1018899-04-1

Basic information

• Product Name: LX-4211
• Synonyms: LX-4211;(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(Methylthio)tetrahydro-2H-pyran-3,4,5-triol;(5S)-Methyl 5-C-[4-chloro-3-[(4-ethoxyphenyl)Methyl]phenyl]-1-thio-beta-L-xylopyranoside;Sotagliflozin;LX4211/LX-4211;LP 802034;(5S)-Methyl 5-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-thio-beta-L-xylopyranoside Sotagliflozin LP 802034;LX4211 - L10525
• CAS NO: 1018899-04-1
• Molecular Formula: C₂₁H₂₅ClO₅S
• Molecular Weight: 424.9382
• Mol File: 1018899-04-1.mol
• Article Data: 16

Chemical Properties

• Boiling Point: 607.9±55.0 °C(Predicted)
• Appearance: /
• Density: 1.37±0.1 g/cm3(Predicted)
• PKA: 12.87±0.70(Predicted)
• CAS DataBase Reference: LX-4211(CAS DataBase Reference)
• NIST Chemistry Reference: LX-4211(1018899-04-1)
• EPA Substance Registry System: LX-4211(1018899-04-1)

Safety Data

• Hazardous Substances Data: 1018899-04-1(Hazardous Substances Data)

Usage

Uses

Sotagliflozin is used for the treatment of patients with type 1 diabetes mellitus.

Clinical Use

Two of the current SGLT-2 inhibitors (canagliflozin and LX-4211) have effects on SGLT-1. LX-4211 is a dual SGLT1/2 inhibitor and higher doses of canagliflozin transiently inhibit SGLT-1 in the gut due to high canagliflozin concentrations within the intestinal lumen during the period of drug absorption.

Synthesis

Sotagliflozin is a dual SGLT-1/SGLT-2 inhibitor which is currently under development by Lexicon Pharmaceuticals (phase III). It follows a similar strategy to ertugliflozin, i.e. aryl addition on an acyclic precursor. The synthesis starts from L-xylose 53, and the aryl moiety (same aryl moiety as for dapagliflozin) is introduced on an amide derivative (morpholine amide 54) via Grignard addition. A subsequent transformation leads to the sotagliflozin (Scheme 10). The overall yield of the synthesis is around 30%. Sotagliflozin synthesis

Upstream product

• 461432-22-4 (5-bromo-2-chlorophenyl)(4-ethyloxyphenyl)methanone 
• 21900-52-7 5-bromo-2-chloro-benzoyl chloride 
• 21739-92-4 5-bromo-2-chlorobenzoic acid 
• 1103738-17-5 (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxolane-5-carboxylic acid 

Downstream Products

• 1018899-03-0 [(2S,3S,4R,5S,6R)-4,5-diacetoxy-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylthiotetrahydropyran-3-yl]acetate 

Relevant articles and documents

Hydrogen-bonded structures and interaction energies in two forms of the SGLT-2 inhibitor sotagliflozin

The sotagliflozin molecule exhibits two fundamentally different molecular conformations in form 1 {systematic name: (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(methylsulfanyl)tetrahydro-2H-pyran-3,4,5-triol, C21H25 ClO5 S, (I)} and the monohydrate [C21H25ClO5 S·H2O, (II)]. Both crystals display hydrogen-bonded layers formed by intermolecular interactions which involve the three-OH groups of the xyloside fragment of the molecule. The layer architectures of (I) and (II) contain a non-hydrogen-bonded molecule-molecule interaction along the short crystallographic axis (a axis) whose total PIXEL energy exceeds that of each hydrogen-bonded molecule-molecule pair. The hydrogen-bonded layer of (I) has the topology of the 4-connected sql net and that formed by the water and sotagliflozin molecules of (II) has the topology of a 3,7-connected net.

Three compounds as well as preparations method and application thereof in synthesis of sotagliflozin

The invention provides compounds shown in formulas IV, V and VI as well as preparation methods of the compounds. The invention further provides application of the compounds shown in formulas IV, V andVI in synthesis of sotagliflozin. Raw materials related to the method are easy to obtain and low in price, and the method is simple and convenient to operate, saving, environmentally friendly and facilitates industrial production.

Process development of sotagliflozin, a dual inhibitor of sodium- Glucose cotransporter-1/2 for the treatment of diabetes

The development of an efficient manufacturing process for sotagliflozin (LX4211), a dual inhibitor of sodium- glucose cotransporter-1/2 (SGLT-1/2) for the treatment of diabetes, is described. Sotagliflozin features five contiguous chiral centers on the carbohydrate core flanked by a thioether group and a biaryl moiety. Three chiral centers are obtained from the starting material L-xylose, while the other two were established (or modified) via three highly stereoselective transformations: Luche reduction (dr: 97/3), dynamic kinetic resolution of anomeric hemiacetal (dr: 95/5), and Lewis acid-promoted thiolation (dr: 1000/ 1). Global deprotection of the resulting penultimate intermediate with catalytic sodium methoxide followed by recrystallization furnishes sotagliflozin. The longest linear sequence consists of 10 steps from L-xylose with an overall yield of 40%. This process has been performed on multi-hundred kilogram batches to satisfy the drug substance development demands.