CN102070612A - Method for preparing hydroxyl fasudil compounds - Google Patents

Method for preparing hydroxyl fasudil compounds Download PDF

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Publication number
CN102070612A
CN102070612A CN2010106105494A CN201010610549A CN102070612A CN 102070612 A CN102070612 A CN 102070612A CN 2010106105494 A CN2010106105494 A CN 2010106105494A CN 201010610549 A CN201010610549 A CN 201010610549A CN 102070612 A CN102070612 A CN 102070612A
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fasudil
isoquinoline
water
methylene dichloride
dichloromethane
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CN102070612B (en
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黄毅
彭国强
张颀
黄伟
熊骏宇
徐敏华
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Zhuhai morning Ann Pharmaceutical Co., Ltd.
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TONGYUAN PHARMACEUTICAL IND CO Ltd WUHAN
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Abstract

The invention relates to a method for preparing hemangiectasis medicine, in particular to the method for preparing hydroxyl fasudil compounds, which belongs to the field of medicine synthesis. In the preparation process, the method of using column chromatography for elution and purification in a hydroxyl fasudil impurity removal method is omitted for realizing large-scale mass production.

Description

A kind of preparation method of compound Fasudil Hydrochloride
Technical field
The invention belongs to the synthetic field of medicine, relate to a kind of preparation method of vasodilation medicine, be specifically related to a kind of preparation method of compound Fasudil Hydrochloride.
Background technology
Fasudil Hydrochloride is the vasodilator of Japanese rising sun company exploitation, rising sun company of former research producer discloses synthetic route in its patent US4678783, be reacted into acyl chlorides by isoquinoline 99.9 sulfonic acid warp with sulfur oxychloride, obtain the product Fasudil Hydrochloride with high piperazine reaction again, reaction can be expressed as follows:
In the building-up reactions, the quality of control intermediate is crucial, particularly the final step intermediate.
Obtain closing the Fasudil Hydrochloride of symbol standards of pharmacopoeia, must guarantee its final step intermediate fasudil high purity, because if fasudil is impure many, enters salt-forming reaction and generate Fasudil Hydrochloride, its impurity is difficult to remove.
Disclose synthetic fasudil method among the US4678783: 5-isoquinoline 99.9 chloride solution and high piperazine react in dichloromethane solvent and obtain the fasudil reaction solution, after washing reaction solution with water then, use anhydrous magnesium sulfate drying, the evaporated under reduced pressure reaction solution, obtain the oily residue, the oily residue is purified with silica gel column chromatography (200 orders, chloroform wash-out), obtain fasudil then.
Chinese patent CN101092413A discloses synthetic fasudil method:
5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride is added in the frozen water, and stirring and regulating the pH value with saturated sodium bicarbonate solution down is 5～6, uses twice of 500ml chloroform extraction, combining extraction liquid, anhydrous sodium sulfate drying filters, it is standby that filtrate is concentrated into 200ml, is 5-isoquinoline 99.9 chloride solution.
Take by weighing high piperazine 125g(1.25mol) join in the four-hole bottle, add the 250ml chloroform, stir and make dissolving.Under the condition of ice bath, to go up made 5-isoquinoline 99.9 chloride solution of step (about 0.48mol) slowly is added drop-wise in the four-hole bottle, 0～5 ℃ of temperature control, finish and continued insulation reaction 4 hours, after reaction finishes, add 200ml2N hydrochloric acid, stirred ten minutes, divide water-yielding stratum, water layer is transferred pH to 10 with 10% sodium hydroxide solution, uses dichloromethane extraction then, the extraction liquid concentrating under reduced pressure, residue post layer silica gel (200～300 order) purifying, methyl alcohol and chloroform (v:5v) wash-out is collected required component, is concentrated into dried, get faint yellow oily thing 95g, total recovery: 69.7%.
Above-mentioned two kinds of synthetic fasudil methods, in order to remove impurity, after the extraction, demand pole chromatographies all, wash-out, not only time-consuming, consume a large amount of elutriants, also, can't realize the big production of mass-producing because be subjected to the column chromatography process technology limit.
Summary of the invention
Purpose of the present invention is exactly easypro ground of an improved synthetic method that technology, gets rid of the method that demand pole chromatography wash-out is purified in the fasudil decon method, to realize the big production of Fasudil Hydrochloride mass-producing.
