L-Leucine, N-acetyl-, compd. with (αS)-3-ethoxy-4-methoxy-α-[(methylsulfonyl)methyl]benzenemethanamine (1:1)

A solution of bis(1, 5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (17 mg, 0.037 mmol) and (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (20 mg, 0.037 mmol) in 10 mL of 2, 2, 2-trifluoroethanol was prepared under nitrogen. To this solution was then charged 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (2.0 g, 7.4 mmol). The resulting mixture was heated to 50° C. and hydrogenated under 90 psig hydrogen pressure. After 18 h, the mixture was cooled to ambient temperature and removed from the hydrogenator. Ecosorb C-941 (200 mg) was added and the mixture was stirred at ambient temperature for 3 h. The mixture was filtered through Celite, and the filter was washed with additional trifluoroethanol (2 mL). Then, the mixture was heated to 55° C., and a solution of N-acetyl-L-leucine (1.3 g, 7.5 mmol) was added dropwise over the course of 1 h. Stirring proceeded at the same temperature for 1 h following completion of the addition, and then the mixture was cooled to 22° C. over 2 h and stirred at this temperature for 16 h. The crystalline product was filtered, rinsed with methanol (2×5 mL), and dried under vacuum at 45° C. to provide the product as a white solid (2.6 g, 80percent yield); achiral HPLC (Hypersil BDS CA 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3 -ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered andwashed with methanol (250 mL). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98percent yield) of the crude product (85.8percent ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried invacuo at 30°C. to a constant weight, yielding 49.6 g (90percent recovery) of(S)-2-(3-ethoxy-4-methoxyphenyl)- 1 -(methylsulphonyl)-eth-2-ylamine-N-acety l-L-leucine salt (98.4percent ee). ChiralHPLC (1/99 EtOH/20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm4.6 mm, 0.5 mL/min., 240 nm): 18.4 mm (S-isomer, 99.2percent), 25.5 mm (R-isomer, 0.8percent)General procedure: [0188] A 3 L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-l - (methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98percent yield) of the crude product (85.8percent ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30 °C to a constant weight, yielding 49.6 gA mixture of 2-(3-ethoxy-4-meth- oxyphenyl)-i -(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), andmethanol (1.0 L) was charged into a 3-L 3-necked round bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser. Afier the reaction mixture was refluxed for 1 hour, the mixture was allowed to cool to ambient temperature and then stirred for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuum at ambient temperature to a constant weight, giving 109.5 g (98percent yield) of the crude product (85.8percent cc). The crude solid (55.0 g) and methanol (440 mE) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mE). The solid was air-dried and then dried in vacuum at 30° C. to a constant weight, yielding 49.6 g (90percent recovery) of (S)-2-(3-ethoxy- 4-methoxyphenyl)-i -(methylsulphonyl)-eth-2-ylamine-N- acetyl-L-leucine salt (98.4percent cc). Chiral HPLC (1/99 EtOH/ 20 mM KH2PO4 pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mmx4.6 mm, 0.5 mE/mm., 240 nm): 18.4 mm (S-isomer, 99.2percent), 25.5 mm (R-isomer, 0.8percent).In a 500 ml round bottom flask, 200 ml of methanol was added followed by 20 gms of 2-(3-ethoxy-4-methoxyphenyl)-l-(methanesulfonyl)-eth-2-ylamine. The reaction mass was stirred and 76 gms of N-Acetyl-L-Leucine added and reaction mass was stirred. The reaction mass was heated for 2 hours at 60 to 65°C, After heating, the reaction masswas cooled at room temperature and it was stirred at room temperature for 3 to 4 hours. The slurry was filtered. Washed with 30 ml methanol, material was unloaded and dried under vacuum for 2 hours at 45°C. Yield: 14.36 gm. Further, this material is purified with methanol.A mixture of 27.3 g (100 mmol) of 1- (3-ethoxy-4-methoxy) phenyl-2-methanesulfonyl ethylamine (4), 10.4 g(60 mmol) of N-acetyl-L-leucine was dissolved in 200 mL of methanol, heated under reflux for 2 h, and then cooled to room temperature to a large amountThe slurry was precipitated, filtered and washed with methanol to give the crude product. The crude product was again dissolved in 80 mL of methanol, heated to reflux for 2 h, and cooled againTo a large amount of slurry to the slurry, filter, and wash the filter cake with methanol. The solid was dried in vacuo to give 9.1 g (41percent recovery)(S) -1- (3-ethoxy-4-methoxy) phenyl-2-methanesulfonylethylamine N-acetyl-L-leucine salt (97.9percent ee). Preparation of (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine N-acetyl-L-leucine salt (IV) A mixture of 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L) was charged into a 3-L 3-necked round bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser. After the reaction mixture was refluxed for 1 hour, the mixture was allowed to cool to ambient temperature and then stirred for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuum at ambient temperature to a constant weight, giving 109.5 g (98percent yield) of the crude product (85.8percent ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuum at 30° C. to a constant weight, yielding 49.6 g (90percent recovery) of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine-N-acetyl-L-leucine salt (98.4percent ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 (at)pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm.x.4.6 mm, 0.5 mL/min., (at)240 nm): 18.4 min (S-isomer, 99.2percent), 25.5 min (R-isomer, 0.8percent).6.2.3. The compound of formula V 0. 