WO2012153312A1 - Procédé pour la purification de pioglitazone - Google Patents
Procédé pour la purification de pioglitazone Download PDFInfo
- Publication number
- WO2012153312A1 WO2012153312A1 PCT/IB2012/052370 IB2012052370W WO2012153312A1 WO 2012153312 A1 WO2012153312 A1 WO 2012153312A1 IB 2012052370 W IB2012052370 W IB 2012052370W WO 2012153312 A1 WO2012153312 A1 WO 2012153312A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pioglitazone
- dhp
- solution
- dimethylformamide
- mixture
- Prior art date
Links
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 title claims abstract description 123
- 229960005095 pioglitazone Drugs 0.000 title claims abstract description 61
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000000746 purification Methods 0.000 title abstract description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 16
- 238000002360 preparation method Methods 0.000 abstract description 8
- 238000006243 chemical reaction Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
Definitions
- the present invention provides an improved process for the preparation of pioglitazone which is substantially free of dehydropioglitazone impurity.
- Pioglitazone of Formula I chemically ( ⁇ )-5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin- dependent diabetes mellitus or "NIDDM").
- NIDDM non-insulin- dependent diabetes mellitus
- pioglitazone is its monohydrochloride salt.
- Dehydropioglitazone (hereinafter referred to as "DHP” or “DHP of Formula II") is known as an intermediate in the synthesis of pioglitazone or salts thereof.
- DHP is also present as a process impurity or degradation product in pioglitazone or salts thereof.
- reasons are attributed for the generation of DHP in pioglitazone. Some factors linked to the generation of this impurity include the incomplete reduction of DHP and the oxidation of pioglitazone during isolation or while on stability.
- U.S. Publication 2006/0252803 provides a process for the preparation of pioglitazone which involves dissolving DHP of Formula II in formic acid and hydrogenating with hydrogen in the presence of 10% Palladium on Carbon under 2 atmospheric pressures and a temperature of 80°C. This process reportedly provides pioglitazone having less than about 0.14 % of the impurity at RRT 0.64 (HPLC).
- U.S. Publication 2009/118514 provides various purification methods for pioglitazone. It provides obtaining a solution of pioglitazone with a mixture of dimethylformamide (DMF) and 4% water, DMF and 5% methanol, DMF and 10% methanol, 1 ,4-dioxane or DMF and isopropyl alcohol at a temperature of about 90°C and precipitating pioglitazone from the solution by cooling to a temperature of about 25°C.
- DMF dimethylformamide
- U.S. Publication 2007/0078170 provides a process for the preparation of pioglitazone which involves obtaining a clear solution of pioglitazone in
- dimethylformamide at 85°C and adding methanol at a temperature of 60°C and further cooling to 10°C to precipitate pioglitazone.
- API active pharmaceutical ingredient
- the purity of an API is critical for commercialization.
- the product of a chemical reaction is rarely just the target compound.
- Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product in varying amounts. Extra effort is often required to get pharmaceutically acceptable levels of purity of the target compound.
- the present invention provides a process for the preparation of pioglitazone substantially free of DHP which comprises:
- step b) treating the solution obtained in step a) with a mixture of acetone and
- pioglitazone substantially free of DHP in the context of the present invention relates to pioglitazone having DHP in an amount of 0.1% or less, preferably 0.05% or less, more preferably 0.03% or less, most preferably undetectable as determined by HPLC analysis.
- the pioglitazone may be prepared by any of the methods known in the art including those described in U.S. Patent Nos. 4,687,777; 5,585,495; 4,812,570; 5,554,758; 5,952,509 and 6, 100,403; U.S. Publication Nos. 2002/0106762 and 2002/0050563; WO 03/53367; WO 03/80056; WO 2004/07490; WO 2004/024059; WO 2004/101560 and WO 2004/101561.
- the present invention provides a process for the preparation of pioglitazone substantially free of DHP which comprises:
- step b) treating the solution obtained in step a) with a mixture of acetone and
- the solution of pioglitazone in dimethylformamide may be obtained by treating pioglitazone or a salt thereof with dimethylformamide at a suitable temperature of 20°C to reflux under stirring.
- the volume of dimethylformamide may be 3 to 10 times, preferably 4 to 7 times, to the weight of pioglitazone.
- the solution of pioglitazone obtained in step a) can be optionally clarified to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities.
- the solution of pioglitazone obtained in step a) may be optionally concentrated to reduce the amount of solvent.
- Step b) treating the solution obtained in step a) with a mixture of antisolvent involves adding the solution of pioglitazone thereof obtained in step a) to a mixture of acetone and methanol or adding a mixture of acetone and methanol to the solution of pioglitazone obtained in step a) in optional order of succession at a temperature of about 65°C to about 75°C optionally under stirring. Preferably, it may be added at about 70°C to about 75 °C. The addition may be carried out dropwise for a time period of 15 minutes to 3 hours optionally under stirring.
- the resultant mixture may be cooled to about 20°C to about 40°C in about 15 minutes to about 3 hours optionally under stirring.
- it may to be cooled at about 30°C to about 35°C optionally under stirring.
- the mixture of acetone and methanol can be taken in any ratio, preferably in 1 : 1 ratio.
- the combined volume of the mixture of acetone and methanol may be about 5 times to about 15 times, preferably 7 to 12 times, more than the weight of pioglitazone.
- the combined volume of acetone and methanol is about 20 ml (10 ml: 10 ml) for about 2 g of pioglitazone.
- Step c) of isolating pioglitazone substantially free of DHP involves common isolation techniques such as one or more of washing, crystallization, precipitation, cooling, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
- the isolated pioglitazone substantially free of DHP may be further dried at about 40°C to about 60°C under vacuum.
- the pioglitazone obtained has a content of DHP in an amount of 0.05% or less.
- the obtained purified pioglitazone can then be further converted into its pharmaceutically acceptable salts, preferably the hydrochloride salt, by any of the methods known in the art.
- Dimethylformamide (10 mL) was heated to 80°C to 82°C and pioglitazone (2 g) was added to the hot solution and stirred at 80°C to get a clear solution.
- the solution was cooled to 75 °C and mixture of acetone (10 mL) and methanol (10 mL) was added to the solution in 30 to 45 minutes at 70°C to 75°C. After complete addition, the reaction mass was cooled to 30°C to 35°C slowly in about 2 hours and was filtered. The solid was washed with dimethylformamide/acetone/methanol mixture (6 mL).
- Dimethylformamide 200 mL was heated to 80°C to 85 °C and pioglitazone (40 g) was added to the hot solution and stirred at 80°C to get a clear solution.
- the solution was cooled to 75°C and mixture of acetone (200 mL) and methanol (200 mL) was added to this solution in 30 minutes to 45 minutes at 65°C to 75°C. After complete addition, the reaction mass was cooled to 30°C to 35°C slowly in about 2 hours and was filtered. The solid was washed with acetone/methanol mixture (100 mL).
- Dimethylformamide 25 mL was heated to 80°C to 85 °C and pioglitazone (5 g) was added at 85°C.
- the solution was cooled to 55°C and a mixture of acetone (25 mL) and methanol (25 mL) was added to the solution in 30 minutes to 45 minutes at 55°C to 60°C.
