Preparation method of vincristine sulfate

Abstract

The invention discloses a preparation method of vincristine sulfate. The preparation method comprises the following steps that vinblastine sulfate total alkali serves as a raw material and then dissociated and subjected to formylation and chromatographic purification to obtain high-content vinblastine and vincristine; oxidation is carried out, and salt is directly formed to obtain the vincristinesulfate. The process is simple to operate and easy in post-treatment, the purity of the salt-forming product can be 97% or above without refining, and the yield can reach 46-55%. The cost is greatly reduced, the production feasibility is achieved, and the economic value is high.

Description

technical field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a preparation method of vincristine sulfate. Background technique

[0002] Periwinkle is an important medicinal plant of the genus Apocynaceae, native to South Asia, East Africa and tropical America. It has been cultivated in Southwest, Central South and East China. Vinca contains a lot of valuable indole alkaloids, among which vinblastine and vincristine are anti-tumor drugs widely used in clinical practice, and have unique pharmacological activity, while vinblastine and ventolin are the synthesis of vinblastine drugs. Raw materials also have medicinal value. The research on the extraction and separation of vinblastine has a long history at home and abroad, because there are many types of alkaloids in the whole plant of periwinkle, and the content of vinblastine, vincristine and norvinblastine in the plant summary is very low, generally in 1 / 10,000 Recently, the pr...

Examples

preparation example Construction

[0030] Such as figure 1 Shown, a kind of preparation method of vincristine sulfate comprises:

[0031] The preparation steps of Changchun total alkaloids: take Changchun total alkaloid sulfate, dissolve it in water, adjust the pH value, then perform extraction, take the organic phase and concentrate to dryness, and obtain Changchun total alkaloid I;

[0032] Formylation reaction steps: take vinblast total alkaloid I, dissolve it in a mixture of formic acid and acetic anhydride, stir and react, add ice water, then adjust the pH value, stir evenly, extract with an organic solvent, obtain the extract and removing the water in the extract, and then recovering the solvent in the extract to obtain vinblastine II;

[0033]Purification steps: take Changchun total alkaloid II, dissolve it in an organic solvent, put it on the elution column (not to be reused), and elute with the first mixture of dichloromethane and methanol, and control the elution flow rate to 35-55mL / min (preferabl...

Embodiment 1

[0053] A preparation method of vincristine sulfate, comprising the following steps:

[0054] The preparation steps of Changchun total alkali: take 50g of Changchun total alkali sulfate, add 150ml of purified water to dissolve, dropwise add ammonia water, adjust the pH value to 9, then add 1000ml of dichloromethane to extract four times, combine the organic phases, and remove the supernatant , The lower organic phase was concentrated to dryness to obtain vinblastine total alkaloids I: 48.5g.

[0055] Formylation reaction step: Take the above-mentioned vinblast total alkaloid I: 48.5g, add (pre-cooled to 0-5°C) in the mixed solution of 48.5g formic acid and 24.5g acetic anhydride to dissolve, and stir at -5°C-0°C React for 60 minutes, then add 500ml of ice water, then slowly add reagent ammonia, adjust the pH to 7-9, stir well, extract with 2500ml of dichloromethane four times, combine the extracts, wash with purified water until the pH of the water layer Neutral, then add 100g...

Embodiment 2

[0064] A preparation method of vincristine sulfate, comprising the following steps:

[0065]The preparation steps of Changchun total alkali: take Changchun total alkali sulfate 50g, add 150ml purified water to dissolve, add dropwise sodium bicarbonate aqueous solution, adjust the pH value to 8, then add 1000ml dichloromethane to extract four times, combine the organic phase, remove For the supernatant, the lower organic phase was concentrated to dryness to obtain vinblastine I: 48.1 g.

[0066] Formylation reaction step: take the above-mentioned vinblast total alkaloid I: 48.1g, add (pre-cooled to 0-5°C) in the mixed solution of formic acid 48g and acetic anhydride 25g to dissolve, and stir and react at -5°C-0°C for 60 Minutes, then add 500ml ice water, then slowly add reagent ammonia water, adjust the pH value to 8, stir evenly, extract with 2500ml dichloromethane four times, combine the extracts, wash with purified water until the pH value of the water layer is neutral, The...

technical field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a preparation method of vincristine sulfate. Background technique

[0002] Periwinkle is an important medicinal plant of the genus Apocynaceae, native to South Asia, East Africa and tropical America. It has been cultivated in Southwest, Central South and East China. Vinca contains a lot of valuable indole alkaloids, among which vinblastine and vincristine are anti-tumor drugs widely used in clinical practice, and have unique pharmacological activity, while vinblastine and ventolin are the synthesis of vinblastine drugs. Raw materials also have medicinal value. The research on the extraction and separation of vinblastine has a long history at home and abroad, because there are many types of alkaloids in the whole plant of periwinkle, and the content of vinblastine, vincristine and norvinblastine in the plant summary is very low, generally in 1 / 10,000 Recently, the pr...

Examples

preparation example Construction

[0030] Such as figure 1 Shown, a kind of preparation method of vincristine sulfate comprises:

[0031] The preparation steps of Changchun total alkaloids: take Changchun total alkaloid sulfate, dissolve it in water, adjust the pH value, then perform extraction, take the organic phase and concentrate to dryness, and obtain Changchun total alkaloid I;

[0032] Formylation reaction steps: take vinblast total alkaloid I, dissolve it in a mixture of formic acid and acetic anhydride, stir and react, add ice water, then adjust the pH value, stir evenly, extract with an organic solvent, obtain the extract and removing the water in the extract, and then recovering the solvent in the extract to obtain vinblastine II;

[0033]Purification steps: take Changchun total alkaloid II, dissolve it in an organic solvent, put it on the elution column (not to be reused), and elute with the first mixture of dichloromethane and methanol, and control the elution flow rate to 35-55mL / min (preferabl...

Embodiment 1

[0053] A preparation method of vincristine sulfate, comprising the following steps:

[0054] The preparation steps of Changchun total alkali: take 50g of Changchun total alkali sulfate, add 150ml of purified water to dissolve, dropwise add ammonia water, adjust the pH value to 9, then add 1000ml of dichloromethane to extract four times, combine the organic phases, and remove the supernatant , The lower organic phase was concentrated to dryness to obtain vinblastine total alkaloids I: 48.5g.

[0055] Formylation reaction step: Take the above-mentioned vinblast total alkaloid I: 48.5g, add (pre-cooled to 0-5°C) in the mixed solution of 48.5g formic acid and 24.5g acetic anhydride to dissolve, and stir at -5°C-0°C React for 60 minutes, then add 500ml of ice water, then slowly add reagent ammonia, adjust the pH to 7-9, stir well, extract with 2500ml of dichloromethane four times, combine the extracts, wash with purified water until the pH of the water layer Neutral, then add 100g...

Embodiment 2

[0064] A preparation method of vincristine sulfate, comprising the following steps:

[0065]The preparation steps of Changchun total alkali: take Changchun total alkali sulfate 50g, add 150ml purified water to dissolve, add dropwise sodium bicarbonate aqueous solution, adjust the pH value to 8, then add 1000ml dichloromethane to extract four times, combine the organic phase, remove For the supernatant, the lower organic phase was concentrated to dryness to obtain vinblastine I: 48.1 g.

[0066] Formylation reaction step: take the above-mentioned vinblast total alkaloid I: 48.1g, add (pre-cooled to 0-5°C) in the mixed solution of formic acid 48g and acetic anhydride 25g to dissolve, and stir and react at -5°C-0°C for 60 Minutes, then add 500ml ice water, then slowly add reagent ammonia water, adjust the pH value to 8, stir evenly, extract with 2500ml dichloromethane four times, combine the extracts, wash with purified water until the pH value of the water layer is neutral, The...

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