Joseph M. Fortunak

Enantioselective synthesis of α-hydroxy carboxylic acids: Direct conversion of α-oxocarboxylic acids to enantiomerically enriched α-hydroxy carboxylic acids via neighboring group control

Abstract α-Oxocarboxylic acids can be reduced to the corresponding α-hydroxy carboxylic acids employing DIP-C1 tm as a reducing agent. The α-carboxylic substituent exerts a remarkable neighboring group effect on the reduction. The reaction presumably proceeds in an intramolecular fashion through a “rigid” bicyclic transition state assembly, which produces enantioselectivities approaching 99%.

Isoerization of allylic acetates catalyzed by palladium. New method for stereocontrol.

Abstract Reaction of allylic acetates with tetrakis (triphenylphosphine) palladium leads to positional and stereochemical isomerism. A mechanism is proposed. Elimination of allyl acetates to dienes is also observed and constitutes a useful synthetic procedure. The use of bis(benzenesulfonyl)methane as a Θ CH 2 Θ equivalent is reported.

An approach to the synthesis of gelsemine: the intramolecular reaction of an allylsilane with an acyliminium ion for the synthesis of one of the quaternary centres

Abstract We describe an efficient synthesis (summarised in Schemes 8 and 10) of an advanced intermediate (34) suitable for the synthesis of gelsemine. The key steps in the synthesis are (i) the Diels-Alder reaction between 1-tetrahydropyranyloxycyclohexa-1,3-diene (10) and methyl β-nitroacrylate (11) giving an adduct (12), in which the chiral centre in the tetrahydropyranyl ring is produced substantially in only one sense, (ii) the rearrangement of a bicyclo [2.2.2] octane (23) into a bicyclo[ 3.2.1] octane (24), where control of which bridge migrates is achieved by a choice of the counterion in the Lewis acid, and (iii) the efficient formation of the quaternary centre by an intramolecular reaction between an allylsilane group and an acyliminium ion (33 → 34).

Near-Infrared Investigations of Novel Anti-HIV Tenofovir Liposomes

Near-infrared (NIR) approaches is considered one of the most well-studied process analyzers evolving from the process analytical technology initiatives. The objective of this study was to evaluate NIR spectroscopy and imaging to assess individual components within a novel tenofovir liposomal formulation. By varying stearylamine, as a positive charge imparting agent, five batches were prepared by the thin film method. Each formulation was characterized in terms of drug entrapment efficiency, release characteristics, particle sizing, and zeta potential. Drug excipients compatibility was tested using Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The obtained results showed an increase in drug entrapment and a slower drug release by increasing the incorporated percentage of stearylamine. The compatibility testing revealed a significant interaction between the drug and some of the investigated excipients. The developed NIR calibration model was able to assess drug, phospholipid, and stearylamine levels along the batches. The calibration and prediction plots were linear with correlation coefficients of more than 0.9. The root square standard errors of calibration and prediction did not attain 5% of the measured values confirming the accuracy of the model. In contrast, NIR spectral imaging was capable of clearly distinguishing the different batches, both qualitatively and quantitatively. A linear relationship was obtained correlating the actual drug entrapped and the predicted values obtained from the partial least squares images.

Target prices for mass production of tyrosine kinase inhibitors for global cancer treatment

Objective To calculate sustainable generic prices for 4 tyrosine kinase inhibitors (TKIs). Background TKIs have proven survival benefits in the treatment of several cancers, including chronic myeloid leukaemia, breast, liver, renal and lung cancer. However, current high prices are a barrier to treatment. Mass production of low-cost generic antiretrovirals has led to over 13 million people being on HIV/AIDS treatment worldwide. This analysis estimates target prices for generic TKIs, assuming similar methods of mass production. Methods Four TKIs with patent expiry dates in the next 5 years were selected for analysis: imatinib, erlotinib, lapatinib and sorafenib. Chemistry, dosing, published data on per-kilogram pricing for commercial transactions of active pharmaceutical ingredient (API), and quotes from manufacturers were used to estimate costs of production. Analysis included costs of excipients, formulation, packaging, shipping and a 50% profit margin. Target prices were compared with current prices. Global numbers of patients eligible for treatment with each TKI were estimated. Results API costs per kg were

Novel syntheses of camptothecin alkaloids, part I. Intramolecular [4+2] cycloadditions of N-arylimidates and 4H-3,1-benzoxazin-4-ones as 2-aza-1,3-dienes

347–

Novel syntheses of camptothecin alkaloids, part 2. concise synthesis of (S)-camptothecins

746 for imatinib,

A new and practical synthesis of vinyl dichlorides via a non-Wittig-type approach

2470 for erlotinib,

Pharmaceutical development and specification of stereoisomers

4671 for lapatinib, and

Palladium catalyzed fragmentation reaction as an approach to vitamin A ester

3000 for sorafenib. Basing on annual dose requirements, costs of formulation/packaging and a 50% profit margin, target generic prices per person-year were