WO2006035459A1 - Procede ameliore pour la production de derives de thiozolidinediones et de leurs precurseurs - Google Patents

Procede ameliore pour la production de derives de thiozolidinediones et de leurs precurseurs Download PDF

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WO2006035459A1
WO2006035459A1 PCT/IN2005/000323 IN2005000323W WO2006035459A1 WO 2006035459 A1 WO2006035459 A1 WO 2006035459A1 IN 2005000323 W IN2005000323 W IN 2005000323W WO 2006035459 A1 WO2006035459 A1 WO 2006035459A1
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improved process
iso
solvents
reaction
ethers
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PCT/IN2005/000323
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Sanjay Suri
Gurdeep Singh Sarin
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Morepen Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention relates to An Improved Process For The Production Of Derivatives of Thiozolidinediones And Their Precursors. FIELD OF INVENTION:
  • This invention particularly, relates to an improved process for the production of 2,4- thiozolidinediones and pharmaceutically acceptable salts thereof. More particularly, the invention provides a process for the production of pioglitazone, its hydrochloride salt and its precursors exemplified by aromatic nitro ether derivatives, it's corresponding aniline ethers, ⁇ halo (preferably bromo) derivatives of the said corresponding aniline ethers and corresponding 2-imino-4-thiazolidinines having anti- diabetic activity. Further, the invention provides a process that employs, commercially available, substituted pyridine alcohols or their alkali metal salts and substituted 1-halo (preferably fluoro)-4-nitro benzenes as the basic raw materials.
  • the invention provides a process that is technically and commercially feasible. Even more particularly, the invention provides a process with minimal risk factors during production. Additionally the process does not require any stringent operational conditions and special infrastructure. Yet more particularly, the process of the present invention is easy to operate, safe, simple, cost effective, environment friendly, high yielding. Further, the title product obtained by the process of the present invention is more pure compared to the one obtained by existing processes and meets ICH guidelines in respect of residual solvent. BACKGROUND OF THE INVENTION:
  • the invention described herein relates to an improved process for producing substituted 2, 4-thiazolidinediones and their hydrochloride salts as well as their intermediates possessing hypoglycemic and hypolipidemic activities which are useful for the treatment of diabetes.
  • Blood sugar lowering activities of Pioglitazone hydrochloride are well documented.
  • Carbamoyl derivatives of substituted l-fluoro-4- nitro benzenes are known to exhibit herbicidal and fungicidal activities (JP 59110673).
  • These methods invariably comprise the steps of diazotizing an aniline derivative, condensing it with an acrylic ester in the presence of copper catalyst by the so-called Meerwein Arylation reaction to give haloester, which is then reacted with thiourea followed by hydrolysis to afford corresponding 2, 4- thiazolidinediones.
  • These methods include multi-step reaction process.
  • the relevant literature including patents known to the inventor includes US Patent Nos. (a) 4,687,777 ('777), (b) 4,582,839 ('839) both granted to K. Meguro et al, (Chem. Pharm.Bull. 32, 2267-2278 1984; Chem. Pharm.Bull. 30, 3580-3600, 1982; Chem.
  • Compound of formula XI is obtained from reaction between pyridine alcohols and halogenating agent or sulfonyl halide.
  • the compound of formula XIII then undergoes facile base assisted Knoevengel condensation with 2, 4-thiazolidinedione (XIV) to afford the benzylidine-2, 4-thiazolidinediones (XV).
  • Purification followed by reduction of the double bond of compound (XV) results in the formation of crude compound of formula IX, which after purification and treatment with dilute hydrochloric acid yield the corresponding hydrochloride salts (X).
  • the base assisted Williamson coupling is effected in presence of phase transfer catalyst.
  • EP0618915 teaches an alternate route involving cobalt-catalyzed reduction of the double bond of the compound of formula XV.
  • the new reduction method described in the said EP patent is faster, easier, results in improved yield and convenient to scale up to production equipment.
  • the cobalt-catalyzed reduction of double bond is carried out using sodium borohydride in the presence of ligand, polar solvent such as water or tetrahydrfuran (THF) and dilute solution of sodium hydroxide.
