WO2011128911A2 - Improved process for ll-[(z)-3-(dimethylamino)propyiidenel-6-ll- dihydrodibenz[b,el oxepin-2-aceticacid - Google Patents

Improved process for ll-[(z)-3-(dimethylamino)propyiidenel-6-ll- dihydrodibenz[b,el oxepin-2-aceticacid Download PDF

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WO2011128911A2
WO2011128911A2 PCT/IN2011/000246 IN2011000246W WO2011128911A2 WO 2011128911 A2 WO2011128911 A2 WO 2011128911A2 IN 2011000246 W IN2011000246 W IN 2011000246W WO 2011128911 A2 WO2011128911 A2 WO 2011128911A2
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formula
reaction mixture
oxepin
compound
propylidene
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PCT/IN2011/000246
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WO2011128911A3 (en
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Manne Satyanarayana Reddy
Sajja Eswaraiah
Komati Satyanarayana
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Msn Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)

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  • the present invention relates to an improved process for the preparation of 11- [(Z)-3-(dimethylamino)propylidene]-6- 11 -dihydrodibenz[b,e]oxepin-2-aceticacid compound of formula- 1 and its harmaceutically acceptable salts.
  • the patent discloses the preparation of 11 -[(Z)-3-(dimethylamino)propylidene]-6- 11 -dihydrodibenz[b,e]oxepin-2-aceticacid through Wittig reaction by reacting l l-oxo-6,l l-dihydrodibenzo[b,e]oxepin-2-aceticacid compound of formula-2 with 3 -dimethyl aminopropyl triphenyl phosphonium bromide hydrobromide compound of formula-3 in presence of base n-butyl lithium and solvent tetrahydrofuran.
  • the obtained compound is purified by column chromatography and isolate pure 11 - [(Z)-3 -(dimethylamino)propylidene] -6-11 -dihydrodibenz[b,e] oxepin-2- aceticacid compound of formula- 1.
  • the detailed description of the synthesis of 1 l-[(Z)-3- (dimemylammo)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid and its salts has been disclosed Ohshima E. et., al by in J. Med. Chem. 1992, 35, 2074-2084.
  • the cis: trans ratio of the product has not been reported.
  • the preparation of l l-[(Z)-3-(dimethylamino)propylidene]-6-l l- dihydrodibenz[b,e] oxepin-2-aceticacid involves use of excess base and Wittig reagent.
  • the isolation of pure cis isomer l l-[(Z)-3-(dimethylamino)propylidene]-6-l l- dihydrodibenz[b,e] oxepin-2-aceticacid employs the use of column chromatography. The final yield of the product is low.
  • the compound of formula- 1 may be prepared by means of a
  • the present invention provides pure >99% z-isomer of l l-[(Z)-3-(dimethylamino)propylidene]-6-l l- dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride with high yield.
  • the present invention avoids the purification in the final stage and provides a pure >99% of Z-isomer of 1 l-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride according to HPLC.
  • the present invention relates to an improved process for the preparation of
  • the first aspect of the present invention is to provide pure z-isomer of
  • Second aspect of the present invention is to provide pure z-isomer of l l-[(Z)-3- (dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula- la, which comprises of reacting the 1 l-oxo-6, 11-dihydrobenz (b,e)oxepin-2- acetic acid compound of formula-2 with (3-dimethylaminopropyl)-triphenyl phosphoniumbromide hydrobromide compound of formula-3 in presence of n-hexyl lithium in a suitable solvent, at a temperature of about 35°C to 80°C.
  • the third aspect of the present invention is to provide a process for the preparation of l l-[(Z)-3-(dimemylammo)propylidene]-6-l l-dihydrodibenz[b,e] oxepin- 2-aceticacid hydrochloride.
  • the fourth aspect of the present invention is to provide a process for the conversion of E-isomer or the mixture of E&Z isomers to Z-isomer of l l-[3- (dimethylamino)propylidene]-6- 11 -dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride.
  • Another aspect of the present invention provides an improved process for the preparation of l l-[(Z)-3-(dimemylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin- 2-aceticacid hydrochloride comprising the following steps.
  • suitable solvent refers to the solvent selected from “polar solvents” such as water; "polar aprotic solvents” such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; “nitrile solvents” such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like; “ether solvents” such as di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane; "alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t- butanol and the like; “chloro solvents” such as methylene chloride, ethylene dichloride
  • acid refers to hydrochloric acid, sulphuric acid, nitric acid and anic acid such as acetic acid, lactic acid, formic acid, citric acid and oxalic acid
  • the present invention relates to an improved process for the preparation of 11- [(Z)-3-(dimemylammo)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid or its pharmaceutically acceptable salts.
  • the first aspect of the present invention is to provide 11 -[(Z)-3-(dimethylamino)propylidene]-6- 11 -dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula- 1 a, which comprises of
  • the process for the preparation of pure z-isomer of l l-[(Z)-3-(dimemylammo)propylidene]-6-l l-dmyckodibenz[b,e]oxepin-2-aceticacid hydrochloride compound of formula- la comprises of the following steps,
  • the second aspect of the present invention is to provide l l-[(Z)-3- (dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula- 1 a, which comprises of
  • Preferred embodiment of the present invention is to provide pure z-isomer of 11 -[(Z)-3-(dimethylamino)propylidene]-6-l 1 -dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride compound of formula- la, which comprises of
  • the third aspect of the present invention is to provide l l-[(Z)-3-(dimemylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula- la from aqueous acetone.
  • the third aspect of the present invention is to provide l l-[(Z)-3-
  • the fourth aspect of the present invention is the conversion process of E-isomer of ll-[3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride or a mixture of E&Z-isomer into its Z-isomer.
  • the conversion E or a mixture of E&Z isomers of 1 l-[3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid into required Z-isomer is carried in the following manner, a) Adding hydrochloric acid to a solution containing the mixture of E and Z isomers of 11 -[3 -(dimethylamino)propylidene] -6,11 -dihydrodibenzo [b,e]oxepin-2-l ⁇ acetic acid hydrochloride having major amount of E-isomer,
  • Another aspect of the present invention provides an improved process for the preparation of l l-[(Z)-3-(dimemylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin- 2-aceticacid hydrochloride comprising the following steps,
  • the related substance of olopatadine hydrochloride was analyzed by HPLC using the following conditions: A liquid chromatograph equipped with variable wavelength UV detector and Column: Symmetry shield RP18, 250X4.6 mm, 5 um or equivalent; Flow rate: 1.0 ml/min; wavelength: 220 nm; Temperature: 25°C; Load: 20 ⁇ ; Run time: 45 min; Elution: Gradient; and using buffer and acetonitrile as a mobile phase. Buffer aqueous mixture of octane- 1 -sulfonic acid sodium salt and sodium dihydrogen phosphate dehydrate solution,
  • the related substance of olopatadine hydrochloride was analyzed by HPLC using the following conditions: A liquid chromatograph equipped with variable wavelength UV detector and Column: UNISON C8, 150X4.6 mm, 5 um or equivalent; Flow rate: 1.0 ml/min; wavelength: 299 nm; Temperature: 25°C; Load: 30 ⁇ ; Run time: 30 min; Elution: Isocratic; and using buffer : acetonitrile(72:28) as a mobile phase.
  • Buffer Dissolve 13.6 gms of monobasic potassium phosphate in to 1000 mL of water, add 1 mL of triethylamine and adjust pH to 3.0 with diluted phosphoric acid. Filter this through 0.45 um Nylon filter paper and sonicate to degas.
  • the PXRD of crystalline olopatadine hydrochloride obtained in the present invention is represented in figure- 1.
  • Olopatadine hydrochloride obtained as per the present invention is further micronized or milled to get the desired particle size. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, with out limitation, ball, roller and ⁇ hammer mills, and jet mills.
  • pure refers to the compound having purity greater than 98.00%, preferably greater than 99.00% and more preferably greater than 99.50% by HPLC.
  • Example-1 Preparation of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la
  • n-Butyl lithium (100 ml) was added to the solution of 3-dimethylaminopropyl)- triphenyl phosphoniumbromide HBr compound of formula-3 (37.94 grams) in tetrahydrofuran (200 ml) at 0-5 °C under nitrogen atmosphere. The reaction mixture was stirred for an hour at the same temperature. A mixture of l l-oxo-6, 11-dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml) was added to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 65-70°C and then hated to reflux.
  • the reaction mixture was stirred for 12 hours at 65-70°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and then the aqueous layer was neutralizing with aqueous sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml) was added to the reaction mixture at 25-30°C.
