|
【结 构 式】 
|
【药物名称】Bisoprolol fumarate, TA-4708(free base), CL-297939(hemifumarate), EMD-33512(free base), Euradal, Cardicor, Soprol, Concor COR, Monocor, Emcor, Fondril, Maintate, Zebeta, Concor 【化学名称】(±)-1-[[alpha-(2-Isopropoxyethoxy)-p-tolyl]oxy]-3-(isopropylamino)-2-propanol fumarate 【CA登记号】66722-44-9 (free base), 104344-23-2 (hemifumarate) 【 分 子 式 】C22H35NO8 【 分 子 量 】441.52615 |
【开发单位】Merck KGaA (Originator), Bracco (Not Determined), Wyeth Pharmaceuticals (Not Determined), Barr (Licensee), Lacer (Licensee), Tanabe Seiyaku (Licensee) 【药理作用】Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, beta1-Adrenoceptor Antagonists |
合成路线1
1) The reaction of phenol (I) with epichlorohydrin (II) gives 1,2-epoxy-3-phenoxypropane (III), which is treated with isopropylamine (IV) to afford 3-(isopropylamino)-1-phenoxy-2-propanol (V). Cyclization of (V) with diethyl carbonate (VI) yields 3-isopropyl-5-(phenoxymethyloxazolidin-2-one) (VII), which is chloromethylated with formaldehyde - HCl giving 3-isopropyl-5-(4-chloromethylphenoxymethyl)oxazolidin-2-one (VIII). Etherification of (VIII) with ethylene glycol monoisopropyl ether (IX) yields the corresponding ether (XI), which is finally deprotected by alkaline hydrolysis.
| 【1】 Harting, J.; et al.; Pharmacodynamic profile of the selective beta1-adrenoceptor antagonist bisoprolol. Arzneim-Forsch Drug Res 1986, 36, 2, 200. |
| 【2】 Castaner, J.; Prous, J.; Bisoprolol fumarate. Drugs Fut 1986, 11, 10, 829. |
| 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) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (III) | 23932 | 2-(phenoxymethyl)oxirane; oxiranylmethyl phenyl ether | 122-60-1 | C9H10O2 | 详情 | 详情 |
| (IV) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
| (V) | 23934 | 1-(isopropylamino)-3-phenoxy-2-propanol | C12H19NO2 | 详情 | 详情 | |
| (VI) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (VII) | 23936 | 3-isopropyl-5-(phenoxymethyl)-1,3-oxazolidin-2-one | C13H17NO3 | 详情 | 详情 | |
| (VIII) | 23937 | 5-[[4-(chloromethyl)phenoxy]methyl]-3-isopropyl-1,3-oxazolidin-2-one | C14H18ClNO3 | 详情 | 详情 | |
| (IX) | 23938 | 2-isopropoxy-1-ethanol | 109-59-1 | C5H12O2 | 详情 | 详情 |
| (X) | 23939 | 5-([4-[(2-isopropoxyethoxy)methyl]phenoxy]methyl)-3-isopropyl-1,3-oxazolidin-2-one | C19H29NO5 | 详情 | 详情 |
合成路线2
The condensation of 4-hydroxybenzyl alcohol (I) with 2-isopropoxyethanol (II) by heating at 150 C gives the corresponding benzyl ether (III), which is condensed with epichlorohydrin (IV) to yield the adduct (V). Finally, this compound is treated with isopropylamine in ethanol.
| 【1】 Schliep, H.-J.; Enenkel, H.-J.; Minck, K.; Becker, K.-H.; Jonas, R. (Merck Patent GmbH); Phenoxy-amino-propanols. US 4258062 . |
| 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) | 29474 | 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol | 623-05-2 | C7H8O2 | 详情 | 详情 |
| (II) | 23938 | 2-isopropoxy-1-ethanol | 109-59-1 | C5H12O2 | 详情 | 详情 |
| (III) | 40522 | 4-[(2-isopropoxyethoxy)methyl]phenol | C12H18O3 | 详情 | 详情 | |
| (IV) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (V) | 40523 | 4-[(2-isopropoxyethoxy)methyl]phenyl 2-oxiranylmethyl ether; 2-([4-[(2-isopropoxyethoxy)methyl]phenoxy]methyl)oxirane | C15H22O4 | 详情 | 详情 | |
| (VI) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |