(Prop-1-en-2-yl)boronic acid → (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropenylpyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one

HRID 537988Notes

Reaction equation

HRID 537988 reaction equation
[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:27]4[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=4[O:37][CH3:38])=[CH:25][CH:24]=[C:23](Cl)[N:22]=3)[C@@H:15]([CH3:40])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:43](B(O)O)([CH3:45])=[CH2:44]>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:27]4[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=4[O:37][CH3:38])=[CH:25][CH:24]=[C:23]([C:43]([CH3:45])=[CH2:44])[N:22]=3)[C@@H:15]([CH3:40])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

4

Reactant 2

HCID 10855372(Prop-1-en-2-yl)boronic acidHCID 24739433(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-3-(4-fluoro-5-isopropyl-2-methoxyphenyl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one

Product 1

HCID 24739434(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropenylpyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one

Reagents, catalysts & solvents 1

HCID 86626146potassium carbonate THFSolvent

Procedure

A mixture of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-3-(4-fluoro-5-isopropyl-2-methoxyphenyl)pyridin-2-yl]methyl)}-4-methyl-1,3-oxazinan-2-one (Example 4, 16 mg, 0.026 mmol), isopropenyl boronic acid (22 mg, 0.26 mmol) and 1,1-bis(ditbutylphosphino)ferrocene palladium dichloride (2 mg, 0.0026 mmol) in aqueous potassium carbonate/THF (1 mL, 1 mL) was heated at reflux for 2.5 h under N2. After cooling to room temperature, the aqueous phase was separated and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography on silica gel (0-15% EtOAc in hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropenylpyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one. LCMS=625.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.85 (br s, 3H), 7.51 (m, 2H), 7.05 (m, 1H), 6.71 (d, J=11.9 Hz, 1H), 5.98 (br s, 1H), 5.35 (br s, 1H), 5.31 (br m, 1H), 4.32 (br m, 1H), 3.79 (s, 3H), 3.22 (br m, 1H), 2.28 (s, 3H), 1.89 (m, 2H), 1.27 (br m, 9H).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 2.5 h under N2
  3. customthe aqueous phase was separated
  4. extractionextracted with EtOAc (3×20 mL)
  5. dry with materialThe combined organic layers were dried (Na2SO4)
  6. concentrationconcentrated in vacuo
  7. customto give the crude product
  8. customThis was purified by flash chromatography on silica gel (0-15% EtOAc in hexanes gradient)

Sources & evidence

ORD record
ord-f4e33006595c459393311b496dbf83e6
Source dataset
uspto-grants-2014_10
Patent number
US08865707B2

Reaction notes

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