- Preparation method of 2-(4-methoxyphenyl)-3-hydroxy-2, 3-dihydro-1, 5-benzothiazepine ketone
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The invention provides a preparation method of 2-(4-methoxyphenyl)-3-hydroxy-2, 3-dihydro-1, 5-benzothiazepine ketone. The preparation method comprises the following steps: taking o-aminothiophenol and methyl propiolate as raw materials to synthesize an intermediate product 1, carrying out selective epoxidation to obtain an intermediate product 2, reacting the intermediate product 2 with 4-methoxyphenyl anions, carrying out Mitsunobu reaction to obtain an intermediate product 3, and hydrolyzing to obtain the product. In the cyclization process of the intermediate product 1, the tension of Z-structure olefin is small so that the yield is high, subsequent epoxidation is an asymmetric epoxidation reaction, the obtained intermediate product 2 is high in optical purity and high in yield, the intermediate product 2 and 4-methoxyphenyl anions are subjected to SN2 reaction, configuration inversion is carried out in an ortho-position, and the product is obtained. The whole reaction process doesnot need to be split, the total yield of the route is high, and the method is economical.
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- Selective synthesis method of diltiazem chiral intermediate
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The invention provides a selective synthesis method of diltiazem chiral intermediate. The method is as below: using anisic aldehyde, chloroacetyl chloride and L-menthol as raw materials; first subjecting chloroacetyl chloride and L-menthol to an esterification reaction to obtain an intermediate 1; then subjecting the intermediate 1 with anisic aldehyde to a Darzens condensation reaction to produce diastereomer intermediates 2 and 3; refining to obtain an optically pure intermediate 3; reacting the intermediate 3 with o-aminothiophenol to obtain an intermediate 4; hydrolyzing the intermediate 4 to obtain an intermediate 5; and cyclizing the intermediate 5 to obtain a product. The invention has the advantages that the ester formed by chloroacetyl chloride and L-menthol is selective in the Darzens condensation reaction with anisic aldehyde to generate the more target product, and solubility difference between the target product and the isomer is used to directly obtain optically pure intermediate, without a complicated resolution process, and the yield is greatly improved. The method substantially increases the utilization rate of the main raw material anisic aldehyde and reduces cost.
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- Facile ionic liquid-mediated protocol for the regioselective synthesis of 1,5-benzothiazepines
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An efficient one-step ionic liquid-mediated green protocol for the regioselective synthesis of (+)=(±)-cis-2-(4-methoxy/benzyloxyphenyl)-3- hydroxy-2,3-dihydro-1,5- benzothiazepin-4-[5H]-ones has been developed from the reaction between substituted 2-aminobenzenethiol and methyl-(±)-trans-3- (4-methoxy/benzyloxy phenyl)glycidate, under nitrogen atmosphere, at 60±2 °C. The reaction has been performed in ionic liquids (viz, 1-butyl-3-methylimidazolium bromide/hexafluorophosphate), and the yields of the 1,5-benzothiazepine derivatives were found to be excellent. The cis-stereoisomer was obtained as the major product along with a trans-isomer as minor product.
- Jain, Renuka,Yadav, Tripti,Kumar, Manoj,Yadav, Ashok K.
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experimental part
p. 1889 - 1900
(2011/06/27)
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- Lipase activity of Lecitase Ultra: characterization and applications in enantioselective reactions
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The general properties of Lecitase Ultra, a phospholipase manufactured and marketed by Novozymes, Denmark, have been studied after purification by ultrafiltration. The enzyme has a molecular mass of 35 KD, pH-optimum of 8.5, and appears to possess a single active site which exhibits both the lipase and phospholipase activities that increase in the presence of Ca2+ and Mg2+ ions. The enzyme is inhibited by heavy metal ions and surfactants, and does not accept p-nitrophenyl acetate and glycerol triacetate. Substrates, such as glycerol tributyrate and p-nitrophenyl palmitate, esters of N-acetyl-α-amino acids and α-hydroxy acids are readily accepted. Amino acids with aliphatic residues, such as alanine, isoleucine, and methionine, are hydrolyzed with high enantioselectivity for the l-enantiomer (E >100), but amino acids with aromatic residues such as phenylalanine and phenylglycine, and esters of α-hydroxy acids are hydrolyzed with low enantioselectivity (E = 1-5). Immobilization of the enzyme in a gelatin matrix (gelozyme) leads to a marginal improvement in the enantioselectivity for these substrates. However, a dramatic improvement in enantioselectivity is observed for ethyl 2-hydroxy-4-oxo-4-phenylbutyrate (E value increases from 4.5 to 19.5 with S-selectivity). Similarly, glycidate esters, such as ethyl trans-(±)-3-phenyl glycidate and methyl trans-(±)-3-(4-methoxyphenyl) glycidate, are selectively hydrolyzed with a remarkable selectivity towards the (2S,3R)-enantiomer providing unreacted (2R,3S)-glycidate esters (ee >99%, conversion 52-55%) by the immobilized enzyme.
- Mishra, Mithilesh Kumar,Kumaraguru, Thenkrishnan,Sheelu, Gurrala,Fadnavis, Nitin W.
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experimental part
p. 2854 - 2860
(2010/04/05)
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- Novel protocol for the asymmetric synthesis of 3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one via bakers' yeast reduction
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A novel protocol for the asymmetric synthesis of 3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is reported. Darzens condensation reactions of anisaldehyde with dichloroacetates, followed substitution reaction of sodium o-nitrophenylthiolate and bakers' yeast reduction furnished 2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)-propionates. Further reduction of a nitro group and cyclization gave the title compound.
- Komiyama, Takuzo,Takaguchi, Yutaka,Tsuboi, Sadao
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p. 147 - 151
(2007/10/03)
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- Process for preparing diltiazem using a heterogeneous trifunctional catalyst
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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.
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- PROCESS FOR PREPARING DILTIAZEM USING A HETEROGENEOUS TRIFUNCTIONAL CATALYST
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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.
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- 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
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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.
- Choudary, Boyapati M.,Chowdari, Naidu S.,Madhi, Sateesh,Kantam, Mannepalli L.
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p. 1736 - 1746
(2007/10/03)
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- Stereoselective Synthesis of Diltiazem via Dynamic Kinetic Resolution
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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.
- Mordant, Celine,De Andrade, Cristina Cano,Touati, Ridha,Ratovelomanana-Vidal, Virginie,Hassine, Bechir Ben,Genet, Jean-Pierre
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p. 2405 - 2409
(2007/10/03)
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- Process for the preparation of a benzothiazepine
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Process for the preparation of a 1,5-benzothiazepine derivative, or a salt thereof, of formula 1 STR1 where R1 represents H, an alkyl group or an alkoxy group and R2 represents H or a halogen, in which process a propanoic acid derivative of formula 2 STR2 where R1 and R2 are as defined above and R3 represents H or an alkyl group is subjected to an intramolecular cyclisation reaction in a non-halogenated solvent in the presence of a carboxylic acid. Preferably, R2 is H and R1 is OCH3. Trichloroacetic acid is preferably used as α-chlorinated acid. The benzothiazepine obtained on cyclisation can be subjected to an alkylation reaction and/or an acylation reaction to obtain known pharmaceutical products, in particular diltiazem.
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- Efficient alternative synthetic route to diltiazem via (2R,3S)-3-(4- methoxyphenyl)glycidamide
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An effective new route to diltiazem, a representative coronary vasodilator, through (-)-(2R,3S)-3-(4-methoxyphenyl)glycidamide [(-)-2] has been achieved. The glycidamide (-)-2 was prepared in 43% overall yield by a combination of the enzymatic resolution of methyl (±)2(2RS,3SR)-3-(4- methoxyphenyl)glycidate [(±)-1] with lipase and the following amidation of (-)-1 with ammonia. A one-pot synthesis through the treatment of (-)-2 with 2-aminothiophenol and a following ring closing reaction efficiently gave a key intermediate of diltiazem synthesis, (2S,3S)-2,3-dihydro-3-hydroxy-2-(4- methoxyphenyl)-1,5-benzothiazepin-4(5H)-one [cis-(+)-5] in 80% overall yield.
