Efficient Multikilogram Synthesis of a VLA-4 Antagonist via a Povarov Reaction

Abstract

Herein we describe the practical synthesis of a novel VLA-4 antagonist 1 as a potential treatment for multiple sclerosis. The key step is based on the Povarov reaction of an imine with an alkene to access a tetrahydroquinoline intermediate, leading to the corresponding quinoline core after an oxidative aromatization step. The development of the synthesis of 1 led to decreased complexity and the elimination of chromatographic purifications. These improvements were demonstrated at scale by the production of 32 kg of 1 in high yield with excellent purity.

Multicomponent Reactions for the Synthesis of Active Pharmaceutical Ingredients

“…The resulting Povarov adduct, in crude form, w rectly dehydrogenated to a quinoline derivative by treatment with oxygen in the ence of charcoal. A final hydrolysis of the ester group afforded the final comp UCB-108770 with a 40% global yield over six steps [62] (Scheme 22).…”

“…The resulting Povarov adduct, in crude form, was directly dehydrogenated to a quinoline derivative by treatment with oxygen in the presence of charcoal. A final hydrolysis of the ester group afforded the final compound UCB-108770 with a 40% global yield over six steps [62] (Scheme 22). Torcetrapib is another remarkable example of a drug candidate that can be prepared by a route involving a Povarov reaction as the key step.…”

The Povarov Reaction: A Versatile Method to Synthesize Tetrahydroquinolines, Quinolines and Julolidines

“…The Povarov reaction and its variants can be catalyzed by a wide variety of Brønsted and Lewis acids: BF 3 ·Et 2 O, 33 34 35 36 37 38 39 40 BiCl 3 , 41–44 CAN, 45 46 47 48 49 50 51 cerium sulfate, 52 Amberlyst 15, 53 phthalic acid, 54 p -toluenesulfonic acid 55 56 and its supramolecular analogue CX4SO 3 H, 57 ferric sulfate, 58 59 60 iodine, 61 62 63 InCl 3 , 64 65 66 67 68 69 NH 4 Br, 70 Sc(OTf) 3 , 71 72 73 74 75 and Sc(III)-loaded resin, 76 Y(OTf) 3 , 77 78 79 80 81 bistriflimide, 28 TFA 82 and zinc chloride. 83 Moreover, mixed catalytic systems may be employed, such as Ca(OTf) 2 /Bu 4 NPF 6 84 and CeCl 3 /NaI.…”

“…Concerning the reaction medium, polar solvents such as acetonitrile 34,37,41,45,47,51,54 and alcohols 53,65,87,88 were the most typical, but not a requirement since apolar solvents including dichloromethane, 35,74,89 dichloroethane 28,60,90 and toluene 78,91,92 were also well represented in the literature. Fluorinated alcohols, such as hexafluoroisopropanol (HFIP) 71 and trifluoroethanol (TFE) 50,93 can be employed to dissolve reagents that are insoluble in the most common solvents, 71 or can even act as the catalyst itself, thereby removing the requirement for the addition of acids. 93 Greener approaches towards the use of solvents have also been explored by using biodegradable carbonates, 61 water, 55,57,86 a deep eutectic solvent (DES), 94 or simply no solvent at all.…”

“…Cerfontaine et al 50 employed the Povarov reaction in their optimization of the synthesis of an integrin-41 inhibitor, UCB-108770 (81), on a multikilogram scale. The imine was synthesized in situ in TFE, followed by annulation with N-vinyl-pyrrolidinone (79) catalyzed by CAN.…”