CN114380794A - Preparation method of fasudil - Google Patents
Preparation method of fasudil Download PDFInfo
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- CN114380794A CN114380794A CN202011135975.7A CN202011135975A CN114380794A CN 114380794 A CN114380794 A CN 114380794A CN 202011135975 A CN202011135975 A CN 202011135975A CN 114380794 A CN114380794 A CN 114380794A
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- ethyl acetate
- fasudil
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- 229960002435 fasudil Drugs 0.000 title claims abstract description 23
- NGOGFTYYXHNFQH-UHFFFAOYSA-N fasudil Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000001953 recrystallisation Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 84
- 238000006243 chemical reaction Methods 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 21
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 239000008213 purified water Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 5
- 229960001701 chloroform Drugs 0.000 claims description 4
- 239000000543 intermediate Substances 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 2
- 238000007867 post-reaction treatment Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract 2
- IFPJFPROEPHIMI-UHFFFAOYSA-N 3-(2-hydroxyethylamino)propan-1-ol Chemical compound OCCCNCCO IFPJFPROEPHIMI-UHFFFAOYSA-N 0.000 abstract 1
- 238000004440 column chromatography Methods 0.000 abstract 1
- BFIWZEKPARJYJE-UHFFFAOYSA-N isoquinoline-5-sulfonamide Chemical compound N1=CC=C2C(S(=O)(=O)N)=CC=CC2=C1 BFIWZEKPARJYJE-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 23
- 239000012044 organic layer Substances 0.000 description 9
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 5
- 239000000539 dimer Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- WHIDHHUCCTYJKA-UHFFFAOYSA-N isoquinoline-5-sulfonyl chloride Chemical compound N1=CC=C2C(S(=O)(=O)Cl)=CC=CC2=C1 WHIDHHUCCTYJKA-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- YFMJTLUPSMCTOQ-UHFFFAOYSA-N isoquinoline-5-sulfonic acid Chemical compound N1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 YFMJTLUPSMCTOQ-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000007670 refining Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- -1 5-carbonylhomopiperazine Chemical compound 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 210000005013 brain tissue Anatomy 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000006277 sulfonation reaction Methods 0.000 description 2
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SCQYOVPNVUOKLQ-UHFFFAOYSA-N 5-sulfonyl-6H-isoquinoline Chemical compound S(=O)(=O)=C1C=2C=CN=CC2C=CC1 SCQYOVPNVUOKLQ-UHFFFAOYSA-N 0.000 description 1
- 238000006237 Beckmann rearrangement reaction Methods 0.000 description 1
- 102000011131 Myosin-Light-Chain Phosphatase Human genes 0.000 description 1
- 108010037801 Myosin-Light-Chain Phosphatase Proteins 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- YROXEBCFDJQGOH-UHFFFAOYSA-N ditert-butyl piperazine-1,4-dicarboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)CC1 YROXEBCFDJQGOH-UHFFFAOYSA-N 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- GZZCYMXZJQCAJU-UHFFFAOYSA-N isoquinoline-1-sulfonamide Chemical class C1=CC=C2C(S(=O)(=O)N)=NC=CC2=C1 GZZCYMXZJQCAJU-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- YAZGADZUKMSMOV-UHFFFAOYSA-N n-piperidin-4-ylidenehydroxylamine Chemical compound ON=C1CCNCC1 YAZGADZUKMSMOV-UHFFFAOYSA-N 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000003590 rho kinase inhibitor Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000002602 strong irritant Substances 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of fasudil. The preparation method of fasudil provided by the invention comprises the following steps: and cyclizing isoquinoline-5-sulfonamide and 3- ((2-hydroxyethyl) amino) propanol under the action of a catalyst to obtain the fasudil. The novel fasudil synthesis method provided by the invention is simple, the fasudil is prepared by the preparation process through the retaining ring, the use of high-price piperazine in the existing process is avoided, the production cost is reduced, meanwhile, the target product is obtained only through simple recrystallization operation, the complicated column chromatography operation is effectively avoided, and the operation is simple and convenient.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of fasudil.
