Sulfone-Mediated SNAr Reaction as a Powerful Tool for the Synthesis of 4-Quinolinyl Ethers and More-Application to the Synthesis of HCV NS3/4a Protease Inhibitor BI 201420.

An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive SNAr reaction of 4-quinolinyl sulfones with a range of structurally diversified 1°, 2°, and 3° alcohols with a wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a complex target of HCV NS3/4a protease inhibitor BI 201420 was accomplished.

Application of a Preformed Pd-BIDIME Precatalyst to Suzuki-Miyaura Cross-Coupling Reaction in Flow.

The application of a Buchwald's third generation palladacycle containing a dihydrobenzooxaphosphole-based ligand (e.g., BIDIME) was reported in the Suzuki cross-coupling reaction. Using flow technology, high yield and reproducible Suzuki cross-coupling reaction for one of our key intermediates was achieved with Pd loadings as low as 0.5 mol %. This continuous flow approach overcomes catalyst deactivation and scale dependence issues that can be a problem in some traditional batch-mode operations and responds to the challenge of improving process greenness.

Synthesis of highly potent lymphocyte function-associated antigen-1 antagonists labeled with carbon-14 and with stable isotopes, part 3.

The drug candidates (2) and (3) are highly potent LFA-1 inhibitors. They were efficiently prepared labeled with carbon-14 using a palladium-catalyzed carboxylation of an iodo-precursor (5) and sodium formate-14 C to afford acid [14 C]-(6), which was coupled via an amide bond to chiral amines (7) and (8) in 52% and 48% overall yield, respectively, and with specific activities higher than 56 mCi/mmol and radiochemical purities of 99%. For stable isotopes synthesis, the amine [2 H8 ]-(7) was synthesized in three steps from 2-cyanopyridine-2 H4 using Kulinkovich-Szymonik aminocyclopropanation, followed by coupling to L-alanine-2,3,3,3-2 H4 -N-t-BOC, and then removal of the BOC-protecting group. Amide bond formation with acid (6) gave [2 H8 ]-(2) in 36% overall yield. The amine [13 C4 ,15 N]-(8) was obtained in two steps using L-threonine-14 C4 ,15 N and then coupled to acid [13 C]-(6) to give [13 C5 ,15 N]-(3) in 56% overall yield.

Development of a Scalable, Chromatography-Free Synthesis of t-Bu-SMS-Phos and Application to the Synthesis of an Important Chiral CF3-Alcohol Derivative with High Enantioselectivity Using Rh-Catalyzed Asymmetric Hydrogenation.

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).

Synthesis of P-Chiral Dihydrobenzooxaphosphole Core for BI Ligands in Asymmetric Transformations.

An efficient and practical synthesis of enantiomerically pure P-chiral dihydrobenzooxaphosphole (BOP) core 1 is developed that is amenable to large scale preparation of the related ligand series. The unique epimerization of the P-chiral center of the undesired (R,R)-diastereomeric phosphine oxide 19 through chlorination followed by crystallization makes this chemical resolution method achieve 65% yield of desired (R,S)-diastereomer 12.

Sequential C-H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11ß-HSD-1 Inhibitor.

A concise asymmetric synthesis of an 11ß-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.

An Enantioselective Synthesis of an 11-ß-HSD-1 Inhibitor via an Asymmetric Methallylation Catalyzed by (S)-3,3'-F2-BINOL.

An efficient asymmetric synthesis of 11-ß-HSD inhibitor 1 has been accomplished in five linear steps and 53% overall yield, starting from the readily available 3-chloro-1-phenylpropan-1-one. The key feature of the synthesis includes an asymmetric methallylation of 3-chloro-1-phenylpropan-1-one catalyzed by the highly effective organocatalyst (S)-3,3'-F2-BINOL under solvent-free and metal-free conditions.

Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor.

A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.

Development of a large scale asymmetric synthesis of the glucocorticoid agonist BI 653048 BS H3PO4.

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size.

