Preparation of 4-substituted 3-amino-2-chloropyridines, synthesis of a nevirapine analogue

Article abstract of DOI:10.1002/jhet.5570380114

A new method for preparing 3-amino-2-chloropyridines with a substituent (methyl, phenyl, carboxamide, methoxycarbonyl, acetyl, benzoyl and cyano) at the 4-position has been developed. An isoquinoline analogue of the reverse transcriptase inhibitor Nevirapine has been synthesized from the 4-amino-3-chloroisoquinoline.

Full text of DOI:10.1002/jhet.5570380114

Jan-Feb 2001
Preparation of 4-Substituted 3-Amino-2-chloropyridines,
Synthesis of a Nevirapine Analogue
J. M. Bakke* and J. Riha
99
Department of Chemistry, Norwegian University of Science and Technology, N-7491 Trondheim, Norway
Received April 17, 2000
A new method for preparing 3-amino-2-chloropyridines with a substituent (methyl, phenyl, carbox-
amide, methoxycarbonyl, acetyl, benzoyl and cyano) at the 4-position has been developed. An isoquinoline
analogue of the reverse transcriptase inhibitor Nevirapine has been synthesized from the 4-amino-3-
chloroisoquinoline.
J. Heterocyclic Chem., 38, 99 (2001).
Introduction.
acetate with cyanoacetamide to form the pyridine skeleton
giving 44% and 59% overall yields of 3-amino-2-chloro-
4-methylpyridine in 6 steps. Two other five-step routes
via the 3-amino-4-methylpyridine involve initial nitration
of the starting 2-amino-4-methylpyridine, but the required
3-nitro-isomer was obtained in 28-32% yields only, with
the 5-nitro-isomer as the major reaction product together
with extensive oxidative decomposition of the starting
substrate [3]. The easiest way of producing 3-amino-4-
methylpyridine would be nitration of the 4-methyl-
pyridine and subsequent reduction. However, due to the
electron-deficient nature of the pyridine ring, direct nitra-
tion of methylpyridines affords very poor yields [4].
Similar results have been obtained with other pyridine
substrates; for example, pyridine itself has been nitrated
under harsh conditions [5] in a 5% yield. Usually at least
two electron-donating substituents are necessary for the
nitration to take place successfully.
3-Amino- and 3-amino-2-chloropyridines with
substituents at the 4-position are simple, but valuable
substrates. These compounds are used as pharmaceuticals
or their intermediates. For instance, 3,4-diaminopyridine
[1,2] is a drug for the treatment of Lambert-Eaton
myasthenic syndrome and Nevirapine (I) is the first
non-nucleoside HIV-1 reverse transcriptase inhibitor [3]
approved for clinical use. In addition, an amino group at
the 3-position on a pyridine ring can react with a number
of electrophiles or be replaced by a diazotization reaction.
Halides at the 2-position can, on the other hand, undergo
nucleophilic substitution reactions. These transformations
potentially lead to a wide variety of 2,3,4-substituted
pyridines, compounds that have not been readily available
before due to low yielding, multi-step preparations.
We now wish to report a general synthetic route to
4-substituted 3-amino-2-chloropyridines, based on direct
nitration of the pyridine substrates, followed by reduction
and chlorination (Scheme 1).
Some time ago we discovered a new nitration procedure
for pyridine compounds at the 3-position [6]. Pyridine
substrates were reacted with dinitrogen pentoxide and the
resulting N-nitropyridinium nitrate reacted further with an
aqueous solution of sulfur dioxide and hydrogen sulfite
-
ion (SO /HSO ). This gave moderate to good yields of
2
3
3-nitropyridines. The mechanism of the nitration reaction
has also been thoroughly studied [7,8]. This method was
used to prepare compounds 2a-h; the yields of the nitra-
tions are summarized in Table 1.
There are generally two methods of introducing chlo-
rine at the 2-position on the pyridine ring; one involves a
nucleophilic chlorination of the 3-nitropyridines, the other
an electrophilic chlorination reaction on the 3-amino-
pyridines.
Scheme 1
First we applied a 'nucleophilic approach'.
Unfortunately, the nitropyridines were not sufficiently
reactive and treatment with phosphorus oxychloride under
reflux did not afford the desired product. To activate the
pyridine ring for nucleophilic attack, nitropyridine
compounds were transformed to 1-oxides and then
reacted with phosphorus oxychloride. In this case, the
chlorination reaction took place with simultaneous
deoxygenation [9]. The product mixture contained 2- and
6-chloro-3-nitropyridines, deoxygenated 3-nitropyridine
Results and discussion.
