3-(3-Chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-benzazepin-2-one

A mixture of 7, 8 -dimethoxy- 1, 3 -dihydro-2H-3 -benzazepin-2-one (5 Og) and dimethylsulfoxide (350mL) was stirred for about 10mm and potassium tert-butoxide (30.7g) wasadded to it. The reaction mixture was stirred for about 30mm at about room temperature. A solution of 1-bromo-3-chloropropane (43.lg) in dimethyl sulfoxide (1 lOmL) was added to the stirred reaction mixture. The reaction mixture was cooled to about 15°C to about 20°C and stirred for about 30mm at about the same temperature. The reactionmixture was quenched into ice water and was stirred for about 3h. The solid obtained was filtered, washed with. water and dried under vacuum.Yield: 60g. (89percent); HPLC purity:> 95percent7, 8-Dimethoxy- l, 3-dihydro-2H-3-benzazepine-2-one (90 g) prepared as above, was. taken in dimethylformamide (270 ml) and potassium hydroxide (45 g) was added. The resulting reaction mixture was stirred at a temperature of 0°C to 5°C for 15 minutes. Thereafter, l-bromo-3-chloro-propane (67.5 ml) was added, and maintained the reaction mixture at same temperature for 3 hours. After completion of reaction (monitored by HPLC), demineralized water (270 ml) was slowly added at a temperature of 0°C to 5°C, and reaction mixture was further stirred at a temperature of 25°C to 30°C for 1 hour. The resultant product was filtered, washed with demineralized water and dried at 50-60°C to obtain 102 g of title compound, having purity 98.5percent measured by HPLC.At room temperature, 20 g of compound (II) was taken, 200 ml of N, N-dimethylformamide was stirred well, and 12.4 g of potassium tert-butoxide was added to activate it for 30 minutes and then transferred to a container containing 17.2 g of a dilute solution of bromochloropropane.Temperature control 25±5°C, reaction for 30min, reaction is completed and transferred to 1L ice water to quench and crystallize for 5h.After filtration, the crude product was recrystallized from acetone/water (volume ratio of 1:6) to obtain 20.1 g of a white solid.A mixture of the chloride of formula (Ilia) (50.00 g; 169 mmol) and sodium iodide (32.75 g; 218 mmol) in methyl isobutyl ketone (375 ml) was heated to 117 - 118C with stirring under an argon atmosphere. Reaction progress was monitored by HPLC. After completion, the reaction mixture was concentrated in vacuo and the residue was diluted with dichloro methane (375 ml) and water (190 ml). The organic layer was separated, washed with water (190 ml) and concentrated in vacuo. The residue was treated with methyl t- butyl ether (190 ml) and the resulting suspension was cooled to 0C. After 1 hour of stirring at 0C, the suspension was filtered, washed with methyl i-butyl ether (40 ml) and dried for two hour at 23C/100 mbar to afford 60.10 g of yellowish solid (92% yield).A mixture of 7, 8-Dimethoxy-3-[3-chloropropyl]-l, 3-dihydro-2H-3-benzazepin-2- one (50 gm) prepared as in Example 12, and methyl ethyl ketone (400 ml) was stirred for about 10 minutes and sodium iodide (50.7 gm) was slowly added to the mixture at about room temperature. The reaction mixture was heated to reflux temperature and stirred for about 8 hours. The reaction mixture was concentrated at below 50C under reduced pressure and a mixture of Acetone (125 ml) and water (125 ml) was added to it. The reaction mixture was heated to about 55C to 60C and stirred for about 1 hour at the same temperature and then cooled to room temperature. The solid obtained was filtered, washed with water and dried at about (0157) 55C - 60C for about 12 hours. (0158) Yield: 86%; Purity: 98.6%A mixture of 7, 8-dimethoxy-3 -[3 -chloropropyl]- 1, 3 -dihydro-2H-3 -benzazepin-2-one (40g) prepared as in Example 1, and acetone (320mL) was stirred for about 10mm and sodium iodide (20g) was added to it. The reaction mixture was stirred at about reflux temperature for about 24h. The reaction mixture was cooled to about room temperature, filtered and washed with acetone. The