Diisopropylethylamine → (S)-N-(1-cyanocyclopropyl)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanamide

HRID 405038Notes

Reaction equation

HRID 405038 reaction equation
[CH:1]1([CH2:4][C:5]([F:24])([F:23])[CH2:6][C@H:7]([NH:11][C@@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])[C:8](O)=[O:9])[CH2:3][CH2:2]1.CN(C(ON1N=[N:40][C:35]2[CH:36]=[CH:37]C=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.C(C1CC1)#N>CN(C=O)C>[C:34]([C:35]1([NH:40][C:8](=[O:9])[C@@H:7]([NH:11][C@@H:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([F:15])([F:14])[F:16])[CH2:6][C:5]([F:23])([F:24])[CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH2:37][CH2:36]1)#[N:39]

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 59850368(S)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanoic acidHCID 669399151-Cyanocyclopropane hydrochloride

Product 1

HCID 59850371(S)-N-(1-cyanocyclopropyl)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanamideYield 39.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A stirred solution of (S)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanoic acid (150 mg, 0.4 mmol) in DMF (15 mL) was treated with HATU (253 mg, 0.5 mmol) and DIPEA (0.3 mL, 1.7 mL mmol). After 15 min, 1-cyanocyclopropane hydrochloride (61 mg, 0.5 mmol) was added and the reaction mixture was stirred under a nitrogen atmosphere for 2 h. Once the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate & washed with 1HCl solution and brine, dried over Na2SO4, filtered and was concentrated. The crude compound was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane followed by re-crystallization from DCM and pentane to provide (S)—N-(1-cyanocyclopropyl)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanamide (65 mg, 37%) as white solid. 1H-NMR (500 MHz, DMSO-d6): 8.88 (1H, s, NH), 7.38 (5H, s, Ar—H), 4.23 (1H, m, CHCF3), 3.39 (1H, m, CH), 3.18 (1H, m, NH), 2.23 (2H, m, CH2), 1.94 (2H, m, CH2), 1.32 (2H, m, CH2), 0.82 (2H, m, CH2), 0.57 (1H, m, CH), 0.45 (2H, m, CH2), 0.12 (2H, m, CH2). 19F-NMR (500 MHz, CD3OD): −74.609 (CF2), −95.308, −95.507 (CF3). EIMS (m/z): 416 (M+H)1. HPLC: 97.37% (RT 16.39) Column used zorbax SB, C8, 250×4.6 mm, 5 uMobile Phase: ACN (B): 0.1% TFA in water (A) Flow rate: 1.0 mL/Min

Workup

  1. customthe reaction mixture was quenched with saturated sodium bicarbonate solution
  2. extractionextracted with ethyl acetate
  3. washwashed with 1HCl solution and brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationwas concentrated
  7. customThe crude compound was purified by silica gel column chromatography
  8. washeluting with 10% ethyl acetate in hexane
  9. customfollowed by re-crystallization from DCM and pentane

Sources & evidence

ORD record
ord-9171057b3c7841b1ab8179304de76c38
Source dataset
uspto-grants-2014_06
Patent number
US08748649B2

Reaction notes

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