CN104803922A - Preparation method of pyrimidine derivative - Google Patents
Preparation method of pyrimidine derivative Download PDFInfo
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- CN104803922A CN104803922A CN201510112035.9A CN201510112035A CN104803922A CN 104803922 A CN104803922 A CN 104803922A CN 201510112035 A CN201510112035 A CN 201510112035A CN 104803922 A CN104803922 A CN 104803922A
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- NKMGFCQXROGXET-UHFFFAOYSA-N CC(C)OC(c1cc(-c2nc(C)ncc2)ccc1OC)=O Chemical compound CC(C)OC(c1cc(-c2nc(C)ncc2)ccc1OC)=O NKMGFCQXROGXET-UHFFFAOYSA-N 0.000 description 1
- AKRYUGBIZYXUKK-UHFFFAOYSA-N Cc1nccc(-c(cc2C(O)=O)ccc2OC)n1 Chemical compound Cc1nccc(-c(cc2C(O)=O)ccc2OC)n1 AKRYUGBIZYXUKK-UHFFFAOYSA-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
- C07D239/26—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of a pyrimidine derivative 2-methoxy-5-(2-methylpyrimidine-4-yl)benzoic acid. Isopropyl salicylate is taken as a starting material, and a target product is obtained through acetylation, methylation, acryl acylation, ring closing and hydrolysis reactions. A variety of compound libraries are synthesized with the products serving as template micro-molecules.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, particularly a kind of pyrimidine derivatives 2-methoxyl group-5-(2-methylpyrimidine-4-base) benzoic preparation method.
Technical background
Compound 2-methoxyl group-5-(2-methylpyrimidine-4-base) phenylformic acid, structural formula is:
This compound 2-methoxyl group-5-(2-methylpyrimidine-4-base) phenylformic acid and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.Current 2-methoxyl group-5-(2-methylpyrimidine-4-base) benzoic synthesis 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 pyrimidine derivatives 2-methoxyl group-5-(2-methylpyrimidine-4-base) benzoic preparation method; take isopropyl salicylate as starting raw material; through acetylize, methylate, polyacryl, Guan Huan, hydrolysis reaction obtain target product 6, synthetic route is as shown in Figure 1.Synthesis step is as follows:
(1) be starting raw material with isopropyl salicylate, obtain 2 through acetylization reaction,
(2) carry out methylation reaction 2, obtain 3,
(3) carry out polyacryl 3 and be obtained by reacting 4,
(4) carry out ring closure reaction 4 and obtain 5,
(4) be hydrolyzed 5 and be obtained by reacting 6,
One preferred embodiment in, the catalyzer that described acetylization reaction prepares compound 2 used is selected from aluminum chloride; Described methyl reacts the reagent preparing compound 3 used and is selected from methyl iodide; Described polyacryl reaction is prepared compound 4 reagent used and is selected from DMF dimethylacetal; The reagent that described ring closure reaction prepares compound 5 used is selected from acetamidine hydrochloride; The alkali that described hydrolysis reaction prepares compound 6 used is selected from sodium hydroxide.
One preferred embodiment in, the solvent that described acetylization reaction prepares compound 2 used is selected from methylene dichloride; Described methyl reacts the solvent preparing compound 3 used and is selected from DMF; Described polyacryl reacts the solvent preparing compound 4 used and is selected from toluene; The solvent that described ring closure reaction prepares compound 5 used is selected from toluene; Described hydrolysis reaction prepares the mixture of compound 6 solvent selected from methanol used and water.
One preferred embodiment in, it is room temperature that described acetylization reaction prepares compound 2 temperature of reaction used; It is 50 DEG C that compound 3 temperature used is prepared in described methyl reaction; The reflux temperature that compound 4 temperature used is solvent is prepared in described polyacryl reaction; Described ring closure reaction prepares the reflux temperature that compound 5 temperature used is solvent; It is room temperature that described hydrolysis reaction prepares compound 6 temperature used.
The present invention relates to a kind of pyrimidine derivatives 2-methoxyl group-5-(2-methylpyrimidine-4-base) benzoic preparation method, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is compound thing 2-methoxyl group-5-(2-methylpyrimidine-4-base) benzoic synthetic route chart.
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 5-ethanoyl-2 hydroxybenzoic acid isopropyl ester
20g isopropyl salicylate is joined in 250ml methylene dichloride, adds 31g aluminum trichloride (anhydrous) and 29g Acetyl Chloride 98Min., stirring at room temperature 3 hours; add frozen water and ethyl acetate, extraction separatory, collects organic phase; drying, concentrated, obtain 23g 5-ethanoyl-2 hydroxybenzoic acid isopropyl ester.
(2) synthesis of 5-ethanoyl-O-Anisic Acid isopropyl ester
22g 5-ethanoyl-2 hydroxybenzoic acid isopropyl ester is joined in 160ml DMF, adds 25g Anhydrous potassium carbonate; add 27g methyl iodide again; be heated to 50 DEG C, return stirring 2 hours, cooling; add water and extraction into ethyl acetate separatory; collect organic phase, wash three times with water, organic phase is dry; concentrated, cross post separation and obtain 19g 5-ethanoyl-O-Anisic Acid isopropyl ester.
(3) synthesis of (E)-sec.-propyl-5-(3-(dimethylamino) acryl)-O-Anisic Acid
19g 5-ethanoyl-O-Anisic Acid isopropyl ester is joined in 200ml toluene; add 34ml N; dinethylformamide dimethylacetal; reflux stirs 5 hours; concentrating under reduced pressure, residuum ethyl alcohol recrystallization obtains 13g (E)-sec.-propyl-5-(3-(dimethylamino) acryl)-O-Anisic Acid.
(4) synthesis of sec.-propyl-2-methoxyl group-5-(2-methylpyrimidine-4-base) methyl benzoate
12g (E)-sec.-propyl-5-(3-(dimethylamino) acryl)-O-Anisic Acid is joined in 140ml toluene; add 9.6g acetamidine hydrochloride; reflux 48 hours; cooling; filter; filtrate concentrates, and residuum is crossed post separation and obtained 8g (E)-sec.-propyl-5-(3-(dimethylamino) acryl)-O-Anisic Acid.
(5) 2-methoxyl group-5-(2-methylpyrimidine-4-base) benzoic synthesis
8g (E)-sec.-propyl-5-(3-(dimethylamino) acryl)-O-Anisic Acid is joined in 100ml methyl alcohol; add the NaOH aqueous solution of 40ml 2N again; stirring at room temperature reacts 6 hours; add dilute hydrochloric acid and ethyl acetate; extraction separatory; collect organic phase, concentrated, the mixed solvent recrystallization of residuum second alcohol and water obtains 6.1g 2-methoxyl group-5-(2-methylpyrimidine-4-base) phenylformic acid.
Claims (5)
1. the benzoic preparation method of pyrimidine derivatives 2-methoxyl group-5-(2-methylpyrimidine-4-base); take isopropyl salicylate as starting raw material; through acetylize, methylate, polyacryl, Guan Huan, hydrolysis reaction obtain target product 6, synthetic route is as follows
2. method according to claim 1, it is characterized by 5 described step reactions is,
(1) be starting raw material with isopropyl salicylate, obtain 2 through acetylization reaction,
(2) carry out methylation reaction 2, obtain 3,
(3) carry out polyacryl 3 and be obtained by reacting 4,
(4) carry out ring closure reaction 4 and obtain 5,
(4) be hydrolyzed 5 and be obtained by reacting 6,
3. according to the method for claim 1-2, it is characterized in that, described acetylization reaction is prepared compound 2 catalyzer used and is selected from the mixture of one or more in aluminum chloride, iron trichloride, tin protochloride, zinc chloride; Described methyl reaction is prepared compound 3 reagent used and is selected from one or both mixture in methyl iodide, methyl-sulfate; Described polyacryl reaction is prepared compound 4 reagent used and is selected from DMF dimethylacetal; The reagent that described ring closure reaction prepares compound 5 used is selected from acetamidine hydrochloride; Described hydrolysis reaction is prepared compound 6 alkali used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus.
4. according to the method for claim 1-2, it is characterized in that, described acetylization reaction 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; Compound 3 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N are prepared in described methyl reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile, water; 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 polyacryl reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile, phosphorus oxychloride; Described ring closure 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, water; Described hydrolysis reaction prepares compound 6 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, water.
5. according to the method for claim 1-2, it is characterized in that, described acetylization reaction prepares the reflux temperature that compound 2 temperature of reaction used is 0 DEG C ~ solvent; The reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent is prepared in described methyl reaction; The reflux temperature that compound 4 temperature used is 0 DEG C ~ solvent is prepared in described polyacryl reaction; Described ring closure reaction prepares the reflux temperature that compound 5 temperature used is 0 DEG C ~ solvent; Described hydrolysis reaction prepares the reflux temperature that compound 6 temperature used is 0 DEG C ~ solvent.
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| WO2015005499A1 (en) * | 2013-07-12 | 2015-01-15 | 住友化学株式会社 | Tetrazolinone compound and use thereof |
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2015
- 2015-03-14 CN CN201510112035.9A patent/CN104803922A/en active Pending
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| CN102137860A (en) * | 2008-06-20 | 2011-07-27 | 阿斯利康(瑞典)有限公司 | Compositions with and process for methylmorpholin -subsituted pyrido [2, 3-D] pyrimidines |
| CN101684098A (en) * | 2008-09-24 | 2010-03-31 | 中国科学院上海药物研究所 | 5-lipoxygenase inhibitor and preparation method, medical composite and application thereof |
| CN102781923A (en) * | 2010-01-26 | 2012-11-14 | 贝林格尔.英格海姆国际有限公司 | 5-alkynyl-pyrimidines |
| CN103842356A (en) * | 2011-10-07 | 2014-06-04 | 武田药品工业株式会社 | 1 - arylcarbonyl - 4 - oxy - piperidine compounds useful for the treatment of neurodegenerative diseases |
| WO2015005499A1 (en) * | 2013-07-12 | 2015-01-15 | 住友化学株式会社 | Tetrazolinone compound and use thereof |
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