CN111574409A - Recrystallization process method of nafamostat mesylate - Google Patents
Recrystallization process method of nafamostat mesylate Download PDFInfo
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- CN111574409A CN111574409A CN202010409337.3A CN202010409337A CN111574409A CN 111574409 A CN111574409 A CN 111574409A CN 202010409337 A CN202010409337 A CN 202010409337A CN 111574409 A CN111574409 A CN 111574409A
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- recrystallization
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
Abstract
The invention belongs to the technical field of pharmaceutical intermediate processing, and particularly relates to a recrystallization process method of nafamostat mesilate, which comprises the steps of preparing a crude nafamostat mesilate product by controlling the using amounts of anhydrous pyridine, p-guanidinobenzoic acid hydrochloride and 6-amidine-2 naphthol mesylate and combining the preparation method, and performing gradient recrystallization by using mixed solvents of ethanol, water and acetone, 1:1:4, 1:1:3, 1:1:2 and 1:1:1 respectively to achieve the purposes of effectively decoloring, removing impurities and improving purity, balance purity and yield, and is simple in raw materials, simple and convenient to operate, low in cost and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical intermediate processing, and particularly relates to a recrystallization process method of nafamostat mesilate.
Background
Nafamostat mesylate is a non-peptide synthetic protease inhibitor and has the chemical name: 4-guanidinobenzoic acid-6-amidino-2-naphthyl ester dimesylate, of the formula: c21H25N5O8S2It was first marketed by Daidanhataju (Tokuai beer) in 1986 for treating pancreatitis, and was suggested to have anti-DIC effect and anticoagulant effect in hemodialysis in 1987Patents have been filed in many countries, such as: US4454338, JP57/179146 EP Appl 48,433 et al. The synthetic process of nafamostat mesilate is complex, the chemical property is unstable, and decomposition and deterioration are easy, so that the high-purity chemical raw material medicine is prepared with certain difficulty, wherein p-guanidinobenzoic acid hydrochloride and 6-amidine-2 naphthol mesylate are used as intermediate raw materials, DCC is added as a dehydrating agent, catalytic esterification is carried out to obtain nafamostat carbonate, the nafamostat carbonate is reacted with methanesulfonic acid to obtain a nafamostat mesilate crude product, and the nafamostat crude product is recrystallized by using ethanol or water as a solvent.
But the nafamostat mesilate has unstable chemical property, can start to deteriorate when heated and exposed to light, is extremely easy to deteriorate in a solution state, can be completely decomposed after being refluxed for 30 minutes in methanol and ethanol, and has the recrystallization process equivalent to that impurities are generated while purification is carried out, so that the purity of a sample is difficult to meet the requirement. The solid obtained by recrystallization with ethanol as a solvent is generally powdery, generally yellow, has a melting point of 217 ℃, has high impurity content, has poor recrystallization effect and unsatisfactory yield; the solid obtained by recrystallization by using water as a solvent is usually powdery solid crystals, generally has light or heavy pink color, is related to heating time, has a melting point of 261 ℃, has better impurity removal effect than ethanol, still cannot meet the quality requirement, and has low yield. The characters reported by the current data are yellow brown to light orange solid, and the quality level of the medicine is lower. The recrystallization times have to be increased to improve the purity and the property level of the medicine, the recrystallization effect cannot be ensured, and the raw material loss and the cost are increased.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a recrystallization process method of nafamostat mesilate, which can achieve the purposes of effectively decoloring, removing impurities and improving purity.
