DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

IMPROVED PROCESS FOR THE PREPARATION OF ANTIHISTAMINIC AGENT

We, Tyche Industries Limited,
a company incorporated under the companies act, 1956 having address at
C-21/A, Road No.9, Film Nagar, Jubilee Hills, Hyderabad – 500096, India

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved and industrially advantageous process for the preparation of 5-methyl-3-pyridine methanol or its salts of Formula I.

This compound is a key intermediate in the synthesis of Rupatadine, an antihistaminic agent.

BACKGROUND OF THE INVENTION
Rupatadine fumarate is a potent dual antagonist of histamine and PAF, with good activity and long duration of action when given by oral route. General pharmacology and toxicity studies reveal a good safety profile. Although compounds with either potent antihistamine properties or PAF antagonist activity are available, Rupatadine fumarate possesses a unique profile as it combines both activities with a high level of potency. This dual activity is an advantage over other drugs in the treatment of clinical conditions such as allergic rhinitis, urticaria, atopic eczema or asthma.

Chemical name for Rupatadine fumarate is 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate. Its empirical formula is C26H26ClN3.C4H4O4 and molecular weight of 532.04. It has the following structural formula:

Rupatadine is currently marketed in 10 mg oral tablets as Rupatadine fumarate for the treatment of allergic rhinitis and urticaria in adults and teenagers. Rupatadine free base was first disclosed in EP 0 577 957 B1.

Spanish patent ES 2 087 818 B1 discloses the monofumarate salt of Rupatadine i.e. Rupatadine fumarate. The patent also discloses process for the preparation of Rupatadine fumarate as shown in the scheme given below:

Scheme I

Evan P. Kyba et. al, Journal of Organic Chemistry, 53, 3513-3521, 1988 discloses the process for the preparation of 5-methyl-3-pyridine methanolby reduction of methyl 5-methyl pyridine-3-carboxylate using LAH at -78ºC. The process is shown in the scheme given below:

Scheme II

Indian Patent Application IN 2102/MUM/2006 discloses a process for the preparation of Rupatadine through 5-methyl-3-pyridine methanol intermediate. The process comprises esterification of 5-methyl nicotinic acid with methanol to give 5-methyl nicotinic acid methyl ester followed by reduction of the methyl ester with lithium aluminium hydride to obtain 5-methyl-3-pyridylmethanol; treating the obtained alcohol with thionyl chloride to obtain 5-methyl-3-(chloromethyl)-pyridine hydrochloride; and finally condensing the chloro compound with Desloratadine to yield Rupatadine. The process is shown in the scheme given below:

Scheme III

Indian Patent Application IN 1020/MUM/2007discloses a process for the preparation of Rupatadine through 5-methyl-3-pyridine methanol intermediate which comprises reacting 5-methyl nicotinic acid methyl esterwith sodium borohydride in presence of methanol to give compound of Formula I in the yield of 80%. The process is shown in the scheme given below:

Scheme IV

Despite the existence of various processes for the preparation of 5-methyl-3-pyridine methanol or its salts, there remains a need for improved processes for the preparation of the same, producing high yields and purity, and being well-suited for use on an industrial scale.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple and cost-effective process for the preparation of 5-methyl-3-pyridine methanol or its salts of high purity on commercial scale.

Another objective of the present invention is to provide an improved process for the preparation of Rupatadine with high yield and purity.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of 5-methyl-3-pyridine methanol or its salt of compound of Formula I

which comprises the steps of reduction of methyl 5-methylnicotinate of compound of Formula III

in a solvent in the presence of a reducing agent selected from synhydride to give compound of Formula I.

In another aspect, the present invention provides an improved process for the preparation of Rupatadine of Formula II

which comprises the steps of:
i) reduction of methyl 5-methylnicotinate of compound of Formula III

in a solvent in the presence of a reducing agent selected from synhydride to give compound of Formula I

ii) converting the compound of Formula I to Rupatadine of Formula II.
In a preferred aspect, the present invention provides an improved process for the preparation of 5-methyl-3-pyridine methanol or its salt of compound of Formula I

which comprises the steps of:
i) providing a solution of 5-methylnicotinate of compound of Formula III in a suitable solvent,
ii) adding a solution of synhydride to the step i) solution at -10 to 30ºC,
iii) adding acid to the reaction mass of step ii),
iv) optionally adding a solvent to the reaction mass of step iii),
v) isolating compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, reduction is carried out in the presence of an inert solvent selected from methanol, ethanol, isopropyl alcohol or butanol, toluene, acetonitrile, DMF (Dimethylformamide), DMSO, tetrahydrofuran (THF), ethyl ether, tert-butylmethylether, water or mixtures thereof.
The acid as herein used is selected from an inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid; organic acid selected from formic acid, acetic acid.

Conversion of intermediate compound of Formula I to Rupatadine of Formula II may be carried out by the methods known in the art.
In a preferred embodiment, the present invention provides an improved process for the preparation of 5-methyl-3-pyridine methanol hydrochloride salt of compound of Formula I

which comprises the steps of
i) reduction of methyl 5-methylnicotinate of compound of Formula III

in toluene in the presence of synhydride to give compound of Formula I
ii) converting the compound of Formula I to its hydrochloride salt using IPA-HCl.

In another preferred embodiment, the present invention provides an improved process for the preparation of Rupatadine of Formula II

which comprises the steps of:
i) reduction of methyl 5-methylnicotinate of compound of Formula III

in toluene in the presence of synhydride to give compound of Formula I

ii) optionally converting the compound of Formula I to its hydrochloride salt using IPA-HCl and
iii) converting the compound of Formula I or its salt to Rupatadine of Formula II.
In yet another preferred embodiment, the present invention provides an improved process for the preparation of 5-methyl-3-pyridine methanol or its salt of compound of Formula I

which comprises the steps of:
i) providing a solution of 5-methylnicotinate of compound of Formula III in a suitable solvent,
ii) adding a solution of synhydride to the step i) solution at -10 to 30ºC,
iii) adding acid to the reaction mass of step ii),
iv) optionally adding a solvent to the reaction mass of step iii),
v) isolating compound of Formula I.

Advantages of the present invention:
Prior-art process involves the use of reducing agents like lithium aluminium hydride and sodium borohydride which requires special precautions and safety measures to handle in plant scale. Further, it is difficult to reduce the esters with sodium borohydride alone and requires additional reagents like lewis acid such as aluminium chloride or buffers.

The present invention involves the use of synhydride which is not only convenient to handle in scale-up operations in plant but also enables the reaction in decomposition of the unreacted reagent.

The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.
EXAMPLES
Example 1
Preparation of 5-methyl-3-pyridine methanol hydrochloride:
Mixture of methyl 5-methylnicotinate (100gm) in toluene (250 ml) was cooled to 0-5ºC and a prepared solution of synhydride (240 gm) in toluene (720 ml) was added to the mixture over a period of 4 hrs at 0-5ºC. Stirred the reaction mass for about 1 hr at the same temperature. Temperature of the reaction mixture was raised to 25-35ºC and maintained the temperature at RT for 3 hr. After completion of the reaction, cooled the reaction mass to 10-15ºC and water (60 ml) was added followed by the addition of hydrochloric acid (60 ml). The temperature of the reaction mass was raised to 25-35ºC and maintained at the same temperature for 1 hr. Top toluene layer was collected. To the crude compound ethyl acetate (500 ml) was added, heated the reaction mass to reflux and maintained the reaction mass at reflux temperature for about 30min. Cooled the reaction mass to 25-35ºC and filtered the reaction mass to remove the salts. Distilled out toluene layer completely. To the residue ethyl acetate (100 ml) was added and filtered through hyflow bed. To the filtrate IPA-HClwas added till acidic pH and filtered the reaction mass to collect the product (80 g, 98.5% pure).

Example 2
Preparation of 5-methyl-3-pyridine methanol hydrochloride:
Mixture of methyl 5-methylnicotinate (100gm) in toluene (250 ml) and a prepared solution of synhydride (240 gm) in toluene (720 ml) was stirred for 4 hrs at 25-35ºC. The temperature of the reaction mixture was raised to 75-80ºC and maintainedat the same temperature for 3 hr. After completion of the reaction, cooled the reaction mass to 10-15ºC and water (60 ml) was added followed by the addition of hydrochloric acid (60 ml). The temperature of the reaction mass was raised to 25-35ºC and maintained at the same temperature for 1 hr. Top toluene layer was collected. To the crude compound ethyl acetate (500 ml) was added, heated the reaction mass to reflux and maintained the reaction mass at reflux temperature for about 30 min. Cooled the reaction mass to 25-35ºC and filtered the reaction mass to remove the salts. Distilled out toluene layer completely. To the residue ethyl acetate (100 ml) was added and filteredthrough hyflow bed. To the filtrate IPA-HClwas added till acidic pH and filtered the reaction mass to collect the product (78 g, 96.5% pure).

Example 3
Preparation of Rupatadine:
Mixture of 8-chloro-6,11-dihydro-11-(4-piperdinylidene-5H-benzo[5,6] cyclohepta [1,2-b]pyridine (Desloratadine) (50g), 3-(chloromethyl)-5-methylpyridine (45g), potassium carbonate (60g) and methanol (300 ml) were heated to 60-65ºC and stirred the reaction mixture at the same temperature for 10-12 hr till the completion of the reaction. Quenched the reaction mass into water, extracted the compound with methylene dichloride (500 ml) and concentrated the methylene dichloride layer. Ethyl acetate (400 ml), fumaric acid (19g) and methanol (400 ml) was added and heated the reaction mass to 55-60ºC till clear solution. Cooled to room temperature and dried to get Rupatadine fumarate (45 g, HPLC purity 99.78%). ,CLAIMS:We Claim:
1. An improved process for the preparation of 5-methyl-3-pyridine methanol or its salt of compound of Formula I

which comprises the steps of reduction of methyl 5-methylnicotinate of compound of Formula III

in a solvent in the presence of a reducing agent selected from synhydride to give compound of Formula I.
2. An improved process for the preparation of Rupatadine of Formula II

which comprises the steps of:
i) reduction of methyl 5-methylnicotinate of compound of Formula III

in a solvent in the presence of a reducing agent selected from synhydride to give compound of Formula I

ii) converting the compound of Formula I to Rupatadine of Formula II.
3. An improved process for the preparation of 5-methyl-3-pyridine methanol or its salt of compound of Formula I

which comprises the steps of:
i) providing a solution of 5-methylnicotinate of compound of Formula III in a suitable solvent,
ii) adding a solution of synhydride to the step i) solution at -10 to 30ºC,
iii) adding acid to the reaction mass of step ii),
iv) optionally adding a solvent to the reaction mass of step iii),
v) isolating compound of Formula I.

4. The process as claimed in any of the preceding claims, wherein the solvent is selected from methanol, ethanol, isopropyl alcohol or butanol, toluene, acetonitrile, DMF (Dimethylformamide), DMSO, tetrahydrofuran (THF), ethyl ether, tert-butylmethylether, water or mixtures thereof.

5. The process as claimed in any of the preceding claims, wherein the acid is selected from an inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid; organic acid selected from formic acid, acetic acid.

Dated this third (3rd) day of August 2016.
__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883