Hazardous Reagent Substitution

A Pharmaceutical Perspective

Rakesh Kumar Sharma, Rakeshwar Bandichhor

• Publisher: Royal Society of Chemistry
• Year: 2017
• Edition: 1
• eBook ISBN:
  9781788013765
• Topic: Physical Sciences
• Subtopic: Pharmacology

In recent years, a significant amount of progress has been made using green chemistry in the synthesis of synthetically useful compounds and molecules by replacing hazardous chemicals with greener alternatives. However, there is still room for improvement, especially in the pharmaceutical sector where new drugs are being formulated. This book examines green approaches to overcoming hazardous organic transformations. Summarizing recent developments, the book features a detailed description of some of the high impact active pharmaceutical ingredients that have been developed considering green chemistry approaches. It explores the design, engineering and process development and the calculations to account for waste. The book includes strategies to further advance green approaches in the development of generic pharmaceutical industries and features novel, innovative approaches that promote waste-free organic synthesis. This book is of interest to industrialists working in pharmaceuticals and researchers working in green chemistry.

CHAPTER 1

Introduction to Hazardous Reagent Substitution in the Pharmaceutical Industry

RAKESHWAR BANDICHHOR

Integrated Product Development, Innovation Plaza, Dr Reddy’s Laboratories Ltd, Bachupally, Qutubullapur, R.R.Dist. 500090, Telangana, India

Email: [email protected]

1.1 Role of Reagents in the Development of Organic Synthesis

What we have perceived over the years is that in vitro synthesis per se has a reputation of sharing similarities with in vivo chemical transformations (biochemical). Functional enzymes can be considered the most sophisticated green catalysts (a catalyst is different from reagent as it does not get consumed) found to be effective in cascading reactions in biological systems. However, the basic difference between synthesis and biosynthesis is that synthetic processes can be considered by and large inclusive of biosynthetic ones, whereas biosynthetic processes cannot include all possible synthetic transformations. Organic synthesis is a science that dictates the use of reactants, reagents (interchangeably used) and a set of materials towards yielding products. Interaction among all partners in the reaction, functional group susceptibility towards reagents, and their energies are the driving forces in synthetic events.

Since most of the reactions take place in solution, the selection of solvent(s) based on their dielectric constants and polarity is extremely important. There are some reactions where one of the reagents or reactants acts as a solvent. By definition, a reagent is a substance that is added to a reaction mixture to yield a chemical reaction.¹

There are different types of reagents, e.g. inorganic acids, inorganic bases, organic acids, organic bases, epoxides, halides, azides, organometallics, carbenes, carbenoids, diazonium salts, hydrazines, phospines, ylides, silicon based reagents, oxidizing and reducing agents, etc. These reagents play pivotal roles in the manufacturing of goods of varied interests e.g. pharmaceuticals, commodity materials and materials coming from interdisciplinary industries for societal consumption.

1.1.1 Inorganic Material in the Synthesis of APIs

The use of inorganic materials, as one of the few essentials in chemical synthesis including the manufacturing of Active Pharmaceutical Ingredients (APIs), typically leads to waste generation. These are found to be primarily complex due to a variety of reasons, e.g. nature of the material, reaction conditions and unit operations. Chemical processes can generate acids, bases, aqueous or solvent liquors, and cyanides including metal wastes in liquid or slurry form. In organic synthesis waste solvents, either hazardous or non-hazardous, are usually recovered by distillation. Distillation is an excellent way of reusing and reducing liquid hazardous waste. In addition, the distillation left-over (solid residue) needs to be treated in such a way that there is no hazard left before it is dispensed as effluent. There are a number of strategies to achieve this, including the removal of solvents by steam stripping followed by microbiological treatment. Inorganic material in the chemical industry also includes a number of catalysts. The features of heterogeneous inorganic-material-based catalysis can be exploited by understanding the reactivity profile of such materials. Moreover, the same material can perform differently depending on overall unique structure and surfaces; therefore, it is important to measure these attributes and map the reactivity potential towards a variety of chemical transformations. It has become possible to characterize inorganic materials at the molecular level and leverage their catalytic potential. These inorganics also have the potential to offer hazardous reagent substitution to a great extent.²

1.1.2 Organic Material in the Synthesis of APIs

Manufacturing of APIs is an inevitable aspect of continuing health industry³ and this involves the use of a myriad of organic entities to accomplish the material production task. Some of these organics will become integral parts of the molecule but most of them turn out to be unwanted ones contributing to a high Process Mass Intensity (PMI) or E-factor. These unwanted materials may be hazardous in nature as they may be toxic and to a great extent they may cause environmental imbalance due to an ever-increasing carbon footprint.

