Hypochlorous Acid → 1-(1-(4-Chloro-3-methoxyphenyl)-4-methylpiperidin-4-yl)-2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanol

HRID 1804847Notes

Reaction equation

[Cl:1][C:2]1[C:3]([CH3:11])=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[H-].[Na+].[H][H].Cl[CH2:17][CH:18]([C:20]1([CH3:35])[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=2)[CH2:22][CH2:21]1)[OH:19].[Br-].[Li+].ClO>C1COCC1.C(#N)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:23]2[CH2:22][CH2:21][C:20]([CH:18]([OH:19])[CH2:17][N:4]3[C:3]([CH3:11])=[C:2]([Cl:1])[C:6]([C:7]([F:9])([F:10])[F:8])=[N:5]3)([CH3:35])[CH2:25][CH2:24]2)=[CH:27][C:28]=1[O:33][CH3:34]

Participants

Conditions

Temperature: 80 °C

Procedure

A solution of 4-chloro-3-methyl-5-(trifluoromethyl)-1H-pyrazole (55.4 mg, 0.30 mmol) in anhydrous THF (3 mL) was treated with 60% sodium hydride (13.20 mg, 0.330 mmol) and stirred at RT until hydrogen evolution ceased. The mixture was treated with a solution of 2-chloro-1-(1-(4-chloro-3-methoxyphenyl)-4-methylpiperidin-4-yl)ethanol (95 mg, 0.300 mmol) in THF and then stirred at reflux for 1 h. After this time, the mixture was cooled and treated with lithium bromide (0.30 mmol) and acetonitrile (4 mL) before being heated to 80° C. Within 10 min, LC-MS showed the chloro-alcohol had been converted to the epoxide but none of the desired product was detected by LC-MS. Accordingly, the mixture was charged with DMF (5 mL) and heated at 150° C. for 14 h, at which time a product having the mass (m/z=466) for the desired product was evident in the LC-MS. The mixture was concentrated on a rotary evaporator. The resultant residue was treated with EtOAc (10 mL), and the mixture was washed with water and brine. The organic extract was dried (Na2SO4) and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography (10-40% EtOAc/Hex) and then preparative reverse phase HPLC. Example 11 (32 mg, 0.069 mmol, 23% yield) was obtained as a white solid after lyophilization from the HPLC fractions. LC-MS: 466.18, [M+H]+; tR=3.21 min (method b). 1H-NMR (400 MHz, CDCl3) δ ppm 7.46 (1 H, d, J=8.57 Hz), 7.41 (1 H, d, J=2.42 Hz), 6.95 (1 H, dd, J=8.68, 2.53 Hz), 4.24 (1 H, d, J=13.18 Hz), 3.93-4.05 (2 H, m), 3.92 (3 H, s), 3.68-3.77 (2 H, m), 3.43 (2 H, t, J=10.99 Hz), 2.35 (1 H, s), 2.34 (1 H, d, J=6.81 Hz), 2.31 (3 H, s), 1.82-1.94 (2 H, m), 1.23 (3 H, s).

Workup

temperatureat reflux for 1 h
temperatureAfter this time, the mixture was cooled

Sources & evidence

ORD record: ord-b6bf36f53e734e7ca2d12d83d1e199cc
Source dataset: uspto-grants-2013_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08354432B2

Reaction notes

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