- Yamada, Shin-ichi,Tsujioka, Ikuko,Shibatani, Takeji,Yoshioka, Ryuzo
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p. 146 - 150
(2007/10/03)
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- Process for preparing optically active trans-3-phenylglycidamide compounds
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Process for preparing optically active trans-3-phenylglycidamide compound, which comprises subjecting racemic trans-3-phenylglycidamide compound of the formula (I) STR1 wherein Ring A is substituted or unsubstituted benzene, and R1 is H or lower alkyl, to optical resolution using a microorganism having ability of preferentially hydrolyzing one of (2S,3R) isomer or (2R,3S) isomer thereof, and process for preparing an optically active 1,5-benzothiazepine derivative from the thus-obtained optically active trans-3-phenylglycidamide compound.
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- First practical resolution of a 3-(4-methoxyphenyl)glycidic acid ester by preferential crystallization and synthesis of diltiazem
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Among the various esters of 3-(4-methoxyphenyl)glycidic acid, 4-chloro- 3-methylphenyl ester (±)-3 was found to exist as a conglomerate, and could be alternately resolved into (+)- and (-)-3 of >98% ee by a preferential crystallization procedure. Furthermore, a 1,5-benzothiazepine derivative, (+)-6, a significant intermediate of diltiazem, was prepared in one pot in 76% overall yield through the treatment of enantiomerically pure (-)-3 with 2-aminothiophenol followed by a ring closing reaction.
- Yamada, Shin-Ichi,Morimatsu, Katsuji,Yoshioka, Ryuzo,Ozaki, Yasuhiko,Seko, Hiroyasu
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p. 1713 - 1721
(2007/10/03)
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- Process for preparing 1,5-benzothiazepine derivative
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A novel process for preparing 1,5-benzothiazepine derivative ?II!: STR1 wherein Ring A and Ring B are substituted or unsubstituted benzene ring, and R3 is H, (di-lower alkylamino)-lower alkyl or substituted or unsubstituted piperazinyl-lower alkyl, or a salt thereof, in high yield and in a single step from a novel 3-(2-amino-substituted or unsubstituted phenylthio)-2-hydroxy-3-substituted or unsubstituted phenylpropionamide compound. Said 1,5-benzothiazepine derivative ?II! is useful as an intermediate for preparing medicaments such as diltiazem hydrochloride.
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- Improved procedure for Julia-Colonna asymmetric epoxidation of α,β-unsaturated ketones: Total synthesis of diltiazem and Taxol side-chain
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Poly-L-leucine catalyses the asymmetric epoxidation of enones 1-6 efficiently in a non-aqueous medium to provide the epoxy ketones 7-12 (70-91% yield; 80 to ≥95% ee). The strategy was used to make diltiazem 16 and the Taxol side chain 23 in single enantiomer form.
- Adger, Brian M.,Barkley, James V.,Bergeron, Sophie,Cappi, Michael W.,Flowerdew, Benjamin E.,Jackson, Mark P.,McCague, Ray,Nugent, Thomas C.,Roberts, Stanley M.
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p. 3501 - 3507
(2007/10/03)
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- Asymmetric construction of two contiguous stereocenters by diastereoface differentiating addition reaction of thiols to chiral imides: Formal synthesis of (+)-diltiazem
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A high degree of diastereoselectivity has been achieved on the asymmetric construction of two contiguous stereocenters by the conjugate addition of thiols to α,β-unsaturated imides possessing Evans's chiral auxiliary. Addition reactions of thiophenol to chiral E- and Z-2-methylcrotonyl imides 4 proceeded with high diastereoface selectivities. Diastereoselectivities were discussed when E- and Z-imides 4 and 5 were used as the substrates. A successful application was demonstrated by the formal synthesis of a clinically useful cardiac drug, (+)-diltiazem.
