7-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine

Compound 9: To a solution of 8 (0.835 g, 5.5 mmol) in 10 mL thionyl chloride was added 0.5 mL DMF. The resulting mixture was heated to 90° C. under nitrogen for 1 hour. After cooling to room temperature, the solvents were removed under reduced pressure. Water was added to the resulting residue and the mixture was extracted with dichloromethane (.x.3). The combined organics were dried (MgSOCompound 13.1 (100 mg, 0.59 mmol, 1.00 eq.) was dissolved in 5 mL of CH3CN. Then Na2C03 (190 mg, 1.79 mmol, 3.00 eq.) and compound 1.2 (229 mg, 0.89 mmol, 1.50 eq.) were added. The reaction was stirred overnight at 80 C in an oil bath. The resulting mixture was concentrated in vacuo, diluted with 10 mL of H20 and extracted with 3x20 mL of EtOAc. Organic layers were combined and concentrated in vacuo. The crude product was purified by preparative HPLC to furnish 150 mg (80%) of I-13 as a white solid. LC-MS (ESI, m/z): [M+H]+ = 317; 1H- NMR (400 MHz, MeOD): delta 8.23 (s, 1H), 7.88 (s, 1H), 4.86 (s, 1H), 4.20-4.35 (m, 8H), 3.73-3.75 (d, 3H), 3.33 (s, 1H), 2.64-2.66 (d, 3H), 2.32-2.38 (m, 4H), 2.21-2.24 (s, 2H), 1.95-2.11 (m, 4H), 1.44-1.61 (m, H).Preparation of N-[2-[3-methoxy-4-[[2-(trifluoromethyl)-4-pyridyl]oxy]phenyl] ethyl]-1 - methyl-pyrazolo[4, 3-d]pyrimidin-7-amine (1-10) To a solution of 2-[3-methoxy-4-[[2-(trifluoromethyl)-4-pyridyl]oxy]phenyl]ethanamine (0.39 g, 1 .2 mmol) in acetonitrile (30 ml.) was added triethylamine (1 .5 g, 4.8 mmol). The solution was stirred for 5 min at room temperature at which time 7-chloro-1 -methyl-pyrazolo[4, 3-d]pyrimidine (0.25 g, 1 .2 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water was added and was extracted with ethyl acetate (3x). The combined organic layers were washed with water, dried over Na2S04 and concentrated in vacuo. The residue was purified by HPLC to provide 85 mg (0.19 mmol, 17%) of the product.To a solution of 2-[3-methoxy-4-[[2-(trifluoromethyl)-4-pyridyl]oxy]phenyl]ethanamine (0.39 g, 1.2 mmol) in acetonitrile (30 mL) was added triethylamine (1.5 g, 4.8 mmol). The solution was stirred for 5 min at room temperature at which time Compound 10: To a solution of 3 (0.33 g, 1.0 mmol) and Hunig's base (0.52 mL, 3.0 mmol) in 3 mL of DMF was added 9 (0.169 g, 1.0 mmol). The resulting mixture was heated and stirred at 90 C. for 1 hour. After the reaction was cooled to room temperature, water was added and washed with ethyl acetate (×3). The combined organics were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 10 (59 mg, 9%) as the bis TFA salt. 1H NMR (d6-DMSO) delta 3.10-3.13 (m, 2H) 3.90-3.92 (m, 2H) 4.33 (s, 3H) 7.19 (s, 1H) 7.36 (m, 1H) 7.51-7.55 (m, 1H) 7.62-7.64 (m, 1H) 8.01 (s, 1H) 8.16 (s, 1H) 8.72 (s, 1H) 9.02 (bs, 1H) 9.57 (s, 1H); ES (+) MS m/e=463 (M+1).Compound 77: 76 (0.3 g, 0.84 mmol) was added to a solution containing 9 (0.14 g, 0.84 mmol) and Hunig's base (0.7 mL, 4.2 mmol) in DMF (5 mL). The reaction mixture was heated to 90 C. and stirred for 1 hour. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with H2O and extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel using 5% CH3CN in EtOAc to afford 77 (0.11 g, 31%), ES (+) MS m/e=421 (M+1).Compound 9: To a solution of 8 (0.835 g, 5.5 mmol) in 10 mL thionyl chloride was added 0.5 mL DMF. The resulting mixture was heated to 90 C. under nitrogen for 1 hour. After cooling to room temperature, the solvents were removed under reduced pressure. Water was added to the resulting residue and the mixture was extracted with dichloromethane (×3). The combined organics were dried (MgSO4) and concentrated under reduced pressure to afford 9 (0.94 g, 100%), ES (+) MS m/e=169 (M+1).

Molecular Weight:168.58
XLogP3:0.9
Hydrogen Bond Acceptor Count:3
Exact Mass:168.0202739
Monoisotopic Mass:168.0202739
Topological Polar Surface Area:43.6
Heavy Atom Count:11
Complexity:154
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes