Preparation of 2,4-diarylquinolines and substituted dihydrobenz-[c]acridines by the condensation of certain c(α),o-dilithiooximes with 2-aminobenzophenones

C(α),O-Dilithiooximes were prepared in an excess of lithium diisopropylamide and condensed with several 2-aminobenzophenones, followed by acid hydrolysis of the oximes to the ketones, which then underwent cyclodehydration and linear dehydration to give substituted quinolines or dihydrobenz[c]acridines.     

Reactions of 14-hydroxy-14-azadispiro[5.1.5.2]pentadec-9-ene-7,15-dione and related compounds. II

3 When 11-diethyl- and 3, 11-di-n-propyl-14-hydroxy-14-azadispiro[5.1. 5.2]pentadec-9-ene-7, 15-dione (E-IV and n-Pr-IV) are heated with polyphosphoric acid at 55–65°, the 14-hydroxyl group cyclizes at the 11-carbon to form E-VI and n-Pr-VI, the structures of which have been established. Compounds P-IV, i-Pr-IV and t-B-IV do not cyclize under these conditions. The Beckmann rearrangement of 12-hydroxy-12-azadispiro[4.1.4.2]tridec-8-ene-6, 13-dione-6-oxime (P-I) with polyphosphoric acid at 40–50° formed only the normal product, P-II, which could not be cyclized. Compound P-IV was the only ketone of this series which would add hydrogen cyanide to form a cyanohydrin.     

Synthesis of 8,9-dioxabicyclo[5.2.1]decane derivatives from cyclooctene

Singlet oxygenation of cyclooctene gives 2-cyclooctenyl hydroperoxide which affords isomeric 2, $\text{cis}$-10-dibromo-8,9-dioxabicyclo[5.2.1]decanes on treatment with mercury(II) trifluoroacetate then bromine, and yields $\text{cis}$-10-bromo-8,9-dioxabicyclo[5.2.1]decane on treatment with bromine then silver trifluoroacetate.     

Hydride donor abilities and bond dissociation free energies of transition metal formyl complexes

The hydride complex [Pt(dmpe)2H]+ (dmpe = 1,2-bis(dimethylphosphino)ethane) reversibly transfers H- to the rhenium carbonyl complex [CpRe(PMe3)(NO)(CO)]+, giving the formyl CpRe(PMe3)(NO)(CHO). From the equilibrium constant for the hydride transfer (16.2), the DeltaGdegrees for the reaction was determined (-1.6 kcal/mol), as was the hydride-donating ability of the formyl (44.1 kcal/mol). The hydride-donating ability, DeltaGdegrees(H-), is defined as the energy required to release the hydride ion into solution by the formyl complex [i.e. M(CHO) right arrow M(CO)+ + H-]. Subsequently, the hydride-donating ability of a series of formyl complexes was determined, ranging from 44 to 55 kcal/mol. With use of this information, two rhenium carbonyl complexes, [CpRe(NO)(CO)2]+ and [Cp*Re(NO)(CO)2]+, were hydrogenated to formyls, employing [Pt(dmpp)2]2+ and Proton-Sponge. Finally, the E(1/2)(I/0) values for five rhenium carbonyl complexes were measured by cyclic voltammetry. Combined with the known DeltaGdegrees(H-) values for the complexes, the hydrogen atom donating abilities could be determined. These values were all found to be approximately 50 kcal/mol.     

Dyeing uric acid crystals with methylene blue

The growth of anhydrous uric acid (UA) and uric acid dihydrate (UAD) crystals from supersaturated aqueous solutions containing methylene blue, a cationic organic dye, has been investigated. Low concentrations of dye molecules were found to be included in both types of crystal matrixes during the growth process. Incorporation of dye into UA crystals occurs with high specificity, affecting primarily [001] and [201] growth sectors, while UAD crystals grown from solutions of similar dye concentration show inclusion but little specificity. The orientation of the UA-trapped species was determined from polarization data obtained from visible light microspectrometry. To achieve charge neutrality, a second anionic species must also be included with the methylene blue into UA and UAD crystal matrices. Under high pH conditions, crystallization of 1:1 stoichiometric mixtures of methylene blue and urate yields methylene blue hexahydrate (MBU.6(H2O). The crystal structure of MBU.6(H2O) reveals continuous pi-pi stacks of planes of dye cations and urate anions mediated by water molecules. This structure provides an optimal geometry for methylene blue-urate pairs and additional support for the incorporation of these dimers in uric acid single-crystal matrices. The strikingly different inclusion patterns in UA and UAD demonstrate that subtle changes in the crystal surfaces and/or growth dynamics can greatly affect recognition events.     

Synthesis of some pyridylamino-1,4-disubstituted phthalazines

Two general procedures involving the condensation of phthalonitrile or 1,3-diiminoisoindoline with various aminopicolines, followed by ring expansion with hydrazine to the corresponding phthalazine are described. Syntheses are reported of 1, 4-di(3′-methyl-2′-pyridyl) aminophthalazine, 1,4-di(5′-methyl-2′-pyridyl)aminophthalazine, and 1,4-di(4′, 6′-dimethyl-2′-pyridyl)aminophthalazine.     

Determination of a novel antifibrotic small molecule GDC‐3280 in human plasma and urine by liquid chromatography tandem mass spectrometry to support its first‐in‐human clinical trial

A specific and robust LC–MS/MS method was developed and validated for the quantitative determination of GDC‐3280 in human plasma and urine. The nonspecific binding associated with urine samples was overcome by the addition of CHAPS. The sample volume was 25 μL for either matrix, and supported liquid extraction was employed for analyte extraction. d6‐GDC‐3280 was used as the internal standard. Linear standard curves (R² > 0.9956) were established from 5.00 to 5000 ng/mL in both matrices with quantitation extended to 50,000 ng/mL through dilution. In plasma matrix, the precision (RSD) ranged from 1.5 to 9.9% (intra‐run) and from 2.4 to 7.2% (inter‐run); the accuracy (RE) ranged from 96.1 to 107% (intra‐run) and from 96.7 to 104% (inter‐run). Similarly, in urine the precision was 1.5–6.2% (intra‐run) and 1.9–6.1% (inter‐run); the accuracy was 83.1–99.3% (intra‐run) and 87.1–98.3% (inter‐run). Good recovery (>94%) and negligible matrix effect were achieved in both matrices. Long‐term matrix stability was established for at least 703 days in plasma and 477 days in urine. Bench‐top stability of 25 h and five freeze–thaw cycles were also confirmed in both matrices. The method was successfully implemented in GDC‐3280's first‐in‐human trial for assessing its pharmacokinetic profiles.