WO2008018090A2 - Procédé de préparation amélioré de zolmitriptan - Google Patents

Procédé de préparation amélioré de zolmitriptan Download PDF

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Publication number
WO2008018090A2
WO2008018090A2 PCT/IN2007/000328 IN2007000328W WO2008018090A2 WO 2008018090 A2 WO2008018090 A2 WO 2008018090A2 IN 2007000328 W IN2007000328 W IN 2007000328W WO 2008018090 A2 WO2008018090 A2 WO 2008018090A2
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WO
WIPO (PCT)
Prior art keywords
process according
zolmitriptan
water
solvent
reduction
Prior art date
Application number
PCT/IN2007/000328
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English (en)
Other versions
WO2008018090A3 (fr
Inventor
Amit Rohatgi
Purna Chandra Ray
Vutukuru Naga Chandra Sekhar
Aviraboina Siva Prasad
Original Assignee
Matrix Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2008018090A2 publication Critical patent/WO2008018090A2/fr
Publication of WO2008018090A3 publication Critical patent/WO2008018090A3/fr

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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

  • This invention in general related to a process for producing Zolmitriptan. More particularly, the present invention provides a process for producing pure Zolmitriptan employing novel reaction conditions as well as without using column.
  • Zolmitriptan has the chemical name (S)-4-[[3-[2-(dimethylamino)ethyl]-lH-indol-5- yl]methyl]-2-oxazolidinone (I). Zolmitriptan is a selective 5HTl -receptor agonist.
  • 5HTl -receptor mediates vasoconstriction and thus modifies blood flow to the carotid vascular bed.
  • 5HTl-receptor agonists are beneficial in the treatment (including prophylaxis) of disease conditions wherein vasoconstriction in the carotid vascular bed is indicated, for example migraine, cluster headache and headache associated with vascular disorders, herein after referred to collectively as migraine.
  • Zolmitriptan has been developed for the acute treatment of migraine in the form of a 2.5 mg and 5 mg tablet intended to be taken up to maximum of 15 mg per day.
  • the resultant compound was converted to (4S)-4-[3-(2-dimethylaminoethyl)-lH-5-indolyl methyl]- l,3-oxazolan-2-one by standard N-alkylation methods.
  • the disadvantages lie in low overall yields and column chromatography as a part of process.
  • PCT application WO 2001/34561 discloses the preparation of intermediate compounds, for use in preparing Zolmitriptan.
  • the preparation involves a Fischer indole synthesis.
  • PCT application WO 2004/014901 discloses the process for preparing
  • Zolmitriptan in which the ⁇ -keto- ⁇ -valerolactone is used as starting material which is not a commonly used chemical for industrial purposes. Also, optical purity is not disclosed.
  • the disclosed embodiment of the present invention deals with a process for producing Zolmitriptan by employing cheap and easily available raw materials and reagents.
  • the present invention in its aspect is a new, improved, economical and industrially feasible method for preparing Zolmitriptan.
  • the present invention is provided an improved process for the preparation of Zolmitriptan as hereinbefore defined, which process comprises the steps of
  • process for the preparation of Zolmitriptan Step (a) includes the treatment of 4-nitrophenylalanine or its hydrate with a thionyl chloride to get methyl (S)-4-nitrophenylalaninate hydrochloride.
  • the reaction is carried out in the presence of the solvent e.g. methanol.
  • the reaction is conveniently carried out at room temperature to reflux temperature, preferably at reflux temperature.
  • the reduction step (b) is conveniently carried out in the presence of polar protic solvent such as water, methanol, ethanol, isopropyl alcohol, n-butanol and/or mixture thereof.
  • Step (b) is carried out by hydrogenation, preferably in the presence of sodium borohydride.
  • the reaction is carried out at normal atmospheric pressure at -15 0 C to 6O 0 C, preferably at -1O 0 C to 5O 0 C, more preferably 0°C-25°C.
  • the reaction mixture is filtered and the filtrate is concentrated under vacuum, followed by cooling to get precipitate.
  • the obtained precipitate is filtered and washed with the solvent to get desired compound i.e. (S)-2-amino3 ⁇ (4-niuOphenyl)propanol.
  • step (c) the above obtained compound i.e. (S) ⁇ 2- amino-3-(4-nitrophenyl)propanol is then treated with triphosgene in presence of base and a solvent to get (S)-4-(4-nitrobcnzyl)-l,3-oxazolidine-2-one.
  • the used base in this reaction is selected from the group consisting of but not limited to such as alkali metal carbonates such as sodium carbonate, potassium carbonate, alkali metal hydrogen carbonates such as sodium bicarbonate, potassium bicarbonate, alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, preferably sodium carbonate and potassium carbonate more preferably potassium carbonate.
  • the solvent used herein is selected from the group consisting of aliphatic and aromatic hydrocarbon such as toluene, benzene, xylene, hexane, heptane, pentane, cyclohcxane, cyclopcntane, cycloheptane; water and/or mixture thereof.
  • solvent used herein is toluene and toluene water mixture thereof.
  • the above said reaction is carried out at 0°C-35°C, preferably 1O 0 C- 35 0 C, more preferably 10°C-25°C.
  • the reduction step (d) of the present invention is conveniently carried out in the presence of solvent e.g. methanol, ethanol, isopropyl alcohol preferably methanol.
