WO2021197339A1 - Crystal form of quinopyrrolidine-2-one compound serving as atm inhibitor and use thereof - Google Patents

Crystal form of quinopyrrolidine-2-one compound serving as atm inhibitor and use thereof Download PDF

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WO2021197339A1
WO2021197339A1 PCT/CN2021/084062 CN2021084062W WO2021197339A1 WO 2021197339 A1 WO2021197339 A1 WO 2021197339A1 CN 2021084062 W CN2021084062 W CN 2021084062W WO 2021197339 A1 WO2021197339 A1 WO 2021197339A1
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crystal form
compound
formula
angles
ray powder
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PCT/CN2021/084062
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Chinese (zh)
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钱文远
杨纯道
代国强
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202180025093.1A priority Critical patent/CN115380031A/en
Publication of WO2021197339A1 publication Critical patent/WO2021197339A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D491/20—Spiro-condensed systems

Definitions

  • the invention relates to a crystal form of a quinopyrrolidin-2-one compound as an ATM inhibitor and a preparation method thereof, and its application in the preparation of a medicine for treating diseases related to solid tumors.
  • Ataxia telangiectasia mutated gene is an autosomal recessive genetic gene, homozygous shows a progressive neurodegenerative disease, the patient is about 1 year old, showing the cerebellum Sexual ataxia, tumor-like small blood vessels dilated in the eyes, face and neck around 6 years old, and often died of infection.
  • ATM gene is an important gene related to DNA damage repair, so patients generally show that they are particularly sensitive to X-rays and their DNA repair ability is significantly reduced. Approximately 1% of humans are heterozygous for ATM mutant genes. Although they do not show disease, they also increase the risk of cancer.
  • the ATM gene is located on chromosome 11q22-q23, with a total length of 150kb, a coding sequence of 12kb, and a total of 66 exons. It is one of the human genes with the most exons found so far, and one of the most important genes. Kind of nursing gene.
  • ATM protein which is a serine/threonine protein kinase containing 3056 amino acids and a relative molecular weight of 370,000. It is mainly located in the nucleus and microsomes, and is involved in the progress of the cell cycle and the cell cycle checkpoint for DNA damage. reaction.
  • ATM protein kinase belongs to the phosphatidylinositol 3-kinase-related kinase family (PIKK). It is an autophosphorylated protein and usually exists in the form of an inactive dimer. When a double-strand break occurs in DNA, ATM protein kinase is phosphorylated and depolymerized within a few minutes at the earliest, and the phosphorylated ATM protein kinase reaches its maximum in 2 to 3 hours.
  • PIKK phosphatidylinositol 3-kinase-related kinase family
  • the signaling pathways of ATM protein in DNA damage repair mainly include: 1ATM-CHK2-Cdc25A/B/C signaling pathway; 2ATM-CHK2-p53 signaling pathway; 3ATM-Nbs1-Smc1/3 signaling pathway; 4ATM-p38MAPK-MK2 signaling path.
  • M means MRE11 (meiotic recombinant protein) has nuclease activity and the ability to bind DNA; R is Rad50 has ATPase activity; N It means that NBS1 is involved in the localization of the complex in the nucleus and helps its normal assembly at DNA breakpoints.
  • the various proteins in the MRN complex must coordinate with each other to adjust the ATM protein to bind to the broken end of the DNA and help the broken DNA to complete the repair.
  • ATM plays a key role in the repair of DNA double-strand breaks. Since the probability of double-strand breaks in normal cells is relatively small, selective ATM inhibitors have little effect when used alone, but because ATM is the entire DNA damage repair pathway
  • the key link of ATM inhibitors is that there are many possible combinations of ATM inhibitors. At present, it has been combined with radiotherapy, combined with chemotherapy, and other target inhibitors such as PARP inhibitors for DNA damage repair in preclinical and clinical studies. The combination and so on.
  • AstraZeneca’s AZD0156 is the first compound to enter Phase I clinical studies. At present, AZD1390 and Merck’s M-3541 have also entered Phase I clinical studies.
  • ATM kinase inhibitors are used to treat related diseases as solid tumors, where the solid tumors include but are not limited to: lung cancer, breast cancer, head and neck cancer, prostate cancer, lymphoma, ovarian cancer, cell carcinoma, esophageal cancer, leukemia, Bladder cancer, stomach cancer, melanoma, urothelial cancer, brain tumor, colorectal cancer, liver cancer, mesothelioma, intrahepatic cholangiocarcinoma, etc.
  • the present invention provides crystal form A of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.96 ⁇ 0.20°, 14.85 ⁇ 0.20°, 20.51 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 4.96 ⁇ 0.20°, 12.74 ⁇ 0.20°, 14.85 ⁇ 0.20°, 18.00 ⁇ 0.20°, 19.86 ⁇ 0.20°, 20.51 ⁇ 0.20°, 21.14 ⁇ 0.20°, 29.19 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 4.96 ⁇ 0.20°, 12.74 ⁇ 0.20°, 14.85 ⁇ 0.20°, 18.00 ⁇ 0.20°, 19.86 ⁇ 0.20°, 20.51 ⁇ 0.20°, 21.14 ⁇ 0.20°, 23.76 ⁇ 0.20°, 24.89 ⁇ 0.20°, 29.19 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction at the following 2 ⁇ angles: 4.96°, 12.74°, 14.53°, 14.85°, 17.63°, 18.00°, 19.86°, 20.51° , 22.14°, 23.76°, 24.50°, 24.89°, 27.96°, 28.22°, 29.19°.
  • the XRPD pattern of the above-mentioned crystal form A is shown in FIG. 1.
  • the XRPD pattern analysis data of the above-mentioned crystal form A is shown in Table 1:
  • the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 178.69 ⁇ 3.0°C.
  • the DSC spectrum of the above-mentioned crystal form A is shown in FIG. 2.
  • thermogravimetric analysis curve of the above-mentioned crystal form A has a weight loss of 0.2038% at 178.29°C ⁇ 3.0°C.
  • the TGA pattern of the above-mentioned crystal form A is shown in FIG. 3.
  • the present invention also provides the B crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 19.19 ⁇ 0.20°, 21.76 ⁇ 0.20°, 22.39 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.94 ⁇ 0.20°, 9.35 ⁇ 0.20°, 15.47 ⁇ 0.20°, 16.35 ⁇ 0.20°, 19.19 ⁇ 0.20°, 21.76 ⁇ 0.20°, 22.39 ⁇ 0.20°, 25.09 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.94 ⁇ 0.20°, 9.35 ⁇ 0.20°, 13.06 ⁇ 0.20°, 14.80 ⁇ 0.20°, 15.47 ⁇ 0.20°, 16.35 ⁇ 0.20°, 19.19 ⁇ 0.20°, 19.81 ⁇ 0.20°, 21.76 ⁇ 0.20°, 22.39 ⁇ 0.20°, 24.21 ⁇ 0.20°, 25.09 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction at the following 2 ⁇ angles: 4.94°, 9.35°, 10.52°, 10.84°, 11.13°, 12.04°, 13.06°, 14.24° , 14.80°, 15.13°, 15.47°, 16.35°, 16.61°, 16.82°, 17.61°, 18.43°, 19.19°, 19.81°, 20.36°, 20.60°, 21.76°, 22.13°, 22.39°, 23.77°, 24.21 °, 24.82°, 25.09°, 26.97°, 28.72°, 28.92°, 32.79°, 33.27°.
  • the XRPD pattern of the above-mentioned crystal form B is shown in FIG. 4.
  • the XRPD pattern analysis data of the above-mentioned crystal form B is shown in Table 2:
  • the differential scanning calorimetry curve of the above-mentioned crystal form B has an endothermic peak at 167.54.0 ⁇ 3.0°C, 177.98 ⁇ 3.0°C, and 246.93 ⁇ 3.0°C, respectively; at 168.36 ⁇ 3.0°C There is a peak of exothermic peak.
  • the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 5.
  • thermogravimetric analysis curve of the above-mentioned crystal form B has a weight loss of 0.3265% at 56.15°C ⁇ 3.0°C, a weight loss of 0.3400% at 99.48°C ⁇ 3.0°C, and a weight loss of 0.3400% at 165.87°C ⁇ 3.0°C. Weightlessness reached 0.1831%.
  • the TGA pattern of the above-mentioned crystal form B is shown in FIG. 6.
  • the present invention also provides crystal form C of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.62 ⁇ 0.20°, 9.21 ⁇ 0.20°, 20.46 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 4.62 ⁇ 0.20°, 9.21 ⁇ 0.20°, 12.69 ⁇ 0.20°, 14.46 ⁇ 0.20°, 16.53 ⁇ 0.20°, 17.97 ⁇ 0.20°, 18.48 ⁇ 0.20°, 20.46 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction at the following 2 ⁇ angles: 4.62°, 4.95°, 9.21°, 12.69°, 13.84°, 14.46°, 14.82°, 15.27° , 16.16°, 16.53°, 17.63°, 17.97°, 18.48°, 19.43°, 20.46°, 20.71°, 21.85°, 22.08°, 23.79°, 27.95°, 28.22°, 29.25°.
  • the XRPD pattern of the above-mentioned crystal form C is shown in FIG. 7.
  • the XRPD pattern analysis data of the above-mentioned crystal form C is shown in Table 3:
  • the differential scanning calorimetry curve of the above-mentioned crystal form C has an endothermic peak at 177.38 ⁇ 3.0°C and 253.96 ⁇ 3.0°C, respectively.
  • the DSC spectrum of the above-mentioned crystal form C is shown in FIG. 8.
  • thermogravimetric analysis curve of the above crystal form C has a weight loss of 0.4696% at 120.00°C ⁇ 3.0°C.
  • the TGA pattern of the above-mentioned crystal form C is shown in FIG. 9.
  • the present invention also provides the D crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.95 ⁇ 0.20°, 15.49 ⁇ 0.20°, 19.21 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 4.95 ⁇ 0.20°, 9.37 ⁇ 0.20°, 15.49 ⁇ 0.20°, 16.37 ⁇ 0.20°, 19.21 ⁇ 0.20°, 21.78 ⁇ 0.20°, 22.41 ⁇ 0.20°, 25.13 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 4.95 ⁇ 0.20°, 9.37 ⁇ 0.20°, 13.08 ⁇ 0.20°, 14.28 ⁇ 0.20°, 14.59 ⁇ 0.20°, 16.37 ⁇ 0.20°, 17.63 ⁇ 0.20°, 19.21 ⁇ 0.20°, 21.78 ⁇ 0.20°, 22.41 ⁇ 0.20°, 24.23 ⁇ 0.20°, 25.13 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction at the following 2 ⁇ angles: 4.24°, 4.62°, 4.95°, 9.37°, 10.55°, 12.07°, 13.08°, 13.77° , 14.28°, 14.84°, 15.13°, 15.49°, 16.37°, 16.85°, 17.63°, 17.88°, 18.45°, 19.21°, 19.94°, 20.42°, 20.67°, 21.10°, 21.78°, 22.17°, 22.41 °, 23.79°, 24.23°, 25.13°, 25.66°, 27.01°, 27.61, 28.94°, 29.21°, 31.26°, 32.85°, 33.24°.
  • the XRPD pattern of the above-mentioned crystal form D is shown in FIG. 10.
  • the XRPD pattern analysis data of the above-mentioned crystal form D is shown in Table 4:
  • the differential scanning calorimetry curve of the above-mentioned crystal form D has an endothermic peak at 178.09 ⁇ 3.0°C and 251.68 ⁇ 3.0°C, respectively.
  • the DSC spectrum of the above-mentioned crystal form D is shown in FIG. 11.
  • thermogravimetric analysis curve of the above-mentioned crystal form D has a weight loss of 0.5113% at 73.63°C ⁇ 3.0°C, and a weight loss of 0.6314% at 177.27°C ⁇ 3.0°C.
  • the TGA spectrum of the above-mentioned crystal form D is shown in FIG. 12.
  • the present invention also provides the application of the above crystal form A or B crystal form or C crystal form or D crystal form in the preparation of drugs for treating diseases related to ATM inhibitors.
  • the present invention also provides a method for preparing the compound of formula (I),
  • Catalyst F is selected from bis(dibenzylideneacetone)palladium, tetratriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium/2-biscyclohexylphosphine-2,6-dimethoxybiphenyl, bis(dibenzylideneacetone)palladium, (Dibenzylideneacetone)palladium/2-biscyclohexylphosphine-2,6-dimethoxybiphenyl, [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane and Palladium acetate/4,5-bis(diphenylphosphorus)-9,9-dimethylxanthene;
  • the base G is selected from potassium phosphate, sodium carbonate and potassium acetate
  • Solvent H is selected from dimethyl sulfoxide/water, isopropanol/water, ethanol/water and 1,4-dioxane/water;
  • the above preparation method includes the following reaction route:
  • Reagent A is selected from lithium diisopropylamide
  • Solvent B is selected from tetrahydrofuran
  • Reagent C is selected from n-butyl lithium and dual pinacol borate;
  • Reagent D is selected from triisopropyl borate and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;
  • Solvent E is selected from tetrahydrofuran and 1,4-dioxane;
  • Catalyst I is selected from Raney nickel/hydrogen, palladium carbon/hydrogen and zinc powder/ammonium chloride;
  • Solvent J is selected from ethanol, methanol and tetrahydrofuran/water.
  • Reagent K is selected from potassium carbonate
  • Reagent L is selected from dimethyl carbonate
  • the solvent M is selected from dimethyl sulfoxide.
  • the compound of the present invention has stable crystal forms, is less affected by light, heat and humidity, has good drug efficacy in vivo, and has broad prospects for preparation of medicines; the compound of the present invention has a significant ATM kinase inhibitory effect and has good selectivity for DNA-PK kinase.
  • the process for synthesizing the compound of formula (I) and its intermediates provided by the present invention has the beneficial effects of low-cost and easy-to-obtain raw materials, mild and controllable reaction conditions, easy separation and purification, and easy industrialization.
  • the raw materials of the process method are conventional or common reagents, which are easily available in the market and low in price;
  • the reagents used in each step of the reaction are all small molecules, which are easy to purify and do not need to be purified by column chromatography in the whole process.
  • the present invention has high industrial application value and economic value in preparing the compound of formula (I) and its intermediates.
  • 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.
  • 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 uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultured single crystal.
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • TFA trifluoroacetic acid
  • TsOH stands for p-toluenesulfonic acid
  • mp stands for melting point
  • EtSO 3 H stands for ethanesulfonic acid
  • MeSO 3 H stands for methanesulfonic acid
  • THF stands for tetrahydrofuran
  • EtOAc stands for ethyl acetate
  • DCM stands for dichloromethane
  • DMF stands for N,N-dimethylformamide
  • LDA stands for lithium diisopropylamide
  • NBS stands for N-bromosuccinimide
  • n- BuLi stands for n-butyl lithium
  • DIPA stands for diisopropylamine
  • TBAB stands for tetrabutylammonium bromide
  • Pd 2 (dba) 3 stands for tris(dibenzylideneacetone) dipall
  • Test method Approximately 10-20mg sample is used for XRPD detection.
  • Light tube voltage 40kV
  • light tube current 40mA
  • Test method Take a sample (0.5 ⁇ 1mg) and place it in a DSC aluminum pot for testing. Under the condition of 50mL/min N 2 and at a heating rate of 10°C/min, heat the sample from 30°C (or room temperature) to 300°C.
  • TGA Thermal Gravimetric Analyzer
  • Test method Take a sample (2 ⁇ 5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL/minN 2 and at a heating rate of 10°C/min, heat the sample from room temperature to 300°C or a weight loss of 20%.
  • Test method Take a sample (10-15mg) and place it in the DVS sample pan for testing.
  • Hygroscopicity classification ⁇ W% deliquescence Absorb enough water to form a liquid Very hygroscopic ⁇ W% ⁇ 15% Hygroscopic 15%> ⁇ W% ⁇ 2% Slightly hygroscopic 2%> ⁇ W% ⁇ 0.2% No or almost no hygroscopicity ⁇ W% ⁇ 0.2%
  • ⁇ W% represents the moisture absorption and weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • Fig. 1 is an XRPD spectrum of Cu-K ⁇ radiation of the crystal form of compound A of formula (I).
  • Figure 2 is a DSC spectrum of the crystal form of compound A of formula (I).
  • Figure 3 is a TGA spectrum of the crystal form of compound A of formula (I).
  • Fig. 4 is an XRPD spectrum of Cu-K ⁇ radiation of the crystal form of compound B of formula (I).
  • Figure 5 is a DSC chart of the crystal form of compound B of formula (I).
  • Figure 6 is a TGA spectrum of the crystal form of compound B of formula (I).
  • Fig. 7 is an XRPD spectrum of Cu-K ⁇ radiation of the crystalline form C of compound of formula (I).
  • Fig. 8 is a DSC chart of the crystal form of compound C of formula (I).
  • Figure 9 is a TGA spectrum of the crystal form of compound C of formula (I).
  • Fig. 10 is an XRPD spectrum of Cu-K ⁇ radiation of the crystal form D of compound of formula (I).
  • Figure 11 is a DSC chart of the crystalline form D of compound of formula (I).
  • Figure 12 is a TGA spectrum of the crystal form D of compound of formula (I).
  • Figure 13 is a DVS spectrum of the crystal form of compound A of formula (I).
  • Figure 14 shows the relative weight change
  • Figure 15 shows the tumor growth curve.
  • the mixed solution of compound 1-2 was cooled to 30°C, and ice (80 g) and concentrated hydrochloric acid (15 mL) were added.
  • the above mixed solution was added to a solution of compound 1-3 (34.3 g, 146.57 mmol) in HCl (12M, 90 mL) and H 2 O (200 mL), and stirred at 30°C for 12 hours.
  • N,N-dimethylformamide 35.62mg, 487.30 ⁇ mol, 37.49 ⁇ L
  • 1-5 10g, 34.84mmol
  • thionyl chloride 100mL
  • the solvent was removed by rotary evaporation under reduced pressure, and the residual solid was slurried with ethyl acetate (20 mL)/petroleum ether (50 mL) at 20° C. for 30 minutes to obtain compound 1-6.
  • n-BuLi (2.5M, 3.93mL) was slowly added to DIPA (993.72mg, 9.82mmol, 1.39mL) in THF (10mL) solution, and the reaction system was stirred at -30°C for 30 minutes , And then slowly added methyl tetrahydropyran-4-carboxylate (1.49g, 10.31mmol, 1.38mL) in THF (10mL) solution, the reaction system was stirred at -65°C for 1 hour, and finally compound 1-6 ( 1.5 g, 4.91 mmol) in THF (10 mL), and the reaction system was stirred at -65°C for 2 hours.
  • reaction was quenched by adding water (5mL), then diluted with saturated brine (10mL), extracted with EtOAc (30mL, 10mL*3), and the combined organic phase was washed with saturated brine (30mL, 10mL*3), Dry with anhydrous sodium sulfate, concentrate to obtain a residual solid, and go through column chromatography (0-5% THF/PE) to obtain compound 1-7.
  • compound 1-9 (200mg, 547.65 ⁇ mol), 2-fluoropyridine-5-boronic acid (154.34mg, 1.10mmol), Na 2 CO 3 (116.09mg, 1.10mmol), Pd 2 (dba ) 3 (50.15mg, 54.77 ⁇ mol) and Xphos (50.15mg, 54.77 ⁇ mol) in dioxane (18mL) and water (2mL) solutions were stirred at 100°C for 2 hours. The reaction mixture was concentrated to obtain a residual solid, and the solid was subjected to column chromatography (0-50% EtOAc/PE) to obtain compound 1-10.
  • 2-fluoropyridine-5-boronic acid 154.34mg, 1.10mmol
  • Na 2 CO 3 116.09mg, 1.10mmol
  • Pd 2 (dba ) 3 50.15mg, 54.77 ⁇ mol
  • Xphos 50.15mg, 54.77 ⁇ mol
  • reaction solution was naturally warmed to room temperature about 15°C, reacted for 16h, stirring at 220rpm, and 170mL of 2M HCl solution was added to the reaction solution.
  • the quenching temperature was controlled at 10-15°C; the mixture was rotary evaporated under reduced pressure to remove THF (2300 mL).
  • 1250 mL of 2M HCl solution was added to the remaining mixture to adjust the pH to 5.5-6, which was monitored by a precision pH test paper with a pH monitoring range of 5.5-9.
  • stirring for 0.5 hours at 15°C a light yellow solid precipitated out, and the solid (crude product) was collected by suction filtration under reduced pressure.
  • the 50L reactor was evacuated and filled with nitrogen repeatedly three times, and the reactor was always filled with nitrogen flow.
  • 1.4 kg of compound 1-7, 1.34, compound 2-7, and 97.09 g of bis(dibenzylideneacetone) palladium were sequentially added using an addition funnel. Wash the feeding bottle and the feeding port of the reactor with 3L dimethyl sulfoxide, and add the lotion to the system. Under a nitrogen atmosphere, the reaction system was heated to 60-65°C, and stirring was continued within this temperature range for 14 hours.
  • the reaction solution is diluted with 14L ethyl acetate at about 60 ⁇ 65°C (to prevent the product from separating out and becomes turbid at this time). After stirring evenly (temperature 40 ⁇ 50°C), it is spread with 1000g diatomaceous earth (thickness 2 ⁇ 3cm) while it is hot. ) Filter under reduced pressure, rinse the diatomaceous earth layer with 2L ethyl acetate (30-40°C), combine the filtrate and transfer it to a temporary storage bucket. Control the temperature of the water bath at 45 ⁇ 50°C, and the vacuum degree ⁇ -0.1MPa. Concentrate the solution in the temporary storage tank until no distillate drops to obtain the crude product and DMSO system.
  • the organic phase is concentrated until no distillate drops to obtain 1.50kg of a yellow solid compound.
  • the temperature of the water bath is controlled at 45-50°C, and the degree of vacuum is ⁇ -0.1MPa, and the organic phase is concentrated until no distillate drops to obtain 1.31kg of yellow solid.
  • the solid was slurried with 4L methanol at 40-45°C for 2 hours, filtered under reduced pressure, rinsed with 4L methanol, pumped to a drip-free flow, and 1.2kg of yellow solid was collected. Transfer the solid material to be baked into a dry and clean vacuum drying oven, control the temperature at 45 ⁇ 50°C, the degree of vacuum is ⁇ -0.1MPa, bake the material for 4-6 hours, start weighing from 4 hours until the weight loss is ⁇ 0.2g. A yellow-green powder compound 2-8 (1.17 kg, 62.5% yield) was obtained.
  • the stirring speed is adjusted to 250r/min, then the heating system is heated to 75-80°C, and the temperature is kept for 30-96 hours.
  • the temperature at the end of the reaction dropped to 30-40°C.
  • the Raney nickel is sucked out of the reaction system with a magnetic rod, and quickly transferred to a cup for quenching (the magnetic rod can be stopped if there is no adsorbent on the surface of the magnetic rod).
  • reaction solution was pumped into a 5L three-necked flask, and then 0.5L of dichloromethane was used to flush the residue in the kettle into the three-necked flask, and then 3L of dichloromethane dissolved product was added to the three-necked flask (to prevent product precipitation),
  • filter under reduced pressure through a funnel spread with 200.32g diatomaceous earth (3 ⁇ 4cm thickness) (wet with 0.5L dichloromethane before filtering), rinse the diatomaceous earth layer with 0.5L dichloromethane, and pump to Drop the filtrate drop by drop to stop, combine the filtrate and transfer to the temporary storage bucket.
  • the crude product 826.2g obtained from 11 batches was slurried with 4.13L of methanol at 20 ⁇ 30°C for 12-48 hours.
  • the system was always a suspension, filtered (under reduced pressure), and filtered with methanol (50mL ⁇ 3 times) rinsing, pumping until no droplets drip, and collecting 820.2 g of white solid.
  • the filter cake was dissolved with 385 mL of dichloromethane and separated to obtain the crude compound.
  • the reaction system was filtered under reduced pressure, and the filter cake was rinsed once with 71 mL of ethanol until no liquid dripped. Collect the filter cake, evaporate the solvent until no distillate drops, control the temperature of the water bath at 45-50°C and the vacuum degree ⁇ -0.1Mpa to obtain 298 g of light yellow powder with a yield of 83.5%.
  • the reaction solution was filtered, and the filter cake was rinsed once with 105 mL of methanol until there was no dripping.
  • the filter cake is transferred to a vacuum drying oven, the temperature is controlled at 40 °C, the vacuum degree is ⁇ -0.1 MPa, and the filter cake is baked for 43 hours.
  • An off-white powder was obtained, namely 491.02 g of compound A crystal form of formula (I), yield: 94.7%.
  • the sample placed under the conditions of 60°C high temperature, 92.5%RH high humidity, 40°C/75%RH and 60°C/75%RH is wrapped with aluminum foil paper, and then some small holes are pierced on the aluminum foil paper to ensure that the sample can be Full exposure to ambient air means complete exposure lofting; ICH specified illumination (visible light 1.2 ⁇ 10 6 Lux.hr + ultraviolet light 200W.hr/m 2 ) samples are fully exposed at room temperature (25°C) except for Photo-dark, The photo-dark sample is completely wrapped in tin foil and placed under the light of ICH specified illuminance at room temperature (25°C) for illumination; the 0-day sample is the initial sample, the 0-day sample is sealed with a screw cap and the bottle is wrapped with a sealing film Store it at -20°C after covering it for testing. The sample is placed under high temperature and high humidity conditions for 10 days; placed at 40°C/75% RH for 3 months, and at 60°C/75% RH for 1 month.
  • the test results
  • the sample placed under the conditions of 60°C high temperature, 92.5%RH high humidity, 40°C/75%RH and 60°C/75%RH is wrapped with aluminum foil paper, and then some small holes are pierced on the aluminum foil paper to ensure that the sample can be Full exposure to ambient air means complete exposure lofting; ICH specified illumination (visible light 1.2 ⁇ 10 6 Lux.hr + ultraviolet light 200W.hr/m 2 ) samples are fully exposed at room temperature (25°C) except for Photo-dark, The photo-dark sample is completely wrapped in tin foil and placed under the illumination of ICH specified illuminance at room temperature (25°C) for light; 0 day sample is the initial sample, 0 day sample is sealed with a screw cap and the cap is wrapped with a sealing film Then store it at -20°C for testing. The sample is placed under high temperature and high humidity conditions for 10 days; placed at 40°C/75% RH for 3 months, and at 60°C/75% RH for 1 month.
  • Human-derived ATM kinase was incubated in a buffer solution containing 30 nM GST-cMyc-p53 and Mg/ATP. The concentration of Mg/ATP was determined according to different needs. The reaction was initiated by adding a Mg/ATP complex. After about 30 minutes of incubation at room temperature, add stop solution containing EDTA to terminate the reaction. Finally, for phosphorylated p53, a detection buffer containing d2-labeled anti-GST monoclonal antibody and europium-labeled phosphorylated Ser15 antibody was added.
  • HTRF homogeneous time-resolved fluorescence
  • the human DNA-PK kinase is incubated in a buffer solution containing 50 nM GST-cMyc-p53 and Mg/ATP. The concentration of Mg/ATP is determined according to different needs.
  • the reaction is initiated by adding a Mg/ATP complex. After about 30 minutes of incubation at room temperature, add stop solution containing EDTA to terminate the reaction. Finally, for phosphorylated p53, a detection buffer containing d2-labeled anti-GST monoclonal antibody and europium-labeled phosphorylated Ser15 antibody was added.
  • HTRF homogeneous time-resolved fluorescence
  • the compound of formula (I) has a significant inhibitory effect on ATM kinase and has good selectivity for DNA-PK kinase.
  • test drugs ATM inhibitor and etoposide were administered intraperitoneally or orally in a BALB/c nude mouse model of human lung cancer H446 cell subcutaneous xenograft tumor.
  • IP intraperitoneal injection
  • PO oral
  • QD once a day
  • BIW twice a week
  • QD PG-D0, 3D on, 4D off from PG-D1
  • BIW+QD PG-D0, 3D on, 4D off from PG-D1 ⁇ 4W: give etoposide on Monday, and ATM inhibitors from Tuesday to Thursday, once a day, once a week Circulate, dosing for four weeks.
  • Human lung cancer cells H446 (ATCC, Manassas, VA, HTB-171) were cultured in a monolayer in vitro under RPMI-1640, with 10% fetal bovine serum, 100U/mL penicillin and 100 ⁇ g/mL streptomycin, 37 Cultivation with 5% CO2. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and seeded.
  • the experimental index is to investigate whether the tumor growth is inhibited, delayed or cured.
  • the tumor diameter was measured with vernier calipers twice a week.
  • TGI (%) [1- (Average tumor volume at the end of a certain treatment group-the average tumor volume at the beginning of the treatment group) / (Average tumor volume at the end of the solvent control group- The average tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • T/C (%) where T is the average tumor volume obtained from the last measurement (PG-D26) of the treatment group, and C is the average tumor volume obtained from the last measurement (PG-D26) of the control group.
  • the body weight of experimental animals is used as a reference index for indirect determination of drug toxicity. In this model, none of the administration groups showed significant weight loss (Figure 14). Mice No. 42161 was found dead on the 15th day after the etoposide, 15mg/kg and AZD0156, 5mg/kg combination groups were administered. In the treatment group where etoposide was combined with the compound of formula (I) and AZD0156, some animals lost more than 10% but not less than 15% in body weight.
  • the test drugs ATM inhibitor and etoposide affect the body weight of the H446 cell subcutaneous xenograft female BALB/c nude mouse model. Figure 14 shows. The relative weight change is calculated based on the weight of the animal at the beginning of the administration. The data points represent the average weight change percentage within the group, and the error bars represent the standard error (SEM).
  • the tumor volume changes in each group after the treatment of the test drug ATM inhibitor and etoposide in the female BALB/c nude mouse model of subcutaneous xenotransplanted tumor with H446 cells are shown in Table 11.
  • the tumor growth curve is shown in Figure 15.
  • the data points represent the average tumor volume within the group, and the error bars represent the standard error (SEM).
  • Anti-tumor efficacy evaluation index (calculated based on tumor volume on the 26th day after administration)
  • c.p value is calculated based on tumor volume.

Abstract

Provided are a crystal form of a quinopyrrolidine-2-one compound (I), which serves as an ATM inhibitor, a preparation method therefor, and the use thereof in the preparation of a drug for treating solid tumor-related diseases.

Description

作为ATM抑制剂的喹啉并吡咯烷-2-酮类化合物的晶型及其应用Crystal forms of quinopyrrolidin-2-one compounds as ATM inhibitors and their applications
本申请主张如下优先权This application claims the following priority
CN202010237923.4，申请日：2020.03.30。CN202010237923.4, application date: 2020.03.30.
技术领域Technical field
本发明涉及一种作为ATM抑制剂的喹啉并吡咯烷-2-酮类化合物的晶型及其制备方法，及其在制备治疗与实体瘤相关疾病的药物中的应用。The invention relates to a crystal form of a quinopyrrolidin-2-one compound as an ATM inhibitor and a preparation method thereof, and its application in the preparation of a medicine for treating diseases related to solid tumors.
背景技术Background technique
毛细血管扩张性共济失调突变基因(ATM，Ataxia telangiectasia mutated gene)是一种常染色体隐性遗传基因，纯合子表现出一种进行性神经变性性疾病，患者1岁左右患病，表现为小脑性共济失调，6岁左右眼和面颈部出现瘤样小血管扩张，常死于感染。ATM基因是与DNA损伤修复相关的一种重要基因，因此患者一般表现为对X射线特别敏感，DNA修复能力明显下降。人类中大约有1％的人是ATM突变基因的杂合子，虽然不表现出疾病，但也增加了患癌的风险。ATM基因位于染色体11q22-q23，全长150kb，编码序列12kb，共有66个外显子，是到目前为止所发现的外显子最多的人类基因之一，也是最重要的基因之一，是一种看护基因。Ataxia telangiectasia mutated gene (ATM, Ataxia telangiectasia mutated gene) is an autosomal recessive genetic gene, homozygous shows a progressive neurodegenerative disease, the patient is about 1 year old, showing the cerebellum Sexual ataxia, tumor-like small blood vessels dilated in the eyes, face and neck around 6 years old, and often died of infection. ATM gene is an important gene related to DNA damage repair, so patients generally show that they are particularly sensitive to X-rays and their DNA repair ability is significantly reduced. Approximately 1% of humans are heterozygous for ATM mutant genes. Although they do not show disease, they also increase the risk of cancer. The ATM gene is located on chromosome 11q22-q23, with a total length of 150kb, a coding sequence of 12kb, and a total of 66 exons. It is one of the human genes with the most exons found so far, and one of the most important genes. Kind of nursing gene.
ATM基因编码产物为ATM蛋白，是一种丝/苏氨酸蛋白激酶，包含3056个氨基酸，相对分子量370000，主要位于细胞核和微粒体内，参与细胞周期的进行及对DNA损伤的细胞周期检查点的反应。ATM蛋白激酶属于磷脂酰肌醇3-激酶相关激酶家族(PIKK)中的一员，是一种自动磷酸化蛋白，通常以无活性的二聚体的形式存在，当DNA发生双链断裂时，ATM蛋白激酶最早在数分钟就出现磷酸化而解聚，在2到3小时磷酸化的ATM蛋白激酶达到最大值。The ATM gene encoded product is ATM protein, which is a serine/threonine protein kinase containing 3056 amino acids and a relative molecular weight of 370,000. It is mainly located in the nucleus and microsomes, and is involved in the progress of the cell cycle and the cell cycle checkpoint for DNA damage. reaction. ATM protein kinase belongs to the phosphatidylinositol 3-kinase-related kinase family (PIKK). It is an autophosphorylated protein and usually exists in the form of an inactive dimer. When a double-strand break occurs in DNA, ATM protein kinase is phosphorylated and depolymerized within a few minutes at the earliest, and the phosphorylated ATM protein kinase reaches its maximum in 2 to 3 hours.
ATM蛋白在DNA的损伤修复中的信号通路主要有：①ATM-CHK2-Cdc25A/B/C信号通路；②ATM-CHK2-p53信号通路；③ATM-Nbs1-Smc1/3信号通路；④ATM-p38MAPK-MK2信号通路。ATM蛋白识别DNA双链断裂并发生自动磷酸化的过程涉及MRN复合物的参与，M即MRE11(减数分裂重组蛋白)具有核酸酶活性及结合DNA的能力；R为Rad50具有ATP酶活性；N指NBS1涉及该复合物在细胞核内的定位及帮助其在DNA断裂点正常装配。MRN复合物中各种蛋白必须相互协调才能调节ATM蛋白结合到DNA的断端点，帮助断裂的DNA完成修复。The signaling pathways of ATM protein in DNA damage repair mainly include: ①ATM-CHK2-Cdc25A/B/C signaling pathway; ②ATM-CHK2-p53 signaling pathway; ③ATM-Nbs1-Smc1/3 signaling pathway; ④ATM-p38MAPK-MK2 signaling path. The process of ATM protein recognizing DNA double-strand breaks and auto-phosphorylation involves the participation of MRN complexes. M means MRE11 (meiotic recombinant protein) has nuclease activity and the ability to bind DNA; R is Rad50 has ATPase activity; N It means that NBS1 is involved in the localization of the complex in the nucleus and helps its normal assembly at DNA breakpoints. The various proteins in the MRN complex must coordinate with each other to adjust the ATM protein to bind to the broken end of the DNA and help the broken DNA to complete the repair.
ATM在DNA双链断裂的修复中起关键作用，由于正常细胞发生双链断裂的几率较小，因此选择性的ATM抑制剂单用时几乎没有什么作用，但由于ATM是整个DNA损伤修复的通路中的关键一环，ATM抑制剂存在多种联用的可能，目前临床前以及临床研究中已出现与放疗联用，与化疗联用，以及与DNA损伤修复的其它靶点抑制剂如PARP抑制剂的联用等。阿斯利康的AZD0156是最早进入一期临床的化合物，目前AZD1390和德国默克的M-3541也相继进入一期临床的研究。ATM plays a key role in the repair of DNA double-strand breaks. Since the probability of double-strand breaks in normal cells is relatively small, selective ATM inhibitors have little effect when used alone, but because ATM is the entire DNA damage repair pathway The key link of ATM inhibitors is that there are many possible combinations of ATM inhibitors. At present, it has been combined with radiotherapy, combined with chemotherapy, and other target inhibitors such as PARP inhibitors for DNA damage repair in preclinical and clinical studies. The combination and so on. AstraZeneca’s AZD0156 is the first compound to enter Phase I clinical studies. At present, AZD1390 and Merck’s M-3541 have also entered Phase I clinical studies.
ATM激酶抑制剂用于治疗相关的疾病为实体瘤，其中所述实体瘤包括但不限于：肺癌、乳腺癌、头颈癌、前列腺癌、淋巴瘤、卵巢癌、旨细胞癌、食管癌，白血病、膀胱癌、胃癌、黑色素瘤、尿路 上皮癌、脑肿瘤、结直肠癌、肝癌、间皮瘤、肝内胆管癌等。ATM kinase inhibitors are used to treat related diseases as solid tumors, where the solid tumors include but are not limited to: lung cancer, breast cancer, head and neck cancer, prostate cancer, lymphoma, ovarian cancer, cell carcinoma, esophageal cancer, leukemia, Bladder cancer, stomach cancer, melanoma, urothelial cancer, brain tumor, colorectal cancer, liver cancer, mesothelioma, intrahepatic cholangiocarcinoma, etc.
发明内容Summary of the invention
本发明提供了式(I)化合物的A晶型，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.96±0.20°，14.85±0.20°，20.51±0.20°。The present invention provides crystal form A of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.96±0.20°, 14.85±0.20°, 20.51±0.20°.
Figure PCTCN2021084062-appb-000001
Figure PCTCN2021084062-appb-000001
在本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.96±0.20°，12.74±0.20°，14.85±0.20°，18.00±0.20°，19.86±0.20°，20.51±0.20°，21.14±0.20°，29.19±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 4.96±0.20°, 12.74±0.20°, 14.85±0.20°, 18.00±0.20°, 19.86± 0.20°, 20.51±0.20°, 21.14±0.20°, 29.19±0.20°.
在本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.96±0.20°，12.74±0.20°，14.85±0.20°，18.00±0.20°，19.86±0.20°，20.51±0.20°，21.14±0.20°，23.76±0.20°，24.89±0.20°，29.19±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 4.96±0.20°, 12.74±0.20°, 14.85±0.20°, 18.00±0.20°, 19.86± 0.20°, 20.51±0.20°, 21.14±0.20°, 23.76±0.20°, 24.89±0.20°, 29.19±0.20°.
在本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射：4.96°，12.74°，14.53°，14.85°，17.63°，18.00°，19.86°，20.51°，22.14°，23.76°，24.50°，24.89°，27.96°，28.22°，29.19°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction at the following 2θ angles: 4.96°, 12.74°, 14.53°, 14.85°, 17.63°, 18.00°, 19.86°, 20.51° , 22.14°, 23.76°, 24.50°, 24.89°, 27.96°, 28.22°, 29.19°.
