A preparation method of nafamostat mesylate

Abstract

The present invention relates to the field of chemical pharmaceutical technology, and specifically discloses a preparation method of nafamostat mesylate. 6-amidino-2-naphthol mesylate, p-guanidinobenzoic acid hydrochloride and EDCI are added to a first solvent to carry out a condensation reaction; then a saturated sodium bicarbonate aqueous solution is added to obtain an intermediate; the intermediate is added to a second solvent, and then methanesulfonic acid is added to form a salt, and purified to obtain nafamostat mesylate. EDCI first reacts with the first solvent to be activated, and the oxygen atom on the carbonyl carbon of the carboxylic acid is positively charged in the activated EDCI, thereby increasing the electrophilicity of the carboxylic acid and forming an active intermediate, making it easier for it to undergo a nucleophilic substitution reaction with an alcohol, and undergoing dehydration condensation to form an ester bond. The present invention uses EDCI as a condensing agent, improves the production efficiency and yield of nafamostat mesylate, improves the purity of nafamostat mesylate, reduces the impurity content, and is low in cost and easy to industrialize.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical pharmacy, and in particular to a preparation method of nafamostat mesylate. Background Art

[0002] Nafamostat mesylate, chemical formula: C 21 H 25 N5O8S2, with its molecular structure shown in Formula I, is a synthetic serine protease inhibitor used as an anticoagulant in hemodialysis. It has a wide range of pharmacological activities and is commonly used clinically to treat diseases such as acute pancreatitis and disseminated intravascular coagulation.

[0003]

[0004] Formula I

[0005] However, existing methods for preparing nafamostat mesylate are less than satisfactory in removing impurities. The presence of impurities not only affects the activity and stability of the drug but can also trigger adverse reactions, posing a potential threat to patient health. Certain impurities may interact with the target compound, altering the drug's pharmacological properties and leading to reduced or uncertain therapeutic efficacy. With the growing market demand for nafamostat mesylate, higher requirements are being placed on its production efficiency and quality to ensure its full efficacy and safety. Furthermore, traditional methods for preparing nafamostat mesylate (including purification) generally rely on complex and expensive equipment and reagents, increasing production costs and operational difficulty, limiting the drug's widespread application.

[0006] How to quickly and efficiently produce high-purity nafamostat mesylate, reduce the impurity content, and facilitate industrial production is a problem that needs to be solved. Summary of the Invention

[0007] In response to the above problems, the present invention provides a preparation method of nafamostat mesylate, which uses 6-amidino-2-naphthol mesylate and p-guanidinobenzoic acid hydrochloride as reactants and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) as a condensing agent. The method improves the production efficiency and yield of nafamostat mesylate, significantly improves the purity of nafamostat mesylate, and reduces the impurity content.

[0008] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0009] A preparation method of nafamostat mesylate comprises the following steps:

[0010] S1, adding 6-amidino-2-naphthol methanesulfonate, p-guanidinobenzoic acid hydrochloride, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to a first solvent to carry out a condensation reaction; then adding a saturated sodium bicarbonate aqueous solution to obtain an intermediate as shown in Formula 1;

[0011] S2, adding the intermediate to a second solvent, then adding methanesulfonic acid to form a salt, and purifying to obtain nafamostat mesylate;

[0012]

[0013] Formula 1.

[0014] Compared with the prior art, the present invention provides a method for preparing nafamostat mesylate, which uses 6-amidino-2-naphthol mesylate (whose molecular structure is shown in Formula II) and p-guanidinobenzoic acid hydrochloride (whose molecular structure is shown in Formula III) as reactants, and uses EDCI as a condensing agent. EDCI reacts with a reaction solvent (a first solvent) in a reaction system to be first activated. The activated EDCI reacts with a carboxylic acid, where the nitrogen atom in EDCI is positively charged, and the oxygen atom on the carbonyl carbon of the carboxylic acid is partially positively charged. This positive charge increases the electrophilicity of the carboxylic acid, further forming an active intermediate, making it more susceptible to subsequent reaction with an alcohol. The electrophilic active intermediate is attacked by the alcohol, and the oxygen atom in the alcohol undergoes nucleophilic substitution on the carbonyl carbon of the active intermediate. The carboxyl group of the carboxylic acid undergoes dehydration condensation with the hydroxyl group of the alcohol to form an ester bond, while generating byproducts (such as water-soluble urea generated by the reaction of EDCI and the carboxylic acid). The byproducts are easy to handle and can be effectively separated and removed by simply adding a saturated sodium bicarbonate aqueous solution.

[0015]

[0016] Formula II

[0017]

[0018] Formula III.

[0019] Compared with DCC (dicyclohexylcarbodiimide) and DIC (diisopropylcarbodiimide), using EDCI as a condensation agent has the following advantages:

[0020] (1) By-products are easy to handle: Dicyclohexylurea produced by the DCC reaction has a certain solubility in general organic phases and is relatively difficult to handle; diisopropylurea produced by DIC has relatively good solubility in organic solvents, but is still not as easy to handle as the water-soluble urea produced after the EDCI reaction.

[0021] (2) Avoiding the occurrence of certain side reactions: The use of EDCI can avoid the combination of amine and carboxyl groups, making the condensation reaction more selective, reducing the generation of by-products, and helping to improve the purity and yield of the target product.

[0022] (3) High catalytic efficiency: The stronger electrophilicity of EDCI molecules makes it easier for EDCI to react with carboxylic acids. EDCI can more effectively activate carboxylic acids in the reaction system, making it easier for them to react with p-guanidinobenzoic acid hydrochloride. This means that under the same reaction conditions, EDCI can promote the reaction more quickly, improving the reaction efficiency and yield.

[0023] (4) Cost savings: In condensation esterification reactions involving DCC or DIC, a catalytic amount of DMAP (4-dimethylaminopyridine) is usually required to accelerate the reaction. DMAP acts as a nucleophilic acyl transfer reagent, reacting with O-acylisourea to form an active amide ("active ester") intermediate, thereby reducing side reactions and accelerating ester formation. However, the use of EDCI eliminates the need for DMAP, thereby improving reaction efficiency and yield, and increasing the purity of nafamostat mesylate.

[0024] The preparation method of nafamostat mesylate provided by the present invention is simple to operate, low in cost, and easy to industrialize; it not only improves the production efficiency and yield of nafamostat mesylate, but also significantly improves the purity of nafamostat mesylate and reduces the impurity content.

[0025] Preferably, in S1, the preparation method of 6-amidino-2-naphthol methanesulfonate comprises the following steps:

[0026] S1-1, hydrogen chloride is introduced into solvent a, and 6-cyano-2-naphthol is added to carry out an alkalization reaction to obtain compound 1 as shown in formula 2;

[0027] S1-2, adding solvent b and an aminating agent to the compound 1 to carry out an aminolysis reaction, cooling and crystallizing to obtain compound 2 as shown in formula 3;

[0028] S1-3, adding the compound 2 to solvent c, then adding methanesulfonic acid to form a salt, cooling and crystallizing to obtain the 6-amidino-2-naphthol methanesulfonate;

[0029]

[0030] Formula 2

[0031]

[0032] Formula 3.

[0033] The invention further improves the yield and purity of 6-amidino-2-naphthol methanesulfonate by limiting the preparation method of 6-amidino-2-naphthol methanesulfonate.

[0034] Further preferably, in S1-1, the solvent a is selected from methanol, ethanol or isopropanol.

[0035] Further preferably, in S1-1, the mass ratio of the 6-cyano-2-naphthol, the solvent a and the hydrogen chloride is 1:(1-20):(1-10), and further preferably 1:(10-20):(3-7).

[0036] More preferably, in S1-1, the alkalization reaction temperature is 10°C to 50°C, and the reaction time is 10 hours to 25 hours. More preferably, in S1-1, the alkalization reaction temperature is 20°C to 30°C, and the reaction time is 11 hours to 15 hours.

[0037] Further preferably, in S1-2, the solvent b is selected from methanol or ethanol.

[0038] More preferably, in S1-2, the aminating agent is aqueous ammonia.

[0039] Further preferably, in S1-2, the mass ratio of the compound 1, the solvent b and the aminating agent is 1:(1-20):(1-10), and further preferably 1:(10-15):(3-7).

[0040] Further preferably, in S1-2, the temperature of the ammonolysis reaction is 20°C to 80°C, and the reaction time is 2 hours to 10 hours. More preferably, in S1-2, the temperature of the ammonolysis reaction is 50°C to 60°C, and the reaction time is 3 hours to 4 hours.

[0041] Further preferably, in S1-2, the temperature of the cooling crystallization is 0°C to 10°C, and the crystallization time is 1h to 2h.

[0042] Further preferably, in S1-3, the solvent c is selected from methanol or ethanol.

[0043] Further preferably, in S1-3, the mass ratio of the compound 2, the solvent c and the methanesulfonic acid is 1:(5~10):(0.01~1), and further preferably 1:(6~8):(0.4~0.8).

[0044] Further preferably, in S1-3, the salt formation temperature is 10°C to 50°C, and the salt formation time is 0.5h to 2h. More preferably, in S1-3, the salt formation temperature is 20°C to 30°C, and the salt formation time is 1.5h to 2h.

[0045] Further preferably, in S1-3, the temperature of the cooling crystallization is 0°C to 10°C, and the crystallization time is 1h to 3h.

[0046] Preferably, in S1, the preparation method of p-guanidinobenzoic acid hydrochloride comprises the following steps:

[0047] S1-4, adding p-aminobenzoic acid to solvent d, adding cyanamide for addition reaction, adding hydrochloric acid aqueous solution, cooling and crystallizing to obtain the p-guanidinobenzoic acid hydrochloride.

[0048] The invention further improves the yield and purity of p-guanidinobenzoic acid hydrochloride by limiting the preparation method of p-guanidinobenzoic acid hydrochloride.

[0049] Further preferably, in S1-4, the solvent d is a 14 wt% to 17 wt% aqueous solution of hydrochloric acid; the mass concentration is more preferably 55% to 60%.

[0050] Further preferably, in S1-4, the mass ratio of the p-aminobenzoic acid, the solvent d and the cyanamide is 1:(1~10):(1~10), and further preferably 1:(1~5):(1~3).

[0051] More preferably, in S1-4, the temperature of the addition reaction is 20°C to 80°C, and the reaction time is 2h to 12h. More preferably, in S1-4, the temperature of the addition reaction is 20°C to 30°C, and the reaction time is 2h to 4h.

[0052] Further preferably, in S1-4, the mass concentration of the hydrochloric acid aqueous solution is 1% to 10%, and further preferably 3% to 5%.

[0053] Further preferably, in S1-4, the mass ratio of the p-aminobenzoic acid to the aqueous hydrochloric acid solution is 1:(2.5~3.5).

[0054] Further preferably, in S1-4, the temperature of the cooling crystallization is 0°C to 10°C, and the crystallization time is 1h to 2h.

[0055] Preferably, in S1, the mass ratio of the 6-amidino-2-naphthol methanesulfonate, the p-guanidinobenzoic acid hydrochloride, the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and the first solvent is 1:(0.5~3):(0.5~5):(8~12), and more preferably 1:(0.7~1.5):(0.8~1.8):(9~11).

[0056] Preferably, in S1, the first solvent is dichloromethane.

[0057] The present invention selects dichloromethane as the first solvent, which can promote the condensation reaction and achieve a technical effect equivalent to or even better than that of pyridine, overcoming the defects of pyridine such as high toxicity and high cost.

[0058] Preferably, in S1, the condensation reaction temperature is -30°C to 30°C, and the reaction time is 1 hour to 12 hours. Further preferably, in S1, the condensation reaction temperature is 5°C to 15°C, and the reaction time is 4 hours to 5 hours.

[0059] Preferably, in S1, the mass ratio of the 6-amidino-2-naphthol methanesulfonate to the saturated sodium bicarbonate aqueous solution is 1:(3-3.5).

[0060] The present invention further promotes the progress of the condensation reaction by limiting the conditions of the condensation reaction, thereby improving the purity and yield of the intermediate.

[0061] Preferably, in S2, the second solvent is selected from acetone aqueous solution or dichloromethane aqueous solution.

[0062] Further preferably, in S2, the mass ratio of acetone or dichloromethane to water in the second solvent is 1:(3.5~4.5).

[0063] Preferably, in S2, the mass ratio of the intermediate, the second solvent and the methanesulfonic acid is 1:(10-30):(1-10), more preferably 1:(15-25):(3-5).

[0064] Preferably, in S2, the salt formation temperature is 10°C to 50°C, and the salt formation time is 0.5h to 10h. More preferably, in S2, the salt formation temperature is 10°C to 15°C, and the salt formation time is 1h to 2h.

[0065] Preferably, in S2, the purification comprises the following steps:

[0066] The crude product of nafamostat mesylate obtained after the salt formation is added to a third solvent, activated carbon is added for decolorization, and the mixture is filtered; the obtained filtrate is cooled and crystallized to obtain nafamostat mesylate.

[0067] Further preferably, in S2, the third solvent is selected from at least two of water, acetone, methyl tert-butyl ether, tert-butyl acetate, methanol or ethanol.

[0068] Further preferably, in S2, the mass ratio of the crude nafamostat mesylate, the third solvent and the activated carbon is 1:(1-5):(0.01-1), more preferably 1:(3-3.5):(0.05-0.15).

[0069] Further preferably, in S2, the decolorization temperature is 40°C to 60°C, and the decolorization time is 30 min to 60 min.

[0070] Further preferably, in S2, the temperature of the cooling and crystallization is 0°C to 20°C, and the crystallization time is 1 to 10 hours. More preferably, in S2, the temperature of the cooling and crystallization is 0°C to 10°C, and the crystallization time is 1 to 2 hours.

[0071] The present invention adopts a specific purification method, which is simple, reduces labor costs and training costs, has high purification efficiency, can achieve efficient purification of nafamostat mesylate in a relatively short time, and has low raw material costs, is suitable for large-scale industrial production, and has high market competitiveness. The specific third solvent can fully dissolve the target compound, laying a good foundation for subsequent impurity removal, and can also be recycled; the specific amount of activated carbon can accurately adsorb impurities while having minimal adsorption effect on the target compound, thereby retaining the active ingredient to the greatest extent and improving the yield of the nafamostat mesylate product. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 is a high-resolution mass spectrometer of nafamostat mesylate in Example 1 of the present invention;

[0073] Figure 2 For the nafamostat mesylate in Example 1 of the present invention 1 HNMR spectrum;

[0074] Figure 3 For the nafamostat mesylate in Example 1 of the present invention 13 CNMR spectrum;

[0075] Figure 4 HPLC spectrogram of nafamostat mesylate in Example 1 of the present invention;

[0076] Figure 5 HPLC spectrogram of nafamostat mesylate in Example 2 of the present invention;

[0077] Figure 6 HPLC spectrogram of nafamostat mesylate in Example 3 of the present invention;

[0078] Figure 7 HPLC spectrogram of nafamostat mesylate in Example 4 of the present invention;

[0079] Figure 8 HPLC spectrogram of nafamostat mesylate in Example 5 of the present invention;

[0080] Figure 9 HPLC spectrogram of the crude product of nafamostat mesylate in Comparative Example 1 of the present invention;

[0081] Figure 10 HPLC spectrogram of the crude product of nafamostat mesylate in Comparative Example 2 of the present invention;

[0082] Figure 11 The HPLC spectrum of the crude product of nafamostat mesylate in Comparative Example 3 of the present invention is shown. DETAILED DESCRIPTION

[0083] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0084] A method for preparing nafamostat mesylate (reaction equation is shown in Formula IV), comprising the following steps:

[0085] S1, prepare 6-amidino-2-naphthol methanesulfonate and p-guanidinobenzoic acid hydrochloride respectively:

[0086] S1-1, hydrogen chloride is introduced into solvent a, and 6-cyano-2-naphthol is added to carry out an alkalization reaction to obtain compound 1 as shown in formula 2;

[0087] S1-2, adding solvent b and an aminating agent to the compound 1 to carry out an aminolysis reaction, cooling and crystallizing to obtain compound 2 as shown in formula 3;

[0088] S1-3, adding the compound 2 to solvent c, then adding methanesulfonic acid to form a salt, cooling and crystallizing to obtain the 6-amidino-2-naphthol methanesulfonate;

[0089] S1-4, adding p-aminobenzoic acid to solvent d, adding cyanamide for addition reaction, adding aqueous hydrochloric acid, cooling and crystallizing to obtain the p-guanidinobenzoic acid hydrochloride;

[0090] S2, adding the 6-amidino-2-naphthol methanesulfonate, the p-guanidinobenzoic acid hydrochloride, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to a first solvent to carry out a condensation reaction; then adding a saturated sodium bicarbonate aqueous solution to obtain an intermediate as shown in Formula 1;

[0091] S3, adding the intermediate to a second solvent, and then adding methanesulfonic acid to form a salt to obtain a crude product of nafamostat mesylate;

[0092] S4, adding the crude product of nafamostat mesylate to a third solvent, adding activated carbon for decolorization, filtering to remove the activated carbon; cooling the obtained filtrate for crystallization to obtain nafamostat mesylate.

[0093]

[0094] Formula IV.

[0095] It should be noted that there is no order between S1-1~S1-3 and S1-4.

[0096] Example 1

[0097] This embodiment provides a preparation method of nafamostat mesylate, comprising the following steps:

[0098] S1, prepare 6-amidino-2-naphthol methanesulfonate and p-guanidinobenzoic acid hydrochloride respectively:

[0099] S1-1. Add 75.01 g of hydrogen chloride to 225.00 g of methanol. After the addition is complete, add 15.00 g (0.09 mol) of 6-cyano-2-naphthol. The mass ratio of 6-cyano-2-naphthol, methanol, and hydrogen chloride is 1:15:5. Mix well, and carry out alkalization reaction at 25°C. Keep warm for 13 h, and filter to obtain compound 1.

[0100] S1-2, add 13 times the mass of methanol and 5 times the mass of ammonia water to compound 1, mix well, and carry out ammonolysis reaction at 50°C and keep warm for 4 hours; after the reaction is completed, cool the ice bath to 5°C, crystallize for 1 hour, and filter to obtain compound 2.

[0101] S1-3, compound 2 was added to 6.6 times the mass of methanol and 0.6 times the mass of methanesulfonic acid, mixed evenly, and stirred at 20°C for 2 h to form a salt. The temperature was lowered to 5°C, crystallized for 2 h, and filtered to obtain 23.21 g (0.08 mol) of 6-amidino-2-naphthol methanesulfonate, with a yield of 92.73%.

[0102] S1-4, add 25.00 g (0.18 mol) of p-aminobenzoic acid to a hydrochloric acid aqueous solution (25.00 g of purified water and 37.50 g of concentrated hydrochloric acid), and stir to add 50.00 g of cyanamide. The mass ratio of p-aminobenzoic acid, hydrochloric acid aqueous solution, and cyanamide is 1:2.5:2. The addition reaction is carried out at 20°C and kept warm for 4 hours. After the reaction is completed, add 75.00 g of 4 wt% dilute hydrochloric acid, mix well, cool to 5°C, crystallize for 1 hour, and filter to obtain 38.00 g (0.18 mol) of p-guanidinobenzoic acid hydrochloride in a yield of 96.67%.

[0103] There is no order between S1-1~S1-3 and S1-4.

[0104] S2, take 20.00g (0.07mol) of 6-amidino-2-naphthol methanesulfonate, 30.00g (0.14mol) of p-guanidinobenzoic acid hydrochloride, and 26.00g of EDCI and add them to 200.00g of dichloromethane. The mass ratio of 6-amidino-2-naphthol methanesulfonate, p-guanidinobenzoic acid hydrochloride, EDCI and dichloromethane is 1:1.5:1.3:10. Mix well and carry out condensation reaction at 10°C for 5h. After completion of the reaction, add 65.08g of saturated sodium bicarbonate aqueous solution and filter to obtain 32.98g (0.07mol) of the intermediate with a yield of 98.75%.

[0105] S3. The intermediate was added to a second solvent (527.68 g purified water and 131.92 g acetone), and 131.92 g methanesulfonic acid was added dropwise at room temperature. The mass ratio of the intermediate, the second solvent, and methanesulfonic acid was 1:20:4. After the addition, the mixture was stirred at 10°C for 3 h to form a salt. The mixture was filtered and dried under vacuum at 50°C for 6 h to obtain 34.88 g (0.06 mol) of crude nafamostat mesylate. The yield was 92.40%, the purity was 99.449%, and the maximum single impurity was 0.135%.

[0106] S4, taking 10.0g of the crude product of nafamostat mesylate, adding it to 35.0g of the third solvent (a mixed solution of water, acetone and tert-butyl acetate in a mass ratio of 1:1:1), mixing them evenly, adding 0.5g of activated carbon, the mass ratio of the crude product of nafamostat mesylate, the third solvent and the activated carbon being 1:3.5:0.05, stirring and decolorizing at 50°C for 45min, filtering to remove the activated carbon; cooling the resulting filtrate to 5°C for crystallization, collecting the crystals by filtration, and drying them in vacuo at 60°C for 4h to obtain 8.6g of nafamostat mesylate (its HPLC spectrum is shown in Figure 4 ), the purity is 99.905%, and the maximum single impurity is 0.067%.

[0107] The structure of nafamostat mesylate was identified by nuclear magnetic resonance (NMR) analysis. Figures 1-3 As shown, its chemical structure is confirmed to be nafamostat mesylate. Figure 1 In the mass spectrometry, no salt peak appears.

[0108] Example 2

[0109] This embodiment provides a preparation method of nafamostat mesylate, comprising the following steps:

[0110] S1, prepare 6-amidino-2-naphthol methanesulfonate and p-guanidinobenzoic acid hydrochloride respectively:

[0111] S1-1. 50.00 g of hydrogen chloride was introduced into 270.00 g of ethanol. After the introduction, 15.00 g (0.09 mol) of 6-cyano-2-naphthol was added. The mass ratio of 6-cyano-2-naphthol, ethanol, and hydrogen chloride was 1:18:3.3. The mixture was mixed evenly and alkalized at 30°C. The mixture was kept warm for 11 h and filtered to obtain compound 1.

[0112] S1-2, add 10 times the mass of ethanol and 7 times the mass of ammonia water to compound 1, mix well, and carry out ammonolysis reaction at 60°C and keep warm for 3 hours; after the reaction is completed, cool the ice bath to 0°C, crystallize for 1 hour, and filter to obtain compound 2.

[0113] S1-3, compound 2 was added with 6 times the mass of methanol and 0.4 times the mass of methanesulfonic acid, mixed evenly, and stirred at 25°C for 1.5 h to form a salt. The temperature was then lowered to 0°C for crystallization for 1 h, and filtered to obtain 22.89 g (0.08 mol) of 6-amidino-2-naphthol methanesulfonate, with a yield of 91.45%.

[0114] S1-4, add 25.00 g (0.18 mol) of p-aminobenzoic acid to a hydrochloric acid aqueous solution (50.00 g of purified water and 75.00 g of concentrated hydrochloric acid), and stir to add 75.00 g of cyanamide. The mass ratio of p-aminobenzoic acid, hydrochloric acid aqueous solution, and cyanamide is 1:5:3. The addition reaction is carried out at 30°C and kept warm for 2 hours. After the reaction is completed, add 87.50 g of 3 wt% dilute hydrochloric acid, mix well, cool to 0°C, crystallize for 1 hour, and filter to obtain 38.81 g (0.18 mol) of p-guanidinobenzoic acid hydrochloride, with a yield of 98.73%.

[0115] There is no order between S1-1~S1-3 and S1-4.

[0116] S2, take 20.00g (0.07mol) of 6-amidino-2-naphthol methanesulfonate, 20.00g (0.09mol) of p-guanidinobenzoic acid hydrochloride, and 16.00g of EDCI and add them to 180.00g of dichloromethane. The mass ratio of 6-amidino-2-naphthol methanesulfonate, p-guanidinobenzoic acid hydrochloride, EDCI and dichloromethane is 1:1:0.8:9. Mix well and carry out condensation reaction at 15°C for 4h. After completion of the reaction, add 60.00g of saturated sodium bicarbonate aqueous solution and filter to obtain 30.57g (0.06mol) of the intermediate with a yield of 91.53%.

[0117] S3, the intermediate was added to the second solvent (626.00 g purified water and 139.00 g acetone), and 152.85 g methanesulfonic acid was added dropwise at room temperature. The mass ratio of the intermediate, the second solvent, and methanesulfonic acid was 1:25:5. After the addition, the mixture was stirred at 15°C for 2 h to form a salt. The mixture was filtered and dried under vacuum at 50°C for 6 h to obtain 33.02 g (0.06 mol) of crude nafamostat mesylate. The yield was 94.37%, the purity was 99.325%, and the maximum single impurity was 0.155%.

[0118] S4, taking 10.0g of the crude product of nafamostat mesylate, adding it to 32.5g of the third solvent (a mixed solution of water, methyl tert-butyl ether and tert-butyl acetate in a mass ratio of 1:1:1), mixing them evenly, adding 1g of activated carbon, the mass ratio of the crude product of nafamostat mesylate, the third solvent and the activated carbon being 1:3.25:0.1, stirring and decolorizing at 60°C for 30min, filtering to remove the activated carbon; cooling the resulting filtrate to 10°C for crystallization, collecting the crystals by filtration, and drying them in vacuo at 60°C for 4h to obtain 8.3g of nafamostat mesylate (its HPLC spectrum is shown in FIG. Figure 5 ), the purity is 99.851%, and the maximum single impurity is 0.081%.

[0119] The structure of nafamostat mesylate was identified by nuclear magnetic resonance (NMR) analysis technology, and its chemical structure was confirmed to be nafamostat mesylate.

[0120] Example 3

[0121] This embodiment provides a preparation method of nafamostat mesylate, comprising the following steps:

[0122] S1, prepare 6-amidino-2-naphthol methanesulfonate and p-guanidinobenzoic acid hydrochloride respectively:

[0123] S1-1. 100.00 g of hydrogen chloride was introduced into 180.00 g of isopropanol. After the introduction, 15.00 g (0.09 mol) of 6-cyano-2-naphthol was added. The mass ratio of 6-cyano-2-naphthol, isopropanol, and hydrogen chloride was 1:12:6.7. The mixture was mixed evenly and alkalized at 20°C. The mixture was kept warm for 15 h and filtered to obtain compound 1.

[0124] S1-2, add 15 times the mass of methanol and 3 times the mass of ammonia water to compound 1, mix well, and carry out ammonolysis reaction at 55°C and keep warm for 4.5 hours; after the reaction is completed, cool the ice bath to 10°C, crystallize for 1.5 hours, and filter to obtain compound 2.

[0125] S1-3, compound 2 was added with 8 times the mass of methanol and 0.8 times the mass of methanesulfonic acid, mixed evenly, and stirred at 30°C for 1.5 h to form a salt. The temperature was lowered to 10°C, crystallized for 2.5 h, and filtered to obtain 23.02 g (0.08 mol) of 6-amidino-2-naphthol methanesulfonate, with a yield of 91.97%.

[0126] S1-4, add 25.00 g (0.18 mol) of p-aminobenzoic acid to an aqueous hydrochloric acid solution (16.30 g of purified water and 21.20 g of concentrated hydrochloric acid), and stir to add 37.50 g of cyanamide. The mass ratio of p-aminobenzoic acid, aqueous hydrochloric acid solution, and cyanamide is 1:1.5:1.5. The addition reaction is carried out at 25°C and kept warm for 3 hours. After the reaction is completed, add 62.50 g of 5 wt% dilute hydrochloric acid, mix well, cool to 10°C, crystallize for 2 hours, and filter to obtain 38.20 g (0.18 mol) of p-guanidinobenzoic acid hydrochloride in a yield of 97.18%.

[0127] There is no order between S1-1~S1-3 and S1-4.

[0128] S2, take 20.00g (0.07mol) of 6-amidino-2-naphthol methanesulfonate, 25.00g (0.12mol) of p-guanidinobenzoic acid hydrochloride, and 36.00g of EDCI and add them to 220.00g of dichloromethane. The mass ratio of 6-amidino-2-naphthol methanesulfonate, p-guanidinobenzoic acid hydrochloride, EDCI and dichloromethane is 1:1.25:1.8:11. Mix well and carry out condensation reaction at 5°C for 5h. After completion of the reaction, add 70.00g of saturated sodium bicarbonate aqueous solution and filter to obtain 33.01g (0.07mol) of the intermediate with a yield of 98.84%.

[0129] S3. The intermediate was added to a second solvent (410.67 g purified water and 117.33 g dichloromethane), and 99.03 g methanesulfonic acid was added dropwise at room temperature. The mass ratio of the intermediate, the second solvent, and methanesulfonic acid was 1:16:3. After the addition, the mixture was stirred at 10°C for 3 h to form a salt. The mixture was filtered and dried under vacuum at 50°C for 6 h to obtain 34.87 g (0.06 mol) of crude nafamostat mesylate. The yield was 92.29%, the purity was 98.743%, and the maximum single impurity was 0.255%.

[0130] S4, taking 10.0g of the crude product of nafamostat mesylate, adding it to 30.0g of the third solvent (a mixed solution of water, acetone and methyl tert-butyl ether in a mass ratio of 1:1:1), mixing them evenly, adding 1.5g of activated carbon, the mass ratio of the crude product of nafamostat mesylate, the third solvent and the activated carbon being 1:3:0.15, stirring and decolorizing at 40°C for 55min, filtering to remove the activated carbon; cooling the resulting filtrate to 0°C for crystallization, collecting the crystals by filtration, and drying them in vacuo at 60°C for 4h to obtain 8.4g of nafamostat mesylate (its HPLC spectrum is shown in FIG. Figure 6 ), the purity is 99.802%, and the maximum single impurity is 0.093%.

[0131] The structure of nafamostat mesylate was identified by nuclear magnetic resonance (NMR) analysis technology, and its chemical structure was confirmed to be nafamostat mesylate.

[0132] Example 4

[0133] This embodiment provides a preparation method of nafamostat mesylate, comprising the following steps:

[0134] S1, prepare 6-amidino-2-naphthol methanesulfonate and p-guanidinobenzoic acid hydrochloride respectively:

[0135] S1-1. 150.00 g of hydrogen chloride was introduced into 300.00 g of methanol. After the introduction, 15.00 g (0.09 mol) of 6-cyano-2-naphthol was added. The mass ratio of 6-cyano-2-naphthol, methanol, and hydrogen chloride was 1:20:10. The mixture was mixed evenly and alkalized at 50°C. The mixture was kept warm for 10 h and filtered to obtain compound 1.

[0136] S1-2, add 20 times the mass of methanol and 10 times the mass of ammonia water to compound 1, mix well, and carry out ammonolysis reaction at 80°C and keep warm for 2 hours; after the reaction is completed, cool the ice bath to 5°C, crystallize for 1 hour, and filter to obtain compound 2.

[0137] S1-3, compound 2 was added with 9 times the mass of ethanol and 0.9 times the mass of methanesulfonic acid, mixed evenly, and stirred at 50°C for 0.5 h to form a salt. The temperature was then lowered to 5°C for crystallization for 2 h, and filtered to obtain 23.22 g (0.08 mol) of 6-amidino-2-naphthol methanesulfonate, with a yield of 92.78%.

[0138] S1-4, 25.00 g (0.18 mol) of p-aminobenzoic acid was added to a hydrochloric acid aqueous solution (83.33 g of purified water and 116.67 g of concentrated hydrochloric acid), and 175.00 g of cyanamide was added with stirring. The mass ratio of p-aminobenzoic acid, hydrochloric acid aqueous solution, and cyanamide was 1:8:7. The addition reaction was carried out at 80°C and kept warm for 2 hours. After the reaction was completed, 75.00 g of 3 wt% dilute hydrochloric acid was added, mixed evenly, cooled to 5°C, crystallized for 1 hour, and filtered to obtain 38.28 g (0.18 mol) of p-guanidinobenzoic acid hydrochloride in a yield of 97.39%.

[0139] There is no order between S1-1~S1-3 and S1-4.

[0140] S2, take 20.00g (0.17mol) of 6-amidino-2-naphthol methanesulfonate, 25.00g (0.12mol) of p-guanidinobenzoic acid hydrochloride, and 80.00g of EDCI and add them to 240.00g of dichloromethane. The mass ratio of 6-amidino-2-naphthol methanesulfonate, p-guanidinobenzoic acid hydrochloride, EDCI and dichloromethane is 1:1.25:4:12. Mix well and carry out condensation reaction at 30°C for 1.5h. After completion of the reaction, add 65.00g of saturated sodium bicarbonate aqueous solution and filter to obtain 31.85g (0.07mol) of the intermediate with a yield of 95.36%.

[0141] S3. The intermediate was added to a second solvent (191.1 g purified water and 764.4 g acetone), and 254.80 g methanesulfonic acid was added dropwise at room temperature. The mass ratio of the intermediate, the second solvent, and methanesulfonic acid was 1:30:8. After the addition, the mixture was stirred at 50°C for 40 min to form a salt. The mixture was filtered and dried under vacuum at 50°C for 6 h to obtain 33.58 g (0.06 mol) of crude nafamostat mesylate. The yield was 92.13%, the purity was 98.12%, and the maximum single impurity was 0.395%.

[0142] S4, taking 10.0g of the crude product of nafamostat mesylate, adding it to 40.0g of the third solvent (a mixed solution of water, acetone and methanol in a mass ratio of 1:1:1), mixing evenly, adding 0.3g of activated carbon, the mass ratio of the crude product of nafamostat mesylate, the third solvent and the activated carbon being 1:4:0.3, stirring and decolorizing at 50°C for 30min, filtering to remove the activated carbon; cooling the resulting filtrate to 15°C for crystallization, collecting the crystals by filtration, and drying them in vacuo at 60°C for 4h to obtain 8.0g of nafamostat mesylate (its HPLC spectrum is shown in Figure 7 ), the purity is 99.778%, and the maximum single impurity is 0.076%.

[0143] The structure of nafamostat mesylate was identified by nuclear magnetic resonance (NMR) analysis technology, and its chemical structure was confirmed to be nafamostat mesylate.

[0144] Example 5

[0145] This embodiment provides a preparation method of nafamostat mesylate, comprising the following steps:

[0146] S1, prepare 6-amidino-2-naphthol methanesulfonate and p-guanidinobenzoic acid hydrochloride respectively:

[0147] S1-1. 15.00 g of hydrogen chloride was introduced into 15.00 g of methanol. After the introduction, 15.00 g (0.09 mol) of 6-cyano-2-naphthol was added. The mass ratio of 6-cyano-2-naphthol, methanol, and hydrogen chloride was 1:1:1. The mixture was mixed evenly and alkalized at 10°C. The mixture was kept warm for 20 h and filtered to obtain compound 1.

[0148] S1-2, add 5 times the mass of methanol and 2 times the mass of ammonia water to compound 1, mix well, and carry out ammonolysis reaction at 20°C and keep warm for 8 hours; after the reaction is completed, cool the ice bath to 5°C, crystallize for 1 hour, and filter to obtain compound 2.

[0149] S1-3, compound 2 was added with 5 times the mass of methanol and 0.1 times the mass of methanesulfonic acid, mixed evenly, and stirred at 10°C for 2 h to form a salt. The temperature was lowered to 5°C, crystallized for 2 h, and filtered to obtain 22.53 g (0.08 mol) of 6-amidino-2-naphthol methanesulfonate, with a yield of 90.01%.

[0150] S1-4, add 25.00 g (0.18 mol) of p-aminobenzoic acid to an aqueous hydrochloric acid solution (10.00 g of purified water and 15.00 g of concentrated hydrochloric acid), and stir to add 25.00 g of cyanamide. The mass ratio of p-aminobenzoic acid, aqueous hydrochloric acid solution, and cyanamide is 1:1:1. The addition reaction is carried out at 20°C and kept warm for 10 hours. After the reaction is completed, add 75.00 g of 3 wt% dilute hydrochloric acid, mix well, cool to 5°C, crystallize for 1 hour, and filter to obtain 35.87 g (0.17 mol) of p-guanidinobenzoic acid hydrochloride, with a yield of 91.25%.

[0151] There is no order between S1-1~S1-3 and S1-4.

[0152] S2, take 20.00g (0.07mol) of 6-amidino-2-naphthol methanesulfonate, 15.00g (0.07mol) of p-guanidinobenzoic acid hydrochloride, and 12.00g of EDCI and add them to 160.00g of dichloromethane. The mass ratio of 6-amidino-2-naphthol methanesulfonate, p-guanidinobenzoic acid hydrochloride, EDCI and dichloromethane is 1:0.75:0.6:8. Mix well and carry out condensation reaction at -18°C for 10h. After completion of the reaction, add 65.00g of saturated sodium bicarbonate aqueous solution and filter to obtain 29.97g (0.06mol) of the intermediate with a yield of 89.74%.

[0153] S3, the intermediate was added to the second solvent (60.00 g purified water and 24.00 g acetone), and 45.00 g methanesulfonic acid was added dropwise at room temperature. The mass ratio of the intermediate, the second solvent, and methanesulfonic acid was 1:10:1.5. After the addition, the mixture was stirred at 10°C for 7 h to form a salt. The mixture was filtered and dried under vacuum at 50°C for 6 h to obtain 30.59 g (0.06 mol) of crude nafamostat mesylate. The yield was 89.16%, the purity was 97.437%, and the maximum single impurity was 0.324%.

[0154] S4, taking 10.0g of the crude product of nafamostat mesylate, adding it to 20.0g of the third solvent (a mixed solution of water and acetone in a mass ratio of 1:1), mixing them evenly, adding 5.0g of activated carbon, the mass ratio of the crude product of nafamostat mesylate, the third solvent and the activated carbon being 1:2:0.5, stirring and decolorizing at 50°C for 30min, filtering to remove the activated carbon; cooling the resulting filtrate to 18°C ​​for crystallization, collecting the crystals by filtration, and drying them in vacuo at 60°C for 4h to obtain 8.1g of nafamostat mesylate (its HPLC spectrum is shown in Figure 8 ), the purity is 99.707%, and the maximum single impurity is 0.086%.

[0155] The structure of nafamostat mesylate was identified by nuclear magnetic resonance (NMR) analysis technology, and its chemical structure was confirmed to be nafamostat mesylate.

[0156] Comparative Example 1

[0157] This comparative example provides a method for preparing a crude product of nafamostat mesylate, comprising the following steps:

[0158] S1, 20.00 g (0.07 mol) of 6-amidino-2-naphthol methanesulfonate prepared according to steps S1-1 to S1-3 of Example 1 and 32.50 g (0.15 mol) of p-guanidinobenzoic acid hydrochloride prepared according to step S1-4 of Example 1 were added to 160.00 g of pyridine, and then 11.83 g of DCC and 0.33 g of DMAP were added. The mixture was mixed uniformly and condensed at room temperature for 12 h. After completion of the reaction, the mixture was filtered, and 40 g of pyridine was added to the filter cake for washing. 65.00 g of a saturated aqueous sodium bicarbonate solution was added to the filtered filtrate, and the mixture was filtered with suction to obtain a filter cake. The filter cake was combined with the washed filter cake to obtain 22.10 g (0.05 mol) of the intermediate, with a yield of 66.17%.

[0159] S2, the intermediate was added to the second solvent (353.60 g purified water and 88.40 g acetone), and 88.40 g methanesulfonic acid was added dropwise at room temperature. The mass ratio of the intermediate, the second solvent and the methanesulfonic acid was 1:20:4. After the addition, the mixture was stirred at 10°C for 3 h to form a salt, filtered, and dried under vacuum at 50°C for 6 h to obtain 23.00 g (0.04 mol) of crude nafamostat mesylate (its HPLC spectrum is shown in Figure 9 ), the yield was 90.93%, the purity was 86.84%, and the maximum single impurity was 3.47%.

[0160] Comparative Example 2

[0161] This comparative example provides a method for preparing a crude product of nafamostat mesylate, comprising the following steps:

[0162] S1, add 34.00g (0.20mol) of 6-cyano-2-naphthol and 300mL of anhydrous ethanol to a 1000mL three-necked flask, introduce dry hydrogen chloride gas to saturation under ice bath conditions, react at 25℃ with stirring for 24h, evaporate until the reaction liquid remains about 150mL, add 150mL of anhydrous ethanol, raise the temperature to 50℃, introduce dry ammonia gas for 3h, and evaporate; after the rotary evaporation, add 400mL of saturated sodium bicarbonate solution to precipitate solid, filter, wash the filter cake with water, and vacuum dry at 50℃ for 6h; add the dried solid to the flask. Add 100 mL of methanol, add 21.25 g of methanesulfonic acid dropwise under ice bath conditions, and stir at room temperature for 0.5 h to form a salt; add 100 mL of ether to precipitate a solid, filter with suction, wash the filter cake twice with 30 mL of ether, add 300 mL of anhydrous ethanol, heat and reflux at 80 ° C. After the solid is completely dissolved, add activated carbon for decolorization, and filter while hot; cool to 5 ° C for crystallization, filter with suction, and dry in vacuo at 50 ° C for 6 h to obtain 46.52 g (0.16 mol) of light yellow crystals of 6-amidino-2-naphthol methanesulfonate, with a yield of 81.99%.

[0163] S2, 28.23 g (0.10 mol) of 6-amidino-2-naphthol methanesulfonate and 21.56 g of p-guanidinobenzoic acid hydrochloride prepared according to step S1-4 of Example 1 were added to a 500 mL three-necked flask, and 250 mL of anhydrous pyridine, 24.76 g of DCC and 24.43 g of DMAP were added, and the mixture was stirred at 25°C for 5 h. After the reaction, the mixture was filtered and the filter cake was washed twice with 30 mL of pyridine to obtain 31.08 g (0.06 mol) of crude nafamostat mesylate (its HPLC spectrum is shown in FIG. Figure 10 ), the yield was 57.60%, the purity was 81.28%, and the maximum single impurity was 6.16%.

[0164] Comparative Example 3

[0165] This comparative example provides a method for preparing a crude product of nafamostat mesylate, comprising the following steps:

[0166] S1, 20.00 g (0.12 mol) of 6-cyano-2-naphthol was placed in a 250 mL three-necked flask, and 120 mL of a 30 wt% hydrochloric acid ethanol solution was added. The mixture was stirred at 25°C for 12 h. After the reaction was complete, the mixture was rotary evaporated to obtain a yellow solid.

[0167] Add 200 mL of methanol to the yellow solid, pass ammonia gas until the yellow color disappears completely, and then rotary evaporate to obtain 6-amidino-2-naphthol;

[0168] To 6-amidino-2-naphthol, add 100 mL of methanol, cool to 0°C, and add methanesulfonic acid dropwise under temperature control. The addition is completed within 2 h. Stir for 1 h after the addition. The solution turns from turbid to clear. Add 100 mL of isopropyl ether and stir for 0.5 h. Filter with suction to obtain 27.49 g (0.10 mol) of light yellow 6-amidino-2-naphthol methanesulfonate, with a yield of 82.37%.

[0169] S2, 10.00 g (0.05 mol) of p-guanidinobenzoic acid hydrochloride prepared according to steps S1-4 of Example 1 was added to a 250 mL three-necked flask, 100 mL of pyridine was added, and the mixture was stirred until dissolved. Then, 5.30 g of DIC was added and stirred for 1 h. 0.057 g of DMAP and 13.09 g (0.05 mol) of 6-amidino-2-naphthol methanesulfonate were added, and the mixture was stirred at 25° C. for 12 h. After the reaction was completed, the mixture was filtered to obtain a white solid. 50 mL of methanol and 10 mL of ethyl acetate were added to the white solid, and the mixture was slurried for 1 h. The mixture was filtered to obtain 9.52 g (0.25 mol) of crude nafamostat, with a yield of 59.10%.

[0170] S3, add 32 mL of methanol and 8 mL of water to a 100 mL three-necked flask, heat to 50°C, add 8.00 g (0.02 mol) of crude nafamostat, stir until dissolved, add 5.6 g of methanesulfonic acid dropwise, add 0.4 g of activated carbon after the addition, stir for 20 min, filter while hot, crystallize the filtrate at 0°C for 6 h, filter with suction, and obtain 10.31 g (0.02 mol) of crude nafamostat mesylate (its HPLC spectrum is shown in Figure 11 ), the yield was 82.97%, the purity was 84.83%, and the maximum single impurity was 4.45%.

[0171] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing nafamostat mesylate, characterized in that: The following steps are involved: S1, adding 6-amidino-2-naphthol methanesulfonate, p-guanidinobenzoic acid hydrochloride, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to a first solvent to carry out a condensation reaction; then adding a saturated sodium bicarbonate aqueous solution to obtain an intermediate as shown in Formula 1; The first solvent is dichloromethane; the mass ratio of the 6-amidino-2-naphthol methanesulfonate to the first solvent is 1:(8-12); S2, adding the intermediate to a second solvent, then adding methanesulfonic acid to form a salt, and purifying to obtain nafamostat mesylate; The second solvent is selected from an acetone aqueous solution or a dichloromethane aqueous solution, and the mass ratio of acetone or dichloromethane to water is 1:(3.5-4.5); the mass ratio of the intermediate, the second solvent and the methanesulfonic acid is 1:(10-30):(1.5-8); Formula 1.

2. The preparation method of nafamostat mesylate as claimed in claim 1, wherein In S1, the mass ratio of the 6-amidino-2-naphthol methanesulfonate, the p-guanidinobenzoic acid hydrochloride and the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide is 1:(0.5-3):(0.5-5).

3. The preparation method of nafamostat mesylate as claimed in claim 1, wherein In S1, the condensation reaction temperature is -30°C to 30°C, and the reaction time is 1 hour to 12 hours.

4. The preparation method of nafamostat mesylate as claimed in claim 1, wherein In S2, the salt formation temperature is 10°C to 50°C, and the salt formation time is 0.5h to 10h.

5. The preparation method of nafamostat mesylate according to claim 1, wherein In S2, the purification comprises the following steps: The crude product of nafamostat mesylate obtained after the salt formation is added to a third solvent, activated carbon is added for decolorization, and the mixture is filtered; the obtained filtrate is cooled and crystallized to obtain nafamostat mesylate.

6. The method for preparing nafamostat mesylate as claimed in claim 5, wherein In S2, the third solvent is selected from at least two of water, acetone, methyl tert-butyl ether, tert-butyl acetate, methanol or ethanol; In S2, the mass ratio of the crude nafamostat mesylate, the third solvent and the activated carbon is 1:(1-5):(0.01-1).

7. The method for preparing nafamostat mesylate according to claim 1, wherein In S1, the preparation method of 6-amidino-2-naphthol methanesulfonate comprises the following steps: S1-1, hydrogen chloride is introduced into solvent a, and 6-cyano-2-naphthol is added to carry out an alkalization reaction to obtain compound 1 as shown in formula 2; S1-2, adding solvent b and an aminating agent to the compound 1 to carry out an aminolysis reaction, cooling and crystallizing to obtain compound 2 as shown in formula 3; S1-3, adding the compound 2 to solvent c, then adding methanesulfonic acid to form a salt, cooling and crystallizing to obtain the 6-amidino-2-naphthol methanesulfonate; Formula 2 Formula 3.

8. The method for preparing nafamostat mesylate as claimed in claim 7, wherein In S1-1, the solvent a is selected from methanol, ethanol or isopropanol; In S1-1, the mass ratio of the 6-cyano-2-naphthol, the solvent a, and the hydrogen chloride is 1:(1-20):(1-10); In S1-1, the temperature of the alkalization reaction is 10°C to 50°C, and the reaction time is 10h to 25h; In S1-2, the solvent b is selected from methanol or ethanol; In S1-2, the aminating agent is aqueous ammonia; In S1-2, the mass ratio of the compound 1, the solvent b and the aminating agent is 1:(1-20):(1-10); In S1-2, the temperature of the aminolysis reaction is 20°C to 80°C, and the reaction time is 2h to 10h; In S1-3, the solvent c is selected from methanol or ethanol; In S1-3, the mass ratio of the compound 2, the solvent c, and the methanesulfonic acid is 1:(5-10):(0.01-1); In S1-3, the salt formation temperature is 10°C to 50°C, and the salt formation time is 0.5h to 2h.

9. The method for preparing nafamostat mesylate according to claim 1, wherein In S1, the preparation method of p-guanidinobenzoic acid hydrochloride comprises the following steps: S1-4, adding p-aminobenzoic acid to solvent d, adding cyanamide for addition reaction, adding hydrochloric acid aqueous solution, cooling and crystallizing to obtain the p-guanidinobenzoic acid hydrochloride.

10. The method for preparing nafamostat mesylate according to claim 9, wherein In S1-4, the solvent d is a 14 wt% to 17 wt% aqueous hydrochloric acid solution; In S1-4, the mass ratio of the p-aminobenzoic acid, the solvent d and the cyanamide is 1:(1-10):(1-10); In S1-4, the temperature of the addition reaction is 20° C. to 80° C., and the reaction time is 2 h to 12 h.

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