Organic Chemistry of Drug Synthesis. Volume 7

The fact that the final compound will contain chiral atoms at two remote
locations on the fused piperidine ring and on the yet-to-be added gluta-
mine moiety adds complications to the preparation of an enantiometrically
pure product. The problem was solved by resorting to the use of enzymes.
The first step comprises treatment of intermediate 209 with base to hydro-
lyze the ester. The secondary amine on the fused piperidine ring is then
converted to an oxamate ( 210 ) by reaction with the half acid chloride of
ethyl oxalate. The glutamate side chain is then added ( 211 ). Digestion of
this intermediate with a lipase fromCandida antarcticaselectively hydro-
ylizes the terminal ester on the glutamate of the (S) enantiomer allowing
this compound to be easily separated from its epimers. Base hydrolysis
of this compound then providespelitrexol( 213 ).^31

HN

N N

O

tBuCOHN

S CO 2 H

H 3 C

COCl

COC 2 H 5

O O

OC 2 H 5

HN

CO 2 C 2 H 5

HN CO 2 C 2 H 5

N N

O

tBuCOHN

S

H 3 C

O O

OC 2 H 5

209

1.NaOH

2. Et-L-glutamineEDC

EDC = 1-ethyl-3-(3-dimethylaminopropyl) carbodeimide hydrochloride

(^210211)
Enzymatic
HN
CO 2 C 2 H 5
HN CO^2 H
N N
O
tBuCOHN
S
H 3 C
O O
OC 2 H 5
NaOH
HN
CO 2 H
HN CO 2 H
N NH
O
H 2 N
S
H 3 C
(^213212)
O
O O

3. MISCELLANEOUS COMPOUNDS WITH TWO FUSED

HETEROCYCLIC RINGS: BETA LACTAMS

The overwhelming majority of semisynthetic beta-lactam antibiotics, the
penicillins and cephalosporin, currently available to physicians trace
their origins to the intense research effort devoted to this field several
decades ago. The emergence of pathogens resistant to those antibiotics
has led some laboratories to revisit this field. The modified cephalosporin
ceftobiprole ( 220 ), a compound with a rather complex extended side
chain, has shown activity in the clinic against some strains of multidrug
resistant bacteria. The synthesis starts with the well-precedented acylation
of the of the cephalosporin ( 215 ), available in several steps from the com-
mercially available 7-acetoxy cephalosporanic acid, with the activated

3. MISCELLANEOUS COMPOUNDS WITH TWO FUSED HETEROCYCLIC RINGS 213