Synthesis and antibacterial activity of thienopyrimidine amide derivatives

Article abstract of DOI:10.14233/ajchem.2017.20545

Thienopyrimidine amide derivatives are important class of organic compounds and show wide range of biological activity. Hence the researchers are paying more attention towards the synthesis of these compounds. A series of thienopyrimidine amide derivatives (13a-m) were synthesized. The newly synthesized amide derivatives (13a-m) were characterized by 1H NMR, ¹³C NMR, Mass and IR spectral data. Further these compounds were also evaluated for their antibacterial activity.

Full text of DOI:10.14233/ajchem.2017.20545

Asian Journal of Chemistry; Vol. 29, No. 7 (2017), 1515-1521
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20545
Synthesis and Antibacterial Activity of Thienopyrimidine Amide Derivatives
1
1,*
2
GIRI THARIKOPPULA , LAXMINARAYANA EPPAKAYALA , THIRUMALA CHARY MARINGANTI ,
1
3
CHIRANJEEVI KAMALAPURAM and KARUNAKAR RAO KUDLE
1Sreenidhi Institute of Science and Technology, Yamnampet, Ghatkesar, Hyderabad-501301 India
2Jawaharlal Nehru Technological University Hyderabad, College of Engineering, Hyderabad-505 327, India
3Department of Chemistry, Osmania University, Main Road, Hyderabad-500 007, India
*Corresponding author: E-mail: elxnkits@yahoo.co.in
Received: 27 January 2017;
Accepted: 21 March 2017;
Published online: 13 May 2017;
AJC-18385
Thienopyrimidine amide derivatives are important class of organic compounds and show wide range of biological activity. Hence the
researchers are paying more attention towards the synthesis of these compounds. A series of thienopyrimidine amide derivatives (13a-m)
1
were synthesized. The newly synthesized amide derivatives (13a-m) were characterized by H NMR, 13C NMR, Mass and IR spectral
data. Further these compounds were also evaluated for their antibacterial activity.
Keywords: Thienopyrimidine, Ampicilline, Antibacterial activity.
promising antibacterial drug agents, a series of novel thieno-
pyrimidine derivatives (13a-m) were designed and synthesized.
Further, all target compounds were evaluated for antibacterial
activity.
INTRODUCTION
Nearly two million cases of hospital associated infections
occur annually within the U.S. The microorganism pathogens
typically enter patients via canulation, urinary catheters and
intravascular lines [1]. Treatments of microbic infections, that
involve microorganism, is changing into tough as a result of
everlasting downside of microbic resistance towards antibiotics
[2]. Infections with drug resistant organisms stay a crucial
downside in clinical observe that’s tough to unravel. Several
researchers are well productive within the recent years in
reshaping the scaffolds of earlier antibiotics [3,4].Heterocycles
area unit a part of chemical science and plays a lead role within
the biological activities.
EXPERIMENTAL
The solvents were purified according to standard proce-
dures prior to use and all commercial chemicals were as such
used. For thin-layer chromatography (TLC) analysis, Merck
pre-coated plates (silica gel 60 F254) were used and spots
were visualized under UV light. Merck silica gel 60 (230-400
mesh) was used for flash column chromatography and the
eluting solvents are indicated in the procedures. Melting point
determinations were performed by using Mel-temp apparatus
Recent studies reveal that little heterocyclic frameworks,
supply a plus in style of antibacterial drug agents as they mimic
several biomolecules. Thienopyrimidines are nitrogen and
sulfur atoms containing bicyclic heterocycle and it encompasses
a thiophene ring unit with the pyrimidine moiety [5]. This
scaffold shows a broad spectrum of biological activities. The
thienopyrimidines were assessed as antitumour [6-9],medicine
[10], enzyme [11-14], phosphodiesterase inhibitors [15],
antioxidative [16,17], antimalarial drug [18,19], antibacterial
drug [20], antiviral [21], antifungal [22,23], medication [24],
antiplatelet [25] and medicament [26]. In view of these
observations, the varied biological property of thienopyrimidine
pharmacophore impelled to synthesize the title compounds.
Consequently, with associate in nursing aim to develop
1
13
and were uncorrected. H NMR and C NMR spectra were
recorded inVarian MR-400 MHz instrument. The mass spectra
were recorded on Agilent ion trap MS and infrared spectra
were recorded on a Perkin Elmer FT-IR spectrometer.
Synthesis of thieno[3,2-d]pyrimidine-2,4-diol (2): To a
solution of methyl 3-aminothiophene-2-carboxylate (1) (10
g, 63.69 mmol) in acetic acid (60 mL) and water (35 mL) was
added slowly KOCN (10.3 g, 127.3 mmol) in water (35 mL)
by drop wise at 0 °C over a period of 30 min and the reaction
mixture was stirred at room temperature for 16 h. The resultant
solid was filtered and treated with 50 % NaOH (40 mL) solu-
tion and stirred at room temperature for 4 h. After completion
of the reaction, reaction mixture was cooled to 0 °C and

1516 Tharikoppula et al.
Asian J. Chem.
acidified with conc. HCl provided as off white solid 2. Yield:
1
88 %; m.p: 166-170 °C; H NMR (300 MHz, DMSO-d6): δ
TEA (1.44 g, 14.32 mmol) followed by ethyl bromo acetate
(9) (1.31 g, 7.8 mmol) at 0 °C and stirred the reaction at room
temperature for 16 h. After completion, reaction mixture was
poured into ice cold water, extracted with ethyl acetate (25
mL × 3), combined extracts were washed with water, brine
solution, dried the organic phase over anhy. Na2SO4 and evapo-
rated the solvent to afford the cude product. The crude product
was purified by column chromatography (elutent: 80 % EtOAc:
pet ether) to afford pure compound 10 as off white solid.Yield:
89 %; m.p.: 245-249 °C;1H NMR (400 MHz, CDCl3): δ 7.73-
7.71 (d, J = 5.5 Hz, 1H, ArH), 7.13-7.12 (d, J = 5.5 Hz 1H,
ArH), 4.22-4.20 (q, J = 7.5 Hz 2H, CH2-ester), 3.92 (brs, 4H,
CH2- piperazine), 3.39 (s, 3H, CH3), 3.27 (s, 2H, NCH2CO),
2.67 (s, 4H, CH2-piperazine), 1.52 (s, 9H, C(CH3)3) 1.30-1.26
(q, J = 8 Hz, 2H, OCH2-ester); ESI-MS: m/z, 436.4 (M+H)+.
Synthesis of 2-(4-4-[(tert-butoxycarbonyl)(methyl)-
amino]thieno[3,2-d]pyrimidin-2-ylpiperazino)acetic acid
(11): To a solution of compound 10 (2.5 g, 5.74 mmol) in
methanol (25 mL) at 0 °C was added 6N NaOH (12 mL) and
stirred the reaction at room temperature for 8 h.After comple-
tion, reaction mixture was poured into ice cold water, neutralized
with aq. citric acid solution up to pH 5 and filtered the formed
precipitate to afford 11 as off white solid (Scheme-I). Yield:
93 %; m.p.: 128-129 °C; IR (KBr, νmax, cm-1): 3435, 3004,
2979, 2940, 2869, 1698, 1638,1564, 1374, 1284, 1138, 983,
910, 794, 772; 1H NMR (400 MHz, CDCl3): δ 8.18-8.17 (d, J
= 5.2 Hz, 1H,ArH), 7.19-7.17 (d, J = 5.2, 1H, ArH), 3.78 (brs,
4H, CH2-piperazine), 3.30 (s, 3H, CH3), 3.20 (s, 2H, NCH2CO),
2.64 (s, 4H, CH2-piperazine), 1.46 (s, 9H, C(CH3)3); ESI-MS:
m/z, 408.3(M+H)+.
11.55 (brs, 1H, OH), 11.20 (brs, 1H, OH), 8.05 (d, J = 5.2 Hz,
1H, ArH), 6.91 (d, J = 5.2 Hz, 1H, ArH); ESI-MS: m/z, 167.2
(M-H)–.
Synthesis of 2,4-dichlorothieno[3,2-d]pyrimidine (3):
To a suspention of thieno[3,2-d]pyrimidine-2,4-diol (2) (8.0
g, 47.61 mmol) in toluene was added N-methyl-2-pyrrolidone
(NMP) (1.0 mL, catalytic), followed by the addition and POCl3
(35 mL) at room temperature and heated to reflux for 16 h.
After completion of reaction, excess POCl3 was removed by
distillation, crude residue was poured into ice cold water and
filtered the formed precipitate compound 3 as off white solid.
1
Yield: 7.7g, 80 %; m.p. 136-140 °C; H NMR (300 MHz,
DMSO-d6): 8.70 (t, J = 4.4 Hz, 1H, ArH), 7.72 (d, J = 5.5 Hz,
1H, ArH), ESI-MS: m/z, 204.9 (M+H)+.
Synthesis of N-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-
N-methylamine (5): To a solution of 2,4-dichlorothieno[3,2-
d]pyrimidine (3) (7 g, 34.31 mmol) in THF (80 mL) was added
40 % methyl amine (4) aqueous solution (9 mL) and stirred at
room temperature for 3 h. After completion, reaction mixture
was concentrated and poured into ice water to afford solid of
N-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-N-methylamine (5)
as off white solid. Yield: 88 %; m.p.: 294-303 °C; 1H NMR
(300 MHz, DMSO-d6): δ 8.34 (d, J = 4.7 Hz, 1H, ArH), 8.16
(d, J = 4.7 Hz, 1H, ArH), 7.32 (s, 1H, NH), 2.96 (d, J = 4.5 Hz,
3H); ESI-MS: m/z, 200.1 (M+H)+.
Synthesis of tert-butyl-N-(2-chlorothieno[3,2-d]pyri-
midin-4-yl)-N-methylcarbamate (6): To a solution of N-(2-
chlorothieno[3,2-d]pyrimidin-4-yl)-N-methylamine (5) (6.0 g,
30.15 mmol) in DMF (42 mL) was added TEA (6 g, 60.30),
(Boc)2O (7.9 g, 36.18 mmol) at room temperature for 4 h.After
completion, reaction mixture was poured into ice cold water
to get precipitate and dried the product under vacuum to afford
pure compound 6 as off white solid. Yield: 82 %; m.p:126-
130 °C; IR (KBr, νmax, cm-1) 3068, 2978, 1716, 1532, 1378,
1247, 1144, 886, 793;1H NMR (400 MHz, DMSO-d6): δ 8.51
(d, J = 5.5 Hz, 1H,ArH), 7.54 (d, J = 5.5 Hz, 1H,ArH), 3.39 (s,
3H, CH3), 1.50 (s, 9H, C(CH3)3); ESI-MS: m/z, 299.9 (M+H)+.
Synthesis of tert-butyl-N-methyl-N-(2-piperazino-
thieno[3,2-d]pyrimidin-4-yl)carbamate (8): To a solution of
piperazine (7) (3.45 g, 40.13 mmol) in DMF (30 mL) at 0 °C
was added potassium carbonate (1.38 g, 10.03 mmol) followed
by tert-butyl- N-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-N-
methylcarbamate (6) (3 g, 10.03 mmol) and stirred the reaction
at room temperature for 12 h.After completion, reaction mixture
was poured into ice cold water, filters the formed precipitate,
washed the precipitate with water and dried the product under
vacuum to afford 8 as off white solid. Yield: 2.6 g. m.p. 136-
140 °C; IR (KBr, νmax, cm-1): 3452, 2932, 2862, 1711, 1668,
1567, 1389, 1370, 1269, 1151, 1101, 1001, 763, 750, 662; 1H
NMR (400 MHz, CDCl3): δ 8.19-8.18 (d, J = 5.6 Hz, 1H,
ArH), 7.19-7.18 (d, J = 5.6 Hz, 1H, ArH), 3.80 (brs, 4H, CH2),
3.3 (s, 3H, CH3), 2.93 (s, 4H, CH2), 1.46 (s, 9H, C(CH3)3);
ESI-MS: m/z, 359.3 (M+H)+.
General experimental procedure for synthesis of novel
thienopyrimidine amide derivatives (13a-m): To a stirred
solution of compound 11 (100 mg, 0.245 mmol) in DMF (4
mL) was added diisopropylethylamine (DiPEA) (95 mg, 0.735
mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-
uronium hexafluorophosphate (HATU) (112 mg, 0.294 mmol)
followed by addition of aryl or aliphatic amines (12a-m) (0.279
mmol) and stirred at room temperature for 18 h. After comp-
letion reaction mixture was poured into ice cold water extracted
with ethyl acetate (2 × 15 mL), combined extracts were washed
with brine solution, dried over anhy. Na2SO4 and concentrated
under reduced pressure to afford crude product. This crude
compound was purified by column chromatography (elutent:
2 % methaol: CH2Cl2) to affords pure compounds 13a-m as
yields of the products varied between 80-94 %. By adapting
this procedure the compounds 13a-13m were synthesized
(Scheme-II).
tert-Butyl-2-(4-((cyclohexylcarbamoyl)methyl)piperazin-
1-yl)thieno[3,2-d]pyrimidin-4-ylmethylcarbamate (13a):
Yield: 81 %; m.p.: 148-152 °C; IR (KBr, νmax, cm-1): 3536,
2972, 2855, 1712,1642, 1448, 1333, 1294, 1135, 1094, 1004,
930, 854, 578; 1H NMR (400 MHz, CDCl3): δ 7.74-7.71 (d,
J = 12, 1H, ArH), 7.14-7.13 (d, J = 4 Hz, 1H, ArH), 3.84 (brs,
4H, CH2-piperazine), 3.80 (brs, 1H, CH-Cy.Hexyl), 3.39 (s,
3H, CH3), 3.04 (s, 2H, NCH2CO), 2.61 (brs, 4H, CH2-
piperazine), 1.92-1.89 (m, 2H. CH2-Cy.Hexyl), 1.68-1.58 (m,
2H, CH2-Cy.Hexyl), 1.52 (s, 9H, C(CH3)3), 1.50-1.42 (m, 2H,
CH2-Cy.Hexyl); 1.27-1.20 (m, 4H, CH2-Cy.Hexyl); 13C NMR
Synthesis of ethyl 2-(4-4-[(tert-butoxycarbonyl)(methyl)-
amino]thieno[3,2-d]pyrimidin-2-ylpiperazino)acetate (10):
To a solution of 8 (2.5 g, 7.1 mmol) in DMF (25 mL) was added

Vol. 29, No. 7 (2017)
Synthesis and Antibacterial Activity of Thienopyrimidine Amide Derivatives 1517
Me
OH
Cl
NH
CO2Me
NH2
S
S
S
N
N
S
a
NH2
b
N
c
Me
4
N
2
OH
N
3
Cl
1
N
Cl
5
d
Me
Boc
N
Me
Boc
Me
Boc
N
N
N
N
N
H
N
O
S
S
S
N
N
N
e
f
Br
OEt
9
N
Cl
O
N
H
7
N
6
10
8
N
NH
OEt
g
Reagents and conditions:
a i) KOCN, AcOH, H2O, room temperature, 16 h; ii) NaOH, room temperature, 4 h;
b Toluene, NMP, POCl3, reflux, 16 h;
c THF, room temperature, 3 h;
Me
Boc
N
S
d (Boc)2O, DMF, TEA, room temperature, 4 h;
e DMF, K2CO3, room temperature, 12 h;
f DMF, TEA, room temperature, 16 h;
N
N
N
O
g MeOH, 6N NaOH, room temperature, 8 h
11
N
OH
Scheme-I
(400 MHz, CDCl3): δ 22.7, 27.9, 29.6, 33.7, 36.3, 42.3, 43.6,
48.5, 54.42, 62.8, 81.4, 115.9, 123.6, 134.2, 154.2, 158.2,
160.2, 163.7, 168.6; ESI-MS: m/z, 489.4 (M+H)+.
tert-Butyl-N-methyl-N-[2-(4-2-[(4-nitrobenzyl)amino]-
2-oxoethylpiperazino)thieno[3,2-d]pyrimidin-4-yl]carba-
mate (13d):Yield: 80 %; m.p.: 94-97 °C ; IR (KBr, νmax, cm-1):
3528, 3466, 3320, 3080, 2976, 2931, 2842, 1711, 1649, 1550,
1525,1453, 1370, 1335, 1261, 1150, 1001, 1002, 850, 928,
854, 797, 765, 701, 581; 1H NMR (400 MHz, CDCl3): δ 8.22-
8.20 (d, J = 8 Hz, 2H, Ar-H), 7.75-7.71 (d, J = 4 Hz, 1H,ArH),
7.47-7.45 (d, J = 8 Hz, 2H, Ar-H), 7.13-7.12 (d, J = 4 Hz, 1H,
ArH), 4.62-4.61 (d, J = 4 Hz, 2H, NCH2Ar), 3.86 (brs, 4H,
CH2-piperazine), 3.40 (s, 3H, CH3), 3.16 (s, 2H, NCH2CO),
2.64 (brs, 4H, CH2-piperazine), 1.52 (s, 9H, C(CH3)3); 13C
NMR (400 MHz, CDCl3): δ 28.1, 34.9, 42.2, 44.2, 46.2, 53.0,
61.3, 67.0, 82.2, 114.8, 122.7, 135.2, 153.3, 157.4, 160.0,
164.6, 168.0; ESI-MS: m/z, 542.40 (M+H)+.
