FORM 2 THE PATENTS ACT, 1970 (39 of 1970)& The Patents Rules, 2003 PROVISIONAL / COMPLETE SPECIFICATION(See section 10 and rule 13) 1. TITLE OF THE INVENTION : "A PROCESS FOR PREPARING DULOXETINE AND INTERMEDIATES FOR USE THEREIN" 2. APPLICANT (S)(a) NAME : CIPLA LIMITED(b) NATIONALITY : INDIAN (c) ADDRESS : 289 Bellasis Road, Mumbai Central, Mumbai 400 008, India. 3 PREAMBLE TO THE DESCRIPTION PROVISIONALThe following specification describes the invention COMPLETEThe following specification particularly describes the invention and the manner in which it is to be performed. 4. DESCRIPTION (Description shall start from next page) 5. CLAIMS (not applicable for provisional specification. Claims should start with the preamble -"I/we claim" on separate page) 6. DATE AND SIGNATURE (to be given at the end of last page of specification) 7. ABSTRACT OF THE INVENTION (to be given along with complete specification on separate page) Note:-*Repeat boxes in case of more than one entry.*To be signed by the applicants) or by authorized registered patent agent.*Name of the applicant should be given in full, family name in the beginning.* Complete address of the applicant should be given stating the postal index no./code, state and country*Strike out the column which is/are not applicable. WO 2004/056795 PCT/GB2O03/O05357 2 A PROCESS FOR PREPARING PULOXETINE AND INTERMEDIATES FOR USE THEREIN The present invention is concerned with a process for preparing duloxetine, in particular a process for preparing (+)duloxetine in enantiomerically pure form, and to intermediates for use therein. Duloxetine, N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, is a dual serotonin and norepinephrine reuptake inhibitor. (+)Duloxetine has particular therapeutic utility as an anti-depressant. Duloxetine, and the preparation thereof, is described in US patents 5023269 and 49563S8, and also Tetrahedron Letters, 31, (49), 7101-04, 1990. Seven different routes of synthesis have also been reported in Drugs of the Future 2000, 25(9) 907-916. These syntheses have involved either a resolution of a key intermediate or a stereospecific reduction of a keto group to the alcohol. We have now observed that a particular chiral intermediate employed in the synthesis of (+)duloxetine, namely undergoes considerable racemisation during coupling with a 1-naphthyl halide under the reaction conditions employed in the prior art. In particular, in die presence of a strong base, such as sodium hydride, and a protic polar solvent, such as DMSO, the dimesyl anion can be generated which can cause partial or complete racemisation of the condensed product. 2 WO 2iMM/»56795 PCT/CB2003/005357 There is, therefore, a need for an improved process for the preparation of (+)duloxetine which alleviates the problems associated with prior art processes as referred to above. We have developed such a process which is advantageous in obviating racemisation, so as to yield an enantiomerically pure form of (+)duloxetine. In particular, our process can be seen to achieve the above described advantage, by carrying out resolution as a final step in the reaction process (thereby obviating the opportunity for racemisation during preceeding intermediate process steps) and / or avoiding conditions that would result in the production of intermediate products that would be prone to racemisation. According to the present invention, therefore, there is provided a process for preparing (+)duloxetine, or an acid addition salt thereof, which process comprises: (i) resolving racemic (±)duloxetine with a chiral acid so as to obtain a salt of the chiral acid and (+)duloxetine, substantially free of (-)duloxetine; and (ii) if desired, converting the salt prepared in step (i) to the free base or another acid addition salt as appropriate. The resolution step (i) is achieved with a suitable chiral acid in a suitable solvent. The chiral acid can typically be selected from the group consisting of mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid and the like. Other suitable chiral acids may be determined by testing and the use thereof in a process as described above falls within the scope of the present invention. Preferably the chiral acid employed in a process according to the present invention is (-)di-p-toluyl tartaric acid. Suitably, the solvent employed is a lower alkanol, such as methanol or ethanol, although again other suitable solvents can be determined by testing and the use thereof in a process as described above falls within the scope of the present invention. A preferred solvent is methanol. The salts of (+)duloxetine prepared by resolution step (i) represent a further aspect of the present invention and there is further provided by the present invention, therefore, a salt of a chiral acid and (+)duloxetine, substantially free of (-)duloxetine. Such salts of a chiral acid 3 WO 2004/056795 PCT/CB2003/005357 and (+)duloxetine, substantially free of (-)duloxetine, are useful as intermediates for preparing the free base or another acid addition salt as appropriate. Suitable salts provided by the present invention include (+)duloxetine mandelate, (-f-)duloxetine tartrate, (+)duloxetine di-p-toluyl tartrate, (+)duloxetine dibenzoyf tartrate, (-r)duloxetine camphor sulfonate and the like. A preferred salt according to the present invention is (+)duloxetine di-p-toluyl tartrate, which is useful as an intermediate for preparing the free base or another acid addition salt as appropriate. Intermediate salts prepared according to the present invention as described above can be converted to the free base or another acid addition salt according to step (ii) of a process according to the present invention. Suitably, an intermediate salt of the chiral acid and (+)duloxetine can be treated with a base, such as sodium hydroxide, to yield the free base. The free base itself can, if desired, be converted into an acid addition salt thereof. Suitable acid addition salts which may be formed in step (ii) include those formed with pharmaceutical^ acceptable organic or inorganic acids and are well known to those of skill in the art. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutical acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate. fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, 3-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonates, naphthalene-1-sulfonate, naphthaIene-2-sulfonate, mandeiate and the like salts. Preferred pharmaceutical^ acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic 4 WO 2004/056795 PCT/GB2003/005357 acids such as oxalic acid and maleic acid. A particularly preferred acid addition salt is the hydrochloride. A particularly preferred process according to the present invention comprises: (i) resolving racemic (±)duloxetine with di-p-toluyl tartaric acid so as to obtain (+)duloxetine di-p-toluyl tartrate, substantially free of (-)duloxetine; and (ii) converting (+)duloxetine di-p-toluyl tartrate prepared in step (i) to (+)duloxetine hydrochloride. A process according to the present invention preferably yields (+)duloxetine in substantially pure enantiomeric form. Thus the ratio of (+)duloxetine: (-)duloxetine as prepared by the present invention may be at least about 94:6, such as at least about 98:2, or more preferably at least about 99:1. Preferably (+)duloxetine prepared by a process according to the present invention has an enantiomeric purity of at least about 99%, or more particularly at least about 99.5%. The proportion of (+)duloxetine achieved by a process according to the present invention can be increased by effecting one or more, for example two or three, recrystallisations in step (i). To this end, a crystalline salt obtained as a result of resolution may be dissolved in a solvent therefor and the salt recrystallised from the resulting solution. In this way the proportion of a salt with (+)duloxetine can thus be increased until it is substantially pure, that is substantially only a salt with (+)duloxetine is present. The mother liquor from resolution step (i), or the mother liquor from the or each recrystallisation step, is enriched with (-)duloxetine. (-)Duloxetine present in one or more of these liquors, or the pooled liquors, may be converted into (±)duloxetine for reuse in a process according to the present invention substantially as hereinbefore described. A further preferred aspect of a process according to the present invention comprises: 5 WO 20(M/H5