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The muscle relaxant methocarbamol 2 and tranquilizer mephenoxalone 3, as well as intermediate cyclic carbonate 4, have been prepared in enantiopure form by starting from enantiopure guaifenesin 1 easily available by an entrainment resolution procedure. Thermal investigations reveal that 2 is probably a conglomerate forming substance, 3 forms a stable racemic compound, and 4 occupies an intermediate position. The enantiomeric excess of a binary phase eutectic point for these substances comprises 0%, 85%, and 10%, respectively.

Racemic expectorant guaifenesin, 3-(2-methoxyphenoxy)-1,2-propanediol 2 undergoes spontaneous resolution upon crystallization. This fact is confirmed by thermal analysis (single eutectic V-shape binary melting phase diagram, adequate entropy and free energy characteristics). Racemic 2 could be effectively resolved into (S)- and (R)-2 by a preferential crystallization procedure. Single enantiomer drugs levomoprolol and levotensin were obtained by starting from enantiomeric 2 through the sulfite route.

Racemic and enantiopure cis-and trans-4-(1-naphthyloxy)methyl-2-oxo-1,3,2-dioxathiolanes were studied by X-ray diffraction. The factors responsible for their crystal packings were revealed. The conformation of the exocyclic fragment varies from synclinal to antiperiplanar depending on both the local (cis-trans isomerism of the molecule) and external (homochiral/heterochiral environment) stereochemical factors. Data on the structures of five-membered sulfites in crystals were generalized. It was concluded that the heterocycle has considerable conformational flexibility.

Specific features of melting of crystalline samples of 3-(2-R-phenoxy)propane-1,2-diols with different enantiomeric compositions were studied by differential scanning calorimetry. The melting points and enthalpies of melting for the racemate and individual stereoisomers were determined. Binary phase diagrams were constructed. The entropy of mixing of individual enantiomers in the liquid phase and the free energy of formation of the racemic compound were calculated. The thermochemical data indicate that the racemates are formed upon the crystallization of phenoxy-and 2-fluorophenoxy-containing compounds, while crystallization of the chloro-, bromo-, and iodo-substituted analogs would form racemic conglomerates.

Racemic 1,2-epoxy-3-(2-methoxyphenyloxy)-propane 1 undergoes spontaneous resolution upon crystallization. This fact is confirmed by coincidence of the IR spectra of racemic and scalemic crystalline samples of 1 , by thermal analysis (single eutectic V-shape binary melting phase diagram), and X-ray analysis (space group P 2 1 2 1 2 1 , Z = 4). Racemic 1 could be resolved into ( S )-(+)- and ( R )-(−)- 1 by a preferential crystallization procedure.

Electrochemical reduction of phthalazines and 1,2,5-thiadiazoles containing nucleofugaceous groups at the carbon α-atoms are studied in aprotic and proton-donating media. Heteroatoms, substituents, and media are found to affect potentials and reaction path for the electroreduction. The factors determining the reductive opening of heterocycles are revealed. In diazines the heterocycle opening in annelated systems is induced by the electron transfer, provided there exist (a) a heteroatom–heteroatom bond and (b) an easily splitting-off group at the carbon α-atom, whose nucleofugacity is comparable with or exceeds that of the chloride ion. Stability of the 1,2,5-thiadiazole cycle toward its reduction is determined by the substituent and the medium nature. On adding a nucleofugaceous group to the molecule, the transfer of two electrons in an aprotic medium results in the heterocycle opening with the formation of iminonitrile; when two easily splitting-off groups are present, the electron transfer makes the cycle decompose into inorganic anions.

The stereoisomers of 5-phenoxy-1,3,2-dioxathiane 2-oxide both exist as chair conformers with an axial S = O bond. The features of conformational behavior, distinguishing this diastereomeric pair from earlier studied are explained in terms of the conformational energies of substituents in the 1,3-dioxane series.

Catalytic electroreduction of several substituted gem-dihalocyclopropanes was studied in the presence of metal salen-complexes by polarography, cyclic voltammetry, and preparative electrolysis. Monohalocyclopropanes (54—59%) and the corresponding allene (5—9%) were the main reduction products. The reaction rate constants were determined. The inner-sphere electron transfer was shown to occur under these conditions.

Crystalline specimens of homochiral and racemic glycidyl p-toluenesulfonate were studied by IR spectroscopy, differential scanning calorimetry, and X-ray diffraction analysis. The melting phase diagram of glycidyl p-toluenesulfonate was constructed. The stacking effect in the crystals of the racemic sulfonate is responsible for a more dense molecular packing, with the result that a heterochiral type of crystallization becomes more favorable.

The data from IR spectroscopy, differential scanning calorimetry, and X-ray diffraction analysis are compared for crystalline specimens of homochiral and racemic propranolol and its hydrochloride. The stabilities of the racemates were quantitatively characterized and the factors responsible for the order of their stability are revealed.

The reaction of 2-phenyl-1,3,2-dioxaphospholane with HCl gives a mixture of phenylphosphinic acid, bis(2-chloroethyl) phenylphosphonate, and phenylphosphine; therewith, intermediate oligomeric phosphonites, hydrophosphoryl compounds, and phosphoranes were detected. Thermal treatment of the reaction mixture results in formation of ethylene phenylphosphonate and (2-chloroethyl)phenylphosphinate.

The electron-acceptor nitrogen and sulfur atoms in 3,4-disubstituted 1,2,5-thiadiazoles are responsible for much decreased reduction potentials and much increased oxidation potentials of these compounds compared with the corresponding carbocyclic derivatives. The thiadiazole ring is resistant to oxidation, and the reversible electron transfer gives rise to fairly stable radical cations. Reductive stability of the heterocycle depends on the nature of its substituents and on the medium: When nucleofuge substituents are present, two-electron transfer in aprotic media results in heteroring opening with iminonitrile formation, whereas in the presence of two readily leaving groups, the electron transfer induces cleavage of the complete heteroring into inorganic anions.

The regioisomeric composition of the adducts of unsymmetrical oxiranes with achiral and chiral phosphorochloridites was studied. Factors allowing enantiomeric assessment of chiral oxiranes with the aid of chiral derivatizing organophosphorus reagents were revealed.

The character of the first stage of reduction of 5-X-5-nitro-1,3-dioxanes 1—10 and 2-X-2-nitro-1,3-propanediols 11 and 12 is independent of the nature of halogen (X = Br, Cl) and substituents in position 2 of the dioxane cycle. The transfer of two electrons to a molecule of compound 1—12 is accompanied by the anionoid elimination of halogen and formation of the anion of nitronic acid. The high mobility of halogen is mainly due to the acceptor nitro group capable of further transformations in the α-position to halogen. The direction of further reduction involving the electron transfer to electrochemically active groups in the aromatic fragment of the molecule is determined by the nature of these groups. Chloro-, bromo-, and iodophenyl-substituted derivatives 4, 5, and 8—10 are reduced as typical halobenzenes. In the case of nitrophenyl-substituted compounds 3 and 7, the dioxane cycle opens to form dianions of p- and m-nitrobenzaldehydes along with the reduction of the nitroso group through the stages of formation of the radical anion and radical anion of the nitroso group. The radical anions of the nitro and nitroso derivatives were identified by ESR.

By treating glycidol with phenols a number of 3-aryloxypropanedioles were obtained. The latter with thionyl chloride afforded 4-aryloxymethyl-1,3,2-dioxathiolane 2-oxides. These compounds were also obtained from 4-chloromethyl-1,3,2-dioxathiolane 2-oxides by substitution aryloxy group for chlorine. The cyclic sulfides synthesized are universal intermediates in the synthesis of chiral aryloxypropanolamines among which are known β-adrenoblockaders, cardiovascular drugs. From (S)-glycidol were synthesized (S)-alprenolol, (S)-propanolol, and (S)-thymolol.

The solubility of 3-(2-methoxyphenoxy)-propane-1,2-diol, the well-known chiral drug guaifenesin 1, in water has been investigated by means of polythermal and isothermal approaches. It was found that the solubilities of racemic and enantiomeric diols rac- and (R)-1 depend strongly on temperature. The ternary phase diagram of the guaifenesin enantiomers in water in the temperature range between 10°C and 40°C was constructed. Clear evidence was obtained that rac-1 crystallizes as a stable conglomerate. The Meyerhoffer coefficient for the guaifenesin–water system is more than two and strongly depends on temperature. Neither crystalline hydrates nor polymorphs were detected within the range of conditions covered. Metastable zone width data with regard to primary nucleation were also collected for rac-1 and (R)-1. On the basis of the knowledge acquired, the resolution of racemic guaifenesin by preferential crystallization from solution could be realized successfully. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3176–3182, 2014

Nonracemic β-blockers, viz., (S)-propranolol and (S)-timolol, were prepared from (S)-glycidol in three steps consisting in the reaction with SOCl2 followed by the reaction of the resulting (4S)-4-chloromethyl-2-oxo-1,3,2-dioxathiolanes with the corresponding phenol and the final cleavage of (4R)-aryloxymethyl sulfites under the action of amines in DMF.

Reactions of 2,3-epoxyalcohols (glycidols) with thionyl chloride or sulfuryl chloride afford cyclic sulfites or sulfates, respectively. These reactions yield predominantly 4-chloroalkyl-1,3,2-dioxathiolane oxides. The configuration of the C(4) atom in the latter compounds exactly corresponds to that of the C(2) atom of the parent glycidol, whereas the configuration of the exocyclic atom is almost completely reversed with respect to that of the C(3) atom of the precursor.

The use of cyclic phosphorochloridites which were prepared based on PCl3 and chiral butane-2,3-diol or hydrobenzoin as possible reagents for the analysis of the enantiomeric composition of chiral alcohols by31P NMR spectroscopy is considered. The diastereomeric dispersion of chemical shifts of the resulting phosphites as well as of derived phosphates and thiophosphates is compared with that of structurally similar reagents.

The conglomerate-forming nature of 3-(2-hydroxyphenoxy)propane-1,2-diol was established by IR, DSC, and XRD methods; racemic diol could be resolved by a moderate efficiency preferential crystallization procedure.

Some aspects of phosphorylation of 2,2′-dihydroxy-1,1′-binaphthalene (BINOL) and 1,4∶3,6-dianhydro-d-mannitol (isomannide) were investigated. The possibility of using the corresponding cyclic chloro- and amidophosphites for the analysis of enantiomeric compositions of chiral primary and secondary alcohols by31P NMR was examined.

Both enantiomers of 1,2-epoxy-3-(2-cyanophenoxy)propane 1a were obtained and converted into enantiomeric bunitrolol hydrochlorides 3 to confirm the configuration of the formers; racemic 1a undergoes spontaneous resolution upon crystallization and could be resolved into individual enantiomers by a preferential crystallization with low efficiency.

Glycidol (1) reacts with PCl3 at low temperature in the absence of base forming (E)-2-chloro-4-chloromethyl-1,3,2-dioxaphospholane ((E)-2) in a highly diastereoselective manner. At room temperature (slow) or during the distillation (fast) (E)-2 turns into an equilibrium mixture of isomeric (E)- and (Z)-2. The original configuration on the phosphorus centre may be conserved by low temperature oxidation of (E)-2 to (E)-2-oxo-2-chloro-4-chloromethyl-1,3,2-dioxaphospholane ((E)-3). The phosphorylation of 1 proceeds through the formation of P-H spiro-phosphorane (5). A new, simple and efficient method of the generation of stable hydrophosphoranes is proposed.

Scalemic diethyl phosphates of glycerol and glycidol were prepared by partial enantioselective hydrolysis of racemic glycidyl diethyl phosphate in the presence of chiral Co(salen) catalyst. The enantiomeric composition of the products was analyzed by 31P NMR spectroscopy with organophosphorus reagents.

The crystal structure of racemic propranolol hydrochloride was reinvestigated and the main supramolecular solid-state motif (infinite homochiral chains) was found. Changes in the size of the central anion are accompanied by substantial differences in crystal packing leading to a homochiral crystal lattice of racemic conglomerate.

By treating glycidol with phenols a number of 3-aryloxypropanedioles were obtained. The latter with thionyl chloride afforded 4-aryloxymethyl-1,3,2-dioxathiolane 2-oxides. These compounds were also obtained from 4-chloromethyl-1,3,2-dioxathiolane 2-oxides by substitution aryloxy group for chlorine. The cyclic sulfides synthesized are universal intermediates in the synthesis of chiral aryloxypropanolamines among which are known β-adrenoblockaders, cardiovascular drugs. From (S)-glycidol were synthesized (S)-alprenolol, (S)-propanolol, and (S)-thymolol.

The reaction between acetone monoalkylhydrazones and aldehydes in the presence of boric acid derivatives has given five-membered boron-nitrogen heterocycles, the stability of which is to a large extent dependent on the substituents in the ring. An x-ray structural examination of the boroxadiazolidine (VI) has been carried out.

