Citric Acid → 1-N-BOC-4-(6-Methoxy-3-methylisoquinolin-1-yloxy)pyrrolidine-2-carboxylic acid

HRID 1895871Notes

Reaction equation

HRID 1895871 reaction equation
[C:1]([N:8]1[CH2:15][CH:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[C:18](C)([O-:20])C.[K+].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1.[C:33](O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:1]([N:8]1[CH2:15][CH:14]([O:16][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:20][CH3:18])=[CH:30][CH:31]=3)[CH:26]=[C:25]([CH3:33])[N:24]=2)[CH2:13][CH:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]

Participants

6

Reactant 4

HCID 311Citric AcidHCID 8405IsoquinolineHCID 111389801-(1,1-Dimethylethyl) (2S)-4-hydroxy-1,2-pyrrolidinedicarboxylateHCID 23665647Potassium tert-butoxide2×

Product 1

HCID 667867461-N-BOC-4-(6-Methoxy-3-methylisoquinolin-1-yloxy)pyrrolidine-2-carboxylic acid

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent2×

Procedure

N-BOC-4-hydroxy-L-proline (A; 281 mg; 1.21 mmol) was dissolved in DMSO (3 mL) at RT then potassium t-butoxide (270 mg; 2.4 mmol) was added. The resulting solution was stirred at RT for 2 h then cooled to 0° C. Next a solution of isoquinoline 14 in DMSO (3 mL) was added dropwise to the cold solution of A and t-BuOK, then the mixture was allowed to warm up to RT. The solution was stirred for 16 h, and an addition 0.2 equivalents of A was added and the mixture stirred for an additional 1.5 h. The reaction mixture was acidified to pH=4 with 5% aq. citric acid. The solution was extracted with ethyl acetate and the organic phase washed with water followed by saturated aq. NaCl. The organic phase was concentrated in vacuo to give the title compound.

Workup

  1. temperaturethen cooled to 0° C
  2. temperatureto warm up to RT
  3. stirringThe solution was stirred for 16 h
  4. additionan addition 0.2 equivalents of A
  5. additionwas added
  6. stirringthe mixture stirred for an additional 1.5 h
  7. extractionThe solution was extracted with ethyl acetate
  8. washthe organic phase washed with water
  9. concentrationThe organic phase was concentrated in vacuo

Sources & evidence

ORD record
ord-4d98f2221b1b4ac3806184c1f6f8e7b0
Source dataset
uspto-grants-2013_08
Patent number
US08518874B2

Reaction notes

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