Process for making geminal bisphosphonates

Details Process for making geminal bisphosphonates Process for making geminal bisphosphonates

2001-01-29

2003-05-13

Gerstl, Robert (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C562S013000

Reexamination Certificate

active

06562974

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel process for making geminal bisphosphonates. The process provides for bisphosphorylation using phosphorus trihalide, molten phosphorous acid as a reactant/solvent, and a base as an acid acceptor/solvent.
BACKGROUND OF THE INVENTION
Polyphosphonic acids and their pharmaceutically-acceptable salts have been proposed for use in the treatment of diseases of bone and calcium metabolism. Such diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions. In particular bisphosphonates, like ethane-1-hydroxy-1,1-diphosphonic acid (EHDP), propane-3-amimo-1-hydroxy-1,1-diphosphonic acid (APD), dichloromethane diphosphonic acid (C12MDP), 3-amino-1-hydroxy-propylidene-diphosphonic acid. (PAMIDRONATE), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ALENDRONATE) and 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid (RISEDRONATE) have been the subject of considerable research efforts in this area. Paget's disease and heterotropic ossification are currently successfully treated with EHDP. The diphosphonates tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss. However, in spite of certain analogies in activity, bisphosphonates do not exhibit the same degree of activity and some have serious drawbacks with respect to the degree of toxicity in animals and the tolerability or the negative side effects in humans.
Several methods for making bisphosphonates have been disclosed. For example, European Patent Application 0 494 644, Instituto Gentili and PCT application WO96/33199 disclose methods for making amino-bisphosphonates. However, just as there are differences in the activities of the different bisphosphonates, so too are there differences in the method of making these compounds. Depending on the reaction conditions, the viscosity of the reaction mixture and/or the formation of large amounts of elemental phosphorus by-products limit the scale on which the bisphosphorylation reaction can be readily carried out.
It is therefore desirable to use a scaleable process to produce geminal bisphosphonates that achieves high yields with little residual elemental phosphorous by-products and that can be safely practiced on the commercial scale.
SUMMARY OF THE INVENTION
The present invention is directed to a process for making geminal bisphosphonates of the general formula:
wherein Q is oxygen, —NR
4
—, 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; R
1
is independently 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 R
2
is independently, hydrogen, or substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms; R
3
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; R
4
is hydrogen, substituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms, or acyl; resulting from bisphosphorylation of an aminocarboxylic acid in the presence of phosphorus trihalide, molten phosphorous acid and base such as morpholine to form a geminal bisphosphonate.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention is directed to a novel process for making geminal bisphosphonates. Said process involves the use of molten phosphorous acid, an amino carboxylic acid, phosphorous trihalide, and base in the bisphosphorylation step. The reaction is carried out at a temperature of from about 45° C. to about 90° C., preferably from about 55° C. to about 85° C., more preferably from about 60° C. to about 75° C. The presence of an additional solvent is optional. Particularly preferred geminal bisphosphonates made by this process are 1-hydroxy-2-(3-pyridinyl)ethylidine bisphosphonic acid, 4-amino-1-hydroxybutylidene-1,1-bisphonic acid, and 3-amino-1-hydroxypropylidene-diphosphonic acid. Most preferred is risedronate, 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonicacid.
Definitions and Usage of Terms
The following is a list of definitions for terms used herein:
As used herein, “alendronate” denotes 4-amino-1-hydroxybutylidene-1,1-bisphonic acid.
As used herein, “alkenyl” means a hydrocarbon substituent with one or more double bonds, straight or branched chain, unsubstituted or substituted.
As used herein, “alkoxy” means a substituent having the structure Q-O-, where Q is alkyl or alkenyl.
As used herein, “alkyl” means a saturated hydrocarbon substituent, straight or branched chain, unsubstituted or substituted.
As used herein, “alkylthio” means a substituent having the structure Q-S-, where Q is alkyl or alkenyl.
As used herein, “aminocarboxylic acid” is a saturated or unsaturated substituted or unsubstituted alkyl with a carboxylic acid group attached to one end and an amine group either attached to one of the carbons of the alkyl chain or as a heteroatom in a saturated or unsaturated substituted or unsubstituted heterocyclic ring.
As used herein, “base” means a basic reagent which is added to a reaction mixture to facilitate bisphosphorylation. Bases include organic and inorganic bases. Preferred bases include those which have easily filterable or otherwise removable salts. Specifically, preferred bases include N,N-diisopropylethylamine, triethylamine, trimethylamine, 4-dimethylaminopyridine, pyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and morpholine. The more preferred bases are triethylamine, trimethylamine, potassium carbonate, pyridine and morpholine. The most preferred base is morpholine. The base may be added as the free base or in its salt form.
As used herein, “biohydrolyzable ester” is an ester moiety that does not interfere with the therapeutic activity of the compound, or that is readily metabolized by a human or other mammal.
As used herein, “bisphosphorylation” is the chemical reaction resulting in the production of a product containing two phosphoryl groups on the same carbon.
As used herein, “carbocyclic ring” is a saturated, unsaturated, or aromatic, hydrocarbon ring radical. Carbocyclic rings are monocyclic or are fused, bridged, or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 4 to 7 atoms, and most preferably 5 or 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 14 atoms, and most preferably 9 or 10 atoms.
As used herein, “halogen” is a chloro, bromo, fluoro, or iodo atom radical. Bromo and chloro are the most preferred halogens.
As used herein, “heterocyclic ring” is a saturated, unsaturated, or aromatic, ring radical comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings are monocyclic or are fused, bridged, or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 4 to 7 atoms, and most preferably 5 or 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 14 atoms, and most preferably 9 or 10 atoms.
As used herein, “inorganic acid” is a mineral acid such as sulfuric, nitric, hydrochloric, phosphoric, and phosphorous.
As used herein, “methylene” is a —CH
2
— radical.
As used herein, “molten phosphorous acid” means phosphorous acid heated to from about 45° C. to 95° C., preferably from about 55° C. to about 85° C., more preferably from about 60° C. to about 75° C.
As used herein,

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