1mol 200mL of methanol was added and the reaction flask was refluxed clear solution was added portionwise N- acetyl-L- leucine (0.06mol ), a large number of the resulting solid was refluxed 1h, cooled to 25 ° C, stirred 1h, filtered and the filter cake was dried in vacuo at 40 ° C 5h, to give a white solid 22. 6g; The solid was added to the reaction flask and 180mL of methanol, refluxed for 1h, cooled to 25 ° C, stirred for 1h, filtered and the filter cake in and dried in vacuo 40 ° C 5h, to give a white solid 18g, 40 ° C and dried in vacuo 5h, ee: 98 · 6percentTo a reaction mixture of 700 ml methanol and 100 grams (gm) (0.366 moles) of 1-(3-ethoxy-4- methoxy phenyl)-2-(methylsulfonyl) ethanamine, 38gm (0.2196 moles) of N-acetyl-L-leucine was charged. The reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to 25°C to 30°C and stirred for 1 hour. The product was filtered and washed with 100 ml methanol.The obtained solid material was dried under vacuum at 30°C to obtain (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine N-acetyl-L-leucine salt.(Yield = 68.Ogms)R-isomer: 0.5percentTo 1 liter RBF the product of example 3 or 4 (75 g; 0.2743 moles), N- acetyl-L-leucine (47.5 g ; 0.2743) and methanol (545 mL) were charged and the suspension was stirred at 60 °C to 65 °C for 1 hour, the suspension was cooled to room temperature and stirred for another 3 hours. The solid was filtered and dried under reduced pressure to obtain 60 g of title compound with chiral purity of 85percent desired isomer. It was further purified by methanol to give 35 g of pure title compound having chiral purity 99.5percent.A mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2 g, 7.34 mmol) and ammonium acetate (0.90 g, 11.7 mmol) in TFE (75 mL) was heated to reflux, and anhydrous ammonia was bubbled through the solution for 45 min while distilling off solvent until the total volume was reduced to 20 mL. Then, the distillation was discontinued and the batch was held at reflux for 24 h. The batch was cooled and evaporated to dryness. Methanol (10 mL) was then added to the residue and the resultant slurry was stirred for 30 min. Then, the solids were filtered, washed with MeOH (5 mL), and dried under vacuum. The solids were then transferred to a hydrogenation reaction vessel. To this vessel was also charged a solution of bis(1, 5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (12.6 mg, 0.027 mmol), (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (14.4 mg, 0.027 mmol), and TFE (7.2 mL). The mixture was warmed to 50° C. and hydrogenated under 90 psig hydrogen gas for 18 h. Then Ecosorb C-941 (150 mg) was added and the mixture was stirred at 20° C. for 4 h. The mixture was filtered through Celite and the filtrate was transferred into a clean vessel. The mixture was warmed to 55° C. with stirring, and a solution of N-acetyl-L-leucine (0.79 g, 3.7 mmol) in methanol (7.25 mL) was added over 1 h, resulting in precipitation of the product as the N-acetyl-L-leucine salt. The mixture was stirred at 55° C. for 1 h and then a mixture 1:1 TFE-MeOH (5 mL) was added. The mixture was cooled to 25° C. over 2 h, and stirring proceeded at this temperature for 16 h. The mixture was filtered and washed 1:1 TFE-MeOH (10 mL) and with MeOH (10 mL), and was dried under vacuum. The product was obtained as a white solid (1.35 g, 41percent yield); achiral HPLC (Hypersil BDS CThe product from Step 1 (0.5 g, 1.670 mmol) was dissolved in TFE, and then 10percent Pd—C (0.05 g) was added. The resulting mixture was hydrogenated at ambient temp under 40 psig hydrogen for 9 h, and then the mixture was filtered through Celite. The filtrate was warmed to 55° C. with stirring, and a solution of N-Acetyl-L-Leu (0.29 g, 1.67 mmol) in MeOH (10 mL) was added to the mixture in dropwise fashion over 1 h. The mixture was stirred at the same temperature for 2 h and was then cooled to 21° C. over 2 h and stirred at this temperature for 16 h. The mixture was filtered and rinsed with 1:1 (v/v) TFE-MeOH (10 mL), and the solids were dried under vacuum to provide (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-acetyl-L-leucine salt as a white solid (0.33 g, 44percent yield); achiral HPLC (Hypersil BDS CUnder a nitrogen atmosphere, a dry 1000 ml glass flask equipped with a mechanical stirrer, a thermometer and a condenser was added (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine (110 g), N-acetylleucine 69.3 g (0.4 mol) and 500g of methanol, Heated to reflux for 1 hour with stirring and then cooled to ambient temperature in a stirred state and stirred at room temperature for 3 hours, filtered and the filter cake was washed with methanol, then the cake was dried under vacuum to constant weight. To give 176.3 g of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-1-leucine (Optical purity 99.6percent) yield 98.3percent. Chiral HPLC (ethanol: 20 mM KH2PO4 = 1:99, pH = 7.0, Agilent's ES-OVM chiral column, 150 mm x 4.6 mm, flow rate 0.5 ml/min, detection wavelength 240 nm): 18.1 min (S-isomer, 99.6percent), 25.0 min (R-isomer, 0.4percent).To a stirred solution l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (2500gm) in methanol (20.01it) was added N-acetyl-L-Leucine (950.0gm) slowly at 25°C and then the reaction mixture was heated to reflux temperature and maintained for 1.Ohr. The reaction mass was cooled to 25-30°C and stirred for 4.0 hr at 25-30°C. The product was filtered and washed with methanol and dried under vacuum at 60°C for 4.0 hr to obtain 2000.0gm of crude product. The crude product was subjected to methanol purification to obtain 1670gm of N-acetyl L-leucine salt of (5)-2-(3-ethoxy-4- methoxyphenyl)-l-(methylsulphonyl) eth-2-ylamine. chiral purity >99.5percent.

Molecular Weight:446.6
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:9
Exact Mass:446.20867260
Monoisotopic Mass:446.20867260
Topological Polar Surface Area:158
Heavy Atom Count:30
Complexity:510
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes