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

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

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

       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)

       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.

       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

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