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Kyung Hee Lee - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of the intermediate of gemifloxacin by the chemoselective hydrogenation of 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrroidine. Part 1. Screening of metal catalysts
Organic Process Research & Development, 2004Co-Authors: Hyun Kuk Noh, Jae Sung Lee, Yeongdae Kim, Gyohyun Hwang, Jay Hyok Chang, Hyunik Shin, Do-hyun Nam, Kyung Hee LeeAbstract:A novel synthetic route was devised for 4-Aminomethyl-3-Z-methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate of gemifloxacin, based on chemoselective hydrogenation of the cyano group in 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) with minimum reduction of the methyloxime group employing (t-Boc)2O (BOC) as in situ protecting agent. Over Raney nickel or cobalt catalysts, without in situ BOC protection of amine, the side reaction to 4-Aminomethyl-3-amino-1-(N-tert-butoxycarbonyl)pyrrolidine (AABP) was extensive by simultaneous hydrogenation of the methyloxime and cyano groups in CMBP, resulting in over-reduction of the desired intermediate, 4-Aminomethyl-3-Z-methoxyimino 1-(N-tert-butoxycarbonyl)pyrrolidine (Z-AMBP) all the way to AABP. When in situ BOC protection was performed, the selectivity to the desired 4-(N-tert-butoxycarbonyl)Aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (Z-BAMBP) rose to as high as 91% over Raney cobalt by suppressing the...
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Synthesis of the Intermediate of Gemifloxacin by the Chemoselective Hydrogenation of 4-Cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine. Part 2. The Palladium Catalysts in Acidic Media
Organic Process Research & Development, 2004Co-Authors: Hyun Kuk Noh, Jae Sung Lee, Yeongdae Kim, Gyohyun Hwang, Jay Hyok Chang, Hyunik Shin, Hyun Nam, Kyung Hee LeeAbstract:Chemoselective hydrogenation of 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) to 4-Aminomethyl-3-Z-methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate for gemifloxacin, was investigated over Pd catalysts with in situ acid protection. Addition of more than 1.6 equiv of acidic protons for CMBP was found to drastically elevate both the reaction rate and selectivity to 4-Aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (Z-AMBP) over Pd catalyst with a complete suppression of the major side reaction to 4-cyano-3-amino-1-(N-tert-butoxycarbonyl)-3,4-pyrroline (CABP). Methanol as the organic solvent was found to increase the hydrogenation rate greatly compared to other solvents with a negligible decrease of selectivity. The leaching of Pd by acid and consequent accumulation of Pd ion in the reaction mixture was negligible in CMBP hydrogenation. The novel process of chemoselective CMBP hydrogenation in acidic media over Pd catalyst was thus much simpler yet m...
Jay Hyok Chang - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of the intermediate of gemifloxacin by the chemoselective hydrogenation of 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrroidine. Part 1. Screening of metal catalysts
Organic Process Research & Development, 2004Co-Authors: Hyun Kuk Noh, Jae Sung Lee, Yeongdae Kim, Gyohyun Hwang, Jay Hyok Chang, Hyunik Shin, Do-hyun Nam, Kyung Hee LeeAbstract:A novel synthetic route was devised for 4-Aminomethyl-3-Z-methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate of gemifloxacin, based on chemoselective hydrogenation of the cyano group in 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) with minimum reduction of the methyloxime group employing (t-Boc)2O (BOC) as in situ protecting agent. Over Raney nickel or cobalt catalysts, without in situ BOC protection of amine, the side reaction to 4-Aminomethyl-3-amino-1-(N-tert-butoxycarbonyl)pyrrolidine (AABP) was extensive by simultaneous hydrogenation of the methyloxime and cyano groups in CMBP, resulting in over-reduction of the desired intermediate, 4-Aminomethyl-3-Z-methoxyimino 1-(N-tert-butoxycarbonyl)pyrrolidine (Z-AMBP) all the way to AABP. When in situ BOC protection was performed, the selectivity to the desired 4-(N-tert-butoxycarbonyl)Aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (Z-BAMBP) rose to as high as 91% over Raney cobalt by suppressing the...
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Synthesis of the Intermediate of Gemifloxacin by the Chemoselective Hydrogenation of 4-Cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine. Part 2. The Palladium Catalysts in Acidic Media
Organic Process Research & Development, 2004Co-Authors: Hyun Kuk Noh, Jae Sung Lee, Yeongdae Kim, Gyohyun Hwang, Jay Hyok Chang, Hyunik Shin, Hyun Nam, Kyung Hee LeeAbstract:Chemoselective hydrogenation of 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) to 4-Aminomethyl-3-Z-methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate for gemifloxacin, was investigated over Pd catalysts with in situ acid protection. Addition of more than 1.6 equiv of acidic protons for CMBP was found to drastically elevate both the reaction rate and selectivity to 4-Aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (Z-AMBP) over Pd catalyst with a complete suppression of the major side reaction to 4-cyano-3-amino-1-(N-tert-butoxycarbonyl)-3,4-pyrroline (CABP). Methanol as the organic solvent was found to increase the hydrogenation rate greatly compared to other solvents with a negligible decrease of selectivity. The leaching of Pd by acid and consequent accumulation of Pd ion in the reaction mixture was negligible in CMBP hydrogenation. The novel process of chemoselective CMBP hydrogenation in acidic media over Pd catalyst was thus much simpler yet m...
