CN113735784A - Preparation method of 6-fluoro-3-hydroxypyrazine-2-formamide - Google Patents
Preparation method of 6-fluoro-3-hydroxypyrazine-2-formamide Download PDFInfo
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- CN113735784A CN113735784A CN202010481659.9A CN202010481659A CN113735784A CN 113735784 A CN113735784 A CN 113735784A CN 202010481659 A CN202010481659 A CN 202010481659A CN 113735784 A CN113735784 A CN 113735784A
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- dimethyl sulfoxide
- hydroxypyrazine
- fluoro
- hydrogen peroxide
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- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 title description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 18
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- -1 pyrazine compound Chemical class 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 229940123973 Oxygen scavenger Drugs 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 7
- 239000001301 oxygen Substances 0.000 abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 abstract description 7
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 abstract 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 abstract 1
- 230000003321 amplification Effects 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 4
- ONECIHYIQJRNTP-UHFFFAOYSA-N 3,6-difluoropyrazine-2-carbonitrile Chemical compound FC1=CN=C(F)C(C#N)=N1 ONECIHYIQJRNTP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- UZHXXRRBFJSFCV-UHFFFAOYSA-N 3,6-dichloropyrazine-2-carbonitrile Chemical compound ClC1=CN=C(Cl)C(C#N)=N1 UZHXXRRBFJSFCV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229950008454 favipiravir Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- IECSXEDBAMFMCB-UHFFFAOYSA-N NC(N1NC(F)=CC=C1O)=O Chemical group NC(N1NC(F)=CC=C1O)=O IECSXEDBAMFMCB-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 238000010792 warming 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of a pyrazine compound shown in a formula (I). According to the invention, 6-fluoro-3-hydroxypyrazine-2-methyl cyanide is used as a starting material, and dimethyl sulfoxide is added under the conditions of hydrogen peroxide and sodium hydroxide, so that the generation of oxygen in a system is avoided, and the production safety is greatly improved. The generation process is safe, is suitable for industrial amplification, and is greatly helpful for industrial large-scale production of Pilazvir API.
Description
Technical Field
The invention relates to a preparation method of a pyridazine compound, belonging to the field of medicine and chemical synthesis.
Background
Favipiravir is a compound that shows excellent effects on various viruses, particularly influenza viruses, and studies have shown that it shows good therapeutic activity against the novel coronavirus sars-cov-2. The structural formula is as follows:
the main route for the synthesis of piravir is to use 3, 6-dichloropyrazine-2-carbonitrile as starting material followed by fluorination, followed by hydrolysis of the fluorine to the hydroxy group, followed by further hydrolysis of the cyano group to the amide to give the piravir API. The reaction scheme is as follows.
In the synthesis process of the route, a large amount of oxygen is generated in the last step of hydrogen peroxide oxidation, so that the liquid level of the system rises to influence stirring, and meanwhile, a large amount of oxygen is accumulated in the system to cause potential safety hazards for large-scale production safety. In the research process, the addition of dimethyl sulfoxide unexpectedly finds that oxygen generated by a system can be consumed, the dimethyl sulfoxide is oxidized into dimethyl sulfone, the system has no oxygen emission, the reaction is stable, and meanwhile, the generated dimethyl sulfone can be removed in post-treatment without influencing the quality of API. The new process ensures the production safety to the greatest extent without adding extra cost basically, and has important help for industrialization of Favipiravir API.
Disclosure of Invention
The invention provides a method for preparing 6-fluoro-3-hydroxypyrazine-2-formamide (I) by using dimethyl sulfoxide as a deoxidant, aiming at solving the problems that in the existing process, oxygen is released in the process of preparing 6-fluoro-3-hydroxypyrazine-2-formamide (I), so that the system is difficult to amplify and the safety risk is high.
