WO2020177658A1 - 一种三并环化合物的制备方法及其中间体 - Google Patents

一种三并环化合物的制备方法及其中间体 Download PDF

Info

Publication number
WO2020177658A1
WO2020177658A1 PCT/CN2020/077413 CN2020077413W WO2020177658A1 WO 2020177658 A1 WO2020177658 A1 WO 2020177658A1 CN 2020077413 W CN2020077413 W CN 2020077413W WO 2020177658 A1 WO2020177658 A1 WO 2020177658A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
hours
molar equivalent
less
Prior art date
Application number
PCT/CN2020/077413
Other languages
English (en)
French (fr)
Inventor
黄振华
郭鹏飞
李承�
Original Assignee
山东亨利医药科技有限责任公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MX2021010511A priority Critical patent/MX2021010511A/es
Priority to CN202080018246.5A priority patent/CN113874371B/zh
Priority to PE2021001428A priority patent/PE20212179A1/es
Priority to US17/435,181 priority patent/US20220144824A1/en
Priority to NZ779681A priority patent/NZ779681A/en
Priority to CA3132075A priority patent/CA3132075A1/en
Priority to JP2021551807A priority patent/JP7291426B2/ja
Priority to SG11202109564U priority patent/SG11202109564UA/en
Application filed by 山东亨利医药科技有限责任公司 filed Critical 山东亨利医药科技有限责任公司
Priority to AU2020230627A priority patent/AU2020230627B2/en
Priority to BR112021017276A priority patent/BR112021017276A2/pt
Priority to KR1020217031105A priority patent/KR102704291B1/ko
Priority to EP20765627.3A priority patent/EP3932920A4/en
Priority to UAA202105530A priority patent/UA127368C2/uk
Priority to IL286015A priority patent/IL286015B1/en
Publication of WO2020177658A1 publication Critical patent/WO2020177658A1/zh
Priority to ZA2021/06376A priority patent/ZA202106376B/en
Priority to CONC2021/0012061A priority patent/CO2021012061A2/es

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Definitions

  • the invention discloses a method for preparing a tri-fold compound and its intermediates, and specifically relates to (3S,3aR)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3 ,4-f] Quinoline compound preparation method, especially (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5- Tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid or 2-chloro-4-[(3S,3aR)-3-cyclopentyl-7-(4-hydroxypiperidine -1-carbonyl)-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinolin-2-yl]benzonitrile preparation method, and disclosed can be used in the synthesis of The intermediate of the compound.
  • the purpose of the present invention is to provide a preparation of (3S,3aR)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinolines
  • a chiral base is used instead of supercritical liquid chromatography (SFC) for chiral resolution, and the production scale is increased to a batch size suitable for commercial-scale preparation, achieving the purpose of large-scale industrial production.
  • SFC supercritical liquid chromatography
  • the present invention has tried a series of chiral purification methods, such as enzymatic hydrolysis, chiral acid/base resolution, chiral group induction, simulated fluidized bed chromatography (SMB) resolution, asymmetric derivatives Separation of crystals and silica gel column separation of asymmetric derivatives.
  • chiral base resolution has a relatively good resolution effect, and other resolution methods have not achieved the purpose of resolution.
  • dozens of chiral base reagents have been tried, among which (1S,2S)-cyclohexanediamine, (1R,2R)-cyclohexanediamine, Quinine, Quinine Quinidine or its deuterated derivatives have better resolution.
  • ketone solvents selected from acetone, methyl ethyl ketone, pentanone or methyl isobutyl ketone, and preferably acetone.
  • ester solvent is selected from ethyl acetate, isopropyl acetate or tert-butyl acetate, etc., preferably ethyl acetate.
  • (1S,2S)-cyclohexanediamine or (1R,2R)-cyclohexanediamine is better resolved in acetone, and quinine or quinidine is resolved in ethyl acetate. The effect is better.
  • Scheme 1 A method for preparing a compound of formula (III), the compound of formula (IV) is reacted with a chiral base Y to obtain a compound of formula (III), and the chiral base Y is selected from (1S, 2S)-cyclohexanedi Amine, (1R,2R)-cyclohexanediamine, quinine, quinidine or its deuterated derivatives.
  • Scheme 2 The method as described in Scheme 1, reacting in ketone solvent, ester solvent or tetrahydrofuran.
  • a compound of formula (IX) is prepared from a compound of formula (X), preferably a compound of formula (IX) is prepared from a compound of formula (X) and an acid chloride compound, wherein the acid chloride compound is selected from phosphorus oxychloride, phosgene, and sulfur Acid chlorides, such as phosphorus oxychloride, acetyl chloride, thionyl chloride;
  • a compound of formula (IX) is prepared from a compound of formula (X), preferably a compound of formula (IX) is prepared from a compound of formula (X) and an acid chloride compound, wherein the acid chloride compound is selected from phosphorus oxychloride, phosgene, and sulfur Acid chlorides, such as phosphorus oxychloride, acetyl chloride, thionyl chloride;
  • the compound of formula (VIII) is prepared by the compound of formula (IX) and ROH, preferably the compound of formula (VIII) is prepared by the compound of formula (IX) and ROH in the presence of CO, wherein R is C 1-6 alkyl;
  • reaction of Scheme 5 can be found in the following aspects 1-12 of the present invention, especially aspects 2 and 3.
  • the compound of formula (I) is obtained by reacting the compound of formula (II) with 4-hydroxypiperidine.
  • reaction of Scheme 6 can be found in the following aspects 1-12 of the present invention, especially aspects 1, 2 and 3.
  • the method includes reacting a compound of formula (III) with 4-hydroxypiperidine to obtain a compound of formula (I), wherein Y is selected from (1S,2S)-cyclohexanediamine, (1R,2R)-cyclohexanediamine , Quinine, Quinidine or its deuterated derivatives.
  • Y is selected from (1S,2S)-cyclohexanediamine, (1R,2R)-cyclohexanediamine, quinine, quinidine or deuterated derivatives thereof.
  • Scheme 8 can be found in the following aspects 1-12 of the present invention, especially the fifth aspect.
  • a compound of formula (IX) is prepared from a compound of formula (X), preferably a compound of formula (IX) is prepared from a compound of formula (X) and an acid chloride compound, wherein the acid chloride compound is selected from phosphorus oxychloride, phosgene, and sulfur Acid chlorides, such as phosphorus oxychloride, acetyl chloride, thionyl chloride;
  • the compound of formula (VIII) is prepared by the compound of formula (IX) and ROH, preferably the compound of formula (VIII) is prepared by the compound of formula (IX) and ROH in the presence of CO, wherein R is C 1-6 alkyl;
  • the compound of formula (I) is obtained by reacting the compound of formula (II) with 4-hydroxypiperidine.
  • a compound of formula (IX) is prepared from a compound of formula (X), preferably a compound of formula (IX) is prepared from a compound of formula (X) and an acid chloride compound, wherein the acid chloride compound is selected from phosphorus oxychloride, phosgene, and sulfur Acid chlorides, such as phosphorus oxychloride, acetyl chloride, thionyl chloride;
  • the compound of formula (VIII) is prepared by the compound of formula (IX) and ROH, preferably the compound of formula (VIII) is prepared by the compound of formula (IX) and ROH in the presence of CO, wherein R is C 1-6 alkyl;
  • reaction of Scheme 10 can be found in the following aspects 1-12 of the present invention, especially the 12th aspect.
  • the method includes reacting a compound of formula (IV) with a chiral base Y to obtain a compound of formula (III), and the method is reacted in a ketone solvent, an ester solvent or tetrahydrofuran; preferably, the reaction temperature is 10-70°C , Such as 10-50°C, 10-40°C, 20-30°C, such as 25°C, the reaction time is not less than 1 hour, such as 1-48 hours, 4-24 hours, 8-16 hours, if not less than In 10 hours, the ratio of the compound of formula (IV) to the chiral base Y is less than or equal to 1:1.
  • the chiral base Y is selected from (1S,2S)-cyclohexanediamine, (1R,2R)-cyclohexanediamine, Quinine, Quinidine or deuterated derivatives thereof, etc., (1S,2S)-cyclohexanediamine or (1R,2R)-cyclohexanediamine or a deuterated derivative thereof is preferred, and (1S,2S)-cyclohexanediamine or a deuterated derivative thereof is more preferred.
  • the method is reacted in a ketone solvent, an ester solvent or tetrahydrofuran
  • the ketone solvent is selected from acetone, methyl ethyl ketone, pentanone, methyl isobutyl ketone, etc., preferably acetone
  • the ester solvent is selected from ethyl acetate Ester, isopropyl acetate or tert-butyl acetate, etc., preferably ethyl acetate.
  • the method uses the addition of a chiral base Y to achieve the resolution of the isomers.
  • a chiral base Y to achieve the resolution of the isomers.
  • SFC supercritical liquid chromatography
  • the method includes mixing the compound of formula (III) with an alcohol solvent, adding excess acid solution, and reacting to obtain the compound of formula (II); preferably, the reaction temperature is 0-40°C, for example, 20-30°C, such as 25°C
  • the reaction time is not less than 0.5 hours, such as 0.5-10 hours, 1-5 hours, such as 2 hours.
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol and the like.
  • the acid solution is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, trifluoroacetic acid and the like.
  • the reaction temperature is 0-40°C, such as 20-30°C, such as 25°C, and the reaction time is not less than 0.2 hours, such as 0.2-20 hours, 0.5-10 hours, 1-5 hours, such as 2 hours.
  • the condensation reagent is selected from 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), benzotriazole-N,N ,N',N'-tetramethylurea hexafluorophosphate (HBTU), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide/1-hydroxybenzotriazole (EDCI/HOBT), N,N'-dicyclohexylcarbodiimide/4- Dimethylaminopyridine (DCC/DMAP) and the like, preferably 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU).
  • HATU 2-(7-benzotriazo
  • the polar solvent is selected from N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), etc., preferably N-methylpyrrolidone ( NMP).
  • the non-polar solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or chloroform, etc., preferably dichloromethane.
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA), tetramethylethylenediamine, pyrrolidine, pyridine, 4-dimethylaminopyridine (DMAP) or N-methyl Morphine (NMM) and the like, preferably triethylamine.
  • DIPEA diisopropylethylamine
  • tetramethylethylenediamine pyrrolidine
  • pyridine 4-dimethylaminopyridine
  • NMM N-methyl Morphine
  • the method includes mixing a compound of formula (III), a condensation reagent, a polar solvent and a non-polar solvent, and then adding an organic base and 4-hydroxypiperidine to react to obtain a compound of formula (I).
  • the reaction temperature is 0-40°C, such as 20-30°C, such as 25°C
  • the reaction time is not less than 0.2 hours, such as 0.2-20 hours, 0.5-10 hours, 1-5 hours, such as 2 hours.
  • the condensation reagent is selected from 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), benzotriazole-N,N ,N',N'-tetramethylurea hexafluorophosphate (HBTU), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide/1-hydroxybenzotriazole (EDCI/HOBT), N,N'-dicyclohexylcarbodiimide/4- Dimethylaminopyridine (DCC/DMAP) and the like, preferably 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU).
  • HATU 2-(7-benzotriazo
  • the polar solvent is selected from N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), etc., preferably N-methylpyrrolidone ( NMP).
  • the non-polar solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or chloroform, etc., preferably dichloromethane.
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA), tetramethylethylenediamine, pyrrolidine, pyridine, 4-dimethylaminopyridine (DMAP) or N-methyl Morphine (NMM) and the like, preferably triethylamine.
  • DIPEA diisopropylethylamine
  • tetramethylethylenediamine pyrrolidine
  • pyridine 4-dimethylaminopyridine
  • NMM N-methyl Morphine
  • an intermediate compound of formula III is disclosed, the structural formula of which is as follows, for preparing the compound of formula (I) or compound of formula (II).
  • the chiral base Y is selected from (1S,2S)-cyclohexanediamine, (1R,2R)-cyclohexanediamine, Quinine, Quinidine or deuterated derivatives thereof, etc., (1S,2S)-cyclohexanediamine or (1R,2R)-cyclohexanediamine or a deuterated derivative thereof is preferred, and (1S,2S)-cyclohexanediamine or a deuterated derivative thereof is more preferred.
  • the method includes:
  • a compound of formula (X) is reacted with an acid chloride compound to obtain a compound of formula (IX).
  • a compound of formula (X) is reacted with phosphorus oxychloride to obtain a compound of formula (IX);
  • the reaction temperature is 40-90°C
  • the reaction time is not less than 0.5 hours, such as 0.5-10 hours, 1-5 hours, such as 2 hours.
  • R represents a C 1-6 alkyl group, which refers to a straight or branched alkyl group derived from a hydrocarbon moiety containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4- Methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2
  • the acid chloride compound is selected from phosphorous oxychloride, phosgene, and sulfuryl chloride, such as phosphorus oxychloride, acetyl chloride, and thionyl chloride.
  • the polar solvent is selected from N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), etc., preferably N,N-dimethylformamide (DMA), etc. Methyl formamide (DMF).
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA), tetramethylethylenediamine, pyrrolidine, pyridine, 4-dimethylaminopyridine (DMAP) or N-methyl Morphine (NMM) and the like, preferably triethylamine.
  • DIPEA diisopropylethylamine
  • tetramethylethylenediamine pyrrolidine
  • pyridine 4-dimethylaminopyridine
  • NMM N-methyl Morphine
  • the catalyst is selected from palladium catalysts, including Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , Pd 2 (dba) 3 or Pd(dba) 2 .
  • WO2014094664 discloses the preparation method of the compound of formula (VIII), but the yield is very low, and the reactant m-chloroperoxybenzoic acid (mCPBA) has the risk of explosion and the risk is high. In addition, the reactant trimethylsilyl cyanide has severe poison.
  • mCPBA m-chloroperoxybenzoic acid
  • the method for preparing the compound of formula (VIII) not only improves the yield, but also avoids the use of m-chloroperoxybenzoic acid (mCPBA) and the highly toxic reactant trimethylsilyl cyanide.
  • mCPBA m-chloroperoxybenzoic acid
  • the method includes:
  • a compound of formula (X) is reacted with an acid chloride compound to obtain a compound of formula (IX).
  • a compound of formula (X) is reacted with phosphorus oxychloride to obtain a compound of formula (IX);
  • the reaction temperature is 40-90°C
  • the reaction time is not less than 0.5 hours, such as 0.5-10 hours, 1-5 hours, such as 2 hours.
