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【结 构 式】 
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【药物名称】 【化学名称】(3S,6S,13R)-6-(4-Aminobutyl)-3-isopropyl-13-nonyl-1,4,7,10-tetraazacyclotridecane-2,5,8,11-tetraone 【CA登记号】 【 分 子 式 】C25H47N5O4 【 分 子 量 】481.68444 |
【开发单位】Daiichi Pharmaceutical (Originator), Mercian (Originator) 【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY |
合成路线1
The Wittig condensation of decanal (I) with phosphorane (II) in benzene gives trans-2-dodecenoic acid methyl ester (III), which by thermal Michael addition of benzylamine yields the protected beta-aminoester (IV). The debenzylation of (IV) with H2 over Pd/C in methanol affords the free aminoester (V), which is condensed with N-(tert-butoxycarbonyl)-L-valine (VI) by means of 1-[3-(dimethylamino)propyl]-1-ethyl carbodiimide (WSC) in dichloromethane to give the dipeptide (VII) as a diastereomeric mixture, from which the desired isomer (VIII) is isolated by crystallization. The deprotection of the amino group of (VIII) with TFA in dichloromethane affords the peptide (IX), which is coupled with the conveniently protected glycyl-L-lysine dipeptide (X) by means of WSC as before to give the tetrapeptide (XI). The hydrolysis of the methyl ester group of (XI) with LiOH in THF/methanol/water yields the acidic tetrapeptide (XII). The intermediate glycyl-L-lysine dipeptide (X) has been obtained by coupling N-(tert-butoxycarbonyl)glycine (XV) with Nomega-(benzyloxycarbonyl)-L-lysine methyl ester (XVI) by means of WSC as before to give dipeptide (XVI), which is submitted to alkaline hydrolysis to provide the intermediate dipeptide (X).
| 【1】 Sakai, K.; Yoshioka, T.; Agematu, H.; Chiba, H.; Dobashi, K.; Rhodopeptins, novel cyclic tetrapeptides with antifungal activities from Rhodococcus sp. III. Synthetic study of rhodopeptins. J Antibiot 1999, 52, 8, 710. |
| 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) | 31059 | decanal | 112-31-2 | C10H20O | 详情 | 详情 |
| (II) | 14686 | 2-phenyl-1,3-dioxane | C10H12O2 | 详情 | 详情 | |
| (III) | 31060 | methyl (E)-2-dodecenoate | C13H24O2 | 详情 | 详情 | |
| (IV) | 31061 | methyl 3-(benzylamino)dodecanoate | C20H33NO2 | 详情 | 详情 | |
| (V) | 31062 | methyl 3-aminododecanoate | C13H27NO2 | 详情 | 详情 | |
| (VI) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (VII) | 31063 | methyl 3-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)dodecanoate | C23H44N2O5 | 详情 | 详情 | |
| (VIII) | 31064 | methyl (3R)-3-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)dodecanoate | C23H44N2O5 | 详情 | 详情 | |
| (IX) | 31065 | methyl (3R)-3-[[(2S)-2-amino-3-methylbutanoyl]amino]dodecanoate | C18H36N2O3 | 详情 | 详情 | |
| (X) | 31066 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)hexanoic acid | C21H31N3O7 | 详情 | 详情 | |
| (XI) | 31067 | methyl (9S,12S,15R)-9-(4-[[(benzyloxy)carbonyl]amino]butyl)-12-isopropyl-2,2-dimethyl-15-nonyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazaheptadecan-17-oate | C39H65N5O9 | 详情 | 详情 | |
| (XII) | 31068 | (9S,12S,15R)-9-(4-[[(benzyloxy)carbonyl]amino]butyl)-12-isopropyl-2,2-dimethyl-15-nonyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazaheptadecan-17-oic acid | C38H63N5O9 | 详情 | 详情 | |
| (XV) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (XVI) | 31069 | methyl (2S)-2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate | C15H22N2O4 | 详情 | 详情 | |
| (XVII) | 31070 | methyl (2S)-6-[[(benzyloxy)carbonyl]amino]-2-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)hexanoate | C22H33N3O7 | 详情 | 详情 |
合成路线2
Elimination of the tert-butoxycarbonyl group of (XII) by treatment with TFA in dichloromethane gives the tetrapeptide (XIII), which is cyclized by means of diphenylphosphorylazide (DPPA) and NaHCO3 in DMF yielding the protected target compound (XIV). Finally, this compound is hydrogenated with H2 over Pd/C in THF to eliminate the benzyloxycarbonyl protecting group.
| 【1】 Sakai, K.; Yoshioka, T.; Agematu, H.; Chiba, H.; Dobashi, K.; Rhodopeptins, novel cyclic tetrapeptides with antifungal activities from Rhodococcus sp. III. Synthetic study of rhodopeptins. J Antibiot 1999, 52, 8, 710. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 31068 | (9S,12S,15R)-9-(4-[[(benzyloxy)carbonyl]amino]butyl)-12-isopropyl-2,2-dimethyl-15-nonyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazaheptadecan-17-oic acid | C38H63N5O9 | 详情 | 详情 | |
| (XIII) | 31071 | (9S,12S,15R)-9-[(2-aminoacetyl)amino]-12-isopropyl-15-nonyl-3,10,13-trioxo-1-phenyl-2-oxa-4,11,14-triazaheptadecan-17-oic acid | C33H55N5O7 | 详情 | 详情 | |
| (XIV) | 31072 | benzyl 4-[(5S,8S,11R)-8-isopropyl-11-nonyl-3,6,9,13-tetraoxo-1,4,7,10-tetraazacyclotridecan-5-yl]butylcarbamate | C33H53N5O6 | 详情 | 详情 |