【结 构 式】 |
【分子编号】30404 【品名】1-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazine 【CA登记号】 |
【 分 子 式 】C17H19ClN2 【 分 子 量 】286.80404 【元素组成】C 71.19% H 6.68% Cl 12.36% N 9.77% |
合成路线1
该中间体在本合成路线中的序号:(II)The resolution of racemic 1-[(4-chlorophenyl)phenylmethyl]piperazine (I) with L-tartaric acid provided the required (R)-enantiomer (II), which was condensed with (2-chloroethoxy)acetonitrile (III) in the presence of Na2CO3 and KI in refluxing n-butanol to give the alkylated piperazine (IV). The nitrile group of (IV) was finally hydrolyzed by means of concentrated hydrochloric acid to yield the target carboxylic acid.
【1】 Cossement, E.; Motte, G.; Gobert, J.; Bodson, G. (UCB SA); Process for preparation of a 1-piperazine-ethoxyacetic acid. GB 2225321 . |
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) | 28775 | p-Chloro benzhydryl piperazine; 1-[(4-Chlorophenyl)(phenyl)methyl]piperazine; N-(Chloro-1-benzhydryl)piperazine; 1-(4-Chlorobenzhydryl)piperazine | 303-26-4 | C17H19ClN2 | 详情 | 详情 |
(II) | 30404 | 1-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazine | C17H19ClN2 | 详情 | 详情 | |
(III) | 30405 | 2-(2-chloroethoxy)acetonitrile | C4H6ClNO | 详情 | 详情 | |
(IV) | 30406 | 2-(2-[4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl]ethoxy)acetonitrile | C21H24ClN3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(X)In a further procedure, racemic (4-chlorophenyl)phenylmethyl amine (V) was resolved by means of L-tartaric acid. The undesired (S)-enantiomer (VII) could be recovered by racemization to (V) upon treatment with 2-hydroxybenzaldehyde and NaOMe. The required (R)-enantiomer (VI) was condensed with N,N-bis(chloroethyl)-p-toluenesulfonamide (VIII) in refluxing diisopropylethylamine to provide the N-tosyl piperazine (IX). Deprotection of the p-toluenesulfonamide of (IX) was achieved by treatment with HBr in the presence of 4-hydroxybenzoic acid. The resulting piperazine (X) was alkylated with either (2-chloroethoxy)acetamide (XI) or methyl (2-chloroethoxy)acetate (XIII), affording the N-alkylated piperazines (XII) and (XIV), respectively. The title carboxylic acid was then obtained by hydrolysis of amide (XII) with aqueous HCl or, alternatively, by hydrolysis of ester (XIV) with ethanolic KOH.
【1】 Bodson, G.; Gobert, J.; Cossement, E. (UCB SA); Enantiomers of 1-[4-(chlorophenyl)phenylmethyl]-4-(methylphenyl)sulfonyl piperazine. EP 0617028 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(V) | 30407 | p-Chloro benzhydryl amine; (4-Chlorophenyl)(phenyl)methylamine; (4-Chlorophenyl)(phenyl)methanamine | C13H12ClN | 详情 | 详情 | |
(VI) | 30408 | (R)-(4-chlorophenyl)(phenyl)methylamine; (R)-(4-chlorophenyl)(phenyl)methanamine | C13H12ClN | 详情 | 详情 | |
(VII) | 30413 | (S)-(4-chlorophenyl)(phenyl)methylamine; (S)-(4-chlorophenyl)(phenyl)methanamine | C13H12ClN | 详情 | 详情 | |
(VIII) | 30409 | N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide | 42137-88-2 | C11H15Cl2NO2S | 详情 | 详情 |
(IX) | 30410 | 1-[(R)-(4-chlorophenyl)(phenyl)methyl]-4-[(4-methylphenyl)sulfonyl]piperazine | C24H25ClN2O2S | 详情 | 详情 | |
(X) | 30404 | 1-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazine | C17H19ClN2 | 详情 | 详情 | |
(XI) | 16839 | 2-(2-chloroethoxy)acetamide | C4H8ClNO2 | 详情 | 详情 | |
(XII) | 30411 | 2-(2-[4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl]ethoxy)acetamide | C21H26ClN3O2 | 详情 | 详情 | |
