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WO2021047616A1 - 氧氮杂环庚烷类螺环化合物、中间体及其制备方法 - Google Patents

氧氮杂环庚烷类螺环化合物、中间体及其制备方法 Download PDF

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WO2021047616A1
WO2021047616A1 PCT/CN2020/114629 CN2020114629W WO2021047616A1 WO 2021047616 A1 WO2021047616 A1 WO 2021047616A1 CN 2020114629 W CN2020114629 W CN 2020114629W WO 2021047616 A1 WO2021047616 A1 WO 2021047616A1
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温剑锋
冯建鹏
吴清泉
王传申
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苏州亚盛药业有限公司
亚盛医药集团(香港)有限公司
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Definitions

  • the invention belongs to the field of medicinal chemistry and relates to an oxazepane type spiro compound, an intermediate and a preparation method thereof.
  • the oxazepine spiro compound is an important nitrogen-containing heterocyclic compound, and its structure is Many drugs and their intermediates contain the above structural units, for example:
  • 6-chloro-3,4-dihydro-1(2H) naphthone can obtain epoxy compound in the presence of trimethylsulfonium iodide, and obtain aldehyde group by the action of boron trifluoride ether.
  • the compound is in the presence of diethylene glycol and formaldehyde to obtain glycol compounds, continue to add 4-bromobenzoyl chloride to obtain monosubstituted ester compounds, and then in the presence of the oxidant Dess-Martin periodinane, the alcohol hydroxyl group is oxidized Formed into an aldehyde group, in the presence of p-toluenesulfonic acid and trimethyl orthoformate to form a ketone group protection, and then etherified with 4-fluoro-3-nitro-benzoic acid tert-butyl ester, and then added trifluoromethane
  • the erbium sulfonate hydrate is converted into an aldehyde compound, the nitro group is reduced, and the intramolecular reductive amination is used to obtain the oxazepane spiro compound.
  • This route requires a large number of reaction materials, a long route, post-processing requires column chromatography, poor stereo selectivity,
  • the invention provides an oxazepane spirocyclic compound, an intermediate and a preparation method thereof.
  • the present invention provides a method for preparing a compound represented by formula 7a or formula 8a,
  • the preparation method of the compound represented by formula 7a includes the following steps: in an organic solvent, the compound represented by formula 6 and the chiral resolving agent X 1 are subjected to the salt formation reaction shown below; Wherein, X 1 is a chiral resolving agent of R configuration;
  • the method for preparing the compound represented by formula 8a includes the following steps: in an organic solvent, the compound represented by formula 6 and the chiral resolving agent X 2 are subjected to the salt-forming reaction shown below; wherein, X 2 is a chiral resolving agent with S configuration;
  • R 1-1 , R 1-2 , R 1-3 and R 1-4 are independently a hydroxyl group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 3 -C 5 ring Alkyl group or NR 1-1a R 1-1b ;
  • R 1-1a and R 1-1b are independently hydrogen or a C 1 -C 4 alkyl group.
  • the number of R 1-1 can be one or more, such as 1, 2 or 3, when there are multiple R 1- At 1 , the R 1-1 may be the same or different.
  • the number of R 1-2 can be one or more, such as 1, 2 or 3, when there are multiple R 1- At 2 , the R 1-2 can be the same or different.
  • the number of R 1-3 can be one or more, such as 1, 2 or 3, when there are multiple R 1- At 3 , the R 1-3 can be the same or different.
  • the halogen may be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • the C 1 -C 4 alkyl groups may be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the C 1 -C 4 haloalkyl group is preferably substituted by 1, 2 or 3 halogens, and the halogens can be fluorine, chlorine, bromine. Or iodine, the C 1 -C 4 haloalkyl group is preferably -CHF 2 or -CF 3 .
  • the The C 1 -C 4 alkoxy group may independently be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy .
  • R 1 , R 2 , R 3 and R 4 is independently hydrogen and halogen.
  • the compound represented by formula 7a is preferably a compound represented by formula 7a-1,
  • the compound represented by formula 8a is preferably a compound represented by formula 8a-1,
  • the chiral resolving agent of R configuration can be a chiral resolving agent of R configuration conventional in the art, preferably R configuration.
  • Amine chiral resolving agents such as (R)-1-(1-naphthyl)-ethylamine, (R)-phenethylamine, (R)-phenylalanine, (R)-N-benzyl Phenylethylamine or (R)-quinidine, more preferably (R)-1-(1-naphthyl)-ethylamine.
  • the chiral resolving agent of S configuration can be a conventional chiral resolving agent of S configuration in the art, preferably S configuration Amine chiral resolving agents, such as (S)-1-(1-naphthyl)-ethylamine, (S)-phenethylamine, (S)-phenylalanine, (S)-N-benzyl Phenylethylamine or (S)-quinidine, more preferably (S)-1-(1-naphthyl)-ethylamine.
  • Amine chiral resolving agents such as (S)-1-(1-naphthyl)-ethylamine, (S)-phenethylamine, (S)-phenylalanine, (S)-N-benzyl Phenylethylamine or (S)-quinidine, more preferably (S)-1-(1-naphthyl)-ethylamine
  • the organic solvent can be a conventional solvent in the art, preferably a C 1 -C 4 alcohol solvent and/or ester solvent, and more preferably an ester solvent.
  • Class solvent preferably one or more of methanol, ethanol and isopropanol (IPA).
  • the ester solvent is preferably ethyl acetate.
  • the molar ratio of the compound represented by formula 6 to the chiral resolving agent can be a conventional molar ratio in the art, preferably 1:1-1 :5, more preferably 1:1-1:3, still more preferably 1:1-1:1.5, such as 1:1.
  • the mass-volume ratio of the compound represented by formula 6 and the organic solvent may be a conventional mass-volume ratio in the art, preferably 1:1 -1:10g/mL, more preferably 1:1-1:6g/mL, for example 1:5.2g/mL.
  • the temperature of the salt formation reaction can be a conventional temperature in the art, preferably 20-30°C.
  • the progress of the salt-forming reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS), and the reaction is The time is preferably 1-5h, for example 3h.
  • the salt-forming reaction is completed and before the neutralization reaction operation, it may further include a post-treatment operation.
  • the post-treatment operation includes the following steps: filtering the reaction solution, and recrystallizing the filtered cake.
  • the filtration is preferably suction filtration.
  • the recrystallization operation can be a conventional operation in the field.
  • the solvent for the recrystallization is preferably an alcohol solvent (such as ethanol) and water, and the volume ratio of the alcohol solvent to water is preferably 5:1-15:1. (E.g. 10:1).
  • the method for preparing the compound represented by formula 6 may include the following steps: in an organic solvent, in the presence of a reducing agent, The compound shown is subjected to the reduction reaction shown below to obtain the compound shown in formula 6;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the organic solvent may be a conventional organic solvent in the art, preferably C 1 -C 4 alcohol solvents, ester solvents, ether solvents, ketone solvents One or more of nitrile solvents, amide solvents and sulfoxide solvents, more preferably C 1 -C 4 alcohol solvents.
  • the C 1 -C 4 alcohol solvent is preferably one or more of methanol, ethanol and isopropanol, more preferably isopropanol.
  • the ester solvent is preferably ethyl acetate.
  • the ether solvent is preferably diethyl ether and/or tetrahydrofuran (THF).
  • the ketone solvent is preferably acetone and/or 2-butanone.
  • the nitrile solvent is preferably acetonitrile.
  • the amide solvent is preferably N,N-dimethylformamide (DMF).
  • the sulfoxide solvent is preferably dimethyl sulfoxide (DMSO).
  • the reducing agent can be a reducing agent commonly used in the art, preferably an alkali metal hydride.
  • the alkali metal hydride can be lithium aluminum hydride (LiAlH 4 ), lithium borohydride (LiBH 4 ), sodium borohydride (NaBH 4 ), potassium borohydride (KBH 4 ), diisobutyl aluminum hydride [(i -Bu) 2 AlH], sodium cyanoborohydride (NaBH 3 CN), sodium thioborohydride (NaBH 2 S 3 ) and lithium tri-sec-butyl borohydride [LiBH(CH 3 CH 2 CH(CH 3 )) 3 ], preferably one or more of lithium borohydride, sodium borohydride and potassium borohydride, more preferably lithium borohydride.
  • the mass-volume ratio of the compound represented by formula 5 and the organic solvent may be a conventional mass-volume ratio in the art, preferably 1:10-1: 20 g/mL, more preferably 1:10-1:15 g/mL, for example 1:13.3 g/mL.
  • the molar ratio of the compound represented by formula 5 to the reducing agent can be a conventional molar ratio in the art, preferably 1:1-1:5, More preferably 1:1-1:2, for example 1:2.
  • the temperature of the reduction reaction may be a temperature conventional in the art, preferably -5-30°C, more preferably 20-30°C, for example 20°C or 25°C.
  • the progress of the reduction reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS), and the time of the reduction reaction is preferably 1 -3h, such as 2h or 2.5h.
  • the post-treatment operation includes the following steps: cooling the reaction liquid to -10-0°C (for example -5°C), adjust the pH to 1-2 with acid (preferably hydrochloric acid, such as 1N hydrochloric acid), add organic solvent (preferably ester solvent, such as ethyl acetate), then add water, and separate Take the water layer, extract (the extraction solvent is preferably an ester solvent, such as ethyl acetate) the water layer and collect the organic layer, wash (the washing solvent is preferably brine, such as saturated brine), dry, and concentrate.
  • acid preferably hydrochloric acid, such as 1N hydrochloric acid
  • organic solvent preferably ester solvent, such as ethyl acetate
  • the preparation method of the compound represented by formula 5 may further include the following steps: in the solvent, in the presence of a base, the compound represented by formula 4 is carried out as follows The hydrolysis reaction yields the compound represented by formula 5;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the solvent is preferably a C 1 -C 4 alcohol solvent, ester solvent, ether solvent, ketone solvent, nitrile solvent, amide solvent or sub One or more of the sulfone solvents, more preferably a C 1 -C 4 alcohol solvent.
  • the C 1 -C 4 alcohol solvent is preferably one or more of methanol, ethanol and isopropanol, more preferably ethanol.
  • the ester solvent is preferably ethyl acetate.
  • the ether solvent is preferably diethyl ether and/or tetrahydrofuran.
  • the ketone solvent is preferably acetone and/or 2-butanone.
  • the nitrile solvent is preferably acetonitrile.
  • the amide solvent is preferably N,N-dimethylformamide.
  • the sulfoxide solvent is preferably dimethyl sulfoxide.
  • the base may be a conventional base in the art, such as an inorganic base.
  • the inorganic base is preferably an alkali metal carbonate and/or alkali metal hydroxide, more preferably an alkali metal hydroxide, and the alkali metal carbonate is preferably K 2 CO 3 and/or Cs 2 CO 3 , so
  • the alkali metal hydroxide is preferably one or more of LiOH, NaOH and KOH.
  • the mass-volume ratio of the compound represented by formula 4 to the solvent is preferably 1:1-1:20 g/mL, more preferably 1:5-1 :13g/mL, for example 1:5g/mL, 1:6g/mL or 1:13g/mL.
  • the molar ratio of the compound represented by formula 4 to the base is preferably 1:1-1:5, more preferably 1:1-1:3, For example 1:2.9.
  • the temperature of the hydrolysis reaction can be a conventional temperature in the art, for example, -5°C to 30°C, preferably 20°C to 30°C.
  • the progress of the hydrolysis reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS), and the time of the hydrolysis reaction is preferably 1 -3h, more preferably 2-3h.
  • the post-treatment operation includes the following steps: cooling the reaction liquid to -10-0°C (for example -5°C), add acid (preferably hydrochloric acid, such as 1N hydrochloric acid) to adjust the pH to 1-2, extract with an organic solvent (preferably halogenated hydrocarbon solvent, such as dichloromethane), and combine the organic layers , Wash (the washing solvent is preferably saline, such as saturated saline), dry, and concentrate.
  • acid preferably hydrochloric acid, such as 1N hydrochloric acid
  • organic solvent preferably halogenated hydrocarbon solvent, such as dichloromethane
  • the method for preparing the compound represented by formula 4 may further include the following steps: in the presence of an acid and an oxidizing agent under a protective gas atmosphere, The compound shown below undergoes the intramolecular cyclization reaction shown below to obtain the compound shown in formula 4;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the protective gas can be a conventional protective gas in the art, such as nitrogen or argon.
  • the acid may be a conventional acid in the art, such as an inorganic acid and/or an organic acid.
  • the inorganic acid is preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
  • the organic acid is preferably formic acid and/or acetic acid.
  • the oxidant may be a single-electron oxidant, and the single-electron oxidant may be a conventional single-electron oxidant in the art, preferably a manganese salt and/or a cerium salt.
  • the manganese salt is preferably manganese acetate.
  • the cerium salt is preferably cerium ammonium nitrate.
  • the intramolecular cyclization reaction can also be carried out with the participation of copper salt.
  • the copper salt may be a conventional copper salt in the field, such as one of cuprous acetate, copper acetate, copper oxide, cuprous oxide, cupric chloride, cuprous chloride, copper bromide and cuprous bromide Or more, preferably copper acetate.
  • the molar ratio of the copper salt to the compound represented by formula 3 can be a conventional molar ratio in the art, preferably 1:1-2:1, more preferably 1:1-1.5:1, such as 1:1 .
  • the mass-volume ratio of the compound represented by formula 3 to the acid is 1:1-1:20 g/mL, more preferably 1:1-1 : 15g/mL, for example 1:8.9g/mL.
  • the molar ratio of the compound represented by formula 3 to the oxidant can be a conventional molar ratio in the art, preferably 1:1-5:1, more It is preferably 1:1-3:1, more preferably 1:1-2.5:1, for example 2.5:1.
  • the temperature of the intramolecular cyclization reaction can be a conventional temperature in the art, preferably 90-110°C, such as 95°C.
  • the progress of the intramolecular cyclization reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS), and the intramolecular ring
  • the reaction time is preferably 8-20h, more preferably 8-12h, for example 12h.
  • the post-treatment operation includes the following steps: concentrating the reaction solution , Add water and an organic solvent (preferably an ether solvent, such as tert-butyl methyl ether), separate the water layer, extract with an organic solvent (preferably an ether solvent, such as tert-butyl methyl ether), combine the organic layers, wash with alkali to neutral, and dry, Concentrate, you can.
  • an organic solvent preferably an ether solvent, such as tert-butyl methyl ether
  • the method for preparing the compound represented by formula 3 may include the following steps: in an organic solvent, in the presence of a metal catalyst, the compound represented by formula 2 is combined with Hydrogen undergoes the reduction reaction shown below to obtain the compound shown in formula 3;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the organic solvent may be a conventional organic solvent in the art, preferably one of C 1 -C 4 alcohol solvents, ester solvents and ether solvents Or more, more preferably ester solvents.
  • the C 1 -C 4 alcohol solvent is preferably one or more of methanol, ethanol and isopropanol.
  • the ester solvent is preferably ethyl acetate.
  • the ether solvent is preferably diethyl ether and/or tetrahydrofuran.
  • the metal catalyst may be a conventional metal catalyst in the art, preferably Pd/C, Pd(OH) 2 , Raney nickel, Pt/C and PtO 2 One or more, more preferably Pd/C.
  • the mass-volume ratio of the compound of formula 2 and the organic solvent can be a conventional mass-volume ratio in the art, preferably 1:1-10:1g/ mL, more preferably 1:1-8:1 g/mL, still more preferably 1:1-5:1 g/mL, for example, 3:1 g/mL.
  • the mass ratio of the compound represented by formula 2 to the metal catalyst is 10:1-100:1, more preferably 20:1-100:1 , For example 20:1.
  • the amount of hydrogen is not particularly limited, and the pressure of hydrogen in the reaction system shall prevail.
  • the pressure of hydrogen may be a conventional pressure in the field, preferably 14.5-72.5psi, more preferably 15-50psi, such as 15psi, 30psi or 50psi.
  • the reduction reaction is carried out in the presence of an acid.
  • the acid may be a conventional acid in the art, such as an organic acid and/or an inorganic acid.
  • the organic acid is preferably formic acid and/or acetic acid.
  • the inorganic acid is preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
  • the molar ratio of the compound represented by formula 2 to the acid can be a conventional molar ratio in the art, preferably 1:1-1:2, more preferably 1:1-1:1.5, such as 1:1.5.
  • the temperature of the reduction reaction may be a temperature conventional in the art, preferably 20-50°C, more preferably 15-30°C, for example 15°C or 30°C.
  • the reduction reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS), and the reduction reaction time is preferably 0.5-8h , Further preferably 0.5-5h, such as 0.5h, 1h or 2h.
  • the preparation method of the compound represented by formula 3 may further include a post-treatment operation, and the post-treatment operation may include the following steps: filtering the reaction liquid , Concentrate, you can.
  • the preparation method of the compound represented by formula 2 may include the following steps: under a protective gas atmosphere, in an organic solvent, in the presence of a base and a catalyst, The compound represented by formula 1 and the compound represented by formula A are subjected to the following coupling reaction to obtain the compound represented by formula 2;
  • the catalyst includes a ligand and a palladium compound;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the protective gas may be a conventional protective gas in the art, such as nitrogen and/or argon.
  • the organic solvent is preferably one or more of aromatic hydrocarbon solvents, nitrile solvents, amide solvents, sulfoxide solvents, ether solvents and ketone solvents.
  • aromatic hydrocarbon solvents are more preferred.
  • the aromatic hydrocarbon solvent is preferably toluene and/or xylene, more preferably toluene.
  • the nitrile solvent is preferably acetonitrile.
  • the amide solvent is preferably N,N-dimethylformamide (DMF) and/or N,N-dimethylacetamide (DMA).
  • the sulfoxide solvent is preferably dimethyl sulfoxide (DMSO).
  • the ether solvent is preferably tetrahydrofuran (THF) and/or 1,4-dioxane.
  • the ketone solvent is preferably N-methylpyrrolidone (DMP).
  • the base can be a conventional base in the art, such as an organic base and/or an inorganic base.
  • the organic base is preferably pyridine, piperidine, 1,8-diazabicycloundec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) , Alkali metal alkoxides and One or more of, more preferably For example, triethylamine (Et 3 N) and/or N-methyldicyclohexylamine (Cy 2 NMe); wherein R 1a , R 2a and R 3a are independently hydrogen, C 1 ⁇ C 4 alkyl ( e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) or C 5 -C 6 cycloalkyl (e.g.
  • the alkali metal alkoxide may be an alkali metal alkoxide of a C 1 -C 4 alcohol, such as potassium tert-butoxide and/or sodium tert-butoxide.
  • the inorganic base can be one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide.
  • the alkali metal carbonate may be K 2 CO 3 and/or Cs 2 CO 3 .
  • the alkali metal hydride may be NaH.
  • the alkali metal hydroxide can be NaOH and/or KOH.
  • the ligand may be a phosphine ligand
  • the phosphine ligand may be a conventional phosphine ligand in the art, such as monodentate phosphine ligand, bidentate One or more of phosphine ligands and multidentate phosphine ligands, preferably monodentate phosphine ligands.
  • the monodentate phosphine ligands are preferably triphenylphosphine, tris(2-tolyl)phosphine, tris(3-tolyl)phosphine, tri-p-tolylphosphine, tris(4-fluorophenyl)phosphine, tris( One or more of 2-methoxyphenyl)phosphine, tris(4-methoxyphenyl)phosphine and 2-(di-tert-butylphosphine)biphenyl, more preferably triphenylphosphine and/or triphenylphosphine (2-Tolyl)phosphine.
  • the multidentate phosphine ligand is preferably triphenylphosphine, tris(2-tolyl)phosphine, tris(3-tolyl)phosphine, tri-p-tolylphosphine, tris(4-fluorophenyl)phosphine
  • the palladium compound may be zero-valent palladium and/or divalent palladium.
  • the zero-valent palladium may be Pd 2 (dba) 3 (dba: dibenzylidene acetone).
  • the divalent palladium can be one or more of Pd(OAc) 2 , PdCl 2 , Pd(TFA) 2 and Pd(MeCN) 2 Cl 2.
  • the palladium compound and the ligand can be added separately, the palladium compound and the ligand can be added to form a complex, or 1.
  • the palladium compound and the ligand can form a complex first, and then added separately from the ligand; the ligand can be independently a phosphine ligand.
  • the complex formed by the palladium compound and the ligand may be a complex formed by zero-valent palladium and the ligand and/or two
  • the complex formed by the valence palladium and the ligand; the complex formed by the zero-valent palladium and the ligand is preferably Pd(PPh 3 ) 4 ; the complex formed by the divalent palladium and the ligand is preferably Pd( PPh 3 ) 2 Cl 2 and/or Pd(dppf)Cl 2 .
  • the molar ratio of the compound represented by formula 1 to the compound represented by formula A may be a conventional molar ratio in the art, preferably 1:1. 1:3, more preferably 1:1-1:2, such as 1:1.2.
  • the mass-volume ratio of the compound represented by formula 1 and the organic solvent may be a conventional mass-volume ratio in the art, preferably 1:1-1: 10 g/mL, more preferably 1:1-1:5 g/mL, still more preferably 1:1-1:2 g/mL.
  • the molar ratio of the compound represented by formula 1 to the base can be a conventional molar ratio in the art, preferably 1:1-1:5, more It is preferably 1:1-1:3, more preferably 1:1-1:2.
  • the molar ratio of the compound represented by formula 1 to the ligand may be a conventional molar ratio in the art, preferably 1:1-10:1, It is more preferably 1.25:1-10:1, still more preferably 2:1-10:1.
  • the molar ratio of the compound represented by formula 1 to the palladium compound can be a conventional molar ratio in the art, preferably 10:1-1000:1 , More preferably 100:1-1000:1, still more preferably 100:1-500:1, for example 124:1.
  • the temperature of the coupling reaction can be a conventional temperature in the art, preferably 90-110°C.
  • the progress of the coupling reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS), and the time of the coupling reaction It is preferably 8-20h, more preferably 8-12h.
