【结 构 式】 |
【分子编号】29904 【品名】ethyl (1R,5R,6R)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate 【CA登记号】 |
【 分 子 式 】C14H23NO3 【 分 子 量 】253.34156 【元素组成】C 66.37% H 9.15% N 5.53% O 18.95% |
合成路线1
该中间体在本合成路线中的序号:(XI)1) The reaction of (-)-quinic acid (I) with 2,2-dimethoxypropane (II) and p-toluenesulfonic acid in refluxing acetone gives the protected lactone (III), which by treatment with sodium ethoxide in ethanol yields the ethyl ester (IV). The acylation of (IV) with mesyl chloride and TEA in dichloromethane affords the mesylate (V), which is dehydrated with SO2Cl2 in dichloromethane, giving the cyclohexenecarboxylate (VI). The transketalization of (VI) with 3-pentanone and HClO4 affords the 3,4-pentylidene ketal (VII), which is cleaved with borane methyl sulfide complex to the 3-pentyl ether (VIII). The epoxidation of (VIII) by treatment with KHCO3 in hot ethanol affords the epoxide (IX), which is opened with sodium azide and ammonium chloride in ethanol/water, resulting in the the azido alcohol (X). The cyclization of (X) with triphenylphosphine in refluxing THF/acetonitrile or trimethylphosphine in anhydrous acetonitrile yields aziridine (XI), which is opened by means of sodium azide in hot DMF to the azidoamine (XII). The acetylation of (XII) with acetic anhydride provides the azidoacetamide (XIII), which is reduced with H2 over Lindlar catalyst or over RaNi in ethanol and treated with 85% phosphoric acid.
【1】 Rohloff, J.C.; Kent, K.M.; Postich, M.J.; et al.; Practical total synthesis of the anti-influenza drug GS-4104. J Org Chem 1998, 63, 13, 4545. |
【2】 Castañer, J.; Leeson, P.A.; Graul, A.; Oseltamivir Phosphate. Drugs Fut 1999, 24, 11, 1189. |
【3】 McGee, L.R.; Kent, K.M.; Portich, M.J.; Kim, C.U.; Williams, M.A.; Zhang, L.; Prisbe, E.J.; Rohloff, J.C.; Munger, J.D.; St. John, D.E. (Gilead Sciences Inc.); Preparation of cyclohexene carboxylate derivs.. WO 9807685 . |
【4】 Postich, M.J.; Williams, M.A.; Rohloff, J.C.; Prisbe, E.J.; McGee, L.R.; Kent, K.M.; Munger, J.D.; Zhang, L.; Kim, C.U.; Kelly, D.E. (Gilead Sciences Inc.); Preparation of carbocyclic cpds.. US 5886213 . |
【5】 Bischofberger, N.W.; Kim, C.U.; Williams, M.A.; Mills, R.G.; Hitchcock, M.J.M.; Dahl, T.C.; Lew, W.; Liu, H. (Gilead Sciences Inc.); Cpds. containing six-membered rings, processes for their preparation, and their use as medicaments. EP 1015417; WO 9914185 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XIIII) | 29906 | ethyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C16H26N4O4 | 详情 | 详情 | |
(I) | 11524 | D-Quinic acid; D-(-)-Chinic acid; D-(-)-Quinic acid; (3R,5R)-1,3,4,5-Tetrahydroxycyclohexanecarboxylic acid | 77-95-2 | C7H12O6 | 详情 | 详情 |
(II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
(III) | 29896 | (1R,2R,6R,8S)-8-hydroxy-4,4-dimethyl-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undecan-9-one | C10H14O5 | 详情 | 详情 | |
(IV) | 29897 | ethyl (3aR,5R,7R,7aS)-5,7-dihydroxy-2,2-dimethylhexahydro-1,3-benzodioxole-5-carboxylate | C12H20O6 | 详情 | 详情 | |
(V) | 29898 | ethyl (3aR,5S,7R,7aR)-5-hydroxy-2,2-dimethyl-7-[(methylsulfonyl)oxy]hexahydro-1,3-benzodioxole-5-carboxylate | C13H22O8S | 详情 | 详情 | |
