|
【结 构 式】 
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【分子编号】12824 【品名】2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine 【CA登记号】95-54-5 |
【 分 子 式 】C6H8N2 【 分 子 量 】108.143 【元素组成】C 66.64% H 7.46% N 25.9% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of 1 2-benzenediamine (I) with methyltetrahydro-5-methyl 4-oxo-3-thiophenecarboxylate (II) in toluene using a Dean-Stark trap gives the triyclic system (III), which is dehydrogenated to 4,9-dihydro-3-methyl-10H-thienol[3,4-b][1,5]benzodiazepin-10-one (IV). Treatment of (IV) with chloroacetyl chloride in dioxane in the presence of K2CO3 yields 4-chloroacetyl-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one (V), which is finally reacted with N-methylpiperazine to produce telenzepine, which is isolated as the hydrochloride.
| 【1】 Borner, H.; Haffer, G.; Sauer, G. (Schering AG); Process for the preparation of 2-bromo-8-ergolinyl. DE 3340025; US 4970314 . |
| 【2】 Galvan, M.; Eltze, M.; Figala, V.; TELENZEPINE HYDROCHLORIDE < Rec INN >. Drugs Fut 1988, 13, 4, 327. |
| 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) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (A) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (I) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (II) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (II) | 22082 | methyl (5R)-5-methyl-4-oxotetrahydro-3-thiophenecarboxylate | C7H10O3S | 详情 | 详情 | |
| (III) | 22083 | (3R)-3-methyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one | C12H12N2OS | 详情 | 详情 | |
| (III) | 22088 | 2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl 3-oxobutanoate | C16H20Cl2N2O3 | 详情 | 详情 | |
| (IV) | 22084 | 3-methyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one | C12H10N2OS | 详情 | 详情 | |
| (V) | 22085 | 4-(2-chloroacetyl)-3-methyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one | C14H11ClN2O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)PHIC is prepared from the diaquo derivative cis-[Pt(diaminocyclohexane)(H2O)2](NO3)2 (II), which is obtained by addition of a stoichiometric amount of silver nitrato to cis-[PtCl2(diaminocyclohexane)] (I). Then isocitrate trisodium salt is added to the diaquo species (II) (1:1), and the mixtures heated to 60 C in the dark for 20 h. The yellow solution is concentrated. then treated with cold ethanol acetona (1:1) to give white PHIC precipitate. After the usual workup, PHIC is obtained (85%). The binding sites of the isocitrate ion to the platinum: diamino cyclohexane moiety have not been characterized.
| 【1】 Ross, W.C.J.; Khokkar, A.R.; Connors, T.A.; Jones, M.; Braddock, P.D.; Tobe, M.L.; New platinum complexes with anti-tumor activity. Chem Biol Interact 1972, 5, 415-424. |
| 【2】 Speer, R.J.; Zapata, A.; Hill, J.M.; Stewart, D.P.; Ridgway, H.; Hall, L.M.; Sulfato 1,2-diaminocyclohexane platinum (II): A potencial new antitumor agent. J Clin Hematol Oncol 1977, 7, 210-219. |
| 【3】 Macquet, J.P.; Armand, J.P.; Cros, S.; Pharmacological and preclinical toxicological studies of 1,2-diaminocyclohexane(isocitrato)platinum (II). Cancer Res 1984, 44, 9, 3736. |
| 【4】 Chang, P.; PHIC. Drugs Fut 1985, 10, 10, 827. |
| 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) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (II) | 29737 | Phenylene-1,2-diamine dichloroplatinum complex | C6H8Cl2N2Pt | 详情 | 详情 | |
| (III) | 29738 | Phenylene-1,2-diamine diaqua platinum complex dinitrate | C8H14N2Pt | 详情 | 详情 | |
| (IV) | 29739 | trisodium 1-hydroxy-1,2,3-propanetricarboxylate | C6H5Na3O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)A synthesis for [14C]-labeled E-3810 has been described: The cyclization of o-phenylenediamine (I) with [14C]-labeled carbon disulfide (II) by means of aqueous KOH gives the potassium salt of [14C]-2-mercaptobenzimidazole (III), which is treated with acetic acid to obtain the corresponding thiol (IV). The condensation of (IV) with 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine (V) by means of NaOH in refluxing ethanol yields [14C]-labeled 2-[4-(3-methoxypropoxy)-3-methylpyridin-3-ylmethylthio]benzimidazole (VI). The oxidation of (VI) with m-chloroperbenzoic acid in dichloromethane affords the corresponding sulfoxide (VIII), which is finally treated with 0.1 N NaOH in ethanol.
