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A synthetic methodology for a protecting-group-free formation of 3-aryl-substituted 4-aminopyrazoles from acetophenones via a telescoped oximation and hydrazine condensation of 1,3-ketoaldehydes to generate nitrosopyrazoles, and copper-catalyzed NaBH4 reduction of the nitroso group, was demonstrated. The synthesis tolerates a broad scope of substrates with a variety of substituents on the phenyl ring to afford the desired products.

The development of an improved kilogram-scale synthesis of the JAK1 inhibitor GDC-4379 for the treatment of asthma is described. The new process is highlighted by a step-economical construction of ...

The concise early development route to the Nav1.7 inhibitor GDC-0310 is described. The active pharmaceutical ingredient (API) contains one stereocenter, which was obtained with high enantiomeric excess (>99:1) by using an SN2 displacement approach to connect two intermediates: a chiral benzyl alcohol and a piperidine. The synthesis of the piperidine building block proceeded via a regioselective SNAr reaction on 1-chloro-2,4-difluorobenzene by N-Boc-4-piperidinemethanol, followed by installation of the methyl ester group by electrophilic aromatic bromination and a palladium-catalyzed alkoxycarbonylation. A subsequent Suzuki–Miyaura cross-coupling reaction was then telescoped directly into cleavage of the Boc group to provide the advanced piperidine intermediate. The key feature of the synthesis is the highly selective SN2 displacement of the chiral mesylate of (R)-1-(3,5-dichlorophenyl)ethan-1-ol with the piperidine intermediate, followed by a chiral purity upgrade via the corresponding (1S)-(+)-camphorsulfonic acid salt. After standard hydrolysis of the methyl ester and CDI mediated amidation to couple the resulting acid with methanesulfonamide, enantiomerically pure GDC-0310 was obtained in high overall yield (37%) on a 6.5 kilogram scale.

A highly regioselective Mg-catalyzed alkylation of 3-substituted pyrazoles has been developed to provide N2-alkylated regioisomers. Using α-bromoacetates and acetamides as alkylating agents, this new method was applied to a variety of 3-substituted and 3,4-disubstituted pyrazoles to produce the N2-alkylated products with high regioselectivities ranging from 76:24 to 99:1 and 44–90% yields.

The development of a redesigned and improved second-generation synthesis of the Nav1.7 inhibitor GDC-0276 based on experience gained from a fit-for-purpose first-generation synthesis will be described. The first-generation synthesis proceeded via a regioselective SNAr reaction on the advanced starting material t-butyl 5-chloro-2,4-difluorobenzoate with 1-adamantanemethanol. In the newly developed second-generation synthesis, the much improved regioselective SNAr reaction was performed on the readily available starting material 1-chloro-2,4-difluorobenzene, followed by installation of the carboxylate group by electrophilic aromatic bromination and a palladium-catalyzed alkoxycarbonylation. A subsequent Suzuki–Miyaura cross-coupling reaction was then telescoped directly into a phase-transfer-catalyzed ester hydrolysis. Amidation of the resulting acid intermediate with 1-azetidine sulfamide in turn provided GDC-0276 in high overall yield and purity on a 100 kg scale.

A practical convergent synthesis of PI3K inhibitor GDC-0908 (1) is described. The process features a dihydrobenzothienooxepine formation via palladium-catalyzed intramolecular direct C-H arylation and a Negishi coupling to construct the key C-C bonds. We further developed a general synthesis of dihydrobenzothienooxepines in good to excellent yields via palladium-catalyzed intramolecular direct C-H arylation, which tolerates both electronically and sterically diverse substituents on the phenyl ring.

Boronic acids and boronate esters are commonly used reagents in Suzuki–Miyaura coupling chemistry which are known to be weakly mutagenic in microbial assays. In this paper, we describe an inductively coupled plasma mass spectrometer method (ICP-MS) for the analysis of boron at low parts per million levels. Boronic acid and ester levels are then calculated stoichiometrically in a drug substance based on the determination of boron with good sensitivity (LOQ of 0.8 ppm). The paper outlines some of the important aspects of the method and instrument features such as use of organic diluent, spray chamber configuration, and its optimization which are critical for analysis of trace inorganic species in drug substances.

An improved, efficient process with a significantly reduced process mass intensity (PMI) led to the multikilogram synthesis of a brain penetrant PI3K inhibitor GDC-0084. Highlights of the synthesis include a phase transfer catalyzed annulation in water, an efficient Suzuki-Miyaura cross-coupling of a chloropyrimidine with an arylboronic acid using a low palladium catalyst loading, and the development of a controlled crystallization to provide the API. The process delivered GDC-0084 with low levels of both impurities and residual metals.

