Resolution of N-methylamphetamine enantiomers with tartaric acid derivatives by supercritical fluid extraction

The resolution of N-methylamphetamine (MA) was carried out with the resolution agents O,O′-dibenzoyl-(2R,3R)-tartaric acid monohydrate (DBTA) and O,O′-di-p-toluoyl-(2R,3R)-tartaric acid (DPTTA). After partial diastereomeric salt formation, the unreacted enantiomers were extracted by supercritical fluid extraction (SFE). The effects of resolution agent molar ratio to the racemic mixture (mr), extraction pressure (P) and temperature (T) on the resolution efficiency were studied. The best chiral separation was obtained at a quarter of an equivalent resolution agent molar ratio for both resolution agents. Extraction conditions [pressure (100–200 bar), temperature (33–63 °C)] did not influence the resolution efficiency, which makes the enantiomer separation robust. In one extraction step, both enantiomers can be produced with high enantiomeric excess (ee) and remarkable yield (Y). Using DBTA as a resolution agent ee_E=83%, Y_E=45% for the extract and ee_R=82%, Y_R=42% for the raffinate were obtained.     

Desymmetrisation of (4R,5S)-4,5-diphenylimidazolidine-2-thione using pentafluorophenyl active esters

(4R,5S)-4,5-Diphenylimidazolidine-2-thione is efficiently desymmetrised by stereorandom deprotonation with NaHMDS, followed by kinetic resolution of the resulting racemic intermediate with an enantiomerically pure pentafluorophenyl active ester. The levels of diastereocontrol were found to be excellent (86-92% de at ∼30% conversion). This desymmetrisation reaction is an example of a masked resolution.     

Highly enantioselective enzymatic resolution of aromatic β-amino acid amides with Pd-catalyzed racemization

The kinetic resolution of an aromatic β-amino acid amide 3a–d via N-acylation was explored with two lipases, Candida antarctica lipase A (CALA) and Pseudomonas stutzeri lipase (PSL). The PSL-catalyzed resolution proceeded with excellent enantioselectivity (E = >400) to give both acylated products and unreacted substrates in enantiopure forms. Three additional aromatic β-amino acid amides 3b–d were also resolved by PSL with a high level of enantioselectivity (E = >200). The PSL-catalyzed resolution of 3a was coupled with a Pd-catalyzed racemization to obtain enantiopure N-acylated product (R)-4a (>99% ee) in high yield (90%).     

Classical and dynamic resolution of 1-amino-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one

Two efficient production processes of enantioenriched 1-amino-3-methyl-1,3,4,5-tetrahydro-benzo[d]azepin-2-one 1 were achieved using the readily available starting materials. A key step in the methodologies is a classical resolution or a dynamic resolution that provides excellent chemical (>80%) yields and enantiomeric excesses (>99.8% ee). The classical resolution was developed on a preparative scale while the dynamic resolution was implemented on a pilot plant scale.     

High-yielding metalloenzymatic dynamic kinetic resolution of fluorinated aryl alcohols

Dynamic kinetic resolution (DKR) of various fluorinated aryl alcohols by a combination of lipase-catalyzed enzymatic resolution with in situ ruthenium-catalyzed alcohol racemization is described. (R)-Selective Candida antarctica lipase B (CALB) was employed for transesterification of different fluoroaryl alcohols in DKR reactions delivering the corresponding acetates in high yield (?97%) with excellent enantiomeric excess (?98%).     

Resolution of Racemic Ofloxacin Based on Co-Technology of Bubble Fractionation and Extraction

A method of bubble fractionation, with the help of solvent extraction, was developed for the resolution of racemic ofloxacin (rac OFLX). In this method, dibenzoyl-L-tartaric (L-DBTA), di-(2-ethylhexyl) phosphoric acid (D2EHPA) and sodium lauryl sulfate (SDS) were used as chiral collector, co-extractant and foamer, respectively. Several important parameters influencing the resolution performances, such as pH in aqueous phase, concentration of OFLX, concentration of L-DBTA, concentration of SDS and volume ratio of D2EHPA to n-octanol in solution, were investigated. The optimal resolution conditions were obtained with the aqueous phase pH 7, volume ratio of D2EHPA to n-octanol 6/14 in organic phase, concentration of SDS 0.42 mg mL^?1, concentration of OFLX 1.67 mg mL^?1, and concentration of L-DBTA 0.11 g mL^?1. Under the optimal extraction conditions, the enantiomeric excess value (e.e.%) was 60.08% and the enantioselectivity (??) was 5.58. It was found that the capacity of enantioselective separation can be greatly improved by the co-technology.     

Enantioselective synthesis of (S)-timolol via kinetic resolution of terminal epoxides and dihydroxylation of allylamines

An efficient enantioselective synthesis of (S)-timolol has been described using chiral Co-salen-catalyzed kinetic resolution of less expensive (±)-epichlorohydrin with 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole in good overall yield (55%) and excellent enantioselectivity (98%). Synthesis of (S)-timolol has also been achieved using hydrolytic kinetic resolution as well as asymmetric dihydroxylation routes in 90% ee and 56% ee, respectively.     

The synthesis of 1-hydroxy phosphonates of high enantiomeric excess using sequential asymmetric reactions: titanium alkoxide-catalyzed PC bond formation and kinetic resolution

Titanium alkoxide-catalyzed asymmetric phosphonylation of aldehydes yields hydroxy phosphonates in moderate to good enantiomeric excess (e.e.s ∼70%). The hydroxy phosphonates were acetylated and the acetates were subjected to enzyme-catalyzed kinetic resolution. The non-racemic acetates 2 (predominantly (R)-enantiomer) were hydrolyzed with an (R)-enantiomer-selective lipase, resulting predominantly in the hydrolysis of the (R)-isomer (at 85% conversion) to give the alcohols 3 with high e.e. Alternatively, hydrolysis of the minor enantiomeric (S)-acetate to approximately 20% conversion left the enriched (R)-configured acetate with improved e.e. (>90%). The moderate enantioselectivities obtained in the catalytic PC bond formation are enhanced during the enzymatic hydrolysis. Furthermore, availability of the non-racemic phosphonates permits the use of less selective enzymes, resulting in higher yields in comparison with the standard resolution of racemic materials.     

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).     

Highly enantioselective enzymatic resolution of cis-fused octalols mediated by Candida antarctica lipase (Novozym 435)

Optically active cis-fused octalin acetates have been prepared by esterification of cis-fused octalols using Candida antarctica lipase (CALB—Novozym 435). The enzyme efficiently resolved the racemic octalols by kinetic resolution, to afford cis-fused octalols and cis-fused octalin acetates with high enantiomeric excesses (up to >99%) and good yields (>40%).     

Enantioselective one-pot synthesis of β-sulfonyl ketones and trisubstituted tetrahydrothiophenes via β-elimination/cycloaddition sequence

A mild and efficient enantioselective one-pot synthesis of β-sulfonyl ketones and trisubstituted tetrahydrothiophenes via introducing 1,4-dithiane-2,5-diol to the simple kinetic resolution of β-sulfonyl ketones has been described herein. The one-pot reaction sequence including kinetic resolution and cascade sulfa-Michael/Aldol reaction proceeded successively to afford corresponding sulfonyl ketones and tetrahydrothiophenes with high enantioselectivities (85%–98% ee and 84%–95% ee, respectively).     

Quantification of very low enantiomeric impurity of efaroxan using a dual cyclodextrin system by capillary electrophoresis

A rapid method for the enantiomeric purity determination of efaroxan has been developed by capillary electrophoresis (CE) using a dual cyclodextrin (CD) system. The influence of the nature and the concentration of CDs on separation parameters has been studied. High resolution (R_s = 7) and peak efficiency (104 000-121 000 theoretical plates) values were obtained for efaroxan enantiomers by adding two cyclodextrins, one neutral (7.5 mM DM-β-CD) and the other negatively charged (3 mM CM-β-CD) to the running buffer composed of 100 mM phosphoric acid-triethanolamine (pH 3). These resolution and peak efficiencies values allowed the quantitation of the (S)-enantiomer of efaroxan at very low enantiomeric excess even if the minor component migrates after the major one. This method was fully validated for the enantiomeric impurity determination of the (S)-form of efaroxan at the 0.05% level. Calibration curve, expressed by the peak areas ratio versus the enantiomeric purity was linear over the 0.05-1% enantiomeric impurity range (r² = 0.9996). Limits of detection (LOD) and quantification (LOQ), expressed in term of (S)-enantiomer impurity were 0.02% and 0.05%, respectively. The accuracy of the method at 0.12%, 0.50% and 0.80% enantiomeric impurity levels for the (S)-form were determined. Recoveries were in 94-102% range for each quality control sample and were determined with good precision (intra-day R.S.D. = 3.54%, inter-day R.S.D. = 5.33%).     

Lipase-mediated kinetic resolution of (RS)-1-bromo-3-[4-(2-methoxy-ethyl)-phenoxy]-propan-2-ol to (R)-1-bromo-3-(4-(2-methoxyethyl) phenoxy) propan-2-yl acetate

A novel biocatalytic method for the enantioselective synthesis of (R)-bromo-3-[4-(2-methoxy-ethyl) phenoxy]-2-propanol [(R)-BMEPP], a precursor for the synthesis of (S)-metoprolol, an anti hypertensive drug is described. We have developed kinetic resolution of rac-BMEPP by transesterification using Candida rugosa lipase and vinyl acetate as the acyl donor affording the product with excellent conversion (49%) and ee (>99%). Various reaction parameters (source of enzyme, reaction media, and concentration of substrate and acylating agent) for the enzymatic kinetic resolution have been reported.     

‘Easy-on,easy-off’ resolution of chiral 1-phenylethylamine catalyzed by Candida antarctica lipase B

An ‘easy-on, easy-off’ process for the effective resolution of (±)-1-phenylethylamine was designed using the lipase B of Candida antarctica. This two step lipase-catalyzed process for the resolution of a chiral arylalkylamine involves a high-conversion enantioselective condensation of (R)-(+)-1-phenylethylamine with capric acid (conversion 99%, <24 h), followed by the hydrolysis of the corresponding synthesized (R)-(+)-amide (conversion 98%, 48 h). As a result, this efficient enzymatic process yields both (R)- and (S)-enantiomers of 1-phenylethylamine in high enantiomeric purity.     

Preparation of the four stereoisomers of 3-bromo-2-butanol or their acetates via lipase-catalysed resolutions of the racemates derived from dl- or meso-2,3-butanediol

The four stereoisomeric 3-bromo-2-butanols and/or their acetates were prepared via lipase-catalysed kinetic resolution by hydrolyses of the acetates of the (±)-syn- and (±)-anti-3-bromo-2-butanols, or via esterifications of the alcohols. The diastereomeric bromoacetates were obtained by syntheses from the dl- and meso-2,3-butanediols, respectively. On a preparative scale, the four stereoisomers, either as the free alcohols or as their acetates, were obtained in >95% ee, and in 35–40% yield (based on the starting racemates).     

Enantioselective synthesis of 2-alkylidenetetrahydrofurans based on a ‘cyclization/enzymatic resolution’ strategy

Enantiomerically pure 2-alkylidenetetrahydrofurans have been prepared by TiCl₄ mediated enantiospecific reactions of 1,3-bis-silyl enol ethers with enantiomerically pure epichlorohydrin. In addition, the enzymatic kinetic resolution of 2-alkylidenetetrahydrofurans, using Candida antarctica lipase B (CAL-B), was studied. Enzymatic kinetic resolution of monocyclic 5-vinyl-2-alkylidenetetrahydrofuran with CAL-B afforded the enantiomerically pure ester with 97% ee. For a bicyclic 2-alkylidenetetrahydrofuran, this proceeded with excellent enantioselectivity (E >100) affording the enantiomerically pure acid with 98% ee. 2-Alkylidenetetrahydrofurans were prepared by [3+2] cyclization reactions of 1,3-dicarbonyl dianions (‘free dianions’) or 1,3-bis-silyl enol ethers (‘masked dianions’).     

Synthesis of novel chiral 1,3-aminophenols and application for the enantioselective addition of diethylzinc to aldehydes

Novel chiral 1,3-aminophenols were efficiently synthesized by applying a Friedel–Crafts reaction and optical resolution. The catalytic activity of the aminophenols was studied for the addition of diethylzinc to benzaldehyde. The results showed that (S)-5a with bulky tert-butyl groups on the stereogenic carbon atom and 4,6-positions of phenol favored higher enantioselectivity (94% ee). The same ligand was also used with other aldehydes, to give optically active alcohols in good chemical yields and ee values (up to 99%).     

Enantioselective synthesis of a key intermediate of Levofloxacin using microbial resolution

The important key intermediate in the synthesis of Levofloxacin, (S)-7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine, was prepared enantioselectively by microbial resolution. When lyophilized microorganism selected from soil was treated with the corresponding amide, the (S)-amine was obtained with high enantiomeric purity (99% ee).     

Multivariate resolution of rank-deficient near-infrared spectroscopy data from the reaction of curing epoxy resins using the rank augmentation strategy and multivariate curve resolution alternating least squares approach

A model of the curing reaction between phenyl glycidyl ether (PGE) and aniline as the curing agent was studied isothermally at 95 °C and monitored in situ by near-infrared spectroscopy (NIR). The spectra were recorded every 5 min. The ubiquitous problem of rank deficiency in reaction network systems was solved by assembling an augmented column-wise matrix containing five process runs from different initial conditions. The data were analyzed using a two-way multivariate curve resolution alternating least squares method (MCR-ALS). Initial estimates of spectra required by MCR-ALS were given by a SIMPLe-to-use Interactive Self-modeling Mixture Analysis (SIMPLISMA) approach. The reactants, product and intermediate spectra were successfully resolved and the concentration profiles properly represented the system studied. The performance of the model was evaluated by two parameters: ALS lack of fit (lof=0.88%) and explained variance (R²=99.99%). To validate the MCR-ALS results, the similarity coefficients (r) between the recovered spectra and the pure species spectra were calculated. These were: PGE (r=0.998), aniline (r=0.994) and tertiary amine (r=0.999).     

Enantioselectivity of a recombinant epoxide hydrolase from Agrobacterium radiobacter

The recombinant epoxide hydrolase from Agrobacterium radiobacter AD1 was used to obtain enantiomerically pure epoxides by means of a kinetic resolution. Epoxides such as styrene oxide and various derivatives thereof and phenyl glycidyl ether were obtained in high enantiomeric excess and in reasonable yield. The enantioselectivity (E-value) of the resolution was calculated from progress curves for styrene oxide (E=16.2) and para-chlorostyrene oxide (E=32.2).