WO2023185597A1 - Intermédiaire de letermovir et son procédé de préparation - Google Patents

Intermédiaire de letermovir et son procédé de préparation Download PDF

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Publication number
WO2023185597A1
WO2023185597A1 PCT/CN2023/083173 CN2023083173W WO2023185597A1 WO 2023185597 A1 WO2023185597 A1 WO 2023185597A1 CN 2023083173 W CN2023083173 W CN 2023083173W WO 2023185597 A1 WO2023185597 A1 WO 2023185597A1
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WO
WIPO (PCT)
Prior art keywords
acetate
piperazin
methoxyphenyl
fluoro
methoxy
Prior art date
Application number
PCT/CN2023/083173
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English (en)
Chinese (zh)
Inventor
胡猛
祁道冉
张国斌
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上海迪赛诺化学制药有限公司
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Application filed by 上海迪赛诺化学制药有限公司 filed Critical 上海迪赛诺化学制药有限公司
Publication of WO2023185597A1 publication Critical patent/WO2023185597A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms

Definitions

  • the invention belongs to the field of drug synthesis. Specifically, the invention relates to a letermovir intermediate and a preparation method thereof.
  • Letermovir is mainly used to prevent CMV infection in adult patients who are seropositive for cytomegalovirus after allogeneic hematopoietic stem cell transplantation.
  • Route 1, Route 2, and Route 4 all require (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]-succinic acid to resolve ⁇ 8-fluoro-2-[4- (3-Methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4- base ⁇ methyl acetate to obtain (S)- ⁇ 8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-( Trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl ⁇ acetate methyl ester (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy] -succinate, which is subsequently freed and hydrolyzed to give letermovir.
  • the main defect of the above process is: ⁇ 8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl )Phenyl]-3,4-dihydroquinazolin-4-yl ⁇ enantiomers of methyl acetate.
  • the salt obtained after separation is only 98.0% e.e., with a yield of 89%. It needs to be crystallized again to obtain 99.9% e.e. Product, yield 80%, long cycle.
  • the enantiomeric content in raw materials containing chiral centers is a very critical quality indicator, and usually the enantiomeric content needs to be strictly controlled below 0.15%.
  • multiple recrystallization extractions are required. High optical purity will inevitably bring disadvantages such as extended production cycle, increase of three wastes, and low yield.
  • the object of the present invention is to provide a letermovir intermediate with high yield and high optical purity and a preparation method thereof.
  • a first aspect of the invention provides a letermovir intermediate (S)- ⁇ 8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[ 2-Methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl ⁇ acetic acid methyl ester chiral modified salt, the intermediate is (S)- ⁇ 8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3, D-(+)-dibenzoyl tartrate of methyl 4-dihydroquinazolin-4-yl ⁇ acetate,
  • the second aspect of the present invention provides a method for preparing the intermediate described in the first aspect of the present invention.
  • the method includes the steps of: in an inert solvent, ⁇ 8-fluoro-2-[4-(3- Methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl ⁇ acetic acid
  • the methyl ester is crystallized with chiral modified tartaric acid to obtain (S)- ⁇ 8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy Tartrate of methyl-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl ⁇ acetate;
  • the chiral modified tartaric acid is selected from the following group: D-(+)-dibenzoyltartaric acid, D-(+)-di-p-methoxybenzoyltartaric acid.
  • the method further includes post-processing.
  • the post-processing includes: filtration, washing, extraction and drying.
  • the chirally modified tartaric acid is D-(+)-di-p-methoxybenzoyltartaric acid.
  • the inert solvent is selected from the following group: C1-C10 ester solvents, C6-C10 aromatic hydrocarbon solvents, C2-C6 ether solvents, or combinations thereof.
  • the solvent is selected from the following group: ethyl acetate, methyl acetate, isopropyl acetate, acetic acid Tert-butyl ester, butyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, or combinations thereof.
  • the volume (v/v) ratio of fluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl ⁇ acetate to inert solvent is 1:3-10.
  • the ⁇ 8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(tri) is 1:1.0-1.5.
  • the crystallization temperature is 0-80°C, preferably 20-40°C.
  • the crystallization process includes: stirring.
  • the crystallization time is 2-15h, preferably 5-8h.
  • the method further includes: filtering the reaction mixture after the reaction is completed, washing the filter cake with an inert solvent at 0-10°C, then adding MTBE, and adding alkali and water for cleaning.
  • the base is NaHCO 3 , Na 2 HPO 4 , or a combination thereof.
  • MTBE can also be replaced with a solvent selected from the following group: toluene, ethyl acetate, isopropyl acetate, or a combination thereof.
  • a third aspect of the present invention provides a method for preparing letermovir, which method includes:
  • the step (2) includes: dissolving the chiral modified salt in a first inert solvent, and then adding a base, water and a second inert solvent to react; preferably, the The first inert solvent is methyl tert-butyl ether; the second inert solvent is methanol;
  • the reaction After the reaction is completed, add water and a third inert solvent, and separate the aqueous phase; preferably, the third inert solvent is methyl tert-butyl ether;
