WO2024083182A1 - 一种膦酰衍生物的制备方法 - Google Patents

一种膦酰衍生物的制备方法 Download PDF

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WO2024083182A1
WO2024083182A1 PCT/CN2023/125384 CN2023125384W WO2024083182A1 WO 2024083182 A1 WO2024083182 A1 WO 2024083182A1 CN 2023125384 W CN2023125384 W CN 2023125384W WO 2024083182 A1 WO2024083182 A1 WO 2024083182A1
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compound
acid
alkoxy
sodium
cycloalkyl
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PCT/CN2023/125384
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English (en)
French (fr)
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范江
蒋西
胡健湧
林瀚文
王志刚
郭军辉
杨代胜
窦赢
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西藏海思科制药有限公司
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Publication of WO2024083182A1 publication Critical patent/WO2024083182A1/zh

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Definitions

  • the present invention relates to a method for preparing a compound represented by formula (A) and an intermediate thereof.
  • the method has mild reaction conditions, simple operation, high reaction yield, high product purity, convenient post-treatment, and is suitable for industrial production.
  • Epidermal growth factor receptor is a transmembrane protein tyrosine kinase that acts as a receptor for EGF family members to trigger the EGFR signaling pathway in human epithelial cells, thereby regulating cell proliferation, invasion, metastasis, apoptosis and angiogenesis (Nat. Rev. Cancer, 2007, 7, 169-181; Expert Opin. Ther. Targets, 2012, 16, 15-31.).
  • EGFR gene Overexpression, mutation or amplification of the EGFR gene in the human body leads to abnormal increase in EGFR activity, which can lead to the occurrence of many malignant tumors such as esophageal cancer, glioblastoma, anal cancer, head and neck epithelial cancer, breast cancer, lung cancer, especially non-small cell lung cancer (NSCLC) (Cells, 2019, 8, 350-361.).
  • malignant tumors such as esophageal cancer, glioblastoma, anal cancer, head and neck epithelial cancer, breast cancer, lung cancer, especially non-small cell lung cancer (NSCLC) (Cells, 2019, 8, 350-361.).
  • NSCLC non-small cell lung cancer
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • Such compounds can be recognized by the cell's proteasome, causing the degradation of the target protein, and can effectively reduce the content of the target protein in the cell.
  • ligands that can bind to different target proteins By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology can be applied to the treatment of various diseases. This technology has also received widespread attention in recent years (ACS Chem. Biol. 2017, 12, 892-898; Drug Discovery Today Technol. 2019, 31, 15-27.).
  • Patent PCT/CN2022/090243 describes a class of compounds that have excellent inhibitory activity against NCI-H1975 (EGFR-L858R-T790M) and NCI-H1975 EGFR-L858R-T790M-C797S cells.
  • the purpose of the present invention is to provide a method for preparing a compound represented by formula (A) and an intermediate thereof, wherein the method has low-cost starting materials, mild reaction conditions, simple operation, high yield, high product purity, convenient post-treatment, and is suitable for industrial production.
  • the present invention provides a method for preparing a compound represented by formula (A), wherein compound (Ba) or a salt thereof formed with an acidic reagent 1 reacts with compound (Bb) in the presence of a reducing agent to obtain compound (A) (i.e., step (a));
  • R 1 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl, 4 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl; in some embodiments, R 1 is selected from F, Cl, Br, CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, phenyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I,
  • R 2 is selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl; in some embodiments, R 2 is selected from F, Cl, Br; in some embodiments, R 2 is selected from Cl, Br;
  • R 3 is selected from H, C 1-4 alkyl, C 1-4 alkoxy, -OC 3-6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl; in some embodiments, R 3 is selected from methoxy, ethoxy, -O-cyclopropyl; in some embodiments, R 3 is selected from methoxy;
  • R 4 is selected from H, C 1-4 alkyl, C 1-4 alkoxy, -OC 3-6 cycloalkyl, C 3-6 cycloalkyl, 4 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl; in some embodiments, R 4 is selected from H, methyl, ethyl, cyclopropyl, pyrazolyl, pyrrolyl, wherein the methyl, ethyl, cyclopropyl, pyrazolyl, pyrrolyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • R 5 is selected from H, F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl; in some embodiments, R 5 is selected from H, F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl In some embodiments, R 5 is selected from H, F,
  • the compound represented by formula (A) is selected from one of the following structures:
  • step (a) when compound (B-a) is reacted in the form of a free base in step (a), an acidic reagent 2 with a pKa ⁇ 5 is further added to the reaction;
  • the reducing agent in step (a) is selected from a boron reducing agent
  • the reducing agent in step (a) is selected from one or more of sodium acetate borohydride, sodium borohydride, sodium cyanoborohydride, 9-borabicyclo[3.3.1]nonane, 2-methylpyridine borane, sodium triacetoxyborohydride, potassium borohydride or lithium borohydride;
  • the reducing agent in step (a) is selected from sodium triacetoxyborohydride or 2-methylpyridine borane;
  • the reducing agent in step (a) is sodium triacetoxyborohydride
  • the solvent used in the reaction of step (a) is selected from one or more of a polar aprotic solvent or a non-polar solvent;
  • the solvent used in the reaction of step (a) is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, ethyl acetate, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, and tetrahydrofuran;
  • the acidic reagent 1 is selected from hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid;
  • the acidic reagent 1 is selected from hydrochloric acid or methanesulfonic acid;
  • the acidic reagent 1 is selected from hydrochloric acid
  • the acidic reagent 2 in step (a) is selected from one or more of acetic acid or formic acid;
  • the acidic reagent 2 is selected from acetic acid
  • the acidic reagent 1 is selected from hydrochloric acid or methanesulfonic acid, and an additive is further added in the reaction, and the additive is selected from a dehydrating agent (such as one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate or molecular sieves), an alkaline agent (such as sodium bicarbonate, sodium carbonate, dipotassium hydrogen phosphate, potassium bicarbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, sodium hydride, sodium hydroxide, potassium hydroxide, N,N-diisopropylethylamine, triethylamine, 1,8-diazabicycloundec-7-ene, one or more);
  • a dehydrating agent such as one or more of anhydrous sodium sul
  • the acidic reagent 1 is selected from hydrochloric acid or methanesulfonic acid, and an additive is further added to the reaction, the additive being selected from a dehydrating agent (such as one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate or molecular sieves), an acidic reagent 3 (such as an acidic reagent with pKa ⁇ 5, such as acetic acid or formic acid);
  • a dehydrating agent such as one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate or molecular sieves
  • an acidic reagent 3 such as an acidic reagent with pKa ⁇ 5, such as acetic acid or formic acid
  • an additive is further added to the reaction of step (a), and the additive is selected from a dehydrating agent (such as one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate or molecular sieve);
  • a dehydrating agent such as one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate or molecular sieve
  • the reducing agent is selected from sodium triacetoxyborohydride, and the molar ratio of sodium triacetoxyborohydride: B-b is (1.0-4.0):1;
  • the reducing agent is selected from sodium triacetoxyborohydride, and the molar ratio of sodium triacetoxyborohydride: B-b is (1.0-2.0):1;
  • the reducing agent is selected from sodium triacetoxyborohydride, and the molar ratio of sodium triacetoxyborohydride: B-b is 1.5:1;
  • the molar ratio of B-a:B-b in step (a) is (0.9-2.0):1.0;
  • the molar ratio of B-a:B-b in step (a) is (0.9-1.5):1.0;
  • the molar ratio of B-a:B-b in step (a) is (0.95-1.3):1.0;
  • the molar ratio of B-a:B-b in step (a) is 1.2:1.0.
  • the salt formed by compound (B-a) and acidic reagent 1 is selected from a monosalt or a disalt;
  • reaction temperature of step (a) is 0°C to 40°C;
  • reaction temperature of step (a) is 20°C to 30°C.
  • the raw material (B-b) of step (a) is prepared by step (b).
  • the present invention provides a method for preparing a compound represented by formula (Bb), wherein a compound represented by formula (Ca) is reacted in the presence of an acidic reagent to obtain a compound represented by formula (Bb) (i.e., step (b));
  • R 1 , R 2 , R 3 , and R 4 are defined as any of the above corresponding definitions;
  • R6 is an acetal group, preferably More preferably
  • the acidic reagent in step (b) is selected from hydrochloric acid, p-toluenesulfonic acid, acetic acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrobromic acid, methanesulfonic acid;
  • the acidic reagent in step (b) is hydrochloric acid
  • the solvent used in the reaction of step (b) is selected from a polar aprotic solvent or a polar protic solvent;
  • the solvent used in the reaction of step (b) is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, and water;
  • the solvent used in the reaction of step (b) is selected from water, a mixture of water and a polar solvent (such as N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, acetone);
  • a polar solvent such as N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, acetone
  • the solvent used in the reaction of step (b) is selected from water, water/tetrahydrofuran, water/acetone, water/N,N-dimethylformamide, water/acetonitrile, water/2-methyltetrahydrofuran;
  • the acidic reagent in step (b) is selected from hydrochloric acid
  • the solvent used in the reaction is selected from water, water/tetrahydrofuran, water/acetone, water/N,N-dimethylformamide, water/acetonitrile, water/2-methyltetrahydrofuran, preferably water;
  • the molar ratio of C-a: acidic reagent in step (b) is 1.0:(6.0-25.0);
  • the molar ratio of C-a: acidic reagent in step (b) is 1.0:(8.0-20.0);
  • the molar ratio of C-a: acidic reagent in step (b) is 1.0:(10.0-15.0);
  • reaction temperature of step (b) is 0 to 70°C;
  • reaction temperature of step (b) is 20-30° C.
  • the raw material (Ca) of step (b) is prepared by step (c).
  • the present invention also provides a method for preparing compound (A), comprising: 1) reacting compound (Ca) in the presence of an acidic reagent to obtain a compound represented by compound (Bb) (i.e., step (b)); 2) reacting compound (Ba) or a salt thereof formed with acidic reagent 1 with compound (Bb) in the presence of a reducing agent to obtain compound (A) (i.e., step (a));
  • R 1 , R 2 , R 3 , R 4 , and R 5 are the same as any of the corresponding definitions above;
  • step (a) and step (b) are the same as any of the corresponding definitions above.
  • the present invention provides a method for preparing a compound (Ca), wherein a compound (Db) and a compound (Da) react in the presence of an acidic catalyst to obtain a compound (Ca) (i.e., step (c));
  • R 1 , R 2 , R 3 , R 4 , and R 6 are defined as any of the corresponding definitions above;
  • X is a leaving group, in some embodiments, X is selected from F, Cl, Br or I, in some embodiments, X is Cl;
  • the acidic catalyst in step (c) is selected from one or more of methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, ethanedisulfonic acid, hydroiodic acid, phosphoric acid, zinc chloride, zinc acetate, pyridine hydrochloride, 4-methylbenzenesulfonic acid pyridine, triethylamine hydrochloride, oxalic acid, aluminum trichloride, and boron trifluoride;
  • the acidic catalyst in step (c) is selected from one or more of acetic acid, pyridine hydrochloride, pyridine p-toluenesulfonate, triethylamine hydrochloride, p-toluenesulfonic acid, trifluoroacetic acid, phosphoric acid, and methanesulfonic acid;
  • the solvent used in the reaction of step (c) is selected from one or more of amide solvents, alkane solvents, halogenated alkane solvents, alcohol solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents, sulfone solvents and water, preferably one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol, n-butanone, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, tetrahydrofuran and water;
  • the solvent used in the reaction of step (c) is selected from alcohol solvents (such as ethylene glycol);
  • the acidic catalyst in step (c) is selected from methanesulfonic acid, and the solvent used in the reaction is selected from ethylene glycol;
  • the molar ratio of D-b:D-a:acidic catalyst in step (c) is (0.2-1.5):1.0:1.0;
  • the molar ratio of D-b:D-a:acidic catalyst in step (c) is 0.5:1.0:1.0;
  • reaction temperature of step (c) is 40°C to 110°C;
  • reaction temperature of step (c) is 85°C to 105°C.
  • the starting material (D-b) of step (c) is prepared by step (d).
  • the present invention provides a method for preparing a compound (Db), wherein a compound (Ea) and a compound (Eb) react in the presence of an alkaline agent to obtain a compound (Db) (i.e., step (d)):
  • R 1 and R 2 are the same as any of the corresponding definitions above;
