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 2170364노트

반응식

HRID 2170364 반응식
[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

참가 물질

6

반응물 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

생성물 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

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

반응 조건

온도
0 °C

실험 절차

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]+.

후처리

  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)

출처 및 근거

ORD 기록
ord-54de2a44e3d14ddd93f275f86d538d4c
출처 데이터셋
uspto-grants-2015_06
특허 번호
US09050344B2

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