(VI) | 29899 | ethyl (3aR,7R,7aR)-2,2-dimethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C13H20O7S | 详情 | 详情 | |
(VII) | 29900 | ethyl (3aR,7R,7aR)-2,2-diethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C15H24O7S | 详情 | 详情 | |
(VIII) | 29901 | ethyl (3R,4R,5R)-3-(1-ethylpropoxy)-4-hydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate | C15H26O7S | 详情 | 详情 | |
(IX) | 29902 | ethyl (1S,5R,6S)-5-(1-ethylpropoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C14H22O4 | 详情 | 详情 | |
(X) | 29903 | ethyl (3R,4S,5R)-5-azido-3-(1-ethylpropoxy)-4-hydroxy-1-cyclohexene-1-carboxylate | C14H23N3O4 | 详情 | 详情 | |
(XI) | 29904 | ethyl (1R,5R,6R)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate | C14H23NO3 | 详情 | 详情 | |
(XII) | 29905 | ethyl (3R,4R,5S)-4-amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C14H24N4O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VII)A new synthesis of oseltamivir phosphate has been described: The opening of the oxirane ring of the already reported oseltamivir intermediate (I) by reaction with allylamine (II) in t-BuOMe/MeCN 9:1 provides the allylamino derivative (III), which is deallylated with Pd/C and ethanolamine to give the primary amine (IV). The direct conversion of the amino alcohol (IV) into the vicinal diamine (VIII) is achieved, without isolation of the intermediates, by reaction of compound (IV) with benzaldehyde to give the benzaldehyde imine (V), mesylation of (V) with MsCl and TEA to the mesylate (VI) and treatment of (VI) with allylamine (II) to yield the aziridine intermediate (VII) that opens to the vicinal diamine (VIII). Acylation of the primary amino group of (VIII) with acetic anhydride in acetic acid provides the acetamide (IX), which is finally deallylated with Pd/C and ethanolamine as before and treated with H3PO4.
【1】 Trussardi, R.; Karpf, M.; New, azide-free transformation of epoxides into 1,2-diamino compounds: Synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu). J Org Chem 2001, 66, 6, 2044. |
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) | 29902 | ethyl (1S,5R,6S)-5-(1-ethylpropoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C14H22O4 | 详情 | 详情 | |
(II) | 13672 | Allylamine; 2-Propen-1-amine | 107-11-9 | C3H7N | 详情 | 详情 |
(III) | 49440 | ethyl (3R,4S,5R)-5-(allylamino)-3-(1-ethylpropoxy)-4-hydroxy-1-cyclohexene-1-carboxylate | C17H29NO4 | 详情 | 详情 | |
(IV) | 49441 | ethyl (3R,4S,5R)-5-amino-3-(1-ethylpropoxy)-4-hydroxy-1-cyclohexene-1-carboxylate | C14H25NO4 | 详情 | 详情 | |
(V) | 49444 | ethyl (3R,4R,5S)-5-(allylamino)-4-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C17H30N2O3 | 详情 | 详情 | |
(VI) | 49443 | ethyl (3R,4S,5R)-3-(1-ethylpropoxy)-4-[(methylsulfonyl)oxy]-5-[[(Z)-benzylidene]amino]-1-cyclohexene-1-carboxylate | C22H31NO6S | 详情 | 详情 | |
(VII) | 29904 | ethyl (1R,5R,6R)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate | C14H23NO3 | 详情 | 详情 | |
(VIII) | 49444 | ethyl (3R,4R,5S)-5-(allylamino)-4-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C17H30N2O3 | 详情 | 详情 | |
(IX) | 49445 | ethyl (3R,4R,5S)-4-(acetamido)-5-(allylamino)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C19H32N2O4 | 详情 | 详情 |