A method for preparing fasudil

Abstract

This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing fasudil. The method uses isoquinoline-5-sulfonyl chloride hydrochloride and a piperazine one compound as raw materials, which are sulfonated to obtain an intermediate. This intermediate is then reduced with sodium borohydride to obtain fasudil. The preparation method described in this invention effectively avoids the generation of dimer impurities, is simple to operate, and yields a product with high yield and purity, making it 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 fasudil. Background Technology

[0002] Fasudil hydrochloride, chemically named hexahydro-1-(5-sulfonylisoquinoline)-1(H)-1,4-diazazoline hydrochloride, is a novel isoquinoline sulfonamide derivative developed through a collaboration between Asahi Kasei Corporation and Nagoya University. It serves as a RHO kinase inhibitor and a novel intracellular calcium... 2+ This antagonist drug dilates blood vessels, reduces endothelial cell tension, improves cerebral microcirculation, and protects ischemic brain tissue by increasing the activity of myosin light chain phosphatase. It also antagonizes inflammatory factors, protects neurons against apoptosis, and promotes nerve regeneration. Launched by Asahi Kasei Corporation of Japan in June 1995 and in China in 2004, it is primarily used to improve symptoms of ischemic cerebrovascular diseases such as cerebral vasospasm caused by subarachnoid hemorrhage. Its clinical application scope is expected to continue to expand, indicating a broad market prospect. Therefore, researching and optimizing its synthesis process and establishing a suitable process route is of great significance. Its chemical structure is as follows:

[0003]

[0004] Currently, there are numerous reports on the synthesis methods of fasudil hydrochloride, but they are all based on the synthetic strategies in the original patents, with improvements and optimizations. Examples include patents US4678783A, EP0187371B1, JPH11171885A, JPH11158177A, CN1183782A, CN101863880A, CN102020636A, CN102070612B, CN103030629A, CN103145695A, CN102603715A, CN103044403A, and the literature Chem. Pharm. B. ull.,40(3),1992,770-773、Synthesis of Fasudil Hydrochloride, Qilu Pharmaceutical Affairs,2012,31(8),438-439. Starting from isoquinoline or its downstream intermediate, isoquinoline-5-sulfonic acid is obtained by sulfonation with fuming sulfuric acid (or chlorosulfonic acid, etc.), and then reacted with excess dichlorosulfoxide (or oxalyl chloride, cyanuric chloride, etc.) to generate isoquinoline-5-sulfonyl chloride hydrochloride. After alkali treatment, it is reacted with excess piperazine to finally form salt to obtain fasudil hydrochloride. The synthetic route is shown below:

[0005]

[0006] However, the above process will encounter the following problems to varying degrees during actual operation: The reaction of isoquinoline-5-sulfonyl chloride with piperazine inevitably results in the formation of dimer impurities. To reduce dimer formation and increase yield, excessive piperazine is used, increasing production costs. Furthermore, the dimer byproducts generated during the reaction are difficult to separate from the product, even requiring purification with silica gel column chromatography, which limits large-scale production. The structural formula of the dimer impurity is shown below:

[0007]

[0008] To address the aforementioned issues and obtain target products that meet pharmaceutical standards, various purification methods have been disclosed. For example, Chinese patent applications CN101812051A, CN101962379A, CN102002036A, CN101723934A, CN102775387A, CN103509002A, CN102924436A, CN103724326A, CN104098547A, CN104327052A, CN109970712A, CN109705096A, and CN111217794A all report methods for obtaining products with higher purity. However, these methods all involve additional unit operations, and the purification process directly results in the loss of a portion of the target product, leading to a decrease in the final purification yield and an increase in production costs.

[0009] Furthermore, to address the aforementioned dimer impurities, patent CN102120739A uses 4-piperidinone hydrochloride hydrate as a starting material. It first reacts with an amino protecting agent to obtain amino-protected 4-piperidinone, then undergoes oxime reaction to obtain 4-piperidinone oxime, followed by Beckmann rearrangement to obtain amino-protected 5-carbonyl-perpiperazine. Subsequently, the carbonyl group undergoes a reduction reaction to obtain the key intermediate, monoamine-protected perpiperazine. Finally, 5-isoquinoline sulfonyl chloride reacts with the monoamine-protected perpiperazine via sulfonation, amino deprotection, and salt formation to obtain the target product. The synthetic route is shown below:

[0010]

[0011] However, the above process has a long synthesis unit when preparing mono-N-protected piperazine, resulting in a low overall yield and cumbersome operation; at the same time, the corresponding protecting group needs to be removed in different reaction systems, which leads to large differences in yield.

