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【结 构 式】 
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【分子编号】11418 【品名】methyl 3-sulfanylpropanoate; Methyl 3-mercaptopropionate 【CA登记号】2935-90-2 |
【 分 子 式 】C4H8O2S 【 分 子 量 】120.17232 【元素组成】C 39.98% H 6.71% O 26.63% S 26.68% |
合成路线1
该中间体在本合成路线中的序号：(VII)A new enantioselective synthesis of SK&F-104353 has been reported: The compound can be prepared in two related ways: 1) The condensation of 2-(8-phenyloctyl)benzaldehyde (I) with 2'-acetonaphthone (II) by means of NaOEt in ethanol gives (E)-1-(2-naphthyl)-3-[2-(8-phenyloctyl)phenyl]-2-propen-1-one (III), which is regioselectively epoxidized with H2O2 and poly-L-leucine in hexane/water to yield the corresponding (2R-trans)-epoxide (IV). The oxidation of (IV) with m-chloroperbenzoic acid in CH2Cl2 affords (2R-trans)-3-[2-(8-phenyloctyl)phenyl]oxirane-2-carboxylic acid 2-naphthyl ester (V), which is hydrolyzed with LiOH in ethanol to the corresponding lithium salt (VI). Finally, (VI) is condensed with 3-mercaptopropionic acid methyl ester (VII) by means of NaOMe in methanol to give a mixture of regioisomers that are separated by column chromatography. 2) The reaction of the oxiranyl ester (V) with ammonia in acetone/water yields the corresponding amide (VIII), which is condensed with the sodium salt of propenoate (VII) by means of titanium tetrapropoxide in CH2Cl2 to afford the amide ester (X). The basic hydrolysis of (X) with NaOH in methanol gives the corresponding acid amide (XI), which is finally submitted to acid hydrolysis with aqueous HCl.
| 【1】 Flisak, J.R.; Lantos, I.; Snyder, L.; Gombatz, K.J.; Mendelson, W.L.; Jarmas, A.A.; Holmes, M.M.; Remich, J.J.; Novack, V.J.; A practical, enantioselective synthesis of SK&F 104353. J Org Chem 1993, 58, 23, 6247. |
| 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) | 11408 | 2-(8-Phenyloctyl)benzaldehyde | C21H26O | 详情 | 详情 | |
| (II) | 11413 | 1-(2-Naphthyl)-1-ethanone; Methyl 2-naphthyl ketone | 93-08-3 | C12H10O | 详情 | 详情 |
| (III) | 11414 | (E)-1-(2-Naphthyl)-3-[2-(8-phenyloctyl)phenyl]-2-propen-1-one | C33H34O | 详情 | 详情 | |
| (IV) | 11415 | 2-Naphthyl[(2R,3S)-3-[2-(8-phenyloctyl)phenyl]oxiranyl]methanone | C33H34O2 | 详情 | 详情 | |
| (V) | 11416 | 2-naphthyl (2R,3S)-3-[2-(8-phenyloctyl)phenyl]-2-oxiranecarboxylate | C33H34O3 | 详情 | 详情 | |
| (VI) | 11417 | lithium (2R,3S)-3-[2-(8-phenyloctyl)phenyl]-2-oxiranecarboxylate | C23H27LiO3 | 详情 | 详情 | |
| (VII) | 11418 | methyl 3-sulfanylpropanoate; Methyl 3-mercaptopropionate | 2935-90-2 | C4H8O2S | 详情 | 详情 |
| (VIII) | 11419 | (2R,3S)-3-[2-(8-Phenyloctyl)phenyl]-2-oxiranecarboxamide | C23H29NO2 | 详情 | 详情 | |
| (IX) | 11420 | Methyl 3-sulfanylpropionate sodium salt | C4H7NaO2S | 详情 | 详情 | |
| (X) | 11421 | methyl 3-([(1R,2S)-3-amino-2-hydroxy-3-oxo-1-[2-(8-phenyloctyl)phenyl]propyl]sulfanyl)propanoate | C27H37NO4S | 详情 | 详情 | |
| (XI) | 11422 | 3-([(1R,2S)-3-Amino-2-hydroxy-3-oxo-1-[2-(8-phenyloctyl)phenyl]propyl]sulfanyl)propionic acid | C26H35NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Aromatic nucleophilic substitution of 3-chloro-4-fluorobenzaldehyde (I) with methyl 3-mercaptopropionate (II) yielded the mercapto aldehyde (III). This was subjected to Knoevenagel condensation with malonic acid to furnish the cinnamic acid derivative (IV), which was further converted to the corresponding acid chloride (V) by using oxalyl chloride. Condensation of acid chloride (V) with N-acetylpiperazine (VI) yielded the diacyl piperazine (VII). The protected benzenethiol of (VII) was released by treatment of the beta-mercaptopropionate (VII) with potassium tert-butoxide to give the potassium thiolate (VIII). Finally, Ullmann coupling of (VIII) with 6-iodobenzodioxan (IX) furnished the title compound.
| 【1】 Liu, G.; Okasinski, O.F.; DeVries, P.; Mendoza, R.; Leitza, S.; Olejniczak, E.T.; von Geldern, T.W.; Huth, J.R.; Fesik, S.W.; Reilly, E.B.; Novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 2. Mechanism of inhibition and structure-based improvement of pharmaceutical properties. J Med Chem 2001, 44, 8, 1202. |
| 【2】 Jae, H.-S.; Pei, Z.; Staeger, M.A.; Gunawardana, I.W.; Winn, M.; Freeman, J.C.; Liu, G.; Link, J.; Boyd, S.A.; Zhu, G.-D.; Von Geldern, T.W.; Xin, Z.; Lynch, J.K.; Wang, S. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. WO 0059880 . |
| 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) | 49749 | 3-Chloro-4-fluorobenzaldehyde; 4-Fluoro-3-chlorobenzaldehyde | 34328-61-5 | C7H4ClFO | 详情 | 详情 |
| (II) | 11418 | methyl 3-sulfanylpropanoate; Methyl 3-mercaptopropionate | 2935-90-2 | C4H8O2S | 详情 | 详情 |
| (III) | 48173 | methyl 3-[(2-chloro-4-formylphenyl)sulfanyl]propanoate | C11H11ClO3S | 详情 | 详情 | |
| (IV) | 48174 | (E)-3-[3-chloro-4-[(3-methoxy-3-oxopropyl)sulfanyl]phenyl]-2-propenoic acid | C13H13ClO4S | 详情 | 详情 | |
| (V) | 48175 | methyl 3-([2-chloro-4-[(E)-3-chloro-3-oxo-1-propenyl]phenyl]sulfanyl)propanoate | C13H12Cl2O3S | 详情 | 详情 | |
| (VI) | 20674 | N-Acetyl piperazine; 1-(1-piperazinyl)-1-ethanone | 13889-98-0 | C6H12N2O | 详情 | 详情 |
| (VII) | 48176 | methyl 3-([4-[(E)-3-(4-acetyl-1-piperazinyl)-3-oxo-1-propenyl]-2-chlorophenyl]sulfanyl)propanoate | C19H23ClN2O4S | 详情 | 详情 | |
| (VIII) | 48177 | potassium 4-[(E)-3-(4-acetyl-1-piperazinyl)-3-oxo-1-propenyl]-2-chlorobenzenethiolate | C15H16ClKN2O2S | 详情 | 详情 | |
| (IX) | 49750 | 3,4-Ethylenedioxyiodobenzene | 57744-67-9 | C8H7IO2 | 详情 | 详情 |