Preparation method for high purity L-calcium levofolinate

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

Inactive Publication Date: 2014-09-17
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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  • Preparation method for high purity L-calcium levofolinate
  • Preparation method for high purity L-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 of the reaction system to 8.0 with NaOH solution, and pass in N 2 For protection, add 200g of NaBH 4 Use hydrochloric acid to adjust the pH value to 3.0 to precipitate tetrahydrofolate solid and filter; add the filtered solid to 300mL formic acid, after stirring to dissolve, add 6mL of trifluoroacetic acid as a catalyst, Place it at temperature (room temperature) for 14 hours; then add 75 mL, 6 mol / L hydrochloric acid to the system to precipitate the formylation intermediate-5,10-methylenetetrahydrofolate hydrochloride;

[0066] 2) Re-dissolve 150g of the precipitated 5,10-methylenetetrahydrofolate hydrochloride in 300mL of formic acid, after stirring to dissolve, add 75mL, 6mol / L of hydrochloric acid, at a temperature of 10℃-30℃ (Room temperature), the refined product of 5,10-methylenetetrahydrofolate hydrochloride is precipitated, and the detection specific rotation is +24°;

[0067] 3) Add 1...

Embodiment 2

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

[0071] 2) Dissolve 300g of the precipitated 5,10-methylenetetrahydrofolate hydrochloride in 1.5L of formic acid. After stirring to dissolve, add 3.75L, 1mol / L of hydrochloric acid, at a temperature of 10℃-30℃ (Room temperature), the refined product of 5,10-methylenetetrahydrofolate hydrochloride is precipitated, and the detection specific rotation is +18°;

[0072...

Embodiment 3

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

[0076] 2) Dissolve 700g of the precipitated 5,10-methylenetetrahydrofolate hydrochloride in 2.1L of formic acid. After stirring to dissolve, add 2.1L, 2mol / L of hydrochloric acid at 10℃-30℃ Placed at temperature (room temperature), the refined product of 5,10-methylenetetrahydrofolate hydrochloride is precipitated, and the detection specific rotation is +26°...

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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 synthetic field of chemical raw materials, and specifically relates to a method for preparing high-purity levofolinate calcium. Background technique [0002] L-Calcium Levofolinate, molecular formula is C 20 H 21 CaN 7 O 7 , Molecular weight 511.5, CAS No.: 80433-71-2. Chemical name: (-)-N-[4-[[[(6S)-2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6- Pteridinyl]methyl]amino]benzoyl]-L-glutamate calcium salt, its structural formula is as follows: [0003] [0004] Levoleucovorin is the calcium salt of levofolinic acid, which is the pharmacologically active L-optical isomer of 5-formyltetrahydrofolate (ie, folinic acid). Levofolinic acid does not need to be reduced by dihydrofolate reductase in order to participate in the reaction using folate as a source of one carbon unit, and levofolinic acid can actively or passively pass through the cell membrane. The basic function of levofolinic acid is the same as that of folic acid, but the...

Claims

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Application Information

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Patent Type & Authority Applications(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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