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【结 构 式】 
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【药物名称】CVS-2589 【化学名称】N-Isobutoxy-D-seryl-L-alanine 1-amidino-2-hydroxypiperidin-3(S)-ylamide 【CA登记号】 【 分 子 式 】C17H32N6O6 【 分 子 量 】416.48119 |
【开发单位】Corvas (Originator) 【药理作用】ONCOLYTIC DRUGS, Angiogenesis Inhibitors, Urokinase Inhibitors |
合成路线1
The title compound has been prepared by either solid-phase or solution-phase synthesis. In the first case, N(alpha)-Boc-N(omega)-nitro-L-arginine (I) was coupled with N,O-dimethylhydroxylamine, and the resulting N-methoxy-amide (II) was reduced with LiAlH4 to the corresponding aldehyde, isolated as the cyclic hemiaminal (III). Deprotection of the N-nitro group of (III) by hydrogenation over Pd/C afforded guanidine (IV), which was condensed with allyl chloroformate to give the allyl carbamate (V). Subsequent acid-catalyzed condensation with ethyl 6-hydroxyhexanoate (VI) at the aminal hydroxyl group provided ketal (VII). After hydrolysis of the ethyl ester of (VII), the resulting carboxylic acid (VIII) was coupled to amino-resin to produce the amide-resin (IX).
| 【1】 Cohen, C.R.; Weinhouse, M.I.; Roberts, C.; et al.; Synthesis and biological activity of transition-state urokinase inhibitors. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 090. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 29372 | N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine | C11H21N5O6 | 详情 | 详情 | |
| (II) | 29373 | N-alpha-(tert-butoxycarbonyl)-N1-methoxy-N1-methyl-N-omega'-nitro-L-argininamide | C13H26N6O6 | 详情 | 详情 | |
| (III) | 29374 | 3(S)-(Tert-butoxycarbonylamino)-2-hydroxy-N2-nitropiperidine-1-carboxamidine | C11H21N5O5 | 详情 | 详情 | |
| (IV) | 29375 | tert-butyl (3S)-1-[amino(imino)methyl]-2-hydroxypiperidinylcarbamate | C11H22N4O3 | 详情 | 详情 | |
| (V) | 29376 | allyl (E)-amino[(3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxypiperidinyl]methylidenecarbamate | C15H26N4O5 | 详情 | 详情 | |
| (VI) | 29377 | ethyl 6-hydroxyhexanoate | C8H16O3 | 详情 | 详情 | |
| (VII) | 29378 | ethyl 6-([(3S)-1-[[[(allyloxy)carbonyl]imino](amino)methyl]-3-[(tert-butoxycarbonyl)amino]piperidinyl]oxy)hexanoate | C23H40N4O7 | 详情 | 详情 | |
| (VIII) | 29379 | 6-([(3S)-1-[[[(allyloxy)carbonyl]imino](amino)methyl]-3-[(tert-butoxycarbonyl)amino]piperidinyl]oxy)hexanoic acid | C21H36N4O7 | 详情 | 详情 | |
| (IX) | 29380 | allyl (E)-amino[(3S)-2-[(6-amino-6-oxohexyl)oxy]-3-[(tert-butoxycarbonyl)amino]piperidinyl]methylidenecarbamate | C21H37N5O6 | 详情 | 详情 |
合成路线2
Further solid-phase peptide synthesis by means of sequential coupling of resin (IX) with L-alanine, D-serine and isobutyl chloroformate yielded the peptide-resin (X). The allyloxycarbonyl group of (X) was then removed by treatment with morpholine and palladium catalyst to give resin (XI). The target peptide was finally liberated from the resin (XI) by treatment with trifluoroacetic acid.
| 【1】 Cohen, C.R.; Weinhouse, M.I.; Roberts, C.; et al.; Synthesis and biological activity of transition-state urokinase inhibitors. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 090. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 29380 | allyl (E)-amino[(3S)-2-[(6-amino-6-oxohexyl)oxy]-3-[(tert-butoxycarbonyl)amino]piperidinyl]methylidenecarbamate | C21H37N5O6 | 详情 | 详情 | |
| (X) | 29381 | allyl (E)-amino((3S)-2-[(6-amino-6-oxohexyl)oxy]-3-[[(2S)-2-([(2R)-3-hydroxy-2-[(isobutoxycarbonyl)amino]propanoyl]amino)propanoyl]amino]piperidinyl)methylidenecarbamate | C27H47N7O9 | 详情 | 详情 | |
| (XI) | 29382 | isobutyl (1R)-2-[[(1S)-2-([(3S)-1-[amino(imino)methyl]-2-[(6-amino-6-oxohexyl)oxy]piperidinyl]amino)-1-methyl-2-oxoethyl]amino]-1-(hydroxymethyl)-2-oxoethylcarbamate | C23H43N7O7 | 详情 | 详情 |
合成路线3
The compound was also prepared by solution-phase synthesis. Treatment of O-tert-butyl-D-serine (XIII) with isobutyl chloroformate (XII) produced carbamate (XIV). Subsequent coupling of (XIV) with L-alanine tert-butyl ester (XV) by means of EDC and HOBt yielded the protected dipeptide (XVI). Deprotection of both tert-butyl groups of (XVI) with trifluoroacetic acid produced dipeptide (XVII), which was coupled to nitro-L-arginine ethyl aminal (XVIII) to furnish tripeptide (XIX). Hydrogenolysis of the nitro group of (XIX) over Pd/C gave (XX). The ethyl acetal of (XX) was finally hydrolyzed in 3M HCl to yield the title compound.
| 【1】 Cohen, C.R.; Weinhouse, M.I.; Roberts, C.; et al.; Synthesis and biological activity of transition-state urokinase inhibitors. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 090. |
| 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) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (XIII) | 29383 | (2R)-2-amino-3-(tert-butoxy)propionic acid | C7H15NO3 | 详情 | 详情 | |
| (XIV) | 29384 | (2R)-3-(tert-butoxy)-2-[(isobutoxycarbonyl)amino]propionic acid | C12H23NO5 | 详情 | 详情 | |
| (XV) | 29385 | tert-butyl (2S)-2-aminopropanoate | C7H15NO2 | 详情 | 详情 | |
| (XVI) | 29386 | tert-butyl (2S)-2-([(2R)-3-(tert-butoxy)-2-[(isobutoxycarbonyl)amino]propanoyl]amino)propanoate | C19H36N2O6 | 详情 | 详情 | |
| (XVII) | 29387 | (2S)-2-([(2R)-3-hydroxy-2-[(isobutoxycarbonyl)amino]propanoyl]amino)propionic acid | C11H20N2O6 | 详情 | 详情 | |
| (XVIII) | 29388 | 3(S)-Amino-2-ethoxy-N2-nitropiperidine-1-carboxamidine | C8H17N5O3 | 详情 | 详情 | |
| (XIX) | 29389 | Isobutoxycarbinyl-D-seryl-L-alanine 1-[2-ethoxy-1-(N2-nitroamidino)piperidin-3(S)-ylamide | C19H35N7O8 | 详情 | 详情 | |
| (XX) | 29390 | isobutyl (1R)-2-[[(1S)-2-([(3S)-1-[amino(imino)methyl]-2-ethoxypiperidinyl]amino)-1-methyl-2-oxoethyl]amino]-1-(hydroxymethyl)-2-oxoethylcarbamate | C19H36N6O6 | 详情 | 详情 |