List of synthetic routes of the second generation ALK inhibitor Alectinib

Introduction to Alectinib

Alectinib is an oral ALK inhibitor developed by Chugai, a Japanese company controlled by Roche.

In December 2015, Alectinib was approved by the US FDA for the treatment of non-small cell lung cancer (NSCLC) patients who were resistant to crizotinib.

Previous research results have shown that Alectinib can not only significantly prolong the progression-free survival of NSCLC patients, but also that in patients with brain transfer, the efficacy of Alectinib after first-line use is also very significant.

At the same time, Alectinib has the characteristics of high efficiency and low toxicity.

In 2020, Alectinib has cut prices across the board and entered the national Class B medical insurance, which has greatly reduced the economic burden of patients.

List of synthetic routes of Alectinib

Bioorganic and Medicinal Chemistry, 2012, 20, 1271-1280

Figure 1 The laboratory discovery route

This route is a laboratory synthetic route in the discovery stage of medicinal chemistry.

EP 3556754 A1

In order to further optimize the introduction of ethyl groups, Fresenius Kabi Company reported a process route for the synthesis of Alectinib from Intermediate 6 through the "one-pot method".

In the dry Schlenk tube, add Intermediate 6, PdCl2 (PPh3), trimethylsilyl acetylene, TEA and DMF in sequence under nitrogen.

The route in the patent can only get about 100mg of product, and it is uncertain whether it is suitable for larger-scale production.

US 9126931 B2

Figure 2 US 9126931 B2 route

Based on the shortcomings of the laboratory route, an improved route was subsequently reported in US 9126931 B2, which optimized the introduction of ethyl groups and the construction of indole heterocycles.

This route uses bromophenylacetic acid compound 10 as the starting material, and uses the Molander variation of Suzuki-Miyaura cross-coupling reaction to couple with vinyl trifluoroboric acid to obtain alkenyl intermediate 11, which is then reduced and hydrogenated to obtain ethyl intermediate 12.

Then, the piperidinyl side chain was connected to 16 through Pd-catalyzed CN cross-coupling to obtain intermediate 17.

According to the patent report, the maximum feed rate per batch of this route can reach 1.

WO 2016074532

Figure 3 Route of WO 2016074532

Patent WO 2016074532 provides another synthetic route for the synthesis method of the key intermediate 18 in the above route.

At the same time, the author took compound 22 as the starting material, and nucleophilic reaction with piperidine heterocycle under microwave conditions to obtain the ketone intermediate 23.

This route requires microwave catalyzed reaction, which is difficult to realize in industrial production.

CN106518842A

Figure 4 CN106518842 Route

Chinese patent CN106518842 takes 6-cyano-1H-indole-3-carboxylic acid ethyl ester 25 as raw material, and undergoes condensation with 4-ethyl-3-hydroxybenzyl alcohol 26 to obtain indole-3-carboxylic acid ethyl ester intermediate 27, Then the ester group is hydrolyzed, acidified to acid, and cyclized under the action of DBU to obtain 28.
Then, it is prepared by trifluoroacetic anhydride protection of the hydroxyl group, methylation of dimethyl carbonate, and 4-(4-piperidinyl)morpholine substitution reaction.
The total yield of Alectinib was 38.
8%.

references

1.
Org.
Process Res.
Dev.
2016, 20, 11, 1855-1869

2.
Bioorganic and Medicinal Chemistry, 2012, 20, 1271-1280

3.
EP 3556754 A1

4.
US 9126931 B2

5.
WO 2016074532

6.
CN 106518842 A