Synthesis of Nonracemic Tetrazole GABA Analogs

Article abstract of DOI:10.1134/S1070428018110155

Nonracemic 3-substituted 4-(1H-tetrazol-1-yl)butanoic acids, analogs of the neurotropic drugs phenibut, tolibut, and baclofen, were synthesized by a three-component reaction of the R-isomers of the corresponding amino acids, triethyl orthoformate, and sod

Full text of DOI:10.1134/S1070428018110155

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 11, pp. 1715–1721. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © A.N. Reznikov, V.A. Ostrovskii, Yu.N. Klimochkin, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 11,
pp. 1699–1704.
Synthesis of Nonracemic Tetrazole GABAAnalogs
A. N. Reznikova, V. A. Ostrovskiib, and Yu. N. Klimochkina*
a Samara State Technical University, ul. Molodogvardeiskaya 244, Samara, 443100 Russia
*e-mail: orgphosphorus@yandex.ru
b St. Petersburg State Institute of Technology (Technical University), Moskovskii pr. 26, St. Petersburg, 190013 Russia
Received September 12, 2018
Revised September 12, 2018
Accepted September 12, 2018
Abstract—Nonracemic 3-substituted 4-(1H-tetrazol-1-yl)butanoic acids, analogs of the neurotropic drugs
phenibut, tolibut, and baclofen, were synthesized by a three-component reaction of the R-isomers of the
corresponding amino acids, triethyl orthoformate, and sodium azide. The key stage of the synthesis is the
asymmetric addition of diethyl malonate to nitroalkenes, catalyzed by a Ni(II) complex of (S,S)-N,N'-
dibenzylcyclohexane-1,2-diamine.
DOI: 10.1134/S1070428018110155
The chemical modification of biomolecules,
including amino acids, by the introduction of the
tetrazole fragment is a promising approach to drug
design in medicinal chemistry [1–6]. The tetrazole
fragments can impart to pharmaceutical preparations a
higher metabolic stability and ability to penetrate
biological membranes. The tetrazole fragments are
frequently used as bioisosteres of carboxyls in
biologically active compounds [7–9]. This approach
was used to success in the design of drugs with
improved pharmaceutical profiles, including
antibacterial [10–12], antiviral [13–17], anticancer [18
–21], and neurotropic agents [22–26].
Tetrazole analogs of amino acids attract attention of
researchers focused on the design of new-generation
drugs for curing CNS diseases [23–26].
The presently known tetrazole analogs of amino
acids can be divided into four main groups: (i)
tetrazole analogs of amino acids, where the tetrazole
fragment plays the role of an isostere of the carboxyl
group; (ii) derivatives, where the tetrazole fragment
replaces the amino group; (iii) derivatives, where the
tetrazole fragment is a structural unit of the substituent
at the amino group; and (iv) tetrazole analogs of
nonionogenic amino acids, in particular, γ-
Scheme 1.
Cl
n-Pr
O
C(O)NH2
H2N
COOH
H2N
COOH
H2N
COOH
Et
Brivaracetam
Phenibut
Tolibut
Baclofen
1d
1a
1b
1c
NH2
COOH
H2N
COOH
Gabapentin
Pregabalin
1e
1f
1715

REZNIKOV et al.
1716
aminobutyric acid (GABA) [27]. The latter group of
compounds holds the greatest promise as potential
neurotropic agents.
Preliminary analysis of the available literature
allows us to expect that some tetrazole GABA analogs
will exhibit anxiolytic, nootropic, and antiepileptic
activity.
The modification of GABA, primarily via aliphatic,
aromatic, or heterocyclic substitution in the 3-position,
as well as synthesis of cyclic GABA derivatives
(pyrrolidin-2-ones) resulted in the development of
highly efficient neurotropic drugs [28–32].
One more problem is that enantiomeric GABA
analogs differ from each other in neurotropic activity.
As known, the neurotropic activity is characteristic of
the R-isomers of 3-aryl-substituted derivatives of
GABA [33] and (S)-pregabalin [34]. This fact should
be taken into account in the searching for potential
drugs among tetrazole derivatives (in view of the
present high international requirements to the
enantiomeric purity of pharmaceutical substances).
