WO2009125430A2 - Procédé perfectionné pour la fabrication de darifénacine - Google Patents

Procédé perfectionné pour la fabrication de darifénacine Download PDF

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Publication number
WO2009125430A2
WO2009125430A2 PCT/IN2009/000160 IN2009000160W WO2009125430A2 WO 2009125430 A2 WO2009125430 A2 WO 2009125430A2 IN 2009000160 W IN2009000160 W IN 2009000160W WO 2009125430 A2 WO2009125430 A2 WO 2009125430A2
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WO
WIPO (PCT)
Prior art keywords
pyrrolidine
diphenylmethyl
darifenacin
give
tosyl
Prior art date
Application number
PCT/IN2009/000160
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English (en)
Other versions
WO2009125430A8 (fr
WO2009125430A3 (fr
Inventor
Om Dutt Tyagi
Purna Chandra Ray
Yogendhra Kumar Chauhan
K. Babu Rao
N. Mahhander Reddy
D. Siva Prasad Reddy
Original Assignee
Matrix Laboratoires Limited
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 Laboratoires Limited filed Critical Matrix Laboratoires Limited
Publication of WO2009125430A2 publication Critical patent/WO2009125430A2/fr
Publication of WO2009125430A8 publication Critical patent/WO2009125430A8/fr
Publication of WO2009125430A3 publication Critical patent/WO2009125430A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention provides an improved process for producing darifenacin and its pharmaceutical acceptable salts thereof.
  • Darifenacin is used to treat urinary incontinence. Darifenacin works by blocking M 3 muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions. It thereby decreases the urgency to urinate. Darifenacin is administered as the hydrobromide salt and is chemically known as
  • the compound of formula (Via) is reacted with 5-(2-bromoethyl)-2,3-dihydrobenzofuran in potassium carbonate and crystallized using diisopropyl ether to give darifenacin.
  • Darifenacin so obtained is further converted to pharmaceutically acceptable salts by conventional methods.
  • the tosylation and decarboxylation reaction is carried out in separate steps, thereby requiring extra steps, time and decrease in yield.
  • preparation of 1- tosyl-3-(S)-(-)-tosyloxypyrrolidine is carried out by using concentrated DEAD which remains undecomposed in the reaction mixture after completion of the condensation reaction thereby resulting in explosive and toxic problems during distillation of the reaction mixture to remove the solvent.
  • condensation of 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l- tosylpyrrolidine with diphenyl acetonitrile is carried out in presence of a strong base such as sodium hydride that requires more safety precautions during commercial production.
  • the solvent medium is selected from the group consisting of a C 6-9 aromatic hydrocarbon, a polar organic solvent, water and mixtures thereof, followed by addition of hydrobromic acid to obtain darifenacin hydrobromide.
  • the processes disclosed in the prior arts require cumbersome steps for the preparation and purification of darifenacin, thereby making the process time consuming and uneconomical. Further the process steps involve use of solvents that are difficult to handle during commercial production.
  • a process for producing darifenacin and its pharmaceutically acceptable salts comprising the steps of decorboxylating (2S,4R)-4-hydroxy-2- pyrrolidinecarboxylic acid followed by in-situ tosylation to give l-tosyl-3-(R)- hydroxypyrrolidine, tosylating l-tosyl-3-(R)-hydroxypyrrolidine to obtain l-tosyl-3-(S) ⁇
  • a process for producing darifenacin wherein the step of tosylating l-tosyl-3-(R)- hydroxypyrrolidine to obtain l-tosyl-3-(S)-(-)-tosyloxy pyrrolidine employs a tosylating agent in presence of dilute condensing agent, preferably diethylazodicarboxylate (DEAD), wherein the tosylating agent is selected from p-tolylsulfonyl chloride and methyl-p-tolylsulfonate.
  • DEAD diethylazodicarboxylate
  • a process for producing darifenacin wherein the step of reacting l-tosyl-3-(S)-(-)-tosyloxy pyrrolidine with diphenyl acetonitrile to obtain 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl) ⁇ 1-tosylpyrrolidine employs a base in presence of a solvent, wherein the base is selected from alkali metal oxide, alkali metal hydroxide, alkaline earth metal oxide, alkaline earth metal hydroxide and the solvent is selected from in polar protic or aprotic solvent.
  • a process for producing darifenacin wherein the step of condensing 3-(S)-(+)-(l- carbamoyl-l,l-diphenylmethyl) pyrrolidine.L-(+)-tartrate with 5-(2- bromoethyl)benzo[2,3-b]furan employs a base in presence of a solvent to obtain darifenacin, wherein the base is selected from alkali metal oxide, alkali metal hydroxide, alkaline earth metal oxide, alkaline earth metal hydroxide and the solvent is selected from polar protic or aprotic solvent.
  • Figure 1 is the X-ray powder diffraction pattern of darifenacin hydrobromide.
  • the present invention relates to an improved process for the preparation of darifenacin wherein decarboxylation of (2S,4R)-4-hydroxy-2-pyrrolidine carboxylic acid of formula-I, followed by in-situ tosylation to give l-tosyl-3-(R)-(-)-hydroxypyrrolidine of formula-II.
  • the present invention relates to the improved process for the preparation of darifenacin and its pharmaceutically acceptable addition salts which comprising the steps of: a) decorboxylating (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid of formula (I) followed by in-situ tosylation to give l-tosyl-3-(R)-hydroxypyrrolidine of formula (H), b) tosylating formula (II) with tosylating agent in presence of dilute condensing reagent to give l-tosyl-3-(S)-(-)-tosyloxy pyrrolidine of formula (III), c) reacting formula (III) with diphenyl acetonitrile in presence of alkali, alkaline earth metal hydroxides or oxides to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l- tosylpyrrolidine of formula (IV), d) de-protecting 3-(
  • (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid of formula-I undergoes decarboxylation in the presence of 2-cyclohexene-l-one in cyclohexanol followed by in-situ tosylation with /7-toluene sulphonyl chloride then crystallization from alcohol to give l-tosyl-3-(R)-hydroxypyrrolidine of formula-II.
  • the alcohol solvent is selected from methanol, ethanol, isopropyl alcohol, preferred alcohol is isopropyl alcohol.
  • decorboxylation and tosylation reaction is carried out in single step.
  • l-tosyl-3-(R)-hydroxypyrrolidine of formula- II is subjected to tosylation reaction with methyl-p-toluene sulphonate in diluted diethylazodicarboxylate (DEAD) in halogenated solvent.
  • the halogenated solvent is selected from dichloromethane, dichloroethane, chloroform and preferred halogenated solvent is dichloromethane.
  • reaction mass is diluted with water to quench unreacted DEAD and further subjected to distillation.
  • reaction mass is as such taken for distillation.
  • DEAD is thermally unstable at higher temperature, hence it leads to safety hazard.
  • Base is selected from alkali, alkaline earth metal hydroxides or oxides such as sodium hydroxides, potassium hydroxide, magnesium oxide or calcium oxide. Preferred base is potassium hydroxide.
  • Condensation reaction is carried out in polar protic or aprotic solvent selected from methanol, ethanol, isopropyl alcohol, dimethylformamide, dimethylsulfoxide, acetonitrile or tetrahydrofuran.
  • polar protic or aprotic solvent selected from methanol, ethanol, isopropyl alcohol, dimethylformamide, dimethylsulfoxide, acetonitrile or tetrahydrofuran.
  • the preferred organic solvent is tetrahydrofuran.
  • condensation reaction is carried out in presence of alkali, alkaline earth metal hydroxides or oxides in tetrahydrofuran.
  • condensation reaction is carried out in the presence of strong base such as sodium hydride, handling sodium hydride at commercial level is more difficult as compared to potassium hydroxide.
  • the compound of formula IV is de-protected in presence of phenol in acidic medium, preferably using hydrobromic acid to give 3- (S)-(+)-(l-cyano-l,l-diphenylmethyl) pyrrolidine (formula V).
  • Compound of formula V is hydrolyzed using sulphuric acid in dichloromethane followed by salt formation to obtain 3 -(S)-(+)-( 1 -carbamoyl- 1 , 1 -diphenylmethyl)pyrrolidine.L-(+)-tartrate (Formula VI);
  • 3-(S)-(+)-(l-carbamoyl-l,l- diphenylmethyl)pyrrolidine L-(+)-tartrate or base of formula (VI) is reacted with 5-(2- bromoethyl)benzo[2,3-b]furan in presence of base and polar protic or aprotic solvent to obtain darifenacin.
  • Base is selected from alkali, alkaline earth metal hydroxides or oxides such as sodium hydroxides, potassium hydroxide, magnesium oxide or calcium oxide. Preferred base is potassium hydroxide.
  • Condensation reaction is carried out in polar protic or aprotic solvent selected from methanol, ethanol, isopropyl alcohol, dimethylformamide, dimethylsulfoxide, acetonitrile or tetrahydrofuran.
  • polar protic or aprotic solvent selected from methanol, ethanol, isopropyl alcohol, dimethylformamide, dimethylsulfoxide, acetonitrile or tetrahydrofuran.
  • the preferred organic solvent is acetonitrile.
  • condensation reaction is carried out in the presence of alkali, alkaline earth metal hydroxides or oxides in acetonitrile and is completed in less maintenance time as compared to prior art process.
  • formation of impurities is less.
  • this process requires fewer purification steps at final stage.
  • the above darifenacin base is dissolved in a solvent selected from methanol, ethanol, isopropyl alcohol, and acetone and further treated with pharmaceutically acceptable acids, preferably hydrochloric acid or hydrobromic acid to give corresponding darifenacin acid addition salts.
  • darifenacin base is dissolved in acetone and treated with hydrobromic acid to give crystalline darifenacin hydrobromide.
  • crystallization is carried out in alcohol or ketone solvent to give crystalline darifenacin hydrobromide.
  • Darifenacin hydrombromide is characterized by powder X-Ray Diffraction peaks at 8.99 ⁇ 0.2, 11.42 ⁇ 0.2, 16.97 ⁇ 0.2, 18.17 ⁇ 0.2, 18.74 ⁇ 0.2, 19.48 ⁇ 0.2, 20.26 ⁇ 0.2, 22.04 ⁇ 0.2, 27.26 ⁇ 0.2, 27.54 ⁇ 0.2, 28.04 ⁇ 0.2, 28.81 ⁇ 0.2, 30.22 ⁇ 0.2 ⁇ as shown in Fig-I. .
  • Methyl-j9-toluenesulfonate (56 g) was added to the slurry of dichloromethane (250 ml), l-tosyl-3-(R)-hydroxypyrrolidine (50 g), and triphenylphosphine (77.5 g) under nitrogen gas at 0-5 ° C.
  • the reaction mass was cooled to -20 to -25° C and a solution of diethylazodicarboxylate (69 g) and dichloromethane (400 ml) was added to the reaction mass. The temperature was maintained for 1-2 hours followed by heating to 40-50° C.
  • reaction mass was washed with 10% sodium carbonate solution followed by washing with DM Water to quench excess diethylazodicarboxylate.
  • reaction mass was then extracted with dichloromethane and the solvent distilled off under vacuum followed by crystallization from «-propanol to give l-tosyl-3-(S)-(-)-tosyloxypyrrolidine.
  • Example-4 Preparation of 3 -(S)-(+)-(l-cyano- 1,1 -diphenylmethyl) pyrrolidine HBr A mixture containing 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l-tosylpyrrolidine
  • reaction mass was basified with sodium hydroxide solution in water and toluene, the layers seperated and the reaction mass extracted from aqueous layer. Reaction mass was filtered after subjecting to carbon treatment. L-(+)-Tartaric acid solution was added to the reaction mass at 50-60° C and the reaction mass cooled and filtered to give 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine L-(+)-tartrate.
  • Darifenacin hydrobromide 50 g was dissolved in methanol 300 ml, treated with carbon and filtered. Methanol was distilled off from the clear filtrate and ethanol (400 ml) was added and the reaction mass was heated to reflux. The resulting reaction mass was cooled to 25-30° C and the separated solid was filtered to give darifenacin hydrobromide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention porte sur un procédé perfectionné pour la fabrication de darifénacine, le procédé comprenant la décarboxylation de l'acide (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylique suivie par une tosylation in situ pour donner de la 1-tosyl-3-(R)-(-)-hydroxypyrrolidine, la tosylation de la 1-tosyl-3-(R)-(-)-hydroxypyrrolidine avec du p-toluènesulfonate de méthyle pour donner de la 1-tosyl-3-(S)-(-)-tosyloxypyrrolidine, la réaction de la 1-tosyl-3-(S)-(-)-tosyloxypyrrolidine avec du diphénylacétonitrile en présence d'une base pour donner de la 3-(S)-(+)-(1-cyano-1,1-diphénylméthyl)-1-tosylpyrrolidine et la déprotection de la 3-(S)-(+)-(1-cyano-1,1-diphénylméthyl)-1-tosylpyrrolidine en présence de phénol dans un milieu acide pour donner de la 3-(S)-(+)-(1-cyano-1,1-diphénylméthyl)pyrrolidine, l'hydrolyse de la 3-(S)-(+)-(1-cyano-1,1-diphénylméthyl)pyrrolidine suivie par la formation d'un sel pour obtenir du L-(+)-tartrate de 3-(S)-(+)-(1-carbamoyl-1,1-diphénylméthyl)pyrrolidine, la condensation du L(+)-tartrate de 3-(S)-(+)-(1-carbamoyl-1,1-diphénylméthyl)pyrrolidine avec du 5-(2-bromoéthyl)-2,3-dihydrobenzofurane à l'aide d'une base dans un solvant pour donner de la darifénacine.
PCT/IN2009/000160 2008-03-17 2009-03-09 Procédé perfectionné pour la fabrication de darifénacine WO2009125430A2 (fr)

Applications Claiming Priority (2)

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IN662CH2008 2008-03-17
IN662/CHE/2008 2008-03-17

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WO2009125430A2 true WO2009125430A2 (fr) 2009-10-15
WO2009125430A8 WO2009125430A8 (fr) 2010-01-21
WO2009125430A3 WO2009125430A3 (fr) 2010-04-22

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5096890A (en) * 1989-03-17 1992-03-17 Pfizer Inc. Pyrrolidine derivatives
WO2008029257A2 (fr) * 2006-09-07 2008-03-13 Medichem, S.A. Procédé amélioré pour préparer des composés de pyrrolidine 1,3-disubstituée

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5096890A (en) * 1989-03-17 1992-03-17 Pfizer Inc. Pyrrolidine derivatives
US5096890B1 (en) * 1989-03-17 1995-03-28 Pfizer Pyrrolidine derivatives
WO2008029257A2 (fr) * 2006-09-07 2008-03-13 Medichem, S.A. Procédé amélioré pour préparer des composés de pyrrolidine 1,3-disubstituée

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WO2009125430A3 (fr) 2010-04-22

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