Explaining dissolution properties of rivaroxaban cocrystals.

The aim of this study was to improve rivaroxaban water-solubility by cocrystal preparation and to understand this process. The screening with water-soluble coformers was performed via both mechanochemical and solution-mediated techniques. Two cocrystals of rivaroxaban with malonic acid and oxalic acid were prepared, and the structure of the cocrystal with oxalic acid was solved. Both cocrystals exhibit improved dissolution properties. The mechanism of the supersaturation maintenance was studied by in-situ Raman spectroscopy. The transformation into rivaroxaban dihydrate was identified as the critical step in the improved dissolution properties of both cocrystals. Moreover, the transformation kinetics and solubilization effects of the coformers were identified as responsible for the differences in the dissolution behavior of the cocrystals. In-vivo experiments proved that the use of cocrystal instead of form I of free API helped to increase the bioavailability ofrivaroxaban.

Regioselective direct C-H arylations of protected uracils. Synthesis of 5- and 6-aryluracil bases.

A new regioselective synthesis of 5- and 6-aryluracil bases based on direct C-H arylations of diverse 1,3-protected uracils has been developed. Benzyl-protected uracils were selected as the most practical in terms of stability during the arylation and facile cleavage of the benzyl groups. Pd-catalyzed C-H arylations in the absence of CuI gave preferentially 5-aryl-, whereas the reactions in the presence of CuI gave 6-aryl-1,3-dibenzyluracils. Final deprotection either by transfer hydrogenolysis over Pd/C or by treatment with BBr(3) gave the desired free arylated uracil bases in good yields.

Intramolecular direct C-H arylation approach to fused purines. Synthesis of purino[8,9-f]phenanthridines and 5,6-dihydropurino[8,9-a]isoquinolines.

Intramolecular C-H arylations were employed as a key step in the synthesis of hitherto unknown fused purine systems: 13-substituted purino[8,9-f]phenanthridines and 11-substituted 5,6-dihydropurino[8,9-a]isoquinolines. The purino[8,9-f]phenanthridines were prepared in moderate yields by double C-H arylations of 9-phenylpurines with 1,2-diiodobenzene or, more efficiently, by consecutive Suzuki coupling of 9-(2-bromophenyl)purines with 2-bromophenylboronic acid followed by intramolecular C-H arylation. 5,6-Dihydropurino[8,9-a]isoquinolines were prepared in quantitative yields by intramolecular C-H arylations of 9-(2-chlorophenethyl)purines.

Synthesis of 6,8,9-tri- and 2,6,8,9-tetrasubstituted purines by a combination of the Suzuki cross-coupling, N-arylation, and direct C-H arylation reactions.

Novel practical methodology of synthesis of a several types of di-, tri-, and tetraarylpurine derivatives by a combination of regioselective Suzuki cross-coupling reactions and/or Cu-catalyzed N-arylation with direct C-H arylations was developed. 6,8-Diaryl- and 2,6,8-triaryl-9-isopropylpurines were prepared by one or two cross-couplings of 6-chloro- or 2,6-dichloro-9-isopropylpurine with arylboronic acids followed by Pd-catalyzed C-H arylation by aryl halides to position 8. 6-Chloropurine and adenine underwent Cu-catalyzed N-arylation to position 9 with boronic acids, followed by cross-coupling with AlMe3 and/or C-H arylation to obtain 8,9-diaryl-6-methylpurines or 8,9-diaryladenines (accompanied by products of partial N-arylation of adenine in position 6). The methodology is suitable for construction of small libraries of modified purines.

The first direct C-H arylation of purine nucleosides.

Pd-catalyzed direct C-H arylation of unprotected purine nucleosides with aryl iodides at position 8 was developed to allow a straightforward single-step introduction of diverse aryl groups.

Direct C-H arylation of purines: development of methodology and its use in regioselective synthesis of 2,6,8-trisubstituted purines.

[Structure: see text] Direct C-H arylation of purines to position 8 by diverse aryl iodides was achieved with Pd catalysis in the presence of CuI and Cs2CO3. The methodology is general and efficient and was applied in the consecutive regioselective synthesis of 2,6,8-trisubstituted purines bearing three different C-substituents in combination with two cross-coupling reactions.

Palladium-catalyzed borylation of phenyl bromides and application in one-pot Suzuki-Miyaura biphenyl synthesis.

The coupling reaction of pinacolborane with various aryl bromides in the presence of a catalytic amount of Pd(OAc)(2) together with DPEphos as ligand and Et(3)N as base provided arylboronates. High yields were obtained in the case of electron-donor substituted aryl bromides. The direct preparation of arylboronates allowed the one-pot, two-step synthesis of unsymmetrical biaryls in high yields. [reaction: see text]