FIELD OF THE INVENTION
The present invention relates to an industrially advantageous, economical and improved process for preparation of minodronic acid of formula I including salts and hydrates thereof.

Formula I

The present invention also provides a process for the preparation of key intermediates of minodronic acid in high yield and high purity.

BACKGROUND OF THE INVENTION
Minodronic acid of formula I, is a third-generation bisphosphonate drug for the treatment of osteoporosis, and is chemically known as (1-hydroxy-2-(imidazo[1,2-a]-pyridin-3-yl)ethylidene)bisphosphonic acid.

Formula I

The drug has been jointly developed by two Japanese companies, Ono Pharmaceutical Co. Ltd. and Astellas Pharma Inc; and marketed under the brand name RECALBON®/Bonoteo®.

Minodronic acid, as a product was first disclosed in US patent US4,990,503 wherein, minodronic acid is prepared from 2-(imidazo[1,2-a] pyridine-3-yl)acetic acid as shown below in scheme:

Minodronic acid is prepared by the reaction of 2-(imidazo[1,2-a]pyridine-3-yl) acetic acid with phosphorous acid in the presence of phosphorous trichloride in chlorobenzene,heated at 110ºC and after adding phosphorous trichloride, reaction mass is stirred for 8 hours and the obtained product i.e., minodronic acid is recrystallized from water-methanol. Further patent is silent about the preparation of intermediate 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid.

Several synthesis of minodronic acid have been reported in literature wherein 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid is used as a key intermediate. For example in US patent US7,038,083, 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid, phosphorous acid, halophosphorous compound is heated in the presence of diluents such as aromatic hydrocarbon or a silicone fluid. However preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid or minodronic acid is not exemplified. Similarly, US patents US7,361,761; US7,528,280; US7,872,144 disclose preparation of minodronic acid by reacting 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid with phosphorous acid in the presence of halophosphorous compound in different solvent system. Here too process for the preparation of 2-(imidazo[1,2-a]pyridine-3-yl) acetic acid is not disclosed.

In quest of preparing minodronic acid in high yield and high purity, emphasis is given on the preparation of highly pure key intermediates in fairly good yields. There exist few patents/publications which disclose the preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid which is a key intermediate of minodronic acid. An article, namely, Journal of Medicinal Chemistry 1969, 12(1), 122-126 discloses a process for the preparation of 3-imidazo[1,2-a] pyridine acetic acid starting from 3-dimethylaminomethyl-imidazo[1,2-a]pyridine methiodide. The process comprises cyanation of 3-dimethylaminomethyl-imidazo[1,2-a]pyridine methiodide using sodium cyanide, wherein trimethylamine and ammonia gas are collected separately, followed by subsequent hydrolysis of resulting compound and finally 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid is recrystallized from ethanol. The disclosure is silent about purity and product is isolated in 53% yield. In the given process, besides the low yield of 2-imidazo[1,2-a] pyridine acetic acid, use of poisonous material sodium cyanide, removal of poisonous gases and side reactions render the process unattractive. An alternate methodology to prepare several acids has also been disclosed, wherein 2-aminopyridine or 2-aminopicolines is reacted with methyl bromolevulinate and resulting ester is hydrolyzed to the corresponding acid. Although in this discloser, preparation of 2-(imidazo[1,2-a]pyridine-3-yl) acetic acid is not exemplified but another analog namely 2,7-dimethyl-3-carboxymethylimidazo[1,2-a]pyridine is exemplified from 2-amino-4-methyl pyridine and final compound is isolated in about less than 15% yield, which is very less.

A Chinese patent publication CN101531681A discloses a synthesis of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid, as represented below:

The process involves reaction of 2-aminopyridine with 3-bromo-4-oxo-ethylbutyrate to give 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid ethyl ester which upon hydrolysis gives 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid with yield in the range of 29-31 %. Further process to prepare 3-bromo-4-oxo-ethylbutyrate is also disclosed, starting from 4-chloro ethyl ester which undergoes reduction using lithium alkoxyaluminium hydride and the resulting compound is brominated at 3-position using bromine and trimethyl silane chlorine. Such a low yielding process with use of highly irritant and volatile reagents is not favorable to industrial scale production.

