Sodium Carbonate → HCID 117993486, compound

HRID 922589Notes

Reaction equation

HRID 922589 reaction equation
Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C@@:10]2([CH3:16])[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[CH:4][CH:3]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23](B(O)O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:9][O:8][C:6]1[C:5]([C@@:10]2([CH3:16])[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[CH:4][CH:3]=[C:2]([C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:18]([CH3:17])[CH:19]=[CH:20]3)[N:7]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 27598671-Methyl-1H-indole-5-boronic acidHCID 117992994(R)-3-(6-chloro-2-methoxypyridin-3-yl)-3-methylpyrrolidin-2-one

Product 1

HCID 117993486HCID 117993486, compoundYield 99%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

To a vial was added (R)-3-(6-chloro-2-methoxypyridin-3-yl)-3-methylpyrrolidin-2-one (56.6 mg, 0.24 mmol) which was evaporated with dioxane (2.0 mL). 1-methyl-1H-indol-5-ylboronic acid (63.4 mg, 0.36 mmol) was next added followed by Pd(dppf)Cl2 (7.5 mg, 0.01 mmol). The mixture was sealed and degassed with nitrogen. Degassed dioxane (1.9 mL) and degassed 2 M Na2CO3 (0.27 mL, 2.3 equiv) were then added to the solid mixture. The reaction was stirred for 16 h at 110° C. The reaction was concentrated and partitioned between EtOAc/10% (w/v) aq. Na2CO3. The organic layer was washed with brine, dried over Na2SO4, and concentrated to provide a crude brown glass. Purification by column chromatography (4 g RediSep Gold column) with a 40-100% EtOAc/heptane gradient provided the title compound (78 mg, 99%) as a pale yellow glass. 1H NMR (600 MHz, CDCl3) δ: 1.62 (s, 3H), 2.10 (ddd, 1H), 2.67-2.76 (m, 1H), 3.37-3.47 (m, 2H), 3.82 (s, 3H), 4.10-4.12 (m, 3H), 5.59 (br. s., 1H), 6.56 (d, 1H), 7.07 (d, 1H), 7.34-7.39 (m, 2H), 7.67 (d, 1H), 7.92-7.96 (m, 1H), 8.30 (s, 1H); MS (AP+)(M+H) 336. The absolute stereochemistry was obtained via X-ray crystallographic analysis of single crystals obtained via crystallization from a mixture of DCM and EtOH. FIG. 2 is an ORTEP drawing of (R)-3-(2-methoxy-6-(1-methyl-H-indol-5-yl)pyridin-3-yl)-3-methylpyrrolidin-2-one.

Workup

  1. customwas evaporated with dioxane (2.0 mL)
  2. additionnext added
  3. customThe mixture was sealed
  4. customdegassed with nitrogen
  5. additionwere then added to the solid mixture
  6. concentrationThe reaction was concentrated
  7. custompartitioned between EtOAc/10% (w/v) aq. Na2CO3
  8. washThe organic layer was washed with brine
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated
  11. customto provide a crude brown glass
  12. customPurification by column chromatography (4 g RediSep Gold column) with a 40-100% EtOAc/heptane gradient

Sources & evidence

ORD record
ord-2ceca911454f420b9589d2be75a8014e
Source dataset
uspto-grants-2016_03
Patent number
US09278953B2

Reaction notes

Loading…