Co-crystals, Salts or Mixtures of Both? The Case of Tenofovir Alafenamide Fumarates.

Tenofovir alafenamide fumarate (TAF) is the newest prodrug of tenofovir that constitutes several drug products used for the treatment of HIV/AIDS. Although the solid-state properties of its predecessor tenofovir disoproxil fumarate have been investigated and described in the literature, there are no data in the scientific literature on the solid state properties of TAF. In our report, we describe the preparation of two novel polymorphs II and III of tenofovir alafenamide monofumarate (TA MF2 and TA MF3). The solid-state structure of these compounds was investigated in parallel to the previously known tenofovir alafenamide monofumarate form I (TA MF1) and tenofovir alafenamide hemifumarate (TA HF). Interestingly, the single-crystal X-ray diffraction of TA HF revealed that this derivative exists as a co-crystal form. In addition, we prepared a crystalline tenofovir alafenamide free base (TA) and its hydrochloride salt (TA HCl), which enabled us to determine the structure of TA MF derivatives using 15N-ssNMR (15N-solid state nuclear magnetic resonance). Surprisingly, we observed that TA MF1 exists as a mixed ionization state complex or pure salt, while TA MF2 and TA MF3 can be obtained as pure co-crystal forms.

Profiling the tuneable R-SMS-Phos structure in the rhodium(I)-catalyzed hydrogenation of olefins: the last stand?

A diversified family of enantiopure P-stereogenic "R-SMS-Phos" {R-SMS-Phos = 1,2-bis[(o-RO-phenyl)(phenyl)phosphino]ethane} ligands wherein R = branched or heteroatom-substituted alkyl, aralkyl, silyl, acyl, sulfonyl, etc. was screened for the Rh(I)-catalyzed hydrogenation of a representative set of olefinic substrates. This systematic and detailed investigation revealed a marked beneficial impact on enantioselectivity and catalyst activity in comparison to Knowles' ultimate DiPAMP {DiPAMP = 1,2-bis[(o-anisyl)(phenyl)phosphino]ethane} design. Mutant ligands with highly enhanced properties possessing particular features wherein the DiPAMP structure is found embedded were identified.

Study of the reaction of bulky aryllithium reagents with 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane derived from ephedrine.

The ring opening of enantiomerically pure 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane (1) with a variety of bulky aryllithium reagents was studied. Our results are not in total agreement with those obtained by others. In fact, several 2,6-disubstituted aryl groups were successfully appended to the phosphorus atom, furnishing the corresponding (N-ephedrino)phosphine boranes 2a-g with dr>99:1. However, when the attack on the phosphorus atom is hindered, deprotonation on the benzylic position occurs, leading to the formation of enantiomerically pure trans-(N-methylamino)(phenyl)(1-phenyl-1-propenyloxy)phosphine-P-borane (3). While the attack of 2,2'-dilithio-1,1'-biarenes leads to the corresponding (P-phenyl)phosphole derivatives (4i,j) and to [bis(N-ephedrino)](phenyl)phosphine-P-borane (5), the attack of 1,1'-dilithiometallocenes (M=Fe, Ru) leads to a separable diastereomeric mixture of 1,1'-bis[(N-ephedrino)(phenyl)phosphino-P-borane]metallocenes (2k,l/2k',l') with dr approximately 80:20.

Highly enantioselective transfer hydrogenation of fluoroalkyl ketones.

[Structure: see text] The asymmetric transfer hydrogenation of fluoroalkyl ketones mediated by [Ru(eta6-arene)((S,S)-R2NSO2DPEN)] catalysts using HCO2H-Et3N afforded the corresponding alcohols with high ee's and in excellent yields.