ꢀꢀꢀꢁ
204ꢀ ꢀJ. Guo et al.: 3-(Bromomethyl)-5-methylpyridine hydrobromide
COOH
COOCH3
CH3OH, SOCl2
95.5%
OH
NaBH4
CH3OH
N
N
N
1
2
3
HBr/H2O
84.6%
OH
Br
HBr/xylene
79.5%
HBr
HBr
N
N
4
5
Scheme 1ꢀ
starting with 5-methylnicotinic acid. This method is envi- 5-Methyl-3-pyridinemethanol hydrobromide (4)
ronmentally friendly and is suitable for a large-scale
industrial production.
Hydrobromic acid (5 mL, 40%, 0.036 mol) was added dropwise
to compound 3 (4.2 g) cooled in an ice bath. The mixture was then
concentrated under reduced pressure, and the residue was treated
with tetrahydrofuran/ethanol (1:1, 20 mL). The mixture was stirred
for 30 min and the resultant white precipitate of 4 was filtered: yield
5.7 g, (84.6%); mp 126.8–128.4°C; MS: m/z 123.95 ([M-Br] ); H NMR
(DMSO-d6): δ 8.76 (1H, s), 8.70 (1H, s), 8.41 (1H, s), 4.69 (2H, s), 2.50
(3H, s); IR: 3312, 3172, 3028, 2687, 2064, 1623, 1557, 1442, 1405, 1330,
1059, 863, 681 cm-1. Anal. Calcd for C7H10BrNO: C, 41.20; H, 4.94; Br,
39.16; N, 6.86. Found: C, 41.20; H, 4.94; Br, 39.12; N, 6.85.
Experimental details
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1H NMR spectra (400 MHz) were recorded on a Bruker AV 400
spectrometer. Mass spectra were acquired in a positive mode
using a mass spectrometer equipped with electrospray ioniza-
tion (ESI) source. FT-IR spectra were obtained on an Avatar360
spectrometer.
3-(Bromomethyl)-5-methylpyridine bromide (5)
Methyl 5-methylnicotinate (2)
A mixture of compound 4 (5.0 g, 0.0245 mol), hydrobromic acid
(50 mL, 40%, 0.34 mol), and xylene (25 mL) was heated under reflux
with azeotropic removal of water with xylene. Xylene was evaporated
under reduced pressure, and a residue was treated with acetone
(45 mL). The mixture was sonicated for 1 h to wash out adsorbed
impurities; then product 5 was filtered and dried: white solid; yield
5.2 g, (79.5%). mp 158.1158.8°C; MS: m/z 185.95 ([M-HBr] ); H NMR
(DMSO-d6): δ 8.84 (2H, s), 8.58 (1H, s), 4.88 (2H, s), 2.50 (3H, s); IR:
3225, 3110, 3014, 2964, 2924, 2553, 2036, 1556, 1462, 1344, 1317, 1229,
1030, 862, 736, 681 cm-1 [1].
Thionyl chloride (110 mL, 1.50 mol) was added dropwise to a solu-
tion of 5-methylnicotinic acid (1, 102.8 g, 0.75 mol) in methanol
(500 mL) under a nitrogen atmosphere at 20–25°C, and then the
mixture was heated under reflux for 4 h. Afer completion of the
reaction, as monitored by TLC, methanol was removed under
a reduced pressure and the residue was treated with cold water
(200 mL). The mixture was neutralized by addition of saturated
sodium carbonate solution and extracted with ethyl acetate
(2ꢀ×ꢀ250 mL). The extract was washed by brine, dried with anhy-
drous sodium sulfate, filtered, and concentrated under a reduced
pressure. Compound 2 as obtained as a white solid; yield 108.3 g
(95.5%); mp 44.9–45.4°C (Lit. [15] mp 45–46°C); ESI-MS: m/z 151.95
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References
[1] Izquierdo, I.; Merlos, M.; Rafanell, J. G. Rupatadine: a new selec-
tive histamine H1 receptor and platelet-activating factor (PAF)
antagonist. Drugs Today 2003, 39, 451–468.
[2] Zhang, W. J.; Luo, Y.; Zhang, Y. M. Synthesis of rupatadine. Chin.
J. Pharm. 2006, 37, 433–434.
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([M+H] ); H NMR (CDCl3): δ 9.03 (s, 1H), 8.60 (s, 1H), 8.11 (s, 1H),
3.95 (s, 3H), 2.40 (s, 3H); FT-IR: 3417, 3055, 2957, 1721, 1579, 1439,
1384, 1320, 1296, 1219, 1110, 768 cm-1.
5-Methyl-3-pyridinemethanol (3)
[3] Mao, L.; Zhao, L.; Liu, J.; Wang, X. B.; Xu, X. Pyrazolopyrimidine
derivatives and uses as anticancer agents. WO Patent 2012097196;
2012.
[4] Selness, S. R.; Monahan, J. B.; Schindler, J. F.; Devadas, B.;
Hockerman, S. L. Methyl/difluorophenyl-methoxy substituted
pyridinone-pyridinyl compounds, methyl-pyridinyl-methoxy sub-
stituted pyridinone-pyridinyl compounds, and methyl-pyrimidi-
nyl-methoxy substituted pyridinone-pyridinyl compounds. US
Patent 20130274272; 2013.
Sodium borohydride (4.4 g, 0.12 mol) was added to a suspension of
5-methylnicotinic acid methyl ester (5.0 g, 0.033 mol) in methanol
(50 mL). The mixture was stirred for 1 h at 55°C, and then treated with
water (5 mL) and concentrated under reduced pressure. The residue
was extracted with ethyl acetate (2ꢀ×ꢀ50 mL). The extract was washed
by brine, dried with anhydrous sodium sulfate, and filtered. The fil-
trate was concentrated under reduced pressure. The oily residue of 3
(4.2 g) was used directly in the next step.
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