- Preparation method of benidipine hydrochloride
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The invention belongs to the field of chemical synthesis of drugs, and particularly relates to a preparation method of a hypotensive drug benidipine hydrochloride. The method comprises the following steps: carrying out a Knoevenagel reaction, a Michael addition reaction, cyclization and hydrolysis on starting raw materials 3-nitrobenzaldehyde and methyl acetoacetate in the presence of a catalyst, reacting with thionyl chloride, directly reacting with 1-benzyl-3-hydroxypiperidine, and refining to obtain the benidipine hydrochloride. The benidipine hydrochloride obtained by adopting the preparation method of the benidipine hydrochloride is high in purity, column chromatography isolation is not needed, and the HPLC purity of the product is 99.5% or above. The yield of the obtained benidipine hydrochloride is relatively high and can reach 68% or above.
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- Barnidipine hydrochloride compound and preparation method thereof
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The invention discloses a barnidipine hydrochloride compound and a preparation method thereof. The preparation method comprises the following steps: (1) using 3-hydroxypropionitrile to react with diketene, to obtain an intermediate 1; (2) enabling the intermediate 1 to react with m-nitrobenzaldehyde and Beta-amino methyl crotonate, to obtain an intermediate 2; (3) enabling the intermediate 2 to behydrolyzed by strong base, to obtain an intermediate 3; (4) enabling the intermediate 3 to be resolved by chiral organic base, to obtain an intermediate 4; (5) enabling the intermediate 4 to react with thionyl chloride, (S)-1-benzyl-3-pyrrolidinol, and HCI ethanol solution, to obtain a crude product of barnidipine hydrochloride; and (6) performing ethyl alcohol pulping and refining, and ethyl alcohol recrystallization on the crude product of the barnidipine hydrochloride, to obtain the barnidipine hydrochloride.
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Paragraph 0042; 0046; 0056; 0060
(2019/01/16)
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- Preparation method for 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid monomethyl ester
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The invention relates to a preparation method for an important intermediate of dihydropyridine hypotensive drugs, in particular to a preparation method for 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid monomethyl ester. The problems of severe reaction conditions, long reaction time, more by-products and bad purity in the existing preparation method for 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid monomethyl ester are solved. The preparation method comprises the steps that lipase and 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate are added in an aqueous solution/organic solvent mixed system and react, and a mixture is obtained through the reaction; the organic solvent is removed, NaOH aqueous solution is added, and powder is obtained through suction filtration, stirring, suction filtration and recrystallization one after another, wherein the powder is 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid monomethyl ester. The preparation method for 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid monomethyl ester is applied to the field of the dihydropyridine hypotensive drugs.
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Paragraph 0032; 0033; 0034; 0035; 0036; 0037; 0038
(2017/02/17)
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- Process for synthesis of hydrochloric acid ramiah of lercanidipine (by machine translation)
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The invention discloses a process for synthesizing hydrochloric acid ramiah of lercanidipine, its synthesis process comprises the following steps : (1) 3 -? Hydroxy-propionitrile (I) and (II) reaction of ketene dimer, to obtain compound (VI) ; (2) compound (III) with (VI) reaction between formaldehyde nitrobenzene, to obtain compound (VII) ; (3) compound (VII) with β-amino-crotonic acid ethyl ester (IV) reaction, to obtain compound (VIII) ; (4) by strong alkali hydrolysis of compound (VIII), to obtain compound (IX) ; (5) compound (IX) using chiral organic alkali splitting, to obtain compound (X) ;? (6) compound (X) with benzyl quick (V) reaction, to obtain compound (XI) ; (7) a solution of compound (XI) by adding hydrogen chloride, hydrochloric acid ramiah horizontal (XII) can be obtained. Synthetic process of this invention has the following several advantages : (1) mild reaction conditions, each step the product is easy to separate, purification, controllable quality ; (2) higher yield for each step, the used original helping material is easy to obtain, the total cost is low ; (3) do not need to be too column, is suitable for industrial production. (by machine translation)
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Paragraph 0010
(2016/12/01)
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- Design, synthesis, in Silico and in vitro studies of substituted 1, 2, 3, 4-Tetrahydro pyrimidine phosphorus derivatives
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Molecular docking studies of the designed two series (4a-l, 6a-l, 9 and 10) of novel substituted phosphorylated 1, 4-dihydropyridine and 1,2,3,4-Tetrahydropyrimidine derivatives against the drug targets of DHFR from Bacillus cereus, LpxC from Pseudomonas aeruginosa, IDH from E. coli and MurB from Staphylococcus aureus were encouraged for their synthesis. These compounds were synthesized from substituted aromatic aldehydes, thiourea/urea and ethyl acetoacetate in the presence of polyphosphoric acid (PPA). These were further phosphorylated with diethyl (2-chloroethoxy) methyl phosphonate to get the desired products. In vitro anti-bacterial activity against the specified bacterial strains related to docked protein exhibited good inhibitory activity at different dose concentrations. Quantitative Structure Activity Relationship (QSAR) descriptors of the designed structures have demonstrated their satisfactory drug like properties. The results from Molecular Docking, QSAR descriptors and in vitro anti-bacterial activities led to the identification of safer and potential antibacterial agents of the title compounds screened. Compounds 4a, 4d, 4i, 6a, 6d, 9 and 10 were found to be potent antibacterial agents.
- Babu, Kilaru Ravendra,Kumar, Yellapu Nanda,Raghavendra, Aminedi,Phanindra, Venukadasula,Madhava, Golla,Ravi, Nuchu,Bhaskar, Matcha,Raju, Chamarthi Naga
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p. 862 - 871
(2015/11/17)
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- Synthesis and characterization of impurities of barnidipine hydrochloride, an antihypertensive drug substance
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Barnidipine hydrochloride is a long term dihydropyridine calcium channel blocker used for the treatment of hypertension. During the process development of barnidipine hydrochloride, four barnidipine impurities were detected by high-performance liquid chromatography (HPLC) with an ordinary column (Agilent ZORBAX Eclipse XDB-C18, 150 mm × 4.6 mm, 5 m). All these impurities were identified, synthesized, and subsequently characterized by their respective spectral data (MS, 1H-NMR, and 13C-NMR). The identification of these impurities should be useful for quality control in the manufacture of barnidipine.
- Cheng, Zhi-Gang,Dai, Xu-Yong,Li, Li-Wei,Wan, Qiong,Ma, Xiang,Xiang, Guang-Ya
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p. 1344 - 1352
(2014/02/14)
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- 1,4-dihydropyridine-3,5-dicarboxylate Derivatives And Preparation And Use Thereof
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The present invention relates to a 1,4-dihydropyridine-3,5-dicarboxylate compound of general compound (I), a process for preparing the same, a use thereof for the manufacture of a medicament for treating and/or preventing kidney injury, cardiovascular diseases and/or endocrine diseases, as well as a pharmaceutical composition and a pharmaceutical formulation containing said compounds, wherein the definitions of R1, R2, R3, R4, R5, R6, R7, R8, m, n1, n2, p and q are the same as those defined in the description.
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Paragraph 0071; 0072
(2014/03/21)
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- 1,4-DIHYDROPYRIDINE -3,5-DICARBOXYLATE DERIVATIVES, PREPARATION METHODS AND USES THEREOF
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The present invention relates to a 1,4-dihydropyridine-3,5-dicarboxylate compound of general compound (I), a process for preparing the same, a use thereof for the manufacture of a medicament for treating and/or preventing kidney injury, cardiovascular diseases and/or endocrine diseases, as well as a pharmaceutical composition and a pharmaceutical formulation containing said compounds, wherein the definitions of R1, R2, R3, R4, R5, R6, R7, R8, m, n1, n2, p and q are the same as those defined in the description.
