FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION.
(See section 10]
1. Title of the invention: "Process for the synthesis of Rupatadine"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at304 - 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.

Technical Field of the Invention
The present invention relates to an improved and industrially feasible process for the
synthesis of 8-chloro-6, 11-dihydro-l l-[l-[(methyl-3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo [5, 6] cyclohepta [1, 2b] pyridine, having International nonproprietary name Rupatadine.
Background of the Relevant Art
In art rupatadine is disclosed as a potent orally active dual antagonist of Histamine (Hi) and Platelet-Activating Factor (PAF) due to interaction with specific receptors (J. Pharmacology & Experimental Therapeutics, 1997 280, 114-121). Also referred as UR-12592 in literature and exemplified in the U.S. Patent No. 5,407,941 assigned to Uriach of Spain, rupatadine is chemically 8-chloro-6, 11-dihydro-l l-[l-[(methyl-3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo [5, 6] cyclohepta [1, 2b] pyridine) having structural formula I


In U.S. Patent No. 5,407,941 rupatadine is chemically synthesized by the reaction of
desloratadine with 3-(bromomethyl)-5-methyl pyridine, prepared by the bromination of 3, 5-Lutidine. This synthetic route results rupatadine in 40% over all yield. However, the bromination of 3, 5-Lutidine also yields mono and dibromo compounds with unreacted 3, 5-Lutidine resulting into poor over all yield of rupatadine.
According to Spanish Patent ES 2087818 disclosure rupatadine is obtained by condensing 5-methyl nicotinic acid with desloratadine to obtain amide, which is further treated with phosphorus oxychloride/sodium borohydride to yield rupatadine. The condensation of 5-methyl nicotinic acid with desloratadine is carried out in the presence of 1, 3-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate, generating dicyclohexyl urea which cannot be easily removed during the work-up and subsequent purification of the impure N-(5-methylnicotinyl)-4-hydroxypiperidine leads to loss of overall yield of rupatadine (46.8%).
Another Spanish Patent ES 2120899 involves the reaction of 8-chloro-6,l l-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine-11-one with 3-[(4-M-piperidin-l-yl)methyl]-5-methylpyridine (where M is -Mg X or -Li; X being a halogen atom) to give 4-[8-chloro-6,11-dihydro-l l-hydroxy-5H-benzo[5,6] cyclohepta [1,2-b] piperidin-1 l-yl]-l [(5-methyl-3-pyridinyl) methyl piperidine which on dehydration yield rupatadine in overall yield of 42.0%.
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Summary of the Invention
All the method of synthesis of rupatadine published to date, suffer from one or more
shortcomings with regard to poor yields and difficulties in isolation to get the pure product. The inventors of the present invention has invented a novel process to synthesize rupatadine resulting in 85.27% overall yield. The synthesis is designed based on the retrosynthetic analysis outlined in Scheme 1.

In scheme 1, rupatadine on disconnection give desloratadine (2) and 5-methyl-3-L-methyl pyridine (3). Functional group interconversion of the pyridyl sidechain revealed 5-methyl nicotinic acid (6) as an ideal starting material. Inventors of the present invention identified 5-methyl-3-L-methyl pyridine (3), where L being a leaving group, as one of the key intermediate. In particular, three molecules such as methanesulfonic acid-5-methyl pyridine-3-yl methyl ester (3a), 5-Methyl-3-bromo methyl pyridine (3b) and 5-Methyl-3-cholromethyl pyridine (3C) are considered as key intermediates. On synthesis of
methanesulfonic acid-5-methyl pyridine-3-yl methyl ester (3fl) it is found that mesilate is

highly unstable and decomposes during work-up. Another key intermediate 5-methyl-3-
bromomethyl pyridine (3 J if found unfavorable candidate due to lachrymatory nature of
the bromo compound. 5-methyl-3-cholromethyl pyridine isolated as hydrochloride salt (3C) is found to be the ideal candidate, since it is stable and being in solid state is easy in handling. In art, 5-methyl-3-chloromethyl pyridine (3C) is synthesized (Bell and coworkers) by the chlorination of 3, 5-Lutidine with N-chlorosuccinimide. The reported yields are very poor (19%) (J.Med.Chem.1998, 41, 2146-2163). So an alternate strategy is been employed for the synthesis of (3C). In one of the embodiment of the present invention, esterification of 5-methyl nicotinic
acid (6) is carried out with methanol to yield 5-methyl nicotinic acid methyl ester (5). The ester (5) on reaction with Lithium aluminum hydride provides 5-methyl-3-pyridylmethanol (4) which on treatment with thionyl chloride furnishes 5-methyl-3-(chloromethyl)-pyridine (3C) as hydrochloride salt in good yields. 5-methyl-3-(cholromethyl) - pyridine hydrochloride on base catalyzed condensation with Desloratadine yields Rupatadine (1). Rupatadine (1) on further treatment with fumaric acid yielded the pharmaceutically acceptable salt of Rupatadine as Fumarate (Scheme 2).
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Scheme 2: Reagents and conditions: (i) Methanol, SOCb, 60-65°C, Diisopropyl ether (ii) LiAlH4, Tetrahydrofuran,-70 to -75°C (iii) 1, 4-Dioxane, SOCl2, 65-70°C (iv) desloratadine, DMF, K2CO3. (v) Fumaric acid, Methanol, Ethylacetate.
It is object of the present invention to synthesis rupatadine with an overall yield of
85.27%.
It is further object of the present invention to synthesis key intermediate 5-methyl-3-
chloromethyl pyridine with an overall yield of 87.36% against the 19% overall yield
reported for the chlorination of 3, 5-Lutidine using N-chlorosuccinimde.
Detailed Description of the Invention
All reagents were commercially obtained and used as received unless otherwise noted. All non-aqueous reactions are performed in dry glassware under an atmosphere of dry nitrogen. Organic solutions are concentrated by rotary evaporation at ~ 80.0 mm Hg at less than 60° C except where noted. Thin layer chromatography is performed on Merck
pre-coated silica gel 60F254 plates. Visualization of the developed chromatogram is

performed by fluorescence quenching or phosphomolybdic acid stain or 50% sulfuric
acid char. 1H NMR spectra are measured on a Varian-Gemini-300 MHz spectrometer
.Chemical shifts are reported in parts per million (ppm), relative to tetramethyl silane. 1H NMR signals are described as s-singlet; d-doublet; t-triplet; q-quartet m-multiplet and br.s-broad singlet. IR spectra are recorded on KBr discs/neat on a Shimadzu FT-IR. Melting points were obtained by open capillary method and are uncorrected. HPLC analyses are carried out on a Hypersil BDS C-18 column (25 cm X 4.6 mm X 5μ.) equipped with UV detector, running in gradient mode. Buffer used is K2HPO4 (pH-7.2) and the injection volumes are 20 μL.
Example 1: Methyl nicotinic acid methyl ester (5)
Thionyl chloride (110.0 ml; 1.50 moles) is added drop wise to a solution of 5-Methyl nicotinic acid (l00.0g; 0.73moles) in methanol (500.0 ml) kept under nitrogen atmosphere at 20-25° C and heated the reaction mixture to 60-65° C for 2-3 hrs. Completion of the reaction is monitored by TLC. After completion of the reaction methanol is evaporated under reduced pressure to get a residue. Chilled water (150.0 ml) is added to the residue and pH of the reaction mass is adjusted to 7.0 with liquor ammonia. The reaction mass is extracted with diisopropyl ether (250.0 ml X2). The organic layers were combined and washed with brine( 150.0 ml),dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated under reduced pressure to obtain the title compound (105.0 g; Yield=95.5%); HPLC Purity=97.34%; mp=45-47°C (lit.7mp-45-46°C); IR (ycm1): 2594, 2345, 1731, 1438, 1296, 1218, 1110;
1H NMR δ(ppm):2A 1 (3H,s),3.95(3H,s),8.13(1 H,br.s),8.61 (1 H,d),9.03( 1 H,d);
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MS(ESI)152.31(M+H) +
Example 2: Methyl-3-pyridylmethanol (4)
5-Methyl nicotinic acid methyl ester (140.0 g; 0.93 moles) in THF (200.0 ml) is added to a suspension of Lithium aluminum hydride (35.0 g; 0.92moles) in THF (550.0 ml) kept under an inert atmosphere at -70 to -75°C. The reaction mass is stirred for half an hour at -70 to -75°C.The completion of the reaction is monitored by TLC. After completion of the reaction, ethyl acetate (100.0ml) is added, followed by saturated ammonium chloride
solution (500.0 ml) at -50°C. The reaction mass is allowed to warm up to 5-10°C and filtered the separated solids. The filtrate is evaporated under reduced pressure to remove most of the solvents to get a residue. Water (150.0 ml) is added to the residue to get a uniform solution, which is saturated with sodium chloride and extracted with dichloromethane (250.0 ml x 2). The organic layers are pooled together and washed with brine and dried over anhydrous Sodium sulfate. The sodium sulphate is filtered off and the filtrate on evaporation under reduced pressure furnished the alcohol as an oil (108.0 g; Yield=95.0%); HPLC purity=98.8%; \R(cm'):2974, 2881, 2835, 1589, 1454, 1377, 1164, 1029. 1H NMR δ (ppm):233(3H, S), 4.67(2H, S), 7.54(1H, br.s), 8.27- 8.29(2H, d); MS (ESI) 124.39(M+H) +
Example 3: 5-Methyl-3-cholromethyl pyridine HC1 (3C)
To a solution of 2 (220.0 g; 1.79 moles) in 1, 4-dioxane (1.0 L) is added thionyl chloride
(196.0 ml; 2.68 moles) at 20-25°C drop wise. After the addition of thionyl chloride the
reaction mass is heated and maintained at 65-70° C for 2.0 hrs. After completion of the
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reaction (TLC) the solvents are distilled under reduced pressure to get a solid residue. The solid residue is stirred with Diisopropyl ether (500.0 ml) and filtered the solids,
which was dried to get the title compound (306.4 g; Yield=96.3); HPLC purity =96.20%;
mp= 154-157°C; IR (vcm-1):3035, 2927, 2345, 1558, 1288, 1261, 856,740;
1H NMR δ(5cp/«;:2.63(3H,s),4.77(2H,s),8.27(lH,br.s),8.63(lH,br.s),8.80(lH,br.s); MS (ESI) 142.28 (M+H) + - HC1
Example 4: (8-Chloro-6, 11-dihydro-11-[l-[(5-methyl3-pyridinyl) methyl]-4-piperidinyIidene]-5//-benzo [5, 6] cyclohepta [1, 2-b] pyridine): Rupatadine (1)
To a solution of 5-Methyl-3-cholromethyl pyridine hydrochloride (175.0 g; 0.98 moles) in N, N- dimethyl formamide (875.0 ml) kept under nitrogen, is added Desloratadine (208.0 g; 0.67 moles) and powdered potassium carbonate (203.4 g; 1.47 moles) at 20-25°C. The reaction mass stirred for 16.0 hrs at 20-25°C. After completion of the reaction (by TLC), the reaction mass is filtered to separate the solids. The solids are washed with dichloromethane(200.0 ml). The filtrate is evaporated under reduced pressure to get a paste, which is diluted with Dichloromethane (500.0 ml) and washed with a saturated solution of KH2PO4(200.0 ml).The organic layer is further washed with water (250.0ml X3),brine (250.0 ml) and dried over anhydrous sodium sulfate. The sodium sulfate is separated by filtration and the filtrate on evaporation under reduced pressure furnished Rupatadine (300.0 g; 97.6%); HPLC purity=96.33 %; {?cm'\ 3024,2920,2796,2754,1634,1581,1438,1365,1118,991,871;
1H NMR δ(ppm-1);2.11-2.19(5H,m),2.27(3H,s),2.57-2.60(2H,m),2.77-2.84(2H,m),3.22-
3.32(3H,m),3.44(2H,s),7.03-7.06( 1 H,d),7.16-7.19(2H,m),
7.28(1 H,d),7.50(lH,br.s),7.52,7.58(lH,dd),8.26-8.28(3H,m)
;MS(ESI)416(M+H) +
Example 5: Rupatadine Fumarate
Ethyl acetate (1590.0 ml) is added to Rupatadine (318.0 g; 0.76 moles) and refluxed to
get a clear solution. A solution of Fumaric acid (88.7 g; 0.76 moles) in methanol (1519.0
ml) is added to the refluxing solution of Rupatadine drop wise. After completion of
addition of fumaric acid solution, the reaction mass is stirred for 12 hrs at 20-25°C and
cooled to 0-5°C.Filtered the separated solids and washed the cake with ethylacetate:
methanol mixture (319.0 ml; 1:1). The solids are dried at 50°C for 6.0 hrs to yield the title
compound (290.0 g; 71.82%); HPLC purity=99.55%; mp by DSC=194°C (onset)-201°C
(end set) (lit.4mp=199-201°C);IR (Vcm-'):3031, 2977,
2923,2896,1701,1562,1438,1164,1095,972; 1H NMR S(ppm ): 2.38(4H,s),2.59-2.60(3H,m),2.78-2.88(4H,m),3.12-3.14(2H,m),3.38-3.41(2H,m), 4.02(2H,s), 6.71(2H,s), 7.11-7.13(lH,m),7.17-7.19(lH,m),7.24-7.29(2H,m),7.66-7.77((lH,d),7.77(lH,s),8.32-8.46(lH,m),8.40(2H,s);13CNMRδ(ppm): 17.96, 30.10, 30.22, 30.73, 31.21, 53.97, 58.66,122.5,125.81,129.11,130.90,131.72,132.23,132.67,132.72,133.42,134.37,137.20,13 7.48,137.56,138.02,140.28,146.49,147.62,149.06,157.14,166.50;
MS (ESI) 416(M+H)+-C4H404
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.

