FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
&
PATENTS RULES, 2006
PROVISIONAL SPECIFICATION (SECTION 10; RULE 13)
"PROCESS FOR THE SYNTHESIS OF BISPHOSPHONIC ACIDS AND SALTS
THEREOF"
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI -400013, MAHARASHTRA, INDIA


THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to a process of preparing bisphosphonic acids and salts thereof.
BACKGROUND OF THE INVENTION
The bisphosphonic acid or its pharmaceutically acceptable salts are important class of therapeutically beneficial phosphonate compounds which are useful in the treatment of diseases of bone and calcium metabolism. Bisphosphonic acids and their pharmaceutical acceptable salts have been known for use in the treatment of diseases of bone and calcium metabolism. Such diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossificans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions. In particular bisphosphonates, like ethane-l-hydroxy-l-l-diphosphonic acid (EHDP), propane-3-amino-l-hydroxy-l,l-diphosphonic acid (APD), dichloromethane diphosphonic acid, 3-amino-l-hydroxypropylidenediphosphonic acid (Pamidronic Acid), 4-amino-i-hydroxybutylidene-1,1 -diphosphonic acid (Alendronic Acid), 1 -hydroxy-2-(1-imidazolyl)ethylidine-l,l-diphosphonic acid (Zoledronic Acid) and l-hydroxy-2-(3-pyridinyl)ethylidene-l,l-diphosphonic acid (Risedronic Acid) have been the subject of considerable research efforts in this area. Paget's disease and heterotropic ossification are currently successfully treated with EHDP and Risedronic acid. The diphosphonates tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss.
United States Patent No. 4,927,814 discloses a process to make analogues of ibandronic acid, which involves the use of chlorobenzene, phosphorous acid and phosphorous trichloride. The formed ibandronic acid is isolated by using Ion exchange resin chromatography, employing Amberlite IR-120 H+ column and eluted with water, where elution is monitored electrophoretically. However these operations are very difficult and time consuming on an industrial scale.
United States Patent No. 5,583,122 claims diphosphonic acids, its salt or ester, further specifically claims risedronic acid. The specification discloses the use of 2-pyridine acetic acid, phosphorus acid, chlorobenzene, and phosphorous trichloride for the preparation of risedronic acid. Further the invention relates to pharmaceutical compositions containing compounds which are useful in treating or preventing diseases characterized by abnormal calcium and phosphate metabolism, in particular characterized by abnormal bone metabolism.
PCT Application No. 01/57052 discloses a process for making geminal bisphosphonates comprising the steps of providing an amino carboxylic acid,
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dissolving the amino carboxylic acid in phosphorus acid, and reacting the solution with phosphorous trichloride in the presence on a base.
PCT Application No. 03/097655 discloses a method of preparing bisphosphonic acid comprising the step of combining a carboxylic acid, phosphorous acid and a halophosphorous compound in the presence of a diluent that is an aromatic hydrocarbon or a silicon fluid.
PCT Application No. 2005/044831 discloses a method of preparing bisphosphonic acids, comprising reacting a carboxylic acid with phosphorous acid and a phosphorous chloride in sulfolane.
PCT Application No. 2005/063779 discloses a method for preparing alkyl- and aryl-phosphonic acid, wherein an alkyl- or aryl carboxylic acid is reacted with a mixture of phosphorous acid and phosphorus oxychloride, where a molar ratio of carboxylic acid: phosphorous oxychloride: phosphorous acid of 1:2-4:8-12 is used.
PCT Application No. 2007/069049 provides a process for preparing pure zoledronic acid or its salts. The process involves reacting imidazol-1-yl acetic acid or salt thereof with phosphorous acid at 80°C or less, adding phosphorous trichloride at 80°C or less; and then isolating the zoledronic acid or salts thereof from the reaction mass. Further another aspect of this invention relates to reacting imidazole with alkyl haloacetate in one or more organic solvents in the absence of a phase transfer catalyst, to get alkyl imidazole- 1-yl acetate which hydrolyzing the alkyl imidazole- 1-yl acetate in water to get iirridazol-1-yi acetic acid. The obtained imidazol-1-yl acetic acid or salts thereof is reacted with phosphorous acid and phosphorous trichloride optionally in the presence of one or more solvents to get zoledronic acid or salts.
PCT Application No. 2008/014510 discloses a crystalline form A of ibandronic acid and a process for the preparation thereof. The process involves several steps like esterification of valeric acid condensed with methylamine to give N-methyl pentylamide; reduction of N-methyl pentylamide to give N-methyl pentyl amine; condensation of obtained N-methyl pentyl amine with methyl acrylate to give methyl 3- (N-methyl- N-penrylamino) propanoate and further hydrolysis of obtained compound to give 3-(N-methyl-N-pentylamino) propanoic acid.
PCT Application No. 2008/058722 discloses new beneficial reagents useful for the synthesis of geminal bisphosphonates in particular ibandronic acid. The invention uses tertiary amines which forms a liquid mixture with phosphorous acid in a molar ratio of 5:1 to approximately 1:5.
The prior art processes described above, disclose bisphosphonic acids like zoledronic acid, pamidronic acid, alendronic acid, risedronic acid, etc., which have been
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prepared by the reaction of corresponding carbonyl compounds (Fig. 1) with phosphorous acid, phosphorous halides, (example: phosphorous trichloride, phosphorous oxychloride, or phosphorous pentachloride) and then quenching the reaction mixture with water, heating the reaction mass to get bisphosphonic acid, which is isolated and converted to the sodium salt of respective acid.
Fig l:
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Despite various processes disclosed in the prior art for the preparation of bisphosphonic acids and salts thereof, there is still a need for improved process for producing bisphosphonic acids and pharmaceutically acceptable acid addition salts thereof. As mentioned before, prior art generally used carboxylic acids as reactant for the preparation of bisphosphonic acids and salts thereof. The use of a-substituted acetates as reactant instead of the carboxylic acid is also disclosed in some prior art references. The a-substituted acetate used in these prior arts is subsequently converted in to carboxylic acid, which is further used for the preparation of bisphosphonic acids and salts thereof. Thus the use of a-substituted acetate as a reactant in the prior art adds an additional step and extends the reaction time for the preparation of bisphosphonic acids and salts thereof. The methods described in the art are not satisfactory with regard to manufacture at commercial level, extended reaction time, yield, and purity. The present invention provides a process for the preparation of bisphosphonic acids in high yields, purity, is easy to handle, economical and suitable for large-scale manufacturing, which helps to overcome the deficiencies of the prior art.
The present invention also provides a simple process involving a-substituted acetates as the starting reactant which shortens the reaction time for the preparation of bisphosphonic acids and salts thereof.
SUMMARY OF THE INVENTION
According to an aspect of the present invention is provided an improved process for the synthesis of bisphosphonates and its pharmaceutically acceptable salts
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According to another aspect of the present invention, there is provided a method of making bisphosphonic acid or salts thereof, comprising the step of combining a a--substituted acetate and /or a salt thereof in the presence of phosphorous acid and/or phosphoric acid, halophosphorous compound and hydrocarbon as solvent resulting in corresponding bisphosphonic acid.
According to another aspect of the present invention is provided a process for manufacturing bisphosphonic acid, wherein the hydrocarbon solvent is selected from the group comprising aliphatic or aromatic hydrocarbon, substituted cyclic aliphatic hydrocarbon or bicyclic aliphatic hydrocarbon and the like and mixtures thereof.
According to another aspect of the present invention is provided a process for manufacturing bisphosphonic acid, wherein the halophosphorus compound used in the process is selected from the group comprising PC13, PC15, POCl3, PBr3, PBr5 and POBr3 and the like and mixtures thereof
BRIEF DESCRIPTION OF DRAWING FIGURES
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein:
Fig 1 is a schematic representation of the prior art process involved for the preparation of bisphosphonic acid and its sodium salt using carboxylic acid as the starting intermediate.
