【结 构 式】 |
【分子编号】42875 【品名】methyl (2S)-2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate 【CA登记号】 |
【 分 子 式 】C14H16N2O4 【 分 子 量 】276.29212 【元素组成】C 60.86% H 5.84% N 10.14% O 23.16% |
合成路线1
该中间体在本合成路线中的序号:(III)The common intermediate (IV) was obtained by coupling of 4-formylbenzoic acid (I) with methyl 2-L-amino-5-phthalimidopentanoate.HCl (III) via the mixed anhydride (II).
【1】 Rosowsky, A.; Vaidya, C.M.; Wright, J.E.; Forsch, R.A.; Bader, H.; Analogues of the potent nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: Synthesis and in vitro antitumor activity. J Med Chem 2000, 43, 8, 1620. |
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) | 18922 | 4-formylbenzoic acid | 619-66-9 | C8H6O3 | 详情 | 详情 |
(II) | 42874 | C13H14O5 | 详情 | 详情 | ||
(III) | 42875 | methyl (2S)-2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C14H16N2O4 | 详情 | 详情 | |
(IV) | 42876 | methyl (2S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(4-formylbenzoyl)amino]pentanoate | C22H20N2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(III)In the third synthetic route, 3-methoxy-1-propyne (XVI) was isomerized to 1-methoxyallene (XVII) by means of potassium tert-butoxide and then treated with HCl to give 1-chloro-4-methoxy-2-butene (XVIII). Alkylation of the dilithio derivative of p-toluic acid (XIX) with chloride (XVIII) yielded (XX). Bromination of the enol ether (XX), followed by acid hydrolysis furnished bromo aldehyde (XXI). This was cyclized with tetraaminopyrimidine (XXII), affording the dihydropteridine (XXIII), which was subsequently dehydrogenated to pteridine (XXIV) employing KI3. The carboxylic acid group of (XXIV) was activated as the mixed anhydride (XXV) with isobutyl chloroformate and then coupled to aminoester (III), yielding amide (IX).
【1】 Rosowsky, A.; Vaidya, C.M.; Wright, J.E.; Forsch, R.A.; Bader, H.; Analogues of the potent nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: Synthesis and in vitro antitumor activity. J Med Chem 2000, 43, 8, 1620. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(III) | 42875 | methyl (2S)-2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C14H16N2O4 | 详情 | 详情 | |
(IX) | 42880 | methyl (2S)-2-([4-[2-(2,4-diamino-6-pteridinyl)ethyl]benzoyl]amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C29H28N8O5 | 详情 | 详情 | |
(XVI) | 42888 | 3-methoxy-1-propyne; methyl 2-propynyl ether | 627-41-8 | C4H6O | 详情 | 详情 |
(XVII) | 19517 | methyl 1,2-propadienyl ether; 1-methoxyallene | C4H6O | 详情 | 详情 | |
(XVIII) | 19518 | (E)-3-chloro-1-propenyl methyl ether; (E)-3-chloro-1-methoxy-1-propene | C4H7ClO | 详情 | 详情 | |
(XIX) | 42889 | 4-toluic acid; 4-methylbenzoic acid | 99-94-5 | C8H8O2 | 详情 | 详情 |
(XX) | 42890 | 4-[(E)-4-methoxy-3-butenyl]benzoic acid | C12H14O3 | 详情 | 详情 | |
(XXI) | 42891 | 4-(3-bromo-4-oxobutyl)benzoic acid | C11H11BrO3 | 详情 | 详情 | |
(XXII) | 19522 | 2,4,6-triamino-5-pyrimidinylamine; 2,4,5,6-pyrimidinetetramine | 1004-74-6 | C4H8N6 | 详情 | 详情 |
(XXIII) | 42892 | 4-[2-(2,4-diamino-7,8-dihydro-6-pteridinyl)ethyl]benzoic acid | C15H16N6O2 | 详情 | 详情 | |
(XXIV) | 42893 | 4-[2-(2,4-diamino-6-pteridinyl)ethyl]benzoic acid | C15H14N6O2 | 详情 | 详情 | |
(XXV) | 42894 | C20H22N6O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(V)Condensation between phthaloyl ornithine methyl ester (V) and 4-iodobenzoic acid (VI), via activation with isobutyl chloroformate, furnishes the iodobenzamide (VII). Subsequent coupling of iodo amide (VII) with the ethynyl quinazoline (IV) employing Pd(PPh3)4 and CuI leads to the disubstituted acetylene (VIII). Catalytic hydrogenation of the triple bond in the presence of Pd/C affords (IX). Then, basic hydrolysis of phthalimido ester (IX) by means of Ba(OH)2 produces the target compound.
【1】 Vaidya, C.M.; Wright, J.E.; Rosowsky, A.; Synthesis and in vitro antitumor activity of new deaza analogues of the nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Nalpha-hemiphtaloyl-L-ornithine (PT523). J Med Chem 2002, 45, 8, 1690. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IV) | 65104 | 2-amino-6-ethynyl-4-quinazolinylamine; 6-ethynyl-2,4-quinazolinediamine | C10H8N4 | 详情 | 详情 | |
(V) | 42875 | methyl (2S)-2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C14H16N2O4 | 详情 | 详情 | |
(VI) | 53872 | 4-iodobenzoic acid | 619-58-9 | C7H5IO2 | 详情 | 详情 |
(VII) | 65108 | methyl (2S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(4-iodobenzoyl)amino]pentanoate | C21H19IN2O5 | 详情 | 详情 | |
(VIII) | 65107 | methyl (2S)-2-({4-[2-(2,4-diamino-6-quinazolinyl)ethynyl]benzoyl}amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C31H26N6O5 | 详情 | 详情 | |
(IX) | 65106 | methyl (2S)-2-({4-[2-(2,4-diamino-6-quinazolinyl)ethyl]benzoyl}amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C31H30N6O5 | 详情 | 详情 |