1-(2-CHLORO-ETHYL)-4-METHYL-PIPERAZINE

10 ml of 25percent NaOH and 1 ml (9 mmol) of 4-methyl piperazine were added successively into a reaction flask. The mixture was heated up to 50° C., and 1.8 ml (18 mmol) 1-bromo-2-chloroethane was added dropwise. The mixture was reacted at 50° C. for 6 h, then cooled to room temperature. The reaction solution was extracted with ethyl acetate, and the extraction was washed with saturated saline solution and dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dry in a reduced pressure and a small amount of ethanol/NaOH solution was added dropwise into the residue. The mixture was shaken and placed in a refrigerator for standing, then concentrated to dry in a reduced pressure to obtain 0.43 g white solid with the yield of 23percent. m.p. 227-230° C.0.29 g (0.72 mmol) of Compound VIa, 0.2 g (1.44 mmol) of potassium carbonate, 0.14 g (1.44 mmol) of Compound VIIg and 30 ml acetone were added successively into a reaction flask. The mixture was heated to the reflux temperature and reacted for 12 h, then filtrated while it is still hot. The filtrate was concentrated to dry in a reduced pressure. The residue was dissolved with 20 ml dichloromethane, and the substance undissolved was filtered off. The filtrate was concentrated to dry in a reduced pressure and the residue was purified by column chromatography to obtain 0.09747 g red solid with the yield of 23%. m.p. 136-140 C. 1H-NMR (CDCl3): 5.65-8.74 (12H, m, Ar-H), 4.24 (2H, t, J=5.4 Hz, OCH2), 2.94 (2H, t, J=5.4 Hz, NCH2), 2.67-2.79 (8H, m, N (CH2CH2)2N), 2.43 (3H, s, NCH3). EI-MS m/z: 465[M]+.10 ml of 25% NaOH and 1 ml (9 mmol) of 4-methyl piperazine were added successively into a reaction flask. The mixture was heated up to 50 C., and 1.8 ml (18 mmol) 1-bromo-2-chloroethane was added dropwise. The mixture was reacted at 50 C. for 6 h, then cooled to room temperature. The reaction solution was extracted with ethyl acetate, and the extraction was washed with saturated saline solution and dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated to dry in a reduced pressure and a small amount of ethanol/NaOH solution was added dropwise into the residue. The mixture was shaken and placed in a refrigerator for standing, then concentrated to dry in a reduced pressure to obtain 0.43 g white solid with the yield of 23%. m.p. 227-230 C.The N'-methyl-N-2-chloroethylpiperazine dihydrochloride (10.0 g, 45.4 mmol) was added slowly to a mixture of 50% aqueous potassium carbonate (200 mL) and ether (200 mL) and the mixture was stirred for 30 min., layers were separated, aqueous layer extracted with ether ( 2 x 200 mL). Combined organic extracts were dried on anhydrous sodium sulfate and concentrated to give N'-methyl-N-2-chloroethylpiperazine (6.2g).To a solution of 5.7 g of 1, 3-dihydro-5-phenyl-7-chloro-2H-1, 4-benzodiazepine-2-thione in a solvent mixture comprising 57 ml of a 10% aqueous potassium hydroxide solution and 6 ml of tetrahydrofuran is added at room temperature with stirring 7.0 g of (a) A mixture of 8.5 g of 9-acridanone, 180 ml of dimethylformamide and 3.3 g of sodium hydride is stirred for 0.5 hour, treated portionwise with 10.3 g of EXAMPLE 102 (3aRS, 7aRS)-2-[(2-hydroxyphenyl)acetyl]-7, 7-diphenyl-4-perhydroisoindolone (2.55 g) is added to a suspension of sodium hydride (0.32 g) (50% dispersion in oil) in toluene (10 cc) and, at 25 C., a solution of 1-(4-methyl-1-piperazinyl)-2-chloroethane in dry toluene (10 cc) (obtained by liberation from the corresponding dihydrochloride (1.14 g) by the action of caustic potash) is then added. The reaction mixture is refluxed for 18 hours and then treated with water (20 cc) and ethyl acetate (30 cc). The aqueous phase is extracted with ethyl acetate (10 cc) and the combined organic phases are washed with water until neutral, dried over sodium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is washed with petroleum ether and then dissolved in a mixture of ethyl acetate and dilute methanesulphonic acid (pH 2). The organic phase is washed with water and the combined acid aqueous phases are washed with ethyl acetate and neutralized by the action of normal sodium hydroxide solution. The neutral phase is extracted with ethyl acetate and the organic phase obtained is then washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). After chromatography on a column of silica gel (50 g) (0.2- 0.045 mm), eluding with a mixture of toluene and diethylamine (90/10 by volume), the expected product (0.6 g) is isolated and is triturated in petroleum ether (15 cc) and dried. (3aRS, 7aRS)-2-{2-[2-(4-methyl-1-piperazinyl)ethoxy]phenylacetyl)-7, 7-diphenyl-4-perhydroisoindolone (0.36 g) melting at 78 C. is obtained. 1-(4-Methyl-1-piperazinyl)-2-chloroethane dihydrochloride is prepared by the method of G. Emptoz et al., Chim. Ther., 4 (4), 283 (1969).b. 4-Methyl- 1-(2-chloroethyl)piperazine dihydrochloride A mixture of 20.0 g (0.092 mol) of 4-methyl-1-(2-hydroxyethyl)piperazine dihydrochloride in 60 ml of thionyl chloride was refluxed under nitrogen for 6 hours. The mixture was cooled, filtered, and washed with methylene chloride to give 20.8 g (96%) of the hygroscopic dihydrochloride salt.

Molecular Weight:199.12
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:198.0690539
Monoisotopic Mass:198.0690539
Topological Polar Surface Area:6.5
Heavy Atom Count:11
Complexity:89.6
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes