Dimethylformamide → 2,2-difluoro-N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide

HRID 468722

Reaction equation

HRID 468722 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([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:7]=1.[F:20][C:21]1([F:27])[CH2:23][CH: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.CN(C)C=O.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:20][C:21]1([F:27])[CH2:23][CH: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:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:19])[CH:17]=2)=[O:25]

Participants

8

Reactant 5

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 27828232,2-Difluorocyclopropane-1-carboxylic acidHCID 11038641((7-Azabenzotriazol-1-YL)oxy)tris(pyrrolidino)phosphonium hexafluorophosphateHCID 574102447-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine

Product 1

HCID 574101272,2-difluoro-N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamideYield 73%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

To a mixture of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (103.2 mg, 0.4090 mmol), 2,2-difluorocyclopropanecarboxylic acid (79.6 mg, 0.652 mmol) and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (326.5 mg, 0.6298 mmol) in N,N-dimethylformamide (2 mL, 20 mmol) was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.055 mmol). The reaction mixture was stirred at 50° C. for 2.5 hours. The reaction mixture was then poured into ethyl acetate, which was washed with two portions water, dried with brine and MgSO4, and filtered through a plug of silica gel, which was rinsed with ethyl acetate, and evaporated in vacuo. The resulting residue was purified via reverse phase HPLC and lyophilized to yield 106.4 mg (73%) of 2,2-difluoro-N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=5.701, M+H=357.1, Method=E; 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.21 (s, 1H), 8.50 (s, 1H), 8.07 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.39 (s, 1H), 7.18 (d, J=8.7 Hz, 2H), 3.07 (d, J=10.0 Hz, 1H), 2.25 (s, 3H), 2.07 (s, 2H).

Workup

  1. washwas washed with two portions water
  2. dry with materialdried with brine and MgSO4
  3. filtrationfiltered through a plug of silica gel, which
  4. washwas rinsed with ethyl acetate
  5. customevaporated in vacuo
  6. customThe resulting residue was purified via reverse phase HPLC

Sources & evidence

ORD record
ord-1c8ef281ad6445dc84d8ee552c67053e
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Linked notes

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