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Novel fluoroquinolone antibacterial agents containing oxime-substituted (Aminomethyl)pyrrolidines: synthesis and antibacterial activity of 7-(4-(Aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6- fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine
Journal of medicinal chemistry, 1997Co-Authors: Chang Yong Hong, Jay Hyok Chang, Nam, Do Hyun, Young Kwan Kim, Hoon Choi, Y.‐z. Kim, Jin Hwan KwakAbstract:New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an Aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C5-NH2) > F (C5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C5-NH2) > naphthyridine = F (C5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonstrated by their comparison to a desoximino compound 30. In addition, the oxime moiety greatly improved the pharmacokinetic parameters of the novel quinolones. Among these compounds, compound 20 (LB20304) showed the best in vivo efficacy and pharmacokinetic profile in animals, as well as good physical properties. The MICs (microgram/mL) of LB20304, compound 30, and ciprofloxacin against several test organisms are as follows: S. aureus 6538p (0.008, 0.031, and 0.13), methicillin resistant S. aureus 241 (4, 16, and 128), Streptococcus epidermidis 887E (0.008, 0.016, and 0.13), methicillin resistant S. epidermidis 178 (4, 32, and 128), Enterococcus faecalis 29212 (0.063, 0.13, and 1), Pseudomonas aeruginosa 1912E (0.25, 0.5, and 0.13), Escherichia coli 3190Y (0.008, 0.016, and 0.008), Enterobacter cloacae P99 (0.008, 0.031, and 0.008), Actinobacter calcoaceticus 15473 (0.063, 0.13, and 0.25). On the basis of these promising results, LB20304 was selected as a candidate for further evaluation.
Jin Hwan Kwak - One of the best experts on this subject based on the ideXlab platform.
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Novel fluoroquinolone antibacterial agents containing oxime-substituted (Aminomethyl)pyrrolidines: synthesis and antibacterial activity of 7-(4-(Aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6- fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine
Journal of medicinal chemistry, 1997Co-Authors: Chang Yong Hong, Jay Hyok Chang, Nam, Do Hyun, Young Kwan Kim, Hoon Choi, Y.‐z. Kim, Jin Hwan KwakAbstract:New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an Aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C5-NH2) > F (C5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C5-NH2) > naphthyridine = F (C5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonstrated by their comparison to a desoximino compound 30. In addition, the oxime moiety greatly improved the pharmacokinetic parameters of the novel quinolones. Among these compounds, compound 20 (LB20304) showed the best in vivo efficacy and pharmacokinetic profile in animals, as well as good physical properties. The MICs (microgram/mL) of LB20304, compound 30, and ciprofloxacin against several test organisms are as follows: S. aureus 6538p (0.008, 0.031, and 0.13), methicillin resistant S. aureus 241 (4, 16, and 128), Streptococcus epidermidis 887E (0.008, 0.016, and 0.13), methicillin resistant S. epidermidis 178 (4, 32, and 128), Enterococcus faecalis 29212 (0.063, 0.13, and 1), Pseudomonas aeruginosa 1912E (0.25, 0.5, and 0.13), Escherichia coli 3190Y (0.008, 0.016, and 0.008), Enterobacter cloacae P99 (0.008, 0.031, and 0.008), Actinobacter calcoaceticus 15473 (0.063, 0.13, and 0.25). On the basis of these promising results, LB20304 was selected as a candidate for further evaluation.
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novel fluoroquinolone antibacterial agents containing oxime substituted Aminomethyl pyrrolidines synthesis and antibacterial activity of 7 4 Aminomethyl 3 methoxyimino pyrrolidin 1 yl 1 cyclopropyl 6 fluoro 4 oxo 1 4 dihydro 1 8 naphthyridine 3 carbo
Journal of Medicinal Chemistry, 1997Co-Authors: Chang Yong Hong, Hoon Choi, Junbiao Chang, Jin Hwan KwakAbstract:New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an Aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C5-NH2) > F (C5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C5-NH2) > naphthyridine = F (C5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonst...
