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【结 构 式】 
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【分子编号】12420 【品名】N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine 【CA登记号】100-36-7 |
【 分 子 式 】C6H16N2 【 分 子 量 】116.20652 【元素组成】C 62.02% H 13.88% N 24.11% |
合成路线1
该中间体在本合成路线中的序号：(B)Prepared by reacting 2-methoxy-5-methylsulfonylbenzoic acid (I) with isobutyl chloroformate (A) in dioxane to give the corresponding anhydride (II), which is finally condensed with N,N-diethylethylenediamine (B).
| 【1】 Bulteau, G.; Acher, J.; Process for preparing benzamides. CH 585699; DE 2327192; GB 1394563; JP 49085037 . |
| 【2】 Neuman, M.; Prous, J.R.; Tiapride. Drugs Fut 1976, 1, 2, 88. |
| 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) | 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 |
| (A) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (I) | 34068 | 2-methoxy-5-(methylsulfonyl)benzoic acid | 50390-76-6 | C9H10O5S | 详情 | 详情 |
| (II) | 34069 | C14H18O7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)A new synthesis for [14C]-labeled batanopride has been described: The starting material is 4-amino-2-hydroxybenzoic acid labeled with [14C] at the carboxy group (I). The methylation of (I) in the usual way gives 4-amino-2-methoxybenzoic acid methyl ester (II), which is treated with acetic anhydride to yield the corresponding acetamido derivative (III). Chlorination of (III) with Cl2 in acetic acid affords 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester (IV), which is hydrolyzed with aqueous NaOH to 4-amino-5-chloro-2-methoxybenzoic acid (V). The condensation of (V) with 2-(diethylamino)ethylamine (VI) by means of triethylamine and isobutyl chloroformate in THF gives the corresponding amide (VII), which is demethylated with sodium ethanethiolate in DMF to yield the phenolate (VIII). The condensation of (VIII) with 3-chloro-2-butanone (IX) in DMF affords batanopride free base (X), which is finally treated with HCl in acetone - water.
| 【1】 Standridge, R.T.; Swigor, J.E.; Synthesis of 4-amino-5-chloro-N[2-(diethylamino)ethyl]-2-[(butan-2-on-3-yl)oxy]-[carbonyl-C-14]benzamide hydrochloride (C-14-batanopride). J Label Compd Radiopharm 1991, 29, 9, 983. |
| 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) | 12415 | 4-Aminosalicylic Acid; 4-Amino-2-hydroxybenzoic acid | 65-49-6 | C7H7NO3 | 详情 | 详情 |
| (I) | 45126 | 4-amino-2-hydroxybenzoic acid | C7H7NO3 | 详情 | 详情 | |
| (II) | 12416 | methyl 4-amino-2-methoxybenzoate | 27492-84-8 | C9H11NO3 | 详情 | 详情 |
| (II) | 45127 | methyl 4-amino-2-methoxybenzoate | C9H11NO3 | 详情 | 详情 | |
| (III) | 12417 | methyl 4-(acetamido)-2-methoxybenzoate; Methyl 4-acetamido-2-methoxybenzoate | 4093-28-1 | C11H13NO4 | 详情 | 详情 |
| (III) | 45128 | methyl 4-(acetamido)-2-methoxybenzoate | C11H13NO4 | 详情 | 详情 | |
| (IV) | 12418 | 4-Acetamido-5-chloro-2-methoxy methyl benzoate; methyl 4-(acetamido)-5-chloro-2-methoxybenzoate; Methyl 4-acetamido-5-chloro-2-methoxybenzoate; 4-Acetamido-5-chloro-2-methoxybenzoic acid methyl ester; 4-Acetamido-5-chloro-o-anisic acid methyl ester | 4093-31-6 | C11H12ClNO4 | 详情 | 详情 |
| (IV) | 45129 | methyl 4-(acetamido)-5-chloro-2-methoxybenzoate | C11H12ClNO4 | 详情 | 详情 | |
| (V) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (V) | 45130 | 4-amino-5-chloro-2-methoxybenzoic acid | C8H8ClNO3 | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 12421 | 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide | 364-62-5 | C14H22ClN3O2 | 详情 | 详情 |
| (VII) | 45131 | 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide | C14H22ClN3O2 | 详情 | 详情 | |
| (VIII) | 12422 | sodium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate | C13H19ClN3NaO2 | 详情 | 详情 | |
| (VIII) | 45132 | sodium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate | C13H19ClN3NaO2 | 详情 | 详情 | |
| (IX) | 12423 | 3-Chloro-2-butanone | 4091-39-8 | C4H7ClO | 详情 | 详情 |
| (X) | 12424 | 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide | C17H26ClN3O3 | 详情 | 详情 | |
| (X) | 45133 | 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide | C17H26ClN3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Reaction of p-aminobenzoic acid methyl ester (I) with methanesulfonyl chloride using pyridine as base provides the methanesulfonyl derivative (II). Heating (II) in heat N,N-diethyl-1,2-ethanediamine (III) at 140-50 C until complete disappearance of (II) gives the crude sematilide, which, after removal of excess diamine under vacuum, is crystallized as the hydrochloride salt from isopropanol/aqueous HCl.