The inventor is surprised to find that: the impurity that is difficult to remove in the synthetic fasudil is 5-isoquinoline 99.9 sulfonic acid.5-isoquinoline 99.9 sulfonic acid and salt thereof are at water, and ester solvent such as chloroform all have certain dissolubility in the methylene dichloride, so simple with transferring pH, method of extraction can not be removed 5-isoquinoline 99.9 sulfonic acid.Therefore, the generation that reduces 5-isoquinoline 99.9 sulfonic acid is the key of the impurity removed.
The inventor finds: 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride is extremely unstable, can be hydrolyzed to 5-isoquinoline 99.9 sulfonic acid rapidly in water.
The inventor is according to Chinese patent CN101092413A: 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride is added in the frozen water, stirring and regulating the pH value with saturated sodium bicarbonate solution down is 5～6, with twice of 500ml chloroform extraction, combining extraction liquid, anhydrous sodium sulfate drying, filter, it is standby that filtrate is concentrated into 200ml, is 5-isoquinoline 99.9 chloride solution.
After testing, this 5-isoquinoline 99.9 chloride solution contains 5～8% 5-isoquinoline 99.9 sulfonic acid.
The inventor has invented the method that is prepared as follows 5-isoquinoline 99.9 chloride solution:
With 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride, solid alkali A, methylene dichloride add in the reaction vessel, stir, be cooled to-12 ℃, drip water, drip and finish, continue to stir 15 minutes at-8 ℃～12 ℃, standing demix is told the dichloromethane solution layer that contains the isoquinoline 99.9 SULPHURYL CHLORIDE, and is standby.
Present method and CN101092413A are relatively, adopted anti-reinforced mode, 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride is in methylene dichloride surrounds, water is that the dropping mode enters this system, and the time of 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride contact water is very short, reacts in case contact promptly with water, generated 5-isoquinoline 99.9 SULPHURYL CHLORIDE, 5-isoquinoline 99.9 SULPHURYL CHLORIDE promptly enters the ester layer, simultaneously, has also stoped the generation of hydrolysis reaction at-8 ℃～-12 ℃ low temperature.
After testing, this 5-isoquinoline 99.9 chloride solution contain 5-isoquinoline 99.9 sulfonic acid≤0.5%.
Substantially the reaction solution that does not have 5-isoquinoline 99.9 sulfonic acid impurity can be merely with transferring pH, and method of extraction is removed fasudil impurity, obtains the high purity fasudil.
The inventor has invented the method for following processing fasudil reaction solution again:
After the reaction of 5-isoquinoline 99.9 SULPHURYL CHLORIDE and high piperazine, processing reaction liquid as follows:
(a) add hydrochloric acid in the reaction solution and transfer pH to 5～6, divide and remove methylene dichloride, stay water layer.
(b) water layer dripping alkali liquid B transfers pH to 9～10.
(c) water layer adds dichloromethane extraction, stays dichloromethane layer.
(d) dichloromethane layer washes with water, stays dichloromethane layer.
(e) evaporated under reduced pressure methylene dichloride promptly gets fasudil.
Described alkali lye B be sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate or, potassium bicarbonate aqueous solution.
Processing reaction liquid as stated above, reaction solution did not need chromatography column, can obtain purity greater than 98% highly purified fasudil.
Aforesaid method processing reaction liquid, the reason that obtains highly purified fasudil is as follows:
In 5-isoquinoline 99.9 SULPHURYL CHLORIDE and the reaction of high piperazine, high piperazine is all excessive greatly, and impurity mainly is high piperazine in the reaction solution, also has the unreacted 5-isoquinoline 99.9 of minute quantity SULPHURYL CHLORIDE.High piperazine is water-soluble, is insoluble to methylene dichloride, and 5-isoquinoline 99.9 SULPHURYL CHLORIDE is dissolved in methylene dichloride, and is water insoluble.
(1) adds hydrochloric acid in the reaction solution and transfer PH to 5～6, divide and remove methylene dichloride, stay water layer.
In this process, minute quantity 5-isoquinoline 99.9 SULPHURYL CHLORIDE is dissolved in dichloromethane layer, is at first discarded.Transfer PH to 5～6, fasudil becomes fasudil hydrochloride, stays water layer, and high piperazine is water-soluble, also stays water layer.Because of 5-isoquinoline 99.9 sulphonyl chlorine dose seldom, water layer does not have 5-isoquinoline 99.9 SULPHURYL CHLORIDE substantially.
(2) the water layer dripping alkali liquid is transferred pH to 9～10.
In this process, fasudil hydrochloride becomes fasudil.
(3) water layer adds dichloromethane extraction, stays dichloromethane layer.
In this process, fasudil enters dichloromethane layer, and most high piperazines enter water layer and discarded, but because the limitation of extraction process still has a small amount of high piperazine to stay dichloromethane layer.
(4) dichloromethane layer washes with water, stays dichloromethane layer.
In this process, generally wash dichloromethane layer with water 4～5 times, to till can not detect high piperazine.
(5) evaporated under reduced pressure methylene dichloride promptly gets fasudil.
In this process, obtain the high purity fasudil.
