Improved and Flexible Synthetic Access to the Spiroindole Backbone of Cebranopadol

Abstract

By changing the dimethylamino to a nitro group, a novel synthetic access to the spirocyclic opioid analgesic cebranopadol was developed that is much more efficient compared with the established route. On the basis of the α-acidity of α-nitrotoluene, the two-fold Michael addition to acrylate gave an acyclic precursor compound, which was easily transformed by Dieckmann condensation and decarboxylation to the cyclohexanone derivative needed for the annulation of the indole ring by an oxa-Pictet–Spengler reaction. As an additional benefit, the reduction of the nitro group furnished an amine, which could be late-stage-diversified to carboxamides, sulfonamides, ureas, and N-alkyl congeners. The transformation of the nitro group at the spirocyclic scaffold to the dimethylamino function of the actual title compound was achieved in one step with zinc/formic acid/formaldehyde in 83% yield.

Investigation into a Tetrahydroquinazoline Scaffold

“…Application of elevated temperature lead to unspecific reduction of the aromatic rings. Thus, we tried the reduction with base metals like zinc [6a] or iron, [12] but only sluggish conversion was observed. When using trichlorosilane in the presence of triethylamine as reducing agent, [13] compound 11 c was formed, although it could be isolated only in moderate yield (45 %, entry 3).…”

Recent synthetic strategies of spiro-azetidin-2-one, -pyrrolidine, -indol(one) and -pyran derivatives-a review

“…Synthesis of spiro-pyran 246 111 was established as shown in Scheme 64 . The relative configuration of one representative was established by the trans -isomer 243; it was subsequently submitted to the reduction of the nitro group with zinc to furnish the primary amine 245 (89%) ( Scheme 65 ).…”

“…Formic acid was chosen because it was also used in the next step, the reductive amination with formaldehyde according to an Eschweiler–Clarke protocol, 112 which gave the corresponding dimethylamino derivative 246. 111 …”

“…The supernatants contained the cis-diastereo-isomers 244 together with residual amounts of the trans-isomers 243, which were separated and puried by chromatography. 110 Synthesis of spiro-pyran 246 111 was established as shown in Scheme 64. The relative conguration of one representative was established by the trans-isomer 243; it was subsequently submitted to the reduction of the nitro group with zinc to furnish the primary amine 245 (89%) (Scheme 65).…”

Naturally Inspired Molecules for Neuropathic Pain Inhibition—Effect of Mirogabalin and Cebranopadol on Mechanical and Thermal Nociceptive Threshold in Mice

“…Finally, drug development studies led to discovery the cebranopadol (trans-6 -fluoro-4 ,9 -dihydro- [3,4-b]indol]-4-amine) a novel analgesic drug candidate, a NOR and opioid receptor agonist. Cebranopadol acts as a full agonist of MOR (Ki = 0.7 nM) and DOR (Ki = 18 nM) and as a partial agonist of NOR (Ki = 0.9 nM) and KOR (Ki = 2.6 nM) [15][16][17]. The similarity of the MOR and NOR binding sites allows for similar π-π stacking interactions of aromatic moieties of ligands, and hydrophobic cavities are conserved in both receptors [18].…”