Synthesis of new 1,2-dihydrophthalazines

Article abstract of DOI:10.1002/jhet.5570390520

New 6-chloro- and 6,7-dichloro-4-(4-aminophenyl)-2-(N-alkylcarbamoyl)-1,2-dihydrophthalazines (12, 18) were synthesized starting from 6-chloro- and 6,7-dichloro-4-(4-nitrophenyl)phthalazine (8). Routes to 1-unsubstituted (12) and 1-methyl (18) derivatives are different. Key intermediates 8 were prepared from 4-chloro- and 3,4-dichlorotoluene via ortho-formylbenzophenone derivatives 7.

Full text of DOI:10.1002/jhet.5570390520

Sep-Oct 2002
Synthesis of New 1,2-Dihydrophthalazines
989
Gyula Lukács and Gyula Simig*
Chemical Research Division, EGIS Pharmaceuticals Ltd., H-1475. Budapest, P.O. Box 100
Received February 11, 2002
New 6-chloro- and 6,7-dichloro-4-(4-aminophenyl)-2-(N-alkylcarbamoyl)-1,2-dihydrophthalazines
(12, 18) were synthesized starting from 6-chloro- and 6,7-dichloro-4-(4-nitrophenyl)phthalazine (8). Routes
to 1-unsubstituted (12) and 1-methyl (18) derivatives are different. Key intermediates 8 were prepared from
4-chloro- and 3,4-dichlorotoluene via ortho-formylbenzophenone derivatives 7.
J. Heterocyclic Chem., 39, 989 (2002).
The amino acid L-glutamate plays a key role in the
Structurally related 1,2-dihydrophthalazines 3 and 4
were also shown to selectively and noncompetitively
inhibit currents associated activation of AMPA recector [4].
It was found that AMPA antagonist activity was retained
when the dioxolane ring of 2,3-benzodiazepine 2 was
substituted with chlorine atoms [5] and the corresponding
7-fluoro analogue was approximately equipotent with 1,2-
dihydrophthalazine 3 in the electrophysiological assay [6].
normal function of the central nervous system [1].
However, under pathological conditions (e.g. stroke,
trauma) excessive extracellular concentrations of
glutamate are associated with neuronal damage and cell
death. AMPA receptor is a subtype of ionotropic gluta-
mate receptors, which can be selectively activated by
a -amino-3-hydroxy-4-methylisoxazolepropionic acid
(AMPA). It is recognized that AMPA receptor antago-
nists reduce injury in animal models of stroke and
epilepsy. Therefore the synthesis of new AMPA receptor
modulators is an interesting target.The 2,3-benzo-
diazepine derivative GYKI 52466 (1) was the first of its
class showing noncompetitive AMPA antagonist activity.
One of the most potent derivatives of 1, GYKI 53773 (2,
LY 300164, talampanel) is in clinical evaluation [2,3]
(Scheme 1).
We now report the synthesis of new chlorine substituted
1,2-dihydrophthalazines 5 [7] structurally related to
methylenedioxy derivatives 3 and 4.
Phthalazine intermediates 8 were synthesized starting
from 3,4-dichloro-, or 4-chlorotoluene (Scheme 2).
Friedel-Crafts nitrobenzoylation of 3,4-dichlorotoluene [8]
followed by oxidation of the resulting benzophenone 6a
with chromium(VI) oxide [9] in a mixture of acetic
anhydride and concentrated sulfuric acid gave

990
G. Lukács and G. Simig
Vol. 39

Sep-Oct 2002
Synthesis of New 1,2-Dihydrophthalazines
991
4,5-Dichloro-2-(4-nitrobenzoyl)toluene (6a).
4,5-dichloro-2-(4-nitrophenyl)benzaldehyde acylal 7a.
Similar reaction sequence starting from Friedel-Crafts
nitrobenzoylation of 4-chlorotoluene [10] gave a mixture
of regioisomers containing 4-chloro-2-(4-nitrophenyl)-
benzaldehyde acylal 7b. Dichlorophthalazine 8a was
prepared by the reaction of ortho-aroylbenzaldehyde
acylal 7a with hydrazine in good yield. Since only ortho-
dicarbonyl derivatives can undergo cyclisation with
hydrazine to give phthalazine, chlorophthalazine 8b was
obtained easily by the reaction of hydrazine with the corre-
sponding mixture of regioisomers containing 7b.
The 2-carbamoyl moiety of compounds 3 and 4 was
introduced by reacting the corresponding 1,2-dihydro-
phthalazine with isocyanates [4,6]. The use of
isocyanates for the introduction of the N(2)-carbamoyl
group has two major disadvantages: relatively few
organic isocyanates are commercially available and
N,N-disubstituted carbamoyl substituents can not be
introduced by this method. Our strategy for the
introduction of N(2)-carbamoyl moiety of 1,2-dihydro-
phthalazines was N(2)-alkoxy(aryloxy)carbonylation
followed by treatment with various primary and
secondary amines.
The synthesis of 2-carbamoyl-4-(4-aminophenyl)-1,2-
dihydrophthalazines 12 is shown on Scheme 3. 1,2-
Dihydrophthalazines 9 were obtained by sodium
borohydride reduction [11] of phthalazines 8. N(2)-
Acylation of compounds 9 with chloroformic acid esters
and acetic anhydride provided compounds 10 which were
transformed to the corresponding 11 amines by catalytic
reduction of the nitro group. Amidation of N(2)-phenoxy-
carbonyl derivatives 11a and 11d with various amines
provided our target compounds 12. Attempts to convert
N(2)-ethoxycarbonyl derivative 11b to compounds 12
failed.
A solution of 3,4-dichlorotoluene (64 ml, 80.5 g, 0.5 mole) in
1,2-dichloroethane (50 ml) was added to a solution of anhydrous
aluminum chloride (76.0 g, 0.57 mole) and 4-nitrobenzoyl
chloride (74.0 g, 0.4 mole) in 1,2-dichloroethane (80 ml) and the
mixture was refluxed for 5 hours. The reaction mixture was
poured into ice (1000 g) and extracted with chloroform (3 x
100 ml). The organic layer was washed with water (3 x 100 ml),
dried (MgSO4) and evaporated. The residual oil was triturated
with hexane (200 ml), the crystalline product was collected by
filtration and washed with hexane (50 ml). The crude product
was recrystallized from acetic anhydride to give 6a (65.8 g,
53 %) as colourless crystals: mp 121-122 °C. 1H nmr (deuterio-
chloroform, 200 MHz): d 8.33 (2H, d, J = 8.8 Hz), 7.94 (2H, d,
J = 8.8 Hz), 7.45 (2H, s), 7.29 (2H, s), 2.33 (3H, s).
