UCB-35440, -Drug Synthesis Database

【结构式】

【药物名称】UCB-35440

【化学名称】5-[4-(N-Carbamoyl-N-hydroxyamino)-1-butynyl]-2-[2-[4-[1(R)-(4-chlorophenyl)-1-phenylmethyl]piperazin-1-yl]ethoxy]benzamide

【CA登记号】299460-62-1, 299461-20-4 (citrate (1:1)), 299460-91-6 (diHCl), 299461-16-8 (fumarate salt (1:1)), 299461-19-1 (L-tartrate), 2994

【分子式】C₃₁H₃₄ClN₅O₄

【分子量】576.10073

【开发单位】UCB (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, 5-Lipoxygenase Inhibitors, Histamine H1 Antagonists

合成路线1 合成路线2

合成路线1

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

参考文献中间体

【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2

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

参考文献中间体

【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

Drug NewChemical Entity Original Patent(1)