  • polar solvent such as water or tetrahydrfuran (THF)
  • dilute solution of sodium hydroxide The method claims to eliminate the operational and safety problems associated with handling of pyrophoric Pd/C as catalyst and high pressure hydrogenation using hydrogen gas externally. However, it is not always reproducible during scale up as a number of impurities can be generated via cleavage of the 2, 4-thiazolidinedione ring by sodium hydroxide. Thus, the resulting crude product of formula IX obtained through cobalt-catalyzed reduction also requires repeated purification so as to obtain the product of acceptable purity to be used as a drug.
  • the method also suffers from the disadvantage of the possibility of higher heavy metal content in the final product since cobalt salts are used in the penultimate stage of the sequence.
  • the starting material i.e. compound of formula XV is prepared as described in Y. Momose et al., Chem. Pharm. Bull, 39:1440 (1991); Japan Patent 139182 (1988);and Chem. Abstr., 109:6504(1988).
  • the extent of impurity profiling varies considerably and depends on the route being followed for their generation.
  • One of the objects of the present invention is to provide a process for the production of 2,4- thiozolidinediones and pharmaceutically acceptable salts thereof obviating most of the problems associated with hither to known processes.
  • object of the present invention is to provide a process for the production of pioglitazone its pharmaceutically acceptable salts preferably hydrochloride salt and its precursors exemplified by aromatic nitro ether derivatives, it's corresponding aniline ethers, ⁇ halo (preferably bromo) derivatives of the said corresponding aniline ethers and corresponding 2-imino-4-thiazolidinines having anti-diabetic activity.
  • pharmaceutically acceptable salts preferably hydrochloride salt and its precursors exemplified by aromatic nitro ether derivatives, it's corresponding aniline ethers, ⁇ halo (preferably bromo) derivatives of the said corresponding aniline ethers and corresponding 2-imino-4-thiazolidinines having anti-diabetic activity.
  • Another object of the present invention is to provide a process that employs, commercially available or easily prepared, substituted pyridine alcohols or their alkali metal salts and substituted 1-halo (preferably fluoro)-4-nitro benzenes as the basic raw materials.
  • Still other object of the present invention is to provide a process that is technically and commercially feasible.
  • Still another object of the present invention is to provide a process with minimal risk factors during production. Specifically, the process does not require any stringent operational conditions and special infrastructure.
  • Yet other object of the present invention is to provide a process that is easy to operate, safe, simple, cost effective, environment friendly, high yielding.
  • Yet another object of the present invention is to provide a process resulting in to a product that is more pure compared to the one obtained by existing processes and meets ICH guidelines in respect of residual solvent.
  • Further object of the present invention is to provide a process, which replaces employing highly moisture sensitive and explosive sodium hydride and expensive, pyrophoric palladium on Carbon (Pd/C).
  • the process also eliminates use of Pd/C under external pressure of hydrogen.
  • the novelty of the invention resides in (i) eliminating employing sodium hydride, palladium on carbon, high pressure hydrogenation using hydrogen gas externally;(ii) using commercially and readily available starting materials; (iii) providing simple economic alternate purification process for carboxylic acid derivative(s); (iv) minimizing solvent requirement and producing the title compound and it's pharmaceutically acceptable salts with increased purity and yield specifically with reference to the amount of residual solvents in the final product.
  • the present invention provides an improved process for the production of derivatives of thiozolidinediones and their precursors which comprises,
  • 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
  • Ri or R 2 or R 3 and X is halogen in presence or absence of solvent(s) and
  • an alkali metal salt such as hydroxide or carbonate is required to be added while conducting the said reaction
  • step (d) cyclising the said purified derivative of ⁇ halo substituted carboxylic acid as obtained in step (c) with thiourea to yield 2-imino -4-thiazolidinones VI,
  • alkyl groups with 1-6 carbon atoms may be such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-pentyl, iso-pentyl, neo-pentyl or n-hexyl, preferably those having 1 to 4 carbon atoms; alicyclic groups may include without restriction cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; alkoxy groups having 1 to 4 carbon atoms may be such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, or t-butoxy, preferably those having 1-3 carbon atoms.
  • the halogen atoms in formula II may be such as fluorine, chlorine, bromine, iodine preferably fluorine.
  • the alkali metal salt when used may be hydroxide, carbonate, preferably hydroxide.
