合成路线1

Terikalant, the (S)-enantiomer of RP 58866, was synthesized as follows: After hydrolysis of the ethyl ester (III) with NaOH in refluxing methanol, the corresponding acid (VIII) is converted into the acid chloride by refluxing in thionyl chloride. After removal of excess thionyl chloride, the residue is distilled off under reduced pressure to yield the carboxylic acid chloride (IX). Subsequent reaction of (IX) with (R)-(-)-phenylglycinol yields a mixture of the (SR)-3,4-dihydro-N-(2-hydroxy-1-phenethyl)-2H-1-benzopyran-4-acetamide (Xa) [m.p. 143 C; alpha(D) -43 (c 1.5, EtOH)] and (RR)-3,4-dihydro-N-(2-hydroxy-1-phenethyl)-2H-1-benzopyran-4-acetamide (Xb) [m.p. 140 C; alpha(D) -6.5 (c 1.5, EtOH)] diastereoisomers, which are separated by silica gel column chromatography using methylene chloride/ethanol (95/5) as eluent and subsequently hydrolyzed to give the two pure enatiomeric carboxylic acids: (S)-(XIa) [alpha(D) -18.5 (c 1.1, EtOH)], e.e. 99.3% determined by analytical HPLC on the amide derived from (R)-(-)-phenylglycinol, and (R)-(XIb) [alpha(D) +17.4 (c 1, EtOH)]; m.p. 77-8 C. Reduction of (XIa) with lithium aluminum hydride in tetrahydrofuran gives the alcohol (XII), which is converted into the bromide (XIII) and, subsequently, to (S)-1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)piperidine (E)-2-butenedioate (1:1) , analogously with the racemic compound described in scheme 16777901a. RP 62719 is recrystallized from isopropanol and the absolute configuration is obtained through single crystal x-ray analysis of the bromhydrate. The pure (R)-isomer, RP 62718, is obtained according to the same reaction scheme as that described for (XIa), but starting with (XIb).