Phosphonium, [3-(dimethylamino)propyl]triphenyl-, bromide, hydrobromide (1:1:1)

Preparation of (3-(Dimethylamino)propyl)triphenylphosphonium bromide hydrobromide salt. To a suspension of 3-bromopropyltriphenylphosphonium bromide (1.0 g, 2.1 mmol) in ethanol (5 mL) was added a solution of 40percent dimethylamine in water (3 mL) at room temperature. The mixture was stirred and heated at 100 °C for 30 min in a sealed microwave tube. After the reaction mixture was concentrated under reduced pressure, the solid residue was recrystallized in acetonitrile to afford (3- (dimethylamino)propyl)triphenylphosphonium bromide hydrobromide salt (0.90 g, 82percent) as a white solid, and was used in the following step. ESI MS m/z 348.3(Ph Synthesis of the Wittig Reagent 3-dimethylaminopropyltriphenylphosphonium Bromide *HBr (Olo-IM4) To a stirred suspension of 3-bromopropyltriphenylphosphonium bromide (Olo-IM3) (420 g, 0.90 mol) in absolute ethanol (664 g) a solution of dimethylamine in absolute ethanol (368 g, 2.69 mol, assay: 33percent) was added slowly within 30 minutes at room temperature. After complete addition the suspension was stirred 1 hour at reflux whereupon a solution was obtained. The solution was cooled to a temperature of 0-10° C. and acetyl bromide (202.7 g, 1.65 mol) was added dropwise until the pH was 1, and the resulting suspension was allowed to warm to 20-25° C. After the white suspension was filtered the wet product washed with absolute ethanol (237 g) and then dried under vacuum (15 h, 70° C.) to give 3-dimethylaminopropyltriphenylphosphonium bromide*HBr (Olo-IM4) as a white solid (yield: 471.2 g, 0.77 mol, 85.1percent; HPLC assay: 83.2percent, HPLC purity: 98.72percent). The crude material (460 g, 0.75 mol; assay: 83.2percent) was further purified by suspending it in absolute ethanol (395 g) and stirring at reflux temperature. After addition of further absolute ethanol (435 g) all material was dissolved and the solution was allowed to cool to room temperature, with seeding at 69° C. to initiate crystallization. After 4 hours stirring at room temperature the product was filtered off, washed with ethanol (140 g) and then dried under vacuum (15 h, 70° C.) to give 3-dimethylaminopropyltriphenylphosphonium bromide*HBr (Olo-IM4) as a crystalline white solid (yield: 333.7 g, 0.66 mol, 87.2percent; HPLC assay >99.9percent, HPLC purity: 99.85percent, overall yield: 74.2percent).Preparation of (3-(Dimethylamino)propyl)triphenylphosphonium bromide hydrobromide salt. To a suspension of 3-bromopropyltriphenylphosphonium bromide (1.0 g, 2.1 mmol) in ethanol (5 mL) was added a solution of 40percent dimethylamine in water (3 mL) at room temperature. The mixture was stirred and heated at 100 °C for 30 min in a sealed microwave tube. After the reaction mixture was concentrated under reduced pressure, the solid residue was recrystallized in acetonitrile to afford (3- (dimethylamino)propyl)triphenylphosphonium bromide hydrobromide salt (0.90 g, 82percent) as a white solid, and was used in the following step. ESI MS m/z 348.3(Ph Synthesis of the Wittig Reagent 3-dimethylaminopropyltriphenylphosphonium Bromide *HBr (Olo-IM4) To a stirred suspension of 3-bromopropyltriphenylphosphonium bromide (Olo-IM3) (420 g, 0.90 mol) in absolute ethanol (664 g) a solution of dimethylamine in absolute ethanol (368 g, 2.69 mol, assay: 33percent) was added slowly within 30 minutes at room temperature. After complete addition the suspension was stirred 1 hour at reflux whereupon a solution was obtained. The solution was cooled to a temperature of 0-10° C. and acetyl bromide (202.7 g, 1.65 mol) was added dropwise until the pH was 1, and the resulting suspension was allowed to warm to 20-25° C. After the white suspension was filtered