Metabolic switching of BILR 355 in the presence of ritonavir. I. Identifying an unexpected disproportionate human metabolite.

11-Ethyl-5,11-dihydro-5-methyl-8-[2-[(1-oxido-4-quinolinyl)oxy] ethyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (BILR 355) is an inhibitor of the human immunodeficiency virus-1. BILR 355 exhibited a nonlinear pharmacokinetic profile and low exposure after oral administration to humans. This article describes the in vitro metabolism of BILR 355, which is correlated with the in vivo nonlinearity findings. Our in vitro studies had demonstrated that BILR 355 was extensively metabolized by cytochrome P450 3A. Thus, BILR 355 was concomitantly administered with ritonavir (RTV) in an attempt to boost systemic exposure, which did occur in humans. In addition, the expectation was that the overall metabolism of BILR 355 would be decreased with concomitant administration of RTV. Subsequent metabolite profiling was performed using human plasma samples obtained from clinical phase Ib studies with concomitant administration of BILR 355 and RTV. A total of 18 metabolites was observed. Their structures were proposed on the basis of high-performance liquid chromatography-tandem mass spectrometry technologies, and 10 metabolites were confirmed by comparison with synthetic standards. We were surprised to find that a disproportionate human metabolite, BILR 516, was uncovered during this metabolite profiling study and pharmacokinetic analysis of BILR 516 showed that it had a longer half-life and higher exposure than the parent compound at steady state. Of interest, BILR 516 was not detected in human plasma when BILR 355 was administered alone. Therefore, whereas RTV boosted the exposure of BILR 355, it resulted in a significant metabolic switching of BILR 355. Overall, this article demonstrates an unusual example of metabolic switching and raises concern about the consequence of metabolic switching during drug development.

Large-scale asymmetric synthesis of a cathepsin S inhibitor.

A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.

Asymmetric hydrogenation of unsaturated ureas with the BIPI ligands.

Asymmetric hydrogenation of unsaturated urea esters with the BIPI Ligands has been examined. Optimization of the P-N ligand structure has led to the development of chiral rhodium catalysts capable of producing the targets with >99% ee. The critical phosphine borane SNAr reaction needed for ligand synthesis has been optimized to give the adducts in high yield at ambient temperature with no racemization. An extremely concise, economical, and scalable sequence to these important new ligands for catalysis of asymmetric hydrogenation has been developed.

A superior method for the reduction of secondary phosphine oxides.

[reaction: see text] Diisobutylaluminum hydride (DIBAL-H) and triisobutylaluminum have been found to be outstanding reductants for secondary phosphine oxides (SPOs). All classes of SPOs can be readily reduced, including diaryl, arylalkyl, and dialkyl members. Many SPOs can now be reduced at cryogenic temperatures, and conditions for preservation of reducible functional groups have been found. Even the most electron-rich and sterically hindered phosphine oxides can be reduced in a few hours at 50-70 degrees C. This new reduction has distinct advantages over existing technologies.

Asymmetric methallylation of ketones catalyzed by a highly active organocatalyst 3,3'-F2-BINOL.

(S)-3,3'-F2-BINOL has been synthesized for the first time and demonstrated as a highly active organocatalyst for asymmetric methallylation of ketones. Up to 98:2 enantioselectivity and 99% yield were obtained with 5 mol % catalyst loading. The catalyst (S)-3,3'-F2-BINOL could be easily recovered and reused.

Synthesis of a potent cathepsin s inhibitor labeled with deuterium and carbon-14.

Morpholine-4-carboxylic acid {(S)-1-[4-cyano-1-(3-morpholin-4-yl-propyl)-piperidin-4-ylcarbamoyl]-4,4- dimethyl-hexyl}-amide, (1) is a potent reversible and selective cathepsin S inhibitor. Deuterium labeled (1) was prepared in four steps in 62% overall yield from [2H8]- morpholine and chiral acid (6). Carbon-14 labeled (1) was obtained in two steps using sodium [14C]-cyanide in a modified Strecker reaction followed by amide bond formation with acid (6) in 74% overall radiochemical yield. The phosphate salt of this compound was produced by treatment with phosphoric acid in methanol in 97% yield.

