Synthesis of p-aminobenzoic acid diamides based on 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxylic acid and [4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]methylamine

Article abstract of DOI:10.1134/S1070363215050096

Reaction of 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxyl chloride with anesthesin followed by hydrolysis of the formed ester has afforded 4-[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carbonylamino]benzoic acid. The acid chloride has been used for acyl

Full text of DOI:10.1134/S1070363215050096

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 5, pp. 1057–1062. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © A.A. Agekyan, G.G. Mkryan, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 5, pp. 760–764.
Synthesis of p-Aminobenzoic Acid Diamides Based
on 4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-carboxylic Acid
and [4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-yl]methylamine
A. A. Agekyan and G. G. Mkryan
Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of the Republic of Armenia, Institute of Fine Organic Chemistry
ave. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: aaghekyаn@mail.ru
Received January 12, 2015
Abstract—Reaction of 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxyl chloride with anesthesin
followed by hydrolysis of the formed ester has afforded 4-[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-
carbonylamino]benzoic acid. The acid chloride has been used for acylation of various amines to yield the
corresponding diamides. Reaction of [4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]methylamine with chlorides
of N-substituted p-aminobenzoic acids has led to formation of diamides.
Keywords: p-aminobenzoic acid, diamide, acylation
DOI: 10.1134/S1070363215050096
p-Aminobenzoic acid plays an important part in
biochemical processes, and the presence of this pharma-
cophore fragment causes the utilitarian properties of a
number of drugs [1–3]. Recent studies have identified
compound with a broad range of biological activity
among phenyltetrahydropyran derivatives [4, 5].
used as starting compound. The nitrile preparation via
condensation of 4-metoxyphenylacetonitrile with
dichloroethyl ether in the presence of sodium hydride
under nitrogen atmosphere has been described
elsewhere [5]. We prepared that nitrile in yield of 65–
70% via condensation in DMF in the presence of
sodium hydroxide. Alkaline hydrolysis of nitrile I
followed by acidification yielded 4-(4-methoxyphenyl)
tetrahydro-2H-pyran-4-carboxylic acid II, and
reduction of compound I with lithium aluminum
hydride afforded [4-(4-methoxyphenyl)tetrahydro- 2H-
pyran-4-yl]methylamine III. The resulting compounds
In order to prepare novel biologically active com-
pounds of this series, we performed synthesis of p-amino-
benzoic acid diamides containing 4-(4-methoxyphenyl)-
tetrahydro-2H-pyran moiety. Nitrile of 4-(4-methoxy-
phenyl)tetrahydro-2H-pyran-4-carboxylic acid I was
Scheme 1.
O
OH
O
(1) NaOH
(2) H+
O
CH3O
II
Cl2(CH2CH2)2O
CN
CN
O
DMF
LiAlH4
CH3O
CH3O
I
NH2
CH3O
III
1057

1058
AGEKYAN, MKRYAN
Scheme 2.
O
H
N
(1) SOCl2
(2) EtOOCC6H4NH2
O
O
II
CH3O
O
IV
O
O
H
H
N
SOCl2
(1) NaOH
(2) H+
N
O
O
O
O
CH3O
CH3O
VI
V
Cl
OH
O
NHR1R2
H
N
O
O
CH3O
NR1R2
VIIa_VIIh
NR1R2 = N(CH2)5 (a), N(CH2CH2)2O (b); R1 = H, R2 = (CH2)2N(CH2CH2)2O (c), furan-2-ylmethyl (d), pyridin-2-yl (e),
1,3,4-thiadiazol-2-yl (f), 3-СF3C6H4 (g), 2-ОСН3-5-СН3C6H3 (h).
were used to obtain diamides of p-aminobenzoic acid
(Scheme 1).
furfurylamine, pyridin-2-ylamine thiadiazol-2-ylamine,
and substituted aniline in anhydrous dioxane in the
presence of triethylamine gave diamides VIIa–VIIh
with yields of 70–75% (Scheme 2).
4-Amido substituted benzoic acids could be obtained
via reaction of p-aminobenzoic acid with the corres-
ponding acid chlorides [6]. In particular, we used
chlorides of 4-(4-methoxyphenyl)tetrahydro-2H-pyran-
4-carboxylic, benzoic, 4-methoxy- and 4-bromo-
benzoic, phenoxyacetic, diphenylacetic, and 2-furoic
acids.
