Potassium Carbonate → 7-(2-chlorophenyl)-7-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylheptanoic acid ethyl ester

HRID 1801529Notes

Reaction equation

HRID 1801529 reaction equation
[S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([O:20][C:21](=[O:38])[C:22]([CH3:37])([CH3:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[CH3:19]>O.CN(C=O)C>[CH2:18]([O:20][C:21](=[O:38])[C:22]([CH3:37])([CH3:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)[CH3:19]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 30850764,5,6,7-Tetrahydrothieno(3,2-c)pyridineHCID 675123617-Bromo-7-(2-chlorophenyl)-2,2-dimethylheptanoic acid ethyl ester

Product 1

HCID 569711527-(2-chlorophenyl)-7-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylheptanoic acid ethyl esterYield 49%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
75 °C

Procedure

The hydrochloride salt of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (3.2 g, 18.9 mmol) was dissolved in water (120 mL) and 50% sodium hydroxide solution (10 mL) was added. The corresponding free base was extracted with dichloromethane (2×25 mL), which was dried over sodium sulfate, filtered, and concentrated. The remaining oil (2.58 g, 18.9 mmol) was dissolved in DMF (10 mL) under an argon atmosphere. Potassium carbonate (5 g) and 7-bromo-7-(2-chlorophenyl)-2,2-dimethylheptanoic acid ethyl ester (7.0 g, 18.63 mmol) were added and the mixture stirred for 44 hours at 75° C. The flask was cooled to room temperature and water (50 mL) was added. The product was extracted with dichloromethane (2×75 mL), which was dried over sodium sulfate, filtered, and concentrated. The remaining brown oil (8.94 g) was purified by column chromatography on silica gel (140 g), eluting with heptane-ethyl acetate (4:1 to 2:1). The product containing fractions were combined, concentrated, and dried to a constant weight under high vacuum at room temperature to provide 7-(2-chlorophenyl)-7-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylheptanoic acid ethyl ester (Compound Ih, 3.85 g, 49% yield) as a clear oil. 1H NMR (300 MHz, CDCl3/TMS): δ=7.53 (dd, 1H, J=7.5, 1.2 Hz), 7.40 (dd, 1H, J=7.8, 1.2 Hz), 7.31-7.18 (m, 2H), 7.08 (d, 1H, J=5.1 Hz), 6.74 (d, 1H, J=5.1 Hz), 4.22 (dd, 1H, J=8.7, 4.5 Hz), 4.12 (q, 2H, J=7.2 Hz), 3.83 (d, 1H, J=14.1 Hz), 3.49 (d, 1H, J=14.1 Hz), 2.92-2.68 (m, 4H), 2.08-1.73 (m, 2H), 1.46 (m, 2H), 1.30-1.19 (m, 7H), 1.15 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ=178.00, 139.41, 134.99, 134.26, 133.62, 129.53, 128.13, 128.03, 126.87, 125.51, 122.67, 63.69, 60.37, 50.79, 48.15, 42.33, 40.84, 33.11, 26.19, 25.40, 14.55. HRMS (DIP-CI): Calculated for (M+H+): 434.1921, found 434.1871.

Workup

  1. extractionThe corresponding free base was extracted with dichloromethane (2×25 mL), which
  2. dry with materialwas dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. temperatureThe flask was cooled to room temperature
  6. extractionThe product was extracted with dichloromethane (2×75 mL), which
  7. dry with materialwas dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe remaining brown oil (8.94 g) was purified by column chromatography on silica gel (140 g)
  11. washeluting with heptane-ethyl acetate (4:1 to 2:1)
  12. additionThe product containing fractions
  13. concentrationconcentrated
  14. customdried to a constant weight under high vacuum at room temperature

Sources & evidence

ORD record
ord-1fdbd755467e48db8edecd124039b97f
Source dataset
uspto-grants-2013_01
Patent number
US08349833B2

Reaction notes

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