Hyun Kuk Noh - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of the intermediate of gemifloxacin by the chemoselective hydrogenation of 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrroidine. Part 1. Screening of metal catalysts
Organic Process Research & Development, 2004Co-Authors: Hyun Kuk Noh, Jae Sung Lee, Yeongdae Kim, Gyohyun Hwang, Jay Hyok Chang, Hyunik Shin, Do-hyun Nam, Kyung Hee LeeAbstract:A novel synthetic route was devised for 4-Aminomethyl-3-Z-methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate of gemifloxacin, based on chemoselective hydrogenation of the cyano group in 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) with minimum reduction of the methyloxime group employing (t-Boc)2O (BOC) as in situ protecting agent. Over Raney nickel or cobalt catalysts, without in situ BOC protection of amine, the side reaction to 4-Aminomethyl-3-amino-1-(N-tert-butoxycarbonyl)pyrrolidine (AABP) was extensive by simultaneous hydrogenation of the methyloxime and cyano groups in CMBP, resulting in over-reduction of the desired intermediate, 4-Aminomethyl-3-Z-methoxyimino 1-(N-tert-butoxycarbonyl)pyrrolidine (Z-AMBP) all the way to AABP. When in situ BOC protection was performed, the selectivity to the desired 4-(N-tert-butoxycarbonyl)Aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (Z-BAMBP) rose to as high as 91% over Raney cobalt by suppressing the...
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Synthesis of the Intermediate of Gemifloxacin by the Chemoselective Hydrogenation of 4-Cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine. Part 2. The Palladium Catalysts in Acidic Media
Organic Process Research & Development, 2004Co-Authors: Hyun Kuk Noh, Jae Sung Lee, Yeongdae Kim, Gyohyun Hwang, Jay Hyok Chang, Hyunik Shin, Hyun Nam, Kyung Hee LeeAbstract:Chemoselective hydrogenation of 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) to 4-Aminomethyl-3-Z-methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate for gemifloxacin, was investigated over Pd catalysts with in situ acid protection. Addition of more than 1.6 equiv of acidic protons for CMBP was found to drastically elevate both the reaction rate and selectivity to 4-Aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (Z-AMBP) over Pd catalyst with a complete suppression of the major side reaction to 4-cyano-3-amino-1-(N-tert-butoxycarbonyl)-3,4-pyrroline (CABP). Methanol as the organic solvent was found to increase the hydrogenation rate greatly compared to other solvents with a negligible decrease of selectivity. The leaching of Pd by acid and consequent accumulation of Pd ion in the reaction mixture was negligible in CMBP hydrogenation. The novel process of chemoselective CMBP hydrogenation in acidic media over Pd catalyst was thus much simpler yet m...
Chang Yong Hong - One of the best experts on this subject based on the ideXlab platform.
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Novel fluoroquinolone antibacterial agents containing oxime-substituted (Aminomethyl)pyrrolidines: synthesis and antibacterial activity of 7-(4-(Aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6- fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine
Journal of medicinal chemistry, 1997Co-Authors: Chang Yong Hong, Jay Hyok Chang, Nam, Do Hyun, Young Kwan Kim, Hoon Choi, Y.‐z. Kim, Jin Hwan KwakAbstract:New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an Aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C5-NH2) > F (C5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C5-NH2) > naphthyridine = F (C5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonstrated by their comparison to a desoximino compound 30. In addition, the oxime moiety greatly improved the pharmacokinetic parameters of the novel quinolones. Among these compounds, compound 20 (LB20304) showed the best in vivo efficacy and pharmacokinetic profile in animals, as well as good physical properties. The MICs (microgram/mL) of LB20304, compound 30, and ciprofloxacin against several test organisms are as follows: S. aureus 6538p (0.008, 0.031, and 0.13), methicillin resistant S. aureus 241 (4, 16, and 128), Streptococcus epidermidis 887E (0.008, 0.016, and 0.13), methicillin resistant S. epidermidis 178 (4, 32, and 128), Enterococcus faecalis 29212 (0.063, 0.13, and 1), Pseudomonas aeruginosa 1912E (0.25, 0.5, and 0.13), Escherichia coli 3190Y (0.008, 0.016, and 0.008), Enterobacter cloacae P99 (0.008, 0.031, and 0.008), Actinobacter calcoaceticus 15473 (0.063, 0.13, and 0.25). On the basis of these promising results, LB20304 was selected as a candidate for further evaluation.
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novel fluoroquinolone antibacterial agents containing oxime substituted Aminomethyl pyrrolidines synthesis and antibacterial activity of 7 4 Aminomethyl 3 methoxyimino pyrrolidin 1 yl 1 cyclopropyl 6 fluoro 4 oxo 1 4 dihydro 1 8 naphthyridine 3 carbo
Journal of Medicinal Chemistry, 1997Co-Authors: Chang Yong Hong, Hoon Choi, Junbiao Chang, Jin Hwan KwakAbstract:New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an Aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C5-NH2) > F (C5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C5-NH2) > naphthyridine = F (C5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonst...
