Developing a Multistep Continuous Manufacturing Process for (1R,2R)-2-Amino-1-methylcyclopentan-1-ol

Abstract

A multistep continuous manufacturing process to synthesize (1R,2R)-2-amino-1-methylcyclopentan-1-ol (2) was developed. The step 1/2 flow process mitigated the safety hazard associated with high exothermicity during epoxidation, the epoxide-opening reaction, and the low onset of the epoxide intermediate. Process improvements included a hybrid plug flow reactor (PFR)/continuous stirred tank reactor (CSTR) reaction and a continuous quench/work-up process in step 1; a continuous reaction, extraction, washing, and thin-film distillation work-up in step 2; and a continuous trickle bed hydrogenation in step 3, which provided the desired product with high purity and high ee. The end-to-end continuous process provided significant advantages of cost-saving, minimization of manufacturing space and utilities, and reduction of the cycle time.

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

“…[8] with permission from the Royal Society of Chemistry), (d) process flow diagram of the epoxidation reaction using catalytic methyltrioxorhenium (MTO) and aqueous H 2 O 2 (Reprinted with permission from Ref. [68].…”

“…[ 8 ] with permission from the Royal Society of Chemistry), ( d ) process flow diagram of the epoxidation reaction using catalytic methyltrioxorhenium (MTO) and aqueous H 2 O 2 (Reprinted with permission from Ref. [ 68 ]. Copyright 2020 American Chemical Society), ( e ) the two CSTRs-in-series system used in the synthesis of benzoxazole from N-pivaloyl 3,4-dichloro aniline (Reproduced with permission from Ref.…”

“…Duan et al [ 68 ] investigated the flow epoxidation using catalytic methyltrioxorhenium (MTO) and aqueous H 2 O 2 (Table 5d and Fig. 8d ).…”

Application of Biocatalytic Reductive Amination for the Synthesis of a Key Intermediate to a CDK 2/4/6 Inhibitor

“…Our key strategy to enable the synthesis of 4 (Figure 2) utilized an epoxide opening by benzylamine followed by a classical resolution. 3 While the multistep continuous process was successful in providing 4 at scale, the low yield during chiral resolution proved to be a bottleneck for further process enhancement. In addition, the high energy of the epoxide required flow processing in the earlier steps, which put some constraints on vendor selection.…”

Continuous Hydrogenation: Triphasic System Optimization at Kilo Lab Scale Using a Slurry Solution

“…A very common practice is the use of a trickle bed reactor (Saroha and Nigam, 1996;Al-Dahhan et al, 1997;Deutschmann et al, 2009) containing a packed bed of catalyst, which the reactants flow through (Gulotty et al, 2018). This is widely used in industry (Perry and Green 2008;Johnson et al, 2012;Rinaldi 2014;Carangio et al, 2020;Fernandez-Puertas et al, 2020), as it allows good control of reaction conditions and simplified scale-up (Jiménez-González et al, 2011;Hickman et al, 2013;Gutmann et al, 2015;Russell et al, 2017;Duan et al, 2020). In this case, the nature and particle size of the catalyst has to be optimized to obtain good results.…”