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WO2016066116A1 - Procédé de préparation d'aprémilast et ses intermédiaires - Google Patents

Procédé de préparation d'aprémilast et ses intermédiaires Download PDF

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Publication number
WO2016066116A1
WO2016066116A1 PCT/CN2015/093149 CN2015093149W WO2016066116A1 WO 2016066116 A1 WO2016066116 A1 WO 2016066116A1 CN 2015093149 W CN2015093149 W CN 2015093149W WO 2016066116 A1 WO2016066116 A1 WO 2016066116A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
reacting
acid
formula iii
Prior art date
Application number
PCT/CN2015/093149
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English (en)
Chinese (zh)
Inventor
王小龙
李鑫源
李志亚
刘彦龙
张喜全
Original Assignee
南京安源生物医药科技有限公司
连云港润众制药有限公司
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.)
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Application filed by 南京安源生物医药科技有限公司, 连云港润众制药有限公司 filed Critical 南京安源生物医药科技有限公司
Publication of WO2016066116A1 publication Critical patent/WO2016066116A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide

Definitions

  • the present application relates to the field of pharmaceutical and chemical industry, and in particular to a method for synthesizing Apster.
  • Apremilast is a PDE4 inhibitor developed by Celgene and its chemical name is 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-4 -Acetylaminoisoindoline-1,3-dione having a structure as shown in Formula A.
  • Apster was approved by the US FDA on March 25, 2014. It has clinically developed multiple indications for rheumatoid arthritis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and the first approved by the FDA. The indication is adult psoriatic arthritis (PsA). Different from the commonly used anti-TNF monoclonal antibody in clinical practice, Apster is an oral anti-rheumatic drug with a new mechanism of action, which has great market potential.
  • US 2013/0217919 Al discloses a method for synthesizing a Pust, which requires a solution of n-butyllithium n-hexane, which is inconvenient to operate and has a greater risk; in addition, 3-acetylaminophthalic anhydride The yield is lower.
  • the application provides a compound of Formula III,
  • L is a halogen, preferably Cl, Br or I, more preferably Cl or Br.
  • Another aspect of the present application provides a process for the preparation of a compound of formula III, comprising the steps of reacting a compound of formula II with a halogenating reagent to provide a compound of formula III,
  • L is a halogen, preferably Cl, Br or I, more preferably Cl or Br.
  • the halogenating agent is selected from the group consisting of dichlorohydantoin, liquid bromine, N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), or phenyl trimethyl Ammonium tribromide, preferably dichlorohydantoin or phenyltrimethylammonium tribromide.
  • the molar ratio of the compound of Formula II to the halogenating agent is from 1:0.5 to 1:2, preferably from 1:0.75 to 1:1.
  • the compound of formula II is prepared by reacting a compound of formula I with an ethylating agent,
  • the compound of formula I and the ethylating agent are preferably reacted in the presence of an alkaline agent, which may be potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide, preferably potassium carbonate.
  • an alkaline agent which may be potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide, preferably potassium carbonate.
  • the molar ratio of the compound of Formula I to the ethylating agent is from 1:0.5 to 1:2, preferably from 1:1 to 1:1.5.
  • the ethylating agent can be It is selected from a halogenated ethane, preferably 1-chloroethane, 1-bromoethane or 1-iodoethane, and further preferably 1-bromoethane.
  • a further aspect of the application provides the use of a compound of formula III in the preparation of a Plast.
  • the present application provides a method for preparing Apster, comprising the following steps:
  • L is a halogen, preferably Cl, Br or I, more preferably Cl or Br;
  • B is an asymmetric acid selected from the group consisting of L-aspartic acid, L-pyroglutamic acid or N-acetyl-L- bright Amino acid, preferably N-acetyl-L-leucine.
