1,1'-Carbonyldiimidazole → cis-Methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

HRID 1963352노트

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HRID 1963352 반응식
[C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([K])[CH3:9].[Mg+2].[Cl-].[Cl-].[CH:14]1([CH2:20][CH:21]2[CH2:26][CH:25]([C:27]([OH:29])=O)[CH2:24][CH2:23][N:22]2[C:30]([O:32][CH3:33])=[O:31])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N1C=CN=C1)(N1[CH:40]=[CH:39]N=C1)=O>C1COCC1>[CH:14]1([CH2:20][C@H:21]2[CH2:26][C@H:25]([C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:24][CH2:23][N:22]2[C:30]([O:32][CH3:33])=[O:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1.[CH:14]1([CH2:20][C@H:21]2[CH2:26][C@@H:25]([C:27](=[O:29])[CH2:2][C:3]([O:5][CH2:39][CH3:40])=[O:4])[CH2:24][CH2:23][N:22]2[C:30]([O:32][CH3:33])=[O:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1

참가 물질

7

반응물 4

HCID 682631,1'-CarbonyldiimidazoleHCID 5360315Magnesium ChlorideHCID 667322852-(Cyclohexylmethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2회HCID 178461627HCID 178461627, 화합물

생성물 2

HCID 131730376trans-Methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate수율 16%HCID 131730377cis-Methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate수율 53%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매2회

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온도
50 °C

실험 절차

Ethyl potassium malonate (1.75 g, 10.3 mmol) and MgCl2 (0.665 g, 6.88 mmol) were added to dry THF (50 mL). The reaction flask was stirred vigorously 4 h at 50° C. (flask 1). 2-(Cyclohexylmethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (1.95 g, 6.88 mmol) (Reference Compound 8) and carbonyldiimidazole (1.34 g, 8.26 mmol) were added to dry THF (50 mL) at 5° C. (flask 2). The contents of flask 2 was added to flask 1 at room temperature. The reaction mixture was evaporated to remove most of the THF. The crude was partitioned between water and diethyl ether. The organic phase was isolated, dried with MgSO4, filtered through Celite® and the solvent was evaporated. The residue was purified by automated column chromatography using the Biotage equipment. Gradient eluation using ethylacetate-heptane, started 15-85 and ended 40-60 which gave trans-methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.38 g, 16%) and cis-methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.28 g, 53%). Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 0.88 (d, 2H), 0.99-1.32 (m, 8H), 1.38-1.56 (m, 2H), 1.68 (dd, 8H), 2.80 (t, 2H), 3.45 (s, 2H), 3.66 (s, 3H), 3.93-4.21 (m, 3H), 4.47 (d, 1H). Cis-isomer 1H NMR (600 MHz, cdcl3) δ 0.72-0.95 (m, 2H), 1.04-1.31 (m, 8H), 1.38-1.49 (m, 1H), 1.53-1.69 (m, 6H), 1.70-1.92 (m, 3H), 2.02 (dt, 1H), 2.61-2.71 (m, 1H), 2.95-3.07 (m, 1H), 3.48 (s, 2H), 3.66 (s, 3H), 3.85 (dd, 1H), 4.09-4.21 (m, 3H).

후처리

  1. additionThe contents of flask 2 was added to flask 1 at room temperature
  2. customThe reaction mixture was evaporated
  3. customto remove most of the THF
  4. customThe crude was partitioned between water and diethyl ether
  5. customThe organic phase was isolated
  6. dry with materialdried with MgSO4
  7. filtrationfiltered through Celite®
  8. customthe solvent was evaporated
  9. customThe residue was purified by automated column chromatography

출처 및 근거

ORD 기록
ord-9417db6c4a934396bdde3db635ce078f
출처 데이터셋
uspto-grants-2013_04
특허 번호
US08415378B2

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