Cesium carbonate → 1-​Piperazinecarboxylic acid, 4-​[6-​[[7-​cyclopentyl-​6-​[(dimethylamino)​carbonyl]​-​7H-​pyrrolo[2,​3-​d]​pyrimidin-​2-​yl]​amino]​-​3-​pyridinyl]​-​, 1,​1-​dimethylethyl ester

Participants

Reaction Conditions

Reaction Steps

A nitrogen-flushed, 3 L, Argonaut reactor system is charged with 43.9 g (0.15 mol. 1.0 eq) of 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, (crude A1, from Step 1.4 above), 45.9 g (0.165 mol, 1.1 eq.) of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (A2), 0.67 g (3.0 mmol, 0.02 eq) of palladium (II) acetate, 3.73 g (6.0 mmol, 0.04 eq) of (±) 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, ±BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and 275 g (344 mL) of 4-methyl-2-pentanone. The resulting suspension is stirred and heated to 40±3° C. 73.3 g (0.225 mol, 1.5 eq) of cesium carbonate is added in 5 to 10 g portions over 15 min. The resulting suspension is stirred and heated to 100±3° C. This temperature is maintained for 3 h or until the remaining starting material, A1, is ≦2% (area normalization) as determined by HPLC analysis. The progress of the reaction is checked using the Process Steering Control. The sample is cooled to 70±3° C. and 344 g (344 mL) of water is added over 5 min. The sample is cooled to 50±3° C. and held at this temperature for 30 min. 353 g (516 mL) of heptane is added over 30 minutes and the sample is stirred for 2 h. The mixture is then cooled to 22±3° C. and held at least 4 h (hold point). The solids are filtered through a polypropylene filter pad. The filter cake is washed with a cold (4° C.) mixture of 24 g (30 mL) of 4-methyl-2-pentanone and 41 g (60 mL) of heptane. The solids are dried at 60° C. until HSGC PSC shows organic solvents to be 1%, to afford 72.6 g of A3 as a tan solid mp 215-217° C. (dec.).

Provenance & Evidence