WO2008155777A2 - Procédé de préparation de l'efletrizine - Google Patents

Procédé de préparation de l'efletrizine Download PDF

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Publication number
WO2008155777A2
WO2008155777A2 PCT/IN2008/000279 IN2008000279W WO2008155777A2 WO 2008155777 A2 WO2008155777 A2 WO 2008155777A2 IN 2008000279 W IN2008000279 W IN 2008000279W WO 2008155777 A2 WO2008155777 A2 WO 2008155777A2
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formula
bis
efletrizine
fluorophenyl
crystalline
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WO2008155777A3 (fr
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Rajendra Gokalbhai Chavda
Ketan Ambalal Doshi
Shriprakash Dhar Dwivedi
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Zydus Lifesciences Ltd
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Cadila Healthcare Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a new process for preparing Efletrizine or its pharmaceutically acceptable salts thereof.
  • the present invention also relates to the process of preparation of novel intermediate thereof in crystalline form.
  • the present invention further provides the process for preparation of substantially pure 2- ⁇ -2- [4- (bis(4-flourophenyl-)methyl)-l-piperazinyl]ethoxy ⁇ acetic acid dihydrochloride.
  • Efletrizine is useful as therapeutic agents for the treatment of allergic diseases and other disorders.
  • Efletrizine is chemically known 2- ⁇ -2-[4-(bis(4-flourophenyl-)methyl)-l- piperazinyl]ethoxy ⁇ acetic acid of Formula I, have been proven useful as therapeutic agents for the treatment of allergic diseases and other disorders.
  • Efletrizine is a substituted benzhydrylpiperazine derivative encompassed within general formula (I) of European patent No. 0058146. It has been demonstrated to have antiallergic and antihistaminic properties and has been suggested for the treatment of seasonal and perennial allergic rhinitis.
  • Efletrizine has been found to possess excellent antihistaminin properties. It belongs to the pharamcological class of second generation histamine Hi-receptor antagonists and shows in vitro high affinity and selectivity for Hi -receptors. Efletrizine is useful as an antiallergic, antihistaminic, bronochodilator and antispasmodic agent. Recent clinical studies have shown the utility of efletrizine when administered in the form of a nasal spray for the treatment of allergic rhinitis and rhino-conjunctivities (J.F Dessanges et.al. Allergy and Clin. Immunol .News (1994), Suppl. No. 2, abstract 1864; C.
  • Efletrizine is encompassed within the general formula of European patent No. 0 058 146 and may be prepared according to the general process described in this patent.
  • Said process for the synthesis of 2- ⁇ -2-[4-(bis(4-flourophenyl-)rnethyl)-l- piperazinyl]ethoxy ⁇ acetic acid derivatives comprises reacting a l-(diphenylmethyl)- piperazine derivative with methyl(2-chloroethoxy)acetate or 2-(2- chloroethoxy)acetamide to form a methyl 2- ⁇ -2-[4-(diphenylmethyl)-l- piperazinyljethoxy ⁇ acetate or a 2- ⁇ -2-[4-(diphenylmethyl)-l-piperazinyl]ethoxy ⁇ acetamide, respectively.
  • methyl ester or acetamide is then subjected to basic hydrolysis followed by acidification and isolation of the free carboxylic acid. This material is then transformed into
  • WO 2006/050909 Al discloses an amorphous form of efletrizine dihydrochloride obtained by freeze-drying.
  • the patent also discloses various solvate form of efletrizine dihydrochloride characterized by x-ray powder diffraction.
  • U.S. Patent 6,335,331 B2 discloses the pseudopolymorphic forms of efletrizine dihydrochloride characterized by x-ray powder diffraction pattern and their process of preparation.
  • US '331 B2 provides two pseudopolymorphic forms, namely anhydrous efletrizine dihydrochloride and efletrizine dihydrochloride monohydrate.
  • the anhydrous efletrizine dihydrochloride is designated as "Form A”
  • efletrizine dihydrochloride monohydrate is designated as "Form B".
  • L 2 represents a leaving group and Y in the presence of an inert solvent and a proton acceptor.
  • the total impurities are less than about 0.4% by area percentage of HPLC.
  • Efletrizine hydrochloride can be in the form of Anhydrous Form A or monohydrate form.
  • the present invention further provides the process for the preparation of N,N- bis(2-chloroethyl)-4-methylbenzenesulfonamide of formula (V), which is a key intermediate for the preparation of Eflitrizine
  • N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide of formula (V) is isolated by the conventional method.
