A process for the preparation of nafamostat mesylate

Abstract

The present application relates to the technical field of compound preparation, and specifically discloses a preparation method of nalmefene mesylate. The method of the present application first uses 6-amidino-2-naphthol mesylate and p-guanidino benzoic acid hydrochloride as raw materials to carry out a condensation reaction in the presence of an impurity inhibitor to obtain a condensation product, the solvent for the condensation reaction is DMSO or DMF, the condensing agent is CDI, and the impurity inhibitor is methanesulfonic acid; then, the obtained condensation product is mixed with a sodium bicarbonate aqueous solution, stirred and crystallized to obtain nalmefene carbonate; in acetone, the nalmefene carbonate is mixed with methanesulfonic acid to obtain crude nalmefene mesylate; in the condensation reaction, the raw materials and the impurity inhibitor are first dissolved in the solvent for the condensation reaction, and then the condensing agent is added; the molar ratio of the impurity inhibitor to 6-amidino-2-naphthol mesylate is (0.1-0.5):1; and the amount of the solvent for the condensation reaction is 15-30 times the mass of 6-amidino-2-naphthol mesylate. The product prepared by the method of the present application has high yield and high purity.

Description

Technical Field

[0001] This invention relates to the field of compound preparation technology, and more specifically, to a method for preparing naphthalenemostat mesylate. Background Technology

[0002] Nafamostat mesylate is a synthetic serine proteolytic enzyme inhibitor with anticoagulant, antifibrinolytic, and antiplatelet aggregation effects. Specifically, it exhibits enzyme inhibitory activity, selectively inhibiting trypsin, kallikrein, plasmin, fibrinogen, and trypsin-like serine proteases. It also inhibits trypsin bound to phospholipase A2 and α2-macroglobulin. Nafamostat mesylate can also inhibit the increase in pancreatic enzyme activity caused by pancreatitis and the activity of enzymes entering the bloodstream, improve the reduction in total kininogen caused by kallikrein activation, and produce an anticoagulant effect.

[0003] In summary, nafamostat mesylate for injection has a strong and broad inhibitory effect on trypsin, complement system, coagulation fibrinolysis system and platelet aggregation, and does not affect the patient's coagulation system, providing patients with a more ideal medication option and showing good application prospects.

[0004] In the existing technology, the main method for synthesizing naphthostat mesylate is to react p-guanidinobenzoic acid and 6-amidinyl-2-naphthol to prepare naphthostat mesylate. This process has a low yield and the product is difficult to purify. The byproduct DCU of the condensing agent DCC is difficult to remove completely, which affects the product quality.

[0005] Based on the above situation, it is necessary to further study the preparation process of naphthostat mesylate in order to overcome the shortcomings of the existing technology. Summary of the Invention

[0006] This invention provides an optimized process for preparing naphthostat mesylate, which can better avoid the generation of impurities during the preparation process.

[0007] The specific technical solution of the present invention is as follows:

[0008] A method for preparing naphthostat mesylate involves first using 6-amidinyl-2-naphthol mesylate and p-guanidinobenzoate as raw materials, and carrying out a condensation reaction in the presence of an impurity inhibitor to obtain a condensation product. The solvent for the condensation reaction is DMSO or DMF, the condensing agent is CDI, and the impurity inhibitor is methanesulfonic acid. Then, the obtained condensation product is mixed with an aqueous sodium bicarbonate solution and stirred to crystallize, obtaining naphthostat carbonate. Finally, the obtained naphthostat carbonate is mixed with methanesulfonic acid in acetone to obtain crude naphthostat mesylate.

[0009] In carrying out the condensation reaction, the 6-amidinyl-2-naphthol methanesulfonate, p-guanidinobenzoate, and impurity inhibitor are first dissolved in the solvent of the condensation reaction, and then the condensing agent is added to carry out the condensation reaction.

[0010] The molar ratio of the impurity inhibitor to 6-amidinyl-2-naphthol methanesulfonate is (0.1-0.5):1; the amount of solvent used in the condensation reaction is 15-30 times (preferably 22.5 times) the mass of 6-amidinyl-2-naphthol methanesulfonate.

[0011] This invention, through extensive research, discovered that the use of pyridine as a conventional reaction solvent in the preparation of naphthostat mesylate produces a large, unknown impurity that is difficult to remove. While various conventional recrystallization methods have been optimized to reduce this impurity to 0.2%–0.3%, it still falls short of the pharmaceutically acceptable limit (0.10%). Furthermore, the inventors conducted extensive investigations under the conditions disclosed in the prior art (i.e., pyridine as the reaction solvent and DCC or EDCI as the condensing agent), examining factors such as reaction concentration, temperature, feed ratio, and reaction time, but found that none of these conditions could remove the unknown impurity.

