Synthesis Of4-(4-amino-3-bromophenyl) Piperidine-1-carboxylic Acid Tert-butyl Ester

Rheumatoid arthritis is a chronic autoimmune disease, which has the character like arthrosynovitis and symmetry destructive of arthropathy.5-cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[2-(dimethylamino) acetyl]-4-piperidinyl] phenyl]-1H-Imidazole-2-carboxamide, hydrochloride (JNJ-28312141) is a well developed inhibitor of macrophage colony-stimulating factor receptor for the treatment of rheumatoid arthritis in clinical research, but there are several disadvantages in the traditional preparation of the key intermediate:The synthesis process is expensive as it needs a homogeneous noble metal catalyst, which is easy to reside, and can’t be separated from the product easily. Besides, the synthesis process needs Pd/C catalyst to hydrogenation, so the unit product is expensive for small batch preparation. What’s more, the synthetic process requires the use of two raw materials which are not easy to obtain. To sum up, the synthesis process of the intermediate costs much and requires high equipment investment, and it is difficult to operate and not easy for large-scale industrialized production. Therefore, it is necessary to develop an new industrial mass production method for manufacturing this intermediate.Based on the retrosynthesis analysis, this paper developed a new method for the synthesis of4-(4-Amino-3-bromophenyl) piperidine-1-carboxylic acid tert-butyl ester. The main contents are as follows:Using p-nitrobenzaldehyde and ethyl acetoacetate as raw materials through condensation, hydrolysis, and acidification, the3-(4-nitrophenyl)-pentanedioic acid was obtained. The4-(4-nitrophenyl)-2,6-piperidine-dione was synthesized using the3-(4-nitrophenyl)-pentanedioic acid and urea. Through dropping (BOC)2O, the functional group of BOC was introduced into the molecular structure obtaining the BOC-aminopiperidine, to obtain the4-(4-Amino-3-bromophenyl) piperidine-l-carboxylic acid tert-butyl ester by bromination. Finally, the pilot study was carried out to provide basis for its industrial production. This new method has the advantages of mild reaction conditions and low production cost, and without using the noble metal catalyst, thus avoiding the residual of metal. Through the process optimization, only four steps are required for the separation of solid and drying, which shortens the production cycle, and reduces the production cost further.