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【结 构 式】 
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【分子编号】47046 【品名】(8S,11R,14R)-14-[(tert-butoxycarbonyl)amino]-11-(4-fluoro-3-nitrobenzyl)-5,18-dimethoxy-10,13-dioxo-2-oxa-9,12-diazatricyclo[13.3.1.1(3,7)]icosa-1(19),3(20),4,6,15,17-hexaene-8-carboxylic acid 【CA登记号】 |
【 分 子 式 】C32H33FN4O11 【 分 子 量 】668.6327832 【元素组成】C 57.48% H 4.97% F 2.84% N 8.38% O 26.32% |
合成路线1
该中间体在本合成路线中的序号：(XXI)The synthesis of intermediate (XXI) has been performed as follows: The condensation of 4-fluoro-3-nitrobenzyl bromide (XII) with the chiral dihydropyrazine (XIII) by means of BuLi and CuCN gives the chiral adduct (XIV), which is treated with TFA to yield the 4-fluoro-3-nitro-D- phenylalanine (XV). The N-protection of (XV) with Teoc-Cl gives the N-protected phenylalanine (XVI), which is condensed with the already described intermediate (XI) by means of PyBop to yield the amide (XVII). The oxidation of the primary OH group of (XVII) with DMP and NaClO2 affords the carboxylic acid (XVIII), which is cyclized to the cyclic amide (XIX). The cleavage of he protecting groups of (XIX) with HCl, followed by selective N-protection with Boc2O, provides primary carbinol (XX), which is finally oxidized with DMP and NaClO2 to give the desired carboxylic acid intermediate (XXI).
| 【1】 Boger, D.L.; et al.; First and second generation total synthesis of the teicoplanin aglycon. J Am Chem Soc 2001, 123, 9, 1862. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 47037 | tert-butyl (1R)-1-[3-(3-[(1S)-1-amino-2-[(2-methoxyethoxy)methoxy]ethyl]-5-methoxyphenoxy)-4-methoxyphenyl]-2-hydroxyethylcarbamate | C27H40N2O9 | 详情 | 详情 | |
| (XII) | 47038 | 4-(bromomethyl)-1-fluoro-2-nitrobenzene | C7H5BrFNO2 | 详情 | 详情 | |
| (XIII) | 10296 | (R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine; (3R)-3-Isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether; (2R)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine | 109838-85-9 | C9H16N2O2 | 详情 | 详情 |
| (XIV) | 47039 | (2R,5S)-2-(4-fluoro-3-nitrobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine; (3R,6S)-3-(4-fluoro-3-nitrobenzyl)-6-isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether | C16H20FN3O4 | 详情 | 详情 | |
| (XV) | 47040 | (2R)-2-amino-3-(4-fluoro-3-nitrophenyl)propionic acid | C9H9FN2O4 | 详情 | 详情 | |
| (XVI) | 47041 | (2R)-3-(4-fluoro-3-nitrophenyl)-2-([[2-(trimethylsilyl)ethoxy]carbonyl]amino)propionic acid | C15H21FN2O6Si | 详情 | 详情 | |
| (XVII) | 47042 | 2-(trimethylsilyl)ethyl (1R,4S)-4-[3-(5-[(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl]-2-methoxyphenoxy)-5-methoxyphenyl]-1-(4-fluoro-3-nitrobenzyl)-2-oxo-6,8,11-trioxa-3-azadodec-1-ylcarbamate | C42H59FN4O14Si | 详情 | 详情 | |
| (XVIII) | 47043 | (2R)-2-[(tert-butoxycarbonyl)amino]-2-[3-[3-((1S,4R)-4-(4-fluoro-3-nitrobenzyl)-1-[[(2-methoxyethoxy)methoxy]methyl]-10,10-dimethyl-3,6-dioxo-7-oxa-2,5-diaza-10-silaundec-1-yl)-5-methoxyphenoxy]-4-methoxyphenyl]ethanoic acid | C42H57FN4O15Si | 详情 | 详情 | |
| (XIX) | 47044 | tert-butyl (8S,11R,14R)-11-(4-fluoro-3-nitrobenzyl)-5,18-dimethoxy-8-[[(2-methoxyethoxy)methoxy]methyl]-10,13-dioxo-2-oxa-9,12-diazatricyclo[13.3.1.1(3,7)]icosa-1(19),3(20),4,6,15,17-hexaen-14-ylcarbamate | C36H43FN4O12 | 详情 | 详情 | |
| (XX) | 47045 | tert-butyl (8S,11R,14R)-11-(4-fluoro-3-nitrobenzyl)-8-(hydroxymethyl)-5,18-dimethoxy-10,13-dioxo-2-oxa-9,12-diazatricyclo[13.3.1.1(3,7)]icosa-1(19),3(20),4,6,15,17-hexaen-14-ylcarbamate | C32H35FN4O10 | 详情 | 详情 | |
| (XXI) | 47046 | (8S,11R,14R)-14-[(tert-butoxycarbonyl)amino]-11-(4-fluoro-3-nitrobenzyl)-5,18-dimethoxy-10,13-dioxo-2-oxa-9,12-diazatricyclo[13.3.1.1(3,7)]icosa-1(19),3(20),4,6,15,17-hexaene-8-carboxylic acid | C32H33FN4O11 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXI)Assembly of the target compound: The condensation of the carboxylic acid intermediate (XXI) with the free amino group of the intermediate cyclopeptide (XXII) by means of DEPBT gives the corresponding amide (XXIII), which is cyclized by means of CsF in DMSO yielding the macrocyclic ether (XXIV). The reduction of the nitro group of (XXIV) with H2 over Pd/C affords the corresponding amino derivative (XXV).