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Paragraph 0067; 0068
(2014/03/25)
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- Antagonism of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylates toward voltage-dependent L-type Ca2+ channels CaV1.3 and CaV1.2
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L-type Ca2+ channels in mammalian brain neurons have either a CaV1.2 or CaV1.3 pore-forming subunit. Recently, it was shown that CaV1.3 Ca2+ channels underlie autonomous pacemaking in adult dopaminergic neurons in the substantia nigra pars compacta, and this reliance renders them sensitive to toxins used to create animal models of Parkinson's disease. Antagonism of these channels with the dihydropyridine antihypertensive drug isradipine diminishes the reliance on Ca2+ and the sensitivity of these neurons to toxins, pointing to a potential neuroprotective strategy. However, for neuroprotection without an antihypertensive side effect, selective CaV1.3 channel antagonists are required. In an attempt to identify potent and selective antagonists of CaV1.3 channels, 124 dihydropyridines (4-substituted-1,4-dihydropyridine-3,5-dicarboxylic diesters) were synthesized. The antagonism of heterologously expressed CaV1.2 and CaV1.3 channels was then tested using electrophysiological approaches and the FLIPR Calcium 4 assay. Despite the large diversity in substitution on the dihydropyridine scaffold, the most CaV1.3 selectivity was only about twofold. These results support a highly similar dihydropyridine binding site at both CaV1.2 and CaV1.3 channels and suggests that other classes of compounds need to be identified for CaV1.3 selectivity.
- Chang, Che-Chien,Cao, Song,Kang, Soosung,Kai, Li,Tian, Xinyong,Pandey, Prativa,Dunne, Sara Fernandez,Luan, Chi-Hao,Surmeier, D. James,Silverman, Richard B.
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scheme or table
p. 3147 - 3158
(2010/07/08)
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- Synthesis and biological activity of the calcium modulator (R) and (S)-3-methyl 5-pentyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
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An efficient total synthesis of (R) and (S)-3-methyl 5-pentyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate in high optical purities is reported. The useful step is the resolution of racemic 2, 6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid by using commercially available Cinchona alkaloids cinchonidine and quinidine as the resolving agents. Under the optimum conditions, the optical purities for R- and S-enantiomers are extremely high (ee >99.5%). The further dihydropyridine receptor binding activity assay shows that the S-enantiomer is more potent than R-enantiomer both in rat cardiac (approximately 19 times) and cerebral cortex membrane (12 times).
- Zhang, Bang-le,He, Wei,Shi, Xin,Huan, Meng-lei,Huang, Qiu-ju,Zhou, Si-yuan
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scheme or table
p. 805 - 808
(2010/05/18)
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- Synthesis and biological evaluation of novel hybrid chalcone derivatives as vasorelaxant agents
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With the aim to further improve the vasorelaxant activities of chalcones, nine hybrid chalcone derivatives conjugated with nitric oxide (NO) donor or 1,4-dihydropyridyl (1,4-DHP) moiety were designed and synthesized based on molecular hybridization strategy. Their vasorelaxant activities were evaluated in aortic rings with endothelium pre-contracted with phenylephrine (PE). All of these compounds showed preferable vasorelaxant activities which were more potent than their parent compounds. Compounds 8c and 15c, the most potent compounds, would be promising structural templates for the development of novel vasorelaxant agents. Nine hybrid chalcone derivatives conjugated with nitric oxide (NO) donors or 1,4-dihydropyridyl moiety were designed, synthesized and biological evaluated for their vasorelaxant activities.
- Dong, Xiaowu,Du, Lilin,Pan, Zhichao,Liu, Tao,Yang, Bo,Hu, Yongzhou
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scheme or table
p. 3986 - 3992
(2010/09/14)
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- DIHYDROPYRIDINE COMPOUNDS HAVING SIMULTANEOUS ABILITY TO BLOCK L-TYPE CALCIUM CHANNELS AND TO INHIBIT PHOSPHODIESTERASE TYPE 3 ACTIVITY
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The present invention provides compounds that possess inhibitory activity against PDE-3 and L-type calcium channels. The present invention further provides pharmaceutical compositions comprising such compounds and methods of using such compounds for treating cardiovascular disease, stroke, epilepsy, ophthalmic disorder or migraine.
