WO2006032218A1 - Method for the preparation of rosiglitazone - Google Patents

Method for the preparation of rosiglitazone Download PDF

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Publication number
WO2006032218A1
WO2006032218A1 PCT/CZ2005/000066 CZ2005000066W WO2006032218A1 WO 2006032218 A1 WO2006032218 A1 WO 2006032218A1 CZ 2005000066 W CZ2005000066 W CZ 2005000066W WO 2006032218 A1 WO2006032218 A1 WO 2006032218A1
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Prior art keywords
formula
mixture
solvent
formic acid
rosiglitazone
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PCT/CZ2005/000066
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French (fr)
Inventor
Ales Halama
Josef Jirman
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Zentiva, A.S.
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Publication of WO2006032218A1 publication Critical patent/WO2006032218A1/en

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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
    • A61P3/08—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 a new method of carrying out the reduction of 5-[4-[2-(N-methyl-N- (2-pyridyl)-amino)ethoxy]benzylidene]thiazolidine-2,4-dione yielding rosiglitazone, i. e. a substance which is used for the preparation of a drug for the treatment of hyperglycaemia in patients who suffer from diabetes mellitus of second type.
  • Rosiglitazone 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]-thiazolidine-2,4-dione of formula I, is a well-known antihyperglycaemic, chemical synthesis of which was first described in patent EP306228 (1989) of Beecham.
  • Rosiglitazone of formula I is usually prepared by the reduction of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]- thiazolidine-2,4-dione of formula II, see the following equation.
  • the reduction of the compound of formula II to rosiglitazone of formula I may be carried out by various methods.
  • patent application WO 9923095 has described possibilities to carry out the catalytic hydrogenation in mediums other than the initially used dioxane, e. g. in acetic acid and its mixtures with water, in alcohols, mineral acids, and in mixtures of these solvents.
  • the reduction was carried out under the catalysis of 10% palladium on carbon at higher temperatures (80 to 115 0 C) and under the pressure of hydrogen of 0.35 to 10.5 MPa.
  • the catalyst consumption was, in comparison with the aforementioned method, lower; nevertheless, it was still very high (5 to 100 %, preferably 25 to 50 %, based on the weight of the substance of formula H).
  • the product was obtained after filtration and evaporation of the solvent with a yield in the interval of 70 to 80 %.
  • the invention relates to a new method of carrying out the reduction of 5-[4-[2-(N-methyl-N- (2-pyridyl)-amino)ethoxy]benzylidene]thiazolidine-2,4-dione of formula II, which consists in the use of a mixture of formic acid of formula III and a basic amine of formula IV, or directly of the ammonium salt of formic acid of formula V as the reducing agent under the catalysis of a transition metal.
  • the catalyst is preferably chosen from the group of palladium, platinum, or rhodium; use of 5 to 10% palladium on carbon as the catalyst of the reaction is advantageous (5 to 20 % based on the weight of the compound of formula II).
  • the reaction can be carried out without adding another solvent or in a suitable solvent from the group of acetic acid, dimethylformamide, methanol, and ethanol, or their mixtures.
  • This method does not require the use of hydrogen as the reducing agent, which makes it possible to carry out the reaction without using pressure equipment.
  • the substance of formula II in the form of its E-isomer or Z-isomer, or a mixture of both isomers (E/Z) in any ratio, or a mixture of tautomeric forms and solvates of the compound of formula II may be used as the starting material.
  • the reduction is carried out at temperatures of the reaction mixture in the interval of from 40 0 C to the boiling point of the reaction mixture.
  • the method used is described in the following equation:
  • SOLVENT R i , R 2 and R 3 stand for an alkyl or hydrogen
  • the reduction of the substance of formula II to rosiglitazone of formula I is, on the basis of the method we invented, carried out in the following way.
  • the starting substance of formula II is dissolved in the medium of formic acid of formula III, or a mixture of formic acid with water, and a catalyst (preferably palladium on carbon) and a basic amine of formula IV or an ammonium salt of formic acid of formula V are added.
  • the reduction itself proceeds under heating and stirring of the obtained mixture, preferably at the boiling point.
  • Isolation of the raw product is carried out after filtration of the catalyst, evaporation of the solvent, neutralization of the distillation residue, and extraction of the product with a suitable solvent.
  • crystallization of the residue from a suitable solvent can be carried out directly after evaporation of the solvent from the reaction mixture.
  • a chemically pure product is obtained after the solvent used for the extraction is distilled off, and crystallization of the residue from a suitable solvent, preferably ethanol, is carried out.
  • the described method leads with 55 to 75% yields to a free base of rosiglitazone of formula I, i. e. 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, and is applicable on an industrial scale.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Preparation of rosiglitazone of formula (I) by reduction of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]-benzylidene]thiazolidine-2,4-dione of formula (II) using a mixture of formic acid of formula (III) and a basic amine of formula (IV), or the ammonium salt of formic acid of formula (V), wherein R1, R2, and R3 stand for hydrogen or an alkyl group (C1-C5), under the catalysis of a transition metal.

Description

Method for the preparation of rosiglitazone
Technical Field
The invention relates to a new method of carrying out the reduction of 5-[4-[2-(N-methyl-N- (2-pyridyl)-amino)ethoxy]benzylidene]thiazolidine-2,4-dione yielding rosiglitazone, i. e. a substance which is used for the preparation of a drug for the treatment of hyperglycaemia in patients who suffer from diabetes mellitus of second type.
Background Art
Rosiglitazone, 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]-thiazolidine-2,4-dione of formula I, is a well-known antihyperglycaemic, chemical synthesis of which was first described in patent EP306228 (1989) of Beecham. Rosiglitazone of formula I is usually prepared by the reduction of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]- thiazolidine-2,4-dione of formula II, see the following equation. The reduction of the compound of formula II to rosiglitazone of formula I may be carried out by various methods.
Figure imgf000002_0001
Catalytic hydrogenation of the substance of formula II was described as the first method for the preparation of rosiglitazone of formula I in EP 306228 (1989). The reaction was carried out in 1,4-dioxane under the catalysis of 10% palladium on carbon. Nevertheless, there was a high consumption of the very expensive catalyst, about 150 % (w/w) based on the weight of the substance of formula II being reduced. Besides an excessive consumption of the catalyst, a high consumption of the solvent, caused by low solubility of the substance undergoing reduction in 1,4-dioxane, presents another disadvantage of this method. No yield of rosiglitazone of formula I was given in EP 306228 (1989).
More recently, patent application WO 9923095 has described possibilities to carry out the catalytic hydrogenation in mediums other than the initially used dioxane, e. g. in acetic acid and its mixtures with water, in alcohols, mineral acids, and in mixtures of these solvents. The reduction was carried out under the catalysis of 10% palladium on carbon at higher temperatures (80 to 115 0C) and under the pressure of hydrogen of 0.35 to 10.5 MPa. The catalyst consumption was, in comparison with the aforementioned method, lower; nevertheless, it was still very high (5 to 100 %, preferably 25 to 50 %, based on the weight of the substance of formula H). The product was obtained after filtration and evaporation of the solvent with a yield in the interval of 70 to 80 %.
A similar method of the reduction was described in patent application WO 03/053367 of TEVA, where catalytic hydrogenation of analogous substrates was carried out in formic acid under the catalysis of 10% palladium on carbon at pressures of 0.2 to 0.6 MPa with yields over 80 %.
Another method of the preparation of I was published in patent application WO 9837073. The reduction of the compound of formula II was carried out using complex lithium borohydrides under the catalysis of pyridine in tetrahydrofuran, e. g. LiB(secBu)3H, LiBH4, NaBH4 in a mixture with LiCl.
A method of the reduction of the compound of formula II using magnesium turnings in boiling methanol was published in J.Med.Chem. 37, 3977 (1994). The product was isolated from the reaction mixture, after adjustment of pH to 7.5 to 8 (using diluted hydrochloric acid), by extraction to dichloromethane. The crude product was, after evaporation of solvent, purified using chromatography (SiO2, 2% methanol in dichloromethane). The yield of the product was, however, only 62 %.
Reduction of the double bond in benzylidene of formula II was also carried out biochemically using yeasts of the genus Rhodotorula. The carrying-out of the biochemical conversion under different conditions (type of buffer, pH, yeast species) influences both the conversion itself and the ratio of the enantiomers of the final substance. The synthesis was published in patent US 5,726,055 (1998) and in journal J.Chem.Soc. Perkin Trans. 1, 3319 (1994). We submit a new solution which makes it possible to obtain rosiglitazone of formula I in a quality needed for pharmaceutical substances by a method which can be applied on an industrial scale.
Disclosure of Invention
The invention relates to a new method of carrying out the reduction of 5-[4-[2-(N-methyl-N- (2-pyridyl)-amino)ethoxy]benzylidene]thiazolidine-2,4-dione of formula II, which consists in the use of a mixture of formic acid of formula III and a basic amine of formula IV, or directly of the ammonium salt of formic acid of formula V as the reducing agent under the catalysis of a transition metal.
Figure imgf000004_0001
(IV)
O O /~\ ff +J) R1M
H-C-OH H-C-O H-N-R2
R3
(III) (V)
The catalyst is preferably chosen from the group of palladium, platinum, or rhodium; use of 5 to 10% palladium on carbon as the catalyst of the reaction is advantageous (5 to 20 % based on the weight of the compound of formula II).
The reaction can be carried out without adding another solvent or in a suitable solvent from the group of acetic acid, dimethylformamide, methanol, and ethanol, or their mixtures. This method, as opposed to the previous solutions, does not require the use of hydrogen as the reducing agent, which makes it possible to carry out the reaction without using pressure equipment. The substance of formula II in the form of its E-isomer or Z-isomer, or a mixture of both isomers (E/Z) in any ratio, or a mixture of tautomeric forms and solvates of the compound of formula II may be used as the starting material. The reduction is carried out at temperatures of the reaction mixture in the interval of from 40 0C to the boiling point of the reaction mixture. The method used is described in the following equation:
HCOOH QIl) N (IV)
R3" "R2
Figure imgf000005_0001
SOLVENT Ri, R2 and R3 stand for an alkyl or hydrogen
The reduction of the substance of formula II to rosiglitazone of formula I is, on the basis of the method we invented, carried out in the following way. The starting substance of formula II is dissolved in the medium of formic acid of formula III, or a mixture of formic acid with water, and a catalyst (preferably palladium on carbon) and a basic amine of formula IV or an ammonium salt of formic acid of formula V are added. The reduction itself proceeds under heating and stirring of the obtained mixture, preferably at the boiling point. Isolation of the raw product is carried out after filtration of the catalyst, evaporation of the solvent, neutralization of the distillation residue, and extraction of the product with a suitable solvent. Alternatively, crystallization of the residue from a suitable solvent can be carried out directly after evaporation of the solvent from the reaction mixture. A chemically pure product is obtained after the solvent used for the extraction is distilled off, and crystallization of the residue from a suitable solvent, preferably ethanol, is carried out. The described method leads with 55 to 75% yields to a free base of rosiglitazone of formula I, i. e. 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, and is applicable on an industrial scale.
The invention is clarified in greater detail in the following examples, which have no influence on the scope of the invention defined in the claims. EXAMPLES
EXAMPLE l
3.55 g of the substance of formula II was dissolved in 45 ml of formic acid, 2 g of 5% palladium on carbon were added, and, under stirring, 20 ml of triethylamine were slowly added dropwise. The reaction mixture was refluxed for 20 hours, the catalyst was then filtered off and the solvent evaporated. The residue was neutralized with a solution of sodium hydroxide, extraction with ethyl acetate was carried out, the solvent was evaporated, and crystallization of the crude product from ethanol was carried out. The product obtained had a melting point of 152-154 0C, and the yield was 55 %.
EXAMPLE 2
10 g of the substance of formula II was dissolved in 100 ml of formic acid, 10 g of
5% palladium on carbon was added, and, under stirring, 10 ml of triethylamine were slowly added dropwise. The reaction mixture was refluxed for 18 hours, the catalyst was then filtered off and the solvent evaporated. The residue was neutralized with a solution of sodium hydroxide, extraction with ethyl acetate was carried out, the solvent was evaporated, and crystallization of the crude product from ethanol was carried out. The product obtained had a melting point of 153-155 °C, and the yield was 75 %.
EXAMPLE 3
20 g of the substance of formula II was dissolved in 100 ml of acetic acid, a solution of 15 g of ammonium formate in 100 ml of formic acid was poured therein and 5 g of 5% palladium on carbon added. The mixture was closed in an autoclave and heated to 100 0C for 25 hours; the catalyst was then filtered off and the solvent evaporated. The residue was neutralized with a solution of sodium hydroxide, extraction with ethyl acetate was carried out, the solvent was evaporated, and crystallization of the crude product from ethanol was carried out. The product obtained had a melting point of 152-154 °C, and the yield was 60 %.
EXAMPLE 4
5 g of the substance of formula II was dissolved in 50 ml of formic acid, 5 g of 5% palladium on carbon was added, and, under stirring, 3.5 ml of triethylamine were slowly added dropwise. The reaction mixture was refluxed for 22 hours, the catalyst was then filtered off and the solvent evaporated. Ethanol (100 ml) was added, the obtained solution was stirred for 7 hours, and filtration of the product was carried out. The product obtained had a melting point of 152- 153 0C, and the yield was 51 %.

Claims

1. A method of the preparation of rosiglitazone of formula I by the reduction of 5-[4- [2-(N-methyl-N-(2-pyridyl)ammo)ethoxy]-benzylidene]thiazolidine-2,4-dione of formula II, characterized in that the reduction is carried out using a mixture of formic acid of formula III and a basic amine of formula W, or an ammonium salt of formic acid of formula V,
Figure imgf000008_0001
HCOOH (HI) N P^
Figure imgf000008_0002
π SOLVENT
Ri, R2 and R3 stand for an alkyl or hydrogen
wherein Rj, R2, and R3 stand for hydrogen or an alkyl group (C1-C5), under the catalysis of a transition metal.
2. The method according to claim 1, characterized in that the catalyst is chosen from the series of palladium, platinum, or rhodium.
3. The method according to claim 1 or 2, characterized in that the substance of formula II in the form of E-isomer or Z-isomer, or a mixture of both isomers (E/Z) in any ratio, or a mixture of tautomeric forms and solvates of the compound of formula II is used as the starting material.
4. The method according to any of claims 1 to 3, characterized in that the reaction is carried out in a solvent from the series of acetic acid, ethyl acetate, alcohols (Cl- C5), water, or mixtures of these solvents.
5. The method according to any of claims 1 to 4, characterized in that 5% palladium on carbon in an amount of 1 to 50 % (w/w), based on the weight of the compound of formula II, preferably 5 to 20 % (w/w), based on the weight of the compound of formula II is used as the catalyst.
6. The method according to any of claims 1 to 5, characterized in that it is carried out at temperatures of the reaction mixture of from 40 0C to the boiling point of the reaction mixture.
7. The method according to any of claims 1 to 6, characterized in that the following steps are included: a) Dissolving the starting compound of formula II in formic acid of formula III, or in a mixture of formic acid and a solvent from the series of acetic acid, ethyl acetate, alcohols (Cl -C5), and water, b) Adding a catalyst containing a metal from the series of palladium, platinum, or rhodium, preferably palladium on carbon containing up to 10 % palladium, c) Adding a basic amine of formula IV or the ammonium salt of formic acid of formula V, wherein R1, R2; and R3 are as defined in claim 1, and d) Stirring and heating the obtained mixture at temperatures of from 40 0C to the boiling point of the reaction mixture.
8. The method according to claim 7, characterized in that rosiglitazone of formula I is further isolated from the reaction mixture using a process which includes the following steps: a) filtration of the catalyst, b) evaporation of the solvent, c) neutralization of the distillation residue, d) extraction of the product, e) distilling-off of the extraction solvent, and f) crystallization of the distillation residue.
. The method according to claim 8, characterized in that it is carried out in ethanol.
10. The method according to any of claims 1 to 9, characterized in that it leads to the free base of rosiglitazone of formula I, i. e. 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]-thiazolidine-2,4-dione.
11. The use of rosiglitazone of formula I prepared by a method according to any of claims 1 to 10 for the preparation of a medical preparation with an antihyperglycaemic effect.
PCT/CZ2005/000066 2004-09-21 2005-08-31 Method for the preparation of rosiglitazone WO2006032218A1 (en)

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CZ20040983A CZ297347B6 (en) 2004-09-21 2004-09-21 Process for preparing rosiglitazone
CZPV2004-983 2004-09-21

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EP1887006A1 (en) * 2006-08-07 2008-02-13 Krka Polymorphic forms of rosiglitazone base

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WO2003053367A2 (en) * 2001-12-20 2003-07-03 Teva Pharmaceutical Industries Ltd. Hydrogenation of precursors to thiazolidinedione antihyperglycemics
US20040059121A1 (en) * 2001-02-14 2004-03-25 Ppg-Sipsy, A Corporation Of France Method for preparing compounds derived from thiazolidinedione, oxazolidinedione or hydantoin

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GB9723295D0 (en) * 1997-11-04 1998-01-07 Smithkline Beecham Plc Novel process
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US20040059121A1 (en) * 2001-02-14 2004-03-25 Ppg-Sipsy, A Corporation Of France Method for preparing compounds derived from thiazolidinedione, oxazolidinedione or hydantoin
WO2003053367A2 (en) * 2001-12-20 2003-07-03 Teva Pharmaceutical Industries Ltd. Hydrogenation of precursors to thiazolidinedione antihyperglycemics

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N.A.CORTESE ET AL.: "Palladium-Catalyzed Reductions of alpha,beta-unsaturated Carbonyl Compounds, Conjugated Dienes and Acetylenes with Trialkalammonium Formates", J.ORG.CHEM., vol. 43, no. 20, 1978, pages 3985 - 3987, XP002363882 *
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1887006A1 (en) * 2006-08-07 2008-02-13 Krka Polymorphic forms of rosiglitazone base
WO2008017398A2 (en) * 2006-08-07 2008-02-14 Krka Polymorphic forms of rosiglitazone base
WO2008017398A3 (en) * 2006-08-07 2008-04-17 Krka Polymorphic forms of rosiglitazone base

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