Synthesis, crystal and antiproliferative activity of 2-[2-(2-fluorobenzylidene) hydrazinyl]-4-(1-methyl-1H-indol-3-yl)thieno[3,2-d]pyrimidine

Article abstract of DOI:10.1080/15421406.2019.1706268

The title compound 2-[2-(2-fluorobenzylidene)hydrazinyl]-4-(1-methyl-1H-indol-3-yl) thieno[3,2-d]pyrimidine (C₂₂H₁₆FN₅S) was prepared and its structure was confirmed by IR, ¹H NMR, MS, elemental analyses and X-ray diffraction. The crystal of the title compound belongs to the monoclinic system, space group P2₁/c with a = 14.4546(17) ?, b = 17.0895(19) ?, c = 17.9621(15) ?, α = 90°, β = 122.717(6), γ = 90°, V = 3733.1(7) ?³, Z = 4, and R = 0.0412 for 4816 observed reflections with I > 2σ(I). In addition, the compound possesses distinct effective inhibition on the proliferation of HT-29, A549 and MKN45 cell lines.

Full text of DOI:10.1080/15421406.2019.1706268

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Molecular Crystals and Liquid Crystals
ISSN: 1542-1406 (Print) 1563-5287 (Online) Journal homepage: https://www.tandfonline.com/loi/gmcl20
Synthesis, crystal and antiproliferative activity
of 2-[2-(2-fluorobenzylidene) hydrazinyl]-4-(1-
methyl-1H-indol-3-yl)thieno[3,2-d]pyrimidine
Ju Liu, Jian–Tao Shi, Yi-Lin Gong, Shi Ding & Ye Chen
To cite this article: Ju Liu, Jian–Tao Shi, Yi-Lin Gong, Shi Ding & Ye Chen (2019) Synthesis,
crystal and antiproliferative activity of 2-[2-(2-fluorobenzylidene) hydrazinyl]-4-(1-methyl-1H-
indol-3-yl)thieno[3,2-d]pyrimidine, Molecular Crystals and Liquid Crystals, 692:1, 53-61, DOI:
10.1080/15421406.2019.1706268
To link to this article: https://doi.org/10.1080/15421406.2019.1706268
Published online: 19 Feb 2020.
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MOLECULAR CRYSTALS AND LIQUID CRYSTALS
2019, VOL. 692, NO. 1, 53–61
https://doi.org/10.1080/15421406.2019.1706268
Synthesis, crystal and antiproliferative activity
of 2-[2-(2-fluorobenzylidene) hydrazinyl]-4-(1-
methyl-1H-indol-3-yl)thieno[3,2-d]pyrimidine
Ju Liu, Jian–Tao Shi, Yi-Lin Gong, Shi Ding, and Ye Chen
Key Laboratory of New Drug Research and Development of Liaoning Province, College of Pharmacy,
Liaoning University, Shenyang, China
KEYWORDS
ABSTRACT
antiproliferative activity;
synthesis; thieno[3,2-d]
pyrimidine; X-ray diffraction
The title compound 2-[2-(2-fluorobenzylidene)hydrazinyl]-4-(1-methyl-
1H-indol-3-yl) thieno[3,2-d]pyrimidine (C22H16FN5S) was prepared and
its structure was confirmed by IR, 1H NMR, MS, elemental analyses
and X-ray diffraction. The crystal of the title compound belongs to
the monoclinic system, space group P21/c with a ¼ 14.4546(17) Å,
b ¼ 17.0895(19) Å, c ¼ 17.9621(15) Å, a ¼ 90ꢀ, b ¼ 122.717(6), c ¼ 90ꢀ,
V ¼ 3733.1(7) Å3, Z ¼ 4, and R ¼ 0.0412 for 4816 observed reflections
with I > 2r(I). In addition, the compound possesses distinct effective
inhibition on the proliferation of HT-29, A549 and MKN45 cell lines.
Introduction
In recent years, fused bicyclic pyrimidines are attractive scaffolds for drug design due to
their biological importance [1–3], especially the thienopyrimidine ring. The thienopyri-
midine derivatives often exhibit diverse biological activities, including anticancer [4,5],
anti-microbial [6], anti-inflammatory activities [7]. Among these active compounds,
thieno[3,2-d]pyrimidines have been reported to show remarkable antitumor activities
with different biotargets and mechanisms [5], and some of them are already being
marketed or are under clinical/preclinical studies, such as Olmutinib [8], Pictilisib
(GDC-0941) [9], SNS-314 [10], PF-03758309 [11] and Fimepinostat (CUDC-907) [12].
On the other hand, indoles are N-heterocycles with a wide range of pharmacological
and biological properties, such as anticancer [13], anti-inflammatory [14], antioxidant
[15], antihistamine [16] and antiviral [17] agents. One of the noteworthy drugs based
on indole moiety is Osimertinib (AZD9291) which is a FDA-approved targeted therapy
medicine for the treatment of metastatic epidermal growth factor receptor (EGFR)
T790M mutation-positive non-small cell lung cancer (NSCLC) [18].
In view of the facts mentioned above and also as a part of our work [19,20] on the
synthesis of bioactive lead compounds for the anticancer drug discovery, the title com-
pounds were designed by introducing indole scaffold into the thieno[3,2-d]pyrimidine
CONTACT Shi Ding
dingshi_Destiny@163.com; Ye Chen
sy-Chenye@163.com
Key Laboratory of New Drug
Research and Development of Liaoning Province, College of Pharmacy, Liaoning University, Shenyang, 110036, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gmcl.
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15421406.2019.1706268
ß 2019 Taylor & Francis Group, LLC

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54 J. LIU ET AL.
pharmacophore. A new thieno[3,2-d]pyrimidine derivative, 2-[2-(2-fluorobenzylidene)
hydrazinyl]-4-(1-methyl-1H-indol -3-yl)thieno[3,2-d]pyrimidine, was synthesized and
1
characterized by IR, H NMR, MS and elemental analyses. The single crystal structure
of the title compound was determined by X-ray diffraction. The antiproliferative activity
of the title compound against human cancer cell lines HT-29 and MKN45 was tested.
Experimental
Materials and methods
Unless specified otherwise, all starting materials and reagents were obtained from com-
mercial supplies without further purification. All melting points (ꢀC) were taken on a
1
Beijing Taike X-4 microscopy melting point apparatus and were uncorrected. H NMR
spectra were recorded on a Bruker Biospin 600 MHz instrument using TMS as the
internal standard. All chemical shifts were reported in ppm. IR spectra were recorded as
KBr pellets on a Perkin-Elmer Spectrum one FT-IR spectrometer. Crystal data were
obtained on a Bruker P4 X-diffractometer.
Synthesis of thieno[3,2-d]pyrimidine-2,4-diol (2)
A mixture of 3-amino-2-thiophene carboxylic acid methyl ester (12.48 g, 79.38 mmol)
and urea (27.54 g, 397.02 mmol) was heated at 190 ꢀC. After 2 h, 7.5% NaOH solution
(60 mL) was poured into the reaction mixture and a white solid precipitated. The solid
was filtered off and the filtrate washed with 2 M HCl. A large amount of white solid
was precipitated, filtered and the filter cake was dried to give 12.10 g of thieno[3,2-
d]pyrimidine-2,4-diol as a white solid. Yield: 90.6%. m.p. 102–104 ꢀC (lit. [21] 102.9 ꢀC);
MS (ESI) m/z(%): 169.0 [M þ H]þ.
Synthesis of 2,4-dichlorothieno[3,2-d]pyrimidine (3)
A mixture of thieno[3,2-d]pyrimidine-2,4-diol (7.4 g, 44.0 mmol), phosphorus oxychlor-
ide (40 mL) was heated at reflux for 10 h. After cooling to room temperature, the reac-
tion mixture was slowly added to ice/water with vigorous stirring. The mixture was
then filtered, washed with cold water and dried to yield 6.36 g of 2,4-dichlorothieno[3,2-
d]pyrimidine as an off-white solid. Yield: 70.5%. m.p. 138–140 ꢀC (lit. [22] 138.8 ꢁ 139.3 ꢀC);
MS (ESI) m/z(%): 169.0 [M þ H]þ.
Synthesis of 2-chloro-4-(1-methyl-1H-indol-3-yl)thieno[3,2-d]pyrimidine (5)
A suspension of 2,4-dichlorothieno [3,2-d]pyrimidine (4.10 g, 20.00 mmol) and aluminum
chloride (3.20 g, 24.00 mmol) in dried 1,4-dioxane (50 mL) was stirred at ambient temperature
for 10 min. To this was added 1-methylindole (2.90 g, 22.10 mmol), and the mixture was
heated to 80 ꢀC for 3 h. The cool reaction mixture was added dropwise to vigorously stirring
water (250 mL) over 15 min. Upon complete addition the mixture was stirred for 1 h, filtered
and the solid washed with water (50 mL). The crude product was purified by flash silica chro-
matography to give 4.70 g of 2-chloro-4-(1-methyl-1H-indol-3-yl)thieno[3,2-d]pyrimidine as a

