WO2011033532A1 - Procédé de préparation d'hydrochlorure d'olopatadine - Google Patents

Procédé de préparation d'hydrochlorure d'olopatadine Download PDF

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Publication number
WO2011033532A1
WO2011033532A1 PCT/IN2010/000627 IN2010000627W WO2011033532A1 WO 2011033532 A1 WO2011033532 A1 WO 2011033532A1 IN 2010000627 W IN2010000627 W IN 2010000627W WO 2011033532 A1 WO2011033532 A1 WO 2011033532A1
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WIPO (PCT)
Prior art keywords
formula
olopatadine
reaction
compound
oxepin
Prior art date
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PCT/IN2010/000627
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English (en)
Inventor
Ranjeet Nair
P. V. Ramesan
Sandip Kacharu Deshmukh
Somnath Khabale
Aditi Milind Panandikar
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Indoco Remedies Limited
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Publication of WO2011033532A1 publication Critical patent/WO2011033532A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed

Definitions

  • the present invention relates to an improved process for preparation of 11 - (Z) - [3 - (Dimethylamino) propylidene] - 6, 11 - dihydrodibenz [b, e] oxepin -2 - yl - acetic acid and its pharmaceutical acceptable salts.
  • Olopatadine hydrochloride was disclosed as dibenz [b, e] oxepin derivative in US Patent No 5,116,863 (herein after '863') 'in 1992, assigned to Kyowa Hakko Kogyo Co., Ltd.
  • the patent discloses the preparation of Olopatadine through Wittig reaction by reacting 11 - oxo - 6, 11 - Dihydrodibenz [b, e] oxepin - 2 - acetic acid (Formula - II) with 3 - dimethylaminopropyl triphenyl phosphonium bromide hydro bromide (Formula - III) in presence of base n - butyl lithium and solvent tetrahydrofuran. The crude compound is passed through column chromatography to isolate pure olopatadine. The reaction sequence is as shown in scheme - 1,
  • the preparation of olopatadine involves excess use of base and the Wittig reagent.
  • the isolation of pure cis olopatadine employs the use of column chromatography. The final yield of the compound is low.
  • J. Med. Chem. 35, 2074, (1992) discloses the preparation of olopatadine HC1 as per the above scheme, wherein the separation of the Z / E diastereomer is disclosed. As per the disclosure, the diastereo selectivity of the dehydration step is poor and leads to the formation of predominantly undesired ⁇ ' isomer.
  • PCT application WO2006129781 discloses the preparation of olopatadine hydrochloride wherein Methyl 2-(4-(2-chlorobenzyloxy)phenyl)acetate is iodinated using iodine and silver sulfate to give methyl 2-(4-(2-chlorobenzyloxy)-3-iodophenyl)acetate; which is coupled with but-3-yn-l-ol in presence of Copper iodide and palladium catalyst results methyl 2-(4-(2-chlorobenzyloxy)-3-(4-hydroxybut-l-ynyl)phenyl)acetate; which on palladium catalyzed cyclization yields methyl [(l lZ)-l l-(3-hydroxypropylidene)-6,l l- dihydrodibenz[b,e]oxepin-2-yl]acetate; which is converted to Olopatadine via mesylate salt followed by
  • the drawback in the process is, longer time for Grignard reaction and lower yield of desired cis - olopatadine hydrochloride.
  • WO2007119120 describes the preparation of olopatadine hydrochloride by employing Grignard reaction, wherein 1 1 - oxo - 6, 11 - Dihydrodibenz [b, e] oxepin - 2 - acetic acid is reacted with 3 - dimethylamino propyl magnesium chloride at 25 - 30°C for 15 hours.
  • the work up is carried out by decomposition with ammonium chloride followed by treatment with hydrochloric acid to isolate olopatadine hydrochloride.
  • the drawback in the process is longer time required during Grignard reaction and formation of olopatadine hydrochloride.
  • the patent application JP2009114166 discloses the preparation of Olopatadine hydrochloride involving Grignard reaction, wherein tert-butyl ester of l l-oxo-6,11- dihydrodibenz[b,e]oxepin-2-yl acetic acid (Formula - VIII) is reacted with 3 - dimethylaminopropylmagnesium chloride yields tert-butyl ester of 11 -hydroxy- 11 -(3- dimethylaminopropyl)-6,l l-dihydrodibenz[b,e]oxepin-2-yl acetic acid (Formula - IX), which is decomposed by heating in presence of solvent and acid to give racemic olopatadine of Formula - X.
  • the compound of Formula - X obtained is isomerized by heating in presence of solvent and hydrochloric acid, with simultaneous removal of water yields required isomer Cis - Olopatadine hydrochloride of Formula - I.
  • the reaction sequence is as shown in scheme - IV.
