General Description of the Chemistry

Although the initial process, route 1, has only four stages and on paper looks a reasonable synthesis, the process had several chemical issues and could not be considered environmentally acceptable. For example, bromination of 3 -chloropro-piophenone, although straightforward, did necessitate several base and aqueous washes to remove the hydrogen bromide by-product during the work-up and a change of solvent for the displacement reaction with 2-methyl-2-aminopropan-l-ol. 

This required an extra purification stage, reducing yield and adding time to the process. 

2) The 2 1 salt is extremely insoluble and is formed as a mixture of all possible enantiomeric combinations, that is two (S,S)- units, two (R,R)- units and an (S,S)- and (,2,2)- unit, generating material of low chiral purity. 

The result of these studies provided a procedure for effectively doubling the reachon yield and improving the crystal form of the key intermediate, leading to an increase in the overall yield and produchvity. 

Route 3 had addressed many of the problems associated with the previous routes it avoided the potential 50% loss of the unwanted enantiomer, produced radafaxine in an overall yield of 64% from 3 -chloropropriophenone (an increase of nearly 400%), dramatically improved tfie throughput, reduced cost, and had a significantly lower environmental impact Two key issues remained large quanh-ties of DTTA were still required to effect the DKR and the recovery and re-use of the DTTA. 

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