tert-Butyl-2-(4-((cycloheptylcarbamoyl)methyl)-
piperazin-1-yl)thieno[3,2-d]pyrimidin-4-ylmethylcarba-
mate (13b): Yield: 85 %; m.p.: 174-178 °C; IR (KBr, νmax
,
cm-1): 3555, 2928, 1714, 1673, 1572, 1504, 1371, 1266, 1146,
1003; 1H NMR (400 MHz, CDCl3): δ 7.75-7.73 (d, J = 8 Hz,
1H, ArH), 7.20-7.18 (d, J = 8 Hz, 1H, ArH), 4.03 (brs, 1H,
CH-Cy.Heptyl), 3.87 (brs, 4H, CH2-piperazine), 3.39 (s, 3H,
CH3), 3.03 (s, 2H, NCH2CO), 2.60 (brs, 4H, CH2-piperazine),
1.92-1.90 (m, 2H, CH2-Cy. heptyl), 1.70 -1.60 (m, 10H, CH2-
Cy. Heptyl), 1.53 (s, 9H, C(CH3)3); 13C NMR (400 MHz,
CDCl3): δ 23.9, 28.1, 29.7, 34.9, 35.0, 44.4, 49.4, 44.4, 53.3,
61.7, 82.3, 114.9, 122.7, 135.3, 153.3, 157.4, 160.0, 164.6,
168.5; ESI-MS: m/z, 503.1 (M+H)+.
tert-Butyl-2-(4-((benzylcarbamoyl)methyl)piperazin-
1-yl)thieno[3,2-d]pyrimidin-4-ylmethylcarbamate (13e):
Yield: 87 %; m.p.: 146-150 °C; IR (KBr, νmax, cm-1): 3531, 3468,
3101, 3080, 2971, 2838, 1713, 1665, 1556, 1520, 1371, 1328,
1266, 1152, 1091, 1001, 929, 799, 766, 622, 583; 1H NMR
(400 MHz, CDCl3): δ 7.76-7.74 (d, J = 6 Hz, 1H, ArH), 7.53
(brs, 1H, NH), 7.37-7.26 (m, 5H), 7.15-7.12 (d, J = 6 Hz, 1H,
ArH), 4.52-4.51 (d, J = 4 Hz, 2H, NCH2Ar-H), 3.88-3.82 (brs,
4H,, CH2-piperazine), 3.38 (s, 3H, CH3), 3.13 (s, 2H, NCH2CO),
2.63 (brs, 4H,, CH2-piperazine), 1.52 (s, 9H, (CH3)3); 13C NMR
(400 MHz, CDCl3): δ 28.1, 34.9, 44.6, 53.5, 62.4, 82.4,115.1,
118.3, 119.7, 122.6, 124.9, 125.8, 125.9, 126.0,126.3,128.9,
132.1, 134.0, 135.5, 153.3, 157.5, 159.8, 164.5, 168.2; ESI-
MS: m/z, 497.42 (M+H)+.
tert-Butyl-N-methyl-N-[2-(4-2-[(2-morpholinoethyl)-
amino]-2-oxoethylpiperazino)thieno[3,2-d]pyrimidin-4-
yl]carbamate (13c):Yield: 92 %; m.p.: 106-110 °C; IR (KBr,
νmax, cm-1): 3526, 3469, 3320, 3091, 2930, 2795, 2840, 2761,
1710, 1651, 1564, 1525,1450, 1372, 1334, 1269, 1151, 1116,
850,1002, 928, 861, 796, 762, 662, 584; 1H NMR (400 MHz,
CDCl3): δ 7.75-7.7 (d, J = 8 Hz, 1H, ArH), 7.14-7.13 (d, J = 4,
1H, ArH), 3.89 (brs, 4H, OCH2-Morpholine,), 3.71 (s, 4H,
CH2-piperazine), 3.44-3.39 (m, 2H, CH2NHCO); 3.39 (s, 3H,
CH3), 3.07 (s, 2H, NCH2CO), 2.62 (brs, 4H, CH2-piperazine),
2.54-2.49 (m, 6H, NCH2-Morpholine & NCH2C), 1.52 (s, 9H,
13
C(CH3)3); C NMR (400 MHz, CDCl3): δ 28.1, 34.9, 35.1,
44.5, 53.3, 53.4, 57.1, 61.6, 67.1, 82.4, 114.9, 122.7, 135.3,
153.35, 157.4, 159.9, 164.6, 169.9; ESI-MS: m/z, 520.4
(M+H)+.
tert-Butyl-2-(4-(((pyridin-2-yl)methylcarbamoyl)-
methyl)piperazin-1-yl)thieno[3,2-d]pyrimidin-4-ylmethyl-
carbamate (13f): Yield: 83 %; m.p.: 142-146 °C; IR (KBr,

1518 Tharikoppula et al.
Asian J. Chem.
