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WO2024017150A1 - Procédé de synthèse de deucravacitinib - Google Patents

Procédé de synthèse de deucravacitinib Download PDF

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Publication number
WO2024017150A1
WO2024017150A1 PCT/CN2023/107369 CN2023107369W WO2024017150A1 WO 2024017150 A1 WO2024017150 A1 WO 2024017150A1 CN 2023107369 W CN2023107369 W CN 2023107369W WO 2024017150 A1 WO2024017150 A1 WO 2024017150A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
reaction
conditions
add
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/107369
Other languages
English (en)
Chinese (zh)
Inventor
李丕旭
王鹏
周鹏
赵星
魏强
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangxi Longlife Bio-Pharmaceutical Co Ltd
SUZHOU PENGXU PHARMATECH Co Ltd
Original Assignee
Jiangxi Longlife Bio-Pharmaceutical Co Ltd
SUZHOU PENGXU PHARMATECH Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN202210843475.1A external-priority patent/CN117447411B/xx
Priority claimed from CN202211378029.4A external-priority patent/CN118027005A/zh
Application filed by Jiangxi Longlife Bio-Pharmaceutical Co Ltd, SUZHOU PENGXU PHARMATECH Co Ltd filed Critical Jiangxi Longlife Bio-Pharmaceutical Co Ltd
Publication of WO2024017150A1 publication Critical patent/WO2024017150A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/02—Compounds containing any of the groups, e.g. carbazates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/58—Derivatives of thiocarboxylic acids, the doubly-bound oxygen atoms being replaced by nitrogen atoms, e.g. imino-thio ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present application relates to the field of drug synthesis, specifically, to a method for synthesizing heterocyclic drug active molecules.
  • RA rheumatoid arthritis
  • PsA psoriatic arthritis
  • JAK inhibitors are one of the effective treatments for such immune system diseases.
  • TYK2 is a member of the JAK family and plays an important role in mediating the signaling of pro-inflammatory cytokines (including IL-12, IL-23 and type I interferon). Its important role in regulating many of the cytokines responsible for inflammatory diseases makes it a popular target for the treatment of inflammatory or autoimmune diseases.
  • Deucravacitinib (code BMS986165) is Bristol-Myers-Squibb’s experimental new drug for the treatment of moderate to severe plaque psoriasis. It uses the new target TYK2 in the treatment of diseases in related fields. It shows better curative effect. It is also being evaluated for the treatment of a wide range of immune-mediated diseases, including psoriasis, psoriatic arthritis, lupus and inflammatory bowel disease.
  • the first-generation synthesis route uses A1 hydrolysis, chlorination, condensation of deuterated methylamine, and then electrophilic substitution and coupling to obtain the target compound BMS986165.
  • the stability of compounds A3 and A4 in the first-generation route is poor.
  • the chlorine atom at the alpha position of the acyl group of A3 and A4 is easily hydrolyzed; the more expensive reagent deuterated methylamine is used first; the overall yield is low. Many factors cause problems in stable production and material costs in this route.
  • the process patent WO2018183649 and related research documents Org. Process Res. Dev. 2022, 26, 1202 ⁇ 1222 report the research process of BMS986165.
  • a stable intermediate compound A12 was developed, and the use of zinc acetate was optimized to promote the electrophilic substitution reaction of the A5 compound A12 compound.
  • Intermediates A13 and A14 exist in the form of zinc salts with high yields.
  • the final step uses the high-cost deuterated methylamine raw material to undergo a condensation reaction to obtain the final product BMS986165; placing the high-cost material in the last reaction is beneficial to reducing the overall cost of the final product.
  • the disadvantage is that in the last step of the reaction from compound A14 to BMS986165, a large amount of condensing agents and other auxiliaries are used, which makes the purification of the final product more difficult.
  • the yield after purification is only 70 ⁇ 79%. From compound A1, The total yield is 48 ⁇ 65%.
  • the WO2009105500 patent of Schering Company reports that in the following synthetic route, the total yield of the three-step reaction is about 40%.
  • Bayer's WO2011045224 patent reports that in the following synthesis route, the total yield of the two-step reaction is about 50%, and it requires a high-temperature reaction above 140°C, which consumes energy and is not conducive to safe production.
  • the purpose of this application is to provide a method for preparing compounds of formula V.
  • the chlorinated reagent is phosphorus oxychloride
  • the deuterated methylamine is deuterated methylamine free base or deuterated methylamine salt
  • the coupling reaction condition is a coupling reaction in which transition metal participates in catalysis.
  • Compound I which can be prepared through reference documents, is a starting material that undergoes chlorination and electrophilic substitution to obtain compound III.
  • Compound V is then prepared through a total of four steps of chemical reactions such as amine transesterification and coupling reaction. The overall yield is about 55%.
  • amine ester exchange needs to occur in an alkaline environment, and the boiling point of methylamine compounds is only -6°C. It is a gas at room temperature, and there is a risk of escaping in the reaction solution. It is generally understood that when methylamine and the corresponding aromatic ester are used to complete amine transesterification, the dosage of methylamine or methylamine hydrochloride is generally greatly excessive. For example, in the following synthesis process reported in Pfizer's process research literature ( Organic Process Research and Development , 2012 , vol. 16, # 11, p. 1805-181), the amount of methylamine used is 5 times the molar amount of another reaction substrate. .
  • the present application provides a method for obtaining compounds of formula VI by reducing compound X-a with cheap metals:
  • R1 is the protective group of hydroxyl group
  • R2 is the protective group of ester group.
  • noble metal catalysts such as palladium/carbon, palladium hydroxide, platinum oxide, etc.
  • R 1 is a phenolic hydroxyl group or a methoxy group
  • R 2 is hydrogen, tert-butoxycarbonyl or a similar protective group that can be removed under acidic conditions.
  • the present application provides a preparation method for synthesizing the compound of formula VI .
  • Compound XI which can be prepared through the reference document, is the starting material and undergoes a total of five steps of chemical reactions including thio, methylation, condensation, cyclization, and reduction to prepare compound VI.
  • the overall yield is about 65 ⁇ 70%.
  • the implementation conditions used in the examples can be further adjusted according to specific requirements. Unspecified implementation conditions are usually the conditions in routine experiments.
  • the aqueous phase of the filtrate is extracted with EA (3* 300 mL), the combined organic phases were washed with 300 ml saturated brine, and concentrated to obtain 6.9 g of compound 2 product, with a yield of 12.4%, and a total yield of 91.3%.
  • compound IV (0.40g, 1.0eq), compound VII (0.23g, 2.5eq), XantPhos (0.115g, 0.18eq), dioxane (5ml) and Cs 2 CO 3 (0.85g, 2.5eq)
  • Column chromatography obtained 0.36g of the product, with a yield of 80.1%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente demande concerne un procédé de synthèse de deucravacitinib. Le procédé comprend : la soumission d'un composé de formule (I) à une chloration et une substitution électrophile avec le composé de formule (VI) pour synthétiser le composé de formule (III) ; puis la réalisation d'une réaction de transestérification d'amine sur le composé de formule (III) et la méthylamine deutérée pour synthétiser le composé de formule (IV) ; et enfin la réalisation d'une réaction de couplage sur le composé de formule (VII) et le composé de formule (IV) pour préparer le composé (V). Le procédé de synthèse d'un intermédiaire de médicament hétérocyclique a un procédé simple, un post-traitement pratique, des matériaux de départ bon marché et facilement disponibles, un intermédiaire isolé stable et une production industrielle facile.
PCT/CN2023/107369 2022-07-18 2023-07-14 Procédé de synthèse de deucravacitinib Ceased WO2024017150A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202210843475.1A CN117447411B (zh) 2022-07-18 一种杂环药物中间体的合成方法
CN202210843475.1 2022-07-18
CN202211378029.4A CN118027005A (zh) 2022-11-04 2022-11-04 一种氘可来昔替尼的合成方法
CN202211378029.4 2022-11-04

