CN104788386A - Preparation method of fluorine-containing pyrimidine compound - Google Patents
Preparation method of fluorine-containing pyrimidine compound Download PDFInfo
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- CN104788386A CN104788386A CN201510202730.4A CN201510202730A CN104788386A CN 104788386 A CN104788386 A CN 104788386A CN 201510202730 A CN201510202730 A CN 201510202730A CN 104788386 A CN104788386 A CN 104788386A
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- XOCSVDWQTBGTOM-ONEGZZNKSA-N CCOC(/C=C/c(cn1)cnc1F)=O Chemical compound CCOC(/C=C/c(cn1)cnc1F)=O XOCSVDWQTBGTOM-ONEGZZNKSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a reparation method of a fluorine-containing pyrimidine compound, that is, 2-fluoro-5-hydroxy methyl pyridine. 2-fluoro-5-bromopyrimidine is taken as a starting material, and the starting material is subjected to Heck reaction to obtain a product I, the product I is subjected to oxidization reaction to obtain a product II, and the product II is subjected to reduction reaction to obtain a target product 4. The fluorine-containing pyrimidine compound is taken as a small template molecule to synthetize various compound banks.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, particularly a kind of preparation method containing the fluoro-5-oxymethylpyrimidine of fluoropyrimidine compound 2-.
Technical background
The fluoro-5-oxymethylpyrimidine of compound 2-, structural formula is:
This compound 2-fluoro-5-oxymethylpyrimidine and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 2-fluoro-5-oxymethylpyrimidine 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 a kind of preparation method containing the fluoro-5-oxymethylpyrimidine of fluoropyrimidine compound 2-, with the fluoro-5-bromo pyrimi piperidine of 2-for starting raw material, obtain target product 4 through Heck, oxidation, reduction reaction, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with the fluoro-5-bromo pyrimi piperidine of 2-for starting raw material, be obtained by reacting 2 through Heck,
(2) carry out oxidizing reaction 2, obtain 3,
(3) carry out reduction reaction 3 and obtain 4,
One preferred embodiment in, described Heck reacts the reagent preparing compound 2 used and is selected from ethyl propenoate; The reagent that described oxidizing reaction prepares compound 3 used is selected from ozone; The reductive agent that described reduction reaction prepares compound 4 used is selected from sodium borohydride.
One preferred embodiment in, described Heck reacts the solvent preparing compound 2 used and is selected from DMF; Described oxidizing reaction prepares compound 3 solvent selected from methanol used; Described reduction reaction prepares compound 4 solvent selected from ethanol used.
One preferred embodiment in, it is 110 DEG C that compound 2 temperature of reaction used is prepared in described Heck reaction; Described oxidizing reaction prepare compound 3 temperature used be-78 DEG C to room temperature; It is room temperature that described reduction reaction prepares compound 4 temperature used.
The present invention relates to a kind of preparation method containing the fluoro-5-oxymethylpyrimidine of fluoropyrimidine compound 2-, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of the fluoro-5-oxymethylpyrimidine of compound 2-.
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-(2-chloropyrimide-5-base) ethyl propenoate
Fluoro-for 14g 2-5-bromo pyrimi piperidine is joined 100ml N, in dinethylformamide, add 0.2g palladium and 11g ethyl propenoate, 110 DEG C of stirring reactions spend the night, and filter, add water and ethyl acetate, extraction separatory, collects organic phase, dry, concentrated, obtain 8g 3-(2-chloropyrimide-5-base) ethyl propenoate.
(2) synthesis of 2-chloropyrimide-5-formaldehyde
8g 3-(2-chloropyrimide-5-base) ethyl propenoate is joined in 90ml methyl alcohol, be cooled to-78 DEG C, pass into ozone stirring reaction 2 hours, rise to room temperature, continue stirring 2 hours, concentrated, add water and extraction into ethyl acetate separatory, collect organic phase, dry, concentrate and obtain 5g 2-chloropyrimide-5-formaldehyde.
(3) synthesis of the fluoro-5-oxymethylpyrimidine of 2-
5g 2-chloropyrimide-5-formaldehyde is joined in 60ml ethanol, and add 6g sodium borohydride, stirring at room temperature 6 hours, adds dilute hydrochloric acid, add water and ethyl acetate again, extraction separatory, collects organic phase, drying, concentrated, on residuum, silicagel column is separated to obtain the fluoro-5-oxymethylpyrimidine of 3g 2-.
Claims (5)
1., containing a preparation method for the fluoro-5-oxymethylpyrimidine of fluoropyrimidine compound 2-, with the fluoro-5-bromo pyrimi piperidine of 2-for starting raw material, obtain target product 4 through Heck, oxidation, reduction reaction, synthetic route is as follows:
2. method according to claim 1, it is characterized by 3 described step reactions is,
(1) with the fluoro-5-bromo pyrimi piperidine of 2-for starting raw material, be obtained by reacting 2 through Heck,
(2) carry out oxidizing reaction 2, obtain 3,
(3) carry out reduction reaction 3 and obtain 4,
3. according to the method for claim 1-2, it is characterized in that, described Heck reacts the reagent preparing compound 2 used and is selected from ethyl propenoate; The reagent that described oxidizing reaction prepares compound 3 used is selected from ozone; Described reduction reaction is prepared compound 4 reductive agent used and is selected from the mixture of one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, Lithium Aluminium Hydride.
4. according to the method for claim 1-2, it is characterized in that, described Heck 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 oxidizing 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 reduction 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.
5. according to the method for claim 1-2, it is characterized in that, it is the reflux temperature of room temperature to solvent that compound 2 temperature of reaction used is prepared in described Heck reaction; Described oxidizing reaction prepare compound 3 temperature used be-78 DEG C to room temperature; It is the reflux temperature of room temperature to solvent that described reduction reaction prepares compound 4 temperature used.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510202730.4A CN104788386A (en) | 2015-04-24 | 2015-04-24 | Preparation method of fluorine-containing pyrimidine compound |
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| CN201510202730.4A CN104788386A (en) | 2015-04-24 | 2015-04-24 | Preparation method of fluorine-containing pyrimidine compound |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009111501A1 (en) * | 2008-03-04 | 2009-09-11 | Smithkline Beecham Corporation | Derivatives of imidazo [4, 5-d] pyridazine and their use as anti-viral compounds |
| CN101663278A (en) * | 2007-02-02 | 2010-03-03 | Irm责任有限公司 | It is used as the compound and composition of GPR119 activity regulation agent |
| WO2011147951A1 (en) * | 2010-05-28 | 2011-12-01 | Prosidion Limited | Cycloamino derivatives as gpr119 antagonists |
-
2015
- 2015-04-24 CN CN201510202730.4A patent/CN104788386A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101663278A (en) * | 2007-02-02 | 2010-03-03 | Irm责任有限公司 | It is used as the compound and composition of GPR119 activity regulation agent |
| WO2009111501A1 (en) * | 2008-03-04 | 2009-09-11 | Smithkline Beecham Corporation | Derivatives of imidazo [4, 5-d] pyridazine and their use as anti-viral compounds |
| WO2011147951A1 (en) * | 2010-05-28 | 2011-12-01 | Prosidion Limited | Cycloamino derivatives as gpr119 antagonists |
Non-Patent Citations (5)
| Title |
|---|
| BARUN OKRAM等: "A General Strategy for Creating "Inactive-Conformation" Abl Inhibitors", 《CHEMISTRY & BIOLOGY》 * |
| ZEBIN XIA等: "Heteroatom-Substituted Analogues of Orphan Nuclear Receptor Small Heterodimer Partner Ligand and Apoptosis Inducer (E)-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic Acid", 《J. MED. CHEM.》 * |
| 蒋先明等: "《大学化学教材中的问题与讨论》", 30 September 1984 * |
| 贺庆国等: "《分子材料与薄膜器件》", 31 October 2010 * |
| 邢其毅等: "《基础有机化学 下》", 31 December 2005 * |
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Application publication date: 20150722 |