CN113999145B - Synthetic method of nafamostat mesylate - Google Patents
Synthetic method of nafamostat mesylate Download PDFInfo
- Publication number
- CN113999145B CN113999145B CN202111338004.7A CN202111338004A CN113999145B CN 113999145 B CN113999145 B CN 113999145B CN 202111338004 A CN202111338004 A CN 202111338004A CN 113999145 B CN113999145 B CN 113999145B
- Authority
- CN
- China
- Prior art keywords
- reaction
- ethyl alcohol
- absolute ethyl
- methyl
- sodium ethoxide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
- C07C273/1863—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety from urea
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method of nafamostat mesilate. Firstly, 6-cyano-2-naphthol, sodium ethoxide, absolute ethyl alcohol and ammonium chloride solution are used as raw materials to react, and 6-amidino-2-naphthol hydrochloride is obtained after treatment; then reacting the methoxy isourea hydrochloride, sodium ethoxide, absolute ethyl alcohol and p-chlorobenzoic acid ethanol solution, and processing to obtain 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid; then adding 6-amidino-2-naphthol hydrochloride, 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid, dicyclohexylcarbodiimide DCC and 4-dimethylaminopyridine DMAP into an ethanol solution of sodium ethoxide for reaction, then adding ammonia water for reaction, and processing to obtain a filter cake; and adding water and methanesulfonic acid into the filter cake to react, and treating after the reaction to obtain nafamostat mesylate. The synthesis of nafamostat mesylate by the method has less side reaction in the synthesis process, and the purity of the obtained crude product is more than 95%.
Description
1. The technical field is as follows:
the invention relates to the technical field of drug synthesis, in particular to a method for synthesizing nafamostat mesilate.
2. Background art:
nafamostat mesylate (nafamostat) with the chemical name of 6-amidino-2-naphthyl-4-guanidinobenzoate is a non-peptide protease inhibitor developed by Japan Tobacco, has strong selective inhibition effect on trypsin, kallikrein, plasmin, fibrin protease and serine protease in a complement system, has inhibition effect on phospholipase A2, can reduce the death rate of various experimental pancreatitis caused by reverse injection of trypsin and endotoxin through pancreatic duct chemical book, can inhibit the pancreatic enzyme activity increase caused by pancreatitis, and has inhibition effect on alpha 2 macroglobulin-bound trypsin in vitro; can be clinically used for treating acute pancreatitis and acute exacerbation of chronic pancreatitis; can also be used for anticoagulation in hemodialysis, coronary artery bypass surgery and liver resection, and glomerulonephritis accompanied with systemic lupus erythematosus or mixed cryoglobulinemia.
At present, the synthesis method of nafamostat mesylate mainly comprises two methods: the first method is that 4-guanidinobenzoic acid reacts with 6-amidino-2-naphthol to generate nafamostat; the second method is to synthesize nafamostat from 4-guanidinobenzoyl chloride and 6-amidino-2-naphthol. The two existing synthetic methods have the following defects: hydroxyl and amino in the 6-amidino-2-naphthol can participate in the reaction, and impurities are easily generated in the reaction process.
3. The invention content is as follows:
the technical problem to be solved by the invention is as follows: in order to overcome the defects of the existing synthesis method of nafamostat mesilate, the invention provides a novel synthesis method of nafamostat mesilate. The synthesis method has mild reaction conditions and few side reactions in the synthesis process, and the purity of the obtained crude product of the nafamostat mesylate is more than 95 percent.
