CN103030629A - Method for preparing fasudil hydrochloride - Google Patents
Method for preparing fasudil hydrochloride Download PDFInfo
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- CN103030629A CN103030629A CN201110304358XA CN201110304358A CN103030629A CN 103030629 A CN103030629 A CN 103030629A CN 201110304358X A CN201110304358X A CN 201110304358XA CN 201110304358 A CN201110304358 A CN 201110304358A CN 103030629 A CN103030629 A CN 103030629A
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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, be specifically related to the preparation technology of the Fasudil Hydrochloride bulk drug of the ischemic cerebrovascular doing well,improving that causes for cerebral vasospasm after subarachnoid hemorrhage etc., belong to medical technical field.
Background technology
Subarachnoid hemorrhage (Subarachnoid hemorrhage, SAH) is the acute hemorrhagic cerebrovascular diseases that brain bottom or brain and spinal cord vascular surface break due to the Different types of etiopathogenises.Blood flows directly into subarachnoid space, is called primary subarachnoid hemorrhage; Critical clinical be also shown in because of in the brain essence, ventricular hemorrhage, the blood such as angiorrhexis is worn out cerebral tissue and is flowed into subarachnoid space under epidural or the dura mater, is referred to as secondary subarachnoid hemorrhage, also has 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 flowed into arachnoid of brain cavity of resorption, the cranial cavity content increased, increased pressure, and secondary cerebral vasospasm.Latter system is because of hemorrhage rear blood clot with around the traction (mechanical factor) of the fiber rope of vessel wall, and the neuromuscular junction that the vascular smooth muscle iuntercellular forms produces extensive ischemia infringement and oedema.A large amount of hematoceles or sludged blood are deposited on basis cranii in addition, the red corpuscle of partial coagulation also can stop up the ditch between arachnoid villi, the resorption receipts of cerebrospinal fluid are hindered, thereby acute communicating hydrocephalus can occur, make the hurried rising of intracranial pressure, further reduce cerebral blood flow (CBF), increased the weight of cerebral edema, even caused hernia cerebri to form.After the 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 1985 are identified is the homologue of mammal Ras gene, is called as little gtp binding protein.Rho kinases (Rho associated kinase, ROCK) be one of important kinases of participating in a series of cell biological phenomenas 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.The 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 by myosin hydrogen chain (myosin light chain, the MLC) combination of MBS and phosphorylation, and makes its dephosphorylation, makes the smooth muscle relaxation that is in contraction schedule.But Rho kinases phosphorylation MBS, thus the MLCPh inactivation caused, and vascular smooth muscle can not stop contraction schedule.The Rho kinases not only can phosphorylation MBS, but also Direct Phosphorylation MLC makes smooth muscle contraction.Therefore, the Rho kinases can and make MLCPh inactivation double route strengthen the phosphorylation level of MLC by Direct Phosphorylation MLC, promotes the contraction of SMC.The high expression level of ROCK and the excessive activation of ROCK all can cause disease, and inhibition Rho kinases can reverse pathologic process separately.
Fasudil (Fasudil) is present unique useful clinically Rho kinase inhibitor; it also is the iloquinoline derivative Rho kinase inhibitor of finding the earliest; by Japanese Asahi Kasei Corporation (Asahi Kasei Pharma) and Nagoya University pharmaceutical research chamber joint study exploitation, the effect with 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), be used for improving the cerebral vasospasm after the subarachnoid hemorrhage and the symptoms of cerebral ischemia that thereupon causes in calendar year 2001.
Fasudil Hydrochloride (Fasudil Hydrochloride); chemistry six hydrogen by name-1-(5-alkylsulfonyl isoquinoline 99.9)-1 (H)-1; 4-diazepine hydrochloride (hexahydro-1-(5-isoquinolylsulfony)-1H-1; 4-diazepime hydrochloride), structural formula is as follows:
Fasudil Hydrochloride can effectively be alleviated cerebral vasospasm as novel, an efficient vasodilation medicine, improves Subarachnoid Hemorrhage (SAH) patient's prognosis, has huge potentiality aspect the control cardiovascular and cerebrovascular diseases.Therefore, its synthesis technique is studied optimization, it is significant to set up its suitable operational path.
