CN107176926A - A kind of preparation method of pyridine derivatives - Google Patents
A kind of preparation method of pyridine derivatives Download PDFInfo
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- CN107176926A CN107176926A CN201610132605.5A CN201610132605A CN107176926A CN 107176926 A CN107176926 A CN 107176926A CN 201610132605 A CN201610132605 A CN 201610132605A CN 107176926 A CN107176926 A CN 107176926A
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a kind of pyrimidine derivatives 5- amino -2- (3,5- 3,5-dimethylphenyls) pyrimidine -4- formamides preparation method, using 5- aminopyrimidine -4- carboxylic acids as initiation material, target product is obtained through over-churning, amidatioon, upper bromine, coupling reaction, the compound is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of preparation method of pyrimidine derivatives 5- amino -2- (3,5- 3,5-dimethylphenyl) pyrimidine -4- formamides.
Technical background
Compound 5- amino -2- (3,5- 3,5-dimethylphenyl) pyrimidine -4- formamides, structural formula is：
This compound 5- amino -2- (3,5- 3,5-dimethylphenyls) pyrimidine -4- formamides and the derivative of correlation have extensive use in pharmaceutical chemistry and organic synthesis.The synthesis of current 5- amino -2- (3,5- 3,5-dimethylphenyls) pyrimidine -4- formamides 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
Pyrimidine derivatives 5- amino -2- (3 is prepared the invention discloses one kind, 5- 3,5-dimethylphenyls) pyrimidine -4- formamides preparation method, using 5- aminopyrimidine -4- carboxylic acids as initiation material, target product 5 is obtained through over-churning, amidatioon, upper bromine, coupling reaction, synthesis step is as follows：
(1) using 5- aminopyrimidine -4- carboxylic acids as initiation material, 2 are obtained by esterification；
(2) amidation process is carried out 2, obtains 3；
(3) carry out upper bromine reaction 3 and obtain 4；
(4) 4 progress coupling reactions are obtained 5；
In a preferred embodiment, the reagent used in described esterification prepare compound 2 is selected from the mixture of thionyl chloride and methanol；Reagent used in described amidation process prepare compound 3 is selected from ammoniacal liquor；Reducing agent used in described upper bromine reaction prepare compound 4 is selected from bromine；Reagent used in described coupling reaction prepare compound 5 is selected from tetrakis triphenylphosphine palladium.
In a preferred embodiment, the solvent used in described esterification prepare compound 2 is selected from methanol；Solvent used in described amidation process prepare compound 3 is selected from ammoniacal liquor；Solvent used in described upper bromine reaction prepare compound 4 is selected from acetic acid；Solvent used in described coupling reaction prepare compound 5 is selected from tetrahydrofuran.
In a preferred embodiment, the reaction temperature used in described esterification prepare compound 2 is room temperature；Temperature used in described amidation process prepare compound 3 is room temperature；Temperature used in described upper bromine reaction prepare compound 4 is the reflux temperature of solvent；Temperature used in described coupling reaction prepare compound 5 is the reflux temperature of solvent.
The present invention relates to a kind of preparation method of pyrimidine derivatives 5- amino -2- (3,5- 3,5-dimethylphenyl) pyrimidine -4- formamides, 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 5- aminopyrimidines -4- carboxylate methyl esters
15g 5- aminopyrimidine -4- carboxylic acids are added in 200ml methanol, 10ml thionyl chlorides are added dropwise, are stirred overnight at room temperature, are concentrated, 200ml toluene is added, concentration obtains 18g 5- aminopyrimidine -4- carboxylate methyl esters.
(2) synthesis of 5- aminopyrimidines -4- formamides
17g 5- aminopyrimidine -4- carboxylate methyl esters are added in 300ml ammoniacal liquor, are stirred at room temperature 22 hours, ethyl acetate extraction point liquid is added, collects organic phase, dry, concentration obtains 12g 5- aminopyrimidine -4- formamides.
(3) synthesis of 5- amino -2- Bromopyrimidines -4- formamides
12g 5- aminopyrimidine -4- formamides are added in 150ml acetic acid, 19g bromines are slowly added to, stirring 3 hours is heated to reflux, concentration, add water and ethyl acetate carries out silica gel post separation on extraction point liquid, concentration, residue and obtains 10g 5- amino -2- Bromopyrimidine -4- formamides.
(4) synthesis of 5- amino -2- (3,5- 3,5-dimethylphenyls) pyrimidine -4- formamides
10g 5- amino -2- Bromopyrimidine -4- formamides are added in 120ml tetrahydrofurans, 0.1g tetrakis triphenylphosphine palladiums and 12.6g sodium carbonate are added, 14g 3 is then added, 5- dimethylphenyl boronic acids are heated to reflux stirring 5 hours, concentration, add water and ethyl acetate, extraction, point liquid, collect organic phase, silicagel column isolated 7g 5- amino -2- (3,5- 3,5-dimethylphenyl) pyrimidine -4- formamides on concentration, residue.
Claims (5)
1. one kind prepares the preparation method of pyrimidine derivatives 5- amino -2- (3,5- 3,5-dimethylphenyl) pyrimidine -4- formamides, with 5- amino
Pyrimidine -4- carboxylic acids are initiation material, and target product 5 is obtained through over-churning, amidatioon, upper bromine, coupling reaction, synthesize road
Line is as follows：
2. according to claim 1-2 method, it is characterised in that the reagent used in described esterification prepare compound 2 is selected from
Thionyl chloride, sulfuric acid, hydrogen chloride, N, N- carbonyl dimidazoles, dicyclohexylcarbodiimide, p-methyl benzenesulfonic acid, methanol
In one or more of mixtures；Reagent used in described amidation process prepare compound 3 is selected from ammoniacal liquor, ammonia
One or both of mixture；Reducing agent used in described upper bromine reaction prepare compound 4 is selected from bromine, bromination
One or more of mixtures in hydrogen, N- bromo-succinimides；Used in described coupling reaction prepare compound 5
Reagent is selected from palladium, palladium bichloride, [double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex, four (three
Phenylphosphine) one or more of mixtures in palladium.
3. according to claim 1-2 method, it is characterised in that the solvent used in described esterification prepare compound 2 is selected from
Methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene,
One or more in dimethylbenzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, triethylamine, pyridine, acetonitrile
Mixture；Solvent used in described amidation process prepare compound 3 is selected from methanol, ethanol, normal propyl alcohol, isopropyl
Alcohol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide,
One or more of mixing in DMAC N,N' dimethyl acetamide, acetonitrile, water, ammoniacal liquor, hydrochloric acid, the concentrated sulfuric acid, oleum
Thing；Solvent used in described upper bromine reaction prepare compound 4 is selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrochysene
Furans, dioxane, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N, N-
One or more of mixtures in dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, acetic acid；Described coupling
React prepare compound 5 used in solvent be selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane,
Dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N- dimethyl second
One or more of mixtures in acid amides.
4. according to claim 1-2 method, it is characterised in that the reaction temperature used in described esterification prepare compound 2
It is the reflux temperature of -80 DEG C~solvent；Temperature used in described amidation process prepare compound 3 is returning for 0 DEG C~solvent
Flow temperature；Temperature used in described upper bromine reaction prepare compound 4 is the reflux temperature of 0 DEG C~solvent；Described coupling
Temperature used in reaction prepare compound 5 is the reflux temperature of 0 DEG C~solvent.
5. according to claim 1-2 method, it is characterised in that the reaction temperature used in described esterification prepare compound 2
It is room temperature；Temperature used in described amidation process prepare compound 3 is room temperature；Described upper bromine reaction prepares chemical combination
Temperature used in thing 4 is the reflux temperature of solvent；Temperature used in described coupling reaction prepare compound 5 is solvent
Reflux temperature.
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| CN201610132605.5A CN107176926A (en) | 2016-03-09 | 2016-03-09 | A kind of preparation method of pyridine derivatives |
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| CN201610132605.5A CN107176926A (en) | 2016-03-09 | 2016-03-09 | A kind of preparation method of pyridine derivatives |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104387331A (en) * | 2014-10-27 | 2015-03-04 | 湖南华腾制药有限公司 | Preparation method of pyrazine derivative |
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- 2016-03-09 CN CN201610132605.5A patent/CN107176926A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104387331A (en) * | 2014-10-27 | 2015-03-04 | 湖南华腾制药有限公司 | Preparation method of pyrazine derivative |
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Application publication date: 20170919 |
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