Ammonia → 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-((1S,4R)-4-{3-[methyl-(2-morpholin-4-yl-ethyl)-amino]-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy}-1,2,3,4-tetrahydro-naphthalen-1-yl)-urea

HRID 630757Notes

Reaction equation

HRID 630757 reaction equation
[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([N:22]([CH3:31])[CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:20][N:21]=3)[CH:18]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:35][C:36](=O)[NH:37][C:38]1[N:39]([C:47]2[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=2)[N:40]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:42]=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO.C(Cl)Cl>[C:43]([C:41]1[CH:42]=[C:38]([NH:37][C:36]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:5]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([N:22]([CH3:31])[CH2:23][CH2:24][N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[N:20][N:21]=4)[CH:18]=3)[CH2:4][CH2:3]2)=[O:35])[N:39]([C:47]2[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=2)[N:40]=1)([CH3:46])([CH3:44])[CH3:45]

Participants

8

Reactant 4

HCID 222AmmoniaHCID 81531DiisopropylethylamineHCID 99310942,2,2-Trichloroethyl 3-tert-butyl-1-P-tolyl-1H-pyrazol-5-ylcarbamateHCID 89612379[6-((1R,4S)-4-Amino-1,2,3,4-tetrahydro-naphthalen-1-yloxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

Product 1

HCID 896122231-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-((1S,4R)-4-{3-[methyl-(2-morpholin-4-yl-ethyl)-amino]-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy}-1,2,3,4-tetrahydro-naphthalen-1-yl)-ureaYield 14%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of Intermediate 45d (270 mg, 0.63 mmol), (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; 380 mg, 0.95 mmol) and DIPEA (325 mg, 2.52 mmol) in DMF (8 mL) was stirred at 60° C. for 1 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave a stiff yellow gum which was further purified by HPLC (C18 column, 10-45% MeCN in H2O, 0.1% HCO2H). The residue was recrystallized from boiling EtOAc to give the title compound as a white powder (60.0 mg, 14%). LCMS (Method 5): Rt 3.65 min, m/z 678.3 [MH+]. 1H NMR (400 MHz, d4-MeOH): 1.30 (9H, s), 1.87-2.15 (3H, m), 2.18-2.27 (1H, m), 2.32 (4H, t, J 4.4), 2.38 (3H, s), 2.55 (2H, t, J 5.6), 2.96 (3H, s), 3.31-3.40 (6H, m), 4.89 (1H, m), 5.40 (1H, t, J 4.2), 6.33 (1H, s), 7.19-7.36 (9H, m), 7.53 (1H, d, J 10.0), 7.92 (1H, d, J 1.6).

Workup

  1. washwashed with MeOH
  2. washThe product was eluted with 2M NH3 in MeOH
  3. concentrationconcentration in vacuo
  4. customgave a residue
  5. customgave a stiff yellow gum which
  6. customwas further purified by HPLC (C18 column, 10-45% MeCN in H2O, 0.1% HCO2H)
  7. customThe residue was recrystallized

Sources & evidence

ORD record
ord-dad1e0a8d265428c83d465b1d225e06d
Source dataset
uspto-grants-2016_04
Patent number
US09315503B2

Reaction notes

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