WO2023088370A1 - Crystal form of fused-ring derivative and preparation method therefor - Google Patents

Crystal form of fused-ring derivative and preparation method therefor Download PDF

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WO2023088370A1
WO2023088370A1 PCT/CN2022/132579 CN2022132579W WO2023088370A1 WO 2023088370 A1 WO2023088370 A1 WO 2023088370A1 CN 2022132579 W CN2022132579 W CN 2022132579W WO 2023088370 A1 WO2023088370 A1 WO 2023088370A1
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crystal form
compound
formula
angles
added
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PCT/CN2022/132579
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French (fr)
Chinese (zh)
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冯嘉杰
卢京京
李鹏
贺海鹰
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辰欣药业股份有限公司
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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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the invention relates to a crystal form of a condensed ring derivative and a preparation method thereof, and also includes the application of the crystal form in pharmacy.
  • Influenza virus namely influenza virus (IFV) is a segmented single-stranded antisense RNA virus that can cause influenza in humans and animals. Influenza viruses can cause very high morbidity and mortality, especially type A influenza viruses can also lead to global pandemics, such as the "Spanish flu” (H1N1 subtype) from 1918 to 1920, the "Asian flu” from 1957 to 1958 “(H2N2 subtype), 1968-1969 "Asian flu” (H3N2 subtype), 1977-1978 "Hong Kong flu” (H1N1 subtype), and the H1N1 influenza that first broke out in Mexico in March 2009. The flu outbreak caused tens of thousands of deaths, caused great social panic and increased social instability.
  • IMV influenza virus
  • Influenza A virus is a single negative-strand RNA virus, the genome contains 8 RNA segments, encoding 11 kinds of proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), M1, M2, NS1, NS2, PA, PB1, PB1-F2, and PB2.
  • Influenza A viruses can be divided into multiple subtypes based on the two proteins, hemagglutinin (HA) and neuraminidase (NA) on the surface of the virus. There are currently 18 known subtypes of HA and 11 subtypes of NA.
  • the hemagglutinin (HA) of influenza virus is responsible for recognizing the sialic acid glycoprotein of the host cell, mediating the fusion of the outer membrane of the virus and the membrane of the inner body of the cell to release the viral nucleocapsid into the cytoplasm.
  • Ceramidase (NA) of influenza virus can remove sialic acid on the surface of virus particles during the replication process, so that virus particles cannot continue to accumulate on the surface of host cells, thereby facilitating the release of virions and further infecting more host cells.
  • the synthesis of influenza virus protein is based on the host cell translation mechanism, and even the virus can suspend the translation of host protein and speed up the synthesis of its own protein.
  • Viral mRNA needs to be capped at the 5' end of host mRNA to start translation. This process is called “cap snatching", which is mainly completed by the viral RNA-dependent RNA polymerase (RdRp), whose PA subunit has RNA endonuclease activity, responsible for cleaving host mRNA.
  • RdRp viral RNA-dependent RNA polymerase
  • the viral mRNA is exported from the nucleus, enters the cytoplasm, and is translated like the mRNA of the host cell.
  • the nuclear export of the viral vRNA fragment is mediated by the viral M1 protein and NS2 protein Guided, when M1 protein can interact with vRNA and NP protein, it also interacts with the nuclear export protein NS2; thus, the nuclear export protein NS2 mediates the export of M1-RNP into the cytoplasm of the host cell in the form of nuclear protein.
  • influenza Current treatment options for influenza include vaccination and chemotherapy and chemoprophylaxis with antiviral drugs.
  • a flu shot against the flu is often recommended for high-risk groups, such as children and the elderly, or people with asthma, diabetes, or heart disease.
  • vaccination cannot completely prevent influenza, and influenza viruses undergo some degree of antigenic drift. If more than one virus infects a single cell, eight separate vRNA segments in the genome mix or reassort, resulting in rapid changes in viral genetics that produce an antigenic shift and allow the virus to infect and rapidly overcome new host species Protective immunity.
  • Antiviral drugs can be used to treat influenza, among which neuraminidase (NA) inhibitors, such as oseltamivir (Tamiflu), have obvious effects on influenza A virus, but it has been found through clinical observation that for this type of neuraminidase Enzyme inhibitor resistant virus strains have emerged.
  • NA neuraminidase
  • Tamiflu oseltamivir
  • WO2016175224 reports the following compounds and their prodrugs:
  • the present invention provides compounds represented by formula (I),
  • n is selected from 0.5 ⁇ 2;
  • n is selected from 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2;
  • n is selected from 1.
  • the present invention provides A crystal form of the compound represented by formula (I),
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.942 ⁇ 0.200°, 13.159 ⁇ 0.200°, 16.479 ⁇ 0.200°, 19.980 ⁇ 0.200°, 21.561 ⁇ 0.200°, 23.501 ⁇ 0.200°, 25.758 ⁇ 0.200°, 29.159 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.942 ⁇ 0.200°, 13.159 ⁇ 0.200°, 13.898 ⁇ 0.200°, 16.479 ⁇ 0.200°, 19.980 ⁇ 0.200°, 20.881 ⁇ 0.200°, 21.561 ⁇ 0.200°, 23.501 ⁇ 0.200°, 24.518 ⁇ 0.200°, 25.758 ⁇ 0.200°, 28.299 ⁇ 0.200°, 29.159 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.942 ⁇ 0.200°, 10.637 ⁇ 0.200°, 13.159 ⁇ 0.200°, 13.898 ⁇ 0.200°, 16.479 ⁇ 0.200°,17.001 ⁇ 0.200°,19.980 ⁇ 0.200°,20.881 ⁇ 0.200°,21.561 ⁇ 0.200°,23.501 ⁇ 0.200°,24.518 ⁇ 0.200°,25.758 ⁇ 0.200°,27.600 ⁇ 0.200°,28 .299 ⁇ 0.200°, 29.159 ⁇ 0.200°, 29.719 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.942°, 10.419°, 10.637°, 12.661°, 13.159°, 13.898°, 16.084°, 16.479 °, 17.001°, 17.540°, 18.843°, 19.199°, 19.980°, 20.881°, 21.561°, 22.384°, 23.137°, 23.501°, 23.776°, 24.122°, 24.518°, 25.758°, 26.362° , 27.600°, 27.997°, 28.299°, 28.840°, 29.159°, 29.719°, 30.822°, 31.042°, 31.597°, 32.220°, 32.638°, 33.136°, 34.140°, 35.582°, 36.140°, 37.037°, 3 7.467°.
  • the present invention provides crystal form A of Compound 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.942 ⁇ 0.200°, 21.561 ⁇ 0.200°, 25.758 ⁇ 0.200°. It can also be at 23.501 ⁇ 0.200°, and/or 13.159 ⁇ 0.200°, and/or 29.159 ⁇ 0.200°, and/or 19.980 ⁇ 0.200°, and/or 16.479 ⁇ 0.200°, and/or 13.898 ⁇ 0.200°, and/or or 20.881 ⁇ 0.200°, and/or 28.299 ⁇ 0.200°, and/or 24.518 ⁇ 0.200°, and/or 17.001 ⁇ 0.200°, and/or 12.661 ⁇ 0.200°, and/or 22.384 ⁇ 0.200°, and/or 10.637 ⁇ 0.200°, and/or 29.719 ⁇ 0.200°, and/or 27.600 ⁇ 0.200°, and/or 26.362 ⁇ 0.200°, and/or 30.822 ⁇ 0.200°, and
  • the XRPD pattern of the above crystal form A is shown in FIG. 1 .
  • the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 164.37 ⁇ 3°C.
  • the DSC spectrum of the above crystal form A is shown in FIG. 2 .
  • thermogravimetric analysis curve of the above crystal form A has a weight loss of 2.966% at 150 ⁇ 3°C, and a weight loss of 14.111% at 225 ⁇ 3°C.
  • the TGA spectrum of the above crystal form A is shown in FIG. 3 .
  • the present invention also provides the application of the above crystal form A in the preparation of anti-influenza virus medicaments.
  • the compound of the invention has a stable crystal form and is less affected by light and heat.
  • the compound of the present invention exhibits a protective effect in drug efficacy experiments of animal treatment models, and meanwhile, the pharmacokinetic properties meet the requirements of pharmaceutical preparations.
  • the intermediate compound 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 its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • aq. and H 2 O represent water; eq represents equivalent, equivalent; Boc represents tert-butoxycarbonyl; PE represents petroleum ether; MeCN or ACN represents acetonitrile; EtOAc represents ethyl acetate; Represents benzyl; PMB represents p-methoxybenzyl; Boc represents tert-butoxycarbonyl; EtOH represents ethanol; MeOH represents methanol; DBU represents 1,8-diazacyclo[5,4,0]undecene-7 ; PPTS stands for pyridine p-toluenesulfonate; DMA stands for dimethylacetamide; DMP stands for Dess-Martin oxidant; T 3 P stands for 1-propyl phosphoric acid cyclic anhydride; HPLC stands for high performance liquid chromatography; LCMS stands for liquid phase Chromatography-mass spectrometry; rt stands for room temperature; mp stands for melting point; °
  • Test method Place an appropriate amount of sample on the sample plate, press it into a flat sample plate, and perform XRPD test with the following parameters.
  • Phototube voltage 40kV
  • phototube current 30mA
  • the present invention 's differential thermal analysis (Differential Scanning Calorimeter, DSC) method
  • Test method Take a sample (2.7mg) and place it in a perforated aluminum crucible for testing. Heat the sample from 25°C (room temperature) to 350°C at a heating rate of 10°C/min.
  • Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
  • Test method Take a sample ( ⁇ 10mg) and place it in an aluminum crucible, and place the aluminum crucible in a platinum hanging basket for testing. Under the condition of 40mL/min N 2 , heat the sample from room temperature to 500°C at a heating rate of 10°C/min .
  • Fig. 1 is the XRPD spectrogram of the Cu-K ⁇ radiation of formula (I) compound A crystal form
  • Fig. 2 is the DSC spectrogram of formula (I) compound A crystal form
  • Fig. 3 is the TGA spectrogram of formula (I) compound A crystal form
  • Fig. 4 is the absolute configuration structural diagram of formula (I) compound
  • Fig. 5 is an ellipsoid diagram of the three-dimensional structure of the compound of formula (I).
  • 1,3-propanediol (25.0g, 328.54mmol, 23.81mL, 1eq) was dissolved in dimethylsulfoxide (120mL), and potassium hydroxide (18.43g, 328.54mmol, 1eq) and p-methoxybenzyl Chlorine (51.45g, 328.54mmol, 44.74mL, 1eq), the reaction solution was stirred at 25°C for 14 hours. The reaction solution was poured into 125 mL of water and extracted with ethyl acetate (150 mL ⁇ 2).
  • the concentrated filtrate was subjected to the previous operation three times to obtain the crude product.
  • Compound 1A was separated by SFC (separation column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5 ⁇ m); mobile phase: A[CO 2 ]; B(Neu-EtOH)%: 15%-15%, min) to obtain compound 1 and 2.
  • the configuration of compound 1 was determined by X-ray single crystal diffraction analysis.
  • the detected crystal is a colorless block (0.30 ⁇ 0.30 ⁇ 0.30mm 3 ), which belongs to the space group P212121 of the orthorhombic crystal system.
  • the absolute configuration structure diagram of the hydrate of compound 1 is shown in Figure 4, and the three-dimensional structure ellipsoid diagram of the hydrate is shown in Figure 5.
