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6a. 8-{4-[3-(4-Fluoro-2-methyl-phenoxy)-propyl]-piperazin-1-yl}-2,3-dihydro-benzo[1,4]dioxine-5-carbonitrile, oxalate. Ethyl 2,3 dihydroxybenzoic acid (103 g) and 1,2-dibromoethane (250 mL) was dissolved in ethanol (1.0 L), to this stirred mixture was a solution of potassium tert-butoxide (316 g) in ethanol (1.5 L) added dropwise over 8 hrs, the reaction was stirred for 16 hrs. 1,2 dibromoethane (100 mL) more was added, and also potassium tert-butoxide (126 g) in ethanol (700 mL) added dropwise and reaction was again stirred for 16 hrs. When the reaction was complete it was filtered and evaporated followed by standard washing procedure from ethylacetate. The crude dioxane (108 g) was obtained sufficiently pure for direct use in the subsequent reaction. 5-Carboxyethyl benzodioxane was dissolved in an ethanol:water mixture (400 mL, 1:1) and sodiumhydroxide (68 mL) was added dropwise at ambient temperature, followed by stirring for 16 hrs. The reaction was evaporated, redissolved in ethylacetate and pH was adjusted to 3, followed by washing using standard procedure to give the free acid (86.5 g). The acid (229 g) was dissolved in thionyl chloride (2.0 L) and heated at reflux temperature for 3 hrs, and then cooled and evaporated, the remaines was co-evaporated 3 times with toluene. The crude chloride was dissolved in toluene and added dropwise to ammoniumhydroxide solution (1.5 L) at 0 C. Further stirring at room temperature for 30 min gave the full precipitation of the amido-derivative. The precipitated product was filtered and washed (water and ethylacetate) to give the pure amido-derivative (267 g) containing some moisture. This compound was mixted with thionylchloride (1.5 L) and heated at reflux temperature for 7 hrs, cooled, evaporated and co-evaporated with toluene (3 times) followed by standard washing to give the 5-cyano benzodioxane (202 g) as clear pure oil.
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