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Methanol → 1-cyclohexylmethyl-3-(5-hydroxymethyl-4-methylthiazol-2-yl)-7-methoxy-1H-indole

HRID 644046
ノート
印刷プレビュー

反応式

HRID 644046 の反応式
[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[S:20][C:21]([C:25](OCC)=[O:26])=[C:22]([CH3:24])[N:23]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>C1COCC1.ClCCl>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[S:20][C:21]([CH2:25][OH:26])=[C:22]([CH3:24])[N:23]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

6

反応物 3

HCID 887MethanolHCID 21226445Aluminium lithium hydrideHCID 68699956HCID 68699956、化合物

生成物 1

HCID 686916871-cyclohexylmethyl-3-(5-hydroxymethyl-4-methylthiazol-2-yl)-7-methoxy-1H-indole収率 87.3%

試薬・触媒・溶媒 2

HCID 6344Dichloromethane溶媒
HCID 8028
Tetrahydrofuran
溶媒

反応条件

温度
0 °C

実験手順

To a solution of 1-cyclohexylmethyl-3-(5-ethoxycarbonyl-4-methylthiazol-2-yl)-7-methoxy-1H-indole (680 mg, 1.65 mmol) in THF (20 ml) was added lithium aluminium hydride (125 mg, 3.30 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, then quenched with ice water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography eluting with 25-50% (v/v) ethyl acetate in heptane then 10% (v/v) methanol in dichloromethane to afford 1-cyclohexylmethyl-3-(5-hydroxymethyl-4-methylthiazol-2-yl)-7-methoxy-1H-indole (532 mg, 1.44 mmol). To a solution of 1-cyclohexylmethyl-3-(5-hydroxymethyl-4-methylthiazol-2-yl)-7-methoxy-1H-indole (74 mg, 0.20 mmol) and triethylamine (26 mg, 0.26 mmol) in dichloromethane (1.0 ml), was added methanesulfonyl chloride (28 mg, 0.24 mmol). The mixture was stirred at room temperature for 40 min. and partitioned between dichloromethane and 5% aqueous sodium hydrogen carbonate. The aqueous layer was extracted with dichloromethane, then combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford crude 1-cyclohexylmethyl-3-(5-methanesulfonyloxymethyl-4-methylthiazol-2-yl)-7-methoxy-1H-indole (65 mg, 0.15 mmol). A mixture of crude 1-cyclohexylmethyl-3-(5-methanesulfonyloxymethyl-4-methylthiazol-2-yl)-7-methoxy-1H-indole (64 mg, 0.14 mmol), potassium carbonate (29 mg, 0.21 mmol), sodium iodide (31 mg, 0.21 mmol) and diethylamine (21 mg, 0.28 mmol) in THF (1.5 ml) and acetonitrile (1.5 ml) was subjected to microwave irradiation for 5 min at 160° C. The resulting mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography eluting with 50-100% (v/v) ethyl acetate in heptane to afford 1-cyclohexylmethyl-3-(5-diethylaminomethyl-4-methylthiazol-2-yl)-7-methoxy-1H-indole (27 mg, 0.064 mmol). Hydrochloride salt formation was achieved by the addition of hydrogen chloride (1M solution in diethyl ether; 1 ml) to a solution of the free base in diethyl ether (1 ml) and ethanol (2 ml). The solvent was removed in vacuo and the precipitate was dried to afford title compound as a 1:1 hydrochloride salt (26 mg, 0.056 mmol). 1H NMR (400 MHz, DMSO-d6) δ 0.95-1.25 (5H, m), 1.29 (6H, t, J 7.2), 1.40-1.52 (2H, m), 1.55-1.70 (3H, m), 1.72-1.84 (1H, m), 3.10-3.25 (4H, m), 3.93 (3H, s), 4.27 (2H, d, J 7.0), 4.56 (2H, d, J 5.0), 6.82 (1H, d, J 7.6), 7.14 (1H, t, J 7.6), 7.72 (1H, d, J 7.6), 8.00 (1H, s), 9.90 (1H, br s); EsIMS: m/z 426.3 [M+H]+, 353.1.

後処理

  1. customquenched with ice water
  2. extractionextracted with dichloromethane
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. customThe residue was purified by flash chromatography
  7. washeluting with 25-50% (v/v) ethyl acetate in heptane

出典と根拠

ORDレコード
ord-2e1feaca8616405e98a38d0298759972
出典データセット
uspto-grants-2010_04
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US07700634B2

反応ノート

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