Preparation method for R-(+)-alpha-phenylethylamine salt and R-(+)-alpha-phenylethylamine

A technology of dextrophenylethylamine salt and phenethylamine salt, which is applied in the field of compound preparation, can solve the problems of short resolution and crystallization time, less solvent consumption, and large solvent consumption, and achieve short resolution and crystallization time and mild reaction conditions , The effect of cheap resolving agent

Active Publication Date: 2015-08-26
NORTHEAST PHARMA GRP
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The object of the present invention is to provide a kind of preparation method of D-phenylethylamine salt and D-phenylethylamine, the waste water that the method of this invention produces is little, and single-pass resolution yield is high, and solvent consumption is few, resolution crystallization time is short, High optical purity (e.e. more than 98%), high recovery rate of resolving agent, mild reaction conditions, convenient operation, low cost, recyclable resolving agent, suitable for industrialization, and solve the problem of splitting DSPA into right In the phenethylamine process, there are many auxiliary raw materials, more waste water, large solvent consumption, low single-pass resolution yield, long resolution and crystallization time, low optical purity of the product, and high production cost.

Method used

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  • Preparation method for R-(+)-alpha-phenylethylamine salt and R-(+)-alpha-phenylethylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] In a 5000 ml four-necked bottle, put N-p-nitrobenzoyl-L-glutamic acid (1588 g, 5.05 mol after drying, the resolving agent can be recovered), add 2500 ml of acetone, stir mechanically, Raise the temperature to 54°C, add dicyclophenethylamine (612g, 5.05 mol, 1.0eqv.) dropwise over 30 minutes, keep stirring for 45 minutes to carry out the salt formation reaction, cool to -5°C, and keep cold for 1 hour until the crystallization is complete, and white precipitates Solid (D-phenethylamine salt), filtered, washed with 800 grams of acetone at 0°C, and dried at 60°C to obtain 899 grams of D-phenethylamine salt, the yield of D-phenethylamine salt was 85.3%, m.p. 128.1- 129.5 oC . D-phenethylamine / L-phenethylamine=99.05% / 0.95% (HPLC area ratio) in D-phenethylamine salt. Put D-phenethylamine salt into a 2000 ml four-necked bottle, add 600 grams of water, neutralize to pH 11 with 40% sodium hydroxide, separate the organic layer (upper layer), and extract the aqueous layer twice ...

Embodiment 2

[0023] In a 5000 ml four-necked bottle, put N-p-nitrobenzoyl-L-glutamic acid (1588g, 5.05mol, available resolving agent), add 2500 ml of acetone, stir mechanically, and heat up to 54 ℃, drop vortex phenethylamine (673g, 5.55 mol, 1.1eqv.) in 30 minutes, keep stirring for 45 minutes to carry out salt formation reaction, cool to -5 ℃, keep cold for 1 hour until the crystallization is complete, and a white solid (right phenethylamine salt), filtered, washed with 800 grams of acetone at 0°C, and dried at 60°C to obtain 939.4 grams of dextrophenethylamine salt, the yield of dextrophenethylamine salt was 81.1%, m.p. 128.1-129.4 oC . D-phenethylamine / L-phenethylamine = 98.8% / 1.2% in D-phenethylamine salt.

Embodiment 3

[0025]In a 5000 ml four-necked bottle, put N-p-nitrobenzoyl-L-glutamic acid (1588g, 5.05mol, available resolving agent), add 2500 ml of acetone, stir mechanically, and heat up to 54 ℃, drop vortex phenethylamine (796g, 6.57 mol, 1.3eqv.) in 30 minutes, keep stirring for 45 minutes to carry out the salt formation reaction, cool to -5 ℃, keep cold for 1 hour until the crystallization is complete, and a white solid (right phenethylamine salt), filtered, washed with 800 grams of acetone at 0°C, and dried at 60°C to obtain 1072.3 grams of dextrophenethylamine salt, the yield of dextrophenethylamine salt was 78.2%, m.p. 128.0-129.4 oC . D-phenethylamine / L-phenethylamine = 98.8% / 1.2% in D-phenethylamine salt.

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Abstract

The invention provides a preparation method for R-(+)-alpha-phenylethylamine salt and R-(+)-alpha-phenylethylamine. The preparation method comprises a step of subjecting DL-alpha-phenylethylamine and a resolving agent to a salt formation reaction in a reaction solvent, wherein the resolving agent is one selected from the group consisting of N-p-nitrobenzoyl-L-glutamic acid, L-glutamic acid and gulonic acid, the reaction solvent is one or more selected from the group consisting of acetone and ethanol, the salt formation reaction is to add the resolving agent into the reaction solvent, then add DL-alpha-phenylethylamine and carry out the reaction, DL-alpha-phenylethylamine is added drop by drop for 20 to 40 min, the ethanol is 95% ethanol, and a ratio of the volume of the reaction solvent to the mass of DL-alpha-phenylethylamine is 2-8: 1, preferably 3-5: 1. The method is finished in only one step, does not need refining, produces little waste water, has high yield, enables high-optical purity R-(+)-alpha-phenylethylamine salt and R-(+)-alpha-phenylethylamine to be obtained, uses commercially available reagents and raw materials and is applicable to industrialization.

Description

technical field [0001] The invention relates to a d-phenethylamine salt and a preparation method of d-phenethylamine in the field of compound preparation. Background technique [0002] Phenylethylamine (α-Phenylethylamine), the molecular formula is C 8 h 11 N, the molecular weight is 121.18, and the structural formula is: [0003] [0004] It is a colorless liquid. There is an asymmetric carbon atom in the molecule, there are R and S chiral isomers, and the optical rotations are dextrorotatory and levorotatory respectively under solvent-free conditions. They are important basic resolving agents. Among them, dextro(rotary) phenylethylamine is used For the resolution of fosfomycin, mandelic acid, levetiracetam, pregabalin, etc., and for the resolution of ibuprofen, etc. [0005] At present, the global market for dexphenethylamine is about 1800 tons per year, while the market for left-phenylethylamine is only about 300 tons per year, so it is particularly important to sp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/27C07C209/00C07C209/88
Inventor 刘琰张海宏胡勇男许良宋红军谢占武杨宗乾
Owner NORTHEAST PHARMA GRP
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