Carbon 14 and Carbon 13 Syntheses of Velagliflozin.

Velagliflozin is the active ingredient of the first oral liquid medication approved by the Food and Drug Administration for the treatment of diabetes in cats. This compound belongs to the known class of sodium-glucose cotransporter 2 inhibitors approved to treat diabetes in human. Here, we report the detailed synthesis of velagliflozin labeled with carbon 14 and carbon 13.

Simultaneous determination of imigliptin and its three metabolites in human plasma and urine by liquid chromatography coupled to tandem mass spectrometry.

A specific and sensitive method was firstly developed using high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) to simultaneously quantify imigliptin (KBP-3853) and its three metabolites (KBP-3926, KBP-3902, KBP-5493) in human plasma and urine. Solid-phase extraction (SPE) and direct dilution were used to extract imigliptin and its three metabolites from plasma and urine, respectively. The extracts were injected onto a SymmetryShield RP8 column with a gradient elution of acetonitrile and water containing 5mM ammonium acetate (pH 7). Ionization of KBP-3853, KBP-3926, KBP-3902, KBP-5493, and XZP-3244 (internal standard, IS) was performed using an electrospray ionization (ESI) source in positive mode and detection was carried out with multiple reaction monitoring (MRM) mode. The lower limits of quantitation (LLOQ) of KBP-3853/KBP-3926/KBP-3902/KBP-5493 in human plasma and urine were 0.500/0.500/0.500/0.500ng/mL and 20.0/20.0/10.0/10.0ng/mL, respectively. Inter- and intra-batch precision of imigliptin and its three metabolites were less than 15% and the accuracy was within 85-115% for both plasma and urine. The extraction recoveries of all analytes at three concentration levels were consistent. The specificity, matrix effect, linearity and stabilities under various conditions were validated for imigliptin and its three metabolites in human plasma and urine. In conclusion, the validation results showed that this method was robust, specific, and sensitive and it can successfully fulfill the requirement of clinical pharmacokinetic study of imigliptin hydrochloride in Chinese healthy subjects.

Discovery of Imigliptin, a Novel Selective DPP-4 Inhibitor for the Treatment of Type 2 Diabetes.

We report our discovery of a novel series of potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. Starting from a lead identified by scaffold-hopping approach, our discovery and development efforts were focused on exploring structure-activity relationships, optimizing pharmacokinetic profile, improving in vitro and in vivo efficacy, and evaluating safety profile. The selected candidate, Imigliptin, is now undergoing clinical trial.

A highly convergent and efficient synthesis of a macrocyclic hepatitis C virus protease inhibitor BI 201302.

A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved, in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1-0.2 M concentration) and the efficient sulfone-mediated SNAr reaction.

Palladium-catalyzed cross-coupling of cyclopropylmagnesium bromide with aryl bromides mediated by zinc halide additives.

The key Pd-catalyzed cross-coupling of aryl bromides or triflates and cyclopropylmagnesium bromide in the presence of substoichiometric amounts of zinc bromide produces cyclopropyl arenes in good to excellent yields. The cross-coupling of other alkyl, cycloalkyl, and aryl Grignard reagents with aryl bromides under the same conditions gives the corresponding substituted arenes in good yields.

RCM macrocyclization made practical: an efficient synthesis of HCV protease inhibitor BILN 2061.

We report here that dramatic improvement of the key RCM reaction in the synthesis of HCV protease inhibitor BILN2061 can be achieved by N-substitution of the diene substrate with an electron-withdrawing group. Mechanistic studies using 1H NMR spectroscopy showed an unprecedented switch of the initiation sites and the correlation between such switch and the results of RCM, from the unmodified to the modified substrates. We also provided theoretical evidence that such modification may also increase the thermodynamic preference of the macrocyclic product over the diene substrate.

Effects of catalyst activation and ligand steric properties on the enantioselective allylation of amines and phenoxides.

[reaction: see text] The yields, enantioselectivities, and regioselectivities of the reactions of amines and phenoxides with allylic carbonates in the presence of a metallacyclic iridium catalyst were compared. These data show that both preactivation of the catalyst and the size of the ligand affect the yield, enantioselectivity, and regioselectivity. With the activated catalyst containing a bis-naphthethylamino group, the allylic amination and etherification of a broad range of allylic carbonates occurred in high yields and with high regioselectivities and enantioselectivities.

Editing the stereochemical elements in an iridium catalyst for enantioselective allylic amination.

Individual diastereomeric phosphoramidites and mixtures of diastereomeric phosphoramidites were evaluated in the iridium-catalyzed amination of allylic carbonates. The original process was conducted with a phosphoramidite ligand containing a resolved 2,2-dihydroxy-1,1-binaphthyl (BINOL) group and a diastereomerically and enantiomerically pure bis(phenethyl)amino group. Evaluation of the structure of the active catalyst and relative rates for reactions in the presence of catalysts containing diastereomeric ligands led to the identification of a phosphoramidite that provided the amination product with enantiomeric excess similar to the original, more structurally and stereochemically complex ligand and that contains a racemic BINOLate and an N-benzylphenethylamino group on phosphorus.

Identification of an activated catalyst in the iridium-catalyzed allylic amination and etherification. Increased rates, scope, and selectivity.

Studies were conducted to determine possible intermediates in the highly enantioselective, iridium-catalyzed amination and etherification of allylic carbonates, and these studies revealed that cyclometalation of the phosphoramidite ligand is likely to generate the active catalyst. The square-planar [Ir(COD)(L1)Cl] (L1 = P(BINOL)(bisphenethylamine)) did not react with cinnamyl carbonate, but did react with amine to generate an Ir(I) trigonal bipyramidal complex coordinated by COD, a cyclometalated kappa2-phosphoramidite, and a kappa1-phosphoramidite. This complex reacted with phosphines to generate products from replacement of the kappa1-phosphoramidite. These cyclometalated complexes were highly active catalysts for allylic amination and etherification and retained the high selectivity of the original catalyst system. In addition, these complexes combined with [Ir(cod)Cl]2 catalyzed reactions of amines with lower loadings, catalyzed reactions of alkylamines and aromatic amines that did not react with the original catalyst system, and catalyzed reactions of phenoxides under milder conditions.

Enantiocontrolled synthesis of 2,6-disubstituted piperidines by desymmetrization of meso-eta-(3,4,5)-dihydropyridinylmolybdenum complexes. application to the total synthesis of (-)-dihydropinidine and (-)-andrachcinidine.

A conceptually new approach to the enantiocontrolled synthesis of 2,6-disubstituted piperidines was achieved by desymmetrization of meso-2,6-dimethoxy-eta-(3,4,5)-dihydropyridinylmolybdenum complexes. After protection of the piperidine nitrogen as a urethane derived from (+)- or (-)-trans-2-(alpha-cumyl)cyclohexyl (TCC), a sequential, one-pot methoxide abstraction/nucleophilic addition/methoxide abstraction/nucleophilic addition generated good yields of 2,6-disubstituted-eta-(3,4,5)-dihydropyridinylmolybdenum complexes. This sequence proceeds by way of a highly diastereoselective methoxide abstraction (>40:1). High yielding protodemetalation and N-deprotection provided a simple and enantiocontrolled synthetic entry to a variety of 2,6-disubstituted piperidines. This new method was used for the total synthesis of (-)-dihydropinidine and (-)-andrachcinidine.