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

【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%

与该中间体有关的原料药合成路线共 5 条

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
Extended Information