Diisopropylethylamine → 5-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-5-(1,3-dioxoisoindolin-2-yl)pyridin-3-yl)-2-fluorobenzamide

HRID 2170364Notes

Reaction equation

HRID 2170364 reaction equation
[F:1][C:2]1([F:19])[C:6]2[N:7]([CH2:14][C:15]([OH:17])=O)[N:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:5]=2[C@H:4]2[CH2:18][C@@H:3]12.Cl.[NH2:21][C@H:22]([C:32]1[C:37]([C:38]2[CH:39]=[CH:40][C:41]([F:47])=[C:42]([CH:46]=2)[C:43]([NH2:45])=[O:44])=[CH:36][C:35]([N:48]2[C:56](=[O:57])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]2=[O:58])=[CH:34][N:33]=1)[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=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>[F:19][C:2]1([F:1])[C:6]2[N:7]([CH2:14][C:15]([NH:21][C@H:22]([C:32]3[C:37]([C:38]4[CH:39]=[CH:40][C:41]([F:47])=[C:42]([CH:46]=4)[C:43]([NH2:45])=[O:44])=[CH:36][C:35]([N:48]4[C:49](=[O:58])[C:50]5[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=5)[C:56]4=[O:57])=[CH:34][N:33]=3)[CH2:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)=[O:17])[N:8]=[C:9]([C:10]([F:11])([F:13])[F:12])[C:5]=2[C@H:4]2[CH2:18][C@@H:3]12

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 90281284(S)-5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(1,3-dioxoisoindolin-2-yl)pyridin-3-yl)-2-fluorobenzamide hydrochlorideHCID 90281286(3bS,4aR)-5,5-Difluoro-3b,4,4a,5-tetrahydro-3-(trifluoromethyl)-1H-cyclopropa(3,4)cyclopenta(1,2-c)pyrazole-1-acetic acid

Product 1

HCID 902814515-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-5-(1,3-dioxoisoindolin-2-yl)pyridin-3-yl)-2-fluorobenzamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (13 mg, 0.045 mmol), (S)-5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(1,3-dioxoisoindolin-2-yl)pyridin-3-yl)-2-fluorobenzamide hydrochloride (30I, 25 mg, 0.045 mmol) and HATU (21 mg, 0.054 mmol) were dissolved in 10 mL DMF, cooled to 0° C., then N,N-diisopropylethylamine (0.032 mL, 0.18 mmol) was added dropwise. 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 (sat'd aq.) and brine. After dried over MgSO4, it was filtered and concentrated. The residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title compound. 1H NMR (400 MHz, CD3OD): δ 8.87 (s, 1H), 7.98 (m, 2H), 7.88 (m, 2H), 7.76 (d, 1H), 7.54-7.30 (m, 2H), 7.24 (dd, 1H), 6.67 (t, 1H), 6.39 (m, 2H), 5.51-5.26 (m, 1H), 4.88 (s, 2H), 3.18-2.98 (m, 2H), 2.63-2.41 (m, 2H), 1.40 (m, 1H), 1.11 (m, 1H). MS (m/z) 781.03 [M+H]+.

Workup

  1. custompartitioned between EtOAc and 5% LiCl aqueous solution
  2. customThe organic layer was separated
  3. washwashed with NaHCO3 (sat'd aq.) and brine
  4. dry with materialAfter dried over MgSO4, it
  5. filtrationwas filtered
  6. concentrationconcentrated
  7. customThe residue was purified by RP-HPLC
  8. washeluting with acetonitrile/H2O (with 0.1% TFA)

Sources & evidence

ORD record
ord-54de2a44e3d14ddd93f275f86d538d4c
Source dataset
uspto-grants-2015_06
Patent number
US09050344B2

Reaction notes

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