【结 构 式】 |
【分子编号】20068 【品名】(2,4-diamino-6-pteridinyl)methanol 【CA登记号】945-24-4 |
【 分 子 式 】C7H8N6O 【 分 子 量 】192.18036 【元素组成】C 43.75% H 4.2% N 43.73% O 8.33% |
合成路线1
该中间体在本合成路线中的序号:(III)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2
该中间体在本合成路线中的序号:(VIII)The synthetic scheme of tritiated MX-68 ia also presented in Scheme 22540503a. Treatment of compound (I) with triphenylphosphine, followed by Wittig reaction with 4-ethylbenzoic aldehyde (II) yields an olefin (III). To improve the solubility of (III) in routine organic solvents, the amino group of compound (III) is acylated with anhydride (IV) to give a lipophilic olefin (V). The olefin moiety is next oxidized by treatment of ozone to give an aldehyde (VI). Reduction of compound (VI) with NaBT4 is performed in isopropanol to give the corresponding tritiated alcohol (VII). The alohol (VII) is deacylated to yield acyl-free pteridine (VIII). The conversion of compound (VIII) to HBr salt, followed by bromination of alcohol with dibromotriphenylphosphorane, amination with compound (IX) and alkali hydrolysis produces [9-3H]-MX-68.
【1】 Matsuoka, H.; et al.; Synthesis of tritiated N-[4-(2, 4-diaminopteridine-6-methyl)-3,4-dihydro-2H-1, 4-benzothiazine-7-carbonyl]-L-homo glutamic acid (MX-68). J Label Compd Radiopharm 1997, 39, 5, 363. |
【2】 Mihara, M.; Matsuoka, H.; The synthesis and biological evaluation of new methotrexate derivatives in rheumatoid arthritis. Drugs Fut 1998, 23, 9, 1015. |
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 |
(II) | 25045 | 4-ethylbenzaldehyde | 4748-78-1 | C9H10O | 详情 | 详情 |
(III) | 25046 | 6-(4-ethylstyryl)-2,4-pteridinediamine | C16H16N6 | 详情 | 详情 | |
(IV) | 25047 | butyric anhydride | 106-31-0 | C8H14O3 | 详情 | 详情 |
(V) | 25048 | N-[2-(butyrylamino)-6-(4-ethylstyryl)-4-pteridinyl]butanamide | C24H28N6O2 | 详情 | 详情 | |
(VI) | 25049 | N-[2-(butyrylamino)-6-formyl-4-pteridinyl]butanamide | C15H18N6O3 | 详情 | 详情 | |
(VII) | 25050 | N-[2-(butyrylamino)-6-(hydroxymethyl)-4-pteridinyl]butanamide | C15H20N6O3 | 详情 | 详情 | |
(VIII) | 20068 | (2,4-diamino-6-pteridinyl)methanol | 945-24-4 | C7H8N6O | 详情 | 详情 |
(IX) | 19823 | dimethyl (2S)-2-[(3,4-dihydro-2H-1,4-benzothiazin-7-ylcarbonyl)amino]hexanedioate | C17H22N2O5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(V)The first synthetic method started from 2,4-diamino-6-(hydroxymethyl)-pteridine (V). Conversion of (V) into the corresponding bromide (VI) was achieved by treatment with triphenylphosphine dibromide. Ylide (VII) was then prepared by reaction of bromide (VI) with triphenylphosphine, followed by deprotonation using potassium tert-butoxide. Wittig reaction between ylide (VII) and aldehyde (IV) produced the olefin (VIII), assumed to be a mixture of geometric isomers. Catalytic hydrogenation of olefin (VIII), followed by reoxidation of the pteridine ring with H2O2, yielded (IX). Finally, hydrolysis of (IX) with NaOH gave rise to the title compound.
【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 |
---|---|---|---|---|---|---|
(VIIIa) | 42878 | methyl (2S)-2-([4-[(E)-2-(2,4-diamino-6-pteridinyl)ethenyl]benzoyl]amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C29H26N8O5 | 详情 | 详情 | |
(VIIIb) | 42879 | methyl (2S)-2-([4-[(Z)-2-(2,4-diamino-6-pteridinyl)ethenyl]benzoyl]amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C29H26N8O5 | 详情 | 详情 | |
(IV) | 42876 | methyl (2S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(4-formylbenzoyl)amino]pentanoate | C22H20N2O6 | 详情 | 详情 | |
(V) | 20068 | (2,4-diamino-6-pteridinyl)methanol | 945-24-4 | C7H8N6O | 详情 | 详情 |
(VI) | 11006 | 2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine | 52853-40-4 | C7H7BrN6 | 详情 | 详情 |
(VII) | 42877 | triphenyl-N-[2-[(triphenylphosphoranylidene)amino]-6-[(triphenylphosphoranylidene)methyl]-4-pteridinyl]phosphine imide; 2,4-bis[(triphenylphosphoranylidene)amino]-6-[(triphenylphosphoranylidene)methyl]pteridine | C61H47N6P3 | 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 |