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【结 构 式】 
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【分子编号】10398 【品名】2-Ethoxy-4-iodo-1-(pentyloxy)benzene; 2-Ethoxy-4-iodophenyl pentyl ether 【CA登记号】 |
【 分 子 式 】C13H19IO2 【 分 子 量 】334.19713 【元素组成】C 46.72% H 5.73% I 37.97% O 9.57% |
合成路线1
该中间体在本合成路线中的序号：(I)This compound can be obtained by three related ways: 1) The carboxylation of 3-ethoxy-4-pentyloxyiodobenzene (I) with CO2 and butyllithium in ether gives 3-ethoxy-4-pentyloxybenzoic acid (II), which is reduced with LiAlH4 in refluxing ether to yield the corresponding benzyl alcohol (III). The controlled oxidation of (III) with pyridinium chlorochromate in dichloromethane affords 3-ethoxy-4-pentyloxybenazldehyde (IV), which is treated wtih NaCN and acetic acid - water giving 2-(3-ethoxy-4-pentyloxyphenyl)-2-hydroxyacetonitrile (V). Finally, this compound is cyclized with thiourea (VI) and HCl in 2-methoxyethanol. 2) The alkylation of ethyl-vanilline (VII) with c and K2CO3 in hot DMF gives aldehyde (IV), which by reaction with NaCH in methanol - HCl yields the cyanohydrine (V). The reaction of (V) with SOCl2 in refluxing CHCl3 affords 2-chloro-2-(3-ethoxy-5-pentyloxyphenyl)acetonitrile (VIII), which is finally cyclized with thiourea (VI) in ethylene glycol monomethyl ether - HCl at 110 C in refluxing ethanol - HCl. 3) The cyclization of 2-(3-ethoxy-4-pentyloxyphenyl)-2-hydroxyacetic acid (IX) with thiourea (VI) under acidic conditions gives 5-(3-ethoxy-4-pentyloxyphenyl)-2-iminothiazolidin-4-one (X), which is then hydrolyzed to the desired product.
| 【1】 Awata, T.; Maenaka, T.; Kawamatsu, Y. (Senju Pharmaceuticals Co., Ltd.); Ophthalmic topical agent for remedy of diseases of iris and ciliary body. EP 0170237; JP 1986043114; US 4602026 . |
| 【2】 Kawamatsu, Y.; Yamamoto, Y. (Senju Pharmaceuticals Co., Ltd.; Takeda Chemical Industries, Ltd.); Thiazolidine derivs. and their production and use. EP 0033617 . |
| 【3】 Imanishi, M.; Imamiya, E.; Kawamatsu, Y.; Hayashi, N.; Synthesis of 5-(3-ethoxy-4-pentyloxyphenyl)-2,4-[5-14C]thiazolidinedione ([14C]CT-112). J Takeda Res Lab 1983, 42, 3/4, 238-40. |
| 【4】 Tawada, H.; Mizuno, K.; Meguro, K.; Sohda, T.; Imamiya, E.; Kawamatsu, Y.; Yamamoto, Y.; Studies on antidiabetic agents. III. 5-Arylthiazolidine-2,4-diones as potent aldose reductase inhibitors. Chem Pharm Bull 1982, 30, 10, 3601-16. |
| 【5】 Prous, J.; Castaner, J.; CT-112. Drugs Fut 1991, 16, 10, 895. |
| 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) | 10398 | 2-Ethoxy-4-iodo-1-(pentyloxy)benzene; 2-Ethoxy-4-iodophenyl pentyl ether | C13H19IO2 | 详情 | 详情 | |
| (II) | 10399 | 3-Ethoxy-4-(pentyloxy)benzoic acid | C14H20O4 | 详情 | 详情 | |
| (III) | 10400 | [3-Ethoxy-4-(pentyloxy)phenyl]methanol | C14H22O3 | 详情 | 详情 | |
| (IV) | 10401 | 3-Ethoxy-4-(pentyloxy)benzaldehyde | C14H20O3 | 详情 | 详情 | |
| (V) | 10402 | 2-[3-Ethoxy-4-(pentyloxy)phenyl]-2-hydroxyacetonitrile | C15H21NO3 | 详情 | 详情 | |
| (VI) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VII) | 10404 | Ethyl vanillin; 3-Ethoxy-4-hydroxybenzaldehyde | 121-32-4 | C9H10O3 | 详情 | 详情 |
| (VIII) | 10405 | 2-Chloro-2-[3-ethoxy-4-(pentyloxy)phenyl]acetonitrile | C15H20ClNO2 | 详情 | 详情 | |
| (IX) | 10406 | 2-[3-Ethoxy-4-(pentyloxy)phenyl]-2-hydroxyacetic acid | C15H22O5 | 详情 | 详情 | |
| (X) | 10407 | 5-[3-Ethoxy-4-(pentyloxy)phenyl]-2-imino-1,3-thiazolidin-4-one | C16H22N2O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The intermediate stannane derivative (XVI) has been obtained as follows: The esterification of propynoic acid (XII) with diphenyldiazomethane (XIII) in benzene gives the corresponding ester (XIV), which is then condensed with Me3Sn-Cu(CN)Li (XV) in THF/methanol to yield the desired intermediate (XVI). 3-Hydroxy-2(S)-methylpropionic acid methyl ester (I) is converted into the chiral tosylate (II) by conventional methods. The condensation of (II) with 4-pentenylmagnesium bromide (III) in THF gives the chiral tetrahydropyranyl ether (IV), which is condensed with the phosphonate (V) by means of KHMDS in THF/toluene yielding the chiral nonenoic ester (VI). The reduction of (VI) with DIBAL in the same solvent, followed by protection of the resulting alcohol with TBDPSCl and TEA in dichloromethane affords the protected diol (VII). The selective elimination of the THP protecting group, followed by reaction with TsCl and TEA in dichloromethane affords the tosylate (VIII), which is condensed with lithium acetylide (IX) in DMSO to provide the terminal acetylene (X). The deprotection of (X) with TBAF, followed by reaction with Me3Al, Cp2ZrCl2, and I2 in THF gives the omega iodoundecadienol (XI), which is condensed with the stannane derivative (XVI) by means of PdCl2 in DMF yielding the tetradecatrienoic diphenylmethyl ester (XVII). The chiral epoxidation of (XVII) with Ti(OiPr)4, BuOOH and (R,R)(+)-diisopropyl tartrate (DIPT) in dichloroethane affords the hydroxymethyl-oxirane (XVIII), which is oxidized with tetrapropylammonium perruthenate (TPAP) to provide the oxirane carbaldehyde (XIX).
| 【1】 Bates, R.W.; et al.; Total synthesis of the cholesterol biosynthesis inhibitor 1233A via a (Pi-allyl)tricarbonyliron lactone complex. J Chem Soc - Perkins Trans I 1999, 14, 1917. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 41854 | (2S)-2-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butyl 4-methylbenzenesulfonate | C17H26O5S | 详情 | 详情 | |
| (III) | 39424 | bromo(4-pentenyl)magnesium | C5H9BrMg | 详情 | 详情 | |
| (IV) | 41855 | (3R)-3-methyl-8-nonenyl tetrahydro-2H-pyran-2-yl ether; 2-[[(3R)-3-methyl-8-nonenyl]oxy]tetrahydro-2H-pyran | C15H28O2 | 详情 | 详情 | |
| (V) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (VI) | 41857 | methyl (Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenoate | C17H30O4 | 详情 | 详情 | |
| (VII) | 41858 | tert-butyl[[(Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenyl ether | C32H48O3Si | 详情 | 详情 | |
| (VIII) | 41859 | (2R,7Z)-9-[[tert-butyl(diphenyl)silyl]oxy]-2-methyl-7-nonenyl 4-methylbenzenesulfonate | C33H44O4SSi | 详情 | 详情 | |
| (IX) | 17461 | ethynyllithium | C2HLi | 详情 | 详情 | |
| (X) | 41860 | tert-butyl[[(Z,8R)-8-methyl-2-undecen-10-ynyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (Z,8R)-8-methyl-2-undecen-10-ynyl ether | C28H38OSi | 详情 | 详情 | |
| (XI) | 41861 | (2Z,8R,10E)-11-iodo-8,10-dimethyl-2,10-undecadien-1-ol | C13H23IO | 详情 | 详情 | |
| (XII) | 10398 | 2-Ethoxy-4-iodo-1-(pentyloxy)benzene; 2-Ethoxy-4-iodophenyl pentyl ether | C13H19IO2 | 详情 | 详情 | |
| (XIII) | 40585 | 1-[diazo(phenyl)methyl]benzene | C13H10N2 | 详情 | 详情 | |
| (XIV) | 41862 | benzhydryl 2-butynoate | C17H14O2 | 详情 | 详情 | |
| (XVI) | 41863 | benzhydryl (E)-3-(trimethylstannyl)-2-butenoate | C20H24O2Sn | 详情 | 详情 | |
| (XVII) | 41864 | benzhydryl (2E,4E,7R,12Z)-14-hydroxy-3,5,7-trimethyl-2,4,12-tetradecatrienoate | C30H38O3 | 详情 | 详情 | |
| (XVIII) | 41865 | benzhydryl (2E,4E,7R)-11-[(2R,3S)-3-(hydroxymethyl)oxiranyl]-3,5,7-trimethyl-2,4-undecadienoate | C30H38O4 | 详情 | 详情 | |
| (XIX) | 41866 | benzhydryl (2E,4E,7R)-11-[(2R,3R)-3-formyloxiranyl]-3,5,7-trimethyl-2,4-undecadienoate | C30H36O4 | 详情 | 详情 |