The present invention finds: contain the dichloromethane layer of fasudil, wash with water 4～5 times, the evaporated under reduced pressure methylene dichloride promptly obtains the high purity fasudil then.
The invention provides a kind of preparation method of compound Fasudil Hydrochloride, this technology comprises the steps :
(1) with 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride, solid alkali A, methylene dichloride add in the reaction vessel, stir, be cooled to-12 ℃, drip water, drip and finish, continue to stir 15 minutes at-8 ℃～-12 ℃, standing demix is told the dichloromethane solution layer that contains the isoquinoline 99.9 SULPHURYL CHLORIDE, and is standby;
(2) with high piperazine, methylene dichloride adds in the reaction vessel, and stirring and dissolving becomes uniform solution, be cooled to 0 ℃,, add in 0～5 ℃ of dichloromethane solution that contains the isoquinoline 99.9 SULPHURYL CHLORIDE that dropping is standby, continue to stir 5 hours, detection reaction is complete, as follows processing reaction liquid:
(a) add hydrochloric acid in the reaction solution and transfer PH to 5～6, divide and remove methylene dichloride, stay water layer,
(b) water layer dripping alkali liquid B transfers pH to 9～10,
(c) water layer adds dichloromethane extraction, stays dichloromethane layer,
(d) dichloromethane layer washes with water, stays dichloromethane layer,
(e) evaporated under reduced pressure methylene dichloride promptly gets fasudil;
(3) dehydrated alcohol is joined in the fasudil, stir, drip concentrated hydrochloric acid and transfer pH to 5～6, add in 0 ℃ of left and right sides stirring and crystallizing 1 hour, growing the grain filters, and cold ethanol drip washing is drained, 60 ℃ of oven dry, Fasudil Hydrochloride.
(1) 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride in: solid sodium bicarbonate=1:1.1～2.0 mol/mol.
(1) methylene dichloride: water=1:0.7 in～0.9 V/V.
Described alkali A be sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate or, saleratus.
Described alkali lye B be sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate or, potassium bicarbonate aqueous solution.
The invention provides a kind of preparation method of compound Fasudil Hydrochloride; this method has been got rid of the method that demand pole chromatography wash-out is purified in the fasudil decon method; it is not only time-consuming to have overcome column chromatography; consume a large amount of elutriants; also, can't realize the defective of the big production of mass-producing because be subjected to the column chromatography process technology limit.Make Fasudil Hydrochloride can realize the big production of mass-producing
Description of drawings
The fasudil HPLC figure that Fig. 1 obtains for embodiment 1.
Embodiment
Following embodiment is used for further narrating the present invention.
Embodiment 1
With 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride 100g(0.38mol), sodium bicarbonate solid 50g(0.60mol), methylene dichloride 700 ml join in the there-necked flask of 2L, be cooled to-12 ℃, drip water 600ml, drip and finish at-8 ℃～-12 ℃, continue to stir 15 minutes, standing demix is told the dichloromethane solution layer that contains the isoquinoline 99.9 SULPHURYL CHLORIDE, and is standby;
In the 2L there-necked flask, add high piperazine 100g(1mol), add the 200ml methylene dichloride, mechanical stirring is dissolved into uniform solution, ice-cold to 0 ℃, in 0～5 ℃ of isoquinoline 99.9 SULPHURYL CHLORIDE dichloromethane solution that dropping is standby, add, continue to stir 5 hours, detection reaction is complete.
Add 2N hydrochloric acid and transfer pH to 5～6, divide and remove methylene dichloride, go to reclaim, water layer drips 10% sodium hydroxide solution and transfers pH to 9～10, add methylene dichloride 500ml and extract, dichloromethane layer water 800ml * 4 is again washed 4 times, tells dichloromethane layer, be lower than 60 ℃ of water-bath evaporated under reduced pressure dichloromethane solutions, promptly get oily matter fasudil 96.5g.Yield: 87.6 %.HPLC detects fasudil purity, and purity is 99.4%.
Dehydrated alcohol 900ml is joined in the fasudil, stir, drip concentrated hydrochloric acid and transfer pH to 5～6, add in 0 ℃ of left and right sides stirring and crystallizing 1 hour, growing the grain filters, and cold ethanol drip washing is drained, 60 ℃ of oven dry, Fasudil Hydrochloride.
The fasudil method for detecting purity:
Get this product, add the moving phase dilution and make the solution that contains 0.3mg among every 1ml, as need testing solution; Precision is measured 1ml, puts in the 100ml measuring bottle, is diluted to scale with moving phase, shakes up, in contrast solution.Measure according to high performance liquid chromatography (2005 editions two appendix V D of Chinese Pharmacopoeia), with the octadecylsilane chemically bonded silica is weighting agent, with the 0.05mol/L ammonium dihydrogen phosphate: acetonitrile (65:10) is a moving phase, the detection wavelength is 275nm, and number of theoretical plate must not calculate by the Fasudil Hydrochloride peak and is lower than 3000; The resolution of fasudil peak and adjacent impurity peaks should meet the requirements.
 
Embodiment 2
With 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride 100g(0.38mol), potash solid 60g(0.43mol), methylene dichloride 700 ml join in the there-necked flask of 2L, add methylene dichloride 700 ml, are cooled to-12 ℃, drip water 500ml at-8 ℃～-12 ℃, drip and finish, continue to stir standing demix 15 minutes, tell the dichloromethane solution layer that contains the isoquinoline 99.9 SULPHURYL CHLORIDE, standby;
In the 2L there-necked flask, add high piperazine 100g(1mol), add the 200ml methylene dichloride, mechanical stirring is dissolved into uniform solution, ice-cold to 0 ℃, in 0～5 ℃ of isoquinoline 99.9 SULPHURYL CHLORIDE dichloromethane solution that dropping is standby, add, continue to stir 5 hours, detection reaction is complete.
Add 2N hydrochloric acid and transfer pH to 5～6, divide and remove methylene dichloride, go to reclaim, water layer drips 10% sodium carbonate solution and transfers pH to 9～10, add methylene dichloride 500ml and extract, dichloromethane layer water 800ml * 4 is again washed 4 times, tells dichloromethane layer, be lower than 60 ℃ of water-bath evaporated under reduced pressure dichloromethane solutions, promptly get oily matter fasudil 96.5g.Yield: 87.6 %.HPLC detects fasudil purity, and purity is 98.4%.
Dehydrated alcohol 900ml is joined in the fasudil, stir, drip concentrated hydrochloric acid and transfer pH to 5～6, add in 0 ℃ of left and right sides stirring and crystallizing 1 hour, growing the grain filters, and cold ethanol drip washing is drained, 60 ℃ of oven dry, Fasudil Hydrochloride.
Embodiment 3
With 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride 100g(0.38mol), yellow soda ash solid 80g(0.75mol), methylene dichloride 700 ml join in the there-necked flask of 2L, be cooled to-12 ℃, drip water 630ml, drip and finish at-8 ℃～-12 ℃, continue to stir 15 minutes, standing demix is told the dichloromethane solution layer that contains the isoquinoline 99.9 SULPHURYL CHLORIDE, and is standby;
In the 2L there-necked flask, add high piperazine 100g(1mol), add the 200ml methylene dichloride, mechanical stirring is dissolved into uniform solution, ice-cold to 0 ℃, in 0～5 ℃ of isoquinoline 99.9 SULPHURYL CHLORIDE dichloromethane solution that dropping is standby, add, continue to stir 5 hours, detection reaction is complete.
Add 2N hydrochloric acid and transfer pH to 5～6, divide and remove methylene dichloride, go to reclaim, water layer drips 10% potassium hydroxide solution and transfers pH to 9～10, add methylene dichloride 500ml and extract, dichloromethane layer water 800ml * 4 is again washed 4 times, tells dichloromethane layer, be lower than 60 ℃ of water-bath evaporated under reduced pressure dichloromethane solutions, promptly get oily matter fasudil 96.5g.Yield: 87.6 %.HPLC detects fasudil purity, and purity is 98.5%.
Dehydrated alcohol 900ml is joined in the fasudil, stir, drip concentrated hydrochloric acid and transfer pH to 5～6, add in 0 ℃ of left and right sides stirring and crystallizing 1 hour, growing the grain filters, and cold ethanol drip washing is drained, 60 ℃ of oven dry, Fasudil Hydrochloride.

