Monsanto Research Corporation

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The United States of America As Represented by the Secretary of

The United States of America As Represented by the Department of Health

James A Ellard

John M Butler

James A Webster

John L Schaar

Joseph Satanek, Jr

An improvement in the production of methotrexate as set out in Ellard U.S. Pat. No. 4,080,325. It has been found that magnesium oxide facilitates the coupling reaction by acting as an acid acceptor. The dense grade of magnesium oxide is preferred in molar proportions of 2 to 4 moles of magnesium oxide per mole of 2,4-diamino-6-hydroxymethylpteridine. Further, the triphenylphosphine oxide which is generated by hydrolysis of the protecting groups is removed from the reaction stream by utilization of toluene or BTX-type solvents.

Separation of triphenylphosphine oxide from methotrexate ester and

In a method of preparing methotrexate from a coupling of 2,4-bis(triphenylphosphazino)-6-bromomethylpteridine hydrobromide with ethyl N-(p-methylamino)-benzoyl-L-glutamate to produce the phosphazino derivative of methotrexate ester and subsequently hydrolyzing the phosphazino and ester groups to produce the free methotrexate, the pteridine synthesis step wherein molecular oxygen is substituted for reaction air and the pH throughout the pteridine synthesis is regulated to between 2.5 and 5.4, the preferred pH being about 3.0 and producing from tetraaminopyrimidine and dihydroxyacetone the isomer 2,4-diamino-6-hydroxymethylpteridine over 2,4-diamino-7-hydroxymethylpteridine in a ratio of about 20:1. Exemplary of other situations involving pteridine where the molecular oxygen may be substituted for reaction air are: in the production of folic acid, tetrahydrofolic acid, etc.

Synthesis of 2,4-diamino-6-hydroxymethylpteridine

Fire-resistant organic materials including foams, are made by heating at temperatures sufficient to cause polymerization and elimination of nitrogen and sulfur precursor aromatic polymers having sulfonamide linkages and aromatic compounds capable of forming said polymers, e.g. sulfamyl-type aminoaromatic compounds such as sulfanilamide, sulfaguanadine and the like. Preferred compounds are those providing para linkages in the sulfonamide polymer chain, those which are substantially free of oxidizing substituents, for example nitro groups, and those which are not fused-ring aromatic. Preferred foams are the high expansion foams, i.e. those having expansion ratios of at least about 3:1, more preferably at least about 8:1. The precursors of these fire-resistant organic materials can be incorporated into polymers such as polyvinylidene chloride, polyisocyanates, aminoplasts, and the like either physically by mixing or by chemical reaction to give improved fire-resistance. Also inorganic fillers such as titanium dioxide, silica, alumina and the like can be added to the polymers and/or the precursor to give compositions having improved fire resistance.

Fire-resistant material and process

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%.

Synthesis of methotrexate

Intumescent compositions are described which when deposited on a substrate protect the substrate against heat and fire damage for an appreciable time, and these compositions are readily removed from the substrate by water washing or water scrubbing both before and after intumescing. Another advantage of these compositions is that they give off very little smoke when exposed to heat and fire. The most effective of these compositions comprise monoammonium phosphate and/or diammonium phosphate as a heat- and fireproofing agent, urea and/or cyanoguanidine (dicyandiamide) as a gas forming or gas generating agent to promote the intumescence, sucrose (sugar) together with the phosphate to promote initial intumescence at low temperature and titanium dioxide as a heat-reflecting agent. Certain possible alternatives to the compounds named above are also named.

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Dayton, OH, United States of America

James A Ellard