[0012] To address the aforementioned issues, this invention further explored the conventional preparation conditions for naphthostat mesylate, adjusting the condensation reaction system. Specifically, the reaction solvent was changed to DMF or DMSO, and the condensing agent was changed to CDI (which improved the reaction conversion rate and reduced byproduct formation; the imidazole byproduct of CDI could be completely removed during post-treatment water washing, solving the problem of difficult removal of the conventional DCC byproduct DCU). At this point, it was found that the amount of the aforementioned impurities was reduced, but still not achieving the desired effect. Subsequently, through further analysis and experiments, the inventors discovered that adding a specific inhibitor to the condensation reaction system could both maintain the reaction and suppress the formation of the aforementioned impurities (reducing the impurity to below 0.06%). Then, through systematic process investigation, the inventors finally determined a new preparation process for naphthostat.

[0013] Specifically, during the research and development process, this invention also discovered that the amount of methanesulfonic acid used as an impurity inhibitor directly affects the production yield of difficult-to-remove impurities. Too low a dosage fails to initiate the inhibition effect, while too high a dosage inhibits the main reaction, reducing the yield. The amount of reaction solvent also affects the amount of difficult-to-remove impurities generated. Too low a dosage increases the reaction concentration and the amount of impurities generated, while too high a dosage, although without negative effects, increases costs. Furthermore, the feeding method for the condensation reaction is also crucial. The conventional method of first activating the substrate carboxylic acid and CDI before adding the substrate hydroxyl group cannot be used, as this would increase the amount of difficult-to-remove impurities generated. Ultimately, the process of this invention achieves high product purity and yield, saves production costs, and is conducive to industrial application. See the schematic diagram of the preparation route of this invention. Figure 1 .

[0014] In the condensation reaction described in this invention, the molar ratio of 6-amidinyl-2-naphthol methanesulfonate, p-guanidinobenzoate, and the condensing agent is 1:(1-1.2):(1.2-1.5), preferably 1:1:1.2; the reaction temperature of the condensation reaction is 0-30°C, and the reaction time is 1-2 hours.

[0015] By employing the reaction time and temperature described above in this invention, it is possible to balance yield and reduce the risk of increased difficult-to-remove impurities.

[0016] Preferably, during the condensation reaction, the reactants and the inhibitor methanesulfonic acid are first dissolved in a solvent, and then the condensing agent is added all at once at a controlled temperature of 0–30°C to carry out the reaction.

[0017] In the preparation method of the present invention, the mixing of the condensation product with the sodium bicarbonate aqueous solution is carried out at 0-10°C, and the stirring and crystallization are carried out at 0-10°C.

[0018] The sodium bicarbonate aqueous solution is a saturated sodium bicarbonate aqueous solution, and the amount of the saturated sodium bicarbonate aqueous solution is 0.5 to 1 times the mass of DMSO or DMF.

[0019] Preferably, after the condensation product is mixed with the sodium bicarbonate aqueous solution and stirred to crystallize, the step further includes washing with water, wherein the amount of water used is 1 to 2 times the mass of the saturated sodium bicarbonate aqueous solution.

[0020] In the preparation method of the present invention, when naphthalmosat carbonate and methanesulfonic acid are mixed, the temperature is controlled at 0-10°C, the amount of acetone used is 3-5 times (preferably 4 times) the mass of naphthalmosat carbonate, and the molar ratio of naphthalmosat carbonate to methanesulfonic acid is 1:(2-2.2), preferably 1:2.1.

[0021] The preparation method of the present invention further includes a purification step after obtaining crude nafamostat mesylate;

[0022] The purification method is as follows: the crude naphthostat mesylate is mixed with water and dissolved at 50-60°C, then mixed with acetone and cooled, and crystallized at 0-10°C.

[0023] Preferably, in the refining process, the amount of water used is 3-5 times (preferably 4 times) the mass of naphthostat carbonate, and the amount of acetone used is 18-30 times (preferably 24 times) the mass of naphthostat carbonate.

[0024] In the purification process described in the preparation method of the present invention, after crystallization, the process further includes rinsing with acetone and drying. During rinsing, the amount of acetone used is 2 to 4 times the mass of naphthalmostar carbonate, and the drying conditions are: vacuum drying at 40-50°C for 4-5 hours.

[0025] The preparation method of the present invention includes:

[0026] (1) First, mix and dissolve p-guanidinobenzoate, 6-amidinyl-2-naphthol methanesulfonate, and impurity inhibitor with the solvent for condensation reaction. Then, add the condensing agent at a controlled temperature of 0-30°C and react at 0-30°C for 1-2 hours. After the reaction is completed, mix with saturated sodium bicarbonate aqueous solution at a controlled temperature of 0-10°C and stir at a controlled temperature of 0-10°C to precipitate crystals. Filter and wash with purified water to obtain naphthalmostat carbonate.

[0027] (2) Disperse the obtained naphthostat carbonate in acetone, add methanesulfonic acid at a controlled temperature of 0-10℃, then add purified water, heat to 50-60℃ to dissolve, then add acetone, cool down and maintain at 0-10℃ for crystallization for 1-2 hours, filter, wash with acetone, and vacuum dry at 40-50℃ for 4-5 hours to obtain naphthostat methanesulfonic acid.

[0028] The beneficial effects of this invention are at least as follows:

[0029] The present invention provides a method for preparing naphthostat mesylate. Through process optimization, it solves the problems of poor product purity and low yield in the existing process flow, reduces production costs, and obtains a product with good quality and high yield, which is beneficial for industrial applications. Attached Figure Description

[0030] Figure 1 This is a schematic diagram of the preparation method of the present invention.

[0031] Figure 2 This is the detection chromatogram of the final product obtained by the method in Reference 1 in the experimental example of this invention.

[0032] Figure 3 This is the detection chromatogram of the final product prepared using the method in Reference 2 in the experimental example of this invention.

[0033] Figure 4 The NMR spectrum is shown for the final product prepared in Example 1 of this invention. Detailed Implementation

[0034] The preferred embodiments of the present invention will be described in detail below with reference to examples. It should be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the present invention. Those skilled in the art can make various modifications and substitutions to the present invention without departing from its spirit and intent. Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0035] Unless otherwise specified, all materials and reagents used in the following examples are commercially available. Where specific techniques or conditions are not specified in the following examples, they should be performed in accordance with the techniques or conditions described in the literature in this field, or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0036] In this invention, DCC refers to N,N'-dicyclohexylcarbodiimide, DCU refers to N,N'-dicyclohexylurea, CDI refers to N,N'-carbonyldiimidazole, EDCI refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, DMF refers to N,N-dimethylformamide, and DMSO refers to dimethyl sulfoxide.

[0037] Experimental Example

[0038] This experimental example investigated the conventional method for preparing naftomostat using pyridine as the reaction solvent, and revealed the formation of a large, unknown impurity. The specific preparation method and the process of discovering the single impurity are as follows:

[0039] (1) The method reported in Reference 1, "Synthesis of Naphthostat Mesylate" (Chen Baoquan, Zhao Yusong, Ouyang Jie, Ma Ning, Li Caiwen. China Pharmaceutical Industry Journal, 2007(08):545-546), used anhydrous pyridine as the reaction solvent, p-guanidinylbenzoate and 6-amidinyl-2-naphthol mesylate as raw materials, DCC as the condensing agent, and DMAP as the catalyst. The reaction was stirred at room temperature for 5 h, and a white solid precipitated. The filter cake was washed with pyridine, dispersed in water, and filtered to remove the byproduct DCU. The filtrate was poured into a saturated sodium bicarbonate aqueous solution under stirring, and a solid precipitated. The filter cake was suspended in methanol, and mesylate was added dropwise in an ice bath. The mixture was stirred at room temperature for 0.5 h, ether was added, and the mixture was filtered. The mixture was recrystallized with a mixture of acetone and water to obtain naphthostat mesylate. Chromatographic detection showed a large unknown impurity (peak time of about 28 minutes), with a content of 5.1%. Specific chromatographic information is shown in Table 1, and the chromatogram is shown in [reference missing]. Figure 2 .

[0040] Table 1

[0041] 1 5.637 10945 0.033 1320 9248 1.243 -- 2 7.626 16968 0.051 1647 11420 1.124 7.650 3 14.764 269567 0.812 36413 78289 1.159 28.752 4 16.277 54103 0.163 8694 127314 1.170 7.686 5 16.689 20072 0.060 3360 144333 1.160 2.304 6 17.940 37623 0.113 4791 104926 1.218 6.297 7 20.057 31081484 93.611 2887717 72046 1.267 8.137 8 22.703 4323 0.013 269 41633 1.319 7.113 9 24.594 12752 0.038 641 40140 1.473 4.041 10 28.282 1694935 5.105 71376 37060 0.866 6.837 total 33202771 100.000 3016229

[0042] (2) The method reported in Reference 2, "Improved Synthesis Process of p-Guidinobenzoic Acid Salt and Research on Synthesis Process of Naphthostat Mesylate" (Zhao Yusong, Hebei Medical University, 2004), uses p-guanidinobenzoic acid salt and 6-amidinyl-2-naphthol methanesulfonate as raw materials. First, p-guanidinobenzoic acid salt is prepared into p-guanidinobenzoyl chloride hydrochloride in thionyl chloride. Then, 6-amidinyl-2-naphthol methanesulfonate is stirred in pyridine in an ice bath for 1 hour, followed by stirring at room temperature overnight. Diethyl ether is added, and the oily substance is separated. The oily substance is dispersed in water, filtered, and the filtrate is added to a saturated sodium bicarbonate aqueous solution. A solid precipitates, is filtered, washed with water and acetone, and the filter cake is added to ethanol, followed by the addition of methanesulfonic acid and then diethyl ether to obtain naphthostat mesylate. Chromatographic detection revealed a large unknown impurity (elution time of approximately 28 minutes), with a content of 4.9%. Specific chromatographic information is shown in Table 2, and the chromatogram is shown in [reference missing]. Figure 3 .

[0043] Table 2

[0044] 1 5.661 10689 0.043 1347 10008 1.208 -- 2 7.690 45231 0.183 4350 11768 1.154 7.958 3 14.845 253360 1.024 34036 79903 1.171 28.990 4 16.329 84289 0.341 13238 124196 1.178 7.504 5 16.733 15285 0.062 2499 137425 1.182 2.210 6 18.008 35118 0.142 4199 94468 1.238 6.149 7 18.457 34635 0.140 3912 88749 1.127 1.859 8 20.133 23043435 93.094 2066633 70399 1.222 6.081 9 24.731 11022 0.045 499 31443 1.483 10.675 10 28.003 1219935 4.928 51094 38826 1.579 5.811 total 24752999 100.000 2181806

[0045] The present invention found that naphthostat mesylate prepared by two existing technical methods both contained a large unknown impurity, which could not meet the high quality requirements.

[0046] This experimental example further investigated the method for removing single impurities, as detailed below:

[0047] (1) It is proposed to remove larger unknown impurities by refining. Specifically, based on the method in Reference 1, the refining solvent and the number of refining times are studied. The research results are shown in Table 3 below.

[0048] Table 3

[0049]

[0050] This experimental example investigated different solvents, different mixed solvents, different ratios of mixed solvents, and different purification times, but none of these methods could remove the unknown impurities to below 0.1%. Therefore, this invention continues to attempt to reduce the content of larger unknown impurities by controlling the reaction conditions.

[0051] (2) The method of condensation with condensing agent is adopted. It is intended to reduce the content of large unknown impurities by optimizing the reaction conditions. The research is based on the method in Reference 1. The research results are shown in Table 4 below.

[0052] Table 4

[0053]

[0054]

[0055]

[0056] The chromatographic detection method used in this invention is as follows:

[0057] Test solution: Weigh approximately 10 mg of this product accurately, place it in a 10 ml volumetric flask, dissolve and dilute to the mark with methanol, and shake well.

[0058] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; mobile phase A was prepared by dissolving 6.07 g sodium heptanesulfonate in 6 ml acetic acid and diluting it with water to 1000 ml; acetonitrile was used as mobile phase B, and gradient elution was performed according to Table 5; column temperature was 30 ℃; detection wavelength was 260 nm; flow rate was 1.0 ml / min; injection volume was 10 μl.

[0059] Table 5

[0060]

[0061] Ultimately, through the above experiments, this invention found that the aforementioned single impurities found in conventional preparation methods cannot be removed by adjusting reaction conditions, nor can ideal removal effects be achieved through recrystallization or other methods.

[0062] Example 1

[0063] Step 1: Preparation of naphthalenemostat carbonate

[0064] First, 282.32 g of 6-amidinyl-2-naphthol methanesulfonate, 215.64 g of p-guanidinyl benzoate, 9.61 g of methanesulfonic acid, and 4.24 kg of DMSO were added to a 10 L reactor and stirred to dissolve. Then, 194.58 g of CDI was added at a controlled temperature of 0–2 °C, and the reaction was carried out at 0 °C for 1 h. After the reaction was completed, 2.82 kg of saturated sodium bicarbonate aqueous solution was added at a controlled temperature of 0–10 °C, and the mixture was stirred at 0 °C to allow crystallization for 0.5 h. After filtration, the product was washed with 2.82 kg of purified water to obtain naphthalenemostat carbonate (in 100% yield), which was directly used in the next step.

[0065] Step 2: Preparation of naphthostat mesylate

[0066] The naphthostat carbonate obtained in the previous step was dispersed in 1885.72 g of acetone. 201.60 g of methanesulfonic acid was added at a controlled temperature of 0–10 °C, followed by 1885.72 g of purified water. The mixture was heated to 55 °C to dissolve, and then 8.54 kg of acetone was added. The mixture was cooled and kept at 0 °C for 1.5 h to allow crystallization. After filtration, the crystals were washed with 948.8 g of acetone and dried under vacuum at 45 °C for 4.5 h to obtain 404.68 g of naphthostat mesylate. In this example, the synthesized naphthostat mesylate was confirmed by NMR (see NMR spectrum). Figure 4 Yield: 74.99%, HPLC purity: 99.858%, maximum single impurity: 0.07%.

[0067] Example 2

[0068] Step 1: Preparation of naphthalenemostat carbonate

[0069] First, 282.32 g of 6-amidinyl-2-naphthol methanesulfonate, 215.64 g of p-guanidinyl benzoate, 48.00 g of methanesulfonic acid, and 8.47 kg of DMSO were added to a 20 L reactor and stirred to dissolve. Then, 194.58 g of CDI was added at a controlled temperature of 25–30 °C, and the reaction was carried out at 30 °C for 1 h. After the reaction was completed, 8.47 kg of saturated sodium bicarbonate aqueous solution was added at a controlled temperature of 0–10 °C, and the mixture was stirred at 10 °C for 0.5 h to crystallize. After filtration, the product was washed with 16.94 kg of purified water to obtain naphthalenemostat carbonate (in 100% yield), which was directly used in the next step.

[0070] Step 2: Preparation of naphthostat mesylate

[0071] The naphthostat carbonate obtained in the previous step was dispersed in 1885.72 g of acetone. 201.60 g of methanesulfonic acid was added at a controlled temperature of 0–10 °C, followed by 1885.72 g of purified water. The mixture was heated to 60 °C to dissolve, and then 14.14 kg of acetone was added. The mixture was cooled and kept at 10 °C for 2 hours to allow crystals to crystallize. After filtration, the crystals were washed with 1.88 kg of acetone and dried under vacuum at 40 °C for 5 hours. 410.12 g of naphthostat methanesulfonic acid was obtained, with a yield of 76.01%, HPLC purity of 99.804%, and maximum single impurity of 0.07%.

[0072] Example 3

[0073] Step 1: Preparation of naphthalenemostat carbonate

[0074] First, 282.32 g of 6-amidinyl-2-naphthol methanesulfonate, 215.64 g of p-guanidinyl benzoate, 28.83 g of methanesulfonic acid, and 6.35 kg of DMSO were added to a 10 L reactor and stirred to dissolve. Then, 194.58 g of CDI was added at a controlled temperature of 12–15 °C, and the reaction was carried out at 15 °C for 2 h. After the reaction was completed, 4.76 kg of saturated sodium bicarbonate aqueous solution was added at a controlled temperature of 0–10 °C, and the mixture was stirred at 5 °C for 0.5 h to crystallize. After filtration, the product was washed with 7.14 kg of purified water to obtain naphthalenemostat carbonate (in 100% yield), which was directly used in the next step.

[0075] Step 2: Preparation of naphthostat mesylate

[0076] The naphthostat carbonate obtained in the previous step was dispersed in 1885.72 g of acetone. 201.60 g of methanesulfonic acid was added at a controlled temperature of 0–10 °C, followed by 1885.72 g of purified water. The mixture was heated to 50 °C to dissolve, and then 11.3 kg of acetone was added. The mixture was cooled and kept at 5 °C for 1 hour to allow crystallization. After filtration, the crystals were washed with 1 L of acetone and dried under vacuum at 50 °C for 4 hours. 412.88 g of naphthostat methanesulfonic acid was obtained, with a yield of 76.52%, HPLC purity of 99.851%, and maximum single impurity of 0.07%.

[0077] Example 4

[0078] Step 1: Preparation of naphthalenemostat carbonate

[0079] First, 282.32 g of 6-amidinyl-2-naphthol methanesulfonate, 215.64 g of p-guanidinyl benzoate, 28.83 g of methanesulfonic acid, and 6.35 kg of DMF were added to a 10 L reactor and stirred to dissolve. Then, 194.58 g of CDI was added at a controlled temperature of 12–15 °C, and the reaction was carried out at 15 °C for 2 h. After the reaction was completed, 4.76 kg of saturated sodium bicarbonate aqueous solution was added at a controlled temperature of 0–10 °C, and the mixture was stirred at 5 °C for 0.5 h to crystallize. After filtration, the product was washed with 7.14 kg of purified water to obtain naphthalenemostat carbonate (in 100% yield), which was directly used in the next step.

[0080] Step 2: Preparation of naphthostat mesylate

[0081] The naphthostat carbonate obtained in the previous step was dispersed in 1885.72 g of acetone. 201.60 g of methanesulfonic acid was added at a controlled temperature of 0–10 °C, followed by 1885.72 g of purified water. The mixture was heated to 50 °C to dissolve, and then 11.3 kg of acetone was added. The mixture was cooled and kept at 5 °C for 1 hour to allow crystallization. After filtration, the crystals were washed with 1 L of acetone and dried under vacuum at 50 °C for 4 hours. 406.21 g of naphthostat methanesulfonic acid was obtained, with a yield of 75.28%, HPLC purity of 99.790%, and maximum single impurity of 0.07%.

[0082] Comparative Example 1

[0083] This comparative example provides a method for preparing naphamostat mesylate, which is basically the same as the method in Example 1, except that in step one, EDCI is used as the condensing agent, with an amount of 230.04 g, while other conditions remain unchanged. Ultimately, the yield of naphamostat mesylate was 15.38%, with an HPLC purity of 99.528% and a maximum single impurity of 0.06%.

[0084] Comparative Example 2

[0085] This comparative example provides a method for preparing naphthostat mesylate, which is basically the same as the method in Example 1, except that in step one, pyridine is used instead of DMSO as the reaction solvent, while other conditions remain unchanged. Ultimately, the yield of naphthostat mesylate was 50.46%, with an HPLC purity of 98.074% and a maximum single impurity of 1.5%.

[0086] Comparative Example 3

[0087] This comparative example provides a method for preparing naphthostat mesylate, which is basically the same as the method in Example 1, except that in step one, dimethylacetamide (DMA) is used instead of DMSO as the reaction solvent, while other conditions remain unchanged. Ultimately, the yield of naphthostat mesylate was 65.51%, with an HPLC purity of 99.637% and a maximum single impurity of 0.07%.

[0088] Comparative Example 4

[0089] This comparative example provides a method for preparing naphamostat mesylate, which is basically the same as the method in Example 1, except that in step one, sulfuric acid is used as an impurity inhibitor, with an amount of 9.81 g, while other conditions remain unchanged. Ultimately, the yield of naphamostat mesylate was 12.29%, with an HPLC purity of 99.752% and a maximum single impurity of 0.08%.

[0090] Comparative Example 5

[0091] This comparative example provides a method for preparing naphthostat mesylate, which is basically the same as the method in Example 1, except that in step one, the feeding method is changed. First, p-guanidinyl benzoate, methanesulfonic acid, and CDI are mixed and dissolved in DMSO for carboxyl activation. Then, 6-amidinyl-2-naphthol methanesulfonate is added at a controlled temperature of 0-2°C, while other conditions remain unchanged. Finally, the yield of naphthostat mesylate is 75.35%, HPLC purity: 99.420%, and maximum single impurity: 0.13%.

[0092] Comparative Example 6

[0093] This comparative example provides a method for preparing naphamostat mesylate, which is basically the same as the method in Example 2, except that in step one, the amount of impurity inhibitor added is changed to 57.67 g, while other conditions remain unchanged. Finally, the yield of naphamostat mesylate was 62.82%, the HPLC purity was 99.789%, and the maximum single impurity was 0.07%.

[0094] Comparative Example 7

[0095] This comparative example provides a method for preparing naphthostat mesylate, which is basically the same as the method in Example 1, except that in step one, the amount of solvent used in the condensation reaction is changed to 3.67 kg, while other conditions remain unchanged. Finally, the yield of naphthostat mesylate was 76.21%, the HPLC purity was 99.518%, and the maximum single impurity was 0.15%.

[0096] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A method for preparing naphthalenemostat mesylate, characterized in that, First, 6-amidinyl-2-naphthol methanesulfonate and p-guanidinobenzoate were used as raw materials, and a condensation reaction was carried out in the presence of an impurity inhibitor to obtain a condensation product. The solvent for the condensation reaction was DMSO or DMF, the condensing agent was CDI, and the impurity inhibitor was methanesulfonic acid. Then, the obtained condensation product was mixed with an aqueous sodium bicarbonate solution and stirred to crystallize and obtain naphthalmostat carbonate. In acetone, the obtained naphthalmostat carbonate was mixed with methanesulfonic acid to obtain crude naphthalmostat methanesulfonate. In carrying out the condensation reaction, the 6-amidinyl-2-naphthol methanesulfonate, p-guanidinobenzoate, and impurity inhibitor are first dissolved in the solvent of the condensation reaction, and then the condensing agent is added to carry out the condensation reaction. The molar ratio of the impurity inhibitor to 6-amidinyl-2-naphthol methanesulfonate is (0.1-0.5):1; the amount of solvent used in the condensation reaction is 15-30 times the mass of 6-amidinyl-2-naphthol methanesulfonate.

2. The preparation method according to claim 1, characterized in that, In the condensation reaction, the molar ratio of 6-amidinyl-2-naphthol methanesulfonate, p-guanidinobenzoate, and the condensing agent is 1:(1-1.2):(1.2-1.5); the reaction temperature of the condensation reaction is 0~30℃, and the reaction time is 1-2h.

3. The preparation method according to claim 1 or 2, characterized in that, The condensation product was mixed with the sodium bicarbonate aqueous solution at 0-10°C, and the stirring and crystallization were carried out at 0-10°C.

4. The preparation method according to claim 3, characterized in that, The sodium bicarbonate aqueous solution is a saturated sodium bicarbonate aqueous solution, and the amount of the saturated sodium bicarbonate aqueous solution is 0.5 to 1 times the mass of DMSO or DMF.

5. The preparation method according to claim 3, characterized in that, The condensation product is mixed with an aqueous sodium bicarbonate solution, stirred, and crystallized. The mixture is then washed with water, the amount of which is 1 to 2 times the mass of the saturated sodium bicarbonate aqueous solution.

6. The preparation method according to claim 4, characterized in that, The condensation product is mixed with an aqueous sodium bicarbonate solution, stirred, and crystallized. The mixture is then washed with water, the amount of which is 1 to 2 times the mass of the saturated sodium bicarbonate aqueous solution.

7. The preparation method according to any one of claims 1-2 and 4-6, characterized in that, When mixing naphthostat carbonate and methanesulfonic acid, the temperature is controlled at 0~10℃, the amount of acetone is 3-5 times the mass of naphthostat carbonate, and the molar ratio of naphthostat carbonate to methanesulfonic acid is 1:(2-2.2).

8. The preparation method according to claim 3, characterized in that, When mixing naphthostat carbonate and methanesulfonic acid, the temperature is controlled at 0~10℃, the amount of acetone is 3-5 times the mass of naphthostat carbonate, and the molar ratio of naphthostat carbonate to methanesulfonic acid is 1:(2-2.2).

9. The preparation method according to any one of claims 1-2, 4-6, and 8, characterized in that, The preparation method further includes a purification step after obtaining crude naphthostat mesylate; The purification method is as follows: the crude naphthostat mesylate is mixed with water and dissolved at 50-60°C, then mixed with acetone and cooled, and crystallized at 0-10°C.

10. The preparation method according to claim 3, characterized in that, The preparation method further includes a purification step after obtaining crude naphthostat mesylate; The purification method is as follows: the crude naphthostat mesylate is mixed with water and dissolved at 50-60°C, then mixed with acetone and cooled, and crystallized at 0-10°C.

11. The preparation method according to claim 7, characterized in that, The preparation method further includes a purification step after obtaining crude naphthostat mesylate; The purification method is as follows: the crude naphthostat mesylate is mixed with water and dissolved at 50-60°C, then mixed with acetone and cooled, and crystallized at 0-10°C.

12. The preparation method according to claim 9, characterized in that, In the purification process, the amount of water used is 3-5 times the mass of naphthostat carbonate, and the amount of acetone used is 18-30 times the mass of naphthostat carbonate.

13. The preparation method according to claim 10 or 11, characterized in that, In the purification process, the amount of water used is 3-5 times the mass of naphthostat carbonate, and the amount of acetone used is 18-30 times the mass of naphthostat carbonate.

14. The preparation method according to claim 9, characterized in that, The refining process includes rinsing with acetone and drying after crystallization. During rinsing, the amount of acetone used is 2 to 4 times the mass of naphthostat carbonate, and the drying conditions are: vacuum drying at 40-50℃ for 4-5 hours.

15. The preparation method according to any one of claims 10-12, characterized in that, The refining process includes rinsing with acetone and drying after crystallization. During rinsing, the amount of acetone used is 2 to 4 times the mass of naphthostat carbonate, and the drying conditions are: vacuum drying at 40-50℃ for 4-5 hours.

16. The preparation method according to claim 13, characterized in that, The refining process includes rinsing with acetone and drying after crystallization. During rinsing, the amount of acetone used is 2 to 4 times the mass of naphthostat carbonate, and the drying conditions are: vacuum drying at 40-50℃ for 4-5 hours.

17. The preparation method according to any one of claims 1-2, 4-6, 8, 10-12, 14, and 16, characterized in that, include: (1) Dissolve p-guanidinobenzoate, 6-amidinyl-2-naphthol methanesulfonate and impurity inhibitor in the solvent of the condensation reaction, then add the condensing agent at 0-30°C and react at 0-30°C for 1-2 hours. After the reaction is completed, mix with saturated sodium bicarbonate aqueous solution at 0-10°C and stir at 0-10°C to crystallize. Filter and wash with purified water to obtain naphthalmostat carbonate. (2) Disperse the obtained naphthostat carbonate in acetone, add methanesulfonic acid at a controlled temperature of 0-10℃, then add purified water, heat to 50-60℃ to dissolve, then add acetone, cool down and maintain at 0-10℃ for crystallization for 1-2 hours, filter, wash with acetone, and vacuum dry at 40-50℃ for 4-5 hours to obtain naphthostat methanesulfonic acid.

18. The preparation method according to claim 3, characterized in that, include: (1) Dissolve p-guanidinobenzoate, 6-amidinyl-2-naphthol methanesulfonate and impurity inhibitor in the solvent of the condensation reaction, then add the condensing agent at 0-30°C and react at 0-30°C for 1-2 hours. After the reaction is completed, mix with saturated sodium bicarbonate aqueous solution at 0-10°C and stir at 0-10°C to crystallize. Filter and wash with purified water to obtain naphthalmostat carbonate. (2) Disperse the obtained naphthostat carbonate in acetone, add methanesulfonic acid at a controlled temperature of 0-10℃, then add purified water, heat to 50-60℃ to dissolve, then add acetone, cool down and maintain at 0-10℃ for crystallization for 1-2 hours, filter, wash with acetone, and vacuum dry at 40-50℃ for 4-5 hours to obtain naphthostat methanesulfonic acid.

19. The preparation method according to claim 7, characterized in that, include: (1) Dissolve p-guanidinobenzoate, 6-amidinyl-2-naphthol methanesulfonate and impurity inhibitor in the solvent of the condensation reaction, then add the condensing agent at 0-30°C and react at 0-30°C for 1-2 hours. After the reaction is completed, mix with saturated sodium bicarbonate aqueous solution at 0-10°C and stir at 0-10°C to crystallize. Filter and wash with purified water to obtain naphthalmostat carbonate. (2) Disperse the obtained naphthostat carbonate in acetone, add methanesulfonic acid at a controlled temperature of 0-10℃, then add purified water, heat to 50-60℃ to dissolve, then add acetone, cool down and maintain at 0-10℃ for crystallization for 1-2 hours, filter, wash with acetone, and vacuum dry at 40-50℃ for 4-5 hours to obtain naphthostat methanesulfonic acid.

20. The preparation method according to claim 9, characterized in that, include: (1) Dissolve p-guanidinobenzoate, 6-amidinyl-2-naphthol methanesulfonate and impurity inhibitor in the solvent of the condensation reaction, then add the condensing agent at 0-30°C and react at 0-30°C for 1-2 hours. After the reaction is completed, mix with saturated sodium bicarbonate aqueous solution at 0-10°C and stir at 0-10°C to crystallize. Filter and wash with purified water to obtain naphthalmostat carbonate. (2) Disperse the obtained naphthostat carbonate in acetone, add methanesulfonic acid at a controlled temperature of 0-10℃, then add purified water, heat to 50-60℃ to dissolve, then add acetone, cool down and maintain at 0-10℃ for crystallization for 1-2 hours, filter, wash with acetone, and vacuum dry at 40-50℃ for 4-5 hours to obtain naphthostat methanesulfonic acid.

21. The preparation method according to claim 13, characterized in that, include: (1) Dissolve p-guanidinobenzoate, 6-amidinyl-2-naphthol methanesulfonate and impurity inhibitor in the solvent of the condensation reaction, then add the condensing agent at 0-30°C and react at 0-30°C for 1-2 hours. After the reaction is completed, mix with saturated sodium bicarbonate aqueous solution at 0-10°C and stir at 0-10°C to crystallize. Filter and wash with purified water to obtain naphthalmostat carbonate. (2) Disperse the obtained naphthostat carbonate in acetone, add methanesulfonic acid at a controlled temperature of 0-10℃, then add purified water, heat to 50-60℃ to dissolve, then add acetone, cool down and maintain at 0-10℃ for crystallization for 1-2 hours, filter, wash with acetone, and vacuum dry at 40-50℃ for 4-5 hours to obtain naphthostat methanesulfonic acid.

22. The preparation method according to claim 15, characterized in that, include: (1) Dissolve p-guanidinobenzoate, 6-amidinyl-2-naphthol methanesulfonate and impurity inhibitor in the solvent of the condensation reaction, then add the condensing agent at 0-30°C and react at 0-30°C for 1-2 hours. After the reaction is completed, mix with saturated sodium bicarbonate aqueous solution at 0-10°C and stir at 0-10°C to crystallize. Filter and wash with purified water to obtain naphthalmostat carbonate. (2) Disperse the obtained naphthostat carbonate in acetone, add methanesulfonic acid at a controlled temperature of 0-10℃, then add purified water, heat to 50-60℃ to dissolve, then add acetone, cool down and maintain at 0-10℃ for crystallization for 1-2 hours, filter, wash with acetone, and vacuum dry at 40-50℃ for 4-5 hours to obtain naphthostat methanesulfonic acid.

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