- Preparation method for key intermediate of Barnidipine
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he preparation method of the intermediate is characterized by comprising the following steps: with chiral hydroxy acid as a starting material, the chiral hydroxy acid reacts with isopropanol under the catalysis of lewis acid, then reacts with an acetoacetic acid reagent, and is directly cyclized with m-nitrobenzaldehyde and methyl 3-aminocrotonate in an alcohol solvent, then crystallization is performed in a low temperature environment for realizing chiral resolution, hydrolysis is performed by sodium hydroxide, and then acidization is performed by hydrochloric acid to obtain a product. the intermediate is characterized by being prepared by the following steps: with chiral hydroxy acid as a starting material,the chiral hydroxy acid reacts with isopropanol under the catalysis of lewis acid, then reacts with an acetoacetic acid reagent, and is directly cyclized with m-nitrobenzaldehyde and methyl 3-aminocrotonate in an alcohol solvent, crystallization and chiral resolution are realized in a low temperature environment, hydrolysis is performed by sodium hydroxide, and then acidization is performed by hydrochloric acid to obtain a product. The preparation method disclosed by the invention has the advantages that the preparation technology is simple, the resolution is easy, the product yield is high, the optical purity is good, the quality is stable, and the large-scale industrial production is easy.
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Paragraph 0058; 0068-0070; 0080-0082; 0092-0094; 0104-0105
(2019/10/07)
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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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- 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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- 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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- 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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- 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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experimental part
p. 805 - 808
(2010/05/18)
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- 1,4-dihydropyridine derivatives
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Disclosed are 1,4-dihydropyridine derivatives represented by the general formula (I) and salts thereof, as well as optical active 1,4-dihydropyridine derivatives represented by the general formula (II) and salts thereof which are obtained from the derivat
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- Optically active 1,4-dihydropyridine compounds and the microbial process for the stereoselection thereof
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(4R)-3-(Substituted aminoalkyl)oxycarbonyl-1,4-dihydro-2,6-dimethyl-4-(nitrophenyl)pyridine-5-carboxylic acids can be prepared efficiently, by reacting bis(substituted aminoalkyl) 1,4-dihydro-2,6-dimethyl-4-(nitrophenyl)pyridine-3,5-dicarboxylates with a microorganism capable of asymmetric hydrolysis and belonging to the genus Streptomyces, the genus Paecilomyces, the genus Botryodioplodia, the genus Alternaria or the genus Helminthosporium, or a treated product thereof. The compounds are extremely useful as important intermediates for preparation of pharmaceuticals useful for the prevention and treatment of angina pectoris, hypertension, etc.
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- Examination of metabolic pathways and identification of human liver cytochrome P450 isozymes responsible for the metabolism of barnidipine, a calcium channel blocker
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1. In a human liver microsomal system, barnidipine was converted into three primary metabolites, an N-debenzylated product (M-1), a hydrolyzed product of the benzylpyrrolidine ester (M-3) and an oxidized product of the dihydropyridine ring (M-8). 2. Involvement of CYP3A in the three primary metabolic pathways was revealed by the following studies: (a) inhibition of CYP3A, (b) a correlation study using 10 individual human liver microsomes and (c) cDNA-expression studies. The secondary metabolites, M-2 and M-4 (pyridine forms of M-1 and M-3), were most likely generated from M-8 but were unlikely from M-1 or M-3. Involvement of CYP3A in the secondary pathways of metabolism is also suggested. 3. The possibility of interactions between barnidipine and coadministered drugs was examined in vitro. The formation rate of the primary metabolites was little affected by warfarin, theophylline, phenytoin, diclofenac and amitriptyline at concentrations of 200 μM, but was inhibited by glibenclamide, simvastatin and cyclosporin A. IC50 for the latter drugs was estimated to be > 200, 200 and 20 μM respectively, which was roughly > 200, 6000 and 50 times higher than their respective therapeutic plasma levels, suggesting that interactions with cyclosporin A, a CYP3A inhibitor, are of possible clinical relevance.
