【结 构 式】 |
【分子编号】26794 【品名】3-Chloro-4-methylaniline; 4-Amino-2-chlorotoluene 【CA登记号】95-74-9 |
【 分 子 式 】C7H8ClN 【 分 子 量 】141.59996 【元素组成】C 59.38% H 5.69% Cl 25.04% N 9.89% |
合成路线1
该中间体在本合成路线中的序号:(I)Alkylation of 3-chloro-4-methylaniline (I) with bromoacetaldehyde diethyl acetal (II) afforded secondary amine (III). Subsequent cyclization of (III) in boiling trifluoroacetic acid/trifluoroacetic anhydride provided a (3:2) mixture of indoles (IV) and (V), from which the desired 6-chloro isomer (IV) was isolated by column chromatography, and then reduced to indoline (VI) using NaBH3CN in AcOH. 5-Aminoquinoline (VII) was treated with carbonyl diimidazole to give intermediate (VIII). This was finally coupled with indoline (VI) in DMF at 100 C to yield the corresponding urea.
【1】 Ham, P.; Jones, G.E.; Forbes, I.T. (SmithKline Beecham plc); Indoline derivs. as 5HT2C antagonists. EP 0707581; JP 1996512299; US 5834494; WO 9501976 . |
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) | 26794 | 3-Chloro-4-methylaniline; 4-Amino-2-chlorotoluene | 95-74-9 | C7H8ClN | 详情 | 详情 |
(II) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
(III) | 26795 | 3-chloro-N-(2,2-diethoxyethyl)-4-methylaniline | C13H20ClNO2 | 详情 | 详情 | |
(IV) | 26796 | 6-chloro-5-methyl-1H-indole | C9H8ClN | 详情 | 详情 | |
(V) | 26797 | 4-chloro-5-methyl-1H-indole | C9H8ClN | 详情 | 详情 | |
(VI) | 26798 | 6-chloro-5-methylindoline | C9H10ClN | 详情 | 详情 | |
(VII) | 26799 | 5-Aminoquinoline; 5-quinolinamine | 611-34-7 | C9H8N2 | 详情 | 详情 |
(VIII) | 26800 | N-(5-quinolinyl)-1H-imidazole-1-carboxamide | C13H10N4O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VII)Acylation of 3-chloro-4-methylaniline (VII) with chloroacetonitrile in the presence of BCl3 and Et2AlCl produced the chloroacetophenone (VIII). Subsequent condensation of (VIII) with ethylmalonyl chloride gave amide (IX), which was cyclized to the quinolinone (X) upon treatment with ethanolic NaOEt. Reaction of the quinolinone (X) with POCl3 afforded chloroquinoline (XI). The ester group of (XI) was then reduced to alcohol (XII) by means of diisobutylaluminum hydride. Condensation of (XII) with 4-methylpiperidine (XIII) gave adduct (IV), which was further coupled with pyridinone (VI) under Mitsunobu conditions to yield (Xv). Finally, intramolecular Heck reaction in the presence of palladium diacetate and triphenylphosphine provided the desired pentacyclic compound, which was isolated as the hydrochloride salt.
【1】 Coulomb, H.; Huchet, M.; Harnett, J.; Rolland, A.; Lanco, C.; Lavergne, O.; Demarquay, D.; Lesueur-Ginot, L.; Bigg, D.C.H.; BN 80927: A novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg Med Chem Lett 1999, 9, 17, 2599. |
【2】 Cazaux, J.-B.; Manginot, E.; Lavergne, O.; Le Breton, C.; Bigg, D. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same. EP 1007527; FR 2768431; WO 9911646 . |
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) | 33100 | (5R)-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H13NO4 | 详情 | 详情 | |
(VII) | 26794 | 3-Chloro-4-methylaniline; 4-Amino-2-chlorotoluene | 95-74-9 | C7H8ClN | 详情 | 详情 |
(VIII) | 33102 | 1-(2-amino-4-chloro-5-methylphenyl)-2-chloro-1-ethanone | C9H9Cl2NO | 详情 | 详情 | |
(IX) | 33013 | O-[tert-butyl(diphenyl)silyl]hydroxylamine; (aminooxy)(tert-butyl)diphenylsilane | C16H21NOSi | 详情 | 详情 | |
(X) | 33104 | ethyl 7-chloro-4-(chloromethyl)-6-methyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate | C14H13Cl2NO3 | 详情 | 详情 | |
(XI) | 33105 | ethyl 2,7-dichloro-4-(chloromethyl)-6-methyl-3-quinolinecarboxylate | C14H12Cl3NO2 | 详情 | 详情 | |
(XII) | 33106 | [2,7-dichloro-4-(chloromethyl)-6-methyl-3-quinolinyl]methanol | C12H10Cl3NO | 详情 | 详情 | |
(XIII) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |
(XIV) | 33107 | [2,7-dichloro-6-methyl-4-[(4-methyl-1-piperidinyl)methyl]-3-quinolinyl]methanol | C18H22Cl2N2O | 详情 | 详情 | |
(XV) | 33101 | (5R)-8-[(2-chloro-6,7-difluoro-3-quinolinyl)methyl]-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C21H17ClF2N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(I)Bromination of 3-chloro-4-methylaniline (I) in HOAc-Et2O afforded a mixture of the desired 2-bromo-5-chloro-4-methylaniline (II) and the dibromo derivative (III), which were separated by column chromatography. In an alternative procedure, aniline (I) was converted to the acetanilide (IV), which was then brominated to give (V). Subsequent acid hydrolysis of amide (V) provided the bromo aniline (II). Treatment of (II) with CuCN in hot NMP furnished nitrile (VI). This was hydrolyzed to the corresponding carboxylic acid (VII) using potassium hydroperoxide generated in situ. Cyclization of (VII) with chloroacetonitrile in the presence of NaOMe generated the quinazolinone system (VIII). The acetate ester (IX) was then obtained by displacement of the chloride group of (VIII) with cesium acetate in hot DMF. Further N-alkylation of quinazoline (IX) using methyl iodide and NaH produced (X). The bromomethyl derivative (XI) was prepared by benzylic bromination of (X) with N-bromosuccinimide in the presence of benzoyl peroxide. Condensation of bromide (XI) with tert-butyl 4-(N-propargylamino)benzoate (XII) yielded adduct (XIII). The acetate ester of (XIII) was then hydrolyzed with NaOH to give the hydroxymethyl quinazoline (XIV), which was subsequently converted to the mesylate (XV) upon treatment with methanesulfonic anhydride and Et3N.
【1】 Bavetsias, V.; et al.; The design and synthesis of water-soluble analogues of CB30865, a quinazolin-4-one-based antitumor agent. J Med Chem 2002, 45, 17, 3692. |
【2】 Bavetsias, V.; Jackman, A.; Skelton, L. (Cancer Research Campaign Technology Ltd.); Anti-cancer dihydroquinazoline derivs.. WO 0050417 . |
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) | 26794 | 3-Chloro-4-methylaniline; 4-Amino-2-chlorotoluene | 95-74-9 | C7H8ClN | 详情 | 详情 |
(II) | 46858 | 2-bromo-5-chloro-4-methylaniline; 2-bromo-5-chloro-4-methylphenylamine | C7H7BrClN | 详情 | 详情 | |
(III) | 46859 | 2,6-dibromo-3-chloro-4-methylaniline; 2,6-dibromo-3-chloro-4-methylphenylamine | 84483-22-7 | C7H6Br2ClN | 详情 | 详情 |
(IV) | 46860 | N-(3-chloro-4-methylphenyl)acetamide | 7149-79-3 | C9H10ClNO | 详情 | 详情 |
(V) | 46861 | N-(2-bromo-5-chloro-4-methylphenyl)acetamide | C9H9BrClNO | 详情 | 详情 | |
(VI) | 46862 | 2-amino-4-chloro-5-methylbenzonitrile | C8H7ClN2 | 详情 | 详情 | |
(VII) | 46863 | 2-amino-4-chloro-5-methylbenzoic acid | C8H8ClNO2 | 详情 | 详情 | |
(VIII) | 46864 | 7-chloro-2-(chloromethyl)-6-methyl-4(3H)-quinazolinone | C10H8Cl2N2O | 详情 | 详情 | |
(IX) | 46865 | (7-chloro-6-methyl-4-oxo-3,4-dihydro-2-quinazolinyl)methyl acetate | C12H11ClN2O3 | 详情 | 详情 | |
(X) | 46866 | (7-chloro-3,6-dimethyl-4-oxo-3,4-dihydro-2-quinazolinyl)methyl acetate | C13H13ClN2O3 | 详情 | 详情 | |
(XI) | 46867 | [6-(bromomethyl)-7-chloro-3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methyl acetate | C13H12BrClN2O3 | 详情 | 详情 | |
(XII) | 46868 | tert-butyl 4-(2-propynylamino)benzoate | C14H17NO2 | 详情 | 详情 | |
(XIII) | 46869 | tert-butyl 4-[([2-[(acetoxy)methyl]-7-chloro-3-methyl-4-oxo-3,4-dihydro-6-quinazolinyl]methyl)(2-propynyl)amino]benzoate | C27H28ClN3O5 | 详情 | 详情 | |
(XIV) | 46870 | tert-butyl 4-[[[7-chloro-2-(hydroxymethyl)-3-methyl-4-oxo-3,4-dihydro-6-quinazolinyl]methyl](2-propynyl)amino]benzoate | C25H26ClN3O4 | 详情 | 详情 | |
(XV) | 46871 | tert-butyl 4-[[(7-chloro-3-methyl-2-[[(methylsulfonyl)oxy]methyl]-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]benzoate | C26H28ClN3O6S | 详情 | 详情 |