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2000
Volume 22, Issue 5
  • ISSN: 1570-1794
  • E-ISSN: 1875-6271

Abstract

Background

Timolol maleate is clinically used for the treatment of hypertension, angina pectoris, tachycardia, and glaucoma.

Objective

The aim of this study was to enhance the safe use of timolol maleate and investigate a synthesis method for 3-S-timolol, a newly identified impurity in timolol API (Active Pharmaceutical Ingredients).

Methods

()-3-(-butylamino)propane-1,2-diol () was used as a raw material. 3-S-timolol maleate () was synthesized through a five-step reaction. Overall yield was 57.7%, with a purity of 98%.

Results

The structure of the target compound was confirmed analysis of its 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and high-resolution mass spectrometry spectra.

Conclusion

The synthesis method was straightforward and yielded a high-purity product suitable for use as a reference in the analysis and identification of timolol maleate-related substances.

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References

  1. PakzadY. FathiM. OmidiY. MozafariM. ZamanianA. Synthesis and characterization of timolol maleate-loaded quaternized chitosan-based thermosensitive hydrogel: A transparent topical ocular delivery system for the treatment of glaucoma.Int. J. Biol. Macromol.202015911712810.1016/j.ijbiomac.2020.04.274 32380105
     [Google Scholar]
  2. JunI. ChoiY.J. KimB.R. SeoK.Y. KimT. Activation of ADRB2/PKA signaling pathway facilitates lipid synthesis in meibocytes, and beta-blocker glaucoma drug impedes PKA-induced lipid synthesis by inhibiting ADRB2.Int. J. Mol. Sci.20222316947810.3390/ijms23169478 36012741
     [Google Scholar]
  3. MayG. MillerD. FuchsD. Bradycardia from a non-selective beta-adrenergic antagonist, timolol, applied ophthalmologically for glaucoma.Cureus2022146e2581510.7759/cureus.25815 35822138
     [Google Scholar]
  4. HaganJ.C. III First world literature report: Attention pharma & headache researchers! Nasal spray timolol may be the next great thing for acute migraine.Mo. Med.2024121145 38404425
     [Google Scholar]
  5. KosaS.C. HaganJ.C. III Nasally delivered 0.5% timolol beta blocker successfully treats acute migraines in a referral headache clinic: A case series.Mo. Med.202412113336 38404426
     [Google Scholar]
  6. Hongjian Zhu Hua Luo Wenjuan Lai Efficacy of timolol in the treatment of facial hemangioma and its effect on the proliferation and apoptosis of hemangioma stem cells.Cell. Mol. Biol.2023691011512010.14715/cmb/2023.69.10.16 37953576
     [Google Scholar]
  7. HanK. WeiJ.J. ZhengH. LiX.D. ZhangA.X. MaY.H. MengJ. HuY.Y. Efficacy and safety of oral propranolol or topical timolol for the treatment of superficial infantile hemangiomas.Craniofacial surgery20243525425710.1097/SCS.0000000000010001
     [Google Scholar]
  8. Lopez-BernalT. AraneguiB. RF-FTopical Timolol in dermatology.Actas dermo-sifiliograficas2023114433433510.1016/j.ad.2021.09.014
     [Google Scholar]
  9. TokerM. AntohiD.R. SrivastavaP. AminB. WuB. COVID–19-associated diffuse dermal angiomatosis managed with pentoxifylline and topical timolol.JAAD Case Rep.202339343610.1016/j.jdcr.2023.07.002 37593377
     [Google Scholar]
  10. GummiR. StahlE.D. MarshJ.D. Topical timolol for an iris hemangioma.J. AAPOS201822215615810.1016/j.jaapos.2017.10.015 29412149
     [Google Scholar]
  11. YinR.R. HaoD. WuQ. WangJ. WangB.H. ChenP. FengY.T. JiR.F. Clinical observation of topical timolol maleate ophthalmic solution for the treatment of superficial infantile hemangiomas of the scalp.J. Clin. Dermatol20225129930210.16761/j.cnki.1000‑4963.2022.05.015
     [Google Scholar]
  12. MazharA. GhouseA.N. MallickY.A. SamadL. Efficacy of 0.5% timolol maleate gel in the management of infantile hemangiomas.Pak. J. Med. Sci.2023402(ICON)Suppl.S75S7910.12669/pjms.40.2(ICON).8983 38328662
     [Google Scholar]
