AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Nov 162013
 
MK 6096
IUPAC Name: [(2R,5R)-5-[(5-fluoropyridin-2-yl)oxymethyl]-2-methylpiperidin-1-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone | CAS Registry Number: 1088991-73-4
Synonyms: FILOREXANT, MK6096, MK-6096, Filorexant [USAN], UNII-E6BTT8VA5Z, SureCN1716633, CHEMBL2107822, MK 6096, ((2R,5R)-5-(((5-Fluoropyridin-2-yl)oxy)methyl)-2-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone, 1088991-73-4, Methanone, ((2R,5R)-5-(((5-fluoro-2-pyridinyl)oxy)methyl)-2-methyl-1-piperidinyl)(5-methyl-2-(2-pyrimidinyl)phenyl)-
Girardin M, Ouellet SG, Gauvreau D, Moore JC, Hughes G, Devine PN, O’Shea PD, Campeau L.-C * Merck Frosst Center for Therapeutic Research, Kirkland, Canada and Merck Research Laboratories, Rahway, USA
Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor Antagonist.
Figure
MK-6096 is an orexin receptor antagonist in clinical trials for the treatment of insomnia. Herein we describe its first kilogram-scale synthesis. Chirality on the α-methylpiperidine core was introduced in a biocatalytic transamination using a three-enzyme system with excellent enantioselectivity (>99% ee). Low diastereoselectivity of the lactam reduction was overcome by development of a camphor sulfonic acid salt formation and dr upgrade. A chemoselectiveO-alkylation with 5-fluoro-2-hydroxypyridine was optimized and developed. Overall, 1.2 kg of MK-6069 was prepared in nine steps and 13% overall yield.

Org. Process Res. Dev. 2013; 17: 61-68

DOI: 10.1021/op3002678
Publication Date (Web): November 30, 2012

The orexins are peptides that act as neurotransmitters in the central nervous system. MK-6096 is a dual orexin receptor antagonist that is a candidate for the treatment of insomnia. A noteworthy feature of the synthesis depicted is the biocatalytic transamination reaction on prochiral substrate A using a three-enzyme cocktail that delivers piperidinone B (>99% ee) on a multikilogram scale.

kilogram-scale synthesis of an orexin receptor analyst that is in clinical trials for treating insomnia. In a key step, (6R)-methylpiperidine-3-methanol is prepared from dimethyl 2-(3-oxobutyl)malonate, which was synthesized by a Michael addition of dimethyl malonate to methyl vinyl ketone.

The synthesis of the chiral piperidine is a three-enzyme biocatalytic transamination–cyclization–reduction sequence. The authors used a transaminase enzyme as the catalyst, D-alanine as the amine donor, and pyridoxal-5’-phosphate as a cofactor to transfer the amine to the malonate substrate. The product spontaneously cyclizes to a piperidone ester.

Two additional enzymes help drive the reaction: Lactate dehydrogenase, with NADH as a cofactor, reduces the lactate byproduct; and glucose dehydrogenase recycles the NAD coproduct back to NADH. Reducing the methyl ester to a hydroxymethyl group with NaBH4 and CaCl2, followed by LiAlH4 reduction of the piperidone, completes the synthesis of the piperidine building block.

The diastereoisomeric ratio of the α-hydroxymethyl lactam (dr = 1.7:1) was improved to >40:1 by reduction of the lactam followed by salt formation using d-(+)-camphorsulfonic acid [d-(+)-CSA]. For the development of transaminase ATA-117 in the manufacture of sitagliptin, see: C. K. Savile et al. Science 2010, 329, 305.

 

 

http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201200025/full

 

MK-6096 is an orally bioavailable potent and selective reversible antagonist of Orexin 1 Receptor (OX(1)R) and Orexin 2 Receptor (OX(2)R). In radioligand binding and functional cell based assays MK-6096 demonstrated potent binding and antagonism of both human OX(1)R and OX(2)R (<3 nM in binding, 11 nM in FLIPR), with no significant off-target activities against a panel of >170 receptors and enzymes. MK-6096 occupies 90% of human OX(2)Rs expressed in transgenic rats at a plasma concentration of 142 nM, and dose-dependently reduced locomotor activity and significantly increased sleep in rats (3-30 mg/kg) and dogs (0.25 and 0.5 mg/kg). MK-6096 represents a novel and selective therapeutic for the treatment of insomnia. MK-6096 has exceptional in vivo activity in preclinical sleep models.

References:

Discovery of [(2R,5R)-5-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): a dual orexin receptor antagonist with potent sleep-promoting properties.
Coleman PJ, et al. ChemMedChem. 2012 Mar 5;7(3):415-24, 337. PMID: 22307992.Pharmacological characterization of MK-6096 – a dual orexin receptor antagonist for insomnia.
Winrow CJ, et al. Neuropharmacology. 2012 Feb;62(2):978-87. PMID: 22019562.

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