  • X is a leaving group; in some embodiments, X is selected from F, Cl, Br or I; in some embodiments, X is Cl;
  • Y is a leaving group, in some embodiments, selected from I, Br, Cl, OTf; in some embodiments, Y is Cl;
  • the alkaline agent is selected from one or more of sodium bicarbonate, sodium carbonate, dipotassium hydrogen phosphate, potassium bicarbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, sodium hydride, sodium hydroxide, potassium hydroxide, N,N-diisopropylethylamine, triethylamine, and 1,8-diazabicycloundec-7-ene;
  • the alkaline agent is selected from one or more of sodium bicarbonate, sodium carbonate, dipotassium hydrogen phosphate, potassium bicarbonate, potassium carbonate, lithium carbonate, cesium carbonate, potassium phosphate, sodium hydride, sodium hydroxide, potassium hydroxide, N,N-diisopropylethylamine, triethylamine or 1,8-diazabicycloundec-7-ene;
  • the alkaline agent in step (d) is selected from N,N-diisopropylethylamine
  • the solvent used in step (d) is selected from polar aprotic solvents and polar Sub-solvent;
  • the solvent used in the reaction of step (d) is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, acetone, n-butyl ketone, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, isopropanol, methanol and ethanol;
  • the solvent used in the reaction of step (d) is selected from one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide;
  • the solvent used in the reaction of step (d) is N-methylpyrrolidone and isopropanol
  • the molar ratio of E-a to E-b in step (d) is 1.0:(1.1-1.5);
  • the molar ratio of E-a to E-b in step (d) is 1.0:1.3;
  • the molar ratio of E-a to E-b in step (d) is 1.0:1.05;
  • reaction temperature of step (d) is 80°C to 135°C;
  • reaction temperature of step (d) is 110°C to 125°C;
  • reaction temperature of step (d) is 115°C to 125°C;
  • the starting material (E-a) of step (d) is prepared by step (e).
  • the present invention provides a method for preparing a compound represented by formula (Ea), comprising reacting a compound (Fa) or a salt thereof with a compound (Fb) in the presence of a palladium catalyst system and an alkaline reagent to obtain the compound (Ea) (i.e., step (e)).
  • R1 is defined as any of the above corresponding definitions
  • R 1 is cyclopropyl
  • the salt of compound (F-a) is selected from hydrochloride, hydrobromide, methanesulfonate, p-toluenesulfonate, trifluoroacetate;
  • the salt of compound (F-a) is a methanesulfonate salt
  • the palladium catalytic system of step (e) is selected from palladium catalyst/phosphine ligand or Pd(dppf)Cl 2 ;
  • the palladium catalytic system of step (e) is selected from [(cinnamyl)PdCl] 2 /dppf, Pd(OAc) 2 / dppf, Pd(MeCN) 2Cl2/dppf, Pd2dba3/dppf, Pd(TFA)2 / dppf , [PdCl( C3H5 ) ] 2 /dppf . or Pd(dppf)Cl 2 ;
  • the palladium catalyst in step (e) is selected from one or more of [(cinnamyl)PdCl] 2 , Pd(OAc) 2 , Pd(MeCN) 2 Cl 2 , Pd 2 dba 3 , Pd(TFA) 2 , [PdCl(C 3 H 5 )] 2 , and the phosphine ligand is selected from one or more of dppf, dppb, dppp, and DPEpHos;
  • the palladium catalyst in step (e) is selected from one or more of [(cinnamyl)PdCl] 2 , Pd(OAc) 2 , Pd(MeCN) 2 Cl 2 , Pd 2 dba 3 , Pd(TFA) 2 , [PdCl(C 3 H 5 )] 2 ;
  • the phosphine ligand in step (e) is selected from one or more of dppf, dppb, dppp, and DPEPhos;
  • the palladium catalyst in step (e) is selected from one or more of [(cinnamyl)PdCl] 2 , Pd(OAc) 2 , Pd(MeCN) 2 Cl 2 , Pd 2 dba 3 , Pd(TFA) 2 , [PdCl(C 3 H 5 )] 2 , and the phosphine ligand is selected from dppf;
  • the alkaline reagent in step (e) is selected from one or more of DIPEA, TEA, Cy 2 NMe, Cy 2 NH, and diethylamine;
  • the solvent used in the reaction of step (e) is selected from one or more of t-AmylOH, DMF, and MeCN;
  • the molar ratio of (Fa):(Fb):alkaline agent:Pd(dppf)Cl 2 is 1.0:(1.0-1.2):(2.0-5.0):(0.001-0.06);
  • the molar ratio of (Fa):(Fb):alkaline agent:Pd(dppf)Cl 2 is 1.0:1.2:4.0:0.02;
  • the palladium catalyst system in step (e) is a palladium catalyst/phosphine ligand
  • the molar ratio of (F-a):(F-b):alkaline agent:palladium catalyst:phosphine ligand is 1.0:1.2:(3.0-4.0):(0.005-0.05):(0.01-0.10);
  • the molar ratio of the palladium catalyst to the phosphine ligand in step (e) is 1:2;
  • the molar amount of Pd(dppf)Cl 2 is 0.1% to 4% of the molar amount of (Fa);
  • the molar amount of Pd(dppf)Cl 2 is 0.5% to 4% of the molar amount of (Fa);
  • the molar amount of Pd(dppf)Cl 2 is 1% to 2% of the molar amount of (Fa);
  • the palladium catalytic system of step (e) is selected from [(cinnamyl)PdCl] 2 /dppf, Pd(OAc) 2 / dppf, Pd(MeCN) 2Cl2/dppf, Pd2dba3/dppf, Pd(TFA)2 / dppf , [PdCl( C3H5 ) ] 2 /dppf .
  • the molar amount of the palladium catalyst [(cinnamyl)PdCl] 2 , Pd(OAc) 2 , Pd(MeCN) 2 Cl 2 , Pd 2 (dba) 3 ), Pd(TFA) 2 or [PdCl(C 3 H 5 )] 2 is 0.1% to 10%, 0.5% to 5% or 0.8% to 4% of the molar amount of (Fa);
  • reaction temperature of step (e) is 60°C to 120°C;
  • reaction temperature of step (e) is 70°C to 115°C;
  • reaction temperature of step (e) is 85°C to 105°C.
  • the starting material (F-a) of step (e) is prepared by step (f).
  • the present invention provides a method for preparing a compound (Fa), wherein a compound (Ga) reacts with a bromination reagent to obtain a compound (Fa) (i.e., step (f)).
  • R1 is defined as any of the above corresponding definitions
  • R 1 is cyclopropyl
  • the bromination reagent of step (f) is selected from NBS;
  • the solvent in step (f) reaction is selected from acetonitrile
  • the molar ratio of step (f) G-a to the brominating agent is 1:(1.0-1.2);
  • the molar ratio of step (f) G-a to the brominating agent is 1:(1.0-1.1);
  • reaction temperature of step (f) is -30°C to 0°C;
  • reaction temperature of step (f) is -25°C to -5°C;
  • reaction temperature of step (f) is -25°C to -15°C.
  • the raw material (G-a) of step (f) is prepared by step (g).
  • the present invention provides a method for preparing a compound (Ga), wherein a compound (Ha) and a compound (Hb) react in the presence of a palladium catalyst system and an alkaline agent to obtain a compound (Ga) (i.e., step (g));
  • R1 is defined as any of the above corresponding definitions
  • the palladium catalytic system of step (g) is selected from palladium catalyst/phosphine ligand, Pd(dppf)Cl2, Pd(dtbpf)Cl2, SPhosPdG2, cataCXiumAPdG2, [Pd(amphos)2Cl2 ] , RuPhosPdG2 , One or more of SPhosPdG2;
  • the palladium catalyst in step (g) is selected from one or more of [(cinnamyl)PdCl] 2 , Pd(OAc) 2 , Pd(MeCN) 2 Cl 2 , Pd 2 dba 3 , Pd(TFA) 2 , [PdCl(C 3 H 5 )] 2 ;
  • the palladium catalytic system of step (g) is selected from Pd(dppf) Cl2 , Pd(dtbpf) Cl2 , SPhosPdG2, cataCXiumAPdG2, [Pd(amphos) 2Cl2 ], RuPhosPdG2, SPhosPdG2, Pd(MeCN) 2Cl2 /AmgenPhos, Pd (TFA) 2 /AmgenPhos, Pd2(dba) 3 /AmgenPhos, [(cinnamyl)PdCl] 2 /AmgenPhos, [PdCl( C3H5 ) ] 2 /AmgenPhos, Pd(OAc) 2 /AmgenPhos, Pd ( MeCN) 2Cl2 / dtbpf, Pd(TFA) 2 /dtbpf, Pd2(dba) 3 /dtbpf, [(cinnamyl)PdCl]
  • the phosphine ligand in step (g) is selected from one or more of dppf, dppb, dppp, dtbpf, Catacxium PtB, DPEPhos, and AmgenPhos;
  • the phosphine ligand in step (g) is selected from one or more of dppf, dtbpf, AmgenPhos, and Catacxium PtB;
  • the alkaline reagent in step (g) is selected from one or more of K 2 CO 3 , K 3 PO 4 , DIPEA, TEA, Cy 2 NMe, Cy 2 NH, and diethylamine;
  • the alkaline agent of step (g) is selected from K 2 CO 3 or K 3 PO 4 ;
  • the solvent in the reaction of step (g) is selected from one or more of t-AmylOH, DMF, MeCN, toluene, CPME, DMAc, i-PrOH, MeCN and water;
  • the solvent used in the reaction of step (g) is selected from toluene/water, CPME/water, t-AmylOH/water, the volume mass ratio of toluene, CPME, t-AmylOH to H-a is (10-20):1, preferably 15:1, and the volume mass ratio of water to H-a is (1-20):1, preferably (4-10):1;
  • the palladium catalyst system in step (g) is selected from Pd(dppf)Cl 2 , Pd(dtbpf)Cl 2 , SPhosPdG2, cataCXiumAPdG2, [Pd(amphos) 2 Cl 2 ], RuPhosPdG2, SPhosPdG2, the molar amount of the palladium catalyst system is 0.1% to 4% of the molar amount of (Ha);
  • the palladium catalyst system in step (g) is selected from Pd(dppf)Cl 2 , Pd(dtbpf)Cl 2 , SPhosPdG2, cataCXiumAPdG2, [Pd(amphos) 2 Cl 2 ], RuPhosPdG2, SPhosPdG2, the molar amount of the palladium catalyst system is 0.2% to 4% of the molar amount of (Ha);
  • the palladium catalytic system in step (g) when the palladium catalytic system in step (g) is selected from Pd(dppf)Cl 2 , Pd(dtbpf)Cl 2 , SPhosPdG2, cataCXiumAPdG2, [Pd(amphos) 2 Cl 2 ], RuPhosPdG2, SPhosPdG2, the palladium
  • the molar amount of the catalyst system is 0.5% to 4% of the molar amount of (Ha);
  • the palladium catalytic system in step (g) is selected from Pd(dppf)Cl 2 , Pd(dtbpf)Cl 2 , SPhosPdG2, cataCXiumAPdG2, [Pd(amphos) 2 Cl 2 ], RuPhosPdG2, SPhosPdG2, the molar ratio of (Ha):(Hb):alkaline agent:palladium catalytic system is 1.0:(1.0-1.5):(2.0-4.0):(0.001-0.05);
  • the palladium catalytic system in step (g) is selected from Pd(dppf)Cl 2 , Pd(dtbpf)Cl 2 , SPhosPdG2, cataCXiumAPdG2, [Pd(amphos) 2 Cl 2 ], RuPhosPdG2, SPhosPdG2, the molar ratio of (Ha):(Hb):alkaline agent:palladium catalytic system is 1.0:(1.2-1.5):(3.0-4.0):(0.005-0.04);
  • the molar ratio of palladium catalyst to phosphine ligand is 1:2;
  • the molar ratio of (H-a):(H-b):alkaline agent:palladium catalyst is 1.0:(1.0-1.5):(2.0-4.0):(0.001-0.05), and the molar ratio of palladium catalyst to phosphine ligand is 1:2;
  • the molar amount of the palladium catalyst is 0.1% to 4% of the molar amount of (H-a);
  • the molar amount of the palladium catalyst is 0.1% to 2% of the molar amount of (H-a);
  • the molar amount of the palladium catalyst is 0.2% to 1% of the molar amount of (H-a);
  • reaction temperature of step (g) is 40°C to 120°C;
  • reaction temperature of step (g) is 60°C to 100°C;
  • reaction temperature of step (g) is 70°C to 90°C.
  • the starting material (D-a) of step (g) is prepared by step h.
  • the present invention also provides a method for preparing compound (C-a),
  • R 1 , R 2 , R 3 , and R 4 are the same as any of the corresponding definitions above;
  • step (c), step (d), step (e), step (f) and step (g) is the same as any of the corresponding definitions above.
  • the present invention provides a method for preparing compound (Da), which comprises reducing compound (Ia) with a reducing system to obtain (Da) (i.e., step (h)), wherein:
  • R 3 and R 4 are defined as any of the above corresponding definitions
  • R 6 is the same as any of the corresponding definitions above;
  • the reduction system in step (h) includes a reducing agent and a catalyst
  • the reducing agent in step (h) is selected from H 2 , triethylsilyl hydride, sodium borohydride;
  • the catalyst in step (h) is selected from Pd, Pd/C, Au, Pt, Ni, preferably 10% Pd/C
  • the catalyst in step (h) further comprises an acid catalyst, preferably acetic acid;
  • the reaction solvent in step (h) is selected from one or more of methanol, ethanol, 1,4-dioxane, water, ethyl acetate, tetrahydrofuran, acetonitrile, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide.
  • the reducing agent is selected from trimethylsilyl hydride
  • the catalyst is selected from 10% Pd/C, acetic acid, (Ia):
  • the mass ratio of trimethylsilyl hydride: 10% Pd/C: acetic acid is selected from 1: (1.0-2.0): (0.05-0.15): (0.01-0.05), preferably 1: 1.5: 0.10: 0.03.
  • the starting material (I-a) of step (h) is prepared by step (i).
  • the present invention provides a method for preparing compound (Ia), wherein compound (Ja) and compound (Jb) react in the presence of an alkaline reagent to obtain compound (Ia) (i.e., step (i)).
  • R 3 and R 4 are defined as any of the above corresponding definitions
  • R 6 is the same as any of the corresponding definitions above;
  • the alkaline agent is selected from one or more of sodium bicarbonate, sodium carbonate, dipotassium hydrogen phosphate, potassium bicarbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, sodium hydride, sodium hydroxide, potassium hydroxide, N,N-diisopropylethylamine, triethylamine or 1,8-diazabicycloundec-7-ene;
  • the alkaline agent is selected from cesium carbonate, and the mass ratio of (J-a):(J-b):alkaline agent is selected from 1:(0.5-1.0):(1.5-2.5);
  • the solvent used in step (i) is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, acetone, n-butyl ketone, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or toluene, preferably one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, more preferably N,N-dimethylformamide.
  • the present invention also provides a method for preparing compound (D-a),
  • R 3 , R 4 , and R 6 are the same as any of the corresponding definitions above;
  • step (i) and step (h) are the same as any of the corresponding definitions above.
  • the present invention provides a compound, The compound is selected from compound (Bb) and compound (Ca), wherein
  • R 1 , R 2 , R 3 , and R 4 are defined as any of the above corresponding definitions;
  • R 6 has the same meaning as defined above.
  • the present invention provides a compound, the compound is selected from compound (Da), compound formula (Ia), wherein,
  • R 3 is selected from C 1-4 alkoxy, -OC 3-6 cycloalkyl, wherein the alkoxy or cycloalkyl is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • R 4 has the same meaning as any one of the above definitions.
  • the present invention provides a compound, the compound is selected from (B1-b), (C1-a), (C1-a1), (D1-a), (I1-a),
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, Isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, and isotopes of bromine include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include
  • Halogen refers to F, Cl, Br or I.