  • the first inert solvent is selected from the following group: methyl tert-butyl ether, toluene, isopropyl acetate, or a combination thereof; preferably methyl tert-butyl ether.
  • the second inert solvent is selected from the following group: methyl tert-butyl ether, toluene, isopropyl acetate, or a combination thereof; preferably, it is methanol.
  • the third inert solvent is selected from the following group: methanol, ethanol, isopropyl alcohol, or a combination thereof.
  • the base is KOH, NaOH, or a combination thereof.
  • reaction time is 4-12h, preferably 6-8h.
  • the reaction temperature is 20-80°C, preferably 40-60°C.
  • the present invention developed a novel letermovir intermediate and its preparation method for the first time.
  • the method of the present invention has the characteristics of simple operation, high yield and high product purity. On this basis, the present invention was completed.
  • room temperature or "normal temperature” refers to a temperature of 4-40°C, preferably 25 ⁇ 5°C.
  • each substance in the reaction system of each reaction step, can independently participate in the reaction in any suitable ratio, such as 1: (0.1-10), 1: (0.2- 5), 1: (0.5-2), 1: (0.8-1.5) or 1: (1.0-1.2).
  • Letermovir intermediate of the present invention has a structure selected from the following group:
  • the present invention provides a new preparation method of letermovir intermediate, which requires only one crystallization, has a short production cycle, and obtains letermovir intermediate with high e.e. value.
  • the letermovir intermediate of the present invention can be prepared by the following method.
  • the conditions of the method such as reactants, solvents, bases, acids, amounts of compounds used, reaction temperature, reaction time required, etc. are not limited to the following explanations.
  • the preparation method of the letermovir intermediate is as follows:
  • the proportion of reaction materials is not particularly limited, for example, ⁇ 8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy
  • the molar ratio of methyl-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl ⁇ acetate and chiral modified tartaric acid is 1:1.0-1.5; ⁇ 8- Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-di
  • the volume (v/v) ratio of hydroquinazolin-4-yl ⁇ acetate to inert solvent is 1:3-10.
  • the inert solvent, reaction time, reaction crystallization temperature, etc. can be selected according to specific circumstances.
  • the inert solvent is selected from the following group: C1-C10 ester solvents, C6-C10 aromatic hydrocarbon solvents, C2-C6 ether solvents, or combinations thereof; preferably ethyl acetate, methyl acetate, isopropyl acetate, tertiary acetate Butyl ester, butyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, or combinations thereof.
  • the reaction temperature is 0-80°C, preferably 20-40°C; the crystallization time is 2-15h, preferably 5-8h.
  • the advantages of the present invention mainly include:
  • the preparation method of the present invention requires only one crystallization to make the e.e. value of the previous step intermediate of letermovir API reach more than 99.9%, fully ensuring the optical purity of letermovir API.
  • the preparation method of the present invention has a short production cycle and high yield, and is suitable for industrial production.
  • the obtained filter cake was added to MTBE (80 mL), and Na 2 HPO 4 (12.10 g) and water (80 mL) were added. The mixture was stirred at 20-30°C for 1 hour, separated into layers, and the organic layer was washed once with water (40 mL). The organic layer was concentrated to dryness, and the obtained solid was vacuum dried at 50°C for 18 hours. The total amount of solid obtained was 17.48g (99.93%ee, yield 95.0%).
  • the obtained filter cake was added to MTBE (80 mL), and Na 2 HPO 4 (12.10 g) and water (80 mL) were added. The mixture was stirred at 20-30°C for 1 hour, separated into layers, and the organic layer was washed once with water (40 mL). The organic layer was concentrated to dryness, and the obtained solid was vacuum dried at 50°C for 18 hours. The total amount of solid obtained was 17.57g (99.94%ee, yield 95.5%)
  • the single impurity content is required to be less than 0.1%.
  • secondary crystallization is required to increase the ee value of the product to 99.90% (i.e., the single impurity qualifying standard).
  • the method of the present invention one crystallization can make the ee value of the product far exceed the qualified standard, so it is very suitable for industrial production.
  • the preparation method of the letermovir intermediate of the present invention requires fewer crystallizations, requires only one crystallization, and has low three-waste treatment costs; in addition, the preparation method of the present invention has a short production cycle, but the product purity is high, and is suitable for industrial production.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un intermédiaire de letermovir et son procédé de préparation. Plus particulièrement, le procédé comprend l'étape consistant à : cristalliser de l'acétate de {8-fluoro-2-[4-(3-méthoxyphényl)pipérazin-1-yl]-3-[2-méthoxy-5-(trifluorométhyl)phényl]-3,4-dihydroquinazolin-4-yl} de méthyle avec de l'acide tartrique modifié chiral dans un solvant inerte pour obtenir un sel de tartrate d'acétate de (S)-méthyl {8-fluoro-2-[4-(3-méthoxyphényl)pipérazin-1-yl]-3-[2-méthoxy-5-(trifluorométhyl)phényl]-3,4-dihydroquinazolin-4-yl}. Le procédé selon la présente invention présente les caractéristiques d'un mode opératoire simple, d'un rendement élevé, d'une pureté de produit élevée, d'une aptitude à la production industrielle, etc
PCT/CN2023/083173 2022-04-01 2023-03-22 Intermédiaire de letermovir et son procédé de préparation WO2023185597A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210371221 2022-04-01
CN202210371221.4 2022-04-01

