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【结 构 式】 
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【分子编号】15838 【品名】(2R)-2-[(tert-butoxycarbonyl)amino]-3-(methylsulfanyl)propionic acid 【CA登记号】 |
【 分 子 式 】C9H17NO4S 【 分 子 量 】235.30432 【元素组成】C 45.94% H 7.28% N 5.95% O 27.2% S 13.63% |
合成路线1
该中间体在本合成路线中的序号：(VI)1) The reaction of 3-(tert-butoxycarbonyl)thiazolidine-4(R)-carboxylic acid (I) with tert-butylamine by means of dicyclohexylcarbodiimide (DCC) in THF gives the corresponding protected amide (II), which is deprotected with HCl or methanesulfonic acid to the free amide (III). The condensation of (III) with (2S,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutyric acid (IV) by means of 1-hydroxybenzotriazole (HOBT) and DCC in DMF affords the dipeptide (V), which by deprotection with HCl in dioxane and condensation with 2(R)-(tert-butoxycarbonylamino)-3-(methylsulfanyl)propionic acid (VI) by means of HBOT and DCC as before yields the tripeptide (VII). Finally, this compound is deprotected with HCl as before and condensed with 2-(5-isoquinolinyloxy)acetic acid (VIII) by means of HBOT and DCC or HBOT and 5-norbornene-2,3-dicarboxyimide (NDPP) in DMF.
| 【1】 Ireland, C.D.; Castaner, J.; KNI-272. Drugs Fut 1996, 21, 10, 1022. |
| 【2】 Kiso, Y.; Design and synthesis of HIV protease inhibitors containing allophenylorstatine as a transition-state mimic. Adv Exp Med Biol 1995, 362(Aspartic Proteinases), Aspartic Proteinases, 413-23. |
| 【3】 Maeda, S.; Moriwaki, H. (Hamari Chemicals Ltd.; Japan Energy Corp.); Manufacturing method for peptide derivs. and their salts. JP 1994220031 . |
| 【4】 Mimoto, T.; Kisanuki, S.; Takahasihi, O.; Kiso, Y. (Japan Energy Corp.); Process for producing peptide derivs. and salts thereof. EP 0574135 . |
| 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) | 15833 | (4R)-3-(tert-butoxycarbonyl)-1,3-thiazolane-4-carboxylic acid; N-t-BOC-4-thio-L-proline | 51077-16-8 | C9H15NO4S | 详情 | 详情 |
| (II) | 15834 | tert-butyl (4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolane-3-carboxylate | C13H24N2O3S | 详情 | 详情 | |
| (III) | 15835 | (4R)-N-(tert-butyl)-1,3-thiazolane-4-carboxamide | C8H16N2OS | 详情 | 详情 | |
| (IV) | 15836 | N-t-BOC-(2R,3R)-3-Amino-2-hydroxy-4-phenylbutyric acid; (2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyric acid | 116661-86-0 | C15H21NO5 | 详情 | 详情 |
| (V) | 15837 | tert-Butyl N-((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolan-3-yl]-2-hydroxy-3-oxopropyl)carbamate | C23H35N3O5S | 详情 | 详情 | |
| (VI) | 15838 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(methylsulfanyl)propionic acid | C9H17NO4S | 详情 | 详情 | |
| (VII) | 15839 | tert-butyl (1R)-2-[((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropyl)amino]-1-[(methylsulfanyl)methyl]-2-oxoethylcarbamate | C27H42N4O6S2 | 详情 | 详情 | |
| (VIII) | 15840 | 2-(5-isoquinolinyloxy)acetic acid | C11H9NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)2) The intermediate (V) of the preceding synthesis is submitted to a deprotection - protection sequence [hydrolysis with HCl in dioxane and protection with benzyl succinimidyl carbonate (PhCH2-OSu)] giving the benzyloxycarbonyl protected compound (IX), which is condensed with (VI) by means of DCC and dimethylaminopyridine (DMAP) to yield (X) [the ester isomer of (VII)]. The deprotection of (X) with HCl and condensation with (VIII) by means of HBOT and DCC as before affords (XI) [the benzyloxycarbonyl protected prodrug of KNI-272], which is deprotected with trifluoroacetic acid (TFA)/anisole and HCl affording the ester prodrug (XII). Finally, this compound is converted into KNI-272 by incubation at 37 C in a phosphate buffered saline at pH 7.4.
| 【1】 Kimura, T.; Ohtake, J.; Nakata, S.; Enomoto, H.; Moriwaki, H.; Akaji, K.; Kiso, Y.; Synthesis and prodrugs of HIV protease inhibitors. Peptide Chem 1994, 157-60. |
| 【2】 Ireland, C.D.; Castaner, J.; KNI-272. Drugs Fut 1996, 21, 10, 1022. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 15837 | tert-Butyl N-((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolan-3-yl]-2-hydroxy-3-oxopropyl)carbamate | C23H35N3O5S | 详情 | 详情 | |
| (VI) | 15838 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(methylsulfanyl)propionic acid | C9H17NO4S | 详情 | 详情 | |
| (VIII) | 15840 | 2-(5-isoquinolinyloxy)acetic acid | C11H9NO3 | 详情 | 详情 | |
| (IX) | 15841 | benzyl N-((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolan-3-yl]-2-hydroxy-3-oxopropyl)carbamate | C26H33N3O5S | 详情 | 详情 | |
| (X) | 15842 | (1S,2S)-2-[[(benzyloxy)carbonyl]amino]-1-([(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolidin-3-yl]carbonyl)-3-phenylpropyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(methylsulfanyl)propanoate | C35H48N4O8S2 | 详情 | 详情 | |
| (XI) | 15843 | (1S,2S)-2-[[(benzyloxy)carbonyl]amino]-1-([(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolidin-3-yl]carbonyl)-3-phenylpropyl (2R)-2-[[2-(5-isoquinolinyloxy)acetyl]amino]-3-(methylsulfanyl)propanoate | C41H47N5O8S2 | 详情 | 详情 | |
| (XII) | 15844 | (1S,2S)-2-amino-1-([(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolidin-3-yl]carbonyl)-3-phenylpropyl (2R)-2-[[2-(5-isoquinolinyloxy)acetyl]amino]-3-(methylsulfanyl)propanoate | C33H41N5O6S2 | 详情 | 详情 |