Patent ID: 6403824
Filing Date: 2002-06-11
Classification: C07C,C07D,Y02P

Abstract:
A process for the preparation of a 4,5-diamino shikimic acid derivative of formula and pharmaceutically acceptable addition salts thereofwhereinR1 is an alkyl group of 1 to 20 carbon atoms, R2 is an alkyl group of 1 to 12 carbon atoms, R3 is an amino-protecting group and R4 is H or an amino-protecting group; the process comprising steps a), b), c), d), e), f), g11), g12) and g,13): step a) reacting, by a Diels-Alder reaction, furan with an acrylic acid derivative of the formula wherein R2 is as above to form a mixture of a 2R-exo isomer and other stereoisomers of a bicyclo compound of formula wherein R2 is as above; step b) isolating the 2R-exo isomer of the bicyclo compound of formula (III) from the mixture of 2R-exo isomer and other stereoisomers of the bicyclo compound of formula (III); step c) reacting the isolated 2R-exo isomer of the bicyclo compound of formula (III) with an organic azide R5-N3 in an inert solvent to form an aziridine of formula wherein R2 is as above and R5 is a residue of the organic azide; step d) reacting the aziridine of formula (IV) in the presence of an organic base to yield a cyclohexene aziridine derivative of formula wherein R2 and R5 are as above; step e) introducing an OH-protecting group R6 in the free OH-position of the cyclohexene aziridine derivative of formula (V) and reacting the aziridine ring of the cyclohexene aziridine derivative of formula (V) with R1OH to form a cyclohexene derivative of formula wherein R1, R2 and R5 are as above and R6 is an OH-protecting group; step f) removing R5 from the cyclohexene derivative of formula (VI) to yield a 4-amino cyclohexene derivative of formula wherein R1, R2 and R6 are as above; step g11) reacting the 4-amino cyclohexene derivative of formula (VII) with a tertiary amine to form an aziridine of formula wherein R1 and R2 are as above; step g12) converting the aziridine of formula (VIII) to an azide of formula wherein R1, R2, R3 and R4 are as above by aziridine ring opening by reaction with an azide to form an azidoamine, followed by acylation of the azidoamine with at least one amino-protecting group; and step g13) reducing the azide of formula (IX) to form the 4,5-diamino shikimic acid derivative of formula (I).