Diisopropylethylamine → 1-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2-chloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

HRID 75619Notes

Reaction equation

HRID 75619 reaction equation
ClC(Cl)(Cl)CO[C:5](=[O:19])[NH:6][C:7]1[N:8]([CH2:16][CH2:17][OH:18])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:33]2[CH:34]=[C:35]([O:38][C@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[C@@H:42]([NH2:49])[CH2:41][CH2:40]3)[CH:36]=[CH:37][C:32]2=[N:31][N:30]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:49][C@@H:42]2[C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:39]([O:38][C:35]3[CH:36]=[CH:37][C:32]4[N:33]([C:29]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[Cl:22])=[N:30][N:31]=4)[CH:34]=3)[CH2:40][CH2:41]2)=[O:19])[N:8]([CH2:16][CH2:17][OH:18])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 86686717[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl esterHCID 86686723(1S,4R)-4-[3-(2-Chloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine

Product 1

HCID 866867241-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2-chloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaYield 94%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of Intermediate 26a (340 mg, 0.95 mmol), Intermediate 31c (372 mg, 0.95 mmol), and DIPEA (248 μL, 1.43 mmol) in dioxane (5 mL) was stirred at 70° C. for 18 h. After cooling to RT, the reaction mixture was partitioned between DCM and water. The organic layer was dried through a phase separator and then concentrated in vacuo. The resultant residue was purified by FCC, using 0-10% MeOH in DCM to afford the title compound (536 mg, 94%) as a brown solid. An aliquot of the compound thus obtained (100 mg) was further purified by MDAP (Method 7) to afford the title compound (45 mg). LCMS (Method 5): Rt 4.08 min, m/z 600 [MH+]. 1H NMR (400 MHz, DMSO): 1.20 (9H, s), 1.81-2.19 (4H, m), 3.66 (2H, d, J=6.1 Hz), 3.93 (2H, t, J=6.0 Hz), 4.78-4.84 (1H, m), 4.98 (1H, br s), 5.51 (1H, t, J=4.3 Hz), 6.05 (1H, s), 7.06 (1H, d, J=8.6 Hz), 7.23-7.30 (1H, m), 7.32-7.38 (4H, m), 7.60 (1H, td, J=7.5, 1.3 Hz), 7.68 (1H, td, J=7.7, 1.9 Hz), 7.73 (2H, td, J=7.5, 1.3 Hz), 7.82-7.92 (2H, m), 8.17 (1H, s).

Workup

  1. temperatureAfter cooling to RT
  2. customthe reaction mixture was partitioned between DCM and water
  3. customThe organic layer was dried through a phase separator
  4. concentrationconcentrated in vacuo
  5. customThe resultant residue was purified by FCC

Sources & evidence

ORD record
ord-2f5b9daa5806438cbed7aa0dfeb658b2
Source dataset
uspto-grants-2014_09
Patent number
US08835431B2

Reaction notes

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