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 1804847ノート

反応式

HRID 1804847 の反応式
[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]

参加物

9

反応物 6

HCID 24341Hypochlorous AcidHCID 24758Sodium hydrideHCID 82050Lithium BromideHCID 685589292-Chloro-1-(1-(4-chloro-3-methoxyphenyl)-4-methylpiperidin-4-yl)ethanolHCID 178418361HCID 178418361、化合物HCID 178434610HCID 178434610、化合物

生成物 1

HCID 248637191-(1-(4-Chloro-3-methoxyphenyl)-4-methylpiperidin-4-yl)-2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanol

試薬・触媒・溶媒 2

HCID 6342Acetonitrile溶媒HCID 8028Tetrahydrofuran溶媒2 回

反応条件

温度
80 °C

実験手順

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).

後処理

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

出典と根拠

ORDレコード
ord-b6bf36f53e734e7ca2d12d83d1e199cc
出典データセット
uspto-grants-2013_01
特許番号
US08354432B2

反応ノート

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