methyl 2-hydroxy-5-iodobenzoate -Drug Synthesis Database

【结构式】

【分子编号】37875

【品名】methyl 2-hydroxy-5-iodobenzoate

【CA登记号】

【分子式】C₈H₇IO₃

【分子量】278.04625

【元素组成】C 34.56% H 2.54% I 45.64% O 17.26%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

Palladium-catalyzed coupling of methyl 5-iodosalycilate (I) with trimethylsilyl acetylene (II) produced the ethynyl salycilate (III). The trimethylsilyl protecting group of (III) was then cleaved by treatment with KF in DMF to give (IV). On the other hand, sulfonamide (VII) was obtained by condensation of 4-iodobenzenesulfonyl chloride (V) with 2-amino-3-methylpyridine (VI). A further Suzuki coupling between acetylene (IV) and iodosulfonamide (VII) furnished diaryl acetylene (VIII). The methyl ester group of (VIII) was finally saponified with NaOH to provide the target carboxylic acid.

参考文献中间体

合成目标

【1】 Agback, H.; Ahrgren, L.; Berglindh, T.; Haraldsson, M.; Smedegard, G.; Olsson, L.-I. (Pharmacia & Upjohn AB); Substd. salicylic acids. JP 1995501330; US 5403930; WO 9310094 .

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)	37875	methyl 2-hydroxy-5-iodobenzoate		C₈H₇IO₃	详情	详情
(II)	23897	ethynyl(trimethyl)silane；trimethylsilyl acetylene	1066-54-2	C₅H₁₀Si	详情	详情
(III)	37876	methyl 2-hydroxy-5-[2-(trimethylsilyl)ethynyl]benzoate		C₁₃H₁₆O₃Si	详情	详情
(IV)	37877	methyl 5-ethynyl-2-hydroxybenzoate		C₁₀H₈O₃	详情	详情
(V)	27811	4-iodobenzenesulfonyl chloride	98-61-3	C₆H₄ClIO₂S	详情	详情
(VI)	13016	3-Methyl-2-pyridinylamine; 3-Methyl-2-pyridinamine; 2-Amino-3-picoline; 2-Amino-3-methylpyridine	1603-40-3	C₆H₈N₂	详情	详情
(VII)	37878	4-iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide		C₁₂H₁₁IN₂O₂S	详情	详情
(VIII)	37879	methyl 2-hydroxy-5-[2-(4-[[(3-methyl-2-pyridinyl)amino]sulfonyl]phenyl)ethynyl]benzoate		C₂₂H₁₈N₂O₅S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

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

合成目标

【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3

该中间体在本合成路线中的序号：(II)

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

合成目标

【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