  • the compound of formula (I) or its pharmaceutically acceptable salts i.e. efletrizine dihydrochloride monohydrate in crystalline form is having particle size D50 less than or equal to 250 ⁇ m.
  • the compound of formula (I) or its pharmaceutically acceptable salts i.e. efletrizine dihydrochloride monohydrate in crystalline form is substantially pure having purity greater about 99% by area percentage of HPLC and having dimer impurity less than about 0.1% by area percentage of HPLC.
  • the total impurities is less than about 0.4% by area percentage of HPLC is also within the scope of the present invention.
  • the compound of formula (I) or its pharmaceutically acceptable salts i.e. efletrizine dihydrochloride monohydrate in crystalline form is substantially pure having purity greater about 99% by area percentage of HPLC and having dimer impurity less than about 0.1% by area percentage of HPLC.
  • the total impurities is less than about 0.4% by area percentage of HPLC is also within the scope of the present invention.
  • the compound of formula (I) or its pharmaceutically acceptable salts i.e. efletrizine dihydrochloride monohydrate in crystalline form
  • (I) or its pharmaceutically acceptable salts i.e. efletrizine dihydrochloride anhydrous in crystalline form is substantially pure having purity greater about 99% by area percentage of HPLC and having dimer impurity less than about 0.1% by area percentage of HPLC.
  • the total impurities is less than about 0.4% by area percentage of HPLC is also within the scope of the present invention.
  • FIG.l is a differential scanning calorimetry (DSC) thermogram of compound of formula (III)
  • FIG.2 is powder X-ray diffraction pattern of compound of formula (III)
  • FIG.3 is an FTIR spectrum of compound of formula (III).
  • FIG.4 is a differential scanning calorimetry (DSC) thermogram of compound of formula (IV)
  • FIG.5 is powder X-ray diffraction pattern of compound of formula (IV)
  • FIG.6 is an FTIR spectrum of compound of formula (IV)
  • FIG.7 is a differential scanning calorimetry (DSC) thermogram of compound of formula (VI).
  • FIG.8 is powder X-ray diffraction pattern of compound of formula (VI)
  • FIG.9 is an FTIR spectrum of compound of formula (VI).
  • FIG.10 is a differential scanning calorimetry (DSC) thermogram of efletrizine dihydrochloride monohydrate
  • FIG.l 1 is powder X-ray diffraction pattern of efletrizine dihydrochloride monohydrate
  • FIG.12 is an FTIR spectrum of efletrizine dihydrochloride monohydrate
  • FIG.13 is a differential scanning calorimetry (DSC) thermogram of efletrizine dihydrochloride anhydrous
  • FIG.14 is powder X-ray diffraction pattern of efletrizine dihydrochloride anhydrous
  • FIG.15 is an FTIR spectrum of efletrizine dihydrochloride anhydrous
  • the present invention provides a process for the preparation of Eflitrizine of the formula (I) or its non-toxic pharmaceutically acceptable salts thereof
  • step (a) 4,4'-diflourobenzophenone of formula (II) is reacted with ammonium formate in a suitable organic solvent to give N-(bis(4- fluorophenyl)methyl)formamide of formula (III).
  • the suitable organic solvent as used in step (a) is polar solvent.
  • 4,4'-diflourobenzophenone of formula (II) with ammonium formate is carried out at ambient temperature to the reflux temperature.
  • reaction step (a) is carried out at about 100 0 C to 25O 0 C, preferably 15O 0 C to 200 0 C, most preferably 175°C to 18O 0 C.
  • N-(bis(4-fluorophenyl)methyl)formamide of formula (III) is hydrolyzed in suitable solvent to provide bis(4-fluorophenyl)methanamine of formula (IV) or its salt such as hydrochloride by using suitable reagent
  • the suitable reagents for hydrolysis as mentioned is step (b) may be selected from the group of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid.
  • the reaction is preferably carried out in water or water miscible solvent such as alcohols like methanol, isopropanol, ethanol, n-propanol, butanol.
  • the hydrolysis reaction is preferably carried out at temperature about 75 0 C to 150 0 C, preferably 9O 0 C to 120 0 C, most preferably 95°C to 100 0 C.
