Codeinone dimethyl ketal

Codeine has also been prepared in 70% overall yield, again without purification of intermediate compounds, from dihydrothebainone (132) by the route (132) — (137) shown in Scheme 4. The initial product of the action of bromine and then alkali on dihydrothebainone is the 1,7-dibromo-derivative of dihydro-codeinone, which can be reduced to dihydrocodeinone (133). This may be converted into 7-bromodihydrocodeinone dimethyl ketal (136), which on treatment with potassium t-butoxide in DMSO at 120 °C is converted exclusively into thebaine, but at 60 °C the product is codeinone dimethyl ketal (137), which can be hydrolysed to codeinone (131).154 The process has obvious value in the possible synthesis of codeine via dihydrothebainone, for which a patent has been filed covering a process that proceeds from the reduced isoquinoline (138) 155 the conversion of A-formylnordihydrothebainone into dihydrothebainone by hydrolysis and reductive methylation and by ketalization, reduction, and hydrolysis has been reported.156... 

These investigators succeeded in preparing codeinone dimethyl ketal (CCCLXXXV) starting with A -dihydrothebaine, which can itself be prepared by methylation of dihydrocodeinone with sodium <-butoxide and dimethyl sulfate (426). Addition of bromine in methanol to the enol ether gave a bromoketal which was dehydrobrominated to CCCLXXXV with potassium i-amyloxide. Direct preparation of codeinone dimethyl ketal from codeinone was not successful. Thebaine was obtained by warming CCCLXXXV with p-toluenesulfonic acid in chloroform. 

A mixture of codeinone dimethyl ketal, anhydrous K-carbonate, cyanogen bromide, and chloroform refluxed 2.5 hrs. under Ng N-cyanonorcodeinone... 

Labeled compounds. A soln. of codeinone dimethyl ketal[6-O GH3] in toluene mixed with a suspension of POGI3 in pyridine, and heated 6 hrs. at 115-120° under Ng -> thebaine[6-O GH3]. Y 70-75% retention of radioactivity 90%. -By this method, the quasi-axial methoxy group is czs-eliminated, whereas K-ethoxide in xylene frans-eliminates the quasi-equatorial labeled methoxy group causing 85% loss of radioactivity. U. Eppenberger, M. E. Warren, and H. Rapo-port, Helv. 51, 381 (1968). 

A greatly improved conversion of (-)-sinomenine into (+)-morphine with an overall yield of 28% has been recorded. Reduction of sinomenine to sinomenol followed by treatment with polyphosphoric acid gives (+)-dihydrocodeinone, the dimethyl ketal of which suffers elimination of methanol to give dihydrothebaine, which can be converted by standard procedures into (+)-codeinone, and hence into (+)-codeine and (+)-morphine. 

---