Specifically, the invention provides a preparation method of a pyridazine compound, which comprises the steps of taking dimethyl sulfoxide as an oxygen scavenger in the presence of inorganic base, and preparing 3-hydroxy-6-fluoropyrazine-2-methyl cyanide and an oxidant at 0-60 ℃. The reaction equation is as follows:
in an embodiment of the present invention, the inorganic base used in said step is selected from the group consisting of sodium hydroxide, potassium hydroxide, cesium hydroxide and potassium carbonate, with sodium hydroxide being preferred.
In an embodiment of the present invention, the oxidant used in the step is selected from hydrogen peroxide and peroxyacetic acid, wherein hydrogen peroxide is preferred.
In an embodiment of the present invention, the oxygen scavenger used in said step is dimethyl sulfoxide.
In an embodiment of the invention, the solvent used in said step is water.
In an embodiment of the invention, the reaction temperature of said step is 0 to 60 ℃, wherein 0 to 45 ℃ is preferred.
In an embodiment of the invention, the amount of inorganic base used in said step is 1.0 to 3.0 equivalents, preferably 1.7 equivalents.
In an embodiment of the invention, the oxidizing agent used in said step has an equivalent weight of 1.0 to 3.0 equivalents, preferably 1.7 equivalents.
In an embodiment of the invention, the oxygen scavenger dimethyl sulfoxide used in said step has an equivalent weight of 1.0 to 3.0 equivalents, preferably 1.7 equivalents.
Compared with the prior art, the process provided by the invention has the advantage that the safety of industrial mass production is greatly improved by using dimethyl sulfoxide to remove oxygen generated in the preparation process of the 6-fluoro-3-hydroxypyrazine-2-formamide (I).
According to the present invention, it is possible to make various modifications, substitutions and alterations without departing from the basic technical idea of the present invention as described above, according to the common technical knowledge and conventional means in the field.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed description of the invention
The starting materials and equipment used in the embodiment of the present invention are known products and are obtained by purchasing commercially available products.
Example 1: synthesis of 3, 6-difluoropyrazine-2-carbonitrile
Compound 3, 6-dichloropyrazine-2-carbonitrile (10g) was added to DMF (60mL), followed by TBAF (catalytic amount) and potassium fluoride (20g), and the system was heated to 60 ℃ for 12 hours. After the reaction was complete, the system was cooled to room temperature, quenched with water, the aqueous phase extracted 3 times with methyl tert-butyl ether (50mL), and the organic phases combined. The organic phase was washed with water (50mL), then dried, and concentrated to give 3, 6-difluoropyrazine-2-carbonitrile (crude product was directly reacted without further purification)
Example 2: synthesis of 3-hydroxy-6-fluoropyridazine-2-cyano
Adding a compound 3, 6-difluoropyrazine-2-carbonitrile (crude product, 7g) into DMF (30mL), cooling the system in an ice-water bath, sequentially adding acetic acid (6g) and triethylamine (10g) into the reaction system, and after the addition is finished, warming the system and stirring overnight. After the reaction was complete, the first was added to ice water, followed by pH adjustment to 3-4, extraction with methyl tert-butyl ether (100mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, which was then slurried with n-heptane to give: 3-hydroxy-6-fluoropyridazine-2-cyano (6g as a tan solid).
Example 3: synthesis of 3-hydroxy-6-fluoropyridazin-2-acylamino
Adding a compound 3-hydroxy-6-fluoropyridazine-2-cyano (2g) into an aqueous solution of NaOH, then adding DMSO (1.91g) into the system, cooling to 0-5 ℃, dropwise adding hydrogen peroxide (2.77g) into the reaction system, and controlling the temperature of the system to be not more than 5 ℃. After the addition was complete, the system was slowly warmed to 40 ℃ and stirring was continued for 1 hour. After the reaction was completed, the system was adjusted to pH 3-4 with hydrochloric acid, followed by filtration, the filter cake was rinsed with purified water, the filter cake was collected, and dried under vacuum to give 3-hydroxy-6-fluoropyridazin-2-carboxamide group (1.65g of off-white solid, purity by HPLC: 99.95%, maximum single impurity: 0.03%).
Claims (6)
1. A preparation method of a pyridazine compound shown in a formula (I) comprises the steps of taking dimethyl sulfoxide as an oxygen scavenger in the presence of inorganic base, and preparing 3-hydroxy-6-fluoropyrazine-2-methyl cyanide and an oxidant at 0-60 ℃.
2. The process of claim 1, wherein the inorganic base used in said step is selected from the group consisting of sodium hydroxide, potassium hydroxide, cesium hydroxide and potassium carbonate, preferably sodium hydroxide.
3. The method as claimed in claim 1, wherein the oxidant used in the step is selected from hydrogen peroxide and peroxyacetic acid, preferably hydrogen peroxide.
4. The method of claim 1 wherein said oxygen scavenger used in said step is dimethyl sulfoxide.
5. The method of claim 1, wherein the solvent used in said step is water.
6. The process according to claim 1, wherein the reaction temperature of said step is 0-60 ℃, preferably 0-45 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010481659.9A CN113735784A (en) | 2020-05-28 | 2020-05-28 | Preparation method of 6-fluoro-3-hydroxypyrazine-2-formamide |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010481659.9A CN113735784A (en) | 2020-05-28 | 2020-05-28 | Preparation method of 6-fluoro-3-hydroxypyrazine-2-formamide |
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| Publication Number | Publication Date |
|---|---|
| CN113735784A true CN113735784A (en) | 2021-12-03 |
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|---|---|---|---|
| CN202010481659.9A Pending CN113735784A (en) | 2020-05-28 | 2020-05-28 | Preparation method of 6-fluoro-3-hydroxypyrazine-2-formamide |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1418220A (en) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | Novel pyrazine derivatives or salts thereof, containing the derives or the salts and intermediates for the preparation of both |
| CN102307865A (en) * | 2009-01-28 | 2012-01-04 | 日本曹达株式会社 | Method for producing dichloropyrazine derivative |
| CN103347884A (en) * | 2010-11-12 | 2013-10-09 | 富士胶片株式会社 | Pyrazino[2,3-d]isooxazole derivative |
| TW201402556A (en) * | 2012-05-30 | 2014-01-16 | Toyama Chemical Co Ltd | Deuterated nitrogen-containing heterocyclic carboxamide derivative and salt thereof |
| CN106866553A (en) * | 2017-03-28 | 2017-06-20 | 中南大学 | A kind of synthetic method of Favipiravir |
| CN107226794A (en) * | 2017-07-17 | 2017-10-03 | 郑州大学 | A kind of synthetic method of Favipiravir |
| CN108840809A (en) * | 2018-07-17 | 2018-11-20 | 常州大学 | A kind of method of continuous synthesis dimethyl sulfone |
-
2020
- 2020-05-28 CN CN202010481659.9A patent/CN113735784A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1418220A (en) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | Novel pyrazine derivatives or salts thereof, containing the derives or the salts and intermediates for the preparation of both |
| CN102307865A (en) * | 2009-01-28 | 2012-01-04 | 日本曹达株式会社 | Method for producing dichloropyrazine derivative |
| CN103347884A (en) * | 2010-11-12 | 2013-10-09 | 富士胶片株式会社 | Pyrazino[2,3-d]isooxazole derivative |
| TW201402556A (en) * | 2012-05-30 | 2014-01-16 | Toyama Chemical Co Ltd | Deuterated nitrogen-containing heterocyclic carboxamide derivative and salt thereof |
| CN106866553A (en) * | 2017-03-28 | 2017-06-20 | 中南大学 | A kind of synthetic method of Favipiravir |
| CN107226794A (en) * | 2017-07-17 | 2017-10-03 | 郑州大学 | A kind of synthetic method of Favipiravir |
| CN108840809A (en) * | 2018-07-17 | 2018-11-20 | 常州大学 | A kind of method of continuous synthesis dimethyl sulfone |
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| Title |
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| 刘涛，等: "法匹拉韦合成路线图解", 《中国药物化学杂志》 * |
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Application publication date: 20211203 |