(4-Fluoro-5-isopropyl-2-methoxyphenyl)boronic acid → (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

HRID 537987Notes

Reaction equation

HRID 537987 reaction equation
[F:1][C:2]([F:31])([F:30])[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](Br)=[CH:25][CH:24]=[C:23]([Cl:28])[N:22]=3)[C@@H:15]([CH3:29])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:32][C:33]1[C:38]([CH:39]([CH3:41])[CH3:40])=[CH:37][C:36](B(O)O)=[C:35]([O:45][CH3:46])[CH:34]=1>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:31])([F:30])[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:36]4[CH:37]=[C:38]([CH:39]([CH3:41])[CH3:40])[C:33]([F:32])=[CH:34][C:35]=4[O:45][CH3:46])=[CH:25][CH:24]=[C:23]([Cl:28])[N:22]=3)[C@@H:15]([CH3:29])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

4

Reactant 2

HCID 53363739(4-Fluoro-5-isopropyl-2-methoxyphenyl)boronic acid2×HCID 57544404(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazinan-2-one2×

Product 1

HCID 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

Reagents, catalysts & solvents 1

HCID 86626146potassium carbonate THFSolvent

Procedure

A mixture of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 2, 49 mg, 0-092 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Intermediate 6, 21 mg, 0.101 mmol) and 1,1-bis(ditbutylphosphino)ferrocene palladium dichloride (6 mg, 0.0092 mmol) in aqueous potassium carbonate/THF (3 mL, 3 mL) was heated at reflux for 2 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-{[6-chloro-3-(4-fluoro-5-isopropyl-2-methoxyphenyl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a colorless oil. LCMS=619.0 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.88 (br s, 2H), 7.84 (s, 1H), 7.68 (brs, 2H), 7.49 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.28 (br s, 1H), 6.71 (d, J=12.1 Hz, 1H), 5.88 (brs, 1H), 5.25 (br d, J=16.7 Hz, 1H), 4.21 (br m, 2H), 3.95 (br m, 2H), 3.81 (s, 3H), 3.21 (m, 1H), 2.39 (m, 2H), 1.92 (m, 1H), 2.11 (3H, s), 1.29 (br d, 9H).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 2 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-e8afa6d64ee84a2086294c3b2bcaa634
Source dataset
uspto-grants-2014_10
Patent number
US08865707B2

Reaction notes

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