Current Research in Bioorganic & Organic Chemistry (ISSN: 2639-4685)

Article / research article

"Separation of Diastereomers Taking Advantage for the Kinetic Control and Structure of Resolving Agent"

Dombrády ZS1, Pálovics E2*, Fogassy E2

1Chinoin Private Co. Ltd. - a Sanofi company, Tó utca, Budapest, Hungary

2Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, Hungary

*Corresponding author: Emese Pálovics, Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521 Budapest, PO Box 91, Hungary. Tel: +36 1 463 2101; Email:

Received Date: 19 September, 2019; Accepted Date: 03 October, 2019; Published Date: 08 October, 2019


The preparation of pure enantiomers of (1-methyl-2-phenyl)-ethylamine (A) is described. The resolution of racemic compound (A) was accomplished using half equivalent of tartaric acid. The purification of enantiomeric mixtures by a non-usual method are also described.


The enantiomers of (1-methyl-2-phenyl)-ethylamine (A) (Figure 1) have not only therapeutical effect, but they could be important base material both for the pharmacetical industry and the organic chemical research (eg. for preparation of the Selegiline [1], Tamsulozine [2], or for other types of molecules). Our aim was to work out an effective, quick and practicable resolution method of racemic compound 1-phenylpropane-amine (A) to obtain the pure enantiomers.

According to earlier literature, the resolution was accomplished using (R,R)-Tartaric Acid (TA), or N-acetyl-aminoacids in 25 volumes of ethanol [3] and i-propyl alcohol [4,5]. In case of the above mentioned methods were used an equivalent amount of resolving agent and, not rare, 25-fold of solvent, obtaining the pure enantiomers after recrystallisation of diastereomers one or more times. The crystallization time was often over 12 hours in each case. The yield was under 60% referring to one of the enantiomers in the racemate.

Results and Discussion

The method described in this paper is based on our earlier works when we examined the possibilities of resolution of the racemic N-acyl amino acids with the structurally similar bases (PhEA, and its derivative MEA) in aqueous solution (Table 1) [6-11]. The applied resolving agents didn’t work for acetyl-phenyl glycine, but in case of acetyl-phenylalanine enantiomeric enrichment was obtained.

Based on our earlier findings [12] we have attempted the reciprocal resolution of A using enantiomers of N-acyl amino acids. An influence of the applied solvent was also observed in these processes The obtained results are shown in the Table 2.

Was observed that using structurally similar resolving agents (N-substituted A, FoPhA (1), AcPhA (2), PPhA (3)) the increase of the length of the N-substituents don’t produces a linear change in the resolution results (ee, F). The correlation between substituents and the results obtained are plotted in Figure 2.

The Tartaric Acid (TA) was also applied as resolving agent for enantiomeric separation of A, in isopropanol, using 0.5 eq. of TA, 0.5 eq of sulfuric acid, since A had been successfully resolved under similar conditions.

The resolution of the racemic 1-methyl-2-phenyl-ethylamine (A) was effectuated by half equivalent of (S, S)-TA (the other half part was replaced with hydrochloric acid) and as solvent was applied IPA. Since the crystallization time and temperature could influence significantly the results of separation, these resolutions were effectuated in different conditions, varying the crystallization time and temperature. Was examined the influence of temperature and time of crystallization. If the solution is inoculated hot (about 60 °C) with the pure diastereomer or the enantiomeric hydrochloride after mixing the reagents, crystallization almost complete within a few minutes. If it is frozen (-7 °C) or the filtration is started in approximatively 15 minutes the enantiomeric purity remains high (83.5-89.1%). However, keeping overnight at 5 °C gives low enantiomeric purity (44.0%) with a high (97.0%) yield. The best results are shown below (Table 3, Figure 3).

So not only the influence of temperature but that of the kinetic controll was also observed, as the (S)-(+)-A*(S,S)-TA diastereomeric salt crystallizesd faster than the other corresponding salt. So the crystalls obtained must be filtrated quickly (less than one hour after start of crystallization) to obtain the wanted higher results. In this case the yield was about 90% as well as the ee (90%). These values of resolvabilty (F=ee*Y) are much higher (0.8) than the results described in literature.

In most cases a purity of enantiomers of almost 100% is needed. The purification of enantiomeric mixture can be effectuated by recrystalization (utilized in literature as mentioned above) or by re-resolution. The latter method resulted in high losses in our hands (Table 4).

In this case the purification of enantiomeric mixture was not achieved by the usual method (multiple recrystallization) but by using a digestion process. The crystalls were boiled for a short period (1-2 minutes) in a mixture of aqueous hydrochloric acid (37%) and IPA (in equivalent amount with the racemic proportion of the diastereomeric salt).

The filtration must be effectuated quickly (preferably in no more than one hour), and so the purity of enantiomer can reach ee>80%. (If higher purity is required, this step can be repeated.) The results of purification by digestion are shown in the Table 5.

During the resolution, the unusually fast crystallization of the diastereomeric salt is enabled by the kinetic control, and the ratio is assured by the rapid separation of the diastereomeric salt. By increasing the crystallization time the system is moved to thermodynamic control. As a consequencethe efficacy of resolution decreased in 12 hours from 0.716 to 0.427, and the enantiomeric purity (ee diastereomer) from 89 to 44.0 % as well.

The enantiomer A was eliberated by aqueous sodium hydroxide from the diastereomeric salt. After liberation the enantiomer was extracted with an solvent unmiscible with water (e.g. DCM) followed by the distillation of the solvent. To the remained enantiomer was added hydrochlorid acid in solution of ethylacetate, followed by filtration of the precipitated hydrochloride salt. With this method the enantiomeric excess was increased to ee ~ 97%.


Chemicals were the products of Aldrich (Steinheim, Germany).

Optical rotation data were measured with a Perkin-Elmer 241 automatic polarimeter.

The preparation of pure enantiomers of (-) -(1-methyl-2-phenyl) ethylamine is shown in the Figure 4.

The preparation of (-) (1-methyl-2-phenyl)ethylamine*(-)-Tartric acid diastereomeric salt

Was dissolved 5 g of the racemic compound (2-phenyl-1methyl)-ethylamine in a mixture of 12 cm3of IPA and 1,53 cm3 of aquaeous hydrochloric acid (37%), and it was heated to boiling. Was added 2,81 g (-)-tartaric acid to the hot mixture. The obtained diastereomeric salt was filtrated quickly and washed with 2x4 cm3 IPA. The obtained salt was suspended with 10 cm3 hexane, filtrated and dried on air.

The weight of the obtained salt 4.62 g (87.5%), [α]D= -25..3 (c=1, water), ee: 83.5%.

The purification of the diastereomeric salt

The diastereomeric salt obtained was suspended in a solution of 11 cm3 IPA and 0,3 cm3 diluted hydrochlorid acid (37%) and stirring heat to boiling twice (the diastereomeric salt remained suspension). The mixture was cooled to 30 °C in 10 minutes. The obtained salt was suspended with 10 cm3 hexane, filtrated and dried on air.

The weight of the obtained salt 3.7 g (70.0%), [α]D= -28.8 (c=1, water), ee: 95%.

The preparation of (-) (1-methyl-2-phenyl)ethylamine hydrochlorid salt

To the (-)A*(-)-TA diastereomeric salt (3.7g [α]D= -28.8 (c=1, water), ee: 95%) was added 14 cm3 solution of NaOH (1 molar) and 6 cm3 water. The emulsion obtained was extracted with 3x20 cm3 Dichloromethane (DCM). The combined organic phases were dried on Na2SO4, filtrated and evaporated. The remained base (1.69g) was dissolved in 21 cm3 ether and to this solution was added 2.7 cm3 (8,7 molar) a mixture of hydrochlorid acid and ethyl acetate under stirring. After 20 minutes continue stirring the crystals were separated by filtration and washed with 2x3 cm3 ether followed by 2x5 cm3 hexane. The weight of (-)-A. HCl salt: 1.17 g (66.7%, counted on diastereomeric salt), [α]D= -23,9 (c=5, water), ee: 96.4%.


The authors are grateful for the financial support of the National Office for Research, Development and Innovation (NKFIH grant number: K 124180 for E. Fogassy).

Figure 1: Racemic (1-methyl-2-phenyl)-ethylamine (A).

Figure 2: Tendency of correlation between the NH-substituents of A and the ee and F.

Figure 3: Tendency of correlation between crystallization time, ee and F.

Figure 4: The general scheme for preparation of pure enantiomers of (-) -(1-methyl-2-phenyl) ethylamine.

Table 1: Results of resolutions of racemic N-acyl amino acids with structurally similar derivatives.

Table 2:  Results* of the resolution of A.

Crystallization Time

Temperature °C

Y (%)

ee (%)


12 hours





12 min.





15 min.





Table 3: Influence of crystallization time and temperature.

ee0 (%)

Ratio of TA

Ratio of HCl

Y (%)

ee (%)

ee-ee0 (%)
















ee0: the starting enantiomeric excess

Table 4: The results of re-resolution of the mixture of enantiomers of A by TA.

ee0 (%)

Molar ratio HCl/diast. salt


/diast. salt

Y (%)

ee (%)

ee-ee0 (%)





































Table 5: Purification of diastereomeric salts by digestion.


  1. 1a). Hung Pat No 169 845 (1974).
    1b). Ács M, Kozma D, Fogassy E (1995) ACH Mod Chem 132: 475.
  2. Gizur T, Fogassy E, Bálint J, Egri G, Törley J, et al. (2008) Chirality: The pharmacological biological and chemical consequences of molecular asymmetry 20: 790-795.
  3. Leithe W (1932) Die Konfiguration der Ephedrin‐Basen. Chem Ber 65: 660-666.
  4. Blackburn D, Burghard GI (1965) Radio synthesis of Dextroamphetamine-14C Sulfate. J Pharm Sci 54: 1586-1588.
  5. Gilligham J.M. S.P. 3028430 (1962).
  7. Pálovics E, Schindler J, Faigl F, Fogassy E (2010) The influence of molecular structure and crystallization time on the efficiency of diastereoisomeric salt forming resolutions. Tetrahedron: Asymmetry 21: 2429-2434.
  8. Pálovics E, Faigl F, Fogassy E (2012) New trends and strategies in the chemistry of advanced materials., (Ed. S.G. Muntean, R. Tudose) 16-21.
  9. Pálovics E, Schindler J, Faigl F, Fogassy E (2012) Behavior of Structurally Similar Molecules in the Resolution Processes. In Comprehensive Chirality, Carreira, EM, Yamamoto H, Eds. Elsevier: Amsterdam.
  10. Pálovics E, Szeleczky Z, Fődi B, Faigl F, Fogassy E (2014) Prediction of the efficiency of diastereoisomer separation on the basis of the behaviour of enantiomeric mixtures. RSC Advances 4: 21254-21261.
  11. Szeleczky Z, Bagi P, Pálovics E, Fogassy E (2015) The effect of the eutectic composition on the outcome of kinetically and thermodynamically controlled resolutions that are based on the formation of diastereomers. Tetrahedron: Asymmetry 26: 377-384.
  12. Pálovics E, Schindler J, Faigl F, Fogassy E (2009) The possibilities of reciprocal resolution within the domain of compounds with relative structures Műszaki Szemle 48: 14-18.

Citation: Dombrády ZS, Pálovics E, Fogassy E (2019) Separation of Diastereomers Taking Advantage for the Kinetic Control and Structure of Resolving Agent. Curr Res Bioorg Org Chem 02: 123. DOI: 10.29011/2639-4685.100023

free instagram followers instagram takipçi hilesi