Potassium Carbonate → 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid ethyl ester

HRID 1801544Notes

Reaction equation

HRID 1801544 reaction equation
Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[OH-].[Na+].S1C2CCNCC=2C=C1.[CH2:22]([O:24][C:25](=[O:43])[C:26]([CH3:42])([CH3:41])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[CH2:22]([O:24][C:25](=[O:43])[C:26]([CH3:42])([CH3:41])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[N:7]1[CH2:8][CH2:9][C:10]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[CH3:23]

Participants

8

Reactant 5

HCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 30850764,5,6,7-Tetrahydrothieno(3,2-c)pyridineHCID 101763424,5,6,7-Tetrahydrothieno(3,2-c)pyridinium chlorideHCID 675129798-Bromo-8-(2-chlorophenyl)-2,2-dimethyloctanoic acid ethyl ester

Product 1

HCID 569713878-(2-chlorophenyl)-8-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid ethyl esterYield 43.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
67.5 °C

Procedure

4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (1.30 g, 7.19 mmol) was added to sodium hydroxide (1.38 g) in water (86 mL) and extracted with dichloromethane (3×20 mL). The dichloromethane was dried over sodium sulfate, filtered, and concentrated to prepare the free base (1.0 g). 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine free base (1.0 g, 7.19 mmol) and 8-bromo-8-(2-chlorophenyl)2,2-dimethyloctanoic acid ethyl ester (2.8 g, 7.19 mmol) were dissolved in DMF (75 mL) with potassium carbonate (1.49 g, 10.79 mmol). The mixture was heated to 65-70° C. overnight. After 18 hours, the mixture was cooled to room temperature and water (50 mL) was added. The product was extracted with diethyl ether (3×50 mL). The combined organic extracts were washed with water (3×50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate/heptane (1/10) to provide 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid ethyl ester (Compound In, 1.4 g, 43.5%) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.49 (dd, 1H, J=7.5, 1.5 Hz), 7.35 (dd, 1H, J=8.1, 1.2 Hz), 7.24 (dt, 1H, J=7.5, 1.0 Hz), 7.16 (dt, 1H, J=7.8, 1.5 Hz), 7.02 (d, 1H, J=5.0 Hz), 6.68 (d, 1H, J=5.0 Hz), 4.18 (dd, 1H, J=8.7, 4.2 Hz), 4.08 (q, 2H, J=6.9 Hz), 3.82 (d, 1H, J=14.1 Hz), 3.48 (d, 1H, J=14.1 Hz), 2.88-2.66 (m, 4H), 1.96-1.76 (m, 2H), 1.46-1.41 (m, 2H), 1.26-1.18 (m, 6H), 1.21 (t, 3H, J=6.9 Hz), 1.11 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 177.92, 134.92, 134.21, 133.53, 129.48, 129.06, 127.94, 126.77, 125.44, 122.60, 63.67, 60.27, 50.73, 48.08, 42.29, 40.85, 33.02, 30.52, 26.13, 25.39, 25.01, 14.51. HRMS (FIA-ESI-TOFM): Calculated for C25H34ClNO2S (M+H)+: 448.2072, found 448.2067.

Workup

  1. extractionextracted with dichloromethane (3×20 mL)
  2. dry with materialThe dichloromethane was dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customto prepare the free base (1.0 g)
  6. temperaturethe mixture was cooled to room temperature
  7. extractionThe product was extracted with diethyl ether (3×50 mL)
  8. washThe combined organic extracts were washed with water (3×50 mL)
  9. dry with materialdried over sodium sulfate
  10. concentrationconcentrated under reduced pressure
  11. customThe crude product was purified by column chromatography on silica gel
  12. washeluting with ethyl acetate/heptane (1/10)

Sources & evidence

ORD record
ord-baa96e667fd14a96ba2327fed3082104
Source dataset
uspto-grants-2013_01
Patent number
US08349833B2

Reaction notes

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