  • Halogen substituted refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I.
  • Halogen substituted is abbreviated as "halo”.
  • Alkyl refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; the alkyl groups appearing in this article are defined in accordance with this definition. Alkyl groups can be monovalent, divalent, trivalent, or tetravalent.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl groups appearing herein are defined as above. Cycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S, and the selectively substituted N and S in the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and heterocycloalkyl can be connected to an aromatic ring or a non-aromatic ring.
  • Heterocycloalkyl can be connected to a bridge ring or a spiro ring, and non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl.
  • Heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent.
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and the carbocyclyl can be attached to the aromatic ring or the non-aromatic ring, and the aromatic ring or the non-aromatic ring can be optionally a monocyclic ring, a bridged ring or a spirocyclic ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohex ... Cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring.
  • Carbocyclyl or “carbocycle” may be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, or a 10-15-membered tricyclic ring system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S.
  • the N and S selectively substituted in the heterocyclyl ring may be oxidized to various oxidation states.
  • the heterocyclyl may be attached to a heteroatom or a carbon atom, may be attached to an aromatic ring or a non-aromatic ring, may be attached to a bridged ring or a spirocyclic ring, and non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazine 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazoly
  • Acetal group means Ra1 is selected from substituted or unsubstituted C 1-6 alkyl, or two Ra1 are directly connected to form a substituted or unsubstituted ring; non-limiting examples include
  • the salt of a compound refers to a salt obtained by reacting a free acid with an inorganic base or an organic base, or a salt obtained by reacting a free base with an inorganic acid or an organic acid.
  • Alcohol solvent refers to a solvent containing hydroxyl groups in its molecular structure. Non-limiting examples include ethylene glycol, methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, sec-pentanol, 3-pentanol, isopentanol, tert-pentanol, n-hexanol and cyclohexanol.
  • Ether solvents refer to solvents with ether bonds in their molecular structure.
  • Non-limiting examples include tetrahydrofuran, 2-methyltetrahydrofuran, ethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, diisopropyl ether, ethyl butyl ether, dibutyl ether, diamyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether and anisole, etc.
  • Aromatic hydrocarbon solvents refer to solvents containing 0-3 heteroatoms (heteroatoms selected from O, S or N) and aromatic rings in their molecular structures.
  • Non-limiting examples include benzene, pyridine, toluene, ethylbenzene, xylene, chlorobenzene and o-dichlorobenzene.
  • Halogenated alkane solvents refer to alkane solvents containing halogens (fluorine, chlorine, bromine, iodine) in their molecular structures.
  • halogens fluorine, chlorine, bromine, iodine
  • Non-limiting examples include dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, carbon tetrachloride, pentachlorohexane, 1-chlorobutane and bromoform.
  • Alkane solvent refers to a solvent containing only alkanes in its molecular structure, and non-limiting examples include n-hexane, n-heptane, n-octane, n-pentane, cyclohexane and cycloheptane.
  • Ester solvents refer to solvents containing carboxylic acid esters in their molecular structure. Non-limiting examples include ethyl acetate, isopropyl acetate, triacetin, ethyl acetoacetate, isoamyl acetate, isopropyl acetate, n-butyl acetate, n-propyl acetate, n-amyl acetate, methyl acetate, sec-butyl acetate, butyl formate, propyl formate, n-amyl formate and diethyl carbonate, etc.
  • Ketone solvent refers to a solvent containing a ketone carbonyl group in its molecular structure.
  • Non-limiting examples include acetone, butanone, acetophenone, methyl isobutyl ketone, 2,6-dimethyl-2,5-heptadien-4-one, 3,5,5-trimethyl-2-cyclohexenone and mesityl oxide, etc.
  • Nirile solvent refers to a solvent containing a cyano group in its molecular structure, and non-limiting examples include acetonitrile, propionitrile, butyronitrile and benzyl cyanide.
  • Amide solvents refer to solvents containing amides in their molecular structure. Non-limiting examples include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, hexamethylphosphoramide, and N-methylpyrrolidone.
  • a "polar aprotic solvent” is one that does not contain hydrogen atoms directly attached to electronegative atoms and does not have Non-limiting examples include acetone, dimethyl sulfoxide, HMF (hydroxymethyl furfural), crown ethers, acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone, etc.
  • Polar protic solvents refer to solvents capable of hydrogen bonding (because they contain at least one hydrogen atom directly attached to an electronegative atom (e.g., an O-H or N-H bond)), non-limiting examples of which include methanol, water, ethanol, ammonia, acetic acid, and the like.
  • the reaction process of the present invention is tracked by HPLC, HNMR or thin layer chromatography to determine whether the reaction is completed.
  • the internal temperature refers to the temperature of the reaction system.
  • V or “V/M” refers to the multiple of the volume of the reaction solvent relative to the mass of 1 eq of the raw material fed to the step.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SC-A18 100 ⁇ 4.6 mm, 3.5 ⁇ M);
  • Example of using polar aprotic solvent as reaction solvent Add 825.00 g E1-a (3.943 mol, 1.00 eq.), 943.4 g 5-bromo-2,4-dichloropyrimidine (E1-b) (4.140 mol, 1.05 eq.), 4125 mL NMP (5 V/M) into a 20 L reactor, start stirring, add 764.40 g N, N-diisopropylethylamine (5.915 mol, 1.50 eq.), heat to 120 °C for 4 hours, and cool. To room temperature, 8L saturated brine was added, and 4L dichloromethane was used for extraction.
  • the aqueous phase was extracted once with 4L dichloromethane.
  • the organic phases were combined and washed four times with 8L saturated brine.
  • the organic phase was concentrated under reduced pressure until the reaction solution was thick, and 15L isopropanol was added to continue concentration. When the reaction solution was concentrated to 10L, the reduced pressure concentration was stopped.
  • the reaction solution was heated to 80°C and refluxed for 1h, cooled to 5-10°C and stirred for 2h to crystallize, filtered, and the filter cake was rinsed with 2L isopropanol and dried to obtain 1342.0g D1-b with a yield of 78.3%.
  • the aqueous phase was extracted once with dichloromethane, the organic phases were combined, and saturated sodium chloride solution was added to wash the organic phase twice.
  • the organic phase was concentrated under reduced pressure until no solvent flowed out, 750 ml (5 V/M) of acetonitrile was added, the temperature was raised to 80 ° C and refluxed (a white solid precipitated), and the mixture was stirred for 1-2 h.
  • the mixture was cooled to 5-10 ° C and kept warm for 2 h for crystallization.
  • the mixture was filtered, and the filter cake was rinsed with acetonitrile to obtain a mixture of C1-a and C1-a1.
  • the mixture was dried to obtain 235 g, with a yield of 86.9% (calculated based on the molecular weight of C1-a).
  • Example of B1-a hydrochloride In a 3000ml three-necked flask, add 122g B1-b (180mmol, 1.0eq.), 81.73g B1-a (216mmol, 1.2eq., B1-a is hydrochloride), 1220ml N,N-dimethylacetamide (15V/M), start stirring, cool to -15 ⁇ -10°C and keep warm for 30min, control the temperature at -15 ⁇ -10°C and add 57.16g triacetyl Sodium oxyborohydride (270 mmol, 1.5 eq.) was dissolved in 610 ml N,N-dimethylacetamide (5 V/M), and the mixture was kept warm for 2 h.
  • Example of B1-a mesylate salt In a 250ml three-necked flask, add 15.00g B1-b (22.1mmol, 1.0eq.), 11.63g B1-a (26.5mmol, 1.2eq., B1-a is mesylate salt), 150ml N,N-dimethylacetamide (10V/M), start stirring, cool to 10-20°C and keep warm for 2h, control the temperature at -10-0°C, add 7.03g triacetoxy Sodium borohydride (33.2mmol, 1.5eq) was added, and the mixture was kept warm for 2h. 900ml of water and 450ml of dichloromethane were added.
  • the aqueous phase was extracted once with 450ml of dichloromethane.
  • the organic phases were combined, and the organic phases were washed once with 450ml of water and 225ml of dichloromethane.
  • the mixture was concentrated under reduced pressure, and 300ml of tetrahydrofuran (20V/M) was added.
  • the mixture was heated to 60°C and kept warm for 1h.
  • the mixture was cooled, filtered, and dried to obtain 67.48g of A1 with a yield of 85%.
  • Preparation method Prepared according to the method of step 5 of Example 2, the reaction results of different catalytic systems and conditions are shown in Table 1 below.
  • Solvent volume The volume of the solvent is the multiple of the mass of the feed D1-b.
  • the reducing agent is selected from sodium triacetoxyborohydride
  • the molar ratio of sodium triacetoxyborohydride: B-b is (1.0-2.0):1
  • the molar ratio of B-a: B-b is (0.9-1.5):1.0, and the reaction can achieve good results.
  • sequence number 16 The conditions of sequence number 16 were enlarged, the feeding amount of H-a was 20 mmol, and the other conditions were the same as sequence number 16. After conventional separation and purification, 2.6 g G1-a (HPLC purity 97.46%) was obtained, and the separation yield was 95%.
  • the molar ratio of G1-a to NBS is 1:(1.0-1.2), the solvent is acetonitrile, and the reaction temperature is -30°C-0°C, and the reaction can achieve good results.
  • the catalytic system composed of phosphine-free metal catalysts (such as Pd(OAc) 2 , [(cinnamyl)PdCl] 2 , [PdCl(C 3 H 5 )] 2 , Pd(MeCN) 2 Cl 2 , Pd(TFA) 2 , Pd 2 (dba) 3 ) and phosphine ligand reagents dppf or dppb can achieve high conversion rates in different alkaline reagents (such as Cy 2 NMe, DIPEA, Et 3 N, Cs 2 CO 3 , K 3 PO 4 ) and different solvents (t-AmylOH, DMF, DMAc), with E1-a (%) greater than 85%;
  • phosphine-free metal catalysts such as Pd(OAc) 2 , [(cinnamyl)PdCl] 2 , [PdCl(C 3 H 5 )] 2 , Pd(MeCN) 2 Cl
  • the catalytic dosage of the phosphine-free metal catalyst (such as 0.8 mol%, 1 mol%, 1.2 mol%, 1.5 mol%, 2 mol%, 4 mol%) can achieve high conversion rate, and E1-a (%) is greater than 85%.
  • the metal catalyst Pd(dppf)Cl 2 was used in different amounts (such as 1 mol%, 1.5 mol%, 2 mol%) and alkaline test solution.
  • Reagents such as DIPEA, Cy 2 NMe
  • Test Example 1 Proliferation Inhibitory Activity of NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) Cells
  • NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells were purchased from ATCC, and the culture medium was RPMI1640 + 10% FBS and DMEM + 10% FBS, respectively, and cultured in a 37 ° C, 5% CO 2 incubator. On the first day, NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells in the exponential growth phase were collected, and live cells were counted using an automatic cell analyzer (countstar).
  • the cell suspension was adjusted with culture medium and plated on a 96-well cell culture plate, with 1000 NCI-H1975 (EGFR-L858R-T790M) cells per well and 3000 A431 cells per well.
  • the culture medium was aspirated, and 90 ⁇ L of fresh culture medium and 10 ⁇ L of different concentrations of compounds were added to each well, with a final DMSO concentration of 0.1% per well.
  • the cells were cultured in an incubator at 37°C and 5% CO 2 for 72 hours.
  • CTG solution promega, G7572
  • 50 ⁇ L of CTG solution pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes before measuring the fluorescence signal value with a microplate reader (PHERAstar FSX).
  • Cell viability was calculated using the formula V sample /V vehicle control x 100%, where V sample was the reading of the drug-treated group and V vehicle control was the average value of the solvent control group.
  • V sample was the reading of the drug-treated group and V vehicle control was the average value of the solvent control group.
  • origin9.2 software a nonlinear regression model was used to draw a S-shaped dose-survival curve and calculate the IC 50 value.
  • the inhibitory activity of the test compound on the proliferation of A431 (WT) cells was ⁇ 10 ⁇ M.
  • the compounds of the present invention have good proliferation inhibitory activity against NCI-H1975 (EGFR-L858R-T790M) cells; poor proliferation inhibitory activity against A431 (EGFR-WT) cells, and have good selectivity.
  • Test Example 2 Proliferation Inhibitory Activity on Cells NCI-H1975 EGFR-L858R-T790M-C797S
  • Cells NCI-H1975 EGFR-L858R-T790M-C797S were cultured in a 37°C, 5% CO 2 incubator in a medium containing RPMI1640 + 10% FBS + 100 ⁇ g/mL hygromycin. Cells in the exponential growth phase were collected, and the cell suspension was adjusted to an appropriate concentration using a medium without hygromycin and then plated in a 96-well plate at a density of 1500 cells/well. Wells, volume 90 ⁇ L. Add 10 ⁇ L of compounds of different concentrations, and set up a solvent control group of cells plus DMSO, the concentration of DMSO is 0.1%. The cell culture plate was placed in a 37°C, 5% CO 2 incubator for 72 hours.
  • the compounds of the present invention have good proliferation inhibitory activity on NCI-H1975 EGFR-L858R-T790M-C797S cells.

