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【结 构 式】 
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【分子编号】11328 【品名】ethyl 2-(bromomethyl)acrylate 【CA登记号】17435-72-2 |
【 分 子 式 】C6H9BrO2 【 分 子 量 】193.04026 【元素组成】C 37.33% H 4.7% Br 41.39% O 16.58% |
合成路线1
该中间体在本合成路线中的序号：(II)The cyclization of 4-benzoyloxycyclohexanone (I) with ethyl 2-bromomethylacrylate (II) and propylamine (III) in refluxing toluene gives ethyl 1-propyl-6-benzoyloxy-1,2,3,4,5,6,7,8-octahydroquinoline-3-carboxylate (IV), which is reduced with sodium cyanoborohydride in methanol yielding the corresponding decahydro derivative (V). Debenzoylation of (V) with NaOH in methanol affords the hydroxyquinoline (VI), which is oxidized with CrO3-pyr giving ethyl 1-propyl-6-oxodecahydroquinoline-3-carboxylate (VII). The reaction of (VII) with dimethylformamide dimethylacetal (VIII) in refluxing toluene yields ethyl 1-propyl-6-oxo-7-(dimethylaminomethylene)decahydroquinoline-3-carboxylate (IX), which is cyclized with hydrazine in ethanol affording ethyl 5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline-7-carboxylic acid (X). The reduction of (X) with LiAlH4 in THF gives the corresponding hydroxymethyl derivative (XI), which is esterified with methanesulfonyl chloride to the mesyl ester (XII). Finally, this compound is treated with methyl mercaptane and NaH in DMF.
| 【1】 Bach, N.; Kornfeld, E.C. (Eli Lilly and Company); Prolactin inhibiting octahydropyrazolo[3,4-g]quinolines. DD 148517; EP 0013787; ES 482087; FR 2446820; FR 2446821; FR 2446822; GB 2040915; GB 2092579; US 4198415 . |
| 【2】 Nohria, Y.; Castaner, J.; Serradell, M.N.; Blancafort, P.; LY-141,865. Drugs Fut 1983, 8, 10, 858. |
| 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) | 16767 | 4-oxocyclohexyl benzoate | C13H14O3 | 详情 | 详情 | |
| (II) | 11328 | ethyl 2-(bromomethyl)acrylate | 17435-72-2 | C6H9BrO2 | 详情 | 详情 |
| (III) | 23923 | 1-propanamine | 107-10-8 | C3H9N | 详情 | 详情 |
| (IV) | 36234 | ethyl 6-(benzoyloxy)-1-propyl-1,2,3,4,5,6,7,8-octahydro-3-quinolinecarboxylate | C22H29NO4 | 详情 | 详情 | |
| (V) | 36235 | ethyl (4aR,8aR)-6-(benzoyloxy)-1-propyldecahydro-3-quinolinecarboxylate | C22H31NO4 | 详情 | 详情 | |
| (VI) | 36236 | ethyl (4aR,8aR)-6-hydroxy-1-propyldecahydro-3-quinolinecarboxylate | C15H27NO3 | 详情 | 详情 | |
| (VII) | 36237 | ethyl (4aR,8aR)-6-oxo-1-propyldecahydro-3-quinolinecarboxylate | C15H25NO3 | 详情 | 详情 | |
| (VIII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (IX) | 36238 | ethyl (4aR,8aR)-7-[(Z)-(dimethylamino)methylidene]-6-oxo-1-propyloctahydro-3(1H)-quinolinecarboxylate | C18H30N2O3 | 详情 | 详情 | |
| (X) | 36239 | ethyl (4aR,8aR)-5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline-7-carboxylate | C16H25N3O2 | 详情 | 详情 | |
| (XI) | 36240 | [(4aR,8aR)-5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolin-7-yl]methanol | C14H23N3O | 详情 | 详情 | |
| (XII) | 36241 | [(4aR,8aR)-5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolin-7-yl]methyl methyl sulfone; (4aR,8aR)-7-[(methylsulfonyl)methyl]-5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline | C15H25N3O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)An improved synthesis of ilmofosine has been reported: The reaction of 2-(hydroxymethyl)-2-propenoic acid ethyl ester (I) with PBr3 in ethyl ether gives the corresponding 2-bromomethyl derivative (II), which is condensed with hexadecylthiol (III) by means of triethylamine to afford 2-(hexadecylsulfanyl)-2-propenoic acid ethyl ester (IV). The reduction of (IV) with diisobutylaluminum hydride (DIBAL) yields 3-(hexadecylsulfanyl)-2-methylene-1-propanol (V), which is methylated with NaH and MeI to the methyl ether (VI). The hydroboration of (VI) with BH3.S(CH3)2 followed by oxidation with NaBO3 gives 3-(hexadecylsulfanyl)-2-(methoxymethyl)-1-propanol (VII), which is finally phosphorylated with PCl3 and condensed with choline p-toluenesulfonate (VIII).
| 【1】 Reddy, K.C.; Byun, H.S.; Bittman, R.; Antitumor ether lipids: An improved synthesis of ilmofosine and an enantioselective synthesis of an ilmofosine analog. Tetrahedron Lett 1994, 35, 17, 2679. |
| 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) | 11327 | ethyl 2-(hydroxymethyl)acrylate | 10029-04-6 | C6H10O3 | 详情 | 详情 |
| (II) | 11328 | ethyl 2-(bromomethyl)acrylate | 17435-72-2 | C6H9BrO2 | 详情 | 详情 |
| (III) | 41266 | 1-hexadecanethiol; hexadecylhydrosulfide | 2917-26-2 | C16H34S | 详情 | 详情 |
| (IV) | 11329 | ethyl 2-[(hexadecylsulfanyl)methyl]acrylate | C22H42O2S | 详情 | 详情 | |
| (V) | 11330 | 2-[(Hexadecylsulfanyl)methyl]-2-propen-1-ol | C20H40OS | 详情 | 详情 | |
| (VI) | 11331 | 2-[(Hexadecylsulfanyl)methyl]-2-propenyl methyl ether; 3-(Hexadecylsulfanyl)-2-(methoxymethyl)-1-propene | C21H42OS | 详情 | 详情 | |
| (VII) | 11332 | 3-(Hexadecylsulfanyl)-2-(methoxymethyl)-1-propanol | C21H44O2S | 详情 | 详情 | |
| (VIII) | 11333 | N,N,N-Trimethyl-2-[(phenylsulfonyl)oxy]-1-ethanaminium chloride | C11H18ClNO3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)6-Hydroxyquinolin-2-one (I) was O-alkylated with 2-bromoacetophenone (II) by means of K2CO3 to give the phenacyl ether (III). Then, a Reformatsky-type condensation of (III) with ethyl 2-(bromomethyl)acrylate (IV) and Zn, with concomitant cyclization, yielded the target methylenebutyrolactone.
| 【1】 Wang, T.-C.; et al.; alpha-Methylidene-gamma-butyrolactones: Synthesis and evaluation of quinolin-2(1H)-one derivatives. Helv Chim Acta 1998, 81, 6, 1038. |
| 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) | 13913 | 6-Hydroxy-2(1H)-quinolinone | C9H7NO2 | 详情 | 详情 | |
| (II) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (III) | 21429 | 6-(2-oxo-2-phenylethoxy)-2(1H)-quinolinone | C17H13NO3 | 详情 | 详情 | |
| (IV) | 11328 | ethyl 2-(bromomethyl)acrylate | 17435-72-2 | C6H9BrO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Swern oxidation of N-Boc-S-valinol (I) provided aldehyde (II). After conversion of (II) to the corresponding oxime (III) upon treatment with hydroxylamine, chlorination with N-chlorosuccinimide gave the hydroximinoyl chloride (IV). Reaction of ethyl 2-(bromomethyl)acrylate (V) with phenyllithium (VI) in the presence of CuCN produced ethyl 2-benzylacrylate (VII). The dipolar cycloaddition of the nitrile oxide generated from (IV) to acrylate (VII) furnished the isoxazoline (VIII) as a diastereomeric mixture. The N-Boc protecting group of (VIII) was then cleaved with trifluoroacetic acid to give amine (IX), which was coupled with 2-naphthoic acid (X), yielding amide (XI). The carboxylic acid (XII), resulting from the basic hydrolysis of ethyl ester (XI), was then coupled with the glutamate ester (XIII) to give (XIV).
| 【1】 Chung, H.-H.; Park, M.-J.; Min, C.-H.; Kang, C.-Y.; Park, T.-K.; Chang, H.-K.; Lee, T.-H.; Moon, K.-Y.; Kim, E.E.-K.; Oh, Y.-L.; Kim, Y.-M. (LG Chem Ltd.); Caspase inhibitor. WO 0121599; WO 0121600 . |
| 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) | 48024 | tert-butyl (1S)-1-(hydroxymethyl)-2-methylpropylcarbamate | C10H21NO3 | 详情 | 详情 | |
| (II) | 47805 | tert-butyl (1S)-1-formyl-2-methylpropylcarbamate | C10H19NO3 | 详情 | 详情 | |
| (III) | 48025 | tert-butyl (1S)-1-[(hydroxyimino)methyl]-2-methylpropylcarbamate | C10H20N2O3 | 详情 | 详情 | |
| (IV) | 48026 | tert-butyl (1S)-1-[chloro(hydroxyimino)methyl]-2-methylpropylcarbamate | C10H19ClN2O3 | 详情 | 详情 | |
| (V) | 11328 | ethyl 2-(bromomethyl)acrylate | 17435-72-2 | C6H9BrO2 | 详情 | 详情 |
| (VI) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (VII) | 48027 | ethyl 2-benzylacrylate | C12H14O2 | 详情 | 详情 | |
| (VIII) | 48028 | ethyl 5-benzyl-3-[(1S)-1-[(tert-butoxycarbonyl)amino]-2-methylpropyl]-4,5-dihydro-5-isoxazolecarboxylate | C22H32N2O5 | 详情 | 详情 | |
| (IX) | 48029 | ethyl 3-[(1S)-1-amino-2-methylpropyl]-5-benzyl-4,5-dihydro-5-isoxazolecarboxylate | C17H24N2O3 | 详情 | 详情 | |
| (X) | 10106 | 1-Naphthoic acid | 86-55-5 | C11H8O2 | 详情 | 详情 |
| (XI) | 48030 | ethyl 5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolecarboxylate | C28H30N2O4 | 详情 | 详情 | |
| (XII) | 48031 | 5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolecarboxylic acid | C26H26N2O4 | 详情 | 详情 | |
| (XIII) | 48032 | 4-(tert-butyl) 1-methyl (2S)-2-aminobutanedioate | C9H17NO4 | 详情 | 详情 | |
| (XIV) | 48033 | 4-(tert-butyl) 1-methyl (2S)-2-[([5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolyl]carbonyl)amino]butanedioate | C35H41N3O7 | 详情 | 详情 |