2,5-bis(hydroxymethyl)-1,4-dioxane-2,5-diol -Drug Synthesis Database

【结构式】

【分子编号】20067

【品名】2,5-bis(hydroxymethyl)-1,4-dioxane-2,5-diol

【CA登记号】89727-88-8

【分子式】C₆H₁₂O₆

【分子量】180.15768

【元素组成】C 40% H 6.71% O 53.28%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

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：(II)

The condensation of piperonylamine (I) with dihydroxyacetone dimer (II) in the presence of potassium thiocyanate produced the mercaptoimidazole (III), which was desulfurized upon treatment with nitric acid and sodium nitrite. The resulting (hydroxymethyl)imidazole (IV) was then converted to the corresponding chloride (V) employing thionyl chloride in chloroform.

参考文献中间体

合成目标

【1】 Lee, J.; Lee, H.; Shin, Y.; et al.; Synthesis and structure-activity relationships of 1-(1(3)H-imidazole-5(4)-yl)-methylpyrroles as farnesyl protein transferase inhibitors (FTPI). 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 210.
【2】 Lee, J.H.; Yoo, J.K.; Koh, J.S.; Choi, T.S.; Shin, Y.S.; Kim, K.H.; Jung, W.H.; Kim, J.H.; Lee, S.H.; Ahn, I.A.; Ro, S.G.; Lee, H.I.; Kim, H.S.; Chung, H.H.; Jeong, S.W.; Kwak, T.H. (LG Chem Ltd.); Imidazole derivs. having an inhibitory activity for farnesyl transferase and process for preparation thereof. WO 9928315 .

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)	33669	1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine	2620-50-0	C₈H₉NO₂	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)	33670	[1-(1,3-benzodioxol-5-ylmethyl)-2-sulfanyl-1H-imidazol-5-yl]methanol		C₁₂H₁₂N₂O₃S	详情	详情
(IV)	33671	[1-(1,3-benzodioxol-5-ylmethyl)-1H-imidazol-5-yl]methanol		C₁₂H₁₂N₂O₃	详情	详情
(V)	33672	1-(1,3-benzodioxol-5-ylmethyl)-5-(chloromethyl)-1H-imidazole		C₁₂H₁₁ClN₂O₂	详情	详情

Extended Information