2-Bromo-3-methylthiophene → HCID 86716133, compound

HRID 627562Notes

Reaction equation

HRID 627562 reaction equation
[Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[C:5]([CH3:28])[CH:6]=[C:7]([C:19]([C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[O:20])[CH:8]=2)[N:3]=1.Br[C:30]1[S:31][CH:32]=[CH:33][C:34]=1[CH3:35].[Li]CCCC>C1COCC1>[Cl:1][C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[C:5]([CH3:28])[CH:6]=[C:7]([C:19]([C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)([C:30]3[S:31][CH:32]=[CH:33][C:34]=3[CH3:35])[OH:20])[CH:8]=2)[N:3]=1

Participants

5

Reactant 3

HCID 843142-Bromo-3-methylthiopheneHCID 86716091HCID 86716091, compound2×HCID 178418339Butyllithium

Product 1

HCID 86716133HCID 86716133, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-70 °C

Procedure

A yellow mixture of (2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(6-methylpyridin-3-yl)methanone (35 mg, 0.0859 mmol, Intermediate 47, step c) and 2-bromo-3-methylthiophene (25.2 mg, 0.142 mmol) in THF (0.52 mL) was stirred at ˜−70° C. under argon while n-BuLi (0.0811 mL, 1.59 M in hexane, 0.129 mmol) was added dropwise over 1.5 min. The reddish-amber reaction was stirred for an additional 15 min at ˜−70° C. before transferring it to an ice bath. The resulting solution was stirred at 0° C. for 5 min, and was then quenched with 5 M NH4Cl (1 mL) and extracted with EtOAc (2×3 mL). The combined yellow organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by C18 HPLC (20% to 100% CH3CN, with 0.1% TFA throughout) and then, after neutralization, further purified with flash chromatography with a 2% EtOAc/heptane to 100% EtOAc gradient to yield the title compound as a white powder. 1H NMR (400 MHz, MeOH-d4) δ 8.38-8.46 (m, 1H), 8.08 (s, 1H), 7.78 (s, 1H), 7.73 (dd, J=2.08, 8.19 Hz, 1H), 7.43-7.57 (m, 3H), 7.26-7.38 (m, 3H), 7.22 (d, J=5.13 Hz, 1H), 6.93 (d, J=5.13 Hz, 1H), 2.73 (s, 3H), 2.54 (s, 3H), 1.97 (s, 3H); MS m/e 505.0 [M+H]+.

Workup

  1. additionwas added dropwise over 1.5 min
  2. customThe reddish-amber reaction
  3. stirringThe resulting solution was stirred at 0° C. for 5 min
  4. customwas then quenched with 5 M NH4Cl (1 mL)
  5. extractionextracted with EtOAc (2×3 mL)
  6. dry with materialThe combined yellow organic layers were dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by C18 HPLC (20% to 100% CH3CN, with 0.1% TFA throughout)
  10. customafter neutralization, further purified with flash chromatography with a 2% EtOAc/heptane to 100% EtOAc gradient

Sources & evidence

ORD record
ord-94fd0c8efb444353ba9e4d4b76d1b381
Source dataset
uspto-grants-2016_04
Patent number
US09309222B2

Reaction notes

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