3,3-dimethyldihydro-2,5-furandione -Drug Synthesis Database

【结构式】

【分子编号】29295

【品名】3,3-dimethyldihydro-2,5-furandione

【CA登记号】17347-61-4

【分子式】C₆H₈O₃

【分子量】128.12772

【元素组成】C 56.25% H 6.29% O 37.46%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(II)

Betulinic acid (I) was extracted from the dried leaves of Syzygium claviforum. Acylation of (I) with 2,2-dimethylsuccinic anhydride (II) in the presence of DMAP in refluxing pyridine furnished the target 3’,3’-dimethylsuccinyl betulinic acid along with minor amounts of the undesired 2’,2’-dimethyl regioisomer (III), which were separated by means of preparative HPLC.

参考文献中间体

合成目标

【3】 Kashiwada, Y.; Wang, H.K.; Nagao, T.; Kitanaka, S.; Yasuda, I.; Fujioka, T.; Yamagishi, T.; Cosentino, L.M.; Kozuka, M.; Okabe, H.; Ikeshiro, Y.; Hu, C.Q.; Yeh, E.; Lee, K.H.; Anti-AIDS agents.30. Anti-HIV activity of oleanolic acid, pomolic acid, and structurally related triterpenoids. J Nat Prod 1998, 61, 9, 1090.
【1】 Kashiwada, Y.; et al.; Betulinic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents. J Med Chem 1996, 39, 5, 1016.
【2】 Hashimoto, F.; et al.; Anti-AIDS agents - XXVII. Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives. Bioorg Med Chem 1997, 5, 12, 2133.
【4】 Lee, K.-H.; Kashiwada, Y.; Hashimoto, F.; Cosentino, L.M.; Manak, M. (Biotech Research Laboratories; University of North Carolina); Betulinic acid derivs. and uses thereof. US 5679828; WO 9639033 .

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)	51630	(1R,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-3aH-cyclopenta[a]chrysene-3a-carboxylic acid		C₃₀H₄₈O₃	详情	详情
(II)	29295	3,3-dimethyldihydro-2,5-furandione	17347-61-4	C₆H₈O₃	详情	详情
(III)	51631	(1R,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-[(3-carboxy-2,2-dimethylpropanoyl)oxy]-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-3aH-cyclopenta[a]chrysene-3a-carboxylic acid		C₃₆H₅₆O₆	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 amine (I) with 2,2-dimethylsuccinic anhydride (II) afforded amide (III). This was then coupled with azidothymidine (IV) using DCC and DMAP to furnish the title compound.

参考文献中间体

合成目标

【1】 Kiso, Y.; Kimura, T.; Akaji, K.; Matsuda, T.; Matsumoto, H.; Hamawaki, T.; A new class of potent anti-HIV agents, conjugates of HIV protease inhibitors containing carboxylic acid with reverse transcriptase inhibitor. Symp Med Chem 1998, Abst 1-P-17.

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)	29294	(4R)-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-N-(tert-butyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide		C₂₀H₃₁N₃O₃S	详情	详情
(II)	29295	3,3-dimethyldihydro-2,5-furandione	17347-61-4	C₆H₈O₃	详情	详情
(III)	29296	4-[((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropyl)amino]-2,2-dimethyl-4-oxobutyric acid		C₂₆H₃₉N₃O₆S	详情	详情
(IV)	25317	1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione	101703-35-9	C₁₀H₁₃N₅O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The title compound was prepared following two alternative synthetic sequences: Condensation of the known dipeptide amide (I) with 2,2-dimethylsuccinic anhydride (II) in the presence of DMAP produced regioselectively the succinic monoamide (III). This was then coupled to AZT (IV) by using DCC and DMAP to furnish the corresponding AZT ester.

参考文献中间体

合成目标

【1】 Kimura, T.; Matsuda, T.; Akaji, K.; Kiso, Y.; Matsumoto, H.; Hamawaki, T.; Synthesis and activity of a new type of anti-HIV agents, conjugate of HIV protease inhibitor with reverse transcriptase inhibitor. Pept Sci 1999, 305.
【2】 Kimura, T.; Kiso, Y.; Matsumoto, H.; Akaji, K.; Hamawaki, T.; Matsuda, T.; A new class of anti-HIV agents: Synthesis and activity of conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor. Bioorg Med Chem Lett 1999, 9, 6, 803.

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)	51181	(4R)-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-N-(2-methylbenzyl)-1,3-thiazolidine-4-carboxamide		C₂₄H₃₁N₃O₃S	详情	详情
(II)	29295	3,3-dimethyldihydro-2,5-furandione	17347-61-4	C₆H₈O₃	详情	详情
(III)	51182	4-[[(1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-hydroxy-3-oxopropyl]amino]-2,2-dimethyl-4-oxobutyric acid		C₃₀H₃₉N₃O₆S	详情	详情
(IV)	25317	1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione	101703-35-9	C₁₀H₁₃N₅O₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(II)

In an alternative procedure, 2,2-dimethylsuccinic anhydride (II) was reacted with p-methoxybenzyl alcohol (V) in the presence of dicyclohexylamine to afford the beta,beta-dimethyl p-methoxybenzyl ester (VI) as the major product, along with minor amounts of the alpha,alpha-dimethyl regioisomer. Condensation of hemiester (VI) with AZT (IV) by using DCC and DMAP produced diester (VII). The p-methoxybenzyl group of (VII) was then removed by treatment with trifluoroacetic acid to give (VIII). Acid (VIII) was finally coupled with the dipeptide amide (I) in the presence of BOP and HOBt.