| 【1】 Lumma, W.C. Jr.; Davey, D.D.; Wohl, R.A. (Berlex Laboratories, Inc.); Substituted sulfonamidobenzamides, antiarrhythmic agents and compositions thereof.. EP 0158775; JP 85209559; US 4544654 . |
| 【2】 Lumma, W.C. Jr.; SEMATILIDE HYDROCHLORIDE < Rec INNM; USAN >. Drugs Fut 1989, 14, 3, 234. |
合成路线4
该中间体在本合成路线中的序号：(II)The synthetic procedure was carried out according to Cholody et al. (1). The starting 1-chloro-7-hydroxy-4-nitro-9(10H)-acridinone (I) was synthesized by the method of Capps (2). The condensation of (I) with 2-(diethylamino)ethylamine (II) in DMF gave 1-[2-(diethyl-amino)ethylamino]-7-hydroxy-4-nitro-9(10H)-acridinone (III) in good yield and purity. The reduction of the nitro group of (III) with hydrazine hydrate and Raney Ni in THF yielded the amino intermediate (IV), extremely unstable due to its sensitivity to oxidation, which was immediately used in the next step as crude hydrochloride salt. The salt (IV) was refluxed with 95% formic acid giving the imidazoacridinone derivative. The final product was isolated directly from the reaction mixture as hydrochloride salt after acidification with concentrated HCl and recrystalized from a mixture of methanol/acetone.
| 【1】 Cholody, W.M.; Martelli, S.; Konopa, J.; Chromophore-modified antineoplastic imidazoacridinones. Synthesis and activity against murine leukemias. J Med Chem 1992, 35, 2, 378-82. |
| 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) | 17548 | 1-chloro-7-hydroxy-4-nitro-9(10H)-acridinone | C13H7ClN2O4 | 详情 | 详情 | |
| (II) | 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 |
| (III) | 17550 | 1-[[2-(diethylamino)ethyl]amino]-7-hydroxy-4-nitro-9(10H)-acridinone | C19H22N4O4 | 详情 | 详情 | |
| (IV) | 17551 | 4-amino-1-[[2-(diethylamino)ethyl]amino]-7-hydroxy-9(10H)-acridinone | C19H24N4O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The bromination of 3-methoxybenzoic acid (I) with Br2 in refluxing acetic acid gives 2-bromo-5-methoxybenzoic acid (II), which is condensed with 3-chlorothiophenol (III) by means of cupric acetate in DMF at 150 C yielding the sulfide (IV). The cyclization of (IV) in sulfuric acid affords the thioxanthenone (V), which is condensed with 2-(diethylamino)ethylamine (VI) in pyridine at 115 C giving the corresponding 2-(diethylamino)ethylamino derivative (VII). The hydroxymethylation of (VII) with formaldehyde in hot 5N acetic acid yields the hydroxymethyl derivative (VIII), which is oxidized with MnO2 in hot toluene affording the corresponding aldehyde (IX). Finally, this compound is treated with formamide and formic acid at 170 C.
| 【1】 Perni, R.B.; Wentland, M.P.; Huang, J.I.; Powles, R.G.; Aldous, S.; Klingbeil, K.M.; Peverly, A.D.; Robinson, R.G.; Corbett, T.H.; Jones, J.L.; Mattes, K.C.; Rake, J.B.; Coughlin, S.A.; Synthesis and antitumor activity of 4-aminomethylthioxanthenone and 5-aminomethylbenzothiopyranoindazole derivatives. J Med Chem 1998, 41, 19, 3645. |
| 【2】 Miller, T.C.; Collins, J.C.; Wentland, M.P.; Perni, R.B.; Corbett, T.H.; Mattes, K.C. (Sanofi-Synthelabo); Thioxanthenone antitumor agents. EP 0518414; EP 0619315; EP 0882723; JP 1993178853; JP 1994340655; US 5346917 . |
| 【3】 Wentland, M.P.; et al.; Anti-solid tumor efficacy and preparation of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxo-9H-thioxanthen-4-yl]methyl]methanesulfonamide (WIN 33377) and related derivatives. Bioorg Med Chem Lett 1994, 4, 4, 609. |
| 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) | 28559 | m-Anisic acid; 3-Methoxybenzoic acid | 586-38-9 | C8H8O3 | 详情 | 详情 |
| (II) | 17819 | 2-bromo-5-methoxybenzoic acid | 22921-68-2 | C8H7BrO3 | 详情 | 详情 |
| (III) | 30443 | 3-chlorophenylhydrosulfide; 3-chlorobenzenethiol | 2037-31-2 | C6H5ClS | 详情 | 详情 |
| (IV) | 30444 | 2-[(3-chlorophenyl)sulfanyl]-5-methoxybenzoic acid | C14H11ClO3S | 详情 | 详情 | |
| (V) | 30445 | 1-chloro-7-methoxy-9H-thioxanthen-9-one | C14H9ClO2S | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 30446 | 1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9H-thioxanthen-9-one | C20H24N2O2S | 详情 | 详情 | |
| (VIII) | 30447 | 1-[[2-(diethylamino)ethyl]amino]-4-(hydroxymethyl)-7-methoxy-9H-thioxanthen-9-one | C21H26N2O3S | 详情 | 详情 | |
| (IX) | 30448 | 1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxo-9H-thioxanthene-4-carbaldehyde | C21H24N2O3S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)The cyclization of 2,2,5,5-tetramethyl-3,4-dithiahexane-1,6-dial (I) with 2-methylpropane-1,2-diamine (II) in hoot ethanol gives 3,3,6,6,10,10-hexamethyl-1,2-dithia-5,8-diazacyclodeca-4,8-diene (III), which is reduced with NaBH3CN in ethanol to afford the corresponding cyclodecane compound (IV). The condensation of (IV) with 4-(bromomethyl)benzoic acid methyl ester (V) by means of K2CO3 in refluxing acetonitrile yields the adduct (VI), which is condensed with 2-(diethylamino)ethylamine (VII) by means of Al(CH3)3 in refluxing dichloromethane to provide the corresponding amide (VIII). Ring opening of (VIII) at the S-S bond by means of dithiothreitol (DTT) and TEA in MeOH gives the dithiol (IX), which is finally treated with TcO4Na, SnCl2 and NaOH in ethanol/water.