  • reaction mixture was stirred for an hour at 25-30°C and filtered the solid. Washed the solid with acetone and dried to get the pure ⁇ (11Z)-1 l-[3-(dimethylamino)propylidene]-6,l l-dihydrodibenzo[b,e]oxepin-2-yl ⁇ acetic acid hydrochloride.
  • Example-3 Preparation of ll-[(Z)-3-(dimethyIamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la
  • n-Hexyl lithium (123.3 ml) was added to the solution of (3- dimemylaminopropyl)-triphenyl phosphoniumbromide HBr compound of formula-3 (59.3 grams) in tetrahydrofuran (500 ml) at 0-5°C under nitrogen atmosphere. The reaction mixture was stirred for an hour at same temperature. A mixture of 1 l-oxo-6,11- dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2 (25 grams) and tetrahydrofuran (75 ml) to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and then hated to 65-70°C.
  • the reaction mixture was stirred for 12 hours at 65-70°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (50 ml) and acetic acid (100 ml) was added to the reaction mixture at 25-30°C.
  • Example-4 Purification of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride
  • reaction mixture was stirred for an hour at 25-30°C and filtered the solid. Washed the solid with acetone and dried to get the pure ⁇ (llZ)-l l-[3-(dimethylamino)propylidene]-6,ll- dihydrodibenzo[b,e]oxepin-2-yl ⁇ acetic acid hydrochloride.
  • the reaction mixture was stirred for 24 hours at 40-45°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and then neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml) was added to the reaction mixture at 25-30°C.
  • Example-6 Preparation of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,ej oxepin-2-aceticacid hydrochloride compound of formula-la
  • reaction mixture was stirred for 18 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and then neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml) was added to the reaction mixture at 25-30°C.
  • Example-7 Preparation of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la
  • n-Hexyl lithium 49.32 ml was added to the solution of (3-dimethylaminopropyl)- triphenyl phosphoniumbromide HBr compound of formula-3 (23.72 grams) in teti ⁇ yclrofuran (100 ml) at 0-5°C under nitrogen atmosphere. The reaction mixture was stirred for an hour at same temperature. A mixture of l l-oxo-6,l l-dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml) to the reaction mixture at 0-5°C.
  • reaction mixture Slowly raised the temperature of the reaction mixture to 25-30°C and then hated to 40-45°C. The reaction mixture was stirred for 24 hours at 40- 45°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate.
  • Example-8 Preparation of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la
  • n-Hexyl lithium (49.32 ml) was added to the solution of (3- dimethylaminopropyl)-triphenyl phosphoniumbromide HBr compound of formula-3 (23.72 grams) in tetrahydrofuran (100 ml) at 0-5°C under nitrogen atmosphere. The reaction mixture was stirred for an hour at same temperature. A mixture of 1 l-oxo-6,11- dihydrobenz(b,e) oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml) to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and then hated to 50-55°C.
  • the reaction mixture was stirred for 18 hours at 50-55°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml) was added to the reaction mixture at 25-30°C.
  • a mixture of p-hydroxy phenylacetic acid (50 g), dimethylformamide (180 ml) and phthalide (47 g) was heated to 130-135°C for about 45 minutes and then cooled to 120-125°C.
  • 25% methanolic sodium methoxide (136 g) was added to the reaction mixture slowly at 120-125°C and then stirred for 10 minutes at 120-125°C. Distilled off methanol completely from the reaction mixture and then heated the reaction mixture to 130-135°C.
  • Phthalide (10 g) was added to the reaction mixture and stirred for 12 hours at 130-135°C. The reaction mixture was cooled to 5-10°C and then quenched it with 10% hydrochloric acid.
  • Example 12 Preparation of ll-oxo-6,ll-dihydrobenz[b,e]oxepin-2-acetic acid formula-2.
  • a mixture of polyphosphoric acid (385 g), 2-((4-(carboxymethyl)phenoxy) methyl)benzoic acid (110 g) and acetic acid (330 ml) was heated to 70-75°C and stirred for 2 1 ⁇ 2 hours at same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C, further to 10-15°C. Quenched the reaction mixture with water at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at same temperature. Filtered the precipitated solid, washed with water and dried. Ethylacetate (300 ml) was added to the obtained solid and heated the reaction mixture to 70-75°C and then stirred for 15 minutes at same temperature.
  • Example 13 Preparation of ll-oxo-6,H-dihydrobenz[b,e]oxepin-2-acetic acid formula-2.
  • Iodine 0.5 g was added to a mixture of magnesium (43 g) and tetrahydrofuran (150 ml) under nitrogen condition. Heated the reaction mixture to reflux temperature. 3- dimethyl amino propyl chloride (5 ml) followed by 1,2-dibromo ethane (2 g) were added to the reaction mixture at same reflux temperature. A solution of 3 -dimethyl amino propyl chloride (225 g) in tetrahydrofuran (200 ml) was added drop wise to the reaction mixture at reflux temperature and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C, further cooled to 5-10°C.
  • Toluene was added to the reaction mixture and stirred for 10 minutes. Both the toluene and aqueous layers were separated and the aqueous layer was washed with toluene. Both the toluene layers were combined and washed with hydrochloric acid. Both the aqueous layer and hydrochloric acid layers were combined. Heated the aqueous layer to 90-95 °C and stirred for 24 hours at same temperature Cooled the reaction mixture to 25-30°C and dichloromethane was added to the reaction mixture. Stirred the reaction mixture for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane.
  • Iodine 0.5 g was added to a mixture of magnesium (43 g) and tetrahydrofuran (150 ml) under nitrogen condition. Heated the reaction mixture to reflux temperature. 3- dimethyl amino propyl chloride (5 ml) followed by 1,2-dibromo ethane (2 g) were added to the reaction mixture at same reflux temperature. A solution of 3 -dimethyl amino propyl chloride (225 g) in (200 ml) was added drop wise to the reaction mixture at reflux temperature and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C, further cooled to 5-10°C.
  • Aqueous hydrochloric acid [hydrochloric acid (300 ml) in water (100 ml)] was added to the reaction mixture at a temperature 25-30°C. Heated the reaction mixture to 90-95°C and stirred for 3 hours at same temperature Cooled the reaction mixture to 25-30°C, toluene was added to it and stirred for 10 minutes. Both the toluene and aqueous layers were separated and the aqueous layer was washed with toluene. Acetic acid was added to the aqueous layer and stirred for 20 minutes at 25-30°C. Methylene chloride was added to the reaction mixture. Stirred the reaction mixture for 15 minutes at 25-30°C.
  • the PXRD of the compound obtained from process of the present invention is similar to the PXRD of prior art form-I disclosed in WO2007/105234 A2.
  • Example 16 Purification of (Z)-ll-[3-(dimehylamino)propyIidene]-6,ll- dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride A solution of (Z)-l l-[3-(dimehylamino)propylidene]-6,l l-dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride (2 g) in 10% aqueous acetone (35 ml) was heated to 50-55°C and stirred for 15 minutes at 50-55°C.
  • Carbon (0.2 g) was added to the reaction mixture and stirred for 15 minutes at 50-55°C. Filtered the reaction mixture through highflow bed and washed with 10% aqueous acetone. Distilled off the solvent from the filtrate under reduced pressure and co-distilled twice with aqueous acetone. The reaction mixture was cooled to 25-30°C, added acetone to it and stirred for 45 minutes at 25-30°C. Filtered the precipitated solid, washed with acetone and dried the material to get pure title compound.
  • the reaction mixture was cooled to 25-30°C, added acetone to it and stirred for 45 minutes at 25-30°C. Filtered the precipitated solid, washed with acetone. Acetone and water were added to the obtained wet compound and heated the reaction mixture to 50-60°C. Filter the reaction mixture and the obtained filtrate was heated to 40-45°C. Acetone was slowly added to the reaction mixture at 40-45°C. Cooled the reaction mixture to 0-5°C and stirred for 90 minutes at same temperature. Filtered the precipitated solid, washed with acetone and dried the compound to get the pure title compound.
  • the PXRD of the compound obtained from process of the present invention is similar to the PXRD of prior art form-I disclosed in WO2007/105234A2.

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Abstract

An improved process for the preparation of 11 -[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-acetic acid compound of formula-1 and pharmaceutically acceptable salts thereof are disclosed.

Description

Improved process for ll-[(Z)-3-(Dimethylamino)propylidenel-6-ll- dihydrodibenzfb,e] oxepin-2-aceticacid
Related Application:
This application claims the benefit of priority of our Indian patent application number 1003/CHE/2010 filed on 12th April 2010, which is incorporated herein by reference.
Field of the Invention:
The present invention relates to an improved process for the preparation of 11- [(Z)-3-(dimethylamino)propylidene]-6- 11 -dihydrodibenz[b,e]oxepin-2-aceticacid compound of formula- 1 and its harmaceutically acceptable salts.
Figure imgf000002_0001
Formula- 1
1 l-[(Z)-3-(dimemylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride pharmaceutically active substance known to be a known anti-allergy drug, useful for the treatment of the signs and symptoms of allergic conjunctivitis. In the United States, it is marketed by Kyowa Hakko Kogyo Co under the brand name Patanol® and, in Europe it is marketed under the brand name Opatanol®. It has been approved for the treatment of the signs and symptoms of allergic conjunctivitis.
Background of the Invention:
1 l-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-acetic acid free base and its pharmaceutically acceptable salts are described in U.S. Patent No. 4,871,865, although no specific examples for the preparation of 1 l-[(Z)-3-(dimethyl amino) propylidene]-6-l l-dihydrodibenz[b,e]oxepin-2-aceticacid or its pharmaceutically acceptable salts are provided therein. 1 l-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-acetic acid free base is specifically described in U.S. Patent No. 5,116,863. This U.S. patent does not provide any example describing the preparation of l l-[(Z)-3-(dimemylarnino) propylidene]-6-l l-dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride. It is believed that the l l-[(Z)-3-(dimethylammo)propylidene]-6-l l-dihydrodiberiz[b,e]oxepin-2- aceticacid hydrochloride was disclosed in US Patent No 5,116,863 (herein after "863') in 1992, assigned to Kyowa Hakko Kogyo Co., Ltd. The patent discloses the preparation of 11 -[(Z)-3-(dimethylamino)propylidene]-6- 11 -dihydrodibenz[b,e]oxepin-2-aceticacid through Wittig reaction by reacting l l-oxo-6,l l-dihydrodibenzo[b,e]oxepin-2-aceticacid compound of formula-2 with 3 -dimethyl aminopropyl triphenyl phosphonium bromide hydrobromide compound of formula-3 in presence of base n-butyl lithium and solvent tetrahydrofuran. The obtained compound is purified by column chromatography and isolate pure 11 - [(Z)-3 -(dimethylamino)propylidene] -6-11 -dihydrodibenz[b,e] oxepin-2- aceticacid compound of formula- 1. The detailed description of the synthesis of 1 l-[(Z)-3- (dimemylammo)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid and its salts has been disclosed Ohshima E. et., al by in J. Med. Chem. 1992, 35, 2074-2084.
In the above process, the cis: trans ratio of the product has not been reported. In the above method, the preparation of l l-[(Z)-3-(dimethylamino)propylidene]-6-l l- dihydrodibenz[b,e] oxepin-2-aceticacid involves use of excess base and Wittig reagent. The isolation of pure cis isomer l l-[(Z)-3-(dimethylamino)propylidene]-6-l l- dihydrodibenz[b,e] oxepin-2-aceticacid employs the use of column chromatography. The final yield of the product is low. Alternatively, the compound of formula- 1 may be prepared by means of a
Grignard reaction, reacting compound of formula-2 with Ν,Ν-dimethyl propyl magnesium halide, the compound of formula-4 followed by dehydration with a strong acid. The major disadvantages of the above process are non-selectivity in the formation of the E/Z isomers, and also the preparation of 1 l-[(Z)-3-(dimethylamino)propylidene]-6- l l-dihydrodibenz[b,e] oxepin-2-aceticacid which involves the protection and deprotection of the carboxylic acid group in formula-2 increasing the number of steps. Further, the isolation of pure compound employs the use of column chromatography. On following the above process the obtained cis: trans ratio was 10-15:90-85. However all the processes described earlier to the present invention could not control the formation of impurities especially the E-isomer. Therefore it is necessary to develop an alternative process for preparing 1 l-[(Z)-3-(dimethylamino) propylidene]-6- l l-dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride which overcomes the formation of E-isomer of l l-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin- 2-aceticacid hydrochloride as well as above discussed problems. The present invention provides pure >99% z-isomer of l l-[(Z)-3-(dimethylamino)propylidene]-6-l l- dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride with high yield. The present invention avoids the purification in the final stage and provides a pure >99% of Z-isomer of 1 l-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride according to HPLC.
Advantage of the Present invention:
The processes which were reported previous to the present invention used alkyl lithium bases for the preparation of l l-[(Z)-3-(dimethylarnino)propylidene]-6-l l- dihydrodibenz[b,e] oxepin-2-aceticacid, but the reactions were preformed at low temperatures below 25-30°C, and the yield was very poor and the purity was not satisfactory due to the formation of a mixture of E and Z isomers. It was identified that when the temperature of reaction medium was increased, the selectivity for the formation of Z-isomer in the final product increased, providing product with high purity and yield.
Brief description of the Invention:
The present invention relates to an improved process for the preparation of
I l-[(Z)-3-(dimemylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid or its pharmaceutically acceptable salts.
The first aspect of the present invention is to provide pure z-isomer of
I I - [(Z)-3 -(dimethylamino)propylidene] -6- 11 -dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula- la, which comprises of reacting the l l-oxo-6, 11-dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2 with (3 -dimethyl aminopropyl)- triphenyl phosphoniumbromide hydrobromide compound of formula-3 in presence of n- butyl lithium in a suitable solvent, at a temperature of about 35°C to 80°C.
Second aspect of the present invention is to provide pure z-isomer of l l-[(Z)-3- (dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula- la, which comprises of reacting the 1 l-oxo-6, 11-dihydrobenz (b,e)oxepin-2- acetic acid compound of formula-2 with (3-dimethylaminopropyl)-triphenyl phosphoniumbromide hydrobromide compound of formula-3 in presence of n-hexyl lithium in a suitable solvent, at a temperature of about 35°C to 80°C.
The third aspect of the present invention is to provide a process for the preparation of l l-[(Z)-3-(dimemylammo)propylidene]-6-l l-dihydrodibenz[b,e] oxepin- 2-aceticacid hydrochloride.
The fourth aspect of the present invention is to provide a process for the conversion of E-isomer or the mixture of E&Z isomers to Z-isomer of l l-[3- (dimethylamino)propylidene]-6- 11 -dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride.
Another aspect of the present invention provides an improved process for the preparation of l l-[(Z)-3-(dimemylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin- 2-aceticacid hydrochloride comprising the following steps.
a) Reacting p-hydroxyphenyl acetic acid compound of formula-5 with phthalide compound of formula-6 in presence of a base in a suitable solvent provides 2-((4- (carboxymethyl)phenoxy)methyl)benzoic acid compound of formula-7, b) reacting compound of formula-7 with polyphosphoric acid in presence of acetic acid provides l l-oxo-6, 11-dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2,
c) reacting compound of formula-2 with Grignard reagent of l-chloro-3 -dimethyl amino propane in a suitable solvent, followed by treatment with HC1 provides 11- [(Z)-3-(dimemylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin -2- aceticacid hydrochloride d) Optionally purifying the compound from a suitable solvent provides pure 11-[(Z)- 3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride compound of formula- la
Detailed description of the Invention:
As used herein the present invention, the term "suitable solvent" refers to the solvent selected from "polar solvents" such as water; "polar aprotic solvents" such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like; "ether solvents" such as di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t- butanol and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene and the like; "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane; "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like; "esters solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; and their mixtures thereof.
As used here in "acid" refers to hydrochloric acid, sulphuric acid, nitric acid and anic acid such as acetic acid, lactic acid, formic acid, citric acid and oxalic acid
The present invention relates to an improved process for the preparation of 11- [(Z)-3-(dimemylammo)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid or its pharmaceutically acceptable salts.
The first aspect of the present invention is to provide 11 -[(Z)-3-(dimethylamino)propylidene]-6- 11 -dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula- 1 a, which comprises of
a) Adding n-butyl lithium to the mixture of (3-dimemylaminopropyl)-triphenyl phosphoniumbromide hydrobromide compound of formula-3 in a suitable solvent, b) adding a solution of 11 -oxo-6, l l-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 in a suitable solvent,
c) heating the reaction mixture to a temperature of about 40°C to 80°C,
d) stirring the reaction mixture till the completion of the reaction,
e) quenching the reaction mixture with aqueous acid,
f) washing the aqueous layer with a suitable solvent,
g) neutralizing the reaction mixture with a suitable basic solution,
h) washing the aqueous layer with a suitable solvent,
i) adding hydrochloric acid and organic acid to the reaction mixture, to reduce the pH, j) extracting the reaction mixture with suitable solvent,
k) distilling off the solvent from organic layer,
1) isolating the obtained residue in a suitable solvent,
m) purifying the l l-[(Z)-3-(dimemylanimo)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula- la.
