Chapter 8
Preparation of Novel Delivery Agents for Delivery of Macromolecular Drugs Using Boric Acid Mediated Amidation of Carboxylic Acids and Amines
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Pingwah Tang Chemistry Department, Emisphere Technologies, Inc., 765 Old Saw Mill River Road, Tarrytown, NY 10591-6715
Delivery agents comprising a carboxamide moiety are useful for the delivery of macromolecular drugs to the systemic circulation via oral administration. A practical synthetic pathway to these delivery agents has been developed by the direct amidation between a carboxylic acid and an amine using a catalytic amount of boric acid as a mediator. Boric acid is nontoxic, environmentally safe, and inexpensive. This method eliminates the preparation of acid chlorides, and is amenable for large-scale preparation providing excellent yields of the desired carboxamides. This boric acid mediated amidation between the carboxylic acids and amines with a variety of functional groups was achieved in a simple, single-step process using an equal molar mixture of acids and amines. This amidation works well with weakly nucleophilic amine, such as arylamines. The utility of the boric acid mediated amidation will be discussed.
© 2003 American Chemical Society
In Advances in Controlled Drug Delivery; Dinh, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.
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104 Progress in the field of biotechnology has resulted in increasing number of novel macromolecular drugs with great clinical promise. Unfortunately, the delivery of these macromolecular drugs by routes other than parenteral is difficult. The delivery of such macromolecular drugs to the systemic circulation via oral administration has often been severely limited by biological, chemical and physical barriers, such as low p H in the stomach, powerful digestive enzymes, and impermeable gastrointestinal epithelium. Macromolecular drugs are easily rendered ineffective or destroyed in the stomach, by acid hydrolysis, and/or enzymatic degradation. Heparin, for example, by virtue of its anionic charge, high molecular weight, and hydrophilic nature, is not readily absorbed in the gastrointestinal tract (GI). To overcome die above-identified problems, specific compounds termed as delivery agents, or carriers, have been developed by Emisphere Technologies, Inc. These delivery agents are orally administered in combination with macromolecular drugs to facilitate the gastrointestinal absorption, and the subsequent delivery of the drugs. Carboxamides (formula 1) are known as a highly interesting class of compounds, and research directed to their formation is continuously attracting great interest in die synthetic organic chemistry community. Recendy, the uses of carboxamides as delivery agents for the delivery of macromolecular drugs in a wide range of settings have gained great attention (1,2,3). One such example is the use of carboxamides for delivery of a protein drug, recombinant human growth hormone (rhGH) via oral adnunistration (3,4). Since an increasing number of structurally diverse carboxamides are found to be useful for delivery of macromolecular drugs, our interest in this field is directed to a practical synthetic methodology of carboxamides to be used as delivery agents for oral delivery of macromolecular drugs. Ο
Η ι wherein R* is an aromatic group. The chemistry of amide bond formation (amidation) is a vital chemical transformation in organic chemistry (5). Amide bonds are responsible for linking amino acids to form proteins. Despite many methods for the formation of carboxamides, new and effective methodologies are still needed, To develop a general program to prepare structurally diverse delivery agents of formula 1 for
In Advances in Controlled Drug Delivery; Dinh, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.
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the delivery of macromolecular drugs via oral administration, we sought a facile method for the preparation of delivery agents comprising a carboxamide moiety. The preparation of carboxamides 1 generally involves an amidation reaction between a carboxylic acid and an amine. Many different methods to accomplish this amidation are known. In most cases, a carboxylic acid is activated by conversion into a more electrophilic intermediate, like an acid chloride. The latter then reacts with an amine in the presence of an activating agent to form a carboxamide. While the method involving the acid chloride intermediate is commonly used for the preparation of carboxamides, it suffers severe difficulty and sometimes fails to work because many acid chlorides are unstable or not compatible with other functional groups present in the carboxylic acid and/or in the amine molecules. Therefore, before the conversion of a carboxylic acid into an acid chloride, the non-compatible functional groups present in the carboxylic acid molecule, such as hydroxy, thio, or amino groups must be protected. Once the protections have been accomplished, the acid chloride can be prepared and the subsequent coupling step can be carried out. The non-compatible functional groups must then be deprotected. Thus, the duration and the cost of the amidation increase because of the need of the protection / deprotection steps. Furthermore, the preparation of acid chlorides requires the use of hazardous materials such as thionyl chloride, oxalyl chloride, or phosgene. In addition, the volatile by-products generated from the reaction are highly corrosive. Coupling agents like D C C or E D C in the presence of 1-hydroxybenzotriazole, HOBt, HOAt (6) PS-HOBt, PS-HBTU, PS-TFP, H A T U can also be employed in the amidation reaction of carboxylic acids. However, the by-products are not always easily removed, especially in large-scale preparations. There are limited reports in the literature about amidation using boron reagents such as boron trifluoride etherate (7), trimethylamine-borane (
