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Preparation method of (1r, 2s)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol

A pyrrolidinyl and phenyl technology, applied in the field of medicine, can solve the problems such as non-racemization of dextro-norephedrine, high reaction safety risk, low recovery rate of a resolving agent, etc., and achieves low cost, easy availability of raw materials, Easy to recycle effect

Active Publication Date: 2018-05-11
CHIFENG ARKER PHAMACEUTICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Process 1 uses propiophenone as the starting material, uses Raney nickel as the catalyst for hydrogenation, and the reaction pressure is 0.8 MPa. The reaction is violently exothermic, the yield is low, and the waste water produced is not easy to handle. Racemization, low recovery rate of resolving agent and high cost
[0010] Process 2 uses bromopropiophenone as the starting material, and the yield of L-phenethylaminopropiophenone generated by reacting with L-phenylethylamine is only 40%. The hydrogenation reaction pressure is 3-4MPa, and the reaction temperature is 80-90°C. High security risk and high cost

Method used

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  • Preparation method of (1r, 2s)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol
  • Preparation method of (1r, 2s)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol
  • Preparation method of (1r, 2s)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol

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Effect test

Embodiment 1

[0031] Embodiment 1: a kind of preparation method of (1R, 2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol, it comprises resolution, racemization, reduction three steps:

[0032] (1) Resolution: Put 100g of DL-1-phenyl-2-(1-pyrrolidinyl)-1-propanone, 92.6g of L-(-)-dibenzoyl tartaric acid, and 500ml of acetonitrile into a 1000ml three-hole circle In a bottom flask, heat to 60°C with stirring, add 100ml of water dropwise, keep warm at 60°C for 1 hour, cool down to 40°C and add seed crystals, keep warm at 15-20°C for 5 hours, filter with suction, wash with acetonitrile, and dry to obtain L-1- 127 g of phenyl-2-(1-pyrrolidinyl)-1-propanone-L-(-)-dibenzoyl tartrate, the yield was 44.5%, and the mother liquor was used for racemization.

[0033] (2) Racemization: Distill the above mother liquor out of acetonitrile under reduced pressure, add 100ml of water and 100ml of ethyl acetate, add dropwise hydrochloric acid until the pH value is 2-3, let stand to separate layers, and extract the wa...

Embodiment 2

[0035] Embodiment 2: a kind of preparation method of (1R, 2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol, it comprises resolution, racemization, reduction three steps:

[0036] (1) Resolution: Put 100g of DL-1-phenyl-2-(1-pyrrolidinyl)-1-acetone, 71.6g of D-(-)-tartaric acid, and 350ml of isopropanol into a 1000ml three-neck round bottom flask , heated to 50°C with stirring, added dropwise 50ml of water, kept at 50°C for 1 hour, then cooled to below 10°C, filtered with suction, washed with isopropanol, and dried to obtain L-1-phenyl-2-(1-pyrrole Alkyl)-1-propanone-D-(-)-tartrate 68.7g, the yield is 39.5%, and the mother liquor is used for racemization.

[0037] (2) Racemization: Distill the above mother liquor to remove isopropanol under reduced pressure, add 100ml of water, add ammonia water until the pH value is 11, add ethyl acetate for extraction three times, recover D-(-)-tartaric acid from the water layer, and combine ethyl acetate Add 80ml of water to the ester layer, add ...

Embodiment 3

[0039] Embodiment 3: a kind of preparation method of (1R, 2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol, it comprises resolution, racemization, reduction three steps:

[0040](1) Resolution: put 100g of DL-1-phenyl-2-(1-pyrrolidinyl)-1-propanone, 44.9g of D-(-)-mandelic acid, and 400ml of acetone into a 1000ml three-neck round bottom flask , heated to 50°C with stirring, added dropwise 75ml of water, kept at 50°C for 1 hour, then cooled to below 10°C, filtered with suction, washed with acetone, and dried to obtain L-1-phenyl-2-(1-pyrrolidinyl) - 63.4 g of 1-acetone-D-(-)-mandelic acid, the yield is 36.3%, and the mother liquor is used for racemization.

[0041] (2) Racemization: evaporate the acetone from the above mother liquor under reduced pressure, add 100ml of water, add hydrochloric acid until the pH value is 2, cool to 0°C, filter, wash with cold water to obtain mandelic acid, add sodium hydroxide solution to the filtrate to adjust the pH value 8.5, heated to 80°C, kept w...

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Abstract

The invention discloses a preparation method of (1R,2S)-1-phenyl-2-(1-pyrrolidyl)-1-propanol. According to the preparation method, DL-1-phenyl-2-(1-pyrrolidyl)-1-acetone is taken as a starting material and subjected to resolution, racemization and reduction, and (1R,2S)-1-phenyl-2-(1-pyrrolidyl)-1-propanol is prepared. The yield of one-time resolution is higher than 35%, a resolving agent is easy to recover, and the recovery rate is higher than 90%; the racemization process is performed under the slightly alkaline condition, and the racemization yield is higher; the yield of (1R,2S)-1-phenyl-2-(1-pyrrolidyl)-1-propanol obtained through reduction is higher than 85%. The preparation method has the advantages of mild reaction conditions, stable process, high product optical purity, low cost, high production safety and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of (1R, 2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol. Background technique [0002] Efavirenz (Efavirenz), developed and produced by Merck, is the first-line anti-AIDS (HIV) virus drug of choice. (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol is an intermediate in the production of efavirenz, and its structural formula is: [0003] [0004] There are two production processes for (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol: [0005] Process one: [0006] [0007] Process two: [0008] [0009] Process 1 uses propiophenone as the starting material, uses Raney nickel as the catalyst for hydrogenation, and the reaction pressure is 0.8 MPa. The reaction is violently exothermic, the yield is low, and the waste water produced is not easy to handle. Racemization, and the recovery rate of the resolving agent is low, and the cost is high. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/06
CPCC07B2200/07C07D207/06
Inventor 李渤崔宏鹏杨晓杰于志鹏聂鹏飞王资
Owner CHIFENG ARKER PHAMACEUTICAL TECH