Diastereomeric Salt Formation Research Articles

Modulating Helix-preference of an Axially-twisted Molecular Scaffold Through Diastereomeric Salt Formation with Tartaric Acid Stereoisomers.

Herein, we designed a chiral, axially-twisted molecular scaffold (ATMS) using pyridine-2,6-dicarboxamide (PDC) unit as pivot, chiral trans-cyclohexanediamine (CHDA) residues as linkers, and pyrene residues as fluorescent reporters. R,R-ATMS exclusively adopted M-helicity and produced differential response in UV-vis, fluorescence, and NMR upon addition of tartaric acid (TA) stereoisomers allowing naked-eye detection and enantiomeric excess determination. Circular dichroism (CD) profile of R,R-ATMS underwent unique changes during titration with TA stereoisomers - while loss of CD signal at 345 nm was observed with equimolar D-TA and meso-TA, inversion was seen with equimolar L-TA. Temperature increase weakened these interactions to partially recover the original CD signature of R,R-ATMS. 2D NMR studies also indicated the significant structural changes in R,R-ATMS in the solution state upon addition of L-TA. Single crystal X-ray diffraction (SCXRD) studies on the crystals of the R,R-ATMS⊃D-TA salt revealed the interacting partners stacked in arrays and ATMS molecules stabilized by π-π stacking between its PDC and pyrene residues. Contrastingly, tightly-packed supramolecular cages comprised of four molecules each of R,R-ATMS and L-TA were seen in R,R-ATMS⊃L-TA salt, and the ATMS molecules contorted to achieve CH-π interactions between its pyrene residues. These results may have implications in modulating the helicity of topologically-similar larger biomolecules.

Enantioselective Synthesis of β-l-5-[(E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) Uracil)] (l-BHDU) via Chiral Pure l-Dioxolane.

β-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (l-BHDU, 17) is a potent and selective inhibitor of the varicella-zoster virus (VZV). l-BHDU (17) has demonstrated excellent anti-VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-l-BHDU-MP, 24) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-l-BHDU-MP (24), in vivo, effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-l-BHDU-MP (24) is needed. In this article, an efficient approach for the synthesis of l-BHDU (17) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure l- & d-dioxolane 11 and 13 were developed via diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of l-dioxolane 10 provides enantiomerically pure l-dioxane 11 (ee ≥ 99%). Optically pure 11 was utilized to construct the final nucleoside l-BHDU (17) and its monophosphate ester prodrug (POM-l-BHDU-MP, 24). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure l- & d-dioxolane, which offers avenues for the development and structure-activity relationship studies of l- & d-dioxolane-derived nucleosides.

New methods for resolution of hydroxychloroquine by forming diastereomeric salt and adding chiral mobile phase agent on RP-HPLC.

Hydroxychloroquine (HCQ), 2-([4-([7-Chloro-4-quinolyl]amino)pentyl]ethylamino)ethanol, exhibited significant biological activity, while its side effects cannot be overlooked. The RP-HPLC enantio-separation was investigated for cost-effective and convenient optical purity analysis of HCQ. The thermodynamic resolution of Rac-HCQ, driven by enthalpy and entropy, was achieved on the C18 column using Carboxymethyl-β-cyclodextrin (CM-β-CD) as the chiral mobile phase agent (CMPA). The effects of CCM-β-CD, pH, and triethylamine (TEA) V% on the enantio-separation process were explored. Under the optimum conditions at 24°C, the retention times for the two enantiomers were and , resulting in . The resolution via diastereomeric salt formation of Rac-HCQ was developed to obtain the active pharmaceutical ingredient of single enantiomer S-HCQ. Di-p-Anisoyl-L-Tartaric Acid (L-DATA) was proved effective as the resolution agent for Rac-HCQ. Surprisingly, it was found that refluxing time was a key fact affecting the resolution efficiency, which meant the kinetic dominate during the process of the resolution. Four factors-solvent volume, refluxing time, filtration temperature, and molar ratio-were optimized using the single-factor method and the response surface method. Two cubic models were established, and the reliability was subsequently verified. Under the optimal conditions, the less soluble salt of 2L-DATA:S-HCQ was obtained with a yield of 96.9% and optical purity of 63.0%. The optical purity of this less soluble salt increases to 99.0% with a yield of 74.2% after three rounds recrystallization.

Enantiomer separation of 2-halomandelic acids via diastereomeric salt formation with chiral N-substituted 2-amino-2-phenylethanols.

