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

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

• 1018898-85-5 acetic acid (2S,3S,4R,5S,6S)-4,5-diacetoxy-2-bromo-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydropyran-3-yl ester 
• 5188-07-8 sodium thiomethoxide 
• 1018899-03-0 [(2S,3S,4R,5S,6R)-4,5-diacetoxy-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylthiotetrahydropyran-3-yl]acetate 
• 281652-58-2 2-chloro-5-iodobenzoylchloride 
• 19094-56-5 2-chloro-5-iodobenzoic acid 
• 1103738-30-2 (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxolan-5-yl)methanone 
• 1103738-29-9 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene 
• 1103738-26-6 (2-chloro-5-iodo-phenyl)-(4-ethoxyphenyl)methanone 
• 67-63-0 isopropyl alcohol 
• 114861-22-2 1,2-O-isopropylidene-α-L-xylofuranose 
• 1103738-19-7 ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholin-4-yl)methanone 
• 945621-29-4 (3aS,5S,6R,6aS)-5-[(tert-butyldimethylsilyloxy)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol 
• 391201-57-3 [(3aS,5S,6R,6aS)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanol 

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.

PROCESS FOR PREPARING THE CRYSTALLINE FORM II OF SOTAGLIFLOZIN

The present document relates to a process for the preparation of the crystallineform II of sotagliflozin, wherein said crystalline form II of sotagliflozin is directly obtained from the following compound of formula (A) and by using toluene or xylene or mixture thereof as solvent medium for the crystallization.

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.

Radical Dehydroxymethylative Fluorination of Carbohydrates and Divergent Transformations of the Resulting Reverse Glycosyl Fluorides

A mild and convenient method for the synthesis of reverse glycosyl fluorides (RGFs) has been developed that is based on the silver-promoted radical dehydroxymethylative fluorination of carbohydrates. A salient feature of the reaction is that furanoid and pyranoid carbohydrates furnish structurally diverse RGFs bearing a wide variety of functional groups in good to excellent yields. Intramolecular hydrogen atom transfer experiments revealed that the reaction involves an underexploited radical fluorination that proceeds via β-fragmentation of sugar-derived primary alkoxyl radicals. Structurally divergent RGFs were obtained by catalytic C?F bond activation, and our method thus offers a concise and efficient strategy for the synthesis of reverse glycosides by late-stage diversification of RGFs. The potential of this method is showcased by the preparation and diversification of sotagliflozin, leading to the discovery of a promising SGLT2 inhibitor candidate.

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 FOR THE PREPARATION OF SOTAGLIFLOZIN

Sotagliflozin may be prepared using schemes and intermediates disclosed herein. Sotagliflozin may be incorporated into pharmaceutical dosage forms for treatment of diabetes.

Synthetic method for sotagliflozin and its analogues

The invention discloses a synthetic method for sotagliflozin and its analogues. The method comprises the following steps: with dapagliflozin acetate 1 as a raw material, carrying out oxidation so as to obtain diaryl ketone 2; selectively removing an acetyl group in the compound 2 so as to obtain primary alconol 3; carrying out dehydroxymethyl fluorination so as to obtain fluoroglucoside 4; then subjecting a carbonyl group to reductive alkylation so as to obtain a compound 5; reacting an activated C-F bond and a nucleophilic reagent to obtain a glycosylation product 6a-6c; and finally removingan acetyl group so as to obtain sotagliflozin and its analogue 7a-7c, or subjecting the compound 5 to removal of the acetyl group to obtain a sotagliflozin analogue 7d. The synthetic method of the invention has the following advantages: the raw material dapagliflozin acetate can be prepared from inexpensive and easily available 1,5-gluconolactone; only the acetyl group is used as a protecting group which can be removed under mild conditions; a reducing agent sodium borohydride used in the method is cheap, easily available, and stable in water and air; stereoselective reduction is not involved,so the difficulty of synthesis is lowered, experimental operation is simplified, and the method is suitable for large-scale preparation.

SOLID STATE FORMS OF SOTAGLIFLOZIN

Disclosed are solid state forms of Sotagliflozin, processes for preparation thereof, and pharmaceutical compositions thereof.

COMPOSITIONS COMPRISING (2S,3R,4R,5S,6R)-2-(4- CHLORO-3-(4-ETHOXYBENZYL)PHENYL)-6-(METHYLTHIO)TETRAHYDRO-2H-PYRAN-3,4,5-TRIOL

Pharmaceutical dosage forms useful for improving the cardiovascular and/or metabolic health of patients, particularly those suffering from type 2 diabetes, are disclosed, as well as methods of their manufacture.

Sotagliflozin preparing method and an intermediate thereof

The invention provides a Sotagliflozin preparing method. The structure of an L-xylose derivative 1 is improved, the hydroxyl group is protected with a benzyl group or PMB group to obtain a compound 2,or series derivative reaction is conducted on the L-xylose derivative 1A to obtain the compound 2, the conditions of Grignard docking reaction of the compound 2 and 4-halogenated-1-chloro-2-(4-oxyethylbenzyl) benzene compound 3 are optimized, the reaction yield is increased to 85% or more, usage of excessive Grignard reagents or lithium reagents is avoided, material consumption is reduced, and the route efficiency is improved.