Less-soluble Diastereomeric Salt Research Articles

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.

Direct enantioseparation of 1-(2-hydroxyphenyl) ethylamines via diastereomeric salt formation: chiral recognition mechanism based on the crystal structure

In this study, the direct enantioseparation of unprotected 1-(2-hydroxyphenyl)ethylamines (1a and 1b) via diastereomeric salt formation is reported. After the one-pot synthesis of racemic 1, the screening of seven acidic chiral resolving agents showed that the extraction of (S)-naproxen (6) with dibenzoyl-L-tartaric acid (5) afforded the corresponding 1 : 1 diastereomeric salts that were suitable for the resolution of 1a and 1b. The optimization of the solvents resulted in high efficiencies for the resolution of 1a·6 in aqueous alcohols, which was consistent with the fact that the incorporated water molecules in the less-soluble diastereomeric salt reinforced its hydrogen-bonding network. For the efficient enantioseparation of rac-1b with 5, the intramolecular CH⋯O hydrogen bond played an important role in the chiral recognition.

Dielectrically controlled resolution (DCR) of 3-aminopiperidine via diastereomeric salt formation with N-tosyl-(S)-phenylalanine

A useful key intermediate for the dipeptidyl peptidase-4 (DPP-4) inhibitor, 3-aminopiperidine 1, was successfully resolved with an enantiomerically pure resolving agent, N-tosyl-(S)-phenylalanine 2, to give both stereoisomers (R)-1 and (S)-1 as a less-soluble diastereomeric salt with (S)-2, via a dielectrically controlled resolution (DCR) phenomenon.

Crystal structures and chiral recognition of the diastereomeric salts prepared from 2-methoxy-2-(1-naphthyl)propanoic acid

This paper is the first to report the structures of crystalline diastereomeric salts 8 and 9 prepared from (R)-2-methoxy-2-(1-naphthyl)propanoic acid [(R)-MαNP acid, (R)-1] and (S)-1 with (R)-1-phenylethylamine [(R)-PEA, (R)-7], respectively. These crystal structures helped elucidate a novel chiral recognition mechanism characteristic of MαNP salts. The less-soluble diastereomeric salt 8 prepared from (R)-1 and (R)-7 formed an ammonium–carboxylate ion pair by means of a methoxy-assisted salt bridge and an aromatic CH⋯π interaction. The more-soluble diastereomeric salt 9 prepared from (S)-1 and (R)-7 formed an ion pair by a methoxy-assisted salt bridge in which the 1-naphthyl and phenyl groups did not overlap. Instead, salt 9 formed a close ion pair by means of a salt bridge, a CH⋯O hydrogen bond, and a π⋯π interaction. These crystal structures suggest that the molecular length from the MαNP plane containing the carboxy and methoxy groups is critical to the crystallisation of diastereomeric salts. The crystal packing in both salts was investigated with regard to the weak interactions (i.e., salt bridges, NH⋯O and CH⋯O hydrogen bonds, and aromatic CH⋯π, CH⋯π, and π⋯π interactions). Finally, diastereomeric amides 11 and 12 were prepared from (S)-2-methoxy-2-(2-naphthyl)propanoic acid [(S)-MβNP acid, (S)-2] and (R)-2 with (S)-1-(1-naphthyl)ethylamine [(S)-10]. The solution-phase structures of the MβNP amides, and their separation, was investigated by NMR spectroscopy and high-performance liquid chromatography (HPLC). The less-stereochemically demanding and longer 2-naphthyl group made the MβNP amide more flexible and less polar than the MαNP amide. Acid 2 was more efficient than acid 1 in separating amides 11 and 12.

ジアステレオマー塩法による光学分割の効率化を目指して

In order to overcome trial-and-error situation in the enantioseparation by the diastereomeric salt formation, we carried out systematic studies on the enantioseparation of racemic 1-arylethylamines with/without a substituent on the aryl group by using enantiopure arylglycolic acids. The studies revealed that there are three factors for the growth and stabilization of less-soluble diastereomeric salt crystals; 1)infinite hydrogen bonding interaction to form a 21-column, which enables a crystal to grow in one dimension, 2)effective van der Waals interaction between the columns to make the crystal growable in a three-dimensional manner, and 3)sufficient CH-π interaction in/between the columns, which also play an important role for three-dimensional crystal growth. On the basis of the observations, we propose molecular length rule and aromatic ring rule, which realize efficient van der Waals interaction and CH-π interaction, respectively.Keeping in mind of these requirements for the molecular structure of a resolving agent, we industrialized an elegant process for the enantioseparation of racemic 1-phenylethylamine into the (R)-form, which is one of the most valuable chiral auxiliaries in the synthesis of drugs/drug intermediates in industrial scales, with (R)-mandelic acid upon optimizing conditions such as solvent, molar ratio, concentration, temperature, and additive, as well as the recycling process of (R)-mandelic acid and the racemizing process of (S)-1-phenylethylamine remained.

Hydrogen-bonding sheets in crystals for chirality recognition: synthesis and application of (2 S,3 S) -2,3-dihydroxy- and (2 S,3 S) -2,3-dibenzyloxy-1,4-bis(hydroxyamino)butanes

Two enantiopure bis(hydroxyamino) compounds were successfully prepared from dialkyl tartrate by a chiral-pool method and applied as basic resolving agents in the enantioseparation of 2-arylpropanoic acids and arylglycolic acids. (2 S,3 S) -2,3-Dihydroxy-1,4-bis(hydroxyamino)butane (2 S,3 S) - 1a could moderately recognize the chirality of the 2-arylpropanoic acids, while (2 S,3 S) -2,3-dibenzyloxy-1,4-bis(hydroxyamino)butane (2 S,3 S) - 1b could not due to the low crystallinity of both the corresponding diastereomeric salts. On the other hand, (2 S,3 S) - 1b showed a similar chirality-recognition ability for the arylglycolic acids. The ability of (2 S,3 S) - 1b was different from those generally observed for widely used primary amine-type resolving agents with regard to the relationship between the resolution efficiency and the similarity in the relative molecular length of a resolving agent and a target racemate. The X-ray crystallographic analyses of the less-soluble diastereomeric salts revealed that in the salts (2 S,3 S) - 1a formed a supramolecular sheet, of which the distance was variable to make the resultant dissymmetric space fit to the shape of the target acids, and that (2 S,3 S) - 1b was constructed from a robust supramolecular sheet, consisting of hydrogen-bonding 2 1 columns, with the participation of the hydroxy group of the arylglycolic acids. These X-ray crystallographic analyses also suggested that for the formation of a supramolecular sheet, the coexistence of two hydroxyamino groups is essential.

Practical resolution of 3-aminopyrrolidine via diastereomeric salt formation with ( S)-2-methoxy-2-phenylacetic acid

The resolution of 3-aminopyrrolidine 1, a versatile key intermediate for chiral pharmaceuticals, via diastereomeric salt formation was investigated. The resolution conditions were optimized focusing on an industrial-scale production to afford enantiopure ( R)- 1, while ( S)-methoxy-2-phenylacetic acid 5 was found to be a suitable resolving agent. The less-soluble diastereomeric salt, 1:2 ( R)- 1:( S)- 5, was obtained with high resolution efficiency ( E) (yield 44%, 98% de, E 86%) under the best resolution conditions; ( RS)- 1/( S)- 5/HCl molar ratio = 1.0/1.0/1.0 in water solvent in the presence of sodium chloride. The optimized resolution process was scaled up to a pilot-scale production using 50 kg of ( RS)- 1 dihydrochloride as a starting racemate, and the resolution efficiency successfully reproduced the laboratory results.

Resolution of racemic 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid with enantiopure ( S)-phenylalanine N-benzylamide via diastereomeric salt formation

The resolution of racemic 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid 1, a potent chiral synthon with high pharmacological activity, was investigated with a variety of basic chiral resolving agents via diastereomeric salt formation. The findings in the optimization of resolution conditions aiming at an industrial-scale production revealed that ( S)-phenylalanine benzylamide ( S)- 10 and 2-propanol containing ca. 4 mol % of water to ( RS)- 1 were the best conditions for obtaining enantiopure less-soluble diastereomeric salt, ( S)- 1/( S)- 10/0.5H 2O (81%, 98% de, E 79%). X-ray crystallographic analysis of the salt clearly revealed that water molecules play a key role in crystallizing the enantiopure salt crystals, while stabilizing the crystal structure via three types of hydrogen-bond network associated with water molecules in addition to usual acid–base hydrogen bond.

Resolution of 1-cyclohexylethylamine via diastereomeric salt formation with enantiopure 2-phenylacetic acids

The resolution of 1-cyclohexylethylamine 1 with enantiopure 2-phenylacetic acids via diastereomeric salt formation was investigated. ( R)-2-Methoxy-2-phenylacetic acid 3 and the ( S)-2-phenylpropionic acid 5 were found to be efficient resolving agents for obtaining the single enantiomer ( S)- 1 as the correspondingly less-soluble diastereomeric salt (resolution efficiency = 48% and 52%, respectively).

