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 631017Notes

Reaction equation

HRID 631017 reaction equation
[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]

Participants

4

Reactant 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

Product 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]ureaYield 35.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-a6149e72381746f0a6f190277ec8952b
Source dataset
uspto-grants-2016_04
Patent number
US09315503B2

Reaction notes

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