Phenibut 1a [28] and Baclofen 1c [29, 30], agonists
of GABAB receptors, are presently successfully used in
the therapy of asthenic and neurotic anxiety disorders,
multiple sclerosis, strokes, traumatic brain injuries,
meningitis, various spinal diseases, cerebral palsy, as
well as in the complex therapy of alcoholism. Tolibut
1b [31] exhibits analgesic and neuroprotective, but,
however, has not still found application in clinical
practice. The mentioned drugs also showed nootropic
activity (Scheme 1).
The known methods of synthesis of enantio-
merically pure 3-substituted GABA derivatives [35]
generally make use of costly hydrogenation catalysts
(platinum metal complexes) [36–38], organic catalysts
[39], or chiral auxiliary groups at different stages of
synthesis [40–43].
The cyclic GABA analog brivaracetam {(2S)-2-
[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide} 1d
[32] was approved by FDA in 2016 as an antiepileptic
drug. This fact provides evidence for the relentless
interest in GABA derivatives as broad-spectrum
neurotropic agents and for the considerable promise of
this line of research.
We earlier reported the synthesis of nonracemic 3-
substituted GABA derivatives with the Ni(II)-
catalyzed asymmetric Michael addition as the key
stage [44]. Taking a step further in this approach, in
the present work we have developed a simple and an
efficient method of synthesis of nonracemic tetrazol-
containing GABA derivatives.
At the same time, at present the tetrazole derivatives
of GABA and its analogs, where the tetrazole fragment
acts as an isostere of carboxyl, is the only group of
GABA derivatives well documented in terms of synthesis
and biological activity. In particular, Yuan and
Silverman reported the synthesis of 3-(1H-tetrazol-5-
yl)propan-1-amine, an analog of unsubstituted GABA
[24]. Isosteres of racemic pregabalin 1e [25] and
gabapentin 1f [26] were also synthesized. These com-
pounds present interest as anticonvulsants (Scheme 1).
Chiral nitro esters (R)-5a–5c were synthesized by
the reaction of malonates 3a and 3b with nitroalkenes
2a–2c in the presence of Ni(II) N,N'-dibezylcyclo-
hexane-1,2-diamine complex 4 (Scheme 2).
Scheme 2.
Ph
Ph
Br
Ni
Br
NH
NH
HN
HN
The tetrazole analogs of 3-alkyl- and 3-aryl-
substituted GABA analogs, including those
neurotropic drugs, where the amino group is replaced
by the tetrazole fragment, have scarcely been reported.
At the same time, tetrazoles and amines have quite
different acid–base properties (tetrazole is a fairly
strong NH-acid) and the tetrazole nitrogen can be
involved in multicenter intermolecular interactions
with functional groups in the surrounding molecules,
including enzyme active sites, and, as a result, the
neurotropic activity profile of such tetrazole GABA
analog may prove much different from that of the
parent molecule.
Ph
Ph
4
The subsequent reductive cyclization of nitro esters
(R)-5a–5c and hydrolysis of the resulting pyrrolidones
6a–6c afforded the hydrochlorides of corresponding
amino acids 7a–7c (Scheme 3).
The tetrazole derivatives were prepared using the
three-component reaction of the amino acids, triethyl
orthoformate, and sodium azide [45]. The efficiency of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 11 2018

SYNTHESIS OF NONRACEMIC TETRAZOLE GABA ANALOGS
1717
Scheme 3.
COOR'
4
R'OOC
R
COOR'
NO2
R
R
COOR'
H2, Ni-Ra
HClaq.
(2 mol %)
.
COOH
R
H2N
O
HCl
+
NO2
NH
COOR'
2a_2c
7a_7c
6a_6c
5a_5c
3a, 3b
2, 7, R = Ph (a), 4-MeC6H4 (b), 4-ClC6H4 (c); 3, R' = Et (a), Me (b); 5, 6, R = Ph, R' = Et (a); R = 4-MeC6H4, R' = Et (b);
R = 4-ClC6H4, R' = Me (c).
Scheme 4.
R
N
R
N
NaN3, (EtO)3CH
AcOH
.
H2N
COOH HCl
N
COOH
N
1a_1c
8a_8c
this approach was previously demonstrated by Popova
et al. [18] by the synthesis of the tetrazole derivative of
racemic phenibut 7a.
The HPLC analysis was performed using a
Chiralpak AD-3 column; solvent system hexane–
propan-2-one, 80 : 20, flow rate 1.2 mL/min;
wavelength 210 nm).