  • the molar ratio of the compound of formula III to methyl sulfinate in step (a) is from 1:0.5 to 1:2, preferably from 1:1.2 to 1:1.5.
  • the methyl sulfinate salt in step (a) is preferably sodium methyl sulfinate.
  • the compound of formula III and the methyl sulfinate salt in step (a) can be reacted in a solvent, which may be selected from the group consisting of methanol, acetonitrile, ethanol, and the like, preferably ethanol.
  • the reductive amination in step (b) may comprise ammonium formate reduced amine Ammonia, hydrogen and ammonia reductive amination or Leuckart reaction, preferably ammonium formate reductive amination.
  • reaction described in step (c) can be carried out in an alcohol solvent, preferably methanol.
  • reaction described in step (d) can be carried out in acetic acid.
  • the compound of formula IX in step (d) is prepared by reacting a compound of formula VII with compound C to form a compound of formula VIII, which is then reacted with acetic anhydride.
  • the compound C is selected from the group consisting of hydrochloric acid, sulfuric acid or hydrobromic acid, preferably concentrated hydrochloric acid, further preferably 37% concentrated hydrochloric acid.
  • the compound of formula III described in step (a) is prepared by the process of the preparation of a compound of formula III as hereinbefore described.
  • the present application also provides a process for the preparation of a compound of formula IX comprising the steps of reacting a compound of formula VII with compound C to form a compound of formula VIII, and reacting the compound of formula VIII with acetic anhydride to provide a compound of formula IX,
  • the compound C is selected from the group consisting of hydrochloric acid, sulfuric acid or hydrobromic acid, preferably concentrated hydrochloric acid, further preferably 37% concentrated hydrochloric acid.
  • the ethanol is anhydrous ethanol unless otherwise specified.
  • h refers to hours.
  • EA means ethyl acetate
  • DMF means N,N-dimethylformamide
  • NBS means N-bromosuccinimide
  • NIS means N-iodosuccinimide
  • 37% hydrochloric acid means that the mass ratio of the hydrogen chloride solute to the hydrochloric acid solution is 37%.
  • dichlorohydantoin refers to 1,3-dichloro-5,5-dimethylhydantoin.
  • the preparation method of the apster provided by the present application can avoid the use of n-butyl lithium n-hexane solution. This not only reduces the production cost, but also facilitates the operation process, and greatly improves the safety in industrial production, and is more suitable for industrial continuous production.
  • the yield of 3-acetylaminophthalic anhydride is increased to 81%, and the yield is high, which is extremely suitable for industrial production of Apster.
  • the reagents used in the examples are all commercially available products.
  • the compound of formula II (50 mmol), DMF (100 mL) and NIS (75 mmol) were added to a 250 mL four-necked flask and stirred at room temperature for 15 h.
  • the reaction system was added to 100 mL of water, and the mixture was combined with EtOAc (50 mL, EtOAc). It was washed with 2 mL of EA, filtered, and the filter cake was dried under vacuum at 40 ° C for 5 h to give 7.7 g of compound of formula III-3 as a white solid.
  • the compound of the formula III-2 (34.6 mmol), ethanol (160 mL) and sodium methylsulfinate (52 mmol) were placed in a 250 mL four-necked flask, and refluxed for 15 h. The solvent was evaporated under reduced pressure. The mixture was shaken, and the mixture was combined with methylene chloride (50 mL ⁇ 3). It was washed with 2 mL of EA, filtered, and the filter cake was dried under vacuum at 40 ° C for 5 h to give 9.1 g of compound of formula IV as a white solid.
  • the compound of the formula VII (0.55 mol) and 37% concentrated hydrochloric acid (500 mL) were added to a 1 L single-necked flask, and the mixture was stirred at 25 ° C for 15 h, and the water was evaporated under reduced pressure, and the mixture was stirred for 10 min with tetrahydrofuran (300 mL).
  • the white solid was obtained in an amount of 120 g, and the Karl Fischer method was used to determine a water content of 0.5%.