Background
Fasudil hydrochloride (fasudil hydrochloride) with the chemical name hexahydro-1- (5-sulfonyl isoquinoline) -1(H) -1, 4-diazepine hydrochloride is a novel isoquinoline sulfonamide derivative cooperatively developed by Asahi Kasei corporation and Minggu university. As RHO kinase inhibitor and novel intracellular Ca2+The antagonist can expand blood vessels, reduce tension of endothelial cells, improve microcirculation of brain tissues, protect ischemic brain tissues, antagonize inflammatory factors, protect nerves against apoptosis and promote nerve regeneration by increasing activity of myosin light chain phosphatase. The composition is marketed by Asahi Kasei Corp 6 in 1995, is marketed in China in 2004, is mainly used for improving ischemic cerebrovascular disease symptoms caused by cerebral vasospasm after subarachnoid hemorrhage, and has a wide market prospect, and the clinical application range of the composition is continuously expanded. Therefore, it is important to research and optimize the synthesis process and establish a proper process routeMeaning. The chemical structural formula is as follows:
at present, a plurality of reports on the synthesis method of fasudil hydrochloride exist, but the synthesis method is based on the synthesis strategy in the original patent and is improved and optimized. For example, in U.S. Pat. No. 4, 4678783A, EP0187371B1, JPH11171885A, JPH11158177A, CN1183782A, CN101863880A, CN102020636A, CN102070612B, CN103030629A, CN103145695A, CN102603715A, CN103044403A, and the documents chem.Pharm.Bull.,40(3),1992,770-773, the synthesis of fasudil hydrochloride, in Zilu Yao 2012,31(8),438-439, isoquinoline or its downstream intermediate is used as the starting material, and undergoes sulfonation reaction with fuming sulfuric acid (or chlorosulfonic acid, etc.) to obtain isoquinoline-5-sulfonic acid, which reacts with excess thionyl chloride (or oxalyl chloride, cyanuric chloride, etc.) to produce isoquinoline-5-sulfonyl chloride hydrochloride, which reacts with excess homopiperazine after alkali treatment, and finally forms salt to obtain fasudil hydrochloride, the chemical reaction formula is as follows:
however, the above process has more or less of the following problems in the actual operation:
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, so that the production cost is high;
2. because isoquinoline-5-sulfonyl chloride hydrochloride is unstable, free deacidification is needed in the next reaction with homopiperazine, but the free deacidification is easy to hydrolyze into isoquinoline-5-sulfonic acid, and isoquinoline-5-sulfonic acid and salts thereof have certain solubility in water and organic solvents such as chloroform and dichloromethane, so that the removal is difficult to say by a simple method of pH adjustment and simple solvent extraction washing; and pigment impurities which generate yellow green color by isoquinoline-5-sulfonic acid are introduced into the next reaction, and in order to remove color, activated carbon, silica gel or resin are required for adsorption, so that the operation is complicated, and the refining cost is increased.
3. Isoquinoline-5-sulfonyl chloride reacts with homopiperazine, inevitably generates dimer impurities (the chemical structural formula of which is shown as the following), and excessive homopiperazine is adopted to reduce the generation of dimer and improve the yield, thereby increasing the 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 limited in large-scale production, and the chemical structural formula of the dimer impurity is as follows:
in order to solve the above problems and obtain a target product meeting the pharmaceutical standard, various refining and purification methods are disclosed, for example, chinese patent applications CN101812051A, CN101962379A, CN102002036A, CN101723934A, CN102775387A, CN103509002A, CN102924436A, CN103724326A, CN104098547A, CN104327052A, CN109970712A, CN109705096A, and CN111217794A all report how to obtain a product with higher purity, but the above methods all increase unit operations, and simultaneously, a part of the target product is directly lost during refining, so that the final refining yield is reduced, and the production cost is increased.
In addition, in order to solve the generation of the dimer impurities, the chinese patent application CN102120739A uses 4-piperidone hydrochloride hydrate as a starting material, and firstly reacts with an amino protective agent to prepare 4-piperidone with protected amino, then the 4-piperidone oxime is prepared through an oximation reaction, and then 5-carbonylhomopiperazine with protected amino is prepared through Beckmann rearrangement, and then the key intermediate monoamino protected homopiperazine is prepared through a reduction reaction of carbonyl. Finally, the 5-isoquinoline sulfonyl chloride and the homopiperazine protected by the monoamino are subjected to sulfonylation reaction, amido deprotection reaction, salification and other reactions to prepare a target product, wherein the chemical reaction formula is as follows:
however, the process has the disadvantages of longer synthesis unit, lower overall yield and complicated operation when the mono-N-protected piperazine is prepared; meanwhile, corresponding protecting groups need to be removed in different reaction systems, so that the yield difference is large.
