112529-15-4

Basic information

• Product Name: [5-[[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione hydrochloride
• Synonyms: Pioditazone hydrochloride;5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzylidine]-2,4-thiazolidinedionehydrochloride;AD-4833;pioglitazone hydrochioride;PIODLITAZONE HYDROCHLORIC;5-{4-[2-(5-ETHYL-PYRIDIN-2-YL)-ETHOXY]-BENZYL}-THIAZOLIDINE-2,4-DIONE HCL;5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-;5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione hydrochloride
• CAS NO: 112529-15-4
• Molecular Formula: C₁₉H₂₀N₂O₃S*ClH
• Molecular Weight: 392.9
• EINECS: 1308068-626-2
• Product Categories: Active Pharmaceutical Ingredients;Antidiabetic;Diabetes;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;API's;Pioglitazone;Inhibitor;API;Cardiovascular Series
• Mol File: 112529-15-4.mol

Chemical Properties

• Melting Point: 193-194°C
• Boiling Point: 575.4 ºC at 760 mmHg
• Flash Point: 301.8 ºC
• Appearance: white to off-white/
• Density: 1.26 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.64
• Storage Temp.: Desiccate at RT
• Solubility: DMSO: ≥10mg/mL
• Water Solubility: Soluble in water (<1 mg/ml at 25°C), DMF, methanol, ethanol (4 mg/ml at 25°C), and DMSO (79 mg/ml at 25°C).
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• Merck: 14,7452
• CAS DataBase Reference: [5-[[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: [5-[[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione hydrochloride(112529-15-4)
• EPA Substance Registry System: [5-[[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione hydrochloride(112529-15-4)

Safety Data

• Hazard Codes: Xi
• Statements: 36/38-36
• Safety Statements: 22-24/25-26
• WGK Germany: 3
• RTECS: XJ5813440
• HazardClass: IRRITANT
• Hazardous Substances Data: 112529-15-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
[5-[[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione hydrochloride is used as an antidiabetic agent for the treatment of type 2 diabetes mellitus. It helps improve glycemic control, demonstrates a beneficial effect on insulin resistance, and positively influences other clinically relevant parameters such as plasma levels of triglycerides or HDL-cholesterol.
Used in Research and Development:
In the field of pharmaceutical research and development, [5-[[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione hydrochloride serves as a key compound for studying the mechanisms of insulin resistance and the development of new treatments for diabetes and related metabolic disorders.

Originator

Takeda (Japan)

Therapeutic Function

Antidiabetic

Biochem/physiol Actions

Selective PPARγ agonist

References

1) Merck 14:7452 2) Sakamoto et al. (2000), Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone; Biochem. Biophys. Res. Commun., 278 704 3) Wilson et al. (2000), The PPARs: From Orphan Receptors to Drug Discovery; J. Med. Chem., 43 527 4) Shannon et al. (2017), Pioglitazone Inhibits Mitochondrial Pyruvate Metabolism and Glucose Production in Hepatocytes; FEBS J., 284 451 5) Zhao et al. (2016), The Antidepressant-Like Effects of Pioglitazone in a Chronic Mild Stress Mouse Model Are Associated With PPARγ-Mediated Alteration of Microglial Activation Phenotypes; Neuroinflamm., 13 259

InChI:InChI=1S/C19H20N2O3S.ClH/c1-2-13-3-6-15(20-12-13)9-10-24-16-7-4-14(5-8-16)11-17-18(22)21-19(23)25-17;/h3-8,12,17H,2,9-11H2,1H3,(H,21,22,23);1H

Synthetic route

Pioglitazone (105355-27-9) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
With hydrogenchloride In ethanol at 10 - 65℃; for 4.25h; Product distribution / selectivity;	95%
With hydrogenchloride In ethanol; water at 10 - 65℃; for 4.25h; Product distribution / selectivity;	90%
With hydrogenchloride In methanol; water at 20℃; for 1h;	90.5%

5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methylene]-thiazolidine-2,4-dione hydrogen chloride → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Stage #1: 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methylene]-thiazolidine-2,4-dione hydrogen chloride With hydrogen; palladium 10% on activated carbon In methanol; water at 50 - 60℃; under 3750.38 - 4500.45 Torr; for 15h; Stage #2: With hydrogenchloride In water at 0 - 5℃; for 3h;	84%

