Partnership for sustainable solutions

Presence of excess Fluoride in water causes dental and skeletal fluorosis in addition to several ailments such as body aches and head ache, gastrointestinal problems, and also neurological, muscular and urinary tract manifestations. The problem has been a concern in many developing countries including India where excess of fluoride in water affects approximately 25 million people living in 8700 villages (NEERI, 1992). Gujarat is one of the Indian states where excess fluoride has been a cause of concern. Most of the water supply systems are conceived and implemented as engineering projects with very little scope for the involvement of people in the planning, implementation and management of the project. In the project district of Mehsana where 300 villages are affected, an attempt has been made in one village to illustrate the demand driven approach by fostering partnership amongst the communities, corporate and implementing agency

Crystallization-Induced Dynamic Resolution toward the Synthesis of (<i>S</i>)‑7-Amino‑5<i>H</i>,7<i>H</i>‑dibenzo[<i>b</i>,<i>d</i>]‑azepin-6-one: An Important Scaffold for γ‑Secretase Inhibitors

An enantioselective synthesis of (<i>S</i>)-7-amino-5<i>H</i>,7<i>H</i>-dibenzo­[<i>b</i>,<i>d</i>]­azepin-6-one (<i>S</i>-<b>1</b>) is described. The key step in the sequence involved crystallization-induced dynamic resolution (CIDR) of compound <b>7</b> using Boc-d-phenylalanine as a chiral resolving agent and 3,5-dichlorosalicylaldehyde as a racemization catalyst to afford <i>S</i>-<b>1</b> in 81% overall yield with 98.5% enantiomeric excess

Regioselective Synthesis of Substituted 4‑Alkylamino and 4‑Arylaminophthalazin-1(2<i>H</i>)‑ones

An efficient regioselective synthesis of substituted 4-alkylamino and 4-arylaminophthalazin-1­(1<i>H</i>)-ones <b>5</b> is described. This new method features the formation of substituted phthalazin-1­(1<i>H</i>)-ones <b>3</b> by the reaction of 2-formylbenzoic acids <b>1</b> or 3-hydroxyisobenzofuran-1­(3<i>H</i>)-ones <b>2</b> with hydrazine to generate phthalazin-1­(2<i>H</i>)-ones <b>3</b>. Subsequent regioselective bromination of phthalazin-1­(2<i>H</i>)-ones <b>3</b> with benzyltrimethylammonium tribromide (BTMA-Br₃) followed by mixed copper–copper oxide-catalyzed amination of 4-bromophthalazin-1­(2<i>H</i>)-ones <b>4</b> with primary amines generates aminophthalazin-1­(2<i>H</i>)-ones in good overall yields

AUC values (s.e.) corresponding to ROC analyses comparing the morning, afternoon, and evening portions of the second evaluation with the full day in the same evaluation.

<p>AUC values (s.e.) corresponding to ROC analyses comparing the morning, afternoon, and evening portions of the second evaluation with the full day in the same evaluation.</p

Mean±SD of affect measures for each set and overall in the test and the retest. <i>p</i>-values associated to paired <i>t</i>-tests and ICC values.

<p>Note: PA = Positive affect;</p><p>NA = Negative affect.</p>*<p>Considering only sets A, B, and C.</p

Demographic characteristics of participants who completed sets A, B, C, or D in baseline.

*<p><i>p</i>-value associated to differences among sets using χ² test (categorical variables) or ANOVA test (quantitative variables).</p

Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug

This paper describes the efficient scale-up synthesis of the potent negative allosteric glutamate N2B (GluN2B) inhibitor <b>1</b> (BMS-986169), which relies upon a stereospecific S_N2 alkylation strategy and a robust process for the preparation of its phosphate prodrug <b>28</b> (BMS-986163) from parent <b>1</b> using POCl₃. A deoxyfluorination reaction employing bis­(2-methoxyethyl)­aminosulfur trifluoride (Deoxo-Fluor) is also used to stereospecifically introduce a fluorine substituent. The optimized routes have been demonstrated to provide APIs suitable for toxicological studies in vivo

Challenges with the Synthesis of a Macrocyclic Thioether Peptide: From Milligram to Multigram Using Solid Phase Peptide Synthesis (SPPS)

We describe an optimization and scale-up of the 45-membered macrocyclic thioether peptide BMS-986189 utilizing solid-phase peptide synthesis (SPPS). Improvements to linear peptide isolation, macrocyclization, and peptide purification were demonstrated to increase the throughput and purification of material on scale and enabled the synthesis and purification of >60 g of target peptide. Taken together, not only these improvements resulted in a 28-fold yield increase from the original SPPS approach, but also the generality of this newly developed SPPS purification sequence has found application in the synthesis and purification of other macrocyclic thioether peptides

Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology

Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure–activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents

Development of the Large-Scale Synthesis of Tetrahydropyran Glycine, a Precursor to the HCV NS5A Inhibitor <b>BMS-986097</b>

An efficient large-scale synthesis of acid <b>1</b>, a penultimate precursor to the HCV NS5A inhibitor <b>BMS-986097</b>, along with the final API step are described. Three routes were devised for the synthesis of <b>1</b> at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of <i>t</i>-butyl 2-((diphenylmethylene)­amino)­acetate (<b>24</b>) to (<i>E</i>)-benzyl 4-(1-hydroxycyclopropyl)­but-2-enoate (<b>28</b>) followed by cyclization and chiral separation to form <b>27c</b>, the core skeleton of cap piece <b>1</b>. The epimerization and chiral resolution of <b>27c</b> followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran <b>1</b>. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API <b>BMS-986097</b> for toxicology studies