  • Bis(4-fluorophenyl)methanamine of formula (IV) is condensed with compound of formula (V) in suitable organic solvent, wherein organic solvent selected from, but not limited to, members from the classes: ketonic solvents such as acetone, ethylmethyl ketone, methyl isobutyl ketone and the like; ether solvents such as diethyl ether, dimethyl ether, di-isoopropyl ether, methyltertiarybutyl ether, tetrahydrofuran, 1,4- dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; halogenated solvents such as dichloromethane, 1,2-dichloromethane, chloroform, carbon tetrachloride and the like; aprotic polar solvents such as dimethylsulfoxide (DMSO), N,N-d
  • the reaction is carried out in presence of suitable base preferably but not limited to sodium hydroxide, potassium hydroxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, amines such as ammonia, methyl amine, ethyl amine, tri ethyl amine, diethyl amine, isopropyl amine, diisopropyl amine or mixtures thereof.
  • suitable base preferably but not limited to sodium hydroxide, potassium hydroxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, amines such as ammonia, methyl amine, ethyl amine, tri ethyl amine, diethyl amine, isopropyl amine, diisopropyl amine or mixtures thereof.
  • step (c) The condensation reaction as mentioned in step (c) is preferably carried out at temperature about 50 0 C to 200 0 C, preferably 100 0 C to 15O 0 C, most preferably 125°C to 130 0 C.
  • the compound of formula (VI) is isolated by gradual cooling is at room temperature initially followed by chilling to 0 0 C to 5 0 C.
  • the compound of formula (VI) is converted to l-(bis(4- fluorophenyl)methyl)piperazine formula (VII) using hydroxy acid like p-hydroxy benzoic acid in presence of HBr in acetic acid reagent.
  • reaction step (d) is carried out at O 0 C 5O 0 C, preferably 45°C to 47 0 C.
  • l-(bis(4-fluorophenyl)methyl)piperazine formula (VII) reacted with amide of formula (VIII) in presence of base to obtain 2-(2-(4-(bis(4- fluorophenyl)methyl)piperazin- 1 -yl)ethoxy)acetamide of formula (IX).
  • the base can be used in the reaction is selected from inorganic base or organic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide, tri ethyl amine, diisopropyl amine and the like.
  • the reaction is preferably carried out in polar solvent such as alcohols like methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, water and the like or mixtures thereof.
  • polar solvent such as alcohols like methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, water and the like or mixtures thereof.
  • Eflitrizine of formula (I) is converted to Eflitrizine by treatment with mineral acid.
  • the preferred mineral acid is selected from Hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid.
  • the preferred acid is hydrochloric acid.
  • the obtained compound of formula (I) can be converted to efletrizine dihydrochloride monohydrate or efletrizine dihydrochloride anhydrous being characterized by their X-ray powder diffraction patterns and DSC as depicted in the respective figures.
  • the present invention further provides the process for the preparation of N 5 N- bis(2-chloroethyl)-4-methylbenzenesulfonamide of formula (V), which is a key intermediate for the preparation of Eflitrizine
  • N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide of formula (V) is isolated by the conventional method.
  • Base can selected from like sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, organic bases like isopropyl amine, diisopropyl amine, triethylamine, ammonia, pyridine etc. preferably inorganic base like sodium hydroxide.
  • N-(bis(4-fluorophenyl)methyl)formamide of formula (III) in its crystalline form and having powder X-ray diffraction pattern as depicted in FIG.2 is another most preferred embodiment of the present invention.
  • Crystalline N-(bis(4-fluorophenyl)methyl)formamide of formula (III) is being characterized by differential scanning calorimeter profile as depicted in FIG.l and having endothermic peak at 117.20 0 C.
  • Crystalline N-(bis(4-fluorophenyl)methyl)formamide of formula (III) is being characterized by powder X-ray diffraction pattern having characteristic peaks at 2 ⁇ ( ⁇ 0.2) values 7.7°, 11.1°, 15.5°, 21.1° and 25.2°.
  • the crystalline N-Formyl-N-(4,4'-diflourobenzhydraryl) of formula (III) is being characterized by powder X-ray diffraction pattern peaks at 2 ⁇ ( ⁇ 0.2) values 7.7°, 8.9°, 11.1°, 15.5°, 16.0°, 18.5°, 19.3°, 20.1°,21.1°, 21.5°, 22.4°, 23.4°, 24.5°, 25.2°, 27.0°, 28.9° and 31.3°.
  • Crystalline N-(bis(4-fluorophenyl)methyl)formamide of formula (III) is being characterized by FTIR spectrum as depicted in FIG. 3 with characteristics peaks at about 3278, 1658, 1602, 1390, 833 and 732 cm “1 .
  • the crystalline N-(bis(4-fluorophenyl)methyl)formamide of formula (III) is being characterized by FTIR spectrum with peaks at about 3278, 2889, 1658, 1602, 1531, 1390, 1228, 1159, 1101, 1033, 1014, 893, 833, 813, 732 and 557 cm “1 .
  • a crystalline bis(4-fiuorophenyl)methanamine hydrochloride of formula (IVa) is being characterized by x-ray powder diffraction as depicted in FIG. 4 is also the scope of the present invention.
  • a crystalline bis(4-fluorophenyl)methanamine hydrochloride of formula (IVa), is being characterized by differential scanning calorimeter profile as depicted in FIG. 5 and having endothermic peak at about 277.1°C.
  • a crystalline bis(4-fluorophenyl)methanamine of formula (IV), is being characterized by x-ray powder diffraction pattern having characteristic peaks at 2 ⁇ ( ⁇ 0.2) values 7.4°, 15.1°, 19.8° and 25.0°.
  • crystalline bis(4-fluorophenyl)methanamine of formula (IV) characterized by x-ray powder diffraction pattern having peaks at 2 ⁇ ( ⁇ 0.2) values 7.4°, 10.8°, 13.6°, 15.1°, 16.6°, 18.6°, 19.8°, 22.0°, 22.7°, 24.0°, 25.0°, 26.6°, 27.9°, 29.5°, 30.5° and 31.6°.
  • a crystalline bis(4-fluorophenyl)methanamine of formula (IV), is being characterized by FTIR spectrum as depicted in FIG. 6 with peaks at about 2962, 2908, 1602, 1514, 1244 and 553 cm “1 .
  • the crystalline bis(4-fiuorophenyl)methanamine of formula (IV) is being characterized by FTIR spectrum with peaks at about 2962, 2908, 2040, 1602, 1514, 1425, 1382, 1244, 1193, 1165, 1120, 1014, 835, 775, 721, 586 and 553 cm “1 .
  • a crystalline l-(bis(4-fluorophenyl)methyl)-4-tosylpiperazine (VI) is being characterized by x-ray powder diffraction as depicted in FIG. 7 is also the scope of the present invention.
  • a crystalline compound l-(bis(4-fluorophenyl)methyl)-4-tosylpiperazine (VI), is being characterized by differential scanning calorimeter profile as depicted in FIG. 8 and having endothermic peak at about 196.9 0 C.
  • a crystalline compound l-(bis(4-fluorophenyl)methyl)-4-tosylpiperazine (VI), is being characterized by x-ray powder diffraction pattern having characteristic peaks at 2 ⁇ ( ⁇ 0.2) values 6.2°, 12.5, 15.3, 16.0° and 22.3°.
  • crystalline compound l-(bis(4-fluorophenyl)methyl)-4- tosylpiperazine (VI) characterized by x-ray powder diffraction pattern having peaks at 20 ( ⁇ 0.2) values 6.2°, 9.1, 12.5°, 14.3°, 15.3, 16.0, 17.7°, 18.0°, 18.6°, 19.6°, 20.4°, 21.0°, 22.3°, 23.5°, 24.7, 25.7, 26.5, 27.0, 27.5 and 30.1°.
  • a crystalline compound l-(bis(4-fluorophenyl)methyl)-4-tosylpiperazine (VI) is being characterized by FTIR spectrum as depicted in FIG. 9 with peaks at about 2989, 1896, 1600, and 584 cm "1 .
  • the crystalline compound l-(bis(4-fiuorophenyl)methyl)-4- tosylpiperazine (VI) is being characterized by.
  • FTIR spectrum with peaks at about 2989, 2816, 1896, 1780, 1600, 1502, 1456, 1328, 1220, 1 172, 1060, 1006, 937, 829, 788, 732, 650, 621, 584, 518, and 443 cm "1 .
  • the monohydrate of efletrizine dihydrochloride is substantially pure having purity greater than about 99% by area percentage of HPLC, preferably purity greater than about 99.6% by area percentage of HPLC.
  • the monohydrate of efletrizine dihydrochloride may contain less than or about 0.4% total impurities and having not detectable level of dimer impurity at RRT 3.80 as measured by area percentage of HPLC.
