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 1487554Notes

Reaction equation

HRID 1487554 reaction equation
[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]

Participants

8

Reactant 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

Product 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 esterYield 61.2%

Reagents, catalysts & solvents 4

HCID 24290Palladium ChlorideCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 702EthanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

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.

Workup

  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%)

Sources & evidence

ORD record
ord-54fa114eac154bdcbbcf1a8968d58fff
Source dataset
uspto-grants-2016_08
Patent number
US09428528B2

Reaction notes

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