CN111303120A - Preparation method of fasudil hydrochloride - Google Patents
Preparation method of fasudil hydrochloride Download PDFInfo
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- CN111303120A CN111303120A CN202010178659.1A CN202010178659A CN111303120A CN 111303120 A CN111303120 A CN 111303120A CN 202010178659 A CN202010178659 A CN 202010178659A CN 111303120 A CN111303120 A CN 111303120A
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
The invention belongs to the technical field of medicines, and relates to a preparation method of fasudil hydrochloride. The specific process of the method comprises the steps of reacting isoquinoline-5-sulfonic acid with 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine in an organic solvent under the action of organic base, then reacting with homopiperazine, and obtaining the high-purity fasudil hydrochloride through water washing, alkali washing, salt formation and recrystallization. The fasudil hydrochloride prepared by the method has the impurity content of less than 0.1 percent and the purity of more than 99.5 percent. The preparation method completely avoids the problem of product pigment caused by corrosion and hydrolysis of acyl chloride, has the advantages of safety, environmental protection, low production cost, high product quality, convenient operation and the like, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of fasudil hydrochloride.
Background
Fasudil (Fasudil) is the earliest discovered isoquinoline Rho kinase inhibitor, which was developed by Asahi Kasei Pharma and Pharmacology research laboratory of Minggu university, and has a strong vasodilation effect and an ischemic brain tissue protection effect. Marketed in japan in 6 months of 1995. Chinese approved fasudil hydrochloride injection (trade name: Ellipu) imported by Asahi chemical industry Co., Ltd. in 2001, and used for improving cerebral vasospasm after subarachnoid hemorrhage and cerebral ischemia symptoms caused thereby.
Fasudil Hydrochloride (Fasudil Hydrochloride), chemically known as hexahydro-1- (5-isoquinolinesulfonyl) -1(H) -1, 4-diazepine Hydrochloride, has the following structural formula:
fasudil hydrochloride is used as a novel and efficient vasodilator, can effectively relieve cerebral vasospasm, improves prognosis of patients with subarachnoid hemorrhage (SAH), and has great potential in preventing and treating cardiovascular and cerebrovascular diseases. Therefore, the research and optimization of the synthesis process and the establishment of a proper process route are of great significance.
At present, the traditional preparation routes (such as US4678783, CN101863880A, CN10172934A and CN101010629A) adopt isoquinoline to be sulfonated (the sulfonation reagent is fuming sulfuric acid or chlorosulfonic acid) to obtain 5-sulfonic acid isoquinoline, the 5-sulfonic acid isoquinoline reacts with a chlorination reagent to prepare 5-isoquinoline sulfonyl chloride hydrochloride solid (the chlorination reagent is thionyl chloride, chlorosulfonic acid, oxalyl chloride or cyanuric chloride), the latter is dissociated by sodium bicarbonate aqueous solution, and then CH is used for dissociating, and then CH 101010629A is used for dissociating2Cl2Extracting to obtain dichloromethane solution of 5-isoquinoline sulfonyl chloride, reacting the dichloromethane solution with homopiperazine to prepare fasudil, and then forming hydrochloride to complete the synthesis of the fasudil hydrochloride. Or 5-isoquinoline sulfonyl chloride hydrochloride and homopiperazine are directly adopted to react under the alkaline condition to prepare fasudil (refer to CN109574992A and CN102070612A), and then the fasudil hydrochloride is obtained by refining.
The traditional process has the following problems:
1. excessive thionyl chloride is used, equipment is seriously corroded, a large amount of waste acid and sulfur dioxide are generated, and the environmental pollution is serious; in the process of adopting chlorosulfonic acid, oxalyl chloride and cyanuric chloride as chlorinating reagents, even if excessive chlorinating reagents are used, the product yield is low and the cost is high;
2. due to the fact that isoquinoline-5-sulfonyl chloride hydrochloride is unstable and is easy to hydrolyze into isoquinoline-5-sulfonic acid, and pigment impurities generating yellow green are introduced into the next reaction, in order to remove color, activated carbon, silica gel or resin are required to be used for adsorption, so that operation is complex, and refining cost is increased.
3. Isoquinoline-5-sulfonyl chloride reacts with homopiperazine, inevitably has dimer impurity generation, and excessive homopiperazine is adopted to reduce dimer generation and improve yield, thereby increasing production cost of enterprises; and the by-product generated in the reaction is difficult to separate from the product, even purified by column layer silica gel, and is limited in large-scale production.