5-ethyl-2-(2-hydroxyethyl)pyridine (5223-06-3) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: 63 percent / NaH / dimethylformamide 2: H2 / 10percent Pd-C / methanol / 760 Torr / Ambient temperature 3: 1.)47percent HBr, NaNO2, 2.)Cu2O / 1.)MeOH, H2O, 5 deg C, 20 min., 2.)40 deg C 4: 53 percent / NaOAc / ethanol / Heating 5: 2N HCl / 6 h / Heating 6: 12.2 g / 11percent ethanolic HCl / 1 h / Ambient temperature View Scheme
Multi-step reaction with 10 steps 1: dihydrogen peroxide / acetic acid / 14 h / 100 °C 2: 0.5 h / 120 °C 3: sodium hydroxide / water / 2 h / 40 °C 4: thionyl chloride; triethylamine / dichloromethane / 1.25 h / 0 - 5 °C 5: N,N-dimethyl-formamide / 14 h / 80 °C 6: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 7: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 4 h / 65 - 85 °C / Large scale 8: triethylamine / dichloromethane / 2 h / 0 °C 9: acetic acid; sodium tetrahydroborate / 15 h / 40 - 45 °C 10: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 10 steps 1: dihydrogen peroxide / acetic acid / 14 h / 100 °C 2: 0.5 h / 120 °C 3: sodium hydroxide / water / 2 h / 40 °C 4: thionyl chloride; triethylamine / dichloromethane / 1.25 h / 0 - 5 °C 5: N,N-dimethyl-formamide / 14 h / 80 °C 6: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 7: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 4 h / 65 - 85 °C / Large scale 8: triethylamine 9: acetic acid; sodium tetrahydroborate / 15 h / 40 - 45 °C 10: hydrogenchloride / water; ethanol View Scheme

4-[2-(5-ethylpyridin-2-yl)ethoxy]aniline (85583-40-0) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.)47percent HBr, NaNO2, 2.)Cu2O / 1.)MeOH, H2O, 5 deg C, 20 min., 2.)40 deg C 2: 53 percent / NaOAc / ethanol / Heating 3: 2N HCl / 6 h / Heating 4: 12.2 g / 11percent ethanolic HCl / 1 h / Ambient temperature View Scheme

4-(2-(5-ethyl-2-pyridyl)ethoxy)nitrobenzene (85583-54-6) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: H2 / 10percent Pd-C / methanol / 760 Torr / Ambient temperature 2: 1.)47percent HBr, NaNO2, 2.)Cu2O / 1.)MeOH, H2O, 5 deg C, 20 min., 2.)40 deg C 3: 53 percent / NaOAc / ethanol / Heating 4: 2N HCl / 6 h / Heating 5: 12.2 g / 11percent ethanolic HCl / 1 h / Ambient temperature View Scheme

methyl 2-bromo-3-{4-[2-(5-ethyl-pyridin-2-yl)ethoxy]phenyl}propionate (105355-25-7) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 53 percent / NaOAc / ethanol / Heating 2: 2N HCl / 6 h / Heating 3: 12.2 g / 11percent ethanolic HCl / 1 h / Ambient temperature View Scheme

5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2-imino-4-thiazolidinone (105355-26-8) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2N HCl / 6 h / Heating 2: 12.2 g / 11percent ethanolic HCl / 1 h / Ambient temperature View Scheme
With hydrogenchloride; water for 15h; Product distribution / selectivity; Heating / reflux;
Stage #1: 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2-imino-4-thiazolidinone With methanol; oxalic acid In dichloromethane at 20℃; for 0.5h; Stage #2: With hydrogenchloride; water for 12h; Product distribution / selectivity; Heating / reflux;

4-Fluoronitrobenzene (350-46-9) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: 63 percent / NaH / dimethylformamide 2: H2 / 10percent Pd-C / methanol / 760 Torr / Ambient temperature 3: 1.)47percent HBr, NaNO2, 2.)Cu2O / 1.)MeOH, H2O, 5 deg C, 20 min., 2.)40 deg C 4: 53 percent / NaOAc / ethanol / Heating 5: 2N HCl / 6 h / Heating 6: 12.2 g / 11percent ethanolic HCl / 1 h / Ambient temperature View Scheme

2-bromo-3-{4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl}propionic acid (674798-32-4) + thiourea (17356-08-0) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Stage #1: 2-bromo-3-{4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl}propionic acid; thiourea With sodium acetate In ethanol for 3h; Heating / reflux; Stage #2: With hydrogenchloride In ethanol; water for 18h; Heating / reflux; Stage #3: With ammonia In ethanol; water at 20℃;

5-{4-[2-(5-ethyl-pyridin-2-yl)ethoxy]-benzyl}-2-morpholin-4-yl-thiazol-4-one (1034515-30-4) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
With hydrogenchloride; water; isopropyl alcohol for 8h; Product distribution / selectivity; Heating / reflux;

N-(5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-4-oxo-4,5-dihydrothiazol-2-yl)-methanesulfonamide (1034515-42-8) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
With hydrogenchloride; water for 3h; Product distribution / selectivity; Heating / reflux;

N-(5-{4-[2-(5-ethyl-pyridin-2-yl)ethoxy]benzyl}-4-oxo-4,5-dihydrothiazol-2-yl)-4-methylbenzenesulfonamide (1034515-24-6) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Stage #1: N-(5-{4-[2-(5-ethyl-pyridin-2-yl)ethoxy]benzyl}-4-oxo-4,5-dihydrothiazol-2-yl)-4-methylbenzenesulfonamide With hydrogenchloride; water for 8h; Heating / reflux; Stage #2: With hydrogenchloride In ethyl acetate at 25 - 30℃; for 2h; Product distribution / selectivity;

