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WO2008100651A2 - Préparation de darifénacine et ses sels - Google Patents

Préparation de darifénacine et ses sels Download PDF

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Publication number
WO2008100651A2
WO2008100651A2 PCT/US2008/050388 US2008050388W WO2008100651A2 WO 2008100651 A2 WO2008100651 A2 WO 2008100651A2 US 2008050388 W US2008050388 W US 2008050388W WO 2008100651 A2 WO2008100651 A2 WO 2008100651A2
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WIPO (PCT)
Prior art keywords
formula
compound
darifenacin
solvent
hplc
Prior art date
Application number
PCT/US2008/050388
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English (en)
Other versions
WO2008100651A3 (fr
Inventor
Srinivas Katkam
Pattabhiramayya Vaddadi
Vishnuvardhan Sunkara
Muralimohan Muttavarapu
Lalitha Dattatray Kulkarni
Rajeshwar Reddy Sagyam
Jaya Prakash Pitta
Ravinder Buchnikonda
Sridhar Munagala
Original Assignee
Dr. Reddy's Laboratories Ltd.
Dr. Reddy's Laboratories, Inc.
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Application filed by Dr. Reddy's Laboratories Ltd., Dr. Reddy's Laboratories, Inc. filed Critical Dr. Reddy's Laboratories Ltd.
Priority to EP08772573A priority Critical patent/EP2109601A2/fr
Publication of WO2008100651A2 publication Critical patent/WO2008100651A2/fr
Publication of WO2008100651A3 publication Critical patent/WO2008100651A3/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • the present patent application relates to processes for the preparation of darifenacin and its salts. It also relates to substantially pure darifenacin hydrobromide and a process for its preparation.
  • D Darifenacin is useful as a potent muscarinic receptor antagonist and is marketed as its hydrobromide salt under the brand name ENABLEX as extended release tablets containing 7.5 or 15 mg darifenacin as its hydrobromide salt.
  • US Patent No. 5,096,890 discloses darifenacin, its derivatives, salts and processes for preparing them.
  • the patent discloses several routes for preparing darifenacin as described below.
  • Route A involves a reaction of 3-(S)-(-)-(1-carbamoyl-1 ,1- diphenylmethyl)pyrrolidone ( Formula XIII) with 5-(2-bromoethyl)-2,3- dihydrobenzofuran (Formula XIV) in the presence of potassium carbonate to give a free base of darifenacin (Formula V), which is in-turn converted to its hydrobromide salt using aqueous hydrobromic acid in acetone.
  • Route B involves hydrolysis of 3-(S )-(cyanodiphenylmethyl)-1-[2-(2,3- dihydrobenzofuran-5-yl)ethyl] pyrrolidine (Formula IV) using concentrated aqueous mineral acid to give the free base of darifenacin.
  • Route D involves reduction of (S)-2- ⁇ 1-[2-(benzofuran-5-yl)-ethyl]-3- pyrrolidinyl ⁇ -2,2-diphenylacetamide (Formula Vb) using palladium carbon in the presence of acetic acid .
  • Route E involves a reduction of 3-(S)-(1-carbamoyl-1 ,1-diphenylmethyl)-1- [2-(2,3-dihydrobenzofuran-5-yl)-2-oxoethyl]pyrrolidone using palladium carbon to give the free base of darifenacin (Formula V).
  • a pharmaceutical intermediate that includes:
  • a process for the preparation of darifenacin hydrobromide including: a) providing a solution of free base of darifenacin in an organic solvent to form a reaction medium substantially free from moisture; b) adding the source of hydrobromic acid to obtain a solution of darifenacin hydrobromide, the source of hydrobromic acid being added in a non-aqueous carrier; and c) recovering the darifenacin hydrobromide as a solid; wherein the reaction medium is maintained substantially free from moisture during the providing step and the adding step.
  • a solid active ingredient for use in pharmaceutical compositions that includes: a) a major portion that includes darifenacin hydrobromide; and b) a minor portion that includes one or more of the impurities of the Formula Ia, Ib, Ic, Id, Ie, If, and/or Ig:
  • a process for purifying darifenacin hydrobromide including: a) providing a solution of darifenacin hydrobromide in a C1-C3 alcoholic solvent; b) cooling the solution; and c) isolating the separated solid, which is the purified darifenacin hydrobromide.
  • a process for preparing darifenacin hydrobromide substantially free from residual organic solvents including: a) providing a solution of darifenacin hydrobromide in an alcoholic or a chlorinated solvent; b) removing the solvent from the solution obtained in step a); c) adding an anti-solvent to the residue obtained; and d) isolating the solid.
  • compounds that are an amorphous form of darifenacin and an amorphous form of darifenacin hydrobromide.
  • a process for preparing an amorphous solid of darifenacin or its hydrobromide salt including: a) providing a solution of darifenacin or its hydrobromide salt in a volatile organic solvent; and b) removing the solvent to obtain the amorphous solid.
  • Fig. 1 XRPD pattern for a sample of crystalline darifenacin hydrobromide (prepared as per Example 17).
