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【结 构 式】 
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【分子编号】11966 【品名】2-(Dimethylsulfonium)acetic acid ethyl ester inner salt 【CA登记号】 |
【 分 子 式 】C6H12O2S 【 分 子 量 】148.22608 【元素组成】C 48.62% H 8.16% O 21.59% S 21.63% |
合成路线1
该中间体在本合成路线中的序号：(IL)The intermediate trans-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetra-hydronaphtho[2,3-d][1,3]benzodioxole-6-carboxylic acid ethyl ester (XI) has been obtained by several different ways: (a) The condensation of benzophenone (XXXVIII) with diethyl malonate (XXXIX) by means of t-BuOK gives the alkylidenemalonate (XL), which is hydrogenated with H2 over Pd/C to the alkylmalonate hemiester (XLI). The reaction of (XLI) with acetyl chloride affords the mixed anhydride (XLII), which is finally cyclized to the target (XI) by means of SnCl4. (b) The cyclization of the malonic ester derivative (XLIII) by means of Ti(CF3--CO2)3 gives the 5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho [2,3-d][1,3]dioxole-6,6-dicarboxylic acid dimethyl ester (XLIV), which is finally oxidized and decarboxylated with NBS and NaOH in methanol to afford the target intermediate (XI). (c) The cyclization of the benzylidenemalonate (XLV) with the aryllithium derivative (XLVI) gives the 8-methoxy-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6,6-dicarboxylic acid dimethyl ester (XLVII), which is demethylated with TFA and oxidized with CrO3 and pyridine to the target compound (XI). (d) The cyclopropanation of the chalcone (XLVIII) with (ethoxycarbonyl) (dimethylsulfonium)methylide (XLIX) gives the cyclopropanecarboxylate (L), which is finally rearranged with BF3/Et2O to the target intermediate (IX).
| 【1】 Ward, R.S.; Synthesis of podophyllotoxin and related compounds. Synthesis 1992, 719. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 11966 | 2-(Dimethylsulfonium)acetic acid ethyl ester inner salt | C6H12O2S | 详情 | 详情 | |
| (XI) | 34966 | ethyl (5R,6R)-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C23H24O8 | 详情 | 详情 | |
| (XXXVIII) | 34992 | 1,3-benzodioxol-5-yl(3,4,5-trimethoxyphenyl)methanone | C17H16O6 | 详情 | 详情 | |
| (XXXIX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (XL) | 34993 | (E)-4-(1,3-benzodioxol-5-yl)-3-(ethoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)-3-butenoic acid | C23H24O9 | 详情 | 详情 | |
| (XLI) | 34994 | 4-(1,3-benzodioxol-5-yl)-3-(ethoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)butyric acid | C23H26O9 | 详情 | 详情 | |
| (XLII) | 34995 | acetic 3-(1,3-benzodioxol-5-yl)-2-(ethoxycarbonyl)-3-(3,4,5-trimethoxyphenyl)butyric anhydride | C25H28O10 | 详情 | 详情 | |
| (XLIII) | 34996 | diethyl 2-[2-(1,3-benzodioxol-5-yl)ethyl]-2-(3,4,5-trimethoxybenzyl)malonate | C26H32O9 | 详情 | 详情 | |
| (XLIV) | 34997 | diethyl 5-(3,4,5-trimethoxyphenyl)-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6,6(5H)-dicarboxylate | C26H30O9 | 详情 | 详情 | |
| (XLV) | 34998 | diethyl 2-(3,4,5-trimethoxybenzylidene)malonate | C17H22O7 | 详情 | 详情 | |
| (XLVI) | 34999 | [6-(2-bromo-1-methoxyethyl)-1,3-benzodioxol-5-yl]lithium | C10H10BrLiO3 | 详情 | 详情 | |
| (XLVII) | 35000 | diethyl 8-methoxy-5-(3,4,5-trimethoxyphenyl)-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6,6(5H)-dicarboxylate | C27H32O10 | 详情 | 详情 | |
| (XLVIII) | 35001 | (E)-1-(1,3-benzodioxol-5-yl)-3-(3,4,5-trimethoxyphenyl)-2-propen-1-one | C19H18O6 | 详情 | 详情 | |