Fig 2 is a schematic representation of an embodiment of a process of preparation of bisphosphonic acid and its salts thereof, according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening
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value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
it must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
In accordance with an embodiment of the present invention, there is provided a method of making a bisphosphonic acid or salts thereof comprising the step of combining a-substituted acetate and /or its quaternary salt in the presence of phosphorous acid and/or phosphoric acid, halophosphorous compound and hydrocarbon as solvent resulting in corresponding bisphosphonic acid.
In accordance with an embodiment of the present invention, a process is provided for preparing bisphosphonic acids and their salts thereof which process comprises the step of reacting an acetate compound of Formula [1] with phosphorous acid and halophosphorus compound:
Fig 2:
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wherein, R1 is C1- C8 linear or branched alkyl selected from methyl, ethyl, propyl, n-butyl, iso-butyl, secondary butyl, tertiary-butyl and isopropyl.
R1is selected from hydrogen, alkyl, aryl or heteroaryl, or R2 is either imidazol-1-yl, 3-pyridyl, 2-aminoethyl, (N-(n-pentyl)N-methylamino) methyl, imidazo[ 1,2-a] pyridin-3-yl, 4-aminobutyl, N,N-dimethylamino) methyl, hydrogen or aminomethyl
R3 is selected from hydrogen, alkyl, aryl or heteroaryl, or R2 is either imidazol-1-yl, 3-pyridyl, 2-aminoethyl, (N-(n-pentyl)N-methylamino) methyl, imidazo[ 1,2-a] pyridin-3-yl, 4-aminobutyl, N,N-dimethylamino) methyl, hydrogen or aminomethyl
In particularly preferred embodiments of the present invention, R2 or R3 is either imidazol-1-yl (i.e. II is zoledronic acid), 3-pyridyl (i.e. II is risedronic acid), 2-aminoethyl (i.e. II is alendronic acid), (N-(n-pentyl)N-methylamino) methyl (i.e. II is ibandronic acid), imidazoll,2-a]pyridin-3-yl (i.e. II is minodronic acid), 4-aminobutyl (i.e. II is neridronic acid) , (N,N-dimethylainino)methyl (i.e. II is olpadronic acid), hydrogen (i. e. II is etidronic acid) or aminomethyl {i.e. II is pamidronic acid) and its quaternary salt.
The halophosphorus compound used in the process of the present invention is selected from the group comprising PC13, PC15, POCl3, PBr3, PBr5 and POBr3 and the like and mixtures thereof. The amount of halophosphorus compound used in the process of the present invention is up to 6.0 mole equivalents per equivalent of a-substituted acetate, most preferably 3.5 to 4.5 mole equivalents.
Phosphorous acid is used in the process of the invention along with the hydrocarbon solvent. Phosphoric acid may also be optionally used in combination with the hydrocarbon solvent in the process of the present invention. Phosphoric acid also known as orthophosphoric acid may be used in the process of the present invention is amounts ranging from about 1.0 to 6.0 mole equivalents per equivalent of a-substituted acetate, most preferably 3.5 to 4.5 mole equivalents.
The hydrocarbon solvent used in the process of the present invention is selected from the group comprising aliphatic or aromatic hydrocarbon, substituted or

unsubstituted cyclic aliphatic hydrocarbon or bicyclic aliphatic, saturated, or unsaturated, and linear or branched hydrocarbon and the like and mixtures thereof. More particularly, the solvent may be selected from the group comprising aliphatic hydrocarbon, having C6-C10 atoms selected from n-octane, iso-octane, cyclooctane, n-heptane, cycloheptane, n-hexane and cyclohexane, or water miscible cyclic ethers such as tetrahydrofuran and dioxane, more preferably n-octane, n-heptane, cyclohexane, tetrahydrofuran and dioxane. substituted cyclic aliphatic hydrocarbon is selected from the group comprising methyl cyclohexane, trans-dimethyl cyclohexane, cis-dimethyl cyclohexane and the like and mixtures thereof. The solvent may also be selected from the group comprising aromatic hydrocarbon selected from toluene, xylenes and the like and mixtures thereof. Bicyclic saturated hydrocarbon may be selected from the group comprising decalin, tetralin and the like and mixtures thereof. The solvent used is in an amount ranging from 5 to 40 volumes per weight (volumes per weight is milliliters per gram) of a-substituted acetate, preferably about 15-25 volumes per weight of the a-substituted acetate.
The bisphosphonic acids prepared by the process of present invention may be further isolated by using solvents such as isopropyl alcohol, methanol, ethanol, acetone, tetrahydrofuran and dioxane, acetonitrile and the like and mixtures thereof.
The skilled person will appreciate that the method according to the invention may result in the preparation of bisphosphonic acids or bisphosphonate salts depending solely on the pH conditions of the penultimate or final step of the method- It is also within the skills of the average practitioner to select the pH condition in the penultimate or final step in order to secure that the product is obtained as the free acid or its quaternary salt thereof. It should therefore be understood that the method according to the invention applies likewise to the preparation of bisphosphonic acids as of bisphosphonate salts and that the preparation of bisphosphonic acids and bisphosphonate salts both are contemplated to be within the scope of the present invention.
The method according to the invention may result in the preparation of bisphosphonic acids or bisphosphonate salts having the moisture content and particle size in the suitable range for the preparation of pharmaceutical formulation.
The bisphosphonic acids produced by said process comprise zoledronic acid, risedronic acid, alendronic acid, minodronic acid, neridronic acid, pamidronic acid, ibandronic acid, olpadronic acid or etidronic acid and their pharmaceutical^ acceptable salts.
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The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in any way.
Example 1
Preparation of Risedronate Sodium
A l.Oltr, 4 necked RBF equipped with a mechanical stirrer, a thermometer, a reflux condenser, dean stark and a dropping funnel was charged with 3-pyridine methyl acetate hydrochloride (32.0gm, 0.182) phosphorous acid (45gm, 0.548) Orthophosphoric acid (53.8gm, 0.548) and methylcyclohexane (180ml). The suspension was heated to reflux 104°C and separate out water azeotropically. The reaction mixture was than cooled to 85°C and phosphorous oxychloride (51.16ml, 0.548) was added dropwise during 1.5hrs. The reaction mixture was than heated to 95°C and maintained for 20hrs. (180ml) water was added after cooling the reaction mixture to 75°C. The reaction mixture was stirred for lhr. The organic and aqueous phase were separated and aqueous phase was heated to 95°C for 8hrs. The reaction was cooled to 25°C and isopropyl alcohol (180ml) was added to precipitate the Risedronic acid. The mixture was cooled to 5°C. Product was filtered off and washed with Isopropyl alcohol and dried at 50°C for 8hrs. The risedronic acid was dried to obtain 26.0 gm.
Example 2
Preparation of Ibandronate Sodium
A 2.0 ltr, 4 necked RBF equipped with overhead stirrer, a thermometer, a reflux condensor, and dropping funnel was charged with Methyl 3-[Methyl (pentyl) amino] propanoate (l00gm, 0.534), Phosphorous acid (104.35gm, 1.27) and methyl cyclohexane (360ml). The suspension was cooled to 25°C and added Phosphorous oxychloride (112.3gm, 0.732) within lhour. The reaction mixture was heated to reflux at 80°C for 3 hours. The reaction mixture was then cooled to 60°C and water (500ml) was added dropwise within lhour. The organic and aqueous phases were separated and aqueous phase was heated to 95°C for 8 hours. The reaction mixture was concentrated to thick oily mass by distilling out 360ml of H20 at atmospheric pressure. The reaction mixture was cooled to 25°C and water (720ml) was added within 30 minutes and 50% NaOH solution was added drop wise till pH was in range of 4.2 - 4.6. The reaction mixture was allowed to attain room temperature and isopropyl alcohol (880 ml) was added. Resulting reaction mixture was further cooled
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to 20°C and maintained for 12 hours. Product was filtered off and washed with isopropyl alcohol and the ibandronate sodium was dried at 50°C for 10 hours.
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.
Dated this 24th day of September 2008
Dated this 24* day of September 2008


To:
The Controller of Patents, Patent Office, Mumbai 400 037

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