filtrate obtained was concentrated under reducedpressure to give a solid residue. The residue obtained was dissolved in dichioromethane (400rnL). The solution obtained was washed with aqueous sodium dithionate solution and demineralized water and was concentrated under reduce pressure. The solid obtained was recrystallized with acetone and then with acetonitrile and dried under vacuum.Yield: 44.5g (85%); HPLC purity: > 95%Example 10Charge 55.0 g of [3-(3-chloropropyl)-7, 8-dimethoxy-l, 3- dihydro-2H-3-benzazepine-2-one] (XI), 330 ml of acetone and 55.74 g of sodium iodide in a RB flask equipped with mechanical stirrer, condenser and thermometer pocket at 25C. Heat the reaction mixture to 60-65C. Reflux for 30 hours with stirring and monitor the reaction by HPLC. If starting compound (XI) remains additional NaI is added and continue refluxing till compound (XI) comes below 1.0%. Evaporate the acetone and add 225 ml of dichloromethane at 25C and stir for 10 minutes. Filter the solid and wash the solid with dichloromethane (2 x 100 ml). Combine the dichloromethane solutions and charge 400 ml of 5% sodium thiosulfate solution and stir for 10 minutes. Separate the layers and wash the organic layer with 400 ml of water. Dry the organic layer over anhydrous Na2SO4 and evaporate dichloromethane under vacuum at below 40C to result a brown colored residue. Weight: 55.0 gCharge 110 ml of acetone to the above brown colored residue and stir for 30 minutes. Filter the precipitated material and wash with 25 ml of acetone and dry under vacuum to give off white colored solid. Charge 100 ml of acetonitrile to the above obtained off white solid. Stir for 30 minutes and filter the precipitate. Wash with 25 ml acetonitrile to give off-white colored solid (XII). Dry the compound at 50C under vacuum for 12 hours. Weight: 37. 0 g Yield: 51. 4 % HPLC purity: 98. 3%EXAMPLE-2: Preparation of 7, 8-Dimethoxy-3-(3-iodopropyl)-l, 3-dihydro-2H-3- benzazepin-2-one (Formula-4) 7, 8-Dimethoxy-3-(3-chloropropyl)- 1 , 3-dihydro-2H-3-benzazepin-2-one (Formula-3) (15g, 0.0507mol.) is added in 90ml. of Acetone. Sodium iodide (19g, 0.1268mol.) is added to the mass and stirred the mass at 55 - 58 for 20hr. The reaction mass is filtered through celite bed at 35 - 40C. Filtrate is concentrated under reduced pressure at 45 - 50C to residual volume of about 3 - 4vol. To the mass, 300ml of water is added at 25 - 30C and stirred for 2hr. The mass is filtered and the wet material washed with water. The wet material on drying resulted in the yield of about 17.67g (90%>) of 7, 8-Dimethoxy-3-(3-iodopropyl)-l, 3-dihydro-2H-3-benzazepin- 2-one (Formula-4) having the purity >90%.7, 8-Dimethoxy- l, 3-dihydro-2H-3-benzazepine-2-one (90 g) from Example-l 1 was taken in Dimethylformamide (270 ml) and Potassium hydroxide (45 gm) was added. The resulting reaction mixture was stirred at a temperature of 0C to 5C for 15 minutes. Thereafter, l-Bromo-3-chloro-propane (67.5 ml) was added slowly, and maintained the reaction at the same temperature for 3 hours. After completion of reaction (monitored by HPLC), D.M. water (270 ml) was slowly added at same temperature of 0C to 5C. The reaction mixture was cooled to 25C to 30C and further stirred for 1 hour. The resultant product was filtered, washed with D.M. water and dried at 50-60C to obtain the title compound. (0154) Yield: 85%, Purity: 98.32%24.6 g of the compound (II) and 20 g of the compound (III) hydrochloride were added to 200 mL of toluene, and 80 g of sodium carbonate, 4 g of sodium iodide and 2 g of tetrabutylammonium bromide were added.The temperature was raised to 98 to 102 C for 10 hours.The purity of the reaction solution is greater than 85%.The impurity (A) content is less than 1% (HPLC, area normalization method).The temperature was lowered to 40-60 C., 200 g of drinking water was added, and the mixture was allowed to stand still and liquid was separated after stirring to obtain a dehydrogenated ivabradine toluene solution. Dehydrogenation