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The large and steadily growing demand for medicines combined with their inherent resource-intensive manufacturing necessitates a relentless push for their sustainable production. Pharmaceutical companies are constantly seeking to perform reliable life cycle assessments of their medicinal products and assess the true value of their sustainable development achievements; however, they find themselves impeded by the lack of a universal metric system that allows for objective quantification of the underlying core denominators. Guided by the unambivalent purpose of the United Nations Sustainable Development Goal 12, which aims at substantially reducing production waste by 2030, and driven by a vision to catalyze greener active pharmaceutical ingredient (API) manufacturing around the globe, the authors set out to overcome current obstacles by defining an improved model for the metric named innovation green aspiration level, iGAL 2.0. We propose yield and convergence as new key sustainability indicators and include a new formula for convergence with potential applicability in computer assisted synthesis planning (CASP) algorithms. The improved statistical model of iGAL 2.0 represents a valuable extension to the common API process waste metrics, process mass intensity (PMI) and complete E factor (cEF), by putting those measures into perspective: iGAL 2.0 enables determination of relative process greenness (RPG) to identify potentially underperforming and environmentally concerning processes early and thereby deliver environmental value. At the same time, iGAL 2.0 generates economic value since reduced waste correlates to lower API production costs. The metric is complemented by its scorecard companion to highlight the impact of innovation on reductions of API manufacturing waste, enabling scientists to readily communicate the value of their work to their peers, managers, and the general public. We believe that iGAL 2.0 can readily be adopted by pharmaceutical firms around, BT/Biocatalysis

A scalable and safe process for the oxidative rearrangement of beta-carboline to quinolone derivatives, intermediates in the synthesis of PDE-V inhibitors RWJ387273 (R301249) and RWJ444772 (R290629), has been developed.

Three strategies for the synthesis of the novel, doubly constrained, 3,4-methano-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and its derivatives were evaluated. Only cyclocondensation of the mono(triphenyl)phosphonium salt derived from 1,2-bis(bromomethyl)benzene with N-alkoxycarbonyloxamates in 1,2-dimethoxyethane in the presence of potassium carbonate and subsequent cyclopropanation with dimethylsulfoxonium methylide in dimethyl sulfoxide furnished suitable O- and N-protected derivatives of 3,4-methano-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in a convenient way. A detailed 2D DQF-COSY and 2D NOESY NMR analysis of the rotational isomerism of the latter bicyclic amino acid derivatives was performed. Various O- and N-protection protocols were worked out to afford access to a whole range of new derivatives of the title amino acid, suitable for peptide synthesis., SCOPUS: ar.j, info:eu-repo/semantics/published

The direct cyclization of 2-amino-4-chloro-3,3-dimethylbutanenitrile with potassium tert-butoxide in THF afforded 1-amino-2,2-dimethylcyclopropane-1-carbonitrile and a dimerization product. Various new cis- and trans-1-(teri-butylamino)-2-benzyl- 2-methylcyclopropane-carbonitriles and the corresponding cyclopropanecarboxamides have been synthesized, with focus on the isolation of the pure stereoisomeric cyclopropanecarboxamides. The relative configuration of the stereoisomers was established by X-ray crystallographic analysis of one of the model compounds. A new route to the latter functionalized cyclopropanes was developed by reaction of 1-methoxycyclopropylamines with potassium cyanide. Some remarkable rearrangements of 1-aminocyclopropane-1-carbonitriles into azetidine and oxazine derivatives via Favorskii-derived intermediates are reported. Various aspects of the chemistry of geminally functionalized cyclopropanes are discussed.

The direct cyclization of 2-amino-4-chloro,3,3-dimethylbutanenitrile with potassium tert-butoxide in THF afforded 1-amino-2,2- dimethylcyclopropane-1-carbonitrile and a dimerization product. Various new cis- and trans-1-(tert-butylamino)-2-benzyl-2-methylcyclopropane- carbonitriles and the corresponding cyclopropanecarboxamides have been synthesized, with focus on the isolation of the pure stereoisomeric cyclopropanecarboxamides. The relative configuration of the stereoisomers was established by X-ray crystallographic analysis of one of the model compounds. A new route to the latter functionalized cyclopropanes was developed by reaction of 1-methoxycyclopropylamines with potassium cyanide. Some remarkable rearrangements of 1-aminocyclopropane-1-carbonitriles into azetidine and oxazine derivatives via Favorskil-derived intermediates are reported. Various aspects of the chemistry of geminally functionalized cyclopropanes are discussed., SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published

cis-2-Alkoxy-3-aminooxolanes 4 were synthesized in a remarkably stereospecific manner by alcoholysis of alpha-chloro-gamma-((trimethylsilyl)oxy)ketimines 2, obtained by alkylation of alpha-chloroketimines 1 with 2-bromo-1-((trimethylsilyl)oxy)ethane. The stereospecificity of the cyclization was lost when the alcoholysis was performed in the presence of base. However, complete transformation of the mixtures of cis- and trans-2-alkoxy-3-aminooxolanes into the more stable cis-compounds was achieved with hydrogen chloride in methanol. A mechanistic rationale for these stereochemical aspects is presented.