Pranedipine tartrate, Servier-12968, S-12968, -Drug Synthesis Database

【结构式】

【药物名称】Pranedipine tartrate, Servier-12968, S-12968

【化学名称】(-)-2-[2-(2-Aminoethoxy)ethoxymethyl]-4-(2,3-dichlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl diester L-(+)-tartrate

【CA登记号】132194-66-2 (HCl)

【分子式】C₂₆H₃₄Cl₂N₂O₁₂

【分子量】637.47308

【开发单位】Servier (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, L-Type Calcium Channel Blockers

合成路线1 合成路线2 合成路线3

合成路线1

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

【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

The starting compound phthalimido derivative (I) could be obtained as follows: The condensation of 2-[2-(2-chloroethoxy)ethoxy]ethanol (VI) with potassium phthalimide (VII) in refluxing DMF gives the expected phthalimido derivative (VIII), which is oxidized with the Jones reagent in acetone yielding 2-[2-(2-phthalimidoethoxy)ethoxy]acetic acid (IX). The condensation of (IX) with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (X) by means of carbonyldiimidazole (CDI) and pyridine in dichloromethane affords 2,2-dimethyl-5-[2-[2-(2-phthalimidoethoxy)ethoxy]acetyl]-1,3-dioxane-4,6-dione (XI), which is finally treated with refluxing ethanol to obtain the phthalimido derivative (I) used as starting material.

参考文献中间体

【1】 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
(VI)	14748	2-[2-(2-Chloroethoxy)ethoxy]-1-ethanol; 2-(2-(2-Chloroethoxy)ethoxy)ethanol	5197-62-6	C₆H₁₃ClO₃	详情	详情
(VII)	10926	(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium		C₈H₄KNO₂	详情	详情
(VIII)	14750	2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethyl]-1H-isoindole-1,3(2H)-dione		C₁₄H₁₇NO₅	详情	详情
(IX)	14751	2-[2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]acetic acid		C₁₄H₁₅NO₆	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
(XI)	14752	2-(2-[2-[2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxoethoxy]ethoxy]ethyl)-1H-isoindole-1,3(2H)-dione		C₂₀H₂₁NO₉	详情	详情

合成路线3

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

【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