  • the compound of formula (IX) is passed through carbon monoxide in ROH, polar solvent, organic base and catalyst solvent to obtain the compound of formula (VIII); preferably, the reaction temperature is 40-90°C, for example, 70-80°C, such as 75°C, the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the compound of formula (VIII) is added to cyclopentylformaldehyde in alcohol solvent, acetonitrile or THF, and then an organic base is added to react to obtain the compound of formula (VII); preferably, the reaction temperature is 0-40°C, such as 10-30°C, For example, at 25°C, the reaction time is not less than 2 hours, such as 2-40 hours, 4-24 hours, 4-16 hours, such as 8 hours;
  • the reaction temperature is 40-90°C, such as 75-85°C,
  • the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the compound of formula (VII) is reacted with the compound of formula (VI) under the conditions of alcohol solvent, acetonitrile or THF and hydrogen chloride to obtain the compound of formula (V); preferably, the reaction temperature is 40-90°C, for example 70-80°C, such as 75°C, the reaction time is not less than 3 hours, such as 3-80 hours, 8-48 hours, 8-32 hours, such as 16 hours;
  • the compound of formula (V) is dissolved in an alcohol solvent and a tetrahydrofuran solution, dropped into an inorganic alkali solution, and reacted to prepare a compound of formula (IV); preferably, the reaction temperature is 0-40°C, such as 0-20°C, 0- At 10°C, such as 5°C, the reaction time is not less than 0.1 hour, such as 0.1-10 hours, such as 0.1-5 hours, 0.5-2 hours, such as 1 hour.
  • R represents a C 1-6 alkyl group, which refers to a straight or branched alkyl group derived from a hydrocarbon moiety containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4- Methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2
  • the acid chloride compound is selected from phosphorous oxychloride, phosgene, and sulfuryl chloride, such as phosphorus oxychloride, acetyl chloride, and thionyl chloride.
  • the polar solvent is selected from N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), etc., preferably N,N-dimethylformamide (DMA), etc. Methyl formamide (DMF).
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA), tetramethylethylenediamine, pyrrolidine, pyridine, 4-dimethylaminopyridine (DMAP) or N-methyl Morphine (NMM) and so on.
  • DIPEA diisopropylethylamine
  • tetramethylethylenediamine pyrrolidine
  • pyridine pyridine
  • 4-dimethylaminopyridine DMAP
  • NMM N-methyl Morphine
  • the catalyst is selected from palladium catalysts, including Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , Pd 2 (dba) 3 or Pd(dba) 2, etc., preferably Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 .
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol, etc., preferably ethanol.
  • the inorganic base is selected from NaOH, KOH or LiOH, etc., preferably NaOH or KOH.
  • the method includes:
  • a compound of formula (X) is reacted with an acid chloride compound to obtain a compound of formula (IX).
  • a compound of formula (X) is reacted with phosphorus oxychloride to obtain a compound of formula (IX);
  • the reaction temperature is 40-90°C
  • the reaction time is not less than 0.5 hours, such as 0.5-10 hours, 1-5 hours, such as 2 hours.
  • the compound of formula (IX) is passed through carbon monoxide in ROH, polar solvent, organic base and catalyst solvent to obtain the compound of formula (VIII); preferably, the reaction temperature is 40-90°C, for example, 70-80°C, such as 75°C, the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the compound of formula (VIII) is added to cyclopentylformaldehyde in alcohol solvent, acetonitrile or THF, and then an organic base is added to react to obtain the compound of formula (VII); preferably, the reaction temperature is 0-40°C, such as 10-30°C, For example, at 25°C, the reaction time is not less than 2 hours, such as 2-40 hours, 4-24 hours, 4-16 hours, such as 8 hours;
  • the reaction temperature is 40-90°C, such as 75-85°C,
  • the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the compound of formula (VII) is reacted with the compound of formula (VI) under the conditions of alcohol solvent, acetonitrile or THF and hydrogen chloride to obtain the compound of formula (V); preferably, the reaction temperature is 40-90°C, for example 70-80°C, such as 75°C, the reaction time is not less than 3 hours, such as 3-80 hours, 8-48 hours, 8-32 hours, such as 16 hours;
  • the compound of formula (V) is dissolved in an alcohol solvent and a tetrahydrofuran solution, dropped into an inorganic alkali solution, and reacted to prepare a compound of formula (IV); preferably, the reaction temperature is 0-40°C, such as 0-20°C, 0- At 10°C, such as 5°C, the reaction time is not less than 0.1 hour, such as 0.1-10 hours, 0.1-5 hours, 0.5-2 hours, such as 1 hour;
  • the compound of formula (IV) is reacted with a chiral base Y to obtain the compound of formula (III).
  • the method is reacted in a ketone solvent, an ester solvent or tetrahydrofuran; preferably, the reaction temperature is 10-70°C, such as 10-50 °C, 10-40°C, 20-30°C, such as 25°C, the reaction time is not less than 1 hour, such as 1-48 hours, 4-24 hours, 8-16 hours, if not less than 10 hours, as described
  • the ratio of the compound of formula (IV) to the chiral base Y is less than or equal to 1:1.
  • R represents a C 1-6 alkyl group, which refers to a straight or branched alkyl group derived from a hydrocarbon moiety containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4- Methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2
  • the acid chloride compound is selected from phosphorous oxychloride, phosgene, and sulfuryl chloride, such as phosphorus oxychloride, acetyl chloride, and thionyl chloride.
  • the polar solvent is selected from N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), etc., preferably N,N-dimethylformamide (DMA), etc. Methyl formamide (DMF).
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA), tetramethylethylenediamine, pyrrolidine, pyridine, 4-dimethylaminopyridine (DMAP) or N-methyl Morphine (NMM) and so on.
  • DIPEA diisopropylethylamine
  • tetramethylethylenediamine pyrrolidine
  • pyridine pyridine
  • 4-dimethylaminopyridine DMAP
  • NMM N-methyl Morphine
  • the catalyst is selected from palladium catalysts, including Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , Pd 2 (dba) 3 or Pd(dba) 2, etc., preferably Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 .
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol, etc., preferably ethanol.
  • the inorganic base is selected from NaOH, KOH or LiOH, etc., preferably NaOH or KOH.
  • the chiral resolution reagent is selected from (1S, 2S)-cyclohexanediamine, (1R, 2R)-cyclohexanediamine, Quinine, Quinidine or its deuterated derivatives, etc. , Preferably (1S,2S)-cyclohexanediamine or (1R,2R)-cyclohexanediamine or its deuterated derivatives, more preferably (1S,2S)-cyclohexanediamine or its deuterated derivatives.
  • the ketone solvent is selected from acetone, methyl ethyl ketone, pentanone or methyl isobutyl ketone, and preferably acetone.
  • the ester solvent is selected from ethyl acetate, isopropyl acetate or tert-butyl acetate, etc., preferably ethyl acetate.
  • the method includes:
  • a compound of formula (X) is reacted with an acid chloride compound to obtain a compound of formula (IX).
  • a compound of formula (X) is reacted with phosphorus oxychloride to obtain a compound of formula (IX);
  • the reaction temperature is 40-90°C
  • the reaction time is not less than 0.5 hours, such as 0.5-10 hours, 1-5 hours, such as 2 hours.
  • the compound of formula (IX) is passed through carbon monoxide in ROH, polar solvent, organic base and catalyst solvent to obtain the compound of formula (VIII); preferably, the reaction temperature is 40-90°C, for example, 70-80°C, such as 75°C, the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the compound of formula (VIII) is added to cyclopentylformaldehyde in alcohol solvent, acetonitrile or THF, and then an organic base is added to react to obtain the compound of formula (VII); preferably, the reaction temperature is 0-40°C, such as 10-30°C, For example, at 25°C, the reaction time is not less than 2 hours, such as 2-40 hours, 4-24 hours, 4-16 hours, such as 8 hours;
  • the reaction temperature is 40-90°C, such as 75-85°C,
  • the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the compound of formula (VII) is reacted with the compound of formula (VI) under the conditions of alcohol solvent, acetonitrile or THF and hydrogen chloride to obtain the compound of formula (V); preferably, the reaction temperature is 40-90°C, for example 70-80°C, such as 75°C, the reaction time is not less than 3 hours, such as 3-80 hours, 8-48 hours, 8-32 hours, such as 16 hours;
  • the compound of formula (V) is dissolved in an alcohol solvent and a tetrahydrofuran solution, dropped into an inorganic base solution, and reacted to prepare a compound of formula (IV); preferably, the reaction temperature is 0-40°C, such as 0-20°C, 0- At 10°C, such as 5°C, the reaction time is not less than 0.1 hours, such as 0.1-10 hours, such as 0.1-5 hours, 0.5-2 hours, such as 1 hour;
  • the compound of formula (IV) is reacted with a chiral base Y to obtain the compound of formula (III).
  • the method is reacted in a ketone solvent, an ester solvent or tetrahydrofuran; preferably, the reaction temperature is 10-70°C, such as 10-50 °C, 10-40°C, 20-30°C, such as 25°C, the reaction time is not less than 1 hour, such as 1-48 hours, 4-24 hours, 8-16 hours, if not less than 10 hours, as described
  • the ratio of the compound of formula (IV) to the chiral base Y is less than or equal to 1:1.
  • the compound of formula (III) is mixed with an alcohol solvent, and excess acid solution is added to react to obtain a compound of formula (II); preferably, the reaction temperature is 0-40°C, for example, 20-30°C, such as 25°C, and the reaction time is different Less than 0.5 hours, such as 0.5-10 hours, 1-5 hours, such as 2 hours.
  • R represents a C 1-6 alkyl group, which refers to a straight or branched alkyl group derived from a hydrocarbon moiety containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4- Methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2
  • the acid chloride compound is selected from phosphorous oxychloride, phosgene, and sulfuryl chloride, such as phosphorus oxychloride, acetyl chloride, and thionyl chloride.
  • the polar solvent is selected from N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), etc., preferably N,N-dimethylformamide (DMA), etc. Methyl formamide (DMF).
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA), tetramethylethylenediamine, pyrrolidine, pyridine, 4-dimethylaminopyridine (DMAP) or N-methyl Morphine (NMM) and so on.
  • DIPEA diisopropylethylamine
  • tetramethylethylenediamine pyrrolidine
  • pyridine pyridine
  • 4-dimethylaminopyridine DMAP
  • NMM N-methyl Morphine
  • the catalyst is selected from palladium catalysts, including Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , Pd 2 (dba) 3 or Pd(dba) 2, etc., preferably Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 .
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol, etc., preferably ethanol.
  • the inorganic base is selected from NaOH, KOH or LiOH, etc., preferably NaOH or KOH.
  • the chiral resolution reagent is selected from (1S, 2S)-cyclohexanediamine, (1R, 2R)-cyclohexanediamine, Quinine, Quinidine or its deuterated derivatives, etc. , Preferably (1S,2S)-cyclohexanediamine or (1R,2R)-cyclohexanediamine or its deuterated derivatives, more preferably (1S,2S)-cyclohexanediamine or its deuterated derivatives.
  • the ketone solvent is selected from acetone, methyl ethyl ketone, pentanone or methyl isobutyl ketone, and preferably acetone.
  • the ester solvent is selected from ethyl acetate, isopropyl acetate or tert-butyl acetate, etc., preferably ethyl acetate.
  • the acid solution is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, trifluoroacetic acid, etc., preferably hydrochloric acid.
  • the method includes:
  • a compound of formula (X) is reacted with an acid chloride compound to obtain a compound of formula (IX).
  • a compound of formula (X) is reacted with phosphorus oxychloride to obtain a compound of formula (IX);
  • the reaction temperature is 40-90°C
  • the reaction time is not less than 0.5 hours, such as 0.5-10 hours, 1-5 hours, such as 2 hours.
  • the compound of formula (IX) is passed through carbon monoxide in ROH, polar solvent, organic base and catalyst solvent to obtain the compound of formula (VIII); preferably, the reaction temperature is 40-90°C, for example, 70-80°C, such as 75°C, the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the compound of formula (VIII) is added to cyclopentylformaldehyde in alcohol solvent, acetonitrile or THF, and then an organic base is added to react to obtain the compound of formula (VII); preferably, the reaction temperature is 0-40°C, such as 10-30°C, For example, at 25°C, the reaction time is not less than 2 hours, such as 2-40 hours, 4-24 hours, 4-16 hours, such as 8 hours;
  • the reaction temperature is 40-90°C, such as 75-85°C,
  • the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the compound of formula (VII) is reacted with the compound of formula (VI) under the conditions of alcohol solvent, acetonitrile or THF and hydrogen chloride to obtain the compound of formula (V); preferably, the reaction temperature is 40-90°C, for example 70-80°C, such as 75°C, the reaction time is not less than 3 hours, such as 3-80 hours, 8-48 hours, 8-32 hours, such as 16 hours;
  • the compound of formula (V) is dissolved in an alcohol solvent and a tetrahydrofuran solution, dropped into an inorganic alkali solution, and reacted to prepare a compound of formula (IV); preferably, the reaction temperature is 0-40°C, such as 0-20°C, 0- At 10°C, such as 5°C, the reaction time is not less than 0.1 hour, such as 0.1-10 hours, 0.1-5 hours, 0.5-2 hours, such as 1 hour;
  • the compound of formula (IV) is reacted with a chiral base Y to obtain the compound of formula (III).
  • the method is reacted in a ketone solvent, an ester solvent or tetrahydrofuran; preferably, the reaction temperature is 10-70°C, such as 10-50 °C, 10-40°C, 20-30°C, such as 25°C, the reaction time is not less than 1 hour, such as 1-48 hours, 4-24 hours, 8-16 hours, if not less than 10 hours, as described
  • the ratio of the compound of formula (IV) to the chiral base Y is less than or equal to 1:1.
  • the compound of formula (III) is mixed with an alcohol solvent, and excess acid solution is added to react to obtain a compound of formula (II); preferably, the reaction temperature is 0-40°C, for example, 20-30°C, such as 25°C, and the reaction time is different Less than 0.5 hours, such as 0.5-10 hours, 1-5 hours, such as 2 hours.
  • the reaction temperature is 0-40°C, such as 20-30°C, such as 25°C, and the reaction time is not less than 0.2 hours, such as 0.2-20 hours, 0.5-10 hours, 1-5 hours, such as 2 hours.
  • R represents a C 1-6 alkyl group, which refers to a straight or branched alkyl group derived from a hydrocarbon moiety containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4- Methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2
  • the acid chloride compound is selected from phosphorus oxychloride, phosgene, and sulfuryl chloride, such as phosphorus oxychloride, acetyl chloride, and thionyl chloride.
  • the polar solvent is selected from N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), etc., preferably N,N-dimethylformamide (DMA), etc.
  • NMP N-methylpyrrolidone
  • DMF N,N-dimethylformamide
  • DMA N,N-dimethylacetamide
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA), tetramethylethylenediamine, pyrrolidine, pyridine, 4-dimethylaminopyridine (DMAP) or N-methyl Morphine (NMM) and so on.
  • DIPEA diisopropylethylamine
  • tetramethylethylenediamine pyrrolidine
  • pyridine pyridine
  • 4-dimethylaminopyridine DMAP
  • NMM N-methyl Morphine
  • the catalyst is selected from palladium catalysts, including Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , Pd 2 (dba) 3 or Pd(dba) 2, etc., preferably Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 .
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol, etc., preferably ethanol.
  • the inorganic base is selected from NaOH, KOH or LiOH, etc., preferably NaOH or KOH.
  • the chiral resolution reagent is selected from (1S, 2S)-cyclohexanediamine, (1R, 2R)-cyclohexanediamine, Quinine, Quinidine or its deuterated derivatives, etc. , Preferably (1S,2S)-cyclohexanediamine or (1R,2R)-cyclohexanediamine or its deuterated derivatives, more preferably (1S,2S)-cyclohexanediamine or its deuterated derivatives.
  • the ketone solvent is selected from acetone, methyl ethyl ketone, pentanone or methyl isobutyl ketone, and preferably acetone.
  • the ester solvent is selected from ethyl acetate, isopropyl acetate or tert-butyl acetate, etc., preferably ethyl acetate.
  • the acid solution is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, trifluoroacetic acid, etc., preferably hydrochloric acid.
  • the condensation reagent is selected from 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), benzotriazole-N,N ,N',N'-tetramethylurea hexafluorophosphate (HBTU), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide/1-hydroxybenzotriazole (EDCI/HOBT), N,N'-dicyclohexylcarbodiimide/4- Dimethylaminopyridine (DCC/DMAP) and the like, preferably 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU).
  • HATU 2-(7-benzotriazo
  • the non-polar solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or chloroform, etc., preferably dichloromethane.
  • the method includes:
  • a compound of formula (X) is reacted with an acid chloride compound to obtain a compound of formula (IX).
  • a compound of formula (X) is reacted with phosphorus oxychloride to obtain a compound of formula (IX);
  • the reaction temperature is 40-90°C
  • the reaction time is not less than 0.5 hours, such as 0.5-10 hours, 1-5 hours, such as 2 hours.
  • the compound of formula (IX) is passed through carbon monoxide in ROH, polar solvent, organic base and catalyst solvent to obtain the compound of formula (VIII); preferably, the reaction temperature is 40-90°C, for example, 70-80°C, such as 75°C, the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the compound of formula (VIII) is added to cyclopentylformaldehyde in alcohol solvent, acetonitrile or THF, and then an organic base is added to react to obtain the compound of formula (VII); preferably, the reaction temperature is 0-40°C, such as 10-30°C, For example, at 25°C, the reaction time is not less than 2 hours, such as 2-40 hours, 4-24 hours, 4-16 hours, such as 8 hours;
  • the reaction temperature is 40-90°C, such as 75-85°C,
  • the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the compound of formula (VII) is reacted with the compound of formula (VI) under the conditions of alcohol solvent, acetonitrile or THF and hydrogen chloride to obtain the compound of formula (V); preferably, the reaction temperature is 40-90°C, for example 70-80°C, such as 75°C, the reaction time is not less than 3 hours, such as 3-80 hours, 8-48 hours, 8-32 hours, such as 16 hours;
  • the compound of formula (V) is dissolved in an alcohol solvent and a tetrahydrofuran solution, dropped into an inorganic alkali solution, and reacted to prepare a compound of formula (IV); preferably, the reaction temperature is 0-40°C, such as 0-20°C, 0- At 10°C, such as 5°C, the reaction time is not less than 0.1 hour, such as 0.1-10 hours, 0.1-5 hours, 0.5-2 hours, such as 1 hour;
  • the compound of formula (IV) is reacted with a chiral base Y to obtain the compound of formula (III).
  • the method is reacted in a ketone solvent, an ester solvent or tetrahydrofuran; preferably, the reaction temperature is 10-70°C, such as 10-50 °C, 10-40°C, 20-30°C, such as 25°C, the reaction time is not less than 1 hour, such as 1-48 hours, 4-24 hours, 8-16 hours, if not less than 10 hours, as described
  • the ratio of the compound of formula (IV) to the chiral base Y is less than or equal to 1:1.
  • the reaction temperature is 0-40°C, such as 20-30°C, such as 25°C, and the reaction time is not less than 0.2 hours, such as 0.2-20 hours, 0.5-10 hours, 1-5 hours, such as 2 hours.
  • R represents a C 1-6 alkyl group, which refers to a straight or branched alkyl group derived from a hydrocarbon moiety containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4- Methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2
  • the acid chloride compound is selected from phosphorous oxychloride, phosgene, and sulfuryl chloride, such as phosphorus oxychloride, acetyl chloride, and thionyl chloride.
  • the polar solvent is selected from N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), etc., preferably N,N-dimethylformamide (DMA), etc.
  • NMP N-methylpyrrolidone
  • DMF N,N-dimethylformamide
  • DMA N,N-dimethylacetamide
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA), tetramethylethylenediamine, pyrrolidine, pyridine, 4-dimethylaminopyridine (DMAP) or N-methyl Morphine (NMM) and so on.
  • DIPEA diisopropylethylamine
  • tetramethylethylenediamine pyrrolidine
  • pyridine pyridine
  • 4-dimethylaminopyridine DMAP
  • NMM N-methyl Morphine
  • the catalyst is selected from palladium catalysts, including Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , Pd 2 (dba) 3 or Pd(dba) 2, etc., preferably Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 .
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol, etc., preferably ethanol.
  • the inorganic base is selected from NaOH, KOH or LiOH, etc., preferably NaOH or KOH.
  • the chiral resolution reagent is selected from (1S, 2S)-cyclohexanediamine, (1R, 2R)-cyclohexanediamine, Quinine, Quinidine or its deuterated derivatives, etc. , Preferably (1S,2S)-cyclohexanediamine or (1R,2R)-cyclohexanediamine or its deuterated derivatives, more preferably (1S,2S)-cyclohexanediamine or its deuterated derivatives.
  • the ketone solvent is selected from acetone, methyl ethyl ketone, pentanone or methyl isobutyl ketone, and preferably acetone.
  • the ester solvent is selected from ethyl acetate, isopropyl acetate or tert-butyl acetate, etc., preferably ethyl acetate.
  • the condensation reagent is selected from 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), benzotriazole-N,N ,N',N'-tetramethylurea hexafluorophosphate (HBTU), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide/1-hydroxybenzotriazole (EDCI/HOBT), N,N'-dicyclohexylcarbodiimide/4- Dimethylaminopyridine (DCC/DMAP) and the like, preferably 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU).
  • HATU 2-(7-benzotriazo
  • the non-polar solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or chloroform, etc., preferably dichloromethane.
  • the method includes:
  • a compound of formula (X) is reacted with an acid chloride compound to obtain a compound of formula (IX).
  • a compound of formula (X) is reacted with phosphorus oxychloride to obtain a compound of formula (IX);
  • the reaction temperature is 40-90°C
  • the reaction time is not less than 0.5 hours, such as 0.5-10 hours, 1-5 hours, such as 2 hours.
  • the compound of formula (IX) is passed through carbon monoxide in ROH, polar solvent, organic base and catalyst solvent to obtain the compound of formula (VIII); preferably, the reaction temperature is 40-90°C, for example, 70-80°C, such as 75°C, the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the compound of formula (VIII) is added to cyclopentylformaldehyde in alcohol solvent, acetonitrile or THF, and then an organic base is added to react to obtain the compound of formula (VII); preferably, the reaction temperature is 0-40°C, such as 10-30°C, For example, at 25°C, the reaction time is not less than 2 hours, such as 2-40 hours, 4-24 hours, 4-16 hours, such as 8 hours;
  • the reaction temperature is 40-90°C, such as 75-85°C,
  • the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the compound of formula (VII) is reacted with the compound of formula (VI) under the conditions of alcohol solvent, acetonitrile or THF and hydrogen chloride to obtain the compound of formula (V); preferably, the reaction temperature is 40-90°C, for example 70-80°C, such as 75°C, the reaction time is not less than 3 hours, such as 3-80 hours, 8-48 hours, 8-32 hours, such as 16 hours;
  • the compound of formula (V) is resolved by SFC to obtain the compound of formula (V');
  • the reaction temperature is 0-40°C, such as 20-30°C, such as 25°C, and the reaction time is not less than 0.2 hours, such as 0.2-20 hours, 0.5-10 hours, 1-5 hours, such as 2 hours.
  • R represents a C 1-6 alkyl group, which refers to a straight or branched alkyl group derived from a hydrocarbon moiety containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4- Methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2
  • the acid chloride compound is selected from phosphorous oxychloride, phosgene, and sulfuryl chloride, such as phosphorus oxychloride, acetyl chloride, and thionyl chloride.
  • the polar solvent is selected from N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), etc., preferably N,N-dimethylformamide (DMA), etc.
  • NMP N-methylpyrrolidone
  • DMF N,N-dimethylformamide
  • DMA N,N-dimethylacetamide
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA), tetramethylethylenediamine, pyrrolidine, pyridine, 4-dimethylaminopyridine (DMAP) or N-methyl Morphine (NMM) and so on.
  • DIPEA diisopropylethylamine
  • tetramethylethylenediamine pyrrolidine
  • pyridine pyridine
  • 4-dimethylaminopyridine DMAP
  • NMM N-methyl Morphine
  • the catalyst is selected from palladium catalysts, including Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , Pd 2 (dba) 3 or Pd(dba) 2, etc., preferably Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 .
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol, etc., preferably ethanol.
  • the inorganic base is selected from NaOH, KOH or LiOH, etc., preferably NaOH or KOH.
  • any step of the preparation method of the present invention is carried out under normal pressure.
  • room temperature means 10-30°C, such as 26°C.
  • the present invention provides the following embodiments:
  • the chiral base Y is selected from (1S,2S)-cyclohexanediamine, (1R,2R)-cyclohexanediamine, Quinine, Quinidine or deuterated derivatives thereof, preferably (1S,2S)-cyclohexanediamine or (1R,2R)-cyclohexanediamine or its deuterated derivatives, more preferably (1S,2S)-cyclohexanediamine or its deuterated derivatives.
  • step (g) is a reaction in a ketone solvent, an ester solvent or tetrahydrofuran
  • the reaction temperature is 10-70°C, such as 10-50°C, 10-40°C, 20-30°C, such as 25°C;
  • the reaction time is not less than 1 hour, such as 1-48 hours, 4-24 hours , 8-16 hours, if not less than 10 hours;
  • the ratio of the compound of formula (IV) to the chiral base Y is less than or equal to 1:1;
  • the ketone solvent is selected from acetone, methyl ethyl ketone, pentanone or methyl isobutyl ketone, etc., preferably acetone;
  • the ester solvent is selected from ethyl acetate, isopropyl acetate or tert-butyl acetate Etc., ethyl acetate is preferred.
  • R is C 1-6 alkyl
  • step (f) is to dissolve the compound of formula (V) in an alcohol solvent and a tetrahydrofuran solution, drip into an inorganic alkali solution, and react to obtain a compound of formula (IV);
  • the reaction temperature is 0-40°C, such as 0-20°C, 0-10°C, such as 5°C, and the reaction time is not less than 0.1 hours, such as 0.1-10 hours, 0.1-5 hours, 0.5-2 Hour, such as 1 hour;
  • the alcohol solvent is selected from methanol, ethanol, isopropanol or tert-butanol, etc., preferably ethanol;
  • the inorganic base is selected from NaOH, KOH, LiOH, etc., preferably NaOH or KOH.
  • R is C 1-6 alkyl
  • step (e) is to react a compound of formula (VII) with a compound of formula (VI) in an alcohol solvent, acetonitrile or THF and hydrogen chloride to obtain a compound of formula (V);
  • the reaction temperature is 40-90°C, such as 70-80°C, 75°C, and the reaction time is not less than 3 hours, such as 3-80 hours, 8-48 hours, 8-32 hours, such as 16 hours;
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol, etc., preferably ethanol.
  • step (d) is to mix 2-chloro-4-fluorobenzonitrile with hydrazine hydrate in an alcohol solvent, acetonitrile or THF, and react to obtain a compound of formula (VI);
  • the reaction temperature is 40-90°C, such as 75-85°C, such as 80°C, and the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol, etc., preferably ethanol.
  • R is C 1-6 alkyl
  • step (c) is to add cyclopentylformaldehyde to the compound of formula (VIII) in an alcohol solvent, acetonitrile or THF, and then add an organic base to react to obtain a compound of formula (VII);
  • the reaction temperature is 0-40°C, such as 10-30°C, such as 25°C, and the reaction time is not less than 2 hours, such as 2-40 hours, 4-24 hours, 4-16 hours, such as 8 hours ;
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol, etc., preferably ethanol;
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA) , Tetramethylethylenediamine, pyrrolidine, pyridine, 4-dimethylaminopyridine (DMAP) or N-methylmorpholine (NMM), etc., preferably pyrrolidine.
  • R is C 1-6 alkyl
  • step (b) is to pass the compound of formula (IX) into ROH, a polar solvent, an organic base and a catalyst solvent, and pass carbon monoxide to react to obtain a compound of formula (VIII);
  • the reaction temperature is 40-90°C, such as 70-80°C, such as 75°C, and the reaction time is not less than 0.5 hours, such as 0.5-15 hours, 1-5 hours, such as 3 hours;
  • the polar solvent is selected from N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), etc., preferably N, N-dimethylformamide (DMF);
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA), tetramethylethylenediamine, pyrrolidine, pyridine, 4-diethylamine Methylaminopyridine (DMAP) or N-methylmorpholine (NMM), etc., preferably triethylamine;
  • the catalyst is selected from palladium catalysts, including Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , Pd 2 (dba) 3 or Pd(db
  • a compound of formula (IX) is prepared from a compound of formula (X), preferably a compound of formula (IX) is prepared from a compound of formula (X) and an acid chloride compound
  • the acid chloride compound is selected from phosphorous oxychloride, phosgene, and sulfuryl chloride, such as phosphorus oxychloride, acetyl chloride, and thionyl chloride;
  • the reaction temperature is 40-90°C, such as 75-85°C, such as 80°C, and the reaction time is not less than 0.5 hours, such as 0.5-10 hours, 1-5 hours, such as 2 hours.
  • a compound of formula (IX) is prepared from a compound of formula (X), preferably a compound of formula (IX) is prepared from a compound of formula (X) and an acid chloride compound,
  • R is C 1-6 alkyl
  • step (a) is to react a compound of formula (X) with an acid chloride compound to obtain a compound of formula (IX), preferably, to react a compound of formula (X) with phosphorus oxychloride to obtain a compound of formula (IX); wherein the acid chloride
  • the compound is selected from phosphorus oxychloride, phosgene, sulfuryl chloride, such as phosphorus oxychloride, acetyl chloride, thionyl chloride;
  • step (b) is to put the compound of formula (IX) in ROH, polar solvent, organic base and catalyst solvent In, pass carbon monoxide, and react to obtain a compound of formula (VIII);
  • the polar solvent is selected from N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), etc., preferably N, N-dimethylformamide (DMF);
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA), tetramethylethylenediamine, pyrrolidine, pyridine, 4-diethylamine Methylaminopyridine (DMAP) or N-methylmorpholine (NMM), etc., preferably triethylamine;
  • the catalyst is selected from palladium catalysts, including Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , Pd 2 (dba) 3 or Pd(db
  • Y is selected from (1S,2S)-cyclohexanediamine, (1R,2R)-cyclohexanediamine, quinine, quinidine or deuterated derivatives thereof;
  • step (h) is to mix the compound of formula (III) with an alcohol solvent, add excess acid solution, and react to obtain the compound of formula (II);
  • the reaction temperature is 0-40°C, such as 20-30°C, such as 25°C, and the reaction time is not less than 0.5 hours, such as 0.5-10 hours, 1-5 hours, such as 2 hours;
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol, etc., preferably ethanol;
  • the acid solution is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or trifluoroacetic acid, etc., preferably hydrochloric acid.