In order to solve the problems, the invention adopts the technical scheme that:
the invention provides a synthetic method of nafamostat mesilate, which comprises the following steps:
a. preparation of 6-amidino-2-naphtholate salt:
firstly, adding absolute ethyl alcohol and sodium ethoxide into a reaction vessel for stirring and dissolving, then adding 6-cyano-2-naphthol in batches at room temperature, and stirring and reacting for 8-10 h at room temperature after the addition; after the reaction, adding an ammonium chloride aqueous solution with the mass percentage concentration of 20-35%, continuously stirring and reacting for 8-10 h at room temperature, filtering after the reaction is finished, decompressing the filtrate to remove the solvent, and drying to obtain 6-amidino-2-naphthol hydrochloride;
b. preparation of 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid:
adding absolute ethyl alcohol and sodium ethoxide into a reaction container for dissolving, then adding methoxy isourea hydrochloride, heating to 40-60 ℃, and carrying out stirring reaction for 1-3 hours; cooling the obtained reactant to room temperature after the reaction, and then filtering to obtain filtrate which is an ethanol solution of methoxy isourea;
dissolving p-chlorobenzoic acid in absolute ethyl alcohol, dripping the obtained p-chlorobenzoic acid ethanol solution into the obtained methoxy isourea ethanol solution at low temperature (the dripping time is 20-40 min), and then reacting for 5-8 h at 40-50 ℃; filtering after the reaction, and removing the solvent ethanol from the obtained filtrate to obtain 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid;
c. preparing nafamostat:
b, adding absolute ethyl alcohol and sodium ethoxide into a reaction vessel for dissolving, adding the 6-amidino-2-naphthol hydrochloride prepared in the step a after dissolving, and stirring and reacting for 1-3 h at the temperature of 40-60 ℃; cooling to room temperature after reaction, filtering, transferring the obtained filtrate to a reaction vessel, adding the 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid, dicyclohexylcarbodiimide DCC and 4-dimethylaminopyridine DMAP prepared in the step b, and reacting at the temperature of 30-50 ℃ for 5-8 hours; adding 25% ammonia water into the reactant obtained after the reaction, continuously stirring and reacting for 1-3 h, cooling to room temperature after the reaction, and filtering;
d. preparation of nafamostat mesylate:
and c, adding water into the filter cake obtained after filtering in the step c, stirring for 10-30 min, dropwise adding methanesulfonic acid at low temperature for 15-30 min, continuously stirring for 20-40 min after dropwise adding, then adding absolute ethyl alcohol, stirring for 20-40 min at low temperature, filtering, drying the obtained filter cake, and drying to obtain nafamostat mesylate.
According to the synthesis method of nafamostat mesylate, the molar ratio of the 6-cyano-2-naphthol to the sodium ethoxide and the ammonium chloride added in the step a is 1:1.1 to 1.5:1.1 to 1.5; the mass volume ratio of the 6-cyano-2-naphthol to the absolute ethyl alcohol is 1g:3 to 5mL.
According to the synthesis method of nafamostat mesylate, the drying temperature in the step a is 60-80 ℃ and the drying time is 4-6 h.
According to the synthesis method of nafamostat mesylate, the molar ratio of the methoxy isourea hydrochloride, the sodium ethoxide and the p-chlorobenzoic acid added in the step b is 1:1 to 1.5:1;
when the p-chlorobenzoic acid is dissolved in the absolute ethyl alcohol, the mass volume ratio of the p-chlorobenzoic acid to the absolute ethyl alcohol is 1g: 5-10 mL;
when the sodium ethoxide is dissolved in the absolute ethyl alcohol, the mass volume ratio of the sodium ethoxide to the absolute ethyl alcohol is 1g:7 to 10mL.
According to the synthesis method of the nafamostat mesylate, the low temperature in the step b is-10 to-5 ℃.
According to the above synthesis method of nafamostat mesylate, the molar ratio of the 6-amidino-2-naphthol hydrochloride, the 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid, the Dicyclohexylcarbodiimide (DCC), the 4-Dimethylaminopyridine (DMAP), the sodium ethoxide and the ammonia water in step c is 1:1.0 to 1.2: 1.2-1.5: 0.1 to 0.3:1.1 to 1.5:1.2 to 1.5;
when the sodium ethoxide is dissolved in the absolute ethyl alcohol, the mass volume ratio of the sodium ethoxide to the absolute ethyl alcohol is 1g:8 to 10mL.
According to the above synthesis method of nafamostat mesylate, the molar ratio of the 6-amidino-2-naphthol hydrochloride and the methanesulfonic acid added in the step d is 1: 1-1.3, wherein when water is added into the obtained filter cake and the filter cake is stirred, the weight ratio of the added amount of the filter cake to the added amount of the water is 1:5 to 10.