Anal. Calcd. for C14H9Cl2NO3 (310.14): C, 54.22, H, 2.92, Cl,
22.86, N, 4.52. Found C, 53.84, H, 2.87, Cl, 22.73, N, 4.51.
4,5-Dichloro-2-(4-nitrobenzoyl)benzaldehyde Acylal (7a).
Chromium(VI) oxide (20.0 g, 0.20 mole) was added to a
solution of 6a (20.0 g, 0.064 mole) in acetic anhydride (400 ml)
at 5 °C. After addition of concentrated sulfuric acid (20 ml), the
mixture was kept at 0-5 °C for 4 hours. It was poured into ice
(1000 g), the resulting crystalline precipitate was collected by
filtration, washed with ethanol and recrystallized from acetic
anhydride to give 7a (11.5 g, 42 %) as colourless crystals: mp
167-168 °C. 1H nmr (deuteriochloroform, 200 MHz): d 8.34 (2H,
d, J = 8.9 Hz), 7.95 (2H, d, J = 8.9 Hz), 7.83 (1H, s), 7.68 (1H, s),
7.43 (1H, s), 2.02 (6 H, s).
Anal. Calcd. for C18H13Cl2NO7 (426.22): C, 50.72, H, 3.07,
Cl, 16.64, N, 3.29. Found: C, 50.42, H, 2.99, Cl, 16.35, N, 3.28.
6,7-Dichloro-1-(4-nitrophenyl)phthalazine (8a).
Hydrazine monohydrate (8 ml, 0.16 mole) was added to a
solution of 7a (6.8 g, 0.021 mole) in ethanol (120 ml) and the
mixture was refluxed for 3 hours. The crystalline product was
collected by filtration and washed with ethanol and recrystallized
from methanol to give 8a (6.1 g, 91 %) as yellow crystals: mp
1
288-289 °C. H nmr (dimethyl sulfoxide-d6, 400 MHz): d 9.77
The required 2-carbamoyl-1-methyl-1,2-dihydrophtha-
lazines 18 were synthesized by a sequence starting with
the reduction [12] of nitro compound 8 to the
corresponding anilines 13 and subsequent acetylation to
acetanilides 14 (Scheme 4). Addition of methyllithium
[4,6,13] followed by 2-phenoxycarbonylation of the
resulting 1-methyl-1,2-dihydrophthalazines 15 afforded
phenylcarbamates 16, which were treated with various
amines to provide the corresponding 2-carbamoyl deriva-
tives 17. Final products 18 were obtained by deacetylation
of compounds 17.
(1H, s), 8.72 (1H, s), 8.47 (2H, d, J = 8.7 Hz), 8.15 (1H, s), 8.06
(2H, d, J = 8.7 Hz).
Anal. Calcd. for C14H7Cl2N3O2 (320.14): C, 52.53, H, 2.20,
Cl, 22.15, N, 13.13. Found: C, 52.23, H, 2.16, Cl, 21.75, N,
12.95.
7-Chloro-1-(4-nitrophenyl)phthalazine (8b).
Step 1: A solution of 4-chlorotoluene (10.8 ml, 11.5 g,
0.09 mole) and 4-nitrobenzoyl chloride (27.1 g, 0.15 mole) in
1,2-dichloroethane (20 ml) was added to a mixture of anhydrous
aluminium chloride (27.8 g, 0.21 mole) and 4-chlorotoluene
(10.8 ml, 11.5 g, 0.09 mole) in 1,2-dichloroethane (30 ml) and the
mixture was refluxed for 5 hours. It was poured into ice (200 g)
and extracted with chloroform (3 x 20 ml). The organic layer was
washed with water (3 x 50 ml), dried (MgSO4) and evaporated.
The oily residue was recrystallized from ethanol (100 ml) to give
a mixture of regioisomers (30.0 g) containing 4-chloro-2-(4-
nitrobenzoyl)toluene (6b) as colourless solid.
EXPERIMENTAL
Melting points were determined on a Büchi 535 apparatus and
were not corrected. The 1H nmr spectra were recorded on a
Varian Gemini-200, or a Varian Unity Inova 400 spectrometer, at
200 or 400 MHz and at 50.3 or 101 MHz, respectively. Chemical
shifts were reported as d values (ppm) down field from internal
tetramethylsilane.
Step 2: The mixture obtained in Step 1 (30.0 g, 0.11 mole) was
dissolved in acetic anhydride (600 ml) and chromium(VI) oxide
(30.0 g, 0.30 mole) and concentrated sulfuric acid (30 ml) was

992
G. Lukács and G. Simig
Vol. 39
added at 5 °C and the mixture was kept at 0-5 °C for 4 hours. It
was poured into ice (1000 g) and extracted with ethyl acetate (3 x
300 ml). The organic layer was washed with brine (3 x 300 ml),
dried (MgSO4) and evaporated. The oily residue was crystallized
from ethanol (300 ml) to give a mixture of regioisomers (19.1 g)
containing 4-chloro-2-(4-nitrobenzoyl)benzaldehyde acylal (7b)
as colourless solid.
Step 3: Hydrazine monohydrate (34.0 ml, 0.68 mole) was
added to a solution of the mixture of isomers obtained in Step 2
(19.1 g, 0.049 mole) in ethanol (100 ml) and it was refluxed for 3
hours. The crystalline product was collected by filtration and
washed with ethanol and recrystallized from methanol to give 8b
(4.6 g, 11 %, based on 4-nitrobenzoyl chloride used in step 1) as
colourless crystals: mp 225-226 °C. 1H nmr (dimethyl sulfoxide-
d6, 400 MHz): d 9.82 (1H, d, J = 0.9 Hz), 8.47 (2H, d, J = 8.9
Hz), 8.38 (1H, d, J = 8.6 Hz), 8.16 (1H, dd, J = 8.6, 2.0 Hz), 8.06
(2H, d, J = 8.9 Hz), 7.94 (1H, m).
6,7-Dichloro-2-ethoxycarbonyl-4-(4-nitrophenyl)-1,2-dihydro-
phthalazine (10b).
This compound was prepared analogously to 10a starting from
9a (1.0 g, 3.1 mmoles) and ethyl chloroformate (10 ml, 11.4 g,
104.6 mmoles) and recrystallized from ethanol to give 10b
(1.04 g, 85 %) as yellow crystals: mp 238-240 °C. 1H nmr
(dimethyl sulfoxide-d6, 200 MHz): d 8.37 (2H, d, J = 8.8 Hz),
7.87 (2H, d, J = 8.8 Hz), 7.43 (1H, s), 7.30 (1H, s), 4.91 (2H, d),
4.40 (2H, q, J = 7.0 Hz), 1.42 (3H, t, J = 7.0 Hz).
Anal. Calcd. for C17H13Cl2N3O4 (394.22): C, 51.79, H, 3.32,
Cl, 17.99, N, 10.66. Found: C, 51.50, H, 3.34, Cl, 18.03, N,
10.49.
2-Acetyl-6,7-dichloro-4-(4-nitrophenyl)-1,2-dihydrophthalazine
(10c).
This compound was prepared analogously to 10a starting from
9a (0.53 g, 1.6 mmoles) and acetic anhydride (5 ml, 5.4 g,
53.0 mmoles) and recrystallized from methanol to give 10c
(0.46 g, 79 %) as yellow crystals: mp 274-275 °C. 1H nmr
(deuteriochloroform, 400 MHz): d 8.38 (2H, d, J = 8.9 Hz), 7.82
(2H, d, J = 8.9 Hz), 7.41 (1H, s), 7.31 (1H, s), 4.97 (2H, s), 2.43
(3H, s).
Anal. Calcd. for C16H11Cl2N3O3 (364.20): C, 52.76, H, 3.04,
Cl, 19.47, N, 11.54. Found: C, 52.72, H, 3.07, Cl, 19.16, N,
11.52.
Anal. Calcd. for C14H8ClN3O2 (285.68): C, 58.86, H, 2.82, Cl,
12.41, N, 14.71. Found: C, 58.73, H, 2.75, Cl, 12.20, N, 14.46.
6,7-Dichloro-4-(4-nitrophenyl)-1,2-dihydrophthalazine (9a).
Sodium borohydride (1.5 g, 40 mmoles) was added to a
solution of 8a (4.0 g, 12.5 mmoles) in a mixture of methanol
(30 ml) and chloroform (100 ml). After stirring at 25 °C for
3 hours aqueous acetic acid (50 %, 20 ml) was added and the
reaction mixture was extracted with chloroform (3 x 100 ml). The
combined organic layer was washed with water (3 x 50 ml), dried
(MgSO4) and evaporated and recrystallized from methanol to
give 9a (3.5 g, 87 %) as yellow crystals: mp 253-254 °C. 1H nmr
(dimethyl sulfoxide-d6, 400 MHz): d 8.56 (1H, s), 8.33 (2H, d,
J = 9.2 Hz), 7.84 (2H, d, J = 9.2 Hz), 7.63 (1 H, s), 7.27 (1 H, s),
4.20 (2 H, s).
6-Chloro-4-(4-nitrophenyl)-2-phenyloxycarbonyl-1,2-dihydro-
phthalazine (10d).
This compound was prepared analogously to 10a starting from
9b (3.5 g, 12 mmoles) and phenyl chloroformate (30 ml, 37.4 g,
239.1 mmole) and recrystallized from ethanol to give 10d (4.0 g,
82 %) as yellow crystals: mp 208-210 °C. 1H nmr (deuterio-
chloroform, 200 MHz): d 8.37 (2H, d, J = 9.0 Hz), 7.92 (2H, d,
J = 9.0 Hz), 7.52 (1H, dd, J = 8.1, 2.2 Hz), 7.43-7.20 (7H, m),
5.03 (2H, s).
Anal. Calcd. for C14H9Cl2N3O2 (322.15): C, 52.20, H, 2.82,
Cl, 22.01, N, 13.04. Found: C, 51.89, H, 2.83, Cl, 21.82, N,
12.87.
Anal. Calcd. for C21H14ClN3O4 (407.81): C, 61.85, H, 3.46,
Cl, 8.70, N, 10.30. Found: C, 61.64, H, 3.57, Cl, 8.49, N, 10.22.
6-Chloro-4-(4-nitrophenyl)-1,2-dihydrophthalazine (9b).
This compound was prepared analogously to 9a starting from
8b (8.6 g, 30 mmoles) and recrystallized from methanol to give 9b
(5.5 g, 64%) as yellow crystals: mp 220-222 °C. 1H nmr (dimethyl
sulfoxide-d6, 400 MHz): d 8.51 (1H, s), 8.30 (2H, d, J = 8.9 Hz),
7.84 (2H, d, J = 8.9 Hz), 7.51 (1H, dd, J = 8.1, 2.1 Hz), 7.35 (1H,
d, J = 8.1 Hz),7.10 (1H, d, J = 2.1 Hz), 4.19 (2H, s).
Anal. Calcd. for C14H10ClN3O2 (287.70): C, 58.44, H, 3.50,
Cl, 12.32, N, 14.60. Found: C, 58.19, H, 3.57, Cl, 12.65, N,
14.36.
4-(4-Aminophenyl)-6,7-dichloro-2-phenyloxycarbonyl-1,2-
dihydrophthalazine (11a).
A solution of 10a (0.8 g, 1.8 mmoles) in tetrahydrofuran
(30 ml) was hydrogenated in the presence of Raney-Ni (0.4 g) at
room temperature under 10 bar hydrogen pressure. The catalyst
was removed, and the solvent was evaporated. The residue was
recrystallized from methanol (10 ml) to give 11a (0.6 g, 81 %) as
yellow crystals: mp 245-247 °C. 1H nmr (dimethyl sulfoxide-d6,
200 MHz): d 7.92 (1H, s), 7.49-7.21 (8H, m), 6.70 (2H, d, J = 8.5
Hz), 5.60 (2H, s), 4.95 (2H, s).
6,7-Dichloro-4-(4-nitrophenyl)-2-phenoxycarbonyl-1,2-dihydro-
Anal. Calcd. for C21H15Cl2N3O2 (412.28): C, 61.17, H, 3.64,
Cl, 17.23, N, 10.19. Found: C, 60.89, H, 3.67, Cl, 17.01, N, 9.98.
phthalazine (10a).
Phenyl chloroformate (10 ml, 12.5 g, 80 mmoles) was added to
9a (1.0 g, 2.3 mmoles) and the mixture was stirred at 140 °C for
2 hours. After cooling to ambient temperature, the crystalline
product was collected by filtration and recrystallized from
ethanol (20 ml) to give 10a (0.9 g, 89 %) as yellow crystals: mp
4-(4-Aminophenyl)-6,7-dichloro-2-ethoxycarbonyl-1,2-dihydro-
phthalazine (11b).
This compound was prepared analogously to 11a starting from
10b (1.0 g, 2.5 mmoles) and Raney-Ni (0.2 g) in dichloro-
methane (60 ml) and methanol (30 ml) and recrystallized from
methanol to give 11b (0.90 g, 98 %) as yellow crystals: mp
182-184 °C. 1H nmr (deuteriochloroform, 200 MHz): d 7.46 (2H,
d, J = 8.4 Hz), 7.45 (1H, s), 7.37 (1H, s), 6.74 (2H, d, J = 8.4 Hz),
4.81 (2H, s), 4.35 (2H, q, J = 7.3 Hz), 1.38 (3 H, t, J = 7.3 Hz).
1
206-207 °C. H nmr (dimethyl sulfoxide-d6, 200 MHz): d 8.38
(2 H, d, J = 8.8 Hz), 7.90 (2H, d, J = 8.8 Hz), 7.47-7.19 (7H, m),
5.07 (2H, s).
Anal. Calcd. for C21H13Cl2N3O4 (442.26): C, 57.03, H, 2.96,
Cl, 16.03, N, 9.50. Found: C, 56.97, H, 2.93, Cl, 15.93, N, 9.47.

Sep-Oct 2002
Synthesis of New 1,2-Dihydrophthalazines
993
Anal. Calcd. for C17H15Cl2N3O2 (364.24): C, 56.06, H, 4.15,
Cl, 19.47, N, 11.54. Found: C, 55.80, H, 4.21, Cl, 19.29, N,
11.50.
4-(4-Aminophenyl)-2-(N-cyclopropylcarbamoyl)-6,7-dichloro-
1,2-dihydrophthalazine (12c).
This compound was prepared analogously to 12a starting from
11a (0.8 g, 1.9 mmoles) and cyclopropylamine (2.0 ml, 1.63 g,
28.5 mmoles) in dimethylformamide (5 ml) and recrystallized
from isopropanol to give 12c (0.63 g, 91 %) as yellow crystals:
2-Acetyl-4-(4-aminophenyl)-6,7-dichloro-1,2-dihydrophtha-
lazine (11c).
This compound was prepared analogously to 10a starting from
10c (0.86 g, 2.4 mmole) and Raney-Ni (0.2 g) in dichloro-
methane (60 ml) and methanol (30 ml) and recrystallized from
methanol to give 11c (0.78 g, 97 %) as yellow crystals: mp
1
mp 233-234 °C. H nmr (deuteriochloroform, 200 MHz): d 7.38
(1H, s), 7.36 (2H, d, J = 8.4 Hz), 7.36 (1H, s), 6.77 (2H, d, J = 8.4
Hz), 6.65 (1H, s), 4.84 (2H, s), 3.93 (2H, bs), 2.73-2.67 (1H, m),
0.78 (2H, m ), 0.58 (2 H, m).
Anal. Calcd. for C18H16Cl2N4O (375.27): C, 57.61, H, 4.30,
Cl, 18.90, N, 14.93. Found: C, 57.37, H, 4.47, Cl, 19.23, N,
14.97.
1
218-220 °C. H nmr (dimethyl sulfoxide-d6, 200 MHz): d 7.86
(1H, s), 7.40 (1H, s), 7.36 (2H, d, J = 8.5 Hz), 6.67 (2H, d, J = 8.5
Hz), 5.59 (2H, s), 4.87 (2H, s), 2.29 (3H, s).
Anal. Calcd. for C16H13Cl2N3O (334.21): C, 57.50, H, 3.92,
Cl, 21.22, N, 12.57. Found: C, 57.44, H, 4.02, Cl, 21.62, N,
12.31.
4-(4-Aminophenyl)-6,7-dichloro-2-(pyrrolidine-1-carbonyl)-1,2-
dihydrophthalazine (12d).
This compound was prepared analogously to 12a starting from
11a (1.0 g, 2.4 mmoles) and pyrrolidine (0.6 ml, 0.52 g,
7.3 mmoles) in dimethylformamide (8 ml) and recrystallized
from isopropanol to give 12d (0.9 g, 96 %) as yellow crystals: mp
124-126 °C. 1H nmr (deuteriochloroform, 200 MHz): d 7.41 (2H,
d, J = 8.4 Hz), 7.39 (1H, s), 7.36 (1H, s), 6.84 (2H, d, J = 8.4 Hz),
4.61 (2H, s), 4.3 (2H, bs), 3.63 (4H, m), 1.88 (4H, m).
4-(4-Aminophenyl)-6-chloro-2-phenyloxycarbonyl-1,2-dihydro-
phthalazine (11d).
This compound was prepared analogously to 11a starting from
10d (2.0 g, 4.9 mmole) and Raney-Ni (0.4 g) in dichloromethane
(120 ml) and methanol (60 ml) and recrystallized from methanol
to give 11d (1.6 g, 86 %) as yellow crystals: mp 224-226 °C. 1H
nmr (deuteriochloroform, 200 MHz): d 7.54 (2H, d, J = 8.4 Hz),
7.49-7.23 (8H, m), 6.78 (2H, d, J = 8.4 Hz), 4.95 (2H, s), 3.95
(2H, bs).
Anal. Calcd. for C21H16ClN3O2 (377.83): C, 66.75, H, 4.27,
Cl, 9.39, N, 11.12. Found: C, 66.49, H, 4.18, Cl, 9.52, N,
11.33.
Anal. Calcd. for C19H18Cl2N4O (389.29): C, 58.62, H, 4.66, Cl,
18.22, N, 14.39. Found: C, 58.34, H, 4.77, Cl, 17.82, N, 14.05.
4-(4-Aminophenyl)-2-(N-butylcarbamoyl)-6-chloro-1,2-
dihydrophthalazine (12e).
This compound was prepared analogously to 12a starting from
11a (2.0 g, 5.3 mmoles) and butylamine (0.7 ml, 0.51 g,
7.0 mmoles) in dimethylformamide (20 ml). The product was
dissolved in ethyl acetate (10 ml) and hydrochloric acid solution
in ethyl acetate was added to give the hydrochloride salt of 12e
(1.70g, 61 %) as yellow crystals: mp 123-124 °C. 1H nmr
(dimethyl sulfoxide-d6, 400 MHz): d 7.81 (2H, d, J = 8.2), 7.59
(1H, dd, J = 8.0, 2.0), 7.51 (1H, d, J = 8.0), 7.38 (2H, d, J = 8.2),
7.32 (2H, s), 7.14 (1H, d, J = 2.0), 4.76 (2H, s), 3.17 (2H, q,
J =3.6), 1.46 (2H, m), 1.28 (2H, m), 0.88 (3H, t, J = 7.2).
