FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
&
THE PATENTS RULE 2003 (SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"IMPROVED PROCESS FOR THE PREPARATION OF TADALAFIL"
Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and
having its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
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FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Tadalafil (I) and its intermediates.
BACKGROUND OF THE INVENTION
Tadalafil, (6R12aR)-2,3,6,7,12,12a-hexahydro- 2-methyl-6- (3,4-
methylenedioxyphenyl)-pyrazino[2',I,6,l]pyrido[3,4b]indole-l,4-dione is an orally administered phosphodiesterase type 5 (PDE5) inhibitor. Tadalafil has been developed as a treatment for erectile dysfunction and the treatment of female sexual dysfunction. The molecular structure of Tadalafil is represented by formula (I)

In WO 95/19978, Alain Daugan describes Tadalafil (I) as tetracyclic derivatives and the process for its preparation and their therapeutic use as PDE5 inhibitor. James Butler in the patent WO 96/38131 also describes a process for the preparation of Tadalafil (I) and its intermediates.
In W002/36593, Mark Orme describes the preparation of Tadalafil (I) as indole derivatives and their use as therapeutic agents.
Similarly, in the patents US 6,140,329, Alain Daugan et al. has described the uses of Tadalafil (I) and processes for its preparation.
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SUMMARY OF THE INVENTION
The object of the present invention is to provide an improved process for preparing Tadalafil (I).
Another objective of the present invention is to provide improved processes for the preparation of the intermediates involved in Tadalafil (I) preparation.
Still another objective of the present invention is to provide suitable pharmaceutical compositions containing Tadalafil (I) prepared according to the present invention and their use in medicine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Tadalafil (I) and its intermediates.
The present invention provides process for the preparation of Tadalafil (I) which comprises cyclisation of compound of formula (IV) wherein R represents -OH or -NH Ri, wherein R\ can be selected from the group hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, which process

In which X is halogen atom, The cyclization of compound of formula (IV) can be carried out in presence of a base such as, for example, an alkali metal hydroxide, alkali metal
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carbonate, metal carbonate e.g., sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate etc., in presence of suitable solvent. Suitable solvents include, but not limited to, alcoholic solvents ranging from 1 to 6 carbon atoms, aromatic solvents and non-aromatic solvents. The cyclisation can be carried out at a temperature ranging from about 20°C to about 180°C.
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The specific embodiment of the present invention can be represented as


Tadalafil obtained by above methods can be purified by using suitable solvent. Suitable solvents include, but not limited to, alcoholic solvents ranging from 1 to 6 carbon atoms, aromatic solvents and non-aromatic solvents. The process of the present invention advantageously provides tadalafil in relatively high purity, e.g., greater than about 98% and preferably greater than about 99%.
In yet another aspect of the present invention, when a pharmaceutical composition comprising Tadalafil thereof prepared according to the present invention is formulated for oral administration. Accordingly, D90 particle size of the unformulated Tadalafil used as starting material in preparing a pharmaceutical composition generally is less than 300 microns and more than 40 microns, preferably less than about 200 microns and more than 40 microns, more preferably less than 150 microns and more than 40 microns, still more preferably less than about 100 microns and more than 40 and still more preferably less than about 90 microns and more than 40 microns.
Any milling, grinding micronizing or other particle size reduction method known in the art can be used to bring the solid state Tadalafil thereof into any desired particle size range as set forth above.
Another aspect of the present invention is directed to a pharmaceutical dosage form containing Tadalafil. The substantially Tadalafil mixture may be in any form, for example, compacted tablets, powder suspensions, capsules, and the like. The compositions of the present invention can be administered to humans and animals in such dosage forms as oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), intracistemal, intravaginal, intraperitoneal, local (powders, ointments or drops), ophthalmic, transdermal, or sublingual forms or as a buccal or nasal spray. Oral dosage forms include, but are not limited to, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs, tablets, capsules (including soft gel capsules), ovules, solutions, and the like which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, or controlled-release such as sustained-, dual-, or pulsatile delivery applications. Tadalafil disclosed herein also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are
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administered by other routes. The most preferred route of administration of the Tadalafil of the present invention is oral.
The active ingredient of the invention may also be administered via fast dispersing or fast dissolving dosage forms or in the form of high energy dispersion or as coated particles. Suitable pharmaceutical composition of the invention may be in coated or uncoated form as desired.
Tabletting compositions may have few or many components depending upon the tabletting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
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Capsule dosages will contain the solid composition within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric coating.
Dated this Seventeenth (17th) day of July, 2006