Tetrahydrofuran → 1-tert-butyl 4-ethyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate

HRID 880892ノート

反応式

HRID 880892 の反応式
[N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O1CCCC1.[Br:34][C:35]1[N:39]([CH:40]([CH3:42])[CH3:41])[N:38]=[CH:37][C:36]=1[CH2:43]Br>CC1CCCO1.O>[Br:34][C:35]1[N:39]([CH:40]([CH3:42])[CH3:41])[N:38]=[CH:37][C:36]=1[CH2:43][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1

参加物

7

反応物 4

HCID 8028TetrahydrofuranHCID 2733832Lithium HexamethyldisilazideHCID 27588121-Tert-butyl 4-ethyl piperidine-1,4-dicarboxylateHCID 674916565-Bromo-4-(bromomethyl)-1-isopropyl-1H-pyrazole

生成物 1

HCID 674915091-tert-butyl 4-ethyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate収率 46.9%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 73012-Methyltetrahydrofuran溶媒2 回

実験手順

To a stirred solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (14.5 g, 56.3 mmol) in 2-methyl tetrahydrofuran (120 mL) was added, dropwise, 1 M LiHMDS in tetrahydrofuran (57 mL, 56.3 mmol) at −78° C. under argon. After 20 min, 5-bromo-4-(bromomethyl)-1-isopropyl-1H-pyrazole (12.2 g, 43.3 mmol) in 2-methyltetrahydrofuran (10 mL) was added. The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with water (200 mL) and the mixture was separated. The organic phase was washed with 10% citric acid solution (2×100 mL), then brine (100 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product was purified by flash column chromatography (10-30% ethyl acetate in heptane) to give 1-tert-butyl 4-ethyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate (9.3 g). Also isolated from the column was a 7.1 g mixed fraction of starting ester and desired product. This was stirred with 1 equivalent of sodium hydroxide in 90% ethanol/methanol for 2 hours at room temperature. The solvent was removed in vacuo and ethyl acetate (100 mL) was added. The mixture was washed with 2 N sodium hydroxide (2×50 mL) and then brine (100 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo to give a second crop of 1-tert-butyl 4-ethyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate (5.1 g). The combined yield is 14.4 g (72%). +ESI (M+H) 404.0; 1H NMR (400 MHz, CDCl3, δ): 4.62 (m, 1H), 4.12 (q, 2H), 3.90 (br. s., 2H), 2.82 (m, 2H), 2.63 (s, 2H), 2.08 (d, 2H), 1.66 (m, 2H), 1.42 (s, 9H), 1.21 (t, 3H).

後処理

  1. customat −78° C.
  2. customthe mixture was separated
  3. washThe organic phase was washed with 10% citric acid solution (2×100 mL)
  4. dry with materialbrine (100 mL), dried over sodium sulfate
  5. filtrationfiltered
  6. customthe solvent removed in vacuo
  7. customThe crude product was purified by flash column chromatography (10-30% ethyl acetate in heptane)

出典と根拠

ORDレコード
ord-8f1c3ada4a6a40bb8a2281ad7f6580bd
出典データセット
uspto-grants-2015_03
特許番号
US08993586B2

反応ノート

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