Synthesis of Isoflavone–Amino-Acid Conjugates

Article abstract of DOI:10.1007/s10600-019-02821-5

Conjugates of natural and synthetic amino acids and 7-hydroxyisoflavone in which the amino-acid residue was bonded to the isoflavone through a hydroxyacetate linker were prepared using the activated ester method.

Full text of DOI:10.1007/s10600-019-02821-5

DOI 10.1007/s10600-019-02821-5
Chemistry of Natural Compounds, Vol. 55, No. 5, September, 2019
SYNTHESIS OF ISOFLAVONE–AMINO-ACID CONJUGATES
1
2*
M. M. Garazd and M. S. Frasinyuk
Conjugates of natural and synthetic amino acids and 7-hydroxyisoflavone in which the amino-acid residue
was bonded to the isoflavone through a hydroxyacetate linker were prepared using the activated ester method.
Keywords: flavonoids, isoflavone, amino acids, amino-acid derivatives, conjugates.
Isoflavones comprise a group of natural flavonoids that play important roles by affecting in vivo biochemical processes
[1]. On the other hand, the huge significance of amino acids in metabolic processes stimulated a search for novel biologically
active natural amino acids, their synthetic analogs, and various compounds containing amino acids. In this respect, conjugation
of flavonoids and amino acids is interesting for both the theory of organic synthesis and targeted preparation of new biologically
active compounds. Flavonoids with amino acids in their structures are known to act as cyclin-dependent kinase 2 (CDK2)
inhibitors [2, 3] and antitumor agents [4, 5].
The goal of the present work was to functionalize an isoflavonoid by introducing an additional pharmacophore, i.e.,
a natural or synthetic amino acid. Such modification is an important tool for increasing the bioavailability of biologically
active flavonoids [6].
Derivatives of 4′-chloroisoflavone are promising from a pharmacological aspect as analogs of natural compounds
[7]. Also, we recently showed that 4′-chloroisoflavone derivatives containing cytisine are inhibitors of hydroxysteroid
17β-dehydrogenase-4 (HSD17B4) [8], an enzyme playing an important role in carcinogenesis [9].
Cyclization of 1-(2,4-dihydroxyphenyl)-2-(4-chlorophenyl)ethanone (1) by an Ac O–Et N mixture gave
2
3
acetoxyisoflavone 2, which was converted by NaOH in EtOH into 7-hydroxy-2-methylisoflavone (3). Alkylation of isoflavone
3 by ethyl bromoacetate in the presence of potash in Me CO afforded ester 4, further heating of which in AcOH in the presence
2
of H SO synthesized chromonoxyacetic acid 5, the synthon required to construct isoflavone–amino-acid conjugates.
2
4
OR
8
1
RO
O
Me
O
O
O
Me
HO
OH
O
O
a
c
2'
5'
6
4
O
Cl
Cl
Cl
4, 5
1
2, 3
2: R = Ac
3: R = H
4: R = CH CH
5: R = OH
2
3
b
d
a. Ac O, Et N, 140°C; b. NaOH, EtOH, 78°C; c. BrCH COOEt, K CO , Me CO, 78°C; d. H SO , AcOH, 100–110°C
2
3
2
2
3
2
2
4
The carboxylic acids were activated using N-hydroxysuccinimide esters, which were highly reactive and did not
racemize the synthetic products [10], which could also be used successfully to synthesize such compounds [11, 12].
The intermediate activated ester was produced by treating acid 5 with N-hydroxysuccinimide (SuOH) in anhydrous
dioxane using diisopropylcarbodiimide (DIC). Reaction of the activated ester and amino-acid sodium salts in dioxane–H O
2
(1:1) at room temperature followed by acidolysis of the resulting salts gave in high yields (61–89%) amino-acid derivatives
6–19 containing free carboxylic acids.
1) Eximed, 50 Kharkovskoe Shosse, Kiev, 02160, Ukraine; 2) V. P. Kukhar Institute of Bioorganic Chemistry and
Petrochemistry, National Academy of Sciences of Ukraine, 1 Murmanskaya St., Kiev, 02094, Ukraine;
e-mail: mykhaylo.frasinyuk@ukr.net. Translated from Khimiya Prirodnykh Soedinenii, No. 5, September–October, 2019,
pp. 702–705. Original article submitted March 5, 2019.
