Dimethylformamide → (1S,2S)-2-fluoro-N-(7-(5-fluoro-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

HRID 1502452Notes

Reaction equation

HRID 1502452 reaction equation
[F:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1.[F:20][C@H:21]1[CH2:23][C@H:22]1[C:24](O)=[O:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:20][C@H:21]1[CH2:23][C@H:22]1[C:24]([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]([F:1])[C:3]=1[CH3:19])[CH:17]=2)=[O:25]

Participants

8

Reactant 5

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 9793716cis-2-Fluorocyclopropanecarboxylic acidHCID 11038641((7-Azabenzotriazol-1-YL)oxy)tris(pyrrolidino)phosphonium hexafluorophosphateHCID 679748447-(5-Fluoro-4-methylpyridin-3-yl)isoquinolin-3-amine

Product 1

HCID 71114972(1S,2S)-2-fluoro-N-(7-(5-fluoro-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamideYield 57.3%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of 7-(5-fluoro-4-methylpyridin-3-yl)isoquinolin-3-amine (161.4 mg; 0.6372 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (80.3 mg; 0.772 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (496.9 mg; 0.9149 mmol), N,N-diisopropylethylamine (0.30 mL; 1.7 mmol), 4-(dimethylamino)pyridine (0.06372 mmol) and N,N-dimethylformamide (5 mL; 64.4 mmol) was heated at 40° C. for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (25 g silica, solvent gradient: 30-90% ethyl acetate in dichloromethane) followed by preparatory reverse-phase HPLC to yield 124 mg (57%) of the title compound. LCMS (ESI): RT (Min)=8.33, M+H=340.2, method=G; 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.21 (s, 1H), 8.55 (d, J=4.5 Hz, 2H), 8.42 (s, 1H), 8.13 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.78 (dd, J=8.5, 1.6 Hz, 1H), 5.06-4.85 (m, 1H), 2.34-2.27 (m, 1H), 2.26 (d, J=1.9 Hz, 3H), 1.75-1.65 (m, 1H), 1.25-1.16 (m, 1H).

Workup

  1. washwashed with water and brine
  2. dry with materialdried over magnesium sulfate
  3. filtrationfiltered
  4. customevaporated in vacuo
  5. customThe crude product was purified via flash chromatography on silica gel (25 g silica, solvent gradient: 30-90% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-f7912f86fd8a4d28bd16ed03610ca2b1
Source dataset
uspto-grants-2015_12
Patent number
US09206175B2

Reaction notes

Loading…