-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】2-(4'-Cyanobiphenyl-4-yloxymethyl)-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)butyrohydroxamic acid

【CA登记号】253442-03-4

【分子式】C₂₅H₂₁N₅O₄

【分子量】455.47722

【开发单位】Servier (Originator)

【药理作用】Antiarthritic Drugs, Oncolytic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Angiogenesis Inhibitors, MMP-13 (Collagenase 3) Inhibitors, MMP-2 (Gelatinase A) Inhibitors, MMP-3 (Stromelysin 1) Inhibitors, MMP-9 (Gelatinase B) Inhibitors

合成路线1 合成路线2

合成路线1

Condensation of 1,4-dichloro-2-butene (I) with phenolic derivative (II) in the presence of K2CO3 yields compound (III), which is then converted into acetate (IV) after treatment with ammonium tetrabutyl acetate in acetone. Saponification of (IV) with NaOH in MeOH affords alcohol (V), which is then subjected to Claisen rearrangement by refluxing in ethyl orthoacetate to provide ester (VI). Reduction of (VI) with LiAlH4 in Et2O gives alcohol (VII), which is then condensed with benzotriazine-4-one (VIII) by means of a Mitsunobu reaction with PPh3 and DEAD in THF to furnish compound (IX). Treatment of (IX) with Zn(CN)2 and Pd(PPh3)4 in DMF yields cyano derivative (X), which is then converted into carboxylic acid (XI) either by treatment with NaIO4 and RuCl3 in CCl4:ACN:H2O or by treatment with H5IO6 and RuCl3 followed by reaction with CrO3 and H2SO4. Finally, the target product is obtained by reaction of (XI) with protected hydroxylamine (either benzylhydroxylamine or allyl hydroxylamine) by means of EDC, HOBt, Et3N (or DIEA) in CH2Cl2 and removal of the protecting group (either by hydrogenation over Pd/C or by treatment with Pd(PPh3)2Cl2, Bu3SnH, HOAc in CH2Cl2, respectively).

参考文献中间体

【1】 Tucker, G.C.; Bonnet, J.; Bertrand, M.; Le Diguarher, T.; Chollet, A.-M.; Murray, L.; Atassi, G.; Sabatini, M.; Pierré, A.; Casara, P.; General synthesis of alpha-substituted 3-bisaryloxy propionic acid derivatives as specific MMP inhibitors. Bioorg Med Chem Lett 2001, 11, 3, 295.
【2】 Guilbaud, N.; Atassi, G.; Le Diguarher, T.; Bonnet, J.; Sabatini, M.; Casara, P.; Chollet, A.-M.; Pierre, A.; Tucker, G. (ADIR et Cie.); Carboxylic and hydroxamic acid cpds. inhibiting metalloproteases, method for preparing same and pharmaceutical compsns. containing them. EP 1091937; FR 2780402; WO 0000473 .

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)	32186	(E)-1,4-dichloro-2-butene	110-57-6	C₄H₆Cl₂	详情	详情
(II)	48853	4-(4-Bromophenyl)phenol; 4-(4'-Bromophenyl)phenol; 4-Bromo-4'-hydroxybiphenyl	29558-77-8	C₁₂H₉BrO	详情	详情
(III)	48854	4-bromo-4'-[[(E)-4-chloro-2-butenyl]oxy]-1,1'-biphenyl; 4'-bromo[1,1'-biphenyl]-4-yl (E)-4-chloro-2-butenyl ether		C₁₆H₁₄BrClO	详情	详情
(IV)	48855	(E)-4-[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]-2-butenyl acetate		C₁₈H₁₇BrO₃	详情	详情
(V)	48856	(E)-4-[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]-2-buten-1-ol		C₁₆H₁₅BrO₂	详情	详情
(VI)	48857	ethyl 3-[[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]methyl]-4-pentenoate		C₂₀H₂₁BrO₃	详情	详情
(VII)	48858	3-[[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]methyl]-4-penten-1-ol		C₁₈H₁₉BrO₂	详情	详情
(VIII)	36890	1,2,3-benzotriazin-4(3H)-one		C₇H₅N₃O	详情	详情
(IX)	48859	3-(3-[[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]methyl]-4-pentenyl)-1,2,3-benzotriazin-4(3H)-one		C₂₅H₂₂BrN₃O₂	详情	详情
(X)	48860	4'-[(2-[2-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]ethyl]-3-butenyl)oxy][1,1'-biphenyl]-4-carbonitrile		C₂₆H₂₂N₄O₂	详情	详情
(XI)	48861	2-[[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]methyl]-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butyric acid		C₂₅H₂₀N₄O₄	详情	详情

合成路线2

Alternatively, intermediate (VI) can be obtained as follows: 1,4-Dichloro-2-butene (I) is condensed with p-bromophenol (XII) by means of Cs2CO3 in acetonitrile to give compound (XIII), which is then converted into acetate (XIV) after treatment with ammonium tetrabutyl acetate in refluxing acetone. Saponification of (XIV) with NaOH in MeOH affords alcohol (XV), which is then subjected to Claisen rearrangement by refluxing in ethyl orthoacetate in propionic acid to provide ester (XVI). Reduction of (XVI) with LiAlH4 Et2O gives alcohol (XVII), which is finally condensed with 4-bromophenyltributyl tin (XVIII) by means of Pd(PPh3)4 and LiCl in toluene.

参考文献中间体

【1】 Guilbaud, N.; Atassi, G.; Le Diguarher, T.; Bonnet, J.; Sabatini, M.; Casara, P.; Chollet, A.-M.; Pierre, A.; Tucker, G. (ADIR et Cie.); Carboxylic and hydroxamic acid cpds. inhibiting metalloproteases, method for preparing same and pharmaceutical compsns. containing them. EP 1091937; FR 2780402; WO 0000473 .

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)	32186	(E)-1,4-dichloro-2-butene	110-57-6	C₄H₆Cl₂	详情	详情
(VI)	48857	ethyl 3-[[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]methyl]-4-pentenoate		C₂₀H₂₁BrO₃	详情	详情
(XII)	25313	4-bromophenol	106-41-2	C₆H₅BrO	详情	详情
(XIII)	48862	1-bromo-4-[[(E)-4-chloro-2-butenyl]oxy]benzene; 4-bromophenyl (E)-4-chloro-2-butenyl ether		C₁₀H₁₀BrClO	详情	详情
(XIV)	48863	(E)-4-(4-bromophenoxy)-2-butenyl acetate		C₁₂H₁₃BrO₃	详情	详情
(XV)	48864	(E)-4-(4-bromophenoxy)-2-buten-1-ol		C₁₀H₁₁BrO₂	详情	详情
(XVI)	48865	ethyl 3-[(4-bromophenoxy)methyl]-4-pentenoate		C₁₄H₁₇BrO₃	详情	详情
(XVII)	48866	3-[(4-bromophenoxy)methyl]-4-penten-1-ol		C₁₂H₁₅BrO₂	详情	详情
(XVIII)	48867	(4-bromophenyl)(tributyl)stannane		C₁₈H₃₁BrSn	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)