2-amino-5-bromo-6-methyl-4(3H)-quinazolinone -Drug Synthesis Database

【结构式】

【分子编号】49523

【品名】2-amino-5-bromo-6-methyl-4(3H)-quinazolinone

【CA登记号】

【分子式】C₉H₈BrN₃O

【分子量】254.08614

【元素组成】C 42.54% H 3.17% Br 31.45% N 16.54% O 6.3%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

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.

参考文献中间体

合成目标

【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：(IX)

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.

参考文献中间体

合成目标

【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

Extended Information