A concise synthesis of 2-chloro-3-amino-4-methylpyridine

Article abstract of DOI:10.1007/s11164-011-0238-6

An improved and commercially valuable process is developed for the scalable synthesis of 2-chloro-3-amino-4-methylpyridine (CAPIC), a key intermediate of Nevirapine. The synthesis was accomplished in four steps, featuring condensation starting from 4,4-dimethoxyl-2-butanone and cyanoacetamide with ammonium acetate and acetic acid as catalysts. The total yield of the process is 62.1%. The pure CAPIC sample was confirmed with FTIR, ¹H NMR, and ¹³C NMR spectra.

Full text of DOI:10.1007/s11164-011-0238-6

Res Chem Intermed (2011) 37:599–604
DOI 10.1007/s11164-011-0238-6
A concise synthesis of 2-chloro-3-amino-4-
methylpyridine
Xin Ge
Jin-qiang Liu
•
Han-geng Chen
Chao Qian
•
Chang-hui Cao
Xin-zhi Chen
•
•
•
Received: 28 May 2010 / Accepted: 17 December 2010 / Published online: 28 January 2011
Ó Springer Science+Business Media B.V. 2011
Abstract An improved and commercially valuable process is developed for the
scalable synthesis of 2-chloro-3-amino-4-methylpyridine (CAPIC), a key interme-
diate of Nevirapine. The synthesis was accomplished in four steps, featuring con-
densation starting from 4,4-dimethoxyl-2-butanone and cyanoacetamide with
ammonium acetate and acetic acid as catalysts. The total yield of the process is
1
13
6
2.1%. The pure CAPIC sample was confirmed with FTIR, H NMR, and C NMR
spectra.
Keywords 2-Chloro-3-amino-4-methylpyridine Á 4,4-Dimethoxyl-2-butanone Á
Cyanoacetamide
Introduction
Nevirapine (1, Fig. 1) is a non-nucleoside reverse transcriptase inhibitor, which has
been established to be clinically useful for the treatment of infection by HIV-1 [1].
2-Chloro-3-amino-4-methylpyridine (CAPIC, 2) is the key intermediate for
Nevirapine [2, 3].
Several methods for the synthesis of CAPIC (2) have been reported in the
literature, which are mainly divided into two strategies: the substitution and the
construction of pyridine ring. The reduction of 2-chloro-4-methyl-3-nitropyridine
gave 2 in 61% yield [4]. Chlorination of 2-hydroxy-4-methyl-3-nitropyridine with
X. Ge Á H. Chen Á C. Cao Á J. Liu Á C. Qian Á X. Chen (&)
Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027,
People’s Republic of China
e-mail: chemtec@163.com
J. Liu
Colloge of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022,
People’s Republic of China
123

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X. Ge et al.
Fig. 1 The structure of
Nevirapine, 1
O
HN
N
N
N
1
POCl and PCl , and, subsequently, reduction with 5% Rh/C or SnCl /HCl as
4
3
5
catalysts could afford 2 in 58% yield [2, 3]. Groziger et al. [5] reported the synthesis
of 2, starting from ethyl acetoacetate and cyanoacetamide. And 2,6-dihydroxy-4-
methyl-3-cyanopyridine was obtained by cyclization, after which the subsequent
chlorination, dechlorination, hydrolysis, Hofmann condensation, and selective
rechlorination with chlorine giving a total yield of about 26%. Gupton [6] obtained
2
by employing malononitrile and 4,4-dimethoxyl-2-butanone as raw materials, by
condensation and successive cyclization, chlorination, hydrolysis, and Hofmann
condensation in 52.1% yield. This method suffers from several disadvantages, such
as the expensive and scare raw materials, the long route, and the low overall yield.
In this paper, a new process for CAPIC was developed, which started from the
condensation of 4,4-dimethoxyl-2-butanone (3) and 2-cyanoacetamide (4) as raw
materials. And the subsequently successive cyclization, chlorination, and hydrolysis
in ‘‘one-pot’’ and Hofmann condensation gave the title compound 2 (Scheme 1).
Results and discussion
It was reported [7, 8] that 2-hydroxy-3-cyano-6-methylpyridine, an isomer of
2-hydroxy-3-cyano-4-methylpyridine 6, was obtained from the condensation of 3
and 4 in alkaline solution. However, Shrestha-Dawadi and Lugtenburg [9] found
NH2
O
OCH3
NH2
O
NC
+
OCH3
OCH3
OCH3
O
4
NC
NH Ac/HAc
4
3
5
H SO
2
4
NH2
Cl
CONH2
POCl ,H SO
CN
OH
N
N
7
Cl
3
2
4
N
6
2
Scheme 1 Concise synthesis of CAPIC
1
23

A concise synthesis of 2-chloro-3-amino-4-methylpyridine
601
O
OCH3
OCH
3 H2N
-
H
O
C
O-
NH2
NH2
OH-
NC
NC
O
O
NC
NH2
OMe
MeO
O
H N
2
OH
O
BH
-H O
2
OCH3
OCH3
NC
OMe
NC
MeO
Scheme 2 The possible mechanism of condensation of 3 and 4
that the extended Knoevenagel reaction had a protected carbonyl moiety linked
directly to the reactive free carbonyl function in the synthesis of 3-cyano-4-methyl-
3
-pyrroline-2-ones. So, we presumed the possible mechanism of the condensation of
and 4 as in Scheme 2.
Azeotropic distillation was adopted in the condensation of 3 and 4 to remove the
3
water produced in the reaction. Different solvents such as cyclohexane and toluene
were explored and the results demonstrated that toluene was the more suitable (the
molar ratio of 4:3 was 1.25:1).
Catalyst in the Knoevenagel condensation is usually a variety of amines, urea,
and so on. It was found that 4 wt% ammonium acetate and 30 wt% acetic acid were
more suitable to obtain an 82.1% yield (Table 1, entry 4). 2-Hydroxy-3-cyano-6-
methylpyridine, the isomer of 6, was obtained by employing sodium methoxide as
the catalyst (Table 1, entry 1), and a lower yield was obtained due to the poor
solubility of 4 and acetamide in toluene with ammonium acetate as the sole catalyst.
The addition of acetic acid could make cyano acetamide more soluble in toluene.
The high boiling point of the intermediate 5 made it difficult to purify with
distillation, so the acetal of intermediate 5 was directly hydrolyzed to aldehyde
under acidic conditions, and then condensed with amino to prepare 6. It was
indicated that the cyclization reagent played an important role. 50% sulfuric acid
was found to be the suitable cyclization reagent with a yield of 82.1% (Table 2,
entry 2). The molar ratio of 50% sulfuric acid and 3 was set to be 2:1. More black oil
was produced with higher acid concentration. Longer reaction time was needed with
acetic acid as the cyclization reagent. The temperature of the hydrolysis was tested
Table 1 Effects of catalysts on the yield
Entry
Catalyst
Yield (%)
1
2
3
4
5
6
4 wt% sodium methoxide
–
4 wt% ammonium acetate
33.2
76.5
82.1
81.9
82
2 wt% ammonium acetate/25 wt% acetic acid
4 wt% ammonium acetate/30 wt% acetic acid
4 wt% ammonium acetate/40 wt% acetic acid
7 wt% ammonium acetate/40 wt% acetic acid
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02
X. Ge et al.
Yield (%)
Table 2 Effect of cyclization reagents on the reaction
Entry
Cyclization reagent
Reaction time (h)
1
2
3
4
5
30% Sulfuric acid
50% Sulfuric acid
70% Sulfuric acid
98% Sulfuric acid
Acetic acid
6
3.5
2.5
1
77.7
82.1
60.1
37.4
70.9
20
at 30, 40, 50, and 60 °C, with 50 °C being shown to be best, with a high yield and
short reaction time (4 h).
2-Chloro-3-amido-4-methylpyridine (7) may be produced by chlorination and
then hydrolysis of 6 in a ‘‘one-pot’’ method. With POCl as the chloride reagent, the
3
chlorination can run at a higher temperature of 105 °C under atmospheric pressure
for 2 h. When the chlorination finished, POCl was hydrolyzed into hydrochloric
3
acid and phosphoric acid, with the addition of water. The hydrolysis of cyano group
was run under acidic conditions at 60 °C. The total yield of 86.1% was obtained.
The target compound 2 was obtained from the Hofmann condensation of 7.
Compared to Br /NaOH in the literature [5], 10% NaClO solution was explored at
2
6
0 °C for 3 h and a better yield (85.1%) was achieved.
Conclusion
A four-step synthetic route was developed for 2, starting from 3 and 4. The key
improved steps in the process are that the condensation of 3 and 4 are carried out
with ammonium acetate and acetic acid as catalysts and the ‘‘one-pot’’ method is
introduced in chlorination and then hydrolysis of 6. This synthetic route is a more
scalable commercial manufacturing process with a better overall yield (62.1%).
Experimental section
Melting points were determined with the WRR melting point apparatus without
1
correction. H NMR and C NMR were recorded in DMSO or CDCl at 400 MHz
13
3
using an NMR spectrometer. HPLC analyses were executed on HPLC Agilent 1100
series charged with a C18 column. TLC analyses were performed on a glass plate
(30 mm 9 100 mm). Raw materials and reagents were purchased commercially and
used without further purification.
2
-Hydroxy-3-cyano-4-methylpyridine (6)
A mixture of 3 (37.0 g, 0.28 mol), 4 (29.4 g, 0.35 mol), ammonium acetate (1.5 g,
.019 mol), and toluene (200.0 g) was heated to reflux with stirring for 8 h. Water
generated was removed through azeotropic distillation. Then, the toluene was distilled
0
1
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A concise synthesis of 2-chloro-3-amino-4-methylpyridine
603
under reduced pressure. The residue was cooled to room temperature, followed by the
addition of ethanol (100 mL), and 50% sulfuric acid (110 g, 0.561 mol) was added
slowly over 40 min. The mixture was heated to 50 °C and stirred for about 3 h. The
content was cooled to 5 °C with an ice-water bath. Water (80 mL) was added slowly
over 20 min and stirred for another 30 min. Then, the mixture was filtered, washed
with ethanol, and dried to give 30.3 g brown solid 6 with 82.1% yield. Melting point:
6
1
2
34.7–236.1 °C (lit mp: 236.0–238.0 °C); H-NMR (400 MHz, DMSO) d: 2.34 (s,
3
H, CH ), 6.29–6.31 (d, 1H, C–CH=C, J = 6.8 Hz), 7.64–7.65 (d, 1H, N–CH=C,
3
J = 6.8 Hz), 12.32 (s, 1H, OH); C-NMR (100 MHz, DMSO) d: 21.17, 103.09,
3
1
1
2
08.092, 116.14, 140.04, 160.68, 161.57.
-Chloro-3-amido-4-methylpyridine (7)
To a stirred solution of POCl (37.0 g, 0.24 mol) at 35 °C was added 2-hydroxy-3-
3
cyano-4-methylpyridine 6 (26.8 g, 0.2 mol). The mixture was heated to reflux and
held under those conditions for 2 h, and the dark brown mixture was obtained.
When the mixture was cooled to 50 °C, 98% sulfuric acid (59.0 g, 0.6 mol) was
added in dropwise, and the mixture was stirred for about 4 h after being heated to
1
00–105 °C. The mixture was cooled to 60 °C and then water (59.0 g) was added
and stirred for 1.5 h at 60–65 °C. After the mixture was cooled with an ice-water
bath, 28% ammonia was added until the pH was adjusted to 7. The brown solid was
isolated from the reaction mixture by filtration, washed with water and dried to give
2
1
3
9.4 g (86.2% yield) of 2-chloro-3-amido-4-methylpyridine (7). Melting point:
1
6
76.4–177.9 °C (lit mp: 178.0–179.0 °C); H NMR (DMSO, 400 MHz) d: 2.34 (s,
H, CH ), 7.33–7.34 (d, 1H, C–CH=C, J = 4.4 Hz), 7.83 (s, 1H, NH), 8.08 (s, 1H,
1
3
3
NH), 8.27–8.28 (d, 1H, N–CH=C, J = 4.8 Hz); C NMR (DMSO, 100 MHz) d:
1
2
8.97, 125.05, 134.34, 146.48, 147.35, 149.05, 167.02.
-Chloro-3-amino-4-methylpyridine (2)
To a stirred solution of NaOH (15.6 g, 0.39 mol) and water (85 g) at 10 °C was
added 10% NaClO (96.8 g, 0.13 mol) and ethanol (80 g). 2-Chloro-3-amido-4-
methylpyridine 7 (22 g, 0.13 mol) was added to the reaction mixture followed by
stirring for 1 h. The mixture was heated to 60 °C and held for 3 h. After ethanol was
removed in vacuum, the mixture was cooled with an ice-water bath for 15–20 min
to precipitate solid. Then, the mixture was filtered, washed with water, and dried to
give 15.8 g (85.1% yield) of light yellow solid. 14.7 g of the white solid 2 was
6
obtained via recrystallization in toluene. Melting point: 67.4–68.2 °C (lit mp: 69
1
°
J = 4.4 Hz), 7.83 (s, 1H, NH), 8.08 (s, 1H, NH), 8.27–8.28 (d, 1H, N–CH=C,
C); H NMR (DMSO, 400 MHz) d: 2.34 (s, 3H, CH ), 7.33–7.34 (d, 1H, C–CH=C,
3
1
3
J = 4.8 Hz); C NMR (DMSO, 100 MHz) d: 18.97, 125.05, 134.34, 146.48,
47.35, 149.05, 167.02.
1
Acknowledgment We are grateful to the generous financial support from the National Natural Science
Foundation of China (20776127) and the Natural Science Foundation of Zhejiang Province (Y4090045,
R4090358).
123

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X. Ge et al.
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