  • Fig. 2 XRPD pattern for a sample of amorphous darifenacin (prepared as per Example 18).
  • Fig. 3 XRPD pattern for a sample of amorphous darifenacin hydrobromide (prepared as per Example 19).
  • composition may contain one compound or a mixture of compounds.
  • pharmaceutical composition is any composition useful or potentially useful in producing physiological response in a subject to whom such pharmaceutical composition is administered.
  • pharmaceutically acceptable with respect to excipients is used to denote non-toxic substances generally suitable for use in human or animal pharmaceutical products.
  • external solvent means a dissolving substance ("a solvent”) intentionally added to a reaction mass to provide a dissolution medium for the reaction without participating in the reaction from the chemical standpoint.
  • organic solvent means a solvent the molecules of which contain at least atoms of carbons and hydrogen.
  • the “organic solvent” may contain other atoms such as oxygen and nitrogen as well.
  • non-aqueous with regards to solvent or carrier is used to denote a medium that does not contain water other than residual moisture.
  • anti-solvent is used to denote a liquid substance that functions by reducing the solubility of a solute in the primary solvent without affecting the solute from the chemical standpoint.
  • the solute e.g., a compound
  • anti-solvent is added to cause precipitation of purified solute.
  • organic base means a base the molecule of which contains at least atoms of carbons and hydrogen.
  • the “organic base” may contain other atoms such as oxygen and nitrogen as well.
  • active ingredient is used to denote a substance, usually a powder, which forms the physiologically active portion of pharmaceutical products.
  • Active pharmaceutical ingredients are usually commercial products sold to formulators of final pharmaceutical products.
  • pharmaceutical intermediate is used to denote a compound that is useful as an intermediate in preparation of APIs, or a composition, which contains a major portion of such compound.
  • purifying with respect to a mixture is used with respect to the ingredient of interest to denote a process for increasing the content of the ingredient of interest in the mixture.
  • substantially free of moisture denotes a reaction medium with total moisture content of the reaction medium does not exceed about 5%.
  • substantially free with regards to residual organic solvents denotes substances in which the weight content of total residual organic solvent(s) is less than 1 % by weight.
  • Scheme-1 may be useful to illustrate the process for making a free base of darifenacin according to an aspect(s) of the invention.
  • step a) the secondary amine of the formula (II) is reacted with the compound of the formula (III) that contains a leaving group X in the presence of an
  • the reaction is conducted without an external solvent, with the organic base itself acting as the dissolution medium for the reaction.
  • Organic bases which are particularly useful for the reaction of step a) include, but are not limited to salts of primary, secondary, and tertiary amines such as triethylamine, methyl amine, tertiary butyl amine, dicyclohexylamine, and substituted amines including naturally occurring substituted amines.
  • the preferred organic base is triethylamine.
  • An acid addition salt of 3-(S)-(+)-(1-cyano-1 ,1-diphenylmethyl)-pyrrolidine may be used as the starting material instead of the free amine.
  • Acid addition salts of organic or inorganic acids capable of forming a salt with the amine of the compound of the Formula Il are suitable.
  • the acid addition salt of the compound of the formula (II) is first treated with the base and then reacted with 5- haloethyl-2,3-dihydrobenzofuran of the Formula III.
  • Temperatures for conducting the reaction range from about 25 to about 200
  • 3-(S)-(cyanodiphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine of the Formula IV may be obtained and/or isolated as a free base or as acid addition salt by reacting the free base with the corresponding acid.
  • the compound of the formula (IV) is treated with an external base to convert the nitrile group of the compound of the formula (IV) to the amide of the free base of darifenacin.
  • the conversion of the nitrile intermediate to the amide with a base was disclosed, for example, in the U.S. Patent No. 6,930,188.
  • the inventors of the present patent application have discovered that the reaction condition used therein result in the formation of significant amount of the impurity of the Formula Ic in the reaction medium as determined by HPLC.
  • the inventors have discovered the need for maintaining the impurity of the formula (Ic) below 0.5% upon completion of the reaction that converts the nitrile group of the compound of the formula (IV) into the amide group of the free base of darifenacin.
  • this convertion reaction is best carried out in a solvent other than 2-methyl-2-butanol under controlled reaction conditions.
  • the inventors have also discovered that if the content of the impurity of Formula Ic does not exceed 0.5% in the reaction medium after the free base is prepared, the subsequent conversion of the free base to darifenacin hydrobromide results in the final product containing less than 0.15 % of the impurity of Formula Ic.
  • the conversion reaction of the step b) is carried out in the presence of a base.
  • Bases which are useful for the reaction of step b) include, but are not limited to alkali metal hydrides such as lithium hydride, sodium hydride; alkali metal
  • hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; carbonates of alkali metals such as sodium carbonate, and potassium carbonate; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate; ammonia; and mixtures thereof.
  • the preferred base is potassium hydroxide.
  • Solvents which are useful for conducting the reaction of the step b) include, but are not limited to alcohols such as ethanol, n-propanol, isopropanol, 2-butanol, isobutanol; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform; hydrocarbon solvents such as toluene, xylene, n-heptane, n-hexane, cyclohexane, methylcyclohexane, and mixtures thereof.
  • the preferred solvent is 2-butanol.
  • the concentration of the base in the reaction medium may range from about 0.1 g/ml, to about 0.3 g/ml.
  • the reaction is maintained for durations which result in the conversion of at least about 80%, or at least about 85% of the starting material of Formula IV to the corresponding product of Formula V.
  • Temperatures for conducting the reaction range from about 50 °C to about 150 0 C, or from about 50 0 C to about 120 0 C.
  • the reaction is conducted using potassium hydroxide as base, and 2-butanol as solvent.
  • the reaction is conducted at a temperature of about 100 0 C for a period of about 50 hours to achieve the desired results.
  • the compounds may be isolated, or progressed further downstream without isolation.
  • the preferred isolation temperatures are lower than about 50 0 C, or lower than about 40 0 C. It has been discovered that the lower temperatures act to minimize or prevent the formation of the corresponding oxidized impurities of Formula IVb, and Formula Vb, respectively.
  • Formula Il or its acid addition salt may be accomplished, for example, as follow: a) decarboxylation of (2S, 4R)-(-)-4-hydroxy-2-pyrrolidinecarboxylic acid of Formula Vl to give 3-(R)-(-)-hydroxypyrrolidine and subsequent conversion to hydrochloride of Formula VII.
  • Solvents which are useful for conducting the reaction at each stage include, but are not limited to: ketones such as acetone, methyl isobutyl ketone, and cyclohexanone; alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexan-1-ol, ethylene glycol; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; hydrocarbon
  • solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane; and mixtures thereof.
  • Bases which are useful in steps b) and d) include inorganic bases such as alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate.
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide
  • carbonates of alkali metals such as sodium carbonate, potassium carbonate
  • bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate.
  • diisopropylazodicarboxylate (DIAD) in combination with triphenylphosphine is used for inversion of configuration in step c) instead of diethylazodicarboxylate (DEAD) used on the prior art, which is difficult to handle on large scale.
  • DIAD diisopropylazodicarboxylate
  • DEAD diethylazodicarboxylate
  • Formula Il can be converted to its acid addition salt by reacting with an acid in an aqueous or a non-aqueous solution.
  • the acid for preparing the salt may be hydrobromic acid in the form of a non-aqueous solution in acetic acid to form the corresponding hydrobromide salt of the compound of Formula II.
  • the preparation of 5-haloethyl-2,3-dihydrobenzofuran of the Formula III may be accomplished, for example, as follows: a) reaction of 2,3-dihydrobenzofuran of Formula Xl with haloacetyl halide to give 5-haloacetyl-2,3-dihydrobenzofuran of Formula XII;
  • Solvents which are useful in step a) include, but are not limited to halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, or mixtures thereof.
  • Reducing agents which are useful in step b) include, but are not limited to triethyl silane and trifluoroacetic acid, sodium bis(2-methoxyethoxy) aluminum hydride (Vitride), lithium aluminium hydride, sodium borohydride/acetic acid, diisobutyl aluminium hydride (DIBAL H), silanes, boranes, metal hydrides like sodium borohydride, lithium aluminium hydride, formates, hypophosphorous acid salts.
  • Triethyl silane and trifluoroacetic acid sodium bis(2-methoxyethoxy) aluminum hydride (Vitride), lithium aluminium hydride, sodium borohydride/acetic acid, diisobutyl aluminium hydride (DIBAL H), silanes, boranes, metal hydrides like sodium borohydride, lithium aluminium hydride, formates, hypophosphorous acid salts.
  • 5-haloacetyl-2,3-dihydrobenzofuran of Formula XII and 5- haloethyl-2,3-dihydrobenzofuran of Formula III obtained can be further purified by recrystallization or slurry in a suitable solvent.
  • Solvents which can be used for recrystallization or slurry include, but are not limited to ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, petroleum ether; alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile, propionitrile, or mixtures thereof, or their mixtures with water in various proportions.
  • ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, petroleum ether
  • alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol
  • ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone
  • 5-haloethyl-2,3-dihydrobenzofuran of the Formula III is the key intermediate in the synthesis, e.g., of darifenacin.
  • ⁇ 00010077.1 ⁇ contemplated is a pharmaceutical intermediate that contains a major portion of 5- haloethyl-2,3-dihydrobenzofuran and minor portion of certain impurity compounds.
  • the major portion represents more than about 95% of the intermediate, more preferably, more than about 97%.
  • the minor portion represents less than about 5% of the intermediate, and preferably, includes less than about 2%, more preferably, less than about 1 % of 2-chloro-1- (2,3-dihydro-benzofuran-7-yl)- ethanone of Formula IMa, 2-chloro-1-[3-(2-chloro-ethyl)-4-hydroxy-phenyl]- ethanone of Formula IMb, and/or 2-chloro-1 -[3-(2-chloro-ethyl)-2-hydroxy-phenyl]- ethanone of Formula IMc as characterized by a high performance liquid chromatography ("HPLC") chromatogram obtained from a mixture containing the desired compound and one or more of the impurities.
  • HPLC high performance liquid chromatography
  • HPLC High Performance Liquid Chromatography
  • a process for making a hydrobromide salt of darifenacin that includes the steps of: a) providing a solution of free base of darifenacin in an organic solvent to form a reaction medium substantially free from moisture; b) adding the source of hydrobromic acid to obtain a solution of darifenacin hydrobromide, the source of hydrobromic acid being added in a non-aqueous carrier; and c) recovering the darifenacin hydrobromide as a solid;
  • reaction medium is maintained substantially free from moisture during the providing step and the adding step.
  • a solution of the free base in a solvent is provided while taking care to keep the reaction medium as moisture free as possible.
  • ⁇ 00010077.1 ⁇ which are useful for preparing the solution of darifenacin include, but are not limited to C 2 -C 6 ketone solvents such as acetone, ethyl methyl ketone, and diethyl ketone; CrC 4 alcohols; chlorinated solvents, such as Ci-C 6 straight chain, branched, or aromatic chlorohydrocarbons including dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene, or mixtures thereof.
  • the preferred solvents are acetone and methanol.
  • Step b) involves adding a source of hydrobromic acid to form the hydrobromide salt in solution while maintaining the reaction medium substantially free from moisture.
  • Suitable sources of hydrobromic acid include but are not limited to ammonium bromide, hydrobromic acid gas, salts containing hydrobromic acid, or the gas purged in organic solvents like acetic acid are for the purpose.
  • reaction mass may be maintained further at temperatures lower than the reaction temperatures such as for example below about 10° C to about 25° C, for a period of time as required for a more complete isolation of the product.
  • the present invention provides substantially pure darifenacin hydrobromide. In yet another embodiment, the present invention provides substantially pure darifenacin.
  • substantially pure darifenacin it is meant that darifenacin or any of the pharmaceutically acceptable salts of darifenacin prepared in accordance with the present invention contains less than about 0.5%, or less than about 0.1% of one or more of the corresponding impurities like the desnitrile impurity, the acid impurity, the compound of Formula IV, and the impurities having the Formulas Ic, Id, Ie, If, and Ig as characterized by HPLC obtained from a mixture comprising the desired compound and one or more of the said impurities. It is also free of the impurities at RRT (Relative retention time) 1.37 having a mass number 500, and at RRT 1.77 having a mass number 570 as determined by HPLC.
  • RRT Relative retention time
  • acid impurity refers to ⁇ 1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl ⁇ - diphenyl-acetic acid, represented by Formula Ib;
  • compound of Formula Ic refers to 2- ⁇ 1-[2-(4-hydroxy-3-vinyl-phenyl)-ethyl]- pyrrolidin-3-yl ⁇ -2,2-diphenyl-acetamide;
  • compound of Formula Id refers to (R)-2- ⁇ 1-[2-(2,3-dihydrobenzofuran-5-yl)-ethyl]- 3-pyrrolidinyl ⁇ -2,2-diphenylacetamide;
  • compound of Formula Ie refers to 2- ⁇ 1-[2-(2,3-dihydro-benzofuran-6-yl)-ethyl]- pyrrolidin-3-yl ⁇ -2,2-diphenyl-acetamide;
  • compound of Formula Ig refers to 2- ⁇ 1-[2-(2.3-dihydro-benzofuran-5-yl)-2- hydroxy-ethyl]-pyrrolidin-3-yl ⁇ -2,2-diphenyl-acetamide
  • the pharmaceutically acceptable salts of darifenacin refer to salts prepared form pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.
  • Salts derived from inorganic acids include hydrochloride, hydrobromide, hydroiodide.
  • Salts derived from organic non-toxic acids include tartarate, oxalate, maleate, acetate.
  • Ie were analyzed by the High Performance Liquid Chromatography (HPLC) method using a C-18 column, 250 x 4.6 mm ID, 5 ⁇ particle size or equivalent.
  • HPLC High Performance Liquid Chromatography
  • the impurity of Formula If was analyzed by the High Performance Liquid Chromatography (HPLC) method using a C-18 column, 250 x 4.6 mm ID, 5 ⁇ particle size or equivalent. Remaining parameters are as shown in Table 4.
  • the isomeric impurity of Formula 1 d was analyzed by the Chiral High Performance Liquid Chromatography (HPLC) method using a Chiral CeI-OD, 250 x 4.6 mm ID x 5 ⁇ m. Remaining parameters are as shown in Table 5.
  • an active pharmaceutical ingredient that contains a) a major portion that includes 95% or more of darifenacin hydrobromide; and b) a minor portion that includes one or more of the impurities of the Formula Ia, Ib, Ic, Id, Ie, If, and/or Ig, wherein the minor portion contains less than about 1 % of one or more impurities of the Formula Ia, Ib, Ic, Id, If, and/or Ig, as measured by area % in HPLC with respect to the total area % of all compound peaks in the HPLC chromatogram of the solid active pharmaceutical ingredient.
  • the major portion represents more than about 95% of the active pharmaceutical ingredient, more preferably, more than about 97%.