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Abstract

本发明涉及一种膦酰衍生物的制备方法，具体涉及式(A)所示的化合物及其中间体的制备方法，该方法反应条件温和，操作简单，反应产率高，产品纯度高，后处理方便，适合于工业化生产。

Description

一种膦酰衍生物的制备方法 技术领域
本发明涉及式(A)所示的化合物及其中间体的制备方法，该方法反应条件温和，操作简单，反应产率高，产品纯度高，后处理方便，适合于工业化生产。
背景技术
表皮生长因子受体(EGFR)是一种跨膜蛋白酪氨酸激酶，可作为EGF家族成员触发人类上皮细胞中EGFR信号通路的受体，从而调节细胞增殖，侵袭，转移，凋亡和血管生成(Nat.Rev.Cancer,2007,7,169-181；Expert Opin.Ther.Targets,2012,16,15-31.)。人体内EGFR基因的过度表达、突变或扩增致使EGFR活性异常增加，会导致许多恶性肿瘤如食道癌、胶质母细胞瘤、肛门癌、头颈部上皮癌、乳腺癌、肺癌、特别是非小细胞肺癌(NSCLC)的产生(Cells,2019,8,350-361.)。
PROTAC(proteolysis targeting chimera)分子是一类能够同时结合靶向蛋白和E3泛素连接酶的双功能化合物，此类化合物能够被细胞的蛋白酶体识别，引起靶向蛋白的降解，能够有效地降低靶向蛋白在细胞中的含量。通过在PROTAC分子引入能结合不同靶向蛋白的配体，使PROTAC技术应用于各种疾病的治疗成为可能，该技术近年来同时得到了广泛的关注(ACS Chem.Biol.2017,12,892-898；Drug Discovery Today Technol.2019,31,15-27.)。
PCT/CN2022/090243专利中记载一类化合物，这类化合物对NCI-H1975(EGFR-L858R-T790M)和NCI-H1975 EGFR-L858R-T790M-C797S细胞具有优异的抑制活性。
发明内容
本发明的目的是提供一种式(A)所示化合物及其中间体的制备方法，该方法反应起始物价格低廉、反应条件温和、操作简单、产率高、产品纯度高、后处理方便、适合于工业化生产。
本发明提供一种式(A)所示化合物的制备方法，化合物(B-a)或其与酸性试剂1形成的盐与化合物(B-b)在还原剂存在下反应得到化合物(A)(即步骤(a))；
R1选自H、卤素、C1-4烷基、C1-4烷氧基、C3-6碳环基、4至6元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；在一些实施方案中，R1选自F、Cl、Br、CF3、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、苯基，所述的甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、苯基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；在一些实施方案中，R1选自F、Cl、Br、CF3、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、苯基；在一些实施方案中，R1选自环丙基；
R2选自卤素、C1-4烷基、C1-4烷氧基，所述的烷基或烷氧基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；在一些实施方案中，R2选自F、Cl、Br；在一些实施方案中，R2选自Cl、Br；
R3选自H、C1-4烷基、C1-4烷氧基、-O-C3-6环烷基，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；在一些实施方案中，R3选自甲氧基、乙氧基、-O-环丙基；在一些实施方案中，R3选自甲氧基；
R4选自H、C1-4烷基、C1-4烷氧基、-O-C3-6环烷基、C3-6环烷基、4至6元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；在一些实施方案中，R4选自H、甲基、乙基、环丙基、吡唑基、吡咯基，所述的甲基、乙基、环丙基、吡唑基、吡咯基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；在一些实施方案中，R4选自
R5选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；在一些实施方案中，R5选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基，所述的烷基、烷氧基或环烷 基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；在一些实施方案中，R5选自H、F、Cl、Br、I、OH、NH2、甲基、乙基、甲氧基或环丙基，所述的甲基、乙基、甲氧基或环丙基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；在一些实施方案中，R5选自H；
在一些实施方案中，式(A)所示化合物自如下结构之一：
在一些实施方案中，步骤(a)中当化合物(B-a)以游离碱形式反应时，反应中进一步加入pKa≤5的酸性试剂2；
在一些实施方案中，步骤(a)中的还原剂选自硼还原剂；
在一些实施方案中，步骤(a)中的还原剂选自醋酸硼氢化钠、硼氢化钠、氰基硼氢化钠、9-硼双环[3.3.1]壬烷、2-甲基吡啶硼烷、三乙酰氧基硼氢化钠、硼氢化钾或硼氢化锂中的一种或多种；
在一些实施方案中，步骤(a)中的还原剂选自三乙酰氧基硼氢化钠或2-甲基吡啶硼烷；
在一些实施方案中，步骤(a)中的还原剂为三乙酰氧基硼氢化钠；
在一些实施方案中，步骤(a)反应所使用的溶剂选自极性非质子性溶剂或非极性溶剂中的一种或多种；
在一些实施方案中，步骤(a)反应所使用的溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二氯甲烷、1,2-二氯乙烷、乙酸乙酯、甲基叔丁基醚、二甲亚砜、乙腈、乙醚、四氢呋喃中的一种或多种；
在一些实施方案中，步骤(a)中酸性试剂1选自盐酸、氢溴酸、甲基磺酸、对甲苯磺酸、苯磺酸、三氟乙酸；
在一些实施方案中，步骤(a)中酸性试剂1选自盐酸或甲基磺酸；
在一些实施方案中，步骤(a)中酸性试剂1选自盐酸；
在一些实施方案中，步骤(a)中酸性试剂2选自醋酸或甲酸中的一种或多种；
在一些实施方案中，步骤(a)中酸性试剂2选自为醋酸；
在一些实施方案中，步骤(a)中酸性试剂1选自盐酸或甲基磺酸，反应中进一步加入添加剂，添加剂选自除水试剂(如无水硫酸钠、无水硫酸镁或分子筛中的一种或多种)、碱性试剂(如碳酸氢钠、碳酸钠、磷酸氢二钾、碳酸氢钾、碳酸钾、碳酸锂、碳酸铯、甲醇钠、乙醇钠、甲醇钾、乙醇钾、叔丁醇钠、叔丁醇钾、磷酸钾、氢化钠、氢氧化钠、氢氧化钾、N,N-二异丙基乙胺、三乙胺、1,8-二氮杂二环十一碳-7-烯中的一种或多种)；
在一些实施方案中，步骤(a)中酸性试剂1选自盐酸或甲基磺酸，反应中进一步加入添加剂，添加剂选自除水试剂(如无水硫酸钠、无水硫酸镁或分子筛中的一种或多种)、酸性试剂3(如pKa≤5的酸性试剂，例如醋酸或甲酸)；
在一些实施方案中，步骤(a)反应中进一步加入添加剂，添加剂选自除水试剂(如无水硫酸钠、无水硫酸镁或分子筛中的一种或多种)；
在一些实施方案中，步骤(a)中还原剂选自三乙酰氧基硼氢化钠，三乙酰氧基硼氢化钠：B-b的摩尔比为(1.0～4.0):1；
在一些实施方案中，步骤(a)中还原剂选自三乙酰氧基硼氢化钠，三乙酰氧基硼氢化钠：B-b的摩尔比为(1.0～2.0):1；
在一些实施方案中，步骤(a)中还原剂选自三乙酰氧基硼氢化钠，三乙酰氧基硼氢化钠：B-b的摩尔比为1.5:1；
在一些实施方案中，步骤(a)中B-a:B-b的摩尔比为(0.9～2.0):1.0；
在一些实施方案中，步骤(a)中B-a:B-b的摩尔比为(0.9～1.5):1.0；
在一些实施方案中，步骤(a)中B-a:B-b的摩尔比为(0.95～1.3):1.0；
在一些实施方案中，步骤(a)中B-a:B-b的摩尔比为1.2:1.0。
在一些实施方案中，化合物(B-a)与酸性试剂1形成的盐选自单盐或二盐；
在一些实施方案中，步骤(a)的反应温度为0℃～40℃；
在一些实施方案中，步骤(a)的反应温度为20℃～30℃。
在一些实施方案中，步骤(a)的原料(B-b)通过步骤(b)制备得到。
本发明提供一种式(B-b)所示化合物的制备方法，式(C-a)化合物在酸性试剂存在下反应得式(B-b)所示化合物(即步骤(b))；
R1、R2、R3、R4的定义与前述相应的定义任一项相同；
R6为缩醛基，优选为更优选为
在一些实施方案中，步骤(b)中酸性试剂选自盐酸、对甲苯磺酸、醋酸、硫酸、三氟乙酸、甲酸、氢溴酸、甲基磺酸；
在一些实施方案中，步骤(b)中酸性试剂为盐酸；
在一些实施方案中，步骤(b)反应所使用的溶剂选自极性非质子性溶剂或极性质子性溶剂；
在一些实施方案中，步骤(b)反应所使用的溶剂选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、乙腈、四氢呋喃、2-甲基四氢呋喃、丙酮、水的一种或多种；
在一些实施方案中，步骤(b)反应所使用的溶剂选自水、水与极性溶剂(如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、乙腈、四氢呋喃、2-甲基四氢呋喃、丙酮)的混合物；
在一些实施方案中，步骤(b)反应所使用的溶剂选自水、水/四氢呋喃、水/丙酮、水/N,N-二甲基甲酰胺、水/乙腈、水/2-甲基四氢呋喃；
在一些实施方案中，步骤(b)中酸性试剂选自盐酸，反应所使用的溶剂选自水、水/四氢呋喃、水/丙酮、水/N,N-二甲基甲酰胺、水/乙腈、水/2-甲基四氢呋喃，优选溶剂为水；
在一些实施方案中，步骤(b)中C-a:酸性试剂的摩尔比为1.0:(6.0～25.0)；
在一些实施方案中，步骤(b)中C-a:酸性试剂的摩尔比为1.0:(8.0～20.0)；
在一些实施方案中，步骤(b)中C-a:酸性试剂的摩尔比为1.0:(10.0～15.0)；
在一些实施方案中，步骤(b)反应温度为0～70℃；
在一些实施方案中，步骤(b)反应温度为20～30℃。在一些实施方案中，步骤(b)的原料(C-a)通过步骤(c)制备得到。
本发明还提供一种化合物(A)的制备方法，1)化合物(C-a)在酸性试剂存在下反应得化合物(B-b)所示化合物(即步骤(b))；2)化合物(B-a)或其与酸性试剂1形成的盐与化合物(B-b)在还原剂存在下反应得到化合物(A)(即步骤(a))；
；其中，R1、R2、R3、R4、R5的定义与前述相应的定义任一项相同；
步骤(a)，步骤(b)中各定义与前述相应的定义任一项相同。
本发明提供一种化合物(C-a)的制备方法，化合物(D-b)与化合物(D-a)在酸性催化剂存在下反应得到化合物(C-a)(即步骤(c))；
R1、R2、R3、R4、R6的定义与前述相应的定义任一项相同；
X为离去基团，在一些实施方案中，X选自F、Cl、Br或I，在一些实施方案中，X为Cl；
在一些实施方案中，步骤(c)中酸性催化剂选自甲基磺酸、对甲苯磺酸、三氟乙酸、醋酸、盐酸、氢溴酸、硫酸、乙二磺酸、氢碘酸、磷酸、氯化锌、醋酸锌、吡啶盐酸盐、4-甲基苯磺酸吡啶、三乙胺盐酸盐、草酸、三氯化铝、三氟化硼中的一种或多种；
在一些实施方案中，步骤(c)中酸性催化剂选自醋酸、吡啶盐酸盐、吡啶对甲苯磺酸盐、三乙胺盐酸盐、对甲苯磺酸、三氟乙酸、磷酸、甲基磺酸中的一种或多种；
在一些实施方案中，步骤(c)反应所使用的溶剂选自酰胺类溶剂、烷烃类溶剂、卤代烷烃类溶剂、醇类溶剂、酮类溶剂、酯类溶剂、醚类溶剂、腈类溶剂、砜类溶剂和水中的一种或多种，优选N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二氯甲烷、1,2-二氯乙烷、乙酸乙酯、丙酮、甲醇、乙醇、异丙醇、正丁醇、三氟乙醇、乙二醇、正丁酮、甲基叔丁基醚、二甲亚砜、乙腈、乙醚、四氢呋喃和水中的一种或多种；
在一些实施方案中，步骤(c)反应所使用的溶剂选自醇类溶剂(如乙二醇)；
在一些实施方案中，步骤(c)中酸性催化剂选自甲基磺酸，反应所使用的溶剂选自乙二醇；
在一些实施方案中，步骤(c)中D-b：D-a：酸性催化剂的摩尔比为(0.2～1.5):1.0:1.0；
在一些实施方案中，步骤(c)中D-b：D-a：酸性催化剂的摩尔比为0.5:1.0:1.0；
在一些实施方案中，步骤(c)反应温度为40℃～110℃；
在一些实施方案中，步骤(c)反应温度为85℃～105℃。
在一些实施方案中，步骤(c)的原料(D-b)通过步骤(d)制备得到。
本发明提供一种化合物(D-b)的制备方法，化合物(E-a)和化合物(E-b)在碱性试剂存在下反应得到化合物(D-b)(即步骤(d)):
R1、R2的定义与前述相应的定义任一项相同；
X为离去基团；在一些实施方案中，X选自F、Cl、Br或I；在一些实施方案中，X为Cl；
Y为离去基团，在一些实施方案中，选自I，Br，Cl，OTf；在一些实施方案中，Y为Cl；
在一些实施方案中，步骤(d)中碱性试剂选自碳酸氢钠、碳酸钠、磷酸氢二钾、碳酸氢钾、碳酸钾、碳酸锂、碳酸铯、甲醇钠、乙醇钠、甲醇钾、乙醇钾、叔丁醇钠、叔丁醇钾、磷酸钾、氢化钠、氢氧化钠、氢氧化钾、N,N-二异丙基乙胺、三乙胺、1,8-二氮杂二环十一碳-7-烯中的一种或多种；
在一些实施方案中，步骤(d)中碱性试剂选自碳酸氢钠、碳酸钠、磷酸氢二钾、碳酸氢钾、碳酸钾、碳酸锂、碳酸铯、磷酸钾、氢化钠、氢氧化钠、氢氧化钾、N,N-二异丙基乙胺、三乙胺或1,8-二氮杂二环十一碳-7-烯中的一种或多种；
在一些实施方案中，步骤(d)中碱性试剂选自N,N-二异丙基乙胺；
在一些实施方案中，步骤(d)反应中使用的溶剂选自极性非质子性溶剂和极性质 子溶剂；
在一些实施方案中，步骤(d)反应中使用的溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二氯甲烷、1,2-二氯乙烷、乙酸乙酯、乙酸异丙酯、丙酮、正丁酮、甲基叔丁基醚、二甲亚砜、乙腈、乙醚、四氢呋喃、2-甲基四氢呋喃、甲苯、异丙醇、甲醇和乙醇中的一种或多种；
在一些实施方案中，步骤(d)反应中使用的溶剂选自N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜的一种或多种；
在一些实施方案中，步骤(d)反应中使用的溶剂为N-甲基吡咯烷酮和异丙醇；
在一些实施方案中，步骤(d)中E-a和E-b的摩尔比为1.0:(1.1～1.5)；
在一些实施方案中，步骤(d)中E-a和E-b的摩尔比为1.0:1.3；
在一些实施方案中，步骤(d)中E-a和E-b的摩尔比为1.0:1.05；
在一些实施方案中，步骤(d)反应温度为80℃～135℃；
在一些实施方案中，步骤(d)反应温度为110℃～125℃；
在一些实施方案中，步骤(d)反应温度为115℃～125℃；
在一些实施方案中，步骤(d)的原料(E-a)通过步骤(e)制备得到。
本发明提供一种式(E-a)所示化合物的制备方法，由化合物(F-a)或其盐和化合物(F-b)在钯催化体系、碱性试剂存在下反应得化合物(E-a)(即步骤(e))，
R1的定义与前述相应的定义任一项相同；
在一些实施方案中，化合物(F-a)与化合物(E-a)中R1为环丙基；
在一些实施方案中，化合物(F-a)的盐选自盐酸盐、氢溴酸盐、甲基磺酸盐、对甲苯磺酸盐、三氟乙酸盐；
在一些实施方案中，化合物(F-a)的盐为甲基磺酸盐；
在一些实施方案中，步骤(e)钯催化体系选自钯催化剂/膦配体或Pd(dppf)Cl2；
在一些实施方案中，步骤(e)钯催化体系选自[(cinnamyl)PdCl]2/dppf、Pd(OAc)2/dppf、Pd(MeCN)2Cl2/dppf、Pd2dba3/dppf、Pd(TFA)2/dppf、[PdCl(C3H5)]2/dppf 或Pd(dppf)Cl2；
在一些实施方案中，步骤(e)钯催化剂选自[(cinnamyl)PdCl]2、Pd(OAc)2、Pd(MeCN)2Cl2、Pd2dba3、Pd(TFA)2、[PdCl(C3H5)]2中的一种或多种，膦配体选自dppf、dppb、dppp、DPEPhos中的一种或多种；
在一些实施方案中，步骤(e)钯催化剂选自[(cinnamyl)PdCl]2、Pd(OAc)2、Pd(MeCN)2Cl2、Pd2dba3、Pd(TFA)2、[PdCl(C3H5)]2中的一种或多种；
在一些实施方案中，步骤(e)膦配体选自dppf、dppb、dppp、DPEPhos中的一种或多种；
在一些实施方案中，步骤(e)钯催化剂选自[(cinnamyl)PdCl]2、Pd(OAc)2、Pd(MeCN)2Cl2、Pd2dba3、Pd(TFA)2、[PdCl(C3H5)]2中的一种或多种，膦配体选自dppf；
在一些实施方案中，步骤(e)碱性试剂选自DIPEA、TEA、Cy2NMe、Cy2NH、二乙胺中的一种或多种；
在一些实施方案中，步骤(e)反应所使用的溶剂选自t-AmylOH、DMF、MeCN中的一种或多种；
在一些实施方案中，步骤(e)钯催化体系为Pd(dppf)Cl2时，(F-a):(F-b):碱性试剂:Pd(dppf)Cl2的摩尔比为1.0:(1.0～1.2):(2.0～5.0):(0.001～0.06)；
在一些实施方案中，步骤(e)钯催化体系为Pd(dppf)Cl2时，(F-a):(F-b):碱性试剂:Pd(dppf)Cl2的摩尔比为1.0:1.2:4.0:0.02；
在一些实施方案中，步骤(e)钯催化体系为钯催化剂/膦配体时，(F-a):(F-b):碱性试剂：钯催化剂：膦配体的摩尔比为1.0:1.2:(3.0～4.0):(0.005～0.05):(0.01～0.10)；
在一些实施方案中，步骤(e)中钯催化剂与膦配体的摩尔比为1:2；
在一些实施方案中，步骤(e)钯催化体系为Pd(dppf)Cl2时，Pd(dppf)Cl2的摩尔量为(F-a)摩尔量的0.1％～4％；
在一些实施方案中，步骤(e)钯催化体系为Pd(dppf)Cl2时，Pd(dppf)Cl2的摩尔量为(F-a)摩尔量的0.5％～4％；
