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【结 构 式】 
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【分子编号】47776 【品名】tert-butyl (3S,6R)-6-hydroxy-2-oxoazepanylcarbamate 【CA登记号】 |
【 分 子 式 】C11H20N2O4 【 分 子 量 】244.29088 【元素组成】C 54.08% H 8.25% N 11.47% O 26.2% |
合成路线1
该中间体在本合成路线中的序号：(X)Cyclization of 5(R)-hydroxy-L-lysine (VIII) by means of EDC and HOBt, followed by treatment of the resulting amino lactam (IX) with Boc2O, furnished the N-Boc aminolactam (X). The configuration of the (R)-secondary alcohol was inverted by Mitsunobu coupling with p-nitrobenzoic acid (XI) to produce the (S)-p-nitrobenzoate ester (XII). Methylation of the lactam N of (XII) yielded (XIII), and hydrolysis of the p-nitrobenzoate ester of (XIII) with LiOH afforded the (S)-hydroxy lactam (XIV). Esterification of (XIV) with myristic acid (XV) in the presence of EDC and DMAP produced the myristate ester (XVI). Treatment of (XVI) with trifluoroacetic acid removed the Boc protecting group to yield amine (XVII). This was then condensed with the intermediate lactone (VIII) in refluxing isopropanol to produce amide (XVIII). Finally, acetonide hydrolysis in (XVIII) employing trifluoroacetic acid generated the title compound.
| 【1】 Kinder, F.R. Jr.; et al.; Total synthesis of bengamides B and E. J Org Chem 2001, 66, 6, 2118. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 47773 | (4R,4aR,7R,7aS)-7-methoxy-2,2-dimethyl-4-[(E)-3-methyl-1-butenyl]tetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one | C14H22O5 | 详情 | 详情 | |
| (VIII) | 47774 | (2S,5R)-2,6-diamino-5-hydroxyhexanoic acid | C6H14N2O3 | 详情 | 详情 | |
| (IX) | 47775 | (3S,6R)-3-amino-6-hydroxy-2-azepanone | C6H12N2O2 | 详情 | 详情 | |
| (X) | 47776 | tert-butyl (3S,6R)-6-hydroxy-2-oxoazepanylcarbamate | C11H20N2O4 | 详情 | 详情 | |
| (XI) | 18119 | 4-nitrobenzoic acid; p-nitrobenzoic acid | 62-23-7 | C7H5NO4 | 详情 | 详情 |
| (XII) | 47777 | (3S,6S)-6-[(tert-butoxycarbonyl)amino]-7-oxoazepanyl 4-nitrobenzoate | C18H23N3O7 | 详情 | 详情 | |
| (XIII) | 47778 | (3S,6S)-6-[(tert-butoxycarbonyl)amino]-1-methyl-7-oxoazepanyl 4-nitrobenzoate | C19H25N3O7 | 详情 | 详情 | |
| (XIV) | 47779 | tert-butyl (3S,6S)-6-hydroxy-1-methyl-2-oxoazepanylcarbamate | C12H22N2O4 | 详情 | 详情 | |
| (XV) | 47780 | myristic acid | C14H28O2 | 详情 | 详情 | |
| (XVI) | 47781 | (3S,6S)-6-[(tert-butoxycarbonyl)amino]-1-methyl-7-oxoazepanyl myristate | C26H48N2O5 | 详情 | 详情 | |
| (XVII) | 47783 | (3S,6S)-6-amino-1-methyl-7-oxoazepanyl myristate | C21H40N2O3 | 详情 | 详情 | |
| (XVIII) | 47782 | (3S,6S)-6-[((2R)-2-[(4R,5R,6R)-5-hydroxy-2,2-dimethyl-6-[(E)-3-methyl-1-butenyl]-1,3-dioxan-4-yl]-2-methoxyethanoyl)amino]-1-methyl-7-oxoazepanyl myristate | C35H62N2O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Cyclization of (5R)-5-hydroxy-L-lysine (VIII) by means of EDC and HOBt afforded the caprolactam (IX). The amino group of (IX) was then protected as the N-Boc derivative (X) by treatment with Boc2O. Hydroxyl group acylation in (X) with cyclohexanecarbonyl chloride (XI) produced ester (XII). The Boc protecting group of (XII) was then removed by treatment with trifluoroacetic acid, yielding the aminocaprolactam (XIII). Coupling of amine (XIII) with lactone (VII) in refluxing isopropanol produced amide (XIV). The title compound was then obtained by acidic hydrolysis of the remaining acetonide function of (XIV).
| 【1】 Kinder, F.R. Jr.; Versace, R.W.; Bair, K.W.; et al.; Synthesis and antitumor activity of ester-modified analogues of bengamide B. J Med Chem 2001, 44, 22, 3692. |
| 【2】 Bair, K.W.; Kinder, F.R. Jr.; Jagoe, C.T. (Novartis AG); Certain substd. caprolactams, pharmaceutical compsns. containing them and their use in treating tumors. EP 1131297; WO 0029382 . |
| 【3】 Bair, K.W.; Wattanasin, S.; Versace, R.W.; Kinder, F.R. Jr.; Jagoe, C.T. (Novartis AG); Certain substd. caprolactams, pharmaceutical compsns. containing them and a process for their preparation. US 6239127 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 54665 | (4R,4aR,7R,7aS)-4-[(E)-3,3-dimethyl-1-butenyl]-7-methoxy-2,2-dimethyltetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one | C15H24O5 | 详情 | 详情 | |
| (VIII) | 47774 | (2S,5R)-2,6-diamino-5-hydroxyhexanoic acid | C6H14N2O3 | 详情 | 详情 | |
| (IX) | 47775 | (3S,6R)-3-amino-6-hydroxy-2-azepanone | C6H12N2O2 | 详情 | 详情 | |
| (X) | 47776 | tert-butyl (3S,6R)-6-hydroxy-2-oxoazepanylcarbamate | C11H20N2O4 | 详情 | 详情 | |
| (XI) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |
| (XII) | 54666 | (3R,6S)-6-[(tert-butoxycarbonyl)amino]-7-oxoazepanyl cyclohexanecarboxylate | C18H30N2O5 | 详情 | 详情 | |
| (XIII) | 54667 | (3R,6S)-6-amino-7-oxoazepanyl cyclohexanecarboxylate | C13H22N2O3 | 详情 | 详情 | |
| (XIV) | 54668 | (3R,6S)-6-[((2R)-2-{(4R,5R,6R)-6-[(E)-3,3-dimethyl-1-butenyl]-5-hydroxy-2,2-dimethyl-1,3-dioxan-4-yl}-2-methoxyethanoyl)amino]-7-oxoazepanyl cyclohexanecarboxylate | C28H46N2O8 | 详情 | 详情 |