CZ2004983A3 - Process for preparing rosiglitazone - Google Patents
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- CZ2004983A3 CZ2004983A3 CZ20040983A CZ2004983A CZ2004983A3 CZ 2004983 A3 CZ2004983 A3 CZ 2004983A3 CZ 20040983 A CZ20040983 A CZ 20040983A CZ 2004983 A CZ2004983 A CZ 2004983A CZ 2004983 A3 CZ2004983 A3 CZ 2004983A3
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- formic acid
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- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 229960004586 rosiglitazone Drugs 0.000 title claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 title description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 40
- 235000019253 formic acid Nutrition 0.000 claims abstract description 21
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- HCDYSWMAMRPMST-UHFFFAOYSA-N 5-[[4-[2-[methyl(pyridin-2-yl)amino]ethoxy]phenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1C=C1SC(=O)NC1=O HCDYSWMAMRPMST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001412 amines Chemical class 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 5
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 4
- 150000003624 transition metals Chemical class 0.000 claims abstract description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 22
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- 239000011541 reaction mixture Substances 0.000 claims description 11
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 230000008020 evaporation Effects 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 230000002058 anti-hyperglycaemic effect Effects 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims 1
- -1 N-methyl-N- (2-pyridyl) amino Chemical group 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 claims 1
- 238000006386 neutralization reaction Methods 0.000 claims 1
- 150000003283 rhodium Chemical class 0.000 claims 1
- 238000005303 weighing Methods 0.000 claims 1
- 239000000047 product Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910014033 C-OH Inorganic materials 0.000 description 2
- 229910014570 C—OH Inorganic materials 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000223252 Rhodotorula Species 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Endocrinology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Catalysts (AREA)
Abstract
Príprava rosiglitazonu vzorce I redukcí 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]-benzyliden]thiazolidin-2,4-dionu vzorce II za pouzití smesi kyseliny mravencí vzorce III a bazického aminu vzorce IV nebo amoniové soli kyseliny mravencí vzorce V, kde R.sub.1.n., R.sub.2.n. a R.sub.3.n. znací vodík nebo alkyl (C1-C5), za katalýzy prechodovým kovem.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 formic acid mixture of formula III and basic of an amine of formula IV or an ammonium salt of the formic acid of formula V, wherein R 1, R 2, R 2, R 2. and R.sub.3.n. hydrogen or alkyl (C1-C5), under transition metal catalysis.
Description
Nad Štolou 12, Praha 7, 17000 (54) Název přihlášky vynálezu:Nad Stolou 12, Praha 7, 17000 (54)
Způsob přípravy rosiglitazonu (57) Anotace:Preparation of rosiglitazone (57)
Příprava rosiglitazonu vzorce I redukcí 5-[4-[2-(N-methyl-N(2-pyridyl)amino)ethoxy]-benzyliden]thiazolidin-2,4-dionu vzorce II za použití směsi kyseliny mravenčí vzorce III a bazického aminu vzorce IV nebo amoniové soli kyseliny mravenčí vzorce V, kde Rb R2 a R3 značí vodík nebo alkyl (C1-C5), za katalýzy přechodovým kovem.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 R b R 2 and R 3 denote hydrogen or alkyl (C 1 -C 5), under transition metal catalysis.
3') oj3 ')
CO <CO <
co co σ>what what σ>
o O
IIII
H-C-OH (III)H-C-OH
RiRi
R, R, (IV) (V) ©?' ii-n-r2 R, R, (IV) (V)? ' ii-nr 3
UAT
CMCM
NN
O O
ZPŮSOB PŘÍPRAVY ROSIGLITAZONUMETHOD OF PREPARING ROSIGLITAZONE
OBLAST TECHNIKYTECHNICAL FIELD
Vynález se týká nového způsobu provedení redukce 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyliden]thiazolidin-2,4-dionu za vzniku rosiglitazonu, tj. substance, která slouží k přípravě léčiva pro léčbu hyperglykémie u pacientů s diabetes mellitus druhého typu.The present invention relates to a novel process for reducing 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzylidene] thiazolidine-2,4-dione to form rosiglitazone, a substance that serves for the preparation of a medicament for the treatment of hyperglycemia in patients with type 2 diabetes mellitus.
