FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
PROVISIONAL SPECIFICATION
(See section 10; rule 13)

1. Title of the invention.

NOVEL PROCESS FOR MANUFACTURING RISEDRONIC ACID

2. Applicant(s)
(a) NAME :
(b) NATIONALITY:
(c) ADDRESS :

Alkem Laboratories Limited
Indian.
Alkem House, "Devashish", Senapati Bapat Marg, Lower parel, Mumbai-400013

3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Field of invention:
The present invention relates to a process for manufacturing Risedronic acid, also known as [l-hydroxy-2-(3-pyridinyl) ethylidene] bisphosphonic acid and its pharmaceutically acceptable salt. In particular it relates to a process for manufacturing Risedronic acid, which is useful in the treatment of osteoporosis and Paget disease.
Background of the invention:
Risedronic acid belonging to bisphosphonate family, is chemically known as [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid and has the general structure represented by Formula (I). Its monosodium salt i.e. sodium Risedronate having general structure represented by Formula (II) is marketed under brand name Actonel®. It is useful in the treatment of osteoporosis and Paget disease. It is also used in the treatment of postmenopausal osteoporosis and particularly used to reduce the risk of vertebral body fracture and femoral neck fracture. Another known use is for treating women and men with osteoporosis resulting from the use of long-term steroid medications or for preventing osteoporosis related steroid use.
° OH

Formula -I
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Formula-II
The synthesis of Risedronic acid was first disclosed in EPO186405 involving the reaction of 3-pyridyl acetic acid with phosphorous acid along with phosphorous chloride using chlorobenzene as diluent. The diluent is removed from the reaction mass by decantation followed by isolation of product. But this operation is not feasible on plant scale and yield is also low (52%).
US4407761 discloses a process for manufacturing bisphosphonic acids from aminocarboxylic acid and phosphonating reactant in presence of halogenated hydrocarbons as diluents. But use of halogenated hydrocarbons has many disadvantages such as solidification; reactor fouling; and making process non-amenable to large scale.
US4922007 also discloses a similar process for preparing bisphosphonic acid using methanesulfoic acid as diluent, which solublizes reaction product and keep reaction fluid up to completion of reaction; and eliminates the problems with physical characterization of reaction. But this process also suffers from disadvantages such as exothermic reaction.
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US 7038083 discloses a process for preparing bisphosphonic acid derivatives including Risedronic acid comprising the steps of condensation of (3-pyridyl)ethanoic acid or its hydrochloride with phosphorous acid and halophosphorus acid in presence of toluene as diluent and orthophosphoric acid as co-diluent; hydrolysis and then precipitation. It is well known that toluene contains traces of benzene which is class-I solvent having the limit of 2 ppm as per ICH. It is practically quite difficult and troublesome to control benzene at this level.
The literature survey reveals that several diluents e.g. fluorobenzene, diphenyl oxide, methane sulphonic acid, methane sulphonic anhydride, sulpholane and the like have been used by different innovators, but in all the case yield is low as well as process operations are not feasible on plant scale.
Thus the prior art processes for Risedronic acid has the disadvantages in using aromatic hydrocarbon e.g. toluene or chlorinated aromatic hydrocarbon like chlorobenzene as solvent. Hence there is a need for a process for preparing bisphosphonic acids, particularly to Risedronic acid or its salt, which avoids the use of aromatic hydrocarbons as diluent. The present invention surprisingly provides a solution to these problems by using aliphatic cyclic hydrocarbons as diluents along with orthophosphoric acid as co-diluent. It was found by the present inventors that the use of aliphatic cyclic hydrocarbons along with orthophosphoric acid provides a process which is cost-effective and can be commercialized on a large scale with no disadvantages of solidification and reactor fouling.
OBJECT OF INVENTION
The basic object of the present invention is to provide a novel, cost effective and commercial viable process for the preparation of Risedronic Acid.
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Further object of the present invention is to provide a novel process for manufacturing Risedronic acid, which is useful in the treatment of osteoporosis and Paget disease.
Another object of the present invention is to provide a novel process for manufacturing Risedronic acid eliminating the use of aromatic hydrocarbon.
Yet another object of the present invention is to provide a novel process for manufacturing Risedronic acid, where the process is free from problems such as solidification, reactor fouling and exothermic reaction.
Summary of the invention:
According to an aspect of the present invention is provided a novel process for the preparation of Risedronic Acid of formula (I).

Formula (I)
According to another aspect is provided a process for preparing of Risedronic acid comprising the steps as follows:
a) preparing hydrochloride salt of 3-pyridyl acetic acid;
b) reacting said 3-pyridyl acetic acid hydrochloride with phosphorus acid and phosphorus oxychloride in an organic solvent to form a reaction mixture;
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c) hydrolyzing said mixture;
d) adding an alcohol to said reaction mixture to precipitate Risedronic acid.
Detailed description of the invention:
The present invention provides a novel and commercially viable industrial process for the preparation of Risedronic Acid ([l-hydroxy-2(3-pyridyl) ethylidene] Bisphosphonic acid).
The process for preparing Risedronic acid comprises the steps as follows:
a) preparing hydrochloride salt of 3-pyridyl acetic acid;
b) reacting said 3-pyridyl acetic acid hydrochloride with phosphorus acid and phosphorus oxychloride in an organic solvent;
c) hydrolyzing said mixture;
d) adding an alcohol to said reaction mixture to precipitate Risedronic acid.
The hydrochloride salt of 3-pyridyl acetic acid was formed by reacting 3-pyridyl acetic acid in toluene with aqueous solution of hydrochloric acid at a temperature range of 30-40°C for around 60 minutes.
The above process further involves purification of the hydrochloride salt of 3-pyridyl acetic acid before subjecting to step b).
The organic solvent used in the step b) is a mixture of an aliphatic cyclic hydrocarbon and orthophosphoric acid, wherein the aliphatic cyclic hydrocarbon is selected from the group consisting of cyclohexane, trans-dimethyl cyclohexane, cis-dimethyl cyclohexanes, decalin and the mixture thereof, preferably methyl cyclohexane.
Step b) in the above said process comprises heating the mixture of 3-pyridyl acetic acid hydrochloride with phosphoric acid in methyl cyclohexane at 80-100°C , most
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preferably at 90-95°C temperature; followed by addition of phosphorus oxychloride. Then the reaction mass is heated at a temperature range of 90-100° C, most preferably at 95°C; followed by addition of water.
The process further involves separation of organic and aqueous layers; heating the aqueous layer containing the product at a temperature of 90-100°C for 4-6 hrs, most preferably 95°C temperature for hydrolysis.
The process further involves isolating the crystalline Risedronic acid monohydrate by adding an alcohol. The preferred alcohol used is isopropyl alcohol and the product is obtained in 70% yield.
The present invention is illustrated by the following examples, but which not limit of the invention is as defined in the claims.
Example
1. Preparation of 3-Pyridyl acetic acid hydrochloride Salt:
100 gm 3-pyridyl acetic acid was dissolved in 250 ml toluene and 133 gm 30% aq solution of hydrochloric acid was added at 30-40°C temperature in 60 minutes. After completion of addition of hydrochloric acid, the temperature of reaction mass was raised to 90-95°C and the temperature was maintain for 4-6 hrs with continuous removal of water azeotropically. After complete removal of water, the reaction mass was cooled to room temperature (25-30° C) and the solid was collected by filtration under nitrogen atmosphere followed by washing with 633 ml petroleum ether. The obtained cake was dried under vacuum at 30-40° C. 120 gm of dried 3-Pyridyl acetic acid hydrochloride is obtained.
2. Purification of 3-Pyridyl acetic acid hydrochloride:
The obtained 3-Pyridyl acetic acid. Hydrochloride salt (120 gm) was suspended in 300ml ethyl acetate and the reaction mass was heated to 75-80 ° C for 1 hr. The
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reaction mass was cooled to 28-30° C & the product was collected by filtration under nitrogen atmosphere followed by washing with 2x20 ml ethyl acetate. The obtained cake was dried under vacuum at 30-40° C temperature giving 108 gm pure 3-Pyridyl acetic acid Hydrochloride.
3. Preparation of Risedronic Acid:
100 gm 3-Pyridyl acetic acid hydrochloride in 500 ml methyl cyclohexane and l42 gm phosphorous acid and water was removed by azeotropically. Then 170 gm orthophosphoric acid was added. The reaction mass was further heated and water was removed azeotropically. After cooling to 90-92°C, 162 ml phosphorous oxy chloride was added in 30 min. Then temperature was raised to 95°C and maintained for 20 hrs. After 20 hrs, 720 ml water was added in reaction mass and the reaction mass was heated for 30 min. Methyl cyclohexane layer was separated. The obtained aqueous layer was heated at 95°C for 5-6 hrs. The reaction mass was cooled to 25-30°C temperature &144 ml isopropyl alcohol was added slowly in 30-45 min. Then again reaction mass was cooled to 5°C temperature and same was maintained for 1 hr. The product was collected by filtration was washed with 100 ml chilled IPA. The obtained wet cake was dried at 65-70°C temperature to get 120 gm Risedronic acid monohydrate.

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Abstract
A novel process for preparing Risedronic acid, useful for treating osteoporosis and Paget diseases. The steps comprise of reacting 3-pyridyl acetic acid with phosphorus acid and phosphorus oxychloride in aliphatic cyclic hydrocarbon and orthophosphoric acid; followed by hydrolysis to obtain Risedronic acid.
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