G-7453, -Drug Synthesis Database

【结构式】

【药物名称】G-7453

【化学名称】3-[8-(4-Amidinobenzamido)-6-oxo-5,6-dihydro-4H-tetrazolo[1,5-a][1,4]benzodiazepin-5-yl]propionic acid

【CA登记号】167854-60-6

【分子式】C₂₀H₁₈N₈O₄

【分子量】434.41766

【开发单位】Genentech (Originator)

【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【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

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.

参考文献中间体

【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