WO2023231826A1 - Composé intermédiaire de létermovir, son procédé de préparation et son application - Google Patents

Composé intermédiaire de létermovir, son procédé de préparation et son application Download PDF

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Publication number
WO2023231826A1
WO2023231826A1 PCT/CN2023/095672 CN2023095672W WO2023231826A1 WO 2023231826 A1 WO2023231826 A1 WO 2023231826A1 CN 2023095672 W CN2023095672 W CN 2023095672W WO 2023231826 A1 WO2023231826 A1 WO 2023231826A1
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compound
acid
compound iii
salt
preparation
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PCT/CN2023/095672
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English (en)
Chinese (zh)
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李延洁
陈恬
王乃星
吴佳炜
朱燕萍
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浙江车头制药股份有限公司
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Publication of WO2023231826A1 publication Critical patent/WO2023231826A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the invention belongs to the technical field of chemical drug synthesis and relates to a new intermediate of letermovir and its preparation method, as well as the application of the intermediate in the preparation of key intermediates of letermovir and letermovir.
  • Letermovir is a powerful anti-cytomegalovirus drug that mainly acts on the pUL56 subunit to prevent viral replication and achieve therapeutic effects. It has been approved in the U.S. market for the past 15 years for anti-cytomegalovirus. The only drug for cellular viruses. It was originally developed by the German company AiCuris anti-infective cures GmbH. It was acquired by Merck & Co., a subsidiary of Merck in the United States, on October 15, 2012. It is responsible for clinical trials, marketing approval, production and sales. Clinical studies have shown that letermovir has good safety and efficacy. After 28 days of treatment, no cytomegalovirus was detected in the patient's body. Compared with other approved drugs, there is no cross-resistance and it has good market prospects. , the chemical structure is as follows:
  • the compound patent WO2004096778A discloses the following synthetic route in the specification: starting from 2-halogen-substituted aniline, it is converted into a 2-aminocinnamic acid derivative through Heck coupling.
  • the imine phosphine is prepared by reaction with triphenylphosphine in carbon tetrachloride, which is subsequently reacted with an isocyanate to release triphenylphosphine oxide to give the carbodiimide.
  • dihydroquinazoline methyl esters are formed, which are separated into enantiomers by a chiral chromatography column, followed by hydrolysis to dihydroquinazoline acids under standard conditions.
  • Method two, preparation patent WO2006133822A provides the following preparation method: react 2-halogen-substituted aniline directly with isocyanate, and then react with alkyl acrylate to obtain ⁇ 8-fluoro-3-[2-methoxy Methyl-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl ⁇ acetate.
  • Patent WO2015088931A mentions an improved synthesis method of letermovir using 2-bromo-6-fluoroaniline as raw material, in which the asymmetric intramolecular cyclization of guanidinyl cinnamate is the key step: 2-Bromo-6-fluoroaniline is used as the starting material. After palladium-catalyzed coupling, amino protection, 2-methoxy-5-trifluoromethylaniline substitution, chlorination, docking with side chains, chiral synthesis, and hydrolysis and other steps to finally obtain letermovir, whose synthesis route is shown in the figure below:
  • the fraction is only about 30%, and the inventor found through a large number of repetitive experiments that the addition of crystal seeds in the splitting process is very important. Without crystal seeds, there is no way to carry out the splitting step, and obtaining the crystal seeds is relatively difficult. It is difficult. In addition, the use of 1-(2-methoxyphenyl)piperazine in the route also increases the cost of the entire route and is not suitable for industrial production.
  • the third method uses an asymmetric synthesis method, but the carbodiimide compound is unstable and a chiral catalyst is used during the reaction. The chiral catalyst is difficult to recover, making the entire route costly and unsuitable for industrial production.
  • the present invention provides a new intermediate compound II, III, and IV of letermovir and a preparation method thereof , and the application of this new intermediate in the preparation of key intermediates of letermovir and letermovir.
  • the present invention provides a compound II, or a salt, solvate or hydrate thereof;
  • R is an alkyl group, an aryl group or a benzyl group, where * represents a chiral carbon atom, and compound II has no optical activity.
  • the aryl group is phenyl or naphthyl.
  • the alkyl group is an alkyl group with 1 to 6 carbon atoms.
  • the R is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or benzyl. More preferably, R is methyl.
  • the present invention provides a preparation method of Compound II, which preparation method includes the following steps:
  • the inert solvent in step (1) is toluene, dioxane, tetrahydrofuran (THF), methyl tert-butyl ether (MTBE), chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate and one or more of dichloromethane (DCM); dichloromethane is further preferred.
  • the volume of the inert solvent is 5-20 mL/g based on the mass of Compound I.
  • the base described in step (1) is: triethylamine (TEA), diisopropylethylamine (DIPEA) and 1,8-diazabicycloundec-7-ene (DBU) One or more of them, DBU is further preferred.
  • TAA triethylamine
  • DIPEA diisopropylethylamine
  • DBU 1,8-diazabicycloundec-7-ene
  • DBU 1,8-diazabicycloundec-7-ene
  • the molar ratio of compound I to anhydrous piperazine and alkali is 1:(1-4):(2-6), and more preferably, the compound I to anhydrous piperazine is 1:(1-4):(2-6).
  • the feeding molar ratio is 1:1.5-2.5, and the most preferred is 1:2.
  • the reaction in step (1) needs to be carried out in a nitrogen atmosphere, so the air in the reactor needs to be fully replaced with nitrogen during the reaction.
  • the nitrogen replacement operation can be performed multiple times; reaction temperature
  • the temperature is room temperature to 110°C (more preferably room temperature), and the reaction time is 1-24h (more preferably 12-24h).
  • step (1) is specifically implemented as follows: dissolve the anhydrous piperazine solid and alkali in an inert solvent at room temperature, replace the air in the reactor with nitrogen, and slowly add dropwise the solution in the inert solvent in a nitrogen atmosphere.
  • Compound I was kept at room temperature and stirred for 12-24 hours.
  • compound II was obtained through post-treatment.
  • the post-treatment may specifically include the following operations: after the reaction is completed, the reaction solution is washed with water, left to stand to separate the aqueous layer, and the solvent layer is spun dry to obtain compound II.
  • the invention provides compound III or IV, or their respective salts, solvates or hydrates;
  • R is alkyl, aryl or benzyl.
  • the aryl group is phenyl or naphthyl.
  • the alkyl group is an alkyl group with 1 to 6 carbon atoms.
  • the R is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or benzyl. More preferably, R is methyl.
  • the salt of compound III or IV according to the present invention can be a salt formed by compound III and resolving agent A, or a salt formed by compound IV and resolving agent B; said resolving agent A is: D-tartaric acid, D-apple Acid, D-camphoric acid, D-camphorsulfonic acid, diacetone-D-gulonic acid, D-mandelic acid, D-dibenzoyltartaric acid monohydrate, D-dibenzoyltartaric acid anhydrous, D- One or more of di-p-toluoyl tartaric acid monohydrate, D-di-p-toluoyl tartaric acid anhydrous (D-DTTA), and D-diethyl tartrate; the resolving agent B is: L-tartaric acid, L-malic acid, L-camphoric acid, L-camphorsulfonic acid, diacetone-L-gulonic acid, L-mandelic acid, L-dibenzoy
  • the present invention provides a preparation method of Compound III or Compound IV, which preparation method includes the following steps:
  • the resolving agent A is: D-tartaric acid, D-malic acid, D-camphoric acid, D -Camphorsulfonic acid, diacetone-D-gulonic acid, D-mandelic acid, D-dibenzoyltartaric acid monohydrate, D-dibenzoyltartaric acid anhydrous, D-di-p-methylbenzoyltartaric acid Monohydrate, one or more of D-di-p-toluoyl tartaric acid anhydrous (D-DTTA), D-diethyl tartrate;
  • D-DTTA D-di-p-toluoyl tartaric acid anhydrous
  • compound II is salted out under the action of the corresponding resolving agent B, and the salt of compound IV is obtained by filtration;
  • the resolving agent B is: L-tartaric acid, L-malic acid, L-camphoric acid, L- Camphorsulfonic acid, diacetone-L-gulonic acid, L-mandelic acid, L-dibenzoyltartaric acid monohydrate, L-dibenzoyltartaric acid anhydrous, L-di-p-methylbenzoyltartaric acid monohydrate Water, one or more of L-di-p-methylbenzoyltartaric acid anhydrous, L-diethyl tartrate;
  • the resolving agent A described in step (2) is D-di-p-toluoyl tartaric acid anhydrous.
  • the resolving agent B described in step (2) is L-di-p-toluoyl tartaric acid anhydrous.
  • the molar ratio of compound II to resolving agent A or resolving agent B is 1:0.5-3, more preferably 1:0.8-1.5, even more preferably 1:0.9-1.1 .
  • step (2) specifically adopts the following operation: Dissolve compound II and resolving agent A or resolving agent B in a solvent at room temperature, slowly add water dropwise under stirring, stir until solid precipitates, and slowly cool to 0-10 Incubate at °C for 1-4 hours, filter, and obtain the corresponding salt solid of compound III or compound IV.
  • the solvent described in step (2) is: toluene, dioxane, THF, MTBE, chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate, dichloromethane, heptane, hexane One or more alkanes; it is further preferred that the solvent is THF.
  • step (2) the amount of solvent used is 5-20 mL/g based on the mass of compound II.
  • step (2) the temperature is slowly lowered to 2-5°C and kept for 2-3 hours.
  • step (3) of the present invention freeing the salt of compound III or the salt of compound IV means to free compound III or IV from the salt.
  • the following operation can be used for the dissociation: the salt of compound III or the salt of compound IV is dissolved with an organic solvent and an alkali solution, and then the liquids are separated, and the organic phase is taken to remove the solvent to obtain compound III or compound IV;
  • the organic solvent is selected from at least one of dichloromethane, ethyl acetate, isopropyl acetate, and toluene, and dichloromethane is further preferred.
  • the alkali solution is selected from a saturated aqueous solution of sodium bicarbonate or a saturated aqueous solution of potassium bicarbonate.
  • the present invention provides a method for preparing Compound V, comprising the following steps:
  • the step (4) is specifically implemented as follows: add compound III, 3-methoxyphenylboronic acid, catalyst, acid binding agent and organic solvent to the reaction vessel, and obtain compound V after sufficient reaction;
  • the catalyst is : One or more of Cu(OAc) 2 , CuI, CuCl, CuCO 3 , CuBr, NiCl 2 , Cu 2 O, Cu(OTf) 2 , CuSO 4 ;
  • the acid binding agent is: triethylamine, One or more of DBU, pyridine, DMAP, 2,6-dimethylpyridine, potassium carbonate, potassium tert-butoxide.
  • the catalyst is copper acetate.
  • the acid binding agent is triethylamine.
  • the organic solvent in step (4) is one or more of acetonitrile, toluene, dioxane, THF, MTBE, chlorobenzene, and methylene chloride, and more preferably acetonitrile.
  • the molar ratio of compound III, 3-methoxyphenylboronic acid, catalyst, and acid binding agent is 1:(1.5-5)(0.1-3):(1- 4), it is further preferred that the molar ratio of compound III and 3-methoxyphenylboronic acid is 1:1.8-2.5, and it is further preferred that the molar ratio of compound III and catalyst is 1:0.8-1.2.
  • step (4) the amount of organic solvent used is 5-40 mL/g based on the mass of compound III.
  • the reaction temperature in step (4) is 40-100°C; the reaction time is 1-48h.
  • a post-treatment operation is required, specifically: after the reaction is completed, the reaction is quenched with water, and then the aqueous phase is extracted with EtOAc, the organic phases are combined, and the solvent is removed to obtain compound V.