In addition, the Chinese patent application CN101973982A uses mono-N-Boc-piperazine to react with isoquinoline-5-sulfonyl chloride hydrochloride, and then removes the protecting group to prepare the target product. However, the process uses fuming sulfuric acid with corrosive and strong irritant odor to carry out sulfonation reaction, has low operation safety, and has low selectivity when the bis-N-Boc-piperazine is hydrolyzed to prepare the mono-N-Boc piperazine, so that the generation of the N-mono-Boc piperazine is difficult to accurately control, and the chemical reaction formula is as follows:
in view of the defects of the existing preparation method of fasudil. Therefore, the research and search of a reaction route which has mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost and is suitable for industrial production of fasudil still needs to be solved at present.
Disclosure of Invention
Aiming at the problems of the existing fasudil preparation technology, the invention provides a novel preparation method of fasudil. The target product prepared by the method has higher purity and yield.
The specific technical scheme of the invention is as follows:
a preparation method of fasudil shown as a formula I specifically comprises the following steps:
and (3) adding the compound SM-1, the compound SM-2 and a catalyst into the organic solvent A at room temperature, controlling the temperature until the reaction is finished, and performing post-treatment to obtain the target product I.
Preferably, the catalyst is selected from one of trifluoromethanesulfonic anhydride, silver trifluoromethanesulfonate, trifluoromethanesulfonic acid and sulfuric acid, wherein trifluoromethanesulfonic anhydride is particularly preferred.
Preferably, the feeding molar ratio of the intermediate SM-1 and SM-2 to the catalyst is 1: 1.1-2.0: 0.1 to 0.3, wherein 1: 1.6: 0.2.
preferably, the organic solvent A is selected from one of toluene, p-xylene, N-dimethylformamide, dimethyl sulfoxide or a combination thereof.
Preferably, the reaction temperature is 90-130 ℃.
The post-treatment steps are as follows: and cooling the reaction system to room temperature, adding the reaction solution into a saturated sodium bicarbonate solution, adding an organic solvent B for extraction, washing an organic layer by purified water, drying by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dried, and recrystallizing to obtain the target product.
Preferably, in the post-treatment step, the organic solvent B is selected from one of ethyl acetate, dichloromethane, trichloromethane or a combination thereof.
Preferably, in the post-treatment step, the recrystallization solvent is selected from one of n-hexane/ethyl acetate, n-pentane/ethyl acetate, petroleum ether/ethyl acetate, n-hexane/dichloromethane system or a combination thereof.
Preferably, in the post-treatment step, the volume ratio of the poor solvent to the benign solvent in the recrystallization solvent is 5: 1-2: 1.
Preferably, in the post-treatment step, the recrystallization temperature is-10 ℃ to 25 ℃.
The invention has the beneficial effects that:
1. the invention provides a novel preparation method of fasudil, which takes SM-1 and SM-2 as starting materials to prepare a target product through cyclization reaction under the action of a catalyst, and the obtained product has higher yield and purity;
2. the preparation process prepares the homopiperazine through the retaining ring, avoids the use of the high-price homopiperazine in the prior art, and reduces the production cost.
3. The fasudil hydrochloride can be obtained by simple salification of the fasudil obtained by the process, and the generation of dimer impurities can be effectively avoided.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
The structure of the fasudil compound obtained by the invention is confirmed as follows:
ESI-HRMS(m/z)：292.1640[M+H]+；1H-NMR(400MHz,DMSO-d6)δ：9.12(s,1H),8.42(d,J＝6.8Hz,1H),8.35～8.23(m,2H),7.81(t,J＝7.2Hz,1H),7.75(d,J＝6.8Hz,1H),3.65～3.53(m,3H),3.44(t,J＝7.8Hz,1H),3.41～3.34(m,3H),3.27(t,J＝7.6Hz,1H),1.81～1.70(m,2H)；13C-NMR(100MHz,DMSO-d6)δ：157.72,157.19,150.92,134.99,134.80,133.63,132.15,127.34,123.52,117.13,80.96,47.77,47.05,46.70,43.00.
in the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1
Adding a compound SM-1(20.82g, 0.10mol), a compound SM-2(19.07g, 0.16mol) and trifluoromethanesulfonic anhydride (5.64g, 0.02mol) into p-xylene (150ml) at room temperature, controlling the temperature to be 115-120 ℃ for reaction, cooling the reaction system to room temperature after detection reaction is finished, adding the reaction solution into a saturated sodium bicarbonate solution (450ml), adding ethyl acetate (150ml multiplied by 3) for extraction, washing an organic phase with purified water (200ml multiplied by 2), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and then passing the filtrate through an n-hexane/ethyl acetate system (V/ethyl acetate system)N-hexane:VEthyl acetate3:1, 300ml) and the product obtained after recrystallization at 0 ℃ is I, the yield is 96.6% and the purity is 99.91%.
