Practical total synthesis unnatural enantiomers of opium-derived morphinans

In the preparation of compounds 23 and 24

• ______________________________________ ##STR2## wherein R.sub.1 = H or lower alkoxy and R.sub.2 = H or lower alkoxy and R.sub.3 = H or OH or lower alkoxy and R.sub.4 = H or OH or lower alkoxy and R.sub.3 + R.sub.4 = O and R.sub.5 = H, methyl or lower alkyl or lower alkmonaryl and R.sub.6 = H, Br, or Cl ##STR3## wherein R.sub.1 = H or lower alkoxy and R.sub.2 = H, methyl or lower alkyl or alkmonoaryl and R.sub.3 = H, OH or lower alkoxy and R.sub.4 = H, OH or lower alkoxy and R.sub.3 + R.sub.4 = O and R.sub.5 = H, Br or Cl and An optional 7,8-double bond indicates coverage of the unnatural codeine series. ______________________________________
• by a total synthesis method, the steps which comprise:
• (a) heating a mixture of an amine compound of the formula 4 ##STR4## and pure acid compound, formula 5 R1 ? ? ##STR5## at 200.degree. C. for about 2 hours under argon or other inert gas to obtain amide compound 6 of the following formula ##STR6## (b) contacting compound 6 with phosphorous oxychloride to produce the 1,2-dehydro derivative of compound 7 shown below:
• ##STR7## which need not be isolated;
• (c) neutralizing the 1,2-dehydro derivative of compound 7 with aqueous ammonia and reducing with sodium cyanoborohydride or sodium borohydride to give racemic 7 which is then resolved by optically active acids to the compound tetrahydroisoquinoline (+)-7 to (-)-7 ##STR8## (d) treating of (-)-7 with lithium or sodium in liquid ammonia as a reducing agent to give hexahydroisoquinoline, compound (-)-8 ##STR9## and formylating compound (-)-8 to give 10 ##STR10## and introducing a protective group for the nitrogen in the subsequent steps of the reaction where the reagent for formylation of 8 to 10 is phenylformate chloral or ethyl formate
• (e) alternately, N-methylating compound (-)-7 or (-)-8 by treatment with methyl halides or sulfonate to give the N-methyl derivative of 7 or compound 9 ##STR11## (f) contacting compound 10 with ethylene glycol in dry methane sulfonic acid in dry tetrahydrofuran to afford the ketal product, 11 ##STR12## (g) brominating of ketal 11 with N-bromoacetamide (NBA) to give bromo ketal 12 ##STR13## (h) deketalizing bromo ketal 12 with aqueous formic acid to yield beta, gamma unsaturated ketone 13 ##STR14## (i) treating beta, gamma unsaturated bromo ketone 13 with a super acid alone or with ammonium fluoride HF complex with trifluoromethanesulfonic acid to give 1-bromo-N-formylnordihydrothebainone (+)-17 ##STR15## (j) acid hydrolyzing 1-bromo-N-formylnordihydrothebainone (+)-17 with aqueous acid and methanol to give the intermediate 1-bromonordihydrothebainone, compound (+)-18 ##STR16## (k) converting intermediate (+)-18, 1-bromonordihydrothebainone, to dihydrothebainone (+)-19, a codeine precursor by hydrogenation in the presence of formaldehyde with palladium on carbon catalyst in 2-normal (2N) acetic acid containing sodium acetate;
• or
• (l) treating intermediate (+)-18 with bromine in acetic acid or chloroform followed by treating with sodium hydroxide to close the oxide bridge and afford as an intermediate (+)-1-bromonordihydrocodeinone which need not be isolated but is hydrogenated in the presence of formaldehyde to give dihydrocodeinone (+)-22, a codeine precursor or ##STR17## (m) alternately, converting compound (+)-18 into compound (+)-21, nordihydrocodeinone ##STR18## by bromination in acetic acid followed by treating with an aqueous base to close the oxide bridge, and hydrogenating the unisolated intermediate with palladium on carbon catalyst in 2-norman (2N) acetic acid containing sodium acetate.