The synthesis of 4-substituted 3-amino-2-chloro-
pyridines, especially 3-amino-2-chloro-4-methylpyridine
has previously been extensively studied [3] as it is a piv-
otal intermediate in the commercial production of
Nevirapine. Four different routes have been evaluated.
Two of them involve initial condensation of ethylaceto-

Vol. 38
J. M. Bakke and J. Riha
100
Table 1
Substrate
Procedure yields (%)
Nitration
Reduction
Chlorination
Dichlorination
at 2-position[a]
(2- and 6-
positions)[b]
1a (R = methyl)
1b (R = phenyl)
70 (2a)
68 (2b)
50 (2c)
75 (2d)
75 (2e)
74 (2f)
45 (2g)
42 (2h)
97 (3a)
98 (3b)
98 (3c)
97 (3d)
69 (3e)
83 (3f)
88 (3g)
97 (3h)
89 (4a)
87 (4b)
58 (4c)
42 (4d)
46 (4e)
47 (4f)
12 (4g)
86 (4h)
5
5
1c (R = carboxamide)
1d (R = methoxycarbonyl)
1e (R = acetyl)
1f (R = benzoyl)
1g (R = cyano)
13
22
14
17
12
6
1h Isoquinoline
[a] Isolated yields. [b] Yields determined by GC.
substrate and some starting compound. Although the
'nucleophilic approach' did not fail, the yields were only
moderate. In addition, the chlorination was not selective
and afforded barely separable 2- and 6-chloro-isomers.
The other approach involved an electrophilic chlorina-
tion reaction on the 3-aminopyridines. The 4-substituted
3-nitropyridines 2a-g and 4-nitroisoquinoline 2h were
therefore reduced to the amino derivatives 3a-h.
Substrates 2a, 2b, 2c, 2d, 2g and 2h were reduced with
hydrogen in the presence of a palladium catalyst.
Compounds 2e and 2f, possessing a ketone group, were
reduced with sodium hyposulfite [10] to prevent reduction
of the ketone group to an alcohol group.
Electrophilic chlorination reactions on compounds 3a-h
gave 3-amino-2-chloropyridines 4a-g and 4-amino-3-
chloroisoquinoline 4h. Four different chlorination
methods [11] have been tried: 1. Gaseous chlorine from a
cylinder, 2. sodium hypochlorite solution, 3. chlorine
generated in situ by oxidation of concentrated hydro-
chloric acid with potassium chlorate and 4. chlorine
generated in situ by oxidation of hydrochloric acid with
hydrogen peroxide. Procedure 4 [12] run at 20 °C gave
the best results both as to yield and composition of the
product mixture. Yields were generally higher for
substrates with an electron-donating 4-substituent [12],
however chlorination was possible even with electron-
withdrawing groups at the 4-position. A typical side-reac-
tion was dichlorination at the 2- and 6-positions of the
pyridine ring. Previously unreported chlorination of
4-aminoisoquinoline 3h proceeded at the 3-position,
analogously to the reaction on the pyridine ring.
As mentioned above, 3-amino-2-chloro-4-methyl-
pyridine is an intermediate in the synthesis of the
non-nucleoside reverse transcriptase inhibitor Nevirapine
(I). However, due to the rapid reverse transcriptase muta-
tion [13], there is a constant need to develop new drugs
with improved profiles. The SAR study of dipyrido-
diazepinones [14] showed that the best activity was
achieved with a methyl group at the 4-position, although
4-chloro and 4-ethyl compounds were also highly active.
In contrast, electron-donating, electron-withdrawing,
and/or hydrophilic groups reduced the activity. With
4-amino-3-chloroisoquinoline 4h in our hands, we synthe-
sized an isoquinoline analogue of Nevirapine 7h (Scheme
2) with a fused benzene ring instead of a methyl group
that would likely fulfil the above mentioned activity crit-
eria. The 4-amino-3-chloropyridine 4h was first
condensed [14,15] with 2-chloronicotinoyl chloride to
Scheme 2

Jan-Feb 2001
Preparation of 4-Substituted 3-Amino-2-chloropyridines
101
evaporated to give a light beige solid, yield 8.43 g (74%), mp
105-106 °C, H NMR (300 MHz, deuteriochloroform): δ 7.44
give 2-chloro-N-(3-chloro-4-isoquinolyl)-3-pyridine-
carboxamide 5h in 75% yield that was further reacted
with cyclopropylamine in dimethyl sulfoxide to yield
N-(3-chloro-4-isoquinolyl)-2-cyclopropylamino-3-
pyridinecarboxamide 6h in 86% yield.Treatment o6fh
with sodium hydride resulted in cyclization of the diazepin
ring to afford the Nevirapine analogue 7h in 15%. The
antiviral activity of 7h has not yet been evaluated.
