A Fully Continuous-Flow Process for the Synthesis of <i>p</i>-Cresol: Impurity Analysis and Process Optimization

Yu, Zhiqun; Ye, Xin; Xu, Qilin; Xie, Xiaoxuan; Dong, Hei

doi:10.1021/acs.oprd.7b00250

Cited by 28 publications

(15 citation statements)

References 54 publications

(12 reference statements)

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“…The important point here is the concentration of dil.H 2 SO 4 during heating. A high concentration of dil.H 2 SO 4 might lead to sulfonation as a side reaction, 18) so we examined various concentrations up to 20% (Table 1, entries 1-4). In this experiment, the reaction mixture was diluted to about 50 µM, and the reaction progress was monitored by HPLC.…”

Section: Examination Of Conditions For Each Reaction Stepmentioning

confidence: 99%

“…As a side reaction of hydroxylation by means of the Sandmeyer reaction, dimer formation between the produced phenol and unreacted aniline has been reported. 18) Heating the dil.H 2 SO 4 after adding an organic solvent has been reported to prevent such dimerization and to increase the product yield. 18) Since CPME works as the organic solvent in the Sandmeyer reaction, 19) we examined CPME in the present reaction.…”

Section: Examination Of Conditions For Each Reaction Stepmentioning

confidence: 99%

“…18) Heating the dil.H 2 SO 4 after adding an organic solvent has been reported to prevent such dimerization and to increase the product yield. 18) Since CPME works as the organic solvent in the Sandmeyer reaction, 19) we examined CPME in the present reaction. When CPME was added to the dil.H 2 SO 4 and the mixture was directly refluxed, the area% reached 72% (Table 1, entry 6).…”

Section: Examination Of Conditions For Each Reaction Stepmentioning

confidence: 99%

See 2 more Smart Citations

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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Section: Examination Of Conditions For Each Reaction Stepmentioning

confidence: 99%

Section: Examination Of Conditions For Each Reaction Stepmentioning

confidence: 99%

Section: Examination Of Conditions For Each Reaction Stepmentioning

confidence: 99%

See 1 more Smart Citation

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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“…There are other publications that report on reactions performed in PFRs [23,[49][50][51][52][53][54][55][56][57][58][59][60][61][62][63], which are not discussed in detail here.…”

Section: J Flow Chemmentioning

confidence: 99%

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

2021

J Flow Chem

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Pharmaceutical production remains one of the last industries that predominantly uses batch processes, which are inefficient and can cause drug shortages due to the long lead times or quality defects. Consequently, pharmaceutical companies are transitioning away from outdated batch lines, in large part motivated by the many advantages of continuous manufacturing (e.g., low cost, quality assurance, shortened lead time). As chemical reactions are fundamental to any drug production process, the selection of reactor and its design are critical to enhanced performance such as improved selectivity and yield. In this article, relevant theories, and models, as well as their required input data are summarized to assist the reader in these tasks, focusing on continuous reactions. Selected examples that describe the application of plug flow reactors (PFRs) and continuous-stirred tank reactors (CSTRs)-in-series within the pharmaceutical industry are provided. Process analytical technologies (PATs), which are important tools that provide real-time in-line continuous monitoring of reactions, are recommended to be considered during the reactor design process (e.g., port design for the PAT probe). Finally, other important points, such as density change caused by thermal expansion or solid precipitation, clogging/fouling, and scaling-up, are discussed.

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“…The microreactor, also called micro structured reactor or micro channel reactor, has received extensive attention as an efficient and strong tool for continuous synthesis. [16][17][18][19] With its numerous advantages such as large surface area-to-volume ratios, high mixing efficiency, fast mass and heat transfer rates, inherent safety, and precise control over process parameters, this technology has been widely applied in drug synthesis, [20][21][22][23][24] organic chemistry methodology, [25][26][27][28] chemical engineering [29][30][31][32][33][34][35][36][37] and so on.…”

mentioning

confidence: 99%

Continuous flow synthesis of N‑(2‑aminophenyl) benzamide with high selectivity and its kinetic study in a microreactor

Yao

Fan

et al. 2020

Preprint

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The monobenzoylation of o-phenylenediamines (DA) is an important process to synthesis N-(2-aminophenyl) benzamide (MP), which is a key intermediate of many active compounds. But the monoacylation is difficult to control because this process is a kind of consecutive reaction system and the two amine groups located in a similar chemical environment. To understand the effects of reaction parameters on the selectivity and further optimize operating conditions, a microreactor platform was developed to evaluate the kinetics of the acylation reaction of DA and benzoic anhydride (BH). A kinetic model was established, and the reaction order of each reactant, the values of kinetic constants, pre-exponential factors and activation energies were determined. Validation experiments showed the model is in good agreement with the experimental results. The model simulation indicated that high reaction temperature and molar ratio of DA and BH is necessary to improve reaction efficiency and selectivity.

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A Fully Continuous-Flow Process for the Synthesis of p-Cresol: Impurity Analysis and Process Optimization

Cited by 28 publications

References 54 publications

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

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

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

Continuous flow synthesis of N‑(2‑aminophenyl) benzamide with high selectivity and its kinetic study in a microreactor

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