WO2021083345A1 - Procédé de préparation d'un composé pyrazolopyrimidine et d'un intermédiaire de celui-ci - Google Patents

Procédé de préparation d'un composé pyrazolopyrimidine et d'un intermédiaire de celui-ci Download PDF

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Publication number
WO2021083345A1
WO2021083345A1 PCT/CN2020/125371 CN2020125371W WO2021083345A1 WO 2021083345 A1 WO2021083345 A1 WO 2021083345A1 CN 2020125371 W CN2020125371 W CN 2020125371W WO 2021083345 A1 WO2021083345 A1 WO 2021083345A1
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compound
preparation
formula
solvents
solvent
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PCT/CN2020/125371
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English (en)
Chinese (zh)
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王建非
孙继奎
杨广文
张杨
黎健
陈曙辉
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先声药业有限公司
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Priority to CN202080069538.1A priority Critical patent/CN114641478A/zh
Publication of WO2021083345A1 publication Critical patent/WO2021083345A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a method for preparing pyrazolopyrimidine compounds.
  • the present invention also relates to a method for preparing compounds of formula (I) and intermediate compounds thereof.
  • Protein kinases are closely related to cell proliferation, differentiation, metabolism, and apoptosis. The oncogenic forms of protein kinases are abundantly expressed in many different human tumor types and are highly responsive to some specific kinase inhibitors. Among them, Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase (RTK) belonging to the insulin receptor superfamily. It is mainly expressed in the central and peripheral nervous system and is involved in the normal development of the nervous system. It plays a role in the function and has been extensively studied in a large number of preclinical and clinical studies.
  • ALK Anaplastic Lymphoma Kinase
  • RTK receptor tyrosine kinase
  • ALK was first discovered in a type of anaplastic large cell lymphoma (ALCL) as a continuously activated carcinogenic form due to chromosomal translocation. It is produced by the normally expressed protein nuclear phosphate NPM The fusion protein NPM-ALK is formed by fusion between the N-terminus and ALK kinase domain.
  • ALK fusion proteins have been identified and are considered to be powerful oncogenic drivers of some tumors (such as inflammatory myofibroblastoma). Therefore, ALK fusion proteins have also become important targets for cancer treatment intervention.
  • a variety of ALK inhibitors have entered clinical trials and have been approved for marketing.
  • Crizotinib (crizotinib) was approved in 2011 for the treatment of ALK-positive non-small cell lung cancer (NSCLC) patients.
  • Ceritinib was approved for the treatment of ALK-positive metastatic NSCLC patients.
  • ALK inhibitors have been proven effective in the initial clinical practice, relapses and ALK-acquired resistance mutations have always been observed in treated patients.
  • the emergence of brain metastases is an obvious cause of disease recurrence in patients treated with crizotinib.
  • Tropomyosin-related kinase is a type of nerve growth factor receptor (NGF), which is highly expressed in nerve cells.
  • the Trk family is composed of highly homologous tropomyosin-related kinase A (TrkA), tropomyosin-related kinase B (TrkB), and tropomyosin-related kinase C (TrkC), which encode respectively NTRK1, NTRK2, and NTRK3, involving 4 ligands including NGF, BDNF, NT-4 and NT-3, are widely involved in cell development by regulating the main signal pathways such as PI3K-AKT, RAS-RAF-ERK, and PLC ⁇ -PKC.
  • Trk Oncogenic Trk gene fusion does not require ligand activation to promote cancer cell proliferation and affect cancer-related downstream signaling pathways, such as ERK and AKT.
  • Drugs targeting TRK gene fusion such as Entrectinib (RXDX-101) and Larotrectinib (LOXO-101), have also been proven effective in the initial clinical trials. However, under sustained action, acquired resistance mutations were also produced in the treated patients. New drugs that target TRK gene fusion, such as TPX-0005 and LOXO-195, partially solve the problem of resistance mutations.
  • Ros1 kinase is a type of receptor tyrosine kinase, which has an important effect on normal physiological functions.
  • the continuously activated oncogenic form of Ros1 fusion protein has also been found in a variety of human cancers, including glioblastoma, non-small cell lung cancer, and colorectal cancer.
  • a variety of drugs targeting Ros1 fusion protein, such as crizotinib, have been clinically proven effective, but after continuous administration, acquired resistance mutations have also been found in patients.
  • the present invention provides a method for preparing the compound of formula (I),
  • Step 1 reacting a compound of formula 1-3, a compound of formula 1B and a compound of formula 1C to obtain a compound of formula 1-4,
  • Step 2 Reacting the compound of formula 1-4 to obtain the compound of formula 1-5,
  • Step 3 Reacting the compound of formula 1-5 to obtain the compound of formula 1-6,
  • R 1 is selected from F, Cl, Br, I, OH, NH 2 , COOH, CH 3 and OCH 3 ;
  • R 2 is selected from H, F, Cl, Br and I.
  • the method for preparing the compound of formula (I) includes the following steps: Step 1: reacting the compound of formula 1-3, the compound of formula 1B and the compound of formula 1C to obtain the compound of formula 1-4,
  • Step 2 Reacting the compound of formula 1-4 to obtain the compound of formula 1-5,
  • Step 3 Reacting the compound of formula 1-5 to obtain the compound of formula 1-6,
  • R 1 is selected from F, Cl, Br, I, OH, NH 2 , COOH, CH 3 and OCH 3 ;
  • R 2 is selected from H, F, Cl, Br and I;
  • Reagent A is selected from benzoic acid, hydrochloric acid, acetic acid and zinc chloride;
  • Solvent B is selected from alkane solvents and halogenated alkane solvents
  • the reducing agent C is selected from sodium borohydride, lithium tetrahydroaluminum, potassium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium cyanoborohydride;
  • Reagent D is selected from triphenylphosphine and tri-n-butylphosphine;
  • Reagent E is selected from diisopropyl azodicarboxylate, dimethyl azodicarboxylate, diethyl azodicarboxylate, di-tert-butyl azodicarboxylate and azodicarboxydipiperidine;
  • the solvent F is selected from ether solvents, halogenated alkane solvents and nitrile solvents.
  • R 1 is selected from F, Cl, Br, I, OH, NH 2 , COOH, CH 3 and OCH 3 ;
  • R 2 is selected from H, F, Cl, Br and I;
  • Reagent A is selected from benzoic acid, hydrochloric acid, acetic acid and zinc chloride;
  • Solvent B is selected from dichloromethane and chloroform
  • the reducing agent C is selected from sodium borohydride and lithium aluminum tetrahydrogen;
  • Reagent D is selected from triphenylphosphine
  • Reagent E is selected from diisopropyl azodicarboxylate
  • the solvent F is selected from tetrahydrofuran.
  • R 1 is selected from OCH 3 .
  • R 2 is selected from F.
  • the above-mentioned preparation method includes the following reaction route:
  • Acid G is selected from hydrochloric acid/ethyl acetate, hydrochloric acid/methanol, trifluoroacetic acid and hydrochloric acid/methyl tert-butyl ether;
  • Solvent H is selected from ester solvents, alcohol solvents, halogenated alkane solvents and ether solvents;
  • Base I is selected from N,N-diisopropylethylamine, potassium carbonate, cesium carbonate, cesium fluoride and triethylamine;
  • Solvent J is selected from sulfone solvents, amide solvents and alcohol solvents;
  • Reagent K is selected from trimethylchlorosilane/sodium iodide, trimethylsilyl iodide and boron tribromide;
  • Solvent L is selected from nitrile solvents and halogenated alkane solvents
  • the base M is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium trimethylsiloxide and triethylamine/lithium chloride;
  • Solvent N is selected from alcohol solvents, ether solvents and nitrile solvents
  • Condensing agent O is selected from 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3 -Ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole, carbonyl diimidazole and 1-n-propyl phosphoric anhydride;
  • the base P is selected from N,N-diisopropylethylamine and triethylamine;
  • Solvent Q is selected from ether solvents, nitrile solvents, halogenated alkane solvents and amide solvents;
  • Condensing agent R is selected from tri-n-butylphosphine/azodicarbonate, triphenylphosphine/dimethyl azodicarboxylate and triphenylphosphine/diethyl azodicarboxylate;
  • the solvent S is selected from ether solvents, nitrile solvents and halogenated alkane solvents.