Claims (5)

1. the preparation method of a compound Fasudil Hydrochloride, it is characterized in that: this method comprises the steps:
(1) with 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride, solid alkali A, methylene dichloride add in the reaction vessel, stir, be cooled to-12 ℃, drip water, drip and finish, continue to stir 15 minutes at-8 ℃～-12 ℃, standing demix is told the dichloromethane solution layer that contains the isoquinoline 99.9 SULPHURYL CHLORIDE, and is standby;
(2) with high piperazine, methylene dichloride adds in the reaction vessel, and stirring and dissolving becomes uniform solution, be cooled to 0 ℃,, add in 0～5 ℃ of dichloromethane solution that contains the isoquinoline 99.9 SULPHURYL CHLORIDE that dropping is standby, continue to stir 5 hours, detection reaction is complete, as follows processing reaction liquid:
(a) add hydrochloric acid in the reaction solution and transfer PH to 5～6, divide and remove methylene dichloride, stay water layer,
(b) water layer dripping alkali liquid B transfers pH to 9～10,
(c) water layer adds dichloromethane extraction, stays dichloromethane layer,
(d) dichloromethane layer washes with water, stays dichloromethane layer,
(e) evaporated under reduced pressure methylene dichloride promptly gets fasudil;
(3) dehydrated alcohol is joined in the fasudil, stir, drip concentrated hydrochloric acid and transfer pH to 5～6, add in 0 ℃ of left and right sides stirring and crystallizing 1 hour, growing the grain filters, and cold ethanol drip washing is drained, 60 ℃ of oven dry, Fasudil Hydrochloride.
2. method according to claim 1 is characterized in that: 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride in (1): solid alkali=1:1.1～2.0 mol/mol.
3. method according to claim 1 is characterized in that: methylene dichloride: water=1:0.7 in (1)～0.9 V/V.
4. preparation method according to claim 1 is characterized in that: described alkali A be sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate or, saleratus.
5. preparation method according to claim 1 is characterized in that: described alkali lye B be sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate or, potassium bicarbonate aqueous solution.
CN 201010610549 2010-12-29 2010-12-29 Method for preparing hydroxyl fasudil compounds Active CN102070612B (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103030629A (en) * 2011-10-10 2013-04-10 南京亿华药业有限公司 Method for preparing fasudil hydrochloride
CN103145695A (en) * 2011-12-07 2013-06-12 海门慧聚药业有限公司 Novel technology for preparing fasudil hydrochloride
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
CN108593831A (en) * 2018-05-08 2018-09-28 山东新华制药股份有限公司 HPLC detection method of the Fasudic hydrochloride in relation to substance
CN109374811A (en) * 2018-11-14 2019-02-22 昆药集团股份有限公司 The detection method of 5- isoquinolin sulfonic acid in a kind of Fasudic hydrochloride
CN109374812A (en) * 2018-11-14 2019-02-22 昆药集团股份有限公司 The detection method of 5- isoquinolin methylmesylate in a kind 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
CN110441449A (en) * 2019-08-14 2019-11-12 昆药集团股份有限公司 In relation to the detection method of substance in Fasudic hydrochloride raw material or injection
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