  • the minor portion represents less than about 5% of the intermediate, and preferably, represents less than about 1 %, as characterized by a high performance liquid chromatography ("HPLC") chromatogram.
  • HPLC high performance liquid chromatography
  • Step a) involves providing a solution of darifenacin hydrobromide in a C1 to
  • ⁇ 00010077.1 ⁇ may be one prepared according to the processes described in the prior art, or using a process similar to the one described above.
  • the solution of darifenacin hydrobromide may be obtained by dissolving the darifenacin hydrobromide in a suitable solvent, or such a solution may be obtained directly from a reaction in which darifenacin hydrobromide is formed.
  • any form of darifenacin hydrobromide such as any crystalline or amorphous form including any salts, solvates and hydrates may be utilized for preparing the solution.
  • Suitable alcoholic solvents which may be used for dissolving darifenacin hydrobromide include but are not limited to methanol, ethanol, isopropyl alcohol, n-propanol.
  • the dissolution temperatures range from about 20 to 120 0 C depending on the solvent used for dissolution. Any other temperature is also acceptable as long as the stability of darifenacin hydrobromide is not compromised and a clear solution is obtained.
  • the quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted.
  • the concentration of darifenacin hydrobromide in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.
  • the solution is optionally treated with activated charcoal, or similar adsorbing agents like silica gel, and others to enhance the color of the compound followed by filtration through a medium such as through a flux calcined diatomaceous earth (Hyflow) bed to remove the carbon.
  • the carbon treatment can be given either at the temperatures of the preparation of the mixture or after cooling the solution to lower temperatures.
  • Step b) involves cooling the solution.
  • the reaction mass may be maintained further at temperatures lower than the concentration temperatures such as for example below about 10° C to about 25° C, for a period of time as required for a more complete isolation of the product.
  • cooling temperature and time required for complete isolation can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.
  • isolation may be enhanced by methods such as cooling, partial removal of the solvent from the mixture, by adding an anti-solvent to the reaction mixture or a combination thereof.
  • Step c) involves recovering the separated solid.
  • the crystals so isolated will carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired the crystals can be washed on the filter with a solvent to wash out the mother liquor.
  • the above described process may be adapted to form the basis of a continuous crystallization process.
  • the purity of the product obtained in step c) is periodically to ascertain the percentage of the impurities. If required the purification process is repeated till impurity levels attained are nil or less than about 0.15 area
  • the wet cake obtained in step c) may be further dried. Drying is suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer. The drying is carried out at temperatures of about 25° C to about 70° C for any desired time periods from about 1 to 20 hours.
  • Darifenacin hydrobromide having a reduced level of impurities typically also contains residual solvents.
  • any residual solvents in purified darifenacin hydrobromide are also considered as impurities. Residual solvents can be quantified by application of known chromatographic techniques.
  • darifenacin hydrobromide substantially free from residual organic solvents. In yet another embodiment, there is provided darifenacin hydrobromide substantially free of residual organic solvents.
  • Darifenacin hydrobromide obtained using the process described herein contains less than about 5000 ppm, or less than about 3000 ppm, or less than about 1000 ppm of individual residual organic solvents. In particular, it has less than about 1000 ppm, or less than about 600 ppm of the solvents selected from methanol, acetone, n-propanol, ethyl acetate, 2-butanol, cyclohexane, and acetic acid.
  • Alcoholic or chlorinated solvents which are used include, but are not limited to alcoholic solvents like methanol, ethanol, isopropyl alcohol; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride.
  • Removal of the solvent in step b) may be carried out suitably using techniques such as evaporation, atmospheric distillation, distillation under vacuum. Distillation of the solvent may be conducted under vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at temperatures such as below about 70 0 C.
  • Anti-solvents which are useful include, but are not limited to water, hydrocarbons such as n-hexane, n-heptane, cyclohexane, toluene, xylene, or mixtures thereof.
  • the mass may be maintained further at temperatures of the range of about 10 0 C to about 50 0 C, for a period of time as required for a more complete isolation of the product.
  • the exact cooling temperature and time required for complete precipitation is readily determined by a person skilled in the art.
  • the wet solid obtained may be dried. Drying is carried out at reduced pressures, at temperatures of below about 80 0 C. The drying is carried out for any desired or required time periods, times about 1 to 20 hours being suitable.
  • Substantially pure darifenacin hydrobromide prepared according to the process described herein is characterized by its XRPD pattern substantially in accordance with the pattern of Fig. 1. It is also characterized by an XRPD pattern having significant peaks at about 8.1 , 9.0, 1 1.4, 16.9, 18.1 , 18.7, 20.1 , 20.2, 22.0, and 25.8, ⁇ 0.2 degrees 2 ⁇ .
  • Darifenacin hydrobromide prepared according to the process described herein has particle size of less than about 100 ⁇ m or less than about 50 ⁇ m.
  • the D 10 , D 50 and D 90 values are useful ways for indicating a particle size distribution.
  • D 90 refers to the value for the particle size for which at least 90 volume percent of
  • D 50 and D-io refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value.
  • Methods for determining Di 0, D 50 and D9 0 include laser diffraction, such as using Malvern Instruments Ltd. (of Malvern, Worcestershire, United Kingdom) equipment.
  • darifenacin hydrobromide prepared according to the process described herein has D 10 less than about 10 ⁇ m or less than about 5 ⁇ m
  • Amorphous darifenacin and its hydrobromide salt and amorphous premix of darifenacin and its hydrobromide salt in combination with a pharmaceutically acceptable carrier are characterized by their XRPD pattern. All XRPD data reported herein were obtained using Cu Ka radiation, having the wavelength 1.541 A and were obtained using a Bruker Axe D8 Advance Powder X-ray Diffractometer.
  • Amorphous forms of darifenacin and its hydrobromide salt are characterized by their XRPD patterns showing no peaks substantially in accordance with Fig. 2 and Fig. 3, respectively.
  • the amorphous solid of darifenacin or its hydrobromide salt may be prepared by a process that includes the steps of: a) providing a solution of darifenacin or its hydrobromide salt in a volatile organic solvent; and b) removing said solvent.
  • Step a) involves providing a solution of darifenacin or its hydrobromide salt either_alone or in combination with a pharmaceutically acceptable carrier in a suitable solvent.
  • the solution of darifenacin or its hydrobromide salt may be obtained by dissolving them in a suitable solvent, or such a solution may be obtained directly from a reaction in which they are formed.
  • any polymorphic form such as any crystalline form including any salts, solvates and hydrates may be utilized for preparing the solution.
  • the order of charging the different materials is not critical for the product obtained. A specific order may be preferred with respect to the equipment actually used and will be easily determined by a person skilled in the art.
  • Solvents which are useful for dissolving darifenacin or its hydrobromide salt either alone or along with a pharmaceutically acceptable carrier include but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, n-hexane; nitriles such as ace
  • the pharmaceutically acceptable carriers that are useful for the preparation of amorphous combinations of darifenacin and its hydrobromide salt include but are not limited to pharmaceutical hydrophilic carriers such as polyvinyl pyrrolidone (homopolymers or copolymers of N-vinyl pyrrolidone), gums, cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose and others), cyclodextrins, gelatins, hypromellose phthalate, sugars, polyhydric alcohols, polyethylene glycol, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohol, propylene glycol derivatives.
  • pharmaceutical hydrophilic carriers such as polyvinyl pyrrolidone (homopolymers or copolymers of N-vinyl pyrrolidone), gums, cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose and others), cyclodextrins, gelatins, hypromel
  • the use of mixtures of more than one of the pharmaceutical carriers to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, mixtures are all within the scope of this invention without limitation.
  • the solution may optionally be treated with materials such as carbon or similar adsorbing agents like silica gel, or sodium sulfate for clarification. Step b) involves removing the solvent.
  • Removal of the solvent may be carried out suitably using evaporation, atmospheric distillation, or distillation under vacuum.
  • Distillation of the solvent may be conducted under a vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 20° C to about 70° C.
  • Techniques which are useful for distillation include, distillation using a rotational evaporator device such as a Buchi Rotovap, spray drying, agitated thin film drying ("ATFD").
  • a rotational evaporator device such as a Buchi Rotovap
  • spray drying agitated thin film drying
  • the amorphous material obtained from step b) is be collected from the equipment using techniques such as by scraping, or by shaking the container.
  • the solid product may be dried.
  • the drying is carried out at reduced pressures, such as below about 200 mm Hg or below about 50 mm Hg, at temperatures such as about 35° C to about 70° C.
  • the drying is carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications.
  • a pharmaceutical composition that includes substantially pure darifenacin or its pharmaceutically acceptable salts and with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • Darifenacin or its pharmaceutical acceptable salts are formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active product is mixed with one or more pharmaceutically acceptable excipients.
  • the drug substance is formulated as liquid compositions for oral administration including for example solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin, may be used.
  • Compositions for parenteral administration include suspensions, emulsions or aqueous or non-aqueous, sterile solutions.
  • propylene glycol polyethylene glycol
  • vegetable oils especially olive oil
  • injectable organic esters e.g. ethyl oleate
  • These compositions may contain adjuvants, especially wetting, emulsifying and dispersing agents. Sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating.
  • the compositions may be prepared in the form of sterile compositions, which can
  • ⁇ 00010077.1 ⁇ be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • Pharmaceutically acceptable carriers that include but are not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pregelatinized starch; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide; lubricants such as stearic acid, magnesium stearate, zinc stearate; glidants such as colloidal silicon dioxide; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, complex forming agents such as various grades of cyclodextrins, resins; release rate
  • Para toluene sulfonyl chloride (17.17 kg) and dichloromethane (112 liters) were taken into a reactor and sodium carbonate (14.3 kg) was added to it at 25 - 35 0 C.
  • DAN-1 (1 1.15 kg) was added to the above reaction mass and the reaction mass was heated to about 38 0 C and maintained for about 3 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the reaction wass was cooled to about 35 °C. The unwanted solids were filtered and the filtered bed was washed with dichloromethane (44.5 liters). The filtrate was washed with water (56 liters) followed by washing with 10% NaCI solution (56 liters).
  • EXAMPLE 3 PREPARATION OF 1-TOSYL-3-(S)-(-)-TOSYLOXYPYRROLIDINE (FORMULA IX): Charge DAN-2 (19.0 kg), and toluene (190 liters) were taken into a reactor and stirred at abour 25 0 C for 10 minutes. Triphenylphosphine (29.45 kg), and methyl-4-toluene sulfonate (20.9 kg) were added to the above reaction mass at the same temperature and then the reaction mass was cooled to about 0 to 5 0 C.
  • the reaction mass was then again washed with another 110 liters of water at the same temperature and then cooled to about 30 0 C.
  • the organic layer was then distilled off at about 65 0 C under reduced pressure to distill off about 50 % of the solvent.
  • the remaining residue was cooled to about 40 0 C and methanol (44 liters) was added to it.
  • Methanol was distilled off completely at about 65 0 C under reduced pressure and to the residue another 66 liters of methanol was added.
  • the mixture was cooled to about 30 0 C and maintained for about 2 hours.
  • the separated solid was filtered and the filtered solid was washed with methanol (44 liters).
  • the wet solid was dried at 70 to 75 0 C for about 5 hours to yield 19.9 kg of the title compound (% yield: 86%). Purity by HPLC: 99.6%.
  • the aqueous layer was extracted into toluene (96 liters) in two equal lots. The aqueous layer was then cooled to 0 to 5 °C, toluene (48 liters) was added to it and pH of the aqueous layer was adjusted to about 13 using caustic lye (48 liters). After the desired pH is
  • the temperature of the mixture is raised to 30 to 35 0 C and stirred for about 30 minutes.
  • the toluene layer was separated and the aqueous layer was extracted into another 48 liters of toluene.
  • the combined organic layer was washed with water (96 liters) in two equal lots.
  • the organic layer was then distilled off at a temperature of below 75 0 C under reduced pressure to get a residue.
  • the residue obtained was co-distilled with ethyl acetate (32 liters) and then another 27 liters of ethyl acetate was added to the residue obtained.
  • EXAMPLE 7 PREPARATION OF 3-(S)-(+)-(1 -CARBAMYOL-1 ,1- DIPHENYLMETHYL)-PYRROLIDINE L (+) -TARTRATE (FORMULA XIII): 3-(S)-(+)-1 -cyano-1 ,1-diphenylmethyl)-pyrrolidine (39.5 g) and 95% sulphuric acid (97 ml) were taken into a clean and dry round bottom flask followed by heating to about 80 0 C for about 10 hours. The reaction mass was cooled to about 10 to 15 0 C and the pH was adjusted to about 10 by adding caustic lye (150 ml).
  • the resultant reaction solution was extracted using dichloromethane (315 ml) followed by separation of organic and aqueous layers.
  • the organic layer was washed with water (315 ml) followed by separation of organic and aqueous layers.
  • the solvent from the organic layer was distilled below 60 0 C completely under reduced pressure.
  • L (+) tartaric acid (11.6 g) and ethanol (210 ml) were taken into a clean and dry round bottom flask.
  • the crude material obtained above was dissolved in ethanol (1 16 ml)and added to the above material over a period of about 45 minutes.
  • the reaction mass was stirred for about an hour.
  • the solid that was separated was filtered and the solid was washed with 42 ml of ethanol.
  • dichloromethane 150 liters was added to it and stirred for about 15 minutes.
  • the reaction mixture was then added to a reactor containing water (450 liters) precooled to 5 to 10 0 C.
  • the reaction mixture was stirred for about 1 hour and the organic layer was separated.
  • the aqueous layer was then extracted into dichloromethane (100 liters), and the combined organic layer was washed with 5% aqueous sodium bicarbonate solution (150 liters) followed by washing with water (200 liters). 70 to 80 % of the solvent was distilled off from the organic layer atmospherically below 45 0 C followed by complete distillation of the solvent under reduced pressure.
  • the organic layer was washed with 5% sodium bicarbonate solution (50 liters) in two equal lots followed by washing with water (25 liters).
  • the organic layer was treated with a mixture of silica gel (10 kg) and carbon (1 kg) at 25 to 35 0 C and filtered.
  • the filtered bed was washed with petroleum ether (60 liters) in 3 equal lots.
  • the combined filtrate was distilled off completely below 45 0 C under reduced pressure and 20 liters of petroleum ether was added to the residue and cooloed to 0 to 5 0 C.
  • the mixture was maintained at 0 to 5 0 C for about 1 hour and the separated solid was filtered and washed with chilled petroleum ether (5 liters).
  • EXAMPLE 12 ALTERNATE PROCESS FOR THE PREPARATION OF 3-(S)-(-)- (1 -CARBAMOYL-I 1 I -DIPHENYLMETHYL)-I -P- ⁇ 1 S-DIHYDROBENZOFURAN-S- YL)-ETHYL]-PYRROLIDINE (FORMULA XV):
  • the dry compound was again taken into another round bottom flask and ethyl acetate (56 ml), and water (56 ml) were added to it and stirred at 25 to 35 0 C for about 10 minutes.
