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【结 构 式】 
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【分子编号】53946 【品名】8-anilino-8-oxooctanoic acid 【CA登记号】 |
【 分 子 式 】C14H19NO3 【 分 子 量 】249.3098 【元素组成】C 67.45% H 7.68% N 5.62% O 19.25% |
合成路线1
该中间体在本合成路线中的序号：(VII)2. The reaction of the diacid monoester (IV) with oxalyl chloride in benzene gives the corresponding acyl chloride (V), which is treated with aniline (II) and pyridine in THF, yielding the monoester monoamide (VI). The hydrolysis of the ester group of (VI) with OH in refluxing methanol affords the monoamide carboxylic acid (VII), which is condensed with O-benzylhydroxylamine (VIII) by means of DCC in pyridine to provide the protected hydroxamic acid (IX). Finally, this compound is debenzylated with H2 over Pd/C in methanol to furnish the target hydroxamic acid with yields of 35-65%. 3. A mixture of diacid dichloride (I), aniline (II) and O-benzylhydroxylamine (VIII) in pyridine gives, after chromatographic purification, the protected hydroxamic acid (IX), which is debenzylated as before to provide the target hydroxamic acid with yields of 20-35%. 4. The reaction of acid dichloride (I) with aniline (II) and O-(trimethylsilyl)hydroxylamine (X) by means of TEA in chloroform gives the trimethylsilyl protected compound (XI), which is desilylated with NH4Cl in hot methanol to afford the target hydroxamic acid with yields of 20-33%.
| 【1】 Breslow, R.; Rifkind, R.A.; Jursic, B. (Columbia University; Sloan-Kettering Institute); Novel potent inducers of terminal differentiation and methods of use thereof. WO 9307148 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IV) | 53943 | Ethyl hydrogen suberate; Monoethyl suberate; Suberic acid monoethyl ester | 14113-01-0 | C10H18O4 | 详情 | 详情 |
| (V) | 53944 | ethyl 8-chloro-8-oxooctanoate | C10H17ClO3 | 详情 | 详情 | |
| (VI) | 53945 | ethyl 8-anilino-8-oxooctanoate | C16H23NO3 | 详情 | 详情 | |
| (VII) | 53946 | 8-anilino-8-oxooctanoic acid | C14H19NO3 | 详情 | 详情 | |
| (VIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (IX) | 53947 | N~1~-(benzyloxy)-N~8~-phenyloctanediamide | C21H26N2O3 | 详情 | 详情 | |
| (X) | 26091 | O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane | 22737-36-6 | C3H11NOSi | 详情 | 详情 |
| (XI) | 53948 | N~1~-phenyl-N~8~-[(trimethylsilyl)oxy]octanediamide | C17H28N2O3Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)5. The condensation of diacid (XII) with aniline (II) by heating at 190 C gives the monoamide (VII), which is esterified by means of Dowex 50W-X2 in refluxing methanol to yield the monoamide monoester (XIII). Finally, this compound is treated with hydroxylamine and NaOMe in methanol to afford the target hydroxamic acid with overall yields of around 37%.
| 【1】 Stowell, J.C.; et al.; The synthesis of N-hydroxy-N'-phenyloctanediamide and its inhibitory effect on proliferation of AXC rat prostate cancer cells. J Med Chem 1995, 38, 8, 1411. |
合成路线3
该中间体在本合成路线中的序号：(VII)6. The reaction of acid (XII) with refluxing acetic anhydride gives the cyclic anhydride (XIV), which is treated with aniline (II) in THF to yield the monoamide (VII). The reaction of (VII) with ethyl chloroformate and TEA in THF affords the mixed anhydride (XV), which is finally treated with hydroxylamine in methanol to afford the target hydroxamic acid with overall yields of around 58%.
| 【1】 Mai, A.; et al.; A new facile and expeditious synthesis of N-hydroxy-N'-phenyloctanediamide, a potent inducer of terminal cytodifferentiation. Org Prep Proced Int 2001, 33, 4, 391. |