Although racemic allylbenzylmethylphenylammonium iodide 1b displays spontaneous resolution crystallizing in a homochiral mode as a conglomerate, its phosphonium analogue rac-2b crystallizes in a heterochiral lattice forming racemic compound in the solid state. The more pronounced conformation freedom for 2b molecules manifests itself by multiple molecules crystallization (Z' = 3) of (S)-2b with the three independent molecules having different conformation.

Seven chiral arylglycerol ethers 2-R-C6H4-O-CH2CH(OH)CH2OH (R = H, Me, Et, Allyl, n-Pr, i-Pr, tert-Bu) were synthesized in racemic and scalemic form. The IR spectra, melting points, and enthalpies of fusion for racemic and scalemic samples of every species were measured, the entropies of enantiomers mixing in the liquid state and Gibbs free energies of a racemic compound formation were derived and binary phase diagrams were reconstructed for the whole family. Solid racemic compounds stabilities were ranked for the four substances. Spontaneous resolution was established for the registered chiral drug mephenesin and its ethyl analogue. Metastable anomalous conglomerate, forming crystals having three independent R* and one independent S* molecules in the unit cell, is formed during solution crystallization of tert-butyl derivative; metastable phase transforms slowly into traditional racemic conglomerate. Chirality, 2008. © 2008 Wiley-Liss, Inc.

The use of enantiomerically pure cyclic chlorophosphite obtained by the reaction of PCl3 withN,N,N′,N′-tetramethyldiamide of naturall-(+)-tartaric acid for analysis of the enantiomeric composition of chiral primary and secondary alcohols by31P NMR spectroscopy is considered.

The chiral drug methocarbamol, which is prone to spontaneous resolution, is an effective molecular hydrogelator as both an enantiomer and a racemate; the samples of methocarbamol having an intermediate enantiomeric composition generate clearly visible periodic structures (Liesegang rings) during the gelation process.

For a family of chiral terminal ortho-alkylphenyl glycerol ethers [alkyl = Me (1), Et (2), n-Pr (3), i-Pr (4), t-Bu (5)] nine different crystalline modifications have been obtained and investigated by X-ray analysis. All possible types for chiral compound crystallization, including a very rare type of false conglomerate (polymorph of rac-4.1) and extremely rare case of anomalous conglomerate (metastable form of rac-5) have been found within this set. Three tested substances crystallize as normal conglomerates, while two are capable of forming normal racemic compounds. Centrosymmetrical dimers of enantiomers, which are typical for most racemates, are absent in all the investigated crystals. The samples of the enantiopure compound 2 and 3 form stable supramolecular gels in hydrocarbon solvents. Some assumptions have been made linking the features of the molecular and crystal structures in the investigated series.

Within the family of biologically active 3-aryloxy-1,2-propanediols, three new conglomerate-forming compounds have been found and resolved into enantiomers using the entrainment procedure.

p-Tolyl glycerol ether not belonging to any of the known gelator families forms stable transparent gels in hydrocarbon media showing very good quantitative characteristics of gelling abilities, which are, in turn, strongly dependent on the chiral characteristics of the gelator. The crystal packing differences between the rac- and scal-substances could be the reason for such behaviour.

By reaction of arylhydrazones of benzoyl chloride with 4-aminomethylthiazole in the presence of triethylamine, the corresponding amidrazones were obtained, which upon oxidation gave 5-(thiazol-4-yl)-1,2,4-triazoles with fungicidal and bactericidal activity.

The 31P NMR method is intensively used for enantiomeric composition control during the last years [1]. Among all other derivatizing agents the C2-symmetrical ones have some advantages.

Dipole moments for the acetylenic organophosphorus compounds have already been obtained through an additive scheme based on m(P § O) = 1.2D [3]. The mean value m(P + C) resulting from that earlier work was ~0.4D. Later, the additive bond-polarity scheme (including polarities of C atom in various hybridizations) was analyzed in light of experimentally determined DM values for molecules whose polarity was~independent of free rotation, and an effective diethylphosphonium group conformation established. This same additive scheme was used in the DM analysis of the present work. Interest also attaches to a study of the conformations of acetylenic organophosphorus compounds with internal rotation. Although rotation affects the DM of compounds with an irregular ethoxy group substituted at the P atom, hydrocarbon radical rotation has no effect on either the magnitude or direction of the DM, at least in the additive scheme approximation. In the latter case, the spatial orientation can be established from the molar Kerr constant [4]. This can be measured, or calculated for the various conformations, in the case of compounds (I) and (II). Valence angles and bond moments required in the present calculations were taken from