Synthesis and HPLC enantioseparation of novel derivatives of 3-alkoxy-4-hydroxyphenylalkanones of a potential α/β-blocker type


Authors: Ružena Čižmáriková;  Ladislav Habala;  Jindra Valentová;  Dana Šmátralová
Authors‘ workplace: Katedra chemickej teórie liečiv, Farmaceutická fakulta UK, Bratislava, SR
Published in: Čes. slov. Farm., 2021; 70, 51-58
Category: Original Article
doi: 10.5817/CSF2021-2-51

Overview

The present paper reports the synthesis of a series of seven compounds with a hetero aminopropanol chain. The compounds were prepared by the conversion of 3-alkoxy-4-hydroxyphenyl alkanones with 2-chloromethyl oxirane and subsequent reaction of the products with heterocyclic amines (pyrrolidine, azepane, 4-methylpiperazine and 2-methoxyphenyl piperazine). The target compounds were synthesized in the form of racemates. The purity of the products was confirmed by thin layer chromatography and their IR, UV-VIS and 1H-NMR spectra were recorded. Enantioseparation of the racemic products was accomplished by HPLC on a Chiralpak AD chiral chromatographic column with tris(3,5-dimethylphenyl)carbamate as the chiral selector. The efficiency of enantioseparation was determined in relation to the composition of the mobile phase (hexane : ethanol : methanol : ethylethanamine) and to the structure of the prepared compounds. Baseline separation was achieved with all compounds using mobile phases A (78 : 11 : 11 : 0,1 v/v/v/v) and B (80 : 10 : 10 : 0,1 v/v/v/v),
with selectivity factor ranging from 1.07 to 1.42 and resolution from 0.76 to 5.47. The mobile phase containing a higher amount of hexane did not allow for successful enantioseparation of the piperazine derivatives. 

Keywords:

3-alkoxy-4-hydroxyphenylalkanones – beta-blockers – enantioseparation – HPLC – Chiralpak AD


