Citric Acid → HCID 57411091, compound

HRID 468774Notes

Reaction equation

HRID 468774 reaction equation
[C:1](OCC[C@@H](OS(C)(=O)=O)C)(=[O:8])[C:2]1C=CC=[CH:4][CH:3]=1.CN(C)C=O.[OH:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[C:30]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:31]=[CH:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:8][CH2:1][CH2:2][C@H:3]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[C:30]([NH:35][C:36]([CH:38]3[CH2:39][CH2:40]3)=[O:37])[N:31]=[CH:32]2)=[CH:27][CH:26]=1)[CH3:4]

Participants

8

Reactant 6

HCID 311Citric AcidHCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 14797Potassium HydroxideHCID 67975011N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamideHCID 86674940HCID 86674940, compound

Product 1

HCID 57411091HCID 57411091, compoundYield 45.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of (S)-3-(methylsulfonyloxy)butyl benzoate (82.6 mg, 0.303 mmol) in N,N-dimethylformamide (2.0 mL, 26 mmol) was added N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamide (49.7 mg, 0.218 mmol) and cesium carbonate (147.4 mg, 0.4524 mmol). The reaction mixture was stirred at 50° C. for 4 hours. To the reaction mixture was then added 2.0 M of potassium hydroxide in methanol (1.0 mL), and the temperature was maintained at 50° C. for one hour. The reaction was neutralized with 10% aqueous citric acid and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 29.5 mg (45%) of (R)—N-(7-(4-hydroxybutan-2-yloxy)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=3.446, M+H=301.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.98 (s, 1H), 8.36 (s, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.32 (dd, J=8.9, 2.5 Hz, 1H), 4.73 (h, J=6.1 Hz, 1H), 4.52 (t, J=5.0 Hz, 1H), 3.56 (dd, J=11.5, 6.1 Hz, 2H), 2.10-1.98 (m, 1H), 1.92 (td, J=12.9, 6.2 Hz, 1H), 1.74 (td, J=12.6, 6.5 Hz, 1H), 1.33 (d, J=6.1 Hz, 3H), 0.90-0.73 (m, 4H).

Workup

  1. temperaturethe temperature was maintained at 50° C. for one hour
  2. extractionextracted with dichloromethane (3×50 mL)
  3. dry with materialThe combined organic extracts were dried over MgSO4
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. customThe crude product was purified via reverse phase HPLC

Sources & evidence

ORD record
ord-1a62e667435740cf95f537b88a01cf67
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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