  • the hydrate crystal structure data and parameters of Compound 1 are shown in Tables: 2, 3, 4, 5 and 6.
  • Table 2 Crystal structure refinement information table
  • Embodiment 2 Preparation of formula (I) compound A crystal form
  • the DSC spectrum of the crystal form of compound A of formula (I) is shown in FIG. 2 .
  • Embodiment 3 the solid stability test of formula (I) compound A crystal form
  • Test conditions point in time crystal form - 0 days Form A High temperature (60°C, open) 10 days Form A High humidity (room temperature/relative humidity 92.5%, open) 10 days Form A Strong light (5000lx, sealed) 10 days Form A
  • mice BALB/c strain
  • virus flu virus strain Baloxavir-resistant PR/8/PAI38T
  • intranasal drip on day 0
  • the inoculation dose was 150p.f.u./mouse.
  • vehicle 5% DMSO+10% polyethylene glycol-15 hydroxystearate+85% water
  • 30mpk formula (I) Compound A crystal form were treated continuously for 7 days, every Twice a day, the way of administration is intragastric administration, a total of 14 administrations, the first administration time is 2 hours before virus inoculation. Animals were continuously observed from day 0 to day 14, and body weight, health and survival were recorded.
  • Table 8 The protective effect (body weight) of formula (I) compound A crystal form on mice in the influenza A prevention model

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Abstract

A crystal form of a fused-ring derivative having the structure represented by formula (I), a preparation method therefor, and an application thereof in pharmacy.

Description

一种稠环衍生物的晶型及其制备方法Crystal form of a fused ring derivative and preparation method thereof
本申请要求申请日为2021年11月17日的中国专利申请2021113658103的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 2021113658103 with a filing date of November 17, 2021. This application cites the full text of the above-mentioned Chinese patent application.
技术领域technical field
本发明涉及一种稠环衍生物的晶型及其制备方法，还包括所述晶型在药学中的应用。The invention relates to a crystal form of a condensed ring derivative and a preparation method thereof, and also includes the application of the crystal form in pharmacy.
背景技术Background technique
流行性感冒病毒，即流感病毒(influenza virus,IFV)，是一种能够导致人和动物患流行感冒的分节状单链反义RNA病毒。流感病毒可引起非常高的发病率和死亡率，尤其A型流感病毒还能够导致全球性的大流行，比如1918～1920年的“西班牙流感”(H1N1亚型)、1957～1958年“亚洲流感”(H2N2亚型)、1968～1969年“亚洲流感”(H3N2亚型)、1977～1978年“香港流感”(H1N1亚型)以及2009年3月在墨西哥首先暴发的甲型H1N1流感。流感大爆发导致成千上万人死亡，引起巨大社会恐慌并增加社会不稳定因素。Influenza virus, namely influenza virus (IFV), is a segmented single-stranded antisense RNA virus that can cause influenza in humans and animals. Influenza viruses can cause very high morbidity and mortality, especially type A influenza viruses can also lead to global pandemics, such as the "Spanish flu" (H1N1 subtype) from 1918 to 1920, the "Asian flu" from 1957 to 1958 "(H2N2 subtype), 1968-1969 "Asian flu" (H3N2 subtype), 1977-1978 "Hong Kong flu" (H1N1 subtype), and the H1N1 influenza that first broke out in Mexico in March 2009. The flu outbreak caused tens of thousands of deaths, caused great social panic and increased social instability.
A型流感病毒为单负链RNA病毒，基因组包含8个RNA片段，编码11种蛋白质：血凝素(HA)、神经氨酸酶(NA)、核蛋白(NP)、M1、M2、NS1、NS2、PA、PB1、PB1-F2和PB2。A型流感病毒根据病毒表面的血凝素(HA)和神经氨酸酶(NA)这两种蛋白可分为多个亚型。目前已知HA亚型有18种，NA亚型有11种。其中，流感病毒的血凝素(HA)负责识别宿主细胞的唾液酸糖蛋白，介导病毒外膜与细胞内小体膜融合释放病毒核衣壳进入胞浆。流感病毒的神经酰胺酶(NA)在复制过程中可除去病毒颗粒表面的唾液酸，使病毒颗粒不能继续在宿主细胞表面聚集，从而有利于病毒子的释放并进一步感染更多的宿主细胞。Influenza A virus is a single negative-strand RNA virus, the genome contains 8 RNA segments, encoding 11 kinds of proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), M1, M2, NS1, NS2, PA, PB1, PB1-F2, and PB2. Influenza A viruses can be divided into multiple subtypes based on the two proteins, hemagglutinin (HA) and neuraminidase (NA) on the surface of the virus. There are currently 18 known subtypes of HA and 11 subtypes of NA. Among them, the hemagglutinin (HA) of influenza virus is responsible for recognizing the sialic acid glycoprotein of the host cell, mediating the fusion of the outer membrane of the virus and the membrane of the inner body of the cell to release the viral nucleocapsid into the cytoplasm. Ceramidase (NA) of influenza virus can remove sialic acid on the surface of virus particles during the replication process, so that virus particles cannot continue to accumulate on the surface of host cells, thereby facilitating the release of virions and further infecting more host cells.
流感病毒蛋白的合成是利用宿主细胞翻译机制，甚至病毒可以暂停宿主蛋白的翻译，加快自身蛋白的合成。病毒mRNA需要借用宿主mRNA 5’端进行加帽才能开始翻译，这个过程称为“cap snatching”，主要通过病毒的RNA依赖性RNA聚合酶(RdRp)来完成，其PA亚基具有RNA内切酶活性，负责切断宿主mRNA。在完成了多聚腺苷酸化过程和加帽过程，病毒的mRNA即出核，进入细胞质，并像宿主细胞的mRNA一样进行翻译，病毒vRNA片段的核输出是由病毒的M1蛋白和NS2蛋白介导的，M1蛋白可以与vRNA和NP蛋白相互作用时，同时也与核输出蛋白NS2作用；由此，核输出蛋白NS2介导M1-RNP以核蛋白形式出核进入宿主细胞的细胞质。The synthesis of influenza virus protein is based on the host cell translation mechanism, and even the virus can suspend the translation of host protein and speed up the synthesis of its own protein. Viral mRNA needs to be capped at the 5' end of host mRNA to start translation. This process is called "cap snatching", which is mainly completed by the viral RNA-dependent RNA polymerase (RdRp), whose PA subunit has RNA endonuclease activity, responsible for cleaving host mRNA. After the polyadenylation process and capping process are completed, the viral mRNA is exported from the nucleus, enters the cytoplasm, and is translated like the mRNA of the host cell. The nuclear export of the viral vRNA fragment is mediated by the viral M1 protein and NS2 protein Guided, when M1 protein can interact with vRNA and NP protein, it also interacts with the nuclear export protein NS2; thus, the nuclear export protein NS2 mediates the export of M1-RNP into the cytoplasm of the host cell in the form of nuclear protein.
目前的流感治疗选择包括接种疫苗和用抗病毒药物进行化疗和化学预防。经常向高危群体，例如儿童和老年人，或有哮喘、糖尿病或心脏病的人推荐接种抗流感的流感疫苗。但是接种疫苗不能完全避免患流感，并且流感病毒会发生一定程度的抗原漂移。如果超过一种病毒感染了单个细胞，则基因组中8个单独的vRNA片段发生混合或重配，所导致的病毒遗传学上的快速变化可产生抗原转变并使得病毒能感染新宿主物种并迅速克服保护性免疫。Current treatment options for influenza include vaccination and chemotherapy and chemoprophylaxis with antiviral drugs. A flu shot against the flu is often recommended for high-risk groups, such as children and the elderly, or people with asthma, diabetes, or heart disease. However, vaccination cannot completely prevent influenza, and influenza viruses undergo some degree of antigenic drift. If more than one virus infects a single cell, eight separate vRNA segments in the genome mix or reassort, resulting in rapid changes in viral genetics that produce an antigenic shift and allow the virus to infect and rapidly overcome new host species Protective immunity.
抗病毒药物可以用于治疗流感，其中神经氨酸酶(NA)抑制剂，如奥司他韦(达菲)，对于甲型流感病毒效果明显，但是经过临床观察发现，对于该类神经氨酸酶抑制剂已经出现了耐药的病毒株。在抗流感病毒领域，临床上亟需全新作用机制的抗流感病毒药物，能够支持单药使用治疗甲型流感，或者通过和已上市的其他作用机制的抗流感病毒药物联用，用于甲型流感的预防和治疗。其中WO2016175224报道了如下化合物及其前药：Antiviral drugs can be used to treat influenza, among which neuraminidase (NA) inhibitors, such as oseltamivir (Tamiflu), have obvious effects on influenza A virus, but it has been found through clinical observation that for this type of neuraminidase Enzyme inhibitor resistant virus strains have emerged. In the field of anti-influenza virus, there is an urgent need for anti-influenza virus drugs with a new mechanism of action in clinical practice, which can support single drug use in the treatment of influenza A, or can be used in combination with anti-influenza virus drugs with other mechanisms of action already on the market. Influenza prevention and treatment. Among them, WO2016175224 reports the following compounds and their prodrugs:
Figure PCTCN2022132579-appb-000001
Figure PCTCN2022132579-appb-000001
发明内容Contents of the invention
本发明提供式(I)所示化合物，The present invention provides compounds represented by formula (I),
Figure PCTCN2022132579-appb-000002
Figure PCTCN2022132579-appb-000002
其中，n选自0.5～2；Wherein, n is selected from 0.5～2;
优选地，n选自0.5、0.6、0.7、0.8、0.9、1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9或2；Preferably, n is selected from 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2;
更优选地，n选自1。More preferably, n is selected from 1.
本发明提供式(I)所示化合物的A晶型，The present invention provides A crystal form of the compound represented by formula (I),
Figure PCTCN2022132579-appb-000003
Figure PCTCN2022132579-appb-000003
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：6.942±0.200°，21.561±0.200°，25.758±0.200°。It is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.942±0.200°, 21.561±0.200°, 25.758±0.200°.
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：6.942±0.200°，13.159±0.200°，16.479±0.200°，19.980±0.200°，21.561±0.200°，23.501±0.200°，25.758±0.200°，29.159±0.200°。In some solutions 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: 6.942±0.200°, 13.159±0.200°, 16.479±0.200°, 19.980±0.200°, 21.561± 0.200°, 23.501±0.200°, 25.758±0.200°, 29.159±0.200°.
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：6.942±0.200°，13.159±0.200°，13.898±0.200°，16.479±0.200°，19.980±0.200°，20.881±0.200°，21.561±0.200°，23.501±0.200°，24.518±0.200°，25.758±0.200°，28.299±0.200°，29.159±0.200°。In some solutions 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: 6.942±0.200°, 13.159±0.200°, 13.898±0.200°, 16.479±0.200°, 19.980± 0.200°, 20.881±0.200°, 21.561±0.200°, 23.501±0.200°, 24.518±0.200°, 25.758±0.200°, 28.299±0.200°, 29.159±0.200°.
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：6.942±0.200°，10.637±0.200°，13.159±0.200°，13.898±0.200°，16.479±0.200°，17.001±0.200°，19.980±0.200°，20.881±0.200°，21.561±0.200°，23.501±0.200°，24.518±0.200°，25.758±0.200°，27.600±0.200°，28.299±0.200°，29.159±0.200°，29.719±0.200°。In some solutions 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: 6.942±0.200°, 10.637±0.200°, 13.159±0.200°, 13.898±0.200°, 16.479± 0.200°,17.001±0.200°,19.980±0.200°,20.881±0.200°,21.561±0.200°,23.501±0.200°,24.518±0.200°,25.758±0.200°,27.600±0.200°,28 .299±0.200°, 29.159± 0.200°, 29.719±0.200°.
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：6.942°，10.419°，10.637°，12.661°，13.159°，13.898°，16.084°，16.479°，17.001°，17.540°，18.843°，19.199°，19.980°，20.881°，21.561°，22.384°，23.137°，23.501°，23.776°，24.122°，24.518°，25.758°，26.362°，27.600°，27.997°，28.299°，28.840°，29.159°，29.719°，30.822°，31.042°，31.597°，32.220°，32.638°，33.136°，34.140°，35.582°，36.140°，37.037°，37.467°。In some solutions 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: 6.942°, 10.419°, 10.637°, 12.661°, 13.159°, 13.898°, 16.084°, 16.479 °, 17.001°, 17.540°, 18.843°, 19.199°, 19.980°, 20.881°, 21.561°, 22.384°, 23.137°, 23.501°, 23.776°, 24.122°, 24.518°, 25.758°, 26.362° , 27.600°, 27.997°, 28.299°, 28.840°, 29.159°, 29.719°, 30.822°, 31.042°, 31.597°, 32.220°, 32.638°, 33.136°, 34.140°, 35.582°, 36.140°, 37.037°, 3 7.467°.
本发明提供了化合物1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：6.942±0.200°，21.561±0.200°，25.758±0.200°。还可以在23.501±0.200°，和/或13.159±0.200°，和/或29.159±0.200°，和/或19.980±0.200°，和/或16.479±0.200°，和/或13.898±0.200°，和/或20.881±0.200°，和/或28.299±0.200°，和/或24.518±0.200°，和/或17.001±0.200°，和/或12.661±0.200°， 和/或22.384±0.200°，和/或10.637±0.200°，和/或29.719±0.200°，和/或27.600±0.200°，和/或26.362±0.200°，和/或30.822±0.200°，和/或28.840±0.200°，和/或17.540±0.200°，和/或31.042±0.200°，和/或19.199±0.200°，和/或32.220±0.200°，和/或10.419±0.200°，和/或27.997±0.200°，和/或37.037±0.200°，和/或36.140±0.200°，和/或23.776±0.200°，和/或32.638±0.200°，和/或37.467±0.200°，和/或16.084±0.200°，和/或24.122±0.200°，和/或31.597±0.200°，和/或34.140±0.200°，和/或33.136±0.200°，和/或18.843±0.200°，和/或23.137±0.200°，和/或35.582±0.200°处有特征衍射峰。The present invention provides crystal form A of Compound 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.942±0.200°, 21.561±0.200°, 25.758±0.200°. It can also be at 23.501±0.200°, and/or 13.159±0.200°, and/or 29.159±0.200°, and/or 19.980±0.200°, and/or 16.479±0.200°, and/or 13.898±0.200°, and/or or 20.881±0.200°, and/or 28.299±0.200°, and/or 24.518±0.200°, and/or 17.001±0.200°, and/or 12.661±0.200°, and/or 22.384±0.200°, and/or 10.637 ±0.200°, and/or 29.719±0.200°, and/or 27.600±0.200°, and/or 26.362±0.200°, and/or 30.822±0.200°, and/or 28.840±0.200°, and/or 17.540±0.200 °, and/or 31.042±0.200°, and/or 19.199±0.200°, and/or 32.220±0.200°, and/or 10.419±0.200°, and/or 27.997±0.200°, and/or 37.037±0.200°, and/or 36.140±0.200°, and/or 23.776±0.200°, and/or 32.638±0.200°, and/or 37.467±0.200°, and/or 16.084±0.200°, and/or 24.122±0.200°, and/or Or 31.597±0.200°, and/or 34.140±0.200°, and/or 33.136±0.200°, and/or 18.843±0.200°, and/or 23.137±0.200°, and/or 35.582±0.200° with characteristic diffraction peaks .
在本发明的一些方案中，上述A晶型的XRPD图谱如图1所示。In some solutions of the present invention, the XRPD pattern of the above 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 solutions of the present invention, the XRPD spectrum analysis data of the above crystal form A are shown in Table 1:
表1Table 1
Figure PCTCN2022132579-appb-000004
Figure PCTCN2022132579-appb-000004
Figure PCTCN2022132579-appb-000005
Figure PCTCN2022132579-appb-000005
本发明的一些方案中，上述A晶型的差示扫描量热曲线在164.37±3℃处有一个吸热峰的峰值。In some solutions of the present invention, the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 164.37±3°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 solutions of the present invention, the DSC spectrum of the above 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150±3℃处失重达2.966％，在225±3℃处失重达14.111％。In some solutions of the present invention, the thermogravimetric analysis curve of the above crystal form A has a weight loss of 2.966% at 150±3°C, and a weight loss of 14.111% at 225±3°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 solutions of the present invention, the TGA spectrum of the above crystal form A is shown in FIG. 3 .
本发明还提供上述A晶型在制备抗流感病毒的药物中的应用。The present invention also provides the application of the above crystal form A in the preparation of anti-influenza virus medicaments.
技术效果technical effect
本发明化合物晶型稳定、受光热影响小。The compound of the invention has a stable crystal form and is less affected by light and heat.
本发明化合物在动物治疗模型药效实验中展示出保护效应，同时药代动力学性质符合成药的要求。The compound of the present invention exhibits a protective effect in drug efficacy experiments of animal treatment models, and meanwhile, the pharmacokinetic properties meet the requirements of pharmaceutical preparations.
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 indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name 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 compound 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 its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
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 reactions of the specific embodiments of the present invention are completed in a suitable solvent, and the solvent must be suitable for the chemical changes 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 synthetic steps or reaction schemes on the basis of existing embodiments.
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。The present invention will be specifically described by examples below, and these examples do not imply any limitation to the present invention.
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 used without further purification.
本发明采用下述缩略词：aq.和H 2O代表水；eq代表当量、等量；Boc代表叔丁氧羰基；PE代表石油醚；MeCN或ACN代表乙腈；EtOAc代表乙酸乙酯；Bn代表苄基；PMB代表对甲氧基苄基；Boc代表叔丁氧羰基；EtOH代表乙醇；MeOH代表甲醇；DBU代表1,8-二氮杂环[5,4,0]十一烯-7；PPTS代表吡啶对甲苯磺酸盐；DMA代表二甲基乙酰胺；DMP代表戴斯-马汀氧化剂；T 3P代表1-丙基磷酸环酐；HPLC代表高效液相色谱；LCMS代表液相色谱-质谱联用；r.t.代表室温；mp代表熔点；℃代表摄氏度；h代表小时；mL代表毫升；mM代表毫摩尔每升；mmol代表毫摩尔；μmol代表微摩尔；HNMR代表核磁共振氢谱；MS代表质谱；min代表分钟；pH代表氢离子摩尔浓度负对数。 The present invention adopts the following abbreviations: aq. and H 2 O represent water; eq represents equivalent, equivalent; Boc represents tert-butoxycarbonyl; PE represents petroleum ether; MeCN or ACN represents acetonitrile; EtOAc represents ethyl acetate; Represents benzyl; PMB represents p-methoxybenzyl; Boc represents tert-butoxycarbonyl; EtOH represents ethanol; MeOH represents methanol; DBU represents 1,8-diazacyclo[5,4,0]undecene-7 ; PPTS stands for pyridine p-toluenesulfonate; DMA stands for dimethylacetamide; DMP stands for Dess-Martin oxidant; T 3 P stands for 1-propyl phosphoric acid cyclic anhydride; HPLC stands for high performance liquid chromatography; LCMS stands for liquid phase Chromatography-mass spectrometry; rt stands for room temperature; mp stands for melting point; ℃ stands for Celsius; h stands for hour; mL stands for milliliter; mM stands for millimole per liter; MS stands for mass spectrum; min stands for minute; pH stands for negative logarithm of hydrogen ion molar concentration.
化合物经本领域常规命名原则或者
Figure PCTCN2022132579-appb-000006
软件命名，市售化合物采用供应商目录名称。 Compounds are conventionally named in the field or
Figure PCTCN2022132579-appb-000006
The software is named, and the commercially available compounds adopt 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：丹东浩元仪器有限公司的DX-2700BH型X射线衍射仪Instrument model: DX-2700BH X-ray diffractometer of Dandong Haoyuan Instrument Co., Ltd.
测试方法：将适量样品放置在样品板上，压制成表明平整的样品板后，用以下描述参数进行XRPD测试。Test method: Place an appropriate amount of sample on the sample plate, press it into a flat sample plate, and perform XRPD test with the following parameters.
详细的XRPD参数如下：The detailed XRPD parameters are as follows:
光管：Cu,kα,
Figure PCTCN2022132579-appb-000007
Light pipe: Cu, kα,
Figure PCTCN2022132579-appb-000007
光管电压：40kV，光管电流：30mAPhototube voltage: 40kV, phototube current: 30mA
发散狭缝：1mmDivergence slit: 1mm
探测器狭缝：0.3mmDetector slit: 0.3mm
防散射狭缝：1mmAnti-scatter slit: 1mm
扫描范围：3-40°Scanning range: 3-40°
步径：0.02°Step diameter: 0.02°
扫描时长：0.5秒Scanning time: 0.5 seconds
本发明差热分析(Differential Scanning Calorimeter,DSC)方法The present invention's differential thermal analysis (Differential Scanning Calorimeter, DSC) method
仪器型号：梅特勒DSC1差示扫描量热仪Instrument Model: Mettler DSC1 Differential Scanning Calorimeter
测试方法：取样品(2.7mg)置于打孔铝坩埚内进行测试，以10℃/min的升温速率，加热样品从25℃(室温)到350℃。Test method: Take a sample (2.7mg) and place it in a perforated aluminum crucible for testing. Heat the sample from 25°C (room temperature) to 350°C at a heating rate of 10°C/min.
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
仪器型号：TA TGA550热重分析仪Instrument Model: TA TGA550 Thermogravimetric Analyzer
测试方法：取样品(～10mg)置于铝坩埚，铝坩埚置于铂金吊篮内进行测试，在40mL/min N 2条件下，以10℃/min的升温速率，加热样品从室温到500℃。 Test method: Take a sample (~10mg) and place it in an aluminum crucible, and place the aluminum crucible in a platinum hanging basket for testing. Under the condition of 40mL/min N 2 , heat the sample from room temperature to 500°C at a heating rate of 10°C/min .
附图说明Description of drawings
图1为式(I)化合物A晶型的Cu-Kα辐射的XRPD谱图；Fig. 1 is the XRPD spectrogram of the Cu-Kα radiation of formula (I) compound A crystal form;
图2为式(I)化合物A晶型的DSC谱图；Fig. 2 is the DSC spectrogram of formula (I) compound A crystal form;
图3为式(I)化合物A晶型的TGA谱图；Fig. 3 is the TGA spectrogram of formula (I) compound A crystal form;
图4为式(I)化合物的绝对构型结构图；Fig. 4 is the absolute configuration structural diagram of formula (I) compound;
图5为式(I)化合物的立体结构椭球图。Fig. 5 is an ellipsoid diagram of the three-dimensional structure of the compound of formula (I).
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, the following will be further described in conjunction with specific examples, but the specific implementation is not a limitation to the content of the present invention.
实施例1Example 1
Figure PCTCN2022132579-appb-000008
Figure PCTCN2022132579-appb-000008
合成路线：synthetic route:
Figure PCTCN2022132579-appb-000009
Figure PCTCN2022132579-appb-000009
Figure PCTCN2022132579-appb-000010
Figure PCTCN2022132579-appb-000010
步骤1：化合物1a的合成Step 1: Synthesis of Compound 1a
将1,3-丙二醇(25.0g,328.54mmol,23.81mL,1eq)溶于二甲基亚砜(120mL)，往其中加入氢氧化钾(18.43g,328.54mmol,1eq)和对甲氧基苄氯(51.45g,328.54mmol,44.74mL,1eq)，反应液在25℃下搅拌14小时。反应液与倒入125mL水中，用乙酸乙酯(150mL×2)萃取。有机相合并，经水(250mL)和饱和食盐水(250mL×3)洗涤，无水硫酸钠干燥后浓缩得到粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:0-50:50)纯化得到化合物1a。1,3-propanediol (25.0g, 328.54mmol, 23.81mL, 1eq) was dissolved in dimethylsulfoxide (120mL), and potassium hydroxide (18.43g, 328.54mmol, 1eq) and p-methoxybenzyl Chlorine (51.45g, 328.54mmol, 44.74mL, 1eq), the reaction solution was stirred at 25°C for 14 hours. The reaction solution was poured into 125 mL of water and extracted with ethyl acetate (150 mL×2). The organic phases were combined, washed with water (250 mL) and saturated brine (250 mL×3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-50:50) to obtain compound 1a.
1H NMR(400MHz,CDCl 3)δ＝7.26(br d,J＝8.6Hz,2H),6.89(br d,J＝8.6Hz,2H),4.46(s,2H),3.81(s,3H),3.77(t,J＝5.7Hz,2H),3.64(t,J＝5.8Hz,2H),1.90-1.81(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ=7.26(br d,J=8.6Hz,2H),6.89(br d,J=8.6Hz,2H),4.46(s,2H),3.81(s,3H) , 3.77(t, J=5.7Hz, 2H), 3.64(t, J=5.8Hz, 2H), 1.90-1.81(m, 2H).
步骤2：化合物1b的合成Step 2: Synthesis of Compound 1b
将1a(10.0g,50.96mmol,1eq)溶于二氯甲烷(130mL)，往其中缓慢分批加入DMP(22.69g,53.51mmol,16.56mL,1.05eq)，反应液在25℃氮气保护下搅拌1小时。反应液用硅胶过滤，滤饼用二氯甲烷(25mL×4)洗涤，滤液合并浓缩。往浓缩后的滤液中加入石油醚/乙酸乙酯(5:1，50mL)，搅拌20分钟，过滤，滤饼用石油醚/乙酸乙酯(5:1，30mL×2)洗涤，滤液合并浓缩。浓缩后的滤液按前面的操作重复三次后得到粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:0-80:20)纯化得到化合物1b。1a (10.0g, 50.96mmol, 1eq) was dissolved in dichloromethane (130mL), and DMP (22.69g, 53.51mmol, 16.56mL, 1.05eq) was slowly added in portions, and the reaction solution was stirred at 25°C under nitrogen protection 1 hour. The reaction solution was filtered through silica gel, the filter cake was washed with dichloromethane (25 mL×4), and the filtrates were combined and concentrated. Add petroleum ether/ethyl acetate (5:1, 50mL) to the concentrated filtrate, stir for 20 minutes, filter, wash the filter cake with petroleum ether/ethyl acetate (5:1, 30mL×2), combine the filtrates and concentrate . The concentrated filtrate was subjected to the previous operation three times to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-80:20) to obtain compound 1b.
1H NMR(400MHz,CDCl 3)δ＝9.79(t,J＝1.9Hz,1H),7.28-7.24(m,2H),6.92-6.86(m,2H),4.47(s,2H),3.81(s,3H),3.81-3.78(m,2H),2.69(dt,J＝1.9,6.1Hz,2H)。 1 H NMR (400MHz, CDCl 3 ) δ=9.79(t, J=1.9Hz, 1H), 7.28-7.24(m, 2H), 6.92-6.86(m, 2H), 4.47(s, 2H), 3.81( s, 3H), 3.81-3.78 (m, 2H), 2.69 (dt, J = 1.9, 6.1 Hz, 2H).
步骤3：化合物1c的合成Step 3: Synthesis of Compound 1c
25℃下，向装有MeCN(30mL)的三颈烧瓶中加入4,5-二氟水杨醛(40g,253.00mmol,1eq)，对甲氧基苄氯(43.58g,278.30mmol,37.90mL,1.1eq)，碳酸钾(52.45g,379.50mmol,1.5eq)后，开启搅拌，然后升温到55℃后持续反应3个小时。将反应液过滤除去不溶的杂质后，滤饼用二氯甲烷(2×50mL)洗涤，合并有机相并减压浓缩去除溶剂得粗产品。粗产品使用石油醚(200mL)和乙酸乙酯(20mL)在20℃下打浆，过滤得固体为化合物1c。At 25°C, add 4,5-difluorosalicylaldehyde (40g, 253.00mmol, 1eq), p-methoxybenzyl chloride (43.58g, 278.30mmol, 37.90mL) into a three-necked flask filled with MeCN (30mL) , 1.1eq), potassium carbonate (52.45g, 379.50mmol, 1.5eq), the stirring was started, and then the temperature was raised to 55°C and the reaction was continued for 3 hours. After the reaction solution was filtered to remove insoluble impurities, the filter cake was washed with dichloromethane (2×50 mL), and the organic phases were combined and concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was slurried at 20° C. with petroleum ether (200 mL) and ethyl acetate (20 mL), and the solid was obtained by filtration as compound 1c.
1H NMR(400MHz,CDCl 3)δ＝10.36(d,J＝3.0Hz,1H),7.66(t,J＝9.7Hz,1H),7.34(d,J＝8.8Hz,2H),6.97-6.85(m,3H),5.07(s,2H),3.83(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ=10.36(d, J=3.0Hz, 1H), 7.66(t, J=9.7Hz, 1H), 7.34(d, J=8.8Hz, 2H), 6.97-6.85 (m,3H), 5.07(s,2H), 3.83(s,3H).
步骤4：化合物1d的合成Step 4: Synthesis of Compound 1d
于0℃，氮气保护下往1c(35g,125.79mmol,1eq)的四氢呋喃(70mL)溶液中滴加苯基溴化镁***溶液(3M,44.03mL,1.05eq)，然后反应温度升至20℃，并在此温度下搅拌4个小时。合并两个平行反应，然后向反应液中加入饱和氯化铵水溶液(80mL)淬灭反应，然后加入乙酸乙酯(4×90mL)萃取得有机相，有机相经无水硫酸钠干燥后减压浓缩得粗产品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:0-70:30)分离提纯，得到化合物1d。Add phenylmagnesium bromide ether solution (3M, 44.03mL, 1.05eq) dropwise to a solution of 1c (35g, 125.79mmol, 1eq) in tetrahydrofuran (70mL) under nitrogen protection at 0°C, then the reaction temperature rose to 20°C , and stirred at this temperature for 4 hours. Combine two parallel reactions, then add saturated ammonium chloride aqueous solution (80mL) to the reaction solution to quench the reaction, then add ethyl acetate (4×90mL) to extract the organic phase, the organic phase is dried over anhydrous sodium sulfate and then reduced pressure Concentrated crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-70:30) to obtain compound 1d.
1H NMR(400MHz,CDCl 3)δ＝7.32-7.20(m,6H),7.11(d,J＝8.5Hz,2H),6.91-6.84(m,2H),6.74(dd,J＝6.5,12.0Hz,1H),5.99(d,J＝4.8Hz,1H),4.88(s,2H),3.82(s,3H)； 1 H NMR (400MHz, CDCl 3 ) δ=7.32-7.20(m,6H),7.11(d,J=8.5Hz,2H),6.91-6.84(m,2H),6.74(dd,J=6.5,12.0 Hz,1H),5.99(d,J=4.8Hz,1H),4.88(s,2H),3.82(s,3H);
19F NMR(377MHz,CDCl 3)δ＝-136.47--137.23(m,1F),-147.20--147.96(m,1F)。 19 F NMR (377 MHz, CDCl 3 ) δ=-136.47--137.23 (m, 1F), -147.20--147.96 (m, 1F).
步骤5：化合物1f的合成Step 5: Synthesis of Compound 1f
将1e(100g,406.15mmol,1eq)加入到DMA(500mL)中，然后加入碳酸氢钠(40.94g,487.38mmol,18.96mL,1.2eq)和硫酸二甲酯(56.74g,449.85mmol,42.66mL,1.11eq)，反应液在20℃下搅拌12个小时。加入水(750mL)，用乙酸乙酯萃取两次(1000mL+500mL)。有机相合并，用水洗(450mL)，饱 和食盐水洗(300mL)，无水硫酸钠干燥，过滤，滤液减压浓缩干。得到化合物1f，无需提纯直接用于下一步。1e (100 g, 406.15 mmol, 1 eq) was added to DMA (500 mL), followed by sodium bicarbonate (40.94 g, 487.38 mmol, 18.96 mL, 1.2 eq) and dimethyl sulfate (56.74 g, 449.85 mmol, 42.66 mL , 1.11eq), the reaction solution was stirred at 20°C for 12 hours. Water (750 mL) was added and extracted twice with ethyl acetate (1000 mL+500 mL). The organic phases were combined, washed with water (450 mL), washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound 1f was obtained, which was directly used in the next step without purification.
1H NMR(400MHz,CDCl 3)δ＝7.74(d,J＝5.6Hz,1H),7.45(br d,J＝6.5Hz,2H),7.39-7.28(m,3H),6.47(d,J＝5.5Hz,1H),5.30(s,2H),3.86(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ=7.74(d,J=5.6Hz,1H),7.45(br d,J=6.5Hz,2H),7.39-7.28(m,3H),6.47(d,J =5.5Hz, 1H), 5.30(s, 2H), 3.86(s, 3H).
步骤6：化合物1g的合成Step 6: Synthesis of Compound 1g
将1f(126g,484.16mmol,1eq)加入到DMA(650mL)中，然后加入PPTS(316.35g,1.26mol,2.6eq)，反应液在60℃下搅拌，然后滴加Boc-肼(83.18g,629.41mmol,1.3eq)的DMA(100mL)溶液，反应液继续在60℃下搅拌4个小时。反应液冷却到室温，搅拌下加入水(1.55L)，用乙酸乙酯洗涤两次(2×1L)，合并有机相，用饱和食盐水(1L)洗涤一次。减压浓缩后油状液体加入乙酸乙酯(500mL)，搅拌下加入水(1L)，有固体析出，过滤，用乙酸乙酯洗涤滤饼。干燥后得到化合物1g。1f (126g, 484.16mmol, 1eq) was added to DMA (650mL), then PPTS (316.35g, 1.26mol, 2.6eq) was added, the reaction solution was stirred at 60°C, and Boc-hydrazine (83.18g, 629.41mmol, 1.3eq) in DMA (100mL), and the reaction solution was stirred at 60°C for 4 hours. The reaction solution was cooled to room temperature, water (1.55 L) was added with stirring, washed twice with ethyl acetate (2×1 L), the combined organic phases were washed once with saturated brine (1 L). After concentration under reduced pressure, ethyl acetate (500 mL) was added to the oily liquid, and water (1 L) was added with stirring. A solid precipitated out, filtered, and the filter cake was washed with ethyl acetate. Compound 1g was obtained after drying.
