Dichloromethane → 5-{4-[(4S,5R)-3-(dichloroacetyl)-4-(fluoromethyl)-2,2-dimethyl-1,3-oxazolidin-5-yl]phenyl}-2-(3-fluorooxetan-3-yl)pyridine

HRID 1500296Notes

Reaction equation

HRID 1500296 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([F:12])[CH2:11][O:10][CH2:9]2)=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].ClCCl.[Cl:39][CH:40]([Cl:59])[C:41]([N:43]1[C@H:47]([CH2:48][F:49])[C@@H:46]([C:50]2[CH:55]=[CH:54][C:53](I)=[CH:52][CH:51]=2)[O:45][C:44]1([CH3:58])[CH3:57])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[Cl:59][CH:40]([Cl:39])[C:41]([N:43]1[C@H:47]([CH2:48][F:49])[C@@H:46]([C:50]2[CH:55]=[CH:54][C:53]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([F:12])[CH2:11][O:10][CH2:9]4)=[N:6][CH:7]=3)=[CH:52][CH:51]=2)[O:45][C:44]1([CH3:57])[CH3:58])=[O:42]

Participants

10

Reactant 6

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 86695394(4S,5R)-3-(dichloroacetyl)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyl-1,3-oxazolidineHCID 867131825-Bromo-2-(3-fluorooxetan-3-yl)pyridine

Product 1

HCID 867131835-{4-[(4S,5R)-3-(dichloroacetyl)-4-(fluoromethyl)-2,2-dimethyl-1,3-oxazolidin-5-yl]phenyl}-2-(3-fluorooxetan-3-yl)pyridineYield 81.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

To a degassed solution of the product of step 1, Example 17 (300.0 mg, 1.29 mmol), bis(pinacolato)diboron (354 mg, 1.39 mmol), and potassium acetate (342 mg, 3.48 mmol) in 1,4-dioxane (4.65 mL) is added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (81.2 mg, 0.099 mmol) and the reaction mixture is heated at 80-90° C. After 3 hours (4S,5R)-3-(dichloroacetyl)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyl-1,3-oxazolidine (see WO2013057619, 444 mg, 0.994 mmol) is added to the reaction mixture followed by a degassed solution of sodium carbonate (422 mg, 3.98 mmol) in water (2.5 mL). The reaction mixture is heated at 80-90° C. for 4 hours before being cooled to room temperature, diluted with ethyl acetate, and washed with water, then brine, dried, and concentrated. The residue is purified by chromatography on silica gel eluting with a gradient of 0-30% EtOAc in hexanes to afford the title compound (380 mg): MS (ESI+) m/z of 471.1/473.0 [M+H].

Workup

  1. temperatureThe reaction mixture is heated at 80-90° C. for 4 hours
  2. temperaturebefore being cooled to room temperature
  3. washwashed with water
  4. dry with materialbrine, dried
  5. concentrationconcentrated
  6. customThe residue is purified by chromatography on silica gel eluting with a gradient of 0-30% EtOAc in hexanes

Sources & evidence

ORD record
ord-73141a432ffc4d059bf991af761c8cca
Source dataset
uspto-grants-2015_12
Patent number
US09206126B2

Reaction notes

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