In addition, we synthesized diamides IXa–IXf via
reaction of [4-(4-methoxyphenyl)tetrahydro-2H-pyran-
4-yl]methylamine III with chlorides of 4-acylamino-
benzoic acids VIIIa–VIIIf prepared by interacting the
corresponding acid chloride with p-aminobenzoic acid
(Scheme 3).
We revealed that the reaction of 4-(4-methoxy-
phenyl)tetrahydro-2H-pyran-4-carbonyl chloride with
p-aminobenzoic acid was accompanied with resin
formation. Therefore, we developed another approach
towards synthesis of the amido acid through the acid
ester. Condensation of chloride II with p-amino-
benzoic acid (anesthesin) yielded amido ester IV;
alkaline hydrolysis of the latter followed by
acidification led to formation of amido acid V.
Interaction of chloride VI with various amines such as
piperidine, morpholine, 2-(morpholin-4-yl)ethylamine,
Structures and purity of the products were con-
firmed by physico-chemical methods and TLC analysis.
EXPERIMENTAL
IR spectra were recorded with a Nicolet Avatar 330
1
FT-IR spectrometer (suspension in Vaseline oil). H
NMR spectra were registered using a Varian Mercury-
300 spectrometer (solution in DMSO-d6) relative to
TMS as internal reference. Melting points were
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 5 2015

SYNTHESIS OF p-AMINOBENZOIC ACID DIAMIDES
1059
Scheme 3.
(1) SOCl2
O
O
(2) III
H
O
N
HN
O
OCH3
R
OH
N
R
O
H
VIIIa_VIIIf
IХa_IXf
R = С6Н5 (a), 4-СН3ОС6Н4 (b), 4-BrC6H4 (c), CH2OC6H5 (d), CH(C6H5)2 (e), furan-2-yl (f).
determined using a Boetius apparatus. The reaction
progress was monitored by TLC on Silufol UV-254
plates, eluting with a benzene–acetone mixture (4 : 1)
and detecting with iodine vapor.
Ethyl [4-(4-methoxyphenyl)tetrahydro-2H-pyran-
4-carbonylamino]benzoate (IV). A mixture of 18.9 g
(0.08 mol) of 4-(4-methoxyphenyl)tetrahydro-2H-
pyran-4-carboxylic acid II and 11.9 g (0.1 mol) of
thionyl chloride in 80 mL of benzene was refluxed
during 6 h. The solvent was distilled off, 20 mL of
benzene was added, and the solvent was distilled off to
dryness. The residue was dissolved in 100 mL of
toluene, and the resulting solution was added dropwise
to a mixture of 15.3 g (0.08 mol) anesthesin and 8 g
(0.08 mol) of triethylamine in 100 mL of toluene. The
mixture was refluxed during 4 h. Triethylamine hydro-
chloride was filtered off; the filtrate was sequentially
washed with diluted hydrochloric acid, water, 10%
sodium hydroxide and water, dried over Na2SO4, and
evaporated. Yield 24 g (78.4%), mp 145–146°C (benzene),
Rf 0.65. IR spectrum, ν, cm–1: 3310 (NH), 1706 (Ar,
[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-yl]-
methylamine III was prepared according to [5].
4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-
carbonitrile (I). 24 g (0.6 mol) of finely powdered
NaOH was added to a solution of 29.5 g (0.2 mol) of
4-methoxyphenylacetonitrile in 50 mL of anhydrous
dimethylformamide, and the reaction mixture was
stirred during 0.5 h. 29 g (0.2 mol) of 2,2-dichloro-
diethyl ether was then added dropwise to the mixture,
maintaining the temperature at 80–90°C, and the
mixture was stirred at 100°C during 5 h. After cooling,
300 mL of water was added, and the reaction product
was extracted with benzene (3 × 100 mL). The extract
was dried over Na2SO4 and evaporated. The residue
was distilled. Yield 30 g (69%), bp 180–184°C
(3 mmHg), mp 85–87°C (methanol), Rf 0.65 (benzene–
ether, 8 : 1). IR spectrum, ν, cm–1: 2210 (CN), 1606
1
С=O), 1680 (NС=O). H NMR spectrum, δ, ppm
(J, Hz): 1.38 t (3Н, СН3, J 7.1), 1.90–2.02 m and 2.53–
2.62 m (4Н, СН2), 3.53–3.63 m and 3.74–3.81 m (4Н,
ОСН2), 3.77 s (ОСН3), 4.29 q (2Н, СН2СН3, J 7.1),
6.82–6.88 m and 7.30–7.35 m (4Н, С6Н4ОМе), 7.70–
7.75 m and 7.82–7.87 m (4Н,С6Н4NH), 9.14 br.s (1Н,
NН). Found, %: С 68.70; Н 6.69; N 3.78. С22Н25NО5.
