GSK 189254 synthesis

Yield:945493-87-8 77%

Reaction Conditions:

with methanol;acetyl chloride at 0 - 55; for 0.5 h;

Steps:

1

Example 1 : Preparation of e-fS-Cyclobutyl^SAS-tetrahydro-IH- benzoIc/lazepin-Z-yloxyJ-N-methyl-nicotinamide hydrochloride; 6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1 H-benzo[c/]azepin-7-yloxy)-N-methyl- nicotinamide (4.0kg) and methanol (7.9kg) are charged to a reactor with stirring at 20 to 25°C for at least 30 minutes. Acetyl chloride (1.0kg) is added in methanol (7.9kg) at 0 to 10⁰C and then slowly charged into the above reaction solution at 15 to 25°C. The reaction is then stirred at 45 to 55°C until reaction mixture becomes brown clear solution. The reaction solution is filtered hot and then vacuum concentrated at not more than 50⁰C to about 1/2 volume to afford white slurry mixture. Ethyl acetate (18.0kg) is slowly charged into the reaction solution at 45 to 55°C and then stirred at this temperature for at least 1 hour. The white slurry mixture is cooled to 15 to 25°C at ramping rate 10⁰C /hr and then stirred at this temperature for not less than 24 hours. The slurry mixture is filtered, and the cake is washed by Ethyl acetate (3.6Kg x 2) twice to give the "wet cake" 6-(3- cyclobutyl-2,3,4,5-tetrahydro-1 H-benzo[c/]azepin-7-yloxy)-N-methyl-nicotinamide hydrochloride as a white solid (6.203 Kg).The intermediate grade 6-(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-benzo[c/]azepin-7- yloxy)-N-methyl-nicotinamide hydrochloride (6.203 Kg) and methanol (7.2 Kg) are charged into a reactor and then heated to 45 to 55°C. Ethyl acetate (17.7Kg) is slowly charged at 45 to 55°C, and then the solution is stirred at this temperature for at least 1 hour. The white slurry mixture is cool to 15-25°C for at ramping rate 10⁰C /hr and then stirred at this temperature for not less than 24 hours. The slurry mixture is filtered, and the wet cake is washed with ethyl acetate (3.6Kg x 2). The product is vacuum dried at not more than 50⁰C to give 6-(3-cyclobutyl- 2,3,4,5-tetrahydro-1H-benzo[c/]azepin-7-yloxy)-N-methyl-nicotinamide hydrochloride as a white solid (3.034 Kg, 77%th).

References:

WO2008/104589,2008,A1 Location in patent:Page/Page column 12