Landscapes

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

Abstract

L'invention concerne un procédé de préparation d'aprémilast et ses intermédiaires. L'invention concerne également un intermédiaire d'aprémilast représenté par la formule III, l'aprémilast étant obtenu avec le composé représenté par la formule III par réaction séquentielle avec du sulfinate de méthyle aminé par réduction, salifié avec des acides asymétriques, et par réaction avec un anhydride 3-acétyl amino phtalique . Le procédé de préparation de l'aprémilast de l'invention permet d'éviter d'utiliser une solution de n-butyle lithium n-hexane, ce qui réduit le coût de production, facilite le processus de fonctionnement, améliore la sécurité de la production industrielle, et est plus approprié pour une production industrialisée. Le rendement du procédé de préparation de l'anhydride 3-acétyl amino phtalique de l'invention est augmenté à 81 %, ce qui est un rendement plus élevé et convient parfaitement à la production industrialisée d'aprémilast.
PCT/CN2015/093149 2014-10-29 2015-10-29 Procédé de préparation d'aprémilast et ses intermédiaires WO2016066116A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410591952.5 2014-10-29
CN201410591952.5A CN105622380B (zh) 2014-10-29 2014-10-29 一种阿普斯特的制备方法及其中间体

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WO2016066116A1 true WO2016066116A1 (fr) 2016-05-06

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017033116A1 (fr) 2015-08-26 2017-03-02 Glenmark Pharmaceuticals Limited Procédé de préparation d'aprémilast
WO2017059040A1 (fr) * 2015-09-29 2017-04-06 Pliva Hrvatska D.O.O. Procédés de préparation d'aprémilast, et ses intermédiaires

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106008315A (zh) * 2016-06-16 2016-10-12 珠海联邦制药股份有限公司 一种阿普斯特晶型s及其制备方法
CN118851979A (zh) * 2024-09-25 2024-10-29 潍坊市海欣药业有限公司 一种阿普斯特的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050267196A1 (en) * 2002-03-20 2005-12-01 Muller George W Methods of using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4 acetylaminoisoindoline 1,3-dione
CN102558022A (zh) * 2010-12-22 2012-07-11 康塞特医药品有限公司 取代的异吲哚啉-1,3二酮衍生物
US20130217919A1 (en) * 2012-02-21 2013-08-22 Celgene Corporation Asymmetric synthetic processes for the preparation of aminosulfone compounds
WO2013126360A2 (fr) * 2012-02-21 2013-08-29 Celgene Corporation Procédés pour la préparation de (s)-l-(3-éthoxy-4-méthoxyphényl)-2- méthanesulfonyléthylamine
CN103864670A (zh) * 2014-03-17 2014-06-18 苏州明锐医药科技有限公司 阿普司特的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101462935B (zh) * 2009-01-13 2011-10-05 湖北大学 一种α-溴代苯乙酮类化合物的合成方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050267196A1 (en) * 2002-03-20 2005-12-01 Muller George W Methods of using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4 acetylaminoisoindoline 1,3-dione
CN102558022A (zh) * 2010-12-22 2012-07-11 康塞特医药品有限公司 取代的异吲哚啉-1,3二酮衍生物
US20130217919A1 (en) * 2012-02-21 2013-08-22 Celgene Corporation Asymmetric synthetic processes for the preparation of aminosulfone compounds
WO2013126360A2 (fr) * 2012-02-21 2013-08-29 Celgene Corporation Procédés pour la préparation de (s)-l-(3-éthoxy-4-méthoxyphényl)-2- méthanesulfonyléthylamine
CN103864670A (zh) * 2014-03-17 2014-06-18 苏州明锐医药科技有限公司 阿普司特的制备方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017033116A1 (fr) 2015-08-26 2017-03-02 Glenmark Pharmaceuticals Limited Procédé de préparation d'aprémilast
US10494342B2 (en) 2015-08-26 2019-12-03 Glenmark Life Sciences Limited Process for the preparation of apremilast
EP3341359B1 (fr) * 2015-08-26 2022-03-23 Glenmark Life Sciences Limited Procédé de préparation d'aprémilast
WO2017059040A1 (fr) * 2015-09-29 2017-04-06 Pliva Hrvatska D.O.O. Procédés de préparation d'aprémilast, et ses intermédiaires

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CN105622380B (zh) 2020-06-30
CN105622380A (zh) 2016-06-01

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