Water → 3-[7-Chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

HRID 1621302Notes

Reaction equation

HRID 1621302 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]2=[O:14])=[CH:6][C:5]=1F.O.[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][CH:36]([OH:41])[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CC(N(C)C)=O>[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][CH:36]([O:41][C:5]1[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=1[Cl:3])[C:11](=[O:14])[N:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:9]=[CH:8]3)[CH2:37]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 21187725tert-Butyl 3-hydroxy-8-azabicyclo(3.2.1)octane-8-carboxylateHCID 598182477-Chloro-6-fluoro-2-[(4-methoxyphenyl)methyl]isoquinolin-1(2H)-one

Product 1

HCID 670228553-[7-Chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl esterYield 80.1%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent3×

Procedure

528 mg of sodium hydride (60%) were suspended in 8 mL of dimethyl acetamide and 1.00 g of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70), dissolved in 4 mL of dimethyl acetamide, were added dropwise. After 1 h, 1.40 g of 7-Chloro-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (62), dissolved in another 8 mL of dimethyl acetamide, were added. The reaction mixture was stirred at room temperature until the reaction was complete. 30 mL of water were added, the resulting suspension extracted three times with a mixture of dichloromethane and 2-propanol (3:1) and the combined organic layers were evaporated. Water was added and the crude product was subjected to lyophilization to remove remainders of dimethyl acetamide. The obtained crude product was purified by silica gel chromatography to yield 1.85 g of the title compound as a mixture of diastereoisomers (71). Rt=1.95 min, 2.03 min (Method C). Detected mass: 525.0 (M+H+).

Workup

  1. additionwere added dropwise
  2. additionwere added
  3. extractionthe resulting suspension extracted three times
  4. additionwith a mixture of dichloromethane and 2-propanol (3:1)
  5. customthe combined organic layers were evaporated
  6. additionWater was added
  7. customto remove remainders of dimethyl acetamide
  8. customThe obtained crude product
  9. customwas purified by silica gel chromatography

Sources & evidence

ORD record
ord-bf6d0eddf15b47dfa383d9f3ec55c17f
Source dataset
uspto-grants-2014_07
Patent number
US08772492B2

Reaction notes

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