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Preparation method of high-purity calcium levofolinate

A technology for calcium levofolinate and calcium leucovorin is applied in the field of preparation of high-purity calcium levofolinate, and can solve the problems of affecting drug safety, difficult to meet requirements for the purity of calcium levofolinate, unable to meet the standard of chloride ion content, and the like, Achieve the effect of shortening the crystallization time, stabilizing the splitting system, and avoiding chlorine pollution

Pending Publication Date: 2021-11-19
ZHEJIANG DAVI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, at present, the purity of calcium leucovorin is difficult to meet the requirements, and the price is several times higher than that of calcium folinate; the purity of raw materials directly affects the safety of drugs, and the price of drugs is directly related to their production costs and benefits. It determines whether the drug can be used safely on a large scale
Moreover, chloride ions are introduced in most of the preparation process, so that the content of chloride ions in the product cannot meet the standard

Method used

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  • Preparation method of high-purity calcium levofolinate
  • Preparation method of high-purity calcium levofolinate
  • Preparation method of high-purity calcium levofolinate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Using calcium folinate as raw material, prepare high-purity calcium levofolinate, as follows:

[0070] Suspend 51.1g (0.1 mol) of calcium folinate and 25g of sodium bromide in 400ml of water, heat up to 50°C to dissolve, cool down to 10°C to crystallize for 6 hours, precipitate solids, filter, wash the solids with water, and combine the filtrates.

[0071] Add 10g of calcium acetate and 2g of R-(α)-phenylethylamine to the filtrate, cool the solution to 10°C to crystallize for 6 hours, and precipitate a solid, filter, and wash the solid with water to obtain 59g of a single-resolution solid, with a yield of 90%. One-time split heterogeneous map as attached figure 1 , a split impurity map as attached figure 2 .

[0072] Suspend the whole amount of the first split solid in 400ml of water, raise the temperature to 50°C, add acetic acid to dissolve it, add 10g calcium acetate and 2g R-(α)-phenylethylamine to the solution, cool the solution to 10°C to crystallize for 6 hour...

Embodiment 2

[0100] Using calcium folinate as raw material, prepare high-purity calcium levofolinate, as follows:

[0101] Suspend 51.1g (0.1 mol) calcium folinate and 25g sodium bromide in 400ml water, heat up to (40-60)°C to dissolve, cool down to (0-20)°C to crystallize (5-20)h , precipitated solids, filtered, washed the solids, and combined the filtrates.

[0102] Add 8g of calcium formate and 2g of R-(α)-phenylethylamine to the filtrate, cool down the solution to (0-20)°C and crystallize for (5-20) hours, precipitate solids, filter and wash the solids to obtain a resolution Solid 59.5g, yield = 91%.

[0103] Suspend the whole amount of the first split solid in 400ml water, raise the temperature to (40-60)°C, add formic acid to dissolve it, add 8g calcium formate and 2g R-(α)-phenylethylamine to the solution, and cool the solution to ( 0-20) ℃ crystallization (5-20) h, precipitated solid, filtered, washed solid, 50g of secondary resolution solid can be obtained ， Yield = 89%.

[01...

Embodiment 3

[0107] Using calcium folinate as raw material, prepare high-purity calcium levofolinate, as follows:

[0108] Suspend 51.1g (0.1 mol) calcium folinate and 25g sodium bromide in 400ml water, heat up to (40-60)°C to dissolve, cool down to (0-20)°C to crystallize (5-20)h , precipitated solids, filtered, washed the solids, and combined the filtrates.

[0109] Add 12g of calcium propionate and 2g of R-(α)-phenylethylamine to the filtrate, cool the solution to (0-20)°C and crystallize for (5-20) hours, precipitate solids, filter, and wash the solids to obtain a one-time solution. Divide solid 60g, yield=90.5%.

[0110] Suspend the whole amount of the first split solid in 400ml water, raise the temperature to (40-60)°C, add propionic acid to dissolve it, add 12g calcium propionate and 2g R-(α)-phenylethylamine to the solution, and cool down the solution Crystallize at (0-20)°C for (5-20) h, precipitate solids, filter, wash the solids with water, and obtain 51.5 g of secondary resol...

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Abstract

The invention belongs to the field of synthesis of chemical raw material medicines, and particularly relates to a preparation method of high-purity calcium levofolinate, wherein the preparation method comprises the following steps: S-1, adding calcium levofolinate and a resolving agent into water, stirring to dissolve the calcium levofolinate and the resolving agent, and filtering to obtain filtrate; S-2, adding calcium acetate and a resolving agent into the filtrate, crystallizing and filtering to obtain a primary resolved solid; S-3, dissolving, crystallizing, filtering and drying the primary resolved solid to obtain a calcium levofolinate crude product; and S-4, purifying the calcium levofolinate crude product to obtain a calcium levofolinate finished product. The resolving agent is R-(alpha)-phenylethylamine. Calcium ions are introduced in the form of calcium acetate, introduction of chloride ions is avoided, and the finished product is free of chloride ion impurities. In addition, R-(alpha)-phenylethylamine is adopted as the resolving agent and is matched with calcium acetate, so that the isomer content of the finished product is less than 0.1% (the isomer content is less than 0.5% according to the specification of pharmacopoeia).

Description

technical field [0001] The invention belongs to the field of synthesis of chemical raw materials, and in particular relates to a preparation method of high-purity calcium levofolinate. Background technique [0002] Leucovorin calcium is the calcium salt of leucovorin, which is the pharmacologically active L-optical isomer of 5-formyltetrahydrofolate (ie, leucovorin). Leucovorin does not need to be reduced by dihydrofolate reductase to participate in reactions utilizing folate as a source of one-carbon units, and it can pass through cell membranes either actively or passively. The basic effect of folinic acid is the same as that of folic acid, but the effect is better than that of folic acid, because folic acid must first be converted into folinic acid in the liver and bone marrow to function. And this product, calcium levofolinate, is the active form of leucovorin, which also has the effect of stimulating the growth and maturation of white blood cells, and can improve megal...

Claims

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Application Information

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IPC IPC(8): C07D475/04
CPCC07D475/04C07B2200/07
Inventor 俞旭峰朱华柴志善
Owner ZHEJIANG DAVI PHARMA
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