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【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%

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:(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
Extended Information