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Method for synthesizing impurity isomers of bupropion hydrochloride sustained-release tablets and application of impurity isomers

A technology of bupropion hydrochloride and its synthetic method, which is applied in the field of chemical pharmacy, can solve problems such as unfavorable quality control of bupropion hydrochloride, achieve chiral control stereospecificity, simple and efficient synthetic route, and improve accurate positioning and qualitative Effect

Active Publication Date: 2017-08-18
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there is no report on the preparation of these two impurities in the prior art, and even these two compounds have not been reported in the open literature, and their CAS numbers have not been registered, which is not conducive to the quality control of bupropion hydrochloride

Method used

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  • Method for synthesizing impurity isomers of bupropion hydrochloride sustained-release tablets and application of impurity isomers
  • Method for synthesizing impurity isomers of bupropion hydrochloride sustained-release tablets and application of impurity isomers
  • Method for synthesizing impurity isomers of bupropion hydrochloride sustained-release tablets and application of impurity isomers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055](1) Preparation of methyl (S)-2-amino-3-(tritylmercapto)propionate: Add 80mL N,N-dimethylformamide and 20g D-cysteine ​​to a 250mL single-necked bottle Methyl ester hydrochloride (compound I, 0.12 mol) was stirred at room temperature to dissolve, and 45.2 g of triphenylchloromethane (0.16 mol) was added, and reacted at 20-25°C for 48 hours. Complete conversion of starting material was monitored by TLC. Add the reaction solution to 180mL of 10% sodium acetate solution, stir to obtain a white viscous oil, remove the upper water layer, dissolve the white viscous oil with 200mL of dichloromethane, add 40mL of saturated sodium chloride solution to wash, divide Remove the aqueous phase. The organic phase was concentrated under reduced pressure to obtain 42.7 g of a yellow oil, with a yield of 97.1%.

[0056] (2) Preparation of (S)-2-(1-(3-chlorophenyl)-1-oxopropane-2-amino)-3-(tritylmercapto)propionic acid methyl ester: 100mL one-mouth bottle Add 16mL N,N-dimethylformamide,...

Embodiment 2

[0065] (1) Preparation of methyl (S)-2-amino-3-(benzyloxycarbonylmercapto)propionate: 17.6g of D-cysteine ​​methyl ester hydrochloride (compound I, 0.10mol) was added to a 500mL three-neck flask , 200mL 1N NaHCO 3 Solution, stir to dissolve, then add 100mL methyl tert-butyl ether, cool down to 0°C, add 17.3g benzyl chloroformate (0.13mol) at one time, stir at 0°C for 1h, slowly heat up to 10°C, at this temperature Stirring was continued for 1 h, filtered with suction, the filter cake was washed with water, then with acetone and methyl tert-butyl ether, and dried in vacuo to obtain 20.7 g of a white solid with a yield of 75%.

[0066] (2) Preparation of (S)-2-(1-(3-chlorophenyl)-1-oxopropane-2-amino)-3-(benzyloxycarbonylmercapto)propionic acid methyl ester: in a 100mL single-necked bottle Add 16mL N,N-dimethylformamide, 10g (R)-2-amino-3-(benzyloxycarbonylmercapto) propionate methyl ester (37mmol), stir at room temperature to dissolve, add 6.7g triethylamine, and then Add 12....

Embodiment 3

[0071](1) Preparation of (S)-2-amino-3-(benzylmercapto)propionic acid methyl ester: add 50mL dichloromethane, 20mL water, 10g D-cysteine ​​methyl ester hydrochloride to a 250mL single-necked bottle (Compound I, 58mmol), 9.6g of potassium carbonate, cooled in an ice bath, slowly added 12.2g of benzyl bromide (71mmol), removed from the ice bath, stirred overnight at 35-40°C, separated the layers, and extracted the aqueous phase with dichloromethane for 2 Once, the organic phase was washed by adding 20 mL of saturated sodium chloride solution, the water phase was separated, and the organic phase was concentrated under reduced pressure to obtain 11.2 g of yellow oil, with a yield of 85.3%.

[0072] (2) Preparation of (S)-2-(1-(3-chlorophenyl)-1-oxopropane-2-amino)-3-(benzylmercapto)propionic acid methyl ester: add 16mL N,N-dimethylformamide, 10g (R)-2-amino-3-(benzylmercapto) propionate methyl ester (44mmol), stirred at room temperature to dissolve, add 7.8g potassium carbonate, t...

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Abstract

The invention discloses a method for synthesizing impurity enantiomers of bupropion hydrochloride, and belongs to the field of pharmaceutical and chemical engineering. The method includes carrying out mercapto protection, condensation and de-protection cyclization consecutive reaction on D-cysteine methyl ester hydrochloride (a compound I) which is used as a starting material; separating and hydrolyzing isomers by means of column chromatography to obtain (3S, 5S, 6S)-6-(3-chlorphenyl)-6-hydroxyl-5-methyl thiomorpholine-3-carboxylic acid and (3S, 5R, 6R)-6-(3-chlorphenyl)-6-hydroxyl-5-methyl thiomorpholine-3-carboxylic acid. The method has the advantages of concise and efficient synthetic route, stereospecific chiral control, high reaction yield and inexpensive and easily available materials, solvents and reagents. Besides, the impurity enantiomers can be used for controlling the quality of bupropion hydrochloride sustained-release tablets or can be used as impurity reference substances.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, in particular to a kind of impurity (3S, 5S, 6S)-6-(3-chlorophenyl)-6-hydroxyl-5-methylthio Synthesis of morpholine-3-carboxylic acid and (3S,5R,6R)-6-(3-chlorophenyl)-6-hydroxy-5-methylthiomorpholine-3-carboxylic acid. Background technique [0002] Bupropion Hydrochloride (Bupropion Hydrochloride), chemical name (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride, It was successfully developed by the British company Glaxo-Wellcome and first listed in the United States in 1989. The trade name is Zyban and Wellbutrin. Due to its good therapeutic effect and small side effects, it is widely used in depression, smoking addiction and other diseases. in the treatment of diseases. [0003] (3S, 5S, 6S)-6-(3-chlorophenyl)-6-hydroxyl-5-methylthiomorpholine-3-carboxylic acid (structure as shown in formula V) in bupropion hydrochloride sustained-release tablets Shown) ...

Claims

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Application Information

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IPC IPC(8): C07D279/12
CPCY02P20/55C07D279/12C07B2200/07
Inventor 庄程翰李常青邱建华周雄飞王磊李大臣
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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