【结 构 式】 |
【分子编号】42880 【品名】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 【CA登记号】 |
【 分 子 式 】C29H28N8O5 【 分 子 量 】568.59224 【元素组成】C 61.26% H 4.96% N 19.71% O 14.07% |
合成路线1
该中间体在本合成路线中的序号:(IX)The first synthetic method started from 2,4-diamino-6-(hydroxymethyl)-pteridine (V). Conversion of (V) into the corresponding bromide (VI) was achieved by treatment with triphenylphosphine dibromide. Ylide (VII) was then prepared by reaction of bromide (VI) with triphenylphosphine, followed by deprotonation using potassium tert-butoxide. Wittig reaction between ylide (VII) and aldehyde (IV) produced the olefin (VIII), assumed to be a mixture of geometric isomers. Catalytic hydrogenation of olefin (VIII), followed by reoxidation of the pteridine ring with H2O2, yielded (IX). Finally, hydrolysis of (IX) with NaOH gave rise to the title compound.
【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 |
---|---|---|---|---|---|---|
(VIIIa) | 42878 | methyl (2S)-2-([4-[(E)-2-(2,4-diamino-6-pteridinyl)ethenyl]benzoyl]amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C29H26N8O5 | 详情 | 详情 | |
(VIIIb) | 42879 | methyl (2S)-2-([4-[(Z)-2-(2,4-diamino-6-pteridinyl)ethenyl]benzoyl]amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C29H26N8O5 | 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 | |
(V) | 20068 | (2,4-diamino-6-pteridinyl)methanol | 945-24-4 | C7H8N6O | 详情 | 详情 |
(VI) | 11006 | 2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine | 52853-40-4 | C7H7BrN6 | 详情 | 详情 |
(VII) | 42877 | triphenyl-N-[2-[(triphenylphosphoranylidene)amino]-6-[(triphenylphosphoranylidene)methyl]-4-pteridinyl]phosphine imide; 2,4-bis[(triphenylphosphoranylidene)amino]-6-[(triphenylphosphoranylidene)methyl]pteridine | C61H47N6P3 | 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 |
合成路线2
该中间体在本合成路线中的序号:(IX)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 |