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【结 构 式】 
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【分子编号】49517 【品名】3-Bromo-p-toluidine; 4-Amino-2-bromotoluene; 3-Bromo-4-methylaniline 【CA登记号】7745-91-7 |
【 分 子 式 】C7H8BrN 【 分 子 量 】186.05126 【元素组成】C 45.19% H 4.33% Br 42.95% N 7.53% |
合成路线1
该中间体在本合成路线中的序号：(II)Catalytic hydrogenation of 2-bromo-4-nitrotoluene (I) over Raney-Ni provided aniline (II). Reaction of (II) with chloral hydrate and hydroxylamine gave rise to the isonitrosoacetanilide (III), which was subsequently cyclized to the isatin (IV) by heating in concentrated H2SO4. Oxidative cleavage of isatin (IV) produced the anthranilic acid (V). This was converted to the benzoxazinone (VI) upon refluxing with acetic anhydride. Ring opening of benzoxazinone (VI) with MeOH, followed by acidic hydrolysis of the acetamide function, yielded the anthranilate ester (VII). The quinazoline derivative (VIII) was then obtained by treatment of anthranilate (VII) with chloroformamidine hydrochloride in refluxing diglyme. Finally, displacement of the bromide group of (VIII) with the sodium thiolate of 4-mercaptopyridine (IX) under Ullmann conditions afforded the title pyridyl sulfide.
| 【1】 Webber, S.E.; Bleckman, T.M.; Attard, J.; Jones, T.R.; Varney, M.D. (Agouron Pharmaceuticals, Inc.); Antiproliferative quinazolines. EP 0637300; US 5430148; WO 9320055 . |
| 【2】 Webber, S.E.; et al.; Design of thymidylate synthase inhibitors using protein crystal structures: The synthesis and biological evaluation of a novel class of 5-substituted quinazolinones. J Med Chem 1993, 36, 6, 733. |
| 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) | 38642 | 2-bromo-1-methyl-4-nitrobenzene | 7745-93-9 | C7H6BrNO2 | 详情 | 详情 |
| (II) | 49517 | 3-Bromo-p-toluidine; 4-Amino-2-bromotoluene; 3-Bromo-4-methylaniline | 7745-91-7 | C7H8BrN | 详情 | 详情 |
| (III) | 49518 | N-(3-bromo-4-methylphenyl)-2-(hydroxyimino)acetamide | C9H9BrN2O2 | 详情 | 详情 | |
| (IV) | 49519 | 4-bromo-5-methyl-1H-indole-2,3-dione | C9H6BrNO2 | 详情 | 详情 | |
| (V) | 49520 | 6-amino-2-bromo-3-methylbenzoic acid | C8H8BrNO2 | 详情 | 详情 | |
| (VI) | 49521 | 5-bromo-2,6-dimethyl-4H-3,1-benzoxazin-4-one | C10H8BrNO2 | 详情 | 详情 | |
| (VII) | 49522 | methyl 6-amino-2-bromo-3-methylbenzoate | C9H10BrNO2 | 详情 | 详情 | |
| (VIII) | 49523 | 2-amino-5-bromo-6-methyl-4(3H)-quinazolinone | C9H8BrN3O | 详情 | 详情 | |
| (IX) | 27936 | 4-Mercaptopyridine; 4-pyridinethiol | 4556-23-4 | C5H5NS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)3-Bromo-4-methylaniline (I) was converted to the isonitrosoacetanilide (II) upon treatment with chloral hydrate and hydroxylamine. Cyclization of (II) in hot sulfuric acid produced the isatin (III) along with its 6-bromo regioisomer. Anthranilic acid (IV) was then obtained by oxidative cleavage of isatin (III). Esterification of anthranilic acid (IV) was achieved by conversion to the benzoxazinone (V) with acetic anhydride, followed by conversion to methyl anthranilate (VI) in boiling methanol. Alternatively, anthranilic acid (IV) was activated as the isatoic anhydride (VII) with triphosgene and then reacted with MeOH. Anthranilate (VI) was converted to the aminoquinazolinone (IX) upon condensation with chloroformamidine hydrochloride (VIII) at elevated temperature. Coupling of bromide (IX) with methyl 4-mercaptobenzoate (X) under Ullmann reaction conditions furnished thioether (XI). The methyl ester group was then hydrolyzed to the acid (XII) with NaOH in aqueous EtOH.