In a preferred embodiment, the process for the preparation of pure z-isomer of l l-[(Z)-3-(dimemylammo)propylidene]-6-l l-dmyckodibenz[b,e]oxepin-2-aceticacid hydrochloride compound of formula- la comprises of the following steps,
a) Adding n-butyl lithium to the mixture of (3-dimethylaminopropyl)-triphenyl phosphoniumbromide HBr compound of formula-3 in tetrahydrofuran,
b) adding the solution of 11 -oxo-6, 11 -dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 in tetrahydrofuran,
c) heating the reaction mixture to 65-70°C,
d) stirring the reaction mixture for 10-16 hours,
e) quenching the reaction mixture with aqueous hydrochloric acid,
f) washing the aqueous layer with toluene,
g) neutralizing the reaction mixture with sodium carbonate solution,
h) washing the aqueous layer with ethyl acetate,
i) adding acetic acid and hydrochloric acid to the reaction mixture, to reduce the pH ~ 1 to 2,
j) extracting the reaction mixture with dichloromethane, k) distilling off the solvent from organic layer,
1) isolating the obtained residue in acetone,
m) purifying the l l-[(Z)-3-(dimemylamino)propylidene]-6-l l-dmydrodibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula- la from aqueous acetone.
The second aspect of the present invention is to provide l l-[(Z)-3- (dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula- 1 a, which comprises of
a) Adding n-hexyllithium to the mixture of (3-dimemylaminopropyl)-triphenyl phosphoniumbromide hydrobromide compound of formula-3 in a suitable solvent, b) adding the solution of 1 l-oxo-6,1 l-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 in a suitable solvent,
c) heating the reaction mixture to temperature of about 40°C to 80°C,
d) stirring the reaction mixture till the completion of the reaction,
e) quenching the reaction mixture with aqueous acid,
f) washing the aqueous layer with a suitable solvent,
g) neutralizing the reaction mixture with a suitable basic solution,
h) washing the aqueous layer with a suitable solvent,
i) adding hydrochloric acid and organic acid to the reaction mixture, to reduce the pH, j) extracting the reaction mixture with suitable solvent,
k) distilling off the solvent from organic layer,
1) isolating the obtained residue in a suitable solvent,
m) purifying the ll-[(Z)-3-(dimemylaniino)propylidene]-6-n-dmydrodibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula- la.
Preferred embodiment of the present invention is to provide pure z-isomer of 11 -[(Z)-3-(dimethylamino)propylidene]-6-l 1 -dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride compound of formula- la, which comprises of
a) Adding n-hexyllithium to the mixture of (3-dimethylaminopropyl)-triphenyl phosphoniumbromide HBr compound of formula-3 in tetrahydrofuran,
b) adding the solution of 1 l-oxo-6,1 l-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-3 in tefrahydrofuran, c) heating the reaction mixture to reflux,
d) stirring the reaction mixture for 10-16 hours,
e) quenching the reaction mixture with aqueous hydrochloric acid,
f) washing the aqueous layer with toluene,
g) neutralizing the reaction mixture with sodium carbonate solution,
h) washing the aqueous layer with ethyl acetate,
i) adding hydrochloric acid and organic acid to the reaction mixture, to reduce the pH ~ 1 to 2,
j) extracting the reaction mixture with dichloromethane,
k) distilling off the solvent from organic layer,
1) isolating the obtained residue in acetone,
m) purifying the l l-[(Z)-3-(dimemylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula- la from aqueous acetone. The third aspect of the present invention is to provide l l-[(Z)-3-
(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula- la, which comprises of
a) Adding n-alkyllithium to the mixture of (3-dimethylaminopropyl)-triphenyl phosphoniumbromide hydrobromide compound of formula-3 in a suitable solvent, b) heating the reaction mixture to temperature of about 40°C to 80°C,
c) adding the solution of 1 l-oxo-6,1 l-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 in a suitable solvent,
d) stirring the reaction mixture till the completion of the reaction,
e) quenching the reaction mixture with aqueous acid,
f) washing the aqueous layer with a suitable solvent,
g) neutralizing the reaction mixture with a suitable basic solution,
h) washing the aqueous layer with a suitable solvent,
i) adding hydrochloric acid and organic acid to the reaction mixture, to reduce the pH-1-2,
j) extracting the reaction mixture with suitable solvent,
k) distilling off the solvent from organic layer, 1) isolating the obtained residue in a suitable solvent,
m) purifying the l l-[(Z)-3-(dimemylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula- la.
The present invention is schematically represented in Scheme-I
Scheme-I
Figure imgf000010_0001
The fourth aspect of the present invention is the conversion process of E-isomer of ll-[3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride or a mixture of E&Z-isomer into its Z-isomer.
The process comprising of;
a) Adding hydrochloric acid to a solution containing the mixture of E&Z isomers of 11 -[3-(dimethylamino)propylidene]-6- 11 -dihydrodibenz[b,e]oxepin-2-aceticacid hydro- chloride having major amount of E-isomer,
b) heating the reaction mixture,
c) cooling down and adding an organic acid to the reaction mixture,
d) washing the reaction mixture with a suitable hydrocarbon solvent,
e) adding a suitable chloro solvent to the aqueous layer,
f) separating both aqueous layer and organic layer,
g) distilling off the solvent from organic layer,
h) adding ethyl acetate HC1 to obtained residue,
i) distilling off the solvent from reaction mixture,
j) isolating the solid from the residue using a suitable solvent.
In the preferred embodiment, the conversion E or a mixture of E&Z isomers of 1 l-[3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid into required Z-isomer is carried in the following manner, a) Adding hydrochloric acid to a solution containing the mixture of E and Z isomers of 11 -[3 -(dimethylamino)propylidene] -6,11 -dihydrodibenzo [b,e]oxepin-2-l } acetic acid hydrochloride having major amount of E-isomer,
b) heating the reaction mixture to 90-95 °C for 10-12 hours,
c) cooling it to 25-30°C and adding acetic acid to the reaction mixture,
d) washing the reaction mixture with toluene,
e) adding dichloromethane to the aqueous layer,
f) separating both aqueous layer and organic layer,
g) distilling off the solvent from organic layer,
h) adding ethyl acetate HCI to obtained residue at 40-45°C,
i) stirring the reaction mixture at 40-45°C for 20-30 minutes,
j) distilling off the solvent from the reaction mixture,
k) isolating the solid from the residue using acetone.
The present invention is schematically represented in Scheme-II
Scheme-II
Figure imgf000011_0001
(major) (minor)
Ethyl acetate HCI Acetone
Figure imgf000011_0002
Pure Z-isomer Another aspect of the present invention provides an improved process for the preparation of l l-[(Z)-3-(dimemylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin- 2-aceticacid hydrochloride comprising the following steps,
a) Reacting p-hydroxyphenyl acetic acid compound of formula-5
Figure imgf000012_0001
Formula-5
with phthalide compound of formul -6
Figure imgf000012_0002
Formula-6
in presence of methanolic sodium methoxide in dimethyl formamide provides 2-((4- (carboxymethyl)phenoxy)methyl)benzoic acid compound of formula-7,
Figure imgf000012_0003
Formula-7
b) reacting compound of formula-7 with polyphosphoric acid in presence of acetic acid provides 1 l-oxo-6, 11-dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2,
Figure imgf000012_0004
Formula-2
c) reacting compound of formula-2 with Grignard reagent of l-chloro-3 -dimethyl amino propane compound of in tetrahydrofuran, followed by treatment with HC1 provides 1 l-[(Z)-3-(dimemylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin -2-aceticacid hydrochloride compound of formula- la
d) Optionally purifying the compound from a suitable solvent preferably aqueous acetone provides pure l l-[(Z)-3-(dimethylamino)propylidene]-6-l l- dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride compound of formula- la
The present invention schematically represented in scheme-Ill Scheme-Ill:
Figure imgf000013_0001
The related substance of olopatadine hydrochloride was analyzed by HPLC using the following conditions: A liquid chromatograph equipped with variable wavelength UV detector and Column: Symmetry shield RP18, 250X4.6 mm, 5 um or equivalent; Flow rate: 1.0 ml/min; wavelength: 220 nm; Temperature: 25°C; Load: 20 μΐ; Run time: 45 min; Elution: Gradient; and using buffer and acetonitrile as a mobile phase. Buffer aqueous mixture of octane- 1 -sulfonic acid sodium salt and sodium dihydrogen phosphate dehydrate solution,
(or)
The related substance of olopatadine hydrochloride was analyzed by HPLC using the following conditions: A liquid chromatograph equipped with variable wavelength UV detector and Column: UNISON C8, 150X4.6 mm, 5 um or equivalent; Flow rate: 1.0 ml/min; wavelength: 299 nm; Temperature: 25°C; Load: 30 μΐ; Run time: 30 min; Elution: Isocratic; and using buffer : acetonitrile(72:28) as a mobile phase. Buffer: Dissolve 13.6 gms of monobasic potassium phosphate in to 1000 mL of water, add 1 mL of triethylamine and adjust pH to 3.0 with diluted phosphoric acid. Filter this through 0.45 um Nylon filter paper and sonicate to degas.
The PXRD of crystalline olopatadine hydrochloride obtained in the present invention is represented in figure- 1.
Further Olopatadine hydrochloride obtained as per the present invention is further micronized or milled to get the desired particle size. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, with out limitation, ball, roller and · hammer mills, and jet mills.
As used herein the term "pure" refers to the compound having purity greater than 98.00%, preferably greater than 99.00% and more preferably greater than 99.50% by HPLC.
PXRD analysis of Olopatadine hydrochloride was carried out using SIEMENS/D- 5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:
Example-1: Preparation of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la
n-Butyl lithium (100 ml) was added to the solution of 3-dimethylaminopropyl)- triphenyl phosphoniumbromide HBr compound of formula-3 (37.94 grams) in tetrahydrofuran (200 ml) at 0-5 °C under nitrogen atmosphere. The reaction mixture was stirred for an hour at the same temperature. A mixture of l l-oxo-6, 11-dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml) was added to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 65-70°C and then hated to reflux. The reaction mixture was stirred for 12 hours at 65-70°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and then the aqueous layer was neutralizing with aqueous sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 15 minutes and then dichloromethane was added to it. Both organic and aqueous layers were separated. The organic layer was washed with brine solution and the organic layer was distilled off under reduced pressure. Acetone (100 ml) was added to the residue at 25-30°C and stirred the reaction mixture for 45 minutes at 25-30°C. The solid was filtered, washed with acetone and dried to get the title compound. Yield: 5 grams,
M.P: 238-241°C (Decomposition)
Purity by HPLC: 97.7% (Z-isomer), 1.15% (E-isomer) Example-2: Purification of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll- dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride
33%aqueous acetone (31.5 ml) was added to {(HZ)-l l-[3- (dimethylamino)propylidene] -6,11 -dihydrodibenzo [b,e] oxepin-2-yl } acetic acid hydrochloride (4.5 grams) obtained in example- 1 and then carbon was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 30 minutes and filtered the reaction mixture on high flow bed and washed with 33%aqueous acetone (13.5 ml). Distilled off the solvent from the filtrate and then acetone (22.5 ml) was added to the obtained solid at 25-30°C. The reaction mixture was stirred for an hour at 25-30°C and filtered the solid. Washed the solid with acetone and dried to get the pure {(11Z)-1 l-[3-(dimethylamino)propylidene]-6,l l-dihydrodibenzo[b,e]oxepin-2-yl} acetic acid hydrochloride.
Yield: 2.6 grams,
M.P: 244-248.5°C (Decomposition)
Purity by HPLC: 98.19% (Z-isomer), 0.5% (E-isomer)
Example-3: Preparation of ll-[(Z)-3-(dimethyIamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la
n-Hexyl lithium (123.3 ml) was added to the solution of (3- dimemylaminopropyl)-triphenyl phosphoniumbromide HBr compound of formula-3 (59.3 grams) in tetrahydrofuran (500 ml) at 0-5°C under nitrogen atmosphere. The reaction mixture was stirred for an hour at same temperature. A mixture of 1 l-oxo-6,11- dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2 (25 grams) and tetrahydrofuran (75 ml) to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and then hated to 65-70°C. The reaction mixture was stirred for 12 hours at 65-70°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (50 ml) and acetic acid (100 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 15 minutes and dichloromethane was added to it. Both organic and aqueous layers were separated. The organic layer was washed with brine solution and the organic layer was distilled off under reduced pressure. Acetone (250 ml) was added to the residue at 25-30°C and stirred the reaction mixture for 45 minutes at 25-30°C. The solid was filtered, washed with acetone and dried to get the title compound.
Yield: 13 grams,
M.P: 237-239°C (Decomposition) Example-4: Purification of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride
33%aqueous acetone (87.5 ml) was added to {(11Z)-1 l-[3-(dimethylamino)propylidene]- 6,1 l-dihydrodibenzo b,e]oxepin-2-yl} acetic acid hydrochloride (12.5 grams) obtained in example-3 and then carbon was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 30 minutes and filtered the reaction mixture on high flow bed and washed with 33% aqueous acetone (37.5 ml). Distilled off the solvent from the filtrate and then acetone (62.5 ml) was added to the obtained solid at 25-30°C. The reaction mixture was stirred for an hour at 25-30°C and filtered the solid. Washed the solid with acetone and dried to get the pure {(llZ)-l l-[3-(dimethylamino)propylidene]-6,ll- dihydrodibenzo[b,e]oxepin-2-yl}acetic acid hydrochloride.
Yield: 10 grams,
M.P: 246.7-248.5°C (Decomposition)
Purity by HPLC: 99.22% (Z-isomer), 0.12% (E-isomer) ExampIe-5: Preparation of ll-[(Z)-3-(dimethylamino)propyIidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la
n-Butyl lithium (100 ml) was added to the solution of 3-dimethylaminopropyl)- triphenyl phosphoniumbromide HBr compound of formula-3 (37.94 grams) in teh^ydrofuran (100 ml) at 0-5°C under nitrogen atmosphere. The reaction mixture was stirred for an hour at same temperature. A mixture of l l-oxo-6,11- dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml) was added to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and then hated to 40-45°C. The reaction mixture was stirred for 24 hours at 40-45°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and then neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 15 minutes and then dichloromethane was added to it. Both organic and aqueous layers were separated. The organic layer was washed with brine solution and the organic layer was distilled off under reduced pressure. Acetone (100 ml) was added to the residue at 25-30°C and stirred the reaction mixture for 45 minutes at 25-30°C. The solid was filtered, washed with acetone and dried to get the title compound.
Yield: 8.5 grams,
M.P: 203-207°C (Decomposition)
Example-6: Preparation of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,ej oxepin-2-aceticacid hydrochloride compound of formula-la
n-Butyl lithium (100 ml) was added to the solution of 3-dimemylaminopropyl)-triphenyl phosphoniumbromide HBr compound of formula-3 (37.94 grams) in tetrahydrofuran (100 ml) at 0-5 °C under nitrogen atmosphere. The reaction mixture was stirred for an hour at same temperature. A mixture of l l-oxo-6,l l-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml) was added to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and then hated to 50-55°C. The reaction mixture was stirred for 18 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and then neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 15 minutes and then dichloromethane was added to it. Both organic and aqueous layers were separated. The organic layer was washed with brine solution and the organic layer was distilled off under reduced pressure. Acetone (100 ml) was added to the residue at 25- 30°C and stirred the reaction mixture for 45 minutes at 25-30°C. The solid was filtered, washed with acetone and dried to get the title compound.
Yield: 7.5 grams,
M.P: 223-227°C (Decomposition)
Example-7: Preparation of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la
n-Hexyl lithium (49.32 ml) was added to the solution of (3-dimethylaminopropyl)- triphenyl phosphoniumbromide HBr compound of formula-3 (23.72 grams) in teti^yclrofuran (100 ml) at 0-5°C under nitrogen atmosphere. The reaction mixture was stirred for an hour at same temperature. A mixture of l l-oxo-6,l l-dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml) to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and then hated to 40-45°C. The reaction mixture was stirred for 24 hours at 40- 45°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 15 minutes and dichloromethane was added to it. Both organic and aqueous layers were separated. The organic layer was washed with brine solution and the organic layer was distilled off under reduced pressure. Acetone (100 ml) was added to the residue at 25- 30°C and stirred the reaction mixture for 45 minutes at 25-30°C. The solid was filtered, washed with acetone and dried to get the title compound.
