CN109574992A - A kind of preparation method of Fasudic hydrochloride - Google Patents

A kind of preparation method of Fasudic hydrochloride Download PDF

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Publication number
CN109574992A
CN109574992A CN201811486576.8A CN201811486576A CN109574992A CN 109574992 A CN109574992 A CN 109574992A CN 201811486576 A CN201811486576 A CN 201811486576A CN 109574992 A CN109574992 A CN 109574992A
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reaction
hydrochloride
fasudic hydrochloride
fasudic
isoquinolin
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CN109574992B (en
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崔海龙
马莉艳
王晓雪
石勇志
安晓敏
时惠峰
张炜
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HENAN RUNHONG PHARMACEUTICAL CO Ltd
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HENAN RUNHONG PHARMACEUTICAL CO Ltd
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    • 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

Abstract

The invention belongs to heterocyclic compound preparation technical fields, and in particular to a kind of preparation method of Fasudic hydrochloride.Preparation method of the invention is the following steps are included: 1) by isoquinolin -5- sulfonyl chloride hydrochloride, homopiperazine and liquefied ammonia in organic solvent in 10~15 DEG C of 2~4h of reaction, to the water extraction and separation of the reaction system after reaction, separation of oil object is concentrated to get intermediate；2) intermediate for obtaining step 1) and hydrochloric acid carry out salt-forming reaction to get.Preparation method of the invention uses isoquinolin -5- sulfonyl chloride hydrochloride directly to react to obtain intermediate with homopiperazine for raw material, reduces operating procedure, and preparation process is simple.

Description

A kind of preparation method of Fasudic hydrochloride
Technical field
The invention belongs to heterocyclic compound preparation technical fields, and in particular to a kind of preparation method of Fasudic hydrochloride.
Background technique
Fasudic hydrochloride (Fasudil Hydrochloride), the entitled hexahydro -1- (5- sulfonyl isoquinolin) -1 of chemistry (H)-Isosorbide-5-Nitrae-diazepine hydrochloride, structural formula are as follows:Fasudic hydrochloride is as a kind of novel, high Cerebral angiospasm can be effectively relieved in the blood vessel dilatation drug of effect, improve the prognosis of the first blood patient of subarachnoid space, in the prevention and treatment heart There are huge potentiality in terms of cranial vascular disease, therefore research optimization is carried out to its synthesis technology, establish suitable process route It is of great significance.
A kind of system of High-purity fasudil hydrochloride is disclosed in the Chinese patent application that publication No. is CN104327052A Preparation Method.This method is using isoquinolin -5- sulfonyl chloride hydrochloride as raw material, first by isoquinolin -5- sulfonyl chloride hydrochloride in bicarbonate Salt is solved in sodium solution and obtains isoquinolin -5- sulfonic acid chloride, and then isoquinolin -5- sulfonic acid chloride successively reacts to obtain with homopiperazine, hydrochloric acid Crude Fasudic hydrochloride, by the Fasudic hydrochloride for being refining to obtain high-purity.The hydrochloric acid as made from the preparation method The purity of Fasudil is 99.5% or more, but the preparation method complex process.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of the Fasudic hydrochloride of simple process.
To achieve the above object, the technical scheme adopted by the invention is as follows:
A kind of preparation method of Fasudic hydrochloride, includes the following steps:
1) by isoquinolin -5- sulfonyl chloride hydrochloride, homopiperazine and liquefied ammonia in organic solvent in 10~15 DEG C react 2~ Separation of oil object is concentrated to get intermediate to the water extraction and separation of the reaction system after reaction by 4h；
2) intermediate for obtaining step 1) and hydrochloric acid carry out salt-forming reaction to get.
The present invention directly reacts to obtain intermediate with homopiperazine as raw material using isoquinolin -5- sulfonyl chloride hydrochloride, reduces Operating procedure, preparation process are simple.It is removed in isoquinolin -5- sulfonyl chloride hydrochloride in preparation process of the invention using liquefied ammonia Hydrochloric acid, so that reaction is single step reaction and is single organic phase.Simultaneously liquefied ammonia easily remove in subsequent processing, reduce at Residual in product；The price of liquefied ammonia is lower, can reduce production cost.
To make isoquinoline-5-sulfonic acid acyl chloride hydrochloride fully reacting, the step 1) isoquinolin -5- sulfonyl chloride hydrochloride with The mass ratio of homopiperazine is 30~60:50~70.
To completely remove the hydrochloric acid in isoquinoline-5-sulfonic acid acyl chloride hydrochloride, the step 1) isoquinolin -5- sulfonic acid chloride The mass ratio of hydrochloride and liquefied ammonia is 30~60:33~45.
Step 1) the water extraction and separation the following steps are included:
A) add water mixing in the reaction system, liquid separation, water phase is mixed with organic solvent, and liquid separation is then combined with organic phase；
B) organic phase merged in step a) mix with water, adjusting pH is 4.5~5.5, liquid separation, obtains water phase and organic Phase；
C) water phase obtained by step b) is adjusted pH is 8.0~9.5, is then mixed with organic solvent, liquid separation is to get the oil Phase isolate.
The extraction process of step a) can remove the ammonium salt generated in reaction process and unreacted liquefied ammonia；It will extraction in step b) System is taken to be adjusted to acidity, it is ensured that remove double sulfonylation by-products on the basis of product loses less；It will extraction in step c) System is adjusted to alkalinity, the intermediate product that be dissolved in water phase in step b) extraction process can be transferred in organic phase, in reduction Between product loss.
To avoid introducing other in impurity, step b) the adjusting pH agents useful for same is hydrochloric acid.
Step c) the pH agents useful for same that adjusts is one in sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus Kind.Mentioned reagent is conventional common alkaline reagent, is conveniently easy to get.
Salt-forming reaction described in step 2) includes the following steps: solid-liquid point after mixing the solution of intermediate with active carbon From separating liquid is reacted with hydrochloric acid, obtains crude product.The partial impurities in the solution of intermediate can be adsorbed using active carbon, played Decolorization.
The pH value of reaction system is 4.5~5.0 when the separating liquid is reacted with hydrochloric acid.The pH for controlling reaction system can be indirect The pH value for the product to be obtained is controlled, can get when the verified pH value in reaction system is 4.5~5.0 with qualified pH It is worth product.
Due to containing impurity in crude product, the crude product need to pass through purification processes, and the purification processes include: that crude product is made Solution is simultaneously mixed with active carbon, and flow back 40~50min, is separated by solid-liquid separation, and removes solvent.
The quality of the active carbon is the 30%~50% of crude product quality.The dosage of active carbon is the pass of product colour qualification The purpose of decoloration is not achieved if activated carbon dosage is very little in key.
Specific embodiment
Preferably, the step 1) isoquinolin -5- sulfonic acid chloride hydrochloric acid in the preparation process of Fasudic hydrochloride of the invention The mass ratio of salt and homopiperazine is 35~37:50~70.
Preferably, the step 1) isoquinolin -5- sulfonic acid chloride hydrochloric acid in the preparation process of Fasudic hydrochloride of the invention The mass ratio of salt and liquefied ammonia is 35~37:33~45.
In the preparation process of Fasudic hydrochloride of the invention organic solvent used be DMF, it is methylene chloride, methanol, anhydrous One of ethyl alcohol.
Isoquinolin -5- sulfonyl chloride hydrochloride in the preparation process of Fasudic hydrochloride of the invention in step 1) is by including The method of following steps is made: by isoquinoline-5-sulfonic acid and SOCl2In organic solvent 2~3h of back flow reaction to get.Due to Reaction time determines the conversion ratio of isoquinoline-5-sulfonic acid, to make isoquinoline-5-sulfonic acid fully reacting, reflux time 2 ~3h.
Above-mentioned -5 sulfonic acid of isoquinolin and SOCl2Mass ratio be 30:200~500.
When using water extraction and separation in the preparation process of Fasudic hydrochloride of the invention, addition adjusts extraction system pH institute With, to be added dropwise dropwise, system temperature is not higher than 40 DEG C during dropwise addition when reagent.
Each reaction in the preparation process of Fasudic hydrochloride of the invention is as shown in formula (I):
Combined with specific embodiments below and formula (I) the invention will be further described.
Embodiment 1
The preparation method of the Fasudic hydrochloride of the present embodiment, specifically includes the following steps:
1) SOCl is put into respectively in 1000L reaction kettle2200kg, isoquinoline-5-sulfonic acid (FZ010-SM in formula (I)) 30kg and DMF 600mL is warming up to reflux, and after reacting 2h, with cooling water temperature, reaction was completed.Remove SOCl under reduced pressure2Afterwards toward paste Methylene chloride 100L is added in shape object, 1h is then stirred under room temperature, is then filtered, white powder solid-state is dried under reduced pressure to obtain, weight About 36.4kg, as product isoquinolin -5- sulfonyl chloride hydrochloride (FZ010-1), yield 96.0%.
2) methylene chloride 500L, homopiperazine 50kg and liquefied ammonia 33kg are put into respectively in 1000L reaction kettle, stirs dissolved clarification, The FZ010-1 that step 1) obtains is added.When 10 DEG C of insulation reactions to TLC are detected without FZ010-1 residual, reaction was completed, when reaction Between be 2~4h.Purified water 300L is mended in reaction kettle, is stirred evenly, after sufficient standing, is separated dichloromethane layer.Water layer uses 100L again Methylene chloride extracts, and repeats to extract twice, then collects dichloromethane layer；Purified water 300L is mended into dichloromethane layer, is added dropwise The hydrochloric acid solution regulation system pH of 4mol/L is 4.5~5.0, keeps temperature to be not higher than 40 DEG C during being added dropwise, layering；Collect water Layer, it is 8.0 that the NaOH solution for being 20% with mass fraction, which adjusts water layer pH, keeps temperature to be not higher than 40 DEG C during being added dropwise.With 200L methylene chloride extracts, and repeats to extract 3 times, then collects dichloromethane layer, is evaporated under reduced pressure, obtains lurid sticky oil Object, about 21.8kg, as intermediate hexahydro -1- (5- isoquinolinesulfonylcompounds) -1H-1,4- diazepine salt is (in formula (I) FZ010-2), yield 54.5%.
3) FZ010-2 obtained by upper step is dissolved with methanol, active carbon about 6kg is added, continued to stir 30min, then filter Active carbon is removed, is eluted, is repeated 2 times with 10L methanol, collects simultaneously merging filtrate and washing lotion.Then plus purified water 80L, stirring are equal It is even, interior 30 DEG C of temperature is kept, the hydrochloric acid solution of 1mol/L is gradually added dropwise under stirring, until pH is 4.5~5.0.Evaporating solvent under reduced pressure, Obtain grease.Dehydrated alcohol 30L is added, removes ethyl alcohol under reduced pressure, the paste of precipitation is transferred in reaction kettle, is added 100kg dehydrated alcohol stirs 2 hours under room temperature, drains, obtain off-white powder 24.5kg (wet product), as Fasudic hydrochloride Crude product (FZ010-00 in formula (I)).
4) add 100L methanol in FZ010-00 crude product, active carbon 7.4kg is added after dissolved clarification, flow back 40min, filtering removal Active carbon is drained, and methanol solution is collected.Remove methanol under reduced pressure.Dehydrated alcohol 20L is supplemented, is shaken up, then it is evaporated off.It is eventually adding Dehydrated alcohol 70L, and stir 2 hours at normal temperature, it drains, collects wet cake.By wet cake 80 DEG C forced air drying 3 hours, The white powdery solids of about 15.7kg, as Fasudic hydrochloride finished product (the FZ010-00- fine work in formula (I)) are obtained, Yield is 34.9%.
Embodiment 2
The preparation method of the Fasudic hydrochloride of the present embodiment the following steps are included:
1) SOCl is put into respectively in 1000L reaction kettle2300kg, isoquinoline-5-sulfonic acid (FZ010-SM) 30kg and DMF 700mL is warming up to reflux, and after reacting 3h, with cooling water temperature, reaction was completed.Remove SOCl under reduced pressure2It is added afterwards into paste Then methylene chloride 120L stirs 2h, then filters under room temperature, be dried under reduced pressure to obtain white powder solid-state, weigh about 35.8kg, i.e., For product isoquinolin -5- sulfonyl chloride hydrochloride (FZ010-1), yield 94.6%.
2) methylene chloride 600L, homopiperazine 60kg and liquefied ammonia 40kg are put into respectively in 1000L reaction kettle, stirs dissolved clarification, The FZ010-1 that step 1) obtains is added.When 13 DEG C of insulation reactions to TLC are detected without FZ010-1 residual, reaction was completed, when reaction Between be 2~4h.Purified water 300L is mended in reaction kettle, is stirred evenly, after sufficient standing, is separated dichloromethane layer.Water layer uses 100L again Methylene chloride extracts, and repeats to extract 2 times, then collects dichloromethane layer；Purified water 300L is mended into dichloromethane layer, is added dropwise The hydrochloric acid solution regulation system pH of 4mol/L is 4.5~5.0, keeps temperature to be not higher than 40 DEG C during being added dropwise, layering；Collect water Layer, it is 8.7 that the NaOH solution for being 20% with mass fraction, which adjusts water layer pH, keeps temperature to be not higher than 40 DEG C during being added dropwise.So 200L methylene chloride is used afterwards, is repeated to extract 3 times, is then collected dichloromethane layer, is evaporated under reduced pressure, obtains lurid sticky oil Object, about 22.6kg, as intermediate hexahydro -1- (5- isoquinolinesulfonylcompounds) -1H-1,4- diazepine salt (FZ010-2), yield It is 57.4%.
3) FZ010-2 obtained by upper step is dissolved with methanol, active carbon about 6kg is added, continued to stir 45min, then filter Active carbon is removed, is eluted, is repeated 2 times with 10L methanol, collects simultaneously merging filtrate and washing lotion.Add purified water 80L, stir evenly, protects Holding temperature is 45 DEG C, and the hydrochloric acid solution of 1mol/L is gradually added dropwise under stirring, until pH is 4.5~5.0.Evaporating solvent under reduced pressure obtains To grease.Dehydrated alcohol 50L is added, removes ethyl alcohol under reduced pressure, the paste of precipitation is transferred in reaction kettle, 100kg is added Dehydrated alcohol stirs 2 hours under room temperature, drains, obtain off-white powder 25.3kg (wet product), as Fasudic hydrochloride crude product (FZ010-00)。
4) add 120L methanol in FZ010-00 crude product, active carbon 7.6kg is added after dissolved clarification, flow back 50min, filtering removal Active carbon is drained, and methanol solution is collected.Remove methanol under reduced pressure.Dehydrated alcohol 40L is supplemented, is shaken up, then it is evaporated off.It is eventually adding Dehydrated alcohol 90L, and stir 2 hours at normal temperature, it drains, collects wet cake.Wet cake is small in 83 DEG C of forced air dryings 2.5 When, the white powdery solids of about 16kg, as Fasudic hydrochloride finished product (FZ010-00- fine work) are obtained, yield is 36.0%.
Embodiment 3
The preparation method of the Fasudic hydrochloride of the present embodiment the following steps are included:
1) SOCl is put into respectively in 1000L reaction kettle2500kg, isoquinoline-5-sulfonic acid (FZ010-SM) 30kg and DMF 900mL is warming up to reflux, and after reacting 3h, with cooling water temperature, reaction was completed.Remove SOCl under reduced pressure2It is added afterwards into paste Then methylene chloride 130L stirs 3h, then filters under room temperature, be dried under reduced pressure to obtain white powder solid-state, weigh about 35.9kg, i.e., For product isoquinolin -5- sulfonyl chloride hydrochloride (FZ010-1), yield 94.7%.
2) methylene chloride 800L, homopiperazine 70kg and liquefied ammonia 45kg are put into respectively in 1000L reaction kettle, stirs dissolved clarification, The FZ010-1 that step 1) obtains is added.When 15 DEG C of insulation reactions to TLC are detected without FZ010-1 residual, reaction was completed, when reaction Between be 2~4h.Purified water 300L is mended in reaction kettle, is stirred evenly, after sufficient standing, is separated dichloromethane layer.Water layer uses 100L again Methylene chloride extracts, and repeats to extract 2 times, then collects dichloromethane layer；Purified water 300L is mended into dichloromethane layer, is added dropwise The hydrochloric acid solution regulation system pH of 4mol/L is 4.5~5.0, keeps temperature to be not higher than 40 DEG C during being added dropwise, layering；Collect water Layer, it is 9.5 that the NaOH solution for being 20% with mass fraction, which adjusts water layer pH, keeps temperature to be not higher than 40 DEG C during being added dropwise.With 200L methylene chloride extracts, and is repeated 3 times, then collects dichloromethane layer, is evaporated under reduced pressure, obtains lurid sticky oil object, About 21.4kg, as intermediate hexahydro -1- (5- isoquinolinesulfonylcompounds) -1H-1,4- diazepine salt (FZ010-2), yield are 54.3%.
3) FZ010-2 obtained by upper step is dissolved with methanol, active carbon about 6kg is added, continued to stir 30min, then filter Active carbon is removed, is eluted, is repeated 2 times with 10L methanol, collects simultaneously merging filtrate and washing lotion.Add purified water 80L, stir evenly, protects Holding temperature is 65 DEG C.The hydrochloric acid solution of 1mol/L is gradually added dropwise under stirring, until pH is 4.5~5.0.Evaporating solvent under reduced pressure obtains To grease.Dehydrated alcohol 60L is added, removes ethyl alcohol under reduced pressure.The paste of precipitation is transferred in reaction kettle, 100kg is added Dehydrated alcohol stirs 2 hours under room temperature, drains, obtain off-white powder 24.8kg (wet product), as Fasudic hydrochloride crude product (FZ010-00)。
4) add 140L methanol in FZ010-00 crude product, active carbon 12.4kg is added after dissolved clarification, flow back 40min, filters off It except active carbon, drains, collects methanol solution.Remove methanol under reduced pressure.Dehydrated alcohol 50L is supplemented, is shaken up, then it is evaporated off.Finally plus Enter dehydrated alcohol 100L, and stir 2 hours at normal temperature, drain, collects wet cake.Wet cake is small in 85 DEG C of forced air dryings 2 When, the white powdery solids of about 15.9kg, as Fasudic hydrochloride finished product (FZ010-00- fine work) are obtained, yield is 35.8%.
Embodiment 4
The preparation method of the Fasudic hydrochloride of the present embodiment, includes the following steps:
1) methylene chloride 750L, homopiperazine 65kg and liquefied ammonia 40kg are put into respectively in 1000L reaction kettle, stirs dissolved clarification, It is added 36kg isoquinolin -5- sulfonyl chloride hydrochloride (FZ010-1, Beijing lark waffle Technology Co., Ltd.).It is kept the temperature at 15 DEG C Reaction was completed when reaction is remained to TLC detection without FZ010-1, and the reaction time is 2~4h.Purified water 300L is mended in reaction kettle, It stirs evenly, after sufficient standing, separates dichloromethane layer.Water layer uses 100L methylene chloride to extract again, is repeated 2 times, and collects methylene chloride Layer；Purified water 300L is mended into dichloromethane layer, the hydrochloric acid solution regulation system pH that 4mol/L is added dropwise is 4.5~5.0, is added dropwise Temperature is kept to be not higher than 40 DEG C in journey, layering；Water layer is collected, the NaOH solution for being 20% with mass fraction adjusts water layer pH and is 9.5, keep temperature to be not higher than 40 DEG C during being added dropwise.It is extracted, is repeated 3 times with 200L methylene chloride, collected dichloromethane layer, subtract Pressure distillation, obtains lurid sticky oil object, about 26.1kg, as intermediate hexahydro -1- (5- isoquinolinesulfonylcompounds) -1H- Isosorbide-5-Nitrae-diazepine salt (FZ010-2), yield 54.4%.
2) FZ010-2 obtained by upper step is dissolved with methanol, active carbon about 6kg is added, continued to stir 30min, then filter Active carbon is removed, is eluted, is repeated 2 times with 10L methanol, collects simultaneously merging filtrate and washing lotion.Add purified water 80L, stir evenly, protects Holding temperature is 65 DEG C, and the hydrochloric acid solution of 1mol/L is gradually added dropwise under stirring, until pH is 4.5~5.0.Evaporating solvent under reduced pressure obtains To grease.Dehydrated alcohol 60L is added, removes ethyl alcohol under reduced pressure.The paste of precipitation is transferred in reaction kettle, 100kg is added Dehydrated alcohol stirs 2 hours under room temperature, drains, obtain off-white powder 26.1kg (wet product), as Fasudic hydrochloride crude product (FZ010-00)。
3) add 140L methanol in FZ010-00 crude product, active carbon 10.44kg is added after dissolved clarification, flow back 40min, filters off It except active carbon, drains, collects methanol solution.Remove methanol under reduced pressure.Dehydrated alcohol 50L is supplemented, is shaken up, then it is evaporated off.Finally plus Enter dehydrated alcohol 100L, and stir 2 hours at normal temperature, drain, collects wet cake.Wet cake is small in 85 DEG C of forced air dryings 2 When, the white powdery solids of about 16.0kg, as Fasudic hydrochloride finished product (FZ010-00- fine work) are obtained, yield is 35.8%.
