PROCESO PARA FABRICAR BISFOSFONATOS GEMINALES

SE REFIERE A UN PROCESO PARA FABRICAR UN BISFOSFONATO GEMINAL DE FORMULA I DONDE Q ES O, NR4, S, Se, ENLACE INDIVIDULA; m + n ES 0-5; Z ES UN ANILLO DE PIRIDINA, PIRIDAZINA, PIRIMIDINA, PIRAZINA; R1 ES H, AMINO, AMIDO, OH, ALCOXI, ENTRE OTROS; R2 ES H, ALQUILO C1-C4; R3 ES H, ALQUILO C1-C6, ARILO, OH, HALO, CARBONILO, ALCOXI, ENTRE OTROS; R4 ES H, ALQUILO C1-C4. EL PROCEDIMENTO PARA LA PREPARACION CONSISTE EN: a) PROVEER UN ACIDO AMINOCARBOXILICO; b) DISOLVER EL ACIDO AMINOCARBOXILICO EN ACIDO FOSFOROS Y c) REACCIONAR LA SOLUCION DEL PASO b) CON TRIHALURO DE FOSFORO TAL COMO OXICLORURO DE FOSFORO, OXIBROMURO DE FOSFORO, ENTRE OTROS EN PRESENCIA DE UNA BASE TAL COMO N,N-DIISOPROPILETILAMINA, TRIETILAMINA, TRIMETILAMINA, ENTRE OTROS. EL ACIDO FOSFOROSO SE CALIENTA DE 45° A 95°C HASTA FUNDIRSE. LA RELACION DE ACIDO FOSFOROSO Y BASE ES DE 0,2 A 0,8 EQUIVALENTES. EL BISFOSFONATO GEMINAL SE SELECCIONA DE 1-HIDROXI -2- (3-PIRIDINIL) ETILIDENOBISFOSFONICO (RISEDRONATO), ACIDO 4-AMINO-1- HIDROXIBUTILIDEN-1,1-BISFOSFONICO, ACIDO (3-AMINO-1-HIDROXI-PROPILIDENO) DIFOSFONICO The present invention relates to a novel process for making geminal bisphosphonates. The process provides for bisphosphorylation using phosphorus trihalide, phosphorous acid as a reactant/solvent, and a base as an acid acceptor/solvent. The present invention is directed to a process for making geminal bisphosphonates of the general formula:wherein Q is oxygen, -NR4-, sulfur, selenium, or a single bond; m+n is an integer from 0 to about 5, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine, and pyrazine; R1 is hydrogen, substituted or unsubstituted amino, amido, hydroxy, alkoxy, halogen, carboxylate, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 6 carbon atoms, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl; each R2 is independently, hydrogen, or substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms; R3 is one or more substituents selected from the group consisting of hydrogen, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 6 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy, nitro, amido, amino, substituted amino, carboxylate, and combinations thereof; R4 is hydrogen, substituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atom