Hydrochloric Acid → HCID 56971604, compound

HRID 1801523Notes

Reaction equation

HRID 1801523 reaction equation
CC(OC)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:14][C:15]([C@@H:17]([N:25]1[CH2:33][C:29]2[CH:30]=[CH:31][S:32][C:28]=2[CH2:27][CH2:26]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=1[Cl:24])=O.Cl>C(OCC)C.C(OCC)(=O)C>[Cl:24][C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:17]([N:25]1[CH2:26][CH2:27][C:28]2[S:32][CH:31]=[CH:30][C:29]=2[CH2:33]1)[CH2:15][OH:14]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 15413tert-Butyl methyl etherHCID 60606Clopidogrel2×HCID 21226445Aluminium lithium hydride3×

Product 1

HCID 56971604HCID 56971604, compoundYield 75.4%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of clopidogrel hydrosulfate (10 g, 23.8 mmol) in deionized water (300 mL) was added sodium bicarbonate (4 g, 47.6 mmol) in small portions. After mixing, t-butyl methyl ether (200 mL) was added and the solution was stirred for one hour. The layers were separated and the aqueous layer was extracted again with t-butyl methyl ether (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining brown oil was dried under high vacuum to a constant weight to afford clopidogrel free base (8.24 g, 106% yield which includes a trace of MTBE). While under a nitrogen atmosphere, a solution of lithium aluminum hydride (0.46 g, 12 mmol) in anhydrous diethyl ether (8 mL) was added drop wise to a solution of clopidogrel free base (3.22 g, 10 mmol) in anhydrous diethyl ether (4 mL). The lithium aluminum hydride was added at a rate to keep the ether refluxing gently. The addition was completed and the mixture was stirred at reflux temperature for an additional 30 minutes. After 30 minutes, the solution was cooled to 0° C. in an ice/water bath. The excess LiAlH4 was decomposed with ethyl acetate (2 mL, added slowly), followed by 6N HCl solution (20 mL added slowly with vigorous stirring). The mixture was transferred to a separatory funnel. The aqueous fraction was separated and extracted with ether (30 mL, which was discarded). The aqueous fraction was adjusted to pH=7 with 6 N NaOH solution (20 mL) and extracted with ether (4×15 mL). The combined ether extracts were washed with brine (20 mL), dried over MgSO4, and concentrated under vacuum to yield 2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridine-5-yl)ethanol (Compound Is, 2.12 g, 75.4% yield) as a white solid. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.45-7.40 (m, 2H), 7.23 (m, 2H), 7.04 (d, 1H, J=5.1 Hz), 6.70 (d, 1H, J=5.1 Hz), 4.47 (dd, 1H, J=6.9, 5.8 Hz), 3.97-3.91 (m, 1H), 3.81-3.74 (m, 2H), 3.62 (d, 1H, J=14.4 Hz), 3.01-2.95 (m, 1H), 2.84 (m, 2H) 2.76-2.68 (m, 1H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 135.31, 134.92, 133.81, 133.26, 130.03, 129.35, 128.85, 126.72, 125.34, 122.82, 64.53, 61.55, 50.20, 47.67, 26.15. MS (HR, DIP-CI): Calculated for C15H17ClNOS (MH)+: 294.0714, found 294.0715

Workup

  1. additionThe addition
  2. temperatureat reflux temperature for an additional 30 minutes
  3. additionadded slowly),
  4. additionadded slowly
  5. stirringwith vigorous stirring)
  6. customThe mixture was transferred to a separatory funnel
  7. customThe aqueous fraction was separated
  8. extractionextracted with ether (30 mL, which was discarded)
  9. extractionextracted with ether (4×15 mL)
  10. washThe combined ether extracts were washed with brine (20 mL)
  11. dry with materialdried over MgSO4
  12. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-07a47068e7244ff68cc59f9d2afa7696
Source dataset
uspto-grants-2013_01
Patent number
US08349833B2

Reaction notes

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