Disclosure of Invention
Aiming at the problems, the invention aims to overcome the defects of the prior art and provide the preparation method of the high-purity fasudil hydrochloride, which has the advantages of safety, environmental protection, low production cost, high product quality, convenience in operation and the like, and is suitable for industrial production.
The synthetic route of the invention is as follows:
the method specifically comprises the following steps:
(1) adding isoquinoline-5-sulfonic acid and 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine into an organic solvent, and dropwise adding organic base under the stirring condition to react to prepare an isoquinoline-5-sulfonic acid active ester solution;
the method is characterized in that in the step (1), trichloromethane or dichloromethane is used as a solvent to stir and disperse isoquinoline-5-sulfonic acid and 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine, the volume-to-weight ratio of the organic solvent to isoquinoline-5-sulfonic acid is 8-10 ml/g, and the molar ratio of isoquinoline-5-sulfonic acid to 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine is 1: 1-1.5.
The method is characterized in that triethylamine or N-methylmorpholine is adopted as the organic base in the step (1), the dropping temperature is kept at 10-30 ℃, and the molar ratio of isoquinoline-5-sulfonic acid to the organic base is 1: 1-1.5. After the dropwise addition, the reaction temperature is increased to 30-60 ℃, and the reaction time is 2-4 h.
(2) Dripping organic solvent solution of homopiperazine into isoquinoline-5-sulfonic acid active ester solution for continuous reaction;
the method is characterized in that in the step (2), the same solvent as the reaction is adopted as the organic solvent for dissolving the homopiperazine, the weight ratio of the amount of the organic solvent to the volume of the homopiperazine is 2-3 ml/g, the dropping time is 1-2 h, the dropping temperature is 10-30 ℃, and the molar ratio of isoquinoline-5-sulfonic acid to homopiperazine is 1: 1-1.5.
(3) After the reaction is finished, sequentially carrying out water washing, alkali washing and salifying to obtain a fasudil hydrochloride crude product;
the method is characterized in that in the step (3), after the reaction is finished, water is added into the organic phase for washing, the water phase is discarded, the organic phase is reserved for standby, the purpose of washing with water is to remove organic base hydrochloride generated by condensation and excessive homopiperazine, and the volume ratio of the water to the organic solvent is 1: 1-2.
The method is characterized in that in the step (3), after the organic phase is washed by water, an alkali solution is added for washing, and the purpose of alkali washing is to remove 2-hydroxy-4, 6-dimethoxy-1, 3, 5-triazine and excessive 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine. The volume ratio of the alkali solution to the organic solvent is 1: 1-2, the alkali can be one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, and the concentration of the alkali solution is 10-20%.
The method is characterized in that in the step (3), after the alkali washing is finished, concentrated hydrochloric acid is added, the pH value of the solution is adjusted to 5-6, a fasudil hydrochloride crude product is separated out, and the fasudil hydrochloride crude product is filtered, dried and collected as a filter cake. The organic impurities formed by the reaction remain in the organic solvent.
The invention is characterized in that in the step (3), the drying temperature is 20-30 ℃, and the drying time is 1-2 h.
(4) And recrystallizing the fasudil hydrochloride crude product to obtain a fasudil hydrochloride refined product.
The method is characterized in that in the step (4), the obtained fasudil hydrochloride crude product is stirred by methanol and ethyl acetate, heated to reflux, slowly cooled to 0-10 ℃ for crystallization for 1-2 hours, filtered and dried to obtain fasudil hydrochloride refined product. The volume ratio of the recrystallized methanol to the ethyl acetate is 1: 1-4, and the volume weight ratio of the mixed solvent to the fasudil hydrochloride crude product is 8-10.
The invention has the beneficial effects that:
1. the method completely avoids the adoption of a chlorination reagent, does not generate a large amount of acid water and waste gas, and is green and environment-friendly; the reaction conditions are very mild, and only ordinary reaction equipment is adopted, so that the equipment investment is reduced;
2. because acyl chloride intermediates are not generated in the reaction process, impurities and pigments introduced by acyl chloride decomposition are completely avoided, and therefore, the single impurities of the fasudil hydrochloride finished product obtained by the preparation method are less than 0.1 percent, and the content of the fasudil hydrochloride finished product is more than 99.5 percent;
3. the method adopts the reaction of the isoquinoline-5-sulfonic acid active ester and the homopiperazine, completely avoids the generation of dimer impurities, and completely avoids the adoption of a column chromatography purification or repeated recrystallization method, so the method has the advantages of high yield, controllable quality, simple operation and suitability for industrial production.
