Diisopropylethylamine → 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[8-methyl-3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

HRID 2285174Notes

Reaction equation

HRID 2285174 reaction equation
[CH3:1][C:2]1[C:3]2[N:4]([C:20]([C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH3:28])=[N:21][N:22]=2)[CH:5]=[C:6]([O:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]([NH2:19])[CH2:11][CH2:10]2)[CH:7]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:19][C@@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]([O:8][C:6]3[CH:7]=[C:2]([CH3:1])[C:3]4[N:4]([C:20]([C@@H:23]5[CH2:27][CH2:26][CH2:25][N:24]5[CH3:28])=[N:21][N:22]=4)[CH:5]=3)[CH2:10][CH2:11]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 99310942,2,2-Trichloroethyl 3-tert-butyl-1-P-tolyl-1H-pyrazol-5-ylcarbamateHCID 89624296(1S,4R)-4-[8-Methyl-3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine

Product 1

HCID 896125091-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[8-methyl-3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaYield 74%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of Intermediate 105e (53 mg, 0.14 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (for reference procedure see Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 67 mg, 0.168 mmol) and DIPEA (49 μL, 0.28 mmol) in DMF (2 mL) was stirred at 100° C. for 1.5 h under argon atmosphere. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc in cyclohexane followed by 10% [2M NH3 in MeOH] in EtOAc. The product containing fractions were concentrated in vacuo and the resultant residue was purified by HPLC (C18 Phenomenex Gemini column, 5-98% gradient MeCN in H2O, 0.1% NH4OH), to afford the title compound (52 mg, 74%). LCMS (Method 5): Rt 3.76 min, m/z 633 1H NMR (400 MHz, d6-DMSO): 1.23 (9H, s), 1.75-2.30 (13H, m), 2.32 (3H, s), 2.48 (3H, s), 3.19 (1H, br s), 4.72-4.83 (1H, m), 5.30-5.38 (1H, m), 6.28 (1H, s), 7.03-7.11 (2H, m), 7.20-7.36 (8H, m), 8.00 (1H, s), 8.11 (1H, s).

Workup

  1. washwashed with brine
  2. dry with materialThe organic layer was dried (MgSO4)
  3. concentrationconcentrated in vacuo
  4. customThe resultant residue was purified by FCC on silica
  5. additionThe product containing fractions
  6. concentrationwere concentrated in vacuo
  7. customthe resultant residue was purified by HPLC (C18 Phenomenex Gemini column, 5-98% gradient MeCN in H2O, 0.1% NH4OH)

Sources & evidence

ORD record
ord-82280415ecba4949953c614bbdab6610
Source dataset
uspto-grants-2015_09
Patent number
US09145413B2

Reaction notes

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