Anal. Calcd. for C19H22Cl2N4O (393.32): C, 58.02, H, 5.60,
Cl, 18.07, N, 14.25. Found: C, 57.71, H, 5.73, Cl, 17.82, N,
13.89.
4-(4-Aminophenyl)-2-(N-butylcarbamoyl)-6,7-dichloro-1,2-
dihydrophthalazine (12a).
Butylamine (0.7 ml, 0.51 g, 7.0 mmoles) was added to a
solution 11a (2.5 g, 6.0 mmoles) in dimethylformamide
(20 ml). After stirring at 60 °C for 3 hours the mixture was
poured into ice (50 g). The crystalline product was filtered and
recrystallized from 2-propanol (5 ml) to give 12a (1.8 g,
77 %) as yellow crystals: mp 169-172 °C. 1H nmr (deuterio-
chloroform, 400 MHz): d 7.40-7.35 (4H, m), 6.78 (2H, d, J =
8.4 Hz), 6.55 (1H, t, J = 6.8 Hz), 4.83 (2H, s), 3.28 (2H, q, J =
6.8 Hz), 1.57-1.51 (2H, m), 1.41-1.35 (2H, m), 0.94 (3H, t, J =
7.6 Hz).
1-(4-Aminophenyl)-6,7-dichlorophthalazine (13a).
A mixture 8a (14.6 g, 46 mmoles), iron powder (15.0 g),
concentrated hydrochloric acid (25 ml) and ethanol (150 ml) was
refluxed for 1 hour. It was filtered, the ethanol was evaporated
and the residue was extracted with chloroform (3 x 100 ml). The
organic layer was washed with water (3 x 50 ml), dried (MgSO4)
and evaporated and recrystallized from ethanol to give 13a
(11.3 g, 85 %) as yellow crystals: mp 198-200 °C. 1H nmr
(dimethyl sulfoxide-d6, 400 MHz): d 9.38 (1H, s), 8.28 (1H, s),
8.10 (1H, s), 7.58 (2H, d, J = 8.8 Hz), 6.87 (2H, d, J = 8.8 Hz),
3.62 (2H, bs).
Anal. Calcd. for C19H20Cl2N4O (391.31): C, 58.32, H, 5.15,
Cl, 18.12, N, 14.32. Found: C, 58.09, H, 5.15, Cl, 17.86, N,
14.04.
4-(4-Aminophenyl)-6,7-dichloro-2-(N-propylcarbamoyl)-1,2-
dihydrophthalazine (12b).
This compound was prepared analogously to 12a starting from
11a (0.75 g, 1.8 mmoles) and propylamine (0.5 ml, 0.36 g,
6.1 mmoles) in dimethylformamide (5 ml) and recrystallized
from isopropanol to give 12b (0.62 g, 91 %) as yellow crystals:
Anal. Calcd. for C14H9 Cl2N3 (290.15): C, 57.95, H, 3.12, Cl,
24.44, N, 14.48. Found: C, 57.63, H, 3.09, Cl, 24.20, N, 14.36.
1
mp 218-219 °C. H nmr (deuteriochloroform, 400 MHz): d 7.39
(2H, s), 7.36 (2H, d, J = 8.4 Hz), 6.77 (2H, d, J = 8.4 Hz), 6.58
(1H, t, J = 6.3), 4.84 (2H, s), 3.93 (2H, bs), 3.30 (2H, q, J = 6.3),
1.59 (2H, m), 0.95 (3H, t, J = 7.4).
Anal. Calcd. for C18H18Cl2N4O (377.28): C, 57.30, H, 4.81,
Cl, 18.79, N, 14.85. Found: C, 57.02, H, 4.84, Cl, 18.77, N,
14.63.
1-(4-Aminophenyl)-7-chlorophthalazine (13b).
This compound was prepared analogously to 13a starting from
6-chloro-4-(4-nitrophenyl)phthalazine 8b (10.86 g, 38 mmoles)
and iron powder (10.0 g, 179 mmoles) in ethanol (100 ml) and
recrystallized from ethanol to give 13b (8.9 g, 92 %) as yellow

994
G. Lukács and G. Simig
Vol. 39
Anal. Calcd. for C17H16ClN3O (313.79): C, 65.07, H, 5.14, Cl,
11.30, N, 13.39. Found: C, 65.31, H, 4.94, Cl, 11.24, N, 13.59.
crystals: mp 224-226 °C. 1H nmr (dimethyl sulfoxide-d6, 200
MHz): d 9.62 (1 H, s), 8.25 (1 H, d, J = 9.5 Hz), 8.07-8.01 (2 H, m),
7.50 (2 H, d, J = 8.4 Hz), 6.83 (2 H, d, J = 8.4 Hz), 5.68 (2 H, s).
Anal. Calcd. for C14H10ClN3 (255.70): C, 65.76, H, 3.94, Cl,
13.87, N, 16.43. Found: C, 65.39, H, 3.99, Cl, 13.97, N, 16.21.
4-(4-Acetaminophenyl)-6,7-dichloro-1-methyl-2-phenyloxycar-
bonyl-1,2-dihydrophthalazine (16a).
A solution of phenyl chloroformate (6 ml, 7.5 g, 47.8 mmoles),
15a (3.2 g, 9 mmoles) and triethylamine (3 ml, 2.18 g,
22 mmoles) in tetrahydrofuran (50 ml) was stirred at 0 °C for 1
hour. The reaction mixture was washed with water (3 x 50 ml),
dried (MgSO4) and evaporated. The residue was separated by
column chromatography (eluent: dichloromethane:methanol,
100:1) and recrystallized from ethanol to give 16a (2.6 g, 62 %)
as yellow crystals: mp 300-302 °C. 1H nmr (dimethyl sulfoxide-
d6, 200 MHz): d 10.20 (1H, s), 7.97 (1H, s), 7.77 (2 H, d, J = 8.9
Hz), 7.62 (2 H, d, J = 8.9 Hz), 7.50-7.25 (6 H, m), 5.76 (1 H, q,
J = 6.4 Hz), 2.09 (3 H, s), 1.36 (3 H, d, J = 6.4 Hz).
