|
【结 构 式】 
|
【分子编号】19522 【品名】2,4,6-triamino-5-pyrimidinylamine; 2,4,5,6-pyrimidinetetramine 【CA登记号】1004-74-6 |
【 分 子 式 】C4H8N6 【 分 子 量 】140.14796 【元素组成】C 34.28% H 5.75% N 59.97% |
合成路线1
该中间体在本合成路线中的序号：(IVb)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：(I)1) The condensation of 2,4,5,6-tetraaminopyrimidine sulfate (I) with dihydroxyacetone dimer (II) in the presence of cysteine and O2 furnished 2,4-diamino-6-(hydroxymethyl)pteridine (III). Subsequent reaction of (III) with dibromotriphenylphosphorane in dimethylacetamide afforded bromide (IV) which, without isolation, was condensed with 4-aminobenzoic acid (V) in the presence of BaO to give 4-amino-4-deoxypteroic acid (VI). Formylation of (VI) with acetic-formic anhydride yielded formamide (VII), and subsequent activation as the 4-nitrophenyl ester (IX) was carried out upon reaction with bis(4-nitrophenyl)carbonate (VIII). Then Nd-Boc-L-ornithine, after conversion to the corresponding Na,O-bis(trimethylsilyl) derivative (X) by treatment with ClSiMe3 and triethylamine, was condensed with active ester (IX) to furnish amide (XI). Subsequent deprotection of the Boc group of (XI) with cold trifluoroacetic acid provided (XII), which was then condensed with phthalic anhydride (XIII) in the presence of triethylamine in N-methylpyrrolidinone, yielding the hemiphthaloyl amide (XIV). Finally, the formamide function was hydrolyzed with aqueous NaOH at r.t. to provide the target compound, after chromatographic separation of some phthaloyl-hydrolyzed byproduct.
| 【1】 Rosowsky, A.; et al.; Methotrexate analogues. 26. Inhibition of dihydrofolate reductase and folypolyglutamate synthetase activity and in vitro tumor cell growth by methotrexate and aminopterin analogues containing a basic amino acid side chain. J Med Chem 1986, 29, 655. |
| 【2】 Rosowsky, A.; et al.; Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin. J Med Chem 1985, 28, 5, 660. |
| 【3】 Rosowsky, A.; et al.; Methotrexate analogues. 33. Ndelta-Acyl-Nalpha-(4-amino-4-deoxypteroyl)-L-ornithine derivatives: Synthesis and in vitro antitumor activity. J Med Chem 1988, 31, 1332-7. |
| 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) | 19522 | 2,4,6-triamino-5-pyrimidinylamine; 2,4,5,6-pyrimidinetetramine | 1004-74-6 | C4H8N6 | 详情 | 详情 |
| (II) | 20067 | 2,5-bis(hydroxymethyl)-1,4-dioxane-2,5-diol | 89727-88-8 | C6H12O6 | 详情 | 详情 |
| (III) | 20068 | (2,4-diamino-6-pteridinyl)methanol | 945-24-4 | C7H8N6O | 详情 | 详情 |
| (IV) | 20069 | 6-(bromomethyl)pyrido[3,2-d]pyrimidine-2,4-diamine; 2-amino-6-(bromomethyl)pyrido[3,2-d]pyrimidin-4-ylamine | C8H8BrN5 | 详情 | 详情 | |
| (V) | 20004 | p-aminobenzoic acid; 4-aminobenzoic acid | 150-13-0 | C7H7NO2 | 详情 | 详情 |
| (VI) | 20071 | 4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoic acid | C14H13N7O2 | 详情 | 详情 | |
| (VII) | 20072 | 4-[[(2,4-diamino-6-pteridinyl)methyl](formyl)amino]benzoic acid | C15H13N7O3 | 详情 | 详情 | |
| (VIII) | 20073 | bis(4-nitrophenyl) carbonate;bis(4-nitrophenyl) carbonate;4,4'-Dinitrodiphenyl carbonate;Carbonic acid,bis(4-nitrophenyl) ester;Di-4-nitrophenylcarbonate;Di-p-nitrophenyl carbonate;p,p'-Dinitrodiphenylcarbonate | 5070-13-3 | C13H8N2O7 | 详情 | 详情 |
| (IX) | 20074 | 4-nitrophenyl 4-[[(2,4-diamino-6-pteridinyl)methyl](formyl)amino]benzoate | C21H16N8O5 | 详情 | 详情 | |
| (X) | 20075 | trimethylsilyl (2S)-5-[(tert-butoxycarbonyl)amino]-2-[(trimethylsilyl)amino]pentanoate | C16H36N2O4Si2 | 详情 | 详情 | |
| (XI) | 20076 | (2S)-5-[(tert-butoxycarbonyl)amino]-2-([4-[[(2,4-diamino-6-pteridinyl)methyl](formyl)amino]benzoyl]amino)pentanoic acid | C25H31N9O6 | 详情 | 详情 | |
| (XII) | 20077 | (2S)-5-amino-2-([4-[[(2,4-diamino-6-pteridinyl)methyl](formyl)amino]benzoyl]amino)pentanoic acid | C20H23N9O4 | 详情 | 详情 | |
| (XIII) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (XIV) | 20079 | 2-([[(4S)-4-carboxy-4-([4-[[(2,4-diamino-6-pteridinyl)methyl](formyl)amino]benzoyl]amino)butyl]amino]carbonyl)benzoic acid | C28H27N9O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXII)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 |