At present, synthesizing take isoquinoline 99.9 as starting raw material of the Fasudil Hydrochloride of having reported, warp and oleum generation sulfonation reaction, get isoquinoline-5-sulfonic acid, generate isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride with the reaction of excessive thionyl chloride again, through alkaline purification, isoquinoline 99.9-5-SULPHURYL CHLORIDE is reacted with excessive homopiperazine, salify obtains Fasudil Hydrochloride.Perhaps adopting isoquinoline-5-sulfonic acid is starting raw material, obtains Fasudil Hydrochloride through chlorination, N-sulfonylation, reduces the use of excessive oleum in the production process.Reported that the problem that exists in the production comprises the use of excess chlorination sulfoxide, 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 is good, productive rate is high; Adopt chlorsulfonic acid, oxalyl chloride, cyanuric chloride to do in the process of chlorination reagent, even use a large amount of excessive chlorination reagents, product yield is low, and cost is high; The use of excessive homopiperazine has increased the production cost of enterprise; The by product that generates in the reaction, difficulty and product separation adopt post layer silica gel to carry out purifying, are restricted in scale operation; Some needs repeatedly recrystallizing and refining, and yield is low etc.
Take isoquinoline-5-sulfonic acid as starting raw material, under the sulfur oxychloride effect, generate isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride.Because isoquinoline 99.9-5-SULPHURYL 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-SULPHURYL CHLORIDE hydrochloride to contact with water as far as possible.Isoquinoline 99.9-5-SULPHURYL CHLORIDE and homopiperazine reaction inevitably have the generation of dimer impurity, and the homopiperazine appropriateness is excessive can to reduce dimeric generation, and product yield also increases, in this step reaction, and also can chromogenesis impurity.Therefore, need generation and characteristic according to impurity, make itself and product separation.
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
For Effective Raise and control quality product, overcome the difficulty that in industrial production, runs into, on the basis in conjunction with patent literature, the present invention conducts in-depth research the synthesis technique of Fasudil Hydrochloride, comprise washing, hydrochloric acid extraction, the post-processing steps such as recrystallization, obtain a kind of preparation method of Fasudil Hydrochloride, the method satisfies the demand of large-scale commercial production.
The concrete following steps that adopt are carried out:
(1) take DMF as catalyzer, behind isoquinoline-5-sulfonic acid and the sulfur oxychloride back flow reaction 5～8h, decompression steams unreacted sulfur oxychloride, and add methylene dichloride and stir, suction filtration, drying under reduced pressure gets isoquinoline 99.9-5-SULPHURYL 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; in research process, find; the by product 1-chloro-5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride that exists reaction to generate in isoquinoline 99.9-5-SULPHURYL 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) take methylene dichloride and water as mixed solvent, under the low temperature, add successively isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride and sodium bicarbonate, transfer pH to 6～7, standing demix, the dichloromethane solution that gets 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 is controlled at 0～10 ℃.Concrete feed way is: add first isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride, the sodium bicarbonate of adding and isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride equimolar amount can be added an amount of sodium bicarbonate again, transfers pH to 7.Because isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride is unstable, facile hydrolysis becomes isoquinoline-5-sulfonic acid, and produces yellowish green pigment impurity and introduce in next step reaction, so the reaction times is controlled at 20～30min.
(3) take methylene dichloride as solvent, under the low temperature, isoquinoline 99.9-5-SULPHURYL CHLORIDE and homopiperazine reaction, through the alkali neutralization, washing, acid extraction adds the organic solvent that dissolves each other with water, and cooling crystallization filters, and gets the Fasudil Hydrochloride crude product.
The present invention is characterized in that in the step (3), the mol ratio of homopiperazine and isoquinoline 99.9-5-SULPHURYL CHLORIDE is 2.5～4.5: 1, and temperature is controlled at-10～10 ℃, reaction 3～5h.