在一些实施方案中，步骤(e)钯催化体系为Pd(dppf)Cl2时，Pd(dppf)Cl2的摩尔量为(F-a)摩尔量的1％～2％；
在一些实施方案中，步骤(e)钯催化体系选自[(cinnamyl)PdCl]2/dppf、Pd(OAc)2/dppf、Pd(MeCN)2Cl2/dppf、Pd2dba3/dppf、Pd(TFA)2/dppf、[PdCl(C3H5)]2/dppf 时，钯催化剂[(cinnamyl)PdCl]2、Pd(OAc)2、Pd(MeCN)2Cl2、Pd2(dba)3)、Pd(TFA)2或[PdCl(C3H5)]2的摩尔量为(F-a)摩尔量的0.1％～10％、0.5％～5％或0.8％～4％；
在一些实施方案中，步骤(e)反应温度为60℃～120℃；
在一些实施方案中，步骤(e)反应温度为70℃～115℃；
在一些实施方案中，步骤(e)反应温度为85℃～105℃。
在一些实施方案中，步骤(e)的原料(F-a)通过步骤(f)制备得到。
本发明提供一种化合物(F-a)的制备方法，化合物(G-a)与溴化试剂反应得化合物(F-a)(即步骤(f))，
R1的定义与前述相应的定义任一项相同；
在一些实施方案中，化合物(F-a)与化合物(G-a)中R1为环丙基；
在一些实施方案中，步骤(f)溴化试剂选自NBS；
在一些实施方案中，步骤(f)反应中的溶剂选自乙腈；
在一些实施方案中，步骤(f)G-a与溴化试剂的摩尔比为1:(1.0～1.2)；
在一些实施方案中，步骤(f)G-a与溴化试剂的摩尔比为1:(1.0～1.1)；
在一些实施方案中，步骤(f)反应温度为-30℃～0℃；
在一些实施方案中，步骤(f)反应温度为-25℃～-5℃；
在一些实施方案中，步骤(f)反应温度为-25℃～-15℃。
在一些实施方案中，步骤(f)的原料(G-a)通过步骤(g)制备得到。
本发明提供一种化合物(G-a)的制备方法，化合物(H-a)和化合物(H-b)在钯催化体系和碱性试剂的存在下反应得化合物(G-a)(即步骤(g))；
R1的定义与前述相应的定义任一项相同；
在一些实施方案中，步骤(g)钯催化体系选自钯催化剂/膦配体、Pd(dppf)Cl2、Pd(dtbpf)Cl2、SPhosPdG2、cataCXiumAPdG2、[Pd(amphos)2Cl2]、RuPhosPdG2、 SPhosPdG2中的一种或多种；
在一些实施方案中，步骤(g)钯催化剂选自[(cinnamyl)PdCl]2、Pd(OAc)2、Pd(MeCN)2Cl2、Pd2dba3、Pd(TFA)2、[PdCl(C3H5)]2中的一种或多种；
在一些实施方案中，步骤(g)钯催化体系选自Pd(dppf)Cl2、Pd(dtbpf)Cl2、SPhosPdG2、cataCXiumAPdG2、[Pd(amphos)2Cl2]、RuPhosPdG2、SPhosPdG2、Pd(MeCN)2Cl2/AmgenPhos、Pd(TFA)2/AmgenPhos、Pd2(dba)3/AmgenPhos、[(cinnamyl)PdCl]2/AmgenPhos、[PdCl(C3H5)]2/AmgenPhos、Pd(OAc)2/AmgenPhos、Pd(MeCN)2Cl2/dtbpf、Pd(TFA)2/dtbpf、Pd2(dba)3/dtbpf、[(cinnamyl)PdCl]2/dtbpf、[PdCl(C3H5)]2/dtbpf、Pd(OAc)2/dtbpf、Pd(MeCN)2Cl2/Catacxium PtB；
在一些实施方案中，步骤(g)所述膦配体选自dppf、dppb、dppp、dtbpf、Catacxium PtB、DPEPhos、AmgenPhos中的一种或多种；
在一些实施方案中，步骤(g)所述膦配体选自dppf、dtbpf、AmgenPhos、Catacxium PtB中的一种或多种；
在一些实施方案中，步骤(g)碱性试剂选自K2CO3、K3PO4、DIPEA、TEA、Cy2NMe、Cy2NH、二乙胺中的一种或几种多种；
在一些实施方案中，步骤(g)碱性试剂选自K2CO3或K3PO4；
在一些实施方案中，步骤(g)反应中的溶剂选自t-AmylOH、DMF、MeCN、甲苯、CPME、DMAc、i-PrOH、MeCN和水中的一种或多种；
在一些实施方案中，步骤(g)反应中使用的溶剂选自甲苯/水、CPME/水、t-AmylOH/水，所述甲苯、CPME、t-AmylOH与H-a的体积质量比为(10～20):1，优选为15:1，所述水与H-a的体积质量比为(1～20):1，优选为(4～10):1；
在一些实施方案中，步骤(g)钯催化体系选自Pd(dppf)Cl2、Pd(dtbpf)Cl2、SPhosPdG2、cataCXiumAPdG2、[Pd(amphos)2Cl2]、RuPhosPdG2、SPhosPdG2时，钯催化体系的摩尔用量为(H-a)摩尔量的0.1％～4％；
在一些实施方案中，步骤(g)钯催化体系选自Pd(dppf)Cl2、Pd(dtbpf)Cl2、SPhosPdG2、cataCXiumAPdG2、[Pd(amphos)2Cl2]、RuPhosPdG2、SPhosPdG2时，钯催化体系的摩尔用量为(H-a)摩尔量的0.2％～4％；
在一些实施方案中，步骤(g)钯催化体系选自Pd(dppf)Cl2、Pd(dtbpf)Cl2、SPhosPdG2、cataCXiumAPdG2、[Pd(amphos)2Cl2]、RuPhosPdG2、SPhosPdG2时，钯 催化体系的摩尔用量为(H-a)摩尔量的0.5％～4％；
在一些实施方案中，步骤(g)钯催化体系选自Pd(dppf)Cl2、Pd(dtbpf)Cl2、SPhosPdG2、cataCXiumAPdG2、[Pd(amphos)2Cl2]、RuPhosPdG2、SPhosPdG2时，(H-a):(H-b):碱性试剂:钯催化体系的摩尔比为1.0:(1.0～1.5):(2.0～4.0):(0.001～0.05)；
在一些实施方案中，步骤(g)钯催化体系选自Pd(dppf)Cl2、Pd(dtbpf)Cl2、SPhosPdG2、cataCXiumAPdG2、[Pd(amphos)2Cl2]、RuPhosPdG2、SPhosPdG2时，(H-a):(H-b):碱性试剂:钯催化体系的摩尔比为1.0:(1.2～1.5):(3.0～4.0):(0.005～0.04)；
在一些实施方案中，步骤(g)钯催化体系选自钯催化剂/膦配体时，钯催化剂与膦配体的摩尔比为1:2；
在一些实施方案中，步骤(g)钯催化体系选自钯催化剂/膦配体时，(H-a):(H-b):碱性试剂:钯催化剂的摩尔比为1.0:(1.0～1.5):(2.0～4.0):(0.001～0.05)，钯催化剂与膦配体的摩尔比为1:2；
在一些实施方案中，步骤(g)钯催化体系选自钯催化剂/膦配体时，钯催化剂的摩尔用量为(H-a)摩尔量的0.1％～4％；
在一些实施方案中，步骤(g)钯催化体系选自钯催化剂/膦配体时，钯催化剂的摩尔用量为(H-a)摩尔量的0.1％～2％；
在一些实施方案中，步骤(g)钯催化体系选自钯催化剂/膦配体时，钯催化剂的摩尔用量为(H-a)摩尔量的0.2％～1％；
在一些实施方案中，步骤(g)反应温度为40℃～120℃；
在一些实施方案中，步骤(g)反应温度为60℃～100℃；
在一些实施方案中，步骤(g)反应温度为70℃～90℃。
在一些实施方案中，步骤(g)的原料(D-a)通过步骤h制备得到。
本发明还提供一种化合物(C-a)的制备方法，
1)化合物(H-a)和化合物(H-b)在钯催化体系和碱性试剂的存在下反应得化合物(G-a)(即步骤(g))；
2)化合物(G-a)与溴化试剂反应得化合物(F-a)(即步骤(f))；
3)由化合物(F-a)或其盐和化合物(F-b)在钯催化体系、碱性试剂存在下反应得化合物(E-a)(即步骤(e))；
4)化合物(E-a)和化合物(E-b)在碱性试剂存在下反应得到化合物(D-b)(即步骤(d))；
5)化合物(D-b)与化合物(D-a)在酸性催化剂存在下反应得到化合物(C-a)(即步骤(c))；
其中，R1、R2、R3、R4的定义与前述相应的定义任一项相同；
步骤(c)、步骤(d)、步骤(e)、步骤(f)、步骤(g)中各定义与前述相应的定义任一项相同。
本发明提供一种化合物(D-a)制备方法，其是由化合物(I-a)经过还原体系还原制得(D-a)(即步骤(h))，其中，
R3、R4的定义与前述相应的定义任一项相同；
R6的定义前述相应的定义任一项相同；
在一些实施方案中，步骤(h)中还原体系包括还原剂、催化剂；
在一些实施方案中，步骤(h)中还原剂选自H2、三乙基硅氢、硼氢化钠；
在一些实施方案中，步骤(h)中催化剂选自Pd、Pd/C、Au、Pt、Ni，优选为10％Pd/C
在一些实施方案中，步骤(h)中催化剂还包括酸催化剂，优选自醋酸；
在一些实施方案中，步骤(h)中反应溶剂选自甲醇、乙醇、1,4-二氧六环、水、乙酸乙酯、四氢呋喃、乙腈、2-甲基四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中的一种或多种。
在一些实施方案中，还原剂选自三甲基硅氢，催化剂选自10％Pd/C、醋酸，(I-a): 三甲基硅氢:10％Pd/C:醋酸的质量比选自1:(1.0～2.0):(0.05～0.15):(0.01～0.05)，优选为1:1.5:0.10:0.03。
在一些实施方案中，步骤(h)的原料(I-a)通过步骤(i)制备得到。
本发明提供一种化合物(I-a)制备方法，化合物(J-a)和化合物(J-b)在碱性试剂存在下反应得到化合物(I-a)(即步骤(i))，
R3、R4的定义与前述相应的定义任一项相同；
R6的定义前述相应的定义任一项相同；
在一些实施方案中，步骤(i)中碱性试剂选自碳酸氢钠、碳酸钠、磷酸氢二钾、碳酸氢钾、碳酸钾、碳酸锂、碳酸铯、甲醇钠、乙醇钠、甲醇钾、乙醇钾、叔丁醇钠、叔丁醇钾、磷酸钾、氢化钠、氢氧化钠、氢氧化钾、N,N-二异丙基乙胺、三乙胺或1,8-二氮杂二环十一碳-7-烯中的一种或多种；
在一些实施方案中，碱性试剂选自碳酸铯，(J-a):(J-b):碱性试剂的质量比选自1：(0.5～1.0)：(1.5～2.5)；
在一些实施方案中，步骤(i)中使用的溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二氯甲烷、1,2-二氯乙烷、乙酸乙酯、乙酸异丙酯、丙酮、正丁酮、甲基叔丁基醚、二甲亚砜、乙腈、乙醚、四氢呋喃、2-甲基四氢呋喃或甲苯中的一种或多种，优选为N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜中的一种或多种，更优选N,N-二甲基甲酰胺。
本发明还提供一种化合物(D-a)的制备方法，
1)化合物(J-a)和化合物(J-b)在碱性试剂存在下反应得到化合物(D-b)(即步骤(i))；
2)由化合物(I-a)经过还原体系还原制得(D-a)(即步骤(h))；
其中，R3、R4、R6的定义与前述相应的定义任一项相同；
步骤(i)、步骤(h)中各定义与前述相应的定义任一项相同。本发明提供一种化合物， 化合物选自化合物(B-b)、化合物(C-a)，其中，
R1、R2、R3、R4的定义与前述相应的定义任意一项相同；
R6的定义与其前述的定义相同。
本发明提供一种化合物，化合物选自化合物(D-a)，化合物式(I-a)，其中，
R3选自C1-4烷氧基、-O-C3-6环烷基，所述的烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
R4与其前述的定义任意一项相同。
本发明提供一种化合物，化合物选自(B1-b)、(C1-a)、(C1-a1)、(D1-a)、(I1-a)，
除非有相反的陈述，在本申请说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N， 氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
“卤素”是指F、Cl、Br或I。
“卤素取代的”是指F、Cl、Br或I取代，包括但不限于1至10个选自F、Cl、Br或I的取代基所取代，1至6个选自F、Cl、Br或I的取代基所取代，1至4个选自F、Cl、Br或I的取代基所取代。“卤素取代的”简称为“卤代”。
“烷基”是指取代的或者未取代的直链或支链饱和脂肪族烃基，包括但不限于1至20个碳原子的烷基、1至8个碳原子的烷基、1至6个碳原子的烷基、1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；本文中出现的烷基，其定义与本定义一致。烷基可以是一价、二价、三价或四价。
“环烷基”是指取代的或者未取代的饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。本文中出现的环烷基，其定义如上所述。环烷基可以是一价、二价、三价或四价。
“杂环烷基”是指取代的或者未取代的饱和的含有杂原子的环烃基，包括但不限于3至10个原子、3至8个原子，包含1至3个选自N、O或S的杂原子，杂环烷基的环中选择性取代的N、S可被氧化成各种氧化态。杂环烷基可以连接在杂原子或者碳原子上，杂环烷基可以连接在芳香环上或者非芳香环上，杂环烷基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢-2H-吡喃基、二氧戊环基、二氧六环基、吡咯烷基、哌啶基、咪唑烷基、噁唑烷基、噁嗪烷基、吗啉基、六氢嘧啶基、哌嗪基。杂环烷基可以是一价、二价、三价或四价。
“烷氧基”是指取代的或者未取代的-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。
“碳环基”或“碳环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接在芳香环上或者非芳香环上，芳香环或者非芳香环任选为单环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1- 环己基-3-烯基、环己烯基、苯环、萘环。“碳环基”或“碳环”可以是一价、二价、三价或四价。
“杂环基”或“杂环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，且包含1个或多个(包括但不限于2、3、4或5个)个选自N、O或S的杂原子，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接在芳香环上或者非芳香环上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基。“杂环基”或“杂环”可以是一价、二价、三价或四价。
“缩醛基”是指Ra1选自取代或者未取代的C1-6烷基，或者两个Ra1直接连接成取代或者未取代的环；非限制性实施例包括
指“取代”或“取代的”是指被1个或多个(包括但不限于2、3、4或5个)取代基所取代，取代基包括但不限于H、F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、 环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。
化合物的盐是指游离酸通过与无机碱或者有机碱，游离碱通过与无机酸或者有机酸反应获得的盐。
“醇类溶剂”是指分子结构中含有羟基的溶剂，非限制性实施例包括乙二醇、甲醇、乙醇、正丙醇、异丙醇、正丁醇、正戊醇、仲戊醇、3-戊醇、异戊醇、特戊醇、正己醇和环己醇等。
“醚类溶剂”是指分子结构中醚键的溶剂，非限制性实施例包括四氢呋喃、2-甲基四氢呋喃、乙醚、1,4-二氧六环、甲基叔丁基醚、乙二醇二甲醚、二异丙醚、乙基丁基醚、二丁醚、二戊醚、二乙二醇二甲醚、三甘醇二甲醚和苯甲醚等。
“芳烃类溶剂”是指分子结构中含有0-3个杂原子(杂原子选自O、S或N)芳环的溶剂，非限制性实施例包括苯、吡啶、甲苯、乙苯、二甲苯、氯苯和邻二氯苯等。
“卤代烷烃类溶剂”是指分子结构中含有卤素(氟、氯、溴、碘)的烷烃溶剂，非限制性实施例包括二氯甲烷、1,2-二氯乙烷、氯仿、三氯乙烷、四氯化碳、五氯己烷、1-氯丁烷和三溴甲烷等。
“烷烃类溶剂”是指分子结构中只含有烷烃的溶剂，非限制性实施例包括正己烷、正庚烷、正辛烷、正戊烷、环己烷和环庚烷等。
“酯类溶剂”是指分子结构中含有羧酸酯的溶剂，非限制性实施例包括乙酸乙酯、乙酸异丙酯、三乙酸甘油酯、乙酰乙酸乙酯、乙酸异戊酯、乙酸异丙酯、乙酸正丁酯、乙酸正丙酯、乙酸正戊酯、乙酸甲酯、乙酸仲丁酯、甲酸丁酯、甲酸丙酯、甲酸正戊酯和碳酸二乙酯等。
“酮类溶剂”是指分子结构中含有酮羰基的溶剂，非限制性实施例包括丙酮、丁酮、苯乙酮、甲基异丁基酮、2,6-二甲基-2,5-庚二烯-4-酮、3,5,5-三甲基-2-环己烯酮和异丙叉丙酮等。
“腈类溶剂”是指分子结构中含有氰基的溶剂，非限制性实施例包括乙腈、丙腈、丁腈和苯乙腈等。
“酰胺类溶剂”是指分子结构中含有酰胺的溶剂，非限制性实施例包括N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基乙酰胺、六甲基磷酰胺和N-甲基吡咯烷酮等。
“极性非质子性溶剂”是指不包含直接与负电性原子连接的氢原子，并且不具有氢 键键合能力的溶剂。非限制性实施例包括丙酮、二甲基亚砜、HMF(羟甲基糠醛)、冠醚、乙腈、N,N-二甲基甲酰胺、N,N-二乙基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜或N-甲基-2-吡咯烷酮等。
“极性质子性溶剂”是指能够氢键结合(因为它们包含至少一个直接与负电性原子相连的氢原子(例如O-H或N-H键))的溶剂，非限制性实施例包括甲醇、水、乙醇、氨、乙酸等。
“可选择性地”或“作为选择”意味着随后所描述的事件或环境可以但不必发生，包括该事件或环境发生或不发生的场合。
本发明反应过程通过HPLC、HNMR或薄层色谱法跟踪反应进程，判断反应是否结束。
本发明中,所述内温表示反应体系温度。
本申请中，“V”或“V/M”均是指反应溶剂的体积相对于该步骤投料量为1eq的原料的质量的倍数。
本申请中，实际投料量或得到的产物实际量为：若标注了含量，原料量或产物量＝原料或产物称重量×含量，未标注含量的按照含量为100％计算。
具体实施方式
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SC-A18 100×4.6mm,3.5μM)；