在本发明的一些方案中，上述A晶型，其XRPD图谱如图1所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned crystal form A is shown in FIG. 1.
本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表1所示：In some aspects of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form A is shown in Table 1:
表1.式(I)化合物A晶型的XRPD图谱解析数据Table 1. XRPD pattern analysis data of the crystal form of compound A of formula (I)
Figure PCTCN2021084062-appb-000002
Figure PCTCN2021084062-appb-000002
在本发明的一些方案中，上述A晶型的差示扫描量热曲线在178.69±3.0℃有一个吸热峰的峰值。In some aspects of the present invention, the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 178.69±3.0°C.
在本发明的一些方案中，上述A晶型的DSC图谱如图2所示。In some aspects of the present invention, the DSC spectrum of the above-mentioned crystal form A is shown in FIG. 2.
在本发明的一些方案中，上述A晶型的热重分析曲线在178.29℃±3.0℃时失重达0.2038％。In some aspects of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form A has a weight loss of 0.2038% at 178.29°C±3.0°C.
在本发明的一些方案中，上述A晶型的TGA图谱如图3所示。In some aspects of the present invention, the TGA pattern of the above-mentioned crystal form A is shown in FIG. 3.
本发明还提供了式(I)化合物的B晶型，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：19.19±0.20°，21.76±0.20°，22.39±0.20°。The present invention also provides the B crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 19.19±0.20°, 21.76±0.20°, 22.39±0.20°.
在本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.94±0.20°，9.35±0.20°，15.47±0.20°，16.35±0.20°，19.19±0.20°，21.76±0.20°，22.39±0.20°，25.09±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2θ angles: 4.94±0.20°, 9.35±0.20°, 15.47±0.20°, 16.35±0.20°, 19.19± 0.20°, 21.76±0.20°, 22.39±0.20°, 25.09±0.20°.
在本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.94±0.20°，9.35±0.20°，13.06±0.20°，14.80±0.20°，15.47±0.20°，16.35±0.20°，19.19±0.20°，19.81±0.20°，21.76±0.20°，22.39±0.20°，24.21±0.20°，25.09±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2θ angles: 4.94±0.20°, 9.35±0.20°, 13.06±0.20°, 14.80±0.20°, 15.47± 0.20°, 16.35±0.20°, 19.19±0.20°, 19.81±0.20°, 21.76±0.20°, 22.39±0.20°, 24.21±0.20°, 25.09±0.20°.
在本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射：4.94°，9.35°，10.52°，10.84°，11.13°，12.04°，13.06°，14.24°，14.80°，15.13°，15.47°，16.35°，16.61°，16.82°，17.61°，18.43°，19.19°，19.81°，20.36°，20.60°，21.76°，22.13°，22.39°，23.77°，24.21°，24.82°，25.09°，26.97°，28.72°，28.92°，32.79°，33.27°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction at the following 2θ angles: 4.94°, 9.35°, 10.52°, 10.84°, 11.13°, 12.04°, 13.06°, 14.24° , 14.80°, 15.13°, 15.47°, 16.35°, 16.61°, 16.82°, 17.61°, 18.43°, 19.19°, 19.81°, 20.36°, 20.60°, 21.76°, 22.13°, 22.39°, 23.77°, 24.21 °, 24.82°, 25.09°, 26.97°, 28.72°, 28.92°, 32.79°, 33.27°.
在本发明的一些方案中，上述B晶型，其XRPD图谱如图4所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned crystal form B is shown in FIG. 4.
本发明的一些方案中，上述B晶型的XRPD图谱解析数据如表2所示：In some aspects of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form B is shown in Table 2:
表2.式(I)化合物B晶型的XRPD图谱解析数据Table 2. XRPD pattern analysis data of compound B crystal form of formula (I)
Figure PCTCN2021084062-appb-000003
Figure PCTCN2021084062-appb-000003
在本发明的一些方案中，上述B晶型的差示扫描量热曲线分别在167.54.0±3.0℃、177.98±3.0℃和246.93±3.0℃有一个吸热峰的峰值；在168.36±3.0℃有一个放热峰的峰值。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form B has an endothermic peak at 167.54.0±3.0°C, 177.98±3.0°C, and 246.93±3.0°C, respectively; at 168.36±3.0°C There is a peak of exothermic peak.
在本发明的一些方案中，上述B晶型的DSC图谱如图5所示。In some aspects of the present invention, the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 5.
在本发明的一些方案中，上述B晶型的热重分析曲线在56.15℃±3.0℃时失重达0.3265％，在99.48℃±3.0℃时又失重达0.3400％，在165.87℃±3.0℃时又失重达0.1831％。In some aspects of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form B has a weight loss of 0.3265% at 56.15°C±3.0°C, a weight loss of 0.3400% at 99.48°C±3.0°C, and a weight loss of 0.3400% at 165.87°C±3.0°C. Weightlessness reached 0.1831%.
在本发明的一些方案中，上述B晶型的TGA图谱如图6所示。In some aspects of the present invention, the TGA pattern of the above-mentioned crystal form B is shown in FIG. 6.
本发明还提供了式(I)化合物的C晶型，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.62±0.20°，9.21±0.20°，20.46±0.20°。The present invention also provides crystal form C of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 9.21±0.20°, 20.46±0.20°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.62±0.20°，9.21±0.20°，12.69±0.20°，14.46±0.20°，16.53±0.20°，17.97±0.20°，18.48±0.20°，20.46±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 9.21±0.20°, 12.69±0.20°, 14.46±0.20°, 16.53± 0.20°, 17.97±0.20°, 18.48±0.20°, 20.46±0.20°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射：4.62°，4.95°，9.21°，12.69°，13.84°，14.46°，14.82°，15.27°，16.16°，16.53°，17.63°，17.97°，18.48°，19.43°，20.46°，20.71°，21.85°，22.08°，23.79°，27.95°，28.22°，29.25°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction at the following 2θ angles: 4.62°, 4.95°, 9.21°, 12.69°, 13.84°, 14.46°, 14.82°, 15.27° , 16.16°, 16.53°, 17.63°, 17.97°, 18.48°, 19.43°, 20.46°, 20.71°, 21.85°, 22.08°, 23.79°, 27.95°, 28.22°, 29.25°.
在本发明的一些方案中，上述C晶型，其XRPD图谱如图7所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned crystal form C is shown in FIG. 7.
本发明的一些方案中，上述C晶型的XRPD图谱解析数据如表3所示：In some aspects of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form C is shown in Table 3:
表3.式(I)化合物C晶型的XRPD图谱解析数据Table 3. XRPD pattern analysis data of compound C crystal form of formula (I)
Figure PCTCN2021084062-appb-000004
Figure PCTCN2021084062-appb-000004
在本发明的一些方案中，上述C晶型的差示扫描量热曲线分别在177.38±3.0℃和253.96±3.0℃有一个吸热峰的峰值。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form C has an endothermic peak at 177.38±3.0°C and 253.96±3.0°C, respectively.
在本发明的一些方案中，上述C晶型的DSC图谱如图8所示。In some aspects of the present invention, the DSC spectrum of the above-mentioned crystal form C is shown in FIG. 8.
在本发明的一些方案中，上述C晶型的热重分析曲线在120.00℃±3.0℃时失重达0.4696％。In some aspects of the present invention, the thermogravimetric analysis curve of the above crystal form C has a weight loss of 0.4696% at 120.00°C±3.0°C.
在本发明的一些方案中，上述C晶型的TGA图谱如图9所示。In some aspects of the present invention, the TGA pattern of the above-mentioned crystal form C is shown in FIG. 9.
本发明还提供了式(I)化合物的D晶型，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.95±0.20°，15.49±0.20°，19.21±0.20°。The present invention also provides the D crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.95±0.20°, 15.49±0.20°, 19.21±0.20°.
在本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.95±0.20°，9.37±0.20°，15.49±0.20°，16.37±0.20°，19.21±0.20°，21.78±0.20°，22.41±0.20°，25.13±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2θ angles: 4.95±0.20°, 9.37±0.20°, 15.49±0.20°, 16.37±0.20°, 19.21± 0.20°, 21.78±0.20°, 22.41±0.20°, 25.13±0.20°.
在本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.95±0.20°，9.37±0.20°，13.08±0.20°，14.28±0.20°，14.59±0.20°，16.37±0.20°，17.63±0.20°，19.21±0.20°，21.78±0.20°，22.41±0.20°，24.23±0.20°，25.13±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2θ angles: 4.95±0.20°, 9.37±0.20°, 13.08±0.20°, 14.28±0.20°, 14.59± 0.20°, 16.37±0.20°, 17.63±0.20°, 19.21±0.20°, 21.78±0.20°, 22.41±0.20°, 24.23±0.20°, 25.13±0.20°.
在本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射：4.24°，4.62°，4.95°，9.37°，10.55°，12.07°，13.08°，13.77°，14.28°，14.84°，15.13°，15.49°，16.37°，16.85°，17.63°，17.88°，18.45°，19.21°，19.94°，20.42°，20.67°，21.10°，21.78°，22.17°，22.41°，23.79°，24.23°，25.13°，25.66°，27.01°，27.61，28.94°，29.21°，31.26°，32.85°，33.24°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction at the following 2θ angles: 4.24°, 4.62°, 4.95°, 9.37°, 10.55°, 12.07°, 13.08°, 13.77° , 14.28°, 14.84°, 15.13°, 15.49°, 16.37°, 16.85°, 17.63°, 17.88°, 18.45°, 19.21°, 19.94°, 20.42°, 20.67°, 21.10°, 21.78°, 22.17°, 22.41 °, 23.79°, 24.23°, 25.13°, 25.66°, 27.01°, 27.61, 28.94°, 29.21°, 31.26°, 32.85°, 33.24°.
在本发明的一些方案中，上述D晶型，其XRPD图谱如图10所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned crystal form D is shown in FIG. 10.
本发明的一些方案中，上述D晶型的XRPD图谱解析数据如表4所示：In some aspects of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form D is shown in Table 4:
表4.式(I)化合物D晶型的XRPD图谱解析数据Table 4. XRPD pattern analysis data of compound D crystal form of formula (I)
Figure PCTCN2021084062-appb-000005
Figure PCTCN2021084062-appb-000005
在本发明的一些方案中，上述D晶型的差示扫描量热曲线分别在178.09±3.0℃和251.68±3.0℃有一个吸热峰的峰值。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form D has an endothermic peak at 178.09±3.0°C and 251.68±3.0°C, respectively.
在本发明的一些方案中，上述D晶型的DSC图谱如图11所示。In some aspects of the present invention, the DSC spectrum of the above-mentioned crystal form D is shown in FIG. 11.
在本发明的一些方案中，上述D晶型的热重分析曲线在73.63℃±3.0℃时失重达0.5113％，在177.27℃±3.0℃时又失重达0.6314％。In some aspects of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form D has a weight loss of 0.5113% at 73.63°C±3.0°C, and a weight loss of 0.6314% at 177.27°C±3.0°C.
在本发明的一些方案中，上述D晶型的TGA图谱如图12所示。In some aspects of the present invention, the TGA spectrum of the above-mentioned crystal form D is shown in FIG. 12.
本发明还提供上述A晶型或B晶型或C晶型或D晶型在制备治疗与ATM抑制剂相关疾病的药物上的应用。The present invention also provides the application of the above crystal form A or B crystal form or C crystal form or D crystal form in the preparation of drugs for treating diseases related to ATM inhibitors.
本发明还提供了式(I)化合物的制备方法，The present invention also provides a method for preparing the compound of formula (I),
Figure PCTCN2021084062-appb-000006
Figure PCTCN2021084062-appb-000006
其包含如下步骤：It includes the following steps:
Figure PCTCN2021084062-appb-000007
Figure PCTCN2021084062-appb-000007
其中，in,
催化剂F选自双(二亚苄基丙酮)钯、四三苯基膦钯、三(二亚苄基丙酮)二钯/2-双环己基膦-2，6-二甲氧基联苯、双(二亚苄基丙酮)钯/2-双环己基膦-2，6-二甲氧基联苯、[1，1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷和醋酸钯/4，5-双(二苯基磷)-9，9-二甲基氧杂蒽；Catalyst F is selected from bis(dibenzylideneacetone)palladium, tetratriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium/2-biscyclohexylphosphine-2,6-dimethoxybiphenyl, bis(dibenzylideneacetone)palladium, (Dibenzylideneacetone)palladium/2-biscyclohexylphosphine-2,6-dimethoxybiphenyl, [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane and Palladium acetate/4,5-bis(diphenylphosphorus)-9,9-dimethylxanthene;
碱G选自磷酸钾、碳酸钠和醋酸钾；The base G is selected from potassium phosphate, sodium carbonate and potassium acetate;
溶剂H选自二甲亚砜/水、异丙醇/水、乙醇/水和1，4-二氧六环/水；Solvent H is selected from dimethyl sulfoxide/water, isopropanol/water, ethanol/water and 1,4-dioxane/water;
在本发明的一些方案中，上述制备方法，其包含如下反应路线：In some aspects of the present invention, the above preparation method includes the following reaction route:
Figure PCTCN2021084062-appb-000008
Figure PCTCN2021084062-appb-000008
其中，in,
试剂A选自二异丙基氨基锂；Reagent A is selected from lithium diisopropylamide;
溶剂B选自四氢呋喃；Solvent B is selected from tetrahydrofuran;
试剂C选自正丁基锂和双联频哪醇硼酸酯；Reagent C is selected from n-butyl lithium and dual pinacol borate;
试剂D选自硼酸三异丙酯和[1，1′-双(二苯基膦基)二茂铁]二氯化钯；Reagent D is selected from triisopropyl borate and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;
溶剂E选自四氢呋喃和1，4-二氧六环；Solvent E is selected from tetrahydrofuran and 1,4-dioxane;
催化剂I选自雷尼镍/氢气、钯碳/氢气和锌粉/氯化铵；Catalyst I is selected from Raney nickel/hydrogen, palladium carbon/hydrogen and zinc powder/ammonium chloride;
溶剂J选自乙醇、甲醇和四氢呋喃/水。Solvent J is selected from ethanol, methanol and tetrahydrofuran/water.
试剂K选自碳酸钾；Reagent K is selected from potassium carbonate;
试剂L选自碳酸二甲酯；Reagent L is selected from dimethyl carbonate;
溶剂M选自二甲亚砜。The solvent M is selected from dimethyl sulfoxide.
技术效果Technical effect
本发明化合物各晶型稳定、受光热湿度影响小且具有良好的体内给药药效，成药前景广阔；本发明化合物具有显著的ATM激酶抑制作用，并且对DNA-PK激酶具有良好的选择性。The compound of the present invention has stable crystal forms, is less affected by light, heat and humidity, has good drug efficacy in vivo, and has broad prospects for preparation of medicines; the compound of the present invention has a significant ATM kinase inhibitory effect and has good selectivity for DNA-PK kinase.
本发明给出的合成式(I)化合物及其中间体的工艺，有益效果为：原料廉价易得、反应条件温和可控、易于分离纯化、易于工业化。The process for synthesizing the compound of formula (I) and its intermediates provided by the present invention has the beneficial effects of low-cost and easy-to-obtain raw materials, mild and controllable reaction conditions, easy separation and purification, and easy industrialization.
具体地：specifically:
1)工艺方法原料为常规或常见试剂，在市场上容易获得且价格低廉；1) The raw materials of the process method are conventional or common reagents, which are easily available in the market and low in price;
2)由原来的单线合成变成现在的聚合式路线，提高了工艺生产的效率；2) Change from the original single-line synthesis to the current polymerization route, which improves the efficiency of process production;
3)整个路线中不再需要钠氢，消除了安全隐患；3) Sodium hydrogen is no longer needed in the entire route, eliminating safety hazards;
4)通过Suzuki反应制备化合物2-8可以避免原路线中氟取代的选择性问题；4) Preparation of compound 2-8 by Suzuki reaction can avoid the selective problem of fluorine substitution in the original route;
5)最后一步使用碳酸二甲酯替换碘甲烷，反应干净，后处理简单，利于得到纯度高的式(I)化合物。5) In the last step, dimethyl carbonate is used to replace methyl iodide, the reaction is clean, the post-treatment is simple, and it is beneficial to obtain the compound of formula (I) with high purity.
6)各步骤反应中所使用试剂均为小分子，易于纯化，全程无需进行柱层析纯化。6) The reagents used in each step of the reaction are all small molecules, which are easy to purify and do not need to be purified by column chromatography in the whole process.
因此，本发明在制备式(I)化合物及其中间体方面，具有很高的工业应用价值和经济价值。Therefore, the present invention has high industrial application value and economic value in preparing the compound of formula (I) and its intermediates.
定义和说明Definition and description
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific phrase or term should not be considered uncertain or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。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.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2021084062-appb-000009
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。 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. For example, the single crystal X-ray diffraction method (SXRD) uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultured single crystal. The light source is CuKα radiation, and the scanning method:
Figure PCTCN2021084062-appb-000009
After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reaction in the specific embodiment of the present invention is completed in a suitable solvent, and the solvent must be suitable for the chemical change of the present invention and the required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the existing embodiments.
本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本发明中的氨基)选择合适的保护基。An important consideration in the planning of any synthetic route in the art is to select a suitable protecting group for the reactive functional group (such as the amino group in the present invention).
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。Hereinafter, the present invention will be specifically described through examples, and these examples are not meant to limit the present invention in any way.
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。All solvents used in the present invention are commercially available and can be used without further purification.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：EtOH代表乙醇；MeOH代表甲醇；TFA代表三氟乙酸；TsOH代表对甲苯磺酸；mp代表熔点；EtSO 3H代表乙磺酸；MeSO 3H代表甲磺酸；THF代表四氢呋喃；EtOAc代表乙酸乙酯；DCM代表二氯甲烷；DMF代表N，N-二甲基甲酰胺；LDA代表二异丙基氨基锂；NBS代表N-溴代琥珀酰亚胺；n-BuLi代表正丁基锂；DIPA代表二异丙胺；TBAB代表四丁基溴化铵；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；Xphos代表2-二环己基磷-2，4，6-三异丙基联苯。 The solvent used in the present invention is commercially available. The present invention uses the following acronyms: EtOH stands for ethanol; MeOH stands for methanol; TFA stands for trifluoroacetic acid; TsOH stands for p-toluenesulfonic acid; mp stands for melting point; EtSO 3 H stands for ethanesulfonic acid; MeSO 3 H stands for methanesulfonic acid; THF stands for tetrahydrofuran; EtOAc stands for ethyl acetate; DCM stands for dichloromethane; DMF stands for N,N-dimethylformamide; LDA stands for lithium diisopropylamide; NBS stands for N-bromosuccinimide; n- BuLi stands for n-butyl lithium; DIPA stands for diisopropylamine; TBAB stands for tetrabutylammonium bromide; Pd 2 (dba) 3 stands for tris(dibenzylideneacetone) dipalladium; Xphos stands for 2-dicyclohexylphosphorus-2 , 4,6-Triisopropylbiphenyl.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2021084062-appb-000010
软件命名，市售化合物采用供应商目录名称。 Compounds are based on conventional naming principles in the field or use
Figure PCTCN2021084062-appb-000010
The software is named, and the commercially available compounds use the supplier catalog name.
本发明粉末X-射线衍射(X-ray powder diffractometer，XRPD)方法Powder X-ray diffraction (X-ray powder diffractometer, XRPD) method of the present invention
仪器型号：Bruker D8 Advance X-射线衍射仪Instrument model: Bruker D8 Advance X-ray diffractometer
测试方法：大约10～20mg样品用于XRPD检测。Test method: Approximately 10-20mg sample is used for XRPD detection.
详细的XRPD参数如下：The detailed XRPD parameters are as follows:
射线源：
Figure PCTCN2021084062-appb-000011
Ray source:
Figure PCTCN2021084062-appb-000011
光管电压：40kV，光管电流：40mALight tube voltage: 40kV, light tube current: 40mA
发散狭缝：0.60mmDivergence slit: 0.60mm
探测器狭缝：10.50mmDetector slit: 10.50mm
防散射狭缝：7.10mmAnti-scatter slit: 7.10mm
扫描范围：3-40degScanning range: 3-40deg
步径：0.02degStep diameter: 0.02deg
步长：0.12秒Step length: 0.12 seconds
样品盘转速：15rpm/0rpmSample plate speed: 15rpm/0rpm
本发明差热分析(Differential Scanning Calorimeter，DSC)方法The differential thermal analysis (Differential Scanning Calorimeter, DSC) method of the present invention
仪器型号：TA Q2000差示扫描量热仪Instrument model: TA Q2000 Differential Scanning Calorimeter
测试方法：测试方法：取样品(0.5～1mg)置于DSC铝锅内进行测试，在50mL/min N 2条件下，以10℃/min的升温速率，加热样品从30℃(或室温)到300℃。 Test method: Test method: Take a sample (0.5～1mg) and place it in a DSC aluminum pot for testing. Under the condition of 50mL/min N 2 and at a heating rate of 10℃/min, heat the sample from 30℃ (or room temperature) to 300°C.
本发明热重分析(Thermal Gravimetric Analyzer，TGA)方法Thermal Gravimetric Analyzer (TGA) method of the present invention
仪器型号：TA Q5000IR热重分析仪Instrument model: TA Q5000IR thermogravimetric analyzer
测试方法：取样品(2～5mg)置于TGA铂金锅内进行测试，在25mL/minN 2条件下，以10℃/min的 升温速率，加热样品从室温到300℃或失重20％。 Test method: Take a sample (2～5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL/minN 2 and at a heating rate of 10℃/min, heat the sample from room temperature to 300℃ or a weight loss of 20%.
本发明动态蒸汽吸附分析(Dynamic Vapor Sorption，DVS)方法The dynamic vapor adsorption analysis (Dynamic Vapor Sorption, DVS) method of the present invention
仪器型号：SMS DVS Advantage动态蒸汽吸附仪Instrument model: SMS DVS Advantage Dynamic Vapor Sorption Apparatus
测试方法：取样品(10～15mg)置于DVS样品盘内进行测试。Test method: Take a sample (10-15mg) and place it in the DVS sample pan for testing.
详细的DVS参数如下：The detailed DVS parameters are as follows:
平衡：dm/dt＝0.01％/min(最短：10min，最长：180min)Balance: dm/dt=0.01%/min (shortest: 10min, longest: 180min)
干燥：0％RH下干燥120minDrying: 120min under 0%RH
RH(％)测试梯级：10％RH (%) test step: 10%
RH(％)测试梯级范围：0％-90％-0％RH(%) test step range: 0%-90%-0%
引湿性评价分类如下：The classification of hygroscopicity evaluation is as follows:
吸湿性分类Hygroscopicity classification ΔW％ΔW%
潮解deliquescence 吸收足量水分形成液体Absorb enough water to form a liquid
极具吸湿性Very hygroscopic ΔW％≥15％ΔW％≥15％
有吸湿性Hygroscopic 15％＞ΔW％≥2％15%＞ΔW%≥2%
略有吸湿性Slightly hygroscopic 2％＞ΔW％≥0.2％2%＞ΔW%≥0.2%
无或几乎无吸湿性No or almost no hygroscopicity ΔW％＜0.2％ΔW％＜0.2％
注：ΔW％表示受试品在25±1℃和80±2％RH下的吸湿增重。Note: ΔW% represents the moisture absorption and weight gain of the test product at 25±1°C and 80±2%RH.
附图说明Description of the drawings
图1为式(I)化合物A晶型的Cu-Kα辐射的XRPD谱图。Fig. 1 is an XRPD spectrum of Cu-Kα radiation of the crystal form of compound A of formula (I).
图2为式(I)化合物A晶型的DSC谱图。Figure 2 is a DSC spectrum of the crystal form of compound A of formula (I).
图3为式(I)化合物A晶型的TGA谱图。Figure 3 is a TGA spectrum of the crystal form of compound A of formula (I).
图4为式(I)化合物B晶型的Cu-Kα辐射的XRPD谱图。Fig. 4 is an XRPD spectrum of Cu-Kα radiation of the crystal form of compound B of formula (I).
图5为式(I)化合物B晶型的DSC谱图。Figure 5 is a DSC chart of the crystal form of compound B of formula (I).
图6为式(I)化合物B晶型的TGA谱图。Figure 6 is a TGA spectrum of the crystal form of compound B of formula (I).
图7为式(I)化合物C晶型的Cu-Kα辐射的XRPD谱图。Fig. 7 is an XRPD spectrum of Cu-Kα radiation of the crystalline form C of compound of formula (I).
图8为式(I)化合物C晶型的DSC谱图。Fig. 8 is a DSC chart of the crystal form of compound C of formula (I).
图9为式(I)化合物C晶型的TGA谱图。Figure 9 is a TGA spectrum of the crystal form of compound C of formula (I).
图10为式(I)化合物D晶型的Cu-Kα辐射的XRPD谱图。Fig. 10 is an XRPD spectrum of Cu-Kα radiation of the crystal form D of compound of formula (I).
图11为式(I)化合物D晶型的DSC谱图。Figure 11 is a DSC chart of the crystalline form D of compound of formula (I).
图12为式(I)化合物D晶型的TGA谱图。Figure 12 is a TGA spectrum of the crystal form D of compound of formula (I).
图13为式(I)化合物A晶型的DVS谱图。Figure 13 is a DVS spectrum of the crystal form of compound A of formula (I).
图14为相对体重变化。Figure 14 shows the relative weight change.
图15为肿瘤生长曲线。Figure 15 shows the tumor growth curve.
具体实施方式Detailed ways
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。In order to better understand the content of the present invention, a further description will be given below in conjunction with specific examples, but the specific implementation is not a limitation on the content of the present invention.
实施例1：式(I)化合物的制备Example 1: Preparation of the compound of formula (I)
Figure PCTCN2021084062-appb-000012
Figure PCTCN2021084062-appb-000012
合成路线：synthetic route:
Figure PCTCN2021084062-appb-000013
Figure PCTCN2021084062-appb-000013
步骤1：化合物1-3的合成Step 1: Synthesis of compound 1-3
在0℃氮气保护下，将NBS(30.12g，169.22mmol)的DMF(100mL)溶液加入到化合物3a(25g，161.16mmol)的DMF(100mL)溶液中，反应体系在30℃搅拌2小时。反应完毕后，减压浓缩除去反应溶剂，然后用水(100mL)打浆30分钟，再用乙腈(10mL)洗涤，得到化合物1-3。Under nitrogen protection at 0°C, a DMF (100 mL) solution of NBS (30.12 g, 169.22 mmol) was added to a DMF (100 mL) solution of compound 3a (25 g, 161.16 mmol), and the reaction system was stirred at 30°C for 2 hours. After the completion of the reaction, the reaction solvent was removed by concentration under reduced pressure, and then slurried with water (100 mL) for 30 minutes, and washed with acetonitrile (10 mL) to obtain compound 1-3.
MS m/z：233.8[M+H] +； MS m/z: 233.8[M+H] + ;
1H NMR(400MHz，DMSO-d 6)δ7.88(br d，J＝7.88Hz，1H)，6.69(br d，J＝11.38Hz，1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.88 (br d, J = 7.88 Hz, 1H), 6.69 (br d, J = 11.38 Hz, 1H).
步骤2：化合物1-2的合成Step 2: Synthesis of compound 1-2
在圆底烧瓶中，将硝基甲烷(18g，294.89mmol，15.93mL)缓慢加入到NaOH(17.69g，442.33mmol)的H 2O(100mL)溶液中，保持内部温度在30℃，然后加热到40℃搅拌30分钟，冷却，再缓慢加入另一部分硝基甲烷(18.00g，294.89mmol，15.93mL)，反应体系被加热到45℃搅拌30分钟，然后升高到50℃-55℃搅拌5分钟，得到化合物1-2的混合液，直接用于下一步反应。 In a round bottom flask, slowly add nitromethane (18g, 294.89mmol, 15.93mL) to NaOH (17.69g, 442.33mmol) in H 2 O (100mL) solution, keep the internal temperature at 30 ℃, and then heat to Stir at 40°C for 30 minutes, cool, and then slowly add another part of nitromethane (18.00g, 294.89mmol, 15.93mL), the reaction system is heated to 45°C and stirred for 30 minutes, then raised to 50°C-55°C and stirred for 5 minutes , The mixed solution of compound 1-2 is obtained, which is directly used in the next reaction.
步骤3：化合物1-4的合成Step 3: Synthesis of compound 1-4
将化合物1-2的混合溶液冷却到30℃，加入冰(80g)和浓盐酸(15mL)。将上述混合液加入到化合物1-3(34.3g，146.57mmol)的HCl(12M，90mL)和H 2O(200mL)溶液中，30℃搅拌12小时。有固体析出，过滤，收集滤饼，然后用乙腈(50mL)洗涤，得到化合物1-4。 The mixed solution of compound 1-2 was cooled to 30°C, and ice (80 g) and concentrated hydrochloric acid (15 mL) were added. The above mixed solution was added to a solution of compound 1-3 (34.3 g, 146.57 mmol) in HCl (12M, 90 mL) and H 2 O (200 mL), and stirred at 30°C for 12 hours. A solid precipitated out, filtered, collected the filter cake, and then washed with acetonitrile (50 mL) to obtain compound 1-4.
MS m/z：304.7[M+H] +； MS m/z: 304.7[M+H] + ;
1H NMR(400MHz，DMSO-d 6)δ12.99(br d，J＝12.5Hz，1H)，8.23-8.13(m，1H)，8.08-7.96(m，1H)，7.88(br d，J＝10.5Hz，1H)，6.80(br s，1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.99 (br d, J = 12.5 Hz, 1H), 8.23-8.13 (m, 1H), 8.08-7.96 (m, 1H), 7.88 (br d, J = 10.5 Hz, 1H), 6.80 (br s, 1H).
步骤4：化合物1-5的合成Step 4: Synthesis of compound 1-5
在氮气保护下，将化合物1-4(44g，111.06mmol)的乙酸酐(397.79g，3.90mol，364.94mL)溶液在100℃加热1小时，然后停止加热，加入乙酸钠(9.38g，114.39mmol)，在150℃回流15分钟，最后加入另一部分乙酸钠(9.38g，114.39mmol)，反应体系在150℃回流1小时。反应完毕后，浓缩除去溶剂，残留固体用水(200mL)打浆1小时，然后再用EtOAc和甲醇混合液(55mL，EtOAc∶MeOH＝10∶1)打浆1小时，过滤得到化合物1-5。Under the protection of nitrogen, a solution of compound 1-4 (44g, 111.06mmol) in acetic anhydride (397.79g, 3.90mol, 364.94mL) was heated at 100°C for 1 hour, then the heating was stopped, and sodium acetate (9.38g, 114.39mmol) was added. ), reflux at 150°C for 15 minutes, and finally add another portion of sodium acetate (9.38 g, 114.39 mmol), and reflux the reaction system at 150°C for 1 hour. After the reaction was completed, the solvent was removed by concentration, and the remaining solid was slurried with water (200 mL) for 1 hour, and then slurried with a mixture of EtOAc and methanol (55 mL, EtOAc:MeOH=10:1) for 1 hour, and filtered to obtain compound 1-5.
MS m/z：287.0[M+H] +； MS m/z: 287.0[M+H] + ;
1H NMR(400MHz，DMSO-d 6)δ9.25(s，1H)，8.44(d，J＝7.5Hz，1H)，7.63(br d，J＝9.3Hz，1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.25 (s, 1H), 8.44 (d, J=7.5 Hz, 1H), 7.63 (br d, J=9.3 Hz, 1H).
步骤5：化合物1-6的合成Step 5: Synthesis of compound 1-6
在20℃氮气保护下，将N，N-二甲基甲酰胺(35.62mg，487.30μmol，37.49μL)加入到1-5(10g，34.84mmol)的二氯亚砜(100mL)溶液中，反应体系在80℃搅拌17小时。反应完毕后，减压旋蒸除去溶剂，残留固体经乙酸乙酯(20mL)/石油醚(50mL)在20℃打浆30分钟，得到化合物1-6。Under the protection of nitrogen at 20℃, add N,N-dimethylformamide (35.62mg, 487.30μmol, 37.49μL) to 1-5 (10g, 34.84mmol) thionyl chloride (100mL) solution, and react The system was stirred at 80°C for 17 hours. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and the residual solid was slurried with ethyl acetate (20 mL)/petroleum ether (50 mL) at 20° C. for 30 minutes to obtain compound 1-6.
MS m/z：304.7[M+H] +； MS m/z: 304.7[M+H] + ;
1H NMR(400MHz，CDCl 3)δ＝9.28(s，1H)，8.70(d，J＝7.0Hz，1H)，7.91(d，J＝8.5Hz，1H)。 1 H NMR (400 MHz, CDCl 3 ) δ=9.28 (s, 1H), 8.70 (d, J=7.0 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H).
步骤6：化合物1-7的合成Step 6: Synthesis of compounds 1-7
在-60℃氮气保护下，将n-BuLi(2.5M，3.93mL)缓慢加入到DIPA(993.72mg，9.82mmol，1.39mL)的THF(10mL)溶液中，反应体系在-30℃搅拌30分钟，然后缓慢加入四氢吡喃-4-甲酸甲酯(1.49g，10.31mmol，1.38mL)的THF(10mL)溶液中，反应体系在-65℃搅拌1小时，最后缓慢加入化合物1-6(1.5g，4.91mmol)的THF(10mL)溶液，反应体系在-65℃搅拌2小时。反应完毕后，加入水(5mL)淬灭反应，再加入饱和食盐水(10mL)稀释，用EtOAc萃取(30mL，10mL*3)，合并有机相用饱和食盐水洗涤(30mL，10mL*3)，无水硫酸钠干燥，浓缩得到残留固体，经过柱层析(0～5％THF/PE)得到化合物1-7。Under the protection of nitrogen at -60℃, n-BuLi (2.5M, 3.93mL) was slowly added to DIPA (993.72mg, 9.82mmol, 1.39mL) in THF (10mL) solution, and the reaction system was stirred at -30℃ for 30 minutes , And then slowly added methyl tetrahydropyran-4-carboxylate (1.49g, 10.31mmol, 1.38mL) in THF (10mL) solution, the reaction system was stirred at -65°C for 1 hour, and finally compound 1-6 ( 1.5 g, 4.91 mmol) in THF (10 mL), and the reaction system was stirred at -65°C for 2 hours. After the reaction was completed, the reaction was quenched by adding water (5mL), then diluted with saturated brine (10mL), extracted with EtOAc (30mL, 10mL*3), and the combined organic phase was washed with saturated brine (30mL, 10mL*3), Dry with anhydrous sodium sulfate, concentrate to obtain a residual solid, and go through column chromatography (0-5% THF/PE) to obtain compound 1-7.
MS m/z：412.8[M+H] +。 MS m/z: 412.8 [M+H] + .
步骤7：化合物1-8的合成Step 7: Synthesis of compounds 1-8
在氮气保护下，将锌粉(1.14g，17.43mmol)加入到化合物1-7(720mg，1.74mmol)和NH 4Cl(932.10mg，17.43mmol，609.22μL)的THF(10mL)和H 2O(10mL)溶液中，反应体系在70℃搅拌3小时。反应完毕后过滤，滤液浓缩得到残留固体，固体用水(20mL)打浆30分钟，得到化合物1-8。 Under the protection of nitrogen, zinc powder (1.14 g, 17.43 mmol) was added to compound 1-7 (720 mg, 1.74 mmol) and NH 4 Cl (932.10 mg, 17.43 mmol, 609.22 μL) in THF (10 mL) and H 2 O (10 mL) In the solution, the reaction system was stirred at 70°C for 3 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated to obtain a residual solid. The solid was slurried with water (20 mL) for 30 minutes to obtain compound 1-8.
MS m/z：350.9[M+H] +。 MS m/z: 350.9 [M+H] + .
步骤8：化合物1-9的合成Step 8: Synthesis of compounds 1-9
在氮气保护下，将碘甲烷(347.68mg，2.45mmol，152.49μL)的二氯甲烷(10mL)溶液加入到化合物1-8(500mg，1.07mmol)，TBAB(34.33mg，106.50μmol)和NaOH(63.90mg，1.60mmol)的DCM(10mL)和H 2O(10mL)溶液中，反应体系在30℃搅拌1小时。反应完毕后，过滤，滤液浓缩得到残留固体，残留固体用水(20mL)打浆30分钟得到化合物1-9。 Under the protection of nitrogen, a solution of methyl iodide (347.68 mg, 2.45 mmol, 152.49 μL) in dichloromethane (10 mL) was added to compound 1-8 (500 mg, 1.07 mmol), TBAB (34.33 mg, 106.50 μmol) and NaOH ( In a solution of 63.90 mg, 1.60 mmol) in DCM (10 mL) and H 2 O (10 mL), the reaction system was stirred at 30° C. for 1 hour. After the reaction was completed, it was filtered and the filtrate was concentrated to obtain a residual solid. The residual solid was slurried with water (20 mL) for 30 minutes to obtain compound 1-9.
MS m/z：364.9[M+H] +。 MS m/z: 364.9 [M+H] + .
步骤9：化合物1-10的合成Step 9: Synthesis of compound 1-10
在氮气保护条件下，将化合物1-9(200mg，547.65μmol)，2-氟吡啶-5-硼酸(154.34mg，1.10mmol)，Na 2CO 3(116.09mg，1.10mmol)，Pd 2(dba) 3(50.15mg，54.77μmol)和Xphos(50.15mg，54.77μmol) 的二氧六环(18mL)和水(2mL)溶液100℃搅拌2小时。反应混合液浓缩得到残留固体，固体经过柱层析(0～50％EtOAc/PE)得到化合物1-10。 Under nitrogen protection, compound 1-9 (200mg, 547.65μmol), 2-fluoropyridine-5-boronic acid (154.34mg, 1.10mmol), Na 2 CO 3 (116.09mg, 1.10mmol), Pd 2 (dba ) 3 (50.15mg, 54.77μmol) and Xphos (50.15mg, 54.77μmol) in dioxane (18mL) and water (2mL) solutions were stirred at 100°C for 2 hours. The reaction mixture was concentrated to obtain a residual solid, and the solid was subjected to column chromatography (0-50% EtOAc/PE) to obtain compound 1-10.
MS m/z：382.0[M+H] +。 MS m/z: 382.0 [M+H] + .
步骤10：式(I)化合物的合成Step 10: Synthesis of the compound of formula (I)
在20℃氮气保护条件下，将化合物1-10(100mg，262.21μmol)加入到1-哌啶丙醇(75.11mg，524.42μmol，28.71μL)和NaH(41.95mg，1.05mmol，60％纯度)的DMF(10mL)溶液中，反应体系70℃搅拌2小时。反应结束加入水(2mL)淬灭，浓缩得到残留固体，固体经过柱层析(0～10％MeOH/DCM)和制备HPLC(column：Boston Prime C18 150×30mm 5μm；mobile流动相：[水(0.05％氢氧化铵v/v)-乙腈]；乙腈％：50％-80％，8min)分离得到式(I)化合物。Under nitrogen protection at 20°C, compound 1-10 (100 mg, 262.21 μmol) was added to 1-piperidine propanol (75.11 mg, 524.42 μmol, 28.71 μL) and NaH (41.95 mg, 1.05 mmol, 60% purity) In the DMF (10 mL) solution, the reaction system was stirred at 70°C for 2 hours. At the end of the reaction, water (2mL) was added for quenching, and concentrated to obtain a residual solid. The solid was subjected to column chromatography (0-10% MeOH/DCM) and preparative HPLC (column: Boston Prime C18 150×30mm 5μm; mobile mobile phase: [水( 0.05% ammonium hydroxide v/v)-acetonitrile]; acetonitrile%: 50%-80%, 8 min) to obtain the compound of formula (I).
MS m/z：505.3[M+H] +； MS m/z: 505.3[M+H] + ;
1H NMR(400MHz，CDCl 3)δ8.71(s，1H)，8.42(s，1H)，8.07(d，J＝8.0Hz，1H)，7.93-7.84(m，2H)，6.89(d，J＝8.8Hz，1H)，4.56-4.34(m，4H)，3.97(dd，J＝4.8，11.5Hz，2H)，3.39(s，3H)，2.78-2.60(m，2H)，2.52(br s，2H)，2.50-2.33(m，4H)，2.10-1.99(m，2H)，1.69(br d，J＝14.3Hz，2H)，1.60(br s，4H)，1.50-1.40(m，2H)。 1 H NMR (400MHz, CDCl 3 ) δ 8.71 (s, 1H), 8.42 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.93-7.84 (m, 2H), 6.89 (d, J=8.8Hz, 1H), 4.56-4.34(m, 4H), 3.97(dd, J=4.8, 11.5Hz, 2H), 3.39(s, 3H), 2.78-2.60(m, 2H), 2.52(br s, 2H), 2.50-2.33 (m, 4H), 2.10-1.99 (m, 2H), 1.69 (br d, J = 14.3 Hz, 2H), 1.60 (br s, 4H), 1.50-1.40 (m, 2H).
实施例2：式(I)化合物A晶型的制备Example 2: Preparation of Compound A of Formula (I)
Figure PCTCN2021084062-appb-000014
Figure PCTCN2021084062-appb-000014
步骤1：化合物2-2的合成Step 1: Synthesis of compound 2-2
向DCM(10L)中加入化合物2-1(1250g，4.29mol，1eq)，DMF(15.69g，214.69mmol，16.52mL，0.05eq)，向混合液中缓慢滴加草酰氯(1.67kg，12.88mol，1.15L，3eq)，反应在50L反应釜中，外温27-29℃(内温24-27℃)下搅拌16小时(转速约为150rpm)。反应液内温经高低温循环浴降温至10-15℃，向反应液中缓慢滴加水(4.4L)，过程中保持搅拌(转速约为300rpm)。将混合液转移至50L分液器中，搅拌5分钟后分液，水相中加入DCM(5L)并搅拌5分钟后分液，水相中再次加入DCM(5L)并搅拌5分钟后分液，合并有机相，向反应液中加入水(10L*5)搅拌5分钟后分液，直到水相pH为6-7且稳定，有机相用硅藻土过滤，减压旋蒸除去溶剂(旋蒸2小时)直到恒重，得到淡黄色固体化合物2-2(1.11kg，3.60mol，83.77％收率，98.81％纯度)。Compound 2-1 (1250g, 4.29mol, 1eq), DMF (15.69g, 214.69mmol, 16.52mL, 0.05eq) were added to DCM (10L), and oxalyl chloride (1.67kg, 12.88mol) was slowly added dropwise to the mixture. , 1.15L, 3eq), the reaction was carried out in a 50L reactor, and stirred at an external temperature of 27-29°C (internal temperature of 24-27°C) for 16 hours (rotating speed is about 150rpm). The internal temperature of the reaction liquid was cooled to 10-15° C. through a high-low temperature circulating bath, and water (4.4L) was slowly added dropwise to the reaction liquid, and stirring was maintained during the process (rotational speed was about 300 rpm). Transfer the mixed solution to a 50L separator, stir for 5 minutes and then separate. Add DCM (5L) to the aqueous phase and stir for 5 minutes and then separate. Add DCM (5L) to the aqueous phase again and stir for 5 minutes before separating. Combine the organic phases, add water (10L*5) to the reaction solution, stir for 5 minutes, and then separate until the pH of the aqueous phase is 6-7 and stable. The organic phase is filtered with diatomaceous earth, and the solvent is removed by rotary evaporation under reduced pressure. Steam for 2 hours) until constant weight to obtain a pale yellow solid compound 2-2 (1.11 kg, 3.60 mol, 83.77% yield, 98.81% purity).
1H NMR(400MHz，CDCl 3)δ9.28(s，1H)，8.70(d，J＝7.0Hz，1H)，7.91(d，J＝8.8Hz，1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.28 (s, 1H), 8.70 (d, J=7.0 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H).
步骤2：化合物1-7的合成Step 2: Synthesis of compounds 1-7
在-25～-15℃，氮气保护下向THF(940mL)中滴加LDA(2M，718.30mL，1.89eq)(5分钟)，向其中缓慢滴入化合物2-3(126.89g，836.12mmol，117.49mL，1.1eq)的THF(235mL)溶液(40分钟)，温度控制在-25～-15℃，搅拌75分钟，向其中缓慢滴加化合物2-2(235g，760.11mmol，1eq)的THF(1175mL)溶液(3小时)，反应液缓慢升温至15℃搅拌16小时(机械搅拌转速约为200rpm)。在-15℃下，向反应液中加入饱和NH 4Cl(1.2L)淬灭反应，向混合液中加入EA(234mL)后分液，水相中用EA(1.2L*2)萃取，合并有机相，用食盐水(1.2L)洗涤，减压旋蒸除去溶剂(约6L)至恒重，得到粗品(黑色油状化合物)。向粗品中加入EtOH(200mL)搅拌16小时(搅拌至体系中无大颗粒)，减压抽滤，滤饼用EtOH(80mL*2)洗涤，滤饼经减压旋蒸除去溶剂至恒重，得到黑棕色固体化合物化合物1-7(109g，214.31mmol，收率：28.19％，纯度：81.24％)。 LDA (2M, 718.30mL, 1.89eq) (5 minutes) was added dropwise to THF (940mL) at -25～-15°C under nitrogen protection, and compound 2-3 (126.89g, 836.12mmol, 117.49mL, 1.1eq) in THF (235mL) solution (40 minutes), the temperature was controlled at -25～-15℃, stirred for 75 minutes, to which compound 2-2 (235g, 760.11mmol, 1eq) in THF was slowly added dropwise (1175mL) solution (3 hours), the reaction solution was slowly heated to 15°C and stirred for 16 hours (mechanical stirring speed was about 200rpm). At -15°C, add saturated NH 4 Cl (1.2L) to the reaction solution to quench the reaction, add EA (234 mL) to the mixed solution and then separate the layers, extract the aqueous phase with EA (1.2L*2) and combine The organic phase was washed with brine (1.2L), and the solvent (about 6L) was removed by rotary evaporation under reduced pressure to a constant weight to obtain a crude product (black oily compound). EtOH (200mL) was added to the crude product and stirred for 16 hours (stirred until there are no large particles in the system), filtered under reduced pressure, the filter cake was washed with EtOH (80mL*2), and the filter cake was evaporated under reduced pressure to remove the solvent to a constant weight. A dark brown solid compound compound 1-7 (109 g, 214.31 mmol, yield: 28.19%, purity: 81.24%) was obtained.
1H NMR(400MHz，DMSO-d 6)δ9.19(s，1H)，8.59(d，J＝7.0Hz，1H)，8.19(d，J＝9.0Hz，1H)，3.86-3.73(m，4H)，3.63(s，3H)，2.40(br d，J＝12.8Hz，2H)，2.25-2.16(m，2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.19 (s, 1H), 8.59 (d, J = 7.0 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H), 3.86-3.73 (m, 4H), 3.63 (s, 3H), 2.40 (br d, J=12.8 Hz, 2H), 2.25-2.16 (m, 2H).
步骤3：化合物2-6的合成Step 3: Synthesis of compound 2-6
将化合物2-4(546.8g，3.04mol，319.77mL，1eq)，化合物2-5(489.51g，3.35mol，1.1eq)溶于DMSO(1650mL)中，向其中加入Cs 2CO 3(1.98kg，6.09mol，2eq)，反应在内温65-75℃(外温75-85℃)下搅拌16小时(转速约为250rpm)。将反应液分批、缓慢加入到水(7.5L)中，10-25℃下搅拌3小时。减压抽滤，滤饼中加入水(1.5L)和乙腈(130mL)搅拌，减压抽滤收集滤饼并用水(300mL*3)洗涤，滤饼在45℃下真空干燥箱敞口烘干至恒重。得到淡黄色固体化合物2-6(463.9g，1.55mol，收率：50.92％，纯度：100％)。 Compound 2-4 (546.8g, 3.04mol, 319.77mL, 1eq), compound 2-5 (489.51g, 3.35mol, 1.1eq) were dissolved in DMSO (1650mL), and Cs 2 CO 3 (1.98kg , 6.09mol, 2eq), and the reaction was stirred at an internal temperature of 65-75°C (external temperature of 75-85°C) for 16 hours (rotating speed is about 250rpm). The reaction solution was slowly added to water (7.5L) in batches, and stirred at 10-25°C for 3 hours. Vacuum filtration, add water (1.5L) and acetonitrile (130mL) to the filter cake and stir, collect the filter cake by vacuum filtration and wash it with water (300mL*3). The filter cake is dried in a vacuum drying oven at 45°C. To constant weight. A pale yellow solid compound 2-6 (463.9 g, 1.55 mol, yield: 50.92%, purity: 100%) was obtained.
1H NMR(400MHz，DMSO-d 6)δ8.25(d，J＝2.4Hz，1H)，7.86(dd，J＝2.6，8.8Hz，1H)，6.80(d，J＝8.9Hz，1H)，4.22(t，J＝6.6Hz，2H)，2.36-2.26(m，6H)，1.83(quin，J＝6.9Hz，2H)，1.46(quin，J＝5.5Hz，4H)，1.38-1.33(m，2H)。 1H NMR (400MHz, DMSO-d 6 ) δ 8.25 (d, J = 2.4 Hz, 1H), 7.86 (dd, J = 2.6, 8.8 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 4.22(t, J=6.6Hz, 2H), 2.36-2.26(m, 6H), 1.83(quin, J=6.9Hz, 2H), 1.46(quin, J=5.5Hz, 4H), 1.38-1.33(m , 2H).
步骤4：化合物2-7的合成Step 4: Synthesis of compound 2-7
将化合物2-6(405g，1.35mol，1eq)加入到THF(2025mL)中，搅拌溶解，乙酸乙酯干冰浴降温至-65℃.N 2保护下，将n-BuLi(2.5M，649.72mL，1.2eq)缓慢滴加至反应液液中，滴加过程控制反应液温度-65℃至-55℃，滴加完毕搅拌1小时之后在N 2保护下，将硼酸三异丙酯(311.72g，1.62mol，381.07mL，98％purity，1.2eq)滴加至反应液中，滴加完毕，反应液自然升温至室温约15℃，反应16h，搅拌速度220rpm向反应液中加入170mL浓度2MHCl溶液进行淬灭，淬灭温度控制在10～15℃；将混合液减压旋蒸以除去THF(2300mL)。然后向剩余混合物加入1250mL浓度2M HCl溶液调节pH至5.5～6，通过pH监测范围为5.5-9的精密pH试纸监测。15℃下搅拌0.5小时后，有淡黄色固体析出，减压抽滤收集固体(粗品)。向粗品中加入1200mL乙腈，搅拌12小时后，减压抽滤收集固体(白色)，将固体减压旋蒸至恒重，再次向固体中加入1200mL乙腈，搅拌48小时后，减压抽滤收集固体减压旋蒸至恒重，得到化合物2-7(263g，995.73mmol，收率：73.56％，纯度：100％)。 Compound 2-6 (405g, 1.35mol, 1eq) was added to THF (2025mL), stirred to dissolve, and ethyl acetate dry ice bath was cooled to -65°C. Under N 2 protection, n-BuLi (2.5M, 649.72mL) , 1.2eq) was slowly added dropwise to the reaction solution. The temperature of the reaction solution was controlled by the dropping process from -65°C to -55°C. After the dropwise addition was completed and stirred for 1 hour, under the protection of N 2 , triisopropyl borate (311.72g , 1.62mol, 381.07mL, 98% purity, 1.2eq) was added dropwise to the reaction solution. After the addition was completed, the reaction solution was naturally warmed to room temperature about 15°C, reacted for 16h, stirring at 220rpm, and 170mL of 2M HCl solution was added to the reaction solution. For quenching, the quenching temperature was controlled at 10-15°C; the mixture was rotary evaporated under reduced pressure to remove THF (2300 mL). Then, 1250 mL of 2M HCl solution was added to the remaining mixture to adjust the pH to 5.5-6, which was monitored by a precision pH test paper with a pH monitoring range of 5.5-9. After stirring for 0.5 hours at 15°C, a light yellow solid precipitated out, and the solid (crude product) was collected by suction filtration under reduced pressure. Add 1200 mL of acetonitrile to the crude product. After stirring for 12 hours, collect the solid (white) by suction filtration under reduced pressure. Rotate the solid to constant weight under reduced pressure. Add 1200 mL of acetonitrile to the solid again. After stirring for 48 hours, collect the solid (white) by suction filtration under reduced pressure. The solid was rotary evaporated to constant weight under reduced pressure to obtain compound 2-7 (263 g, 995.73 mmol, yield: 73.56%, purity: 100%).
1H NMR(400MHz，DMSO-d 6)δ10.53(br s，1H)，8.94(d，J＝1.5Hz，1H)，8.57(br s，1H)，8.45(dd，J＝2.0，8.3 Hz，1H)，7.19(d，J＝8.3Hz，1H)，4.76(t，J＝6.1Hz，2H)，3.86(br d，J＝11.8Hz，2H)，3.57(td，J＝5.3，10.5Hz，2H)，3.34-3.23(m，2H)，2.64-2.55(m，2H)，2.25-2.15(m，4H)，2.12(br d，J＝12.8Hz，1H)，1.90-1.70(m，1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.53 (br s, 1H), 8.94 (d, J = 1.5 Hz, 1H), 8.57 (br s, 1H), 8.45 (dd, J = 2.0, 8.3 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 4.76 (t, J = 6.1 Hz, 2H), 3.86 (br d, J = 11.8 Hz, 2H), 3.57 (td, J = 5.3, 10.5Hz, 2H), 3.34-3.23(m, 2H), 2.64-2.55(m, 2H), 2.25-2.15(m, 4H), 2.12(br d, J=12.8Hz, 1H), 1.90-1.70( m, 1H).
步骤5：化合物2-8的合成Step 5: Synthesis of compound 2-8
将50L反应釜抽真空充氮气反复三次，并一直使反应釜中充斥氮气流。向反应釜中加入11L二甲亚砜和1.4L纯化水，搅拌下加入2.15kg无水磷酸钾。在25～26℃，用加料漏斗依次加入1.4kg的化合物1-7，1.34，的化合物2-7，97.09g的双(二亚苄基丙酮)钯。用3L二甲亚砜洗涤加料瓶及反应釜进料口，洗液加入体系。氮气氛围下，将反应体系加热升温至60～65℃，在此温度范围内继续搅拌14小时。反应液在60～65℃左右用14L乙酸乙酯稀释(防止产物析出，此时悬浊)，搅拌均匀后(温度40～50℃)，趁热经过铺有1000g硅藻土(厚度2～3cm)减压过滤，硅藻土层用2L乙酸乙酯(30～40℃)淋洗，将滤液合并转移至暂存桶中。控制水浴温度45～50℃，真空度≤-0.1MPa条件，将暂存桶中溶液浓缩至无馏分滴下，得到粗品与DMSO体系。31℃下，搅拌向DMSO溶液中滴加纯化水2L(有轻微放热，25分钟滴加完毕)，固体析出。温度降到19℃，减压过滤，用2.5L纯化水淋洗，抽至无液滴流下，收集固体。析出的固体15～20℃下用17L纯化水打浆1小时，减压过滤，用5L纯化水淋洗，抽至无液滴流下，收集土黄色固体4.07kg。用12L乙醇(3L/kg粗品)，搅拌下加热至76～79℃下溶解后，关闭加热，自然降温，14个小时后温度缓慢降低到20℃，固体析出。减压过滤，用2L乙醇淋洗滤饼，抽至无液滴滴下，收集红棕色固体1.99kg。用20L乙醇(10L/kg粗品)，76～79℃下溶解后，乙醇回流下慢慢加入活性炭200g(约0.1kg/kg)，继续在回流下搅拌3小时，趁热经1000g硅藻土(2～3cm厚度)过滤，用6L乙酸乙酯(50～60℃)淋洗，收集滤液。控制水浴温度45～50℃，真空度≤-0.1MPa条件，将有机相浓缩至无馏分滴下，得到黄色固体化合物1.50kg。粗品用15L乙醇(10L/kg)，76～78℃下溶解后，乙醇回流下慢慢加入活性炭150g(约0.1kg/kg)，继续在回流下搅拌3小时，趁热经1000g硅藻土(2～3cm厚度)过滤，用8L乙酸乙酯(40～50℃)淋洗，收集滤液。控制水浴温度45～50℃，真空度≤-0.1MPa条件，将有机相浓缩至无馏分滴下，得到黄色固体1.31kg。固体40～45℃下用4L甲醇打浆2小时，减压过滤，用4L甲醇淋洗，抽至无液滴流下，收集黄色固体1.2kg。将待烘料固体转移至干燥洁净的真空干燥箱中，控制温度45～50℃，真空度≤-0.1MPa，烘料4～6小时，自4小时开始称量至减重≤0.2g。得到黄绿色粉末化合物2-8(1.17kg，收率为62.5％)。The 50L reactor was evacuated and filled with nitrogen repeatedly three times, and the reactor was always filled with nitrogen flow. Add 11L of dimethyl sulfoxide and 1.4L of purified water to the reaction kettle, and add 2.15kg of anhydrous potassium phosphate with stirring. At 25 to 26°C, 1.4 kg of compound 1-7, 1.34, compound 2-7, and 97.09 g of bis(dibenzylideneacetone) palladium were sequentially added using an addition funnel. Wash the feeding bottle and the feeding port of the reactor with 3L dimethyl sulfoxide, and add the lotion to the system. Under a nitrogen atmosphere, the reaction system was heated to 60-65°C, and stirring was continued within this temperature range for 14 hours. The reaction solution is diluted with 14L ethyl acetate at about 60～65℃ (to prevent the product from separating out and becomes turbid at this time). After stirring evenly (temperature 40～50℃), it is spread with 1000g diatomaceous earth (thickness 2～3cm) while it is hot. ) Filter under reduced pressure, rinse the diatomaceous earth layer with 2L ethyl acetate (30-40°C), combine the filtrate and transfer it to a temporary storage bucket. Control the temperature of the water bath at 45～50℃, and the vacuum degree ≤-0.1MPa. Concentrate the solution in the temporary storage tank until no distillate drops to obtain the crude product and DMSO system. At 31°C, 2L of purified water was added dropwise to the DMSO solution with stirring (a slight exotherm, the addition was completed in 25 minutes), and a solid precipitated. The temperature was dropped to 19°C, filtered under reduced pressure, rinsed with 2.5L of purified water, pumped until there was no droplet flow, and the solid was collected. The precipitated solid was slurried with 17L of purified water at 15-20°C for 1 hour, filtered under reduced pressure, rinsed with 5L of purified water, pumped to a drip-free flow, and 4.07kg of ochre solid was collected. Use 12L ethanol (3L/kg crude product), stir and heat to 76-79°C to dissolve, turn off the heating, and cool down naturally. After 14 hours, the temperature is slowly reduced to 20°C, and solids precipitate out. Filter under reduced pressure, rinse the filter cake with 2L ethanol, pump to no dripping, and collect 1.99 kg of reddish-brown solids. Use 20L ethanol (10L/kg crude product), after dissolving at 76～79℃, slowly add 200g activated carbon (about 0.1kg/kg) under ethanol reflux, continue to stir under reflux for 3 hours, and pass 1000g diatomaceous earth ( 2～3cm thickness) filter, rinse with 6L ethyl acetate (50～60℃), and collect the filtrate. The temperature of the water bath is controlled at 45-50°C, and the degree of vacuum is less than or equal to -0.1MPa. The organic phase is concentrated until no distillate drops to obtain 1.50kg of a yellow solid compound. Use 15L ethanol (10L/kg) to dissolve the crude product at 76～78℃, slowly add 150g activated carbon (about 0.1kg/kg) under ethanol reflux, continue to stir under reflux for 3 hours, then pass 1000g diatomaceous earth ( 2～3cm thickness) filter, rinse with 8L ethyl acetate (40～50℃), and collect the filtrate. The temperature of the water bath is controlled at 45-50°C, and the degree of vacuum is ≤-0.1MPa, and the organic phase is concentrated until no distillate drops to obtain 1.31kg of yellow solid. The solid was slurried with 4L methanol at 40-45°C for 2 hours, filtered under reduced pressure, rinsed with 4L methanol, pumped to a drip-free flow, and 1.2kg of yellow solid was collected. Transfer the solid material to be baked into a dry and clean vacuum drying oven, control the temperature at 45～50℃, the degree of vacuum is ≤-0.1MPa, bake the material for 4-6 hours, start weighing from 4 hours until the weight loss is ≤0.2g. A yellow-green powder compound 2-8 (1.17 kg, 62.5% yield) was obtained.
1H NMR(400MHz，CDCl 3)δ8.75(s，1H)，8.45(d，J＝7.8Hz，1H)，8.37(s，1H)，7.90(d，J＝10.8Hz，1H)，7.82(td，J＝2.1，8.7Hz，1H)，6.88(d，J＝8.5Hz，1H)，4.41(t，J＝6.4Hz，2H)，3.98-3.84(m，4H)，3.66(s，3H)，2.56-2.47(n，4H)，2.47-2.34(m，6H)，2.07-1.97(m，2H)，1.59(quin，J＝5.6Hz，4H)，1.44(br d，J＝4.8Hz，2H)。 1 H NMR (400MHz, CDCl 3 ) δ 8.75 (s, 1H), 8.45 (d, J = 7.8 Hz, 1H), 8.37 (s, 1H), 7.90 (d, J = 10.8 Hz, 1H), 7.82 (td, J = 2.1, 8.7 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 4.41 (t, J = 6.4 Hz, 2H), 3.98-3.84 (m, 4H), 3.66 (s, 3H), 2.56-2.47 (n, 4H), 2.47-2.34 (m, 6H), 2.07-1.97 (m, 2H), 1.59 (quin, J = 5.6 Hz, 4H), 1.44 (br d, J = 4.8 Hz, 2H).
步骤6：化合物2-9的合成Step 6: Synthesis of compound 2-9
配制雷尼镍的乙醇混悬液：在氩气流下，向玻璃量杯中依次加入1L乙醇和25g雷尼镍。配制化合物2-8的乙醇混悬液：向塑料量杯中加入1L乙醇和100g化合物2-8配成混悬液。在氩气流下，向洗好的10L高压夹套釜中加入2L乙醇，并依次加入上述配制好的雷尼镍乙醇混悬液和化合物2-8的乙醇 混悬液，最后用1L乙醇洗涤上述两个量杯，洗液倒入釜中。反应釜用氩气置换3次，再用氢气置换3次，最后氢气的压力保持在0.5MPa。调节搅拌速度为250r/min，然后加热体系升温至75～80℃，保温反应30～96小时。反应结束温度降至30～40℃。在氩气流下，用吸磁棒将雷尼镍从反应体系中吸出，快速转移至盛水杯中淬灭(磁棒表面无吸附物即可停止)。然后将反应液抽至5L的三口瓶中，再用二氯甲烷0.5L冲洗釜中残留物一并抽至三口瓶中，接着向三口瓶中加入3L二氯甲烷溶解产物(防止产物析出)，搅拌均匀后，经过铺有200.32g硅藻土(3～4cm厚度)的漏斗减压过滤(滤前用0.5L二氯甲烷湿润)，硅藻土层用二氯甲烷0.5L淋洗，抽到滤液逐滴滴下，即可停止，将滤液合并，并转移至暂存桶中。控制水浴温度50～55℃，真空度≤-0.09MPa条件，将暂存桶中溶液浓缩至无馏分滴下，得到浅黄色固体粉末88.6g。粗品加乙醇178mL在20～30℃下打浆12-24小时，体系一直是混悬液，(减压)过滤，用乙醇(10mL×3)淋洗，抽至无液滴滴下，收集固体。控制水浴温度50～55℃，真空度≤-0.09Mpa，将收集到的固体粗品在旋转蒸发仪上旋至无馏出液滴下，不需控制溶残得到白色固体粉末82.8g。粗品82.8g用乙醇1.74L(21L/kg)，78℃(内温)溶解，关闭加热，继续在油浴中缓慢降低温度到22℃，固体析出，过滤，用乙醇(10mL×3)淋洗，收集固体得到白色固体粉末75g。控制水浴温度50～55℃，真空度≤-0.09MPa，将收集到的固体粗品在旋转蒸发仪上旋至无馏出液滴下，得到白色固体粉末70.7g，收率：79.6％。将11批(化合物2-8：1.15kg)得到的粗品826.2g加甲醇4.13L在20～30℃下打浆12-48小时，体系一直是混悬液，(减压)过滤，用甲醇(50mL×3次)淋洗，抽至无液滴滴下，收集白色固体820.2g。将待烘料固体转移至干燥洁净的真空干燥箱中，检查好气密性后，打开温度控制开关和真空阀，将真空干燥箱内温度升温至40～45℃，压力-0.1MPa，控制此条件烘料2～24小时，称量至减重≤0.1g，最终得化合物2-9(805.2g，该步收率：97.5％，总收率：78.8％)。To prepare an ethanol suspension of Raney nickel: under an argon flow, 1L of ethanol and 25 g of Raney nickel were sequentially added to a glass measuring cup. To prepare an ethanol suspension of compound 2-8: add 1 L of ethanol and 100 g of compound 2-8 to a plastic measuring cup to form a suspension. Under argon flow, add 2L of ethanol to the washed 10L high-pressure jacketed kettle, and then add the prepared Raney nickel ethanol suspension and the ethanol suspension of compound 2-8 in sequence, and finally wash the above with 1L ethanol Two measuring cups, pour the lotion into the kettle. The reactor was replaced with argon for 3 times, and then with hydrogen for 3 times, and finally the pressure of hydrogen was maintained at 0.5 MPa. Adjust the stirring speed to 250r/min, then the heating system is heated to 75-80°C, and the temperature is kept for 30-96 hours. The temperature at the end of the reaction dropped to 30-40°C. Under argon gas flow, the Raney nickel is sucked out of the reaction system with a magnetic rod, and quickly transferred to a cup for quenching (the magnetic rod can be stopped if there is no adsorbent on the surface of the magnetic rod). Then the reaction solution was pumped into a 5L three-necked flask, and then 0.5L of dichloromethane was used to flush the residue in the kettle into the three-necked flask, and then 3L of dichloromethane dissolved product was added to the three-necked flask (to prevent product precipitation), After stirring uniformly, filter under reduced pressure through a funnel spread with 200.32g diatomaceous earth (3～4cm thickness) (wet with 0.5L dichloromethane before filtering), rinse the diatomaceous earth layer with 0.5L dichloromethane, and pump to Drop the filtrate drop by drop to stop, combine the filtrate and transfer to the temporary storage bucket. Control the temperature of the water bath at 50-55°C, and the vacuum degree ≤ -0.09MPa. Concentrate the solution in the temporary storage tank until no distillate drops to obtain 88.6g of light yellow solid powder. The crude product is slurried with 178 mL of ethanol at 20-30°C for 12-24 hours. The system is always a suspension, filtered (under reduced pressure), rinsed with ethanol (10 mL×3), pumped until no droplets drip, and the solids are collected. Control the temperature of the water bath from 50 to 55°C, and the degree of vacuum ≤ -0.09Mpa, spin the collected crude solid product on the rotary evaporator until there is no drop of distillate, without controlling the dissolution residue to obtain 82.8g of white solid powder. 82.8g of crude product is dissolved in ethanol 1.74L (21L/kg), 78℃ (internal temperature), turn off the heating, continue to slowly reduce the temperature to 22℃ in the oil bath, solids precipitate, filter, and rinse with ethanol (10mL×3) , The solid was collected to obtain 75 g of white solid powder. The temperature of the water bath is controlled to be 50-55°C, the vacuum degree is ≤-0.09MPa, and the collected crude solid product is rotated on the rotary evaporator until there is no drop of distillate to obtain 70.7 g of white solid powder, with a yield of 79.6%. The crude product 826.2g obtained from 11 batches (compound 2-8: 1.15kg) was slurried with 4.13L of methanol at 20～30℃ for 12-48 hours. The system was always a suspension, filtered (under reduced pressure), and filtered with methanol (50mL ×3 times) rinsing, pumping until no droplets drip, and collecting 820.2 g of white solid. Transfer the solid to be dried into a dry and clean vacuum drying oven. After checking the air tightness, turn on the temperature control switch and the vacuum valve, and raise the temperature in the vacuum drying oven to 40～45℃ and the pressure -0.1MPa. Control this condition Dry the material for 2-24 hours, weigh it until the weight loss is ≤0.1g, and finally obtain compound 2-9 (805.2g, the yield of this step: 97.5%, the total yield: 78.8%).
1H NMR(400MHz，DMSO-d 6)δ10.87(br s，1H)，8.70(s，1H)，8.49(s，1H)，8.05-7.99(m，2H)，7.92(d，J＝11.9Hz，1H)，6.98(d，J＝8.6Hz，1H)，4.35(t，J＝6.6Hz，2H)，4.24(br t，J＝11.2Hz，2H)，3.83(br dd，J＝4.8，11.1Hz，2H)，2.64-2.55(m，2H)，2.42-2.28(m，6H)，1.90(quin，J＝6.8Hz，2H)，1.68(br d，J＝13.8Hz，2H)，1.48(quin，J＝5.4Hz，4H)，1.37(br d，J＝5.0Hz，2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.87 (br s, 1H), 8.70 (s, 1H), 8.49 (s, 1H), 8.05-7.99 (m, 2H), 7.92 (d, J= 11.9 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 4.35 (t, J = 6.6 Hz, 2H), 4.24 (br t, J = 11.2 Hz, 2H), 3.83 (br dd, J = 4.8, 11.1Hz, 2H), 2.64-2.55 (m, 2H), 2.42-2.28 (m, 6H), 1.90 (quin, J=6.8Hz, 2H), 1.68 (br d, J=13.8Hz, 2H) , 1.48 (quin, J=5.4 Hz, 4H), 1.37 (br d, J=5.0 Hz, 2H).
步骤10：式(I)化合物A晶型的合成Step 10: Synthesis of Compound A of Formula (I)
在5～30℃，向反应釜中加入3.85L二甲亚砜，搅拌下加入389g化合物2-9，438.38g碳酸钾。加热，体系温度在70～75℃，倒入碳酸二甲酯33.41mL。反应体系温度保持在70～75℃范围，继续搅拌。补加0.25eq碳酸二甲酯，继续搅拌反应。反应完成，停止加热，自然降温至30～40℃，将反应液倒入搅拌着的19.5L纯化水中。加完后继续搅拌0.5小时。减压过滤，用1.5L纯水淋洗一次，至无液滴滴下，收集滤饼。滤饼用385mL二氯甲烷溶解，分液，得粗品化合物。有机相将粗品减压通过25～30cm高的硅胶层(100～200目，柱直径20cm，高30cm)，继而用二氯甲烷/甲醇(V)＝20/1的混合溶剂49.9L冲洗，收集所有洗出液。控制水浴温度40～45℃，真空度≤-0.07MPa条件，将有机相浓缩至无馏分滴下。收集得到浅红色固体389.2g。在5～30℃，向反应釜中加入3.9L乙醇，搅拌下加入387.69g粗品，26g活性炭。体系加热到75～80℃，搅拌16小时。反应液趁热(79℃)过滤， 滤饼用热乙醇各195mL(79℃)淋洗两次。至无液滴滴下。收集滤液，蒸除溶剂至无馏分滴下，控制水浴温度45～50℃，真空度≤-0.1MPa条件，至无馏分滴下，得到淡黄色固体368.1g。At 5-30°C, 3.85L of dimethylsulfoxide was added to the reaction kettle, and 389g of compound 2-9 and 438.38g of potassium carbonate were added with stirring. Heating, the system temperature is 70 ~ 75 ℃, pour 33.41mL of dimethyl carbonate. The temperature of the reaction system is maintained in the range of 70-75°C, and stirring is continued. Add 0.25 eq of dimethyl carbonate and continue to stir the reaction. After the reaction is completed, the heating is stopped, the temperature is naturally lowered to 30-40°C, and the reaction liquid is poured into 19.5L of purified water with stirring. After the addition, stirring was continued for 0.5 hours. Filter under reduced pressure, rinse once with 1.5L of pure water until no droplets drip, and collect the filter cake. The filter cake was dissolved with 385 mL of dichloromethane and separated to obtain the crude compound. In the organic phase, the crude product was passed through a 25-30cm high silica gel layer (100-200 mesh, column diameter 20cm, height 30cm) under reduced pressure, and then washed with 49.9L mixed solvent of dichloromethane/methanol (V)=20/1, and collected All eluates. Control the temperature of the water bath at 40-45°C, and the vacuum degree ≤ -0.07MPa, and concentrate the organic phase until no distillate drips. 389.2 g of a light red solid was collected. At 5-30°C, 3.9L ethanol was added to the reaction kettle, and 387.69g crude product and 26g activated carbon were added with stirring. The system was heated to 75-80°C and stirred for 16 hours. The reaction solution was filtered while it was hot (79°C), and the filter cake was rinsed twice with 195 mL of hot ethanol (79°C). Until no droplets drip. Collect the filtrate, evaporate the solvent until there is no distillate dripping, control the temperature of the water bath at 45-50°C, and the vacuum degree≤-0.1MPa condition, until there is no distillate dripping, and 368.1g of light yellow solid is obtained.
在25℃，向反应瓶加入766mL乙醇，搅拌下加入352.75g上述淡黄色固体。加热升温至内温79℃搅拌反应，保持温度搅拌20分钟，使溶液澄清。然后按照下表进行程序降温：At 25°C, 766 mL of ethanol was added to the reaction flask, and 352.75 g of the above-mentioned pale yellow solid was added with stirring. Heat up to an internal temperature of 79°C and stir to react, keep the temperature and stir for 20 minutes to make the solution clear. Then follow the table below to cool down the program:
Figure PCTCN2021084062-appb-000015
Figure PCTCN2021084062-appb-000015
将反应体系减压过滤，滤饼用乙醇71mL淋洗一次，直至无液滴滴下。收集滤饼，蒸除溶剂至无馏分滴下，控制水浴温度45～50℃，真空度≤-0.1Mpa条件，得到淡黄色粉末298g，收率83.5％。The reaction system was filtered under reduced pressure, and the filter cake was rinsed once with 71 mL of ethanol until no liquid dripped. Collect the filter cake, evaporate the solvent until no distillate drops, control the temperature of the water bath at 45-50°C and the vacuum degree ≤ -0.1Mpa to obtain 298 g of light yellow powder with a yield of 83.5%.
在25℃，向反应瓶中加入740mL乙酸乙酯，搅拌下加入296g样品。体系温度20～25℃搅拌18小时。反应体系减压过滤，滤饼用乙醇60mL淋洗一次，直至无液滴滴下。收集滤饼，蒸除溶剂至无馏分滴下，控制水浴温度45～50℃，真空度≤-0.1MPa条件，至无馏分滴下，得到类白色粉末256.3g，收率：86.6％。另一批使用相同重结晶和打浆方法制备类白色粉末261.87g。At 25°C, 740 mL of ethyl acetate was added to the reaction flask, and 296 g of sample was added with stirring. The temperature of the system was 20-25°C and stirred for 18 hours. The reaction system was filtered under reduced pressure, and the filter cake was rinsed once with 60 mL of ethanol until no liquid dripped. Collect the filter cake, evaporate the solvent until there is no distillate dripping, control the temperature of the water bath at 45-50°C, and the vacuum degree ≤ -0.1MPa condition, until there is no distillate dripping, and obtain 256.3g of off-white powder with a yield of 86.6%. Another batch used the same recrystallization and beating method to prepare 261.87g of off-white powder.
将上一步得到的两批共518g样品用680mL二氯甲烷溶清。蒸除溶剂，控制水浴温度45～50℃，真空度≤-0.1Mpa条件，至无馏分滴下，将大块颗粒捣碎成细粉末状。在28℃，向反应釜中加入1554mL甲醇，搅拌下加入518g样品。加热升温至内温65℃搅拌反应，保持温度搅拌1.5小时。然后按照下表进行程序降温：The two batches of 518 g samples obtained in the previous step were dissolved in 680 mL of dichloromethane. Evaporate the solvent, control the temperature of the water bath at 45～50℃, the vacuum degree ≤-0.1Mpa, until there is no dripping, the large particles are crushed into fine powder. At 28°C, 1554 mL of methanol was added to the reactor, and 518 g of sample was added with stirring. Heat to an internal temperature of 65°C and stir to react, keep the temperature and stir for 1.5 hours. Then follow the table below to cool down the program:
Figure PCTCN2021084062-appb-000016
Figure PCTCN2021084062-appb-000016
将反应液过滤，滤饼用甲醇105mL淋洗一次，至无液滴滴下。滤饼转移至真空干燥箱，控制温度40℃，真空度≤-0.1MPa，将滤饼烘43h。得到类白色粉末，即式(I)化合物A晶型491.02g，收率：94.7％。The reaction solution was filtered, and the filter cake was rinsed once with 105 mL of methanol until there was no dripping. The filter cake is transferred to a vacuum drying oven, the temperature is controlled at 40 ℃, the vacuum degree is ≤ -0.1 MPa, and the filter cake is baked for 43 hours. An off-white powder was obtained, namely 491.02 g of compound A crystal form of formula (I), yield: 94.7%.
1H NMR(400MHz，CDCl 3)δ8.71(s，1H)，8.42(s，1H)，8.07(d，J＝8.0Hz，1H)，7.93-7.84(m，2H)，6.89 (d，J＝8.8Hz，1H)，4.56-4.34(m，4H)，3.97(dd，J＝4.8，11.5Hz，2H)，3.39(s，3H)，2.78-2.60(m，2H)，2.52(br s，2H)，2.50-2.33(m，4H)，2.10-1.99(m，2H)，1.69(br d，J＝14.3Hz，2H)，1.60(br s，4H)，1.50-1.40(m，2H)。 1 H NMR (400MHz, CDCl 3 ) δ 8.71 (s, 1H), 8.42 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.93-7.84 (m, 2H), 6.89 (d, J=8.8Hz, 1H), 4.56-4.34(m, 4H), 3.97(dd, J=4.8, 11.5Hz, 2H), 3.39(s, 3H), 2.78-2.60(m, 2H), 2.52(br s, 2H), 2.50-2.33 (m, 4H), 2.10-1.99 (m, 2H), 1.69 (br d, J = 14.3 Hz, 2H), 1.60 (br s, 4H), 1.50-1.40 (m, 2H).
