The Reactions of Thebaine

Further work on the reduction of thebaine by chemical means has been published since Chapter 8 of Volume II was written. This supports the conclusions outlined previously (Vol. II, pp. 199-203), (402, 403). A careful search of the mother liquors from the commercial hydrogenation of thebaine has led to the isolation of about 1 % of neopine methyl ether (CCCLIII) (404). It is, of course, possible that more of this substance is formed than can be isolated since most of it might well be reduced further to tetrahydrothebaine which is also produced in the reduction. 

It has been proposed that the dihydrothebaine formed hy sodium reduction of thebaine (so-called phenolic dihydrothebaine) be renamed dihydrothebaine- p (405). This substitution of a new trivial name for an older one does not appear legitimate once a structure is established beyond doubt. We would prefer the term A -dehydrothebainol methyl ether for the sodium-ethanol or sodium-ammonia reduction product (CCCLIV), The lithium aluminum hydride reduction product would then be A h4).(jeijy(ji.o hel3ajnol methyl ether (CCCLV), and the third isomer, obtained by base-catalyzed rearrangement of codeine methyl ether, would be A -dehydrothebainol methyl ether (CCCLVI). 

The course of the hydrolysis of A -dehydrothebainol methyl ether has been reinvestigated by Bentley and co-workers (406, 407). It has been shown that the simple hydrolysis product, thebainone 

Under the vigorous conditions of hot sulfurous acid hydrolysis the reasonable assumption has been made (407) that )S-elimination of the amine chain takes place, followed by readdition to yield a-thebainone (CCCLVIII). 

The experimental details on which the assignment of the structure of phenyldihydrothebaine was based have now been given. The crucial experiment was the oxidation of the exhaustive methylation product from the methyl ether of phenyldihydrothebaine to 6,6,5 -trimethoxy-diphenic acid, also obtained by oxidation of acetylthebaol quinone with hydrogen peroxide and acetic acid, followed by methylation (410). 

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The product (6-2) from the reaction of thebaine with hydrogen peroxide can be viewed as the result from fromal 1,4 addition of two hydroxyl groups across the diene. The perspective depiction of thebaine reveals that the addition in fact occurs at the far more open face of the molecule. The product from this oxidation incorporates a new hydroxyl group at the 14(3 position and a hemiacetal at the 6 position. Treatment with a nuld acid leads to the hydrolysis of this last function and the formation of enone (6-3). 

The decomposition of eserethole methiodide to yield physostigmol ethyl ether is analogous to the reaction of thebaine methiodide (XI)... 

The first indication that derivatives of 14-aminocodeinone and 14-aminomorphi-none could be accessible came from the reaction of thebaine with nitrosobenzene to yield a cyclic adduct (10a) which yielded 14p-phenylaminodihydrocodeinone (11a) on sequential hydrolysis and reduction (Scheme 1) [5]. Schwab then utilised this chemistry for the synthesis of a small series of 14-phenylaminodihydrocodei-nones and derivatives (11) [6]. Some codeinone derivatives produced by these reactions were evaluated in antinociceptive assays, showing that the (V-methyl derivatives (11a,b) had substantial activity in the writhing assay but only weak... 

Full details of the reaction of thebaine with tetranitro-methane previously reported have been published. The peroxide (110), obtained in the presence of oxygen on treatment with sodium iodide... 

The transient C-nitrosoimine 193 (Ar = 4-CIC6H4) is formed by the action of ethyl cyanoformate on the sulfimide 191 and also by the oxidation of the amidoxime 192 with lead tetraacetate. In the presence of thebaine, both reactions yield an identical dihydrooxazine101. 

The groups of Kirby224,340 and of Revesz477 have studied the Diels-Alder reactions of thebaine 134 with ethyl thioxoacetate (equation 140) and other thioaldehydes, thus preparing several opiate antagonists. 

A new method for the demethylation of codeine to morphine, previously a capricious reaction, has been reported, the product being obtained in good yield. Demethylation by boron tribromide in chloroform gives 90—91%150 and by potassium t-butoxide in propanethiol gives 80% morphine.151 A patent describes an improved method for the preparation of codeinone from thebaine, by adding the alkaloid to anhydrous hydrogen bromide in solution in methylene chloride and dibutyl ether at -20 °C, in the presence of small quantities of iodine, followed by hydrolysis with aqueous sodium bicarbonate. The claimed yields of codeinone are 95% crude and 90% after purification.152 Codeinohe is an intermediate in the conversion of thebaine into codeine. An overall yield of 85% of codeine from thebaine, without purification of any of the intermediates, has been claimed for an... 

The Diels-Alder reaction of thebaine with various electrophiles yields compounds (Fig. 7.19) that have extremely high potencies, over 1000-fold higher than morphine in some cases (see Refs. 370, 371). X-ray (372) and NMR (373) analysis of 19-propylthevinol, the 3-methyl ether of etorphine (42 above), indicates that the 6,14-etheno bridge is held inside (endo) the tetrahydrothebaine ring system and below the plane (a) of the Cy-Cg bond (see Fig. 7.19 and Ref 283) the C ring is held in a boat conformation by the 6,14-endo etheno bridge. 

The cause of the isomerism is the asymmetric carbon atom C-14, which in thebainone-A and its derivatives is configured as in codeine but has the opposite configuration in /3-thebainone-A. Although the latter could arise from /3-dihydrothebaine [nr] by a 1 4-hydrolysis of the system MeO C=C—C=C, such a mechanism seems unlikely as it cannot be operative in the hydrolysis of dihydrothebaine- cf> [iv] during which /3-thebainone-A must be formed by the isomerization of thebain-one-B, a reaction that has been independently realized [13] (see below). 

THE REACTION OF 0-CODEINE AND THEBAINE DERIVATIVES WITH GRIGNARD REAGENTS... 

It was at this time that we, at Reckitt and Colman became interested in the work of Professor Gordon Kirby on Diels-Alder reactions of thebaine with nitroso derivatives with the objective of providing a viable synthesis of 14-aminocodei-none. This would allow access to a wide range of 14-acylamino- and 14-alkyla-mino-codeinones and morphinones which could be improvements on the available derivatives of 14-hydroxycodeinone and oxycodone. 

New Diels-Alder adducts of thebaine with aromatic nitroso-compounds of structure (118 R = H, Me, Cl) have been prepared. These are unstable and can be hydrolysed to 14-aryIhydroxylaminocodeinones (119), which can be reduced to derivatives of the hitherto inaccessible 14-aminodihydrocodeinone (120). The base (119 R = H) is susceptible to base-catalysed displacement of the oxide bridge, the product being the 5,14-bridged thebainone derivative (121). ° The reaction between thebaine and excess of ethyl azodicarboxylate involves Diels-Alder addition and addition of the N-CH3 group to a second molecule of azo-ester. The primary product (122) has not been isolated pure, but yields ethyl hydrazodicarboxylate and the substituted codeinone (123) on hydrolysis. ... 

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