Publications (1)

Publication Number Publication Date
WO2024017150A1 true WO2024017150A1 (fr) 2024-01-25

Family

ID=89617115

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/107369 Ceased WO2024017150A1 (fr) 2022-07-18 2023-07-14 Procédé de synthèse de deucravacitinib

Country Status (1)

Country Link
WO (1) WO2024017150A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117447411A (zh) * 2022-07-18 2024-01-26 苏州鹏旭医药科技有限公司 一种杂环药物中间体的合成方法
WO2025131031A1 (fr) * 2023-12-22 2025-06-26 上海奥博生物医药股份有限公司 Inhibiteur de tyk2 et son procédé de préparation
CN117447411B (zh) * 2022-07-18 2025-12-23 苏州鹏旭医药科技有限公司 一种杂环药物中间体的合成方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020019370A1 (en) * 2000-04-14 2002-02-14 Hegde Vidyadhar Babu 1,2,4-triazole based compounds that can be used as insecticides or acaricides and processes
CN102573478A (zh) * 2009-10-12 2012-07-11 拜尔农作物科学股份公司 作为杀虫剂的1-(吡啶-3-基)-吡唑和1-(嘧啶-5-基)-吡唑
CN110475774A (zh) * 2017-03-30 2019-11-19 百时美施贵宝公司 用于制备6-(环丙烷酰氨基)-4-((2-甲氧基-3-(1-甲基-1h-1,2,4-三唑-3-基)苯基)氨基)-n-(甲基-d3)哒嗪-3-甲酰胺的方法
CN113735836A (zh) * 2020-05-28 2021-12-03 江苏先声药业有限公司 哒嗪类化合物及其应用
WO2022100710A1 (fr) * 2020-11-12 2022-05-19 Cullgen (Shanghai) , Inc. Composés de dégradation de la tyrosine kinase 2 (tyk2) et procédés d'utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020019370A1 (en) * 2000-04-14 2002-02-14 Hegde Vidyadhar Babu 1,2,4-triazole based compounds that can be used as insecticides or acaricides and processes
CN102573478A (zh) * 2009-10-12 2012-07-11 拜尔农作物科学股份公司 作为杀虫剂的1-(吡啶-3-基)-吡唑和1-(嘧啶-5-基)-吡唑
CN110475774A (zh) * 2017-03-30 2019-11-19 百时美施贵宝公司 用于制备6-(环丙烷酰氨基)-4-((2-甲氧基-3-(1-甲基-1h-1,2,4-三唑-3-基)苯基)氨基)-n-(甲基-d3)哒嗪-3-甲酰胺的方法
CN113735836A (zh) * 2020-05-28 2021-12-03 江苏先声药业有限公司 哒嗪类化合物及其应用
WO2022100710A1 (fr) * 2020-11-12 2022-05-19 Cullgen (Shanghai) , Inc. Composés de dégradation de la tyrosine kinase 2 (tyk2) et procédés d'utilisation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117447411A (zh) * 2022-07-18 2024-01-26 苏州鹏旭医药科技有限公司 一种杂环药物中间体的合成方法
CN117447411B (zh) * 2022-07-18 2025-12-23 苏州鹏旭医药科技有限公司 一种杂环药物中间体的合成方法
WO2025131031A1 (fr) * 2023-12-22 2025-06-26 上海奥博生物医药股份有限公司 Inhibiteur de tyk2 et son procédé de préparation

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