实施例1：D1-a的制备：
第一步：制备I1-a
4-(1,3-二氧戊环-2-基)-1-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌啶
4-(1,3-dioxolan-2-yl)-1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidine(I1-a)
50L反应釜中加入2.20kg J1-a，1.65kg J1-b，4.27kg碳酸铯，20L DMF，开启搅拌，升温至100℃，反应22h，降温至20-30℃，将反应液加入到100L反应釜中，加入50L水，搅拌4h后抽滤，用水漂洗滤饼，60℃烘干得到I1-a，2.59kg，黄色固体，收率83.8％，HPLC纯度95％。
第二步：制备D1-a
4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯胺
4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)aniline
100L反应釜中加入2.59kg I1-a，13L乙醇，13L 1,4-二氧六环，开启搅拌，升温至50-60℃，加入0.26kg 10％Pd/C，0.08kg醋酸，滴加3.88kg三乙基硅氢，反应3h，降温至20-30℃，过滤除掉Pd/C，母液加入30L水和15L二氯甲烷萃取，分液后有机相用30L洗一次，减压浓缩至无溶剂流出，加入10L异丙醇，析出固体，升 温至80℃搅拌2h后降温至5-10℃抽滤，得到D1-a 1.56kg红色固体，收率65.3％，纯度98.3％。
LC-MS:m/z＝359.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.78(s,1H),6.73(s,1H),6.65(s,1H),4.64(d,1H),4.37(s,2H),3.91–3.86(m,2H),3.84(s,3H),3.81–3.77(m,2H),3.75(s,3H),2.93–2.89(m,2H),2.56–2.47(m,2H),1.74–1.63(m,2H),1.59–1.38(m,3H).
实施例2：A1的制备
5-(4-((1-(4-((5-溴-4-((4-环丙基-2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮(化合物A1)
5-(4-((1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步：制备G1-a
将1140.23g K2CO3(3.0eq)和1892.3g(4V/M)纯化水加入到反应釜中，氮气置 换，加入4101.6g(10V/M)甲苯。加入501.15g H-a(含量94.4wt％，折合后为投料量473.08g)，283.47g环丙基硼酸(H1-b)，氮气置换。加入3.57g(0.5mol％)Pd(MeCN)2Cl2，7.30g(1.0mol％)AmgenPhos，加热至内温80℃反应16h。冷却，去除水相，收集有机相，过滤。有机相中加入纯化水萃取分液。氯化钠水溶液洗涤有机相。有机相浓缩至干，向反应器中加入MeCN，加入草酸溶液。搅拌，过滤得滤饼。向反应器中加入湿滤饼、7.1kg水和2.1kg i-PrOAc。加入402.1g NaHCO3，搅拌16小时，分液。向反应釜中加入2.71kg氯化钠水溶液，洗涤有机相，有机相浓缩至干,得G1-a 354.94g，含量为93.59％，收率为90.7％。
HPLC纯度：99.54％。
LCMS m/z＝134.09[M+H]+
第二步：制备F1-a的甲基磺酸盐
将322.89g G1-a(含量93.59％，折算后投料量为302.18g，2268.8mmol)，2359.6g(20V/M)MeCN加入反应釜中。内温降至-25至-20℃。将424.4g NBS(含量为98％，折合后投料量为415.9g,1.03eq)溶解在2359g乙腈中配制成NBS的乙腈溶液。保持内温将NBS乙腈溶液滴加至反应釜，滴加完毕，在-25至-20℃搅拌1h。将反应混合物浓缩至干。加入i-PrOAc，搅拌，过滤，滤液中加入5％NaHCO3水溶液，萃取分液，加入氯化钠水溶液洗涤有机相。有机相中加入428.2g MsOH，搅拌，过滤，干燥，得到F1-a的甲基磺酸盐680.71g，游离碱的含量为65.58％，收率为92.8％。
HPLC:98.46％
LCMS m/z＝213.00[M+H]+
第三步：制备E1-a
将632.8g F1-a(含量65.58％，折算后游离碱为415g)，7511.5g(折算后的20V/M)叔戊醇和1011.7g DIPEA(4eq)加入到反应釜中，氮气置换。加入192.9g(含量95％，折算后投料量183.3g，1.2eq)二甲基氧化膦(F-b)和28.6g(2mol％)Pd(dppf)Cl2，氮气置换，95～100℃反应16h。有机相浓缩至干。加入纯化水，体系浓缩至干。加入3.32kg纯化水，搅拌。过滤，收集水溶液。加入3.74kg乙酸乙酯、104.0gNa2CO3，分液，收集有机相。将有机相浓缩至200-400ml。加入0.15kgMTBE。搅拌，过滤，干燥获得362.52g E1-a，含量为97.52％，收率为86.4％。
HPLC:99.91％
LCMS m/z＝210.10[M+H]+
第四步：制备D1-b
极性非质子溶剂作为反应溶剂示例：20L反应釜中加入825.00g E1-a(3.943mol,1.00eq.)，943.4g 5-溴-2,4-二氯嘧啶(E1-b)(4.140mol,1.05eq.)，4125mL NMP(5V/M)，开启搅拌，加入764.40g N,N-二异丙基乙胺(5.915mol,1.50eq.)，升温至120℃反应4小时，冷却至室温，加入8L饱和食盐水，4L二氯甲烷萃取，分液后水相再用4L二氯甲烷萃取水相一次，合并有机相后用8L饱和食盐水洗4次，有机相减压浓缩浓缩至反应液较浓稠时加入15L异丙醇继续浓缩，浓缩至反应液10L时停止减压浓缩，反应液升温至80℃回流1h，降温至5-10℃搅拌2h析晶，抽滤，滤饼用2L异丙醇漂洗，烘干得到1342.0g D1-b，收率78.3％。
HPLC纯度：98.6％。
1H NMR(400MHz,DMSO-d6)δ11.40-11.50(s,1H),8.40-8.50(s,1H),8.00-8.40(m,1H),7.00-7.50(m,2H),1.80-1.90(m,1H),1.50-1.90(s,6H),0.50-0.90(m,4H)。
LCMS m/z＝400.1[M+H]+
极性质子溶剂作为反应溶剂示例：3L反应瓶中加入300.05g E1-a(1.434mol,1.00eq.)，359.49g 5-溴-2,4-二氯嘧啶(E1-b)(1.577mol,1.10eq.)，1500mL异丙醇(5V)，开启搅拌，加入203.99g N,N-二异丙基乙胺(1.577mol,1.10eq.)，升温至75-85℃反应7小时，降温至3℃，保温析晶4h，抽滤，滤饼用300mL异丙醇(1V)漂洗，烘干得到523.49g D1-b，收率91％。
HPLC纯度：99.54％。
第五步：制备C1-a和C1-a1
(2-((2-((4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)氨基)-5-溴嘧啶-4-基)氨基)-5-环丙基苯基)二甲基氧化磷(C1-a)
(2-((2-((4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide
(2-((2-((4-(4-(双(2-羟基乙氧基)甲基)哌啶-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)氨基)-5-溴嘧啶-4-基)氨基)-5-环丙基苯基)二甲基氧化磷(C1-a1)
(2-((2-((4-(4-(bis(2-hydroxyethoxy)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide
5L四口瓶中，加入150.00g D1-b(0.374mol,1.0eq.)，134.20g D1-a(0.374mol,1.0eq.)，1.5L乙二醇(15V/M)，开启搅拌，加入17.97g对甲苯磺酸一水合物(0.187mol,0.5eq.)，体系升温至85-90℃，反应22h。冷却至室温，加入饱和碳酸氢钠水溶液将pH调至7-8，加入二氯甲烷萃取，分液后水相用二氯甲烷萃取一次，合并有机相，加入饱和氯化钠溶液洗涤两次有机相，减压浓缩有机相至无溶剂流出，加入750ml(5V/M)乙腈升温至80℃回流(有白色固体析出)，搅拌1-2h，降温至5-10℃保温2h析晶，抽滤，滤饼用乙腈漂洗，得C1-a和C1-a1混合物，干燥得到235g，收率86.9％(以C1-a分子量计算)。
HPLC:C1-a：88.17％，C1-a1：10.58％，合并纯度为98.7％。
1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.17–8.14(m,3H),7.93(s,1H),7.88(s,1H),7.57(s,1H),7.22(dd,1H),6.79(s,1H),6.45(br.s,1H),4.68(d,1H),3.92–3.89(m,2H),3.88–3.78(m,5H),3.78(s,3H),3.09(d,2H),2.59(t,2H),1.85–1.73(m,3H),1.76(s,3H),1.73(s,3H),1.61–1.47(m,3H),0.91–0.86(m,2H),0.51–0.47(m,2H).
C1-a：LCMS m/z＝722.21[M+H]+
1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.21–8.09(m,3H),7.96(s,1H),7.88(s,1H),7.58(s,1H),7.22(dd,1H),6.79(s,1H),6.46(br.s,1H),4.58(t,1H),4.37(d,1H),4.32(t,1H),3.84(s,3H),3.78(s,3H),3.64–3.59(m,2H),3.56–3.39(m,6H),3.09(d,2H),2.61–2.52(m,2H),1.84–1.77(m,3H),1.76(s,3H),1.73(s,3H),1.70–1.61(m,1H),1.51–1.38(m,2H),0.94–0.83(m,2H),0.54–0.45(m,2H).
C1-a1：LCMS m/z＝784.25[M+H]+
第六步：制备B1-b
1-(4-((5-溴-4-((4-环丙基-2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-甲醛(B1-b)
1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine-4-carbaldehyde
3L三口瓶中，加入150ml浓盐酸，1600ml水(配成1N HCl)，开启搅拌，控温20-25℃，加入70g上步制得的C1-a和C1-a1混合物(0.554mol,以C1-a分子量计算，1.0eq.)，20-30℃反应20h，加入1000ml二氯甲烷，用碳酸氢钠将pH调至7-8，分液，有机相减压浓缩至无溶剂流出，加入210ml乙腈(3V/M)升温至80℃回流搅拌，降温析晶，抽滤，滤饼用100ml乙腈漂洗，烘干得到56.40g B1-d，收率85.8％。
HPLC:97.4％
1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),9.69(s,1H),8.17–8.14(m,3H),7.97(s,1H),7.85(s,1H),7.59(s,1H),7.22(dd,1H),6.79(s,1H),6.46(br.s,1H),3.84(s,3H),3.78(s,3H),3.07–3.02(m,2H),2.70(td,2H),2.42(dq,1H),2.00–1.89(m,2H),1.81–1.78(m,1H),1.76(s,3H),1.76–1.73(m,2H),1.73(s,3H),0.94–0.83(m,2H),0.50(dt,2H).
LCMS m/z＝678.19[M+H]+
第七步：制备A1
B1-a盐酸盐示例：3000ml三口瓶中，加入122g B1-b(180mmol,1.0eq.)，81.73g B1-a(216mmol,1.2eq.，B1-a为盐酸盐)，1220ml N,N-二甲基乙酰胺(15V/M)，开启搅拌，降温至-15～-10℃保温30min，控制温度-15～-10℃加入57.16g三乙酰氧基硼氢化钠(270mmol,1.5eq.)溶于610ml N,N-二甲基乙酰胺(5V/M)，保温反应2h，加入100ml水析出固体，加入100ml二氯甲烷萃取两次，合并有机相，减压浓缩至无溶剂流出，加入2440ml四氢呋喃(20V/M)升温至60℃，保温1h，降温，抽滤，干燥，得到153.5g A1，收率85％。
HPLC:98.6％
1H NMR(400MHz,D2O/CF3COOD(v/v＝1:1))δ8.23(s,1H),7.96–7.75(m,5H),7.46(s,1H),7.35(s,1H),7.31–7.15(m,2H),6.91(d,1H),5.12(dd,1H),4.22–4.07(m,5H),4.03(s,3H),3.93–3.70(m,6H),3.62-3.48(m,2H),3.39–3.18(m,4H),2.95–2.85(m,2H),2.82–2.67(m,1H),2.63–2.44(m,1H),2.37–2.16(m,3H),2.12–1.88(m,9H),1.19–1.08(m,2H),0.73–0.65(m,2H)。
LCMS m/z＝1004.33[M+H]+
B1-a甲磺酸盐示例：250ml三口瓶中，加入15.00g B1-b(22.1mmol,1.0eq.)，11.63g B1-a(26.5mmol,1.2eq.，B1-a为甲磺酸盐)，150ml N,N-二甲基乙酰胺(10V/M)，开启搅拌，降温至10～20℃保温2h，控制温度-10～0℃加入7.03g三乙酰氧基硼氢化钠(33.2mmol,1.5eq)，保温反应2h，加入900ml水和450ml二氯甲烷，水相用450mL二氯甲烷萃取一次，合并有机相，有机相用450mL水和225mL二氯甲烷洗1次，减压浓缩干，加入300ml四氢呋喃(20V/M)升温至60℃，保温1h，降温，抽滤，干燥，得到67.48g A1，收率85％。
HPLC:99％
实施例3：C1-a/C1-a1的制备
制备方法：按照实施例2第五步的方法制备，不同催化体系、条件反应结果如下表1。
表1不同催化体系、条件下反应结果(反应时间22h)

