Hydrochloric Acid → HCID 131730483, 화합물

HRID 1963604노트

반응식

HRID 1963604 반응식
[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]

참가 물질

10

반응물 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66732104HCID 66732104, 화합물2회

생성물 2

HCID 131730482HCID 131730482, 화합물수율 18%HCID 131730483HCID 131730483, 화합물수율 69%

시약·촉매·용매 3

HCID 962Water용매HCID 15413tert-Butyl methyl ether용매HCID 178479889HCID 178479889, 화합물용매2회

실험 절차

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)+

후처리

  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

출처 및 근거

ORD 기록
ord-009f25c7cbdc49ae8db7bbb7c15e0317
출처 데이터셋
uspto-grants-2013_04
특허 번호
US08415378B2

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