WO2008007390A2 - An improved process for purification of zolmitriptan - Google Patents

An improved process for purification of zolmitriptan Download PDF

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Publication number
WO2008007390A2
WO2008007390A2 PCT/IN2007/000267 IN2007000267W WO2008007390A2 WO 2008007390 A2 WO2008007390 A2 WO 2008007390A2 IN 2007000267 W IN2007000267 W IN 2007000267W WO 2008007390 A2 WO2008007390 A2 WO 2008007390A2
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Prior art keywords
zolmitriptan
product
water
purification
filtering
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PCT/IN2007/000267
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French (fr)
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WO2008007390A3 (en
WO2008007390B1 (en
Inventor
Amala Kisham Kompella
Sreenivas Rachakonda
Bhujanga Rao Adibhatla Kali Satya
Nannapaneni Venkaiah Chowdary
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Natco Pharma Limited
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Publication of WO2008007390A2 publication Critical patent/WO2008007390A2/en
Publication of WO2008007390A3 publication Critical patent/WO2008007390A3/en
Publication of WO2008007390B1 publication Critical patent/WO2008007390B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to an improved and novel process for the purification of the Zolmitriptan (I) to get highly pure drug substance of greater than 99.8% purity.
  • Zolmitriptan is a 5HT 1 -like receptor agonist useful in the treatment and prophylaxis of migraine and is chemically known as (S)-4-[(3-[2-(Dimethylamino) ethyl]- lH-indol-5-yl] methyl] -2-oxazolidinone (I)
  • Zolmitriptan (I) is generally prepared according to the methods described in the patents like WO 91/18897, WO 97/06162, and EP 1227095.
  • the product prepared by any of these methods is initially obtained in the crude form and needs extensive purification to meet the pharmacological standards.
  • Zolmitriptan (I) is generally prepared according to the following scheme by indolization of the intermediate, (S)-4-(4-Aminobenzyl)-l,3-oxazolidin-2-one (II) by known processes described in WO 91/18897
  • the dry product as 'ethyl acetate solvate' is treated with a mixture of 20% .acetone.in-water,- cooled.an ⁇ - ⁇ .ltered ⁇ -T-h ⁇ -fil-tered-pr ⁇ duet is again- washed-witir ethyl : ⁇ acetate and finally dried to get purified Zolmitriptan
  • the main objective of the present invention is to provide an improved process for the preparation of highly pure (> 99.8%) zolmitriptan overcoming the drawbacks of the hitherto known prior art processes.
  • Still another objective of the present invention is to provide an improved process for the preparation of highly pure (> 99.8%) zolmitriptan of the formula (I) avoiding the solvate formation thereby making the process simple.
  • Yet another objective of the present process is to provide an improved process for the preparation of highly pure (> 99.8%) zolmitriptan by isolating crude zolmitriptan by extracting with chloroform at room temperature thereby avoiding extractions at 50 0 C.
  • Yet another objective of the present process is to provide an improved process for the preparation of highly pure (> 99.8%) zolmitriptan by crystallization with aqueous acetonitrile, which is hitherto not known.
  • Still another objective of the present invention is to provide an improved process for the . . preparation of highly pure (> 99.8%) zolmitriptan of the formula (I) by using Isopropanol (IPA) as a second crystallization solvent.
  • IPA Isopropanol
  • Yet another objective of the present invention is to provide a process for the preparation of highly pure zolmitriptan (>99.8%) of the formula (I) is to distill off IPA to the desired residual volume and add water to precipitate zolmitriptan
  • Another objective of the present invention is to provide an improved process for the purification of highly pure (> 99.8%) zolmitriptan by separating it from the unwanted by products and other impurities formed during the course of indolization
  • Still another objective of the present invention is to provide an improved process for the preparation of highly pure (>99.8%) zolmitriptan of the formula (I) avoiding additional purification steps and reducing operational time thereby making the process economical.
  • the present invention provides an improved process for the preparation of highly pure (>99.8%) zolmitriptan of the formula (I) and therefore obviates the 'desolvation step' of purification.
  • step (c) Washing with DM water and then drying The decolourization of step (c) is carried out at temperature 45-55 0 C, which is more preferably at 50 0 C.
  • the drying stage of step (d) is preferably carried out under vacuum.
  • the product is dried at temperature 40-60 0 C, which is more preferably at 50 0 C.
  • the preferable refluxing mixture of step e) is 40% acetonitrile in water.
  • the cooled solution of step (f) is suitably stirred over a prolonged period, which is preferably approximately 8 hours.
  • step ( i) The decolourization of step ( i) is carried out at temperature 50-70 0 C, which is preferably approximately 60 0 C.
  • the desired IPA volume of step (j) is preferably approximately 3 volumes with respect to the weight of the crude product of step d).
  • step (1) is preferably carried out under vacuum.
  • the product is dried at temperature 40-60 0 C, which is more preferably at 50 0 C.
  • the solution is maintained at about 60 DEG C for about 18 hours. Dilute the reaction mixture with 5L of water and heat to about 90 DEG C. Under a nitrogen atmosphere slowly add 246 gms of 4,4-diethoxy-N, N-dimethylbutylamine and heat at reflux for about 3 hours. Cool, and adjust the mixture to about pH7 using sodium hydroxide solution. Extract with chloroform and then adjust the aqueous layer to about pHIO, again using sodium hydroxide solution. Extract the product using chloroform. Treat the combined chloroform extracts (containing the product) with decolorizing charcoal, and filter through filter aid. Distil off most of the solvent and chill the suspension to about 0 DEG C. Centrifuge the crude product, wash with chloroform and vacuum dry at 50 DEG C. (150 gms, pale yellow powder, 99.4% HPLC purity)
  • Example- 1 The crude product of example- 1 is dissolved in a refluxing mixture of 1.5L of 40% acetonitrile in water, treated with decolourising charcoal and filtered hot through filter aid. The solution is slowly cooled to above 0 DEG C and stirred for 8 hours. The purified product is then filtered, washed with water and vacuum dried at 50 DEG C, the wet solid is dissolved in 3L of refluxing IPA, treated with decolourising charcoal and filtered hot through filter aid. The filtrate is concentrated to approximately 0.5L cooled to about 25 DEG C treated with 750 ml water and stirred for 2 hrs before filtering the product, washing with water and drying in vacuum at about 50 DEG C. (60 gms, white powder, 99.87% HPLC purity)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to an improved and novel process for the purification of the Zolmitriptan (I) to get highly pure drug substance of greater than 99.8% purity. Zolmitriptan is a 5HT1-like receptor agonist useful in the treatment and prophylaxis of migraine and is chemically known as (S)-4-[(3-[2-(Dimethylamino) ethyl]-1H-indol-5-yl] methyl]-2-oxazolidinone. Formula (I). A novel method of purification of the drug substance Zolmitriptan (I) is developed and is described.

