-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-[4-[2-(2-Amino-4-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid

【CA登记号】

【分子式】C₂₂H₂₅N₅O₅

【分子量】439.47505

【开发单位】Duquesne University (Originator), Tufts University (Originator)

【药理作用】ONCOLYTIC DRUGS, Dihydrofolate Reductase (DHFR) Inhibitors, Thymidylate Synthase Inhibitors

合成路线1 合成路线2

合成路线1

2-Pivaloylamino-pyrrolo[2,3-d]pyrimidine-4-one (I) is chlorinated to (II) in refluxing POCl3. Subsequent, Stille coupling of (II) with tributyl vinyltin gives the vinyl pyrrolopyrimidine (III), which is further reduced to the corresponding ethyl derivative (IV) by catalytic hydrogenation over Pd/C. Regioselective iodination of (IV) by means of N-iodosuccinimide provides (V). Aryl iodide (V) is then subjected to palladium-catalyzed cross-coupling with trimethylsilylacetylene (VI), leading to the silylethynyl adduct (VII). Desilylation of (VII) employing tetrabutylammonium fluoride furnishes intermediate (VIII).

参考文献中间体

【1】 Gangjee, A.; Yu, J.; Kisliuk, R.L.; Haile, W.H.; Sobrero, G.; McGuire, J.J.; Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl]-L-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and. J Med Chem 2003, 46, 4, 591.

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)	14794	2,2-dimethyl-N-(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)propanamide		C₁₁H₁₄N₄O₂	详情	详情
(II)	63357	N-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide		C₁₁H₁₃ClN₄O	详情	详情
(III)	63358	N-(4-ethenyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide		C₁₃H₁₆N₄O	详情	详情
(IV)	63359	N-(4-ethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide		C₁₃H₁₈N₄O	详情	详情
(V)	63360	N-(4-ethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide		C₁₃H₁₇IN₄O	详情	详情
(VI)	23897	ethynyl(trimethyl)silane；trimethylsilyl acetylene	1066-54-2	C₅H₁₀Si	详情	详情
(VII)	63361	N-{4-ethyl-5-[2-(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-2,2-dimethylpropanamide		C₁₈H₂₆N₄OSi	详情	详情
(VIII)	63362	N-(4-ethyl-5-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide		C₁₅H₁₈N₄O	详情	详情

合成路线2

Coupling of acetylene (VIII) with diethyl N-(4-iodobenzoyl)-L-glutamate (IX) gives rise to the disubstituted acetylene (X). This is then hydrogenated to (XI) in the presence of Pd/C. Finally, hydrolysis of (XI) under alkaline conditions leads to the title compound.

参考文献中间体

【1】 Gangjee, A.; Yu, J.; Kisliuk, R.L.; Haile, W.H.; Sobrero, G.; McGuire, J.J.; Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl]-L-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and. J Med Chem 2003, 46, 4, 591.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	63362	N-(4-ethyl-5-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide	C₁₅H₁₈N₄O	详情	详情
(IX)	14283	diethyl (2S)-2-[(4-iodobenzoyl)amino]pentanedioate	C₁₆H₂₀INO₅	详情	详情
(X)	63363	diethyl 2-({[4-(2-{2-[(2,2-dimethylpropanoyl)amino]-4-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)phenyl]carbonyl}amino)pentanedioate	C₃₁H₃₇N₅O₆	详情	详情
(XI)	63364	diethyl 2-({[4-(2-{2-[(2,2-dimethylpropanoyl)amino]-4-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}ethyl)phenyl]carbonyl}amino)pentanedioate	C₃₁H₄₁N₅O₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)