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【结 构 式】

【分子编号】36918

【品名】methyl (2S)-3-[4-(benzyloxy)phenyl]-2-[[(E)-(4-methoxyphenyl)methylidene]amino]propanoate

【CA登记号】

【 分 子 式 】C25H25NO4

【 分 子 量 】403.47784

【元素组成】C 74.42% H 6.25% N 3.47% O 15.86%
与该中间体有关的原料药合成路线共 2 条
合成路线1合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

The condensation of 4-O-benzyl-L-tyrosine methyl ester (I) with 4-methoxybenzaldehyde (II) in methanol gives the imine (III), which is oxidized with MCPBA yielding the oxaziridine (IV). The reaction of (IV) with NH2OH affords the 4-O-benzyl-N-hydroxy-L-tyrosine methyl ester (V), which is condensed with cyclohexane-1,4-dione monobutyleneketal (VI) in ethanol giving the imine oxide (VII). The cyclization of (VII) with ethyl acrylate (VIII) in refluxing toluene yields the spiranic isoxazolidine (IX). The hydrogenolysis of the O-N bond of (IX) with H2 over Pd/C, followed by lactam formation by means of AcOH affords the spiranic hydroxypyrrolidinone (X), which is alkylated at the phenolic OH with 3-methyl-2-butenyl bromide (XI) and Cs2CO3 in hot acetone providing the phenolic ether (XII). The reaction of (XII) with tosyl chloride, TEA and DMAP gives the tosylate (XIII), which is treated with sodium azide in DMF to affords the azide (XIV). The reduction of (XIV) with LiAlH4 followed by reductive methylation of the resulting amine with formic acetic anhydride and LiAlH4 provides the methyl-amino derivative (XV).

参考文献 中间体
合成目标
【1】 Lin, H.; Snider, B.B.; Biomimeric total syntheses of (-)-TAN1251A, (+)-TAN1251B, (+)-TAN1251C, and (+)-TAN1251D. Org Lett 2000, 2, 5, 643.
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) 36917 methyl (2S)-2-amino-3-[4-(benzyloxy)phenyl]propanoate C17H19NO3 详情 详情
(II) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(III) 36918 methyl (2S)-3-[4-(benzyloxy)phenyl]-2-[[(E)-(4-methoxyphenyl)methylidene]amino]propanoate C25H25NO4 详情 详情
(IV) 36919 methyl (2S)-3-[4-(benzyloxy)phenyl]-2-[3-(4-methoxyphenyl)-1,2-oxaziridin-2-yl]propanoate C25H25NO5 详情 详情
(V) 36920 methyl (2S)-3-[4-(benzyloxy)phenyl]-2-(hydroxyamino)propanoate C17H19NO4 详情 详情
(VI) 36921 7,12-dioxaspiro[5.6]dodecan-3-one C10H16O3 详情 详情
(VII) 36922 [(1S)-1-[4-(benzyloxy)benzyl]-2-methoxy-2-oxoethyl](7,12-dioxaspiro[5.6]dodec-3-ylidene)ammoniumolate C27H33NO6 详情 详情
(VIII) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(IX) 36923 ethyl (3R)-1-[(1S)-1-[4-(benzyloxy)benzyl]-2-methoxy-2-oxoethyl]-2,9,14-trioxa-1-azadispiro[4.2.6.2]hexadecane-3-carboxylate C32H41NO8 详情 详情
(X) 36924 methyl (2S)-2-[(3R)-3-hydroxy-2-oxo-9,14-dioxa-1-azadispiro[4.2.6.2]hexadec-1-yl]-3-(4-hydroxyphenyl)propanoate C23H31NO7 详情 详情
(XI) 12989 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene 870-63-3 C5H9Br 详情 详情
(XII) 36925 methyl (2S)-2-[(3R)-3-hydroxy-2-oxo-9,14-dioxa-1-azadispiro[4.2.6.2]hexadec-1-yl]-3-[4-[(3-methyl-2-butenyl)oxy]phenyl]propanoate C28H39NO7 详情 详情
(XIII) 36926 methyl (2S)-3-[4-[(3-methyl-2-butenyl)oxy]phenyl]-2-((3R)-3-[[(4-methylphenyl)sulfonyl]oxy]-2-oxo-9,14-dioxa-1-azadispiro[4.2.6.2]hexadec-1-yl)propanoate C35H45NO9S 详情 详情
(XIV) 36927 methyl (2S)-2-[(3S)-3-azido-2-oxo-9,14-dioxa-1-azadispiro[4.2.6.2]hexadec-1-yl]-3-[4-[(3-methyl-2-butenyl)oxy]phenyl]propanoate C28H38N4O6 详情 详情
(XV) 36928 methyl (2S)-2-[(3S)-3-(methylamino)-9,14-dioxa-1-azadispiro[4.2.6.2]hexadec-1-yl]-3-[4-[(3-methyl-2-butenyl)oxy]phenyl]propanoate C29H44N2O5 详情 详情