The present invention is characterized in that, HPLC detection reaction terminal point, react complete after, the alkali neutralization reaction, transfer pH to 7～8, wash three times, described alkali is 5～20% sodium hydroxide solutions, 10～30% sodium hydrogen carbonate solution, 10～30% sodium carbonate solution, 10～30% solution of potassium carbonate.Preferred 5～10% sodium hydroxide, 10～20% sodium bicarbonate.
The present invention is characterized in that after the washing, hydrochloric acid extraction discards organic layer.Acid extraction liquid adds 1～1.5 times of methylene dichloride with after twice of the organic solvent washing, adds the organic solvent that dissolves each other with water in the water layer, and cooling crystallization filters to get the 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, water and organic phase impurity has been carried out two-way rejecting, comprises pigment impurity, homopiperazine and dimer impurity.
The present invention is characterized in that; in the Fasudil Hydrochloride crude product that obtains in this way, content (HPLC) is greater than 99%, without the 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) take methyl alcohol and ethyl acetate as mixed solvent, the Fasudil Hydrochloride crude product gets content (HPLC) greater than the Fasudil Hydrochloride more than 99.95% through recrystallization;
The present invention is characterized in that recrystallizing and refining can be removed 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 that dissolves 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, calculates with isoquinoline-5-sulfonic acid, and total recovery is 70～80%.
The invention has the beneficial effects as follows:
The Fasudil Hydrochloride finished product list foreign matter content that obtains by this preparation method is lower than 2/10000ths, and content (HPLC) reaches more than 99.95%, and aftertreatment technology is simple, avoid adopting the method for column chromatography purification, yield is high, and is quality controllable, simple to operate, be suitable for suitability for industrialized production.
Description of drawings
The HPLC figure of the Fasudil Hydrochloride crude product that accompanying drawing 1 obtains for embodiment 1
HPLC figure behind the Fasudil Hydrochloride crude product refining that accompanying drawing 2 obtains for embodiment 1
The HPLC figure of the Fasudil Hydrochloride crude product that accompanying drawing 3 obtains for embodiment 2
HPLC figure behind the Fasudil Hydrochloride crude product refining that accompanying drawing 4 obtains for 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 only limits to following examples.
The preparation of embodiment 1 Fasudil Hydrochloride
(1) in the 1000mL there-necked flask, adds isoquinoline-5-sulfonic acid (60g, 0.287mol), add sulfur oxychloride (500ml, 6.893mol), drip simultaneously the DMF of 4mL, mechanical stirring, and heat temperature raising back flow reaction 6h.The sodium hydroxide solution that produces hydrogenchloride and sulfur dioxide gas body and function 40% absorbs.Slightly cooling, excessive sulfur oxychloride is removed in underpressure distillation.Temperature is down to room temperature, adds 160mL methylene dichloride stirring 30min in reaction flask, be chilled to below 20 ℃, and suction filtration, filter cake washed with dichloromethane three times, drying under reduced pressure gets 61.9g white solid powder isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride.
(2) in the 2000mL there-necked flask, add entry and each 454mL of methylene dichloride, be cooled to about 0 ℃, stir lower isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride (61.9g that adds, 0.234mol) and sodium bicarbonate (19.4g, 0.234mol), temperature is no more than 10 ℃, adjust pH to 7.Stir 25min, tell organic layer.Water layer merges organic layer with dichloromethane extraction twice, more than the anhydrous magnesium sulfate drying 2h, and suction filtration, for subsequent use.
(3) add methylene dichloride 454mL and homopiperazine (93.7g, 0.234mol) in the 2000mL there-necked flask, be cooled to about 0 ℃, beginning slowly drips above-mentioned dry methylene chloride solution under the mechanical stirring, and the control temperature is no more than 10 ℃.After dropwising, holding temperature is reacted 3.5h at-10～10 ℃.10% sodium bicarbonate is transferred pH to 8, washing below 10 ℃ three times.Organic layer 6mol/L hydrochloric acid extraction discards organic layer.The acid layer is washed twice with ethyl acetate.Add ethanol, cooling crystallization filters to get the Fasudil Hydrochloride crude product.
