Landiolol hydrochloride:synthesis and pharmacology

Introduction

β-blockers have been reported to be effective regulators of heart rate and sinus rhythm in postoperative atrial fibrillation and flutter, and for prevention of these conditions following open-heart surgery. Esmolol hydrochloride, the first ultra short-acting adrenergic β1 receptor blocking agent, has been widely used to aid in control of postoperative tachycardia.[1] Landiolol hydrochloride (Figure 1) was developed in Japan.[2] Landiolol , (-)-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl3-[4-[(S)-2-hydroxy-3- (2- morpholinocarbonylamino) ethylamino] propoxy]phenylpropionate, is an ultra-short-acting β-blocher that appears to be more cardioselective and less toxic than esmolol . Landiolol shows high b1 selectivity, with its cardioselectivity (b1/b2-receptor activation) being reported to be 8 times that of esmolol and 375 times that of propranolol.[3] Landiolol hydrochloride is rapidly hydrolyzed to an inactive form by both carboxylesterase in the liver and pseudocholinesterase in the plasma, resulting in an elimination half-life of about 4 min.  Landiolol hydrochloride has already been used in an emergency treatment for supraventricular tachyarrhythmias in perioperative patients in Japan. Dosage of landiolol hydrochloride for the treatment of perioperative supraventricular tachyarrhythmias begins with a loading dose of 0.125 mg/kg/min for 1 min followed by a maintenance infusion of 0.01-0.04 mg/kg/min. In postoperative patients, circulatory hemodynamics  is unstable and there are many individual differences in response to drugs that affect the circulatory system. Therefore, dosage for the treatment of postoperative supraventricular tachyarrhythmia patients begins with a low dose for safety .[1]

Synthesis of Landiolol Hydrochloride

Report 1

With the raw material of 4S-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl -3-(4-hydroxyphenyl)propanoale, a substitution reaction with (S) -m-nitrobenzenesulfonic acid glycidyl ester under the condition of potassium carbonate as a binding agent produced the intermediate 4- [2S) -3-cyclopropyloxy] phenylpropionicacid [4S) -2,2-dimethyl-1,3-dioxcyclopentane-4-yl] methyl ester (1), and then compound 1 undergoed a substitution reaction with N-(2-aminoethyl) -4-morpholine formamide, and the epoxy bond opened to obtain 4- [2S) -2-hydroxy-3-[2- [4-morpholine carbonyl) amino] ethyl] amino] propyl] phenylpropanoic acid [4S) -2,2-dimethyl-1, 3-dioxpentyl-4-yl] methyl ester (2). Finally, it was salted and refined to obtain high-purity Landilol hydrochloride. This process has mild experimental conditions, easy operation, simple processing, low production cost, and is suitable for industrial production.[4]

Report 2

In this study, the synthesis process of landiolol hydrochloride was optimized. The key intermediateI[(4S)-2, 2-dimethyl-1, 3-dioxolane-4-y1] methyl1-3-14-1[(2S) -ethoxyethane-2-y1] methoxy phenylpropionate (B5) was prepared by substitution, esterification and O-alkylation reaction using 3-(4-hydroxyphenyl) propionic acid as the raw material. Intermediate N-(2-aminoethyl) morpholine-4-carboxamide (B10) was synthesized by two-step reaction with morpholine and ethylenediamine using carbonyldimidazole as starting material. Intermediates B5 and B10 were subjected to amination reaction to obtain landiolol. Landiolol hydrochloride was prepared by freeing landiolol into oxalate and then salting with hydrochloric acid. The structure of the target compound was confirmed by ESI-MS and NMR spectra. The total yield was 52. 3% (based on 3-(4-hydroxyphenyl) propionic acid),and the purity was 99. 9% (HPLC).This route has the advantages of easy availability of raw materials, lower production cost, milder reaction conditions, simpler separation and purification of intermediates, and is more suitable for large-scale production.[5]

Pharmacokinetics of landiolol hydrochloride

The main pharmacokinetic parameters of landiolol hydrochloride in healthy Chinese subjects after infusion were as follows: doses of 2 groups (0.125 mg/kg/min + 0.02 mg/kg/min, 0.25 mg/kg/min + 0.04 mg/kg/min); C_max of 400 ± 110 and 731 ± 246 ng/mL; C_21min of 327 ± 109 and 508 ± 141 ng/mL; t_1/2 of 4.7 ± 1.6 and 6.5 ± 1.7 min. No significant differences were found in C_L/F and Tmax between the 2 groups. Significant differences were found in V_d/F and t_1/2 between the 2 groups. C_max , C_21min ,and AUC were proved to be dose-proportional across the studied doses.[1]

Pharmacodynamics of landiolol hydrochloride

For pharmacodynamics of landiolol hydrochloride, significant changes in heart rate were observed after the initiation of administration in the L and groups and dissipated after the completion of administration.The effect of  landiolol hydrochloride is likely to dissipate rapidly according to the blood concentration change, and the drug might be superior for control. The QTc interval was not significantly changed at 21 and 81 min after the initiation of administration. In group L, significant differences in heart rate were observed from 1 min after initiation, and the blood concentrations reached C_max (400±110 ng/mL) at 10.1 min after initiation. In group H, significant differences in heart rate were observed from 2 min after initiation,and the blood concentrations reached C_max (731 ± 246 ng/mL) at 6.2 min after initiation. C_21min for the L and H groups were 327±109 and 508±141 ng/mL, respectively. No significant clinical changes were observed. No adverse events were observed in any subject.[1]

References

[1] Wang M, Zhang Q, Hua W, Zhou W, Huang M, Wang H. Pharmacokinetics, pharmacodynamics, and safety of landiolol hydrochloride in healthy Chinese subjects. Drug Res (Stuttg). 2014;64(3):141-145. doi:10.1055/s-0033-1354368

[2] Landiolol Hydrochloride. Am J Health Syst Pharm. 2025;82(10):508-510. doi:10.1093/ajhp/zxaf018

[3] Ashida A, Ozaki N, Kishi K, et al. Safety and Efficacy of Landiolol Hydrochloride in Children with Tachyarrhythmia of Various Etiologies. Pediatr Cardiol. 2021;42(8):1700-1705. doi:10.1007/s00246-021-02653-7

[4] JI JJ,etal.,Synthesis of Landiolol Hydrochloride[J].Guangzhou Chemical Industry,2024,52(20):45-47.

[5] Wang Y, et al. Study on the synthesis process of landiolol[J].Chinese Journal of Medicinal Chemistry,2025,35(04):264-272.DOI:10.14142/j.cnki.cn21-1313/r.2025.04.003.

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