3-(2-bromoethynyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole; 4-[3-(2-bromoethynyl)-5-(4-chlorophenyl)-1H-pyrazol-1-yl]phenyl methyl ether -Drug Synthesis Database

【结构式】

【分子编号】34720

【品名】3-(2-bromoethynyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole; 4-[3-(2-bromoethynyl)-5-(4-chlorophenyl)-1H-pyrazol-1-yl]phenyl methyl ether

【CA登记号】

【分子式】C₁₈H₁₂BrClN₂O

【分子量】387.66286

【元素组成】C 55.77% H 3.12% Br 20.61% Cl 9.15% N 7.23% O 4.13%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

Condensation of 4-methylacetophenone (I) with ethyl diethoxyacetate (II) in the presence of lithium hexamethyldisilazide afforded diketoacetal (III). Formation of pyrazole (V) was accomplished by treatment of (III) with 4-methoxy-phenylhydrazine (IV). Subsequent acid hydrolysis of the diethyl acetal gave aldehyde (VI), which was condensed with carbon tetrabromide using triphenyl phosphine to furnish dibromoethylene compound (VII). Elimination of HBr in (VII) by treatment with tetrabutylammonium fluoride produced bromo-acetylene (VIII). After lithium-bromine exchange, addition of paraformaldehyde yielded the propargyl alcohol (IX). Further Mitsunobu coupling of (IX) with N,O-bis(phenoxycarbonyl)hydroxylamine (X) gave the N,O-bis-protected N-alkyl hydroxylamine (XI). This was finally converted to the title N-hydroxyurea by treatment with methanolic ammonia.

参考文献中间体

合成目标

【1】 Wetter, S.K.; Connolly, P.J.; Beers, K.N.; et al.; N-Hydroxyurea and hydroxamic acid inhibitors of cyclooxygenase and 5-lipoxygenase. Bioorg Med Chem Lett 1999, 9, 7, 979.
【2】 Chen, R.; Wachter, M.; Connolly, P. (Ortho-McNeil Pharmaceutical, Inc.); Acetylenic 1,5-diarylpyrazoles as antiinflammatory agents. US 5925769 .

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)	12685	4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone	99-91-2	C₈H₇ClO	详情	详情
(II)	25674	ethyl 2,2-diethoxyacetate	6065-82-3	C₈H₁₆O₄	详情	详情
(III)	34716	1-(4-chlorophenyl)-4,4-diethoxy-1,3-butanedione		C₁₄H₁₇ClO₄	详情	详情
(IV)	12688	4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine	3471-32-7	C₇H₁₀N₂O	详情	详情
(V)	34717	4-[5-(4-chlorophenyl)-3-(diethoxymethyl)-1H-pyrazol-1-yl]phenyl methyl ether; 5-(4-chlorophenyl)-3-(diethoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazole		C₂₁H₂₃ClN₂O₃	详情	详情
(VI)	34718	5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carbaldehyde		C₁₇H₁₃ClN₂O₂	详情	详情
(VII)	34719	4-[5-(4-chlorophenyl)-3-(2,2-dibromovinyl)-1H-pyrazol-1-yl]phenyl methyl ether; 5-(4-chlorophenyl)-3-(2,2-dibromovinyl)-1-(4-methoxyphenyl)-1H-pyrazole		C₁₈H₁₃Br₂ClN₂O	详情	详情
(VIII)	34720	3-(2-bromoethynyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole; 4-[3-(2-bromoethynyl)-5-(4-chlorophenyl)-1H-pyrazol-1-yl]phenyl methyl ether		C₁₈H₁₂BrClN₂O	详情	详情
(IX)	34725	3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-propyn-1-ol		C₁₉H₁₅ClN₂O₂	详情	详情
(X)	19646	1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene		C₁₄H₁₁NO₅	详情	详情
(XI)	34726	5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(3-[(phenoxycarbonyl)[(phenoxycarbonyl)oxy]amino]-1-propynyl)-1H-pyrazole		C₃₃H₂₄ClN₃O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Condensation of 4-chloroacetophenone (I) with ethyl diethoxyacetate (II) in the presence of lithium hexamethyldisilazide afforded diketoacetal (III). Formation of pyrazole (V) was accomplished by treatment of (III) with 4-methoxy-phenylhydrazine (IV). Subsequent acid hydrolysis of the diethyl acetal gave aldehyde (VI), which was condensed with carbon tetrabromide using triphenyl phosphine to furnish dibromoethylene compound (VII). Elimination of HBr in (VII) by treatment with tetrabutylammonium fluoride produced bromoacetylene (VIII). After lithium-bromine exchange, addition of acetaldehyde yielded the propargyl alcohol (IX). Further Mitsunobu coupling of (IX) with N,O-bis(tert-butoxycarbonyl)hydroxylamine (X) gave the N,O-bis-protected N-alkyl hydroxylamine (XI). After Boc deprotection of (XI) by means of trifluoroacetic acid, coupling with acetyl chloride provided the O-acetyl hydroxamic acid (XII). Finally, cleavage of the O-acyl group of (XII) with methanolic NaOH furnished the title compound.

