FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"A PROCESS FOR THE PREPARATION OF HIGHLY PURE RUPATADINE AND ITS INTERMEDIATE"
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad-380015, Gujarat, India.
The following specification describes the invention:


A PROCESS FOR THE PREPARATION OF HIGHLY PURE RUPATADINE AND ITS INTERMEDIATE.
Field of the Invention
The present invention relates to the process for preparing Rupatadine or a
pharmaceutical acceptable salts. More, particularly, the present invention relates to the intermediate compounds of formula (III), wherein R represents C1-C4 alkyl, substituted or unsubstituted aryl; and its process for preparation, as well as the process of preparation of Rupatadine. Rupatadine is chemically known as 8-Chloro-6,ll-dihydro-ll-(l-((5-methyl-3-pyridyl)methyl)-4-piperidylidene)-5H-benzo(5,6)cyclohepta(l,2-b)pyridine and represented by formula (I)

Background and Prior art
Allergic rhinitis (AR) is a global health concern and shares a high comorbidity with asthma. Recent research suggests that different allergic diseases, such as AR, asthma, allergic conjunctivitis and chronic idiopathic urticaria (CIU), are evoked by common pathological mechanisms characterised by the release of histamine and other inflammatory mediators.
Rupatadine is useful for the management of diseases with allergic inflammatory conditions, such as seasonal and perennial rhinitis. The pharmacological profile of rupatadine offers particular benefits in terms of a strong antagonist activity towards both histamine HI receptors and platelet-activating factor (PAF) receptors. Rupatadine has a rapid onset of action, and its long-lasting effect permits once-daily dosing. Rupatadine is clinically effective in relieving symptoms in patients with seasonal and perennial allergic rhinitis.
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The process for the preparation of Rupatadine is disclosed in US patent no. 5,407,941. Accordingly, 3,5-lutidine is treated with N-bromosucccinimide to yield 3-bomomethyl-5-methyl pyridine, which is condensed with 8-chloro-ll-(4-piperidyliden)-6,ll-dihydro-5H-benzo[5,6]cyclohepta [l,2-b]pyridine of formula (II) in presence of 4-(dimethylamino)pyridine and triethyl amine in carbon tetrachloride to give Rupatadine, which is isolated by column chromatography and depicted in below Scheme -1

However, the said process requires column chromatography and usage of carbon tetrachloride as solvent, which is not advisable to use for commercial production. Moreover, it is low yielding as only gives 40% yields.
ES 2087818 discloses two approaches for the preparation of Rupatadine and its fumarate salts, according to the process, hydrolytic removal of the N-ethoxycarbonyl group of Loratadine to give compound of formula (II) which is N-acylated with 5-methylnicotinic acid using DCC and HOBT to give Rupatadine or 5-methylnicotinic acid is chlorinated with POCI3 and subsequently condensed with formula (II) is to give compound of formula (V), which upon reduction by using NaBH4 gives Rupatadine as shown in below Scheme -2.
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However, the processes are not easy and cost effective because of the below mentioned reasons:
a) the process requires commercially limited available and costly raw materials such as 1,3-dicyclohexylcabodiimide (DCC) and 1-hydroxybenzotriazole hydrate (HOBT).
b) the process generates lot of effluent waste such as dicyclohexyl urea and hence is not eco-friendly.
c) dicyclohexyl urea generated during the reaction cannot be easily removed during the work up at large scale and repeated purification of crude and impure N-(5-methylnicotinoyl)4-hydroxy piperidine leads to overall loss of yield and makes this process less economically viable.
Therefore, there is a need to have easy and simple process for the preparation of Rupatadine, which devoid of costlier material and does not involve tedious column chromatography technique.
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Objects of the Invention
It is an object of the present invention to provide a process for the preparation of Rupatadine.
It is another object of the invention to provide novel intermediates for the preparation of Rupatadine.
Yet another object of the invention is to provide substantially pure Rupatadine fumarate.
Still another object of the invention is to provide a process for the preparation of substantially pure Rupatadine fumarate.
Description of the Invention
According to the first aspect of the present invention, there is provided a process for
the preparation of Rupatadine of formula (I) or its pharmaceutically acceptable salts, which
comprises condensing 8-chloro-11 -(4-piperidyliden)-6,11 -dihydro-5H-benzo[5,6]
cyclohepta[l,2-b]pyridine of formula (II) with compound of formula (III), wherein R represents C1-C4 alkly, substituted or unsubstituted aryl to give Rupatadine of formula (I), optionally converting in to its pharmaceutically acceptable salts thereof.