| 【1】 Sohda, S.; Tagami, K.; Chiku, S.; Synthesis of 14C-labelled sodium pariprazole (E3810). J Label Compd Radiopharm 1993, 33, 9, 849. |
| 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) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (III) | 12825 | 2-Sulfanyl-1H-benzimidazole potassium salt | C7H5KN2S | 详情 | 详情 | |
| (III) | 45155 | 1H-benzimidazol-2-ylsulfide; 1H-benzimidazole-2-thiolate | C7H5KN2S | 详情 | 详情 | |
| (IV) | 12821 | 2-Mercaptobenzinidiazole; 1H-Benzimidazol-2-ylhydrosulfide; 1H-Benzimidazole-2-thiol; 2-Benzimidazolethiol; o-Phenylenethiourea; 2-Benzimidazolinethione; 1,3-Dihydro-2H-benzimidazole-2-thione | 583-39-1 | C7H6N2S | 详情 | 详情 |
| (IV) | 45156 | 1H-benzimidazol-2-ylhydrosulfide; 1H-benzimidazole-2-thiol | C7H6N2S | 详情 | 详情 | |
| (V) | 12820 | 2-(Chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine; 2-(Chloromethyl)-3-methyl-4-pyridinyl 3-methoxypropyl ether | 117977-20-5 | C11H16ClNO2 | 详情 | 详情 |
| (VI) | 12822 | 2-([[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfanyl)-1H-benzimidazole; 2-[(1H-Benzimidazol-2-ylsulfanyl)methyl]-3-methyl-4-pyridinyl 3-methoxypropyl ether | 117977-21-6 | C18H21N3O2S | 详情 | 详情 |
| (VI) | 45157 | 1H-benzimidazol-2-yl [4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl sulfoxide; 2-([[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl)-1H-benzimidazole | C18H21N3O3S | 详情 | 详情 | |
| (VII) | 12823 | 2-([[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl)-1H-benzimidazole; 1H-Benzimidazol-2-yl [4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl sulfoxide | C18H21N3O3S | 详情 | 详情 | |
| (VII) | 45158 | 2-([[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfanyl)-1H-benzimidazole; 2-[(1H-benzimidazol-2-ylsulfanyl)methyl]-3-methyl-4-pyridinyl 3-methoxypropyl ether | C18H21N3O2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The condensation of 4-(1-benzyloxy-N-methylformamido)butyric acid (I) with o-phenylenediamine (II) and isobutyl chloroformate (III) by means of triethylamine gives N-[3-[N-(2-aminophenyl)carbamoyl]propyl]-N-methylcarbamic acid benzyl ester (IV), which is cyclized by means of p-toluenesulfonic acid in refluxing toluene to the benzimidazole derivative (V). Hydrogenation of (V) with H2 over Pd/C in methanol affords 2-[3-(methylamino)propyl]benzimidazole (VI), which is condensed with the chiral p-toluenesulfonate (VII) by heating at 120 C to give the chiral tetrahydronaphthol (VIII). Finally, this alcohol is esterified with 2-methoxyacetyl chloride and ethyl diisopropylamine in chloroform.
| 【1】 Merlos, M.; Castaner, J.; Casa, A.; Graul, A.; Mibefradil Hydrochloride. Drugs Fut 1997, 22, 10, 1091. |
| 【2】 Branca, Q.; Jaunin, R.; Marki, H.P.; Marti, F.; Ramuz, H. (F. Hoffmann-La Roche AG); Tetrahydronaphthalene derivs. and medicines containing them. EP 0268148; JP 1988139171; US 4808605 . |
| 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) | 13421 | 4-[[(Benzyloxy)carbonyl](methyl)amino]butyric acid | C13H17NO4 | 详情 | 详情 | |
| (II) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (III) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (IV) | 13424 | benzyl 4-(2-aminoanilino)-4-oxobutyl(methyl)carbamate | C19H23N3O3 | 详情 | 详情 | |
| (V) | 13425 | benzyl 3-(1H-benzimidazol-2-yl)propyl(methyl)carbamate | C19H21N3O2 | 详情 | 详情 | |
| (VI) | 13426 | N-[3-(1H-Benzimidazol-2-yl)propyl]-N-methylamine; 3-(1H-Benzimidazol-2-yl)-N-methyl-1-propanamine | C11H15N3 | 详情 | 详情 | |
| (VII) | 13427 | 2-[(1S,2S)-6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-2-naphthalenyl]ethyl 4-methylbenzenesulfonate | C22H27FO4S | 详情 | 详情 | |
| (VIII) | 13428 | (1S,2S)-2-[2-[[3-(1H-Benzimidazol-2-yl)propyl](methyl)amino]ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydro-2-naphthalenol | C26H34FN3O | 详情 | 详情 | |
| (IX) | 13429 | 2-Methoxyacetyl chloride; Methoxyacetyl chloride | 38870-89-2 | C3H5ClO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The reaction of 4-(aminomethyl)benzoic acid (I) with 3-pyridinylmethanol (II) and CDI by means of DBU and TEA in THF gives the carbamate (III), which is treated with oxalyl chloride in toluene to yield the corresponding acyl chloride (IV). Finally, the condensation of (IV) with 1,2-phenylenediamine (V) by means of imidazole in THF affords the target compound. Alternatively, the condensation of acyl chloride (IV) with 2-nitroaniline (VI) by means of pyridine gives the corresponding amide (VII), which is finally reduced with SnCl2 and ammonium acetate in methanol.
| 【1】 Suzuki, T.; Fukazawa, N.; Ando, T.; Tsuchiya, K.; Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. J Med Chem 1999, 42, 15, 3001. |
| 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) | 27823 | 4-(aminomethyl)benzoic acid | 56-91-7 | C8H9NO2 | 详情 | 详情 |
| (II) | 15798 | 3-Pyridinemethanol; 3-pyridinylmethanol | 100-55-0 | C6H7NO | 详情 | 详情 |
| (III) | 36524 | 4-([[(3-pyridinylmethoxy)carbonyl]amino]methyl)benzoic acid | C15H14N2O4 | 详情 | 详情 | |
| (IV) | 36525 | 3-pyridinylmethyl 4-(chlorocarbonyl)benzylcarbamate | C15H13ClN2O3 | 详情 | 详情 | |
| (V) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (VI) | 11608 | o-Nitroaniline; 2-Nitroaniline; 2-Nitrophenylamine | 88-74-4 | C6H6N2O2 | 详情 | 详情 |
| (VII) | 36526 | 3-pyridinylmethyl 4-[(2-nitroanilino)carbonyl]benzylcarbamate | C21H18N4O5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The cyclization of a mixture of phenylene-1,2-diamine (I), 2-sulfanylpropionic acid (II) and 2,6-difluorobenzaldehyde (III) in refluxing benzene gives a mixture of the two diastereomers of 1-(2,6-difluorophenyl)-3-methyl-1H,3H-thiazolo[3,4-a]benzimidazole, from which the trans-(racemic)-(IV) isomer has been isolated by silica gel column chromatography. The enantiomeric resolution has been performed by chiral HPLC affording the (1R, 3R)-(IV) isomer, the target compound.
