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【结 构 式】 
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【分子编号】68760 【品名】5-bromo-2-methylpyridine 1-oxide；5-bromo-2-Picoline-1-oxide；3-Bromo-6-methylpyridine 1-oxide;5-bromo-2-methylpyridine N-oxide;5-Bromo-2-picoline N-oxide 【CA登记号】31181-64-3 |
【 分 子 式 】C6H6BrNO 【 分 子 量 】188.02378 【元素组成】C 38.33% H 3.22% Br 42.5% N 7.45% O 8.51% |
合成路线1
该中间体在本合成路线中的序号：(LXVII)Rearrangement of 5-bromo-2-methylpyridine 1-oxide (LXVII) with trifluoroacetic anhydride gives (5-bromopyridin-2-yl)methyl trifluoroacetate (LXVIII), which, without isolation, is hydrolyzed in MeOH solution, yielding (5-bromopyridin-2-yl)methanol trifluoroacetate salt (LXIX). Basification of compound (LXIX) with K2CO3 followed by chlorination with SOCl2 affords 5-bromo-2-(chloromethyl)pyridine (LXX), which is subsequently condensed with diethyl phosphite in the presence of LiHMDS, affording phosphonate (LXXI). Finally, Suzuki coupling of bromopyridine derivative (LXXI) with 3-fluorophenylboronic acid (V) by means of Na2CO3 and Pd/C in H2O at 75 °C provides the phenylpyridine compound (XII) .
O-Protection of 6-methyl-3-pyridinol (LXXII) with TIPSCl in DMF gives the corresponding silyl ether (LXXIII), which is then condensed with diethyl chlorophosphate (LXXIV) in the presence of BuLi and DIEA in THF, yielding diethyl phosphonate (II) .
| 【1】 Chackalamannil, S., Wang, Y., Greenlee, W.J. et al. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem 2008, 51(11): 3061-4. |
| 【2】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 68703 | diethyl ((5-((triisopropylsilyl)oxy)pyridin-2-yl)methyl)phosphonate | C19H36NO4PSi | 详情 | 详情 | |
| (V) | 68704 | 3-fluorophenylboronic acid;3-Fluorobenzeneboronic acid | 768-35-4 | C6H6BFO2 | 详情 | 详情 |
| (XII) | 68705 | diethyl ((5-(3-fluorophenyl)pyridin-2-yl)methyl)phosphonate | C16H19FNO3P | 详情 | 详情 | |
| (LXVII) | 68760 | 5-bromo-2-methylpyridine 1-oxide；5-bromo-2-Picoline-1-oxide；3-Bromo-6-methylpyridine 1-oxide;5-bromo-2-methylpyridine N-oxide;5-Bromo-2-picoline N-oxide | 31181-64-3 | C6H6BrNO | 详情 | 详情 |
| (LXVIII) | 68761 | (5-bromopyridin-2-yl)methyl trifluoroacetate；(5-bromopyridin-2-yl)methyl 2,2,2-trifluoroacetate | C8H5BrF3NO2 | 详情 | 详情 | |
| (LXIX) | 68762 | (5-bromopyridin-2-yl)methanol 2,2,2-trifluoroacetate | C6H6BrNO.C2HF3O2 | 详情 | 详情 | |
| (LXX) | 68763 | 5-bromo-2-(chloromethyl)pyridine | 168823-76-5 | C6H5BrClN | 详情 | 详情 |
| (LXXI) | 68764 | diethyl ((5-bromopyridin-2-yl)methyl)phosphonate | C10H15BrNO3P | 详情 | 详情 | |
| (LXXII) | 25748 | 6-methyl-3-pyridinol; 5-Hydroxy-2-methylpyridine | 1121-78-4 | C6H7NO | 详情 | 详情 |
| (LXXIV) | 68765 | 2-methyl-5-((triisopropylsilyl)oxy)pyridine | C15H27NOSi | 详情 | 详情 | |
| (LXXV) | 23623 | Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate | 814-49-3 | C4H10ClO3P | 详情 | 详情 |