  • the post-treatment operation includes the following steps: cooling the reaction liquid (Preferably cooled to room temperature), adjust the pH to 3-4 with acid (preferably hydrochloric acid, such as 2M hydrochloric acid), extract with an organic solvent (preferably ether solvent, such as tert-butyl methyl ether), and wash (the washing solvent is preferably sodium chloride solution,
  • the organic phase obtained by extraction with saturated sodium chloride solution, drying, separation and purification preferably column chromatography analysis, the column chromatography separation is preferably ether solvents and ester solvents, such as petroleum ether and ethyl acetate ), you can.
  • the present invention provides a method for preparing a compound represented by formula 7 or formula 8, which includes the following steps: subjecting a compound represented by formula 7a or 8a to an acid and a neutralization reaction as shown below to obtain formula 7 Or the compound represented by formula 8; wherein, X 1 and X 2 are the same as described above; the preparation method of the compound represented by formula 7a or formula 8a is as described in any one of the preceding schemes;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the conditions and operations of the neutralization reaction can be conventional conditions and operations in the art.
  • the present invention provides a method for preparing a compound represented by formula 6, which comprises the following steps: in an organic solvent, in the presence of a reducing agent, the compound represented by formula 5 is subjected to a reduction reaction as shown below to obtain the result Said compound is represented by formula 6;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the present invention provides a method for preparing a compound represented by formula 5, which comprises the following steps: in a solvent, in the presence of a base, the compound represented by formula 4 is subjected to the following hydrolysis reaction to obtain the The compound shown in formula 5;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the present invention provides a method for preparing a compound represented by formula 4, which comprises the following steps:
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the present invention provides a method for preparing a compound represented by formula 3, which comprises the following steps: in an organic solvent, in the presence of a metal catalyst, the compound represented by formula 2 and hydrogen are subjected to a reduction reaction as shown below, namely To obtain the compound represented by formula 3;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the present invention provides a method for preparing a compound represented by formula 2, which comprises the following steps: under a protective gas atmosphere, in an organic solvent, in the presence of a base and a catalyst, the compound represented by formula 1 is combined with the compound represented by formula A.
  • the coupling reaction shown below is carried out on the compound to obtain the compound shown in formula 2;
  • the catalyst includes a ligand and a palladium compound;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the present invention also provides a method for preparing the compound represented by formula I, which is method one or method two:
  • method one includes the following steps: in an organic solvent, in the presence of an acid and a silane compound, the compound represented by formula B13 is subjected to the reductive amination reaction as shown below;
  • Method two includes the following steps: in an organic solvent, in the presence of a base, the compound represented by formula C13 is subjected to the ether-forming reaction shown below;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the organic solvent can be a conventional organic solvent in the art, preferably one or more of C 1 -C 4 alcohol solvents, aromatic hydrocarbon solvents and ether solvents, more preferably ethers Solvent.
  • the C 1 -C 4 alcohol solvent is preferably one or more of methanol, ethanol, n-propanol and isopropanol.
  • the aromatic hydrocarbon solvent is preferably toluene and/or xylene.
  • the ether solvent is preferably one or more of diethyl ether, tetrahydrofuran and 1,4-dioxane, more preferably tetrahydrofuran.
  • the acid may be a conventional acid in the art, and may be an inorganic acid and/or an organic acid.
  • the inorganic acid is preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
  • the organic acid is preferably one or more of formic acid, acetic acid and trifluoroacetic acid, more preferably trifluoroacetic acid.
  • the silane compound is preferably one or more of phenylsilane, diethylsilane, triethylsilane, trichlorosilane and diethoxymethylsilane, more preferably phenylsilane , One or more of diethylsilane and triethylsilane, more preferably phenylsilane.
  • the mass-volume ratio of the compound represented by formula B13 and the organic solvent can be a conventional mass-volume ratio in the art, preferably 1:1-1:20 g/mL, more preferably 1 :1-1:15g/mL, for example 1:12g/mL.
  • the mass-volume ratio of the compound represented by formula B13 to the acid can be a conventional mass-volume ratio in the art, preferably 1:1-1:5g/mL, more preferably 1: 1-1:3g/mL, for example 1:2.67g/mL.
  • the molar ratio of the compound represented by formula B13 to the silane compound is preferably 1:1-1:10, more preferably 1:1-1:5, such as 1:4.6.
  • the temperature of the reductive amination reaction can be a conventional temperature in the art, preferably 20-30°C.
  • the progress of the reductive amination reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the time of the reductive amination reaction is preferably 1-5 h, More preferably 1-3h.
  • the reductive amination reaction may further include a post-treatment operation, and the post-treatment operation includes the following steps: removing the solvent (preferably spin-drying) to obtain a residue , Add an organic solvent (preferably a halogenated hydrocarbon solvent, such as dichloromethane), wash (the washing solvent is preferably sodium bicarbonate solution and brine, such as saturated sodium bicarbonate solution and saturated brine) the organic layer, and then concentrate can.
  • a post-treatment operation includes the following steps: removing the solvent (preferably spin-drying) to obtain a residue , Add an organic solvent (preferably a halogenated hydrocarbon solvent, such as dichloromethane), wash (the washing solvent is preferably sodium bicarbonate solution and brine, such as saturated sodium bicarbonate solution and saturated brine) the organic layer, and then concentrate can.
  • an organic solvent preferably a halogenated hydrocarbon solvent, such as dichloromethane
  • wash is preferably sodium bicarbonate solution and brine, such as saturated sodium bicarbonate solution and saturated brin
  • the organic solvent may be a conventional organic solvent in the art, such as one of aromatic hydrocarbon solvents, nitrile solvents, amide solvents, sulfoxide solvents, ether solvents, and ketone solvents. Or more, preferably amide solvents and/or sulfoxide solvents, such as sulfoxide solvents.
  • the aromatic hydrocarbon solvent is preferably toluene and/or xylene, more preferably toluene.
  • the nitrile solvent is preferably acetonitrile.
  • the amide solvent is preferably N,N-dimethylformamide and/or N,N-dimethylacetamide.
  • the sulfoxide solvent is preferably dimethyl sulfoxide.
  • the ether solvent is preferably one or more of tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether.
  • the ketone solvent is preferably N-methylpyrrolidone.
  • the base can be a conventional base in the art, such as an organic base and/or an inorganic base.
  • the organic base is preferably pyridine, piperidine, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, alkali metal alkoxide and One or more of them; wherein R 1a , R 2a and R 3a are independently hydrogen, C 1 ⁇ C 4 alkyl (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) or C 5 -C 6 cycloalkyl (e.g.
  • the alkali metal alkoxide may be an alkali metal alkoxide of a C 1 -C 4 alcohol, such as potassium tert-butoxide and/or sodium tert-butoxide.
  • the inorganic base can be one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide.
  • the alkali metal carbonate may be K 2 CO 3 and/or Cs 2 CO 3 , preferably Cs 2 CO 3 .
  • the alkali metal hydride may be NaH.
  • the alkali metal hydroxide can be NaOH and/or KOH.
  • the mass-volume ratio of the compound represented by formula C13 and the organic solvent can be a conventional mass-volume ratio in the art, preferably 1:1-1:30 g/mL, and more preferably 1 :1-1:20g/mL, for example 1:20g/mL.
  • the molar ratio of the compound represented by formula C13 to the base can be a conventional molar ratio in the art, preferably 1:1-1:5, more preferably 1:1-1: 3. More preferably 1:1-1:2, such as 1:2.
  • the temperature of the ether formation reaction may be a temperature conventional in the art, preferably 50-100°C, more preferably 90-100°C, for example 90°C.
  • the progress of the ether formation reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the ether formation reaction time is preferably 1-20 h, and more preferably 1-15h, for example 15h.
  • the second method may further include a post-treatment operation, and the post-treatment operation includes the following steps: mixing the reaction solution with water, and an organic solvent (preferably Ester solvent, such as ethyl acetate) extraction, drying the organic layer, filtering, concentrating, and purifying.
  • the purification is preferably recrystallization or column chromatography separation, and the conditions and operations of the recrystallization and column chromatography separation are the same as those conventional in the art.
  • the preparation method of the compound represented by formula B13 may include the following steps: in a solvent, in the presence of a reducing agent, the compound represented by formula B12 is subjected to a reduction reaction as shown below, namely Obtain the compound represented by formula B13;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the solvent can be a conventional solvent in the art, such as one or more of C 1 -C 4 alcohols, ester solvents and ether solvents.
  • the C 1 -C 4 alcohol can be one or more of methanol, ethanol and isopropanol.
  • the ester solvent can be ethyl acetate.
  • the ether solvent can be tetrahydrofuran and/or 1,4-dioxane.
  • the reducing agent can be a conventional reducing agent in the art, or can be sodium dithionite, lithium aluminum hydride, sodium borohydride or an active metal with reducing ability.
  • the active metal can be one or more of iron, zinc or tin, preferably iron and/or zinc.
  • the reduction reaction needs to be carried out with the participation of an acid.
  • the acid can be used as a solvent.
  • the acid can be a conventional acid in the art, such as an inorganic acid and/or an organic acid.
  • the inorganic acid can be hydrochloric acid, sulfuric acid and/or phosphoric acid.
  • the organic acid can be formic acid and/or acetic acid, preferably acetic acid.
  • a salt electrolyte may be added to the reduction reaction, and the salt electrolyte is used to activate the metal and promote the reduction reaction.
  • the salt electrolyte may be a conventional salt electrolyte in the art, such as an ammonium salt, and the ammonium salt is preferably ammonium chloride.
  • the mass-volume ratio of the compound represented by the formula B12 to the solvent may be a conventional mass-volume ratio in the art, preferably 1:10-1:30g /mL, more preferably 1:10-1:20 g/mL.
  • the molar ratio of the compound represented by formula B12 to the reducing agent can be a conventional molar ratio in the art, preferably 1:1-1:8, More preferably 1:1-1:6.
  • the temperature of the reduction reaction may be a temperature conventional in the art, preferably 20-75°C, more preferably 50-75°C, for example 70-75°C.
  • the progress of the reduction reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS), and the time of the reduction reaction is preferably 1 -5h, more preferably 1-3h.
  • the post-treatment operation includes the following steps: cooling the reaction liquid ( Preferably cooling to room temperature), adding an organic solvent (preferably a halogenated hydrocarbon solvent, such as dichloromethane), filtering (preferably Celite filtration), and washing the filter cake (the washing solvent is preferably a halogenated hydrocarbon solvent, such as Dichloromethane), dry, and that's all
  • the preparation method of the compound represented by formula C13 may include the following steps: in an organic solvent, in the presence of a reducing agent, the compound represented by formula C12 is subjected to a reduction reaction as shown below, That is, the compound represented by formula C13 is obtained;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the organic solvent may be a conventional organic solvent in the art, such as aromatic hydrocarbon solvents, nitrile solvents, amide solvents, sulfoxide solvents, ether solvents, One or more of ketone solvents and C 1 -C 4 alcohol solvents, preferably C 1 -C 4 alcohol solvents.
  • the aromatic hydrocarbon solvent is preferably toluene and/or xylene.
  • the nitrile solvent is preferably acetonitrile.
  • the amide solvent is preferably N,N-dimethylformamide and/or N,N-dimethylacetamide.
  • the sulfoxide solvent is preferably dimethyl sulfoxide.
  • the ether solvent is preferably one or more of tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether.
  • the ketone solvent is preferably N-methylpyrrolidone.
  • the C 1 -C 4 alcohol solvent is preferably one or more of methanol, ethanol and isopropanol, more preferably isopropanol.
  • the reducing agent may be a conventional reducing agent in the art, such as an alkali metal hydride.
  • the alkali metal hydride can be one of lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, diisobutyl aluminum hydride, sodium cyanoborohydride and lithium tri-sec-butyl borohydride or There are multiple types, preferably one or more of lithium borohydride, sodium borohydride, and potassium borohydride, and more preferably lithium borohydride.
  • the mass-volume ratio of the compound represented by formula C12 to the organic solvent can be a conventional mass-volume ratio in the art, preferably 1:1-1: 20 g/mL, more preferably 1:1-1:12 g/mL, for example 10.6 g/mL.
  • the molar ratio of the compound represented by formula C12 to the reducing agent can be a conventional molar ratio in the art, preferably 1:1-1:5, More preferably 1:1-1:2, for example 1:2.
  • the temperature of the reduction reaction can be a conventional temperature in the art, preferably 20-90°C.
  • the progress of the reduction reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS), and the time of the reduction reaction is preferably 1 -5h, more preferably 1-3h.
  • the post-treatment operation includes the following steps: The reaction is quenched by mixing (preferably ice water), extraction (the extraction solvent is preferably an ester solvent, preferably ethyl acetate), the organic layer is dried, filtered, concentrated to dryness, and purified.
  • the purification is preferably recrystallization or column chromatography separation, and the conditions and operations of the recrystallization and column chromatography separation are the same as those conventional in the art.
  • the method for preparing the compound represented by formula B12 may include the following steps: in an organic solvent, in the presence of an oxidizing agent, the compound represented by formula B11 is processed as follows As shown in the oxidation reaction, the compound represented by formula B12 is obtained;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the organic solvent may be a conventional organic solvent in the art, such as one of halogenated hydrocarbon solvents, amide solvents, sulfoxide solvents and ketone solvents.
  • the halogenated hydrocarbon solvent is preferably one or more of dichloromethane, chloroform and 1,2-dichloroethane, more preferably dichloromethane.
  • the amide solvent is preferably N,N-dimethylformamide.
  • the sulfoxide solvent is preferably dimethyl sulfoxide.
  • the ketone solvent is preferably acetone and/or 2-butanone.
  • the oxidizing agent may be a conventional oxidizing agent in the art, such as a metal oxidizing agent and/or a non-metal oxide.
  • the metal oxidant can be chromium oxide and/or manganese oxide.
  • the chromium oxide may be pyridinium chlorochromate (PCC).
  • the manganese oxide can be manganese dioxide.
  • the non-metal oxide can be Dess-Martin reagent (DMP).
  • the mass-volume ratio of the compound represented by formula B11 and the organic solvent may be a conventional mass-volume ratio in the art, preferably 1:1-1: 20 g/mL, more preferably 1:1-1:15 g/mL, still more preferably 1:1-1:12 g/mL.
  • the molar ratio of the compound represented by formula B11 and the oxidant can be a conventional molar ratio in the art, preferably 1:1-1:3, more Preferably 1:1-1:1.5.
  • the temperature of the oxidation reaction can be a conventional reaction in the art, preferably 20-30°C.
  • the progress of the oxidation reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS), and the time of the oxidation reaction is preferably 1 -5h, more preferably 1-3h.
  • the post-treatment operation includes the following steps: filtering the reaction solution ( It is preferable to filter with diatomaceous earth), wash the filtrate (the washing solvent is preferably a mixed solution of sodium sulfite and sodium bicarbonate, more preferably a mixed solution of saturated sodium sulfite and sodium bicarbonate), separate the organic phase and concentrate.
  • the preparation method of the compound represented by formula C12 may include the following steps: in an organic solvent, in the presence of an acid and a silane compound, the compound of formula C11 Carry out the reductive amination reaction as shown below with the compound represented by formula C10 to obtain the compound represented by formula C12;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the organic solvent can be a conventional organic solvent in the art, preferably one of C 1 -C 4 alcohol solvents, aromatic hydrocarbon solvents and ether solvents.
  • C 1 -C 4 alcohol solvent is preferably one or more of methanol, ethanol, n-propanol and isopropanol.
  • aromatic hydrocarbon solvent is preferably toluene and/or xylene.
  • the ether solvent is preferably one or more of diethyl ether, THF and 1,4-dioxane, more preferably THF.
  • the acid may be a conventional acid in the art, and may be an inorganic acid and/or an organic acid.
  • the inorganic acid is preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
  • the organic acid is preferably one or more of formic acid, acetic acid and trifluoroacetic acid, more preferably trifluoroacetic acid.
  • the silane compound is preferably one of phenylsilane, diethylsilane, triethylsilane, trichlorosilane and diethoxymethylsilane or There are multiple types, more preferably one or more of phenylsilane, diethylsilane, and triethylsilane, and still more preferably phenylsilane.
  • the mass-volume ratio of the compound represented by formula C11 to the organic solvent is a mass-volume ratio conventional in the art, preferably 1:1-1 : 20g/mL, more preferably 1:1-1:12g/mL.
  • the molar ratio of the compound represented by formula C11 to the compound represented by formula C10 may be a conventional molar ratio in the art, preferably 1:1. 1:5, more preferably 1:1-1:2, for example 1:1.2.
  • the mass-volume ratio of the compound represented by formula C11 and the acid can be a conventional mass-volume ratio in the art, preferably 1:1-1:5g /mL, more preferably 1:1-1:3g/mL, for example 1:3g/mL.
  • the molar ratio of the compound represented by formula C11 to the silane compound is preferably 1:1-1:10, more preferably 1:1-1: 6, for example 1:5.14.
  • the temperature of the reductive amination reaction is preferably 20-30°C.
  • the progress of the reductive amination reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS).
  • the time is preferably 1-30h, more preferably 1-20h.
  • the post-treatment operation includes the following steps: Mix with water to quench the reaction, extract with an organic solvent (preferably an ester solvent, preferably ethyl acetate), dry the organic layer, filter, concentrate to dryness, and purify (preferably column chromatography).
  • an organic solvent preferably an ester solvent, preferably ethyl acetate
  • the preparation method of the compound represented by formula B11 can be any one of method A, method B, method C and method D,
  • the method A includes the following steps: in an organic solvent, in the presence of a reducing agent, the compound represented by formula B10 is subjected to the hydrolysis reaction shown below to obtain the compound represented by formula B11;
  • the method B includes the following steps:
  • step (b2) The acid chloride obtained in step (b1) and the reducing agent are subjected to the reduction reaction shown below to obtain the compound represented by formula B11;
  • the method C includes the following steps:
  • step (c2) The ester obtained in step (c1) and the reducing agent are subjected to the reduction reaction shown below to obtain the compound represented by formula B11;
  • the method D includes the following steps:
  • step (d2) The acid anhydride obtained in step (d1) and the reducing agent are subjected to the reduction reaction shown below to obtain the compound represented by formula B11;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any one of the preceding schemes;
  • R 5 and R 6 are independently a C 1 -C 4 alkyl group (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).
  • the organic solvent may be a conventional organic solvent in the art, preferably aromatic hydrocarbon solvents, nitrile solvents, amide solvents, sulfoxide solvents, One or more of ether solvents, ketone solvents, and C 1 -C 4 alcohol solvents, and ether solvents are more preferred.
  • the aromatic hydrocarbon solvent can be toluene and/or xylene.
  • the nitrile solvent can be acetonitrile.
  • the amide solvent can be N,N-dimethylformamide and/or N,N-dimethylacetamide (DMA).
  • the sulfoxide solvent can be dimethyl sulfoxide.
  • the ether solvent can be one or more of tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether (DME), preferably DME.
  • the ketone solvent can be N-methylpyrrolidone.
  • the C 1 -C 4 alcohol solvent can be one or more of methanol, ethanol and isopropanol.
  • the reducing agent can be a conventional reducing agent in the art, such as an alkali metal hydride.
  • the alkali metal hydride can be lithium aluminum hydride (LiAlH 4 ), lithium borohydride (LiBH 4 ), sodium borohydride (NaBH 4 ), potassium borohydride (KBH 4 ), diisobutyl aluminum hydride, cyano One or more of sodium borohydride (NaBH 3 CN) and lithium tri-sec-butyl borohydride, preferably one or more of lithium borohydride, sodium borohydride, and potassium borohydride, and more preferably sodium borohydride.
  • the mass-volume ratio of the compound represented by formula B10 to the organic solvent may be a conventional mass-volume ratio in the art, preferably 1: 1-1:20g/mL, more preferably 1:1-1:15g/mL, still more preferably 1:1-1:12g/mL, for example 1:10.26g/mL.
  • the molar ratio of the compound represented by formula B10 to the reducing agent can be a conventional molar ratio in the art, preferably 1:1-1:5, More preferably 1:1-1:2, for example 1:1.1.
  • the temperature of the reduction reaction can be a conventional temperature in the art, preferably -10-10°C, more preferably -5-5°C, such as -5-0 °C.
  • the progress of the reduction reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS), and the reduction reaction
  • the time is preferably 1-5h, more preferably 1-3h.
  • the halogenating agent in the method for preparing the compound represented by formula B11, in step (b1), can be a conventional halogenating agent in the art, such as phosphorus trichloride, phosphorus pentachloride, thionyl chloride and grass One or more of the acid chlorides, preferably thionyl chloride and/or oxalyl chloride.
  • the molar ratio of the compound represented by formula B10 and the halogenating agent may be a conventional molar ratio in the art, preferably 1: 1-1:3, more preferably 1:1-1:2.
  • step (b1) the other conditions and operations of the acylation reaction are the same as the conventional conditions and operations of this type of reaction in the art.
  • step (b2) the conditions and operations of the reduction reaction are the same as those conventional in this type of reaction in the art.
  • the alcohol in the method for preparing the compound represented by formula B11, in step (c1), can be a conventional alcohol in the art, preferably a C 1 -C 4 alcohol, such as methanol, ethanol, n-propanol, Isopropanol, n-butanol or isobutanol.
  • the molar ratio of the compound represented by formula B10 and the alcohol may be a conventional molar ratio in the art, preferably 1:1 -1:2, more preferably 1:1-1:1.5.
  • step (c1) the other conditions and operations of the esterification reaction are the same as the conventional conditions and operations of this type of reaction in the art.
  • step (c2) the conditions and operations of the reduction reaction are the same as those conventionally used in this type of reaction in the art.
  • the activator in the preparation method of the compound represented by formula B11, in step (d1), can be a conventional activator in the art, such as ethyl chloroformate, isobutyl chloroformate, trichlorochloroformate One or more of methyl chloroformate and benzyl chloroformate, preferably ethyl chloroformate and/or isobutyl chloroformate.
  • the base in step (d1), can be a conventional base in the art, preferably an organic base, such as Et 3 N, diisopropylethylamine (i -One or more of Pr 2 Net), DBU, DABCO, pyridine, piperidine and N-methylmorpholine.
  • organic base such as Et 3 N, diisopropylethylamine (i -One or more of Pr 2 Net), DBU, DABCO, pyridine, piperidine and N-methylmorpholine.
  • the molar ratio of the compound represented by formula B10 and the activator may be a conventional molar ratio in the art, preferably 1: 1-1:2, more preferably 1:1-1:1.5.
  • the molar ratio of the compound represented by formula B10 and the base may be a conventional molar ratio in the art, preferably 1:1 -1:2, more preferably 1:1-1:1.5.
  • step (d2) the conditions and operations of the reduction reaction are the same as those conventionally used in this type of reaction in the art.
  • the reaction may further include a post-treatment operation, and the post-treatment operation includes the following steps:
  • the reaction is quenched by mixing (preferably ice water), extraction (the extraction solvent is preferably an ester solvent, preferably ethyl acetate), the organic layer is dried, filtered, concentrated to dryness, and purified.
  • the purification is preferably recrystallization or column chromatography separation, and the conditions and operations of the recrystallization and column chromatography separation are the same as those conventional in the art.
  • the method for preparing the compound represented by formula C11 may include the following steps: in an organic solvent, in the presence of an oxidizing agent, the compound represented by formula C9 is processed as follows As shown in the oxidation reaction, the compound represented by formula C11 is obtained;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the organic solvent may be a conventional organic solvent in the art, such as one of halogenated hydrocarbon solvents, amide solvents, sulfoxide solvents and ketone solvents.
  • the halogenated hydrocarbon solvent can be one or more of dichloromethane, chloroform and 1,2-dichloroethane, preferably dichloromethane.
  • the amide solvent can be N,N-dimethylformamide.
  • the sulfoxide solvent can be dimethyl sulfoxide.
  • the ketone solvent can be acetone and/or 2-butanone.
  • the oxidant may be a conventional oxidant in the art, such as a metal oxidant and/or a non-metal oxide.
  • the metal oxidant can be chromium oxide and/or manganese oxide.
  • the chromium oxide may be pyridinium chlorochromate.
  • the manganese oxide can be manganese dioxide.
  • the non-metal oxide can be Dess-Martin reagent.
  • the mass-volume ratio of the compound represented by formula C9 and the organic solvent may be a conventional mass-volume ratio in the art, preferably 1:1-1: 30 g/mL, more preferably 1:1-1:22 g/mL, for example 20.3 g/mL.
  • the molar ratio of the compound represented by formula C9 and the oxidant can be a conventional molar ratio in the art, preferably 1:1-1:3, more Preferably 1:1-1:1.5, for example 1: 1.48.
  • the temperature of the oxidation reaction can be a conventional reaction in the art, preferably 20-50°C, more preferably 20-30°C.
  • the progress of the oxidation reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS), and the time of the oxidation reaction is preferably 1 -5h, more preferably 1h-3h.
  • the post-treatment operation includes the following steps: (Preferably a mixed solution of sodium sulfite and sodium bicarbonate) mix, separate the organic layer, extract with an organic solvent (preferably an ester solvent, such as ethyl acetate), dry the organic layer, filter, concentrate, and purify (preferably column chromatography separation), namely can.
  • an organic solvent preferably an ester solvent, such as ethyl acetate
  • the method for preparing the compound represented by formula B10 may include the following steps: in an organic solvent, in the presence of a base, the compound represented by formula 7 is combined with The compound represented by formula B9 undergoes the ether formation reaction shown below to obtain the compound represented by formula B10;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the ether formation reaction is preferably carried out under a protective gas atmosphere, and the protective gas may be a conventional protective gas in the art, such as nitrogen.
  • the organic solvent may be a conventional organic solvent in the art, such as aromatic hydrocarbon solvents, nitrile solvents, amide solvents, sulfoxide solvents, ether solvents and One or more of ketone solvents, preferably amide solvents and/or sulfoxide solvents.
  • the aromatic hydrocarbon solvent is preferably toluene and/or xylene, more preferably toluene.
  • the nitrile solvent is preferably acetonitrile.
  • the amide solvent is preferably N,N-dimethylformamide and/or N,N-dimethylacetamide.
  • the sulfoxide solvent is preferably dimethyl sulfoxide.
  • the ether solvent is preferably one or more of tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether.
  • the ketone solvent is preferably N-methylpyrrolidone.
  • the base may be a conventional base in the art, such as an organic base and/or an inorganic base.
  • the organic base is preferably pyridine, piperidine, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, alkali metal alkoxide and One or more of them; wherein R 1a , R 2a and R 3a are independently hydrogen, C 1 ⁇ C 4 alkyl (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) or C 5 -C 6 cycloalkyl (e.g.
  • the alkali metal alkoxide may be an alkali metal alkoxide of a C 1 -C 4 alcohol, such as potassium tert-butoxide and/or sodium tert-butoxide.
  • the inorganic base can be one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide.
  • the alkali metal carbonate may be K 2 CO 3 and/or Cs 2 CO 3 .
  • the alkali metal hydride may be NaH.
  • the alkali metal hydroxide can be NaOH and/or KOH.
  • the mass-volume ratio of the compound represented by formula 7 to the organic solvent may be a conventional mass-volume ratio in the art, preferably 1:1-1: 20 g/mL, more preferably 1:1-1:15 g/mL, more preferably 1:1-1:12 g/mL.
  • the molar ratio of the compound represented by formula 7 to the compound represented by formula 9 may be a conventional molar ratio in the art, preferably 1:1. 1:5, more preferably 1:1-1:3, still more preferably 1:1-1:2.
  • the molar ratio of the compound represented by formula 7 to the base can be a conventional molar ratio in the art, preferably 1:1-1:5, More preferably, 1:1-1:4.
  • the temperature of the ether formation reaction can be a conventional temperature in the art, preferably -10-10°C, more preferably -5-5°C, such as -2- 2°C.
  • the progress of the ether-forming reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS), and the time of the ether-forming reaction It is preferably 1-5h, more preferably 1-3h.
  • the post-treatment operation includes the following steps: Mix with water (preferably ice water), adjust the pH to 3-4 with acid (preferably hydrochloric acid, such as 1N hydrochloric acid), extract with an organic solvent (preferably ester solvent, such as ethyl acetate), dry the organic layer, filter, and concentrate to dryness. Purify it.
  • the purification is preferably recrystallization or column chromatography separation, and the conditions and operations of the recrystallization and column chromatography separation are the same as those conventional in the art.
  • the method for preparing the compound represented by formula C9 may include the following steps: in an organic solvent, in the presence of a base, the compound represented by formula 8 is combined with a The methylation reagent undergoes the methylation reaction shown below to obtain the compound represented by formula C9;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the organic solvent may be a conventional organic solvent in the art, such as aromatic hydrocarbon solvents, nitrile solvents, amide solvents, sulfoxide solvents, ether solvents and One or more of ketone solvents, preferably amide solvents.
  • the aromatic hydrocarbon solvent is preferably toluene and/or xylene, more preferably toluene.
  • the nitrile solvent is preferably acetonitrile.
  • the amide solvent is preferably N,N-dimethylformamide and/or N,N-dimethylacetamide, such as N,N-dimethylformamide.
  • the sulfoxide solvent is preferably dimethyl sulfoxide.
  • the ether solvent is preferably tetrahydrofuran and/or 1,4-dioxane.
  • the ketone solvent is preferably N-methylpyrrolidone.
  • the base may be a conventional base in the art, such as an organic base and/or an inorganic base.
  • the organic base is preferably pyridine, piperidine, 1,8-diazabicycloundec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) , Alkali metal alkoxides and One or more of them; wherein R 1a , R 2a and R 3a are independently hydrogen, C 1 ⁇ C 4 alkyl (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) or C 5 -C 6 cycloalkyl (e.g.
  • the alkali metal alkoxide may be an alkali metal alkoxide of a C 1 -C 4 alcohol, such as potassium tert-butoxide and/or sodium tert-butoxide.
  • the inorganic base can be one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide, preferably alkali metal carbonate.
  • the alkali metal carbonate may be K 2 CO 3 and/or Cs 2 CO 3 , preferably K 2 CO 3 .
  • the alkali metal hydride may be NaH.
  • the alkali metal hydroxide can be NaOH and/or KOH.
  • the methylating reagent can be a conventional methylating reagent in the art, such as one of methyl halide, dimethyl sulfate and dimethyl carbonate Or more, preferably halogenated methane.
  • the methyl halide is preferably methyl iodide.
  • the mass-volume ratio of the compound represented by formula 8 and the organic solvent may be a conventional mass-volume ratio in the art, preferably 1:1-1: 30 g/mL, more preferably 1:1-1:20 g/mL, for example 1:20 g/mL.
  • the molar ratio of the compound represented by formula 8 to the base can be a conventional molar ratio in the art, preferably 1:1-1:5, more It is preferably 1:1-1:3, more preferably 1:1-1:2, for example 1:1.7.
  • the molar ratio of the compound represented by formula 8 to the methylating reagent may be a conventional molar ratio in the art, preferably 1:1-1: 2. More preferably 1:1-1:1.5, for example 1:1.2.
  • the temperature of the methylation reaction can be a conventional temperature in the art, preferably 20-30°C.
  • the progress of the methylation reaction can be monitored by conventional means in the art (for example, TLC, HPLC or LC-MS).
  • the time is preferably 1-5h, more preferably 1-3h.
  • the post-treatment operation includes the following steps: adding a solvent (preferably, an acid solvent, such as hydrochloric acid, or 1N hydrochloric acid, is used to quench the reaction, an organic solvent (preferably an ester solvent, such as ethyl acetate) is extracted, the organic layer is dried, filtered, concentrated, and purified (preferably separated by column chromatography), namely can.
  • a solvent preferably, an acid solvent, such as hydrochloric acid, or 1N hydrochloric acid, is used to quench the reaction, an organic solvent (preferably an ester solvent, such as ethyl acetate) is extracted, the organic layer is dried, filtered, concentrated, and purified (preferably separated by column chromatography), namely can.
  • the method for preparing the compound represented by formula 8 is as described in any one of the preceding schemes.
  • the present invention provides a method for preparing a compound represented by formula B13, which comprises the following steps: in a solvent, in the presence of a reducing agent, the compound represented by formula B12 is subjected to a reduction reaction as shown below to obtain the formula Compound represented by B13;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the present invention provides a method for preparing a compound represented by formula B12, which comprises the following steps: in an organic solvent, in the presence of an oxidizing agent, the compound represented by formula B11 is subjected to the oxidation reaction shown below to obtain the The compound represented by formula B12;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the present invention provides a method for preparing a compound represented by formula B11, which can be any one of method A, method B, method C and method D,
  • the method A includes the following steps: in an organic solvent, in the presence of a reducing agent, the compound represented by formula B10 is subjected to the hydrolysis reaction shown below to obtain the compound represented by formula B11;
  • the method B includes the following steps:
  • step (b2) The acid chloride obtained in step (b1) and the reducing agent are subjected to the reduction reaction shown below to obtain the compound represented by formula B11;
  • the method C includes the following steps:
  • step (c2) The ester obtained in step (c1) and the reducing agent are subjected to the reduction reaction shown below to obtain the compound represented by formula B11;
  • the method D includes the following steps:
  • step (d2) The acid anhydride obtained in step (d1) and the reducing agent are subjected to the reduction reaction shown below to obtain the compound represented by formula B11;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as those described in any of the previous schemes.
  • the present invention provides a method for preparing a compound represented by formula B10, which comprises the following steps: in an organic solvent, in the presence of a base, the compound represented by formula 7 and the compound represented by formula B9 are subjected to the following steps: Ether formation reaction, that is, the compound represented by formula B10 is obtained;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the present invention provides a method for preparing a compound represented by formula C13, which comprises the following steps: in an organic solvent, in the presence of a reducing agent, the compound represented by formula C12 is subjected to a reduction reaction as shown below to obtain the result Said compound represented by formula C13;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the present invention provides a method for preparing a compound represented by formula C12, which includes the following steps: in an organic solvent, in the presence of an acid and a silane compound, a compound represented by formula C11 and a compound represented by formula C10 are subjected to the following steps: The reductive amination reaction as shown, namely, the compound represented by formula C12 is obtained;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the present invention provides a method for preparing a compound represented by formula C11, which comprises the following steps: in an organic solvent, in the presence of an oxidizing agent, the compound represented by formula C9 is subjected to the oxidation reaction shown below to obtain the Is a compound represented by formula C11;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the present invention provides a method for preparing a compound represented by formula C9, which comprises the following steps: in an organic solvent, in the presence of a base, the compound represented by formula 8 and a methylating reagent are subjected to methylation as shown below Chemical reaction to obtain the compound represented by formula C9;
  • R 1 , R 2 , R 3 and R 4 are the same as those described in any of the previous schemes.
  • the present invention also provides a method for preparing the compound represented by formula I-1, and its synthetic route can be any of the following routes 1 to 4:
  • the present invention also provides a method for preparing the compound represented by formula 7-1 or formula 8-1,
  • the present invention also provides a compound represented by the following formula:
  • R 1 , R 2 , R 3 , R 4 , X 1 and X 2 are the same as those described in any of the previous schemes.
  • the present invention also provides a compound represented by the following formula:
  • the present invention provides a crystal form of compound 7a-1 or compound 8a-1,
  • the crystal form parameters of the compound 7a-1 are the parameters in Table 1;
  • crystal form parameters of 8a-1 are the parameters in Table 2;
  • the temperature is particularly emphasized, it usually means that the reaction is carried out at room temperature, and the room temperature in the present invention means 20-30°C.
  • min or “mins” in the present invention refers to minutes.
  • reagents and raw materials used in the present invention are all commercially available.
  • the present invention provides a new method for preparing oxazepine spirocyclic compounds and intermediates thereof, which is easy to operate, and the synthesized oxazepine spirocyclic compounds and intermediates thereof have better performance Stereoselectivity.
  • Figure 1 is a single crystal diffraction pattern of compound 7a-1.
  • Figure 2 is a single crystal diffraction pattern of compound 8a-1.
  • Example 1 Pd(ACN) 2 Cl 2 was replaced with Pd(pph 3 ) 2 Cl 2 , tris(o-tolyl)phosphine was replaced with triphenylphosphine, Cy 2 Nme was replaced with Et 3 N, and toluene was replaced with 1,4-dioxane, other conditions are the same as in Example 1, and the yield of the compound of formula 2-1 is 35%.
  • Example 1 Pd(ACN) 2 Cl 2 was replaced with Pd(pph 3 ) 4 , tris(o-tolyl)phosphine was replaced with tri-o-methoxytriphenylphosphine, and Cy 2 Nme was replaced with Et 3 N Other conditions are the same as in Example 1, and the yield of the compound of formula 2-1 is 45%.
  • Example 4 Replace the compound of formula 2-1 in Example 4 with 10g, the amount of acetic acid used is 1.5 times the equivalent of the compound of formula 2-1, the mass of 5% Pd/C is 5% of the mass of the compound of formula 2-1, and the reaction temperature is The reaction was carried out at 50°C for 8 hours, and other conditions were the same as in Example 4. The reaction was complete, and LCMS monitoring showed 1.0% dehalogenated impurities.
  • Example 4 Replace the compound of formula 2-1 in Example 4 with 10g, the amount of acetic acid used is 1.5 times the equivalent of the compound of formula 2-1, the mass of 5% Pd/C is 5% of the mass of the compound of formula 2-1, and the reaction temperature is The reaction was carried out at 50°C for 2 hours, and other conditions were the same as in Example 4. The reaction was complete, and LCMS monitoring showed 1.0% dehalogenated impurities.
  • Example 4 Replace the compound of formula 2-1 in Example 4 with 20 g, the amount of acetic acid used is 1.5 times the equivalent of the compound of formula 2-1, and the mass of 5% Pd/C is 5% of the mass of the compound of formula 2-1.
  • the same as in Example 4. The reaction was complete, and LCMS monitoring showed 0.3% dehalogenated impurities.
  • Example 4 Change the compound of formula 2-1 in Example 4 to 10g, without adding acetic acid, the mass of 5% Pd/C is 5% of the mass of compound of formula 2-1, the reaction temperature is 50°C, the reaction is 1h, and the other conditions are the same Example 4. The reaction was complete, and LCMS monitoring showed 1.0% dehalogenated impurities.
  • Example 4 Change the compound of formula 2-1 in Example 4 to 10g, without adding acetic acid, the mass of 5% Pd/C is 5% of the mass of compound of formula 2-1, the hydrogen pressure is 30psi, the reaction is 1h, and other conditions are the same.
  • Example 4. The reaction was complete, and LCMS monitoring showed 0.4% of dehalogenated impurities.
  • Example 4 The compound of formula 2-1 in Example 4 was replaced with 10 g, acetic acid was not added, and the mass of 5% Pd/C was 2% of the mass of compound of formula 2-1.
  • the reaction was carried out for 1 hour, and the other conditions were the same as in Example 4.
  • the reaction was complete, and LCMS monitoring showed that there were 2.3% dehalogenated impurities.
  • Example 4 Change the compound of formula 2-1 in Example 4 to 10g, without adding acetic acid, the mass of 5% Pd/C is 2% of the mass of compound of formula 2-1, the hydrogen pressure is 30psi, the reaction is 2h, and the other conditions are the same.
  • Example 4 The reaction was complete, and LCMS monitoring showed that there were 0.1% dehalogenated impurities.
  • Example 4 Change the compound of formula 2-1 in Example 4 to 10g, without adding acetic acid, the mass of 5% Pd/C is 2% of the mass of compound of formula 2-1, the hydrogen pressure is 15psi, the reaction is 2h, and the other conditions are the same.
  • Example 4 The reaction was complete, and LCMS monitoring showed that there were 0.17% dehalogenated impurities.
  • Example 15 The reaction temperature in Example 15 was changed to 0-5°C for 2 hours, and other conditions were the same as in Example 15. The yield of the compound of formula 5-1 was 67%.
  • Example 17 The lithium borohydride in Example 17 was replaced by BH 3 ⁇ Me 2 S, the amount was 1.2 equivalents of the compound of formula 5-1, and the reaction was carried out at 25°C for 7 hours. The remaining conditions were the same as in Example 17. The yield of the compound of formula 6-1 was 40%.
  • Example 17 The solvent in Example 17 was changed to isopropanol, and the reaction was carried out at 25° C. for 1 hour. The remaining conditions were the same as those in Example 17. The yield of the compound of formula 6-1 was 82%.
  • Example 17 The solvent in Example 17 was changed to isopropanol, and the reaction was conducted at 0° C. for 6 hours. The rest of the conditions were the same as in Example 17. The yield of the compound of formula 6-1 was 70%.
  • the Ee value is measured by HPLC, and the test conditions are shown in Table 3 below:
  • Compound 7a-1 Add 10 mg of compound 7a-1 and 10 ⁇ L of ethanol to a 5 ml test tube, filter, and stand for 4 days to crystallize. Single crystals are precipitated. The single crystals are collected for single crystal diffraction test.
  • Compound 8a-1 Add 10mg of compound 8a-1 to a 5ml test tube, and 10 ⁇ L DMSO to dissolve it, place it in a wide-mouth flask with an appropriate amount of n-heptane, and let it stand for 4 days. Single crystals precipitate out. Collect single crystals for single crystal diffraction test .

