Discovery synthesis

For a review, see M. Casely-Hayford, M. Searcey, The azinomycins. Discovery, synthesis and DNA-binding studies. in DNA and RNA hinders. From small molecules to drugs, Wiley-VCH, Weinheim, 2002. pp. 676 696. 

Smith PW, Sollis SL, Howes PD, Cherry PC, Starkey ID, Cobley KN, Weston H, Scicinski J, Merritt A, Whittington A, Wyatt P, Taylor N, Green D, BetheU R, Madar S, Fenton RJ, Motley PJ, Pateman T, Beresford A (1998) Dihydropyrancarboxamides related to zanamivir a new series of inhibitors of influenza virus sialidases. 1. Discovery, synthesis, biological activity, and structure-activity relationships of 4-guanidino- and 4-amino H-pyran-6-carboxamides. J Med Chem 41 787-797... 

The technical leadership by Professors J.C. Jansen and Th. Maschmeyer is greatly appreciated. They played a visionary role in the early discovery, synthesis, and characterization of the TUD-1 family. 

Jesse May Research/Discovery Synthesis, Research and Development, Alcon Laboratories, Inc., Fort Worth, Texas 76134, USA... 

Iwanowicz EJ, Lau WF, Lin J, Roberts DGM, Seiler SM. Retro-binding tripeptide thrombin active inhibitors discovery, synthesis and molecular modeling. J Med Chem 1994 37 2122-2124. 

Fischer R., (2008) Spirotetramat (Movento ) - discovery, synthesis and physicochemical properties. Bayer... 

Scheme 1. The initial Hoffmann-La Roche discovery synthesis.

Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery Synthesis,... 

The use of fluorine in molecules of pharmacological interest is well known and there has been widespread research into methodologies for the introduction of this atom. Within the discovery synthesis of maraviroc, the initial preparation required the use of diethyl amino sulfur trifluoride (DAST), which is commercially available but does require careful handling due its well known thermal instability. Initial use of DAST for the fluorination of the ketone 19 gave an inseparable 1 1 mixture of the required difluoro compound 20 and the vinyl fluoride 21. The formation of vinyl fluoride co-products from the treatment of ketones with DAST is known in the literature and is difficult to control. 

The de novo discovery synthesis of capecitabine (1) was reported by the Nippon Roche Research Center scientists9,19 and was followed up with a preparation invented by a team at the Hoffinann-La Roche laboratories in New Jersey for the conversion to 1 from 5 -DFCR (10).2° In the first route, 5-fluorocytosine (15) was mono-silated using one equivalent of hexamethyldisilazane in toluene at 100 °C followed by stannic chloride-catalyzed glycosidation with known 5-deoxy-l,2,3-tri-0-acetyl-p-D-ribofuranoside (17) in ice-cooled methylene chloride. While this procedure provided the 2, 3 -di-0-acetyl 5-fluorocytidine 18 in 76% yield on a 25-g scale, an alternative method was also devised using in situ-generated trimethylsilyl iodide in acetonitrile at 0°C to provide a 49% yield of 18 on smaller scale. Acylation of the N -amino group of the bis-protected 5 -DFCR derivative was accomplished by the slow addition of two equivalents of -pentyl chloroformate to a solution of 18 in a mixture of pyridine and methylene chloride at -20 °C, followed by a quench with methanol at room temperature to provide the penultimate intermediate 19 on 800-g scale. The yield of intermediate 19 was assumed to be quantitative and was subjected to the final deprotection step, with only a trituration to... 

In summary, sunitinib maleate (1) is a multitargeted receptor tyrosine kinase inhibitor with potent anti-angiogenic and antitumor activity. It is approved for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors, and is currently undergoing clinical trials for a number of additional malignancies. The discovery synthesis of 1 along with its process development approaches were described in this chapter. 

Access to 10 allowed the Yamanouchi process group to turn their attention to two shortcomings of the discovery synthesis (1) capricious imidazole ring formation (14—>1), which led to the formation of oxazolobenzazepine byproduct 15 and necessitated the chromatographic purification of 1, and (2) the installation biphenyl-2-carbonyl chloride (derived from costly biphenyl-2-carboxylic acid) early in the synthetic sequence, which led to considerable waste of this costly material through losses over the subsequent steps of the synthesis. 

Specific concerns for process chemistry and manufacture in the discovery synthesis of benzazepine (8) included the following ... 

In the discovery synthesis of 8 (Scheme 1), diol 12 was converted to benzyl benzazepine 13 in a two-step procedure. Oxidative cleavage of 12 with NaI04 (1 eq.) in aqueous dichloroethane gave dialdehyde intermediates that likely exist as bridged... 

Early in the twentieth century, the chemical industry was considered to have two parts the discovery, synthesis, and manufacture of inorganic and organic chemicals. Later, and until about 1997, the Standard Industrial Classification (SIC) of the U.S. Bureau of the... 

G. Munzenberg, Discovery, Synthesis and Nuclear Properties of the Heaviest Elements, Radiochim. Acta 70/71, 193 (1995)... 

D.H. Catlin, M.H. Sekera, B.D. Ahrens, B. Starcevic, Y.-C. Chang, C.K. Hatton, Tetrahydrogestrinone discovery, synthesis, and detection in urine. Rapid Commun. Mass Spectrom., 18 (2004) 1245. 

In an effort to find new agricultural herbicides a new class of broad spectrum soybean herbicides, the 3-isoxazolidinones, was discovered. The discovery, synthesis, and structure - activity relationships of this new class of herbicides and the related compounds will be discussed. 

Silylmethyltriazoles represent a new, highly active class of triazole fungicides, whose success in a wide variety of crops and climatic conditions confirms the utility of organosilicon compounds as agrichemicals. This paper describes their discovery, synthesis, and structure-activity relationships. Based on the results of worldwide field evaluations, some of which are presented, a member of this class, DPX-H6573, is being developed as a broad spectrum foliar fungicide. 

Development usually starts with the discovery synthesis, a process designed to produce only small quantities, and often involving chemicals and procedures not amenable to a manufacturing process. Early development converts the discovery route to a synthetic route that does not have chemical, safety, environmental, or operational issues that would prevent it from being commercially viable. This must be done before the drug substance solid form and impurity profile become set by formulation development and toxicological studies. 

Historical Review—A Pathway to Discovery Synthesis—A Survey of Methods Nongrafted Types Grafted Types Derivatization... 

Varenicline Discovery Synthesis and Process Chemistry Developments... 

Varenicline, a small (molecular weight 211.27) achiral alkaloid, was identified in 1997 as a potential treatment for smoking cessation. Its selection as our clinical candidate came after years of effort to identify an effective and safe partial agonist selective for the a4(32 nAChR subtype. A majority of the analogs explored in the course of our work were structurally related to the natural product (-)-cytisine and variations thereof.The discovery synthesis shown in Scheme 3.1 is rooted in... 

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