The Reduction of Thebaine. Neopine Methyl Ether

Abstract

In a brief investigation of the hydrogenation of thebaine, Small, Fitch, and Smith (1) announced the intention of examining the products other than the well-known diand tetra-hydrothebaines and dihydrothebainone. The opportunity to do this was presented in 1947, in the large-scale hydrogenation of thebaine involved in the commercial production of metopon (methyldihydromorphinone). This communication deals with the concentrated extract from the reduction of 89 kg. of thebaine, after removal of dihydrothebaine and before

Practical and High-Yield Syntheses of Dihydromorphine from Tetrahydrothebaine and Efficient Syntheses of (8S)-8-Bromomorphide

“…We have now examined the conversion of THT ( 1 ) to DHM ( 8 ) using material from the catalytic reduction of 89 kg of thebaine ( 2 ) to 8,14-dihydrothebaine ( 3 ) accomplished at Merck and Co. in 1947. The latter was required for the synthesis of methyldihydromorphinone (metapon, 11 , Scheme ) and related compounds in an early opiate program , aimed at the development of strong analgesics with fewer side effects than morphine ( 6 ).…”

“…The latter was required for the synthesis of methyldihydromorphinone (metapon, 11 , Scheme ) and related compounds in an early opiate program , aimed at the development of strong analgesics with fewer side effects than morphine ( 6 ). Crude crystalline THT ( 1 ) hydrochloride trihydrate from the Merck reduction showed about 7% of a higher R f spot on thin-layer chromatography (TLC) that we identified as neopine methyl ether ( 12 , Scheme ) from the NMR spectrum, by comparison with the original sample of Small . Hydrogenation of the crude mixture converted the neopine methyl ether ( 12 ) to the desired THT ( 1 ) that was purified to give starting material for O-demethylation to DHM ( 8 ).…”