In one another Chinese patent publication CN101973993A, an alternate synthesis of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid is disclosed, as shown below.


In the disclosed process, 2-aminopyridine is condensed with 4-chloroacetoacetic ester in presence of triethylamine in dioxane and the resulting ester compound is hydrolyzed to give 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid. In exemplified process, 2-aminopyridine in dioxane is cooled to 0-5°C, followed by addition of triethylamine and thereafter 4-chloro acetoacetic ester is added slowly in 1.5 hours, after complete addition, temperature of reaction mixture was raised to 80°C and heated for further 20 hours. After workup and chromatographic purification, corresponding ester compound is obtained in 51% yield, which on further hydrolysis using sodium hydroxide in methanol gives 2-(imidazo[1,2-a]pyridine-3-yl) acetic acid in 55.4% yield. The said process suffers major drawbacks like heating for 20 hours, use of cumbersome column chromatographic purification and overall yield of just 28.25%.

The similar process for preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid is also reported in CN102153585A, wherein 4-chloro acetoacetic acid is condensed with 2-aminopyridine in presence of ethanol to obtain 2-(imidazo[1,2-a]pyridine-3-yl) acetic acid ethyl ester, which upon hydrolysis gives 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid. The yield of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid from corresponding 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid ethyl ester reported is more than theoretical yield and patent is silent about the purities of ester as well as acid compound. It leaves the assumption that in the claimed reaction conditions pure material is not obtained, since yield obtained is more than the calculated theoretical yield, which is not practical, and hence makes the process unattractive.

Further when the above reaction is repeated in our hands, it is observed that an regioisomeric impurity, 3-(imidazo[1,2-a]pyridine-3-yl)acetic acid forms as a major product and this impurity can not be separated from desired isomer by simple purification and needs chromatographic purification. Said impurity cannot be converted to desired compound i.e., minodronic acid.

Another Chinese patent publication CN101812062A, discloses a process for the preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid employing reaction of 2-aminopyridine with 4-oxo-but-2-enoic acid ethyl ester as represented below:

In exemplified processes, a solution of 2-aminopyridine in a suitable solvent like ethanol or dioxane is cooled, and 4-oxo-but-2-enoic acid ethyl ester is added dropwise and the temperature is maintained to -5ºC, thereafter temperature of reaction mass is raised to 70-80ºC and maintained for further 2.5 hours. After work up, the resulting ester product is hydrolyzed using caustic soda in ethanol and after work up produces 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid, which is further purified using alcoholic solvents. The reported yields of crude compound are between 47.3-54.5% which further decreased upon crystallization to an overall yield in the range of 26-43%. Such a low yield is not worth for commercial scale and makes the process unattractive from cost point of view.

A very similar process is disclosed in another Chinese patent publication CN102344463A, wherein 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid ethyl ester is prepared by reaction of 2-aminopyridine with 4-oxo-but-2-enoic acid ethyl ester in acetonitrile at reflux temperature for a period of 5-6 hours. Thereafter, solvent is distilled out completely from reaction mass. The resulting ester is isolated in 50% yield after work up and purification from petroleum ether. The resulting ester upon alkaline hydrolysis using 10% caustic soda solution produces 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid in 95% yield, leading to an overall yield of 47.5%. Major drawback of this process is refluxing for longer hours during condensation step and distillation of solvent from reaction mass, which may lead to decomposition and results in low yields.