There are situations during manufacturing operations where organic and hazardous substance emissions should be controlled by appropriate control devices e.g. condensers, scrubbers, etc. Waste effluents from manufacturing operations contain organic and inorganic components, wash water, discharges from pumps, scrubbers and temperature controlling systems, and fleeting leaks and spills. These effluent chemicals may be of different chemical compositions, and toxic and/or genotoxic in nature. In order to minimize these hazardous unwanted materials one needs to design such a process that provides only the desired product along with the minimum possible unwanted materials. The challenges associated with this would offer opportunities to substitute hazardous chemicals/reagents with non-hazardous ones giving rise to safer by-products.

1.2 Process Mass Intensity (PMI)

PMI⁴ is directly linked to the use of reactants/reagents, including water. Higher PMIs that are linked with hazardous reagents will have an exponentially high impact on cost, health and the environment. PMI is the ratio of the sum of inputs and desired product output as shown in Scheme 1.1.

Scheme 1.1 Equation accounting for PMI towards synthesis of ‘D’.

As shown in Scheme 1.1, raw materials (starting material, reagents and solvents) A, B and C have been used with the quantities of 50, 20 and 5 kg respectively to give rise 5 kg D. The calculated PMI of 15 clearly reflects that the process is inefficient.

In another case, if this reaction outcome featured in Scheme 1.1 goes to a next step as an intermediate to afford product H (3 kg), after reacting with reaction partners E (40 kg), F (15 kg) and G (4 kg) as shown in Scheme 1.2, the overall PMI for product H will be calculated by omitting the value of D.

Scheme 1.2 Equation accounting for overall PMI towards synthesis of ‘H’.

PMI is the biggest problem that any industry faces and the nature of the waste generated is another negative paradigm. There is no well-defined widely accepted mechanism in place to monitor the health impacts of chemical waste post its disposal in water streams. In fact, life cycle management of chemical waste—that may prove extremely hazardous even at ppm and ppb levels—is poorly established.

PMI-related health hazards can never be avoided but can be minimized by chemistry and engineering excellence by design at the beginning of the process.

1.3 Stoichiometry of the Reagent

Stoichiometry and atom economy are closely associated with any chemical transformation. A highly atom economical chemical process is considered as a transformation where most of the atoms present in the reactant or reagents (but not in all cases) are incorporated in the product.⁵ The atom economy is measured as a ratio of product and all reactant and reagents (when used as reactants) used multiplied by 100, and reflects that lesser amounts of reactants used is directly proportional to higher atom economy. This calculation is widely accepted for multistep processes too. Usually in such a calculation, intermediates that are formed and consumed in the next step are omitted. There are certain assumptions made about all the components of the reaction as shown in Scheme 1.3.

Scheme 1.3 Atom economy calculation for multistep processes.

In this hypothetical synthesis, in order to calculate the atom economy for intermediate EE, reactants G and R are factored in, whereas the calculation of atom economy for product Y, all the reactants G, R, N, H, M, S are considered.

For instance, a reactant is considered as any material that gets incorporated into an intermediate, product or by-product during the synthesis e.g. certain component of protecting groups and reagents used in stoichiometric quantities (or more than that). Anything used in catalytic quantities is omitted from the calculation as they do not contribute to any of the intermediates or product(s). Solvents are also not considered as part of the atom economy calculation.

The higher the stoichiometry of the reactant/reagent, i.e. >1 equivalence would lead to poor atom economy and higher PMI. There are many reactions that require more than one equivalence of reactants or reagents. Historically, it was perceived that not all reagents and reactants were safe, therefore it has been imperative to design a process that would not involve stoichiometric amounts or (more than that) of these. Comparatively, catalytic processes are considered to be much safer than conventional reagent-based transformations.

1.4 Green Chemistry: Selection of Reagent

Understandably, Green Chemistry is seen as the ‘right way’ of doing chemistry in any phase of t...

Table of contents

• Cover
• Title
• Copyright
• Foreword
• Intoduction
• Contents
• Chapter 1 Introduction to Hazardous Reagent Substitution in the Pharmaceutical Industry
• Chapter 2 Recyclability of Reagents
• Chapter 3 Recoverable Polymer-supported DMAP Derivatives
• Chapter 4 Synthesis of Atorvastatin
• Chapter 5 Synthesis of Raloxifene
• Chapter 6 Synthesis of Montelukast
• Chapter 7 Development of a Safe, Scalable, Azide-free Synthesis of 1-Aryl-1H-tetrazoles Using Diformylhydrazine
• Chapter 8 New Directions from Academia
• Subject Index