  13. AlzaidM. Al-NaseemA. Al-NiaimiF. AliF.R. Topical timolol in dermatology: Infantile haemangiomas and beyond.Clin. Exp. Dermatol.202247581983210.1111/ced.15021 34798680
     [Google Scholar]
  14. AgrawalS. ModaboyinaS. BajajM.S. GuptaS. DasD. Effectiveness of treatment of acquired capillary haemangioma using timolol.Clin. Exp. Optom.2022105555655710.1080/08164622.2021.1952843 34315341
     [Google Scholar]
  15. HildebrandG.D. SipkovaZ. Topical Timolol for infantile haemangioma of the orbit.Klin. Monatsbl. Augenheilkd.2021238101069107610.1055/a‑1645‑1665 34662921
     [Google Scholar]
  16. HwangA.S. HossE. PittelkowM.R. YangY.W. Treatment of Hydroxyurea-induced ulcers with Timolol.JAMA Dermatol.2023159111277127910.1001/jamadermatol.2023.2765 37728912
     [Google Scholar]
  17. PriluckA. BacornC. RajaiiF. Rapid involution of presumed pyogenic granuloma with topical Timolol.Ophthalmology202313012710.1016/j.ophtha.2022.04.019 35777985
     [Google Scholar]
  18. BrentG. Al-WahabY. NatkunarajahJ. Topical timolol 0.5% as a novel therapeutic approach for Hailey–Hailey disease.Clin. Exp. Dermatol.2023491767810.1093/ced/llad296 37652061
     [Google Scholar]
  19. PawarM.K. Treatment of painful and deep fissures of the heel with topical timolol.J. Am. Acad. Dermatol.2021851e3e410.1016/j.jaad.2020.05.100 32479981
     [Google Scholar]
  20. AbdelmaksoudA. FiloniA. GiudiceG. VestitaM. Topical timolol for Kaposi sarcoma: An innovation.Australas. J. Dermatol.201859434034110.1111/ajd.12817 29624656
     [Google Scholar]
  21. VolotinenM. HakkolaJ. PelkonenO. VapaataloH. MäenpääJ. Metabolism of ophthalmic timolol: New aspects of an old drug.Basic Clin. Pharmacol. Toxicol.2011108529730310.1111/j.1742‑7843.2011.00694.x 21385322
     [Google Scholar]
  22. British PharmacopoeiaThe Stationery Officon behalf of the Medicines and Healthcare products Regulatory Agency (MHRA)London2016210801082
     [Google Scholar]
  23. ShuiQ.H. LiZ.M. YuS.M. Determination of the related substances in timolol maleate eye drops by HPLC.Food and Drug200574142
     [Google Scholar]
  24. HuB. ShanX.Y. Determination of related substances in Timolol Maleate eye drops by HPLC.Chinese Pharmacists20121211381140
     [Google Scholar]
  25. LiuH.Y. ChengQ.Z. ZhouM. YiQ. Determination of related substance and impurities qualitative study of Timolol Maleate eye drops.Chinese Pharmacy20182922082214
     [Google Scholar]
  26. TianH. WuC.M. YanQ.H. Identification and determination of related substances of timolol maleate.J. Pharm. Anal.20244445046110.16155/j.0254‑1793.2024.03.10
     [Google Scholar]
  27. FeiL.H. FeiH.Y. WuJ. Determination of Timolol Maleate and related substances in Travoprost and Timolol Maleate eye drops by HPLC.Herald of Medicine2022411116761680
     [Google Scholar]
  28. JiX.R. LiuY.Y. GaoZ. KongY. Determination of related substances in Timolol Maleate by HPLC.Pharm. Biotechnol.202128326126510.19526/j.cnki.1005‑8915.20210308
     [Google Scholar]
  29. HuoX.M. Determination of related substances in Timolol Maleate and its eye drops by reversed phase Ion-pair HPLC.J. Pharm. Anal.2000200318118410.16155/j.0254‑1793.2000.03.016
     [Google Scholar]
  30. LacroixP.M. DawsonB.A. SearsR.W. BlackB. HPLC and NMR methods for the quantitation of the (R)-enantiomer in (-)-(S)-timolol maleate drug raw materials.Chirality19946648449110.1002/chir.530060607
     [Google Scholar]
  31. Djang’eing’a MariniR. ChiapP. BoulangerB. DeweW. HubertP. CrommenJ. LC method for the simultaneous determination of R ‐timolol and other closely related impurities in S ‐timolol maleate: Optimization by use of an experimental design.J. Sep. Sci.2003269-1080981710.1002/jssc.200301367
     [Google Scholar]
  32. SharmaN. RaoS.S. ReddyA.M. A novel and rapid validated stability-indicating UPLC method of related substances for dorzolamide hydrochloride and timolol maleate in ophthalmic dosage form.J. Chromatogr. Sci.201250974575510.1093/chromsci/bms025 22562819
