Study On The Process Of Long-chain Alkyl Dicarboxylic Acid Derivatives Of Peptide Drugs

Objective To synthesize intermediate 16-（Tert-butoxy）-16-oxohexadecanoic acid of long-acting insulin degludec side chain and intermediate 18-（Tert-butoxy）-18-oxooctadecanoic acid of glucagon-like peptide-1（GLP-1）analogue semaglutide side chain.The process optimization and scale-up were carried out.A stable,feasible and environmentally friendly synthetic route has been studied.Methods 1.The synthesis of 16-（Tert-butoxy）-16-oxohexadecanoic acid:16-（Tert-butoxy）-16-oxohexadecanoic acid was obtained by condensation,reduction,hydrolysis,and esterification.The synthesis of 18-（Tert-butoxy）-18-oxooctadecanoic acid:Firstly,Hexadecanedioic acid was obtained by condensation,reduction and hydrolysis,18-（Tert-butoxy）-18-oxooctadecanoic acid was finally obtained through condensation,reduction,hydrolysis and esterification of Hexadecanedioic acid.2.Process optimization:In the condensation reaction,the feeding ratio of the Meldrum’s acid,DIC and DMAP,feeding temperature,reaction time,reaction solvent,and the purification solvent were optimized.In the reduction reaction,the feeding ratio of Na BH₄ and acetic acid,reaction temperature,reaction time,reaction solvent,and the purification solvent were optimized.In the hydrolysis reaction,the concentration of hydrochloric acid was optimized.In the esterification reaction,the feeding ratio of oxalyl chloride,feeding temperature,reaction time,and the reaction solvent were optimized.3.Scale-up experiments:The preparation of 16-（Tert-butoxy）-16-oxohexadecanoic acid was 100 times（500 g）scaled up.The preparation of 18-（Tert-butoxy）-18-oxooctadecanoic acid was 100 times（2 kg）scaled up.Results After process optimization,the final yield of 16-（Tert-butoxy）-16-oxohexadecanoic acid was increased from 7.99%to 41.66%.The final yield of 18-（Tert-butoxy）-18-oxooctadecanoic acid was increased from 1.04%to 8.81%.The structure was characterized correctly by NMR and MS.The purity of the product was more than 95%detected by HPLC,and the content of single impurity was less than 0.5%.Conclusion After process optimization,the yield is significantly improved,the synthesis cost is reduced,and the process is more operable.The scale-up experiment results showed that the process is stable and feasible,green and environment friendly,and suitable for scale-up production.