A process for the preparation of nafamostat mesylate

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of nafamostat mesilate. The compound 6-methylformamidinyl naphthalen-2-yl 4-aminobenzoate is used as a starting material, is reacted with methyl isothiourea, is salified, and the target product nafamostat mesilate is prepared. The process can effectively avoid the use of acyl chloride which is high in toxicity and irritancy, and is safer in operation.

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] Regarding the research on the synthesis methods of naphamostat mesylate, the publicly disclosed synthesis methods of naphamostat mesylate include:

[0004] The literature Chem. Pharm. Bull, 33(4) 1458-1471 (1985) discloses the detailed preparation process of naphthostat mesylate:

[0005]

[0006] 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.

[0007] 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.

[0008] 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

[0009] 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.

[0010] The specific technical solution of the present invention is as follows:

[0011]

[0012] A method for preparing naphthostat mesylate specifically includes the following steps:

[0013] At room temperature, methyl isothiourea sulfate and an aqueous solution of alkali are added to a reaction vessel and stirred. Then, compound I-2 is added, and the reaction is controlled at temperature T1. After the reaction is detected to be complete, the temperature is lowered to T2, stirred, and crystallized. The mixture is filtered, and the filter cake is added to an aqueous solution of methanesulfonic acid and stirred. Then, an organic solvent is added, stirred, and crystallized. The mixture is then filtered, and the resulting filter cake is dried under reduced pressure to obtain the target product I.

[0014] In a preferred embodiment, the molar ratio of compound I-2 to alkali and methyl isothiourea sulfate is 1:3.0-4.0:1-1.6, with a particularly preferred ratio of 1:3.2:1.1.

[0015] In a preferred embodiment, the alkali is selected from one or a combination of sodium hydroxide, barium hydroxide, sodium carbonate, and potassium carbonate, with sodium hydroxide being particularly preferred.

[0016] In a preferred embodiment, the reaction temperature T1 is 10–50°C, with a particularly preferred temperature of 20–25°C.

[0017] In a preferred embodiment, the reaction temperature T2 is -20 to 10°C, with a particularly preferred temperature of -5 to 0°C.

[0018] In a preferred embodiment, the organic solvent is one or a combination of methanol, ethanol, acetone, diethyl ether, isopropyl ether, and methyl tert-butyl ether, with methanol being particularly preferred.

[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 methyl isothiourea 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] At room temperature, methyl isothiourea sulfate (15.30 g, 0.055 mol) and sodium hydroxide aqueous solution (2 mol / L, 80 mL) were added to a reaction vessel and stirred. Then, compound I-2 (18.91 g, 0.05 mol) was slowly added, and the reaction was carried out at 20–25 °C. After the reaction was detected to be complete, the temperature was lowered to -5–0 °C and stirred to induce crystallization. The mixture was filtered, and the filter cake was added to methanesulfonic acid aqueous solution (1 mol / L, 105 mL) and stirred for 1 hour. Then, methanol (600 mL) was added and stirred for 2–3 hours to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain the target product I, with a yield of 98.8% and a purity of 99.96%.

[0036] Example 4

[0037] At room temperature, methyl isothiourea sulfate (15.30 g, 0.055 mol) and sodium hydroxide aqueous solution (2 mol / L, 75 mL) were added to a reaction vessel and stirred. Then, compound I-2 (18.91 g, 0.05 mol) was slowly added, and the reaction was carried out at a controlled temperature of 10–15 °C. After the reaction was detected to be complete, the temperature was lowered to -20–-15 °C and stirred to induce crystallization. The mixture was filtered, and the filter cake was added to a methanesulfonic acid aqueous solution (1 mol / L, 105 mL) and stirred for 1 hour. Then, ethanol (600 mL) was added, and the mixture was stirred for 2–3 hours to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain the target product I, with a yield of 94.3% and a purity of 99.70%.

[0038] Example 5

[0039] At room temperature, methyl isothiourea sulfate (15.30 g, 0.055 mol) and sodium hydroxide aqueous solution (2 mol / L, 100 mL) were added to a reaction vessel and stirred. Then, compound I-2 (18.91 g, 0.05 mol) was slowly added, and the reaction was carried out at 45–50 °C. After the reaction was detected to be complete, the temperature was lowered to 5–10 °C and stirred to induce crystallization. The mixture was filtered, and the filter cake was added to methanesulfonic acid aqueous solution (1 mol / L, 105 mL) and stirred for 1 hour. Then, acetone (600 mL) was added and stirred for 2–3 hours to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain the target product I, with a yield of 95.4% and a purity of 99.66%.

[0040] Example 6

[0041] At room temperature, methyl isothiourea sulfate (13.92 g, 0.05 mol) and barium hydroxide aqueous solution (2 mol / L, 88 mL) were added to a reaction vessel and stirred. Then, compound I-2 (18.91 g, 0.05 mol) was slowly added, and the reaction was carried out at 20–25 °C. After the reaction was detected to be complete, the temperature was lowered to -5–0 °C and stirred to induce crystallization. The mixture was filtered, and the filter cake was added to a methanesulfonic acid aqueous solution (1 mol / L, 105 mL). The mixture was stirred for 1 hour, and then isopropyl ether (600 mL) was added. 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 95.3% and a purity of 99.77%.

[0042] Example 7

[0043] At room temperature, 22.27 g (0.08 mol) of methyl isothiourea sulfate and 88 mL of sodium carbonate aqueous solution (2 mol / L) were added to a reaction vessel and stirred. Then, compound I-2 (18.91 g (0.05 mol) was slowly added, and the reaction was carried out at 20–25 °C. After the reaction was detected to be complete, the temperature was lowered to -5–0 °C and stirred to induce crystallization. The mixture was filtered, and the filter cake was added to 105 mL of methanesulfonic acid aqueous solution and stirred for 1 hour. Then, 600 mL of methyl tert-butyl ether was added and stirred for 2–3 hours to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain the target product I, with a yield of 96.1% and a purity of 99.60%.

[0044] Example 8

[0045] At room temperature, methyl isothiourea sulfate (13.92 g, 0.05 mol) and sodium hydroxide aqueous solution (2 mol / L, 70 mL) were added to a reaction vessel and stirred. Then, compound I-2 (18.91 g, 0.05 mol) was slowly added, and the reaction was carried out at 5–10 °C. After the reaction was detected to be complete, the temperature was lowered to -25–-20 °C and stirred to induce crystallization. The mixture was filtered, and the filter cake was added to methanesulfonic acid aqueous solution (1 mol / L, 105 mL) and stirred for 1 hour. Then, methanol (600 mL) was added and stirred for 2–3 hours to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain the target product I, with a yield of 83.9% and a purity of 98.86%.

[0046] Example 9

[0047] At room temperature, methyl isothiourea sulfate (25.05 g, 0.09 mol) and potassium carbonate aqueous solution (2 mol / L, 110 mL) were added to a reaction vessel and stirred. Then, compound I-2 (18.91 g, 0.05 mol) was slowly added, and the reaction was carried out at 50–55 °C. 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 methanesulfonic acid aqueous solution (1 mol / L, 105 mL) and stirred for 1 hour. Then, methanol (600 mL) was added and stirred for 2–3 hours to induce crystallization. The mixture was then 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 97.89%.

Claims

1. A method for preparing naphthalenemostat mesylate, characterized in that, The preparation method includes the following steps: At room temperature, methyl isothiourea sulfate and an aqueous solution of alkali were added to a reaction vessel and stirred. Then, compound I-2 was added, and the reaction was controlled at temperature T1. After the reaction was detected to be complete, the temperature was lowered to T2, and the mixture was 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, and then an organic solvent was added. After stirring to induce crystallization, the mixture was filtered again. 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 alkali and methyl isothiourea sulfate is 1:3.0-4.0:1-1.

6.

3. The preparation method according to claim 1, characterized in that, The alkali is selected from one of sodium hydroxide, barium hydroxide, sodium carbonate, and potassium carbonate.

4. The preparation method according to claim 1, characterized in that, The reaction temperature T1 is 10–50 °C.

5. The preparation method according to claim 1, characterized in that, The reaction temperature T2 is -20 to 10℃.

6. The preparation method according to claim 1, characterized in that, The organic solvent is selected from one or a combination of methanol, ethanol, acetone, diethyl ether, isopropyl ether, and methyl tert-butyl ether.

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