Calculated, %: С 68.91; Н 6.57; N 3.65.
1
(arom). H NMR spectrum, δ, ppm: 1.97–2.11 m (4Н,
СН2С), 3.71–3.80 m (2Н, ОСН2), 3.80 s (ОСН3),
3.97–4.03 m (2Н, ОСН2), 6.89–6.94 m and 7.36–7.41
m (4Н, С6Н4).
4-[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-
carbonylamino]benzoic acid (V). A mixture of 15.3 g
(0.04 mol) of ester amide IV and 60 mL of 20% NaOH
in 50 mL of methanol was refluxed during 2 h. The
solution was cooled, diluted with 100 mL of water, and
acidified with diluted hydrochloric acid (1 : 1). The
formed crystals were filtered off and recrystallized
from ethanol. Yield 12.0 g (85%), mp 195–196°C, Rf
0.49 (benzene–acetone, 1 : 1). IR spectrum, ν, cm–1:
3340 (NH), 2700–2550 (СООН), 1690 (Ar, С=O),
4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-
carboxylic acid (II). A mixture of 21.7 g (0.1 mol) of
nitrile II and 14 g (0.25 mol) of KOH in 150 mL of
ethylene glycol was refluxed during 10 h. After
cooling, 100 mL of water was added. The mixture was
acidified with diluted HCl (1 : 1). The formed crystals
were filtered off. Yield 21 g (89%), mp 162–164°C
1
(ethanol), Rf 0.43 (benzene–acetone, 1 : 1). H NMR
spectrum, δ, ppm: 1.73–1.83 m (2Н, СН2С), 2.38–3.41
m (2Н, СН2С), 3.71–3.80 m (2Н, ОСН2), 3.77 s
(ОСН3), 3.80–3.86 m (2Н, ОСН2), 4.66 br.s (1Н, ОН),
6.78–6.83 m and 7.26–7.31 m (4Н, С6Н4). Found, %:
С 66.21; Н 6.72. С13Н16О4. Calculated, %: С 66.09; Н
6.83.
1
1660 (NС=O). H NMR spectrum, δ, ppm: 1.90–2.01
m and 2.53–2.61 m (4Н, СН2), 3.53–3.62 m and 3.73–
3.81 m (4Н, ОСН2), 3.76 s (ОСН3), 6.82–6.87 m and
7.30–7.35 m (4Н, С6Н4ОМе), 7.67–7.72 m and 7.81–
7.86 m (4Н,С6Н4NH), 9.10 s (1Н, NН), 12.19 br.s
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 5 2015

1060
AGEKYAN, MKRYAN
(1Н,СООН). Found, %: С 67.85; Н 5.78; N 3.79.
С20Н21NО5. Calculated, %: С 67.59; Н 5.96; N 3.94.
2.54–2.62 m (2Н, СН2), 3.38 t. d (2Н, СН2NН, J 6.5,
5.4), 3.54–3.63 m and 3.73–3.81 m (8Н, ОСН2), 3.77 s
(3Н, ОСН3), 6.82–6.88 m and 7.30–7.36 m (4Н,
С6Н4О), 7.61–7.74 m (4Н, С6Н4 N), 7.88 br.t (1Н,
СН2NН, J 5.4), 9.06 s (1Н, NН). Found, %: С 66.57;
Н 7.24; N 8.71. С26Н33N3О5. Calculated, %: С 66.79;
Н 7.11; N 8.99.
