JP2009155327A - New method for producing 2-hydroxyethyloxyamine compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new method for producing a 2-hydroxyethyloxyamine compound. <P>SOLUTION: The method for producing a 2-hydroxyethyloxyamine compound represented by formula (2) uses an O-(1-(2-hydroxyethyl))oxyimine compound represented by formula (1). In the formulas, R<SP>1</SP>is a 1-8C alkyl group, a phenyl group, a benzyl group, or a naphthyl group; R<SP>2</SP>is a hydrogen atom or R<SP>1</SP>; R<SP>3</SP>, R<SP>4</SP>, R<SP>5</SP>, and R<SP>6</SP>are each independently a hydrogen atom or a 1-3C alkyl group, provided that at least one of R<SP>3</SP>, R<SP>4</SP>, R<SP>5</SP>, and R<SP>6</SP>is a 1-3C alkyl group. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing a 2-hydroxyethoxyamine compound useful as an intermediate for producing agricultural drugs.

  As a method for producing a 2-hydroxyethyloxyamine compound, a method in which N-hydroxyphthalimide is reacted with an alkyl halide or oxirane compound and then hydrolyzed is generally known. For example, N-hydroxyphthalimide and propylene oxide are reacted in the presence of triethylamine to synthesize 2- (2-hydroxybutoxy) isoindoline-1,3-dione, and further reacted with hydrazine to produce O- (1- ( A method for producing 2-hydroxypropyl)) oxyamine is known (Non-Patent Document 1). However, in this method, it is necessary to filter out the phthalic hydrazide compound produced as a by-product, and the burden of equipment costs increases particularly in industrial production. In addition, disposal costs increase and there are concerns about environmental impact.

Further, as a method of hydrolysis of a 2-hydroxyethyloxyimine compound which is one of the subjects of the present invention, for example, O- (2-hydroxyethyl) acetoxime is protected with an acetyl group and hydrolyzed with hydrochloric acid to give an amine. A method for producing O- (1- (2-hydroxyethyl)) oxyamine by deprotecting after synthesis of N is known (Non-patent Document 2). However, there is no specific description of an example in which the desired product is obtained by hydrolysis in the hydroxy group state.
Pharmazie, 1970, 25, 7, 400 Journal of Molecular Catalysis B: Enzymatic, 2001, Vol. 11, p. 255

  It is to find a novel method for producing a 2-hydroxyethoxyamine compound useful as an intermediate for producing agricultural pharmaceuticals.

  As a result of intensive studies in view of such a situation, the present inventors have found a method for producing a 2-hydroxyethoxy compound and have reached the present invention.

That is, the present invention
[1] Formula (1)

(In the formula, R ¹ represents a C _{1 to} C ₈ alkyl group, a phenyl group, a benzyl group or a naphthyl group, and R ² represents a hydrogen atom, a C _{1 to} C ₈ alkyl group, a phenyl group, a benzyl group or a naphthyl group. , R ³ , R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom or a C ₁ -C ₃ alkyl group, provided that at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is C _1. -C ₃ expression, which comprises using an alkyl group.) 2-hydroxyethyl-oxy imine compound represented by as a raw material (2)

(Wherein R ³ , R ⁴ , R ⁵ and R ⁶ represent the same meaning as described above) [2]
The production method [3] according to [1], wherein R ³ , R ⁵ and R ⁶ are hydrogen atoms, and R ⁴ is a methyl group.
[1] or [2], wherein R ¹ is a phenyl group or a methyl group, and R ² is a methyl group or an ethyl group.
About.

  According to the production method of the present invention, in order to obtain the target product, the filtration operation that is essential in the method using phthalimide can be omitted. Further, since the target product is distributed to the aqueous layer and the by-product ketone compound is distributed to the organic layer by the extraction operation, the ketone compound can be recovered and reused for the production of the starting material. Therefore, it is possible to efficiently produce a 2-hydroxyethoxyamine compound that is important as an intermediate for producing agricultural pharmaceuticals at low cost.

Specific examples of the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ in the compound in the present invention are shown, but the present invention is not limited to these.
[Specific Examples of Substituent R ¹ ]
Methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, tertiary butyl, phenyl, benzyl, 1-naphthyl, 2-naphthyl [specific examples of substituent R ² ]
Hydrogen atom, methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, tertiary butyl, phenyl, benzyl, 1-naphthyl, 2-naphthyl (specific examples of substituents R ³ , R ⁴ , R ⁵ and R ⁶ )
Hydrogen atom, methyl, ethyl, normal propyl, isopropyl Preferable R ¹ includes, for example, a phenyl group and a methyl group, and preferable R ² includes, for example, a methyl group and an ethyl group.

  There may be optical isomers in the compounds according to the present invention, for example, intermediates and objects of the production process of the present invention, and all of the optical isomers are included in the present invention.

  A method for producing the 2-hydroxyethoxyamine compound represented by the formula (2) from the 2-hydroxyethyloxyimine compound represented by the formula (1) is represented by a reaction formula 1.

[Reaction Formula 1]

  The reagents and reaction conditions used in this reaction are shown below, but are not limited thereto.

  In this reaction, water is usually used in an amount of 1-fold mol to the amount of solvent relative to (1). Although this reaction proceeds even without a solvent other than water, a solvent can be used if necessary.

  The solvent is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, heptane, cyclohexane, benzene and toluene, carbon tetrachloride, chloroform, 1,2-dichloroethane, chlorobenzene and the like Halogenated hydrocarbons, alcohols such as methyl alcohol, ethyl alcohol and ethylene glycol, ethers such as diethyl ether, diisopropyl ether, diglyme, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, N, N- Examples thereof include amides such as dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, ureas such as N, N′-dimethylimidazolinone, and mixed solvents thereof. Among these, for example, inexpensive methanol and industrially usable toluene are preferable.

  Examples of the base used in this reaction include pyridine, triethylamine, tri-n-butylamine, di (isopropyl) ethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] -7-undecene and 1 Organic bases such as 1,4-diazabicyclo [2.2.2] octane, quaternary ammonium hydroxides such as tetramethylammonium hydroxide, trimethylbenzylammonium hydroxide and tetrabutylammonium hydroxide, sodium hydroxide, hydroxide Examples include inorganic bases such as potassium, magnesium hydroxide, calcium hydroxide, barium hydroxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, and sodium hydrogen carbonate. The base is generally used in an amount of 0.05 to 10-fold mol, preferably 0.05 to 2-fold mol based on (1).

  Examples of acids used in this reaction include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, boron trifluoride, Metal chlorides such as aluminum trichloride, tin tetrachloride, magnesium dichloride, iron trichloride and titanium tetrachloride, metal alkoxides such as triisopropoxyaluminum, diethoxymagnesium and tetraisopropoxytitanium, bis (trifluoromethanesulfonyl ) Metal triflates such as tin, bis (trifluoromethanesulfonyl) copper and tris (trifluoromethanesulfonyl) scandium. The acid is generally used in an amount of 0 to 10 moles, preferably 0 to 2 moles compared to (1).

  The reaction temperature is usually -90 to 200 ° C, preferably 0 to 100 ° C.

  The reaction time is usually 0.05 to 100 hours, preferably 0.5 to 10 hours.

  The 2-hydroxyethyloxyimine compound represented by the formula (1) may have geometric isomers, but both isomers exhibit the same reactivity and are represented by the 2-hydroxyethyloxyimine compound represented by the formula (2). A hydroxyethyloxyamine compound can be produced.