  • Acid G is selected from hydrochloric acid/ethyl acetate (4M), hydrochloric acid/methanol (4M) and hydrochloric acid/methyl tert-butyl ether (4M);
  • Solvent H is selected from ethyl acetate, methanol and methyl tert-butyl ether;
  • the base I is selected from N,N-diisopropylethylamine and triethylamine;
  • Solvent J is selected from dimethyl sulfoxide, N-methylpyrrolidone and n-butanol;
  • Reagent K is selected from trimethylchlorosilane/sodium iodide, trimethylsilyl iodide and boron tribromide;
  • Solvent L is selected from acetonitrile and dichloromethane
  • the base M is selected from sodium hydroxide
  • the solvent N is selected from methanol
  • Condensing agent O is selected from 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3 -Ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole and 1-n-propyl phosphoric anhydride;
  • the base P is selected from N,N-diisopropylethylamine
  • Solvent Q is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and N,N-dimethylformamide;
  • Condensing agent R is selected from tri-n-butylphosphine/azodicarbonate and triphenylphosphine/diethyl azodicarboxylate;
  • the solvent S is selected from 2-methyltetrahydrofuran, dichloromethane and tetrahydrofuran.
  • the solvent B is selected from dichloromethane and chloroform
  • Solvent F is selected from 2-methyltetrahydrofuran, dichloromethane, acetonitrile and tetrahydrofuran;
  • Solvent H is selected from ethyl acetate, methanol, dichloromethane, dioxane and methyl tert-butyl ether;
  • Solvent J is selected from dimethyl sulfoxide, N-methylpyrrolidone, isopropanol and n-butanol;
  • Solvent L is selected from acetonitrile and dichloromethane
  • Solvent N is selected from methanol, tetrahydrofuran and acetonitrile
  • Solvent Q is selected from tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane and N,N-dimethylformamide;
  • the solvent S is selected from 2-methyltetrahydrofuran, dichloromethane, acetonitrile and tetrahydrofuran.
  • step 1 of preparing compound 1-4 when feeding the materials into the reaction system, the temperature range of the reaction system is controlled to be 5 ⁇ 5°C.
  • step 1 of preparing compound 1-4 in the above-mentioned preparation method, in step 1 of preparing compound 1-4, after reagents are added, the temperature range of the reaction system is controlled to be 25 ⁇ 5°C.
  • the molar ratio of compound 1-3 to compound 1B is 1:0.2-0.5.
  • the molar ratio of compound 1-3 to compound 1C is 1:1.2 to 1.5.
  • the molar ratio of compound 1-3 to reagent A is 1:0.2-0.5.
  • step 2 of preparing compound 1-5 in the above preparation method, in step 2 of preparing compound 1-5, the temperature range of the reaction system is controlled to be 10 ⁇ 5°C.
  • step 2 of preparing compound 1-5 in the above-mentioned preparation method, in step 2 of preparing compound 1-5, the reaction time is 2 ⁇ 1 hours after reagents are added.
  • step 3 of preparing compound 1-6 when feeding materials into the reaction system, the temperature range of the reaction system is controlled to be 15 ⁇ 5°C.
  • step 3 of preparing compound 1-6 in the above-mentioned preparation method, in step 3 of preparing compound 1-6, after reagents are added, the temperature range of the reaction system is controlled to be 25 ⁇ 5°C.
  • the molar ratio of compound 1-5 to reagent D is 1:1.1-1.3.
  • the molar ratio of compound 1-5 to reagent E is 1:1.1 to 1.5.
  • the temperature range of the reaction system is controlled to be 5 ⁇ 5°C.
  • the temperature range of the reaction system is controlled to be 25 ⁇ 5°C.
  • the molar ratio of compound 1-6 to acid G is 1:10-15.
  • the temperature range of the reaction system is controlled to be 70 ⁇ 5°C.