| 【1】 Chimirri, A.; Grasso, S.; Monforte, A.M.; Monforte, P.; Rao, A.; Zappala, M.; Bruno, G.; Nicolo, F.; Pannecouque, C.; Witvrouw, M.; De Clercq, E.; Synthesis, structure and in vitro anti-human immunodeficiency virus activity of novel 3-methyl-1H,3H-thiazolo[3,4-a]benzimidazoles. Antivir Chem Chemother 1998, 9, 5, 431. |
| 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) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (II) | 24361 | 2-sulfanylpropionic acid; 2-mercaptopropionic acid | 57965-30-7 | C3H6O2S | 详情 | 详情 |
| (III) | 25504 | 2,6-difluorobenzaldehyde | 637-55-8 | C7H4F2O | 详情 | 详情 |
| (IV) | 25505 | (1R,3R)-1-(2,6-difluorophenyl)-3-methyl-3H-[1,3]thiazolo[3,4-a]benzimidazole | C16H12F2N2S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)The reaction of 8-methyl-8-azabicyclo[3.2.1]octan-3-one (I) with hydroxylamine and pyridine in refluxing ethanol gives the oxime (II), which is reduced with LiAlH4 in refluxing 10% H2SO4 yielding endo-methyl-8-azabicyclo[3.2.1]octan-3-amine (III). Finally, this compound is condensed with 1-isopropylbenzimidazole-2-carboxylic acid isopropyl ester (IV) by means of Al(CH3)3 in refluxing toluene. The intermediate 1-isopropylbenzimidazole-2-carboxylic acid isopropyl ester (IV) has been obtained as follows: The cyclization of o-phenylenediamine (V) with 2-hydroxyacetic acid (VI) in refluxing 4N HCl gives 1H-benzyldazole-2-ylmethanol (VII), which is oxidized with KMnO4 to the corresponding carboxylic acid (VIII). Finally, this compound is alkylated and esterified with isopropyl chloride and NaH in DMF.
| 【1】 Labeaga, L.; Alonso-Cires, L.; Tapia, I.; Mosquera, R.; Orjales, A.; Lopez-Tudanca, P.; Benzimidazole-2-carboxylic acid amides and esters: A new structural class of 5-HT3 ligands. Eur J Med Chem 1999, 34, 5, 415. |
| 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) | 38416 | Tropinone; 3-Tropanone; Tropionone; 8-methyl-8-azabicyclo[3.2.1]octan-3-one | 532-24-1 | C8H13NO | 详情 | 详情 |
| (II) | 38412 | 8-methyl-8-azabicyclo[3.2.1]octan-3-one oxime | C8H14N2O | 详情 | 详情 | |
| (III) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 | |
| (IV) | 38413 | isopropyl 1-isopropyl-1H-benzimidazole-2-carboxylate | C14H18N2O2 | 详情 | 详情 | |
| (V) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (VI) | 29856 | 2-hydroxyacetic acid;glycolic acid | 79-14-1 | C2H4O3 | 详情 | 详情 |
| (VII) | 38414 | 1H-benzimidazol-2-ylmethanol | 4856-97-7 | C8H8N2O | 详情 | 详情 |
| (VIII) | 38415 | 1H-benzimidazole-2-carboxylic acid | C8H6N2O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Oxidative oxidation of p-nitrobenzaldehyde (I) and 1,2-phenylenediamine (II) in DMF in the presence of nitrobenzene produced benzimidazole (III). Subsequent reduction of the nitro group of (III) by means of NaBH4 and CuCl afforded aniline (IV). Bromide (VI) was prepared by treatment of 4'-demethyl epipodophyllotoxin (V) with HBr. The title compound was then obtained by coupling aniline (IV) with bromide (VI) using BaCO3 in 1,2-dichloroethane.