  • the anhydrate of efletrizine dihydrochloride is substantially pure having purity greater than about 99% by area percentage of HPLC, preferably purity greater than about 99.6% by area percentage of HPLC.
  • the anhydrate of efletrizine dihydrochloride may contain less than or about 0.4% total impurities and having not detectable level of dimer impurity at RRT 3.80 as measured by area percentage of HPLC.
  • a crystalline efletrizine dihydrochloride monohydrate having particle size D 50 less than or equal to 400 ⁇ m as measured by Malvern light scattering instrument, preferably less than or equal to 250 ⁇ m, more preferably less than or equal to 200 ⁇ m, most preferably less than or equal to 175 ⁇ m as measured by Malvern light scattering instrument and being characterized by x-ray powder diffraction pattern as depicted in FIG. 11.
  • a crystalline efletrizine dihydrochloride monohydrate as disclosed herein above is being characterized by differential scanning calorimetry profile as depicted in FIG. 10 and having endothermic peak at 160.22 0 C.
  • a crystalline efletrizine dihydrochloride monohydrate is characterized by powder x-ray diffraction pattern having characteristic peaks at 2 ⁇ ( ⁇ 0.2) values 7.3°, 10.3°, 17.7° and 24.5° and as shown in FIG.l 1
  • crystalline efletrizine dihydrochloride monohydrate is characterized by powder x-ray diffraction pattern having peaks at 2 ⁇ ( ⁇ 0.2) values 7.3°, 10.3°, 10.6°, 15.6°, 17.7°, 18.8°, 19.4°, 20.3°, 20.8°,21.5°, 22.1°, 22.4°, 24.5°, 25.8°, 26.6° and 29.2°.
  • a crystalline efletrizine dihydrochloride monohydrate is also characterized by FTIR spectrum as depicted in FIG. 12 with peaks at about 3398, 2922, 1712, 1512, 1120, 869 and 574 cm “1 .
  • crystalline efletrizine dihydrochloride monohydrate is characterized by FTIR spectrum with peaks at about 3398, 2922, 2357, 1712, 1604, 1512, 1433, 1313, 1232, 1163, 1087, 995, 902, 869, 792, 651 and 574 cm “1 .
  • efletrizine anhydrous having particle size D 50 less than or equal to 400 ⁇ m as measured by Malvern light scattering instrument, preferably less than or equal to 350 ⁇ m, more preferably less than or equal to 250 ⁇ m, most preferably less than or equal to 225 ⁇ m as measured by Malvern light scattering instrument and being characterized by x-ray powder diffraction pattern as depicted in FIG. 14. It is also the preferred embodiment of the present invention that efletrizine dihydrochloride monohydrate is having moisture content of about 3.75%
  • a crystalline efletrizine dihydrochloride anhydrous as disclosed herein above is being characterized by differential scanning calorimetry profile as depicted in FIG. 13 and having endothermic peak at about 226 0 C.
  • a crystalline efletrizine dihydrochloride anhydrous is characterized by powder x-ray diffraction pattern having characteristic peaks at 2 ⁇ ( ⁇ 0.2) values 13.6°, 14.8°, 18.4° and 25.0° and as shown in FIG. 14
  • crystalline efletrizine dihydrochloride anhydrous is characterized by powder x-ray diffraction pattern having peaks at 2 ⁇ ( ⁇ 0.2) values 8.2°, 13.6°, 14.8°, 18.4°, 20.7°, 22.9°, 23.9°, 25.0°, 26.6°, 28.2°, 30.1°, 30.7°, 31.3° and 32.2°.
  • a crystalline efletrizine dihydrochloride anhydrous is also characterized by FTIR spectrum as depicted in FIG. 15 with peaks at about 2949, 1749, 1514, and 829 cm "1 .
  • crystalline efletrizine dihydrochloride anhydrous is characterized by FTIR spectrum with peaks at about 2949, 2418, 2349, 1749, 1604, 1514, 1454, 1352, 1230, 1166, 1138, 1055, 920, 829 and 576 cm “1 .
  • efletrizine dihydrochloride anhydrous is having moisture content of about 0.13%
  • the Impurity Profile Determination of Efletrizine dihydrochloride comprised testing a sample using HPLC.
