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【结 构 式】 
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【分子编号】12688 【品名】4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine 【CA登记号】3471-32-7 |
【 分 子 式 】C7H10N2O 【 分 子 量 】138.16928 【元素组成】C 60.85% H 7.29% N 20.27% O 11.58% |
合成路线1
该中间体在本合成路线中的序号：(V)3) The reaction of p-methoxyphenylhydrazine (V) with benzyl levulinate (IV) in acetic acid gives the corresponding hydrazone (VI), which, without isolation, is cyclized to benzyl 5-methoxy-2-methylindole-3-acetoxyacetate (VII) at 80 C in acetic acid. Then this compound is benzoylated with p-chlorobenzoyl chloride (B) by means of NaH in DMF. 4) The hydrazone (VI) can also be benzoylated first giving the corresponding hydrazone (VIII), which is then cyclized at 80 C in acetic acid.
| 【1】 Boltze, K.; Brendler, O.; Dell, H.-D.; Jacobi, H.; Novel substituted indole compound, process for the preparation and therapeutic compositions containing it.. DE 2234651; ES 416877; FR 2192828; JP 49043970; US 3910952 . |
| 【2】 Leeson, P.A.; Castaner, J.; Acemetacin. Drugs Fut 1977, 2, 7, 423. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (I) | 33962 | 2-(benzyloxy)-2-oxoethyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate | C28H24ClNO6 | 详情 | 详情 | |
| (IV) | 33963 | 2-(benzyloxy)-2-oxoethyl 4-oxopentanoate | C14H16O5 | 详情 | 详情 | |
| (V) | 12688 | 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine | 3471-32-7 | C7H10N2O | 详情 | 详情 |
| (VI) | 33964 | 2-(benzyloxy)-2-oxoethyl 4-[(Z)-2-(4-methoxyphenyl)hydrazono]pentanoate | C21H24N2O5 | 详情 | 详情 | |
| (VII) | 33966 | 2-(benzyloxy)-2-oxoethyl 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetate | C21H21NO5 | 详情 | 详情 | |
| (VIII) | 33965 | 2-(benzyloxy)-2-oxoethyl 4-[(Z)-2-(4-chlorobenzoyl)-2-(4-methoxyphenyl)hydrazono]pentanoate | C28H27ClN2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)A new synthesis of tepoxalin has been described: The condensation of 4-chloroacetophenone (I) with succinic anhydride (II) by means of lithium bis(trimethylsilyl)amide in THF at -20 C gives 6-(4-chlorophenyl)-4,6-dioxohexanoic acid (III), which is cyclized with 4-methoxyphenylhydrazine (IV) by means of triethylamine in methanol at room temperature to afford 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)pyrazol-3-yl]propanoic acid (V); finally this compound is condensed with methylhydroxylamine (VI) by means of oxalyl chloride and triethylamine at room temperature.
| 【1】 Forerokelly, Y.; Murray, W.; Wachter, M.; Barton, D.; The regioselective synthesis of tepoxalin, 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl]-N-hydroxy-N-methylpropanamide and related 1,5-diarylpyrazole antiinflammatory agents. Synthesis 1991, 1, 1, 18. |
| 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) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (III) | 12687 | 6-(4-Chlorophenyl)-4,6-dioxohexanoic acid | C12H11ClO4 | 详情 | 详情 | |
| (IV) | 12688 | 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine | 3471-32-7 | C7H10N2O | 详情 | 详情 |
| (V) | 12689 | 3-[5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]propionic acid | C19H17ClN2O3 | 详情 | 详情 | |
| (VI) | 12690 | (Hydroxyamino)methane; N-Methylhydroxylamine | 593-77-1 | CH5NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)A new method for the synthesis of tepoxalin has been reported: The cyclization of 6-(4-chlorophenyl)-4,6-dioxohexanoic acid (I) with refluxing acetic anhydride gives 5-[2-(4-chlorophenyl)-2-oxoethylidene]tetrahydrofuran-2-one (II), which is treated with methylhydroxylamine to afford the corresponding N-hydroxy-N-methylamide (III). Finally, this compound is cyclized with 4-methoxyphenylhydroazine (IV) by means of Na2CO3 in refluxing ethanol.
| 【1】 Murray, W.V.; Hadden, S.K.; A facile synthesis of tepoxalin, 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-propanamide. J Org Chem 1992, 57, 24, 6662. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12690 | (Hydroxyamino)methane; N-Methylhydroxylamine | 593-77-1 | CH5NO | 详情 | 详情 | |
| (I) | 12687 | 6-(4-Chlorophenyl)-4,6-dioxohexanoic acid | C12H11ClO4 | 详情 | 详情 | |
| (II) | 12692 | 5-[(Z)-2-(4-Chlorophenyl)-2-oxoethylidene]dihydro-2-furanone | C12H9ClO3 | 详情 | 详情 | |
| (III) | 12693 | 6-(4-Chlorophenyl)-N-hydroxy-N-methyl-4,6-dioxohexanamide | C13H14ClNO4 | 详情 | 详情 | |
| (IV) | 12688 | 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine | 3471-32-7 | C7H10N2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Title compound has been prepared by several routes: Condensation of 4'-methoxyacetophenone (I) with diethyl oxalate in the presence of lithium hexamethyldisilazide provided lithium ethyl 4-methoxybenzoylpyruvate (II). Subsequent condensation of (II) with 4-methoxyphenylhydrazine hydrochloride (III) yielded diarylpyrazole (IV). This was coupled with bromide (V) in the presence of n-BuLi to afford ketone (VI). The oxazoline ring of (VI) was then hydrolyzed to carboxylic acid (VII) by successive treatments with HCl and with NaOH. Activation of the carboxylic acid of (VII) as the mixed anhydride with ethyl chloroformate, followed by treatment with gaseous ammonia provided amide (VIII). The required dimethyl ketal was finally introduced in (VIII) by means of trimethyl orthoformate in MeOH in the presence of p-TsOH.
| 【1】 Lamari, L.; Zitouni, A.; Boudjella, H.; et al.; J Heterocycl Chem 1989, 26, 8, 1389-1392. |
| 【2】 Numata, H.; Okamoto, Y.; Shinoda, M.; Kobayashi, N.; Miyazawa, S.; Kawahara, T.; Shirota, H.; Nagakura, N.; Horizoe, T.; Abe, S.; Kobayashi, S.; Yamanaka, T. (Eisai Co., Ltd.); Pyrazole derivs. exhibiting anti-inflammatory and analgesic effects. JP 1998509140; WO 9614302 . |
| 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) | 11041 | 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone | 100-06-1 | C9H10O2 | 详情 | 详情 |
| (II) | 25533 | 2-Hydroxy-4-(4-methoxyphenyl)-3-oxo-2(E)-butenoic acid ethyl ester lithium salt | C13H13LiO5 | 详情 | 详情 | |
| (III) | 12688 | 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine | 3471-32-7 | C7H10N2O | 详情 | 详情 |
| (IV) | 25534 | ethyl 1,5-bis(4-methoxyphenyl)-1H-pyrazole-3-carboxylate | C20H20N2O4 | 详情 | 详情 | |
| (V) | 25535 | 2-(5-bromo-2-chlorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole | C11H11BrClNO | 详情 | 详情 | |
| (VI) | 25536 | [1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl][4-chloro-3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]methanone | C29H26ClN3O4 | 详情 | 详情 | |
| (VII) | 25537 | 5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl]-2-chlorobenzoic acid | C25H19ClN2O5 | 详情 | 详情 | |
| (VIII) | 25538 | 5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl]-2-chlorobenzamide | C25H20ClN3O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)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.
| 【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6
该中间体在本合成路线中的序号：(IV)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.
| 【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 |
合成路线7
该中间体在本合成路线中的序号：(VII)Ethyl 2,4-dioxopentanoate (V) was converted into the O-methyloxime (VI) and subsequently cyclized with 4-methoxyphenylhydrazine (VII) to furnish pyrazole (VIII) (1,2). Optionally, ester (VIII) was hydrolyzed and then converted to acid chloride (IX) by treatment with oxalyl chloride (1). Biphenylamine (IV) was coupled with ester (VIII) in the presence of trimethylaluminium (2) or, alternatively, with acid chloride (IX) (1) to give amide (X). The N-tert-butyl group of (X) was finally removed by refluxing in trifluoroacetic acid.
| 【1】 Galemmo, R.A. Jr.; Fevig, J.; Lam, P.Y.; et al.; New functional groups for interaction with the S1 pocket of factor Xa: The discovery of 1-(4-methoxyphenyl)pyrazole inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 290. |
| 【2】 Dominguez, C.; Fevig, J.M.; Galemmo, R.A. Jr.; Pinto, D.J.P.; Pruitt, J.R.; lma, P.; Quan, M.L.; Han, Q. (DuPont Pharmaceuticals Co.); Inhibitors of factor Xa with a neutral P1 specificity group. US 5998424; WO 9857937 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 | |
| (V) | 42500 | ethyl 2,4-dioxopentanoate | 615-79-2 | C7H10O4 | 详情 | 详情 |
| (VI) | 44129 | ethyl 2-(methoxyimino)-4-oxopentanoate | C8H13NO4 | 详情 | 详情 | |
| (VII) | 12688 | 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine | 3471-32-7 | C7H10N2O | 详情 | 详情 |
| (VIII) | 44130 | ethyl 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxylate | C14H16N2O3 | 详情 | 详情 | |
| (IX) | 44131 | 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carbonyl chloride | C12H11ClN2O2 | 详情 | 详情 | |
| (X) | 44132 | N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxamide | C28H30N4O4S | 详情 | 详情 |