Detailed Description
The present invention will be described in further detail with reference to the following examples. However, it should be understood that the above description of the present invention is not limited to the following examples.
EXAMPLE 1 preparation of fasudil hydrochloride
(1) To a 500mL three-necked flask were added isoquinoline-5-sulfonic acid (20.9g, 0.1mol), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (21.1g, 0.12mol), and 170mL dichloromethane, followed by stirring. Dropwise adding triethylamine (18ml, 0.13mol), controlling the dropwise adding temperature to be 10-30 ℃, after the dropwise adding is finished, heating to reflux, reacting for 4 hours, and then cooling to 10-15 ℃.
(2) Adding 25ml of dichloromethane and homopiperazine (12g, 0.12mol) into a 250m three-necked bottle, stirring and dissolving, then dropwise adding the solution into the reaction system, wherein the dropwise adding time is 2 hours, the dropwise adding temperature is 10-30 ℃, after the dropwise adding is finished, heating to reflux, continuing to react for 2 hours, and cooling to 10-15 ℃ after the reaction is finished;
(3) transferring the reaction solution into a 1000ml three-necked bottle, adding 220ml water, stirring for 5min, standing for layering, and collecting an organic phase; transferring the organic phase into a 1000ml three-necked bottle, adding 220ml 10% sodium bicarbonate solution, stirring for 5min, standing for layering, and collecting the organic phase; the organic phase was transferred to a 1000ml three-necked flask, concentrated hydrochloric acid was added dropwise, and the pH of the solution was adjusted to 5.5.
(4) Suction filtration was carried out and the filter cake was washed with 25ml dichloromethane. Collecting the filter cake, and drying the filter cake for 2 hours in vacuum at 25 ℃ to obtain 27.2g of crude internally white fasudil hydrochloride with the yield of 82.93 percent.
(5) Adding 50ml of methanol, 200ml of ethyl acetate and 26g of fasudil hydrochloride crude product into a 500m three-necked bottle, stirring and heating until the mixture is dissolved under reflux, adding 1g of activated carbon for decoloring for 15min, filtering, and collecting filtrate. Transferring the filtrate into a three-necked bottle with the diameter of 500m, stirring, slowly cooling to 5 ℃, and crystallizing for 2 hours. Filtration was carried out, and the filter cake was washed with 20ml of ethyl acetate and collected. Vacuum drying at 40 deg.c for 4 hr to obtain fine fasudil hydrochloride 21.8g, refining yield 83.84%, maximum single impurity content 0.08% and purity 99.6%.
EXAMPLE 2 preparation of fasudil hydrochloride
(1) To a 500mL three-necked flask were added isoquinoline-5-sulfonic acid (20.9g, 0.1mol), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (17.6g, 0.1mol), and 200mL of chloroform, followed by stirring. Dropwise adding N-methylmorpholine (14ml, 0.1mol), controlling the dropwise adding temperature to be 10-30 ℃, after the dropwise adding is finished, heating to reflux, reacting for 2 hours, and then cooling to 10-15 ℃.
(2) Adding 25ml of trichloromethane and homopiperazine (10.0g, 0.1mol) into a 250m three-necked bottle, stirring and dissolving, then dropwise adding the solution into the reaction system, wherein the dropwise adding time is 2 hours, the dropwise adding temperature is 10-30 ℃, after the dropwise adding is finished, heating to reflux, continuing to react for 1.5 hours, and cooling to 10-15 ℃ after the reaction is finished;
(3) transferring the reaction solution into a 1000ml three-necked bottle, adding 220ml water, stirring for 5min, standing for layering, and collecting an organic phase; transferring the organic phase into a 1000ml three-necked bottle, adding 220ml 10% potassium carbonate solution, stirring for 5min, standing for layering, and collecting the organic phase; the organic phase was transferred to a 1000ml three-necked flask, concentrated hydrochloric acid was added dropwise, and the pH of the solution was adjusted to 5.2.
(4) Suction filtration was carried out and the filter cake was washed with 25ml dichloromethane. Collecting the filter cake, and drying the filter cake for 1.5h at 30 ℃ in vacuum to obtain 27.9g of crude fasudil hydrochloride with an internal white color, wherein the yield is 85.12%.
(5) Adding 50ml of methanol, 200ml of ethyl acetate and 25g of fasudil hydrochloride crude product into a 500m three-necked bottle, stirring and heating until the mixture is dissolved under reflux, adding 1g of activated carbon for decoloring for 10min, filtering, and collecting filtrate. Transferring the filtrate into a three-necked bottle with the diameter of 500m, stirring, slowly cooling to 10 ℃, and crystallizing for 2 hours. Filtration was carried out, and the filter cake was washed with 20ml of ethyl acetate and collected. Vacuum drying at 40 deg.c for 4 hr to obtain refined fasudil hydrochloride product in 20.3g, refining yield 81.13%, maximum single impurity content 0.06% and purity 99.7%.
EXAMPLE 3 preparation of fasudil hydrochloride
(1) To a 500mL three-necked flask were added isoquinoline-5-sulfonic acid (20.9g, 0.1mol), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (26.3g, 0.15mol), and 200mL of chloroform, followed by stirring. Dropwise adding N-methylmorpholine (16ml, 0.15mol), controlling the dropwise adding temperature to be 10-30 ℃, after the dropwise adding is finished, heating to reflux, reacting for 4 hours, and then cooling to 10-15 ℃.
(2) Adding 25ml of trichloromethane and homopiperazine (15.0g, 0.15mol) into a 250m three-necked bottle, stirring and dissolving, then dropwise adding the solution into the reaction system, wherein the dropwise adding time is 2 hours, the dropwise adding temperature is 10-30 ℃, after the dropwise adding is finished, heating to reflux, continuing to react for 1.5 hours, and cooling to 10-15 ℃ after the reaction is finished;
(3) transferring the reaction solution into a 1000ml three-necked bottle, adding 220ml water, stirring for 5min, standing for layering, and collecting an organic phase; transferring the organic phase into a 1000ml three-necked bottle, adding 220ml 10% potassium carbonate solution, stirring for 5min, standing for layering, and collecting the organic phase; the organic phase was transferred to a 1000ml three-necked flask, concentrated hydrochloric acid was added dropwise, and the pH of the solution was adjusted to 5.2.
(4) Suction filtration was carried out and the filter cake was washed with 25ml dichloromethane. Collecting the filter cake, and drying the filter cake for 1.5h at 30 ℃ in vacuum to obtain 29.2g of crude fasudil hydrochloride with the yield of 89.0%.
(5) Adding 50ml of methanol, 200ml of ethyl acetate and 25g of fasudil hydrochloride crude product into a 500m three-necked bottle, stirring and heating until the mixture is dissolved under reflux, adding 1g of activated carbon for decoloring for 10min, filtering, and collecting filtrate. Transferring the filtrate into a three-necked bottle with the diameter of 500m, stirring, slowly cooling to 10 ℃, and crystallizing for 2 hours. Filtration was carried out, and the filter cake was washed with 20ml of ethyl acetate and collected. Vacuum drying at 40 deg.c for 4 hr to obtain 21.1g refined fasudil hydrochloride product in the refining yield of 84.4%, maximum single impurity content of 0.04% and purity of 99.8%.
Claims (9)
1. A preparation method of fasudil hydrochloride is characterized by comprising the following steps:
(1) adding isoquinoline-5-sulfonic acid and 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine into an organic solvent, and dropwise adding organic base under the stirring condition to react to prepare an isoquinoline-5-sulfonic acid active ester solution;
(2) dripping organic solvent solution of homopiperazine into isoquinoline-5-sulfonic acid active ester solution for continuous reaction;
(3) after the reaction is finished, sequentially carrying out water washing, alkali washing and salifying to obtain a fasudil hydrochloride crude product;
(4) and recrystallizing the fasudil hydrochloride crude product to obtain the fasudil hydrochloride with the content of more than 99.5 percent.
2. The preparation method of fasudil hydrochloride according to claim 1, wherein in the step (1), the organic solvent is chloroform or dichloromethane, the volume-to-weight ratio of the amount of the organic solvent to the isoquinoline-5-sulfonic acid is 8-10 ml/g, and the molar ratio of the isoquinoline-5-sulfonic acid to the 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine is 1: 1-1.5.
3. The preparation method of fasudil hydrochloride according to claim 1, wherein triethylamine or N-methylmorpholine is used as the organic base in the step (1), the dropping temperature is kept at 10-30 ℃, and the molar ratio of isoquinoline-5-sulfonic acid to organic base is 1: 1-1.5.
