A method for synthesizing nafamostat mesilate
By combining the esterification and hydrolysis reactions of compounds SM-1 and SM-2 with the salt formation step of aminoiminomethanesulfonic acid, the problems of high impurities, low yield, and environmental pollution in the synthesis of naphthalenesulfonic acid in the prior art have been solved, realizing a high-purity and high-yield synthesis method suitable for industrial application.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- LUNAN PHARMA GROUP CORPORATION
- Filing Date
- 2024-11-29
- Publication Date
- 2026-05-29
AI Technical Summary
Existing methods for synthesizing naphthostat mesylate involve incomplete reaction conversion, resulting in numerous impurities in the product, long production cycles, low yields, and environmental pollution problems.
Compound SM-1 and compound SM-2 were reacted in pyridine to generate intermediate compound I-1, which was then hydrolyzed in 30% hydrochloric acid ethanol to generate compound I-2. I-2 was then reacted with aminoiminomethanesulfonic acid in the presence of a base, and finally reacted with methanesulfonic acid to form a salt to generate the target product I.
The synthesis of naphthostat mesylate with high purity and high yield has been achieved, simplifying the operation process, avoiding the use of toxic reagents, and making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for synthesizing naphthostat mesylate. Background Technology
[0002] Nafamostat mesilate, chemically known as 6-amidinyl-2-naphthyl-4-guanidinylbenzoate dimethylsulfonate, is a non-peptide synthetic protease inhibitor.
[0003] The detailed preparation process of naphthostat methanesulfonate is disclosed in the synthetic literature Chem. Pharm. Bull, 33(4) 1458-1471 (1985). 6-Amino-2-naphthol methanesulfonate, p-guanidinylbenzoate, and N,N-dicyclohexylcarbodiimide (DCC) are reacted in pyridine to obtain naphthostat carbonate. Then, the naphthostat carbonate is 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. Studies have found that this method is prone to incomplete reaction conversion, resulting in a high amount of impurities in the product. It also requires a large amount of solvent for impurity removal, has a long production cycle, a low overall yield, and causes serious environmental pollution.
[0004]
[0005] Patent CN103012214A describes a reaction between p-guanidinobenzoyl chloride hydrochloride and a 6-amidinyl-2-naphthol methanesulfonic acid compound, followed by a pyridine reaction to synthesize nabumostat hydrochloride. Then, nabumostat hydrochloride is reacted with methanesulfonic acid in a mixture of water and an organic solvent to synthesize nabumostat methanesulfonate. This reaction process easily generates impurities, requiring multiple purification steps, making the operation cumbersome and further reducing the yield.
[0006]
[0007] 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
[0008] 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.
[0009] The specific technical solution of the present invention is as follows:
[0010]
[0011] A method for preparing naphthostat mesylate specifically includes the following steps:
[0012] Step 1: Preparation of intermediate compound I-1
[0013] Compounds SM-1, SM-2, DCC, and DMAP were added to pyridine at room temperature and reacted at 30–35 °C. After the reaction was completed, the reaction solution was cooled to room temperature, stirred to induce crystallization, and then filtered. The resulting solid was dried under reduced pressure to obtain intermediate compound I-1. The synthetic route is shown below:
[0014]
[0015] In a preferred embodiment, the molar ratio of compound SM-1 to compounds SM-2, DCC, and DMAP in step 1 is 1:1.1:1.3:0.025.
[0016] In a preferred embodiment, the mass-to-volume ratio of compound SM-1 to solvent pyridine in step 1 is 1:12, g / mL.
[0017] Step 2: Preparation of compound I-2
[0018] Compound I-1 was added to 30% hydrochloric acid ethanol at room temperature and reacted at a controlled temperature of 20–25°C. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure to obtain the target product I-2. The synthetic route is shown below:
[0019]
[0020] In a preferred embodiment, the mass-to-volume ratio of compound I-1 to 30% hydrochloric acid ethanol in step 2 is 1:7, g / mL.
[0021] Step 3: Preparation of Compound I
[0022] At room temperature, compound I-2, alkali, and purified water were added to a reaction vessel and stirred. Then, aminoiminomethanesulfonic acid was added, and the reaction was carried out at temperature T3. After the reaction was confirmed to be complete, the mixture was filtered. The filter cake was added to an aqueous methanesulfonic acid solution, stirred, and then an organic solvent was added. After stirring and crystallization, the mixture was filtered again. The resulting filter cake was dried under reduced pressure to obtain the target product I. The synthetic route is shown below:
[0023]
[0024] In a preferred embodiment, the alkali mentioned in step 3 is selected from one or a combination of potassium carbonate, potassium bicarbonate, and potassium hydroxide, with potassium carbonate being particularly preferred.
[0025] In a preferred embodiment, the molar ratio of compound I-2 to alkali and aminoiminomethanesulfonic acid in step 3 is 1:1 to 1.5:1 to 1.9, with a particularly preferred ratio of 1:1.1:1.6.
[0026] In a preferred embodiment, the molar ratio of compound I-2 to methanesulfonic acid in step 3 is 1:2.1.
[0027] In a preferred embodiment, the reaction temperature T3 in step 3 is 10–50°C, with a particularly preferred temperature of 20–25°C.
[0028] In a preferred embodiment, the organic solvent in step 3 is one or a combination of methanol, ethanol, acetone, diethyl ether, isopropyl ether, and methyl tert-butyl ether, with acetone being particularly preferred.
[0029] The beneficial effects of this invention are:
[0030] 1. This invention provides a novel method for preparing naphthostat mesylate, using compound SM-1 as the starting material, first reacting it with compound SM-2 via esterification to obtain compound I-1, then hydrolyzing it to obtain compound I-2, and then reacting compound I-2 with aminoiminomethanesulfonic acid to form a salt, thereby obtaining the target product I.
[0031] 2. It can effectively avoid the use of highly toxic and irritating acyl chlorides, making operation safer;
[0032] 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
[0033] 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.
[0034] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.
[0035] Synthesis of intermediate I-1
[0036] Example 1
[0037] 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%.
[0038] Synthesis of intermediate I-2
[0039] Example 2
[0040] 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%.
[0041] Synthesis of target product I
[0042] Example 3
[0043] At room temperature, compound I-2 (18.91 g, 0.05 mol), potassium carbonate (7.60 g, 0.055 mol), and purified water (180 mL) were added to a reaction vessel and stirred. Then, aminoiminomethanesulfonic acid (9.93 g, 0.08 mol) was added, and the reaction was carried out at a controlled temperature of 20–25 °C. After the reaction was detected to be complete, the mixture was filtered. The filter cake was added to a methanesulfonic acid aqueous solution (1 mol / L, 105 mL), stirred for 1 hour, and then acetone (500 mL) was added. After stirring for 2–3 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 98.8% and a purity of 99.98%.
[0044] Example 4
[0045] At room temperature, compound I-2 (18.91 g, 0.05 mol), potassium carbonate (6.91 g, 0.05 mol), and purified water (180 mL) were added to a reaction vessel and stirred. Then, aminoiminomethanesulfonic acid (9.93 g, 0.08 mol) was added, and the reaction was carried out at a controlled temperature of 10–15 °C. After the reaction was detected to be complete, the mixture was filtered. The filter cake was added to a methanesulfonic acid aqueous solution (1 mol / L, 105 mL), stirred for 1 hour, and then methanol (500 mL) was added. After stirring for 2–3 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 95.3% and a purity of 99.71%.
[0046] Example 5
[0047] At room temperature, compound I-2 (18.91 g, 0.05 mol), potassium carbonate (10.37 g, 0.075 mol), and purified water (180 mL) were added to a reaction vessel and stirred. Then, aminoiminomethanesulfonic acid (9.93 g, 0.08 mol) was added, and the reaction was carried out at 45–50 °C. After the reaction was detected to be complete, the mixture was filtered. The filter cake was added to a methanesulfonic acid aqueous solution (1 mol / L, 105 mL), stirred for 1 hour, and then ethanol (500 mL) was added. After stirring for 2–3 hours, crystals were precipitated and filtered. The resulting filter cake was dried under reduced pressure to obtain the target product I, with a yield of 96.2% and a purity of 99.62%.
[0048] Example 6
[0049] At room temperature, compound I-2 (18.91 g, 0.05 mol), potassium bicarbonate (5.51 g, 0.055 mol), and purified water (180 mL) were added to a reaction vessel and stirred. Then, aminoiminomethanesulfonic acid (6.21 g, 0.05 mol) was added, and the reaction was carried out at 20–25 °C. After the reaction was detected to be complete, the mixture was filtered. The filter cake was added to a methanesulfonic acid aqueous solution (1 mol / L, 105 mL), stirred for 1 hour, and then ether (500 mL) was added. After stirring for 2–3 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 94.4% and a purity of 99.77%.
[0050] Example 7
[0051] At room temperature, compound I-2 (18.91 g, 0.05 mol), potassium bicarbonate (5.51 g, 0.055 mol), and purified water (180 mL) were added to a reaction vessel and stirred. Then, aminoiminomethanesulfonic acid (11.79 g, 0.095 mol) was added, and the reaction was carried out at 20–25 °C. After the reaction was detected to be complete, the mixture was filtered. The filter cake was added to a methanesulfonic acid aqueous solution (1 mol / L, 105 mL), stirred for 1 hour, and then isopropyl ether (500 mL) was added. After stirring for 2–3 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 99.65%.
[0052] Example 8
[0053] At room temperature, compound I-2 (18.91 g, 0.05 mol), potassium carbonate (11.75 g, 0.085 mol), and purified water (180 mL) were added to a reaction vessel and stirred. Then, aminoiminomethanesulfonic acid (18.62 g, 0.15 mol) was added, and the reaction was carried out at 50–55 °C. After the reaction was detected to be complete, the mixture was filtered. The filter cake was added to a methanesulfonic acid aqueous solution (1 mol / L, 105 mL), and stirred for 1 hour. Then, methyl tert-butyl ether (500 mL) was added, and the mixture was stirred for 2–3 hours to induce crystallization. After filtration, the resulting filter cake was dried under reduced pressure to obtain the target product I, with a yield of 87.6% and a purity of 98.23%.
Claims
1. A method for synthesizing naphthalenemostat mesylate, characterized in that, The synthesis method includes the following steps: Step 1: At room temperature, add compounds SM-1, SM-2, DCC, and DMAP to pyridine and react at a controlled temperature of 30-35°C. After the reaction is completed, cool the reaction solution to room temperature, stir to induce crystallization, and filter. The resulting solid is dried under reduced pressure to obtain intermediate compound I-1. Step 2: Add compound I-1 to 30% hydrochloric acid ethanol and react at a controlled temperature of 20-25℃. After the reaction is completed, concentrate the reaction solution under reduced pressure to dryness to obtain the target product I-2. Step 3: Add compound I-2, alkali, and purified water to a reaction vessel and stir. Then add aminoiminomethanesulfonic acid and react at temperature T3. After the reaction is complete, filter the mixture. Add the filter cake to an aqueous methanesulfonic acid solution, stir, add an organic solvent, stir to induce crystallization, and then filter. The resulting filter cake is dried under reduced pressure to obtain the target product I. The reaction route is as follows:
2. The synthesis method according to claim 1, characterized in that, The molar ratio of compound SM-1 to compounds SM-2, DCC, and DMAP in step 1 is 1:1.1:1.3:0.
025.
3. The synthesis method according to claim 1, characterized in that, The mass-to-volume ratio of compound I-1 to 30% hydrochloric acid ethanol in step 2 is 1:7, g / mL.
4. The synthesis method according to claim 1, characterized in that, The alkali mentioned in step 3 is selected from one or a combination of potassium carbonate, potassium bicarbonate, and potassium hydroxide.
5. The synthesis method according to claim 1, characterized in that, The molar ratio of compound I-2, alkali, and aminoiminomethanesulfonic acid in step 3 is 1:1 to 1.5:1 to 1.
9.
6. The synthesis method according to claim 1, characterized in that, The molar ratio of compound I-2 to methanesulfonic acid in step 3 is 1:2.
1.
7. The synthesis method according to claim 1, characterized in that, The reaction temperature T3 mentioned in step 3 is 10 to 50°C.
8. The synthesis method according to claim 1, characterized in that, The organic solvent mentioned in step 3 is selected from one or a combination of methanol, ethanol, acetone, diethyl ether, isopropyl ether, and methyl tert-butyl ether.