Synthesis of the Quinolone ABT-492:  Crystallizations for Optimal Processing

Abstract

ABT-492 has been under development at Abbott Laboratories as a quinolone antibiotic. A convergent syntheses was utilized to prepare the compound on a multi-kilogram scale. Difficulties in isolation of intermediates were overcome by developing control of the physical forms. Examples of controlling the agglomeration, crystal habit, and polymorphism of intermediates and the API are described.

An Efficient and Scalable Synthesis of Quinolone 006

“…The chelation group of 4 was deprotected in 5% aqueous acetic acid solution to provide the free acid 5. Then compound 5 was reacted with L-arginine in an acetone/water mixture to give quinolone (S)-9-fluoro-10-(4-hydroxypiperidin-1-yl)-3methyl-7-oxo-3,7-dihydro-2H- [1,4] oxazino [2,3,4-ij] quinoline-6-carboxylic acid L-arginine tetrahydrate 1 (006). The scale-up route is shown in Chart 2, while the optimal crystallization and workup process are also described.…”

“…The acetone-water volume ratio required to obtain the desired L-arginine salts was 1 to 1.5. If other organic solvents were added to the acetone-water mixture such as ethanol, i-propyl alcohol or n-propyl alcohol, only (S)-9-fluoro-10-(4hydroxypiperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H- [1,4]oxazino[2,3,4-ij] quinoline-6-carboxylic acid L-arginine tetrahydrate (polymorph I) was obtained. Polymorph I, at an ambient temperature of 35°C and relative humidity of 50%, was found to be a tetrahydrate from the elemental analysis.…”

“…Moreover, because many quinolone candidates have been tested in the clinic, the effective syntheses of these compounds has become the focus of process chemistry initiatives. [1][2][3][4][5] While crystallization from solution is an established technique for the separation and purification of organic compounds, challenges arising from the complex interactions of variables including polymorphism, crystal nucleation and growth, and impurity profile are common. 6) For drug substances, understanding and controlling the polymorphism, particle size, morphology, and crystal habit have become fundamental steps in pharmaceutical development programs.…”

“…Quinolone 006 ((S)-9-fluoro-10-(4-hydroxypiperidin-1-yl)-3methyl-7-oxo-3,7-dihydro-2H- [1,4] oxazino [2,3,4-ij] quinoline-6-carboxylic acid L-arginine tetrahydrate) has been under development as a novel quinolone antibiotic. 006 (Chart 1) has superior antibacterial activities against multidrug-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP).…”

“…Understanding and controlling the polymorphism and impurity profile of drug substances have become fundamental steps in early research and development programs. 8) Less effort has been focused on the manipulation of the temperature and vacuum pressure when drying the APIs, which can affect the polymorphic properties of the API. 9) To ensure an uninterrupted supply of 006, we describe the development of a multi-kilogram scale linear synthetic route and crystallization process.…”