ivabradine was obtained by concentration under reduced pressure at 80 C. MS is shown in Figure 2: 467.57, which is the free base hydrogenation ion peak, and the oxalic acid ion has no peak; the free base hydrogenation ion has a theoretical molecular weight of 467.25.24.6 g of compound (II) and 20 g of compound (III) hydrochloride were added to 400 mL of toluene, 160 g of sodium carbonate, 20 g of sodium iodide and 4 g of tetrabutylammonium bromide were added.Warm up to 108-110C for 10 hours. The purity of the reaction solution is more than 85%.The impurity (A) content is less than 1% (HPLC, area normalization method).Cool down to 40-60C, add 200g of drinking water, stir and evenly separate and dispense.A dehydrogenation ivabradine toluene solution was obtained (decompression and concentration below 80 C. gave dehydrogenation ivabradine).3-(3-chloropropyl)-1, 3-dihydro-7, 8-dimethoxy-211-3-benzazepin-2-one was charged into the reaction vessel. 2.0kg, (1S) -4, 5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride 1.5 kg, sodium iodide 2.3 kg, potassium carbonate 3.4 kg, 13L of acetone, stir evenly, and warm to reflux.After stirring the reaction for 28 hours, the reaction was monitored.Compound II = 8.9%, dropped to room temperature. Filtration, the filtrate was concentrated to a liquid-free drop; the concentrate was dissolved in ethyl acetate, then purified water was added, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was combined and washed three times with saturated sodium hydrogen carbonate solution. , monitoring the residual amount of compound II in the organic phase, the first washing compound II = 4.4%, the second washing compound II = 2.6%, the third washing compound II = 1.5%; adding 10L 2N hydrochloric acid solution to the organic layer , stirring, standing, liquid separation; the lower layer of water is added with ethyl acetate extraction; ethyl acetate is added to the aqueous layer, the pH is adjusted to 9 to 10 with 50% potassium carbonate solution, stirred, allowed to stand, liquid separation; lower water The layer was extracted with ethyl acetate; the combined organic layer was combined and washed twice with saturated sodium hydrogen carbonate solution; the organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The filtrates were combined and concentrated under reduced pressure until no liquid was dropped. The intermediate product of ivabradine hydrochloride was dehydrogenated ivabradine 2.37 kg.82.54%.Take 1.0g of compound (II) into 20mL of NMP (N-methylpyrrolidone), 10 mL of drinking water and 5 g of potassium carbonate were added and the reaction was heated at 70-80C for 12 hours.Remove the NMP by vacuum distillation under reduced pressure and add 20 mL of drinking water and 50 mL of methylene chloride.Stir and then stand and dispense. The organic layer is anhydrous sodium sulfate high school, filtered and concentrated under reduced pressure.Ivabradine hydrochloride impurity (A) was obtained.Ivabradine hydrochloride impurity (A) can be purified by silica gel column chromatography.The eluent was dichloromethane:methanol (10:1).1.0 g of the compound (II) was added to 20 mL of NMP (N-methylpyrrolidone), 10 mL of drinking water and 5 g of potassium carbonate were added, and the mixture was heated at 70 to 80 C for 12 hours. The NMP was distilled off under high vacuum under reduced pressure, and 20 mL of drinking water and 50 mL of dichloromethane were added, stirred well, and then left to stand for liquid separation. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give yybrybramine hydrochloride (III). The ivabradine hydrochloride impurity (III) can be purified by silica gel column chromatography, and the eluent is dichloromethane: methanol (10:1).

Molecular Weight:295.76
XLogP3:2.3
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:5
Exact Mass:295.0975211
Monoisotopic Mass:295.0975211
Topological Polar Surface Area:38.8
Heavy Atom Count:20
Complexity:361
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes