Dimethylformamide → tert-Butyl ((1S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl)carbamate

HRID 2374636Notes

Reaction equation

HRID 2374636 reaction equation
[CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:39][C@@H:40]1[CH2:44][NH:43][C@H:42]([C:45]#[N:46])[CH2:41]1.CN(C=O)C.CCN(C(C)C)C(C)C>O.CC(OC)(C)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH:10]([C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:25]([N:43]1[CH2:44][C@@H:40]([F:39])[CH2:41][C@H:42]1[C:45]#[N:46])=[O:27])([CH3:3])([CH3:1])[CH3:4]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 15981034(S)-2-((tert-butoxycarbonyl)amino)-3,3-bis(4-fluorophenyl)propanoic acidHCID 72699082(2S,4S)-4-Fluoropyrrolidine-2-carbonitrile 4-methylbenzenesulfonate

Product 1

HCID 68536750tert-Butyl ((1S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl)carbamate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
0 °C

Procedure

A reactor was charged with N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-β-(4-fluorophenyl)-L-phenylalanine (400 g, 1 wt, 1 eq.), (2S,4S)-4-fluoropyrrolidine-2-carbonitrile para-toluenesulfonic acid (307.7 g, 0.77 wt, 1.01 eq.), O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexaflurophosphate [i.e. HATU] (408 g, 1.02 wt, 1.01 equiv.), and DMF (2.8L, 7 vol). The mixture was cooled to approximately 0° C. Hunig's base (376 mL, 0.94 vol, 2.04 equiv.) was added over at least 30 minutes. The mixture was heated to approximately 25° C. and was stirred at this temperature until the reaction was complete (ca. 3 hours). MTBE (2.8L mL, 7 vol) was added, followed by water (2L, 5 vol) over at least 30 minutes to quench the reaction. The aqueous phase was extracted with MTBE (1.2L, 3 vol). The combined organic phases were washed with water (2L, 5 vol). The organic phase was concentrated under vacuum to 3 volumes, and ethanol (1.6L, 4 vol) was added. The reaction was further concentrated under vacuum to 3 volumes, and ethanol (1.6 L, 4 vol) was added. The reaction was further concentrated under vacuum to 3 volumes. Added ethanol (2L, 5 vol). The ethanol solution of tert-Butyl {(1 S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamatewas used directly in the next step.

Workup

  1. temperatureThe mixture was heated to approximately 25° C.
  2. custom(ca. 3 hours)
  3. customto quench
  4. customthe reaction
  5. extractionThe aqueous phase was extracted with MTBE (1.2L, 3 vol)
  6. washThe combined organic phases were washed with water (2L, 5 vol)
  7. concentrationThe organic phase was concentrated under vacuum to 3 volumes, and ethanol (1.6L, 4 vol)
  8. additionwas added
  9. concentrationThe reaction was further concentrated under vacuum to 3 volumes, and ethanol (1.6 L, 4 vol)
  10. additionwas added
  11. concentrationThe reaction was further concentrated under vacuum to 3 volumes

Sources & evidence

ORD record
ord-c6a25f3cad864ac39422706bae52688c
Source dataset
uspto-grants-2008_12
Patent number
US07462641B2

Reaction notes

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