  • the alkali metal hydroxides could be sodium, potassium or lithium hydroxides and may be used singly or as mixtures in any suitable composition.
  • the amount of alkali metal hydroxide employed may vary between 1-8 molar equivalents, preferably between 2-6 molar equivalents and most suitably 3-4 molar equivalents.
  • the amount of alkali metal carbonates employed may preferably be potassium carbonate and the amount added may vary between 1 to 25 molar equivalents, preferably 2 to 15 molar equivalents, more preferably 5 to 10 molar equivalents.
  • the reaction temperature may vary between 5-100 0 C, preferably between 5-7O 0 C and most suitably between 20-40 0 C.
  • the quantity of water used may be between 3-30 times v/w w.r.t the alcohol (I), preferably between 3-10 times v/w and most appropriately between 3-5 times v/w.
  • step (a) works equally well in the of presence all common and easily available Phase transfer catalysts (PTC) selected from quaternary ammonium compounds like tetrabutyl ammonium chloride, tetra butyl ammonium hydrogen sulfate etc, which may be used singly or as mixtures in any suitable composition.
  • PTC Phase transfer catalysts
  • the quantity of PTC when used may vary between 0.5% to 100% w/w and above with reference to pyridine alcohols (I).
  • reaction may be performed with equal efficiency in a mixture of water and most water miscible organic solvents like dimethyl sulfoxide, acetonitirile, 1,4- dioxane, acetone, diethyl ketone, methyl isobutyl ketone, dimethylacetamide, tetrahydrofuran, 1, 2-dimethoxy ethane and diglyme etc and aliphatic alcohols where C ⁇ 3 and ⁇ 8 without making any changes in the reaction or work up conditions.
  • water miscible organic solvents like dimethyl sulfoxide, acetonitirile, 1,4- dioxane, acetone, diethyl ketone, methyl isobutyl ketone, dimethylacetamide, tetrahydrofuran, 1, 2-dimethoxy ethane and diglyme etc and aliphatic alcohols where C ⁇ 3 and ⁇ 8 without making any changes in the reaction or work up conditions.
  • the nitro ethers III can also be prepared under anhydrous conditions by reacting the compound of formula II with the anhydrous powder of the alkali metal salts such as sodium or potassium salts.
  • the reduction of nitro ethers may be carried out by in the absence of external source of hydrogen gas pressure.
  • the nitro ethers (III) may be reduced in the presence of Raney nickel and hydrazine.
  • the reduction may be performed, preferably, in polar water
  • miscible organic solvents like alcohol with C 3 to Cs exemplified by methanol, ethanol
  • n-propanol iso-propanol, n-butanol, iso-butanol; tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxye thane, 1,2-diethoxy ethane, dimethylsulf oxide, dimethylformamide, dimethylacetamide preferably dimethylformamide, dimethylacetamide either in isolation or as a mixture in any suitable composition and the reaction may be preformed in the presence or a absence of water.
  • the quantity of Raney Nickel used may vary between 25 to 100% w/w and that of hydrazine hydrate between 2-6 or more molar equivalents preferably between 2-4 molar equivalents at a temperature between 5-7O 0 C.
  • the reaction may be performed in an efficient hood with an easy out let for the smooth release of the in situ generated hydrogen gas.
  • hydrazine hydrate is slowly added to a stirred suspension of nitro ethers and Raney Nickel in alcoholic solvents like methanol, ethanol, n-propanol, iso- propanol etc. at 30-55 0 C under TLC monitoring.
  • the nitroethers III may also be reduced by subjecting them to hydrogen gas pressure in the presence of Raney Nickel in polar solvent mixture over a period of time.
  • the reaction time may vary between 6-24 hrs.
  • the reaction temperature may vary between -15 to 9O 0 C and the pressure of the applied hydrogen gas could be between 2-6 kg per cm "2 .
  • the reactions can be can be performed in all polar water miscible and organic solvents like methanol, ethanol, n-propanol, iso-propanol, butanol, iso-butanol dimethylformamide, dimethylacetamide, ethers like 1,4-dioxane, 1,2-dimethyl ether, tetrahydrofuran in isolation or mixtures thereof.
  • the reaction may also be performed in a suitable mixture of water immiscible solvents like diethyl ether, diisopropyl ether, diphenyl ether, dibutyl ether, tertiary butyl methyl ether, aromatic hydrocarbon solvents like, benzene, toluene, ortho and para xylenes and halogenated solvents like methylene dichloride, chloroform and dichloro ethane and polar protic solvents like methanol, ethanol, n-proponol, iso-propanol, n-butanol, iso-butanol.
  • water immiscible solvents like diethyl ether, diisopropyl ether, diphenyl ether, dibutyl ether, tertiary butyl methyl ether, aromatic hydrocarbon solvents like, benzene, toluene, ortho and para xylenes and halogenated solvents like methylene
  • the oc-bromo derivatives (V) may be purified by successively extracting with aliphatic or alicyclic nonpolar hydrocarbon solvents then treating the pooled organic layer with activated charcoal followed by filtration and recovery of solvent
  • the derivative V may be purified by extracting with highly polar water immiscible halogenated solvents such as methylene dichloride, chloroform, 1,2- dichloroethane.
  • the invention provides alternate routes for the preparation of nitro ethers avoiding employing explosive reagent such as NaH, it's corresponding aniline replacing palladium on carbon by Raney nickel and using hydrogen gas externally under high pressure by hydrazine. Further a simple purification was adopted over complex chromatographic purification. Thus the novel steps are involved in the preparation of precursors of formulae III, IV, V and VI.
  • the invention particularly relates to the preparation of pioglitazone and its hydrchloride salt, which is illustrated by the following synthetic scheme.
  • the wet crude product after filtration can also be dissolved in hot isopropyl ether and crystallized at 0 to 5°C to obtain the pure product.
  • IR(KBr, Cm .- " U 1 ) 2972.44, 2928.67, 1602.22, 1593.00, 1508.2, 1339.73, 1264.27, 1109.55, 853.89, 751.44, 657.50.
  • Process B To a stirred solution of 2-(5-Ethyl-2-pyridyl)ethanol (I)(100.0 g, 0.66 mol), l-fluoro-4-nitrobenzene (H), (100 g, 0.7 mol), dimethyl sulfoxide (200 ml) and water (50 ml ) at 20 to 25 0 C, sodium hydroxide (70.0 g 1.75 mol) dissolved in water (200 ml) was slowly added keeping the temperature below 30 to 35°C. The reaction mixture was stirred at 30 to 35 0 C for 12 hr. and progress of the reaction was monitored by TLC.
  • Example 3 Preparation of 4-[2-(5-Ethyl-2-pyridyl)ethoxy]nitrobenzene (III)
  • Process C To a stirred solution of 2-(5-Ethyl-2-pyridyl)ethanol (I) (100.0 g, 0.66 mol), l-fluoro-4-nitrobenzene (II), (100.0 g, 0.7 mol), tetra butyl ammonium chloride (5.0 g, 70% solution in water), and water (250 ml) at 20 to 25 0 C, sodium hydroxide (70.0 g, 1.75 mol) dissolved in water (200 ml) was slowly added keeping the temperature below 30 to 35 0 C.
  • the reaction mixture was stirred at 30 to 35 0 C for 12 hrs and progress of the reaction was monitored by TLC. After the reaction was over, ice cold water (2.0 It., 5 to 1O 0 C) was added and the mixture was stirred for 1.5 hrs, filtered washed with ice-cold water (2 x 250 ml, 5 to 1O 0 C) and suck dried under vacuum for 30 minutes. The light green to yellow solid was dried at 35 0 C for 15 hrs to get crude product, which was then dissolved in hot diisopropyl ether (350 to 400 ml, 50 to 6O 0 C) and filtered hot through cloth to remove un-dissolved particles.
  • hot diisopropyl ether 350 to 400 ml, 50 to 6O 0 C
  • Example 4 Preparation of 4-[2-(5-Ethyl-2-pyridyI)ethoxy]nitrobenzene (III).
  • Process D To a stirred solution of 2-(5-Ethyl-2-pyridyl)ethanol (I) (100.0 g, 0.66 mol), l-fluoro-4-nitrobenzene (II), (100.0 g, 0.7mol), tetra butyl ammonium chloride (5.0 g, 70% solution in water), dimethylsulf oxide (200 ml) and water (50 ml) at 20 to 25°C, sodium hydroxide (70.0 g 1.75 mol) dissolved in water (200 ml) was slowly added keeping the temperature below 35°C.
