Pyrrolidine → 1-{5-tert-Butyl-2-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

HRID 630949Notes

Reaction equation

HRID 630949 reaction equation
[NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:10]1[CH:14]=[C:13]([NH:15][C:16]([NH:18][C@@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:22]([O:29][C:30]3[CH:31]=[CH:32][C:33]4[N:34]([C:36]([N:39]5[C@H:44]([CH3:45])[CH2:43][CH2:42][CH2:41][C@@H:40]5[CH3:46])=[N:37][N:38]=4)[CH:35]=3)[CH2:21][CH2:20]2)=[O:17])[N:12]([C:47]2[CH:48]=[C:49]([CH:58]=[CH:59][CH:60]=2)[O:50][CH2:51][CH2:52]OS(C)(=O)=O)[N:11]=1)([CH3:9])([CH3:8])[CH3:7]>C1COCC1>[C:6]([C:10]1[CH:14]=[C:13]([NH:15][C:16]([NH:18][C@@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:22]([O:29][C:30]3[CH:31]=[CH:32][C:33]4[N:34]([C:36]([N:39]5[C@H:40]([CH3:46])[CH2:41][CH2:42][CH2:43][C@@H:44]5[CH3:45])=[N:37][N:38]=4)[CH:35]=3)[CH2:21][CH2:20]2)=[O:17])[N:12]([C:47]2[CH:60]=[CH:59][CH:58]=[C:49]([O:50][CH2:51][CH2:52][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:48]=2)[N:11]=1)([CH3:7])([CH3:8])[CH3:9]

Participants

4

Reactant 2

HCID 31268PyrrolidineHCID 86687259Methanesulfonic acid 2-{3-[3-tert-butyl-5-(3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-pyrazol-1-yl]-phenoxy}-ethyl ester

Product 1

HCID 866872581-{5-tert-Butyl-2-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaYield 25.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

Pyrrolidine (36 μL, 0.43 mmol) was added to a solution of Intermediate 96f (111 mg, 0.14 mmol) in THF (2 mL). The reaction was heated to 60° C. in a sealed vial overnight. The mixture was cooled, evaporated in vacuo and the residue was purified by FCC, using 0-15% MeOH in DCM, then triturated with Et2O to give the title compound (27 mg, 25%) as an off-white solid. LCMS (Method 5): Rt 3.87 min, m/z 746.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.55 (3H, d, J=6.0 Hz), 0.58 (3H, d, J 6.0 Hz), 1.23 (9H, s), 1.32-1.54 (3H, m), 1.53-1.78 (7H, m), 1.79-1.95 (2H, m), 1.96-2.10 (2H, m), 2.49-2.60 (2H, m), 2.68-2.94 (2H, m), 3.06-3.20 (3H, m), 3.27 (1H, m, obscured by water), 4.03-4.14 (2H, m), 4.74-4.83 (1H, m), 5.49 (1H, t, J=4.0 Hz), 6.29 (1H, s), 6.90-6.96 (1H, m), 7.01-7.09 (3H, m), 7.16 (1H, dd, J=9.7, 2.0 Hz), 7.19-7.25 (2H, m), 7.26-7.32 (2H, m), 7.33-7.39 (1H, m), 7.62 (1H, d, J=9.7 Hz), 7.84 (1H, m), 8.06 (1H, s).

Workup

  1. temperatureThe mixture was cooled
  2. customevaporated in vacuo
  3. customthe residue was purified by FCC
  4. customtriturated with Et2O

Sources & evidence

ORD record
ord-d57635910a4b407992b86093e5f51e04
Source dataset
uspto-grants-2016_04
Patent number
US09315503B2

Reaction notes

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