Sources
  1. Čižmáriková R., Borovanský A., Kozlovský J., Béderová E., Dingová A. 4-(3-Alkylamino-2-hydroxypropoxy)-3-(alkoxymethyl)acetophenones. Collect. Czech. Chem. Commun. 1985; 50, 2289–2298. 
  2. Čižmáriková R., Račanská E., Hroboňová K., Lehotay J., Ághová Z., Halešová D. Synthesis, pharmacological activity and chromatographic separation of some novel potential β-blockers of the aryloxyaminopropanol type. Pharmazie 2003; 58, 237–241. 
  3. Tran V. A., Tran N. H. T., Bach L. G., Nguyen T. D., Nguyen T. T., Nguyen T. T., Nguyen T. A. N., Vo T. K., Vo T. T. T., Le V. T. Facile synthesis of propranolol and novel derivatives. J. Chem. 2020; 2020, art. no. 9597426.
  4. Čižmáriková R., Habala L.Markuliak M.Valentová J. Survey of pharmacological activity and pharmacokinetics of selected β-adrenergic blockers in regard to their stereochemistry. Appl. Sci. 2019; 9, 625. 
  5. Čižmáriková R., Valentová J., Hutt A. J., Sedláková S. Blokátory β-adrenergických receptorov – skupina chirálnych liečiv. Stereoselektívna syntéza β-blokátorov. Čes. slov. Farm. 2005; 54, 201–206.
  6. Agustian J., Kamaruddin A. H., Bhatia S. Single enantiomeric β-blockers – the existing technology. Process Biochem. 2010; 45, 1587–1604.
  7. Saddique F. A., Zahoor A. F., Yousaf M., Irfan M., Ahmad M., Mansha A., Khan Z. A., Naqvi S. A. R. Synthetic approaches towards the synthesis of beta-blockers (betaxolol, metoprolol, sotalol, and timolol). Turk. J. Chem. 2016; 40, 193–224.
  8. Muntean D. L., Hancu G., Hajnal K., Rusu A., Ciurba A. Cyclodextrine screening for the chiral separation of beta-blocker derivatives. Rev. Chim. 2015; 66, 1019–1023.
  9. Yang Y., Wang Y., Bao Z., Yang Q., Zhang Z., Ren Q. Progress in the enantioseparation of β-blockers by chromatographic methods. Molecules 2021; 26, 468.
  10. Pirkle W. H., Lee W. J. Separation of the enantiomers of β-blockers using brush type chiral stationary phase derived from conformationally rigid α-amino β-lactam. Bull. Korean Chem. Soc. 2010; 31, 620–623.
  11. Barbato F., Carpentiero C., Grumetto L., La Rotonda M. I. Enantioselective retention of β-blocking agents on human serum albumin and α1-acid glycoprotein HPLC columns: Relationships with different scales of lipophilicity. Eur. J. Pharm. Sci. 2009; 38, 472–478. 
  12. Imre S., Ormenişan A., Tero-Vescan A., Muntean D. L., Vari C. E. HPLC enantioseparation of β-blockers on ovomucoid stationary phase. J. Chromatogr. Sci. 2016; 54, 1578–1583.
  13. Adhikari S., Lee W. Chiral separation using chiral crown ethers as chiral selectors in chirotechnology. J. Pharm. Investig. 2018; 48, 225–231.
  14. Hyun M. H. Development of HPLC chiral stationary phases based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid and their applications. Chirality 2015; 27, 576–588.
  15. George N., Herz M., Aboul-Enein H. Y., Shihata L., Hanafi R. Surface design of enantiomeric HPLC separation on vancomycin and teicoplanin-based stationary phases, a tool for chiral recognition of model β-blockers. J. Chromatogr. Sci. 2019; 57, 485–494. 
  16. Pocrnić M., Ansorge M., Dovhunová M., Habinovec I., Tesařová E., Galić N. Chiral separation of beta-blockers by high-performance liquid chromatography and determination of bisoprolol enantiomers in surface waters. Arh. Hig. Rada Toksikol. 2020; 71, 56–62.
  17. Xu B. J., Zhang D. T., Shen B. C., Xu X. Z. Enantioseparation of seven amino alcohols on teicoplanin chiral column. Chinese J. Anal. Chem. 2007; 35, 55–60.
  18. Li M., Jiang Z., Di X., Song Y. Enantiomeric separation of six beta-adrenergic blockers on Chiralpak IB column and identification of chiral recognition mechanisms by molecular docking techni-que. Biomed. Chromatogr. 2020; 34, e4803.
  19. Kalíková K., Martínková M., Schmid M. G., Tesařová E. Cellulose tris-(3,5-dimethylphenylcarbamate)-based chiral stationary phase for the enantioseparation of drugs in supercritical fluid chromatography: comparison with HPLC. J. Sep. Sci. 2018; 41, 1471–1478.
  20. Mosiashvili L., Chankvetadze L., Farkas T., Chankvetadze B. On the effect of basic and acidic additives on the separation of the enantiomers of some basic drugs with polysaccharide-based chiral selectors and polar organic mobile phases. J. Chromatogr. A 2013; 1317, 167–174.
  21. Čižmáriková R., Polakovičová M., Mišíková E. Synthesis, physicochemical properties, and conformational studies of (3-alkoxymethyl-4-hydroxyphenyl)ethanones. Chem. Pap. 2002; 56, 256–260.
  22. Čižmáriková R., Markuliak M., Habala L., Valentová J., Bílková A. Synthesis, antimicrobial and antiradical activity of (3-alkoxymethyl-4-hydroxyphenyl)propan-1-ones intermediates of biological active compounds. Eur. Pharm. J. 2020; (v tlači).
  23. Čižmáriková R., Némethy A., Valentová J., Hroboňová K., Bruchatá K. Synthesis and HPLC enantioseparation of derivatives of the 3-hydroxyphenylethanone. Acta Fac. Pharm. Univ. Comen. 2012; 59, 15–27.
  24. ChemicalBook: Propiophenone (93-55-0) 1H NMR. https://www.chemicalbook.com/spectrumen_93-55-0_1hnmr.htm
  25. ChemicalBook: Fumaric acid (110-17-8) 1H NMR. https://www.chemicalbook.com/SpectrumEN_110-17-8_1HNMR.htm
  26. ChemicalBook: Monoethyl fumarate (2459-05-4) 1H NMR. https://www.chemicalbook.com/SpectrumEN_2459-05-4_1HNMR.htm
  27. Milata M., Sedľa P., Brezová V., Gatial A., Kováčik V., Miglierini M., Stankovský Š., Šima J. Aplikovaná molekulová spektroskopia. Slovenská technická univerzita Bratislava 2008; 76.
  28. Zielinsky-Pisklak M. A., Pisklak D. M., Wawer I. 1H and 13C NMR characteristics of β-blockers. Magn. Reson. Chem. 2011; 49, 284–290.
  29. Valentová J., Čižmáriková R., Bui T. T. T., Drake A. F., Hutt A. J. Enantiomeric resolution of novel aryloxyaminopropanol derivatives with β-adrenoceptor antagonist activity on a derivatised amylose chiral stationary phase. Chromatography 2003; 58, 733–740.
  30. Hroboňová K., Lehotay J., Čižmáriková R., Armstrong D. W. Study of mechanism of enantioseparation. Part I. Chiral analysis of alkylaminoderivatives of aryloxypropanols by HPLC using macrocyclic antibiotics as chiral selectors. J. Liq. Chromatogr. 2001; 24, 2225–2238.
  31. Huang J. J., Huang Y. J., Zhu L., Yuan M., Huang L. Design, synthesis and α1-adrenoceptor blocking activity of new arylpiperazines containing acetophenone substituents. Pharmazie 2014; 69, 578–584.
  32. Némethy A., Vavrinec P., Vavrincová-Yaghi D., Čepcová D., Mišúth S., Kráľová E.Čižmáriková R., Račanská E. Synthesis and biological evaluation of new combined α/β-adrenergic blockers. Arch. Pharm. 2017; 350, e201600394.
  33. Huang J. J., Zhang Z. H., He F., Liu X. W., Xu X. J., Dai L. J., Liu Q. M., Yuan M. Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on α1D/1A-adrenoreceptor subtypes. Bioorg. Med. Chem. Lett. 2018; 28, 547–551.
  34. Čižmáriková R., Némethy A.Habala L., Račanská E., Valentová J., Hroboňová K. Synthesis, pharmacological activity and chromatographic enantioseparation of new heterocyclic compounds of the aryloxyaminopropanol type derived from 4-hydroxyphenylalkanones. Monatsh. Chem. 2018; 149, 969–976.
  35. Malík I., Csöllei J., Jampílek J., Stanzel L., Zadražilová I., Hošek J., Pospíšilová Š., Čížek A., Coffey A., O’Mahony J. The structure–antimicrobial activity relationships of a promising class of the compounds containing the N-arylpiperazine scaffold. Molecules 2016; 21, 1274–1299.
  36. Cecchetti V., Schiaffella F., Tabarrini O., Fravolini A. (1,4-benzothiazinyloxy)alkyl piperazine derivatives as potential antihypertensive agents. Bioorg. Med. Chem. Lett. 2000; 10, 465–468.
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