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    The chemical name of duloxetine hydrochloride is (S)-( )-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine hydrochloride (1). There are several reports on optical resolution of racemic duloxetine and it's racemic intermediates by using resolving chiral acids such as tartaric acid, dibenzoyl-L-tartaric acid, di-p-toluoyl-L-tartaric acid, mandelic acid, camphor sulphonic acid, (S)-2-pyrrolidine-2-one-5-carboxylic-acid and (−)-2,3,4,6-di-O-isopropylidine-2-keto-L-gulonic acid. WO 2006/045255 teaches the use of D-tartaric acid to resolve racemic N, N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine (5a 5b) followed by two recrystallizations of the resulting tartarate salt from tetrahydrofuran as solvent to preferentially isolate (S)—N, N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine-(D)-tartarate salt in 25% yield and 99% chiral purity. The use of phase transfer catalysts render the process economically non viable since they are much costlier. Thus, the methods described in prior art for condensation of racemic hydroxy compound with 1-fluoronaphthalene that utilizes sodium hydride, alkoxide or phase transfer catalyst for large-scale reactions suffers from several drawbacks, such as: These drawbacks of the condensation reactions associated with the prior art processes are overcome by the present invention in which the condensation is achieved by using milder bases such as sodamide potassium amide and potassium bis(trimethylsilyl)amide (see scheme II). This patent although mentions that the resolution of racemic mixture 5a 5b can be carried out using resolving agent such as dibenzoyl-D-tartaric acid and dibenzoyl-L-tartaric acid (referred to as DBTA hereafter) and the like, however, it does not provide an enabling disclosure for the same. The inventors of WO 2004/056,795 have successfully replaced sodium hydride with alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates preferably with potassium hydroxide but the condensation reaction requires to be carried out in presence of phase transfer catalyst such as crown ethers, quaternary ammonium salts, quaternary phosphonium salts to facilitate the reaction. WO 2006/126,213 describe condensation of racemic hydroxy compound with 1-fluoronaphthalene in organic polar solvent such as dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide in presence of alkoxide base such as sodium methoxide, sodium ethoxide and potassium tert. As mentioned above, the alkoxides are very strong bases and hazardous which restrict their use on plant scale reactions. 5,023,269 discloses general method for preparation of (R, S)N, N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine (5a 5b) that is isolated as its oxalate salt. Sodium hydride is very hazardous reagent because it is pyrophoric and reacts violently with water with evolution of hydrogen gas. The alkoxides are very strong bases and therefore are hazardous that brings limitation on their use on large scale. Most of the literature data indicate that the initial step of duloxetine synthesis is condensation of either racemic hydroxy compound i.e. N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine or enantiomerically pure (S)—N. N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine with 1-fluoronaphthalene by using sodium hydride as base in polar aprotic solvent. 6,541,668 describes synthesis of 3-aryloxy-3-arylpropanamines by reaction of alkoxide of 3-hydroxy-3-arylpropanamine with a halo-aromatic in 1,3-dimethyl-2-imidazolidinone or N-methylpyrrolidinone as solvent. These pathways are illustrated in the following synthetic scheme I. Numbers of documents are cited in the patent as well as academic literature for the synthesis of duloxetine and its enantiomerically pure intermediate compounds via an optical resolution of racemic duloxetine or racemic intermediates that are formed in the synthesis of duloxetine at different steps. Augmentation of antidepressant effects of duloxetine and. doxycycline injectable Duloxetine - Wikipedia Duloxetine Sigma-Aldrich
     
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