Chemistry Reference
In-Depth Information
condenser with gas outlet (HCl!), and thermometer, cooled by immersion in a
dry-ice/ethanol bath, phosgene (for a safe source, see Chapter 7) (100 g, 1.01 mol)
was condensed at
50
C. The gas inlet was then replaced by a dropping funnel
and benzyl alcohol (108 g, 1.00 mol) was added dropwise at
10
C over a
period of 1.5 h. The reaction mixture was stirred for a further 12 h at 0
C (ice
bath), with monitoring of the reaction by TLC. Thereafter, the cooling bath was
replaced by an oil bath and the flask was fitted with a distillation apparatus. The
crude product was distilled in vacuo to afford 165.1 g (97%) of colorless benzyl
chloroformate 1,bp41
C (0.03 Torr). Analyses (
1
H and
13
C NMR, IR, TLC) were
indicative of a pure product (free from benzyl chloride). Important: During the
course of the distillation, the temperature of the oil bath must be kept below
65
C! At higher temperatures, benzyl chloride will be increasingly generated. The
dry-ice/ethanol bath also serves as a safety device (accidentally overflowing phos-
gene reacts immediately with the ethanol).
In a study of the chlorination of the cephem nucleus at the C-3 position using
triphosgene, a clean conversion to cephem chloride 4 has been observed [13]. The
reaction is thought to proceed through an unstable cephem chloroformate 3.
20 to
HH
HH
R'
S
R'
S
(CCl
3
O)
2
CO
N
OH
N
O
Cl
O
Pyridine
O
COOR
COOR
O
2
3
CO
2
HH
R'
S
N
Cl
O
COOR
4
R' =
CH
2
CONH
S
R =
p
-methoxybenzyl or benzhydryl
Typical procedure. Methoxybenzyl-7b-(2-thienylacetamido)-3-(chloromethyl)-3-cephem-4-
carboxylate 4 [13]:
A solution of p-methoxybenzyl 7b-(2-thienylacetamido)-3-
(hydroxymethyl)-3-cephem-4-carboxylate (750 mg, 1.6 mmol) and triphosgene
(160 mg, 0.54 mmol) in dry THF (20 mL) was stirred at room temperature. The
progress of the reaction could be conveniently monitored by measuring CO
2
evo-
lution. Subsequently, dry pyridine (270
L, 3.2 mmol) was added over a period of
30 s; pyridinium hydrochloride precipitated immediately. The mixture was stirred
for 30 min, concentrated to dryness, and the residue was purified by column
chromatography on silica gel (10% ethyl acetate in benzene). p-Methoxybenzyl-7b-
(2-thienylacetamido)-3-(chloromethyl)-3-cephem-4-carboxylate 4, was isolated as a
white solid (640 mg, 81%).
m