(4) crude product is joined in the 1000mL beaker, add 100mL methyl alcohol, suitably heating makes it entirely molten.Add the 300mL ethyl acetate, cooling crystallization, suction filtration, drying under reduced pressure 6h gets 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 the 20L reactor, mechanical stirring adds 40mLDMF again, back flow reaction 4.5～6h.React complete, reaction solution is cooled to about 50～55 ℃, after decompression steams sulfur oxychloride, is cooled to 20～30 ℃, adds the CH of 1.6L
2Cl
2, stir,, suction filtration, the filter cake washed with dichloromethane obtains the isoquinoline 99.9 of 0.705kg-5-SULPHURYL CHLORIDE hydrochloride behind the drying under reduced pressure.
(2) add 4.5L water and 4.5L methylene dichloride in the 20L reactor, mechanical stirring, the isoquinoline 99.9 of adding 0.705kg-5-SULPHURYL CHLORIDE hydrochloride and 0.2kg NaHCO
3, temperature control is no more than 10 ℃, adjust pH to 7.Behind the stirring reaction 30min, standing demix, organic layer is emitted, and adds the methylene dichloride of 0.5L in the water layer, stirs 10min, and standing demix, organic layer are emitted rear merging organic layer, anhydrous MgSO
4 Dry 2～3h filters, and is used for the next step.
(3) homopiperazine of adding 5L methylene dichloride and 0.94kg in the 20L reactor, be cooled to about-5 ℃, begin to drip the dichloromethane solution of above-mentioned drying, temperature is no more than 5 ℃, dropwise in 2～3h, the control temperature behind stirring reaction 2.5～3.5h, adds 10%NaHCO between-10～10 ℃
3Solution is transferred pH to 8, stirs 22min, standing demix, and organic layer washing 3 times, under stirring, 6mol/L hydrochloric acid extraction in the organic layer, standing demix.Add 2L ethanol in the acid layer, be cooled to crystallization, suction filtration gets the Fasudil Hydrochloride crude product.
(4) add above-mentioned Fasudil Hydrochloride crude product in the 20L reactor, add first the methyl alcohol of 1.6L, be warming up to backflow, if insolubles is arranged, can add 20% methyl alcohol, behind stirring 10～20min, heat filtering is cooled to room temperature, stirs lower, add the 3L ethyl acetate, cooling crystallization, suction filtration, drying under reduced pressure, the 0.738kg Fasudil Hydrochloride of weighing to get, yield is 78%.
Claims (10)
1. the preparation method of a Fasudil Hydrochloride is characterized in that, carries out according to the following steps:
(1) take DMF as catalyzer, behind isoquinoline-5-sulfonic acid and the sulfur oxychloride back flow reaction 4～8h, decompression steams unreacted sulfur oxychloride, and add methylene dichloride and stir, suction filtration, drying under reduced pressure gets isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride;
(2) take methylene dichloride and water as mixed solvent, under the low temperature, add successively isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride and sodium bicarbonate, transfer pH to 6～7, standing demix, the dichloromethane solution that gets isoquinoline 99.9-5-SULPHURYL CHLORIDE is continued to employ;
(3) take methylene dichloride as solvent, under the low temperature, isoquinoline 99.9-5-SULPHURYL CHLORIDE and homopiperazine reaction, through the alkali neutralization, washing, acid extraction adds the organic solvent that dissolves each other with water, and cooling crystallization filters, and gets the Fasudil Hydrochloride crude product;
(4) take methyl alcohol and ethyl acetate as mixed solvent, the Fasudil Hydrochloride crude product gets content (HPLC) greater than the Fasudil Hydrochloride more than 99.95% through recrystallization.
2. the preparation method of a kind of Fasudil Hydrochloride according to claim 1 is characterized in that, in the step (1), N, dinethylformamide is catalytic amount, and the time of back flow reaction is 5～6h, and the mol ratio of sulfur oxychloride and isoquinoline-5-sulfonic acid is 12～24: 1.