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- Process for producing optically pure 1,4-dihydropyridines
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The invention relates to a process which comprises the crystallization of a calcium salt of chiral (R or S) lactic acid esterified with a racemic dihydropyridine.
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- Facile synthesis of 1,4-dihydropyridine monocarboxylic acids and unsymmetric dicarboxylates via quaternary ammonium salts of 2-aminoethyl 1,4-dihydropyridine-3,5-dicarboxylates
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Useful 1,4-dihydropyridine unsymmetric dicarboxylates [nitrendipine (1), nicardipine (2)] and monocarboxylic acid 4 were prepared from unsymmetric 2-aminoethyl methyl 1,4-dihydropyridine-3,5-dicarboxylates 2 and 3 via their corresponding quaternary ammonium salts 5-9.
- Kinugawa, Masahiko,Ogasa, Takehiro
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p. 3321 - 3331
(2007/10/03)
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- Mild and facile cleavage of 2-cyanoethyl ester using sodium sulfide or tetrabutylammonium fluoride. Synthesis of 1,4-dihydropyridine monocarboxylic acids and unsymmetrical 1,4-dihydropyridine dicarboxylates
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Several 3-(2-cyanoethyl)-1,4-dihydropyridine carboxylates (16) were prepared in moderate to good yields by means of the Hantzsch reaction. Treatment of these carboxylates with a weak base such as sodium sulfide or tetrabutylammonium fluoride at room temperature afforded smoothly the corresponding 1,4-dihydropyridine monocarboxylic acids (18) in good yields. The monocarboxylic acids 18n and 18o were esterified with 2-nitrooxypropanol or N-(2-hydroxyethyl)nicotinamide p-toluenesulfonic acid salt to afford the selective coronary vasodilators CD-349 (5) and CD-832 (6), respectively.
- Ogawa,Hatayama,Maeda,Kita
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p. 1579 - 1589
(2007/10/02)
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- Derivatives of 1,4-dihydropyridine, their preparation procedure and therapeutic compositions containing them
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The invention relates to compounds having the formula: STR1 in which Ar represents a group selected from 2-nitrophenyl, 3-nitrophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2-trifluoromethylphenyl and 3-trifluoromethylphenyl; R1 represents a C1 -C4 alkyl group or a group having the formula: STR2 A represents a group selected from groups having the formulae: STR3 and R2 represents a group selected from 2,4,6-trimethoxyphenyl, 2-thienyl and phenyl, and their addition salts with pharmaceutically acceptable acids. These compounds are calcium inhibitors with therapeutic applications.
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- Process for preparation of enantiomerically pure polysubstituted 1,4-dihydropyridines
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A process for the optical resolution of racemic 1,4-dihydropyridines, containing isothioureido groups. Salification of racemic isothioureas with optically active acids produces diasteroisomeric mixtures of isothiouronium salts, that, using conventional techniques, are separated in the individual components to give optically pure isothioureides of 1,4-dihydropyridines and salts thereof with conventional acids. Said optically pure 1,4-dihydropyridines can then be subjected to desulphuration and to different transformations to give to other enantiomerically pure and therapeutically useful 1,4-dihydropyridines.
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- Biotransformation of nitrendipine in rat, dog, and mouse
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14C-Labelled Nitrendipine (Bay e 5009; Baypress, Bayotensin; CAS 39562-70-4) was administered by the oral and intraduodenal route to rats, dogs, and mice (oral dosing only) to elucidate the biotransformation pathways in these three species. The drug was extensively metabolized: 20 biotransformation products were identified by comparison with synthetic reference compounds using two-dimensional TLC, HPLC, GC/radio-GC, combined GC/MS (EI-, CI-mode), FAB-MS, and 1H-NMR-spectroscopy. The metabolites identified accounted for approx. 72 to 73% of the dose administered in rats and dogs (bile and urine) and 48 to 56% in male and female mice (urine only). Based on the structures identified the following biotransformation reactions occurred: Dehydrogenation of the 1,4-dihydropyridine (primary metabolic step), oxidative ester cleavage as further basic biotransformation reaction (also at the dihydropyridine state), hydroxylation of the methyl groups in 2- or 6-position as separated and important metabolic reaction (at the dihydropyridine as well as pyridine state), reduction of the aromatic nitro group (important only in mice) and subsequent acetylation (dog only), and glucuronidation as phase II reaction forming ether and ester type glucuronides.
- Scherling,Karl,Ahr,Kern,Siefert
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p. 1009 - 1021
(2007/10/02)
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- 1,4-dihydropyridine-threonine compounds with cardiovascular activity
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Cardioactive dihydropyridines of the formula STR1 in which Y is STR2 A is H or CH3, B is --NH, --NH--CO--, --NH--CS--, --NH--COO--, --NH--SO2 --or --NH--CO--NH-- or --NH--CS--NH--, and R13 and R14 each independently is H or an organic radical, and salts thereof. The Y can be hydrolyzed off. The other radicals on the dihydropyridine moiety can also be varied.
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- Resolution of 1,4-dihydropyridine derivatives
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Optically active compounds of formula 1 STR1 wherein R1 is H or lower alkyl; R2 and R6 are each independently lower alkyl, aryl, or arylalkyl; R3 is CN, NO2, CO2 R5, CONHR5, SO2 R5, or P(O)(OR5)2, where R5 is lower alkyl, lower alkoxyalkyl, aryl, or arylalkyl; R4 is aryl, heterocyclyl, or fused-ring heterocyclyl, optionally substituted with one, two, or three halo, NO2, CN, lower alkyl, lower alkoxy, lower alkylamino, CF3, OCH2 F, or OCF3 ; are prepared by fractional crystallization from hot organic solvent and water in the presence of a suitable optically active amine base.
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- Antihypertensive dihydropyridine derivatives
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Compound of formula 1 are calcium entry antagonists useful for treating hypertension, congestive heart failure, angina, and vasospastic disorders: STR1 wherein n is an integer from 1 to 4; R1 and R2 are lower alkyl; R3 is lower alkyl or alkoxyalkyl; A is alkylene of two to eight carbon atoms; X1 and X2 are each independently --NO2, --CF3, CH3 O--, --CN, --H, lower alkyl or halo; Y is --O--, --S--, --S(O)--, or --S(O)2 --; and R is H, lower alkyl, cycloalkyl, alkoxyalkyl, cycloalkyloxy-alkyl, alkoxycycloalkyl, acyl, or saturated or unsaturated 5- or 6-membered heterocyclyl optionally substituted with lower alkyl or alkoxy, wherein the heteroatom is one oxygen atom.
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- Process for the preparation of 2-(N-benzyl-N-methylamino)-ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride salt
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A new, technologically easily feasible process for the preparation of 2-(N-benzyl-N-methylamino)ethyl methyl 2,6-dimethyl-4(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, comprising a partrial hydrolysis of dimethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate in an inert organic solvent at a temperature between room temperature and the reflux temperature of the reaction mixture with an aqueous solution of alkali hydroxide and the reaction of the obtained 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid either with N-(2-hydroxyethyl)-N-benzyl-methylamine in the presence or absence of an organic solvent in the presence of N,N'-dicyclohexylcarbodiimide at a temperature of between 25° and 120° C. or with N-(2-haloethyl)-N-benzyl-methylamine in the presence of an inert organic solvent and of a proton acceptor at a temperature of between 25° and 140° C., to yield the title compound, which can be, if desired, converted to its hydrochloride salt. The hydrochloride salt is known under the generic name "nicardipine hydrochloride" and is used as a valuable therapeutic in the therapy of cerebral insufficiency.
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