【结 构 式】 |
【药物名称】Ontazolast, BIRM-270, BI-RM-270 【化学名称】N-[2-Cyclohexyl-1(S)-(2-pyridyl)ethyl]-5-methylbenzoxazol-2-amine 【CA登记号】147432-77-7 【 分 子 式 】C21H25N3O 【 分 子 量 】335.4529 |
【开发单位】Boehringer Ingelheim (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Leukotriene Synthesis Inhibitors |
合成路线1
The required chiral auxiliary hydroxyketone (II) was prepared from (S)-alpha-pinene (I) either by dihydroxylation with K2OsO4 and NMO, followed by Swern oxidation of the secondary alcohol, or by direct oxidation using KMnO4 under phase-transfer conditions. Condensation of (II) with 2-(aminomethyl)pyridine (III) in the presence of titanium isopropoxide or thionyl chloride as the dehydrating reagents provided the chiral imine (IV), which was estereoselectively alkylated with cyclohexylmethyl bromide (V) and n-BuLi, yielding (VI). Cleavage of the chiral auxiliary of (VI) was carried out by treatment with hydroxylamine hydrochloride. Enantiomeric enrichment of the resulting (S)-pyridylamine was achieved by recrystallization of the corresponding L-tartrate salt (VII). Finally, the amine was condensed with chlorobenzoxazole (VIII) in the presence of NaOAc and Na2CO3 in refluxing methylcyclohexane.
【1】 Roth, G.P.; et al.; Optimization and scale-up of an asymetric route to the LTB4 inhibitor ontazolast. Org Process Res Dev 1997, 1, 5, 331. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 16643 | Poly-alpha-pinene; (1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene | 7785-26-4 | C10H16 | 详情 | 详情 |
(II) | 31762 | (1S,2R,5S)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one | C10H16O2 | 详情 | 详情 | |
(III) | 13582 | 2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine | 3731-51-9 | C6H8N2 | 详情 | 详情 |
(IV) | 31763 | (1S,2R,5S)-2,6,6-trimethyl-3-[(2-pyridinylmethyl)imino]bicyclo[3.1.1]heptan-2-ol | C16H22N2O | 详情 | 详情 | |
(V) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
(VI) | 31764 | (1S,2R,5S)-3-[[(1S)-2-cyclohexyl-1-(2-pyridinyl)ethyl]imino]-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol | C23H34N2O | 详情 | 详情 | |
(VII) | 31765 | (1S)-2-cyclohexyl-1-(2-pyridinyl)ethylamine; (1S)-2-cyclohexyl-1-(2-pyridinyl)-1-ethanamine | C13H20N2 | 详情 | 详情 | |
(VIII) | 31766 | 2-chloro-5-methyl-1,3-benzoxazole | C8H6ClNO | 详情 | 详情 |