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Example 3; Preparation of Olopatadine Hydrochloride Form A Through Wittig Reaction Using Sodium Hydride3-[bromo(triphenyl)phosphoranyl]-N,N-dimethyl propan-1-amine hydrobromide (phosphonium salt) (205 g; 0.40 mol) was suspended in 545.5 g (615 mL) of tetrahydrofuran under a nitrogen atmosphere. After stirring for 40 minutes, 64.48 g (1.61 mol) of sodium hydride 60percent in mineral oil was added over five minutes. After addition of the sodium hydride, the reaction mixture was heated to reflux (approximately 65° C.) with continuous stirring and maintained at this temperature for 1 hour. An intense orange suspension was obtained. The reactor contents were then cooled to room temperature and 36 g (0.13 mol) of (11-oxo-6,1'-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid (Compound II, R1H) was added with stirring. The mixture was then stirred for 15 hours at room temperature.Thereafter, a mixture of 153.5 g (153.5 mL) of deionized water and 136.1 g (153.5 mL) of tetrahydrofuran was slowly added with continuous stirring. Next, 615 g (615 mL) of deionized water was added, and stirring was continued for 20 minutes. The resulting two phase mixture was then acidified with hydrochloric acid (37percent) with stirring to adjust the pH to approximately 3 (actual reading 2.27). The aqueous and organic phases were then separated, and the aqueous phase was salified with 180 g of sodium chloride and extracted with 607.5 g (750 mL) of 1-butanol. The phases were then separated, and the organic phase was washed three times with water.The solvent of the organic phase was then removed by distillation under reduced pressure to yield 119.61 g of an orange oil. To this oil was added 157 g (200 mL) of 2-propanol, which produced a yellow suspension. The mixture was then stirred and maintained at this temperature for 1 hour. Thereafter, the suspension was filtered, and the collected wet solid was dried under vacuum at 60° C. until constant weight to yield 37.23 g (0.10 mol, 74.21percent) of olopatadine hydrochloride. (HPLC Purity: 54.28percent, cis: 6.44percent, trans; Cis/Trans Ratio: 8.43).A 36 g portion of the olopatadine hydrochloride obtained was then suspended in 226.08 g (288 mL) of 2-propanol. The mixture was heated to reflux (approximately 82° C.) with continuous stirring and maintained at this temperature for a minimum 20 minutes. The reactor was then cooled to room temperature, and the suspension was filtered to yield a slight yellow solid that was dried under vacuum at 60° C. (Partial Yield 37.62percent; HPLC Purity: 97.23percent cis, 0.76percent trans; Cis/Trans Ratio: 128. 50).A 17 g portion of the olopatadine hydrochloride obtained in the previous step was then treated with 120.1 g (153 mL) of 2-propanol. The white to white off suspension obtained was stirred and heated to reflux for 55 minutes. Then, it was allowed to cool to room temperature. The suspension was then filtered, and the solid was washed with 2-propanol and dried under vacuum at 60° C. (Partial Yield 35.67percent; HPLC Purity: 99.56percent cis, 0.18percent trans; Cis/Trans Ratio: 538.54).A 15 g portion of the olopatadine hydrochloride obtained in the previous step was then treated with 58.8 g (75 mL) of 2-propanol. The resulting white suspension was stirred and heated to reflux for 30 minutes. Thereafter, the reactor content was cooled to room temperature. The white suspension was then filtered, and the solid was washed with 2-propanol and dried under vacuum at 60° C. to yield 14.42 g of olopatadine hydrochloride. (Global Yield 34.29percent; HPLC Purity: 99.73percent cis; 0.10percent trans; Cis/Trans Ratio: 760.46).A 10 g portion of the olopatadine hydrochloride obtained in the previous step was treated with a mixture of 23.5 g (30 mL) of 2-propanol and 15 g of deionized water. The resulting white suspension was stirred and heated to reflux for 15 minutes. Thereafter, the reactor content was cooled to room temperature. The white suspension was then filtered, and the solid was washed with 2-propanol and dried under vacuum at 60° C. to yield 7.49 g of olopatadine hydrochloride. (Global Yield 25.68percent; HPLC Purity: 99.98percent cis; 0.02percent trans; Cis/Trans Ratio: 4999.35).A 6.7 g portion of the olopatadine hydrochloride obtained in the previous step was treated with a mixture of 15.8 g (20 mL) of 2-propanol and 10 g of deionized water. The resulting white suspension was then stirred and heated to reflux for 10 minutes. Thereafter, the reactor content was cooled to room temperature. The white suspension was then filtered, and the solid was washed with 2-propanol and dried under vacuum at 60° C. to yield 3.44 g of olopatadine hydrochloride Form A. (Global Yield 13.18percent; HPLC Purity: 99.91percent cis, 0.01percent trans; Cis/Trans Ratio: 11708.08).Analytical data: HPLC purity: 99.91percent; Assay: 101.62percent; XRD (2psi): 6.33°, 10.92°, 12.66°, 15.44°, 17.60°, 18.30°, 19.04°, 19.34°; 20.61°, 24.08°, 25.45°, 28.34° (substantially identical to FIG. 1); ... |
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Example-1: Preparation of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-lan-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: 97.7percent (Z-isomer), 1.15percent (E-isomer) |
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