Potassium Carbonate → N,N-Dibutyl-4-chloro-1-(4-(1-ethyl-5-morpholinoindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-methyl-1H-pyrazole-3-carboxamide

HRID 528850Notes

Reaction equation

HRID 528850 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[C:27]([CH3:28])=[C:26]([Cl:29])[C:25]([C:30]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[N:24]3)=[C:19]([C:41]([N:43]3[CH2:52][CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44]3)=[O:42])[CH:18]=1)=[O:16])(=[O:13])=[O:12])[N:7]([CH2:53][CH3:54])[CH2:6][CH2:5]2.[NH:55]1[CH2:62][CH2:61]C[C@H:56]1[C:57](O)=[O:58].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.Cl.CCOC(C)=O.[Cu]I>[CH2:33]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[C:30]([C:25]1[C:26]([Cl:29])=[C:27]([CH3:28])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[NH:14][S:11]([C:10]3[CH:9]=[C:8]4[C:4]([CH2:5][CH2:6][N:7]4[CH2:53][CH3:54])=[CH:3][C:2]=3[N:55]3[CH2:56][CH2:57][O:58][CH2:61][CH2:62]3)(=[O:13])=[O:12])=[CH:18][C:19]=2[C:41]([N:43]2[CH2:52][CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)=[O:42])[N:24]=1)=[O:31])[CH2:34][CH2:35][CH3:36]

Participants

8

Reactant 3

HCID 11430Potassium CarbonateHCID 145742L-ProlineHCID 710625451-(4-(5-bromo-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide

Product 1

HCID 71062200N,N-Dibutyl-4-chloro-1-(4-(1-ethyl-5-morpholinoindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-methyl-1H-pyrazole-3-carboxamideYield 16.9%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 313Hydrochloric AcidSolventHCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
102 °C

Procedure

A solution of 1-(4-(5-bromo-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 71, 35 mg, 0.042 mmol), L-(−)-proline (5 mg, 0.042 mmol), K2CO3 (12 mg, 0.084 mmol) and CuI (4 mg, 0.021 mmol) in DMSO (1.5 mL) was purged with air for 1 min. The resulting mixture was heated at 102° C. open to air for 20 h. The reaction mixture was then diluted with 1N aq. HCl solution and EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (6 mg, 16%) as a white solid after lyophilization. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.24 (dd, J=8.3, 1.9 Hz, 1H), 8.13-8.10 (m, 1H), 7.60-7.50 (m, 1H), 7.48 (s, 1H), 7.25-7.09 (m, 3.5H), 6.95 (s, 1H), 6.93 (d, J=7.5 Hz, 0.5H), 4.90-4.50 (m, 2H), 4.20-3.99 (m, 4H), 3.71-3.60 (m, 4H), 3.55-3.49 (m, 2H), 3.26-3.20 (m, 4H), 3.09-3.03 (m, 2H), 2.90-2.60 (m, 4H), 2.33 (s, 2H), 2.28 (s, 1H), 1.55-1.00 (m, 13H), 0.95-0.88 (m, 3H), 0.79-0.75 (m, 2H), 0.72-0.68 (m, 1H); MS(ESI+) m/z 844.5 (M+H)+.

Workup

  1. customThe organic layer was separated
  2. dry with materialdried over MgSO4
  3. concentrationconcentrated in vacuo
  4. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-74ddf7adece34eeabe64fc82343534d3
Source dataset
uspto-grants-2016_05
Patent number
US09346795B2

Reaction notes

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