  • the compound of Formula XI is further isomerised to Z-isomer from E-isomer in an organic solvent and hydrochloric acid where the reaction proceeds with deesterification reaction of compound of Formula XI simultaneously. After isomerization cools the reaction solution to deposit crystals, and filtered the precipitated crystals, and compound of Formula - 1 is isolated as acid addition salt corresponding to acid used.
  • the reaction sequence is as shown in the following scheme - V.
  • Japanese application JP2007031363 describes the preparation of olopatadine hydrochloride wherein 2 -(Bromomethyl) benzonitrile is reacted with methyl 2-(4- hydroxyphenyl)acetate in presence of potassium carbonate followed by hydrolysis of the ester with sodium hydroxide to get methyl 2-(4-hydroxyphenyl)acetate; which is cyclized with acetic anhydride results in 11 - oxo - 6, 11 - Dihydrodibenz [b, e] oxepin - 2 - acetic acid; Wittig reaction of the acid formed with (3-dimethylaminopropyl) triphenyl phosphonium bromide hydro bromide in presence of n-Butyl lithium gives Olopatadine; which is treated with hydrochloric acid and water to give Olopatadine hydrochloride.
  • the major drawbacks of the prior art processes include:
  • the present invention tackles the problem of providing process for the preparation of (Z)
  • the objective of the present invention is to prepare (Z) - 1 1 - [(3 - Dimethylamino) propylidene] - 6, 11 - dihydrodibenz [b,e] oxepin - 2 - acetic acid of higher purity.
  • Another objective of the present invention is to prepare (Z) - 11 - [(3 - Dimethylamino) propylidene] - 6, 11 - dihydrodibenz [b, e] oxepin - 2 - acetic acid by an industrially useful and cost effective process.
  • Yet another objective of the present invention is to prepare the pharmaceutically acceptable salt of (Z) - 1 1 - [(3 - Dimethylamino) propylidene] - 6, 11 - dihydrodibenz [b, e] oxepin - 2 - acetic acid with good yield.
  • the present invention provides a process for the preparation of compound 1 1 - (Z) - [3 - (Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b, e] oxepin -2— yl— acetic acid of Formula I and its pharmaceutically acceptable salt
  • R 1 & R 2 independently represent H, or C ⁇ - C 4 alkyl group
  • X is Chlorine, bromine or iodine.
  • the present invention describes an improved process for the preparation of 11 - (Z) - [3 - (Dimethylamino) propylidene] - 6, 1 1 - dihydrodibenz [b, e] oxepin -2 - yl - acetic acid of Formula I and its pharmaceutically acceptable salt.
  • the compound 1 1 - (Z) - [3 - (Dimethylamino) propylidene] - 6, 11 - dihydrodibenz [b, e] oxepin - 2 - acetic acid of Formula - 1 is prepared by carrying out Grignard reaction of the carboxamido compound of 11 - oxo - 6, 11 - Dihydrodibenz [b, e] oxepin - 2 - acetic acid of Formula - XII
  • R 1 & R 2 independently represent H, or Cj - C 4 alkyl group; with 3 - Dimethylaminopropyl magnessium halide of Formula - XIII,
  • X is chlorine, bromine or iodine
  • the Grignard reaction is carried out in presence of solvent at temperature ranging from -10°C to 30°C.
  • the solvent used for Grignard reaction is selected from toluene, tetrahydrofuran and hexane, wherein the most preferred solvent for the Grignard reaction is tetrahydrofuran.
  • the temperature range for Grignard reaction is maintained between - 10°C to 30°C; wherein the preferred temperature range is -5°C to 10°C and the most preferred temperature range is from 0°C to 5°C.
  • the compound of Formula XII used for the Grignard reaction is selected from where R 1 and R 2 independently represent hydrogen, methyl, ethyl, n— propyl, iso-propyl, n-butyl and iso-butyl group.
  • the preferred compound used for Grignard reaction is where both R 1 and R 2 are methyl group viz. N, N-dimethyl-2-(l l-oxo-6, 1 1-dihydrodibenz [b, e] oxepin-2- yl) acetamide.
  • the preferred Grignard reagent of Formula XIII used for the Grignard reaction is 3 - dimethylaminopropyl magnesium chloride.
  • the compound N, N-dimethyl-2-(l l-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-yl) acetamide is charged in flask containing solvent tetrahydrofuran. Under nitrogen atmosphere the mixture is cooled to -5 - 10°C and the compound 3 - dimethylaminopropyl magnessium chloride is charged maintaining the temperature between -5 to 5°C. After complete addition of the reagent the reaction mass is maintained at 0 - 5°C under stirring for 1 to 4 hours. The preferred time of Grignard reaction is between 1 to 2 hours.
