Synthesis and molecular and crystal structure of 1-(5-benzyl-2-tetrazolyl)-1-cyclopentanecarboxylic acid. Penicillin and cephalosporins based on this acid

Full text of DOI:10.1023/A:1010466114698

Pharmaceutical Chemistry Journal
Vol. 35, No. 3, 2001
SYNTHESIS AND MOLECULAR AND CRYSTAL STRUCTURE
OF 1-(5-BENZYL-2-TETRAZOLYL)-1-CYCLOPENTANECARBOXYLIC
ACID. PENICILLIN AND CEPHALOSPORINS BASED ON THIS ACID
A. O. Martirosyan,1 M. V. Aleksanyan,1 S. S. Terzyan,2 Yu. Z. Ter-Zakharyan,1
R. V. Agababyan,1 A. A. Karapetyan,2 Sh. L. Mndzhoyan,1 and R. A. Tamazyan2
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 3, pp. 49 – 50, March, 2001.
Original article submitted September 5, 2000.
In continuation of our previous investigation devoted to
the synthesis and study of the structure – activity relationship
for some 7-[1-(tetrazolyl)acetamido]cephalosporanic acids
[1], we synthesized 1-(5-benzyl-2-tetrazolyl)-1-cyclopenta-
necarboxylic acid (II) and related penicillin (IV) and
cephalosporins (III, V). The synthesis of compounds III – V
was of special interest because many of the known penicil-
lins containing trisubstituted acetic acids in the side chain
[2], especially some of the 6-[1-(aryl)-1-cyclopentanecarbo-
xamido]penicillanic acids [3], are resistant to staphylococcal
penicillase and active with respect to both sensitive staphylo-
cocci and resistant strains.
hydrolysis of the ester group. The x-ray diffraction measure-
ments showed that the alkylation takes place regioselectively
at the second position of the tetrazole ring. The target prod-
ucts III – V were obtained by the chloroanhydride method
involving acylation of 7-aminocephalosporanic acid
(7-ACA), 6-aminopenicillanic acid (6-APA), and 7-amino-
deacetoxycephalosporanic acid (7-ADCA), respectively.
The proposed structures and purity of the reaction prod-
1
ucts were confirmed by TLC and by the IR and H NMR
spectroscopic data. The IR spectra of compounds III – V
contain characteristic absorption bands due to the carbonyl
groups of b-lactam (1760 – 1780 cm – 1), acetoxymethyl
(1710 – 1740 cm – 1), amide (1670 – 1680 cm – 1), and
carboxy (1610 – 1625 cm – 1) fragments. The 1H NMR spec-
tra exhibit signals due to protons of the aromatic ring
(6.9 – 7.2 ppm), benzyl CH2 group (4.3 – 4.4 ppm), 2-CH2
cephem nucleus (3.6 – 3.8 ppm), acetoxymethyl moiety
(2.0 – 2.2 ppm), and methyl groups of penicillanic acid (1.7
and 1.8 ppm).
N
NH
N
N
N
N
COOH
N
N
I
II
N
N
N
S
CONH
N
A
N
EXPERIMENTAL CHEMICAL PART
O
COONa
The data of elemental analyses (N, S) agree with the val-
ues calculated using the empirical formulas. The IR absorp-
tion spectra were recorded on a UR-20 spectrophotometer
using samples prepared as nujol mulls. The 1H NMR spectra
were measured on a Mercury 300 spectrometer. TLC analy-
ses were performed on Silufol UV-254 plates (Czech Repub-
lic).
1-(5-Benzyl-2-tetrazolyl)-1-cyclopentanecarboxylic acid
(II). To sodium ethylate prepared from 0.46 g (0.02 mole) of
metallic sodium and 20 ml of anhydrous ethyl alcohol were
added 3.2 g (0.02 mole) of 5-benzyltetrazole (I) and the reac-
tion mixture was heated to boiling. To this boiling mixture
were added with stirring 4.5 g (0.02 mole) of 1-bromo-1-
cyclopentanecarboxylic acid ethyl ester and boiling was con-
III – V
CH2OCOCH3
CH3
H3C
CH3
A =
(V).
