Hydrochloric Acid → HCID 131730483、化合物

HRID 1963604ノート

反応式

HRID 1963604 の反応式
[F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([OH:13])=O)[CH2:8][CH2:7][N:6]1[C:14]([O:16][CH3:17])=[O:15].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:35]([O:37][C:38](=[O:43])[CH2:39][C:40]([O-:42])=O)[CH3:36].[K+].[Cl-].[Mg+2].[Cl-].Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.CC(OC)(C)C.O>[F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:13])[CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:43])[CH2:8][CH2:7][N:6]1[C:14]([O:16][CH3:17])=[O:15].[F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:40](=[O:42])[CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:43])[CH2:8][CH2:7][N:6]1[C:14]([O:16][CH3:17])=[O:15]

参加物

10

反応物 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66732104HCID 66732104、化合物2 回

生成物 2

HCID 131730482HCID 131730482、化合物収率 18%HCID 131730483HCID 131730483、化合物収率 69%

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 15413tert-Butyl methyl ether溶媒HCID 178479889HCID 178479889、化合物溶媒2 回

実験手順

To a mixture of 2-(2,5-difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (7.4 g, 23.62 mmol) (reference compound 54) in anhydrous methyl-THF (150 mL) was added di(1H-imidazol-1-yl)methanone (5.74 g, 35.43 mmol) at room temperature under nitrogen. The suspension was stirred at room temperature for 4 h (flask 1). To a mixture of potassium 3-ethoxy-3-oxopropanoate (7.24 g, 42.52 mmol) in anhydrous methyl-THF (150 mL) was added magnesium chloride (4.05 g, 42.52 mmol) at room temperature under nitrogen. The mixture was heated at 50° C. for 4 h, and then allowed to cool to room temperature (flask 2). The suspension in flask 1 was added to the suspension in flask 2. The reaction mixture was stirred at room temperature for 48 h. The mixture was acidified to pH 1 with 4 M HCl and then water and MTBE was added. The organic phase was separated, washed with water, satd NaHCO3, dried and evaporated. The diastereomers were separated by flash chromatography on silica gel using iso-hexane/EtOAc (100:15 and 100:50) as eluent. Trans-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.6 g, 18%) and cis-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (6.2 g, 69%) were isolated as oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.32 (m, 3H), 1.64-2.00 (m, 4H), 2.67-3.15 (m, 4H), 3.48 (s, 2H), 3.58 (s, 3H), 3.87-3.99 (m, 1H), 4.07-4.32 (m, 3H), 6.82-7.01 (m, 3H). Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.22-1.32 (m, 3H), 1.45-2.01 (m, 4H), 2.52-3.12 (m, 4H), 3.41-3.74 (m, 5H), 4.04-4.34 (m, 3H), 4.48-4.74 (m, 1H), 6.82-7.06 (m, 3H). MS m/z 384 (M+H)+

後処理

  1. temperatureThe mixture was heated at 50° C. for 4 h
  2. temperatureto cool to room temperature (flask 2)
  3. additionThe suspension in flask 1 was added to the suspension in flask 2
  4. stirringThe reaction mixture was stirred at room temperature for 48 h
  5. customThe organic phase was separated
  6. washwashed with water
  7. customdried
  8. customevaporated
  9. customThe diastereomers were separated by flash chromatography on silica gel

出典と根拠

ORDレコード
ord-009f25c7cbdc49ae8db7bbb7c15e0317
出典データセット
uspto-grants-2013_04
特許番号
US08415378B2

反応ノート

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