluene solution of the target product
[containing 34.9 mmol of the target product (23)] was cooled to 10°C. To the reaction

45 solution, 1.27 g (12.6 mmol) of triethylamine and 1.00 g (10.2 mmol) of maleic
anhydride were added. After the completion of the addition, the reaction solution was
stirred at the same temperature for 5 hours. After the completion of the reaction, the
reaction solution was qualitatively analyzed using HPLC.
5 Of the two peaks newly detected, a peak at Rt = 22.8 min was estimated to be from
a compound of formula (25) below [hereinafter abbreviated as the "compound (25)"],
which is a product formed by the reaction of the target product (23) and maleic anhydride,
and a peak at Rt =* 25.3 min was estimated to be from a compound of formula (26) below
[hereinafter abbreviated as the "compound (26)"], which is a product formed by the
10 reaction of the isomer (24) and maleic anhydride. As a result of qualitative analysis, the
area ratio of the target product (23), the isomer (24), the compound (25), and the
compound (26) was 70.0/0.2/20.7/9.2.
That is, the area ratio of the target product (23) to the isomer (24) was determined to
be 99.8/0.2 (Rt= 12.1 min/13.0min).


(25)
CH, O ^V

15
[0113] As a result of analysis of the reaction solution using LC/MS (ESI±), two peaks were observed. MS determined that one peak was at m/z 172 (MH+) (Rt = 3.8 min), and the other peak was at m/z 268 (MH-) (Rt = 2.1 min). The compounds (25) and (26) were estimated to be detected at Rt = 2.1 min in an overlapping manner.
20
[0114] Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous solution of potassium carbonate (6 g x 2) at the same temperature. After the completion of washing, quantitative analysis of the resulting organic phase was performed using HPLC, which determined that the target product (23) was obtained at a

46 yield of 49% (calculated based on cyclohexanone oxime). The area ratio of the target
product (23) to the isomer (24) was determined to be 99.7/0.3 (Rt= 12.1 min/13.0 min).
[0115] The conditions described in Example 6 were used for the qualitative and quantitative analysis using HPLC, and ethoxybenzene was used as the internal standard 5 substance used for the quantitative analysis. The conditions described in Example 1 were used for the analysis, using GC/MS and LC/MS.
[0116] [Example 15] Synthesis of 0-[l-(2-hydroxypropyl)]acetophenone oxime
Step (a): 15.1 g (112 mmol) of acetophenone oxime was suspended in 23 g of water, and 1.12 g (11.2 mmol) of a 40% by mass aqueous solution of sodium hydroxide was 10 added thereto. The reaction solution was heated to 30°C, and then 8.50 g (146 mmol) of propylene oxide was added thereto. After the completion of the addition, the reaction solution was stirred at the same temperature for 6 hours, cooled to 10°C, and then stirred for 16 hours. After the completion of the reaction, 3.31 g (32.0 mmol) of 95% by mass sulfuric acid was added to the reaction solution at the same temperature. After the 15 completion of the addition, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated at the same temperature using toluene (15 g x 2). As a result, 49.0 g of the toluene solution of a target product was obtained.
As a result of qualitative analysis of the target product using HPLC, the area ratio of the target product of formula (27) below [hereinafter abbreviated as the "target product 20 (27)"] to its isomer 0-[2-(l-hydroxypropyI)] acetophenone oxime of formula (28) below [hereinafter abbreviated as the "isomer (28)"] was determined to be 94.2/5.8 (Rt - 27.1 mm/29.9 min). Moreover, as a result of analysis using GC/MS (CI+), one peak (Rt = 9.3 min) was observed, and MS determined that the peak was at m/z 194 (MH+).
CH3 CH3 9H3
OH f ^ N ^r "OH
(27) ^ (28)
I J k ^ CH

r^N^N^0"^
25 [0117] Step (b): 20.1 gofthe obtained toluene solution of the target product
[containing 25.6 mmol of the target product (27)] was cooled to 10°C. To the reaction

10

47 solution, 0.93 g (9.2 mmol) of triethylamine and 0.78 g (8.0 mmol) of maleic anhydride
were added. After the completion of the addition, the reaction solution was stirred at the
same temperature for 24 hours. After the completion of the reaction, the reaction
solution was qualitatively analyzed using HPLC.
Of the two peaks newly detected, a peak at Rt = 54.2 min was estimated to be from a compound of formula (29) below [hereinafter abbreviated as the "compound (29)"], which is a product formed by the reaction of the target product (27) and maleic anhydride, and a peak at Rt = 63.5 min was estimated to be from a compound of formula (30) below [hereinafter abbreviated as the "compound (30)"], which is a product formed by the reaction of the isomer (28) and maleic anhydride. As a result of qualitative analysis, the area ratio of the target product (27), the isomer (28), the compound (29), and the compound (30) was 76.0/0.1/16.6/7.3.
That is, the area ratio of the target product (27) to the isomer (28) was determined to be 99.8/0.2 (Rt = 27.3 min/30.1 min).

^~
O
(27)

CH3 OH

CH

O^ .OH
CH* o ^r

15

KjJ CH3
(28)

CH3
O^

j^

o

CH3
(30)

OH
Xr

20

[0118] As a result of analysis of the reaction solution using LC/MS (ESI±), two peaks were observed. MS determined that one peak was at m/z 194 (MH+) (Rt = 6.0 min), and the other peak was at m/z 290 (MH-) (Rt = 2.3 min). The compounds (27) and (28) were estimated to be detected at Rt = 2.3 min in an overlapping manner.
[0119] Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous solution of potassium carbonate (6 g x 2) at the same temperature. After the completion of washing, quantitative analysis of the resulting organic phase was

48 performed using HPLC, which determined that the target product (27) was obtained at a
yield of 39% (calculated based on acetophenone oxime). The area ratio of the target
product (27) to the isomer (28) was determined to be 99.8/0.2 (Rt = 27.3 min/30.1 min).
[0120] The conditions described in Example 6 were used for the qualitative and
5 quantitative analysis using HPLC, and 2-nitrotoluene was used as the internal standard
substance used for the quantitative analysis. The conditions described in Example 1
were used for the analysis using GC/MS and LC/MS.
[0121] [Example 16] Synthesis of 0-[l-(2-hydroxypropyl)]butanone oxime
Step (a): 20.0 g (230 mmol) of butanone oxime was suspended in 30 g of water, and
10 2.31 g (23.1 mmol) of a 40% by mass aqueous solution of sodium hydroxide was added
thereto. The reaction solution was heated to 30°C, and then 17.4 g (300 mmol) of
propylene oxide was added thereto. After the completion of the addition, the reaction
solution was stirred at the same temperature for 5 hours. After the completion of the
reaction, the reaction solution was cooled to 10°C, and then 6.76 g (65.5 mmol) of 95%
15 by mass sulfuric acid was added thereto. After the completion of the addition, the
reaction solution was stirred at the same temperature for 17 hours. The reaction solution
was separated at the same temperature using toluene (20 g x 2). As a result, 65.8 g of
the toluene solution of a target product was obtained.
As a result of qualitative analysis of the target product using HPLC, the area ratio of
20 the target product (7) to the isomer (8) was determined to be 94.8/5.2 (Rt = 6.7 min/7.2
min).
[0122] Step (b): 20.0 g of the obtained toluene solution of the 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
25 anhydride were added. After the 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 the
completion of the addition, the reaction solution was stirred at the same temperature for
74 hours.