(III);
(IV);
Acid II was synthesized by alkylating 5-benzyltetrazole
(I) with 1-bromo-1-cyclopentanecarboxylic acid ethyl ester
in the presence of sodium ethylate in ethanol, followed by
1
Mndzhoyan Institute of Fine Organic Chemistry, National Academy of
Sciences of the Republic of Armenia, Yerevan, Armenia.
Center for Investigation of the Structure of Molecules, National Academy
of Sciences of the Republic of Armenia, Yerevan, Armenia.
2
169
0091-150X/01/3503-0169$25.00 © 2001 Plenum Publishing Corporation

170
A. O. Martirosyan et al.
Rf values of the sodium salts determined in a propanol – wa-
ter system (7 : 2).
Ñ20
Ñ14
N13
C7
Ñ19
C6
C8
Ñ15
N9
Ñ12
N11
EXPERIMENTAL BIOLOGICAL PART
C4
Ñ18
C5
Ñ16
N10
The antibacterial properties of the sodium salts of acids
III – V were studied by the method of double serial dilutions
in a meat-infusion broth (pH 7.2 – 7.4) with a load of 2 ´ 106
microbial cells per ml. The tests were performed with
Gram-positive staphylococci (standard strains 209p, Smith,
and penicillinase-forming strain 18b) and Gram-negative ba-
cilli (E.coli, B. typhi, Sh. dysenteriae). The activity was char-
acterized by the minimum inhibiting concentration (MIC).
It was found that compound IV exhibits activity with re-
spect to staphylococci (MIC = 0.1, 0.05, and 31.2 mg/ml for
the strains 209p, Smith, and 18b, respectively) and inhibits
the growth of Sh. dysenteriae with a MIC = 100 mg/ml,
while being inactive toward E.coli and B. typhi. Compounds
III and V were significantly less active than IV.
X-Ray diffraction study of 1-(5-Benzyl-2-tetrazolyl)-
1-cyclopentanecarboxylic acid (II). The monoclinic unit
cell parameters of the first modification, measured at room
temperature on an Enraf-Nonius CAD-4 automated diffracto-
meter and refined using 24 reflections with 14 < J < 18°, are
as follows: a = 6.008(1) Å, b = 10.900(2) Å, c = 20.898(4) Å;
b = 96.99(3)°; V = 1358.3(5) Å3. A diffraction experiment
performed on the same instrument included the measurement
of 3211 reflections with 1 > 2s(I ) for –7 £ h £ 7, 0 £ k £ 12,
Ñ17
O1
C3
O2
Fig. 1. Molecular structure of 1-(5-benzyl-2-tetrazolyl)-1-cyclo-
pentanecarboxylic acid (II) by x-ray diffraction data.
tinued for 16 h. Then ethanol was evaporated and the residue
was dissolved in ether and washed with a 5% NaHCO3 solu-
tion. The solvent (ether) was evaporated again and the oily
residue was dissolved in 15 ml of methanol. To this solution
were added 10 ml of 3 M KOH solution in methanol and the
mixture was boiled for 3 h. Then ethanol was evaporated and
the residue mixed with water and hydrochloric acid to pH 2.
The precipitated crystals were separated by filtration and
recrystallized from ethanol to obtain 3.2 g (59%) of acid II;
m.p., 124 – 125°C; Rf, 0.5 (acetone – hexane, 1 : 2).
7-[1-(5-Benzyl-2-tetrazolyl)-1-cyclopentylcarbamoyl]
cephalosporanic acid (III). A mixture of 2.7 g (0.01 mole)
of 7-ACA, 2.5 g (0.03 mole) NaHCO3, 80 ml water, and
60 ml acetone was cooled to 0 – 2°C. To this mixture was
added with stirring a solution of 2.7 g (0.01 mole) acid I in
20 ml of acetone. The mixture was stirred for 4 h and al-
lowed to stand overnight in a refrigerator. Then acetone was
evaporated in vacuum and the aqueous solution washed with
ethyl acetate. To this aqueous solution were added 50 ml of
ethyl acetate and 1 N HCl solution to pH 2. The organic layer
was separated, washed with glacial acetic acid, and dried
over anhydrous sodium sulfate. Finally, ethyl acetate was
evaporated and the residue crystallized from hexane or petro-
leum ether to obtain compound III.