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Abstract

提供了一种氧氮杂环庚烷类螺环化合物、中间体及其制备方法。涉及一种如式7a或式8a所示化合物的制备方法，所述的如式7a所示化合物的制备方法包括以下步骤：有机溶剂中，将如式6所示的化合物和手性拆分剂X 1进行如下所示的成盐反应，即可；其中，X 1为R构型的手性拆分剂；所述的如式8a所示化合物的制备方法包括以下步骤：有机溶剂中，将如式6所示的化合物和手性拆分剂X 2进行如下所示的成盐反应，即可；其中，X 2为S构型的手性拆分剂。

Description

氧氮杂环庚烷类螺环化合物、中间体及其制备方法
本发明要求申请日为2019年9月12日的PCT专利申请PCT/CN2019/105686的优先权。本申请引用上述PCT专利申请的全文。
技术领域
本发明属于药物化学领域，涉及一种氧氮杂环庚烷类螺环化合物、中间体及其制备方法。
背景技术
氧氮杂环庚烷类螺环化合物是一类重要的含氮杂环化合物，其结构为
Figure PCTCN2020114629-appb-000001
很多药物及其中间体都含有上述结构单元，例如：
Figure PCTCN2020114629-appb-000002
目前关于这类化合物的合成工艺报道非常少，例如：专利申请WO2016033486A1公开了类似化合物的制备方法，其合成路线如下所述：
Figure PCTCN2020114629-appb-000003
在上述路线中，6-氯-3,4-二氢-1(2H)萘酮在三甲基碘化锍的存在下得到环氧化合物，经三氟化硼乙醚作用得到醛基，醛基化合物在二乙二醇，甲醛的存在下，得到二醇类化合物，继续加入4-溴苯甲酰氯，得到单取代酯类合物，随后在氧化剂Dess-Martin periodinane的存在下，醇羟基被氧化成醛基，在对甲苯磺酸，原甲酸三甲酯的存在下形 成酮基保护物，再与4-氟-3-硝基-苯甲酸叔丁酯进行醚化反应，再加入三氟甲磺酸铒水合物转变成醛化合物，还原硝基，分子内还原胺化得到氧氮杂环庚烷类螺环化合物。该路线所需的反应原料众多，路线长，后处理需要柱层析，立体性选择性差，收率低等缺陷。
鉴于目前市场对氧氮杂环庚烷类螺环化合物存在巨大需求，迫切需要开发新的工艺路线。
发明内容
本发明提供了一种氧氮杂环庚烷类螺环化合物、中间体及其制备方法。
本发明提供了一种如式7a或式8a所示化合物的制备方法，
其中，所述的如式7a所示化合物的制备方法包括以下步骤：有机溶剂中，将如式6所示的化合物和手性拆分剂X 1进行如下所示的成盐反应，即可；其中，X 1为R构型的手性拆分剂；
Figure PCTCN2020114629-appb-000004
所述的如式8a所示化合物的制备方法包括以下步骤：有机溶剂中，将如式6所示的化合物和手性拆分剂X 2进行如下所示的成盐反应，即可；其中，X 2为S构型的手性拆分剂；
Figure PCTCN2020114629-appb-000005
其中，R 1、R 2、R 3和R 4独立地为氢、羟基、氰基、氨基、硝基、醛基、卤素、C 1-C 4的烷基、R 1-1取代的C 1-C 4的烷基、C 1-C 4的卤代烷基、R 1-2取代的C 1-C 4的卤代烷基、C 1-C 4的烷氧基、R 1-3取代的C 1-C 4的烷氧基、或-C(＝O)R 1-4；
R 1-1、R 1-2、R 1-3和R 1-4独立地为羟基、C 1-C 4的烷基、C 1-C 4的烷氧基、C 3-C 5的环烷基或NR 1-1aR 1-1b；
R 1-1a和R 1-1b独立地为氢或C 1-C 4的烷基。
所述的如式7a或式8a所示化合物的制备方法中，所述的R 1-1的个数可为1个或多个，例如1、2或3个，当存在多个R 1-1时，所述的R 1-1可相同或不同。
所述的如式7a或式8a所示化合物的制备方法中，所述的R 1-2的个数可为1个或多个，例如1、2或3个，当存在多个R 1-2时，所述的R 1-2可相同或不同。
所述的如式7a或式8a所示化合物的制备方法中，所述的R 1-3的个数可为1个或多个，例如1、2或3个，当存在多个R 1-3时，所述的R 1-3可相同或不同。
所述的如式7a或式8a所示化合物的制备方法中，所述的卤素可为氟、氯、溴或碘，优选氟或氯。
所述的如式7a或式8a所示化合物的制备方法中，所述的C 1-C 4的烷基、和R 1-1取代的C 1-C 4的烷基中，所述的C 1-C 4的烷基可独立地为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
所述的如式7a或式8a所示化合物的制备方法中，所述的C 1-C 4的卤代烷基优选被1、2或3个卤素取代，所述的卤素可为氟、氯、溴或碘，所述的C 1-C 4的卤代烷基优选-CHF 2或-CF 3。
所述的如式7a或式8a所示化合物的制备方法中，所述的C 1-C 4的烷氧基、和R 1-3取代的C 1-C 4的烷氧基中，所述的C 1-C 4的烷氧基可独立地为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。
本发明一优选实施方案中，所述的如式7a或式8a所示化合物的某些基团如下定义(未定义的基团如前任一方案所述)：R 1、R 2、R 3和R 4独立地为氢和卤素。
本发明一优选实施方案中，所述的如式7a或式8a所示化合物的某些基团如下定义(未定义的基团如前任一方案所述)：R 1和R 2为氢，R 3和R 4独立地为卤素。
本发明一优选实施方案中，所述的如式7a或式8a所示化合物的某些基团如下定义(未定义的基团如前任一方案所述)：R 1和R 2为氢，R 3为氯，R 4为氟。
所述的如式7a或式8a所示化合物的制备方法中，所述的如式7a所示化合物优选为如式7a-1所示化合物，
Figure PCTCN2020114629-appb-000006
所述的如式7a或式8a所示化合物的制备方法中，所述的如式8a所示化合物优选为 如式8a-1所示化合物，
Figure PCTCN2020114629-appb-000007
所述的如式7a或式8a所示化合物的制备方法中，所述的R构型的手性拆分剂可为本领域常规的R构型的手性拆分剂，优选R构型的胺类手性拆分剂，例如(R)-1-(1-萘基)-乙胺、(R)-苯乙胺、(R)-苯丙氨醇、(R)-N-苄基苯基乙胺或(R)-奎宁丁，更优选(R)-1-(1-萘基)-乙胺。
所述的如式7a或式8a所示化合物的制备方法中，所述的S构型的手性拆分剂可为本领域常规的S构型的手性拆分剂，优选S构型的胺类手性拆分剂，例如(S)-1-(1-萘基)-乙胺、(S)-苯乙胺、(S)-苯丙氨醇、(S)-N-苄基苯基乙胺或(S)-奎宁丁，更优选(S)-1-(1-萘基)-乙胺。
所述的如式7a或式8a所示化合物的制备方法中，所述的有机溶剂可为本领域常规的溶剂，优选C 1-C 4的醇类溶剂和/或酯类溶剂，更优选酯类溶剂。所述的C 1-C 4的醇类溶剂优选甲醇、乙醇和异丙醇(IPA)中的一种或多种。所述的酯类溶剂优选乙酸乙酯。
所述的如式7a或式8a所示化合物的制备方法中，所述的如式6所示化合物与手性拆分剂的摩尔比可为本领域常规的摩尔比，优选1:1-1:5，更优选1:1-1:3，进一步优选1:1-1:1.5，例如1:1。
所述的如式7a或式8a所示化合物的制备方法中，所述的如式6所示化合物与所述的有机溶剂的质量体积比可为本领域常规的质量体积比，优选1:1-1:10g/mL，更优选1:1-1:6g/mL，例如1:5.2g/mL。
所述的如式7a或式8a所示化合物的制备方法中，所述的成盐反应的温度可为本领域常规的温度，优选20-30℃。
所述的如式7a或式8a所示化合物的制备方法中，所述的成盐反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的反应的时间优选1-5h，例如3h。
所述的如式7a或式8a所示化合物的制备方法中，较佳地，所述的成盐反应结束后，所述的中和反应操作之前，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液进行过滤，过滤后的滤饼进行重结晶，即可。所述的过滤优选抽滤。所述 的重结晶的操作可为本领域常规的操作，所述重结晶的溶剂优选醇类溶剂(例如乙醇)和水，所述醇类溶剂和水的体积比优选5:1-15:1(例如10:1)。
所述的如式7a或式8a所示化合物的制备方法中，所述的如式6所示化合物的制备方法可包括以下步骤：有机溶剂中，在还原剂的存在下，将如式5所示化合物进行如下所示的还原反应，即得所述的如式6所示化合物；
Figure PCTCN2020114629-appb-000008
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式6所示化合物的制备方法中，所述的有机溶剂可为本领域常规的有机溶剂，优选C 1-C 4的醇类溶剂、酯类溶剂、醚类溶剂、酮类溶剂、腈类溶剂、酰胺类溶剂和亚砜类溶剂中的一种或多种，更优选C 1-C 4的醇类溶剂。所述的C 1-C 4的醇类溶剂优选甲醇、乙醇和异丙醇中的一种或多种，更优选异丙醇。所述的酯类溶剂优选乙酸乙酯。所述的醚类溶剂优选乙醚和/或四氢呋喃(THF)。所述的酮类溶剂优选丙酮和/或2-丁酮。所述的腈类溶剂优选乙腈。所述的酰胺类溶剂优选N,N-二甲基甲酰胺(DMF)。所述的亚砜类溶剂优选二甲基亚砜(DMSO)。
所述的如式6所示化合物的制备方法中，所述的还原剂可为本领域常用的还原剂，优选碱金属氢化物。所述的碱金属氢化物可为氢化铝锂(LiAlH 4)、硼氢化锂(LiBH 4)、硼氢化钠(NaBH 4)、硼氢化钾(KBH 4)、二异丁基氢化铝[(i-Bu) 2AlH]、氰基硼氢化钠(NaBH 3CN)、硫代硼氢化钠(NaBH 2S 3)和三仲丁基硼氢化锂[LiBH(CH 3CH 2CH(CH 3)) 3]中的一种或多种，优选硼氢化锂、硼氢化钠和硼氢化钾中的一种或多种，更优选硼氢化锂。
所述的如式6所示化合物的制备方法中，所述的如式5所示化合物与所述的有机溶剂的质量体积比可为本领域常规的质量体积比，优选1:10-1:20g/mL，更优选1:10-1:15g/mL，例如1:13.3g/mL。
所述的如式6所示化合物的制备方法中，所述的如式5所示化合物与所述的还原剂的摩尔比可为本领域常规的摩尔比，优选1:1-1:5，更优选1:1-1:2，例如1:2。
所述的如式6所示化合物的制备方法中，所述的还原反应的温度可为本领域常规的温度，优选-5-30℃，更优选20-30℃，例如20℃或25℃。
所述的如式6所示化合物的制备方法中，所述的还原反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的还原反应的时间优选1-3h，例如2h或2.5h。
所述的如式6所示化合物的制备方法中，较佳地，所述的还原反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液降温至-10-0℃(例如-5℃)，用酸(优选盐酸，例如1N盐酸)调节pH至1-2，加入有机溶剂(优选酯类溶剂，例如乙酸乙酯)，再加入水，分液取水层，萃取(所述萃取的溶剂优选酯类溶剂，例如乙酸乙酯)水层并收集有机层，洗涤(所述洗涤的溶剂优选食盐水，例如饱和食盐水)，干燥，浓缩，即可。
所述的如式6所示化合物的制备方法中，所述的如式5所示化合物的制备方法还可包括以下步骤：溶剂中，在碱的存在下，将如式4所示化合物进行如下所述的水解反应，即得所述的如式5所示化合物；
Figure PCTCN2020114629-appb-000009
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式5所示化合物的制备方法中，所述的溶剂优选C 1-C 4的醇类溶剂、酯类溶剂、醚类溶剂、酮类溶剂、腈类溶剂、酰胺类溶剂或亚砜类溶剂中的一种或多种，更优选C 1-C 4的醇类溶剂。所述的C 1-C 4的醇类溶剂优选甲醇、乙醇和异丙醇中的一种或多种，更优选乙醇。所述的酯类溶剂优选乙酸乙酯。所述的醚类溶剂优选乙醚和/或四氢呋喃。所述的酮类溶剂优选丙酮和/或2-丁酮。所述的腈类溶剂优选乙腈。所述的酰胺类溶剂优选N,N-二甲基甲酰胺。所述的亚砜类溶剂优选二甲基亚砜。
所述的如式5所示化合物的制备方法中，所述的碱可为本领域常规的碱，例如无机碱。所述的无机碱优选碱金属碳酸盐和/或碱金属氢氧化物，更优选碱金属氢氧化物，所述的碱金属碳酸盐优选K 2CO 3和/或Cs 2CO 3，所述的碱金属氢氧化物优选LiOH、NaOH和KOH中的一种或多种。
所述的如式5所示化合物的制备方法中，所述的如式4所示化合物与所述的溶剂的质量体积比优选1:1-1:20g/mL，更优选1:5-1:13g/mL，例如1:5g/mL、1:6g/mL或1:13g/mL。
所述的如式5所示化合物的制备方法中，所述的如式4所示化合物与所述的碱的摩 尔比优选1:1-1:5，更优选1:1-1:3，例如1:2.9。
所述的如式5所示化合物的制备方法中，所述的水解反应的温度可为本领域常规的温度，例如-5℃-30℃，优选20℃-30℃。
所述的如式5所示化合物的制备方法中，所述的水解反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的水解反应的时间优选1-3h，进一步优选2-3h。
所述的如式5所示化合物的制备方法中，较佳地，所述的水解反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液冷却至-10-0℃(例如-5℃)，加入酸(优选盐酸，例如1N盐酸)调节pH至1-2，用有机溶剂(优选卤代烃类溶剂，例如二氯甲烷)萃取，合并有机层，洗涤(所述洗涤的溶剂优选食盐水，例如饱和食盐水)，干燥，浓缩，即可。
所述的如式5所示化合物的制备方法中，所述的如式4所示化合物的制备方法还可包括以下步骤：保护气体氛围下，在酸和氧化剂的存在下，将如式3所示化合物进行如下所示的分子内环合反应，即得所述的如式4所示化合物；
Figure PCTCN2020114629-appb-000010
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式4所示化合物的制备方法中，所述的保护气体可为本领域常规的保护气体，例如氮气或氩气。
所述的如式4所示化合物的制备方法中，所述的酸可为本领域常规的酸，例如无机酸和/或有机酸。所述的无机酸优选盐酸、硫酸和磷酸中的一种或多种。所述的有机酸优选甲酸和/或乙酸。
所述的如式4所示化合物的制备方法中，所述的氧化剂可为单电子氧化剂，所述的单电子氧化剂可为本领域常规的单电子氧化剂，优选锰盐和/或铈盐。所述的锰盐优选醋酸锰。所述的铈盐优选硝酸铈铵。
所述的如式4所示化合物的制备方法中，较佳地，所述的分子内环合反应还可在铜盐的参与下进行。所述的铜盐可为本领域常规的铜盐，例如醋酸亚铜、醋酸铜、氧化铜、氧化亚铜、氯化铜、氯化亚铜、溴化铜和溴化亚铜中的一种或多种，优选醋酸铜。所述的 铜盐与所述的如式3所示化合物的摩尔比可为本领域常规的摩尔比，优选1:1-2:1，更优选1:1-1.5:1，例如1:1。
所述的如式4所示化合物的制备方法中，所述的如式3所示化合物与所述的酸的质量体积比为1:1-1:20g/mL，更优选1:1-1:15g/mL，例如1:8.9g/mL。
所述的如式4所示化合物的制备方法中，所述的如式3所示化合物与所述的氧化剂的摩尔比可为本领域常规的摩尔比，优选1:1-5:1，更优选1:1-3:1，进一步优选1:1-2.5:1，例如2.5:1。
所述的如式4所示化合物的制备方法中，所述的分子内环合反应的温度可为本领域常规的温度，优选90-110℃，例如95℃。
所述的如式4所示化合物的制备方法中，所述的分子内环合反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的分子内环合反应的时间优选8-20h，更优选8-12h，例如12h。
所述的如式4所示化合物的制备方法中，较佳地，所述的分子内反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液浓缩，加入水和有机溶剂(优选醚类溶剂，例如叔丁基甲醚)，分离出水层，用有机溶剂(优选醚类溶剂，例如叔丁基甲醚)萃取，合并有机层，碱洗至中性，干燥，浓缩，即可。
所述的如式4所示化合物的制备方法中，所述的如式3所示化合物的制备方法可包括以下步骤：有机溶剂中，在金属催化剂的存在下，将如式2所示化合物与氢气进行如下所示的还原反应，即得所述的如式3所示化合物；
Figure PCTCN2020114629-appb-000011
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式3所示化合物的制备方法中，所述的有机溶剂可为本领域常规的有机溶剂，优选C 1-C 4的醇类溶剂、酯类溶剂和醚类溶剂中的一种或多种，更优选酯类溶剂。所述的C 1-C 4的醇类溶剂优选甲醇、乙醇和异丙醇中的一种或多种。所述的酯类溶剂优选乙酸乙酯。所述的醚类溶剂优选乙醚和/或四氢呋喃。
所述的如式3所示化合物的制备方法中，所述的金属催化剂可为本领域常规的金属催化剂，优选Pd/C、Pd(OH) 2、Raney镍、Pt/C和PtO 2中的一种或多种，更优选Pd/C。
所述的如式3所示化合物的制备方法中，所述的如式2化合物与所述的有机溶剂的质量体积比可为本领域常规的质量体积比，优选1:1-10:1g/mL，更优选1:1-8:1g/mL，进一步优选1:1-5:1g/mL，例如3:1g/mL。
所述的如式3所示化合物的制备方法中，所述的如式2所示化合物与所述的金属催化剂的质量比为10:1-100:1，进一步优选20:1-100:1，例如20:1。
所述的如式3所示化合物的制备方法中，对所述的氢气的用量不作特殊限定，以反应体系中氢气的压力为准，所述的氢气的压力可为本领域常规的压力，优选14.5-72.5psi，更优选15-50psi，例如15psi、30psi或50psi。
所述的如式3所示化合物的制备方法中，较佳地，所述的还原反应在酸的存在下进行。所述的酸可为本领域常规的酸，例如有机酸和/或无机酸。所述的有机酸优选甲酸和/或乙酸。所述的无机酸优选盐酸、硫酸和磷酸中的一种或多种。所述的如式2所示化合物与所述的酸的摩尔比可为本领域常规的摩尔比，优选1:1-1:2，更优选1:1-1:1.5，例如1:1.5。
所述的如式3所示化合物的制备方法中，所述的还原反应的温度可为本领域常规的温度，优选20-50℃，更优选15-30℃，例如15℃或30℃。
所述的如式3所示化合物的制备方法中，所述的还原反应可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的还原反应的时间优选0.5-8h，进一步优选0.5-5h，例如0.5h、1h或2h。
所述的如式3所示化合物的制备方法中，较佳地，所述的还原反应结束后，其还可进一步包括后处理操作，所述的后处理操作可包括以下步骤：将反应液过滤，浓缩，即可。
所述的如式3所示化合物的制备方法中，所述的如式2所示化合物的制备方法可包括以下步骤：保护气体氛围下，有机溶剂中，在碱、催化剂的存在下，将如式1所示化合物与如式A所示化合物进行如下所示的偶联反应，即得所述的如式2所示化合物；所述的催化剂包括配体和钯类化合物；
Figure PCTCN2020114629-appb-000012
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式2所示化合物的制备方法中，所述的保护气体可为本领域常规的保护气体，例如氮气和/或氩气。
所述的如式2所示化合物的制备方法中，所述的有机溶剂优选芳烃类溶剂、腈类溶剂、酰胺类溶剂、亚砜类溶剂、醚类溶剂和酮类溶剂中的一种或多种，更优选芳烃类溶剂。所述的芳烃类溶剂优选甲苯和/或二甲苯，更优选甲苯。所述的腈类溶剂优选乙腈。所述的酰胺类溶剂优选N,N-二甲基甲酰胺(DMF)和/或N,N-二甲基乙酰胺(DMA)。所述的亚砜类溶剂优选二甲基亚砜(DMSO)。所述的醚类溶剂优选四氢呋喃(THF)和/或1,4-二氧六环。所述的酮类溶剂优选N-甲基吡咯烷酮(DMP)。
所述的如式2所示化合物的制备方法中，所述的碱可为本领域常规的碱，例如有机碱和/或无机碱。所述的有机碱优选吡啶、哌啶、1,8-二氮杂二环十一碳-7-烯(DBU)、1,4-二氮杂二环[2.2.2]辛烷(DABCO)、碱金属醇盐和
Figure PCTCN2020114629-appb-000013
中的一种或多种，更优选
Figure PCTCN2020114629-appb-000014
例如三乙胺(Et 3N)和/或N-甲基二环己基胺(Cy 2NMe)；其中，R 1a、R 2a和R 3a独立地为氢、C 1～C 4的烷基(例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)或C 5-C 6的环烷基(例如环戊基或环己基)。所述的碱金属醇盐可为C 1～C 4醇的碱金属醇盐，例如叔丁醇钾和/或叔丁醇钠。所述的无机碱可为碱金属碳酸盐、碱金属氢化物和碱金属氢氧化物中的一种或多种。所述的碱金属碳酸盐可为K 2CO 3和/或Cs 2CO 3。所述的碱金属氢化物可为NaH。所述的碱金属氢氧化物可为NaOH和/或KOH。
所述的如式2所示化合物的制备方法中，所述的配体可为膦配体，所述的膦配体可为本领域常规的膦配体，例如单齿膦配体、双齿膦配体和多齿膦配体中的一种或多种，优选单齿膦配体。所述的单齿膦配体优选三苯基膦、三(2-甲苯基)膦、三(3-甲苯基)膦、三对甲苯基膦、三(4-氟苯基)膦、三(2-甲氧基苯基)膦、三(4-甲氧苯基)膦和2-(二叔丁基膦)联苯中的一种或多种，更优选三苯基膦和/或三(2-甲苯基)膦。所述的多齿膦配体优选
Figure PCTCN2020114629-appb-000015
所述的如式2所示化合物的制备方法中，所述的钯类化合物可为零价钯和/或二价钯。所述的零价钯可为Pd 2(dba) 3(dba：二亚苄基丙酮)。所述的二价钯可为Pd(OAc) 2、PdCl 2、 Pd(TFA) 2和Pd(MeCN) 2Cl 2中的一种或多种。
所述的如式2所示化合物的制备方法中，所述的钯类化合物和所述的配体可分开加入、所述的钯类化合物和所述的配体可形成络合物加入、或者、所述的钯类化合物和所述的配体可先形成络合物，再和所述的配体分开加入；所述的配体可独立地为膦配体。
所述的如式2所示化合物的制备方法中，当所述的钯类化合物和所述的配体可形成络合物加入、或者、所述的钯类化合物和所述的配体可先形成络合物，再和所述的配体分开加入时，所述的钯类化合物和所述的配体形成的络合物可为零价钯与配体形成的络合物和/或二价钯与配体形成的络合物；所述的零价钯与配体形成的络合物优选Pd(PPh 3) 4；所述的二价钯与配体形成的络合物优选Pd(PPh 3) 2Cl 2和/或Pd(dppf)Cl 2。
所述的如式2所示化合物的制备方法中，所述的如式1所示化合物与所述的如式A所示化合物的摩尔比可为本领域常规的摩尔比，优选1:1-1:3，进一步优选1:1-1:2，例如1:1.2。
所述的如式2所示化合物的制备方法中，所述的如式1所示化合物与所述的有机溶剂的质量体积比可为本领域常规的质量体积比，优选1:1-1:10g/mL，更优选1:1-1:5g/mL，进一步优选1:1-1:2g/mL。
所述的如式2所示化合物的制备方法中，所述的如式1所示化合物与所述的碱的摩尔比可为本领域常规的摩尔比，优选1:1-1:5，更优选1:1-1:3，进一步优选1:1-1:2。
所述的如式2所示化合物的制备方法中，所述的如式1所示化合物与所述的配体的摩尔比可为本领域常规的摩尔比，优选1:1-10:1，更优选1.25:1-10:1，进一步优选2:1-10:1。
所述的如式2所示化合物的制备方法中，所述的如式1所示化合物与所述的钯类化合物的摩尔比可为本领域常规的摩尔比，优选10:1-1000:1，更优选100:1-1000:1，进一步优选100:1-500:1，例如124:1。
所述的如式2所示化合物的制备方法中，所述的偶联反应的温度可为本领域常规的温度，优选90-110℃。
所述的如式2所示化合物的制备方法中，所述的偶联反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的偶联反应的时间优选8-20h，更优选8-12h。