Chiral N-substituted secondary 1,2-aminoalcohols have been developed for the enantioseparation of ortho-halomandelic acids (o-X-MAs) via diastereomeric salt formation. Two structural isomers, N-methyl-2-amino-1,2-diphenylethanol and N-benzyl-2-amino-2-phenylethanol, showed high separation abilities for o-X-MAs (X = Cl, Br, I). The chiral recognition mechanism was elucidated by crystallographic analysis of the less-soluble salts. The substituents on the nitrogen atom of the resolving agents and the inclusion of the crystallization solvent stabilized the salt and enhanced their separation ability.

Axially Chiral Sulfonic Acids for Brønsted Acid Catalysis: 8-Benzoimidazolylnaphthalene-1-sulfonic Acids and Their Derivatives.

A new type of axially chiral sulfonic acid was developed. The synthesis is based on cheap commercially available materials and a practical method for optical resolution via diastereomeric salt formation, which can provide both enantiomers. Eleven benzoimidazolylnaphthalenesulfonic acids were prepared and four of them were isolated as pure and stable atropisomers. Moreover, several of these sulfonic acids were transformed into triflyl imides to further expand the range of dissociation constants.

Green and Strategic Approach for Chiral Resolution by Diastereomeric Salt Formation: The Study of Racemic Ibuprofen

As diastereomeric salt formation is the most popular method for the industrial preparation of single enantiomers, this method is chosen to resolve enantiomers of ibuprofen (IBU) in the present study. This type of chiral resolution process involves three steps: formation of a diastereomeric salt pair of racemic ibuprofen (Rac-IBU) with a chiral resolving agent, (S)-(−)-α-methylbenzylamine (S-MBA) in the presence/absence of a nonchiral agent, potassium hydroxide (KOH), resolution by cooling crystallization in a common solvent, and recovery of the compound with one enriched enantiomer. The present study is to investigate each of the three steps individually toward the chiral resolution of S-IBU, including the effects of (1) equivalent ratio of Rac-IBU-to-S-MBA-to-KOH on diastereomeric excess (%de) and yield upon the formation of the diastereomeric salts, (2) solvent and (3) temperature range for cooling crystallization on %de and yield upon the resolution by cooling crystallization, (4) solvent-to-antisolvent ratio, (5) aging time, and (6) addition rate of antisolvent on enantiomeric excess (%ee) and yield upon the recovery of the S-enriched IBU. Each step is optimized, and the integrated chiral resolution process is scaled up to a 0.5 L scale. Furthermore, practical guidelines are suggested for the future development of chiral resolution processes by diastereomeric salt formation.

Enantioseparation of 3-Hydroxycarboxylic Acids via Diastereomeric Salt Formation by 2-Amino-1,2-diphenylethanol (ADPE) and Cinchonidine

Enantioseparation of 3-hydroxycarboxylic acids via diastereomeric salt formation was demonstrated using 2-amino-1,2-diphenylethanol (ADPE) and cinchonidine as the resolving agents. Racemic 3-hydroxy-4-phenylbutanoic acid (rac-1), 3-hydroxy-4-(4-chlorophenyl)butanoic acid (rac-2), and 3-hydroxy-5-phenylpentanoic acid (rac-3) were efficiently resolved using these resolving agents. Moreover, the successive crystallization of the less-soluble diastereomeric salt of 1 and cinchonidine using EtOH yielded pure (R)-1 · cinchonidine salt in a high yield. The crystal structures of less-soluble diastereomeric salts were elucidated and it was revealed that hydrogen bonding and CH/π interactions play an important role in reinforcing the structure of the less-soluble diastereomeric salts.

Synthesis and Resolution of a Chiral Open-Chain Host Having a Partial Structure of p-tert-Butylsulfinylcalix[4]arene

Abstract An open-chain carboxylic acid host with a chiral sulfinyl group (4) was synthesized from 3,3′-thiobis[(5-tert-butyl-2-hydroxyphenyl)acetic acid] (2) by oxidation of the epithio linkage with mCPBA, followed by acid-catalyzed monoesterification with propan-1-ol. The monoester was resolved via diastereomeric salt formation using quinidine as a resolving agent. The absolute configuration of (+)-4 was assigned to be (R) by X-ray analysis.

“Solvent-induced chirality switching” in the enantioseparation of chlorine-substituted tropic acids via diastereomeric salt formation by (1R,2S)-(−)-2-amino-1,2-diphenylethanol (ADPE)

The optical resolution of chlorine-substituted tropic acids (TAs) by diastereomeric salt formation with (1R,2S)-(−)-2-amino-1,2-diphenylethanol ((−)-ADPE) has been demonstrated. Efficient solvent-induced chirality switching was observed in the case of racemic 2-chlorotropic acid (rac-2-Cl-TA). The recrystallization of the diastereomeric salts of rac-2-Cl-TA from branched alcohols such as i-PrOH and s-BuOH afforded (R)-2-Cl-TA, whereas (S)-2-Cl-TA was obtained from linear alcohols such as MeOH, EtOH, and n-PrOH. The chirality switching mechanism was elucidated from the crystal structures of the diastereomeric salts, which revealed that the incorporation of solvent in the (S)-2-Cl-TA salt crystals played a key role in chirality switching by reinforcing the supramolecular structure of the salt. However, no chirality switching was achieved for racemic 3-chlorotropic acid and 4-chlorotropic acid. The position of the chlorine substituent plays an important role in the solvent-induced chirality switching effect.

Attrition-Enhanced Asymmetric Transformation of Axially Chiral Nicotinamides by Dynamic Chiral Salt Formation.

Atroposelective resolution for axially chiral nicotinamides was achieved by dynamic chiral salt formation with L-DBTA using six types of nicotinamides that could not be optically resolved by the preferential crystallization method. Kinetic studies of their racemization indicated that the chiral conformation was retained for a significant period of time. Two methods of crystallization-induced asymmetric transformation were examined by dynamic diastereomeric salt formation: solvent evaporation from a supersaturated solution, and attrition-enhanced asymmetric transformation. The attrition method was more effective for asymmetric amplification of diastereomeric salts of axially chiral materials. Attrition of equimolar amount of the nicotinamide salts with L-DBTA converged to one diastereomer salts, and the corresponding enantiomers in 87-99 % ee were obtained after the chiral acid was removed. Changing the ratio of two of the nicotinamides with L-DBTA to 1 : 2 inverted the axial chirality.

Continuous chiral resolution of racemic Ibuprofen by diastereomeric salt formation in a Couette-Taylor crystallizer

S-Ibuprofen has been proved to be more efficient than racemic Ibuprofen, one the best sell drugs over the world. Thus, there is a strong interest in implementing chiral resolution of racemic Ibuprofen in the continuous mode.Chiral resolution by diastereomeric salt formation of racemic Ibuprofen has been successfully implemented in a Couette-Taylor (CT) crystallizer. Among the seven parameters identified as impacting, a screening has been performed on the four factors expected to have the strongest influence: temperature gradient in the CT crystallizer, rotation speed, residence time and target temperature within the crystallizer.Thanks to the rationalization of the study through a design of experiments approach, only 14 distinct experiments were performed to identify the influence of these factors on global productivity/yield, diastereomeric excess and diastereomeric productivity/yield, and to find a first operating point.If the obtained yields were unsurprisingly low, global productivity and diastereomeric productivity are increased by 16 and 8 times respectively, in comparison with batch mode. Also, continuous mode gives an easy access to a higher diastereomeric excess, in a repeatable manner.Surprisingly, under the selected process conditions, the steady state does not seem to be reached before 14–15 residence times, which is longer than expected from previous results.

New Formula for the Hydrogen-Bonding Hansen Component of Methanol, Ethanol, and n-Propanol for Non-ambient Conditions-Application in Gas Antisolvent Fractionation-Based Optical Resolution.

Optical resolution by diastereomeric salt formation based on gas antisolvent fractionation is influenced by the chemical equilibrium of the salt formation, the solubility, and the extraction of the compounds. Selectivity, also known as resolution efficiency, is highly solvent-dependent and is also affected by process parameters both in atmospheric and supercritical processes. For the first time in the literature, a mathematical model that employs all three Hansen parameters and operating parameters is constructed to describe the selectivity of a gas antisolvent fractionation process. The satisfying goodness of fit of the models suggests that the outcome of the three subprocesses in the gas antisolvent fractionation process (i.e., salt formation reaction, precipitation, and extraction) can be described in a single model. A new formula for pressure and temperature correction of the hydrogen-bonding component of the Hansen parameter for non-ambient conditions for liquid methanol, ethanol, and n-propanol is also suggested in this paper.

Preparation of (R)-3-aminopiperidine by resolution with optically active cyclic phosphoric acids.

(R)-3-aminopiperidine ((R)-APD), a key intermediate for alogliptin, trelagliptin, and linagliptin, was successfully resolved from racemic 3-aminopiperidine with an enantiomerically pure resolving agent, namely, (R)-4-(2-chlohydroxy-1.3.2-dioxaphosphorinane 2-oxide ((R)-CPA), via diastereomeric salt formation. By this resolution approach, (R)-3-aminopiperidine was obtained in 99.5% yield with 99.6%e.e.

