Semisynthetic .BETA.-lactam antibiotics. III Synthesis and antibacterial activity of 7.BETA.-(2-(2-aminothiazol-4-yl)-2-(substituted carbamoylmethoxyimino)acetamido)cephalosporins.

Arimoto, Masao; Hayano, Takeshi; Soga, Tsunehiko; Yoshioka, Toshiyuki; Tagawa, Hiroaki; Furukawa, M.

doi:10.7164/antibiotics.39.1243

Cited by 10 publications

(5 citation statements)

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“…First, the amino functionality (i.e., piperidin-1-yl) was introduced at the 2-position by a method analogous to that described for the N 3 -methylated derivatives; the N 3 substituent was then introduced by reacting 28 with the appropriate electrophile (e.g., methyl bromoacetate to prepare 29a ) in DMF using NaH as the base. N,N -Diethylbromoacetamide and 1-(bromoacetyl)piperidine, required for the preparation of 31b and 31c , respectively, were prepared following the literature procedures. , Alkylation of quinazolin-4-ones has previously been reported to lead to N 3 -substituted products or a mixture of N 3 and O 4 products . Only N 3 -substituted quinazolin-4-ones were observed in this study, as confirmed by 1 H NMR spectroscopy.…”

Section: Chemistrymentioning

confidence: 99%

The Design and Synthesis of Water-Soluble Analogues of CB30865, a Quinazolin-4-one-Based Antitumor Agent

et al. 2002

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4-[N-[7-Bromo-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide (CB30865) is a quinazolin-4-one antitumor agent whose high growth-inhibitory activity (W1L2 IC(50) = 2.8 +/- 0.50 nM) is believed to have a folate-independent locus of action. In addition, CB30865 represents a class of compounds with unique biochemical characteristics such as a delayed, non-phase specific, cell-cycle arrest. The low aqueous solubility of CB30865 prompted a search for more water-soluble analogues for in vivo evaluation of this class of compounds. It was thought that aqueous solubility could be increased by the introduction of amino functionalities at the 2-position of the quinazolin-4-one ring. A variety of compounds (5a-j, 31a-c, 32, and 33) were synthesized in a linear fashion starting from 3-chloro-4-methylaniline. Most of these compounds (e.g., 5a, 5b, 5g) were significantly more water-soluble than CB30865 (636 microM for 5a at pH 6 and 992 microM for 5g at pH 6). In addition, some of them were up to 6-fold more cytotoxic than CB30865 (e.g., for 5a, W1L2 IC(50) = 0.49 +/- 0.24 nM) and retained its novel biochemical characteristics.

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Section: Chemistrymentioning

confidence: 99%

The Design and Synthesis of Water-Soluble Analogues of CB30865, a Quinazolin-4-one-Based Antitumor Agent

et al. 2002

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“…Attention was then turned to the aminolysis of the mesylate ( 24 ). In our hands the literature conditions did indeed result in poor yields of 8 . Our initial modification of the procedure used the more readily handled aqueous 28% ammonium hydroxide (10 L/kg) and isopropanol (15 L/kg) at 75 °C in a standard reaction flask open to the atmosphere.…”

Section: Discussion and Resultsmentioning

confidence: 50%

“…Another method (Scheme , steps a / h / i ) employs azide displacement of the sulfonate followed by reduction This chemistry was not pursued due to the process safety hazard associated with handling azides. The most attractive chemistry in the literature is the direct aminolysis (Scheme , steps a / e ) of the mesylate 24 , but the procedure as described gave a poor yield (27%) of 8 …”

Section: Discussion and Resultsmentioning

confidence: 99%

Process Development of a Novel Azetidinyl Ketolide Antibiotic

Magee

Buzon

et al. 2012

Org. Process Res. Dev.

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Process development and the multikilogram synthesis of a novel azetidinyl ketolide antibiotic is described. Starting with clarithromycin, the eight-step synthesis features several telescoped operations and direct isolations, which results in a significant improvement in throughput and a major reduction in solvent usage and waste stream volume over the first scale-up campaign. Particular highlights of this effort include the development of an efficient synthesis of 3-hydroxy-1,5-naphthyridine-4carbaldehyde via a Skraup process and engineering a robust final API synthesis. We also discovered a crystalline monotosylate salt that addressed significant formulation and degradation issues experienced when using the noncrystalline freebase.

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“…The most attractive chemistry in the literature is the direct aminolysis of the mesylate 3, but the procedure as described gave a poor yield (27%) of 1a. 9 Given the limitations of existing methods for the synthesis of 3-aminoazetidines, we undertook development a more readily scalable synthesis of 1a. Our initial approach is a threestep sequence and is shown in Scheme 2.…”

mentioning

confidence: 99%

“…In our hands, the literature conditions did indeed result in poor yields of 1a. 9 Our initial modification of the procedure used the more readily handled aqueous 28% ammonium hydroxide (10 vol) and isopropanol (15 vol) at 75°C in a standard reaction flask open to the atmosphere. Under these conditions the desired product 1a was observed as the major product, but the dimeric byproduct (7, Fig.…”

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confidence: 99%

An Efficient Two-Step Synthesis of 3-Amino-1-Benzhydrylazetidine

Witt

Brandt

et al. 2006

Journal of Chemical Research

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A streamlined process for the synthesis of 3-amino-1-benzhydrylazetidine is described. Commercially available 1-benzhydrylazetidin-3-ol was reacted with methanesulfonyl chloride in the presence of triethylamine in acetonitrile, upon quench with water, the mesylate intermediate (3) was isolated by filtration. The wet filter cake was subsequently treated with ammonium hydroxide/isopropanol in a Parr reactor at ~70°C. The procedure afforded the titled compound as mono acetate salt in 72-84% yield.

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Semisynthetic .BETA.-lactam antibiotics. III Synthesis and antibacterial activity of 7.BETA.-(2-(2-aminothiazol-4-yl)-2-(substituted carbamoylmethoxyimino)acetamido)cephalosporins.

Cited by 10 publications

References 0 publications

The Design and Synthesis of Water-Soluble Analogues of CB30865, a Quinazolin-4-one-Based Antitumor Agent

The Design and Synthesis of Water-Soluble Analogues of CB30865, a Quinazolin-4-one-Based Antitumor Agent

Process Development of a Novel Azetidinyl Ketolide Antibiotic

An Efficient Two-Step Synthesis of 3-Amino-1-Benzhydrylazetidine

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