- the reaction mass was cooled to 35°C to 37°C slowly in about 2 hours and was filtered. The solid was washed with acetone/methanol mixture (10+lOmL).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
La présente invention concerne un procédé efficace pour la purification de pioglitazone de Formule I. L'invention fournit une purification améliorée pour la préparation de pioglitazone sensiblement exempte de l'impureté DHP de Formule II.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1385DE2011 | 2011-05-11 | ||
| IN1385/DEL/2011 | 2011-05-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2012153312A1 true WO2012153312A1 (fr) | 2012-11-15 |
Family
ID=46210328
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2012/052370 WO2012153312A1 (fr) | 2011-05-11 | 2012-05-11 | Procédé pour la purification de pioglitazone |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2012153312A1 (fr) |
Citations (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4687777A (en) | 1985-01-19 | 1987-08-18 | Takeda Chemical Industries, Ltd. | Thiazolidinedione derivatives, useful as antidiabetic agents |
| US4812570A (en) | 1986-07-24 | 1989-03-14 | Takeda Chemical Industries, Ltd. | Method for producing thiazolidinedione derivatives |
| US5554758A (en) | 1991-03-25 | 1996-09-10 | Takeda Chemical Industries, Ltd. | Method for producing ethers |
| US5585495A (en) | 1991-12-20 | 1996-12-17 | The Upjohn Company | Reduction method for substituted 5-methylene-thiazolidinediones |
| US5952509A (en) | 1996-06-27 | 1999-09-14 | Takeda Chemical Industries, Ltd. | Production of benzaldehyde compounds |
| US20020050563A1 (en) | 1991-11-19 | 2002-05-02 | Smithkline Beecham P.L.C. | Process for the preparation of pharmaceutically active thiazolidine or oxazolidine compounds by a yeast reductase |
| US20020106762A1 (en) | 1991-11-19 | 2002-08-08 | Smith Kline Beecham Plc | Process for the preparation of pharmaceutically active thiazolidine or oxazolidine compounds by a yeast reductase |
| WO2003053367A2 (fr) | 2001-12-20 | 2003-07-03 | Teva Pharmaceutical Industries Ltd. | Hydrogenation de precurseurs de substances anti-hyperglycemiantes de thiazolidinedione |
| WO2003080056A2 (fr) | 2002-03-21 | 2003-10-02 | Teva Pharmaceutical Industries Ltd. | Pioglitazone a particules de taille fine |
| WO2004007490A2 (fr) | 2002-07-16 | 2004-01-22 | Cadila Healthcare Limited | Procede de preparation de pioglitazone via plusieurs intermediaires. |
| WO2004024059A2 (fr) | 2002-09-12 | 2004-03-25 | Themis Laboratories Private Limited, | Procede ameliore de fabrication de derives thiazolidinedione |
| WO2004101561A1 (fr) | 2003-05-13 | 2004-11-25 | Synthon B.V. | Sels de pioglitazone tels que le sulfate de pioglitazone, et leurs compositions pharmaceutiques et leurs procedes d'utilisation |
| WO2004101560A1 (fr) | 2003-05-13 | 2004-11-25 | Synthon B.V. | Procedes de fabrication de derives de thiazolidinedione et composes associes |
| WO2005049610A1 (fr) | 2003-10-28 | 2005-06-02 | Sandoz Ag | Procede de preparation de thiazolidinediones |
| WO2005058827A1 (fr) | 2003-12-19 | 2005-06-30 | Richter Gedeon Vegyészeti Gyár Rt. | Procede de synthese de chlorure d'hydrogene de pioglitazone |
| US20060252803A1 (en) | 2001-12-20 | 2006-11-09 | Ben-Zion Dolitzky | Hydrogenation of precursors to thiazolidinedione antihyperglycemics |
| WO2006117654A1 (fr) | 2005-05-03 | 2006-11-09 | Ranbaxy Laboratories Limited | Procedes de preparation de pioglitazone ou de sels de ce compose |
| US20070078170A1 (en) | 2003-08-28 | 2007-04-05 | Khanduri Chandra H | Process for the preparation of pioglitazone |
| WO2008075380A2 (fr) | 2006-12-21 | 2008-06-26 | Ind-Swift Laboratories Limited | Procédé de préparation de dérivés de thiazolidine |
| WO2008142706A2 (fr) | 2007-05-18 | 2008-11-27 | Matrix Laboratories Ltd | Nouveau procédé pour la synthèse de la pioglitazone et de ses sels |
