A practical synthesis of codeine from dihydrothebainone

Weller, Dwight D.; Rapoport, Henry

doi:10.1021/jm00232a001

Cited by 60 publications

(25 citation statements)

References 9 publications

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“…After 5 h, the reaction reached the equilibrium with 6a : 2b = 1 : 4. Ease of methanol elimination in this case can obviously be explained by the gain upon the for mation of extended system of the conjugated π bonds in compound 2b, which included diene fragment of the ring C and phenylethenyl moiety in the position C (8). Thus, the presence in the codeinone derivatives of the type of ketal 6a the substituents at the position C(8) capable of effective π,π conjugation with the C-C multiple bonds of the ring C turned them into "masked" thebaine derivatives.…”

Section: Resultsmentioning

confidence: 93%

“…6 Reaction of bromide 5d with Bu t OK in DMSO at higher temperature (120 °C) afforded thebaine (2a) in nearly quantitative yield. 8 However, reaction of bromide 5c with Bu t OK under the same conditions resulted in a complex product mixture. Probably, these conditions is too severe for triene 2b.…”

Section: Resultsmentioning

confidence: 99%

“…For this rea son, both the elimination of HBr from bromide 5d and hydrolysis (acidolysis) of codeinone dimethyl ketal (6c) were studied in detail in the framework of the developed earlier procedure for the preparation of 2a from codeinone (6d), which is readily available from 4a. 7,8 Ketal 6c can be synthesized from bromide 5d by both the prolonged refluxing with potassium tert amylate in tert amyl alcohol 7 and the action of Bu t OK in DMSO at 60 °C. 8 Similar reaction of 8 [(1E) 2 phenylethenyl] substituted bromide 5c with Bu t OK in DMSO proceeded at ambient temperature to give ketal 6a.…”

Section: Resultsmentioning

confidence: 99%

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On the features of reactivity of 8-[(1E)-2-phenylethenyl]-substituted thebaine and codeinone derivatives

2011

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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 unsubsti tuted codeinone and thebaine derivatives. Thevinone (1a) is a key intermediate on the synthetic route from natural alkaloid thebaine (2a) toward orvinols (3a), so called "semi synthetic" opioid derivatives exhibit ing marked affinity to opioid receptors (e.g., buprenor phine, diprenorphine, ethorphine, dihydroethorphine). 1,2 Therefore, compounds 3a for decades are the subjects for intense search for potent analgetics for treatment of severe and chronic pain with decreased level of unwanted side effects. Compound 1a is formed by [4+2] cycloaddition of AcCH=CH 2 to diene system of 2a and serve as the starting compound for the synthesis of large scope of thevinols 3b, O demethylation of the latter leading to compounds 3a. A variety of compounds 3b and 3a resulted mainly from altering the substituents R 2 and R 3 . However, recently, modification of the C(6)-C(14) etheno or ethano bridge of compounds 3 became of interest. Functionalization of these positions can be achieved by either preliminary in troduction of the substituent at the positions 7 or 8 of diene 2a (which correspond to positions 18 and 19 of ad duct 1a) followed by [4+2] cycloaddition 3 or by modifica tion of the ethene bridge in the Diels-Alder adduct. 4,5Recently, in the framework of the design of novel pro cedures for the modification of the C ring of the morphi nan alkaloids, we carried out the Pd catalyzed Heck reac tion of codeine (4a) and PhCH=CHBr to give 7,8 di hydro 8β [(1E) 2 phenylethenyl]codeinone (5a), from which 8 [(1E) 2 phenylethenyl]codeinone dimethyl ket al (6a) was synthesized in four steps. 6 It was found that ketal 6a bearing conjugated diene system reacts with di enophiles to give adducts 7 including 19 [(1E) 2 phenyl ethenyl]thevinone (1b) (in the reaction with AcCH=CH 2 ) instead of the expected 7,8 fused compounds. The use of ketal 6a as "masked" 8 [(1E) 2 phenylethenyl]thebaine (2b) opens the route toward derivatives of compounds 3 substituted at the position 19. Moreover, the hydrolysis of ketal 6a and subsequent reduction of the carbonyl group afforded 8 [(1E) 2 phenylethenyl]codeinone (4b), which in the "ordinary" Diels-Alder reaction gives derivatives with the additional cycle fused to the C ring at the posi tions C(7)-C(8). 6 Thus, ketal 6a is the key intermediate toward both the 7,8 fused derivatives of morphinan alkaloids and de 1, 2: R = H (a), trans CH=CHPh (b) 3: R 1 = H (a), Me (b); Z∼Z = CH 2 CH 2 , CH=CH

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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On the features of reactivity of 8-[(1E)-2-phenylethenyl]-substituted thebaine and codeinone derivatives

2011

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“…The yield of the resulting N-methylamine (10), over the three steps of borohydride reduction of the enone, and Periodane (Dess-Martin Reagent [1,1,1-triacetoxy-1,1dihydro-1,2-benziodoxol-3(1H)-one]) oxidation of the allylic alcohol (10) in methylene chloride produced the corresponding ketone (74%) which, on standing for 24 hr in ethanolic aqueous ammonium chloride in the presence of zinc dust underwent the remarkable transformation to morphinane (11) in a reported 73% yield; Fig. (9).…”

Section: : Marcus a Tius And Michael A Kerr [5]mentioning

confidence: 99%

Syntheses of Morphine and Codeine (1992 - 2002): Templates for Exploration of Synthetic Tools

Mascavage¹,

Wilson²,

Dalton³

2006

COS

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Morphine (1) and its O-methylated analogue codeine (2), analgesic alkaloids of the opium poppy (Papaver Somniferium), have been targets of organic chemists engaged in synthetic activities for at least half a century. The "first" (Gates) and "most efficient" (Rice) syntheses of morphine (1) and codeine (2) are well known and have been reviewed and analyzed extensively numerous times. However, syntheses of the same two alkaloids that have been reported since 1992 and which have been used as devices to advance the art of organic synthesis are not as widely recognized and they have not been as thoroughly reviewed. Here they are analyzed in the spirit of the use of these two compounds as templates. Further, since both racemic and enantiospecific syntheses are important and since all eight (8) approaches (since 1992) are sufficiently different so as to warrant more tha n superficial examination, they are all considered.

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“…They used Rapoport's procedure [47] published in 1976 which is based on mainly the one presented in Fig. (3).…”

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confidence: 99%

Recent Developments in the Chemistry of Thebaine and its Transformation Products as Pharmacological Targets

Berényi¹,

Csutorás²,

Sipos

2009

CMC

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The most practical synthetic routes to the preparation of as important pharmaceuticals as oxycodone, naloxone, naltrexone, nalbuphine and buprenorphine have utilized the alkaloid, thebaine, as a starting material. This review intends to focus on chemical transformations of morphinans which resulted in morphinandiene derivatives with well-established and novel pharmacological potencies. These chemical transformations were mainly associated with the formation and substitution of the unique diene structure of the ring C of the morphinan backbone.

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A practical synthesis of codeine from dihydrothebainone

Cited by 60 publications

References 9 publications

On the features of reactivity of 8-[(1E)-2-phenylethenyl]-substituted thebaine and codeinone derivatives

On the features of reactivity of 8-[(1E)-2-phenylethenyl]-substituted thebaine and codeinone derivatives

Syntheses of Morphine and Codeine (1992 - 2002): Templates for Exploration of Synthetic Tools

Recent Developments in the Chemistry of Thebaine and its Transformation Products as Pharmacological Targets

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