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MOLECULAR CRYSTALS AND LIQUID CRYSTALS
55
1
yellow solid. Yield: 78.4%. m.p. 202–204 ꢀC; H NMR (600 MHz, CDCl3) d 8.80 (s, 1 H), 7.94
(br, 2 H), 7.47 (s, 1 H), 7.37 (s, 3 H), 3.92 (s, 3 H); MS (ESI) m/z(%): 205.0 [M þ H]þ.
Synthesis of 2-hydrazinyl-4-(1-methyl-1H-indol-3-yl)thieno[3,2-d]pyrimidine (6)
A
mixture of 2-chloro-4- (1-methyl-1H-indol-3-yl)thieno[3,2-d]pyrimidine (5.10g,
17.00mmol) and 80% hydrazine monohydrate (15mL) in EtOH (60mL) was refluxed
overnight with vigorous agitation. Most of the solvent was evaporated under reduced
pressure when white solid appeared. After cooling to 10ꢀC, the resulting precipitate was
filtered off, washed with water, and dried under vacuum to afford 3.50g of 2-hydrazinyl-
4-(1-methyl-1H-indol-3-yl)thieno[3,2-d]pyrimidine as a yellow solid, yield: 69.65%. m.p.
1
251–253 ꢀC; H NMR (600 MHz, CDCl3) d 8.69 (d, J ¼ 7.9 Hz, 1 H), 7.95 (s, 1 H), 7.79
(d, J ¼ 5.4 Hz, 1 H), 7.43 – 7.27 (m, 4 H), 6.43 (s, 1 H), 4.57 – 3.93 (m, 2 H), 3.90 (s, 3 H);
MS (ESI) m/z(%): 296.1 [Mþ H]þ.
Synthesis of 2-[2-(2-fluorobenzylidene)hydrazinyl]-4-(1-methyl-1H-indol-3-
yl)thieno[3,2-d] pyrimidine (8)
To
a
solution of 2-hydrazinyl-4-(1-methyl-1H-indol-3-yl)thieno[3,2-d]pyrimidine
(0.40 g, 1.35 mmol) in EtOH (8 mL), 2-fluorobenzaldehyde (0.20 g, 1.61 mmol) and acetic
acid (2 drop) were added, and the mixture was refluxed for 8 h until TLC showed the
completion of the reaction. After cooling to room temperature, the resultant precipitate
was filtered and dried under vacuum to afford 0.41 g of the title compound as a light
yellow solid, yield: 75.41%. m.p. 253–255 ꢀC;.IR (KBr) ꢀ: 3436.7, 31998, 1576.0, 1523.3,
1
1469.8, 1412.5, 1353.2, 1303.1, 1233.1, 1140.2, 1088.8, 853.9, 788.6, 749.2, 704.3; H
NMR (600 MHz, DMSO-d6) d 11.45 (s, 1 H), 9.22 (s, 1 H), 8.45 (s, 1 H), 8.37 (s, 1 H),
8.33 (d, J ¼ 5.4 Hz, 1 H), 8.15 (t, J ¼ 7.2 Hz, 1 H), 7.61 (d, J ¼ 7.2 Hz, 1 H), 7.48 – 7.25
(m, 6 H), 4.01 (s, 3 H); MS (ESI) m/z(%): 402.1 [M þ H]þ; Elemental analysis for
C22H16FN5S (%), calculated: C 65.82, H 4.02, N 17.44. Found (%): C 65.94, H 3.96,
N 17.40.
Crystal data structure determination
The light yellow powder of the title compound was dissolved in ethanol/ethyl acetate
mixed solvents ¼ 5:5 (V/V). After slowly evaporating the solvents for several days,
some single crystals suitable for X-ray analysis were obtained. A light yellow crystal
(C22H16FN5S) with dimensions of 0.28 mm ꢂ 0.26 mm ꢂ 0.22 mm was selected for data
collection which was performed on a Bruker APEX-II CCD automatic diffractometer
with a graphite-monochromatic Mo Ka radiation (k ¼ 0.71073 Å) by using the u and
x-scan mode at 293(2) K. A total of 18811 reflections were collected in the range of
2.6<h < 26.2ꢀ (index ranges: –17<h < 15, –12<k < 20, –21<l < 21) and 6568 were inde-
pendent (Rint ¼ 0.027), of which 4816 observed reflections with I > 2r(I) were used
in the structure determination and refinements. The structure was solved by direct
methods with SHELXS-97 program [23] and expanded by Fourier technique. The non-
hydrogen atoms were refined anisotropically. The hydrogen atoms bound to carbon