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US4678783A (en) * 1983-11-04 1987-07-07 Asahi Kasei Kogyo Kabushiki Kaisha Substituted isoquinolinesulfonyl compounds
CN101092413A (en) * 2006-06-23 2007-12-26 黄振华 Hydrate of medicinal salt of Fasudil
CN101863880A (en) * 2010-06-12 2010-10-20 陶灵刚 Fasudil hydrochloride compound and novel method thereof

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Publication number Priority date Publication date Assignee Title
US4678783A (en) * 1983-11-04 1987-07-07 Asahi Kasei Kogyo Kabushiki Kaisha Substituted isoquinolinesulfonyl compounds
US4678783B1 (en) * 1983-11-04 1995-04-04 Asahi Chemical Ind Substituted isoquinolinesulfonyl compounds
CN101092413A (en) * 2006-06-23 2007-12-26 黄振华 Hydrate of medicinal salt of Fasudil
CN101863880A (en) * 2010-06-12 2010-10-20 陶灵刚 Fasudil hydrochloride compound and novel method thereof

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103030629A (en) * 2011-10-10 2013-04-10 南京亿华药业有限公司 Method for preparing fasudil hydrochloride
CN103030629B (en) * 2011-10-10 2015-02-25 南京亿华药业有限公司 Method for preparing fasudil hydrochloride
CN103145695A (en) * 2011-12-07 2013-06-12 海门慧聚药业有限公司 Novel technology for preparing fasudil hydrochloride
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
CN103724326B (en) * 2013-12-13 2015-08-12 四川升和药业股份有限公司 A kind of preparation method of High-purity 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
CN108593831A (en) * 2018-05-08 2018-09-28 山东新华制药股份有限公司 HPLC detection method of the Fasudic hydrochloride in relation to substance
CN108593831B (en) * 2018-05-08 2020-05-19 山东新华制药股份有限公司 HPLC detection method of fasudil hydrochloride related substances
CN109374812A (en) * 2018-11-14 2019-02-22 昆药集团股份有限公司 The detection method of 5- isoquinolin methylmesylate in a kind of Fasudic hydrochloride
CN109374812B (en) * 2018-11-14 2020-11-03 昆药集团股份有限公司 Method for detecting 5-isoquinoline methyl sulfonate in fasudil hydrochloride
CN109374811A (en) * 2018-11-14 2019-02-22 昆药集团股份有限公司 The detection method of 5- isoquinolin sulfonic acid in a kind of Fasudic hydrochloride
CN110441449A (en) * 2019-08-14 2019-11-12 昆药集团股份有限公司 In relation to the detection method of substance in Fasudic hydrochloride raw material or injection
CN110441449B (en) * 2019-08-14 2021-06-29 昆药集团股份有限公司 Method for detecting related substances in fasudil hydrochloride raw material or injection
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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