CN104829575A - Preparation method of 6-fluoropyran derivative - Google Patents
Preparation method of 6-fluoropyran derivative Download PDFInfo
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- CN104829575A CN104829575A CN201510228888.9A CN201510228888A CN104829575A CN 104829575 A CN104829575 A CN 104829575A CN 201510228888 A CN201510228888 A CN 201510228888A CN 104829575 A CN104829575 A CN 104829575A
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- 0 CNC(C1)COC2=C1CC(F)=CC=*2 Chemical compound CNC(C1)COC2=C1CC(F)=CC=*2 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
Abstract
The invention discloses a preparation method of a 6-fluoropyran derivative namely 6-fluoro-N-methyl-3,4-dihydro-2H-pyran-3-amine. 2-(5-fluoro-2-hydroxyphenyl)methyl acetate is taken as the start material, and the target product (5) is obtained after reactions of etherification, ring closing, decarboxylation, and amination-reduction. The provided derivative can be used as a micromolecular template to synthesize various compounds.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, particularly the preparation method of the preparation method of a kind of 6-fluorine pyran derivate 6-fluoro-N-methyl-3,4-dihydro-2H-pyrans-3-amine.
Technical background
Compound 6-fluoro-N-methyl-3,4-dihydro-2H-pyrans-3-amine, structural formula is:
This compound 6-fluoro-N-methyl-3,4-dihydro-2H-pyrans-3-amine and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 6-fluoro-N-methyl-3,4-dihydro-2H-pyrans-3-amine 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 fluoro-N-methyl-3 of a kind of 6-fluorine pyran derivate 6-, the preparation method of 4-dihydro-2H-pyrans-3-amine, with 2-(5-fluoro-2-hydroxyphenyl) methyl acetate for starting raw material, obtain target product 5 through etherificate, Guan Huan, decarboxylation, ammonification reduction reaction, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) for starting raw material, 2 are obtained through etherification reaction with 2-(5-fluoro-2-hydroxyphenyl) methyl acetate,
(2) carry out ring closure reaction 2, obtain 3,
(3) carry out decarboxylic reaction 3 and obtain 4,
(4) carry out ammonification reduction reaction 4 and obtain 5,
One preferred embodiment in, the reagent that described etherification reaction prepares compound 2 used is selected from ethyl bromoacetate; The reagent that described ring closure reaction prepares compound 3 used is selected from sodium ethylate; The reductive agent that described decarboxylic reaction prepares compound 4 used is selected from sodium hydroxide; The reductive agent that described ammonification reduction reaction prepares compound 5 used is selected from methylamine hydrochloride.
One preferred embodiment in, the solvent that described etherification reaction prepares compound 2 used is selected from DMF; Described ring closure reaction prepares compound 3 solvent selected from ethanol used; The solvent that described decarboxylic reaction prepares compound 4 used is selected from DMF; Described ammonification reduction reaction prepares compound 5 solvent selected from methanol used.
One preferred embodiment in, described etherification reaction prepares the reflux temperature that compound 2 temperature of reaction used is solvent; It is 0 DEG C of reflux temperature to solvent that described ring closure reaction prepares compound 3 temperature used; Described decarboxylic reaction prepares the reflux temperature that compound 4 temperature used is solvent; It is room temperature that described ammonification reduction reaction prepares compound 5 temperature used.
The present invention relates to the preparation method of a kind of 6-fluorine pyran derivate 6-fluoro-N-methyl-3,4-dihydro-2H-pyrans-3-amine, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound 6-fluoro-N-methyl-3,4-dihydro-2H-pyrans-3-amine.
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 2-(6-fluoro-2-phenoxyethanoic acid ethyl ester) ethyl acetate
27g 2-(5-fluoro-2-hydroxyphenyl) methyl acetate is joined 200ml N, in dinethylformamide, add 21g ethyl bromoacetate and 16g salt of wormwood, heated and stirred refluxes, and is cooled to room temperature, add water and ethyl acetate, extraction separatory, collects organic phase, dry, concentrated, obtain 13g 2-(6-fluoro-2-phenoxyethanoic acid ethyl ester) ethyl acetate.
(2) synthesis of 6-fluoro-3-oxo-3,4-dihydro-2H-chromene-4-ethyl formate
13g 2-(6-fluoro-2-phenoxyethanoic acid ethyl ester) ethyl acetate is joined in 90ml ethanol, be cooled to 0 DEG C, add 11g sodium ethylate, heated and stirred back flow reaction 3 hours, cooling room temperature, concentrated, add water and extraction into ethyl acetate separatory, collect organic phase, dry, concentrate and obtain 9g 6-fluoro-3-oxo-3,4-dihydro-2H-chromene-4-ethyl formate.
(3) synthesis of 6-fluoro-2H-chromene-3 (4H)-one
Fluoro-for 9g 6-3-oxo-3,4-dihydro-2H-chromene-4-ethyl formate joins 100mlN, in dinethylformamide, adds 6g sodium hydroxide, reflux stirs 20 hours, filter, then add water and ethyl acetate, extraction separatory, collect organic phase, drying, concentrated, on residuum, silicagel column is separated to obtain 6g 6-fluoro-2H-chromene-3 (4H)-one.
(4) synthesis of 6-fluoro-N-methyl-3,4-dihydro-2H-pyrans-3-amine
Bromo-for 6g 6-3-oxo-3,4-dihydro-2H-chromene-4-ethyl formate is joined in 50ml methyl alcohol, adds 4g methylamine hydrochloride, stirring at room temperature 20 hours, then add 5g sodium borohydride, stirring at room temperature 2 hours, filter, add water and ethyl acetate again, extraction separatory, collects organic phase, dry, concentrated, on residuum, silicagel column is separated to obtain 3.2g 6-fluoro-N-methyl-3,4-dihydro-2H-pyrans-3-amine.
Claims (5)
1. the fluoro-N-methyl-3 of 6-fluorine pyran derivate 6-, the preparation method of 4-dihydro-2H-pyrans-3-amine, with 2-(5-fluoro-2-hydroxyphenyl) methyl acetate for starting raw material, obtain target product 5 through etherificate, Guan Huan, decarboxylation, ammonification reduction reaction, synthetic route is as follows:
2. method according to claim 1, it is characterized by 4 described step reactions is,
(1) for starting raw material, 2 are obtained through etherification reaction with 2-(5-fluoro-2-hydroxyphenyl) methyl acetate,
(2) carry out ring closure reaction 2, obtain 3,
(3) carry out decarboxylic reaction 3 and obtain 4,
(4) carry out ammonification reduction reaction 4 and obtain 5,
3. according to the method for claim 1-2, it is characterized in that, the reagent that described etherification reaction prepares compound 2 used is selected from ethyl bromoacetate; The reagent that described ring closure reaction prepares compound 3 used is selected from sodium ethylate; Described decarboxylic reaction is prepared compound 4 reductive agent used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, salt of wormwood; The reductive agent that described ammonification reduction reaction prepares compound 5 used is selected from methylamine hydrochloride.
4. according to the method for claim 1-2, it is characterized in that, described etherification reaction is prepared compound 2 solvent used and is selected from tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile; Described ring closure 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; Described decarboxylic reaction prepares compound 4 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, acetonitrile, 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; Described ammonification reduction reaction prepares compound 5 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.
5. according to the method for claim 1-2, it is characterized in that, described etherification reaction prepares the reflux temperature that compound 2 temperature of reaction used is solvent; It is 0 DEG C of reflux temperature to solvent that described ring closure reaction prepares compound 3 temperature used; It is the reflux temperature of room temperature to solvent that described decarboxylic reaction prepares compound 4 temperature used; It is room temperature that described ammonification reduction reaction prepares compound 5 temperature used.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831681A (en) * | 2017-01-17 | 2017-06-13 | 湖南华腾制药有限公司 | A kind of preparation method of 5 nitro pyran derivate |
| CN106905282A (en) * | 2017-02-26 | 2017-06-30 | 长沙深橙生物科技有限公司 | A kind of preparation method of benzo oxa- ring derivatives |
| CN106995426A (en) * | 2017-05-31 | 2017-08-01 | 湖南华腾制药有限公司 | A kind of preparation method of 5 chlorine pyran derivate |
| CN108129434A (en) * | 2016-12-01 | 2018-06-08 | 湖南华腾制药有限公司 | A kind of preparation method of 5- cyano chroman derivatives |
-
2015
- 2015-05-07 CN CN201510228888.9A patent/CN104829575A/en active Pending
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| -: "RN 1520663-31-3", 《STN REGISTRY》 * |
| A DANAN ET AL.: "Les chroman-3-ones", 《BULL SOC CHIM FR》 * |
| DERVILLA M. X. DONNELLY ET AL.: "Synthesis of neoflavenes by ligand coupling reactions with aryllead triacetates", 《TETRAHEDRON》 * |
| JIVKO VELKOV ET AL.: "A New Route for the Synthesis of 5-Methoxychroman-3-One", 《SYNTHETIC COMMUNICATIONS》 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108129434A (en) * | 2016-12-01 | 2018-06-08 | 湖南华腾制药有限公司 | A kind of preparation method of 5- cyano chroman derivatives |
| CN106831681A (en) * | 2017-01-17 | 2017-06-13 | 湖南华腾制药有限公司 | A kind of preparation method of 5 nitro pyran derivate |
| CN106905282A (en) * | 2017-02-26 | 2017-06-30 | 长沙深橙生物科技有限公司 | A kind of preparation method of benzo oxa- ring derivatives |
| CN106995426A (en) * | 2017-05-31 | 2017-08-01 | 湖南华腾制药有限公司 | A kind of preparation method of 5 chlorine pyran derivate |
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