the wet product washed with absolute ethanol (237 g) and then dried under vacuum (15 h, 70° C.) to give 3-dimethylaminopropyltriphenylphosphonium bromide*HBr (Olo-IM4) as a white solid (yield: 471.2 g, 0.77 mol, 85.1percent; HPLC assay: 83.2percent, HPLC purity: 98.72percent). The crude material (460 g, 0.75 mol; assay: 83.2percent) was further purified by suspending it in absolute ethanol (395 g) and stirring at reflux temperature. After addition of further absolute ethanol (435 g) all material was dissolved and the solution was allowed to cool to room temperature, with seeding at 69° C. to initiate crystallization. After 4 hours stirring at room temperature the product was filtered off, washed with ethanol (140 g) and then dried under vacuum (15 h, 70° C.) to give 3-dimethylaminopropyltriphenylphosphonium bromide*HBr (Olo-IM4) as a crystalline white solid (yield: 333.7 g, 0.66 mol, 87.2percent; HPLC assay >99.9percent, HPLC purity: 99.85percent, overall yield: 74.2percent).[3-(Dimethylamino)propyl]triphenylphosphonium bromide hydrobromide (230 g) and anhydrous tetrahydrofuran (1200 ml) were added to a 3 L glass reactor (mechanical stirring), and cooled to below -10 C. Add butyl lithium solution (2.5N, 250ml), the reaction exotherm is obvious, keep the temperature below -10 C, stir for 1-2 hours, add dropwise a solution of 2-benzyloxy-2-(11-oxo-6, 11-dihydro-dibenzo[b, e]oxepin-2-yl)acetic acid (37.4 g) in anhydrous tetrahydrofuran (200 ml). The reaction exotherm was obvious, the temperature was kept below -5 C, the mixture was stirred for 1-2 hours, slowly raised to room temperature, stirring was continued for 4-5 hours, and deionized water (200 ml) was slowly added dropwise to destroy excess butyl lithium. The reaction solution was concentrated to dryness under reduced pressure, water (1200 ml of) dissolve, extracted with methyl tert-butyl ether (500ml × 2) was added, the aqueous phase with hydrochloric acid (1N) was adjusted to pH less than 2, was added methyl tert-butyl Ether extraction (500 ml x 2). The aqueous phase was adjusted to a pH of about 6, and the aqueous phase was concentrated to dryness under reduced pressure. Recrystallization 3 times by adding acetone water (400 ml, volume ratio 8:1) to obtain (Z)-11-[3-(dimethylamino)propenyl]-6, 11-dihydrodibenzo[b, e ]gheptin-2-benzyloxy-2-acetic acid (21.1 g). The yield is about 72.8%.[3-(Dimethylamino)propyl]triphenylphosphonium bromide hydrobromide (230 g) and anhydrous tetrahydrofuran (1200 ml) were added to a 3 L glass reactor (mechanical stirring), and cooled to below -10 C. Add butyl lithium solution (2.5N, 250ml) dropwise, the reaction exotherm is obvious, keep the temperature below -10 C, stir for 1-2 hours, add 2-allyloxy-2-(11-oxo-6, 11-dihydro-dibenzo[b, e]oxepin-2-yl)acetic acid (32.4g) in anhydrous tetrahydrofuran (200ml), the reaction exotherm is obvious, keep the temperature below -5 C, keep warm Stir for 1-2 hours, slowly warm to room temperature, continue stirring for 4-5 hours, slowly add deionized water (200 ml), and destroy excess butyl lithium. The reaction solution was concentrated under reduced pressure toDry, add water (1200ml) to dissolve, add methyl tert-butyl ether extraction (500ml × 2), the aqueous phase is adjusted to pH less than 2 with hydrochloric acid (1N), extracted with methyl tert-butyl ether (500ml × 2). The aqueous phase was adjusted to a pH of about 6, and the aqueous phase was concentrated to dryness under reduced pressure. The mixture was recrystallized three times with a mixture of methyl isobutyl ketone and acetone (400 ml, volume ratio 1:1) to obtain 2-allyloxy-2-((Z)-11-[3-(dimethylamino)propenyl]-6, 11-dihydro-dibenzo[b, e]oxepin-2-yl)acetic acid (21.1 g).To the 50L dry reaction kettle without