  • the present invention provides a method for preparing letermovir, which includes the following steps in sequence:
  • R is alkyl, aryl or benzyl.
  • the aryl group is phenyl or naphthyl.
  • the alkyl group is an alkyl group with 1 to 6 carbon atoms.
  • the R is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or benzyl. More preferably, R is methyl.
  • steps (1)-(4) are as described above and will not be described again here.
  • step (5) For the hydrolysis reaction in step (5), refer to the hydrolysis reaction operation in the compound patent WO2006133822A to obtain letermovir.
  • the present invention provides another method for preparing letermovir, which includes the following steps in sequence:
  • R 1 is selected from Br, I or Cl, further preferably Br;
  • R is an alkyl group, an aryl group or a benzyl group.
  • the aryl group is phenyl or naphthyl.
  • the alkyl group is an alkyl group with 1 to 6 carbon atoms.
  • the R is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or benzyl. More preferably, R is methyl.
  • steps (1)-(3) are as described above and will not be described again here.
  • the step (4) is specifically implemented as follows: add compound III, 3-methoxyhalobenzene represented by formula VI, oxalamide ligand, catalyst, acid binding agent and organic solvent in the reaction vessel, Control the temperature to fully react to obtain letermovir;
  • the catalyst is selected from one of Cu(OAc) 2 , CuI, CuCl, CuCO 3 , CuBr, NiCl 2 , Cu 2 O, Cu(OTf) 2 , and CuSO 4 or several;
  • the acid-binding agent is selected from one or more of potassium tert-butoxide, potassium hydroxide, potassium carbonate, sodium tert-butoxide, sodium hydroxide, sodium carbonate, potassium phosphate, and potassium dihydrogen phosphate.
  • the catalyst is selected from cuprous iodide.
  • the organic solvent is selected from: one or more of ethanol, methanol, acetonitrile, toluene, dioxane, THF, MTBE, chlorobenzene, and methylene chloride, and more Ethanol is further preferred.
  • the acid binding agent is selected from potassium phosphate.
  • the molar ratio of compound III, 3-methoxyhalobenzene represented by formula VI, oxalamide ligand, catalyst, and acid binding agent is 1:2-3:0.1 -1:0.1-1:1-3, further preferably the molar ratio of compound III and oxalamide ligand is 1:0.1-0.3, the molar ratio of oxalamide ligand to catalyst is 1:1; the amount of organic solvent Based on the mass of compound III, it is 10-15mL/g.
  • the reaction needs to be carried out under a nitrogen atmosphere, so the air in the reactor needs to be fully replaced with nitrogen first.
  • the nitrogen replacement operation can be performed multiple times; the reaction temperature The temperature is 40-90°C; the reaction time shown is 24-36h.
  • post-processing operations are required, specifically: after the reaction is completed, MTBE is added to the reaction system, and then washed with water, and the aqueous phase is taken. The aqueous phase is fully washed with MTBE, then methylene chloride is added, and hydrochloric acid is used to adjust the aqueous phase.
  • the pH is 7, the organic phase is obtained by liquid separation, dried over sodium sulfate, concentrated, and spun to dryness to obtain letermovir.
  • the present invention Compared with the existing letermovir preparation method, the present invention has the following technical advantages:
  • the new intermediate compounds II, III, and IV of letermovir of the present invention can be used to prepare key intermediates of letermovir, letermovir and its salts or analogs thereof, based on the origin of the intermediate compounds.
  • the preparation route of termovir has the advantages of low cost, high yield, and is more suitable for large-scale industrial production;
  • the new intermediate compound II of the present invention is relatively easy to crystallize and resolve with a resolving agent to obtain the corresponding enantiomers.
  • a chiral purity of 99.9% can be achieved in one resolution, and there is no need to add seed crystals during the resolution process. It can be crystallized, the overall operation is simple, the separation rate is high, and the cost is low;
  • the preparation method of letermovir of the present invention uses compound I as the starting material, first introduces the piperazine fragment during the preparation process, and then introduces the anisole fragment after splitting, which has low cost and high yield, and Avoid the generation of phosphine amine intermediates and eliminate the generation of by-product triphenoxyphosphonate. Therefore, the production process of the present invention is more conducive to large-scale industrial production.
  • the technical solutions will be clearly and completely described below through further examples. If the specific conditions are not specified in the examples, the conditions should be carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer is not indicated on the instruments used, they are all conventional products that can be purchased commercially. If the manufacturer is not indicated for the reagents used, they are all conventional products that can be purchased commercially or prepared according to known literature.
  • R is methyl, which was prepared according to the method of WO2006133822A.
  • R is also methyl.
  • the optical rotation is measured by the chiral HPLC method.
  • the specific test method is: instrument: high performance liquid chromatography; column: chromatographic column, 150mm*4.6mm, 5 ⁇ m; eluent A: n-hexane, eluent B: ethanol; Isocratic: 10% B; flow rate: 0.8mL/min; temperature: 25°C; UV detection: 260nm, collection time 25min.
  • the chiral purity of the product is measured by the chiral HPLC method.
  • the specific test method is: instrument: high performance liquid chromatography; column: chromatographic column, 150mm*4.6mm, 5 ⁇ m; eluent A: n-hexane, eluent B: Ethanol; isocratic: 10% B; flow rate: 0.8mL/min; temperature: 25°C; UV detection: 260nm, collection time 25min.

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  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention concerne un composé intermédiaire de létermovir, son procédé de préparation et son application. En particulier, l'invention concerne des composés (II), (III) et (IV), et les structures des composés sont présentées ci-dessous. La présente invention concerne une application du composé dans la préparation de létermovir. La solution présente les avantages de présenter une utilisation simple et pratique, une efficacité de division élevée, un rendement plus élevé et d'être plus appropriée pour une production industrielle.
PCT/CN2023/095672 2022-06-02 2023-05-23 Composé intermédiaire de létermovir, son procédé de préparation et son application WO2023231826A1 (fr)

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CN202210625868.5A CN115322157B (zh) 2022-06-02 2022-06-02 来特莫韦中间体化合物及其制备方法和应用
CN202210625868.5 2022-06-02

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CN115322157B (zh) * 2022-06-02 2023-12-05 浙江车头制药股份有限公司 来特莫韦中间体化合物及其制备方法和应用

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
CN101213180A (zh) * 2005-06-15 2008-07-02 艾库里斯有限及两合公司 制备二氢喹唑啉的方法
CN104144678A (zh) * 2012-02-29 2014-11-12 艾库里斯有限及两合公司 含有抗病毒活性二氢喹唑啉衍生物的药物制剂
WO2016109360A1 (fr) * 2014-12-29 2016-07-07 Auspex Pharmaceuticals, Inc. Dihydroquinazolines comme inhibiteurs de terminase virale
CN115322157A (zh) * 2022-06-02 2022-11-11 浙江车头制药股份有限公司 来特莫韦中间体化合物及其制备方法和应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10392353B2 (en) * 2015-11-24 2019-08-27 Merck Sharp & Dohme Corp. Processes for making substituted quinazoline compounds using hydrogen bonding catalysts

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
CN101213180A (zh) * 2005-06-15 2008-07-02 艾库里斯有限及两合公司 制备二氢喹唑啉的方法
CN104144678A (zh) * 2012-02-29 2014-11-12 艾库里斯有限及两合公司 含有抗病毒活性二氢喹唑啉衍生物的药物制剂
WO2016109360A1 (fr) * 2014-12-29 2016-07-07 Auspex Pharmaceuticals, Inc. Dihydroquinazolines comme inhibiteurs de terminase virale
CN115322157A (zh) * 2022-06-02 2022-11-11 浙江车头制药股份有限公司 来特莫韦中间体化合物及其制备方法和应用

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