Cesium carbonate → N-((1R,2S)-1-(4'-(1-aminocyclopropyl)-[1,1'-biphenyl]-4-yl)-3-fluoro-1-hydroxypropan-2-yl)-2,2-dichloroacetamide

HRID 2283176Notes

Reaction equation

HRID 2283176 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:18]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)O1.[Cl:27][CH:28]([Cl:47])[C:29]([N:31]1[C@H:35]([CH2:36][F:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=2)[O:33]C1(C)C)=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:15]1([C:12]2[CH:11]=[CH:10][C:9]([C:41]3[CH:42]=[CH:43][C:38]([C@@H:34]([OH:33])[C@H:35]([NH:31][C:29](=[O:30])[CH:28]([Cl:27])[Cl:47])[CH2:36][F:37])=[CH:39][CH:40]=3)=[CH:14][CH:13]=2)[CH2:16][CH2:17]1

Participants

8

Reactant 3

HCID 10796Cesium carbonateHCID 69087646tert-Butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamateHCID 86695394(4S,5R)-3-(dichloroacetyl)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyl-1,3-oxazolidine

Product 1

HCID 89515057N-((1R,2S)-1-(4'-(1-aminocyclopropyl)-[1,1'-biphenyl]-4-yl)-3-fluoro-1-hydroxypropan-2-yl)-2,2-dichloroacetamideYield 39.1%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 1140TolueneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate (252 mg, 0.7 mmol), 2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidin-3-yl)ethanone (250 mg, 0.56 mmol), Cs2CO3 (365 mg, 1.12 mmol) in dioxane (4 mL) and water (1 mL) is bubbled with nitrogen gas for 2 minutes. Pd(PPh3)4 (64 mg, 0.056 mmol) is added and the resulting reaction mixture heated at 80° C. for 4 hours. After cooling to room temperature, the reaction is diluted with water (10 ml) and extracted with ethyl acetate (3×10 mL). Combined organic extracts are dried over Na2SO4 and concentrated. Crude compound dissolved in DCM (3 mL) and stirred with TFA (0.6 mL) at room temperature for 1 hour. Reaction is diluted with toluene (10 mL) and concentrated to a syrup. Crude compound is basified slowly using saturated aq. NaHCO3, saturated with NaCl, and extracted with ethyl acetate (3×30 mL). Combined extracts dried over Na2SO4 and concentrated. Solid dissolved in DMF (2 mL) and purified using HPLC eluting from 5 to 95% water/acetonitrile to give the title compound (90 mg): 1HNMR (400 MHz, DMSO-d6) δ: 1.16-1.28 (m, 2H), 1.31-1.41 (m, 2H), 4.15-4.36 (m, 1.5H), 4.38-4.47 (m, 0.5H) 4.55-4.62 (m, 0.5H), 4.65-4.74 (m, 0.5H), 4.90 (bs, 1H) 5.98 (bs, 1H), 6.54 (bs, 1H), 7.41-7.53 (m, 4H), 7.64 (d, 2H, J=8.0 Hz), 7.72 (d, 2H, J=8.0 Hz), 8.63 (d, 1H, J=8 Hz), 8.66-8.79 (bs, 3H), m/z (Cl) 411 [M+1].

Workup

  1. customis bubbled with nitrogen gas for 2 minutes
  2. customthe resulting reaction mixture
  3. temperatureAfter cooling to room temperature
  4. extractionextracted with ethyl acetate (3×10 mL)
  5. dry with materialCombined organic extracts are dried over Na2SO4
  6. concentrationconcentrated
  7. dissolutionCrude compound dissolved in DCM (3 mL)
  8. customReaction
  9. concentrationconcentrated to a syrup
  10. extractionsaturated with NaCl, and extracted with ethyl acetate (3×30 mL)
  11. dry with materialCombined extracts dried over Na2SO4
  12. concentrationconcentrated
  13. dissolutionSolid dissolved in DMF (2 mL)
  14. custompurified
  15. washeluting from 5 to 95% water/acetonitrile

Sources & evidence

ORD record
ord-3d536fc1566e4689827203f4703428cf
Source dataset
uspto-grants-2015_09
Patent number
US09145355B2

Reaction notes

Loading…