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WO2023185597A1 true WO2023185597A1 (fr) 2023-10-05

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1784390A (zh) * 2003-05-02 2006-06-07 拜耳医药保健股份公司 具有抗病毒性能的取代二氢喹唑啉
CN101863843A (zh) * 2005-06-15 2010-10-20 艾库里斯有限及两合公司 制备二氢喹唑啉的方法
WO2015088931A1 (fr) * 2013-12-12 2015-06-18 Merck Sharp & Dohme Corp. Procédé de préparation de composés quinazoline substitués
WO2017091453A1 (fr) * 2015-11-24 2017-06-01 Merck Sharp & Dohme Corp. Nouveaux procédés de production de composés de quinazoline substitués à l'aide de catalyseurs de liaison hydrogène
WO2022018625A1 (fr) * 2020-07-21 2022-01-27 Olon S.P.A. Procédé de préparation d'un intermédiaire utilisé dans la synthèse du létermovir

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1784390A (zh) * 2003-05-02 2006-06-07 拜耳医药保健股份公司 具有抗病毒性能的取代二氢喹唑啉
CN101863843A (zh) * 2005-06-15 2010-10-20 艾库里斯有限及两合公司 制备二氢喹唑啉的方法
WO2015088931A1 (fr) * 2013-12-12 2015-06-18 Merck Sharp & Dohme Corp. Procédé de préparation de composés quinazoline substitués
WO2017091453A1 (fr) * 2015-11-24 2017-06-01 Merck Sharp & Dohme Corp. Nouveaux procédés de production de composés de quinazoline substitués à l'aide de catalyseurs de liaison hydrogène
WO2022018625A1 (fr) * 2020-07-21 2022-01-27 Olon S.P.A. Procédé de préparation d'un intermédiaire utilisé dans la synthèse du létermovir

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