WO2005116030A1 - Procede d'elaboration de tadalafil - Google Patents
Procede d'elaboration de tadalafil Download PDFInfo
- Publication number
- WO2005116030A1 WO2005116030A1 PCT/IN2005/000136 IN2005000136W WO2005116030A1 WO 2005116030 A1 WO2005116030 A1 WO 2005116030A1 IN 2005000136 W IN2005000136 W IN 2005000136W WO 2005116030 A1 WO2005116030 A1 WO 2005116030A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tadalafil
- volumes
- methyl
- reaction mass
- pyrido
- Prior art date
Links
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 title claims abstract description 37
- 229960000835 tadalafil Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims description 19
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 239000002798 polar solvent Substances 0.000 claims abstract description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 3
- JUKHNCNDFOAFLT-UHFFFAOYSA-N methyl 1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2OCOC2=CC(C2C3=C(C4=CC=CC=C4N3)CC(N2C(=O)CCl)C(=O)OC)=C1 JUKHNCNDFOAFLT-UHFFFAOYSA-N 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 238000010791 quenching Methods 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000003495 polar organic solvent Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 abstract description 6
- 238000013386 optimize process Methods 0.000 abstract description 4
- 238000004821 distillation Methods 0.000 abstract description 3
- 238000001704 evaporation Methods 0.000 abstract description 2
- 230000008020 evaporation Effects 0.000 abstract 1
- 238000000605 extraction Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000002955 isolation Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000790917 Dioxys <bee> Species 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- KCUNTYMNJVXYKZ-SNVBAGLBSA-N methyl (2r)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C[C@@H](N)C(=O)OC)=CNC2=C1 KCUNTYMNJVXYKZ-SNVBAGLBSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- -1 (6R Chemical compound 0.000 description 1
- FFCZQVKVWGGQFB-UHFFFAOYSA-N 9h-pyrido[3,4-b]indole-1,4-dione Chemical compound N1C2=CC=CC=C2C2=C1C(=O)N=CC2=O FFCZQVKVWGGQFB-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- YSVZGWAJIHWNQK-UHFFFAOYSA-N [3-(hydroxymethyl)-2-bicyclo[2.2.1]heptanyl]methanol Chemical compound C1CC2C(CO)C(CO)C1C2 YSVZGWAJIHWNQK-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Definitions
- the present invention relates to an optimized process for the preparation of pure (6R,12aR)-6-(l,3-Benzodioxol-5-yl)-2-methyl-l,2,3,4,6,7,12,12a-octahydropyrazino T , : 6, 1 ]pyrido [3 ,4-b] indole- 1 ,4-dione (Tadalafil) .
- Tadalafil namely (6R,12aR)-6-( 1,3 -Benzodioxol-5-yl)-2-methyl- 1,2,3 ,4,6,7, 12, 12a- octahydropyrazino[2',l':6,l]pyrido[3,4-b]indole-l,4- dione has the formula
- Tadalafil is a potent and selective inhibitor of cyclic guanosine S' ⁇ -monophosphate specific phosphodiesterase having a utility in a variety of therapeutic areas where such inhibition is thought to be beneficial including the treatment of cardiovascular disorders. Tadalafil and its similar compounds are reported in US Patent 5,859,006 (Equivalent to EP 740,668).
- solubility of Tadalafil in isopropanol is only less than 1% and herein any recrystallization process which involve very large volumes of the solvent isopropanol thereby making the process unwieldy and nonoperable.
- the main object of the present invention is to provide an optimized process for the preparation of Tadalafil.
- Another object of the invention is to provide a process for recrystallisation of Tadalafil without the usage of large volumes of solvents.
- Another object of the invention is to provide a process for the isolation of the Tadalafil from the reaction mass without involving the usage of large volumes of solvents, extensive workup like distillation of one solvent and dissolution in second solvent, removal of second solvent and crystallization from a third solvent.
- Another object of the invention is to provide a process for recrystallization of Tadalafil with reduced cycle times and minimizing loss of material.
- the present invention relates to a process for the preparation of Tadalafil from D-Tryptophan methyl ester through (6R, 12aR)-methyl l,2,3,4-tetrahydro-2- chloroacetyl-l-(3,4-methylene dioxyphenyl) - 9H - pyrido [3,4-b] indole-3-carboxylate (chloroacetyl intermediate) which on reaction with methylamine solution in short chain alcohol followed by cooling gives crude Tadalafil. Recrystallization is carried out by dissolution of crude Tadalafil in minimum volume of organic polar solvent followed by quenching the solution into water/water miscible solvents to give the pure Tadalafil in quantitative yields.
- Tadalafil Detailed description of the Invention: The preparation and recrystallization of Tadalafil from (6R, 12aR)-Methyl 1,2,3,4- tetrahydro-2-chloroacetyl-l-(3,4-methylenedioxyphenyl) - 9H-pyrido [3,4-b]indole-3- carboxylate comprises the following steps:
- the crude Tadalafil is recrystallized by dissolving it in about 2 to 12 volumes, preferably 4 to 8 volumes of a polar solvent selecting from DMF, 1,4-Dioxane and DMSO, followed by quenching the mass into 6 to 30 volumes of water/water miscible solvent such as methanol, ethanol, isopropanol, acetone or mixtures thereof over a period of 30 rnin to 2 hrs or water/water miscible solvent can be added to the solution of crude Tadalafil in a polar solvent.
- a polar solvent selecting from DMF, 1,4-Dioxane and DMSO
- Reaction mass is cooled and maintained at -10°C to 10°C preferably at -5°C to 5°C for 1 hr to 6 hrs followed by isolation, washing with acetone and drying gives the pure Tadalafil in quantitative yields of pharmaceutically acceptable quality.
- (6R, 12aR)-Methyl-l,2,3,4-tetrahydro-2-chloroacetyl-l-(3,4-methylene dioxy phenyl) - 9H-pyrido[3,4-b]indole-3-carboxylate (Chloroacetyl intermediate) is prepared as per the reported prior art methods.
- Methyl amine solution (25% in methanol, 163 ml) is added to a suspension of (6R,12aR) - Methyl 1,2,3,4 -tetrahydro-2 - chloroacetyl -l-(3,4 -methylenedioxy phenyl) -9H- pyrido[3,4-b]indole-3-carboxylate (Chloro acetyl intermediate) (79 g) in methanol (790 ml). Temperature of the reaction mass is raised and maintained at 50°C to 55°C for 6 hrs. The reaction mass is then cooled and maintained at 25°C to 30°C for 1 hr, filtered, washed with methanol (50 ml) and dried at 45°C to 50°C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
La présente invention concerne un procédé optimisé pour l'élaboration de Tadalafil à partir de (6R, 12aR)-méthyle 1,2,3,4-tétrahydro-2-chloro-acétyle-1-(3,4-méthylène-dioxy-phényle)-9H-pyrido[3,4-b]indole-3-carboxylate (intermédiaire chloro-acétyle) sans avoir à utiliser de grands volumes de solvant ni effectuer de distillation, d'extraction ni d'évaporation de solvants. En l'occurrence, le Tadalafil cru est isolé par refroidissement et recristallisation à partir de solvants polaires tels que le DMF, le 1,4-dioxane ou le DMSO. On procède ensuite à une adjonction de la masse de réaction dans l'eau ou un solvant miscible dans l'eau, puis on refroidit et on maintient à basse température.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN491/CHE/2004 | 2004-05-31 | ||
| IN491CH2004 | 2004-05-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005116030A1 true WO2005116030A1 (fr) | 2005-12-08 |
Family
ID=35450828
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2005/000136 WO2005116030A1 (fr) | 2004-05-31 | 2005-05-02 | Procede d'elaboration de tadalafil |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2005116030A1 (fr) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006091975A1 (fr) * | 2005-02-25 | 2006-08-31 | Teva Pharmaceutical Industries Ltd. | Processus pour synthetiser le tadalafil |
| US7417044B2 (en) | 2005-02-25 | 2008-08-26 | Teva Pharmaceutical Industries Ltd. | Tadalafil having a large particle size and a process for preparation thereof |
| EP2238979A1 (fr) * | 2009-04-06 | 2010-10-13 | LEK Pharmaceuticals d.d. | Ingrédient pharmaceutique actif absorbé sur un support solide |
| US8063214B2 (en) * | 2004-10-28 | 2011-11-22 | Dr. Reddy's Laboratories Limited | Polymorphic forms of tadalafil |
| CN104262340A (zh) * | 2014-09-19 | 2015-01-07 | 济南诚汇双达化工有限公司 | 一种他达拉非的制备方法 |
| CN116574102A (zh) * | 2023-04-11 | 2023-08-11 | 广东九明制药有限公司 | 一种他达拉非的制备方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5859006A (en) * | 1994-01-21 | 1999-01-12 | Icos Corporation | Tetracyclic derivatives; process of preparation and use |
| WO2002036593A1 (fr) * | 2000-11-06 | 2002-05-10 | Lilly Icos Llc | Derives d'indole utilises comme inhibiteurs de pde5 |
| WO2004011463A1 (fr) * | 2002-07-31 | 2004-02-05 | Lilly Icos, Llc. | Reaction de pictet-spengler modifiee et produits prepares a partir de cette derniere |
-
2005
- 2005-05-02 WO PCT/IN2005/000136 patent/WO2005116030A1/fr active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5859006A (en) * | 1994-01-21 | 1999-01-12 | Icos Corporation | Tetracyclic derivatives; process of preparation and use |
| WO2002036593A1 (fr) * | 2000-11-06 | 2002-05-10 | Lilly Icos Llc | Derives d'indole utilises comme inhibiteurs de pde5 |
| WO2004011463A1 (fr) * | 2002-07-31 | 2004-02-05 | Lilly Icos, Llc. | Reaction de pictet-spengler modifiee et produits prepares a partir de cette derniere |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8063214B2 (en) * | 2004-10-28 | 2011-11-22 | Dr. Reddy's Laboratories Limited | Polymorphic forms of tadalafil |
| WO2006091975A1 (fr) * | 2005-02-25 | 2006-08-31 | Teva Pharmaceutical Industries Ltd. | Processus pour synthetiser le tadalafil |
| US7417044B2 (en) | 2005-02-25 | 2008-08-26 | Teva Pharmaceutical Industries Ltd. | Tadalafil having a large particle size and a process for preparation thereof |
| EP2238979A1 (fr) * | 2009-04-06 | 2010-10-13 | LEK Pharmaceuticals d.d. | Ingrédient pharmaceutique actif absorbé sur un support solide |
| CN104262340A (zh) * | 2014-09-19 | 2015-01-07 | 济南诚汇双达化工有限公司 | 一种他达拉非的制备方法 |
| CN104262340B (zh) * | 2014-09-19 | 2016-08-31 | 济南诚汇双达化工有限公司 | 一种他达拉非的制备方法 |
| CN116574102A (zh) * | 2023-04-11 | 2023-08-11 | 广东九明制药有限公司 | 一种他达拉非的制备方法 |
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