112052-11-6

Usage

Uses

Used in Pharmaceutical Industry:
(S)-3-P-MESYLOXYTETRAHYDROFURAN is used as a key intermediate in the synthesis of Empagliflozin (E521510), a novel, potent, and selective SGLT-2 inhibitor. Empagliflozin is an important drug for improving glycemic control and addressing features of metabolic syndrome in diabetic patients.
Additionally, it is used in the synthesis of 3''-Epi-Empagliflozin (E586000), which is an impurity of Empagliflozin. The presence of (S)-3-P-MESYLOXYTETRAHYDROFURAN in the synthesis process helps ensure the purity and efficacy of the final pharmaceutical product.

Synthetic route

(S)-3-hydroxytetyrahydrofurane (86087-23-2) + p-toluenesulfonyl chloride (98-59-9) → toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6)

Conditions	Yield
With 1H-imidazole; dmap In dichloromethane at 20℃; for 16h;	100%
With pyridine	100%
With trimethylamine hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 4h;	99%

(S)-3-hydroxytetyrahydrofurane (86087-23-2) + toluene-4-sulfonic acid (104-15-4) → toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6)

Conditions	Yield
Stage #1: (S)-3-hydroxytetyrahydrofurane With dmap; triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: toluene-4-sulfonic acid at 20 - 50℃; for 1.66667h;	96%

(R)-3-Hydroxytetrahydrofuran (86087-24-3) + p-toluenesulfonyl chloride (98-59-9) → toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6)

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; for 8h; Product distribution / selectivity;	83%

(S)-3-hydroxytetyrahydrofurane (86087-23-2) + tosylating reagent → toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6)

Conditions	Yield
	80%

(S)-3-hydroxytetyrahydrofurane (86087-23-2) + benzenesulfonyl chloride (98-09-9) → toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6)

Conditions	Yield
With pyridine at 0 - 20℃; for 1h;	40%

C12H13NO5S + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → C16H19NO6S

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; Product distribution / selectivity;	100%

4-bromo-phenol (106-41-2) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → (3R)-3-(4-bromophenoxy)tetrahydrofuran (857854-81-0)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 16h;	97.6%
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 15h;

tert-butyl (2R,4R)-4-amino-2-methylpiperidine-1-carboxylate + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → C15H28N2O3

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 95℃; for 48h;	95%

3-bromo-5-hydroxy-benzoic acid methyl ester (192810-12-1) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → methyl 3-bromo-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

Conditions	Yield
With caesium carbonate In acetonitrile at 100℃;	92%

4-(2-chloro-5-iodobenzyl)phenol (1459754-32-5) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran (915095-94-2)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; potassium iodide In acetonitrile at 50 - 55℃; Large scale;	90.1%

4-bromo-3,5-dimethylphenol (7463-51-6) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → (R)-3-(4-bromo-3,5-dimethyl-phenoxy)-tetrahydro-furan (1447325-52-1)

Conditions	Yield
With potassium carbonate at 80℃; for 16h;	90%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h;	3.7 g

(R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidine-1(6H)-yl)-1-phenylethyl)carbamate (1062642-68-5) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → tert-butyl ((R)-2-(5-(2-fluoro-3-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidine-1(6H)-yl)-1-phenylethyl)carbamate

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 12h;	89%

toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) + phenol (108-95-2) → (S)-3-phenoxytetrahydrofuran

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 20h;	87%

4-bromo-3-methoxyphenol (102127-34-4) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → C11H13BrO3

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 16h;	86%

4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline (949152-45-8)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 27h;	83%

4-nitrobenzaldehdye (555-16-8) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → (R)-tetrahydrofuran-3-yl 4-nitrobenzoate (1358604-08-6)

Conditions	Yield
With oxygen; 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,3-bis(mesityl)imidazolium chloride In tetrahydrofuran at 50℃; under 760.051 Torr; for 72h; optical yield given as %ee;	80%

6-bromo-4-hydroxyquinoline-2-carboxylic acid methyl ester (145369-93-3, 262586-62-9) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → methyl (R)-6-bromo-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylate

Conditions	Yield
With potassium carbonate In acetonitrile at 80℃; for 16h;	73%
With potassium carbonate In acetonitrile at 110℃; for 4h; Sealed tube;	73%

toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) + phenol (108-95-2) → (R)-3-phenoxytetrahydrofuran

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 12h;	71%

toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) + Diphenylphosphine oxide (4559-70-0) → C16H17O2P

Conditions	Yield
With N,N,N,N,-tetramethylethylenediamine; lithium methanolate In 1-methyl-pyrrolidin-2-one at 40℃; for 24h;	71%

2-hydroxybromobenzene (95-56-7) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → 3-(2-Bromo-phenoxy)-tetrahydro-furan

Conditions	Yield
With potassium hydroxide at 100℃; for 0.5h;	69%

6-(4-hydroxy-1,2-dihydrofuro[3,2-f]quinolin-9-yloxy)-N-methyl-1-naphthamide + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → (R)-6-((4-((tetrahydrofuran-3-yl)oxy)-1,2-dihydrofuro[3,2-f] quinolin-9-yl)oxy)-Ν-methyl-1-naphthamide

Conditions	Yield
With caesium carbonate In N,N-dimethyl acetamide at 60℃; for 2h; Inert atmosphere;	68%

4-(3-(3-fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → (R)-4-(3-(3-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thi oxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile

Conditions	Yield
With caesium carbonate In N,N-dimethyl acetamide at 50℃; for 3h; Inert atmosphere;	67.6%
With caesium carbonate In N,N-dimethyl acetamide; water at 50℃; for 3h;	67.6%

methyl 6-bromo-3-hydroxypyridine-2-carboxylate (321601-48-3) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → methyl (R)-6-bromo-3-((tetrahydrofuran-3-yl)oxy)picolinate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 16h;	67.2%

toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) + 2-methyl-6-(1H-pyrazol-3-yl)pyridine (203569-23-7) → (R)-2-methyl-6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridine

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 16h;	66.5%

3,5-Dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester (35691-93-1) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → C12H18N2O3 (1589005-28-6)

Conditions	Yield
Stage #1: 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester In N,N-dimethyl-formamide; mineral oil at 25℃; for 16h;	63%

4-((7-hydroxy-6-nitroquinolin-4-yl)oxy)-N-(pyridine-2-yl)benzamide + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → 4-{[6-nitro-7-{[(3R)-tetrahydrofuran-3-yl]oxy}quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 50 - 60℃; for 12h;	56%

(2S,3R,4R,5S)-2-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → C23H27ClO7

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 15h;	55%

toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) + 4-hydroxy-benzaldehyde (123-08-0) → (R)-4-((tetrahydrofuran-3-yl)oxy)benzaldehyde

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 14h;	50%

5-bromo-1H-indazole (53857-57-1) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → 5-bromo-1-[(3R)-oxolan-3-yl]indazole

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 2h;	49%

(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (864070-37-1) + toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester (112052-11-6) → (2S,3R,4R,5S,6R)-2-{4-chloro-3-[4-(tetrahydrofuran-3(R)-yloxy)benzyl]phenyl}-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 18h;	44%

Upstream product

• 86087-23-2 (S)-3-hydroxytetyrahydrofurane 
• 104-15-4 toluene-4-sulfonic acid 
• 98-09-9 benzenesulfonyl chloride 
• 86087-24-3 (R)-3-Hydroxytetrahydrofuran 
• 98-59-9 p-toluenesulfonyl chloride 

Downstream Products

• 1620758-33-9 (2S,3R,4R,5S,6R)-2-{4-chloro-3-[4-(tetrahydrofuran-3(R)-yloxy)benzyl]phenyl}-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol 
• 1358604-08-6 (R)-tetrahydrofuran-3-yl 4-nitrobenzoate 
• 857854-81-0 (3R)-3-(4-bromophenoxy)tetrahydrofuran 
• 915095-94-2 (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran 
• 1447325-52-1 (R)-3-(4-bromo-3,5-dimethyl-phenoxy)-tetrahydro-furan 
• 1416157-65-7 2-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 
• 1309166-24-2 (S)-methyl 2-(4-(tetrahydrofuran-3-yloxy)phenyl)acetate 
• 1309166-20-8 (S)-methyl 2-(tetrahydrofuran-3-yloxy)benzoate 
• 949152-45-8 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline 

Relevant academic research and scientific papers

2-AZASPIRO[3.4]OCTANE DERIVATIVES AS M4 AGONISTS

Provided herein are compounds according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R5, and R7 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) as well as the use of such compounds as M4 receptor agonists.

