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【结 构 式】 
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【分子编号】14652 【品名】salicylamide 【CA登记号】65-45-2 |
【 分 子 式 】C7H7NO2 【 分 子 量 】137.13812 【元素组成】C 61.31% H 5.14% N 10.21% O 23.33% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of salicylamide (I) with cyclopropylmethyl bromide in the presence of potassium hydroxide gives the ether (II). This intermediate is converted to the benzoyl isocyanate (III) by refluxing with oxalyl chloride in 1,2-dichloroethane. The isocyanate is converted without further purification to endo-2-(cyclopropylmethoxy)-N-[[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl) amino]-carbonyl]benzamide (WAY100289) by reaction with endo-3-aminotropane.
| 【1】 Ward, T.J.; White, J.C.; Bradley, G. (John Wyeth & Brother Ltd.); Aroyl-ureas. AU 9163749; EP 0422846; GB 2236528; JP 1991133986 . |
| 【2】 Ward, T.J.; Taylor, A.; White, J.C.; Coleman, J.; Bradley, G.; Rhodes, K.F.; Novel antagonists of the 5-HT3 receptor. Synthesis and structure activity relationships of (2-alkoxybenzoyl)ureas. J Med Chem 1992, 35, 9, 1515-9. |
| 【3】 Ward, T.J.; WAY 100289. Drugs Fut 1993, 18, 1, 23. |
合成路线2
该中间体在本合成路线中的序号：(XI)The reaction of 2-hydroxybenzamide (XI) with cyclohexanone (XII) by means of Ts-OH in toluene gives the spiranic benzoxazine (XIII), which is condensed with 2-bromopropionyl bromide (XIV) by means of pyridine in toluene, yielding the corresponding acylated benzoxazine (XV). The condensation of (XV) with chiral azetidinone (XVI) by means of Zn in refluxing THF affords the adduct (XVII), which is finally hydrolyzed with LiOH and H2O2 to furnish the target azetidinonepropionic acid (I).
| 【1】 Lu, X.; et al.; Process development on (3S,4S)-[(R)-1'((tert-butyldimethylsilyl)oxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone: 1-beta-methylcarbapanem key intermediate. Org Process Res Dev 2001, 5, 2, 186. |
| 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) | 30029 | (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid | C14H27NO4Si | 详情 | 详情 | |
| (XI) | 14652 | salicylamide | 65-45-2 | C7H7NO2 | 详情 | 详情 |
| (XII) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (XIII) | 46246 | C13H15NO2 | 详情 | 详情 | ||
| (XIV) | 13127 | 2-Bromopropionyl bromide; 2-Bromopropanoyl bromide | 563-76-8 | C3H4Br2O | 详情 | 详情 |
| (XV) | 37738 | 3-(2-Bromo-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one | 158299-05-9 | C16H18BrNO3 | 详情 | 详情 |
| (XVI) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (XVII) | 46247 | C27H40N2O5Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Cyclization of salicylamide (I) with salicyloyl chloride (II) by heating at 170 oC provides 2-(2-hydroxyphenyl)-benz[e][1,3]oxazin-4-one (III), which is finally cyclized with 4-hydrazinobenzoic acid (IV) in refluxing ethanol.
| 【1】 Lattmann, R.; Acklin, P. (Novartis AG); Substd. 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators. EP 0914118; JP 2000507601; WO 9749395 . |
| 【2】 McIntyre, J.A., Castaner, J., Mealy, N.E., Bayes, M.; Deferasirox. Drugs Fut 2004, 29 (4): 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) | 14652 | salicylamide | 65-45-2 | C7H7NO2 | 详情 | 详情 |
| (II) | 32668 | 2-hydroxybenzoyl chloride | C7H5ClO2 | 详情 | 详情 | |
| (III) | 49109 | 2-(2-hydroxyphenyl)-4H-1,3-benzoxazin-4-one | C14H9NO3 | 详情 | 详情 | |
| (IV) | 49110 | 4-Carboxyphenyl hydrazine; p-Hydrazinobenzoic acid; p-Carboxyphenyl hydrazine; 4-Hydrazinobenzoic acid | 619-67-0 | C7H8N2O2 | 详情 | 详情 |