CN103724263B - A kind of preparation method of isoquinoline 99.9-5-SULPHURYL CHLORIDE - Google Patents
A kind of preparation method of isoquinoline 99.9-5-SULPHURYL CHLORIDE Download PDFInfo
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- CN103724263B CN103724263B CN201310680560.1A CN201310680560A CN103724263B CN 103724263 B CN103724263 B CN 103724263B CN 201310680560 A CN201310680560 A CN 201310680560A CN 103724263 B CN103724263 B CN 103724263B
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- isoquinoline
- sulphuryl chloride
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- aminoisoquinoline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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Abstract
The present invention relates to a kind of preparation method of medicine intermediate isoquinoline 99.9-5-SULPHURYL CHLORIDE, with 5-aminoisoquinoline for raw material and Sodium Nitrite and concentrated hydrochloric acid carry out diazotization reaction, again the diazo solution obtained and sulfurous gas are carried out sulfonating chlorinating in acetate solvate and obtain isoquinoline 99.9-5-SULPHURYL CHLORIDE, this reaction only needs a step can obtain isoquinoline 99.9-5-SULPHURYL CHLORIDE.Process of the present invention is simple, and easy to operate, raw material is cheap to be easy to get, and environmental pollution is comparatively light, and yield reaches more than 80%, is more suitable for suitability for industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of preparation method of medicine intermediate isoquinoline 99.9-5-SULPHURYL CHLORIDE.
Background technology
Isoquinoline 99.9-5-SULPHURYL CHLORIDE is colourless liquid, and chemical formula is C
9h
6clNO
2s, molecular weight is 227.7, and boiling point is 371.2 DEG C, is the important intermediate of synthetic hydrochloric acid fasudil.Fasudil Hydrochloride is RHO kinase inhibitor, and by increasing the activity of Myosin light chain phosphatase, vasodilation reduces the tension force of endotheliocyte, improves cerebral tissue microcirculation, simultaneously can antagonism inflammatory factor, and neuroprotective anti-apoptotic, promotes neurotization.
Japanese Patent JP11158177, JP11171885, Chinese patent CN102020636A etc. synthesize isoquinoline 99.9-5-SULPHURYL CHLORIDE and still adopt traditional synthesis mode, take isoquinoline 99.9 as raw material, through sulfuric acid salify, react with oleum again and generate 5-isoquinoline 99.9 sulfonic acid, be finally obtained by reacting isoquinoline 99.9-5-SULPHURYL CHLORIDE with sulfur oxychloride again.Synthesis equation is as follows:
But the method route is longer, and last handling process is loaded down with trivial details, raw material oleum, sulfur oxychloride belongs to strongly-acid material, expensive, and produces more spent acid contaminate environment, is not suitable for suitability for industrialized production.
Summary of the invention
The present invention is directed to the deficiency of existing technique, provide a kind of raw material and be easy to get, cost is lower, and reaction process is simple, the preparation method of the isoquinoline 99.9-5-SULPHURYL CHLORIDE of applicable suitability for industrialized production of reduced contamination.
Concrete technical scheme of the present invention is as follows:
A preparation method for medicine intermediate isoquinoline 99.9-5-SULPHURYL CHLORIDE, comprises the steps:
(1) 5-aminoisoquinoline adds in concentrated hydrochloric acid, is cooled to-10 DEG C, drips sodium nitrite solution and carry out diazotization reaction at temperature control-10 DEG C ~ 10 DEG C, and it is for subsequent use that reaction end obtains diazotization liquid.
(2) sulfurous gas is passed in acetate solvate at the temperature of 10 DEG C ~ 25 DEG C, pass into complete, add catalyzer, drip diazo solution, reaction terminates rear dichloromethane extraction, organic phase washing twice, drying, namely removed under reduced pressure acetic acid obtain isoquinoline 99.9-5-SULPHURYL CHLORIDE.
5-aminoisoquinoline described in step (1) and Sodium Nitrite weight ratio be 1 ︰ 0.3 ~ 0.8; The weightmeasurement ratio of 5-aminoisoquinoline and concentrated hydrochloric acid and acetic acid is 1 ︰ 14 ~ 16 ︰ 15 ~ 18.
Carry out under the sulfonating chlorinating reaction described in step (2) is existence at copper chloride catalyst, cupric chloride is after by sulfurous gas, adds before dripping diazo solution.
The present invention synthesizes equation and is shown below:
Technical solution of the present invention tool has the following advantages:
(1) route of the present invention shortens, and process is simple, and easy to operate, the reaction times shortens greatly.
(2) the present invention avoids using expensive oleum, and cost is lower.
(3) environmental pollution of the present invention is comparatively light, meets the theory of green chemical industry, is more suitable for suitability for industrialized production.
Embodiment
Embodiment 1
The concentrated hydrochloric acid of 38.7g5-aminoisoquinoline 590mL is added in the reaction flask of 1000mL, less than 0 DEG C is cooled under stirring, drip the nitrous acid aqueous solution (Sodium Nitrite containing 22g) of 100mL, temperature controls at 0 DEG C ~ 10 DEG C, after dropwising, it is for subsequent use that continuation insulation reaction 1h obtains diazo solution.
The acetic acid of 650mL is added in the reaction flask of another 2000mL, temperature control 10 DEG C ~ 20 DEG C passes into sulfurous gas to saturated, then adds the Cupric Chloride Solution (containing cupric chloride 8.7g) of 80mL, then drips above-mentioned diazo solution, after dripping off, reaction is spent the night, with the dichloromethane extraction of 2 × 500mL, and organic layer washing twice, dry, desolvation acetic acid, obtains the 5-isoquinoline sulfonyl chloride of 42.8g, yield 70.3%
Embodiment 2
The concentrated hydrochloric acid of 38.7g5-aminoisoquinoline 590mL is added in the reaction flask of 1000mL, less than-5 DEG C are cooled under stirring, drip the nitrous acid aqueous solution (Sodium Nitrite containing 22g) of 100mL, temperature controls at-5 DEG C ~ 5 DEG C, after dropwising, it is for subsequent use that continuation insulation reaction 1h obtains diazo solution.
The acetic acid of 650mL is added in the reaction flask of another 2000mL, temperature control 10 DEG C ~ 20 DEG C passes into sulfurous gas to saturated, then adds the Cupric Chloride Solution (containing cupric chloride 8.7g) of 80mL, then drips above-mentioned diazo solution, after dripping off, reaction is spent the night, with the dichloromethane extraction of 2 × 500mL, and organic layer washing twice, dry, desolvation acetic acid, obtains the 5-isoquinoline sulfonyl chloride of 46.8g, yield 76.8%
Embodiment 3
The concentrated hydrochloric acid of 77.4g5-aminoisoquinoline 1180mL is added in the reaction flask of 2000mL, less than-10 DEG C are cooled under stirring, drip the nitrous acid aqueous solution (Sodium Nitrite containing 44g) of 200mL, temperature controls at-10 DEG C ~ 0 DEG C, after dropwising, it is for subsequent use that continuation insulation reaction 1h obtains diazo solution.
The acetic acid of 1300mL is added in the reaction flask of another 5000mL, temperature control 10 DEG C ~ 20 DEG C passes into sulfurous gas to saturated, then adds the Cupric Chloride Solution (containing cupric chloride 17.4g) of 160mL, then drips above-mentioned diazo solution, after dripping off, reaction is spent the night, with the dichloromethane extraction of 2 × 1000mL, and organic layer washing twice, dry, desolvation acetic acid, obtains the 5-isoquinoline sulfonyl chloride of 102.1g, yield 83.7%.
Claims (2)
1. a preparation method for medicine intermediate isoquinoline 99.9-5-SULPHURYL CHLORIDE, comprises the steps:
(1) with 5-aminoisoquinoline for raw material and Sodium Nitrite and concentrated hydrochloric acid carry out diazotization reaction, the diazo solution obtained; In step (1) 5-aminoisoquinoline and Sodium Nitrite weight ratio be 1 ︰ 0.3 ~ 0.8; The weightmeasurement ratio of 5-aminoisoquinoline and concentrated hydrochloric acid and acetic acid is 1 ︰ 14 ~ 16 ︰ 15 ~ 18;
(2) in the presence of a catalyst, diazo solution and sulfurous gas carry out sulfonating chlorinating in acetate solvate, and reaction terminates rear dichloromethane extraction, and organic phase is washed, and dry, namely removed under reduced pressure acetic acid obtain isoquinoline 99.9-5-SULPHURYL CHLORIDE; Described sulfonating chlorinating reaction is what to carry out under the existence of copper chloride catalyst; Cupric chloride is after logical sulfurous gas, adds before dripping diazo solution.
2. preparation method according to claim 1, is characterized in that: in step (1), diazotization reaction temperature is-10 DEG C ~ 10 DEG C.
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| CN103724263A CN103724263A (en) | 2014-04-16 |
| CN103724263B true CN103724263B (en) | 2015-11-18 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020636A (en) * | 2010-11-25 | 2011-04-20 | 江苏万邦生化医药股份有限公司 | Method for synthesizing and purifying Fasudil hydrochloride |
| CN102603715A (en) * | 2012-03-31 | 2012-07-25 | 苏州工业园区南华生物科技有限公司 | Synthesis and preparation method of fasudil hydrochloride |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020636A (en) * | 2010-11-25 | 2011-04-20 | 江苏万邦生化医药股份有限公司 | Method for synthesizing and purifying Fasudil hydrochloride |
| CN102603715A (en) * | 2012-03-31 | 2012-07-25 | 苏州工业园区南华生物科技有限公司 | Synthesis and preparation method of fasudil hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| (Arylsulfonyl)acetones and -acetonitriles: New Activated Methylenic Building Blocks for Synthesis of 1,2,3-Triazoles;Nazariy T,et al.;《Synthesis》;20090529(第14期);2321-2323 * |
| m-TRIFLUOROMETHYLBENZENESULFONYL CHLORIDE;R. V. Hoffman;《Organic Syntheses, Coll.》;19901231;第7卷;508 * |
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