Preparation method of calcium levofolinate impurity and impurity calcium salt

A technology for calcium levofolinate and impurities, applied in the field of chemical pharmacy, can solve the problems of low purity of 10-formyl dihydrofolate, etc., and achieve the effects of low equipment requirements, simple process and high calibration content

Active Publication Date: 2019-09-13
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The prior art has its own advantages and disadvantages for the preparation methods of 10-formyl dihydrofolate. For example, in the patent US4148999, the calcium levofolinate intermediate 5,10-methine-6(R)-tetrahydrofolate is used The acid salt is reacted in an aqueous s

Method used

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  • Preparation method of calcium levofolinate impurity and impurity calcium salt
  • Preparation method of calcium levofolinate impurity and impurity calcium salt
  • Preparation method of calcium levofolinate impurity and impurity calcium salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Dissolve 10g (22.7mmol) of folic acid in 200ml of water, adjust the pH of the reaction solution to 8.5 with aqueous sodium hydroxide solution, stir to dissolve, add 17.2g (90.7mmol) of sodium metabisulfite, heat up to 30°C and keep it for 2 hours, then cool down to 0°C At ~5°C, add hydrochloric acid dropwise, adjust the pH of the reaction solution to 0.5, keep warm at 0°C-5°C for 24 hours, filter, and dry under reduced pressure at 50°C to obtain 8.6 g of dihydrofolic acid, with a yield of 79.6%.

[0034] Dissolve 8.6g (19.4mmol) of dihydrofolate in 104g of formic acid, keep it warm at 25°C and react for 30 hours. After the reaction is complete, distill the formic acid under reduced pressure at 50°C, add 86ml of purified water, stir and crystallize, filter, and dry at 50°C , to obtain 7.0 g of 10-formyl dihydrofolate, with a yield of 83.1%.

Embodiment 2

[0036] Dissolve 8.6g (19.4mmol) of dihydrofolate in 104g of formic acid, keep warm at 25°C and react for 30h. After the reaction is complete, distill the formic acid under reduced pressure at 50°C, add 86ml of purified water, stir and crystallize, and filter to obtain 10- Formyl dihydrofolate. Dissolve 10-formyl dihydrofolic acid in 86ml of purified water, adjust the pH of the solution to 7.0 with aqueous sodium hydroxide solution, add 1.1g (9.7mmol) of calcium chloride, react at room temperature for 1 hour, filter, and dry under pressure at 50°C to obtain 6.3g calcium 10-formyl dihydrofolate, yield 67.7%.

Embodiment 3

[0038] Dissolve 15g (34.0mmol) of folic acid in 300ml of water, adjust the pH of the reaction solution to 8.0 with aqueous potassium hydroxide solution, stir to dissolve, add 21.2g (204mmol) of sodium bisulfite, heat up to 40°C for 2 hours, and cool down to 0 ℃~5℃, add hydrochloric acid dropwise, adjust the pH of the reaction solution to 0.8, keep warm at 0℃~5℃ for 24 hours, filter, and dry under reduced pressure at 50℃ to obtain 10.7g of dihydrofolic acid with a yield of 71.0%.

[0039] Dissolve 10.7g (24.2mmol) of dihydrofolate in 257g of formic acid, keep warm at 40°C and react for 24h. After the reaction is complete, distill the formic acid under reduced pressure at 50°C, add 107ml of purified water, stir and crystallize, filter, and depressurize at 50°C After drying, 8.6 g of 10-formyl dihydrofolate was obtained, with a yield of 81.6%.

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Abstract

Belonging to the field of chemical pharmacy, the invention relates to a preparation method of a standard drug impurity substance, in particular to the preparation method of a calcium levofolinate impurity and an impurity calcium salt. Firstly, the invention provides a preparation method of calcium levofolinate impurity, and the method includes: taking the compound folic acid shown as formula I asthe raw material for reaction with a reductant in an aqueous solution, and adjusting the pH value of the reaction solution with an alkali aqueous solution and inorganic acid respectively to obtain thecompound dihydrofolic acid shown as formula II; and reacting the compound shown as II with formic acid, adding purified water, and performing stirring and filtering to obtain the compound 10-formyl dihydrofolate shown as formula III. The invention also provides a preparation method of 10-calcium formyl dihydrofolate, and the method includes: taking folic acid as the raw material, firstly preparing dihydrofolic acid, then reacting dihydrofolic acid with formic acid to obtain 10-formyl dihydrofolate, then adding a calcium salt, and carrying out reaction to obtain 10-calcium formyl dihydrofolate.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and relates to a preparation method of a drug impurity standard product, in particular to a preparation method of calcium levofolinate impurity and impurity calcium salt. Background technique [0002] Calcium levofolinate is a drug mainly used to treat symptoms related to folic acid antagonism after high-dose methotrexate treatment of osteosarcoma. It can also be used to treat giant cell anemia caused by folic acid deficiency. It can also be used in combination with fluorouracil to prolong Survival or remission of symptoms in patients with advanced colon cancer. [0003] In the European Pharmacopoeia, it is stipulated that the impurity of calcium levofolinate, that is, 10-formyl dihydrofolate should be quantitatively studied and included in the quality standard. The prior art has its own advantages and disadvantages for the preparation methods of 10-formyl dihydrofolate. For example, in the pate...

Claims

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Application Information

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IPC IPC(8): C07D475/04
CPCC07D475/04
Inventor 冉勇邓青均
Owner CHONGQING HUABANGSHENGKAI PHARM
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