Process for the preparation of morphine analogs via the reaction of organometallic reagents with an oxazolidine derived from morphinans

A process for the preparation of a compound of Formula I:

• wherein
• represents a single or double bond, provided that two double bonds are not adjacent to each other;
• R1 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
• and
• R2 and R3 are independently selected from H, C1-10alkyl, C1-10acyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl, except when O represents ═O, then R3 is not present;
• the process comprising:
• (a) reacting a compound of Formula II or a protected form thereof:
• wherein
• represents a single or double bond, provided that two double bonds are not adjacent to each other;
• and
• R2 and R3 are independently selected from H, C1-10alkyl, C1-10acyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl, except when O represents ═O, then R3 is not present;
• with a reagent of Formula III:
• R1A III,
• wherein R1 is selected from C1-10alkyl, C2-10alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
• and
• A is a suitable metallic or organometallic countercation;
• and
• (b) optionally deprotecting the compound derived from reacting the compound of Formula II or protected form thereof with the reagent of Formula III;
• under conditions to provide a compound of Formula I;
• wherein in the compounds of Formulae I, II and III one or more available hydrogens in R1, R2 and R3 is/are optionally replaced with F and/or one or more of available atoms in R1, R2 and R3 is/are optionally replaced with an isotopic label.