356
6. Experimental
mixture was stirred vigorously for 1 h maintaining the
cold conditions throughout the course of reaction. The
reaction mixture was then poured into ice-cold water with
stirring. The solid separated was filtered off and crystal-
lized from a cyclohexane/chloroform mixture.
6.1. General
Melting points were determined in open capillaries and
are uncorrected. The IR spectra were recorded in potas-
sium bromide on a Perkin Elmer 841 grating spectropho-
tometer (Perkin-Elmer, USA). The mass spectra were
obtained on a Varian Atlas CH-7 spectrometer at 70 eV
ionizing beam, using direct insertion probe. Satisfactory
microanalysis (± 0.4% of the calculated values) was
obtained for all the compounds.
6.1.4. Synthesis of the ethyl 2-(phenylsulphonamido)-
4,5-disubstituted thiophene-3-carboxylates and
benzoates (8g, 8h, 8o, 8v and 8w). General procedure
A solution of the appropriate ethyl 2-(aryloxy)
acetamidothiophene-3-carboxylate/benzoates (0.02 mol)
was prepared in glacial acetic acid (20 mL) and was kept
stirring in an ice-bath (0–5 °C). To this well stirred
solution was added 1-(phenylsulphonylamino)acetyl
chloride (0.02 mol) gradually, ensuring thorough stirring
of the entire mixture. The reaction mixture was stirred
vigorously for 30–45 min maintaining the cold conditions
throughout the course of reaction. About 100 mL of
ice-cold water was added to the reaction while continuing
the stirring. The light brown coloured solid obtained was
filtered off, washed with water and recrystallized from
cyclohexane.
The 2-aminothiophene-3-carboxylic acid ethyl esters
were synthesized according to the literature method [21].
All the other reagents were of reagent grade.
6.1.1. Synthesis of the aryloxyacetic acids (4a–f)
Accurately measured quantities of chloroacetic acid
(0.05 mol) and an appropriate phenol (0.05 mol) were
taken in a conical flask. An aqueous solution of sodium
hydroxide (0.12 mol in 25 mL water) was slowly added
to it with constant stirring. Considerable amounts of heat
evolve during the reaction. Stirring was continued for 2 h
and after the solution turned clear, greenish or yellow, the
whole reaction mixture was evaporated in an evaporating
dish until the solid sodium salt precipitated out. The salt
was isolated and dried. The salt was then dissolved in
water and concentrated hydrochloric acid was added
dropwise till the congo-red paper turned blue. The pre-
cipitated aryloxy acetic acid was filtered off and recrys-
tallized from water.
6.1.5. Synthesis of
2-phenoxymethyl-3-amino-5,6,7,8-
tetrahydrobenzo(b)thieno[2,3-d]pyrimidin-4(3H)-one
(10a)
To an accurately weighed quantity of ethyl 2-phenoxy-
acetamido-4,5,6,7-tetrahydrobenzo(b)thiophene-3-carbo-
xylate (8a) (0.01 mol, 3.8 g) in a round bottomed flask
was added approximately 20 mL of hydrazine hydrate
(99%). The reaction mixture was then refluxed for
16–20 h. After completion of the reaction (TLC), the
reaction mixture was allowed to stand at room tempera-
ture. The compound was allowed to crystallize, then
filtered off, washed with ethanol/water (1:1) and recrys-
tallized from ethanol/chloroform. Yield: 1.9 g, 58%, m.p.
168–170 °C, IR (KBr, cm–1) 3 354, 3 301, 1 650; MS
(m/z): 327 (M+), 311, 250, 234, 93, 77; 1H-NMR (δ ppm)
δ 5.2 (s) 2H, NH2 (D2O exchange), δ 2.4–1.8, (m), 8H,
CH2CH2CH2CH2- on thiophene, δ 5.3, (s) 2H, -CH2O-, δ
7.5–7.2, (m), 5H, Ar–H; Microanalysis: % calc. (found)
C 62.39 (62.51), H 5.20 (5.43), N 12.84 (12.76).
All the target compounds (10a–w, table III) were
synthesized by the above procedure and characterized.
6.1.2. Synthesis of aryloxyacetyl chlorides (5a–f)
An accurately weighed quantity of the appropriate
aryloxyacetic acid (0.05 mol) was dissolved in benzene in
a round bottomed flask, to which thionyl chloride
(0.1 mol) was added. The reaction mixture was refluxed
for 5–6 h. After completion of the reaction (TLC), excess
of thionyl chloride and benzene were distilled off com-
pletely under the reduced pressure. The aryloxyacetyl
chloride, which remains behind as a dark yellow to brown
(depending on the aryloxyacetic acid) viscous liquid, was
immediately used for the next step.
6.1.3. Synthesis of the ethyl
2-(aryloxy)acetamidothiophene-3-carboxylate/benzoates
(8a–f, 8i–n and 8p–u). General procedure
6.2. Biological activity
A
solution of ethyl 2-amino-4,5-disubstituted-
thiophene-3-carboxylate (0.02 mol) was prepared in gla-
cial acetic acid and was kept stirring in an ice-bath
(0–5 °C). To this well stirred solution was added the
aryloxyacetyl chloride (0.02 mol) gradually, ensuring
thorough stirring of the entire mixture. The reaction
6.2.1. H1-antagonistic activity [23, 24] (IC50 and pA2)
H1-antagonistic activity of this series (10) was deter-
mined in terms of IC50 values and pA2 values on the
guinea-pig ileum tissue. The animals were fasted for 24 h
prior to use. Responses were taken on the 2 cm long