Benzoate Salt Research Articles

Alogliptin and its benzoate salt

The crystal structure of the free base of the antidiabetic drug alogliptin [systematic name: 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl}methyl)benzonitrile], C18H21N5O2, displays a two-dimensional N-H···O hydrogen-bonded network. It contains two independent molecules, which have the same conformation but differ in their hydrogen-bond connectivity. In the crystal structure of the benzoate salt (systematic name: (3R)-1-{3-[(2-cyanophenyl)methyl]-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl}piperidin-3-aminium benzoate), C18H22N5O2(+)·C7H5O2(-), the NH3(+) group of the cation is engaged in three intermolecular N-H···O hydrogen bonds to yield a hydrogen-bonded layer structure. The benzoate salt and the free base differ fundamentally in the conformations of their alogliptin moieties.

Crystal Structure and Experimental and Theoretical Studies of the Second-Order Nonlinear Optical Properties of Salts of Triphenylguanidine with Carboxylic Acids

N,N',N''-triphenylguanidinium carboxylate salts have been prepared by acid-base reactions of triphenylguanidine with formic, benzoic, and m-methoxybenzoic acids, and their single-crystal X-ray structure analysis has been performed. The salts were found to crystallize into noncentrosymmetric structures with an orthorhombic space group P2(1)2(1)2(1) for the formate and m-methoxybenzoate salts and a monoclinic space group Cc for the benzoate salt. The anions and cations are linked by intermolecular hydrogen bonds with the same motifs in the three salts. By using the molecular structures, the molecular first hyperpolarizabilities of several clusters were determined by semiempirical methods, and the components of the second-order susceptibility tensor, d, of triphenylguanidine and those of the reported crystals were evaluated using the oriented gas model with two different local-field corrections. The efficiency of the second-harmonic generation of triphenylguanidine and that of the reported triphenylguanidinium salts were measured using the Kurtz and Perry powder method.

Vibrational Spectroscopic Studies of Cocrystals and Salts. 2. The Benzylamine−Benzoic Acid System

X-ray powder diffraction, differential scanning calorimetry, infrared absorption spectroscopy, and Raman spectroscopy have been used to study the phenomenon of salt formation in the 1:1 stoichiometric product formed by benzylamine and benzoic acid. Full understanding of the effects of salt formation on the energies of the vibrational modes of motion was obtained by the complete assignment of the spectra of the starting materials and of the benzylammonium benzoate product. In addition, benzoic acid was found to form a 1:1 cocrystal with the benzylammonium benzoate salt, and this product was also characterized using the full range of techniques. Both infrared absorption and Raman spectroscopies were found to be useful vibrational spectroscopic techniques for characterization of the products, with the phenomenon of salt formation leading to the strongest perturbations in the vibrational modes associated with the carboxylic acid group of benzoic acid and the amine group of benzylamine. Little change in the energies of the vibrational modes associated with the carbon−carbon and carbon−hydrogen portions of the compounds was observed, demonstrating that the structural changes associated with the salt formation only affected the energies of the vibrational modes directly involved in the proton transfer and ion association. However, perturbations in the carbon−carbon and carbon−hydrogen vibrational modes were observed in the benzoic acid cocrystal with benzylammonium benzoate, demonstrating the importance of the phenyl rings in the cocrystal formation.

C–H···O-Brückenbindungen in Imidazolium-Carboxylaten / C–H···O Hydrogen Bonds in Imidazolium Carboxylates

2,3-Dihydro-1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene (1) reacts with benzoic acid to give the corresponding 1,3-diisopropyl-4,5-dimethylimidazolium benzoate salt 2. Similarly, 1,3-diisopropyl-4,5-dimethylimidazolium formiate (3) is obtained from 1 and ammonium formiate. In crystals of 2, the anions are linked to the imidazolium ions by monofunctional O···H-C bonds while in 3 bifurcated O・・・H-C bonds are observed. In 1,3-diisopropyl-4,5-dimethylimidazolium hydrogenoxalate (4), obtained from 1 and oxalic acid, hydrogen bonds connect both imidazolium ions to the hydrogenoxalate ions in a bifurcated mode as well as the anions to each other.

Optimization and Scale-up of a Pd-Catalyzed Aromatic C−N Bond Formation: A Key Step in the Synthesis of a Novel 5-HT1B Receptor Antagonist

Searching for the best synthetic route for a given target molecule is a complex task and, by the same token, a key deliverable from a process R&D department. In this vein the challenge for our group was to identify a sustainable manufacturing process for a chiral compound, AR-A2, to be developed for the treatment of certain neurological disorders. Besides designing a method for assembling the core (R)-2-aminotetralin nucleus, a key feature in the overall synthesis was to provide a robust procedure for creating a new C−N bond between an aromatic ring and a heterocyclic moiety. The methodology employed a Buchwald−Hartwig coupling, and a highly efficient catalytic process was developed using Pd(OAc)2 as precatalyst, with loadings as low as 0.47 mol % (in laboratory trials one order of magnitude lower) together with (R)-BINAP as ligand. Optimizing the reaction conditions allowed a virtually quantitative conversion of the brominated aromatic substrate after heating to 110−115 °C in toluene for 4 h. Telescoping this step with a succeeding catalytic hydrogenation to effect an N-debenzylation, followed by precipitation of the benzoate salt offered an overall yield for the two consecutive steps of 88% at 125-kg batch size, combined with excellent stereochemical product purity of 98% ee.

Pyrolysis of Aromatic Carboxylic Acid Salts: Does Decarboxylation Play a Role in Cross-Linking Reactions?

The pyrolysis of sodium benzoate, potassium benzoate, and calcium benzoate has been investigated between 435 and 500 °C as models for carboxylic acid salts in low-rank coals to determine if the decarboxylation of benzoate salts can contribute to cross-linking reactions during the thermal processing of low-rank coals. Decarboxylation was the dominant reaction pathway for all three salts. However, char formation (leading to poor mass balance) was also observed in all cases. The reaction proceeds via an anionic pathway, where the initial decarboxylation of benzoate salt leads to the formation of a phenyl anion as the key intermediate. Proton abstraction by the phenyl anion from another molecule of benzoate leads to the formation of benzene and benzoate dianion, which can react with CO2 to form a di-salt of phthalic acid (i.e., the Henkel reaction). Both benzene and phthalate account for >95% of the total products in the pyrolysis of sodium and potassium benzoates. The minor products diphenylmethane, benzophenone, triphenylmethane, and 9-phenylfluorene can form by a mechanism involving the reaction of phenyl anion with alkali benzoate to generate benzophenone, which reacts further to form the other products. Contrary to previous reports, calcium benzoate pyrolysis proceeds via an anionic mechanism to form benzene and benzophenone as the major products. No evidence of any calcium phthalate formation is observed in the pyrolysis of calcium benzoate. Furthermore, the reaction of benzophenone with the phenyl anion to form diphenylmethane, triphenylmethane, and 9-phenylfluorene seems to be slowed considerably (compared to sodium and potassium benzoates), based on the observed yield of these minor products. The rate constant for the pyrolysis of these benzoate salts, which decarboxylate slower than corresponding acids, decreases in the following order: potassium benzoate > sodium benzoate ≫ calcium benzoate. The pyrolysis rate is increased by at least a factor of 3 in the presence of water. Water traps the intermediate phenyl anion very efficiently to form benzene almost exclusively. Based on these findings, it can be concluded that the presence of water can drastically reduce cross-linking reactions and significantly improve liquefaction.

Thermally induced polymerization inm- andp-halogenomethyl-benzoates to poly(hydroxymethylbenzoic acid)

Heating alkali salts of m- and p-halogenomethylbenzoic acid above ca. 100°C leads to elimination of alkali halide and formation of the corresponding poly(hydroxymethylbenzoic acid). The salt is precipitated as small cubes (ca. 0.3 μm) in a matrix of the polyester and can be washed out with water to leave a porous material (pore size <1 μm). The degree of polymerisation of the polymers is between 30 and 100, depending on the benzoate salt and the reaction conditions. The reaction appears to occur at least partially in the solid state.

