Synthesis of 2′-amino-17-cyclopropylmethyl-6,7-dehydro-3,14-dihydroxy-4,5α-epoxy-6,7:4′,5′-thiazolomorphinan from naltrexone

✍ Scribed by Yang Nan; Wei Xu; Kyaw Zaw; Kathrine E. Hughes; Liang-Fu Huang; William J. Dunn III; Ludwig Bauer; Hemendra N. Bhargava

• Publisher: Journal of Heterocyclic Chemistry
• Year: 1997
• Tongue: English
• Weight: 718 KB
• Volume: 34
• Category: Article
• ISSN: 0022-152X
• DOI: 10.1002/jhet.5570340417

✦ Synopsis

Abstract

Fusion of an azole moiety at C‐6 and C‐7 of naltrexone (1) is illustrated by the synthesis of the title compound 8. Bromination of 3‐O‐methylnaltrexone led to the 1,7α‐dibromo derivative which reacted with thiourea to attach the 2‐aminothiazole ring to C‐6 and C‐7 of naltrexone. After converting the amino and alcohol groups to trimethylsilyl derivatives, the aromatic bromo group was removed by halo‐lithium interchange with butyllithium, followed by hydrolysis with water. In the final step of the synthesis, the methyl ether was cleaved by boron tribromide to generate 8. An alternate synthesis of 8 commenced with 3‐O‐acetylnaltrexone (9). Bromination of 9 in acetic acid in the presence of hydrobromic acid produced a mixture of 3‐O‐acetyl‐7α‐bromonaltrexone (10) and 7α‐bromonaltrexone (11), both, as hydrobromides. Reaction of this mixture with thiourea furnished 8 (62% from 1). While ^1^H and ^13^C chemical shifts of all compounds are reported, those of 11 hydrobromide and 8 dihydrochloride were established unequivocally.