|
【结 构 式】 
|
【分子编号】22700 【品名】methyl (E)-3-methoxy-2-propenoate 【CA登记号】34846-90-7 |
【 分 子 式 】C5H8O3 【 分 子 量 】116.11672 【元素组成】C 51.72% H 6.94% O 41.34% |
合成路线1
该中间体在本合成路线中的序号：(XII)Synthesis of intermediate (I): 1a) Dimethyl acetonedicarboxylate (IV) is treated with MgCl2 and triethylamine, giving the corresponding magnesium complex (V), which by cyclocondensation with chloroacetyl chloride and thiourea yields methyl 2-(2-aminothiazol-4-yl)-3-hydroxy-4-(methoxycarbonyl)-2-butenoate (VI). The reduction of (VI) with NaBH4 affords dimethyl 2-(2-aminothiazol-4-yl)-3-hydroxyglutarate (VII), which by successive treatments with benzyloxycarbonyl chloride (to protect the amino group), and with mesyl chloride - triethylamine (to dehydrate the OH group) is converted to methyl 2-[2 (benzyloxycarbonylamino)thiazol-4-y]-4-(methoxycarbonyl)-2-butenoate (VIII). The hydrolysis of (VIII) with aqueous NaOH in toluene gives the corresponding diacid (IX), which is selectively esterified with benzyl alcohol in acidic medium yielding (I). 1b) The reaction of methyl 2-(2-aminothiazol-4-yl)acetate (X) with beozyloxycarbonyl chloride and NaHCO3 gives the protected compound (XI), which is condensed with methyl 3-methoxyacrylate (XII) by means of sodium methoxide in DMF to yield dimethyl ester (VIII), already obtained.
| 【1】 Yoshioka, M.; Synthetic studies related to oral beta-lactam antibiotics. Pure Appl Chem 1987, 59, 8, 1041. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 | |
| 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 | |
| (I) | 22689 | (Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid | C23H20N2O6S | 详情 | 详情 | |
| (IV) | 22692 | dimethyl 3-oxopentanedioate | 1830-54-2 | C7H10O5 | 详情 | 详情 |
| (V) | 22693 | Bis(3-Hydroxy-2-pentenoic acid dimethyl ester) magnesium salt | C14H18MgO10 | 详情 | 详情 | |
| (VI) | 22694 | dimethyl (E)-2-(2-amino-1,3-thiazol-4-yl)-3-hydroxy-2-pentenedioate | C10H12N2O5S | 详情 | 详情 | |
| (VII) | 22695 | dimethyl 2-(2-amino-1,3-thiazol-4-yl)-3-hydroxypentanedioate | C10H14N2O5S | 详情 | 详情 | |
| (VIII) | 22696 | dimethyl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioate | C18H18N2O6S | 详情 | 详情 | |
| (IX) | 22697 | (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioic acid | C16H14N2O6S | 详情 | 详情 | |
| (X) | 22698 | methyl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)acetate | 64987-16-2 | C6H8N2O2S | 详情 | 详情 |
| (XI) | 22699 | methyl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)acetate | C14H14N2O4S | 详情 | 详情 | |
| (XII) | 22700 | methyl (E)-3-methoxy-2-propenoate | 34846-90-7 | C5H8O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)3-Cyanobenzaldehyde oxime (I) was treated with N-chlorosuccinimide to afford hydroxyiminoyl chloride (II). Subsequent cycloaddition of the intermediate nitrile oxide, generated in situ from (II) and Et3N, with methyl methoxyacrylate (III) produced isoxazole (IV). Then, basic hydrolysis of the ester group, followed by treatment with SOCl2 provided acid chloride (V). Aminobiphenyl (VIII) was obtained by Suzuki coupling of 4-bromoaniline (VI) with boronic acid (VII) using a palladium catalyst. Condensation of (VIII) with acid chloride (V) in the presence of Et3N then gave amide (IX). Alternatively, amide (IX) was obtained by AlMe3-catalyzed condensation of ester (IV) with amine (VIII). Treatment of nitrile (IX) with HCl in MeOH-CHCl3 generated the corresponding iminoester (X) with concomitant cleavage of the N-tert-butyl group. Finally, reaction of this iminoester with methanolic ammonium carbonate afforded the target amidine.
| 【1】 Wexler, R.R.; Bostrom, L.L.; Pinto, D.J.; Wrong, P.C.; Pruitt, J.R.; Knabb, R.M.; Estrella, M.J.; Quan, M.L.; Isoxazolines and isoxazoles as factor Xa inhibitor. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 077. |
| 【2】 Quan, M.L.; Pinto, D.J.P.; Fevig, J.M.; Pruitt, J.R. (DuPont Pharmaceuticals Co.); Oxygen or sulfur containing heteroaromatics as fac. WO 9828282 . |
| 【3】 Pinto, D.J.P.; Pruitt, J.R.; Fevig, J.M.; Quan, M.L. (DuPont Pharmaceuticals Co.); Phenyl-isoxazoles as factor Xa inhibitors. US 6187797 . |
| 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) | 23357 | 3-[(hydroxyimino)methyl]benzonitrile | C8H6N2O | 详情 | 详情 | |
| (II) | 23358 | 3-cyano-N-hydroxybenzenecarboximidoyl chloride | C8H5ClN2O | 详情 | 详情 | |
| (IV) | 23360 | methyl 3-(3-cyanophenyl)-4-isoxazolecarboxylate | C12H8N2O3 | 详情 | 详情 | |
| (V) | 23361 | 3-(3-cyanophenyl)-4-isoxazolecarbonyl chloride | C11H5ClN2O2 | 详情 | 详情 | |
| (VII) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 | |
| (VIII) | 23364 | 3-(3-cyanophenyl)-4-isoxazolecarbonyl chloride | C11H5ClN2O2 | 详情 | 详情 | |
| (IX) | 23365 | N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-3-(3-cyanophenyl)-4-isoxazolecarboxamide | C27H24N4O4S | 详情 | 详情 | |
| (X) | 23366 | methyl 3-[4-([[2'-(aminosulfonyl)[1,1'-biphenyl]-4-yl]amino]carbonyl)-3-isoxazolyl]benzenecarboximidoate | C24H20N4O5S | 详情 | 详情 | |
| (XII) | 22700 | methyl (E)-3-methoxy-2-propenoate | 34846-90-7 | C5H8O3 | 详情 | 详情 |
| (XVI) | 22531 | 4-Bromoaniline; 4-Bromophenylamine | 106-40-1 | C6H6BrN | 详情 | 详情 |