CN113234030A - Preparation method of 6-bromo-3-hydroxy-2-pyrazinecarboxamide - Google Patents
Preparation method of 6-bromo-3-hydroxy-2-pyrazinecarboxamide Download PDFInfo
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- CN113234030A CN113234030A CN202110472654.4A CN202110472654A CN113234030A CN 113234030 A CN113234030 A CN 113234030A CN 202110472654 A CN202110472654 A CN 202110472654A CN 113234030 A CN113234030 A CN 113234030A
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- China
- Prior art keywords
- hydroxy
- bromo
- pyrazinecarboxamide
- stirring
- carbamoylpyrazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- KZBREXQQUFIWKD-UHFFFAOYSA-N 5-bromo-2-oxo-1h-pyrazine-3-carboxamide Chemical compound NC(=O)C1=NC(Br)=CN=C1O KZBREXQQUFIWKD-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 238000003756 stirring Methods 0.000 claims abstract description 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 238000001914 filtration Methods 0.000 claims abstract description 6
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Inorganic materials Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000002425 crystallisation Methods 0.000 claims abstract description 3
- 230000008025 crystallization Effects 0.000 claims abstract description 3
- 239000005457 ice water Substances 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000498 cooling water Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims 2
- 239000011734 sodium Substances 0.000 claims 2
- 230000035484 reaction time Effects 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- MLCNOCRGSBCAGH-UHFFFAOYSA-N 2,3-dichloropyrazine Chemical class ClC1=NC=CN=C1Cl MLCNOCRGSBCAGH-UHFFFAOYSA-N 0.000 description 1
- GFQBSQXXHYLABK-UHFFFAOYSA-N 2-aminopropanediamide Chemical compound NC(=O)C(N)C(N)=O GFQBSQXXHYLABK-UHFFFAOYSA-N 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing 6-bromo-3-hydroxy-2-pyrazinecarboxamide by using 2-carbamoylpyrazine-3-sodium hydroxide, which belongs to the field of chemical industry, and comprises the steps of dissolving 2-carbamoylpyrazine-3-sodium hydroxide and a catalyst in a solvent, dropwise adding a bromine reagent, stirring for reaction to generate 6-bromo-3-hydroxy-2-pyrazinecarboxamide, stirring in ice water for crystallization, and filtering to obtain a pure 6-bromo-3-hydroxy-2-pyrazinecarboxamide; the method of dripping bromine water is adopted, compared with the traditional method, the method greatly shortens the reaction time, simplifies the production operation, improves the production efficiency, has clean and environment-friendly whole reaction route, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of chemical industry, in particular to a preparation method of 6-bromo-3-hydroxy-2-pyrazinecarboxamide.
Background
The 6-fluoro-3-hydroxy-2-pyrazine carboxamide is a compound for preventing and treating viral infectious diseases, in particular influenza viral infectious diseases. At present, 6-bromo-3-hydroxy-2-pyrazinamide is known as a main raw material for preparing 6-fluoro-3-hydroxy-2-pyrazinamide, and a patent with an authorization publication number of CN 102307865B proposes a preparation method of a dichloropyrazine derivative and provides a synthesis method of 6-bromo-3-hydroxypyrazine-2-formamide, which comprises the steps of dropwise adding a glyoxal solution into a cooled sodium hydroxide aqueous solution of 2-aminomalonic diamide, repeatedly stirring to obtain 2-carbamoylpyrazine-3-sodium hydroxide, suspending the 2-carbamoylpyrazine-3-sodium hydroxide in a mixed solution of methanol and acetonitrile or ethyl acetate, dropwise adding bromine, stirring, filtering to obtain a solid product, and obtaining the 6-bromo-3-hydroxypyrazine-2-formamide, in addition, as for patent No. CN111978263A, a microchannel reactor is used to prepare 6-bromo-3-hydroxypyrazine-2-carboxamide, which is simple in reaction operation and energy-saving, and the yield can reach 90.0%, but the microchannel reactor is expensive, not suitable for large-scale use, and is not suitable for a lot of reactions, and is easy to cause the instrument to be idle.
In the existing process for preparing 6-bromo-3-hydroxy-2-pyrazinamide, tetrabutylammonium bromide is adopted to replace bromine, and the tetrabutylammonium bromide needs to be continuously supplemented in the reaction process, so that the overall reaction time is prolonged, the production efficiency is reduced, and the conversion rate of raw materials is low due to continuous supplementation of the raw materials, so that the yield of the product is reduced.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of 6-bromo-3-hydroxy-2-pyrazinecarboxamide, which can shorten the reaction time, improve the production efficiency and the conversion rate and improve the yield.
The invention relates to a preparation method of 6-bromo-3-hydroxy-2-pyrazinecarboxamide, which comprises the following steps: dissolving 2-carbamoylpyrazine-3-sodium hydroxide and a catalyst in a solvent, dropwise adding a bromine reagent, stirring to react to generate 6-bromo-3-hydroxy-2-pyrazine formamide, stirring in ice water to crystallize, and filtering to obtain the pure 6-bromo-3-hydroxy-2-pyrazine formamide.
Further, the reaction of the process is as follows:
further, the bromine reagent is selected from bromine water.
Further, the catalyst is selected from tetrabutylammonium bromide.
Further, the molar ratio of the 2-carbamoylpyrazine-3-sodium hydroxide to the catalyst is 1: 0.01-1: 0.2; most preferably 1: 0.05.
Further, the molar ratio of the 2-carbamoylpyrazine-3-sodium hydroxide to the bromine reagent is 1: 0.8-1: 1.5; most preferably 1: 0.99.
Further, the stirring reaction is carried out in a solvent selected from any one or more of the following: acetonitrile, methanol, ethanol, isopropanol; most preferably selected from mixed solvents: acetonitrile and methanol.
Further, the mass ratio of the acetonitrile to the methanol is 1: 1-1: 5; most preferably 1: 3.7.
Further, the mass ratio of the 2-carbamoylpyrazine-3-sodium hydroxide to the solvent is 1: 3-1: 8; most preferably 1: 4.73.
Further, the temperature of the stirring reaction is 5-50 ℃; most preferably from 30 ℃ to 35 ℃.
Further, the dropping mode of the bromine reagent is slow dropping.
Further, the method comprises the following steps: after the reaction is finished, dropwise adding cooling water, stirring for crystallization, centrifuging, filtering and drying to obtain the 6-bromo-3-hydroxy-2-pyrazinecarboxamide.
Compared with the prior art, the invention has the beneficial effects that:
the method of dripping bromine water greatly shortens the reaction time by more than 3h, simplifies the production operation, improves the production efficiency, has clean and environment-friendly whole reaction route, is suitable for industrial production, can improve the conversion rate of raw materials, and improves the yield by about 20 percent compared with the traditional method.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1
1) Adding methanol (160kg) and acetonitrile (600kg) into a reaction kettle, and adding 2-carbamoylpyrazine-3-sodium hydroxide (161kg) and tetrabutylammonium bromide (16kg) with stirring;
2) controlling the temperature of the system to be 30-35 ℃, slowly dripping liquid bromine into the system, after dripping is finished, controlling the temperature of the system to be 30-35 ℃, stirring and reacting for 4 hours, fading the bromine color of the reaction system, and detecting whether the reaction is finished or not by adopting a TLC point plate;
3) after the reaction is finished, cooling the reaction liquid to 0-10 ℃, and slowly dripping cooling water;
4) after the cooling water is dripped, controlling the temperature to be 0-10 ℃, continuously stirring and crystallizing for 2 hours, centrifuging, and leaching with a proper amount of drinking water in the centrifuging process to obtain a light yellow solid wet product;
5) and (3) carrying out forced air drying on the wet product at the temperature of 70-80 ℃, and collecting to obtain 181kg of light yellow solid with the yield of 83%.
1H-NMR(600M，DMSO-d6)δ13.52(brs,1H),8.66(s,1H),8.52(s,1H),8.42(s,1H)。
Compared with the mode of continuously supplementing tetrabutylammonium bromide, the method for preparing 6-bromo-3-hydroxy-2-pyrazinecarboxamide has the advantages that the reaction time is greatly reduced, and the reaction time is shortened by more than 3 hours, so that the production efficiency is improved, the conversion rate of raw materials can be improved, the yield is 83%, and the yield is improved by about 20% compared with the prior art.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A preparation method of 6-bromo-3-hydroxy-2-pyrazinecarboxamide is characterized by comprising the following steps: dissolving 2-carbamoylpyrazine-3-sodium hydroxide and a catalyst in a solvent, dropwise adding a bromine reagent, stirring to react to generate 6-bromo-3-hydroxy-2-pyrazine formamide, stirring in ice water to crystallize, and filtering to obtain the pure 6-bromo-3-hydroxy-2-pyrazine formamide.
2. The process for preparing 6-bromo-3-hydroxy-2-pyrazinecarboxamide according to claim 1, wherein said bromine reagent is selected from the group consisting of bromine water.
3. The process of claim 1, wherein the catalyst is selected from tetrabutylammonium bromide.
4. The preparation method of 6-bromo-3-hydroxy-2-pyrazinecarboxamide according to claim 1, wherein the molar ratio of 2-carbamoylpyrazine-3-hydroxy sodium to catalyst is 1:0.01 to 1: 0.2.
5. The preparation method of 6-bromo-3-hydroxy-2-pyrazinecarboxamide according to claim 1, wherein the molar ratio of 2-carbamoylpyrazine-3-hydroxy sodium to bromine reagent is 1:0.8 to 1: 1.5.
6. The process for preparing 6-bromo-3-hydroxy-2-pyrazinecarboxamide according to claim 1, wherein said stirring reaction is carried out in a solvent selected from any one or more of: acetonitrile, methanol, ethanol, isopropanol.
7. The preparation method of 6-bromo-3-hydroxy-2-pyrazinecarboxamide according to claim 1, wherein the solvent is preferably a mixed solvent of acetonitrile and methanol, and the mass ratio of acetonitrile to methanol is 1:1 to 1: 5.
8. The preparation method of 6-bromo-3-hydroxy-2-pyrazinecarboxamide according to claim 1, wherein the use mass ratio of the 2-carbamoylpyrazine-3-sodium hydroxide to the solvent is 1:3 to 1: 8.
9. The method for preparing 6-bromo-3-hydroxy-2-pyrazinecarboxamide according to claim 1, wherein the bromine reagent is added dropwise slowly.
10. The process for preparing 6-bromo-3-hydroxy-2-pyrazinecarboxamide according to claim 1, further comprising the steps of: after the reaction is finished, dropwise adding cooling water, stirring for crystallization, centrifuging, filtering and drying to obtain the 6-bromo-3-hydroxy-2-pyrazinecarboxamide.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461622A (en) * | 2021-08-11 | 2021-10-01 | 海正药业南通有限公司 | Synthesis method of Favipiravir intermediate 6-bromo-3-hydroxypyrazine-2-formamide |
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| CN105732523A (en) * | 2014-12-10 | 2016-07-06 | 青岛市黄岛区中医医院 | Preparation method for 6-fluoro-3-hydroxyl-2-pyrazinamide |
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| CN112300083A (en) * | 2020-04-20 | 2021-02-02 | 常州制药厂有限公司 | Preparation method of Favipiravir |
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- 2021-04-29 CN CN202110472654.4A patent/CN113234030B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732523A (en) * | 2014-12-10 | 2016-07-06 | 青岛市黄岛区中医医院 | Preparation method for 6-fluoro-3-hydroxyl-2-pyrazinamide |
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| CN112300083A (en) * | 2020-04-20 | 2021-02-02 | 常州制药厂有限公司 | Preparation method of Favipiravir |
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Non-Patent Citations (1)
| Title |
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| 杨锦宗: "《工业有机合成基础》", 中国石化出版社, pages: 100 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461622A (en) * | 2021-08-11 | 2021-10-01 | 海正药业南通有限公司 | Synthesis method of Favipiravir intermediate 6-bromo-3-hydroxypyrazine-2-formamide |
| WO2023015811A1 (en) * | 2021-08-11 | 2023-02-16 | 浙江海正药业股份有限公司 | Method for synthesizing favipiravir intermediate 6-bromo-3-hydroxypyrazine-2-formamide |
| CN113461622B (en) * | 2021-08-11 | 2023-04-07 | 海正药业南通有限公司 | Synthesis method of Favipiravir intermediate 6-bromo-3-hydroxypyrazine-2-formamide |
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| CN113234030B (en) | 2024-06-11 |
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