Yield: 8 grams,
M.P:203-205°C (Decomposition)
Example-8: Preparation of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la
n-Hexyl lithium (49.32 ml) was added to the solution of (3- dimethylaminopropyl)-triphenyl phosphoniumbromide HBr compound of formula-3 (23.72 grams) in tetrahydrofuran (100 ml) at 0-5°C under nitrogen atmosphere. The reaction mixture was stirred for an hour at same temperature. A mixture of 1 l-oxo-6,11- dihydrobenz(b,e) oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml) to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and then hated to 50-55°C. The reaction mixture was stirred for 18 hours at 50-55°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 15 minutes and dichloromethane was added to it. Both organic and aqueous layers were separated. The organic layer was washed with brine solution and the organic layer was distilled off under reduced pressure. Acetone (100 ml) was added to the residue at 25-30°C and stirred the reaction mixture for 45 minutes at 25-30°C. The solid was filtered, washed with acetone and dried to get the title compound.
Yield: 7 grams,
M.P:213-215°C (Decomposition) Example-9: Preparation of Z-isomer of ll-[3-(dimethylamino)propylidene]-6-ll- dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride from the mixture of E&Z isomers
Added aqueous hydrochloric acid (15 ml) into the mixture of E&Z isomers of 1 l-[-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride (5 grams) at 25-30°C and then heated the reaction mixture to 90-95°C. Stirred the reaction mixture for 12 hours at the same temperature. The reaction mixture was cooled to 25-30°C and then added acetic acid (10 ml) to it. The reaction mixture was washed with toluene and then reaction mixture was extracted with dichloromethane. Distilled off the solvent from the organic layer under reduced pressure and co-distillation with ethyl acetate. Ethyl acetate HC1 (5 ml) was added to the obtained residue at 40-45°C and stirred the reaction mixture for 30 minutes at the same temperature. Distilled off the solvent from the reaction mixture under reduced pressure and acetone (15 ml) was added to the obtained residue at 25-30°C. The reaction mixture was stirred for 45 minutes at the same temperature. The obtained solid was filtered, washed with acetone and dried get pure Z-isomer of l l-[(Z)-3-(dmiemylammo)propylidene]-6-l l-dihydrodibenz[b,e] oxepinr2-aceticacid hydrochloride.
Yield: 3 grams
Purity by HPLC: 96.93% (Z-isomer), 0.9% (E-isomer)
Example 10: Preparation of 2-((4-(carboxymethyl)phenoxy)methyl)benzoic acid compound of formula-7
A mixture of p-hydroxy phenylacetic acid (50 g), dimethylformamide (180 ml) and phthalide (47 g) was heated to 130-135°C for about 45 minutes and then cooled to 120-125°C. 25% methanolic sodium methoxide (136 g) was added to the reaction mixture slowly at 120-125°C and then stirred for 10 minutes at 120-125°C. Distilled off methanol completely from the reaction mixture and then heated the reaction mixture to 130-135°C. Phthalide (10 g) was added to the reaction mixture and stirred for 12 hours at 130-135°C. The reaction mixture was cooled to 5-10°C and then quenched it with 10% hydrochloric acid. Water was added to the reaction mixture and temperature of the reaction mixture was raised to 25-30°C. Stirred the reaction mixture for 45 minutes at 25- 30°C. Filtered the precipitated solid, washed with water and then dried to get the title compound. Cyclohexane (250 ml) was added to the obtained solid. Heated the reaction mixture to 75-80°C and stirred for 45 minutes at same temperature. Cooled the reaction mixture to 25-30°C. Filtered the solid, washed with cyclohexane and then dried to get the pure title compound.
Yield: 80 grams;
MR: 172-175°C
Example 11: Preparation of 2-((4-(carboxymethyl)phenoxy)methyl)benzoic acid compound of formula- 7
25% Methanolic sodium methoxide (136 g), phthalide (47 g) were added to the mixture of p-hydroxy phenylacetic acid (50 g), dimethylformamide (180 ml) at 25-30°C. Stirred the reaction mixture for 15 minutes at same temperature. Raised the temperature of the reaction mixture to 75-80°C and distill off the solvent from reaction mixture under reduced pressure. Heated the reaction mixture to 130-135°C and stirred for 12 hours at same temperature. Cooled the reaction mixture to 50-55°C and water was added to it. Cooled the reaction mixture to 25-30°C. Acidifying the reaction mixture with aqueous hydrochloric acid. Stirred the reaction mixture for 60 minutes at 25-30°C. Filtered the precipitated solid, and washed with water. Aqueous sodium hydroxide solution was added to the obtained compound and stirred for 15 minutes. Washed the reaction mixture with toluene. Acidifying the reaction mixture with aqueous hydrochloric acid and stirred for 15 minutes. Filtered the precipitated solid and washed with aqueous acetone. Dried the material to get the pure title compound.
Yield: 78 grams;
MR: 172-175°C
Example 12: Preparation of ll-oxo-6,ll-dihydrobenz[b,e]oxepin-2-acetic acid formula-2.
A mixture of polyphosphoric acid (385 g), 2-((4-(carboxymethyl)phenoxy) methyl)benzoic acid (110 g) and acetic acid (330 ml) was heated to 70-75°C and stirred for 2 ½ hours at same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C, further to 10-15°C. Quenched the reaction mixture with water at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at same temperature. Filtered the precipitated solid, washed with water and dried. Ethylacetate (300 ml) was added to the obtained solid and heated the reaction mixture to 70-75°C and then stirred for 15 minutes at same temperature. Carbon (6 g) was added to the reaction mixture and stirred for 15 minutes. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Cooled the obtained filtrate to 0-5 °C and stirred for 1 hour at same temperature. Filtered the precipitated solid, washed with cyclohexane and then dried to get the title compound.
Yield: 55 gms
MR: 137-138°C.
Example 13: Preparation of ll-oxo-6,H-dihydrobenz[b,e]oxepin-2-acetic acid formula-2.
A mixture of polyphosphoric acid (385 g), 2-((4- (carboxymethyl)phenoxy)methyl)benzoic acid (110 g) and acetic acid (330 ml) was heated to 70-75°C and stirred for 2 ½ hours at same temperature. After completion of the reaction, the reaction mixture was cooled to 50-55°C. Quenched the reaction mixture with water. Cooled the reaction mixture to 25-30°C. Filtered the precipitated solid, washed with water. Water was added to the obtained solid and basified the reaction mixture with aqueous ammonia. Washed the reaction mixture with methylene chloride and separated the both aqueous and organic layers. Carbon (6 g) was added to the aqueous layer and stirred for 15 minutes. Filtered the reaction mixture through hyflow bed and washed with water. Distilled off the methylene chloride traces from the reaction mixture and cooled the reaction mixture to 25-30°C. Isopropyl alcohol was added to the reaction mixture and acidifying the reaction mixture with aqueous hydrochloric acid. Stirred the reaction mixture for 3 hours at 25-30°C. Filtered the precipitated solid and washed with water. Dried the material to get the title compound.
Yield: 57 gms
MR: 137-138°C.
Example 14: Preparation of (Z)-ll-[3-(dimehylamino)propylidene]-6,ll- dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride
Iodine (0.5 g) was added to a mixture of magnesium (43 g) and tetrahydrofuran (150 ml) under nitrogen condition. Heated the reaction mixture to reflux temperature. 3- dimethyl amino propyl chloride (5 ml) followed by 1,2-dibromo ethane (2 g) were added to the reaction mixture at same reflux temperature. A solution of 3 -dimethyl amino propyl chloride (225 g) in tetrahydrofuran (200 ml) was added drop wise to the reaction mixture at reflux temperature and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C, further cooled to 5-10°C. A solution of l l-oxo-6,11- dihydrobenz[b,e]oxepin-2-acetic acid (50 g) in tetrahydrofuran (150 ml) was added to the reaction mixture slowly at 5-10°C and stirred for 45 minutes at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred the reaction mixture for 5 hours at same temperature. After completion of the reaction, the reaction mixture was quenched with aqueous acetic acid. Aqueous hydrochloric acid [hydrochloric acid (300 ml) in water (100 ml)] was added to the reaction mixture at a temperature below 25 °C and stirred for 10 minutes at 25-30°C. Toluene was added to the reaction mixture and stirred for 10 minutes. Both the toluene and aqueous layers were separated and the aqueous layer was washed with toluene. Both the toluene layers were combined and washed with hydrochloric acid. Both the aqueous layer and hydrochloric acid layers were combined. Heated the aqueous layer to 90-95 °C and stirred for 24 hours at same temperature Cooled the reaction mixture to 25-30°C and dichloromethane was added to the reaction mixture. Stirred the reaction mixture for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both the dichloromethane layers were combined and then dried with sodium sulfate. Distilled off the solvent completely under reduced pressure and co- distilled with acetone. Acetone was added to the reaction mixture and stirred for 45 minutes at 25-30°C. Filtered the precipitated solid, washed with acetone and then dried to get the title compound.
