WO2023087747A1 - Procédé de préparation d'un inhibiteur du vih et de forme cristalline intermédiaire de celui-ci - Google Patents

Procédé de préparation d'un inhibiteur du vih et de forme cristalline intermédiaire de celui-ci Download PDF

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WO2023087747A1
WO2023087747A1 PCT/CN2022/105060 CN2022105060W WO2023087747A1 WO 2023087747 A1 WO2023087747 A1 WO 2023087747A1 CN 2022105060 W CN2022105060 W CN 2022105060W WO 2023087747 A1 WO2023087747 A1 WO 2023087747A1
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compound
preparation
add
reaction
formula
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PCT/CN2022/105060
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English (en)
Chinese (zh)
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郭万成
张靖达
张富昌
房杰
田鑫
王国平
于振鹏
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奥锐特药业(天津)有限公司
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Publication of WO2023087747A1 publication Critical patent/WO2023087747A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention specifically relates to a preparation method of an HIV inhibitor and an intermediate crystal form thereof.
  • Polycyclic carbamoyl pyrimidine derivatives are well-known HIV integrase strand transfer inhibitors, combined with other antiretroviral drugs to treat HIV-1 infection in adults and children over 12 years old with a weight of more than 40 kg.
  • Dolutegravir Sodium was approved by the US Food and Drug Administration (FDA) on August 12, 2013.
  • An anti-AIDS drug jointly developed by GlaxoSmithKline (GSK) and Japan's Shionogi Pharmaceutical Company (Shionogi). It is the third HIV integrase inhibitor approved by FDA after Raltegravir and Elvitegravir. Its structural formula is as follows:
  • Cabotegravir is an integrase inhibitor that can be given orally or injected intramuscularly or subcutaneously. Oral administration of 30 mg of CAB once a day can effectively inhibit HIV.
  • Bictegravir is a new type of integrase inhibitor developed by Gilead. Unlike the previously developed integrase inhibitors, Bictegravir only needs to be used once a day and does not require the synergist cobicistat.
  • Route 2 uses lithium bromide to remove methyl groups, and the by-product methyl bromide is a highly toxic gas. During industrial production, multiple devices are required to absorb methyl bromide to reduce toxicity risks and reduce environmental pollution, which greatly increases industrial costs. However, the ethyl removal reported in WO2015110897A2 has a low yield of only 66%.
  • the problem to be solved by the present invention is to overcome the problems of low key reaction yield, cumbersome post-processing, and unsuitability for industrialization in the preparation method of HIV inhibitor in the prior art, and propose a preparation method of HIV inhibitor and its intermediate bulk crystal form.
  • the preparation method of the present invention has high reaction yield, simple post-treatment, and is suitable for industrial production; the yield and purity of the final product obtained by using the intermediate crystal form in subsequent reactions are relatively high.
  • the present invention provides a kind of preparation method of the compound shown in formula I, it comprises the steps:
  • the deprotection reaction is carried out in the presence of a base, or in the absence of a base;
  • One or more hydrogens on the phenyl group are replaced by F;
  • n 0 or 1
  • A is methyl, B is hydrogen; or, A, B and the carbon between them form a five-membered ring structure;
  • R is C 2 -C 6 alkyl
  • the base is M 1 OH, and one or more of R 1 OM 2 ; M 1 and M 2 are independently alkali metals; R 1 , R 2 , R 3 and R 4 are independently C 1 to C 4 alkyl;
  • Carbons marked with * are S-configuration or R-configuration chiral carbons.
  • n preferably A is methyl and B is hydrogen.
  • n 1, preferably A is methyl and B is hydrogen.
  • n 1
  • A, B and the carbon between them form a five-membered ring structure.
  • R is preferably a C 2 -C 4 alkyl group, such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably ethyl.
  • the C 1 -C 4 alkyl is preferably methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl or tert-butyl, eg ethyl.
  • the alkali metal is preferably one or more of sodium, potassium and cesium.
  • the M 1 OH is preferably sodium hydroxide and/or potassium hydroxide.
  • the R 1 OM 2 is preferably one or more of sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide and potassium methoxide.
  • Preference is given to triethylamine and/or DIPEA.
  • A is on the same side as the hydrogen on the 1 carbon.
  • A is methyl
  • B is hydrogen
  • the structural formula of the compound shown in formula I is
  • n 1, A, B and the carbon between them form a five-membered ring structure, and the structural formula of the compound shown in formula I is
  • the amount of tetrahydrofuran used may be the usual amount used in this field for this type of reaction, and the volume molar ratio of tetrahydrofuran to compound N-3 is preferably 0.5-2.0 L/mol, for example, 1.21 L/mol.
  • the amount of the base used for this type of reaction can be conventionally used in the art, and the molar ratio of the base to the compound N-3 is preferably 1.0 to 1.5, for example , 1.13.
  • the amount of lithium bromide used may be the conventional amount used in this field for this type of reaction, and the molar ratio of lithium bromide to compound N-3 is preferably 2.5-3.5, for example, 3.02.
  • the reaction temperature of the deprotection reaction may be a conventional temperature for this type of reaction in the art, preferably 50-80°C, for example, 60-70°C.
  • the progress of the deprotection reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance of compound N-3 is generally used as the end point of the reaction.
  • the reaction time is preferably 18-36 hours, for example, 24 hours.
  • Described deprotection reaction can also further comprise post-treatment;
  • Described post-treatment method is the conventional post-treatment method of this type of reaction, preferably comprises the following steps: after reaction finishes, cooling, adding water to quench reaction, decompression removes solvent , dilute hydrochloric acid was added, crystals were precipitated, and the crude product was obtained by suction filtration. After drying, the crude product was recrystallized in acetonitrile/water to obtain compound N-2.
  • the preparation method of the compound N-2 may also include the following steps: (1) reacting the compound N-4 with lithium hydroxide; (2) adding acetic acid and methanesulfonic acid, and continuing the reaction at 60-80°C; (3) Cool down to 40-50°C, add triethylamine and reagent A, react at 70-80°C to obtain compound N-3; reagent A is (R)-3-aminobutanol, (S)-2-amino propanol or The steps (1) and (2) are directly carried out in the next step without any post-treatment;
  • n, A, B and * are as mentioned above.
  • the preparation method of the compound shown in formula I may further include the following steps: in dichloromethane, in the presence of a condensing agent, compound N-2 and Carry out the condensation reaction shown below to obtain the compound shown in formula I;
  • the present invention also provides a crystal form of compound N-2', using Cu-K ⁇ radiation, the X-ray powder diffraction pattern represented by 2 ⁇ angle has characteristic peaks at one or more of the following positions: 7.7° ⁇ 0.2° , 10.3° ⁇ 0.2°, 13.3° ⁇ 0.2°, 14.3° ⁇ 0.2°, 17.8° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.9° ⁇ 0.2°, 27.4° ⁇ 0.2°, 28.5 ° ⁇ 0.2°, 29.8° ⁇ 0.2°;
  • the X-ray powder diffraction pattern represented by 2 ⁇ angle has characteristic peaks at one or more of the following positions: 7.7° ⁇ 0.2°, 10.3° ⁇ 0.2°, 11.5 ⁇ 0.2°, 12.8 ⁇ 0.2°, 13.3° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.0° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.5° ⁇ 0.2°, 17.8° ⁇ 0.2°, 19.1° ⁇ 0.2°, 20.9° ⁇ 0.2 °, 21.9° ⁇ 0.2°, 27.4° ⁇ 0.2°, 28.5° ⁇ 0.2°, 29.8° ⁇ 0.2°.
  • FIG. 1 Furthermore, the X-ray powder diffraction is shown in FIG. 1 .
  • the differential scanning calorimetry chart of the crystal form of compound N-2' provided by the present invention has an endothermic peak with an initial value of 273.72°C and a peak value of 277.12°C.
  • the infrared absorption spectrum of the crystal form of compound N-2' provided by the present invention is at 3455, 3051, 2974, 2889, 1733, 1634, 1544, 1525, 1461, 1451, 1442, 1371, 1304, 1255, 1237, 1215 , 1190, 1176, 996, 980, 695, 540cm -1 have absorption peaks.
  • the crystal form thermogravimetric analysis (TGA) of compound N-2' provided by the present invention has a weight loss of about 15.1% in the range of 260°C to 310°C, and a weight loss of 38.2% in the range of 310°C to 400°C.
  • thermogravimetric analysis (TGA) of the crystal form of compound N-2' provided by the present invention is basically shown in Figure 5.
  • Fig. 1 is the XRPD pattern of the typical example of compound N-2'.
  • Fig. 2 is the DSC spectrum of compound N-2'.
  • Fig. 3 is the 1 H NMR spectrum of compound N-2'.
  • Figure 4 is the IR spectrum of compound N-2'.
  • Figure 5 is the TGA spectrum of compound N-2'.
  • X-ray powder diffractometer BRUKER AXS D2 PHASER X-ray powder diffractometer; radiation source: k Intensity ratio ⁇ 1/ ⁇ 2 is 0.50000; generator (Generator) kv: 30.0kv; generator (Generator) mA: 10.0mA; initial 2 ⁇ : 2.000°, scanning range: 2.0000 ⁇ 40.000°.
  • the model of the DSC detector is: METTLER TOLEDO DSC1 differential scanning calorimeter; the heating program: the initial temperature is 25°C, rising to 400°C at 10°C/min, and the temperature range: 25°C to 400°C.
  • the nuclear magnetic detection instrument model is BRUKERAVANCEIII, 300MHz, and the deuterated reagent is DMSO-d6.
  • Infrared Spectrophotometer Model PerkinElmer Spectrum Two Fourier Transform Infrared Spectrometer; Operation Method: KBr tablet method, scanning range 450-4000cm -1 .
  • the TGA detector model is METTLER TOLEDO TGA/DSC1 thermogravimetric analyzer; heating program: the initial temperature is 25°C, rising to 400°C at 10°C/min; temperature range: 25°C to 400°C.
  • Compound N-5 was prepared from reference Organic Letters (2015), 17(3), 564-567 and was directly used in subsequent steps.
  • the spectrogram is shown in Figure 3; the IR test is performed, and the spectrogram is shown in Figure 4; the TGA test is performed, and the spectrogram is shown in Figure 5.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • AIDS & HIV (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne un procédé de préparation d'un inhibiteur du VIH et d'une forme cristalline intermédiaire de celui-ci. La formule de réaction de l'inhibiteur du VIH est la suivante. Le procédé de préparation de la présente invention présente un rendement de réaction élevé, permet d'obtenir un post-traitement simple et convient à une production industrielle ; le rendement et la pureté du produit final obtenu à l'aide de la forme cristalline intermédiaire dans des réactions ultérieures sont relativement élevés.
PCT/CN2022/105060 2021-11-17 2022-07-12 Procédé de préparation d'un inhibiteur du vih et de forme cristalline intermédiaire de celui-ci WO2023087747A1 (fr)

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CN202111359127.9A CN113816972B (zh) 2021-11-17 2021-11-17 一种hiv抑制剂的制备方法及其中间体晶型
CN202111359127.9 2021-11-17

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CN113816972B (zh) * 2021-11-17 2022-03-18 奥锐特药业(天津)有限公司 一种hiv抑制剂的制备方法及其中间体晶型

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Publication number Priority date Publication date Assignee Title
CN102933080A (zh) * 2010-03-23 2013-02-13 Viiv保健公司 制备氨基甲酰基吡啶酮衍生物和中间体的方法
WO2016113372A1 (fr) * 2015-01-16 2016-07-21 Lek Pharmaceuticals D.D. Procédés de préparation de cabotégravir dolutégravir et d'analogues de ceux-ci
CN113816972A (zh) * 2021-11-17 2021-12-21 奥锐特药业(天津)有限公司 一种hiv抑制剂的制备方法及其中间体晶型

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WO2019159199A1 (fr) * 2018-02-16 2019-08-22 Cipla Limited Procédé à flux continu pour la préparation de dérivés de carbamoylpyridone polycycliques à ingrédients pharmaceutiquement actifs et intermédiaires de ceux-ci

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102933080A (zh) * 2010-03-23 2013-02-13 Viiv保健公司 制备氨基甲酰基吡啶酮衍生物和中间体的方法
WO2016113372A1 (fr) * 2015-01-16 2016-07-21 Lek Pharmaceuticals D.D. Procédés de préparation de cabotégravir dolutégravir et d'analogues de ceux-ci
CN113816972A (zh) * 2021-11-17 2021-12-21 奥锐特药业(天津)有限公司 一种hiv抑制剂的制备方法及其中间体晶型

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