Ammonia → HCID 86687089, compound

HRID 2285064Notes

Reaction equation

HRID 2285064 reaction equation
ClC(Cl)(Cl)CO[C:5](=[O:23])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:26][C:27]([CH:40]1[CH2:45][CH2:44][N:43]([C:46]2[N:50]3[CH:51]=[C:52]([O:55][C@H:56]4[C:65]5[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=5)[C@@H:59]([NH2:66])[CH2:58][CH2:57]4)[CH:53]=[CH:54][C:49]3=[N:48][N:47]=2)[CH2:42][CH2:41]1)([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH3:28].CCN(C(C)C)C(C)C.N>O1CCOCC1.CO.C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:66][C@@H:59]2[C:60]3[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=3)[C@H:56]([O:55][C:52]3[CH:53]=[CH:54][C:49]4[N:50]([C:46]([N:43]5[CH2:42][CH2:41][CH:40]([C:27]([CH3:26])([O:29][Si:30]([CH:31]([CH3:33])[CH3:32])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH3:28])[CH2:45][CH2:44]5)=[N:47][N:48]=4)[CH:51]=3)[CH2:57][CH2:58]2)=[O:23])[N:8]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:9]=1)([CH3:13])([CH3:14])[CH3:15]

Participants

8

Reactant 4

HCID 222AmmoniaHCID 81531DiisopropylethylamineHCID 99310942,2,2-Trichloroethyl 3-tert-butyl-1-P-tolyl-1H-pyrazol-5-ylcarbamateHCID 86687088HCID 86687088, compound

Product 1

HCID 86687089HCID 86687089, compound

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

A brown solution of (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 89.6 mg, 0.221 mmol), Intermediate 74c (128 mg, 0.221 mmol) and DIPEA (0.048 mL, 0.277 mmol) in dioxane (3 mL) was stirred at 60° C. for 16 h, and at 80° C. for 6 h. The cooled solution was concentrated in vacuo, suspended in water (4 mL) and extracted with DCM (2×4 mL). The combined organics were passed through a hydrophobic fit and concentrated in vacuo to leave a viscous brown oil. FCC, using 1-4% [2M NH3 in MeOH] in DCM) gave 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-((1S,4R)-4-{3-[4-(1-methyl-1-triisopropylsilanyloxy-ethyl)-piperidin-1-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy}-1,2,3,4-tetrahydro-naphthalen-1-yl)-urea as a yellow solid (125 mg). The solid was dissolved in THF (3 mL), treated with TBAF (1M in THF, 0.161 mL, 0.161 mmol) and the solution stirred at RT for 2 h, and then at reflux for 1 h. The solution was cooled to ˜40° C., then TBAF (1M in THF, 0.161 mL, 0.161 mmol) added and the solution stirred at reflux for 16 h. The cooled solution was concentrated in vacuo, suspended in water (10 mL) and extracted with EtOAc-MeOH (19:1, 2×10 mL). The combined organics were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave a dark green residue. FCC, using 2-7% MeOH in DCM, gave the title compound as a pale yellow solid (60.6 mg, 41%). LCMS (Method 5): Rt 4.42 min, m/z 677 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.09 (6H, s), 1.27 (9H, s), 1.37-1.44 (1H, m), 1.49-1.61 (2H, m), 1.80 (2H, d, J 12.6), 1.83-1.96 (2H, m), 2.01-2.10 (2H, m), 2.36 (3H, s), 2.81-2.90 (2H, m), 3.49 (2H, t, J 11.2), 4.16 (1H, s), 4.81 (1H, td, J 8.5, 5.5), 5.56 (1H, t, J 4.4), 6.32 (1H, s), 7.08 (1H, d, J 8.6), 7.14 (1H, dd, J 9.9, 2.1), 7.27-7.40 (8H, m), 7.61 (1H, d, J 9.9), 7.66 (1H, d, J 2.0), 8.04 (1H, s).

Workup

  1. concentrationThe cooled solution was concentrated in vacuo
  2. extractionextracted with DCM (2×4 mL)
  3. concentrationconcentrated in vacuo
  4. customto leave a viscous brown oil

Sources & evidence

ORD record
ord-a474b69840da4fe48dbc26c8e95cf62d
Source dataset
uspto-grants-2015_09
Patent number
US09145413B2

Reaction notes

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