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Diphenylphosphinic chloride → 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 1807313
Notes
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Reaction equation

HRID 1807313 reaction equation
FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:76]=[CH:75][C:67]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])=[C:66]([F:77])[CH:65]=1>C(Cl)Cl>[C:71]([O:70][C:68](=[O:69])[C:67]1[CH:75]=[CH:76][C:64]([NH:63][C:35]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:32])[CH3:34])[NH:17]2)=[O:36])=[CH:65][C:66]=1[F:77])([CH3:74])([CH3:72])[CH3:73]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 73910Diphenylphosphinic chlorideHCID 81531DiisopropylethylamineHCID 10058989Tert-butyl 4-amino-2-fluorobenzoateHCID 86642695CID 86642695

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

In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (200 mg, 344 μmol, Eq: 1.00), was combined with CH2Cl2 (4.5 ml) to give a yellow solution. DIPEA (178 mg, 1.38 mmol, Eq: 4) and diphenylphosphinic chloride (244 mg, 1.03 mmol, Eq: 3) were added and the reaction was stirred at RT for 20 minutes. Tert-butyl 4-amino-2-fluorobenzoate (72.7 mg, 344 μmol, Eq: 1.00) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 20% EtOAc in hexanes) to give a white solid as the product. 215 mg. MS (ES+) m/z Calcd: [(M+H)+]: 660, fund: 660.

Workup

  1. customto give a yellow solution
  2. stirringthe reaction mixture was stirred at RT overnight
  3. customThe crude reaction mixture
  4. concentrationwas concentrated under vacuum
  5. customThe crude material was purified by flash chromatography (silica gel, 40 g, 10% to 20% EtOAc in hexanes)
  6. customto give a white solid as the product

Sources & evidence

ORD record
ord-97cfb664b16245328d2d9090f791059f
Source dataset
uspto-grants-2013_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08354444B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes