Efficient Synthesis of a Key Intermediate for Moxifloxacin Via Intramolecular Double Stereodifferentiation

Abstract

An intramolecular double stereodifferentiation methodology was developed during the synthetic process development of (S,S)-2,8-diazobicylo[4.3.0] nonane (1), the key intermediate of the fourth-generation fluoroquinolone Moxifloxacin. The dual chiral-auxiliary strategy employed in this process guaranteed high stereoselectivity of the hydrogenation reaction to build the cis-[5,6] bicyclic system with desired stereochemistry. 1,6-Bis((R)-1-phenylethyl)-3,4,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-2,5dione (11f), the precursor of the hydrogenation reaction, was prepared from commercially available and affordable chemicals ethyl acetoacetate, (R)-(+)-1-methylbenzylamine, and acryloyl chloride, and the process was further facilitated by telescoping the first three steps into one pot. Moreover, this process has been proven robust at a hectogram scale, providing 450 g of intermediate 1 with a total yield of 56.2% over seven steps and enantiomeric excess of more than 99%, demonstrating the potential for commercial-scale applicability.

Revisitation of the Preparation of (S,S)‐2,8‐Diazabicyclo[4.3.0]nonane Through Enzymatic Resolution.

“…The industrial process for the preparation of chiral nonane intermediate (1) involves the resolution of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0]-nonane (3) by D-tartaric acid (Scheme 1). [1][2][3] It was also synthesised via a double nucleophilic substitution of tosylamine and 2,3-bischloromethylpyridine (5), followed by catalytic reduction of the resultant bicycle (6) in acetic acid with palladium on carbon. The corresponding sulfonamide was resolved by using (D)-(+)-O,O-dibenzoyltartaric acid (Scheme 2).…”

“…Recently, the overall yield was improved to 56.2 % by using a double stereo-differentiation approach (Scheme 3). [5] In view of green chemistry aspects, biocatalytic approaches have been developed as an alternative to chemical resolution. Enzymes play a crucial role in green chemistry as they function as catalysts, accelerating chemical reactions without requiring harsh reaction conditions or chemicals, and are also reusable.…”

“…Recently, the overall yield was improved to 56.2 % by using a double stereo‐differentiation approach (Scheme 3). [5] …”