Description

AN IMPROVED PROCESS FOR PURIFICATION OF ZOLMITRIPTAN
Introduction
The present invention relates to an improved and novel process for the purification of the Zolmitriptan (I) to get highly pure drug substance of greater than 99.8% purity.
Zolmitriptan is a 5HT1 -like receptor agonist useful in the treatment and prophylaxis of migraine and is chemically known as (S)-4-[(3-[2-(Dimethylamino) ethyl]- lH-indol-5-yl] methyl] -2-oxazolidinone (I)
Figure imgf000002_0001
(I)
10 Zolmitriptan (I) is generally prepared according to the methods described in the patents like WO 91/18897, WO 97/06162, and EP 1227095. The product prepared by any of these methods is initially obtained in the crude form and needs extensive purification to meet the pharmacological standards.
A novel method of purification of the drag substance Zolmitriptan (I) is developed and is -1-5- deseribed-herer-
Background of the invention
Zolmitriptan (I) is generally prepared according to the following scheme by indolization of the intermediate, (S)-4-(4-Aminobenzyl)-l,3-oxazolidin-2-one (II) by known processes described in WO 91/18897
Figure imgf000003_0001
(I)
Crude Zolmitriptan (I) obtained as above is usually contaminated with impurities and a method of purification is disclosed in the patents WO 97/06162 and EP 1227095. In this procedure, Zolmitriptan obtained from the reaction mixture is extracted with ethyl acetate at 50°C and the solvent is distilled off after charcoal treatment. The concentrated mass is chilled to 50C and the crude product is centrifuged and dried. The crude dry product thus obtained is dissolved in a mixture of 10% ethanol in ethyl acetate, treated with decolorizing charcoal and filtered hot. On cooling and filtering, Zolmitriptan is obtained as, a 'solvated product' . To remove the solvated ethyl acetate from the semi -purified product, the dry product as 'ethyl acetate solvate' is treated with a mixture of 20% .acetone.in-water,- cooled.anά-β.lteredτ-T-h©-fil-tered-prθduet is again- washed-witir ethyl :~ acetate and finally dried to get purified Zolmitriptan
Objective and summary of the present invention
The process of purification described in the prior art procedure described above is complex and cumbersome and involves preparation and isolation of the drug substance Zolmitripan as 'ethylacetate solvate'. Further purification of this isolated solvate is essential to 'desolvate' this intermediate product rendering the process further complicated. Therefore, a need is felt to develop a simplified method of purification of crude Zolmitriptan free of intermediate formation of solvates.
Taking into consideration the above mentioned shortcomings of the hitherto known prior art processes for the preparation of zolmitriptan of the formula I, our aim was directed towards developing an improved environmentally safe and industrially applicable process, which is devoid of the above-mentioned insufficiencies.
Therefore the main objective of the present invention is to provide an improved process for the preparation of highly pure (> 99.8%) zolmitriptan overcoming the drawbacks of the hitherto known prior art processes.
Still another objective of the present invention is to provide an improved process for the preparation of highly pure (> 99.8%) zolmitriptan of the formula (I) avoiding the solvate formation thereby making the process simple.
Yet another objective of the present process is to provide an improved process for the preparation of highly pure (> 99.8%) zolmitriptan by isolating crude zolmitriptan by extracting with chloroform at room temperature thereby avoiding extractions at 500C.
Yet another objective of the present process is to provide an improved process for the preparation of highly pure (> 99.8%) zolmitriptan by crystallization with aqueous acetonitrile, which is hitherto not known.
Still another objective of the present invention is to provide an improved process for the. . preparation of highly pure (> 99.8%) zolmitriptan of the formula (I) by using Isopropanol (IPA) as a second crystallization solvent.
Yet another objective of the present invention is to provide a process for the preparation of highly pure zolmitriptan (>99.8%) of the formula (I) is to distill off IPA to the desired residual volume and add water to precipitate zolmitriptan Another objective of the present invention is to provide an improved process for the purification of highly pure (> 99.8%) zolmitriptan by separating it from the unwanted by products and other impurities formed during the course of indolization
Still another objective of the present invention is to provide an improved process for the preparation of highly pure (>99.8%) zolmitriptan of the formula (I) avoiding additional purification steps and reducing operational time thereby making the process economical.
Accordingly, the present invention provides an improved process for the preparation of highly pure (>99.8%) zolmitriptan of the formula (I) and therefore obviates the 'desolvation step' of purification.
The process of this invention consists of the following steps:
a) After indolization, extracting the impurity from the reaction mixture with Chloroform by adjusting reaction mass pH to 7.0 at room temperature.
b) Extracting the Product with Chloroform by adjusting the reaction mass pH to 10.0 at room temperature. c) Decolourizing the chloroform layer using activated charcoal in hot condition. d) Isolating the zolmitriptan crude by distilling off the Chloroform layer, filtering and drying e) Dissolving the crude Zolmitriptan in refluxing mixture of aqueous acetonitrile f) Slowly cooling the solution to a temperature of about 00C. g) Filtering the product and washing with DM water, h) Dissolving the product in refluxing Isopropanol. i-> Deeolourizing-suitably-me-IsopropanσHayerusing activated charcoal" in hot" condition j) Concentrating, filtering Isopropanol to the desired volume and adding DM water to it.
k) Filtering the product from step (j)
1) Washing with DM water and then drying The decolourization of step (c) is carried out at temperature 45-55 0C, which is more preferably at 500C. The drying stage of step (d) is preferably carried out under vacuum. Suitably the product is dried at temperature 40-600C, which is more preferably at 500C. The preferable refluxing mixture of step e) is 40% acetonitrile in water. The cooled solution of step (f) is suitably stirred over a prolonged period, which is preferably approximately 8 hours.
The decolourization of step ( i) is carried out at temperature 50-700C, which is preferably approximately 600C.
The desired IPA volume of step (j) is preferably approximately 3 volumes with respect to the weight of the crude product of step d).
The drying stage of step (1) is preferably carried out under vacuum. Suitably the product is dried at temperature 40-600C, which is more preferably at 500C.
The details of the invention are given in the Example, which is provided for illustration only and therefore the Example should not be construed to limit the scope of the invention.
Example
The starting material (S)-4-(4-Aminobenzyl)-2-oxazolidinone is made in accordance with Example-as per Natco's granted patent IN 198915 titled 'Novel Process for the preparation of (S)-4-(4-Aminobenzyl)-2-oxazolidinone' granted on 17-02-2006. The corresponding PCT application has been published with publication no. WO/2004/063175. Example - 1
The preparation of (SV4-[(3-[2-(DimethγlaminokthyIl-lH-indol-5-γl1methvn-2- oxazolidinone (I):
Charge to the flask 300 ml of cone, hydrochloric acid, 3L of demineralised water and 250 gms of (S)-4-(4-arninobenzyl)-2-oxazolidinone. Cool the reactor contents to between 0-5 DEG C and add aqueous sodium nitrite solution (99 gms in 900ml water), maintaining the temperature below 5 DEG C. After stirring for about 30 minutes add the diazonium salt solution to a chilled aqueous solution of sodium sulphite (492 gms in 800 ml water) maintaining the temperature below 10 DEG C. After stirring for 15 minutes slowly heat the resulting mixture to about 55-60 DEG C, and then slowly add 50 ml of cone. hydrochloric acid. The solution is maintained at about 60 DEG C for about 18 hours. Dilute the reaction mixture with 5L of water and heat to about 90 DEG C. Under a nitrogen atmosphere slowly add 246 gms of 4,4-diethoxy-N, N-dimethylbutylamine and heat at reflux for about 3 hours. Cool, and adjust the mixture to about pH7 using sodium hydroxide solution. Extract with chloroform and then adjust the aqueous layer to about pHIO, again using sodium hydroxide solution. Extract the product using chloroform. Treat the combined chloroform extracts (containing the product) with decolorizing charcoal, and filter through filter aid. Distil off most of the solvent and chill the suspension to about 0 DEG C. Centrifuge the crude product, wash with chloroform and vacuum dry at 50 DEG C. (150 gms, pale yellow powder, 99.4% HPLC purity)
Example - 2
Purification of rSV4-f3-r2-('dimethylamino')ethyl1-lH-indol-5-yllmethvU-2- QxazohVdinone. :
The crude product of example- 1 is dissolved in a refluxing mixture of 1.5L of 40% acetonitrile in water, treated with decolourising charcoal and filtered hot through filter aid. The solution is slowly cooled to above 0 DEG C and stirred for 8 hours. The purified product is then filtered, washed with water and vacuum dried at 50 DEG C, the wet solid is dissolved in 3L of refluxing IPA, treated with decolourising charcoal and filtered hot through filter aid. The filtrate is concentrated to approximately 0.5L cooled to about 25 DEG C treated with 750 ml water and stirred for 2 hrs before filtering the product, washing with water and drying in vacuum at about 50 DEG C. (60 gms, white powder, 99.87% HPLC purity)
Advantages of the process of the present invention:
1. The isolation and purification process of zolmitriptan described here does not involve any 'solvated form' of zolmitriptan.
2. The process does not necessitate any 'desolvation step' and free of any rigorous monitoring control needed to ensure that 'desolvation' is complete.
3. Pure pharmaceutical grade of zolmitriptan with HPLC purity of more than 99.8% is obtained.

Claims

We Claim:
1. An improved process for the purification of zolmitriptan (I) which process comprises the steps of
Figure imgf000009_0001
(I)
a) Extracting the impurity with Chloroform by adjusting reaction mass pH to 7.0 at room temperature b) Extracting the Product with Chloroform by adjusting the reaction mass pH to 10.0 at room temperature c) Decolorizing suitably the chloroform layer using activated charcoal in hot condition. d) Isolating the zolmitriptan crude by distilling off the Chloroform layer, filtering and drying e) Dissolving the crude Zolmitriptan in refluxing mixture of aqueous acetonitrile f) Slowly cooling the solution to a temperature of about 00C. g) Filtering the product and washing with DM water h) Dissolving the product in refluxing Isopropanol i) Decolourizing the Isopropanol layer using decolourising charcoal in hot condition j) Concentrating, filtering Isopropanol to the desired volume and adding DM water to it. k) Filtering the product
I) Washing with DM water then drying
2. An improved process as claimed in claim 1 wherein the preferable refluxing mixture of step (e) is 40% acetonitrile in water.
3. Non-solvated highly pure (> 99.8%) zolmitriptan
4. A novel method of preparing Non-solvated highly pure (> 99.8%) zolmitriptan essentially as herein described with reference to examples 1 & 2.
PCT/IN2007/000267 2006-07-10 2007-06-29 An improved process for purification of zolmitriptan WO2008007390A2 (en)

Applications Claiming Priority (2)

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IN1203/CHE/2006 2006-07-10
IN1203CH2006 2006-07-10

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008018090A2 (en) * 2006-08-09 2008-02-14 Matrix Laboratories Ltd An improved process for the preparation of zolmitriptan
CN103275075A (en) * 2013-06-24 2013-09-04 成都天台山制药有限公司 Zolmitriptan and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1227095A2 (en) * 1995-08-07 2002-07-31 AstraZeneca AB A process for the purification of (S)-4-((3-(dimethylamino)ethyl)-1H-indol-5yl)-methyl)-2-oxazolidinone
US20050245585A1 (en) * 2004-04-22 2005-11-03 Islam Aminul Process for preparing optically pure zolmitriptan

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1227095A2 (en) * 1995-08-07 2002-07-31 AstraZeneca AB A process for the purification of (S)-4-((3-(dimethylamino)ethyl)-1H-indol-5yl)-methyl)-2-oxazolidinone
US20050245585A1 (en) * 2004-04-22 2005-11-03 Islam Aminul Process for preparing optically pure zolmitriptan

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008018090A2 (en) * 2006-08-09 2008-02-14 Matrix Laboratories Ltd An improved process for the preparation of zolmitriptan
WO2008018090A3 (en) * 2006-08-09 2009-09-24 Matrix Laboratories Ltd An improved process for the preparation of zolmitriptan
CN103275075A (en) * 2013-06-24 2013-09-04 成都天台山制药有限公司 Zolmitriptan and preparation method thereof
CN103275075B (en) * 2013-06-24 2015-01-07 成都天台山制药有限公司 Zolmitriptan and preparation method thereof

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WO2008007390B1 (en) 2008-04-17

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