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Method for recovering L-valsartan from valsartan mother liquor containing D-valsartan

A technology of valsartan methyl ester and mother liquor, which is applied in the field of recovering valsartan, can solve problems such as waste of resources, and achieve the effects of simple operation and good recovery effect.

Pending Publication Date: 2021-08-17
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, in the process of valsartan synthesis, in order to meet the quality requirements of the pharmacopoeia standards, multiple crystallization methods are usually used to obtain qualified valsartan raw materials, and the resulting valsartan mother liquor usually contains both L-valsartan Sartan also contains D-valsartan, as well as other impurities. In the prior art, there is no effective method to recover the L-valsartan in the valsartan mother liquor, resulting in a great waste of resources

Method used

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  • Method for recovering L-valsartan from valsartan mother liquor containing D-valsartan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] The content of isomers in the valsartan mother liquor is 40%-45%. Add 5kg of concentrated valsartan mother liquor, 10L of toluene, and 1L of methanol to the reaction kettle, add 1kg of sulfuric acid dropwise within 20°C of temperature control, and raise the temperature to 60°C. ℃ for 8 hours, after the reaction was completed, 5 kg of water was added to wash, and washed twice, and the organic layer was obtained by separating layers.

[0019] Concentrate the organic layer to dryness, add a mixed solvent of 2kg methyl acetate and 5kg isopropyl ether for heating to dissolve, cool down to crystallize, and filter to obtain crude valsartan methyl ester. Put the crude product of valsartan methyl ester in 10kg of methyl acetate solvent, beat at 35°C for 7 hours at a beating speed of 200r / min, and filter to remove the isomers of valsartan methyl ester. The filtrate is added to alkali solution for hydrolysis and then acidified to obtain valsartan. The organic layer was obtained b...

Embodiment 2

[0021] The content of isomers in the valsartan mother liquor is 40%-45%. Add 500kg of concentrated valsartan mother liquor, 1000L of toluene, and 100L of methanol to the reaction kettle, add 100kg of sulfuric acid dropwise within 20°C of temperature control, and raise the temperature to 65 ℃ for 8 hours, after the reaction was completed, 500 kg of water was added to wash, and washed twice, and the organic layer was obtained by separating layers.

[0022] Concentrate the organic layer to dryness, add a mixed solvent of 200kg ethyl acetate and 500kg diethyl ether for heating to dissolve, cool down to crystallize, and filter to obtain crude valsartan methyl ester. The crude valsartan methyl ester was beaten in 1000 kg of ethyl acetate solvent at 45° C. for 5 hours at a beating speed of 250 r / min, and the isomers of valsartan methyl ester were removed by filtration. The filtrate is added to alkali solution for hydrolysis and then acidified to obtain valsartan. The organic layer w...

Embodiment 3

[0024] The content of isomers in the valsartan mother liquor is 40%-45%. Add 500kg of concentrated valsartan mother liquor, 1000L of toluene, and 100L of methanol to the reaction kettle, add 100kg of sulfuric acid dropwise within 20°C of temperature control, and raise the temperature to 70 ℃ for 8 hours, after the reaction was completed, 500 kg of water was added to wash, and washed twice, and the organic layer was obtained by separating layers.

[0025] Concentrate the organic layer to dryness, add a mixed solvent of 200kg methyl propionate and 500kg methyl tert-butyl ether to dissolve it by heating, cool down and crystallize, and filter to obtain the crude product of valsartan methyl ester. The crude product of valsartan methyl ester was beaten in 1000 kg of methyl propionate solvent at 53° C. for 3 hours at a beating speed of 180 r / min, and the isomers of valsartan methyl ester were removed by filtration. The filtrate is added to alkali solution for hydrolysis and then acid...

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Abstract

The invention provides a method for recovering L-valsartan from valsartan mother liquor containing D-valsartan, which comprises the following steps: mixing the valsartan mother liquor with methanol, dropwise adding sulfuric acid or thionyl chloride at controlled temperature, heating for reaction, adding water for washing after the reaction is completed, and layering to obtain an organic layer; concentrating an organic layer to be dry, adding a mixed solvent of esters and ethers, heating, dissolving and clarifying, cooling, crystallizing, and filtering to obtain a valsartan methyl ester crude product; pulping a valsartan methyl ester crude product in an ester solvent, and filtering to remove a valsartan methyl ester isomer; adding the filtrate into alkali liquor to demodulate acid with water to obtain valsartan; and layering to obtain an organic layer, concentrating the organic layer, adding ethyl acetate after concentrating, heating for dissolving, cooling for crystallization, filtering to obtain a valsartan wet product, and drying to obtain the valsartan. According to the method, valsartan isomer impurities in the valsartan mother liquor with high isomer content can be removed, valsartan with high optical purity is finally obtained, waste of resources is prevented, and the environment is protected.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a method for recovering valsartan from valsartan mother liquor. Background technique [0002] Valsartan is an angiotensin II receptor antagonist antihypertensive drug, which can block the type I (AT1) receptor of angiotensin II, increase the plasma level of angiotensin II, stimulate Unblocked AT2 receptors counteract the effect of AT1 receptors at the same time, so as to achieve the effect of dilating blood vessels and lowering blood pressure. Its chemical name is [(L)-N-(1-pentanoyl)-[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]-L-valine], There is a chiral center in the molecular structure, which has a pair of enantiomers. At present, L-valsartan is a single enantiomer for commercial use, mainly because the pharmaceutical activity of the L-enantiomer is far away from that of the enantiomer. Higher than the D-enantiomer, so D-valsartan should be removed during the sy...

Claims

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Application Information

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IPC IPC(8): C07D257/04
CPCC07D257/04C07B2200/07
Inventor 范志雄周文祥游学海彭定良祁红林
Owner 珠海润都制药股份有限公司
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