Use of Modeling and Process Analytical Technologies in the Design of a Catalytic Amination Reaction: Understanding Oxygen Sensitivity at the Lab and Manufacturing Scales

Jeremy M. Merritt; Jonas Y. Buser; Alison N. Campbell; Jared W. Fennell; Neil J. Kallman; Thomas M. Koenig; Hossam Moursy; Mark A. Pietz; Norma Scully; Utpal K. Singh

doi:10.1021/op400226m

Step-by-Step Real Time Monitoring of a Catalytic Amination Reaction

10.26434/chemrxiv.8345594 ◽

2019 ◽

Author(s):

Gilian T. Thomas ◽

Eric Janusson ◽

Harmen S. Zijlstra ◽

J Scott McIndoe

Keyword(s):

Real Time ◽

Multiple Reaction Monitoring ◽

Catalyst Loading ◽

Quadrupole Mass ◽

Triple Quadrupole Mass Spectrometer ◽

Amination Reaction ◽

Catalytic Amination ◽

Multiple Reaction Monitoring Mode ◽

Sequential Addition ◽

The Individual

The multiple reaction monitoring mode of a triple quadrupole mass spectrometer is used to examine the Buchwald-Hartwig amination reaction at 0.1% catalyst loading in real-time using sequential addition of reagents to probe the individual steps in the cycle. This is a powerful new method for probing reactions under realistic conditions.

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Step-by-Step Real Time Monitoring of a Catalytic Amination Reaction

10.26434/chemrxiv.8345594.v1 ◽

2019 ◽

Author(s):

Gilian T. Thomas ◽

Eric Janusson ◽

Harmen S. Zijlstra ◽

J Scott McIndoe

Keyword(s):

Real Time ◽

Multiple Reaction Monitoring ◽

Catalyst Loading ◽

Quadrupole Mass ◽

Triple Quadrupole Mass Spectrometer ◽

Amination Reaction ◽

Catalytic Amination ◽

Multiple Reaction Monitoring Mode ◽

Sequential Addition ◽

The Individual

The multiple reaction monitoring mode of a triple quadrupole mass spectrometer is used to examine the Buchwald-Hartwig amination reaction at 0.1% catalyst loading in real-time using sequential addition of reagents to probe the individual steps in the cycle. This is a powerful new method for probing reactions under realistic conditions.

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Step-by-step real time monitoring of a catalytic amination reaction

Chemical Communications ◽

10.1039/c9cc05076k ◽

2019 ◽

Vol 55 (78) ◽

pp. 11727-11730 ◽

Cited By ~ 3

Author(s):

Gilian T. Thomas ◽

Eric Janusson ◽

Harmen S. Zijlstra ◽

J. Scott McIndoe

Keyword(s):

Real Time ◽

Multiple Reaction Monitoring ◽

Reaction Monitoring ◽

Quadrupole Mass ◽

Triple Quadrupole Mass Spectrometer ◽

Amination Reaction ◽

Catalytic Amination ◽

Multiple Reaction Monitoring Mode ◽

Sequential Addition ◽

The Individual

The multiple reaction monitoring mode of a triple quadrupole mass spectrometer is used to examine the Buchwald–Hartwig amination reaction in real-time using sequential addition of reagents to probe the individual steps in the cycle.

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Progress in arylpiperazine synthesis by the catalytic amination reaction

Bioorganic & Medicinal Chemistry ◽

10.1016/s0968-0896(02)00303-6 ◽

2002 ◽

Vol 10 (12) ◽

pp. 4023-4027 ◽

Cited By ~ 3

Author(s):

Yasuhiro Torisawa ◽

Takao Nishi ◽

Jun-ichi Minamikawa

Keyword(s):

Amination Reaction ◽

Catalytic Amination

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Pd Catalyzed N1/N4 Arylation of Piperazine for Synthesis of Drugs, Biological and Pharmaceutical Targets: An Overview of Buchwald Hartwig Amination Reaction of Piperazine in Drug Synthesis

Current Organic Synthesis ◽

10.2174/1570179415666171206151603 ◽

2018 ◽

Vol 15 (2) ◽

pp. 208-220 ◽

Cited By ~ 3

Author(s):

Vaibhav Mishra ◽

Tejpal Singh Chundawat

Keyword(s):

Bond Formation ◽

Catalyst Design ◽

Biologically Active ◽

Reaction Conditions ◽

Biological Targets ◽

Amination Reaction ◽

Drug Synthesis ◽

Substituted Piperazine ◽

Approved Drugs ◽

Fda Approved Drugs

Background: Substituted piperazine heterocycles are among the most significant structural components of pharmaceuticals. N1/N4 substituted piperazine containing drugs and biological targets are ranked 3rd in the top most frequent nitrogen heterocycles in U.S. FDA approved drugs. The high demand of N1/N4 substituted piperazine containing biologically active compounds and U.S. FDA approved drugs, has prompted the development of Pd catalyzed C-N bond formation reactions for their synthesis. Buchwald-Hartwig reaction is the key tool for the synthesis of these compounds. Objective: This review provides strategies for Pd catalyzed C-N bond formation at N1/N4 of piperazine in the synthesis of drugs and biological targets with diverse use of catalyst-ligand system and reaction parameters. Conclusion: It is clear from the review that a vast amount of work has been done in the synthesis of N1/N4 substituted piperazine containing targets under the Pd catalyzed Buchwald-Hartwig amination of aryl halides by using different catalyst-ligand systems. These methods have become increasingly versatile as a result of innovation in catalyst design and improvements in reaction conditions. This review gives an overview of recent utilization of Buchwald-Hartwig amination reaction in drug/target synthesis.

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Oxygen-Sensitivity and Pulmonary Selectivity of Vasodilators as Potential Drugs for Pulmonary Hypertension

Antioxidants ◽

10.3390/antiox10020155 ◽

2021 ◽

Vol 10 (2) ◽

pp. 155

Author(s):

Daniel Morales-Cano ◽

Bianca Barreira ◽

Beatriz De Olaiz Navarro ◽

María Callejo ◽

Gema Mondejar-Parreño ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Gas Exchange ◽

Pulmonary Circulation ◽

Pulmonary Arteries ◽

Blood Perfusion ◽

Mesenteric Arteries ◽

Oxygen Sensitivity ◽

Low Oxygen ◽

Oxygen Selectivity

Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary vs. the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH.

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