1-(4-Acetaminophenyl)-6,7-dichlorophthalazine (14a).
A solution of 13a (14.8 g, 51 mmoles) and acetic anhydride
(20 ml, 21.6 g, 212.0 mmoles) in methanol (400 ml) was stirred at
reflux for 4 hours. The crystalline product was collected by
filtration and washed with methanol to give 14a (14.2 g, 84 %) as
yellow crystals: mp 270-272 °C. 1H nmr (dimethyl sulfoxide-d6,
400 MHz): d 10.22 (1H, s), 9.66 (1H, s), 8.64 (1H, s), 8.15 (1H,
s), 7.84 (2H, d, J = 8.6 Hz), 7.72 (2H, d, J = 8.6 Hz), 2.12 (3H, s).
Anal. Calcd. for C16H11Cl2N3O (332.20): C, 57.85, H, 3.34,
Cl, 21.35, N, 12.65. Found: C, 57.49, H, 3.31, Cl, 20.91, N,
12.65.
Anal. Calcd. for C24H19Cl2N3O3 (468.34): C, 61.55, H, 4.09,
Cl, 15.14, N, 8.97. Found: C, 61.41, H, 4.13, Cl, 14.98, N, 8.90.
1-(4-Acetaminophenyl)-7-chlorophthalazine (14b).
4-(4-Acetaminophenyl)-6-chloro-1-methyl-2-phenyloxy-
This compound was prepared analogously to 14a starting from
13b (5.32 g, 21 mmoles) and acetic anhydride (10 ml, 10.8 g,
106.0 mmoles) in methanol (100 ml) to give 14b (4.6 g, 74 %) as
yellow crystals: mp 224-225 °C. 1H nmr (dimethyl sulfoxide-d6,
200 MHz): d 10.24(1H, s), 9.72 (1H, s), 8.33(1H, d, J = 8.5 Hz),
8.11 (1H, dd, J = 8.5, 1.8 Hz), 7.97 (1H, d, J = 1.8 Hz), 7.85 (2H,
d, J = 8.6 Hz), 7.71 (2H, d, J = 8.6 Hz), 2.13 (3H, s).
carbonyl-1,2-dihydrophthalazine (16b).
This compound was prepared analogously to 16a starting from
15b (1.7 g, 5.4 mmoles), triethylamine (1.2 ml, 0.87 g,
8.6 mmoles) and phenyl chloroformate (1.0 ml, 1.25 g,
8.0 mmoles) in tetrahydrofuran (10 ml) and recrystallized from
isopropanol to give 16b (1.75 g, 75 %) as yellow crystals: mp
1
130-131 °C. H nmr (dimethyl sulfoxide-d6, 200 MHz): d 10.20
Anal. Calcd. for C16H12ClN3O (297.74): C, 64.54, H, 4.06, Cl,
11.91, N, 14.11. Found: C, 64.29, H, 4.03, Cl, 11.73, N, 13.77.
(1H, s), 7.77 (2 H, d, J = 8,4 Hz), 7.69 (1 H, d, J = 8.1, 1.8 Hz),
7.64 (1 H, s), 7.62 (2 H, d, J = 8.4 Hz), 7.49-7.41 (2 H, m),
7.33-7.23 (4 H, m), 5.74 (1 H, q, J = 6.6 Hz), 2.10 (3 H, s), 1.35
(3 H, d, J = 6.6 Hz).
4-(4-Acetaminophenyl)-6,7-dichloro-1-methyl-1,2-dihydroph-
thalazine (15a).
Anal. Calcd. for C24H20ClN3O3 (433.89): C, 66.43, H, 4.65,
Cl, 8.17, N, 9.68. Found: C, 66.05, H, 4.73, Cl, 7.98, N, 9.54.
Methyllithium (1 M solution in tetrahydrofuran, 50 ml,
50 mmoles) was added to a solution of 14a (5.2 g, 16 mmoles) in
tetrahydrofuran (30 ml) at 0 °C and the mixture was stirred at
0 °C for 1 hour. It was poured into water (150 ml), acidified with
aqueous hydrochloric acid solution (10 %) and extracted with
tetrahydrofuran (3 x 50 ml). The organic layer was washed with
brine (3 x 50 ml), dried (MgSO4) and evaporated. The residue
was separeted by column chromatography (eluent:
dichloromethane:methanol, 100:1) and recrystallized from
ethanol to give 15a (3.2 g, 58 %) as yellow crystals: mp
222-224 °C. 1H nmr (dimethyl sulfoxide-d6, 200 MHz): d 10.05
(1H, s), 8.04 (1H, s), 7.66 (2H, d, J = 8.8 Hz), 7.57 (1H, s), 7.46
(2H, d, J = 8.8 Hz), 7.21 (1H, s), 4.27 (1H, q, J = 6.6 Hz), 2.07
(3H, s), 1.37 (3H, d, J = 6.6 Hz).
4-(4-Acetaminophenyl)-2-(N-butylcarbamoyl)-6,7-dichloro-1-
methyl-1,2-dihydrophthalazine (17a).
A solution of 16a (2.5 g, 5.3 mmoles) and butylamine (0.7 ml,
0.51 g, 7 mmoles) in dimethylformamide (20 ml) was stirred at
60 °C for 3 hours. The reaction mixture was poured into ice
(50 g). After filtration the product was recrystallized from
isopropanol to give 17a (1.8 g, 76 %) as yellow crystals: mp
127-128 °C. 1H nmr (deuteriochloroform, 200 MHz): d 7.67 (2H,
d, J = 8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.45 (1H, s), 7.37 (1H, s),
7.33 (1H, s), 6.55 (1H, t, J = 5.9 Hz), 5.75 (1H, q, J = 6.6 Hz),
3.37-3.32 (2H, m), 2.24 (3H, s), 1.62-1.52 (2H, m), 1.43-1.32
(2H, m), 1.27 (3H, d, J = 6.6 Hz), 0.94 (3H, t, J = 7.0 Hz).
Anal. Calcd. for C22H24Cl2N4O2 (447.37): C, 59.03, H, 5.40,
Cl, 15.84, N, 12.52. Found: C, 58.89, H, 5.47, Cl, 15.63, N,
12.14.
Anal. Calcd. for C17H15Cl2N3O (348.24): C, 58.62, H, 4.31,
Cl, 20.40, N, 12.07. Found: C, 58.54, H, 4.25, Cl, 20.33, N,
12.04.
4-(4-Acetaminophenyl)-6-chloro-1-methyl-1,2-dihydrophtha-
lazine (15b).
