The Development of a Scalable, Chemoselective Nitro Reduction

Gallagher, William P.; Marlatt, M.; Livingston, R. C.; Kiau, Susanne; Müslehiddinoğlu, Jale

doi:10.1021/op3002239

Cited by 18 publications

(7 citation statements)

References 45 publications

(21 reference statements)

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“…The addition of the E ring was achieved with 3.5 equivalents of 6-chloro-2,4-bis- tert -butoxy-5-nitropyrimidine 20 produced from 5-nitrobarbituric acid in two stepsvia condensation of deprotected amine 19 to deliver 21 in 77% yield. The D ring was forged via reduction of the nitropyrimidine with Raney Ni, followed by condensation promoted by camphorsulfonic acid . The enamine 6 had noted oxygen sensitivity, and all attempts to isolate the intermediate led to degradation.…”

Section: Resultsmentioning

confidence: 99%

Access to the Surugatoxin Alkaloids: Chemo-, Regio-, and Stereoselective Oxindole Annulation

2015

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Section: Resultsmentioning

confidence: 99%

Access to the Surugatoxin Alkaloids: Chemo-, Regio-, and Stereoselective Oxindole Annulation

2015

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“…10) Since Pd-catalytic reduction is potentially dangerous in process chemistry when the reaction is scaled up, this reduction was performed after sufficient degassing to remove oxygen. 23) Reduction conditions using CPME as a solvent at normal pressure were examined, but without success. Therefore, in anticipation of promoting the reaction, we used EtOH, which is a protonic solvent.…”

Section: Examination Of Conditions For Each Reaction Stepmentioning

confidence: 99%

Development of Scaled-Up Synthetic Method for Retinoid X Receptor Agonist NEt-3IB Contributing to Sustainable Development Goals

Takamura

Morishita

Kikuzawa

et al. 2022

CHEMICAL & PHARMACEUTICAL BULLETIN

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Small-molecular drugs, which are generally inexpensive compared with biopharmaceuticals and can often be taken orally, may contribute to the Sustainable Development Goals (SDGs) adopted by the United Nations. We previously reported the retinoid X receptor (RXR) agonist 4-(ethyl(3-isobutoxy-4-isopropylphenyl)amino)benzoic acid (NEt-3IB, 1) as a small-molecular drug candidate to replace biopharmaceuticals for the treatment of inflammatory bowel disease. The previous synthetic method to 1 required a large amount of organic solvent and extensive purification. In line with the SDGs, we aimed to develop an environmentally friendly, inexpensive method for the large-scale synthesis of 1. The developed method requires only a hydrophobic ether and EtOH as reaction and extraction solvents. The product was purified by recrystallization twice to afford 99% pure 1 at 100 mmol scale in about 30% yield. The optimized process showed a 35-fold improvement of the E-factor (an index of environmental impact) compared to the original method. This work, which changes the solvent used to environmentally preferable ones based on the existing synthetic method for 1, illustrates how synthetic methods for small-molecular drugs can be adapted and improved to contribute to the SDGs.

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“…An example of a large scale nitro reduction was reported by Gallagher and co-workers, 24 during the study for the preparation of a drug candidate with several sensitive functional groups (Scheme 2).…”

Section: Hydrogenationmentioning

confidence: 99%

Recent Developments in the Reduction of Aromatic and Aliphatic Nitro Compounds to Amines

Orlandi

Brenna

Harms³

et al. 2016

Org. Process Res. Dev.

311

195

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The reduction of the nitro group represents a powerful and widely used transformation that allows to introducing an amino group in the molecule. New synthetic strategies for complex functionalized molecular architectures are deeply needed, including highly efficient and selective nitro reduction methods, tolerant of a diverse array of functional moieties and protecting groups. Since chiral amino groups are ubiquitous in a variety of bioactive molecules such as alkaloids, natural products, drugs, and medical agents, the development of reliable catalytic methodologies for the nitro group reduction is attracting an increasing interest also in the preparation of enantiomerically pure amines. In this context, the modern reduction methods should be chemoselective and respectful of the stereochemical integrity of the stereogenic elements of the molecule. The review will offer an overview of the different possible methodologies available for this fundamental transformation, with special attention on the most recent contributions in the field, especially in the last ten years: hydrogenations, metal dissolving and hydride transfer reductions, catalytic transfer hydrogenations, and metal-free reductions. The main advantages or limitations for the proposed methods will be briefly discussed, highlighting in some cases the most important features of the presented reduction methodologies from an industrial point of view. ■ CONTENTSAuthor Information 444 Corresponding Authors 444 Notes 444 Acknowledgments 444 References 444

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The Development of a Scalable, Chemoselective Nitro Reduction

Cited by 18 publications

References 45 publications

Access to the Surugatoxin Alkaloids: Chemo-, Regio-, and Stereoselective Oxindole Annulation

Access to the Surugatoxin Alkaloids: Chemo-, Regio-, and Stereoselective Oxindole Annulation

Development of Scaled-Up Synthetic Method for Retinoid X Receptor Agonist NEt-3IB Contributing to Sustainable Development Goals

Recent Developments in the Reduction of Aromatic and Aliphatic Nitro Compounds to Amines

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