1H NMR(400MHz,CDCl 3)δ＝7.35-7.30(m,2H),7.30-7.26(m,2H),7.25-7.21(m,2H),7.19(s,1H),6.35(d,J＝7.9Hz,1H),5.18(s,2H),3.70(s,3H),1.38(s,9H)。 1 H NMR (400MHz, CDCl 3 )δ=7.35-7.30(m,2H),7.30-7.26(m,2H),7.25-7.21(m,2H),7.19(s,1H),6.35(d,J =7.9Hz, 1H), 5.18(s, 2H), 3.70(s, 3H), 1.38(s, 9H).
步骤7：化合物1h的合成Step 7: Synthesis of Compound 1h
1g(20g,53.42mmol,1eq)加入到四氢呋喃(200mL)中，依次加入DBU(2.44g,16.03mmol,2.42mL,0.3eq)和甲胺醇溶液(50.28g,534.21mmol,33％浓度,10eq)。反应在60℃下反应12个小时。向反应液中加入二氯甲烷(50mL)，并用柠檬酸水溶液(2×50mL)洗涤两次。有机相减压浓缩，往浓缩的溶液中加入乙酸乙酯(20mL)，在20℃进行打浆2个小时，得到化合物1h。1g (20g, 53.42mmol, 1eq) was added to tetrahydrofuran (200mL), followed by adding DBU (2.44g, 16.03mmol, 2.42mL, 0.3eq) and methylamino alcohol solution (50.28g, 534.21mmol, 33% concentration, 10eq ). The reaction was carried out at 60°C for 12 hours. Dichloromethane (50 mL) was added to the reaction and washed twice with aqueous citric acid (2×50 mL). The organic phase was concentrated under reduced pressure, ethyl acetate (20 mL) was added to the concentrated solution, and beating was performed at 20° C. for 2 hours to obtain compound 1h.
步骤8：化合物1i的盐酸盐的合成Step 8: Synthesis of the hydrochloride salt of compound 1i
将1h(13g,34.82mmol,1eq)加入到乙酸乙酯(130mL)中，依次加入盐酸的乙酸乙酯溶液(4M,130mL,14.32eq)。反应在25℃下反应12个小时。反应液减压浓缩，除去溶剂。得到化合物1i的盐酸盐，无需提纯直接用于下一步。1h (13g, 34.82mmol, 1eq) was added to ethyl acetate (130mL), followed by the addition of hydrochloric acid in ethyl acetate (4M, 130mL, 14.32eq). The reaction was carried out at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the solvent was removed. The hydrochloride of compound 1i was obtained, which was directly used in the next step without purification.
1H NMR(400MHz,CD 3OD)δ＝8.37(br d,J＝7.3Hz,1H),7.47-7.34(m,5H),7.30-7.24(m,1H),5.24(s,2H),2.91(s,3H)。 1 H NMR (400MHz, CD 3 OD) δ = 8.37 (br d, J = 7.3Hz, 1H), 7.47-7.34 (m, 5H), 7.30-7.24 (m, 1H), 5.24 (s, 2H), 2.91(s,3H).
步骤9：化合物1j的合成Step 9: Synthesis of compound 1j
往化合物1i的盐酸盐(800mg,2.58mmol,1eq)和1b(551.80mg,2.84mmol,1.1eq)的乙腈(8mL)悬浊液加入碳酸钾(1.43g,10.33mmol,4eq)，在20℃下搅拌18个小时。反应液加入乙酸乙酯/水(1:1,20mL)稀释，过滤，滤饼用水洗三次(3×5mL)，乙酸乙酯洗三次(3×5mL)。滤液分相，有机相直接浓缩蒸干。粗品经硅胶柱层析(二氯甲烷/甲醇＝100:0-95:5)分离提纯，产品组分浓缩后与先前所得滤饼合并，得到化合物1j。Add potassium carbonate (1.43g, 10.33mmol, 4eq) to compound 1i hydrochloride (800mg, 2.58mmol, 1eq) and 1b (551.80mg, 2.84mmol, 1.1eq) in acetonitrile (8mL) suspension, at 20 Stir for 18 hours at °C. The reaction solution was diluted with ethyl acetate/water (1:1, 20 mL), filtered, and the filter cake was washed three times with water (3×5 mL) and three times with ethyl acetate (3×5 mL). The filtrate was separated into phases, and the organic phase was directly concentrated and evaporated to dryness. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol=100:0-95:5), and the product components were concentrated and combined with the previously obtained filter cake to obtain compound 1j.
1H NMR(400MHz,CDCl 3)δ＝7.46(dd,J＝1.6,7.7Hz,2H),7.28-7.21(m,6H),6.91(d,J＝8.5Hz,2H),6.32(d,J＝7.5Hz,1H),6.21(d,J＝2.8Hz,1H),5.42(d,J＝10.5Hz,1H),5.21(d,J＝10.5Hz,1H),4.53-4.46(m,1H),4.46-4.38(m,2H),3.84(s,3H),3.46-3.37(m,1H),3.30(td,J＝5.2,10.0Hz,1H),2.89(s,3H),1.58-1.41(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ=7.46(dd, J=1.6, 7.7Hz, 2H), 7.28-7.21(m, 6H), 6.91(d, J=8.5Hz, 2H), 6.32(d, J＝7.5Hz, 1H), 6.21(d, J＝2.8Hz, 1H), 5.42(d, J＝10.5Hz, 1H), 5.21(d, J＝10.5Hz, 1H), 4.53-4.46(m, 1H), 4.46-4.38(m, 2H), 3.84(s, 3H), 3.46-3.37(m, 1H), 3.30(td, J=5.2, 10.0Hz, 1H), 2.89(s, 3H), 1.58 -1.41(m,2H).
步骤10：化合物1k的合成Step 10: Synthesis of Compound 1k
1j(800mg,1.78mmol,1eq)和1d(951.36mg,2.67mmol,1.5eq)溶于乙酸乙酯(25mL)中，加入T3P的乙酸乙酯溶液(2.27g,3.56mmol,2.12mL,浓度：50％,2eq)，加热至65℃，搅拌12个小时。补加T 3P的乙酸乙酯溶液(1.13g,1.78mmol,1.06mL,50％浓度,1eq)，继续搅拌30个小时，补加1d(317.12mg,889.88μmol,0.5eq)，继续搅拌12个小时。反应液冷却至20℃，溶剂浓缩蒸干。加入二氯甲烷(15mL)，有机相用水(2×20mL)洗两次后，加硅胶后浓缩蒸干。粗品经硅胶柱层析(二氯甲烷/甲醇＝100:0-95:5)分离提纯，得到化合物1k。 1j (800mg, 1.78mmol, 1eq) and 1d (951.36mg, 2.67mmol, 1.5eq) were dissolved in ethyl acetate (25mL), and a solution of T3P in ethyl acetate (2.27g, 3.56mmol, 2.12mL, concentration: 50%, 2eq), heated to 65°C and stirred for 12 hours. Add T 3 P ethyl acetate solution (1.13g, 1.78mmol, 1.06mL, 50% concentration, 1eq), continue to stir for 30 hours, add 1d (317.12mg, 889.88μmol, 0.5eq), continue to stir for 12 Hours. The reaction solution was cooled to 20°C, and the solvent was concentrated and evaporated to dryness. Dichloromethane (15 mL) was added, the organic phase was washed twice with water (2×20 mL), silica gel was added, concentrated and evaporated to dryness. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol=100:0-95:5) to obtain compound 1k.
步骤11：化合物1l的合成Step 11: Synthesis of Compound 1l
1k(1.33g,1.69mmol,1eq)溶于预先混合好的盐酸(12M,557.04μL,3.96eq)的甲醇(12.8mL)溶液(～0.5M)，于60℃搅拌14.5个小时。反应冷却至20℃，加入饱和碳酸氢钠水溶液(10mL)，混合物用二氯甲烷/甲醇(10:1,10mL×4)萃 取四次。有机相合并后，加入硅胶浓缩蒸干。粗品经硅胶柱层析(二氯甲烷/甲醇＝100:0-95:5)分离提纯，得到化合物1l。1k (1.33g, 1.69mmol, 1eq) was dissolved in a premixed methanol (12.8mL) solution (~0.5M) of hydrochloric acid (12M, 557.04μL, 3.96eq) and stirred at 60°C for 14.5 hours. The reaction was cooled to 20 °C, saturated aqueous sodium bicarbonate (10 mL) was added, and the mixture was extracted four times with dichloromethane/methanol (10:1, 10 mL×4). After the organic phases were combined, silica gel was added to concentrate and evaporate to dryness. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol=100:0-95:5) to obtain compound 1l.
步骤12：化合物1m的合成Step 12: Synthesis of Compound 1m
1l(250mg,456.58μmol,1eq)先在乙腈中蒸干以除去水分，然后悬浮于二氯甲烷(4mL)中，20℃下往其中加入三苯基膦(179.63mg,684.87μmol,1.5eq)。反应在此温度下搅拌15分钟，然后加入四溴化碳(227.12mg,684.87μmol,1.5eq)，体系变得澄清，继续搅拌14个小时。往反应液加入甲醇(2mL)淬灭，直接加入硅胶，浓缩蒸干。粗品经硅胶柱层析(二氯甲烷/甲醇＝100:0-95:5)分离提纯，得到化合物1m。1l (250mg, 456.58μmol, 1eq) was first evaporated to dryness in acetonitrile to remove water, then suspended in dichloromethane (4mL), and triphenylphosphine (179.63mg, 684.87μmol, 1.5eq) was added thereto at 20°C . The reaction was stirred at this temperature for 15 minutes, then carbon tetrabromide (227.12 mg, 684.87 μmol, 1.5 eq) was added, the system became clear and stirring was continued for 14 hours. Methanol (2 mL) was added to the reaction liquid to quench, and silica gel was added directly, concentrated and evaporated to dryness. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol=100:0-95:5) to obtain compound 1m.
步骤13：化合物1n的合成Step 13: Synthesis of Compound 1n
1m(193mg,316.16μmol,1eq)溶于乙腈(1000mL)中，加入碳酸铯(2.06g,6.32mmol,20eq)，在60℃下搅拌18个小时。反应液冷却至20℃，过滤，滤渣用乙腈(4×10mL)洗涤，滤液浓缩蒸干。粗品用制备薄层色谱(二氯甲烷/甲醇＝20:1)分离提纯，得到化合物1n。1m (193mg, 316.16μmol, 1eq) was dissolved in acetonitrile (1000mL), cesium carbonate (2.06g, 6.32mmol, 20eq) was added, and stirred at 60°C for 18 hours. The reaction solution was cooled to 20°C, filtered, and the filter residue was washed with acetonitrile (4×10 mL), and the filtrate was concentrated and evaporated to dryness. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane/methanol=20:1) to obtain compound 1n.
1H NMR(400MHz,CDCl 3)δ＝7.54(br d,J＝6.8Hz,2H),7.33-7.21(m,3H),7.16-6.90(m,5H),6.86(dd,J＝7.1,10.3Hz,1H),6.79-6.65(m,1H),6.52(d,J＝7.8Hz,1H),5.67(d,J＝7.8Hz,1H),5.40-5.29(m,2H),5.05(dd,J＝7.1,11.4Hz,1H),4.87(s,1H),4.48-4.39(m,1H),4.07(td,J＝2.8,11.4Hz,1H),2.94(s,3H),2.09-1.98(m,1H),1.88-1.81(m,1H)； 1 H NMR (400MHz, CDCl 3 ) δ=7.54(br d, J=6.8Hz, 2H), 7.33-7.21(m, 3H), 7.16-6.90(m, 5H), 6.86(dd, J=7.1, 10.3Hz, 1H), 6.79-6.65(m, 1H), 6.52(d, J=7.8Hz, 1H), 5.67(d, J=7.8Hz, 1H), 5.40-5.29(m, 2H), 5.05( dd,J=7.1,11.4Hz,1H),4.87(s,1H),4.48-4.39(m,1H),4.07(td,J=2.8,11.4Hz,1H),2.94(s,3H),2.09 -1.98(m,1H),1.88-1.81(m,1H);
19F NMR(377MHz,CDCl 3)δ＝-133.79(br d,J＝22.6Hz,1F),-139.65(br d,J＝22.6Hz,1F)。 19 F NMR (377MHz, CDCl 3 ) δ=-133.79 (br d, J=22.6Hz, 1F), -139.65 (br d, J=22.6Hz, 1F).
步骤14：化合物1o的合成Step 14: Synthesis of compound 1o
1n(20mg,37.77μmol,1eq)溶于二氯甲烷(1mL)中，加入无水氯化镁(71.92mg,755.38μmol,20eq)，于20℃下搅拌15个小时。反应液用甲醇(2mL)稀释，过滤，滤渣用甲醇(2mL)润洗。粗品溶液经过制备反向液相色谱(分离柱:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[H 2O(0.225％FA)- ACN]；ACN％:25％-55％,7min)提纯，得到化合物1o。MS(ESI,m/z):440.0[M+1]； 1H NMR(400MHz,CD 3OD)δ＝7.23(br s,4H),7.16-7.07(m,2H),7.02(br d,J＝7.4Hz,1H),5.71(br d,J＝7.3Hz,1H),5.56(br t,J＝8.9Hz,1H),5.41(s,1H),4.63(br d,J＝4.9Hz,1H),4.25(br d,J＝11.1Hz,1H),3.13(s,3H),2.22(br s,2H)； 1n (20mg, 37.77μmol, 1eq) was dissolved in dichloromethane (1mL), anhydrous magnesium chloride (71.92mg, 755.38μmol, 20eq) was added, and stirred at 20°C for 15 hours. The reaction solution was diluted with methanol (2 mL), filtered, and the filter residue was rinsed with methanol (2 mL). The crude product solution was subjected to preparative reverse liquid chromatography (separation column: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [H 2 O(0.225%FA)-ACN]; ACN%: 25%-55%, 7min ) purification to obtain compound 1o. MS (ESI, m/z): 440.0[M+1]; 1 H NMR (400MHz, CD 3 OD) δ = 7.23 (br s, 4H), 7.16-7.07 (m, 2H), 7.02 (br d, J=7.4Hz, 1H), 5.71(br d, J=7.3Hz, 1H), 5.56(br t, J=8.9Hz, 1H), 5.41(s, 1H), 4.63(br d, J=4.9Hz ,1H),4.25(br d,J=11.1Hz,1H),3.13(s,3H),2.22(br s,2H);
19F NMR(377MHz,CD 3OD)δ＝-137.66(br d,J＝19.8Hz,1F),-143.64(br d,J＝22.6Hz,1F)。 19 F NMR (377MHz, CD 3 OD) δ=-137.66 (br d, J=19.8Hz, 1F), -143.64 (br d, J=22.6Hz, 1F).
步骤15：化合物1A的合成Step 15: Synthesis of Compound 1A
将1o(12mg,27.31μmol,1eq)溶于DMA(0.5mL)，往其中加入碳酸钾(7.55mg,54.62μmol,2eq)，碘化钾(4.53mg,27.31μmol,1eq)和氯甲基甲基碳酸酯(9.81mg,78.80μmol,2eq)，然后加热至70℃，搅拌3个小时。补加氯甲基甲基碳酸酯(34.01mg,273.10μmol,26.16μL,10eq)，继续搅拌1.5个小时，补加碳酸钾(37.74mg,273.10μmol,10eq)，继续搅拌15个小时后补加氯甲基甲基碳酸酯(68.01mg,546.20μmol,52.32μL,20eq)，搅拌1个小时后反应完毕。反应液冷却到室温，加入水(2mL)，用乙酸乙酯萃取(4mL×2)。有机相经饱和食盐水(2mL×2)洗涤两次，无水硫酸钠干燥后浓缩干得粗品。粗品经硅胶柱层析(二氯甲烷/甲醇＝100:0-95:5)纯化后，得到化合物1A。MS(ESI,m/z):528.1[M+1]； 1H NMR(400MHz,CDCl 3)δ＝7.25-7.09(m,5H),6.96(dd,J＝7.2,10.4Hz,1H),6.86-6.78(m,1H),6.69(d,J＝7.8Hz,1H),6.00(d,J＝6.3Hz,1H),5.79(dd,J＝4.1,7.2Hz,2H),5.34(br dd,J＝6.9,11.2Hz,1H),5.06(s,1H),4.57(br t,J＝11.9Hz,1H),4.20(br d,J＝11.5Hz,1H),3.90(s,3H),3.07(s,3H),2.26-2.13(m,2H)； 1o (12mg, 27.31μmol, 1eq) was dissolved in DMA (0.5mL), and potassium carbonate (7.55mg, 54.62μmol, 2eq), potassium iodide (4.53mg, 27.31μmol, 1eq) and chloromethylmethyl carbonate were added Ester (9.81mg, 78.80μmol, 2eq), then heated to 70°C and stirred for 3 hours. Add chloromethyl methyl carbonate (34.01mg, 273.10μmol, 26.16μL, 10eq), continue stirring for 1.5 hours, add potassium carbonate (37.74mg, 273.10μmol, 10eq), continue stirring for 15 hours and then add Chloromethyl methyl carbonate (68.01mg, 546.20μmol, 52.32μL, 20eq), the reaction was completed after stirring for 1 hour. The reaction solution was cooled to room temperature, added with water (2 mL), and extracted with ethyl acetate (4 mL×2). The organic phase was washed twice with saturated brine (2 mL×2), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=100:0-95:5) to obtain compound 1A. MS (ESI, m/z): 528.1 [M+1]; 1 H NMR (400MHz, CDCl 3 ) δ=7.25-7.09 (m, 5H), 6.96 (dd, J=7.2, 10.4Hz, 1H), 6.86-6.78(m,1H),6.69(d,J=7.8Hz,1H),6.00(d,J=6.3Hz,1H),5.79(dd,J=4.1,7.2Hz,2H),5.34(br dd,J=6.9,11.2Hz,1H),5.06(s,1H),4.57(br t,J=11.9Hz,1H),4.20(br d,J=11.5Hz,1H),3.90(s,3H ),3.07(s,3H),2.26-2.13(m,2H);
19F NMR(376MHz,CDCl 3)δ＝-133.11--134.54(m,1F),-138.71--140.65(m,1F)。 19 F NMR (376 MHz, CDCl 3 ) δ=-133.11--134.54 (m, 1F), -138.71--140.65 (m, 1F).
步骤16：化合物1和2的合成Step 16: Synthesis of Compounds 1 and 2
化合物1A经SFC(分离柱:DAICEL CHIRALCEL OJ- H(250mm*30mm,5μm)；流动相:A[CO 2]；B(Neu-EtOH)％:15％-15％,min)分离得到化合物1和2。 Compound 1A was separated by SFC (separation column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5μm); mobile phase: A[CO 2 ]; B(Neu-EtOH)%: 15%-15%, min) to obtain compound 1 and 2.
手性分析方法(分离柱:DAICEL CHIRALCEL OJ-H(100mm*4.6mm,3μm)；流动相:A[CO 2]；B(0.05％DEA/EtOH)％:5％-40％,4min；40％,2.5min；5％,1.5min)。 Chiral analysis method (separation column: DAICEL CHIRALCEL OJ-H (100mm*4.6mm, 3μm); mobile phase: A[CO 2 ]; B (0.05%DEA/EtOH)%: 5%-40%, 4min; 40 %, 2.5min; 5%, 1.5min).
化合物1(保留时间:2.490min,ee值:97.90％)：Compound 1 (retention time: 2.490min, ee value: 97.90%):
MS(ESI,m/z):528.2[M+1]； 1H NMR(400MHz,CDCl 3)δ＝7.22(br s,3H),7.15(br s,2H),6.96(dd,J＝7.0,10.3Hz,1H),6.82(dd,J＝8.8,10.3Hz,1H),6.69(d,J＝7.8Hz,1H),5.99(d,J＝6.3Hz,1H),5.79(dd,J＝3.3,7.0Hz,2H),5.35(dd,J＝6.9,11.4Hz,1H),5.06(s,1H),4.58(t,J＝11.4Hz,1H),4.24-4.16(m,1H),3.90(s,3H),3.07(s,3H),2.27-2.14(m,1H),2.09-2.01(m,1H)。 MS (ESI, m/z): 528.2 [M+1]; 1 H NMR (400 MHz, CDCl 3 ) δ=7.22 (br s, 3H), 7.15 (br s, 2H), 6.96 (dd, J=7.0 ,10.3Hz,1H),6.82(dd,J=8.8,10.3Hz,1H),6.69(d,J=7.8Hz,1H),5.99(d,J=6.3Hz,1H),5.79(dd,J =3.3,7.0Hz,2H),5.35(dd,J=6.9,11.4Hz,1H),5.06(s,1H),4.58(t,J=11.4Hz,1H),4.24-4.16(m,1H) ,3.90(s,3H),3.07(s,3H),2.27-2.14(m,1H),2.09-2.01(m,1H).
化合物2(保留时间：2.218min,ee值:99.44％)：Compound 2 (retention time: 2.218min, ee value: 99.44%):
MS(ESI,m/z):528.2[M+1]； 1H NMR(400MHz,CDCl 3)δ＝7.22(br d,J＝2.5Hz,3H),7.15(br s,2H),6.96(dd,J＝7.0,10.3Hz,1H),6.82(dd,J＝8.5,10.5Hz,1H),6.69(d,J＝7.8Hz,1H),5.99(d,J＝6.5Hz,1H),5.79(d,J＝3.0Hz,1H),5.77(d,J＝1.8Hz,1H),5.36(dd,J＝7.0,11.3Hz,1H),5.06(s,1H),4.58(t,J＝11.4Hz,1H),4.20(td,J＝2.9,11.5Hz,1H),3.89(s,3H),3.07(s,3H),2.25-2.12(m,1H),2.09-2.00(m,1H)。 MS (ESI, m/z): 528.2 [M+1]; 1 H NMR (400MHz, CDCl 3 ) δ = 7.22 (br d, J = 2.5Hz, 3H), 7.15 (br s, 2H), 6.96 ( dd,J=7.0,10.3Hz,1H),6.82(dd,J=8.5,10.5Hz,1H),6.69(d,J=7.8Hz,1H),5.99(d,J=6.5Hz,1H), 5.79(d,J=3.0Hz,1H),5.77(d,J=1.8Hz,1H),5.36(dd,J=7.0,11.3Hz,1H),5.06(s,1H),4.58(t,J =11.4Hz,1H),4.20(td,J=2.9,11.5Hz,1H),3.89(s,3H),3.07(s,3H),2.25-2.12(m,1H),2.09-2.00(m, 1H).