合成路线2

该中间体在本合成路线中的序号：(III)

The condensation of 4-O-benzyl-L-tyrosine methyl ester (I) with 4-methoxybenzaldehyde (II) in methanol gives the imine (III), which is oxidized with MCPBA yielding the oxaziridine (IV). The reaction of (IV) with NH2OH affords the 4-O-benzyl-N-hydroxy-L-tyrosine methyl ester (V), which is condensed with cyclohexane-1,4-dione monobutyleneketal (VI) in ethanol giving the imine oxide (VII). The cyclization of (VII) with ethyl acrylate (VIII) in refluxing toluene yields the spiranic isoxazolidine (IX). The hydrogenolysis of the O-N bond of (IX) with H2 over Pd/C, followed by lactam formation by means of AcOH affords the spiranic hydroxypyrrolidinone (X), which is alkylated at the phenolic OH with 3-methyl-2-butenyl bromide (XI) and Cs2CO3 in hot acetone providing the phenolic ether (XII). The reaction of (XII) with tosyl chloride, TEA and DMAP gives the tosylate (XIII), which is treated with sodium azide in DMF to affords the azide (XIV). The reduction of (XIV) with LiAlH4 followed by reductive methylation of the resulting amine with formic acetic anhydride and LiAlH4 provides the methylamino derivative.

参考文献 中间体
合成目标
【1】 Lin, H.; Snider, B.B.; Biomimeric total syntheses of (-)-TAN1251A, (+)-TAN1251B, (+)-TAN1251C, and (+)-TAN1251D. Org Lett 2000, 2, 5, 643.
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) 36917 methyl (2S)-2-amino-3-[4-(benzyloxy)phenyl]propanoate C17H19NO3 详情 详情
(II) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(III) 36918 methyl (2S)-3-[4-(benzyloxy)phenyl]-2-[[(E)-(4-methoxyphenyl)methylidene]amino]propanoate C25H25NO4 详情 详情
(IV) 36919 methyl (2S)-3-[4-(benzyloxy)phenyl]-2-[3-(4-methoxyphenyl)-1,2-oxaziridin-2-yl]propanoate C25H25NO5 详情 详情
(V) 36920 methyl (2S)-3-[4-(benzyloxy)phenyl]-2-(hydroxyamino)propanoate C17H19NO4 详情 详情
(VI) 36921 7,12-dioxaspiro[5.6]dodecan-3-one C10H16O3 详情 详情
(VII) 36922 [(1S)-1-[4-(benzyloxy)benzyl]-2-methoxy-2-oxoethyl](7,12-dioxaspiro[5.6]dodec-3-ylidene)ammoniumolate C27H33NO6 详情 详情
(VIII) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(IX) 36923 ethyl (3R)-1-[(1S)-1-[4-(benzyloxy)benzyl]-2-methoxy-2-oxoethyl]-2,9,14-trioxa-1-azadispiro[4.2.6.2]hexadecane-3-carboxylate C32H41NO8 详情 详情
(X) 36924 methyl (2S)-2-[(3R)-3-hydroxy-2-oxo-9,14-dioxa-1-azadispiro[4.2.6.2]hexadec-1-yl]-3-(4-hydroxyphenyl)propanoate C23H31NO7 详情 详情
(XI) 12989 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene 870-63-3 C5H9Br 详情 详情
(XII) 36925 methyl (2S)-2-[(3R)-3-hydroxy-2-oxo-9,14-dioxa-1-azadispiro[4.2.6.2]hexadec-1-yl]-3-[4-[(3-methyl-2-butenyl)oxy]phenyl]propanoate C28H39NO7 详情 详情
(XIII) 36926 methyl (2S)-3-[4-[(3-methyl-2-butenyl)oxy]phenyl]-2-((3R)-3-[[(4-methylphenyl)sulfonyl]oxy]-2-oxo-9,14-dioxa-1-azadispiro[4.2.6.2]hexadec-1-yl)propanoate C35H45NO9S 详情 详情
(XIV) 36927 methyl (2S)-2-[(3S)-3-azido-2-oxo-9,14-dioxa-1-azadispiro[4.2.6.2]hexadec-1-yl]-3-[4-[(3-methyl-2-butenyl)oxy]phenyl]propanoate C28H38N4O6 详情 详情
(XV) 36928 methyl (2S)-2-[(3S)-3-(methylamino)-9,14-dioxa-1-azadispiro[4.2.6.2]hexadec-1-yl]-3-[4-[(3-methyl-2-butenyl)oxy]phenyl]propanoate C29H44N2O5 详情 详情
Extended Information