Synthesis method for 1-methyl-1H-indazole-6-carboxylic acid
The present application provides a synthesis method for 1-methyl-1H-indazole-6-carboxylic acid. The synthesis method comprises: using 2-fluoro-4-bromobenzaldehyde and methylhydrazine as raw materials to obtain 6-bromo-1-methylindazole by means of an annulation reaction, and then performing a methyl formate reaction and a hydrolysis reaction, so as to obtain the 1-methyl-1H-indazole-6-carboxylic acid. The synthesis method provided in the present application can directly synthesize a 1-position methyl substituted indazole without isomers, thereby avoiding the problem that impurities are difficult to be removed in subsequent separation, thus improving the purity of a product. The yield of the annulation reaction can reach 85%.
1. A synthesis method for 1-methyl-1H-indazole-6-carboxylic acid, comprising:
subjecting 2-fluoro-4-bromobenzaldehyde and methylhydrazine as raw materials to an annulation reaction to obtain 6-bromo-1-methylindazole;
dissolving the 6-bromo-1-methylindazole in methanol and performing a reaction under a carbon monoxide atmosphere in the presence of a first base and a catalyst to obtain methyl 1-methyl-1H-indazole-6-carboxylate; and
subjecting the methyl 1-methyl-1H-indazole-6-carboxylate to a hydrolysis reaction to obtain the 1-methyl-1H-indazole-6-carboxylic acid;
wherein in the annulation reaction a solvent is used, and the solvent is N,N-dimethylacetamide.
2. The synthesis method according to claim 1 , wherein the annulation reaction is carried out in the presence of a second base; and the second base is any one or a combination of at least two selected from the group consisting of potassium carbonate, cesium carbonate, triethylamine, potassium tert-butoxide, and sodium ethanol.
3. The synthesis method according to claim 2 , wherein the second base is potassium carbonate.
4. The synthesis method according to claim 2 , wherein a molar ratio of the 2-fluoro-4-bromobenzaldehyde, the methylhydrazine and the second base is in a range of 1:(1-1.2):(1.5-2).
5. The synthesis method according to claim 1 , wherein the annulation reaction is performed at a temperature of 95° C. to 105° C.; and
the annulation reaction is performed for 35 h to 40 h.
6. The synthesis method according to claim 1 , wherein a molar ratio of the 6-bromo-1-methylindazole, the first base and the catalyst is in a range of 1:(2-3):(0.02-0.5);
the first base in the reaction is any one or a combination of at least two selected from the group consisting of triethylamine, potassium carbonate, and sodium bicarbonate;
the catalyst is [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex;
a pressure under the carbon monoxide atmosphere is 4.5 MPa to 5.0 MPa;
the reaction is performed at a temperature of 100° C. to 110° C.; and
the reaction is performed for 15 h to 20 h.
7. The synthesis method according to claim 1 , wherein the hydrolysis reaction is performed by hydrolyzing the methyl 1-methyl-1H-indazole-6-carboxylate under an alkaline condition to obtain the 1-methyl-1H-indazole-6-carboxylic acid.
8. The synthesis method according to claim 7 , wherein the alkaline condition is provided by sodium hydroxide;
a molar ratio of the methyl 1-methyl-1H-indazole-6-carboxylate to the sodium hydroxide is in a range of 1:0.9-1;
a solvent for the hydrolysis reaction is a mixed solution of methanol and water;
the hydrolysis reaction is performed at a temperature of 20° C. to 30° C.; and
the hydrolysis reaction is performed for 15 h to 20 h.
9. The synthesis method according to claim 1 , wherein the synthesis method comprises the following steps:
(1) subjecting the 2-fluoro-4-bromobenzaldehyde and the methylhydrazine as raw materials to the annulation reaction in the presence of a second base at a temperature of 95-105° C. for 35-40 h, and after that, crystallizing from n-heptane to obtain the 6-bromo-1-methylindazole, wherein a molar ratio of the 2-fluoro-4-bromobenzaldehyde, the methylhydrazine and the second base is in a range of 1:(1-1.2):(1.5-2);
(2) dissolving the 6-bromo-1-methyl-indazole in the methanol, putting a resulting solution into an autoclave, and performing the reaction at 100-110° C. for 15-20 h under the carbon monoxide atmosphere and a pressure of 4.5-5.0 MPa in the presence of the first base and the catalyst, washing with methyl tert-butyl ether after the reaction, and crystallizing from the n-heptane to obtain the methyl 1-methyl-1H-indazole-6-carboxylate, wherein a molar ratio of the 6-bromo-1-methyl indazole, the first base and the catalyst is in a range of 1:(2-3):(0.02-0.5); and
(3) dissolving the methyl 1-methyl-1H-indazole-6-carboxylate in a mixed solution of methanol and water, cooling to 0-10° C., adding with a third base, heating a resulting mixture to a temperature of 20-30° C., and performing the hydrolysis reaction for 15-20 h to obtain the 1-methyl-1H-indazole-6-carboxylic acid, wherein a molar ratio of the methyl 1-methyl-1H-indazole-6-carboxylate to the third base is in a range of 1:0.9-1.
10. The synthesis method according to claim 6 , wherein the first base in the reaction is the triethylamine.
11. The synthesis method according to claim 9 , wherein the first base is any one or a combination of at least two selected from the group consisting of triethylamine, potassium carbonate, and sodium bicarbonate.
12. The synthesis method according to claim 9 , wherein the second base is any one or a combination of at least two selected from the group consisting of potassium carbonate, cesium carbonate, triethylamine, potassium tert-butoxide, and sodium ethoxide.
13. The synthesis method according to claim 9 , wherein the third base is sodium hydroxide.