CN107286100A - A kind of preparation method of 2- substituted pyrimidines derivative - Google Patents
A kind of preparation method of 2- substituted pyrimidines derivative Download PDFInfo
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- CN107286100A CN107286100A CN201610206678.4A CN201610206678A CN107286100A CN 107286100 A CN107286100 A CN 107286100A CN 201610206678 A CN201610206678 A CN 201610206678A CN 107286100 A CN107286100 A CN 107286100A
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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
Abstract
The invention discloses a kind of preparation method of the carboxylate methyl ester of 2 substituted pyrimidines derivative, 6 chlorine 2 (4 fluorophenyl) pyrimidine 4, using diethy-aceto oxalate as initiation material, target product is obtained by condensation, cyclization, chlorination, esterification, the compound is important medicine intermediate.
Description
Technical field
The present invention relates to the preparation method of a kind of novel processing step of medicine intermediate, the more particularly to a kind of chloro- 2- of 2- substituted pyrimidines derivative 6- (4- fluorophenyls) pyrimidine -4- carboxylate methyl esters.
Technical background
The chloro- 2- of compound 6- (4- fluorophenyls) pyrimidine -4- carboxylate methyl esters, structural formula is：
The chloro- 2- of this compound 6- (4- fluorophenyls) pyrimidine -4- carboxylate methyl esters and the derivative of correlation have extensive use in pharmaceutical chemistry and organic synthesis.The synthesis of current 6- chloro- 2- (4- fluorophenyls) pyrimidine -4- carboxylate methyl esters is more difficult.It is easy to get accordingly, it would be desirable to develop a raw material, it is easy to operate, react easily controllable, the suitable synthetic method of overall yield.
The content of the invention
The invention discloses the method that one kind prepares the chloro- 2- of 6- (4- fluorophenyls) pyrimidine -4- carboxylate methyl esters, using diethy-aceto oxalate as initiation material, target product 5 is obtained by condensation, cyclization, chlorination, esterification, synthesis step is as follows：
(1) using diethy-aceto oxalate as initiation material, 2 are obtained by condensation reaction；
(2) ring closure reaction is carried out 2, obtains 3；
(3) 3 progress chlorination reactions are obtained 4；
(4) 4 progress esterifications are obtained 5；
In a preferred embodiment, the alkali used in described condensation reaction prepare compound 2 is selected from caustic alcohol；Alkali used in described ring closure reaction prepare compound 3 is selected from sodium hydroxide；Reagent used in described chlorination reaction prepare compound 4 is selected from POCl3；Reagent used in described esterification prepare compound 5 is selected from p-methyl benzenesulfonic acid and methanol.
In a preferred embodiment, the solvent used in described condensation reaction prepare compound 2 is selected from tetrahydrofuran；Solvent used in described ring closure reaction prepare compound 3 is selected from water；Solvent used in described chlorination reaction prepare compound 4 is selected from POCl3；Solvent used in described esterification prepare compound 5 is selected from methanol.
In a preferred embodiment, the reaction temperature used in described condensation reaction prepare compound 2 is the reflux temperature of solvent；Temperature used in described ring closure reaction prepare compound 3 is the reflux temperature of solvent；Temperature used in described chlorination reaction prepare compound 4 is the reflux temperature of solvent；Temperature used in described esterification prepare compound 5 is room temperature.
The present invention relates to the preparation method of a kind of chloro- 2- of 6- (4- fluorophenyls) pyrimidine -4- carboxylate methyl esters, reported currently without other Patents documents.
The present invention is further described by the following embodiment, and these descriptions are not that present invention is further limited.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or be correspondingly improved, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of methyl-oxalacetic ester
30g ethyl acetate is added in 400ml anhydrous tetrahydro furans, add 46g caustic alcohols, it is heated to reflux 1 hour, it is cooled to room temperature, 50g diethy-aceto oxalates are added, return stirring 4 hours, concentration adds ethyl acetate and water, divide liquid, drying, concentration, the isolated 38g methyl-oxalacetic esters of residue upper prop.
(2) synthesis of 6- hydroxyls -2- (4- fluorophenyls) pyrimidine -4- carboxylic acid, ethyl esters
35g methyl-oxalacetic esters are added in 500ml water, add 16g sodium hydroxides and 41g 4- fluorobenzene carbonamidines, it is heated to reflux stirring 5 hours, it is cooled to room temperature, add ethyl acetate extraction, silica gel post separation on liquid, drying, concentration, residue is divided to obtain 22g 6- hydroxyls -2- (4- fluorophenyls) pyrimidine -4- carboxylic acid, ethyl esters.
(3) synthesis of the chloro- 2- of 6- (4- fluorophenyls) pyrimidine -4- carboxylic acids
20g 6- hydroxyls -2- (4- fluorophenyls) pyrimidine -4- carboxylic acid, ethyl esters are added in 120ml POCl3s, it is heated to reflux stirring 2 hours, it is stirred at room temperature 6 hours, concentration removes POCl3, residue is poured into frozen water, ethyl acetate extraction is added, dries, concentrate, silica gel post separation obtains the chloro- 2- of 12g 6- (4- fluorophenyls) pyrimidine -4- carboxylic acids on residue.
(4) synthesis of the chloro- 2- of 6- (4- fluorophenyls) pyrimidine -4- carboxylate methyl esters
The chloro- 2- of 10g 6- (4- fluorophenyls) pyrimidine -4- carboxylic acids are added in 150ml methanol, add 0.5g p-methyl benzenesulfonic acid, it is stirred at room temperature 12 hours, concentration removes methanol, add ethyl acetate and water extraction, dry, concentrate, silica gel post separation obtains the chloro- 2- of 8g 6- (4- fluorophenyls) pyrimidine -4- carboxylate methyl esters on residue.
Claims (6)
1. one kind prepares the preparation method of 2- substituted pyrimidines derivative 6- chloro- 2- (4- fluorophenyls) pyrimidine -4- carboxylate methyl esters, with oxalic acid two
Ethyl ester is initiation material, obtains target product 5 by condensation, cyclization, chlorination, esterification, synthetic route is as follows.
2. method according to claim 1, it is characterized in that described 4 steps reaction is,
(1) using diethy-aceto oxalate as initiation material, 2 are obtained by condensation reaction；
(2) ring closure reaction is carried out 2, obtains 3；
(3) 3 progress chlorination reactions are obtained 4；
(4) 4 progress esterifications are obtained 5；
3. according to claim 1-2 method, it is characterised in that the alkali used in described condensation reaction prepare compound 2 is selected from hydrogen
Sodium oxide molybdena, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, triethylamine, sodium acid carbonate, pyridine, triisopropyl
Amine, saleratus, sodium methoxide, caustic alcohol, sodium tert-butoxide, lithium amide, lithium diisopropylamine, tert-butyl lithium, just
One or more of mixtures in butyl lithium；Alkali used in described ring closure reaction prepare compound 3 be selected from sodium hydroxide,
Potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, triethylamine, sodium acid carbonate, pyridine, triisopropylamine, carbonic acid
One or more of mixtures in one or more of mixtures in hydrogen potassium, sodium methoxide, caustic alcohol, sodium tert-butoxide；
The one kind of reagent in thionyl chloride, POCl3, phosphorus pentachloride used in described chlorination reaction prepare compound 4
Or several mixtures；Reagent used in described esterification prepare compound 5 is selected from p-methyl benzenesulfonic acid, orthoformic acid
One or more of mixtures in trimethyl, thionyl chloride, methanol.
4. according to claim 1-2 method, it is characterised in that the solvent used in described condensation reaction prepare compound 2 is selected from
Methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene,
One or more of mixtures in dimethylbenzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide；Described cyclization
React prepare compound 3 used in solvent be selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane,
In toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, water
One or more of mixtures；Solvent used in described chlorination reaction prepare compound 4 is selected from methanol, ethanol, just
Propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N, N-
One or more of mixtures in dimethylformamide, DMAC N,N' dimethyl acetamide, POCl3, thionyl chloride；Institute
The solvent used in esterification prepare compound 5 stated be selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran,
Dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N- dimethyl second
One or more of mixtures in acid amides.
5. according to claim 1-2 method, it is characterised in that the reaction temperature used in described condensation reaction prepare compound 2
It is the reflux temperature of 0 DEG C~solvent；Temperature used in described ring closure reaction prepare compound 3 is the backflow of 0 DEG C~solvent
Temperature；Temperature used in described chlorination reaction prepare compound 4 is the reflux temperature of 0 DEG C~solvent；Described esterification is anti-
Answer the reflux temperature that the temperature used in prepare compound 5 is 0 DEG C~solvent.
6. according to claim 1-2 method, it is characterised in that the reaction temperature used in described condensation reaction prepare compound 2
It is the reflux temperature of solvent；Temperature used in described ring closure reaction prepare compound 3 is the reflux temperature of solvent；It is described
Chlorination reaction prepare compound 4 used in temperature be solvent reflux temperature；Described esterification prepare compound 5
Temperature used is room temperature.
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| CN201610206678.4A CN107286100A (en) | 2016-04-05 | 2016-04-05 | A kind of preparation method of 2- substituted pyrimidines derivative |
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| CN201610206678.4A CN107286100A (en) | 2016-04-05 | 2016-04-05 | A kind of preparation method of 2- substituted pyrimidines derivative |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101910184A (en) * | 2007-11-08 | 2010-12-08 | 西特里斯药业公司 | Solubility thiazole and pyridine |
| CN102503825A (en) * | 2011-11-11 | 2012-06-20 | 上海华谊（集团）公司 | Preparation method of medicine intermediate butanone diacid diester compound |
| CN103254137A (en) * | 2007-08-30 | 2013-08-21 | 陶氏益农公司 | 2-(substituted phenyl)-6-amino-5-alkoxy, thioalkoxy and aminoalkyl-4-pyrimidinecarboxylates and use thereof as herbicides |
-
2016
- 2016-04-05 CN CN201610206678.4A patent/CN107286100A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103254137A (en) * | 2007-08-30 | 2013-08-21 | 陶氏益农公司 | 2-(substituted phenyl)-6-amino-5-alkoxy, thioalkoxy and aminoalkyl-4-pyrimidinecarboxylates and use thereof as herbicides |
| CN101910184A (en) * | 2007-11-08 | 2010-12-08 | 西特里斯药业公司 | Solubility thiazole and pyridine |
| CN102503825A (en) * | 2011-11-11 | 2012-06-20 | 上海华谊（集团）公司 | Preparation method of medicine intermediate butanone diacid diester compound |
Non-Patent Citations (1)
| Title |
|---|
| 何敬文: "《药物合成反应》", 31 December 1995, 中国医药科技出版社 * |
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Application publication date: 20171024 |