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at 20 °C for 8 h, the precipitate of inorganic salts was filtered off,
washed with MeCN, the solvent was evaporated in vacuo. Ether
(50 mL) was added to the oilꢀlike residue, the etheral solution
was filtered, and 2 M HCl in ether (5 mL, 10 mmol) was added
to the filtrate. The precipitate formed was filtered off, washed
with hot benzene, ether, and dried in vacuo to furnish hydroꢀ
chloride 4c (0.84 g).
group with chemical shift of 10.1 ppm, whereas in
the spectrum of alanine hydrochloride 4d, protons for
the NH2+ group are nonequivalent, which results in the two
broadened singlets with chemical shifts of 9.8 and 10.4 ppm.
From the results obtained, we conclude that
among the two proposed methods for the synthesis of
Nꢀ(2ꢀchloroethyl)glycine and ꢀDLꢀalanine esters, the alkyꢀ
lation of 2ꢀchloroethylаmine with αꢀhalocarboxylates in
twoꢀphase system K2CO3/MeCN has undoubted advanꢀ
tage. The developed method can be recommended for the
synthesis of Nꢀ(2ꢀchloroethyl)ꢀsubstituted derivatives of
other αꢀamino acids.
B. Synthesis from ethyl iodoacetate (5´a) was carried
out similarly to the procedure in method
А
from
ClCH2CH2NH2•HCl (1.39 g, 12 mmol), ICH2COOEt (2.14 g,
10 mmol), and K2CO3 (16.26 g, 120 mmol) in MeCN (60 mL).
After the precipitate of inorganic salts and the solvent were
removed, ether (50 mL) was added to the residue, the precipiꢀ
tate of KI was filtered off, washed with ether, the etheral soluꢀ
tion was filtered, and 1.5 M HCl in ether (7 mL, 10.5 mmol) was
added to it. The precipitate formed was filtered off, washed with
hot benzene, ether, and dried in vacuo to give hydrochloride 4c
(0.96 g).
Nꢀ(2ꢀChloroethyl)ꢀDLꢀalanine ethyl ester hydrochloride (4d).
A. Synthesis from ethyl 2ꢀbromopropionate (5b). A suspension of
ClCH2CH2NH2•HCl (4.64 g, 40 mmol) and K2CO3 (27.60 g,
200 mmol) in MeCN (50 mL) was stirred at 20 °C for 2.5 h, after
that another portions of K2CO3 (27.60 g, 200 mmol) and MeCN
(30 mL) were added followed by the dropwise addition (for 1 h)
of BrCH(Me)COOEt (6.97 g, 38.5 mmol) in MeCN (40 mL)
under vigorous stirring at 20 °C. The reaction mixture was stirred
at 20 °C for 13 h. The precipitate of inorganic salts was filtered
off, washed with MeCN, the solvent was evaporated in vacuo.
Ether (100 mL) was added to the residue, the etheral solution
was separated from the oil formed, filtered, and 1.5 M HCl in
ether (26.6 mL, 40 mmol) was added to it; the oil formed solidiꢀ
fied on trituration. The precipitate was filtered off, washed with
hot benzene and ether, dried in vacuo to give hydrochloride 4d
(2.70 g).
Experimental
Reactions were carried out in anhydrous solvents. 1H and
13C NMR spectra were recorded on a Bruker AVANCEꢀ400
spectrometer (400.13 and 100.61 MHz, respectively) in D2O,
CD3OD, and CDCl3 with the use of signal of the residual proꢀ
tons in a deuterated solvent as the internal standard. IR spectra
were recorded on a Nicolet MagnaꢀIR 750 Fourier spectrometer
(in KBr pellets). Commercial ClCH2CH2NH2•HCl,
OCHCOOH•H2O, MeCOCOOH, BrCH2COOEt (Acros), and
BrCH(Me)COOEt (Aldrich) were used for the synthesis. The
starting ICH2COOEt and ICH(Me)COOEt were obtained acꢀ
cording to the known procedure.9 The yields, melting points,
elemental analysis data, and parameters of 1H and 13C NMR
spectra of the synthesized hydrochlorides 4a—d are given in
Tables 1 and 2.
Nꢀ(2ꢀChloroethyl)glycine methyl ester hydrochloride (4a).
2ꢀChloroethylamine hydrochloride (2.32 g, 20 mmol) was disꢀ
solved in 0.75 M NaOH in methanol (26.7 mL, 20 mmol). After
1 h, the precipitate of NaCl was filtered off and washed with
methanol. Solutions of OCHCOOH•H2O (1.84 g, 20 mmol) in
methanol (10 mL) and NaBH3CN (1.26 g, 20 mmol) in methaꢀ
nol (10 mL) were added to the filtrate. The reaction mixture was
stirred at 20 °C for 22 h, then a flow of HCl was passed through
it until complete saturation was achieved and this was refluxed
for 2 h. After cooling, the precipitate formed was filtered off and
washed with methanol, the filtrate was concentrated in vacuo
with addition of benzene for the removal of water. The residue
was recrystallized from MeOH—AcOEt to give hydrochloride
4a (0.74 g).
Nꢀ(2ꢀChloroethyl)ꢀDLꢀalanine methyl ester hydrochloride (4b)
was obtained similarly to 4a from ClCH2CH2NH2•HCl (1.22 g,
10.5 mmol), 1.25 M NaOH in methanol (8.4 mL, 10.5 mmol),
MeCOCOOH (2.92 g, 10.5 mmol) in methanol (5 mL), and
NaBH3CN (0.66 g, 10.5 mmol) in methanol (3 mL). The reacꢀ
tion mixture was stirred at 20 °C for 10 h and treated as in the
preceding experiment to furnish hydrochloride 4b (0.90 g).
Nꢀ(2ꢀChloroethyl)glycine ethyl ester hydrochloride (4c). А.
Synthesis from ethyl bromoacetate (5a). A suspension of
ClCH2CH2NH2•HCl (1.16 g, 10 mmol) and K2CO3 (6.90 g,
50 mmol) in MeCN (30 mL) was stirred at 20 °C for 2.5 h, then,
another portion of K2CO3 (6.90 g, 50 mmol) in MeCN (20 mL)
was added followed by the dropwise addition (for 1 h) of a
solution of BrCH2COOEt (1.34 g, 8 mmol) in MeCN (10 mL)
under vigorous stirring at 20 °C. The reaction mixture was stirred
B. Synthesis from ethyl 2ꢀiodopropionate (5´b) was carried
out similarly to the procedure in method
А
from
ClCH2CH2NH2•HCl (3.48 g, 30 mmol), ICH(Me)COOEt
(6.84 g, 30 mmol), and K2CO3 (41.40 g, 300 mmol) in MeCN
(100 mL). After the precipitate of inorganic salts and the solvent
were removed, benzene (100 mL) was added to the residue, the
precipitate of KI was filtered off, washed with benzene, and
benzene was evaporated dry. Ether (100 mL) was added to the
residue, the etheral solution was separated from the oil formed,
filtered, and 1.5 M HCl in ether (20 mL, 30 mmol) was added to
the filtrate. The oil formed solidified at once, the precipitate was
filtered off, washed with hot benzene and ether, dried in vacuo to
isolate hydrochloride 4d (3.80 g).
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 05ꢀ03ꢀ
33091).
References
1. K. Afarinkia, J. I. G. Cadogan, and Ch. W. Rees, J. Chem.
Soc., Chem. Commun., 1992, 285.
2. E. R. H. Jones and W. Wilson, J. Chem. Soc., 1949, 550.
3. J.F. Schwieger and B. Unterhalt, Arch. Pharm. (Weinheim),
1992, 325, 709.