The invention adopts the specific technical scheme that: the key point of the recrystallization process method of nafamostat mesylate is that the method comprises the following steps:
A. according to the molar parts, p-guanidinobenzoic acid hydrochloride: 10-12 parts of 6-amidine-2 naphthol mesylate: 10 parts of DCC: 11-13 parts, DMAP 1: 1-2 parts of the raw materials are continuously stirred for 24-72 hours in ice bath, and the whole reaction process is protected from light; filtering until white solid is completely generated, pouring excessive saturated sodium bicarbonate solution into the filtrate while stirring to separate out brown powdery solid, washing with water, thoroughly cleaning to remove excessive sodium salt, and drying to obtain nafamostat carbonate;
B. suspending the nafamostat carbonate solid prepared in the step A in 150mL of methanol, dropwise adding methanesulfonic acid in ice bath until the solution is clear, adding 300-700mL of diethyl ether until the precipitation is complete, and separating out yellow solid to obtain a nafamostat mesylate crude product;
C. performing primary recrystallization, adding 30mL of mixed solvent (ethanol: water is 1:1) into a beaker every 8g of crude product, quickly stirring, quickly putting into a water bath at 60-90 ℃, adding 1-3g of activated carbon, stirring and decoloring after the crude product is dissolved, performing reduced pressure suction filtration by using a preheated hot filter funnel, and enabling the filtrate to have no solid precipitation; adding 60mL of acetone into the filtrate, uniformly mixing, refrigerating in a dark place, standing, precipitating a pure white solid, and repeating the steps until the crude product is completely used, wherein the integral solvent ratio in the step is as follows: ethanol, water, acetone 1:1: 4.
As a further scheme, the method also comprises a step D of carrying out secondary recrystallization, wherein every 20g of a product obtained by primary recrystallization is added with 60mL of mixed solvent (ethanol: water: 1) in a beaker, after dissolution, 1-3g of activated carbon is added, stirring and decoloring are carried out, and a preheated hot filtering funnel is used for carrying out vacuum filtration, so that no solid is precipitated in the filtrate; adding 60mL of acetone into the filtrate, uniformly mixing, refrigerating and standing; separating out pure white solid; the overall solvent ratio is: ethanol, water, acetone 1:1: 2.
As a further scheme, in the step D, if the content of impurities is high, the ratio of the mixed solvent in the second recrystallization is 1:1: 3; carrying out third recrystallization according to the proportion of ethanol-water-acetone being 1:1:2 or 1:1: 1; a pure white solid was obtained.
As a further scheme, the method comprises the following steps of (1) counting the molar parts of p-guanidinobenzoic acid hydrochloride: 10 parts of 6-amidine-2 naphthol mesylate: 10 parts of DCC: 12 parts, DMAP 1:1 part.
As a further scheme, the reaction time in the step a is 48 hours.
As a further scheme, the molar ratio of nafamostat carbonate to methanesulfonic acid in the step B is 1: 1.2.
As a further proposal, the dosage of the activated carbon in the step C is 1g, and the temperature of the water bath is 80 ℃.
As a further scheme, in the above method for recrystallizing nafamostat mesylate, the operation time of the recrystallization process in the step C is not longer than 5 minutes.
As a further proposal, the operation time of the recrystallization process in the step D is 5 to 10 minutes.
As a further scheme, the solid obtained by recrystallization is quickly protected from light, dried under reduced pressure at normal temperature, stored in a sealed and protected manner, and stored in a shady and dry place.
The invention has the beneficial effects that: the first recrystallization of the invention adopts ethanol: dissolving a crude product in a mixed solvent of water and acetone in a ratio of ethanol to water to acetone of 1:1:4, and adding acetone to separate out, wherein the aim of primary recrystallization is to decolor and remove most impurities, and the yield is high and can reach 90%; then, carrying out secondary recrystallization, improving the purity, removing most impurities, and reducing the yield by about 50-70%; and the purity is improved by limiting the operation time of the recrystallization process, meanwhile, the yield can be ensured by the higher acetone proportion, impurities can be effectively removed after the acetone proportion is reduced, and the balance between the purity and the yield is realized.
The invention adopts a gradient recrystallization method with mixed solvents of ethanol, water and acetone being 1:1:4, 1:1:3, 1:1:2 and 1:1:1 respectively, so as to achieve the purposes of effectively decoloring, removing impurities and improving purity. The raw materials are the most common reagents, so that the influence of solvent residues is reduced to the maximum extent, and the cost is low; simple operation, suitability for industrial production, and the content is more than 98.5 percent and the melting point is 246 ℃ through liquid chromatography determination.
Detailed Description
The invention will be further illustrated with reference to specific examples:
example 1
A. P-guanidinobenzoic acid hydrochloride: 12 parts of 6-amidine-2 naphthol mesylate: 10 parts of DCC: 11 parts, DMAP 1:1 part of the mixture is continuously stirred for 24 hours in ice bath, the reaction is kept in the dark until white solid is completely generated, the mixture is filtered, excessive saturated sodium bicarbonate solution is poured into the filtrate while stirring, brown powdery solid is separated out, the mixture is washed by water, and the excessive sodium salt is thoroughly cleaned and removed, and the mixture is dried to obtain nafamostat carbonate;
B. suspending the nafamostat carbonate solid prepared in the step A in 150mL of methanol, dropwise adding methanesulfonic acid in ice bath until the solution is clear, adding 300mL of diethyl ether, and separating out yellow solid to obtain a nafamostat mesylate crude product;
C. carrying out primary recrystallization, adding 30mL of mixed solvent (ethanol: water is 1:1) and 8g of crude product into a beaker, rapidly putting the beaker into a 70 ℃ water bath under rapid stirring, adding 1g of activated carbon into the beaker after the crude product is dissolved, stirring and decoloring the mixture, and carrying out vacuum filtration by using a preheated hot filter funnel until no solid is separated out from the filtrate; adding 60mL of acetone into the filtrate, uniformly mixing, refrigerating in a dark place, standing, and precipitating a pure white solid, wherein the solvent ratio in the step is as follows: ethanol, water, acetone 1:1: 4.
D. The second recrystallization, adding 60mL of mixed solvent (ethanol: water 1:1) and 20g of the product of the first recrystallization into a beaker, and repeating the above operation; adding 60mL of acetone into the filtrate, uniformly mixing, refrigerating and standing; separating out pure white solid; the overall solvent ratio is: ethanol, water, acetone 1:1: 2. Filtering, drying the obtained solid rapidly at room temperature under reduced pressure in dark place, storing in sealed dark place, and storing in dry place in shade.
Example 2
A. P-guanidinobenzoic acid hydrochloride: 12 parts of 6-amidine-2 naphthol mesylate: 10 parts of DCC: 12 parts, DMAP 1:1 part of the mixture is continuously stirred for 48 hours in ice bath, the reaction is kept in the dark until white solid is completely generated, the mixture is filtered, excessive saturated sodium bicarbonate solution is poured into the filtrate while stirring, brown powdery solid is separated out, the mixture is washed by water, and the excessive sodium salt is thoroughly cleaned and removed, and the mixture is dried to obtain nafamostat carbonate;
B. suspending the nafamostat carbonate solid prepared in the step A in 150mL of methanol, dropwise adding methanesulfonic acid in ice bath until the solution is clear, adding 500mL of diethyl ether, and separating out yellow solid to obtain a nafamostat mesylate crude product;
C. carrying out primary recrystallization, adding 30mL of mixed solvent (ethanol: water is 1:1) and 8g of crude product into a beaker, rapidly putting the beaker into a water bath at 80 ℃ under rapid stirring, adding 2g of activated carbon into the beaker after the crude product is dissolved, stirring and decoloring, and carrying out vacuum filtration by using a preheated hot filter funnel until no solid is separated out from the filtrate; adding 60mL of acetone into the filtrate, uniformly mixing, refrigerating in a dark place, standing, and precipitating a pure white solid, wherein the solvent ratio in the step is as follows: ethanol, water, acetone 1:1: 4.
D. The second recrystallization, adding 60mL of mixed solvent (ethanol: water 1:1) and 20g of the product of the first recrystallization into a beaker, and repeating the above operation; adding 90mL of acetone into the filtrate, uniformly mixing, refrigerating and standing; separating out pure white solid; the overall solvent ratio is: ethanol, water, acetone 1:1: 3.
Carrying out third recrystallization on the product obtained in the step D according to the proportion of ethanol-water-acetone being 1:1: 2; obtaining pure white solid, filtering, quickly drying the obtained solid at normal temperature and reduced pressure in the dark, storing in a sealed and dark place, and storing in a cool and dry place.
Example 3
A. P-guanidinobenzoic acid hydrochloride: 11 parts of 6-amidine-2 naphthol mesylate: 10 parts of DCC: 13 parts, DMAP 1:1 part of the mixture is continuously stirred for 72 hours in ice bath, and the whole reaction process is protected from light; filtering until white solid is completely generated, pouring excessive saturated sodium bicarbonate solution into the filtrate while stirring to separate out brown powdery solid, washing with water, thoroughly cleaning to remove excessive sodium salt, and drying to obtain nafamostat carbonate;
B. suspending the nafamostat carbonate solid prepared in the step A in 150mL of methanol, dropwise adding methanesulfonic acid in ice bath until the solution is clear, adding 700mL of diethyl ether, and separating out yellow solid to obtain a nafamostat mesylate crude product;
C. carrying out primary recrystallization, adding 30mL of mixed solvent (ethanol: water is 1:1) and 8g of crude product into a beaker, rapidly putting the beaker into a water bath at 90 ℃ under rapid stirring, adding 3g of activated carbon into the beaker after the crude product is dissolved, stirring and decoloring, and carrying out vacuum filtration by using a preheated hot filter funnel until no solid is separated out from the filtrate; adding 60mL of acetone into the filtrate, uniformly mixing, refrigerating in a dark place, standing, and precipitating a pure white solid, wherein the solvent ratio in the step is as follows: ethanol, water, acetone 1:1: 4.
D. The second recrystallization, adding 60mL of mixed solvent (ethanol: water 1:1) and 20g of the product of the first recrystallization into a beaker, and repeating the above operation; adding 60mL of acetone into the filtrate, uniformly mixing, refrigerating and standing; separating out pure white solid; the overall solvent ratio is: ethanol, water and acetone in a ratio of 1:1:2, filtering, quickly drying the obtained solid under reduced pressure at normal temperature in a dark place, sealing and storing in a dark place, and storing in a cool and dry place.
Second, experimental results
The preparation method in example 2 was selected to prepare 5 batches of nafamostat mesilate, and the experimental data are shown in table 1:
the nafamostat mesylate of batch 2 is selected to be subjected to an accelerated test to test the stability and the quality guarantee period according to a pharmacopoeia method under the conditions of 40 ℃ and RH 75%, and the experimental effects are shown in Table 2:
the final product obtained according to example 2 is of the best quality. Parallel experiments of 5 batches show that the appearance of the powder is white powder, the melting points are 246.0 ℃ respectively, and the purity is 97.83%; 246.5 ℃ and 99.00 percent of purity; purity of 99.73% at 246.0 deg.C; 246.2 ℃ and 98.86 percent of purity; 247.0 ℃, 99.64 percent of purity (the purity is measured by an HPLC normalization method), and 50 to 70 percent of recrystallization yield.
Samples of batch 2, which were preserved in low temperature and dark state, were selected for long-term sample retention, and the experimental effects are shown in table 3:
accelerated tests and stability researches confirm that the sample has stable properties, long shelf life and good stability within at least two years of shelf life.
A comparison was made by selecting batch 3 in Table 1 as group A, ethanol production as group B, and water production as group C, with the data shown in Table 4:
the solid obtained by recrystallization with ethanol as a solvent is generally powdery, is usually yellow or yellowish green, has a melting point of 217 ℃, has high impurity content, has poor recrystallization effect and is not ideal in yield; the solid obtained by recrystallization with water as a solvent is usually powdery solid crystals, generally has light or heavy pink, is related to heating time and heating temperature, has a melting point of 261 ℃, has better impurity removal effect than ethanol, still cannot meet the quality requirement, has low yield (30-50%), mostly adopts yellow brown to light orange solid in the characters reported by the existing data, has low medicine quality level, has to increase recrystallization times when improving purity and medicine property level, cannot ensure recrystallization effect, and increases raw material loss and cost. The invention adopts a method of gradient recrystallization with mixed solvents of ethanol, water and acetone being 1:1:4, 1:1:3, 1:1:2 and 1:1:1, respectively, to successfully prepare pure white powdery crystals, the melting point is 246 ℃, the content exceeds 99.0 percent, the product quality requirements are met, effective decoloration and impurity removal are realized, and the purity is improved; and the preparation method is simple, the raw material cost is low, and the method is suitable for industrial production.
