CN110878071A

CN110878071A - Preparation method of α -amino-gamma-butyrolactone and salt thereof

Info

Publication number: CN110878071A
Application number: CN201911147154.2A
Authority: CN
Inventors: 张耀谋; 邓国为; 单志炜; 王忠耀
Original assignee: South China Agricultural University
Current assignee: South China Agricultural University
Priority date: 2019-11-21
Filing date: 2019-11-21
Publication date: 2020-03-13

Abstract

The invention discloses a preparation method of α -amino-gamma-butyrolactone and salts thereof, which has the advantages of mild reaction, simple operation and high yield, and meanwhile, a byproduct methyl phenyl methyl sulfide compound prepared by the preparation method can be recovered into corresponding benzyl halide by introducing halogen and other methods, the recovery rate is 72.9 percent, and the production cost of a reagent is greatly reduced.

Description

Preparation method of α -amino-gamma-butyrolactone and salt thereof

Technical Field

The invention relates to the field of preparation of α -amino-gamma-butyrolactone, in particular to a preparation method of α -amino-gamma-butyrolactone and salts thereof.

Background

α -amino-gamma-butyrolactone and salts thereof have great market space as intermediates for the manufacture of pharmaceuticals and pesticides, for example, schemes 69 and 70 of US2010/0189687 describe the use of α -amino-gamma-butyrolactone as an intermediate for cytochrome P450 monooxygenase inhibitors.

In addition, ancillary data such as Tetrahedron Letters, Vol.50, p.5067-5067, (2009) and CN 103282355A describe methods for producing α -amino- γ -butyrolactone and salts thereof by reacting methionine and chloroacetic acid, specifically, water is used as a main solvent, methionine and chloroacetic acid are added to react, the solvent is distilled off after washing with dichloromethane several times, and concentrated hydrochloric acid or hydrogen chloride gas is added to obtain α -amino- γ -butyrolactone hydrochloride.

However, the yield of the method can only be about 60 percent, and because the added chloroacetic acid reagent is strong acid, the consumption of a reaction vessel and a conveying pipeline is high, the water solubility of the chloroacetic acid reagent is high, and the final purification is difficult to a certain extent.

Disclosure of Invention

The invention aims to provide a preparation method of α -amino-gamma-butyrolactone and salts thereof, which has the advantages of mild reaction, simple operation and high yield, and meanwhile, the byproduct methyl phenyl thioethers compound prepared by the preparation method can be recovered into corresponding benzyl halide by introducing halogen and other methods, the recovery rate is 72.9%, and the reagent production cost is greatly reduced.

In order to achieve the aim, the technical scheme provided by the invention is that the preparation method of α -amino-gamma-butyrolactone and salts thereof comprises the following steps of reacting methionine and a benzyl halide reagent in an organic solution to obtain α -amino-gamma-butyrolactone and salts thereof, wherein the reaction temperature is 35-120 ℃, and preferably 65-95 ℃.

The organic solution is a mixed solution of 33% of alcohol solvent or ether solvent or acidic solvent or nitrogen-containing solvent and 66% of water. The ether solvent is tetrahydrofuran, 1, 2-dimethoxyethane, diethylene glycol dimethyl ether, 1, 4-dioxane, 1, 3-dioxolane and/or dioxane. The acidic solvent is formic acid, acetic acid, propionic acid and/or lactic acid. The nitrogen-containing solvent is acetonitrile and/or N, N dimethylformamide. The alcohol solvent is methanol.

The benzyl halide reagent is benzyl chloride and/or benzyl bromide and a benzene ring substituted derivative thereof.

The methionine is any one of a mixture of D bodies and L bodies of racemes and the L bodies and the D bodies.

The dosage of the benzyl halide reagent is 0.5-2.0 times of the molar equivalent of methionine; preferably 0.9 to 1.3 times the molar equivalent.

The amount of the organic solution is 5-50 times of equivalent weight of the methionine, preferably 5-10 times of equivalent weight.

The following will give a supplementary explanation of the isolation of α -amino- γ -butyrolactone as a salt, but the resulting salt may also be decomposed, for example with a base or the like, to give free α -amino- γ -butyrolactone:

in addition, α -amino- γ -butyrolactone and homoserine may be present in the reaction mixture as an equilibrium mixture, and in this case, as described later, α -amino- γ -butyrolactone salt is crystallized, and the salt is precipitated out of the reaction system to shift the equilibrium, whereby α -amino- γ -butyrolactone can be obtained in a good yield.

When optically active α -amino- γ -butyrolactone and its salts are produced using optically active methionine as a raw material, α -amino- γ -butyrolactone and its salts having high optical purity can be produced by setting the pH of the reaction mixture to weakly acidic and causing little isomerization and hydrolysis reaction of α -amino- γ -butyrolactone and its salts to homoserine, the pH is 1 to 7, preferably 3 to 6, and the pH can be adjusted by adding acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, and the like.

In order to accelerate the two-phase reaction, a reaction promoter may also be added in an amount of two-phase catalyst. The reaction accelerator may be tetrabutylammonium bromide, tetrapropylammonium bromide, etc. The amount of the reaction accelerator to be used may be any amount, and is preferably 0.001 to 0.5 times by weight, more preferably 0.01 to 0.1 times by weight, based on the weight of methionine.

After the reaction is completed, the reaction mixture is washed with a hydrophobic solvent and then treated. The hydrophobic solvent is ethyl acetate, methyl tert-butyl ether, diethyl ether, etc., preferably ethyl acetate. The cleaning temperature is 0-70 ℃, preferably 5-35 ℃.

In addition, when the crystallization of the salt is subsequently performed, it is preferable to distill off water before or after the washing step, since the yield of the crystals is higher as the amount of water contained in the reaction mixture is smaller.

α -amino- γ -butyrolactone salt is an acid addition salt, and the acid used is selected depending on the type of the salt, and includes inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and nitric acid, and organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, and succinic acid, and preferably hydrogen chloride and hydrogen bromide.

In the case of using hydrogen chloride or hydrogen bromide as one embodiment of the present invention, hydrogen chloride or hydrogen bromide may be added in a gaseous form or in the form of an aqueous solution. In order to increase the yield of the crystals, it is preferable to add the crystals as a gas. The amount of the acid used is preferably 1 to 10-fold molar equivalent, more preferably 1 to 3-fold molar equivalent, relative to the molar equivalent of methionine used. The temperature at which the acid is added is usually 0 to 100 ℃ and preferably 30 to 60 ℃. The temperature of the reaction mixture is cooled to 0 to 50 ℃, preferably 5 to 25 ℃, and crystals can be precipitated.

As an embodiment of the present invention, a clear aqueous organic solvent is added before cooling to precipitate crystals. The hydrophilic organic solvent is alcohol solvent such as methanol, ethanol, 2-propanol, etc., or ether solvent such as tetrahydrofuran, dioxane, etc., or ketone solvent such as acetone, etc.

The α -aminobutyrolactone salt obtained may be further subjected to washing treatment, and the washing solvent may be any organic solvent that is insoluble or poorly soluble in the salt, such as carboxylic acid solvents such as acetic acid and propionic acid, ether solvents such as tetrahydrofuran, 1, 2-dimethoxyethane, diglyme, 1, 4-dioxane, and 1, 3-dioxolane, pure solvents such as methanol, ethanol, 1-propanol, 2-methoxyethanol, 2-ethoxyethanol, 2-butanol, and tert-butanol, ketone solvents such as acetone, sulfur-containing solvents such as dimethyl sulfoxide and sulfolane, nitrogen-containing solvents such as acetonitrile, and the like.

The obtained crystals are filtered off with suction and dried by a conventional method, for example, under reduced pressure, to obtain α -amino- γ -butyrolactone salt.

In the present production method, when the amount of the water-miscible solvent such as an alcohol solvent used in the above reaction is small, particularly, the reaction mixture can be washed with a hydrophobic solvent as it is, and the salt of α -amino- γ -butyrolactone can be isolated as it is in a crystalline form by adding an acid to the reaction mixture, thereby improving the operability.

Compared with the prior art, the invention has the following advantages:

the invention aims to provide a preparation method of α -amino-gamma-butyrolactone and salts thereof, which has the advantages of mild reaction, simple operation and high yield (up to 78.6%), and meanwhile, the byproduct methyl phenyl thioethers compound prepared by the preparation method can be recovered into corresponding benzyl halide by introducing halogen and other methods, the recovery rate is 72.9%, and the reagent production cost is greatly reduced.

Detailed Description

The following claims are presented in further detail with reference to specific examples, but are not intended to limit the scope of the claims in any way.

Example 1

100g (0.67mol) of methionine, 200mL of water, 100mL of methanol, 8g of tetrabutylammonium bromide and 93.3g (0.737mol) of benzyl chloride are added to a reaction kettle, the mixture is stirred at 90 ℃ for 7 hours, the reaction mixture is cooled to 25 ℃ and then subjected to liquid separation, then the water layer is washed with ethyl acetate (200mL 2 times), the methyl phenyl methyl sulfide as a byproduct is separated, the water layer is distilled under reduced pressure and concentrated to about 120g, 37% hydrochloric acid (50mL) is added to the residue at about 50 ℃, the mixture is stirred at 90 ℃ for 2 hours, then the solvent is distilled off, the residue is cooled to 50 ℃ and then 100mL of glacial ethanol is added, the mixture is cooled to about 5 ℃ under stirring and is subjected to suction filtration, then the mixture is washed with 50mL of ethanol and dried under reduced pressure, and α -amino-gamma-butyrolactone hydrochloride as a white powder is obtained, the yield is 69.5%.

Example 2

100g (0.67mol) of methionine, 200mL of water, 100mL of methanol, 8g of tetrapropylammonium bromide and 126.5g (0.737mol) of p-nitrobenzyl chloride were added to a reaction kettle, the mixture was stirred at 90 ℃ for 7 hours, the reaction mixture was cooled to 25 ℃ and then subjected to liquid separation, the aqueous layer was washed with ethyl acetate (200mL × 2 times), the by-product methyl p-nitrobenzyl sulfide was separated, the aqueous layer was then concentrated to about 120g by distillation under reduced pressure, 37% hydrochloric acid (50mL) was added to the residue at about 50 ℃, the mixture was stirred at 90 ℃ for 2 hours and then the solvent was distilled off, the residue was cooled to 50 ℃ by adding 100mL of glacial ethanol, cooled to about 5 ℃ under stirring and subjected to suction filtration, then washed with 50mL of ethanol and dried under reduced pressure to obtain α -amino- γ -butyrolactone hydrochloride 72.4g of a white powdery solid, with a yield of 78.6%.

Example 3

100g (0.67mol) of methionine, 200mL of water, 100mL of methanol, 8g of tetrapropylammonium bromide and 131.9g (0.737mol) of 2-chloro-6-fluoro-benzylchloride were added to a reaction vessel, the reaction mixture was stirred at 90 ℃ for 7 hours, the reaction mixture was cooled to 25 ℃ and then subjected to liquid separation, then the aqueous layer was washed with ethyl acetate (200mL × 2 times), the by-product methyl 2-chloro-6-fluoro-benzylsulfide was separated, the aqueous layer was then subjected to vacuum distillation and concentrated to about 120g, 37% hydrochloric acid (50mL) was added to the residue at about 50 ℃ and stirred at 90 ℃ for 2 hours, the solvent was distilled off, the residue was cooled to 50 ℃ and 100mL of glacial ethanol was added, stirred, cooled to about 5 ℃ and then subjected to suction filtration, then washed with 50mL of ethanol and dried under reduced pressure to obtain α -amino- γ -butyrolactone hydrochloride as a white powder with a yield of 73.3%.

The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.

Claims

1. A process for producing α -amino-gamma-butyrolactone and its salts, characterized by comprising the step of reacting methionine with a benzylic halogen reagent in an organic solvent to obtain α -amino-gamma-butyrolactone and its salts.

2. The method of α -aminojy-butyrolactone and its salts according to claim 1, wherein said organic solution is a mixed solution of 33% alcohol solvent or ether solvent or acidic solvent or nitrogen-containing solvent with 66% water.

3. The method of claim 2 for preparing α -amino- γ -butyrolactone and salts thereof, wherein the ethereal solvent is tetrahydrofuran, 1, 2-dimethoxyethane, diethylene glycol dimethyl ether, 1, 4-dioxane, 1, 3-dioxolane and/or dioxane.

4. The process for the preparation of α -aminojy-butyrolactone and salts thereof according to claim 2, wherein said acidic solvent is formic acid, acetic acid, propionic acid and/or lactic acid.

5. The process for producing α -aminojy-butyrolactone and salts thereof according to claim 2, wherein the nitrogen-containing solvent is acetonitrile and/or N, N dimethylformamide.

6. The process for producing α -aminojy-butyrolactone and salts thereof according to claim 2, wherein said alcoholic solvent is methanol.

7. The process for the preparation of α -aminojy-butyrolactone and its salts according to claim 1, wherein the benzyl halide reagent is benzyl chloride and/or benzyl bromide and its benzene ring substituted derivatives.

8. The method of producing α -amino- γ -butyrolactone and its salts according to claim 1, wherein methionine is any one of a mixture of racemate D and L, L and D.

9. The method of α -aminojy-butyrolactone and salts thereof according to claim 1 or 7, wherein the amount of benzyl halide used is 0.5 to 2.0 times the molar equivalent of methionine.

10. The method of producing α -amino- γ -butyrolactone and salts thereof according to any of claims 1-6, wherein the amount of the organic solution used is 5 to 50 times the equivalent weight of the weight of methionine.