Sodium Bicarbonate → 2-(5-{4-[(4S,5R)-3-(2,2-Difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1520551노트

반응식

HRID 1520551 반응식
[F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][N:43]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]1[CH:47]=[CH:46][C:45]([C:15]2[CH:16]=[CH:17][C:12]([C@H:8]3[O:7][C:6]([CH3:27])([CH3:28])[N:5]([C:3](=[O:4])[CH:2]([F:29])[F:1])[C@@H:9]3[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:44][N:43]=1)=[O:36])([CH3:33])([CH3:31])[CH3:32]

참가 물질

8

반응물 3

HCID 516892Sodium BicarbonateHCID 866954142,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-3-yl)ethanoneHCID 86695506Tert-butyl 2-(5-bromopyridin-2-YL)pyrrolidine-1-carboxylate

생성물 1

HCID 866955072-(5-{4-[(4S,5R)-3-(2,2-Difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester수율 61.2%

시약·촉매·용매 4

HCID 24290Palladium Chloride촉매HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)촉매HCID 702Ethanol용매HCID 1140Toluene용매

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온도
80 °C

실험 절차

To a solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (634 mg, 1.53 mmol) in a mixture of toluene (12 ml) and ethanol (9 ml) is added 2-(5-Bromo-pyridin-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.53 mmol), aqueous sodium bicarbonate solution (2M, 6 mmol, 3 ml), and 1,1′Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (57 mg, 0.08 mmol). The stirred reaction mixture is heated at 80° C. under a blanket of nitrogen for 1 hour. The reaction is concentrated to ⅓ its volume and partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase is washed with saturated brine (25 ml) and concentrated on to silica gel (3 g). Purification by column chromatography (40 g silica gel, ethyl acetate/heptane 0-100%) affords the title compound (500 mg): 1H NMR (400 MHz, CDCl3) 1.25 (s, 5H) 1.48 (s, 4H), 1.64 (s, 3H), 1.70 (s, 3H), 1.85-1.98 (m, 2H), 1.99-2.1 (1H), 2.3-2.48 (m, 1H), 3.5-3.74 (m, 2H), 4.54-5.1 (m, 4H), 5.23-5.33 (m, 1H), 6.13 (t, 1H), 7.23-7.31 (m, 1H) 7.5-7.57 (m, 2H), 7.57-7.67 (m, 2H), 7.78-7.87 (m, 1H), 8.77 (s, 1H). m/z M+H 534.2.

후처리

  1. customThe stirred reaction mixture
  2. concentrationThe reaction is concentrated
  3. custompartitioned between ethyl acetate (25 ml) and water (25 ml)
  4. washThe organic phase is washed with saturated brine (25 ml)
  5. concentrationconcentrated on to silica gel (3 g)
  6. customPurification by column chromatography (40 g silica gel, ethyl acetate/heptane 0-100%)

출처 및 근거

ORD 기록
ord-741af116e0f74be880c724fe40b00d38
출처 데이터셋
uspto-grants-2015_07
특허 번호
US09073894B2

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