US patent US 7,405,305 also discloses similar process for preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid ethyl ester by reacting 2-aminopyridine and 4-oxo-but-2-enoic acid ethyl ester. In exemplified process, a reaction mixture containing 2-aminopyridine and 4-oxo-but-2-enoic acid ethyl ester in acetonitrile is heated at 80ºC for 6 hours. Thereafter, solvent is removed under reduced pressure and the resulting oily product is purified using flash chromatography which gives impure corresponding ester as brown solid containing 2-aminopyridine in 50% yield. Further, the patent does not disclose conversion of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid ethyl ester to 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid.

It is clear from reported literature that 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid is generally isolated in low yield of about 26% to 47.5% with no revelation of purity of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid. The said low yield leads to overall poor yield of final compound i.e., minodronic acid, which is not acceptable for industrial production due to cost burden. In view of the above, there exists a need for an improved process for preparing 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid which results in better yield along with high purity. Therefore, present invention fulfill the need in the art and provides an cost effective and commercially viable process for preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid in high yield and high purity.

OBJECTIVES OF THE INVENTION
It is the foremost objective of the present invention to provide industrially advantageous, economical and improved process for preparation of minodronic acid including salts and hydrates thereof.
Another objective of the present invention is to provide a process for the preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester.
Another objective of the present invention is to provide a process for the preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid in high yield and high purity.
Another objective of the present invention is to provide a process for the conversion of these intermediates into minodronic acid.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to an industrially advantageous, economical and improved process for the preparation of minodronic acid of formula I including salts and hydrates thereof,

Formula I

using intermediates such as 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid of compound of formula II

Formula II
and 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester of compound of formula III.

Formula III
wherein R is C1-C4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl etc.
According to one embodiment, the present invention provides a process for preparation of minodronic acid of formula I including salts and hydrates thereof, comprising the steps of;
a). heating 2-aminopyridine with 4-oxo-but-2-enoic acid alkyl ester of formula IV

Formula IV

wherein R is C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl etc.
in presence of a suitable solvent and at a suitable temperature to obtain 2-(imidazo[1,2-a] -pyridine-3-yl)acetic acid alkyl ester of compound of formula III;

Formula III
wherein R is C1-C4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl etc.
b). hydrolyzing the resulting 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester compound of formula III with a suitable hydrolyzing agent to obtain 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid of compound of formula II;

Formula II
c). phosphorylating 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid of compound of formula II in suitable solvent to obtain minodronic acid of compound of formula I.

Formula I

According to another embodiment, the present invention provides a process for preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid of compound of formula II, comprising the steps of:
a). adding slowly a solution of 4-oxo-but-2-enoic acid alkyl ester of formula IV

Formula IV

wherein R is C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl etc.
to a hot solution of 2-aminopyridine,
b). heating the reaction mass for sufficient time at suitable temperature to prepare 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester of formula III;
c). optionally isolating 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester of formula III;
d). adding alkali hydroxide to 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester of formula III in a suitable solvent;
e). refluxing the reaction mass for sufficient time;
f). adjusting the pH of reaction mass to 4-6 using a suitable acid; and
g). isolating pure 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid of compound of formula II.
According to one other embodiment, the present invention provides 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid of compound of formula II having purity greater than 98.5 % by HPLC, in more than 80% overall yield.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to an industrially advantageous, economical and improved process for preparation of minodronic acid of formula I including salts and hydrates thereof. Particularly the present invention provides an improved process for preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid with high purity and high yield.

2-(Imidazo[1,2-a]pyridine-3-yl)acetic acid is prepared by condensation of 2-aminopyridine with 4-oxo-but-2-enoic acid alkyl ester, followed by hydrolysis of resulting ester.

Accordingly, the process comprises heating a solution of 2-aminopyridine in suitable solvent at suitable temperature, slowly adding a solution of 4-oxo-but-2-enoic acid alkyl ester in hot reaction mixture and further heating the reaction mass for sufficient time at a suitable temperature. The completion of reaction can be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-high pressure liquid chromatography (UPLC), and the like.

The suitable solvent used for the nucleophilic addition reaction can be selected from the class of solvents viz; nitrile such as acetonitrile, propionitrile, butryronitrile or like; alcohols such as methanol, ethanol, propanol, isopropanol or like; ethers such as tetrahydrofuran, 2-methyl ether, 1,2-dimethyl ether, 1,2-diethyl ether or like; aprotic solvent such as dimethyl formamide, dimethyl acetamide, dimethylsulfoxide or like or mixtures thereof. The suitable temperature for heating can be varied form 60 to 100ºC and preferably 65-80ºC. The heating time depends on nature of solvent used and till the completion of reaction. Preferably heating time may not be more than 90 minutes and more preferably the reaction can be completed in 60 minutes and most preferably reaction can be completed in less than 60 minutes. In a preferred specific embodiment of invention, a solution of 2-aminopyridine in an organic solvent such as acetonitrile is heated to 65-80ºC and a solution of 4-oxo-but-2-enoic acid ethyl ester in suitable solvent is slowly added to hot 2-aminopyridine solution, and reaction is completed in about 45 minutes.

Generally, after completion of reaction, the resulting ester intermediate of formula III can be isolated from the reaction mixture using suitable techniques known in the art. For the purpose of present invention, the resulting compound of formula III can be isolated from the reaction mixture by generation of biphasic system in reaction mixture. Preferably reaction mass is cooled to ambient temperature and diluted with a water immiscible organic solvent followed by addition of brine solution to facilitate the separation of layers. After layer separation, organic layer can optionally be washed with brine solution, water and can be dried over using a suitable drying agent such as sodium sulphate or like.The water immiscible organic solvent can be selected from halogenated solvents such as dichloromethane, chloroform or like; aliphatic ester such as ethyl acetate, propyl acetate or like; aliphatic ethers such as diethyl ether, diisopropylether, methyl tertiary butyl ether or like; hydrocarbons such as pentane, hexane, heptane, benzene, toluene, xylene or like or mixtures thereof.

The organic layer containing desired ester compound can be concentrated by any known technique such as evaporation, distillation or like to isolate the desired compound of formula III i.e., 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester.

It is observed by the inventors of present invention that when 4-oxo-but-2-enoic acid alkyl ester is added to 2-aminopyridine solution at temperature lower than 50oC or in one lot then a large amount of unreacted 2-aminopyridine is left in reaction mass while consuming all the 4-oxo-but-2-enoic acid alkyl ester, which leads to impure product with low yield. It is advantageous to add slowly a solution of 4-oxo-but-2-enoic acid alkyl ester to a hot solution of 2-aminopyridine, preferably temperature above 60°C.

The slow addition of a solution of 4-oxo-but-2-enoic acid alkyl ester in a hot solution of 2-aminopyridine is not only ensures the complete consumption of 2-aminopyridine to form the imine intermediate, but also facilitate the intramolecular cyclization via the attack of pyridine nitrogen atom in the 1,4-position of the a, ß unsaturated moiety, followed by rearrangement to generates the desired, 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester.

On the other hand, at temperatures, below 50ºC, although the imine intermediate is formed, it does not undergo further 1,4-attack on the imine ester functionality of the intermediate to form the desired cyclized product. Rather, it probably undergoes attack of the insitu generated water and dissociates to form back the starting materials, 2-amino pyridine and 4-oxo-but-2-enoic acid alkyl ester, thereby showing the presence of unreacted 2-aminopyridine in the reaction mass in large amounts. Contrary to above, by using the present set of reaction conditions, a pure compound i.e., 2-imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester is prepared in high yields, which inturn can be converted to pure and high yielding 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid which is an key intermediate for the preparation of minodronic acid.