| (L) | 35002 | ethyl 2-(1,3-benzodioxol-5-ylcarbonyl)-3-(3,4,5-trimethoxyphenyl)cyclopropanecarboxylate | C23H24O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Several related syntheses for AA-193 have been reported: 1) The Friedel-Crafts' condensation of 2,5-dichlorophenol (I) with benzoyl chloride (II) by means of AlCl3 gives 2,5-dichloro-4-hydroxybenzophenone (III), which by reaction with hydroxylamine and KOH is converted to 5-chloro-6-hydroxy-3-phenylbenzisoxazole (IV). The condensation of (IV) with allyl bromide (V) by means of K2CO3 affords the 7-allyl derivative (VI), which is cyclized by means of N-bromosuccinimide and NaOH to 5-chloro-7-(hydroxymethyl)-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisox azole (VII). Finally, this compound is oxidized to the final product with KMnO4 in refluxing dichloromethane. 2) The chlorination of 1,3-dimethoxybenzene (VIII) with SO2Cl2 gives 1-chloro-2,4-dimethoxybenzene (IX), which is condensed with benzoyl chloride (II) as before, yielding 5-chloro-2,4-dihydroxybenzophenone (X). Tosylation of (X) with tosyl chloride gives the corresponding ditosyl derivative (XI), which by reaction with hydroxylamine is converted to the oxime (XII). Finally, this compound is treated with KOH in order to cyclize to the benzisoxazole (IV). 3) The reaction of the benzisoxazole (IV) with formaldehyde and dimethylamine gives 5-chloro-7-(dimethylaminomethyl)-6-hydroxy-3-phenylbenzisoxazole (XIII), which is condensed and cyclized with the ylide (XIV) to yield the ethyl ester of the desired product (XV). Finally, this compound is hydrolyzed with NaOH.
| 【1】 Koga, H.; Kuromaru, K.; Ishizawa, T.; Aoki, B.; Sato, H.; Studies on uricosuric diuretics. V. Convenient and efficient synthesis of 2,3-dihydrobenzofuran derivatives. Chem Pharm Bull 1992, 40, 10, 2597. |
| 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) | 11953 | 2,5-Dichlorophenol | 583-78-8 | C6H4Cl2O | 详情 | 详情 |
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (III) | 11955 | (2,5-Dichloro-4-hydroxyphenyl)(phenyl)methanone | C13H8Cl2O2 | 详情 | 详情 | |
| (IV) | 11945 | 5-Chloro-3-phenyl-1,2-benzisoxazol-6-ol | C13H8ClNO2 | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 11950 | 7-Allyl-5-chloro-3-phenyl-1,2-benzisoxazol-6-ol | C16H12ClNO2 | 详情 | 详情 | |
| (VII) | 11941 | (5-Chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol | C16H12ClNO3 | 详情 | 详情 | |
| (VIII) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (IX) | 11942 | 1-Chloro-2,4-dimethoxybenzene; 2-Chloro-5-methoxyphenyl methyl ether | 7051-13-0 | C8H9ClO2 | 详情 | 详情 |
| (X) | 11962 | (5-Chloro-2,4-dihydroxyphenyl)(phenyl)methanone | C13H9ClO3 | 详情 | 详情 | |
| (XI) | 11963 | 2-benzoyl-4-chloro-5-[[(4-methylphenyl)sulfonyl]oxy]phenyl 4-methylbenzenesulfonate | C27H21ClO7S2 | 详情 | 详情 | |
| (XII) | 11964 | 4-chloro-2-[(hydroxyimino)(phenyl)methyl]-5-[[(4-methylphenyl)sulfonyl]oxy]phenyl 4-methylbenzenesulfonate | C27H22ClNO7S2 | 详情 | 详情 | |
| (XIII) | 11946 | 5-Chloro-7-[(dimethylamino)methyl]-3-phenyl-1,2-benzisoxazol-6-ol | C16H15ClN2O2 | 详情 | 详情 | |
| (XIV) | 11966 | 2-(Dimethylsulfonium)acetic acid ethyl ester inner salt | C6H12O2S | 详情 | 详情 | |
| (XV) | 11948 | ethyl 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazole-7-carboxylate | C18H14ClNO4 | 详情 | 详情 |