| 【1】 Cheng, H.-H.; Guan, J.; Zhu, X.-K.; Cheng, Y.-C.; Tachibana, Y.; Bastow, K.F.; Lee, K.-H.; Gurwith, M.; Cho, S.J.; Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, -di-, and -trisubstituted aniline-4'-O-demethyl-podophyllotoxin and related compounds with improved pharmacological profiles. J Med Chem 1999, 42, 13, 2441. |
| 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) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (II) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (III) | 33735 | 2-(4-nitrophenyl)-1H-benzimidazole | C13H9N3O2 | 详情 | 详情 | |
| (IV) | 33736 | 4-(1H-benzimidazol-2-yl)aniline; 4-(1H-benzimidazol-2-yl)phenylamine | C13H11N3 | 详情 | 详情 | |
| (V) | 13053 | (5R,5aR,8aR,9S)-9-Hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one | 6559-91-7 | C21H20O8 | 详情 | 详情 |
| (VI) | 14609 | (5R,5aR,8aR,9S)-9-bromo-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one | C21H19BrO7 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)Condensation between 1,2-phenylenediamine (I) and 2-chloronicotinic acid (II) in refluxing cyclohexanol generated the tricyclic system (III). Reduction of keto group of (III) with borane-dimethyl sulfide complex afforded 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (IV). Acid chloride (VI), prepared from 4-fluoro-2-(trifluoromethyl)benzoic acid (V), was then condensed with tricyclic amine (IV) to produce amide (VII). Finally, displamecement of the 4-fluoro group of (VII) by the sodium salt of 3-methylpyrazole (VIII) in hot DMF yielded a 5:1 mixture of the title 3-methylpyrazole derivative and its 5-methyl regioisomer (IX), which were separated by column chromatography.
| 【1】 Failli, A.A.; Steffan, R.J.; Sumsky, J.S.; et al.; Pyridobenzodiazepines: Synthesis and structure-activity relationship of a novel class of orally active vasopressin V2 receptor agonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 201. |
| 【2】 Failli, A.A.; Shumsky, J.S.; Steffan, R.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000059; WO 9906403 . |
| 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) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (II) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (III) | 38946 | 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one | C12H9N3O | 详情 | 详情 | |
| (IV) | 38947 | 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine | C12H11N3 | 详情 | 详情 | |
| (V) | 38951 | 4-fluoro-2-(trifluoromethyl)benzoic acid | 141179-72-8 | C8H4F4O2 | 详情 | 详情 |
| (VI) | 38948 | 4-fluoro-2-(trifluoromethyl)benzoyl chloride | C8H3ClF4O | 详情 | 详情 | |
| (VII) | 38949 | 5,11-dihydro-6H-pyrido[2,3-b][1,5]benzodiazepin-6-yl[4-fluoro-2-(trifluoromethyl)phenyl]methanone | C20H13F4N3O | 详情 | 详情 | |
| (VIII) | 37998 | 3-methyl-1H-pyrazole | 1453-58-3 | C4H6N2 | 详情 | 详情 |
| (IX) | 38950 | 5,11-dihydro-6H-pyrido[2,3-b][1,5]benzodiazepin-6-yl[4-(5-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)phenyl]methanone | C24H18F3N5O | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(I)Phenylenediamine (I) was condensed with phenylpropargyl aldehyde (II) in the presence of formic acid to generate the benzimidazole derivative (III). Subsequent N-alkylation of (III) with trimethyloxonium tetrafluoroborate gave the title benzimidazolium salt.
| 【1】 Kerwin, S.M.; et al.; DNA cleavage chemistry of 1-methyl-2-phenylethynyl-3-(prop-2-ynyl)-3H-benzoimidazolium salts. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 146. |
| 【2】 David, W.M.; et al.; Synthesis of a heterocyclic aza-enediyne and its DNA-cleavage properties. Bioorg Med Chem Lett 2000, 10, 22, 2509. |
| 【3】 Kerwin, S.M.; David, W. (Research Development Foundation ; University of Texas System); Novel DNA-cleaving antitumor agents. EP 1109552; US 6297284; WO 0003709; WO 0170217 . |
合成路线11
该中间体在本合成路线中的序号：(I)3-Methylquinoxalin-2-one (III) was prepared by condensation of 1,2-phenylenediamine (I) with pyruvic acid (II). Alkylation of (III) with benzyl chloride furnished a mixture of the desired N-benzyl quinoxalinone (IV) and the O-benzyl isomer (V). These compounds were separated by means of radial chromatography. Bromination of (IV) with N-bromosuccinimide in the presence of benzoyl peroxide furnished the bromomethyl derivative (VI). Finally, condensation of bromide (VI) with salicylanilide (VII) under phase-transfer conditions provided the title compound.
| 【1】 Copper, J.E.; Smith, C.D.; Lawrence, D.S.; Structure-activity studies of substituted quinoxalinones as multiple-drug-resistance antagonists. J Med Chem 2001, 44, 4, 594. |
| 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) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (II) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (III) | 48019 | 3-methyl-2(1H)-quinoxalinone | 14003-34-0 | C9H8N2O | 详情 | 详情 |
| (IV) | 48020 | 1-benzyl-3-methyl-2(1H)-quinoxalinone | C16H14N2O | 详情 | 详情 | |
| (V) | 48021 | benzyl 3-methyl-2-quinoxalinyl ether; 2-(benzyloxy)-3-methylquinoxaline | C16H14N2O | 详情 | 详情 | |
| (VI) | 48022 | 1-benzyl-3-(bromomethyl)-2(1H)-quinoxalinone | C16H13BrN2O | 详情 | 详情 | |
| (VII) | 48023 | 2-hydroxy-N-phenylbenzamide | 87-17-2 | C13H11NO2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(IX)The reaction of o-phenylenediamine (IX) with 4-chloropyridine (VIII) gives 2-(4-pyridylamino)aniline (X), which is condensed with 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (I) to give the corresponding pyridinium salt (XI). The reduction of (XI) with NaBH4 yields amino compound (VII). Finally this compound is cyclized with carbon disulfide and KOH
| 【1】 JP 76095096 . |
| 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) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
| (VII) | 60704 | N-(2-aminophenyl)-N-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)amine; N~1~-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)-1,2-benzenediamine | C23H30FN3O2 | 详情 | 详情 | |
| (VIII) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (IX) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (X) | 60705 | N-(2-aminophenyl)-N-(4-pyridinyl)amine; N~1~-(4-pyridinyl)-1,2-benzenediamine | C11H11N3 | 详情 | 详情 | |
| (XI) | 60706 | 4-(2-aminoanilino)-1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}pyridinium chloride | C23H25ClFN3O2 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(VIII)MGCD-0103 can be prepared as follows. Reaction of 4-(aminomethyl)benzoic acid methyl ester hydrochloride (I) with pyrazole-1-carboxamidine hydrochloride (II) affords guanidine (III). 3-Acetylpyridine (IV) is then heated with dimethylformamide dimethyl acetal to furnish the enaminone (V), which is cyclized with guanidine (III), giving the pyridyl pyrimidine (VI). After saponification of the methyl ester (VI) by means of LiOH, the resulting carboxylic acid (VII) is coupled with o-phenylenediamine (VIII) to provide the title compound (1). Scheme 1.
| 【1】 Delorme, D., Zhou, Z. (MethylGene, Inc.). Inhibitors of histone deacetylase. EP 1590340, JP 2006514998, US 2004142953, US 6897220, WO 2004069823. |
| 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) | 65629 | Methyl 4-(aminomethyl)benzoate hydrochloride | 6232-11-7 | C9H11NO2.HCl | 详情 | 详情 |
| (II) | 65630 | 1H-Pyrazole-1-carboxamidine hydrochloride; 1-Amidinopyrazole hydrochloride; Praxadine | 4023-02-3 | C4H6N4.HCl | 详情 | 详情 |
| (III) | 65631 | 4-Guanidinomethylbenzoic acid methyl ester; 4-[[(Aminoiminomethyl)amino]methyl]benzoic acid methyl ester | 736080-30-1 | C10H13N3O2 | 详情 | 详情 |
| (IV) | 12027 | 1-(3-Pyridinyl)-1-ethanone; 1-(3-Pyridinyl)ethanone | 350-03-8 | C7H7NO | 详情 | 详情 |
| (V) | 47516 | (E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one | 123367-26-0 | C10H12N2O | 详情 | 详情 |
| (VI) | 65632 | 4-[[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]methyl]benzoic acid methyl ester | 849235-67-2 | C18H16N4O2 | 详情 | 详情 |
| (VII) | 65633 | 4-[[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]methyl]benzoic acid | C17H14N4O2 | 详情 | 详情 | |
| (VIII) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |