(4R)-6-[[2-(2-aminoethoxy)ethoxy]methyl]-4-(2,3-dichlorophenyl)-5-(ethoxycarbonyl)-2-methyl-1,4-dihydro-3-pyridinecarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】14747

【品名】(4R)-6-[[2-(2-aminoethoxy)ethoxy]methyl]-4-(2,3-dichlorophenyl)-5-(ethoxycarbonyl)-2-methyl-1,4-dihydro-3-pyridinecarboxylic acid

【CA登记号】

【分子式】C₂₁H₂₆Cl₂N₂O₆

【分子量】473.35272

【元素组成】C 53.29% H 5.54% Cl 14.98% N 5.92% O 20.28%

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：(V)

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

合成路线2

该中间体在本合成路线中的序号：(V)

This compound has been obtained by three related ways: 1. Dihydropyridine amino acid (V) is methylated with (11C-labeled)-diazomethane (VI) in ethyl ether/methanol to afford the target compound. 2. The methylation of the dihydropyridine amino acid (V) can also be performed with (11C-labeled)-methyl iodide (VII) and trimethylbenzylammonium hydroxide in DMF/EtOH. 3. The preceding methylation can also been performed with (11C-labeled)-methyl triflate (VIII) and trimethylbenzylammonium hydroxide in DMF/EtOH. The (11C-labeled)-diazomethane (VI), (11C-labeled)-methyl iodide (VII) and (11C-labeled)-methyl triflate (VIII) have been obtained as follows: a. The chlorination of (11C-labeled)-methane (IX) with chlorine and CuCl2 at 330 C gives labeled chloroform (X), which is then treated with hydrazine and KOH in ethanol to yield the desired (11C-labeled)-diazomethane (VI). b. The reduction of (11C-labeled)-CO2 (XI) with LiAlH4 in THF gives (11C-labeled)-methanol (XII), which is treated with 57% IH to yield the desired (11C-labeled) methyl iodide (VII). c. Finally, the reaction of (11C-labeled)-methyl iodide (VII) with silver triflate affords the desired (11C-labeled)-methyl triflate (VIII).

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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(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

Extended Information