WO2004106327A1 - Process for the preparation of anhydrous eleptritan hemisulphate - Google Patents
Process for the preparation of anhydrous eleptritan hemisulphate Download PDFInfo
- Publication number
- WO2004106327A1 WO2004106327A1 PCT/IB2004/001694 IB2004001694W WO2004106327A1 WO 2004106327 A1 WO2004106327 A1 WO 2004106327A1 IB 2004001694 W IB2004001694 W IB 2004001694W WO 2004106327 A1 WO2004106327 A1 WO 2004106327A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- volume
- eletriptan
- hours
- water content
- hemisulphate
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
Definitions
- the present invention relates to an improved process for the preparation of a particular crystalline form of eletriptan hemisulphate.
- Eletriptan, 3- ⁇ [1 -methylpyrrolidin-2(R)-yl]methyl ⁇ -5-(2-phenylsulfonylethyl)-1 H- indole, and a process for its manufacture, are disclosed in United States Patent number 5,607,951.
- Eletriptan hemisulphate has the structure of formula (I) below.
- the hemisulphate salt of mixed morphology is slurried in refluxing tetrahydrofuran (THF), ethanol, isopropanol or industrial methylated spirit (IMS) and then filtered, washed and dried to yield eletriptan hemisulphate form I.
- THF refluxing tetrahydrofuran
- IMS industrial methylated spirit
- a C ⁇ -C 6 alkyl acetate is a compound of the formula CH 3 COOR, wherein R is a C ⁇ -C 6 alkyl group.
- Preferred solvents are ethyl acetate and n-propyl acetate. Ethyl acetate is particularly preferred.
- the volume of solvent used, in relation to the weight of eletriptan hemisulphate, is not determinative of success.
- ethyl acetate is used as the solvent, an amount of from 8 to 12 litres of ethyl acetate per kilogram of eletriptan hemisulphate is preferably employed.
- the amount of water present in the reaction is crucial to the success of the process and must be no more than 3% volume/volume.
- the amount of bound water present must be calculated [Karl Fischer (KF) analysis is the most convenient analytical tool] and taken into consideration. If necessary, the starting material can be dried to reduce its water content.
- the water content of the reaction mixture is preferably from 0.2 to 2% volume/volume, most preferably from 1.3 to 2% volume/volume.
- those forms of eletriptan that are less resistant to conversion, having a low crystallinity, can be easily converted in a reaction mixture having a lower water content whilst more resistant batches are more conveniently converted in a reaction mixture having a higher water content.
- the heating should be continued until all the hemisulphate salt present has been converted into the form I polymorph. This will typically take several hours, usually from 4 to 24 hours.
- the conversion time will depend on the temperature selected, a higher temperature resulting in a lower conversion time.
- the slurry is heated at from 60 to 80°C. Most preferably, when ethyl acetate is chosen as the solvent, the slurry is heated under reflux.
- the reaction mixture may also be pressurised to increase the rate of conversion. Differential scanning calorimetry (DSC), performed on a sample taken from the reaction mixture, can be used as a crude indication of how far the conversion has progressed.
- DSC Differential scanning calorimetry
- the product can be recovered by filtration. Typically, the reaction mixture is cooled to from 20 to 25°C, filtered, washed with solvent (preferably about 1 litre per kilogram of product) and dried (preferably at 70°C in vacuo). De-lumping may be necessary in certain instances.
- the average yield of eletriptan hemisulphate form I is 94%.
- the starting material for the conversion may be amorphous eletriptan hemisulphate, any single polymorphic form of eletriptan hemisulphate, any hydrated/solvated form of either or any mixture of the forgoing, including mixtures comprising form I itself.
- polymorphic forms of eletriptan hemisulphate that are known are listed below along with characterising data.
- Polymorphic forms l-XI are known as well as two ethyl acetate solvates XII and XIII and an n-propyl acetate solvate XIV, these solvates containing varying amounts of water.
