Demethylation cyanogen bromide

The key to clinical agents in this series, the secondary amine, 65, is obtained by a sequence analogous to that used to obtain desmethymorphine. Thus, the phenol (63) is first acetyl-ated (64), and then demethylated by treatment with cyanogen bromide hydrolysis gives the desired aminophenol (65). Alkylation... 

Demethylation of the tricyclic antihistamine 9, with cyanogen bromide gives the secondary amine 10 acylation of that intermediate with ethyl chloroformate affords the nonsedating H-1 antihistaminic agent loratidine (11) [3], It is of interest that this compound does not contain the zwitterionic funcrion which is thought to prevent passage through the blood-brain barrier, characteristic of this class of compounds. 

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action. To accomplish this, reduction of 24 followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27. The N-methyl group is then removed by the classic von Braun procedure. Thus, reaction with cyanogen bromide leads to the N-cyano derivative (28) hydrolysis affords the secondary amine 29. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide 30. Reduction with lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9... 

Omission of the phenolic group from cyclazocine results in a molecule which retains analgesic activity. In a classical application of the Grewe synthesis,15 the methylated pyridinium salt 54 is condensed with benzylmagnesium bromide. There is thus obtained the dihydropyridine 55. Treatment of that intermediate with sodium borohydride results in reduction of the iminium function to afford the tetrahydro derivative 56. Cyclization of 56 on treatment with acid leads to the desired benzomorphan nucleus. The cis compound (57) is separated from the mixture of isomers and demethylated by the cyanogen bromide procedure (58,... 

Nalorphine Nalorphine, N-allylnormorphine (3.1.75), is synthesized from morphine by its complete acetylation, i.e. by transformation into heroin (3.1.21), in order to temporarily protect the hydroxyl groups, and then by undergoing demethylation. In order to do this, heroin (3.1.21) is processed with cyanogen bromide. The resulting N-cyano derivative (3.1.73) is hydrolyzed by a solution of hydrochloric acid into the N-demethylated morphine, normorphine (3.1.74), whose secondary amine group undergoes alkylation with allylbromide to give desired nalorphine [47,48]. 

Synthesis Diacetylmorphine (Heroin) is demethylated with cyanogene bromide and hydrolyzed to normorphine, which is alkylated to ally bromide (, Weijlard and Erickson (Merck Co.), 1944 Weijlard (Merck Co), 1959 Klee-mann et al. 1999). 

Radiolabeled 3-demethyl-3-chloroacetylthiocolchicine with a l4C label in the chloroacetyl moiety (DCTC) was found to be a potent inhibitor of tubulin polymerization and of colchicine binding to tubulin. The reaction was 80-90% inhibited in the presence of saturating, amounts of known antitubulin compounds such as podophyllotoxin, combretastatin A-4, and colchicine itself. The tubulin /3 subunit was labeled 5-6 times faster than the a subunit. Cyanogen bromide digestion of the /3 subunit which had reacted covalently with DCTC indicated that at least three positions in /3-tubulin had reacted with DCTC. Purification and amino acid sequencing of these peptides are in progress (138). 

Demethylation at the nitrogen in position 6 could be realized by new modifications of the von Braun degradation. The 6-nor-6-cyano derivatives 46, obtained in the usual way by the action of cyanogen bromide on the parent compounds, could be reduced directly with zinc in acetic acid in good yield (46) to the 6-nor compounds (47). An alternative procedure was published independently by a Japanese group (47), using a two-step process via a urea-type compound 48. 

The lactone ring in decinine (2) was reduced to the cyclic ether (34) with diborane generated from sodium borohydride and boron trifluoride. The Emde degradation of (34) afforded a piperidine derivative (35a). The Cyanogen bromide N-demethylation of the methyl ether (35b) followed by... 

Demethylation of 1-methyl-3-piperideines may be accomplished with the use of the von Braun cyanogen bromide procedure.60,128 A certain drawback of this method consists in loss of half of the tertiary amine in formation of a quaternary salt (e.g., 146), in addition to the required 1-cyano derivative (e.g., 147), which is then hydrolyzed to the required secondary amine. 3-Piperideine was obtained by this procedure in the form of a stable free base.128... 

Generation of benzomorphan secondary amines, for conversion to appropriate N-substituted derivatives, usually requires N-demethylation of the corresponding tertiary amine. This may be effected by the von Braun reaction with cyanogen bromide or by the use of alkyl-, halogenated alkyl-, and arylchloroformates or diethylazodicarboxylate. Methods for N-demethylation in the series have been summarized by Rice.(62) Removal of an N-benzyl substituent affords an alternative path to norbenzomorphans and is exemplified by Michne and co-workers(63) and Kametani and Aoyama.(s4)... 

The precursor was obtained by demethylation of the parent N-Me compound by the use of well-established reagent, cyanogen bromide. Others are butorphanol (the only compound derived from a non-natural source) a 14-hydroxy-N-cyclobutylmethyl compound in which the oxide... 

Attempts to demethylate himbacine with a variety of reagents under several conditions were unsuccessful but dihydrohimbacine was readily converted by cyanogen bromide into the cyanamide (XXVI). This was stable to acid and only slowly hydrolyzed by alkali but catalytic hydrogenation afforded dihydrohimbeline in good yield. By standard methods the following iV-substituted derivatives were prepared ethyl, p-hydroxyethyl (p-nitrobenzoate and trimethylgallate), allyl, m-butyl, ethoxycarbonylmethyl, cyclohexyl, benzyl, /3-phenylethyl, y-phenyl-propyl, and phenylcarbamido. 

Desoxycodeine-E [xxx] pan be prepared by the lithium aluminium hydride reduction of codeine [n] p-toluenesulphonyl ester [17-18], Its structure is shown to be [xxx] by hydrogenation of the base to dihydrodesoxycodeine-D [xiii], degradation of the methiodide to desoxy-a-codeimethine [xxix], and isomerization of the latter to desoxy-/3-codeimethine [xxvin], production of cyanonordesoxy codeine-E [xxxi] by the action of cyanogen bromide on the base, and by the facts that desoxycodeine-E is neither a phenol nor an enol ether [17]. Desoxycodeine-E can be demethylated to desoxymorphine-E [62]. 

Actually hydrogenation is carried out before the Grignard reaction. Cyanogen bromide N-demethylates the compounds. 

The second issue, the exchange of the A -alkyl group, is much more challenging. The current methods include the use of reagents such as cyanogen bromide (von Braun demethylation) [85, 86] or methyl chloroformate [87-91]. Neither is... 

The synthesis of buprenorphine has a certain similarity to that of etorphine. After the Diels-Alder reaction of thebaine with methyl vinyl ketone, the double bond is hydrogenated. Then follows a Grignard reaction with t-butyhnagnesium chloride. For modification of the tertiary amine, this is demethylated with cyanogen bromide (von Braun reaction) and treated with cyclopropanecarbonyl chloride. Following reduction with lithium aluminium hydride, the aromatic methoxy-group is finally replaced by nucleophihc substitution under forcing conditions. 

The synthesis of pentazocine is comparatively short. The Grignard reaction with a pyridinium salt is followed by partial hydrogenation. Cleavage of the methyl ether is accompanied by acid-catalysed alkylation, which leads to the buildup of the quaternary centre. Finally, the amino-function is demethylated with cyanogen bromide and alkylated with isopentenyl bromide. 

The selective removal of C-5 from 2 -deoxynucleosides via de-carboxylative degradation has been reported . Some N-methyl-pyridi-nium, -quinolinium, and -isoquinolinium iodides have been successfully demethylated by simply refluxing their dimethylformamide solution . The solvolytic cyanogen bromide-degradation of alkaloids has been improved by addition of bases such as MgO . 

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