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【结 构 式】 
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【分子编号】16549 【品名】methyl 2-[1-(hydroxymethyl)cyclopropyl]acetate 【CA登记号】 |
【 分 子 式 】C7H12O3 【 分 子 量 】144.17048 【元素组成】C 58.32% H 8.39% O 33.29% |
合成路线1
该中间体在本合成路线中的序号：(XXVII)Compound (XIX) is condensed with 2-[1-(acetylsulfanylmethyl)cyclopropyl]acetic acid methyl ester (XX) by means of Cs2CO3 in acetonitrile yielding the expected condensation product (XXI). Finally, this compound is treated successively with pyridine and p-toluenesulfonic acid to eliminate the tetrahydropyranyl protecting group, and with NaOH to hydrolyzed the acetate ester group of (XXI). 4) The 2-[1-(acetylsulfanylmethyl)cyclopropyl]acetic acid methyl ester (XX) has been obtained as follows: The reduction of diethyl cyclopropane-1,1-dicarboxylate (XXII) with LiAlH4 in THF gives 1,1-cyclopropanedimethanol (XI), which is monobenzoylated with benzoyl chloride (XXIII) and pyridine in dichloromethane yielding benzoic acid 1-(hydroxymethyl)cyclopropylmethyl ester (XXIV). The mesylation of (XXIV) as usual affords the mesylate (XXV), which is treated with NaCN in DMSO to give 2-[1-(benzoyloxymethyl)cyclopropyl]acetonitrile (XXVI). The hydrolysis of (XXVI) with KOH in refluxing ethanol, followed by methylation with diazomethane, yields methyl 2-[1-(hydroxymethyl)cyclopropyl]acetate (XXVII), which is mesylated as usual affording the mesylate (XXIII). Finally, this compound is treated with cesium thiocetate in dichloromethane to give (XX).
| 【1】 Graul, A.; Martín, L.; Castañer, J.; Montelukast Sodium. Drugs Fut 1997, 22, 10, 1103. |
| 【2】 Labelle, M.; Belley, M.; Gareau, Y.; et al.; Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enzyme induction. Bioorg Med Chem Lett 1995, 5, 3, 283-8. |
| 【3】 Belley, M.L.; Leger, S.; Roy, P.; Xiang, Y.B.; Labelle, M.; Guay, D. (Merck Frosst Canada Inc.); Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists. EP 0480717; JP 1993105665 . |
| 【4】 Bhupathy, M.; McNamara, J.M.; Sidler, D.R.; Volante, R.P.; Bergan, J.J. (Merck & Co., Inc.); Process for the preparation of leukotriene antagonists. WO 9518107 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 16533 | [1-(hydroxymethyl)cyclopropyl]methanol | C5H10O2 | 详情 | 详情 | |
| (XVIII) | 16540 | (1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]-1-propanol | C34H36ClNO3 | 详情 | 详情 | |
| (XIX) | 16541 | (1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]propyl methanesulfonate | C35H38ClNO5S | 详情 | 详情 | |
| (XX) | 16542 | methyl 2-[1-[(acetylsulfanyl)methyl]cyclopropyl]acetate | C9H14O3S | 详情 | 详情 | |
| (XXI) | 16543 | methyl 2-(1-[[((1R)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]propyl)sulfanyl]methyl]cyclopropyl)acetate | C41H46ClNO4S | 详情 | 详情 | |
| (XXII) | 16544 | diethyl 1,1-cyclopropanedicarboxylate | 1559-02-0 | C9H14O4 | 详情 | 详情 |
| (XXIII) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XXIV) | 16546 | [1-(hydroxymethyl)cyclopropyl]methyl benzoate | C12H14O3 | 详情 | 详情 | |
| (XXV) | 16547 | (1-[[(methylsulfonyl)oxy]methyl]cyclopropyl)methyl benzoate | C13H16O5S | 详情 | 详情 | |
| (XXVI) | 16548 | [1-(cyanomethyl)cyclopropyl]methyl benzoate | C13H13NO2 | 详情 | 详情 | |
| (XXVII) | 16549 | methyl 2-[1-(hydroxymethyl)cyclopropyl]acetate | C7H12O3 | 详情 | 详情 |