Process for the preparation and isolation of the individual stereoisomers of 1-amino-3-substituted phenylcyclopentane-1-carboxylates

Abstract

The present invention discloses processes for the prepn. and isolation of the individual 4 stereoisomers of 1-amino-3-substituted phenylcyclopentane-carboxylates (I, II, III, and IV; R = Br, OMe; R1 = H, Me). The processes comprise (1) stereoselective Michael addn. reaction of 2-cyclopenten-1-one with arylboronic acid in the presence of a rhodium catalyst and (R)- or (S)-BINAP ligand to form chiral 3-arylcyclopenten-1-one (V or VI; R = same as above), (2) addn. reaction of the resulting chiral V (R = same as above) with NH3 and a cyanide salt to form a mixt. of 1-amino-3-arylcyclopentane-1-carbonitrile (VII and VIII; R = same as above) followed by sepn. of the diastereomer VII using L-tartaric acid and hydrolysis to 1-amino-3-substituted phenylcyclopentane-carboxylic acid I (R = same as above), or (3) conversion of the resulting chiral 3-arylcyclopenten-1-one VI (R = same as above) to hydantoins (IX and X; R = same as above; R2 = H) by reaction with an ammonium carbonate and a cyanide salt. Thus, a soln. of 11.0 g (R)-3-(4-Methoxyphenyl)cyclopentanone in 7 M methanolic ammonia soln. (120 mL) was treated with 6.21 g ammonium chloride and 5.68 g NaCN. The reaction mixt. was stoppered and stirred at room temp. for 2 days to give a mixt. of (1R,3R)-1-amino-3-(4-methoxyphenyl)cyclopentanecarbonitrile and (1S,3R)-1-amino-3-(4-methoxyphenyl)cyclopentanecarbonitrile as an oil (12.4 g). The latter mixt. (12.4 g) was dissolved in 100 mL MeOH and added to a soln. of 8.69 g L-tartaric acid in 100 mL MeOH. The resulting solid was filtered off and triturated repeatedly with 80 mL portions of MeOH to give (1R,3R)-1-amino-3-(4-methoxyphenyl)cyclopentanecarbonitrile (2R,3R)-2,3-dihydroxysuccinic acid salt. The latter diastereomer salt (5.0 g) in 50 mL 6 N HCl soln. and 5 mL p-dioxane was heated overnight at 100° to give (1R,3R)-1-amino-3-(4-methoxyphenyl)cyclopentanecarboxylic acid hydrochloride II (R = OMe, R1 = H). [on SciFinder(R)]