According to the synthesis method of the nafamostat mesylate, the low temperature in the step d is 2-5 ℃.
According to the synthesis method of nafamostat mesylate, the mass of the absolute ethyl alcohol added in the step d is 2-5 times of that of water.
According to the synthesis method of nafamostat mesilate, the drying temperature in the step d is 50-80 ℃, and the drying time is 4-6 h.
The technical scheme of the invention is utilized to synthesize nafamostat mesylate, and the synthesis process route is as follows:
the invention has the following positive beneficial effects:
1. in the synthetic method, the reaction condition is mild, high temperature is not needed in the reaction process, and the post-treatment process is simple, so that the energy consumption can be effectively saved.
2. The synthesis process provided by the invention has the advantages that the adopted raw materials are easy to obtain, the main reaction solvent is ethanol, the process is more environment-friendly, and the process is beneficial to environmental protection.
3. The synthesis process of nafamostat mesilate has less side reaction, and the product has purity over 95%.
In conclusion, the invention has obvious economic benefit and social benefit.
4. Description of the drawings:
FIG. 1 is a liquid chromatogram of nafamostat mesylate, a product prepared in example 1 of the invention;
FIG. 2 shows the nuclear magnetic hydrogen spectrum of nafamostat mesylate, a product prepared in example 1 of the invention.
In fig. 2: 1H NMR (400mhz, dmso) δ 10.28 (s, 1H), 9.48 (s, 2H), 9.24 (s, 2H), 8.59 (s, 1H), 8.27-8.15 (m, 4H), 8.02 (d, J =2.1hz, 1h), 7.90 (s, 4H), 7.88 (d, J = 1.8hz, 1h), 7.65 (dd, J =8.9,2.3hz, 1h), 7.46 (d, J =8.7hz, 2h), 2.45 (s, 6H).
5. The specific implementation mode is as follows:
the invention is further illustrated by the following examples, which do not limit the scope of the invention.
Example 1:
the invention relates to a synthetic method of nafamostat mesilate, which comprises the following detailed steps:
a. preparation of 6-amidino-2-naphtholate salt:
firstly, adding 300mL of absolute ethyl alcohol and 40.8g (0.6 mol) of sodium ethoxide into a 2L reaction bottle, stirring and dissolving, then adding 84.6g (0.5 mol) of 6-cyano-2-naphthol in batches at room temperature, and stirring and reacting for 8 hours at 25 ℃; after the reaction, an aqueous ammonium chloride solution (prepared by dissolving 32.1g (0.6 mol) of ammonium chloride in 100mL of water) was added, the mixture was further stirred at 25 ℃ for 9 hours, after the reaction was completed, the reaction mixture was filtered, the solvent was removed from the filtrate under reduced pressure, the obtained solid was dried (drying temperature 80 ℃ C., drying time 4 hours), and 99.2g of 6-amidino-2-naphtholate was obtained after drying;
b. preparation of 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid:
adding 500mL of absolute ethyl alcohol and 51.0g (0.75 mol) of sodium ethoxide into a three-neck flask for dissolving, then adding 55.3g (0.5 mol) of methoxyisourea hydrochloride, heating to 50 ℃, and stirring for reaction, wherein the reaction time is 1h; cooling the obtained reactant to room temperature after the reaction, and then filtering to obtain filtrate which is an ethanol solution of methoxy isourea;
dissolving 78.3g (0.5 mol) of p-chlorobenzoic acid in 780mL of absolute ethanol, dropwise adding the obtained p-chlorobenzoic acid ethanol solution into the obtained methoxy isourea ethanol solution at the temperature of-10 ℃ (the dropwise adding time is 30 min), and then reacting for 6h at the temperature of 45 ℃; filtering after reaction, evaporating the obtained filtrate at 50 ℃ and under the condition of-0.085 Mpa to remove the solvent ethanol, and obtaining 84.4g of 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid;
c. preparing nafamostat:
adding 300mL of absolute ethanol and 34g (0.5 mol) of sodium ethoxide into a three-mouth reaction bottle for dissolving, then adding the 6-amidino-2-naphtholate prepared in the step a, and stirring and reacting for 2h at the temperature of 50 ℃; cooling to room temperature after the reaction, filtering, transferring the obtained filtrate to a reaction bottle, adding the 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid prepared in the step b, 92.8g (0.45 mol) of dicyclohexylcarbodiimide DCC and 11.0g (0.09 mol) of 4-dimethylaminopyridine DMAP, and reacting at 50 ℃ for 6 hours; adding 42.12g of ammonia water with the mass percentage concentration of 25% into the reactant obtained after the reaction, continuing stirring for reacting for 2 hours, cooling to room temperature after the reaction, and filtering to obtain 139.5g of a filter cake;
d. preparing nafamostat mesylate:
1120g of water is added into the obtained filter cake, the mixture is stirred for 20min, 43.2g (0.45 mol) of methanesulfonic acid is added dropwise at the temperature of 3 ℃, the dropwise adding time is 20min, the stirring is continued for 30min after the dropwise adding is finished, then 4480g of absolute ethyl alcohol is added, the mixture is stirred for 30min at the temperature of 3 ℃ and filtered, the obtained filter cake is dried (the drying temperature is 60 ℃, the drying time is 5 h), and 192.6g of nafamostat mesylate is obtained after the drying (the liquid chromatogram of the obtained product is detailed in figure 1, and the nuclear magnetic hydrogen chromatogram is detailed in figure 2).
Example 2:
the invention relates to a synthetic method of nafamostat mesilate, which comprises the following detailed steps:
a. preparation of 6-amidino-2-naphtholate salt:
firstly, adding 300mL of absolute ethyl alcohol and 51.0g (0.75 mol) of sodium ethoxide into a 2L reaction bottle for stirring and dissolving, then adding 84.6g (0.5 mol) of 6-cyano-2-naphthol in batches at room temperature, and stirring and reacting for 10 hours at 25 ℃; after the reaction, an aqueous ammonium chloride solution (prepared by dissolving 40.1g (0.75 mol) of ammonium chloride in 100mL of water) was added, the mixture was further stirred at 25 ℃ for 10 hours, after the reaction, the mixture was filtered, the solvent was removed from the filtrate under reduced pressure, and the obtained solid was dried (drying temperature 60 ℃ C., drying time 6 hours) to obtain 92.4g of 6-amidino-2-naphtholate;
b. preparation of 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid:
adding 500mL of absolute ethyl alcohol and 51.0g (0.75 mol) of sodium ethoxide into a three-neck flask for dissolving, then adding 55.3g (0.5 mol) of methoxyisourea hydrochloride, heating to 60 ℃, and stirring for reaction, wherein the reaction time is 1h; cooling the obtained reactant to room temperature after the reaction, and then filtering to obtain filtrate, wherein the filtrate is an ethanol solution of methoxy isourea;
dissolving 78.3g (0.5 mol) of p-chlorobenzoic acid in 700mL of absolute ethanol, dropwise adding the obtained p-chlorobenzoic acid ethanol solution into the obtained methoxy isourea ethanol solution at the temperature of-7 ℃ (the dropwise adding time is 40 min), and then reacting for 5h at the temperature of 50 ℃; filtering after reaction, evaporating the obtained filtrate at 50 ℃ and under the condition of-0.085 Mpa to remove the solvent ethanol, and obtaining 81.5g of 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid;
c. preparing nafamostat:
adding 420mL of absolute ethanol and 42.4g (0.6 mol) of sodium ethoxide into a three-mouth reaction bottle for dissolving, then adding the 6-amidino-2-naphtholate prepared in the step a, and stirring and reacting for 1h at the temperature of 60 ℃; cooling to room temperature after reaction, filtering, transferring the obtained filtrate to a reaction bottle, adding the 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid prepared in the step b, 130.0g (0.6 mol) of dicyclohexylcarbodiimide DCC and 15.4g (0.13 mol) of 4-dimethylaminopyridine DMAP, and reacting at the temperature of 40 ℃ for 5 hours; adding 45.4g of ammonia water with the mass percentage concentration of 25% into the reactant obtained after the reaction, continuously stirring for reacting for 3 hours, cooling to room temperature after the reaction, and filtering to obtain 120.0g of filter cake;
d. preparation of nafamostat mesylate:
adding 600g of water into the obtained filter cake, stirring for 30min, dropwise adding 52.5g (0.55 mol) of methanesulfonic acid at 5 ℃, dropwise adding for 30min, continuously stirring for 30min after dropwise adding, then adding 1800g of absolute ethanol, stirring for 40min at 5 ℃, filtering, drying the obtained filter cake (the drying temperature is 60 ℃, the drying time is 5 h), and drying to obtain 183.6g of nafamostat mesylate.
Example 3:
the invention relates to a synthetic method of nafamostat mesilate, which comprises the following detailed steps:
a. preparation of 6-amidino-2-naphtholate salt:
firstly, adding 260mL of absolute ethyl alcohol and 37.4g (0.55 mol) of sodium ethoxide into a 2L reaction bottle, stirring and dissolving, then adding 84.6g (0.5 mol) of 6-cyano-2-naphthol in batches at room temperature, and stirring and reacting for 9 hours at 25 ℃; after the reaction, an aqueous ammonium chloride solution (prepared by dissolving 29.4g (0.55 mol) of ammonium chloride in 100mL of water) was added, the mixture was further stirred at 25 ℃ for 8 hours, after the reaction, the mixture was filtered, the solvent was removed from the filtrate under reduced pressure, and the obtained solid was dried (drying temperature: 70 ℃ C., drying time: 5 hours) to obtain 89.0g of 6-amidino-2-naphtholate;
b. preparation of 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid:
adding 240mL of absolute ethyl alcohol and 34.0g (0.5 mol) of sodium ethoxide into a three-neck flask for dissolving, then adding 55.3g (0.5 mol) of methoxy isourea hydrochloride, heating to 40 ℃, and stirring for reacting for 3h; cooling the obtained reactant to room temperature after the reaction, and then filtering to obtain filtrate which is an ethanol solution of methoxy isourea;
dissolving 78.3g (0.5 mol) of p-chlorobenzoic acid in 550mL of absolute ethanol, dropwise adding the obtained p-chlorobenzoic acid ethanol solution into the obtained methoxy isourea ethanol solution at the temperature of-5 ℃ (the dropwise adding time is 20 min), and then reacting for 8h at the temperature of 40 ℃; filtering after reaction, evaporating the obtained filtrate at 50 ℃ and under the condition of-0.085 Mpa to remove the solvent ethanol, and obtaining 78.6g of 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid;
c. preparing nafamostat:
adding 240mL of absolute ethyl alcohol and 29.9g (0.44 mol) of sodium ethoxide into a three-mouth reaction bottle for dissolving, then adding the 6-amidino-2-naphtholate prepared in the step a, and stirring and reacting for 1h at the temperature of 50 ℃; cooling to room temperature after reaction, filtering, transferring the obtained filtrate to a reaction bottle, adding the 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid prepared in the step b, 99.0g (0.48 mol) of dicyclohexylcarbodiimide DCC and 4.9g (0.04 mol) of 4-dimethylaminopyridine DMAP, and reacting at 30 ℃ for 8 hours; adding 34.6g of ammonia water with the mass percentage concentration of 25% into the reactant obtained after the reaction, continuing stirring for reacting for 3 hours, cooling to room temperature after the reaction, and filtering to obtain 136.7g of a filter cake;
d. preparation of nafamostat mesylate:
1300g of water is added into the obtained filter cake and stirred for 10min, 38.4g (0.40 mol) of methanesulfonic acid is dropwise added at the temperature of 2 ℃, the dropwise adding time is 20min, stirring is continued for 30min after the dropwise adding is finished, 6500g of absolute ethyl alcohol is then added, stirring is carried out for 20min at the temperature of 2 ℃, filtering is carried out, the obtained filter cake is dried (the drying temperature is 60 ℃, the drying time is 5 h), and 172.7g of nafamostat mesylate is obtained after drying.
