CN103030629B - Method for preparing fasudil hydrochloride - Google Patents
Method for preparing fasudil hydrochloride Download PDFInfo
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- CN103030629B CN103030629B CN201110304358.XA CN201110304358A CN103030629B CN 103030629 B CN103030629 B CN 103030629B CN 201110304358 A CN201110304358 A CN 201110304358A CN 103030629 B CN103030629 B CN 103030629B
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- isoquinoline
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Abstract
The invention relates to a method for preparing fasudil hydrochloride. A fasudil hydrochloride synthetic technology is researched deeply. The method for preparing fasudil hydrochloride comprises aftertreatment steps of washing, hydrochloric acid extracting, recrystallizing and the like to obtain the fasudil hydrochloride, the single impurity content of the obtained fasudil hydrochloride finished product is lower than 0.02%, the content (high performance liquid chromatography (HPLC)) is higher than 99.95%, an aftertreatment technology is simple, a column chromatographic extraction method is not adopted, and the method has the advantages of high yield, controllable quality, simplicity in operation and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation technology of bulk drug, the preparation technology of the Fasudil Hydrochloride bulk drug that the ischemic cerebrovascular symptom being specifically related to cause for cerebral vasospasm after subarachnoid hemorrhage etc. is improved, belongs to medical art.
Background technology
Subarachnoid hemorrhage (Subarachnoid hemorrhage, SAH) is bottom brain caused by Different types of etiopathogenises or brain and the spinal cord vascular surface acute hemorrhagic cerebrovascular diseases of breaking.Blood flows directly into subarachnoid space, is called primary subarachnoid hemorrhage; Critical medical be also shown in because of in brain essence, ventricular hemorrhage, the blood such as epidural or Subdural space angiorrhexis are worn out cerebral tissue and are flowed into subarachnoid space, are referred to as secondary subarachnoid hemorrhage, also have traumatic cause hemorrhage etc.Patient with subarachnoid hemorrhage shows as headache, vomiting, the disturbance of consciousness, mental symptom and meningeal irritation sign etc. clinically.
After angiorrhexis blood flows into arachnoid of brain cavity of resorption, cranial cavity content increases, and pressure increases, and secondary cerebral vasospasm.The latter is the traction (mechanical factor) because of hemorrhage rear blood clot and the fiber rope around vessel wall, and the neuromuscular junction that vascular smooth muscle iuntercellular is formed produces extensive ischemia infringement and oedema.A large amount of hematocele or sludged blood are deposited on basis cranii in addition, the red corpuscle of partial coagulation also can block the ditch between arachnoid villi, the resorption of cerebrospinal fluid is received hindered, thus acute communicating hydrocephalus can be there is, make the hurried rising of intracranial pressure, further reduce cerebral blood flow (CBF), increased the weight of cerebral edema, even cause hernia cerebri to be formed.After subarachnoid hemorrhage, the incidence that the cerebrovascular is fullyed recover from an illness twin raises, and subarachnoid hemorrhage accounts for 10% of acute apoplexy, accounts for 20% of hemorrhagic apoplexy.
Rho is distributed widely in the histocyte of mammal, and within 1985, being identified is the homologue of mammal Ras gene, is called as little Bloch space.Rho kinases (Rho associated kinase, ROCK) be one of important kinases participating in a series of cell life phenomenons such as cell mitogen sticks, cytoskeleton adjustment, muscle cell contraction, tumor cell invasion, being distributed widely in the histocyte of mammal, is the signal polypeptide with Information Conduction and molecular switch function.Rho kinases is protein serine/threonine, and its Main Function substrate is the myosin binding subunit (myosin-binding subunit, MBS) of myosin hydrogen chain dephosphorylase (MLCPh).MLCPh is combined by the myosin hydrogen chain (myosin light chain, MLC) of MBS and phosphorylation, and makes its dephosphorylation, makes the smooth muscle relaxation being in contraction schedule.Rho kinases can phosphorylation MBS, thus causes MLCPh inactivation, and vascular smooth muscle can not stop contraction schedule.Rho kinases not only can phosphorylation MBS, also can Direct Phosphorylation MLC, makes smooth muscle contraction.Therefore, Rho kinases is by Direct Phosphorylation MLC and make MLCPh inactivation double route strengthen the phosphorylation level of MLC, promotes the contraction of SMC.The high expression level of ROCK and the excessive activation of ROCK all can cause disease, suppress Rho kinases can reverse respective pathologic process.
Fasudil (Fasudil) is current unique useful clinically Rho kinase inhibitor; also be the iloquinoline derivative Rho kinase inhibitor found the earliest; developed by Japanese Asahi Kasei Corporation (Asahi Kasei Pharma) and the joint study of Nagoya University pharmaceutical research room, there is the effect of powerful vasodilative effect and protection ischemic tissue of brain.June nineteen ninety-five, go on the market in Japan.China ratifies Japanese Asahi Kasei Corporation import fasudil hydrochloride injection (trade(brand)name: Yi Lilu), for the symptoms of cerebral ischemia improving the cerebral vasospasm after subarachnoid hemorrhage and cause thereupon in calendar year 2001.
Fasudil Hydrochloride (Fasudil Hydrochloride); chemistry six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1 (H)-1 by name; 4-diazepine hydrochloride (hexahydro-1-(5-isoquinolylsulfony)-1H-1; 4-diazepime hydrochloride), structural formula is as follows:
Fasudil Hydrochloride, as novel, an efficient vasodilation medicine, effectively can alleviate cerebral vasospasm, improves the prognosis of Subarachnoid Hemorrhage (SAH) patient, in control cardiovascular and cerebrovascular diseases, have huge potentiality.Therefore, research optimization is carried out to its synthesis technique, set up its suitable operational path significant.
At present, the synthesis of the Fasudil Hydrochloride reported take isoquinoline 99.9 as starting raw material, warp and oleum generation sulfonation reaction, obtain isoquinoline-5-sulfonic acid, react with excessive thionyl chloride and generate isoquinoline 99.9-5-sulfonyl chloride hydrochloride, through alkaline purification, isoquinoline 99.9-5-SULPHURYL CHLORIDE and excessive homopiperazine react, salify, obtains Fasudil Hydrochloride.Or employing isoquinoline-5-sulfonic acid is starting raw material, obtain Fasudil Hydrochloride through chlorination, N-sulfonylation, reduce the use of excessive oleum in production process.Reported that in production, Problems existing comprises the use of excess thionyl chloride, equipment corrosion is serious, produces a large amount of spent acid and sulfurous gas, and environmental pollution is serious, but products obtained therefrom purity is high, proterties good, productive rate is high; Adopt chlorsulfonic acid, oxalyl chloride, cyanuric chloride to do in the process of chlorination reagent, even if use chlorination reagent excessive in a large number, product yield is low, and cost is high; The use of excessive homopiperazine, adds the production cost of enterprise; The by product generated in reaction, more difficult and product separation, adopts post layer silica gel to carry out purifying, is restricted in scale operation; Some needs repeatedly recrystallizing and refining, and yield is low.
Take isoquinoline-5-sulfonic acid as starting raw material, under sulfur oxychloride effect, generate isoquinoline 99.9-5-sulfonyl chloride hydrochloride.Because isoquinoline 99.9-5-sulfonyl chloride hydrochloride is unstable, facile hydrolysis becomes isoquinoline-5-sulfonic acid, and produces yellowish green pigment impurity and introduce in next step reaction, so avoid isoquinoline 99.9-5-sulfonyl chloride hydrochloride to contact with water as far as possible.Isoquinoline 99.9-5-SULPHURYL CHLORIDE and homopiperazine react, and inevitably have the generation of dimer impurity, and homopiperazine appropriateness is excessive can reduce dimeric generation, and product yield also increases, in this step reaction, and also can chromogenesis impurity.Therefore, according to the generation of impurity and characteristic, itself and product separation need be made.
