CN112047884A - Synthesis method of 4-fluoroisoquinoline sulfate - Google Patents
Synthesis method of 4-fluoroisoquinoline sulfate Download PDFInfo
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- CN112047884A CN112047884A CN202010953645.2A CN202010953645A CN112047884A CN 112047884 A CN112047884 A CN 112047884A CN 202010953645 A CN202010953645 A CN 202010953645A CN 112047884 A CN112047884 A CN 112047884A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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Abstract
The invention discloses a synthesis method of 4-fluoroisoquinoline sulfate, which comprises the following steps: s1: putting 1-bromoisoquinoline, NFSI reagent and acetonitrile into a reaction kettle, fully and uniformly stirring, and then starting the reaction kettle to enable the reaction temperature to be about 60-65 ℃, wherein the reaction time is set to be 6-24 h; after the reaction is finished, the organic solvent in the reaction solution is dried by a vacuum rotary dryer, water is added into the reaction solution, dichloromethane is used for aqueous phase extraction, and organic phases are combined; and then adjusting the pH value of the organic phase by using a sodium bicarbonate solution, washing the organic phase by using a sodium chloride solution after the adjustment is finished, and performing vacuum spin-drying on the organic phase by using a vacuum rotary dryer to synthesize the 1-bromo-4-fluoroisoquinoline. The method has reasonable design, can shorten the preparation steps of the isoquinoline compounds, can improve the production synthesis efficiency of the isoquinoline compounds, and further meets the market demand.
Description
Technical Field
The invention relates to the technical field of sulfate preparation, in particular to a synthesis method of 4-fluoroisoquinoline sulfate.
Background
At present, with the continuous development of economic level, the development of each industry is very rapid, isoquinoline compounds are very important compounds in alkaloids, and have remarkable physiological activity and wide application prospect, the isoquinoline alkaloids can respectively play an anti-tumor role from different mechanisms such as alkylation, receptor regulation, anti-apoptosis genes inhibition, angiogenesis inhibition and the like, isoquinoline plays a great role in medicaments, such as narcotics, antihypertensive medicaments, antifungal medicaments, vasodilators and the like, and the isoquinoline compounds can also be used for manufacturing dyes, paints, insecticides, preservatives and disinfectants;
with the annual increase of market demand, the traditional preparation and synthesis methods of isoquinoline compounds gradually show the disadvantages, such as more synthesis steps and low production efficiency, and therefore, a synthesis method of 4-fluoroisoquinoline sulfate is designed to solve the problems.
Disclosure of Invention
The invention aims to solve the problems in the prior art, and provides a method for synthesizing 4-fluoroisoquinoline sulfate, which can shorten the preparation steps of isoquinoline compounds, improve the production synthesis efficiency and further meet the market demand.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing 4-fluoroisoquinoline sulfate comprises the following steps:
s1: putting 1-bromoisoquinoline, NFSI reagent and acetonitrile into a reaction kettle, fully and uniformly stirring, and then starting the reaction kettle to enable the reaction temperature to be about 60-65 ℃, wherein the reaction time is set to be 6-24 h; after the reaction is finished, the organic solvent in the reaction solution is dried by a vacuum rotary dryer, water is added into the reaction solution, dichloromethane is used for aqueous phase extraction, and organic phases are combined; regulating the pH value of the organic phase by using a sodium bicarbonate solution, washing the organic phase by using a sodium chloride solution after the regulation is finished, and performing vacuum spin-drying on the organic phase by using a vacuum rotary dryer to synthesize the 1-bromo-4-fluoroisoquinoline;
s2: preparing a reaction kettle again, performing hydrogen replacement work on the interior of the reaction kettle for 3-6 times, dissolving 1-bromo-4-fluoroisoquinoline in methanol, then putting the methanol into the reaction kettle, adding a catalyst and an alkali aqueous solution, starting the reaction kettle to enable the reaction temperature to be 20-30 ℃, and setting the reaction time to be 6-54 h; after the reaction is finished, filtering out the catalyst by using a suction filtration device, spin-drying an organic solvent in a reaction solution by using a vacuum rotary dryer, performing water-phase extraction by using dichloromethane, combining organic phases, washing the organic phases by using water, purifying by using silica gel, and spin-drying the dichloromethane by using the vacuum rotary dryer to synthesize 4-fluoroisoquinoline;
s3: dissolving 4-fluoroisoquinoline in acetone, putting the acetone into a reaction device, starting a refrigerating device and the reaction device to enable the reaction temperature to be-5-5 ℃, dropwise adding sulfuric acid by using a constant-pressure titration funnel, and setting the reaction time to be 2-5h after the dropwise adding is finished, thus synthesizing the 4-fluoroisoquinoline sulfate.
