A kind of preparation method of pyrazole derivativesTechnical field
The present invention relates to a kind of novel processing step of medicine intermediate, particularly the preparation method of a kind of pyrazole derivatives 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol.
Technical background
Compound 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol, structural formula is:
This compound 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol 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 method that one prepares 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol, take methyl aceto acetate as starting raw material, obtain target product 4 through the ring that reaches a standard, condensation, reduction, synthetic route is as shown in Figure 1.Synthesis step is as follows:
(1) be starting raw material with methyl aceto acetate, obtain 2 through ring closure reaction;
(2) carry out condensation reaction 2, obtain 3;
(3) carry out tertbutyloxycarbonyl protective reaction 3 and obtain 4;
One preferred embodiment in, the reagent that described ring closure reaction prepares compound 2 used is selected from hydrazine hydrate; The alkali that described condensation reaction prepares compound 3 used is selected from salt of wormwood; The reductive agent that described reduction reaction prepares compound 4 used is selected from lithium aluminium hydride.
One preferred embodiment in, the solvent that described ring closure reaction prepares compound 2 used is selected from toluene; The solvent that described condensation reaction prepares compound 3 used is selected from DMF; The solvent that described reduction reaction prepares compound 4 used is selected from tetrahydrofuran (THF).
One preferred embodiment in, described ring closure reaction prepares the reflux temperature that compound 2 temperature of reaction used is solvent; Described reduction reaction prepares the reflux temperature that compound 3 temperature used is solvent; Described reduction reaction prepare compound 4 used be 0 DEG C ~ room temperature.
The present invention relates to the preparation method of a kind of 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol.
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-methylpyrazole-5-alcohol
20g methyl aceto acetate is joined in 130ml toluene, and add 26g hydrazine hydrate, return stirring spends the night, and concentrated adds ethyl acetate and water again, separatory, drying, concentrated, and residuum upper prop is separated and obtains 17g 3-methylpyrazole-5-alcohol.
(2) synthesis of 3-methyl isophthalic acid-(3-nitrophenyl)-1H-pyrazoles-5-alcohol
16g 3-methylpyrazole-5-alcohol is joined 250ml N, in dinethylformamide, add 9g Anhydrous potassium carbonate and 24g3-Nitrobromobenzene again, reflux stirs 2 hours, be cooled to room temperature again, slowly add ethyl acetate and water, extract separatory, drying, concentrate, on residuum, silicagel column is separated to obtain 19g 3-methyl isophthalic acid-(3-nitrophenyl)-1H-pyrazoles-5-alcohol.
(3) synthesis of 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol
18g 3-methyl isophthalic acid-(3-nitrophenyl)-1H-pyrazoles-5-alcohol joins in 200ml anhydrous tetrahydro furan, cool 0 DEG C, slowly add 6g Lithium Aluminium Hydride again, stirring at room temperature 6 hours, adds aqueous sodium hydroxide solution in batches, filter, collect mother liquor, add ethyl acetate, extraction separatory, dry, concentrated, on residuum, silicagel column is separated to obtain 9g 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol.