Cesium carbonate → N,N-Dibutyl-4-chloro-1-(4-(1-(3,4-dichlorobenzyl)indolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-methyl-1H-pyrazole-3-carboxamide

HRID 528852

Reaction equation

HRID 528852 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][C:54]1[CH:59]=[CH:58][C:57]([Cl:60])=[C:56]([Cl:61])[CH:55]=1)[CH2:6][CH2:5]2.C(C1C=C(C(C)(C)C)C=CC=1OP(OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C)OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CC(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:37]([N:32]([CH2:33][CH2:34][CH2:35][CH3:36])[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][C:54]4[CH:59]=[CH:58][C:57]([Cl:60])=[C:56]([Cl:61])[CH:55]=4)=[CH:3][CH:2]=3)(=[O:12])=[O:13])=[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])[CH2:38][CH2:39][CH3:40]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 91601Tris(2,4-di-tert-butylphenyl) phosphiteHCID 867188911-(4-(5-bromo-1-(3,4-dichlorobenzyl)indolin-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 71062147N,N-Dibutyl-4-chloro-1-(4-(1-(3,4-dichlorobenzyl)indolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-methyl-1H-pyrazole-3-carboxamideYield 54.3%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 1-(4-(5-bromo-1-(3,4-dichlorobenzyl)indolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 72, 30 mg, 0.031 mmol) in i-PrOH (4.0 mL) were added Pd2(dba)3 (23 mg, 0.025 mmol), tris(2,4-di-tert-butylphenyl)phosphite (10 mg, 0.015 mmol) and Cs2CO3 (13 mg, 0.040 mmol). The resulting reaction mixture was heated at 80° C. for 20 h, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC to give the title compound (15 mg, 52%) as a pale yellow solid after lyophilization. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.05 (dd, J=8.4, 2.2 Hz, 1H), 7.97-7.96 (m, 1H), 7.71-7.67 (m, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.38 (dd, J=7.7, 1.5 Hz, 1H), 7.31 (dd, J=8.4, 2.0 Hz, 1H), 7.25-7.10 (m, 5.5H), 6.93 (d, J=7.5 Hz, 0.5H), 4.88-4.60 (m, 2H), 4.36 (s, 2H), 4.10-3.50 (m, 2H), 3.48 (t, J=8.5 Hz, 2H), 3.15-3.05 (m, 2H), 3.08 (t, J=8.5 Hz, 2H), 2.90-2.70 (m, 2H), 2.35 (s, 2H), 2.30 (s, 1H), 1.53-0.98 (m, 10H), 0.95-0.88 (m, 3H), 0.79-0.75 (m, 2H), 0.70 (t, J=7.3 Hz, 1H); MS(ESI+) m/z 891.4 (M+H)+.

Workup

  1. customThe resulting reaction mixture
  2. temperaturecooled to room temperature
  3. filtrationfiltered
  4. concentrationThe filtrate was concentrated in vacuo
  5. customthe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-f8c1bf2d818649eca1fc72c8d35d0b11
Source dataset
uspto-grants-2016_05
Patent number
US09346795B2

Linked notes

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