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【结 构 式】 
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【药物名称】alpha-Tocopherol, alpha-Tocoferol, Vitamin E 【化学名称】2(R),5,7,8-Tetramethyl-2-[4(R),8(R),12-trimethyltridecyl]-3,4-dihydro-2H-1-benzopyran-6-ol 【CA登记号】59-02-9 【 分 子 式 】C29H50O2 【 分 子 量 】430.72065 |
【开发单位】 【药理作用】 |
合成路线1
The intermediate triphenylphosphonium salt (XXI) has been obtained as follows: The Reformatsky condensation of 4-methoxybenzaldehyde (I) with methyl 2-bromopropionate (II) gives a mixture of the syn and anti hydroxyesters (III) and (IV). The syn isomer (III) was dehydrated by means of MsOH yielding the unsaturated ester (V), which is reduced with LiAlH4 to the unsaturated alcohol (VI). The hydroboration of (VI) affords the diol (rac)-anti-(VII), which is also obtained by direct reduction of the anti-hydroxyester (IV) with LiAlH4. The optical resolution of (rac)-(VII) with lipase Amano P and vinyl acetate affords the chiral monoacetate (2R,3R)-(VIII), which is fully acetylated with Ac2O giving the diacetate (IX). Selective catalytic hydrogenolysis of (IX) with H2 over Pd/C in methanol yields the primary monoacetate (X), which is hydrolyzed with K2CO3 in methanol to affords the primary alcohol (XI). The reaction of (XI) with CBr4 and PPh3 in THF provides the bromide (XII), which by treatment with sodium phenylsulfinate (A) affords the phenylsulfone (XIII). Ozonolysis of (XIII) with O3, followed by oxidation with H2O2 gives the carboxylic acid (XIV), which is methylated with diazomethane to the ester (XV). The reduction of (XV) with LiBH4 in THF yields the alcohol (XVI), which is protected with DHP and PPTS yielding the tetrahydropyranyl ether (XVII). The condensation of sulfone (XVII) with the iodoalkane (XVIII) by means of LDA, followed by treatment with HCl in ethanol affords the intermediate addition compound (XIX), which by elimination of the THP group provides the alcohol (XX). Finally, the reaction of (XX) with CBr4 and PPh3 affords the target intermediate phosphonium salt (XXI).
| 【1】 Nozawa, M.; et al.; Enantioselective synthesis of (2R,4'R,8'R)-alpha-tocopherol (vitamin E) based on enzymatic function. Chem Pharm Bull 2000, 48, 2, 272. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)-(VII) | 40895 | (1R,2R)-1-(4-methoxyphenyl)-2-methyl-1,3-propanediol | C11H16O3 | 详情 | 详情 | |
| (2R,3R)-(VIII) | 40896 | (2R,3R)-3-hydroxy-3-(4-methoxyphenyl)-2-methylpropyl acetate | C13H18O4 | 详情 | 详情 | |
| (A) | 40901 | (phenylsulfonyl)sodium | C6H5NaO2S | 详情 | 详情 | |
| (I) | 27251 | 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde | 123-11-5 | C8H8O2 | 详情 | 详情 |
| (II) | 34941 | methyl 2-bromopropanoate; 2-bromopropionic acid methyl ester | 5445-17-0 | C4H7BrO2 | 详情 | 详情 |