adding water treatment of tetrahydrofuran 24L, dimethyl sulfoxide 900ml, water bath cold1.64 kg (41.0 mol) of sodium hydride (60percent) was added with stirring, and triphenylphosphonium bromide (3-dimethylaminopropyl) hydrobromide(16.0 mol) were added, and the mixture was stirred at room temperature for 1.5 to 2 hours. The temperature was raised to 45 ° C and reacted for 1.5 hours. Cool to 20 & lt; 0 & gt; C and add Isoxepac Acid (2.15 g, 8.0 mol) at room temperature for 10 to 12 hours. The reaction was complete by TLC. The mixture was cooled to 10 to 15 ° C, and water and tetrahydrofuran solution (water: 0.8 L, THF: 2.0 L) was added dropwise thereto over about 1 hour.Stirred for 30 minutes, filtered, and the filter cake rinsed with 1 L of THF. The filtrate was combined, concentrated hydrochloric acid was added with stirring to pH ~ 3, and stirring was continued for 30 minutesClock, filter. The filter cake was washed with 2 L of tetrahydrofuran and allowed to dry. The solid was transferred to a reaction vessel, 12 L of water was added and the pH was adjusted with 10 N sodium hydroxide(About 65 ° C), stirred for 5 hours at 5 to 10 ° C, and filtered. The solids were then washed 3 L x 2 in deionized waterTimes, drained. 80 degrees for 2 hours in the blast drying dry olorotatin 1.5kg. Purity 98.72percent (HPLC), Isomer: 0.48percent(HPLC), Yield: 55.63percentAt room temperature and under an argon atmosphere, a solution of 6, 1 1-dihydro-li- oxo-dibenz[b, e]oxepin-2-acetic acid (5.0 g, 18.64 mmol, I eq) in anhydrous THF (20 ml) was prepared. N, O-bis(trimethyl-silyl)acetamide (4.56 ml, 18.64 mmol, 1 eq) was added and the solution stirred for 1 hour. At room temperature and under an argon atmosphere, a suspension of 3-dimethylaminopropyltriphenylphosphoniumbromide hydrobromide (23.7 g, 46.6 mmol, 2.5 eq) in anhydrous THF (80 ml) was prepared. To this suspension the previously prepared solution of trimethylsilyl ester was then added, followed by the sodium hydride (60% in mineral oil, 6.08 g, 152.1 mmol, 7.85 eq). The resulting mixture was heated at 60C for 3 hours and the consumption of the starting material was followed by LC-MS. The reaction mixturewas cooled to 0C and carefully quenched with 40 ml of THF/H20 1/1 (v/v). After dilution with water (100 ml), the mixture was washed with toluene (100 ml) and two times with 2-methylTllF (100 ml). The aqueous phase was acidified to pH 1 with 37% hydrochloric acid (8 ml) and then washed with toluene (100 ml). Sodium acetate was added up to pH 5 and the aqueous phase was extracted two times with a mixture of 2-methylTHF/2-propanol 2:1 (v/v) (300 ml). The organic layer wasevaporated under reduced pressure. The crude material (8.7 g) was taken up with acetone (90 ml) and acidified with 37% hydrochloric acid, obtaining the precipitation of the cis isomer of olopatadine hydrochloride. The white solid was filtered and washed with acetone. Yield = 55%.Preparation of Dimethyl-{3-[2-triisopropylsiianyloxy-10, ll-dihydro- dibenzo[ , (/]cyclohepten-(5)-ylidene]-propyl}-amine (16). 2-Triisopropylsilanyloxy-10, l 1- dihydro-dibenzo[a, if]cyclohepten-5-one (15) (2.00 g, 5.26 mmol) was dissolved in 40 mL dry tetrahydrofuran. In a separate flask, (3-dimethylamino-propyl)-triphenyl-phosphonium bromide hydrobromide salt (2, 72 g, 6.32 mmol) was suspended in 40 mL dry tetrahydrofuran and cooled to 5 C in an ice bath. 2.5 M n-Butyllithium in hexanes (2.94 mL, 7.36 mmol) was added slowly and then the reaction was allowed to stir for 20 minutes. The 2- triisopropylsilanyloxy-10, 1 l-dihydro-dibenzo[a, d]cyclohepten-5-one solution was then added slowly and the reaction heated to 60 C. When the reaction was complete, it was cooled in an ice bath and water was added slowly to quench