注：溶剂量：溶剂的体积相对于D1-b的投料质量的倍数。
结论：使用醋酸、Py HCl、PPTS、Et3N HCl、TsOH.H2O、三氟乙酸、磷酸、MsOH作为酸催化剂，反应温度为80℃～110℃，D-b：D-a：酸的摩尔比为(0.2～1.5):1.0:1.0，产物C1-a/C1-a1比例高，反应效果好。
实施例4：B1-b制备
按照实施例2第六步的方法制备，不同条件反应结果如下表2。
表2不同条件反应结果

r.t代表室温，温度为20-30℃
*(C1-a+C1-a1)的摩尔量以C1-a分子量计算。
结论：由表2可知使用盐酸、TsOH作为酸性试剂，取得好的效果。
实施例5：A1制备
按照实施例2第七步的方法制备，不同条件下其反应结果见表3：
表3不同条件下制备A1的反应结果
还原剂选自三乙酰氧基硼氢化钠时，三乙酰氧基硼氢化钠：B-b的摩尔比为(1.0～2.0):1，B-a:B-b的摩尔比为(0.9～1.5):1.0，反应能取得好的效果。
实施例6：G1-a制备
参照实施例2第一步的制备方法，不同条件下反应结果见表4-1和表4-2，
表4-1含膦的金属催化剂的催化体系不同条件下反应结果
结论：由表4-1可以得出，含膦的金属催化剂在不同的溶剂(如甲苯/水、CPME/水、叔戊醇/水、异丙醇/水、DMAc/水)下均能实现高转化率，G1-a(％)大于85％。
将序号16条件进行放大，H-a的投料量为20mmol，其余条件同序号16，经过常规分离提纯后得到2.6g G1-a(HPLC纯度97.46％)，分离收率为95％。
表4-2无膦的金属催化剂/膦配体的催化体系反应结果(溶剂均为甲苯/水，溶剂量为10V/4V，时间16h)

结论：由表4-2可以得出，无膦的金属催化剂与不同的膦配体试剂(如AmgenPhos、dtbpf、Catacxium PtB)组合成的催化体系在不同的温度(如70℃、80℃、95℃)、无膦的金属催化剂的催化用量(如0.2mol％、0.3mol％、0.4mol％、0.6mol％、0.8mol％、1mol％)均能实现高转化率，G1-a(％)大于85％。
实施例7：F1-a制备
参照实施例2第二步操作，不同反应条件的反应结果见表5，反应中检测到主要副产物为F1-a1。
表5不同条件下的反应结果

注：“-”表示未统计。
由表5可知，G1-a与NBS的摩尔比为1:(1.0～1.2)，溶剂为乙腈，反应温度为-30℃～0℃，反应能取得好的效果。
实施例8：E1-a的制备
与实施例2第三步操作相同，对不同的反应条件进行了筛选，结果见表6-1与表6-2。
表6-1不同碱性试剂与金属催化剂(95℃，反应时间16h,溶剂用量为30V)的反应结果



