【结 构 式】 |
【分子编号】49989 【品名】tert-butyl (3S)-3-[[(2S)-2-amino-3-methylbutanoyl]amino]-4-hydroxy-5-(2,3,5,6-tetrafluorophenoxy)pentanoate 【CA登记号】 |
【 分 子 式 】C20H28F4N2O5 【 分 子 量 】452.4464128 【元素组成】C 53.09% H 6.24% F 16.8% N 6.19% O 17.68% |
合成路线1
该中间体在本合成路线中的序号:(IX)Aspartic acid beta-tert-butyl ester (II) was silylated using bis(trimethylsilyl)acetamide and subsequently coupled with the hydroxysuccinimidyl ester of Z-valine (I) to furnish dipeptide (III) (1). This was converted to the corresponding mixed anhydride (IV) with isobutyl chloroformate and N-methylmorpholine. Reaction of anhydride (IV) with ethereal diazomethane, followed by treatment of the intermediate diazo ketone with HBr in HOAc, gave rise to the bromo ketone (V). Tetrafluorophenol (VI) was alkylated with bromide (V) to yield ether (VII). The ketone function of (VII) was then reduced to alcohol (VIII) employing NaBH4. Further hydrogenolysis of the benzyloxycarbonyl group of (VIII) provided amine (IX).
【1】 Ternansky, R.J.; et al.; Structure-activity relationship of a series of oxamyl dipeptide caspase inhibitors developed for the treatment of stroke. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 75. |
【2】 Karanewsky, D.S.; Ternansky, R.J. (Idun Pharmaceuticals, Inc.); C-Terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases. EP 1091930; WO 0001666 . |
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) | 49982 | benzyl (1S)-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-methylpropylcarbamate | C17H20N2O6 | 详情 | 详情 | |
(II) | 26564 | (2S)-2-amino-4-(tert-butoxy)-4-oxobutyric acid | 3057-74-7 | C8H15NO4 | 详情 | 详情 |
(III) | 49983 | (2S)-2-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)amino]-4-(tert-butoxy)-4-oxobutyric acid | C21H30N2O7 | 详情 | 详情 | |
(IV) | 49984 | C26H38N2O9 | 详情 | 详情 | ||
(V) | 49985 | tert-butyl (3S)-3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)amino]-5-bromo-4-oxopentanoate | C22H31BrN2O6 | 详情 | 详情 | |
(VI) | 49986 | 2,3,5,6-Tetrafluorophenol | 769-39-1 | C6H2F4O | 详情 | 详情 |
(VII) | 49987 | tert-butyl (3S)-3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoate | C28H32F4N2O7 | 详情 | 详情 | |
(VIII) | 49988 | tert-butyl (3S)-3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)amino]-4-hydroxy-5-(2,3,5,6-tetrafluorophenoxy)pentanoate | C28H34F4N2O7 | 详情 | 详情 | |
(IX) | 49989 | tert-butyl (3S)-3-[[(2S)-2-amino-3-methylbutanoyl]amino]-4-hydroxy-5-(2,3,5,6-tetrafluorophenoxy)pentanoate | C20H28F4N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(IX)Acylation of tetrachloroaniline (X) with methyl oxalyl chloride (XI) provided the oxamate ester (XII), which was further hydrolyzed to the N-(tetrachlorophenyl)oxamic acid (XIII) by using LiOH. Coupling of acid (XIII) with the intermediate amine (IX) in the presence of HATU furnished the oxalic diamide (XIV). The alcohol function of (XIV) was then reoxidized to ketone (XV) employing the Dess-Martin periodinane reagent. Finally, the tert-butyl ester group of (XV) was cleaved by treatment with trifluoroacetic acid.
【1】 Ternansky, R.J.; et al.; Structure-activity relationship of a series of oxamyl dipeptide caspase inhibitors developed for the treatment of stroke. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 75. |
【2】 Karanewsky, D.S.; Ternansky, R.J. (Idun Pharmaceuticals, Inc.); C-Terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases. EP 1091930; WO 0001666 . |
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) | 49989 | tert-butyl (3S)-3-[[(2S)-2-amino-3-methylbutanoyl]amino]-4-hydroxy-5-(2,3,5,6-tetrafluorophenoxy)pentanoate | C20H28F4N2O5 | 详情 | 详情 | |
(X) | 49990 | 2,3,5,6-Tetrachloroaniline | 3481-20-7 | C6H3Cl4N | 详情 | 详情 |
(XI) | 26971 | 2-methoxy-2-oxoacetyl chloride | 5781-53-3 | C3H3ClO3 | 详情 | 详情 |
(XII) | 49991 | methyl 2-oxo-2-(2,3,5,6-tetrachloroanilino)acetate | C9H5Cl4NO3 | 详情 | 详情 | |
(XIII) | 49992 | 2-oxo-2-(2,3,5,6-tetrachloroanilino)acetic acid | C8H3Cl4NO3 | 详情 | 详情 | |
(XIV) | 49993 | tert-butyl (3S)-4-hydroxy-3-[((2S)-3-methyl-2-[[2-oxo-2-(2,3,5,6-tetrachloroanilino)acetyl]amino]butanoyl)amino]-5-(2,3,5,6-tetrafluorophenoxy)pentanoate | C28H29Cl4F4N3O7 | 详情 | 详情 | |
(XV) | 49994 | tert-butyl (3S)-3-[((2S)-3-methyl-2-[[2-oxo-2-(2,3,5,6-tetrachloroanilino)acetyl]amino]butanoyl)amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoate | C28H27Cl4F4N3O7 | 详情 | 详情 |