Design and Synthesis of

N-heterocyclic Building Blocks

for Pharmaceutical R&D

Feb 2016

Who we are

Liverpool ChiroChem (LCC) supplies chiral building blocks for pharmaceutical R&D. LCC also develop

synthetic routes for complex intermediates and API.

Established in Liverpool, U.K., June 2014. Currently based within the Department of Chemistry, University of

Liverpool.

Core technology: LCC’s methods give access to a wide range of chiral building blocks in excellent

enantiomeric purity. Our initial focus is on the production and supply of chiral piperidines and other sp3-

rich nitrogen heterocycles, which are of great importance to drug discovery and development.

Core strengths: Unique products; excellent chemical and enantiomeric purity.

Expert service; specialist experience in method development and tech transfer.

Management Team

Dr Jianjun Wu, CEO and Director

Industrial Chemist and Entrepreneur. Founder

of Shanghai Boc Chemical.

Dr Paul Colbon, COO and Director

Industrial Chemist. Previously worked with

Redx Pharma and AstraZeneca.

Dr Jiwu Ruan, CSO and Director

Industrial Chemist. Previously worked with Dr

Reddys, Cambridge.

Prof Jianliang Xiao, Director

Professor of Chemistry at the University of

Liverpool. Previously worked with Prof. Noyori

(winner of the Nobel Prize in chiral chemistry).

Mr Bernard Ross, Non-exec Director

CEO and Founder of Sky Medical

Technology.

Dr David Lathbury, Non-exec Chairman

Industrial Chemist. Former director of

AstraZeneca and AMRI.

• The founding team consists of chemists with academic and industrial experience that have developed

state-of-the-art synthetic methods in asymmetric hydrogenation / transfer hydrogenation and palladium

chemistry. The team is also experienced in process development and tech transfer.

Our expertise

Asymmetric Hydrogenation /Transfer Hydrogenation (AH /ATH)

– Offering access to a wide variety of chiral products or APIs

J. Am. Chem. Soc. 2008,130, 14450.

J. Am. Chem. Soc. 2008, 130, 13208.

J. Am. Chem. Soc. 2009, 131, 6967.

J. Am. Chem. Soc. 2014, 136, 4031.

Angew. Chem. Int. Ed. 2006, 45, 6718.

Angew. Chem. Int. Ed. 2009, 48, 6524.

Angew. Chem. Int. Ed. 2010, 49, 7548.

Angew. Chem. Int. Ed. 2011, 123, 1104.

Angew. Chem. Int. Ed. 2013, 52, 1668 .

• Pd-Catalysed Coupling Reactions – powerful strategy for construction of new C–C and C–X bonds,

widely applied in APIs synthesis

Our expertise

Acc. Chem. Res. 2011, 44, 614.

J. Am. Chem. Soc. 2005, 127, 751.

J. Am. Chem. Soc. 2008, 130, 2424.

J. Am. Chem. Soc. 2008, 130, 10510.

J. Am. Chem. Soc. 2010, 132, 16689.

Angew. Chem. Int. Ed. 2006, 45, 4152.

• Production of chiral nitrogen heterocycles, that can be used as building blocks, fragments or screening

compounds. Examples:

• Specific example of our building blocks can be browsed on our website under the catalogue tab.

• www.liverpoolchirochem.com

Our products

• 4-substituted piperidines:

Our products – examples of current stock

• 3-substituted piperidines (provided as single enantiomers or racemic mixtures):

Our products – examples of current stock

• 2-substituted piperidines (provided as single enantiomers or racemic mixtures):

Our products – examples of current stock

• di-substituted piperidines:

• 2 and 3-substituted pyrrolidines: Trifunctionalised Piperidines:

• N-substituted piperidines:

Our products – in the pipeline

• Building Block Design – LCC’s heterocyclic building blocks are designed in partnership with

MedChemica and Dr Neil Berry from the department of chemistry, University of Liverpool:

• Heterocyclic Synthesis - LCC’s products are synthesised by our teams of expert chemists in the UK

and China. Our wealth of experience in asymmetric synthesis and heterocyclic chemistry allows for

efficient synthesis of novel molecules based upon our heterocyclic cores.

• Library Philosophy - Our sp3-rich heterocylcic cores ensure the molecules we produce occupy 3D

space and have desirable pharmacokinetic properties. We design low molecular weight compounds with

a wide range of functional groups and synthetic handles, so that hit fragments can be easily elaborated

and optimised.

Product Design

• LCC’s synthetic technologies allow the production of novel, heterocyclic based small molecules. Our

patented technology provides access to chiral piperidines.

• Upon analysis of the FDA approved drugs, we noticed that piperidines are the most frequently occurring

heterocylce. In addition, piperidines are also the most prevalent heterocycle in clinically approved CNS

(Central Nervous System) compounds.

• Therefore, we set out to apply our technology to the synthesis of a focussed library targeted at the CNS.

Focussed Library Design – CNS

• Examination of the physicochemical/Lipinski space of LCC compounds cf CNS approved drugs there is

a high degree of similarity, i.e. low MW (<400), low logP (<5), #H bond donors (95% library <5), #H bond

acceptors (<8).

Focussed Library Design – CNS

• LCC produced an initial library set of ~11,000 molecules, which was designed in partnership with

Medchemica, using MMPA and their grand rule database. The library was also designed in order to

ensure a good range of functionality was incorporated.

• We then decided on the criteria upon which to optimise the library:

• Physicochemical and CNS penetration criteria were selected based on published literature (e.g. Ro3),

experience (solubility > 1 miliM) and targeting the CNS (MPO >4).

• MPO score devised by Pfizer:

• CNS penetration required

• Guidelines suggested - different to Lipinski’s

• MPO score - probability of CNS penetration

• 74% CNS drugs have MPO score > 4

• 6 key physicochemical parameters (logP, logD, TPSA, MW, HBD, HBA, pKa) drive library design

Focussed Library Design – CNS

• Final set of criteria:

o Calculated solubility > 1 milliM

o MPO score > 4

o AlogP < 3

o Molecular weight < 300

o #H bond donors < 3

o #H bond acceptors < 3

Focussed Library Design – CNS

• Results: Out of the initial set of ~11,000 compounds, ~3,000 (27%) successfully met all of the criteria.

Focussed Library Design – CNS

MW Solubility

(mM)

MPO logP

Average 200 5 4.87 0.75

SD 26 20 0.48 0.94

• Results continued:

• A library of ~3000 small, fragment like, highly soluble, CNS penetrant compounds has been designed.

Focussed Library Design – CNS

• Results continued: As can be seen below, the ~3000 compounds sit in a favourable area of

MPO/logP/Solubility space – all compounds have MPO score >4 (green).

Focussed Library Design – CNS

• Results continued:

In terms of shape, the 3000 compound library show a similar distribution in shape to currently approved CNS

compounds. Concentrated near the rod-disc axis but with considerable 3D character (towards sphere point).

Focussed Library Design – CNS

• 4 Highly experienced PhD chemists in all aspects of asymmetric hydrogenation, Pd-coupling and method

development.

• 10 production chemists, 2 analysts and 1 procurement specialist.

• Carousel reactors and parallel hydrogenator.

• Process development and scale-up laboratory with 50L reactor and 20L rotary evaporator.

• 250mL, 1L and 5L Autoclaves for hydrogenation up to 50 barr.

• NMR, HPLC and GC analysis and quality control.

• Synthesis in the range of mg’s to Kg’s.

Our services – chemistry capabilities

Website: www.liverpoolchirochem.com

Email: info@liverpoolchirochem.co.uk

Office Phone: +44 (0)151 794 2936