4-[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-
carbonylamino]benzoyl chloride (VI). A solution of
17.7 g (0.05 mol) of acid V and 7.2 g (0.06 mol) of
thionyl chloride in 100 mL of anhydrous toluene was
refluxed until complete dissolution (10–12 h). After
removal of the solvent, 30 mL of anhydrous diethyl
ether was added, and acid chloride was filtered off.
Yield 14.5 g (77%), mp 132°C. IR spectrum, ν, cm–1:
1730 (C=O), 1610 (Ar). The resulting acid chloride
was used without further purification.
4-(4-Methoxyphenyl)-N-[4-(furan-2-ylmethylcar-
bamoyl)phenyl]tetrahydro-2H-pyran-4-carboxamide
(VIId). Yield 73%, mp 170–172°C (ethanol), Rf 0.49.
1H NMR spectrum, δ, ppm (J, Hz): 1.90–2.01 m and
2.53–2.61 m (4Н, СН2), 3.53–3.62 m and 3.72–3.81 m
(4Н, ОСН2), 3.76 s (ОСН3), 4.45 d (2Н, NСН2, J 5.7),
6.20 d.d (1Н, Н3furan, J 3.2, 0.9), 6.30 d.d (1Н, Н4,
furan, J 3.2, 1.9), 6.82–6.87 m and 7.30–7.35 m (4Н,
С6Н4О), 7.38 d.d (1Н, Н5, furan, J 1.9, 0.9), 7.60–7.65
m and 7.75–7.80 m (4Н, С6Н4N), 8.52 br.t (1Н,
NНСН2, J 5.7), 9.07 br.s (1Н, NН). Found, %: С 69.35;
Н 5.94; N 6.36. С25Н26N2О5. Calculated, %: С 69.11;
Н 6.03; N 6.45.
Diamides VIIa–VIIh. A mixture of 0.05 mol of
chloride VI and 20 mL of anhydrous dioxane was added
dropwise to a solution of 0.05 mol of the amine and
0.05 mol of triethylamine in 50 mL of anhydrous
dioxane. The reaction mixture was refluxed during 5 h,
cooled, and poured into 100–150 mL of water. The
formed crystals were filtered off, washed sequentially
with diluted hydrochloric acid (1 : 3), water, 5%
sodium hydroxide solution, and water, dried, and
recrystallized.
4-(4-Methoxyphenyl)-N-[4-(pyridin-2-ylcarbamoyl)-
phenyl]tetrahydro-2H-pyran-4-carboxamide (VIIe).
Yield 70%, mp 153–155°C (ethanol), Rf 0.48. 1H NMR
spectrum, δ, ppm (J, Hz): 1.91–2.03 m and 2.54–2.64
m (4Н, СН2), 3.54–3.65 m and 3.74–3.82 m (4Н,
ОСН2), 3.77 s (ОСН3), 6.83–6.88 m (2Н, С6Н4О),
7.02 d.d. d (1Н, Н5, pyridine, J 7.2, 4.9, 0.9), 7.31–
7.36 m (2Н, С6Н4О), 7.68–7.75 m (3Н, С6Н4N, Н4,
pyridine), 7.93–7.99 m (2Н, С6Н4N), 8.26–8.30 m
(2Н, Н3,6, pyridine), 9.12 br.s (1Н, NН), 10.13 br.s
(1Н, NНPy). Found, %: С 69.83; Н 5.71; N 9.68.
С25Н25N3О4. Calculated, %: С 69.59; Н 5.84; N 9.74.
4-(4-Methoxyphenyl)-N-[4-(piperidin-1-carbonyl)-
phenyl]tetrahydro-2H-pyran-4-carboxamide (VIIa).
Yield 72%, mp 156–158°C (ethanol), Rf 0.42. 1H NMR
spectrum, δ, ppm: 1.49–1.61 m (4Н, β,β'-СН2), 1.63–
1.73 m (2Н, γ-СН2, piperidine), 1.88–2.00 m and 2.53–
2.62 m (4Н, СН2С), 3.39–3.51 m (4Н, α,α'-СН2,
piperidine), 3.53–3.62 m and 3.73–3.81 m (4Н, ОСН2),
3.77 s (3Н, ОСН3), 6.82–6.87 m (2Н, С6Н4ОМе),
7.19–7.24 m and 7.29–7.35 m (4Н, С6Н4 N), 7.63–7.68
m (2Н, С6Н4О), 9.04 br.s (1Н, NН). Found, %: С
71.31; Н 7.02; N 6.50. С25Н30N2О4. Calculated, %: С
71.07; Н 7.16; N 6.63.
4-(4-Methoxyphenyl)-N-[4-(1,3,4-thiadiazol-2-
ylcarbamoyl)phenyl]tetrahydro-2H-pyran-4-
carboxamide (VIIf). Yield 75%, mp 246–248°C (ethanol),
4-(4-Methoxyphenyl)-N-[4-(morpholin-4-ylcarbonyl)-
phenyl]tetrahydro-2H-pyran-4-carboxamide (VIIb).
Yield 71%, mp 171–173°C (toluene), Rf 0.46. 1H NMR
spectrum, δ, ppm: 1.90–2.02 m and 2.54–2.62 m (4Н,
СН2), 3.49 m and 3.54 m (8Н, С4Н8NО), 3.59–3.66 m
and 3.70–3.79 m (4Н, ОСН2), 3.77 s (3Н, ОСН3),
6.83–6.88 m (2Н, С6Н4ОМе), 7.21–7.26 m and 7.30–
7.37 m (4Н, С6Н4N), 7.65–7.70 m (2Н, С6Н4О), 9.06
br.s (1Н, NН). Found, %: С 67.69; Н 6.78; N 6.81.
С24Н28N2О5. Calculated, %: С 67.91; Н 6.65; N 6.60.
1
Rf 0.51. H NMR spectrum, δ, ppm: 1.91–2.03 m and
2.53–2.63 m (4Н, СН2), 3.54–3.63 m and 3.74–3.82 m
(4Н, ОСН2), 3.77 s (3Н, ОСН3), 6.82–6.87 m and
7.30–7.36 m (4Н, С6Н4О), 7.73–7.79 m and 8.04–8.10
m (4Н, С6Н4N), 8.90 s (1Н, N=CH), 9.17 br.s (1Н,
NН), 12.74 br.s (1Н, NН, thiazole). Found, %: С 60.43;
Н 5.20; N 12.56. С22Н22N4О4S. Calculated, %: С 60.26;
Н 5.06; N 12.78.
4-(4-Methoxyphenyl)-N-[4-(3-trifluoromethyl-
phenylcarbamoyl)phenyl]tetrahydro-2H-pyran-4-
carboxamide (VIIg). Yield 75%, mp 178–180°C
4-(4-Methoxyphenyl)-N-{4-[2-(morpholin-4-yl)-
ethylcarbamoyl]phenyl}tetrahydro-2H-pyran-4-
carboxamide (VIIc). Yield 70%, mp 140–142°C
1
(ethanol), Rf 0.53. H NMR spectrum, δ, ppm (J, Hz):
1
(toluene), Rf 0.40. H NMR spectrum, δ, ppm (J, Hz):
1.92–2.03 m and 2.54–2.63 m (4Н, СН2), 3.54–3.64 m
and 3.74–3.82 m (4Н, ОСН2), 3.77 s (3Н, ОСН3),
1.90–2.02 m (2Н, СН2), 2.43–2.52 m [6Н, СН2N(СН2)2],
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SYNTHESIS OF p-AMINOBENZOIC ACID DIAMIDES
1061
1
6.83–6.89 m (2Н, С6Н4О), 7.28 br.d (1Н, Н4, С6Н4СF3,
J 7.7), 7.31–7.37 m (2Н, С6Н4О), 7.45 br.t (1Н, Н5,
С6Н4СF3, J 8.0), 7.71–7.76 m and 7.88–7.93 m (4Н,
С6Н4N), 8.08 br.d (1Н, Н6, С6Н4СF3, J 8.2), 8.19 br.t
(1Н, Н2, С6Н4СF3, J 1.9), 9.17 br.s (1Н, NНС6Н4),
9.04 br.s (1Н, NНС6Н4СF3). Found, %: С 65.31; Н
4.93; N 5.49. С27Н25F3N2О4. Calculated, %: С 65.05;
Н 5.05; N 5.62.
(IXb). Yield 75%, mp 202–204°C, Rf 0.50. H NMR
spectrum, δ, ppm (J, Hz): 1.83–1.95 m and 2.00–2.10
m (4H, СН2С), 3.40 d (2Н, NСН2, J 6.1), 3.42–3.47 m
and 3.68–3.76 m (4Н, СН2О), 3.79 s and 3.87 s (6Н,
ОСН3), 6.82 m and 6.97 m (4Н, С6Н4О), 7.27 m and
7.68 m (4Н, С6Н4СО), 7.47 br.t (1Н, NНСН2, J 6.1),
7.83 m and 7.98 m (4Н, С6Н4N), 10.02 s (1Н, NН).
Found, %: С 70.67; Н 6.52; N 6.02. С28Н30N2О5.
Calculated, %: С 70.87; Н 6.37; N 5.90.
4-(4-Methoxyphenyl)-N-[4-(2-methoxy-5-methyl-
phenylcarbamoyl)phenyl]tetrahydro-2H-pyran-4-
carboxamide (VIIh). Yield 73%, mp 210–212°C
4-Bromo-N-{4-[4-(4-methoxyphenyl)tetrahydro-
2H-pyran-4-ylmethylcarbamoyl]phenyl}benzamide
1
1
(ethanol), Rf 0.49. H NMR spectrum, δ, ppm: 1.91–
(IXc). Yield 72%, mp 208–210°C, Rf 0.54. H NMR
2.03 m (2Н, СН2), 2.33 s (3Н, СН3), 2.54–2.63 m (2Н,
СН2), 3.53–3.63 m and 3.74–3.82 m (4Н, ОСН2), 3.77
s (3Н, ОСН3), 3.89 s (3Н, СН3ОС6Н3), 6.81–6.83 m
(2Н, Н3,4, С6Н3), 6.83–6.88 m and 7.30–7.36 m (4Н,
С6Н4О), 7.73–7.81 m (4Н, С6Н4N), 8.03 br.s (1Н, Н6,
С6Н3), 8.65 br.s (1Н, NНС6Н3), 9.16 br.s (1Н, NН).
Found, %: С 70.59; Н 6.51; N 5.79. С28Н30N2О5. Cal-
culated, %: С 70.87; Н 6.37; N 5.90.
spectrum, δ, ppm (J, Hz): 1.85–1.95 m and 1.98–2.05
m (4H, СН2С), 3.39 d (2Н, NСН2, J 6.1), 3.42–3.48 m
and 3.68–3.76 m (4Н, СН2О), 3.79 s (3Н, ОСН3), 6.83
m and 7.23 m (4Н, С6Н4О), 7.48 br.t (1Н, NНСН2, J
6.1), 7.63 m and 7.83 m (4Н, С6Н4Br), 7.79 m and
7.98 m (4Н, С6Н4N), 10.12 s (1Н, NН). Found, %: С
61.73; Н 5.32; N 5.51. С27Н27 BrN2О4. Calculated, %:
С 61.96; Н 5.20; N 5.35.
Amic acids VIIIa–VIIIf were obtained according
to procedure described in Refs. [7, 8].
N-[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-
ylmethyl]-4-(2-phenoxyacetylamino)benzamide (IXd).
Yield 75%, mp 172–174°C, Rf 0.56. 1H NMR spectrum,
δ, ppm (J, Hz): 1.85–1.95 m and 1.98–2.07 m (4H,
СН2С), 3.39 d (2Н, NСН2, J 6.1), 3.42–3.48 m and
3.70–3.77 m (4Н, СН2ОСН2), 3.79 s (3Н, ОСН3), 4.61
s (2Н, ОСН2), 6.82–6.91 m and 6.95–7.00 m (5Н,
С6Н5), 7.24–7.32 m (4Н, С6Н4О), 7.53 br.t (1Н, NНСН2,
J 6.1), 7.69 s (4Н, С6Н4), 9.98 s (1Н, NН). Found, %:
С 70.66; Н 6.52; N 5.77. С28Н30N2О5. Calculated, %:
С 70.87; Н 6.37; N 5.90.