In a preferred embodiment of the present invention, the ester compound of formula III i.e., 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester can be obtained in high yield and high purity and can be converted insitu to compound of formula II i.e., 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid. Alkyl ester can preferably be selected from C1-C4 ester namely methyl, ethyl, propyl, isopropyl, butyl, isobutyl or like. In a specific embodiment, ester compound of formula III i.e., 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid ethyl ester is prepared having purity of greater than 90% by HPLC and in greater than 88% yield. The ester compound of formula III as such is carry forward to the next stage without further purification, leading to acid compound of formula II.

For the purpose of the invention 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester of compound of formula III can be hydrolyzed by methods known in the art such as acidic or basic hydrolysis conditions. Generally, the acidic hydrolysis can be carried out using an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, or like; organic acid such as methane or ethane sulphonic acid, formic acid, acetic acid, trifluoroacetic acid or like; and/or basic hydrolysis can be carried out using inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, or like.

In a preferred embodiment, 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester of compound of formula III is hydrolyzed by basic hydrolysis. Basic hydrolysis can be carried out in a suitable solvent for providing the reaction media and can be selected from water, C1-C4 alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol or like; alkyl nitrile such as acetonitrile, propionitrile, butyronitrile or like; ethers such as tetrahydrofuran, 1,2-dimethyl ether, 1,4-diethyl ether or the like or mixtures thereof. Usually hydrolysis can be carried out at a temperature of 0ºC to 80ºC for a period of 30 minutes to 10 hours. In a general course of reaction, after the completion of hydrolysis reaction, reaction mass is neutralized to isolate desired acid compound. In case of base assisted hydrolysis the reaction mass is acidified to obtain the compound of formula II. The acid used can be selected from hydrochloric acid, sulfuric acid, acetic acid or like.

Acid compound of formula II can be isolated from the reaction mixture by a suitable technique such as filtration or centrifugation or like. The resulting product can optionally be purified using a suitable solvent system. The solvent selected at this stage can be C1-C4 alcohol such as methanol, ethanol, isopropyl alcohol, n-butanol or like; water, C1-C4 alkyl nitrile such as acetonitrile, propionitrile, butyronitrile or like; aliphatic ester such as ethyl acetate, 2-ethyl acetate or like; ethers such as isopropyl ether, methyl tertiary butyl ether or the like or mixtures thereof. Although, the crystallized product, optionally, can be purified or can be directly used for the next stage for the preparation of minodronic acid.

2-(Imidazo[1,2-a]pyridine-3-yl)acetic acid of formula II, obtained by above process is highly pure and having purity greater than 98.5% when analyzed by HPLC and isolated in high overall yields of more than 80% from starting compound.

The starting materials, 2-aminopyridine and 4-oxo-but-2-enoic acid alkyl ester compound used in present invention can be prepared by methods known in the prior art or procured from commercial source.

The compound of formula II i.e., 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid can be converted to minodronic acid by methods known in the art or the methods as described herein. Preferably the minodronic acid is prepared by reacting compound of formula II with phosphorous acid in the presence of phosphorous halide in a suitable solvent. In a preferred embodiment, 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid of compound of formula II is reacted with phosphorous acid in the presence of phosphorous halide, in a water miscible neutral solvent such as nitrile solvent, like acetonitrile at temperature 40-80ºC, preferably 70-75ºC till phosphorylation is complete, preferably for a period of about 1-12 hours. The phosphorous halide can be selected from the group comprising phosphorous trichloride, phosphorous tribromide, phosphorous pentachloride, phosphorous pentabromide, phosphorous oxychloride, phosphorous oxybromide or the like. After completion of reaction, optionally solvent is distilled off and the reaction mixture is cooled and quenched with demineralized water. The resulting solid, can be isolated from the reaction mixture by a suitable techniques such as filtration or centrifugation or like.

The resulting wet crude product i.e., minodronic acid, thus prepared, can be optionally purified using acid base treatment. Particularly the wet solid is treated with base to adjust pH above seven, optionally the resultant reaction mass is charcolized to decolorize the reaction mass and further treated with mineral acid to bring pH at 1-2.