Reference: US5942505; EP0287696; US4634770; US4678783; US4709032; US4798897; Cardiac vascular activity medicine---fasudil, Chinese Journal of New Drugs and Clinical Remedies [J], 2006,25 (12): 941-945; The pharmacological action of fasudil and the progress of clinical application thereof, Mountain Western Medicine S University's journal [J], 2007,38 (4): 369-373; The hydrate of the pharmaceutical salts of fasudil, CN101092413A; 1-(5-isoquinolinesulfonylcompounds) homopiperazine hydrochloride hydrate, WO97/02260.
Summary of the invention
In order to effectively improve and control quality product, overcome the difficulty run in the industrial production, in conjunction with on the basis of patent literature, the synthesis technique of the present invention to Fasudil Hydrochloride conducts in-depth research, comprise washing, hydrochloric acid extraction, the post-processing steps such as recrystallization, obtain a kind of preparation method of Fasudil Hydrochloride, the method meets the demand of large-scale commercial production.
Concrete employing following steps are carried out:
(1) take DMF as catalyzer, after isoquinoline-5-sulfonic acid and sulfur oxychloride back flow reaction 5 ~ 8h, decompression steams unreacted sulfur oxychloride, and add methylene dichloride and stir, suction filtration, drying under reduced pressure, obtains isoquinoline 99.9-5-sulfonyl chloride hydrochloride;
The present invention is characterized in that, DMF is catalytic amount, and the mol ratio of sulfur oxychloride and isoquinoline-5-sulfonic acid is 12 ~ 24: 1.
The present invention is characterized in that; find in research process; the by product 1-chloro-5-isoquinoline sulfonyl chloride hydrochloride that reaction generates is there is in isoquinoline 99.9-5-sulfonyl chloride hydrochloride; because its character is close with isoquinoline-5-sulfonic acid; also react with homopiperazine; generate six hydrogen-1-(1-chloro-5-alkylsulfonyl isoquinoline 99.9)-1 (H)-Isosorbide-5-Nitrae-diazepine hydrochloride.
(2) with methylene dichloride and water for mixed solvent, under low temperature, add isoquinoline 99.9-5-sulfonyl chloride hydrochloride and sodium bicarbonate successively, adjust pH to 6 ~ 7, stratification, the dichloromethane solution obtaining isoquinoline 99.9-5-SULPHURYL CHLORIDE is continued to employ.
The present invention is characterized in that, the volume ratio of water and methylene dichloride is 1: 1 ~ 2, and temperature controls at 0 ~ 10 DEG C.Concrete feed way is: first add isoquinoline 99.9-5-sulfonyl chloride hydrochloride, then adds the sodium bicarbonate with isoquinoline 99.9-5-sulfonyl chloride hydrochloride equimolar amount, can add appropriate sodium bicarbonate, adjusts pH to 7.Because isoquinoline 99.9-5-sulfonyl chloride hydrochloride is unstable, facile hydrolysis becomes isoquinoline-5-sulfonic acid, and produces yellowish green pigment impurity and introduce in next step reaction, therefore the reaction times controls at 20 ~ 30min.
(3) be solvent with methylene dichloride, under low temperature, isoquinoline 99.9-5-SULPHURYL CHLORIDE and homopiperazine react, and through alkali neutralization, washing, acid extraction, adds the organic solvent dissolved each other with water, cooling crystallization, filters, obtains Fasudil Hydrochloride crude product.
The present invention is characterized in that, in step (3), the mol ratio of homopiperazine and isoquinoline 99.9-5-SULPHURYL CHLORIDE is 2.5 ~ 4.5: 1, and temperature controls at-10 ~ 10 DEG C, reaction 3 ~ 5h.
The present invention is characterized in that, HPLC detection reaction terminal, after completion of the reaction, and alkali neutralization reaction, adjust pH to 7 ~ 8, wash three times, described alkali is 5 ~ 20% sodium hydroxide solutions, the sodium hydrogen carbonate solution of 10 ~ 30%, the sodium carbonate solution of 10 ~ 30%, the solution of potassium carbonate of 10 ~ 30%.Preferably 5 ~ 10% sodium hydroxide, the sodium bicarbonate of 10 ~ 20%.
