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    Home > Active Ingredient News > Drugs Articles > Development of Merck's new ROMK inhibitor MK-7145 kilogram-level synthesis process

    Development of Merck's new ROMK inhibitor MK-7145 kilogram-level synthesis process

    • Last Update: 2021-07-17
    • Source: Internet
    • Author: User
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           ROMK (Renal Outer Medullary Potassium Channel, Renal Outer Medullary Potassium Channel) is mainly expressed in the thick ascending branches and collecting ducts of the renal cortex and medulla.
    It is an important channel protein for the kidney to regulate the body's ion homeostasis

    .
    Among them, the
    ROMK of ascending thick epithelial cells mainly drives K+ circulation across the apical membrane and basement membrane, maintains the negative potential of tubule cells, and can promote Na+-K+-2Cl- cotransporter (NKCC2) and Na+ by adjusting the K+ concentration in the tubules The NaCl reabsorption of -K+-ATPase plays a key role in the concentration of urine
    .
    The ROMK expressed on the luminal membrane of the main cells of the collecting duct is the main way for the kidney to secrete K+ and is closely related to the maintenance of the body's potassium balance

    .
    Existing research shows that ROMK is a potential therapeutic target for hypertension and heart failure, and many researchers are working on drug development for this target

    .

           Figure 1 Structural formula of ROMK inhibitor MK-7145

           MK-7145 is a new type of ROMK inhibitor developed by Merck.
    A number of clinical studies have been carried out for hypertension and heart failure (Figure 2)

    .

           Figure 2 Clinical research status of MK-7145

           In order to meet the needs of clinical research and future clinical medications, researchers have been committed to the development of large-scale preparation process of MK-7145
    .

           Figure 3 MK-7145 reverse synthesis analysis

           The reverse synthesis analysis of the new process of MK-7145 is shown in Figure 3.
    The reverse synthesis analysis is mainly based on the pre-existing medicinal process route, in which intermediate 4 is a key intermediate in the medicinal chemical synthesis process

    .
    Reverse synthesis analysis indicated that intermediate 4 could be obtained from bromoketone 3 through enzymatic reduction-cyclization, while further analysis showed that the relatively cheap raw material 5 (80 USD/kg) could be converted to intermediate 3

    .

           Figure 4 Synthesis of Intermediate 7

           According to the reverse synthesis analysis, the researchers first used compound 5 as a raw material to explore the synthesis of intermediate 7
    .
    As shown in Figure 4, the carboxyl group of raw material 5 is reduced under sodium borohydride conditions to obtain Intermediate 6, and Intermediate 7 can be obtained after Intermediate 6 is brominated by NBS

    .
    In the bromination step, abnormally substituted brominated impurities 8, dibromo impurities 9 and trifluoroacetic acid esterification impurities 10 are generated

    .
    After optimization, the researchers found that lowering the temperature to -45°C can greatly reduce the production of by-products, and finally intermediate 7 was obtained with a yield of 84%

    .

           Figure 5 Synthesis of Intermediate 12

           Next, the researchers used the obtained Intermediate 7 as a raw material to explore the synthesis of Intermediate 12
    .
    As shown in Figure 5, the researchers used Intermediate 7 as a raw material to obtain Intermediate 12 through cyano substitution and hydrolysis and ring closure, but the yield was only 62% (Figure 5a)

    .
    For this reason, the research has further developed the Pd-catalyzed carbonylation reaction.
    Through a one-step reaction, intermediate 12 can be obtained with a yield of 80% (Figure 5b)

    .

           Figure 6 Synthesis of key intermediate 4

           After successfully preparing Intermediate 12, the researchers used it as a raw material to obtain Intermediate 3 through Tf hydroxyl protection, Pd-catalyzed Heck reaction and NBS bromination reaction
    .
    Intermediate 3 is KRED MIF-20, a mild carbonyl reductase that has been commercialized.
    Through screening, researchers found that intermediate 3 can reduce the carbonyl group in KRED MIF-20 and undergo cyclization to obtain chiral cyclic ether 4.
    The yield is 82%, and the ee value can be as high as 99.
    85% after recrystallization

    .

           Figure 7 Synthesis of MK-7145

           Finally, the researchers used 4 as the reaction precursor and reacted with piperazine to obtain the target product MK-7145 with a yield of 75%
    .
    This step will produce by-products 12 of the off-normal cyclic ether and mono-substituted products 15

    .
    Based on the initial raw material 5, the total yield of the process route is 25%

    .
    Through this route, researchers have successfully achieved the 50 kg scale synthesis of MK-7145, which provides a strong guarantee for the clinical research and future clinical needs of MK-7145, and also provides a model for the development of
    synthetic processes for drugs with similar structures
    .

           Reference materials:

           1.
    https://go.
    drugbank.
    com/drugs/DB11968;

           2.
    https://clinicaltrials.
    gov/ct2/results?recrs=&cond=&term=+MK-7145&cntry=&state=&city=&dist=;

           3.
    Bio- and Chemocatalysis for the Synthesis of Late Stage SAR Enabling Intermediates for ROMK Inhibitors and MK-7145 for the Treatment of Hypertension and Heart Failure, 2021.
           

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