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【结 构 式】

【分子编号】15836

【品名】N-t-BOC-(2R,3R)-3-Amino-2-hydroxy-4-phenylbutyric acid; (2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyric acid

【CA登记号】116661-86-0

【 分 子 式 】C15H21NO5

【 分 子 量 】295.33548

【元素组成】C 61% H 7.17% N 4.74% O 27.09%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IV)

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:(IV)

Coupling of carboxylic acid (I) with tert-butylamine (II) by means of EDC-HOBt in CH2Cl2 affords carboxamide (III), whose Boc group is removed by treatment with HCl/dioxane to provide compound (IV). Coupling of thiazolidine (IV) to Boc-protected allophenylnorstatine (V) by means of DCC and HOBt in EtOAc provides derivative (VI), whose is deprotected by treatment with HCl/dioxane to yield (VII), which is then coupled to Boc-Val-OH (VIII) with EDC-HOBt in DMF to furnish compound (IX). On the other hand, aminophenol derivative (XI) is condensed with benzyl chloroacetate (XII) in DMF in the presence of K2CO3 to furnish derivative (XIII), which is then debenzylated by hydrogenation over Pd/C in MeOH to yield acetic acid derivative (XIV). Finally, the Boc group of (IX) is removed with HCl/dioxane and the resulting amine (X) is coupled to carboxylic acid (XIV) by first treatment with N-hydroxy-5-norbornene-2,3-dicarboximide (HONB) and DCC in CH2Cl2 followed by treatment with Et3N in DMF. Alternatively, the coupling can be performed by means of EDC and HOBt in DMF.

1 Takaku, H.; Hattori, N.; Mimoto, T.; et al.; Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere. Chem Pharm Bull 2000, 48, 9, 1310.
2 Terashima, K.; Mimoto, T.; Takaku, H.; Nojima, S.; Kiso, Y. (Japan Energy Corp.); Novel tripeptide cpds. and anti-AIDS drugs. EP 0900566; WO 9829118 .
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) 34777 (4R)-3-(tert-butoxycarbonyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid C11H19NO4S 详情 详情
(II) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(III) 45695 tert-butyl (4R)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidine-3-carboxylate C15H28N2O3S 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) 45697 tert-butyl (1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropylcarbamate C25H39N3O5S 详情 详情
(VI) 45698 tert-butyl (1S)-1-[[((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropyl)amino]carbonyl]-2-methylpropylcarbamate 1638-63-7 C30H48N4O6S 详情 详情
(VII) 29294 (4R)-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-N-(tert-butyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide C20H31N3O3S 详情 详情
(VIII) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(IX) 45698 tert-butyl (1S)-1-[[((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropyl)amino]carbonyl]-2-methylpropylcarbamate 1638-63-7 C30H48N4O6S 详情 详情
(X) 45699 (4R)-3-((2S,3S)-3-[[(2S)-2-amino-3-methylbutanoyl]amino]-2-hydroxy-4-phenylbutanoyl)-N-(tert-butyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide C25H40N4O4S 详情 详情
(XI) 45700 N,N-Dimethyl-3-aminophenol; 3-Dimethylaminophenol; m-Dimethylaminophenol 99-07-0 C8H11NO 详情 详情
(XII) 45701 benzyl 2-chloroacetate 140-18-1 C9H9ClO2 详情 详情
(XIII) 45702 benzyl 2-[3-(dimethylamino)phenoxy]acetate C17H19NO3 详情 详情
(XIV) 45703 2-[3-(dimethylamino)phenoxy]acetic acid C10H13NO3 详情 详情
Extended Information