The invention belongs to the technical field of organic synthesis and preparation of raw material medicines, and particularly relates to a preparation method and an intermediate of a medicine Irbinitinib for treating breast cancer, which comprises the following steps: the compound of formula 14 is generated by substituting, cyclizing and hydrogenating 2-methyl-4-nitrophenol (formula 8) and 4-chloro-2-nitropyridine (formula 9), the compound of formula 14 and the compound of formula 2 are cyclized and hydrogenated and reduced to generate a compound of formula 16, the compound of formula 19 is generated by cyclizing and substituting 2-amino-2-methyl-1-propanol and di (1H-imidazole-1-yl) methinone, and the compound of formula 16 and the compound of formula 19 react to obtain Irbinitinib of formula 20. The method has the advantages of easily available raw materials, mild reaction conditions, simple and convenient operation, environmental friendliness, low cost, high yield and good industrial production prospect.

Irbinitinib and preparation method of intermediate
Technical Field
The invention belongs to the technical field of organic synthesis and preparation of raw material medicine intermediates, and particularly relates to Irbinitinib, an Irbinitinib synthesis intermediate and a preparation method.
Background
Irbinitinib (ARRY-380, ONT-380) is a highly potent and selective HER2 inhibitor with an IC50 value of 8nM, developed by Array BioPharma, Cascaden Therapeutics, and is currently in phase II clinical studies for the treatment of brain metastatic breast cancer. The chemical structure is shown as formula I:
at present, Irbinitinib is prepared mainly by a method described in WO2013142875, WO2013056108 and WO2007059257, through reactions such as substitution, cyclization and the like of (E) -N' - (2-cyano-4-nitrophenyl) -N, N-dimethylformamidine, 2-amino-2-methyl-1-propanol and di (1H-imidazol-1-yl) methylthioketone, and the synthesis is shown as a route I.
The method uses expensive reagents, such as di (1H-imidazole-1-yl) methylthio ketone, as raw materials to synthesize the compound 6 with a yield of about 34%, so that the cost is high. (E) The total yield of Irbinitinib obtained by the substitution, cyclization and other reactions of (E) -N' - (2-cyano-4-nitrophenyl) -N, N-dimethylformamidine, 2-amino-2-methyl-1-propanol and di (1H-imidazol-1-yl) methylthioketone is about 30 percent, and the industrial production of Irbinitinib is restricted to a certain extent.
Therefore, aiming at the defects in the prior art, the prior art is improved, and the preparation method which has the advantages of easily obtained raw materials, simple process, convenient operation and higher yield is provided, so that the cost is reduced.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a novel preparation method of Irbinitinib, and the method has the advantages of easily available raw materials, simple process, convenient operation, high yield, low cost and easy industrial production.
The invention also provides an intermediate for preparing the Irbinitinib and a preparation method of the intermediate.
The preparation of Irbinitinib of the invention is shown in scheme ii:
a novel intermediate for the synthesis of Irbinitinib, which is a compound of formula 14, 4- ([1,2,4] triazolo [1,5-a ] pyridin-7-yloxy) -3-methylaniline.
A process for the preparation of 4- ([1,2,4] triazolo [1,5-a ] pyridin-7-yloxy) -3-methylaniline, a compound of formula 14, is shown in scheme ii and comprises the steps of:
a. in an organic solvent containing alkali, reacting a compound 2-methyl-4-nitrophenol of a formula 8 with a compound 4-chloro-2-aminopyridine of a formula 9 to prepare a compound 4- (2-methyl-4-nitrophenoxy) pyridine-2-amine of a formula 10;
b. in an organic solvent, after reacting 4- (2-methyl-4-nitrophenoxy) pyridine-2-amine of a compound shown in a formula 10 with N, N-dimethylformamide dimethyl acetal (DMF-DMA), adding hydroxylamine hydrochloride for reaction to obtain a compound shown in a formula 12, namely N-hydroxy-N' - (4- (2-methyl-4-nitrophenoxy) pyridine-2-yl) formamidine;
c. cyclizing the compound N-hydroxy-N' - (4- (2-methyl-4-nitrophenoxy) pyridine-2-yl) formamidine shown as the formula 12 in an organic solvent in an ice bath environment under the action of trifluoroacetic anhydride to obtain a compound 7- (2-methyl-4-nitrophenoxy) - [1,2,4] triazolo [1,5-a ] pyridine shown as the formula 13;
d. in the presence of hydrogen and a catalyst, reducing the compound 7- (2-methyl-4-nitrophenoxy) - [1,2,4] triazolo [1,5-a ] pyridine of the formula 13 in an organic solvent to obtain the compound 4- ([1,2,4] triazolo [1,5-a ] pyridin-7-yloxy) -3-methylaniline of the formula 14.
The concentration of the 2-methyl-4-nitrophenol in the step a is 0.5-1.5 mol/L, preferably 0.7-1 mol/L; the molar ratio of 2-methyl-4-nitrophenol, 4-chloro-2-nitropyridine to base is 1: 0.5-1.5: 1 to 3.5, preferably 1: 0.6-1: 1.2 to 3, more preferably 1: 1: 3; the organic solvent comprises acetonitrile, N-methylpyrrolidone or N, N-dimethylformamide, preferably N-methylpyrrolidone; the base comprises potassium carbonate, diisopropylethylamine or sodium hydroxide, preferably diisopropylethylamine.