Claims (10)
1. A synthetic method of nafamostat mesylate is characterized by comprising the following steps:
a. preparation of 6-amidino-2-naphtholate salt:
firstly, adding absolute ethyl alcohol and sodium ethoxide into a reaction vessel for stirring and dissolving, then adding 6-cyano-2-naphthol in batches at room temperature, and stirring and reacting for 8-10 h at room temperature after the addition; after the reaction, adding an ammonium chloride aqueous solution with the mass percentage concentration of 20-35%, continuously stirring and reacting for 8-10 h at room temperature, filtering after the reaction is finished, decompressing the filtrate to remove the solvent, and drying to obtain 6-amidino-2-naphthol hydrochloride;
b. preparation of 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid:
adding absolute ethyl alcohol and sodium ethoxide into a reaction container for dissolving, then adding methoxy isourea hydrochloride, heating to 40-60 ℃, and stirring for reaction for 1-3 h; cooling the obtained reactant to room temperature after the reaction, and then filtering to obtain filtrate which is an ethanol solution of methoxy isourea;
dissolving p-chlorobenzoic acid in absolute ethyl alcohol, dripping the obtained p-chlorobenzoic acid ethyl alcohol solution into the obtained methoxy isourea ethyl alcohol solution at low temperature, and then reacting for 5-8 h at 40-50 ℃; filtering after the reaction, and removing the solvent ethanol from the obtained filtrate to obtain 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid;
c. preparing nafamostat:
b, adding absolute ethyl alcohol and sodium ethoxide into a reaction container for dissolving, adding the 6-amidino-2-naphthol hydrochloride prepared in the step a after dissolving, and stirring and reacting for 1-3 h at the temperature of 40-60 ℃; cooling to room temperature after reaction, filtering, transferring the obtained filtrate to a reaction vessel, adding the 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid, dicyclohexylcarbodiimide DCC and 4-dimethylaminopyridine DMAP prepared in the step b, and reacting at the temperature of 30-50 ℃ for 5-8 hours; adding 25% ammonia water into the reactant obtained after the reaction, continuously stirring and reacting for 1-3 h, cooling to room temperature after the reaction, and filtering;
d. preparation of nafamostat mesylate:
and c, adding water into the filter cake obtained after filtering in the step c, stirring for 10-30 min, dropwise adding methanesulfonic acid at low temperature for 15-30 min, continuously stirring for 20-40 min after dropwise adding, then adding absolute ethanol, stirring for 20-40 min at low temperature, filtering, drying the obtained filter cake, and drying to obtain nafamostat mesylate.
2. The method for synthesizing nafamostat mesylate according to claim 1, wherein the method comprises the following steps: in the step a, the mol ratio of the 6-cyano-2-naphthol to the sodium ethoxide to the ammonium chloride is 1:1.1 to 1.5:1.1 to 1.5; the mass volume ratio of the 6-cyano-2-naphthol to the absolute ethyl alcohol is 1g:3 to 5mL.
3. The method for synthesizing nafamostat mesylate according to claim 1, wherein the method comprises the following steps: in the step a, the drying temperature is 60-80 ℃ and the drying time is 4-6 h.
4. The method for synthesizing nafamostat mesylate according to claim 1, wherein the method comprises the following steps: in the step b, the molar ratio of the methoxy isourea hydrochloride to the sodium ethoxide to the p-chlorobenzoic acid is 1:1 to 1.5:1;
when the p-chlorobenzoic acid is dissolved in the absolute ethyl alcohol, the mass volume ratio of the p-chlorobenzoic acid to the absolute ethyl alcohol is 1g: 5-10 mL;
when the sodium ethoxide is dissolved in the absolute ethyl alcohol, the mass volume ratio of the sodium ethoxide to the absolute ethyl alcohol is 1g:7 to 10mL.
5. The method for synthesizing nafamostat mesylate according to claim 1, wherein the method comprises the following steps: in the step b, the low temperature is-10 to-5 ℃.
6. The method for synthesizing nafamostat mesylate according to claim 1, wherein the method comprises the following steps: the molar ratio of the 6-amidino-2-naphthol hydrochloride, the 4- [ (2-methyl-isoureido) -methyl ] -benzoic acid, the dicyclohexylcarbodiimide DCC, the 4-dimethylaminopyridine DMAP, the sodium ethoxide and the ammonia added in the step c is 1:1.0 to 1.2: 1.2-1.5: 0.1 to 0.3:1.1 to 1.5:1.2 to 1.5;
when the sodium ethoxide is dissolved in the absolute ethyl alcohol, the mass volume ratio of the sodium ethoxide to the absolute ethyl alcohol is 1g:8 to 10mL.
7. The method for synthesizing nafamostat mesylate according to claim 1, wherein the method comprises the following steps: the molar ratio of the 6-amidino-2-naphthol hydrochloride to the methanesulfonic acid added in step d is 1: 1-1.3, wherein when water is added into the obtained filter cake and the filter cake is stirred, the weight ratio of the added amount of the filter cake to the added amount of the water is 1:5 to 10.
8. The method for synthesizing nafamostat mesylate according to claim 1, wherein the method comprises the following steps: in the step d, the low temperature is 2-5 ℃.
9. The method for synthesizing nafamostat mesylate according to claim 1, wherein the method comprises the following steps: in the step d, the adding mass of the absolute ethyl alcohol is 2-5 times of that of water.
10. The method for synthesizing nafamostat mesylate according to claim 1, wherein the method comprises the following steps: and d, drying at the drying temperature of 50-80 ℃ for 4-6 h in the step d.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111338004.7A CN113999145B (en) | 2021-11-12 | 2021-11-12 | Synthetic method of nafamostat mesylate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111338004.7A CN113999145B (en) | 2021-11-12 | 2021-11-12 | Synthetic method of nafamostat mesylate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113999145A CN113999145A (en) | 2022-02-01 |
| CN113999145B true CN113999145B (en) | 2023-02-03 |
Family
ID=79928678
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111338004.7A Active CN113999145B (en) | 2021-11-12 | 2021-11-12 | Synthetic method of nafamostat mesylate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113999145B (en) |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4454338A (en) * | 1980-09-16 | 1984-06-12 | Torii & Co., Ltd. | Amidine compound |
| US6388122B1 (en) * | 1996-04-10 | 2002-05-14 | Ono Pharmaceutical Co., Ltd. | Tryptase inhibitor and novel guanidino derivatives |
| JP2004284982A (en) * | 2003-03-20 | 2004-10-14 | Kanto Chem Co Inc | Method for esterifying 4-guanidinobenzoic acid or its derivative |
| JP2012087099A (en) * | 2010-10-21 | 2012-05-10 | Katsura Chemical Co Ltd | Method for crystallizing nafamostat mesilate |
| CN103012214A (en) * | 2011-09-28 | 2013-04-03 | 南京长澳医药科技有限公司 | Method for preparing nafamostat hydrochloride and nafamostat mesylate |
| WO2014007326A1 (en) * | 2012-07-04 | 2014-01-09 | 味の素株式会社 | Process for producing nafamostat mesylate |
| CN103641749A (en) * | 2013-12-02 | 2014-03-19 | 山东永泰化工有限公司 | Preparation method of nafamostat mesylate |
| CN103896809A (en) * | 2012-12-25 | 2014-07-02 | 北京蓝贝望生物医药科技股份有限公司 | New 6-amidino-2-naphthol methanesulfonate synthesis method |
| KR20150084165A (en) * | 2014-01-13 | 2015-07-22 | 주식회사 엔지켐생명과학 | Method for preparing of nafamostat mesilate |
| KR102314436B1 (en) * | 2021-01-27 | 2021-10-19 | (주)국전약품 | Process for Preparing Nafamostat Mesilate and Intermediate Thereof |
-
2021
