Process for preparing 1,3-dioxolane derivatives

A process for the preparation of compounds of formula (I):

• ##STR31## wherein:
• n is 1 or 2;
• each R.sup.1 is independently halo or lower alkyl;
• R.sup.2 is nitro or --N(R.sup.3)R.sup.4 where
• R.sup.3 is hydrogen or lower alkyl;
• R.sup.4 is hydrogen, lower alkyl, lower alkylsulfonyl or --C(Y)R.sup.5 where Y is oxygen or sulfur and R.sup.5 is hydrogen, lower alkyl, lower alkoxy or --N(R.sup.6)R.sup.7 where R.sup.6 is hydrogen or lower alkyl and R.sup.7 is hydrogen, lower alkyl or lower alkoxycarbonyl;
• or
• R.sup.3 and R.sup.4 together with N is pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, wherein the piperazino is optionally substituted at the 4-position by --C(O)R.sup.8 where R.sup.8 is hydrogen, lower alkyl, lower alkoxy or amino;
• or a pharmaceutically acceptable salt thereof;
• which process comprises the following steps:
• (1) reacting the compound of formula (B):
• ##STR32## with a compound of formula (D):
• ##STR33## wherein R.sup.9 is halo, tosylate or mesylate, in the presence of a strong acid selected from the group consisting of alkanesulfonic acids, arenesulfonic acids and Lewis acids, to yield a mixture of stereoisomers represented by the following formula (E):
• ##STR34## wherein R.sup.9 is halo, tosylate or mesylate;
• (2) dissolving the mixture of stereoisomers represented by formula (E), as defined above, in a suitable solvent and treating the resulting solution with about 0.5 to about 2.0 molar equivalents of concentrated nitric acid to yield a compound of formula (Eb):
• ##STR35## wherein R.sup.9 is halo, tosylate or mesylate, as a precipitate;
• (3) treating the mother liquor resulting from the preparation of the compound of formula (Eb) with a suitable base and allowing the resulting mixture to crystallize from a suitable solvent to yield a compound of formula (Ea):
• ##STR36## wherein R.sup.9 is halo, tosylate or mesylate;
• and (4) treating a compound of formula (Ea), as defined above, with a compound of formula (F):
• ##STR37## wherein n is 0, 1 or 2;
• each R.sup.1 is independently halo or lower alkyl;
• R.sup.2 is nitro or --N(R.sup.3)R.sup.4 where
• R.sup.3 is hydrogen or lower alkyl;
• R.sup.4 is hydrogen, lower alkyl, lower alkylsulfonyl or --C(Y)R.sup.5 where Y is oxygen or sulfur and R.sup.5 is hydrogen, lower alkyl, lower alkoxy or --N(R.sup.6)R.sup.7 where R.sup.6 is hydrogen or lower alkyl and R.sup.7 is hydrogen, lower alkyl or lower alkoxycarbonyl;
• or
• R.sup.3 and R.sup.4 together with N is pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, wherein the piperazino is optionally substituted at the 4-position by --C(O)R.sup.8 where R.sup.8 is hydrogen, lower alkyl, lower alkoxy or amino;
• in the presence of base to yield a compound of formula (I), as defined above.