Reduction of tertiary phosphine oxides with DIBAL-H.

The reduction of tertiary phosphine oxides (TPOs) and sulfides with diisobutylaluminum hydride (DIBAL-H) has been studied in detail. An extensive solvent screen has revealed that hindered aliphatic ethers, such as MTBE, are optimum for this reaction at ambient temperature. Many TPOs undergo considerable reduction at ambient temperature and then stall due to inhibition. 31P and 13C NMR studies using isotopically labeled substrates as well as competition studies have revealed that the source of this inhibition is tetraisobutyldialuminoxane (TIBAO), which builds up as the reaction proceeds. TIBAO selectively coordinates the TPO starting material, preventing further reduction. Several strategies have been found to circumvent this inhibition and obtain full conversion with this extremely inexpensive reducing agent for the first time. Practical reduction protocols for these critical targets have been developed.

Tandem Pd(II)-catalyzed vinyl ether exchange-Claisen rearrangement as a facile approach to gamma,delta-unsaturated aldehydes.

A sequential allyl vinyl ether formation-Claisen rearrangement process catalyzed by a palladium(II)-phenanthroline complex is reported. The effects of allylic alcohol structure, type of vinylating agent, and palladium catalysts are discussed. This method provides a convenient approach to gamma,delta-unsaturated aldehydes under mild conditions that avoid the use of toxic Hg(II) catalysts. The new methodology has been successfully demonstrated on the kilogram scale.

Transition state studies on the dioxirane-mediated asymmetric epoxidation via kinetic resolution and desymmetrization.

This paper describes an efficient kinetic resolution process of trisubstituted cyclic olefins via a chiral dioxirane generated in situ from a fructose-derived ketone and Oxone. The substrates presented include a variety of 1,3-disubstituted and 1,6-disubstituted cyclohexenes with the stereogenic centers at allylic positions. A sequential desymmetrization and kinetic resolution of 1,4-cyclohexadienes by the chiral dioxirane was also found to be feasible. The initially formed monoepoxides can be kinetically resolved by continuing the reaction, leading to the increase or decrease of the ee values of monoepoxides depending on the diene systems. In some cases, a prochiral directing group is not required and the first formed epoxide stereoselectively directs the second epoxidation. When the coupled desymmetrization and kinetic resolution is used synergistically, high enantiopurity can be obtained for an epoxide from an intrinsically less enantioselective substrate. The observed absolute and relative stereochemistry as well as the changing optical purity can be effectively rationalized by transition state analysis.

Structure elucidation and total synthesis of a unique group of trace impurities in Tipranavir drug product.

Four unknown trace impurities (7-10) were observed in the capsule formulation of the HIV drug Tipranavir after prolonged storage at 30 degrees C/70% RH. Extensive NMR and LC/MS analyses revealed the compounds to be covalent adducts between TRIS, an excipient of the formulation, and diastereomeric Tipranavir alcohols formed via slow air oxidation of the drug substance. The structures were ultimately confirmed by total synthesis with final purification by chiral, preparative supercritical fluid chromatography. A novel Favorskii rearrangement to furnish butyrolactones was also uncovered during the synthesis.

A novel class of tunable zinc reagents (RXZnCH2Y) for efficient cyclopropanation of olefins.

A class of zinc reagents (RXZnCH(2)Y) generated with an appropriate organozinc is very effective for the cyclopropanation of olefins. The reactivity and selectivity of these reagents can be regulated by tuning the electronic and steric nature of the RX group on Zn. A reasonable level of enantioselectivity was obtained for the cyclopropanation of unfunctionalized olefins when a chiral (iodomethyl)zinc species was used, providing a valuable approach for the asymmetric cyclopropanation of unfunctionalized olefins.