Synthesis and chiral recognition ability of O-phenyl ethylphosphonothioic acid with a conformationally flexible phenoxy group for CH/π interaction

Enantiopure O-phenyl ethylphosphonothioic acid 1 was easily obtained by the enantioseparation of racemic 1, which was prepared from commercially available phosphorothioic trichloride in four steps. Enantiopure 1 was found to show an excellent chiral recognition ability for various 1-arylethylamine derivatives during the diastereomeric salt formation. In particular, enantiopure 1 was able to recognize the chirality of o- and m-substituted 1-arylethylamine derivatives, of which the chirality is generally difficult to establish by conventional resolving agents. X-ray crystallographic analyses of the less-soluble diastereomeric salts revealed that the conformation of the phenoxy group in enantiopure 1 could change in the diastereomeric salt crystals and that the excellent chiral recognition ability of enantiopure 1 resulted from the effective CH/π interaction of the phenoxy phenyl group.

Enantiopure O-Substituted Phenylphosphonothioic Acids: Chiral Recognition Ability during Salt Crystallization and Chiral Recognition Mechanism

[structure: see text] The chiral recognition ability of enantiopure O-methyl, O-ethyl, O-propyl, and O-phenyl phenylphosphonothioic acids (1a-d) for various kinds of racemic amines during salt crystallization and the chiral recognition mechanism were thoroughly investigated. The chiral recognition abilities of enantiopure 1a-d for a wide variety of racemic amines varied in a range of 6 to >99% enantiomeric selectivity. Deposited less-soluble diastereomeric salts were classified into two categories, prism- and needle-type crystals; the prism-type crystals were composed of a globular molecular cluster, while there existed a 2(1) column in the needle-type crystals. In contrast to a general observation of a similar 2(1) column in the less-soluble diastereomeric salt crystals of chiral primary amines with chiral carboxylic acids, the globular molecular cluster is a very unique hydrogen-bonding motif that has never been constructed in diastereomeric salt crystals. Excellent chiral recognition was always achieved when the less-soluble diastereomeric salts were prism-type crystals. Significant correlations were found between the degree of the chiral recognition with 1a-d, the crystal shape of the less-soluble diastereomeric salts, and the hydrogen-bonding motif (molecular cluster/2(1) column). The chiral recognition mechanisms via the molecular cluster and the 2(1) column formations are discussed in detail on the basis of X-ray crystallographic analyses.

Synthesis of enantiopure 6-methoxy-2-naphthylglycolic acid and its application as a resolving agent

6-Methoxy-2-naphthylglycolic acid (6- MNGA) was designed as a novel acidic resolving agent, on the model of 2-naphthylglycolic acid (2- NGA). Enantiopure 6- MNGA was easily obtained from commercially available 2-bromo-6-methoxynaphthalene through four steps and was found to show a better chiral recognition ability for racemic 1-arylethylamines than the prototype 2- NGA did. The X-ray crystallographic analyses of less-soluble diastereomeric salts revealed that the introduction of a methoxy group at the 6-position of the 2- NGA skeleton made CH/π interaction(s) effective between 6- MNGA molecules and also between the 6- MNGA molecule and the target amine molecule. The methoxy group was also found to contribute to the realization of effective van der Waals interaction. These interactions played important roles for the stabilization of the less-soluble diastereomeric salts to improve the chiral recognition ability of 6- MNGA, compared to that of 2- NGA.

Design of Resolving Agents Based on Crystal Engineering

AbstractFor Abstract see ChemInform Abstract in Full Text.

Design of Resolving Agents Based on Crystal Engineering

As a result of systematic studies on the optical resolution of racemates via crystallization, we have found that in many cases, common characteristic hydrogen-bond networks were formed in the less-soluble diastereomeric salts or conglomerates. Design of resolving/derivatizing agents could be achieved on the basis of the concept of crystal engineering, by which molecules were designed to achieve stable hydrogen-bond networks with target racemates.

Synthesis, absolute configuration, and application of enantiopure trans‐1‐aminobenz[f]indan‐2‐ol

Both novel enantiopure trans-1-aminobenz[f]indan-2-ols (4) were obtained from the racemate by the diastereomeric salt formation with (+)- and (-)-dibenzoyltartaric acids (8), respectively, and the absolute configuration of the enantiomer 4 in the less-soluble diastereomeric salt of racemic 4 with (+)-8 was determined to be (1S,2S) by an X-ray crystallographic analysis. The chiral recognition ability of the enantiopure amino alcohol was examined for the enantioseparation of racemic 2-arylalkanoic acids by the diastereomeric salt formation. The role of the naphthylene group of the amino alcohol was found to be closely associated with the stabilization of the crystal by CH/pi interactions on the basis of an X-ray crystallographic study.

Practical resolution of 1-phenyl-2-(4-methylphenyl)ethylamine using a single resolving agent controlled by the dielectric constant of the solvent

A practical resolution of 1-phenyl-2-(4-methylphenyl)ethylamine 1 for obtaining ( R)- and ( S)-enantiomers by a dielectrically controlled resolution (DCR) method using a single resolving agent, ( S)-mandelic acid 2, has been studied. The configuration of the excess enantiomer 1 in the less-soluble diastereomeric salt was found to vary depending on the solvent controlled by adjusting the solvent dielectric constant ε and the water content of the alcohol solvent. It was found that the presence of water molecules and the solvent molecular structures was key to controlling the configurational change phenomenon in the chiral discrimination between molecules 1 and 2. Moreover, the reaction environment controlled by the solvent dielectric constant plays a very distinct role in utilizing water molecules for crystallizing the less-soluble diastereomeric salt during the resolution. Based on the results, a practical resolution process for ( R)- 1 and ( S)- 1 production has been developed involving a simple solvent switch method; the ( S)- 1·( S)- 2·H 2O salt (33% yield, 96% de, E 64%) was obtained by the crystallization from 74% (w/w) aqueous ethanol in the first resolution, while the ( R)- 1·( S)- 2 salt (23% yield, 98% de, E 46%) was crystallized from 100% ethanol of the condensate of the mother liquor after the first resolution.

A New Hydrogen-Bonding Motif for Chiral Recognition in the Diastereomeric Salts of Racemic 1-Phenylethylamine Derivatives with Enantiopure O-Ethyl Phenylphosphonothioic Acid

An enantiopure phosphonothioic acid showed a unique and superior chiral recognition ability, arising from its P-stereogenicity, for racemic 1-phenylethylamine derivatives through diastereomeric crystallization. Spherical molecular clusters, associated by hydrogen bonds and CH/pi interactions, aggregated with high symmetry in the less-soluble diastereomeric salts.

Chiral discrimination controlled by the solvent dielectric constant

Chiroselective molecular recognition accompanied by a change in configuration of a target substrate has been studied. ( RS)-α-Amino-ε-caprolactam 1 was used as the target substrate to be resolved while N-tosyl-( S)-phenylalanine 2 was used as the chiral selector. The dielectric constant ( ε) of the solvent was found to have a profound effect on the chiroselective molecular recognition. The specific chiral selector ( S)- 2 not only recognized both enantiomers ( R)- and ( S)- 1 individually to be deposited as the less-soluble salt from the different solvent but also controlled the configuration and diastereomeric excess of the less-soluble diastereomeric salt by simple adjustment of the solvents dielectric constant. The chiroselective recognition mechanism was examined based on the crystal structures of the salts, ( S)- 1·( S)- 2·H 2O and ( R)- 1·( S)- 2, obtained from the resolution process.

Resolution of racemic cis-1-amino-2-indanol by diastereomeric salt formation with ( S)-2-phenylpropionic acid

Resolution of racemic cis-1-amino-2-indanol 1, a key intermediate for the synthesis of indinavir, is reported. The conditions were optimized for an industrial-scale resolution of racemic cis- 1 using ( S)-2-phenylpropionic acid 6 as the resolving agent and ethanol as the solvent. The less-soluble diastereomeric salt, (1 R,2 S)- 1·( S)- 6, was obtained in 35% yield with 99% de ( E >69%) by crystallization. Resolving agent 6 was efficiently recovered from the salt and the mother liquor.

プロセスリサーチ ｍｇからｋｇへ 結晶化法光学分割におけるジアステレオマー塩結晶の晶癖変化とその利用 高化学純度１‐フェニルエアチルアミンの製造

The process of enantiomeric purity improvement in industrial scale resolution is presented. Enantiomeric purity of 1-phenylethylamine (1) obtained from an industrial resolution with enantiomerically pure mandelic acid (2) as resolving agent, was improved by changing the crystal shape of the intermediate, the less-soluble diastereomeric salt [(R) -1 · (R) -2], through coexistence with a chiral secondary amine derived from substrate 1. Mechanism of the crystal habit modification is discussed and its applications to manufacture are described.