(1S)-N-benzyl-1-phenylethanamine

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (S)-N-benzyl-α-methylbenzylamine (2.6 ml) in anhydrous tetrahydrofuran (50 ml), cooled to −70° C. and under nitrogen, was treated dropwise with a solution of butyllithium in hexanes (5 ml, 2.5M) over about 5 minutes to give a red solution. After stirring at −70° C. for a further 40 minutes the mixture was treated dropwise with a solution of methyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)acrylate [2.0 g, Reference Example 7(d)] in tetrahydrofuran (20 ml) over about 10 minutes. Stirring was continued at low temperature for a further 20 minutes and then the reaction mixture was allowed to warm to room temperature. The mixture was partitioned between ether and water, the layers separated, and the organic layer washed with water then with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (initially 1:9 and then 15:85, v/v) to give the title compound as a viscous, colourless oil, 1.5 g. to give a red solution Stirring was continued at low temperature for a further 20 minutes to warm to room temperature The mixture was partitioned between ether and water the layers separated the organic layer washed with water with brine, then dried evaporated The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (initially 1:9

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-(−)-N-benzyl-alpha-methyl-benzylamine (50 mL, 239 mmol) in THF (150 mL) at 0° C. is added nBuLi (2.5 M in THF) (100 mL, 250 mmol) under nitrogen atmosphere. The solution is cooled to −78° C. and ethyl trans-2-hexenoate (16.6 g, 117 mmol) is added. The solution is stirred for 1 hour and saturated NH4Cl solution is added. The solution is warmed to room temperature and is extracted with EtOAc. The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent to afford the (S)-3-[Benzyl-((S)-1-phenyl-ethyl)-amino]-hexanoic acid ethyl ester (20.8 g, 50%) as a colorless oil. The solution is warmed to room temperature is extracted with EtOAc The combined organic layer is dried with MgSO4 is filtered The filtrate is concentrated the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-N-benzyl-1-phenylethanamine (3.64 g, 17.26 mmol) in THF (40 mL) at −70° C., was added dropwise n-BuLi (1.6 M, 14.7 mmol) over a period of 30 min and stirred further. After 1 h, a solution of (E)-tert-butyl 3-(6-methylpyridin-3-yl)acrylate (2.7 g, 12.3 mmol) in THF was added slowly to the above mixture and stirred further. After 2 h, sat. NH4Cl solution was added to the reaction mixture and extracted with EtOAc (3×). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford a residue. Purification of the residue by column chromatography (Neutral Al2O3, Et2O/Pet ether 5:95) afforded the title compound. MS: 431.6 [M+H]+; stirred further After 2 h extracted with EtOAc (3×) The combined organic phase was dried over anhydrous Na2SO4 concentrated in vacuo to afford a residue Purification of the residue by column chromatography (Neutral Al2O3, Et2O/Pet ether 5:95)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-N-benzyl-1-phenylethanamine (3.64 g, 17.26 mmol) in THF (40 mL) at −70° C., was added dropwise n-BuLi (1.6 M, 14.7 mmol) over a period of 30 min and stirred further. After 1 h, a solution of (E)-tert-butyl 3-(6-methylpyridin-3-yl)acrylate (2.7 g, 12.3 mmol) in THF was added slowly to the above mixture and stirred further. After 2 h, sat. NH4Cl solution was added to the reaction mixture and extracted with EtOAc (3×). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford a residue. Purification of the residue by column chromatography (Neutral Al2O3, Et2O/Pet ether 5:95) afforded the title compound. MS: 431.6 [M+H]+; stirred further After 2 h extracted with EtOAc (3×) The combined organic phase was dried over anhydrous Na2SO4 concentrated in vacuo to afford a residue Purification of the residue by column chromatography (Neutral Al2O3, Et2O/Pet ether 5:95)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(phenylmethyl)amino-N-phenylmethyl-N-{1(S)phenylethyl}acetamide hydrochloride: By following the procedure of Example 1(a) but replacing dibenzylamine with α(S)-methyl-N-(phenylmethyl)benzene methanamine, ((S)-N-benzyl-α-methylbenzylamine, Oxford Asymmetry Ltd., Abingdon Oxon, UK), tert-butyl N-{2-oxo-2-{(phenylmethyl){1(S)-phenylethyl}amino}ethyl}carbamate was made. The Boc group was removed following the procedure of Example 1(b) to give N-{2-oxo-2-{(phenylmethyl){1(S)-phenylethyl}amino}ethyl}carbamate hydrochloride, which was subjected to reductive amination with benzaldehyde according the procedure of R. F. Borch, Org. Synth., 1972, 52, 124, to give 2-(phenylmethyl)amino-N-phenylmethyl-N-{1(S)-phenylethyl}acetamide hydrochloride. The Boc group was removed

