Sequential α-lithiation and aerobic oxidation of an arylacetic acid - continuous-flow synthesis of cyclopentyl mandelic acid

Abstract

The development of a multistep continuous-flow process, consisting of a direct α-lithiation stage and subsequent hydroxylation by aerobic oxidation, is reported. The protocol is applied to the synthesis of cyclopentylmandelic acid (CPMA), the main building block for the anticholinergic glycopyrronium bromide (glycopyrrolate). We demonstrate the safe utilization of organolithium reagents and molecular oxygen in combination by using a continuous-flow protocol. The first stage involves the formation of a di-lithium enolate intermediate, which was either pre-formed in batch or formed in flow by using n-hexyllithium as a costeffective and industrially safe base. The subsequent hydroxylation stage utilized molecular oxygen under homogeneous and mild conditions (atmospheric pressure and room temperature) to give the desired product. A diluted form of oxygen gas, consisting of less than 10% O 2 in N 2 (Bsynthetic air^), is used in pharmaceutical batch manufacturing to effectively address safety concerns when handling molecular oxygen. The telescoped flow process afforded the target intermediate in 65% solution NMR yield (50% isolated yield after re-crystallization). The continuous-flow process opens up new opportunities for the manufacture of CPMA, with a protocol which can safely handle pure O 2 , and compares favorably with existing Grignard-based batch processes. Keywords Glycopyrrolate (glycopyrronium bromide). Cyclopentyl mandelic acid (CPMA). Continuous-flow. Gas-liquid transformations. Molecular oxygen. Organometallics The medicinal properties of glycopyrronium bromide (glycopyrrolate, 4) were first identified in the late 1950s [1]. Glycopyrrolate is an antagonist of muscarinic cholinergic receptors and is used for the treatment of drooling or excessive salivation (sialorrhea) [2], excess sweating (hyperhidrosis) [3], and overactive bladder and for presurgery treatment. In addition, it has recently been introduced as an effective bronchodilator for the treatment of chronic obstructive pulmonary disease (COPD) for asthma patients [4]. Glycopyrrolate displays few side effects because it does not pass through the blood brain barrier. Cyclopentyl mandelic acid (CPMA, 1), or its corresponding ester derivatives, are key intermediates in the synthetic routes to 4. CPMA (1) reacts with 1-methylpyrrolidin-3-ol (2) to form tertiary amine 3. N-Methylation of 3 by methyl bromide gives quaternary ammonium salt glycopyrrolate 4 as a racemate (Scheme 1) [5]. CPMA (1) is a synthetically challenging intermediate to prepare (Scheme 2). Routes A to D are most likely to be the commercially applied methods because these procedures are Electronic supplementary material The online version of this article (

Organolithium Bases in Flow Chemistry: A Review

“…Work by Luisi and co-workers illustrates the use of nHexLi in a continuous flow system to generate a dilithium enolate intermediate pivotal in the synthesis of cyclopentyl mandelic acid (CPMA, 41). 53 The authors describe a telescoped process in which nHexLi and phenylcyclopentylacetic acid are mixed in a coiled reactor at 20 °C for a residence time of 5 min to yield the dilithium enolate intermediate. The flow platform designed uses syringe pumps to feed the reagents to the system and a sample loop to deliver nHexLi to the system.…”

The Use of Molecular Oxygen for Liquid Phase Aerobic Oxidations in Continuous Flow

“…The existing manufacturing routes utilize Grignard reagents to afford CPMA in 28–56% yield. Kappe, Luisi and co-workers devised a flow protocol for the sequential α -lithiation and subsequent hydroxylation of α -phenylcyclopentylacetic acid by aerobic oxidation (Scheme 19) [73]. Hexyllithium was utilized as a cost-effective and industrially safe base.…”

N-Acetylation of Amines in Continuous-Flow with Acetonitrile—No Need for Hazardous and Toxic Carboxylic Acid Derivatives

“…A schematic outline of the reactor used in this study is shown in Figure 1. reaction routes that would otherwise only be feasible under regular batch conditions, e.g., higher temperature and pressure than can be used under safe conditions [47][48][49][50][51][52][53][54][55][56][57]. Whilst acetonitrile is a common solvent and is generally used in various fields of chemistry as eluent [41] and polar aprotic organic solvent [58], it is rarely used as reagent in organic chemistry.…”

“…Furthermore, more efficient and selective reaction can be carried out in continuous systems than in regular batch operations [41][42][43][44][45][46]. Additionally, flow reaction conditions can enable reaction routes that would otherwise only be feasible under regular batch conditions, e.g., higher temperature and pressure than can be used under safe conditions [47][48][49][50][51][52][53][54][55][56][57].…”