Morpholine → 1-[3-tert-butyl-1-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]pyrazol-5-yl]-3-[(1S,4R)-4-[[3-[(2S)-2-methylpiperidin-1-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]oxy]-1,2,3,4-tetrahydronaphthalen-1-yl]urea

HRID 2285319노트

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HRID 2285319 반응식
[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47]OS(C)(=O)=O)[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[CH:45]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]

참가 물질

4

반응물 2

HCID 8083MorpholineHCID 86687325Methanesulfonic acid 2-[3-tert-butyl-5-(3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-[1,4']bipyrazolyl-1'-yl]-ethyl ester

생성물 1

HCID 866873261-[3-tert-butyl-1-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]pyrazol-5-yl]-3-[(1S,4R)-4-[[3-[(2S)-2-methylpiperidin-1-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]oxy]-1,2,3,4-tetrahydronaphthalen-1-yl]urea수율 35.7%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

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온도
50 °C

실험 절차

To a solution of Intermediate 187c (0.19 mmol) in THF (3 mL) was added morpholine (166 μL, 1.9 mmol) and the reaction stirred at 50° C. overnight. The crude reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 2.5-10% (2M NH3 in MeOH) in DCM followed by MDAP (Method 7) purification, to give the title compound (49 mg, 35%). LCMS (Method 5): Rt 3.53 min, m/z 722 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.87 (3H, d, J=6.4 Hz), 1.20 (9H, s), 1.43-1.51 (2H, m), 1.58-1.69 (2H, m), 1.70-1.88 (3H, m), 1.88-1.96 (1H, m), 1.96-2.12 (2H, m), 2.37 (4H, t, J=4.5 Hz), 2.69 (2H, t, J=6.5 Hz), 2.87 (1H, ddd, J=12.6, 9.1, 3.9 Hz), 3.12 (1H, dt, J=12.1, 4.2 Hz), 1H UNDER SOLVENT, 3.50 (4H, t, J=4.6 Hz), 4.20 (2H, t, J=6.5 Hz), 4.80 (1H, td, J=8.5, 5.8 Hz), 5.48 (1H, t, J=4.3 Hz), 6.22 (1H, s), 7.11 (1H, d, J=8.5 Hz), 7.15 (1H, dd, J=9.9, 2.2 Hz), 7.21-7.26 (1H, m), 7.28-7.35 (3H, m), 7.60 (1H, d, J=9.8 Hz), 7.60 (1H, s), 7.66 (1H, d, J=2.1 Hz), 7.96 (1H, s), 8.02 (1H, s), 8.12 (0.5H, s).

후처리

  1. customThe crude reaction mixture
  2. customwas partitioned between EtOAc and water
  3. extractionThe aqueous phase was extracted with EtOAc (×3)
  4. washthe combined organic layers were washed with brine
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customThe resultant residue was purified by FCC on silica
  8. customfollowed by MDAP (Method 7) purification

출처 및 근거

ORD 기록
ord-e3ddff9c04fa48438e5260c4a47fb7fa
출처 데이터셋
uspto-grants-2015_09
특허 번호
US09145413B2

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