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【结 构 式】 
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【分子编号】50272 【品名】Malonic acid monomethyl ester chloride; Methyl (chloroformyl)acetate; Methyl malonyl chloride ;Methyl 3-chloro-3-oxopropionate 【CA登记号】37517-81-0 |
【 分 子 式 】C4H5ClO3 【 分 子 量 】136.5346 【元素组成】C 35.19% H 3.69% Cl 25.97% O 35.15% |
合成路线1
该中间体在本合成路线中的序号：(XI)In a different strategy, the dioxinoquinoline system (XII) was prepared by acylation of amino ketone (X) with methyl malonyl chloride (XI), followed by intramolecular Knoevenagel condensation of the intermediate keto malonamide. Chlorination of (XII) with POCl3 afforded the dichloro derivative (XIII), which was subsequently condensed with N-methylpiperazine (IX) to give (XIV). Reduction of the ester group of (XIV) by means of DIBAL provided alcohol (XV). Replacement of the 7-chloro of (XV) by an iodide group required previous oxidation of (XV) to the more reactive aldehyde (XVI). Treatment of (XVI) with NaI and HCl led to the corresponding iodo aldehyde, which was further reduced to alcohol (XVII) using NaBH4.
| 【1】 Fang, F.G.; Xie, S.; Lowery, M.W. (GlaxoSmithKline Inc.); Intermediates in pharmaceutical camptothecin preparation. WO 9529917 . |
| 【2】 Huie, E.M.; Fang, F.G.; Xie, S.; Comins, D.L. (GlaxoSmithKline Inc.; North Carolina State University); Preparation of a camptothecin deriv. by intramolecular cyclisation. WO 9529919 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (X) | 54870 | 1-(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)-2-chloro-1-ethanone | C10H10ClNO3 | 详情 | 详情 | |
| (XI) | 50272 | Malonic acid monomethyl ester chloride; Methyl (chloroformyl)acetate; Methyl malonyl chloride ;Methyl 3-chloro-3-oxopropionate | 37517-81-0 | C4H5ClO3 | 详情 | 详情 |
| (XII) | 54872 | methyl 9-(chloromethyl)-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylate | C14H12ClNO5 | 详情 | 详情 | |
| (XIII) | 54873 | methyl 7-chloro-9-(chloromethyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylate | C14H11Cl2NO4 | 详情 | 详情 | |
| (XIV) | 54874 | methyl 7-chloro-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylate | C19H22ClN3O4 | 详情 | 详情 | |
| (XV) | 54875 | {7-chloro-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol | C18H22ClN3O3 | 详情 | 详情 | |
| (XVI) | 54876 | 7-chloro-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbaldehyde | C18H20ClN3O3 | 详情 | 详情 | |
| (XVII) | 54877 | {7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol | C18H22IN3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Indolinone intermediate (VII): 1. The reductoalkylation of 4-ethoxyaniline (I) with benzaldehyde and NaBH4 in methanol gives the protected aniline (II), which is condensed with methoxymalonyl chloride (III) by means of TEA in dichloromethane to yield the malonamic derivative (IV). The reaction of (IV) with methanesulfonyl azide (V) and TEA affords the diazo compound (VI), which is finally submitted to a decarboxylative cyclization by means of Nafion H (a perfluorinated ion exchange resin) to provide the target indolinone intermediate (VII). 2. The condensation of the protected aniline (II) with diketene (VIII) by means of TEA in THF gives the 3-oxobutyramide (IX), which is treated with methanesulfonyl azide (V) and TEA to yield the diazo compound (X). The deacylation of (X) with KOH in acetonitrile affords the diazoacetamide (XI), which is finally cyclized to the target indolinone intermediate (VII) by means of Rh(OAc)2 in dichloromethane.
| 【1】 Venkatesan, H.; et al.; Total synthesis of SR 121463 A, a highly potent and selective vasopressin V2 receptor antagonist. J Org Chem 2001, 66, 11, 3653. |
| 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) | 45939 | 4-Aminophenetole; 1-Amino-4-ethoxybenzene; 4-Aminoethoxybenzene; 4-Ethoxyphenylamine; p-Phenetidine; 4-Ethoxyaniline | 156-43-4 | C8H11NO | 详情 | 详情 |
| (II) | 50271 | N-benzyl-4-ethoxyaniline; N-benzyl-N-(4-ethoxyphenyl)amine | C15H17NO | 详情 | 详情 | |
| (III) | 50272 | Malonic acid monomethyl ester chloride; Methyl (chloroformyl)acetate; Methyl malonyl chloride ;Methyl 3-chloro-3-oxopropionate | 37517-81-0 | C4H5ClO3 | 详情 | 详情 |
| (IV) | 50273 | methyl 3-(benzyl-4-ethoxyanilino)-3-oxopropanoate | C19H21NO4 | 详情 | 详情 | |
| (V) | 50274 | methanesulfonyl azide | CH3N3O2S | 详情 | 详情 | |
