Synthesis of N-Phthaloyl Derivatives of Amino Acids
441
NMR measurements (see Table 1 and the experimental part
below). In order to characterize N-phthaloylglycine (VII)
and N-phthaloyl-4-aminobenzoic acid (XIV), these com-
pounds were treated with a mixture of MeOH and ClSiMe3
(for compound VII) and with a mixture of N-(chloroace-
tyl)benzylamine (XVI), NaHCO3, KI, and DMSO (for XIV)
so as to obtain the corresponding esters (XVII and XVIII, re-
spectively).
(6 mmole) of acid I and 6.2 mmole of amino acid (III, IV, or
V) was heated for 4 h in 8 ml of AcOH (at 160 – 170°C) or
in 7 ml of EtCOOH (170 – 180°C). Then the mixture is
cooled to ~20°C and evaporated at a reduced pressure (wa-
ter-jet pump). The residue is diluted with water and allowed
to stand for 12 h at ~20°C. The precipitate is separated by fil-
tration, washed with water, and dried in air to obtain PAA
VII, IX, or X; 1H NMR spectrum (d, ppm): compound VIII,
1.60 (d, 3H, CH3), 4.90 (m, CH), 7.9 (m, 4H, Harom); com-
pound IX, 2.61 (t, 2H, CH2), 3.80 (t, 2H, CH2), 7.85 (m, 4H,
The method proposed for the synthesis of N-phthaloyl
amino acids is simple and provides for a high yield of the tar-
get products, which makes it competitive with other reaction
pathways described previously [5 – 9].
H
arom); compound X, 1.85 (s, 2H, CH2), 2.25 (m, 2H, CH2),
3.63 (m, 2H, CH2), 7.86 (m, 4H, Harom).
N-Phthaloyl-d-aminovaleric acid (XI). A mixture of
1 g (6 mmole) of acid I and 0.72 g (6.1 mmole) of DAVA in
10 ml of EtCOOH was heated for 2 h at 170 – 180°C and
cooled to ~20°C. Then 5 ml of ClSiMe3 was added and the
mixture was heated for 3 h at 140 – 150°C, cooled to ~20°C,
and evaporated at reduced pressure (water-jet pump). The
residue was diluted with water and allowed to stand for 42 h
at ~20°C. The precipitate was separated by filtration, washed
with water, and dried in air to obtain compound XI; 1H NMR
spectrum (d, ppm): 1.60 (m, 4H, 2CH2), 2.23 (m, 2H, CH2),
3.60 (m, 2H, CH2), 7.80 (m, 4H, Harom).
N-Phthaloyl derivatives of 4- and 3-aminobenzoic ac-
ids (XIV, XV). General Method. A mixture of 1 g
(6 mmole) of acid I and 6 mmole of 4-aminobenzoic acid
(XII) or 3-aminobenzoic acid (XIII) in 10 ml of caproic acid
was heated for 3 h at 210 – 220°C (for XII) or 220 – 230°C
(for XIII). Then the mixture is cooled to ~20°C and diluted
with acetone. The precipitate is separated by filtration,
washed with acetone, and dried in air to obtain compound
EXPERIMENTAL CHEMICAL PART
The 1H NMR spectra were measured on a Bruker
AM-300 spectrometer using samples dissolved in DMSO-d6.
The course of the reactions was monitored and the purity of
the reaction products was checked by TLC on Silufol
UV-254 plates eluted in a benzene – ethyl acetate (1 : 1) sys-
tem; the spots were visualized under UV illumination. Some
physicochemical characteristics of the synthesized com-
pounds are listed in Table 1, where the melting points and
yields are indicated for nonrecrystallized products. When
necessary, the primary products can be purified by
recrystallization from water (VII – XI) or AcOH (XIV –
XV). The data of elemental analyses agree with the results of
calculations according to the empirical formulas.
N-Phthaloylglycine (VII). A mixture of 1 g (6 mmole)
of phthalic acid (I) and 0.45 g (6.3 mmole) of glycine in 5 ml
of AcOH was treated for 4 h at 160 – 170°C (here and below,
the bath temperature), cooled to ~20°C, diluted with water,
and allowed to stand at this temperature for 24 h. The precip-
itate of compound VII was separated by filtration, washed
1
XIV or XV; H NMR spectrum (d, ppm): compound XIV,
7.60 (m, 2H, Harom), 8.02 (m, 6H, Harom); compound XV,
7.68 (m, 2H, Harom), 7.97 (m, 6H, Harom).
N-Phthaloylglycine methyl ester (XVII). A mixture of
0.5 g of compound VII, 5 ml of MeOH, and 3 ml of ClSiMe3
was kept for 12 h with periodic stirring at ~20°C and treated
with an excess aqueous solution of Na2CO3. The precipitate
1
with water, and dried in air; H NMR spectrum (d, ppm):
4.25 (s, 2H, CH2), 7.90 (m, 4H, Harom).
N-Phthaloyl derivatives of DL-alanine, b-alanine, and
GABA (VIII – X). General Method. A mixture of 1 g
TABLE 1. Physicochemical Characteristics of the Synthesized Compounds
Compound Initial amino acid
Condensing agent
Yield, %
M.p., °C
Empirical formula
C10H7NO4
Ref.
[10]
VII
II
III
IV
V
AcOH
EtCOOH
90
83
74
72
65
82
83
90
64
90
84
193 – 196
VIII
IX
AcOH
160 – 163
149 – 151
114 – 116
C11H9NO4
C11H9NO4
C12H11NO4
[9]
[9]
[9]
EtCOOH
AcOH
EtCOOH
X
AcOH
EtCOOH
XI
VI
XII
XIII
EtCOOH + ClSiMe3
CH3(CH2)4COOH
CH3(CH2)4COOH
115 – 117
290 – 292
285 – 286
C13H13NO4
C15H9NO4
C15H9NO4
[7]
XIV
XV
[11]
[11]