CS217236B1 - Process for the preparation of 4-amino-N, N-methylptaroylglutamic acid - Google Patents

Abstract

The subject of the invention is a method for producing 4-amino-N1°-methylpteroylglutamic acid, also called methotrexate, which is used as a now classic cytostatic agent for the treatment of a number of malignant diseases. The disadvantages of current processes, i.e. technological and economic complexity, are eliminated by a production method consisting in the condensation of 2,4-diaamino-6-chloromethylpteridine hydrochloride of the given formula with N-(p-methylformylaminobenzoyl)ethyl glutamate of the given formula in the presence of water at a pH of 1 to 14.

Description

The invention relates to a process for the preparation of 4-amino-N ¹ ° -methylpteroylglutamic acid, also called Methotrexate, of the formula

NH, N ^CH 2 ^- CO-NH-CH-COOH ^CH3 '-' -CH ₂ -CH ₂ -COOH

Methotrexate is used as a classic cytostatic for the treatment of many malignant diseases.

Most commonly, it is prepared by condensation of 2,4-diamino-6-bromomethylpteridine hydrobromide with N- (p-methyleminobenzoyl) ethyl glutamate (Piper JR, Montgomery JA: J. Org. Chem. Il, 208, (1977)) or by condensation 2, 4-diamino-6-chloromethylpteridine with N- (p-methylaminobenzoylglutamic acid (British Pat. 1,414,752) or condensation of 2,4-diamino-6-chloromethylpteridine hydrochloride with N- (p-methylaminobenzoyl) glutamate (U.S. Pat. The common drawback of these processes is that they use N- (p-methylaminobenzoyl) ethyl glutamate or even N- (p-methylaminobenzoylglutamanoic acid) to condense both of which must be prepared from N- (p-methyl). X-aminobenzoyl) glutamate of ethyl ethyl by cleavage of the protecting group X. X may be eg tosyl, formyl, benzyl, carbalkoxyl.This reaction step is technologically and in some cases economically demanding according to published procedures. The particular difficulty relates in particular to detosylation which is carried out with a solution of hydrogen bromide in acetic acid.

* 1 c

The above disadvantages are overcome by a process for the preparation of 4-amino-N-methylpteroylglutaic acid which comprises condensing 2,4-diamino-6-chloromethylpteridine hydrochloride of the formula I

H ₂ N

NH,

ch ₂ ci. HCl with ethyl (N- (p-methylformylaminobenzoyl) glutamate II)

V \

N

Z ch ₃

O - CO - NH - CH - COOC - H '2 ⁿ 5 ch ₂ ch ₂ cooc ₂ h ₅ in the presence of water at pH up to 14.

The advantage of this procedure is that it uses relatively easily available N- (p-mathylr ητ mistakenly _nn-i. Benzoyljglutaman ethyl II which under the reaction conditions it becomes a nucleophilic reagent and simultaneously adjusts the saponification of the ester groups. Another advantage is that the previously known methods of preparing methotrexate shorten one significant reaction step.

Example

To 1500 ml of 1 N sodium hydroxide is added 70 g of N- (p-methylformylaminobenzoyl) ethyl glutamate. After stirring at room temperature, a solution was formed. The pH of this solution is adjusted to 3-4 with hydrochloric acid. The temperature is raised to 50-60 ° C and 47 g of 2,4-diamino-6-chloromethylpteridine hydrochloride are added with stirring. The reaction mixture was stirred at 50-60 ° C for 5-10 h, in the absence of light. After this time, the suspension was cooled to room temperature, adjusted to pH 9-11 with sodium hydroxide solution. The precipitated impurities were removed by filtration. The pH of the filtrate was adjusted to 7 with hydrochloric acid.

Activated carbon was added and filtration was performed. Dilute the filtrate with 2000 ml of water. The pH of the filtrate was adjusted to 3-4 with hydrochloric acid, leaving yellow methotrexate microcrystals. After aspiration and washing with water and acetone, methotrexate is dried under vacuum at max.

° G in the absence of light. The active substance content in the dry matter is more than 90%. To increase the active ingredient content, methotrexate can be dissolved in water at pH 8-9, adjusted to pH 7, charcoal added, and filtered. By acidifying the filtrate with hydrochloric acid to pH 3-4, methotrexate is precipitated. Isolation, washing and drying are identical to the previous procedure. The yield of methotrexate is 30 to 40 g, the active substance content in the dry matter is more than 95% (by liquid chromatography).

Claims (1)

SUBJECT OF THE INVENTION Process for the preparation of 4-amino-N ¹ β-methylpteroylglutaic acid characterized by condensing 2,4-diamino-6-chloromethylpteridine hydrochloride of the formula I NH ₂ . HCl (I) with N- (p-methylformylaminobenzoyl) glutaate and ethyl acetate of formula II ch ₃ N - (O) - CO - NH - CH - COOC.H, ch ₂ ch ₂ cooc ₂ h ₅ (II) in the presence of water at pH 1 to 14.