This invention relates to an improved process for making 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ABP) or salts thereof, where the end product is obtained in pure form and high yield, and which avoids the use of a strongly-acidic hydrolysis medium.
It is known according to U.S. Pat. No. 4,407,761 to Henkel Kommanditgesellschaft to prepare 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid by bisphosponating an aminocarboxylic acid with phosphonating reactants and then quenching the reaction mixture by addition of a strong non-oxidizing acid, preferably concentrated hydrochloric acid, with heating, to hydrolyze the formed phosphorous intermediates to final product. However, problems result from this reaction because the bisphosphonation reaction mixture does not remain homogeneous and local solidification occurs. This solidification causes variable yields, which in part results from the exothermic nature of the reaction due to the development of "hot spots". Moreover, to make the sodium salt, utilizing the prior art processes, requires isolation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and an additional step to convert this to the monosodium salt. Further, the use of concentrated hydrochloric acid in the quench, whose fumes present an environmental problem, is also required.
Furthermore, U.S. Pat. No. 4,922,007 to G. R. Kieczykowski, et al. (assigned to Merck & Co., Inc.) discloses the use of methanesulfonic acid to overcome the non-homogeneity and solidification problems associated with the bisphosphonation phase, but utilizes a non-pH controlled water quench which leads to the presence of a strongly acidic and corrosive hydrolysis mixture which requires the use of expensive glass reaction vessels with their inherent pressure limitations.
The present invention solves these problems by the use of methanesulfonic acid to allow the bisphosphonation reaction to remain fluid and homogeneous, and using a pH-controlled aqueous quench in the range of 4 to 10, followed by hydrolysis, which eliminates the need for concentrated hydrochloric acid in the quench. The present invention also eliminates the need to handle a corrosive acidic product hydrolysis mixture, such that stainless steel hydrolysis equipment rather than glass equipment can be utilized. Glass equipment has inherent pressure limitations not possessed by stainless steel. This is a big advantage in the instant process since it has been found that, by conducting the hydrolysis under pressure, the hydrolysis rate can be significantly increased.
It has been found that, in the quench, a pH above 10 leads to lower yields due to formed intermediates which resist hydrolysis, and a pH below 4 leads to much longer hydrolysis times. Further, it has been found that ABP is unstable at a pH above 8, thus limiting the reaction times and hydrolysis times at higher pHs.
USPTO Backgrounds
USPTO Backgrounds