| (III) | 40891 | methyl (2R,3R)-3-hydroxy-3-(4-methoxyphenyl)-2-methylpropanoate | C12H16O4 | 详情 | 详情 | |
| (IV) | 40892 | methyl (2S,3R)-3-hydroxy-3-(4-methoxyphenyl)-2-methylpropanoate | C12H16O4 | 详情 | 详情 | |
| (V) | 40893 | methyl (E)-3-(4-methoxyphenyl)-2-methyl-2-propenoate | C12H14O3 | 详情 | 详情 | |
| (VI) | 40894 | (E)-3-(4-methoxyphenyl)-2-methyl-2-propen-1-ol | C11H14O2 | 详情 | 详情 | |
| (IX) | 40897 | (1R,2R)-3-(acetoxy)-1-(4-methoxyphenyl)-2-methylpropyl acetate | C15H20O5 | 详情 | 详情 | |
| (X) | 40898 | (2S)-3-(4-methoxyphenyl)-2-methylpropyl acetate | C13H18O3 | 详情 | 详情 | |
| (XI) | 40899 | (2S)-3-(4-methoxyphenyl)-2-methyl-1-propanol | C11H16O2 | 详情 | 详情 | |
| (XII) | 40900 | 1-[(2S)-3-bromo-2-methylpropyl]-4-methoxybenzene; 4-[(2S)-3-bromo-2-methylpropyl]phenyl methyl ether | C11H15BrO | 详情 | 详情 | |
| (XIII) | 40902 | [(2S)-3-(4-methoxyphenyl)-2-methylpropyl](dioxo)phenyl-lambda(6)-sulfane; (2S)-3-(4-methoxyphenyl)-2-methylpropyl phenyl sulfone | C17H20O3S | 详情 | 详情 | |
| (XIV) | 40903 | (3S)-3-methyl-4-(phenylsulfonyl)butyric acid | C11H14O4S | 详情 | 详情 | |
| (XV) | 40904 | methyl (3S)-3-methyl-4-(phenylsulfonyl)butanoate | C12H16O4S | 详情 | 详情 | |
| (XVI) | 40905 | (3S)-3-methyl-4-(phenylsulfonyl)-1-butanol | C11H16O3S | 详情 | 详情 | |
| (XVII) | 40906 | (2S)-2-methyl-5-(tetrahydro-2H-pyran-2-yloxy)pentyl phenyl sulfone; 2-[[(4S)-4-methyl-5-(phenylsulfonyl)pentyl]oxy]tetrahydro-2H-pyran | C17H26O4S | 详情 | 详情 | |
| (XVIII) | 40907 | (3R)-1-iodo-3,7-dimethyloctane | C10H21I | 详情 | 详情 | |
| (XIX) | 40908 | tetrahydro-2H-pyran-2-yl (4R,8R)-4,8,12-trimethyltridecyl ether; 2-[[(4R,8R)-4,8,12-trimethyltridecyl]oxy]tetrahydro-2H-pyran | C21H42O2 | 详情 | 详情 | |
| (XX) | 40909 | (3R,7R)-3,7,11-trimethyl-1-dodecanol | C15H32O | 详情 | 详情 | |
| (XXI) | 40910 | triphenyl[(3R,7R)-3,7,11-trimethyldodecyl]phosphonium bromide | C33H46BrP | 详情 | 详情 |
合成路线2
The esterification of (rac)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (XXII) with diazomethane gives the methyl ester (XXIII), which is treated with Bn-Br and K2CO3 yielding the benzyl ether (XXIV). The reduction of the ester group of (XXIV) with LiAlH4 provides the carbinol (XXV), which is debenzylated with H2 over Pd/C to afford the racemic phenol (rac)-(XXVI). Optical resolution of (XXVI) by means of lipase PL-266 and vinyl acetate gives the chiral acetate (S)-(XXVII), which is rebenzylated with BnBr yielding the benzyl ether (XXVIII). The deacetylation of (XXVIII) with LiAlH4 in ethyl ether affords the carbinol (XXIX), which is oxidized with oxalyl chloride to the aldehyde (XXX). The condensation of (XXX) with the intermediate phosphonium salt (XXI) by means of n-BuLi in THF gives the olefin (XXXI), which is finally hydrogenated and debenzylated with H2 over Pd/C in ethyl acetate.
| 【1】 Nozawa, M.; et al.; Enantioselective synthesis of (2R,4'R,8'R)-alpha-tocopherol (vitamin E) based on enzymatic function. Chem Pharm Bull 2000, 48, 2, 272. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 40910 | triphenyl[(3R,7R)-3,7,11-trimethyldodecyl]phosphonium bromide | C33H46BrP | 详情 | 详情 | |
| (XXII) | 21255 | Trolox; Trolox C; 6-hydroxy-2,5,7,8-tetramethyl-2-chromanecarboxylic acid | 53188-07-1 | C14H18O4 | 详情 | 详情 |
| (XXIII) | 40911 | methyl 6-hydroxy-2,5,7,8-tetramethyl-2-chromanecarboxylate | C15H20O4 | 详情 | 详情 | |
| (XXIV) | 40912 | methyl 6-(benzyloxy)-2,5,7,8-tetramethyl-2-chromanecarboxylate | C22H26O4 | 详情 | 详情 | |
| (XXV) | 18084 | [6-(benzyloxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]methanol | C21H26O3 | 详情 | 详情 | |
| (XXVI) | 21256 | 2-(hydroxymethyl)-2,5,7,8-tetramethyl-6-chromanol | C14H20O3 | 详情 | 详情 | |
| (XXVII) | 40913 | [(2S)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]methyl acetate | C16H22O4 | 详情 | 详情 | |
| (XXVIII) | 40914 | [(2S)-6-(benzyloxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]methyl acetate | C23H28O4 | 详情 | 详情 | |
| (XXIX) | 40915 | [(2S)-6-(benzyloxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]methanol | C21H26O3 | 详情 | 详情 | |
| (XXX) | 40916 | (2S)-6-(benzyloxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carbaldehyde | C21H24O3 | 详情 | 详情 | |
| (XXXI) | 40917 | (2S)-6-(benzyloxy)-2,5,7,8-tetramethyl-2-[(E,4R,8R)-4,8,12-trimethyl-1-tridecenyl]-3,4-dihydro-2H-chromene; benzyl (2S)-2,5,7,8-tetramethyl-2-[(E,4R,8R)-4,8,12-trimethyl-1-tridecenyl]-3,4-dihydro-2H-chromen-6-yl ether | C36H54O2 | 详情 | 详情 |
合成路线3
The chlorination of myrcene (I) with Cl2 in refluxing pentane gives the choromyrcene (II), and the hydrochlorination of (I) catalyzed by CuCl yields a mixture of geranyl/neryl chloride (III). The reductive coupling of (II) and (III) by means of Mg and CuCl affords beta-springene (IV), which is condensed with 2,3,6-trimethylhydroquinone (V) by means of cyclooctadienyl rhodium chloride dimer [RhCl(COD)]2 and K2CO3 in refluxing toluene to provide the adduct (VI). The cyclization of (VI) by means of MeAlCl2 of Ts-OH in refluxing hexane furnishes the tocotrienol (VII), which is finally hydrogenated with H2 over Pd/C in ethanol to give the target (rac)-vitamin E.
| 【1】 Bienayme, H.; et al.; Rhodium(I)-catalyzed addition of phenols to dienes. A new convergent synthesis of vitamin E. Tetrahedron Lett 2000, 41, 18, 3339. |
| 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) | 49619 | Myrcene; 7-Methyl-3-methylene-1,6-octadiene; beta-Myrcene | 123-35-3 | C10H16 | 详情 | 详情 |
| (II) | 49620 | 3-chloro-2-methyl-6-methylene-1,7-octadiene | C10H15Cl | 详情 | 详情 | |
| (III) | 49621 | Geranyl chloride; trans-1-chloro-3,7-dimethyl-2,6-octadiene | C10H17Cl | 详情 | 详情 | |
| (IV) | 49622 | (6E,10E)-7,11,15-trimethyl-3-methylene-1,6,10,14-hexadecatetraene | C20H32 | 详情 | 详情 | |
| (V) | 26357 | 2,3,5-trimethyl-1,4-benzenediol | 700-13-0 | C9H12O2 | 详情 | 详情 |
| (VI) | 49623 | 2,3,5-trimethyl-6-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]-1,4-benzenediol | C29H44O2 | 详情 | 详情 | |
| (VII) | 49624 | 2,5,7,8-tetramethyl-2-[(3E,7E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]-6-chromanol | C29H44O2 | 详情 | 详情 |