A kind of pyridine connects the preparation method of pyrazole compoundTechnical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of pyridine connects pyrazole compound 1-The preparation method of (2-aminopyridine -4- bases) -3- methyl-1 H- pyrazoles -5- alcohol.
Technical background
Compound 1- (2-aminopyridine -4- bases) -3- methyl-1 H- pyrazoles -5- alcohol, structural formula are：
This compound 1- (2-aminopyridine -4- bases) -3- methyl-1 H- pyrazoles -5- alcohol and relevant derivative are in drugThere is extensive use in and organic synthesis.The synthesis of 1- (2-aminopyridine -4- bases) -3- methyl-1 H- pyrazoles -5- alcohol at presentIt is more difficult.It is easy to operate therefore, it is necessary to develop a raw material to be easy to get, react easily controllable, the overall yield suitably side of synthesisMethod.
The content of the invention
The invention discloses a kind of method for preparing 1- (2-aminopyridine -4- bases) -3- methyl-1 H- pyrazoles -5- alcohol, withEthyl acetoacetate is starting material, obtains target product 4 by cyclization, condensation, reduction, synthesis step is as follows：
(1) using ethyl acetoacetate as starting material, 2 are obtained by ring closure reaction；
(2) condensation reaction is carried out 2, obtains 3；
(3) 3 progress tertbutyloxycarbonyl protection reactions are obtained 4；
In a preferred embodiment, the reagent used in the ring closure reaction prepare compound 2 is selected from hydrazine hydrate；InstituteThe alkali used in condensation reaction prepare compound 3 stated is selected from potassium carbonate；Reduction used in the reduction reaction prepare compound 4Agent is selected from lithium aluminium hydride.
In a preferred embodiment, the solvent used in the ring closure reaction prepare compound 2 is selected from toluene；It is describedCondensation reaction prepare compound 3 used in solvent be selected from N,N-dimethylformamide；The reduction reaction prepare compound 4Solvent used is selected from tetrahydrofuran.
In a preferred embodiment, the reaction temperature used in the ring closure reaction prepare compound 2 is solventReflux temperature；Temperature used in the reduction reaction prepare compound 3 is the reflux temperature of solvent；The reduction reaction systemUsed in standby compound 4 is 0 DEG C~room temperature.
The present invention relates to a kind of preparation method of 1- (2-aminopyridine -4- bases) -3- methyl-1 H- pyrazoles -5- alcohol, at presentIt is reported without other Patents documents.
The present invention is further described by the following embodiment, these descriptions are not present invention to be made into oneThe restriction of step.It should be understood by those skilled in the art that the equivalent substitution made of technical characteristic to the present invention or changing accordinglyInto still falling within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 3- methylpyrazoles -5- alcohol
20g ethyl acetoacetates are added in 130ml toluene, add in 26g hydrazine hydrates, return stirring is overnight, and concentration is againAdd in ethyl acetate and water, liquid separation, drying, concentration, the isolated 17g 3- methylpyrazoles -5- alcohol of residue upper prop.
(2) synthesis of 3- methyl-1s-(2- nitropyridine -4- bases) -1H- pyrazoles -5- alcohol
16g 3- methylpyrazole -5- alcohol is added in 250ml n,N-Dimethylformamide, adds 9g Carbon DioxidesPotassium and the bromo- 2- nitropyridines of 24g4-, be heated to reflux stirring 2 it is small when, be cooled to room temperature, be slowly added to ethyl acetate and water, extractTake liquid separation, drying, concentration, on residue silica gel post separation obtain 19g 3- methyl-1s-(2- nitropyridine -4- bases) -1H- pyrazoles -5- alcohol.
(3) synthesis of 1- (2-aminopyridine -4- bases) -3- methyl-1 H- pyrazoles -5- alcohol
18g 3- methyl-1s-(2- nitropyridine -4- bases) -1H- pyrazoles -5- alcohol is added to 200ml anhydrous tetrahydro furansIn, cool down 0 DEG C, then 6g Lithium Aluminium Hydrides be slowly added portionwise, be stirred at room temperature 6 it is small when, add in sodium hydrate aqueous solution, filter, receiveCollect mother liquor, add in ethyl acetate, extract liquid separation, dry, concentration, on residue silica gel post separation obtain 9g 1- (2-aminopyridine-4- yls) -3- methyl-1 H- pyrazoles -5- alcohol.