49 As a result of qualitative analysis of the reaction solution using HPLC, the area ratio
of the target product (7), the isomer (8), the compound (11), and the compound (12) was
44.5/0/47.9/7.6 (Rt - 6.9 min/7.4 min/12.6 min/14.2 min).
That is, the area ratio of the target product (7) to the isomer (8) was determined to 5 be 100/0 (Rt= 6.9 min/7.4 min).
[0123] Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous solution of potassium carbonate (6 g x 3) at the same temperature. After the completion of washing, quantitative analysis of the resulting organic phase was performed using HPLC, which determined that the target product (7) was obtained at a 10 yield of 23% (calculated based on butanone oxime). The area ratio of the target product (7) to the isomer (8) was determined to be 100/0 (Rt = 6.9 min/7.4 min).
[0124] The conditions described in Example 6 were used for the qualitative and
quantitative analysis using HPLC, and 4-methoxytoluene was used as the internal
standard substance used for the quantitative analysis.
15 [0125] [Example 17] Synthesis of 0-[l-(2-hydroxypropyl)]cyclohexanone oxime
Step (b): 20.3 g of the toluene solution of the target product [containing 34.1 mmol of the target product (23)] obtained in step (a) of Example 14 was cooled to 10°C. To the reaction solution, 2.08 g (20.6 mmol) of triethylamine and 1.68 g (17.1 mmol) of maleic anhydride were added. After the completion of the addition, the reaction 20 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), the isomer (24), the compound (25), and the compound (26) was 52.2/0/39.6/8.1 (Rt = 12.9 min/13.7 min/24.8 min/27.6 min).
That is, the area ratio of the target product (23) to the isomer (24) was determined to 25 be 100/0 (Rt - 12.9 min/13.7 min).
[0126] Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous solution of potassium carbonate (6 g x 2) at the same temperature. After the completion of washing, quantitative analysis of the resulting organic phase was performed using HPLC, which determined that the target product (23) was obtained at a

50 yield of 30% (calculated based on cyclohexanone oxime). The area ratio of the target
product (23) to the isomer (24) was determined to be 100/0 (Rt = 12.9 min/13.7 min).
[0127] The conditions described in Example 6 were used for the qualitative and quantitative analysis using HPLC, and ethoxybenzene was used as the internal standard 5 substance used for the quantitative analysis.
[0128] [Example 18] Synthesis of 0«[l-(2-hydroxypropyl)]-3-methyl-2-butanone oxime
Step (b): 23.0 g of the toluene solution of the target product [containing 39.5 mmol of the target product (15)] obtained in step (a) of Example 12 was cooled to 10°C. To 10 the reaction solution, 2.44 g (24.1 mmol) of triethylamme and 1.95 g (19.9 mmol) of maleic anhydride were added. After the 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), the isomer (16), the compound (17), and the compound (18) 15 was 57.2/0/33.2/9.7 (Rt = 12.9 and 13.7 min/14.3 and 15.2 min/25.3 and 26.4 mm/29.0 and 30.8 min).
That is, the area ratio of the target product (15) to the isomer (16) was determined to be 100/0 (Rt = 12.9 and 13.7 min/14.3 and 15.2 min).
[0129] Step (c): The reaction solution obtained in step (b) was washed with a 15% 20 by mass aqueous solution of potassium carbonate (6 g x 2) at the same temperature.
After the completion of washing, quantitative analysis of the resulting organic phase was performed using HPLC, which determined that the target product (15) was obtained at a yield of 31% (calculated based on 3-methyl-2-butanone oxime). The area ratio of the target product (15) to the isomer (16) was determined to be 100/0 (Rt = 12.9 and 13.7 25 min/14.3 and 15.2 min).
[0130] The conditions described in Example 6 were used for the qualitative and quantitative analysis using HPLC, and 2-nitrotoluene was used as the internal standard substance used for the quantitative analysis.
[0131] [Example 19] Synthesis of 0-[l-(2-hydroxypropyl)]acetophenone oxime