Preferably, in the S1, the molar ratio of the 1-bromoisoquinoline to the acetonitrile is 1 (10-20).
Preferably, in the S1, the molar ratio of the 1-bromoisoquinoline to the NFSI reagent is 1: (2.0-2.3).
Preferably, in the S3, the molar ratio of the 4-fluoroisoquinoline to the sulfuric acid is 1 (1.05-1.10).
Compared with the prior art, the invention has the beneficial effects that:
the preparation raw materials in the application are low in price, excessive raw material cost is avoided, and the raw materials can be easily purchased in the market; compared with the preparation process in the prior art, the preparation method has fewer steps and is convenient to operate; after preparation, the recovery rate of the production raw materials is high, and the waste of the raw materials is reduced.
Detailed Description
The following will clearly and completely describe the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments.
Example 1
A method for synthesizing 4-fluoroisoquinoline sulfate comprises the following steps:
s1: putting 1-bromoisoquinoline, NFSI reagent and acetonitrile into a reaction kettle, fully and uniformly stirring, starting the reaction kettle to enable the reaction temperature to be about 60 ℃, and setting the reaction time to be 6 hours; after the reaction is finished, the organic solvent in the reaction solution is dried by a vacuum rotary dryer, water is added into the reaction solution, dichloromethane is used for aqueous phase extraction, and organic phases are combined; and then the pH value of the organic phase is regulated by sodium bicarbonate solution, after the regulation is finished, the organic phase is washed by sodium chloride solution, and then the vacuum rotary dryer is used for carrying out vacuum rotary drying on the organic phase, so that the 1-bromo-4-fluoroisoquinoline can be synthesized, wherein the molar ratio of the 1-bromoisoquinoline to acetonitrile is 1:10, and the molar ratio of the 1-bromoisoquinoline to the NFSI reagent is 1: 2.0;
s2: preparing a reaction kettle again, performing hydrogen replacement work on the interior of the reaction kettle for 3 times, dissolving 1-bromo-4-fluoroisoquinoline in methanol, then putting the methanol into the reaction kettle, adding a catalyst and an alkali aqueous solution, starting the reaction kettle to enable the reaction temperature to be 20 ℃, and setting the reaction time to be 6 hours; after the reaction is finished, filtering out the catalyst by using a suction filtration device, spin-drying an organic solvent in a reaction solution by using a vacuum rotary dryer, performing water-phase extraction by using dichloromethane, combining organic phases, washing the organic phases by using water, purifying by using silica gel, and spin-drying the dichloromethane by using the vacuum rotary dryer to synthesize 4-fluoroisoquinoline;
s3: dissolving 4-fluoroisoquinoline in acetone, putting the acetone into a reaction device, starting a refrigerating device and the reaction device to enable the reaction temperature to be at-5 ℃, dropwise adding sulfuric acid by using a constant-pressure titration funnel, and after dropwise adding, setting the reaction time to be 2h and the molar ratio of 4-fluoroisoquinoline to sulfuric acid to be 1:1.05 to synthesize the 4-fluoroisoquinoline sulfate.
Example 2
A method for synthesizing 4-fluoroisoquinoline sulfate comprises the following steps:
s1: putting 1-bromoisoquinoline, an NFSI reagent and acetonitrile into a reaction kettle, fully and uniformly stirring, starting the reaction kettle to enable the reaction temperature to be about 62 ℃, and setting the reaction time to be 12 hours; after the reaction is finished, the organic solvent in the reaction solution is dried by a vacuum rotary dryer, water is added into the reaction solution, dichloromethane is used for aqueous phase extraction, and organic phases are combined; and then the pH value of the organic phase is regulated by sodium bicarbonate solution, after the regulation is finished, the organic phase is washed by sodium chloride solution, and then the vacuum rotary dryer is used for carrying out vacuum rotary drying on the organic phase, so that the 1-bromo-4-fluoroisoquinoline can be synthesized, wherein the molar ratio of the 1-bromoisoquinoline to acetonitrile is 1:12, and the molar ratio of the 1-bromoisoquinoline to the NFSI reagent is 1: 2.1;
s2: preparing a reaction kettle again, performing hydrogen replacement work on the interior of the reaction kettle for 4 times, dissolving 1-bromo-4-fluoroisoquinoline in methanol, then putting the methanol into the reaction kettle, adding a catalyst and an alkali aqueous solution, starting the reaction kettle to enable the reaction temperature to be 22 ℃, and setting the reaction time to be 12 hours; after the reaction is finished, filtering out the catalyst by using a suction filtration device, spin-drying an organic solvent in a reaction solution by using a vacuum rotary dryer, performing water-phase extraction by using dichloromethane, combining organic phases, washing the organic phases by using water, purifying by using silica gel, and spin-drying the dichloromethane by using the vacuum rotary dryer to synthesize 4-fluoroisoquinoline;
s3: dissolving 4-fluoroisoquinoline in acetone, putting the acetone into a reaction device, starting a refrigerating device and the reaction device to enable the reaction temperature to be at 0 ℃, dropwise adding sulfuric acid by using a constant-pressure titration funnel, and after dropwise adding, setting the reaction time to be 3h and the molar ratio of 4-fluoroisoquinoline to sulfuric acid to be 1:1.07 to synthesize the 4-fluoroisoquinoline sulfate.
Example 3
A method for synthesizing 4-fluoroisoquinoline sulfate comprises the following steps:
s1: putting 1-bromoisoquinoline, an NFSI reagent and acetonitrile into a reaction kettle, fully and uniformly stirring, starting the reaction kettle to enable the reaction temperature to be about 65 ℃, and setting the reaction time to be 24 hours; after the reaction is finished, the organic solvent in the reaction solution is dried by a vacuum rotary dryer, water is added into the reaction solution, dichloromethane is used for aqueous phase extraction, and organic phases are combined; and then the pH value of the organic phase is regulated by sodium bicarbonate solution, after the regulation is finished, the organic phase is washed by sodium chloride solution, and then the vacuum rotary dryer is used for carrying out vacuum rotary drying on the organic phase, so that the 1-bromo-4-fluoroisoquinoline can be synthesized, wherein the molar ratio of the 1-bromoisoquinoline to acetonitrile is 1:20, and the molar ratio of the 1-bromoisoquinoline to the NFSI reagent is 1: 2.3;
s2: preparing a reaction kettle again, performing hydrogen replacement work on the interior of the reaction kettle for 6 times, dissolving 1-bromo-4-fluoroisoquinoline in methanol, then putting the methanol into the reaction kettle, adding a catalyst and an alkali aqueous solution, starting the reaction kettle to enable the reaction temperature to be 30 ℃, and setting the reaction time to be 54 hours; after the reaction is finished, filtering out the catalyst by using a suction filtration device, spin-drying an organic solvent in a reaction solution by using a vacuum rotary dryer, performing water-phase extraction by using dichloromethane, combining organic phases, washing the organic phases by using water, purifying by using silica gel, and spin-drying the dichloromethane by using the vacuum rotary dryer to synthesize 4-fluoroisoquinoline;
s3: dissolving 4-fluoroisoquinoline in acetone, putting the acetone into a reaction device, starting a refrigerating device and the reaction device to enable the reaction temperature to be at 5 ℃, dropwise adding sulfuric acid by using a constant-pressure titration funnel, and after dropwise adding, setting the reaction time to be 5h and the molar ratio of 4-fluoroisoquinoline to sulfuric acid to be 1:1.10 to synthesize the 4-fluoroisoquinoline sulfate.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (4)
1. A method for synthesizing 4-fluoroisoquinoline sulfate is characterized by comprising the following steps:
s1: putting 1-bromoisoquinoline, NFSI reagent and acetonitrile into a reaction kettle, fully and uniformly stirring, and then starting the reaction kettle to enable the reaction temperature to be about 60-65 ℃, wherein the reaction time is set to be 6-24 h; after the reaction is finished, the organic solvent in the reaction solution is dried by a vacuum rotary dryer, water is added into the reaction solution, dichloromethane is used for aqueous phase extraction, and organic phases are combined; regulating the pH value of the organic phase by using a sodium bicarbonate solution, washing the organic phase by using a sodium chloride solution after the regulation is finished, and performing vacuum spin-drying on the organic phase by using a vacuum rotary dryer to synthesize the 1-bromo-4-fluoroisoquinoline;
s2: preparing a reaction kettle again, performing hydrogen replacement work on the interior of the reaction kettle for 3-6 times, dissolving 1-bromo-4-fluoroisoquinoline in methanol, then putting the methanol into the reaction kettle, adding a catalyst and an alkali aqueous solution, starting the reaction kettle to enable the reaction temperature to be 20-30 ℃, and setting the reaction time to be 6-54 h; after the reaction is finished, filtering out the catalyst by using a suction filtration device, spin-drying an organic solvent in a reaction solution by using a vacuum rotary dryer, performing water-phase extraction by using dichloromethane, combining organic phases, washing the organic phases by using water, purifying by using silica gel, and spin-drying the dichloromethane by using the vacuum rotary dryer to synthesize 4-fluoroisoquinoline;
s3: dissolving 4-fluoroisoquinoline in acetone, putting the acetone into a reaction device, starting a refrigerating device and the reaction device to enable the reaction temperature to be-5-5 ℃, dropwise adding sulfuric acid by using a constant-pressure titration funnel, and setting the reaction time to be 2-5h after the dropwise adding is finished, thus synthesizing the 4-fluoroisoquinoline sulfate.
2. The method for synthesizing 4-fluoroisoquinoline sulfate according to claim 1, wherein in S1, the molar ratio of 1-bromoisoquinoline to acetonitrile is 1 (10-20).
3. The method for synthesizing 4-fluoroisoquinoline sulfate according to claim 1, wherein in the S1, the molar ratio of the 1-bromoisoquinoline to the NFSI reagent is 1: (2.0-2.3).
4. The method for synthesizing 4-fluoroisoquinoline sulfate according to claim 1, wherein in S3, the molar ratio of 4-fluoroisoquinoline to sulfuric acid is 1 (1.05-1.10).
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090209765A1 (en) * | 2005-02-25 | 2009-08-20 | Kowa Co., Ltd. | Process for production of 4-fluoroisoquinoline-5-sulfonyl halide or salt thereof |
| CN108558758A (en) * | 2018-04-12 | 2018-09-21 | 苏州康润医药有限公司 | A kind of synthetic method of 4- fluorine isoquinolin -5- amine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090209765A1 (en) * | 2005-02-25 | 2009-08-20 | Kowa Co., Ltd. | Process for production of 4-fluoroisoquinoline-5-sulfonyl halide or salt thereof |
| CN108558758A (en) * | 2018-04-12 | 2018-09-21 | 苏州康润医药有限公司 | A kind of synthetic method of 4- fluorine isoquinolin -5- amine |
Non-Patent Citations (3)
| Title |
|---|
| DAVID A. PRICE ET AL.: "Selective fluorination of 1-hydroxyisoquinolines using SelectfluorTM", 《TETRAHEDRON LETTERS》, 10 August 2007 (2007-08-10), pages 7371 - 7373 * |
| MICHAEL BECH SOMMER ET AL.: "Application of (2-Cyanoaryl)arylacetonitriles in Cyclization and Annulation Reactions. Preparation of 3-Arylindans,4-Aryl-3,4-dihydronaphthalenes, 4-Arylisoquinolines, 1 -Aminonaphthalenes,and Heterocyclic Analogues", 《J.ORG.CHEM.》, 31 December 1990 (1990-12-31), pages 4822 - 4827 * |
| YANJUN WAN ET AL.: "Aminoisoquinolines as colorimetric Hg2+ sensors: the importance of molecular structure and sacrificial base", 《TETRAHEDRON》, 27 March 2009 (2009-03-27), pages 4293 - 4297 * |
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Application publication date: 20201208 |