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【结 构 式】 
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【分子编号】26393 【品名】4-iodoaniline; 4-iodophenylamine 【CA登记号】540-37-4 |
【 分 子 式 】C6H6IN 【 分 子 量 】219.02485 【元素组成】C 32.9% H 2.76% I 57.94% N 6.4% |
合成路线1
该中间体在本合成路线中的序号：(I)The cyclization of 4-iodoaniline (I) with 1-(phenylsulfanyl)acetone (II) by means of tert-butyl hypochlorite in dichloromethane gives the iodoindole (III), which is condensed with the phenylboronic ester (IV) using a Pd catalyst in DMSO to yield 2-[4-[2-methyl-3-(phenylsulfanyl)-1H-indol-5-yl]phenyl]propionic acid methyl ester (V). The desulfurization of (V) with thiosalicylic acid in hot TFA affords 2-[4-(2-methyl-1H-indol-5-yl)phenyl]propionic acid methyl ester (VI), which is finally hydrolyzed with LiOH in THF/methanol/water.
| 【1】 Black, C.; Leger, S.; Bayly, C.I.; Ouimet, N.; Ouellet, M.; Percival, D. (Merck Frosst Canada Inc.); Biaryl-acetic acid derivs. and their use as COX-2 inhibitors. US 5994379; WO 9941224 . |
| 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) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (II) | 26394 | 1-(phenylsulfanyl)acetone | 1435-53-6 | C9H10OS | 详情 | 详情 |
| (III) | 26395 | 5-iodo-2-methyl-1H-indol-3-yl phenyl sulfide; 5-iodo-2-methyl-3-(phenylsulfanyl)-1H-indole | C15H12INS | 详情 | 详情 | |
| (IV) | 26396 | methyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate | C16H23BO4 | 详情 | 详情 | |
| (V) | 26397 | methyl 2-[4-[2-methyl-3-(phenylsulfanyl)-1H-indol-5-yl]phenyl]propanoate | C25H23NO2S | 详情 | 详情 | |
| (VI) | 26398 | methyl 2-[4-(2-methyl-1H-indol-5-yl)phenyl]propanoate | C19H19NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)5-Iodooxiindole (I) may be prepared by published procedures: 1) Treatment of p-iodoaniline (IV) with the Sandmeyer isonitrosoacetanilide Isatin synthesis, by condensation with chloral hydrate (A) and hydroxylamine followed by cyclization with concentrated sulfuric acid and hydrolysis with water yields isatin (V). The conversion of (V) to (I) may be conducted via the Wolf-Kishner reduction by treatment with hydrazine hydrate in ethanol at 20-80 C to give hydrazide (VI). The conversion from (VI) to (I) may be performed by treatment with sodium ethoxide in a suitable solvent such as ethanol at 0-80 C. 2) Iodoindole (VII) may be converted to the bromo derivative (VIII) by tretment with pyridinium perbromide in tert-butyl alcohol. The last step of the synthesis is the treatment of (VIII) with H2 over Pd/C in anhydrous ethanol, or by treatment with a solution of NH4Cl followed by treatment with activated zinc in THF. 3) Iodoaniline (IV) can be converted to the sulfanylderivative (IX) by treatment with tert-butyl hypochlorite, followed by treatment with ethyl methylthioacetate (B) and triethylamine in dichloromethane. Finally the conversion of (IX) to the desired product may be conducted by means of W-2 Raney-Ni in EtOH or by treatment with activated zinc in THF.
| 【1】 McNutt, R.W. Jr.; Hunter, R.N. III; Jung, D.K.; Lackey, K.E.; Dickerson, S.; Harris, P.A.; Veal, J.M.; Peel, M.R. (Glaxo Group Ltd.); Benzylidene-1,3-dihydro-indol-2-one derivs. as receptor tyrosine kinase inhibitors, particularly of Raf kinases. EP 1003721; WO 9910325 . |
| 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) | 14018 | 2,2,2-Trichloro-1,1-ethanediol; Chloral hydrate | 302-17-0 | C2H3Cl3O2 | 详情 | 详情 |
| (B) | 40985 | ethyl 2-(methylsulfanyl)-2-oxoacetate | C5H8O3S | 详情 | 详情 | |
| (I) | 40979 | 5-iodo-1,3-dihydro-2H-indol-2-one | C8H6INO | 详情 | 详情 | |
| (IV) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (V) | 40981 | 5-iodo-1H-indole-2,3-dione | 20780-76-1 | C8H4INO2 | 详情 | 详情 |
| (VI) | 40982 | 5-iodo-1H-indole-2,3-dione 3-hydrazone | C8H6IN3O | 详情 | 详情 | |
| (VII) | 40983 | 5-iodo-1H-indole | C8H6IN | 详情 | 详情 | |
| (VIII) | 40984 | 3,3-dibromo-5-iodo-1,3-dihydro-2H-indol-2-one | C8H4Br2INO | 详情 | 详情 | |
| (IX) | 40986 | 5-iodo-3-(methylsulfanyl)-1,3-dihydro-2H-indol-2-one | C9H8INOS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The condensation between 4-iodoaniline (I) and diethyl ethoxymethylenemalonate (II) at 130 C, followed by cyclization in diphenyl ether at 250 C, furnished ethyl 4-hydroxy-6-iodoquinoline-3-carboxylate (III). Subsequent reaction of ester (III) with 4-chlorobenzylamine (IV) at 180 C produced the corresponding amide (V). Finally, coupling of (V) with propargyl alcohol (VI) in the presence of CuI and palladium catalyst afforded the desired (hydroxypropynyl)quinoline.
| 【1】 Schnute, M.E.; Turner, S.R.; Cudahy, M.M.; Vaillancourt, V.A.; Thaisrivongs, S.; Strohbach, J.W.; Romines, K.R.; Tucker, J.A. (Pharmacia Corp.); 4-Hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents. EP 1042295; US 6093732; WO 9932450 . |
| 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) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (II) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (III) | 44988 | ethyl 4-hydroxy-6-iodo-3-quinolinecarboxylate | C12H10INO3 | 详情 | 详情 | |
| (IV) | 23378 | (4-chlorophenyl)methanamine; 4-chlorobenzylamine | 104-86-9 | C7H8ClN | 详情 | 详情 |
| (V) | 44989 | N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide | C17H12ClIN2O2 | 详情 | 详情 | |
| (VI) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The 4-hydroxyquinoline (III) was synthesized via Gould-Jacobs reaction from 4-iodoaniline (I) and diethyl ethoxymethylenemalonate (II). Displacement of the ethyl ester group with 4-chlorobenzylamine (IV) at 180 C furnished the chlorobenzyl amide (V). Subsequent palladium-catalyzed carbonylation of iodide (V) provided the methyl carboxylate (VI), which was further reduced to alcohol (VII) using LiAlH4. Methylation of the hydroxyquinoline (VII) with iodomethane gave rise to the N-methyl quinolone (VIII). After conversion of the alcohol function of (VIII) to the corresponding mesylate (IX), displacement with morpholine (X) yielded the target morpholinomethyl quinolone.
| 【1】 Turner, S.R.; Strohbach, J.W.; Scott, A.; Schnute, M.E.; Vaillancourt, V.A.; Thaisrivongs, S. (Pharmacia Corp.); 4-Oxo-1,4-dihydro-3-quinolinecarboxamides as antiviral agents. EP 1140851; WO 0040563 . |
| 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) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (II) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (III) | 44988 | ethyl 4-hydroxy-6-iodo-3-quinolinecarboxylate | C12H10INO3 | 详情 | 详情 | |
| (IV) | 23378 | (4-chlorophenyl)methanamine; 4-chlorobenzylamine | 104-86-9 | C7H8ClN | 详情 | 详情 |
| (V) | 44989 | N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide | C17H12ClIN2O2 | 详情 | 详情 | |
| (VI) | 49889 | methyl 3-[[(4-chlorobenzyl)amino]carbonyl]-4-hydroxy-6-quinolinecarboxylate | C19H15ClN2O4 | 详情 | 详情 | |
| (VII) | 49890 | N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide | C18H15ClN2O3 | 详情 | 详情 | |
| (VIII) | 49891 | N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide | C19H17ClN2O3 | 详情 | 详情 | |
| (IX) | 49892 | (3-[[(4-chlorobenzyl)amino]carbonyl]-1-methyl-4-oxo-1,4-dihydro-6-quinolinyl)methyl methanesulfonate | C20H19ClN2O5S | 详情 | 详情 | |
| (X) | 10338 | 1-[(4S,5S)-5-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanone | C33H42O5Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Acylation of 4-iodoaniline (I) with 3,4-dimethoxybenzenesulfonyl chloride (II), followed by basic methanolysis leads to sulfonamide (III). Heck coupling of aryl iodide (III) with acrylic acid (IV) in the presence of tris(dibenzylideneacetone)dipalladium and tri(o-tolyl)phosphine gives the cinnamic acid derivative (V). This is then coupled to the tetrahydropyranyl-protected hydroxylamine (VI) by means of EDC/HOBt to furnish (VII). The tetrahydropyranyl hydroxamate (VII) is finally deprotected under acidic conditions to produce the title compound.
| 【1】 Bouchain, G.; Leit, S.; Frechette, S.; et al.; Development of potential antitumor agents. Synthesis and biological evaluation of a new set of sulfonamide derivatives as histone deacetylase inhibitors. J Med Chem 2003, 46, 5, 820. |
| 【2】 Lavoie, R.; Bouchain, G.; Frechette, S.; et al.; Design and synthesis of a novel class of histone deacetylase inhibitors. Bioorg Med Chem Lett 2001, 11, 21, 2847. |
| 【3】 Delorme, D.; Ruel, R.; Lavoie, R.; Thibault, C.; Abou-Khalil, E. (MethylGene Inc.); Inhibitors of histone deacetylase. EP 1233958; JP 2003514904; WO 0138322 . |
| 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) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (II) | 47469 | 3,4-dimethoxybenzenesulfonyl chloride | 23095-31-0 | C8H9ClO4S | 详情 | 详情 |
| (III) | 63287 | N-(4-iodophenyl)-3,4-dimethoxybenzenesulfonamide | C14H14INO4S | 详情 | 详情 | |
| (IV) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (V) | 63288 | (E)-3-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-2-propenoic acid | C17H17NO6S | 详情 | 详情 | |
| (VI) | 52106 | 2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine | C5H11NO2 | 详情 | 详情 | |
| (VII) | 63289 | (E)-3-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)-2-propenamide | C22H26N2O7S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XVB)The precursor dihydropyridones (IIa) and (IIb) can be synthesized as follows. Acylation of either 4-nitroaniline (XVa) (1) or 4-iodoaniline (XVb) (2) with 5-bromovaleryl chloride (V) affords the corresponding bromoamides (XVIa) and (XVIb), which are cyclized to piperidones (XVIIa) and (XVIIb) upon treatment with potassium tert-butoxide or with potassium hydroxide under phase-transfer conditions. Piperidones (XVIIa/b) are then chlorinated by means of phosphorus pentachloride in chlorobenzene or chloroform to form the geminal dichlorides (XVIIIa) and (XVIIIb) (1, 2). Dehydrohalogenation of (XVIIIa) by means of lithium carbonate and lithium chloride in DMF at 105-110 °C then provides the chloro dihydropyridone (IIa) (1). Alternatively, the dichloro derivative (XVIIIb) is refluxed with neat morpholine (XIX) to furnish intermediate (IIb) (2). Scheme 3.
| 【1】 Shapiro, R., Rossano, L.T., Mudryk, B.M. et al. (Bristol-Myers Squibb Co.). Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones. WO 2007001385. |
| 【2】 Pinto, D., Quan, M., Orwat, M. et al. (Bristol-Myers Squibb Co.). Lactam-containing compounds and derivatives thereof as factor Xa inhibitors. EP 1427415, JP 2005507889, WO 03026652. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVA) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (XVB) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (XVIa) | 65620 | C11H13BrN2O3 | 详情 | 详情 | ||
| (XVIb) | 65621 | C11H13BrINO | 详情 | 详情 | ||
| (XVIIa) | 65622 | 1-(4-Nitrophenyl)-2-piperidinone | 38560-30-4 | C11H12N2O3 | 详情 | 详情 |
| (XVIIb) | 65618 | 1-(4-Iodophenyl)-2-piperidinone | 385425-15-0 | C11H12INO | 详情 | 详情 |
| (XVIIIa) | 65623 | 3,3-Dichloro-1-(4-nitrophenyl)-2-piperidinone | 881386-01-2 | C11H10Cl2N2O3 | 详情 | 详情 |
| (XVIIIb) | 65624 | 3,3-Dichloro-1-(4-iodophenyl)piperidin-2-one | 545445-10-1 | C11H10Cl2INO | 详情 | 详情 |
| (IIA) | 65610 | 3-Chloro-5,6-dihydro-1-(4-nitrophenyl)-2(1H)-pyridinone | 536760-29-9 | C11H9ClN2O3 | 详情 | 详情 |
| (IIB) | 65611 | 1-(4-Iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one; N-(4-Iodophenyl)-3-morpholino-5,6-dihydro-2H-pyridin-2-one | 473927-69-4 | C15H17IN2O2 | 详情 | 详情 |
| (V) | 39700 | 5-bromopentanoyl chloride | 4509-90-4 | C5H8BrClO | 详情 | 详情 |
| (XIX) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |