Introduction
UR-144 (TMCP-018, KM-X1, MN-001, YX-17; CAS number 1199943-44-6) contains a cyclopropane ring, which is thermally unstable, and this may be of concern as the product is normally consumed by smoking. Cyclopropane itself is susceptible to thermal isomerization to propylene at the temperatures approximately above 420 °C. Other pyrolysis products have been reported, although they formed at much higher temperatures. In general, both substituted and unsubstituted cyclopropanes undergo a variety of ring-opening reactions. As the temperature of the tip of a burning cigarette can exceed 700 °C, this would suggest that cyclopropane moiety in UR-144 may undergo some of these transformations. In the work presented here, a number of herbal, resin-type products and powders purchased from online vendors were analyzed. UR-144 was identified in the products along several related compounds, one being a novel hydrated derivative. The pyrolysis of UR-144 was also studied. In this article, you can read about heating process and thermal decomposition of substances while smoking. There is UR-144 synthesis method from TMCP-indole.
UR-144
The synthetic cannabinoid, UR-144 ((1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone), was identified in commercial ‘legal high’ products (herbal, resin, and powder). Along with this, six related compounds were detected. The most abundant one (2.1) was identified as 4-hydroxy-3,3,4-trimethyl-1-(1-pentyl-1H-indol-3-yl)pentan-1-one, a product of the electrophilic addition of water to the cyclopropane moiety in UR-144. Compound 2.1 was found to be undergoing cyclization which leads to the formation of two additional interconvertible compounds (2.3, tentatively identified as 1-pentyl-3-(4,4,5,5-tetramethyl-4,5-dihydrofuran-2-yl)-1H-indole which is stable only in absence of water and also observed as GC artifact) and 2.2, a protonated derivative of 2.3 which is formed in acidic solutions. The remaining compounds were identified as possible degradation products of the group 2 compounds (4,4,5,5-tetramethyldihydrofuran-2(3H)-one and 1-pentylindoline-2,3-dione) and intermediates or by-products from the synthesis of UR-144 ((1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone, 1-pentyl-1H-indole and 1-(1-pentyl-1H-indol-3-yl)hexan-1-one). Pyrolysis of herbal products containing the group 2 compounds or UR-144 resulted in the formation of 3,3,4-trimethyl-1-(1-pentyl-1H-indol-3-yl)pent-4-en-1-one (3). This was confirmed by separate pyrolysis of 2.1 and UR-144. Also, the two additional minor compounds, 1-(1-pentyl-1H-indol-3-yl)ethanone and 1-(1-pentyl-1H-indol-3-yl)propan-1-one, were detected. Pathways for these transformations are presented.
Discussion
Synthetic cannabinoids have become one of the primary challenges of forensic toxicology and seized drug analysis since their appearance in the mid-2000s. Although the synthetic cannabinoids act on the cannabinoid receptors, the pharmacological effects are markedly different from that of marijuana, which suggests mechanisms of toxicity separate from any caused through binding interactions. It has been noted that pyrolysis products may contribute to the observed psychological effects.
Fig.1 Reported pyrolytic products of two synthetic cannabinoids.
Upper frame: UR-144 forming 3,3,4-trimethyl-1-(1-pentyl-1H-indol-3-yl) pent-4-en-1-one;
Lower frame: XLR11 forming 1-(1-(5-luoropentyl)-1H-indol-3-yl)-3,3,4-trimethylpent-4-en-1-one. In both cases, the cyclopropane ring is broken to create an isobutylene group.UR-144 (33, Fig.1), ((1-pentyl-1H-indol-3-yl) (2,2,3,3-tetramethylcyclopropyl)methanone), is an indole based synthetic cannabinoid which is structurally similar to JWH-018 in that both molecules contain a pentyl side chain off the nitrogen of the in-dole core and a secondary ring structure bridged to the indole via a carbonyl group. This secondary ring structure is the only difference between these two cannabinoids, with the naphthalene substituent of JWH-018 being replaced with a tetramethylcyclopropane group in UR-144. The tetramethylcyclopropane moiety, like other cyclopropane derivatives, is considered thermally unstable. In 2012, an article was published, which tentatively characterized the main pyrolytic product of UR-144 as 3,3,4-trimethyl-1-(1-pentyl-1H-indol-3-yl)pent-4-en-1-one (34, Fig.1). Several commercially available products containing UR-144 were purchased and analyzed with GC-MS and LC-MS/MS. To simulate the burning process, pyrolysis of two herbal samples was carried out in a quartz tube. While this main pyrolytic product (Structure 34) was observed in the pyrolyzed samples using both detection methods, it was also observed in samples that were not pyrolyzed but analyzed using GC-MS. This finding suggests that the compound is thermally unstable and will be observed as an artifact as a result of volatilization in gas chromatography. Other minor products were characterized by the authors in both extracted samples and the two pyrolyzed samples. Quantitative results were not provided, and the identification of the main pyrolysis product was not confirmed using reference standards. A follow-up study evaluated urine samples for the presence of the main pyrolytic structure (34) as well as numerous metabolites of UR-144.
Fig. 2 Proposed scheme of reactions for compounds related to UR-144.
A number of studies have indicated that most aminoalkylindoles based synthetic cannabinoids undergo extensive metabolism and are often times not detectable in human urine samples. Mono-hydroxylation, di-hydroxylation, carboxylation, and dealkylation metabolites of the major pyrolytic product were tentatively identified. Of the 37 metabolites tentatively identified in this article, 21 were reported products of the main pyrolytic product and thus may have utility as biomarkers of smoked UR-144 in screening assays. Quantitative results were not provided, and the identification of the main pyrolytic structure (34) was not confirmed. A 2013 case study on samples collected from an individual under the influence of UR-144 reported the presence of the parent drug and the pyrolytic product (34) in blood, as well as the respective metabolites in urine. Both UR-144 and its main pyrolytic product (structure 34) were also observed upon analysis of powder residue found in a plastic bag confiscated from the intoxicated individual. Finally, a method validation study was published by Amaratunga et al. in 2014 in which a method was developed to detect XLR11 (35, Fig.1) ((1-(5-fluoropentyl)-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)-methanone) and UR-144 parent, metabolites, and pyrolysis products in oral fluid. The main pyrolytic product of XLR11 (1-(1-(5-fluoropentyl)-(1H-indol-3-yl)-3,3,4-trimethylpent-4-en-1-one)) was (36, Fig.1) was confirmed using reference standards.
Conclusion
UR-144 was found to be relatively unstable, and facile cyclopropane ring fusion was noted. The thermal isomerization of UR-144 without air (i.e. GC injector port/column) or in the presence of air (i.e. burning of UR-144 containing products) leads to opening of cyclopropane ring and formation of a trimethylbutene product (3). Hydration of the cyclopropane in UR-144 or the trimethylbutene moiety in compound 3 results in the formation of a group of interconvertible compounds. The pharmacological properties of these compounds are unknown, and they can contribute to intensive psychological effects noted following the consumption of UR-144. These compounds may be of interest as individual novel synthetic cannabinoids for use.
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