Example 2
At room temperature, compound SM-1(20.82g, 0.10mol), compoundAdding SM-2(13.11g, 0.11mol) and silver trifluoromethanesulfonate (5.14g, 0.02mol) into N, N-dimethylformamide (150ml), controlling the temperature to be 120-125 ℃ for reaction, cooling a reaction system to room temperature after detection reaction is finished, adding a reaction solution into a saturated sodium bicarbonate solution (750ml), extracting ethyl acetate (200ml multiplied by 3), washing an organic layer by purified water (150ml multiplied by 2), drying by anhydrous sodium sulfate, filtering, concentrating a filtrate under reduced pressure to dryness, and then passing the filtrate through a normal hexane/ethyl acetate system (V)N-hexane:VEthyl acetateThe product obtained after recrystallization at-10 ℃ of 3:1, 300ml is I, the yield is 92.8%, and the purity is 99.62%.
Example 3
Adding a compound SM-1(20.82g, 0.10mol), a compound SM-2(11.91g, 0.1mol) and trifluoromethanesulfonic acid (3.00g, 0.02mol) into N, N-dimethylformamide (150ml) at room temperature, controlling the temperature to be 120-125 ℃ for reaction, cooling the reaction system to room temperature after detection reaction is finished, adding the reaction solution into a saturated sodium bicarbonate solution (750ml), extracting dichloromethane (200ml multiplied by 3), washing an organic layer with purified water (150ml multiplied by 2), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and then passing the filtrate through an N-hexane/dichloromethane system (V/E, and then carrying out reactionN-hexane:VMethylene dichloride3:1, 300ml) and recrystallized at 25 ℃ to obtain the product I, the yield is 88.3% and the purity is 99.22%.
Example 4
Adding compound SM-1(20.82g, 0.10mol), compound SM-2(23.83g, 0.20mol) and sulfuric acid (omega 98%, 2.00g, 0.02mol) into toluene (150ml), controlling the temperature to be 105-110 ℃ for reaction, cooling the reaction system to room temperature after detecting the reaction is finished, adding the reaction solution into saturated sodium bicarbonate solution (450ml), extracting trichloromethane (150ml multiplied by 3), washing an organic layer with purified water (200ml multiplied by 2), drying anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and then passing through an n-hexane/dichloromethane system (V/dichloromethane system)N-hexane:VMethylene dichloride3:1, 300ml) and the product obtained after recrystallization at 0 ℃ is the product I, the yield is 93.4% and the purity is 99.65%.
Example 5
At room temperature, compound SM-1(20.82g, 0.10mol), compound SM-2(26.22g, 0.22mol), trifluoromethanesulfonic anhydride (5.64 mol) were addedg, 0.02mol) is added into dimethyl sulfoxide (150ml), the temperature is controlled to be 130-135 ℃ for reaction, after the reaction is detected to be finished, the reaction system is cooled to the room temperature, the reaction solution is added into saturated sodium bicarbonate solution (450ml), ethyl acetate (150ml multiplied by 3) is extracted, an organic layer is washed by purified water (200ml multiplied by 2), anhydrous sodium sulfate is dried, filtration is carried out, filtrate is decompressed and concentrated to be dry, and then the dry organic layer is processed by an n-hexane/ethyl acetate system (V)N-hexane:VEthyl acetate2:1, 350ml) and the product obtained after recrystallization at 0 ℃ is the product I, the yield is 88.5 percent, and the purity is 89.89 percent.
Example 6
Adding a compound SM-1(20.82g, 0.10mol), a compound SM-2(19.07g, 0.16mol) and trifluoromethanesulfonic anhydride (2.82g, 0.01mol) into dimethyl sulfoxide (150ml) at room temperature, controlling the temperature to be 115-120 ℃ for reaction, cooling the reaction system to room temperature after detection reaction is finished, adding the reaction solution into a saturated sodium bicarbonate solution (750ml), extracting ethyl acetate (200ml multiplied by 3), washing an organic layer with purified water (150ml multiplied by 2), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and then passing through an n-pentane/ethyl acetate system (V/ethyl acetate system)N-pentane:VEthyl acetateThe product obtained after recrystallization at-15 ℃ of 3:1, 300ml is I, the yield is 92.9%, and the purity is 99.71%.
