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WO2009125430A2 - Improved process for producing darifenacin - Google Patents

Improved process for producing darifenacin 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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Prior art keywords
pyrrolidine
diphenylmethyl
darifenacin
give
tosyl
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PCT/IN2009/000160
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French (fr)
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WO2009125430A8 (en
WO2009125430A3 (en
Inventor
Om Dutt Tyagi
Purna Chandra Ray
Yogendhra Kumar Chauhan
K. Babu Rao
N. Mahhander Reddy
D. Siva Prasad Reddy
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Mylan Laboratories Ltd
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Matrix Laboratories Ltd
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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)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention discloses an improved process for producing darifenacin, the process comprising decarboxylating (2S,4R)-4-hydroxy-2-pyrrolidine carboxylic acid followed by in situ tosylation to give l-tosyl-3-(R)-(-)-hydroxypyrrolidine, tosylating the l-tosyl-3-(R)-(-)-hydroxypyrrolidine with methyl-p-toluenesuolphonate to give l-tosyl-3- (S)-(-)-tosyloxy pyrrolidine, reacting l-tosyl-3-(S)-(-)-tosyloxy pyrrolidine with diphenyl acetonitrile in presence of a base to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l- tosylpyrrolidine, de-protecting 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l- tosylpyrrolidine in the presence of phenol in acidic medium to give 3-(S)-(+)-(l-cyano- 1,1-diphenylmethyl) pyrrolidine, hydrolyzing 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl) pyrrolidine followed by salt formation to obtain 3-(S)-(+)-(l-carbamoyl-l,l- diphenylmethyl)pyrrolidine.L-(+)-tartrate, condensing 3-(S)-(+)-( 1 -carbamoyl- 1,1- diphenylmethyl)pyrrolidine-L(+)-tartrate with 5-(2-bromoethyl)-2,3-dihydrobenzofuran employing a base in a solvent to give darifenacin.

Description

IMPROVED PROCESS FOR PRODUCING DARIFENACIN
Field of the Invention
The present invention provides an improved process for producing darifenacin and its pharmaceutical acceptable salts thereof.
Background of the Invention
Darifenacin is used to treat urinary incontinence. Darifenacin works by blocking M3 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
(S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenyl- acetamide having the chemical structure,
Figure imgf000003_0001
Darifenacin
Darifenacin and its pharmaceutically acceptable acid addition salts are first disclosed in US Pat. No. 5,096,890, wherein the process steps involve decarboxylation of (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid (formula-(I)) in presence of 2- cyclohexen-1-one in cyclohexanol followed by salt formation using saturated ethanolic hydrochloric acid and subsequent crystallization employing isopropyl alcohol to give 3- (R)-(-)-hydroxypyrrolidine hydrochloride (formula-(Ia)), tosylating compound of formula (Ia) with /7-toluenesulphonyl chloride in anhydrous pyridine and recrystallization from ethanol to give l-tosyl-3-(R)-(-)-hydroxypyrrolidine (formula (H)), further tosylating with methyl-p-toluenesulphonate in presence of concentrated diethylazodicarboxylate (DEAD) and triphenyl phosphine in tetrahydrofuran and crystallization from «-propanol to give l-tosyl-3-(S)-(-)-tosyloxypyrrolidine (formula (III)). Subsequently condensation of compound of formula-Ill with diphenylacetonitrile is carried out in sodium hydride to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l-tosylpyrrolidine (formula (IV)).
Figure imgf000004_0001
Formula-VII
Formula-VI Formula-Vla
Synthetic Scheme-1
Compound of formula (IV) is reacted with aqueous hydrobromic acid and phenol to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)pyrrolidine (formula-V), subjected to hydrolysis followed by purification to give 3-(S)-(+)-(l-carbamoyl-l,l- diphenylmethyl)pyrrolidine- L-(H-)- tartrate of formula (VI) and subsequent desaltification to give 3-(S)-(-)-(l-carbomoyl-l,l-diphenylmethyl)pyrrolidine of formula (Via). 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. In addition, 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. Furthermore, 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.
Condensation of 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl) pyrrolidine.L-(+)- tartrate or base with 5-(2-bromoethyl)benzo[2,3-b]furan carried out in presence of potassium carbonate in acetonitrile requires prolonged reaction time to complete the reaction as un-reacted starting material is present and thereby formations of impurities is increased. It requires a number of purification steps in different solvents to give desired quality of final product.
US 2007/0203221 patent publication describes preparation of darifenacin hydrobromide comprising the steps of reacting 3-(S)-(+)-(l-carbamoyl-l,l- diphenylmethyl)pyrrolidine tartrate or free base with ethyldihydrobenzofuran in the presence of base selected from triethylamine, tributylamine, methylmorpholine, N5N- diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate in a solvent medium. The solvent medium is selected from the group consisting of a C6-9 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.
Therefore, there is need to develop a commercially viable process for the preparation of darifenacin and its pharmaceutically acceptable salts.
Object and Summary of the Invention
It is an object of the present invention to provide an improved process for producing darifenacin and its pharmaceutically acceptable addition salts. It is another object of the present invention to provide a high yielding and economical process for producing darifenacin, wherein the process involves minimum steps and less time.
It is yet another object of the present invention to provide a process for producing darifenacin, wherein the process employs reagents that are easy to handle during commercial production.
It is still another object of the present invention to provide a process for producing darifenacin, wherein the process employs non-toxic and non-explosive reagents.
The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments herein after.
In accordance with one embodiment of the present invention, there is provided a process for producing darifenacin and its pharmaceutically acceptable salts, wherein the process comprises 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)~
(-)-tosyloxy pyrrolidine, reacting l-tosyl-3-(S)-(-)-tosyloxy pyrrolidine with diphenyl acetonitrile to obtain 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l-tosylpyrrolidine, de- protecting 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l-tosylpyrrolidine in presence of phenol in acidic medium to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl) pyrrolidine, hydrolyzing 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)pyrrolidine followed by salt formation to obtain 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine.L-(+)- tartrate, condensing 3 -(S)-(+)-(l -carbamoyl- 1,1-diphenylmethyl) pyrrolidine.L-(+)- tartrate with 5-(2-bromoethyl)benzo[2,3-b]furan to obtain darifenacin, and treating darifenacin with acid to produce pharmaceutically acceptable acid addition salts.
In accordance with another embodiment of the invention, there is provided 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.
In accordance with yet another embodiment of the invention, there is provided 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.
In accordance with still another embodiment of the invention, there is provided 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.
Brief Description of the Drawings
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figure, wherein:
Figure 1 is the X-ray powder diffraction pattern of darifenacin hydrobromide.
Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
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. Further tosylation of formula-II with methyl-p-toluenesuolphonate is carried out by using diethylazodicarboxylate(DEAD) in dichloromethane to give 1-tosyl- 3-(S)-(-)-tosyloxy pyrrolidine of formula-Ill, which is reacted 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. Condensation of 3-(S)-(+)- ( 1 -carbamoyl- l,l-diphenylmethyl)pyrrolidine-L(+)-tartrate of formula-VI with 5-(2- bromoethyl)-2,3-dihydrobenzofuran in presence of alkali, alkaline earth metal hydroxides or oxides in acetonitrile to give darifenacin.
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-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l-tosylpyrrolidine in presence of phenol in acidic medium to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl) pyrrolidine (Formula V); e) hydro lyzing 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)pyrrolidine followed by salt formation to obtain 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine.L-(+)- tartrate (Formula VI); f) condensing 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine.L-(+)- tartrate of formula (VI) with 5-(2-bromoethyl)benzo[2,3-b]furan in presence of alkali, alkaline earth metal hydroxides or oxides to give darifenacin and g) treating darifenacin with acid to give pharmaceutically acceptable acid addition salts. I T TπHpFhenyl phosphlnβ
Figure imgf000009_0001
Synthetic Scheme-2
According to the present invention (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. According to our present invention, decorboxylation and tosylation reaction is carried out in single step.
According to the present invention 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. After completion of the condensation reaction, reaction mass is diluted with water, separated the organic layer and subjected to distillation.
According to the present invention, reaction mass is diluted with water to quench unreacted DEAD and further subjected to distillation. As per the prior art process, after completion of the reaction, reaction mass is as such taken for distillation. As DEAD is thermally unstable at higher temperature, hence it leads to safety hazard.
According to the present invention, condensation of l-tosyl-3-(S)-(-)-tosyloxy pyrrolidine of formula-Ill with diphenyl acetonitrile in presence of a base and polar protic or aprotic solvent, further optionally crystallization from C1-8 aliphatic alcohol to yield 3- (S)-(+)-(l-cyano-l,l-diphenylmethyl)-l-tosylpyrrolidine of formula-IV. 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. The preferred organic solvent is tetrahydrofuran.
According to the present invention, condensation reaction is carried out in presence of alkali, alkaline earth metal hydroxides or oxides in tetrahydrofuran. As per the prior art 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.
According to the present invention, 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);
According to the present invention, 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. The preferred organic solvent is acetonitrile.
According to the present invention, 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. In addition formation of impurities is less. Thus this process requires fewer purification steps at final stage.
According to the present invention, 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.
In a typical procedure of the present invention darifenacin base is dissolved in acetone and treated with hydrobromic acid to give crystalline darifenacin hydrobromide. Optionally 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 θ as shown in Fig-I. .
The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.
Example-1 Preparation of l-tosyl-3-(R*)-hydroxypyrrolidine
A mixture of cyclohexanol (200 ml), (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid (100 g) and 2-cyclohexen-l-one (10 ml) was heated to reflux. After completion of the reaction, reaction mass was cooled to room temperature(R.T.). Toluene (400 ml) and triethyl amine (92.4 g) were added to the reaction mass and cooled to 0-5° C. p-toluem sulphonyl chloride was added to the above reaction mass in lots and maintained at 0-5°
C. The reaction mass was heated to R.T. After completion of the reaction, the solvent is distilled off under vacuum and crystallized in isopropyl alcohol to give l-tosyl-3-(R)- hydroxypyrrolidine. Example-2
Preparation of l-tosyl-3-(S)-("-)-tosyloxyρyrrolidine
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. The reaction mass was washed with 10% sodium carbonate solution followed by washing with DM Water to quench excess diethylazodicarboxylate. The 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.
ExampIe-3 Preparation of 3 -(S)-f+)-( 1 -cyano- 1.1 -diphenylmethyl)- 1 -tosylpyrrolidine
A mixture of diphenyl acetonitrile (77.0 g) and potassium hydroxide (40 g) was suspended in tetrahydrofuran (480 ml) at 25-35° C under nitrogen gas atmosphere. The reaction mass was cooled to 10-20° C followed by slow addition of l-tosyl-3-(S)-(-)- tosyloxypyrrolidine (120 g) at 15-20° C and raising the temperature to reflux up to completion of the reaction and subsequent cooling of the reaction mass to 25-35° C. DM water (1200 ml) and dichloromethane (600 ml) were added to reaction mass, the two layers were separated, dichloromethane layer was subjected to distillation under vacuum to give residue. Residue was crystallized from methanol (600 ml) to give 3-(S)-(+)-(l- cyano- 1 , 1 -diphenylmethyl)- 1 -tosylpyrrolidine.
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
(45 g), 48% aqueous hydrobromic acid (225 ml) and phenol (10.12 g) was heated under reflux for 2-4 hours followed by cooling to room temperature. The mixture was extracted with dichloromethane and dichloromethane distilled out under vacuum. Ethyl acetate was added to reaction mass at 40-45° C and maintained at that temperature. The solvent is distilled out under vacuum, the reaction mass cooled to 0-5° C gradually and filtered to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl) pyrrolidine HBr.