| (VI) | 50275 | C19H19N3O4 | 详情 | 详情 | ||
| (VII) | 50276 | 1-benzyl-5-ethoxy-1,3-dihydro-2H-indol-2-one | C17H17NO2 | 详情 | 详情 | |
| (VIII) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (IX) | 50277 | N-benzyl-N-(4-ethoxyphenyl)-3-oxobutanamide | C19H21NO3 | 详情 | 详情 | |
| (X) | 50278 | C19H19N3O3 | 详情 | 详情 | ||
| (XI) | 50279 | C17H17N3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIV)Chlorination of 2-chloro-5-nitrobenzenesulfonic acid (XIV) with SOCl2 in refluxing DMF gives the sulfonyl chloride (XV), which is converted to the corresponding sulfonamide (XVI) by treatment with NH4OH in toluene/THF. Amination of the chloro sulfonamide (XVI) with (NH4)2CO3 and NH4OH in the presence of CuSO4 at 118 °C leads to 2-amino-5-nitrobenzenesulfonamide (XVII). Alternatively, chlorination of 2-amino-5-nitrobenzenesulfonic acid (XVIII) using POCl3 in sulfolane at 110-120 °C provides the corresponding sulfonyl chloride (XIX), which is treated with NH4OH to yield sulfonamide (XVII). Reduction of the nitro moiety of compound (XVII) with H2 over Pd/C in the presence of MsOH in EtOH/H2O at 55 °C affords 2,5-diaminobenzenesulfonamide mesylate (XX), which can also be obtained by chloride substitution in 2-chloro-5-nitrobenzenesulfonamide (XVI) with benzylamine by means of Et3N in acetonitrile at 92 °C, followed by hydrogenolysis of the resulting 2-(benzylamino)-5-nitrobenzenesulfonamide (XXI) over Pd/C in the presence of MsOH in THF/EtOH/H2O. Selective N-sulfonylation of diamine (XX) with methanesulfonyl chloride (XXII) and pyridine in CH2Cl2 or acetonitrile gives rise to 2-amino-5-(methylsulfonamido)benzenesulfonamide (XXIII), which is then condensed with either methyl malonyl chloride (XXIV) in THF or ethyl malonyl chloride (XXV) in DMF/Et2O or DMA , yielding amides (XXVI) or (XXVII). Finally, carbamoyl sulfonamides (XXVI) and (XXVII) are cyclized and simultaneously hydrolyzed by treatment with NaOH (XII) .
| 【1】 Tran, C.V., Ruebsam, F., Murphy, D.E. et al. (Anadys Pharmaceuticals, Inc.). 5,6-Dihydro-1H-pyridin-2-one compounds. CA 2682584, EP 2129224, JP 2010523586, US 2010034773, US 7939524, US 8101800, US 2012130068, US 8236948, WO 2008124450. |
| 【2】 Dragovich, P.S., Thompson, P.A., Ruebsam, F. (Anadys Pharmaceuticals, Inc.). A method of inhibiting hepatitis C virus by combination of a 5,6-dihydro-1H-pyridin-2-one and one or more additional antiviral compounds. EP 2346329, US 2011229438, WO 2010042834. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 68662 | 2-(7-(methylsulfonamido)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)acetic acid | C10H11N3O6S2 | 详情 | 详情 | |
| (XIV) | 68665 | 2-chloro-5-nitrobenzenesulfonic acid;2-Chloro-5-nitrobenzene sulfonic acid;p-Nitrochlorobenzene-o-sulfonic acid;2-chloro-5-nitro-Benzenesulfonic acid;2-chloro-5-nitrobenzenesulphonic acid | 96-73-1 | C6H4ClNO5S | 详情 | 详情 |
| (XV) | 43034 | 2-chloro-5-nitrobenzenesulfonyl chloride;2-Chloro-5-nitro-benzenesulfonyl chloride;2-Chloro-5-nitrophenylsulfonyl chloride;6-Chloro-3-nitrobenzenesulfonyl chloride | 4533-95-3 | C6H3Cl2NO4S | 详情 | 详情 |
| (XVI) | 43035 | 2-chloro-5-nitrobenzenesulfonamide | 96-72-0 | C6H5ClN2O4S | 详情 | 详情 |
| (XVII) | 68666 | 2-amino-5-nitrobenzenesulfonamide | C6H7N3O4S | 详情 | 详情 | |
| (XVIII) | 68668 | 2-amino-5-nitrobenzenesulfonic acid | 96-75-3 | C6H6N2O5S | 详情 | 详情 |
| (XIX) | 68667 | 2-amino-5-nitrobenzene-1-sulfonyl chloride | C6H5ClN2O4S | 详情 | 详情 | |
| (XX) | 68669 | 2,5-diaminobenzenesulfonamide mesylate;2,5-diaminobenzenesulfonamide methanesulfonate | C6H9N3O2S.CH4O3S | 详情 | 详情 | |
| (XXI) | 68670 | 2-(benzylamino)-5-nitrobenzenesulfonamide | C13H13N3O4S | 详情 | 详情 | |
| (XXII) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (XXIII) | 68671 | 2-amino-5-(methylsulfonamido)benzenesulfonamide | C7H11N3O4S2 | 详情 | 详情 | |
| (XXIV) | 50272 | Malonic acid monomethyl ester chloride; Methyl (chloroformyl)acetate; Methyl malonyl chloride ;Methyl 3-chloro-3-oxopropionate | 37517-81-0 | C4H5ClO3 | 详情 | 详情 |
| (XXV) | 13188 | ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride | 36239-09-5 | C5H7ClO3 | 详情 | 详情 |
| (XXVI) | 68672 | methyl 3-((4-(methylsulfonamido)-2-sulfamoylphenyl)amino)-3-oxopropanoate | C11H15N3O7S2 | 详情 | 详情 | |
| (XXVII) | 68673 | ethyl 3-((4-(methylsulfonamido)-2-sulfamoylphenyl)amino)-3-oxopropanoate | C12H17N3O7S2 | 详情 | 详情 |