Sándor Makleit

Stereoselective synthesis of β-naltrexol, β-naloxol β-naloxamine, β-naltrexamine and related compounds by the application of the mitsunobu reac

Abstract As a continuation of our work, aimed at adopting the Mitsunobu reaction in the morphine series, a few representatives of dihydroisocodeines and dihydro

A new and efficient one-pot synthesis of apomorphine and its ring-A halogenated derivatives

Abstract Rearrangement and O-demethylation of codeine (2) and various 6-demethoxythebaine derivatives 6–11 with morphinane skeletone into apomorphine (3) and its halogenated derivatives 20–24 could be efficiently executed in a one-pot operation, by treatment with methanesulfonic acid/methionine.

Rearrangement of morphinandienes in methanesulfonic acid

Besides 2-fluoroapocodeine 7, the methanesulfonic acid-induced rearrangement of 6-fluoro-6-demethoxythebaine 2 gave the C-2 substituted apocodeines 8,11 and 20. Analogous rearrangement of thebaine 1 in the presence of alcohols offers a convenient and high-yielding route to the 2-alkoxymorphothebaine 6, 11, 12 and 13. Formation of the products has been explained in terms of nucleophilic substitution of the cationic intermediates 21 and 22 from the acid-catalysed reaction.

Synthesis of C-3 Halogene-Substituted Apocodeines and Apomorphines

Abstract A new effective method has been elaborated for the preparation of the hitherto unknown C-3 halogene derivatives (Cl, Br) of apocodeine and apomorphine, as well as of their N-demethyl-N-substituted (N-propyl, N-alkyl) analogues. These compounds are expected to possess an effect on the dopamine receptor system.

New nepenthone and thevinone derivatives

The diastereoselective reaction of thevinone (2a) and nepenthone (2c) and their dihydro derivatives (2b and d) with Grignard reagents afforded new N-substituted (20S)- and (20R)-phenyl-6,14-ethenomorphinan derivatives (6a-y). The Grignard reaction of the N-substituted-N-demethyl derivatives 4a-f and 4m-r with methylmagnesium iodide resulted in the (20R)-phenyl tertiary alcohols 5a-f and 5m-r, respectively, but the conversion of 4g-1 and that of the N-substituted-dihydrothevinone derivatives with phenylmagnesium bromide afforded the (20S)-phenyl derivatives 5g-l and 5s-y, respectively. The N-cyclopropylmethyl-, N-beta-phenylethyl-, and N-propyl derivatives were prepared by the 3-O-demethylation of compounds 5. For the synthesis of the N-allyl-, N-dimethylallyl-, and N-propargyl compounds 2a-d were reacted with the corresponding Grignard reagent, and treatment of the products with cyanogen bromide gave the cyanamides 8a-d. These latter compounds were transformed into 10a, b,d, whose alkylation led to the target derivatives 6d-f, j-l, p-r, and w-y. The biochemical investigation of these substances showed that the affinities to the delta-opioid receptors were high, but the selectivity was low. In two cases (6c and 11d) a mu-opioid receptor specificity was observed.

Application of the Mitsunobu Reaction for Morphine Compounds. Preparation of 6β-Aminomorphine and Codeine Derivatives

Abstract By the application of the Mitsunobu reaction several new 7 8 6β-aminomorphine and codeine derivatives, carrying a Δ7,8 double bond in ring C have been synthesized. The catalytic hydrogenation of these compounds offered a new stereoselective way for the synthesis of the corresponding 6β-amino-dihydro analogues. The different conformation of ring C of the saturated and unsaturated amino compounds allows to study the structure-activity relationship, and by tritiation of the unsaturated derivatives the substrate-receptor interactions can be examined.

Synthesis of N-Substituted 7β-Diprenorphine Derivatives

Abstract The separation of thevinone (2a) and β-thevinone (2b), as well as that of dihydrothevinone (3a) and β-dihydrothevinone (3b) was accomplished. By the application of various procedures numerous new N-substituted Diprenorphine analogues (8a-f) with 7R absolute configuration were synthesized. Detailed pharmacological investigation of the prepared compounds may contribute to a better understanding of the structure-activity relationship of morphine alkaloids.

Studies on the synthesis of β-thevinone derivatives

Abstract The reactions of β-thevinone and β-dihydrothevinone with tert-butylmagnesium chloride and n-propylmagnesium bromide were investigated. Further chemical transformations (N-demethylation, N-alkylation, O-demethylation) of the tertiary alcohols afforded the known β-buprenorphine and the hitherto unknown β-etorphine and β-dihydroetorphine. The by-products of these reactions were also isolated, their structures identified, and the mode of their formation was explained.

A new efficient method for the preparation of 2-fluoro-N-propylnorapomorphine

A new synthesis of the highly efficient, selective dopamine D2 agonist, 2-fluoro-N-propylnorapomorphine 1 has been accomplished, involving the transformation of thebaine 13 into 6-fluoro-6-demethoxythebaine 10, followed by sequential N-demethylation, N-alkylation, rearrangement with methanesulfonic acid into the apocodeine derivative 17, and subsequent O-demethylation with boron tribromide.

Synthesis of N-Demethyl-N-Substituted Dihydroisomorphine and Dihydroisocodeine Derivatives+

Abstract Several new N-demethyl-N-alkyl derivatives (1p, 1r, 1s, 1m, 1n and 1o) of dihydroisomorphine and dihydroisocodeine, and N-demethyl-N-cyclopropylmethylisocodeine (2g) have been prepared. The presented synthetic procedure allows a convenient access to a series of structurally related, stereochemically homogeneous substances for studies of the agonist/antagonist properties.