The Stoichiometry, Structure and Possible Formation of Crystalline Diastereomeric Salts

Knowing the eutectic composition of the binary melting point phase diagrams of the diastereomeric salts formed during the given resolution, the achievable F (F = eeDia*Y) value can be calculated. The same value can also be calculated and predicted by knowing the eutectic compositions of the binary melting point phase diagrams of enantiomeric mixtures of the racemic compound or the resolving agent. An explanation was sought as to why and how the crystalline precipitated diastereomeric salt—formed in the solution between a racemic compound and the corresponding resolving agent—may be formed. According to our idea, the self-disproportionation of enantiomers (SDE) has a decisive role when the enantiomers form two nonequal ratios of conformers in solution. The self-organized enantiomers form supramolecular associations having M and P helicity, and double helices are formed. Between these double spirals, with the formation of new double spirals, a dynamic equilibrium is achieved and the salt crystallizes. During this process between acids and bases, chelate structures may also be formed. Acids appear to have a crucial impact on these structures. It is assumed that the behavior of each chiral molecule is determined by its own code. This code validates the combined effect of constituent atoms, bonds, spatial structure, charge distribution, flexibility and complementarity.

Separation of Amlodipine Enantiomers by Diastereomeric Salt Formation

Separation of Amlodipine Enantiomers by Diastereomeric Salt Formation

Chirality switching in the enantioseparation of 2-hydroxy-4-phenylbutyric acid: Role of solvents in selective crystallization of the diastereomeric salt

Chirality switching was induced by solvents in the enantioseparation of 2-hydroxy-4-phenylbutyric acid (HPBA) via diastereomeric salt formation with an enantiopure aminoalcohol. The (S)-salt was crystallized from butanol solutions and the (R)-salt was obtained from aqueous solutions. It was found from crystallographic analysis of the salts that solvent inclusion changed the solubility of both salts. In particular, the (R)-salt afforded multiple pseudo-polymorphic hydrated crystals. Successive crystallization from two different solvents efficiently afforded both pure diastereomeric salts.

Solvent-Induced Chirality Switching in the Enantioseparation of Halogen-Substituted Mandelic Acids: Structural Effects on Molecular Packing

The solvent effect on the enantioseparation of halogen-substituted mandelic acid derivatives via diastereomeric salt formation has been investigated. The diastereomeric salts of para-halogen-substi...

Tandem crystallization strategies for resolution of 3,3,3-trifluorolactic acid [CF3 CH(OH)COOH] by chiral benzylamines.

Resolution of rac-3,3,3-trifluorolactic acid by diastereomeric salt formation was reinvestigated. The use of (S)-1-phenylethylamine gives coprecipitation of two diastereomeric phases, 1 (S)-[NH3 CH(CH3 )Ph](S)-[CF3 CH(OH)COO] and 2 (S)-[NH3 CH(CH3 )Ph](R)-[CF3 CH(OH)COO]·H2 O. Pure phase 1 may be obtained using molecular sieves as desiccants. Resolution by (S,S)-2-amino-1-phenylpropan-1,3-diol gives monoclinic (S,S)-[NH3 CH(CH2 OH)CHOHPh] (R)-[CF3 CH(OH)-COO] 3 with minor (S)-3,3,3-trifluorolactate contamination, which is precluded in the recrystallized orthorhombic form 4. A new resolution using inexpensive phenylglycinol gives pure phase 5 (S)-[NH3 CH(CH2 OH)Ph] (S)-[CF3 CH(OH)COO] in 76% yield, 94% ee in a single step, in preference to its (S)-(R) diastereomer 6. Overall efficient resolution for both enantiomers of the trifluorolactic acid (each ca. 70% yield, 99% ee) may be achieved by various two-step "tandem" crystallizations, involving direct addition of either water or a second base to the filtrate from the initial reaction.

Chiral Resolution of Racemic 2‐Pyrone Diels‐Alder Cycloadduct by Diastereomeric Salt Formation

An efficient protocol was developed that allows resolution of racemic bicyclolactone carboxylic acid obtained from the Diels‐Alder cycloaddition of 3,5‐dibromo‐2‐pyrone by formation of diastereomeric salts with quinidine and cinchonidine.

How To Control Recognition: From Brucinium Double Salts to Racemic Resolution

Studying the mechanisms of racemic resolution of the model compound N-(3-nitrobenzoyl)aspartic acid by formation and fractional crystallization of brucinium diastereomeric salts, we found that depending on the environment (solvents) the recognition leads to effective or ineffective racemic resolution. During successful racemic resolution, bis(brucinium)-N-(3-nitrobenzoyl)-l-aspartate hydrate methanol solvate precipitates as the first fraction. In turn, double salts and solid solution are formed in the fruitless racemic resolution. Formation of the double salt results from recognition of centrosymmetric anionic dimers on the common brucinium corrugated layer. The common brucinium corrugated layer together with its solvation sphere participates in recognition of the anions, leading to formation of the solid solution. Changing the solvent system according to its dielectric constant, more dispersive or more directional interactions gain importance. The racemic resolution and formation of bis(brucinium)-N-(3-n...