Cyclohexanecarboxaldehyde, 4,4-difluoro- (9CI)

Under nitrogen atmosphere, at -78 °C, to a solution of oxalyl chloride (0.35 mL, 4.16 mmol) in dry CH2C12 (15.0 mL), DMSO (0.27 mL, 3.84 mmol) was added dropwise. Afterstirring at -78 °C for 15 mm, a solution of (4, 4-difluorocyclohexyl)-methanol (0.48 g, 3.20 mmol) in dry CH2C12 (10 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h, then Et3N (1.27 mL, 9.60 mmol) was added dropwise. The resulting reaction mixture was warmed up to r.t., then concentrated to dryness. The crude product was taken up in Et20 (30 mL) and washed with sat. NH4C1 solution (30 mL). The organic layer was dried over Na2504, filtered and concentrated to dryness affording the title compound (0.39 g, 82percent), which was used in the next step without any further purification. ‘H NMR (DMSO-d6): ö 9.61 (s, 1H), 2.05—1.73 (m, 7H), 1.64—1.5 1 (m, 2H).Under nitrogen atmosphere, at -78 °C, to a solution of oxalyl chloride (0.35 mL, 4.16 mmol) in dryCH2Cl2 (15.0 mL), DMSO (0.27 mL, 3.84 mmol) was added dropwise. After stirring at -78 °C for 15min, a solution of (4, 4-difluorocyclohexyl)-methanol (0.48 g, 3.20 mmol) in dry CH2Cl2 (10 mL) wasadded dropwise. The reaction mixture was stirred at -78 °C for 1 h, then Et3N (1.27 mL, 9.60 mmol)was added dropwise. The resulting reaction mixture was warmed up to room temperature, thenconcentrated to dryness. The crude product was taken up in Et2O (30 mL) and washed with sat. NH4Clsolution (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated to drynessaffording the title compound (0.39 g, 82percent), which was used in the next step without any furtherpurification. 1H NMR (DMSO-d6): δ 9.61 (s, 1H), 2.05–1.73 (m, 7H), 1.64–1.51 (m, 2H)To a solution of DMSO (710 pL, 10.0 mmol) in 0H2012 (10 mL) was added oxalyl chloride(425 pL, 5.02 mmol) at -78 °O. The resulting mixture was stirred for a further 20 mm at -78 °O before it was cannulated with a 0H2012 (2 mL) solution of 4, 4-difluorocyclohexylmethanol 14 (500 mg, 3.30 mmol) at -78 °O. The reaction mixture was stirred for 30 mm at -78 °O prior to the addition of Et3N (2.33 mL, 16.7 mmol). The mixture was warmed to 0°C and stirred for 30 mm before it was diluted with 0H2012 (10 mL) and quenched with H20 (10 mL). The layers were separated and the aqueous layer was extracted with 0H2012 (2 x 5 mL). The combined organic layers were dried over Na2504and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 4:1) to give compound 15 (315 mg, 64percent) as a pale yellow oil.1H NMR (400 MHz, 0D013) O = 9.64 (s, 1 H), 2.40 —2.26 (m, 1 H), 2.11 —1.91 (m, 3 H), 1.88 — 1.70 (m, 3 H); 19F NMR (376 MHz, 0D013) O = -94.9 (d, J = 237.8 Hz, 1 F), -98.9(d, J= 237.8 Hz, 1 F).To a solution of 173 g (0.900 mol) of 4, 4-difluorocyclohexanecarboxylic acid ethyl ester in 1.0 L toluene, 945 ml (0.945 mol) of 1.0 M diisobutyl aluminum hydride-toluene solution was added dropwise at -55° C. or lower temperatures and then the reaction solution was stirred at -65° C. for 30 minutes. (Reference Example 1) The compound 118a (50.0 mg, 0.195 mmol) was dissolved in dichloromethane (10 mL), the compound 118b (21.5 mg, 0.215 mmol) and acetic acid (0.2 mL) were added, and the mixture was stirred at room temperature for 15 minutes. Then sodium triacetylborohydride (49.6 mg, 0.234 mmol) was added. The reaction solution was stirred at room temperature for another 4 hours. The reaction solution was poured into water (20 mL), and the pH was adjusted to near neutral with sodium bicarbonate. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (15 mL × 2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a white solid compound 118c.4- (4-(((4, 4-difluorocyclohexy l) methyl) amino) -1H-pyrazol-1-yl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidine- 2-amine(51 mg, yield 67.4%, crude).Under protection of nitrogen gas, the mixture solution of allyl bromide (5.72 g, 47.25 mmol), indium (5.43 g, 47.25 mmol), (1S, 2R)-2-amino-1, 2-diphenyl-ethanol (5.04 g, 23.62 mmol) and pyridine (3.74 g, 47.25 mmol) in tetrahydrofuran (50.00 mL) was stirred at 18C for 3 h. The reaction solution was cooled down to -78C, and 4, 4-difluorocyclohexylcarboxaldehyde (3.50 g, 23.62 mmol) was slowly added. The reaction solution was controlled at -78C and stirred for 2 h. The reaction solution was added with saturated ammonium chloride solution (100 mL) to quench reaction, and filtered, and the filtrate was extracted with ethyl acetate (100 mL * 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give the title compound (yellow oil, 3.55 g, yield of 60.78%). 1H NMR (400MHz, CHLOROFORM-d) delta = 5.89 - 5.75 (m, 1H), 5.22 - 5.12 (m, 2H), 3.51 - 3.42 (m, 1H), 2.41 - 2.30 (m, 1H), 2.13 (td, J=8.5, 13.8 Hz, 3H), 1.99 - 1.90 (m, 1H), 1.74 (br dd, J=4.1, 7.2 Hz, 2H), 1.68 - 1.62 (m, 2H), 1.49 - 1.35 (m, 3H).A solution of n-butyllithium (2.5 M, 2.29 mL) in diethyl ether (10.00 mL) was cooled down to -78C and slowly added with diisopropylamine (663.06 mg, 6.26 mmol), and 3-bromothiophene (850 mg, 5.21 mmol) was added after 1 hour. The mixture was maintained at -78C and stirred for 1 h. 4, 4-Difluorocyclohexanecarboxaldehyde (772.37 mg, 5.21 mmol) was further added, and the reaction solution was stirred at -78C for 1 h. The reaction solution was quenched with ammonium chloride solution (30 mL), diluted with water (30 mL) and extracted with ethyl acetate (30 mL * 3). The organic phase was washed with brine (30 mL * 3), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give the title compound (colorless oil, 700 mg, yield of 43.18%). 1H NMR (400MHz, CHLOROFORM-d) delta = 7.30 (d, J=5.3 Hz, 1H), 6.94 (d, J=5.3 Hz, 1H), 4.86 (dd, J=2.4, 7.9 Hz, 1H), 2.29 (d, J=3.0 Hz, 1H), 2.19 - 2.07 (m, 3H), 1.82 - 1.63 (m, 4H), 1.52 - 1.46 (m, 2H).

Molecular Weight:148.15
XLogP3:1.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:148.06997126
Monoisotopic Mass:148.06997126
Topological Polar Surface Area:17.1
Heavy Atom Count:10
Complexity:124
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes