[CH:1]1([NH:6][C:7]2[C:12]([C:13]3[CH:18]=[C:17]([Cl:19])[N:16]=[N:15][C:14]=3Cl)=[CH:11][N:10]=[C:9]([NH2:21])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[NH4+].[Cl-].C(O)(C(F)(F)F)=O>CS(C)=O.C(#N)C.O>[Cl:19][C:17]1[N:16]=[N:15][C:14]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:7]3[N:8]=[C:9]([NH2:21])[N:10]=[CH:11][C:12]=3[C:13]=2[CH:18]=1
A mixture of crude N4-cyclopentyl-5-(3,6-dichloropyridazin-4-yl)pyrimidine-2,4-diamine (323) (0.27 g, 0.83 mmol) and sodium bicarbonate (0.065 mL, 1.7 mmol) in DMSO (10 mL) was heated in an oil bath at 110° C. for 11 h. Then the temperature was raised to 125° C. and stirred at this temperature for 200 min at which time LC-MS showed completion. Upon workup, the mixture was poured into ice and saturated NH4Cl aqueous solution and extracted with ethyl acetate (3×). The combined organics were washed with saturated NH4Cl aqueous solution (1×), dried over Na2SO4, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM). The impure product thus obtained was subjected to subjected to preparative reverse phase HPLC (acetonitrile/H2O containing 0.1% TFA each). After lyophilization, 15 mg of compound 322 was obtained as a TFA salt as an off-white solid.
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