5-{4-[2-(5-ethylpyridn-2-yl)ethoxy]benzylidene}-2,4-thiazolidene dione (144809-28-9) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Stage #1: 5-{4-[2-(5-ethylpyridn-2-yl)ethoxy]benzylidene}-2,4-thiazolidene dione With sodium tetrahydroborate; cobalt(II) nitrate hexahydrate; butane-2,3-dione dioxime; sodium hydroxide In water; N,N-dimethyl-formamide at 35℃; for 6h; Large scale reaction; Stage #2: With acetic acid In water; N,N-dimethyl-formamide at 25℃; for 0.75h; pH=6.5 - 7; Large scale reaction; Stage #3: With hydrogenchloride In water; isopropyl alcohol at 25 - 80℃; Large scale reaction;	49.6 kg
Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 3102.97 Torr 2: hydrogenchloride / water; ethanol View Scheme

5-{4-[2-(5-ethylpyridin-2-yl)-2-mesylethoxy]benzylidene}-2,4-thiazolidene dione (646519-90-6) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 3 h / 60 - 65 °C 2: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 3 steps 1: palladium 10% on activated carbon; hydrogen / methanol / 14 h / 3102.97 Torr 2: acetic acid; sodium tetrahydroborate / 15 h / 40 - 45 °C 3: hydrogenchloride / water; ethanol View Scheme

5-{4-[2-(5-ethylpyridin-2-yl)-2-mesylethoxy]benzyl}-2,4-thiazolidene dione → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid; sodium tetrahydroborate / 15 h / 40 - 45 °C 2: hydrogenchloride / water; ethanol View Scheme

5-{4-[2-(5-ethylpyridin-2-yl)-2-tosylethoxy]benzylidene}-2,4-thiazolidene dione (646519-92-8) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; hydrogen / water; methanol / 14 h / 3102.97 Torr 2: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 3 h / 60 - 65 °C 2: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 3 steps 1: palladium 10% on activated carbon; hydrogen / water; methanol / 14 h / 3102.97 Torr 2: acetic acid; sodium tetrahydroborate / 15 h / 40 - 45 °C 3: hydrogenchloride / water; ethanol View Scheme

5-{4-[2-(5-ethylpyridin-2-yl)-2-tosylethoxy]benzyl}-2,4-thiazolidene dione → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid; sodium tetrahydroborate / 15 h / 40 - 45 °C 2: hydrogenchloride / water; ethanol View Scheme

5-{4-[2-chloro-2-(5-ethylpyridn-2-yl)ethoxy]benzylidene}-2,4-thiazolidene dione (646519-94-0) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen / tetrahydrofuran / 12 h 2: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 4 h / 65 - 70 °C 2: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 3 steps 1: zinc; acetic acid / methanol / 15 h / 25 - 30 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 3102.97 Torr 3: hydrogenchloride / water; ethanol View Scheme

2-(5-ethyl-1-oxypyridin-2-yl)ethanol (90643-32-6) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 10 steps 1: 0.5 h / 120 °C 2: sodium hydroxide / water / 2 h / 40 °C 3: thionyl chloride; triethylamine / dichloromethane / 1.25 h / 0 - 5 °C 4: N,N-dimethyl-formamide / 14 h / 80 °C 5: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 6: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 4 h / 65 - 85 °C / Large scale 7: thionyl chloride / chloroform / 2 h / Reflux 8: hydrogenchloride 9: zinc; propionic acid / ethanol / 12 h 10: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 10 steps 1: 0.5 h / 120 °C 2: sodium hydroxide / water / 2 h / 40 °C 3: thionyl chloride; triethylamine / dichloromethane / 1.25 h / 0 - 5 °C 4: N,N-dimethyl-formamide / 14 h / 80 °C 5: thionyl chloride / chloroform / 1 h / Reflux 6: acetic acid; piperidine / toluene / Heating 7: hydrogen / tetrahydrofuran / 12 h 8: hydrogenchloride 9: zinc; propionic acid / ethanol / 12 h 10: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 10 steps 1: 0.5 h / 120 °C 2: sodium hydroxide / water / 2 h / 40 °C 3: thionyl chloride; triethylamine / dichloromethane / 1.25 h / 0 - 5 °C 4: N,N-dimethyl-formamide / 14 h / 80 °C 5: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 6: thionyl chloride / chloroform / 3 h / Reflux 7: hydrogen / tetrahydrofuran / 12 h 8: hydrogenchloride 9: zinc; propionic acid / ethanol / 12 h 10: hydrogenchloride / water; ethanol View Scheme

1-(5-ethylpyridin-2-yl)ethan-1,2-diol → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: thionyl chloride; triethylamine / dichloromethane / 1.25 h / 0 - 5 °C 2: N,N-dimethyl-formamide / 14 h / 80 °C 3: thionyl chloride / chloroform / 1 h / Reflux 4: acetic acid; piperidine / toluene / Heating 5: hydrogen / tetrahydrofuran / 12 h 6: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 6 steps 1: thionyl chloride; triethylamine / dichloromethane / 1.25 h / 0 - 5 °C 2: N,N-dimethyl-formamide / 14 h / 80 °C 3: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 4: thionyl chloride / chloroform / 3 h / Reflux 5: hydrogen / tetrahydrofuran / 12 h 6: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 6 steps 1: thionyl chloride; triethylamine / dichloromethane / 1.25 h / 0 - 5 °C 2: N,N-dimethyl-formamide / 14 h / 80 °C 3: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 4: triethylamine / dichloromethane / 2 h / 0 °C 5: palladium 10% on activated carbon; hydrogen / water; methanol / 14 h / 3102.97 Torr 6: hydrogenchloride / water; ethanol View Scheme

5-ethyl-2-[2-oxo-(1,3,2)dioxathiolan-4-yl]pyridine → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: N,N-dimethyl-formamide / 14 h / 80 °C 2: thionyl chloride / chloroform / 1 h / Reflux 3: acetic acid; piperidine / toluene / Heating 4: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 4 h / 65 - 70 °C 5: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 5 steps 1: N,N-dimethyl-formamide / 14 h / 80 °C 2: triethylamine / dichloromethane / 4 h / 0 - 5 °C 3: acetic acid; piperidine / toluene / 4 h / 120 - 130 °C 4: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 3 h / 60 - 65 °C 5: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 5 steps 1: N,N-dimethyl-formamide / 14 h / 80 °C 2: triethylamine / dichloromethane / 4 h / 0 - 5 °C 3: acetic acid; piperidine / toluene / 4 h / 120 - 130 °C 4: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 3 h / 60 - 65 °C 5: hydrogenchloride / water; ethanol View Scheme

4-[2-chloro-2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: acetic acid; piperidine / toluene / Heating 2.1: hydrogen / tetrahydrofuran / 12 h 3.1: zinc; acetic acid / 15 h / 25 - 30 °C 4.1: water; N-Bromosuccinimide / tert-butyl alcohol / 1.17 h / 25 - 30 °C 5.1: potassium carbonate / tert-butyl alcohol / 1.17 h / Reflux 5.2: 11 h / Reflux 6.1: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 7.1: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 4 h / 65 - 85 °C / Large scale 8.1: triethylamine 9.1: acetic acid; sodium tetrahydroborate / 15 h / 40 - 45 °C 10.1: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 10 steps 1.1: acetic acid; piperidine / toluene / Heating 2.1: hydrogen / tetrahydrofuran / 12 h 3.1: zinc; acetic acid / 15 h / 25 - 30 °C 4.1: water; N-Bromosuccinimide / dimethyl sulfoxide / 0.5 h / -5 - 0 °C 5.1: potassium carbonate / tert-butyl alcohol / 1.17 h / Reflux 5.2: 11 h / Reflux 6.1: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 7.1: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 4 h / 65 - 85 °C / Large scale 8.1: triethylamine 9.1: acetic acid; sodium tetrahydroborate / 15 h / 40 - 45 °C 10.1: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 10 steps 1.1: acetic acid; piperidine / toluene / Heating 2.1: hydrogen / tetrahydrofuran / 12 h 3.1: zinc; acetic acid / 15 h / 25 - 30 °C 4.1: water; N-Bromosuccinimide / dimethyl sulfoxide / 0.5 h / -5 - 0 °C 5.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.08 h 5.2: 15 h / 25 - 90 °C 6.1: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 7.1: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 4 h / 65 - 85 °C / Large scale 8.1: triethylamine 9.1: acetic acid; sodium tetrahydroborate / 15 h / 40 - 45 °C 10.1: hydrogenchloride / water; ethanol View Scheme

4-[2-(5-ethylpyridin-2-yl)-2-mesylethoxy]benzaldehyde → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetic acid; piperidine / toluene / 4 h / 120 - 130 °C 2: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 3 h / 60 - 65 °C 3: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 4 steps 1: acetic acid; piperidine / toluene / 4 h / 120 - 130 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 14 h / 3102.97 Torr 3: acetic acid; sodium tetrahydroborate / 15 h / 40 - 45 °C 4: hydrogenchloride / water; ethanol View Scheme

4-[2-(5-ethylpyridn-2-yl)-2-tosylethoxy]benzaldehyde → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetic acid; piperidine / toluene / 4 h / 120 - 130 °C 2: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 3 h / 60 - 65 °C 3: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 3 steps 1: acetic acid; piperidine / toluene / 4 h / 120 - 130 °C 2: palladium 10% on activated carbon; hydrogen / water; methanol / 14 h / 3102.97 Torr 3: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 4 steps 1: acetic acid; piperidine / toluene / 4 h / 120 - 130 °C 2: palladium 10% on activated carbon; hydrogen / water; methanol / 14 h / 3102.97 Torr 3: acetic acid; sodium tetrahydroborate / 15 h / 40 - 45 °C 4: hydrogenchloride / water; ethanol View Scheme

5-{4-[2-chloro-2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-2,4-thiazolidene dione hydrochloride (646519-89-3) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: zinc; propionic acid / ethanol / 12 h 2: hydrogenchloride / water; ethanol View Scheme

4-hydroxy-benzaldehyde (123-08-0) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / tert-butyl alcohol; water / 1.5 h / 25 °C / Large scale 1.2: 0.75 h / Large scale 1.3: PEG 4000 / 17 h / 78 °C / Large scale 2.1: thionyl chloride / chloroform / 1 h / Reflux 3.1: acetic acid; piperidine / toluene / Heating 4.1: hydrogen / tetrahydrofuran / 12 h 5.1: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / tert-butyl alcohol; water / 1.5 h / 25 °C / Large scale 1.2: 0.75 h / Large scale 1.3: PEG 4000 / 17 h / 78 °C / Large scale 2.1: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 3.1: triethylamine / dichloromethane / 2 h / 0 °C 4.1: palladium 10% on activated carbon; hydrogen / water; methanol / 14 h / 3102.97 Torr 5.1: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.08 h 1.2: 15 h / 25 - 90 °C 2.1: thionyl chloride / chloroform / 1 h / Reflux 3.1: acetic acid; piperidine / toluene / Heating 4.1: hydrogen / tetrahydrofuran / 12 h 5.1: hydrogenchloride / water; ethanol View Scheme

4-[2-(5-ethylpyridin-2-yl)-2-hydroxyethoxy]benzaldehyde (471295-98-4) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: thionyl chloride / chloroform / 1 h / Reflux 2: acetic acid; piperidine / toluene / Heating 3: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 4 h / 65 - 70 °C 4: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 4 steps 1: thionyl chloride / chloroform / 1 h / Reflux 2: acetic acid; piperidine / toluene / Heating 3: hydrogen / tetrahydrofuran / 12 h 4: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 4 h / 0 - 5 °C 2: acetic acid; piperidine / toluene / 4 h / 120 - 130 °C 3: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 3 h / 60 - 65 °C 4: hydrogenchloride / water; ethanol View Scheme

acetic acid 2-acetoxy-2-(5-ethyl-1-pyridin-2-yl)ethyl ester → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 7 steps 1: sodium hydroxide / water / 2 h / 40 °C 2: thionyl chloride; triethylamine / dichloromethane / 1.25 h / 0 - 5 °C 3: N,N-dimethyl-formamide / 14 h / 80 °C 4: thionyl chloride / chloroform / 1 h / Reflux 5: acetic acid; piperidine / toluene / Heating 6: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 4 h / 65 - 70 °C 7: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 7 steps 1: sodium hydroxide / water / 2 h / 40 °C 2: thionyl chloride; triethylamine / dichloromethane / 1.25 h / 0 - 5 °C 3: N,N-dimethyl-formamide / 14 h / 80 °C 4: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 5: thionyl chloride / chloroform / 3 h / Reflux 6: sodium tetrahydroborate; butane-2,3-dione dioxime; cobalt(II) chloride hexahydrate / water; N,N-dimethyl-formamide / 4 h / 65 - 70 °C 7: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 7 steps 1: sodium hydroxide / water / 2 h / 40 °C 2: thionyl chloride; triethylamine / dichloromethane / 1.25 h / 0 - 5 °C 3: N,N-dimethyl-formamide / 14 h / 80 °C 4: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 5: triethylamine / dichloromethane / 2 h / 0 °C 6: palladium 10% on activated carbon; hydrogen / water; methanol / 14 h / 3102.97 Torr 7: hydrogenchloride / water; ethanol View Scheme

5-ethyl-2-vinyl-pyridine (5408-74-2) → 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / tert-butyl alcohol; water / 1.5 h / 25 °C / Large scale 1.2: 0.75 h / Large scale 1.3: PEG 4000 / 17 h / 78 °C / Large scale 2.1: thionyl chloride / chloroform / 1 h / Reflux 3.1: acetic acid; piperidine / toluene / Heating 4.1: hydrogen / tetrahydrofuran / 12 h 5.1: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / tert-butyl alcohol; water / 1.5 h / 25 °C / Large scale 1.2: 0.75 h / Large scale 1.3: PEG 4000 / 17 h / 78 °C / Large scale 2.1: pyrrolidine / methanol / 2 h / 50 - 55 °C / Large scale 3.1: triethylamine / dichloromethane / 2 h / 0 °C 4.1: palladium 10% on activated carbon; hydrogen / water; methanol / 14 h / 3102.97 Torr 5.1: hydrogenchloride / water; ethanol View Scheme
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / tert-butyl alcohol; water / 1.5 h / 25 °C / Large scale 1.2: 0.75 h / Large scale 1.3: PEG 4000 / 17 h / 78 °C / Large scale 2.1: triethylamine / dichloromethane / 4 h / 0 - 5 °C 3.1: acetic acid; piperidine / toluene / 4 h / 120 - 130 °C 4.1: palladium 10% on activated carbon; hydrogen / water; methanol / 14 h / 3102.97 Torr 5.1: hydrogenchloride / water; ethanol View Scheme

