Synthesis of methotrexate

Details Synthesis of methotrexate Synthesis of methotrexate

1976-11-17

1978-03-21

Coughlan, Jr., Paul M.

Chemistry of carbon compounds

Miscellaneous organic carbon compounds

C-metal

2602564B, 560 41, C07D47508

Patent

active

040803252

ABSTRACT:
The present invention consists of three process improvements in the so-called multi-step Piper-Montgomery process designed especially to produce the antifolate methotrexate which is closely related to both aminopterin and folic acid. 2,4,5,6-tetraaminopyrimidine sulfite is one starting material and is usually produced in the form of the bisulfite in an acetate buffer. The present modification positively produces the hydrochloride from the bisulfite and eliminates the acetate buffer utilized in prior art processes. Subsequently, a pteridine ring is formed from the pyrimidine hydrochloride using dihydroxyacetone at pH 5.5.+-.0.2 to form the second ring. This strict pH control together with the use of hydrochloride salt minus the acetate buffer assists in preferentially favoring the formation of 2,4-diamino-6-hydroxymethylpteridine. Subsequently the 6-hydroxy-methyl compound is converted to the hydrobromide acid salt and reacted with three moles of a triphenyl dibromophosphorane and phosphazine protecting groups are formed on the amine groups of the pteridine ring as the 6-hydroxymethyl group is transformed to 6-bromomethyl, a key intermediate. The present process leaves the protecting phosphazine groups on the primary amino groups to discourage side reactions during subsequent alkylation of the other major reactant, ethyl N-(p-methylaminobenzoyl)-L-glutamate. Furthermore, ethyl N-(p-methylaminobenzoyl)-L-glutamate, the other reactant, is uniquely produced for the present multi-step reaction by a process proceeding from ethyl N-(p-trifluoromethylaminobenzoyl)-L-glutamate by utilizing an alkali metal hydroxide in a lower (C.sub.1 -C.sub.6) alkanol wherein the protective trifluoroacetyl groups are removed. This step uses a special mixture preferably of an alkali metal hydroxide in ethanol and optimally 1 equivalent of KOH in 20% ethanol at or below ambient temperature where the mixture is added slowly to keep the reaction pH below 9. The combination of these improvements results in the increase of an overall yield of methotrexate from the named starting reactants from about 25% to approximately 40-50%.

REFERENCES:
patent: 3989703 (1976-11-01), Nicolesco-Duvaz et al.

Affiliated with

Also associated with

Rating

Synthesis of methotrexate does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Synthesis of methotrexate, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Synthesis of methotrexate will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-570317