Ein einfaches neues Verfahren zur Herstellung 2-substituierter Chinazoline

Sasse, Klaus

doi:10.1055/s-1978-24754

Cited by 12 publications

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“…Hydrolysis of the latter with dilute NaOH, followed by acidification, gave the propionic acid derivatives ( 4a − d ). The precursory dichloroquinazolines ( 2a − d ) were prepared via the following known sequence of reactions: (i) selective photolytic (side chain) dichloronation of the corresponding (commercially available) chloro- o -tolylisocyanates to the benzal chloride derivatives; (ii) conversion of the latter with anhydrous NH 3 to N-substituted ureas; and (iii) cyclization of each urea with NH 4 OH to a chloro-2-quinazolone . The latter, on treatment with POCl 3 , gave the dichloroquinazolines.…”

Section: Chemistrymentioning

confidence: 99%

“…Compound 1 (XK469) (Figure ) is among the most highly and broadly active antitumor agents to have been evaluated in our laboratories. − Subsequent developmental studies involved the National Cancer Institute (NCI), the DuPont Pharmaceuticals Company (DPC), and our laboratories. The collaborative effort led only recently to the entry of ( R )-(+) 1 (NSC 698215) into phase 1 clinical trials (NIH UO1-CA62487).…”

Section: Introductionmentioning

confidence: 99%

“…1 H NMR (400 MHz, DMSO-d6): δ 13.05 (bs, 1H), 8.40 (d, J ) 8.8 Hz, 1H), 7.96 (d, J ) 8 4. Hz, 1H), 7.66 (d, J ) 2.8 Hz, 1H), 7.48 (dd, J ) 8.8, 2.4 Hz, 1H), 7.24 (d, J ) 8.0 Hz, 1H), 7.18-7.13 (m, 2H), 6.94-6.89 an agent against leukemia cells, solid tumor cells (including multidrug resistant solid tumors), and normal cells.…”

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confidence: 99%

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II. Synthesis and Biological Evaluation of Some Bioisosteres and Congeners of the Antitumor Agent, 2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic Acid (XK469)

et al. 2002

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XK469 (1) is among the most highly and broadly active antitumor agents to have been evaluated in our laboratories. Subsequent developmental studies led to the entry of (R)-(+) 1 (NSC 698215) into phase 1 clinical trials (NIH UO1-CA62487). The antitumor mechanism of action of 1 remains to be elucidated, which has prompted a sustained effort to elaborate a pharmacophoric pattern of 1. The present study focused on a strategy of synthesis and biological evaluation of topologically based, bioisosteric replacements of the quinoxaline moiety in the lead compound (1) by quinazoline (4a-d), 1,2,4-benzotriazine (12a-18b), and quinoline (21a-g) ring systems. The synthetic approach to each of the bioisosteres of 1 utilized the methodology developed in previous work (see Hazeldine, S. T.; Polin, L.; Kushner, J.; Paluch, J.; White, K.; Edelstein, M.; Palomino, E.; Corbett, T. H.; Horwitz, J. P. Design, Synthesis, and Biological Evaluation of Analogues of the Antitumor Agent 2-(4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469). J. Med. Chem. 2001, 44, 1758-1776.), which is extended to the procurement of the benzoxazole (23a,b), benzthiazole (23c,d), pyridine (25a,b), and pyrazine (27) congeners of 1. Only quinoline analogues, bearing a 7-halo (21a,b,d,e) or a 7-methoxy substituent (21g), showed antitumor activities (Br > Cl > CH(3)O > F approximately I), at levels comparable to or greater than the range of activities manifested by 1 and corresponding analogues. At high individual dosages, the (S)-(-) enantiomers of 1 and 21b,d all produce a reversible slowing of nerve-conduction velocity in the mice, the onset of which is characterized by a distinctive dysfunction of the hind legs, causing uncoordinated movements. The condition resolves within 5-10 min. However, at higher dosages, which approach a lethal level, the behavior extended to the front legs, lasting from 20 min to 1 h. By contrast, the (R)-(+) forms of these same agents did not induce the phenomenon of slowing of nerve-conduction velocity.

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Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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II. Synthesis and Biological Evaluation of Some Bioisosteres and Congeners of the Antitumor Agent, 2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic Acid (XK469)

et al. 2002

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“…2-Aminoquinazoline is an important substructure for the development of pharmaceutically relevant compounds, especially for the discovery of kinase inhibitors. [1][2][3][4][5][6] A number of methods for the construction of 2-aminoquinazolines are know; [7][8][9][10][11][12][13][14][15][16] However, there are only a few approaches that exploit guanidines as reaction components. ortho-Halobenzaldehydes and aryl ketones can be condensed with guanidines in most cases if they contain an additional electron-withdrawing group that facilitates an S N Ar reaction.…”

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2-Aminoquinazolines by Chan–Evans–Lam Coupling of Guanidines with (2-Formylphenyl)boronic Acids

Solomin

Seins

Jirgensons

2020

Synlett

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A new method is presented for the synthesis of 2-aminoquinazolines, which is based on a Chan–Evans–Lam coupling of (2-formylphenyl)boronic acids with guanidines. Relatively mild conditions involving the use of inexpensive CuI as a catalyst and methanol as a solvent permit the application of the method to a wide range of substrates. Nonsubstituted, N-monosubstituted, and N,N-disubstituted guanidines can be used as reactants to give the corresponding 2-aminoquinazolines in moderate yields from readily available (2-formylphenyl)boronic acids.

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Ammonia

McCullough¹

2001

Encyclopedia of Reagents for Organic Synthesis

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Ein einfaches neues Verfahren zur Herstellung 2-substituierter Chinazoline

Cited by 12 publications

References 0 publications

II. Synthesis and Biological Evaluation of Some Bioisosteres and Congeners of the Antitumor Agent, 2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic Acid (XK469)

II. Synthesis and Biological Evaluation of Some Bioisosteres and Congeners of the Antitumor Agent, 2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic Acid (XK469)

2-Aminoquinazolines by Chan–Evans–Lam Coupling of Guanidines with (2-Formylphenyl)boronic Acids

Ammonia

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