Morphine dihydrocodeinone

Dihydromorphinone, Cj,Hjg03N, and derivatives. Dihydromorphinone (LIII MeO HO) is formed when morphine in solution is treated with relatively large quantities of platinum or palladium catalyst under various conditions.It melts at 262-3° and yields an oxime, m.p. > 234°. The hydrochloride is the drug known as dilaudid. On 0-methyla-tion dihydromorphinone yields dihydrocodeinone (see above), and when dissolved in ether and treated with methyllithium the corresponding tertiary alcohol, 6-methyldihydromorphine, CigHggOgN, m.p. 209-211°, Wd ° 14i7° (EtOH), is formed. This on methylation with diazomethane gives 6-methyldihydrocodeine as described above (Small and Rapoport... 

Numerous derivati es of morphine have been devised for use in medicine including acyl derivatives, of which diacetylmorphine (C], Hj,03N, Ac2, m.p. 173°, [a]J°° — 166° (MeOH) B. HCl. 2H2O, m.p. 231-2°) is the best known, alkyl and other ethers such as the ethyl-and benzyl-morphines, dihydro- and dihydroketo-compounds such as dihydromorphine, dihydrocodeine, dihydromorphinone, dihydrocodeinone and hydroxydihydrocodcinone, and the deoxy-compounds, e.g., dihydro-deoxymorphine and methyldihydrodeoxymorphine. 

Rice, K.C. (1980) Synthetic Opium Alkaloids and Derivatives. A Short Total Synthesis of (ib)-Dihydrothebainone, ( )-Dihydrocodeinone, and ( )-Nordihydrocodemone as an Approach to a Practical Synthesis of Morphine, Codeine, and Congeners. Journal of Organic Chemistry, 45, 3135-3137. 

Hong, C.Y, Kado, N., Overman, L.E. (1993) Asymmetric Synthesis of Either Enantiomer of Opium Alkaloids and Morphinans. Total Synthesis of (—)- and (-f)-Dihydrocodeinone and (—)- and (-F)-Morphine. Journal of the American Chemical Society, 115, 11028-11029. 

Parker, K.A. Fokas, D. (2006) Enantioselective Synthesis of (—)-Dihydrocodeinone A Short Formal Synthesis of (—)-Morphine. Journal of Organic Chemistry, 71,449 55. 

The inifial sfeps in fhe mefabolism of morphine and codeine by Pseudomonas putida MIO involve oxidafion of fhe C-6 hydroxy group and subsequenf reducfion of fhe 7,8-olefinic bond, forming hydromorphone (dihydromorphinone) and hydrocodone (dihydrocodeinone), respectively (Scheme 4) [52], These products have important industrial appUcations hydromorphone is an analgesic some seven times more potent than morphine [53],... 

Dihydromorphinone is 3-4 times more powerful than morphine and dihydrocodeinone is just a little less than morphine in potency. Their pitfall is an addiction liability, as great if not greater than morphine. To produce Hydrogenate morphine or codeine in a warm, strongly acidic solution, in a large excess of palladium or platinum catalyst, as per instructed in the reductions chapter. 

Codeine. Is a narcotic derived from morphine and is addictive. It can be purchased over the counter, but you will have to sign for it. Sometimes you will have to show identification. It creates feelings of euphoria and weightlessness with doses of about 50 to 150 mg. It can also be made much more potent by hydrogenating to dihydrocodeinone as instructed in the analgesic chapter in this book. 

CNS dihydrocodeinone and oxycodone/alkal. dihydro- morphine from opium/alkal. 

The Heck reaction of 1,3 -diene systems via 7r-allylpalladium is also useful. This cyclization, which forms very congested quaternary carbon centers involving the intramolecular insertion of di-, tri- and tetrasubstituted alkenes, is particularly useful for natural products synthesis. In the synthesis of morphine, bis-cyclization of the octahydroisoquninoline precursor 112 by the intramolecular Heck reaction proceeded using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the 7i-allylpalladium intermediate 113, which attacks the phenol intramolecularly to form the benzofuran ring 114. Based on this method, the elegant total syntheses of (—)- and (+)-dihydrocodeinone, and (—)- and (+)-morphine (115) have been achieved [50],... 

Among various recent applications of diastereoselective cuprate addition reactions to cyclic enones in target-oriented synthesis,81,81a 81c,83 87 the synthesis of (—)-dihydrocodeinone and (—)-morphine by Mulzer and co-work-... 

Goto(121 125) has prepared (+)-morphine and related structures from (—)-sinomenine. More recently, (+)-opioids have been required, not for their gross pharmacological actions, although these have been examined/126 but as research tools for probing opioid receptors/67 (+)-Codeine and (+)-morphine were synthesized 128 from (+)-dihydrocodeinone (60) derived in one step from sinomenine/124 Conversion of 60 to the ethyl carbamate (61) facilitated the... 

