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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
Authority
WO
WIPO (PCT)
Prior art keywords
acetate
piperazin
methoxyphenyl
fluoro
methoxy
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/CN2023/083173
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English (en)
Chinese (zh)
Inventor
胡猛
祁道冉
张国斌
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.)
Shanghai Desano Chemical Pharmaceutical Co Ltd
Original Assignee
Shanghai Desano Chemical Pharmaceutical 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
Application filed by Shanghai Desano Chemical Pharmaceutical Co Ltd filed Critical Shanghai Desano Chemical Pharmaceutical Co Ltd
Priority to CN202380024475.1A priority Critical patent/CN118974026A/zh
Publication of WO2023185597A1 publication Critical patent/WO2023185597A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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)
  • Plural Heterocyclic Compounds (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 Ceased WO2023185597A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202380024475.1A CN118974026A (zh) 2022-04-01 2023-03-22 莱特莫韦中间体及其制备方法

Applications Claiming Priority (2)

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

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WO2023185597A1 true WO2023185597A1 (fr) 2023-10-05

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CN (1) CN118974026A (fr)
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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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