- Miyata, Okiko,Shinada, Tetsuro,Ninomiya, Ichiya,Naito, Takeaki
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p. 2421 - 2438
(2007/10/03)
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- Optical resolution of a 1,5-benzothiazepine derivative, a synthetic intermediate of diltiazem, by preferential crystallization and diastereomeric salt formation
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Practical preparation methods of an optically active intermediate of diltiazem, (+)-(2S,3S)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one [(+)-7], have been developed by the use of physicochemical and chemical resolutions. 1) The salt of (+)-7 with 3-amino-4-hydroxy-benzenesulfonic acid (AHS), was found to exist as a conglomerate and could be reproducibly resolved into (+)-7·AHS and (-)- 7·AHS of 94-98% ee by a preferential crystallization procedure. 2) (+)- (1R)-3-Bromocamphor-9-sulfonic acid [(+)-BCS] was found to be an efficient resolving agent for (±)-7 and the diastereomeric resolution provided (+)- 7·(+)-BCS·2H2O salt in >43% yield and >97% ee by fractional crystallization. It is presumed that the crystal water of (+)-7·(+)- BCS·2H2O plays an important role in the selective crystallization during this efficient resolution.
- Yamada, Shin-Ichi,Yoshioka, Ryuzo,Shibatani, Takeji
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p. 1922 - 1927
(2007/10/03)
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- Process for the preparation of a benzothiazepine
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Process for the preparation of a 1,5-benzothiazepine derivative, or a salt thereof, of formula 1 where R1 represents H, an alkyl group or an alkoxy group and R2represents H or a halogen, in which process a propanoic acid derivative of formula 2 where R1and R2are as defined above and R3represents H or an alkyl group is subjected to an intramolecular cyclisation reaction in a non-halogenated solvent in the presence of a carboxylic acid. Preferably, R2is H and R1is OCH3.Trichloroacetic acid is preferablky used as α-chlorinated acid. The benzothiazepine obtained on cyclisation can be subjected to an alkylation reaction and/or an acylation reaction to obtain known pharmaceutical products, in particular diltiazem.
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- A microwave synthesis of the cis and trans isomers of 3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one : The influence of solvent and power output on the diastereoselectivity
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A diastereoselective one-pot synthesis and the trans- and cis-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H) -one nucleus, a key intermediate in the preparation of the calcium channel blocker Diltiazem, is carried out under microwave irradiation in an open vessel. Control of the diastereoselectivity is achieved by varying the reaction time and power output as well as the nature of the solvent.
- Vega, Juan A.,Cueto, Senida,Ramos, Andres,Vaquero, Juan J.,Garcia-Navio, Jose L.,Alvarez-Builla, Julio,Ezquerra, Jesus
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p. 6413 - 6416
(2007/10/03)
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- Asymmetric reduction of a 1,5-benzothiazepine derivative with sodium borohydride-(S)-α-amino acids: An efficient synthesis of a key intermediate of diltiazem
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A key intermediate of diltiazem synthesis, (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4 (5H)-one [(2S,3S)-1], has been efficiently synthesized by an asymmetric reduction of the prochiral ketone, 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (3), with NaBH4 and chiral α-amino acids. As the chiral sources, β-branched-chain amino acids, such as (S)-valine, (S)-isoleucine, and (S)-tert-leucine, were found to be effective. In particular, using (S)-tert-leucine as a ligand resulted in the formation of (2S,3S)-1 with excellent enantioselectivity. (95% ee for cis-isomers). The addition of AcOH to the reaction permitted further improvement of both conversion and stereoselectivity. As a result, optically pure (2S,3S)-1 could be isolated in 86% yield. This asymmetric reduction proceeded via dynamic kinetic resolution and made it possible to control the two adjacent asymmetric carbons through keto-enol tautomerism.
