The Merck Bile Acid Cortisone Process:  The Next-to-Last Word

Pines, Seemon H.

doi:10.1021/op030050z

Cited by 28 publications

(27 citation statements)

References 32 publications

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“…The yearly overview is compiled in Figure 1 15 ). However, from 2005 to 2010 there was a trend towards longer synthetic routes (from 5.0 to 6.9 stages) and commensurately an increased number of reactive intermediates per synthesis (from 4.2 to 6.3).…”

Section: ■ Discussionmentioning

confidence: 99%

Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?

Elder

Teasdale

2015

Org. Process Res. Dev.

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A survey of over 300 synthetic publications published in Organic Process Research & Development over a 10-year period (2001−2010) provides a top-level overview of current synthetic strategies. It reaffirms the widely held view within the pharmaceutical industry that the synthesis of complex, multistage pharmaceuticals is untenable without the use of reactive, potentially mutagenic intermediates and that calls for "avoidance" reflect a lack of awareness of the challenges inherent in modern synthetic chemistry. On the basis of this survey, we can conclude that the average number of steps required to synthesize each active pharmaceutical ingredient (API) was 6 (5.9) and that the average number of reactive intermediates per synthetic route was 4 (4.1). It was also noted that there are four major classes of reactive intermediate that are commonly utilised in the later stages of API syntheses, (i.e., the last four stages): alkyl halides, acid chlorides, aromatic amines, and Michael acceptors. There was minimal usage of highly potent compounds from the "cohort of concern", which suggests that any additional focus on "cohort of concern" would be misplaced. Most of the cited publications gave several different alternative synthetic routes. In all cases there was no evidence to suggest that any of these alternative routes could produce the final API (of typical complexity) without the need to use reactive intermediates at some stage of the synthesis. In addition, the number of reactive intermediates remained broadly similar irrespective of which route was selected, strongly challenging the notion that avoidance was ever a viable option. This again underpins the argument that control, not avoidance or ALARP, is the most appropriate strategy in the overwhelming majority of cases.

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Section: ■ Discussionmentioning

confidence: 99%

Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?

Elder

Teasdale

2015

Org. Process Res. Dev.

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“…Finally, we examined the possibility of using our decarboxylative oxygenation strategy as a method for the oxidative degradation of linear aliphatic chains. Such dehomologations have previously been explored for the depolymerization of lignin into simple aromatic molecules and have also found application in the synthesis of drugs and natural products . As noted above, aliphatic aldehydes can undergo in situ autoxidation to the corresponding carboxylic acids and subsequent decarboxylative oxygenation to give ketone products.…”

Section: Methodsmentioning

confidence: 99%

“…2020, 60, 410 -415 application in the synthesis of drugs and natural products. [21,22] As noted above, aliphatic aldehydes can undergo in situ autoxidation to the corresponding carboxylic acids and subsequent decarboxylative oxygenation to give ketone products. For longer alkyl chains, this decarboxylation-oxidation sequence could be continued until a product which could not undergo further oxidation was formed (Scheme 4).…”

Section: Communicationmentioning

confidence: 95%

Decarboxylative Oxygenation via Photoredox Catalysis

Faraggi

MacMillan

2019

Israel Journal of Chemistry

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The direct conversion of aliphatic carboxylic acids to their dehomologated carbonyl analogues has been accomplished through photocatalytic decarboxylative oxygenation. This transformation is applicable to an array of carboxylic acid motifs, producing ketones, aldehydes, and amides in excellent yields. Preliminary results demonstrate that this methodology is further amenable to aldehyde substrates via in situ oxidation to the corresponding acid and subsequent decarboxylative oxygenation. We have exploited this strategy for the sequential oxidative dehomologation of linear aliphatic chains.

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“…Fifty years ago, chromium(VI)based reagents such as CrO 3 were commonly used for this reaction, and, for example, the Merck synthesis of cortisone from the 1950s used three chromium(VI) oxidations [8] . Fifty years ago, chromium(VI)based reagents such as CrO 3 were commonly used for this reaction, and, for example, the Merck synthesis of cortisone from the 1950s used three chromium(VI) oxidations [8] .…”

Section: Continuous Oxidation Of Alcohols To Aldehydesmentioning

confidence: 99%

Continuous Processing in the Pharmaceutical Industry

Proctor

Dunn

Hawkins

et al. 2010

Green Chemistry in the Pharmaceutical Industry

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IntroductionAs the fi ne chemical and pharmaceutical industries progress into the 21st century there is an ever -increasing necessity to improve the sustainability of their manufacturing processes. In 2006 James Clark stated ' The three cornerstones of sustainable development -economic, environmental, and social benefi t -each provide drivers for change that should help to push the application of green chemistry forward ' [1] . The responsibility, therefore, is on the manufacturer to develop and operate sustainable processes, for example, by (i) reducing waste or treating waste to render it nonhazardous. (ii) improving process effi ciency by using less raw materials and by recycling and re -using solvents whenever appropriate, and (iii) developing cleaner, more energy -effi cient processes and by reducing emissions through effective abatement management.One useful measure of a process ' s sustainability is the E factor [2] . As defi ned by Roger Sheldon, the E factor is the ratio (by weight) of the by -products to the desired product(s). The pharmaceutical and fi ne chemical industries routinely operate processes with E factors one to two orders of magnitude higher than their petrochemical counterparts. There are many reasons for this, including the high level of chemical complexity in pharmaceutical products and the high quality standards in the pharmaceutical industry, but another circumstance contributing to this difference between the E factors is the type of manufacturing technology employed. The petrochemical industry tends to operate continuous processes, whereas the fi ne chemical and pharmaceutical industries predominantly use less effi cient batch manufacturing methods. It could be argued that the different production techniques simply refl ect the volume and complexity of the materials manufactured. Is it correct, however, that relatively simple petrochemical products are produced using modern continuous -based manufacturing technologies whereas pharmaceutical products and intermediates are produced using older batch methods?In the fi eld of organic chemistry, new synthetic strategies and methodologies are developed at an astonishing rate to access a diverse range of molecules.

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The Merck Bile Acid Cortisone Process: The Next-to-Last Word

Abstract: A personal account of the process research and development effort at Merck and Company, leading to the first commercial process for the manufacture of cortisone acetate, is described.

Cited by 28 publications

References 32 publications

Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?

Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?

Decarboxylative Oxygenation via Photoredox Catalysis

Continuous Processing in the Pharmaceutical Industry

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