SynthesisandBiologicalEvaluationofDiazepam
J. Chin. Chem. Soc., Vol. 48, No. 5, 2001 915
hydrazine hy drate (15 mL, 80%) was added and the mix ture
was heated un der re flux for 5 h; most of the eth a nol was re-
moved un der re duced pres sure, cooled and di luted with wa-
ter; when a solid sep a rated out it was fil tered and recrys tal-
lized from eth a nol to give 3 as yel low crys tals (70%); m.p.
260 C; IR: 1615 (C=N), 1660 (CONH), 1690 (CONCH3),
mol) and so dium ac e tate (0.05 mol) in eth a nol (50 mL) was
refluxed and the solid sep a rated af ter cool ing washed with
dil. HCl (1%, 100 mL) and crys tal lized from ben zene to give
6 as brown pow der (75%); m.p. 213 C; IR: 1613, 1620, 1628
(3C=N), 1695 (CONCH3), 1760 cm-1 (COOC2H5); 1H NMR
(CF3COOD): 1.91 (t, 3H, CH2CH3), 2.73 (s, 3H, NCH3),
2.81 (q, 2H, C H2CH3), 3.16 (s, 1H, CH), 3.61 (s, 2H, SCH2CO),
7.0-7.30 (m, 8H, ArH); 13C NMR (CF3COOD): 14.8, 21.5
(2CH3), 43.8 (C3), 61.1 (CH2), 120.3-127.6 (ar o matic car-
bons), 153.5, 159.3, 161.1 (3C=N), 164.9, 167.3 (2C=O).
Anal. Calc. for C22H19ClN4O4S (470.92).
1
3190 (NH), 3300 cm-1 (NH2); H NMR (CDCl3): 2.81 (s,
3H, NCH3), 3.12 (s, 1H, CH), 3.87 (br, 2H, NH2), 7.22-7.53
(br, 8H, Ar-H), 8.62 (br, 1H, CONH); 13C NMR (CDCl3):
21.3 (CH3), 42.1 (C3),124.3-127.9(aromaticcarbons),153.2
(C=N), 162.3, 168.1 (2C=O). Anal. Calc. for C17H15ClN4O2
(342.78).
3-(3 -Amino-3 -thio-1 ,2 ,4 -triazol-5 -yl)-7-chloro-1,3-
dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (7)
A mix ture of 4 (0.01 mol), hydrazine hy drate (0.015
mol) and wa ter (2 mL) was stirred for 3 h, and heated un der
re flux for 5 h. The sep a rated solid was fil tered and recrystal-
lized from eth a nol to give 7 as dark brown pow der (60%);
m.p. 200 C; IR: 1605, 1618 (2C=N), 1215 (C=S), 1685
(C=O), 3280 (NH), 3400 cm-1 (NH2); 1H NMR (CF3COOD):
2.93 (s, 3H, NCH3), 3.33 (s, 1H, CH), 5.63 (s, 2H, NH2),
7.92 (br, 1H, NH), 7.12-7.40 (m, 8H, ArH); 13C NMR
(CF3COOD): 20.3 (CH3), 44.1 (C3),123.8-129.6(aromatic
car bons), 142.3, 153.4 (2C=N), 162.1 (C=S, 165.3 (C=O).
Anal. Calc. for C18H15ClN6OS (398.87).
3-(2 -Thio-1 ,3 ,4 -Oxadiazol-5 -yl)-7-chloro-1,3-dihydro-1-
methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (4)
A so lu tion of4 (0.01 mol) in eth a nol (30 mL), po tas-
siumhydroxide(0.5g)inwater(5mL)andcarbondisulphide
(0.03 mol) were added. The re ac tion mix ture was heated un-
der re flux till the eval u a tion of hy dro gen sul phide ceased.
The mix ture was cooled, di luted with cold wa ter (30 mL) and
acid i fied with ace tic acid. The solid that sep a rated was fil-
teredandcrystallizedfromethanoltogive4 (70%); m.p. 290
C; IR: 1610, 1620 (2C=N), 1220 (C=S), 1695 (CONCH3),
3120 cm-1 (NH); 1H NMR [(CD3)2SO]: 2.99 (s, 3H, NCH3),
3.44 (s, 1H, CH), 7.11-7.39 (br, 8H, ArH), 9.22 (s, 1H, NH);
13C NMR [(CD3)2SO] 22.1 (CH3) 42.9 (C3), 123.9-128.3
(aromaticcarbons), 153.5, 159.4(2C=N), 162.3(C=S), 165.4
(C=O). Anal. Calc. for C18H13ClN4O2S (384.83).
3-[4 -(Formylamino)-3 -thio-1 ,2 ,4 -triazol-5 -yl]-7-chloro-
1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-
one (8)
3-[2 -Thio-3 -(N,N-dimethylamine methyl)-1 ,3 ,4 -
oxadiazol-5 -yl]-7-chloro-1,3-dihydro-1-methyl-5-phenyl-
2H-1,4-benzodiazepin-2-one (5)
Equimolar quan ti ties of7 (0.01 mol) and for mic acid
(0.5 mL) in dry ben zene (20 mL) were refluxed for 2 h; ex cess
ofsolventwasremovedbyevaporationandthereactionmix-
ture cooled. The precipitated product was filtered and
recrystallized from ben zene to give 8 (45%); m.p. > 300 C;
IR: 1615, 1620 (2C=N), 1220 (C=S), 1680, 1650 (2C=O),
3260, 3300 (2NH). Anal. Calc. for C19H15ClN6O2S (486.97).
Toaboilingsolutionof4 (0.01mol)inethanol(50mL)
containing aqeous form al de hyde (40%, 1 mL), dimethyl-
amine (0.01 mol) was added with stir ring. The so lu tion was
heated for 10 min, and left over night. The sep a rated solid was
fil tered and crys tal lized from meth a nol to give 5 as brown
crys tals (52%); m.p. 299 C; IR: 1615, 1620 (2C=N), 1220
3-[4 -Benzylidenamino-3 -thio-1 ,2 ,4 -triazol-5-phenyl-2H-
1,4-benzodiazepin-2-one (9)
1
(C=S), 1685 (CONCH3); H NMR [(CD3)2SO]: 2.55 (s, 3H,
CH3), 3.00 (s, 1H, CH), 3.31-3.63 (m, 6H, 2CH3), 5.33 (s, 2H,
NCH2N), 7.0-7.32 (br, 8H, ArH); 13C NMR [(CD3)2SO]:
21.8, 25.2, 25.4 (3CH3), 43.3 (C3), 56.2 (CH2), 123.6-127.6
(aromaticcarbons), 153.6, 159.1(2C=N), 164.1(C=S), 166.3
(C=O). Anal. Calc. for C21H20ClN5O2S (441.87).
Asolutionof 7 (0.01 mol) in gla cial ace tic acid (20 mL)
and benzaldehyde (0.01 mol) was refluxed for 3 h; the re ac-
tion mix ture was then cooled, di luted with wa ter and the sep-
a rated solid was fil tered and crys tal lized from ben zene to
give 9 (40%); m.p. > 300 C; IR: 1610, 1613, 1618 (3C=N),
1215 (C=S), 3300 cm-1 (NH); 1H NMR (CF3COOD): 2.78
(s, 3H, NCH3), 3.13 (s, 1H, CH), 6.51 (s, 1H, azomethine H),
7.23-7.66 (m, 13H, ArH), 7.82-7.85 (br, 1H, NH); 13C NMR
(CF3COOD): 19.9 (CH3), 40.8 (C3),124.3-130.2(aromatic
car bons), 140.1, 142.3, 142.6 (3C=N), 164.2, (C=S), 167.2
3-[2 -(Carbethoxymethylmercapto)-1 ,3 ,4 -oxadiazol-5 -yl]-
7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzo-
diazepin-2-one (6)
A mix ture of 4 (0.01 mol) ethyl chloroacetate (0.01