p-Toluenesulfonic acid → 8-((5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-fluoropyridin-3-yl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitrile

HRID 930305Notes

Reaction equation

HRID 930305 reaction equation
[NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:29])([F:28])[F:27])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16]C(=O)C3C=CC(Cl)=CN=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1.Cl[C:31]1[N:32]=[CH:33][C:34]([F:43])=[C:35]2[C:40]=1[N:39]=[CH:38][C:37]([C:41]#[N:42])=[CH:36]2.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:27])([F:29])[F:28])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:31]3[N:32]=[CH:33][C:34]([F:43])=[C:35]4[C:40]=3[N:39]=[CH:38][C:37]([C:41]#[N:42])=[CH:36]4)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1

Participants

5

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 78321763N-(5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-fluoropyridin-3-yl)-5-chloropicolinamideHCID 867158748-Chloro-5-fluoro-1,7-naphthyridine-3-carbonitrile2×

Product 1

HCID 867321348-((5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-fluoropyridin-3-yl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitrileYield 45%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (6a, 0.076 g, 0.260 mmol) and 8-chloro-5-fluoro-1,7-naphthyridine-3-carbonitrile (intermediate 17, 0.065 g, 0.312 mmol) in 2-propanol (2.6 ml) was added 4-methylbenzene sulfonic acid (monohydrate, Fluka, 0.099 g, 0.520 mmol). The reaction mixture was heated to 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between DCM and aqueous saturated sodium bicarbonate. The aqueous layer was backextracted with DCM. The combined organic extracts were washed with brine and dried over sodium sulfate. The filtrate was concentrated and the residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min. The product containing fractions were combined and neutralized with aqueous sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound (0.054 g, 0.117 mmol, 44.8% yield) as yellow solid. MS m/z=464.0 [M+H]+. Calculated for C20H14F5N7O: 463.4

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. concentrationconcentrated under reduced pressure
  3. customThe residue was partitioned between DCM and aqueous saturated sodium bicarbonate
  4. washThe combined organic extracts were washed with brine
  5. dry with materialdried over sodium sulfate
  6. concentrationThe filtrate was concentrated
  7. customthe residue was purified by reversed-phase preparative HPLC
  8. customover 20 min
  9. additionThe product containing fractions
  10. extractionThe free-based product was extracted with DCM
  11. dry with materialThe organic phase was dried over MgSO4
  12. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-ec3dc04e55d344e5ae58be43d2e15d12
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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