Chemistry Reference
In-Depth Information
pected, the water wash was quite acidic, turning blue litmus paper red. The ethyl
acetate layer was then washed with 0.5% aq. NaHCO
3
solution, also chilled to 0
C.
This wash was neutral or slightly basic and did not change the color of blue litmus
(faint blue color change to red litmus). For NCAs with short hydrocarbon R groups
(i.e. less than ten carbons), both layers were usually clear during the washing pro-
cedure. Any cloudiness due to unreacted starting material was eliminated during
the washes. For NCAs with long side chains, the separatory funnel was allowed to
stand for a few minutes in a cooler at below 5
C. Vigorous shaking of the layers
was generally avoided. The ethyl acetate layer was then treated with anhydrous
MgSO
4
until no clumping was observed. The clear solution was gravity filtered and
concentrated to about one-third of its original volume in a rotary evaporator. The
temperature of the water bath of the evaporator was kept below 30
C to minimize
or eliminate deleterious reactions due to residual water. At this point, the usual
care in minimizing exposure to moisture was observed. An equal volume of hex-
ane or petroleum ether (30-60
C cut) was then added to induce crystallization of
the NCA. After chilling to
5
C overnight, the NCA crystals were collected by
suction filtration in a dry nitrogen atmosphere. For oily NCAs, the ethyl acetate
was completely evaporated and the oil was immediately vacuum dried. See Table
4.39 for typical yields.
)
a,a-Dichloromethyl methyl ether (CHLOROMYL
2
) 1224, obtained by catalytic
phosgenation of methyl formate in the presence of triphenylphosphine oxide, re-
acts, in excess, with Z- or Cbz-amino acids 1223 providing a practical and
safe access to the N-carboxy anhydride 1225 [902-905] (Table 4.41). This method
is superior to the thionyl chloride process by virtue of the facile removal of
excess reagent and side products under mild conditions, as depicted in the scheme
below.
,
-Dichloromethyl methyl ether (CHLOROMYL
3
a
a
CH
3
OCHCl
2
O
N
O
COOH
1224
O
H
+
HCl
+
Z
+
PhCH
2
Cl
Me
O
R
H
R
O
1223
1225
Tab. 4.41.
N-Carboxy anhydrides prepared with CHLOROMYL3 [905].
N-Carboxy
anhydrides
Yield
(%)
N-Carboxy
anhydrides
Yield
(%)
Glycine
84
S-Benzyl-(l)-cysteine
90
l-Alanine
80
O-Acetyl-(l)-tyrosine
69
d-(l)-Valine
72
N-d-Z-d-(l)-ornithine
68
d-(l)-Phenylalanine
82
N-e-Tos-(l)-lysine
44