A Wittig reaction with dihydrocodeinone (78) afforded the 6-methylene derivative (86, R = Me, R = H) that was hydrogenated to 6-methyldihy-drodeoxycodeine (87, R = Me), another good analgesic (up to 25 x morphine).(l84 235 2 u ) Reaction of nalorphine with carbomethoxymethylene... 

The chemistry of such bridged naphthalenes-benzomorphans and some related compounds has been reviewed previously.<1 3) The first synthesis of a benzomorphan was achieved by Barltrop(4) however, prior to that synthesis, Schopf,(5) in his investigations of the structure of morphine, had isolated the benzomorphan, 2, from a thionyl chloride-induced, second-order Beckmann rearrangement of dihydrocodeinone oxime, 1. Reinvestigation(5a,5b) of the Beckmann rearrangement and a study of the Schmidt reaction of 6-oxomor-phinans confirmed Schopf s work and led to the isolation of the anticipated lactam (2a). 

A total synthesis of morphine (240) employing a palladium-catalyzed coupling in a key step started from the hydroisoquinoline derivative 238 to give dihydrocodeinone 239... 

The alkaloid contents of transformed and non-transformed calli were analyzed by an ELISA and an HPLC. The crude extract can be immediately subjected to the ELISA analysis as described above (sections 3.1, 3.4) using morphine-specific monoclonal antibody [145]. The morphine-specific antibody used has a high affinity for morphine, codeine, ethylmorphine, dihydromorphine, and dihydrocodeine, less reactivity with dihydromorphinone, dihydrocodeinone, and norcodeine, but almost no reactivity with naloxone and naltrexone [145]. 

Dihydrocodeinone and dihydromorphinone can be prepared by the catalytic rearrangement of codeine [i] and morphine respectively on heating solutions of the base in alcohol, with [48-52] or without [53] acid, with [48-50] or without [51-53] hydrogen, in the presence of noble metal catalysts. The yields reported by Knoll and Co. for this method are up to 95 per cent. [52], but Rapoport claims that the maximum is about 50 per cent. [47]. As a by-product in this rearrangement phenolic bases were noted and these may be made the principal products by modifying the conditions. In this way thebainone-A [xix] can be prepared from codeine, and its analogue, O-desmethylthebainone-A, from morphine in 60 per cent, yield [54] (see Chap. XV). 

In fact this sequence of reactions gave a base [xLvm] as final product, showing that C-13 is the point of attachment of the side-chain in dihydrocodeinone, and therefore in the morphine alkaloids generally [68]. 

That 14-hydroxy- and 14-bromocodeinonehave the morphine skeleton intact is demonstrated by the reduction of the latter with ferrous hydroxide to codeinone [vm] and catalytically to dihydrocodeinone [8, 13], and its conversion to 14-hydroxycodeinone oxime on treatment with hydroxylamine [8-9]. 

In 1992, Parker and Fokas reported the short step (11 steps) synthesis of racemic dihydroisocodeine, which completes a formal synthesis of codeine and morphine [58]. The key feature of their synthesis are (1) a construction of an aryl ether moiety (connection of the A and C rings) by Mitsunobu reaction, (2) a tandem radical cyclization of aryl bromide possessing the C-ring precursor to generate the A-B-C-E ring of morphine, and (3) a hydroamination for the construction of the D-ring by the reaction of a tosylamide with Li/NH3. In 2006, they reported the chiral version of the synthesis of dihydrocodeinone [59]. 

Attention was drawn to the 4 -substituted 14-cinnamoylamino-17-cyclopropyl-methyl-7,8-dihydronorcodeinones and equivalent morphinones (40) (Fig. 3). Of particular interest to Reckitt and Colman s target of buprenorphine-like opioid activity were the dihydrocodeinones (40a-c) from which the 4 -chloro derivative, called methoclocinnamox (40a, MC-CAM), was selected for detailed study. The Reckitt and Colman group had shown the three 4 -substituted dihydrocodeinones (40a-c) to be predominantly MOR partial agonists of long duration in vivo [14], Importantly, MC-CAM showed bell-shaped dose-response curves in both tail withdrawal and tail pressure antinociceptive assays. In this respect and in the inability of naltrexone to reverse its antinociceptive effect, as well as its long-lived morphine antagonism, its similarity to buprenorphine was demonstrated. 

Morphine and dihydrocodeinone have been shown to react with... 

Kametani et al. reported the fifth formal total synthesis of morphine and sinomenine (41) via racemic sinoacutine (43a) and thebaine (480). Gafil reviewed the literature on the preparation of dihydrocodeinone (48a) and dihydromorphinone (48b), and he developed his own procedure for the preparation of these two substances (yield ca. 40-47%) (500). 

Synthetic work on morphine and morphinandienone alkaloids continues unabated. Amurine " and O-methylflavinantine have been obtained by the benzyne reaction of appropriate benzyl isoquinoline precursors. A review concerning new synthetic derivatives of dihydrocodeinone is not readily available.Codeine has been prepared in 98% yield from morphine using... 

---