Synthesis of two metabolites of (-)-.DELTA.8-tetrahydrocannabinol

Abstract

Methyl 3-(4'-Methyl-3'-oxo-1 '-cyclohexenyl)butanoate (II).11 -The preceding acid (29.2 g, 0.14 mol) in purified tetrahydrofuran (600 ml) and dry ieri-butyl alcohol (600 ml) was added gradually to distilled, stirred liquid ammonia (1500 ml). With continued stirring, lithium metal (16.7 g, 2.4 mol) was added in small pieces during 45 min. The deep blue solution was stirred for 5 hr, then quenched with methanol (150 ml) and stirred overnight during evaporation of the ammonia. Water was added and the organic solvents were removed in vacuo. The residue was diluted with water to 2 1., then cooled in ice, acidified with cold 4 N hydrochloric acid, and quickly extracted thrice with ether. The combined extracts were dried, cooled in ice, and mixed with an excess of ethereal diazomethane. The ether solution was washed with aqueous sodium bicarbonate and water, dried, and concentrated. The residue was stirred with 2.5 A7 hydrochloric acid (500 ml) for 3 hr, and organic material was isolated with ether. The extract was dried and concentrated, and the residual keto ester 11 distilled: bp 110°( 0.25 mm) 22.4 g, 76%); Xmax-(EtOH) 234 nm (« 11,000); ir (film) 1735, 1720 (weak), 1665,

Two cannabidiol metabolites formed by rat liver

“…The syntheses of 1 "-hydroxy-CBD and 2"-hydroxy-CBD are discussed in a recent review (Agurell & others, 1972). 3"-Hydroxy-CBD was synthesized by the reaction of 1-(3,5-dihydroxyphenyl)pentan-3-0ne ethylene dithioketal (Fahrenholtz, 1972) and (+)trans-p-mentha-2,8-dien-l-ol in the presence of NN-dimethyl-formamide dineopentyl acetal. The resulting 3"-ethylene dithioketal derivative of CBD was treated with mercuric chloride and cadmium carbonate, followed by sodium borohydride to yield 3"-hydroxy-CBD.…”

Structure-Activity Studies on Tetrahydro- and Hexahydrocannabinol Derivatives

“…Compound I was converted to the dithioketal(I1) by treatment with ethanedithiol-boron trifluoride etherate (7), and it gave g-norhexahydrocannabinol (111) after reduction with Raney nickel in refluxing methanol (8). The optically active I afforded an approximate 1:l mixture of the two isomeric 9-nor-9-hydroxyhexahydrocannabinols (IV) in almost quantitative yield by reduction with sodium borohydride in methanol (6).…”

Drugs derived from cannabinoids. 5. .DELTA.6a,10a,-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains

“…Method H. 3-(4-Dimethylamino-l-methylbutyl)-lhydroxy-6,6,9-trimethyl-7,8,9,10-tetrahydro-6if-dibenzo-[6,d]pyran (9). The above pyrone (14p, 6.30 g, 0.0193 mol) was dissolved in 150 ml of THF and treated with 60 ml of 3 M CHsMgBr in ether and refluxed 17 h. The solution was treated with 250 ml of saturated NH4CI solution and extracted with THF.…”

“…The compound with a strongly basic side chain (9) was inactive as compared to the active but weakly basic pyridyl compound (8). All of the intermediates (Table II) were relatively inactive.…”

“…Fahrenholtz synthesized A8-THC with a 1hydroxypentyl and a 3-hydroxypentyl side chain as metabolites of A8-THC. 9 In the preceding papers10-12•18 and earlier communications,13•14 Pars and Razdan have incorporated the 1,-2-dimethylheptyl side chain into various heterocyclic (4a, 5a, 6a, 7a) and carbocyclic analogs (11) of A6a-10a-THC and reported their biological activity in various CNS tests.…”