In the preferred embodiment of the present invention, in the above-mentioned formula (III), R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, benzyl or tolyl. Preferably, it is methyl or tolyl.
According to the embodiment of the present invention, condensation of compound of formula (II) with compound of formula (III) is carried out in presence of base. Base is selected from the organic or inorganic base such as methyl amine, triethylamine, DBB, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide.
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According to the embodiment of the present invention, condensation of compound of formula (II) with compound of formula (III) is carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the condensation reaction and to allow subsequent separation of the resulting Rupatadine (I). Advantageously, both compound of formula (II) and compound of formula (III) are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of compound of formula (II) and a solvent may be contacted with a compound of formula (III), or conversely, a mixture, slurry, or solution of compound of formula (III) and a solvent may be contacted with compound of formula (II). In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for compound of formula (II) may be identical with or different from the solvent system used for compound of formula (III). The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the compound of formula (II) and compound of formula (III) are primarily reacted in one phase and the resulting Rupatadine is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Ci- C^) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, di isoproipyl ether, dioxane, halogenated solvent such as methylene dichloride, chloroform and the like.
The temperature of contact of compound of formula (II) and compound of formula (III) in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e., a slurry or two phase solution are also possible.
The Rupatadine can be isolated or recovered from reaction medium by any convenient means. For example, the Rupatadine can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, reducing the temperature of the solvent can induce the precipitation, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the Rupatadine is less soluble.
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According to another aspect of the present invention, there is provided a compound of formula (II), wherein R represents C1-C4 alkyl, substituted or unsubstituted aryl and its process for the preparation.

According to the present invention, process for the preparation of compound of formula (III) comprising reacting 5-methyl-3-pyridylmethanol (VII) with sulfonic acid of formula (VI)