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(phenylmethyl)amino-N-phenylmethyl-N-{1(S)phenylethyl}acetamide hydrochloride: By following the procedure of Example 1(a) but replacing dibenzylamine with α(S)-methyl-N-(phenylmethyl)benzene methanamine, ((S)-N-benzyl-α-methylbenzylamine, Oxford Asymmetry Ltd., Abingdon Oxon, UK), tert-butyl N-{2-oxo-2-{(phenylmethyl){1(S)-phenylethyl}amino}ethyl}carbamate was made. The Boc group was removed following the procedure of Example 1(b) to give N-{2-oxo-2-{(phenylmethyl){1(S)-phenylethyl}amino}ethyl}carbamate hydrochloride, which was subjected to reductive amination with benzaldehyde according the procedure of R. F. Borch, Org. Synth., 1972, 52, 124, to give 2-(phenylmethyl)amino-N-phenylmethyl-N-{1(S)-phenylethyl}acetamide hydrochloride. The Boc group was removed

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethanol (125 g) was added to (+/−)-3-[2-(4-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (11a, 25 g, 85 mmol) and the resulting solution stirred at 20° C. (S)-N-Benzyl-α-methylbenzylamine (21, 22.5 g, 106 mmol) was added to the solution and the resulting mixture allowed to stir at 20° C. for 23 hours. The mixture was filtered and the product washed with ethanol (10 mL) and vacuum dried at ambient temperature to give (S)-3-[2-(4-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (S)-N-benzyl-α-methylbenzylamine salt (22a): 18.6 g (36.8 mmol, 43% yield or 86% of theory); Chiral assay (HPLC): 99.2 area % (S) isomer 23a; mp: 152-154° C. was added to the solution The mixture was filtered the product washed with ethanol (10 mL) and vacuum dried at ambient temperature

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethanol (125 g) was added to (+/−)-3-[2-(4-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (11a, 25 g, 85 mmol) and the resulting solution stirred at 20° C. (S)-N-Benzyl-α-methylbenzylamine (21, 22.5 g, 106 mmol) was added to the solution and the resulting mixture allowed to stir at 20° C. for 23 hours. The mixture was filtered and the product washed with ethanol (10 mL) and vacuum dried at ambient temperature to give (S)-3-[2-(4-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (S)-N-benzyl-α-methylbenzylamine salt (22a): 18.6 g (36.8 mmol, 43% yield or 86% of theory); Chiral assay (HPLC): 99.2 area % (S) isomer 23a; mp: 152-154° C. was added to the solution The mixture was filtered the product washed with ethanol (10 mL) and vacuum dried at ambient temperature