©
0009-3130/19/5505-0813 2019 Springer Science+Business Media, LLC
813

O
R
O
8
2
O
O
O
Me
O
O
O
Me
H
N
1''
N
H
HOOC
2'
6
(CH )n
2
4
COOH
Cl
Cl
10 - 15
6 - 9
5'
a, b
a, b
O
5
O
O
O
O
Me
R
N
H
O
O
O
Me
N
HOOC
Cl
16, 17
HOOC
Cl
18, 19
17: R =
n = 1 (6), 2 (7), 3 (8), 4 (9)
10: R = Me; 11: R = iPr; 12: R = sec-Bu; 13: R = i-Bu; 14: R = CH CH SMe; 15: R = Ph; 16: R = CONHCH COOH; 18: 3-COOH; 19: 4-COOH
2
3
2
a. SuOH, 1,4-dioxane, DIC, room temp.; b. 1. amino acid, NaHCO , 2. HCl
3
Derivatives of 4′-chloroisoflavone containing glycine (6), β-alanine (7), L-alanine (10), L-valine (11), L-isoleucine
(12), L-leucine (13), L-methionine (14), and L-phenylglycine (15) and 4-aminobutanoic (8), 6-aminohexanoic (9),
trans-4-aminomethylcyclohexanecarboxylic (17), piperidine-3-carboxylic (18), and piperidine-4-carboxylic acids (19) in
addition to glycylglycine (16) were synthesized.
NMR spectra of 6–19 showed resonances for isoflavone and amino-acid protons in addition to the protons of the
resulting amide bond at 8.20–8.95 ppm and the free carboxylic acid at 12.01–13.10 ppm.
Thus, isoflavone–amino-acid conjugates were prepared using activated esters and did not require protection and
subsequent deprotection of the carboxylic acids. This method could be expanded for targeted synthesis and increased
bioavailability of biologically active flavonoids.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Merck plates (Germany). The eluents were
CH Cl –MeOH mixtures (100:1 and 50:1). PMR spectra were measured on the δ-scale vs. TMS (internal standard) using an
2
2
M-400 instrument (Varian, 400 MHz). Elemental analyses of all compounds agreed with those calculated.
1-(2,4-Dihydroxyphenyl)-2-(4-chlorophenyl)ethanone (1). A mixture of 4-chlorophenylacetonitrile (15.1 g,
0.1 mol) and resorcinol (11.0 g, 0.1 mol) in BF ⋅Et O (50 mL) was stirred for 4–6 h with purging by dry HCl, poured after
3
2
12 h with stirring into H O heated to 80°C, refluxed for 1.5–2 h, and cooled. The resulting precipitate was filtered off, rinsed
2
1
with cold H O, and crystallized from MeOH. Yield 20.5 g (78 %), mp 153–154°Ñ, C H ClO . Í NMR spectrum
2
14 11
3
(400 MHz., DMSO-d , δ, ppm, J/Hz): 4.33 (2Í, s, ÑÎÑÍ ), 6.27 (1Í, d, J = 2.4, H-3), 6.41 (1Í, dd, J = 8.8, 2.4, H-5), 7.31
6
2
(2H, d, J = 8.8, Í-3′, 5′), 7.38 (2H, d, J = 8.8, Í-2′, 6′), 7.94 (1Í, d, J = 8.8, H-6), 10.72 (1Í, s, 4-ÎÍ), 12.42 (1Í, s, 2-ÎÍ).
2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl Acetate (2). A solution of 1 (13.1 g, 50 mmol) in a mixture
of Ac O (23 mL, 250 mmol) and NEt (28 mL, 200 mmol) was heated at 120–130°C for 6–10 h. The reaction mixture was
2
3
poured into cold H O (500 mL). The resulting precipitate was filtered off and crystallized from i-PrOH. Yield 11.1 g (68%),
2
1
mp 162–164°Ñ, C H ClO . Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 2.31 (3Í, s, ÑÍ ÑÎÎ-7), 2.36 (3Í, s,
18 13
4
3
3
ÑÍ -2), 7.13 (1Í, dd, J = 8.8, 2.4, H-6), 7.22 (2H, d, J = 8.8, Í-3′, 5′), 7.28 (1Í, d, J = 2.4, H-8), 7.42 (2H, d, J = 8.8, Í-2′, 6′),
3
8.23 (1Í, d, J = 8.8, H-5).
