Investigation On Synthetic Technique Of Cinacalcetone Hydrochloride

In the context of generic drug consistency evaluation,pharmaceutical companies have carried out comprehensive and meticulous quality research on the drugs with good therapeutic effect and broad market prospects.At the same time,the pharmaceutical companies have made corresponding improvements in the quality requirements of the drug,so that the generic drug is consistent with the original research standard in the clinical treatment and quality standard.Cinacalcet hydrochloride is a new type of medicament,which belongs to the second generation of calcium receptor modulators and is one of the representative drugs for the treat ment of hyperparathyroidism.The preparation is cinacalcet hydrochloride tablets.Mainly for s econdary hyperparathyroidism,the effect is significant,compared with its calcium receptor ag onists have better tolerance and lower adverse reactions.In this paper,malonic acid and 3-(trifluoromethyl)benzaldehyde were used as starting m aterials,and the target compound was prepared by five-step reaction.The preparation process is as follows:In the first step,malonic acid and 3-(trifluoromethyl)benzaldehyde undergo Kn oevenagel condensation reaction under the catalysis of pyridine to produce 3-(3-trifluorometh yl)phenyl-2-propenoic acid;In the second step,3-(3-trifluoromethyl)phenyl-2-propenoic aci d and hydrogen were catalyzed by palladium on carbon to synthesize 3-(3-trifluoromethyl)be nzenepropanoic acid;step 3:N-[(1R)-(1-naphthylethyl)]-3-[3-(trifluoromethyl)]benzenep amide was synthesized by the amidation reaction of 3-(3-trifluoromethyl)benzenepropanoic acid and(R)-1-(1-naphthyl)ethylamine;Step 4;N-[(1R)-(1-naphthylethyl)]-3-[3-(triflu oromethyl)]benzenecarboxamide and sodium borohydride are catalyzed by boron trifluoride complex Reduction reaction to synthesize N-[(1R)-(1-(naphthyl)ethyl)]-3-[3-(trifluorom ethyl)phenyl]-1-propanamine;Finally,N-[(1R)-(1-(naphthyl)ethyl)]-3-[3-(trifluoromet hyl)phenyl]-1-propanamine and concentrated hydrochloric acid were salt-forming to synthes ize the desired product cinacalcet hydrochloride,The total yield is 62.4%.The structures of the compounds were characterized by ESI-MS,1HNMR,13CNMR and IR,and were compared with the standard.In addition,the synthetic process of cinacalcet hydrochloride was optimized in this paper.Through the pilot test three batches of experiments on the small test process to verify,after verification confirmed that the process parameters are within the control range,the indicators are in line with standard requirements.The optimized process was suitable for the demand of the industial production.In the amidation reaction,3-(3-trifluoromethyl)benzenepropanoic acid and acid chloride are first reacted in the original patent and then reacted with(R)-1-(1-naphthyl)ethylamine,but we through increase Reaction temperature,reducing the reaction of acid chloride this step to ensure that the product quality at the same time,improve product yield and reduce environ mental pollution.In addition,in the reduction reaction of N-[(1R)-(1-(naphthyl)ethyl]]-3-[3-(trifluoromethyl)phenyl]-1-propanamine,the present reaction of the stability of the proce ss to increase the refining process,so as to enhance the quality of the product for the consisten cy of the evaluation laid the foundation.