  • the reaction mixture was stirred at 35°C for 12 hr. and progress of the reaction was monitored by TLC. After the reaction was over, ice cold water (2.0 It., 5 to 1O 0 C) was added and the mixture was stirred for 2 hrs, filtered washed with ice-cold water (2 x 250 ml, 5 to 1O 0 C) and suck dried under vacuum for 30 minutes. The light green to yellow solid was dried at 35 to 4O 0 C for 15 hrs to get crude product, which was then dissolved in hot diisopropyl ether (350 to 400 ml, 50 to 6O 0 C) and filtered hot through cloth to remove un-dissolved particles.
  • hot diisopropyl ether 350 to 400 ml, 50 to 6O 0 C
  • the wet crude product after filtration can also be dissolved in hot diisopropyl ether and crystallized at 0 to +5°C to obtain the pure product.
  • the reaction can also be performed in other common solvents like methylene dichloride, chloroform, 1, 2-dichloroethane, benzene, toluene, ortho and para xylenes, diethyl ether, diisopropyl ether, dibutyl ether, tertiary butylmethyl ether, 1, 4-dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane and acetonitrile.
  • the compound since the compound was completely or partially soluble in these solvents, it does not crystallized out from the mixture as such and has to be extracted in hot solvent, the aqueous layer was separated, washed with water, dried on sodium sulphate and evaporated to give the crude product which was then re-crystallized from diisopropyl ether. The yield varies between 75 to 91%.
  • the reaction was carried out in methanol and ethanol, in addition to the product, large amounts of other impurities are also formed and the product can not be easily isolated or crystallized.
  • Example-5 Preparation of 4-[2-(5-Ethyl-2-pyridyl)ethoxy]nitrobenzene (III).
  • Process E A suspension of finely powdered anhydrous potassium carbonate (400.0 g, 4.37 mol) 2-(5-ethyl-2-pyridyl)ethanol (I) (100 g, 0.66 mol), l-fluoro-4-nitrobenzene (II) (100.0 g, 0.70 mol) and tetra n-butyl ammonium hydrogen sulfate (20.0 g) in dry dimethylformamide (200 ml) was heated at 55 to 60°C over a period of 24 hrs, when the TLC of the mixture indicated it to be complete.
  • Example-6 Preparation of 4-[2-(5-Ethyl-2-pyridyI)ethoxy]nitrobenzene (III).
  • Process F A suspension of finely powdered anhydrous potassium carbonate (400.0 g, 4.37 mol) 2-(5-ethyl-2-pyridyl)ethanol (T) (50.0 g, 0.33 mol), and l-fluoro-4- nitrobenzene (H) (50.0 g, 0.35 mol) and tetra n-butyl ammonium hydrogen sulfate (20.0 g) in dry dimethylformamide (100 ml) was heated at 85 to 9O 0 C over a period of 60 hrs, when the TLC of the mixture indicated it to be complete.
  • Process B To 3 lt/4 neck round bottom flask with a with a nitrogen gas inlet and a hydrogen gas out let and a stirring blade, Raney Nickel (60.0 g wet) was added to a solution of 4-[2(ethyl-2-pyridyl)ethoxy]nitrobenzene (III) (100.0 g) in methanol (1.0 It ) at 25 to 30 0 C and the mixture was stirred for 15 min under an atmosphere of nitrogen gas. Hydrazine hydrate (100.0 g) was then very slowly added drop wise to the reaction mixture at 25 to 35 0 C and progress of reaction was monitored by TLC.
  • Example 9 Preparation of (+)Ethyl-2-bromo-3- ⁇ 4-[2-(5-ethyl-2- pyridyl)ethoxy] phenyl ⁇ propionate (V): Hydrobromic acid (47% in water) was slowly added to a cooled (10 to 15 0 C) solution of 4-[2-(5-ethyl-2-pyridyl)ethoxy]aniline (TV) (120.0 g) in acetone (852 ml), methanol (340 ml) and the mixture was cooled to 0 to +5°C.
