Diisopropylethylamine → 1-(5-tert-Butyl-2-(3-hydroxy-propyl)-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-(2,6-dichlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl]-urea

HRID 75627Notes

Reaction equation

HRID 75627 reaction equation
ClC(Cl)(Cl)CO[C:5](=[O:20])[NH:6][C:7]1[N:8]([CH2:16][CH2:17][CH2:18][OH:19])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31]1[N:35]2[CH:36]=[C:37]([O:40][C@H:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C@@H:44]([NH2:51])[CH2:43][CH2:42]3)[CH:38]=[CH:39][C:34]2=[N:33][N:32]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:51][C@@H:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C@H:41]([O:40][C:37]3[CH:38]=[CH:39][C:34]4[N:35]([C:31]([C:25]5[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][C:26]=5[Cl:30])=[N:32][N:33]=4)[CH:36]=3)[CH2:42][CH2:43]2)=[O:20])[N:8]([CH2:16][CH2:17][CH2:18][OH:19])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 86686715(1S,4R)-4-[3-(2,6-Dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamineHCID 86686732[5-tert-Butyl-2-(3-hydroxy-propyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloroethyl ester

Product 1

HCID 866867331-(5-tert-Butyl-2-(3-hydroxy-propyl)-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-(2,6-dichlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl]-ureaYield 77.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of Intermediate 35b (200 mg, 0.54 mmol), Intermediate 26d (228 mg, 0.54 mmol), and DIPEA (140 μL, 0.80 mmol) in dioxane (2 mL) was stirred at 70° C. for 18 h. The reaction mixture was cooled to RT, diluted with DCM (10 mL), and washed with water (2×10 mL). The aqueous layer was extracted with DCM, and the combined organics were passed through a phase separator and concentrated in vacuo and the resultant residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM to afford the title compound (270 mg, 76%). A 50 mg sample of this was purified by MDAP (Method 7) to afford the title compound as a glassy solid (17 mg). LCMS (Method 5): Rt 4.24 min, m/z 648.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.20 (9H, s), 1.79-1.87 (2H, m), 1.88-2.14 (4H, m), 3.41 (2H, t, J=5.9 Hz), 3.91 (2H, t, J=7.2 Hz), 4.58 (1H, br s), 4.79-4.87 (1H, m), 5.55 (1H, t, J=4.2 Hz), 6.03 (1H, s), 6.93 (1H, d, J=8.8 Hz), 7.23-7.29 (1H, m), 7.32-7.38 (4H, m), 7.69-7.79 (3H, m), 7.91 (1H, dd, J=9.6 Hz, 0.9 Hz), 7.98 (1H, d, J=1.7 Hz), 8.17 (1H, s).

Workup

  1. temperatureThe reaction mixture was cooled to RT
  2. washwashed with water (2×10 mL)
  3. extractionThe aqueous layer was extracted with DCM
  4. concentrationconcentrated in vacuo
  5. customthe resultant residue was purified by FCC

Sources & evidence

ORD record
ord-690bcf51edb943bb9e067a5007125a42
Source dataset
uspto-grants-2014_09
Patent number
US08835431B2

Reaction notes

Loading…