Stereoselective syntheses of 3-dehydroxynaltrexamines and N-methyl-3-dehydroxynaltrexamines

Abstract

Methodology is presented for the synthesis of 6α/β−3-dehydroxynaltrexamines and 6α/β-Nmethyl-3-dehydroxynaltrexamines. A stereoselective route is provided for each target compound while a novel one-pot method for the synthesis of 6α/β−3-N-methyl-3-dehydroxynaltrexamines is also explored. These results enable the versatile and efficient preparation of key epoxymorphinan intermediates to facilitate future selective opioid ligand discovery and development.

Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure–Activity Relationship Study on Nalfurafine Analogues

“…Eight enantiopure intermediates were required to prepare the target compounds. Part of the protocols to get these essential intermediate amines ( 1–8 ) were made available from previous studies from others and our lab, ,, and a systematic description for all synthetic routes is briefly discussed in the following. For preparing 1–8 , at least one stereoselective synthetic route was adopted and established with reasonable yields.…”

“…Additionally, “one-pot” methods were also explored and established as alternative synthetic routes for the four N-methylated intermediate amines (Scheme ). In such approaches, all starting materials were added together and allowed to reflux for 24 h. In both reactions, starting with naltrexone or 3-deydroxynaltrexone, both C6 epimers were generated, while the 6β epimers ( 4 and 8 ) were the major products, respectively.…”

“…13 C NMR (101 MHz, DMSO-d 6 ): δ 163 48,. 155.83, 145.21, 145.09, 144.99, 144.86, 131.19, 129.96, 129.84, 129.15, 123.42, 119.01, 109.51, 87.61, 70.14, 61.77, 61.65, 57.14, 46.69, 45.68, 45.65, 29.41, 27.40, 24.11, 21.11, 6.19, 5.60, 3.10.…”

Systematic Structure–Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments

“…Briefly, 3-dehydroxynaltrexone was first synthesized from naltrexone . Naltrexone and 3-dehydroxynaltrexone were then subjected to four different stereoselective reductive amination methods followed by catalytic hydrogenation under acidic conditions (where applicable) to yield eight different naltrexamines: namely, 6α-naltrexamine, 6α-3-dehydroxynaltrexamine, 6β-naltrexamine, 6β-3-dehydroxynaltrexamine, 6α- N -methyl-naltrexamine, 6α- N -methyl-3-dehydroxynaltrexamine, 6β- N -methyl-naltrexamine, and 6β- N -methyl-3-dehydroxynaltrexamine. − Then primary amines were coupled to carboxylic acids utilizing the EDCI/HOBt coupling reaction while secondary amines were coupled to acyl chlorides under basic conditions. Acyl chlorides were prepared fresh from their carboxylic acid counterparts prior to coupling if they were commercially unavailable .…”