Chemoenzymatic Synthesis of Sertraline

Abstract

A chemoenzymatic approach has been developed for the preparation of sertraline, an established anti-depressant drug. Ketoreductases (KREDs) were employed to yield a key chiral precursor. The bioreduction of the racemic tetralone exhibited excellent enantioselectivity (>99 % ee) and diastereomeric ratio (99:1) at 29 % conversion (the maximum theoretical yield Scheme 1. Synthesis of the API sertraline (S,S-1). The first step 1) is a KRED-catalysed selective bioreduction to the alcohol precursor (S,S)-4. The second step can either be achieved chemically 2a) by NaOCl/AZADO or enzymatically 2b) by Trametes versicolor laccase/AZADO.Step 3) comprises a direct amination employing methylamine followed by reduction with NaBH 4 .[a] 510 is 50 %) after 7 hours. The resulting (S,S)-alcohol was efficiently oxidized to an enantiopure (S)-ketone, an immediate precursor of sertraline, by using sodium hypochlorite as oxidant and 2azaadamantane N-oxyl (AZADO) as organocatalyst. Alternative routes aiming at the direct biocatatalytic amination using imine reductases and transaminases were unsuccessful.

Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods

“…Many additional synthetic examples using IREDs were developed during the last years, ranging from the asymmetric reduction of ketimines to asymmetric arylations or the resolution of racemic tetralone derivatives followed by diastereoselective reductive amination. − Currently the number of industrial applications of IREDs and RedAms in reductive aminations for API synthesis is increasing, the examples demonstrate the potential of these enzymes, and further large-scale applications can be expected to appear in the next few years.…”

Application of Ketoreductase in Asymmetric Synthesis of Pharmaceuticals and Bioactive Molecules: An Update (2018–2020)

“…Berglund and co‐workers reported a new chemo‐enzymatic synthesis of ( S , S )‐sertraline, the active pharmaceutical ingredient in Zoloft ® , a drug developed by Pfizer for the treatment of depression and anxiety (Scheme 31). [43] Critical to their success was the stereoselective reduction of racemic ketone 78 catalyzed by the commercial ketoreductase P1‐B12, via a kinetic resolution manner, to afford the key chiral alcohol intermediate ( S , S )‐ 79 in 29 % conversion with 99 : 1 cis/trans ratio and >99 % ee. Oxidation of ( S , S )‐ 79 with (2‐azaadamantane‐ N ‐oxyl) (AZADO) and NaOCl resulted in a clean transformation to ketone 80 , which underwent a two‐step diastereoselective amination to furnish ( S , S )‐sertraline of >99 % ee.…”

Stereochemistry in Asymmetric Reduction of Bulky–Bulky Ketones by Alcohol Dehydrogenases

“…57 Several KREDs from Codexis are capable of reducing β-substituted tetralones and a rather bulky tetralone derivative, which can be used as a precursor for (S,S)sertraline. 58 Using 64 as a model substrate, a series of KREDs with different stereoselectivity (−72% to 100% ee, S) were obtained by screening KRED libraries from Biocatalytics (CA, USA) and Julich Chiral Solutions (Julich, Germany). Further results showed that the reaction rate was increased by the addition of toluene and several ionic liquids.…”