• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】22347

【品名】5-Nitroisatoic anhydride; 6-nitro-2H-3,1-benzoxazine-2,4(1H)-dione

【CA登记号】4693-02-1

【 分 子 式 】C8H4N2O5

【 分 子 量 】208.13024

【元素组成】C 46.17% H 1.94% N 13.46% O 38.44%

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:(I)

1) Hydrogenation of 5-nitroisatoic anhydride (I) over Pd/C provided amine (II), which was acylated to amide (IV) with 4-cyanobenzoyl chloride (III). Subsequent reaction of (IV) with beta-alanine ethyl ester (V) yielded diamide (VI). The amino group of (VI) was then protected by alkylation with benzhydryl bromide (VII) yielding (VIII). Further condensation of (VIII) with bromoacetyl bromide (IX), followed by cyclization of the intermediate bromoacetamide in the presence of Cs2CO3 afforded benzodiazepinedione (X). The benzhydryl protecting group of (X) was cleaved by treatment with HF in the presence of ethyl methyl sulfide and anisole to yield (XI). The tetrazole ring of (XII) was then constructed by treatment of (XI) with trimethylsilylazide under Mitsunobu conditions. Subsequent conversion of the cyano group of (XII) into amidine was effected by the sequence of H2S addition, followed by S-methylation with CH3I to give (XIII), and then substitution of the methylthio group of (XIII) for an amino group. Finally, basic hydrolysis with LiOH provided the target carboxylic acid.

1 Robarge, K.D.; Dina, M.S.; Somers, T.C.; Lee, A.; Rawson, T.E.; Olivero, A.G.; Tischler, M.H.; Webb, R.R. II; Weese, K.J.; Aliagas, I.; Blackburn, B.K.; Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists. Bioorg Med Chem 1998, 6, 12, 2345.
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) 22347 5-Nitroisatoic anhydride; 6-nitro-2H-3,1-benzoxazine-2,4(1H)-dione 4693-02-1 C8H4N2O5 详情 详情
(II) 22348 6-amino-2H-3,1-benzoxazine-2,4(1H)-dione C8H6N2O3 详情 详情
(IV) 22350 4-cyano-N-(2,4-dioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)benzamide C16H9N3O4 详情 详情
(VI) 22351 ethyl 3-([2-amino-5-[(4-cyanobenzoyl)amino]benzoyl]amino)propanoate C20H20N4O4 详情 详情
(VII) 17639 beta-Alanine, ethyl ester; ethyl 3-aminopropanoate 924-73-2 C5H11NO2 详情 详情
(VIII) 22353 ethyl 3-([2-(benzhydrylamino)-5-[(4-cyanobenzoyl)amino]benzoyl]amino)propanoate C33H30N4O4 详情 详情
(X) 22355 ethyl 3-[1-benzhydryl-7-[(4-cyanobenzoyl)amino]-2,5-dioxo-1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl]propanoate C35H30N4O5 详情 详情
(XI) 22356 ethyl 3-[7-[(4-cyanobenzoyl)amino]-2,5-dioxo-1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl]propanoate C22H20N4O5 详情 详情
(XII) 22357 ethyl 3-[8-[(4-cyanobenzoyl)amino]-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate C22H19N7O4 详情 详情
(XIII) 22358 ethyl 3-[8-([4-[imino(methylsulfanyl)methyl]benzoyl]amino)-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate C23H23N7O4S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(I)

2) An improved procedure consisted of condensation of 5-nitroisatoic anhydride (I) with beta-alanine ethyl ester (V) to give amide (XIV). The amino group of (XIV) was protected with benzhydryl bromide (VII) yielding (XV), and then the nitro group of (XV) was reduced to aniline (XVI) by catalytic transfer hydrogenation. Protection of the amine of (XVI) as the tert-butyl carbamate (XVIII) was effected using 2-(tert-butoxycarbonyloxymino)-2-phenylacetonitrile (XVII). The sequence of condensation of (XVIII) with bromoacetyl bromide (IX), followed by cyclization of the intermediate bromoacetamide with DBU provided the benzodiazepinedione (XIX). Hydrogenolysis of the N-benzhydryl group of (XIX) in the presence of Pearlman's catalyst, followed by treatment with trimethylsilyl azide furnished the tetrazole (XX). The Boc group of (XX) was deprotected with trifluoroacetic acid, and subsequent coupling with 4-cyanobenzoyl chloride (III) gave amide (XXI). The cyano group was of (XXI) then converted to hydroxyamidine (XXII) with hydroxylamine. Catalytic hydrogenation of (XXII) in the presence of Ac2O and AcOH produced the corresponding amidine. Finally, the ester group was hydrolyzed with LiOH.

1 Robarge, K.D.; Dina, M.S.; Somers, T.C.; Lee, A.; Rawson, T.E.; Olivero, A.G.; Tischler, M.H.; Webb, R.R. II; Weese, K.J.; Aliagas, I.; Blackburn, B.K.; Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists. Bioorg Med Chem 1998, 6, 12, 2345.
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) 22347 5-Nitroisatoic anhydride; 6-nitro-2H-3,1-benzoxazine-2,4(1H)-dione 4693-02-1 C8H4N2O5 详情 详情
(III) 19280 4-cyanobenzoyl chloride 6068-72-0 C8H4ClNO 详情 详情
(VII) 17639 beta-Alanine, ethyl ester; ethyl 3-aminopropanoate 924-73-2 C5H11NO2 详情 详情
(IX) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(XIV) 22360 ethyl 3-[(2-amino-5-nitrobenzoyl)amino]propanoate C12H15N3O5 详情 详情
(XV) 22361 ethyl 3-[[2-(benzhydrylamino)-5-nitrobenzoyl]amino]propanoate C25H25N3O5 详情 详情
(XVI) 22362 ethyl 3-[[5-amino-2-(benzhydrylamino)benzoyl]amino]propanoate C25H27N3O3 详情 详情
(XVII) 22363 2-[[(tert-butoxycarbonyl)oxy]imino]-2-phenylacetonitrile 58632-95-4 C13H14N2O3 详情 详情
(XVIII) 22364 ethyl 3-([2-(benzhydrylamino)-5-[(tert-butoxycarbonyl)amino]benzoyl]amino)propanoate C30H35N3O5 详情 详情
(XIX) 22365 ethyl 3-[1-benzhydryl-7-[(tert-butoxycarbonyl)amino]-2,5-dioxo-1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl]propanoate C32H35N3O6 详情 详情
(XX) 22366 ethyl 3-[8-[(tert-butoxycarbonyl)amino]-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate C19H24N6O5 详情 详情
(XXI) 22357 ethyl 3-[8-[(4-cyanobenzoyl)amino]-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate C22H19N7O4 详情 详情
(XXII) 22368 ethyl 3-[8-([4-[amino(hydroxyimino)methyl]benzoyl]amino)-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate C22H22N8O5 详情 详情
Extended Information