Sodium hydride → HCID 70692164, compound

HRID 528867Notes

Reaction equation

HRID 528867 reaction equation
[CH2:1]([N:5]([CH2:51][CH2:52][CH2:53][CH3:54])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:17][C:16]=2[C:37]([N:39]2[C@H:48]([CH2:49][OH:50])[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:58][CH2:59][CH2:60][O:61][CH3:62]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:51]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:17][C:16]=2[C:37]([N:39]2[C@H:48]([CH2:49][O:50][CH2:58][CH2:59][CH2:60][O:61][CH3:62])[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[N:9]=1)=[O:7])[CH2:52][CH2:53][CH3:54]

Participants

6

Reactant 3

HCID 24758Sodium hydride3×HCID 5245511-Bromo-3-methoxypropane3×HCID 66561645HCID 66561645, compound

Product 1

HCID 70692164HCID 70692164, compoundYield 18%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 6228DimethylformamideSolvent

Procedure

A solution of (S)—N,N-dibutyl-4-chloro-1-(2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(naphthalen-2-ylsulfonylcarbamoyl)phenyl)-5-methyl-1H-pyrazole-3-carboxamide (Example 91, 21 mg, 0.028 mmol) in DMF (900 μL) was cooled to 0° C., and NaH (2 mg, 0.061 mmol, 60% suspension in mineral oil) was added followed by 1-bromo-3-methoxypropane (9 mg, 0.061 mmol). The resulting reaction mixture was stirred warming to room temperature over 1 h and then heated at 130° C. for 3 h. Additional NaH (2 mg, 0.061 mmol, 60% suspension in mineral oil) and 1-bromo-3-methoxypropane (9 mg, 0.061 mmol) were added, and stirring was continued overnight at 130° C. Additional NaH (2 mg, 0.061 mmol, 60% suspension in mineral oil) and 1-bromo-3-methoxypropane (9 mg, 0.061 mmol) were added, and the reaction mixture was stirred at 135° C. for 24 h. TBAI (10 mg, 0.027 mmol) was then added, and stirring was continued at 140° C. for 72 h. After quenching with sat. aq. NH4Cl solution, the reaction mixture was diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Purification using preparative HPLC provided the title compound (4 mg, 18%) as an off-white solid after lyophilization. 1H NMR (CD3OD, mixture of amide rotamers) δ 8.82-8.69 (m, 1H), 8.29-8.20 (m, 1H), 8.16-7.92 (m, 5.5H), 7.78-7.57 (m, 3H), 7.31-7.05 (m, 3H), 6.94-6.85 (m, 0.5H), 5.24-5.36 (m, 1H), 5.09-4.91 (m, 1H), 4.53-4.47 (m, 0.5H), 4.30-4.16 (m, 1.5H), 3.64-2.73 (m, 12H), 2.62-2.49 (m, 1H), 2.38-2.24 (m, 4H), 1.83-0.86 (m, 13H), 0.80-0.70 (m, 2.5H), 0.67-0.60 (m, 0.5H); MS(ESI+) m/z 842.3 (M+H)+.

Workup

  1. customThe resulting reaction mixture
  2. temperatureheated at 130° C. for 3 h
  3. stirringstirring
  4. stirringthe reaction mixture was stirred at 135° C. for 24 h
  5. stirringstirring
  6. waitwas continued at 140° C. for 72 h
  7. customAfter quenching with sat. aq. NH4Cl solution
  8. additionthe reaction mixture was diluted with EtOAc
  9. customThe layers were separated
  10. extractionthe aqueous layer was extracted with EtOAc (3×)
  11. dry with materialThe combined organic extracts were dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customPurification

Sources & evidence

ORD record
ord-5d3434ed111842848de6d1b624c07000
Source dataset
uspto-grants-2016_05
Patent number
US09346795B2

Reaction notes

Loading…