  • a solution of caustic lye (7 ml) in water (7 ml) was then added to the above mixture and stirred for about 20 minutes.
  • the organic layer was separated and the aqueous layer was extracted into ethyl acetate (27 ml).
  • the combined organic layer was washed with 10 % sodium chloride solution (35 ml) and then distilled off completely to get a residue.
  • EXAMPLE 19 PREPARATION OF DARIFENACIN HYDROBROMIDE AMORPHOUS FORM (FORMULA I).
  • Darifenacin hydrobromide (0.5 g) and methanol (25 ml) were taken into a round bottom flask followed by stirring at about 26 °C for about 10 minutes.
  • charcoal carbon (0.05 g) was added followed by stirring for about 15 minutes.
  • the resultant reaction suspension was filtered through a celite bed and the bed was washed with methanol (5 ml). The filtrate was distilled completely at about 55 0 C under reduced pressure to afford 0.4 g of the title compound having an XRPD pattern substantially in accordance with Fig. 3.

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

Abstract

L'invention concerne plusieurs procédés et composés associés à la darifénacine et/ou à ses sels. L'invention concerne par exemple un procédé de préparation d'une base libre de darifénacine : Formule ou de son sel. Le procédé comprend la mise en réaction de la 3-(S)-(cyanodiphénylméthyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)éthyl] pyrrolidine de formule (IV) ou un de ses sels : Formule (IV) avec une base efficace pour transformer le groupement nitrile du composé de formule (IV) en groupement amide de la darifénacine dans un solvant organique, à condition que le solvant ne soit pas le 2-méthyl-butan-2-ol et que la réaction produise une quantité inférieure à environ 0,5 % du composé de formule (Ic) : Formule (Ic) dans la masse réactionnelle, telle que mesurée par HPLC. L'invention concerne également plusieurs modes de réalisation et plusieurs variantes.
PCT/US2008/050388 2007-01-05 2008-01-07 Préparation de darifénacine et ses sels WO2008100651A2 (fr)

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US89471107P 2007-03-14 2007-03-14
US60/894,711 2007-03-14
IN2060CH2007 2007-09-13
IN2060/CHE/2007 2007-09-13

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009010846A3 (fr) * 2007-07-13 2009-03-12 Medichem Sa Forme amorphe du bromhydrate de darifénacine et ses procédés de préparation
WO2009007853A3 (fr) * 2007-06-08 2009-08-06 Actavis Group Ptc Ehf Nouveaux polymorphes de la base libre de darifénacine et son sel d'hydrobromure
CN101973971A (zh) * 2010-09-26 2011-02-16 山东邹平大展新材料有限公司 一种制备5-卤代乙基-2,3-二氢苯并呋喃的方法
WO2008126106A3 (fr) * 2007-04-16 2011-07-14 Manne Satyanarayana Reddy Procédés nouveaux et perfectionnés pour la préparation d'intermédiaires de darifénacine, de la darifénacine et de ses sels pharmaceutiquement acceptables
CN102372699A (zh) * 2010-08-13 2012-03-14 株式会社钟化 1,3位-二取代吡咯烷化合物的盐的改良制造方法
CN109641822A (zh) * 2016-08-12 2019-04-16 拜耳作物科学股份公司 制备取代苯乙烯衍生物的方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8906166D0 (en) * 1989-03-17 1989-05-04 Pfizer Ltd Therapeutic agents
GB0207104D0 (en) * 2002-03-26 2002-05-08 Pfizer Ltd Stable hydrate of a muscarinic receptor antagonist
WO2007076158A2 (fr) * 2005-12-27 2007-07-05 Teva Pharmaceutical Industries Ltd. Procedes de preparation de bromhydrate de darifenacine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008126106A3 (fr) * 2007-04-16 2011-07-14 Manne Satyanarayana Reddy Procédés nouveaux et perfectionnés pour la préparation d'intermédiaires de darifénacine, de la darifénacine et de ses sels pharmaceutiquement acceptables
WO2009007853A3 (fr) * 2007-06-08 2009-08-06 Actavis Group Ptc Ehf Nouveaux polymorphes de la base libre de darifénacine et son sel d'hydrobromure
US20100204296A1 (en) * 2007-06-08 2010-08-12 Actavis Group Ptc Ehf Novel Polymorphs of Darifenacin Free Base and its Hydrobromide Salt
WO2009010846A3 (fr) * 2007-07-13 2009-03-12 Medichem Sa Forme amorphe du bromhydrate de darifénacine et ses procédés de préparation
CN102372699A (zh) * 2010-08-13 2012-03-14 株式会社钟化 1,3位-二取代吡咯烷化合物的盐的改良制造方法
CN101973971A (zh) * 2010-09-26 2011-02-16 山东邹平大展新材料有限公司 一种制备5-卤代乙基-2,3-二氢苯并呋喃的方法
CN109641822A (zh) * 2016-08-12 2019-04-16 拜耳作物科学股份公司 制备取代苯乙烯衍生物的方法

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