CN112592348B - Preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine - Google Patents
Preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine Download PDFInfo
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- CN112592348B CN112592348B CN202011514150.6A CN202011514150A CN112592348B CN 112592348 B CN112592348 B CN 112592348B CN 202011514150 A CN202011514150 A CN 202011514150A CN 112592348 B CN112592348 B CN 112592348B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention relates to a preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, in particular to a preparation method which takes 1-amino-1H-pyrrole-2-carbonitrile hydrochloride and thiourea as raw materials and efficiently synthesizes the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine through two steps of cyclization reaction and desulfurization reaction.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine.
Background
4-aminopyrrolo [2,1-f ] [1,2,4] triazine is a key intermediate of the drug Reidesvir. The antiviral drug Reidevir approved by the United states Food and Drug Administration (FDA) for Jilide science is used for treating Xinguan inpatients in 22/10/2020, and becomes the first officially approved Xinguan therapeutic drug in the United states.
The current general synthetic route for the synthesis of 4-aminopyrrolo [2,1-f ] [1,2,4] triazines is as follows:
EP1945222B1 reports a process for the synthesis of 4-aminopyrrolo [2,1-f ] [1,2,4] triazines, the route being as follows:
the method takes 1-amino-1H-pyrrole-2-carbonitrile hydrochloride and formamidine acetate as raw materials, and synthesizes 4-amino pyrrolo [2,1-f ] [1,2,4] triazine through cyclization reaction. The method has the problems of high cost, poor product purity and chromaticity and large waste liquid amount.
Disclosure of Invention
The invention relates to a preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, in particular to a preparation method which takes 1-amino-1H-pyrrole-2-carbonitrile hydrochloride and thiourea as raw materials and efficiently synthesizes the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine through two steps of cyclization reaction and desulfurization reaction.
The reaction equation is as follows:
the invention provides a preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, which specifically comprises the following steps:
(1) adding ethanol and alkali into a reaction bottle, starting stirring, adding 1-amino-1H-pyrrole-2-carbonitrile hydrochloride and thiourea, heating for reaction, and performing central control tracking. After the reaction is finished, concentrating ethanol, adding water into the residual liquid, stirring and filtering to obtain an intermediate 1.
(2) Adding Raney nickel and water into a reaction bottle, starting stirring, adding ammonia water and the intermediate 1, heating for reaction, and carrying out central control tracking. After the reaction is finished, filtering while the solution is hot, adding ethanol into a filter cake, stirring, filtering, and spin-drying the filtrate to obtain the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine.
In the step (1), the alkali is one of potassium carbonate, sodium ethoxide and sodium hydroxide.
The temperature rise temperature in the step (1) of the invention is 30-80 ℃.
The molar ratio of the 1-amino-1H-pyrrole-2-carbonitrile hydrochloride to thiourea in step (1) of the present invention is 1: 1-1: 2.
in the step (2) of the invention, the mass ratio of the ammonia water to the intermediate 1 is 3: 1-10: 1.
in the step (2), the mass ratio of the raney nickel to the intermediate 1 is 1: 1-3: 1.
in the step (2), the temperature rise is 50-100 ℃.
The preparation method has the advantages that:
1) the cost is low, and the yield is high;
2) the three wastes are less;
3) the product obtained by the process has good quality;
4) is beneficial to industrial production.
Detailed Description
Example 1
A preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine specifically comprises the following steps:
(1) adding 500ml of ethanol and 212g of potassium carbonate into a reaction bottle, starting stirring, adding 100g of 1-amino-1H-pyrrole-2-carbonitrile hydrochloride and 53g of thiourea, heating to 80 ℃ for reaction, and carrying out central control tracking. After the reaction was completed, ethanol was concentrated to about 80%, and the residue was stirred with 600ml of water, followed by filtration to obtain 99.8g of intermediate 1 with a yield of 86%.