  • Step (d) is carried out by hydrogenation, preferably in the presence of a catalyst such as Raney Ni and Pd/C, preferably Raney Ni.
  • the reaction may be carried out under an atmosphere of hydrogen at a pressure of 2.0-8.0 Kg/m 2 , preferably 5.0-7.0 Kg/m 2 , more preferably 6.0 Kg/m 2 .
  • the reaction is carried out at 25 0 C to 4O 0 C, preferably al 3O 0 C.
  • reaction mixture is filtered and the filtrate is concentrated under vacuum, followed by addition of a solvent such as ethyl acetate, methanol, ethanol, isopropyl alcohol or mixture thereof, to the residue and heated at 40-60 0 C preferably at 50-55 0 C, followed by cooling to get precipitate.
  • a solvent such as ethyl acetate, methanol, ethanol, isopropyl alcohol or mixture thereof.
  • the obtained precipitate is filtered and washed with the solvent to get desired compound i.e. (S)-4-(4-aminobenzyl)-l ,3-oxazolidine-2-one.
  • the reduced compound from step (d) is then diazotized using aqueous sodium nitrite solution, preferably in the presence of concentrated hydrochloric acid, at a reduced temperature.
  • the salt formation is carried out at a reduced temperature e.g. 0- 5 0 C.
  • Hydrazine formation is then carried out on the diazonium salt solution by using stannous chloride.
  • the stannous chloride is suitably in the form of an aqueous solution.
  • the reduction is advantageously carried out at temperature below O 0 C during the addition and followed by increase in the temperature to room temperature. Water is added to the reaction mixture after the stirring at room temperature for 6-15 hrs, preferably 10-12 hrs.
  • reaction mixture is then cooled and pH of the reaction mixture is adjusted to 1.0-2.5, preferably 1.5-2.0, more preferably 1.8-2.0 with 75% alkali metal hydroxide preferably sodium hydroxide.
  • the reaction mixture is then heated to 80-100 0 C, preferably 90-95 0 C under nitrogen atmosphere followed by the addition of N,N-dimethylaminobutyraldehyde diethyl acetal.
  • the reaction mixture is then cooled and pH of the reaction mixture is adjusted to 6.0-8.0, preferably 6.9-7.0 using 75% alkali metal hydroxide such as sodium hydroxide.
  • the reaction mixture is the filtered to remove all inorganic salts such as tin oxide and/or other tin salts, if not then it creates the problem in getting the solid product as well as it carries forward to the final product as an impurity where it is very difficult to remove.
  • the filtrate is washed with an organic solvent such as toluene, hexane, dichloromethane or chloroform.
  • the filtrate is treated with activated carbon at 50-65 0 C preferably 55-6O 0 C and filtered.
  • the organic solvent is added to the reaction mixture and then pH is adjusted to 10.0-12.0 preferably 10.5-11.0 using 75% alkali metal hydroxide preferably sodium hydroxide.
  • the layers are separated and aqueous layer is extracted with ethyl acetate and combined both the organic layers.
  • the organic solvent solution is evaporated to dryness to get residue which is then dissolved in alcohol and/or water and stirred.
  • the reaction mixture is then concentrated to get the precipitate of crude Zolmitriptan.
  • the organic solvent used herein is selected from the group consisting of but nol limited to ethyl acetate, methyl acetate, n-butanol, dichloromelhane, chloroform and/or mixture thereof, whereas alcohol used herein is selected from the group consisting of but not limited to methanol and ethanol.
  • the obtained crude Zolmitriptan is then purified using water, isopropyl alcohol or mixture thereof as a solvent.
  • Ethyl acetate (1.331ts) was added to the filtrate and pH adjusted to 10.5 - 1 1.0 with 75% sodium hydroxide. Stirred for 30 min. and the layers were separated. Aqueous layer was again extracted with ethyl acetate (660 ml) and the combined organic extracts washed with water (340 ml). The ethyl acetate layer was concentrated under reduced pressure to recover ethyl acetate completely and added isopropyl alcohol (500 ml) to the residue. The reaction mixture was heated to 65 0 C and treated with activated carbon for 30 min. Filtered through hyflo and washed bed with isopropyl alcohol (200 ml).
  • the filtrate was concentrated under reduced pressure at 45-5O 0 C to recover -500 ml of isopropyl alcohol.
  • the remaining thick mass was slowly cooled to room temperature and stirred for 5 hrs.
  • the slurry obtained was filtered and the solids washed with chilled isopropyl alcohol (150 ml) to obtain crude Zolmitriptan.
  • Zolmitriptan (crude) (25 g) was slurred with D. M. water (100 ml) at room temperature for 4 hrs. The slurry was filtered and solid washed with cold D. M. water (25 ml). The wet material is dried to get pure Zolmitriptan, which is found to be Form A.
  • Zolmitriptan (crude) (7 g) was slurred with a solution of 20% V/V isopropyl alcohol and D. M. water mixture (10.5 ml) at room temperature for 4 hrs. The slurry was filtered and solid washed with cold 20% v/v isopropyl alcohol and D. M. water (3.5 ml). The wet ' material is dried to get pure Zolmitriptan, which is found to be Form A.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne un procédé permettant de produire du Zolmitriptan pur, le procédé étant mis en œuvre dans des conditions réactionnelles améliorées qui excluent l'utilisation d'une chromatographie sur colonne.
PCT/IN2007/000328 2006-08-09 2007-08-06 Procédé de préparation amélioré de zolmitriptan WO2008018090A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1422CH2006 2006-08-09
IN1422/CHE/2006 2006-08-09