the reaction. Tetrahydrofuran was then evaporated off and the residue separated between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with saturated sodium bicarbonate (3 X 100 mL), brine (50 mL), dried over magnesium sulfate, filtered, and evaporated. The residue was re- dissolved in dichloromethane and run through a silica gel plug to remove remaining triphenylphosphine. The resulting solution was evaporated to yield 1.4 g (58%) of dimethyl - {3-[2-triisopropylsilanyloxy-l 0, 1 1 -dihydro-dibenzo[a, d]cyclohepten-(5)-ylidene]-propyl}- amine (16) as a yellow oil. ESI MS m/z 451.0 (M+H)+.b) Preparation of Olopatadine Hydrobromide (Crude)Load 29.6 g of 60% sodium hydride in mineral oil (4.0 eq.), 164.85 g of (3-dimethylaminopropyl)triphenylphosphine bromide-HBr (1.75 eq.) and 360 ml of THF (6 V) into a flask. Stir at T=0/5 C. for 30 minutes, then heat the mixture slowly to T=60 C. and stir at said temperature for 3 hours. Chill to a temperature of 0-5 C. and add a mixture consisting of 60 g of isoxepac butyl ester in 210 ml of THF over molecular sieves (3.5 V). Heat the reaction mixture to T=27-30 C. and stir at said temperature for at least 15 hours.Having verified that the reaction has completed, chill to T=0-5 C., add 80 ml of purified water and then neutralise by adding 32% HCl until reaching pH 7.Distil under vacuum until all the THF (at least 550 ml) is collected. Add 400 ml of toluene and 200 ml of purified water. Stir and then separate the phases.Add 300 ml of heptane to the toluene phase and stir for at least 1 hour. Filter the phosphines obtained and concentrate the organic phase containing the olopatadine butyl ester isomers.Collect the oil thus obtained with 150 ml of n-butanol, chill to T=-10/-15 C. and stir for 1 hour until the product has crystallised. Filter and wash with 20 ml of n-butanol and chill to T=-15 C.The olopatadine butyl ester thus obtained has the following NMR spectrum:(DMSO d6): 0.90 (t, 3H), 1.32 (sest., 2H), 1.60 (quint., 2H), 2.23 (s, 6H), 2.45 (t, 2H), 2.6 (q., 2H), 3.51 (s, 2H), 4.08 (t, 2H), 5.40 (sb, 2H), 5.7 (t, 1H), 6.80 (d, 1H), 7.06 (dd, 2H), 7.30 (m, 4H).EXAMPLE 2The process according to is repeated, but proceeding to isolate the olopatadine butyl ester intermediate in step b) , as described below.Load 29.6 g of 60% sodium hydride in mineral oil (4.0 eq.), 164.85 g of (3-dimethylaminopropyl) triphenylphosphine bromide-HBr (1.75 eq.) and 360 ml of THF (6 V) into a flask. Stir at T=0/5C for 30 minutes and then heat the mixture slowly to T=60C and stir at said temperature for 3 hours. Chill to a temperature of 0-50C and add a mixture consisting of 60 g of isoxepac butyl ester in 210 ml of THF over molecular sieves (3.5 V). Heat the reaction mixture to T=27-30C and stir at said temperature for at least 15 hours.Having verified that the reaction has completed, chill to T=0-5C, add 80 ml of purified water and then neutralise by adding 32% HCl until reaching pH 7.Distil under vacuum until all the THF (at least 550 ml) is collected. Add 400 ml of toluene and 200 ml of purified water. Stir and then separate the phases.Add 300 ml of heptane to the toluene phase and stir for at least 1 hour. Filter the phosphines obtained and concentrate the organic phase containing the olopatadine butyl ester isomers. Collect the oil thus obtained with 150 ml of n-butanol, chill to T=-10/-15C and stir for 1 hour until the product has crystallised. Filter and wash with 20 ml of n-butanol and chill to T=-15C. The olopatadine butyl ester thus obtained has the following NMR spectrum:(DMSO d6) : 0.90 (t, 3H), 1.32 (sest., 2H), 1.60 (quint., 2H), 2.23 (s, 6H), 2.45 (t, 2H), 2.6 (q., 2H), 3.51 (s, 2H), 4.08 (t, 2H), 5.40 (sb, 2H), 5.7 (t, IH), 6.80 (d, IH), 7.06 (dd, 2H), 7.30 (m, 4H).