wherein R represents C1-C4 alkyl, substituted or unsubstituted aryl, X represents -OH, CI or Br.
In the preferred embodiment of the present invention, in the above-mentioned formula (III) and (VI), R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, benzyl or tolyl. Preferably, it is methyl or tolyl and X is CI.
The reaction of compound of formula (VII) with compound of formula (VI) can be preferably carried out in presence of base in solvent. Base is selected from methyl amine, tirethylamine, DBB, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide.
The solvent is selected from water, a lower alcohol (C1- C6) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, di isoproipyl ether, dioxane, halogenated solvent such as methylene dichloride, chloroform and the like.
According to another aspect of the present invention, there is provide a process for preparation of 5-methyl-3-pyridylmethanol (VII), which comprises reducing methyl-5-methylnicotinate of formula (VIII) in presence of metal hydride
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Reduction of methyl-5-methylnicotinate is preferably carried out in suitable solvent. Metal hydride used in the reduction is preferably selected from sodium borohydride, lithium borohydride, lithium aluminum borohydride, more preferably sodium borohydride.
According to another aspect of the present invention, there is provide a process for purification of 5-methyl-3-pyridylmethanol (VII), which comprises converting 5-methyl-3-pyridylmethanol to its acid addition salt, neutralizing said acid addition salt with base to obtain pure 5-methyl-3-pyridylmethanol (VII). In the preferred embodiment, said acid addition salt is hydrochloride salt. Base used in the neutralization of said acid addition salt can be selected from methyl amine, tirethylamine, DBB, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide
According to another aspect of the present invention, there is provided a process for the preparation of substantially pure Rupatadine fumarate, which comprises reacting Rupatadine (I) with methanolic solution of fumaric acid.
The reaction is preferably carried out in suitable solvent. Suitable solvent include ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, diisoproipyl ether, dioxane and the like.
The temperature of contact of Rupatadine and methanolic solution of fumaric acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two phase solution are also possible, though a single solution is generally preferred.
The Rupatadine fumarate can be isolated or recovered from the salt forming reaction
by any convenient means. For example, the substantially pure Rupatadine fumarate can be
precipitated out of a solution or reaction mixture. The precipitation may be spontaneous
depending upon the solvent system used and the conditions. Alternatively, reducing the
temperature of the solvent can induce the precipitation, especially if the initial temperature at
contact is elevated. The precipitation may also be facilitated by reducing the volume of the
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solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the substantially pure Rupatadine fumarate is less soluble. Seed crystals of substantially pure Rupatadine fumarate may also be added to help induce precipitation. The precipitated substantially pure Rupatadine fumarate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.
In the preferred embodiment, Rupatadine (I) is dissolved in ethyl acetate and treated with methanolic solution of fumaric acid at ambient temperature and cooled to about 0°C to about -5°C to obtain Rupatadine fumarate.
The novel salts and process for its preparation described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of invention.
Example 1
Preparation of 5-Methyl-3-pyridylmethanol (VII):
To a solution of 3.536 Kg (2.020 mole) of K2HPO4 in 4.5 L process water stirred for 15 minutes to obtain clear solution at 25°C to 35°C. 1.0 Kg (6.59 mole) of Methyl-5-methyl Nicotinate and 4.5 L of special denatured spirit was added to it. The reaction mixture was stirred for 15 minutes at 25°C to 35°C. 0.541 Kg (1.40 mole) of sodiumborohydride was added under stirring within 3-4 hours at 35°C to 45°C to the reactant mixture and stirred for 6-8 hours at 35°C to 40°C. The layers were separated, to this 1.0 L of special denatured spirit in the buffer layer was added and stirred for 15 minutes at 30°C to 35°C. The layers were separated layers and both the SDS layers were combined, SDS layer was distilled out under vacuum at 50°Cto 55°C. 2.5 L of process water and 6.0 L of MDC was added to SDS layer and was stirred. The pH was adjusted to 2 - 2.5 using 10 % HC1. Further the pH was adjusted to 9 - 10 using 20% NaOH solution. The content was stirred for 30 minutes. The mass was allowed to settle for 15 minutes at 30°C to 35°C. 2.0 L of MDC was added to the aqueous layer and stirred for 30 minutes. The layers were separated and 2.0 L of MDC was added to the aqueous layer and stirred for 30 minutes. MDC layer was distilled out under vacuum to get yellow viscous liquid.
Purification:
To the solution of 1.0 Kg (8.120 mole) of 5-Methyl-3-pyridyl-methanol in 2.0 L of
acetone stirred for 15 minutes to get clear solution at 25°C to 35°C. Solution of IPA.HC1 was
slowly added the till pH is 2. The reaction content was stirred for 2.0 hours. The precipitated
solid was filtered and cake was washed with 100 mL of acetone. The solid was dried for 4 - 5
hours at 60°C to 65°C temperature.
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To the solution of 1.0 Kg (6.263 mole) of 5-Methyl-3-pyridylmethanol.HCl in 500 mL of process water stirred for 15 minutes to get clear solution. 40% solution of NaOH was added to get pH about 9 to 10. Further, MDC (3.0L) was added and stirring was continued at 30°C to 35°C. The NaOH solution was continuously added, after the complete addition was stirred for 45 minutes at 30°C to 35°C temperature. The content was allowed to settle for 15 minutes. 2.0 L of MDC was added in the aqueous layer and stirred for 1.0 hours and allowed the content to settle for 15 minutes. The layers were separated, and the aqueous layer was discarded. Combine both the MDC layers. MDC was distilled out under vacuum at 35°C to 40°C.