4-(4-Acetaminophenyl)-2-(N-cyclopropylcarbamoyl)-6,7-
dichloro-1-methyl-1,2-dihydrophthalazine (17b).
This compound was prepared analogously to 15a starting from
14b (4.3 g, 14.4 mmoles) in tetrahydrofuran (100 ml) and
methyllithium (1 M solution in tetrahydrofuran, 40 ml,
40 mmoles) and recrystallized from ethanol to give 15b (2.3 g,
51 %) as yellow crystals: mp 236-238 °C. 1H nmr (dimethyl
sulfoxide-d6, 200 MHz): d 10.06 (1H, s), 8.31 (1H, s), 7.66 (2H,
d, J = 8.8 Hz), 7.46 (2H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 8.1, 1.8
Hz), 7.30 (1H, d, J = 8.1 Hz), 7.05 (1H, d, J = 1.8 Hz), 4.25 (1H,
q, J = 6.4 Hz), 2.08 (3H, s), 1.37 (3H, d, J = 6.4 Hz).
This compound was prepared analogously to 17a starting from
16a (1.0 g, 2.1 mmoles) in tetrahydrofuran (8 ml) and
cyclopropylamine (2.0 ml, 0.12 g, 29 mmoles) and recrystallized
from ethanol to give 17b (0.67 g, 74 %) as yellow crystals: mp
157-158 °C. 1H nmr (deuteriochloroform, 400 MHz): d 7.75 (1H,
s), 7.69 (2H, d, J = 8.5 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.36 (1H, s),
7.33 (1H, s), 6.65 (1H, d, J = 1.8 Hz), 5.75 (1H, q, J = 6.7 Hz),
2.75-2.69 (1H, m), 2.25 (3H, s), 1.28 (3H, d, J = 6.7 Hz)
0.80-0.77 (2H, m), 0.59-0.58 (2H, m).

Sep-Oct 2002
Synthesis of New 1,2-Dihydrophthalazines
995
1Hnmr (deuteriochloroform, 400 MHz): d 7.44 (2H, d, J = 8.4 Hz),
7.39 (1H, s), 7.33 (1H, s), 6.96 (2H, d, J = 8.4 Hz), 6.63 (1H, d,
J = 1.6 Hz), 5.74 (1H, q, J = 6.7 Hz), 2.74-2.70 (1H, m), 1.27 (3H,
d, J = 6.7 Hz), 0.81-0.76 (2H, m), 0.60-0.56 (2H, m).
Anal. Calcd. for C21H20Cl2N4O2 (431.33): C, 58.48, H, 4.67,
Cl, 16.44, N, 12.99. Found: C, 58.18, H, 4.74, Cl, 16.37, N,
12.62.
4-(4-Acetaminophenyl)-6,7-dichloro-1-methyl-2-(pyrrolidine-1-
Anal. Calcd. for C19H18Cl2N4O (389.29): C, 58.61, H, 4.63,
Cl, 18.25, N, 14.40. Found: C, 58.35, H, 4.53, Cl, 18.05, N,
14.15.
carbonyl)-1,2-dihydrophthalazine (17c).
This compound was prepared analogously to 17a starting
from 16a (0.8 g, 1.7 mmoles) in tetrahydrofuran (8 ml) and
pyrrolidine (2.0 ml, 1.72 g, 24.2 mmoles) and recrystallized
from isopropanol to give 17c (0.6 g, 79 %) as yellow crystals:
mp 119-120 °C. 1H nmr (deuteriochloroform, 200 MHz): d
7.67 (2H, d, J = 8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.38 (1H, s),
7.32 (1H, s), 5.45 (1H, q, J = 6.4 Hz), 3.82-3.66 (2H, m),
3.60-3.44 (2H, m), 2.24 (3H, s), 2.05-1.85 (2H, m), 1.85-1.60
(3H, m), 1.34 (3H, d, J = 6.4 Hz).
4-(4-Aminophenyl)-2-(pyrrolidine-1-carbonyl)-6,7-dichloro-1-
methyl-1,2-dihydrophthalazine (18c).
This compound was prepared analogously to 18a starting
from 17c (1.1 g, 2.5 mmoles), aqueous sodium hydroxide
solution (40 %, 8 ml) in methanol (20 ml) and recrystallized
from ethanol to give 18c (0.8 g, 79 %) as yellow crystals: mp
134-135 °C. 1H nmr (deuteriochloroform, 400 MHz): d 7.43
(1H, s), 7.40 (2H, d, J = 8.5 Hz), 7.30 (1H, s), 6.77 (2H, d, J =
8.5 Hz), 5.43 (1H, q, J = 6.6 Hz), 3.89 (2H, s), 3.80-3.65 (2H,
m), 3.54-3.49 (2H, m), 2.00-1.90 (2H, m), 1.85-1.70 (2H, m),
1.33 (3H, d, J = 6.6).
Anal. Calcd. for C22H22Cl2N4O2 (445.35): C, 59.33, H, 4.98,
Cl, 15.92, N, 12.58. Found: C, 58.99, H, 5.02, Cl, 16.22, N,
12.27.
4-(4-Acetaminophenyl)-2-(N-butylcarbamoyl)-6-chloro-1-
methyl-1,2-dihydrophthalazine (17d).
Anal. Calcd. for C20H20Cl2N4O (403.32): C, 59.56, H, 5.00,
Cl, 17.58, N, 13.89. Found: C, 59.23, H, 5.09, Cl, 17.33, N,
13.58.
This compound was prepared analogously to 17a a starting
from 16b (1.5 g, 3.5 mmoles) in tetrahydrofuran (10 ml) and
butylamine (3.0 ml, 2.2 g, 30 mmoles) and recrystallized from
ethanol to give 17d (1.4 g, 97 %) as yellow crystals: mp
125-127°C. 1H nmr (deuteriochloroform, 200 MHz): d 7.93 (1H,
s), 7.71 (2H, d, J = 8.6 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.41 (1H,
dd, J = 8.1, 2.2 Hz), 7.27 (1H, d, J = 2.2 Hz), 7.16 (1H, d, J = 8.1
Hz), 6.60 (1H, t), 5.77 (1H, q, J = 7.0 Hz), 3.41-3.29 (2H, m),
2.25 (3H, s), 1.63-1.49 (2H, m), 1.47-1.32 (2H, m), 1.27 (3H, d,
J = 6.6 Hz), 0.94 (3H, t, J = 7.0 Hz).
