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Recrystallization process method of nafamostat mesylate

A technology of nafamostat mesylate and a process method, applied in the field of recrystallization process of nafamostat mesylate, can solve the problems of increasing raw material loss and cost, unable to guarantee recrystallization effect, increasing the number of recrystallization times, etc. , to achieve the effect of improving purity, yield balance and purity balance

Pending Publication Date: 2020-08-25
HEBEI INST FOR DRUG & MEDICAL DEVICE CONTROL (HEBEI INST FOR COSMETICS CONTROL)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to improve the purity and the level of drug properties, the number of recrystallizations has to be increased, and the recrystallization effect cannot be guaranteed, which increases the loss of raw materials and costs

Method used

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  • Recrystallization process method of nafamostat mesylate
  • Recrystallization process method of nafamostat mesylate
  • Recrystallization process method of nafamostat mesylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] A. p-guanidinobenzoic acid hydrochloride: 12 parts, 6-amidine-2 naphthol methanesulfonate: 10 parts, DCC: 11 parts, DMAP1: 1 part, stirring continuously under ice bath for 24 hours, the whole reaction Protect from light, until the white solid is completely produced, filter, pour the filtrate into excess saturated sodium bicarbonate solution under stirring, and precipitate a brown powdery solid, wash with water, thoroughly wash to remove excess sodium salt, and dry to obtain nafamostat carbonate;

[0023] B. Suspend the nafamostat carbonate solid prepared in step A in 150mL methanol, add methanesulfonic acid dropwise under ice bath, until the solution is clarified, add 300mL ether, and separate out a yellow solid to obtain nafamostat mesylate Sestat crude;

[0024] C. For the first recrystallization, add 30mL of mixed solvent (ethanol: water = 1:1) and 8g of crude product into the beaker, and quickly put it into a 70°C water bath under rapid stirring. After the crude pro...

Embodiment 2

[0027] A. p-guanidinobenzoic acid hydrochloride: 12 parts, 6-amidine-2 naphthol methanesulfonate: 10 parts, DCC: 12 parts, DMAP1: 1 part, stirring continuously under ice bath for 48 hours, the whole reaction Protect from light, until the white solid is completely produced, filter, pour the filtrate into excess saturated sodium bicarbonate solution under stirring, and precipitate a brown powdery solid, wash with water, thoroughly wash to remove excess sodium salt, and dry to obtain nafamostat carbonate;

[0028] B. Suspend the nafamostat carbonate solid prepared in step A in 150mL methanol, add methanesulfonic acid dropwise under ice bath until the solution is clarified, add 500mL ether, separate out a yellow solid, and obtain nafamostat mesylate Sestat crude;

[0029] C. For the first recrystallization, add 30mL of mixed solvent (ethanol: water = 1:1) and 8g of crude product into the beaker, and quickly put it into an 80°C water bath under rapid stirring. A good hot filter fu...

Embodiment 3

[0033] A. p-guanidinobenzoic acid hydrochloride: 11 parts, 6-amidine-2 naphthol methanesulfonate: 10 parts, DCC: 13 parts, DMAP1: 1 part, stirring continuously under ice bath for 72 hours, the whole reaction Protect from light; until the white solid is completely produced, filter, pour the filtrate into an excess saturated sodium bicarbonate solution under stirring, and separate out a brown powdery solid, wash with water, thoroughly wash to remove excess sodium salt, and dry to obtain nafamostat carbonate;

[0034] B. Suspend the nafamostat carbonate solid prepared in step A in 150mL methanol, add methanesulfonic acid dropwise under ice bath until the solution is clarified, add 700mL ether, and separate out a yellow solid to obtain nafamostat mesylate Sestat crude;

[0035]C. For the first recrystallization, add 30mL of mixed solvent (ethanol: water = 1:1) and 8g of crude product into the beaker, and quickly put it into a 90°C water bath under rapid stirring. A good hot filte...

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Abstract

The invention belongs to the technical field of drug intermediate processing and relates to a recrystallization process method of nafamostat mesylate. According to the recrystallization process method, a crude nafamostat mesylate product is prepared by controlling the use amounts of anhydrous pyridine, 4-guanidinobenzoic acid hydrochloride and 6-amidine-2 naphthol mesylate and combining the preparation method disclosed by the invention; then the purposes of effectively decolorizing, removing impurities and improving the purity are achieved through a gradient recrystallization method in which the ratio of ethanol to water to acetone in a mixed solvent is 1: 1: 4, 1: 1: 3, 1: 1: 2 and 1: 1: 1, and therefore, the purity and the yield are balanced; and the method is simple in adopted raw materials, simple and convenient to operate, low in cost and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical intermediate processing, and in particular relates to a recrystallization process of nafamostat mesylate. Background technique [0002] Nafamostat mesylate is a non-peptide synthetic protease inhibitor, chemical name: 4-guanidinobenzoic acid-6-amidino-2-naphthyl dimesylate, molecular formula: C 21 h 25 N 5 o 8 S 2 In 1986, it was listed for the first time by Japan Shimai (Asahi Beer) Co., Ltd. for the treatment of pancreatitis. In 1987, it was proposed that this product has anti-DIC effect and anticoagulant effect in hemodialysis. This product has applied for patents in many countries, such as : US4454338, JP57 / 179146.EP: Appl 48,433, etc. The synthesis process of nafamostat mesylate is relatively complicated, its chemical properties are unstable, and it is easy to decompose and deteriorate. Therefore, it is difficult to prepare high-purity chemical raw materials. Amidine-2 naphthol m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C279/18C07C277/08C07C303/32C07C303/44C07C309/04
CPCC07C277/08C07C303/32C07C303/44C07C279/18C07C309/04
Inventor 赵煜松曾海霞
Owner HEBEI INST FOR DRUG & MEDICAL DEVICE CONTROL (HEBEI INST FOR COSMETICS CONTROL)
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