467-13-0

The opioid oxycodone was produced from codeine, using a combination of chemical and biological catalysis. The use of novel functionalized ionic liquids permitted this reaction to be performed in a single solvent.

Asymmetric total synthesis of (?)-morphine has been accomplished in 18 steps from commercially available 7-methoxy-2-tetralone. Our synthesis features a simple transformation from a readily prepared chiral intermediate, construction of the E-ring by acid-mediated cyclization, and singlet oxygen-mediated manipulation of the C-ring. Transformation of the final stage involves construction of the morphinan skeleton by means of 1,6-addition of in situ generated secondary amine.

-

-

-

Six 3-O- and 6-O-glucosides of morphine and codeine derivatives were synthesized by means of glucosylation with acetobromo-α-d-glucose. O-Glucosylation at C6 was carried out by the Koenigs-Knorr method, whereas the 3-O-glycoside of morphine was synthesized directly upon stirring morphine with acetobromo-α-d-glucose and aqueous sodium hydroxide in acetone. Complete 1H and 13C NMR assignments are presented for each synthesized compound based on one- and two-dimensional homo- and heteronuclear NMR techniques. Circular dichroism, ultraviolet absorbance, and high-resolution mass spectroscopy data ensure identification and structural characterization of the O-glucoside conjugates. The synthesized glucoside conjugates are potential analgesics; the presented spectral and chromatographic data are useful references for various analytical and metabolic studies including samples of biological origin.

Rationale: Pyridinium chlorochromate (PCC) is the active ingredient of 'Urine Luck', a commercially available in vitro adulterating agent used to conceal the presence of drugs in a urine specimen. The exposure of codeine and its major glucuronide metabolite codeine-6-glucuronide (C6G) to PCC was investigated to determine whether PCC is an effective masking agent for these opiate compounds. Methods: Following the addition of PCC to both spiked and authentic codeine and C6G-positive urine specimens, the samples were monitored using liquid chromatography/mass spectrometry (LC/MS). Stable reaction products were identified and characterized using high-resolution MS analysis and, where possible, nuclear magnetic resonance (NMR) analysis. Results: It was determined that PCC effectively oxidizes codeine and C6G, thus altering the original codeine-to-C6G ratio in the urine specimen. Four reaction products were identified for codeine: codeinone, 14-hydroxycodeinone, 6-O-methylcodeine and 8-hydroxy-7,8-dihydrocodeinone. Similarly, three reaction products were identified for C6G: codeinone, codeine and a lactone of C6G (tentative assignment). Conclusions: Besides addressing the complications added to interpretation, more investigation is warranted to further determine their potential for use as markers for monitoring the presence of codeine and C6G in urine specimens adulterated with PCC. Copyright

-

Methods that may be used for the manufacture of a class of chemical compounds known as morphinans, including neopine, are provided. Compositions useful for the synthesis of morphinans, including neopine, are also provided.

Alkaloids including galanthamine (1) and codeine (2) are reported to be positive allosteric modulators of nicotinic acetylcholine receptors (nAChRs), but the binding sites responsible for this activity are not known with certainty. Analogues of galanthamine (1), codeine (2), and morphine (3) with reactivity towards cysteine thiols were synthesized including conjugated enone derivatives of the three alkaloids 4-6 and two chloro-alkane derivatives of codeine 7 and 8. The stability of the enones was deemed sufficient for use in buffered aqueous solutions, and their reactivity towards thiols was assessed by determining the kinetics of reaction with a cysteine derivative. All three enone derivatives were of sufficient reactivity and stability to be used in covalent trapping, an extension of the substituted cysteine accessibility method, to elucidate the allosteric binding sites of galanthamine and codeine at nAChRs.

An improved method for the synthesis of 8-[(1E)-2-phenylethenyl]codeinone dimethyl ketal was described. The ability of [(1E)-2-phenylethenyl] substituent to stabilize effectively the π-system of the ring C is responsible for the essential difference in both the reactivity and the compositions of products formed in the reactions of the corresponding substituted and unsubstituted codeinone and thebaine derivatives.

We have developed an efficient total synthesis of (-)-morphine in 5% overall yield with the longest linear sequence consisting of 17 steps from 2-cyclohexen-1-one. The cyclohexenol unit was prepared by means of an enzymatic resolution and a Suzuki-Miyaura coupling as key steps. Construction of the morphinan core features an intramolecular aldol reaction and an intramolecular 1,6-addition. Furthermore, mild deprotection conditions to remove the 2,4-dinitrobenzenesulfonyl (DNs) group enabled the facile construction of the morphinan skeleton. We have also established an efficient synthetic route to a cyclohexenol unit containing an N-methyl-DNsamide moiety.

Plants of the order Ranunculales, especially members of the species Papaver, accumulate a large variety of benzylisoquinoline alkaloids with about 2,500 structures. But only the opium poppy, Papaver somniferum, and Papaver setigerum, are able to produce morphinan alkaloids such as the analgesic morphine or the antitussive codeine. We investigated the molecular basis for this exceptional biosynthetic capability by comparison of alkaloid profiles with gene expression profiles between sixteen different Papaver species and identified one cDNA which exhibits very similar expression pattern to previously isolated cDNAs coding for enzymes in benzylisoquinoline biosynthesis and which showed the highest amino acid identity to reductases in menthol biosynthesis. When expressed, the protein encoded by this cDNA reduced the keto group of salutaridine yielding salutaridinol, an intermediate in morphine biosynthesis. The stereoisomer epi-salutaridinol was not formed. The encoded protein was identified as salutaridine reductase (SalR; EC 1.1.1.248) and it was found to belongs to the family of the short chain dehydrogenases / reductases.

From codeine, four different 2-aryl substituted apomorphines were synthesised in 6 steps each. Oxidation of codeine with IBX followed by acid catalysed rearrangement gave morphothebaine, which was selectively triflylated at the 2-position and subsequently O-acetylated at the 11-position. The resulting triflate was coupled in a Suzuki-Miyaura type reaction with a series of 4-substituted arylboronic esters which, after deprotection, gave the desired 2-aryl apomorphines. The analogues were tested for affinity towards a range of dopaminergic, serotonergic and adrenergic receptors. 2-(4-Hydroxyphenyl)- apomorphine exhibited high affinity for the dopamine D2 receptor. A putative ligand-receptor interaction was put forward. The Royal Society of Chemistry 2005.

Disclosed are methods for making aldehydes and ketones comprising allowing the corresponding primary or secondary alcohol to react in the presence of trichoroisocyanuric acid, a compound of formula R1SR2 and a base. In one embodiment, the alcohol is a compound of formula (I) wherein R3 is a protecting group. Also disclosed are methods for making 3-O-protected morphine dienol carboxylates comprising allowing a compound of formula (I) to oxidize in the presence of a chlorine-containing compound and a compound of formula R1SR2; and allowing the product of the oxidation step to react with an acylating agent.

A process for the preparation of thebaine, its salts such as the bitartrate, and analogues thereof, together with a novel intermediate useful in said process are disclosed. Thebaine bitartrate is itself useful in the preparation of oxycodone; analogues are useful in the preparation of analogous 14-hydroxymorphinones.

A process for the preparation of thebaine, its salts such as the bitartrate, and analogues thereof, together with a novel intermediate useful in said process are disclosed. Thebaine bitartrate is itself useful in the preparation of oxycodone; analogues are useful in the preparation of analogous 14-hydroxymorphinones.

The invention provides processes for the conversion of normorphinone and its derivatives, which can be synthesized from morphine, to the corresponding 14-hydroxynormorphinone and its derivatives including oxycodone, oxymorphone, noroxymorphone and naltrexone. Noroxymorphone is a key intermediate for the production of important narcotic analgesics and antagonists. The invention also provides certain novel intermediates.

6-O-α- and β-D-glucopyranosylmorphine and 6-O-β-D-glucopyranosylcodeine have been prepared by condensations of 2,3,4,6-tetra-O-acyl-α-D-glucopyranosyl bromides with 3-O-acetylmorphine and codeine, respectively, followed by deprotection.Depending upon the method of condensation, variable amounts of orthoesters were found among the final products of condensation together with the desired glycosides.Highest yields of glycosides were obtained when 2,3,4,6-tetra-O-benzoyl-α-D-glucopyranosyl bromide was the glycosyl donor, and when the condensation was promoted with silver triflate in the presence of a less than stoichiometric amount of 2,4,6-trimethylpyridine as the acid scavenger.

-

Thebaine is converted to a mixture of codeinone and neopinone in aqueous formic acid solution containing as catalyst a mercuric salt. Thebaine is converted to a neopinone ketal by irradiation in an alkanol or to a mixture of neopinone and codeinone in an acidic aqueous solution. Neopinone ketals, codeinone and neopinone can be converted to codeine.

-

Novel derivatives of morphine having the general formula: STR1 wherein R 2, R 3, R 4, R 5 and R 6 are certain specified values, and their pharmaceutically acceptable salts. The compounds exhibit activity in the central nervous system and may be presented in the form of pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

Conjugate addition of lithium dialkyl cuprates to codeinone (3) gave as the major product a series of 8β-alkyldihydrocodeinones 4a-m. A low yield of the 8α-isomer 6 was isolated in several cases. 8β-Acyldihydrocodeinones 10 were prepared by the addition of acyl carbanion equivalents (protected cyanohydrin method or lithium bis(α-ethoxyvinyl)cuprate) to 3 followed by hydrolysis. 8β-Acetyldihydrocodeine (12) was reacted with MeLi or n-BuLi to give tertiary alcohols 13, which were oxidized to target dihydrocodeinones 14. The 8β-substituted compounds with unsaturated (4c,f,m), branched (4d,g,i-k), or large straight-chain (4h,l) alkyl groups, as well as the acyl (10a-d) and tertiary alcohol (14a,b) derivatives, were less active than dihydrocodeinone (4n) in the mouse writhing and rat tail-flick analgesic assays. The analgesically active 8β-methyl (4a) and 8β-ethyl (4b) compounds were converted to N-(cyclopropylmethyl)- and N-(cyclobutylmethyl)dihydronorcodeinones (17 and 18) and -dihydronormorphinones (19 and 20). Some of these compounds had mixed agonist-antagonist profiles of action. One of these compounds, N-(cyclopropylmethyl)-8β-ethylidihydronorcodeinone (17b), has been selected for further study in man.

Compounds of the general formula STR1 in which X represents halogen. These compounds are useful in the production of codeinone and codeine substantially free from impurities.

A process for the dehydrohalogenation of a 7-halo- or a 1,7-dihalodihydrocodeinone dialkyl ketal of the general formula (I): STR1 in which R represents an alkyl group containing from 1 to 6 carbon atoms, X represents hydrogen or chlorine or bromine and Y represents chlorine or bromine which comprises subjecting the ketal to the action of a base in the presence of a polar aprotic solvent. The process has utility in facilitating the production of codeine.