(2,4-diamino-6-pteridinyl)methanol -Drug Synthesis Database

【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%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

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.

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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

Extended Information