| 【1】 Auzeloux, P.; et al.; Technetium-99m radiolabelling of an N-amino-alkyl-benzamide nitrido- and oxo-technetium bis(aminoethanethiol) derivative synthesis and biological results. Potential melanoma tracer agents. J Label Compd Radiopharm 1999, 42, 6, 567. |
| 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) | 38370 | 2-[(1,1-dimethyl-2-oxoethyl)disulfanyl]-2-methylpropanal | C8H14O2S2 | 详情 | 详情 | |
| (II) | 29645 | 2-amino-1,1-dimethylethylamine; 2-methyl-1,2-propanediamine | 811-93-8 | C4H12N2 | 详情 | 详情 |
| (III) | 38371 | 3,3,6,6,10,10-hexamethyl-3,6,7,10-tetrahydro-1,2,5,8-dithiadiazecine | C12H22N2S2 | 详情 | 详情 | |
| (IV) | 38372 | 3,3,6,6,10,10-hexamethyl-1,2,5,8-dithiadiazecane | C12H26N2S2 | 详情 | 详情 | |
| (V) | 14565 | methyl 4-(bromomethyl)benzoate | 2417-72-3 | C9H9BrO2 | 详情 | 详情 |
| (VI) | 38373 | methyl 4-[(3,3,7,7,10,10-hexamethyl-1,2,5,8-dithiadiazecan-5-yl)methyl]benzoate | C21H34N2O2S2 | 详情 | 详情 | |
| (VII) | 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 |
| (VIII) | 38374 | N-[2-(diethylamino)ethyl]-4-[(3,3,7,7,10,10-hexamethyl-1,2,5,8-dithiadiazecan-5-yl)methyl]benzamide | C26H46N4OS2 | 详情 | 详情 | |
| (IX) | 38375 | N-[2-(diethylamino)ethyl]-4-[[[2-methyl-2-[(2-methyl-2-sulfanylpropyl)amino]propyl](2-methyl-2-sulfanylpropyl)amino]methyl]benzamide | C26H48N4OS2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)The cyclization of 2,2,5,5-tetramethyl-3,4-dithiahexane-1,6-dial (I) with 2-methylpropane-1,2-diamine (II) in hot ethanol gives 3,3,6,6,10,10-hexamethyl-1,2-dithia-5,8-diazacyclodeca-4,8-diene (III), which is reduced with NaBH3CN in ethanol to afford the corresponding cyclodecane compound (IV). The condensation of (IV) with 4-(bromomethyl)benzoic acid methyl ester (V) by means of K2CO3 in refluxing acetonitrile yields the adduct (VI), which is condensed with 2-(diethylamino)ethylamine (VII) by means of Al(CH3)3 in refluxing dichloromethane to provide the corresponding amide (VIII). Ring opening of (VIII) at the S-S bond by means of dithiothreitol (DTT) and TEA in methanol gives the dithiol (IX), which is finally treated with TcO4Na, PPh3 and N,S-dimethyldithiocarbazate (MDTCZ) in ethanol / 1M HCl.
| 【1】 Auzeloux, P.; et al.; Technetium-99m radiolabelling of an N-amino-alkyl-benzamide nitrido- and oxo-technetium bis(aminoethanethiol) derivative synthesis and biological results. Potential melanoma tracer agents. J Label Compd Radiopharm 1999, 42, 6, 567. |
| 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) | 38370 | 2-[(1,1-dimethyl-2-oxoethyl)disulfanyl]-2-methylpropanal | C8H14O2S2 | 详情 | 详情 | |
| (II) | 29645 | 2-amino-1,1-dimethylethylamine; 2-methyl-1,2-propanediamine | 811-93-8 | C4H12N2 | 详情 | 详情 |
| (III) | 38371 | 3,3,6,6,10,10-hexamethyl-3,6,7,10-tetrahydro-1,2,5,8-dithiadiazecine | C12H22N2S2 | 详情 | 详情 | |
| (IV) | 38372 | 3,3,6,6,10,10-hexamethyl-1,2,5,8-dithiadiazecane | C12H26N2S2 | 详情 | 详情 | |
| (V) | 14565 | methyl 4-(bromomethyl)benzoate | 2417-72-3 | C9H9BrO2 | 详情 | 详情 |
| (VI) | 38373 | methyl 4-[(3,3,7,7,10,10-hexamethyl-1,2,5,8-dithiadiazecan-5-yl)methyl]benzoate | C21H34N2O2S2 | 详情 | 详情 | |
| (VII) | 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 |
| (VIII) | 38374 | N-[2-(diethylamino)ethyl]-4-[(3,3,7,7,10,10-hexamethyl-1,2,5,8-dithiadiazecan-5-yl)methyl]benzamide | C26H46N4OS2 | 详情 | 详情 | |
| (IX) | 38375 | N-[2-(diethylamino)ethyl]-4-[[[2-methyl-2-[(2-methyl-2-sulfanylpropyl)amino]propyl](2-methyl-2-sulfanylpropyl)amino]methyl]benzamide | C26H48N4OS2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IV)Condensation of 1,2,3-benzotriazin-4(3H)-one (I) with ethyl bromoacetate (II) in refluxing butanone afforded the 3-(ethoxycarbonylmethyl) derivative (III). The ethyl ester group of (III) was then converted into the target amide by reaction with N,N-diethylethylenediamine (IV) in hot MeOH
| 【1】 Caliendo, G.; De Nucci, G.; Meli, R.; Mattace Raso, G.; Fiorino, F.; Perissutti, E.; Zanesco, A.; Grieco, P.; Santagada, V.; Preparation and local anaesthetic activity of benzotriazinone and benzoyltriazole derivatives. Eur J Med Chem 1999, 34, 12, 1043. |
| 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) | 36890 | 1,2,3-benzotriazin-4(3H)-one | C7H5N3O | 详情 | 详情 | |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 36891 | ethyl 2-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]acetate | C11H11N3O3 | 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 |
合成路线9
该中间体在本合成路线中的序号：(IV)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 |
合成路线10
该中间体在本合成路线中的序号：(XV)Suzuki coupling between 4-bromobenzaldehyde (XII) and 4-trifluoromethylbenzeneboronic acid (XIII) produced the biphenyl compound (XIV). The reductive amination of aldehyde (XIV) with N,N-diethyl ethylenediamine (XV) gave diamine (XVI) (1). This was finally coupled with the intermediate carboxylic acid (XI) to afford the title amide.
| 【1】 Smith, S.A.; Inhibition of lipoprotein-associated phospholipase A2 - A novel approach for the treatment of atherosclerosis. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst . |
| 【2】 Ife, R.J.; Leach, C.A.; Smith, S.A.; Pinto, I.L.; Hickey, D.M.B.; Fenwick, A.E. (GlaxoSmithKline plc); Pyrimidinone cpds.. EP 1175408; WO 0066567 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 53050 | 2-[2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-oxo-1(4H)-pyrimidinyl]acetic acid | n/a | C18H17FN4O3S | 详情 | 详情 |
| (XII) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
| (XIII) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 | |
| (XIV) | 53051 | 4-[4-(trifluoromethyl)phenyl]benzaldehyde | n/a | C14H9F3O | 详情 | 详情 |
| (XV) | 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 |
| (XVI) | 53052 | N-[2-(diethylamino)ethyl]-N-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}amine; N~1~,N~1~-diethyl-N~2~-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1,2-ethanediamine | n/a | C20H25F3N2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VII)Nitrosation of tert-butyl acetoacetate (I) with NaNO2/AcOH produces the oximino ester (II). Reductive cyclization of (II) with ethyl acetoacetate (III) in the presence of Zn/AcOH leads to the pyrrole dicarboxylate (IV). Selective decarboxylation of the t-butyl ester of (IV) under acidic conditions, followed by Vilsmeier formylation of the intermediate ethyl 2,4-dimethylpyrrole-3-carboxylate furnishes the pyrrole aldehyde (V). Alternatively, this compound is directly obtained from (IV) upon treatment with trimethyl orthoformate and trifluoroacetic acid. Basic hydrolysis of the ethyl ester group of (V) yields the pyrrolecarboxylic acid (VI). This is coupled to 2-(diethylamino)ethylamine (VII) to afford the corresponding amide (VIII).
| 【1】 Sun, L.; Liang, C.; Shirazian, S.; Zhou, Y.; Miller, T.; Ciu, J.; Fukuda, J.Y.; Chu, J.-Y.; Nematalla, A.; Wang, X.; Chen, H.; Sistla, A.; Luu, T.C.; Tang, F.; Wei, J.; Tang, C.; Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine. J Med Chem 2003, 46, 7, 1116. |
| 【2】 Wei, C.C.; Miller, T.; Tang, P.C.; Nematalla, A.S.; Li, X.; Liang, C.; Shirazian, S.; Su, L.; Vojkovsky, T. (Sugen, Inc.); Pyrrole substd. 2-indolinone protein kinase inhibitors. EP 1255752; US 2002156292; US 6573293; WO 0160814 . |
| 【3】 Shenoy, N.; Sorasuchart, W. (Sugen, Inc.); Formulations for pharmaceutical agents ionizable as free acids or free bases. JP 2003514851; WO 0137820 . |
| 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) | 27907 | Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate | 1694-31-1 | C8H14O3 | 详情 | 详情 |
| (II) | 63353 | 1,1-dimethylethyl 2-(hydroxyimino)-3-oxobutanoate | 14352-65-9 | C8H13NO4 | 详情 | 详情 |
| (III) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (IV) | 63354 | 2-(1,1-dimethylethyl) 4-ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate | 86770-31-2 | C14H21NO4 | 详情 | 详情 |
| (V) | 60381 | ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate | 2199-59-9 | C10H13NO3 | 详情 | 详情 |
| (VI) | 60382 | 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid | 253870-02-9 | C8H9NO3 | 详情 | 详情 |
| (VII) | 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 |
| (VIII) | 63355 | N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide | 356068-86-5 | C14H23N3O2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VII)5-Fluoroisatin (IX) is heated with neat hydrazine hydrate to produce 2-amino-5-fluorophenylacetic hydrazide (X), which, upon acidic treatment cyclizes to 5-fluorooxindole (XI). Subsequent condensation of oxindole (XI) with the formylpyrrole carboxamide (VIII) in the presence of piperidine in hot EtOH leads to the title compound. In an alternative procedure, oxindole (XI) is condensed with the formylpyrrole carboxylic acid (VI) giving (XII), which is further coupled with 2-(diethylamino)ethylamine (VII) in the presence of EDC/HOBt to yield the target carboxamide.
| 【1】 Sun, L.; Liang, C.; Shirazian, S.; Zhou, Y.; Miller, T.; Ciu, J.; Fukuda, J.Y.; Chu, J.-Y.; Nematalla, A.; Wang, X.; Chen, H.; Sistla, A.; Luu, T.C.; Tang, F.; Wei, J.; Tang, C.; Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine. J Med Chem 2003, 46, 7, 1116. |
| 【2】 Wei, C.C.; Miller, T.; Tang, P.C.; Nematalla, A.S.; Li, X.; Liang, C.; Shirazian, S.; Su, L.; Vojkovsky, T. (Sugen, Inc.); Pyrrole substd. 2-indolinone protein kinase inhibitors. EP 1255752; US 2002156292; US 6573293; WO 0160814 . |
| 【3】 Shenoy, N.; Sorasuchart, W. (Sugen, Inc.); Formulations for pharmaceutical agents ionizable as free acids or free bases. JP 2003514851; WO 0137820 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 60382 | 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid | 253870-02-9 | C8H9NO3 | 详情 | 详情 |
| (VII) | 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 |
| (VIII) | 63355 | N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide | 356068-86-5 | C14H23N3O2 | 详情 | 详情 |
| (IX) | 21552 | 5-fluoro-1H-indole-2,3-dione | 443-69-6 | C8H4FNO2 | 详情 | 详情 |
| (X) | 63356 | 2-(2-amino-5-fluorophenyl)acetohydrazide | 356068-89-8 | C8H10FN3O | 详情 | 详情 |
| (XI) | 60384 | 5-fluoro-1,3-dihydro-2H-indol-2-one | 56341-41-4 | C8H6FNO | 详情 | 详情 |
| (XII) | 60386 | 5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid | 356068-93-4 | C16H13FN2O3 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(XIV)Suzuki coupling between 4-bromobenzaldehyde (XI) and 4-trifluoromethylbenzeneboronic acid (XII) affords the biphenylyl aldehyde (XIII). This is then reductively aminated with N,N-diethylethylenediamine (XIV) and NaBH4 to produce diamine (XV) (1,3). Finally, coupling between amine (XV) and carboxylic acid (VIII) leads to the title carboxamide
| 【1】 The identification of clinical candidate SB-480848: A potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett 2003, 13, 6, 1067. |
| 【2】 Ife, R.J.; Leach, C.A.; Hickey, D.M.B.; Pinto, I.L.; Smith, S.A.; Stanway, S.J. (GlaxoSmithKline plc); Pyrimidine-4-one derivs. as LDL-PLA 2 inhibitors. EP 1263740; JP 2003523335; US 2002103213; US 6649619; WO 0160805 . |
| 【3】 Mulholland, K.R.; Ross, A.R.; Smith, G.E.; Slater, G.R. (GlaxoSmithKline plc); Novel processes. WO 0316287 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 63494 | 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid | C16H15FN2O3S | 详情 | 详情 | |
| (XI) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
| (XII) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 | |
| (XIII) | 53051 | 4-[4-(trifluoromethyl)phenyl]benzaldehyde | n/a | C14H9F3O | 详情 | 详情 |
| (XIV) | 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 |
| (XV) | 53052 | N-[2-(diethylamino)ethyl]-N-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}amine; N~1~,N~1~-diethyl-N~2~-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1,2-ethanediamine | n/a | C20H25F3N2 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(XI)Condensation of methyl 3,5-dihydroxybenzoate (I) with 3-chloro-3-methyl-1-butyne (II) in the presence of CuI, followed by thermal cyclization at 75 C, gives rise to a mixture of two regioisomeric chromenes (III) and (IV). After chromatographic separation, the desired isomer (III) is reduced with LiAlH4 to provide alcohol (V). Copper-catalyzed coupling of the phenolic chromene (V) with sodium 2-iodobenzoate (VI) leads to the diaryl ether (VII), which is further cyclized to the pyranoxanthenone (VIII) in the presence of trifluoroacetic anhydride. After basic hydrolysis of the trifluoroacetate ester (VIII), the resultant alcohol (IX) is converted to mesylate (X) by treatment with methanesulfonyl chloride and triethylamine. Finally, displacement of the mesylate group of (X) with N,N-diethyl ethylenediamine (XI) furnishes the title compound.
| 【1】 Kolokythas, G.; et al.; Design and synthesis of some new pyranoxanthenone aminoderivatives with cytotoxic activity. Bioorg Med Chem Lett 2002, 12, 11, 1443. |
| 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) | 25155 | methyl 3,5-dihydroxybenzoate | 2150-44-9 | C8H8O4 | 详情 | 详情 |
| (II) | 22416 | 3-chloro-3-methyl-1-butyne | 1111-97-3 | C5H7Cl | 详情 | 详情 |
| (III) | 57036 | methyl 7-hydroxy-2,2-dimethyl-2H-chromene-5-carboxylate | C13H14O4 | 详情 | 详情 | |
| (IV) | 57037 | methyl 5-hydroxy-2,2-dimethyl-2H-chromene-7-carboxylate | C13H14O4 | 详情 | 详情 | |
| (V) | 57039 | 5-(hydroxymethyl)-2,2-dimethyl-2H-chromen-7-ol | C12H14O3 | 详情 | 详情 | |
| (VI) | 57038 | sodium 2-iodobenzoate | C7H4INaO2 | 详情 | 详情 | |
| (VII) | 57040 | 2-{[5-(hydroxymethyl)-2,2-dimethyl-2H-chromen-7-yl]oxy}benzoic acid | C19H18O5 | 详情 | 详情 | |
| (VIII) | 57041 | (2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]xanthen-5-yl)methyl 2,2,2-trifluoroacetate | C21H15F3O5 | 详情 | 详情 | |
| (IX) | 57042 | 5-(hydroxymethyl)-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-one | C19H16O4 | 详情 | 详情 | |
| (X) | 57043 | (2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]xanthen-5-yl)methyl methanesulfonate | C20H18O6S | 详情 | 详情 | |
| (XI) | 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 |