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【结 构 式】

【分子编号】26446

【品名】methyl (9S,12S)-4-methoxy-12-(methylamino)-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate

【CA登记号】

【 分 子 式 】C21H24N2O5

【 分 子 量 】384.43204

【元素组成】C 65.61% H 6.29% N 7.29% O 20.81%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XIII)

The condensation of 3-(3-isopropoxy-4-methoxyphenyl)propionic acid (I) with the chiral adjuvant 4(S)-benzyloxazolidin-2-one (II) by means of n-BuLi in THF gives the amide (III), which is treated with triethylsilyl azide and KHMDS in THF to afford the chiral alpha-azido compound (IV). Elimination of the oxazolidin group methoxymagnesium bromide in methanol yields the methyl ester (V), which is reduced with H2 over Pd/C in methanol giving the alpha-aminoester (VI). The condensation of (VI) with N-(tert-butoxycarbonyl)-4-methoxy-3-nitro-L-phenylalanine (VII) by means of EDC and HOBT in dichloromethane provides the dipeptide (VIII), which is des-isopropylated with BCl3 in dichloromethane affording the phenolic compound (IX). The cyclization of (IX) with K2CO3 in DMSO gives the cyclic dipeptide (X), which is reduced with H2 over Pd/C in methanol and treated with H3PO2 and NaNO2 in order to eliminate the activating nitro group to give (XI). The methylation of (XI) with NaH and methyl iodide affords (XII), which is deprotected with TFA providing (XIII) with a free methylamino group.

1 Bigot, A.; et al.; Total synthesis of an antitumor agent RA-VII via an efficient preparation of cycloisodityrosine. J Org Chem 1999, 64, 17, 6283.
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) 26435 3-(3-isopropoxy-4-methoxyphenyl)propionic acid C13H18O4 详情 详情
(II) 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
(III) 26436 (4S)-4-benzyl-3-[3-(3-isopropoxy-4-methoxyphenyl)propanoyl]-1,3-oxazolidin-2-one C23H27NO5 详情 详情
(IV) 26437 (2S)-2-azido-1-[(4S)-4-benzyl-2-methylene-1,3-oxazolidin-3-yl]-3-(3-isopropoxy-4-methoxyphenyl)-1-propanone C24H28N4O4 详情 详情
(V) 26438 methyl (2S)-2-azido-3-(3-isopropoxy-4-methoxyphenyl)propanoate C14H19N3O4 详情 详情
(VI) 26439 methyl (2S)-2-amino-3-(3-isopropoxy-4-methoxyphenyl)propanoate C14H21NO4 详情 详情
(VII) 26440 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-fluoro-3-nitrophenyl)propionic acid C14H17FN2O6 详情 详情
(VIII) 26441 methyl (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-fluoro-3-nitrophenyl)propanoyl]amino]-3-(3-isopropoxy-4-methoxyphenyl)propanoate C28H36FN3O9 详情 详情
(IX) 26442 methyl (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-fluoro-3-nitrophenyl)propanoyl]amino]-3-(3-hydroxy-4-methoxyphenyl)propanoate C25H30FN3O9 详情 详情
(X) 26443 methyl (9S,12S)-12-[(tert-butoxycarbonyl)amino]-4-methoxy-16-nitro-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C25H29N3O9 详情 详情
(XI) 26444 methyl (9S,12S)-12-[(tert-butoxycarbonyl)amino]-4-methoxy-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C25H30N2O7 详情 详情
(XII) 26445 methyl (9S,12S)-12-[(tert-butoxycarbonyl)(methyl)amino]-4-methoxy-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C26H32N2O7 详情 详情
(XIII) 26446 methyl (9S,12S)-4-methoxy-12-(methylamino)-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C21H24N2O5 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XIII)

The condensation of (XIII) with N-protected L-alanine (XIV) by means of PyBrOP and diethylisopropylamine in DMF gives the cyclic tripeptide (XV), which after deprotection with TFA is condensed with the protected tripeptide (XVI) by means of EDC and HOBT to provide the cyclic hexapeptide (XVII). Finally, this compound is cyclized by hydrolysis of the methyl ester with LiOH in THF/methanol/water, deprotection of the amino group with TFA and cyclization with DPPA and NaHCO3 in DMF.

1 Bigot, A.; et al.; Total synthesis of an antitumor agent RA-VII via an efficient preparation of cycloisodityrosine. J Org Chem 1999, 64, 17, 6283.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 26446 methyl (9S,12S)-4-methoxy-12-(methylamino)-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C21H24N2O5 详情 详情
(XIV) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(XV) 26447 methyl (9S,12S)-12-[[(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl](methyl)amino]-4-methoxy-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C29H37N3O8 详情 详情
(XVI) 26448 (6R,9S,12S)-12-(4-methoxybenzyl)-2,2,6,9,11-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid C22H33N3O7 详情 详情
(XVII) 26449 methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C46H60N6O12 详情 详情
Extended Information