FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION.
(See sectionl0]
1. Title of the invention: "Process for the synthesis of (5-methylpyridin-3-yl) methanol, a key intermediate of Rupatadine Fumarate"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.
3. The following specification particularly describes and ascertains the nature of this 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-methylpyridin-3-yl) methanol of Formula I:

BACKGROUND OF THE INVENTION
Chemically, rupatadine is 8-chloro-ll-[l-[(5-methy-3-pyridyi) methyl]-piperidin-4-
ylidene]-6, 1 l-dihydro-5h-benzo [5, 6] cyclohepta [1, 2-b] pyridine having Formula II

Formula II
This compound is known in the literature as UR-12592 and has been disclosed in Spanish Patent No. 2,042,421 (Equivalents: U.S. Pat. No. 5,407,941 and European Patent No. 577957) and assigned to Uriach of Spain. Rupatadine fumarate is a potent dual antagonist of histamine and PAF (platelet-activating factor) with good activity and long duration of action when given by oral route.
General pharmacology and toxicity studies reveal a good safety profile for PAF antagonist. Although compounds with 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.
A previously known method for the synthesis of the intermediate (5-methylpyridin-3-yl) methanol of Formula I is reported in literature Chem. Ber., I960, 93, 286 - 289 as per Scheme 1 in 33 % yield.




Scheme -1
J. O. C, 1988, 53, 3513 - 3521 also reports for this intermediate as per Scheme - 2 in 80
% yields.

Scheme - 2

J. Med. Chem., 2004, 47, 6299 - 6310 also report this intermediate also in the same
method as in Scheme - 2 in 99 % yields.
The above mentioned method described in the prior art for the manufacture of the desired compound of Formula I suffers from the following limitations:
1. The process requires use of difficult to handle pyrophoric Lithium aluminium hydride.
2. Commercially costly aldehyde.
This intermediate has been reported in WO 2006/103688 and WO 2006/114676.
Literature reports preparation of aldehyde from alcohol in J. O. C, 1988, 53, 3513 - 3521 and J. Med. Chem., 2004, 47, 6299-6310. In Chem. Ber., 1960, 93, 286-289, aldehyde is prepared from V205/Mo03-Katalysator at 400 - 410°C.
In order to obtain Rupatadine Fumarate in a commercially viable pure and in simplified process, it is necessary to employ simpler reagents.

SUMMARY OF THE INVENTION
It is an object of the present invention to solve the problems, associated with and to provide an efficient method for the preparation of (5-methylpyridin-3-yl) methanol of Formula I (as shown in the accompanied drawings). The product obtained by the process of the instant invention would be highly useful as a starting material for the preparation of pure Rupatadine.
More particularly, the present invention relates to a process for the preparation of (5-methylpyridin-3-yl) methanol of Formula I (as shown in the accompanied drawings) comprising reacting 5-methylnicotinic acid methyl ester of Formula III with sodium borohydride in presence of methanol to give the required product of Formula I in 80% yield as in Scheme - 3.

Scheme - 3
The starting material used for preparation of (5-methylpyridin-3-yl) methanol of Formula
I is methyl 5-methyl nicotinate.
The solvent used for the reaction is methanol. The reducing agent used is Sodium borohydride. The reaction is done under nitrogen atmosphere.
The reaction was stirred for 18 to 24 hours, preferably 20 hours. The reaction mass after concentrated under vacuum was dissolved in water and extracted with hexanes to remove some low polar impurities formed in the reaction.
In order to maximize the extraction of the product from the aqueous solution, it is saturated with sodium chloride. The solvent used for extraction is methylene dichloride.
DETAILED DESCRIPTION OF THE INVENTION
EXAMPLE
Preparation of (5-methylpyridin-3-yl) methanol
To a solution of methyl 5-methyl nicotinate (500 gm, 3.3 moles) in methanol (2000 ml)
was added sodium borohydride (376 gm, 9.93 moles) lot wise maintaining temperature at
25-30°C under nitrogen atmosphere. It was stirred for 20 hours. The reaction was
monitored by TLC and after completion of reaction, the reaction mass was concentrated
under vacuum at 35 - 40°C. The residue was dissolved in water (1500 ml) and extracted

with 2 x 1.0 lit hexane at 40 - 45°C. The reaction mass was saturated with sodium chloride (600 gm) and cooled to 25 - 30°C. It was extracted with 2 x 1.5 lit and 2 x 1.0 lit methylene dichloride and the methylene dichloride was concentrated under vacuum at 30 - 35°C to get the product as yellow oil. (325 gm, 79.78 %)
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

We claim:
1. A process for the preparation of (5-methylpyridin-3-yl) methanol of Formula I comprises of reacting 5-methylnicotinic acid methyl ester of Formula III with sodium borohydride in presence of methanol to give the required product of Formula I in the yield of 80%.
2. A process as claimed in claim 1, wherein the starting material used for preparation of (5-methylpyridin-3-yl) methanol of Formula I is methyl 5-methyl nicotinate.
3. A process as claimed in claim 1, wherein the solvent used for the reaction is methanol.
4. A process as claimed in claim 1, wherein the reducing agent used is Sodium borohydride.
5. A process as claimed in claim 1, wherein the reaction is performed under nitrogen atmosphere.
6. A process as claimed in claim 1, wherein the reaction is stirred for 18 to 24 hours, preferably 20 hours.
7. A process as claimed in claim 1, wherein the reaction mass concentrated under vacuum is dissolved in water and extracted with hexanes to remove low polar impurities as formed in the reaction.
8. A process as claimed in claim 1, wherein the aqueous solution is saturated with sodium chloride and extracted with methylene dichloride

ABSTRACT
The present invention relates to an improved and industrially advantageous process for the preparation of (5-methylpyridin-3-yl) methanol of Formula I, as shown in the accompanied drawings. This compound is a key intermediate for the synthesis of Rupatadine Fumarate, a potent dual antagonist of histamine and platelet-activating factor (PAF).