-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】2,4-Diamino-6-[N-(3,4,5-trimethoxyphenyl)-N-methylaminomethyl]pyrido[2,3-d]pyrimidine

【CA登记号】

【分子式】C₁₈H₂₂N₆O₃

【分子量】370.41444

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

【药理作用】AIDS Medicines, ANTIINFECTIVE THERAPY, Treatment of Opportunistic Infections, Dihydrofolate Reductase (DHFR) Inhibitors

合成路线1 合成路线2

合成路线1

The title compound has been prepared by two synthetic procedures. Condensation of 2-aminopyridine-3,5-dicarbonitrile (I) with guanidine (II) in refluxing EtOH produced the pyridopyrimidine (III). Subsequent reductive condensation of (III) with 3,4,5-trimethoxyaniline (IV) by hydrogenation over Raney Nickel provided the (arylamino)methyl derivative (V). Final reductive alkylation of (V) by means of formaldehyde and sodium cyanoborohydride then gave the target methylated amine.

参考文献中间体

【1】 Gangjee, A. (Duquesne University); Derivs. of pyrido [2,3-d] and [3,2-d] pyrimidine and methods of using these derivs.. US 5508281 .

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)	31544	2-amino-3,5-pyridinedicarbonitrile		C₇H₄N₄	详情	详情
(II)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(III)	14269	2,4-Diaminopyrido[2,3-d]pyrimidine-6-carbonitrile		C₈H₆N₆	详情	详情
(IV)	31545	3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine；3,4,5-Trimethoxybenzenamine；[3,4,5-Tris(methyloxy)phenyl]amine	24313-88-0	C₉H₁₃NO₃	详情	详情
(V)	31546	2-amino-6-[(3,4,5-trimethoxyanilino)methyl]pyrido[2,3-d]pyrimidin-4-ylamine; 6-[(3,4,5-trimethoxyanilino)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine		C₁₇H₂₀N₆O₃	详情	详情

合成路线2

In an alternative synthesis, 2,4,6-triaminopyrimidine (VI) was condensed with bromomalonaldehyde (VII) under acidic conditions to give pyridopyrimidine (VIII), which was protected with pivaloyl anhydride in pyridine, yielding the bispivaloylamide (IX). Palladium-catalyzed Heck coupling of (IX) with styrene (X) afforded (XI). Subsequent ozonolysis of the styryl derivative (XI), followed by reductive workup with dimethyl sulfide gave aldehyde (XII). Reduction of (XII) to the corresponding alcohol with NaBH4, followed by bromination with PPh3 and Br2 provided bromide (XIII). The N-methyl aniline (XIV) was synthesized by direct alkylation of 3,4,5-trimethoxyaniline (IV) with methyl iodide. Nucleophilic displacement of the bromide (XIII) with aniline (XIV) afforded the tertiary amine (XV). The pivaloyl protecting groups of (XV) were finally removed by treatment with methanolic NaOMe.

参考文献中间体

【1】 Gangjee, A.; et al.; Synthesis and dihydrofolate reductase inhibitory activities of 2,4-diamino-5-deaza and 2,4-diamino-5, 10-dideaza lipophilic antifolates. J Med Chem 1997, 40, 4, 470.

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)	31545	3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine；3,4,5-Trimethoxybenzenamine；[3,4,5-Tris(methyloxy)phenyl]amine	24313-88-0	C₉H₁₃NO₃	详情	详情
(VI)	28977	2,6-diamino-4-pyrimidinylamine	1004-38-2	C₄H₇N₅	详情	详情
(VII)	14278	2-Bromomalonaldehyde		C₃H₃BrO₂	详情	详情
(VIII)	31547	6-bromopyrido[2,3-d]pyrimidine-2,4-diamine; 2-amino-6-bromopyrido[2,3-d]pyrimidin-4-ylamine		C₇H₆BrN₅	详情	详情
(IX)	31548	N-[6-bromo-2-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide		C₁₇H₂₂BrN₅O₂	详情	详情
(X)	19649	1-vinylbenzene	100-42-5	C₈H₈	详情	详情
(XI)	31549	N-[2-[(2,2-dimethylpropanoyl)amino]-6-[(E)-2-phenylethenyl]pyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide		C₂₅H₂₉N₅O₂	详情	详情
(XII)	31550	N-[2-[(2,2-dimethylpropanoyl)amino]-6-formylpyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide		C₁₈H₂₃N₅O₃	详情	详情
(XIII)	31554	3-bromo-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one		C₁₁H₁₁BrO	详情	详情
(XIV)	31552	3,4,5-trimethoxy-N-methylaniline; N-methyl-N-(3,4,5-trimethoxyphenyl)amine		C₁₀H₁₅NO₃	详情	详情
(XV)	31553	N-(2-[(2,2-dimethylpropanoyl)amino]-6-[[3,4,5-trimethoxy(methyl)anilino]methyl]pyrido[2,3-d]pyrimidin-4-yl)-2,2-dimethylpropanamide		C₂₈H₃₈N₆O₅	详情	详情

Extended Information