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【结 构 式】 
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【分子编号】19517 【品名】methyl 1,2-propadienyl ether; 1-methoxyallene 【CA登记号】 |
【 分 子 式 】C4H6O 【 分 子 量 】70.09104 【元素组成】C 68.55% H 8.63% O 22.83% |
合成路线1
该中间体在本合成路线中的序号：(I)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.
| 【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 |
合成路线2
该中间体在本合成路线中的序号：(XVII)In the third synthetic route, 3-methoxy-1-propyne (XVI) was isomerized to 1-methoxyallene (XVII) by means of potassium tert-butoxide and then treated with HCl to give 1-chloro-4-methoxy-2-butene (XVIII). Alkylation of the dilithio derivative of p-toluic acid (XIX) with chloride (XVIII) yielded (XX). Bromination of the enol ether (XX), followed by acid hydrolysis furnished bromo aldehyde (XXI). This was cyclized with tetraaminopyrimidine (XXII), affording the dihydropteridine (XXIII), which was subsequently dehydrogenated to pteridine (XXIV) employing KI3. The carboxylic acid group of (XXIV) was activated as the mixed anhydride (XXV) with isobutyl chloroformate and then coupled to aminoester (III), yielding amide (IX).
| 【1】 Rosowsky, A.; Vaidya, C.M.; Wright, J.E.; Forsch, R.A.; Bader, H.; Analogues of the potent nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: Synthesis and in vitro antitumor activity. J Med Chem 2000, 43, 8, 1620. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 42875 | methyl (2S)-2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C14H16N2O4 | 详情 | 详情 | |
| (IX) | 42880 | methyl (2S)-2-([4-[2-(2,4-diamino-6-pteridinyl)ethyl]benzoyl]amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C29H28N8O5 | 详情 | 详情 | |
| (XVI) | 42888 | 3-methoxy-1-propyne; methyl 2-propynyl ether | 627-41-8 | C4H6O | 详情 | 详情 |
| (XVII) | 19517 | methyl 1,2-propadienyl ether; 1-methoxyallene | C4H6O | 详情 | 详情 | |
| (XVIII) | 19518 | (E)-3-chloro-1-propenyl methyl ether; (E)-3-chloro-1-methoxy-1-propene | C4H7ClO | 详情 | 详情 | |
| (XIX) | 42889 | 4-toluic acid; 4-methylbenzoic acid | 99-94-5 | C8H8O2 | 详情 | 详情 |
| (XX) | 42890 | 4-[(E)-4-methoxy-3-butenyl]benzoic acid | C12H14O3 | 详情 | 详情 | |
| (XXI) | 42891 | 4-(3-bromo-4-oxobutyl)benzoic acid | C11H11BrO3 | 详情 | 详情 | |
| (XXII) | 19522 | 2,4,6-triamino-5-pyrimidinylamine; 2,4,5,6-pyrimidinetetramine | 1004-74-6 | C4H8N6 | 详情 | 详情 |
| (XXIII) | 42892 | 4-[2-(2,4-diamino-7,8-dihydro-6-pteridinyl)ethyl]benzoic acid | C15H16N6O2 | 详情 | 详情 | |
| (XXIV) | 42893 | 4-[2-(2,4-diamino-6-pteridinyl)ethyl]benzoic acid | C15H14N6O2 | 详情 | 详情 | |
| (XXV) | 42894 | C20H22N6O4 | 详情 | 详情 |