AtracuriuM IMpurity D2 (cis-Quaternary Alcohol) synthesis

Yield:-

Reaction Conditions:

in tetrahydrofuran at 10 - 15; for 2 h;

Steps:

12
Cis-acid besylate (0.78 g, 1.327 mmol) was dissolved in dichloromethane (3 ml). The solution was cooled to 10°-15°C and oxalyl chloride (0.171 ml, 1.991 mmol, 1.5 eq.) was added in portions at 10°-15°C. The reaction mixture was stirred at 10°-15°C for about 16 hours. The reaction mixture was concentrated under reduced pressure to remove the dichloromethane and excess oxalyl chloride. The remaining residue containing compound (VIIB) was dissolved in dry tetrahydrofuran (THF) (2 ml) and the resulting solution was added dropwise during about 30 minutes to 1,5-pentanediol (1.4 ml, 13.27 mmoles, 10 eq.) and dry THF (3 ml). The reaction mixture was stirred at 10°-15°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the THF. Water (20 ml) and toluene (20 ml) were added to the remaining residue and the mixture was stirred at ambient temperature to afford two layers. The layers were separated and the aqueous layer was washed with a mixture of ethyl acetate and n-heptane (4:1 v/v, 20 ml). Dichloromethane (80 ml) was added to the aqueous layer and the mixture was stirred at ambient temperature in order to extract the product into the organic layer. The layers were separated and the dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure at ambient temperature to afford compound (VIII) (0.020 g, 2% yield, HPLC purity: 88%).

References:

CHEMAGIS LTD. WO2009/7946, 2009, A1 Location in patent:Page/Page column 21