Edatrexate, CGP-30694, 10-EDAM, -Drug Synthesis Database

【结构式】

【药物名称】Edatrexate, CGP-30694, 10-EDAM

【化学名称】10-Ethyl-10-deazaaminopterin
　　　　　　N-[4-[1-(2,4-Diamino-6-pteridinylmethyl)propyl]benzoyl]-L-glutamic acid

【CA登记号】80576-83-6

【分子式】C₂₂H₂₅N₇O₅

【分子量】467.48845

【开发单位】SRI (Originator)

【药理作用】Lung Cancer Therapy, Oncolytic Drugs, Antimetabolites, Dihydrofolate Reductase (DHFR) Inhibitors

合成路线1 合成路线2

合成路线1

A new synthesis for edatrexate has been described: The reaction of 2,4-diamino-6-(bromomethyl)pteridine (I) with tributylphosphine (II) in DMSO gives the corresponding phosphonium salt (III), which is condensed wtih 4-propionylbenzoic acid methyl ester (IV) by means of NaH in DMSO, affording 4-[1-(2,4-diaminopteridin-6-yl)-1-ethylvinyl]benzoic acid methyl ester (V). The hydrogenation of (V) with H2 and PtO2 in acetic acid gives 4-[1-(2,4-diamino-6,7-dihydropteridin-6-ylmethyl)propyl]benzoic acid methyl ester (VI), which, without isolation, is dehydrogenated with H2O2 in the same solvent yielding 4-[1-(2,4-diaminopteridin-6-ylmethyl)propyl]benzoic acid methyl ester (VII). The hydrolysis of (VII) with NaOH in DMSO - water affords the corresponding free acid (VIII), which is condensed with L-glutamic acid diethyl ester (IX) by means of isobutoxycarbonylchloride and triethylamine in DMF, giving edatrexate diethyl ester (X). Finally, this compound is hydrolyzed with NaOH in methanol.

参考文献中间体

【1】 Johnson, C.A.; Sirotnak, F.M.; Piper, J.R.; Otter, G.M.; Synthesis and antifolate evaluation of 10-ethyl-5-methyl-5,10-dideazaaminopterin and an alternative synthesis of 10-ethyl-10-deazaaminopterin (edatrexate). J Med Chem 1992, 35, 16, 3002.

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)	11006	2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine	52853-40-4	C₇H₇BrN₆	详情	详情
(III)	11007	Tributyl[(2,4-diamino-6-pteridinyl)methyl]phosphonium bromide		C₁₉H₃₄BrN₆P	详情	详情
(IV)	11008	methyl 4-propionylbenzoate		C₁₁H₁₂O₃	详情	详情
(V)	11009	methyl 4-[(E)-2-(2,4-diamino-6-pteridinyl)-1-ethylethenyl]benzoate		C₁₈H₁₈N₆O₂	详情	详情
(VI)	11010	methyl 4-[1-[(2,4-diamino-5,6,7,8-tetrahydro-6-pteridinyl)methyl]propyl]benzoate		C₁₈H₂₄N₆O₂	详情	详情
(VII)	11011	methyl 4-[1-[(2,4-diamino-6-pteridinyl)methyl]propyl]benzoate		C₁₈H₂₀N₆O₂	详情	详情
(VIII)	11012	4-[1-[(2,4-Diamino-6-pteridinyl)methyl]propyl]benzoic acid		C₁₇H₁₈N₆O₂	详情	详情
(IX)	11013	diethyl (2S)-2-aminopentanedioate		C₉H₁₇NO₄	详情	详情
(X)	11014	diethyl (2S)-2-[(4-[1-[(2,4-diamino-6-pteridinyl)methyl]propyl]benzoyl)amino]pentanedioate		C₂₆H₃₃N₇O₅	详情	详情

合成路线2

The synthesis of 10-EDAM is as follows: 3-Methoxyallyl chloride (II) is prepared in situ by treatment of 1-methoxyallene (I) with an equivalent of HCl in ether at low temperature. The dianion of p-n-propylbenzoic acid is generated in THF at 0-5 C by lithium diisopropyl amide and subsequently alkylated with (II). The resulting 4-(p-carboxyphenyl)-1-methoxy-1-hexene (III) is brominated at pH 7-8 to give the alpha-bromoaldehyde acid (IV). Condensation with tetraaminopyrimidine in aqueous AcOH and subsequent in situ oxidation of the resultant dihydropteridine affords crystalline 10-ethyl-10-deaza-4-amino-4-desoxypteroic acid (V). Coupling of (V) with diethyl L-glutamate via the mixed anhydride method using isobutyl chloroformate affords the diethyl ester of 10-EDAM (VI). Following chromatographic purification on silica gel, the diester is saponified with 1N NaOH in methoxyethanol at room temperature to yield 10-EDAM.

参考文献中间体

【1】 DeGraw, J.I.; EDATREXATE. Drugs Fut 1989, 14, 9, 849.
【2】 Hoff, S.; Brandsma, L.; Acid catalyzed ring closure of 1-methoxy or 1-(methylthio)-1-(alpha or beta-hydroxyalkyl)allenes. Recl Trav Chim Pays-Bas 1969, 88, 845.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Va)	11012	4-[1-[(2,4-Diamino-6-pteridinyl)methyl]propyl]benzoic acid		C₁₇H₁₈N₆O₂	详情	详情
(Vb)	13423	1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate	543-27-1	C₅H₉ClO₂	详情	详情
(IIa)	19518	(E)-3-chloro-1-propenyl methyl ether; (E)-3-chloro-1-methoxy-1-propene		C₄H₇ClO	详情	详情
(IIb)	19519	4-propylbenzoic acid	2438-05-3	C₁₀H₁₂O₂	详情	详情
(IVa)	19521	4-(3-bromo-1-ethyl-4-oxobutyl)benzoic acid		C₁₃H₁₅BrO₃	详情	详情
(IVb)	19522	2,4,6-triamino-5-pyrimidinylamine; 2,4,5,6-pyrimidinetetramine	1004-74-6	C₄H₈N₆	详情	详情
(Vc)	19525	diethyl 2-aminopentanedioate		C₉H₁₇NO₄	详情	详情
(I)	19517	methyl 1,2-propadienyl ether; 1-methoxyallene		C₄H₆O	详情	详情
(III)	19520	4-[(E)-1-ethyl-4-methoxy-3-butenyl]benzoate		C₁₄H₁₇O₃	详情	详情
(VI)	19526	diethyl 2-[(4-[1-[(2,4-diamino-6-pteridinyl)methyl]propyl]benzoyl)amino]pentanedioate		C₂₆H₃₃N₇O₅	详情	详情

Extended Information