Study of the exchange reaction of benzoic and 2-chlorobenzoic anhydrides in chloroform. Effects of pyridine 1-oxide and benzoate salts

Benzoic anhydride ((PhCO) 2O) and 2-chlorobenzoic anhydride ((2-ClC 6H 4CO) 2O) undergo slow exchange reaction in CHCl 3 to produce mixed benzoic 2-chlorobenzoic anhydride (2-ClC 6H 4COOCOPh). The rate of conversion changes abnormally with the concentration ratio of [(PhCO) 2O]/[(2-ClC 6H 4CO) 2O]. The reaction is catalyzed by pyridine 1-oxide (PNO). When (2-ClC 6H 4CO) 2O is the limiting reactant, the presence of benzoate salt promotes the reaction substantially with the order of effectiveness being PhCOOLi, PhCOONBu 4>PhCOONa>PhCOOH. This exchange reaction does not follow simple second-order or pseudo-first-order kinetics. However, under pseudo-order reaction condition and in the presence of PNO or benzoate salt, the reaction follows pseudo-first-order kinetics. The mechanism of the reaction is more complicated than expected. Mechanistic rationalization of experimental results is presented.

Determination of 4"-deoxy-4"-(epimethylamino)avermectin B1 benzoate (MK 0244) and its delta 8,9-isomer in celery and lettuce by HPLC with fluorescence detection

An analytical method has been developed for the extraction, derivatization, and fluorescence HPLC determination of MK-0244 [4-deoxy-4-(epimethylamino)avermectin B1 benzoate salt] and its delta 8,9-isomer from lettuce and celery at trace (parts per billion) levels. MK-0244 and its delta 8,9-isomer are extracted with methanol, and the extract is cleaned up on a reverse-phase C8 cartridge followed by a liquid-liquid extraction with ethyl acetate before passing through a propyl sulfonyl cation-exchange cartridge. MK-0244 and its delta 8,9-isomer are then derivatized with trifluoroacetic anhydride/1-methylimidazole/acetonitrile reagent system to form a fluorescent derivative which is separated on a reverse-phase HPLC system and detected with a fluorescence detector. The average recoveries were 95 +/- 10% for celery and 96 +/- 8% for lettuce. For both lettuce and celery matrix, concentrations as low as 2 ppb (S/N = 10) can be detected in a 10-g sample. This method was used to determine the MK-0244 levels in samples from a lettuce field trial.

Steric and Inductive Effects on Ionic Association in Aqueous Solutions Using an ion Selective Electrode Technique. II. Magnesium Salts

AbstractThe stoichiometric association constants, K, the thermodynamic association constants, KA, and the thermodynamic parameters ΔS°, ΔH°, ΔG° for the association between Mg(II) ion with o‐, m and p‐toluates,o‐,m, and p‐chlorobenzoates, and o‐, m‐ and p‐bromobenzoates have been determined at 15°C, 25°C, 35°C and 45°C in aqueous media. Ion selective electrodes were used to measure the Mg2 + activities.The trends in the association behavior of Mg(II) salts of aromatic acids connot be explained on the basis of steric effects but can be explained according to the trend of the pKa of the parent organic acids, and the Hammett function, σ, of the salts themselves relative to the corresponding benzoate salt.

Inosine Pranobex

Inosine pranobex is a synthetic compound formed from the p-acetamido benzoate salt of N-N dimethylamino-2-propanol and inosine in a 3:1 molar ratio. It has been reported to exert antiviral and antitumour activities in vivo which are secondary to an immunomodulating effect, and early results suggest beneficial clinical effects in several diseases and infections including mucocutaneous Herpes simplex infections, subacute sclerosing panencephalitis, genital warts, influenza, zoster, and type B viral hepatitis, as well as in homosexual men with persistent generalised lymphadenopathy. However, many of the studies have been preliminary in nature and deficient in design or in the reporting of their results. One must therefore conclude that while inosine pranobex may prove to be a valuable and innovative therapy for a number of diseases and infections for which no satisfactory therapy exist, further long term well controlled studies in larger numbers of patients are required before definitive conclusions about the efficacy of inosine pranobex in these disorders will be possible.