5-OXA-2-AZASPIRO[3.4]OCTANE DERIVATIVES AS M4 AGONISTS

Provided herein are compounds according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R5, and R7 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) as well as the use of such compounds as M4 receptor agonists.

Design and Synthesis of Pyrrolo[2,3-d]pyrimidine-Derived Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Checkpoint Kinase 1 (CHK1)-Derived Crystallographic Surrogate

Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson’s disease treatment. Fragment hit-derived pyrrolo[2,3-d]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2R)-2-Methylpyrrolidin-1-yl derivative 18 (LRRK2 G2019S cKi0.7 nM, LE 0.66) was identified, with increased potency consistent with an X-ray structure of 18 /CHK1 10-pt. mutant showing the 2-methyl substituent proximal to Ala147 (Ala2016 in LRRK2). Further structure-guided elaboration of 18 gave the 2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino] derivative 32 . Optimization of 32 afforded diastereomeric oxolan-3-yl derivatives 44 and 45 , which demonstrated a favorablein vitroPK profile, although they displayed species disconnects in thein vivoPK profile, and a propensity for P-gp- and/or BCRP-mediated efflux in a mouse model. Compounds 44 and 45 demonstrated high potency and exquisite selectivity for LRRK2 and utility as chemical probes for the study of LRRK2 inhibition.

Fused tricyclic derivative as FGFR4 inhibitor

The present invention provides a fused tricyclic derivative that is the selective inhibitor of fibroblast growth factor receptor 4 (FGFR4), a pharmaceutical composition containing the compound, a method of making the compound and a method of treating cell proliferative diseases, such as cancer, using the compounds of the invention.

HPK1 ANTAGONISTS AND USES THEREOF

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of HPK1, and the treatment of HPK1-mediated disorders.

8-substituted styryl xanthine derivative and application thereof

The invention discloses an 8-substituted styryl xanthine derivative and application thereof, and particularly relates to a novel 8-substituted styryl xanthine derivative and a pharmaceutical composition containing the compound, and the 8-substituted styryl xanthine derivative can be used as a selective adenosine A2A receptor antagonist. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition in preparation of drugs for treating adenosine A2A receptor related diseases, especially Parkinson's disease.

Nitrogen-containing fused tricyclic derivative and application thereof

The invention discloses a nitrogen-containing fused tricyclic derivative and application thereof, and particularly relates to a novel nitrogen-containing fused tricyclic derivative and a pharmaceutical composition containing the nitrogen-containing fused tricyclic derivative, and the nitrogen-containing fused tricyclic derivative can be used as a selective adenosine A2A receptor antagonist. The invention also relates to a method for preparing the compound and the pharmaceutical composition and application of the compound and the pharmaceutical composition in preparation of drugs for treating adenosine A2A receptor related diseases, especially Parkinson's disease.

3,9-DIAZASPIRO[5.5]UNDECANE COMPOUNDS

The present invention covers 3,9-diazaspiro[5.5]undecane compounds of general formula (I) and general formula (I-a), in which R1, R2, R3 and R4 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment and/or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

PYRAZOLOPYRIDINE DERIVATIVE HAVING GLP-1 RECEPTOR AGONIST EFFECT

The present invention provides a compound having the basic structure shown by Formula (I) in which the indole ring and the pyrazolopyridine structure is bound through a substituent, a salt thereof or a solvate of either the compound or a salt of the compound, as well as a preventative agent or a therapeutic agent for non-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesity containing such compound, salt or solvate as an active ingredient.

ALKENE COMPOUNDS AS FARNESOID X RECEPTOR MODULATORS

The present invention provides compounds of Formula (I): Formula (I) or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds modulate the activity of famesoid X receptor (FXR), for example, as agonists. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.