化合物1的构型通过X射线单晶衍射检测分析确定。The configuration of compound 1 was determined by X-ray single crystal diffraction analysis.
仪器型号：Rigaku Oxford Diffraction XtaLAB Synergy四圆衍射仪Instrument model: Rigaku Oxford Diffraction XtaLAB Synergy four-circle diffractometer
详细参数如下：The detailed parameters are as follows:
区域检测器：HyPix-6000HE；低温***:Oxford Cryostream 800；光源：Cu:
Figure PCTCN2022132579-appb-000011
50W微焦点光源(μ-CMF)；晶体到CCD探测器的距离:d＝35mm；灯管电压:50kV，灯管电流:1mA。 Area detector: HyPix-6000HE; cryogenic system: Oxford Cryostream 800; light source: Cu:
Figure PCTCN2022132579-appb-000011
50W micro-focus light source (μ-CMF); distance from crystal to CCD detector: d=35mm; lamp voltage: 50kV, lamp current: 1mA.
化合物1的单晶培养：15mg化合物1在室温条件下溶解于800μL异丙醇/水(3:1)中，将样品溶液置于4mL半密封样品瓶中，在室温条件下缓慢挥发， 第二天得到无色块状晶体。Single crystal cultivation of compound 1: 15 mg of compound 1 was dissolved in 800 μL isopropanol/water (3:1) at room temperature, the sample solution was placed in a 4 mL semi-sealed sample bottle, and slowly evaporated at room temperature, the second A colorless blocky crystal was obtained.
衍射实验收集了44762个衍射点，其中独立衍射点4386个(Rint＝0.0379)。衍射收集范围2θ＝7.014to 133.194°，衍射指标范围-10≤h≤8,-13≤k≤13,-30≤l≤29。结构解析使用SHELXT(Sheldrick,G.M.2015.ActaCryst.A71,3-8)，结构精修使用SHELXL(against F2)(Sheldrick,G.M.2015.ActaCryst.C71,3-8)。4386个独立衍射点中，参加结构精修的参数为357。精修后S＝1.087,R1＝0.0257,wR2＝0.0656。残余电子密度值为0.16和
Figure PCTCN2022132579-appb-000012
Diffraction experiments collected 44762 diffraction points, including 4386 independent diffraction points (Rint=0.0379). Diffraction collection range 2θ=7.014to 133.194°, diffraction index range -10≤h≤8, -13≤k≤13, -30≤l≤29. SHELXT (Sheldrick, GM2015.ActaCryst.A71, 3-8) was used for structure analysis, and SHELXL (against F2) (Sheldrick, GM2015.ActaCryst.C71, 3-8) was used for structure refinement. Among the 4386 independent diffraction points, 357 parameters participated in structure refinement. After refinement, S=1.087, R1=0.0257, wR2=0.0656. The residual electron density value is 0.16 and
Figure PCTCN2022132579-appb-000012
检测晶体为无色块状(0.30×0.30×0.30mm 3)，属于正交晶系P212121空间群。晶胞参数
Figure PCTCN2022132579-appb-000013
α＝90°,β＝90°,γ＝90°,
Figure PCTCN2022132579-appb-000014
Z＝4。计算密度Dc＝1.458g/cm 3，单胞中电子数F(000)＝1136.0，单胞的线性吸收系数μ(Cu Kα)＝1.014mm –1，衍射实验温度T＝150.00(10)K。 The detected crystal is a colorless block (0.30×0.30×0.30mm 3 ), which belongs to the space group P212121 of the orthorhombic crystal system. Cell parameters
Figure PCTCN2022132579-appb-000013
α=90°, β=90°, γ=90°,
Figure PCTCN2022132579-appb-000014
Z=4. The calculated density Dc=1.458g/cm 3 , the number of electrons in the unit cell F(000)=1136.0, the linear absorption coefficient of the unit cell μ(Cu Kα)=1.014mm –1 , and the diffraction experiment temperature T=150.00(10)K.
化合物1的水合物的绝对构型结构图见图4，以及水合物的立体结构椭球图见图5。化合物1的水合物晶体结构数据和参数见表：2、3、4、5和6。The absolute configuration structure diagram of the hydrate of compound 1 is shown in Figure 4, and the three-dimensional structure ellipsoid diagram of the hydrate is shown in Figure 5. The hydrate crystal structure data and parameters of Compound 1 are shown in Tables: 2, 3, 4, 5 and 6.
表2：晶体结构精修信息表Table 2: Crystal structure refinement information table
Figure PCTCN2022132579-appb-000015
Figure PCTCN2022132579-appb-000015
Figure PCTCN2022132579-appb-000016
Figure PCTCN2022132579-appb-000016
表3：晶体的原子坐标(×10 4)和等价各向同性移位参数
Figure PCTCN2022132579-appb-000017
Table 3: Crystal atomic coordinates (×10 4 ) and equivalent isotropic shift parameters
Figure PCTCN2022132579-appb-000017
Figure PCTCN2022132579-appb-000018
Figure PCTCN2022132579-appb-000018
Figure PCTCN2022132579-appb-000019
Figure PCTCN2022132579-appb-000019
Figure PCTCN2022132579-appb-000020
Figure PCTCN2022132579-appb-000020
表4:成键原子的键长
Figure PCTCN2022132579-appb-000021
和键角(°) Table 4: Bond lengths of bonded atoms
Figure PCTCN2022132579-appb-000021
and bond angle (°)
Figure PCTCN2022132579-appb-000022
Figure PCTCN2022132579-appb-000022
Figure PCTCN2022132579-appb-000023
Figure PCTCN2022132579-appb-000023
Figure PCTCN2022132579-appb-000024
Figure PCTCN2022132579-appb-000024
表5：原子间扭角值(°)Table 5: Interatomic torsion angle values (°)
Figure PCTCN2022132579-appb-000025
Figure PCTCN2022132579-appb-000025
Figure PCTCN2022132579-appb-000026
Figure PCTCN2022132579-appb-000026
Figure PCTCN2022132579-appb-000027
Figure PCTCN2022132579-appb-000027
表6:氢键列表Table 6: List of Hydrogen Bonds
Figure PCTCN2022132579-appb-000028
Figure PCTCN2022132579-appb-000028
用于生成等效原子的对称变换:#1x,y,z+1Symmetry transformation for generating equivalent atoms: #1x,y,z+1
实施例2：式(I)化合物A晶型的制备Embodiment 2: Preparation of formula (I) compound A crystal form
Figure PCTCN2022132579-appb-000029
Figure PCTCN2022132579-appb-000029
称取100mg式化合物1加入到4.0mL玻璃小瓶中，加入甲叔醚(1mL)使其成悬浊液。加入磁子后，将上述悬浊液样品置于磁力加热搅拌器上进行试验，20-30℃下搅拌48小时后过滤，滤饼用少量甲叔醚洗涤，抽干后得式(I)化合物的A晶型。Weigh 100 mg of compound 1 of formula 1 into a 4.0 mL glass vial, add tertiary methyl ether (1 mL) to make a suspension. After adding magnets, put the above suspension sample on a magnetic heating stirrer for testing, stir at 20-30°C for 48 hours, then filter, wash the filter cake with a small amount of tertiary methyl ether, and drain to obtain the compound of formula (I) A crystal form.
MS(ESI,m/z):528.2[M+1] +； 1H NMR(400MHz,CDCl 3):δ7.07-7.27(m,5H),6.97(dd,J＝10.3,7.0Hz,1H),6.83(dd,J＝10.4,8.7Hz,1H),6.71(d,J＝7.8Hz,1H),5.99(d,J＝6.3Hz,1H),5.80(t,J＝7.8Hz,2H),5.39(br dd,J＝11.3,7.0Hz,1H),5.07(s,1H),4.60(br t,J＝11.9Hz,1H),4.18-4.24(m,1H),3.90(s,3H),3.08(s,3H),2.20(q,J＝12.1Hz,1H),2.01-2.11(m,1H)。 MS (ESI, m/z): 528.2[M+1] + ; 1 H NMR (400MHz, CDCl 3 ): δ7.07-7.27 (m, 5H), 6.97 (dd, J=10.3, 7.0Hz, 1H ),6.83(dd,J=10.4,8.7Hz,1H),6.71(d,J=7.8Hz,1H),5.99(d,J=6.3Hz,1H),5.80(t,J=7.8Hz,2H ),5.39(br dd,J=11.3,7.0Hz,1H),5.07(s,1H),4.60(br t,J=11.9Hz,1H),4.18-4.24(m,1H),3.90(s, 3H), 3.08(s, 3H), 2.20(q, J=12.1Hz, 1H), 2.01-2.11(m, 1H).
式(I)化合物A晶型的Cu-Kα辐射的XRPD谱图见图1。The Cu-Kα radiation XRPD spectrum of the crystal form of compound A of formula (I) is shown in FIG. 1 .
式(I)化合物A晶型的DSC谱图见图2。The DSC spectrum of the crystal form of compound A of formula (I) is shown in FIG. 2 .
式(I)化合物A晶型的TGA谱图见图3。The TGA spectrum of the crystal form of compound A of formula (I) is shown in FIG. 3 .
以下方法也可以得到式(I)化合物的A晶型：The following method can also obtain the A crystal form of the compound of formula (I):
称取100mg化合物1加入到4.0mL玻璃小瓶中，加入正庚烷(1mL)使其成悬浊液。加入磁子后，将上述悬浊液样品置于磁力加热搅拌器上进行试验，20-30℃下搅拌72小时后过滤，滤饼用少量正庚烷洗涤，抽干后得式(I)化合物的A晶型。Weigh 100 mg of compound 1 into a 4.0 mL glass vial, and add n-heptane (1 mL) to make a suspension. After adding magnets, place the above suspension sample on a magnetic heating stirrer for testing, stir at 20-30°C for 72 hours, then filter, wash the filter cake with a small amount of n-heptane, and drain to obtain the compound of formula (I) A crystal form.
称取100mg化合物1加入到4.0mL玻璃小瓶中，加入乙醇(0.4mL)，搅拌下缓慢滴加水(0.75mL)得到混悬液。将上述悬浊液样品在20-30℃下搅拌16小时后过滤，滤饼抽干后得式(I)化合物的A晶型。Weighed 100 mg of compound 1 into a 4.0 mL glass vial, added ethanol (0.4 mL), and slowly added water (0.75 mL) dropwise under stirring to obtain a suspension. Stir the above suspension sample at 20-30° C. for 16 hours, then filter, and drain the filter cake to obtain Form A of the compound of formula (I).
称取100mg化合物1加入到4.0mL玻璃小瓶中，加入丙酮(0.25mL)，搅拌下缓慢滴加水(0.75mL)得到混悬液。将上述悬浊液样品在20-30℃下搅拌48小时后过滤，滤饼抽干后得式(I)化合物的A晶型。Weighed 100 mg of compound 1 into a 4.0 mL glass vial, added acetone (0.25 mL), and slowly added water (0.75 mL) dropwise under stirring to obtain a suspension. Stir the above suspension sample at 20-30° C. for 48 hours, then filter, and drain the filter cake to obtain Form A of the compound of formula (I).