Thermodynamics of ionic-association in aqueous solutions of Ca and Mg organic salts using ion-selective electrode technique—II. benzoate, o-toloate, o-chlorobenzoate and salycylate

The stoichiometric association constants, K, the thermodynamic association constant, K A, and the other thermodynamic parameters such as Δ S°, Δ H° and ΔG° for the association between each of the Ca and Mg ions with benzoate, o-toloate, o-chlorobenzoate and salycylate have been determined at 25°C, 35°C and 45°C in aqueous media. Ion-selective electrode technique has been used in the measurements of Ca and Mg ion activities The trend of association behavior of both Ca and Mg aromatic salts could not be explained on the basis of p K a of the mother organic acids but could be explained based on the trend of Hammet function σ of these salts themselves relative to the corresponding benzoate salt.

Sodium and potassium benzoate and benzoic acid as eluents for ion chromatography

Benzoic acid is introduced as an eluent and is compared with benzoate salt eluents. Detector response to sample ions in single-column ion chromatogrphy is compared with dual-column (suppressed) ion chromatography. Benzoic acid has a higher background conductance; however, samples separated with benzoate salt eluents. Comparable sample peak areas are found with suppressor column treated benzoate eluents and benzoic acid eluents. Equations are described which predict detector response for a variety of conditions.

ESR investigation of the nitrobenzene anion radical in single crystals of benzoate salts

ESR spectra have been obtained and interpreted for the nitrobenzene anion radical in single crystals of two benzoate salts. In trimethylphenylammonium benzoate, [(CH3)3C6H5N]+[C6H5CO2]−, there is a single magnetically unique site per unit cell, so reasonably simple spectra result. Principal values for the g tensor and the hyperfine tensors of N and the ortho and para protons are reported. Splitting by the meta protons was not resolved. The single crystal ESR data for the nitrobenzene anion radical doped into benzoate sites in this hosts, together with the unit cell dimensions and symmtery obtained from single crystal x-ray measurements on the host enabled a partial crystal structure determination. The crystals are monoclinic with four formula units per unit cell and are of C2/c symmetry with the four benzoate anions lying in special positions on a twofold axis such that the molecular twofold axis of each benzoate anion points along the b axis. Each of the four trimethylphenylammonium cations is likewise constrained under C2/c symmetry to possess either twofold or centrosymmetric symmetry, which necessitates an orientational disorder (not uncommon for tetraalkylammonium cations). In lithium benzoate–dimethylsulfloxide there are four magnetically inequivalent sites in the unit cell. The crystal structure of this host was determined in order to evaluate the principal values for the g tensor and the hyperfine tensors by spectral simulation. Eight formula units crystalize in a monoclinic unit cell P21/c. Two crystallographically distinct complexes were found. In one, the benzoate anion is essentially planar, whereas in the other complex, the CO2 group of the benzoate anion is twisted 8.2° with respect to the benzene ring. Although the chemical environment of the two crystallographically independent benzoate anions is similar, packing and Coulombic forces on the oxygen atom of one of the CO2 groups apparently twist this group out of the plane of the benzene ring. A most interesting feature of this structure is that, instead of the expected three-dimensional array of ions, there exist polymer chains of composition [Li+(C6H5CO2)−⋅ (CH3)2SO]∞ which are propagated by inversion symmetry in the direction of the b axis. The spacing between polymer chains is that characteristic of van der Waals forces, hence the packing of this benzoate salt behaves essentially as an ionic crystal in one dimension, but as a molecular crystal in the other two dimensions. Principal values and axes of the g tensor and the hyperfine tensors are also reported for the nitrobenzene anion radical in this host. In both hosts the para proton hyperfine tensor was found to be that expected for an isolated R2C–H fragment, whereas the ortho proton hyperfine tensor is twisted about 20° with respect to the C–H bond. The data are consistent with a preferred planar geometry for the nitrobenzene anion. A new method for incorporating electrochemically generated ion radicals, which are difficult to isolate, into single crystals of diamagnetic host suitable for ESR studies is also reported.