Me
Boc
N
N
N
NH2
S
R
12a-i
N
O
N
R
13a-i
N
H
H
N
Me
Boc
N
N
S
12j
N
N
O
O
N
13j
Me
N
Boc
N
O
Me
Boc
NH
N
N
N
S
12k
h
S
N
N
13k
N
O
N
O
N
11
N
N
OH
Me
Boc
N
HN
OH
12l
N
S
N
N
O
13l
Me
N
N
NH
Boc
N
OH
N
12m
S
N
N
O
N
13m
N
N
,
NO2
12d; R =
12c; R =
12a; R
=
12b; R =
12e; R =
,
,
,
,
O
Me
N
N
,
N
N
12f; R =
12g; R =
12h; R =
12i; R =
,
.
,
N
N
NO2
13d; R =
13c; R =
13a; R
=
13b; R =
13e; R =
,
,
,
,
,
O
Me
N
N
,
N
N
13f; R =
13g; R =
13h; R =
13i; R =
,
.
,
N
Reagents and conditions: h DMF, DIPEA, HATU, room temperature, 18 h
Scheme-II: Synthesis of thienopyrimidine amide derivatives 13a-m

Vol. 29, No. 7 (2017)
Synthesis and Antibacterial Activity of Thienopyrimidine Amide Derivatives 1519
νmax, cm-1): 3343, 3101, 3043, 2967, 2924, 2855, 2837,1712,
1669, 1564, 1519.9, 1447,1373, 1332, 1303, 1269,1150,1001,
9H, (CH3)3); 13C NMR (400 MHz, CDCl3): δ 28.3, 34.7, 45.4,
54.4, 54.5, 57.54, 62.6, 67.5, 82.4, 115.1, 123.7, 135.5, 154.4,
156.4, 159.9, 165.5, 168.8; ESI-MS: m/z, 477.1 (M+H)+.
tert-Butyl-2-(4-(2-(isoindolin-2-yl)-2-oxoethyl)pipe-
razin-1-yl)thieno[3,2-d]pyrimidin-4-ylmethylcarbamate
(13k):Yield: 93 %; m.p.: 91-95 °C; IR (KBr, νmax, cm-1): 3442,
2977, 924, 2849, 1710, 1646, 1567, 1527, 1453, 1371, 1332,
1
930, 798, 7667, 584; H NMR (500 MHz, CDCl3): δ 8.56-
8.55 (d, J = 5 Hz, 1H, Py-H), 8.24 (brs, 1H, NH), 7.74-7.73
(d, J = 5.5 Hz, 1H, ArH) 7.68-7.71 (t, J = 1.5 Hz, 1H, Py-H),
7.29-7.27 (d, J = 8 Hz, 1H, Py-H), 7.21-7.20 (d, J = 5.5 Hz,
1H, ArH), 7.14-7.13 (d, J = 5.5 Hz, 1H, Py-H), 4.63-4.62 (d, J
= 5 Hz, 2H, NCH2Ar), 3.90 (brs, 4H, CH2-piperazine), 3.39
(s, 3H, CH3), 3.14 (s, 2H, NCH2CO), 2.64 (brs, 4H, CH2-
piperazine),1.52 (s, 9H, (CH3)3); 13C NMR(400 MHz, CDCl3):
δ 28.1, 29.6, 34.9, 44.1, 44.3, 44.6, 53.4, 61.7, 82.4, 114.8,
121.9, 122.3, 122.7, 135.2, 136.7, 149.2, 153.3, 156.8, 157.4,
160.0, 164.6, 170.2; ESI-MS: m/z, 498.4 (M+H)+.
1
1263, 1151, 1002, 930, 846, 796, 758; H NMR (400 MHz,
CDCl3): δ 7.73-7.72 (d, J = 4 Hz, 1H,ArH), 7.31-7.26 (m, 4H,
Ar-H), 7.14-7.13 (d, J = 4 Hz, 1H,ArH), 4.96 (s, 2H, CONCH2),
4.85 (s, 2H, CONCH2), 3.92 (brs, 4H, CH2-piperazine), 3.39 (s,
3H, CH3), 3.30 (s, 2H, NCH2CO), 2.69 (s, 4H, CH2-piperazine),
13
1.54 (s, 9H, (CH3)3); C NMR (400 MHz, CDCl3): δ 28.1,
tert-Butyl-2-(4-((phenethylcarbamoyl)methyl)piperazin-
1-yl)thieno[3,2-d]pyrimidin-4-ylmethylcarbamate (13g):
Yield: 80 %; m.p.: 77-81 °C; IR (KBr, νmax, cm-1):3530. 3469,
3326, 3082, 2975, 2842, 2763, 1710, 1649, 1566, 1453, 1372,
1332, 1263, 1151, 1002, 928, 854, 796, 758, 701,581; 1H NMR
(400 MHz, CDCl3): 7.74-7.73 (d, J = 5.6 Hz, 1H, ArH), 7.32-
7.21 (m, 6H, Ar-H), 7.14-7.12 (d, J = 5.6 Hz, 1H,, ArH), 3.73
(brs, 4H, CH2-piperazine), 3.62-3.60 (q, J = 2.1 Hz, 2H,
NHCH2C), 3.39 (s, 3H, CH3), 3.0 (s, 2H, NCH2CO), 2.89-2.85
(t, J = 6.8 Hz, 2H,CCH2Ar-H), 2.49-2.47 (s, 4H, CH2-
piperazine), 1.53 (s, 9H, (CH3)3); 13C NMR (400 MHz, CDCl3):
δ 28.1, 29.6, 34.8, 35.5, 39.6, 44.2, 53.3, 61.6, 82.3, 114.8,
122.6, 126.6, 128.6,128.7, 135.3,1387, 153.3, 157.4, 159.8,
164.6, 169.9; ESI(M+H)+. MS: m/z, 511.44 (M+H)+.
34.9, 44.13, 44.27, 52.21, 52.37, 53.06, 53.40, 61.4, 82.3,
114.6, 122.5, 122.7, 122.9, 127.5, 127.7, 135.1,136.0, 136.3,
153.3, 157.3,160.0, 164.6, 168.3; ESI-MS: m/z, 509.39
(M+H)+.
tert-Butyl-2-(4-(2-(4-hydroxypiperidin-1-yl)-2-oxo-
ethyl)piperazin-1-yl)thieno[3,2-d]pyrimidin-4-ylmethyl-
carbamate (13l): Yield: 93 %; m.p.: 119-123 °C; IR (KBr,
νmax, cm-1): 545, 3321, 2928, 2855, 1714, 1673, 1572, 1504,
1333, 1266, 1147, 1094, 1050, 1003, 930, 854, 798, 708, 578;
1H NMR (400 MHz, CDCl3): δ 7.73-7.72 (d, J = 4 Hz, 1H,
ArH), 7.14-7.13 (d, J = 4 Hz, 1H, ArH), 4.10 (brs, 1H,CH-
OH), 4.07-3.86 (m, 6H, NCH2CO &CH2-piperazine), 3.38 (s,
3H, CH3), 3.2-3.18 (m, 4H, CH2-piperdine), 2.60-2.59 (s, 4H,
CH2-piperazine) 1.90-1.85 (m, 5H, CH2-piperdine& OH), 1.52
(s, 9H, (CH3)3); ESI-MS: m/z, 491.39 (M+H)+.
tert-Butyl-2-(4-(((1-methyl-1H-pyrazol-4-yl)methyl-
carbamoyl)methyl)piperazin-1-yl)thieno[3,2-d]pyrimidin-
4-ylmethylcarbamate (13h):Yield: 86 %; m.p.: 168-172 °C;
IR (KBr, νmax, cm-1): 3418, 3392, 3331, 2980, 2931, 2850,
2821, 1710, 1568, 1525, 1373, 1335, 1266, 1152, 1000, 931,
797, 763, 663, 582;1H NMR (400 MHz, CDCl3): δ 7.74-7.73
(d, J = 6 Hz, 1H,ArH), 7.43 (s, 1H, Ar-H), 7.36 (s, 1H, CONH),
7.13-7.12 (d, J = 6 Hz 2H,ArH), 4.36-4.34 (d, J = 6 Hz, 2H),
3.88 (s, 3H, NCH3), 3.84 (brs, 4H, CH2-piperazine), 3.38 (s,
3H, CH3), 3.07 (s, 2H, NCH2CO), 2.59 (s, 4H, CH2-piperazine),
1.52 (s, 9H, (CH3)3). ESI-MS: m/z, 501.1(M+H)+.
tert-Butyl-2-(4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-
oxoethyl)piperazin-1-yl)thieno[3,2-d]pyrimidin-4-
ylmethylcarbamate (13m): Yield: 91 %; m.p.: 120-124 °C;
IR (KBr, νmax, cm-1): 33440, 3410, 3095, 2939, 2832, 1710,
1634, 1564, 1373, 1261, 1154, 1001, 929, 849, 797, 763, 579;
1H NMR (400 MHz, CDCl3): δ 7.73-7.72 (d, J = 3 Hz, 1H),
7.26-7.11 (m, 5H), 4.81-4.75 (m, 2H,CONCH2), 3.87-3.81 (m,
6H,CH2), 3.37-3.32 (m, 5H, NCH3, CH2), 2.96-2.88 (m,
2H,CCH2Ar-H), 2.61-2.60 (m, 4H, CH2-piperazine),1.51 (s,
9H, (CH3)3); 13C NMR (400 MHz, CDCl3): δ 28.4, 29.6, 34.9,
40.1, 43.3, 44.1, 44.2, 44.4, 47.2, 53.1, 61.6, 61.8, 82.2, 122.7,
126.4, 126.6, 134.0, 153.3, 157.4, 160.0, 164.6, 168.2, 168.4;
ESI-MS: m/z, 523.4 (M+H)+.
tert-Butyl-2-(4-(((pyrimidin-5-yl)methylcarbamoyl)-
methyl)piperazin-1-yl)thieno[3,2-d]pyrimidin-4-ylmethyl-
carbamate (13i): Yield: 84 %; m.p.: 128-129 °C; IR (KBr,
νmax, cm-1): 3452, 3007, 2983, 1708, 1659, 1566, 1386, 1258,
1
1147, 1003, 850, 728, 634; H NMR (400 MHz, CDCl3): δ
RESULTS AND DISCUSSION
9.16 (s, 1H, Ar-H), 8.73 (s, 1H, Ar-H), 7.75-7.74 (m, 2H,
ArH&Ar-H), 7.14-7.13 (d, J = 6 Hz, 1H,ArH), 4.8 (brs,
1H,CONH), 4.54-4.53 (d, J = 6.4 Hz, 2H. Ar-HCH2N), 3.86
(s, 4H, CH2-piperazine), 3.38 (s, 3H, CH3), 3.14 (s, 2H,
NCH2CO), 2.62 (s, 4H, CH2-piperazine), 1.52 (s, 9H, (CH3)3);
ESI-MS: m/z, 499. 4(M+H)+.
The target compounds 13a-m was prepared as outlined
in Schemes I and II. The compound methyl 3-aminothiophene-
2-carboxylate (1) was reacted with KOCN in acetic acid and
H2O at room temperature for 16 h. The resulting solid was
filtered and treated with 50 % NaOH and reaction mixture was
stirred at room temperature for 4 h to afford pure thieno[3,2-
d]pyrimidine-2,4-diol (2) in good yield. This diol intermediate
(2) was reacted with POCl3 in toluene and NMP at reflux for
16 h to afford pure 2,4-dichlorothieno[3,2-d]pyrimidine (3)
and intermediate 3 was coupled with 40 % methylamine (4)
in methanol and THF at room temperature for 3 h to afford N-
(2-chlorothieno[3,2-d]pyrimidin-4-yl)-N-methylamine (5) in
91 % yield. The intermediate 5 undergoes to protection reacting
with (Boc)2O in DMF and triethylamine at room temperature
tert-Butyl-methyl-2-(4-(2-morpholino-2-oxoethyl)-
piperazin-1-yl)thieno[3,2-d]pyrimidin-4-ylcarbamate
(13j):Yield: 94 %; m.p.: 135-139 °C; IR (KBr, νmax, cm-1): 3434,
3085, 2978, 2919, 2849, 2795, 1710, 1641, 1571, 1523, 1461,
1372, 1264, 1155, 1111, 1001, 968, 932, 850, 798, 583; 1H NMR
(400 MHz, CDCl3): δ 7.74-7.72 (d, J = 8 Hz, 1H, ArH), 7.15-
7.12 (d, J = 8 Hz, 1H, ArH), 3.86 (brs, 4H, OCH2-Morpholine),
3.74-3.64(s, 4H, CH2-piperazine), 3.40(m, 7H, NCH2-Morpholine),
3.24 (s, 2H, NCH2CO), 2.61 (s, 4H, CH2-piperazine), 1.52 (s,

1520 Tharikoppula et al.
Asian J. Chem.
for 4 h to afford protected compound 6, it was coupled with
piperizine (7) in DMF, K2CO3 at room temperature for 12 h to
afford pure tert-butyl N-methyl-N-(2-piperazinothieno[3,2-
d]pyrimidin-4-yl)carbamate (8) in 82 % yield. The piperizine
intermediate 8 was reacted with ethylbromoacetate (9) in DMF,
triethylamine at room temperature for 16 h to afford pure
compound ethyl 2-(4-4-[(tert-butoxycarbonyl)(methyl)amino]-
thieno[3,2-d]pyrimidin-2-ylpiperazino)acetate (10). This
ethylester intermediate 10 was undergoes to basic hydrolysis
with 6N NaOH in methanol at room temperature for 8 h to
afford pure acid intermediate 11 in 82 % yield as shown in
Scheme-I. The acid intermediate 11 was coupled with different
substituted amines (12a-m) in DMF, DIPEA and HATU at
room temperature for 18 h to afford pure amide compounds
(13a-m) in excellent yield.
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