Acetic Anhydride → 5-(3-(Cyclopropanecarboxamido)isoquinolin-7-yl)-6-methylpyridin-3-yl acetate

HRID 468785Notes

Reaction equation

HRID 468785 reaction equation
B(F)(F)F.CCOCC.N[C:11]1[CH:12]=[C:13]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[C:23]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[N:24]=[CH:25]3)=[CH:20][CH:19]=2)[C:14]([CH3:17])=[N:15][CH:16]=1.COCCOC.N(OC(C)(C)C)=O.[C:47]([O:50]C(=O)C)(=[O:49])[CH3:48]>CCCCC>[C:47]([O:50][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[C:13]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[C:23]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[N:24]=[CH:25]3)=[CH:20][CH:19]=2)[CH:12]=1)(=[O:49])[CH3:48]

Participants

7

Reactant 5

HCID 7918Acetic AnhydrideHCID 8000Boron trifluoride etherateHCID 80711,2-DimethoxyethaneHCID 10906Tert-Butyl nitriteHCID 57411326N-(7-(5-amino-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

Product 1

HCID 679748595-(3-(Cyclopropanecarboxamido)isoquinolin-7-yl)-6-methylpyridin-3-yl acetate

Reagents, catalysts & solvents 1

HCID 8003PentaneSolvent

Conditions

Temperature
-15 °C

Procedure

To a flask containing boron trifluoride etherate (0.100 mL, 0.789 mmol) at −15° C. (brine/ice bath) was added a solution of N-(7-(5-amino-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (119.1 mg, 0.3741 mmol) in 1,2-dimethoxyethane (1.0 mL, 9.6 mmol). tert-Butyl nitrite (67.0 uL, 0.563 mmol) was then added dropwise and the reaction mixture was stirred at −15° C. for one hour. 3 mL pentane was added and the mixture stirred for 5 minutes. The pentane layer was decanted, and the remaining oil was then dissolved in acetic anhydride (0.60 mL, 6.4 mmol) and stirred at 100° C. for 1.5 hours. The solvent was evaporated in vacuo, and the residue was suspended in 2M aqueous Na2CO3 and extracted twice with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to yield 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-6-methylpyridin-3-yl acetate. This material was dissolved in tetrahydrofuran (3 mL, 40 mmol) and 1.0 M of lithium hydroxide in Water (1.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then neutralized with 10% aqueous citric acid and extracted 3× with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 30-100% ethyl acetate in dichloromethane) followed by reverse phase HPLC to yield 3.3 mg (3%) of N-(7-(5-hydroxy-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=3.237, M+H=320.1, method=E; 1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 9.17 (s, 1H), 8.49 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.6 Hz, 1H), 7.69 (d, J=9.7 Hz, 1H), 7.04 (s, 1H), 2.33 (s, 3H), 2.14-2.03 (m, 1H), 0.91-0.78 (m, 4H).

Workup

  1. stirringthe mixture stirred for 5 minutes
  2. customThe pentane layer was decanted
  3. stirringstirred at 100° C. for 1.5 hours
  4. customThe solvent was evaporated in vacuo
  5. extractionextracted twice with dichloromethane
  6. dry with materialThe combined organic extracts were dried over MgSO4
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. customThe crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-fe6b806fd5c44b82addb85875518e29e
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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