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【结 构 式】 
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【药物名称】 【化学名称】N-[4-[1(R,S)-(2,4-Diaminofuro[2,3-d]pyrimidin-5-ylmethyl)propyl]benzoyl]-L-glutamic acid 【CA登记号】 【 分 子 式 】C22H25N5O6 【 分 子 量 】455.47445 |
【开发单位】Duquesne University (Originator), Roswell Park Cancer Institute (Originator), Tufts University (Originator) 【药理作用】ONCOLYTIC DRUGS, Dihydrofolate Reductase (DHFR) Inhibitors |
合成路线1
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.
| 【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 |
合成路线2
Condensation of the mixed anhydride (XI) with diethyl L-glutamate (XII) produces amide (XIII). The ethyl ester groups of (XIII) are finally hydrolyzed by means of NaOH to provide the title compound.
| 【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. |