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    Home > Active Ingredient News > Drugs Articles > Development of an efficient preparation process for the key intermediate of the hypertension drug Telmisartan

    Development of an efficient preparation process for the key intermediate of the hypertension drug Telmisartan

    • Last Update: 2021-07-14
    • Source: Internet
    • Author: User
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           Telmisartan (Telmisartan) is a highly selective angiotensin II receptor (AT1 type) antagonist, originally approved by the FDA in 1998 for the treatment of hypertension
    The drug can replace the angiotensin II receptor, and bind to the AT1 receptor subtype (known angiotensin II action site) with high affinity, without any agonist effect at the AT1 receptor site, and binds The effect is lasting

    Existing studies have confirmed that Telmisartan can regulate the cardiovascular system and reduce organ damage caused by high blood pressure

    telmisartan efficiency, low toxicity and only taken once daily benefits, telmisartan has been a high blood pressure medication sales charts in the "leader"
    In order to meet the ever-increasing market demand, researchers have not stopped the development of an efficient synthesis process for telmisartan


           Figure 1 Structural formula of Telmisartan

           According to the analysis of the structure of Telmisartan and previous synthetic routes, compound 1 is the key intermediate for its synthesis
    Therefore, in this study, the researchers systematically explored the efficient synthesis process of key intermediate 1


           Figure 2 Telmisartan (Telmisartan) and its key intermediate 1

           The synthetic route of the key intermediate 1 in the initial synthesis process is shown in Figure 3
    The process uses methyl 4-amino-3-methylbenzoate as the initial raw material, condensed with butyryl chloride and then undergoes nitration to obtain intermediate 4; intermediate 4 undergoes catalytic hydrogenation reaction to reduce the nitro group under Pd catalysis, and then Cyclization in acetic acid conditions to form an imidazole ring to obtain intermediate 5; after intermediate 5 is hydrolyzed under NaOH alkaline conditions, it is condensed with N-methyl-1,2-phenylenediamine 6 under PPA conditions to obtain key intermediate 1

    Although this route can successfully construct a key intermediate 1, it has many problems such as expensive initial raw materials, expensive intermediate reagents, dangerous operation, and environmental hazards to solvents such as PPA

    Therefore, the researchers developed its new synthesis process


           Figure 3 Synthesis of key intermediate 1 in the initial process

           Therefore, researchers have developed a new synthesis process for key intermediate 1

           Figure 4 Efficient synthesis process of key intermediate 1

           The efficient synthesis process of key intermediate 1 is shown in Figure 4
    This process uses o-methylaniline 7 as a raw material, firstly reacts with tert-butyl acid chloride to obtain intermediate 8c; Duff reacts 8c with hexamethylenetetramine to obtain intermediate 9c; and then reacts with N-methyl-1,2- Phenylenediamine 6 is condensed to obtain compound 10; the tert-butyryl group in compound 10 is removed under basic conditions to obtain intermediate 11; the pinner reaction between intermediate 11 and n-butyronitrile under aluminum trichloride conditions obtains intermediate 12; Finally, the intermediate 12 undergoes a cyclization reaction under calcium hypochlorite and alkaline conditions to obtain the target key intermediate 1


           In the exploration of the efficient synthesis process of key intermediate 1, the researchers carried out a systematic step-by-step optimization, mainly including:

    Duff reaction optimization

           By optimizing the equivalent of hexamethylenetetramine in Duff reaction, the equivalent of trifluoroacetic acid, and the reaction temperature, it is found that using 2 eqv of hexamethylenetetramine and 15 eqv of trifluoroacetic acid, it can reach 82% at 115°C.
    The yield of the target intermediate 9c was obtained


    Optimization of Intermediate 10 Cyclization Reaction

           By optimizing the equivalent of raw material 6, the equivalent of sodium bisulfite, and the reaction time for the condensation reaction of compounds 9c and 6, it was found that at 1.
    2 eqv of compound 6 and 1.
    5 eqv of sodium bisulfite, the reaction time for 3 hours can be 85% The yield was 10 cyclized products


    Optimization of calcium hypochlorite oxidation reaction

           By optimizing the oxidation reaction of calcium hypochlorite, it was found that the key intermediate 1 can be obtained with a yield of 82% under the conditions of 3 equivalents of NaOH, 1.
    0 equivalent of calcium hypochlorite, and 15-20°C for 2 hours


           In general, the new synthesis process can obtain key intermediates with a purity of up to 99.
    91% with a total yield of 51.

    The process has cheap raw materials, simple operation, economic, environmentally friendly and many other advantages.
    It is a process route suitable for industrialized large-scale production and
    provides a stronger guarantee for the market demand of

           Reference materials:


    Highly Efficient and Practical Synthesis of the Key Intermediate of Telmisartan, 2021.

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