Synthesis and anti-MRSA Activity of Novel Cephalosporin Derivatives

D'Andrea, Stan V.; Bonner, Daniel P.; Bronson, Joanne J.; Clark, Junius M.; Denbleyker, Ken; Fung‐Tomc, Joan; Hoeft, Shelley E.; Hudyma, Thomas W.; Matiskella, John D.; Miller, Regina; Misco, Peter F.; Pucci, Michael J.; Sterzycki, Roman Z.; Tsai, Yuan-Hwang; Ueda, Yasutsugu; Wichtowski, John A.; Singh, Jagadish; Kissick, Thomas P.; North, Jeffrey T.; Pullockaran, Annie; Humora, Michael; Boyhan, Brenda; Vu, Truc; Fritz, Alan W.; Heikes, James E.; Fox, Rita; Godfrey, Jollie D.; Perrone, Robert; Kaplan, Murray A.; Kronenthal, David R.; Mueller, Richard H.

doi:10.1016/s0040-4020(00)00418-x

Cited by 11 publications

(13 citation statements)

References 12 publications

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“…Since an attempted direct oxidation of 2‐amino‐6‐chloropyridine18 with m ‐chloroperbenzoic acid ( m ‐CPBA) according to the protocol of Pentimalli19 unexpectedly did not give the desired N ‐oxide 20 , it was prepared from 2‐acetamido‐6‐chloropyridine ( 16 )20 or alternatively from 2,6‐dichloropyridine N ‐oxide21 ( 21 ) (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

“…Organic extracts were dried with anhydrous MgSO 4 . tert ‐Butyl ( S )‐ N ‐( tert ‐butyloxycarbonyl)pyroglutamate ( 2 ),28 (2 S ,4 R )‐( N ‐ tert ‐butyloxycarbonyl)‐4‐hydroxyproline ( 7 ),29 (2 S ,4 R )‐( N ‐ tert ‐butyloxycarbonyl)‐4‐hydroxyprolinol tert ‐butyldimethylsilyl ether ( 9 ),11 tetrabutylammonium cyanide,30 2‐acetamino‐6‐chloropyridine ( 16 ),20 2,6‐dichloropyridine N ‐oxide ( 21 )21 were prepared as described elsewhere. (2 S ,1′ R ,2′ R )‐3‐(2′‐Nitrocyclopropyl)alanine was kindly provided by O. V. Larionov (Göttingen) 24…”

Section: Methodsmentioning

confidence: 99%

“…2‐Amino‐6‐chloropyridine N ‐Oxide (20): 2,6‐Dichloropyridine N ‐oxide ( 21 )21 (6.30 g, 38.4 mmol) was heated with 25% NH 3 in MeOH (100 mL) in a sealed tube at 105 °C for 26 h (TLC control). The tube was cooled in an ice‐water bath, then opened, and the reaction mixture was filtered and concentrated under reduced pressure.…”

Section: Methodsmentioning

confidence: 99%

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Convergent Syntheses of N‐Boc‐Protected (2S,4R)‐4‐(Z)‐Propenylproline and 5‐Chloro‐1‐(methoxymethoxy)pyrrol‐2‐carboxylic Acid − Two Essential Building Blocks for the Signal Metabolite Hormaomycin

et al. 2004

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An efficient and scalable synthesis of enantiomerically pure N-Boc-protected 4-(Z)-propenylproline (15) using the conventional Wittig reaction to construct the double bond has been developed [11% yield over 8 steps from N-Boc-pro- (29)] was prepared along a reasonably efficient synthetic route applying the thermal rearrangement of 2-azido-6-chloropyridine N-oxide (22) as a key step in fairly good overall yield [9% over 7 steps from easily accessible 2,6-dichloro-

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Convergent Syntheses of N‐Boc‐Protected (2S,4R)‐4‐(Z)‐Propenylproline and 5‐Chloro‐1‐(methoxymethoxy)pyrrol‐2‐carboxylic Acid − Two Essential Building Blocks for the Signal Metabolite Hormaomycin

et al. 2004

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“…1 H NMR (300 MHz, DMSO-d 6 ): d = 1.59 (s, 3 H), 2.85 (d, J = 4.9 Hz, 1 H), 3.07 (d,J = 4.9 Hz,1 H),7.59 (d,J = 7.9 Hz,1 H),7.94 (d,J = 7.9 Hz, 1 H). 13 …”

Section: 6-dichloro-3-(2-methyloxiran-2-yl)pyridine (2a)mentioning

confidence: 99%

“…The styrene 10 was prepared from 5a in three steps comprising N-oxidation (54%), elimination (96%), and chlorination (38%). An alternative route towards 10 started with the oxidation of 2,6-dichloropyridine (4; 69%) 13 and reaction with acetone after deprotonation (57%) to yield the same product as isolated from the oxidation of 5a. The epoxidation of 10 was significantly slower than for the dichloro derivative 6, and 11 was isolated in 71% yield.…”

Section: Scheme 1 Retrosynthesismentioning

confidence: 99%

A Versatile Synthesis of 7-Azaindoles

Schirok¹

2005

Synlett

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1,3-Disubstituted 7-azaindoles were synthesized from 2,6-dichloropyridine using DoM and intramolecular aromatic substitution after epoxide opening by an amine. Even the sterically demanding adamantylamine may be incorporated leading to derivatives which are not accessible by alkylation of the parent compound.In nature 7-azaindoles (1H-pyrrolo[2,3-b]pyridines) appear only as a substructure in a small number of alkaloids. However, much interest in this heterocyclic moiety has arisen in recent pharmacological programs, wherein it serves as bioisoster of indole or purine. 1 Numerous publications on its synthesis and derivatization reflect the increasing attention paid to this heterocyclic system. 2,3 In connection with a medicinal chemistry program, we required a practical synthesis of 1,3-substituted azaindoles of the general formula 1 (Scheme 1). Inspired by two reports on the synthesis of indoles from 2-(2-chlorophenyl)oxiranes 4 and 2-(2-bromophenyl)oxiranes, 5 we decided to develop a new azaindole synthesis based on the retrosynthetic analysis depicted in Scheme 1. An amine should open the epoxide 2 to an amino alcohol, which expels the adjacent halogen by intramolecular nucleophilic aromatic substitution. Subsequent dehydration should yield the desired heterocycle 1. We planned to start with 2,6-dichloropyridine (4) for the synthesis of oxiranes 2. The directed ortho metalation (DoM) of 4 should allow its functionalization in the 3-position. 6The lithiation 7 of fluoro-and chloropyridines 8 has been thoroughly studied by Quéguiner 9 and Schlosser. 10 In our hands, after deprotonation of 2,6-dichloropyridine (4) with LDA, the addition to ketones like acetone, acetophenone, or trifluoroacetone occurred smoothly (Scheme 2), and the desired tertiary alcohols 5 could be easily separated from unconsumed starting material by column filtration due to their higher polarity. In agreement with repeated reports in the literature, we detected small amounts of the regioisomeric adducts resulting from lithiation at the 4-position. In the course of our investigations it turned out to be unnecessary to separate the regioisomers, since the minor component leads to a polar, unproductive intermediate in the last step of the sequence. The dehydration of 5 yielding a-substituted styrene derivatives 6 was performed in a mixture of acetic and sulfuric acid (3:1) at 130°C for 30 minutes. The elimination products were isolated after basic work-up and did not need further purification. Unfortunately, 5c failed to dehydrate due to the strong electron-withdrawing effect of the trifluoromethyl group. Even after heating in concentrated sulfuric acid to 120°C for 14 hours we recovered the alcohol 5c almost quantitatively. With other reagents like thionyl chloride, thionyl chloride/pyridine 11 or Burgess' reagent we were also unsuccessful, demonstrating that this approach is not applicable for the synthesis of 3-trifluoromethyl 7-azaindole.The epoxides 2 were generated from the alkenes by oxidation with MCPBA in dichloromethane, and were essen...

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Cephalosporins

Alcaide

Aragoncillo

2008

Comprehensive Heterocyclic Chemistry III

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Synthesis and anti-MRSA Activity of Novel Cephalosporin Derivatives

Cited by 11 publications

References 12 publications

Convergent Syntheses of N‐Boc‐Protected (2S,4R)‐4‐(Z)‐Propenylproline and 5‐Chloro‐1‐(methoxymethoxy)pyrrol‐2‐carboxylic Acid − Two Essential Building Blocks for the Signal Metabolite Hormaomycin

Convergent Syntheses of N‐Boc‐Protected (2S,4R)‐4‐(Z)‐Propenylproline and 5‐Chloro‐1‐(methoxymethoxy)pyrrol‐2‐carboxylic Acid − Two Essential Building Blocks for the Signal Metabolite Hormaomycin

A Versatile Synthesis of 7-Azaindoles

Cephalosporins

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