1
(1H, d, J = 4.9, H-5), 7.49 (2H, m, H-3',5'), 7.65 (1H, tt, J = 7.6,
1.2, H-4'), 7.74 (2H, m, H-2',6'), 9.01 (1H, d, J = 4.9, H-6), 9.49
(1H, s, H-2), ir (FT): 636, 700, 850, 1276, 1315, 1354, 1526,
-1
+
1596, 1672 cm , ms: 228 (M ).
Anal. Calcd. for C H N O : C, 63.16; H, 3.53; N, 12.28.
12
8 2 3
Found: C, 63.24; H, 3.97; N, 12.24.
General Hydrogenation Procedure to Prepare Compounds 3a,
3b, 3c, 3d, 3g and 3h.
Conclusion.
We have shown that it is possible to synthesize a
number of 4-substituted 3-amino-2-chloropyridines by a
sequence of nitration, reduction and chlorination of the
pyridine compounds (Scheme 1). An isoquinoline
analogue 7h of the reverse transcriptase inhibitor
Nevirapine (I) has been synthesized (Scheme 2).
A nitropyridine or isoquinoline (5 mmoles) was hydrogenated
for 5 hours at room temperature in methanol (15 ml) in the pres-
ence of 5% Pd/C (100 mg) at a constant hydrogen pressure of 5
bars. The catalyst was removed by filtration and the filtrate
evaporated to give a product.
3-Amino-4-methylpyridine (3a).
Compound 3a was obtained in 97% yield (525 mg) of a color-
1
EXPERIMENTAL
less solid, mp 104-106 °C, H NMR (400 MHz, dimethyl-d
6
sulfoxide): δ 2.05 (3H, s, CH ), 5.05 (2H, broad s, NH ), 6.90
3
2
(1H, d, J = 4.7, H-5), 7.65 (1H, d, J = 4.7, H-6), 7.89 (1H, s,
The NMR spectra were recorded on Bruker DPX 300 and 400
MHz spectrometers (tetramethylsilane as the internal standard).
Mass spectra were recorded on a Fisons Instruments TRIO 1000
GC-MS System and Finnigan MAT 95 XL instrument. Melting
points were determined on a Büchi oil bath apparatus and are
uncorrected. Elemental analyses were determined by the
Laboratory of Organic Elemental Analysis, Prague Institute of
Chemical Technology, Czech Republic. Dinitrogen pentoxide
was prepared from dinitrogen tetroxide and ozone [16],
2-chloronicotinoyl chloride from 2-chloronicotinic acid [15].
Synthesis and spectral data of the nitropyridines 2a, 2b, 2d, 2e,
2g and 4-nitroisoquinoline 2h have previously been reported [6].
H-2), ir (FT): 814, 864, 1067, 1293, 1324, 1415, 1501, 1564,
-1
+
1593, 1631, 3203, 3328, 3443 cm , ms: 108 (M ).
Anal. Calcd. for C H N : C, 66.64; H, 7.46; N, 25.90. Found:
6
8 2
C, 66.25; H, 7.02; N, 25.53.
3-Amino-4-phenylpyridine (3b).
Compound 3b was obtained in 98% yield (835 mg) of a light
1
yellow solid, mp 79-80 °C, H NMR (400 MHz, deuteriochloro-
form): δ 3.81 (2H, broad s, NH ), 7.03 (1H, d, J = 4.8, H-5),
2
7.36-7.51 (5H, m, H-2',3',4',5',6'), 8.07 (1H, d, J = 4.8, H-6),
8.16 (1H, s, H-2), ir (FT): 700, 742, 776, 827, 1229, 1330, 1416,
-1
+
1547, 1634, 3157, 3432 cm , ms: 170 (M ).
Anal. Calcd. for C N : C, 77.62; H, 5.92; N, 16.46.
3-Nitroisonicotinamide (2c).
H
11 10
2
Dinitrogen pentoxide (8.64 g, 80 mmoles) was dissolved in
liquid sulfur dioxide (50 ml) at -38 °C and isonicotinamide
(6.11 g, 50 mmoles) was added in portions. The mixture was
stirred for 5 minutes at -38 °C, then poured onto ice (100 g) and
stirred overnight (16 hours) at room temperature. The mixture
was then neutralized with 5 M sodium hydroxide solution to pH
8 and extracted with ethyl acetate (3 x 200 ml). Combined
organic phase was washed with 1 M hydrochloric acid (50 ml),
dried over potassium carbonate and evaporated to give a color-
Found: C, 77.69; H, 5.94; N, 16.52.
3-Aminoisonicotinamide (3c).
A water/methanol mixture (1:1) was used as the solvent for
hydrogenation, yield 670 mg (98%) of a colorless solid, mp
1
150-152 °C, H NMR (300 MHz, dimethyl-d sulfoxide): δ 6.59
6
(2H, broad s, NH ), 7.39 (1H, d, J = 5.2, H-5), 7.42 (1H, broad
2
s, CONH), 7.71 (1H, d, J = 5.2, H-6), 8.00 (1H, broad s,
CONH), 8.11 (1H, s, H-2), ir (FT): 647, 788, 837, 1082, 1116,
1
-1
+
less solid, yield 4.16 g (50%), mp 168-170 °C, H NMR (300
1230, 1581, 1632, 3167, 3321 cm , ms: 137 (M ).
Anal. Calcd. for C H N O: C, 52.55; H, 5.14; N, 30.64.
MHz, dimethyl-d sulfoxide): δ 7.68 (1H, d, J = 4.9, H-5), 7.97
6
6 7 3
(1H, broad s, CONH), 8.31 (1H, broad s, CONH), 8.96 (1H, d,
Found: C, 52.52; H, 5.34; N, 30.48.
J = 4.9, H-6), 9.23 (1H, s, H-2), ir (FT): 629, 864, 1357, 1390,
Methyl 3-Aminoisonicotinate (3d).
-1
+
1524, 1606, 1682, 3164, 3365 cm , ms: 167 (M ).
Anal. Calcd. for C H N O : C, 43.12; H, 3.02; N, 25.14.
Compound 3d was obtained in 97% yield (740 mg) of a light
6
5 3 3
1
yellow solid, mp 81-83 °C, H NMR (400 MHz, deuteriochloro-
Found: C, 43.33; H, 3.33; N, 25.15.
form): δ 3.91 (3H, s, CH ), 5.70 (2H, broad s, NH ), 7.58 (1H,
d, J = 5.3, H-5), 7.93 (1H, d, J = 5.3, H-6), 8.20 (1H, s, H-2), ir
3
2
4-Benzoyl-3-nitropyridine (2f).
Dinitrogen pentoxide (8.64 g, 80 mmoles) was dissolved in
liquid sulfur dioxide (50 ml) at -38 °C and 4-benzoylpyridine
(9.16 g, 50 mmoles) was added in portions. The mixture was
stirred for 5 minutes at -38 °C, then poured onto ice (300 g) and
stirred overnight (16 hours) at room temperature. The precipitate
was filtered and dissolved in dichloromethane (200 ml). The
solution was washed with saturated sodium bicarbonate solution
(100 ml) and water (100 ml), dried over sodium sulfate and
(FT): 675, 786, 1128, 1198, 1235, 1318, 1425, 1619, 1701,
-1
+
3132, 3435 cm , ms: 152 (M ).
Anal. Calcd. for C H N O : C, 55.26; H, 5.30; N, 18.41.
7
8 2 2
Found: C, 55.18; H, 5.37; N, 18.41.
3-Amino-4-cyanopyridine (3g).
The crude product was crystallized from water, yield 524 mg
1
(88%) of colourless crystals, mp 140-141 °C, H NMR (300

Vol. 38
J. M. Bakke and J. Riha
102
MHz, dimethyl-d sulfoxide): δ 6.41 (2H, broad s, NH ), 7.34
(1H, d, J = 5.0, H-5), 7.77 (1H, d, J = 5.0, H-6), 8.21 (1H, s,
(2x20 ml). The organic phase was dried over sodium sulfate and
evaporated. The residue was purified by flash chromatography
on silica gel (eluent: 2-5% acetone in dichloromethane) to yield
a product.
6
2
H-2), ir (FT): 808, 1247, 1425, 1563, 1651, 2225, 3179, 3397
-1
+
cm , ms: 119 (M ).
Anal. Calcd. for C H N : C, 60.50; H, 4.23; N, 35.27. Found:
6
5 3
3-Amino-2-chloro-4-methylpyridine (4a).
