Process Development and Pilot-Scale Synthesis of New Cyclization Conditions of Substituted Phenylacetamides to Tetrahydroisoquinoline-2-ones Using Eaton’s Reagent

Abstract

Tetrahydroisoquinoline is a ubiquitous structural framework presented in numerous pharmacologically relevant molecules. Although accessible by the Pictet−Spengler cyclization, conditions commonly used for such cyclizations are often difficult to implement on scale. Herein, we report the development of a scaleable approach utilizing Eaton’s reagent for the cyclization of substituted phenylacetamide analogues to tetrahydroisoquinoline-2-one. The development, optimization, and safety hazard evaluations, which outline the benefits and ease of workup of this new process, are discussed.

A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode

“…Bicyclic compounds 68 – 69 (Scheme ) were generated by converting bromophenylacetic acid ( 65 ) into secondary amides 66 – 67 using thionyl chloride and methylamine or ethylamine. These were cyclized to the corresponding dihydroisoquinolinones 68 – 69 via a Pictet‐Spengler condensation/cyclization with paraformaldehyde, using Eaton's reagent (7.7 wt‐% P 2 O 5 in MeSO 3 H) to replace the polyphosphoric acid traditionally used for this cyclization ,. The reaction was initiated with Eaton's reagent activating the aldehyde, followed by the N ‐alkylated amide attacking the activated carbonyl carbon.…”

“…These were cyclized to the corresponding dihydroisoquinolinones 68-69 via a Pictet-Spengler condensation/cyclization with paraformaldehyde, using Eaton's reagent (7.7 wt-% P 2 O 5 in MeSO 3 H) to replace the polyphosphoric acid traditionally used for this cyclization. [38,39] The reaction was initiated with Eaton's reagent activating the aldehyde, followed by the N-alkylated amide attacking the activated carbonyl carbon. Dehydration led to alkylideneacetamide formation and after an intramolecular electrophilic aromatic substitution, the dihydroisoquinolinones 68-69 were formed in 99 % and 94 % yield, respectively.…”

Preparation of Tetrahydroisoquinoline‐3‐ones Via Cyclization of Phenyl Acetamides Using Eaton's Reagent

“…As confirmed by safety assessment evaluated by RC1 calorimetry, the heat output of the amide formation stayed constant during the addition of the acyl chloride, characteristic of a fast reaction with no potential for latent reaction. 2 10. Physical properties and spectral data for 2 are as follows: mp 106-107 °C; 1 H NMR (600 MHz, CDCl 3 ) : 2.77 (d, J = 4.9 Hz, 3 H), 3.53 (s, 2 H), 5.43 (bs, 1 H), 7.20 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2 H); 13 11.…”

“…Safety assessment evaluated by RC1 calorimetry indicated that a mild thermal event took place upon addition of the phenyl acetamide ( H = 35 kJ/mol, T ad = 14 K) which rapidly subsided. 2 13. Paraformaldehyde (95%) and sodium hydroxide solution (19M or 50 wt%) were purchased from Aldrich and used as received.…”

“…RC1 study revealed that addition of paraformaldehyde was marked by an initial endothermic event devoid of any significant thermal activity until the system was heated. 2 15. The thermal profile observed during heating resulted in a net output of 120 kJ/mol ( T ad = 43 K).…”