称取大约50mg式(I)化合物A晶型入到不同的2.0mL玻璃小瓶中，分别加入适量的溶剂或溶剂混合物，使其成悬浊液或溶液。加入磁子后，将上述样品置于磁力加热搅拌器上(40℃，700rpm)进行搅拌。搅拌48小时后混悬的样品离心弃除上清液后置于30℃真空干燥箱过夜，得到式(I)化合物A晶型。Weigh about 50 mg of the crystal form of compound A of formula (I) into different 2.0 mL glass vials, and add appropriate amounts of solvents or solvent mixtures to make them into suspensions or solutions. After adding the magnet, the above-mentioned sample was placed on a magnetic heating stirrer (40°C, 700 rpm) for stirring. After stirring for 48 hours, the suspended sample was centrifuged to discard the supernatant and placed in a vacuum drying oven at 30° C. overnight to obtain the crystal form of compound A of formula (I).
编号serial number 溶剂Solvent 溶剂体积(mL)Solvent volume (mL) 晶型Crystal form
11 水water 0.30.3 A晶型 Crystal Form A
22 乙腈∶水(1∶1)Acetonitrile: water (1:1) 0.30.3 A晶型 Crystal Form A
33 四氢呋喃Tetrahydrofuran 0.20.2 A晶型Crystal Form A
44 甲醇∶水(3∶1)Methanol: water (3:1) 0.20.2 A晶型 Crystal Form A
55 甲基叔丁基醚Methyl tert-butyl ether 0.40.4 A晶型Crystal Form A
实施例3：式(I)化合物B晶型的制备Example 3: Preparation of Compound B of Formula (I)
称取大约50mg式(I)化合物A晶型入到2.0mL玻璃小瓶中，加入0.2mL丙酮，使其成悬浊液。加入磁子后，将上述样品置于磁力加热搅拌器上(40℃，700rpm)进行搅拌。搅拌48小时后混悬的样品离心弃除上清液后置于30℃真空干燥箱过夜，得到式(I)化合物B晶型。Weigh about 50 mg of the crystal form of compound A of formula (I) into a 2.0 mL glass vial, add 0.2 mL of acetone to make it into a suspension. After adding the magnet, the above-mentioned sample was placed on a magnetic heating stirrer (40°C, 700 rpm) for stirring. After stirring for 48 hours, the suspended sample was centrifuged to discard the supernatant and placed in a vacuum drying oven at 30° C. overnight to obtain the crystal form of compound B of formula (I).
称取大约50mg式(I)化合物A晶型mL玻璃小瓶中，加入0.3mL乙腈，使其成悬浊液。加入磁子后，将上述样品置于磁力加热搅拌器上(40℃，700rpm)进行搅拌。搅拌48小时后混悬的样品离心弃除上清液后置于30℃真空干燥箱过夜，得到式(I)化合物B晶型。Weigh approximately 50 mg of compound A of formula (I) into a mL glass vial, add 0.3 mL of acetonitrile to make a suspension. After adding the magnet, the above-mentioned sample was placed on a magnetic heating stirrer (40°C, 700 rpm) for stirring. After stirring for 48 hours, the suspended sample was centrifuged to discard the supernatant and placed in a vacuum drying oven at 30° C. overnight to obtain the crystal form of compound B of formula (I).
称取大约50mg式(I)化合物A晶型2.0mL玻璃小瓶中，加入0.2mL乙酸乙酯，使其成悬浊液。加入磁子后，将上述样品置于磁力加热搅拌器上(40℃，700rpm)进行搅拌。搅拌48小时后混悬的样品离心弃除上清液后置于30℃真空干燥箱过夜，得到式(I)化合物B晶型。Weigh about 50 mg of compound A of formula (I) in a 2.0 mL glass vial, add 0.2 mL of ethyl acetate to make a suspension. After adding the magnet, the above-mentioned sample was placed on a magnetic heating stirrer (40°C, 700 rpm) for stirring. After stirring for 48 hours, the suspended sample was centrifuged to discard the supernatant and placed in a vacuum drying oven at 30° C. overnight to obtain the crystal form of compound B of formula (I).
实施例4：式(I)化合物C晶型的制备Example 4: Preparation of Compound C of Formula (I)
称取大约50mg式(I)化合物A晶型入到2.0mL玻璃小瓶中，加入0.2mL甲醇，使其成悬浊液。加入磁子后，将上述样品置于磁力加热搅拌器上(40℃，700rpm)进行搅拌。搅拌48小时后混悬的样品离心弃除上清液后置于30℃真空干燥箱过夜，得到式(I)化合物C晶型。Weigh about 50 mg of the crystal form of compound A of formula (I) into a 2.0 mL glass vial, add 0.2 mL of methanol to make a suspension. After adding the magnet, the above-mentioned sample was placed on a magnetic heating stirrer (40°C, 700 rpm) for stirring. After stirring for 48 hours, the suspended sample was centrifuged to discard the supernatant and placed in a vacuum drying oven at 30° C. overnight to obtain compound C crystal form of formula (I).
实施例5：式(I)化合物D晶型的制备Example 5: Preparation of Compound D of Formula (I)
称取大约50mg式(I)化合物A晶型入到2.0mL玻璃小瓶中，加入0.3mLEtOH，使其成悬浊液。加入磁子后，将上述样品置于磁力加热搅拌器上(40℃，700rpm)进行搅拌。搅拌48小时后混悬的样品离心弃除上清液后置于30℃真空干燥箱过夜，得到式(I)化合物D晶型。Weigh about 50 mg of the crystal form of compound A of formula (I) into a 2.0 mL glass vial, and add 0.3 mL of LEtOH to make it into a suspension. After adding the magnet, the above-mentioned sample was placed on a magnetic heating stirrer (40°C, 700 rpm) for stirring. After stirring for 48 hours, the suspended sample was centrifuged to discard the supernatant and placed in a vacuum drying oven at 30° C. overnight to obtain the crystal form of compound D of formula (I).
实施例6：式(I)化合物A晶型的吸湿性研究Example 6: Study on the hygroscopicity of the crystal form of compound A of formula (I)
实验材料：Experimental Materials:
SMS DVS Advantage动态蒸汽吸附仪SMS DVS Advantage Dynamic Vapor Sorption Apparatus
实验方法：experimental method:
取式(I)化合物A晶型10～15mg置于DVS样品盘内进行测试。Take 10-15 mg of compound A crystal form of formula (I) and place it in the DVS sample pan for testing.
实验结果：Experimental results:
式(I)化合物A晶型的DVS谱图如图13所示，ΔW＝0.24％。The DVS spectrum of the crystal form of compound A of formula (I) is shown in Figure 13, ΔW=0.24%.
实验结论：Experimental results:
式(II)化合物A晶型在25℃和80％RH下的吸湿增重为0.24％，略有引湿性。The moisture absorption and weight gain of the crystal form of compound A of formula (II) at 25° C. and 80% RH is 0.24%, which is slightly hygroscopic.
实施例7：式(I)化合物A晶型的固体稳定性试验Example 7: Solid stability test of the crystal form of compound A of formula (I)
称取式(I)化合物A晶型26份，每份5.000±0.200mg，置于玻璃样品瓶的底部，摊成薄薄一层。在不同条件下(60℃、92.5％RH、ICH光照、40℃/75％RH和60℃/75％RH)放置相应时间后，分别测试样品化学纯度(HPLC面积纯度)及晶型，以确定样品的物理/化学稳定性。60℃高温、92.5％RH高湿、40℃/75％RH和60℃/75％RH条件下放置的样品用铝箔纸包封住瓶口后在铝箔纸上扎些小孔以保证样品能与环境空气充分接触，为完全暴露放样；ICH规定照度的光照(可见光1.2×10 6Lux.hr+紫外光200W.hr/m 2)样品除Photo-dark外为室温(25℃)下完全暴露放样，Photo-dark样品用锡箔纸完全包裹住样品瓶置于室温(25℃)下ICH规定照度的光照进行光照；0天样品为初始样品，0天的样品用螺纹瓶盖密封并用封口膜包扎好瓶盖后放置在-20℃下保存待测。样品在高温和高湿条件下放置10天；在40℃/75％RH条件下放置3个月、在60℃/75％RH条件下放置1个月。试验结果汇总于表5： Weigh 26 parts of the crystal form of compound A of formula (I), 5.000±0.200 mg each, place them on the bottom of a glass sample bottle and spread them into a thin layer. After being placed for corresponding time under different conditions (60℃, 92.5%RH, ICH light, 40℃/75%RH and 60℃/75%RH), test the chemical purity (HPLC area purity) and crystal form of the samples respectively to determine The physical/chemical stability of the sample. The sample placed under the conditions of 60℃ high temperature, 92.5%RH high humidity, 40℃/75%RH and 60℃/75%RH is wrapped with aluminum foil paper, and then some small holes are pierced on the aluminum foil paper to ensure that the sample can be Full exposure to ambient air means complete exposure lofting; ICH specified illumination (visible light 1.2×10 6 Lux.hr + ultraviolet light 200W.hr/m 2 ) samples are fully exposed at room temperature (25°C) except for Photo-dark, The photo-dark sample is completely wrapped in tin foil and placed under the light of ICH specified illuminance at room temperature (25℃) for illumination; the 0-day sample is the initial sample, the 0-day sample is sealed with a screw cap and the bottle is wrapped with a sealing film Store it at -20°C after covering it for testing. The sample is placed under high temperature and high humidity conditions for 10 days; placed at 40°C/75% RH for 3 months, and at 60°C/75% RH for 1 month. The test results are summarized in Table 5:
表5.式(I)化合物A晶型的稳定性试验结果Table 5. Stability test results of the crystal form of compound A of formula (I)
Figure PCTCN2021084062-appb-000017
Figure PCTCN2021084062-appb-000017
结论：式(I)化合物A晶型在光照、高温、高湿等影响因素条件下具有良好的稳定性。Conclusion: The crystal form of compound A of formula (I) has good stability under the conditions of light, high temperature, high humidity and other influencing factors.
实施例8：式(I)化合物A晶型的固体稳定性试验Example 8: Solid stability test of the crystal form of compound A of formula (I)
每份样品1.5g装入双层低密度聚乙烯袋，每层低密度聚乙烯袋分别用扎扣密封，再放入铝箔袋中热封。然后放入相应的恒温恒湿箱中考察。试验结果汇总于表6：1.5 g of each sample is packed into a double-layer low-density polyethylene bag, each layer of low-density polyethylene bag is sealed with a buckle, and then placed in an aluminum foil bag for heat sealing. Then put it into the corresponding constant temperature and humidity box for inspection. The test results are summarized in Table 6:
表6.式(I)化合物A晶型的稳定性试验结果Table 6. Stability test results of the crystal form of compound A of formula (I)
Figure PCTCN2021084062-appb-000018
Figure PCTCN2021084062-appb-000018
结论：式(I)化合物A晶型在本品在加速试验条件(40℃±2℃/75％RH±5％RH)下放置6个月、长期试验条件(25℃±2℃/60％RH±5％RH)下放置12个月具有良好的稳定性。Conclusion: The crystal form of compound A of formula (I) can be stored for 6 months under accelerated test conditions (40℃±2℃/75%RH±5%RH) and long-term test conditions (25℃±2℃/60%). RH±5%RH) has good stability when placed for 12 months.
实施例9：式(I)化合物B晶型的固体稳定性试验Example 9: Solid stability test of the crystal form of compound B of formula (I)
称取式(I)化合物B晶型26份，每份5.000±0.200mg，置于玻璃样品瓶的底部，摊成薄薄一层。在不同条件下(60℃、92.5％RH、ICH光照、40℃/75％RH和60℃/75％RH)放置相应时间后，分别测试样品化学纯度(HPLC面积纯度)及晶型，以确定样品的物理/化学稳定性。60℃高温、92.5％RH高湿、40℃/75％RH和60℃/75％RH条件下放置的样品用铝箔纸包封住瓶口后在铝箔纸上扎些小孔以保证样品能与环境空气充分接触，为完全暴露放样；ICH规定照度的光照(可见光1.2×10 6Lux.hr+紫外光200W.hr/m 2)样品除Photo-dark外为室温(25℃)下完全暴露放样，Photo-dark样品用锡箔纸完全包裹住样品瓶置于室温(25℃)下ICH规定照度的光照进行光照；0day样品为初始样品，0天的样品用螺纹瓶盖密封并用封口膜包扎好瓶盖后放置在-20℃下保存待测。样品在高温和高湿条件下放置10天；在40℃/75％RH条件下放置3个月、在60℃/75％RH条件下放置1个月。试验结果汇总于表7： Weigh 26 parts of compound B crystal form of formula (I), each of 5.000±0.200 mg, place them on the bottom of a glass sample bottle, and spread them into a thin layer. After being placed for corresponding time under different conditions (60℃, 92.5%RH, ICH light, 40℃/75%RH and 60℃/75%RH), test the chemical purity (HPLC area purity) and crystal form of the samples respectively to determine The physical/chemical stability of the sample. The sample placed under the conditions of 60℃ high temperature, 92.5%RH high humidity, 40℃/75%RH and 60℃/75%RH is wrapped with aluminum foil paper, and then some small holes are pierced on the aluminum foil paper to ensure that the sample can be Full exposure to ambient air means complete exposure lofting; ICH specified illumination (visible light 1.2×10 6 Lux.hr + ultraviolet light 200W.hr/m 2 ) samples are fully exposed at room temperature (25°C) except for Photo-dark, The photo-dark sample is completely wrapped in tin foil and placed under the illumination of ICH specified illuminance at room temperature (25℃) for light; 0 day sample is the initial sample, 0 day sample is sealed with a screw cap and the cap is wrapped with a sealing film Then store it at -20°C for testing. The sample is placed under high temperature and high humidity conditions for 10 days; placed at 40°C/75% RH for 3 months, and at 60°C/75% RH for 1 month. The test results are summarized in Table 7:
表7.式(I)化合物B晶型的稳定性试验结果Table 7. Stability test results of compound B crystal form of formula (I)
Figure PCTCN2021084062-appb-000019
Figure PCTCN2021084062-appb-000019
Figure PCTCN2021084062-appb-000020
Figure PCTCN2021084062-appb-000020
结论：式(I)化合物B晶型在光照、高温、高湿等影响因素条件下具有良好的稳定性。Conclusion: The crystal form of compound B of formula (I) has good stability under the conditions of light, high temperature, high humidity and other influencing factors.
实验例1：体外评价Experimental example 1: In vitro evaluation
实验测试在英国Eurofins公司进行，实验结果由该公司提供，下面的实验过程也由该公司提供。ATM酶活性测试实验过程The experimental test was carried out by Eurofins in the United Kingdom, and the experimental results were provided by the company. The following experimental procedures were also provided by the company. ATM enzyme activity test experiment process
将人源的ATM激酶置于包含30nM的GST-cMyc-p53和Mg/ATP的缓冲溶液中孵化，Mg/ATP的浓度根据不同需要确定，反应通过加入Mg/ATP的复合物引发。大约在室温下孵化30分钟后，加入含有EDTA的停止液终止反应。最后，针对磷酸化的p53加入包含d2标记的抗GST单克隆抗体和铕标记的磷酸化Ser15抗体的检测缓冲液。然后用时间分辨荧光模式读取检测盘，均相时间分辨荧光(HTRF)信号通过公式HTRF＝10000x(Em665nm/Em620nm)计算得到。Human-derived ATM kinase was incubated in a buffer solution containing 30 nM GST-cMyc-p53 and Mg/ATP. The concentration of Mg/ATP was determined according to different needs. The reaction was initiated by adding a Mg/ATP complex. After about 30 minutes of incubation at room temperature, add stop solution containing EDTA to terminate the reaction. Finally, for phosphorylated p53, a detection buffer containing d2-labeled anti-GST monoclonal antibody and europium-labeled phosphorylated Ser15 antibody was added. Then use the time-resolved fluorescence mode to read the detection disk, and the homogeneous time-resolved fluorescence (HTRF) signal is calculated by the formula HTRF=10000x (Em665nm/Em620nm).
DNA-PK酶活性测试实验过程DNA-PK enzyme activity test experiment process
将人源的DNA-PK激酶置于包含50nM的GST-cMyc-p53和Mg/ATP的缓冲溶液中孵化，Mg/ATP的浓度根据不同需要确定，反应通过加入Mg/ATP的复合物引发。大约在室温下孵化30分钟后，加入含有EDTA的停止液终止反应。最后，针对磷酸化的p53加入包含d2标记的抗GST单克隆抗体和铕标记的磷酸化Ser15抗体的检测缓冲液。然后用时间分辨荧光模式读取检测盘，均相时间分辨荧光(HTRF)信号通过公式HTRF＝10000x(Em665nm/Em620nm)计算得到。The human DNA-PK kinase is incubated in a buffer solution containing 50 nM GST-cMyc-p53 and Mg/ATP. The concentration of Mg/ATP is determined according to different needs. The reaction is initiated by adding a Mg/ATP complex. After about 30 minutes of incubation at room temperature, add stop solution containing EDTA to terminate the reaction. Finally, for phosphorylated p53, a detection buffer containing d2-labeled anti-GST monoclonal antibody and europium-labeled phosphorylated Ser15 antibody was added. Then use the time-resolved fluorescence mode to read the detection disk, and the homogeneous time-resolved fluorescence (HTRF) signal is calculated by the formula HTRF=10000x (Em665nm/Em620nm).
表8.本发明化合物体外细胞活性测定结果(IC 50) Table 8. In vitro cell activity assay results (IC 50 ) of the compounds of the present invention
化合物编号Compound number ATM(IC50nM)ATM(IC50nM) DNA-PK(IC50nM)DNA-PK (IC50nM)
式(I)化合物Compound of formula (I) 22 561561
结论：式(I)化合物具有显著的ATM激酶抑制作用，并且对DNA-PK激酶具有良好的选择性。Conclusion: The compound of formula (I) has a significant inhibitory effect on ATM kinase and has good selectivity for DNA-PK kinase.
实验例2：ATM抑制剂与etoposide协同作用于人肺癌H446细胞皮下异种移植肿瘤雌性BALB/c裸小鼠模型的体内药效学研究Experimental example 2: In vivo pharmacodynamic study of ATM inhibitor and etoposide on human lung cancer H446 cell subcutaneous xenograft tumor female BALB/c nude mouse model
实验目的：Purpose:
对受试药ATM抑制剂和etoposide经腹腔或口服在人肺癌H446细胞皮下异种移植瘤BALB/c裸小鼠模型体内药效进行评估。The test drugs ATM inhibitor and etoposide were administered intraperitoneally or orally in a BALB/c nude mouse model of human lung cancer H446 cell subcutaneous xenograft tumor.
实验设计：experimental design:
表9.ATM抑制剂和etoposide体内药效实验动物分组及给药方案Table 9. Grouping and dosing scheme of ATM inhibitors and etoposide in vivo efficacy of experimental animals
Figure PCTCN2021084062-appb-000021
Figure PCTCN2021084062-appb-000021
注：IP：腹腔注射；PO：口服；QD：每日一次；BIW：每周两次；QD(PG-D0，3D on，4D offfrom PG-D1)×4W：周二至周四给药，每日一次，一周一循环，给药四周；BIW+QD(PG-D0，3D on，4D offfrom PG-D1)×4W：周一给etoposide，周二至周四给ATM抑制剂，每日一次，一周一循环，给药四周。Note: IP: intraperitoneal injection; PO: oral; QD: once a day; BIW: twice a week; QD (PG-D0, 3D on, 4D off from PG-D1) × 4W: administration from Tuesday to Thursday, every day Once a day, once a week, administer for four weeks; BIW+QD (PG-D0, 3D on, 4D off from PG-D1)×4W: give etoposide on Monday, and ATM inhibitors from Tuesday to Thursday, once a day, once a week Circulate, dosing for four weeks.
