1) A solution of 2.0 g of t-butyl alanine (S-form) and 3.78 g of ethyl 2-bromo-
4-phenylbutanoate in 25 ml of DMF was treated with 1.8 ml of triethylamine
and the solution was heated at 70°C for 18 hours. The solvent was removed
at reduced pressure and the residue was mixed with water and extracted with
ethyl ether. The organic layer was washed with water and dried over
magnesium sulfate. Concentration of the solvent at reduced pressure gave the
oily ethyl-α-[(1-carboxyethyl)amino]benzene-t-butanoate.
A solution of 143.7 g of this t-butyl ester in 630 ml of trifluoroacetic acid was
stirred at room temperature for one hour. The solvent was removed at
reduced pressure and the residue was dissolved in ethyl ether and again
evaporated. This operation was repeated. Then the ether solution was treated
dropwise with a solution of hydrogen chloride gas in ethyl ether until
precipitation ceased. The solid, collected by filtration, was a mixture of
diastereoisomers of ethyl-α-[(1-carboxyethyl)amino]benzenebutanoate
hydrochloride, melting point 153-165°C; [α]D23 = +3.6° (1% MeOH).
The free amino acid (S,S-form) was prepared by treatment of an aqueous
solution of the hydrochloride with saturated sodium acetate. The product was
filtered, washed efficiently with cold water and recrystallized from ethyl
acetate; melting point 149-151°C; [α]D23 = +29.7°.
2) A stirred solution of 0.0158 mole of ethyl-α-[(1-carboxyethyl)amino]
benzenebutanoate hydrochloride in 200 ml of methylene chloride was treated
successively with 1.60 g (0.0158 mole) of triethylamine, 0.0158 mole of 1-
hydroxybenzotriazole, 0.0158 mole of 1,2,3,4-tetrahydro-6,7-dimethoxy-3-
isoquinolinecarboxylic acid and then with 0.0158 mole of
dicyclohexylcarbodiimide in 10 ml of methylene dichloride. Dicyclohexylurea
gradually separated. The mixture was allowed to stand at room temperature
overnight. Hexane (300 ml) was added and the urea was filtered. The filtrate
was washed with 250 ml of saturated sodium bicarbonate, dried over sodium
sulfate and concentrated to remove solvent. The viscous residue was
triturated with 50 ml of ether and filtered to remove insolubles. The filtrate
was concentrated to give 2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-
oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid.
After addition of hydrochloric acid was obtained 2-[2-[[1-(ethoxycarbonyl)-3-
phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-
isoquinolinecarboxylic acid, hydrochloride.
