WO2004078700A1 - 3,3-diarylpropylamine derivatives and processes for isolation thereof - Google Patents
3,3-diarylpropylamine derivatives and processes for isolation thereof Download PDFInfo
- Publication number
- WO2004078700A1 WO2004078700A1 PCT/IB2004/000638 IB2004000638W WO2004078700A1 WO 2004078700 A1 WO2004078700 A1 WO 2004078700A1 IB 2004000638 W IB2004000638 W IB 2004000638W WO 2004078700 A1 WO2004078700 A1 WO 2004078700A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tolterodine
- pharmaceutically acceptable
- acceptable salt
- dimer
- pure
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
Definitions
- the field of the invention relates to 3,3-diarylpropylamines derivatives and processes for producing them. More particularly, it relates to the preparation of pure tolterodine or a pharmaceutically acceptable salt thereof and pharmaceutical compositions that include the pure tolterodine or a pharmaceutically acceptable salt thereof. It also relates to a novel 3,3-dia ⁇ ylpropylamine derivative, referred to as tolterodine dimer. Chemically, tolterodine dimer is N,N-di-[3-[2-hydroxy-5-methylphenyl]-3- phenylpropyl]isopropylamine and has structural Formula I,
- the invention also relates to use of pure tolterodine or a pharmaceutically acceptable salt thereof or tolterodine dimer as reference standards or reference markers for checking the purity of tolterodine.
- Tolterodine is a new potent and competitive muscarinic receptor antagonist intended for the treatment of urinary urge incontinence and other symptoms of bladder over activity.
- tolterodine tartrate is L-(+)-tartrate salt of (+)-R-3(2-hydroxy-5- methylphenyl), N, N-diisopropyl-3-phenylpropyl amine and has structural Formula II.
- Tolterodine dimer has a possibility of being used as a reference marker compound in identifying the purity of the tolterodine or a pharmaceutically acceptable salt thereof.
- impurities in pharmaceutically active agents and formulations containing them include residual amounts of synthetic precursors to the active agent, by- products which arise during synthesis of the active agent, residual solvents, isomers of active agent, excipients used in the preparation of the pharmaceutical formulation, and unidentified adventitious substances.
- Other impurities which may appear on storage include substances resulting from degradation of the active agent, for instance by oxidation or hydrolysis. Tolterodine easily forms dimer. However, there is no reference of the tolterodine dimer in the literature.
- tolterodine dimer a novel 3,3-diarylpropylamines derivative, which is chemically N,N-di-[3-[2-hydroxy-5-methylphenyl]-3-phenylpropyl] isopropylamine of Formula I (hereinafter referred to as tolterodine dimer).
- tolterodine dimer as a reference standard for determination of the purity of tolterodine or a pharmaceutically acceptable salt thereof.
- composition that includes a therapeutically effective amount of pure tolterodine or a pharmaceutically acceptable salt thereof containing less than 0.5% tolterodine dimer; and one or more pharmaceutically acceptable carriers, excipients or diluents.
- composition that includes a therapeutically effective amount of pure tolterodine or a pharmaceutically acceptable salt thereof containing less than 0.05% tolterodine dimer; and one or more pharmaceutically acceptable carriers, excipients or diluents.
- a process of depletion of tolterodine dimer impurity from tolterodine or a pharmaceutically acceptable salt thereof includes obtaining a solution of crude tolterodine or a pharmaceutically acceptable salt thereof in one or more solvents; and recovering the pure tolterodine or a pharmaceutically acceptable salt thereof by the removal of the solvent.
- the solvent maybe one or more of lower alkanol, ketone, polar aprotic solvent, or mixtures thereof.
- the lower alkanol may include one or more of primary, secondary and tertiary alcohol having from one to six carbon atoms.
- the lower alkanol may include one or more of methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol, isobutanol and t-butanol.
- the ketone may include one or more of acetone, 2-butanone, and 4-methylpentan-
- the polar aprotic solvent may include one or more of tetrahydrofuran, acetonitrile,
- Removing the solvent may include one or more of distillation, distillation under vacuum, filtration, filtration under vacuum, decantation and centrifugation.
- the process may include further drying of the product obtained.
- the solution of crude tolterodine may be obtained by heating the solvent containing crude tolterodine. It maybe heated from about 30°C to about reflux temperature of the solvent used, for example from about 30°C to about 100°C. particular, it may be heated from about 40°C to about 60°C. It may be heated from about 15 minutes to about 10 hours. More particularly, it may be heated for about 2-3 hours.
- the solution containing the crude tolterodine may be treated with charcoal before removing the solvent.
- the charcoal treatment may be carried out under heating conditions or it may be carried out at a lower temperature.
- additional/another solvent may be added to residue obtained after removal of the solvent and it may be cooled before filtration to obtain better yields of the pure tolterodine.
- the process may produce the pure tolterodine or a pharmaceutically acceptable salt thereof containing less than 0.5% tolterodine dimer. In particular, it may produce the pure tolterodine or a pharmaceutically acceptable salt thereof containing less than 0.05% tolterodine dimer.
- the inventors have identified that the tolterodine dimer is formed as an impurity during the synthesis of tolterodine or a pharmaceutically acceptable salt thereof.
- the inventors have isolated tolterodine dimer which can be used as a reference standard for determination of the purity of tolterodine or a pharmaceutically acceptable salt thereof.
- the process involves
- N, N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine may be heated at reflux temperature for 10-12 hours with hydrobromic acid in the presence of acetic acid.
- the reaction mass may be cooled to ambient temperature and the precipitated product may be isolated by conventional means and dried.
- the crude product so obtained may be repeatedly loaded on YMC-Pack ODS-A (500 x 30 mm I. D.) column.
- Mobile phase used may be a gradient of phosphate buffer (2gm KH2PO4 / lit of distilled water) and acetonitrile in 8:2 to 2:8 v/v ratio.
- the fractions containing the dimer impurity may be further combined and concentrated to dryness.
- the pure tolterodine dimer can then be further purified by crystallization or column chromatography.
- the inventors also have developed a process of depletion of tolterodine dimer impurity from tolterodine or a pharmaceutically acceptable salt thereof, by obtaining a solution of crude tolterodine or a pharmaceutically acceptable salt thereof in one or more solvents; and recovering the pure tolterodine or a pharmaceutically acceptable salt thereof by the removal of the solvent.
- the inventors also have developed pharmaceutical compositions that contain the pure tolterodine or a phanuaceutically acceptable salt thereof containing less than 0.5% tolterdine dimer, for example, less than 0.05% tolterodine dimer, in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and/or excipients. These pharmaceutical compositions may be used for treating a patient in need of a treatment for urinary urge incontinence and other symptoms of bladder over activity.
- the tolterodine or a pharmaceutically acceptable salt thereof may be prepared by the methods known in the literature. In particular, it may be prepared using the reactions and techniques described in our PCT patent application WO 03/014060 which is incorporated herein as reference.
- the solution of crude tolterodine may be obtained by dissolving crude tolterodine in a suitable solvent. Alternatively, such a solution may be obtained directly from a reaction in which tolterodine is formed.
- the solvent containing crude tolterodine may be heated to obtain a solution. It can be heated from about 30°C to about reflux temperature of the solvent used, for example from about 30°C to about 100°C. h particular, it can be heated from about 40°C to about 60°C. It can be heated from about 15 minutes to about 10 hours. More particularly, it can be heated for about 2-3 hours.
- the product may be isolated from the solution by a technique which includes, for example, distillation, distillation under vacuum, filtration, filtration under vacuum, decantation, and centrifugation.
- suitable solvent includes any solvent or solvent mixture in which crude tolterodine is soluble, including, for example, lower alkanol, ketone, polar aprotic solvent and mixtures thereof.
- alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
- Suitable lower alkanol solvents include methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol, isobutanol and t- butanol.
- a suitable ketone includes one or more of acetone, 2-butanone, and 4- methylpentan-2-one.
- polar aprotic solvents include solvents such as tetrahydrofuran, acetonitrile, 1,4-dioxane and N-methylpyrrolidone. Mixtures of all of these solvents are also contemplated.
- the solution containing crude tolterodine can be treated with activated carbon and filtered while hot.
- additional or another solvent can be added to the clear solution to precipitate the pure tolterodine or a pharmaceutically acceptable salt thereof.
- the product obtained may be further or additionally dried to achieve the desired moisture values.
- the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
- the solution containing the crude tolterodine may be heated for dissolution, or may be cooled to separate out the product or the slurry may further be cooled prior to filtration or the solution may be seeded with seed crystals of the product to enhance precipitation of the product.
- the crude product was repeatedly loaded on YMC-Pack ODS-A (500 x 30 mm I. D.) column.
- Mobile phase used was gradient of phosphate buffer (2gm KH2PO4 / lit of distilled water) and acetonitrile 8:2 to 2:8.
- the fractions containing the dimer impurity were combined and concentrated to dryness.
- the spectral data of the isolated tolterodine dimer are as follows:
- Tolterodine hydrobromide (230 g) from Example 1 (HPLC Purity: 97.52%), methylene chloride and water were mixed. The pH was adjusted to about 10 - 11 while adding sodium hydroxide (50%, 21 g in 42 ml) and sodium carbonate (26.45 g). After stirring for about 15 minutes, two clear homogeneous phases were formed. The organic layer was separated and washed with water twice (2 x 1150 ml), and was concentrated under reduced pressure. The concentrate was dissolved in acetone (1150 ml) and warmed to 50°C.
- Acetone (2.2 lit.) was added at reflux temperature and gradually cooled to 20 - 25°C. The solid was filtered and washed with acetone (440 ml) and dried under reduced pressure to give pure (R) tolterodine-L-tartrate.
- Tolterodine hydrobromide (230 g) from Example 2 (HPLC Purity: 98.37%), methylene chloride and water were mixed. The pH was adjusted to about 10 - 11 while adding sodium hydroxide (50%, 21 g in 42 ml) and sodium carbonate (26.45 g). After stirring for 15 minutes, two clear homogeneous phases were formed. The organic layer was separated and washed with water twice (2 x 1150 ml), and concentrated under reduced pressure. The concentrate was dissolved in acetone (1150 ml) and warmed to 50°C.
- Tolterodine hydrobromide (230 g) from Example 3 (HPLC Purity: 95.92%), methylene chloride and water were mixed. The pH was adjusted to about 10 - 11 while adding sodium hydroxide (50%, 21 g in 42 ml) and sodium carbonate (26.45 g). After stirring for 15 minutes, two clear homogeneous phases were formed. The organic layer was separated and washed with water twice (2 x 1150 ml), and concentrated under reduced pressure. The concentrate was dissolved in acetone (1150 ml) and warmed to 50°C.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004218178A AU2004218178A1 (en) | 2003-03-06 | 2004-03-08 | 3,3-diarylpropylamine derivatives and processes for isolation thereof |
CA002517824A CA2517824A1 (en) | 2003-03-06 | 2004-03-08 | 3,3-diarylpropylamine derivatives and processes for isolation thereof |
EP04718361A EP1603862A1 (en) | 2003-03-06 | 2004-03-08 | 3,3-diarylpropylamine derivatives and processes for isolation thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN237/DEL/2003 | 2003-03-06 | ||
IN237DE2003 | 2003-03-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004078700A1 true WO2004078700A1 (en) | 2004-09-16 |
Family
ID=32948050
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2004/000638 WO2004078700A1 (en) | 2003-03-06 | 2004-03-08 | 3,3-diarylpropylamine derivatives and processes for isolation thereof |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1603862A1 (en) |
AU (1) | AU2004218178A1 (en) |
CA (1) | CA2517824A1 (en) |
WO (1) | WO2004078700A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006074479A1 (en) * | 2005-01-10 | 2006-07-13 | Teva Pharmaceutical Industries, Ltd. | Process for preparing tolterodine tartrate |
WO2007046001A3 (en) * | 2005-05-27 | 2007-09-07 | Medichem Sa | Process for preparing 3,3-diarylpropylamines |
WO2010092500A2 (en) | 2009-02-12 | 2010-08-19 | Alembic Limited | A process for the preparation of tolterodine tartrate |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0325571A1 (en) * | 1988-01-22 | 1989-07-26 | Kabi Pharmacia AB | New amines, their use and preparation |
US5922914A (en) * | 1996-12-31 | 1999-07-13 | Pharmacia & Upjohn Company | Process to prepare tolterodine |
WO2003014060A1 (en) * | 2001-08-03 | 2003-02-20 | Ranbaxy Laboratories Limited | Process for the preparation of tolterodine |
-
2004
- 2004-03-08 WO PCT/IB2004/000638 patent/WO2004078700A1/en not_active Application Discontinuation
- 2004-03-08 CA CA002517824A patent/CA2517824A1/en not_active Abandoned
- 2004-03-08 EP EP04718361A patent/EP1603862A1/en not_active Withdrawn
- 2004-03-08 AU AU2004218178A patent/AU2004218178A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0325571A1 (en) * | 1988-01-22 | 1989-07-26 | Kabi Pharmacia AB | New amines, their use and preparation |
US5922914A (en) * | 1996-12-31 | 1999-07-13 | Pharmacia & Upjohn Company | Process to prepare tolterodine |
WO2003014060A1 (en) * | 2001-08-03 | 2003-02-20 | Ranbaxy Laboratories Limited | Process for the preparation of tolterodine |
Non-Patent Citations (1)
Title |
---|
BRYNNE N ET AL: "PHARMACOKINETICS AND PHARMACODYNAMICS OF TOLTERODINE IN MAN: A NEW DRUG FOR THE TREATMENT OF URINARY BLADDER OVERACTIVITY", INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, DUSTRI-VERLAG, DEISENHOFEN-MUENCHEN, DE, vol. 35, no. 7, July 1997 (1997-07-01), pages 287 - 295, XP009022477, ISSN: 0946-1965 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006074479A1 (en) * | 2005-01-10 | 2006-07-13 | Teva Pharmaceutical Industries, Ltd. | Process for preparing tolterodine tartrate |
WO2006074478A1 (en) * | 2005-01-10 | 2006-07-13 | Teva Pharmaceuticals Usa, Inc. | Substantially pure tolterodine tartrate and process for preparing thereof |
WO2007046001A3 (en) * | 2005-05-27 | 2007-09-07 | Medichem Sa | Process for preparing 3,3-diarylpropylamines |
US7879912B2 (en) | 2005-05-27 | 2011-02-01 | Medichem S.A. | Process for preparing 3,3-diarylpropylamines |
WO2010092500A2 (en) | 2009-02-12 | 2010-08-19 | Alembic Limited | A process for the preparation of tolterodine tartrate |
Also Published As
Publication number | Publication date |
---|---|
CA2517824A1 (en) | 2004-09-16 |
AU2004218178A1 (en) | 2004-09-16 |
EP1603862A1 (en) | 2005-12-14 |
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