Study On The Quility Control Of Mirabegron And Synthesis Of Dexmethylphenidate Hydrochloride

Mirabegron was the first beta-3 adrenergic receptor agonist,developed by Astellas Pharma Inc and approved by US FDA in June 2012 as a treatment of Overactive bladder(OAB).Dexmethylphenidate Hydrochloride was developed by Celgene and approved by US FDA in January 2002 as a central stimulant to treat Attention-deficit hyperactivity disorder(ADHD).Dexmethylphenidate Hydrochloride was the d-threo diastereomer of methylphenidate hydrochloride,which was already approved by US FDA.Part 1: Study of the quality control of MirabegronOn the basis of previous work of synthesis of Mirabegron,Mirabegron(1)was synthesized in four steps from D-mandelic acid(24)and 4-nitrophenylethanamine hydrochloride(4)via amide condensation,borane reduction,Ammonium formate catalytic transfer hydrogenation and condensation with 2-aminothiazol-4-acetic acid(8).(1)Cause of requirement of the Cooperation manufacturer,we successfully apply ammonium formate catalytic transfer hydrogenation to reduce 5 instead of hydrogen with Pd/C catalyst by experiment reaching;(2)We have completed the synthesis and characterization of 10 impurities after studied on the quality control of Mirabegron.Follow our optimized process,Mirabegron was achieved at an overall yield of 42.3%(based on 4)with the HPLC purity above 99.9%,single impurity below 0.1%,ee above 99.9%,stable process,and every step of the process was verified at kg scale.Part 2: Synthesis of Dexmethylphenidate HydrochlorideIn this paper,Dexmethylphenidate hydrochloride was synthesized from methylphenylglyoxylate(41)via nucleophilic substitutionaddition reaction,cyclization reaction,alcoholysis reaction to give 7-phenyl-1-azabicyclo[4.2.0]octan-8-one(racemate)(47)which was subjected to chiral resolution,salification with HCl(real diagram).(1)The potassium tert-butoxide was chosen as alkali instead of 50% sodium hydroxide aqueous solution in the synthesis of 46,which avoided the use of phase transfer catalyst and increased the fractional conversion of 46;(2)As used herein,thionyl chloride reacted with methanol in situ to produce an anhydrous hydrogen chloride gas in place of using HCl gas In the preparation of 47,avoided the unsafe for using HCl gas and it is easier to operate;(3)Dexmethylphenidate hydrochloride was prepared from 47 via protection,hydrolysis,acidification,resolution,esterification as reported(dotted diagram).A new method was found in preparation of dexmethylphenidate hydrochloride from 47 in two steps by chiral separation,double replacement reaction after optimization.This method has not been reported yet so we applied a patent(Application Number: 201610280758.4);(4)The enantiomers of dexmethylphenidate hydrochloride was prepared so as to analyze its chiral purity.Follow our optimized process,Dexmethylphenidate hydrochloride was achieved at an overall yield of 22.4%(based on 41)with the HPLC purity above 99.9%(real diagram),single impurity below 0.1%,ee above 99.9%.