- Studies on synthesis of the antibacterial agent NM441. II. Selection of a suitable base for alkylation of 1-substituted piperazine with 4- (bromomethyl)-5-methyl-1,3-dioxol-2-one
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Diisopropylamine (DIPA), N,N-diisopropylethylamine (DIPEA), tributylamine (TNBA) and 7-(1-piperazinyl)-4-quinolone-3-carboxylic acid (2) were titrated in water-dimethylformamide (DMF) mixtures containing 45-98% DMF. Apparent pK(a) values in anhydrous DMF (pK(DMF)) were calculated by extrapolation from the variation in the half-neutralization pH values in aqueous DMF. The validity of the relative basicity derived from the pK(DMF)S was confirmed by examination of the kinetics of esterification of a derivative of 2 with 4- (bromomethyl)-5-methyl-1,3-dioxol-2-one (DMDO-Br). Relative basicities in DMF were: the carboxylate anion of 2 >> DIPA > DIPEA > TNBA > the amino group in the piperazinyl part of 2. This order is clearly different from that observed in water. We concluded that DIPEA is a suitable agent to suppress the undesired esterification during the reaction to mask the amino group of 2 with a DMDO group, because it does not remove a proton from the carboxyl group, but only from the protonated amino group.
- Fujii,Nishida,Abiru,Yamamoto,Kise
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Read Online
- A method for preparing of plurichari (by machine translation)
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The invention relates to a prepration method of a compound prulifloxacin as shown in the formula (I), wherein the chemical name of prulifloxacin is 6-floro-1-methyl-7-[4-(5-methyl-2-oxo1,3-dioxo hetercyclopentene-4-yl)methyl-1-piperazinyl-4-oxo-4H-[1,3] thiaazacyclobutane[3,2-a] quinoline-3-carboxylic acid. The preparation method provided by the invention is a preparation method of prulifloxacin suitable for industrialized production, simple in process, high in purity and high in yield.
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- CRYSTALLINE FORM OF PRULIFLOXACIN AND PROCESSES FOR ITS PREPARATION
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The present invention relates to a crystalline polymorphic form of 6-fluoro-1-methyl-7- {4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-4H-[1,3]-thiazeto-[3,2- a]-quinoline-3-carboxylic acid (prulifloxacin). More specifically, the invention relates to a crystalline form of prulifloxacin (herein referred to as Form A), and a method for preparing the crystalline Form A. The present invention further provides a pharmaceutical formulation comprising the novel form of prulifloxacin.
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- PROCESS FOR THE PREPARATION OF HIGHLY PURE PRULIFLOXACIN
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The present invention provides an industrially advantageous process for the preparation of highly pure prulifloxacin of formula I and its pharmaceutically acceptable salts. The present i innvention a also provides a novel process for the purification of prulifloxacin acid addition salt.
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Page/Page column 17
(2009/09/05)
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- PROCESS FOR THE PREPARATION OF PURE PRULIFLOXACIN
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The present invention relates to a process for the preparation of prulifloxacin. The present invention further relates to prulifloxacin having purity of about 99% or above.
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Page/Page column 6
(2008/12/07)
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- PROCESS FOR PREPARATION OF PRULIFLOXACIN USING NOVEL INTERMEDIATES
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The present invention provides a novel process for the preparation of prulifloxacin intermediate, 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid, thereby producing prulifloxacin and its pharmaceutical acceptable acid addition salts thereof in high purity and in high yield using novel intermediates in lesser reaction time. Thus, for example, ethyl 6,7-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate is reacted with boric acid in presence of acetic anhydride and acetic acid to give borane compound, which is then condensed with piperazine in presence of acetonitrile and dimethylsulfoxide, followed by treatment with potassium hydroxide solution to give 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid.
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Page/Page column 8
(2008/12/05)
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- CRYSTALS OF QUINOLINECARBOXYLIC ACID DERIVATIVE SOLVATE
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A main object is to provide a crystal of 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid acetonitrile solvate (Compound B) which is an intermediate for producing preferentially the type III crystal of 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]-thiazeto[3,2-a]quinoline-3-carboxylic acid (Compound A). A crystal of Compound B can be preferentially precipitated by controlling the supersaturation concentration in crystalization using acetonitrile as a solvent. Subsequently, the type III crystal of CompoundA can be produced by performing desolvation of the crystal.
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Page/Page column 6; 7; 15
(2008/06/13)
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- Studies on synthesis of antibacterial agent (NM441). I. Kinetics and mechanism of the reaction of 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one with 1-substituted piperazine (NM394)
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When a tertiary amine (4,NM441) is synthesized from 4-bromomethyl-5-methyl-1,3-dioxol-2-one (DMDO-Br) and a secondary amine (3,NM394) in N,N-dimethylformamide (DMF), the quaternary ammonium salt 5, the ring-opened compound 6, and the 1,2-adduct 7 are formed as by-products. The tertiary amine 4 is formed by nucleophilic attack of 3 on the α-carbon to the bromine atom of DMDO-Br. The ring-opened compound 6 is formed by nucleophilic attack of 3 on carbonyl carbon of DMDO-Br. The quaternary ammonium salt 5 is formed by the reaction of DMDO-Br with 4 (the Menshutkin reaction). Main pathway for the formation of 7 is the Michael addition of 3 to 6. Kinetics of the reactions have been studied and the methods to obtain 4 suppressing the formations of 5, 6, and 7 have been proposed based on the kinetic results.
- Nishida,Fujii,Abiru,Yatsuki,Yamamoto,Shimizu,Kakemi,Mikawa,Kise
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p. 1419 - 1426
(2007/10/02)
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- STUDIES ON PYRIDONECARBOXYLIC ACIDS. 1. SYNTHESIS AND ANTIBACTERIAL EVALUATION OF 7-SUBSTITUTED-6-HALO-4-OXO-4H-THIAZETOQUINOLINE-3-CARBOXYLIC ACIDS
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A series of thiazetoquinoline-3-carboxylic acids and their esters were prepared and evaluated for antibacterial activity.The derivatives with a hydrogen or methyl group at C-1, fluorine at C-6, and piperazinyl or 4-methyl-1-piperazinyl group at C-7 showed superior in vitro antibacterial activity, and the derivatives with 4-methyl-1-piperazinyl group at C-7 had potent in vivo activity.Compound 29a (NM394) showed excellent in vitro antibacterial activity and low toxicity but poor absorption from the gastrointestinal tract.Compound 29ee (NM441), an N- derivative of 29a, was found to possess a favorable pharmacokinetic profile and oral activity superior to that of ciprofloxacin in experimental animals.
- Segawa, Jun,Kitano, Masahiko,Kazuno, Kenji,Matsuoka, Masato,Shirahase, Ichiro,et al.
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p. 4727 - 4738
(2007/10/02)
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