Example-2
Preparation of 3-(para-toluene sulphonyl)methyl- 5-methyl-pyridine:
To the solution of 1.0 Kg of 5-Methyl-3-pyridylmethanol (6.263 mole) in 10.0 L of MDC was added 1.15 Kg (1.136 mole) of Triethylamine at 25°C to 30°C temperature. The content was stirred to obtain clear solution. 2.0 Kg (1.049 mole) of para-toluene sulphonyl chloride was added slowly within 1-2 hours into the reaction at 30°C to 35°C. The content was stirred for 4.0 hours at 30°C to 35°C temperature to obtain 3-(para-toluene sulphonyl)methyl- 5 -methyl-pyridine
Example-3
Preparation of 3-(methanesulphonyl)methyl- 5-methyl-pyridine:
To the solution of 1.0 Kg (6.263 mole) of 5-Methyl-3-pyridylmethanol in 10.0 L of MDC was added 1.97 Kg (1.94 mole) of Triethylamine at 25°C to 30°C temperature. The content was stirred to obtain the clear solution. Slowly within 1-2 hours 1.3 Kg (1.13 mole) of methane sulphonyl chloride was added into the reaction at 30°C to 35°C and was further stirred for 4.0 hours at 30°C to 35°C temperature. 10.0 L water was added into the reaction mass and stirred for 30 minutes. The mass was allowed to settle for 30 minutes till the layers get separated. Aqueous layer was discarded and the 3-(methanesulphonyl)methyl- 5-methyl-pyridine is obtained form.
Example-4
Preparation of Rupatadine:
To the solution of 0.882 kg (3.64 mole) of 8-chloro-ll-(4-piperidyliden)-6,ll-dihydro-5H-benzo[5,6]cyclohepta [l,2-b]pyridine of formula (II) and 10.0 L of acetone was added 2.243 Kg (1.62 mole) of potassium carbonate and stirred for 10 minutes at 30°C to 35°C. To this was added the previously prepared 3-(para-toluenesulphonyl) methyl-5-methyl-pyridine in MDC (From above example) within 15 - 20 minutes under nitrogen atmosphere
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at 30°C to 35°C. TLC were verified and 5.0 L of water and 5.0 L of MDC was added into the reaction mixture and allowed to stir for 15 minutes. The layers were allowed to be separated and 5.0 L of water was added into the MDC layer. Further the reaction was stirred for 15 minutes and the pH was adjusted to ~2 with concentrated HCl and was stirred for 10 minutes at 30°C to 35°C. Again the layers were separated and MDC layer was discarded. To the aqueous layer was added 3.0 L of toluene and 2.0 L of ethyl acetate and the content was stirred for 20 minutes. 20% sodium carbonate solution was added and the pH was adjusted to 7.0 to 7.5. Further the reaction mixture was stirred for 1.0 hour at 30°C to 35°C and the content was allowed to settle till the layers get separated. The MDC layer was collected and distilled under vacuum below 55°C temperature, to afford residue of Rupatadine (0.7 - 0.8 Kg).
Example-5
Preparation of Rupatadine:
To the solution of 0.882 kg (3.64 mole) of 8-chloro-ll-(4-piperidyliden)-6,ll-dihydro-5H-benzo[5,6]cyclohepta [l,2-b]pyridine of formula (II) in 10.0 L of acetone, 2.243 Kg (1.62 mole) of potassium carbonate was added and stirred for 10 minutes at 30°C to 35°C. To this was added the previously prepared 3-(methanesulphonyl)-methyl-5-methyl-pyridine in MDC (From above example) within 15-20 minutes under nitrogen atmosphere at 30°C to 35°C. The TLC was verified, 5.0 L of water and 5.0 L of MDC was added into the reaction mixture and allowed to stir for 15 minutes. The layers were allowed to separate and 5.0 L of water into the MDC layer was added. The reaction content was stirred for 15 minute and pH was adjusted to ~2 with concentrated HCl and stir for 10 minutes at 30°C to 35°C. The layers were separated and the MDC layer was discarded. To the aqueous layer 3.0 L of toluene and 2.0 L of ethyl acetate was added and allowed to stir for 20 minutes. 20% sodium carbonate solution was added to adjust the pH to 7.0 to 7.5. Further the reaction content was stirred for 1.0 hour at 30°C to 35°C, and allowed the content to settle till the layers get separated. The MDC layer was collected and distilled under vacuum below 55°C temperature, to afford residue of Rupatadine (0.7 - 0.8 Kg).
Example-6
Preparation of Rupatadine Fumarate:
The solution of 1.0 Kg (2.40 mole) of 8-Chloro-ll-{l-[(5-methyl-3-pyridyl)methyl]-
piperidin-4-ylidene]-6,ll-dihydro-5H-benzo[5,6]cyclo- hepta[l,2-b]pyridine in 5.6 L of ethyl
acetate was taken. The mixture was stirred for 15 minutes to get clear solution at 25°C to
30°C. 0.307 Kg (2.64 mole) of fumaric acid was dissolved in 5.0 L of methanol to get clear
solution, and the fumaric acid solution was added into the reaction mixture at 25°C to 30°C.
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The content was allowed to stir for 15 minutes and cooled to -5°C to 0°C. The content was stirred under nitrogen atmosphere to get white solid at -5°C to 0°C, The content was filtered and the cake was washed with 200 mL of ethyl acetate and 50 mL of methanol. Dry the solid for 6.0 hours at 55°C to 60°C temperature.
Advantages of Invention:
1) The present invention discloses an improved and industrially advantageous process for preparation of highly pure 3-substituted methyl-5-methyl-pyridine, an important intermediate for rupatadine.
2) The present invention also discloses the use of 3-methylate methyl-5-methyl-pyridine, an important intermediate for rupatadine.
3) The process disclosed is having good industrial applicability.
The process deals with reduction of Methyl-5-methyl nicotinate with sodiumborohydride to obtain 5-Methyl-3-pyridylmethanol as important intermediate for the preparation of 3-substituted methyl-5-methyl-pyridine.
Dated this the 29th day of May 2006
H. Subramaniam
Of SUBRAMANIAM, NATARAJ & ASSOCIATES
Attorney for the applicants

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Abstract
The present invention relates to an improved and industrially advantageous process for preparation of highly pure Rupatadine fumarate of formula-I and its one of the starting material which is used in its synthesis 3-substituted- methyl-5-methyl-pyridine having structure as formula-II as shown in the accompanied drawings. This compound is a key starting material for the synthesis of Rupatadine Fumarate, which is a potential dual anatgonist of histamine and platelet-activating factor (PAF) having chemical structure as formula-I.
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