The base used can be selected from alkali hydroxides, carbonates or bicarbonates preferably alkali metal hydroxides such as sodium hydroxides, potassium hydroxides or like are used. The mineral acid can be selected from the inorganic acids such as hydrochloric acid or like.

The above purification process can be repeated, if required to get the product of desired purity. After achieving the product of desired purity greater than 99%, minodronic acid is converted to minodronic acid monohydrate by the method known in the art.

In a preferred embodiment of invention, the resulting minodronic acid is dissolved in hydrochloric acid by heating it to reflux temperature for a sufficient time till the complete dissolution of minodronic acid. The reaction mass is charcolized, and filtered using hyflo and the bed is washed with hydrochloric acid. The obtained filtrate is cooled at ambient temperature and stirred for 1-6 hours. The solid, thus formed, is filtered, washed with demineralized water or alcohol or mixtures thereof, preferably alcohol is selected from methanol or ethanol, and finally the product is dried at suitable temperature to obtain pure minodronic acid monohydrate. Minodronic acid monohydrate, prepared by using present invention is highly pure having purity greater than 99.5%, more preferably greater than 99.8%, most preferably greater than 99.9%.

It is not the limitations of present invention to use these intermediates for the preparation of minodronic acid only, the process as presented in present invention can be suitably accommodate to prepare the equivalent intermediates used in various bisphosphonic acids.

In another aspect of invention, the compound obtained by following the above process can suitably be formulated to provide a pharmaceutical composition and which is further provided by the present invention a pharmaceutical composition comprising minodronic acid including salts and hydrates thereof.

The main advantage of the present invention is that it provide an industrially advantageous, economical and reproducible process for the preparation of minodronic acid via improved process of key intermediate 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid, which is prepared in high yield of greater than 80% and high purity of greater than 98.5%, and the reaction time is also reduced by six fold as per the reaction parameters set out in present invention.
EXAMPLES:
Example 1: Preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid ethyl ester
To a refluxing solution of 2-aminopyridine (100.0 g) in acetonitrile (200.0 ml) at 75-80oC, 4-oxo-but-2-enoic acid ethyl ester (135.0g) in acetonitrile (100.0 ml) was slowly added and the reaction mass was continued to reflux for further 45 minutes. After completion of reaction, the reaction mass was cooled to 25-30oC and to this, saturated aqueous sodium chloride solution (550.0 ml) and ethyl acetate (450.0 ml) were successively added. The layers were separated and the organic layer was then washed with 10% sodium chloride solution (2 x 550 ml). Combined aqueous layer was extracted with ethyl acetate (300.0 ml) and then the combined organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain 195 g of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid ethyl ester having purity 91.23%, this was advanced to the next step without isolation.

Example 2: Preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid
2-(Imidazo[1,2-a]pyridine-3-yl)acetic acid ethyl ester, as obtained above, was taken in methanol (400.0 ml) and potassium hydroxides pellets (55.0g) and activated carbon (10.0g) were added to it and the reaction mass was heated to 70-75oC and reflux for 1 hour. After completion of reaction, [monitored by HPLC], the hot reaction mass was filtered through hyflo bed and the bed was washed with a mixture of methanol (200.0ml) and water (50.0ml). The reaction mass was cooled to 0-10oC and pH was adjusted to 4-6 with hydrochloric acid and stirred for 60 minutes at 0-10oC. The product, thus crystallized, was filtered, washed with chilled methanol (100.0ml) and methyl tertiary butyl ether (100.0ml) and dried to afford 152 g of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid [81.28% yield] having purity 98.68% by HPLC.

Example 3: Preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid ethyl ester
To a refluxing solution of 2-aminopyridine (100.0 g) in acetonitrile (200.0 ml) at 75-80oC, 4-oxo-but-2-enoic acid ethyl ester (135.0g) in acetonitrile (100.0 ml) was slowly added and the reaction mass was continued to reflux for further 45 minutes. After completion of reaction, the reaction mass was cooled to 25-30oC and to this, saturated aqueous sodium chloride solution (600.0 ml) and ethyl acetate (450.0 ml) were successively added. The layers were separated and the organic layer was then washed with 10% sodium chloride solution (2 x 600 ml). Combined aqueous layer was extracted with ethyl acetate (300.0 ml) and then the combined organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain 193 g of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid ethyl ester having purity 92.15%, which was advanced to the next step without isolation.

Example 4: Preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid
2-(Imidazo[1,2-a]pyridine-3-yl)acetic acid ethyl ester, as obtained above, was taken in methanol (400.0 ml) and potassium hydroxides pellets (55.0g) and activated carbon (10.0g) were added to it and the reaction mass was heated to 70-75oC and reflux for 1 hour. After completion of reaction, [monitored by HPLC], the hot reaction mass was filtered through hyflo bed and the bed was washed with a mixture of methanol (200.0ml) and water (50.0ml). The reaction mass was cooled to 0-10oC and pH was adjusted to 4-6 with hydrochloric acid and stirred for 60 minutes at 0-10oC. The product, thus crystallized, was filtered, washed with chilled methanol (100.0ml) and methyl tertiary butyl ether (100.0ml) and dried to afford 150 g of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid [80.20% yield] having purity 99.66% by HPLC.

Example 5: Preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid
To a refluxing solution of 2-aminopyridine (100.0g) in ethanol (700.0ml), a solution of ethyl trans-4-oxo-2-butenoate (136g) in ethanol (100.0ml) was slowly added and the reaction mass was continue to reflux for further 45 minutes. After completion of reaction [checked by UPLC], a solution of potassium hydroxides (77.0g) in water (100.0ml) was added slowly at reflux temperature and the reaction mass was further refluxed for 1 hour. After completion of reaction, the reaction mass was cooled to room temperature and water (500.0ml) was added. The pH of reaction mass was adjusted to 5.0-6.0 with hydrochloric acid and further cooled to 0-5oC and stirred for 60 minutes at 0-5oC. The crystallized product was filtered, washed with ethanol (200.0 ml) and then washed with methyl tertiary butyl ether (200.0ml) and dried at 60-65oC to afford 182g of 2-(imidazo[1,2-a]pyridine-3-yl) acetic acid (97% yield) having purity 99.07% by HPLC.

Example 6: Preparation of minodronic acid
To a refluxing solution of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid (150.0g) in acetonitrile (1500.0ml) and phosphorous acid (167.58g); phosphorous trichloride (315.69g) was slowly added and the reaction mass was further refluxed for 8 hours. After completion of reaction, [monitored by HPLC], solvent was distilled off under reduced pressure and demineralized water (900.0ml) was added and the reaction mass was stirred at reflux temperature for further 12 hours. Thereafter, reaction mass was cooled to 25-30oC and stirred for 2 hours, filtered, washed with demineralized water (900.0ml). The resulting solid was further taken in demineralized water (600.0ml) and 33% aqueous sodium hydroxide solution was slowly added to reaction mass to adjust the pH 10.0-11.0. After complete dissolution, activated charcoal (22.5g) was added, stirred for 30 minutes at 50-60oC, filtered through hyflo and washed with demineralized water (600ml).The filtrate was acidified using hydrochloric acid to adjust pH 1-2. The reaction mass was cooled to 0-5oC and stirred for 1.0 hour. The product, thus crystallized, was filtered, washed with demineralized water (600 ml) and dried at 50-60oC to afford title compound having purity 99.90% by HPLC.

Example 7: Preparation of minodronic acid monohydrate
Minodronic acid (86.0g), and 1N hydrochloric acid (2580.0ml) were heated to reflux temperature till all the solid dissolved. After complete dissolution, activated charcoal (8.60g) was added and the reaction mass was further refluxed for 30 minutes. The hot reaction mass was filtered through hyflo and the bed was washed with 1N hydrochloric acid (860.0ml). The filtrate was further stirred at reflux temperature for 30 minutes. The reaction mass was cooled to 20-30oC and stirred for 5 hours. The crystallized product was filtered, washed with demineralized water (215ml) and ethanol (215ml). The solid was suck dried for 15 minutes and finally dried at 50-60oC under reduced pressure for 16 hours to afford pure minodronic acid monohydrate having purity 99.94% by HPLC.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

,CLAIMS:We Claim,

1. A process for preparation of minodronic acid of formula I and salts and hydrates thereof comprises;
a) adding slowly a solution of 4-oxo-but-2-enoic acid alkyl ester of formula IV;

Formula IV

wherein R is C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl etc.
to a hot solution of 2-aminopyridine;
b) heating the reaction mass for sufficient time at suitable temperature to prepare 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester of formula III;

Formula III
c) optionally isolating 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester of formula III;
d) adding alkali hydroxide to 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester of formula III in a suitable solvent;
e) refluxing the reaction mass for sufficient time;
f) adjusting the pH of reaction mass to 4-6 using a suitable acid;
g) isolating pure 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid of compound of formula II.

Formula II

h) phosphorylating 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid of compound of formula II in suitable solvent to obtain minodronic acid of compound of formula I;

Formula I
i) optionally purifying minodronic acid using acid-base treatment; and
j) optionally converting minodronic acid to minodronic acid monohydrate.

2. The process as claimed in claim 1, wherein in step a) solvent is selected from the class of solvents such as nitrile; alcohol; ether; aprotic solvent such as dimethyl formamide, dimethyl acetamide, dimethylsulfoxide or mixtures thereof .
3. The process as claimed in claim 1, wherein in step a) addition time is selected from 30-90 minutes preferably 30-60 minutes.
4. The process as claimed in claim 1, wherein in steps a) and b) temperature is selected from 60-100oC preferably 65-80oC.
5. The process as claimed in claim 1, wherein in step d) alkali hydroxides is selected from sodium hydroxides, potassium hydroxide or lithium hydroxide; solvent is selected from water, C1-C4 alcohols; alkyl nitrile; ethers; or mixtures thereof.
6. A process for preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid of compound of formula II, comprises:
a) adding slowly a solution of 4-oxo-but-2-enoic acid alkyl ester of formula IV

Formula IV

wherein R is C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl etc.
to a hot solution of 2-aminopyridine,
b) heating the reaction mass for sufficient time at suitable temperature to prepare 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester of formula III;
c) optionally isolating 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester of formula III;
d) adding alkali hydroxide to 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid alkyl ester of formula III in a suitable solvent;
e) refluxing the reaction mass for sufficient time;
f) adjusting the pH of reaction mass to 4-6 using a suitable acid; and
g) isolating pure 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid of compound of formula II.
7. The process as claimed in claim 6, wherein in step a) solvent is selected from the class of solvents such as nitrile; alcohol; ether; aprotic solvent such as dimethyl formamide, dimethyl acetamide, dimethylsulfoxide or mixtures thereof .
8. The process as claimed in claim 6, wherein in step a) addition time is selected from 30-90 minutes preferably 30-60 minutes and in steps a) and b) temperature is selected from 60-100oC preferably 65-80oC.
9. The process as claimed in claim 6, wherein in step d) alkali hydroxides is selected from sodium hydroxides, potassium hydroxide or lithium hydroxide; solvent is selected from water, C1-C4 alcohols; alkyl nitrile; ethers; or mixtures thereof.
10. A process comprises of converting pure 2-(imidazo[1,2-a]pyridine-3-yl) acetic acid of compound of formula II, prepared as claimed in claim 6, to minodronic acid of formula I