42399-40-6Relevant academic research and scientific papers
High-performance liquid chromatography method for assay of diltiazem hydrochloride and its related compounds in bulk drug and finished tablets
Lacroix,Beaulieu,Cyr,Lovering
, p. 243 - 246 (1989)
The method provides for the resolution of trans-diltiazem and seven known and several unknown related compounds from diltiazem HCl. Minimum detectable amounts were 0.1%, except for an intermediate which originates early in the synthetic process, for which the sensitivity is ~2%. The relative standard deviation of the assay procedure is 0.15%. Total related compounds in four bulk drugs and four tablet samples were 0.25%. The specific rotation of four samples of diltiazem HCl analyzed in duplicate was between +112 and +114°. The UV absorption spectra of all compounds exhibited two maxima, one between 203 and 213 nm and the other between 230 and 244 nm.
Characterization of species differences in tissue diltiazem deacetylation identifies Ces2a as a rat-specific diltiazem deacetylase
Kurokawa, Takaya,Fukami, Tatsuki,Nakajima, Miki
, p. 1218 - 1225 (2015)
Diltiazem, a calcium channel blocker, is mainly metabolized via demethylation or deacetylation in humans. Diltiazem demethylation is catalyzed by cytochrome P450 2D6 and 3A4. Although it was previously reported that the area under the curve ratio of deacetyldiltiazem to diltiazem after oral dosing with diltiazem in rats was sevenfold higher than in humans, the molecular mechanisms underlying this species difference remain to be clarified. In the present study, we compared the diltiazem deacetylase activity in liver, intestinal, renal, and pulmonary microsome preparations of human and experimental animal tissues to identify the specific deacetylase enzyme(s) involved in deacetylation. Diltiazem deacetylase activity was detected in rat liver and small intestine microsome preparations, but not in those from human, monkey, dog, and mouse tissues. Further purification of rat liver microsome (RLM) proteins identified four carboxylesterase (Ces) enzymes (Ces1d, Ces1e, Ces1f, and Ces2a) as potential candidate deacetylases. On the basis of their tissue distribution, the Ces2a enzyme was considered to be the enzyme that was responsible for diltiazem deacetylation. Furthermore, recombinant rat Ces2a expressed in Sf21 cells displayed efficient diltiazem deacetylase activity with similar Km values as RLM. In addition, the inhibitory characteristics of various chemical inhibitors were similar between recombinant rat Ces2a and RLM. In conclusion, we determined that only rat tissues were able to catalyze diltiazem deacetylation. The characterization of Ces enzymes in animal species, as undertaken in this study, will prove useful to predict the species-specific pharmacokinetics differences between the in vivo models used for drug development.
Synthesis of potential drug metabolites by a modified Udenfriend reaction
Slavik, Roger,Peters, Jens-Uwe,Giger, Rudolf,Bürkler, Markus,Bald, Eric
experimental part, p. 749 - 752 (2011/03/21)
The scope and the limitations of a modified Udenfriend reaction for the one-step synthesis of potential drug metabolites were explored. Several drugs (clozapine, chlorpromazine, imipramine, buspirone, diltiazem, and propranolol) were subjected to modified Udenfriend conditions (Fe2+/Mn 2+/EDTA/ascorbic acid/O2). From each reaction, one to four oxidation products were obtained in 1-8% overall yield. Many of these products (9 out of 14) have been reported to be metabolites of the parent drugs in vivo. The products resulted mainly from aromatic hydroxylation, and are not readily accessible by conventional synthesis. Thus, the described reaction may be useful in drug discovery whenever a facile synthetic access is more important than high yields (e.g., for a fast derivatisation of compounds or the preparation of metabolites). Poorly water-soluble compounds cannot be converted, which is an important limitation of this method. 2010 American Chemical Society.
Sequential metabolism of secondary alkyl amines to metabolic-intermediate complexes: Opposing roles for the secondary hydroxylamine and primary amine metabolites of desipramine, (S)-fluoxetine, and N-desmethyldiltiazem
Hanson, Kelsey L.,VandenBrink, Brooke M.,Babu, Kantipudi N.,Allen, Kyle E.,Nelson, Wendel L.,Kunze, Kent L.