| 【1】 Boger, D.L.; et al.; First and second generation total synthesis of the teicoplanin aglycon. J Am Chem Soc 2001, 123, 9, 1862. |
| 【2】 Boger, D.L.; et al.; Total synthesis of the teicoplanin aglycon. J Am Chem Soc 2000, 122, 30, 7416. |
| 【3】 Johnson, T.A.; et al.; Highly diastereoselective and enantioselective carbon- -carbon bond formations in conjugate additions of lithiated N-boc allylamines to nitroalkenes: Enantioselective synthesis of 3,4- and 3,4,5-substituted piperidines including (-)-paroxetine. J Am Chem Soc 2001, 123, 5, 1004. |
| 【4】 Boger, D.L.; et al.; Diasteroselective total synthesis of the vancomycin aglycon with ordered atropisomer equilibrations. J Am Chem Soc 1999, 121, 13, 3226. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 47046 | (8S,11R,14R)-14-[(tert-butoxycarbonyl)amino]-11-(4-fluoro-3-nitrobenzyl)-5,18-dimethoxy-10,13-dioxo-2-oxa-9,12-diazatricyclo[13.3.1.1(3,7)]icosa-1(19),3(20),4,6,15,17-hexaene-8-carboxylic acid | C32H33FN4O11 | 详情 | 详情 | |
| (XXII) | 40571 | (1R,13S,16S,17R,28R)-28-amino-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(35),24,26,33-dodeca; (1R,13S,16S,17R,28R)-28-amino-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(35),24,26,33-dodeca; (1R,13S,16S,17R,28R)-28-amino-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(35),24,26,33-dodeca | C41H45ClN4O13 | 详情 | 详情 | |
| (XXIII) | 47047 | tert-butyl (8S,11R,14R)-8-([[(1R,13S,16S,17R,28R)-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-15,29,31-trioxo-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(35),24,26,33-dodecaen-28-yl]amino]carbonyl)-11-(4-fluoro-3-nitrobenzyl)-5,18-dimethoxy-10,13-dioxo-2-oxa-9,12-diazatricyclo[13.3.1.1(3,7)]icosa-1(19),3(20),4,6,15,17-hexaen-14-ylcarbamate | C73H76ClFN8O23 | 详情 | 详情 | |
| (XXIV) | 47048 | tert-butyl (1S,2R,19R,22R,34S,37R,40R,52S)-5-chloro-2-hydroxy-26,31,44,47,49,66-hexamethoxy-52-(((2-methoxyethoxy)methoxy)methyl)-15-nitro-21,35,38,54,56,58-hexaoxo-7,13,28-trioxa-20,36,39,53,55,57-hexaazaundecacyclo[38.14.2.2(3,6).2(14,17).2(19,34).1(8,12).1(23,27).1(29,33).1(41,45).0(10,37).0(46,51)]hexahexaconta-3,5,8(66),9,11,14,16,23(65),24,26,29(carbamate | C73H75ClN8O23 | 详情 | 详情 | |
| (XXV) | 47049 | tert-butyl (1S,2R,19R,22R,34S,37R,40R,52S)-15-amino-5-chloro-2-hydroxy-26,31,44,47,49,66-hexamethoxy-52-(((2-methoxyethoxy)methoxy)methyl)-21,35,38,54,56,58-hexaoxo-7,13,28-trioxa-20,36,39,53,55,57-hexaazaundecacyclo[38.14.2.2(3,6).2(14,17).2(19,34).1(8,12).1(23,27).1(29,33).1(41,45).0(10,37).0(46,51)]hexahexaconta-3,5,8(66),9,11,14,16,23(65),24,26,29(carbamate | C73H77ClN8O21 | 详情 | 详情 |