Preparation method of calcium folinate

A technology of calcium folinate and methylenetetrahydrofolate, which is applied in the direction of organic chemistry, can solve the problems of multiple impurities, high temperature, and easy production, and achieve the effect of reducing reaction temperature, shortening time, and improving quality

Pending Publication Date: 2022-06-07
JIHENG PHARMA HENGSHUI CITY
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Problems solved by technology

[0003] The traditional preparation method of calcium folinate is to use folic acid as the starting material, reduce it with sodium borohydride to form tetrahydrofolate, and then form tetrahydrofolate through formylation and salt formation with hydrochloric acid to obtain 5,10-methylenetetrahydrofolate Hydrochloride, then hydrolyzed and added calcium source to get calcium folinate; Among them, formic acid is used as the formylation reagent in the traditional process, and formic acid is both the formylation reagent and the reaction solvent, and the dosage is generally 10 to 15 times that of folic acid In the later stage of the reaction, the formic acid as the reaction solvent needs to be concentrated under reduced pressure to obtain 5,10-methylenetetrahydrofolate, and the reduced pressure concentration process temperature of formic acid is high, and the time is long, which is easy to produce more impurities

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

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[0039] The specific embodiment of the present invention provides a kind of preparation method of calcium folinate, comprising the following steps:

[0040] (1) Reduction of folic acid to tetrahydrofolic acid: first dissolve folic acid in an alkaline solution, then slowly add sodium borohydride solution, react at 60-90 °C for 1-3 hours, then cool down to 0-10 °C, and then use concentrated hydrochloric acid The pH is adjusted to 3-5 to obtain an off-white solid, which is filtered with suction to obtain a solid of tetrahydrofolic acid, and the molar ratio of the folic acid to sodium borohydride is 1:8-12.

[0041] (2) Formylation of tetrahydrofolate to obtain 5,10-methylenetetrahydrofolate hydrochloride: first dissolve tetrahydrofolate in an acidic solution, and then add methyl formate and tetrahydrofolate at 20-25°C. Hydrofolate was reacted for 1-2 hours, then the temperature was raised to 55-65°C, and formic acid and trifluoroacetic acid were added to continue the reaction for ...

Embodiment 1

[0045] Embodiment 1 A kind of preparation method of calcium folinate, comprising:

[0046] (1) reduction of folic acid to tetrahydrofolate: put 30g of folic acid and 200g of water into a 1000ml four-necked bottle, stir evenly, add 30g of 18% sodium hydroxide solution to completely dissolve the folic acid; then add 30g of sodium borohydride to 100g In water, stir evenly, slowly add it into the folic acid system with a constant pressure dropping funnel, then heat up to 60 °C, react for 2 h, then cool down to 0-10 °C, adjust the pH to 3-5 with concentrated hydrochloric acid, and obtain off-white solid, Suction filtration to obtain 32 g of solid tetrahydrofolate.

[0047] (2) Formylation of tetrahydrofolate to obtain 5,10-methylenetetrahydrofolate hydrochloride: add the solid tetrahydrofolate obtained in step 1 into 70 g of water, and adjust the pH to about 1 with dilute hydrochloric acid to completely dissolve , add 2.6 g of methyl formate (content ≥ 95%, density 0.974 g / mL), re...

Embodiment 2

[0050] Embodiment 2 A kind of preparation method of calcium folinate, comprising:

[0051] (1) reduction of folic acid to tetrahydrofolate: put 30g of folic acid and 200g of water into a 1000ml four-necked bottle, stir evenly, add 30g of 18% sodium hydroxide solution to completely dissolve the folic acid; then add 30g of sodium borohydride to 100g In water, stir evenly, slowly add it into the folic acid system with a constant pressure dropping funnel, then heat up to 60 °C, react for 2 h, then cool down to 0-10 °C, adjust the pH to 3-5 with concentrated hydrochloric acid, and obtain off-white solid, Suction filtration to obtain 33 g of solid tetrahydrofolate.

[0052] (2) Formylation of tetrahydrofolate to obtain 5,10-methylenetetrahydrofolate hydrochloride: add the solid tetrahydrofolate obtained in step 1 into 70 g of water, and adjust the pH to about 1 with dilute hydrochloric acid to completely dissolve , add 3.0 g of methyl formate (content ≥ 95%, density 0.974 g / mL), re...

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Abstract

The invention provides a preparation method of calcium folinate, which comprises the following steps: firstly, folic acid serving as a raw material is reduced to obtain a reduction product tetrahydrofolic acid, then the tetrahydrofolic acid is subjected to formylation reaction to obtain 5, 10-methylene tetrahydrofolic acid, the 5, 10-methylene tetrahydrofolic acid and hydrochloric acid are salified to obtain 5, 10-methylene tetrahydrofolic acid hydrochloride, and then the 5, 10-methylene tetrahydrofolic acid hydrochloride is added into the 5, 10-methylene tetrahydrofolic acid hydrochloride to obtain the calcium folinate. Hydrolyzing 1, 10-methylenetetrahydrofolic acid hydrochloride, and then generating calcium folinate with calcium salt; wherein in the process of obtaining the 5, 10-methylene tetrahydrofolic acid through formylation reaction of the tetrahydrofolic acid, methyl formate is added at low temperature to react with the tetrahydrofolic acid, then the temperature is increased, formic acid is added, and the reaction is continued; according to the method, the formylation reaction is carried out by adopting two formylation reagents, so that the reaction temperature is reduced, the use amount of formic acid is reduced, the vacuum concentration time is shortened, the purity of the intermediate 5, 10-methylenetetrahydrofolic acid is improved, and the quality of calcium folinate is further improved.

Description

technical field [0001] The invention belongs to the technical field of preparation of raw materials, and in particular relates to a preparation method of calcium folinate. Background technique [0002] Calcium folinate is an antidote for folic acid antagonist drugs, also known as calcium folinate, calcium folate, calcium aldehyde hydrogen folate, calcium leucovorin, and is yellowish white to yellow crystal or amorphous powder at room temperature, odorless, Soluble in water, almost insoluble in ethanol or ether, easily soluble in sodium hydroxide solution. Calcium folinate is a reduced formylation derivative of folic acid, and its function is similar to that of folic acid, which is the activated form of folic acid in the body. Mainly used as (1) antidote for methotrexate and methotrexate overdose; (2) anti-anemia drug; (3) as an adjuvant drug for colon and rectal cancer, combined with fluorouracil to prolong survival. [0003] The traditional preparation method of calcium f...

Claims

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Application Information

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IPC IPC(8): C07D475/04
CPCC07D475/04
Inventor 刘晓莲马宁宁杨藏军韩啸郝新庭王莉莉张晓灿张云李华支永强何晓晨马凤霞段广播王玉虎
Owner JIHENG PHARMA HENGSHUI CITY
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