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【结 构 式】 
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【分子编号】37623 【品名】(2S)-4-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid 【CA登记号】 |
【 分 子 式 】C13H23NO6 【 分 子 量 】289.32876 【元素组成】C 53.97% H 8.01% N 4.84% O 33.18% |
合成路线1
该中间体在本合成路线中的序号：(V)Cilengitide is synthesized using solid-phase Merrifield-type methods by sequentially adding N-Boc-N-Me-L-Val (I), N-Boc-D-Phe (III), N-Boc-4-O-t-Bu-L-Asp (V), N-Boc-Gly (VII) and Nalpha-Fmoc-Nomega-Mtr-L-Arg (IX) in a stepwise manner to a 4-hydroxymethylphenoxymethyl-polystyrene resin (Wang type resin), yielding peptide-resin intermediates (II), (IV), (VI), (VIII) and (X), respectively. Elimination of the resin from the peptide chain with a 1:1 mixture of TFA/dichloromethane results in the linear peptide (XI), which is then deprotected at the amino-terminal group by removing the Fmoc group with a 1:1 mixture of piperidine/DMF, to give peptide (XII).
| 【1】 Graul, A.; Sorbera, L.A.; Castañer, J.; Cilengitide. Drugs Fut 2000, 25, 7, 674. |
| 【2】 Jonczyk, A.; Goodman, S.; Diefenbach, B.; Sutter, A.; Holzmann, G.; Kessler, H.; Dechantsreiter, M. (Merck Patent GmbH); Cyclic adhesion inhibitors. DE 19534177; EP 0770622; JP 1997132593; US 6001961 . |
| 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),(II) | 27154 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylbutyric acid | 45170-31-8 | C11H21NO4 | 详情 | 详情 |
| (X),(XI) | 37627 | (8S,14S,17R,20S)-17-benzyl-14-[2-(tert-butoxy)-2-oxoethyl]-8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-imino-20-isopropyl-1-(4-methoxyphenyl)-19-methyl-9,12,15,18-tetraoxo-1,1-diphenyl-2,4,10,13,16,19-hexaazahenicosan-21-oic acid | C66H76N8O11 | 详情 | 详情 | |
| (III) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (IV) | 37622 | (2S)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl](methyl)amino]-3-methylbutyric acid | C20H30N2O5 | 详情 | 详情 | |
| (V) | 37623 | (2S)-4-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | C13H23NO6 | 详情 | 详情 | |
| (VI) | 37624 | (6S,9R,12S)-9-benzyl-6-[2-(tert-butoxy)-2-oxoethyl]-12-isopropyl-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid | C28H43N3O8 | 详情 | 详情 | |
| (VII) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (VIII) | 37625 | (9S,12R,15S)-12-benzyl-9-[2-(tert-butoxy)-2-oxoethyl]-15-isopropyl-2,2,14-trimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-oic acid | C30H46N4O9 | 详情 | 详情 | |
| (IX) | 37626 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-[(imino[[(4-methoxyphenyl)(diphenyl)methyl]amino]methyl)amino]pentanoic acid | C41H40N4O5 | 详情 | 详情 | |
| (XII) | 37628 | (8S,14S,17R,20S)-8-amino-17-benzyl-14-[2-(tert-butoxy)-2-oxoethyl]-3-imino-20-isopropyl-1-(4-methoxyphenyl)-19-methyl-9,12,15,18-tetraoxo-1,1-diphenyl-2,4,10,13,16,19-hexaazahenicosan-21-oic acid | C51H66N8O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The activation of N-Boc-L-aspartic acid 4-O-tert-butyl ester (I) with isopropyl chloroformate (II) in THF gives the mixed anhydride (III), which is reduced with NaBH4 to yield the hydroxyester (IV). The Swern oxidation of (IV) affords the aldehyde (V), which is condensed with the phosphonate (VI) by means of BuLi to provide the hexenedioic diester (VII). The stepwise reduction of (VII) first by means of H2 over Pd/C and then with NaBH4 gives rise to the omega-hydroxy hexanoate (VIII). This is treated first with MsCl and TEA and then with NaN3 to yield a diastereomeric mixture of azido hexanoates (IX) and (X). After separation, the desired isomer (X) is hydrolyzed with LiOH to afford the corresponding carboxylic acid (XI), which is condensed with 2-(1-methylhydrazino)acetic acid tert-butyl ester (XII) by means of HATU and DIEA to provide the corresponding hydrazide (XIII). The reduction of the azido group of (XIII) by means of H2 over Pd/C or with PPh3 in THF/water provides the corresponding amino derivative (XIV), which is finally hydrolyzed and N-deprotected by means of 4M HCl in dioxane to furnish the target fluorinated deoxynegamycin.
| 【1】 Raju, B.; Anandan, S.K.; Gu, S.; et al.; Fluorinated deoxynegamycin analogs: Synthesis and antimicrobial properties. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1686. |
| 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) | 37623 | (2S)-4-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | C13H23NO6 | 详情 | 详情 | |
| (II) | 26492 | 2-[(chlorocarbonyl)oxy]propane | 108-23-6 | C4H7ClO2 | 详情 | 详情 |
| (III) | 61849 | C17H29NO8 | 详情 | 详情 | ||
| (IV) | 61901 | tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoate | C13H25NO5 | 详情 | 详情 | |
| (V) | 61902 | tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-oxobutanoate | C13H23NO5 | 详情 | 详情 | |
| (VI) | 61903 | propyl 2-(dipropoxyphosphoryl)-2-fluoroacetate | C11H22FO5P | 详情 | 详情 | |
| (VII) | 61904 | 6-(tert-butyl) 1-propyl (Z,4S)-4-[(tert-butoxycarbonyl)amino]-2-fluoro-2-hexenedioate | C18H30FNO6 | 详情 | 详情 | |
| (VIII) | 61905 | tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-5-fluoro-6-hydroxyhexanoate | C15H28FNO5 | 详情 | 详情 | |
| (IX) | 61906 | tert-butyl (3S,5S)-6-azido-3-[(tert-butoxycarbonyl)amino]-5-fluorohexanoate | C15H27FN4O4 | 详情 | 详情 | |
| (X) | 61907 | tert-butyl (3S,5R)-6-azido-3-[(tert-butoxycarbonyl)amino]-5-fluorohexanoate | C15H27FN4O4 | 详情 | 详情 | |
| (XI) | 61908 | (3S,5R)-6-azido-3-[(tert-butoxycarbonyl)amino]-5-fluorohexanoic acid | C11H19FN4O4 | 详情 | 详情 | |
| (XII) | 61909 | tert-butyl 2-(1-methylhydrazino)acetate | C7H16N2O2 | 详情 | 详情 | |
| (XIII) | 61910 | tert-butyl (7S)-7-[(2S)-3-azido-2-fluoropropyl]-3,11,11-trimethyl-5,9-dioxo-10-oxa-3,4,6,8-tetraazadodecan-1-oate | C17H32FN7O5 | 详情 | 详情 | |
| (XIV) | 61911 | tert-butyl (7R)-7-[(2R)-3-amino-2-fluoropropyl]-3,11,11-trimethyl-5,9-dioxo-10-oxa-3,4,6,8-tetraazadodecan-1-oate | C17H34FN5O5 | 详情 | 详情 |