Water → 2-(5-chloro-2-fluoro-phenyl)-4-{5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyridin-3-yl}-[1,8]naphthyridine formate

HRID 1914949Notes

Reaction equation

HRID 1914949 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH:37]=[C:36](B3[O:42][C:41](C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:29][CH2:28]1.[OH2:47]>>[CH:41]([OH:42])=[O:47].[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:36]4[CH:35]=[N:34][N:33]([CH:30]5[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)[CH:37]=4)[CH:3]=3)[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:23]=1

Participants

4

Reactant 3

HCID 962WaterHCID 59231689(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol esterHCID 673643764-(5-Bromo-pyridin-3-yl)-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine

Product 1

HCID 710081402-(5-chloro-2-fluoro-phenyl)-4-{5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyridin-3-yl}-[1,8]naphthyridine formate

Conditions

Temperature
80 °C

Procedure

To a solution of 59.7 mg (0.144 mmol) 4-(5-bromo-pyridin-3-yl)-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine and 55.3 mg (0.190 mmol) 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine 67.2 mg (0.316 mmol) tri-potassiumphosphate trihydrate were added. The mixture was heated to 80° C. under nitrogen. Then 5.5 mg (0.008 mmol) bis(triphenylphosphine)palladium(II)-chloride were added. The reaction mixture was stirred for 4 hours at 80° C. The reaction mixture was cooled to room temperature and water was added. The resulting precipitate was filtered off, washed with water and air-dried. The residue was purified by preparative HPLC yielding 2-(5-chloro-2-fluoro-phenyl)-4-{5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyridin-3-yl}-[1,8]naphthyridine formate as colourless crystals; HPLC-MS: 1.29 min, [M+H] 292. 1H NMR (400 MHz, DMSO) δ=9.22 (dd, J=4.1, 1.9, 1H), 9.07 (d, J=2.1, 1H), 8.63 (d, J=2.1, 1H), 8.50 (s, 1H), 8.38 (dd, J=8.4, 1.9, 1H), 8.30 (t, J=2.1, 1H), 8.18 (m, 2H), 8.11 (d, J=0.5, 1H), 8.10 (d, J=2.0, 1H), 7.70 (m, 2H), 7.53 (dd, J=10.7, 8.9, 1H), 4.15 (m, 1H), 3.4 (m, 2H), 2.88 (d, J=11.7, 2H), 2.23 (s, 3H), 2.03 (m, 4H).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. filtrationThe resulting precipitate was filtered off
  3. washwashed with water
  4. customair-dried
  5. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-05eb0f934cba4fac9cf49f92b61da1df
Source dataset
uspto-grants-2013_12
Patent number
US08614226B2

Reaction notes

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