*反应温度为105℃；**反应温度为95-100℃。
由表6-1可以得出：
1)无膦的金属催化剂(如Pd(OAc)2、[(cinnamyl)PdCl]2、[PdCl(C3H5)]2、Pd(MeCN)2Cl2、Pd(TFA)2、Pd2(dba)3)与膦配体试剂dppf或dppb组合成的催化体系在不同的碱性试剂(如Cy2NMe、DIPEA、Et3N、Cs2CO3、K3PO4)与不同溶剂(t-AmylOH、DMF、DMAc)均能实现高转化率，E1-a(％)大于85％；
2)无膦的金属催化剂的催化用量(如0.8mol％、1mol％、1.2mol％、1.5mol％、2mol％、4mol％)均能实现高转化率，E1-a(％)大于85％。
表6-2 Pd(dppf)Cl2作为金属催化剂的反应结果(溶剂为t-AmylOH(20V/M)，反应时间16h)
由表6-2可以得出：
金属催化剂Pd(dppf)Cl2在不同的用量(如1mol％、1.5mol％、2mol％)与碱性试 剂(如DIPEA、Cy2NMe)能实现高转化率，E1-a(％)大于85％。
生物测试例
测试例1：NCI-H1975(EGFR-L858R-T790M)和A431(EGFR-WT)细胞的增殖抑制活性
NCI-H1975(EGFR-L858R-T790M)和A431(EGFR-WT)细胞购自于ATCC，培养基分别为RPMI1640+10％FBS和DMEM+10％FBS，于37℃，5％CO2孵箱中培养。第一天，收集处于指数生长期的NCI-H1975(EGFR-L858R-T790M)和A431(EGFR-WT)细胞，用自动细胞分析仪(countstar)进行活细胞计数。用培养基将细胞悬液调整后铺板96孔细胞培养板，NCI-H1975(EGFR-L858R-T790M)细胞每孔1000个，A431细胞每孔3000个。第二天，吸去培养基，每孔加入90μL新鲜培养基和10μL不同浓度化合物，每孔DMSO终浓度为0.1％。于37℃，5％CO2孵箱中培养72小时。药物处理72小时后，每孔加入50μL预先融化并平衡到室温的CTG溶液(promega，G7572)，用微孔板震荡器混匀2min，于室温放置10min后用酶标仪(PHERAstar FSX)测定荧光信号值。
细胞存活率用公式Vsample/Vvehicle control x100％计算。其中Vsample为药物处理组的读数，Vvehicle control为溶剂对照组的平均值。应用origin9.2软件,使用非线性回归模型绘制S型剂量-存活率曲线并计算IC50值。
表7测试化合物对NCI-H1975(EGFR-L858R-T790M)细胞的增殖抑制活性结果
测试化合物对A431(WT)细胞的增殖抑制活性：化合物A1对A431(EGFR-WT)细胞增殖抑制活性IC50≥10μM。
结论：本发明化合物对NCI-H1975(EGFR-L858R-T790M)细胞具有良好的增殖抑制活性；对A431(EGFR-WT)细胞增殖抑制活性差，具有良好的选择性。
测试例2:对细胞NCI-H1975 EGFR-L858R-T790M-C797S的增殖抑制活性
细胞NCI-H1975 EGFR-L858R-T790M-C797S培养于37℃，5％CO2孵箱中，培养基为RPMI1640+10％FBS+100μg/mL潮霉素。收集处于指数生长期的细胞，用不含潮霉素的培养基将细胞悬液调整到适当浓度后铺板96孔板，铺板密度为1500个/ 孔，体积90μL。加入10μL不同浓度的化合物，并设置细胞加DMSO的溶媒对照组，DMSO的浓度均为0.1％。细胞培养板置于37℃，5％CO2孵箱中培养72小时。培养结束后，按照CellTiter-Glo试剂盒(Promega，G7572)操作说明，每孔加入50μL预先融化并平衡到室温的CTG溶液，用微孔板震荡器混匀2min，于室温放置10min后用酶标仪(Envision2104)测定荧光信号值。细胞存活率(Surviving cells％)数据采用式(2)处理，并使用GraphPad Prism 5.0软件，使用非线性回归模型绘制S型剂量-存活率曲线并计算IC50值。其中Vsample为药物处理组的读数，Vvehicle control为对照组的读数。
Surviving cells％＝Vsample/Vvehicle control x100％  (式2)
表8化合物对细胞NCI-H1975 EGFR-L858R-T790M-C797S的增殖抑制活性
结论：本发明化合物对细胞NCI-H1975 EGFR-L858R-T790M-C797S具有良好的增殖抑制活性。

Claims (15)

  1. 一种化合物(A)的制备方法，化合物(B-a)或其与酸性试剂1形成的盐与化合物(B-b)在还原剂存在下反应得到化合物(A)，
    当化合物(B-a)以游离碱形式反应时，反应中进一步加入pKa≤5的酸性试剂2；
    R1选自H、卤素、C1-4烷基、C1-4烷氧基、C3-6碳环基、4至6元杂环基，所述的烷基、烷氧基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    R2选自卤素、C1-4烷基、C1-4烷氧基，所述的烷基或烷氧基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    R3选自H、C1-4烷基、C1-4烷氧基、-O-C3-6环烷基，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    R4选自H、C1-4烷基、C1-4烷氧基、-O-C3-6环烷基、C3-6环烷基、4至6元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    R5选自H、F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代。
  2. 根据权利要求1所述的制备方法，
    所述还原剂选自硼还原剂，优选醋酸硼氢化钠、硼氢化钠、氰基硼氢化钠、9-硼双环[3.3.1]壬烷、2-甲基吡啶硼烷、三乙酰氧基硼氢化钠、硼氢化钾或硼氢化锂中的一种或多种；
    所述的酸性试剂1选自盐酸、甲基磺酸、氢溴酸、对甲苯磺酸、苯磺酸或三氟乙酸；
    所述的酸性试剂2选自醋酸或甲酸中的一种或多种；
    反应所使用的溶剂选自极性非质子性溶剂或非极性溶剂中的一种或多种，优选N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二氯甲烷、1,2-二氯乙烷、乙酸乙酯、甲基叔丁基醚、二甲亚砜、乙腈、乙醚、四氢呋喃中的一种或多种。
  3. 一种式(B-b)所示化合物的制备方法，化合物(C-a)在酸性试剂存在下反应得化合物(B-b)所示化合物；
    R1、R2、R3、R4的定义与其在权利要求1中的定义相同；
    R6为缩醛基，优选为
  4. 根据权利要求3所述的制备方法，
    所述酸性试剂选自盐酸、对甲苯磺酸、醋酸、硫酸、三氟乙酸、甲酸、氢溴酸或甲基磺酸中的一种或多种，优选为盐酸；
    反应所使用的溶剂选自极性非质子性溶剂或极性质子性溶剂，优选N,N-二甲基甲酰胺、N-甲基吡咯烷酮、乙腈、四氢呋喃、2-甲基四氢呋喃、丙酮、水中的一种或多种，更优选水、水/四氢呋喃、水/丙酮、水/N,N-二甲基甲酰胺、水/乙腈、水/2-甲基四氢呋喃。
  5. 一种化合物(C-a)的制备方法，化合物(D-b)与化合物(D-a)在酸性催化剂存在下反应得到化合物(C-a)；
    R1、R2、R3、R4的定义与其在权利要求1中的定义相同；
    R6的定义与权利要求3相同；
    X为离去基团，优选F、Cl、Br或I。
  6. 根据权利要求5所述的制备方法，
    所述酸性催化剂选自甲基磺酸、对甲苯磺酸、三氟乙酸、醋酸、盐酸、氢溴酸、硫酸、乙二磺酸、氢碘酸、磷酸、氯化锌、醋酸锌、吡啶盐酸盐、4-甲基苯磺酸吡啶、三乙胺盐酸盐、草酸、三氯化铝、三氟化硼中的一种或多种；
    反应所使用的溶剂选自酰胺类溶剂、烷烃类溶剂、卤代烷烃类溶剂、醇类溶剂、酮类溶剂、酯类溶剂、醚类溶剂、腈类溶剂、砜类溶剂和水中的一种或多种，优选N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二氯甲烷、1,2-二氯乙烷、乙酸乙酯、丙酮、甲醇、乙醇、异丙醇、正丁醇、三氟乙醇、乙二醇、正丁酮、甲基叔丁基醚、二甲亚砜、乙腈、乙醚、四氢呋喃和水中的一种或多种。
  7. 一种化合物(D-b)的制备方法，化合物(E-a)和化合物(E-b)在碱性试剂存在下反应得到化合物(D-b)；
    其中，R1、R2的定义与其在权利要求1中的定义相同；
    X的定义与权利要求5相同；
    Y为离去基团，优选I、Br、Cl、OTf；
    所述碱性试剂选自碳酸氢钠、碳酸钠、磷酸氢二钾、碳酸氢钾、碳酸钾、碳酸锂、碳酸铯、甲醇钠、乙醇钠、甲醇钾、乙醇钾、叔丁醇钠、叔丁醇钾、磷酸钾、氢化钠、氢氧化钠、氢氧化钾、N,N-二异丙基乙胺、三乙胺或1,8-二氮杂二环十一碳-7-烯中的一种或多种；
    反应中使用的溶剂选自极性非质子性溶剂或极性质子溶剂；
    所述E-a和E-b的摩尔比为1.0:(1.1～1.5)。
  8. 根据权利要求7所述的制备方法，
    X选自Cl；
    所述极性非质子性溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二氯甲烷、1,2-二氯乙烷、乙酸乙酯、乙酸异丙酯、丙酮、正丁酮、甲基叔 丁基醚、二甲亚砜、乙腈、乙醚、四氢呋喃、2-甲基四氢呋喃或甲苯中的一种或多种，优选为N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜中的一种或多种，更优选为N-甲基吡咯烷酮；
    所述极性质子性溶剂选自异丙醇、甲醇或乙醇中的一种或多种，更优选为异丙醇；
    所述碱性试剂选自碳酸氢钠、碳酸钠、磷酸氢二钾、碳酸氢钾、碳酸钾、碳酸锂、碳酸铯、磷酸钾、氢化钠、氢氧化钠、氢氧化钾、N,N-二异丙基乙胺、三乙胺或1,8-二氮杂二环十一碳-7-烯中的一种或多种，优选为N,N-二异丙基乙胺。
  9. 一种化合物(E-a)的制备方法，化合物(F-a)或其盐和化合物(F-b)在钯催化体系、碱性试剂存在下反应得化合物(E-a)，
    R1的定义与其在权利要求1中的定义相同；
    所述的钯催化体系选自钯催化剂/膦配体或Pd(dppf)Cl2，
    所述钯催化剂选自[(cinnamyl)PdCl]2、Pd(OAc)2、Pd(MeCN)2Cl2、Pd2dba3、Pd(TFA)2、[PdCl(C3H5)]2中的一种或多种，所述膦配体选自dppf、dppb、dppp、DPEPhos中的一种或多种；
    所述碱性试剂选自DIPEA、TEA、Cy2NMe、Cy2NH、二乙胺中的一种或多种；
    反应中使用的溶剂选自t-AmylOH、DMF、MeCN中的一种或多种。
  10. 一种化合物(F-a)的制备方法，化合物(G-a)与溴化试剂反应得化合物(F-a)，
    其中，R1的定义与其在权利要求1中的定义相同；
    所述溴化试剂选自NBS或Br2；
    反应中的溶剂选自乙腈；
    反应温度为-30℃～0℃，优选为-25℃～-5℃。
  11. 一种化合物(G-a)的制备方法，化合物(H-a)和化合物(H-b)在钯催化体系和碱性试剂的存在下反应得化合物(G-a)；
    其中，R1的定义与其在权利要求1中的定义相同；
    所述的钯催化体系选自钯催化剂/膦配体、Pd(dppf)Cl2、Pd(dtbpf)Cl2、SPhosPdG2、cataCXiumAPdG2、[Pd(amphos)2Cl2]、RuPhosPdG2、SPhosPdG2中的一种或多种，所述的钯催化剂选自[(cinnamyl)PdCl]2、Pd(OAc)2、Pd(MeCN)2Cl2、Pd2dba3、Pd(TFA)2、[PdCl(C3H5)]2中的一种或多种，所述膦配体选自dppf、dppb、dppp、dtbpf、Catacxium PtB、DPEPhos、AmgenPhos中的一种或多种；
    所述碱性试剂选自K2CO3、K3PO4、DIPEA、TEA、Cy2NMe、Cy2NH、二乙胺中的一种或几种多种；
    反应中的溶剂选自t-AmylOH、DMF、MeCN、甲苯、CPME、DMAc、i-PrOH、MeCN和水中的一种或多种。
  12. 一种化合物(D-a)制备方法，其是由化合物(I-a)经过还原体系还原制得，其中，
    R3、R4的定义与其在权利要求1中相应的定义相同；
    R6的定义与其在权利要求8中的定义相同；
    所述还原体系包括还原剂、催化剂，
    所述还原剂选自H2、三乙基硅氢、硼氢化钠；所述催化剂选自Pd、Pd/C、Au、Pt、Ni；
    所述催化剂还包括酸催化剂，优选自醋酸；
    反应中的溶剂选自甲醇、乙醇、1,4-二氧六环、水、乙酸乙酯、四氢呋喃、乙腈、2-甲基四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中的一种或多种。
  13. 一种化合物(I-a)制备方法，化合物(J-a)和化合物(J-b)在碱性试剂存在下反应 得到化合物(I-a)，
    R3、R4的定义与其在权利要求1中相应的定义相同；
    R6的定义与其在权利要求8中的定义相同；
    所述碱性试剂选自碳酸氢钠、碳酸钠、磷酸氢二钾、碳酸氢钾、碳酸钾、碳酸锂、碳酸铯、甲醇钠、乙醇钠、甲醇钾、乙醇钾、叔丁醇钠、叔丁醇钾、磷酸钾、氢化钠、氢氧化钠、氢氧化钾、N,N-二异丙基乙胺、三乙胺或1,8-二氮杂二环十一碳-7-烯中的一种或多种；
    反应中使用的溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二氯甲烷、1,2-二氯乙烷、乙酸乙酯、乙酸异丙酯、丙酮、正丁酮、甲基叔丁基醚、二甲亚砜、乙腈、乙醚、四氢呋喃、2-甲基四氢呋喃或甲苯中的一种或多种，优选为N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜中的一种或多种，更优选N,N-二甲基甲酰胺。
  14. 一种化合物，化合物选自化合物(B-b)、化合物(C-a)，
    R1、R2、R3、R4的定义与其在权利要求1中相应的定义相同；
    R6的定义与其在权利要求8中的定义相同。
  15. 一种化合物，化合物选自化合物(D-a)，化合物(I-a)，
    R3选自C1-4烷氧基、-O-C3-6环烷基，所述的烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    R4选自H、C1-4烷基、C1-4烷氧基、-O-C3-6环烷基、C3-6环烷基、4至6元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；
    R6的定义与其在权利要求8中的定义相同。
PCT/CN2023/125384 2022-10-20 2023-10-19 一种膦酰衍生物的制备方法 WO2024083182A1 (zh)

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