Diisopropylethylamine → tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-fluorobenzoate

HRID 1807180Notes

Reaction equation

HRID 1807180 reaction equation
[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:65]([O:69][C:70](=[O:79])[C:71]1[CH:76]=[CH:75][C:74]([NH2:77])=[CH:73][C:72]=1[F:78])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:79])[C:71]1[CH:76]=[CH:75][C:74]([NH:77][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[CH:73][C:72]=1[F:78])([CH3:68])([CH3:66])[CH3:67]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 10058989Tert-butyl 4-amino-2-fluorobenzoateHCID 666882513-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid

Product 1

HCID 45137136tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-fluorobenzoate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich, 147 mg, 0.39 mmol) was added followed by the addition of DIPEA (0.225 mL, 1.29 mmol) and 4-amino-2-fluoro-benzoic acid t-butyl ester (Aldrich, 44 mg, 0.32 mmol). The mixture was stirred at rt for 5.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 0-15% EtOAc/hexanes) to give a white solid. 19 mg.

Workup

  1. customThe reaction was quenched with addition of water
  2. extractionThe mixture was extracted with methylene chloride (2×10 mL)
  3. dry with materialthe extracts were dried with magnesium sulfate
  4. customThe solvent was removed
  5. customthe residue was purified on an ISCO machine (40 g column, 0-15% EtOAc/hexanes)
  6. customto give a white solid

Sources & evidence

ORD record
ord-ed35b3214b2f46d996c6e57b8209a1fb
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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