- 2021-11-12 CN CN202111338004.7A patent/CN113999145B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4454338A (en) * | 1980-09-16 | 1984-06-12 | Torii & Co., Ltd. | Amidine compound |
| US6388122B1 (en) * | 1996-04-10 | 2002-05-14 | Ono Pharmaceutical Co., Ltd. | Tryptase inhibitor and novel guanidino derivatives |
| JP2004284982A (en) * | 2003-03-20 | 2004-10-14 | Kanto Chem Co Inc | Method for esterifying 4-guanidinobenzoic acid or its derivative |
| JP2012087099A (en) * | 2010-10-21 | 2012-05-10 | Katsura Chemical Co Ltd | Method for crystallizing nafamostat mesilate |
| CN103012214A (en) * | 2011-09-28 | 2013-04-03 | 南京长澳医药科技有限公司 | Method for preparing nafamostat hydrochloride and nafamostat mesylate |
| WO2014007326A1 (en) * | 2012-07-04 | 2014-01-09 | 味の素株式会社 | Process for producing nafamostat mesylate |
| CN103896809A (en) * | 2012-12-25 | 2014-07-02 | 北京蓝贝望生物医药科技股份有限公司 | New 6-amidino-2-naphthol methanesulfonate synthesis method |
| CN103641749A (en) * | 2013-12-02 | 2014-03-19 | 山东永泰化工有限公司 | Preparation method of nafamostat mesylate |
| KR20150084165A (en) * | 2014-01-13 | 2015-07-22 | 주식회사 엔지켐생명과학 | Method for preparing of nafamostat mesilate |
| KR102314436B1 (en) * | 2021-01-27 | 2021-10-19 | (주)국전약품 | Process for Preparing Nafamostat Mesilate and Intermediate Thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113999145A (en) | 2022-02-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111423452B (en) | Intermediate of Rayleigh Lu Geli and preparation method and application thereof | |
| CN105884628B (en) | The preparation method of 2,4- di-t-butyl -5- amino phenols | |
| CN102140086A (en) | Method for synthesizing vitamin C crude product by adopting L-gulonic acid | |
| CN106892950B (en) | Preparation method of high-content troxerutin | |
| CN114920691B (en) | Preparation method of N- (2-hydroxyethyl) nicotinamide and preparation method of nicorandil | |
| CN112300212A (en) | Use of borane-pyridine complexes for the preparation of NK-1 receptor antagonists | |
| CN104387299B (en) | The preparation method of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide | |
| CN113999145B (en) | Synthetic method of nafamostat mesylate | |
| CN109384827A (en) | A kind of budesonide industrialized process for preparing | |
| CN103788010A (en) | Febuxostat intermediate and preparation method thereof | |
| CN103044272B (en) | Preparation method of 4-nitroso-N-ethyl-N-hydroxyethyl aniline | |
| CN111848505A (en) | Preparation method of vatacostat intermediate | |
| CN102464661A (en) | Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester | |
| CN110642789B (en) | Continuous synthesis method of 2-chloropyrimidine-4-formic acid compound | |
| AU2021297767A1 (en) | Preparation method for aromatic ether compound | |
| CN110330447A (en) | A kind of preparation method and applications of Nafamostat Mesilate intermediate | |
| CN109824539B (en) | Novel method for synthesizing tigecycline from demethyl aureomycin | |
| CN108794392B (en) | Method for synthesizing sorafenib by solid-state ball milling | |
| CN112552345A (en) | Preparation method of NK-1 receptor antagonist | |
| CN112047896A (en) | Method for synthesizing aromatic ring group or aromatic heterocyclic group tetrazole | |
| CN111153953A (en) | Efficient synthesis method of nicotinamide riboside chloride | |
| CN112062705A (en) | Synthesis method of 7-methyltryptophan | |
| CN111253369A (en) | Benzene sulfonate, preparation method thereof and application of benzene sulfonate in preparation of dabigatran etexilate | |
| CN112574106B (en) | Synthesis method of 7-amino-5-bromoquinoline | |
| CN113816949B (en) | Preparation method of arotinolol hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |