Cyclization for preparing antifolate compounds

A process for preparing a compound of formula III

• wherein ##STR17## R.sup.1 is bromo, iodo or COOR.sup.2 ;
• R.sup.2 is H, C.sub.1 -C.sub.4 alkyl, phenyl which may be substituted or benzyl;
• and
• A is a 5- or 6-membered aromatic residue which may contain up to three hetero atoms which may optionally be substituted with one or two groups selected from the group consisting of halo, hydroxy, C.sub.1 -C.sub.4 alkyl, and C.sub.1 -C.sub.4 alkoxy;
• or a salt thereof, which comprises cyclizing a compound of formula II ##STR18## wherein R is C.sub.1 -C.sub.4 alkyl or phenyl which may be substituted;
• and
• R.sup.1, R.sup.2, and A are as defined above;
• or a salt thereof, with guanidine;
• and optionally salifying the reaction product of said cyclization.

A process for preparing a compound of formula III ##STR19## wherein R.sup.1 is COOR.sup.2 ;

• R.sup.2 is H;
• and
• A is a 5- or 6-membered aromatic residue which may contain up to three hetero atoms which may optionally be substituted with one or two groups selected from the group consisting of halo, hydroxy, C.sub.1 -C.sub.4 alkyl, and C.sub.1 -C.sub.4 alkoxy;
• or a salt thereof, which comprises
• (a) reacting a compound of formula I ##STR20## wherein R is C.sub.1 -C.sub.4 alkyl or phenyl which may be substituted;
• R.sup.2 is t-butyl;
• and
• R.sup.1 and A are as defined above;
• or a salt thereof, with a sulfurization agent;
• (b) treating the reaction product from step (a) with a strong acid;
• (c) cyclizing the reaction product from step (b) with guanidine;
• and
• (d) optionally salifying the reaction step from step (c).

A process for preparing a compound of formula III ##STR21## wherein R.sup.1 is COOR.sup.2 ;

• R.sup.2 is H;
• and
• A is a 5- or 6-membered aromatic residue which may contain up to three hetero atoms which may optionally be substituted with one or two groups selected from the group consisting of halo, hydroxy, C.sub.1 -C.sub.4 alkyl, and C.sub.1 -C.sub.4 alkoxy;
• or a salt thereof, which comprises cyclizing a compound of formula IIb ##STR22## wherein R is C.sub.1 -C.sub.4 alkyl or phenyl which may be substituted;
• and
• A is as defined above;
• or a salt thereof, with guanidine;
• and optionally salifying the reaction product from said cyclization.