  • the molar ratio of compound 1-7 to compound 1-8 is 1:0.8-1.
  • the temperature of the reaction system is controlled to 20 ⁇ 5°C.
  • the molar ratio of compound 1-9 to reagent K is 1:3.
  • the molar ratio of compound 1-10 to base M is 1:4.
  • the temperature range of the reaction system is controlled to be 20 ⁇ 5°C.
  • the molar ratio of compound 1-11 to condensing agent O is 1:1.1-1.3.
  • the molar ratio of compound 1-11 to compound 12 is 1:1.0-1.3.
  • the molar ratio of compound 1-11 to base P is 1:2.5-5.0.
  • the temperature range of the reaction system is controlled to be 20 ⁇ 10°C.
  • the molar ratio of compound 1-13 to condensing agent R is 1:1.3 to 2.0.
  • the present invention also provides a compound of the following formula:
  • the present invention also relates to the above-mentioned compound of formula 1-4, or compound of formula 1-5, or compound of formula 1-6, or compound of formula 1-7, or compound of formula 1-9, or compound of formula 1-10, or compound of formula 1- Use of compound 11 or compound of formula 1-3 as an intermediate in preparing compound of formula (I).
  • the present invention also relates to the application of the compound of formula (I) obtained by the above preparation method and its intermediates in the preparation of medicines for treating diseases related to Trk, ALK and Ros1 kinase.
  • the above application is characterized in that the drug is a drug for the treatment of solid tumors.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • ether solvent includes, but is not limited to, diethyl ether, methyl ethyl ether, dipropyl ether, dibutyl ether, 1,4-dioxane, furan, methyl furan, and tetrahydrofuran.
  • amide solvent includes but is not limited to N,N-dimethylformamide and N,N-dimethylacetamide.
  • sulfone solvent includes, but is not limited to, dimethyl sulfoxide, dimethyl sulfone, sulfolane, and 2,4-dimethyl sulfolane.
  • ester solvent includes, but is not limited to, methyl acetate, ethyl acetate, hexyl acetate, and phenyl acetate.
  • nitrile solvent includes but is not limited to acetonitrile.
  • alcohol solvent includes but is not limited to methanol, ethanol, propanol, isopropanol, butanol, pentanol, decanol, n-dodecanol, cyclopentanol, cyclohexanol, benzyl alcohol, phenethyl alcohol.
  • alkane solvent includes, but is not limited to, petroleum ether, n-hexane, cyclohexane, methylcyclohexane, n-heptane, and isooctane.
  • halogenated alkane solvent such as monochloromethane, dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • the single crystal X-ray diffraction method (SXRD) uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultivated single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method ⁇ / ⁇ scanning. After the relevant data is collected, the direct method is further adopted. (Shelxs97)
  • the absolute configuration can be confirmed.
  • the compound of the present invention and its absolute configuration can be determined by activity.
  • the SFC detection instrument and method of the compound of formula (I) of the present invention are consistent with those in the patent application with application number PCT/CN2020/111795, the retention time is consistent, and the absolute configuration can also be confirmed.
  • the process for synthesizing the compound of formula (I) and its intermediates provided by the present invention has the beneficial effects that the raw materials are cheap and easily available, and overcome the shortcomings of separation and purification difficulties and difficulty in industrialization.
  • the raw materials of the method for preparing the compound of formula (I) of the present invention are conventional or common reagents, which are easily available in the market and low in price;
  • reaction conditions are mild, easy to control, and simple post-treatment.
  • the solid product is directly precipitated, and a product with higher purity can be obtained through simple recrystallization, with high yield and easy industrialization.
  • the present invention has high industrial application value and economic value in preparing the compound of formula (I) and its intermediates.
  • Ethyl acetate (24.5L, 5V) was added to the combined system, and then water (24.5L, 5V) was added to the combined system. ), after stirring for 30 minutes, let stand to separate the layers, separate the aqueous phase, and then extract once with (ethyl acetate 24.5L, 5V), combine the organic phases, and then wash the organic phase with saturated brine (24.5mL, 5V) twice Then, it was dried, filtered and concentrated to obtain a crude product.