51 Step (b): 20.1 g of the toluene solution of the target product [containing 25.7 mmol
of the target product (27)] obtained in step (a) of Example 15 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 the completion of the addition, the reaction
5 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), the isomer (28), the compound (29), and the compound (30) was 59.8/0/33.2/7.0 (Rt = 29.6 min/32.6 rnin/60.3 min/71.0 min).
That is, the area ratio of the target product (27) to the isomer (28) was determined to 10 be 100/0 (Rt = 29.6 min/32.6 min).
[0132] Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous solution of potassium carbonate (5 g x 3) at the same temperature. After the completion of washing, quantitative analysis of the resulting organic phase was performed using HPLC, which determined that the target product (27) was obtained at a 15 yield of 29% (calculated based on acetophenone oxime). The area ratio of the target product (27) to the isomer (28) was determined to be 100/0 (Rt = 29.6 min/32.6 min).
[0133] The conditions described in Example 6 were used for the qualitative and
quantitative analysis using HPLC, and 2-nitrotoIuene was used as the internal standard
substance used for the quantitative analysis.
20 [0134] [Example 20] Synthesis of 0-[l-(2-hydroxypropyl)]acetone oxime
Step (a): 35.1 g (480 mmol) of acetone oxime was suspended in 54 g of water, and 4.88 g (48.8 mmol) of a 40% by mass aqueous solution of sodium hydroxide was added thereto. The reaction solution was heated to 30°C, and then 36.4 g (627 mmol) of propylene oxide was added thereto. After the completion of the addition, the reaction 25 solution was stirred at the same temperature for 3 hours. After the 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 thereto. After the completion of the addition, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was separated at the same temperature using toluene (36 g x 2). As a result, 113 g of the

52 toluene solution of a target product was obtained.
As a result of qualitative analysis of the target product using HPLC, the area ratio of
the target product of formula (31) below [hereinafter abbreviated as the "target product
(31)"] to its isomer 0-[2-(l-hydroxypropyl)]acetone oxime of formula (32) below
[hereinafter abbreviated as the "isomer (32)"] was determined to be 94.4/5.6 (Rt = 3.9
min/4.2 min). Moreover, as a result of analysis using GC/MS (CI+), one peak (Rt ~ 4.9
min) was observed, and MS determined that the peak was at m/z 132 (MH+).
CH3 CH3 9Hs

^°\^^^u H^C^N^0^ "OH
H3C >r v OH
(31) (32)CH3
[0135] Step (b): 21.5 g of the obtained toluene solution of the target product
10 [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 the completion of the addition, the reaction solution was stirred at the same temperature for 4 hours. After the completion of the reaction, the reaction solution was qualitatively analyzed using HPLC.
15 Of the two peaks newly detected, a peak at Rt = 6.7 min was estimated to be from a
compound of formula (33) below [hereinafter abbreviated as the "compound (33)"], which is a product formed by the reaction of the target product (31) and maleic anhydride, and a peak at Rt = 7.2 min was estimated to be from a compound of formula (34) below [hereinafter abbreviated as the "compound (34)"], which is a product formed by the
20 reaction of the isomer (32) and maleic anhydride. As a result of qualitative analysis, the area ratio of the target product (31), the isomer (32), the compound (33), and the compound (34) was 55.1/0/36.0/8.8.
That is, the area ratio of the target product (31) to the isomer (32) was determined to be 100/0 (Rt = 3.9 min/4.3 min).

