【结 构 式】 |
【分子编号】29912 【品名】methyl (1S,5R,6R)-5-hydroxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate 【CA登记号】 |
【 分 子 式 】C8H10O4 【 分 子 量 】170.165 【元素组成】C 56.47% H 5.92% O 37.61% |
合成路线1
该中间体在本合成路线中的序号:(XIX)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:(LI)The enzymatic resolution of the tricyclic carboxylate (XXIX) with chiralzyme L-2 and vinyl acetate gives the monoacetate (XXX) and the dihydroxy compound (XXXI) that are easily separated. The hydrolysis of the acetate (XXX) with K2CO3 in methanol yields the diol (XLIII), which silylated with TBDMS-Cl and imidazole at the less hindered OH affording the silyl ether (XLIV). The acetylation of (XLIV) with acetyl chloride, TEA and DMAP gives the acetate (XLV), which is desilylated with TBAF in THF yielding the alcohol (XLVI). The oxidation of (XLVI) with ammonium formate and PdCl2(PPh3)2 in refluxing acetonitrile affords the ketone (XLVII), which is epoxidized with H2O2 and Triton B in THF providing the ketoepoxide (XLVIII). The thermolysis of (XLVIII) at 300 C in diphenyl ether gives the epoxycyclohexenone (II), which is reduced with NaBH4 and CeCl3 in methanol yielding a mixture of the two diastereomeric alcohols (L) and (LI) that are separated by column chromatography. The desired alcohol (LI) is treated with refluxing 80% AcOH to afford the methyl ester (XLII) of the target compound. Finally, this compound is hydrolyzed with KOH in THF. The undesired diastereomeric alcohol (L) is recycled to epoxyketone (II) by oxidation with tetrapropylammonium perruthenate (TPAP) and NMMO.
【1】 Yoshida, N.; Ogasawara, K.; An enatioconvergent route to (-)-shikimic acid via a palladium-mediated elimination reaction. Org Lett 2000, 2, 10, 1461. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXIX),(XXXI) | 36851 | methyl (2R,3R,6S)-3,6-dihydroxytricyclo[6.2.1.0(2,7)]undeca-4,9-diene-2-carboxylate | C13H16O4 | 详情 | 详情 | |
(IL) | 36865 | methyl (1S,6S)-5-oxo-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C8H8O4 | 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 |
(XXX) | 36852 | methyl (2S,3S,6R)-6-(acetoxy)-3-hydroxytricyclo[6.2.1.0(2,7)]undeca-4,9-diene-2-carboxylate | C15H18O5 | 详情 | 详情 | |
(XLII) | 29908 | methyl (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate | C8H12O5 | 详情 | 详情 | |
(XLIII) | 36867 | methyl (2S,3S,6R)-3,6-dihydroxytricyclo[6.2.1.0(2,7)]undeca-4,9-diene-2-carboxylate | C13H16O4 | 详情 | 详情 | |
(XLIV) | 36868 | methyl (2S,3S,6R)-6-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxytricyclo[6.2.1.0(2,7)]undeca-4,9-diene-2-carboxylate | C19H30O4Si | 详情 | 详情 | |
(XLV) | 36869 | methyl (2S,3S,6R)-3-(acetoxy)-6-[[tert-butyl(dimethyl)silyl]oxy]tricyclo[6.2.1.0(2,7)]undeca-4,9-diene-2-carboxylate | C21H32O5Si | 详情 | 详情 | |
(XLVI) | 36870 | methyl (2S,3S,6R)-3-(acetoxy)-6-hydroxytricyclo[6.2.1.0(2,7)]undeca-4,9-diene-2-carboxylate | C15H18O5 | 详情 | 详情 | |
(XLVII) | 36863 | methyl (2S,3S)-3-(acetoxy)-6-oxotricyclo[6.2.1.0(2,7)]undeca-4,9-diene-2-carboxylate | C15H16O5 | 详情 | 详情 | |
(XLVIII) | 36864 | methyl (2S,3R,4R,6S)-3-(acetoxy)-7-oxo-5-oxatetracyclo[7.2.1.0(2,8).0(4,6)]dodec-10-ene-2-carboxylate | C15H16O6 | 详情 | 详情 | |
(L) | 36866 | methyl (1S,5S,6R)-5-hydroxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C8H10O4 | 详情 | 详情 | |
(LI) | 29912 | methyl (1S,5R,6R)-5-hydroxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C8H10O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(V)(-)-Quinic acid (I) is converted into the acetonide (II) in the usual way and its secondary alcohol is converted into the tosylate (III) by reaction with tosyl chloride and DMAP in pyridine. The dehydration of (III) with SOCl2 and pyridine in methanol yields the cyclohexenecarboxylate (IV), which is epoxidized by means of DBU inb THF affording the epoxide (V). The protection of the free hydroxy group of (V) with methoxymethyl chloride and DIPEA in dichloromethane gives the ether (VI), which is treated with sodium azide in methanol yielding the azido alcohol (VII). The reaction of (VII) with methanesulfonyl chloride and triethylamine in dichloromethane affords the mesylate (VIII), which is submitted to a reductocyclization with triphenylphosphine in in THF providing the aziridine (IX). The cleavage of the aziridine group of (IX) with sodium azide in DMF gives the amino azide (X), which is deprotected at the methoxymethyl ether by a treatment with HCl in methanol to afford the alcohol (XI). The acetylation of (XI) with acetic anhydride in pyridine gives the N,O-diacetyl derivative (XII), which is condensed with N-(1-ethylpropyl)-N-methylamine (XIII) by means of palladium tetrakis(triphenylphosphine) in THF yielding the tertiary amine (XIV). The azido group of (XIV) in then reduced with triphenylphosphine in THF/water providing the amino intermediate (XV), which is finally hydrolyzed with KOH in aqueous THF.
【1】 Lew, W.; Wu, H.; Mendel, D.B.; Escarpe, P.A.; Chen, X.; Laver, W.G.; Graves, B.J.; Kim, C.U.; A new series of C3-aza carbocyclic influenza neuraminidase inhibitors: Synthesis and inhibitory activity. Bioorg Med Chem Lett 1998, 8, 23, 3321. |
【2】 Williams, M.A.; Lew, W.; Kim, C.U.; et al.; Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: Design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc 1997, 119, 4, 681. |
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 | |
(I) | 30978 | methyl (3R,5R)-1,3,4,5-tetrahydroxycyclohexanecarboxylate | C8H14O6 | 详情 | 详情 | |
(II) | 30979 | methyl (3aR,5R,7R,7aS)-5,7-dihydroxy-2,2-dimethylhexahydro-1,3-benzodioxole-5-carboxylate | C11H18O6 | 详情 | 详情 | |
(III) | 30980 | methyl (3aR,5S,7R,7aR)-5-hydroxy-2,2-dimethyl-7-[[(4-methylphenyl)sulfonyl]oxy]hexahydro-1,3-benzodioxole-5-carboxylate | C18H24O8S | 详情 | 详情 | |
(IV) | 30981 | methyl (3R,4R,5R)-3,4-dihydroxy-5-[[(4-methylphenyl)sulfonyl]oxy]-1-cyclohexene-1-carboxylate | C15H18O7S | 详情 | 详情 | |
(V) | 29912 | methyl (1S,5R,6R)-5-hydroxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C8H10O4 | 详情 | 详情 | |
(VI) | 29913 | methyl (1S,5R,6S)-5-(methoxymethoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C10H14O5 | 详情 | 详情 | |
(VII) | 29914 | methyl (3R,4S,5R)-5-azido-4-hydroxy-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate | C10H15N3O5 | 详情 | 详情 | |
(VIII) | 30982 | methyl (3R,4S,5R)-5-azido-3-(methoxymethoxy)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-cyclohexene-1-carboxylate | C13H21N3O5S | 详情 | 详情 | |
(IX) | 29916 | methyl (1R,5R,6R)-5-(methoxymethoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate | C10H15NO4 | 详情 | 详情 | |
(X) | 29917 | methyl (3R,4R,5S)-4-amino-5-azido-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate | C10H16N4O4 | 详情 | 详情 | |
(XI) | 30983 | methyl (3R,4R,5S)-4-amino-5-azido-3-hydroxy-1-cyclohexene-1-carboxylate | C8H12N4O3 | 详情 | 详情 | |
(XII) | 30984 | methyl (3R,4R,5S)-4-(acetamido)-3-(acetoxy)-5-azido-1-cyclohexene-1-carboxylate | C12H16N4O5 | 详情 | 详情 | |
(XIII) | 30985 | N-methyl-3-pentanamine; N-(1-ethylpropyl)-N-methylamine | C6H15N | 详情 | 详情 | |
(XIV) | 30986 | methyl (3R,4S,5S)-4-(acetamido)-5-azido-3-[(1-ethylpropyl)(methyl)amino]-1-cyclohexene-1-carboxylate | C16H27N5O3 | 详情 | 详情 | |
(XV) | 30987 | methyl (3R,4R,5S)-4-(acetamido)-5-amino-3-[(1-ethylpropyl)(methyl)amino]-1-cyclohexene-1-carboxylate | C16H29N3O3 | 详情 | 详情 |