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

HRID 468901Notes

Reaction equation

HRID 468901 reaction equation
Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([C@@H:15]3[CH2:17][C@@H:16]3[F:18])=[O:14])[N:8]=[CH:9]2)=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:18][C@H:16]1[CH2:17][C@H:15]1[C:13]([NH:12][C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:20]=1[CH3:19])[CH:11]=2)=[O:14]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 27627114-Methylpyridine-3-Boronic AcidHCID 86674973(1S,2S)-N-(7-chloro-2,6-naphthyridin-3-yl)-2-fluorocyclopropanecarboxamide

Product 1

HCID 71115147(1S,2S)-2-fluoro-N-(7-(4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamideYield 50%

Reagents, catalysts & solvents 3

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of (1S,2S)—N-(7-chloro-2,6-naphthyridin-3-yl)-2-fluorocyclopropanecarboxamide (40 mg, 0.2 mmol), 4-methylpyridine-3-boronic acid (62 mg, 0.45 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg, 0.015 mmol), and saturated aqueous sodium carbonate (0.1 mL) in acetonitrile (1 mL) was heated under microwave irradiation (Biotage, 200 watts) at 130° C. for 30 minutes. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (23 mg, 50%). 1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.68 (s, 1H), 8.68 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.19 (s, 1H), 7.39 (d, J=5.0 Hz, 1H), 4.97 (m, 1H), 2.44 (s, 3H), 2.31 (m, 1H), 1.72 (m, 1H), 1.28-1.16 (m, 1H). LCMS (Method E): RT=2.980 min, M+H+=323.1.

Workup

  1. customThe cooled reaction mixture
  2. washwashed with water (50 mL)
  3. customThe organic layer was separated
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. customevaporated in vacuo
  7. customto afford a residue that
  8. customwas purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min)

Sources & evidence

ORD record
ord-b78e41eef2bc4b0fb812c5a62d7dd3f7
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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