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【结 构 式】 
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【分子编号】29639 【品名】4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5-quinazolinyl)sulfanyl]benzoic acid 【CA登记号】 |
【 分 子 式 】C16H13N3O3S 【 分 子 量 】327.36364 【元素组成】C 58.7% H 4% N 12.84% O 14.66% S 9.8% |
合成路线1
该中间体在本合成路线中的序号：(VI)Strecker condensation of 3-hydroxybenzaldehyde (I) with trimethylsilyl cyanide in the presence of (S)-2-phenylglycine (II) yielded the chiral aminonitrile (III) as the major diastereoisomer. Oxidative cleavage of the chiral auxiliary of (III) with lead tetraacetate, followed by acid hydrolysis of the nitrile group provided the (S)-amino acid (IV), which was esterified with MeOH and Me3SiCl. The resulting aminoester (V) was coupled with carboxylic acid (VI) using diphenylphosphoryl azide to form amide ester (VII). Finally, saponification of the methyl ester of (VIII) afforded the target carboxylic acid.
| 【1】 Baek, D.-J.; Park, Y.-K.; Heo, H.I.; Lee, M.; Yang, Z.; Choi, M.; Synthesis of 5-substituted quinazolinone derivatives and their inhibitory activity in vitro. Bioorg Med Chem Lett 1998, 8, 23, 3287. |
| 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) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (II) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (III) | 29636 | (2S)-2-(3-hydroxyphenyl)-2-[[(1R)-2-hydroxy-1-phenylethyl]amino]ethanenitrile | C16H16N2O2 | 详情 | 详情 | |
| (IV) | 29637 | (2S)-2-amino-2-(3-hydroxyphenyl)ethanoic acid | C8H9NO3 | 详情 | 详情 | |
| (V) | 29638 | methyl (2S)-2-amino-2-(3-hydroxyphenyl)ethanoate | C9H11NO3 | 详情 | 详情 | |
| (VI) | 29639 | 4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5-quinazolinyl)sulfanyl]benzoic acid | C16H13N3O3S | 详情 | 详情 | |
| (VII) | 29640 | methyl (2S)-2-([4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5-quinazolinyl)sulfanyl]benzoyl]amino)-2-(3-hydroxyphenyl)ethanoate | C25H22N4O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Strecker condensation of 3-cyanobenzaldehyde (I) with trimethylsilyl cyanide in the presence of (S)-2-phenylglycine (II) yielded the chiral aminonitrile (III) as the major diastereoisomer. Oxidative cleavage of the chiral auxiliary of (III) with lead tetraacetate, followed by acid hydrolysis of the nitrile groups provided the (S)-amino acid (IV), which was esterified with MeOH and Me3SiCl. The resulting aminoester (V) was coupled with carboxylic acid (VI) using diphenylphosphoryl azide to form amide ester (VII). Finally, saponification of both methyl esters of (VII) afforded the target dicarboxylate salt.
| 【1】 Baek, D.-J.; Park, Y.-K.; Heo, H.I.; Lee, M.; Yang, Z.; Choi, M.; Synthesis of 5-substituted quinazolinone derivatives and their inhibitory activity in vitro. Bioorg Med Chem Lett 1998, 8, 23, 3287. |
| 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) | 13245 | 3-Formylbenzonitrile; 3-Cyanobenzaldehyde | 24964-64-5 | C8H5NO | 详情 | 详情 |
| (II) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (III) | 29641 | 3-((S)-cyano[[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)benzonitrile | C17H15N3O | 详情 | 详情 | |
| (IV) | 29642 | 3-[(S)-amino(carboxy)methyl]benzoic acid | C9H9NO4 | 详情 | 详情 | |
| (V) | 29643 | methyl 3-[(1S)-1-amino-2-methoxy-2-oxoethyl]benzoate | C11H13NO4 | 详情 | 详情 | |
| (VI) | 29639 | 4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5-quinazolinyl)sulfanyl]benzoic acid | C16H13N3O3S | 详情 | 详情 | |
| (VII) | 29644 | methyl 3-[(1S)-1-([4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5-quinazolinyl)sulfanyl]benzoyl]amino)-2-methoxy-2-oxoethyl]benzoate | C27H24N4O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)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 |