  • the HPLC testing parameters included a column of Grace Vydac 5 ⁇ m 4.6*250 mm (or equivalent column) at a temperature of 40 0 C and eluted with a two solvent system.
  • a first reservoir, Reservoir A contained 0.0 IM potassium hydrogen phosphate, 1 -octane sulfonic acid, adjusted to pH 3.0 with H 3 PO 4
  • a second reservoir, Reservoir B contained acetonitrile.
  • the gradient was as follows: at the initial time, 65% Reservoir A and 35% Reservoir B; time 15.0 min 65% Reservoir A and 35% Reservoir B; and at time 25.0 min 35% Reservoir A and 65% Reservoir B, and at time 50.0 min 35% Reservoir A and 65% Reservoir B, and at time 55.0 min 65% Reservoir A and 35% Reservoir B, and at time 70.0 min 65% Reservoir A and 35% Reservoir B.
  • the system equilibrated further for 10 min and a flow rate of 1.3 mL/min.
  • the detector was set for 220 nm.
  • the sample volume was 20 ⁇ L and the diluent was acetonitrile: water 50:50.
  • the mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
  • the sample was prepared by weighing accurately about 10 mg of Efletrizine dihydrochloride sample in a 20 ml amber volumetric flask. Dissolving the sample with 10 ml of acetonitrile and diluting to the desired volume with water.
  • Example-1 Preparation of N-(bis(4-fluorophenyl)rnethyl)formamide of formula (III) 4,4'-difluorobenzophenone (100 gm, 0.458 mole) (II), Ammonium Formate (232 gm, 3.67 mole) were taken in 56 mL of foramide in RBF.
  • the reaction mixture was heated slowly to 175 0 C to 18O 0 C within 3 hours and maintained for 6-7 hours.
  • the reaction mass was quenched in 400 mL of water within 1 hour and stir for 30 min.
  • the product was filtered and suck dried.
  • the product was washed with water and suck dried.
  • the product was dried in oven at 5O 0 C to 55 0 C to N-(bis(4- fiuorophenyl)methyl)formamide of formula (III).
  • bis(4-fluorophenyl)methanamine hydrochloride of formula (IVa) (100 gm, 0.391 mole) was taken in 800 mL of water and stirred for 10 min. 25% NaOH solution was added till alkaline pH 12. Methylene dichloride (500 mL) was added and the reaction mass was stirred for 15 min. The layers were separated. The aqueous layer was extracted with 300 mL of methylene dichloride. The organic layer was washed with 300 mL of water and layers were separated. The organic layer was treated with sodium bisulfate and filtered. The methylene dichloride was distilled atmospherically and finally under vacuum to remove the traces of methylene dichloride to give bis(4- fluorophenyl)methanamine of formula (IV).
  • N, N'-Bis (2-chloroethyl)amine hydrochloride 112.5 gm, 0.63 mole
  • methylene dichloride 800 mL
  • triethylamine 182 mL
  • Freshly prepared solution of p-toluene sulfonyl chloride 100 gm, 0.524 mole
  • methylene dichloride 400 mL
  • the reaction mixture was heated to reflux at 4O 0 C to 43 0 C for 6 hours.
  • the reaction mass was cooled to room temperature.
  • the organic solution was washed with water and stirred for 15 minutes. The layers were separated.
  • 4,4'-diflourobenzyhydrarylamine (100 gm, 0.456 mole) were taken in 100 mL of diisopropyl ethyl amine.
  • N,N-bis(2-chloroethyl)-4-methylbenzenesulfonarnide of formula (V) (135 gm, 0.456 mole) in 100 mL of diisopropyl ethyl amine was added to it and the reaction mass was stirred for 10 min.
  • the reaction mixture was heated to reflux temp at 125 0 C to 127 0 C for 17 to 18 hours and cooled to 75°C. 400 mL of methanol was added and refluxed at 65 0 C to 7O 0 C for 1 hour.
  • Example-6 Preparation of l-(bis(4-fluorophenyl)methyl)piperazine formula (VII)
  • the solution of hydrobromic acid acetic acid (550 mL) was prepared and chilled to O 0 C to 5 0 C.
  • 4-hydroxy benzoic acid (152.8 gm, 1.107 mole) was added to the above solution.
  • l-(bis(4-fluorophenyl)methyl)-4-tosylpiperazine (VI) 100 gm, 0.226 mole was added slowly at same temperature.
  • the reaction mass was treated with 50 mL HBr in acetic acid and stirred for 30 min.