- Yamada, Shin-Ichi,Mori, Yoshikazu,Morimatsu, Katsuji,Ishizu, Yoshinori,Ozaki, Yasuhiko,Yoshioka, Ryuzo,Nakatani, Tadashi,Seko, Hiroyasu
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p. 8586 - 8590
(2007/10/03)
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- cis-(±)-5-[2- (Dimethylamino)ethyl]-3-hydroxy-2-(4- methoxyphenyl )-2,3,4,5-tetrahydro-1,5-benzothiazepin-4-one
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The title compound, C20H24N2O3S, is a drug intermediate of diltiazem. The molecule is stabilized by covalent bonding and weak hydrogen bonding, and the crystal packing is stabilized by hydrogen bonding. The seven-membered ring is distorted showing a twist-boat conformation. The methoxyphenyl and hydroxy groups are cis oriented with respect to one another, with the phenyl ring in an axial position. Intermolecular hydrogen bonding produces dimers in the crystal.
- Kumaradhas,Nirmala,Sridhar
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p. 2595 - 2597
(2007/10/03)
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- Enantiomer associations in the crystal structures of racemic and (2S,3R)-(-)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)- one
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The crystal structures of racemic and (2S,3R)-(-)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)- one (C16H15NO3S) have been determined in order to compare the interactions between molecules of the same and opposite chirality. The enantiomeric associations observed in these two crystal structures are analysed, relating the differences to those found in the equivalent diastereomers, (2R, 3R) and/or (2S, 3S). Single-crystal X-ray diffraction data were collected at low temperature with Cu Kα radiation (λ = 1.54184 A). Optically active: monoclinic, space group C2, with a = 24.726(3), b = 5.2426(5), c =12.0726(12) A, β - 112.979(9)°, V = 1440.8(5) A3, Z = 4, Dx= 1.389 g cm-3, μ = 20.35 cm-1, the refinement on 2918 observed reflections gave R=0.0271. Racemic: monoclinic, space group P21/n, with a = 13.308(3), b = 4.8474(8), c = 22.130(4) A, β = 91.782(14), V= 1426.9(5) A3, Z=4, Dx= 1.403 g cm-3, μ= 20.54 cm-1, refined to R = 0.0318 for 2753 observed reflections. An intramolecular hydrogen bond between the hydroxy and carbonyl groups appears to stabilize the benzothiazepinone ring in the (P,2S,3R) boat conformation with the hydroxy and methoxyphenyl substituents in equatorial positions. In both crystal structures two N-H...O hydrogen bonds connect the molecules into dimers. In the optically active compound the two molecules are related by a twofold axis, in the racemate by an inversion centre. The racemate contains an additional hydrogen bond which is reflected by its higher melting enthalpy compared with the optically active compound. The difference in the chiral discrimination in the solutions of the cis-and trans-diastereomers does not appear to have its origin in the strong (O-H...O, N-H...O) hydrogen bonds, but rather in the weak (C-H...O) interactions. Acta Chemica Scandinavica 1996.
- Marthi, Katalin,Larsen, Sine,Acs, Maria,Jaszay, Zsuzsa,Fogassy, Elemer
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p. 906 - 913
(2007/10/03)
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- Method for preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one and chlorinated derivatives thereof
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2-Aminothiophenol is reacted with methyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate, and the intermediate methyl (2S,3S)-3-[(2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionate is cyclized in the presence of methanesulfonic acid, in the same vessel and without isolating said intermediate product, using e.g. chlorobenzene as a solvent.
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- Enantioselective Catalytic Epoxidation of Cinnamate Esters
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A broad study of the (salen)Mn(III)-catalyzed asymmetric epoxidation of cis-cinnamate esters reveals that the steric properties of the ester group have a profound influence on enantioselectivity in the epoxidation reaction, with bulkier esters affording highest ee's.The sensitivity of the reaction selectivity to the steric properties of the cis-alkene are consistent with a "skewed" side-on approach of olefin to the metal -oxo.The electronic properties of the substrate arene ring substituents do not correlate with epoxidation ee, but instead with the cis/trans partitioning of product formation.Evidence is provided for a non-polar inter mediate in a stepwise oxygen-atom-transfer mechanism.The presence of pyridine N-oxide derivatives has a significant effect on catalysts rates and total turnovers, but negligible influence on the stereoselectivity of epoxidation.A mechanistic basis for the role of these additives is proposed.The synthetic applicability of the cinnamate epoxidation methodology is illustrated in the highly enantioslective synthesis of diltiazem.
- Jacobsen, Eric N.,Deng, Li,Furukawa, Yoshiro,Martinez, Luis E.
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p. 4323 - 4334
(2007/10/02)
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- Process for preparing optically active benzothiazepine compounds by asymmetric reduction
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Process for preparing optically active cis-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one compounds [I] of the formula: STR1 wherein Ring A and Ring B are substituted or unsubstituted benzene, R1 is hydrogen or di-lower alkylaminoalkyl, which comprises subjecting 1,5-benzothiazepin-4(5H)-one (II) of the formula [II]: STR2 wherein R4 is hydrogen or lower alkanoyl, and the other symbols are the same as defined above, to asymmetric reduction with a reaction product of optically active α-amino acid and metal hydride, in high optically yield, and said compounds [I] are very important as intermediate for preparing various medicines.
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- Process for the single crystallization of enatiomeric ratio's (2S,3S):(2R,3R) of substituted 1,5-benzothiazepinone
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A purification method of intermediates for the preparation of Diltiazem which consists of the crystallization of a mixture enantiomerically enriched in (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one is described.
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- Process for preparing 1,5-benzothiazepine derivatives
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There is disclosed a process for preparing 1,5-benzothiazepine derivatives of the formula: STR1 wherein R1 is a lower alkyl group, or a salt thereof which comprises subjecting a propionate derivatives of the formula: STR2 wherein R2 is an ester residue and R1 is the same as defined above, to intramolecular cyclization in the presence of a sulfonic acid compound of the formula: wherein R3 is a lower alkyl group or a substituted or unsubstituted phenyl group, in a non-halogenated organic solvent and, if desired, converting the product to a salt thereof.
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- Stereoselective addition of 2-aminothiophenol to α-alkoxycinnamic acid derivatives - Alternative synthesis of (±)-diltiazem
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A stereocontrolled synthesis of (±)-diltiazem by applying nucleophilic addition of 2-aminothiophenol to α-alkoxycinnamic acid derivatives is described.
- Miyata, Okiko,Shinada, Tetsuro,Naito, Takeaki,Ninomiya, Ichiya,Date, Tadamasa,Okamura, Kimio
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p. 8119 - 8128
(2007/10/02)
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- Process for the preparation of benzothiazepines by cyclization with phosphonic acids
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Process for the preparation of (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one of formula STR1 by direct cyclization of the compound of the formula STR2 with a catalytic amount of phosphonic acid.
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- Process for the resolution of intermediates useful in the preparation of 1,5-benzothiazepines
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A process for the resolution of amminoesters of the formula STR1 wherein R1 and R3 have the meanings reported in the specification, by tartaric acid and analogs thereof, is described. The compounds of formula IV-A are intermediates useful in the preparation of optically active (2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)ones.
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- Asymmetric induction at two contiguous stereogenic centers by diastereoface differentiating nucleophilic addition reaction
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Distereoface differentiating nucleophilic of thiophenol to olefins delivers a new concomitant asymmetric construction of two contiguous stereogenic centers and has been successfully applied to the asymmetric synthesis of (+)-diltiazem.