Example 7
Adding a compound SM-1(20.82g, 0.10mol), a compound SM-2(19.07g, 0.16mol) and trifluoromethanesulfonic anhydride (8.46g, 0.03mol) into p-xylene (150ml) at room temperature, controlling the temperature to 125-130 ℃ for reaction, cooling the reaction system to room temperature after detection reaction is finished, adding the reaction solution into a saturated sodium bicarbonate solution (450ml), extracting ethyl acetate (150ml multiplied by 3), washing an organic layer with purified water (200ml multiplied by 2), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and then passing through a petroleum ether/ethyl acetate system (V/ethyl acetate system)Petroleum ether:VEthyl acetate4:1, 250ml) and then recrystallized at 5 ℃, the obtained product is I, the yield is 93.1% and the purity is 99.68%.
Example 8
At room temperature, adding compound SM-1(20.82g, 0.10mol), compound SM-2(19.07g, 0.16mol) and trifluoromethanesulfonic anhydride (14.11g, 0.05mol) into p-xylene (150ml), and controlling the temperature to 90-95Reacting, detecting reaction, cooling the reaction system to room temperature after the reaction is finished, adding the reaction solution into saturated sodium bicarbonate solution (450ml), extracting with ethyl acetate (150ml multiplied by 3), washing an organic layer with purified water (200ml multiplied by 2), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and passing through a normal hexane/ethyl acetate system (V/ethyl acetate system)N-hexane:VEthyl acetateNo. 5:1, 300ml) and recrystallized at 10 ℃ to obtain the product I, the yield is 87.6% and the purity is 98.95%.
Claims (10)
1. A preparation method of fasudil is characterized by comprising the following steps: adding a compound SM-1, a compound SM-2 and a catalyst into an organic solvent A, controlling the temperature until the reaction is finished, and then carrying out post-treatment to obtain a compound I, wherein the reaction route is as follows:
2. the preparation method according to claim 1, wherein the catalyst is selected from one of trifluoromethanesulfonic anhydride, silver trifluoromethanesulfonate, trifluoromethanesulfonic acid and sulfuric acid.
3. The preparation method of claim 1, wherein the molar ratio of the intermediates SM-1 and SM-2 to the catalyst is 1: 1.1-2.0: 0.1 to 0.3.
4. The preparation method according to claim 1, wherein the organic solvent A is selected from one of toluene, p-xylene, N-dimethylformamide, dimethyl sulfoxide or a combination thereof.
5. The method according to claim 1, wherein the reaction temperature is 90 to 130 ℃.
6. The method of claim 1, wherein the post-reaction treatment step is: adding the reaction solution into a saturated sodium bicarbonate solution, adding an organic solvent B for extraction, washing an organic phase by purified water, drying by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dried, and recrystallizing to obtain the compound I.
7. The preparation method according to claim 6, wherein the organic solvent B is selected from one of ethyl acetate, dichloromethane, trichloromethane or a combination thereof.
8. The preparation method according to claim 6, wherein the recrystallization solvent in the recrystallization operation is selected from one of n-hexane/ethyl acetate, n-pentane/ethyl acetate, petroleum ether/ethyl acetate, n-hexane/dichloromethane system or a combination thereof.
9. The method according to claim 8, wherein the volume ratio of the poor solvent to the benign solvent in the recrystallization solvent is 5 to 2: 1.
10. The method according to claim 6, wherein the recrystallization temperature is from-10 ℃ to 25 ℃.
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| CN102408286A (en) * | 2011-09-14 | 2012-04-11 | 浙江工业大学 | Preparation method of N,N-disubstituted sulfonamide compound |
| CN103724326A (en) * | 2013-12-13 | 2014-04-16 | 四川升和药业股份有限公司 | High-purity fasudil hydrochloride preparation method |
| CN111303120A (en) * | 2020-03-14 | 2020-06-19 | 江巨东 | Preparation method of fasudil hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102408286A (en) * | 2011-09-14 | 2012-04-11 | 浙江工业大学 | Preparation method of N,N-disubstituted sulfonamide compound |
| CN103724326A (en) * | 2013-12-13 | 2014-04-16 | 四川升和药业股份有限公司 | High-purity fasudil hydrochloride preparation method |
| CN111303120A (en) * | 2020-03-14 | 2020-06-19 | 江巨东 | Preparation method of fasudil hydrochloride |
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