Dihydro thebaine

Most of the dihydrothebainone produced from thebaine is former under mild conditions of hydrogenation and probably not via dihydro thebaine, but by way of thebainone methyl enolate and dihydrothebainone A-5 6-methyl enolate as described above. 

Steric hindrance around an allylic function will diminish its hydrogenolysis as access of the function to the catalyst surface is impeded. Reduction of 5-methylthebaine (32) proceeds smoothly over Pd-on-C in ethanol at 1 atm to afford 5-methyldihydrothebaine (33), whereas reduction of thebaine itself is less clean and gives dihydrothebainol, dihydrothebainone, and dihydro-thebaine (/b). 

After 10 years of intensive research, no significant dissociation of potent analgesia and dependence liability was accomplished. As an indirect result of the systematic program the identification of the 17-hydroxy-7,8-dihydro compounds oxycodone (patented in 1925 by E. Merck AG, Germany) and oxymorphone, derived from thebaine, are of particular note. 

Details of the Diels-Alder addition of aromatic nitroso-compounds to thebaine to give adducts (117), the ring-opening of these to 14-hydroxylamino-compounds (118 R = OH), the reduction of these to 14-arylamino-compounds (118 R = H), and cyclization to (119) have been published.162 Dihydro-thebaine-< 4-phenyl ether (120 R = OPh) has been transformed into the benzylisoquinoline (121) by potassamide in liquid ammonia, but the same transformation could not be effected with the free phenol (120 R = H) or with the deoxy-compound (120 R = H).163... 

Thebaine was isolated from opium in 1835 by Pelletier (439). The therapeutic applicability of thebaine was studied by Balint et al. (440). It was found to be more toxic than morphine. It is a more effective narcotic but a weaker analgesic than morphine. The analgesic effect of thebaine in doses of 0.01 g/kg is greater than that of amidopyrine this effect persists, however, only over a period of 30 min. Dihydro-thebaine is somewhat more effective but it is more toxic (441). The number and the location of the double bonds in ring D of the morphinane skeleton is of importance for the analgesic effect. Teraoko... 

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... 

Dihydro-electrolytic reduction of desoxycodeine-C [xv] to dihydro-desoxycodeine-B [lxxiv], and dihydro-i/r-codeine-C the structure [lxxhi] by analogy with the sodium and alcohol reduction of desoxycodeine-C to dihydrodesoxycodeine-C [lxxv] sodium and alcohol reductions have a known tendency to effect 1 4 addition of hydrogen to an allylic ether [248, 281, 423]. (Cf. the reduction of thebaine [lxxvii] to dihydrothebaine-< [lxxvih] [265, 405, 424].)... 

Codeinone contains a double bond and is readily reduced to dihydro-codeinone [vm] [3, 13] (see below) it shows the properties of an a /3-unsaturated ketone, e.g. attempts to prepare its oxime in concentrated acid solution, or from a solution of thebaine in concentrated acid, result in an oxime containing an additional molecule of hydroxylamine by addition of the latter to the double bond [9]. 

The first reduction of thebaine [i] was achieved by sodium and boiling alcohol and resulted in the production of a phenolic dihydrothebaine in only moderate yield [1-3]. The same compound, now called dihydro-thebaine-, is more conveniently prepared in yields of up to 95 per cent, by the reduction of thebaine with sodium in liquid ammonia without the addition of alcohol [4-5]. 

Dihydro thebaine-< absorbs only one mole of hydrogen on catalytic reduction, yielding dihydrothebainone AB-enol methyl ether [ix], which is identical with the product of sodium and liquid ammonia reduction of the non-phenolic dihydrothebaine [x] [5]. (A compound of different melting-point and specific rotation was prepared by Small and Brown-ing [3] by the catalytic reduction of dihydrothebaine-< and allotted the structure [xi] owing to a misconception of the structure of the latter. It is probably a mixture [5].) Dihydrothebainone [xn] is produced by the hydrolysis of [ix] showing that no rearrangement of the thebaine skeleton occurs during sodium and alcohol reduction [5]. 

S-Dihydrothebaine [n] absorbs two moles of hydrogen on reduction over platinum oxide, the product being dihydrothebainol-6-methyl ether [xm] [6], identical with the compound obtained in the reduction of thebaine in neutral solution [3]. The configuration at C-14 in [xm] is not known. A dihydro-derivative, dihydrothebainone A6-enol methyl ether [xi], can also be isolated from the products of reduction [12]. 

This isomer is obtained in erratic yield by the hydrolysis of dihydro-thebaine- by sulphurous acid. It was initially allotted the structure [xm] [3], but has since been shown to have the structure [xxv], which is allotted to the base on account of the ultra-violet absorption spectrum, which indicates a highly conjugated system (Figs. 8 and 9), and the infra-red absorption, which indicates that the compound is a /3 y-unsaturated ketone [13]. It is apparently formed during the hydrolysis... 

Schopf [2] reported that neither the anhydride nor the ester could be reduced, but the latter has since been reduced catalytically to ethyl dihydro-(thebaine-maleate) [rv] and with lithium aluminium hydride to the diol [v] [3]. An attempt to prepare the isomeric ester [vi] from fumaryl chloride is in progress [3]. 

Ethyl dihydro-(thebaine-maleate) 147-149 Eton rods. . 3... 

Dihydro-thebaine-quinone . 195-200d. /9-ethoxy- needles 3... 

Fieser and Holmes [35], by the addition of butadiene and dimethyl-butadiene to ethyl 3 4-dihydro-a-naphthoate, were able to prepare [cxn, R = H] and [cxn, R = Me], and also the methoxy-compounds [cxm] and [cxiv] in a similar way [36], Reduction of [cxiv] afforded 3 4-dimethoxy-5 6 7 8 9 10 13 14-octahydrophenanthrene-13 -carb -oxylic acid [cxv], which is theoretically obtainable from [cxvi], a known product of degradation of thebaine [37].. Attempts to convert the carboxyl group of [cxv] to other substituents were made, and in this connexion [oxii, R = Me] was submitted to the Bouveault-Blano reduction followed by treatment of the product with phosphorus... 

ADDITION TO CHAPTER XXI The tetrahydro-thebaine-quinone reported on p. 291 has been shown to be in fact dihydro-thebaine-quinone in which the unsaturated ketone system has suffered saturation. It is also clear from infra-red spectral measurements that ethyl thebaine-maleate suffers no reduction on hydrogenation, contrary to the statement on p. 290 [2],... 

This synthesis of morphine is also a synthesis of thebaine (CCCLXXXVI), as the latter has recently been prepared from dihydro-codeinone by Rapoport et al. (424) ... 

Oxidation of thebaine with m-chloroperbenzoic acid has been shown to give a mixture of 14-hydroxycodeinone and 8-acetoxy-14-hydroxy-dihydro thebaine (143), which can be hydrolysed to 8,14-dihydroxy-dihydrocodeinone and hydrolysed and dehydrated to 14-hydroxy-dihydrocodeinone. ... 

The anodic activity has been only observed in those morphine derivatives exhibiting phenolic functions such as psuedomorphine, dihydro-morphine, dihydromorphinone, nalorphine, apomorphine etc. On the other hand codeine, ethylmorphine, thebaine, benzylmorphine or dia-cetylmorphine (heroine) are inactive. 

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