实验方法与步骤：Experimental methods and steps:
1.细胞培养1. Cell culture
人肺癌细胞H446(ATCC，Manassas，VA，HTB-171)体外单层培养，培养条件为RPMI-1640，培养基中加10％胎牛血清，100U/mL青霉素和100μg/mL链霉素，37℃5％CO2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％时，收取细胞，计数，接种。Human lung cancer cells H446 (ATCC, Manassas, VA, HTB-171) were cultured in a monolayer in vitro under RPMI-1640, with 10% fetal bovine serum, 100U/mL penicillin and 100μg/mL streptomycin, 37 Cultivation with 5% CO2. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and seeded.
2.肿瘤细胞接种2. Tumor cell inoculation
将0.2mL 5×10 6个H446细胞(1∶1加基质胶)皮下接种于每只裸小鼠的右后背。肿瘤平均体积达到125mm 3时开始分组给药(表9)。 0.2 mL of 5×10 6 H446 cells (1:1 plus Matrigel) were inoculated subcutaneously on the right back of each nude mouse. Group administration was started when the average tumor volume reached 125mm 3 (Table 9).
3.受试物的配制3. Preparation of test substance
表10.受试物配制方法Table 10. Preparation method of test substance
Figure PCTCN2021084062-appb-000022
Figure PCTCN2021084062-appb-000022
Figure PCTCN2021084062-appb-000023
Figure PCTCN2021084062-appb-000023
注：在给动物给药前需要轻轻将药物充分混匀。Note: It is necessary to gently mix the drug thoroughly before administering to the animal.
肿瘤测量和实验指标：Tumor measurement and experimental indicators:
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。 The experimental index is to investigate whether the tumor growth is inhibited, delayed or cured. The tumor diameter was measured with vernier calipers twice a week. The calculation formula of the tumor volume is: V=0.5a×b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.
化合物的抑瘤疗效用TGI(％)。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝【1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)】×100％。The compound's anti-tumor efficacy is TGI (%). TGI (%), reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [1- (Average tumor volume at the end of a certain treatment group-the average tumor volume at the beginning of the treatment group) / (Average tumor volume at the end of the solvent control group- The average tumor volume at the start of treatment in the solvent control group)]×100%.
肿瘤增殖率T/C(％)：其中T是治疗组最后一次测量(PG-D26)所得平均肿瘤体积，C是对照组最后一次测量(PG-D26)所得平均肿瘤体积。Tumor growth rate T/C (%): where T is the average tumor volume obtained from the last measurement (PG-D26) of the treatment group, and C is the average tumor volume obtained from the last measurement (PG-D26) of the control group.
统计分析：Statistical Analysis:
包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)(具体数据见表)。治疗组在试验结束时给药后第26天表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。两组间比较用T-test进行分析，三组或多组间比较用one-way ANOVA进行分析，如果方差不齐，应用Games-Howell法进行检验。如果方差齐性，应用Dunnet(2-sided)法进行分析。用SPSS 17.0进行所有数据分析。p＜0.05认为有显著性差异。Including the mean and standard error (SEM) of the tumor volume at each time point in each group (see the table for specific data). The treatment group showed the best treatment effect on the 26th day after the administration at the end of the trial, so based on this data, statistical analysis was performed to evaluate the difference between the groups. The comparison between two groups is analyzed by T-test, and the comparison between three or more groups is analyzed by one-way ANOVA. If the variances are not uniform, the Games-Howell method is used to test. If the variance is homogeneous, use Dunnet (2-sided) method for analysis. Use SPSS 17.0 for all data analysis. p<0.05 considered a significant difference.
实验结果：Experimental results:
死亡率、发病率及体重变化情况Mortality, morbidity, and weight changes
实验动物的体重作为间接测定药物毒性的参考指标。在此模型中所有给药组均未显示有显著性体重下降(附图14)编号42161小鼠在etoposide，15mg/kg和AZD0156，5mg/kg联合组给药后第15天发现死亡。etoposide分别与式(I)化合物和AZD0156联用的治疗组中，有部分动物体重下降超过10％但未低于15％。受试药ATM抑制剂和etoposide，对H446细胞皮下异种移植肿瘤雌性BALB/c裸小鼠模型的体重影响附图14示。相对体重变化基于开始给药时动物体重计算得出。数据点代表组内平均体重变化百分比，误差线代表标准误(SEM)。The body weight of experimental animals is used as a reference index for indirect determination of drug toxicity. In this model, none of the administration groups showed significant weight loss (Figure 14). Mice No. 42161 was found dead on the 15th day after the etoposide, 15mg/kg and AZD0156, 5mg/kg combination groups were administered. In the treatment group where etoposide was combined with the compound of formula (I) and AZD0156, some animals lost more than 10% but not less than 15% in body weight. The test drugs ATM inhibitor and etoposide affect the body weight of the H446 cell subcutaneous xenograft female BALB/c nude mouse model. Figure 14 shows. The relative weight change is calculated based on the weight of the animal at the beginning of the administration. The data points represent the average weight change percentage within the group, and the error bars represent the standard error (SEM).
肿瘤体积Tumor volume
给予H446细胞皮下异种移植肿瘤雌性BALB/c裸小鼠模型在受试药ATM抑制剂与etoposide治疗后各组肿瘤体积变化如表11所示。The tumor volume changes in each group after the treatment of the test drug ATM inhibitor and etoposide in the female BALB/c nude mouse model of subcutaneous xenotransplanted tumor with H446 cells are shown in Table 11.
表11.各组不同时间点的瘤体积Table 11. Tumor volume at different time points in each group
Figure PCTCN2021084062-appb-000024
Figure PCTCN2021084062-appb-000024
注：a.平均值±SEM。Note: a. Mean ± SEM.
肿瘤生长曲线Tumor growth curve
H446异种移植瘤模型荷瘤鼠在给予受试药ATM抑制剂与etoposide后的肿瘤生长曲线。肿瘤生长曲线如附图15所示。数据点代表组内平均肿瘤体积，误差线代表标准误(SEM)。Tumor growth curve of H446 xenograft tumor model tumor-bearing mice after the test drug ATM inhibitor and etoposide were administered. The tumor growth curve is shown in Figure 15. The data points represent the average tumor volume within the group, and the error bars represent the standard error (SEM).
抗肿瘤药效评价指标(基于给药后第26天肿瘤体积计算得出)Anti-tumor efficacy evaluation index (calculated based on tumor volume on the 26th day after administration)
表12.受试药ATM抑制剂与etoposide对H446异种移植瘤模型的抑瘤药效评价Table 12. Antitumor efficacy evaluation of test drugs ATM inhibitor and etoposide on H446 xenograft tumor model
Figure PCTCN2021084062-appb-000025
Figure PCTCN2021084062-appb-000025
注：a.平均值±SEM。第5组动物#42161在PG-D15发现死亡，其数据不计入统计。Note: a. Mean ± SEM. Group 5 animal #42161 was found dead on PG-D15, and its data is not included in the statistics.
b.肿瘤生长抑制由T/C和TGI(TGI(％)＝[1-(T 26-T 0)/(V 26-V 0)]×100)计算。 b. Tumor growth inhibition is calculated by T/C and TGI (TGI(%)=[1-(T 26 -T 0 )/(V 26 -V 0 )]×100).
c.p值根据肿瘤体积计算。c.p value is calculated based on tumor volume.
实验讨论：Experimental discussion:
在本实验中，我们评价了受试药ATM抑制剂和etoposide在人肺癌H446异种移植瘤模型中的体内药效。各组在不同时间点的瘤体积如表11，表12及附图15所示。开始给药后26天，溶剂对照组荷瘤鼠的瘤体积达到2,782mm3，Etoposide+式(I)化合物(15mg/kg+5mg/kg)和 Etoposide+AZD0156(15mg/kg+5mg/kg)组的平均瘤体积分别为930mm 3、和1,344mm 3，T/C分别为33.42％和48.30％，TGI分别为69.70％和54.11％，与溶剂对照相比p值分别为0.006和0.028。 In this experiment, we evaluated the in vivo efficacy of the test drugs ATM inhibitor and etoposide in the human lung cancer H446 xenograft tumor model. The tumor volume of each group at different time points is shown in Table 11, Table 12 and Figure 15. 26 days after the start of administration, the tumor volume of the tumor-bearing mice in the solvent control group reached 2,782 mm3. The average tumor volume was 930mm 3 and 1,344mm 3 , T/C was 33.42% and 48.30%, TGI was 69.70% and 54.11%, and the p-values were 0.006 and 0.028 compared with the solvent control.
实验结论：Experimental results:
在该ATM抑制剂和etoposide在人肺癌H446异种移植瘤模型中的体内药效实验中，式(I)化合物与etoposide联用表现出很好的协同效应，优于AZD0156与etoposide联用的药效。In the in vivo pharmacodynamic experiment of the ATM inhibitor and etoposide in the human lung cancer H446 xenograft tumor model, the combination of the compound of formula (I) and etoposide showed a good synergistic effect, which was better than the pharmacodynamics of AZD0156 and etoposide. .

Claims (21)

  1. 式(I)化合物的A晶型，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.96±0.20°，14.85±0.20°，20.51±0.20°；The crystal form A of the compound of formula (I) is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.96±0.20°, 14.85±0.20°, 20.51±0.20°;
    Figure PCTCN2021084062-appb-100001
    Figure PCTCN2021084062-appb-100001
  2. 根据权利要求1所述的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.96±0.20°，12.74±0.20°，14.85±0.20°，18.00±0.20°，19.86±0.20°，20.51±0.20°，22.14±0.20°，29.19±0.20°。The crystal form A according to claim 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.96±0.20°, 12.74±0.20°, 14.85±0.20°, 18.00±0.20°, 19.86±0.20 °, 20.51±0.20°, 22.14±0.20°, 29.19±0.20°.
  3. 根据权利要求2所述的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射：4.96±0.20°，12.74±0.20°，14.85±0.20°，18.00±0.20°，19.86±0.20°，20.51±0.20°，22.14±0.20°，23.76±0.20°，24.89±0.20°，29.19±0.20°。The crystal form A according to claim 2, its X-ray powder diffraction pattern has characteristic diffraction at the following 2θ angles: 4.96±0.20°, 12.74±0.20°, 14.85±0.20°, 18.00±0.20°, 19.86±0.20° , 20.51±0.20°, 22.14±0.20°, 23.76±0.20°, 24.89±0.20°, 29.19±0.20°.
  4. 根据权利要求3所述的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射：4.96°，12.74°，14.53°，14.85°，17.63°，18.00°，19.86°，20.51°，22.14°，23.76°，24.50°，24.89°，27.96°，28.22°，29.19°。The crystal form A according to claim 3, whose X-ray powder diffraction pattern has characteristic diffraction at the following 2θ angles: 4.96°, 12.74°, 14.53°, 14.85°, 17.63°, 18.00°, 19.86°, 20.51°, 22.14°, 23.76°, 24.50°, 24.89°, 27.96°, 28.22°, 29.19°.
  5. 根据权利要求4所述的A晶型，其XRPD图谱如图1所示。The crystal form A according to claim 4, and its XRPD pattern is shown in Figure 1.
  6. 根据权利要求1～5任意一项所述的A晶型，其差示扫描量热曲线在178.69±3.0℃有一个吸热峰的峰值。The crystal form A according to any one of claims 1 to 5, wherein the differential scanning calorimetry curve has an endothermic peak at 178.69±3.0°C.
  7. 根据权利要求6所述的A晶型，其DSC图谱如图2所示。The crystal form A according to claim 6, and its DSC spectrum is shown in Figure 2.
  8. 根据权利要求1～5任意一项所述的A晶型，其热重分析曲线在178.29℃±3.0℃时失重达0.2038％。The crystal form A according to any one of claims 1 to 5, whose thermogravimetric analysis curve has a weight loss of 0.2038% at 178.29°C±3.0°C.
  9. 根据权利要求8所述的A晶型，其TGA图谱如图3所示。The crystal form A according to claim 8, whose TGA pattern is shown in FIG. 3.
  10. 式(I)化合物的B晶型，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：19.19±0.20°，21.76±0.20°，22.39±0.20°。The crystal form B of the compound of formula (I) is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 19.19±0.20°, 21.76±0.20°, 22.39±0.20°.
  11. 根据权利要求10所述的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.94±0.20°，9.35±0.20°，15.47±0.20°，16.35±0.20°，19.19±0.20°，21.76±0.20°，22.39±0.20°，25.09±0.20°。The crystal form B according to claim 10, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.94±0.20°, 9.35±0.20°, 15.47±0.20°, 16.35±0.20°, 19.19±0.20 °, 21.76±0.20°, 22.39±0.20°, 25.09±0.20°.
  12. 根据权利要求11所述的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射：4.94±0.20°，9.35±0.20°，13.06±0.20°，14.80±0.20°，15.47±0.20°，16.35±0.20°，19.19±0.20°，19.81±0.20°，21.76±0.20°，22.39±0.20°，24.21±0.20°，25.09±0.20°。The crystal form B according to claim 11, its X-ray powder diffraction pattern has characteristic diffraction at the following 2θ angles: 4.94±0.20°, 9.35±0.20°, 13.06±0.20°, 14.80±0.20°, 15.47±0.20° , 16.35±0.20°, 19.19±0.20°, 19.81±0.20°, 21.76±0.20°, 22.39±0.20°, 24.21±0.20°, 25.09±0.20°.
  13. 根据权利要求12所述的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射：4.94°，9.35°，10.52°，10.84°，11.13°，12.04°，13.06°，14.24°，14.80°，15.13°，15.47°，16.35°，16.61°，16.82°，17.61°，18.43°，19.19°，19.81°，20.36°，20.60°，21.76°，22.13°，22.39°，23.77°，24.21°，24.82°，25.09°，26.97°，28.72°，28.92°，32.79°，33.27°。The crystal form B according to claim 12, whose X-ray powder diffraction pattern has characteristic diffraction at the following 2θ angles: 4.94°, 9.35°, 10.52°, 10.84°, 11.13°, 12.04°, 13.06°, 14.24°, 14.80°, 15.13°, 15.47°, 16.35°, 16.61°, 16.82°, 17.61°, 18.43°, 19.19°, 19.81°, 20.36°, 20.60°, 21.76°, 22.13°, 22.39°, 23.77°, 24.21° , 24.82°, 25.09°, 26.97°, 28.72°, 28.92°, 32.79°, 33.27°.
  14. 根据权利要求13所述的B晶型，其XRPD图谱如图4所示。The crystal form B according to claim 13, and its XRPD pattern is shown in Fig. 4.
  15. 根据权利要求10～14任意一项所述的B晶型，其差示扫描量热曲线分别在167.54±3.0℃、177.98±3.0℃和246.93±3.0℃有一个吸热峰的峰值；在168.36±3.0℃有一个放热峰的峰值。The crystal form B according to any one of claims 10-14, its differential scanning calorimetry curves have an endothermic peak at 167.54±3.0°C, 177.98±3.0°C and 246.93±3.0°C, respectively; at 168.36± There is an exothermic peak at 3.0°C.
  16. 根据权利要求15所述的B晶型，其DSC图谱如图5所示。The crystal form B according to claim 15, and its DSC spectrum is shown in Figure 5.
  17. 根据权利要求10～14任意一项所述的B晶型，其热重分析曲线在56.15℃±3.0℃时失重达0.3265％，在99.48℃±3.0℃时又失重达0.3400％，在165.87℃±3.0℃时又失重达0.1831％。The crystal form B according to any one of claims 10-14, the thermogravimetric analysis curve of the weight loss reaches 0.3265% at 56.15℃±3.0℃, and the weight loss reaches 0.3400% at 99.48℃±3.0℃, and at 165.87℃± The weight loss reached 0.1831% at 3.0°C.
  18. 根据权利要求17所述的B晶型，其TGA图谱如图6所示。The crystal form B according to claim 17, whose TGA pattern is shown in FIG. 6.
  19. 根据权利要求1～9任意一项所述的A晶型或权利要求10～18任意一项所述B晶型在制备治疗与ATM抑制剂相关疾病的药物上的应用。The use of the crystal form A according to any one of claims 1 to 9 or the crystal form B according to any one of claims 10 to 18 in the preparation of drugs for treating diseases related to ATM inhibitors.
  20. 式(I)化合物的制备方法，The preparation method of the compound of formula (I),
    Figure PCTCN2021084062-appb-100002
    Figure PCTCN2021084062-appb-100002
    其包含如下步骤：It includes the following steps:
    Figure PCTCN2021084062-appb-100003
    Figure PCTCN2021084062-appb-100003
    其中，in,
    催化剂F选自双(二亚苄基丙酮)钯、四三苯基膦钯、三(二亚苄基丙酮)二钯/2-双环己基膦-2，6-二甲氧基联苯、双(二亚苄基丙酮)钯/2-双环己基膦-2，6-二甲氧基联苯、[1，1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷和醋酸钯/4，5-双(二苯基磷)-9，9-二甲基氧杂蒽；Catalyst F is selected from bis(dibenzylideneacetone)palladium, tetratriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium/2-biscyclohexylphosphine-2,6-dimethoxybiphenyl, bis(dibenzylideneacetone)palladium, (Dibenzylideneacetone)palladium/2-biscyclohexylphosphine-2,6-dimethoxybiphenyl, [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane and Palladium acetate/4,5-bis(diphenylphosphorus)-9,9-dimethylxanthene;
    碱G选自磷酸钾、碳酸钠和醋酸钾；The base G is selected from potassium phosphate, sodium carbonate and potassium acetate;
    溶剂H选自二甲亚砜/水、异丙醇/水、乙醇/水和1，4-二氧六环/水；Solvent H is selected from dimethyl sulfoxide/water, isopropanol/water, ethanol/water and 1,4-dioxane/water;
  21. 根据权利要求20所述的制备方法，其包含如下反应路线：The preparation method according to claim 20, which comprises the following reaction route:
    Figure PCTCN2021084062-appb-100004
    Figure PCTCN2021084062-appb-100004
    其中，in,
    试剂A选自二异丙基氨基锂；Reagent A is selected from lithium diisopropylamide;
    溶剂B选自四氢呋喃；Solvent B is selected from tetrahydrofuran;
    试剂C选自正丁基锂和双联频哪醇硼酸酯；Reagent C is selected from n-butyl lithium and dual pinacol borate;
    试剂D选自硼酸三异丙酯和[1，1′-双(二苯基膦基)二茂铁]二氯化钯；Reagent D is selected from triisopropyl borate and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;
    溶剂E选自四氢呋喃和1，4-二氧六环；Solvent E is selected from tetrahydrofuran and 1,4-dioxane;
    催化剂I选自雷尼镍/氢气、钯碳/氢气和锌粉/氯化铵；Catalyst I is selected from Raney nickel/hydrogen, palladium carbon/hydrogen and zinc powder/ammonium chloride;
    溶剂J选自乙醇、甲醇和四氢呋喃/水。Solvent J is selected from ethanol, methanol and tetrahydrofuran/water.
    试剂K选自碳酸钾；Reagent K is selected from potassium carbonate;
    试剂L选自碳酸二甲酯；Reagent L is selected from dimethyl carbonate;
    溶剂M选自二甲亚砜。The solvent M is selected from dimethyl sulfoxide.
PCT/CN2021/084062 2020-03-30 2021-03-30 Crystal form of quinopyrrolidine-2-one compound serving as atm inhibitor and use thereof WO2021197339A1 (en)

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