(XIII) | 16841 | methyl 2-(2-chloroethoxy)acetate | C5H9ClO3 | 详情 | 详情 | |
(XIV) | 30412 | methyl 2-(2-[4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl]ethoxy)acetate | C22H27ClN2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VII)4-Iodophenol (I) is alkylated with 1,2-dibromoethane (II) to afford 1-(2-bromoethoxy)-4-iodobenzene (III). Subsequent palladium-catalyzed coupling of aryl iodide (III) with 3-butyn-1-ol (IV) furnishes the phenylbutynol adduct (V), which is further hydrogenated in the presence of Pd/C to the saturated alcohol (VI). Condensation of the alkyl bromide (VI) with (R)-p-chlorobenzhydrylpiperazine (VII) produces the dialkylated piperazine (VIII). Then, Mitsunobu coupling of arylbutanol (VIII) with phenoxycarbonylaminophenoxyformate (IX) leads to the protected hydroxamic acid (X). This is finally treated with methanolic ammonia to provide the title N-hydroxyurea derivative.
【1】 Chatelain, P.; Differding, E.; Cai, X.; Hussoin, S.; Grewal, G.; Young, M.; Lewis, T.; Toy-Palmer, A.; Scannel, R.; Ellis, J.; Lassoie, M.-A. (UCB SA); Cpds. and methods for treatment of asthma, allergy and inflammatory disorders. JP 2002540198; US 6451801; WO 0058295 . |
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) | 22242 | 4-iodophenol | 540-38-5 | C6H5IO | 详情 | 详情 |
(II) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
(III) | 64422 | 1-(2-bromoethoxy)-4-iodobenzene; 2-bromoethyl 4-iodophenyl ether | C8H8BrIO | 详情 | 详情 | |
(IV) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
(V) | 64423 | 4-[4-(2-bromoethoxy)phenyl]-3-butyn-1-ol | C12H13BrO2 | 详情 | 详情 | |
(VI) | 64424 | 4-[4-(2-bromoethoxy)phenyl]-1-butanol | C12H17BrO2 | 详情 | 详情 | |
(VII) | 30404 | 1-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazine | C17H19ClN2 | 详情 | 详情 | |
(VIII) | 64425 | 4-[4-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethoxy)phenyl]-1-butanol | C29H35ClN2O2 | 详情 | 详情 | |
(IX) | 19646 | 1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene | C14H11NO5 | 详情 | 详情 | |
(X) | 64426 | 1-[(R)-(4-chlorophenyl)(phenyl)methyl]-4-{2-[4-(4-{(phenoxycarbonyl)[(phenoxycarbonyl)oxy]amino}butyl)phenoxy]ethyl}piperazine | C43H44ClN3O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(VI)Esterification of 5-iodosalicylic acid (I) with methanol and H2SO4 provides the methyl ester (II). Subsequent palladium-catalyzed coupling of (II) with 3-butyn-1-ol (III) yields adduct (IV). Alkylation of the phenolic hydroxyl group of (IV) with 1,2-dibromoethane affords the bromoethyl ether (V). The bromide group of (V) is then displaced with (R)-p-chlorobenzhydryl piperazine (VI) to produce the disubstituted piperazine (VII). Mitsunobu coupling of alcohol (VII) with phenoxycarbonylamino phenoxyformate (VIII) furnishes the protected N-hydroxy carbamate (IX). Finally, ammonolysis of the ester groups of (IX) gives rise to a mixture of the title N-hydroxyurea derivative, along with the analogous methyl ester (X), which can be separated by means of flash chromatography
【1】 Chatelain, P.; Differding, E.; Cai, X.; Hussoin, S.; Grewal, G.; Young, M.; Lewis, T.; Toy-Palmer, A.; Scannel, R.; Ellis, J.; Lassoie, M.-A. (UCB SA); Cpds. and methods for treatment of asthma, allergy and inflammatory disorders. JP 2002540198; US 6451801; WO 0058295 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(A) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
(I) | 60359 | 2-hydroxy-5-iodobenzoic acid | C7H5IO3 | 详情 | 详情 | |
(II) | 37875 | methyl 2-hydroxy-5-iodobenzoate | C8H7IO3 | 详情 | 详情 | |
(III) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
(IV) | 60360 | methyl 2-hydroxy-5-(4-hydroxy-1-butynyl)benzoate | C12H12O4 | 详情 | 详情 | |
(V) | 60361 | methyl 2-[(2-bromoethyl)oxy]-5-(4-hydroxy-1-butynyl)benzoate | C14H15BrO4 | 详情 | 详情 | |
(VI) | 30404 | 1-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazine | C17H19ClN2 | 详情 | 详情 | |
(VII) | 60362 | methyl 2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]-5-(4-hydroxy-1-butynyl)benzoate | C31H33ClN2O4 | 详情 | 详情 | |
(VIII) | 19646 | 1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene | C14H11NO5 | 详情 | 详情 | |
(IX) | 60363 | methyl 2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]-5-[4-([(phenyloxy)carbonyl]{[(phenyloxy)carbonyl]oxy}amino)-1-butynyl]benzoate | C45H42ClN3O8 | 详情 | 详情 | |
(X) | 60364 | methyl 5-{4-[(aminocarbonyl)(hydroxy)amino]-1-butynyl}-2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]benzoate | C32H35ClN4O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(VI)A related method for the synthesis of the title compound has been reported. After esterification of 5-iodosalicylic acid (I), the methyl ester (II) is reacted with 1,2-dibromoethane to give bromide (III). Coupling of aryl iodide (III) with 3-butyn-1-ol (IV) leads to adduct (V). Displacement of bromide (V) with (R)-p-chlorobenzhydryl piperazine (VI) furnishes piperazine (VII). Then, ester group ammonolysis in (VII) leads to amide (VIII). Coupling of alcohol (VIII) with phenoxycarbonylamino phenoxyformate (IX) under Mitsunobu conditions furnishes the protected N-hydroxy carbamate (X). Finally, treatment of (X) with methanolic ammonia provides the desired N-hydroxyurea derivative
【1】 Cai, X.; Arrington, M.; Bayless, L.; et al.; Discovery of UCB 35440: A potent and orally active dual acting 5-lipoxygenase inhibitor and H1 receptor antagonist. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 317. |
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) | 60359 | 2-hydroxy-5-iodobenzoic acid | C7H5IO3 | 详情 | 详情 | |
(II) | 37875 | methyl 2-hydroxy-5-iodobenzoate | C8H7IO3 | 详情 | 详情 | |
(III) | 30366 | 4-(3-Methoxyphenyl)-1,5-dimethyl-4-propyl-1-azoniabicyclo[3,1,0]hexane tetrafluoroborate | C17H26BF4NO | 详情 | 详情 | |
(IV) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
(V) | 60361 | methyl 2-[(2-bromoethyl)oxy]-5-(4-hydroxy-1-butynyl)benzoate | C14H15BrO4 | 详情 | 详情 | |
(VI) | 30404 | 1-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazine | C17H19ClN2 | 详情 | 详情 | |
(VII) | 60362 | methyl 2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]-5-(4-hydroxy-1-butynyl)benzoate | C31H33ClN2O4 | 详情 | 详情 | |
(VIII) | 60367 | 2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]-5-(4-hydroxy-1-butynyl)benzamide | C30H32ClN3O3 | 详情 | 详情 | |
(IX) | 19646 | 1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene | C14H11NO5 | 详情 | 详情 | |
(X) | 60363 | methyl 2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]-5-[4-([(phenyloxy)carbonyl]{[(phenyloxy)carbonyl]oxy}amino)-1-butynyl]benzoate | C45H42ClN3O8 | 详情 | 详情 |