  In this reaction, a ketone or aldehyde compound represented by the formula (3) is obtained as a by-product. The amine compound (2) and the ketone compound (3), which are the target products, can usually be separated by a liquid separation operation with water and an organic solvent. The target product (2) is into the aqueous layer and the ketone compound (3) is into the organic layer. Distributed. Thereby, the filtration operation which was indispensable at the time of manufacture using phthalimide can be omitted. Further, by reacting the separated solution of the ketone compound (3) with hydroxyamine by a usual method and further reacting with an oxirane compound or the like, the production intermediate 2-hydroxyethyloxyimine compound (1) can be easily obtained. By manufacturing, the reagent can be used effectively. At this time, since all work is performed in a liquid state, improvement in work efficiency can be expected as compared with the filtration work.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
Example 1 Production of O- (1- (2-hydroxypropyl)) oxyamine 1
0.69 g (5.3 mmol) of O- (1- (2-hydroxypropyl)) acetoxime was dissolved in 4.4 g (42.2 mmol) of concentrated hydrochloric acid. This solution was heated to 50 ° C. in a reactor connected to a Dean-Stark tube, reacted at 70 mmHg for 1 hour, 50 mmHg for 1 hour, 26 mmHg for 1 hour, and further reacted at 80 ° C. and 46 mmHg for 1 hour. The reaction solution was cooled to room temperature, and subjected to gas chromatography [analysis conditions, column: CP-VOLAMINE 0.32 mm ID × 60 m × 0.25 μm manufactured by Varian, Inc., temperature increase: 100 ° C. (1 minute) − (10 ° C./min)− 240 ° C. (10 minutes)], it was confirmed that the title compound was produced in a quantitative yield of 67.8%.
[Example 2] Production of O- (1- (2-hydroxypropyl)) oxyamine 2
1 g (6.9 mmol) of O- (1- (2-hydroxypropyl)) butanone oxime was dissolved in 5.75 g (55.2 mmol) of concentrated hydrochloric acid. This solution was reacted at 80 ° C. and 70 mmHg for 6 hours in a reactor connected to a Dean-Stark tube. The reaction solution was cooled to room temperature, and subjected to gas chromatography [analysis conditions, column: CP-VOLAMINE 0.32 mm ID × 60 m × 0.25 μm manufactured by Varian, Inc., temperature increase: 100 ° C. (1 minute) − (10 ° C./min)− 240 ° C. (10 minutes)], it was confirmed that the title compound was quantitatively produced.
Example 3 Production of O- (1- (2-hydroxypropyl)) oxyamine 3
1 g (6.9 mmol) of O- (1- (2-hydroxypropyl)) butanone oxime was dissolved in 5 g of water, and 2.65 g (27.5 mmol) of methanesulfonic acid was added. This solution was reacted at 35 to 40 ° C. and 30 mmHg for 3 hours in a reactor connected to a Dean-Stark tube. During the reaction, water reduced by distillation was replenished as needed. The reaction solution was cooled to room temperature, and subjected to gas chromatography [analysis conditions, column: CP-VOLAMINE 0.32 mm ID × 60 m × 0.25 μm manufactured by Varian, Inc., temperature increase: 100 ° C. (1 minute) − (10 ° C./min)− 240 ° C. (10 minutes)], it was confirmed that the title compound was produced in a quantitative yield of 87.2%.
Example 4 Production of O- (1- (2-hydroxypropyl)) oxyamine 4
1 g (5.2 mmol) of O- (1- (2-hydroxypropyl)) acetophenone oxime was dissolved in 3 g of toluene, 2.7 g (26 mmol) of concentrated hydrochloric acid was added, and the mixture was stirred at 50 ° C. for 8 hours. The reaction solution was cooled to room temperature, and the aqueous layer was subjected to gas chromatography [analysis conditions, column: CP-VOLAMINE 0.32 mm ID × 60 m × 0.25 μm, manufactured by Valian, temperature increase: 100 ° C. (1 minute) − (10 ° C. / Min) -240 ° C. (10 min)] to confirm that the title compound was produced in a quantitative yield of 65.6%.
Example 5 Production of O- (1- (2-hydroxypropyl)) oxyamine 5
1.03 g (5.7 mmol) of O- (1- (2-hydroxypropyl)) benzophenone oxime was dissolved in 3 g of toluene, 4.9 g (46.9 mmol) of concentrated hydrochloric acid was added, and the mixture was stirred at 30 ° C. for 8 hours. . After cooling the reaction solution to room temperature, the toluene layer was separated, and the aqueous layer was further washed with 3 g of toluene. The aqueous layer was subjected to gas chromatography [analysis conditions, column: CP-VOLAMINE 0.32 mm ID × 60 m × 0.25 μm, manufactured by Valian, temperature increase: 100 ° C. (1 minute) − (10 ° C./minute)−240° C. (10 minutes )], It was confirmed that the title compound was produced in a quantitative yield of 43.7%.
Example 6 Production of O- (1- (2-hydroxypropyl)) oxyamine 6
1 g (5.2 mmol) of O- (1- (2-hydroxypropyl)) acetophenone oxime was dissolved in 3 g of toluene, 3.2 g (30.7 mmol) of concentrated hydrochloric acid was added, and the mixture was stirred at 30 ° C. for 2 hours. The toluene layer was separated, and 3 g of toluene and 1 g (9.6 mmol) of concentrated hydrochloric acid were added to the aqueous layer, followed by further stirring at 30 ° C. for 2 hours. The toluene layer was separated, and the aqueous layer was subjected to gas chromatography [analysis conditions, column: CP-VOLAMINE 0.32 mm ID × 60 m × 0.25 μm, manufactured by Valian, temperature increase: 100 ° C. (1 min) − (10 ° C./min ) -240 ° C. (10 minutes)], it was confirmed that the title compound was produced in a quantitative yield of 88.5%.
[Example 7] Production of O- (1- (2-hydroxypropyl)) oxyamine 7
1 g (5.2 mmol) of O- (1- (2-hydroxypropyl)) acetophenone oxime was dissolved in 3 g of toluene, 4.3 g (41.2 mmol) of concentrated hydrochloric acid was added, and the mixture was stirred at 30 ° C. for 2 hours. The toluene layer was separated, 3 g of toluene was added to the aqueous layer, 2.8 g (20.8 mmol) of a 30% aqueous sodium hydroxide solution was added, and the mixture was further stirred at 30 ° C. for 1 hour. The toluene layer was separated, and the aqueous layer was subjected to gas chromatography [analysis conditions, column: CP-VOLAMINE 0.32 mm ID × 60 m × 0.25 μm, manufactured by Valian, temperature increase: 100 ° C. (1 min) − (10 ° C./min ) -240 ° C. (10 minutes)], it was confirmed that the title compound was produced in a quantitative yield of 81.1%.
Example 8 Production of O- (1- (2-hydroxypropyl)) oxyamine Part 8
A solution prepared by dissolving 5 g (25.9 mmol) of O- (1- (2-hydroxypropyl)) acetophenone oxime in 15 g of toluene was dropped into 21.6 g (207 mmol) of concentrated hydrochloric acid heated to 30 ° C. over 2 hours. . After the reaction solution was further stirred at 30 ° C. for 1 hour, the toluene layer was separated, 3 g of toluene was added to the aqueous layer, and then the toluene layer was separated. The aqueous layer was washed with 15 g of toluene, and then subjected to gas chromatography [analysis conditions, column: CP-VOLAMINE 0.32 mm ID × 60 m × 0.25 μm, manufactured by Valian, temperature increase: 100 ° C. (1 min) − (10 ° C./min ) -240 ° C. (10 minutes)], it was confirmed that the title compound was produced in a quantitative yield of 78.3%.
Example 9 Production of O- (1- (2-hydroxypropyl)) oxyamine 9
