Recycling procedure to increase the performance of a Grignard reaction in the preparation of opioid alkaloid derivatives

摘要

A process for the preparation of a compound comprising Formula (II), the process comprising (a) forming a reaction mixture comprising a solvent system comprising an aprotic solvent and, optionally, also an organic solvent, a compound comprising Formula (I) and R9MgX1, so that a reaction is produced to provide a reaction product comprising the compound comprising Formula (II) and an amount of the compound comprising the unreacted Formula (I), of according to the following reaction scheme: wherein: R1, R8, R9 and R10 are independently selected from the group consisting of hydrocarbyl; R2 and R3 are independently selected from the group consisting of hydrogen and hydrocarbyl; R4 and R5 are independently selected from the group consisting of hydrogen, hydrocarbyl, halogen, {-} SR10 and {-} OR10; R6 and R7 are independently selected from the group consisting of hydrogen, a protective group and hydrocarbyl; X is a heteroatom; and X1 is a halogen atom, (b) (i) sharply cooling the reaction mixture of step (a) with a quenching agent, (ii) crystallizing the compound comprising Formula (II) by separating most of the solvent system to form a concentrated reaction mixture and add an alkane; (c) filter the concentrated reaction mixture from step (b) to separate crystals of Formula (II) and form a filtrate comprising an amount of the compound comprising Formula (I) and an amount of the compound comprising Formula ( II); and (d) recycle, combining the filtrate from step (c) with the reaction mixture from step (a), and repeat steps (b) and (c).