CN104803921A - Preparation method of benzene-substituted pyrimidine derivative - Google Patents
Preparation method of benzene-substituted pyrimidine derivative Download PDFInfo
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- CN104803921A CN104803921A CN201510111990.0A CN201510111990A CN104803921A CN 104803921 A CN104803921 A CN 104803921A CN 201510111990 A CN201510111990 A CN 201510111990A CN 104803921 A CN104803921 A CN 104803921A
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- BMWLGLDSLNILNL-UHFFFAOYSA-N CC(C)c1nc(-c2cc(Br)cc(C(OC)=O)c2)ccn1 Chemical compound CC(C)c1nc(-c2cc(Br)cc(C(OC)=O)c2)ccn1 BMWLGLDSLNILNL-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
Abstract
The invention discloses a preparation method of a benzene-substituted pyrimidine derivative 3-bromine-5-(2-isopropyl pyrimidine-4-yl) benzoic acid. A 3-acetyl-5-bromobenzoic acid is taken as a starting material and is subjected to esterification, acryloylation and acylation, ring closing and hydrolysis reaction, and a target product is obtained. The product is taken as a small template molecule to synthesize various compound libraries.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, particularly the bromo-5-of a kind of benzene substituted pyrimidines derivative 3-(2-isopropylpyrimidin-4-base) benzoic preparation method.
Technical background
The bromo-5-of compound 3-(2-isopropylpyrimidin-4-base) phenylformic acid, structural formula is:
The bromo-5-of this compound 3-(2-isopropylpyrimidin-4-base) phenylformic acid and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The bromo-5-of current 3-(2-isopropylpyrimidin-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 the bromo-5-of a kind of benzene substituted pyrimidines derivative 3-(2-isopropylpyrimidin-4-base) benzoic preparation method; take isopropyl salicylate as starting raw material; with 3-ethanoyl-5-bromo-benzoic acid for starting raw material; obtain target product 5 through over-churning, polyacryl, Guan Huan, hydrolysis reaction, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with 3-ethanoyl-5-bromo-benzoic acid for starting raw material, obtain 2 through esterification,
(2) carry out polyacryl reaction 2, obtain 3,
(3) carry out ring closure reaction 3 and obtain 4,
(4) be hydrolyzed 4 and be obtained by reacting 5,
One preferred embodiment in, described esterification is prepared compound 2 reagent used and is selected from sulfur oxychloride; Described polyacryl reaction is prepared compound 3 reagent used and is selected from DMF dimethylacetal; Described ring closure reaction is prepared compound 4 reagent used and is selected from 2-methyl propylamine imide salts hydrochlorate; The alkali that described hydrolysis reaction prepares compound 5 used is selected from sodium hydroxide.
One preferred embodiment in, described esterification prepares compound 2 solvent selected from methanol used; Described polyacryl reacts the solvent preparing compound 3 used and is selected from DMF; Described ring closure reaction prepares compound 4 solvent selected from methanol used; Described hydrolysis reaction prepares compound 5 solvent selected from methanol used.
One preferred embodiment in, it is room temperature that described esterification prepares compound 2 temperature of reaction used; The reflux temperature that compound 3 temperature used is solvent is prepared in described polyacryl reaction; Described ring closure reaction prepares the reflux temperature that compound 4 temperature used is solvent; It is room temperature that described hydrolysis reaction prepares compound 5 temperature used.
The present invention relates to the bromo-5-of a kind of benzene substituted pyrimidines derivative 3-(2-isopropylpyrimidin-4-base) benzoic preparation method, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the bromo-5-of compound thing 3-(2-isopropylpyrimidin-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 3-ethanoyl-5-methyl-bromobenzoate
25g 3-ethanoyl-5-bromo-benzoic acid is joined in 240ml anhydrous methanol, drips 35g sulfur oxychloride, stirred overnight at room temperature, concentrated, obtain 28g 3-ethanoyl-5-methyl-bromobenzoate.
(2) synthesis of the bromo-5-of 3-(3-(dimethylamino) acryl) methyl benzoate
22g 3-ethanoyl-5-methyl-bromobenzoate is joined 160ml N; in dinethylformamide, add 30g DMF dimethylacetal; reflux stirs 3 hours; cooling, adds water and extraction into ethyl acetate separatory, collects organic phase; wash three times with water; organic phase is dry, concentrated, crosses post separation and obtains the bromo-5-of 24g 3-(3-(dimethylamino) acryl) methyl benzoate.
(3) synthesis of the bromo-5-of 3-(2-isopropylpyrimidin-4-base) methyl benzoate
Bromo-for 23g 3-5-(3-(dimethylamino) acryl) methyl benzoate is joined in 200ml methyl alcohol; add 25g sodium methylate; add 37g 2-methyl propylamine imide salts hydrochlorate again; reflux stirs 5 hours, concentrating under reduced pressure, adds water and extraction into ethyl acetate separatory; collect organic phase; drying, concentrated, residuum recrystallisation from isopropanol obtains the bromo-5-of 26g 3-(2-isopropylpyrimidin-4-base) methyl benzoate.
(4) the bromo-5-of 3-(2-isopropylpyrimidin-4-base) benzoic synthesis
Bromo-for 25g 3-5-(2-isopropylpyrimidin-4-base) methyl benzoate is joined in 300ml methyl alcohol, add 50ml water, then add 16g sodium hydroxide, stirring at room temperature 24 hours, add dilute hydrochloric acid, concentrated, then add ethyl acetate, extraction separatory, collect organic phase, drying, concentrated, residuum is crossed post separation and is obtained the bromo-5-of 14g 3-(2-isopropylpyrimidin-4-base) phenylformic acid.
Claims (5)
1. the benzoic preparation method of the bromo-5-of benzene substituted pyrimidines derivative 3-(2-isopropylpyrimidin-4-base); with 3-ethanoyl-5-bromo-benzoic acid for starting raw material; obtain target product 5 through over-churning, polyacryl, Guan Huan, 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-ethanoyl-5-bromo-benzoic acid for starting raw material, obtain 2 through esterification,
(2) carry out polyacryl reaction 2, obtain 3,
(3) carry out ring closure 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, described esterification is prepared compound 2 reagent used and is selected from the mixture of one or more in p-methyl benzenesulfonic acid, sulfur oxychloride, N, N'-carbonyl dimidazoles, dicyclohexylcarbodiimide, trimethyl orthoformate, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride; Described polyacryl reaction is prepared compound 3 reagent used and is selected from DMF dimethylacetal; Described ring closure reaction is prepared compound 4 reagent used and is selected from 2-methyl propylamine imide salts hydrochlorate; Described hydrolysis reaction is prepared compound 5 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 esterification 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 polyacryl reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile, water; Described ring closure reaction prepares 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, 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, water.
5. according to the method for claim 1-2, it is characterized in that, described esterification 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 polyacryl reaction; Described ring closure reaction prepares the reflux temperature that compound 4 temperature used is 0 DEG C ~ solvent; Described hydrolysis reaction prepares the reflux temperature that compound 5 temperature used is 0 DEG C ~ solvent.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105384636A (en) * | 2015-11-17 | 2016-03-09 | 湖南尔康制药股份有限公司 | Preparation method of citrate |
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| WO2004032882A2 (en) * | 2002-10-10 | 2004-04-22 | Smithkline Beecham Corporation | Chemical compounds |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105384636A (en) * | 2015-11-17 | 2016-03-09 | 湖南尔康制药股份有限公司 | Preparation method of citrate |
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