Preparation method for CDK4/6 inhibitor

Patent metadata

Field	Value
Publication number	US-12570633-B2
Application number	US-202118011759-A
Country	US
Kind code	B2
Filing date	Jun 21, 2021
Priority date	Jun 22, 2020
Publication date	Mar 10, 2026
Grant date	Mar 10, 2026

Abstract

A preparation method for a CDK4/6 inhibitor for a compound of formula (I):5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)-N-(5-(piperazin-1-yl) pyrazol-2-yl)pyrimidine-2-amine. The preparation method has cheap and readily available starting materials and reagents, greatly simplified total reaction steps, shortened reaction time, improved total yield and a high purity of the key intermediate and final product, being suitable for industrial production.

First claim

The invention claimed is:

1 . A method for preparing a compound of formula (I), comprising:
step 1: reacting compound SMA-1 with compound SMA-8 to give compound SMA-2; step 2: reacting compound SMA-2 with hydrazine hydrate to give compound SMA-3; step 3: subjecting compound SMA-3 to a methylation reaction to give compound SMA-4; step 4: reacting compound SMA-4 with bis(pinacolato)diboron to give compound SMA-5; step 5: reacting compound SMA-5 with compound SMA-9 to give compound SMA-6; step 6: reacting compound SMA-6 with compound SMA-10 to give compound SMA-7; and step 7: reacting compound SMA-7 to give compound of formula (I);

2 . The method for preparing the compound of formula (I) according to claim 1 , wherein step 1 is conducted in the presence of a solvent and a base; wherein
the solvent is selected from one of or a mixed solvent of two or more of dichloromethane, tetrahydrofuran, dioxane, DMF, DMSO, acetonitrile, diethyl ether, isopropyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, n-hexane and n-heptane; and the base is selected from the group consisting of n-butyllithium, tert-butyllithium, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium bis(trimethylsilyl)amide, sodium hydride and lithium hydroxide.

3 . The method for preparing the compound of formula (I) according to claim 2 , wherein the molar ratio of compound SMA-1 to compound SMA-8 is 1:(1-2).

4 . The method for preparing the compound of formula (I) according to claim 2 , wherein the molar-to-volume ratio of compound SMA-1 to the solvent is 1 mmol:(0.5-1.5) mL.

5 . The method for preparing the compound of formula (I) according to claim 2 , wherein the molar ratio of compound SMA-1 to the base is 1:(1-3).

6 . The method for preparing the compound of formula (I) according to claim 1 , wherein step 2 is conducted in the presence of a solvent; wherein
the solvent is selected from the group consisting of ethylene glycol, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diphenyl ether, orthodichlorobenzene, sulfolane, trimethylbenzene, diethylene glycol dimethyl ether and N-methylpyrrolidone.

7 . The method for preparing the compound of formula (I) according to claim 6 , wherein the molar ratio of compound SMA-2 to hydrazine hydrate is 1:(1-3).

8 . The method for preparing the compound of formula (I) according to claim 5 , wherein the molar-to-volume ratio of compound SMA-2 to the solvent is 1 mmol:(0.5-1.5) mL.

9 . The method for preparing the compound of formula (I) according to claim 1 , wherein step 3 is conducted in the presence of a methylating agent and a solvent; wherein
the methylating agent is selected from the group consisting of iodomethane, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, methyl triflate, tetramethylammonium fluoride, trimethyl phosphate, trimethyloxonium tetrafluoroborate and 1-methyl-3-p-tolyltriazole; and the solvent is selected from one of or a mixed solvent of two or more of ethyl acetate, dichloromethane and acetone.

10 . The method for preparing the compound of formula (I) according to claim 9 , wherein
the molar ratio of compound SMA-3 to the methylating agent is 1:(1-3); and the molar ratio of compound SMA-3 to the base is 1:(1-5).

11 . The method for preparing the compound of formula (I) according to claim 1 , wherein step 4 is conducted in the presence of a catalyst, a base and a solvent; wherein
the catalyst is selected from the group consisting of palladium acetate, 1,2-bis(diphenylphosphonyl) ethane palladium dichloride, 1,3-bis(diphenylphosphino) propane palladium dichloride, 1,4-bis(diphenylphosphino) butane palladium dichloride, bis(triphenylphosphine) palladium dichloride, bis(cyanophenyl) palladium dichloride, 1,1′-bis(diphenylphosphino) ferrocenepalladium dichloride and tris(dibenzylideneacetone) dipalladium; the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, piperidine and N-methylpiperidine; and the solvent is selected from one of or a mixed solvent of two or more of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile and water.

12 . The method for preparing the compound of formula (I) according to claim 11 , wherein
the molar ratio of compound SMA-4 to bis(pinacolato)diboron is 1:(1-3); the molar ratio of compound SMA-4 to the catalyst is 1:(0.001-0.01); the molar ratio of compound SMA-4 to the base is 1:(1-3); and the molar-to-volume ratio of compound SMA-4 to the solvent is 1 mmol:(1-2) mL.

13 . The method for preparing the compound of formula (I) according to claim 1 , wherein step 5 is conducted in the presence of a catalyst, a base and a solvent; wherein
the catalyst is selected from the group consisting of palladium acetate, 1,2-bis(diphenylphosphonyl) ethane palladium dichloride, 1,3-bis(diphenylphosphino) propane palladium dichloride, 1,4-bis(diphenylphosphino) butane palladium dichloride, bis(triphenylphosphine) palladium dichloride, bis(cyanophenyl) palladium dichloride, 1,1′-bis(diphenylphosphino) ferrocenepalladium dichloride and tris(dibenzylideneacetone) dipalladium; the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, piperidine and N-methylpiperidine; and the solvent is selected from one of or a mixed solvent of two or more of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile and water.

14 . The method for preparing the compound of formula (I) according to claim 13 , wherein
the molar ratio of compound SMA-5 to compound SMA-9 is 1:(1-2); the molar ratio of compound SMA-5 to the catalyst is 1:(0.005-0.05); the molar ratio of compound SMA-5 to the base is 1:(1-3); and the molar-to-volume ratio of compound SMA-5 to the solvent is 1 mmol:(0.1-2) mL.

15 . The method for preparing the compound of formula (I) according to claim 1 , wherein step 6 is conducted in the presence of a catalyst, a base and a solvent; wherein
the catalyst is selected from the group consisting of palladium acetate, 1,2-bis(diphenylphosphonyl) ethane palladium dichloride, 1,3-bis(diphenylphosphino) propane palladium dichloride, 1,4-bis(diphenylphosphino) butane palladium dichloride, bis(triphenylphosphine) palladium dichloride, bis(cyanophenyl) palladium dichloride, 1,1′-bis(diphenylphosphino) ferrocenepalladium dichloride and tris(dibenzylideneacetone) dipalladium; the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, piperidine and N-methylpiperidine; and the solvent is selected from one of or a mixed solvent of two or more of dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile and water.

16 . The method for preparing the compound of formula (I) according to claim 15 , wherein
the molar ratio of compound SMA-6 to compound SMA-10 is 1:(

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• Liu Guofeng
• Wang Yong
• Guo Meng
• Zhang Xiquan
• Song Kaizhen
• Liu Jinhu
• Luo Junshan

Classifications

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title