Application research of (S)-(-)-α,α-Diphenyl-2-pyrrolidinemethanol

Introduction

α,α-Diphenyl-2-pyrrolidinemethanol,which is a phenethylamine analog and was listed as a designated substance in October 2009, is one such substance, and its widespread distribution as a new illegal drug is a matter of great concern. To prevent the distribution and spread of this substance, it is essential to establish an analytical method beforehand. α,α-Diphenyl-2-pyrrolidinemethanol has one chiral center in its structure, whereas methyl a-phenyl-2-piperidineacetate hydrochloride (MPH) has two, and their enanntiomers possibly exhibit distinct pharmacokinetic and pharmacodynamic properties in humans. α,α-Diphenyl-2-pyrrolidinemethanol includes both (R)-(+)-a,a-Diphenyl-2-pyrrolidinemethanol and (S)-(-)-α,α-Diphenyl-2-pyrrolidinemethanol forms (Figure 1).

HPLC enantioseparation of α,α-diphenyl-2-pyrrolidinemethanol and methylphenidate

Enantioseparation of α,α-diphenyl-2-pyrrolidinemethanol (D2PM) and methylphenidate (MPH; Ritalin(®)) using (R)-(-)-4-(N,N-dimethylaminosulfonyl)-7-(3-isothiocyanatopyrrolidin-1-yl)-2,1,3-benzoxadiazole as the chiral derivatization reagent has been achieved for the first time, and a simple, reliable detection method using HPLC with fluorescence detection has been developed.  A simple, reliable method for the detection of (R)-α,α-Diphenyl-2-pyrrolidinemethanol, (S)-(-)-α,α-Diphenyl-2-pyrrolidinemethanol, D-threo-MPH,and L-threo-MPH using HPLC–FL was developed. To thebest of our knowledge, this is the first report on the enantioseparation of α,α-diphenyl-2-pyrrolidinemethanol and MPH using the chiral derivatization method. The proposed method does not require a relatively expensive chiral column, is quite simple,and does not employ a complicated mass spectrometer. The method was successfully applied to the analysis of ratplasma, where the rats were administered a single oral dose of α,α-Diphenyl-2-pyrrolidinemethanol or MPH (Ritalin). Moreover, the method doesnot involve complicated steps such as liquid-liquid or solidphase extraction for the pretreatment of plasma samples;only the deproteinization is required. The detection limits of (R)- and (S)-(-)-α,α-Diphenyl-2-pyrrolidinemethanol were found to be 6.8 and 13 ng/mL,respectively, and those of D- and L-threo-MPH were found to be 61 and 66 ng/mL, respectively (S/N=3). The calibration curves exhibited good linearity (r2>0.999), and the relative standard deviations of intra- and inter-day variations were below 11.2 and 11.4%, respectively. The proposed method would be applicable in diverse ways not only for drug testing and confirmation of α,α-Diphenyl-2-pyrrolidinemethanol or MPH intake indicating drug abuse but also for weighing the pharmacokinetic differences between α,α-Diphenyl-2-pyrrolidinemethanol or MPH enantiomers. This method isexpected to be beneficial to society in general.[1]

Enantiospecific cocrystals preparation

A novel one-pot deracemization method using a bifunctional chiral agent (BCA) is proposed for the first time to convert a racemate to the desired enantiomer. Specifically, chiral α,α-Diphenyl-2-pyrrolidinemethanol formed enantiospecific cocrystals with racemic dihydromyricetin, and used its own alkaline catalysis to catalyze the racemization between the (2R,3R)-enantiomer and (2S,3S)-enantiomer in solution, achieving a one-pot spontaneous deracemization. This strategy was also successfully extended to the deracemization of three other racemic compound drugs: (R,S)-carprofen, (R,S)-indoprofen, and (R,S)-indobufen. The one-pot deracemization method based on the BCA strategy provides a feasible approach to address the incompatibility between cocrystallization and racemization reactions that are commonly encountered in the cocrystallization-induced deracemization process and opens a new window to develop essential enantiomerically pure pharmaceutical products with atom economy.[2]

Synthesis of a new C(2)-symmetric chiral catalyst

A new C(2)-symmetric chiral catalyst 3,5-bis[(2S)-(hydroxy-diphenylmethyl)- pyrrolidin-1-ylmethyl]-1,3,4-oxadiazole was successfully synthesized by the reaction of 2,5-dichloromethyl-1,3,4-oxadiazole with (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol, and applied to the catalytic asymmetric reduction of prochiral ketones with borane. When the catalyst loading was 1 mol%, enantiomeric excesses of up to 86.8% and 94.5% were observed in reduction of aromatic and alpha-halo ketones, respectively.[3]

Application of (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol derivative

Report 1: In this study, Kowalska and his colleagues demonstrated the usefulness of hydrazone activation for the synthesis of biologically relevant tetrahydroindolizines. A pyrrol-derived hydrazone bearing a Michael acceptor moiety in the N-alkyl side chain has been designed with the aim of participating in the aminocatalytic cascade reaction leading to the annulation of the new six-membered heterocyclic scaffold. The application of (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the aminocatalyst allows for the iminium ion-enamine-mediated cascade to proceed in a fully stereoselective manner.[3]

Report 2: Albrecht and his colleagues described new asymmetric, catalytic strategies for the synthesis of biologically important α-methylene-δ-lactones and δ-lactams. The elaborated protocols utilize iminium-ion-mediated Michael addition of trimethyl phosphonoacetate to α,β-unsaturated aldehydes catalyzed by (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the key step. Enantiomerically enriched Michael adducts are employed in three different reaction pathways. Transformation into α-methylene-δ-lactones is realized by a sequence of reactions involving chemoselective reduction of the aldehyde, followed by a trifluoroacetic acid (TFA)-mediated cyclization and Horner-Wadsworth-Emmons olefination of formaldehyde. On the other hand, indolo[2,3-a]quinolizine-framework-containing products can be accessed when enantiomerically enriched Michael adducts are employed in a Pictet-Spengler reaction with tryptamine, followed by Horner-Wadsworth-Emmons olefination. Finally, reductive amination of the Michael adducts by using methylamine and Horner-Wadsworth-Emmons olefination of formaldehyde is demonstrated to give α-methylene-δ-lactams. The developed strategies can be realized without the purification of intermediates, thus greatly increasing their practicality.[5] 

References

[1] Inagaki S, Taniguchi S, Hirashima H, et al. HPLC enantioseparation of α,α-diphenyl-2-pyrrolidinemethanol and methylphenidate using a chiral fluorescent derivatization reagent and its application to the analysis of rat plasma. J Sep Sci. 2010;33(20):3137-3143. doi:10.1002/jssc.201000479

[2] Su X, Sun J, Liu J, et al. Bifunctional Chiral Agent Enables One-pot Spontaneous Deracemization of Racemic Compounds. Angew Chem Int Ed Engl. 2024;63(22):e202402886. doi:10.1002/anie.202402886

[3] Zhou Y, Wang WH, Dou W, Tang XL, Liu WS. Synthesis of a new C(2)-symmetric chiral catalyst and its application in the catalytic asymmetric borane reduction of prochiral ketones. Chirality. 2008;20(2):110-114. doi:10.1002/chir.20503

[4] Kowalska J, Łukasik B, Frankowski S, Albrecht Ł. Hydrazone Activation in the Aminocatalytic Cascade Reaction for the Synthesis of Tetrahydroindolizines. Org Lett. 2024;26(4):814-818. doi:10.1021/acs.orglett.3c03911

[5] Albrecht A, Morana F, Fraile A, Jørgensen KA. Organophosphorus reagents in organocatalysis: synthesis of optically active α-methylene-δ-lactones and δ-lactams. Chemistry. 2012;18(33):10348-10354. doi:10.1002/chem.201201325

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