- Teramura,Fukunaga,Van Hoogdalem,Watanabe,Higuchi
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p. 885 - 900
(2007/10/03)
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- Lipase-catalyzed enantioselective hydrolysis of bis(acyloxymethyl) 1,4- dihydro-3,5-pyridinedicarboxylates leading to optically active medicines
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Chiral 4-aryl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylates and 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate have been obtained in 80-99%ee by lipase catalyzed hydrolysis of bis(acyloxymethyl) 1,4-dihydro- 3,5-pyridinedicarboxylate in an H2O/organic solvent system. These chiral dihydropyridines were readily converted into chiral drugs, such as nicardipine, felodipine and PCA 4248.
- Ebiike, Hirosato,Maruyama, Kaori,Yamazaki, Yukiyoshi,Hirose, Yoshihiko,Kariya, Kinya,Sasaki, Ikuharu,Kurono, Yoshiaki,Terao, Yoshiyasu,Achiwa, Kazuo
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p. 863 - 868
(2007/10/03)
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- Optically active 1,4-hydropyridine compounds
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Optically active 1,4-dihydropyridine derivatives represented by general formula (I), process for preparing compounds (Ic) (in general formula (I) , R1 is a lower alkyl group), process for preparing compounds represented by general formula (II)
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- Synthesis of Optically Pure 1,4-Dihydropyridine Derivatives by Means of Diastereoisomeric Separation of the Hantzsch Intermediates Bearing (R)-1-Phenylethylamino Group
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Hantzsch intermediates, which were obtained by Michael addition reaction of benzylideneacetoacetates with the enamino esters bearing (R)-1-phenylethylamino group as a chiral auxiliary, were separated into two diastereoisomeric mixtures.Each of them underw
- Kosugi, Yoshiyuki,Hori, Masanori,Nagasaka, Tatsuo
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p. 591 - 602
(2007/10/02)
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- 1,4-dihydropyridine derivatives
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1,4-dihydropyridine derivatives and optically active 1,4-dihydropyridine derivatives with the following formula, having vasodilating activity based on calcium antagonism, and PAF antaognism, and methods of producing the same are disclosed: STR1 wherein (*) indicates a chiral center in the case of the optically active 1,4-dihydropyridine derivatives.
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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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- PROTEASE-CATALYZED ENANTIOSELECTIVE SYNTHESIS OF OPTICALLY ACTIVE 1,4-DIHYDROPYRIDINES
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The first enantioselective protease-catalyzed hydrolyses of 1,4-dihydropyridine-3,5-dicarboxylic diesters were developed.The monoesters obtained had high optical purity and were useful building blocks which could easily lead to optically active Ca-blockers.
- Hirose, Yoshihiko,Kariya, Kinya,Sasaki, Ikuharu,Kurono, Yoshiaki,Achiwa, Kazuo
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p. 3441 - 3444
(2007/10/02)
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- Acyloxymethyl as an activating group in lipase-catalyzed enantioselective hydrolysis. A versatile approach to chiral 4-aryl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylates
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The first practical syntheses of chiral 4-aryl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylates, which are attractive compounds as new calcium antagonists, were realized by lipase-catalyzed enantioselective hydrolysis of the acyloxymethyl esters. The monoesters obtained were revealed to have high optical purity and demonstrated to be useful chiral synthons.
- Ebiike,Terao,Achiwa
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p. 5805 - 5808
(2007/10/02)
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- Synthesis and pharmacological activity of stereoisomers of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester
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1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester 1, a highly potent calcium antagonist, was separated into stereo- and optical isomers to investigate the differences of antihypertensive activities between them. Fractional crystallization of the hydrochlorides of 1 gave α- and β-diasterioisomers. The α-isomer (benidipine hydrochloride, KW-3049) showed very strong hypotensive effect, but little activity was observed in the β-isomer. From optically resolved 1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridi necarboxylic acids 2, and 1-benzyl-3-piperidinols 3, four optical isomers of 1 were synthesized, and their absolute configurations were deduced. The hypotensive activity of (+)-α, namely (S)-(S)-1, was 30 to 100 times stronger than that of (-)-α in intravenously administered spontaneously hypertensive rats.
- Muto,Kuroda,Kawato,Karasawa,Kubo,Nakamizo
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p. 1662 - 1665
(2007/10/02)
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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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