A process leading to the multikilogram GMP synthesis of Chk1 inhibitor GDC-0425 (1) was developed. Highlights of the synthesis include protection of the pyrrole ring of a 1,7-diazacarbazole as propyl ethyl ether, an efficient Pd catalyzed cyanation of an aryl chloride, aryl ether formation by SNAr fluoride displacement, and development of a controlled crystallization providing the API with the required polymorphic form. The process delivered high-quality GDC-0425 with low levels of impurities and residual metals in five steps and 31% overall yield.

Hexafluorophosphoric acid promotes 1,3,4-oxadiazolium hexafluorophosphate formation from N′-acyl-N-aroyl-N-arylhydrazides or N′-acyl-N-acyl-N-arylhydrazides under mild conditions. These 1,3,4-oxadiazolium hexafluorophosphates can be treated with cyanamide in propan-2-ol in the presence of triethylamine to generate 1,5-disubstituted 3-amino-1H-1,2,4-triazoles in good yields. This safe and scalable protocol displays a broad scope with respect to N-substitutions and N′-acyl protecting groups.

Ruthenium-catalyzed asymmetric homogeneous hydrogenation (AHH) is used as the key step of a multi-kilogram scale synthesis of an enantiomeric fluoropiperidine. The AHH of a tetrasubstituted β-fluoroenamide is carried out under mild conditions using a Ru/Josiphos catalyst with high ee (98%).

The major product in the intramolecular Pauson-Khand reaction of 3,4-disubstituted 1,6-heptenynes to form bicyclo[3.3.0]octenones is highly dependent on the relative configurations of the two stereocenters of the substrate. For example, cycloaddition of the “syn,syn” stereoisomer of 3,5-dimethyl-4-propargyl-1,6-heptadiene gives predominantly an enone containing both substituents in more hindered endo orientations; the “syn,anti” stereoisomer, upon reaction across the “syn” linkage similarly gives mostly endo product, but upon reaction across the “anti” portion of the molecule affords almost exclusively an enone in which the C6 methyl group possesses exo stereochemistry. Parallel results obtain from enynes built upon cyclohexane frameworks. Calculated energies of pre-cycloaddition enynes, metallacycles presumed to be the penultimate intermediates in the cyclization mechanism, and the final products are examined in order to develop a reasonable predictive model.

The optically active, facial complex Cr(CO)3(PP′P″) (1) with the tridentade ligand PP′P″ = (R)-(+)-1,2,4-tris (diphenylphosphino)butane has been synthesized and characterized. The complex Cr(CO)3(PP′)P″ (PP′ = (R)-(+)-prophos, P″ = PMe2Ph) forms two pairs of diastereomers, facial (3, 4) and meridional (5, 6), respectively, that can be separated by preparative column chromatography. Surprisingly, the CD spectra of Cr(CO)3(PP′P″) (1) and the facial diastereomer of Cr(CO)3(PP′P″ (3), which have the same configuration at the Cr atom, are dissimilar. The meridional configuration of the two isomers 5 and 6 of Cr(CO)3 (PP′)PMe2Ph is supported by the 31P and 1H NMR spectra of the optically inactive complex Cr(CO)3(PP′)P″ (PP′ = 1-[di (4-methoxyphenyl)phosphinol-2-(diphenylphosphino)ethane P″ = PMePh2) which forms the meridional isomers 9 and 10.

3-Thiabicyclo-[3,3,0]-oct-5-en-7-ones have been prepared by intramolecular Pauson-Khand reaction on allylpropargylsulfide cobalt complexes in benzene with dimethylsulfoxide as promoter and dimethylsulfide in 65-80% yield.

3-Thiabicyclo-[3,3,0]-oct-5-en-7-ones have been prepared by intramolecular Pauson-Khand reaction on allylpropargylsulfide cobalt complexes in benzene with dimethylsulfoxide as promoter and dimethylsulfide in 65-80% yield.

Department of Chemistry and Division of Molecular Engineering and Chemistry, Korea University, Seoul 136-701, KoreaReceived September 16, 2004Key Words : Pauson-Khand reaction, Propargyl aldehyde dicobalt hexacarbonyl, Asymmetric addition,Bis(homoallyl)zincThe preparation of the optically active secondary prop-argyl alcohols has been a subject of intensive researches.