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A kind of synthesis method and application of impurity isomers of bupropion hydrochloride sustained-release tablets

A technology of bupropion hydrochloride and a synthesis method, applied in the field of chemical pharmacy, can solve problems such as unfavorable quality control of bupropion hydrochloride, achieve stereospecificity of chirality control, cheap and easily available reagents, and high reaction yield. Effect

Active Publication Date: 2019-05-24
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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  • A kind of synthesis method and application of impurity isomers of bupropion hydrochloride sustained-release tablets
  • A kind of synthesis method and application of impurity isomers of bupropion hydrochloride sustained-release tablets
  • A kind of synthesis method and application of impurity isomers of bupropion hydrochloride sustained-release tablets

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-neck bottle Methyl ester hydrochloride (compound I, 0.12 mol), stirred at room temperature to dissolve, 45.2 g of triphenylchloromethane (0.16 mol) was added, and reacted at 20-25°C for 48 hours. TLC monitors the complete conversion of raw materials. Add the reaction solution to 180mL 10% sodium acetate solution, stir to obtain a white viscous oil, remove the upper water layer, dissolve the white viscous oil with 200mL dichloromethane, add 40mL saturated sodium chloride solution to wash, divide Go to the water phase. The organic phase was concentrated under reduced pressure to obtain 42.7 g of yellow oil with a yield of 97.1%.

[0056] (2) Preparation of methyl (S)-2-(1-(3-chlorophenyl)-1-oxopropane-2-amino)-3-(tritylmercapto)propionate: 100mL single-neck bottle Add 16mL N,N-dimethylformamide, 10g (S)-2-amino-3-(tritylmercapto) methyl...

Embodiment 2

[0065] (1) Preparation of (S)-2-amino-3-(benzyloxycarbonylmercapto) methyl propionate: add 17.6g D-cysteine ​​methyl ester hydrochloride (compound I, 0.10mol) to a 500mL three-necked flask , 200mL1N NaHCO 3 Dissolve the solution, stir to clear, then add 100mL methyl tert-butyl ether, cool to 0℃, add 17.3g benzyl chloroformate (0.13mol) all at once, stir at 0℃ for 1h, slowly warm up to 10℃, at this temperature Stirring was continued for 1 h, filtered with suction, the filter cake was washed with water, then washed with acetone and methyl tert-butyl ether, and dried under vacuum to obtain 20.7 g of white solid with a yield of 75%.

[0066] (2) Preparation of methyl (S)-2-(1-(3-chlorophenyl)-1-oxopropane-2-amino)-3-(benzyloxycarbonylmercapto)propionate: in a 100mL single-neck bottle Add 16mL N,N-dimethylformamide, 10g (R)-2-amino-3-(benzyloxycarbonylmercapto) methyl propionate (37mmol), stir at room temperature to clear, add 6.7g triethylamine, and then Add 12.7g of 2-bromo-1-(3-ch...

Embodiment 3

[0071] (1) Preparation of (S)-2-amino-3-(benzylmercapto) methyl propionate: add 50 mL of dichloromethane, 20 mL of water, and 10 g of D-cysteine ​​methyl ester hydrochloride to a 250 mL single-mouth bottle (Compound I, 58mmol), 9.6g potassium carbonate, cooling in an ice bath, slowly add 12.2g benzyl bromide (71mmol), remove the ice bath, stir overnight at 35-40°C, separate the liquids, and extract the aqueous phase with dichloromethane 2 Next, the organic phase was washed by adding 20 mL of saturated sodium chloride solution, the aqueous 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 methyl (S)-2-(1-(3-chlorophenyl)-1-oxopropane-2-amino)-3-(benzylmercapto)propionate: add it to a 100mL single-necked bottle 16mL N,N-dimethylformamide, 10g (R)-2-amino-3-(benzylmercapto) methyl propionate (44mmol), stir to clear at room temperature, add 7.8g potassium carbonate, and ...

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PUM

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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, and in particular relates to an impurity (3S, 5S, 6S)-6-(3-chlorophenyl)-6-hydroxy-5-methylthio of bupropion hydrochloride sustained-release tablets 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, chemical name (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-acetone hydrochloride, It was successfully developed by Glaxo-Wellcome in the United Kingdom and was first marketed in the United States in 1989. The trade name is Zyban and Wellbutrin. Because of its good therapeutic effects and small side effects, it is widely used in depression, smoking addiction and many other During the treatment of the disease. [0003] (3S, 5S, 6S)-6-(3-chlorophenyl)-6-hydroxy-5-methylthiomorpholine-3-carboxylic acid (structure as shown in formula V) in bupropion hydrochlorid...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D279/12
CPCY02P20/55
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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