The present invention is characterized in that, after washing, hydrochloric acid extraction, discards organic layer.Acid extraction liquid, with after organic solvent washing twice, adds 1 ~ 1.5 times of methylene dichloride, adds the organic solvent dissolved each other with water, cooling crystallization in water layer, filters to obtain Fasudil Hydrochloride crude product.
The present invention is characterized in that, described hydrochloric acid is the hydrochloric acid of 1 ~ 6mol/L.
The present invention is characterized in that, by the method for regulator solution pH, has carried out two-way rejecting, has comprised pigment impurity, homopiperazine and dimer impurity to aqueous phase and organic phase impurity.
The present invention is characterized in that; in the Fasudil Hydrochloride crude product obtained in this way; content (HPLC) is greater than 99%; without dimer impurity peak; the analysis of single contaminant peak is six hydrogen-1-(1-chloro-5-alkylsulfonyl isoquinoline 99.9)-1 (H)-Isosorbide-5-Nitrae-diazepine hydrochloride.
(4) with methyl alcohol and ethyl acetate for mixed solvent, Fasudil Hydrochloride crude product obtains through recrystallization the Fasudil Hydrochloride that content (HPLC) is greater than more than 99.95%;
The present invention is characterized in that, recrystallizing and refining can remove impurity six hydrogen-1-(1-chloro-5-alkylsulfonyl isoquinoline 99.9)-1 (H)-Isosorbide-5-Nitrae-diazepine hydrochloride.
The present invention is characterized in that, the organic solvent dissolved each other with water refers to the alcohols of C1 ~ 3, acetone, acetonitrile, ether, isopropyl ether, the mixture of tetrahydrofuran (THF) or described solvent, particular methanol, ethanol.Methyl alcohol or (with) volume ratio of ethanol and ethyl acetate is 1: 1 ~ 4, preferred volume ratio is 1: 3.
(5) the present invention is characterized in that, calculate with isoquinoline-5-sulfonic acid, total recovery is 70 ~ 80%.
The invention has the beneficial effects as follows:
The Fasudil Hydrochloride finished product list foreign matter content obtained by this preparation method is lower than 2/10000ths, and content (HPLC) reaches more than 99.95%, and aftertreatment technology is simple, avoid the method adopting column chromatography to purify, yield is high, quality controllable, simple to operate, be suitable for suitability for industrialized production.
Accompanying drawing explanation
Accompanying drawing 1 is the HPLC figure of the Fasudil Hydrochloride crude product that embodiment 1 obtains
Accompanying drawing 2 is the HPLC figure after the Fasudil Hydrochloride crude product refining that obtains of embodiment 1
Accompanying drawing 3 is the HPLC figure of the Fasudil Hydrochloride crude product that embodiment 2 obtains
Accompanying drawing 4 is the HPLC figure after the Fasudil Hydrochloride crude product refining that obtains of embodiment 2
Embodiment:
Embodiment by the following examples, is described in further detail foregoing of the present invention.But this is not interpreted as that foregoing of the present invention is only limitted to following examples.
The preparation of embodiment 1 Fasudil Hydrochloride
(1) in 1000mL there-necked flask, add isoquinoline-5-sulfonic acid (60g, 0.287mol), add sulfur oxychloride (500ml, 6.893mol), drip the DMF of 4mL simultaneously, mechanical stirring, and heat temperature raising back flow reaction 6h.Produce hydrogenchloride and sulfur dioxide gas with 40% sodium hydroxide solution absorption.Slightly lower the temperature, underpressure distillation removes excessive sulfur oxychloride.Temperature is down to room temperature, adds 160mL methylene dichloride and stirs 30min, be chilled to less than 20 DEG C, suction filtration in reaction flask, and filter cake washed with dichloromethane three times, drying under reduced pressure, obtains 61.9g white solid powder isoquinoline 99.9-5-sulfonyl chloride hydrochloride.