Taking into account the importance for neurotropic
activity testing of comparable analysis of the respective
properties of racemic mixtures and individual
enantiomers, from amino acids 1a–1c we prepared
racemic tetrazole derivatives 8a–8c (Scheme 4) and
from corresponding nonracemic amino acids 7a–7c,
pure R-isomers 9a–9c (Scheme 5).
Compounds 4 and 7a were prepared as described in
[46] and [47].
Diethyl (R)-2-[1-(4-methylphenyl)-2-nitroethyl]-
malonate (5b). Complex 4, 1.37 g (1.70 mmol), was
added to a solution of 13.9 g (85.0 mmol) of reagent
2b and 13.6 g (85.0 mmol) of diethyl malonate 3a in
100 mL of toluene. The reaction mixture was stirred
for 18 h at 25°C and then evaporated. The residue
chromatographed on a silica gel column (eluent CCl4).
Scheme 5.
N
R
R
N
N
.
COOH HCl
H2N
COOH
N
7a_7c
9a_9c
HPLC analysis: tr 9.5 (R-isomer), 24.3 min (S-
isomer). Yield 23.7 g (86%), ee 95%, [α]D22 –5.43 (c
2.5, CHCl3). IR spectrum, ν, cm–1: 2982 w, 1732 vs,
1555 s, 1516 w, 1447 w, 1369 m, 1300 w, 1258 m,
Thus, the three-component reaction of 3-substituted
GABA derivatives, triethyl orthoformate, and sodium
azide resulted in the synthesis of previously unknown
nonracemic tetrazole (R)-phenibut, (R)-tolibut, and (R)
-baclofen analogs 9a–9c, which present interest as
potential neurotropic agents.
1
1180 m, 1153 m, 1030 m, 818 m. H NMR spectrum
3
(CDCl3), δ, ppm: 1.02 t (3H, CH3CH2, JHH 7.2 Hz),
3
1.22 t (3H, CH3CH2, JHH 7.2 Hz), 2.27 s (3H, CH3),
3
3.77 d [1H, CH(COOEt)2, JHH 9.6 Hz], 3.96 q (2H,
CH2CH3, 3JHH 6.8 Hz), 4.15–4.22 m (2H, CH2CH3, 1H,
CHCH2NO2), 4.78–4.91 m (2H, CH2NO2), 7.09 m
(4Harom). 13C NMR spectrum (CDCl3), δ, ppm: 13.8
(CH3), 14.1 (CH3), 21.1 (CH3, p-Tol), 42.7
(CHCH2NO2), 55.1 [CH(COOEt)2], 61.9 (CH2CH3),
62.2 (CH2CH3), 76.5 (CH2NO2), 127.9 (2CHarom),
129.7 (2CHarom), 133.2 (C), 138.1 (C), 167.0 (C=O),
167.6 (C=O). Found, %: C 59.55; H 6.51; N 4.38.
C16H21NO6. Calculated, %: C 59.43; H 6.55; N 4.33.
EXPERIMENTAL
Elemental analysis was performed on a Euro-
Vector EA 3000 analyzer. The IR spectra were
obtained on a Shimadzu IRAffinity-1 instrument
1
13
with a Specac Quest ATR accessory. The H and C
NMR spectra were recorded on a Jeol JNM
ECX
-400 spectrometer [400 (1H) and 100 (13C) MHz,
respectively]. The optical rotation angles were
Dimethyl (R)-2-[1-(4-chlorophenyl)-2-nitroethyl]-
malonate (5c). Complex 4, 635 mg (0.780 mmol), was
added to a solution of 7.22 g (39.3 mmol) of reagent 2c
and 5.19 g (39.3 mmol) of dimethyl malonate 3b in
60 mL of toluene. The reaction mixture was stirred for
measured on
a
Rudolph Research Analytical
Autopol V Plus automated polarimeter. The melting
points were determined on an OptiMelt MPA 100
apparatus.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 11 2018

REZNIKOV et al.
1718
18 h at 25°C, left to stand for 12 h at room
temperature, and then evaporated. The residue was
recrystallized from propan-2-ol.
evaporated, the residue was dissolved in toluene, and
filtered through a bed of silica gel. The filtrate was
evaporated in a vacuum, and the residue was
recrystallized from ethanol. Yield 1.21 g (50%), [α]D20
–124.4 (c 1.0, CHCl3), mp 163–166°C. IR spectrum, ν,
cm–1: 3236 m, 2970 w, 2849 m, 2787 w, 1746 vs, 1717
vs, 1611 w, 1587 w, 1516 m, 1493 m, 1462 m, 1371 s,
1325 s, 1301 s, 1285 s, 1261 s, 1221 s, 1088 s, 1028 s,
HPLC analysis: tr 11.3 (R-isomer), 26.7 (S-isomer).
Yield 8.68 g (72%), ee 95%, [α]D20 –11.15 (c 2.5,
CHCl3), mp 94–96°C. IR spectrum, ν, cm–1: 2960
1
(CH), 1747 (C=O), 1552, 1375 (NO2). H NMR
spectrum (CDCl3), δ, ppm: 3.57 s (3H, CH3), 3.74 s
1
1013 s, 991 s, 910 m, 851 m, 824 vs. H NMR
3
(3H, CH3), 3.80 d [1H, CH(COOCH3)2, JHH 8.9 Hz],
spectrum (CDCl3), δ, ppm: 3.36 s (3H, CH3), 3.51 d
4.18–4.33 m (1H, CHCH2NO2), 4.80–4.91 m (2H,
3
(1H, 3-CH, JHH 9.6 Hz), 3.77–3.82 m (2H, C5H2),
CH2NO2), 7.17 d (2Harom, 3JHH 9.6 Hz), 7.27 d (2Harom
,
4.05–4.12 m (1H, H4), 6.94 s (1H, NH), 7.18 d (2Harom
,
3JHH 9.6 Hz). 13C NMR spectrum (CDCl3) δ, ppm: 42.4
(CHCH2), 53.0 (COOCH3), 53.2 (COOCH3), 54.4 [CH
(COOCH3)2], 77.3 (CH2NO2), 129.3 (2CHarom), 129.4
(2CHarom), 134.5 (Carom), 134.7 (Carom), 166.1 (C=O),
167.7 (C=O). Found, %: C 49.39; H 4.51; N 4.47.
C13H14ClNO6. Calculated, %: C 49.46; H 4.47; N 4.44.
3JHH 8.4 Hz), 7.30 d (2Harom, JHH 8.4 Hz). 13C NMR
spectrum (CDCl3), δ, ppm: 47.7 (C4H), 47.8 (C5H2),
53.1 (CH3), 55.2 (C3H), 128.5 (2CHarom), 129.2
(2CHarom), 133.7 (Carom), 138.2 (Carom), 169.4
(COOMe), 172.4 (C=O). Found, %: C 56.76; H 4.82;
N 5.57. C12H12ClNO3. Calculated, %: C 56.82; H 4.77;
N 5.52.
3
Ethyl (3S,4R)-4-(4-methylphenyl)-2-oxopyrrolidine-
3-carboxylate (6b). A solution of 9.80 g (30.3 mmol)
of compound 5b in 50 mL of propan-2-ol was placed
into an autoclave, and 1 g of Raney nickel was added.
Hydrogenation was performed at a pressure of 40 atm
at 50°C for 18 h. The reaction mixture was then
evaporated, the residue was dissolved in toluene, and
filtered through a bed of silica gel. The filtrate was
evaporated in a vacuum, and the residue was
recrystallized from cyclohexane. Yield 5.62 g (75%),
[α]D20 –113.3 (c 2.5, CHCl3), mp 80–83°C. IR spectrum,
ν, cm–1: 3236 m, 2989 w, 2868 w, 1732 vs, 1705 vs,
1518 w, 1445 w, 1375 w, 1333 s, 1285 m, 1271 s,
1256 m, 1171 vs, 1117 m, 1053 m, 1020 s, 814 s, 719
Compounds 7b and 7c (general procedure). To
19.8 mmol of compound 6b and 6c we added 110 mL
of 6 M HCl, and the mixture was refluxed for 18 h.
After cooling, the mixture was treated with ethyl
acetate (4 × 30 mL). The aqueous layer was separated
and evaporated in a vacuum.
(3R)-4-Amino-3-(4-methylphenyl)butanoic acid,
hydrochloride (7b). Yield 4.2 g (90%), [α]D20 –1.4 (c
2.5, H2O), mp 173–175°C. IR spectrum, ν, cm–1: 2924
s, 1711 s, 1562 m, 1503 s, 1404 s, 1254 m, 1192 vs,
1150 vs, 1063 w, 980 m, 829 m, 806 vs, 719 m, 654 s,
1
550 s, 521 s, 419 s. H NMR spectrum (DMSO-d6), δ,
1
s, 700 s, 687 s. H NMR spectrum (CDCl3), δ, ppm:
ppm: 2.22 s (3H, CH3), 2.46 d.d (1H, CH2COOH, 3JHH
1.24 t (3H, CH3, 3JHH 9.6 Hz), 2.32 s (3H, CH3, p-Tol),
3.38 d.d (1H, H5, 3JHH 8.4, 2JHH 9.6 Hz), 3.52 d (1H, H3,
9.7, JHH 16.4 Hz), 2.81–2.89 m (1H, CH2NH2), 3.00–
2
3.05 m (1H, CH2NH2), 3.28–3.35 m (1H, CH2CHCH2),
7.09 d (2Harom, 3JHH 8.0 Hz), 7.15 d (2Harom, 3JHH 8.0 Hz),
8.3 br.s (3H, NH2). 13C NMR spectrum (DMSO-d6), δ,
ppm: 21.2 (CH3), 38.5 (CH2CHCH2), 43.9 (CH2NH3),
128.2 (2CH), 129.7 (2CHarom), 136.7 (Carom), 137.9
(Carom), 173.0 (C=O). Found, %: C 57.46; H 7.09; N
6.15. C11H16ClNO2. Calculated, %: C 57.52; H 7.02; N
6.10.
3
2
3JHH 9.6 Hz), 3.76 d.d (1H, H5, JHH 8.4, JHH 9.6 Hz),
4.03–4.09 m (1H, H4), 4.18–4.26 m (2H, CH2), 6.86 s
(1H, NH), 7.11–7.14 m (4Harom). 13C NMR spectrum
(CDCl3), δ, ppm: 14.2 (CH3), 21.1 (CH3, p-Tol), 44.4
(4-CH), 48.0 (5-CH2) 55.4 (3-CH), 61.9 (CH2), 127.0
(2CHarom), 128.0 (2CHarom), 136.8 (Carom), 137.4
(Carom), 169.3 (COOEt), 172.9 (C=O). Found, %: C
67.95; H 6.99; N 5.72. C14H17NO3. Calculated, %: C
68.00; H 6.93; N 5.66.
(3R)-4-Amino-3-(4-chlorophenyl)butanoic acid,
hydrochloride (7c). Yield 1.40 g (75%), [α]D20 –1.3,
mp 195–198°C. IR spectrum, ν, cm–1: 2937 w, 1720
vs, 1573 w, 1504 m, 1492 s, 1414 s, 1404 s, 1269 w,
1201 s, 1179 vs, 1126 s, 1088 m, 1015 m, 947 m, 826
Methyl (3S,4R)-4-(4-chlorophenyl)-2-oxopyrroli-
dine-3-carboxylate (6c). A solution of 3.00 g (9.50 mmol)
of compound 5c in 50 mL of propan-2-ol was placed
into an autoclave, and 0.5 g of Raney nickel was
added. Hydrogenation was performed at a pressure of
40 atm at 50°C for 18 h. The reaction mixture was then
1
vs, 791 m, 654 m. H NMR spectrum (DMSO-d6), δ,
3
ppm: 2.50 d (1H, CH2COOH, JHH 9.6 Hz), 2.85–2.94
m (2H, CH2NH2), 3.04–3.09 m (1H, CH2COOH), 3.33
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 11 2018

SYNTHESIS OF NONRACEMIC TETRAZOLE GABA ANALOGS
1719
3
–3.40 m (CH2CHCH2), 7.32 d (4Harom, JHH 5.52 Hz),
7.18 s (2H, NH2). 13C NMR spectrum (DMSO-d6), δ,
ppm: 38.3 (CH2COOH), 39.6 (CH2CHCH2), 43.6
(CH2NH2), 129.0 (CCl), 130.4 (2CHarom), 132.3
(2CHarom), 139.8 (ArCH), 172.8 (C=O). Found, %: C
47.96; H 5.30; N 5.64. C10H13Cl2NO2. Calculated, %:
C 48.02; H 5.24; N 5.60.
4-(1H-Tetrazol-1-yl)-3-(4-chlorophenyl)butanoic
acid (8c). Yield 2.16 g (37%), mp 145–147°C. IR
spectrum, ν, cm–1: 3134 w, 2930 m, 2596 w, 1700 vs,
1490 s, 1447 m, 1435 m, 1414 m, 1354 w, 1311 m,
1261 s, 1215 s, 1169 s, 1140 m, 1098 m, 1086 m, 1015
m, 982 m, 934 m, 897 m, 845 w, 825 vs, 754 s, 718 m,
658 m, 613 m. 1H NMR spectrum (DMSO-d6), δ, ppm:
2.54–2.69 m (2H, CH2COOH), 3.51–3.59 m (1H, CH),
4.60–4.72 m (2H, CH2NH2), 7.02 d (2H, 2CHarom, 3JHH
Acids 8a–8c and 9a–9c (general procedure). Triethyl
orthoformate, 9.73 g (65.7 mmol), and then 1.71 g
(26.3 mmol) of sodium azide were added to a stirred
solution of the hydrochloride of amino acid 1a–1c or
7a–7c, 21.9 mmol, in 12 mL of acetic acid. The mixture
was stirred for 7 h at 100°C and then evaporated in a
vacuum. Water, 10 mL, was added to the residue and
then solid NaOH to pH 9. After treatment with ethyl
ether, the aqueous layer was separated and acidified
with conc. HCl to pH 2. The precipitate that formed
was filtered off and washed with 5 mL of water.
3
7.5 Hz), 7.61 d (2H, 2CHarom, JHH 7.5 Hz), 9.05 s
(1Htetrazole), 12.16 s (1H, OH). 13C NMR spectrum (DMSO-
d6), δ, ppm: 38.3 (CH), 42.0 (CH2COOH), 52.9
(CH2NH2), 128.7 (2CHarom), 130.0 (2CHarom), 133.1
(Carom), 138.3 (Carom), 144.4 (Ctetrazole), 174.3 (C=O).
Found, %: C 49.45; H 4.20; N 20.92. C11H11ClN4O2.
Calculated, %: C 49.54; H 4.16; N 21.01.
(3R)-4-(1H-Tetrazol-1-yl)-3-phenylbutanoic acid
(9a). Yield 1.56 g (23%), mp 115–118°C, [α]D20 +54.6
(c 1.0, MeOH). IR spectrum, ν, cm–1: 3126 m, 2929 m,
2601 w, 1707 vs, 1489 m, 1443 m, 1415 m, 1311 m,
1300 m, 1265 s, 1211 s, 1169 s, 1142 m, 1096 m, 980
4-(1H-Tetrazol-1-yl)-3-phenylbutanoic acid (8a).
Yield 1.58 g (31%), mp 114–117°C. IR spectrum, ν,
cm–1: 3126 m, 2929 m, 2601 w, 1707 vs, 1489 m, 1443
m, 1415 m, 1311 m, 1300 m, 1265 s, 1211 s, 1169 s,
1142 m, 1096 m, 980 m, 926 m, 899 m, 775 m, 733 s,
702 vs, 660 s. 1H NMR spectrum (DMSO-d6), δ, ppm:
2.62–2.74 m (2H, CH2COOH), 3.61–3.68 m (1H, CH),
4.62–4.80 m (2H, CH2NH2), 7.13–7.30 m (5Harom),
9.07 s (1Htetrazole), 12.24 br.s (1H, OH). 13C NMR
spectrum (DMSO-d6), δ, ppm: 37.9 (CH), 42.4
(CH2COOH), 52.3 (CH2NH2), 127.7 (CHarom), 128.2
(2CHarom), 129.0 (2CHarom), 140.3 (Carom), 144.6
(Ctetrazole), 172.8 (C=O). Found, %: C 56.81; H 5.24; N
24.08. C11H12N4O2. Calculated, %: C 56.89; H 5.21; N
24.12.
1
m, 926 m, 899 m, 775 m, 733 s, 702 vs, 660 s. H
NMR spectrum (DMSO-d6), δ, ppm: 2.65–2.69 m (2H,
CH2COOH), 3.61 s (1H, CH), 4.68 s (2H, CH2NH2),
7.14–7.27 m (5Harom), 9.08 s (1Htetrazole), 12.24 s (1H,
OH). 13C NMR spectrum (DMSO-d6), δ, ppm: 37.9
(CH), 42.4 (CH2COOH), 52.3 (CH2NH2), 127.7
(CHarom), 128.2 (2CHarom), 129.0 (2CHarom), 140.3
(Carom), 144.6 (Ctetrazole), 172.8 (C=O). Found, %: C
56.75; H 5.29; N 24.02. C11H12N4O2. Calculated, %: C
56.89; H 5.21; N 24.12.
(3R)-3-(4-Methylphenyl)-4-(1H-tetrazol-1-yl)bu-
tanoic acid (9b). Yield 1.40 g (23%), mp 143–146°C,
[α]D20 +29.9 (c 1.0, MeOH). IR spectrum, ν, cm–1: 3169
w, 2993 m, 2927 m, 1717 vs, 1514 m, 1489 m, 1445
m, 1413 m, 1330 w, 1313 w, 1296 m, 1249 s, 1195 s,
1176 vs, 1099 vs, 974 s, 881 m, 868 m, 816 s, 760 w,
3-(4-Methylphenyl)-4-(1H-tetrazol-1-yl)butanoic
acid (8b). Yield 1.56 g (29%), mp 140–142°C. IR
spectrum, ν, cm–1: 3169 w, 2993 m, 2927 m, 1717 vs,
1514 m, 1489 m, 1445 m, 1413 m, 1330 w, 1313 w,
1296 m, 1249 s, 1195 s, 1176 vs, 1099 vs, 974 s, 881
m, 868 m, 816 s, 760 w, 723 w, 665 s, 652 s, 640 m.
1H NMR spectrum (DMSO-d6), δ, ppm: 2.17 s (3H,
CH3), 2.53–2.69 m (2H, CH2COOH), 3.52–3.60 m
(1H, CH), 4.61–4.73 m (2H, CH2NH2), 7.02 s (4H,
4CHarom), 9.07 s (1Htetrazole), 12.18 br.s (1H, OH). 13C
NMR spectrum (DMSO-d6), δ, ppm: 21.1 (CH3), 38.1
(CH), 42.1 (CH2COOH), 52.3 (CH2NH2), 128.0
(2CHarom), 129.5 (2CHarom), 136.7 (Carom), 137.2
(Carom), 144.5 (Ctetrazole), 172.8 (C=O). Found, %: C
58.40; H 5.79; N 22.64. C12H14N4O2. Calculated, %: C
58.53; H 5.73; N 22.75.
1
723 w, 665 s, 652 s, 640 m. H NMR spectrum
(DMSO-d6), δ, ppm: 2.18 s (3H, CH3), 2.56–2.71 m
(2H, CH2COOH), 3.53–3.61 m (1H, CH), 4.61–4.73 m
(2H, CH2NH2), 7.01 s (4Harom), 9.07 s (1Htetrazole),
13
12.18 s (1H, OH). C NMR spectrum (DMSO-d6), δ,
ppm: 21.1 (CH3), 38.1 (CH), 42.1 (CH2COOH), 52.4
(CH2NH2), 128.0 (2CHarom), 129.6 (2CHarom), 136.7
(Carom), 137.2 (Carom), 144.6 (Ctetrazole), 172.9 (C=O).
Found, %: C 58.47; H 5.80; N 22.69. C12H14N4O2.
Calculated, %: C 58.53; H 5.73; N 22.75.
(3R)-4-(1H-Tetrazol-1-yl)-3-(4-chlorophenyl)bu-
tanoic acid (9c). Yield 1.53 g (28%), [α]D20 +51.0 (c
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 11 2018

REZNIKOV et al.
1720
1.0, MeOH), mp 147–150°C. IR spectrum, ν, cm–1:
3134 w, 2930 m, 2596 w, 1700 vs, 1490 s, 1447 m,
1435 m, 1414 m, 1354 w, 1311 m, 1261 s, 1215 s,
1169 s, 1140 m, 1098 m, 1086 m, 1015 m, 982 m, 934
m, 897 m, 845 w, 825 vs, 754 s, 718 m, 658 m, 613 m.
1H NMR spectrum (DMSO-d6), δ, ppm: 2.56–2.71 m
(2H, CH2COOH), 3.53–3.61 m (1H, CH), 4.61–4.73 m
Wilcox, D., Carlson, R.P., Carter, G.W., and Djuric, S.W.,
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3
(2H, CH2NH2), 7.05 d (2Harom, JHH 7.5 Hz), 7.62 d
3
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FUNDING
The work was financially supported by the Russian
Science Foundation (project no. 18-13-00447).
19. Kumar, C.N.S.S.P., Parida, D.K., Santhoshi, A.,
Kota, A.K., Sridhar, B., and Rao, V.J., Med. Chem.
Commun., 2011, vol. 2, p. 486.
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