C, 60.33; H, 4.43; N, 35.40.
Compound 4a was obtained in 89% yield (635 mg) of a color-
less solid, mp 66-67 °C, H NMR (400 MHz, deuteriochloro-
4-Aminoisoquinoline (3h).
1
Compound 3h was obtained in 97% yield (980 mg) of a beige
form): δ 2.21 (3H, s, CH ), 4.03 (2H, broad s, NH ), 6.93 (1H,
3
2
1
solid, mp 107-109 °C, H NMR (300 MHz, deuteriochloro-
d, J = 4.7, H-5), 7.71 (1H, d, J = 4.7, H-6), ir (FT): 820, 860,
-1
+
form): δ 4.09 (2H, broad s, NH ), 7.57 (1H, ddd, J = 8.2, 6.9,
1376, 1418, 1439, 1590, 1629, 3196, 3428 cm , ms: 142 (M ).
Anal. Calcd. for C H N Cl: C, 50.54; H, 4.95; N, 19.65.
2
1.2, H-7), 7.65 (1H, ddd, J = 8.3, 6.9, 1.4, H-6), 7.80 (1H, dd, J
= 8.3, 1.2, H-5), 7.91 (1H, dd, J = 8.2, 1.4, H-8), 8.04 (1H, s, H-
3), 8.73 (1H, s, H-1), ir (FT): 584, 747, 779, 847, 1333, 1403,
6
7 2
Found: C, 50.96; H, 5.02; N, 19.19.
3-Amino-2-chloro-4-phenylpyridine (4b).
-1
+
1461, 1509, 1574, 1646, 3171, 3413 cm , ms: 144 (M ).
Anal. Calcd. for C H N : C, 74.98; H, 5.59; N, 19.43. Found:
9
8
2
Compound 4b was obtained in 87% yield (890 mg) of a
C, 75.17; H, 5.78; N, 19.42.
Compounds 2e and 2f were reduced with sodium hyposulfite
according to procedure described in reference [10].
1
colourless solid, mp 100-102 °C, H NMR (400 MHz, deuteri-
ochloroform): δ 4.21 (2H, broad s, NH ), 6.99 (1H, d, J = 4.7,
2
H-5), 7.41-7.45 (3H, m, H-2',4',6'), 7.48-7.52 (2H, m, H-3',5'),
7.83 (1H, d, J = 4.7, H-6), ir (FT): 709, 766, 1075, 1101, 1276,
4-Acetyl-3-aminopyridine (3e).
-1
+
1412, 1485, 1620, 3306, 2467 cm , ms: 204 (M ).
Anal. Calcd. for C H N Cl: C, 64.56; H, 4.43; N, 13.69.
4-Acetyl-3-nitropyridine (2e, 8.3 g, 50 mmoles) and sodium
hyposulfite (52.2 g, 300 mmoles) in 95% ethanol (500 ml) were
refluxed for 6 hours. The mixture was then cooled and the
solvent evaporated. The residue was partitioned between ethyl
acetate (200 ml) and water (200 ml). The organic phase was
separated, and the aqueous phase was reextracted with ethyl
acetate (200 ml). The combined organic phase was dried over
11
9 2
Found: C, 64.73; H, 4.60; N, 13.63.
3-Amino-2-chloroisonicotinamide (4c).
After chlorination and neutralization, the reaction mixture was
extracted with ethylacetate, dried over sodium sulfate, evapo-
rated and the residue purified by flash chromatography on silica
sodium sulfate and evaporated to give a yellow solid, yield 4.7 g
gel (eluent:ethylacetate) to yield 500 mg (58%) of a colorless
1
(69%), mp 89-91 °C, H NMR (400 MHz, dimethyl-d sulf-
6
1
solid, mp 183-184 °C, H NMR (400 MHz, dimethyl-d sulf-
6
oxide): δ 2.53 (3H, s, CH ), 7.13 (2H, broad s, NH ), 7.54 (1H,
3
2
oxide): δ 6.76 (2H, broad s, NH ), 7.51 (1H, d, J = 5.0, H-5),
2
d, J = 5.3, H-5), 7.77 (1H, d, J = 5.3, H-6), 8.24 (1H, s, H-2), ir
7.61 (1H, d, J = 5.0, H-6), 7.67 (1H, broad s, CONH), 8.18 (1H,
(FT): 616, 1039, 1215, 1358, 1422, 1609, 1658, 3118, 3276,
broad s, CONH), ir (FT): 677, 780, 1117, 1252, 1395, 1575,
-1
+
3441 cm , ms: 136 (M ).
Anal. Calcd. for C H N O: C, 61.75; H, 5.92; N, 20.57.
-1
+
1600, 1698, 3160, 3368 cm , ms: 171 (M ).
Anal. Calcd. for C H N ClO: C, 42.00; H, 3.52; N, 24.49.
7
8 2
6
9 3
Found: C, 61.26; H, 5.94; N, 20.53.
Found: C, 42.03; H, 3.59; N, 24.07.
3-Amino-4-benzoylpyridine (3f).
Methyl 3-Amino-2-chloroisonicotinate (4d).
Compound 4d was obtained in 42% yield (390 mg) of a
4-Benzoyl-3-nitropyridine (2f, 2.23 g, 10 mmoles) and
sodium hyposulfite (10.4 g, 60 mmoles) in 95% ethanol (100
ml) were refluxed for 6 hours. The mixture was then cooled and
the solvent evaporated. The residue was partitioned between
dichloromethane (50 ml) and water (50 ml). The organic phase
was separated, and the aqueous phase was re-extracted with
dichloromethane (50 ml). The combined organic phase was
dried over sodium sulfate and evaporated to give a yellow solid,
1
colourless solid, mp 95-96 °C, H NMR (400 MHz, deuteri-
ochloroform): δ 3.94 (3H, s, CH ), 6.23 (2H, broad s, NH ),
3
2
7.61 (1H, d, J = 5.2, H-5), 7.72 (1H, d, J = 5.2, H-6), ir (FT):
726, 784, 1041, 1224, 1250, 1300, 1420, 1606, 1708, 3305, 3431
-1
+
cm , ms: 186 (M ).
Anal. Calcd. for C H N O Cl: C, 45.06; H, 3.78; N, 15.01.
7
7 2 2
Found: C, 44.86; H, 3.89; N, 15.06.
1
yield 1.64 g (83%), mp 131-133 °C, H NMR (400 MHz,
dimethyl-d sulfoxide): δ 6.87 (2H, broad s, NH ), 7.09 (1H, d,
4-Acetyl-3-amino-2-chloropyridine (4e).
6
2
J = 5.1, H-5), 7.54 (2H, m, H-3',5'), 7.65 (3H, m, H-2',4',6'), 7.75
(1H, d, J = 5.1, H-6), 8.32 (1H, s, H-2), ir (FT): 647, 709, 1222,
Compound 4e was obtained in 46% yield (392 mg) of a
1
yellow solid, mp 159-161 °C, H NMR (300 MHz, deuteriochlo-
-1
+
1296, 1323, 1424, 1632, 3314, 3444 cm , ms: 198.1 (M ).
Anal. Calcd. for C N O: C, 72.71; H, 5.08; N, 14.13.
roform): δ 2.62 (3H, s, CH ), 6.70 (2H, broad s, NH ), 7.46 (1H,
3
2
H
12 10
2
d, J = 5.2, H-5), 7.74 (1H, d, J = 5.2, H-6), ir (FT): 603, 638,
Found: C, 72.47; H, 5.04; N, 14.18.
1092, 1205, 1250, 1287, 1360, 1423, 1578, 1604, 1657, 3307,
General Chlorination Procedure to Prepare Compounds 4a-h.
-1
+
3425 cm , ms: 170 (M ).
Anal. Calcd. for C H N ClO: C, 49.28; H, 4.14; N, 16.42.
An aminopyridine or isoquinoline substrate (5 mmoles) was
dissolved in concentrated hydrochloric acid (10 ml) at 20 °C.
Hydrogen peroxide (35%, 5.5 mmoles) was added dropwise
during 30 minutes and the reaction mixture was stirred for
another 30 minutes. The mixture was neutralized with sodium
hydroxide solution to pH 8 and extracted with dichloromethane
7 7 2
Found: C, 49.36; H, 4.18; N, 16.29.
3-Amino-4-benzoyl-2-chloropyridine (4f).
Compound 4f was obtained in 47% yield (550 mg) of a
1
yellow solid, mp 100-101 °C, H NMR (400 MHz, deuteriochlo-

Jan-Feb 2001
Preparation of 4-Substituted 3-Amino-2-chloropyridines
103
roform): δ 6.35 (2H, broad s, NH ), 7.24 (1H, d, J = 5.1, H-5),
7.50 (2H, m, H-3',5'), 7.61 (1H, m, H-4'), 7.68 (2H, m, H-2',6'),
sodium sulfate and evaporated. The residue was purified by
flash chromatography on silica gel (eluent: ethyl acetate) to
2
7.72 (1H, d, J = 5.1, H-6), ir (FT): 664, 708, 763, 798, 1110,
afford a light yellow solid 6h, yield 580 mg (86%), mp 199-202
-1
1
1216, 1244, 1290, 1422, 1573, 1598, 1641, 3298, 3433 cm ,
°C, H NMR (400 MHz, acetone-d ): δ 0.45 (2H, m,
6
+
ms: 232 (M ).
(CH ) CH), 0.74 (2H, m, (CH ) CH), 2.93 (1H, m, (CH ) CH),
2 2 2 2 2 2
6.74 (1H, dd, J = 7.6, 4.9, H-5), 7.75 (1H, ddd, J = 8.0, 6.8, 1.3,
H-7'), 7.86 (1H, ddd, J = 8.4, 6.8, 1.3, H-6'), 8.04 (1H, ddd,
J = 8.4, 1.3, 1.0, H-5'), 8.24 (1H, ddd, J = 8.0, 1.3, 1.0, H-8'),
Anal. Calcd. for C H N ClO: C, 61.95; H, 3.90; N, 12.04.
Found: C, 61.84; H, 4.19; N, 11.79.
12
9 2
3-Amino-2-chloro-4-cyanopyridine (4g).
8.31 (1H, broad s, (CH ) CHNH), 8.35 (1H, dd, J = 4.9, 1.6,
2 2
Compound 4g was obtained in 12% yield (93 mg) of a
colourless solid, mp 145-146 °C, H NMR (300 MHz, deuteri-
H-6), 8.37 (1H, dd, J = 7.6, 1.6, H-4), 9.17 (1H, s, H-1'), 9.67
1
(1H, broad s, CONH), ir (FT): 765, 1261, 1394, 1497, 1580,
-1
+
ochloroform): δ 4.91 (2H, broad s, NH ), 7.23 (1H, d, J = 5.0,
1631 cm , ms: 338.1 (M ).
Anal. Calcd. for C H N ClO: C, 63.81; H, 4.46; N, 16.54.
2
H-5), 7.82 (1H, d, J = 5.0, H-6), ir (FT): 594, 834, 1080, 1111,
18 15
4
-1
1182, 1426, 1463, 1538, 1634, 2231, 3354, 3477 cm , ms:
Found: C, 63.71; H, 4.64; N, 15.79.
+
153 (M ).
7-Cyclopropyl-7,13-dihydro-11H-isoquino[4,3-b]pyrido-
[2,3-e][1,4]diazepin-11-one (7h).
Anal. Calcd. for C H N Cl: C, 46.93; H, 2.63; N, 27.36.
6
4 3
Found: C, 47.14; H, 2.89; N, 26.97.
N-(3-Chloro-4-isoquinolyl)-2-cyclopropylamino-3-
pyridinecarboxamide (6h, 339 mg, 1 mmole) was dissolved in
2-methoxyethylether (5 ml) and sodium hydride (72 mg, 3
mmoles) was added. The mixture was refluxed for 3 hours, then
cooled, poured into ice water (50 ml) and stirred for 1 hour. The
mixture was extracted with ethyl acetate (50 ml), the organic
phase separated, dried over sodium sulfate and evaporated. The
residue was purified by flash chromatography on silica gel
(eluent: ethyl acetate) to afford a light yellow solid 7h, yield 45
4-Amino-3-chloroisoquinoline (4h).
Compound 4h was obtained in 86% yield (770 mg) of a beige
1
solid, mp 115-116 °C, H NMR (300 MHz, deuteriochloroform):
δ 4.55 (2H, broad s, NH ), 7.58 (1H, ddd, J = 8.2, 6.8, 1.2, H-7),
2
7.68 (1H, ddd, J = 8.5, 6.8, 1.4, H-6), 7.78 (1H, dd, J = 8.5, 1.2,
H-5), 7.91 (1H, dd, J = 8.2, 1.4, H-8), 8.52 (1H, s, H-1),
13
C
NMR (300 MHz, dimethyl-d sulfoxide): δ 121.9, 125.6, 126.5,
6
127.2, 127.4, 128.1, 128.9, 135.2, 138.0 (C-1, dd,
1
1
3
mg (15%), mp 274-278 °C, H NMR (400 MHz, dimethyl-d
J
= 183.8, J
= 5.1), ir (FT): 580, 750, 848, 1077,
6
C-1, H-1
C-1, H-8
-1
+
sulfoxide): δ 0.33-0.50 (2H, m, (CH ) CH), 0.92 (2H, m,
1144, 1407, 1443, 1635, 3194, 3314, 3426 cm , ms: 178 (M ).