Claims
We claim -
1. A process for the preparation of 8-chloro-6, 11-dihydro-l l-[l-[(methyl-3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo [5, 6] cyclohepta [1, 2b] pyridine) comprising
(a) esterification of 5-methyl nicotinic acid with methanol to give 5-methyl nicotinic acid methyl ester;
(b) reacting 5-methyl nicotinic acid methyl ester with lithium aluminium hydride to obtain 5-methyl-3-pyridylmethanol;
(c) treating 5-methyl-3-pyridylmethanol with thionyl chloride to obtain 5-methyl-3-(chloromethyl)-pyridine hydrochloride; and
(d) condensing 5-methyl-3-(chloromethyl)-pyridine hydrochloride with desloratadine to yield Rupatadine.

2. A process as claimed in claim 1, wherein the rupatadine is further reacted with fumaric acid to obtain rupatadine fumarate.
3. A process as claimed in claim 1, wherein rupatadine is obtained by above
exemplified examples.
4. A process as claimed in claim 1, wherein the yield of ruatadine is 85.27%.
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Abstract
An improved and industrially feasible process for the preparation of 8-chloro-6, 11-dihydro-11 -[ 1 -[(methyl-3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo [5, 6] cyclohepta [1, 2b] pyridine (rupatadine).
Dated this 20m day of December 2006.

To
The Controller of Patents The patent Office, At Mumbai.