  • reaction mass After the completion of reaction the reaction mass is decomposed by adding water and followed by concentrated hydrochloric acid or with dilute 1:1 hydrochloric acid maintaining the temperature at 0 - 5°C. Raised the temperature of the reaction solution to 25 - 35 °C and maintained the reaction solution under stirring at 25 - 35°C for 1 to 3 hours. Adjusted the pH of the reaction solution to 9
  • the suitable base is selected from ammonium hydroxide, sodium hydroxide and potassium hydroxide; wherein the preferred base used for pH adjustment is ammonium hydroxide.
  • the suitable base is selected from ammonium hydroxide, sodium hydroxide and potassium hydroxide; wherein the preferred base used for pH adjustment is ammonium hydroxide.
  • the preferred temperature for hydrolysis of amide functional group is 90 - 95°C.
  • the metal hydroxide used for pH adjustment is selected from sodium hydroxide, potassium hydroxide and calcium hydroxide.
  • the preferred metal hydroxide used is potassium hydroxide.
  • the aqueous solution is extracted several times with chlorinated solvent to isolate mixture of E & Z isomer of 11 - [3 - (Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b, e] oxepin -2 - yl - acetic acid of Formula - X.
  • - X is selected from dichloromethane, dichloroethane, trichloroethane, tetrachloroethane and chlorobenzene.
  • the preferred chlorinated solvent used for extraction is dichloromethane and chlorobenzene; wherein the most preferred solvent used is dichloromethane.
  • the combined extract is concentrated under reduced pressure to get the compound (E,Z) - 11 - [3 - (Dimethylamino) propylidene] - 6, 11 - dihydrodibenz [b, e] oxepin -2 - yl - acetic acid of Formula - X having HPLC purity of E: Z ratio 65:35.
  • the reaction sequence can be represented as below in Scheme - VI.
  • N, N-dimethyl-2-(l l-oxo-6, 11-dihydrodibenzo [b,e] oxepin-2-yl) acetamide of Formula XII can be prepared as per the known methods for the preparation of carboxamide from the corresponding carboxylic acid.
  • the compound N, N-dimethyl-2-(l l-oxo-6, 11-dihydrodibenzo [b, e] oxepin-2- l) acetamide of Formula XII is prepared from 1 l-oxo-6, 1 1-dihydrodibenzo [b, e] oxepin-2-acetic acid of Formula - II, where the compound of Formula - II is reacted with thionyl chloride in dichloromethane to get acid chloride which on reaction with dimethyl amine gas results in the formation of N, N-dimethyl-2-(l l-oxo-6, 11-dihydrodibenzo [b,e] oxepin-2-yl) acetamide of Formula XII which is used for the present invention.
  • the compound olopatadine having mixture of E & Z isomer is taken in solvent selected from chlorobenzene and n - butanol for the preparation of pharmaceutically acceptable salt of Formula - I.
  • solvent selected from chlorobenzene and n - butanol for the preparation of pharmaceutically acceptable salt of Formula - I.
  • the preferred solvent used for the preparation of pharmaceutically acceptable salt of Formula - I is chlorobenzene.
  • the isolated racemic compound is taken in chlorobenzene and heated to raise the temperature to 60 - 90°C; wherein the preferred temperature for the preparation of salt is 80 - 85°C.
  • the temperature started passing dry hydrochloric acid gas for 5 - 8 hoiirs maintaining the temperature at 80 - 85°C to complete the salt formation and cooled the reaction mass to 20 - 30°C.
  • the solid crude olopatadine hydrochloride salt thus obtained is filtered, washed with cooled acetone and dried.
  • hydrochloride salt of compound of Formula - 1 at temperature range of 60 - 90°C is done to isolate the required cis isomer of the compound in almost pure form from the mixture of cis and trans compound of Formula - X.
  • the hydrochloride of desired cis isomer formed separates out as solid from the reaction solution and the Trans isomer remains soluble in the solvent.
  • the dried crude olopatadine hydrochloride is purified in solvent selected from acetone, isopropanol, tetrahydrofuran and water or mixture thereof to isolate pure olopatadine hydrochloride having HPLC purity of more than 99.00% of Cis - olopatadine hydrochloride and less than 0.1% to nil of Trans isomer.
  • the preferred solvent for purification is mixture of acetone and water.
  • Step I Preparation of N, N-dimethyl-2-(l l-oxo-6, 11-dihydrodibenz [b, e] oxepin-2- yl) acetamide.
  • Step - ⁇ Preparation of 11 - (Z) - [3-(dimethylamino) propylidine]-6, 11-dihydro - dibenz [b, e] oxepin-2-acetic acid (Olopatadine).
  • Step III Preparation of 11 - (Z) - [3 - (Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b, e] oxepin -2 - yl - acetic acid hydrochloride [Cis - Olopatadine hydrochloride].
  • Step - IV Purification of crude 11 - (Z) - [3 - (Dimethylamino) propylidene] - 6, 11

