N-Demethylation of morphine and structurally related compounds with chloroformate esters

Abdel-Monem, Mahmoud M.; Portoghese, Philip S.

doi:10.1021/jm00272a025

Cited by 64 publications

(24 citation statements)

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“…± The N-dealkylation of narcotine is a difficult process and requires special attention. The N-demethylation of narcotine with cyanogen bromide and various chloroformates such as ethyl chloroformate, phenyl chloroformate [8], 2,2,2-trichloroethyl chloroformate [9], and vinyl chloroformate [10] often results either in no reaction or cleavage at benzylic and tertiary centers, adjacent to the amine function. These cleavage reactions are generally preferred with the formation of enol lactone as similar to hydrastine [11].…”

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confidence: 99%

A Convenient Synthesis of Aryl-Substituted N-Carbamoyl/N-Thiocarbamoyl Narcotine and Related Compounds

Aggarwal¹,

Ghosh²,

Aneja³

et al. 2002

HCA

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The reaction of nornarcotine and 5-bromonornarcotine, synthesized from noscapine, with suitable aromatic isocyanates or isothiocyanates provides a general method for the synthesis of aryl-substituted N-carbamoyl or N-thiocarbamoylnarcotine and related compounds. Similarly, 15a has been prepared via the reduction of the lactone ring moiety of noscapine. Also, an improved procedure, which utilizes narcotine N-oxide ¥ HCl for generation of nornarcotine, is described.Introduction. ± Alkaloids and their analogs are important targets in chemical synthesis mainly because a large number of these compounds possess pronounced biological and pharmacological activities [1]. The basic isoquinoline-skeletal structure of various aporphine alkaloids, namely, (AE)-thaliporphine, (AE)-N-methylaurotetanine, and (AE)-isoboldine have been found to be of significant biological and biogenetic interest [2]. Noscapine, for example, a phthalide-isoquinoline alkaloid derived from opium, known for its antitussive action [3] [4] has recently been described as a prospective antineoplastic agent [5]. Ye et al. reported that noscapine has potent antitumor activity against solid lymphoid tumors induced in mice and, hence, exhibits outstanding therapeutic potential. In our earlier communication, we focussed on structural modulations of papaverine, a naturally occurring isoquinoline-based alkaloid isolated from Papaver somniferum [6], and reported the synthesis of urea/thiourea derivatives of papaverine, which were found to be more efficacious in terms of specificity and action in their antispasmodic effect. On similar lines of thought, we have also synthesized N-carbamoyl/N-thiocarbamoyl analogs of noscapine and other related compounds, which might prove as well to be more efficacious and less cytotoxic. Hence, new synthetic methodologies leading to novel antitumor agents are highly desired. In a recent publication from our laboratory [7], we have discussed the structure and the fragmentation patterns of narcotine and N-carbamoyl/N-thiocarbamoyl analogs of narcotine-related compounds. In the present paper, our interest circumscribes the synthetic procedures of N-demethylation and preparation of N-carbamoyl/N-thiocarbamoyl analogs of narcotine. It is the purpose of this communication to show how the target compound nornarcotine (3a) and other similar N-demethylated narcotine derivatives can be prepared in a few straightforward steps starting from noscapine (1a) and their further derivatization with aryl isocyanates and aryl isothiocyanates yielded the desired title compunds (Scheme 1).

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confidence: 99%

A Convenient Synthesis of Aryl-Substituted N-Carbamoyl/N-Thiocarbamoyl Narcotine and Related Compounds

Aggarwal¹,

Ghosh²,

Aneja³

et al. 2002

HCA

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“…EXPERIMENTAL Materials-Dextromethorphan hydrobromide', dextrorphan tar-trate2, 3-hydroxy-9~,13a,14a-morphinan2, and thebaine3 were available commercially. The 3-methoxy-9a,l3cu,l4a-morphinan hydrochloride was synthesized by N-demethylation of dextromethorphan (6). The internal standard, 3-methoxy-17-methyl-lO-oxo-9cr,13a,l4a-morphinan4 was prepared by a previously described method (7).…”

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Quantitative Determination of Dextromethorphan and Three Metabolites in Urine by Reverse-Phase High-Performance Liquid Chromatography

Park¹,

Kullberg²,

Hinsvark³

1984

Journal of Pharmaceutical Sciences

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“…However, this is not the case for other members of this family like carfentanil and remifentanil with reactive ester sites. Almost fifty years ago, a report from the Portoghese group at the University of Minnesota described their studies on the reaction of various morphine-related compounds with chloroformate esters 33 . In these studies the authors found that treatment of morphine with phenyl chloroformate resulted in its N-demethylation with concomitant replacement of this methyl group by the alkyl portion of the chloroformate employed leading to the formation of a carbamate analog of the alkaloid.…”

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Structural modification of fentanyls for their retrospective identification by gas chromatographic analysis using chloroformate chemistry

Valdez

Leif

Sanner

et al. 2021

Sci Rep

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The one-step breakdown and derivatization of a panel of nine fentanyls to yield uniquely tagged products that can be detected by Electron Ionization Gas Chromatography-Mass Spectrometry (EI-GC-MS) is presented. The method involves the treatment of the synthetic opioids with 2,2,2-trichloroethoxycarbonyl chloride (TrocCl) at 60 °C for 3 h in dichloromethane and furnishes two products from one fentanyl molecule that can be used to retrospectively identify the original opioid. Parameters that were studied and fully optimized for the method included temperature, solvent, nature of scavenging base and reaction time. One of the two resulting products from the reaction bears the trichloroethoxycarbonyl (Troc) tag attached to the norfentanyl portion of the original opioid and greatly aids in the opioid detection and identification process. The methodology has been applied to the chemical modification of a panel of nine fentanyls and in all cases the molecular ion peak for the Troc-norfentanyl product bearing the distinctive trichloroethyl isotopic signature can be clearly observed. The method’s LLOD was determined to be 10 ng/mL while its LLOQ was found to be 20 ng/mL. This methodology represents the first application of chloroformates in the chemical modification of this class of synthetic opioids that are notoriously inert to common derivatization strategies available for GC–MS analysis.

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N-Demethylation of morphine and structurally related compounds with chloroformate esters

Cited by 64 publications

References 1 publication

A Convenient Synthesis of Aryl-Substituted N-Carbamoyl/N-Thiocarbamoyl Narcotine and Related Compounds

A Convenient Synthesis of Aryl-Substituted N-Carbamoyl/N-Thiocarbamoyl Narcotine and Related Compounds

Quantitative Determination of Dextromethorphan and Three Metabolites in Urine by Reverse-Phase High-Performance Liquid Chromatography

Structural modification of fentanyls for their retrospective identification by gas chromatographic analysis using chloroformate chemistry

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