3.4.1 Medicinal Chemistry Route to Vericiguat
The first vericiguat synthesis stemed from a time when rapid and flexible access to many derivatives was key in the project. For this purpose we employed the pyrazolo[3,4‐b]pyridine‐3‐iodide 21 and coupled with 2‐chloro‐5‐nitropyrimidine‐4,6‐diamine, 34, by means of a modified‐Stille coupling using excess amounts of hexabutylditin and 32 mol% of palladium catalyst. Although yielding the desired product 23 in low yields and moderate purity, it was very clear already at that time that this route will not be suitable for scale‐up campaigns for obvious reasons. Nevertheless, after reduction of the respective nitro group to the amine 24, a chemoselective acylation could be performed leading to 2 in overall good yield for the last two steps (Scheme 3.1).
Table 3.5 In vivo pharmacokinetic properties of 17, 20, vericiguat 2 in comparison with riociguat 1.
| Compound | Species | V ss (l/kg) | CLb (l/h/kg) | t 1/2 (h) | Bioavailability (%) |
|---|---|---|---|---|---|
| 17 | Rat | 0.5 | 0.3 | 1.5 | 26 |
| Dog | 1.0 | 0.2 | 4.1 | 56 | |
| 20 | Rat | 0.3 | 0.9 | 0.5 | 37 |
| Dog | 2.0 | 0.9 (Clp)a | 1.8 | n.d.b | |
| 2 | Rat | 1.0 | 0.3 | 3.4 | 65 |
| Dog | 1.4 | 0.2 | 6.2 | 75 | |
| 1 | Rat | 1.2 | 1.3 | 1.4 | 46 |
| Dog | 0.7 | 0.3 (Clp)a | 2.4 | 79 |
a Clp, plasma clearance.
b n.d., not determined.
Scheme 3.1 Early days synthesis of vericiguat 2.
In the further course of the project, we decided to abandon the Stille coupling, which appeared rather unpredictable in terms of yields depending on the scale and thought of a more sustainable and scalable synthetic route with more reliable yields. Thus, the iodide 21 was treated with copper(I) cyanide at 150 °C in DMF to yield the cyano derivative 25. In order to facilitate the formation of the pyrimidine, the cyano functional group was converted into an amidine using standard methodology. Based on experience from the former riociguat project it was planned to transform the amidine 26 to the trisamino pyrimidine derivative 24 using a reaction sequence highlighting a rarely used malonodinitrile derivative 27 for condensation with the amidine 26 and subsequent reduction to the desired trisamino derivative 24. We were pleased to find that this sequence worked nicely also for the novel fluoro core and it proved to be a more efficient route from iodide 21 in our hands (Scheme 3.2).
The synthesis leading to iodide 21 started with a chemoselective dehalogenation of 2,6‐dichloro‐5‐fluoro‐3‐cyanopyridine 29 which can be achieved by the transformations shown in Scheme 3.3. The 5‐fluoro‐1H‐pyrazolo[3,4‐b]pyridine 33 was constructed by reaction of 32 with hydrazine. The amino group was then modified to the corresponding iodide 34 by standard diazotization and subsequent treatment with sodium iodide. Alkylation with 2‐fluorobenzylbromide mediated by cesium carbonate in DMF finally yielded iodide intermediate 21.
3.4.2 Development Chemistry Route to Vericiguat
While the synthesis route to vericiguat described in Section 3.4.1 was straightforward and high yielding, it nevertheless did not fulfill all criteria for an efficient process development synthesis. After significant experimentation and route scouting, our chemical development team finally established a very short, high yielding and more economic synthesis toward the cyano derivative 25 (Scheme 3.4). The key step in this route is the condensation reaction of acrylaldehyde derivative 35 with ethyl 5‐amino‐1‐(2‐fluorobenzyl)‐1H‐pyrazole‐3‐carboxylate [28]36 in ethanol yielding ethyl ester intermediate 37. This ester was then converted in two steps to the nitrile 25.
Scheme 3.2 High yielding route to trisamine 24.
Scheme 3.3 Scale‐up synthesis of iodide 21.
Scheme 3.4 Development route to key intermediate 25.
