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【结 构 式】 
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【分子编号】19250 【品名】2-propanol 【CA登记号】67-63-0 |
【 分 子 式 】C3H8O 【 分 子 量 】60.09592 【元素组成】C 59.96% H 13.42% O 26.62% |
合成路线1
该中间体在本合成路线中的序号：(A)The esterification of 4-hydroxyphenylacetic acid (I) with isopropanol and H2SO4 gives the corresponding isopropyl ester (II), which is then cyclocondensed with 1-isobutoxy-2-chloroethyl isothiocyanate (III) by means of K2CO3 in acetone yielding isopropyl 2-[4-(4-isobutoxy-2-thiazolin-2-yloxy) phenyl]acetate (IV). Elimination of isobutanol from (IV) by means of p-toluenesulfonic acid in hot DMF affords isopropyl 2-[4-(2-thiazolyloxy)phenyl] acetate (V), which is methylated with methyl bromide and KOH in DMF giving isopropyl 2-[4-(2-thiazo)yloxy)phenyl]propionate (VI). Finally, this compound is hydrolyzed with NaOH in aqueous methanol.
| 【1】 Hamada, Y.; Ando, S. (Shionogi & Co. Ltd.); Improved process for the production of 2-(4-(2-thiazolyloxy)phenyl)propionic acid. CA 1188699; EP 0088008; JP 58148870 . |
| 【2】 Castaner, J.; Serradell, M.N.; Arrigoni-Martelli, E.; 480156-S. Drugs Fut 1985, 10, 1, 37. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 19250 | 2-propanol | 67-63-0 | C3H8O | 详情 | 详情 |
| (I) | 18430 | 2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid | 156-38-7 | C8H8O3 | 详情 | 详情 |
| (II) | 28901 | isopropyl 2-(4-hydroxyphenyl)acetate | C11H14O3 | 详情 | 详情 | |
| (III) | 28902 | 1-(2-chloro-1-isothiocyanatoethoxy)butane | C7H12ClNOS | 详情 | 详情 | |
| (IV) | 28903 | isopropyl 2-[4-[(4-butoxy-1,3-thiazol-2-yl)oxy]phenyl]acetate | C18H23NO4S | 详情 | 详情 | |
| (V) | 28904 | isopropyl 2-[4-(1,3-thiazol-2-yloxy)phenyl]acetate | C14H15NO3S | 详情 | 详情 | |
| (VI) | 28905 | isopropyl 2-[4-(1,3-thiazol-2-yloxy)phenyl]propanoate | C15H17NO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The cyclization of 1-(benzyloxy)butadiene (I) with silylated propargyl aldehyde (II) by means of a chiral chromium catalyst gives the chiral dihydropyran (III), which is desilylated with TBAF and Ts-OH, yielding the acetylenic dihydropyran (IV). The reaction of (IV) with Ts-OH and isopropanol (V) affords the isopropoxy dihydropyran (VI). The optical resolution of the acetyloxirane (VII) by reaction with O2 and a chiral Co catalyst gives a mixture of (S)-3,4-dihydroxy-2-butanone (VIII) and (R)-acetyloxirane (IX) that is easily separated. The condensation of the chiral oxirane (IX) with the acetylenic dihydropyran (VI) by means of Cp2Zr(H)Cl and Me2Zn, yields the epoxyalcohol (X), which is protected with Tes-Cl and imidazole in DMF to afford the silyl ether (XI). Ring opening of the epoxy group of (XI) with acetylenic dithiolane (XII) by means of BuLi in THF provides the adduct (XIII), which is treated with PPTS to cleave the isopropyl group and oxidized with MnO2 to give the dihydropyranone compound (XIV). The cleavage of the dithiolane ring of (XIV) with bis(trifluoroacetoxy)iodobenzene (PIFA), followed by protection of the OH group with Pmb-trichloroimidate and BF3/Et2O, yields the protected acetylenic ketone (XV), which is submitted to a enantioselective reduction by transfer hydrogenation with isopropanol catalyzed by a chiral Ru catalyst, affording the chiral alcohol (XVI). The protection of the OH group of (XVI) with Tbdms-OTf and lutidine provides the fully protected compound (XVII), which is treated with AgNO3 and N-iodosuccinimide (NIS), giving the iodoethynyl compound (XVIII).