Diamides IXa–IXf. A mixture of 0.01 mol of acid
VIII and 0.015 mol of thionyl chloride in anhydrous
toluene was refluxed during 8–10 h. After the solvent
removal, the residue was dissolved in 30 mL of
anhydrous dioxane. The obtained mixture was added
dropwise at 15–18°C to a solution of 0.01 mol of [4-
(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]methyl-
amine III and 0.01 mol of triethylamine in 50 mL of
anhydrous dioxane. The reaction mixture was refluxed
during 5 h, cooled, and poured into 100–150 mL of
water. The formed crystals were filtered off, washed
sequentially with dilute hydrochloric acid (1 : 3),
water, 5% sodium hydroxide solution, and water, dried,
and recrystallized from ethanol.
4-(2,2-Diphenylacetylamino)-N-[4-(4-methoxyphenyl)-
tetrahydro-2H-pyran-4-ylmethyl]benzamide (IXe).
Yield 76%, mp 165–167°C, Rf 0.59. 1H NMR spectrum,
δ, ppm (J, Hz): 1.84–1.94 m and 1.97–2.06 m (4Н,
СН2С), 3.38 d (2Н, NСН2, J 6.1), 3.40–3.46 m and
3.68–3.76 m (4Н, СН2ОСН2), 3.78 s (3Н, ОСН3), 5.14
s (1Н, СНPh2), 6.82–6.87 m (2Н, С6Н4О), 7.17–7.31
m and 7.34–7.38 m (12Н, Ph, С6Н4О), 7.46 br.t (1Н,
NНСН2, J 6.1), 7.65 s (4Н, С6Н4N), 10.30 s (1Н, NН).
Found, %: С 76.68; Н 6.29; N 5.15. С34Н34N2О4.
Calculated, %: С 76.38; Н 6.41; N 5.24.
N-{4-[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-
4-ylmethylcarbamoyl]phenyl}benzamide (IXa). Yield
1
79%, mp 195–197°C, Rf 0.53. H NMR spectrum, δ,
ppm (J, Hz): 1.81–1.92 m and 1.99–2.08 m (4H,
СН2С), 3.39 d (2Н, NСН2, J 6.1), 3.41–3.46 m and
3.68–3.76 m (4Н, СН2О), 3.79 s (3Н, ОСН3), 6.83 m
and 7.23 m (4Н, С6Н4О), 7.43 m (3Н, С6Н5), 7.46 br.t
(1Н, NНСН2, J 6.1), 7.68 m (2Н, С6Н5), 7.81 m and
7.98 m (4Н, С6Н4N), 10.19 s (1Н, NН). Found, %: С
72.67; Н 6.51; N 6.18. С27Н28N2О4. Calculated, %: С
72.95; Н 6.35; N 6.30.
N-{4-[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-
4-ylmethylcarbamoyl]phenyl}furan-2-carboxamide
1
(IXf). Yield 69%, mp 153–155°C, Rf 0.55. H NMR
spectrum, δ, ppm (J, Hz): 1.82–1.92 m and 1.99–2.08
m (4H, СН2С), 3.39 d (2Н, NСН2, J 6.1), 3.41–3.47 m
and 3.68–3.75 m (4Н, СН2О), 3.79 s (3Н, ОСН3), 6.59
d.d (1Н, Н4, furan, J 3.5, 1.7), 6.86 m and 7.25 m (5Н,
4-Methoxy-N-{4-[4-(4-methoxyphenyl)tetrahydro-
2H-pyran-4-ylmethylcarbamoyl]phenyl}benzamide
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 5 2015

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AGEKYAN, MKRYAN
С6Н4О, Н3, furan), 7.55 br.t (1Н, NНСН2, J 6.1), 7.71
d (1Н, Н5, furan, J 1.7), 7.63 m and 7.80 m (4Н,
С6Н4N), 10.05 s (1Н, NН). Found, %: С 69.38; Н
6.19; N 6.27. С25Н26N2О5. Calculated, %: С 69.11; Н
6.03; N 6.45.
4. Arustamyan, Zh.S., Markaryan, R.E., Asatryan, T.O.,
Grigoryan, A.V., and Markaryan, E.A., Khim. Zh.
Armenii, 2011, vol. 64, no. 1, p. 97.
5. Bernadelli, P., Cronin, A.M., Denis, A., Denton, S.M.,
Jacobelli, H., Kemp, M.I., Lorthiois, E., Rousseau, F.,
Serradeil-Civit, D., and Vergne, F., EP Patent 1747210
B1, 2010.
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