DOSAVADNÍ STAV TECHNIKYBACKGROUND OF THE INVENTION
Rosiglitazon, chemicky 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]-thiazolidin2,4-dion vzorce I, je známé antihyperglykemikum, jehož chemická syntéza byla prvně popsána v patentu EP 306228 (1989) firmy Beecham. Rosiglitazon vzorce I se připravuje redukcí 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyliden]thiazolidin-2,4-dionu vzorce II, viz. následující rovnice. Redukci sloučeniny vzorce II na rosiglitazon vzorce I lze provést řadou způsobů.Rosiglitazone, chemically 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione of formula I, is a known antihyperglycemic whose chemical synthesis was first described in the patent EP 306228 (1989) to Beecham. Rosiglitazone of formula I is prepared by reduction of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzylidene] thiazolidine-2,4-dione of formula II, cf. the following equation. Reduction of a compound of formula II to rosiglitazone of formula I can be accomplished in a number of ways.
Jako první možnost přípravy rosiglitazonu vzorce I byla v EP 306228 (1989) popsána katalytická hydrogenace sloučeniny vzorce II. Reakce byla provedena v 1,4-dioxanu za katalýzy 10% palladiem na uhlí. Spotřeba velmi drahého katalyzátoru však byla vysoká, ca 150 % (w/w) na navážku redukované látky vzorce II. Nevýhodou postupu je vedle nadměrné spotřeby katalyzátoru i značná spotřeba rozpouštědla vlivem nízké rozpustnosti redukované látky v 1,4-dioxanu. Výtěžek rosiglitazonu vzorce I nebyl v EP 306228 (1989) uveden.As a first possibility for the preparation of rosiglitazone of formula I, catalytic hydrogenation of a compound of formula II has been described in EP 306228 (1989). The reaction was carried out in 1,4-dioxane under catalysis with 10% palladium on carbon. However, the consumption of a very expensive catalyst was high, ca 150% (w / w) per feed of the reduced compound of formula II. The disadvantage of the process is, in addition to the excessive consumption of catalyst, a considerable solvent consumption due to the low solubility of the reduced substance in 1,4-dioxane. The yield of rosiglitazone of formula I was not disclosed in EP 306228 (1989).
Nověji byla v patentové přihlášce WO 9923095 popsána možnost provedení katalytické hydrogenace v jiných prostředích než byl prvně použitý dioxan, například, v kyselině octové a jejich směsích s vodou, v alkoholech, minerálních kyselinách a ve směsích těchto rozpouštědel. Redukce byla provedena za katalýzy 10% palladiem na uhlí za vyšších teplot (80 až 115 °C) a tlaku vodíku 0,35 až 10,5 MPa. Spotřeba katalyzátoru byla ve srovnání • ·More recently, patent application WO 9923095 described the possibility of performing catalytic hydrogenation in media other than the first dioxane used, for example, in acetic acid and mixtures thereof with water, alcohols, mineral acids and mixtures of these solvents. The reduction was carried out with catalysis of 10% palladium on carbon at higher temperatures (80-115 ° C) and a hydrogen pressure of 0.35-10.5 MPa. Catalyst Consumption Compared •
• · · · · · · • ·· · · · · · • · · φ φ φ φ φ · · φ · • · · · · · • · · φ φ φ · s předchozím postupem nižší, přesto stále velmi vysoká (5 až 100 %, přednostně 25 až 50 % na navážku redukované látky vzorce II). Produkt byl získán po filtraci a odpaření rozpouštědla s výtěžkem v intervalu 70 až 80 %.• With the previous procedure lower, but still very high ( 5 to 100%, preferably 25 to 50%, based on the weight of the reduced compound of formula II). The product was obtained after filtration and evaporation of the solvent in a yield of 70-80%.
Podobné řešení redukce bylo popsáno v patentové přihlášce firmy TEVA WO 03/053367, kdy byla katalytická hydrogenace analogických substrátů provedena v prostředí kyseliny mravenčí za katalýzy 10% palladiem na uhlí při tlacích 0,2 až 0,6 MPa s výtěžky nad 80 %.A similar reduction solution was described in the patent application of the company TEVA WO 03/053367, where the catalytic hydrogenation of analogous substrates was carried out in a formic acid medium under catalysis with 10% palladium on carbon at pressures of 0.2 to 0.6 MPa with yields above 80%.
Další způsob přípravy I byl publikován v patentové přihlášce WO 9837073. Redukce sloučeniny vzorce II byla v tomto případě provedena pomocí komplexních borohydridů lithia v tetrahydrofuranu za katalýzy pyridinem, např. LiB(secBu)3H, LiBH4, NaBH4 ve směsi s LÍCI.Another method of preparation I was published in patent application WO 9837073. The reduction of the compound of formula II in this case was carried out using complex lithium borohydrides in tetrahydrofuran under catalysis with pyridine, eg LiB (secBu) 3H, LiBH 4 , NaBH 4 mixed with LiCl.
Způsob redukce sloučeniny vzorce II pomocí hořčíkových hoblin ve vroucím methanolu byl publikována v J.Med.Chem. 37, 3977 (1994). Produkt byl z reakční směsi izolován po úpravě pH na 7,5 až 8 (pomocí zředěné kyseliny chlorovodíkové) extrakcí do dichlormethanu, po odpaření rozpouštědla byl surový produkt čištěn chromatograficky (SÍO2, 2% methanol v dichlormethanu). Výtěžek produktu byl však pouze 62 %.A method for reducing a compound of formula II with magnesium shavings in boiling methanol was published in J. Med. 37, 3977 (1994). The product was isolated from the reaction mixture after adjusting the pH to 7.5-8 (with dilute hydrochloric acid) by extraction into dichloromethane, after evaporation of the solvent the crude product was purified by chromatography (SiO 2, 2% methanol in dichloromethane). However, the yield of the product was only 62%.
Redukce dvojné vazby v benzylidenu vzorce II byla provedena též biochemicky za použití kvasinek rodu Rhodotorula. Provedení biochemické přeměny za různých podmínek (typ pufru, pH, druh kvasinek) ovlivňuje jak samotnou konverzi, tak i zastoupení enantiomerů cílové látky. Syntéza byla publikována v patentu US 5,726,055 (1998) a v časopise J.Chem.Soc. Perkin Trans. 1, 3319 (1994).Reduction of the double bond in the benzylidene of formula II was also performed biochemically using yeasts of the genus Rhodotorula. Performing biochemical conversion under various conditions (buffer type, pH, yeast type) affects both the conversion itself and the enantiomeric representation of the target substance. The synthesis was published in U.S. Patent 5,726,055 (1998) and in J.Chem.Soc. Perkin Trans. 1, 3319 (1994).
Námi předkládané řešení umožňuje získat rosiglitazon vzorce I v kvalitě požadované pro farmaceutické substance způsobem, který je možné aplikovat ve výrobním měřítku.The present invention makes it possible to obtain rosiglitazone of the formula I in the quality required for pharmaceutical substances in a manner which can be applied on a production scale.
PODSTATA VYNÁLEZUSUMMARY OF THE INVENTION
Vynález se týká nového způsobu provedení redukce 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyliden]thiazolidin-2,4-dionu vzorce II, který spočívá v použití směsi kyseliny mravenčí vzorce III a bazického aminu vzorce IV nebo přímo amoniové soli kyseliny mravenčí vzorce V jako redukujícího činidla za katalýzy přechodovým kovem.The present invention relates to a novel process for the reduction of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzylidene] thiazolidine-2,4-dione, which comprises the use of a formic acid mixture of formula III and the basic amine of formula IV or directly the ammonium salt of formic acid of formula V as a reducing agent under transition metal catalysis.
• · · · r3^nr2 • · · · r 3 ^ n r 2
Θ (IV) »· · • · • · · • · · · · oIV (IV) o · o · o · o · o · o
ιιιι
H-C-OH oH-C-OH o
IIII
H-C-0 ©^ h-n-r2 (III) r3 (V)HC-0 © ^ HNR 2 (iii) R 3 (V)
Jako katalyzátor se výhodně použije kov zvolený z řady palladium, platina nebo rhodium; výhdoné je použití 5 až 10% palladia na uhlí jako katalyzátoru reakce (v množství 5 až 20 % na navážku sloučeniny vzorce II).As a catalyst, a metal selected from the series of palladium, platinum or rhodium is preferably used; it is preferred to use 5 to 10% palladium on carbon as the reaction catalyst (in an amount of 5 to 20% based on the weight of the compound of formula II).
Rekci je možné provádět bez přídavku dalšího rozpouštědla nebo ve vhodném rozpouštědle z řady kyselina octová, dimethylformamid, methanol a ethanol, případně jejich směsí. Provedení na rozdíl od předchozích řešení nevyžaduje použití vodíku jako redukčního činidla, což umožňuje provádět reakci vnetlakových zařízeních. Jako výchozí surovina může být použita látka vzorce II ve formě isomeru E nebo Z, případně směs obou isomerů (E/Z) v libovolných poměrech, případně směs tautomemích forem a solvátů látky vzorce II. Redukce se provádí při teplotách reakční směsi od 40 °C do bodu varu reakční směsi.The reaction may be carried out without the addition of another solvent or in a suitable solvent from the series of acetic acid, dimethylformamide, methanol and ethanol, or mixtures thereof. The embodiment, unlike the previous solutions, does not require the use of hydrogen as a reducing agent, which makes it possible to carry out the reaction in low-pressure devices. The starting material can be a compound of formula II in the form of an E or Z isomer, optionally a mixture of both (E / Z) isomers in any ratio, or a mixture of tautomeric forms and solvates of a compound of formula II. The reduction is carried out at temperatures of the reaction mixture from 40 ° C to the boiling point of the reaction mixture.
Použitý proces popisuje následující rovnice:The process used describes the following equations:
R.R.
HCOOH (III) n (IV) r3x r2HCOOH (III) n ( IV ) r 3 x r 2
II ROZPOUŠTĚDLO ISolvent
R,, R2 a R3 značí alkyl nebo vodíkR 1, R 2 and R 3 denote alkyl or hydrogen
Redukce látky vzorce II na rosiglitazon vzorce I se dle námi nalezeného postupu provádí rozpuštěním výchozí látky vzorce II v prostředí kyseliny mravenčí vzorce III, případně směsi kyseliny mravenčí a vody, následném přídavku katalyzátoru (nejlépe palladium na uhlí) a bazického aminu vzorce IV nebo amoniové soli kyseliny mravenčí vzorce V. Vlastní redukce probíhá při zahřívání a míchání získané směsi, nejlépe při bodu varu. Izolace surového produktu se provádí po filtraci katalyzátoru, odpaření rozpouštědla, neutralizaci destilačního zbytku a extrakci produktu do vhodného rozpouštědla, případně může být přímo po odpaření rozpouštědla z reakční směsi provedena krystalizace zbytku z vhodného rozpouštědla. Chemicky čistý produkt se získá po oddestilování rozpouštědla použitého pro extrakci a následné krystalizací zbytku z vhodného rozpouštědla, nejlépe z ethanolu. Popsaný proces vede s výtěžky 55 až 75 % k volné bázi rosiglitazonu vzorce I, tj. 5-[4-[2-(N-methyl-N-(2pyridyl)amino)ethoxy]benzyl]thiazolidin-2,4-dionu, a je využitelný v průmyslovém měřítku.The reduction of the compound of formula II to rosiglitazone of formula I according to our method is carried out by dissolving the starting compound of formula II in a medium of formic acid III or a mixture of formic acid and water, followed by addition of catalyst (preferably palladium on carbon) and basic amine Formic acid of formula V. The reduction itself takes place by heating and stirring the mixture obtained, preferably at the boiling point. Isolation of the crude product is carried out after catalyst filtration, solvent evaporation, distillation of the distillation residue and extraction of the product into a suitable solvent, optionally the residue can be crystallized from a suitable solvent directly after evaporation of the solvent from the reaction mixture. The chemically pure product is obtained by distilling off the solvent used for extraction and then crystallizing the residue from a suitable solvent, preferably ethanol. The described process results in 55-75% yields of rosiglitazone free base 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.
Předmět vynálezu blíže osvětlí následující příklady, které ovšem nemají žádný vliv na šíři vynalezu definovanou v nárocích.The following examples illustrate the invention in more detail, but do not affect the scope of the invention as defined in the claims.
PŘÍKLADY PROVEDENÍ VYNÁLEZUEXAMPLES OF EMBODIMENTS OF THE INVENTION
PŘÍKLAD 1EXAMPLE 1
Ve 45 ml kyseliny mravenčí bylo rozpuštěno 3,55 g látky vzorce II, přidány 2 g 5% palladia na uhlí a za míchání pomalu přikapáno 20 ml triethylaminu. Reakční směs byla refluxována 20 hodin, pak byl odfiltrován katalyzátor a odpařeno rozpouštědlo. Zbytek byl neutralizován roztokem hydroxidu sodného, provedena extrakce do ethylacetátu, odpaření rozpouštědla a krystalizace surové látky z ethanolu. Získán byl produkt s bodem tání 152-154 °C, s výtěžkem 55 %.3.55 g of the compound of formula II were dissolved in 45 ml of formic acid, 2 g of 5% palladium on carbon were added, and 20 ml of triethylamine was added dropwise with stirring. The reaction mixture was refluxed for 20 hours, then the catalyst was filtered off and the solvent was evaporated. The residue was neutralized with sodium hydroxide solution, extracted into ethyl acetate, the solvent was evaporated and the crude material crystallized from ethanol. The product with a melting point of 152-154 ° C was obtained in a yield of 55%.
PŘÍKLAD 2EXAMPLE 2
Ve 100 ml kyseliny mravenčí bylo rozpuštěno 10 g látky vzorce II, přidáno 10 g 5% palladia na uhlí a za míchání pomalu přikapáno 10 ml triethylaminu. Reakční směs byla refluxována 18 hodin, pak byl odfiltrován katalyzátor a odpařeno rozpouštědlo. Zbytek byl neutralizován roztokem hydroxidu sodného, provedena extrakce do ethylacetátu, odpaření rozpouštědla a krystalizace surové látky z ethanolu. Získán byl produkt s bodem tání 153-155 °C, s výtěžkem 75 %.10 g of the compound of formula II were dissolved in 100 ml of formic acid, 10 g of 5% palladium on carbon were added, and 10 ml of triethylamine was slowly added dropwise with stirring. The reaction mixture was refluxed for 18 hours, then the catalyst was filtered off and the solvent was evaporated. The residue was neutralized with sodium hydroxide solution, extracted into ethyl acetate, the solvent was evaporated and the crude material crystallized from ethanol. The product with a melting point of 153-155 ° C was obtained in a yield of 75%.
PŘÍKLAD 3EXAMPLE 3
Ve 100 ml kyseliny octové bylo rozpuštěno 20 g látky vzorce II, přilit roztok 15 g mravenčanu amonného ve 100 ml kyseliny mravenčí a přidáno 5 g 5% palladia na uhlí. Směs • · · • · · · · byla uzavřena v autoklávu a zahřívána na 100 °C po dobu 25 hodin, pak byl odfiltrován katalyzátor a odpařeno rozpouštědlo. Zbytek byl neutralizován roztokem hydroxidu sodného, provedena extrakce do ethylacetátu, odpaření rozpouštědla a krystalizace surové látky z ethanolu. Získán byl produkt s bodem tání 152-154 °C, s výtěžkem 60 %.20 g of the compound of formula II were dissolved in 100 ml of acetic acid, a solution of 15 g of ammonium formate in 100 ml of formic acid was added, and 5 g of 5% palladium on carbon was added. The mixture was sealed in an autoclave and heated to 100 ° C for 25 hours, then the catalyst was filtered off and the solvent was evaporated. The residue was neutralized with sodium hydroxide solution, extracted into ethyl acetate, the solvent was evaporated and the crude material crystallized from ethanol. The product with a melting point of 152-154 ° C was obtained in a yield of 60%.
PŘÍKLAD 4EXAMPLE 4
V 50 ml kyseliny mravenčí bylo rozpuštěno 5 g látky vzorce II, přidáno 5 g 5% palladia na uhlí a za míchání pomalu přikapáno 3,5 ml triethylaminu. Reakční směs byla refluxována 22 hodin, pak byl odfiltrován katalyzátor a odpařeno rozpouštědlo. Ke zbytku byl přidán ethanol (100 ml) a získaný roztok míchán 7 hodin, pak byla provedena filtrace produktu. Získán byl produkt s bodem tání 152-153 °C, s výtěžkem 51 %.5 g of the compound of formula II were dissolved in 50 ml of formic acid, 5 g of 5% palladium on carbon were added, and 3.5 ml of triethylamine was slowly added dropwise with stirring. The reaction mixture was refluxed for 22 hours, then the catalyst was filtered off and the solvent was evaporated. Ethanol (100 mL) was added to the residue and the resulting solution was stirred for 7 hours, then the product was filtered. The product with a melting point of 152-153 ° C was obtained in a yield of 51%.
Claims (11)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ20040983A CZ297347B6 (en) | 2004-09-21 | 2004-09-21 | Process for preparing rosiglitazone |
| PCT/CZ2005/000066 WO2006032218A1 (en) | 2004-09-21 | 2005-08-31 | Method for the preparation of rosiglitazone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ20040983A CZ297347B6 (en) | 2004-09-21 | 2004-09-21 | Process for preparing rosiglitazone |
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| CZ2004983A3 true CZ2004983A3 (en) | 2006-05-17 |
| CZ297347B6 CZ297347B6 (en) | 2006-11-15 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0306228B1 (en) * | 1987-09-04 | 1999-11-17 | Beecham Group Plc | Substituted thiazolidinedione derivatives |
| GB9124513D0 (en) * | 1991-11-19 | 1992-01-08 | Smithkline Beecham Plc | Novel process |
| UY24886A1 (en) * | 1997-02-18 | 2001-08-27 | Smithkline Beecham Plc | TIAZOLIDINDIONA |
| GB9723295D0 (en) * | 1997-11-04 | 1998-01-07 | Smithkline Beecham Plc | Novel process |
| ES2156574B1 (en) * | 1999-11-18 | 2002-02-01 | Vita Invest Sa | NEW DERIVATIVES OF TIAZOLIDINDIONA AS ANTIDIABETIC AGENTS |
| FR2820742B1 (en) * | 2001-02-14 | 2005-03-11 | Ppg Sipsy | PROCESS FOR THE PREPARATION OF COMPOUNDS DERIVED FROM THIAZOLIDINEDIONE, OXAZOLIDINEDIONE OR HYDANTOIN |
| JP2005514390A (en) * | 2001-12-20 | 2005-05-19 | テバ ファーマシューティカル インダストリーズ リミティド | Hydrogenation of Thiazolidinedione Diabetes Drug Precursor |
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| CZ297347B6 (en) | 2006-11-15 |
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