JP2017149686A - Production method of ketoxime compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new catalytic production method of a ketoxime that does not directly use hydroxyamine, nor require severe reaction conditions.SOLUTION: A production method of a ketoxime compound includes a step for transoximizing a ketone compound and ethyl acetohydroxamate in the presence of an organic solvent and a trifluoromethanesulfonic acid metal salt. The trifluoromethanesulfonic acid metal salt is preferably scandium (III) trifluoromethanesulfonate. The organic solvent is preferably methylene chloride, methanol, ethanol, n-propanol, or n-butanol.SELECTED DRAWING: None

Description

The present invention relates to a novel method for producing ketoxime compounds useful as pharmaceuticals, agricultural chemicals, cosmetics, synthetic fibers, perfumes, and raw materials thereof.

As a general method for synthesizing ketoxime compounds, a dehydration condensation reaction between hydroxylamine and a ketone compound is known. However, hydroxylamine itself is hygroscopic, weak against heat, decomposes, and explosive. Because there are dangerous reagents, it is very difficult to handle. Therefore, most of them are treated as hydroxylamine mineral salts (for example, Non-Patent Document 1).

However, this method requires the use of a stoichiometric base and hydroxylamine mineral salt, and has a problem that a large amount of salt is generated after the reaction. Further, although there is a method using acetone oxime instead of hydroxylamine, a reaction under a high temperature condition has been required.

M.M. Cocivera, C.I. A. Fyfe, A .; Effio, S .; P. Vaish, H .; E. Chen, J. et al. Am. Chem. Soc. 1976, 98, 1573-1578.

The object of the present invention is to provide a novel catalytic ketoxime production method that does not directly use hydroxylamine and does not require harsh reaction conditions.

The inventors of the present invention have studied the catalytic transoximation reaction under mild conditions. When trifluoromethanesulfonic acid metal salt is used, hydroxylamine is sequentially generated and reacted with a ketone. A ketoxime was synthesized, and it was found that a ketone compound and ethyl acetohydroxamate can be transoximed under mild conditions, and the present invention was completed.

That is, the present invention relates to a method for producing a ketoxime compound including a step of transoximing a ketone compound and ethyl acetohydroxamic acid in the presence of an organic solvent and a metal salt of trifluoromethanesulfonic acid.

Metal trifluoromethanesulfonate is scandium trifluoromethanesulfonate, iron trifluoromethanesulfonate, nickel trifluoromethanesulfonate, zinc trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, or ytterbium trifluoromethanesulfonate It is preferable that

The organic solvent is preferably methylene chloride, methanol, ethanol, normal propanol, or normal butanol.

According to the present invention, an oxime compound can be handled as a hydroxylamine equivalent, without using an expensive catalyst or reagent, without requiring severe reaction conditions, under mild reaction conditions, with high yield and high yield. An ketoxime compound can be selectively obtained.

The method for producing a ketoxime compound of the present invention comprises a step of transoximing a ketone compound and ethyl acetohydroxamic acid in the presence of an organic solvent and a metal salt of trifluoromethanesulfonic acid. The stereoselectivity of the present invention is very high, and the E form can be synthesized in a high yield.

The ketone compound is not particularly limited as long as it has a chemical structure represented by> C = O. For example, acetyl methyl ketone, (trifluoromethylphenyl) methylketone, (methoxyphenyl) methylketone, phenylmethylketone, (methyl Phenyl) methyl ketone, furyl methyl ketone, thiofuryl methyl ketone, phenyl ethyl ketone, diphenyl ketone, nonyl methyl ketone, cyclododecyl ketone, 1-indanone, α-tetralone, and estrone. Corresponding ketoxime compounds can be synthesized from these ketone compounds.

The organic solvent is not particularly limited, but methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, hexane, toluene, diethyl ether, hexane, toluene, acetonitrile, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, Examples include diethylene glycol, acetone, dimethyl sulfoxide, and dimethylamino formaldehyde. These organic solvents can be used in a mixture of two or more. Of these, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, diethylene glycol, and the like are preferable in terms of environmental load and reaction yield.

The metal salt of trifluoromethanesulfonic acid is not particularly limited, and examples thereof include scandium (III) salt, nickel salt, zinc salt, yttrium salt, lanthanum salt, ytterbium salt, iron salt, copper salt and the like. These metal salts can be used in combination of two or more. Of these, scandium (III) salts are preferred in terms of reaction yield.

1-10 mol is preferable with respect to 1 mol of ketone compounds, and, as for the addition amount of ethyl acetohydroxamic acid with respect to a ketone compound, 1.5-10 mol is more preferable. If it is less than 1 mol, the reaction tends to be incomplete.

The amount of trifluoromethanesulfonic acid metal salt added is preferably 0.01 to 1 mol, more preferably 0.01 to 0.10 mol, relative to 1 mol of the ketone compound. If the amount is less than 0.01 mol, the reaction tends not to be completed.

Although reaction temperature is not specifically limited, 20-80 degreeC is preferable and 40-80 degreeC is more preferable. When it exceeds 80 degreeC, there exists a tendency for a solvent to volatilize. Moreover, although reaction time is not specifically limited, 1 to 72 hours are preferable and 24 to 48 hours are more preferable. If it is less than 1 hour, the reaction tends to be incomplete.

The ketoxime compound obtained by the production method of the present invention is useful as pharmaceuticals, agricultural chemicals, cosmetics, perfumes, and raw materials thereof.

Examples of the present invention will be described below. However, the present invention is not limited to the following examples.

Example 1 Synthesis of (E) -2-naphthoacetophenoxime (compound 3a) 2-naphthoacetophenone (57.9 mg, 0.346 mmol) in a test tube (with a stirring bar) at room temperature under an argon atmosphere. 1.0 eq.), Scandium (III) trifluoromethanesulfonate (8.4 mg, 0.0170 mmol, 5 mol%), ethanol (0.34 ml, 1.0 M), ethyl acetohydroxamate (52.6 μL, 0. 510 mol, 1.5 eq.) Was added and stirred at room temperature for 24 hours. Thereafter, 20 ml of ethyl acetate was added, the reaction solution was filtered through a silica gel pad under reduced pressure, the solvent was distilled off, and NMR was measured. Purification by silica gel column chromatography (manufactured by Kanto Chemical Co., Inc., silica gel 60 (40-50 μm), hexane / methylene chloride = 2/8 to methylene chloride / diethyl ether = 95/5), white (E) -2 -62.3 mg (yield 99%) of naphthoacetophenoxime (compound 3a) was obtained.
The NMR data of compound 3a are as follows.

(E) -3a: ¹ H-NMR (CDCl ₃ , 400 MHz, ppm) δ 2.42 (s, 3H), 7.48-7.52 (m, 2H), 7.83-7.89 (m, 4H), 8.03 (s, 1H), 8.78 (br, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 12.2, 123.4, 126.1, 126.6, 126.8 , 127.8, 128.4, 128.6, 133.2, 133.8, 133.9, 156.1.

Example 2
In Example 1, ketoxime compounds were synthesized as shown by the following chemical formula using various ketone compounds instead of 2-naphthoacetophenone. The obtained ketoxime compound, yield, and E / Z are shown below.

Aromatic ketones having electron withdrawing substituents showed high reactivity. On the other hand, the aromatic ketone having an electron donating substituent or a thiophene ring was obtained in a high yield by increasing the catalyst amount to 5 mol%. In addition, as for the position of the substituent, the reactivity is slightly lowered at the ortho position. Good results were obtained for the para and meta positions. In addition, the yield decreased when benzophenone was used, and aliphatic ketones showed good reactivity. Further, 3n as a raw material of nylon-12 and precursor 3o of a candidate compound for a breast cancer therapeutic agent were also obtained in high yield.

Example 3
Table 1 shows the results of reaction using various catalysts in the transoximation reaction of naphthyl methyl ketone and ethyl acetohydroxamic acid. As a catalyst, it can be seen that scandium (III) trifluoromethanesulfonate of entry 9 is the most excellent.

Example 4
Table 2 shows the results of reaction using various organic solvents in the transoximation reaction of naphthyl methyl ketone and ethyl acetohydroxamate in the presence of scandium (III) trifluoromethanesulfonate. As the solvent, methylene chloride, methanol, ethanol, 1-propanol, and 1-butanol are found to be optimal (entries 1, 5-7, 9).

According to the present invention, an oxime compound can be handled as a hydroxylamine equivalent, and a ketoxime compound can be obtained from a ketone in high yield under mild reaction conditions. The obtained ketoxime compound is useful as pharmaceuticals, agricultural chemicals, cosmetics, synthetic fibers, fragrances and raw materials thereof.

Claims (3)

A method for producing a ketoxime compound, comprising a step of transoximing a ketone compound and ethyl acetohydroxamic acid in the presence of an organic solvent and a metal salt of trifluoromethanesulfonic acid. Metal trifluoromethanesulfonate is scandium trifluoromethanesulfonate, iron trifluoromethanesulfonate, nickel trifluoromethanesulfonate, zinc trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, or trifluoromethanesulfonic acid The method for producing a ketoxime compound according to claim 1, which is ytterbium. The method for producing a ketoxime compound according to claim 1 or 2, wherein the organic solvent is methylene chloride, methanol, ethanol, normal propanol, or normal butanol.