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

HRID 1402299Notes

Reaction equation

HRID 1402299 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][N:27]1[CH2:31][CH2:30][C@@H:29]([C:32]2[N:36]3[CH:37]=[C:38]([O:41][C@H:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[C@@H:45]([NH2:52])[CH2:44][CH2:43]4)[CH:39]=[CH:40][C:35]3=[N:34][N:33]=2)[CH2:28]1.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:52][C@@H:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:42]([O:41][C:38]3[CH:39]=[CH:40][C:35]4[N:36]([C:32]([C@@H:29]5[CH2:30][CH2:31][N:27]([CH3:26])[CH2:28]5)=[N:33][N:34]=4)[CH:37]=3)[CH2:43][CH2:44]2)=[O:23])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)([CH3:14])([CH3:13])[CH3:15]

Participants

8

Reactant 4

HCID 222AmmoniaHCID 81531DiisopropylethylamineHCID 99310942,2,2-Trichloroethyl 3-tert-butyl-1-P-tolyl-1H-pyrazol-5-ylcarbamateHCID 86687141(1S,4R)-4-[3-((R)-1-Methyl-pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine

Product 1

HCID 866871421-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((R)-1-methyl-pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

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; 227 mg, 0.560 mmol), Intermediate 90e (145 mg, 0.400 mmol) and DIPEA (0.111 mL, 0.640 mmol) in dry dioxane (5 mL) was stirred at 65° C. for 15 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2 cartridge (10 g) and washed with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (30 mL); concentration in vacuo gave a brown solid. FCC, using 2-7% [2M NH3 in MeOH] in DCM, gave a pale brown solid (195 mg). Further purification by MDAP (Method 8) gave the title compound as a white powder after freeze-drying (10.0 mg, 4%). LCMS (Method 5): Rt 3.62 min, m/z 619 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.83-1.98 (2H, m), 2.08-2.20 (3H, m), 2.32 (3H, s), 2.33-2.40 (1H, m), 2.36 (3H, s), 2.59-2.70 (2H, m), 2.75 (1H, dd, J 9.2, 6.1), 2.96 (1H, t, J 8.7), 3.93-4.01 (1H, m), 4.83 (1H, td, J 8.4, 5.4), 5.46 (1H, t, J 4.6), 6.32 (1H, s), 7.10 (1H, d, J 8.5), 7.18 (1H, dd, J 9.9, 2.1), 7.27-7.40 (8H, m), 7.69 (1H, dd, J 9.9, 0.8), 8.04 (1H, s), 8.44 (1H, d, J 2.0).

Workup

  1. concentrationThe cooled solution was concentrated in vacuo
  2. dissolutionredissolved in MeOH (2 mL)
  3. washwashed with MeOH (50 mL)
  4. washThe product was eluted with 2M NH3 in MeOH (30 mL)
  5. concentrationconcentration in vacuo
  6. customgave a brown solid

Sources & evidence

ORD record
ord-cdaf7d9fb097400b8b9b12e227218ac6
Source dataset
uspto-grants-2014_12
Patent number
US08907094B2

Reaction notes

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