(3S,4aS,8aS)-2-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-tert-butyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-3-carboxamide

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

Procedure: A solution of 561 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 372 mg of N-(benzyloxycarbonyl)-L-asparagine in 20 ml of dry tetrahydrofuran was cooled in an ice/salt mixture 189 mg of hydroxybenzotriazole, 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 16 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 434 mg of 2-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS, 8aS)-isoquinoline-3(S)-carboxamide as a white solid from methanol/diethyl ether: MS: m/e 650 [M+H]+. were added filtered The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution The solvent was removed by evaporation the residue was chromatographed on silica gel for the elution

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

Procedure: (A)(iii) A solution of 17 mg (0.04 mmol) of 2-[3(S)-azido-2(R)-hydroxy-4-phenylbutyl]--N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide (prepared as described in Example 2 or Example 3) in 5 ml of ethanol was hydrogenated at about 3.4 atmospheres and at room temperature for 2 hours over 10 mg of 10% palladium-on-charcoal. The catalyst was filtered off and washed twice with ethanol. The combined filtrate and washings were evaporated to give 16 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide; MS: m/e 402 [M+H]+. The catalyst was filtered off washed twice with ethanol The combined filtrate and washings were evaporated

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

Procedure: (A)(ii) A suspension of 26.55 g of N-tert.butyl-2-[2(R)-hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (prepared as described in Example 1) in 100 ml of ethanol was treated with 25 ml of a 30% solution of methylamine in ethanol at room temperature for 1 hour. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 250 ml of ethanol, treated with 250 ml of a saturated solution of hydrogen chloride in ethyl acetate and stirred at room temperature for 16 hours. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous phase was separated, made basic with solid sodium carbonate and then extracted with dichloromethane. The dichloromethane extract was washed with sodium chloride solution and evaporated to dryness. The residue was triturated with diethyl ether and, after filtration, there were obtained 17.48 g of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 402 [M+H]+. The mixture was evaporated to dryness under reduced pressure The residue was dissolved in 250 ml of ethanol treated with 250 ml of a saturated solution of hydrogen chloride in ethyl acetate The mixture was evaporated to dryness the residue was partitioned between ethyl acetate and water The aqueous phase was separated extracted with dichloromethane The dichloromethane extract was washed with sodium chloride solution evaporated to dryness The residue was triturated with diethyl ether after filtration

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

Procedure: Process for the production of 2-[3-(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of the formula ##STR20## characterised in that a) L-phenylalanine of the formula ##STR21## is reacted with phthalic anhydride, b) the resultant 3-phenyl-2(S)-phthalimidopropionic acid of the formula ##STR22## is converted into the corresponding acid chloride, c) the resultant 3-phenyl-2(S)-phthalimidopropionic acid chloride of the formula ##STR23## is reduced, d) the resultant 3-phenyl-2(S)-phthalimidopropan-1-al of the formula ##STR24## is transformed into the 1-cyano-3-phenyl-2(S)-phthalimidopropan-1-ol of the formula ##STR25## e) the resultant nitrile of the formula VI is hydrolysed, f) the unisolated 3(S)-amino-2-hydroxy-4-phenylbutyric acid formed of the formula ##STR26## is reacted with a low alkyl ester or the phenyl or benzyl ester of chloroformic acid,

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

Procedure: 34.7 g of (3S,4aS,8aS)-2-[(4S,5R)-4-benzyl-2-oxo-oxazolidin-5-yl methyl]-N-tert.-butyl-decahydro-isoquinoline-3-carboxamide-p-nitrobenzenesulphonate were divided between 110 ml of ethyl acetate and 110 ml of saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the ethyl acetate extracts washed with 110 ml of saturated sodium bicarbonate and with water. The organic extracts were evaporated and the residue diluted with 55 ml of ethanol and combined with stirring with a solution of 11.0 g of sodium hydroxide in 55 ml of water. The mixture was refluxed for 5 hours, diluted with 55 ml of water and cooled to room temperature. The suspension was filtered and the residue washed with water until the filtrate was neutral. The residue was evaporated and yielded 20.7 g (93%) 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.-butyl-decahydro-(4aS, 8aS)-isoquinoline-3(S)-carboxamide, melting point 175°-176°. The aqueous layer was extracted with ethyl acetate the ethyl acetate extracts washed with 110 ml of saturated sodium bicarbonate and with water The organic extracts were evaporated the residue diluted with 55 ml of ethanol The mixture was refluxed for 5 hours diluted with 55 ml of water The suspension was filtered the residue washed with water until the filtrate The residue was evaporated