称取100mg化合物1加入到4.0mL玻璃小瓶中，加入甲叔醚/乙酸乙酯(4/6，0.2mL)使其成悬浊液。加入磁子后，将上述悬浊液样品置于磁力加热搅拌器上进行试验，20-30℃下搅拌16小时后过滤，滤饼用少量甲叔醚/乙酸乙酯洗涤，抽干后得式(I)化合物的A晶型。Weigh 100mg of compound 1 and add it into a 4.0mL glass vial, add tertiary methyl ether/ethyl acetate (4/6, 0.2mL) to make a suspension. After adding magnets, place the above suspension sample on a magnetic heating stirrer for testing, stir at 20-30°C for 16 hours, then filter, wash the filter cake with a small amount of tertiary methyl ether/ethyl acetate, and dry it to obtain the formula (I) Form A of the compound.
实施例3：式(I)化合物A晶型的固体稳定性试验Embodiment 3: the solid stability test of formula (I) compound A crystal form
依据《原料药与制剂稳定性试验指导原则》(中国药典2015版四部通则9001)，考察式(I)化合物A晶型在高温(60℃，敞口)，高湿(室温/相对湿度92.5％，敞口)及强光照(5000lx，密闭)条件下的稳定性。According to the "Guiding Principles for Stability Testing of Raw Materials and Preparations" (Chinese Pharmacopoeia 2015 Edition Four General Rules 9001), investigate formula (I) compound A crystal form at high temperature (60°C, open), high humidity (room temperature/relative humidity 92.5%) , exposure) and strong light (5000lx, airtight) under the conditions of stability.
称取式(I)化合物A晶型15mg若干份，每一份都使之均匀分布于玻璃样品瓶底部。高温及高湿条件下放置的样品用铝箔纸封瓶口，并留气孔以保证样品与环境空气充分接触；强光照条件下放置的样品用螺纹瓶盖密封。不同条件下放置的样品于第10天取样检测(XRPD)，检测结果与0天的初始检测结果进行比较，试验结果见下表7所示：Weigh several portions of 15 mg of the crystal form of compound A of formula (I), and distribute each portion evenly on the bottom of the glass sample vial. Samples placed under high temperature and high humidity conditions were sealed with aluminum foil, and air holes were left to ensure full contact between the samples and ambient air; samples placed under strong light conditions were sealed with screw caps. Samples placed under different conditions were sampled and tested (XRPD) on the 10th day, and the test results were compared with the initial test results on day 0. The test results are shown in Table 7 below:
表7：式(I)化合物A晶型的固体稳定性试验结果Table 7: Solid stability test results of formula (I) compound A crystal form
试验条件Test conditions 时间点point in time 晶型crystal form
-- 0天0 days A晶型Form A
高温(60℃，敞口)High temperature (60°C, open) 10天10 days A晶型Form A
高湿(室温/相对湿度92.5％，敞口)High humidity (room temperature/relative humidity 92.5%, open) 10天10 days A晶型Form A
强光照(5000lx，封口)Strong light (5000lx, sealed) 10天10 days A晶型Form A
结论：式(I)化合物A晶型在高温、高湿、强光照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 high temperature, high humidity and strong light.
生物测试：Biological test:
实验例1式(I)化合物A晶型在小鼠模型的体内药效研究Experimental Example 1 In vivo pharmacodynamic study of formula (I) compound A crystal form in mouse model
实验过程：experiment procedure:
小鼠(BALB/c品系)在第0天经滴鼻方式进行病毒(甲流病毒株Baloxavir-resistant PR/8/PAI38T)接种，接种剂量为150p.f.u./小鼠。从第0天至第6天用溶媒(5％DMSO+10％聚乙二醇-15羟基硬酯酸酯+85％水)或者30mpk的式(I)化合物A晶型连续处理7天，每日2次，给药方式为灌胃，共给药14次，首次给药时间为病毒接种前2小时。从第0天至第14天持续观察动物，记录体重，健康及存活状况。Mice (BALB/c strain) were inoculated with virus (flu virus strain Baloxavir-resistant PR/8/PAI38T) by intranasal drip on day 0, and the inoculation dose was 150p.f.u./mouse. From the 0th day to the 6th day, vehicle (5% DMSO+10% polyethylene glycol-15 hydroxystearate+85% water) or 30mpk formula (I) Compound A crystal form were treated continuously for 7 days, every Twice a day, the way of administration is intragastric administration, a total of 14 administrations, the first administration time is 2 hours before virus inoculation. Animals were continuously observed from day 0 to day 14, and body weight, health and survival were recorded.
实验结果：见表8。Experimental results: see Table 8.
表8：式(I)化合物A晶型在甲流预防模型中对小鼠的保护作用(体重)Table 8: The protective effect (body weight) of formula (I) compound A crystal form on mice in the influenza A prevention model
Figure PCTCN2022132579-appb-000030
Figure PCTCN2022132579-appb-000030
Figure PCTCN2022132579-appb-000031
Figure PCTCN2022132579-appb-000031
N/A：此处不适用N/A: Not applicable here
结论：式(I)化合物A晶型在动物预防模型药效实验中展示出保护效应。Conclusion: The crystal form of compound A of formula (I) exhibits a protective effect in animal prevention model drug efficacy experiments.

Claims (14)

  1. 式(I)所示化合物，Compound shown in formula (I),
    Figure PCTCN2022132579-appb-100001
    Figure PCTCN2022132579-appb-100001
    其中，in,
    n选自0.5～2。n is selected from 0.5-2.
  2. 根据权利要求1所述的化合物，其中，n选自0.5、0.6、0.7、0.8、0.9、1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9或2。The compound according to claim 1, wherein n is selected from 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.
  3. 根据权利要求2所述的化合物，其中，n选自1。The compound according to claim 2, wherein n is selected from 1.
  4. 根据权利要求1～3任意一项所述的式(I)化合物的A晶型，A crystal form of the compound of formula (I) according to any one of claims 1 to 3,
    Figure PCTCN2022132579-appb-100002
    Figure PCTCN2022132579-appb-100002
    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：6.942±0.200°，21.561±0.200°，25.758±0.200°。It is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.942±0.200°, 21.561±0.200°, 25.758±0.200°.
  5. 根据权利要求4所述的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：6.942±0.200°，13.159±0.200°，16.479±0.200°，19.980±0.200°，21.561±0.200°，23.501±0.200°，25.758±0.200°，29.159±0.200°。The crystal form A according to claim 4, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.942±0.200°, 13.159±0.200°, 16.479±0.200°, 19.980±0.200° , 21.561±0.200°, 23.501±0.200°, 25.758±0.200°, 29.159±0.200°.
  6. 根据权利要求5所述的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：6.942±0.200°，13.159±0.200°，13.898±0.200°，16.479±0.200°，19.980±0.200°，20.881±0.200°，21.561±0.200°，23.501±0.200°，24.518±0.200°，25.758±0.200°，28.299±0.200°，29.159±0.200°。The crystal form A according to claim 5, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.942±0.200°, 13.159±0.200°, 13.898±0.200°, 16.479±0.200° , 19.980±0.200°, 20.881±0.200°, 21.561±0.200°, 23.501±0.200°, 24.518±0.200°, 25.758±0.200°, 28.299±0.200°, 29.159±0.200°.
  7. 根据权利要求6所述的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：6.942±0.200°，10.637±0.200°，13.159±0.200°，13.898±0.200°，16.479±0.200°，17.001±0.200°，19.980±0.200°，20.881±0.200°，21.561±0.200°，23.501±0.200°，24.518±0.200°，25.758±0.200°，27.600±0.200°，28.299±0.200°，29.159±0.200°，29.719±0.200°。The crystal form A according to claim 6, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.942±0.200°, 10.637±0.200°, 13.159±0.200°, 13.898±0.200° , 16.479±0.200°, 17.001±0.200°, 19.980±0.200°, 20.881±0.200°, 21.561±0.200°, 23.501±0.200°, 24.518±0.200°, 25.758±0.200°, 27.600±0 .200°, 28.299±0.200° , 29.159±0.200°, 29.719±0.200°.
  8. 根据权利要求7所述的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：6.942°，10.419°，10.637°，12.661°，13.159°，13.898°，16.084°，16.479°，17.001°，17.540°，18.843°，19.199°，19.980°，20.881°，21.561°，22.384°，23.137°，23.501°，23.776°，24.122°，24.518°，25.758°，26.362°，27.600°，27.997°，28.299°，28.840°，29.159°，29.719°，30.822°，31.042°，31.597°，32.220°，32.638°，33.136°，34.140°，35.582°，36.140°，37.037°，37.467°。The crystal form A according to claim 7, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.942°, 10.419°, 10.637°, 12.661°, 13.159°, 13.898°, 16.084 °, 16.479°, 17.001°, 17.540°, 18.843°, 19.199°, 19.980°, 20.881°, 21.561°, 22.384°, 23.137°, 23.501°, 23.776°, 24.122°, 24.518°, 25.758° , 26.362°, 27.600°, 27.997°, 28.299°, 28.840°, 29.159°, 29.719°, 30.822°, 31.042°, 31.597°, 32.220°, 32.638°, 33.136°, 34.140°, 35.582°, 36.140°, 3 7.037°, 37.467° .
  9. 根据权利要求8所述的A晶型，其XRPD图谱如图1所示。The crystal form A according to claim 8, whose XRPD spectrum is as shown in FIG. 1 .
  10. 根据权利要求4～9任意一项所述的A晶型，其差示扫描量热曲线在164.37±3℃处有一个吸热峰的峰值。According to the crystal form A described in any one of claims 4-9, its differential scanning calorimetry curve has an endothermic peak at 164.37±3°C.
  11. 根据权利要求10所述的A晶型，其DSC图谱如图2所示。The crystal form A according to claim 10, its DSC spectrum is as shown in Figure 2.
  12. 根据权利要求4～9任意一项所述的A晶型，其热重分析曲线在150±3℃处失重达2.966％，在225±3℃处失重达14.111％。According to the crystal form A described in any one of claims 4-9, its thermogravimetric analysis curve has a weight loss of 2.966% at 150±3°C and a weight loss of 14.111% at 225±3°C.
  13. 根据权利要求12所述的A晶型，其TGA图谱如图3所示。The crystal form A according to claim 12, whose TGA spectrum is as shown in FIG. 3 .
  14. 根据权利要求1～13任意一项所述A晶型在制备抗流感病毒的药物中的应用。The use of the crystal form A according to any one of claims 1-13 in the preparation of anti-influenza virus medicaments.
PCT/CN2022/132579 2021-11-17 2022-11-17 Crystal form of fused-ring derivative and preparation method therefor WO2023088370A1 (en)

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WO2016175224A1 (en) * 2015-04-28 2016-11-03 塩野義製薬株式会社 Substituted polycyclic pyridone derivative and prodrug thereof
WO2020075080A1 (en) * 2018-10-10 2020-04-16 Janssen Biopharma, Inc. Macrocyclic flu endonuclease inhibitors
WO2021191872A1 (en) * 2020-03-26 2021-09-30 Janssen Biopharma, Inc. Heteroaryl-substituted macrocyclic flu endonuclease inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012039414A1 (en) * 2010-09-24 2012-03-29 塩野義製薬株式会社 Substituted polycyclic carbamoyl pyridone derivative prodrug
WO2016175224A1 (en) * 2015-04-28 2016-11-03 塩野義製薬株式会社 Substituted polycyclic pyridone derivative and prodrug thereof
WO2020075080A1 (en) * 2018-10-10 2020-04-16 Janssen Biopharma, Inc. Macrocyclic flu endonuclease inhibitors
WO2021191872A1 (en) * 2020-03-26 2021-09-30 Janssen Biopharma, Inc. Heteroaryl-substituted macrocyclic flu endonuclease inhibitors

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