148
Q. Zhao, H.-G. Chen, C. Qian, and X.-Z. Chen
Vol 50
glass plate (30 × 100 mm2). GC analyses were performed on GC
Agilent 1790F series. HPLC analyses were executed on HPLC
Agilent 1100 series charged with C18 column. NMR spectrums
were recorded in DMSO or CDCl3 using Bruker, AV 400, 400 MHz.
Starting materials and reagents were commercially purchased
and used without further purification.
1
4
6
2
N
3
5
N
OH
7
Chart 2. 2-Hydroxy-3-cyano-4-methylpyridine (5).
Preparation of 2-hydroxy-3-cyano-4-methylpyridine (5).
To a 500-mL three-necked flask equipped with a mechanic
stirrer, a thermometer, and a water separator, 4,4-dimethoxyl-
2-butanone (2) (37.0 g, 0.28 mol), 2-cyanoacetamide (3) (29.4
g, 0.35 mol), ammonium acetate (1.5 g), acetic acid (11.0 g),
and toluene (200.0 g) were added under vigorous stirring.
The water produced in the reaction was separated. When this
step was finished, the toluene was removed under vacuum at
50ꢁC, and the residual liquid was cooled to room temperature,
ethanol (100 g) was added under stirring at 25ꢁC. After
that, sulfuric acid (50%, 110 g) was added slowly within 40
min, then heated to 50ꢁC for another 30 min, and khaki
crystal was precipitated. The whole process was monitored by
TLC. After the final step, the reaction mixture was cooled to
5ꢁC, and water (80 g) was added in 50 min. 2-Hydroxy-3-
cyano-4-methylpyridine was thus obtained by filtration and
recrystallization in ethanol.
1
O
7
NH2
5
3
6
2
4
N
Cl
Chart 3. 2-Chloro-3-formyl amino-4-methylpyridine (6).
1
3
6
5
NH2
Cl
2
4
N
Chart 4. 2-Chloro-3-amido-4-methylpyridine (1).
(5) (Chart 2). Khaki solid (30.3 g, 82.1% yield), mp: 234.7–
236.1ꢁC (lit. [6] mp: 236.0–238.0ꢁC); 1H-NMR (DMSO, 400
MHz) δ: 2.34 (s, 3H, CH3), 6.29–6.31 (d, 1H, C CH C, J = 6.8
Hz), 7.64–7.65 (d, 1H, N CH C, J = 6.8 Hz), 12.32 (s, 1H,
OH). 13C-NMR (DMSO, 100 MHz). δ: 21.17 (C-1), 103.09
(C-2), 108.092 (C-3), 116.14 (C-4, 140.04 (C-5), 160.68 (C-6),
161.57 (C-7).
were added to the flask. After cooling to 10ꢁC, 2-chloro-3-formyl
amino-4-methylpyridine (6) (22 g, 0.13 mol) was added slowly in
10 min. Under stirring for 60 min, then the temperature was
increased to 60ꢁC for 3 h. The solvent was removed under
vacuum to give crude product. The crude product was cooled to
room temperature and filtered, and thus, 2-chloro-3-amido-4-
methylpyridine was obtained after recrystallization in toluene.
(1) (Chart 4). White solid (14.7 g, 85.6% yield). mp: 67.4–
68.2ꢁC (lit. [6] mp: 69ꢁC); 1H-NMR (DMSO, 400 MHz) 2.16
(s, 3H, CH3), 5.27 (s. 2H, NH2), 6.98–6.99 (d, 1H, C CH C, J =
4.8 Hz), 7.51–7.52 (d, 1H, N CH C, J = 4.4 Hz). 13C-NMR
(DMSO, 100 MHz). δ: 17.92 (C-1), 125.32 (C-2), 131.93 (C-3),
135.48 (C-4), 136.26 (C-5), 139.91 (C-6).
Preparation of 2-chloro-3-formyl amino-4-methylpyridine
(6). To a 500-mL three-necked flask with a mechanic stirrer, a
reflux condenser, and a thermometer, POCl3 (43.7 g, 0.285 mol)
was added. Then 2-hydroxy-3-cyano-4-methylpyridine (5) (30.3
g, 0.23 mol) was added under stirring in 15 min at 35ꢁC. After
that, the reaction mixture was heated to reflux. The chlorination
reaction was completed in 2 h. Thereafter, the reaction mixture
was cooled to 50ꢁC, and sulfuric acid (82.3 g, 0.84 mol) was
added in slowly. After the addition was complete, the mixture
was heated to 100–105ꢁC, under stirring for 4 h and cooled to
60ꢁC, and water (82.3 g) was added to the flask. The reaction
temperature was kept between 65 and 67ꢁC for another 1.5 h.
Then cooling, ammonia aqueous (28%) was added slowly to
make pH = 7. Precipitation was generated. The solid was
filtered and recrystallized in water to give 2-chloro-3-formyl
amino-4-methylpyridine (6) (Chart 3) (34.6 g, 88.3% yield) as
dust-color solid.
Acknowledgment. The authors greatly acknowledge the generous
financial support by grants from the National Natural Science
Foundation of China (No. 21076183, 21006087) and the
Fundamental Research Funds for the Central Universities (No.
2011QNA4018).
1
Melting point: 176.5–177.9ꢁC (lit. [6] mp: 178–179ꢁC); H-
REFERENCES AND NOTES
NMR (DMSO, 400 MHz) δ: 2.32 (s, 3H, CH3), 7.33–7.34 (d,
1H, C CH C, J = 4.4 Hz), 7.83 (s, 1H, NH), 8.08 (s, 1H, NH),
8.27–8.28 (d, 1H, N CH C, J = 4.8 Hz). 13C-NMR (DMSO, 100
MHz). δ: 18.97 (C-1), 125.05 (C-2), 134.34 (C-3), 146.48
(C-4), 147.35 (C-5), 149.05 (C-6), 167.02 (C-7).
Preparation of 2-chloro-3-amido-4-methylpyridine (1).
To a 500-mL three-necked flask with a mechanic stirrer, a
reflux condenser, and a thermometer, NaOH (15.6 g, 0.39 mol)
and water (85 g) were added, stirring until the solid was
completely dissolved, and cooled to room temperature. To the
flask, NaClO (10%, 96.8 g, 0.13 mol) and ethyl alcohol (80 g)
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[3] Gupton, B. F. U.S. Pat. 6,399,781, 2002.
[4] Hargrave, K. D.; Proudfoot, J. R.; Grozinger, K. G.; Ernest, E.;
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[5] Hargrave, K. D.; Schmidt, G.; Engel, W.; Trummlitz, G.;
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[6] Gupton, B. F. U.S. Pat. 0,052,507, 2000.
[7] Shrestha-Dawadi, P. B.; Lugtenburg, J. Eur J Org Chem 2007,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet