Process for the manufacture of 3-amino-pyrrolidine derivatives

A process for producing a vinylpyrrolidinone-cephalosporin derivative of formula A-1

• wherein
• * denotes a center of chirality;
• comprising:
• (a) converting a compound of the formula II
• wherein
• X is a protected hydroxy group;
• Z1 is an amino protecting group;
• and * is as above in the presence of hydroxylamine or an acid addition salt thereof into the N-hydroxy-pyrrolidine derivative of the formula III
• wherein
• Z1 and * have the same meaning as above;
• (b) reducing said N-hydroxy derivative of formula III to the secondary amine derivative of formula IV
• wherein
• Z1 and * have the same meaning as above by hydrogenation with Raney nickel;
• (c) converting said secondary amine of formula IV into a 3-amino pyrrolidine compound of formula I
• wherein
• R1 is an amino protecting group and * is as above;
• by reaction of the 1-amino group of the compound of formula IV with a compound of formula R1X1, in which R1 has the above indicated meaning, and X1 is halogen or a leaving group, and deprotecting the resulting 3-amino group by catalytic hydrogenation;
• (d) reacting said 3-amino-pyrrolidine compound of formula I with 2-bromo-4-chlorobutanoylchloride to yield a compound of formula (1)
• wherein
• R1 and * have the above indicated meaning
• (e) converting said compound of formula (1) into the corresponding triphenylphosphine Wittig salt of formula (2)
• wherein
• Ph is phenyl and R1 and * are as above;
• (f) reacting said Wittig salt of formula (2) with a diprotected 3-ene cephalosporin derivative of formula (3)
• wherein
• BOC is tert.-butoxycarbonyl;
• and
• Ph is phenyl;
• to yield the condensation product (4)
• wherein *, BOC, R1 and Ph are as above
• (g) oxidizing said condensation product of formula (4) to produce the 5-sulfoxide compound of formula (5)
• wherein *, R1, BOC and Ph are as above.
• (h) reducing the sulfoxide group on said 5-sulfoxide compound of formula (5) to form the 2-ene celphalosporin derivative of formula (6)
• wherein *, BOC and Ph are as above.
• (i) deprotecting the 7-amino group of said compound of formula (6) and acylating the deprotected compound of formula (6) with (Z)-(5-amino[1,2,4]thiadiazol-3-yl-trityloximino-thioacetic acid S-benzothiazol-2-yl ester to yield the compound of formula (1)
• wherein *, R1, Y and Ph are as above;
• and
• (j) removing the protecting amino protecting groups R1 and CPh3 from the compound of formula (9) to produce the compound of formula A-1.