- the solvates are readily observed on slurrying amorphous eletriptan hemisulphate in either ethyl acetate or n-propyl acetate, respectively.
- Form IV is observed when a solution of eletriptan in acetonitrile is treated with dilute sulphuric acid.
- Powder X-ray diffraction (PXRD) patterns were typically determined using a SIEMENS D5000 powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter.
- the analyses were typically performed with the goniometer running in continuous mode set for a 5 second count per 0.02° step over a two theta range of 2° to 40°.
- Differential scanning calorimetry was performed using a Perkin Elmerkha Diamond DSC instrument fitted with an automatic sample changer. Approximately 3mg of each sample was accurately weighed into a 50 microlitre aluminium pan and crimp sealed with a perforated lid. The samples were heated at 20°C/minute over the range 30°C to 250°C with a nitrogen gas purge.
- DSC thermograms for forms III and above have a similar profile with dehydration or desolvation and melt up to ⁇ 140°C then a exothermic recrystallisation event to Form II (Peak at about 186°C) and then a second exothermic recrystallisation event to Form I (Peak at about 226°C).
- Eletriptan hemisulphate is usually prepared by the reaction of eletriptan free base with sulphuric acid.
- WO-A-01/23377 describes a process comprising the reaction of eletriptan with concentrated sulphuric acid as a refluxing solution in acetone or as a cooled solution in tetrahydrofuran.
- a new process for the preparation of eletriptan hemisulphate in a form particularly suitable for further processing to the form I polymorph has been developed.
- a cooled solution of eletriptan in acetone is treated with dilute aqueous sulphuric acid and the precipitated product is then recovered.
- the use of dilute sulphuric acid in contrast to the use of concentrated sulphuric acid in the prior art process, is particularly advantageous since it is easier and safer to handle and leads to a cleaner reaction which produces lower levels of by-products.
- the concentration of the solution of eletriptan in acetone is preferably from 7.5 to 15 litres per kg, most preferably about 10 litres per kg and the solution may advantageously be filtered prior to the addition of the dilute sulphuric acid.
- the use of from about 0.45 to 0.55 molar equivalents of sulphuric acid per mole of eletriptan produces optimal results and the dilute aqueous sulphuric acid preferably contains about 0.2 kg/litre of sulphuric acid.
- the reaction is preferably carried out at a temperature of from -5°C to +5°C and a gradual addition (for instance, over a period of 1 to 2 hours) of sulphuric acid is preferred.
- the product may conveniently be recovered by granulation (preferably at a temperature of from -5°C to +5°C, over a period of about 2 hours), filtration, washing with further acetone (preferably two portions of approximately 0.5 litres per kg of product) and drying (preferably at about 50°C, in vacuo).
- the product of this process after drying, is typically a mixture of several hydrated, hygroscopic forms of variable water and acetone content (usually about 1.5 to 6% weight/weight water by Karl Fischer analysis). Forms III, V, VI, VIII and XI have been observed - see the experimental section below for details. Before conversion to the form I polymorph, using the process described above, the product is dried, if necessary, until its water content is no more than 6% weight/weight.
- Differential scanning calorimetry (DSC) was performed using a Mettler-Toledo DSC 822e instrument. The samples were heated at 10°C/minute over the range 30°C to 300°C.
- Infra-red (IR) analysis was performed using a Bruker-Optics Vector 22 instrument. The sample was prepared using Golden- Gate ATR technology. Only characteristic peaks are listed.
- Example 1 Powder X-ray diffraction
- the precipitate was recovered by filtration and washed with acetone (2 x 50 ml). After standing at ambient temperature for 2 hours, 10 g of the product (total weight 119.4 g), contaminated with water and acetone (water by K.F., 8.22 %; acetone by GC -1.85 %), was removed for investigation.
- the precipitate was recovered by filtration, washed with acetone (2 x 35 ml) and dried at 50°C for 16 hours in a forced air dryer to yield eletriptan hemisulphate (80.9 g, 94 %) as a white solid (water by K.F., 1.43 %; acetone by GC, 0.06 %).
- DSC 129 °C endo, 135 °C exo, 171 °C endo, 182 °C exo, 221 °C endo
- the precipitate was recovered by filtration, washed with acetone (2 x 50 ml) and dried at 50°C for 15 hours in a forced air dryer to yield eletriptan hemisulphate (111.5 g, 96 %, 99.84% pure by HPLC) as an off-white solid (water by K.F., 2.94 %; acetone by GC, 1.3 %).
- DSC 116 °C endo, 120 °C exo, 150 °C exo, 179 °C endo, 223 °C endo
- the precipitate was recovered by filtration and dried at 50°C for 10 hours in a forced air dryer to yield eletriptan hemisulphate (22.1 g, 93 %, 99.89% pure by HPLC) as an off-white solid (water by K.F., 5.04 %).
- the precipitate was recovered by filtration and dried at 50°C for 10 hours in a forced air dryer to yield eletriptan hemisulphate (18.0 g, 77 %, 99.89% pure by HPLC) as an off-white solid (water by K.F., 5.32%).
- the precipitate was recovered by filtration, washed with acetone (2 x 50 ml) and dried at 50°C for 14 hours in a forced air dryer to yield eletriptan hemisulphate (110.4 g, 96 %, 99.86% pure by HPLC) as an off-white solid (water by K.F., 3.04 %; acetone by GC, 0.01 %).
- a suspension of eletriptan hemisulphate (the hydrated form III product of Example 4, 5 g) in a mixture of ethyl acetate (50 ml) containing 0.45% volume/volume water was heated under reflux for 24 hours (total water content was 0.95 % volume/volume).
- a portion of the solvent (10 ml, 20 % of the volume) was removed by azeotropic distillation. After cooling to ambient temperature, the precipitate was recovered by filtration, washed with ethyl acetate (5 ml) and dried at 70°C for 15 hours to yield eletriptan hemisulphate form I polymorph (4.7 g, 93 %, 99.79% pure by HPLC) as a white solid.
- a suspension of eletriptan hemisulphate (the product of Example 5, 5 g) in a ethyl acetate (50 ml) containing 0.45% volume/volume water was heated under- reflux for 24 hours (total water content was 1 % volume/volume).
- a portion of the solvent (10 ml, 20 % of the volume) was removed by azeotropic distillation. After cooling to ambient temperature, the precipitate was recovered by filtration, washed with ethyl acetate (5 ml) and dried at 70°C for 15 hours to yield eletriptan hemisulphate form I polymorph (4.7 g, 93 %, 99.84% pure by HPLC) as a white solid.
- a suspension of eletriptan hemisulphate (the hydrated form III product of Example 7, 2.5 g) in a mixture of ethyl acetate (25 ml) containing 0.3% volume/volume water was heated under reflux for 24 hours (total water content was 0.6 % volume/volume).
- a portion of the solvent (5 ml, 20 % of the volume) was removed by azeotropic distillation. After cooling to ambient temperature, the precipitate was recovered by filtration, washed with ethyl acetate (2.5 ml) and dried at 70°C for 4 hours to yield eletriptan hemisulphate form I polymorph (2.1 g, 88 %) as a white solid.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Vaporization, Distillation, Condensation, Sublimation, And Cold Traps (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04733602A EP1633739A1 (en) | 2003-05-30 | 2004-05-18 | Process for the preparation of anhydrous eleptritan hemisulphate |
CA002527127A CA2527127A1 (en) | 2003-05-30 | 2004-05-18 | Process for the preparation of anhydrous eletriptan hemisulphate |
BRPI0410841-8A BRPI0410841A (en) | 2003-05-30 | 2004-05-18 | Process for the preparation of anhydrous electriptan hemisulfate |
MXPA05012838A MXPA05012838A (en) | 2003-05-30 | 2004-05-18 | Process for the preparation of anhydrous eleptritan hemisulphate. |
JP2006530682A JP2006528968A (en) | 2003-05-30 | 2004-05-18 | Method for producing anhydrous eletriptan hemisulphate |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0312478.1 | 2003-05-30 | ||
GBGB0312478.1A GB0312478D0 (en) | 2003-05-30 | 2003-05-30 | Improved process |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004106327A1 true WO2004106327A1 (en) | 2004-12-09 |
Family
ID=9959072
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2004/001694 WO2004106327A1 (en) | 2003-05-30 | 2004-05-18 | Process for the preparation of anhydrous eleptritan hemisulphate |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP1633739A1 (en) |
JP (1) | JP2006528968A (en) |
AR (1) | AR044463A1 (en) |
BR (1) | BRPI0410841A (en) |
CA (1) | CA2527127A1 (en) |
CL (1) | CL2004001132A1 (en) |
GB (1) | GB0312478D0 (en) |
MX (1) | MXPA05012838A (en) |
TW (1) | TWI290923B (en) |
WO (1) | WO2004106327A1 (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992006973A1 (en) * | 1990-10-15 | 1992-04-30 | Pfizer Inc. | Indole derivatives |
WO1996006842A1 (en) * | 1994-08-27 | 1996-03-07 | Pfizer Limited | Salts of an anti-migraine indole derivative |
WO1999001135A1 (en) * | 1997-07-03 | 1999-01-14 | Pfizer Limited | Pharmaceutical compositions containing eletriptan hemisulphate and caffeine |
WO2001023377A2 (en) * | 1999-09-28 | 2001-04-05 | Pfizer Limited | Polymorphic salt |
-
2003
- 2003-05-30 GB GBGB0312478.1A patent/GB0312478D0/en not_active Ceased
-
2004
- 2004-05-18 EP EP04733602A patent/EP1633739A1/en not_active Withdrawn
- 2004-05-18 BR BRPI0410841-8A patent/BRPI0410841A/en not_active IP Right Cessation
- 2004-05-18 JP JP2006530682A patent/JP2006528968A/en active Pending
- 2004-05-18 WO PCT/IB2004/001694 patent/WO2004106327A1/en active Application Filing
- 2004-05-18 MX MXPA05012838A patent/MXPA05012838A/en unknown
- 2004-05-18 CA CA002527127A patent/CA2527127A1/en not_active Abandoned
- 2004-05-19 CL CL200401132A patent/CL2004001132A1/en unknown
- 2004-05-25 TW TW093114789A patent/TWI290923B/en not_active IP Right Cessation
- 2004-05-28 AR ARP040101864A patent/AR044463A1/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992006973A1 (en) * | 1990-10-15 | 1992-04-30 | Pfizer Inc. | Indole derivatives |
WO1996006842A1 (en) * | 1994-08-27 | 1996-03-07 | Pfizer Limited | Salts of an anti-migraine indole derivative |
WO1999001135A1 (en) * | 1997-07-03 | 1999-01-14 | Pfizer Limited | Pharmaceutical compositions containing eletriptan hemisulphate and caffeine |
WO2001023377A2 (en) * | 1999-09-28 | 2001-04-05 | Pfizer Limited | Polymorphic salt |
Also Published As
Publication number | Publication date |
---|---|
AR044463A1 (en) | 2005-09-14 |
GB0312478D0 (en) | 2003-07-09 |
CA2527127A1 (en) | 2004-12-09 |
BRPI0410841A (en) | 2006-06-27 |
MXPA05012838A (en) | 2006-02-13 |
TW200427683A (en) | 2004-12-16 |
CL2004001132A1 (en) | 2005-03-18 |
EP1633739A1 (en) | 2006-03-15 |
JP2006528968A (en) | 2006-12-28 |
TWI290923B (en) | 2007-12-11 |
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