A process for the preparation of nafamostat mesylate

Abstract

This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing naphamostat mesylate. The method uses 6-formamidinylnaphth-2-yl-4-aminobenzoate as a starting material, reacting it with 3,5-dimethyl-1-pyrazoleformamidin nitrate to form a salt, thereby obtaining the target product, naphamostat mesylate. Compared with products obtained by existing technologies, this method has higher yield and purity, and is simpler, safer, and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing naphthostat mesylate. Background Technology

[0002] Naphthostat mesylate is a non-peptide synthetic protease inhibitor, chemically named 4-guanidinobenzoic acid-6-amidinyl-2-naphthyl ester dimethylsulfonate. It was first marketed in 1986 by Shimai (Asahi Breweries) Co., Ltd. in Japan for the treatment of pancreatitis. In 1987, it was also suggested that this product has anti-DIC activity and anticoagulant activity in hemodialysis.

[0003] Patent CN103012214A describes a reaction between p-guanidinobenzoyl chloride hydrochloride and 6-amidinyl-2-naphthol methanesulfonic acid, followed by a pyridine reaction to synthesize naphthostat hydrochloride. Then, naphthostat hydrochloride is reacted with methanesulfonic acid in a mixture of water and an organic solvent to synthesize naphthostat methanesulfonate. However, both the hydroxyl and amino groups in 6-amidinyl-2-naphthol can participate in the reaction, easily generating impurities during the process. This necessitates multiple purification processes, making the operation cumbersome and further reducing the yield.

[0004]

[0005] The literature Chem. Pharm. Bull, 33(4) 1458-1471 (1985) discloses the detailed preparation process of naphthostat mesylate:

[0006]

[0007] This method involves reacting 6-amidinyl-2-naphthol methanesulfonate, p-guanidinylbenzoate, and N,N-dicyclohexylcarbodiimide (DCC) in pyridine to obtain naphthostat carbonate. Naphthostat carbonate is then added to N,N-dimethylformamide (DMF) containing hydrogen chloride to obtain solid naphthostat hydrochloride. Sodium methanesulfonate-water solution is added to prepare solid naphthostat methanesulfonate.

[0008] Studies have found that this method is prone to incomplete reaction and high levels of impurities in the product. It also consumes a lot of solvent for impurity removal, has a long production cycle, low overall yield, and causes serious environmental pollution.

[0009] Given the aforementioned shortcomings in the current preparation process of naphamostat mesylate, finding a process suitable for industrial production of naphamostat mesylate with mild reaction conditions, simple operation, and high product yield and purity remains a problem that needs to be solved. Summary of the Invention

[0010] To address the problems existing in current nafamostat mesylate preparation techniques, this invention provides a novel method for preparing nafamostat mesylate. This method features mild reaction conditions, simple operation, and yields a target product with high purity and yield.

[0011] The specific technical solution of the present invention is as follows:

[0012]

[0013] A method for preparing naphthostat mesylate specifically includes the following steps:

[0014] At room temperature and under nitrogen protection, 3,5-dimethyl-1-pyrazole formamidinium nitrate and an organic solvent were added to a reaction vessel and stirred. Then, compound I-2 was added, and the mixture was refluxed. After the reaction was detected to be complete, the temperature was lowered to T1 and stirred to induce crystallization. The mixture was filtered, and the filter cake was added to an aqueous solution of methanesulfonic acid. The mixture was stirred at a temperature of 15–20 °C, and then methanol was added. The mixture was stirred to induce crystallization at a temperature of 0–10 °C, and then filtered. The resulting filter cake was dried under reduced pressure to obtain the target product I.

[0015] In a preferred embodiment, the molar ratio of compound I-2 to compound 3,5-dimethyl-1-pyrazole formamidinium nitrate is 1:1.1 to 1.7, with a particularly preferred ratio of 1:1.25.

[0016] In a preferred embodiment, the mass-to-volume ratio of compound I-2 to organic solvent is 1:4 to 20, with a particularly preferred ratio of 1:10, g / mL.

[0017] In a preferred embodiment, the organic solvent is one or a combination of ethanol, methanol, isopropanol, and acetonitrile, with ethanol being particularly preferred.

[0018] In a preferred embodiment, the reaction temperature T1 is -10 to 10°C, with a particularly preferred temperature of -5 to 0°C.

[0019] The beneficial effects of this invention are:

[0020] 1. This invention provides a novel method for preparing naphthostat mesylate, which involves reacting compound I-2 as a starting material with 3,5-dimethyl-1-pyrazole formamidinium nitrate to form a salt, thereby obtaining the target product I.

[0021] 2. It can effectively avoid the use of highly toxic and irritating acyl chlorides, making operation safer;

[0022] 3. The preparation process of naphthostat mesylate of the present invention has a higher yield and purity than the product obtained by the prior art, and is simple and safe to operate, making it suitable for industrial production. Detailed Implementation

[0023] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0024] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0025] The synthetic route of this invention is as follows:

[0026]

[0027] Synthesis of intermediate I-1

[0028] Example 1

[0029] At room temperature, compounds SM-1 (23.73 g, 0.10 mol), SM-2 (20.48 g, 0.11 mol), DCC (26.82 g, 0.13 mol), and DMAP (0.31 g, 0.0025 mol) were added to pyridine (285 mL). The reaction was carried out at 30–35 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature, stirred to induce crystallization, and then filtered. The filter cake was washed with purified water (150 mL). The obtained solid was dried under reduced pressure to obtain intermediate compound I-1, with a yield of 97.6% and a purity of 99.95%.

[0030] Synthesis of intermediate I-2

[0031] Example 2

[0032] Compound I-1 (28.38 g, 0.07 mol) was added to 200 mL of 30% hydrochloric acid ethanol at room temperature and reacted at 20–25 °C. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure to obtain the target product compound I-2, with a yield of 98.6% and a purity of 99.96%.

[0033] Synthesis of target product I

[0034] Example 3

[0035] Under nitrogen protection at room temperature, 12.67 g (0.063 mol) of 3,5-dimethyl-1-pyrazole formamidinium nitrate and 190 mL of ethanol were added to a reaction vessel and stirred. Then, compound I-2 (18.91 g (0.05 mol) was added, and the mixture was refluxed. After the reaction was detected to be complete, the temperature was lowered to -5 to 0 °C and stirred to induce crystallization. The mixture was filtered, and the filter cake was added to a 1 mol / L aqueous solution of methanesulfonic acid (105 mL). The mixture was stirred at 15 to 20 °C for 2 to 5 hours. Then, 600 mL of methanol was added, and the temperature was lowered to 0 to 10 °C. After stirring for 2 to 3 hours to induce crystallization, the mixture was filtered. The resulting filter cake was dried under reduced pressure to obtain the target product I, with a yield of 98.6% and a purity of 99.92%.

[0036] Example 4

[0037] Under nitrogen protection at room temperature, 11.07 g (0.055 mol) of 3,5-dimethyl-1-pyrazole formamidinium nitrate and 76 mL of methanol were added to a reaction vessel and stirred. Then, compound I-2 (18.91 g (0.05 mol) was added, and the mixture was refluxed. After the reaction was detected to be complete, the temperature was lowered to -10 to -5 °C and stirred to induce crystallization. The mixture was filtered, and the filter cake was added to a 1 mol / L aqueous solution of methanesulfonic acid (105 mL). The mixture was stirred at 15 to 20 °C for 2 to 5 hours. Then, 600 mL of methanol was added, and the temperature was lowered to 0 to 10 °C. After stirring for 2 to 3 hours to induce crystallization, the mixture was filtered. The resulting filter cake was dried under reduced pressure to obtain the target product I, with a yield of 94.5% and a purity of 99.66%.

[0038] Example 5

[0039] Under nitrogen protection at room temperature, 17.10 g (0.085 mol) of 3,5-dimethyl-1-pyrazole formamidinium nitrate and 380 mL of ethanol were added to a reaction vessel and stirred. Then, compound I-2 (18.91 g (0.05 mol) was added, and the mixture was refluxed. After the reaction was detected to be complete, the temperature was lowered to -5 to 0 °C and stirred to induce crystallization. The mixture was filtered, and the filter cake was added to a 1 mol / L aqueous solution of methanesulfonic acid (105 mL). The mixture was stirred at 15 to 20 °C for 2 to 5 hours. Then, 600 mL of methanol was added, and the temperature was lowered to 0 to 10 °C. After stirring for 2 to 3 hours to induce crystallization, the mixture was filtered. The resulting filter cake was dried under reduced pressure to obtain the target product I, with a yield of 96.3% and a purity of 99.54%.

[0040] Example 6

[0041] Under nitrogen protection at room temperature, 10.06 g (0.05 mol) of 3,5-dimethyl-1-pyrazole formamidinium nitrate and 60 mL of isopropanol were added to a reaction vessel and stirred. Then, compound I-2 (18.91 g (0.05 mol)) was added, and the mixture was refluxed. After the reaction was detected to be complete, the temperature was lowered to -15 to -10 °C and stirred to induce crystallization. The mixture was filtered, and the filter cake was added to a 1 mol / L aqueous solution of methanesulfonic acid (105 mL). The mixture was stirred at 15 to 20 °C for 2 to 5 hours. Then, 600 mL of methanol was added, and the temperature was lowered to 0 to 10 °C. After stirring for 2 to 3 hours to induce crystallization, the mixture was filtered. The resulting filter cake was dried under reduced pressure to obtain the target product I, with a yield of 85.6% and a purity of 98.84%.

[0042] Example 7

[0043] Under nitrogen protection at room temperature, 20.11 g (0.1 mol) of 3,5-dimethyl-1-pyrazolamide nitrate and 400 mL of acetonitrile were added to a reaction vessel and stirred. Then, compound I-2 (18.91 g (0.05 mol) was added, and the mixture was refluxed. After the reaction was detected to be complete, the temperature was lowered to 10–15 °C and stirred to induce crystallization. The mixture was filtered, and the filter cake was added to a 1 mol / L aqueous solution of methanesulfonic acid (105 mL). The mixture was stirred at 15–20 °C for 2–5 hours. Then, 600 mL of methanol was added, and the temperature was lowered to 0–10 °C. After stirring for 2–3 hours to induce crystallization, the mixture was filtered, and the resulting filter cake was dried under reduced pressure to obtain the target product I, with a yield of 88.6% and a purity of 98.32%.

Claims

1. A method for preparing naphthalenemostat mesylate, characterized in that, The preparation method includes the following steps: Under nitrogen protection at room temperature, 3,5-dimethyl-1-pyrazole formamidinium nitrate and an organic solvent were added to a reaction vessel and stirred. Then, compound I-2 was added, and the mixture was refluxed. After the reaction was detected as complete, the temperature was lowered to T1, and the mixture was stirred to induce crystallization. The crystals were filtered, and the filter cake was added to an aqueous solution of methanesulfonic acid. The mixture was stirred at 15–20°C, and then methanol was added. The mixture was stirred to induce crystallization at 0–10°C, and then filtered. The resulting filter cake was dried under reduced pressure to obtain the target product I. The reaction route is as follows:

2. The preparation method according to claim 1, characterized in that, The molar ratio of compound I-2 to compound 3,5-dimethyl-1-pyrazole formamidinium nitrate is 1:1.1 to 1.

7.

3. The preparation method according to claim 1, characterized in that, The mass-to-volume ratio of compound I-2 to organic solvent is 1:4 to 20, with a particularly preferred ratio of 1:10, g / mL.

4. The preparation method according to claim 1, characterized in that, The organic solvent is one or a combination of ethanol, methanol, isopropanol, and acetonitrile.

5. The preparation method according to claim 1, characterized in that, The reaction temperature T1 is -10 to 10℃.

6. The preparation method according to claim 1, characterized in that, The concentration of the methanesulfonic acid aqueous solution is 1 mol / L.

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