Sodium Carbonate → (2S)-4-methyl-2-({(1S)-2,2,2-trifluoro-1-[4'-(methylthio)-1,1'-biphenyl-4-yl]ethyl}amino)pentan-1-ol

HRID 1880500Notes

Reaction equation

HRID 1880500 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:15][OH:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(OC(=O)C)C.CC([O-])=O.CC([O-])=O.[Pd+2].O.C(O)CC>[CH3:19][CH:18]([CH3:20])[CH2:17][C@H:14]([NH:13][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[CH:28][C:23]([S:22][CH3:21])=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)[C:9]([F:12])([F:11])[F:10])[CH2:15][OH:16]

Participants

9

Reactant 4

HCID 10340Sodium CarbonateHCID 11776TriphenylphosphineHCID 27339594-(Methylthio)phenylboronic acidHCID 11256730(S)-2-[[(S)-alpha-(Trifluoromethyl)-4-bromobenzyl]amino]-4-methyl-1-pentanol

Product 1

HCID 11502160(2S)-4-methyl-2-({(1S)-2,2,2-trifluoro-1-[4'-(methylthio)-1,1'-biphenyl-4-yl]ethyl}amino)pentan-1-ol

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 10311-PropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

A stream of nitrogen was passed through a suspension made of the bromide from Step 3 (27.7 g), 4-(methylthio)phenylboronic acid (15.7 g), 2 M Na2CO3 (100 mL) and n-propanol (500 mL) for 15 minutes. A 1:3 mixture (3.5 g) of Pd(OAc)2 and PPh3 was then added and the reaction was warmed to 70° C. and stirred under nitrogen for 8 hours. The mixture was cooled to room temperature, diluted with ethylacetate (500 mL) and poured over water (2 L) and ice (500 g). The ethyl acetate layer was separated and the aqueous further extracted with ethyl acetate (200 mL). The combined ethyl acetate extracts were washed with 0.5 N NaOH (2×200 mL), with aqueous NH4Cl, brine and dried with magnesium sulfate. Removal of the solvent left a residue that was purified by chromatography on SiO2 using a gradient of ethyl acetate and hexanes (1:4 to 1:3) and again with acetone and toluene (1:10). The residue was dissolve in hot hexanes (200 mL) and the solution was allowed to cool to 0° C. under stirring. The obtained solid was filtered and dried to yield the title compound.

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. customThe ethyl acetate layer was separated
  3. extractionthe aqueous further extracted with ethyl acetate (200 mL)
  4. washThe combined ethyl acetate extracts were washed with 0.5 N NaOH (2×200 mL), with aqueous NH4Cl, brine
  5. dry with materialdried with magnesium sulfate
  6. customRemoval of the solvent
  7. waitleft a residue that
  8. customwas purified by chromatography on SiO2 using a gradient of ethyl acetate and hexanes (1:4 to 1:3)
  9. dissolutionThe residue was dissolve in hot hexanes (200 mL)
  10. temperatureto cool to 0° C.
  11. stirringunder stirring
  12. filtrationThe obtained solid was filtered
  13. customdried

Sources & evidence

ORD record
ord-0cf8e15f75b24f10aea4d55300c51cb8
Source dataset
uspto-grants-2012_11
Patent number
US08318748B2

Reaction notes

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