Synthesis And Characterization Of(S)-Timolol Hemihydrate

(S)-Timolol is the most potentβ-receptor blocker.Its action strength is 8 times that of propranolol.It is mainly used for the treatment of hypertension,angina pectoris,glaucoma and hemangioma.In this paper,the synthesis and quality control of（S）-Timolol hemihydrate were studied in detail,using 3-morpholine-4-chloro-1,2,5-thiadia-zole as the starting material,S-timolol hemihydrate is synthesized in four steps:hydrolysis reaction,etherification substitution reaction,amination salt formation reaction,and free crystal transformation.The products were characterized by IR,¹H-NMR,¹³C-NMR,MS,TGA,DSC,XRD.Strive to obtain the best synthesis process of（S）-Timolol hemihydrate to provide more scientific basis for the development ofβ-blocker drugs,the process parameters of each step were optimized.The main conclusions are as follows:（1）3-Morpholine-4-chloro-1,2,5-thiadiazole is used as the starting material,start up hydrolysis reaction under the condition of 8%sodium hydroxide aqueous solution as alkali and the ratio of the amount of sodium hydroxide to the amount of the starting material is 4.After reacting at reflux for 3 hours,post-processing of acidification with hydrochloric acid,intermediate 1（3-morpholine-4-hydroxy-1,2,5-thiadiazole）is obtained.Intermediate 1 undergoes a etherification reaction with R-epoxychloropropane under the condition of triethylamine as an acid binding agent.The molar ratio of the two is 1:8.After the reaction,it is treated with sodium hydroxide and 6 times the volume-to-mass ratio of ethanol recrystallize to obtain intermediate 2（（R）-4-（4-（ethylene oxide-2-ylme-thoxy）-1,2,5-thiadiazol-3-yl）morpholine）.Intermediate 2 and a 4-fold molar ratio of tert-butylamine undergo an amination reaction to obtain an S-timolol oil.S-timolol oil is salted with maleic acid under the condition of ethanol as a solvent and recrystallized from 10 times volumetric mass ratio of ethanol to obtain S-timolol maleate.S-Timolol maleate is freed under the condition of sodium hydroxide and then crystallized with purified water at 5 times the volume to obtain（S）-Timolol hemihydrate solids whose content and related substances are in compliance with Pharmacopoeial standards and the e.e.value is greater than 99.0%.The total process yield is 14.05%,compared with the traditional asymmetric synthesis process,the reagents used in this process are bulk,cheap reagents,and the process is safe and stable,simple in operation,and high in yield.It is suitable for industrial production.（2）The quality purity of intermediate 1 is controlled to be not less than 99.0%（where the content of impurity F is not greater than 0.1%）;that of intermediate 2 is controlled to be not less than 90.0%（where the content of impurity D is not greater than0.1%,and that of impurity K is not greater than 5.0%）;the quality purity of intermediate3 is also controlled to be not less than 99.5%（where the content of impurities C,E,I and the largest single impurity are not more than 0.1%）,the content of isomer is not more than 5.0%.Therefore,through the quality control of intermediates,the quality of the finished product obtained by this process is not less than 99.6%（impurities C,E,I and the maximum single impurity content are not more than 0.1%）,the isomer impurity content is not greater than 1.0%.