CN102603715A - Synthesis and preparation method of fasudil hydrochloride - Google Patents
Synthesis and preparation method of fasudil hydrochloride Download PDFInfo
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- CN102603715A CN102603715A CN2012100904435A CN201210090443A CN102603715A CN 102603715 A CN102603715 A CN 102603715A CN 2012100904435 A CN2012100904435 A CN 2012100904435A CN 201210090443 A CN201210090443 A CN 201210090443A CN 102603715 A CN102603715 A CN 102603715A
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- 229960002435 fasudil Drugs 0.000 title claims abstract description 36
- NGOGFTYYXHNFQH-UHFFFAOYSA-N fasudil Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 230000015572 biosynthetic process Effects 0.000 title abstract description 3
- 238000001308 synthesis method Methods 0.000 title abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 122
- 239000000243 solution Substances 0.000 claims abstract description 61
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 42
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000012074 organic phase Substances 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 15
- 238000005406 washing Methods 0.000 claims abstract description 15
- 238000001035 drying Methods 0.000 claims abstract description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 230000007935 neutral effect Effects 0.000 claims abstract description 4
- 238000010992 reflux Methods 0.000 claims abstract description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- 238000000605 extraction Methods 0.000 claims description 11
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 11
- 238000010189 synthetic method Methods 0.000 claims description 11
- 238000000967 suction filtration Methods 0.000 claims description 10
- ONOBXDPYDHTSBQ-UHFFFAOYSA-N 2,3,4,7-tetrahydro-1h-diazepine Chemical compound C1CC=CCNN1 ONOBXDPYDHTSBQ-UHFFFAOYSA-N 0.000 claims description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- OGKZYCXSIMOMJI-UHFFFAOYSA-N sulfuryl dichloride;hydrochloride Chemical compound Cl.ClS(Cl)(=O)=O OGKZYCXSIMOMJI-UHFFFAOYSA-N 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- KAHVZNKZQFSBFW-UHFFFAOYSA-N n-methyl-n-trimethylsilylmethanamine Chemical compound CN(C)[Si](C)(C)C KAHVZNKZQFSBFW-UHFFFAOYSA-N 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 150000003233 pyrroles Chemical class 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 7
- 150000003839 salts Chemical class 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 abstract 2
- 238000001914 filtration Methods 0.000 abstract 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical class Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 abstract 1
- 239000005457 ice water Substances 0.000 abstract 1
- WHIDHHUCCTYJKA-UHFFFAOYSA-N isoquinoline-5-sulfonyl chloride Chemical compound N1=CC=C2C(S(=O)(=O)Cl)=CC=CC2=C1 WHIDHHUCCTYJKA-UHFFFAOYSA-N 0.000 abstract 1
- GZQNTWHQJJVIAK-UHFFFAOYSA-N isoquinoline-5-sulfonyl chloride;hydrochloride Chemical compound Cl.N1=CC=C2C(S(=O)(=O)Cl)=CC=CC2=C1 GZQNTWHQJJVIAK-UHFFFAOYSA-N 0.000 abstract 1
- 239000007788 liquid Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000013019 agitation Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- -1 fasudil hydrochloride compound compound Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthesis and preparation method of fasudil hydrochloride, which comprises the steps of taking 5-isoquinoline sulfoacid as raw material, refluxing in thionyl chloride to obtain 5-isoquinoline sulfonyl chloride hydrochloride, adding dichloromethane after dissolving with ice water, adjusting pH value of the solution to be neutral and performing liquid eparation; washing organic phase with water and edible salt, drying and filtering to obtain dichloromethane solution of 5-isoquinoline sulfonyl chloride; performing reaction of the solution with high purity piperazine in the presence of other alkaline reagents, washing the reaction solution with hydrochloric acid aqueous solution and sodium hydroxide aqueous solution after reaction, and extracting the washing solution respectively with dichloromethane; combining organic phases, washing with water, drying and filtering, and dropwise adding saturated hydrogen chloride ethanol solution to separate out crude product of fasudil hydrochloride; and recrystalizing the crude product with ethanol aqueous solution to obtain fasudil hydrochloride. The method provided by the invention greatly reduces the usage amount of high purity piperazine that is expensive by using deacidifying agents that are low in cost so as to reduce the preparation cost of fasudil hydrochloride effectively.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of synthetic and preparation method of HA-1077.
Background technology
HA-1077, chemical name are six hydrogen-1-(5-isoquinolinesulfonylcompounds)-1H-1,4-diazepine hydrochloride, molecular formula C
14H
17N
3O
2SHCl, molecular weight are 327.83, and structural formula is:
HA-1077 is that a kind of kinases inhibitor is the intracellular calcium antagonist, and through the terminal stage of blocking-up blood vessel contraction process, myoprotein light chain phosphorylation is come vasodilation, suppresses vasospasm.Brain convulsion after being applicable to improvement clinically and preventing subarachnoid hemorrhage and the symptoms of cerebral ischemia that causes.
In the prior art, the main synthetic route of HA-1077 is:
Though said synthesis route is simple; But in currently known methods, before adding the synthetic fasudil of high piperazine, because a large amount of acidic substance that exist in the reaction solution need neutralize; Therefore high piperazine is both as reaction substrate; Be again the organic bases that is used to deacidify, thereby cause expensive high piperazine usage quantity excessive, cause that the production cost of HA-1077 is difficult to reduce.
This shows in the preparation process, how to reduce the consumption of high piperazine, the production cost that reduces HA-1077 is that the research in the whole process of preparation is crucial.
A kind of fasudil hydrochloride compound compound method is disclosed respectively among patent CN101863880A, the CN102020635A; The equivalence ratio of using of 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride and high piperazine is 1:4 among the preparation method, and it is about 70% that coupling becomes fasudil step productive rate; In addition, in the synthetic and method of purification of the disclosed HA-1077 of patent CN102020636A, the equivalence ratio of using of 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride and high piperazine is 1:6, but productive rate is not announced.
Summary of the invention
It is simple that the technical problem that the present invention mainly solves provides a kind of technology, and product purity is high, the synthetic and preparation method of HA-1077 with low cost.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is: the synthetic and preparation method of a kind of salt acid system ground Shu Er, this preparation method comprises the steps:
(1) at catalyst n, under the condition that dinethylformamide exists, 5-isoquinoline 99.9 sulfonic acid stirs in thionyl chloride, and reflux, and temperature of reaction is 75 ℃-85 ℃, makes 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride;
(2) 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride dissolves with frozen water; Add dichloromethane solution, stir down slowly adding saturated sodium bicarbonate aqueous solution, regulator solution pH value to neutral back separatory; Water once merges organic phase in the back with dichloromethane extraction; This organic phase successively each washing of water and saturated aqueous common salt once, suction filtration behind anhydrous magnesium sulfate drying makes the dichloromethane solution of 5-isoquinoline 99.9 SULPHURYL CHLORIDE;
(3) keeping temperature of reaction system not surpass under 10 ℃; To the dichloromethane solution that high piperazine and the alkaline reagents that is used for deacidifying exist, the dichloromethane solution of slow Dropwise 5-isoquinoline 99.9 SULPHURYL CHLORIDE, the mol ratio of wherein high piperazine and 5-isoquinoline 99.9 SULPHURYL CHLORIDE is 1:1; Finish; Stirring reaction under the room temperature makes six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1 (H)-1, the dichloromethane solution of 4-diazepine;
(4) regulate above-mentioned reacting solution pH value to 5 with aqueous hydrochloric acid, discard organic phase behind the separatory; After aqueous sodium hydroxide solution adjusting aqueous pH values to 10; With dichloromethane extraction water twice, leave standstill separatory, aqueous phase discarded; Organic phase is again with twice of water washing, saturated common salt water washing suction filtration once and behind anhydrous magnesium sulfate drying; In filtrating, drip saturated ethanol solution of hydrogen chloride, separate out the HA-1077 bullion, this bullion makes the pure article of HA-1077 behind the aqueous ethanolic solution recrystallization.
In preferred embodiment of the present invention, in step (1), the described reaction times is 2-5h.
In preferred embodiment of the present invention; In step (3); The described alkaline reagents that is used to deacidify is salt of wormwood, yellow soda ash, saleratus, sodium hydrogencarbonate, sodium hydroxide, Pottasium Hydroxide, Quilonum Retard, diisopropyl ethylamine, 4-N, TMSDMA N dimethylamine base-pyridine, triethylamine, 1,8-diazabicylo-dicyclo (5; 4,0)-a kind of among 7-hendecene, pyridine or the pyrroles.
In preferred embodiment of the present invention, in step (3), the described alkaline reagents that is used to deacidify is 1-6:1 with the amount of substance ratio of 5-isoquinoline 99.9 SULPHURYL CHLORIDE.
In preferred embodiment of the present invention, in step (4), described aqueous hydrochloric acid pH value is 0.5-1.5.
In preferred embodiment of the present invention, in step (4), described aqueous sodium hydroxide solution pH value is 9-11.
In preferred embodiment of the present invention, in step (4), described aqueous ethanolic solution is the aqueous ethanolic solution of 90%-95%.
The invention has the beneficial effects as follows: the present invention through adding the alkaline reagents that all the other are used to deacidify, can effectively reduce the usage quantity of expensive high piperazine, and then reduce production costs in the reaction that becomes fasudil with the coupling of high piperazine.
Embodiment
A kind of synthetic and preparation method of HA-1077, this preparation method comprises the steps:
(1) at catalyst n, under the condition that dinethylformamide exists, 5-isoquinoline 99.9 sulfonic acid stirs in thionyl chloride, and reflux, and temperature of reaction is 75 ℃-85 ℃, makes 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride;
(2) 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride dissolves with frozen water; Add dichloromethane solution, stir down slowly adding saturated sodium bicarbonate aqueous solution, regulator solution pH value to neutral back separatory; Water once merges organic phase in the back with dichloromethane extraction; This organic phase successively each washing of water and saturated aqueous common salt once, suction filtration behind anhydrous magnesium sulfate drying makes the dichloromethane solution of 5-isoquinoline 99.9 SULPHURYL CHLORIDE;
(3) keeping temperature of reaction system not surpass under 10 ℃; To the dichloromethane solution that high piperazine and the alkaline reagents that is used for deacidifying exist, the dichloromethane solution of slow Dropwise 5-isoquinoline 99.9 SULPHURYL CHLORIDE, the mol ratio of wherein high piperazine and 5-isoquinoline 99.9 SULPHURYL CHLORIDE is 1:1; Finish; Stirring reaction under the room temperature makes six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1 (H)-1, the dichloromethane solution of 4-diazepine;
(4) regulate above-mentioned reacting solution pH value to 5 with aqueous hydrochloric acid, discard organic phase behind the separatory; After aqueous sodium hydroxide solution adjusting aqueous pH values to 10; With dichloromethane extraction water twice, leave standstill separatory, aqueous phase discarded; Organic phase is again with twice of water washing, saturated common salt water washing suction filtration once and behind anhydrous magnesium sulfate drying; In filtrating, drip saturated ethanol solution of hydrogen chloride, separate out the HA-1077 bullion, this bullion makes the pure article of HA-1077 behind the aqueous ethanolic solution recrystallization.
Wherein, in step (1), the described reaction times is 2-5h; In step (3); The described alkaline reagents that is used to deacidify is salt of wormwood, yellow soda ash, saleratus, sodium hydrogencarbonate, sodium hydroxide, Pottasium Hydroxide, Quilonum Retard, diisopropyl ethylamine, 4-N; TMSDMA N dimethylamine base-pyridine, triethylamine, 1; A kind of among 8-diazabicylo-dicyclo (5,4,0)-7-hendecene, pyridine, the pyrroles; In step (3), the described alkaline reagents that is used to deacidify is 1-6:1 with the amount of substance ratio of 5-isoquinoline 99.9 SULPHURYL CHLORIDE; In step (4), described aqueous hydrochloric acid pH value is 0.5-1.5; In step (4), described aqueous sodium hydroxide solution pH value is 9-11; In step (4), described aqueous ethanolic solution is the aqueous ethanolic solution of 90%-95%.
Chemical equation of the present invention is:
Embodiment 1 isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride
Add 5-isoquinoline 99.9 sulfonic acid (20g) successively in the 500mL round bottom single port flask, sulfur oxychloride (200 mL), DMF (10g), back flow reaction 5 hours.Remove unreacted sulfur oxychloride under reduced pressure, obtain yellowing look solid.To wherein adding the 50mL methylene dichloride, suction filtration, filter cake obtain white solid through washed with dichloromethane, after vacuumizing drying, i.e. 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride (22g, 88%).
Embodiment 2 5-isoquinoline 99.9 SULPHURYL CHLORIDEs
(19.4g 73.4mmol) puts in the 1L Erlenmeyer flask that fills the 300mL mixture of ice and water, adds the 150mL methylene dichloride again to get the hydrochloride of embodiment 1 obtained 5-isoquinoline 99.9 SULPHURYL CHLORIDE; Stir down with in the saturated sodium bicarbonate aqueous solution with mixture system pH to 7, the separatory extraction keeps organic phase; Water extracts once with methylene dichloride (50mL) again; Merge organic phase, organic phase makes the dichloromethane solution 200ml of 5-isoquinoline 99.9 SULPHURYL CHLORIDE through anhydrous magnesium sulfate drying half a hour behind the suction filtration.
Embodiment 3 six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1 (H)-1, the preparation of the dichloromethane solution of 4-diazepine (triethylamine is the alkaline reagents of deacidification)
Add successively in the 500mL round bottom single port flask high piperazine (7.36g, 73.4mmol), the alkaline reagents triethylamine (44.5g that is used to deacidify; 440.0mmol), methylene dichloride (100mL) starts magnetic agitation; Dropwise drip the dichloromethane solution (200mL) of the 5-isoquinoline 99.9 SULPHURYL CHLORIDE of embodiment 2 existing systems under the ice bath, per second 2-3 drips, about 1 hour consuming time; Naturally be warming up to room temperature then, stirred overnight is after detection reaction is complete; Get six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1 (H)-1, the dichloromethane solution of 4-diazepine.
The preparation of embodiment 4 HA-1077s
Regulate six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1 (H)-1 of embodiment 3 preparations with aqueous hydrochloric acid; The dichloromethane solution pH value to 5 of 4-diazepine; Separatory keeps water, and water with methylene dichloride (50mL) extraction once; Discard the organic phase that leaves dimer impurity, keep and merge the water product; Regulate upward step gained aqueous pH values to 10 with the aqueous sodium hydroxide solution of 1mol/L,, discard the water of residual high piperazine and pigment impurity, keep the organic phase product with dichloromethane extraction water twice; Using pH value is that 10 aqueous sodium hydroxide washes is washed above-mentioned organic phase twice, and with washing once, saturated common salt is washed once again, organic phase behind anhydrous magnesium sulfate drying, suction filtration.Under stirring, ice bath, in gained filtrating, drip saturated ethanol solution of hydrogen chloride and separate out white solid, make the HA-1077 bullion.At last, the aqueous ethanolic solution recrystallization with 91% makes HA-1077 22g, yield 78% (in the hydrochloride of 5-quinoline sulfuryl chloride), purity 99.9% (HPLC detection).
Embodiment 5 six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1 (H)-1, the preparation of the dichloromethane solution of 4-diazepine (1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene is the alkaline reagents of deacidification)
Add successively in the 500mL round bottom single port flask high piperazine (7.36g, 73.4mmol), the alkaline reagents 1 that is used to deacidify, 8-diazabicylo-dicyclo (5; 4,0)-and the 7-hendecene (66.5g, 437.0mmol), methylene dichloride (100mL); Start magnetic agitation, dropwise drip the dichloromethane solution (200mL) of the 5-isoquinoline 99.9 SULPHURYL CHLORIDE of embodiment 2 existing systems under the ice bath, per second 2-3 drips; About 1 hour consuming time, be warming up to room temperature, stirred overnight then naturally; After detection reaction is complete, get six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1 (H)-1, the dichloromethane solution of 4-diazepine.
The preparation of embodiment 6 HA-1077s
Regulate six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1 (H)-1 of embodiment 5 preparations with aqueous hydrochloric acid; The dichloromethane solution pH value to 5 of 4-diazepine; Separatory keeps water, and water with methylene dichloride (50mL) extraction once; Discard the organic phase that leaves dimer impurity, keep and merge the water product; Regulate upward step gained aqueous pH values to 10 with the aqueous sodium hydroxide solution of 1mol/L,, discard the water of residual high piperazine and pigment impurity, keep the organic phase product with dichloromethane extraction water twice; Using pH value is that 10 aqueous sodium hydroxide washes is washed above-mentioned organic phase twice, and with washing once, saturated common salt is washed once again, organic phase behind anhydrous magnesium sulfate drying, suction filtration.Under stirring, ice bath, in gained filtrating, drip saturated ethanol solution of hydrogen chloride and separate out white solid, make the HA-1077 bullion.At last, the aqueous ethanolic solution recrystallization with 91% makes HA-1077 23g, yield 80% (in the hydrochloride of 5-quinoline sulfuryl chloride), purity 99.9% (HPLC detection).
The above is merely embodiments of the invention; Be not so limit claim of the present invention; Every equivalent structure or equivalent flow process conversion that utilizes description of the present invention to do; Or directly or indirectly be used in other relevant technical fields, all in like manner be included in the scope of patent protection of the present invention.
Claims (7)
1. the synthetic and preparation method of a HA-1077 is characterized in that this preparation method comprises the steps:
(1) at catalyst n, under the condition that dinethylformamide exists, 5-isoquinoline 99.9 sulfonic acid stirs in thionyl chloride, and reflux, and temperature of reaction is 75 ℃-85 ℃, makes 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride;
(2) 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride dissolves with frozen water; Add dichloromethane solution, stir down slowly adding saturated sodium bicarbonate aqueous solution, regulator solution pH value to neutral back separatory; Water once merges organic phase in the back with dichloromethane extraction; This organic phase successively each washing of water and saturated aqueous common salt once, suction filtration behind anhydrous magnesium sulfate drying makes the dichloromethane solution of 5-isoquinoline 99.9 SULPHURYL CHLORIDE;
(3) keeping temperature of reaction system not surpass under 10 ℃; To the dichloromethane solution that high piperazine and the alkaline reagents that is used for deacidifying exist, the dichloromethane solution of slow Dropwise 5-isoquinoline 99.9 SULPHURYL CHLORIDE, the mol ratio of wherein high piperazine and 5-isoquinoline 99.9 SULPHURYL CHLORIDE is 1:1; Finish; Stirring reaction under the room temperature makes six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1 (H)-1, the dichloromethane solution of 4-diazepine;
(4) regulate above-mentioned reacting solution pH value to 5 with aqueous hydrochloric acid, discard organic phase behind the separatory; After aqueous sodium hydroxide solution adjusting aqueous pH values to 10; With dichloromethane extraction water twice, leave standstill separatory, aqueous phase discarded; Organic phase is again with twice of water washing, saturated common salt water washing suction filtration once and behind anhydrous magnesium sulfate drying; In filtrating, drip saturated ethanol solution of hydrogen chloride, separate out the HA-1077 bullion, this bullion makes the pure article of HA-1077 behind the aqueous ethanolic solution recrystallization.
2. the synthetic and preparation method of HA-1077 according to claim 1 is characterized in that in step (1), the described reaction times is 2-5h.
3. HA-1077 according to claim 1 synthesizes and the preparation method; It is characterized in that in step (3), the described alkaline reagents that is used to deacidify is salt of wormwood, yellow soda ash, saleratus, sodium hydrogencarbonate, sodium hydroxide, Pottasium Hydroxide, Quilonum Retard, diisopropyl ethylamine, 4-N; TMSDMA N dimethylamine base-pyridine, triethylamine, 1; A kind of among 8-diazabicylo-dicyclo (5,4,0)-7-hendecene, pyridine or the pyrroles.
4. the synthetic and preparation method of HA-1077 according to claim 1 is characterized in that, in step (3), the described alkaline reagents that is used to deacidify is 1-6:1 with the amount of substance ratio of 5-isoquinoline 99.9 SULPHURYL CHLORIDE.
5. the synthetic and preparation method of HA-1077 according to claim 1 is characterized in that in step (4), described aqueous hydrochloric acid pH value is 0.5-1.5.
6. the synthetic and preparation method of HA-1077 according to claim 1 is characterized in that in step (4), described aqueous sodium hydroxide solution pH value is 9-11.
7. the synthetic and preparation method of HA-1077 according to claim 1 is characterized in that in step (4), described aqueous ethanolic solution is the aqueous ethanolic solution of 90%-95%.
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| CN103450157A (en) * | 2013-08-28 | 2013-12-18 | 合肥久诺医药科技有限公司 | Preparation method for high-purity hydroxyfasudil semihydrate |
| 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 |
| CN103724263A (en) * | 2013-12-13 | 2014-04-16 | 武汉武药制药有限公司 | Preparation method of quinoline-5-sulfonyl chloride |
| 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 |
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| CN113358762A (en) * | 2020-03-05 | 2021-09-07 | 昆药集团股份有限公司 | Method for detecting related substances in 5-isoquinoline sulfonyl chloride hydrochloride |
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| 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 |
| CN103724263A (en) * | 2013-12-13 | 2014-04-16 | 武汉武药制药有限公司 | Preparation method of quinoline-5-sulfonyl chloride |
| 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 |
| CN103724263B (en) * | 2013-12-13 | 2015-11-18 | 武汉武药制药有限公司 | A kind of preparation method of isoquinoline 99.9-5-SULPHURYL CHLORIDE |
| 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 |
| CN109557205A (en) * | 2018-11-30 | 2019-04-02 | 成都倍特药业有限公司 | The method of homopiperazine is detected from Fasudic hydrochloride |
| CN109557205B (en) * | 2018-11-30 | 2021-10-29 | 成都倍特药业股份有限公司 | Method for detecting homopiperazine from fasudil hydrochloride |
| CN113358762A (en) * | 2020-03-05 | 2021-09-07 | 昆药集团股份有限公司 | Method for detecting related substances in 5-isoquinoline sulfonyl chloride hydrochloride |
| CN113358762B (en) * | 2020-03-05 | 2023-04-07 | 昆药集团股份有限公司 | Method for detecting related substances in 5-isoquinoline sulfonyl chloride hydrochloride |
| CN111303120A (en) * | 2020-03-14 | 2020-06-19 | 江巨东 | Preparation 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 using BTC/Ph3PO chlorination system |
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