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Chemistries of Chemical Warfare Agents
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Terry J. Henderson, Ilona Petrikovics, Petr Kikilo, Andrew L. Ternay Jr., Harry Salem
Cyanogen chloride slowly hydrolyzes to form hydrochloric acid and hypochlorous acid; the hydrolysis rate increases in the presence of bases (Bailey and Bishop, 1973b) such as sodium hydroxide, and it can also hydrolyze on reaction with hypochlorite at pH 7–8 (Price et al., 1947). The complete hydrolysis (aqueous sodium hydroxide with heat) of cyanogen chloride produces ammonia, and the detection of ammonia from this hydrolysis was the basis for an early, nonspecific test for cyanogen chloride. The ammonolysis of cyanogen chloride using ethanolic ammonia produces cyanamide, NH2CN (Cloez and Cannizzaro, 1851):
Lipids of Histoplasma Capsulatum
Published in Rajendra Prasad, Mahmoud A. Ghannoum, Lipids of Pathogenic Fungi, 2017
Treatment of SPH with 10 N ammonium hydroxide overnight at 150°C cleaves phosphomonoester and -diester bonds but does not affect glycosidic linkages,25 a procedure referred to as ammonolysis. Ammonolysis of compounds V, VIA and VIII produced single, unique oligosaccharides detected with the orcinol-H2S04 reagent that could be separated on silica gel thin-layer plates with double development with acetonitrile.water (2:1, v/v). The ammonolysates of compounds V and VIII were acetylated with acetic anhydride.pyridine (1:1, v/v) for 2 h at 100°C. No free inositol hexa-acetate was found to be associated with the ammonolysates of compounds V and VIII when the acetylated preparations were analyzed by thin-layer and gas-liquid chromatography. This demonstrated that the inositol and all of the hexoses of each compound were linked. Analysis of the alditol acetates of the ammonolysates or oligosaccharide moieties confirmed the results obtained with SPH. Compound V consisted of two mannose molecules and one inositol molecule (Table 3). No differences in carbohydrates were found in the ammonolysates of compounds VIA and VIII. Both contained two mols of mannose, 1 mol of galactose and 1 mol of inositol (Table 3).
Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Also, (S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylicacid,1-(1,1-dimethylethyl)-ester 63 is required in the synthetic scheme for obtaining saxagliptin. Direct chemical ammonolysis was hindered by the requirement for aggressive reaction conditions, which resulted in unacceptable levels of amide racemization and side-product formation, whereas milder two-step hydrolysis condensation protocols using coupling agents suchas 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), were compromised by reduced overall yields (Kunishima et al., 2001). To address this issue, a biocatalytic procedure has been developed, based upon the CAL-B-mediated ammonolysis of (S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester 62 with ammonium carbamate to furnish 63 without racemization and with low levels of side-product formation (Gill and Patel, 2006). Experiments utilized process stream ester feed, which consisted of ∼22% w/v (0.91 M) of the ester in toluene. Since the latter precluded the use of free ammonia due to its low solubility in toluene, solid ammonium carbamate was employed. Reactions were performed using a mixture of neat process feed, ammonium carbamate (71 g/L, 2 mol equiv. of ammonia), and biocatalyst (25 g/L) and shaken at 400 rpm, 50°C. Under these conditions, CAL-B provided racemization-free amide with yields of 69%, together with 21% of side-products (by HPLC). The inclusion of drying agents such as calcium chloride gave significant improvement (79% amide and 13% side-products), as well as the use of sodalime and ascarite, respectively, at 200 g/L in the reaction headspace (increase in amide yield to 84% and 95%), this presumably by way of adsorption of carbon dioxide liberated from the decomposition of ammonium carbamate. A further increase in yield to 98% was attained via the combined use of 100 g/L of calcium chloride and 200 g/L of ascarite. A prep-scale reaction with the process ester feed was used. So, in the optimized process, 62 (220 g/L) was reacted with 90 g/L (1.25 mol equiv) of ammonium carbamate, 33 g/L (15% w/w of ester input) of CAL-B, 110 g/L calcium chloride, and 216 g/L of ascarite (in the headspace) and run at 50°C for 3 days. Complete conversion of ester was achieved, with the formation of 96% (182 g/L) of 63 and 4% of side-products; finally, after workup, 98% potency amide of >99.9% ee was isolated in 81% yield (Gill and Patel, 2006).
Design, synthesis and biological evaluation of N-substituted α-hydroxyimides and 1,2,3-oxathiazolidine-4-one-2,2-dioxides with anticonvulsant activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Laureano L. Sabatier, Pablo H. Palestro, Andrea V. Enrique, Valentina Pastore, María L. Sbaraglini, Pedro Martín, Luciana Gavernet
The synthetic procedure involved the preparation of the α-hydroxyamides from the ammonolysis reaction between 2-hydroxyisobutyl methyl ester and the corresponding amine followed by a cyclization reaction and the oxidation of the product5. Both sets of α-hidroxyamides and oxathiazolidine-4-one-2,2-dioxide derivatives were evaluated against MES test in mice9. Toxicity was also tested by the standardized Rotorod test, which is also included in the primary phase of anticonvulsant screening program9. To get inside into the possible mode of action of the compounds, we analysed the capacity of the structures of blocking the Nav1.2 isoform of the voltage-gated sodium channels (VGSC). The selection of the target was supported on preliminary studies about one compound of the cyclic family, the 3-butyl-5,5-dimethyl oxathiazolidine-4-one-2,2-dioxide (compound D, Figure 1), which has sodium channels (VGSC) blocking properties10. Additionally, it is well known that Nav1.2 isoform is the molecular target of many ACDs like phenytoin, lamotrigine, carbamazepine, oxcarbazepine, eslicarbazepine, zonisamide and lacosamide11,12. First, we simulated the interaction between the compounds synthesized and a 3D model of the Nav1.2 isoform by means of docking protocols. Then, the docking candidates and other structures predicted as inactive were tested on Nav1.2 currents using the patch clamp technique.
Evaluation of WO2014121383 A1: a process for preparation of rufinamide and intermediates
Published in Expert Opinion on Therapeutic Patents, 2019
Barnali Maiti, Balamurali M M, Kaushik Chanda
The second synthetic pathway involved the in-situ formation of activated propiolic esters 6a-d followed by the addition of 2,6-difluoro benzyl azide 3 and Cu catalyst and subsequent ammonolysis to obtain the rufinamide 1 in excellent yields as mentioned in scheme 2.