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Preparation method of medicinal calcium folinate

A technology for calcium folinate and folic acid, which is applied in the field of preparation of medicinal calcium folinate, can solve the problems of high temperature and pH value, the yield and purity need to be improved, and the yield of calcium folinate is not high, etc. The effect of reducing impurities, improving yield and purity

Active Publication Date: 2012-04-04
HUZHOU ZHANWANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the catalyst lead nitrate and dimercaptoethanol are toxic, and if the above two remain in it, it will bring hidden dangers to the quality and safety of calcium folinate raw materials
Simultaneously the temperature and the pH value of cyclic compound acidification in traditional calcium folinate preparation are higher, unfavorable for the stability of acylation product leucovorin hydrochloride, thereby cause the yield of calcium folinate not high
[0004] British patent GB150372 discloses a preparation method of calcium folinate: mix methine tetrahydrofolate (dehydrated leucovorin), amino and water phase solvent, heat the mixture at pH 5-7, then add to In the water-soluble calcium salt of equimolar base tetrahydrofolate, calcium folinate is finally separated, and the yield and purity of the product prepared by this method all need to be improved

Method used

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  • Preparation method of medicinal calcium folinate
  • Preparation method of medicinal calcium folinate
  • Preparation method of medicinal calcium folinate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Put 10kg of water in the metering tank, put it into the hydrogenation kettle after metering, stir, add 1kg of folic acid, stir well, add catalyst zinc citrate 0.01kg, potassium borohydride 1kg, after adding potassium borohydride, the temperature is controlled at 45 ~50°C, stirring and reacting for 2-3 hours, adding 0.3 kg of disodium ethylenediaminetetraacetic acid, adjusting the pH of the feed solution to 4.2-4.5 with hydrochloric acid, and centrifuging to obtain tetrahydrofolate.

[0027] Put the obtained tetrahydrofolate into the acylation kettle, then add 7kg of formic acid and 1.5kg of trifluoroacetic acid, stir, react at a temperature of 60-70°C for 2 hours, recover formic acid by distillation, and centrifuge to obtain formyltetrahydrofolate hydrochloride .

[0028] Put the obtained formyl tetrahydrofolate hydrochloride into a hydrolysis kettle, then add 16kg of water, and hydrolyze at a temperature of 70-75°C and a pH of 7.5-8.0 for 2 hours. Add an appropriate a...

Embodiment 2

[0031] Put 10kg of water in the metering tank, put it into the hydrogenation kettle after metering, stir, add 1kg of folic acid, stir well, add catalyst zinc citrate 0.01kg, potassium borohydride 1kg, after adding potassium borohydride, the temperature is controlled at 45 ~50°C, stirring and reacting for 2-3 hours, adding 0.3 kg of disodium edetate, adjusting the pH of the feed solution to 4.2-4.5 with hydrochloric acid, and centrifuging to obtain tetrahydrofolate.

[0032] Put the obtained tetrahydrofolate into an acylation kettle, then add 6kg of formic acid and 1.1kg of trifluoroacetic acid, stir, react at a temperature of 55-60°C for 1.5 hours, recover formic acid by distillation, and centrifuge to obtain formyltetrahydrofolate hydrochloride .

[0033] Put the obtained formyl tetrahydrofolate hydrochloride into a hydrolysis kettle, then add 14kg of water, hydrolyze at a temperature of 65-70°C and a pH of 7.2-7.5 for 1.5 hours; add an appropriate amount of activated carbon ...

Embodiment 3

[0036] Put 8kg of water in the metering tank, put it into the hydrogenation kettle after metering, stir, add 1kg of folic acid, stir well, add catalyst zinc stearate 0.005kg, potassium borohydride 0.8kg, after adding potassium borohydride, the temperature is controlled at 40-45°C, stirring and reacting for 1-2 hours, adding 0.25-0.3 kg of organic amine carboxylate, adjusting the pH of the feed solution to 3-4 with hydrochloric acid, and centrifuging to obtain tetrahydrofolate;

[0037] Put the obtained tetrahydrofolate into the acylation kettle, then add 7kg of formic acid and 1.5kg of trifluoroacetic acid, stir, react at a temperature of 60-70°C for 2 hours, recover formic acid by distillation, and centrifuge to obtain formyltetrahydrofolate hydrochloride .

[0038] Put the obtained formyl tetrahydrofolate hydrochloride into a hydrolysis kettle, then add 19kg of water, and hydrolyze for 2.5 hours at a temperature of 75-80°C and a pH of 8.3-8.5; add an appropriate amount of ac...

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Abstract

The invention relates to the field of preparation of bulk pharmaceutical chemicals, in particular to a medicinal calcium folinate. The method comprises the following steps of: firstly reducing folic acid to generate tetrahydrofolic acid; then acylating tetrahydrofolic acid to generate leucovorin hydrochloride; and finally salifying leucovorin hydrochloride to generate calcium folinate. By the adoption of the method, the residual risk of toxic substances in medicines in the traditional process can be avoided completely; nontoxic organic acid zinc is used as a catalyst and nontoxic organic amine carboxylate servers as a reduzate and a protective group of aldehyde group, therefore the product is safer and the yield and purity of the product can be improved; a low-temperature and acidification condition is adopted in the method for keeping the leucovorin hydrochloride which serves as an intermediate stable, therefore the yield of the product can be improved, and impurities in the product can be reduced, and the yield of the finished calcium folinate product, based on calcium folinate, is improved to 30-38% from original 15-20%.

Description

technical field [0001] The invention relates to the field of preparation of crude drugs, in particular to a preparation method of medicinal calcium folinate. Background technique [0002] Calcium folinate is white or light yellow crystal or amorphous powder. It is used to relieve the toxic reaction caused by excessive aminopterate and methotrexate. It is also used to treat giant red blood cell anemia. It can also stimulate white blood cells to mature. Leukocytic anemia caused by various causes. [0003] The traditional method of preparing calcium folinate is to use folic acid under weakly alkaline conditions, use lead nitrate as a catalyst, and use it before acidification with hydrochloric acid, the reduction product undergoes formylation reaction and forms a ring before acidification and before the acidification product is formed into a salt. Dimercaptoethanol as a protective agent. Because the catalyst lead nitrate and dimercaptoethanol are toxic, and if the above two re...

Claims

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Application Information

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IPC IPC(8): C07D475/04
CPCY02P20/55
Inventor 潘继成王水根
Owner HUZHOU ZHANWANG PHARMA
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