A Fully Automated Capsule-Based Machine for Organic Chemical Synthesis

Angus McMillan2, Dr. Tuo Jiang1, Dr. Samuele Bordi2, Dr. Benedikt Wanner1, Dr. Paula Nichols1,2 and Prof. Jeffrey Bode2

1Synple Chem AG, Switzerland2Laboratorium für Organische Chemie, ETH Zürich, Switzerland

Introduction

The automation of organic reactions – particularly for applications in drug discovery – is currently a major goal due to its ability to save time, improve safety, and interface with on-going efforts to employ artificial intelligence and reaction optimization. A number of cus-tom-built and commercial instruments for reaction automation and optimization are avail-able or under active development, but these are largely geared towards scale-up and fa-cilitating screening of reaction conditions. The desire for automation in medicinal chemis-try laboratories is easily observed with the widespread adoption of automated purification instruments, which use pre-packed silica-gel cartridges for the purification of organic compounds with little user involvement. We sought to bring the same level of conveni-ence, reliability, and automation to the setup, execution, work-up, and purification of or-ganic reactions, using a compact, user-friendly setup.

Concept

References

Automated Reactions

Jiang, T.; Bordi, S.; McMillan, A.; Chen, K.-Y.; Saito, F.; Nichols, P.; Wanner, B; Bode, J. PrePrint on ChemRxiv: 10.26434/chemrxiv.7882799 2019

We have developed an integrated, capsule-based, fully automated synthesizer for the transformation of aldehydes to a variety of substituted saturated N-heterocycles. Unlike other approaches to reaction automation, the automated synthesizer can utilize new sub-strates without any change to the instrument configuration, requires no weighing or han-dling of any chemicals other than the starting aldehyde. Most importantly, it a delivers pure (> 90%) products without user intervention. Currently, capsules are available to carry out SnAP chemistry, reductive aminations and PROTAC formations. We plan to extend this easy-to-use, capsule-based approach to allow many other reaction types on the fully automated system.

Overview of automated synthesizer

Preparing valuable organic com-poundsQuick and easy reaction setupStart process with one button

No method programming necessaryEasy to use without special trainingRFID reader for capsule

Fludics setup of the synthesizer

Steps to setup a reaction with the synthesizer. A maximum of 5 minutes are necessary to setup a reaction. This will run autonomously and the user can pick up the purified product after the sequence.

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SnAP - N-Heterocycle Formation

Reductive Amination

Automated Multistep Preparation of Drug-like Molecules

O

O

HN N

NO

O

NN N

Me F

NMe

NC

NN

HN

N

OH

N

HN

82% 61%86%"Piribedil"

99% 84% 91%

N

NOH

MeO

HNO

HN

30%(2:1 dr)

HNO

NHO

NH

NNN

17%(2:1 dr)

HN

CF3HN

O

NH

MeO

NH

O

HN

N

N

HNO

NH

F

34%(2:1 dr) 30% 21% 21%

NH

O

53%

F NH

O

46%

CF3

NH

O

27%

BpinNH

BocN

70%

NH

BocN

59%

CN

BrNH

BocN

44%

NH

O

NCbz

36%

Morpholines (SnAP M) Piperazines (SnAP Pip)

69%

Br

O

NH

69%

COOMe

O

NH

70%

O

NH

CN

N

67%

O

NH

61%

F

BocN

NH

Cl

51%

COOMe

BocN

NH O

OEt

37%

BocN

NH N

60%

BocN

NH

Oxazepanes (SnAP OA) Diazepanes (SnAP DA)

NH

BocN

N

N

66%

Ph

NH

BocN

Br

Analytical data of product obtained from the synthesizer directly after the reaction with-out any further purification. Mesitylene was added as internal standard.

waste

pump

valve 2

valve 1

capsule with 4 compartments

reactionvessel

solvents

N2 supply

Reagent capsule with 4 compartments