(2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid → Ethyl (4R)-4-[(7-bromo-6-methoxyisoquinolin-1-yl)oxy]-L-prolinate hydrochloride

HRID 389197Notes

Reaction equation

HRID 389197 reaction equation
[CH3:1][C:2](C)([O-])C.[K+].C([N:14]1[CH2:21][C@H:20]([OH:22])[CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])(OC(C)(C)C)=O.[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[C:31]2[Cl:34])=[CH:26][C:25]=1[O:35][CH3:36]>CS(C)=O>[ClH:34].[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[C:31]2[O:22][C@H:20]2[CH2:21][NH:14][C@H:15]([C:16]([O:18][CH2:1][CH3:2])=[O:17])[CH2:19]2)=[CH:26][C:25]=1[O:35][CH3:36]

Participants

5

Reactant 3

HCID 88804(2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acidHCID 23665647Potassium tert-butoxideHCID 595711467-Bromo-1-chloro-6-methoxyisoquinoline

Product 1

HCID 66782733Ethyl (4R)-4-[(7-bromo-6-methoxyisoquinolin-1-yl)oxy]-L-prolinate hydrochlorideYield 70.3%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
15 °C

Procedure

Potassium t-butoxide (618 mg, 5.5 mmol) was added to a stirred solution of BOC trans-4-hydroxyproline (424 mg, 1.83 mmol) in DMSO (10 mL) at RT. The reaction mixture was stirred for 30 minutes and cooled to 15° C., and the product from Step 3 (500 mg, 1.83 mmol) was added. The reaction mixture was stirred overnight and partitioned between ice-cold 10% citric acid and EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, and the solvent evaporated. The crude product was dissolved in EtOH (100 mL), cooled to 0° C. and HCl bubbled through until saturated. The reaction mixture was allowed to warm to RT and stirred for 24 hours. The volatiles were evaporated and the residue azeotroped with EtOH (4×) to give the title compound as a tan solid (555 mg). LRMS ESI+ (M+H)+ 395.0.

Workup

  1. stirringThe reaction mixture was stirred overnight
  2. custompartitioned between ice-cold 10% citric acid and EtOAc
  3. washThe organic phase was washed with water and brine
  4. dry with materialdried over Na2SO4
  5. customthe solvent evaporated
  6. dissolutionThe crude product was dissolved in EtOH (100 mL)
  7. temperaturecooled to 0° C.
  8. customHCl bubbled through until saturated
  9. temperatureto warm to RT
  10. stirringstirred for 24 hours
  11. customThe volatiles were evaporated
  12. customthe residue azeotroped with EtOH (4×)

Sources & evidence

ORD record
ord-a1132a32497c4dea82510a5d72711b55
Source dataset
uspto-grants-2013_02
Patent number
US08377874B2

Reaction notes

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