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) → rac-5-({p-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl}methyl)-(5-2H)-1,3-thiazolidine-2,4-dione (1134163-24-8)

Conditions	Yield
With triethylamine In dimethylsulfoxide-d6; d(4)-methanol at 20℃; for 108h;	95%
With dimethylsulfoxide-d6; d(4)-methanol; triethylamine at 20℃; for 108h;	95%
With dimethylsulfoxide-d6; d(4)-methanol; triethylamine at 20℃; for 108h;	95%

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) + 1-bromo-2,3,4-tri-O-acetyl-α-D-glucuronic acid methyl ester (21085-72-3) → 3-((2R,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl)-5-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzyl}-thiazolidine-2,4-dione (1296832-69-3)

Conditions	Yield
With caesium carbonate In acetonitrile at 70℃; for 3h;	83%

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) + dimethylbiguanide (657-24-9) → metformin (RS)-5-(4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl)thiazolidine-2,4-dioxothiazolidin-3-ide

Conditions	Yield
In water	64%

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) + zinc(II) chloride (7646-85-7) → C38H38N4O6S2Zn(2+)*2Cl(1-)

Conditions	Yield
With sodium hydroxide In N,N-dimethyl-formamide at 70℃; pH=6 - 6.5;	51.08%

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) → 3-((2R,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxy-tetrahydropyran-2-yl)-5-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzyl}-thiazolidine-2,4-dione (1296832-75-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: caesium carbonate / acetonitrile / 3 h / 70 °C 2: hydrogenchloride / 1,4-dioxane / 76 h / 20 °C 3: morpholine; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 20 °C View Scheme

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) → (2S,3S,4S,5R,6R)-6-(1-carboxy-2-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl}-ethylsulfanylcarbonylamino)-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid (1296832-76-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: caesium carbonate / acetonitrile / 3 h / 70 °C 2: hydrogenchloride / 1,4-dioxane / 76 h / 20 °C 3: morpholine; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 20 °C 4: water; acetonitrile 5: sodium acetate / water; acetonitrile / 296 h / 20 °C View Scheme

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) → 3-((2R,3R,4S,5S,6S)-6-allyloxycarbonyl-3,4,5-trihydroxy-tetrahydropyran-2-yl)-5-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzyl}-thiazolidine-2,4-dione (1296832-72-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: caesium carbonate / acetonitrile / 3 h / 70 °C 2: hydrogenchloride / 1,4-dioxane / 76 h / 20 °C View Scheme

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) → 3-((2R,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxy-tetrahydropyran-2-yl)-5-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzyl}-thiazolidine-2,4-dione trifluoroacetate

Conditions	Yield
Multi-step reaction with 4 steps 1: caesium carbonate / acetonitrile / 3 h / 70 °C 2: hydrogenchloride / 1,4-dioxane / 76 h / 20 °C 3: morpholine; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 20 °C 4: water; acetonitrile View Scheme

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) → (2S,3S,4S,5R,6R)-6-(1-carboxy-2-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl}-ethylsulfanylcarbonylamino)-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid trifluoroacetate

Conditions	Yield
Multi-step reaction with 6 steps 1: caesium carbonate / acetonitrile / 3 h / 70 °C 2: hydrogenchloride / 1,4-dioxane / 76 h / 20 °C 3: morpholine; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 20 °C 4: water; acetonitrile 5: sodium acetate / water; acetonitrile / 296 h / 20 °C 6: water; acetonitrile View Scheme

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) → (5R)-5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione L-tartrate (1263978-84-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: water; methanol / 96 h / Inert atmosphere 2.1: tetrahydrofuran / 1.5 h / 20 - 35 °C / Inert atmosphere 2.2: 20 °C / Reflux; Inert atmosphere View Scheme

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) → (5R)-5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione tosylate (1263978-86-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: water; methanol / 96 h / Inert atmosphere 2: isopropyl alcohol / 0.5 h / 20 - 40 °C / Inert atmosphere View Scheme

L-Tartaric acid (87-69-4) + 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) → (5R)-5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione L-tartrate (1263978-84-2) + C4H6O6*C19H20N2O3S

Conditions	Yield
In methanol; water for 96h; Inert atmosphere;	A n/a B n/a

Di-p-toluoyl-L-tartaric acid (32634-66-5) + 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) → (5R)-5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione (-)-O,O'-di-p-toluoyl-L-tartrate + C19H20N2O3S*C20H18O8

Conditions	Yield
In methanol; water for 96h; Inert atmosphere;	A n/a B n/a

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) + O,O'-dibenzoyl-L-tartaric acid (2743-38-6) → (5R)-5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione (-)-O,O'-dibenzoyl-L-tartrate + (x)C18H14O8*C19H20N2O3S

Conditions	Yield
In methanol; water for 96h; Product distribution / selectivity; Inert atmosphere;	A n/a B n/a

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) → 3-(4-(2-(5-ethylpyridine-2yl)ethoxy)phenyl)-2-mercaptopropanoic acid (1229114-66-2) + 2-(1-carboxy-2-{4-[2-(5-ethylpyridine-2yl)-ethoxy]phenyl}-ethyldisulfanyl)-3-{4-[2-(5-ethylpyridine-2yl)-ethoxy]phenyl}propanoic acid (1229114-67-3)

Conditions	Yield
With sodium hydroxide at 80℃; for 24h;

5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione hydrochloride (112529-15-4) → rac-2-(2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxy}ethyl)-5-ethylpyridine-1-oxide (145350-09-0)

Conditions	Yield
With dihydrogen peroxide at 60 - 80℃; for 24h;

Upstream product

• 5223-06-3 5-ethyl-2-(2-hydroxyethyl)pyridine 
• 105355-25-7 methyl 2-bromo-3-{4-[2-(5-ethyl-pyridin-2-yl)ethoxy]phenyl}propionate 
• 1034515-30-4 5-{4-[2-(5-ethyl-pyridin-2-yl)ethoxy]-benzyl}-2-morpholin-4-yl-thiazol-4-one 
• 1034515-42-8 N-(5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyl}-4-oxo-4,5-dihydrothiazol-2-yl)-methanesulfonamide 
• 1034515-24-6 N-(5-{4-[2-(5-ethyl-pyridin-2-yl)ethoxy]benzyl}-4-oxo-4,5-dihydrothiazol-2-yl)-4-methylbenzenesulfonamide 
• 144809-28-9 5-{4-[2-(5-ethylpyridn-2-yl)ethoxy]benzylidene}-2,4-thiazolidene dione 
• 646519-94-0 5-{4-[2-chloro-2-(5-ethylpyridn-2-yl)ethoxy]benzylidene}-2,4-thiazolidene dione 
• 90643-32-6 2-(5-ethyl-1-oxypyridin-2-yl)ethanol 
• 646519-82-6 5-ethyl-2-[2-oxo-(1,3,2)dioxathiolan-4-yl]pyridine 
• 5408-74-2 5-ethyl-2-vinyl-pyridine 
• 646519-84-8 5-{4-[2-(5-ethylpyridin-2-yl)-2-hydroxyethoxy]benzylidene}-2,4-thiazolidene dione 
• 646519-81-5 2-bromo-1-(5-ethylpyridin-2-yl)ethanol 
• 101931-00-4 5-{4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxyethoxy]benzyl}-2,4-thiazolidinedione 
• 646519-88-2 5-{4-[2-chloro-2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-2,4-thiazolidene dione 

Downstream Products

• 1296832-75-1 3-((2R,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxy-tetrahydropyran-2-yl)-5-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzyl}-thiazolidine-2,4-dione 
• 1296832-76-2 (2S,3S,4S,5R,6R)-6-(1-carboxy-2-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl}-ethylsulfanylcarbonylamino)-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid 
• 1296832-72-8 3-((2R,3R,4S,5S,6S)-6-allyloxycarbonyl-3,4,5-trihydroxy-tetrahydropyran-2-yl)-5-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzyl}-thiazolidine-2,4-dione 
• 1296832-69-3 3-((2R,3R,4S,5S,6S)-3,4,5-triacetoxy-6-methoxycarbonyl-tetrahydropyran-2-yl)-5-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzyl}-thiazolidine-2,4-dione 
• 1263978-84-2 (5R)-5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione L-tartrate 
• 1263978-86-4 (5R)-5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione tosylate 
• 1229114-66-2 3-(4-(2-(5-ethylpyridine-2yl)ethoxy)phenyl)-2-mercaptopropanoic acid 
• 1229114-67-3 2-(1-carboxy-2-{4-[2-(5-ethylpyridine-2yl)-ethoxy]phenyl}-ethyldisulfanyl)-3-{4-[2-(5-ethylpyridine-2yl)-ethoxy]phenyl}propanoic acid 
• 145350-09-0 rac-2-(2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxy}ethyl)-5-ethylpyridine-1-oxide 
• 1134163-24-8 rac-5-({p-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl}methyl)-(5-²H)-1,3-thiazolidine-2,4-dione 

Relevant articles and documents

NOVEL PROCESS TO PREPARE PIOGLITAZONE VIA SEVERAL NOVEL INTERMEDIATES

A novel process for preparing thiazolidinediones, preferably Pioglitazone, as described. Also described are novel intermediates involved in its synthesis and process for their preparation and use in medicine.

An improved process for pioglitazone and its pharmaceutically acceptable salt

An improved process for pioglitazone (1) is described. The process features high-yielding transformations employing inexpensive reagents and recoverable solvents.

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The present invention relates to 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by the following Chemical Formula [1], which is useful as an intermediate for synthesis of thiazolidinedione based compounds, a method for preparing the compound, and a method for preparing pioglitazone or pioglitazone hydrochloride, which is a thiazolidinedione based drug and useful in treating and preventing diabetes, using the 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula [1] as an intermediate:

A PROCESS FOR THE PREPARATION OF 4-[2-(5-ETHYL-2-PYRIDYL)ETHOXY]NITROBENZENE AND PIOGLITAZONE

A process for the preparation of 4-[2-(5-ethyl-2-pyridyi)ethoxy]nitrobenzene is described, which comprises the step of reacting 2-(5-ethyl-2-pyridyl)ethanol with 1-fluoro-4-nitrobenzene in acetone in the presence of an alkali metal hydroxide. The intermediate 4-[2-(5-ethyl-2-pyridyI)ethoxy]nitrobenzene is used for the preparation of pioglitazone.

PROCESS FOR THE PREPARATION OF THIAZOLIDINE DERIVATIVES

The present invention relates to an industrially advantageous process for the preparation of thiazolidine derivatives, such as pioglitazone of formula I and its pharmaceutically acceptable salts.This invention also provides novel synthetic intermediates useful in the process for the preparation of pioglitazone.

NOVEL PROCESS FOR THE SYNTHESIS OF PIOGLITAZONE AND ITS SALTS THEREOF

Present invention relates to an improved process for the preparation of thiazolidinedione derivatives. Further the invention provides the hydrogenation of acid addition salt of benzylidene compound with less reducing agent under low Hydrogen gas pressure to get substantially pure thiazolidinedione derivatives with improved yields.

AN IMPROVED PROCESS FOR THE PRODUCTION OF DERIVATIVES OF THIOZOLIDINEDIONES AND THEIR PRECURSORS

The invention provides a process for preparing derivatives of thiozolidinediones and their precursors comprising, (a) reacting a compound of general formula I wherein R1, R2 and R3 may be same or different and represent H, alkyl or alkoxy with C varying from 1 to 6, halogens, mono or di-substituted alkyl and aryl amines, and M represents hydrogen (H) or alkali metal selected from Na, K or Li with a compound of formula II, wherein R4 has the same meaning as R1 or R2 or R3 and X is halogen in presence or absence of solvent(s) under effective conditions to produce nitro ethers of general formula III, where in R1 to R4 has the same meaning as given above, provided when M is H and not its alkali metal salt, an alkali metal salt such as hydroxide or carbonate is required to be added while conducting the said reaction, (b) subjecting the said nitro ethers, with or without isolation, to Raney nickel-catalyzed reduction under conditions effective to produce corresponding nitro aniline ethers (c) coupling the said aniline ether with acrylates under Meerwein arylation conditions in presence of hydrobromic acid to produce α bromo substituted carboxylic acid derivatives followed by subjecting to solvent extractive purification (d) cyclising the purified derivative of α bromo substituted carboxylic acid as obtained in step (c) with thiourea to yield 2-imino -4-thiazolidinones then (e) hydrolyzing the said 2-imino-4-thiazolidinones to produce 2, 4-thiazolidinones and converting the same to its hydrochloride salts as white crystalline solids known to exhibit antidiabetic activity, by conventional methods.

PROCESS FOR PREPARING THIAZOLIDINEDIONES

This invention provides a process for reducing an exocyclic double bond at the 5-position of a thiazolidinedione moiety of a thiazolidinedione precursor comprising the steps of: a) preparing a solution or suspension of the thiazolidinedione precursor in a non-ether solvent medium with a base, and b) combining the solution or suspension with a dithionite source. Preferred solvent media include aqueous N,N-dimethylformamide. Sodium dithionite is a preferred dithionite source. In particular the application discloses preparation processes for Pioglitazone, Rosilitazone and Troglitazone.

A PROCESS FOR PURIFICATION

The present invention provides a process for purification of pharmaceutically active compounds selected from the group consisting of thiazolidinedione derivatives and trans-3-Ethyl-2,5-dihydro-4-methyl-N- [2-[4-[[[[(4-methylcyclohexyl)amino] carbonyl] amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide comprising extraction in a solvent comprising an alkanol (C1-C4) and ammonia.

PROCESS FOR THE SYNTHESIS OF PIOGLITAZONE HYDROGEN CHLORIDE

The invention relates to a process for the synthesis of pioglitazone hydrogen chloride - which is an antidiabetic drug - via novel intermediates by reacting 4-[2-(5-ethyl-2-pyridinyl)-ethoxy]-benzaldehyde salt of formula (II), wherein HX is: HCI, CF3COOH, C4H4O4, (COOH)2 with a base and then thiazolidine-2,4-dione, and the obtained 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methylene]-2,4-thiazolidinedione base is treated with hydrochloric acid and the obtained 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl] methylene]-2,4-tiazolidinedione hydrogen chloride of formula(III) is hydrogenated in the presence of a catalyst. Further objects of the invention are the salts of general formula (II) and the benzylidene derivative of formula (III).