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrane Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'un composé d'acide 11-(Z)-[3-diméthylamino)propylidène]-6,11-dihydrodibenz[b,e]oxépin-2-yl-acétique (olopatadine) et de ses sels pharmaceutiquement acceptables. Le procédé consiste à mettre en réaction un composé de formule (XII) dans laquelle R1 et R2 représentent indépendamment H ou groupe alkyle C1-C4 avec un halogénure de 3-diméthylaminopropyl magnésium de formule (XIII) dans laquelle X est chlorure, brome ou iode.
PCT/IN2010/000627 2009-09-17 2010-09-16 Procédé de préparation d'hydrochlorure d'olopatadine WO2011033532A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014147647A1 (fr) 2013-03-19 2014-09-25 Council Of Scientific & Industrial Research Procédé de synthèse d'olopatadine

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0235796A2 (fr) * 1986-03-03 1987-09-09 Kyowa Hakko Kogyo Co., Ltd. Dérivés de dibenzo[b,e]oxépine et agent anti-allergique et anti-inflammatoire
WO2006129781A1 (fr) 2005-06-02 2006-12-07 Kyowa Hakko Kogyo Co., Ltd. Procede de production d'un derive de la dibenzoxepine
JP2007031363A (ja) 2005-07-27 2007-02-08 Ohara Yakuhin Kogyo Kk ジベンズ［ｂ，ｅ］オキセピン誘導体の製造方法及びその中間体
WO2007105234A2 (fr) 2006-03-14 2007-09-20 Usv Limited Procédé de préparation d'isomères de chlorhydrate d'acide 11-[3-(diméthylamino)propylidène]-6, 11-dihydrodibenz [b, e] oxépin-2-acétique et leurs polymorphes
WO2007119120A2 (fr) 2005-12-22 2007-10-25 Medichem, S.A. Formes polymorphes cristallines de chlorhydrate d'olopatadine et leurs procédés de préparation
WO2009044838A1 (fr) 2007-10-05 2009-04-09 Sumitomo Chemical Company, Limited Procédé de production de composé dibenzoxépine
JP2009114166A (ja) 2007-02-16 2009-05-28 Sumitomo Chemical Co Ltd ジベンゾオキセピン化合物の製造方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0235796A2 (fr) * 1986-03-03 1987-09-09 Kyowa Hakko Kogyo Co., Ltd. Dérivés de dibenzo[b,e]oxépine et agent anti-allergique et anti-inflammatoire
US5116863A (en) 1986-03-03 1992-05-26 Kyowa Hakko Kogyo Co., Ltd. Dibenz[b,e]oxepin derivative and pharmaceutical compositions thereof
WO2006129781A1 (fr) 2005-06-02 2006-12-07 Kyowa Hakko Kogyo Co., Ltd. Procede de production d'un derive de la dibenzoxepine
JP2007031363A (ja) 2005-07-27 2007-02-08 Ohara Yakuhin Kogyo Kk ジベンズ［ｂ，ｅ］オキセピン誘導体の製造方法及びその中間体
WO2007119120A2 (fr) 2005-12-22 2007-10-25 Medichem, S.A. Formes polymorphes cristallines de chlorhydrate d'olopatadine et leurs procédés de préparation
WO2007105234A2 (fr) 2006-03-14 2007-09-20 Usv Limited Procédé de préparation d'isomères de chlorhydrate d'acide 11-[3-(diméthylamino)propylidène]-6, 11-dihydrodibenz [b, e] oxépin-2-acétique et leurs polymorphes
JP2009114166A (ja) 2007-02-16 2009-05-28 Sumitomo Chemical Co Ltd ジベンゾオキセピン化合物の製造方法
WO2009044838A1 (fr) 2007-10-05 2009-04-09 Sumitomo Chemical Company, Limited Procédé de production de composé dibenzoxépine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. MED. CHEM., vol. 35, 1992, pages 2074
OHSHIMA E ET AL: "SYNTHESIS AND ANTIALLERGIC ACTIVITY OF 11-(AMINOALKYLIDENE)-6,11-DIHY DRODIBENZÚB,E 3/4 OXEPIN DERIVATIVES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 35, no. 11, 1 May 1992 (1992-05-01), pages 2074 - 2084, XP000615220, ISSN: 0022-2623, DOI: DOI:10.1021/JM00089A020 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014147647A1 (fr) 2013-03-19 2014-09-25 Council Of Scientific & Industrial Research Procédé de synthèse d'olopatadine
US9562030B2 (en) 2013-03-19 2017-02-07 Council Of Scientific And Industrial Research Process for the synthesis of olopatadine

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