4-(4-Aminophenyl)-2-(N-butylcarbamoyl)-6-chloro-1-methyl-
1,2-dihydrophthalazine (18d).
This compound was prepared analogously to 18a starting from
17d (1.1 g, 2.7 mmoles), aqueous sodium hydroxide solution
(40 %, 8 ml) in methanol (20 ml). The product was recrystallized
from ethanol, dissolved in ethyl acetate (10 ml) and hydrochloric
acid solution in ethyl acetate was added to give the hydrochloride
1
salt of 18d (0.35 g, 32 %) as yellow crystals: mp 178-180 °C. H
Anal. Calcd. for C22H25ClN4O2 (412.92): C, 63.99, H, 6.10,
Cl, 8.59, N, 13.57. Found: C, 63.69, H, 6.12, Cl, 8.50, N, 13.28.
nmr (dimethyl sulfoxide-d6, 400 MHz): d 7.73 (2H, d, J = 8.3
Hz), 7.61 (1H, dd, J = 8.2, 2.0 Hz), 7.52 (1H, d, J = 8.2 Hz), 7.29
(1H, t, J = 5.8 Hz), 7.19 (1H, d, J = 2.0 Hz), 7.17 (2H, d, J = 8.3
Hz), 5.68 (1H, q, J = 6.6 Hz), 4.65 (2H, bs), 3.19 (2H, q, J = 6.6
Hz), 1.50-1.43 (2 H, m), 1.33-1.24 (2H, m), 1.12 (3H, d, J = 6.6
Hz), 0.89 (3H, t, J = 7.3 Hz).
Anal. Calcd. for C20H24Cl2N4O (406.34): C, 58.97, H, 5.94,
Cl, 17.41, N, 13.75. Found: C, 58.78, H, 6.15, Cl, 17.22, N,
13.94.
4-(4-Aminophenyl)-2-(N-butylcarbamoyl)-6,7-dichloro-1-
methyl-1,2-dihydrophthalazine (18a).
A solution of 17a (2.5 g, 5.6 mmoles) and aqueous sodium
hydroxide solution (40 %, 8 ml) in methanol (20 ml) was
refluxed for 3 hours. The reaction mixture was extracted with
ethylacetate (3 x 20 ml), the organic layer was washed with
brine (3 x 20 ml), dried (MgSO4) and evaporated. Chroma-
tography over silicagel (eluent: dichloromethane:methanol,
100:1) and recrystallization from isopropanol gave 18a (2.1 g,
93 %) as yellow crystals: mp 101-102 °C. 1H nmr (deuteri-
ochloroform, 200 MHz): d 7.43 (2H, d, J = 8.6 Hz), 7.41
(1H, s), 7.32 (1H, s), 6.88 (2H, d, J = 8.6 Hz), 6.55 (1H, t, J =
5.9 Hz), 5.74 (1H, q, J = 6.6 Hz), 3.36-3.32 (2H, m), 1.57-1.53
(2H, m), 1.41-1.35 (2 H, m), 1.26 (3H, d, J = 6.6 Hz), 0.94
(3H, t, J = 7.3 Hz).
REFERENCES AND NOTES
[1] T. P. Hicks, in CNS Neurotransmitter and Neuromodulators,
Glutamate,T. W. Stone, ed, CRC, New York, 1995; pp 201-215.
[2] G. Ábrahám, S. Sólyom, E. Csuzdi, P. Berzsenyi, I. Ling,
I. Tarnawa, T. Hámori, I. Pallagi, K. Horváth, F. Andrási, G. Kapus,
L.G.Hársing, I. Király, M. Patthy and Gy. Horváth, Bioorg. Med. Chem.,
8, 2127 (2000) and references cited therein.
[3] B. A. Anderson, N. K. Harn, M. M. Hansen, A. R. Harkness,
D. Lodge and J. D. Leander, Bioorg. Med. Chem. Lett., 9, 1953 (1999)
and references cited therein.
Anal. Calcd. for C20H22Cl2N4O (405.33): C, 59.26, H, 5.47,
Cl, 17.49, N, 18.82. Found: C, 59.58, H, 5.49, Cl, 17.17, N,
13.61.
4-(4-Aminophenyl)-2-(N-cyclopropylcarbamoyl)-6,7-dichloro-
1-methyl-1,2-dihydrophthalazine (18b).
[4] J. C. Pelletier, D. P. Hesson, K. A. Jones and A.-M. Costa,
J.Med. Chem. 39, 343 (1996).
This compound was prepared analogously to 18a starting from
17b (1.0 g, 2.3 mmoles), aqueous sodium hydroxide solution
(40 %, 8 ml) in methanol (20 ml) and recrystallized from methanol
to give 18b (0.6 g, 67 %) as yellow crystals: mp 240-242 °C.
[5] I. Ling, G. Ábrahám, P. Berzsenyi, I. Tarnawa, S. Sólyom,
F. Andrási, T. Hámori, E. Csuzdi, K. Horváth, M. Gál, I. Moravcsik
and M. Szöllosy, UK Pat. Appl. 2,311,779; Chem. Abstr. 128, 61530f
''
(1998).

996
G. Lukács and G. Simig
Vol. 39
[6] Xue-Feng Pei, M. A. Sturgess, C. F. Valenzuela and M.-L.
E. H. Wood and J. R. Johnson, in Organic Syntheses, Coll. Vol. III.,
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A. Egyed, WO Pat. Appl. 00,39,100 (2000); Chem.Abstr., 133, 89535
(2000).
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P. Eden, J. H. Gogerty, W. J. Houlihan and C. Penberthy, J. Med. Chem.
18, 177 (1975).
[10] For benzoylation of 4-chlorotoluene see: H. de Diesbach and
P. Dobbelmann, Helv. Chim. Acta, 14, 369 (1931).
[11] R. F. Smith and E. D. Otremba, J. Org. Chem. 27, 879 (1962).
[12] For analogy see: S. A. Mahood and P. V. L. Schaffner, in
Organic Syntheses, Coll. Vol. II., Wiley, New York, 1943, p 160 and
B. A. Fox and T. L. Threlfall, in Organic Syntheses,Coll. Vol. V., Wiley,
New York, 1973, p 346.
[13] A. Hirsch and D. G. Orphanos, J. Heterocyclic Chem. 3, 38
(1966).
[9] For analogy see: S. V. Liebermann and R. Connor, in Organic
Syntheses, Coll. Vol. II., Wiley, New York, 1943, p 441 and S. M. Tsang,