Diisopropylethylamine → (1S,2S)-2-fluoro-N-(7-(5-fluoro-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide

HRID 468960Notes

Reaction equation

HRID 468960 reaction equation
[F:1][C:2]1[C:3]([CH3:20])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[C:10](C)[N:9]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:45][C@H:46]1[CH2:48][C@H:47]1[C:49](O)=[O:50].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:45][C@H:46]1[CH2:48][C@H:47]1[C:49]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][N:9]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([F:1])[C:3]=1[CH3:20])[CH:17]=2)=[O:50]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9793716cis-2-Fluorocyclopropanecarboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 679750717-(5-Fluoro-4-methylpyridin-3-yl)-5-methyl-2,6-naphthyridin-3-amine

Product 1

HCID 71115274(1S,2S)-2-fluoro-N-(7-(5-fluoro-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamideYield 44.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 7-(5-fluoro-4-methylpyridin-3-yl)-5-methyl-2,6-naphthyridin-3-amine (80 mg, 0.30 mmol), HATU (246 mg, 0.63 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (62 mg, 0.60 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.19 mmol) in DMF (2 mL) was heated at 70° C. for 8 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC purification (5-85% acetonitrile in water w/0.1% NH4OH, 14 minutes). Desired fractions were combined and evaporated in vacuo to afford the title compound as an off-white solid (45 mg, 43%). 1H NMR (400 MHz, DMSO) δ 11.24 (s, 1H), 9.31 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.56 (s, 1H), 8.07 (s, 1H), 4.98 (m, 1H), 2.90 (s, 3H), 2.36 (s, 3H), 2.30 (m, 1H), 1.78-1.66 (m, 1H), 1.28-1.17 (m, 1H). LCMS (Method G): RT=7.78 min, M+H+=355.0.

Workup

  1. washwashed with water (25 mL)
  2. customThe organic layer was separated
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto provide a residue that
  7. customwas purified by reverse phase HPLC purification (5-85% acetonitrile in water w/0.1% NH4OH, 14 minutes)
  8. customevaporated in vacuo

Sources & evidence

ORD record
ord-1076234bd98f4ae6ab1ca106c305507b
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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