Anal. Calcd. for C9H7N2Cl: C, 60.52; H, 3.95; N, 15.68.
Found: C, 60.17; H, 4.16; N, 15.64.
2 2
(CH ) CH), 3.76 (1H, m, (CH ) CH), 7.17 (1H, dd, J = 7.6, 4.8,
2 2
2 2
H-5), 7.62 (1H, m, H-7'), 7.81 (1H, ddd, J = 8.4, 6.8, 1.2, H-6'),
8.02 (1H, dd, J = 7.6, 2.0, H-4), 8.10 (1H, d, J = 8.0, H-8'), 8.14
(1H, d, J = 8.4, H-5'), 8.50 (1H, dd, J = 4.8, 2.0, H-6), 9.06 (1H,
s, H-1'), 10.61 (1H, broad s, CONH), ir (FT): 748, 1288, 1388,
2-Chloro-N-(3-chloro-4-isoquinolyl)-3-pyridinecarboxamide (5h).
4-Amino-3-chloroisoquinoline (4h, 893 mg, 5 mmoles) was
dissolved in acetonitrile (10 ml) and pyridine (237 mg, 3
mmoles) was added. 2-Chloronicotinoyl chloride (880 mg, 5
mmoles) in acetonitrile (10 ml) was added and the mixture
stirred at room temperature for 1 hour and then at 45 °C for 16
hours. Ethyl acetate (200 ml) and saturated sodium bicarbonate
solution (100 ml) were added and the white precipitate dissolved
at 50 °C. The organic phase was separated, dried at 50 °C over
sodium sulfate and evaporated. The residue was crystallized
from ethyl acetate to afford colourless crystals of 5h, yield
-1
+
1409, 1587, 1654 cm , ms: 302.1 (M ).
Anal. Calcd. for C N O: C, 71.51; H, 4.67; N, 18.53.
H
18 14
4
Found: C, 70.99; H, 4.96; N, 18.00.
REFERENCES AND NOTES
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(1999).
1
1.20 g (75 %), mp 231-233 °C, H NMR (400 MHz,
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Trans. 2, 2477 (1998).
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36, 2244 (1988).
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P. P. Leitner, M. J. Luzzio, G. McIntyre, B. Morton, S. Profeta, J. Sisco,
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[14] K. D. Hargrave, J. R. Proudfoot, K. G. Grozinger, E. Cullen, S.
R. Kapadia, Usha R. Patel, V. U. Fuchs, S. C. Mauldin, J. Vitous, M. L.
dimethyl-d sulfoxide): δ 7.65 (1H, dd, J = 7.5, 4.8, H-5), 7.80
6
(1H, ddd, J = 8.1, 6.8, 0.8, H-7'), 7.96 (1H, ddd, J = 8.4, 6.8, 1.0,
H-6'), 8.13 (1H, dd, J = 8.4, 0.8, H-5'), 8.25 (1H, dd, J = 7.5,
1.9, H-4), 8.29 (1H, dd, J = 8.1, 1.0, H-8'), 8.61 (1H, dd, J = 4.8,
1.9, H-2), 9.25 (1H, s, H-1'), 10.95 (1H, s, CONH), ir (FT): 756,
1080, 1409, 1523, 1581, 1670, 3184 cm , ms: 317.0 (M ),
282.0.
-1
+
Anal. Calcd. for C H N Cl O: C, 56.63; H, 2.85; N, 13.21.
15
9
3
2
Found: C, 56.38; H, 3.26; N, 13.20.
N-(3-Chloro-4-isoquinolyl)-2-cyclopropylamino-3-pyridinecar-
boxamide (6h).
2-Chloro-N-(3-chloro-4-isoquinolyl)-3-pyridinecarboxamide
(5h, 636 mg, 2 mmoles) and cyclopropylamine (571 mg, 10
mmoles) in dimethyl sulfoxide (5 ml) were heated at 120 °C for
12 hours. Solvent was then evaporated and the residue dissolved
in ethyl acetate (50 ml) and saturated sodium bicarbonate solu-
tion (50 ml). The organic phase was separated, dried over

Vol. 38
J. M. Bakke and J. Riha
104
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