7-Hydroxy-2-methyl-3-(4-chlorophenyl)-4H-chromen-4-one (3). A hot solution of 2 (3.3 g, 10 mmol) in EtOH
(20 mL) was treated with NaOH solution (10 mL, 1 N), refluxed for 5 min, diluted with H O (20 mL), refluxed for another
2
10 min, and neutralized with dilute HCl to pH 7. The resulting precipitate was filtered off and crystallized from
1
DMF–MeOH. Yield 2.34 g (82%), mp 295–297°Ñ, C H ClO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz):
16 11
3
6
2.45 (3Í, s, ÑÍ -2), 6.85 (1Í, d, J = 2.0, Í-8), 6.92 (1Í, dd, J = 8.8, 2.0, H-6), 7.31 (2H, d, J = 8.3, Í-3′, 5′), 7.49 (2H, d,
3
J = 8.3, Í-2′, 6′), 7.84 (1Í, d, J = 8.8, Í-5), 10.81 (1Í, s, 7-ÎÍ).
814

Ethyl {[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetate (4). A hot solution of 3 (2.86 g,
10 mmol) in anhydrous Me CO (30 mL) was treated with freshly calcined potash (2.1 g, 15 mmol), stirred, refluxed, treated
2
with ethyl bromoacetate (1.32 mL, 12 mmol), held at 50°C for 1–4 h (end of reaction determined by TLC), and poured into
acidified ice water (100 mL). The resulting precipitate was filtered off and recrystallized from EtOH. Yield 3.20 g (86%),
1
mp 134–136°Ñ, C H ClO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.24 (3Í, t, J = 7.1, CH -2′′), 2.28 (3Í, s,
20 17
5
6
3
ÑÍ -2), 4.19 (2H, q, J = 7.1, CH -1′′), 5.00 (2Í, s, 7-ÎÑÍ ), 7.10 (1Í, dd, J = 8.8, 2.4, H-6), 7.18 (1Í, d, J = 2.4, H-8), 7.33 (2H, d,
3
2
2
J = 8.8, Í-3′, 5′), 7.51 (2H, d, J = 8.8, Í-2′, 6′), 7.96 (1Í, d, J = 8.8, H-5).
{[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetic Acid (5). A solution of 4 (3.72 g, 10 mmol) in
AcOH (20 mL) was treated with conc. H SO (1 mL), heated at 100–110°C for 8–12 h, and poured into cold H O (100 mL).
2
4
2
The resulting precipitate was filtered off and recrystallized from DMF–H O. Yield 2.58 g (75%), mp 227–229°Ñ, C H ClO .
2
18 13
5
1
Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.27 (3Í, s, ÑÍ -2), 4.89 (2Í, s, 7-ÎÑÍ ), 7.08 (1Í, dd, J = 8.8, 2.4,
6
3
2
H-6), 7.12 (1Í, d, J = 2.4, H-8), 7.32 (2H, d, J = 8.8, Í-3′, 5′), 7.50 (2H, d, J = 8.8, Í-2′, 6′), 7.95 (1Í, d, J = 8.8, H-5), 13.18
(1Í, br.s, ÑÎÎÍ).
General Method for Synthesizing N-({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)amino
Acids 6–19. A solution of 5 (1.03 g, 3 mmol) and SuOH (0.38 g, 3.3 mmol) in anhydrous dioxane (20 mL) was stirred
vigorously, treated with DIC (0.52 mL, 3.3 mol), and stirred for 2 h (course of reaction monitored by TLC). The resulting
activated ester was treated with a solution of the appropriate amino acid (3.3 mmol) and NaHCO (0.28 g, 3.3 mmol) in H O
3
2
(20 mL), and stirred vigorously for 2–4 h (course of reaction monitored by TLC). When the reaction was finished,
the precipitate of diisopropylurea was filtered off. The filtrate was treated with H O (200 mL) and acidified to pH 5–6.
2
The resulting precipitate was filtered off and crystallized from aqueous i-PrOH.
N-({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)glycine (6). Yield 0.87 g (72%),
1
mp 221–222°Ñ, C H ClNO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.28 (3H, s, ÑÍ -2), 3.83 (2Í, d,
20 16
6
6
3
J = 5.6, CH -1′′), 4.72 (2Í, s, 7-OCH ), 7.11–7.17 (2H, m, Í-6, 8), 7.33 (2H, d, J = 8.5, Í-3′, 5′), 7.50 (2H, d, J = 8.5, Í-2′, 6′),
2
2
7.97 (1H, d, J = 8.8, Í-5), 8.52 (1H, t, J = 5.6, NÍ).
N-({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)-β-alanine (7). Yield 1.11 g (89%),
1
mp 217–218°Ñ, C H ClNO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.27 (3H, s, ÑÍ -2), 2.45 (2Í, t, J = 7.0,
21 18
6
6
3
CH -2′′), 3.35 (2Í, m, CH -1′′), 4.66 (2H, s, 7-OCH ), 7.07–7.15 (2H, m, Í-6, 8), 7.33 (2H, d, J = 8.5, Í-3′, 5′), 7.50 (2H, d,
2
2
2
J = 8.5, Í-2′, 6′), 7.97 (1H, d, J = 8.8, Í-5), 8.29 (1H, t, J = 5.4, NH).
4-[({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)amino]butanoic Acid (8). Yield 0.95 g
1
(74%), mp 202–203°Ñ, C H ClNO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.62–1.73 (2H, m, CH -2′′),
22 20
6
6
2
2.19–2.25 (2H, m, CH -3′′), 2.27 (3H, s, ÑÍ -2), 3.12–3.21 (2H, m, CH -1′′), 4.67 (2H, s, 7-OCH ), 7.10–7.15 (2H, m, Í-6,
2
3
2
2
8), 7.33 (2H, d, J = 8.5, Í-3′, 5′), 7.50 (2H, d, J = 8.5, Í-2′, 6′), 7.97 (1H, d, J = 8.8, Í-5), 8.27 (1H, t, J = 5.8, NH), 12.13 (br.s, ÑÎÎÍ).
6-[({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)amino]hexanoic Acid (9). Yield 1.12 g
1
(82%), mp 195–196°Ñ, C H ClNO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.19–1.55 (6H, m, CH -2′′,
24 24
6
6
2
3′′, 4′′), 2.12–2.20 (2H, m, CH -5′′), 2.27 (3H, s, ÑÍ -2), 3.09–3.18 (2H, m, CH -1′′), 4.66 (2H, s, 7-OCH ), 7.08–7.16 (2H,
2
3
2
2
m, Í-6, 8), 7.33 (2H, d, J = 8.5, Í-3′, 5′), 7.50 (2H, d, J = 8.5, Í-2′, 6′), 7.97 (1H, d, J = 8.8, Í-5), 8.20 (1H, t, J = 5.6, NH),
12.01 (br.s, ÑÎÎÍ).
N-({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)-L-alanine (10). Yield 1.02 g (82%),
1
mp 209–210°Ñ, C H ClNO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.34 (3H, d, J = 7.1, CH -2′′), 2.27
21 18
6
6
3
(3H, s, ÑÍ -2), 4.27–4.38 (1H, m, CH-1′′), 4.70, 4.75 (1Í each, d, J = 14.9, 7-OCH ), 7.10–7.17 (2H, m, Í-6, 8), 7.32 (2H,
3
2
d, J = 8.5, Í-3′, 5′), 7.50 (2H, d, J = 8.5, Í-2′, 6′), 7.96 (1H, d, J = 8.8, Í-5), 8.52 (1H, d, J = 7.6, NÍ), 12.73 (br.s, ÑÎÎÍ).
