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【结 构 式】 
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【分子编号】29909 【品名】methyl (3aR,7R,7aS)-7-hydroxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate 【CA登记号】 |
【 分 子 式 】C11H16O5 【 分 子 量 】228.24504 【元素组成】C 57.89% H 7.07% O 35.05% |
合成路线1
该中间体在本合成路线中的序号：(XVI)2) The esterification of Shikimic acid (XIV) with MeOH/TsOH gives the methyl ester (XV), which is treated with 2,2-dimethoxypropane (II) and TsOH to yield the acetonide (XVI). The mesylation of (XVI) with mesyl chloride and TEA in dichloromethane gives the mesylated acetonide (XVII), which is hydrolyzed with HCl, yielding the dihydroxy ester (XVIII). The epoxidation of (XVIII) with DBU in THF affords the epoxide (XIX), which is protected with methyl chloromethyl ether to give compound (XX). The reaction of (XX) with sodium azide in refluxing methanol/water provides the hydroxy azide (XXI), which is acylated with mesyl chloride to the mesylate (XXII). The cyclization of (XXII) by means of triphenylphosphine in THF affords the aziridine (XXIII), which is treated with sodium azide in hot DMF to give the amino azide (XXIV). The deprotection of (XXIV) with HCl followed by tritylation of the free amino group with trityl chloride and TEA yields compound (XXV), which is cyclized by means of mesyl chloride and TEA to afford the tritylaziridine (XXVI). The cleavage of the aziridine ring of (XXVI) with 3-pentanol, followed by acetylation of the resulting amino group, affords the acetamido aziridine (XXVII), which is hydrolyzed at the ester group with KOH in THF/water to give the carboxylic acid (XXVIII). The esterification of (XXVIII) with ethanol, DCC and DMAP in dichloromethane affords the azido ester (XIII), which is finally reduced with triphenylphosphine in hot THF/water.
| 【1】 Castañer, J.; Leeson, P.A.; Graul, A.; Oseltamivir Phosphate. Drugs Fut 1999, 24, 11, 1189. |
| 【2】 Bischofberger, N.W.; Kim, C.U.; Lew, W.; Liu, H.; Williams, M.A. (Gilead Sciences Inc.); Novel selective inhibitors of viral or bacterial neuraminidases. EP 0759917; EP 0976734; JP 1999501908; WO 9626933 . |
| 【3】 Bischofberger, N.W.; Kim, C.U.; Williams, M.A.; Lew, W.; Liu, H. (Gilead Sciences Inc.); Carbocyclic cpds.. US 5763483 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 | |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XIII) | 29906 | ethyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C16H26N4O4 | 详情 | 详情 | |
| (XIV) | 29907 | (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid; Shikimic acid | 138-59-0 | C7H10O5 | 详情 | 详情 |
| (XV) | 29908 | methyl (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate | C8H12O5 | 详情 | 详情 | |
| (XVI) | 29909 | methyl (3aR,7R,7aS)-7-hydroxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C11H16O5 | 详情 | 详情 | |
| (XVII) | 29910 | methyl (3aR,7R,7aR)-2,2-dimethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C12H18O7S | 详情 | 详情 | |
| (XVIII) | 29911 | methyl (3R,4R,5R)-3,4-dihydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate | C9H14O7S | 详情 | 详情 | |
| (XIX) | 29912 | methyl (1S,5R,6R)-5-hydroxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C8H10O4 | 详情 | 详情 | |
| (XX) | 29913 | methyl (1S,5R,6S)-5-(methoxymethoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C10H14O5 | 详情 | 详情 | |
| (XXI) | 29914 | methyl (3R,4S,5R)-5-azido-4-hydroxy-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate | C10H15N3O5 | 详情 | 详情 | |
| (XXII) | 29915 | methyl (3R,4S,5R)-5-azido-3-(methoxymethoxy)-4-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate | C11H17N3O7S | 详情 | 详情 | |
| (XXIII) | 29916 | methyl (1R,5R,6R)-5-(methoxymethoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate | C10H15NO4 | 详情 | 详情 | |
| (XXIV) | 29917 | methyl (3R,4R,5S)-4-amino-5-azido-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate | C10H16N4O4 | 详情 | 详情 | |
| (XXV) | 29918 | methyl (3R,4R,5S)-5-azido-3-hydroxy-4-(tritylamino)-1-cyclohexene-1-carboxylate | C27H26N4O3 | 详情 | 详情 | |
| (XXVI) | 29919 | methyl (1S,5S,6S)-5-azido-7-trityl-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate | C27H24N4O2 | 详情 | 详情 | |
| (XXVII) | 29920 | methyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C15H24N4O4 | 详情 | 详情 | |
| (XXVIII) | 29921 | (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid | C14H22N4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)The acceptor alcohol (XII) is synthesized by esterification of shikimic acid (XVI) with MeOH in the presence of H2SO4 to give methyl shikimate (XVII), which is then protected as the 3,4-acetonide (XIX) by transketalization with 2,2-dimethoxypropane (XVIII) by means of TsOH in acetonitrile. Hydrogenation of compound (XIX) over PtO2/C in MeOH affords the saturated ester (XX), which by acetylation with Ac2O in the presence of pyridine and DMAP in CH2Cl2 affords acetate (XXI). Deprotection of compound (XXI) by means of 80% aqueous AcOH at 80 °C provides diol (XXII), which is regioselectively converted to tosylate (XXIII) with TsCl in pyridine. Substitution of tosylate (XXIII) with NaN3 in DMF at 80 °C yields the corresponding azide (XXIV), which is then condensed with thioglycoside (XXV) by means of Br2 and Et4NBr in CH2Cl2/DMF/cyclohexene to obtain ether (XXVI). Finally, intermediate (XXVI) is submitted to deacetylation and simultaneous epimerization by means of NaOMe in MeOH, followed by reesterification with CH2N2 in Et2O .
| 【1】 Magnani, J.L., Patton, J.T. Jr., Sarkar, A.K., Svarovsky, S.A., Ernst, B. (GlycoMimetics, Inc.). Heterobifunctional pan-selectin inhibitors. EP 1934236, EP 2264043, JP 2009507031, US 2007054870, US 7728117, WO 2007028050. |
| 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) | 68493 | (1S,3S,4R,5R)-methyl 3-azido-5-hydroxy-4-(((2S,3S,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexanecarboxylate | C35H41N3O8 | 详情 | 详情 | |
| (XVI) | 29907 | (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid; Shikimic acid | 138-59-0 | C7H10O5 | 详情 | 详情 |
| (XVII) | 29908 | methyl (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate | C8H12O5 | 详情 | 详情 | |
| (XVIII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XIX) | 29909 | methyl (3aR,7R,7aS)-7-hydroxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C11H16O5 | 详情 | 详情 | |
| (XX) | 68500 | (3aS,7S,7aS)-methyl 7-hydroxy-2,2-dimethylhexahydrobenzo[d][1,3]dioxole-5-carboxylate | C11H18O5 | 详情 | 详情 | |
| (XXI) | 68499 | (3aS,7S,7aS)-methyl 7-acetoxy-2,2-dimethylhexahydrobenzo[d][1,3]dioxole-5-carboxylate | C13H20O6 | 详情 | 详情 | |
| (XXII) | 68498 | (3R,4S,5S)-methyl 3-acetoxy-4,5-dihydroxycyclohexanecarboxylate | C10H16O6 | 详情 | 详情 | |
| (XXIII) | 68497 | (3R,4S,5S)-methyl 3-acetoxy-4-hydroxy-5-(tosyloxy)cyclohexanecarboxylate | C17H22O8S | 详情 | 详情 | |
| (XXIV) | 68496 | (3R,4S,5R)-methyl 3-acetoxy-5-azido-4-hydroxycyclohexanecarboxylate | C10H15N3O5 | 详情 | 详情 | |
| (XXV) | 68502 | (3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-2-(ethylthio)-6-methyltetrahydro-2H-pyran | C29H34O4S | 详情 | 详情 | |
| (XXVI) | 68501 | (3S,4S,5R)-methyl 3-acetoxy-5-azido-4-(((2R,3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexanecarboxylate | C37H43N3O9 | 详情 | 详情 |