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Another principal area of business conducted at Topharman is the 1kg to 100 kg scale Custom Manufacturing field.
The scale-up operation requires qualified process chemists who are experienced in industrial circumstances, with a high degree of knowledge about reactions and reactors. They also need to be alert and smart enough to avoid any potential risks during the production process while meeting the customer's deadlines.
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In most cases, such scale-up has been produced in Topharman's pilot plants, although it has sometimes been undertaken in partner's sites.
Following is an example of kg scale preparation of telmisartan, which has no patent protection in China. From 3-methyl-4-nitro-benzoic acid (I), after 7 steps, 4-methyl-2-propyl-1H-benzimidazole-6-carboxylic acid (II) was obtained in yield of 50%, the cyclization of II with N-methyl-1,2-Benzenediamine dihydrochloridein polyphosphoric acid got the bi-benzimidazole derivative, 2-propyl-4-methyl-6-(1'-methylbenzimidazole-2'-yl)-1H-benzimidazole (III). With no further purification, III was linked by the methyl ester of 4'-(bromomethyl)-biphenyl-2-carboxylic acid, and then hydrolyzed to get the final product of crude API, telmisartan, in a yield of 74% (98% HPLC purity). The whole process of the first batch of 2.5 kg was completed in 75 days.
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