Test example
Fasudic hydrochloride prepared by Examples 1 to 4 is conventionally subjected to purity test, test result such as table 1 It is shown.
1 test result of table
Sample Purity
Embodiment 1 99.958%
Embodiment 2 99.965%
Embodiment 3 99.899%
Embodiment 4 99.975%

Claims (10)

1. a kind of preparation method of Fasudic hydrochloride, which comprises the steps of:
1) right by isoquinolin -5- sulfonyl chloride hydrochloride, homopiperazine and liquefied ammonia in organic solvent in 10~15 DEG C of reaction 2~4h Reaction system water extraction and separation after reaction, separation of oil object are concentrated to get intermediate；
2) intermediate for obtaining step 1) and hydrochloric acid carry out salt-forming reaction to get.
2. the preparation method of Fasudic hydrochloride according to claim 1, which is characterized in that the step 1) isoquinolin- The mass ratio of 5- sulfonyl chloride hydrochloride and homopiperazine is 30~60:50~70.
3. the preparation method of Fasudic hydrochloride according to claim 1, which is characterized in that the step 1) isoquinolin- The mass ratio of 5- sulfonyl chloride hydrochloride and liquefied ammonia is 30~60:33~45.
4. the preparation method of Fasudic hydrochloride according to claim 1, which is characterized in that step 1) the water extraction point From the following steps are included:
A) add water mixing in the reaction system, liquid separation, water phase is mixed with organic solvent, and liquid separation is then combined with organic phase；
B) organic phase merged in step a) is mixed with water, adjusting pH is 4.5~5.5, and liquid separation obtains water phase and organic phase；
C) water phase obtained by step b) is adjusted pH is 8.0~9.5, is then mixed with organic solvent, and liquid separation is to get the oily phase point From object.
5. the preparation method of Fasudic hydrochloride according to claim 4, which is characterized in that step b) the adjusting pH institute It is hydrochloric acid with reagent.
6. the preparation method of Fasudic hydrochloride according to claim 4, which is characterized in that step c) the adjusting pH institute It is one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus with reagent.
7. the preparation method of Fasudic hydrochloride according to claim 1, which is characterized in that anti-at salt described in step 2) It should include the following steps: to be separated by solid-liquid separation after mixing the solution of intermediate with active carbon, separating liquid is reacted with hydrochloric acid, is obtained thick Product.
8. the preparation method of Fasudic hydrochloride according to claim 7, which is characterized in that the separating liquid and hydrochloric acid are anti- The pH value of seasonable reaction system is 4.5~5.0.
9. the preparation method of Fasudic hydrochloride according to claim 7, which is characterized in that the crude product is by purification Reason, the purification processes include: that solution is made in crude product and is mixed with active carbon, and flow back 40~50min, is separated by solid-liquid separation, and are removed Solvent.
10. the preparation method of Fasudic hydrochloride according to claim 9, which is characterized in that the quality of the active carbon It is the 30%~50% of crude product quality.
CN201811486576.8A 2018-12-06 2018-12-06 Preparation method of fasudil hydrochloride Active CN109574992B (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080064681A1 (en) * 2006-09-11 2008-03-13 Hiroyoshi Hidaka Therapeutic agent for treating glaucoma
CN102775387A (en) * 2011-05-13 2012-11-14 深圳海王药业有限公司 Method for refining fasudil hydrochloride
CN103044403A (en) * 2013-01-05 2013-04-17 成都天翼医药科技有限公司 Preparation method of fasudil hydrochloride
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

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080064681A1 (en) * 2006-09-11 2008-03-13 Hiroyoshi Hidaka Therapeutic agent for treating glaucoma
CN102775387A (en) * 2011-05-13 2012-11-14 深圳海王药业有限公司 Method for refining 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
CN103044403A (en) * 2013-01-05 2013-04-17 成都天翼医药科技有限公司 Preparation method of fasudil hydrochloride
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

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