Refining technology for dextromethorphan bulk medicine

Abstract

The invention provides a refining technology for dextromethorphan. The refining technology comprises the following steps of dissolving a crude product into heptanes, heating to certain temperature, adding a 20% phenyltrimethylammonium hydroxide methanol solution, heating up, stirring at a heat preservation state, cooling, adding acid and alkali to regulate the pH value, stirring and filtering, washing, drying, adding a right amount of ethanol solution, recrystallizing, leaching and drying. The refining technology is high in yield and purity, and easy for mass production.

Description

technical field

[0001] The invention relates to a process for refining raw materials of antitussive drug dextromethorphan. Background technique

[0002] Dextromethorphan, also known as dextromethorphan (trade name dextromethorphan), is the dextro-isomer of morphine-like levomorphan methyl ether, which exerts a central antitussive effect by inhibiting the medullary cough center. Its antitussive strength is equal to or slightly stronger than that of codeine, and its drug resistance and addiction are low. It is a drug suitable for long-term use or high-dose use. The pharmacopoeias of various countries in the world have been recorded, and it is one of the important varieties that urgently need to be filled in clinical practice in my country.

[0003] At present, the synthesis process of dextromethorphan has been under research, and the main restriction factor is that its yield has been at a low level. The reason is that in the synthesis of dextromethorphan, the produced L-isom...

Examples

Embodiment 1

[0014] Dissolve 10 g of crude dextromethorphan in 250 ml of heptane, heat to 85-95 ° C, slowly add 50 ml of 20% trimethylphenylammonium hydroxide methanol solution under stirring, and the mixture of heptane and methanol is evaporated After adding the quaternary ammonium salt solution, raise the temperature to 100°C, keep stirring for 1.5 h, then cool the reaction solution to 70-75°C, and acidify it to pH=1-2 with 30% acetic acid, then add heptane The N, N-dimethylaniline generated by the reaction of alkanes and distilled off, the residual liquid is decolorized with an appropriate amount of activated carbon, filtered, the filtrate is stirred and added dropwise with NaOH solution to basify to pH = 9, and an oily substance is precipitated and gradually solidifies, continue Stir for 45 minutes, filter, wash with water, and dry to obtain pink dextromethorphan (dextromethorphan) crude product, add 250ml of 95% ethanol for recrystallization, and obtain 8.9g of crystals, the yield is 8...

Embodiment 2

[0016] Dissolve 10 g of crude dextromethorphan in 250 ml of heptane, heat to 85-95 ° C, slowly add 50 ml of 20% trimethylphenylammonium hydroxide methanol solution under stirring, and the mixture of heptane and methanol is evaporated After adding the quaternary ammonium salt solution, raise the temperature to 100°C, keep stirring for 3 hours, then cool the reaction liquid to 70-75°C, and acidify it to pH=1-2 with 30% acetic acid, then add heptane The N, N-dimethylaniline generated by the reaction of alkanes and distilled off, the residual liquid is decolorized with an appropriate amount of activated carbon, filtered, the filtrate is stirred and added dropwise with NaOH solution to basify to pH = 9, and an oily substance is precipitated and gradually solidifies, continue Stir for 45 minutes, filter, wash with water, and dry to obtain pink dextromethorphan (dextromethorphan) crude product, add 250ml of 95% ethanol for recrystallization, and obtain 8.5g of crystals, the yield is 8...

Embodiment 3

[0018] Dissolve 10 g of crude dextromethorphan in 250 ml of heptane, heat to 85-95 ° C, slowly add 20% trimethylphenylammonium hydroxide methanol solution 25 ml under stirring, the mixture of heptane and methanol is evaporated After adding the quaternary ammonium salt solution, raise the temperature to 100°C, keep stirring for 1.5 h, then cool the reaction solution to 70-75°C, and acidify it to pH=1-2 with 30% acetic acid, then add heptane The N, N-dimethylaniline generated by the reaction of alkanes and distilled off, the residual liquid is decolorized with an appropriate amount of activated carbon, filtered, the filtrate is stirred and added dropwise with NaOH solution to basify to pH = 9, and an oily substance is precipitated and gradually solidifies, continue Stir for 45 minutes, filter, wash with water, and dry to obtain pink dextromethorphan (dextromethorphan) crude product, add 250ml of 95% ethanol for recrystallization, and obtain 7.5g of crystals, the yield is 75%, and...

