Patent ID: 7999124
Filing Date: 2011-08-16
Classification: A61P,C07D

Abstract:
1. A process for preparing d-NBV of formula which comprises: a) reacting 2,2-dimethyl-1,3 dioxolane-4-carbaldehyde of formula with a vinyl Grignard reagent, to obtain a compound of formula IIa in the form of diastereoisomeric mixture (S,R+R,R) b) reacting the above compound of formula IIa with 2-bromo-4-fluorophenol to obtain a compound of formula IIIa in the form of diastereoisomeric mixture (S,R+R,R) c) reacting the compound of the above formula IIIa with an organoborane compound of formula wherein each Y is a siamyl group, an isopropyl-prenyl group, a cyclohexyl group, an isopinocampheyl group and a thexyl group; or both Y taken together with the boron atom to which they are linked form a borabicyclo[3.3.1]non-9-yl group or a residue of formula: to obtain a compound of formula IVa in the form of diastereoisomeric mixture (S,R+R,R) d) cyclizing the above compound of formula IVa to obtain a compound of formula Va in the form of diastereoisomeric mixture (S,R+R,R) and, if desired, separating the compound of formula Va (S,R+R,R) into the single diastereomer Va (S,R) and the single diastereomer Va (R,R); e) hydrolysing the diastereoisomeric mixture of formula Va (S,R+R,R) or, alternatively, hydrolysing separately the diastereomer Va (S,R) and the diastereomer Va (RR), to obtain the corresponding diastereoisomeric mixture of formula VIa (S,R+R,R) f) reacting the diastereoisomeric mixture of formula VIa (S,R+R,R), or alternatively reacting separately the diastereomer VIa (S,R) and the diastereomer VIa (R,R) with a reactant able to introduce a good leaving group to obtain the corresponding diastereoisomeric mixture of formula VIIa (S,R+R,R) g) reacting the diastereoisomeric mixture of formula VIIa (S,R+R,R), or alternatively reacting separately the diastereomer VIIa (S,R) and the diastereomer VIIa (R,R) with a base to obtain the corresponding diastereoisomeric mixture of formula VIIIa (S,R+R,R) and separating, if the case, the diastereoisomeric mixture of formula VIIIa (S,R+R,R) into the single diastereomer VIIIa (S,R) and the single diastereomer VIIIa (R,R); h) reacting separately the compound of formula VIIIa (S,R) or the compound of formula VIIIa (R,R) with a protected H i) reacting the compound of formula IXa (S,R) or the compound of formula IXa (R,R) with a compound of formula VIIIa (R,R) or a compound VIIIa (S,R) respectively, to obtain a compound of formula Xa (S,R,R,R) or a compound Xa (R,R,R,S), being the compound of formula Xa (S,R,R,R) the same stereoisomer of the compound Xa (R,R,R,S), because of the presence in the structure of compound Xa of an axis of symmetry which contains the nitrogen atom k) and, if desired, salifying the compound of formula IA.