methyl 4-propionylbenzoate -Drug Synthesis Database

【结构式】

【分子编号】11008

【品名】methyl 4-propionylbenzoate

【CA登记号】

【分子式】C₁₁H₁₂O₃

【分子量】192.21448

【元素组成】C 68.74% H 6.29% O 24.97%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

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

合成目标

【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

该中间体在本合成路线中的序号：(VII)

Condensation of 2,6-diaminopyrimidin-4-one (I) with 1,3-dichloroacetone (II) affords the furopyrimidine (III). Subsequent reaction of (III) with tributylphosphine provides the phosphonium salt (IV). Treatment of 4-hydroxypropiophenone (V) with trifluoromethanesulfonic anhydride leads to the aryl triflate (VI). This is then subjected to palladium-catalyzed carbonylation under modified Gerlach's conditions to furnish ethyl 4-propionylbenzoate (VII). Wittig condensation between the phosphorane derived from (IV) and keto ester (VII) produces olefin (VIIIa-b) as a mixture of Z/E isomers. Subsequent hydrogenation of (VIIIa-b) over Pd/C gives (IX). The methyl ester group of (IX) is hydrolyzed under alkaline conditions to afford acid (X), which is then activated as the mixed anhydride (XI) with isobutyl chloroformate and triethylamine.

参考文献中间体

合成目标

【1】 Mcguire, J.J.; Zeng, Y.; Gangjee, A.; Kisliuk, R.L.; Synthesis of N-[4-[ethyl-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid as an antifolate. J Med Chem 2002, 45, 9, 1942.

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)	58984	methyl 4-[(Z)-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)-1-ethylethenyl]benzoate		C₁₈H₁₈N₄O₃	详情	详情
(VIIIb)	58985	methyl 4-[(E)-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)-1-ethylethenyl]benzoate		C₁₈H₁₈N₄O₃	详情	详情
(I)	14277	2,6-Diamino-4(3H)-pyrimidinone		C₄H₆N₄O	详情	详情
(II)	63907	1,3-dichloroacetone		C₃H₄Cl₂O	详情	详情
(III)	18884	5-(chloromethyl)furo[2,3-d]pyrimidine-2,4-diamine; 2-amino-5-(chloromethyl)furo[2,3-d]pyrimidin-4-ylamine		C₇H₇ClN₄O	详情	详情
(IV)	58981	tributyl[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]phosphonium chloride		C₁₉H₃₄ClN₄OP	详情	详情
(V)	58982	4'-Hydroxypropiophenone; 4-Hydroxypropiophenone; Ethyl 4-Hydroxyphenyl ktone; p-Hydroxypropiophenone; Paroxypropione	70-70-2	C₉H₁₀O₂	详情	详情
(VI)	58983	4-propionylphenyl trifluoromethanesulfonate		C₁₀H₉F₃O₄S	详情	详情
(VII)	11008	methyl 4-propionylbenzoate		C₁₁H₁₂O₃	详情	详情
(IX)	58988	methyl 4-{1-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]propyl}benzoate		C₁₈H₂₀N₄O₃	详情	详情
(X)	58986	4-{1-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]propyl}benzoic acid		C₁₇H₁₈N₄O₃	详情	详情
(XI)	58987			C₂₂H₂₆N₄O₅	详情	详情

Extended Information