Diisopropylethylamine → HCID 72243912, compound

HRID 1807252Notes

Reaction equation

HRID 1807252 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]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:65][C:66]1[CH:71]=[CH:70][C:69]([C:72](=[O:82])[CH2:73][O:74][Si](C(C)(C)C)(C)C)=[CH:68][CH:67]=1>ClCCl.O>[OH:74][CH2:73][C:72]([C:69]1[CH:70]=[CH:71][C:66]([NH:65][C:28]([CH:9]2[CH: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])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:30])=[CH:67][CH:68]=1)=[O:82]

Participants

7

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 592495591-(4-Aminophenyl)-2-(tert-butyldimethylsilyloxy)ethanoneHCID 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 72243912HCID 72243912, compoundYield 38%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a 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 (0.35 g, 0.749 mmol) in dichloromethane (25 ml) was added iPr2NEt (242 mg, 1.87 mmol) was added, followed by the addition of HATU (513 mg, 1.35 mmol) and 1-(4-aminophenyl)-2-(tert-butyldimethylsilyloxy)ethanone (398 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into H2O (50 mL) and extracted with dichloromethane (3×25 mL). The organic layers were combined, washed with H2O (1×50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was dissolved in THF (25 mL) and then an aqueous solution (1 N) of HCl (10 mL) was added. The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo. The residue was poured into 20 mL saturated aqueous NaHCO3 and extracted with ethyl acetate (3×25 mL). The organic layers were combined, washed with H2O (25 mL), brine (25 mL), dried over MgSO4 and concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 20% to 100% EtOAc in hexanes) to give 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 [4-(2-hydroxy-acetyl)-phenyl]-amide as a light yellow solid (0.17 g, 38%).

Workup

  1. additionwas added
  2. extractionextracted with dichloromethane (3×25 mL)
  3. washwashed with H2O (1×50 mL), brine (50 mL)
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in vacuo
  6. dissolutionThe residue was dissolved in THF (25 mL)
  7. additionan aqueous solution (1 N) of HCl (10 mL) was added
  8. stirringThe reaction mixture was stirred at room temperature for 30 min
  9. concentrationThe mixture was concentrated in vacuo
  10. additionThe residue was poured into 20 mL saturated aqueous NaHCO3
  11. extractionextracted with ethyl acetate (3×25 mL)
  12. washwashed with H2O (25 mL), brine (25 mL)
  13. dry with materialdried over MgSO4
  14. concentrationconcentrated
  15. customThe residue was purified by flash chromatography (silica gel, 40 g, 20% to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-6803b53f0a464fa7955d13e3e1d9a190
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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