Publications (2)

Publication Number Publication Date
WO2008018090A2 true WO2008018090A2 (fr) 2008-02-14
WO2008018090A3 WO2008018090A3 (fr) 2009-09-24

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PCT/IN2007/000328 WO2008018090A2 (fr) 2006-08-09 2007-08-06 Procédé de préparation amélioré de zolmitriptan

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009044211A1 (fr) * 2007-10-03 2009-04-09 Generics [Uk] Limited Procédé pour la préparation de zolmitriptan, ses sels et ses solvats
WO2013057739A3 (fr) * 2011-09-02 2013-06-20 Emcure Pharmaceuticals Limited Procédé de préparation amélioré de zolmitriptan
CN103275075A (zh) * 2013-06-24 2013-09-04 成都天台山制药有限公司 佐米曲普坦及其制备方法
CN113620897A (zh) * 2021-09-06 2021-11-09 南京杰运医药科技有限公司 一种噁唑烷酮类化合物的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466699A (en) * 1990-06-07 1995-11-14 Burroughs Wellcome Co. Indolyl compounds for treating migraine
WO1997006162A1 (fr) * 1995-08-07 1997-02-20 Zeneca Limited Synthese en un seul creuset de derives de 2-oxazolidinone
WO2006055964A2 (fr) * 2004-11-19 2006-05-26 Teva Pharmaceutical Industries Ltd. Formes cristallines de zolmitriptan
WO2008007390A2 (fr) * 2006-07-10 2008-01-17 Natco Pharma Limited Procédé amélioré de purification de zolmitriptan

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466699A (en) * 1990-06-07 1995-11-14 Burroughs Wellcome Co. Indolyl compounds for treating migraine
WO1997006162A1 (fr) * 1995-08-07 1997-02-20 Zeneca Limited Synthese en un seul creuset de derives de 2-oxazolidinone
WO2006055964A2 (fr) * 2004-11-19 2006-05-26 Teva Pharmaceutical Industries Ltd. Formes cristallines de zolmitriptan
WO2008007390A2 (fr) * 2006-07-10 2008-01-17 Natco Pharma Limited Procédé amélioré de purification de zolmitriptan

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AMMAZZALORSO, A. ET AL.: 'Synthesis and antibacterial evaluation of oxazolidin-2-ones structurally related to linezolid' IL FARMACO vol. 59, 2004, pages 685 - 690 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009044211A1 (fr) * 2007-10-03 2009-04-09 Generics [Uk] Limited Procédé pour la préparation de zolmitriptan, ses sels et ses solvats
CN101883766A (zh) * 2007-10-03 2010-11-10 基因里克斯(英国)有限公司 制备佐米曲普坦、其盐和溶剂化物的方法
WO2013057739A3 (fr) * 2011-09-02 2013-06-20 Emcure Pharmaceuticals Limited Procédé de préparation amélioré de zolmitriptan
US9006453B2 (en) 2011-09-02 2015-04-14 Emcure Pharmaceuticals Limited Process for preparation of zolmitriptan
CN103275075A (zh) * 2013-06-24 2013-09-04 成都天台山制药有限公司 佐米曲普坦及其制备方法
CN103275075B (zh) * 2013-06-24 2015-01-07 成都天台山制药有限公司 佐米曲普坦及其制备方法
CN113620897A (zh) * 2021-09-06 2021-11-09 南京杰运医药科技有限公司 一种噁唑烷酮类化合物的制备方法

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Publication number Publication date
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