53
CH3 CH3 H3C^N^°^^OH CH3 CH3 0 °y°H
(31) (33)
CH3
H3C^N^°Y^OH CH3 CH3 0 V^ CH3
(32) (34)
[0136] As a result of analysis of the reaction solution using LC/MS (ESI±), two peaks were observed. MS determined that one peak was atm/z 132 (MH+) (Rt= 2.5 min), and the other peak was at m/z 228 (MH-) (Rt = 2.1 min). The compounds (33) 5 and (34) were estimated to be detected at Rt = 2.1 min in an overlapping manner.
[0137] Step (c): The reaction solution obtained in step (b) was washed with a 15% by mass aqueous solution of potassium carbonate (6 g x 2) at the same temperature. After the completion of washing, quantitative analysis of the resulting organic phase was performed using HPLC, which determined that the target product (31) was obtained at a 10 yield of 27% (calculated based on acetone oxime). The area ratio of the target product (31) to the isomer (32) was determined to be 100/0 (Rt = 3.9 min/4.3 min).
[0138] The conditions described in Example 6 were used for the qualitative and quantitative analysis using HPLC, and ethoxybenzene was used as the internal standard substance used for the quantitative analysis. The conditions described in Example 1 15 were used for the analysis using GC/MS and LC/MS.
[0139] [Referential Example 1] Synthesis of 0-[l-(2-hydroxypropyl)]-2-hydroxy-l"propylaldoxime
In 13.4 g of water, 1.34 g (9.21 mmol) of 0-[l-(2-hydroxypropyl)]butanone oxime was suspended, and the suspension was cooled to 0°C in a reactor connected to a 20 Dean-Stark tube. After the completion of cooling, 5.13 g (49.2 mmol) of a 35% by mass aqueous solution of hydrochloric acid was added to the reaction solution. After the completion of the addition, while bubbling nitrogen gas into the reaction solution, the reaction solution was stirred at the same temperature for 2 hours, further stirred at 10°C

54 for 2 hours, further stirred at 20°C for 1 hour, further stirred at 30°C for 2 hours, further
stirred at 40°C for 4 hours, further stirred at 50°C for 4 hours, and further stirred at 40°C
for 9 hours. After the completion of the reaction, the reaction solution was cooled to
room temperature, and washed with dichloromethane (20 g x 2). To the resulting
5 aqueous phase was added 9 g of butanone, and then the aqueous phase was washed with
dichloromethane (20 g x 3). To the resulting aqueous phase was added 30 g of a
saturated aqueous solution of sodium hydrogen carbonate, and then the mixture was
concentrated. To the concentrated residue was added 50 g of ethanol, the insoluble
precipitate was filtered, and the filtrate was concentrated. Furthermore, 10 g of
10 methanol was added to the concentrated residue, the insoluble precipitate was filtered, and a portion of the filtrate was concentrated to obtain 0.03 g of the target product as a pale yellow oil.
'H-NMR (600 MHz, ppm in CDCh): 5 1.18 (d, 3H), 1.35 (d, 3H), 3.00 (bis, 2H), 3.89 (m, 1H), 4.03 (m, 1H), 4.10 (m, 1H), 4.43 (m, 1H), 7.45 (d, 1H)
15 LC/MS (ESI+) m/z: 148 (MH+) GC/MS (CI+) m/z: 148 (MH+)
[0140] The conditions for GC/MS analysis were as follows: Column: Agilent Technologies HP-5, 0.32 mm ID x 30 m x 0.25 urn Temperature elevation time and rate: 40°C (2 min)-(20oC/min)-300°C (7 min)
20 The conditions for LC/MS analysis were as follows:
Column: GL Sciences Inersil ODS-3, 3 u,m, 2.1 mm x 50 mm
Eluent: methanol/0.1% by volume aqueous solution of formic acid = 5/95 (volume ratio)
Flow rate: 0.45 mL/min
Column temperature: 40°C
25 [0141] [Referential Example 2] Synthesis of
3-[l-(2-butylideneaminooxy)-2-propyloxycarbonyl]-2-(Z)-propenoicacid
In 19.9 g of dichloromethane, 1.53 g (10.5 mmol) of 0-[l-(2-hydroxypropyl)]butanone oxime was dissolved, and the solution was cooled to 0°C. After the 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 the completion of the addition, the mixture was stirred at the same temperature for 53 hours. After the completion of the reaction, 20 mL of a saturated aqueous solution of sodium hydrogen carbonate and 100 mL of ethyl acetate were added, and the mixture was separated. To the aqueous phase, 100 mL of ethyl acetate and a 1 mol/L aqueous solution of hydrochloric acid were added until a pH of 3 was achieved, and the mixture was separated. Furthermore, the aqueous phase was extracted with ethyl acetate (200 mL x 3). The resulting organic phase was washed with 20 mL of a saturated sodium chloride solution, and then the organic phase was concentrated and dried to obtain 2.19 g of the title compound as a pale yellow oil.
'H-NMR (300 MHz, ppm in CDC13): 5 1.07 (t, 3H), 1.33 (d, 3H), 1.79 (s, 3H), 2.17(q, 2H), 4J1 (m, 2H), 5.39 (m, 1H), 636 (d, 1H), 6.45 (d, 1H), 9.30 (brs, 1H) LC/MS (ESI+) m/z: 244 (MH+) GC/MS (CI+) m/z: 244 (MH+)
[0142] The conditions for GC/MS analysis were as follows: Column: Agilent Technologies HP-5, 0.32 mm ID x 30 m x 0.25 pm Temperature elevation time and rate: 40°C (2 min)-(20oC/min)-300°C (7 min)
The conditions for LC/MS analysis were as follows: Column: Waters XBridge C18, 5 pm, 2.1 mm x 150 mm
Eluent: acetonitrile/0.2% by volume aqueous solution of formic acid ~ 40/60 (volume ratio)
Flow rate: 0.2 mL/min Column temperature: 40°C
INDUSTRIAL APPLICABILITY
[0143] The present invention is useful as a method for producing an 0-[l-(2-hydroxypropyl)]oxime compound, which is useful as an intermediate for pharmaceuticals, agrochemicals, or electronic materials, for example.

