Route Selection and Optimization in the Synthesis of Two Imidazopyridine Inhibitors of DGAT-2

Article abstract of DOI:10.1021/acs.oprd.8b00005

The scalable syntheses of two imidazopyridine inhibitors of the enzyme diacylglycerol acyltransferase 2 (DGAT-2) are described. 6-Chloro-3-nitro-2-aminopyridine was the starting material for the convergent synthesis of the central imidazopyridine ring. Differentiation in reactivity of the C2- and C3-nitrogen substituents on the pyridine ring and the development of mild cyclodehydration conditions to form the imidazole ring were critical problems that were addressed to deliver a 3-kg batch of compound 1 (PF-06424439) and a 0.1-kg batch of compound 2 (PF-06450561).

Full text of DOI:10.1021/acs.oprd.8b00005

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Full Paper
Route Selection and Optimization in the Synthesis
of Two Imidazopyridine Inhibitors of DGAT-2
Scott J. Bader, Michael Herr, Gary E. Aspnes, Shawn Cabral, Qifang Li, Jianwei Bian, Steven B.
Coffey, Matthew S. Dowling, Dilinie Fernando, Wenhua Jiao, Sophie Lavergne, and Daniel W. Kung
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00005 • Publication Date (Web): 14 Feb 2018
Downloaded from http://pubs.acs.org on February 14, 2018
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Route Selection and Optimization in the Synthesis of Two Imidazopyridine Inhibitors of
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DGAT-2
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Scott J. Bader, Michael Herr, Gary E. Aspnes, Shawn Cabral, Qifang Li, Jianwei Bian, Steven B.
Coffey, Matthew S. Dowling, Dilinie P. Fernando, Wenhua Jiao, Sophie Y. Lavergne, and
Daniel W. Kung.*
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, United
States.
GRAPHICAL ABSTRACT
ABSTRACT
The scalable syntheses of two imidazopyridine inhibitors of the enzyme diacylglycerol
acyltransferase 2 (DGATꢀ2) are described. 6ꢀChloroꢀ3ꢀnitroꢀ2ꢀaminopyridine was the starting
material for the convergent synthesis of the central imidazopyridine ring. Differentiation in
reactivity of the C2ꢀ and C3ꢀnitrogen substituents on the pyridine ring and the development of
mild cyclodehydration conditions to form the imidazole ring were critical problems that were
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addressed to deliver a 3ꢀkg batch of compound 1 (PFꢀ06424439) and a 0.1ꢀkg batch of
compound 2 (PFꢀ06450561).
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KEYWORDS
imidazopyridine, azabenzimidazole, DGAT, diacylglycerol acyltransferase
INTRODUCTION
The enzymes diacylglycerol acyltransferase 1 and 2 (DGATꢀ1 and DGATꢀ2) catalyze the final
step in triglyceride synthesis. Inhibition of one or both of these enzymes has been proposed as a
treatment for metabolic disease.1 Several small molecule inhibitors of DGATꢀ2 have been
disclosed recently.2,3,4,5,6 This manuscript describes the synthetic route development toward
scalable syntheses of the imidazopyridines PFꢀ06424439 (1)7 and PFꢀ06450561 (2)8 which were
evaluated in efficacy and safety studies, leading to decreased cholesterol and triglyceride levels
in preclinical species.
Figure 1. DGATꢀ2 inhibitors.
RESULTS AND DISCUSSION
The discovery synthesis of 1 and related compounds (Scheme 1) employed a modular route that
allowed diversification of both the leftꢀ and rightꢀhand sides of the molecule to investigate SAR.7
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From a process chemistry perspective, the bond constructions leading to intermediate 7 were
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amenable to scale, providing a route to multiꢀkilogram quantities of 7 as shown in Scheme 1.
Starting with the leftꢀhand side of the molecule, the commercially available NꢀBoc protected (R)ꢀ
piperidineꢀ3ꢀcarboxylic acid 3 was activated with CDI and underwent amide coupling with
pyrrolidine to give amide 4. Deprotection with hydrochloric acid in isopropanol led to isolation
of the HCl salt of 5 (84% yield over 2 steps). SNAr reaction of 5•HCl with commercially
available 2ꢀaminoꢀ6ꢀchloroꢀ3ꢀnitropyridine 6 in acetonitrile with triethylamine at 40 °C afforded
the solid product 7 in 66% yield after crystallization from ethyl acetate (4.6 kg; 99.1% purity by
HPLC, 99.5% e.e.).
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From intermediate 7, the remainder of Scheme 1 shows the discovery conditions for synthesis of
1.7 The nitro group of 7 was reduced with hydrogen over palladiumꢀonꢀcarbon to afford triamine
8; the free base of this electronꢀrich compound was unstable to air, and 8 was therefore isolated
as its dihydrochloride salt. The salt proved to be stable to storage for at least a few months, but
without conclusive data on its longꢀterm stability, compound 7 was targeted as the key
intermediate to stage material.
Imidate 11 was utilized as an efficient cyclization partner to incorporate the rightꢀhand side of
the molecule. The cyclopropylꢀpyrazole was prepared by bisꢀalkylation of the acetonitrile 9 with
sodium hydride and 1,2ꢀdibromoethane to give the desired cyclopropylnitrile 10, with DMSO the
solvent that provided the highest yield. This exothermic reaction required cooling below the
freezing point of (pure) DMSO, and safety concerns about the use of NaH–DMSO9 led us to
synthesize compound 10 in batches of less than 10 grams as a safety precaution. Efforts to
identify base–solvent combinations that would be more amenable to scale and that afforded
suitable reaction profiles were not successful (LiHMDS, KHMDS, LTMP, DBU, KOH; THF,
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