Yield: 30 grams; Purity by HPLC: 98.9% (Z-isomer)
Example 15: Preparation of (Z)-ll-[3-(dimehylamino)propylidene]-6,ll- dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride
Iodine (0.5 g) was added to a mixture of magnesium (43 g) and tetrahydrofuran (150 ml) under nitrogen condition. Heated the reaction mixture to reflux temperature. 3- dimethyl amino propyl chloride (5 ml) followed by 1,2-dibromo ethane (2 g) were added to the reaction mixture at same reflux temperature. A solution of 3 -dimethyl amino propyl chloride (225 g) in
Figure imgf000024_0001
(200 ml) was added drop wise to the reaction mixture at reflux temperature and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C, further cooled to 5-10°C. A solution of l l-oxo-6,11- dihydrobenz[b,e]oxepin-2-acetic acid (50 g) in teti^ydrofuran (150 ml) was added to the reaction mixture slowly at 5-10°C and stirred for 45 minutes at 5-10°C. Stirred the reaction mixture at same temperature up to the completion of reaction. Quenched the reaction mixture with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 20 minutes at same temperature. Distilled off the solvent from the reaction mixture. Cooled the obtained reaction mixture to 25-30°C. Aqueous hydrochloric acid [hydrochloric acid (300 ml) in water (100 ml)] was added to the reaction mixture at a temperature 25-30°C. Heated the reaction mixture to 90-95°C and stirred for 3 hours at same temperature Cooled the reaction mixture to 25-30°C, toluene was added to it and stirred for 10 minutes. Both the toluene and aqueous layers were separated and the aqueous layer was washed with toluene. Acetic acid was added to the aqueous layer and stirred for 20 minutes at 25-30°C. Methylene chloride was added to the reaction mixture. Stirred the reaction mixture for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with methylene chloride. Both the methylene chloride layers were combined and then dried with sodium sulfate. Distilled off the solvent completely under reduced pressure and co- distilled with acetone. Ethyl acetate HC1 and acetone were added to the reaction mixture and stirred for 45 minutes at 40-45°C. Distilled off the solvent completely under reduced pressure and acetone was added to the obtained compound. Acetone was added to the obtained compound and heated the reaction mixture to 50-60°C. Stirred the reaction mixture for 30 minutes at same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at same temperature. Filtered the precipitated solid, washed with acetone and dried the material to get the title compound.
Yield: 30 grams; Purity by HPLC: 98.9% (Z-isomer)
The PXRD of the compound obtained from process of the present invention is similar to the PXRD of prior art form-I disclosed in WO2007/105234 A2. Example 16: Purification of (Z)-ll-[3-(dimehylamino)propyIidene]-6,ll- dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride A solution of (Z)-l l-[3-(dimehylamino)propylidene]-6,l l-dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride (2 g) in 10% aqueous acetone (35 ml) was heated to 50-55°C and stirred for 15 minutes at 50-55°C. Carbon (0.2 g) was added to the reaction mixture and stirred for 15 minutes at 50-55°C. Filtered the reaction mixture through highflow bed and washed with 10% aqueous acetone. Distilled off the solvent from the filtrate under reduced pressure and co-distilled twice with aqueous acetone. The reaction mixture was cooled to 25-30°C, added acetone to it and stirred for 45 minutes at 25-30°C. Filtered the precipitated solid, washed with acetone and dried the material to get pure title compound.
Yield: 1.6 grams; Purity by HPLC: 99.91%. (Z-isomer)
Example 17: Purification of (Z)-ll-[3-(dimehylamino)propylidene]-6,ll- dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride
A solution of (Z)-l l-[3-(dimehylan ino)propylidene]-6,l l-dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride (2 g) in 10% aqueous acetone (35 ml) was heated to 40-45°C and stirred for 30 minutes at same temperature. Aqueous hydrochloric acid was added to the reaction mixture at 35-40°C. Carbon (0.2 g) was added to the reaction mixture and stirred for 15 minutes at same temperature. Filtered the reaction mixture through highflow bed and washed with 10% aqueous acetone. Distilled off the solvent from the filtrate under reduced pressure and co-distilled twice with acetone. The reaction mixture was cooled to 25-30°C, added acetone to it and stirred for 45 minutes at 25-30°C. Filtered the precipitated solid, washed with acetone. Acetone and water were added to the obtained wet compound and heated the reaction mixture to 50-60°C. Filter the reaction mixture and the obtained filtrate was heated to 40-45°C. Acetone was slowly added to the reaction mixture at 40-45°C. Cooled the reaction mixture to 0-5°C and stirred for 90 minutes at same temperature. Filtered the precipitated solid, washed with acetone and dried the compound to get the pure title compound.
Yield: 1.6 grams; Purity by HPLC: 99.95%. (Z-isomer)
The PXRD of the compound obtained from process of the present invention is similar to the PXRD of prior art form-I disclosed in WO2007/105234A2.
Particle Size Distribution: D(0.1): 0.911 urn; D(0.5): 6.283 μιη; D(0.9): 28.807 um; D[4,3]: 14.484 um.

Claims

We Claim:
1. A process for the preparation of pure Z-isomer of l l-[(Z)-3- (dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula- la,
Figure imgf000027_0001
Formula- la
Which comprising of the following steps;
a) Adding n-alkyl lithium to the mixture of (3-dimethylaminopropyl)-triphenyl phosphoniumbromide hydro bromide compound of formula-3 in a suitable solvent,
Figure imgf000027_0002
Formula-3
b) adding l l-oxo-6,l l-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula- 2 in a suitable solvent,
Figure imgf000027_0003
Formula-2
c) heating the reaction mixture to a temperature of about 40°C to 80°C,
d) stirring the reaction mixture till the completion of the reaction,
e) quenching the reaction mixture with aqueous acid,
f) washing the aqueous layer with a suitable water immiscible solvent,
g) neutralizing the aqueous layer with a suitable basic solution,
h) washing the aqueous layer with a suitable solvent, i) adding hydrochloric acid and organic acid to the reaction mixture, to reduce the pH to 1-2 ,
j) extracting the reaction mixture with suitable solvent,
k) distilling off the solvent from organic layer,
1) isolating the obtained residue in a suitable solvent,
m) purifying the 11 - [(Z)-3 -(dimethylamino)propylidene] -6-11 -dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula- la.
2. A process for the preparation of pure Z-isomer of l l-[(Z)-3- (dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula- la,
Figure imgf000028_0001
Formula- la
Which comprising of the following steps;
a) Adding n-butyl lithium to the mixture of (3-dimemylaminopropyl)-triphenyl phosphoniumbromide hydrobromide com ound of formula-3 in tetrahydrofuran,
Figure imgf000028_0002
Formula-3
b) adding the l l-oxo-6,l l-dihydrobenz(b,e)oxepin-2-acetic acid compound formula-2 in tetrahydrofuran,
Figure imgf000028_0003
Formula-2
c) heating the reaction mixture to 65-70°C, d) stirring the reaction mixture for 10- 16 hours,
e) quenching the reaction mixture with aqueous hydrochloric acid,
f) washing the aqueous layer with toluene,
g) neutralizing the aqueous layer with sodium carbonate solution,
h) washing the aqueous layer with ethyl acetate,
i) adding hydrochloric acid and acetic acid to the reaction mixture, to reduce the pH ~ 1 to 2,
j) extracting the reaction mixture with dichloromethane,
k) distilling off the solvent from organic layer,
1) isolating the obtained residue in acetone.
m) purifying the l l-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula- la in aqueous acetone.
3. A process for the preparation of pure z-isomer of l l-[(Z)-3- (dimethylarnino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula- la,
Figure imgf000029_0001
Formula- la
Which comprising of the following steps,
a) Adding n-hexyllithium to the mixture of (3-dimethylaminopropyl)-triphenyl phosphoniumbromide hydr bromide compound of formula-3 in tetrahydrofuran,
Figure imgf000029_0002
Formula-3 b) adding the l l-oxo-6,l l-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 in tetrahydrofuran,
Figure imgf000030_0001
Formula-2
c) heating the reaction mixture to 65-70°C,
d) stirring the reaction mixture for 10-16 hours,
e) quenching the reaction mixture with aqueous hydrochloric acid,
f) washing the aqueous layer with toluene,
g) neutralizing the aqueous layer with sodium carbonate solution,
h) washing the aqueous layer with ethyl acetate,
i) adding hydrochloric acid and acetic acid to the reaction mixture, to reduce the pH ~ 1 to 2,
j) extracting the reaction mixture with dichloromethane,
k) distilling off the solvent from organic layer,
1) isolating the obtained residue in acetone,
m) purifying the l l-[(Z)-3-(dimemylarnino)propyIidene]-6-l l-dihydrodibenz b,e] oxepin-2-aceticacid hydrochloride compound of formula- la in aqueous acetone.
A process for the preparation of pure Z-isomer of l l-[(Z)-3-
Figure imgf000030_0002
(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula- la,
Figure imgf000030_0003
Formula- la
Which comprising of the following steps; a) Adding n-alkyl lithium to the mixture of (3-dimethylaminopropyl)-triphenyl phosphoniumbromide hydrobromide com ound of formula-3 in a suitable solvent,
Figure imgf000031_0001
Formula-3
b) heating the reaction mixture to a temperature of about 40°C to 80°C,
c) adding 1 l-oxo-6,1 l-dihydrobenz(b,e)oxepin-2-acetic acid compound of
2 in a suitable solvent,
Figure imgf000031_0002
Formula-2
d) stirring the reaction mixture till the completion of the reaction,
e) quenching the reaction mixture with aqueous acid,
f) washing the aqueous layer with a suitable water immiscible solvent,
g) neutralizing the aqueous layer with a suitable basic solution,
h) washing the aqueous layer with a suitable solvent,
i) adding hydrochloric acid and organic acid to the reaction mixture, to reduce the pH to 1-2 ,
j) extracting the reaction mixture with suitable solvent,
k) distilling off the solvent from organic layer,
1) isolating the obtained residue in a suitable solvent,
m) purifying the 1 l-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula- la.
Use of n-hexyllithium at temperature of 0-80°C for the condensation of 1 l-oxo-6,11- dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 with (3- dimethylaminopropyl)-triphenyl phosphoniumbromide hydrobromide compound of formula-3 to provide 1 l-[(Z)-3-(dimemylamino)propylidene]-6-l l-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride compound of formula- la.
6. Use of n-butyl lithium at temperature of 40-80°C for the condensation of 11-oxo- 6,1 l-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 with (3- dimethylaminopropyl)-triphenyl phosphoniumbromide hydrobromide compound of formula-3 to provide l l-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride compound of formula- la.
7. A process for producing l l-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula- 1 by reacting the 1 l-oxo-6,1 l-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 with
Figure imgf000032_0001
Formula-2
(3-dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide compound of formula-3 in presence of n-butyl lithium in a suitable solvent, at temperature of about 40-80°C.
Figure imgf000032_0002
Formula-3
8. A process for producing n-[(Z)-3-(dimemylamino)propylidene]-6-l l-dihydro dibenz[b,e]oxepin-2-aceticacid hydrochloride compound of formula- 1 by reacting the 1 l-oxo-6,1 l-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2
Figure imgf000032_0003
Formula-2
with (3-dimethylaminopropyl)-triphenylphosphoniumbromide hydrobromide compound of formula-3 in presence of n-hexyllithium in a suitable solvent at a temperature of about 0-80°C.
9. A process according to any of the preceding claims, wherein obtained l l-[(Z)-3- (dimethylamino)propylidene]-6- 11 -dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride containing 1.0% or less of corresponding E-isomer. 10. A process for the conversion of E-isomer of ll-[3-(dimethylamino)propylidene]-6- l l-dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride into its Z-isomer, which comprising of,
a) Adding hydrochloric acid to a solution containing E-isomer,
b) heating the reaction mixture,
c) cooling down and adding acetic acid to the reaction mixture,
d) washing the reaction mixture with toluene,
e) adding dichloromethane to the aqueous layer,
f) separating both aqueous layer and organic layer,
g) distilling off the solvent from organic layer,
h) adding ethyl acetate HC1 to obtained residue,
i) distilling off the solvent from the reaction mixture,
j) isolating the solid from the residue using acetone.
11. A process for the conversion of E-isomer or the mixture of E&Z-isomers of 11 -[3-(dimethylamino)propylidene]-6- 11 -dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride into its Z-isomer, which comprising of,
a) Adding hydrochloric acid to a solution containing the mixture of E and Z isomers having major amount of E-isomer,
b) heating the reaction mixture,
c) cooling down and adding acetic acid to the reaction mixture,
d) washing the reaction mixture with toluene,
e) adding dichloromethane to the aqueous layer,
f) separating both aqueous layer and organic layer,
g) distilling off the solvent from organic layer,
h) adding ethyl acetate HC1 to obtained residue,
i) distilling off the solvent from the reaction mixture, j) isolating the solid from the residue using acetone.
12. A process for the preparation of l l-[(Z)-3-(dimethylamino)propylidene]-6-l l- dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride comprising the following steps, a) Reacting p-hydroxyphenyl acetic acid compound of formula-5
Figure imgf000034_0001
Formula-5
with phthalide compound of formula-6
Figure imgf000034_0002
Formula-6
in presence of methanolic sodium methoxide in dimethyl formamide provides 2 ((4-(carboxymethyl)phenoxy)methyl)benzoic acid compound of formula-7,
Figure imgf000034_0003
Formula-7
b) reacting compound of formula-7 with polyphosphoric acid in presence of acetic acid provides l l-oxo-6, 11-dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2,
Figure imgf000034_0004
Formula-2
c) reacting compound of formula-2 with Grignard reagent of l-chloro-3 -dimethyl amino propane compound of in tetrahydrofuran, followed by treatment with HC1 provides 1 l-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin -2-aceticacid hydrochloride compound of formula- la. d) Optionally purifying the compound from a suitable solvent preferably aqueous acetone provides pure l l-[(Z)-3-(dimethylamino)propylidene]-6-l l- dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride compound of formula- la
13. Olopatadine hydrochloride obtained by any of the preceding claims having purity greater than 99.00% by HPLC, preferably greater than 99.50% by HPLC, more preferably greater than 99.90% by HPLC.
Dated this day of April 2011.
Figure imgf000035_0001
MSN Laboratories Limited.
********
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CN102838582A (en) * 2012-09-19 2012-12-26 湖州恒远生物化学技术有限公司 Preparation method of isoxepac
ITMI20131820A1 (en) * 2013-11-04 2015-05-05 Laboratorio Chimico Int Spa PROCEDURE FOR THE PREPARATION OF OLOPATADIN
CN105693685A (en) * 2016-02-01 2016-06-22 山东罗欣药业集团股份有限公司 Preparation technique of olopatadine hydrochloride
CN106324111A (en) * 2015-06-24 2017-01-11 江苏吉贝尔药业股份有限公司 Olopatadine hydrochloride eye drop detection method
CN106518833A (en) * 2015-09-15 2017-03-22 江苏吉贝尔药业股份有限公司 New method for preparation of 6,11-dihydro-11-oxo dibenzo [b, e] oxepin-2-acetic acid
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CN102838582A (en) * 2012-09-19 2012-12-26 湖州恒远生物化学技术有限公司 Preparation method of isoxepac
CN102838582B (en) * 2012-09-19 2014-03-26 湖州恒远生物化学技术有限公司 Preparation method of isoxepac
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WO2015063579A1 (en) * 2013-11-04 2015-05-07 Laboratorio Chimico Internazionale S.P.A. A process for the preparation of olopatadine and sylil intermediates thereof
ITMI20131820A1 (en) * 2013-11-04 2015-05-05 Laboratorio Chimico Int Spa PROCEDURE FOR THE PREPARATION OF OLOPATADIN
US9708284B2 (en) 2013-11-04 2017-07-18 Laboratorio Chimico Internazionale S.P.A. Process for the preparation of olopatadine and sylil intermediates thereof
CN106324111A (en) * 2015-06-24 2017-01-11 江苏吉贝尔药业股份有限公司 Olopatadine hydrochloride eye drop detection method
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