CN104961691A - Preparation method of 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid - Google Patents
Preparation method of 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid Download PDFInfo
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- CN104961691A CN104961691A CN201510405057.4A CN201510405057A CN104961691A CN 104961691 A CN104961691 A CN 104961691A CN 201510405057 A CN201510405057 A CN 201510405057A CN 104961691 A CN104961691 A CN 104961691A
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- 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
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Abstract
The invention discloses a preparation method of 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid. The method is characterized by carrying out hydroxylation, chlorination, condensation and hydrolysis reactions on 3-aminopyrazine-2-carboxylic acid methyl ester which is used as a starting raw material to obtain a target product which is 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid. The 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid prepared by the method can be used as a template micromolecule for synthesizing various compound libraries.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, particularly the preparation method of 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid.
Technical background
Compound 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid, structural formula is:
This compound 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid is comparatively difficult.Therefore, need exploitation raw material to be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is suitable.
Summary of the invention
The invention discloses the preparation method of 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid, with 3-Aminopyrazine-2-carboxylate methyl ester for starting raw material, obtain target product 5 through hydroxylation, chlorination, condensation, hydrolysis reaction, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with 3-Aminopyrazine-2-carboxylate methyl ester for starting raw material, obtain 2 through hydroxylating,
(2) carry out chlorination reaction 2, obtain 3,
(3) carry out condensation reaction 3 and obtain 4,
(4) be hydrolyzed 4 and be obtained by reacting 5,
One preferred embodiment in, the reagent that described hydroxylating prepares compound 2 used is selected from Sodium Nitrite; The reagent that described chlorination reaction prepares compound 3 used is selected from phosphorus oxychloride; The alkali that described condensation reaction prepares compound 4 used is selected from salt of wormwood; The reagent that described hydrolysis reaction prepares compound 5 used is selected from sodium hydroxide.
One preferred embodiment in, the solvent that described hydroxylating prepares compound 2 used is selected from water; The solvent that described chlorination reaction prepares compound 3 used is selected from phosphorus oxychloride; The solvent that described condensation reaction prepares compound 4 used is selected from DMF; Described hydrolysis reaction prepares compound 5 solvent selected from methanol used.
One preferred embodiment in, it is 0 DEG C that described hydroxylating prepares compound 2 temperature of reaction used; Described chlorination reaction prepares the reflux temperature that compound 3 temperature used is solvent; The reflux temperature that compound 4 temperature used is solvent is prepared in described condensation reaction; It is room temperature that described hydrolysis reaction prepares compound 5 temperature used.
The present invention relates to the preparation method of 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound thing 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid.
The present invention is further described by the following embodiment, and these descriptions are not be further limited content of the present invention.One skilled in the art will understand that the equivalent replacement that technical characteristic of the present invention is done, or improve accordingly, still belong within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 3-HYDROXYPYRAZINE-2-methyl-formiate
15g 3-Aminopyrazine-2-carboxylate methyl ester is joined in 48ml concentrated hydrochloric acid, add 80ml water, be cooled to 0 DEG C, slowly add 9g Sodium Nitrite, 0 DEG C is stirred 0.5 hour, add saturated aqueous sodium carbonate, continue stirring 1 hour, add extraction into ethyl acetate separatory, collect organic phase, drying, concentrated, obtain 11g 3-HYDROXYPYRAZINE-2-methyl-formiate.
(2) synthesis of 3-chloropyrazine-2-methyl-formiate
10g 3-HYDROXYPYRAZINE-2-methyl-formiate is joined in 130ml phosphorus oxychloride, and reflux stirs 3 hours, cooling, concentrated removing phosphorus oxychloride, adds water and extraction into ethyl acetate separatory, collects organic phase, drying, concentrated, cross post separation and obtain 8g 3-chloropyrazine-2-methyl-formiate.
