Early Development Scale-Up of a Novel CXCR Antagonist: Focus on Racemic and Stereoselective Routes of a Key Intermediate

Abstract

Efforts toward a convenient and scalable process for the synthesis of a novel CXCR antagonist 1 are described, with a specific focus on a chiral key intermediate. Two generations of a racemic route have been developed for short-term deliveries, and a stereoselective process has been devised for longer term plans. Key steps involved an enzymatic resolution of racemic tetrahydrothiophene-2-carboxylic acid to install the (2R) stereocenter, the mild and efficient preparation of a sterically hindered sulfinimine under a nitrogen flow, and its stereoselective reduction to set up the (1S) amine stereocenter. The process has been scaled-up to multikilogram scale for the racemic approach, and the stereoselective route was demonstrated on multigram scale.

Optimized Synthesis of Indole Carboxylate Metallo-β-Lactamase Inhibitor EBL-3183

“…Usually, this is converted to a filterable solid upon quenching with 24 wt % aq. NaCl, but the procedure is not always efficient . The addition of Celite can help to decrease time of filtration, , though an improved approach involves conversion of titanium alkoxides to a water-soluble ligand-bound form .…”

“…Synthesis of ( S )- 7 was carried out using a standard approach, wherein the reaction is promoted by Ti­(OEt) 4 , which acts both as a Lewis acid activator and a dehydrating agent (Scheme ). However, most of the commercially available Ti­(OEt) 4 contains a significant amount of Ti­(O i -Pr) 4 (up to 10–15 wt %), which was found to effect formation of an impurity ( S )- 7- i -Pr by transesterification of InC ( S )- 7 . Hence, the quality of the titanium reagent had to be strictly controlled.…”

α‐Functionalisation of Cyclic Sulfides Enabled by Lithiation Trapping

“…The relative stereochemistry was established since 15 had identical 1 H and 13 C NMR spectroscopic data to those reported [6] and they were different to those data for the HCl salt derived from 14 a . In terms of distinct reactions, our approach is more concise than the previous approaches although those routes did deliver kg‐scale quantities of 15 [6] . To show the value of the lithiation/trapping products, pinacol boronate 7 n was arylated using Aggarwal's transition‐metal free stereospecific cross‐coupling of secondary boronic esters with aryl organolithiums (Scheme 4B) [27] .…”

“…Condensation with Ellman's sulfinamide gave separable diastereomeric sulfinyl imines 14 a and 14 b in 40 % and 38 % yields respectively. Next, reduction of the imine functionality of 14 b using 9-BBN (9-borabicyclo-[3.3.1]nonane) [6] occurred with complete diastereoselectivity and subsequent amine deprotection under acidic conditions gave 15 (97 : 3 er) in 88 % yield over the two steps. The relative stereochemistry was established since 15 had identical 1 H and 13 C NMR spectroscopic data to those reported [6] and they were different to those data for the HCl salt derived from 14 a.…”

α‐Functionalisation of Cyclic Sulfides Enabled by Lithiation Trapping

“…Enantiopure five-membered ring sulfide 1 and related sulfides have been used in a range of asymmetric reactions. [3][4][5] Furthermore, tetrahydrothiophene derivative 2 is a potent CXCR (Chemokine receptor) antagonist in inflammation models and is being developed to treat acne; [6] disubstituted thiomorpholine 3 is an orexin antagonist and has been explored for use in the treatment of neurological disorders. [7] The saturated sulfur heterocycles in 1, 2 and 3 were all crafted by cyclisation of a pre-functionalised substrate with the early introduction of the substituent α to sulfur.…”