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【结 构 式】 
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【分子编号】45960 【品名】4-bromobenzoyl chloride 【CA登记号】586-75-4 |
【 分 子 式 】C7H4BrClO 【 分 子 量 】219.46486 【元素组成】C 38.31% H 1.84% Br 36.41% Cl 16.15% O 7.29% |
合成路线1
该中间体在本合成路线中的序号：(I)Coupling of 4-bromobenzoyl chloride (I) with amine (II) by means of Et3N in CH2Cl2 or THF yields bromo derivative (III), which is then converted into boronic acid derivative (IV) by treatment with triisopropyloxyboron and n-BuLi in THF/hexane. Suzuki reaction between (IV) and oxadiazole (V) by means of Pd(PPd3)4 and Na2CO3 in dimethoxyethane (DME)/H2O affords compound (VI), which is finally hydrogenated over Raney-Ni in H2O/MeOH/AcOH to furnish the desired product.
| 【1】 März, J.; Cremers, T.; Harting, J.; Liao, Y.; Wikstrom, H.; Rautenberg, W.; Greiner, H.; Sundell, S.; Böttcher, H.; van Amsterdam, C.; New selective and potent 5-HT1B/1D antagonists: Chemistry and pharmacological evaluation of N-piperazinylphenyl biphenylcarboxamides and biphenylsulfonamides. J Med Chem 2000, 43, 3, 517. |
| 【2】 Van Amsterdam, C.; Harting, J.; Wikstrom, H.V.; Liao, Y.; Bottcher, H. (Merck Patent GmbH); Biphenyl derivs.. WO 0005225 . |
| 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) | 45960 | 4-bromobenzoyl chloride | 586-75-4 | C7H4BrClO | 详情 | 详情 |
| (II) | 25915 | 4-methoxy-3-(4-methyl-1-piperazinyl)phenylamine; 4-methoxy-3-(4-methyl-1-piperazinyl)aniline | C12H19N3O | 详情 | 详情 | |
| (III) | 45961 | 4-bromo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]benzamide | C19H22BrN3O2 | 详情 | 详情 | |
| (IV) | 45964 | 4-[[4-methoxy-3-(4-methyl-1-piperazinyl)anilino]carbonyl]phenylboronic acid | C19H24BN3O4 | 详情 | 详情 | |
| (V) | 45962 | 3-(4-bromo-3-methylphenyl)-5-methyl-1,2,4-oxadiazole | C10H9BrN2O | 详情 | 详情 | |
| (VI) | 45963 | C28H32BrN5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)4-Chloroanthranilic acid (I) is acylated by butyryl chloride (II) in DMF to produce amide (III). This is then cyclized to the benzoxazinone (IV) upon heating with acetic anhydride. Condensation of (IV) with benzylamine (V) in refluxing chloroform, followed by treatment with NaOH in hot ethyleneglycol, gives rise to the quinazolinone (VI). Subsequent benzylic bromination of (VI) at the propyl side chain produces (VII). The bromide group of (VII) is then displaced with N,N-dimethyl-1,3-propanediamine (VIII) to furnish (IX). Finally, amine (IX) is acylated by 4-bromobenzoyl chloride (X) to afford the corresponding benzamide.
| 【1】 Chabala, J.C.; Morgans, D.J. Jr.; Feng, B.; Finer, J.T.; Bergnes, G.; Smith, W.W. (Cytokinetics, Inc.); Methods and compsns. utilizing quinazolinones. WO 0198278 . |
| 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) | 52504 | 4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid | 89-77-0 | C7H6ClNO2 | 详情 | 详情 |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 58445 | 2-(butyrylamino)-4-chlorobenzoic acid | C11H12ClNO3 | 详情 | 详情 | |
| (IV) | 58446 | 7-chloro-2-propyl-4H-3,1-benzoxazin-4-one | C11H10ClNO2 | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 58447 | 3-benzyl-7-chloro-2-propyl-4(3H)-quinazolinone | C18H17ClN2O | 详情 | 详情 | |
| (VII) | 58448 | 3-benzyl-2-(1-bromopropyl)-7-chloro-4(3H)-quinazolinone | C18H16BrClN2O | 详情 | 详情 | |
| (VIII) | 25248 | N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine | 109-55-7 | C5H14N2 | 详情 | 详情 |
| (IX) | 58449 | 3-benzyl-7-chloro-2-(1-{[3-(dimethylamino)propyl]amino}propyl)-4(3H)-quinazolinone | C23H29ClN4O | 详情 | 详情 | |
| (X) | 45960 | 4-bromobenzoyl chloride | 586-75-4 | C7H4BrClO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The reaction of ethyl 7-bromoheptanoate (I) with NaI, Zn, dibromoethane, LiCl and CuCN gives the organometallic derivative (II), which is condensed with 4-bromobenzoyl chloride (III) in THF to yield 8-(4-bromophenyl)-8-oxooctanoic acid ethyl ester (IV). The condensation of (IV) with 4-bromophenylboronic acid (V) by means of Pd(PPh3)4 and K2CO3 in hot toluene affords 8-(4'-bromobiphenyl-4-yl)-8-oxooctanoic acid ethyl ester (VI), which is hydrolyzed with NaOH in THF/methanol to provide the corresponding carboxylic acid (VII). Finally, this compound is treated with hydroxylamine, EDC, HOBt and TEA to obtain the target hydroxamic acid.
| 【1】 Woo, S.H.; et al.; Structurally simple trichostatin A-like straight chain hydroxamates as potent histone deacetylase inhibitors. J Med Chem 2002, 45, 13, 2877. |
| 【2】 Delorme, D.; Woo, S.H.; Vaisburg, A. (MethylGene Inc.); Inhibitors of histone deacetylase. WO 0170675 . |
| 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) | 36428 | ethyl 7-bromoheptanoate | 29823-18-5 | C9H17BrO2 | 详情 | 详情 |
| (II) | 55802 | C10H17CuINO2Zn | 详情 | 详情 | ||
| (III) | 45960 | 4-bromobenzoyl chloride | 586-75-4 | C7H4BrClO | 详情 | 详情 |
| (IV) | 55803 | ethyl 8-(4-bromophenyl)-8-oxooctanoate | C16H21BrO3 | 详情 | 详情 | |
| (V) | 55804 | 4-Bromobenzeneboronic acid; 4-Bromophenylboronic acid | 5467-74-3 | C6H6BBrO2 | 详情 | 详情 |
| (VI) | 55805 | ethyl 8-(4'-bromo[1,1'-biphenyl]-4-yl)-8-oxooctanoate | C22H25BrO3 | 详情 | 详情 | |
| (VII) | 55806 | 8-(4'-bromo[1,1'-biphenyl]-4-yl)-8-oxooctanoic acid | C20H21BrO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)Substitution of 1-chloro-2-methoxy-4-nitrobenzene (I) with 2-(diethylamino)ethanol (II) gives rise to ether (III). Subsequent nitro group reduction in (III) by catalytic hydrogenation affords aniline (IV). Condensation of amine (IV) with triethyl orthoformate, followed by reduction of the resultant formimidate (V) with NaBH4 leads to the N-methyl amine (VI). This is acylated by 4-bromobenzoyl chloride (VII) to furnish the bromobenzamide (VIII). Finally, Suzuki coupling of bromide (VIII) with 4-trifluoromethylphenylboronic acid (IX) produces the title biphenyl compound
| 【1】 Stemp, G.; Johnson, C.N.; Jones, M.; O'Toole, C.A.; Thewlis, K.M.; Witty, D. (GlaxoSmithKline plc); Carboxamide cpds. and their use as antagonists of a human 11CBy receptor. EP 1305304; WO 0210146 . |
| 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) | 60896 | 1-chloro-2-methoxy-4-nitrobenzene; 2-chloro-5-nitrophenyl methyl ether | C7H6ClNO3 | 详情 | 详情 | |
| (II) | 16183 | Diethylaminoethanol; 2-(diethylamino)-1-ethanol | 100-37-8 | C6H15NO | 详情 | 详情 |
| (III) | 60897 | N,N-diethyl-2-(2-methoxy-4-nitrophenoxy)-1-ethanamine; N,N-diethyl-N-[2-(2-methoxy-4-nitrophenoxy)ethyl]amine | C13H20N2O4 | 详情 | 详情 | |
| (IV) | 60898 | N-[2-(4-amino-2-methoxyphenoxy)ethyl]-N,N-diethylamine; 4-[2-(diethylamino)ethoxy]-3-methoxyaniline | C13H22N2O2 | 详情 | 详情 | |
| (V) | 60899 | ethyl 4-[2-(diethylamino)ethoxy]-3-methoxyphenyliminoformate | C16H26N2O3 | 详情 | 详情 | |
| (VI) | 60900 | N-{4-[2-(diethylamino)ethoxy]-3-methoxyphenyl}-N-methylamine; 4-[2-(diethylamino)ethoxy]-3-methoxy-N-methylaniline | C14H24N2O2 | 详情 | 详情 | |
| (VII) | 45960 | 4-bromobenzoyl chloride | 586-75-4 | C7H4BrClO | 详情 | 详情 |
| (VIII) | 60901 | 4-bromo-N-{4-[2-(diethylamino)ethoxy]-3-methoxyphenyl}-N-methylbenzamide | C21H27BrN2O3 | 详情 | 详情 | |
| (IX) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 |