CLAIMS
1. A method for producing an 0[l-(2-hydroxypropyl)]oxime compound of formula (1):
CH3
[wherein R1 and R2 are each independently a Ci-g alkyl group or a phenyl group, or R1 and R2 taken together with the carbon atoms to which they are attached form a 5- to 7-membered carbocyclic ring],
the method comprising steps (a) to (c):
step (a): reacting an oxime compound of formula (2):
R,V°« *>
(wherein R1 and R2 are defined as above) with propylene oxide in the presence of a basic compound;
step (b): reacting the mixture obtained in step (a) with a cyclic acid anhydride in the presence of a basic compound; and
step (c): mixing the mixture obtained in step (b) with an aqueous solution of a basic compound to obtain the 0-[l-(2~hydroxypropyl)]oxime compound of formula (I).
2. The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to claim 1, wherein the cyclic acid anhydride is used in an amount of 0.04 to 1.0 equivalent per equivalent of the compound of formula (1) in the mixture obtained in step (a).
3. The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound 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.

4. The method for producing an 0-[l™(2-hydroxypropyl)]oxime compound according to any one of claims 1 to 3, wherein R1 and R2 are each independently -CH3) ~CH2CH3, -CH2CH2CH3s ~CH(CH3)2, -CH2CH2CH2CH3, "CH(CH3)(CH2CH3)S -CH2CH(CH3)2? -C(CH3)35 or a phenyl group, or Rl and R2 taken together with the carbon atoms to which they are attached form a 6-mernbered carbocyclic ring.
5. The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to claim 4, wherein R1 and R2 are each independently -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, or a phenyl group, or R1 and R2 taken together with the carbon atoms to which they are attached form a 6-membered carbocyclic ring.
6. The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to claim 5, wherein R1 and R2 are each independently -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, or a phenyl group, or R1 and R2 taken together with the carbon atoms to which they are attached form a 6-membered carbocyclic ring.
7. The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of claims 1 to 6, wherein in step (c)5 an organic solvent containing the mixture obtained in step (b) is mixed with the aqueous solution of the basic compound.
8. The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to claim 7, wherein in step (c), the organic solvent containing the mixture obtained in step (b) is dichloromethane, 1,2-dichloroethane, or toluene.
9. The method for producing an 0-[l-(2-hydroxypropyl)]oxime compound according to any one of claims 1 to 8, wherein in step (c), the basic compound is sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, or potassium carbonate.