参考文献中间体

合成目标

【1】 Kimura, T.; Matsuda, T.; Akaji, K.; Kiso, Y.; Matsumoto, H.; Hamawaki, T.; Synthesis and activity of a new type of anti-HIV agents, conjugate of HIV protease inhibitor with reverse transcriptase inhibitor. Pept Sci 1999, 305.
【2】 Kimura, T.; Kiso, Y.; Matsumoto, H.; Akaji, K.; Hamawaki, T.; Matsuda, T.; A new class of anti-HIV agents: Synthesis and activity of conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor. Bioorg Med Chem Lett 1999, 9, 6, 803.
【3】 Mitoguchi, T.; Kiso, Y.; Nakata, S.; Hayashi, Y.; Matsuda, T.; Matsumoto, H.; Kimura, T.; Synthesis and biological evaluation of prodrug-type anti-HIV agents. Ester conjugates of carboxylic acid-containing dipeptide HIV protease inhibitors and a reverse transcriptase inhibitor. Bioorg Med Chem 2001, 9, 2, 417.

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)	51181	(4R)-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-N-(2-methylbenzyl)-1,3-thiazolidine-4-carboxamide		C₂₄H₃₁N₃O₃S	详情	详情
(II)	29295	3,3-dimethyldihydro-2,5-furandione	17347-61-4	C₆H₈O₃	详情	详情
(IV)	25317	1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione	101703-35-9	C₁₀H₁₃N₅O₄	详情	详情
(V)	38861	4-Methoxybenzenemethanol; (4-methoxyphenyl)methanol; 4-Methoxybenzyl alcohol; Anis alcohol; Anisyl Alcohol; 4-Anisic Alcohol; p-Anisyl alcohol; Anise alcohol	105-13-5	C₈H₁₀O₂	详情	详情
(VI)	51183	4-[(4-methoxybenzyl)oxy]-2,2-dimethyl-4-oxobutyric acid		C₁₄H₁₈O₅	详情	详情
(VII)	51184	1-([(2S,3S,5R)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl) 4-(4-methoxybenzyl) 2,2-dimethylsuccinate		C₂₄H₂₉N₅O₈	详情	详情
(VIII)	51185	4-([(2S,3S,5R)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)-3,3-dimethyl-4-oxobutyric acid		C₁₆H₂₁N₅O₇	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VII)

Dihydrooleanolic acid (VI) was prepared from oleanolic acid (I) as follows. Acylation of (I) with Ac2O in pyridine gave 3-acetoxy oleanolic acid (II), which was converted to the corresponding methyl ester (III) upon treatment with diazomethane. Subsequent epoxidation of (III) by means of m-chloroperbenzoic acid afforded the 12,13-epoxy derivative (IV). Rearrangement of epoxide (IV) by refluxing with boron trifluoride etherate in benzene led to ketone (V). Wolff-Kishner reduction of the keto group of (V) with hydrazine and KOH in tripolyethylene glycol furnished dihydrooleanolic acid (VI). The title compound was then obtained by esterification of (VI) with 2,2-dimethylsuccinic anhydride (VII).

参考文献中间体

合成目标

【1】 Zhu, Y.-M.; Shen, J.-K.; Wang, H.-K.; Cosentino, L.M.; Lee, K.-H.; Synthesis and anti-HIV activity of oleanolic acid derivatives. Bioorg Med Chem Lett 2001, 11, 24, 3115.

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)	59920	(6aS,6bR,8aR,10S,12aR,12bR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydro-4a(2H)-picenecarboxylic acid		C₃₀H₄₈O₃	详情	详情
(II)	59921	(6aS,6bR,8aR,10S,12aR,12bR,14bS)-10-(acetyloxy)-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydro-4a(2H)-picenecarboxylic acid		C₃₂H₅₀O₄	详情	详情
(III)	59922	methyl (6aS,6bR,8aR,10S,12aR,12bR,14bS)-10-(acetyloxy)-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydro-4a(2H)-picenecarboxylate		C₃₃H₅₂O₄	详情	详情
(IV)	59923	methyl (4aR,4bR,5aS,6aR,6bR,9S,10aR,12aR,12bS)-9-(acetyloxy)-3,3,6b,10,10,12a,12b-heptamethyloctadecahydro-1H-piceno[12b,13-b]oxirene-14a(5aH)-carboxylate		C₃₃H₅₂O₅	详情	详情
(V)	59924	methyl (6aR,6bR,8aR,10S,12aR,12bR,14aR,14bS)-10-(acetyloxy)-2,2,6a,6b,9,9,12a-heptamethyl-14-oxoicosahydro-4a(2H)-picenecarboxylate		C₃₃H₅₂O₅	详情	详情
(VI)	59925	(6aR,6bR,8aR,10S,12aR,12bR,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethylicosahydro-4a(2H)-picenecarboxylic acid		C₃₀H₅₀O₃	详情	详情
(VII)	29295	3,3-dimethyldihydro-2,5-furandione	17347-61-4	C₆H₈O₃	详情	详情

Extended Information