1430
CHEREVIN et al.
added 18.25 g (100 mmol) of L-lysine hydrochloride.
The reaction mixture was stirred for 1 h, the separated
precipitate was filtered off in a nitrogen flow. To the
filtrate cooled to 5°C slowly dropwise was added at
vigorous stirring 21.3 g (150 mmol) of ethyl trifluoro-
acetate. After the end of addition the reaction mixture
was stirred for 2 h at 5°C, then 1 h at room temperature.
The precipitate separated on adding 6.06 g (101 mmol)
of acetic acid was filtered off and washed in succession
with ethanol and acetone, then dried in a vacuum. Then
it was reprecipitated from water with ethanol. Yield
excess thionyl chloride was distilled off in a vacuum.
The solution obtained was cooled to –5°C, 11.11 g (110
mmol) of triethylamine was added, and to the formed
dispersion cooled to –5°C was added dropwise 10.575 g
(50 mmol) of dimethyl L-glutamate hydrochloride (V)
in 150 ml of butyl acetate. The reaction mixture was
stirred at –5°C for 2 h, the precipitate was filtered off,
the solution was washed with water (2×100 ml), and dried
with sodium sulfate. The butyl acetate was distilled off
in a vacuum, the reaction product was extracted from
the residue with dichloromethane (3×100 ml). The
solution obtained was filtered and concentrated to
a volume of 75 ml. On adding 300 ml of ethyl ether the
separated precipitate was filtered off, washed with ether,
and dried in a vacuum. Then it was reprecipitated from
dichloromethane with ether. Yield 13.365 g (54%),
1
5.01 g (62%), colorless powder, mp 252–254°C
20
(
(
decomp.), [α] +16.7° (c 1.0, 1 N HCl) {260–262°C
decomp.), [α] +18.6° (c 1.0, 1 ν. HCl) [9]}. IR spec-
D
2
5
D
–1
1
trum, ν, cm : 1698 (C=Oamide), 1581 (NHamide). H NMR
spectrum (D O), δ, ppm: 1.3–2.0 m (6H, 3CH ), 3.36 t
2
2
20
(
2H, CH ), 3.72 t (1H, CH). Found, %: C 39.81; H 5.63;
colorless powder, mp 104–106°C, [α] –26.2° (C 3.0,
2
D
–1
N 11.42. C H F N O . Calculated, %: C 39.67; H 5.42;
ethanol). IR spectrum, ν, cm : 1742, 1733 (C=Ocarboxyl),
1702, 1667 (C=Oamide), 1560, 1548 (NHamide). H NMR
8
13
3
2
3
1
N 11.57.
spectrum (CDCl ), δ, ppm: 1.30–2.55 m (10H, 5 CH ),
Simultaneous preparation of compounds II and
III. To a solution of 4.623 g (201 mmol) of sodium in
00 ml of ethanol was added 18.25 g (100 mmol) of
L-lysine hydrochloride. The reaction mixture was stirred
for 1 h, the separated precipitate was filtered off in
a nitrogen flow. To the filtrate cooled to 5°C slowly
dropwise was added at vigorous stirring 24.85 g
3
2
3
.22–3.52 m (2H, CH ), 3.67 s (3H, CH ), 3.75 s (3H,
2 3
CH ), 4.39–4.73 m (2H, 2 CH), 7.15 br.s (1H, NH),
2
3
7
.33 d (1H, NH), 7.60 d (1H, NH). Found, %: C 41.42;
H 4.81; N 8.24. C H F N O . Calculated, %: C 41.22;
17 23
6
3
7
H 4.68; N 8.48.
ε
α
N -Trifluoroacetyl-L-lysine N -carboxyanhydride
(VIII). Through a dispersion of 12.1 g (50 mmol) of
compound III in 200 ml of dioxane was passed for 2 h
a flow of phosgene at room temperature. The reaction
mixture was heated at 45°C for 2 h, dioxane was partially
evaporated at a reduced pressure (100 ml), and to the
mixture obtained 250 ml of hexane was added. The
precipitate was filtered off, washed with hexane, and
dried in a vacuum. Then it was reprecipitated from ethyl
acetate with hexane. Yield 9.38 g (70%), colorless
(
175 mmol) of ethyl trifluoroacetate. After the end of
addition the reaction mixture was stirred for 2 h at 5°C,
then 2 h at room temperature. The precipitate separated
on adding 11.514 g (101 mmol) of trifluoroacetic acid
was filtered off and washed in succession with ethanol
and acetone, then dried in a vacuum.. Yield of compound
III 6.05 g (25%).
From the filtrate after separation of the compound
III precipitate the solvent was distilled off at reduced
pressure, the residue was dissolved in 200 ml of water,
the reaction product was extracted into ether (3×150 ml).
The extract was dried with sodium sulfate. The solution
obtained was filtered and concentrated by distilling off
ether in a vacuum to a volume of 75 ml. The precipitate
separated on addition of 300 ml of hexane was filtered
off, washed with hexane, and dried in a vacuum. Yield
of compound II 18.94 g (56%).
2
0
powder, mp 92–93°C (decomp.), [α] –31.3° (C 3.0,
D
2
0
dioxane) {94°C (decomp.), [α] –32.2°(C 3.0, dioxane)
D
[
13]}. Found, %: C 40.48; H 4.30; N 10.32. C H F N O .
9 11 3 2 4
Calculated, %: C 40.31; H 4.13; N 10.45.
L-Lysyl-L-glutamic acid (VII). a. To a solution of
4.77 g (50 mmol) of compound VI in 150 ml of ethanol
2
was added dropwise a solution of 8.2 g (205 mmol) of
sodium hydroxide in 100 ml of 90% ethanol. The reaction
mixture was stirred for 20 h at room temperature and
then filtered. To the filtrate was added dropwise 11.97 g
(105 mmol) of trifluoroacetic acid. The reaction mixture
was stirred for 2 h, the precipitate was filtered off and
washed in succession with ethanol (2×50 ml) and acetone
(2×50 ml), and dried in a vacuum. Then it was
α
ε
Dimethyl N ,N -bis(trifluoroacetyl)-L-lysyl-L-
glutamate (VI). To cooled to –15°C solution of 16.9 g
(
50 mmol) of compound II and 8.395 g (115 mmol)
dimethylformamide in 150 ml of butyl acetate was slowly
added dropwise 13.685 g (115 mmol) of thionyl chloride.
The reaction mixture was stirred at –15°C for 4 h, and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007