technical field

[0001] The invention relates to a process for refining raw materials of antitussive drug dextromethorphan. Background technique

[0002] Dextromethorphan, also known as dextromethorphan (trade name dextromethorphan), is the dextro-isomer of morphine-like levomorphan methyl ether, which exerts a central antitussive effect by inhibiting the medullary cough center. Its antitussive strength is equal to or slightly stronger than that of codeine, and its drug resistance and addiction are low. It is a drug suitable for long-term use or high-dose use. The pharmacopoeias of various countries in the world have been recorded, and it is one of the important varieties that urgently need to be filled in clinical practice in my country.

[0003] At present, the synthesis process of dextromethorphan has been under research, and the main restriction factor is that its yield has been at a low level. The reason is that in the synthesis of dextromethorphan, the produced L-isom...

Examples

Embodiment 1

[0014] Dissolve 10 g of crude dextromethorphan in 250 ml of heptane, heat to 85-95 ° C, slowly add 50 ml of 20% trimethylphenylammonium hydroxide methanol solution under stirring, and the mixture of heptane and methanol is evaporated After adding the quaternary ammonium salt solution, raise the temperature to 100°C, keep stirring for 1.5 h, then cool the reaction solution to 70-75°C, and acidify it to pH=1-2 with 30% acetic acid, then add heptane The N, N-dimethylaniline generated by the reaction of alkanes and distilled off, the residual liquid is decolorized with an appropriate amount of activated carbon, filtered, the filtrate is stirred and added dropwise with NaOH solution to basify to pH = 9, and an oily substance is precipitated and gradually solidifies, continue Stir for 45 minutes, filter, wash with water, and dry to obtain pink dextromethorphan (dextromethorphan) crude product, add 250ml of 95% ethanol for recrystallization, and obtain 8.9g of crystals, the yield is 8...

Embodiment 2

[0016] Dissolve 10 g of crude dextromethorphan in 250 ml of heptane, heat to 85-95 ° C, slowly add 50 ml of 20% trimethylphenylammonium hydroxide methanol solution under stirring, and the mixture of heptane and methanol is evaporated After adding the quaternary ammonium salt solution, raise the temperature to 100°C, keep stirring for 3 hours, then cool the reaction liquid to 70-75°C, and acidify it to pH=1-2 with 30% acetic acid, then add heptane The N, N-dimethylaniline generated by the reaction of alkanes and distilled off, the residual liquid is decolorized with an appropriate amount of activated carbon, filtered, the filtrate is stirred and added dropwise with NaOH solution to basify to pH = 9, and an oily substance is precipitated and gradually solidifies, continue Stir for 45 minutes, filter, wash with water, and dry to obtain pink dextromethorphan (dextromethorphan) crude product, add 250ml of 95% ethanol for recrystallization, and obtain 8.5g of crystals, the yield is 8...

Embodiment 3

[0018] Dissolve 10 g of crude dextromethorphan in 250 ml of heptane, heat to 85-95 ° C, slowly add 20% trimethylphenylammonium hydroxide methanol solution 25 ml under stirring, the mixture of heptane and methanol is evaporated After adding the quaternary ammonium salt solution, raise the temperature to 100°C, keep stirring for 1.5 h, then cool the reaction solution to 70-75°C, and acidify it to pH=1-2 with 30% acetic acid, then add heptane The N, N-dimethylaniline generated by the reaction of alkanes and distilled off, the residual liquid is decolorized with an appropriate amount of activated carbon, filtered, the filtrate is stirred and added dropwise with NaOH solution to basify to pH = 9, and an oily substance is precipitated and gradually solidifies, continue Stir for 45 minutes, filter, wash with water, and dry to obtain pink dextromethorphan (dextromethorphan) crude product, add 250ml of 95% ethanol for recrystallization, and obtain 7.5g of crystals, the yield is 75%, and...