A method for preparing high-purity calcium levofolinate

A technology of calcium levofolinate and methylenetetrahydrofolate, which is applied in skin diseases, bone diseases, antipyretics, etc., can solve the problems that are difficult to remove, difficult to achieve in industrial production conditions, and heating temperature affects the quality of intermediates and final products and other problems, to achieve the effect of reducing requirements, facilitating large-scale operation, and avoiding corrosive reagents

Inactive Publication Date: 2016-04-06
天津康鸿医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to distill out the formylation reagent at a lower temperature (<60°C), a vacuum of 0.095Mpa to 0.1Mpa is required, which is difficult to achieve under general industrial production conditions, and increasing the heating temperature will inevitably affect the quality of intermediates and final products
[0021] In the ring-opening step, since 5,10-methylenetetrahydrofolate is easy to generate 10-formyltetrahydrofolate under alkaline conditions (a kinetically controlled process, see reference [7]), according to published information, Adjusting the pH value of the ring-opening system with a strong alkaline solution on a production scale can easily cause local pH to be too high and generate by-products of 10-position formylation. Since the solubility of such impurities is lower than that of calcium levofolinate, the resolution process is often Precipitate together with the main product, difficult to remove

Method used

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  • A method for preparing high-purity calcium levofolinate
  • A method for preparing high-purity calcium levofolinate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] 1) Weigh 300g of folic acid, add 2.7L of distilled water, and stir; adjust the pH value of the reaction system to 8.0 with NaOH solution, and inject N 2 For protection, add 200g of NaBH 4 solid, and adjust the pH value to 3.0 with hydrochloric acid, precipitate tetrahydrofolic acid solid, filter; add the filtered solid to 300mL formic acid, after stirring and dissolving, add 6mL of trifluoroacetic acid as a catalyst, at 10°C-30°C Place it at room temperature for 14 hours; then add 75mL, 6mol / L hydrochloric acid to the system to precipitate the formylation intermediate - 5,10-methylenetetrahydrofolate hydrochloride;

[0066] 2) Redissolve 150g of the precipitated 5,10-methylenetetrahydrofolate hydrochloride in 300mL of formic acid, stir and dissolve, then add 75mL of 6mol / L hydrochloric acid, at a temperature of 10°C-30°C (room temperature), the refined product of 5,10-methylenetetrahydrofolate hydrochloride was precipitated, and the detected specific rotation was +24°;...

Embodiment 2

[0070] 1) Weigh 1.0kg of folic acid, add 9.0L of distilled water, and stir; use NaOH solution to adjust the pH value of the reaction system to 8.0, and inject N 2 For protection, add 1.0kgNaBH 4solid, and adjust the pH value to 3.0 with hydrochloric acid, precipitate tetrahydrofolic acid solid, filter; add the filtered solid to 5L formic acid, stir and dissolve, add 200mL of trifluoroacetic acid as a catalyst, at 10°C-30°C Place it at room temperature for 24 hours; then add 12.5 L, 0.5 mol / L hydrochloric acid to the system to precipitate the formylation intermediate - 5,10-methylenetetrahydrofolate hydrochloride;

[0071] 2) Redissolve 300g of the precipitated 5,10-methylenetetrahydrofolate hydrochloride in 1.5L of formic acid, stir to dissolve, add 3.75L, 1mol / L hydrochloric acid, at a temperature of 10°C-30°C (room temperature), the refined product of 5,10-methylenetetrahydrofolate hydrochloride was precipitated, and the detected specific rotation was +18°;

[0072] 3) Add...

Embodiment 3

[0075] 1) Weigh 2.5kg of folic acid, add 25L of distilled water, and stir; use NaOH solution to adjust the pH value of the reaction system to 7.5, and inject N 2 For protection, add 2.5kg of NaBH 4 solid, and adjust the pH value to 3.0 with hydrochloric acid, precipitate tetrahydrofolic acid solid, filter; add the filtered solid to 10L formic acid, stir and dissolve, add 200mL trifluoroacetic acid as a catalyst; After standing at room temperature for 10 hours, add 7.5L of 2mol / L hydrochloric acid to formic acid to precipitate the formylation intermediate - 5,10-methylenetetrahydrofolate hydrochloride;

[0076] 2) Redissolve 700g of the precipitated 5,10-methylenetetrahydrofolate hydrochloride in 2.1L formic acid, stir and dissolve, then add 2.1L, 2mol / L hydrochloric acid, Placed at room temperature, the refined product of 5,10-methylenetetrahydrofolate hydrochloride was precipitated, and the detected specific rotation was +26°;

[0077] 3) Add 500g of the refined product of ...

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Abstract

The invention provides a preparation method for high purity L-calcium levofolinate. With folic acid as a starting raw material, the method relates to reduction, formylation, intermediate recrystallization splitting, hydrolysis ring opening, recrystallization refining and other steps. The L-calcium levofolinate prepared by the invention has a color ranging from white to light yellow, optical purity of not less than 98.5%, in related substance inspection, the total impurities are not greater than 1% and a single impurity is not greater than 0.3%. The preparation method for high purity L-calcium levofolinate provided by the invention has the advantages of simple operation, short process period and high product quality, and can be used for industrialized production of related bulk drugs by drug production enterprises.

Description

technical field [0001] The invention belongs to the field of synthesis of chemical raw materials, in particular to a method for preparing high-purity calcium levofolinate. Background technique [0002] Calcium Levofolinate (L-Calcium Levofolinate), the molecular formula is C 20 h 21 CaN 7 o 7 , molecular weight 511.5, CASNo.: 80433-71-2. Chemical name: (-)-N-[4-[[[(6S)-2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6- Pteridyl] methyl] amino] benzoyl] -L-glutamic acid calcium salt, its structural formula is as follows: [0003] [0004] Leucovorin calcium is the calcium salt of leucovorin, which is the pharmacologically active L-optical isomer of 5-formyltetrahydrofolate (leucovorin). Leucovorin does not need to be reduced by dihydrofolate reductase to participate in the reaction using folate as a source of one-carbon units, and it can pass through the cell membrane actively or passively. The basic function of folinic acid is the same as that of folic acid, but the e...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D475/04A61P37/02A61P17/06A61P19/02A61P29/00
CPCC07D475/04
Inventor 邹美香李祎亮孙歆慧单淇刘钫石玉郭建锋侯文彬周福军华洁
Owner 天津康鸿医药科技发展有限公司
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