Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors

Abstract

Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2-substituted spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50-75 g scale with minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors.

Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models

“…A series of spirocyclic ketone-containing ACC inhibitors was selected, namely PF-05175157 [27], PF-05206574 [28], and PF-06256254 [29] (Figure 1A). All three compounds exhibited good potencies against the two isoforms of the enzyme (ACC1 and ACC2) from human and rat (half-maximal inhibitory concentration [IC 50 ] = 10–27 nM).…”

“…0981 S) was from Extrasynthese (Genay, France). The procedures for the synthesis of PF-05175157 [27], PF-05206574 [28] and PF-06256254 [29] have been previously reported. PF-05175157, PF-05206574 and PF-06256254 were synthesized by Pfizer according to described procedures [27–29].…”

Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes

“…First, during synthetic scale-up, a byproduct arising from ring-opening elimination of oxy-pyrazole was observed, presumably via a retro-Michael reaction analogous to that shown in Scheme 1 , an obstacle that was overcome but which increased concern about potential instability of the β-pyrazoloxy-ketone functionality. 20 Second, crystalline compound 1 exhibited low solubility, requiring a spray-dried dispersion formulation to achieve adequate compound exposure in toxicology studies. Third, the ketone functional group in 1 was reduced in vivo to provide substantial circulating levels of the alcohol metabolite, 1m .…”

“…The reaction solution was stirred at ambient temperature for 16 h. The solution was concentrated, and the resulting residue was twice taken up in dichloromethane and concentrated under reduced pressure. To the resulting acid chloride was added tetrahydrofuran (500 mL), 1-isopropyl-1,4-dihydrospiro[indazole-5,4′-piperidin]-7(6 H )-one hydrochloride 20 (25.9 g, 91 mmol, 1.1 equiv), and triethylamine (71.2 mL, 510 mmol, 6.0 equiv). The solution was stirred at room temperature for 16 h, then saturated aqueous sodium bicarbonate solution (250 mL) was added and the resulting mixture was stirred for 5 min.…”

Cell‐free in vitro reduction of carboxylates to aldehydes: With crude enzyme preparations to a key pharmaceutical building block

“…[43][44][45][46][47] Robinson-type annulation with methylvinylketone delivers 3-azaspiroundecanones, which were used for the synthesis of several biologically active compounds. [48][49][50] Furthermore, the aldehyde moiety was addressed for classical condensation reactions with indanones, [51] Wittig reagents, [52] malonic esters, and ethyl cyanoacetate [53] (Scheme 2). A standard procedure of 1b synthesis is the reduction from the corresponding esters using DIBAL-H at -78 • C requiring strict temperature control and typically resulting in mediocre yields of the product.…”