| 【1】 Webber, S.E.; et al.; Design of thymidylate synthase inhibitors using protein crystal structures: The synthesis and biological evaluation of a novel class of 5-substituted quinazolinones. J Med Chem 1993, 36, 6, 733. |
| 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) | 49517 | 3-Bromo-p-toluidine; 4-Amino-2-bromotoluene; 3-Bromo-4-methylaniline | 7745-91-7 | C7H8BrN | 详情 | 详情 |
| (II) | 49518 | N-(3-bromo-4-methylphenyl)-2-(hydroxyimino)acetamide | C9H9BrN2O2 | 详情 | 详情 | |
| (III) | 49519 | 4-bromo-5-methyl-1H-indole-2,3-dione | C9H6BrNO2 | 详情 | 详情 | |
| (IV) | 49520 | 6-amino-2-bromo-3-methylbenzoic acid | C8H8BrNO2 | 详情 | 详情 | |
| (V) | 49521 | 5-bromo-2,6-dimethyl-4H-3,1-benzoxazin-4-one | C10H8BrNO2 | 详情 | 详情 | |
| (VI) | 49522 | methyl 6-amino-2-bromo-3-methylbenzoate | C9H10BrNO2 | 详情 | 详情 | |
| (VII) | 51981 | 5-bromo-6-methyl-2H-3,1-benzoxazine-2,4(1H)-dione | C9H6BrNO3 | 详情 | 详情 | |
| (VIII) | 51982 | N''-chloroguanidine | CH4ClN3 | 详情 | 详情 | |
| (IX) | 49523 | 2-amino-5-bromo-6-methyl-4(3H)-quinazolinone | C9H8BrN3O | 详情 | 详情 | |
| (X) | 51983 | methyl 4-sulfanylbenzoate | C8H8O2S | 详情 | 详情 | |
| (XI) | 51984 | methyl 4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5-quinazolinyl)sulfanyl]benzoate | C17H15N3O3S | 详情 | 详情 | |
| (XII) | 29639 | 4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5-quinazolinyl)sulfanyl]benzoic acid | C16H13N3O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)The reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine hydrate affords the phthalazinone (V), which was activated as the imidoyl chloride (VI) by means of POCl3 and then reacted with 3-bromo-4-methylaniline (VII) in ethanol to afford the 1-anilino-phthalazine.
| 【1】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43. |
| 【2】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80. |
| 【3】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73. |
| 【4】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310. |
| 【5】 Altmann, K.-H.; Mett, H.; Wood, J.; Stover, D.R.; Frei, J.; Bold, G.; Traxler, P. (Novartis AG); Phthalazines with angiogenesis inhibiting activity. EP 0970070; WO 9835958 . |
| 【6】 Wietfeld, B.; Wood, J.M.; Manley, P.W.; Heng, R.; Frei, J.; Bold, G.; Dawson King, J. (Novartis AG); Phthalazine derivs. for treating inflammatory diseases. WO 0059509 . |
| 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) | 12576 | 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one | 87-41-2 | C8H6O2 | 详情 | 详情 |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (III) | 49917 | 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one | C14H9NO2 | 详情 | 详情 | |
| (IV) | 49918 | 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one | C14H9NO2 | 详情 | 详情 | |
| (V) | 49919 | 4-(4-pyridinylmethyl)-1(2H)-phthalazinone | C14H11N3O | 详情 | 详情 | |
| (VI) | 41367 | 1-chloro-4-(4-pyridinylmethyl)phthalazine | C14H10ClN3 | 详情 | 详情 | |
| (VII) | 49517 | 3-Bromo-p-toluidine; 4-Amino-2-bromotoluene; 3-Bromo-4-methylaniline | 7745-91-7 | C7H8BrN | 详情 | 详情 |