5-Acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione -Drug Synthesis Database

【结构式】

【分子编号】12273

【品名】5-Acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione

【CA登记号】

【分子式】C₈H₁₀O₅

【分子量】186.1644

【元素组成】C 51.61% H 5.41% O 42.97%

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)

This compound can be obtained in two different ways: 1) The reaction of 8-(4-chlorophenyl)-8-aza-1,4-dioxaspiro[4.5]decane-2-methanol (I) with 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (acetylated Meldrum's acid, II) in refluxing toluene gives the corresponding acetylacetic ester (III), which by reaction with NH3 in dry dichloromethane is converted into the 3-aminocrotonic ester (IV). Finally, this compound is cyclized with methyl 2-(3-nitrobenzylidene)acetylacetate (V) in refluxing tert-butanol. 2) The partial hydrolysis of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl) 5-methyl diester (VI) with HCl 1N in methanol gives the corresponding glycerol ester (VII), which is then spiranized with 1-(4-chlorophenyl)-4-piperidone (VIII) by means of p-toluenesulfonic acid in refluxing methanol.

参考文献中间体

合成目标

【1】 Robin, J.; Pruneau, D.; Bellamy, F. (SORI); Disymetric derivs. of 1,4-dihydropyridine-3,5-dicarboxylic acid, method of preparation and use in therapeutics. EP 0240398; FR 2596760; JP 1988017883; US 4806544 .
【2】 Prous, J.; Castaner, J.; CRONIDIPINE. Drugs Fut 1990, 15, 4, 341.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	12272	[8-(4-Chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]dec-2-yl]methanol	C₁₄H₁₈ClNO₃	详情	详情
(II)	12273	5-Acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione	C₈H₁₀O₅	详情	详情
(III)	12274	[8-(4-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]dec-2-yl]methyl 3-oxobutanoate	C₁₈H₂₂ClNO₅	详情	详情
(IV)	12275	[8-(4-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]dec-2-yl]methyl (E)-3-amino-2-butenoate	C₁₈H₂₃ClN₂O₄	详情	详情
(V)	12276	methyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate	C₁₂H₁₁NO₅	详情	详情
(VI)	12277	3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate	C₂₂H₂₆N₂O₈	详情	详情
(VII)	12278	3-(2,3-dihydroxypropyl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate	C₁₉H₂₂N₂O₈	详情	详情
(VIII)	12279	1-(4-Chlorophenyl)tetrahydro-4(1H)-pyridinone	C₁₁H₁₂ClNO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

A synthesis of S-12968 has been published: The cyclization of 4-[2-(2-phthalimidoethoxy)ethoxy]-3-oxobutyric acid ethyl ester (I) with 2-(2,3-dichlorobenzylidene)-3-oxobutyric acid 2-cyanoethyl ester (II) and ammonium formate in hot ethanol gives the protected racemic 1,4-dihydropyridine (III), which is submitted to a chiral preparative HPLC to obtain the (R)-(-)-enantiomer (IV). The deprotection of (IV) with aqueous methylamine affords (S)-(-)-2-[2-(2-aminoethoxy)ethoxymethyl]-4-(2,3-dichlorophenyl)-1,4-di hydropyridine-3,5-dicarboxylic acid 3-monoethyl ester (V). Finally, this compound is methylated with diazomethane in ethyl ether/methanol. The starting compound, the dichlorobenzylidene derivative (II) has been obtained as follows: The condensation of Meldrum's acid (X) with acetic acid (XII) by means of CDI and pyridine as before gives 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (XIII), which is submitted to ring opening with 3-hydroxypropionitrile (XIV) in refluxing toluene yielding 2-cyanoethyl acetoacetate (XV). Finally, the condensation of (XV) with 2,3-dichlorobenzaldehyde (XVI) by means of piperidine and hexanoic acid in refluxing benzene affords the dichlorobenzylidene derivative (II) used as the second starting compound.

参考文献中间体

合成目标

【1】 Dolle, F.; et al.; Highly efficient synthesis of [11C]S12968 and [11C]S12967, for the in vivo imaging of the cardiac calcium channels using PET. J Label Compd Radiopharm 2001, 44, 7, 481.
【2】 Crouzel, C.; Duval, R.; Hinnen, F.; Fuseau, C.; Dollé, F.; Valette, H.; Péglion, J.-L.; Synthesis of two optically active calcium channel antagonists labelled with carbon-11 for in vivo cardiac PET imaging. Bioorg Med Chem 1997, 5, 4, 749.

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)	14743	ethyl 4-[2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]-3-oxobutanoate		C₁₈H₂₁NO₇	详情	详情
(II)	14744	2-cyanoethyl (Z)-2-acetyl-3-(2,3-dichlorophenyl)-2-propenoate		C₁₄H₁₁Cl₂NO₃	详情	详情
(III)	14745	5-(2-cyanoethyl) 3-ethyl 4-(2,3-dichlorophenyl)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate		C₃₂H₃₁Cl₂N₃O₈	详情	详情
(IV)	14746	5-(2-cyanoethyl) 3-ethyl (4S)-4-(2,3-dichlorophenyl)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate		C₃₂H₃₁Cl₂N₃O₈	详情	详情
(V)	14747	(4R)-6-[[2-(2-aminoethoxy)ethoxy]methyl]-4-(2,3-dichlorophenyl)-5-(ethoxycarbonyl)-2-methyl-1,4-dihydro-3-pyridinecarboxylic acid		C₂₁H₂₆Cl₂N₂O₆	详情	详情
(X)	14738	Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester	2033-24-1	C₆H₈O₄	详情	详情
(XIII)	12273	5-Acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione		C₈H₁₀O₅	详情	详情
(XIV)	14029	Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile	109-78-4	C₃H₅NO	详情	详情
(XV)	13993	2-cyanoethyl 3-oxobutanoate		C₇H₉NO₃	详情	详情
(XVI)	14742	2,3-dichlorobenzaldehyde	6334-18-5	C₇H₄Cl₂O	详情	详情

Extended Information