(2) in 2000mL there-necked flask, water and each 454mL of methylene dichloride is added, be cooled to about 0 DEG C, isoquinoline 99.9-5-sulfonyl chloride hydrochloride (61.9g is added under stirring, 0.234mol) with sodium bicarbonate (19.4g, 0.234mol), temperature is no more than 10 DEG C, adjust pH to 7.Stir 25min, separate organic layer.Water layer dichloromethane extraction twice, merges organic layer, more than anhydrous magnesium sulfate drying 2h, suction filtration, for subsequent use.
(3) in 2000mL there-necked flask, add methylene dichloride 454mL and homopiperazine (93.7g, 0.234mol), be cooled to about 0 DEG C, start under mechanical stirring slowly to drip above-mentioned dry methylene chloride solution, control temperature is no more than 10 DEG C.After dropwising, holding temperature, at-10 ~ 10 DEG C, reacts 3.5h.The sodium bicarbonate of 10% adjusts pH to 8, washes three times for less than 10 DEG C.Organic layer 6mol/L hydrochloric acid extraction, discards organic layer.Acid layer ethyl acetate washes twice.Add ethanol, cooling crystallization, filter to obtain Fasudil Hydrochloride crude product.
(4) joined in 1000mL beaker by crude product, add 100mL methyl alcohol, suitably heating makes it entirely molten.Add 300mL ethyl acetate, cooling crystallization, suction filtration, drying under reduced pressure 6h, obtains white crystalline powder 70.8g, is Fasudil Hydrochloride, yield: 75%.
The preparation of embodiment 2 Fasudil Hydrochloride
(1) add 0.6kg isoquinoline-5-sulfonic acid and 5L sulfur oxychloride in 20L reactor, mechanical stirring, then add 40mLDMF, back flow reaction 4.5 ~ 6h.React complete, reaction solution is cooled to about 50 ~ 55 DEG C, after decompression steams sulfur oxychloride, is cooled to 20 ~ 30 DEG C, adds the CH of 1.6L
2cl
2, stir, suction filtration, filter cake washed with dichloromethane, obtains the isoquinoline 99.9-5-sulfonyl chloride hydrochloride of 0.705kg after drying under reduced pressure.
(2) add 4.5L water and 4.5L methylene dichloride in 20L reactor, mechanical stirring, add isoquinoline 99.9-5-sulfonyl chloride hydrochloride and the 0.2kg NaHCO of 0.705kg
3, temperature controls to be no more than 10 DEG C, adjust pH to 7.After stirring reaction 30min, stratification, organic layer is released, and adds the methylene dichloride of 0.5L in water layer, stirs 10min, stratification, and organic layer merges organic layer, anhydrous MgSO after releasing
4dry 2 ~ 3h, filters, for the next step.
(3) homopiperazine of 5L methylene dichloride and 0.94kg is added in 20L reactor, be cooled to about-5 DEG C, start the dichloromethane solution dripping above-mentioned drying, temperature is no more than 5 DEG C, dropwise in 2 ~ 3h, control temperature, between-10 ~ 10 DEG C, after stirring reaction 2.5 ~ 3.5h, adds 10%NaHCO
3solution adjusts pH to 8, and stir 22min, stratification, organic layer washes 3 times, under stirring, 6mol/L hydrochloric acid extraction in organic layer, stratification.Add 2L ethanol in acid layer, be cooled to crystallization, suction filtration obtains Fasudil Hydrochloride crude product.
(4) add above-mentioned Fasudil Hydrochloride crude product in 20L reactor, first add the methyl alcohol of 1.6L, be warming up to backflow, if there is insolubles, the methyl alcohol of 20% can be added, after stirring 10 ~ 20min, heat filtering, is cooled to room temperature, under stirring, add 3L ethyl acetate, cooling crystallization, suction filtration, drying under reduced pressure, weigh to obtain 0.738kg Fasudil Hydrochloride, yield is 78%.
Claims (3)
1. a preparation method for Fasudil Hydrochloride, is characterized in that, carries out according to the following steps:
(1) take DMF as catalyzer, after isoquinoline-5-sulfonic acid and sulfur oxychloride back flow reaction 5 ~ 6h, decompression steams unreacted sulfur oxychloride, and add methylene dichloride and stir, suction filtration, drying under reduced pressure, obtains isoquinoline 99.9-5-sulfonyl chloride hydrochloride;
(2) with methylene dichloride and water for mixed solvent, temperature controls, at 0 ~ 10 DEG C, to add isoquinoline 99.9-5-sulfonyl chloride hydrochloride and sodium bicarbonate successively, and adjust pH to 6 ~ 7, stratification, the dichloromethane solution obtaining isoquinoline 99.9-5-SULPHURYL CHLORIDE is continued to employ;
(3) be solvent with methylene dichloride, under low temperature, isoquinoline 99.9-5-SULPHURYL CHLORIDE and homopiperazine react, and through HPLC detection reaction terminal, after completion of the reaction, alkali neutralization reaction, adjusts pH to 7 ~ 8, wash three times, and recovery is dissolved with the aqueous phase of a large amount of homopiperazine; After washing, hydrochloric acid extraction, discards the organic layer being dissolved with dimer impurity and pigment impurity; After acid extraction liquid ethyl acetate washes twice, add the organic solvent dissolved each other with water, cooling crystallization, filter to obtain Fasudil Hydrochloride crude product;
(4) with methyl alcohol and ethyl acetate for mixed solvent, Fasudil Hydrochloride crude product obtains through recrystallization the Fasudil Hydrochloride that content (HPLC) is greater than more than 99.95%.
2. the preparation method of a kind of Fasudil Hydrochloride according to claim 1, is characterized in that, the organic solvent dissolved each other with water in step (3) refers to ethanol.
3. the preparation method of a kind of Fasudil Hydrochloride according to claim 1, is characterized in that, in step (4), the volume ratio of methyl alcohol and ethyl acetate is 1:3.
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| CN103864760B (en) * | 2014-03-10 | 2016-08-17 | 洪军 | A kind of fasudil hydrochloride compound |
| CN104098547B (en) * | 2014-07-28 | 2016-08-24 | 天津红日药业股份有限公司 | A kind of process for purification of Fasudic hydrochloride |
| CN104945381B (en) * | 2015-06-24 | 2019-05-03 | 山东罗欣药业集团股份有限公司 | A kind of fasudil hydrochloride compound, preparation method and its pharmaceutical composition |
| CN105866263B (en) * | 2016-03-24 | 2018-06-29 | 四川升和药业股份有限公司 | A kind of method of quality control of Fasudic hydrochloride |
| CN109970712A (en) * | 2017-12-27 | 2019-07-05 | 徐州万邦金桥制药有限公司 | A kind of refining methd of Fasudic hydrochloride |
| CN109705096B (en) * | 2019-03-07 | 2023-06-09 | 山东新华制药股份有限公司 | Refining method of fasudil hydrochloride |
| CN111909088B (en) * | 2020-08-04 | 2022-03-01 | 浙江工业大学 | Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by using BTC/Ph3PO chloro-system |
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| CN102020638A (en) * | 2009-09-16 | 2011-04-20 | 深圳微芯生物科技有限责任公司 | 2-indolinone derivative with protein kinase inhibition activity and histone deacetylase inhibition activity and preparation method and application thereof |
| CN102070612A (en) * | 2010-12-29 | 2011-05-25 | 武汉同源药业有限公司 | Method for preparing hydroxyl fasudil compounds |
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| CN102020638A (en) * | 2009-09-16 | 2011-04-20 | 深圳微芯生物科技有限责任公司 | 2-indolinone derivative with protein kinase inhibition activity and histone deacetylase inhibition activity and preparation method and application thereof |
| CN102070612A (en) * | 2010-12-29 | 2011-05-25 | 武汉同源药业有限公司 | Method for preparing hydroxyl fasudil compounds |
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