TRANSITION METAL-CATALYZED PROCESSES FOR THE PREPARATION OF N-ALLYL COMPOUNDS AND USE THEREOF

摘要

The present disclosure provides processes for the N-dealkylation of tertiary amines and the use of transition metal catalysts to prepare tertiary N-allyl amine derivatives and secondary amine derivatives thereof. The tertiary amines can be alkaloids and, more particularly, the tertiary amines can be opioids. In specific embodiments, the present disclosure provides methods for use in processes for the synthesis of naloxone and naltrexone from oripavine.

主权项

1. A method for making a compound of Formula (1)comprising
contacting a compound of Formula (25) with a compound of Formula (26) in a solvent containing a transition metal catalyst to provide the compound of Formula (1), wherein:
R1 and R2 are independently selected from —(C1-C6) alkyl, —(C2-C6) alkenyl, and —(C2-C6) alkynyl, each alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R8 groups, or R1 and R2 are taken together with the nitrogen atom to which they are bound to form a heterocyclic or heteroaryl ring of Formula (5) n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;the heterocyclic or heteroaryl ring of Formula (5) is a monocyclic ring that is saturated, unsaturated non-heteroaryl, or heteroaryl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R52 groups, or is a subunit of a polycyclic ring system comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic, heterocyclic, aryl, or heteroaryl rings, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R52 groups;R4 is selected from the group consisting of —H, —(C1-C6) alkyl, phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl, -2-butynyl, -3-butynyl, -2-pentynyl, R5, R6, and R7 are each independently selected from —H, —(C1-C6) alkyl, —(C2-C6) alkenyl, and —(C2-C6) alkynyl, each alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R8 groups;each R8 is independently selected from —OR51, —F, —Br, —I, phenyl, and —(C1-C6) alkyl;each R51 is independently selected from —(C1-C6) alkyl and an oxygen protecting group;each R52 is independently selected from ═O, ═CH2, —OR53, —O(C1-C6) alkyl, —C(═O)(C1-C6) alkyl, and —(C1-C6) alkyl, each alkyl group being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected —OR53 groups;each R53 is independently selected from —H and an oxygen protecting group;R40 is selected from —OC(O)CH3, —N(CH3)2, and —OC(O)X; andX is selected from —Br, and —I.