| 【1】 Jacobsen, E.N.; Chavez, D.E.; Total synthesis of fostriecin (CI-920). Angew Chem. Int Ed 2001, 40, 19, 3667. |
| 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) | 55477 | 1-{[(1E)-1,3-butadienyloxy]methyl}benzene; benzyl (1E)-1,3-butadienyl ether | C11H12O | 详情 | 详情 | |
| (II) | 55478 | 3-(triisopropylsilyl)-2-propynal | C12H22OSi | 详情 | 详情 | |
| (III) | 55479 | benzyl (2S,6R)-6-[2-(triisopropylsilyl)ethynyl]-5,6-dihydro-2H-pyran-2-yl ether; {2-[(2R,6S)-6-(benzyloxy)-3,6-dihydro-2H-pyran-2-yl]ethynyl}(triisopropyl)silane | C23H34O2Si | 详情 | 详情 | |
| (IV) | 55480 | (2R,6R)-6-(benzyloxy)-2-ethynyl-3,6-dihydro-2H-pyran; benzyl (2R,6R)-6-ethynyl-5,6-dihydro-2H-pyran-2-yl ether | C14H14O2 | 详情 | 详情 | |
| (V) | 19250 | 2-propanol | 67-63-0 | C3H8O | 详情 | 详情 |
| (VI) | 55481 | (2R,6R)-2-ethynyl-6-isopropoxy-3,6-dihydro-2H-pyran; (2R,6R)-6-ethynyl-5,6-dihydro-2H-pyran-2-yl isopropyl ether | C10H14O2 | 详情 | 详情 | |
| (VII) | 55493 | 1-(2-oxiranyl)-1-ethanone | C4H6O2 | 详情 | 详情 | |
| (VIII) | 55482 | (3S)-3,4-dihydroxy-2-butanone | C4H8O3 | 详情 | 详情 | |
| (IX) | 55483 | 1-[(2R)oxiranyl]-1-ethanone | C4H6O2 | 详情 | 详情 | |
| (X) | 55484 | (2R,3E)-4-[(2R,6R)-6-isopropoxy-3,6-dihydro-2H-pyran-2-yl]-2-[(2R)oxiranyl]-3-buten-2-ol | C14H22O4 | 详情 | 详情 | |
| (XI) | 55485 | (1R,2E)-3-[(2R,6R)-6-isopropoxy-3,6-dihydro-2H-pyran-2-yl]-1-methyl-1-[(2R)oxiranyl]-2-propenyl triethylsilyl ether; triethyl({(1R,2E)-3-[(2R,6R)-6-isopropoxy-3,6-dihydro-2H-pyran-2-yl]-1-methyl-1-[(2R)oxiranyl]-2-propenyl}oxy)silane | C20H36O4Si | 详情 | 详情 | |
| (XII) | 55486 | [2-(1,3-dithian-2-yl)ethynyl](trimethyl)silane | C9H16S2Si | 详情 | 详情 | |
| (XIII) | 55487 | (2R,3R,4E)-5-[(2R,6R)-6-isopropoxy-3,6-dihydro-2H-pyran-2-yl]-3-methyl-3-[(triethylsilyl)oxy]-1-{2-[2-(trimethylsilyl)ethynyl]-1,3-dithian-2-yl}-4-penten-2-ol | C29H52O4S2Si2 | 详情 | 详情 | |
| (XIV) | 55488 | (6R)-6-((E,3R,4R)-4-hydroxy-3-methyl-3-[(triethylsilyl)oxy]-5-{2-[2-(trimethylsilyl)ethynyl]-1,3-dithian-2-yl}-1-pentenyl)-5,6-dihydro-2H-pyran-2-one | C26H44O4S2Si2 | 详情 | 详情 | |
| (XV) | 55489 | (6R)-6-[(E,3R,4R)-4-[(4-methoxybenzyl)oxy]-3-methyl-6-oxo-3-[(triethylsilyl)oxy]-8-(trimethylsilyl)-1-octen-7-ynyl]-5,6-dihydro-2H-pyran-2-one | C31H46O6Si2 | 详情 | 详情 | |
| (XVI) | 55490 | (6R)-6-[(E,3R,4R,6R)-6-hydroxy-4-[(4-methoxybenzyl)oxy]-3-methyl-3-[(triethylsilyl)oxy]-8-(trimethylsilyl)-1-octen-7-ynyl]-5,6-dihydro-2H-pyran-2-one | C31H48O6Si2 | 详情 | 详情 | |
| (XVII) | 55491 | (6R)-6-[(E,3R,4R,6R)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]-3-methyl-3-[(triethylsilyl)oxy]-8-(trimethylsilyl)-1-octen-7-ynyl]-5,6-dihydro-2H-pyran-2-one | C37H62O6Si3 | 详情 | 详情 | |
| (XVIII) | 55492 | (6R)-6-{(E,3R,4R,6R)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-iodo-4-[(4-methoxybenzyl)oxy]-3-methyl-3-[(triethylsilyl)oxy]-1-octen-7-ynyl}-5,6-dihydro-2H-pyran-2-one | C34H53IO6Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of chloromethyl chloroformate (I) with isopropyl alcohol (II) by means of pyridine or triethylamine in ether gives the mixed carbonate (III), which is then condensed with (R)-PMPA (IV) by means of diisopropyl ethyl-amine in DMF.
