Antifungal compound process
Inventors
Wirth, David Dale • Yates, Christopher M. • Hoekstra, William J. • BINDL, Martin F. • Hartmann, Eduard
Assignees
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Publication Number
US-10836740-B2
Publication Date
2020-11-17
Expiration Date
Abstract
The present invention relates to a process for preparing a compound of 5 or 5*, or a mixture thereof, that is useful as an antifungal agent. In particular, the invention seeks to provide new methodology for preparing compounds 7 or 7* and 11 or 11* and substituted derivatives thereof.
Core Innovation
The invention provides a process to prepare a compound of Formula 5 or 5* by reacting a compound of Formula 6 or ketone 6 with nitromethane in the presence of a chiral catalyst of Formula 3 to provide a compound of Formula 7 or 7*, or a mixture thereof. The chiral catalyst of Formula 3 is defined by R4 being H, —(C=O)-phenyl, or —(C=O)-haloalkyl-substituted phenyl, and R5 being H or methyl.
The process converts the compound of Formula 7 or 7*, or mixture thereof, to a compound of Formula 5, wherein R2 is —OCF3 or —OCH2CF3 and R3 is halo. The document further describes reduction of compound 7 to compound 11, arylation of compound 11 to compound 12, and formation of the tetrazole of compound 12 to afford compound 5.
Ketone 6 is produced by amidation of ester 9 with X to afford ketone 6, wherein X is halogen, or by reacting ester 9 with morpholine to afford morpholine amide 10 and then arylating morpholine amide 10 with M to afford ketone 6, wherein M is Mg or MgX, Li, or AlX2. The document also includes enantiomeric enrichment by crystallizing enantiomeric mixtures with named chiral acids and salt/adduct formation using sulfonic acids of a Z-S(=O)2-OH type.
Claims Coverage
The consolidated claim coverage includes two independent process claims. Across them, the inventive features center on nitromethane addition using a chiral catalyst of Formula 3 to generate a chiral intermediate, conversion through reduction, arylation, and tetrazole formation to reach compound 5, and defined routes for preparing ketone 6.
Chiral catalyst nitromethane addition to form Formula 7/7*
Reacting a compound of Formula 6 or ketone 6 with nitromethane in the presence of a chiral catalyst of Formula 3, wherein R4 is H, —(C=O)-phenyl, or —(C=O)-haloalkyl-substituted phenyl, and R5 is H or methyl, to provide a compound of Formula 7 or 7*, or mixture thereof.
Conversion of Formula 7/7* to Formula 5 with R2 and R3 constraints
Converting a compound of Formula 7 or 7*, or mixture thereof, to a compound of Formula 5 wherein R2 is —OCF3 or —OCH2CF3 and R3 is halo.
Ketone 6 formation by amidation or morpholine amide route
Producing ketone 6 by either amidation of ester 9 with X, wherein X is halogen, or by reacting ester 9 with morpholine to afford morpholine amide 10 and arylating morpholine amide 10 with M, wherein M is Mg or MgX, Li, or AlX2, to afford ketone 6.
Downstream reduction, arylation, and tetrazole formation to compound 5
Reducing compound 7 to compound 11, arylating compound 11 to compound 12, and forming the tetrazole of compound 12 to afford compound 5.
The independent claim coverage centers on preparation of compound 5 through a chiral nitromethane addition to a defined precursor using Formula 3 catalyst, followed by reduction, arylation, and tetrazole formation. The additional claim content specifies ketone 6 formation by amidation or a morpholine amide/arylating route before the same chiral sequence, with R2 constrained to —OCF3 or —OCH2CF3 and R3 constrained to halo.
Stated Advantages
Improved metal-binding selectivity relevant to metalloenzyme inhibition.
Reduced off-target toxicity compared with existing azoles, as described in the biological/medicinal context.
Documented Applications
Use in the biological/medicinal context of metalloenzyme inhibition, including zinc and iron metalloenzymes, with specific relevance to lanosterol demethylase (heme iron) and off-target effects involving enzymes such as CYP2C9, CYP2C19, and CYP3A4.
CYP51/lanosterol demethylase inhibition, along with pharmaceutical compositions and treatment claims for a subject.
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