  • reaction mixture was cooled to 0 to +5 0 C, neutralized by aqueous ammonia (120 to 150 ml, 30% solution) and pH was raised to ⁇ 6.8 to 7.3 while keeping the temperature at 0 to +5°C.
  • Process A The mixture was extracted with diisopropyl ether (2 x 1.25 It), the combined organic layers are washed with water (2 x 1.0 It), stirred with activated charcoal (10.0 g) for 30 minutes, and filtered through high flow bed.
  • the diisopropyl ether layer was separated and the aqueous layer was again extracted with diisopropyl ether (200 ml).
  • the combined diisopropyl ether layers were washed with water (200 ml), separated and evaporated under vacuum keeping the temperature below 5O 0 C.
  • the dark oily residue thus obtained was successively extracted with hexanes (5 x 500 ml) at 30 to 35°C, and combined hexane layers were treated with activated charcoal (10.0 g) and the mixture was stirred for approx. 30 min.
  • Example 10 Preparation of (+)5- ⁇ 4-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl ⁇ -2- imino-4-thiazolidinone (VI).
  • Thiourea (26.0 gm) and sodium acetate (anhydrous 27.3 gm) were charged into a solution of (+) Ethyl-2-bromo-3- ⁇ 4-[2-(5-ethyl-2- pyridyl)ethoxy]phenyl ⁇ propionate (V) (130.0 g; purity 74.22 %) and iso-propanol
  • Example 11 Preparation of (+)5-(4-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl ⁇ -2, 4- thiazolidinedione (VII).
  • Example 12 Preparation of (+) 5- ⁇ 4-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl ⁇ -2,4- thiazolidinedione hydrochloride (VIII). Purified ( ⁇ ) 5- ⁇ 4-[2-(5-ethyl-2- pyridyl)ethoxy]benzyl-2,4-thiazolidinedione (VII) (35.0 g) was heated at to dissolve in a mixture of water (210 ml), hydrochloric acid (36%, 70 ml) and acetone (52.5 ml).
  • the process involves minimal risk factors during production.
  • the process has minimal risk factors during production.
  • the process eliminates employing sodium hydride, palladium on carbon, high pressure hydrogenation using hydrogen gas externally.

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Abstract

L'invention concerne un procédé de préparation de dérivés de thiozolidinediones et de leurs précurseurs. Ledit procédé consiste à (a) faire réagir un composé de formule générale I, dans laquelle R1, R2 et R3 peuvent être identiques ou différents et représentent H, un alkyle ou un alkoxy avec C variant de 1 à 6, des halogènes, des amines d'alkyle et d'aryle mono ou di-substitués et M représente l'hydrogène (H) ou un métal alcalin sélectionné parmi Na, K ou Li avec un composé de formule II, dans laquelle R4 possède la même signification que R1 ou R2 ou R3 et X désigne un halogène en présence ou en l'absence de solvants dans des conditions efficaces à la production de nitro-éthers de formule générale III, dans laquelle R1 à R4 possèdent la même signification que celle susmentionnée, à condition que lorsque M représente H et non son sel métallique alcalin, un sel métallique alcalin, tel que l'hydroxyde ou le carbonate, doit être ajouté, parallèlement à la réalisation de ladite réaction, (b) à soumettre les nitro-éthers, avec ou sans isolation, à une réduction catalysée par le nickel de Raney dans des conditions efficaces à la production d'éthers de nitro-aniline correspondants, (c) à coupler ledit éther d'aniline avec des acrylates dans des conditions d'arylation de Meerwein en présence d'acide bromhydrique afin de produire des dérivés d'acide carboxylique substitué par a-bromo, puis, à les soumettre à une purification d'extraction de solvants, (d) à cycliser le dérivé purifié d'acide carboxylique substitué par a-bromo tel qu'obtenu à l'étape (c) avec une thio-urée afin d'engendrer 2-imino-4-thiazolidinones, (e) à hydrolyser ces 2-imino-4-thiazolidinones de manière à produire 2, 4-thiazolidinones et à les convertir en solides cristallins blancs connus pour présenter une activité antidiabétique, au moyen des méthodes traditionnelles.
PCT/IN2005/000323 2004-09-28 2005-09-26 Procede ameliore pour la production de derives de thiozolidinediones et de leurs precurseurs WO2006035459A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007017095A1 (fr) * 2005-07-27 2007-02-15 Sandoz Ag Procede de preparation de composes de phenylether substitues et de rosiglitazone
JP2009062313A (ja) * 2007-09-06 2009-03-26 Tokuyama Corp ５−｛４−［２−（５−エチル−２−ピリジル）エトキシ］ベンジル｝チアゾリジン−２，４−ジオン塩酸塩の製造方法
JP2009196936A (ja) * 2008-02-21 2009-09-03 Tokuyama Corp ２−ブロモ−３−｛４−［２−（５−エチル−２−ピリジル）エトキシ］フェニル｝プロピオン酸メチルの製造方法
WO2009133576A1 (fr) 2008-04-28 2009-11-05 Erregierre S.P.A. Procédé de préparation de 4-[2-(5-éthyl-2-pyridyl)éthoxy]nitrobenzène et de pioglitazone
JP2010059068A (ja) * 2008-09-02 2010-03-18 Tokuyama Corp ピオグリタゾンの製造方法
JP2010208957A (ja) * 2009-03-06 2010-09-24 Tokuyama Corp 結晶構造を有する５−｛４−［２−（５−エチル−２−ピリジル）エトキシ］ベンジル｝−２−イミノ−４−チアゾリジノン及びその製造方法
CN103304473A (zh) * 2012-03-07 2013-09-18 浙江九洲药业股份有限公司 亚氨基吡格列酮的制备方法及相关中间体
CN108003090A (zh) * 2018-01-05 2018-05-08 白银亿尔精细化工有限公司 一种制备4-[2-(5-乙基-2-吡啶基)乙氧基]硝基苯的方法
CN111875598A (zh) * 2020-05-23 2020-11-03 白银京宇新药业有限公司 一种吡格亚胺的制备方法

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Cited By (12)

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WO2007017095A1 (fr) * 2005-07-27 2007-02-15 Sandoz Ag Procede de preparation de composes de phenylether substitues et de rosiglitazone
JP2009062313A (ja) * 2007-09-06 2009-03-26 Tokuyama Corp ５−｛４−［２−（５−エチル−２−ピリジル）エトキシ］ベンジル｝チアゾリジン−２，４−ジオン塩酸塩の製造方法
JP2009196936A (ja) * 2008-02-21 2009-09-03 Tokuyama Corp ２−ブロモ−３−｛４−［２−（５−エチル−２−ピリジル）エトキシ］フェニル｝プロピオン酸メチルの製造方法
WO2009133576A1 (fr) 2008-04-28 2009-11-05 Erregierre S.P.A. Procédé de préparation de 4-[2-(5-éthyl-2-pyridyl)éthoxy]nitrobenzène et de pioglitazone
JP2011518877A (ja) * 2008-04-28 2011-06-30 エレジーレ ソシエタ ペル アチオニ ４−［２−（５−エチル−２−ピリジル）エトキシ］ニトロベンゼン及びピオグリタゾンの調製方法
JP2010059068A (ja) * 2008-09-02 2010-03-18 Tokuyama Corp ピオグリタゾンの製造方法
JP2010208957A (ja) * 2009-03-06 2010-09-24 Tokuyama Corp 結晶構造を有する５−｛４−［２−（５−エチル−２−ピリジル）エトキシ］ベンジル｝−２−イミノ−４−チアゾリジノン及びその製造方法
CN103304473A (zh) * 2012-03-07 2013-09-18 浙江九洲药业股份有限公司 亚氨基吡格列酮的制备方法及相关中间体
CN103304473B (zh) * 2012-03-07 2016-07-06 浙江九洲药业股份有限公司 亚氨基吡格列酮的制备方法及相关中间体
CN108003090A (zh) * 2018-01-05 2018-05-08 白银亿尔精细化工有限公司 一种制备4-[2-(5-乙基-2-吡啶基)乙氧基]硝基苯的方法
CN111875598A (zh) * 2020-05-23 2020-11-03 白银京宇新药业有限公司 一种吡格亚胺的制备方法
CN111875598B (zh) * 2020-05-23 2023-10-10 白银京宇新药业有限公司 一种吡格亚胺的制备方法

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