4-{(2S,4S)-1-[(Benzyloxy)carbonyl]-4-ethoxy-2-piperidinyl}benzoic acid
[CAS# 1644667-59-3]

Identification

• Classification: Organic raw materials >> Heterocyclic compound >> Piperidines
• Name: 4-{(2S,4S)-1-[(Benzyloxy)carbonyl]-4-ethoxy-2-piperidinyl}benzoic acid
• Molecular Formula: C₂₂H₂₅NO₅
• Molecular Weight: 383.44
• CAS Registry Number: 1644667-59-3
• SMILES: CCO[C@H]1CCN(C(=O)OCc2ccccc2)[C@H](c2ccc(C(=O)O)cc2)C1

Properties

• Density: 1.3±0.1 g/cm³ Calc.^*
• Boiling point: 552.9±50.0 ºC 760 mmHg (Calc.)^*
• Flash point: 288.2±30.1 ºC (Calc.)^*
• Index of refraction: 1.603 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Discovory and Applicatios

(R)-2S,4S-1-[(Benzyloxy)carbonyl]-4-ethoxy-2-piperidinyl benzoic acid (commonly written as 4-((2S,4S)-1-((benzyloxy)carbonyl)-4-ethoxypiperidin-2-yl)benzoic acid) is a stereodefined piperidine-containing benzoic acid derivative that has been described in the medicinal chemistry literature as a key synthetic intermediate in the discovery and optimisation of the oral factor B inhibitor LNP023 (also known as iptacopan). The compound contains a benzoic acid motif tethered at the para position to a 2-piperidinyl substituent; that piperidine bears an N-Cbz (benzyloxycarbonyl) protecting group and a 4-ethoxy substituent, and the two stereocentres are the 2S,4S configuration used during lead optimisation. The substance itself is not reported as a clinical candidate but appears repeatedly in published experimental sequences and supporting information as an advanced intermediate used to access final clinical candidates.

The appearance of this intermediate in peer-reviewed disclosure reflects a modern medicinal-chemistry workflow in which iterative optimisation of potency, selectivity and pharmacokinetic properties required controlled installation of stereochemistry and substituents on a piperidine scaffold. In the public domain the molecule is documented in the synthetic sequences leading to LNP023: multi-step sequences convert aryl ester precursors into the corresponding piperidinyl benzoic acid derivatives, with protecting-group manipulations (Cbz installation/removal), ether installation (ethoxy group), and stereochemical control being central operations. The absolute configuration of the 2S,4S stereochemical set used in the LNP023 series was ultimately confirmed by X-ray cocrystallography of the inhibitor bound to the Factor B catalytic domain, indicating that intermediates with that stereochemistry were the forms advanced to co-crystallisation and biological evaluation.

From a synthetic perspective, the compound functions as a versatile branching point. The carboxylate functionality (as free acid or ester) allows conversion to activated derivatives (acid chloride, mixed anhydride, or activated esters) for amide formation or further coupling. The N-Cbz protecting group provides orthogonal protection for the piperidine nitrogen, enabling chemists to carry out transformations on the ring or on appended aryl groups without undesired N-alkylation. The 4-ethoxy substituent modulates electronic and steric properties of the piperidine and was one of several alkoxy variations explored to balance potency with drug-like ADME properties. The para-linked benzoic acid serves both as a polar handle for aqueous solubility tuning and as a vector interacting with the protein binding pocket in structure-guided optimisation.

The principal application of this intermediate is therefore within the drug-discovery process: it was employed to prepare series members that were screened for binding and functional inhibition of complement factor B, followed by cell-based assays and in vivo models. The optimisation campaign that used this intermediate led to the identification of LNP023, an orally bioavailable, potent and selective factor B inhibitor that has been evaluated in preclinical and clinical studies for complement-mediated diseases. The role of the intermediate is technical but essential: by enabling modular variation of substituents and stereochemistry it supported structure–activity relationship (SAR) studies and co-crystallographic analyses that guided selection of a clinical candidate.

Available experimental disclosures (supporting information and patent filings associated with the LNP023 programme) document synthetic procedures, yields and purification methods for this and closely related piperidinyl benzoic acid derivatives; they show that such intermediates can be prepared on multigram scale under standard medicinal-chemistry conditions and can be advanced to final salt forms for biological testing. In the scientific literature the intermediate is therefore best regarded as a validated process and design element within the successful discovery of a first-in-class oral factor B inhibitor, rather than as an entity developed for any direct therapeutic use itself.

References

Schubart A, Anderson K, Mainolfi N, et al. (2019) Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proceedings of the National Academy of Sciences of the United States of America 116(16) 7926–7931 DOI: 10.1073/pnas.1820892116

Mainolfi N, Ehara T, Karki R G, et al. (2020) Discovery of 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (LNP023), a Factor B inhibitor specifically designed to be applicable to treating a diverse array of complement mediated diseases. Journal of Medicinal Chemistry 63(11) 5697–5722 DOI: 10.1021/acs.jmedchem.9b01870

James A D, Kulmatycki K, Poller B, et al. (2023) Absorption, distribution, metabolism, and excretion of [14C]iptacopan in healthy male volunteers and in in vivo and in vitro studies. Drug Metabolism and Disposition 51(7) 873–883 DOI: 10.1124/dmd.123.001290