  • the reaction mixture was gradually heated at 45 0 C to 47 0 C within 1 hour to 1.5 hour and stirred for 4 hours at same temperature.
  • the reaction mass was cooled to room temperature and treated with 1000 mL of water with stirring for 1 hour.
  • the product was filtered and washed with water.
  • the product was suck dried.
  • the aqueous filtrate was extracted with toluene.
  • 1000 mL of toluene was added to aqueous filtrate. 50% NaOH solution was added to it till the alkaline pH 9 to 10.
  • the layers were separated.
  • the aqueous layer was again extracted with toluene 500 mL.
  • the organic layer of toluene, acetic acid (100 mL) solution in (642.5 niL) of water was added.
  • the aqueous layer was washed with toluene 600 mL.
  • the separated aqueous layer was treated with IN 725 mL of NaOH and stirred for 10 minutes.
  • 600 mL of methylene dichloride was added.
  • the layers were separated and aqueous layer was extracted with 400 mL of methylene dichloride.
  • the combined methylene dichloride was washed with 400 mL of water.
  • the methylene dichloride was distilled out atmospherically at 50 0 C to 55°C further under vacuum to remove the traces.
  • Diisopropyl ether (200 mL) was added and distilled out under vacuum at 50 0 C.
  • Example-8 Preparation of EFLETRIZINE DIHYDROCHLORIDE MONOH YDRATE
  • Efletrizine dihydrochloride monohydrate (100 gm) was taken in 300 mL of methylethyl ketone. The reaction mixture was refluxed to the reflux temperature of the solvent to get clear solution. The product was cooled to room temperature. The product thus obtained was filtered, washed with methyl ethyl ketone and dried at 5O 0 C to 55°C to obtain Efletrizine dihydrochloride anhydrous. The samples were analyzed by HPLC. The fractions with a purity of > 99.0% were pooled. In the pooled fractions the HPLC purity was about > 99.7%.

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Abstract

L'invention concerne un nouveau procédé de préparation de l'Efletrizine ou de ses sels acceptables d'un point de vue pharmaceutique. La présente invention concerne également un procédé de préparation d'un nouvel intermédiaire de celle-ci sous forme cristalline, ainsi qu'un procédé de préparation du dihydrochlorure d'acide 2-{-2-[4-(bis(4-fiourophenyl-)methyl)-1-piperazinyl]ethoxy} acétique pratiquement pur. L'acide 2-{-2-[4-(bis(4-flourophenyl-)methyl)-1-piperazinyl]ethoxy} acétique est connu habituellement sous le nom d'Efletrizine et est représenté par la formule (I). L'Efletrizine est utile comme agent thérapeutique dans le traitement de maladies allergiques et d'autres troubles.
PCT/IN2008/000279 2007-06-18 2008-05-02 Procédé de préparation de l'efletrizine Ceased WO2008155777A2 (fr)

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IN1164MU2007 2007-06-18
IN1164/MUM/2007 2007-06-18

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WO2008155777A2 true WO2008155777A2 (fr) 2008-12-24
WO2008155777A3 WO2008155777A3 (fr) 2009-07-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119955079A (zh) * 2023-11-07 2025-05-09 中国石油化工股份有限公司 一种耐温抗盐稠油降黏驱油剂及其制备方法

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EP0919550A1 (fr) * 1997-11-26 1999-06-02 Ucb, S.A. Formes pseudopolymorphiques de l'acide 2-2-4-bis(4-fluorophényl)méthyl -1-pipérazinyl-éthoxy acétique dihydrochloride
EP1414460A1 (fr) * 2001-07-26 2004-05-06 Ucb, S.A. Procede de fabrication de derives d'acides 2-(2-(4-(bis(4-fluorophenyl)methyl)-piperazine-1-yl)ethoxy)acetiques ou de sels de ces composes et intermediaires correspondants
EP1535922A4 (fr) * 2002-07-11 2006-10-04 Takeda Pharmaceutical Derive de pyrrolopyridine et utilisation de ce dernier
ES2564804T3 (es) * 2004-02-12 2016-03-29 Mitsubishi Tanabe Pharma Corporation Compuesto de indazol y uso farmacéutico del mismo

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119955079A (zh) * 2023-11-07 2025-05-09 中国石油化工股份有限公司 一种耐温抗盐稠油降黏驱油剂及其制备方法

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