| US20090118514A1 (en) | 2007-11-06 | 2009-05-07 | Raghupathi Reddy Anumula | Processes for preparing pioglitazone and its pharmaceutically acceptable salts |
| WO2009104200A1 (fr) | 2008-02-21 | 2009-08-27 | Biocon Limited | Procédé de préparation de dérivés de thiazolidinedione |
| 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 |
-
2012
- 2012-05-11 WO PCT/IB2012/052370 patent/WO2012153312A1/fr active Application Filing
Patent Citations (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4687777A (en) | 1985-01-19 | 1987-08-18 | Takeda Chemical Industries, Ltd. | Thiazolidinedione derivatives, useful as antidiabetic agents |
| US4812570A (en) | 1986-07-24 | 1989-03-14 | Takeda Chemical Industries, Ltd. | Method for producing thiazolidinedione derivatives |
| US5554758A (en) | 1991-03-25 | 1996-09-10 | Takeda Chemical Industries, Ltd. | Method for producing ethers |
| US20020050563A1 (en) | 1991-11-19 | 2002-05-02 | Smithkline Beecham P.L.C. | Process for the preparation of pharmaceutically active thiazolidine or oxazolidine compounds by a yeast reductase |
| US20020106762A1 (en) | 1991-11-19 | 2002-08-08 | Smith Kline Beecham Plc | Process for the preparation of pharmaceutically active thiazolidine or oxazolidine compounds by a yeast reductase |
| US5585495A (en) | 1991-12-20 | 1996-12-17 | The Upjohn Company | Reduction method for substituted 5-methylene-thiazolidinediones |
| US6100403A (en) | 1996-06-27 | 2000-08-08 | Takeda Chemical Industries, Ltd. | Production of benzaldehyde compounds |
| US5952509A (en) | 1996-06-27 | 1999-09-14 | Takeda Chemical Industries, Ltd. | Production of benzaldehyde compounds |
| WO2003053367A2 (fr) | 2001-12-20 | 2003-07-03 | Teva Pharmaceutical Industries Ltd. | Hydrogenation de precurseurs de substances anti-hyperglycemiantes de thiazolidinedione |
| US20060252803A1 (en) | 2001-12-20 | 2006-11-09 | Ben-Zion Dolitzky | Hydrogenation of precursors to thiazolidinedione antihyperglycemics |
| WO2003080056A2 (fr) | 2002-03-21 | 2003-10-02 | Teva Pharmaceutical Industries Ltd. | Pioglitazone a particules de taille fine |
| WO2004007490A2 (fr) | 2002-07-16 | 2004-01-22 | Cadila Healthcare Limited | Procede de preparation de pioglitazone via plusieurs intermediaires. |
| WO2004024059A2 (fr) | 2002-09-12 | 2004-03-25 | Themis Laboratories Private Limited, | Procede ameliore de fabrication de derives thiazolidinedione |
| WO2004101561A1 (fr) | 2003-05-13 | 2004-11-25 | Synthon B.V. | Sels de pioglitazone tels que le sulfate de pioglitazone, et leurs compositions pharmaceutiques et leurs procedes d'utilisation |
| WO2004101560A1 (fr) | 2003-05-13 | 2004-11-25 | Synthon B.V. | Procedes de fabrication de derives de thiazolidinedione et composes associes |
| US20070078170A1 (en) | 2003-08-28 | 2007-04-05 | Khanduri Chandra H | Process for the preparation of pioglitazone |
| WO2005049610A1 (fr) | 2003-10-28 | 2005-06-02 | Sandoz Ag | Procede de preparation de thiazolidinediones |
| WO2005058827A1 (fr) | 2003-12-19 | 2005-06-30 | Richter Gedeon Vegyészeti Gyár Rt. | Procede de synthese de chlorure d'hydrogene de pioglitazone |
| WO2006117654A1 (fr) | 2005-05-03 | 2006-11-09 | Ranbaxy Laboratories Limited | Procedes de preparation de pioglitazone ou de sels de ce compose |
| WO2008075380A2 (fr) | 2006-12-21 | 2008-06-26 | Ind-Swift Laboratories Limited | Procédé de préparation de dérivés de thiazolidine |
| WO2008142706A2 (fr) | 2007-05-18 | 2008-11-27 | Matrix Laboratories Ltd | Nouveau procédé pour la synthèse de la pioglitazone et de ses sels |
| US20090118514A1 (en) | 2007-11-06 | 2009-05-07 | Raghupathi Reddy Anumula | Processes for preparing pioglitazone and its pharmaceutically acceptable salts |
| WO2009104200A1 (fr) | 2008-02-21 | 2009-08-27 | Biocon Limited | Procédé de préparation de dérivés de thiazolidinedione |
| 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 |
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