Bicyclo[4.2.0]octa-1,3,5-triene-7-methanamine, 3,4-dimethoxy-N-methyl-, hydrochloride (1:1), (7S)-

The (1S)-4, 5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane obtained in the previous step was dissolved in acetic acid.Ethyl (20ml)And Ethanol (5ml)In the mixed solution, Stir at 20°C for 30 minutes, Then pass hydrogen chloride gas into the liquid, The turbid liquid will be stirred at 15°C20°C for 1h.Suction filtrationWash with a mixture of ethyl acetate/ethanol = 4:1, Dry (1S)-4, 5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride (2.38 g, 95percent)Introduce the compound obtained in the previous Step (5 kg), ethyl acetate (40 litres) and ethanol (10 litres) into a reactor. Example 14.Preparation of ((S)-3, 4-dimethoxy-bicyclof 4.2. OJocta-1, 3, 5-triene- 7-yl-methyl)-methyl-amine hydrochloride (VIII)13.0 g (58.8 mmol) (5)-3, 4-dimethoxy-bicyclo[4.2. OJocta-1, 3, 5-triene-7-carboxylic acid-N-methyl-amide of formula (VII) was suspended in 70 ml of anhydrous tetrahydroiurane and 120 ml of 1M borane-tetrahydrofurane solution was added.The reaction mixture was stirred at 20-25°C until clear solution was obtained and then it was stirred at 40-50°C.After the reaction had been completed the solution was cooled to 0-5°C and 20 ml of methanol was added.The reaction mixture was stirred for further 15 minutes and then 20 ml of 20percent hydrogen chloride solution in anhydrous ethyl acetate was added and it was refluxed for 2 hours. Then the mixture was cooled to 0-5°C, stirred for 30 minutes at this temperature, filtered and washed with 3x10ml of cold tetrahydrofurane. It was dried in vacuum at 25°C.12.5 g (88percent) of title compound was obtained.20 mL of a molar solution of BH(S)-N-[(4, 5-dimethoxybenzocyclobut-l-yl)-methyl]-N-(methyl)amine (0139) camphorsulfonic acid salt (50gm) was dissolved in water (150 ml). Then slowly adjusted the pH 10-11 with 40% lye solution and extracted with Diehl oromethane. Layers were separated and aqueous layer was again adjusted to pH 11 with lye solution and extracted with Dichloromethane. Total Diehl oromethane layers were combined and washed with water. Organic layer was separated, dried with Sodium sulphate and distilled under reduced pressure. The resultant crude mass was dissolved in Ethyl acetate (800 ml) and Ethanol mixture (200ml) at room temperature. Then cooled to 0C and HC1 gas was passed up to pH 1-2 at 0-5C and stirred mixture at same temperature for 1 hour and filtered the title compound. Yield: 94%; Chiral purity: 99.2%into a 500mL three-mouth reaction bottle, 20.0 g of the compound of formula III was dissolved into 200 mL of DMF, add 30.0g of anhydrous K2CO3 and stir for 30 minutes, and then add 39.1 g of the compound of formula II (among them the substituent X is Br), 0.8g composite phase transfer catalyst (mixed with benzalkonium bromide and polyethylene glycol-800 in a mass ratio of 5:1), the reaction system was heated at 85 C, the reaction end point was monitored by HPLC, and the reaction was complete after 3.0h. The reaction is completed, get cooled, and the filtrate is collected by filtration, filtrate added into 500 mL of saturated sodium chloride solution, extract twice with 250 mL and 200 ml of ethyl acetate, respectively, combined organic phase, add 20g of anhydrous Na2S04 and filter, the filtrate was concentrated under reduced pressure at 50 C, obtained 37.9 g of dehydrogenated Ivabradine oily substance, the purity is 89.29%, the molar yield based on the compound of formula III is 99.1%. The HPLC diagram of the dehydrogenated Ivabradine related substances is shown in Figure 1, the peak data in Figure 1 is shown in Table 5.1.5 g of the compound of formula 7 and 2.2 g of triethylamine are dissolved in 100 ml of acetone, 2.1 g of (1S)-4, 5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride was added under nitrogen.After the addition was completed, the temperature was raised to reflux reaction for 24 hours.After cooling to room temperature, acetone was evaporated under reduced pressure and extracted with ethyl acetate (EtOAc)Dry over anhydrous sodium sulfate, filter, and EtOAc m.Separation and purification by column chromatography using methanol: dichloromethane = 1:30 (V: V).The target product was collected and concentrated to give 0.7 g of the compound of formula 8.0.5 g of the compound of formula 7 and 0.73 g of triethylamine were dissolved in 30 ml of acetone.0.72 g of (1S)-4, 5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride was added under nitrogen.After the addition was completed, the temperature was raised to reflux reaction for 24 hours. Cool to room temperature and distill off the acetone under reduced pressure.Extracted with 50 ml of EtOAc (EtOAc m.Separation and purification by column chromatography using methanol: dichloromethane = 1:30 (V: V).The target product was collected and concentrated to give 0.3 g of compound of formula 8.20g of the compound of the formula 5', 23 g of 1-bromo-3-chloropropane and 30 g of triethylamine were dissolved in 100 ml of acetone.After stirring uniformly, the temperature was raised to reflux for 24 hours.After cooling to room temperature, acetone was evaporated under reduced pressure and extracted with ethyl acetate (EtOAc)Dry over anhydrous sodium sulfate, filter, Concentrated under reduced pressure to 25 grams6' compound, No need to purify, go directly to the next step.20g of the 6' compound, Mix 15g of sodium iodide and 150ml of acetone and mix well.Set the temperature to 70 C reflux reaction for 24 h, after the reaction is over, Drop to room temperature and remove solids by filtration.The collected filtrate was concentrated under reduced pressure.The residue was added with water and extracted with ethyl acetate.Concentrated organic layer to obtain 16g7'Compound.K2C03 (59.54 g) was added to a stirred, clear solution of (1 S)-4, 5-dimethoxy-1 - [(methylamino)methyl]benzocyclobutane hydrochloride (Formula II) (30. Og) in water (180 mL). The temperature was increased to 40 C. The reaction mixture was stirred for about 5 to about 10 min at 40 C. 1 -bromo-3-chloropropane (Formula III) (67.83 g) was then added and the reaction mixture was stirred for 5 hours at 40 C. The progress of the reaction was monitored using TLC. Upon completion, the reaction was cooled to ambient temperature and a mixture of EtOAc (50 mL) and water (10ml_) was added. The organic layer was collected and the remaining aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with 3M HCI (3 x 50 mL). The combined aqueous extracts were adjusted to a pH of about 13 with 4M NaOH (160 mL). The basic aqueous solution was extracted with EtOAc (1 x 200 mL & 3 x 100 mL). The combined organic extracts were dried (MgSO4), filtered and the volatiles were removed under reduced pressure to afford 32.84 g (94%) of the compound of Formula (IV) as an oil.

Molecular Weight:243.73
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:243.1026065
Monoisotopic Mass:243.1026065
Topological Polar Surface Area:30.5
Heavy Atom Count:16
Complexity:210
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes