Organic Process Research & Development
Page 6 of 9
1
2
3
4
5
6
7
8
9
5-Bromo-6-chloropyridin-2-amine (15). 2-Amino-6-chloropyridine (200 g, 1.56 mol) was added to a
5 L flask containing acetonitrile (2 L), and cooled to 0-5 °C under ice bath. NBS (277.6 g, 1.56 mol)
was then slowly added to the solution over a period of 1 h, and stirred the mixture at 0-5 °C for 4 h,
then removed 1 L of acetonitrile by rotary evaporation. To the remaining solution, 2 L of water was
added, and the mixture was stirred for 1 h. The resulting precipitate was collected by filtration, and the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
filter cake was dried in vacuum at 50 °C to afford 15 (287.4 g, 89%) as an off-white solid. H NMR
(500 MHz, CDCl3): δ 7.58 (d, J = 8.5 Hz, 1H), 6.33 (d, J = 8.5 Hz, 1H), 4.60 (br, 2H). 13C NMR (125
MHz, CDCl3): δ 157.08, 148.30, 143.40, 108.52, 106.20. HRMS (ESI-QTOF): m/z Calcd for
C5H5BrClN2 [M + H]+: 206.9319; found: 206.9321. Melting point 150-151 °C .
N-(5-Bromo-6-chloropyridin-2-yl)acetamide (16). Acetyl chloride (119.3 g, 1.52 mol) was diluted
with CH2Cl2 (500 mL), and it was added dropwise to a solution of 15 (286.3 g, 1.38 mol) and pyridine
(218.3 g, 2.76 mol) in CH2Cl2 (1.5 L) at 0-5 °C over a period of 40 min. The reaction mixture was then
stirred for an additional 2 h at room temperature (25 °C). Added 630 mL of 2M HCl to the solution,
then the organic layer was washed with 500 mL of water, and concentrated by rotary evaporation.
Added 1 L of n-heptane to the mixture, then the precipitate was filtered and dried in vacuum at 50 °C,
providing 16 (319.1 g, 93%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 8.08 (s, 1H), 8.04 (d,
J = 8.6 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 2.20 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 168.90, 149.86,
148.10, 144.33, 113.58, 113.51, 24.79. HRMS (ESI-QTOF): m/z Calcd for C7H7BrClN2O [M + H]+:
248.9425; found: 248.9426. Melting point 166-168 °C .
N-(6-Chloro-5-methylpyridin-2-yl)acetamide (17). 16 (317.0 g, 1.27 mol) and methylboronic acid
(83.8 g, 1.40 mol) were added to a flask containing NaHCO3 (320.1 g, 3.81 mol), Pd(OAc)2 (2.9 g,
12.7 mmol), and DPEphos (6.8 g, 12.7 mmol). A mixture of 1,2-dimethoxyethane (1.5 L) and H2O (1.5
L) were then added. After purging the heterogeneous mixture with nitrogen for 10 min, the solution
was heated to reflux for 10 h under an inert atmosphere of nitrogen. To the hot mixture was added 30 g
activated carbon, and the reaction was cooled to room temperature. The insoluble substances were
filtered, then the solution was concentrated to about 1 L. Added 2 L of CH2Cl2 to the mixture, and the
organic phase was washed with water. Removed the solvent, and added isopropanol (500 mL) to the
residue and stirred for 2 h. The resulting precipitate was collected by filtration, and the filter cake was
1
dried in vacuum at 50 °C, producing 17 (191.8 g, 82%) as a light-yellow solid. H NMR (500 MHz,
CDCl3): δ 8.24 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 2.31 (s, 3H), 2.17 (s, 3H). 13
C
NMR (125 MHz, CDCl3): δ 168.82, 149.10, 148.49, 141.81, 127.79, 112.51, 24.70, 18.85. HRMS
(ESI-QTOF): m/z Calcd for C8H10ClN2O [M + H]+: 185.0476; found: 185.0475. Melting point
151-153 °C .
6-Chloro-5-methylpyridin-2-amine (2). 17 (184.6 g, 1.0 mol) was dissolved in methanol (1.1 L), then
concentrated hydrochloric acid (250 mL) was added dropwise to the solution. After stirring the reaction
mixture at 50 °C for 3-4 h, the solvent was removed under reduced pressure. Ethyl acetate (1 L) was
added to the residue, while saturated sodium carbonate solution was used to regulate the pH of the
mixture to 9-10. The organic layer was separated and concentrated, and a mixture of methanol (600 mL)
and water (1.2 L) was then added to the residue. The precipitate was filtered and dried in vacuum at
50 °C, affording 2 (130.8 g, 92%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 7.27 (d, J = 8.2
ACS Paragon Plus Environment