SYNTHESIS OF MEDCHEM-RELEVANT GEM-DIFLUOROCYCLOALKANE BUILDING BLOCKS

Prof. Dmitriy M. Volochnyuk Prof. Sergey V. Ryabukhin 257th ACS National Meeting April 2019 Orlando

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Enamine profile • Scientifically driven chemical company • Privately owned, founded in 1991 • Research & Production facility in Kiev, Ukraine • Over 500 synthetic chemists • 2.7M Screening Compounds, the world’s largest! • 180k Building Blocks, 50% of the world’s stock! • Biology services: ADME/T tests, animal studies and molecular screening • No own drug research, 100% service orientated • Representative and distribution offices in EU, USA, Japan, and China

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MedChem-Relevant BB

Possible topologies for the library synthesis using mono- (yellow), bi- (green) and trifunctional (red) building blocks (up to four-component reaction sequences are considered; most cyclic topologies formed by three or more bi- and trifunctional building blocks are not shown)

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MedChem-Relevant BB

Drug Discovery Today, 2015, 20, 11-17

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MedChem-Relevant BB

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MedChem-Relevant BB

Synthetic chemistry view:

• Reasonable # of steps (usually 5-10 steps from kilo scale accessible staring materials) • Atom-economy

• Easy scale up of each step (usually BB produced in 5-100 g quantity) • NO expensive / hardly accessible / exotic starting materials / reagents / catalyst

• Minimal hazardous chemistry (e.g SF4, tBuLi etc.) • NO expensive separation / purification (e.g. HPLC)

• NO time / recourses consuming procedures (e.g. extraction from water of hydrophilic compounds)

• Useful “formulation” (e.g no viscous oil, hygroscopic salts etc)

Cost and human recourses effective

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C6, C5, C4 Gem-Difluorocycloalkane BB

This work, published

results

Well known

Org. Process Res. Dev., 2008, 12, 1094–1103

Described, but the synthesis needed “exotic” starting materials

(allene or difluorodicjhloroethylene)

J. Org. Chem. 1987, 52, 1872–1874 Synth. Commun. 2005, 35, 657–662

First disclosure, just submitted

State of art at the our beginning (2008-2009):

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C6, C5, C4 Gem-Difluorocycloalkane BB Current state of art:

(numbers in brackets correspond to number of papers / patents referenced by Reaxys database)

FDA approval: July 2018

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C6, C5, Gem-Difluorocycloalkane BB

J. Fluor. Chem. 2017, 199, 60-66

K. Melnykov

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C6, C5, Gem-Difluorocycloalkane BB

J. Fluor. Chem. 2017, 199, 60-66

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C6, C5, Gem-Difluorocycloalkane BB

J. Fluor. Chem. 2017, 199, 60-66

Dr. D. Sibgatulin

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C4 Gem-Difluorocycloalkane BB

J. Org. Chem. 1987, 52, 1872–1874 Synth. Commun. 2005, 35, 657–662 J. Med. Chem. 2015, 58, 2967–2987

Exotic SM, > 15$/g bp = 19 0C

Exotic SM

Scale up failed

Dr. D. Radchenko Dr. A. Chernykh

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C4 Gem-Difluorocycloalkane BB

Synthesis 2018, 50, 4949-4957

X-Ray

K. Melnykov

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C4 Gem-Difluorocycloalkane BB

Dr. D. Sibgatulin

Synthesis 2018, 50, 4949-4957

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C4 Gem-Difluorocycloalkane BB

Synthesis 2018, 50, 4949-4957

5 steps 21% total yield

> 25 g/run

Dr. Dmitriy Granat

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C4 Gem-Difluorocycloalkane BB

Ishii, S. et al J. Fluor. Chem. 2016, 182, 41–46

Failed

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C4 Gem-Difluorocycloalkane BB

initial approach: scale up is problematical

alternative approach: 5 steps, 38% overall yield 238 g of 22 in 1 synthetic run

Dr. A. Chernykh

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C4 Gem-Difluorocycloalkane BB X-Ray

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C4: pKa

K. Melnykov

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C4: logP and solubility

K. Melnykov

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C3-C6 BB: EVP

RSC Adv., 2016, 6, 17595-17605 New J. Chem., 2018, 42, 8355-8365

Dr. O. Grygorenko

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Conclusion The synthesis of medicinally relevant building blocks:

• Creative • Limited by time and budget • Needs careful optimization of each step, but unlike P@D

would be variable for the analogous synthesis • NOT “pub-like” (e.g. Synthesis, EurJOC) • But in a case unusual central core structure or deep

reaction investigation shifted to “pub-like” (JOC, Org.

Lett, Adv.Synth.Cat, Eur J Chem A) • “Ideal” activity to improve the skills for the synthetic

chemists

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Acknowledgements

Dr. Oleksandr O. Grygorenko Dr. Dmitriy O. Sibgatulin Pavel S. Nosyk Konstantin P. Melnykov Dr. Dmitriy S. Granat Dr. Dmitriy S. Radchenko Dr. Anton Chernykh

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THANK YOU FOR YOUR KIND ATTENTION