| 【1】 Oliyai, R.; Dougherty, J.; Bischofberger, N.; Kim, C.U.; Mulato, A.; Shaw, J.P.; Cundy, K.C.; Arimilli, M.N.; Synthesis, in vitro biological evaluation and oral bioavailability of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) prodrugs. Antivir Chem Chemother 1997, 8, 6, 557. |
| 【2】 Sorbera, L.A.; Castañer, J.; (R)-PMPA and Bis(POC)PMPA. Drugs Fut 1998, 23, 12, 1279. |
| 【3】 Arimilli, M.N.; Cundy, K.C.; Dougherty, J.P.; Kim, C.U.; Oliyai, R.; Stella, V.J. (Gilead Sciences Inc.); Nucleotide analogs. US 5922695; WO 9804569 . |
| 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) | 19249 | Chloromethyl chloroformate; Chloro[(chlorocarbonyl)oxy]methane | 22128-62-7 | C2H2Cl2O2 | 详情 | 详情 |
| (II) | 19250 | 2-propanol | 67-63-0 | C3H8O | 详情 | 详情 |
| (III) | 19251 | chloromethyl isopropyl carbonate | C5H9ClO3 | 详情 | 详情 | |
| (IV) | 19252 | [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonic acid | C9H14N5O4P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Treatment of S-4-benzyl-2-oxazolidinone (II) with n-butyllithium, followed by acylation with valeroyl chloride (I) afforded the N-valeroyloxazolidinone (III). Subsequent alkylation of (III) with isopropyl triflate (V), prepared from isopropyl alcohol (IV) and trifluoromethanesulfonic anhydride, in the presence of LDA produced the (4S,2'R)-2-isopropylvaleroyl derivative (VI). Hydrolysis of (VI) using lithium peroxide yielded the chiral carboxylic acid (VII), which was converted to the corresponding acid chloride (VIII) by treatment with oxalyl chloride. Finally, reaction of (VIII) with ammonia furnished the title amide.
| 【1】 Yagen, B.; Bialer, M.; Spigelstein, O. (Yissum Research Development Co.); Propylisopropyl acetic acid and propylisopropyl acetamide stereoisomers, a method for their synthesis and pharmaceutical compsns. containing them. WO 9954282 . |
| 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) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (II) | 15116 | pentanoyl chloride; valeryl chloride | 638-29-9 | C5H9ClO | 详情 | 详情 |
| (III) | 29431 | (4S)-4-benzyl-3-pentanoyl-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
| (IV) | 19250 | 2-propanol | 67-63-0 | C3H8O | 详情 | 详情 |
| (V) | 35062 | isopropyl trifluoromethanesulfonate | C4H7F3O3S | 详情 | 详情 | |
| (VI) | 35063 | (4S)-4-benzyl-3-[(2R)-2-isopropylpentanoyl]-1,3-oxazolidin-2-one | C18H25NO3 | 详情 | 详情 | |
| (VII) | 35064 | (2R)-2-isopropylpentanoic acid | C8H16O2 | 详情 | 详情 | |
| (VIII) | 35065 | (2R)-2-isopropylpentanoyl chloride | C8H15ClO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The alkylation of 6-chloro-2-fluoropurine (I) with isopropanol (II) under Mitsunobu conditions gives 6-chloro-2-fluoro-9-isopropylpurine (III), which is regioselectively alkylated at the 6 position with 4-methoxybenzylamine (IV) to yield 2-fluoro-9-isopropyl-N6-(4-methoxybenzyl)adenine (V). Finally, the 2-fluoro position of (V) is aminated with perhydroazepine (VI) in n-butanol at high temperature in a sealed tube to afford the target trisubstituted purine.
| 【1】 Verdugo, D.E.; et al.; Discovery of estrogen sulfotransferase inhibitors from a purine library screen. J Med Chem 2001, 44, 17, 2683. |
| 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) | 51672 | 6-chloro-2-fluoro-9H-purine | C5H2ClFN4 | 详情 | 详情 | |
| (II) | 19250 | 2-propanol | 67-63-0 | C3H8O | 详情 | 详情 |
| (III) | 51673 | 6-chloro-2-fluoro-9-isopropyl-9H-purine | C8H8ClFN4 | 详情 | 详情 | |
| (IV) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (V) | 51674 | N-(2-fluoro-9-isopropyl-9H-purin-6-yl)-N-(4-methoxybenzyl)amine; 2-fluoro-9-isopropyl-N-(4-methoxybenzyl)-9H-purin-6-amine | C16H18FN5O | 详情 | 详情 | |
| (VI) | 18672 | azepane | 111-49-9 | C6H13N | 详情 | 详情 |