所述的如式2所示化合物的制备方法中，较佳地，所述的偶联反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液冷却(优选冷却至室温)，用酸(优选盐酸，例如2M盐酸)调节pH至3-4，有机溶剂(优选醚类溶剂，例如叔丁基甲醚)萃取，洗涤(洗涤的溶剂优选氯化钠溶液，例如饱和氯化钠溶液)萃取所 得的有机相，干燥，分离纯化(优选柱层析分析，所述的柱层析分离的展开剂优选醚类溶剂和酯类溶剂，例如石油醚和乙酸乙酯)，即可。
本发明提供了一种如式7或式8所示化合物的制备方法中，其包括以下步骤：将如式7a或8a所示化合物和酸进行如下所示的中和反应，即得如式7或式8所示化合物；其中，X 1和X 2同前所述；所述的如式7a或式8a所示化合物的制备方法如前任一方案所述；
Figure PCTCN2020114629-appb-000016
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式7或式8所示化合物的制备方法中，所述的中和反应的条件和操作可为本领域常规的条件和操作。
本发明提供了一种如式6所示化合物的制备方法，其包括以下步骤：有机溶剂中，在还原剂的存在下，将如式5所示化合物进行如下所示的还原反应，即得所述的如式6所示化合物；
Figure PCTCN2020114629-appb-000017
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式6所示化合物的制备方法中，所述的还原反应的条件和操作与前述该类反应的条件和操作相同。
本发明提供了一种如式5所示化合物的制备方法，其包括以下步骤：溶剂中，在碱 的存在下，将如式4所示化合物进行如下所述的水解反应，即得所述的如式5所示化合物；
Figure PCTCN2020114629-appb-000018
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式5所示化合物的制备方法中，所述的水解反应的条件和操作与前述该类反应的条件和操作相同。
本发明提供了一种如式4所示化合物的制备方法，其包括以下步骤：
保护气体氛围下，在酸和氧化剂的存在下，将如式3所示化合物进行如下所示的分子内环合反应，即得所述的如式4所示化合物；
Figure PCTCN2020114629-appb-000019
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式4所示化合物的制备方法中，所述的内环合反应的条件和操作与前述该类反应的条件和操作相同。
本发明提供了一种如式3所示化合物的制备方法，其包括以下步骤：有机溶剂中，在金属催化剂的存在下，将如式2所示化合物与氢气进行如下所示的还原反应，即得所述的如式3所示化合物；
Figure PCTCN2020114629-appb-000020
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式3所示化合物的制备方法中，所述的还原反应的条件和操作与前述该类 反应的条件和操作相同。
本发明提供了一种如式2所示化合物的制备方法，其包括以下步骤：保护气体氛围下，有机溶剂中，在碱、催化剂的存在下，将如式1所示化合物与如式A所示化合物进行如下所示的偶联反应，即得所述的如式2所示化合物；所述的催化剂包括配体和钯类化合物；
Figure PCTCN2020114629-appb-000021
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式2所示化合物的制备方法中，所述的偶联反应的条件和操作与前述的该类反应的条件和操作相同。
本发明还提供了一种如式I所示化合物的制备方法，其为方法一或方法二：
其中，方法一包括以下步骤：有机溶剂中，在酸和硅烷类化合物的存在下，将如式B13所示化合物进行如下所示的还原胺化反应，即可；
Figure PCTCN2020114629-appb-000022
方法二包括以下步骤：有机溶剂中，在碱的存在下，将如式C13所示化合物进行如下所示的成醚反应，即可；
Figure PCTCN2020114629-appb-000023
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的方法一中，所述的有机溶剂可为本领域常规的有机溶剂，优选C 1-C 4醇类溶 剂、芳烃类溶剂和醚类溶剂中的一种或多种，更优选醚类溶剂。所述的C 1-C 4醇类溶剂优选甲醇、乙醇、正丙醇和异丙醇中的一种或多种。所述的芳烃类溶剂优选甲苯和/或二甲苯。所述的醚类溶剂优选乙醚、四氢呋喃和1,4-二氧六环中的一种或多种，更优选四氢呋喃。
所述的方法一中，所述的酸可为本领域常规的酸，可为无机酸和/或有机酸。所述的无机酸优选盐酸、硫酸和磷酸中的一种或多种。所述的有机酸优选甲酸、乙酸和三氟乙酸中的一种或多种，更优选三氟乙酸。
所述的方法一中，所述的硅烷类化合物优选苯硅烷、二乙基硅烷、三乙基硅烷、三氯硅烷和二乙氧基甲基硅烷中的一种或多种，更优选苯硅烷、二乙基硅烷和三乙基硅烷中的一种或多种，进一步优选苯硅烷。
所述的方法一中，所述的如式B13所示化合物与所述的有机溶剂的质量体积比可为本领域常规的质量体积比，优选1:1-1:20g/mL，更优选1:1-1:15g/mL，例如1:12g/mL。
所述的方法一中，所述的如式B13所示化合物与所述的酸的质量体积比可为本领域常规的质量体积比，优选1:1-1:5g/mL，更优选1:1-1:3g/mL，例如1:2.67g/mL。
所述的方法一中，所述的如式B13所示化合物与所述的硅烷类化合物的摩尔比优选1:1-1:10，更优选1:1-1:5，例如1:4.6。
所述的方法一中，所述的还原胺化反应的温度可为本领域常规的温度，优选20-30℃。
所述的方法一中，所述的还原胺化反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的还原胺化反应的时间优选1-5h，更优选1-3h。
所述的方法一中，较佳地，所述的还原胺化反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：除去溶剂(优选旋干)得残留物，加入有机溶剂(优选卤代烃类溶剂，例如二氯甲烷)，洗涤(所述的洗涤的溶剂优选碳酸氢钠溶液和食盐水，例如饱和碳酸氢钠溶液和饱和食盐水)有机层，浓缩即可。
所述的方法二中，所述的有机溶剂可为本领域常规的有机溶剂，例如芳烃类溶剂、腈类溶剂、酰胺类溶剂、亚砜类溶剂、醚类溶剂和酮类溶剂中的一种或多种，优选酰胺类溶剂和/或亚砜类溶剂，例如亚砜类溶剂。所述的芳烃类溶剂优选甲苯和/或二甲苯，更优选甲苯。所述的腈类溶剂优选乙腈。所述的酰胺类溶剂优选N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺。所述的亚砜类溶剂优选二甲基亚砜。所述的醚类溶剂优选四氢呋喃、1,4-二氧六环和乙二醇二甲醚中的一种或多种。所述的酮类溶剂优选N-甲基吡咯烷酮。
所述的方法二中，所述的碱可为本领域常规的碱，例如有机碱和/或无机碱。所述的有机碱优选吡啶、哌啶、1,8-二氮杂二环十一碳-7-烯、1,4-二氮杂二环[2.2.2]辛烷、碱金属 醇盐和
Figure PCTCN2020114629-appb-000024
中的一种或多种；其中，R 1a、R 2a和R 3a独立地为氢、C 1～C 4的烷基(例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)或C 5-C 6的环烷基(例如环戊基或环己基)。所述的碱金属醇盐可为C 1～C 4醇的碱金属醇盐，例如叔丁醇钾和/或叔丁醇钠。所述的无机碱可为碱金属碳酸盐、碱金属氢化物和碱金属氢氧化物中的一种或多种。所述的碱金属碳酸盐可为K 2CO 3和/或Cs 2CO 3，优选Cs 2CO 3。所述的碱金属氢化物可为NaH。所述的碱金属氢氧化物可为NaOH和/或KOH。
所述的方法二中，所述的如式C13所示化合物与所述的有机溶剂的质量体积比可为本领域常规的质量体积比，优选1:1-1:30g/mL，进一步优选1:1-1:20g/mL，例如1:20g/mL。
所述的方法二中，所述的如式C13所示化合物与所述的碱的摩尔比可为本领域常规的摩尔比，优选1:1-1:5，更优选1:1-1:3，进一步优选1:1-1:2，例如1:2。
所述的方法二中，所述的成醚反应的温度可为本领域常规的温度，优选50-100℃，更优选90-100℃，例如90℃。
所述的方法二中，所述的成醚反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的成醚反应的时间优选1-20h，进一步优选1-15h，例如15h。
所述的方法二中，较佳地，所述的成醚反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液与水混合，有机溶剂(优选酯类溶剂，例如乙酸乙酯)萃取，干燥有机层，过滤，浓缩，纯化，即可。所述的纯化优选重结晶或柱层析分离，所述的重结晶和柱层析分离的条件和操作与本领域常规的条件和操作相同。
所述的方法一中，所述的如式B13所示化合物的制备方法可包括以下步骤：溶剂中，在还原剂的存在下，将如式B12所示化合物进行如下所示的还原反应，即得如式B13所示化合物；
Figure PCTCN2020114629-appb-000025
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式B13所示化合物的制备方法中，所述的溶剂可为本领域常规的溶剂，例如C 1-C 4醇、酯类溶剂和醚类溶剂中的一种或多种。所述的C 1-C 4醇可为甲醇、乙醇和异 丙醇中的一种或多种。所述的酯类溶剂可为乙酸乙酯。所述的醚类溶剂可为四氢呋喃和/或1,4-二氧六环。
所述的如式B13所示化合物的制备方法中，所述的还原剂可为本领域常规的还原剂，又可为连二亚硫酸钠、氢化铝锂、硼氢化钠或具有还原能力的活泼金属。所述的活泼金属可为铁、锌或锡中的一种或多种，优选铁和/或锌。
所述的如式B13所示化合物的制备方法中，当所述的还原剂为具有还原能力的活泼金属时，所述的还原反应需要在酸的参与下进行，较佳地，所述的酸可作为溶剂。所述的酸可为本领域常规的酸，例如无机酸和/或有机酸。所述的无机酸可为盐酸、硫酸和/或磷酸。所述的有机酸可为甲酸和/或乙酸，优选乙酸。
所述的如式B13所示化合物的制备方法中，所述的还原反应中还可加入盐类电解质，所述的盐类电解质用于活化金属，促进还原反应进行。所述的盐类电解质可为本领域常规的盐类电解质，例如铵盐，所述的铵盐优选氯化铵。
所述的如式B13所示化合物的制备方法中，所述的如式B12所示化合物与所述的溶剂的质量体积比可为本领域常规的质量体积比，优选1:10-1:30g/mL，更优选1:10-1:20g/mL。
所述的如式B13所示化合物的制备方法中，所述的如式B12所示化合物与所述的还原剂的摩尔比可为本领域常规的摩尔比，优选1:1-1:8，更优选1:1-1:6。
所述的如式B13所示化合物的制备方法中，所述的还原反应的温度可为本领域常规的温度，优选20-75℃，更优选50-75℃，例如70-75℃。
所述的如式B13所示化合物的制备方法中，所述的还原反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的还原反应的时间优选1-5h，更优选1-3h。
所述的如式B13所示化合物的制备方法中，较佳地，所述的还原反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液冷却(优选冷却至室温)，加入有机溶剂(优选卤代烃类溶剂，例如二氯甲烷)，过滤(优选硅藻土过滤)，洗涤滤饼(所述的洗涤的溶剂优选卤代烃类溶剂，例如二氯甲烷)，干燥，即可。
所述的方法二中，所述的如式C13所示化合物的制备方法可包括以下步骤：有机溶剂中，在还原剂的存在下，将如式C12所示化合物进行如下所示的还原反应，即得所述的如式C13所示化合物；
Figure PCTCN2020114629-appb-000026
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式C13所示化合物的制备方法中，所述的有机溶剂可为本领域常规的有机溶剂，例如芳烃类溶剂、腈类溶剂、酰胺类溶剂、亚砜类溶剂、醚类溶剂、酮类溶剂和C 1-C 4的醇类溶剂中的一种或多种，优选C 1-C 4的醇类溶剂。所述的芳烃类溶剂优选甲苯和/或二甲苯。所述的腈类溶剂优选乙腈。所述的酰胺类溶剂优选N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺。所述的亚砜类溶剂优选二甲基亚砜。所述的醚类溶剂优选四氢呋喃、1,4-二氧六环和乙二醇二甲醚中的一种或多种。所述的酮类溶剂优选N-甲基吡咯烷酮。所述的C 1-C 4的醇类溶剂优选甲醇、乙醇和异丙醇中的一种或多种，更优选异丙醇。
所述的如式C13所示化合物的制备方法中，所述的还原剂可为本领域常规的还原剂，例如碱金属氢化物。所述的碱金属氢化物可为氢化铝锂、硼氢化锂、硼氢化钠、硼氢化钾、二异丁基氢化铝、氰基硼氢化钠和三仲丁基硼氢化锂中的一种或多种，优选硼氢化锂、硼氢化钠和硼氢化钾中的一种或多种，更优选硼氢化锂。
所述的如式C13所示化合物的制备方法中，所述的如式C12所示化合物与所述的有机溶剂的质量体积比可为本领域常规的质量体积比，优选1:1-1:20g/mL，进一步优选1:1-1:12g/mL，例如10.6g/mL。
所述的如式C13所示化合物的制备方法中，所述的如式C12所示化合物与所述的还原剂的摩尔比可为本领域常规的摩尔比，优选1:1-1:5，更优选1:1-1:2，例如1:2。
所述的如式C13所示化合物的制备方法中，所述的还原反应的温度可为本领域常规的温度，优选20-90℃。
所述的如式C13所示化合物的制备方法中，所述的还原反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的还原反应的时间优选1-5h，更优选1-3h。
所述的如式C13所示化合物的制备方法中，较佳地，所述的还原反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液和水(优选冰水)混合淬灭反应，萃取(所述的萃取的溶剂优选酯类溶剂，优选乙酸乙酯)，干燥有机层， 过滤，浓缩至干，纯化，即可。所述的纯化优选重结晶或柱层析分离，所述的重结晶和柱层析分离的条件和操作与本领域常规的条件和操作相同。
所述的如式B13所示化合物的制备方法中，所述的如式B12所示化合物的制备方法可包括以下步骤：有机溶剂中，在氧化剂的存在下，将如式B11所示化合物进行如下所示的氧化反应，即得所述的如式B12所示化合物；
Figure PCTCN2020114629-appb-000027
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式B12所示化合物的制备方法中，所述的有机溶剂可为本领域常规的有机溶剂，例如卤代烃类溶剂、酰胺类溶剂、亚砜类溶剂和酮类溶剂中的一种或多种，优选卤代烃类溶剂。所述的卤代烃类溶剂优选二氯甲烷、氯仿和1,2-二氯乙烷中的一种或多种，更优选二氯甲烷。所述的酰胺类溶剂优选N,N-二甲基甲酰胺。所述的亚砜类溶剂优选二甲基亚砜。所述的酮类溶剂优选丙酮和/或2-丁酮。
所述的如式B12所示化合物的制备方法中，所述的氧化剂可为本领域常规的氧化剂，例如金属氧化剂和/或非金属氧化物。所述的金属氧化剂可为铬氧化物和/或锰氧化物。所述的铬氧化物可为氯铬酸吡啶鎓盐(PCC)。所述的锰氧化物可为二氧化锰。所述的非金属氧化物可为戴斯-马丁试剂(DMP)。
所述的如式B12所示化合物的制备方法中，所述的如式B11所示化合物和所述的有机溶剂的质量体积比可为本领域常规的质量体积比，优选1:1-1:20g/mL，更优选1:1-1:15g/mL，进一步优选1:1-1:12g/mL。
所述的如式B12所示化合物的制备方法中，所述的如式B11所示化合物和所述的氧化剂的摩尔比可为本领域常规的摩尔比，优选1:1-1:3，更优选1:1-1:1.5。
所述的如式B12所示化合物的制备方法中，所述的氧化反应的温度可为本领域常规的反应，优选20-30℃。
所述的如式B12所示化合物的制备方法中，所述的氧化反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的氧化反应的时间优选1-5h，更优选1-3h。
所述的如式B12所示化合物的制备方法中，较佳地，所述的氧化反应结束后，其还 可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液过滤(优选用硅藻土过滤)，洗涤滤液(所述的洗涤的溶剂优选亚硫酸钠和碳酸氢钠的混合溶液，更优选饱和亚硫酸钠和碳酸氢钠的混合溶液)，分离有机相并浓缩，即可。
所述的如式C13所示化合物的制备方法中，所述的如式C12所示化合物的制备方法可包括以下步骤：有机溶剂中，在酸和硅烷类化合物的存在下，将如式C11化合物和如式C10所示化合物进行如下所示的还原胺化反应，即得所述的如式C12所示化合物；
Figure PCTCN2020114629-appb-000028
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式C12所示化合物的制备方法中，所述的有机溶剂可为本领域常规的有机溶剂，优选C 1-C 4醇类溶剂、芳烃类溶剂和醚类溶剂中的一种或多种，更优选醚类溶剂。所述的C 1-C 4醇类溶剂优选甲醇、乙醇、正丙醇和异丙醇中的一种或多种。所述的芳烃类溶剂优选甲苯和/或二甲苯。所述的醚类溶剂优选乙醚、THF和1,4-二氧六环中的一种或多种，更优选THF。
所述的如式C12所示化合物的制备方法中，所述的酸可为本领域常规的酸，可为无机酸和/或有机酸。所述的无机酸优选盐酸、硫酸和磷酸中的一种或多种。所述的有机酸优选甲酸、乙酸和三氟乙酸中的一种或多种，更优选三氟乙酸。
所述的如式C12所示化合物的制备方法中，所述的硅烷类化合物优选苯硅烷、二乙基硅烷、三乙基硅烷、三氯硅烷和二乙氧基甲基硅烷中的一种或多种，更优选苯硅烷、二乙基硅烷和三乙基硅烷中的一种或多种，进一步优选苯硅烷。
所述的如式C12所示化合物的制备方法中，所述的如式C11所示化合物与所述的有机溶剂的质量体积比为可为本领域常规的质量体积比，优选1:1-1:20g/mL，更优选1:1-1:12g/mL。
所述的如式C12所示化合物的制备方法中，所述的如式C11所示化合物与所述的如式C10所示化合物的摩尔比可为本领域常规的摩尔比，优选1:1-1:5，更优选1:1-1:2，例如1:1.2。
所述的如式C12所示化合物的制备方法中，所述的如式C11所示化合物与所述的酸的质量体积比可为本领域常规的质量体积比，优选1:1-1:5g/mL，更优选1:1-1:3g/mL，例 如1:3g/mL。
所述的如式C12所示化合物的制备方法中，所述的如式C11所示化合物与所述的硅烷类化合物的摩尔比优选1:1-1:10，更优选1:1-1:6，例如1:5.14。
所述的如式C12所示化合物的制备方法中，所述的还原胺化反应的温度优选20-30℃。
所述的如式C12所示化合物的制备方法中，所述的还原胺化反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的还原胺化反应的时间优选1-30h，更优选1-20h。
所述的如式C12所示化合物的制备方法中，较佳地，所述的还原胺化反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液与水混合淬灭反应，有机溶剂(优选酯类溶剂，优选乙酸乙酯)萃取，干燥有机层，过滤，浓缩至干，纯化(优选柱层析分离)，即可。
所述的如式B12所示化合物的制备方法中，所述的如式B11所示化合物的制备方法可为方法A、方法B、方法C和方法D中的任意一种，
所述的方法A包括以下步骤：有机溶剂中，在还原剂的存在下，将如式B10所示化合物进行如下所示的水解反应，即得所述的如式B11所示化合物；
Figure PCTCN2020114629-appb-000029
所述的方法B包括以下步骤：
(b1)将所述的如式B10所示化合物与卤化剂进行如下所示的酰化反应，得酰氯；
(b2)将步骤(b1)中得到的酰氯与还原剂进行如下所示的还原反应，即得所述的如式B11所示化合物；
Figure PCTCN2020114629-appb-000030
所述的方法C包括以下步骤：
(c1)将所述的如式B10所示化合物与醇进行如下所示的酯化反应，得酯；
(c2)将步骤(c1)中得到的酯与还原剂进行如下所示的还原反应，即得所述的如式 B11所示化合物；
Figure PCTCN2020114629-appb-000031
所述的方法D包括以下步骤：
(d1)在活化剂和碱的存在下，将所述的如式B10所示化合物进行如下所示的反应，得酸酐；
(d2)将步骤(d1)中得到的酸酐与还原剂进行如下所示的还原反应，即得所述的如式B11所示化合物；
Figure PCTCN2020114629-appb-000032
其中，其中，R 1、R 2、R 3和R 4同前任一方案所述；
R 5和R 6独立地为C 1-C 4的烷基(例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
所述的如式B11所示化合物的制备方法中，方法A中，所述的有机溶剂可为本领域常规的有机溶剂，优选芳烃类溶剂、腈类溶剂、酰胺类溶剂、亚砜类溶剂、醚类溶剂、酮类溶剂和C 1-C 4的醇类溶剂中的一种或多种，更优选醚类溶剂。所述的芳烃类溶剂可为甲苯和/或二甲苯。所述的腈类溶剂可为乙腈。所述的酰胺类溶剂可为N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺(DMA)。所述的亚砜类溶剂可为二甲基亚砜。所述的醚类溶剂可为四氢呋喃、1,4-二氧六环和乙二醇二甲醚(DME)中的一种或多种，优选DME。所述的酮类溶剂可为N-甲基吡咯烷酮。所述的C 1-C 4的醇类溶剂可为甲醇、乙醇和异丙醇中的一种或多种。
所述的如式B11所示化合物的制备方法中，方法A中，所述的还原剂可为本领域常规的还原剂，例如碱金属氢化物。所述的碱金属氢化物可为氢化铝锂(LiAlH 4)、硼氢化锂(LiBH 4)、硼氢化钠(NaBH 4)、硼氢化钾(KBH 4)、二异丁基氢化铝、氰基硼氢化钠(NaBH 3CN)和三仲丁基硼氢化锂中的一种或多种，优选硼氢化锂、硼氢化钠和硼氢化钾中的一种或多种，更优选硼氢化钠。
所述的如式B11所示化合物的制备方法中，方法A中，所述的如式B10所示化合物与所述的有机溶剂的质量体积比可为本领域常规的质量体积比，优选1:1-1:20g/mL，更优选1:1-1:15g/mL，进一步优选1:1-1:12g/mL，例如1:10.26g/mL。
所述的如式B11所示化合物的制备方法中，所述的如式B10所示化合物与所述的还原剂的摩尔比可为本领域常规的摩尔比，优选1:1-1:5，更优选1:1-1:2，例如1:1.1。
所述的如式B11所示化合物的制备方法中，所述的还原反应的温度可为本领域常规的温度，优选-10-10℃，更优选为-5-5℃，例如-5-0℃。
所述的如式B11所示化合物的制备方法中，方法A中，所述的还原反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的还原反应的时间优选1-5h，更优选1-3h。
所述的如式B11所示化合物的制备方法中，步骤(b1)中，所述的卤化剂可为本领域常规的卤化剂，例如三氯化磷、五氯化磷、亚硫酰氯和草酰氯中的一种或多种，优选亚硫酰氯和/或草酰氯。
所述的如式B11所示化合物的制备方法中，步骤(b1)中，所述的如式B10所示化合物和所述的卤化剂的摩尔比可为本领域常规的摩尔比，优选1:1-1:3，更优选1:1-1:2。
所述的如式B11所示化合物的制备方法中，步骤(b1)中，所述的酰化反应的其他条件和操作与本领域该类反应常规的条件和操作相同。
所述的如式B11所示化合物的制备方法中，步骤(b2)中，所述的还原反应的条件和操作与本领域该类反应常规的条件和操作相同。
所述的如式B11所示化合物的制备方法中，步骤(c1)中，所述的醇可为本领域常规的醇，优选C 1-C 4的醇，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇或异丁醇。
所述的如式B11所示化合物的制备方法中，步骤(c1)中，所述的如式B10所示化合物和所述的醇的摩尔比可为本领域常规的摩尔比，优选1:1-1:2，更优选1:1-1:1.5。
所述的如式B11所示化合物的制备方法中，步骤(c1)中，所述的酯化反应的其他条件和操作与本领域该类反应常规的条件和操作相同。
所述的如式B11所示化合物的制备方法中，步骤(c2)中，所述的还原反应的条件和操作与本领域该类反应常规的条件和操作相同。
所述的如式B11所示化合物的制备方法中，步骤(d1)中，所述的活化剂可为本领域常规的活化剂，例如氯甲酸乙酯、氯甲酸异丁酯、氯甲酸三氯甲酯和氯甲酸苄酯中的一种或多种，优选氯甲酸乙酯和/或氯甲酸异丁酯。
所述的如式B11所示化合物的制备方法中，步骤(d1)中，所述的碱可为本领域常 规的碱，优选有机碱，例如Et 3N、二异丙基乙基胺(i-Pr 2Net)、DBU、DABCO、吡啶、哌啶和N-甲基吗啉中的一种或多种。
所述的如式B11所示化合物的制备方法中，步骤(d1)中，所述的如式B10所示化合物和所述的活化剂的摩尔比可为本领域常规的摩尔比，优选1:1-1:2，更优选1:1-1:1.5。
所述的如式B11所示化合物的制备方法中，步骤(d1)中，所述的如式B10所示化合物和所述的碱的摩尔比可为本领域常规的摩尔比，优选1:1-1:2，更优选1:1-1:1.5。
所述的如式B11所示化合物的制备方法中，步骤(d2)中，所述的还原反应的条件和操作与本领域该类反应常规的条件和操作相同。
所述的如式B11所示化合物的制备方法中，较佳地，所述的还原反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液和水(优选冰水)混合淬灭反应，萃取(所述的萃取的溶剂优选酯类溶剂，优选乙酸乙酯)，干燥有机层，过滤，浓缩至干，纯化，即可。所述的纯化优选重结晶或柱层析分离，所述的重结晶和柱层析分离的条件和操作与本领域常规的条件和操作相同。
所述的如式C12所示化合物的制备方法中，所述的如式C11所示化合物的制备方法可包括以下步骤：有机溶剂中，在氧化剂的存在下，将如式C9所示化合物进行如下所示的氧化反应，即得所述的如式C11所示化合物；
Figure PCTCN2020114629-appb-000033
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式C11所示化合物的制备方法中，所述的有机溶剂可为本领域常规的有机溶剂，例如卤代烃类溶剂、酰胺类溶剂、亚砜类溶剂和酮类溶剂中的一种或多种，优选卤代烃类溶剂。所述的卤代烃类溶剂可为二氯甲烷、氯仿和1,2-二氯乙烷中的一种或多种，优选二氯甲烷。所述的酰胺类溶剂可为N,N-二甲基甲酰胺。所述的亚砜类溶剂可为二甲基亚砜。所述的酮类溶剂可为丙酮和/或2-丁酮。
所述的如式C11所示化合物的制备方法中，所述的氧化剂可为本领域常规的氧化剂，例如金属氧化剂和/或非金属氧化物。所述的金属氧化剂可为铬氧化物和/或锰氧化物。所述的铬氧化物可为氯铬酸吡啶鎓盐。所述的锰氧化物可为二氧化锰。所述的非金属氧化物可为戴斯-马丁试剂。
所述的如式C11所示化合物的制备方法中，所述的如式C9所示化合物和所述的有机溶剂的质量体积比可为本领域常规的质量体积比，优选1:1-1:30g/mL，更优选1:1-1:22g/mL，例如20.3g/mL。
所述的如式C11所示化合物的制备方法中，所述的如式C9所示化合物和所述的氧化剂的摩尔比可为本领域常规的摩尔比，优选1:1-1:3，更优选1:1-1:1.5，例如1:1.48。
所述的如式C11所示化合物的制备方法中，所述的氧化反应的温度可为本领域常规的反应，优选20-50℃，更优选20-30℃。
所述的如式C11所示化合物的制备方法中，所述的氧化反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的氧化反应的时间优选1-5h，更优选1h-3h。
所述的如式C11所示化合物的制备方法中，较佳地，所述的氧化反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液与溶剂(优选亚硫酸钠和碳酸氢钠的混合溶液)混合，分离有机层，有机溶剂(优选酯类溶剂，例如乙酸乙酯)萃取，干燥有机层，过滤，浓缩，纯化(优选柱层析分离)，即可。
所述的如式B11所示化合物的制备方法中，所述的如式B10所示化合物的制备方法可包括以下步骤：有机溶剂中，在碱的存在下，将如式7所示化合物与如式B9所示化合物进行如下所示的成醚反应，即得所述的如式B10所示化合物；
Figure PCTCN2020114629-appb-000034
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式B10所示化合物的制备方法中，所述的成醚反应优选在保护气体氛围下进行，所述的保护气体可为本领域常规的保护气体，例如氮气。
所述的如式B10所示化合物的制备方法中，所述的有机溶剂可为本领域常规的有机溶剂，例如芳烃类溶剂、腈类溶剂、酰胺类溶剂、亚砜类溶剂、醚类溶剂和酮类溶剂中的一种或多种，优选酰胺类溶剂和/或亚砜类溶剂。所述的芳烃类溶剂优选甲苯和/或二甲苯，更优选甲苯。所述的腈类溶剂优选乙腈。所述的酰胺类溶剂优选N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺。所述的亚砜类溶剂优选二甲基亚砜。所述的醚类溶剂优选四氢呋喃、1,4-二氧六环和乙二醇二甲醚中的一种或多种。所述的酮类溶剂优选N-甲基吡咯烷酮。
所述的如式B10所示化合物的制备方法中，所述的碱可为本领域常规的碱，例如有机碱和/或无机碱。所述的有机碱优选吡啶、哌啶、1,8-二氮杂二环十一碳-7-烯、1,4-二氮杂二环[2.2.2]辛烷、碱金属醇盐和
Figure PCTCN2020114629-appb-000035
中的一种或多种；其中，R 1a、R 2a和R 3a独立地为氢、C 1～C 4的烷基(例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)或C 5-C 6的环烷基(例如环戊基或环己基)。所述的碱金属醇盐可为C 1～C 4醇的碱金属醇盐，例如叔丁醇钾和/或叔丁醇钠。所述的无机碱可为碱金属碳酸盐、碱金属氢化物和碱金属氢氧化物中的一种或多种。所述的碱金属碳酸盐可为K 2CO 3和/或Cs 2CO 3。所述的碱金属氢化物可为NaH。所述的碱金属氢氧化物可为NaOH和/或KOH。
所述的如式B10所示化合物的制备方法中，所述的如式7所示化合物与所述的有机溶剂的质量体积比可为本领域常规的质量体积比，优选1:1-1:20g/mL，进一步优选1:1-1:15g/mL，更优选1:1-1:12g/mL。
所述的如式B10所示化合物的制备方法中，所述的如式7所示化合物与所述的如式9所示化合物的摩尔比可为本领域常规的摩尔比，优选1:1-1:5，更优选1:1-1:3，进一步优选1:1-1:2。
所述的如式B10所示化合物的制备方法中，所述的如式7所示化合物与所述的碱的摩尔比可为本领域常规的摩尔比，优选为1:1-1:5，进一步优选1:1-1:4。
所述的如式B10所示化合物的制备方法中，所述的成醚反应的温度可为本领域常规的温度，优选-10-10℃，进一步优选为-5-5℃，例如-2-2℃。
所述的如式B10所示化合物的制备方法中，所述的成醚反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的成醚反应的时间优选1-5h，更优选1-3h。
所述的如式B10所示化合物的制备方法中，较佳地，所述的成醚反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：将反应液与水(优选冰水)混合，用酸(优选盐酸，例如1N盐酸)调节pH值3-4，有机溶剂(优选酯类溶剂，例如乙酸乙酯)萃取，干燥有机层，过滤，浓缩至干，纯化，即可。所述的纯化优选重结晶或柱层析分离，所述的重结晶和柱层析分离的条件和操作与本领域常规的条件和操作相同。
所述的如式B10所示化合物的制备方法中，所述的如式7所示化合物的制备方法如前任一方案所述。
所述的如式C11所示化合物的制备方法中，所述的如式C9所示化合物的制备方法 可包括以下步骤：有机溶剂中，在碱的存在下，将如式8所示化合物与甲基化试剂进行如下所示的甲基化反应，即得所述的如式C9所示化合物；
Figure PCTCN2020114629-appb-000036
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式C9所示化合物的制备方法中，所述的有机溶剂可为本领域常规的有机溶剂，例如芳烃类溶剂、腈类溶剂、酰胺类溶剂、亚砜类溶剂、醚类溶剂和酮类溶剂中的一种或多种，优选酰胺类溶剂。所述的芳烃类溶剂优选甲苯和/或二甲苯，更优选甲苯。所述的腈类溶剂优选乙腈。所述的酰胺类溶剂优选N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺，例如N,N-二甲基甲酰胺。所述的亚砜类溶剂优选二甲基亚砜。所述的醚类溶剂优选四氢呋喃和/或1,4-二氧六环。所述的酮类溶剂优选N-甲基吡咯烷酮。
所述的如式C9所示化合物的制备方法中，所述的碱可为本领域常规的碱，例如有机碱和/或无机碱。所述的有机碱优选吡啶、哌啶、1,8-二氮杂二环十一碳-7-烯(DBU)、1,4-二氮杂二环[2.2.2]辛烷(DABCO)、碱金属醇盐和
Figure PCTCN2020114629-appb-000037
中的一种或多种；其中，R 1a、R 2a和R 3a独立地为氢、C 1～C 4的烷基(例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)或C 5-C 6的环烷基(例如环戊基或环己基)。所述的碱金属醇盐可为C 1～C 4醇的碱金属醇盐，例如叔丁醇钾和/或叔丁醇钠。所述的无机碱可为碱金属碳酸盐、碱金属氢化物和碱金属氢氧化物中的一种或多种，优选碱金属碳酸盐。所述的碱金属碳酸盐可为K 2CO 3和/或Cs 2CO 3，优选K 2CO 3。所述的碱金属氢化物可为NaH。所述的碱金属氢氧化物可为NaOH和/或KOH。
所述的如式C9所示化合物的制备方法中，所述的甲基化试剂可为本领域常规的甲基化试剂，例如卤代甲烷、硫酸二甲酯和碳酸二甲酯中的一种或多种，优选卤代甲烷。所述的卤代甲烷优选碘甲烷。
所述的如式C9所示化合物的制备方法中，所述的如式8所示化合物与所述的有机溶剂的质量体积比可为本领域常规的质量体积比，优选1:1-1:30g/mL，更优选1:1-1:20g/mL，例如1:20g/mL。
所述的如式C9所示化合物的制备方法中，所述的如式8所示化合物与所述的碱的摩尔比可为本领域常规的摩尔比，优选1:1-1:5，更优选1:1-1:3，进一步优选1:1-1:2，例如1:1.7。
所述的如式C9所示化合物的制备方法中，所述的如式8所示化合物与所述的甲基化试剂的摩尔比可为本领域常规的摩尔比，优选1:1-1:2，进一步优选1:1-1:1.5，例如1:1.2。
所述的如式C9所示化合物的制备方法中，所述的甲基化反应的温度可为本领域常规的温度，优选20-30℃。
所述的如式C9所示化合物的制备方法中，所述的甲基化反应的进程可通过本领域常规的手段进行监控(例如TLC、HPLC或LC-MS)，所述的甲基化反应的时间优选1-5h，更优选1-3h。
所述的如式C9所示化合物的制备方法中，较佳地，所述的甲基化反应结束后，其还可进一步包括后处理操作，所述的后处理操作包括以下步骤：加入溶剂(优选酸类溶剂，例如盐酸，又例如1N盐酸)淬灭反应，有机溶剂(优选酯类溶剂，例如乙酸乙酯)萃取，干燥有机层，过滤，浓缩，纯化(优选柱层析分离)，即可。
所述的如式C9所示化合物的制备方法中，所述的如式8所示化合物的制备方法如前任一方案所述。
本发明提供了一种如式B13所示化合物的制备方法，其包括以下步骤：溶剂中，在还原剂的存在下，将如式B12所示化合物进行如下所示的还原反应，即得如式B13所示化合物；
Figure PCTCN2020114629-appb-000038
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式B13所示化合物的制备方法中，所述的还原反应的条件和操作与前述该类反应的条件和操作相同。
本发明提供了一种如式B12所示化合物的制备方法，其包括以下步骤：有机溶剂中，在氧化剂的存在下，将如式B11所示化合物进行如下所示的氧化反应，即得所述的如式B12所示化合物；
Figure PCTCN2020114629-appb-000039
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式B12所示化合物的制备方法中，所述的氧化反应的条件和操作与前述该类反应的条件和操作相同。
本发明提供了一种如式B11所示化合物的制备方法，其可为方法A、方法B、方法C和方法D中的任意一种，
所述的方法A包括以下步骤：有机溶剂中，在还原剂的存在下，将如式B10所示化合物进行如下所示的水解反应，即得所述的如式B11所示化合物；
Figure PCTCN2020114629-appb-000040
所述的方法B包括以下步骤：
(b1)将所述的如式B10所示化合物与卤化剂进行如下所示的酰化反应，得酰氯；
(b2)将步骤(b1)中得到的酰氯与还原剂进行如下所示的还原反应，即得所述的如式B11所示化合物；
Figure PCTCN2020114629-appb-000041
所述的方法C包括以下步骤：
(c1)将所述的如式B10所示化合物与醇进行如下所示的酯化反应，得酯；
(c2)将步骤(c1)中得到的酯与还原剂进行如下所示的还原反应，即得所述的如式B11所示化合物；
Figure PCTCN2020114629-appb-000042
所述的方法D包括以下步骤：
(d1)在活化剂和碱的存在下，将所述的如式B10所示化合物进行如下所示的反应，得酸酐；
(d2)将步骤(d1)中得到的酸酐与还原剂进行如下所示的还原反应，即得所述的如式B11所示化合物；
Figure PCTCN2020114629-appb-000043
其中，其中，R 1、R 2、R 3、R 4、R 5和R 6同前任一方案所述。
所述的如式B11所示化合物的制备方法中，各反应的条件和操作均与前述该类反应的条件和操作相同。
本发明提供了一种如式B10所示化合物的制备方法，其包括以下步骤：有机溶剂中，在碱的存在下，将如式7所示化合物与如式B9所示化合物进行如下所示的成醚反应，即得所述的如式B10所示化合物；
Figure PCTCN2020114629-appb-000044
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式B10所示化合物的制备方法中，所述的成醚反应的条件和操作与前述该类反应的条件和操作相同。
本发明提供了一种如式C13所示化合物的制备方法，其包括以下步骤：有机溶剂中，在还原剂的存在下，将如式C12所示化合物进行如下所示的还原反应，即得所述的如式 C13所示化合物；
Figure PCTCN2020114629-appb-000045
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式C13所示化合物的制备方法中，所述的还原反应的条件和操作与前述该类反应的条件和操作相同。
本发明提供了一种如式C12所示化合物的制备方法，其包括以下步骤：有机溶剂中，在酸和硅烷类化合物的存在下，将如式C11化合物和如式C10所示化合物进行如下所示的还原胺化反应，即得所述的如式C12所示化合物；
Figure PCTCN2020114629-appb-000046
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式C12所示化合物的制备方法中，所述的还原胺化反应的条件和操作与前述该类反应的条件和操作相同。
本发明提供了一种如式C11所示化合物的制备方法，其包括以下步骤：有机溶剂中，在氧化剂的存在下，将如式C9所示化合物进行如下所示的氧化反应，即得所述的如式C11所示化合物；
Figure PCTCN2020114629-appb-000047
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式C11所示化合物的制备方法中，所述的氧化反应的条件和操作与前述该 类反应的条件和操作相同。
本发明提供了一种如式C9所示化合物的制备方法，其包括以下步骤：有机溶剂中，在碱的存在下，将如式8所示化合物与甲基化试剂进行如下所示的甲基化反应，即得所述的如式C9所示化合物；
Figure PCTCN2020114629-appb-000048
其中，R 1、R 2、R 3和R 4同前任一方案所述。
所述的如式C9所示化合物的制备方法中，所述的甲基化反应的条件和操作与前述该类反应的条件和操作相同。
本发明还提供了如式I-1所示化合物的制备方法，其合成路线可为以下路线1～路线4中的任意一条：
路线1
Figure PCTCN2020114629-appb-000049
路线2
Figure PCTCN2020114629-appb-000050
路线3
Figure PCTCN2020114629-appb-000051
路线4
Figure PCTCN2020114629-appb-000052
所述的路线1～路线4中任一反应的条件和操作均同前述该反应的条件和操作相同。
本发明还提供了如式7-1或式8-1所示化合物的制备方法，
其中，所述的如式7-1所示化合物的合成路线如下所示：
Figure PCTCN2020114629-appb-000053
所述的如式8-1所示化合物的合成路线如下所示：
Figure PCTCN2020114629-appb-000054
所述的如式7-1或式8-1所示化合物的合成路线中任一反应的条件和操作均同前述该反应的条件和操作相同。
本发明还提供了如下式所示的化合物：
Figure PCTCN2020114629-appb-000055
其中，R 1、R 2、R 3、R 4、X 1和X 2同前任一方案所述。
本发明还提供了如下式所示的化合物：
Figure PCTCN2020114629-appb-000056
Figure PCTCN2020114629-appb-000057
本发明提供了一种化合物7a-1或化合物8a-1的晶型，
Figure PCTCN2020114629-appb-000058
所述的化合物7a-1的晶型的空间群为P 21 21 21，其晶胞参数为
Figure PCTCN2020114629-appb-000059
α＝90°；
Figure PCTCN2020114629-appb-000060
β＝90°；
Figure PCTCN2020114629-appb-000061
γ＝90°；
较佳地，所述的7a-1的晶型属正交晶系，空间群为P 21 21 21，其晶胞参数为
Figure PCTCN2020114629-appb-000062
Figure PCTCN2020114629-appb-000063
α＝90°；
Figure PCTCN2020114629-appb-000064
β＝90°；
Figure PCTCN2020114629-appb-000065
γ＝90°；晶胞体积为
Figure PCTCN2020114629-appb-000066
Figure PCTCN2020114629-appb-000067
晶胞内不对称单位数Z＝4；
更佳地，所述的化合物7a-1的晶型参数为表1中的参数；
所述的化合物8a-1的晶型的空间群为P 21 21 21，其晶胞参数为
Figure PCTCN2020114629-appb-000068
α＝90°；
Figure PCTCN2020114629-appb-000069
β＝90°；
Figure PCTCN2020114629-appb-000070
γ＝90°；
较佳地，所述的8a-1的晶型属正交晶系，空间群为P 21 21 21，其晶胞参数为
Figure PCTCN2020114629-appb-000071
Figure PCTCN2020114629-appb-000072
α＝90°；
Figure PCTCN2020114629-appb-000073
β＝90°；
Figure PCTCN2020114629-appb-000074
γ＝90°；晶胞体积为
Figure PCTCN2020114629-appb-000075
晶胞内不对称单位数Z＝4；
更佳地，所述的8a-1的晶型参数为表2中的参数；
表1化合物7a-1的晶型数据
Figure PCTCN2020114629-appb-000076
Figure PCTCN2020114629-appb-000077
表2化合物8a-1的晶型数据
Figure PCTCN2020114629-appb-000078
Figure PCTCN2020114629-appb-000079
如没有特别强调温度，通常指在室温下进行反应，本发明中的室温是指20～30℃。
如没有特别强调，本发明中的“h”指代小时。
如没有特别强调，本发明中的“min”或“mins”指代分钟。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
若无特殊说明，本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明提供了一种全新的制备氧氮杂环庚烷类螺环化合物及其中间体的方法，操作简便，且合成的氧氮杂环庚烷类螺环化合物及其中间体具有更好的立体选择性。
附图说明
图1为化合物7a-1的单晶衍射图。
图2为化合物8a-1的单晶衍射图。
具体实施方式
为更好地理解本发明的内容，下面结合具体实施例作进一步说明。应理解，下列具体实施例仅仅用于说明本发明，而不是对本发明的限制。
实施例1
Figure PCTCN2020114629-appb-000080
在氮气保护下，向式1-1化合物(3kg,14.3mol)，式A化合物(2.7kg，15.8mol)甲苯溶液(5L)中，加入Pd(ACN) 2Cl 2(29.7g,0.115mol)，Cy 2NMe(5.6kg,28.7mol)和三(邻甲苯基)膦(436g,1.43mol)，反应体系在110±5℃下加热搅拌反应，待反应结束后，降至室温，加入HCl水溶液洗涤，洗涤液用叔丁基甲醚萃取3次，合并有机相，饱和氯化钠洗涤，干燥，柱层析，石油醚和乙酸乙酯混合溶液作为洗脱，收集合格馏份，浓缩得式2-1化合物约2.5kg，收率约58％。
式2-1化合物 1H-NMR(400MHz,CDCl 3)δ7.19-7.32(m,2H),6.94-7.02(t,J＝8.0Hz,1H),6.59(d,J＝16.0Hz,1H),6.18-6.32(m,1H),3.74(s,6H),3.54(t,J＝7.2Hz,1H),2.83(t,J＝7.2Hz,2H)
实施例2
将实施例1中的Pd(ACN) 2Cl 2换成Pd(pph 3) 2Cl 2，三(邻甲苯基)膦换成三苯基膦，Cy 2Nme换成Et 3N，甲苯换成1,4-二氧六环，其余条件均同实施例1，式2-1化合物的收率为35％。
实施例3
将实施例1中的Pd(ACN) 2Cl 2换成Pd(pph 3) 4，三(邻甲苯基)膦换成三-邻甲氧基三苯基膦，Cy 2Nme换成Et 3N，其余条件均同实施例1，式2-1化合物的收率为45％。
实施例4
Figure PCTCN2020114629-appb-000081
向高压釜中依次加入式2-1化合物(150g,0.5mol)，乙酸乙酯(44.9g，0.748mol)，充分搅拌，加入5％Pd/C(7.5g)，乙酸(44.9g，0.748mol)，氮气置换若干次后通入氢气(50psi)，30℃下反应0.5h，待反应结束后进行过滤，浓缩，得到式3-1化合物约136g，收率90％。
式3-1化合物 1H-NMR(400MHz,CDCl 3)δ7.23(s,1H),7.03-7.09(m,1H),6.96-7.02(m,1H),3.73(s,6H),3.39(t,J＝7.6Hz,1H),2.69(t,J＝7.61Hz,2H),1.89-2.01(m,2H),1.58-1.70(m,2H).