TABLE 2. The Coordinates of Nonhydrogen Atoms in the First
Structural Modification of 1-(5-Benzyl-2-tetrazolyl)-1-cyclopenta-
necarboxylic Acid (II) (see Figure 1)
Atom
x/a
y/b
z/c
Ueg., Å2
O1
0.5280(3)
0.45258(14) 0.20846(7)
0.0612(4)
0.1100(8)
0.0537(5)
0.0418(4)
0.0528(5)
0.0687(7)
0.0700(7)
0.0532(5)
0.0371(4)
0.0437(4)
0.0458(4)
0.0422(4)
0.0433(4)
0.0542(5)
0.0456(5)
0.0570(6)
0.0641(6)
0.0671(7)
0.0725(7)
0.0594(6)
O2
0.5895 (4) 0.5560(2)
0.5124 (4) 0.4702 (2)
0.12191(9)
0.14663(10)
0.10629(8)
0.06402(11)
0.01036(12)
0.00729(13)
0.05715(10)
Compounds IV and V were obtained by analogous pro-
cedures from 6-APA and 7-ADCA, respectively (Table 1).
Sodium salts of acids III – V. To an ethyl acetate solu-
tion of acid III (IV, V) was added an 8% aqueous solution of
NaHCO3 to pH 6 – 7. The aqueous layer was separated,
washed with ethyl acetate, and lyophilized. Table 1 gives the
C3
C4
0.3890(3)
0.5410(4)
0.3799(5)
0.3687(2)
0.3026(2)
0.2445(2)
C5
C6
C7
0.1624 (5) 0.3155(3)
C8
0.2001(4)
0.2966(2)
0.4165(2)
N9
0.28061(13) 0.14996(6)
N10
N11
C12
N13
C14
C15
C16
C17
CIS
C19
C20
0.4122 (3) 0.18629(14) 0.17534(7)
0.2977(3)
0.1164(3)
0.1111(2)
0.14415(14) 0.22051(7)
0.2161(2) 0.22107(9)
0.30320(14) 0.17694 (7)
TABLE 1. Yields and Physicochemical Characteristics of Tetrazo-
lyl Penicillanic and Cephalosporanic Acids III – V
– 0.0479(4)
– 0.0287(3)
0.1529(4)
0.2041(2)
0.3052 (2)
0.3835(2)
0.26857(11)
0.31878(9)
0.32814(11)
0.37437(11)
0.41207(11)
0.40353 (12)
0.35737(11)
Com-
pound
Yield,
%
M.p., °C
Empirical
formula
Rf
(with decomp.)
III
54
81
50
88 – 90
78 – 80
C24H26N6SO6
C22H26N6SO4
C22H24N6SO4
0.69
0.66
0.79
0.1660 (4) 0.4744(2)
IV
V
– 0.0027(5)
– 0.1847(5)
– 0.1986(4)
0.4885(2)
0.4116(3)
0.3206(2)
103 – 105
Note. Rf values refer to the corresponding sodium salts.

Synthesis and Molecular and Crystal Structure
171
vergence factor R = 0.0354, S = 0.944. The atomic coordi-
nates and equivalent thermal parameters are listed in Table 2.
The molecular structure is presented in Fig. 1.
–24 £ I £ 24, Jmax = 25° using graphite-monochromatized
Mo Ka radiation.
The systematic extinctions unambiguously determined
the space group P21/c (Z = 4). All calculations were per-
formed using the SHELXTL program package. After averag-
ing of the symmetrically equivalent reflections, the array
contained 1666 inequivalent reflections (Rav = 0.015). The
structure was solved by direct methods, with the coordinates
of hydrogen atoms determined by difference Fourier synthe-
ses. The structure was refined by full-matrix least squares in
an anisotropic approximation for nonhydrogen atoms; the di-
REFERENCES
1. M. V. Aleksanyan, M. S. Kramer, A. O. Martirosyan, et al.,
Khim.-Farm. Zh., 28(6), 33 – 35 (1994).
2. E. G. Brain, F. P. Doyle, A. A. Long, and D. M. Menta, J. Chem.
Soc., 1445 – 1453 (1962).
3. Sh. L. Mndzhoyan, M. G. Tsinker, A. R. Ovakimyan, et al.,
Khim.-Farm. Zh., 14(3), 53 – 58 (1980).