参考文献中间体

合成目标

【1】 Wetter, S.K.; Connolly, P.J.; Beers, K.N.; et al.; N-Hydroxyurea and hydroxamic acid inhibitors of cyclooxygenase and 5-lipoxygenase. Bioorg Med Chem Lett 1999, 9, 7, 979.
【2】 Chen, R.; Wachter, M.; Connolly, P. (Ortho-McNeil Pharmaceutical, Inc.); Acetylenic 1,5-diarylpyrazoles as antiinflammatory agents. US 5925769 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11974	Acetaldehyde	75-07-0	C₂H₄O	详情	详情
	19273	acetyl chloride	75-36-5	C₂H₃ClO	详情	详情
(I)	12685	4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone	99-91-2	C₈H₇ClO	详情	详情
(II)	25674	ethyl 2,2-diethoxyacetate	6065-82-3	C₈H₁₆O₄	详情	详情
(III)	34716	1-(4-chlorophenyl)-4,4-diethoxy-1,3-butanedione		C₁₄H₁₇ClO₄	详情	详情
(IV)	12688	4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine	3471-32-7	C₇H₁₀N₂O	详情	详情
(V)	34717	4-[5-(4-chlorophenyl)-3-(diethoxymethyl)-1H-pyrazol-1-yl]phenyl methyl ether; 5-(4-chlorophenyl)-3-(diethoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazole		C₂₁H₂₃ClN₂O₃	详情	详情
(VI)	34718	5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carbaldehyde		C₁₇H₁₃ClN₂O₂	详情	详情
(VII)	34719	4-[5-(4-chlorophenyl)-3-(2,2-dibromovinyl)-1H-pyrazol-1-yl]phenyl methyl ether; 5-(4-chlorophenyl)-3-(2,2-dibromovinyl)-1-(4-methoxyphenyl)-1H-pyrazole		C₁₈H₁₃Br₂ClN₂O	详情	详情
(VIII)	34720	3-(2-bromoethynyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole; 4-[3-(2-bromoethynyl)-5-(4-chlorophenyl)-1H-pyrazol-1-yl]phenyl methyl ether		C₁₈H₁₂BrClN₂O	详情	详情
(IX)	34721	4-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-3-butyn-2-ol		C₂₀H₁₇ClN₂O₂	详情	详情
(X)	34722	2-[([[(tert-butoxycarbonyl)amino]oxy]carbonyl)oxy]-2-methylpropane		C₁₀H₁₉NO₅	详情	详情
(XI)	34723	3-(3-[(tert-butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino]-1-butynyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole		C₃₀H₃₄ClN₃O₆	详情	详情
(XII)	34724	1-((acetoxy)[3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-1-methyl-2-propynyl]amino)-1-ethanone		C₂₄H₂₂ClN₃O₄	详情	详情

Extended Information