N-({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)-L-valine (11). Yield 1.01 g (76%),
1
mp 201–202°Ñ, C H ClNO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.92 (6H, d, J = 6.8, CH -2′′),
23 22
6
6
3
2.07–2.20 (1H, m, CH-2′′), 2.27 (3H, s, ÑÍ -2), 4.18 (1Í, dd, J = 9.0, 5.6, ÑH-1′′), 4.79, 4.84 (1Í each, d, J = 14.9, 7-OCH ),
3
2
7.07–7.14 (2H, m, Í-6, 8), 7.32 (2H, d, J = 8.5, Í-3′, 5′), 7.50 (2H, d, J = 8.5, Í-2′, 6′), 7.95 (1H, d, J = 9.0, Í-5), 8.33 (1H,
d, J = 9.0, NH), 12.82 (br.s, ÑÎÎÍ).
N-({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)-L-isoleucine (12). Yield 1.20 g (88%),
1
mp 188–189°Ñ, C H ClNO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.80–0.95 (6H, m, CH -2′′, 4′′),
24 24
6
6
3
1.14–1.30, 1.36–1.52 (1H each, m, ÑÍ -3′′), 1.79–1.92 (1Í, m, CH-2′′), 2.27 (3H, s, ÑÍ -2), 4.12–4.28 (1Í, dd, J = 6.6, 7.8,
2
3
CH-1′′), 4.78, 4.82 (1Í each, d, J = 14.9, 7-OCH ), 7.07–7.14 (2H, m, Í-6, 8), 7.33 (2H, d, J = 8.5, Í-3′, 5′), 7.50 (2H, d,
2
J = 8.5, Í-2′, 6′), 7.95 (1H, d, J = 9.0, Í-5), 8.34 (1H, d, J = 7.8, NÍ), 12.80 (br.s, ÑÎÎÍ).
815

N-({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)-L-leucine (13). Yield 1.15 g (84%),
1
mp 196–197°Ñ, C H ClNO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.85, 0.90 (3Í each, d, J = 5.6,
24 24
6
6
CH -4′′, 5′′), 1.52–1.72 (3H, m, ÑÍ -2′′, CH-3′′), 2.27 (3H, s, ÑÍ -2), 4.28–4.37 (1H, m, CH-1′′), 4.72, 4.79 (1Í each, d,
3
2
3
J = 14.9, 7-OCH ), 7.06–7.16 (2H, m, Í-6, 8), 7.33 (2H, d, J = 8.5, Í-3′, 5′), 7.50 (2H, d, J = 8.5, Í-2′, 6′), 7.96 (1H, d, J = 9.0,
2
Í-5), 8.48 (1H, d, J = 7.6, NÍ), 12.68 (br.s, ÑÎÎÍ).
N-({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)-L-methionine (14). Yield 0.91 g (64%),
1
mp 167–168°Ñ, C H ClNO S. Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.88–2.01 (2H, m, CH -2′′), 2.03
23 22
6
6
2
(3H, s, SÑÍ ), 2.27 (3H, s, ÑÍ -2), 2.40–2.50 (2H, m, CH -3′′), 4.38–4.47 (1H, m, CH-1′′), 4.74, 4.79 (1Í each, d, J = 15.0,
3
3
2
7-OCH ), 7.09–7.16 (2H, m, Í-6, 8), 7.33 (2H, d, J = 8.5, Í-3′, 5′), 7.50 (2H, d, J = 8.5, Í-2′, 6′), 7.97 (1H, d, J = 9.0, Í-5),
2
8.52 (1H, d, J = 7.6, NÍ), 12.81 (br.s, ÑÎÎÍ).
(2S)-[({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)amino](phenyl)aceticAcid (15). Yield
1
1.22 g (85%), mp 239–240°Ñ, C H ClNO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.27 (3H, s, ÑÍ -2),
26 20
6
6
3
4.81, 4.86 (1Í each, d, J = 14.9, 7-OCH ), 5.42 (1Í, d, J = 7.6, ÑH-1′′), 7.06–7.13 (2H, m, Í-6, 8), 7.32 (2H, d, J = 8.5, Í-3′,
2
5′), 7.34–7.46 (5Í, m, Ph-1′′), 7.51 (2H, d, J = 8.5, Í-2′, 6′), 7.95 (1H, d, J = 8.5, Í-5), 8.95 (1H, d, J = 7.6, NÍ), 13.10 (br.s,
ÑÎÎÍ).
N-({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)glycylglycine (16). Yield 1.12 g (81%),
1
mp 211–212°Ñ, C H ClN O . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.28 (3H, s, ÑÍ -2), 3.79, 3.84 (2Í
22 19
2
7
6
3
each, d, J = 5.9, CH -1′′, 1′′′), 4.74 (2H, s, 7-OCH ), 7.11–7.20 (2H, m, Í-6, 8), 7.33 (2H, d, J = 8.5, Í-3′, 5′), 7.51 (2H, d,
2
2
J = 8.5, Í-2′, 6′), 7.98 (1H, d, J = 8.8, Í-5), 8.27, 8.48 (1H each, t, J = 5.9, 2 NH), 12.63 (br.s, ÑÎÎÍ).
trans-4-{[({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)amino]methyl}
1
cyclohexanecarboxylic Acid (17). Yield 1.15 g (79%), mp 197–198°Ñ, C H ClNO . Í NMR spectrum (400 MHz,
26 26
6
DMSO-d , δ, ppm, J/Hz): 0.81–0.96, 1.14–1.45, 1.64–1.74, 1.82–1.92, 2.02–2.15 (2H, 3H, 2H, 2H, 1H, 5m, cyclohexane
6
protons), 2.27 (3H, s, ÑÍ -2), 2.95–3.05 (2Í, m, CH -1′′), 4.69 (2H, s, 7-OCH ), 7.09 (1Í, d, J = 2.2, Í-8), 7.12 (1Í, dd,
3
2
2
J = 8.8, 2.2, Í-6), 7.32 (2H, d, J = 8.5, Í-3′, 5′), 7.50 (2H, d, J = 8.5, Í-2′, 6′), 7.97 (1H, d, J = 8.8, Í-5), 8.21 (1H, t, J = 5.3,
NH), 12.02 (br.s, ÑÎÎÍ).
1-({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)piperidine-3-carboxylicAcid (18). Yield
1
0.83 g (61%), mp 174–175°Ñ, C H ClNO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.33–1.80,
24 22
6
6
1.90–2.03, 2.31–2.38, 2.58–2.66, 2.79–2.92, 3.03–3.17, 3.36–3.45, 3.68–3.81, 4.28–4.39 (3H, 1H, 0.5Í, 0.5Í, 0.5H, 1H,
0.5Í, 1.5Í, 0.5Í, 9m, piperidine protons), 2.27 (3H, s, ÑÍ -2), 5.04, 5.11 (1Í each, s, 7-OCH ), 7.07 (1Í, dd, J = 8.8, 2.2,
3
2
Í-6), 7.13 (1Í, d, J = 2.2, Í-8), 7.33 (2H, d, J = 8.5, Í-3′, 5′), 7.50 (2H, d, J = 8.5, Í-2′, 6′), 7.94 (1H, d, J = 8.8, Í-5), 12.52
(br.s, ÑÎÎÍ).
1-({[2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)piperidine-4-carboxylicAcid (19). Yield
1
1.16 g (85%), mp 192–193°Ñ, C H ClNO . Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.33–1.48,
24 22
6
6
1.54–1.68, 1.79–1.94, 2.49–2.59, 2.73–2.85, 3.08–3.18, 3.71–3.83, 4.13–4.24 (1H, 1H, 2H, 1H, 1H, 1H, 1H, 1H, 8m,
piperidine protons), 2.27 (3H, s, ÑÍ -2), 5.02, 5.07 (1H each, d, J = 14.9, 7-OCH ), 7.07 (1Í, dd, J = 8.8, 2.2, Í-6), 7.14
3
2
(1Í, d, J = 2.2, Í-8), 7.33 (2H, d, J = 8.5, Í-3′, 5′), 7.50 (2H, d, J = 8.5, Í-2′, 6′), 7.94 (1H, d, J = 8.8, Í-5), 12.34
(br.s, ÑÎÎÍ).
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