Chemistry process synthesis

In a more proficient process chemistry synthesis and in lieu of (/ )-glycidyl butyrate (42), transformation of carbamate 41 to linezolid (2) was also achieved by the... 

Understanding the chemistry of the process also provides the greatest opportunity in applying the principles of inherent safety at the chemical synthesis stage. Process chemistry greatly determines the potential impact of the processing facility on people and the environment. It also determines such important safety variables as inventory, ancillary unit operations, by-product disposal, etc. Creative design and selection of process chemistry can result in the use of inherently safer chemicals, a reduction in the inventories of hazardous chemicals and/or a minimization of waste treatment requirements. 

Select a process chemistry or synthesis route that is inherently safer. 

Select a process chemistry or synthesis route that is inherently safer (e.g., nontoxic, nonflammable materials, less severe operating condition)... 

Basic process chemistry using less hazardous materials and chemical reactions offers the greatest potential for improving inherent safety in the chemical industry. Alternate chemistry may use less hazardous raw material or intermediates, reduced inventories of hazardous materials, or less severe processing conditions. Identification of catalysts to enhance reaction selectivity or to allow desired reactions to be carried out at a lower temperature or pressure is often a key to development of inherently safer chemical synthesis routes. Some specific examples of innovations in process chemistry which result in inherently safer processes include ... 

In order to probe the influence of Au and KOAc on the vinyl acetate synthesis chemistry, four different catalysts were synthesized. All of these catalysts were prepared in a manner exemplified in prior patent technology [Bissot, 1977], and each contained the same palladium loading in an egg-shell layer on the surface of a spherical silica support. The palladium content in the catalyst was easily controlled by adjusting the solution strength of palladium chloride (PdClj) added to the porous silica beads prior to its precipitation onto the support by reaction with sodium metasilicate (Na SiOj). The other two catalyst components (Au and KOAc) were either present or absent in order to complete the independent evaluation of their effect on the process chemistry, e.g., (1) Pd-i-Au-hKOAc, (2) Pd-i-KOAc, (3) Pd-hAu, and (4) Pd only. 

Early process development and modification of the Medicinal Chemistry synthesis for the first kilogram-scale delivery of finasteride... 

Process development of the synthesis of iodoaniline 28 began with an improved synthesis of l-(4 -aminobenzyl)-l,2,4-triazole (6) (Scheme 4.7), which was prepared in the medicinal chemistry synthesis, albeit with poor regioselectivity (Scheme 4.1). We found that this aniline intermediate 6 could be readily prepared in three steps in >90% overall yield from 4-amino-l,2,4-triazole (30) and 4-nitrobenzyl bromide (4) based on a modified literature procedure [9]. The condensation of 30 and 4 in isopropyl alcohol followed by deamination gave the nitro... 

With a common intermediate from the Medicinal Chemistry synthesis now in hand in enantiomerically upgraded form, optimization of the conversion to the amine was addressed, with particular emphasis on safety evaluation of the azide displacement step (Scheme 9.7). Hence, alcohol 6 was reacted with methanesul-fonyl chloride in the presence of triethylamine to afford a 95% yield of the desired mesylate as an oil. Displacement of the mesylate using sodium azide in DMF afforded azide 7 in around 85% assay yield. However, a major by-product of the reaction was found to be alkene 17, formed from an elimination pathway with concomitant formation of the hazardous hydrazoic acid. To evaluate this potential safety hazard for process scale-up, online FTIR was used to monitor the presence of hydrazoic acid in the head-space, confirming that this was indeed formed during the reaction [7]. It was also observed that the amount of hydrazoic acid in the headspace could be completely suppressed by the addition of an organic base such as diisopropylethylamine to the reaction, with the use of inorganic bases such as... 

Sithambaram, S., Ding, Y., Li, W., Shen, X., Gaenzler, F. and Suib, S.L. (2008) Manganese octahedral molecular sieves catalyzed tandem process for synthesis of quinoxalines. Green Chemistry, 10, 1029-1032. 

Mueller, R.H., A Practical Synthesis of Ifetroban Sodium. In Process Chemistry in the Pharmaceutical Industry (K.G. Gadamasetti, ed.). Chap. 3, Marcel Dekker, Inc., New York, 1999, pp. 37-55. 

Blagden, N., and Davey, R., Polymorphs take shape, Chem. in Brit., March 1999, p. 44. Owen, M., and Dewitt, S., Laboratory Automation in Chemical Development. In Process Chemistry in the Pharmaceutical Industry (K.G. Gadamasetti, ed.), Marcel Dekker, Inc., New York 1999, pp. 429-455 Conner, K., The drive to improve the bottom line. Today s Chemist at Work, November 1999, p. 29. Sullivan, M., Automation accelerates synthesis. Today s Chemist at Work, September 1999, p. 48. Studt, T., Raising the bar on combinatorial discovery, Drug Discovery Development, January/February 2000, p. 24. Harness, J.R., Automated sample handling supports synthesis and screening. Drug Discovery Development, January 1999, p. 69. 

While using the 0.1 % threshold as a determinant for when an impurity should be isolated to meet regulatory requirements is a good practice, there are other times when it becomes necessary to work with extraneous compounds at still lower levels. During the development of process chemistry for the synthesis of the protease inhibitor Tipranavir several synthetic lots of the drug were discolored, appearing pinkish rather than white as they should. It was determined that a low-level ( 0.1%) highly colored material was responsible for the problem with those lots and a request for the isolation and characterization of that contaminant was received [66]. 

A recent example of a product that is demanding in terms of process chemistry is a new herbicide from BASF. The seven-step synthesis requires bromination, chlorination, carbonylation, oxydation (with H2O2), hydrogenation, and a reaction with ethylene. As no fine-chemical manufacturer was in a position to offer the whole range of process technologies, the manufacture will be split between two fine-chemical companies. 

L-Dopa was produced industrially by Hoffrnann-LaRoche, using a modification of the Erlenmeyer synthesis for amino acids. In the 1960s, research at Monsanto focused on increasing the L-Dopa form rather than producing the racemic mixture. A team led by William S. Knowles (1917—) was successful in producing a rhodium-diphosphine catalyst called DiPamp that resulted in a 97.5% yield of L-Dopa when used in the Hoffrnann-LaRoche process. Knowles s work produced the first industrial asymmetric synthesis of a compound. Knowles was awarded the 2001 Nobel Prize in chemistry for his work. Work in the last decade has led to green chemistry synthesis processes of L-Dopa using benzene and catechol. 

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