echemi logo
Product
  • Product
  • Supplier
  • Inquiry
    Home > Medical News > Medical World News > List of synthetic routes of the second generation ALK inhibitor Alectinib

    List of synthetic routes of the second generation ALK inhibitor Alectinib

    • Last Update: 2021-05-03
    • Source: Internet
    • Author: User
    Search more information of high quality chemicals, good prices and reliable suppliers, visit www.echemi.com

    Introduction to Alectinib

    Introduction to Alectinib Introduction to Alectinib

    Alectinib is an oral ALK inhibitor developed by Chugai, a Japanese company controlled by Roche.
    The molecular structure of Alectinib contains a unique skeleton structure of a benzocarbazole derivative, which can completely bind to the ALK kinase domain, thereby showing a higher selectivity and inhibitory effect on ALK.

    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.
    In recent years, with the continuous deepening of clinical research, Alectinib was approved in November 2017 for the first-line treatment of advanced ALK-mutated non-small cell lung cancer.
    In China, Alectinib was approved by China's CFDA in August 2018 for the first-line treatment of advanced ALK-mutated non-small cell lung cancer.

    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.
    Compared with other ALK inhibitors of the same kind, such as crizotinib, ceritinib, and brigatinib, Alectinib has the longest progression-free survival period and the best therapeutic effect, and has attracted clinical attention.

    At the same time, Alectinib has the characteristics of high efficiency and low toxicity.
    The median PFS can reach 34.
    8 months.
    It is currently the first-line preferred option for ALK+ NSCLC patients and the preferred drug after crizotinib is resistant.
    In terms of adverse reactions, common adverse reactions of Alectinib mainly include constipation, fatigue, edema, etc.
    , mainly grade 1-2 adverse reactions.

    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

    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.
    It starts with 7-methoxy-2-tetralone 1 as the starting compound.
    After 9 linear steps, the free base product of Alectinib is obtained.
    The total yield is about 1.
    %.
    The total yield of this route is too low.
    In the step of Fischer indole reaction between Intermediate 3 and hydrazinobenzene, a pair of regioisomers are obtained due to low regioselectivity.
    The target product is obtained after purification by silica gel column chromatography.
    4.
    The yield is only 25%.
    In addition, Intermediate 8 and TIPS-acetylene undergo Sonigashira reaction, TBAF desilylation reaction generates acetylene intermediate 9, and then acetylene intermediate 9 is hydrogenated and reduced to introduce ethyl groups.
    The three-step yield is 14%, and ethyl groups are introduced.
    The efficiency is too low.

    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.
    Close the Schlenk tube and transfer to an oil bath at 80°C.
    The reaction is stirred until the reactants are completely converted.
    Remove the tube from the oil bath and cool at room temperature.
    Under nitrogen, MeOH and K2CO3 were added, and the reaction was stirred for 2 hours.
    The solution was transferred to an autoclave, and THF and Pd/C 10% were added to the reaction mixture.
    The autoclave was filled with H2 at a pressure of 2.
    5 bar and the reaction was stirred for 8 hours.
    The hydrogen was released from the reactor, and the reaction mixture was filtered onto a pad of diatomaceous earth and transferred to a flask.
    After working up, the solid was recrystallized from hot MeOH to obtain a pure product with a yield of 69%.

    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.
    The yields of the two steps are both greater than 90%.
    After intermediate 12 is obtained, the indole heterocyclic intermediate 16 is constructed through four steps of iodine substitution, carbon chain extension, nucleophilic substitution, nitro reduction and ring closure.

    Then, the piperidinyl side chain was connected to 16 through Pd-catalyzed CN cross-coupling to obtain intermediate 17.
    Using trifluoroethanol as a solvent, TMSCl deprotection to obtain the carboxylic acid intermediate 18.
    Finally, the target product alectinib is obtained by ring closure of the intramolecular Friedel-Crafts reaction mediated by acetic anhydride.

    According to the patent report, the maximum feed rate per batch of this route can reach 1.
    4Kg, the total yield of the route is 38%, and the average yield per step is 89%.

    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.
    In this synthetic route, nitrophenyl compound 19 was used as the starting material, and the indole heterocycle 20 was constructed by Leimgruber-Batcho reaction.
    Then the ester group intermediate 21 is obtained through an acylation reaction.

    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.
    Then under the action of the methyl Grignard reagent, the hydroxyl compound 24 is generated.
    Finally, intermediate 24 and indole intermediate 21 undergo an acid-catalyzed Friedel-Crafts reaction to produce intermediate 18.

    This route requires microwave catalyzed reaction, which is difficult to realize in industrial production.
    The starting material 22 is relatively expensive and difficult to obtain from commercial channels, which limits the application value of this route.

    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

    references

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

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

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

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

    3.
    EP 3556754 A1

    3.
    EP 3556754 A1

    4.
    US 9126931 B2

    4.
    US 9126931 B2

    5.
    WO 2016074532

    5.
    WO 2016074532

    6.
    CN 106518842 A

    6.
    CN 106518842 A
    This article is an English version of an article which is originally in the Chinese language on echemi.com and is provided for information purposes only. This website makes no representation or warranty of any kind, either expressed or implied, as to the accuracy, completeness ownership or reliability of the article or any translations thereof. If you have any concerns or complaints relating to the article, please send an email, providing a detailed description of the concern or complaint, to service@echemi.com. A staff member will contact you within 5 working days. Once verified, infringing content will be removed immediately.
    Related Articles

    Contact Us

    The source of this page with content of products and services is from Internet, which doesn't represent Echemi's opinion. If you have any queries, please write to service@echemi.com. It will be replied within 5 days.

    Moreover, if you find any instances of plagiarism from the page, please send email to service@echemi.com with relevant evidence.