[0012] Furthermore, patent CN101973982A describes a process where mono-N-Boc-piperazine reacts with isoquinoline-5-sulfonyl chloride hydrochloride, followed by deprotection to obtain the target product. However, this process uses fuming sulfuric acid, which has a corrosive and strongly irritating odor, for the sulfonation reaction, resulting in low operational safety. Additionally, the hydrolysis of bis-N-Boc-piperazine to prepare mono-N-Boc-piperazine exhibits low selectivity, making it difficult to precisely control the production of N-mono-Boc-piperazine. The synthetic route is shown below:

[0013]

[0014] Given the aforementioned shortcomings in current methods for preparing fasudil, finding a reaction route suitable for industrial-scale production of fasudil that offers mild reaction conditions, simple operation, high product yield and purity, and low production cost remains a problem that needs to be solved. Summary of the Invention

[0015] To address the problems existing in current fasudil preparation techniques, this invention provides a novel method for preparing fasudil. The target product obtained by this method has high purity and yield, and effectively avoids the generation of the aforementioned dimer impurities.

[0016] The specific technical solution of the present invention is as follows:

[0017]

[0018] In compounds SM-2 and I-1, when m = 1, n = 2; when m = 2, n = 1.

[0019] The SM-2 is either piperazine-2-one (i.e., when m=1, n=2) or piperazine-5-one (i.e., when m=2, n=1); preferably piperazine-5-one.

[0020] A method for preparing fasudil as shown in Formula I specifically includes the following steps:

[0021] Step 1: Preparation of compound I-1

[0022] Compound SM-1 was extracted with a saturated sodium bicarbonate aqueous solution and an organic solvent. Then, SM-2 and an acid-binding agent were added to the organic phase, and the reaction was carried out at a controlled temperature (T1). After post-treatment, the target product I-1 was obtained. The synthetic route is shown below:

[0023]

[0024] In compounds SM-2 and I-1, when m = 1, n = 2; when m = 2, n = 1.

[0025] In a preferred embodiment, the organic solvent is one or a combination of dichloromethane and chloroform, with dichloromethane being particularly preferred.

[0026] In a preferred embodiment, the acid-binding agent is one or a combination of sodium bicarbonate, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, and pyridine, with triethylamine being particularly preferred.

[0027] In a preferred embodiment, the molar ratio of SM-1 and SM-2 and the acid-binding agent is 1:1.0 to 1.2:1.1 to 1.5, with a particularly preferred ratio of 1:1.0:1.2.

[0028] In a preferred embodiment, the reaction temperature T1 is 15–50°C, with a particularly preferred temperature of 20–25°C.

[0029] In a preferred embodiment, the post-processing step is as follows: quench the reaction by adding purified water to the reaction system, separate the organic phase, wash the organic phase with purified water, wash with saturated brine, concentrate under reduced pressure to dryness, and recrystallize with ethanol to obtain intermediate I-1.

[0030] Step 2: Preparation of Compound I

[0031] Compound I-1 and sodium borohydride were added to tert-butanol at room temperature, and methanol was added under controlled reflux. After the reaction was completed, the target product I was obtained through post-processing. The synthetic route is shown below:

[0032]

[0033] Compound I-1 corresponds to the restrictions on m and n in SM-2 in step 1.

[0034] In a preferred embodiment, the molar ratio of I-1 to sodium borohydride is 1:8 to 15, with a particularly preferred ratio of 1:12.

[0035] In a preferred embodiment, the mass-to-volume ratio of I-1 to methanol and tert-butanol is 1:4 to 15:8 to 30, with a particularly preferred ratio of 1:10:20.

[0036] In a preferred embodiment, the methanol is added by means of flow addition, drop addition, etc.; preferably, the drop addition method is used, and the time is controlled within 1 to 6 hours.

[0037] In the preferred embodiment, the post-processing steps are as follows: the reaction solution is cooled to room temperature, purified water is added to quench the reaction solution, dichloromethane is used for extraction, the organic phases are combined, saturated brine is used for washing, and the organic phase is concentrated under reduced pressure to dryness to obtain the target product I.

[0038] The beneficial effects of this invention are:

[0039] 1. This invention provides a novel method for preparing fasudil, which uses SM-1 and SM-2 as starting materials and then reduces them with amide to obtain the target product, effectively avoiding the generation of dimer impurities.

[0040] 2. In this process, only sodium borohydride is required for the lactam reduction step, without the need for other activators, making the operation simpler.

[0041] 3. The products obtained through this process have high yield and purity. Detailed Implementation

[0042] 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.

[0043] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0044] Synthesis of compound I-1

[0045] When m = 2 and n = 1, the synthetic route of compound I-1-1 is as follows:

[0046]

[0047] Example 1

[0048] Compound SM-1 (26.41 g, 0.10 mol) was fully liberated with saturated sodium bicarbonate (500 ml) under controlled temperature of 0–5 °C, extracted with dichloromethane (100 ml × 3), washed with saturated brine, and then the organic phase was reacted with piperazine-5-one (11.41 g, 0.10 mol) and triethylamine (12.14 g, 0.12 mol) under controlled temperature of 20–25 °C. After the reaction was detected to be complete, purified water (100 ml) was added to quench the reaction, the organic phase was separated, and the organic phase was washed with purified water (100 ml × 2) and saturated brine (100 ml). The mixture was concentrated to dryness under reduced pressure and recrystallized from ethanol to obtain intermediate I-1-1, with a yield of 95.6% and a purity of 99.7%. ESI-MS (m / z): 306.1 [M+H] + No dimer compounds were detected.

[0049] Example 2

[0050] Compound SM-1 (26.41 g, 0.10 mol) was fully released using saturated sodium bicarbonate (500 ml) at a controlled temperature of 0–5 °C, extracted with dichloromethane (100 ml × 3), and washed with saturated brine. The organic phase was then reacted with piperazine-5-one (13.70 g, 0.12 mol) and sodium bicarbonate (10.08 g, 0.12 mol) at a controlled temperature of 20–25 °C. After the reaction was confirmed to be complete, purified water (100 ml) was added to quench the reaction. The organic phase was then separated, washed with purified water (100 ml × 2), washed with saturated brine (100 ml), and concentrated under reduced pressure to dryness. Recrystallization from ethanol yielded intermediate I-1-1, with a yield of 95.4% and a purity of 99.6%. No dimer compounds were detected.

[0051] Example 3

[0052] Compound SM-1 (26.41 g, 0.10 mol) was fully liberated with saturated sodium bicarbonate (500 ml) under controlled temperature of 0–5 °C, extracted with dichloromethane (100 ml × 3), washed with saturated brine, and then the organic phase was reacted with piperazine-5-one (14.27 g, 0.125 mol) and N,N-diisopropylethylamine (15.51 g, 0.12 mol) under controlled temperature of 15–20 °C. After the reaction was detected to be complete, purified water (100 ml) was added to quench the reaction, and the organic phase was separated. The organic phase was washed with purified water (100 ml × 2), washed with saturated brine (100 ml), concentrated under reduced pressure to dryness, and recrystallized from ethanol to obtain intermediate I-1-1, with a yield of 95.5% and a purity of 99.4%. No dimer compounds were detected.

[0053] Example 4

[0054] Compound SM-1 (26.41 g, 0.10 mol) was fully released using saturated sodium bicarbonate (500 ml) at a controlled temperature of 0–5 °C, extracted with dichloromethane (100 ml × 3), and washed with saturated brine. The organic phase was then reacted with piperazine-5-one (11.41 g, 0.10 mol) and triethylamine (11.13 g, 0.11 mol) at a controlled temperature of 30–35 °C. After the reaction was confirmed to be complete, purified water (100 ml) was added to quench the reaction. The organic phase was then separated, washed with purified water (100 ml × 2), washed with saturated brine (100 ml), and concentrated under reduced pressure to dryness. Recrystallization from ethanol yielded intermediate I-1-1, with a yield of 94.6% and a purity of 99.6%. No dimer compounds were detected.

[0055] Example 5

[0056] Compound SM-1 (26.41 g, 0.10 mol) was fully liberated with saturated sodium bicarbonate (500 ml) under controlled temperature of 0–5 °C, extracted with chloroform (100 ml × 3), washed with saturated brine, and then the organic phase was reacted with piperazine-5-one (11.41 g, 0.10 mol) and potassium carbonate (14.51 g, 0.105 mol) at controlled temperature of 45–50 °C. After the reaction was detected to be complete, purified water (100 ml) was added to quench the reaction, and the organic phase was separated. The organic phase was washed with purified water (100 ml × 2) and then with saturated brine (100 ml). The mixture was concentrated to dryness under reduced pressure and recrystallized from ethanol to obtain intermediate I-1-1, with a yield of 93.2% and a purity of 99.5%. No dimer compounds were detected.

[0057] Example 6

[0058] Compound SM-1 (26.41 g, 0.10 mol) was fully released using saturated sodium bicarbonate (500 ml) at a controlled temperature of 0–5 °C, extracted with dichloromethane (100 ml × 3), and washed with saturated brine. The organic phase was then reacted with piperazine-5-one (11.41 g, 0.10 mol) and pyridine (11.87 g, 0.15 mol) at a controlled temperature of 20–25 °C. After the reaction was confirmed to be complete, purified water (100 ml) was added to quench the reaction. The organic phase was then separated, washed with purified water (100 ml × 2), washed with saturated brine (100 ml), and concentrated under reduced pressure to dryness. Recrystallization from ethanol yielded intermediate I-1-1, with a yield of 95.5% and a purity of 99.6%. No dimer compounds were detected.

[0059] Synthesis of compound I-1

[0060] When m = 1, n = 2, the synthetic route of compound I-1-2 is as follows:

[0061]

[0062] Example 7

[0063] Compound SM-1 (26.41 g, 0.10 mol) was fully liberated with saturated sodium bicarbonate (500 ml) under controlled temperature of 0–5 °C, extracted with chloroform (100 ml × 3), washed with saturated brine, and then the organic phase was reacted with piperazine-2-one (11.41 g, 0.10 mol) and triethylamine (16.19 g, 0.16 mol) at controlled temperature of 15–20 °C. After the reaction was detected to be complete, purified water (100 ml) was added to quench the reaction, and the organic phase was separated. The organic phase was washed with purified water (100 ml × 2) and then with saturated brine (100 ml). The mixture was concentrated to dryness under reduced pressure and recrystallized from ethanol to obtain intermediate I-1-2, with a yield of 95.3% and a purity of 99.5%. ESI-MS (m / z): 306.1 [M+H] + No dimer compounds were detected.

[0064] Synthesis of Compound I

[0065]

[0066] Example 8

[0067] Compound I-1-1 (15.27 g, 0.05 mol) and sodium borohydride (22.70 g, 0.6 mol) were added to tert-butanol (305 ml) at room temperature. Methanol (153 ml) was slowly added under controlled reflux for approximately 4 hours. After the reaction was confirmed to be complete, the reaction solution was cooled to room temperature, quenched and diluted with purified water (500 ml), extracted with dichloromethane (250 ml × 3), and the organic phases were combined. The organic phases were washed with saturated brine (250 ml × 2) and concentrated to dryness under reduced pressure to obtain product I, with a yield of 97.3% and a purity of 99.8%. ESI-MS (m / z): 292.1 [M+H] + No dimer compounds were detected.

[0068] Example 9

[0069] At room temperature, compound I-1-1 (15.27 g, 0.05 mol) and sodium borohydride (15.13 g, 0.4 mol) were added to tert-butanol (305 ml). Methanol (153 ml) was slowly added under controlled reflux for approximately 4 hours. After the reaction was confirmed to be complete, the reaction solution was cooled to room temperature, quenched and diluted with purified water (500 ml), extracted with dichloromethane (250 ml × 3), and the organic phases were combined. The mixture was washed with saturated brine (250 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain the target product I, with a yield of 95.1% and a purity of 99.7%. No dimer compounds were detected.

[0070] Example 10

[0071] At room temperature, compound I-1-1 (15.27 g, 0.05 mol) and sodium borohydride (13.24 g, 0.35 mol) were added to tert-butanol (305 ml). Methanol (153 ml) was slowly added under controlled reflux for approximately 4 hours. After the reaction was confirmed to be complete, the reaction solution was cooled to room temperature, quenched and diluted with purified water (500 ml), extracted with dichloromethane (250 ml × 3), and the organic phases were combined. The mixture was washed with saturated brine (250 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain the target product I, with a yield of 93.4% and a purity of 99.5%. No dimer compounds were detected.

[0072] Example 11

[0073] At room temperature, compound I-1-1 (15.27 g, 0.05 mol) and sodium borohydride (28.37 g, 0.75 mol) were added to tert-butanol (305 ml). Methanol (153 ml) was slowly added under controlled reflux for approximately 4 hours. After the reaction was confirmed to be complete, the reaction solution was cooled to room temperature, quenched and diluted with purified water (500 ml), extracted with dichloromethane (250 ml × 3), and the organic phases were combined. The mixture was washed with saturated brine (250 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain the target product I, with a yield of 96.5% and a purity of 99.7%. No dimer compounds were detected.

[0074] Example 12

[0075] At room temperature, compound I-1-1 (15.27 g, 0.05 mol) and sodium borohydride (22.70 g, 0.6 mol) were added to tert-butanol (122 ml). Methanol (61 ml) was slowly added under controlled reflux for approximately 2 hours. After the reaction was confirmed to be complete, the reaction solution was cooled to room temperature, quenched and diluted with purified water (500 ml), extracted with dichloromethane (250 ml × 3), and the organic phases were combined. The mixture was washed with saturated brine (250 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain the target product I, with a yield of 93.3% and a purity of 99.6%. No dimer compounds were detected.

[0076] Example 13

[0077]

[0078] At room temperature, compound I-1-2 (15.27 g, 0.05 mol) and sodium borohydride (22.70 g, 0.6 mol) were added to tert-butanol (458 ml). Methanol (229 ml) was slowly added under controlled reflux for approximately 5 hours. After the reaction was confirmed to be complete, the reaction solution was cooled to room temperature, quenched and diluted with purified water (500 ml), and extracted with dichloromethane (250 ml × 3). The combined organic phases were washed with saturated brine (250 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain the target product I, with a yield of 96.6% and a purity of 99.6%. No dimer compounds were detected.

Claims

1. A process for the preparation of Fasudil, characterized in that, The isochinoline-5-sulfonyl chloride hydrochloride is used as raw material to react with the homopiperazine ketone compound SM-2 to obtain the corresponding compound I-1, and then the compound I-1 is further reduced to obtain the fasudil; the route is as follows: ； In the SM-2 and the compound I-1, when m = 1, n = 2; when m = 2, n = 1. The method comprises the following specific steps: Step 1: preparation of the compound I-1 After the compound SM-1 is freed with a saturated sodium bicarbonate aqueous solution and extracted with an organic solvent, the organic phase is added with SM-2 and an acid binding agent, and the reaction is carried out at a temperature T1, and the target product I-1 is obtained through post-treatment; Step 2: preparation of the compound I At room temperature, the compound I-1 and sodium borohydride are added into t-butyl alcohol, and methanol is added under reflux at a controlled temperature, and the target product I is obtained through post-treatment after the reaction is detected to be completed. The acid binding agent mentioned in step 1 is sodium bicarbonate, potassium carbonate, sodium carbonate, triethylamine, The reaction temperature T1 in step 1 is 15-50 ℃. - one or a combination of diisopropylethylamine, pyridine; The molar ratio of SM-1 and SM-2 and the acid binding agent in step 1 is 1:1.0-1.2:1.1-1.

5.

2. The production method according to claim 1, characterized by, The organic solvent in step 1 is one or a combination of dichloromethane and chloroform.

3. The preparation method according to claim 2, characterized in that, The reaction temperature T1 in step 1 is 20-25 ℃.

4. The preparation method according to claim 2, characterized in that, The post-treatment step in step 1 is that purified water is added into the reaction system to quench the reaction, the organic phase is separated, the organic phase is purified and washed with water, saturated brine is used for washing, and then the reaction system is concentrated to dryness under reduced pressure, and then the intermediate I-1 is obtained through recrystallization with ethanol.

5. The preparation method according to claim 2, characterized in that, The molar ratio of I-1 and sodium borohydride in step 2 is 1:8-15.

6. The preparation method according to claim 2, characterized in that, The mass-volume ratio of I-1 and methanol and t-butyl alcohol in step 2 is 1:4-15:8-30, g / ml.

7. The preparation method according to claim 2, characterized in that, The post-treatment step in step 2 is that the reaction liquid is cooled to room temperature, purified water is added into the reaction liquid to quench the reaction, dichloromethane is used for extraction, the combined organic phase is washed with saturated brine, and then the target product I is obtained by concentrating the organic phase to dryness under reduced pressure.

8. The preparation method according to claim 2, characterized in that, ​

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