ExampIe-5
Preparation of 3-f S)-(+V( 1 -carbamoyl- 1.1 -diphenylmethvDpyrrolidine L-(+Vtartrate 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl) pyrrolidine HBr (25 g) was dissolved in dichloromethane and treated with sodium hydroxide solution and the reaction mass pH maintained between 10-12. Reaction mass was added to the sulphuric acid solution at 50- 55° C. The solvent is distilled out completely under vacuum and reaction mass was heated to 95-105° C up to completion of the reaction, followed by cooling to room temperature. The 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. Example-6
Preparation of Darifenacin hydrobromide
5-(2-Bromoethyl)benzo[2,3-b]furan (17.2 g) was added to the mixture of 3-(S)- (+)-( 1 -carbamoyl- 1 , 1 -diphenylmethyl)pyrrolidine.L-(+)-tartrate (25 g), potassium hydroxide (11.4 g) in acetonitrile solvent at 25-35° C. Reaction mass was heated to 40- 45° C and maintained up to completion of the reaction . The reaction mass was then cooled to R.T and extracted with dichloromethane, the solvent distilled off under vacuum to give residue. Acetone was added to the residue and cooled to 10-15° C. Hydrobromic acid was added to the above solution and heated to 20-25° C and maintained for 10-12 hours. The reaction mass is filtered to give darifenacin hydrobromide. ExampIe-7
Preparation of darifenacin hydrobromide
5-(2-Bromoethyl)benzo[2,3-b]furan (17.2 g) was added to the mixture of 3-(S)- (+)-(l -carbamoyl- l,l-diphenylmethyl)pyrrolidine.L-(+)-tartrate (25 g), potassium hydroxide (11.4 g) in tetrahydrofuran solvent. Reaction mass was heated refux and maintained up to completion of the reaction. The reaction mass was cooled to R.T and extracted with dichloromethane, the solvent distilled off under vacuum to give residue. Acetone was added to the residue and cooled to 10-15° C. Hydrobromic acid was added to the above solution and heated to 20-25° C and maintained for 10-12 hours. The reaction mass is filtered to give darifenacin hydrobromide. Example-8
Purification of darifenacin Hydrobromide:
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.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations, would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

Claims

We claim:
1. An improved process for producing darifenacin and its pharmaceutically acceptable addition salts, the process comprising the steps of:
(a) decorboxylating (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid followed by in-situ tosylation to give l-tosyl-3-(R)-hydroxypyrrolidine;
(b) tosylating the l-tosyl-3-(R)-hydroxypyrrolidine employing a tosylating agent in presence of dilute condensing agent to obtain l-tosyl-3-(S)-(-)- tosyloxy pyrrolidine;
(c) reacting l-tosyl-3-(S)-(-)-tosyloxy pyrrolidine with diphenyl acetonitrile employing a base in presence of a solvent to obtain 3-(S)-(+)-(l- cyano- 1 , 1 -diphenylmethyl)- 1 -tosylpyrrolidine;
(d) de-protecting 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l- tosylpyrrolidine in presence of phenol in acidic medium to give 3-(S)-(+)-(l- cyano- 1 , 1 -diphenylmethyl) pyrrolidine; (e) hydrolyzing 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)pyrrolidine followed by salt formation to obtain 3-(S)-(+)-(l-carbamoyl-l,l- diphenylmethyl)pyrrolidine.L-(+)-tartrate;
(f) condensing 3-(S)-(+)-(l-carbamoyl-l,l- diphenylmethyl)pyrrolidine.L-(+)-tartrate with 5-(2-bromoethyl)benzo[2,3- b]furan employing a base in presence of a solvent to obtain darifenacin; and
(g) treating darifenacin with acid to produce pharmaceutically acceptable acid addition salts.
2. The process according to claim 1, wherein the tosylating agent is selected from/7-tolylsulfonyl chloride and methyl-^-tolylsulfonate.
3. The process according to claim 1, wherein the condensing agent is diethylazodicarboxylate (DEAD).
4. The process according to claim 1, wherein the base used in step 1 (c) is selected from the group comprising alkali metal oxide or hydroxide or alkaline earth metal oxide or hydroxide.
5. The process according to claim 4, wherein the base is preferably selected from sodium hydroxide, potassium hydroxide, magnesium oxide or calcium oxide.
6. The process according to claim 1, wherein the solvent used in step 1 (c) is selected from the group comprising methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, tetrahydrofuran, dimethylformamide or dimethylsulfoxide.
7. The process according to claim 1, wherein the base used in step 1 (e) for the condensation reaction is selected from the group comprising alkali metal oxide or hydroxide or alkaline earth metal oxide or hydroxide.
8. The process according to claim 7, wherein the base is preferably selected from sodium hydroxide, potassium hydroxide, magnesium oxide or calcium oxide.
9. The process according to claim 1, wherein the solvent used in step 1 (e) is selected from the group comprising methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, tetrahydrofuran, dimethylformamide or dimethylsulfoxide.
10 The process according to claim 1, wherein the acid is selected from hydrochloric acid, hydrobromic acid.
PCT/IN2009/000160 2008-03-17 2009-03-09 Improved process for producing darifenacin Ceased WO2009125430A2 (en)

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