实施例5
将实施例4中的式2-1化合物换为10g，乙酸的用量为式2-1化合物的1.5倍当量，5％Pd/C的质量是式2-1化合物质量的5％，反应温度为50℃，反应8h，其余条件均同实施例4。反应完全，LCMS监测显示有1.0％的脱卤杂质。
实施例6
将实施例4中的式2-1化合物换为10g，乙酸的用量为式2-1化合物的1.5倍当量，5％Pd/C的质量是式2-1化合物质量的5％，反应温度为50℃，反应2h，其余条件均同实施例4。反应完全，LCMS监测显示有1.0％的脱卤杂质。
实施例7
将实施例4中的式2-1化合物换为20g，乙酸的用量为式2-1化合物的1.5倍当量，5％Pd/C的质量是式2-1化合物质量的5％，其余条件均同实施例4。反应完全，LCMS监测显示有0.3％的脱卤杂质。
实施例8
将实施例4中的式2-1化合物换为10g，不加乙酸，5％Pd/C的质量是式2-1化合物质量的5％，反应温度为50℃，反应1h，其余条件均同实施例4。反应完全，LCMS监测显示有1.0％的脱卤杂质。
实施例9
将实施例4中的式2-1化合物换为10g，不加乙酸，5％Pd/C的质量是式2-1化合物质量的5％，氢气压力为30psi，反应1h，其余条件均同实施例4。反应完全，LCMS监测显示有0.4％的脱卤杂质。
实施例10
将实施例4中的式2-1化合物换为10g，不加乙酸，5％Pd/C的质量是式2-1化合物 质量的2％，反应1h，其余条件均同实施例4。反应完全，LCMS监测显示有2.3％的脱卤杂质。
实施例11
将实施例4中的式2-1化合物换为10g，不加乙酸，5％Pd/C的质量是式2-1化合物质量的2％，氢气压力为30psi，反应2h，其余条件均同实施例4。反应完全，LCMS监测显示有0.1％的脱卤杂质。
实施例12
将实施例4中的式2-1化合物换为10g，不加乙酸，5％Pd/C的质量是式2-1化合物质量的2％，氢气压力为15psi，反应2h，其余条件均同实施例4。反应完全，LCMS监测显示有0.17％的脱卤杂质。
实施例13
将实施例4中的式2-1化合物换为10g，不加乙酸，5％Pd/C的质量是式2-1化合物质量的2％，氢气压力为15psi，反应温度为15℃，反应2h，其余条件均同实施例4。反应完全，LCMS监测显示无脱卤杂质。
实施例14
Figure PCTCN2020114629-appb-000082
在氮气保护下，依次向反应釜中加入醋酸铜(997g，5.49mol)，醋酸锰(3.68kg，13.7mol)和乙酸(13L)，氮气置换若干次后加入式3-1化合物(1.8kg，5.49mol)的乙酸溶液，反应溶液在95℃下搅拌12h，反应结束后，浓缩，加入叔丁基甲醚和水，分层，水层再用叔丁基甲醚萃取，合并后的有机层用碱洗涤，干燥，浓缩得到式4-1化合物1.7kg，收率95％。
式4-1化合物 1H-NMR(400MHz,CDCl 3)δ7.18-7.25(m,1H),7.10-7.16(m,1H),3.77(s,6H),2.79(t,J＝6.8Hz,2H),2.37-2.44(m,2H),1.80-1.88(m,2H).
实施例15
Figure PCTCN2020114629-appb-000083
依次加入式4-1化合物(100g，0.33mol)，乙醇(1300mL)，机械搅拌，反应液呈橘黄色悬浊液，控制温度为-10℃，开始缓慢滴加氢氧化钾(53.4g，0.95mol)水溶液800mL，放热明显，控制温度0℃以下，约2h滴加完毕后，升到室温20℃反应2h-3h，待反应结束后，降低温度至-5℃，缓慢滴加1N HCl(约1000ml)，pH调至1-2左右，加入二氯甲烷600ml×3次萃取，合并有机层，加入饱和食盐水洗涤，干燥，浓缩，得到式5-1化合物92.56g，收率97％。
式5-1化合物 1H-NMR(400MHz,DMSO-d 6)δ13.43(s,1H),7.45–7.35(m,1H),7.23-7.15(m,1H),3.69(s,3H),2.80-2.65(m,2H),2.37–2.18(m,2H),1.86–1.63(m,2H).
实施例16
将实施例15中的反应温度换成0-5℃下反应2h，其余条件均同实施例15，式5-1化合物的收率为67％。
实施例17
Figure PCTCN2020114629-appb-000084
依次加入式5-1化合物(91.4g，0.32mol)，异丙醇(900mL)，充分搅拌，控制温度低于-10℃，缓慢滴加2M硼氢化锂(320mL，0.64mol)的THF溶液320mL，控制温度低于0℃，滴加完毕，0±2℃保温反应0.5h，然后升温至20℃反应，继续反应2h，待反应结束后，降低温度至-5℃，缓慢滴加1N HCl(约750ml)，pH调至1-2左右，加入1L乙酸乙酯，1L水洗涤，分液，水层继续用乙酸乙酯萃取(500ml×2次)，合并有机层，加入饱和食盐水洗涤，干燥，浓缩，得到式6-1化合物74.2g，收率90％。
式6-1化合物 1H-NMR(400MHz,DMSO-d6)δ12.61(s,1H),7.35-7.32(m,2H),4.98(s,1H),3.81(d,J＝10.6Hz,1H),3.66(d,J＝10.6Hz,1H),2.79–2.57(m,2H),2.15-2.05(m,1H),1.94-1.68(m,3H)
实施例18
将实施例17中的硼氢化锂换为BH 3·Me 2S，用量为式5-1化合物的1.2当量，25℃反应7h，其余条件均同实施例17，式6-1化合物收率为40％。
实施例19
将实施例17中的溶剂换为异丙醇，25℃反应1h，其余条件均同实施例17，式6-1化合物收率为82％。
实施例20
将实施例17中的溶剂换为异丙醇，0℃反应6h，其余条件均同实施例17，式6-1化合物收率为70％。
实施例21
Figure PCTCN2020114629-appb-000085
依次加入式6-1化合物(86.5g，0.335mol)，乙酸乙酯(450mL)，室温搅拌，滴加(R)-1-(1-萘基)乙胺(57.4g，0.335mol)滴加至上述体系中，继续室温搅拌，瞬间有大量固体析出，室温搅拌3h，抽滤，滤饼真空干燥得化合物7a-1。
化合物7a-1的后处理，将上述干燥后的化合物7a-1用乙醇和水(10v:1v)混合溶剂重结晶，加入盐酸解盐，游离得到式7-1化合物，收率20％，Ee值99％。
式7-1化合物 1H-NMR(400MHz,DMSO-d6)δ12.61(s,1H),7.35-7.32(m,2H),4.98(s,1H),3.81(d,J＝10.6Hz,1H),3.66(d,J＝10.6Hz,1H),2.79–2.57(m,2H),2.15-2.05(m,1H),1.94-1.68(m,3H)
依据上述相同的方法，加入(S)-1-(1-萘基)乙胺(57.4g，0.335mol)拆分，得化合物8a-1，游离得到式8-1化合物，收率19％，Ee值100％。
式8-1化合物 1H-NMR(400MHz,DMSO-d6)δ12.61(s,1H),7.35-7.32(m,2H),4.98(s,1H),3.81(d,J＝10.6Hz,1H),3.66(d,J＝10.6Hz,1H),2.79–2.57(m,2H),2.15-2.05(m,1H),1.94-1.68(m,3H).
Ee值由HPLC测得，测试条件如下表3所示：
表3
色谱柱 AD-H C18 5um，4.6*250mm
流速 1.0mL/min
进样体积 10ul
柱温 25℃
检测器 紫外检测器
检测波长 236nm
运行时间 20min
稀释溶液 Hex/IPA＝9/1
流动相 (Hex/IPA)+0.1％TFA＝(900/100)+1
化合物7保留时间 9.611min
化合物8保留时间 9.120min
实施例22：化合物7a-1和化合物8a-1的单晶衍射实验
1.晶型培养：
化合物7a-1：5ml试管中加入10mg化合物7a-1，10μL乙醇，过滤，静置析晶4天，有单晶析出，收集单晶进行单晶衍射测试。
化合物8a-1：5ml试管中加入10mg化合物8a-1，10μL DMSO溶解，置于有适量正庚烷的广口瓶中，静置4天，有单晶析出，收集单晶进行单晶衍射测试。
2.晶型参数：见上表1和表2。
3.实验结果：化合物7a-1为R构型(晶型结构如图1所示)，化合物8a-1为S构型(晶型结构如图2所示)，由此可以得出化合物7-1为R构型，化合物8-1为S构型。
实施例23
Figure PCTCN2020114629-appb-000086
称取NaH(1.9g)、50mL DMF转移至反应瓶内，N 2置换三次，磁力搅拌，控制温度0℃以下，加入式7-1化合物(6g)，保温搅拌0.5h。称取4-氟-3-硝基苯甲酸叔丁酯(6.86g)溶于22mL DMF中，备用，控制温度为0±2℃时，滴加上述DMF反应溶液，磁力搅拌2h，检测反应，等反应结束后，向反应体系中倒入50ml冰水中，搅拌5mins，用1N HCl调pH至3-4，50ml乙酸乙酯×3洗涤水层，合并有机层，干燥，过滤，浓缩至干，得到粗品14.92g，柱层析得到纯品7.84g，收率70％。
式B10-1化合物 1H-NMR(400MHz,DMSO-d6)δ13.07(s,1H),8.29(d,J＝2.2Hz,1H),8.10(dd,J＝8.8,2.2Hz,1H),7.52(d,J＝8.9Hz,1H),7.38(t,J＝8.1Hz,1H),7.30(d,J＝8.6 Hz,1H),4.63(d,J＝9.5Hz,1H),4.49(d,J＝9.5Hz,1H),2.81-2.69(m,2H),2.30–2.16(m,1H),2.14–2.02(m,1H)，1.88-1.83(m,2H),1.55(s,9H).
实施例24
Figure PCTCN2020114629-appb-000087
将式B10-1化合物(7.8g,16.3mmol)，80mL DME转移至反应瓶内，磁力搅拌，控制反应温度-5℃-0℃，N-甲基吗啉(1.82g,18mmol)滴加至反应瓶中，滴加结束后，控制反应温度-5℃-0℃，氯代甲酸异丁酯(ClCO 2iBu，2.45g)滴加至反应体系中，滴加结束后，充分搅拌2h，将NaBH 4(0.68g)溶于2.5g水中，缓慢滴加至反应体系中，控制反应温度-5℃-0℃，磁力搅拌2h，检测反应，等反应结束后，向反应体系中倒入100ml冰水淬灭，50ml乙酸乙酯×3洗涤水层，合并有机层，干燥，过滤，浓缩至干，柱层析得到5.38g，收率71％。
式B11-1化合物 1H-NMR(400MHz,DMSO-d6)δ8.29(d,J＝2.2Hz,1H),8.10(dd,J＝8.8,2.2Hz,1H),7.45(t,J＝8.4Hz,2H),7.30(t,J＝8.2Hz,1H),5.00(t,J＝5.3Hz,1H),4.41–4.26(m,2H),,3.64(d,J＝5.0Hz,2H),2.74-2.63(m,2H),1.94–1.83(m,4H),1.54(s,9H).
实施例25
Figure PCTCN2020114629-appb-000088
将式B11-1化合物(8.9g)，100mL DCM转移至反应瓶内，磁力搅拌，冰浴降温至0℃以下，加入DMP氧化剂(12.18g)，然后撤去冰浴常温搅拌1h，等反应结束后，垫硅藻土过滤，滤液依次用饱和Na 2S 2O 3和饱和NaHCO 3混合溶液(1:1)洗涤2次，饱和食盐水洗涤1次，有机相浓缩得到8.70g粗品，待用直接下一步反应。
式B12-1化合物 1H-NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.31(d,J＝2.2Hz,1H),8.12(dd,J＝8.8,2.2Hz,1H),7.53(d,J＝8.9Hz,1H),7.45(t,J＝8.1Hz,1H),7.22-7.20(m,1H),4.77(d,J＝9.6Hz,1H),4.53(d,J＝9.6Hz,1H),2.80-2.70(m,2H),2.25-2.15(m,,1H),2.03-1.95(m,1H),1.94–1.84(m,1H),1.83–1.74(m,1H),1.55(s,9H).
实施例26
Figure PCTCN2020114629-appb-000089
将式B12-1化合物(8g，0.017mol)，160mL乙酸转移至反应瓶内，机械搅拌，加入铁粉(4.8g，0.086mol)，70-75℃搅拌3h，等反应结束后，降低至室温，加入DCM搅拌硅藻土过滤，滤饼用DCM洗涤，旋干得12.1g粗品，不经纯化，直接参与下一步反应。
实施例27
Figure PCTCN2020114629-appb-000090
将式B13-1化合物(7.5g，0.017mol)，THF(90mL)转移至反应瓶内，常温下，磁力搅拌，依次加入三氟乙酸(20mL)和苯硅烷(8.4g，0.078mol)，反应1h，检测反应，反应等反应结束后，旋干溶剂，固体用350ml DCM溶解，分别依次用饱和NaHCO 3洗涤2次，饱和食盐水洗涤1次，有机层旋干得9.7g粗品，纯化得5.29g产物(最后三步总收率73.4％)。
式I-1化合物 1H-NMR(400MHz,DMSO-d6)δ7.69(dd,J＝8.6,1.2Hz,1H),7.42(t,J＝8.3Hz,1H),7.33(d,J＝2.1Hz,1H),7.15(dd,J＝8.3,2.1Hz,1H),6.85(d,J＝8.3Hz,1H),6.06(s,1H),4.16–4.06(m,2H),3.35–3.18(m,2H),2.78-2.58(m,2H),1.86–1.71(m,3H),1.60-1.54(m,1H),1.51(s,9H).
实施例28
Figure PCTCN2020114629-appb-000091
将式8-1化合物(7g，0.027mol)，140mL DMF转移至反应瓶内，室温搅拌，加入碳酸钾(6.4g，0.046mol)，室温搅拌0.5h，将碘甲烷(4.62g，0.033mol)滴加至反应瓶中， 室温搅拌3h，检测反应，等反应结束后，加入1N HCl淬灭反应，加入50ml EA×3萃取水层，有机层合并，干燥，过滤、滤液浓缩，得到粗品7.62g，该步反应不经纯化，直接用于下步反应。
式C9-1化合物 1H-NMR(400MHz,DMSO-d6)δ7.40-7.20(m,2H),3.90-3.70(m,1H),3.70-3.64(m,1H),3.60(s,3H),2.82-2.57(m,2H),2.20-2.00(m,1H),1.92–1.60(m,3H).
实施例29
Figure PCTCN2020114629-appb-000092
将式C9-1化合物(7.4g，0.027mol)，150mL DCM转移至反应瓶内，室温搅拌，加入DMP(17.2g，0.04mol)，室温搅拌，等反应结束后，加入(Na 2S 2O 3：NaHCO 3)混合溶液，搅拌20mins，分液，加入50ml EA×3萃取水层，有机层合并，干燥，过滤、滤液浓缩，得到粗品7.0g，柱层析得纯品5.45g，以式8-1化合物计，两步总收率74％。
式C11-1化合物 1H-NMR(400MHz,DMSO-d6)δ9.68(s,1H),7.51–7.42(m,1H),7.10-7.03(m,1H),3.71(s,3H),2.80-2.63(m,2H),2.35-2.25(m,1H),2.23-2.10(m,1H),1.86-1.74(m,1H),1.65-1.55(m,1H).
实施例30
Figure PCTCN2020114629-appb-000093
将式C11-1化合物(5g，0.018mol)，30mL THF转移至反应瓶内，室温搅拌，依次加入3-氨基-4氟苯甲酸叔丁酯(4.7g，0.022mol)，30mLTHF、15mL三氟乙酸、苯硅烷(10g，0.0926mol)，室温搅拌过夜(约18h)，检测反应，等反应结束后，加入100ml水淬灭，加入100ml EA×3萃取水层，有机层合并，干燥，过滤、滤液浓缩，柱层析得纯品8.62g，收率100％。
式C12-1化合物 1H-NMR(400MHz,DMSO-d6)δ7.35-7.25(m,1H),7.23–7.04(m,4H),5.45-5.30(m,1H),3.82-3.73(m,2H),3.60(s,3H),2.82-2.74(m,2H),2.25-2.15(m,1H),2.04–1.92(m,1H),1.90-1.75(m,2H),1.51(s,9H).
实施例31
Figure PCTCN2020114629-appb-000094
将式C12-1化合物(8.5g，18.3mmol)，90mL IPA转移至反应瓶内，室温搅拌，滴加LiBH 4四氢呋喃溶液(36.4mmol，18.2mL)，加热回流搅拌3h，检测反应，等反应结束后，加入150ml水淬灭，搅拌10mins，加入100ml EA×3萃取水层，有机层合并，干燥，过滤、滤液浓缩，得到粗品10.8g，柱层析得纯品6.6g，收率84％。
式C13-1化合物 1H-NMR(400MHz,DMSO-d 6)δ7.33-7.20(m,2H),7.16–7.04(m,3H),5.37-5.30(m,1H),5.12-5.03(m,1H),3.65–3.50(m,2H),3.45-3.35(m,2H),2.80-2.60(m,2H),2.05-1.95(m,1H),1.90-1.70(m,5H),1.50(s,9H).
实施例32
Figure PCTCN2020114629-appb-000095
将式C13-1化合物(6.5g，0.015mol)，130mL DMSO转移至反应瓶内，室温搅拌，加入Cs 2CO 3(9.7g，0.03mol)，90℃搅拌过夜(15h)，检测反应，等反应结束后，加入100ml H2O，100ml EA萃取分液，加入100ml EA×3萃取水层，有机层合并，干燥，过滤、滤液浓缩，得到粗品5.90g，柱层析得纯品3.72g，收率60％。
式I-1化合物 1H-NMR(400MHz,DMSO-d6)δ7.69(dd,J＝8.6,1.2Hz,1H),7.42(t,J＝8.3Hz,1H),7.33(d,J＝2.1Hz,1H),7.15(dd,J＝8.3,2.1Hz,1H),6.85(d,J＝8.3Hz,1H),6.06(s,1H),4.16–4.06(m,2H),3.35–3.18(m,2H),2.78-2.58(m,2H),1.86–1.71(m,3H),1.60-1.54(m,1H),1.51(s,9H).
