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【结 构 式】 
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【分子编号】12685 【品名】4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone 【CA登记号】99-91-2 |
【 分 子 式 】C8H7ClO 【 分 子 量 】154.59568 【元素组成】C 62.15% H 4.56% Cl 22.93% O 10.35% |
合成路线1
该中间体在本合成路线中的序号：(I)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2
该中间体在本合成路线中的序号：(I)Claisen condensation of 4'-chloroacetophenone (I) with ethyl trifluoroacetate in the presence of NaOMe provided diketone (II). Subsequent reaction of (II) with 4-sulfamoylphenylhydrazine (III) provided the title 1,5-diaryl pyrazole along with minor amounts of the 1,3-diaryl regioisomer, which was removed by recrystallization from EtOAc and isooctane.
| 【1】 Penning, T.D.; Talley, J.J.; Bertenshaw, S.R.; et al.; Synthesis and biological evaluation of the 1, 5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, celecoxib). J Med Chem 1997, 40, 9, 1347. |
| 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) | 38969 | 1-(4-chlorophenyl)-4,4,4-trifluoro-1,3-butanedione | C10H6ClF3O2 | 详情 | 详情 | |
| (III) | 17148 | 4-Hydrazinobenzenesulfonamide; 4-Sulfonamidophenylhydrazine | 4392-54-5 | C6H9N3O2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Aldol condensation of 5-bromo-2-propoxybenzaldehyde (I) with 4'-chloroacetophenone in the presence of NaOH produced chalcone (III) (1), which was condensed with pyridine-4-carbaldehyde (IV) using NaCN as the catalyst to yield diketone (V). Finally, the target pyrrole was constructed by Paal-Knorr synthesis using diketone (V) and ammonium acetate in boiling AcOH.
| 【1】 Li, B.; Kim, D.; MacCoss, M.; de Laszlo, S.E.; Koch, G.E.; hacker, C.; Mantlo, N.; Pivinichny, J.V.; Cascieri, M.A.; Hagmann, W.K.; The development of 2-pyridyl-3,5-diaryl-pyrroles a. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.232. |
| 【2】 Li, B.; Hacker, C.; De Laszlo, S.E.; et al.; Potent, orally absorbed glucagon receptor antagonists. Bioorg Med Chem Lett 1999, 9, 5, 641. |
| 【3】 de Laszlo, S.E.; Kim, D.; Chang, L.L.; Mantlo, N.B. (Merck & Co., Inc.); Substd. pyridyl pyrroles, compsns. containing such cpds. and methods of use. US 5776954 . |
| 【4】 De Laszlo, S.E.; Chang, L.L.; Kim, D.; Mantlo, N.B. (Merck & Co., Inc.); Substd. pyridyl pyrroles, compsns. containing such cpds. and methods of use. EP 0859771; JP 1999514651; WO 9716442 . |
| 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) | 23277 | 5-bromo-2-propoxybenzaldehyde | C10H11BrO2 | 详情 | 详情 | |
| (II) | 12685 | 4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone | 99-91-2 | C8H7ClO | 详情 | 详情 |
| (III) | 23279 | (E)-3-(5-bromo-2-propoxyphenyl)-1-(4-chlorophenyl)-2-propen-1-one | C18H16BrClO2 | 详情 | 详情 | |
| (IV) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (V) | 23281 | 2-(5-bromo-2-propoxyphenyl)-4-(4-chlorophenyl)-1-(4-pyridinyl)-1,4-butanedione | C24H21BrClNO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)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5
该中间体在本合成路线中的序号：(I)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6
该中间体在本合成路线中的序号：(I)(4-Chlorophenyl)thioacetic acid morpholide (II) was prepared by Willgerodt-Kindler reaction of 4'-chloroacetophenone (I) with sulfur and morpholine. Subsequent condensation of (II) with triethyl orthoformate and morpholine provided the 3-(4-morpholinyl)thioacrylic acid morpholide (IIIa-b). Finally, ring closure of (IIIa-b) with hydrazine hydrochloride in refluxing EtOH furnished the title pyrazole.
| 【1】 Unverferth, K.; et al.; Synthesis, anticonvulsant activity, and structure-activity relationships of sodium channel blocking 3-aminopyrroles. J Med Chem 1998, 41, 1, 63. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 32943 | (E)-2-(4-chlorophenyl)-1,3-di(4-morpholinyl)-2-propene-1-thione | C17H21ClN2O2S | 详情 | 详情 | |
| (IIIb) | 32944 | (Z)-2-(4-chlorophenyl)-1,3-di(4-morpholinyl)-2-propene-1-thione | C17H21ClN2O2S | 详情 | 详情 | |
| (I) | 12685 | 4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone | 99-91-2 | C8H7ClO | 详情 | 详情 |
| (II) | 32942 | 2-(4-chlorophenyl)-1-(4-morpholinyl)-1-ethanethione | C12H14ClNOS | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Knoevenagel condensation of ketone (I) with ethyl cyanoacetate followed by Michael addition of cyanoacetamide to the resulting alpha-cyanocinnamate (IIa-b) yields cyclic imide (III). Hydrolysis and decarboxylation of (III) with H2SO4 gives diacid (IV), which is cyclized by means of hot H2SO4 to provide indanone (V). Treatment of (V) with oxalyl chloride in CH2Cl2 and catalytic DMF followed by addition of EtOH affords ethyl ester (VI), which is then converted into oxime (VII) by means of t-BuONO in Et2O and HCl. Hydrogenolysis of (VII) with H2 over Pd/C in HOAc/HCl provides alpha-amino derivative (VIII). By reacting (VIII) with ethyl oxalyl chloride (A), in CH2Cl2 in presence of Et3N, (IX) was obtained and then cyclized in presence of NH4OAc in refluxing HOAc to yield pyrazino derivative (X). Finally (X) is hydrolyzed with HCl in dioxane.
| 【1】 Jimonet, P.; Ribeill, Y.; Bohme, A.; et al.; Indeno[1,2-b]pyrazin-2,3-diones: A new class of antagonists at the glycine site of the NMDA receptor with potent in vivo activity. J Med Chem 2000, 43, 12, 2371. |
| 【2】 Jimonet, P.; Ribeill, Y.; Audiau, F.; Aloup, J.-C.; Barreau, M.; Mignani, S.; Genevois-Borella, A.; Damour, D. (Aventis Pharma SA); 5H-Indeno[1,2-b]pyrazine-2,3-dione derivs., their preparation and medicinal products containing them. US 5922716; WO 9526342 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 | |
| 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 | |
| (A) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (IIa) | 41464 | ethyl (Z)-3-(4-chlorophenyl)-2-cyano-2-butenoate | C13H12ClNO2 | 详情 | 详情 | |
| (IIb) | 41465 | ethyl (E)-3-(4-chlorophenyl)-2-cyano-2-butenoate | C13H12ClNO2 | 详情 | 详情 | |
| (I) | 12685 | 4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone | 99-91-2 | C8H7ClO | 详情 | 详情 |
| (III) | 41466 | 4-(4-chlorophenyl)-4-methyl-2,6-dioxo-3,5-piperidinedicarbonitrile | C14H10ClN3O2 | 详情 | 详情 | |
| (IV) | 41467 | 3-(4-chlorophenyl)-3-methylpentanedioic acid | C12H13ClO4 | 详情 | 详情 | |
| (V) | 41468 | 2-(5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetic acid | C12H11ClO3 | 详情 | 详情 | |
| (VI) | 41469 | ethyl 2-(5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate | C14H15ClO3 | 详情 | 详情 | |
| (VII) | 41470 | ethyl 2-[5-chloro-2-(hydroxyimino)-1-methyl-3-oxo-1,3-dihydro-2H-inden-1-yl]acetate | C14H14ClNO4 | 详情 | 详情 | |
| (VIII) | 41471 | ethyl 2-(2-amino-5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate | C14H16ClNO3 | 详情 | 详情 | |
| (IX) | 41472 | ethyl 2-[[5-chloro-1-(2-ethoxy-2-oxoethyl)-1-methyl-3-oxo-2,3-dihydro-1H-inden-2-yl]amino]-2-oxoacetate | C18H20ClNO6 | 详情 | 详情 | |
| (X) | 41473 | ethyl 2-(6-chloro-9-methyl-2,3-dioxo-2,3,4,9-tetrahydro-1H-indeno[1,2-b]pyrazin-9-yl)acetate | C16H15ClN2O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Acetophenone (I) is condensed with gamma-butyrolactone (II) in the presence of NaOMe to afford compound (III), which is finally treated with BF3·Et2O and amine (IV) in dichloromethane/ether. Alternatively, the target compound can be synthesized by regioselective bromination of (III) with PBr3 in dichloromethane to yield bromo derivative (V) followed by heating with primary amine (IV) in MeOH. (Under forceful conditions (V) can be converted into intermediate (VI), which by heating in MeOH in the presence of primary amine (IV) can also lead to the desired product).
| 【1】 Batra, S.; et al.; Syntheses and biological evaluation of 3-substituted amino-1-aryl-6-hydroxy-hex-2-ene-1-ones as antioxidant and hypolipidemic agents. Bioorg Med Chem 2000, 8, 8, 2195. |
| 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) | 20576 | dihydro-2(3H)-furanone | 96-48-0 | C4H6O2 | 详情 | 详情 |
| (III) | 45873 | (Z)-1-(4-chlorophenyl)-3,6-dihydroxy-2-hexen-1-one | C12H13ClO3 | 详情 | 详情 | |
| (IV) | 12420 | N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine | 100-36-7 | C6H16N2 | 详情 | 详情 |
| (V) | 45874 | (Z)-6-bromo-1-(4-chlorophenyl)-3-hydroxy-2-hexen-1-one | C12H12BrClO2 | 详情 | 详情 | |
| (VI) | 45875 | 1-(4-chlorophenyl)-2-dihydro-2(3H)-furanylidene-1-ethanone | C12H11ClO2 | 详情 | 详情 |