Trifluoroacetic acid → HCID 71115154, compound

HRID 1502448Notes

Reaction equation

HRID 1502448 reaction equation
N[C:2]1[C:3]([CH3:25])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([C@@H:21]4[CH2:23][C@@H:22]4[F:24])=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C(O)=[O:29].CCCCCON=O>>[F:24][C@H:22]1[CH2:23][C@H:21]1[C:19]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([OH:29])[C:3]=1[CH3:25])[CH:17]=2)=[O:20]

Participants

4

Reactant 3

HCID 6422Trifluoroacetic acidHCID 10026Pentyl nitriteHCID 71115129HCID 71115129, compound

Product 1

HCID 71115154HCID 71115154, compoundYield 18.2%

Procedure

To a solution of (1S,2S)-N-(7-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide (46.2 mg; 0.137 mmol) in trifluoroacetic acid (1.0 mL; 13 mmol) at 0° C. was added N-amyl nitrite (29 μL; 0.21 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and then partitioned between dichloromethane and 2 M aqueous sodium carbonate. The aqueous layer was neutralized to pH 7 with citric acid, and then extracted twice more with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-10% methanol in dichloromethane) followed by preparatory reverse-phase HPLC to yield 8.4 mg (18%) of the title compound. LCMS (ESI): RT (min)=3.583, M+H=338.1, method=E; 1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 9.94 (broad s, 1H), 9.19 (s, 1H), 8.52 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 4.95 m, 1H), 2.27 (m, 1H), 2.12 (s, 3H), 1.70 (m, 1H), 1.20 (m, 1H).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. custompartitioned between dichloromethane and 2 M aqueous sodium carbonate
  3. extractionextracted twice more with dichloromethane
  4. dry with materialThe combined dichloromethane layers were dried over magnesium sulfate
  5. customevaporated in vacuo
  6. customThe crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-10% methanol in dichloromethane)

Sources & evidence

ORD record
ord-a5e6fc8dcfec4a7fad563e11f741d30e
Source dataset
uspto-grants-2015_12
Patent number
US09206175B2

Reaction notes

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