experimental part, p. 963 - 972 (2011/03/18)
Three secondary amines desipramine (DES), (S)-fluoxetine [(S)-FLX], and N-desmethyldiltiazem (MA) undergo N-hydroxylation to the corresponding secondary hydroxylamines [N-hydroxydesipramine, (S)-N-hydroxyfluoxetine, and N-hydroxy-N-desmethyldiltiazem] by cytochromes P450 2C11, 2C19, and 3A4, respectively. The expected primary amine products, N-desmethyldesipramine, (S)-norfluoxetine, and N,N-didesmethyldiltiazem, are also observed. The formation of metabolic-intermediate (MI) complexes from these substrates and metabolites was examined. In each example, the initial rates of MI complex accumulation followed the order secondary hydroxylamine > secondary amine ? primary amine, suggesting that the primary amine metabolites do not contribute to formation of MI complexes from these secondary amines. Furthermore, the primary amine metabolites, which accumulate in incubations of the secondary amines, inhibit MI complex formation. Mass balance studies provided estimates of the product ratios of N-dealkylation to N-hydroxylation. The ratios were 2.9 (DES-CYP2C11), 3.6 [(S)-FLX-CYP2C19], and 0.8 (MA-CYP3A4), indicating that secondary hydroxylamines are significant metabolites of the P450-mediated metabolism of secondary alkyl amines. Parallel studies with N-methyl-d3-desipramine and CYP2C11 demonstrated significant isotopically sensitive switching from N-demethylation to N-hydroxylation. These findings demonstrate that the major pathway to MI complex formation from these secondary amines arises from N-hydroxylation rather than N-dealkylation and that the primary amines are significant competitive inhibitors of MI complex formation. Copyright
PROCESS FOR PREPARING DILTIAZEM USING A HETEROGENEOUS TRIFUNCTIONAL CATALYST
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Page 7, (2008/06/13)
The present invention comprises a simplified synthesis of (+)-diltiazem through IE-PdOsW wherein IE is ion-exchanger, catalyzed three-component coupling reaction and Fe3+-exchanged clay catalyzed ring opening of sulfite with 2-aminothiophenol followed by cyclization as key steps.
Kinetics of diltiazem hydrochloride in solid phase
Muszalska, Izabela,Siakowski, Maciej
, p. 27 - 30 (2007/10/03)
The influence of temperature (353, 358, 363, 368, and 373K) and relative humidity (76.4, 66.5, 60.5 and 50.9% RH) on the stability of diltiazem hydrochloride in the solid phase was investigated. The decomposition was followed by a HPLC method with UV detection. The kinetic (rate constants, t0.1 and t0.5) and thermodynamic parameters (energy, entalpy and entropy of activation) of the degradation of diltiazem hydrochloride were calculated.
Kinetics of hydrolysis of diltiazem hydrochloride in aqueous solutions
Muszalska, Izabela,Jamszol, Leszek,Grzeskowiak, Dariusz
, p. 163 - 168 (2007/10/03)
The kinetics of hydrolysis of diltiazem hydrochloride in aqueous solution at 313, 323, 333 and 353 K over the pH-range 0.4-9.7 has been investigated. The decomposition was followed by the HPLC method. The pH-rate profile was accounted for by the specific acid- and base-catalysed reactions and also by assuming spontaneous or water-catalysed decomposition of both dissociated and undissociated molecules of diltiazem. Various buffer substances were found to exhibit general acid and base catalysis of the degradation. Thermodynamic parameters of the reaction: energy and enthalpy of activation and the fraquency factor for the specific rate constants were determined.
Stereoselective Synthesis of Diltiazem via Dynamic Kinetic Resolution
Mordant, Celine,De Andrade, Cristina Cano,Touati, Ridha,Ratovelomanana-Vidal, Virginie,Hassine, Bechir Ben,Genet, Jean-Pierre
, p. 2405 - 2409 (2007/10/03)
An efficient synthesis of diltiazem has been developed using dynamic kinetic resolution (DKR) as a key step. The methyl (2S,3S)-2-chloro-3-hydroxy-3- (4-methoxyphenyl)propionate was synthesized from a racemic mixture of α-chloro-β-keto ester, with high anti diastereoselectivity (92%) and enantioselectivity (95%), based on an asymmetric hydrogenation reaction with a chiral ruthenium(II) catalyst, simply prepared by mixing Ru(cod)(2-methylallyl) 2 with the atropisomeric ligand (S)-MeO-BIPHEP. By treatment of this α-chloro-β-hydroxy ester with a base, the corresponding trans methyl glycidate, a key intermediate of diltiazem, was easily obtained.
A trifunctional catalyst for one-pot synthesis of chiral diols via heck coupling-N-oxidation-asymmetric dihydroxylation: Application for the synthesis of diltiazem and taxol side chain
Choudary, Boyapati M.,Chowdari, Naidu S.,Madhi, Sateesh,Kantam, Mannepalli L.
, p. 1736 - 1746 (2007/10/03)
A heterogeneous bifunctional catalyst composed of OsO42--WO42- and a trifunctional catalyst comprising PdCl42--OsO42-- WO42-, designed and prepared by an ion-exchange technique using layered double hydroxides (LDH) as an ion-exchanger and their homogeneous bifunctional analogue, K2OsO4-Na2WO4 and trifunctional analogue, Na2PdCl4-K2OsO4-K2 OSO4-NNa2WO4, devised for the first time are evaluated for the synthesis of chiral vicinal diols. These bifunctional and trifunctional catalysts perform asymmetric dihydroxylation-N-oxidation and Heck-asymmetric dihydroxylation-N-oxidation, respectively, in the presence of Sharpless chiral ligand, (DHQD)2PHAL in a single pot using H2O2 as a terminal oxidant to provide N-methylmorpholine oxide (NMO) in situ by the oxidation of N-methylmorpholine (NMM). The heterogeneous bifunctional catalyst supported on LDH (LDH-OsW) displays superior activity to afford diols with higher yields over the other heterogeneous catalysts developed by the ion exchange on quaternary ammonium salts covalently bound to resin (resin-OsW) and silica (silica-OsW) or homogeneous catalysts in the achiral dihydroxylation reactions. The LDH-OsW and its homogeneous analogue are found to be very efficient in performing a simultaneous asymmetric dihydroxylation (AD)-N-oxidation of a wide and varied range of aromatic, cyclic, and mono, di-, and trisubstituted olefins to obtain chiral vicinal diols with higher yields and ee's using H2O2. Further, the use of OsO42--WO42-- WO42- catalysts as such or in the supported form offers a simplified procedure for catalyst recycling, which shows consistent activity for a number of cycles. In this process, OsVI is recycled to OsVIII by a coupled electron transfer-mediator (ETM) system based on NMO-WO42- using H2O2, leading to a mild and selective electron transfer. The one-pot biomimic synthesis of chiral diols is mediated by a recyclable trifunctional heterogeneous catalyst (LDH-PdOsW) consisting of active palladium, tungsten, and osmium species embedded in a single matrix. This protocol, which provides prochiral olefins and NMO in situ by Heck coupling and N-oxidation of NMM, respectively, required for the AD, unfolds a low cost process. We extended the present method to the one-pot synthesis of trisubstituted chiral vicinal diols with moderate to excellent ee's by AD of trisubstituted olefins that are obtained by in situ Heck arylation of disubstituted olefins. The heterogeneous trifunctional catalysts offers chiral diols with unprecedented ee's and excellent yields in the AD of prochiral cinnamates, which are obtained in situ from acrylates and halobenzenes for the first time. The new variants such as LDH support and Et3N·HX inherently composed in the heterogeneous multicomponent system and slow addition of H202 facilitates the hydrolysis of osmium monogylcolate ester to subdue the formation of bisglycolate ester to achieve higher ee's. Without resorting to recrystallization, the chiral diols of cinnamates thus synthesized with 99% ee's and devoid of osmium contamination are directly put to use in the synthesis of diltiazem and Taxol side chain with an overall improved yield to demonstrate the synthetic utility of the trifunctional heterogeneous catalyst. The high binding ability of the heterogeneous osmium catalyst enables the use of equimolar ratio of ligand to osmium to give excellent ee's in AD in contrast to the homogeneous osmium system in which the excess molar quantities of the expensive chiral ligand to osmium are invariably used. Further, the XRD, FT-IR, UV-vis DRS, and XPS studies indicate the retention of the coordination geometries of the specific divalent anions anchored to LDH matrix in their monomeric form during the ion exchange and after the reaction.
Process for preparing optically active 3-hydroxy-1,5-benzothiazepine derivative and intermediate therefor
-
, (2008/06/13)
An optical resolution process of the compound of the formula (1): STR1 wherein Ring A and Ring B are a substituted or unsubstituted benzene ring and R1 and R2 are the same or different and a lower alkyl group, by utilizing difference in solubility between the two diastereoisomeric salts prepared by treating the racemic compound (1) with an acidic resolution agent. The present process is industrially advantageous with compared to conventional processes for preparing an optically active 3-hydroxy-1,5-benzothiazepine derivative which are useful as an intermediate for preparing medicines.
