Codeine 2- bromo

Methoxycodeine (139) has been prepared 222 from (-)-l-bromo-sinomeninone (138) in three stages (Scheme 2.18), and found to be about 5 codeine (MHP, sc). In view of the acid instability of 7-methoxycodeine it was surprising to find that it was an equivalent analgesic to codeine when administered po. Perhaps the standard error limits of the biological test were wide enough to suggest that the compounds were equipotent. 

Apocodeine [vm], the 3-methylether of apomorphine, is formed when codeine is heated with zinc chloride [209-10, 219, 225], anhydrous oxalic acid [256-9], or phosphoric acid [240], (Cf. the preparation of apomorphine from morphine, Chapters II and XXII.) A substance givon the name apocodeine was prepared by treating bromo- and a-ohlorocodides with alkaline reagents [3 72, 260], but this is not an analogue of apomorphine and is probably a eomplox mixture [261],... 

Two sulphonic acids are obtained by the sulphonation of i/<-codeine-N-oxide [295, 341] and bromination of these, followed by decomposition of the perbromide with sulphurous acid, gives bromo-i/i-codeine dibromide, C HgoOjNBrj, which can be reduced catalytically to tetra-hydro-i/ -codeine [295],... 

Bromocodide is produced when codeine is gently boiled with hydro-bromic acid [81-84] when codeine [18, 37] and (/(-codeine [12] are treated with phosphorus pentachloride and when codeine is. treated with thionyl bromide, excess of which causes production of 1-bromo-bromocodide [85], In the same way morphine [14] and a-isomorphine [16] can be converted to bromomorphide, which yields bromocodide on methylation [17], Attempts to isomerize these bases have failed. 

Thebainone-A can also be prepared by the catalytic rearrangement of codeine [vi] under the influence of palladized charcoal at 80° C. [2] by the hydrolysis of thebainone-A enol methyl ether [vn] (prepared by the rearrangement of codeine methyl ether on heating with sodium ethoxide) [3] by the hydrolysis of /j-ethylthiocodide [vm] (obtained by the action of sodium ethoxide on bromo- or /3-chlorocodide) [4-8] (see Chap. XVII) and, in small amount, by the hydrolysis of dihydrothe-baine- [iv] [3]. 

Methylmorphenol is also obtained as the final product of exhaustive methylation of codeine ethiodide [10], y-codeimethine (the C-6 epimer of [m]) [11] and e-codeimethine methyl ether [vn, R = CH3] (obtained by the degradation of (/(-codeine methyl ether [vi, R = CH3]) [12-13] the other substances produced during the degradation of [vn, R = CH3] are trimethylamine, ethylene, and methyl alcohol [12], 1-Bromomethyl-morphenol [vin] arises in like manner by the degradation of 1-bromo-codeine [10, 14-16] and ethylmorphenol from morphine-3-ethyl ether [17]. 

In withdrawn morphine-dependent rhesus monkeys, the morphinones exacerbated withdrawal at very low doses. Withdrawal effects persisted even after morphine administration (3 mg/kg, 6 hourly) was resumed [23]. Self-administration and drug discrimination studies in rhesus monkeys were also included in this report. In the drug discrimination assay the codeinones all generalised to codeine. The 4 -bromo- and 4 -methylcinnamoylaminodihydrocodeinones (40b, 40c) were also self-administered but at rates that were below those of codeine [22]. These results confirmed the MOR partial agonist character of the codeinones. 

The assignment to /S-chlorocodide, bromocodide, and iodocodide of structure CCCLII (X=C1, Br, I) has been confirmed by a study of their infrared spectra, which are very similar to, but different from, that of a-chlorocodide (393). Normal Sn2 displacement takes place with codeine tosylate and lithium chloride to give a-chlorocodide as would be expected, but the corresponding 6-bromo- and 6-iodocodide are not obtained in a similar manner The substances are rearranged so rapidly that only the 8-bromo- and 8-iodocodide are obtained. 

ACETAMINOPHEN AND ACETAMINOPHEN WITH CODEINE PHOSPHATE (N-Acetyl-P-Aminophenol, APAP, Acephen, Anacin-3, Bromo-Seltzer, Datril, Datril 500, Tempra, Tylenol, Valadol, Valorin)... 

Interfering bromo-STP, codeine-N-oxide, ethylmorphine, 4-hydroxyamphetamine, morphine, morphine-N-oxide, normetanephrine, 2-phenethylamine, prolintane, STP... 

Simultaneous amphetamine, benzphetamine, benzylmorphine, bromo-STP, buprenor-phine, caffeine, codeine, codeine-N-oxide, dextromoramide, dextropropoxyphene, diethyl-propion, dihydrocodeine, dihydromorphine, dimethylamphetamine, ephedrine, ethohep-tazine, ethylmorphine, etorphine, fenethyline, fenfluramine, fentanyl, hydrocodone,... 

Methoxycodeine (154) has been prepared from l-bromo-(—)-sinomeninone (151 R = Br) via l-bromo-(+)-sinomenine (152), which on bromination and cyclization with alkali yields l-bromo-7-methoxycodeinone (153) this, on reduction with lithium aluminium hydride, yields (154). This derivative of codeine is an orally active analgesic, in spite of the fact that it is unstable to acids, which convert it into the inactive (-)-sinomeninone (151 R = H). ... 

Simultaneous acetylcodeine, amphetamine, benzphetamine, benzylmorphine, bromo-STP, buprenorphine, chlorphentermine, codeine, codeine-N-oxide, dextromoramide, dextropro-poxyphene, diamorphine, diethylpropion, dihydrocodeine, dihydromorphine, dimethylam-phetamine, dipipanone, ephedrine, epinephrine, ethoheptazine, ethylmorphine, etorphine, fencamfamin, fenfluramine, fentanyl, hydrocodone, 4-hydroxyamphetamine, levorphanol, mazindol, meperidine, mephentermine, mescaline, methadone, methamphetamine, meth-ylenediojQramphetamine, methylephedrine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-N-oxide, naloxone, norcodeine, norlevorphanol, normetanephrine, normethadone, normorphine, norpethidine, norpseudoephedrine, noscapine, o codone, papaverine, pemoline, pentazocine, 2-phenethylamine, phenoperidine, phentermine, phenylephrine, phenylpropanolamine, pholcodeine, pipradol, piritramide, prolintane, pseudoephedrine, STP, thebacon, thebaine, trimethoxyamphetamine, tyramine... 

Papaver somniferum—contd. [N-mer/iyi- C]Codeine + l-Bromo-[2- H]Codeine... 

---