3. the preparation method of a kind of Fasudil Hydrochloride according to claim 1 is characterized in that, in the step (2), the volume ratio of water and methylene dichloride is 1: 1～2, and temperature is controlled at 0～10 ℃; Concrete feed way is: add first isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride, the sodium bicarbonate of adding and isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride equimolar amount can be added an amount of sodium bicarbonate again, transfers pH to 7.
4. the preparation method of a kind of Fasudil Hydrochloride according to claim 1 is characterized in that, in the step (3), the mol ratio of homopiperazine and isoquinoline 99.9-5-SULPHURYL CHLORIDE is 2.5～4.5: 1, and temperature is controlled at-10～10 ℃, reaction 3～5h.
5. the preparation method of a kind of Fasudil Hydrochloride according to claim 1 is characterized in that, in the step (3), HPLC detection reaction terminal point, react complete after, the alkali neutralization reaction is transferred pH to 7～8, wash three times, recovery is dissolved with the water of a large amount of homopiperazines.
6. alkali according to claim 5 is 5～10% sodium hydroxide, 10～20% sodium bicarbonate.
7. the preparation method of a kind of Fasudil Hydrochloride according to claim 1 is characterized in that, in the step (3), after the washing, hydrochloric acid extraction discards the organic layer that is dissolved with dimer impurity and pigment impurity; Acid extraction liquid adds the organic solvent that dissolves each other with water with after the ethyl acetate washed twice, and cooling crystallization filters to get the Fasudil Hydrochloride crude product.
8. hydrochloric acid according to claim 7 is the hydrochloric acid of 1～6mol/L, and the organic solvent that wherein dissolves each other with water refers to the alcohols of C1～3, acetone, acetonitrile, ether, isopropyl ether, the mixture of tetrahydrofuran (THF) or described solvent.
9. the organic solvent that wherein dissolves each other with water according to claim 8 refers to methyl alcohol, ethanol.
10. the preparation method of a kind of Fasudil Hydrochloride according to claim 1 is characterized in that, in the step (4), the volume ratio of methyl alcohol and ethyl acetate is 1: 1～4.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864760A (en) * | 2014-03-10 | 2014-06-18 | 洪军 | Hydroxyfasudil compound |
| CN104098547A (en) * | 2014-07-28 | 2014-10-15 | 天津红日药业股份有限公司 | Refining method for hydroxyfasudil |
| CN104945381A (en) * | 2015-06-24 | 2015-09-30 | 山东罗欣药业集团股份有限公司 | Fasudil hydrochloride compound and preparation method and medicine composition thereof |
| CN105866263A (en) * | 2016-03-24 | 2016-08-17 | 四川升和药业股份有限公司 | Quality control method for fasudil hydrochloride |
| CN109705096A (en) * | 2019-03-07 | 2019-05-03 | 山东新华制药股份有限公司 | A kind of refining methd 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 |
| CN111909088A (en) * | 2020-08-04 | 2020-11-10 | 浙江工业大学 | Utilizing BTC/Ph3Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by PO chloro system |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2011
- 2011-10-10 CN CN201110304358.XA patent/CN103030629B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864760A (en) * | 2014-03-10 | 2014-06-18 | 洪军 | Hydroxyfasudil compound |
| CN103864760B (en) * | 2014-03-10 | 2016-08-17 | 洪军 | A kind of fasudil hydrochloride compound |
| CN104098547A (en) * | 2014-07-28 | 2014-10-15 | 天津红日药业股份有限公司 | Refining method for hydroxyfasudil |
| CN104945381A (en) * | 2015-06-24 | 2015-09-30 | 山东罗欣药业集团股份有限公司 | Fasudil hydrochloride compound and preparation method and medicine composition thereof |
| CN105866263A (en) * | 2016-03-24 | 2016-08-17 | 四川升和药业股份有限公司 | Quality control method for fasudil 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 |
| CN109705096A (en) * | 2019-03-07 | 2019-05-03 | 山东新华制药股份有限公司 | 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 |
| CN111909088A (en) * | 2020-08-04 | 2020-11-10 | 浙江工业大学 | Utilizing BTC/Ph3Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by PO chloro system |
| 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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