Claims (10)
1. A recrystallization process method of nafamostat mesilate is characterized by comprising the following steps:
A. according to the molar parts, p-guanidinobenzoic acid hydrochloride: 10-12 parts of 6-amidine-2 naphthol mesylate: 10 parts of DCC: 11-13 parts, DMAP 1: 1-2 parts of the raw materials are continuously stirred for 24-72 hours in ice bath, and the whole reaction process is protected from light; filtering until white solid is completely generated, pouring excessive saturated sodium bicarbonate solution into the filtrate while stirring to separate out brown powdery solid, washing with water, thoroughly cleaning to remove excessive sodium salt, and drying to obtain nafamostat carbonate;
B. suspending the nafamostat carbonate solid prepared in the step A in 150mL of methanol, dropwise adding methanesulfonic acid in ice bath until the solution is clear, adding 300-700mL of diethyl ether until the precipitation is complete, and separating out yellow solid to obtain a nafamostat mesylate crude product;
C. performing primary recrystallization, adding 30mL of mixed solvent (ethanol: water is 1:1) into a beaker every 8g of crude product, quickly stirring, quickly putting into a water bath at 60-90 ℃, adding 1-3g of activated carbon, stirring and decoloring after the crude product is dissolved, performing reduced pressure suction filtration by using a preheated hot filter funnel, and enabling the filtrate to have no solid precipitation; adding 60mL of acetone into the filtrate, uniformly mixing, refrigerating in a dark place, standing, precipitating a pure white solid, and repeating the steps until the crude product is completely used, wherein the integral solvent ratio in the step is as follows: ethanol, water, acetone 1:1: 4.
2. The process of claim 1, further comprising a step D of carrying out secondary recrystallization, wherein for every 20g of the product obtained by the primary recrystallization, 60mL of a mixed solvent (ethanol: water: 1) is added into a beaker, after dissolution, 1 to 3g of activated carbon is added, stirring and decoloring are carried out, and a preheated hot filtration funnel is used for carrying out vacuum filtration, so that no solid is precipitated from the filtrate; adding 60mL of acetone into the filtrate, uniformly mixing, refrigerating and standing; separating out pure white solid; the overall solvent ratio is: ethanol, water, acetone 1:1: 2.
3. The process of claim 2, wherein in the step D, if the content of impurities is high, the ratio of the mixed solvent in the second recrystallization is ethanol-water-acetone (1: 1: 3); carrying out third recrystallization according to the proportion of ethanol-water-acetone being 1:1:2 or 1:1: 1; a pure white solid was obtained.
4. The recrystallization process method of nafamostat mesylate according to claim 1, wherein the molar ratio of p-guanidinobenzoic acid hydrochloride is as follows: 10 parts of 6-amidine-2 naphthol mesylate: 10 parts of DCC: 12 parts, DMAP 1:1 part.
5. The process of claim 1, wherein the reaction time in step A is 48 hours.
6. The process of claim 1, wherein the molar ratio of nafamostat carbonate to methanesulfonic acid in step B is 1: 1.2.
7. The process of claim 1, wherein the amount of activated carbon used in step C is 1g, and the temperature of the water bath is 80 ℃.
8. The process of claim 1, wherein the recrystallization process in step C is carried out for not longer than 5 minutes.
9. The process of claim 2 or 3, wherein the recrystallization time in step D is 5-10 min.
10. The process for recrystallizing nafamostat mesylate according to claim 1, wherein the solid obtained by recrystallization is rapidly dried in the dark under reduced pressure at normal temperature, stored in a sealed and light-proof manner, and stored in a cool and dry place.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115141124A (en) * | 2022-06-16 | 2022-10-04 | 重庆华森制药股份有限公司 | Method for preparing gabexate mesylate |
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| CN115141124A (en) * | 2022-06-16 | 2022-10-04 | 重庆华森制药股份有限公司 | Method for preparing gabexate mesylate |
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