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (23)

  1. 一种如式7a或式8a所示化合物的制备方法，其特征在于，
    所述的如式7a所示化合物的制备方法包括以下步骤：有机溶剂中，将如式6所示的化合物和手性拆分剂X 1进行如下所示的成盐反应，即可；其中，X 1为R构型的手性拆分剂；
    Figure PCTCN2020114629-appb-100001
    所述的如式8a所示化合物的制备方法包括以下步骤：有机溶剂中，将如式6所示的化合物和手性拆分剂X 2进行如下所示的成盐反应，即可；其中，X 2为S构型的手性拆分剂；
    Figure PCTCN2020114629-appb-100002
    其中，R 1、R 2、R 3和R 4独立地为氢、羟基、氰基、氨基、硝基、醛基、卤素、C 1-C 4的烷基、R 1-1取代的C 1-C 4的烷基、C 1-C 4的卤代烷基、R 1-2取代的C 1-C 4的卤代烷基、C 1-C 4的烷氧基、R 1-3取代的C 1-C 4的烷氧基、或-C(＝O)R 1-4；
    R 1-1、R 1-2、R 1-3和R 1-4独立地为羟基、C 1-C 4的烷基、C 1-C 4的烷氧基、C 3-C 5的环烷基或NR 1-1aR 1-1b；
    R 1-1a和R 1-1b独立地为氢或C 1-C 4的烷基。
  2. 如权利要求1所述的如式7a或式8a所示化合物的制备方法，其特征在于，R 1、R 2、R 3和R 4独立地为氢和卤素；
    和/或，所述的R构型的手性拆分剂为R构型的胺类手性拆分剂，优选(R)-1-(1-萘基)-乙胺、(R)-苯乙胺、(R)-苯丙氨醇、(R)-N-苄基苯基乙胺或(R)-奎宁丁，更优选(R)-1-(1-萘基)-乙胺；
    和/或，所述的S构型的手性拆分剂为S构型的胺类手性拆分剂，优选(S)-1-(1-萘基)-乙胺、(S)-苯乙胺、(S)-苯丙氨醇、(S)-N-苄基苯基乙胺或(S)-奎宁丁，更优选(S)-1-(1-萘基)- 乙胺；
    和/或，所述的有机溶剂为C 1-C 4的醇类溶剂和/或酯类溶剂，优选酯类溶剂；所述的C 1-C 4的醇类溶剂优选甲醇、乙醇和异丙醇中的一种或多种；所述的酯类溶剂优选乙酸乙酯；
    和/或，所述的如式6所示化合物与手性拆分剂的摩尔比为1:1-1:5，优选1:1-1:3，进一步优选1:1-1:1.5；
    和/或，所述的如式6所示化合物与所述的有机溶剂的质量体积比为1:1-1:10g/mL，更优选1:1-1:6g/mL；
    和/或，所述的成盐反应的温度为20-30℃；
    和/或，所述的成盐反应的时间为1-5h。
  3. 如权利要求1或2所述的如式7a或式8a所示化合物的制备方法，其特征在于，所述的如式6所示化合物的制备方法包括以下步骤：有机溶剂中，在还原剂的存在下，将如式5所示化合物进行如下所示的还原反应，即可；
    Figure PCTCN2020114629-appb-100003
    其中，R 1、R 2、R 3和R 4如权利要求1或2所述。
  4. 如权利要求3所述的如式7a或式8a所示化合物的制备方法，其特征在于，所述的有机溶剂为C 1-C 4的醇类溶剂、酯类溶剂、醚类溶剂、酮类溶剂、腈类溶剂、酰胺类溶剂和亚砜类溶剂中的一种或多种，优选C 1-C 4的醇类溶剂；所述的C 1-C 4的醇类溶剂优选甲醇、乙醇和异丙醇中的一种或多种，更优选异丙醇；所述的酯类溶剂优选乙酸乙酯；所述的醚类溶剂优选乙醚和/或四氢呋喃；所述的酮类溶剂优选丙酮和/或2-丁酮；所述的腈类溶剂优选乙腈；所述的酰胺类溶剂优选N,N-二甲基甲酰胺；所述的亚砜类溶剂优选二甲基亚砜；
    和/或，所述的还原剂为碱金属氢化物；所述的碱金属氢化物优选氢化铝锂、硼氢化锂、硼氢化钠、硼氢化钾、二异丁基氢化铝、氰基硼氢化钠、硫代硼氢化钠和三仲丁基硼氢化锂中的一种或多种，更优选硼氢化锂、硼氢化钠和硼氢化钾中的一种或多种，进一步优选硼氢化锂；
    和/或，所述的如式5所示化合物与所述的有机溶剂的质量体积比为1:10-1:20g/mL， 优选1:10-1:15g/mL；
    和/或，所述的如式5所示化合物与所述的还原剂的摩尔比为1:1-1:5，优选1:1-1:2；
    和/或，所述的还原反应的温度为-5-30℃，优选20-30℃；
    和/或，所述的还原反应的时间为1-3h。
  5. 如权利要求3或4所述的如式7a或式8a所示化合物的制备方法，其特征在于，所述的如式5所示化合物的制备方法包括以下步骤：溶剂中，在碱的存在下，将如式4所示化合物进行如下所述的水解反应，即可；
    Figure PCTCN2020114629-appb-100004
    其中，R 1、R 2、R 3和R 4如权利要求1或2所述。
  6. 如权利要求5所述的如式7a或式8a所示化合物的制备方法，其特征在于，所述的溶剂为C 1-C 4的醇类溶剂、酯类溶剂、醚类溶剂、酮类溶剂、腈类溶剂、酰胺类溶剂或亚砜类溶剂中的一种或多种，优选C 1-C 4的醇类溶剂；所述的C 1-C 4的醇类溶剂优选甲醇、乙醇和异丙醇中的一种或多种，更优选乙醇；所述的酯类溶剂优选乙酸乙酯；所述的醚类溶剂优选乙醚和/或四氢呋喃；所述的酮类溶剂优选丙酮和/或2-丁酮；所述的腈类溶剂优选乙腈；所述的酰胺类溶剂优选N,N-二甲基甲酰胺；所述的亚砜类溶剂优选二甲基亚砜；
    和/或，所述的碱为无机碱；所述的无机碱优选碱金属碳酸盐和/或碱金属氢氧化物，更优选碱金属氢氧化物；所述的碱金属碳酸盐优选K 2CO 3和/或Cs 2CO 3；所述的碱金属氢氧化物优选LiOH、NaOH和KOH中的一种或多种；
    和/或，所述的如式4所示化合物与所述的溶剂的质量体积比为1:1-1:20g/mL，优选1:5-1:13g/mL；
    和/或，所述的如式4所示化合物与所述的碱的摩尔比为1:1-1:5，优选1:1-1:3；
    和/或，所述的水解反应的温度为-5℃-30℃，优选20℃-30℃；
    和/或，所述的水解反应的时间为1-3h，优选2-3h。
  7. 如权利要求5或6所述的如式7a或式8a所示化合物的制备方法，其特征在于，所述的如式4所示化合物的制备方法包括以下步骤：保护气体氛围下，在酸和氧化剂的存在下，将如式3所示化合物进行如下所示的分子内环合反应，即可；
    Figure PCTCN2020114629-appb-100005
    其中，R 1、R 2、R 3和R 4如权利要求1或2所述。
  8. 如权利要求7所述的如式7a或式8a所示化合物的制备方法，其特征在于，所述的如式3所示化合物的制备方法包括以下步骤：有机溶剂中，在金属催化剂的存在下，将如式2所示化合物与氢气进行如下所示的还原反应，即可；
    Figure PCTCN2020114629-appb-100006
    其中，R 1、R 2、R 3和R 4如权利要求1或2所述。
  9. 如权利要求8所述的如式7a或式8a所示化合物的制备方法，其特征在于，所述的有机溶剂为C 1-C 4的醇类溶剂、酯类溶剂和醚类溶剂中的一种或多种，优选酯类溶剂；所述的C 1-C 4的醇类溶剂优选甲醇、乙醇和异丙醇中的一种或多种；所述的酯类溶剂优选乙酸乙酯；所述的醚类溶剂优选乙醚和/或四氢呋喃；
    和/或，所述的金属催化剂为Pd/C、Pd(OH) 2、Raney镍、Pt/C和PtO 2中的一种或多种，优选Pd/C；
    和/或，所述的如式2化合物与所述的有机溶剂的质量体积比为1:1-10:1g/mL，优选1:1-8:1g/mL，进一步优选1:1-5:1g/mL；
    和/或，所述的如式2化合物与所述的金属催化剂的质量比为10:1-100:1，进一步优选20:1-100:1；
    和/或，所述的氢气的压力为14.5-72.5psi，优选15-50psi；
    和/或，所述的还原反应的温度为20-50℃，优选15-30℃；
    和/或，所述的还原反应的时间为0.5-8h，优选0.5-5h；
    和/或，所述的还原反应优选在酸的存在下进行，所述的酸为有机酸和/或无机酸；所述的有机酸优选甲酸和/或乙酸；所述的无机酸优选盐酸、硫酸和磷酸中的一种或多种；所述的如式2所示化合物与所述的酸的摩尔比优选1:1-1:2，更优选1:1-1:1.5。
  10. 如权利要求8或9所述的如式7a或式8a所示化合物的制备方法，其特征在于，所述的如式2所示化合物的制备方法包括以下步骤：保护气体氛围下，有机溶剂中，在碱、催化剂的存在下，将如式1所示化合物与如式A所示化合物进行如下所示的偶联反应，即可；所述的催化剂包括配体和钯类化合物；
    Figure PCTCN2020114629-appb-100007
    其中，R 1、R 2、R 3和R 4如权利要求1或2所述。
  11. 如权利要求10所述的如式7a或式8a所示化合物的制备方法，其特征在于，所述的保护气体为氮气和/或氩气；
    和/或，所述的有机溶剂为芳烃类溶剂、腈类溶剂、酰胺类溶剂、亚砜类溶剂、醚类溶剂和酮类溶剂中的一种或多种，优选芳烃类溶剂；所述的芳烃类溶剂优选甲苯和/或二甲苯，更优选甲苯；所述的腈类溶剂优选乙腈；所述的酰胺类溶剂优选N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺；所述的亚砜类溶剂优选二甲基亚砜；所述的醚类溶剂优选四氢呋喃和/或1,4-二氧六环；所述的酮类溶剂优选N-甲基吡咯烷酮；
    和/或，所述的碱为有机碱和/或无机碱；所述的有机碱优选吡啶、哌啶、1,8-二氮杂二环十一碳-7-烯、1,4-二氮杂二环[2.2.2]辛烷、碱金属醇盐和
    Figure PCTCN2020114629-appb-100008
    中的一种或多种，更优选
    Figure PCTCN2020114629-appb-100009
    R 1a、R 2a和R 3a独立地为氢、C 1～C 4的烷基或C 5-C 6的环烷基；所述的无机碱优选碱金属碳酸盐、碱金属氢化物和碱金属氢氧化物中的一种或多种；所述的碱金属醇盐优选C 1～C 4醇的碱金属醇盐，更优选叔丁醇钾和/或叔丁醇钠；所述的
    Figure PCTCN2020114629-appb-100010
    优选三乙胺和/或N-甲基二环己基胺；所述的碱金属碳酸盐优选K 2CO 3和/或Cs 2CO 3；所述的碱金属氢化物优选NaH；所述的碱金属氢氧化物优选NaOH和/或KOH；
    和/或，所述的配体为膦配体；所述的膦配体为单齿膦配体、双齿膦配体和多齿膦配体中的一种或多种，优选单齿膦配体；所述的单齿膦配体优选三苯基膦、三(2-甲苯基)膦、三(3-甲苯基)膦、三对甲苯基膦、三(4-氟苯基)膦、三(2-甲氧基苯基)膦、三(4-甲氧苯基)膦和2-(二叔丁基膦)联苯中的一种或多种，更优选三苯基膦和/或三(2-甲苯基)膦；所 述的多齿膦配体优选
    Figure PCTCN2020114629-appb-100011
    和/或，所述的钯类化合物为零价钯和/或二价钯；所述的零价钯优选Pd 2(dba) 3；所述的二价钯优选Pd(OAc) 2、PdCl 2、Pd(TFA) 2和Pd(MeCN) 2Cl 2中的一种或多种；
    和/或，所述的钯类化合物和所述的配体分开加入、所述的钯类化合物和所述的配体形成络合物加入、或者、所述的钯类化合物和所述的配体先形成络合物，再和所述的配体分开加入；所述的配体独立地为膦配体；所述的络合物优选零价钯与配体形成的络合物和/或二价钯与配体形成的络合物；所述的零价钯与配体形成的络合物优选Pd(PPh 3) 4；所述的二价钯与配体形成的络合物优选Pd(PPh 3) 2Cl 2和/或Pd(dppf)Cl 2；
    和/或，所述的如式1所示化合物与所述的如式A所示化合物的摩尔比为1:1-1:3，优选1:1-1:2；
    和/或，所述的如式1所示化合物与所述的有机溶剂的质量体积比为1:1-1:10g/mL，优选1:1-1:5g/mL；
    和/或，所述的如式1所示化合物与所述的碱的摩尔比为1:1-1:5，优选1:1-1:3，进一步优选1:1-1:2；
    和/或，所述的如式1所示化合物与所述的配体的摩尔比为1:1-10:1，优选1.25:1-10:1，进一步优选2:1-10:1；
    和/或，所述的如式2所示化合物的制备方法中，所述的如式1所示化合物与所述的钯类化合物的摩尔比为10:1-1000:1，优选100:1-1000:1，进一步优选100:1-500:1；
    和/或，所述的偶联反应的温度为90-110℃；
    和/或，所述的偶联反应的时间为8-20h，优选8-12h。
  12. 一种如式7或式8所示化合物的制备方法，其包括以下步骤：将如式7a或8a所示化合物和酸进行如下所示的中和反应，即可；其中，X 1为R构型的手性拆分剂；X 2为S构型的手性拆分剂；所述的如式7a或式8a所示化合物的制备方法如权利要求1-11中任一项所述；
    Figure PCTCN2020114629-appb-100012
    其中，R 1、R 2、R 3和R 4如权利要求1或2所述。
  13. 一种如式I所示化合物的制备方法，其为方法一或方法二：
    方法一包括以下步骤：有机溶剂中，在酸和硅烷类化合物的存在下，将如式B13所示化合物进行如下所示的还原胺化反应，即可；
    Figure PCTCN2020114629-appb-100013
    方法二包括以下步骤：有机溶剂中，在碱的存在下，将如式C13所示化合物进行如下所示的成醚反应，即可；
    Figure PCTCN2020114629-appb-100014
    其中，R 1、R 2、R 3和R 4如权利要求1或2所述。
  14. 如权利要求13所述的如式I所示化合物的制备方法，其特征在于，方法一中，所述的有机溶剂为C 1-C 4醇类溶剂、芳烃类溶剂和醚类溶剂中的一种或多种，优选醚类溶剂；所述的C 1-C 4醇类溶剂优选甲醇、乙醇、正丙醇和异丙醇中的一种或多种；所述的芳 烃类溶剂优选甲苯和/或二甲苯；所述的醚类溶剂优选乙醚、四氢呋喃和1,4-二氧六环中的一种或多种，更优选四氢呋喃；
    和/或，方法一中，所述的酸为无机酸和/或有机酸；所述的无机酸优选盐酸、硫酸和磷酸中的一种或多种；所述的有机酸优选甲酸、乙酸和三氟乙酸中的一种或多种，更优选三氟乙酸；
    和/或，方法一中，所述的硅烷类化合物为苯硅烷、二乙基硅烷、三乙基硅烷、三氯硅烷和二乙氧基甲基硅烷中的一种或多种，优选苯硅烷、二乙基硅烷和三乙基硅烷中的一种或多种，进一步优选苯硅烷；
    和/或，方法一中，所述的如式B13所示化合物与所述的有机溶剂的质量体积比为1:1-1:20g/mL，优选1:1-1:15g/mL；
    和/或，方法一中，所述的如式B13所示化合物与所述的酸的质量体积比为1:1-1:5g/mL，优选1:1-1:3g/mL；
    和/或，方法一中，所述的如式B13所示化合物与所述的硅烷类化合物的摩尔比为1:1-1:10，优选1:1-1:5；
    和/或，方法一中，所述的还原胺化反应的温度为20-30℃；
    和/或，方法一中，所述的还原胺化反应的时间为1-5h，优选1-3h；
    和/或，方法二中，所述的有机溶剂为芳烃类溶剂、腈类溶剂、酰胺类溶剂、亚砜类溶剂、醚类溶剂和酮类溶剂中的一种或多种，优选酰胺类溶剂和/或亚砜类溶剂；所述的芳烃类溶剂优选甲苯和/或二甲苯，更优选甲苯；所述的腈类溶剂优选乙腈；所述的酰胺类溶剂优选N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺；所述的亚砜类溶剂优选二甲基亚砜；所述的醚类溶剂优选四氢呋喃、1,4-二氧六环和乙二醇二甲醚中的一种或多种；所述的酮类溶剂优选N-甲基吡咯烷酮；
    和/或，方法二中，所述的碱为有机碱和/或无机碱；所述的有机碱优选吡啶、哌啶、1,8-二氮杂二环十一碳-7-烯、1,4-二氮杂二环[2.2.2]辛烷、碱金属醇盐和
    Figure PCTCN2020114629-appb-100015
    中的一种或多种；其中，R 1a、R 2a和R 3a独立地为氢、C 1～C 4的烷基或C 5-C 6的环烷基；所述的无机碱优选碱金属碳酸盐、碱金属氢化物和碱金属氢氧化物中的一种或多种；所述的碱金属醇盐优选C 1～C 4醇的碱金属醇盐，更优选叔丁醇钾和/或叔丁醇钠；所述的碱金属碳酸盐优选K 2CO 3和/或Cs 2CO 3，更优选Cs 2CO 3；所述的碱金属氢化物优选NaH；所述的碱金属氢氧化物优选NaOH和/或KOH；
    和/或，方法二中，所述的如式C13所示化合物与所述的有机溶剂的质量体积比为1:1- 1:30g/mL，优选1:1-1:20g/mL；
    和/或，方法二中，所述的如式C13所示化合物与所述的碱的摩尔比为1:1-1:5，优选1:1-1:3，进一步优选1:1-1:2；
    和/或，方法二中，所述的成醚反应的温度为50-100℃，优选90-100℃；
    和/或，方法二中，所述的成醚反应的时间为1-20h，优选1-15h。
  15. 如权利要求13或14所述的如式I所示化合物的制备方法，其特征在于，
    所述的如式B13所示化合物的制备方法包括以下步骤：溶剂中，在还原剂的存在下，将如式B12所示化合物进行如下所示的还原反应，即可；
    Figure PCTCN2020114629-appb-100016
    或者，所述的如式C13所示化合物的制备方法包括以下步骤：有机溶剂中，在还原剂的存在下，将如式C12所示化合物进行如下所示的还原反应，即可；
    Figure PCTCN2020114629-appb-100017
    其中，R 1、R 2、R 3和R 4如权利要求1或2所述。
  16. 如权利要求15所述的如式I所示化合物的制备方法，其特征在于，
    所述的如式B13所示化合物的制备方法中，所述的如式B12所示化合物的制备方法包括以下步骤：有机溶剂中，在氧化剂的存在下，将如式B11所示化合物进行如下所示的氧化反应，即可；
    Figure PCTCN2020114629-appb-100018
    或者，所述的如式C13所示化合物的制备方法中，所述的如式C12所示化合物的制 备方法包括以下步骤：有机溶剂中，在酸和硅烷类化合物的存在下，将如式C11化合物和如式C10所示化合物进行如下所示的还原胺化反应，即可；
    Figure PCTCN2020114629-appb-100019
    其中，R 1、R 2、R 3和R 4如权利要求1或2所述。
  17. 如权利要求16所述的如式I所示化合物的制备方法，其特征在于，
    所述的如式B12所示化合物的制备方法中，所述的如式B11所示化合物的制备方法为方法A、方法B、方法C和方法D中的任意一种，
    所述的方法A包括以下步骤：有机溶剂中，在还原剂的存在下，将如式B10所示化合物进行如下所示的还原反应，即可；
    Figure PCTCN2020114629-appb-100020
    所述的方法B包括以下步骤：
    (b1)将所述的如式B10所示化合物与卤化剂进行如下所示的酰化反应，得酰氯；
    (b2)将步骤(b1)中得到的酰氯与还原剂进行如下所示的还原反应，即可；
    Figure PCTCN2020114629-appb-100021
    所述的方法C包括以下步骤：
    (c1)将所述的如式B10所示化合物与醇进行如下所示的酯化反应，得酯；
    (c2)将步骤(c1)中得到的酯与还原剂进行如下所示的还原反应，即可；
    Figure PCTCN2020114629-appb-100022
    所述的方法D包括以下步骤：
    (d1)在活化剂和碱的存在下，将所述的如式B10所示化合物进行如下所示的反应，得酸酐；
    (d2)将步骤(d1)中得到的酸酐与还原剂进行如下所示的还原反应，即可；
    Figure PCTCN2020114629-appb-100023
    或者，所述的如式C12所示化合物的制备方法中，所述的如式C11所示化合物的制备方法包括以下步骤：有机溶剂中，在氧化剂的存在下，将如式C9所示化合物进行如下所示的氧化反应，即可；
    Figure PCTCN2020114629-appb-100024
    其中，R 1、R 2、R 3和R 4如权利要求1或2所述；
    R 5和R 6独立地为C 1-C 4的烷基。
  18. 如权利要求17所述的如式I所示化合物的制备方法，其特征在于，
    所述的如式B11所示化合物的制备方法中，所述的如式B10所示化合物的制备方法包括以下步骤：有机溶剂中，在碱的存在下，将如式7所示化合物与如式B9所示化合物进行如下所示的成醚反应，即可；
    Figure PCTCN2020114629-appb-100025
    或者，所述的如式C11所示化合物的制备方法中，所述的如式C9所示化合物的制备方法进一步包括以下步骤：有机溶剂中，在碱的存在下，将如式8所示化合物与甲基化试剂进行如下所示的甲基化反应，即可；
    Figure PCTCN2020114629-appb-100026
    其中，R 1、R 2、R 3和R 4如权利要求1或2所述。
  19. 如权利要求18所述的如式I所示化合物的制备方法，其特征在于，所述的如式7或式8所示化合物的制备方法如权利要求12所述。
  20. 一种如式I-1所示化合物的制备方法，其合成路线为以下路线1～路线4中的任意一条：
    路线1
    Figure PCTCN2020114629-appb-100027
    路线2
    Figure PCTCN2020114629-appb-100028
    路线3
    Figure PCTCN2020114629-appb-100029
    路线4
    Figure PCTCN2020114629-appb-100030
    其中，如式I-1所示化合物的制备方法如权利要求15-19中任一项所述。
  21. 一种如式7-1或式8-1所示化合物的制备方法，
    其中，所述的如式7-1所示化合物的合成路线如下所示：
    Figure PCTCN2020114629-appb-100031
    所述的如式8-1所示化合物的合成路线如下所示：
    Figure PCTCN2020114629-appb-100032
    其中，如式7-1或式8-1所示化合物的制备方法如权利要求12所述。
  22. 如下式所示的化合物：
    Figure PCTCN2020114629-appb-100033
    其中，R 1、R 2、R 3、R 4、X 1和X 2如权利要求1或2所述。
  23. 如权利要求22所述的化合物，其特征在于，其为以下任一化合物：
    Figure PCTCN2020114629-appb-100034
    Figure PCTCN2020114629-appb-100035
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