Study On The Synthetic Process Of Menbutone And Research On Some Substances Related To Menbutone

Menbutone is a veterinary choleretic agent,mainly used to treat digestive dysfunction caused by indigestion,anorexia,constipation,toxemia,liver and pancreatic insufficiency in animals such as pigs,cattle,and sheep.Menbutone stimulates the large secretion of digestive juice by stimulating the gastrointestinal tract,thereby increasing the secretion of bile salts in bile,trypsin in pancreatic juice,pancreatic lipase,pancreatic amylase,pepsin in gastric juice,etc.Digestion and absorption of food in the stomach and intestines,thereby improving the digestive function of sick animals.Because of its mild action,it has no obvious effect on the uterine smooth muscle of female animals.Therefore,the drug can be used in pregnant animals for digestive disorders and other diseases.Menbutone was first developed by Boehringer Ingelheim（Germany）,and was approved by the European Commission for Veterinary Medicinal Products（CVMP）as a choleretic drug for animals in 1996.Subsequently,the drug was approved for marketing in many countries and regions such as the European Union,Japan,South Korea,and Thailand.In recent decades,because the original research company has adopted extremely strict blockade measures on key technologies such as menbutone synthesis methods,process parameters and quality standards,and implemented technical barriers and market monopolies,domestic research reports on the synthesis of menbutone and its related substances have been very few,and no related products are on the market.Existing synthetic patents for menbutone（partially unauthorized or expired）not only have low yields（the yield of intermediate 1-naphthyl ether is only60%to 70%,but the yield of menbutone is only about 70%）,and the reaction of menbutone is very harmful to operators and the environment due to the use of a class of solvents and long time.Aiming at having better introduction,production and clinical value and potential Commercial prospects by improving the yield of menbutone,shortening the reaction time,reducing the harm of the synthesis process to operators and environmental pollution,controlling the quality of menbutone,therefore,we carrying out research on the synthesis of menbutone and related substances.This article focuses on exploratory research on the synthesis optimization of menbutone and some related substances,and aims to provide some laboratory research data for the laboratory team’s application for registration of menbutone in China.The main research contents are as follows:The first part is the synthesis optimization of menbutone.Based on the previous menbutone synthesis test by the laboratory team,the author optimized and established a menbutone synthesis route with higher product yield,shorter reaction time,mild reaction conditions,and solvents used in the reaction,which have less harm to the operator and the environment.The first methylation reaction:BBAN-2（technical confidentiality）as catalyst,ethyl acetate as extraction solvent,1-naphthol as starting material,dimethyl carbonate as methylation reagent,and 1-naphthalene The molar ratio of phenol to dimethyl carbonate was 1:1.1,and the reaction was performed at55°C.The reaction was shortened from 8-24 hours to 2 hours as described in the literature.The recovery rate is increased from 60%-70%to more than 95%,which solves the practical problems of low product yield and long reaction time during the synthesis of 1-Methoxynaphthalene.The second step of the Friedel-Crafts reaction is to replace a type of solvent（benzene or dichloroethane）used in the existing literature as a reaction solvent with a less toxic type II solvent（dichloromethane）,and preferably has a higher catalytic activity.Catalyst—anhydrous Fe Cl₃,with succinic anhydride as the acylating agent,the molar ratio of the reactant succinic anhydride to the catalyst（anhydrous Fe Cl₃）is 1:2.5,the reaction temperature is 40°C,and the reaction time is about 3 h The yield of menbutone was increased from about 70%to85%～90%introduced in the literature,and the content was greater than 98.0%,which was more environmentally friendly and has a higher yield than the methods reported in the literature.The second part is the structural confirmation of menbutone.This article uses elemental analysis（EA）,Ultraviolet-visible spectroscopy（UV-Vis）,infrared spectroscopy（IR）,nuclear magnetic resonance spectroscopy（NMR）for the synthesized menbutone Mass spectrometry（MS）,X-ray powder diffraction（XRPD）,Single Crystal X-ray Diffraction（SC-XRD）,Differential scanning calorimetry（Differential scanning calorimetry,DSC）and Thermogravimetric Analysis（TG）confirmed the structure.As a result,the menbutone drug substance was a white crystalline powder.The molecular weight of the compound was 258.27 by elemental analysis and mass spectrometry.The single crystal and powder X-ray diffraction showed that the compound was a crystalline drug.According to the ultraviolet spectrum,infrared spectrum,nuclear magnetic resonance spectrum and carbon spectrum it was confirmed that the compound was in accordance with the structure of mebubutanone reported in the literature.The endothermic peak of the differential thermal analysis curve was 176.8°C,and the onset temperature of the thermal weight loss curve was 150.0°C.Based on the above series of data and structural analysis,combined with the information provided by the menbutone synthesis process,it is confirmed that the compound synthesized in this paper is completely consistent with the structure of the mebubutone reported in the literature and in the database.The third part is about the substance research of menbutone.Impurities in drugs are divided into residual solvents,inorganic impurities and organic impurities according to their physical and chemical properties.The chemical structure of organic impurities is similar to or related to drugs,so it is called related substances.Based on the previous research of menbutone impurities in the laboratory team,the authors synthesized the starting material（1-naphthol）,intermediate（1-Methoxynaphthalene）and finished product（menbutone）from menbutone.Related substances were analyzed and explored for impurity profile.We established a method for the separation and analysis of certain related substances in menbutone,and verified the method,determined the content of related substances in related samples,initially formulated the limits of related substances,and entered the quality standards for menbutone to control the quality of menbutone.The main methods and results are as follows:（1）Starting materials:After analysis of the synthetic route of 1-naphthol and related literature inquiry,the related substances that may be introduced or existed are mainly 1-naphthalenesulfonic acid and 2-naphthol.According to the division of labor of this laboratory team,this article only carried out relevant research on1-naphthalenesulfonic acid and 2-naphthol in 1-naphthol related substances.The UV absorption spectrum of the 1-naphthalenesulfonic acid and 2-naphthol in the starting material 1-naphthol（PDA detector）is comprehensively considered.At last 220nm is selected as detection wavelength.Through the selection of mobile phases of different proportions,the final determination of the gradient elution method can effectively separate the known impurities,unknown impurities and 1-naphthol.Methodological verification shows that the method has good specificity and good separation of impurities from the main peak.The detection limits of 1-naphthalenesulfonic acid and2-naphthol are 0.00991μg/ml,0.00610μg/ml,and the limit of quantification are0.0248μg/ml,0.0153μg/ml;1-naphthalenesulfonic acid and 2-naphthol have a good linear relationship in the range of LOQ to 1.0%（R²>0.999）;the average recoveries of1-naphthalenesulfonic acid and 2-naphthol are in the range of 90%to 108%.The RSD meets the requirements,and the method has good accuracy and precision.The validated 1-naphthol-related substance analysis method was used to test the1-naphthol used in the test.As a result,1-naphthalenesulfonic acid was not detected,and the content of 2-naphthol was（0.017±0.0046）%.Other single unknown impurities were not detected.（2）Intermediate:After analysis of the synthetic route of 1-methoxynaphthalene and related literature inquiry,the related substances that may be introduced or exist are mainly 1-methoxy-2-methylnaphthalene and other 4 species.According to the division of labor of the laboratory team,this article only established a separation and analysis method for 1-methoxy-2-methylnaphthalene in 1-methoxynaphthalene related substances and verified its methodology.Considering the ultraviolet absorption spectrum（PDA detector）of the intermediate 1-methoxynaphthalene and the related substance 1-methoxy-2-methylnaphthalene,the detection wavelength of the related substance measurement method（HPLC）of 1-methoxynaphthalene was selected as 225 nm.Through the selection of mobile phases of different proportions,the method of isocratic elution was finally determined to effectively separate and analyze each known impurity,unknown impurity and 1-methoxynaphthalene.Methodological verification showed that the method has good specificity and good separation of impurities from the main peak.The detection limit of1-methoxy-2-methylnaphthalene is 0.00626μg/ml and the limit of quantification is0.0209μg/ml.The LOQ～8.3500μg/ml range has a good linear relationship（R²>0.999）.The average recovery of 1-methoxy-2-methylnaphthalene is 92%～105%.The RSD meets the requirements.The accuracy and precision of this method Degree is good.The validated 1-methoxynaphthalene-related substance analysis method was used to test the synthesized 1-methoxynaphthalene,and the results were as follows:the content of 1-methoxy-2-methylnaphthalene was（0.35±0.020）%,and other single unknown impurities were not detected.（3）Finished product:After analysis of menbutone’s synthetic route and related literature query,There may be introduced or existed 15 kinds of,such as 3-（4-methoxy-1-naphthoyl）propionic acid methyl ester.According to the division of labor of our laboratory team,this article only carried out the relevant research on membone methyl ester.Considering the UV absorption spectrum（PDA detector）of the finished menbutone and the related substance 3-（4-methoxy-1-naphthoyl）propionic acid methyl ester,the detection wavelength of HPLC was selected as 235nm.Through the selection of various proportions of mobile phases,the final method of isocratic elution can effectively separate and analyze each known impurity,unknown impurity and menbutone.Methodological verification shows that the method has good specificity,and the impurities are well separated from the main peak.The detection limit of 3-（4-methoxy-1-naphthoyl）propionic acid methyl ester is0.005μg/ml and the limit of quantification is 0.018μg/ml.3-（4-methoxy-1-naphthoyl）propionic acid methyl ester has a good linear relationship in the range of LOQ～4.0880μg/ml（R²>0.999）;the average of 3-（4-methoxy-1-naphthoyl）propionic acid methyl ester The recovery rate is 92%～105%.The RSD meets the requirements.The accuracy and precision of the method are good.Three batches of menbutone synthesized by the test were tested using a validated menbutone-related substance analysis method.The results showed that the content of 3-（4-methoxy-1-naphthoyl）propionic acid methyl ester was（R±0.023）%（technical confidentiality）,and the others were unknown.No impurities were detected.After researching related substances of menbutone in this article and our laboratory team,it was determined that the content of1-methoxy-2-methylnaphthalene in 1-methoxynaphthalene should not be greater than0.5%.Menbutone’s quality standards require that the content of 3-（4-methoxy-1-naphthoyl）propionic acid methyl ester should not be greater than X%（technical confidentiality）.All of the above research provides some basic data for the quality control of menbutone intermediates and their formulations.