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

Procedure: A suspension of 41.37 g of methyl (1S,2R)-[1-benzyl-3-[(3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinolin-2-yl]-2-hydroxy-propyl]-carbamate and 23.0 g of sodium hydroxide in 90 ml of ethanol and 90 ml of water was heated at reflux for 3.5 hours, diluted with 45 ml of water and cooled to 22°, and the separated solid was filtered off, washed with a 1:4 mixture of ethanol/water and dried, there being obtained 35.35 g (98%) of pure 2-[3 (S)-amino-2(R)-hydroxy-4-phenyl-butyl]-N-tert.butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, m.p. 173°-175° C. IR (KBr): 3435 m, hr. (NH, OH), 1665s (C=O), 1562 m (amide II). was heated at reflux for 3.5 hours cooled to 22° the separated solid was filtered off washed with a 1:4 mixture of ethanol/water dried

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

Procedure: A solution of 287 mg of N-(2-quinolylcarbonyl)-L-asparagine and 401 mg of 2-[3(S)-amino-2(R)-hydroxy-4 -phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 3 ml of tetrahydrofuran was cooled to-10° C. and 163 mg of 3-hydroxy-1,2,3-benzotriazin-4(3H)-one and 220 mg of dicyclohexylcarbodiimide were added. The mixture was stirred at-10° C. for 2 hours and at 20° C. for 16 hours, then diluted with ethyl acetate and filtered. The filtrate was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using 4% (by volume) methanol in dichloromethane for the elution to give 537 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid: MS: m/e 671 [M+H]+. were added at 20° C. for 16 hours filtered The filtrate was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution evaporated The residue was chromatographed on silica gel using 4% (by volume) methanol in dichloromethane for the elution

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

Procedure: (A)(iii) A solution of 17 mg (0.04 mmol) of 2-[3(S)-azido-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro- -(4aS,8aS)-isoquinoline-3(S)-carboxamide (prepared as described in Example 2 or Example 3) in 5 ml of ethanol was hydrogenated at about 3.4 atmospheres and at room temperature for 2 hours over 10 mg of 10% palladium-on-charcoal. The catalyst was filtered off and washed twice with ethanol. The combined filtrate and washings were evaporated to give 16 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-iso quinoline-3(S)-carboxamide; MS: m/e 402 [M+H]+. The catalyst was filtered off washed twice with ethanol The combined filtrate and washings were evaporated

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

Procedure: (A)(ii) A suspension of 26.55 g of N-tert.butyl-2-[2(R)-hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (prepared as described in Example 1) in 100 ml of ethanol was treated with 25 ml of a 30% solution of methylamine in ethanol at room temperature for 1 hour. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 250 ml of ethanol, treated with 250 ml of a saturated solution of hydrogen chloride in ethyl acetate and stirred at room temperature for 16 hours. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous phase was separated, made basic with solid sodium carbonate and then extracted with dichloromethane. The dichloromethane extract was washed with sodium chloride solution and evaporated to dryness. The residue was triturated with diethyl ether and, after filtration, there were obtained 17.48 g of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 402 [M+H]+. The mixture was evaporated to dryness under reduced pressure The residue was dissolved in 250 ml of ethanol treated with 250 ml of a saturated solution of hydrogen chloride in ethyl acetate The mixture was evaporated to dryness the residue was partitioned between ethyl acetate and water The aqueous phase was separated extracted with dichloromethane The dichloromethane extract was washed with sodium chloride solution evaporated to dryness The residue was triturated with diethyl ether after filtration

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

Procedure: A solution of 287 mg of N-(2-quinolylcarbonyl)-L-asparagine and 401 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 3 ml of tetrahydrofuran was cooled to -10° C. and 163 mg of 3-hydroxy-1,2,3-benzotriazin-4(3H)-one and 220 mg of dicyclohexylcarbodiimide were added. The mixture was stirred at -10° C. for 2 hours and at 20° C. for 16 hours, then diluted with ethyl acetate and filtered. The filtrate was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using 4% (by volume) methanol in dichloromethane for the elution to give 537 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid: MS: m/e 671 [M+H]+. filtered The filtrate was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution evaporated The residue was chromatographed on silica gel using 4% (by volume) methanol in dichloromethane for the elution

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

Procedure: A solution of 561 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 372 mg of N-(benzyloxycarbonyl)-L-asparagine in 20 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 189 mg of hydroxybenzotriazole, 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 16 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 434 mg of 2-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS )-isoquinoline-3(S)-carboxamide as a white solid from methanol/diethyl ether: MS: m/e 650 [M+H]+. filtered The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution The solvent was removed by evaporation the residue was chromatographed on silica gel for the elution

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

Procedure: A solution of 561 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 372 mg of N-(benzyloxycarbonyl)-L-asparagine in 20 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 189 mg of hydroxybenzotriazole, 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 16 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 434 mg of 2-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS )-isoquinoline-3(S)-carboxamide as a white solid from methanol/diethyl ether: MS: m/e 650 [M+H]+. filtered The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution The solvent was removed by evaporation the residue was chromatographed on silica gel for the elution