Subscriber access provided by - Access paid by the | UCSB Libraries
Full Paper
A Partial Classical Resolution/Preparative Chiral Supercritical Fluid Chromatography Method for the Rapid Preparation of the Pivotal Intermediate in the Synthesis of Two Nonsteroidal Glucocorticoid Receptor Modulators Nuria de Mas, Kenneth J. Natalie, Jr, Fernando Quiroz, Victor W. Rosso, Doris C Chen, and David A. Conlon Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00036 • Publication Date (Web): 26 Apr 2016 Downloaded from http://pubs.acs.org on May 9, 2016
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Organic Process Research & Development is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 19
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Organic Process Research & Development
A Partial Classical Resolution/Preparative Chiral Supercritical Fluid Chromatography Method for the Rapid Preparation of the Pivotal Intermediate in the Synthesis of Two Nonsteroidal Glucocorticoid Receptor Modulators Nuria de Mas,* Kenneth J. Natalie Jr., Fernando Quiroz, Victor W. Rosso, Doris C. Chen, and David A. Conlon* Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, NJ 08901, United States
1
ACS Paragon Plus Environment
Organic Process Research & Development
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
TABLE OF CONTENTS GRAPHIC O
1. classical resolution with cinchonidine
OH
O
N
racemate
Cl
O OH
2. preparative chiral SFC O N Cl 1.0 kg, >99.5% ee
2
ACS Paragon Plus Environment
Page 2 of 19
Page 3 of 19
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Organic Process Research & Development
ABSTRACT Preparative chiral supercritical fluid chromatography (SFC) employing an enantio-enriched feedstock obtained via partial classical resolution enabled rapid access to kilogram quantities of a key intermediate common to two glucocorticoid (GC) receptor modulator candidates for which neither chemical nor enzymatic resolutions provided the desired chiral purity (>99.0 HPLC area percent). We developed a partial classical resolution of the racemate that afforded 85:15 enantioenriched mixtures with a recovery of the desired enantiomer of 90% and reduced the SFC processing time by 54%. The SFC method used a 5 x 28 cm column packed in-house with 20 μm Chiralpak AD, a total column flow rate of 150 g/min, a cosolvent composition of 12% methanol, and a column back pressure of 75 bar. The feed processing rate was up to 80 mL/h, which translated to 67 g/day of the enantioenriched mixture or 57 g/day of the desired enantiomer. This combined classical resolution/SFC process was employed to obtain a total of 1.0 kg of the desired enantiomer with an enantiomeric excess greater than 99.5% in a 79% M isolated yield by running the SFC separation over 23 days, 24 h per day and 5 days per week. Stable column pressure drops of 7–11 bar were measured throughout the manufacturing campaign. This separation approach enabled the first large-scale preparation of the two GC compounds and permitted their evaluation in toxicological and first-in-human studies within a few months of entering development. KEYWORDS Chemical resolution, chiral supercritical fluid chromatography, preparative method, kilogram campaign
3
ACS Paragon Plus Environment
Organic Process Research & Development
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 4 of 19
INTRODUCTION Several preparative chromatographic techniques are commonly used in pharmaceutical development. For example, preparative chiral HPLC, SFC, simulated moving bed (SMB), and Varicol® chromatography are an integral part of the process chromatography platform at our company to enable the rapid delivery of chiral intermediates and active pharmaceutical ingredients (API) for early-stage development in parallel with efforts to develop a chiral synthetic route. Traditional preparative HPLC is also often used to perform multicomponent separations with low selectivity (e.g., removal of isomeric impurities and degradants)1 while flash chromatography may be used for separations with high selectivity (e.g., color removal). Both methods are frequently used for the purification of highly potent compounds (
