Diisopropylethylamine → 1-Oxo-1-(1-(3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-phenyl)carbamoyl)benzyl)-1H-indol-4-yl)-5,8,11-trioxa-2-azatetradecan-14-oic acid

HRID 625273노트

반응식

HRID 625273 반응식
[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=3)[CH2:19][N:20]3[C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:29]([OH:31])=O)[C:23]=4[CH:22]=[CH:21]3)=[O:15])=[C:9]([C:35]3[CH:40]=[C:39]([C:41](=[O:54])[NH:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=4)[CH:38]=[CH:37][N:36]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:31]=[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[CH:22]=[CH:21][N:20]2[CH2:19][C:18]1[CH:32]=[CH:33][CH:34]=[C:16]([C:14](=[O:15])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][C:9]=2[C:35]2[CH:40]=[C:39]([C:41](=[O:54])[NH:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:51])([F:52])[F:53])[CH:45]=3)[CH:38]=[CH:37][N:36]=2)[CH:17]=1)[NH:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68]

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 116082453-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)propanoic acidHCID 665881211-(3-((4-(Piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)-1H-indole-4-carboxylic acid

생성물 1

HCID 867092131-Oxo-1-(1-(3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-phenyl)carbamoyl)benzyl)-1H-indol-4-yl)-5,8,11-trioxa-2-azatetradecan-14-oic acid수율 36.5%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

실험 절차

A mixture of 3 mg of 1-(3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)-benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)-1H-indole-4-carboxylic acid 9.1, 1.7 mg of 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoic acid, and 2.5 mg of HATU in 300 μL of DMF was treated with 1.5 μL of diisopropylethylamine. After 2 h the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate, and the combined organic extracts were washed with brine and dried (Na2SO4). The solvent was evaporated and a fraction of the product was dissolved in 1:1 dichloromethane/TFA. After stirring for 1 h the solvent was evaporated and the residue was purified by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to yield 1.4 mg of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.57 (t, J=5.7 Hz, 1H), 8.98 (d, J=5.1 Hz, 1H), 8.51 (d, J=8.7 Hz, 1H), 8.40 (s, 1H), 7.93 (s, 1H), 7.89 (d, J=5.1 Hz, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.72 (s, 1H), 7.65 (m, 2H), 7.60-7.52 (m, 3H), 7.48 (t, J=7.7 Hz, 1H), 7.24-7.14 (m, 3H), 7.03-6.94 (m, 1H), 4.64 (d, J=5.8 Hz, 2H), 4.36 (s, 2H), 3.47 (s, 4H), 2.15 (t, J=7.3 Hz, 2H), 1.83 (br, 4H), 1.81-1.67 (m, 2H), 1.64 (br, 2H). MS (ES, m/z) 935.32 [M+H]+

후처리

  1. customAfter 2 h the solvent was evaporated
  2. customthe residue was partitioned between ethyl acetate and water
  3. washThe aqueous phase was washed with ethyl acetate
  4. washthe combined organic extracts were washed with brine
  5. dry with materialdried (Na2SO4)
  6. customThe solvent was evaporated
  7. dissolutiona fraction of the product was dissolved in 1:1 dichloromethane/TFA
  8. customwas evaporated
  9. customthe residue was purified by reverse phase HPLC
  10. washeluting with 0.05% TFA in a water/acetonitrile gradient

출처 및 근거

ORD 기록
ord-27e12f4fd79f4bb788ffdc271c37ce50
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09301951B2

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