- Miyata, Okiko,Shinada, Tetsuro,Ninomiya, Ichiya,Naito, Takeaki
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p. 3519 - 3522
(2007/10/02)
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- Glycidic acid ester and process of preparation
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A process for the preparing a compound of the formula STR1 wherein R 1 and R 2 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, trifluoromethyl or nitro; or R 1 and R 2 taken together with the benzene ring to which they are attached are naphthalene, and Ar is p-lower alkoxy phenyl.which comprises reacting STR2 wherein R 1 and R 2 are as described above with the compound of the formula STR3 wherein Ar is as described above, in an aromatic organic compound. The intermediates formed by the process of the invention are useful in the production of thiazepin-4(5H)-ones which have activity as calcium channel blockers and accordingly are useful as agents for lowering blood pressure and agents for treating ischemia.
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- Process for preparing 1,5-benzothiazepin derivatives
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The invention relates to a process for preparing a preferably stereoisomerically pure 1,5-benzothiazepin derivative with the general formula (I) by the cyclization of an ester of the corresponding 2-hydroxy-3-(4-R3-phenyl)--3-(2-aminoarylthio)propanoic acid with the general formula (II) in the presence of a base and in an aprotic, polar solvent where R1 and R2, each independently, represent hydrogen, halogen, or an alkyl group with 1-6 carbon atoms or together with the phenyl group to which they are attached from a naphtalene group, R4 represents a residual group with 1-20 carbon atoms and R3 a hydrogen atom, a hydroxy group or an alkoxy group with 1-6 carbon atoms, at which a 2-hydroxy-3-(4-R3-phenyl)-3-(2-aminoarylthio)propanoic acid ester with the general formula (II) is cyclized in the presence of an alkali metal alkanolate as base. The invention also relates to a process for the preparation of alkylated and/or acylated 1,5-benzothiazepin derivatives and to the new compounds of (2X,3Y)-2-phenyl-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, (2X,3Y)-2-phenyl-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-di hydro-1,5-benzothiazepin-4(5H)-one and (2X,3Y)-2-phenyl--3-acetyloxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benz othiazepin-4(5H)-one, where X and Y each independently represent the R or S configuration. Application of 1,5-benzothiazepin derivatives, obtained according to the process of the present invention, in the preparation of pharmaceuticals and particularly in the preparation of diltiazem.
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- ENANTIOMER-ASSOCIATIONS INFLUENCING CHEMICAL REACTIVITY.
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A comparative study for a ring-closure reaction in solution, melt and solid state is reported.The different behaviour of the different enantio-composition is explained on the basis of enantiomer-associate formation.
- Acs, M.,Gizur, T.,Peter, I.,Harsanyi, K.,Jaszay, Zs.,Fogassy, E.
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p. 289 - 296
(2007/10/02)
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- Process for the resolution of intermediates useful in the preparation of 1,5-benzothiazepines
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A process for the resolution of amminoesters of the formula wherein R1 and R3 have the meanings reported in the specification, by tartaric acid and analogs thereof, is described. The compounds of formula IV-A are intermediates useful in the preparation of optically active 2-(4-methoxyphenyl)-1,5-benzothi-azepin-4(5H)ones.
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- Reaction of 3-Phenylglycidic Esters. III. Reaction of cis-3-Arylglycidic Esters with Various Thiophenols
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The reaction of the cis-3-arylglycidic esters 2 and 10 with thiophenols (3) has been investigated.The reactivity and stereoselectivity of the oxirane ring-opening of these cis-glycidic esters were lower than those of the trans-analogues (1 and 9).These tendencies were more apparent in the 4-MeO derivative (2).On the other hand, the tin-catalyzed reaction of 2 with 3a was highly stereospecific and afforded the cis-opening products (5a).Keywords - cis-3-arylglycidic ester; thiophenol; oxirane ring-opening; tin catalyst; stereoselectivity
- Hashiyama, Tomiki,Inoue, Hirozumi,Konda, Mikihiko,Takeda, Mikio
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p. 1256 - 1259
(2007/10/02)
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