Clinically duodenal and peptic ulceration are the most common diseases. Control of the gastric pH with antisecretory drugs has proven to be an effective method in the treatment of duodenal and peptic ulcers. Proton pump inhibitors have been proved to be the most effective drugs in curing ulcers. The research advance of various synthetic methods of proton pump inhibitors were reviewed. The research advance for the synthesis of key intermediates 2-mercapto-benzimidazoles,2-mercapto-imidazo[4,5-b]pyridines and 2-chloromethyl pyridine compounds were summarized. The optimum synthetic scheme was discussed.