【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 |