     [Google Scholar]
  33. ZhouZ.H. ZuoB. MaX.X. WuL. Synthesis and characterization of (S)-.Timolol Hemihydrate. J. Wuhan Univ. Technol20204262863210.19843/j.cnki.CN42‑1779/TQ.202004012
     [Google Scholar]
  34. HuangJ.X. YuG.G. LiM.X. A new method for synthesis of (E)-6- I-3-methyl-2 -ethyl enlateChemical notification199924951
     [Google Scholar]
  35. LiaoF. XiaoY. LiX. YuZ.Y. LiuX.C. progress of Synthesis of 1-Hydroxyeth oxyethyl- piperazine.Chemistry&Bioengineering2015323182010.3969/j.issn.1672‑5425.2015.03.004
     [Google Scholar]
  36. SunC.B. ZhangZ.B. ChenY.Z. KuangY.H. LiaoX.J. FengP.J. One-pot, three-step synthesis of o-Aminophenol derivatives from nitro arenes.Univ.Chem20223751810.3866/PKU.DXHX202111018
     [Google Scholar]
  37. LiC. WangX. Posaconazole synthetic route diagram.Chin. J. Chem.202030318218610.14142/j.cnki.cn21‑1313/r.2020.03.008
     [Google Scholar]
  38. LiY. Study on Synthesis and Activity of New Timolol Analogues.Jilin Agricultural University2013
     [Google Scholar]
  39. GaoG.T. Improved synthesis of 3-(3-chloro-1‚2‚5- thiadiazol-4-yl)pyridine.Z red fruit Y aw hu A point za value2007173180182
     [Google Scholar]
  40. XiaR. YangS.H. SunL.P. QuG.R. New synthesis of 2-Thioadenosine.Chemical Reagents2016381707210.13822/j.cnki.hxsj.2016.01.017
     [Google Scholar]
  41. MeguroY. NoguchiM. LiG.F. ShodaS.I. Efficient generation of thiolate sugars from glycosyl Bunte salts and its application to S-glycoside synthesis.Tetrahedron Letters2020613615219810.1016/j.tetlet.2020.152198
     [Google Scholar]
  42. ZhouZ.S. ZhuJ.L. Synthesis of optically active timolol.Chem. J. Chin. Univ.19889743745
     [Google Scholar]
  43. ZhouJ.H. SunS.S. YinH.X. XuC.M. WangY.Y. Research of the synthesis of chiral drugS-(-)-Timolol. J. Jining Med. Coll200629022730
     [Google Scholar]
  44. SaddiqueF.A. ZahoorA.F. YousafM. IrfanM. AhmadM. ManshaA. KhanZ.A. NaqviS.A.R. Synthetic approaches towards the synthesis of beta-blockers (betaxolol, metoprolol, sotalol, and timolol).Turk. J. Chem.201640219322410.3906/kim‑1504‑65
     [Google Scholar]
  45. KamalA. KrishnajiT. KhanM.N.A. Lipase-catalyzed resolution of 1-chloro-3-[(4-morpholin-4-yl-1,2,5-thiadiazole-3-yl)oxy]propan-2-ol.J. Mol. Catal., B Enzym.2008541-2555910.1016/j.molcatb.2007.12.003
     [Google Scholar]
  46. WangD.C. LuW. ZhouG.L. YanH.Y. Synthesis of timolol tartrate and preliminarystudies on its lowering the intraocular pressure.Chin. J. Chem.199444289291
     [Google Scholar]
  47. XuL. HeJ.F. YangL.M. Preparation of cellulose tris(benzoate)s and thin-layer chromatographic separation of (DL)-.Timolo Guangdong Chem. Indus20073495557
     [Google Scholar]
  48. BaevaL.A. BiktashevaL.F. NikitinaT.S. FatykhovA.A. LyapinaN.K. Synthesis of 1,1′-{3-[(alkylsulfanyl)methyl]-tetrahydro-2H-thiopyran-3,5-diyl}diethanones from sodium sulfide and thiols.Chem. Heterocycl. Compd.201248460160510.1007/s10593‑012‑1032‑0
     [Google Scholar]
  49. LiZ.F. LuoF.Y. synthesis and characterization of n-substituted phenyl-n′-[6-(2-chlorobenzothiazol)yl]urea.Chem. Res. Application20011318082
     [Google Scholar]
  50. LiuQ. HouX.M. One-pot three-component synthesis of 3-Methyl-4-Arylmethylene- Isoxazol-5(4H)- ones catalyzed by sodium sulfide.Phosphorus Sulfur Silicon Relat. Elem.2012187444845310.1080/10426507.2011.621003
     [Google Scholar]
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Synthesis and Characterization of 3-S-impurities in Timolol Maleate
Curr. Org. Synth. 22, 614 (2025); https://doi.org/10.2174/0115701794344307241027093947
/content/journals/cos/10.2174/0115701794344307241027093947
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  • Article Type:     Research Article
Keyword(s): 3-S-timolol; clinical safety; new impurity; quality control; Timolol maleate; β-adrenergic receptor blocker

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