107.7 g (0.557 mol) of O- (1- (2-hydroxypropyl)) acetophenone oxime was dissolved in 323.2 g of toluene, and 232.4 g (2.23 mol) of concentrated hydrochloric acid was added thereto. This solution was stirred at 30 ° C. for 2 hours, and the toluene layer was separated. After adding 323.2 g of toluene to the aqueous layer and stirring at 30 ° C. for 1 hour, the toluene layer was separated. After adding 323.2 g of toluene to the aqueous layer, 208 g (1.56 mol) of 30% aqueous sodium hydroxide solution was added and stirred at 30 ° C. for 1 hour. The precipitated solid was filtered, and the obtained filtrate was separated to obtain an aqueous solution of the title compound. Gas chromatography [analysis conditions, column: CP-VOLAMINE 0.32 mm ID × 60 m × 0.25 μm, manufactured by Varian, temperature increase: 100 ° C. (1 minute) − (10 ° C./min)−240° C. (10 minutes)] As a result of analysis, it was confirmed that the title compound was produced in a quantitative yield of 79.8% in the obtained aqueous solution.
[Reference Example 1] Production of O- (1- (2-hydroxypropyl)) acetophenone oxime 1
2.05 g (15.17 mmol) of acetophenone oxime was dissolved in 2 g of methanol, and 2.09 g (15.12 mmol) of potassium carbonate and propylene oxide (30.13 mmol) were further added. The solution was stirred at 10 ° C. for 30 hours and further stirred at room temperature overnight. To the reaction solution, 20 g of toluene and 10 g of water were added for liquid separation, and the aqueous layer was extracted with 20 g of toluene. The toluene layer was washed with 5 g of water and then dried over sodium sulfate, and the solvent was distilled off to obtain the title compound in a yield of 80.2% (quantitative purity 82.8%).
Reference Example 2 Production of O- (1- (2-hydroxypropyl)) acetophenone oxime 2
Sodium hydride (purity 55%) 2.62 g (0.06 mol) was weighed and suspended in 40.6 g of dimethyl sulfoxide. A solution prepared by dissolving 81.1 g (0.6 mol) of acetophenone oxime in 162.2 g of dimethyl sulfoxide was added dropwise to this suspension at room temperature over 30 minutes. After further stirring at room temperature for 1 hour, the mixture was heated to 40 ° C., and 34.85 g (0.6 mol) of propylene oxide was added dropwise over 1 hour. The reaction solution was stirred at 40 ° C. for 6 hours, cooled to room temperature, and further stirred at room temperature for 15 hours. To the reaction solution, 240 g of 10% aqueous sodium hydroxide solution was added, stirred at 40 ° C. for 2 hours, cooled to room temperature, and the aqueous layer was separated. The aqueous layer was extracted with 405.5 g of toluene, and the toluene layers were combined and washed twice with 202.8 g of water. The toluene layer was washed with 120 g of a 2% aqueous sodium hydroxide solution, and further washed twice with 202.8 g of water. This toluene solution was subjected to high performance liquid chromatography [analysis conditions, column: Inertsil ODS-SP 4.6 mm × 150 mm, eluent: acetonitrile / 0.1% formic acid aqueous solution = 35/65, flow rate: 0.75 mL / min, column temperature : 40 ° C.], it was confirmed that 107.7 g (quantitative yield: 92.9%) of the title compound was obtained.

The present invention is useful as a method for producing a 2-hydroxyethyloxyamine compound useful as an intermediate for producing agricultural drugs.

Claims (3)

Formula (1)

(In the formula, R ¹ represents a C _{1 to} C ₈ alkyl group, a phenyl group, a benzyl group or a naphthyl group, and R ² represents a hydrogen atom, a C _{1 to} C ₈ alkyl group, a phenyl group, a benzyl group or a naphthyl group. , R ³ , R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom or a C ₁ -C ₃ alkyl group, provided that at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is C _1. -C ₃ expression, which comprises using an alkyl group.) 2-hydroxyethyl-oxy imine compound represented by as a raw material (2)

(Wherein R ³ , R ⁴ , R ⁵ and R ⁶ represent the same meanings as described above), and a method for producing a 2-hydroxyethyloxyamine compound. The process according to claim 1, wherein R ³ , R ⁵ and R ⁶ are hydrogen atoms, and R ⁴ is a methyl group. The production method according to claim 1 or 2, wherein R ¹ is a phenyl group and R ² is a methyl group, or R ¹ is a methyl group and R ² is an ethyl group.