Process for preparing (S) (+)-4,4'-(1-methyl-1,2-ethanediyl)-bis

Details Process for preparing (S) (+)-4,4'-(1-methyl-1,2-ethanediyl)-bis Process for preparing (S) (+)-4,4'-(1-methyl-1,2-ethanediyl)-bis

1994-11-23

1997-04-08

Bernhardt, Emily

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

562553, 562554, C07D24104

Patent

active

056189362

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB92/01942 filed Oct. 22, 1992.
This invention relates to a process for preparing (S) (+)-4,4'-(1-methyl-1,2-ethanediyl)-bis(2,6-piperazinedione) (hereinafter referred to as "ICRF-187"). In particular, the invention is concerned with a practical process, utilizable on a commercial scale for the preparation of ICRF-187, in which process certain operations hitherto regarded as necessary are avoided, but which process still produces ICRF-187 of the same or better quality in very acceptable commercial yield.
ICRF-187 was described by Creighton in, inter alia, U.S. Pat. Nos. 3,941,790 and 4,275,063 as a material useful for aiding regression and palliation of cancer in mammals. In Pathologie Biologie. 1987, 35 (No 1) 49-53, Green described how certain anthracyclines are effective anti-tumour agents but carry the side effect of a tendency to produce cardiotoxicity upon chronic administration, but also disclosed for the first time that ICRF-187 could protect against such cardiotoxicity. One particular widely used anti-cancer drug suffering from the disadvantage of associated cardiotoxicity is doxorubicin hydrochloride- In U.S. Pat. No. 4,963,551, Palepu et al described a method of formulating ICRF-187 in a manner which can facilitate intravenous administration of this substance as a cardioprotective agent to reduce or prevent cardiotoxicity resulting from the administration of doxorubicin hydrochloride.
As for the manufacture of ICRF-187, Creighton, supra, essentially described two methods. In the first method, 1,2-diaminopropane tetraacetic acid is heated with formamide to result in incorporation of nitrogen and ring closure. In the second method, the tetraamide corresponding to the above tetraacid is heated in polyphosphoric acid or phenol, bringing about cyclization.
U.S. Pat. No. 4,764,614 describes an alternative synthesis in which propylenediamine tetraacetic acid tetraamide is treated in a dipolar aprotic solvent with an alkali metal derivative of dimethyl sulfoxide to form a dialkali metal salt of the desired bi-piperazinedione, the desired heterocyclic product.
EP-A-0 330 381 describe yet an alternative process or preparing, inter alia, ICRF-187, in which a corresponding tetranitrile is synthesized by reacting an appropriate diamine with formaldehyde and an alkali metal cyanide. The tetranitrile is then hydrated to yield an acid addition salt of the corresponding tetraamide, and this latter substance may then be cyclized.
These various processes for making ICRF-187 suffer from a number of disadvantage- Thus, the process of U.S. Pat. No 4764614 involves number o different chemical steps, including an esterification and amide formation. Also, the process of EP-A-0 330 381, supra, involves the use of alkali metal cyanides which are extremely toxic and consequently have substantial disadvantages in bulk handling on an industrial scale. On the other hand, the production of intermediate 1,2-diaminopropane tetraacetic acid products in other known alternative processes is generally achieved only together with the production of substantial amounts of alkali metal salt byproduct. The presence of large amounts of alkali metal salts leads to various significant processing difficulties. Furthermore, the tetraacid usually contains co-precipitated diacid and triacid impurities, the presence of which nave hitherto been regarded as prejudicial to the overall chemical efficiency and success of the process.
The problem of the presence of alkali metal salt and other byproducts has spawned significant efforts to remove such materials at the tetraacid stage, before cyclization.
Thus, in Repta et al, J. Pharmaceutical Sciences, 65(No 2) 238-242, the tetraacid product is synthesized from 1,2-diaminopropane dihydrochloride by reaction with chloroacetic acid and sodium hydroxide, and removal of salt byproduct is achieved using a cation-exchange resin column. (Glycolic acid will also De present as a by product derived from the chloroacetic acid.) This technique is very cumbersome, and quite impracti

REFERENCES:
patent: 3941790 (1976-03-01), Creighton
patent: 4963551 (1990-10-01), Palepu et al.
patent: 4963679 (1990-10-01), Tu et al.
patent: 5438057 (1995-08-01), Creighton
Repta et al, Journal of Pharmaceutical Sciences, 65, pp. 238-242 (1976).
Wing et al, Inorg. Chem. 8, pp. 2303-2306 (1969).
Dwyer et al, J. Am. Chem. Soc. 81 pp. 2955-2957 (1959).
"Research Techniques in Organic Chemistry" by Robert B. Bates and John P. Schaefer, pp. 45-49 (1971).

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