The Molecular Industrial Revolution: Automated Synthesis of Small Molecules

Abstract

Today we are poised for a transition from the highly customized crafting of specific molecular targets by hand to the increasingly general and automated assembly of different types of molecules with the push of a button. Creating machines that are capable of making many different types of small molecules on demand, akin to that which has been achieved on the macroscale with 3D printers, is challenging. Yet important progress is being made toward this objective with two complementary approaches: 1) Automation of customized synthesis routes to different targets by machines that enable the use of many reactions and starting materials, and 2) automation of generalized platforms that make many different targets using common coupling chemistry and building blocks. Continued progress in these directions has the potential to shift the bottleneck in molecular innovation from synthesis to imagination, and thereby help drive a new industrial revolution on the molecular scale.

Keywords: artificial intelligence; flow chemistry; iterative synthesis; machine learning; small molecules.

Figure 1

The structure of Vitamin B12 (1) and Albert Eschenmoser and R.B. Woodward with what was dubbed a “B12- and B13-making machine”.

Figure 2

Examples of early automated synthesis systems.

Figure 3

Small molecules are inherently modular.

Figure 4

Small molecules made via iterative cross coupling from MIDA-boronate building blocks.

Figure 5

Robot-scientists (A) Adam and (B) Eve [J. R. Soc. Interface, 2015, 12, 20141289] - Published by The Royal Society of Chemistry.

Figure 6

“Artificial Imagination” of AlphaGo, Published by DeepMind.

Scheme 1

Eli Lilly’s process to synthesize prexasertib monolactate monohydrate (2).

Scheme 2

Flow production of the boronic acid key intermediate (3) for the manufacturing process of TAK-117.

Scheme 3

Example for a batch processes for the synthesis of the radiolabeled drug molecule [¹⁸F]FAZA (4).

Scheme 4

Flow process for the 3 step synthesis of Ibuprofen (5).

Scheme 5

Flow processes for the synthesis of ciprofloxacin hydrochloride (6).

Scheme 6

Schematic process for the automated synthesis and formulation of aliskiren hemifumarate (7); R reactor, S separation, Cr crystallization, W filter/wash, D dilution tank, E extruder, MD mold.

Scheme 7

An examples for integrated batch and flow systems for the Synthesis of 5-methyl-4-propylthiophene-2-carboxylic acid (8) [React. Chem. Eng. 2016, 1, 629–635] - Published by The Royal Society of Chemistry.

Scheme 8

Syntheses performed with MEDLEY and a schematic diagram of MEDLEY (Reprinted (adapted) with permission from Org. Proc. Res. Dev. 2000, 4, 333–336. Copyright 2000 American Chemical Society).

Scheme 9

Synthesis performed with ChemKonzert and a schematic diagram of ChemKonzert including two reaction vessels (RF1 and RF2), a centrifugal separator (SF, 700 mL), two receivers (SF1 and SF2, 500 mL), two glass filters (FF1 and FF2, 500 and 100 mL), 12 substrate and reagent reservoirs (RR1–RR12) (Reprinted (adapted) with permission from Org. Process Res. Dev. 2009, 13, 1111–1121. Copyright 2009 American Chemical Society).

Scheme 10

Reconfigurable modules of a flow reactor and their assembly for the synthesis of different compounds.

Scheme 11

Synthesis performed with the automated synthesis lab developed by Eli Lilly and schematic diagram with (1) Input/output device (2) Bench for heated reactions (3) Bench with special functions as cooling, microwave and flow, (4) work-up bench (5) analytics.

Scheme 12

Automated Synthesis Machine (A) linear structures prepared by the automated synthesizer. (B) Cyclic scaffolds prepared with the automated synthesizer as linear precursors and cyclized by hand.

Scheme 13

Concept with flow diagram for automated Suzuki–Miyaura and optimized yield and TON found in some examples [React. Chem. Eng. 2016, 1, 658–666] - Published by The Royal Society of Chemistry.

Scheme 14

Scheme of the flow-NMR platform and studied model reactions [Chem. Sci. 2015, 6, 1258–1264] - Published by The Royal Society of Chemistry.

Scheme 15

Three examples for self-optimization and online data analysis in flow reactors [React. Chem. Eng. 2017, 2, 103–108] and [React. Chem. Eng. 2016, 1, 366–371] - Published by The Royal Society of Chemistry.