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【结 构 式】

【药物名称】Nolatrexed dihydrochloride, AG-337, Thymitaq

【化学名称】2-Amino-6-methyl-5-(4-pyridylsulfanyl)quinazolin-4(3H)-one dihydrochloride

【CA登记号】147149-76-6 (free base)

【 分 子 式 】C14H14Cl2N4OS

【 分 子 量 】357.26388

【开发单位】Eximias Pharmaceutical (Orphan Drug), Agouron (Originator), Eximias Pharmaceutical (Licensee), LG Chem (Licensee)

【药理作用】Liver Cancer Therapy, Oncolytic Drugs, Solid Tumors Therapy, Antimetabolites, Thymidylate Synthase Inhibitors

合成路线1

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
Extended Information