(3) synthesis of 3-(2-fluorophenoxy) pyrazine-2-methyl-formiate
8g 3-chloropyrazine-2-methyl-formiate is joined 100ml N, in dinethylformamide, add 11g 2-fluorophenol and 10g salt of wormwood, reflux stirs 5 hours, is cooled to room temperature, adds water and extraction into ethyl acetate separatory, collect organic phase, drying, concentrated, obtain 9g 3-(4-fluorophenoxy) pyrazine-2-methyl-formiate.
(4) synthesis of 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid
8g 3-(2-fluorophenoxy) pyrazine-2-methyl-formiate is joined in 90ml methyl alcohol, add 40ml water, add 8g sodium hydroxide again, stirring at room temperature 2 hours, adjusts pH=1 with hydrochloric acid, add ethyl acetate and water again, extraction separatory, collects organic phase, dry, concentrated, residuum is crossed post separation and is obtained 5g 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid.
Claims (5)
1. a preparation method for 3-(2-fluorophenoxy) pyrazine-2-carboxylic acid, with 3-Aminopyrazine-2-carboxylate methyl ester for starting raw material, obtain target product 5 through hydroxylation, chlorination, condensation, hydrolysis reaction, synthetic route is as follows,
2. method according to claim 1, it is characterized by 4 described step reactions is,
(1) with 3-Aminopyrazine-2-carboxylate methyl ester for starting raw material, obtain 2 through hydroxylating,
(2) carry out chlorination reaction 2, obtain 3,
(3) carry out condensation reaction 3 and obtain 4,
(4) be hydrolyzed 4 and be obtained by reacting 5,
3. according to the method for claim 1-2, it is characterized in that, the reagent that described hydroxylating prepares compound 2 used is selected from Sodium Nitrite; Described chlorination reaction is prepared compound 3 reagent used and is selected from the mixture of one or more in phosphorus oxychloride, phosphorus trichloride, sulfur oxychloride; Described condensation reaction is prepared compound 4 alkali used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, pyridine, triethylamine; Described hydrolysis reaction is prepared compound 5 reagent used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood.
4. according to the method for claim 1-2, it is characterized in that, described hydroxylating prepares compound 2 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, triethylamine, pyridine, acetonitrile, water; Described chlorination reaction prepares compound 3 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile, ammoniacal liquor, phosphorus oxychloride; Compound 4 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, toluene, o-Xylol, p-Xylol, m-xylene, N are prepared in described condensation reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile, phosphorus oxychloride; Described hydrolysis reaction prepares compound 5 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetic acid, phosphorus oxychloride.
5. according to the method for claim 1-2, it is characterized in that, described hydroxylating prepares the reflux temperature that compound 2 temperature of reaction used is 0 DEG C ~ solvent; Described chlorination reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; The reflux temperature that compound 4 temperature used is room temperature DEG C ~ solvent is prepared in described condensation reaction; Described hydrolysis reaction prepares the reflux temperature that compound 5 temperature used is 0 DEG C ~ solvent.
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Citations (2)
| 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 |
| WO2014113485A1 (en) * | 2013-01-15 | 2014-07-24 | Intermune, Inc. | Lysophosphatidic acid receptor antagonists |
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2015
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Patent Citations (2)
| 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 |
| WO2014113485A1 (en) * | 2013-01-15 | 2014-07-24 | Intermune, Inc. | Lysophosphatidic acid receptor antagonists |
Non-Patent Citations (3)
| Title |
|---|
| ACS，STN REGISTRY数据库: "RN：1466954-75-5", 《ACS，STN REGISTRY数据库》 * |
| TOMOHIRO OKAWA等: "Methyl 3-(triphenylphosphoranylideneamino)pyrazine-2-carboxylate: synthesis, crystal structure and use in pteridin-4(3H)- ones synthesis", 《JOURNAL OF THE CHEMICAL SOCIETY》 * |
| 刘建华，等: "新型含甲氨甲酰苯基烟酰脲类化合物的设计、合成及生物活性研究", 《有机化学》 * |
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Application publication date: 20151007 |