4. The preparation method of fasudil hydrochloride according to claim 1, wherein in the step (1), the reaction temperature is increased to 30-60 ℃ after the dropwise addition, and the reaction time is 2-4 h.
5. The preparation method of fasudil hydrochloride according to claim 1, wherein in the step (2), the organic solvent is chloroform or dichloromethane, the volume-to-weight ratio of the amount of the organic solvent to the homopiperazine is 2-3 ml/g, the dropping time is 1-2 h, the dropping temperature is 10-30 ℃, and the molar ratio of isoquinoline-5-sulfonic acid to homopiperazine is 1: 1-1.5.
6. The method for preparing fasudil hydrochloride according to claim 1, wherein in the step (3), the volume ratio of water to the organic solvent is 1: 1-2, and the volume ratio of the alkali liquor to the organic solvent is 1: 1-2.
7. The method for preparing fasudil hydrochloride according to claim 1, wherein in the step (3), the alkali is one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, and the concentration of the alkali solution is 10-20%.
8. The preparation method of fasudil hydrochloride according to claim 1, wherein in the step (3), concentrated hydrochloric acid is selected in the salt forming step, and the pH of the solution is adjusted to 5-6.
9. The preparation method of fasudil hydrochloride according to claim 1, wherein in the step (4), methanol and ethyl acetate are used as recrystallization solvents, and the volume ratio of methanol to ethyl acetate is 1: 1-4.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114380794A (en) * | 2020-10-22 | 2022-04-22 | 鲁南制药集团股份有限公司 | Preparation method of fasudil |
| CN114380794B (en) * | 2020-10-22 | 2024-06-28 | 鲁南制药集团股份有限公司 | Preparation method of fasudil |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801954A (en) * | 2007-09-20 | 2010-08-11 | Irm责任有限公司 | Compounds and compositions as modulators of GPR119 activity |
| WO2011156245A2 (en) * | 2010-06-09 | 2011-12-15 | Merck Sharp & Dohme Corp. | Positive allosteric modulators of mglur2 |
| CN102603715A (en) * | 2012-03-31 | 2012-07-25 | 苏州工业园区南华生物科技有限公司 | Synthesis and preparation method of fasudil hydrochloride |
| CN103044403A (en) * | 2013-01-05 | 2013-04-17 | 成都天翼医药科技有限公司 | Preparation method of fasudil hydrochloride |
| CN105753817A (en) * | 2015-01-01 | 2016-07-13 | 成都贝斯凯瑞生物科技有限公司 | Nitrogen-substituted heterocyclic derivatives and application thereof |
| CN105793238A (en) * | 2013-11-27 | 2016-07-20 | 基因泰克公司 | Substituted benzamides and methods of use thereof |
-
2020
- 2020-03-14 CN CN202010178659.1A patent/CN111303120A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801954A (en) * | 2007-09-20 | 2010-08-11 | Irm责任有限公司 | Compounds and compositions as modulators of GPR119 activity |
| WO2011156245A2 (en) * | 2010-06-09 | 2011-12-15 | Merck Sharp & Dohme Corp. | Positive allosteric modulators of mglur2 |
| CN102603715A (en) * | 2012-03-31 | 2012-07-25 | 苏州工业园区南华生物科技有限公司 | Synthesis and preparation method of fasudil hydrochloride |
| CN103044403A (en) * | 2013-01-05 | 2013-04-17 | 成都天翼医药科技有限公司 | Preparation method of fasudil hydrochloride |
| CN105793238A (en) * | 2013-11-27 | 2016-07-20 | 基因泰克公司 | Substituted benzamides and methods of use thereof |
| CN105753817A (en) * | 2015-01-01 | 2016-07-13 | 成都贝斯凯瑞生物科技有限公司 | Nitrogen-substituted heterocyclic derivatives and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| NASSER IRANPOOR ET AL.: ""Synthesis of new surfactant-like triazinefunctionalized ligands for Pd-catalyzed Heck and Sonogashira reactions in water"", 《ROYAL SOCIETY OF CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114380794A (en) * | 2020-10-22 | 2022-04-22 | 鲁南制药集团股份有限公司 | Preparation method of fasudil |
| CN114380794B (en) * | 2020-10-22 | 2024-06-28 | 鲁南制药集团股份有限公司 | Preparation method of fasudil |
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Application publication date: 20200619 |