  • compound 1-11 430.00g, 1.245mol, 1eq
  • 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluoro Phosphate 520.88g, 1.37mol, 1.1eq
  • compound 1-12 169.29g, 1.37mol, 1.1eq
  • N,N-diisopropylethylamine (563.29g, 4.36mol, 3.5eq) was added dropwise to the above solution (control the dropping temperature at 15 ⁇ 25°C ), and continue to react for 12 hours, the white suspension slowly turns into a light yellow clear solution.
  • Saturated ammonium chloride solution (43.5mL) was added to the above reaction solution to quench the reaction, and then combined with the other two batches of reaction (430.00g and 430.00g), the combined reaction solution was concentrated to dryness under reduced pressure, and the temperature was controlled to 55. ⁇ 60°C.
  • the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was then added to ethanol (2560 mL) and stirred vigorously at 15-20°C for 16 hours. Filter with a pad of filter cloth, and rinse the filter cake twice with ethanol, 500 mL each time. The filter cake was vacuum dried at 45-55° C. to obtain the compound of formula (I) (815.05 g, 2.06 mol, 81.93% yield).

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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 procédé de préparation d'un composé pyrazolopyrimidine. La présente invention concerne également un procédé de préparation d'un composé représenté par la formule (I) et d'un composé intermédiaire de celui-ci.
PCT/CN2020/125371 2019-10-30 2020-10-30 Procédé de préparation d'un composé pyrazolopyrimidine et d'un intermédiaire de celui-ci WO2021083345A1 (fr)

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CN202080069538.1A CN114641478A (zh) 2019-10-30 2020-10-30 吡唑并嘧啶类化合物的制备方法及其中间体

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CN201911045269.0 2019-10-30
CN201911045269 2019-10-30

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008129255A1 (fr) * 2007-04-18 2008-10-30 Astrazeneca Ab Dérivés de 5-aminopyrazol-3-yl-3h-imidazo[4,5-b]pyridine et leur utilisation pour le traitement du cancer
WO2011146336A1 (fr) * 2010-05-20 2011-11-24 Array Biopharma Inc. Composés macrocycliques en tant qu'inhibiteurs de kinase trk
WO2016097869A1 (fr) * 2014-12-15 2016-06-23 Cmg Pharmaceutical Co., Ltd. Composés d'hétéroaryle à cycle condensé et leur utilisation à titre d'inhibiteurs de trk
WO2017096301A1 (fr) * 2015-12-04 2017-06-08 Denali Therapeutics Inc. Inhibiteurs dérivés d'isoxazolidine de protéine kinase 1 interagissant avec un récepteur (ripk 1)
WO2019130230A1 (fr) * 2017-12-29 2019-07-04 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques utilisés en tant qu'inhibiteurs de kinase
WO2019165967A1 (fr) * 2018-02-28 2019-09-06 南京明德新药研发有限公司 Dérivé de pyrazolopyrimidine et son utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008129255A1 (fr) * 2007-04-18 2008-10-30 Astrazeneca Ab Dérivés de 5-aminopyrazol-3-yl-3h-imidazo[4,5-b]pyridine et leur utilisation pour le traitement du cancer
WO2011146336A1 (fr) * 2010-05-20 2011-11-24 Array Biopharma Inc. Composés macrocycliques en tant qu'inhibiteurs de kinase trk
WO2016097869A1 (fr) * 2014-12-15 2016-06-23 Cmg Pharmaceutical Co., Ltd. Composés d'hétéroaryle à cycle condensé et leur utilisation à titre d'inhibiteurs de trk
WO2017096301A1 (fr) * 2015-12-04 2017-06-08 Denali Therapeutics Inc. Inhibiteurs dérivés d'isoxazolidine de protéine kinase 1 interagissant avec un récepteur (ripk 1)
WO2019130230A1 (fr) * 2017-12-29 2019-07-04 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques utilisés en tant qu'inhibiteurs de kinase
WO2019165967A1 (fr) * 2018-02-28 2019-09-06 南京明德新药研发有限公司 Dérivé de pyrazolopyrimidine et son utilisation

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