Cesium carbonate → 7-(5-Fluoro-3-methylpyridin-2-yl)-N-(5-(trifluoromethyl)pyrimidin-2-yl)-1,8-naphthyridin-4-amine

HRID 545065Notes

Reaction equation

HRID 545065 reaction equation
Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([F:19])=[CH:14][N:13]=1)=[N:7]2.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:19][C:15]1[CH:16]=[C:17]([CH3:18])[C:12]([C:6]2[N:7]=[C:8]3[C:3]([C:2]([NH:20][C:21]4[N:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][N:26]=4)=[CH:11][CH:10]=[N:9]3)=[CH:4][CH:5]=2)=[N:13][CH:14]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 152735745-(Trifluoromethyl)pyrimidin-2-amineHCID 671931065-Chloro-2-(5-fluoro-3-methylpyridin-2-yl)-1,8-naphthyridine

Product 1

HCID 115821027-(5-Fluoro-3-methylpyridin-2-yl)-N-(5-(trifluoromethyl)pyrimidin-2-yl)-1,8-naphthyridin-4-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

Heat a mixture of 5-chloro-2-(5-fluoro-3-methylpyridin-2-yl)-1,8-naphthyridine (81 mg, 0.3 mmol), 2-amino-5-trifluoromethylpyrimidine (96 mg, 0.6 mmol), xantphos (16.9 mg), Pd2(dba)3 (27.9 mg) and Cs2CO3 (193 mg) in dioxane (2.0 mL) at 100° C. for 4 hours. Cool the mixture, concentrate under vacuum, dilute with EtOAc/water (5.0 mL each), filter through celite, wash celite with EtOAc (2×5 mL) and dry combined organic layers with MgSO4. Filter the dried extract and concentrate under vacuum to afford crude product. Purify by preparative HPLC to afford title compound as a yellow solid. 1H NMR (400 MHZ, DMSO-D6) δ 10.92 (s, 1H), 9.0 (s, 2H), 8.92 (d, 1H, J=2.2 Hz), 8.58 (s, 1H), 8.17(d, 1H, J=1.1 Hz), 8.09 (m, 1H), 7.8 (d, 1H, J=2.4 Hz), 2.69 (s, 3H). MS=401.31 (M+H). The IC50 determined as described in Example 6 is less than 1 micromolar.

Workup

  1. temperatureHeat
  2. temperatureCool the mixture
  3. concentrationconcentrate under vacuum
  4. additiondilute with EtOAc/water (5.0 mL each)
  5. filtrationfilter through celite
  6. washwash celite with EtOAc (2×5 mL)
  7. customdry
  8. filtrationFilter the dried
  9. extractionextract
  10. concentrationconcentrate under vacuum
  11. customto afford crude product
  12. customPurify by preparative HPLC

Sources & evidence

ORD record
ord-a747d2f0967c480ab107695f17dd6fca
Source dataset
uspto-grants-2011_05
Patent number
US07935702B2

Reaction notes

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