Diisopropylethylamine → N-((S)-1-(3-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

HRID 2170379Notes

Reaction equation

HRID 2170379 reaction equation
[F:1][CH:2]([F:18])[C:3]1[C:4]2[C@H:14]3[CH2:15][C@H:13]3[C:12]([F:17])([F:16])[C:5]=2[N:6]([CH2:8][C:9](O)=[O:10])[N:7]=1.[NH2:19][C@H:20]([C:30]1[N:35]=[C:34]([N:36]2[CH2:39][C:38]([CH3:41])([OH:40])[CH2:37]2)[CH:33]=[CH:32][C:31]=1[Br:42])[CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:42][C:31]1[C:30]([C@@H:20]([NH:19][C:9](=[O:10])[CH2:8][N:6]2[C:5]3[C:12]([F:17])([F:16])[C@@H:13]4[CH2:15][C@@H:14]4[C:4]=3[C:3]([CH:2]([F:18])[F:1])=[N:7]2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)=[N:35][C:34]([N:36]2[CH2:39][C:38]([OH:40])([CH3:41])[CH2:37]2)=[CH:33][CH:32]=1

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 90280371(S)-1-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-bromopyridin-2-yl)-3-methylazetidin-3-olHCID 902812892-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid

Product 1

HCID 90281188N-((S)-1-(3-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (33 mg, 0.13 mmol), (S)-1-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-bromopyridin-2-yl)-3-methylazetidin-3-ol (50 mg, 0.13 mmol) and HATU (57 mg, 0.15 mmol) were dissolved in 1 mL of DMF and cooled to 0° C. To it was dropwise added N,N-diisopropylethylamine (0.07 mL, 0.38 mmol). The reaction mixture was allowed to stir at 0° C. for 5 min, and then partitioned between EtOAc and 5% LiCl aqueous solution. The organic layer was separated, washed with NaHCO3 (saturated aqueous) and brine. After dried over MgSO4, it was filtered and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/hexanes to afford the title product. MS (m/z): 644.33[M+H]+.

Workup

  1. custompartitioned between EtOAc and 5% LiCl aqueous solution
  2. customThe organic layer was separated
  3. washwashed with NaHCO3 (saturated aqueous) and brine
  4. dry with materialAfter dried over MgSO4, it
  5. filtrationwas filtered
  6. concentrationconcentrated
  7. customThe residue was purified by silica gel chromatography
  8. washeluting with EtOAc/hexanes

Sources & evidence

ORD record
ord-24fca7582daf4a0f992ad2dcd475646b
Source dataset
uspto-grants-2015_06
Patent number
US09050344B2

Reaction notes

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