Trifluoroacetic acid → HCID 71115154, compound

HRID 468931Notes

Reaction equation

HRID 468931 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 2M 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 2M 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-9f05016cd61440c89072440b50ee5205
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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