A Practical Synthesis of Piperidine-/Tropane-Substituted 1,2,4-Triazoles

Abstract

A robust synthesis of 1,2,4-triazoles is disclosed with a particular focus on developing methodology capable of delivering gram quantities and minimising hazardous waste.Heterocycles are well known as potential isosteres to replace carboxylic acids, esters and amides in the design of orally bioavailable drug candidates. 1 As part of our research it became necessary to design a range of trisubstituted 1,2,4-triazoles wherein the triazole 4-nitrogen is linked to a piperidine or tropane (Figure 1). From a medicinal chemistry perspective this is an attractive motif and a practical synthesis was required. For expedience we were keen that the methodology would enable us to readily vary the alkyl/aryl substituents R and R¢. 2 A recent publication has prompted us to disclose our results in this area of heterocycle synthesis. 3 Figure 1 Targets of interest.Initially attempts to construct the 3,5-dimethyl substituted triazole 2 were made in one step from the corresponding thioamide 1 and acetic hydrazide (Scheme 1). Although precedented in the literature, 4 in our hands we found the reaction to be low yielding and product isolation non-trivial; we suspected the problem to be associated with the quality of the thioamide used in the reaction. Disappointingly, this route presented significant difficulties on scaling due to the use of Lawesson's 5 or Belleau's 6 reagent in formation of the thioamide and disposal of mercuric residues.After a review of the literature we were intrigued at the publications that used the iminoyl chloride as a precursor for reaction with an acyl hydrazide and subsequent cyclisation to the 1,2,4-triazole. 7 In particular the work of Atkinson and Polya was of interest with the one-pot preparation of triazole 4 using conditions that appeared simple to perform. 8 We also felt the reported low yield was open to optimization (Scheme 2).For our initial attempt we focused on the equatorially substituted tropane 5 and used identical conditions to those described by Atkinson and Polya. We were delighted to find complete consumption of the starting material and formation of a new compound, however, the mass spectrum indicated that we had only formed the intermediate N-acyl amidrazone 6. Various conditions were examined to complete the cyclisation and the optimum conditions were determined to be heating under reflux in toluene with addition of a catalytic quantity (typically 5 mol%) of p-toluenesulfonic acid to furnish 7 in a satisfactory yield of 59% (Scheme 3).It is reasonable to postulate that the low yield reported by Atkinson and Polya is due to incomplete cyclisation of the corresponding intermediate to the 1,2,4-triazole. N-Acyl amidrazone 6 is stable to an aqueous work up, and washing out the phosphorous oxychloride residues appeared to make the cyclisation proceed with greater consistency, however, due to the polar nature of the N-acyl amidrazone care is needed with the wash if undertaken. From an analysis of the literature it would appear that cyclisation of amidrazones typically requires forcing cond...

Efficient synthesis and identification of novel propane-1,3-diamino bridged CCR5 antagonists with variation on the basic center carrier

“…Furthermore, the presence of the ethoxycarbonyl group was beneficial for the formation of the tropane-substituted 1,2,4-triazole. As shown in Scheme 4, the 1,2,3-triazole (19,20) was synthesized under acidic conditions [27], so the basic nature of the tropane might interfere with this reaction. Then, the ethoxycarbonyl group dispersed the electron density of the nitrogen bridge by conjugation effect, resulting in neutralized basicity of the tropane alkaloid thus securing the formation of the 1,2,4-triazole functionality.…”

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

“…The 1,2,4-triazole-containing compound 400 was formedinthree steps:1)activation of 399 as the imidoyl chloride with POCl 3 ,2 )formation of the N 1 -acylamidrazone with acetic hydrazide,a nd 3) HCl-catalyzed cyclization. [145,146] Removal of the benzyl protecting group by transfer hydrogenation gave 401,w hich was the first building block in the synthesis of 384 (Scheme50). [137,145] The second fragment, 4,4-difluorocyclohexane-1-carboxylic acid (392), introduces fluorine atoms into the drug molecule.…”

“…Tropanamide 399 was prepared under Schotten–Baumann conditions by the addition of isobutyryl chloride. The 1,2,4‐triazole‐containing compound 400 was formed in three steps: 1) activation of 399 as the imidoyl chloride with POCl 3 , 2) formation of the N 1 ‐acylamidrazone with acetic hydrazide, and 3) HCl‐catalyzed cyclization . Removal of the benzyl protecting group by transfer hydrogenation gave 401 , which was the first building block in the synthesis of 384 (Scheme )…”

Genotoxic Impurities in Pharmaceutical Manufacturing: Sources, Regulations, and Mitigation

“…Maraviroc is the first-in-class CCR5 antagonist for the treatment of HIV . The initial synthesis of maraviroc that produced material for preclinical studies has been published. , One of the reactions is catalyzed by TEMPO, where the alcohol is oxidized to give the required aldehyde, as shown in Scheme…”