TRANS-4-AMINOCYCLOHEXANE CARBOXYLIC ACID ETHYL ESTER

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-{4-[4-(2-Methanesulfonyl-ethoxy)-indazol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester was prepared by reaction of 4-amino-cyclohexanecarboxylic acid ethyl ester with 4-(2-methanesulfonyl-ethoxy)-1-[2-(propane-1-sulfonyl)-pyrimidin-4-yl]-1H-indazole following generally the procedure of Example 5.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Amino-cyclohexanecarboxylic acid ethyl ester (550 g) and 815 mL DIPEA were added to 1-(2-methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (746.7 g) in 2.5 L DMA, and the mixture allowed to heat to 120° C. for 4 h and then allowed to cool to room temperature. Water (3 L) was added dropwise and the resulting precipitate was collected by filtration, washed with H2O and MeOH, and dried in vacuo at 48° C. overnight to yield 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid methyl ester (90%). to cool to room temperature the resulting precipitate was collected by filtration washed with H2O and MeOH dried in vacuo at 48° C. overnight

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 8-benzyloxy-3-(2-chloropyrimidin-4-yl)-imidazo[1,2-a]pyridine (0.19 g) and 4-amino-cyclohexanecarboxylic acid ethyl ester (0.29 g) in NMP (1 mL) was stirred at 100° C. for 1 h. The reaction mixture was cooled to RT, diluted with water, and the resulting solid separated, washed with water, and dried. The solid was titurated with hot EtOAc and filtered to provide 4-[4-(8-benzyloxy-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (compound 8, 0.25 g), which was used without further purification. The reaction mixture was cooled to RT the resulting solid separated washed with water dried filtered

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 8-benzyloxy-3-(2-chloropyrimidin-4-yl)-imidazo[1,2-a]pyridine (0.19 g) and 4-amino-cyclohexanecarboxylic acid ethyl ester (0.29 g) in NMP (1 mL) was stirred at 100° C. for 1 h. The reaction mixture was cooled to RT, diluted with water, and the resulting solid separated, washed with water, and dried. The solid was titurated with hot EtOAc and filtered to provide 4-[4-(8-benzyloxy-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (compound 8, 0.25 g), which was used without further purification. The reaction mixture was cooled to RT the resulting solid separated washed with water dried filtered

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-[3-(2-methylsulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyridin-8-yl]-propan-2-ol (0.19 g), 4-amino-cyclohexanecarboxylic acid ethyl ester (0.31 g) in NMP (2 mL) was stirred at 100° C. for 3 h. The reaction mixture was cooled to RT, and diluted with water. The resulting solid was filtered and dried, then purified by ISCO using 100% DCM to 10% MeOH/DCM. Fractions were collected, concentrated, and titurated with EtOAc/hexane. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide 4-{4-[8-(1-hydroxy-1-methyl-ethyl)-imidazo[1,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (0.215 g). The reaction mixture was cooled to RT The resulting solid was filtered dried purified by ISCO Fractions were collected concentrated The resulting solid was filtered dried at 50° C. under vacuum overnight