Antifolates comprise a well-known class of compounds that have exhibited beneficial medicinal properties in several therapeutic areas. Antifolates have been used for many years as treatments for various cancers, infectious diseases, immunosuppression, inflammatory diseases and others.
Antifolates are so named because of their mode of action, by interfering with the folic acid metabolic pathway. The most well known antifolate, methotrexate (MTX), inhibits dihydrofolate reductase (DHFR), thus preventing the reduction of folic acid to its dihydro and tetrahydro forms. Other antifolates, such as aminopterin (AMT), MDAM and others also act by inhibiting DHFR, while still others, such as MTX polyglutamates, act at different areas of the folic acid pathway, most notably the thymidylate synthetase (TS) inhibitors, Glucineamide Ribonucleotide (GAR) and Aminoimidazole Carboxamide Ribonucleotide (AICAR) inhibition.
Most antifolates used in oncology are similar in chemical structure to the naturally occurring vitamin, folic acid, the structure of which is shown below, along with a few other widely known antifolate structures.

U.S. Pat. No. 5,912,251 discloses an antifolate compound, hereinafter referred to as 5,8-dideaza MDAM that is similar in structure to MDAM. The structure of 5,8-dideaza MDAM (hereinafter referred to as gamma methylene glutamate 5,8,10-trideaza aminopterin or TRIDAM) is shown below as Formula A.

A major mode of action of TRIDAM is TS inhibition in addition to some degree of DHFR inhibition. It has been postulated in the '251 patent that TRIDAM may find application not only in oncology, but also in other medical areas that antifolates have found success. Asthma, rheumatoid arthritis, psoriasis, and other inflammatory diseases are potential targets for TRIDAM.
The previous process for synthesizing TRIDAM and analogues thereof, as disclosed in the '251 patent, is inefficient and not commercially viable due to low overall yields and the impractical application or costs of various reagents and procedures used; the overall yield from the process is less than one percent of the starting materials. The '251 process is depicted below as Scheme A.

M. G. Nair, U.S. Pat. No. 5,912,251 (1999). Another reported synthetic process for making a close analogue of TRIDAM (identical in all respects except for the amino acid residue) was disclosed by N. V. Harris, et, al., Synlett., No. 4,577 (1990), and is shown below as Scheme B.
N. V. Harris. et al., Synlett., No. 4, 577 (1990).