(2) Adding 100g of Raney nickel and 500ml of water into a reaction bottle, starting stirring, adding 1000ml of 20% ammonia water and 99g of intermediate 1, heating to 100 ℃ for reaction, and carrying out central control tracking. After the reaction is finished, the temperature is reduced to room temperature for filtration, 500ml of ethanol is added into a filter cake for stirring, the filtration is carried out, and 74g of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine is obtained after the filtrate is dried by spinning, with the yield of 93%.
Example 2
(1) Adding 900ml of ethanol and 382g of sodium hydroxide into a reaction bottle, starting stirring, adding 180g of 1-amino-1H-pyrrole-2-carbonitrile hydrochloride and 190g of thiourea, heating to 30 ℃ for reaction, and carrying out central control tracking. After the reaction was completed, ethanol was concentrated to about 80%, and the residue was stirred with 110ml of water, followed by filtration to obtain 175g of intermediate 1 with a yield of 84%.
(2) Adding 170g of Raney nickel and 850ml of water into a reaction bottle, starting stirring, adding 510ml of 20% ammonia water and 170g of intermediate 1, heating to 50 ℃ for reaction, and carrying out central control tracking. After the reaction is finished, the temperature is reduced to room temperature for filtration, 850ml of ethanol is added into a filter cake for stirring, the filtration is carried out, and 125g of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine is obtained after the filtrate is dried by spinning, with the yield of 92%.
1H-NMR(CD3OD):δ7.72（s，1H），7.52（dd，1H，J=2.5,1.6Hz），6.85（dd，1H，J=4.5,1.6Hz），6.64（dd，1H,J=4.5,2.7Hz）
The invention has been described in detail in order to avoid obscuring the invention and to enable practice of the same in the various embodiments of the invention, and all changes and modifications that come within the spirit of the invention are desired to be protected.
Claims (7)
1. A preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine is characterized in that: the method specifically comprises the following steps:
adding ethanol and alkali into a reaction bottle, starting stirring, adding 1-amino-1H-pyrrole-2-carbonitrile hydrochloride and thiourea, heating for reaction, and performing central control tracking; after the reaction is finished, concentrating ethanol, adding water into the residual liquid, stirring, and filtering to obtain an intermediate 1;
adding Raney nickel and water into a reaction bottle, starting stirring, adding ammonia water and the intermediate 1, heating for reaction, and carrying out central control tracking; after the reaction is finished, filtering while the solution is hot, adding ethanol into a filter cake, stirring, filtering, and spin-drying the filtrate to obtain the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine.
2. A process for the preparation of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, characterized in that: in the step (1), the alkali is one of potassium carbonate, sodium ethoxide and sodium hydroxide.
3. A process for the preparation of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, characterized in that: the temperature rise temperature in the step (1) is 30-80 ℃.
4. A process for the preparation of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, characterized in that: the mol ratio of the 1-amino-1H-pyrrole-2-carbonitrile hydrochloride to the thiourea in the step (1) is 1: 1-1: 2.
5. a process for the preparation of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, characterized in that: in the step (2), the mass ratio of the ammonia water to the intermediate 1 is 3: 1-10: 1.
6. a process for the preparation of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, characterized in that: in the step (2), the mass ratio of the raney nickel to the intermediate 1 is 1: 1-3: 1.
7. a process for the preparation of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, characterized in that: in the step (2), the temperature rise is 50-100 ℃.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102015714A (en) * | 2008-04-23 | 2011-04-13 | 吉里德科学公司 | 1' -substituted CARBA-nucleoside analogs for antiviral treatment |
| AU2016250419A1 (en) * | 2008-04-23 | 2016-11-17 | Gilead Sciences, Inc. | 1' -substituted carba-nucleoside analogs for antiviral treatment |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2313102A2 (en) * | 2008-07-03 | 2011-04-27 | Biota Scientific Management | Bycyclic nucleosides and nucleotides as therapeutic agents |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102015714A (en) * | 2008-04-23 | 2011-04-13 | 吉里德科学公司 | 1' -substituted CARBA-nucleoside analogs for antiviral treatment |
| AU2016250419A1 (en) * | 2008-04-23 | 2016-11-17 | Gilead Sciences, Inc. | 1' -substituted carba-nucleoside analogs for antiviral treatment |
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