NSC-712783(NH3 salt), NSC-633713, PT-523, Ndelta-Hemiphthaloyl-APA-Orn, -Drug Synthesis Database

【结构式】

【药物名称】NSC-712783(NH3 salt), NSC-633713, PT-523, Ndelta-Hemiphthaloyl-APA-Orn

【化学名称】Nalpha-(4-Amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine

【CA登记号】113857-87-7

【分子式】C₂₇H₂₇N₉O₆

【分子量】573.57294

【开发单位】Hudson Health (Proprietary), Dana-Farber Cancer Institute (Originator)

【药理作用】Oncolytic Drugs, Solid Tumors Therapy, Antimitotic Drugs, Dihydrofolate Reductase (DHFR) Inhibitors, Folylpolyglutamate Synthase Inhibitors

合成路线1 合成路线2

合成路线1

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

【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

2) Alternatively, N10-formyl-4-amino-4-deoxypteroic acid (VII), prepared as before, was converted to the mixed anhydride (XV) with isobutyl chloroformate and triethylamine, and subsequently condensed with the Na,O-bis(trimethylsilyl) derivative of Nd-phthaloyl-L-ornithine (XVI) to give amide (XVII). Then, hydrolysis of the formamide function and concomitant phthalimide ring opening with aqueous NaOH provided the target compound.

参考文献中间体

【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	分子式	供应商	用于合成
(VII)	20072	4-[[(2,4-diamino-6-pteridinyl)methyl](formyl)amino]benzoic acid	C₁₅H₁₃N₇O₃	详情	详情
(XV)	20080	4-[N-(2,4-Diaminopteridin-6-ylmethyl)-N-formylamino]benzoic acid isobutoxycarbonyl anhydride	C₂₀H₂₁N₇O₅	详情	详情
(XVI)	20081	trimethylsilyl (2S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(trimethylsilyl)amino]pentanoate	C₁₉H₃₀N₂O₄Si₂	详情	详情
(XVII)	20082	(2S)-2-([4-[[(2,4-diamino-6-pteridinyl)methyl](formyl)amino]benzoyl]amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoic acid	C₂₈H₂₅N₉O₆	详情	详情

Extended Information