Dichloromethane → 2-Piperidinone, 3-[6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxy-3-pyridinyl]-3-methyl-, (3R)-

HRID 922584Notes

Reaction equation

HRID 922584 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH3:12])=[C:4]([F:13])[CH:3]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.CC([O-])=O.[K+].ClCCl.Cl[C:39]1[N:44]=[C:43]([O:45][CH3:46])[C:42]([C@@:47]2([CH3:54])[CH2:52][CH2:51][CH2:50][NH:49][C:48]2=[O:53])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH2:11]([N:8]1[C:9]2[C:5](=[C:4]([F:13])[CH:3]=[C:2]([C:39]3[N:44]=[C:43]([O:45][CH3:46])[C:42]([C@@:47]4([CH3:54])[CH2:52][CH2:51][CH2:50][NH:49][C:48]4=[O:53])=[CH:41][CH:40]=3)[CH:10]=2)[CH:6]=[N:7]1)[CH3:12]

Participants

8

Reactant 6

HCID 6344Dichloromethane2×HCID 10340Sodium CarbonateHCID 517044Potassium AcetateHCID 2734316Bis(neopentyl glycolato)diboronHCID 117992935HCID 117992935, compoundHCID 117993132HCID 117993132, compound

Product 1

HCID 1179930302-Piperidinone, 3-[6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxy-3-pyridinyl]-3-methyl-, (3R)-Yield 81%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

An oven dried vial was charged with 6-bromo-1-ethyl-4-fluoro-1H-indazole (900 mg, 3.7 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (1000 mg, 4.4 mmol), oven dried KOAc (1450 mg, 14.8 mmol), anhydrous dioxane (5 mL) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (75.9 mg, 0.093 mmol). The mixture was purged with nitrogen gas for 5 min. The reaction vial was sealed and heated at 110° C. for 1.5 h. After being cooled to r.t., to the reaction mixture was added (R)-3-(6-chloro-2-methoxypyridin-3-yl)-3-methylpiperidin-2-one (943 mg, 3.7 mmol), an aqueous solution of sodium carbonate (2 M, 4.6 mL, 9.3 mmol) and an additional [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) complex with dichloromethane (75.9 mg, 0.093 mmol). The reaction mixture was degassed with nitrogen, and heated at 100° C. for 3 h. The reaction mixture was cooled to r.t., diluted with EtOAc, and the organic layer was washed with brine and water, dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0-20% EtOH/DCM) to afford (R)-3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylpiperidin-2-one (1140 mg, 81%). 1H NMR (600 MHz, CDCl3) δ 1.57 (t, 3H), 1.67-1.71 (m, 1H), 1.74 (s, 3H), 1.84 (d, 1H), 1.97-2.07 (m, 1H), 2.35-2.44 (m, 1H), 3.44 (br. s., 1H), 3.55 (br. s., 1H), 4.12 (s, 3H), 4.50 (q, 2H), 5.92 (br. s., 1H), 7.41 (d, 1H), 7.48 (d, 1H), 7.69 (d, 1H), 7.84 (s, 1H), 8.06 (s, 1H). MS (AP+)(M+H) 383.

Workup

  1. customAn oven dried vial
  2. customThe mixture was purged with nitrogen gas for 5 min
  3. customThe reaction
  4. customvial was sealed
  5. temperatureAfter being cooled to r.t., to the reaction mixture
  6. customThe reaction mixture was degassed with nitrogen
  7. temperatureheated at 100° C. for 3 h
  8. temperatureThe reaction mixture was cooled to r.t.
  9. additiondiluted with EtOAc
  10. washthe organic layer was washed with brine and water
  11. dry with materialdried over MgSO4
  12. concentrationconcentrated under reduced pressure
  13. customThe crude residue was purified by silica gel column chromatography (0-20% EtOH/DCM)

Sources & evidence

ORD record
ord-6ba6116be246495c8bc86d8ce3fe4543
Source dataset
uspto-grants-2016_03
Patent number
US09278953B2

Reaction notes

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