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)—N-benzyl-1-phenylethanamine (3.64 g, 17.26 mmol) in THF (40 mL) at −70° C., was added dropwise n-BuLi (1.6 M, 14.7 mmol) over a period of 30 min and stirred further. After 1 h, a solution of (E)-tert-butyl 3-(6-methylpyridin-3-yl)acrylate (2.7 g, 12.3 mmol) in THF was added slowly to the above mixture and stirred further. After 2 h, sat. NH4Cl solution was added to the reaction mixture and extracted with EtOAc (3×). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford a residue. Purification of the residue by column chromatography (Neutral Al2O3, Et2O/Pet ether 5:95) afforded the title compound. stirred further After 2 h extracted with EtOAc (3×) The combined organic phase was dried over anhydrous Na2SO4 concentrated in vacuo to afford a residue Purification of the residue by column chromatography (Neutral Al2O3, Et2O/Pet ether 5:95)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 0.66 ml of (S)-(−)-N-benzyl-α-methylbenzylamine in 10 ml of tetrahydrofuran was cooled to 0° C. and 1.88 ml of a 1.6M solution of n-butyllithium in hexane were added dropwise via a syringe. The resulting dark pink solution was stirred at 0° C. for 45 minutes and then cooled to −78° C. A solution of 0.184 g of tert-butyl (E)-2-heptenoate in 2 ml of anhydrous diethyl ether was added and the mixture was stirred for 2 hours at −78° C. 0.37 g of solid (1S)-(+)-(10-camphorsulphonyl)oxaziridine was added and the mixture was stirred at −78° C. for 1 hour. The mixture was warmed to 0° C. and a saturated ammonium chloride solution was added. The tetrahydrofuran was evaporated and the aqueous phase was diluted with water and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, evaporated and purified by chromatography on silica gel using a 10% solution of diethyl ether in hexane for the elution to give 0.35 g of tert-butyl 3(S)-[N-benzyl-N-(α(S)-methylbenzyl)amino]-2(S)-hydroxyheptanoate as a colorless oil, MS: m/e 412.2 [M+H]+. cooled to −78° C the mixture was stirred for 2 hours at −78° C the mixture was stirred at −78° C. for 1 hour The mixture was warmed to 0° C. The tetrahydrofuran was evaporated the aqueous phase was diluted with water extracted with dichloromethane The organic phase was dried over magnesium sulphate evaporated purified by chromatography on silica gel using a 10% solution of diethyl ether in hexane for the elution

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (S)-N-benzyl-α-methylbenzylamine (2.6 ml) in anhydrous tetrahydrofuran (50 ml), cooled to −70° C. and under nitrogen, was treated dropwise with a solution of butyllithium in hexanes (5 ml, 2.5M) over about 5 minutes to give a red solution. After stirring at −70° C. for a further 40 minutes the mixture was treated dropwise with a solution of methyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)acrylate [2.0 g, Reference Example 7(d)] in tetrahydrofuran (20 ml) over about 10 minutes. Stirring was continued at low temperature for a further 20 minutes and then the reaction mixture was allowed to warm to room temperature. The mixture was partitioned between ether and water, the layers separated, and the organic layer washed with water then with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (initially 1:9 and then 15:85, v/v) to give the title compound as a viscous, colourless oil, 1.5 g. to give a red solution Stirring was continued at low temperature for a further 20 minutes to warm to room temperature The mixture was partitioned between ether and water the layers separated the organic layer washed with water with brine, then dried evaporated The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (initially 1:9

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (S)-N-benzyl-α-methylbenzylamine (2.6 ml) in anhydrous tetrahydrofuran (50 ml), cooled to −70° C. and under nitrogen, was treated dropwise with a solution of butyllithium in hexanes (5 ml, 2.5M) over about 5 minutes to give a red solution. After stirring at −70° C. for a further 40 minutes the mixture was treated dropwise with a solution of methyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)acrylate [2.0 g, Reference Example 7(d)] in tetrahydrofuran (20 ml) over about 10 minutes. Stirring was continued at low temperature for a further 20 minutes and then the reaction mixture was allowed to warm to room temperature. The mixture was partitioned between ether and water, the layers separated, and the organic layer washed with water then with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (initially 1:9 and then 15:85, v/v) to give the title compound as a viscous, colourless oil, 1.5 g. to give a red solution Stirring was continued at low temperature for a further 20 minutes to warm to room temperature The mixture was partitioned between ether and water the layers separated the organic layer washed with water with brine, then dried evaporated The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (initially 1:9