  • step (h) is to mix the compound of formula (III) with an alcohol solvent, add excess acid solution, and react to obtain the compound of formula (II);
  • step (i) is to combine the compound of formula (II), condensation reagent, polar The solvent is mixed with the non-polar solvent, and then an organic base and 4-hydroxypiperidine are added respectively to react to obtain a compound of formula (I);
  • the alcohol solvent is selected from methanol, ethanol, isopropanol or tert-butanol, etc., preferably ethanol
  • the acid solution is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or trifluoroacetic acid, etc., preferably hydrochloric acid
  • the condensation reagent is selected from 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), benzotriazole-N,N, N',N'-tetramethylurea hexafluorophosphate (HBTU), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide/1-hydroxybenzotriazole (EDCI/HOBT), N,N'-dic
  • the above step is to mix the compound of formula (III), the condensation reagent, the polar solvent and the non-polar solvent, and then add the organic base and 4-hydroxypiperidine to react to obtain the compound of formula (I);
  • the reaction temperature in the above step is 0-40°C, such as 20-30°C, such as 25°C, and the reaction time is not less than 0.2 hours, such as 0.2-20 hours, 0.5-10 hours, 1-5 hours, Such as 2 hours;
  • the condensation reagent is selected from 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), benzotriazole-N,N ,N',N'-tetramethylurea hexafluorophosphate (HBTU), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide/1-hydroxybenzotriazole (EDCI/HOBT), N,N'-dicyclohexylcarbodiimide/4- Dimethylaminopyridine (DCC/DMAP), etc., preferably 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU);
  • the polar solvent is selected from N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), etc., preferably N-methylpyrrolidone ( NMP);
  • the non-polar solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or chloroform, etc., preferably dichloromethane;
  • the organic base is selected from triethylamine, diethylamine, diisopropylethylamine (DIPEA), tetramethylethylenediamine, pyrrolidine, pyridine, 4-dimethylaminopyridine (DMAP) or N-methyl Morphine (NMM) and the like, preferably triethylamine.
  • DIPEA diisopropylethylamine
  • tetramethylethylenediamine pyrrolidine
  • pyridine 4-dimethylaminopyridine
  • NMM N-methyl Morphine
  • Y is selected from (1S,2S)-cyclohexanediamine, (1R,2R)-cyclohexanediamine, quinine, quinidine or deuterated derivatives thereof.
  • C 1-6 alkyl refers to a straight or branched alkyl group derived from a hydrocarbon moiety containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethyl Propyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2 -Dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl But
  • the present invention also provides the following technical solutions:
  • Technical solution 5 The method according to any one of technical solutions 1-4, wherein 2-(3-chloro-4-cyano-phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro -2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid is obtained by the following steps:
  • the 2-(3-chloro-4-cyano-phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro -2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid ethyl ester (1 molar equivalent), methanol (not less than 0.18 liters/1 molar equivalent, for example, 0.18-4.49 liters/1 molar equivalent, 0.45-1.80L/1 molar equivalent, such as 898 ml/1 molar equivalent) and tetrahydrofuran (not less than 0.36L/1 molar equivalent, such as 0.36-8.98L/1 molar equivalent, 0.90-3.59L/1 molar equivalent, such as 1796 ml/1 molar equivalent), and the resulting mixture is cooled to 0-40°C (for example, 0-20°C, 0-10°C, such as 5°C);
  • the resulting mixture is heated to 10-40°C (for example, 20-30°C, such as 25°C), stirred, filtered,
  • Technical Solution 6 The method according to Technical Solution 5, wherein 2-(3-chloro-4-cyano-phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo [3,4-f]quinoline-7-carboxylic acid ethyl ester is obtained by the following steps:
  • the 6-cyclopentylmethylene-5-oxo-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid Ethyl ester (1 molar equivalent), 2-chloro-4-hydrazinobenzonitrile (not less than 0.21 molar equivalent, such as 0.21-5.22 molar equivalent, 0.52-2.09 molar equivalent, such as 1.05 molar equivalent), ethanol (not low In 0.19 liters/1 molar equivalent, for example, 0.19-4.79 liters/1 molar equivalent, 0.48-1.92 liters/1 molar equivalent, such as 958 ml/1 molar equivalent) and hydrogen chloride ethanol solution (at a concentration of 2.0 mol/liter, no Less than 0.11 liter/1 molar equivalent, for example, 0.11-2.75 liters/1 molar equivalent, 0.28-1.10 liters/1 molar equivalent, such as 551 m
  • the resulting mixture is cooled to 0-20°C (for example, 0-10°C, such as 5°C), stirred, filtered with suction,
  • Technical Solution 7 The method according to Technical Solution 6, wherein 2-chloro-4-hydrazinobenzonitrile is obtained through the following steps:
  • the resulting mixture is heated to 40-90°C (for example, 75-85°C, such as 80°C) and the reaction is not less than 0.5 hours (for example, 0.5-15 hours, 1-5 hours, such as 3 hours),
  • the filter cake is rinsed with ethanol, and the wet filter cake is vacuum dried to obtain 2-chloro-4-hydrazinobenzonitrile.
  • Technical solution 8 The method according to technical solution 6, wherein 6-cyclopentylmethylene-5-oxo-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid ethyl ester is obtained by the following steps obtain:
  • the reaction system is cooled to about 35-80°C (for example, 50-70°C, such as 60°C), and distilled under reduced pressure until there are no cuts. After concentration, a concentrated solution is obtained.
  • Pyrrolidine (not less than 0.12 molar equivalent, such as 0.12-3 molar equivalent, 0.3-1.2 molar equivalent, such as 0.6 molar equivalent) was added dropwise to the resulting mixture, and the temperature was raised to 0-40°C (such as 10-30°C, such as 25°C),
  • the resulting mixture is protected from light for no less than 2 hours (for example, 2-40 hours, 4-24 hours, 4-16 hours, such as 8 hours),
  • Technical Solution 9 The method according to Technical Solution 8, wherein 2-chloro-7,8-dihydro-6H-quinolin-5-one is obtained through the following steps:
  • the filter cake was rinsed with water and dried in vacuum to obtain 2-chloro-7,8-dihydro-6H-quinolin-5-one.
  • Technical Solution 10 The method according to Technical Solution 1, wherein
  • the prepared (3S,3aR)-2-(3-chloro-4-cyano-phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3, 4-f]quinoline-7-carboxylic acid (1S,2S)-cyclohexanediamine salt is used to prepare (3S,3aR)-2-(3-chloro-4-cyano-phenyl)-3-ring Pentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid, the preparation process includes the following steps:
  • Technical Solution 11 The method according to Technical Solution 11, wherein
  • the prepared (3S,3aR)-2-(3-chloro-4-cyano-phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3, 4-f]quinoline-7-carboxylic acid is used to prepare 2-chloro-4-[(3S,3aR)-3-cyclopentyl-7-(4-hydroxypiperidine-1-carbonyl)-3,3a ,4,5-Tetrahydro-2H-pyrazolo[3,4-f]quinolin-2-yl]benzonitrile, the preparation process includes the following steps:
  • the organic phase is evaporated to dryness to obtain an oil, the oil and isopropanol (not less than 1.01 kg/1 molar equivalent, such as 1.01-25.26 kg/1 molar equivalent, 2.53-10.10 kg/1 molar equivalent, such as 5.05 kg/ 1 molar equivalent), heat to 50-90°C (for example, 75-85°C, such as 80°C), the solution is clear, and after cooling to 10-40°C (for example, 20-30°C, such as 25°C), stir not less than 0.3 Hours (for example, 0.3-30 hours, 1.5-6 hours, such as 3 hours), filter, wash the filter cake with isopropanol, and dry in vacuo to obtain 2-chloro-4-[(3S,3aR)-3-cyclopentyl -7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinolin-2-yl]benzonitrile.
  • Technical Solution 12 The method according to Technical Solution 1, wherein
  • the prepared (3S,3aR)-2-(3-chloro-4-cyano-phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3, 4-f]quinoline-7-carboxylic acid (1S,2S)-cyclohexanediamine salt is used to prepare 2-chloro-4-[(3S,3aR)-3-cyclopentyl-7-(4-hydroxyl Piperidine-1-carbonyl)-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinolin-2-yl]benzonitrile, the preparation process includes the following steps:
  • the organic phase is evaporated to dryness to obtain an oil, the oil and isopropanol (not less than 1.01 kg/1 molar equivalent, such as 1.01-25.26 kg/1 molar equivalent, 2.53-10.10 kg/1 molar equivalent, such as 5.05 kg/ 1 molar equivalent), heat to 50-90°C (for example, 75-85°C, such as 80°C), the solution is clear, and after cooling to 10-40°C (for example, 20-30°C, such as 25°C), stir not less than 0.3 Hours (for example, 0.3-30 hours, 1.5-6 hours, such as 3 hours), filter, wash the filter cake with isopropanol, and dry in vacuo to obtain 2-chloro-4-[(3S,3aR)-3-cyclopentyl -7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinolin-2-yl]benzonitrile.
  • the method for preparing (3S,3aR)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline compound disclosed in the present invention the resolution step
  • the method of chiral alkali resolution is used to replace the resolution of supercritical liquid chromatography, which realizes large-scale industrial production and reduces the cost; the total yield of the process is increased by about 7 times; the post-process operation is simplified, safe, and conducive to quality control and cut costs.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

本申请公开一种三并环化合物的制备方法及其中间体，具体涉及制备(3S,3aR)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉类化合物的方法，所述方法中的中间体和用于制备所述中间体的方法。

Description

一种三并环化合物的制备方法及其中间体 1、技术领域
本发明公开了一种三并环化合物的制备方法及其中间体，具体涉及(3S,3aR)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉类化合物的制备方法，特别涉及(3S,3aR)-2-(3-氯-4-氰基苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸或2-氯-4-[(3S,3aR)-3-环戊基-7-(4-羟基哌啶-1-羰基)-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-2-基]苯甲腈的制备方法，并公开了可用于合成所述化合物的中间体。
2、背景技术
(3S,3aR)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉类化合物(例如(3S,3aR)-2-(3-氯-4-氰基苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(式II化合物)，2-氯-4-[(3S,3aR)-3-环戊基-7-(4-羟基哌啶-1-羰基)-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-2-基]苯甲腈(式I化合物))的制备方法描述于WO2012022121A1或WO2014094664A1中，其中的拆分步骤均采用超临界液相色谱(SFC)进行拆分，制备方法的产物收率低，生产成本非常高。
而且，WO2014094664A1中的工艺反应中使用的反应物间氯过氧苯甲酸危险性高，三甲基氰硅烷有剧毒，因此(3S,3aR)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉类化合物的工艺需要优化，以满足工业化大生产的需求。
Figure PCTCN2020077413-appb-000001
3、发明内容
本发明的目的在于提供了一种(3S,3aR)-3-环戊基-3,3a,4,5-四氢 -2H-吡唑并[3,4-f]喹啉类化合物的制备方法，采用手性碱代替超临界液相色谱(SFC)进行手性拆分，生产规模升高到适于商业规模制备的批次量大小，实现了工业化大生产的目的。较已公开工艺提高了总反应收率，总生产率提高了约7倍，并且，本发明工艺更加安全。
为了达到上述目的，本发明尝试了一系列手性纯化的方法，例如酶催化水解、手性酸/碱拆分、手性基团诱导、模拟流动床色谱(SMB)拆分、不对称衍生物的结晶分离、不对称衍生物的硅胶柱分离。其中，手性碱拆分有比较好的拆分效果，其他拆分方法都没有达到拆分目的。对于手性碱拆分的方法，尝试了几十种手性碱试剂，其中(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁(Quinine)、奎尼丁(Quinidine)或其氘代衍生物的拆分效果较好。对于上述有明显拆分效果的手性碱，尝试了多种实验溶剂，其中酮类溶剂、酯类溶剂或四氢呋喃的拆分效果较好。所述酮类溶剂选自丙酮、丁酮、戊酮或甲基异丁酮等，优选丙酮。所述酯类溶剂选自乙酸乙酯、乙酸异丙酯或乙酸叔丁酯等，优选乙酸乙酯。例如，(1S,2S)-环己二胺或(1R,2R)-环己二胺在丙酮中拆分效果比较好，奎宁(Quinine)或奎尼丁(Quinidine)在乙酸乙酯中拆分效果比较好。
本发明旨在保护下述技术方案：
方案1、一种制备式(III)化合物的方法，将式(IV)化合物与手性碱Y反应得式(III)化合物，所述手性碱Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物。
Figure PCTCN2020077413-appb-000002
方案2、如方案1所述的方法，在酮类溶剂、酯类溶剂或四氢呋喃中反应。
方案1和2的反应的具体实例可以参见下述本发明的第1-12方面，特别是第1方面。
方案3、一种制备式(VIII)化合物的方法，该方法包括以下路线：
Figure PCTCN2020077413-appb-000003
(a)通过式(X)化合物制备得式(IX)化合物，优选地通过式(X)化合物与酰氯类化合物制备得式(IX)化合物，其中酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、乙酰氯、二氯亚砜；
(b)式(IX)化合物与ROH制备得式(VIII)化合物，优选地式(IX)化合物与ROH在CO的存在下制备得式(VIII)化合物，其中R是C 1-6烷基。
方案3的反应的具体实例可以参见下述本发明的第1-12方面，特别是第6方面。
方案4、如方案1所述的方法，该方法包括以下路线：
Figure PCTCN2020077413-appb-000004
(a)通过式(X)化合物制备得式(IX)化合物，优选地通过式(X)化合物与酰氯类化合物制备得式(IX)化合物，其中酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、乙酰氯、二氯亚砜；
(b)式(IX)化合物与ROH制备得式(VIII)化合物，优选地式(IX)化合物与ROH在CO的存在下制备得式(VIII)化合物，其中R是C 1-6烷基；
(c)将式(VIII)化合物与环戊基甲醛反应得式(VII)化合物；
(d)将2-氯-4-氟苯甲腈与水合肼反应得式(VI)化合物；
(e)将式(VII)化合物与式(VI)化合物反应得式(V)化合物；
(f)将式(V)化合物通过水解反应得式(IV)化合物；
(g)将式(IV)化合物与手性碱Y反应得式(III)化合物。
方案4的反应的具体实例可以参见下述本发明的第1-12方面，特别是第8方面。
方案5、一种制备式(I)化合物的方法，包括以下步骤：
Figure PCTCN2020077413-appb-000005
(h)将式(III)化合物加入酸溶液反应得式(II)化合物；
(i)将式(II)化合物和4-羟基哌啶反应得式(I)化合物，其中Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物。
方案5的反应的具体实例可以参见下述本发明的第1-12方面，特别是第2和3方面。
方案6、如方案5所述的方法，包括如下步骤：
Figure PCTCN2020077413-appb-000006
(g)将式(IV)化合物与手性碱Y反应得式(III)化合物；
(h)将式(III)化合物加入酸溶液反应得式(II)化合物；
(i)将式(II)化合物和4-羟基哌啶反应得式(I)化合物。
方案6的反应的具体实例可以参见下述本发明的第1-12方面，特别是第1、2和3方面。
方案7、一种制备式(I)化合物的方法，包括以下步骤：
Figure PCTCN2020077413-appb-000007
所述方法包括，将式(III)化合物和4-羟基哌啶反应得式(I)化合物，其中Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物。
方案7的反应的具体实例可以参见下述本发明的第1-12方面，特别是第4方面。
方案8、式(III)化合物，具有下式结构，
Figure PCTCN2020077413-appb-000008
其中Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物。
方案8的具体实例可以参见下述本发明的第1-12方面，特别是第5方面。
方案9、如方案6所述的方法，包括以下步骤：
Figure PCTCN2020077413-appb-000009
(a)通过式(X)化合物制备得式(IX)化合物，优选地通过式(X)化合物与酰氯类化合物制备得式(IX)化合物，其中酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、乙酰氯、二氯亚砜；
(b)式(IX)化合物与ROH制备得式(VIII)化合物，优选地式(IX)化合物与ROH在CO的存在下制备得式(VIII)化合物，其中R是C 1-6烷基；
(c)将式(VIII)化合物与环戊基甲醛反应得式(VII)化合物；
(d)将2-氯-4-氟苯甲腈与水合肼反应得式(VI)化合物；
(e)将式(VII)化合物与式(VI)化合物反应得式(V)化合物；
(f)将式(V)化合物通过水解反应得式(IV)化合物；
(g)将式(IV)化合物与手性碱Y反应得式(III)化合物；
(h)将式(III)化合物加入酸溶液反应得式(II)化合物；
(i)将式(II)化合物和4-羟基哌啶反应得式(I)化合物。
方案9的反应的具体实例可以参见下述本发明的第1-12方面，特别是第10方面。
方案10、一种制备式(I)化合物的方法，包括以下步骤：
Figure PCTCN2020077413-appb-000010
(a)通过式(X)化合物制备得式(IX)化合物，优选地通过式(X)化合物与酰氯类化合物制备得式(IX)化合物，其中酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、乙酰氯、二氯亚砜；
(b)式(IX)化合物与ROH制备得式(VIII)化合物，优选地式(IX)化合物与ROH在CO的存在下制备得式(VIII)化合物，其中R是C 1-6烷基；
(c)将式(VIII)化合物与环戊基甲醛反应得式(VII)化合物；
(d)将2-氯-4-氟苯甲腈与水合肼反应得式(VI)化合物；
(e)将式(VII)化合物与式(VI)化合物反应得式(V)化合物；
(f’)将式(V)化合物通过SFC拆分得式(V’)化合物；
(g’)将式(V’)化合物通过水解反应得式(II)化合物；
(h’)将式(II)化合物和4-羟基哌啶反应得式(I)化合物。
方案10的反应的具体实例可以参见下述本发明的第1-12方面，特别是第12方面。
根据本发明的第1方面，公开了通过拆分式(IV)化合物获得式(III)化合物的方法。
Figure PCTCN2020077413-appb-000011
所述方法包括，将式(IV)化合物与手性碱Y反应得式(III)化合物，所述方法在酮类溶剂、酯类溶剂或四氢呋喃中反应；优选地，反应温度为10-70℃，例如10-50℃，10-40℃，20-30℃，如25℃，反应时间为不低于1小时，例如1-48小时，4-24小时，8-16小时，如不低于10小时，所述式(IV)化合物与手性碱Y的比例小于或等于1:1。
所述手性碱Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁(Quinine)、奎尼丁(Quinidine)或其氘代衍生物等，优选(1S,2S)-环己二胺或(1R,2R)-环己二胺或其氘代衍生物，更优选(1S,2S)-环己二胺或其氘代衍生物。
所述方法在酮类溶剂、酯类溶剂或四氢呋喃中反应，所述酮类溶剂选自丙酮、丁酮、戊酮或甲基异丁酮等，优选丙酮；所述酯类溶剂选自乙酸乙酯、乙酸异丙酯或乙酸叔丁酯等，优选乙酸乙酯。
所述方法，采用加入手性碱Y实现了异构体的拆分，相比现有技术中的超临界液相色谱(SFC)拆分方法，解决了SFC方法拆分批次量太小的限制，解决了工业化大生产规模的扩大，大大降低了生产成本，并且拆分纯度高。
根据本发明的第2方面，公开了制备式(II)化合物的方法。
Figure PCTCN2020077413-appb-000012
所述方法包括，将式(III)化合物与醇类溶剂混合，加入过量酸溶液，反应得式(II)化合物；优选地，反应温度为0-40℃，例如20-30℃，如25℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时。
所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等。
所述酸溶液选自盐酸、硫酸、磷酸、硝酸或三氟乙酸等。
根据本发明的第3方面，公开了制备式(I)化合物的方法。
Figure PCTCN2020077413-appb-000013
将式(II)化合物、缩合试剂、极性溶剂和非极性溶剂混合，然后分别加入有机碱和4-羟基哌啶，反应得式(I)化合物。优选地，反应温度为0-40℃，例如20-30℃，如25℃，反应时间为不低于0.2小时，例如0.2-20小时，0.5-10小时，1-5小时，如2小时。
所述缩合试剂选自2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺/1-羟基苯并三唑(EDCI/HOBT)、N,N'-二环己基碳二亚胺/4-二甲氨基吡啶(DCC/DMAP)等，优选2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)。
所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N-甲基吡咯烷酮(NMP)。
所述非极性溶剂选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃或氯仿等，优选二氯甲烷。
所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等，优选三乙胺。
根据本发明的第4方面，公开了另一种制备式(I)化合物的方法。
Figure PCTCN2020077413-appb-000014
所述方法包括，将式(III)化合物、缩合试剂、极性溶剂和非极性溶剂混合，然后分别加入有机碱和4-羟基哌啶，反应得式(I)化合物。优选地，反应温度为0-40℃，例如20-30℃，如25℃，反应时间为不低于0.2小时，例如0.2-20小时，0.5-10小时，1-5小时，如2小时。
所述缩合试剂选自2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺/1-羟基苯并三唑(EDCI/HOBT)、N,N'-二环己基碳二亚胺/4-二甲氨基吡啶(DCC/DMAP)等，优选2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)。
所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N-甲基吡咯烷酮(NMP)。
所述非极性溶剂选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃或氯仿等，优选二氯甲烷。
所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N- 甲基吗啡啉(NMM)等，优选三乙胺。
根据本发明的第5方面，公开了中间体式III化合物，其结构式如下，用于制备式(I)化合物或式(II)化合物。
Figure PCTCN2020077413-appb-000015
所述手性碱Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁(Quinine)、奎尼丁(Quinidine)或其氘代衍生物等，优选(1S,2S)-环己二胺或(1R,2R)-环己二胺或其氘代衍生物，更优选(1S,2S)-环己二胺或其氘代衍生物。
根据本发明的第6方面，公开了制备式(VIII)化合物的方法。
Figure PCTCN2020077413-appb-000016
所述方法包括：
将式(X)化合物与酰氯类化合物反应得式(IX)化合物，优选地，将式(X)化合物与三氯氧磷反应得式(IX)化合物；优选地，反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时。
将式(IX)化合物在ROH、极性溶剂、有机碱和催化剂溶剂中，通入一氧化碳，反应得式(VIII)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时。
R代表C 1-6烷基，指含有1-6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1- 二甲基丁基、1,2-二甲基丁基、1，3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1-甲基-2-甲基丙基等。
所述酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、乙酰氯、二氯亚砜。
所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N,N-二甲基甲酰胺(DMF)。
所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等，优选三乙胺。
所述催化剂选自钯催化剂，包括Pd(dppf)Cl 2·CH 2Cl 2、Pd(dppf)Cl 2、Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2、Pd(OAc) 2、Pd 2(dba) 3或Pd(dba) 2。
WO2014094664中公开了式(VIII)化合物的制备方法，但收率很低，而且反应物间氯过氧苯甲酸(mCPBA)有爆炸风险，危险性高，另外，反应物三甲基氰硅烷有剧毒。
上述式(VIII)化合物的制备方法，不仅提高了收率，而且避免了使用危险性高的间氯过氧苯甲酸(mCPBA)和剧毒反应物三甲基氰硅烷。
根据本发明的第7方面，公开了制备式(IV)化合物的方法。
Figure PCTCN2020077413-appb-000017
所述方法包括：
将式(X)化合物与酰氯类化合物反应得式(IX)化合物，优选地，将式(X)化合物与三氯氧磷反应得式(IX)化合物；优选地，反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时。
将式(IX)化合物在ROH、极性溶剂、有机碱和催化剂溶剂中，通入一氧化碳，反应得式(VIII)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
将式(VIII)化合物在醇类溶剂、乙腈或THF中加入环戊基甲醛，然后加入有机碱反应得式(VII)化合物；优选地，反应温度为0-40℃，例如10-30℃，如25℃，反应时间为不低于2小时，例如2-40小时，4-24小时，4-16小时，如8小时；
将2-氯-4-氟苯甲腈在醇类溶剂、乙腈或THF中与水合肼混合，反应得式(VI)化合物；优选地，反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
将式(VII)化合物与式(VI)化合物在醇类溶剂、乙腈或THF和氯化氢条件下反应得式(V)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于3小时，例如3-80小时，8-48小时，8-32小时，如16小时；
将式(V)化合物溶解于醇类溶剂和四氢呋喃溶液中，滴入无机碱溶液，反应制得式(IV)化合物；优选地，反应温度为0-40℃，例如0-20℃，0-10℃，如5℃，反应时间为不低于0.1小时，例如0.1-10小时，例如0.1-5小时，0.5-2小时，如1小时。
R代表C 1-6烷基，指含有1-6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1，3-二甲基丁基、2,3-二甲基丁基、 2-乙基丁基、1-甲基-2-甲基丙基等。
所述酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、乙酰氯、二氯亚砜。
所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N,N-二甲基甲酰胺(DMF)。
所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等。
所述催化剂选自钯催化剂，包括Pd(dppf)Cl 2·CH 2Cl 2、Pd(dppf)Cl 2、Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2、Pd(OAc) 2、Pd 2(dba) 3或Pd(dba) 2等，优选Pd(dppf)Cl 2·CH 2Cl 2。
所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等，优选乙醇。
所述无机碱选自NaOH、KOH或LiOH等，优选NaOH或KOH。
根据本发明的第8方面，公开了制备式(III)化合物的方法。
Figure PCTCN2020077413-appb-000018
所述方法包括：
将式(X)化合物与酰氯类化合物反应得式(IX)化合物，优选地，将式(X)化合物与三氯氧磷反应得式(IX)化合物；优选地，反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时。
将式(IX)化合物在ROH、极性溶剂、有机碱和催化剂溶剂中，通入一氧化碳，反应得式(VIII)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
将式(VIII)化合物在醇类溶剂、乙腈或THF中加入环戊基甲醛，然后加入有机碱反应得式(VII)化合物；优选地，反应温度为0-40℃，例如10-30℃，如25℃，反应时间为不低于2小时，例如2-40小时，4-24小时，4-16小时，如8小时；
将2-氯-4-氟苯甲腈在醇类溶剂、乙腈或THF中与水合肼混合，反应得式(VI)化合物；优选地，反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
将式(VII)化合物与式(VI)化合物在醇类溶剂、乙腈或THF和氯化氢条件下反应得式(V)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于3小时，例如3-80小时，8-48小时，8-32小时，如16小时；
将式(V)化合物溶解于醇类溶剂和四氢呋喃溶液中，滴入无机碱溶液，反应制得式(IV)化合物；优选地，反应温度为0-40℃，例如0-20℃，0-10℃，如5℃，反应时间为不低于0.1小时，例如0.1-10小时，0.1-5小时，0.5-2小时，如1小时；
将式(IV)化合物与手性碱Y反应得式(III)化合物，所述方法在酮类溶剂、酯类溶剂或四氢呋喃中反应；优选地，反应温度为10-70℃，例如10-50℃，10-40℃，20-30℃，如25℃，反应时间为不低于1小时，例如1-48小时，4-24小时，8-16小时，如不低于10小时，所述式(IV)化合物与手性碱Y的比例小于或等于1:1。
R代表C 1-6烷基，指含有1-6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正 丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1，3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1-甲基-2-甲基丙基等。
所述酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、乙酰氯、二氯亚砜。
所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N,N-二甲基甲酰胺(DMF)。
所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等。
所述催化剂选自钯催化剂，包括Pd(dppf)Cl 2·CH 2Cl 2、Pd(dppf)Cl 2、Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2、Pd(OAc) 2、Pd 2(dba) 3或Pd(dba) 2等，优选Pd(dppf)Cl 2·CH 2Cl 2。
所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等，优选乙醇。
所述无机碱选自NaOH、KOH或LiOH等，优选NaOH或KOH。
所述手性拆分试剂选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁(Quinine)、奎尼丁(Quinidine)或其氘代衍生物等，优选(1S,2S)-环己二胺或(1R,2R)-环己二胺或其氘代衍生物，更优选(1S,2S)-环己二胺或其氘代衍生物。
所述酮类溶剂选自丙酮、丁酮、戊酮或甲基异丁酮等，优选丙酮。
所述酯类溶剂选自乙酸乙酯、乙酸异丙酯或乙酸叔丁酯等，优选乙酸乙酯。
根据本发明的第9方面，公开了制备式(II)化合物的方法。
Figure PCTCN2020077413-appb-000019
所述方法包括：
将式(X)化合物与酰氯类化合物反应得式(IX)化合物，优选地，将式(X)化合物与三氯氧磷反应得式(IX)化合物；优选地，反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时。
将式(IX)化合物在ROH、极性溶剂、有机碱和催化剂溶剂中，通入一氧化碳，反应得式(VIII)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
将式(VIII)化合物在醇类溶剂、乙腈或THF中加入环戊基甲醛，然后加入有机碱反应得式(VII)化合物；优选地，反应温度为0-40℃，例如10-30℃，如25℃，反应时间为不低于2小时，例如2-40小时，4-24小时，4-16小时，如8小时；
将2-氯-4-氟苯甲腈在醇类溶剂、乙腈或THF中与水合肼混合，反应得式(VI)化合物；优选地，反应温度为40-90℃，例如75-85℃， 如80℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
将式(VII)化合物与式(VI)化合物在醇类溶剂、乙腈或THF和氯化氢条件下反应得式(V)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于3小时，例如3-80小时，8-48小时，8-32小时，如16小时；
将式(V)化合物溶解于醇类溶剂和四氢呋喃溶液中，滴入无机碱溶液，反应制得式(IV)化合物；优选地，反应温度为0-40℃，例如0-20℃，0-10℃，如5℃，反应时间为不低于0.1小时，例如0.1-10小时，例如0.1-5小时，0.5-2小时，如1小时；
将式(IV)化合物与手性碱Y反应得式(III)化合物，所述方法在酮类溶剂、酯类溶剂或四氢呋喃中反应；优选地，反应温度为10-70℃，例如10-50℃，10-40℃，20-30℃，如25℃，反应时间为不低于1小时，例如1-48小时，4-24小时，8-16小时，如不低于10小时，所述式(IV)化合物与手性碱Y的比例小于或等于1:1。
将式(III)化合物与醇类溶剂混合，加入过量酸溶液，反应得式(II)化合物；优选地，反应温度为0-40℃，例如20-30℃，如25℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时。
R代表C 1-6烷基，指含有1-6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1，3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1-甲基-2-甲基丙基等。
所述酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、乙酰氯、二氯亚砜。
所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N,N-二甲基甲酰胺(DMF)。
所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等。
所述催化剂选自钯催化剂，包括Pd(dppf)Cl 2·CH 2Cl 2、Pd(dppf)Cl 2、Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2、Pd(OAc) 2、Pd 2(dba) 3或Pd(dba) 2等，优选Pd(dppf)Cl 2·CH 2Cl 2。
所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等，优选乙醇。
所述无机碱选自NaOH、KOH或LiOH等，优选NaOH或KOH。
所述手性拆分试剂选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁(Quinine)、奎尼丁(Quinidine)或其氘代衍生物等，优选(1S,2S)-环己二胺或(1R,2R)-环己二胺或其氘代衍生物，更优选(1S,2S)-环己二胺或其氘代衍生物。
所述酮类溶剂选自丙酮、丁酮、戊酮或甲基异丁酮等，优选丙酮。
所述酯类溶剂选自乙酸乙酯、乙酸异丙酯或乙酸叔丁酯等，优选乙酸乙酯。
所述酸溶液选自盐酸、硫酸、磷酸、硝酸或三氟乙酸等，优选盐酸。
根据本发明的第10方面，公开了制备式(I)化合物的方法。
Figure PCTCN2020077413-appb-000020
所述方法包括：
将式(X)化合物与酰氯类化合物反应得式(IX)化合物，优选地，将式(X)化合物与三氯氧磷反应得式(IX)化合物；优选地，反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时。
将式(IX)化合物在ROH、极性溶剂、有机碱和催化剂溶剂中，通入一氧化碳，反应得式(VIII)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
将式(VIII)化合物在醇类溶剂、乙腈或THF中加入环戊基甲醛，然后加入有机碱反应得式(VII)化合物；优选地，反应温度为0-40℃，例如10-30℃，如25℃，反应时间为不低于2小时，例如2-40小时，4-24小时，4-16小时，如8小时；
将2-氯-4-氟苯甲腈在醇类溶剂、乙腈或THF中与水合肼混合，反应得式(VI)化合物；优选地，反应温度为40-90℃，例如75-85℃， 如80℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
将式(VII)化合物与式(VI)化合物在醇类溶剂、乙腈或THF和氯化氢条件下反应得式(V)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于3小时，例如3-80小时，8-48小时，8-32小时，如16小时；
将式(V)化合物溶解于醇类溶剂和四氢呋喃溶液中，滴入无机碱溶液，反应制得式(IV)化合物；优选地，反应温度为0-40℃，例如0-20℃，0-10℃，如5℃，反应时间为不低于0.1小时，例如0.1-10小时，0.1-5小时，0.5-2小时，如1小时；
将式(IV)化合物与手性碱Y反应得式(III)化合物，所述方法在酮类溶剂、酯类溶剂或四氢呋喃中反应；优选地，反应温度为10-70℃，例如10-50℃，10-40℃，20-30℃，如25℃，反应时间为不低于1小时，例如1-48小时，4-24小时，8-16小时，如不低于10小时，所述式(IV)化合物与手性碱Y的比例小于或等于1:1。
将式(III)化合物与醇类溶剂混合，加入过量酸溶液，反应得式(II)化合物；优选地，反应温度为0-40℃，例如20-30℃，如25℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时。
将式(II)化合物、缩合试剂、极性溶剂和非极性溶剂混合，然后分别加入有机碱和4-羟基哌啶，反应得式(I)化合物。优选地，反应温度为0-40℃，例如20-30℃，如25℃，反应时间为不低于0.2小时，例如0.2-20小时，0.5-10小时，1-5小时，如2小时。
R代表C 1-6烷基，指含有1-6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1，3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1-甲基-2-甲基丙基等。
所述酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、 乙酰氯、二氯亚砜。
所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N,N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮(NMP)。
所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等。
所述催化剂选自钯催化剂，包括Pd(dppf)Cl 2·CH 2Cl 2、Pd(dppf)Cl 2、Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2、Pd(OAc) 2、Pd 2(dba) 3或Pd(dba) 2等，优选Pd(dppf)Cl 2·CH 2Cl 2。
所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等，优选乙醇。
所述无机碱选自NaOH、KOH或LiOH等，优选NaOH或KOH。
所述手性拆分试剂选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁(Quinine)、奎尼丁(Quinidine)或其氘代衍生物等，优选(1S,2S)-环己二胺或(1R,2R)-环己二胺或其氘代衍生物，更优选(1S,2S)-环己二胺或其氘代衍生物。
所述酮类溶剂选自丙酮、丁酮、戊酮或甲基异丁酮等，优选丙酮。
所述酯类溶剂选自乙酸乙酯、乙酸异丙酯或乙酸叔丁酯等，优选乙酸乙酯。
所述酸溶液选自盐酸、硫酸、磷酸、硝酸或三氟乙酸等，优选盐酸。
所述缩合试剂选自2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺/1-羟基苯并三唑(EDCI/HOBT)、N,N'-二环己基碳二亚胺/4-二甲氨基吡啶(DCC/DMAP)等，优选2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)。
所述非极性溶剂选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃或氯仿等，优选二氯甲烷。
根据本发明的第11方面，公开了制备式(I)化合物的方法。
Figure PCTCN2020077413-appb-000021
所述方法包括：
将式(X)化合物与酰氯类化合物反应得式(IX)化合物，优选地，将式(X)化合物与三氯氧磷反应得式(IX)化合物；优选地，反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时。
将式(IX)化合物在ROH、极性溶剂、有机碱和催化剂溶剂中，通入一氧化碳，反应得式(VIII)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
将式(VIII)化合物在醇类溶剂、乙腈或THF中加入环戊基甲醛，然后加入有机碱反应得式(VII)化合物；优选地，反应温度为0-40℃，例如10-30℃，如25℃，反应时间为不低于2小时，例如2-40小时，4-24小时，4-16小时，如8小时；
将2-氯-4-氟苯甲腈在醇类溶剂、乙腈或THF中与水合肼混合， 反应得式(VI)化合物；优选地，反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
将式(VII)化合物与式(VI)化合物在醇类溶剂、乙腈或THF和氯化氢条件下反应得式(V)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于3小时，例如3-80小时，8-48小时，8-32小时，如16小时；
将式(V)化合物溶解于醇类溶剂和四氢呋喃溶液中，滴入无机碱溶液，反应制得式(IV)化合物；优选地，反应温度为0-40℃，例如0-20℃，0-10℃，如5℃，反应时间为不低于0.1小时，例如0.1-10小时，0.1-5小时，0.5-2小时，如1小时；
将式(IV)化合物与手性碱Y反应得式(III)化合物，所述方法在酮类溶剂、酯类溶剂或四氢呋喃中反应；优选地，反应温度为10-70℃，例如10-50℃，10-40℃，20-30℃，如25℃，反应时间为不低于1小时，例如1-48小时，4-24小时，8-16小时，如不低于10小时，所述式(IV)化合物与手性碱Y的比例小于或等于1:1。
将式(III)化合物、缩合试剂、极性溶剂和非极性溶剂混合，然后分别加入有机碱和4-羟基哌啶，反应得式(I)化合物。优选地，反应温度为0-40℃，例如20-30℃，如25℃，反应时间为不低于0.2小时，例如0.2-20小时，0.5-10小时，1-5小时，如2小时。
R代表C 1-6烷基，指含有1-6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1，3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1-甲基-2-甲基丙基等。
所述酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、乙酰氯、二氯亚砜。
所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N,N-二甲基甲 酰胺(DMF)、N-甲基吡咯烷酮(NMP)。
所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等。
所述催化剂选自钯催化剂，包括Pd(dppf)Cl 2·CH 2Cl 2、Pd(dppf)Cl 2、Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2、Pd(OAc) 2、Pd 2(dba) 3或Pd(dba) 2等，优选Pd(dppf)Cl 2·CH 2Cl 2。
所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等，优选乙醇。
所述无机碱选自NaOH、KOH或LiOH等，优选NaOH或KOH。
所述手性拆分试剂选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁(Quinine)、奎尼丁(Quinidine)或其氘代衍生物等，优选(1S,2S)-环己二胺或(1R,2R)-环己二胺或其氘代衍生物，更优选(1S,2S)-环己二胺或其氘代衍生物。
所述酮类溶剂选自丙酮、丁酮、戊酮或甲基异丁酮等，优选丙酮。
所述酯类溶剂选自乙酸乙酯、乙酸异丙酯或乙酸叔丁酯等，优选乙酸乙酯。
所述缩合试剂选自2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺/1-羟基苯并三唑(EDCI/HOBT)、N,N'-二环己基碳二亚胺/4-二甲氨基吡啶(DCC/DMAP)等，优选2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)。
所述非极性溶剂选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃或氯仿等，优选二氯甲烷。
根据本发明的第12方面，公开了制备式(I)化合物的方法。
Figure PCTCN2020077413-appb-000022
所述方法包括：
将式(X)化合物与酰氯类化合物反应得式(IX)化合物，优选地，将式(X)化合物与三氯氧磷反应得式(IX)化合物；优选地，反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时。
将式(IX)化合物在ROH、极性溶剂、有机碱和催化剂溶剂中，通入一氧化碳，反应得式(VIII)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
将式(VIII)化合物在醇类溶剂、乙腈或THF中加入环戊基甲醛，然后加入有机碱反应得式(VII)化合物；优选地，反应温度为0-40℃，例如10-30℃，如25℃，反应时间为不低于2小时，例如2-40小时，4-24小时，4-16小时，如8小时；
将2-氯-4-氟苯甲腈在醇类溶剂、乙腈或THF中与水合肼混合，反应得式(VI)化合物；优选地，反应温度为40-90℃，例如75-85℃， 如80℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
将式(VII)化合物与式(VI)化合物在醇类溶剂、乙腈或THF和氯化氢条件下反应得式(V)化合物；优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于3小时，例如3-80小时，8-48小时，8-32小时，如16小时；
将式(V)化合物通过SFC拆分得式(V’)化合物；
将式(V’)化合物溶解于醇类溶剂和四氢呋喃溶液中，滴入无机碱溶液，反应制得式(II)化合物；
将式(II)化合物、缩合试剂、极性溶剂和非极性溶剂混合，然后分别加入有机碱和4-羟基哌啶，反应得式(I)化合物。优选地，反应温度为0-40℃，例如20-30℃，如25℃，反应时间为不低于0.2小时，例如0.2-20小时，0.5-10小时，1-5小时，如2小时。
R代表C 1-6烷基，指含有1-6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1，3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1-甲基-2-甲基丙基等。
所述酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、乙酰氯、二氯亚砜。
所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N,N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮(NMP)。
所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等。
所述催化剂选自钯催化剂，包括Pd(dppf)Cl 2·CH 2Cl 2、Pd(dppf)Cl 2、Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2、Pd(OAc) 2、Pd 2(dba) 3或Pd(dba) 2等，优选Pd(dppf)Cl 2·CH 2Cl 2。
所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等，优选乙醇。
所述无机碱选自NaOH、KOH或LiOH等，优选NaOH或KOH。
在没有相反指出的情况下，本发明的制备方法的任何步骤都是在常压下进行的。
在本发明中，室温是指10-30℃，例如26℃。
具体来说，本发明提供了下述实施方案：
1.一种制备式(III)化合物的方法，其特征在于，所述式(III)化合物是通过下述步骤(g)获得的：
(g)将式(IV)化合物与手性碱Y反应得式(III)化合物，
Figure PCTCN2020077413-appb-000023
所述手性碱Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁(Quinine)、奎尼丁(Quinidine)或其氘代衍生物，优选(1S,2S)-环己二胺或(1R,2R)-环己二胺或其氘代衍生物，更优选(1S,2S)-环己二胺或其氘代衍生物。
2.如实施方案1所述的方法，其特征在于，所述步骤(g)是在酮类溶剂、酯类溶剂或四氢呋喃中反应；
优选地，反应温度为10-70℃，例如10-50℃，10-40℃，20-30℃，如25℃；反应时间为不低于1小时，例如1-48小时，4-24小时，8-16小时，如不低于10小时；
更优选地，所述式(IV)化合物与手性碱Y的比例小于或等于1:1；
进一步更优选地，所述酮类溶剂选自丙酮、丁酮、戊酮或甲基异丁酮等，优选丙酮；所述酯类溶剂选自乙酸乙酯、乙酸异丙酯或乙酸叔丁酯等，优选乙酸乙酯。
3.如实施方案1或2所述的方法，其特征在于，所述式(IV)化合物是通过下述步骤(f)获得的：
(f)将式(V)化合物通过水解反应得式(IV)化合物
Figure PCTCN2020077413-appb-000024
其中R是C 1-6烷基；
优选地，步骤(f)是将式(V)化合物溶解于醇类溶剂和四氢呋喃溶液中，滴入无机碱溶液，反应制得式(IV)化合物；
更优选地，反应温度为0-40℃，例如0-20℃，0-10℃，如5℃，反应时间为不低于0.1小时，例如0.1-10小时，0.1-5小时，0.5-2小时，如1小时；
进一步优选地，所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等，优选乙醇；所述无机碱选自NaOH、KOH或LiOH等，优选NaOH或KOH。
4.如实施方案3所述的方法，其特征在于，所述式(V)化合物是通过下述步骤(e)获得的：
(e)将式(VII)化合物与式(VI)化合物反应得式(V)化合物
Figure PCTCN2020077413-appb-000025
其中R是C 1-6烷基；
优选地，步骤(e)是将式(VII)化合物与式(VI)化合物在 醇类溶剂、乙腈或THF和氯化氢条件下反应得式(V)化合物；
更优选地，反应温度为40-90℃，例如70-80℃，75℃，反应时间为不低于3小时，例如3-80小时，8-48小时，8-32小时，如16小时；
进一步优选地，所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等，优选乙醇。
5.如实施方案4所述的方法，其特征在于，所述式(VI)化合物是通过下述步骤(d)获得的：
(d)将2-氯-4-氟苯甲腈与水合肼反应得式(VI)化合物
Figure PCTCN2020077413-appb-000026
优选地，步骤(d)是将2-氯-4-氟苯甲腈在醇类溶剂、乙腈或THF中与水合肼混合，反应得式(VI)化合物；
更优选地，反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
进一步优选地，所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等，优选乙醇。
6.如实施方案4所述的方法，其特征在于，所述式(VII)化合物是通过下述步骤(c)获得的：
(c)将式(VIII)化合物与环戊基甲醛反应得式(VII)化合物
Figure PCTCN2020077413-appb-000027
其中R是C 1-6烷基；
优选地，步骤(c)是将式(VIII)化合物在醇类溶剂、乙腈或THF中加入环戊基甲醛，然后加入有机碱反应得式(VII)化合 物；
更优选地，反应温度为0-40℃，例如10-30℃，如25℃，反应时间为不低于2小时，例如2-40小时，4-24小时，4-16小时，如8小时；
进一步优选地，所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等，优选乙醇；所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等，优选吡咯烷。
7.如实施方案6所述的方法，其特征在于，所述式(VIII)化合物是通过下述步骤(b)获得的：
(b)式(IX)化合物与ROH制备得式(VIII)化合物，优选地式(IX)化合物与ROH在CO的存在下制备得式(VIII)化合物
Figure PCTCN2020077413-appb-000028
其中R是C 1-6烷基；
优选地，步骤(b)是将式(IX)化合物在ROH、极性溶剂、有机碱和催化剂溶剂中，通入一氧化碳，反应得式(VIII)化合物；
更优选地，反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
进一步优选地，所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N,N-二甲基甲酰胺(DMF)；所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等，优选三乙胺；所述催化剂选自钯催化剂，包括Pd(dppf)Cl 2·CH 2Cl 2、Pd(dppf)Cl 2、Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2、Pd(OAc) 2、Pd 2(dba) 3或Pd(dba) 2等，优选Pd(dppf)Cl 2·CH 2Cl 2。
8.如实施方案7所述的方法，其特征在于，所述式(IX)化合物是通过下述步骤(a)获得的：
(a)通过式(X)化合物制备得式(IX)化合物，优选地通过式(X)化合物与酰氯类化合物制备得式(IX)化合物
Figure PCTCN2020077413-appb-000029
优选地，酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、乙酰氯、二氯亚砜；
更优选地，反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时。
9.如实施方案6所述的方法，其特征在于，所述式(VIII)化合物是通过下述步骤(a)和(b)获得的：
(a)通过式(X)化合物制备得式(IX)化合物，优选地通过式(X)化合物与酰氯类化合物制备得式(IX)化合物，
(b)式(IX)化合物与ROH制备得式(VIII)化合物，优选地式(IX)化合物与ROH在CO的存在下制备得式(VIII)化合物，
Figure PCTCN2020077413-appb-000030
其中R是C 1-6烷基；
优选地，步骤(a)是将式(X)化合物与酰氯类化合物反应得式(IX)化合物，优选地，将式(X)化合物与三氯氧磷反应得式(IX)化合物；其中酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯，如三氯氧磷、乙酰氯、二氯亚砜；步骤(b)是将式(IX)化合物在ROH、极性溶剂、有机碱和催化剂溶剂中，通入一氧化碳，反应得式(VIII)化合物；
更优选地，步骤(a)：反应温度为40-90℃，例如75-85℃，如80℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时；步骤(b)：反应温度为40-90℃，例如70-80℃，如75℃，反应时间为不低于0.5小时，例如0.5-15小时，1-5小时，如3小时；
进一步优选地，所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N,N-二甲基甲酰胺(DMF)；所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等，优选三乙胺；所述催化剂选自钯催化剂，包括Pd(dppf)Cl 2·CH 2Cl 2、Pd(dppf)Cl 2、Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2、Pd(OAc) 2、Pd 2(dba) 3或Pd(dba) 2等，优选Pd(dppf)Cl 2·CH 2Cl 2。
10.如实施方案1-8中任一项所述的方法，其特征在于，所述方法还包括使用式(III)化合物制备式(II)化合物，其包括以下步骤：
(h)将式(III)化合物加入酸溶液反应得式(II)化合物，
Figure PCTCN2020077413-appb-000031
其中Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物；
优选地，步骤(h)是将式(III)化合物与醇类溶剂混合，加入过量酸溶液，反应得式(II)化合物；
更优选地，反应温度为0-40℃，例如20-30℃，如25℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时；
进一步优选地，所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等，优选乙醇；所述酸溶液选自盐酸、硫酸、磷酸、硝酸或 三氟乙酸等，优选盐酸。
11.如实施方案1-8中任一项所述的方法，其特征在于，所述方法还包括使用式(III)化合物制备式(I)化合物，其包括以下步骤：
Figure PCTCN2020077413-appb-000032
(h)将式(III)化合物加入酸溶液反应得式(II)化合物；
(i)将式(II)化合物和4-羟基哌啶反应得式(I)化合物，其中Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物；
优选地，步骤(h)是将式(III)化合物与醇类溶剂混合，加入过量酸溶液，反应得式(II)化合物；步骤(i)是将式(II)化合物、缩合试剂、极性溶剂和非极性溶剂混合，然后分别加入有机碱和4-羟基哌啶，反应得式(I)化合物；
更优选地，步骤(h)：反应温度为0-40℃，例如20-30℃，如25℃，反应时间为不低于0.5小时，例如0.5-10小时，1-5小时，如2小时；步骤(i)：反应温度为0-40℃，例如20-30℃，如25℃，反应时间为不低于0.2小时，例如0.2-20小时，0.5-10小时，1-5小时，如2小时；
进一步优选地，所述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇等，优选乙醇；所述酸溶液选自盐酸、硫酸、磷酸、硝酸或三氟乙酸等，优选盐酸；所述缩合试剂选自2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺/1-羟基苯并三唑(EDCI/HOBT)、N,N'-二环己基碳二亚胺/4-二甲氨基吡啶(DCC/DMAP)等，优选2-(7-氧化苯并三氮 唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)；所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N-甲基吡咯烷酮(NMP)；所述非极性溶剂选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃或氯仿等，优选二氯甲烷；所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等，优选三乙胺。
12.如实施方案1-8中任一项所述的方法，其特征在于，所述方法还包括使用式(III)化合物制备式(I)化合物，其包括以下步骤：
将式(III)化合物和4-羟基哌啶反应得式(I)化合物，
Figure PCTCN2020077413-appb-000033
其中Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物；
优选地，上述步骤是将式(III)化合物、缩合试剂、极性溶剂和非极性溶剂混合，然后分别加入有机碱和4-羟基哌啶，反应得式(I)化合物；
更优选地，上述步骤的反应温度为0-40℃，例如20-30℃，如25℃，反应时间为不低于0.2小时，例如0.2-20小时，0.5-10小时，1-5小时，如2小时；
进一步优选地，
所述缩合试剂选自2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺/1-羟基苯并三唑(EDCI/HOBT)、N,N'-二环己基碳二亚胺/4-二甲氨基吡啶 (DCC/DMAP)等，优选2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)；
所述极性溶剂选自N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)或N,N-二甲基乙酰胺(DMA)等，优选N-甲基吡咯烷酮(NMP)；
所述非极性溶剂选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃或氯仿等，优选二氯甲烷；
所述有机碱选自三乙胺、二乙胺、二异丙基乙胺(DIPEA)、四甲基乙二胺、吡咯烷、吡啶、4-二甲氨基吡啶(DMAP)或N-甲基吗啡啉(NMM)等，优选三乙胺。
13.式(III)化合物，其特征在于，具有下式结构
Figure PCTCN2020077413-appb-000034
其中Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物。
在本发明(包括上述实施方案的任一个)中，C 1-6烷基指含有1-6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1，3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1-甲基-2-甲基丙基等。
特别地，本发明还提供了下述技术方案：
技术方案1：制备(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1S,2S)-环己二胺盐的方 法，包括如下步骤：
Figure PCTCN2020077413-appb-000035
在10-40℃(例如20-30℃，如25℃)，2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1摩尔当量)和(1S,2S)-环己二胺(不低于0.4摩尔当量，例如0.4-10摩尔当量，1-4摩尔当量，如2摩尔当量)被加入丙酮(不低于8.42升/1摩尔当量，例如8.42-210.45升/1摩尔当量，21.04-84.18升/1摩尔当量，如42089毫升/1摩尔当量)中，所得到的混合物在10-70℃(例如10-50℃，10-40℃，20-30℃，如25℃)搅拌不低于1小时(例如1-48小时，4-24小时，8-16小时，如不低于10小时)，过滤，滤饼用丙酮洗涤得到(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1S,2S)-环己二胺盐。
技术方案2：制备(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1R,2R)-环己二胺盐的方法，包括如下步骤：
Figure PCTCN2020077413-appb-000036
在10-40℃(例如20-30℃，如25℃)，2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1摩尔当量)和(1R,2R)-环己二胺(不低于0.4摩尔当量，例如0.4-10摩尔当量，1-4摩尔当量，如2摩尔当量)被加入丙酮(不低于8.42升/1摩尔当量，例如8.42-210.45升/1摩尔当量，21.04-84.18升/1摩尔当量，如42089毫升/1摩尔当量)中，所得到的混合物在10-70℃(例如10-50℃，10-40℃，20-30℃，如25℃)搅拌不低于1小时(例如1-48小时， 4-24小时，8-16小时，如不低于10小时)，过滤，收集母液后蒸馏制得(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1R,2R)-环己二胺盐。
技术方案3：制备(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸奎宁盐的方法，包括如下步骤：
在10-40℃(例如20-30℃，如25℃)，2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1摩尔当量)和奎宁(不低于0.2摩尔当量，例如0.2-5摩尔当量，0.5-2摩尔当量，如1摩尔当量)被加入乙酸乙酯(不低于5.05升/1摩尔当量，例如5.05-126.27升/1摩尔当量，例如12.63-50.51升/1摩尔当量，如25253.4毫升/1摩尔当量)中，所得到的混合物在10-70℃(例如10-50℃，10-40℃，20-30℃，如25℃)搅拌不低于1小时(例如1-48小时，4-24小时，8-16小时，如不低于10小时)，过滤，滤饼用乙酸乙酯洗涤，滤饼经过烘干后制得(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸奎宁盐。
技术方案4：制备(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸奎尼丁盐的方法，包括如下步骤：
在10-40℃(例如20-30℃，如25℃)，2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1摩尔当量)和奎尼丁(不低于0.2摩尔当量，例如0.2-5摩尔当量，0.5-2摩尔当量，如1摩尔当量)被加入乙酸乙酯(不低于5.05升/1摩尔当量，例如5.05-126.27升/1摩尔当量，例如12.63-50.51升/1摩尔当量，如25253.4毫升/1摩尔当量)中，所得到的混合物在10-70℃(例如10-50℃，10-40℃，20-30℃，如25℃)搅拌不低于1小时(例如1-48小时，4-24小时，8-16小时，如不低于10小时)，过滤，收集母液后蒸馏制得(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸奎尼丁盐。
技术方案5：根据技术方案1-4中任一项的方法，其中2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸是通过如下步骤获得：
Figure PCTCN2020077413-appb-000037
在10-40℃(例如20-30℃，如25℃)，将2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸乙酯(1摩尔当量)，甲醇(不低于0.18升/1摩尔当量，例如0.18-4.49升/1摩尔当量，0.45-1.80升/1摩尔当量，如898毫升/1摩尔当量)和四氢呋喃(不低于0.36升/1摩尔当量，例如0.36-8.98升/1摩尔当量，0.90-3.59升/1摩尔当量，如1796毫升/1摩尔当量)混合，将所得的混合物降温至0-40℃(例如0-20℃，0-10℃，如5℃)；
向所得的混合物中滴加10％氢氧化钠水溶液(不低于0.40摩尔当量，例如0.40-10.02摩尔当量，1.00-4.01摩尔当量，如2摩尔当量)，在0-40℃(例如0-20℃，0-10℃，如5℃)下搅拌不低于0.1小时(例如0.1-10小时，0.1-5小时，0.5-2小时，如1小时)；
向所得的混合物中滴加稀盐酸至pH值为3-5，
将所得的混合物升温至10-40℃(例如20-30℃，如25℃)，搅拌，过滤，
滤饼用甲醇洗涤，真空干燥，得到2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸。
技术方案6：根据技术方案5的方法，其中2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸乙酯是通过如下步骤获得：
Figure PCTCN2020077413-appb-000038
在10-40℃(例如20-30℃，如25℃)，将6-环戊基亚甲基-5-氧代-5,6,7,8-四氢-喹啉-2-羧酸乙酯(1摩尔当量)，2-氯-4-肼基苯甲腈(不低于0.21摩尔当量，例如0.21-5.22摩尔当量，0.52-2.09摩尔当量，如1.05摩尔当量)，乙醇(不低于0.19升/1摩尔当量，例如0.19-4.79升/1摩尔当量，0.48-1.92升/1摩尔当量，如958毫升/1摩尔当量)和氯化氢乙醇溶液(在2.0摩尔/升的浓度下，不低于0.11升/1摩尔当量，例如0.11-2.75升/1摩尔当量，0.28-1.10升/1摩尔当量，如551毫升/1摩尔当量)混合，将所得的混合物升温至40-90℃(例如70-80℃，如75℃)，避光反应不低于3小时(例如3-80小时，8-48小时，8-32小时，如16小时)；
将所得的混合物降温至0-20℃(例如0-10℃，如5℃)，搅拌，抽滤，
滤饼用无水乙醇洗涤，真空干燥，得到2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸乙酯。
技术方案7：根据技术方案6的方法，其中2-氯-4-肼基苯甲腈是通过如下步骤获得：
Figure PCTCN2020077413-appb-000039
在10-40℃(例如20-30℃，如25℃)，将2-氯-4-氟苯甲腈(1摩尔当量)，水合肼(不低于0.60摩尔当量，例如0.60-15.04摩尔当量，1.5-6.01摩尔当量，如3摩尔当量)和无水乙醇(不低于156克/1摩尔当量，例如156-3892克/1摩尔当量，389-1557克/1摩尔当量，如778克/1摩尔当量)混合，
将所得的混合物升温至40-90℃(例如75-85℃，如80℃)并且反应不低于0.5小时(例如0.5-15小时，1-5小时，如3小时)，
向所得的混合物中加入水(不低于311克/1摩尔当量，例如 311-7783克/1摩尔当量，778-3113克/1摩尔当量，如1557克/1摩尔当量)，
将所得的混合物降温至5-40℃(例如10-30℃，如20℃)，搅拌，抽滤，
滤饼用乙醇淋洗，湿滤饼真空干燥，得到2-氯-4-肼基苯甲腈。
技术方案8：根据技术方案6的方法，其中6-环戊基亚甲基-5-氧代-5,6,7,8-四氢-喹啉-2-羧酸乙酯是通过如下步骤获得：
Figure PCTCN2020077413-appb-000040
在10-40℃(例如20-30℃，如25℃)，向高压釜内加入2-氯-7,8-二氢-6H-喹啉-5-酮(1摩尔当量)、无水乙醇(不低于0.18升/1摩尔当量，例如0.18-4.54升/1摩尔当量，0.45-1.82升/1摩尔当量，如908毫升/1摩尔当量)、N,N-二甲基甲酰胺(DMF)(不低于18毫升/1摩尔当量，例如18-454毫升/1摩尔当量，45-182毫升/1摩尔当量，如91毫升/1摩尔当量)、三乙胺(不低于1摩尔当量，例如1-4摩尔当量，0.4-10摩尔当量，如2摩尔当量)和Pd(dppf)Cl 2·CH 2Cl 2(不低于3克/1摩尔当量，例如3-73克/1摩尔当量，7-29克/1摩尔当量，如15克/1摩尔当量)，高压釜用一氧化碳气体转换，加压至0.5-8MPa(例如1-4MPa，如2MPa)，升温至内温40-90℃(例如70-80℃，如75℃)，反应0.5-15小时(例如不低于0.5小时，1-5小时，如3小时)，
将反应体系降温至35-80℃(例如50-70℃，如60℃)左右，减压蒸馏至无馏分，浓缩完毕，得到浓缩液，
向浓缩液中加入乙酸乙酯，将所得的混合物在室温搅拌，抽滤，滤饼用乙酯乙酯淋洗，加入盐酸，搅拌静置分液，得到水相和有机相，乙酸乙酯加入水相，搅拌静置分液，合并有机相，有机相减压蒸馏至无馏分，得到油状物直接用于下一步反应；
Figure PCTCN2020077413-appb-000041
在10-40℃(例如20-30℃，如25℃)，将所得的油状物和无水乙醇(不低于127毫升/1摩尔当量，例如127-3178毫升/1摩尔当量，318-1271毫升/1摩尔当量，如636毫升/1摩尔当量)混合并控温在0℃±5℃(例如0℃±2℃，如0℃)左右，
向所得的混合物中加入环戊基甲醛(不低于0.2摩尔当量，例如0.2-5摩尔当量，0.5-2摩尔当量，如1摩尔当量)，
将所得的混合物搅拌2-50分钟(例如不低于2分钟，5-20分钟，如10分钟)，控温0℃±5℃(例如0℃±2℃，如0℃)左右，
向所得的混合物中滴加吡咯烷(不低于0.12摩尔当量，例如0.12-3摩尔当量，0.3-1.2摩尔当量，如0.6摩尔当量)，升温至0-40℃(例如10-30℃，如25℃)，
将所得的混合物避光反应不低于2小时(例如2-40小时，4-24小时，4-16小时，如8小时)，
向所得的混合物中加入水，
将所得的混合物降温至0-20℃(例如0-10℃，如5℃)，搅拌不低于0.1小时(例如0.1-10小时，0.5-2小时，如1小时)，抽滤，滤饼用乙醇/水混合溶剂洗涤，真空干燥，得到6-环戊基亚甲基-5-氧代-5,6,7,8-四氢-喹啉-2-羧酸乙酯。
技术方案9：根据技术方案8的方法，其中2-氯-7,8-二氢-6H-喹啉-5-酮是通过如下步骤获得：
Figure PCTCN2020077413-appb-000042
在室温下，向7,8-二氢-1H,6H-喹啉-2,5-二酮(1摩尔当量)和乙腈(不低于261克/1摩尔当量，例如261-6527克/1摩尔当量，653-2611克/1摩尔当量，如1305克/1摩尔当量)的混合物中加入三氯氧磷(不低于0.34摩尔当量，例如0.34-8.51摩尔当量，0.85-3.4摩 尔当量，如1.7摩尔当量)，将所得的混合物升温至40-90℃(例如75-85℃，如80℃)并且反应不低于0.5小时(例如0.5-10小时，1-5小时，如2小时)，然后将所得的混合物冷却至30-65℃(例如50-60℃，如55℃)，减压蒸馏出25-100wt％(例如50-85wt％，如75wt％)的溶剂后，将混合物降温至10-40℃(例如20-30℃，如25℃)，加入水淬灭反应，在10-40℃(例如20-30℃，如25℃)继续搅拌，用氢氧化钠水溶液调节混合物pH值到5-7，将所得的混合物降温到0-10℃，搅拌，过滤，
滤饼用水淋洗，真空干燥，得到2-氯-7,8-二氢-6H-喹啉-5-酮。
技术方案10：根据技术方案1的方法，其中
所制备的(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1S,2S)-环己二胺盐用于制备(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸，该制备过程包括如下步骤：
Figure PCTCN2020077413-appb-000043
在10-40℃(例如20-30℃，如25℃)，(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1S,2S)-环己二胺盐(1摩尔当量)和乙醇(不低于0.64升/1摩尔当量，例如0.64-16.05升/1摩尔当量，1.61-6.42升/1摩尔当量，如3210毫升/1摩尔当量)被加入1摩尔/升盐酸(不低于0.21摩尔当量，例如0.21-5.35摩尔当量，0.54-2.14摩尔当量，如1.07摩尔当量)中；所得的混合物在0-40℃(例如20-30℃，如25℃)搅拌不低于0.5小时(例如0.5-10小时，1-5小时，如2小时)，过滤，滤饼用乙醇洗涤，真空干燥，得到(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸。
技术方案11：根据技术方案11的方法，其中
所制备的(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸用于制备2-氯-4-[(3S,3aR)-3-环戊基-7-(4-羟基哌啶-1-羰基)-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-2-基]苯甲腈，该制备过程包括如下步骤：
Figure PCTCN2020077413-appb-000044
在10-40℃(例如20-30℃，如25℃)，将(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1摩尔当量)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)(不低于0.24摩尔当量，例如0.24-6摩尔当量，0.6-2.4摩尔当量，如1.2摩尔当量)、二氯甲烷(不低于0.42升/1摩尔当量，例如0.42-10.52升/1摩尔当量，1.05-4.21升/1摩尔当量，如2104毫升/1摩尔当量)、N-甲基吡咯烷酮(NMP)(不低于84毫升/1摩尔当量，例如84-2104毫升/1摩尔当量，210-842毫升/1摩尔当量，如421毫升/1摩尔当量)和三乙胺(不低于0.3摩尔当量，例如0.3-7.5摩尔当量，0.75-3摩尔当量，如1.5摩尔当量)混合，所得的混合物在0-40℃(例如20-30℃，如25℃)搅拌不低于3分钟(例如3-300分钟，15-60分钟，如30分钟)；
然后将4-羟基哌啶(不低于0.24摩尔当量，例如0.24-6摩尔当量，0.6-2.4摩尔当量，如1.2摩尔当量)在二氯甲烷(不低于168毫升/1摩尔当量，例如168-4209毫升/1摩尔当量，421-1684毫升/1摩尔当量，如842毫升/1摩尔当量)中的溶液滴入上述的混合物，所得的混合物在0-40℃(例如20-30℃，如25℃)搅拌不低于0.2小时(例如0.2-20小时，0.5-10小时，1-5小时，如2小时)；
向所得的混合物中加入盐酸水溶液搅拌，静置分相，得到有机相；
向所得的有机相中加入碳酸钠水溶液搅拌，静置分相，得到有机相；
向所得的有机相中加入水溶液搅拌，静置分相，得到有机相；
有机相蒸干得到油状物，将该油状物和异丙醇(不低于1.01千克/1摩尔当量，例如1.01-25.26千克/1摩尔当量，2.53-10.10千克/1摩尔当量，如5.05千克/1摩尔当量)混合，加热至50-90℃(例如75-85℃，如80℃)溶液澄清，冷却至10-40℃(例如20-30℃，如25℃)后，搅拌不低于0.3小时(例如0.3-30小时，1.5-6小时，如3小时)，过滤，滤饼用异丙醇洗涤，真空干燥，得到2-氯-4-[(3S,3aR)-3-环戊基-7-(4-羟基哌啶-1-羰基)-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-2-基]苯甲腈。
技术方案12：根据技术方案1的方法，其中
所制备的(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1S,2S)-环己二胺盐用于制备2-氯-4-[(3S,3aR)-3-环戊基-7-(4-羟基哌啶-1-羰基)-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-2-基]苯甲腈，该制备过程包括如下步骤：
Figure PCTCN2020077413-appb-000045
在10-40℃(例如20-30℃，如25℃)，将(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1S,2S)-环己二胺盐(1摩尔当量)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)(不低于0.24摩尔当量，例如0.24-6摩尔当量，0.6-2.4摩尔当量，如1.2摩尔当量)、二氯甲烷(不低于0.42升/1摩尔当量，例如0.42-10.52升/1摩尔当量，1.05-4.21升/1摩尔当量，如2104毫升/1摩尔当量)、N-甲基吡咯烷酮(NMP)(不低于84毫升/1摩尔当量，例如84-2104毫升/1摩尔当量，210-842毫升/1摩尔当量，如421毫升/1摩尔当量)和三乙胺(不低于0.3摩尔当量，例如0.3-7.5摩尔当量，0.75-3摩尔当量，如1.5摩尔当量)混合，所得的混合物在10-40℃(例如20-30℃，如25℃)搅拌不低于3分钟(例如3-300分钟，15-60分钟，如30分钟)；
然后将4-羟基哌啶(不低于0.24摩尔当量，例如0.24-6摩尔当量， 0.6-2.4摩尔当量，如1.2摩尔当量)在二氯甲烷(不低于168毫升/1摩尔当量，例如168-4209毫升/1摩尔当量，421-1684毫升/1摩尔当量，如842毫升/1摩尔当量)中的溶液滴入上述的混合物，所得的混合物在10-40℃(例如20-30℃，如25℃)搅拌不低于0.2小时(例如0.2-20小时，0.5-10小时，1-5小时，如2小时)；
向所得的混合物中加入盐酸水溶液搅拌，静置分相，得到有机相；
向所得的有机相中加入碳酸钠水溶液搅拌，静置分相，得到有机相；
向所得的有机相中加入水溶液搅拌，静置分相，得到有机相；
有机相蒸干得到油状物，将该油状物和异丙醇(不低于1.01千克/1摩尔当量，例如1.01-25.26千克/1摩尔当量，2.53-10.10千克/1摩尔当量，如5.05千克/1摩尔当量)混合，加热至50-90℃(例如75-85℃，如80℃)溶液澄清，冷却至10-40℃(例如20-30℃，如25℃)后，搅拌不低于0.3小时(例如0.3-30小时，1.5-6小时，如3小时)，过滤，滤饼用异丙醇洗涤，真空干燥，得到2-氯-4-[(3S,3aR)-3-环戊基-7-(4-羟基哌啶-1-羰基)-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-2-基]苯甲腈。
本发明公开的(3S,3aR)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉类化合物的制备方法，拆分步骤采用手性碱拆分的方法替代超临界液相色谱拆分，实现了工业化大生产，降低了成本；工艺总收率提高了约7倍；工艺后处理操作简化，安全，有利于质量控制和降低成本。
4、具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。
实施例1 2-氯-7,8-二氢-6H-喹啉-5-酮的制备
Figure PCTCN2020077413-appb-000046
室温下，将50g 7,8-二氢-1H,6H-喹啉-2,5-二酮(1.0eq)，400g乙腈加入反应釜，加入79.8g三氯氧磷(1.7eq)，反应釜升温至内温80℃，反应2h，冷却反应釜至55℃，减压蒸馏出300g溶剂，蒸馏结束后，反应液降温至25℃，加入水淬灭反应，加完水后在25℃继续搅拌后，25℃下用氢氧化钠水溶液，调节反应液pH值到5-7，降温搅拌，过滤，滤饼用水淋洗，真空干燥，得到49g类白色固体2-氯-7,8-二氢-6H-喹啉-5-酮，收率约88％。
质谱(M+1):182
1H-NMR(DMSO-d 6,400MHz):δ8.17(1H,d),7.51(1H,d),3.05(2H,t),2.65(2H,t),2.07-2.13(2H,m).
实施例2 5-氧代-5,6,7,8-四氢-喹啉-2-羧酸乙酯的制备
Figure PCTCN2020077413-appb-000047
25℃下，向高压釜内加入40g 2-氯-7,8-二氢-6H-喹啉-5-酮(1.0eq)、200ml无水乙醇、20ml DMF、44.5g三乙胺(2.0eq)和3.2g Pd(dppf)Cl 2·CH 2Cl 2，高压釜用一氧化碳气体转换，加压至2Mpa，升温至内温75℃，反应3h至反应完成，体系降温至60℃左右，减压蒸馏至无馏分，浓缩完毕，加入乙酸乙酯，室温搅拌，抽滤，滤饼用乙酯乙酯淋洗，母液合并加入盐酸，搅拌静置分液，得到水相和有机相，乙酸乙酯加入水相，搅拌静置分液，合并有机相，有机相减压蒸馏至无馏分，大约得到50g黑色油状物直接用于下一步反应。
质谱(M+1):220
1H-NMR(DMSO-d 6,400MHz):δ8.32(1H,d),8.00(1H,d),4.35-4.40(2H,q),3.14(2H,t),2.71(2H,t),2.10-2.17(2H,m),1.34(3H,t).
实施例3 6-环戊基亚甲基-5-氧代-5,6,7,8-四氢-喹啉-2-羧酸乙 酯的制备
Figure PCTCN2020077413-appb-000048
25℃下，向反应瓶中加入50g粗品5-氧代-5,6,7,8-四氢-喹啉-2-羧酸乙酯和140ml无水乙醇控温0℃左右，向反应瓶中加入21.7g环戊基甲醛(1.0eq)，加毕，搅拌10min，控温0℃左右，向反应瓶中滴加9.4g吡咯烷(0.6eq)，升温至25℃，避光反应8h，加入水，反应液降温至5±5℃搅拌1h，抽滤，滤饼用乙醇/水混合溶剂洗涤，真空干燥，得到47.6g淡黄色固体6-环戊基亚甲基-5-氧代-5,6,7,8-四氢-喹啉-2-羧酸乙酯，两步收率约72％。
质谱(M+1):300
1H-NMR(DMSO-d 6,400MHz):δ8.38(1H,d),8.03(1H,d),6.78(1H,d),4.35-4.40(2H,q),3.13(2H,t),2.87-2.93(3H,m),1.61-1.88(6H,m),1.34-1.40(5H,t).
实施例4 2-氯-4-肼基苯甲腈的制备
Figure PCTCN2020077413-appb-000049
25℃下向反应瓶中，加入40g 2-氯-4-氟苯甲腈(1.0eq)，45.5g水合肼(3.0eq，85％)和200g无水乙醇，升温至80℃反应3h，加入400g水，降温至20℃，搅拌抽滤，滤饼用乙醇淋洗，湿滤饼真空干燥，得到约40g白色固体2-氯-4-肼基苯甲腈，收率约92％。
质谱(M+1):168
1H-NMR(DMSO-d 6,400MHz):δ8.09(1H,s),7.49(1H,d),6.91(1H,s),6.69(1H,d),4.40(2H,s).
实施例5 2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡 唑并[3,4-f]喹啉-7-羧酸乙酯的制备
Figure PCTCN2020077413-appb-000050
25℃下，向反应瓶中加入20g 6-环戊基亚甲基-5-氧代-5,6,7,8-四氢-喹啉-2-羧酸乙酯(1.0eq)，11.7g 2-氯-4-肼基苯甲腈(1.05eq)，64ml乙醇和36.8ml 2.0mol/L氯化氢乙醇溶液，升温至内温75℃，避光反应16h，降温至5±5℃，搅拌抽滤，滤饼用无水乙醇洗涤，真空干燥，得到22.5g黄色固体2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸乙酯，收率约75％。
质谱(M+1):449
1H-NMR(DMSO-d 6,400MHz):δ8.47(1H,d),7.95(1H,d),7.71(1H,d),7.45(1H,s),7.27(1H,d),5.01-5.05(1H,m),4.34-4.39(2H,q),3.67-3.74(1H,m),3.02-3.19(2H,m),1.40-2.30(14H,m).
实施例6 2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡 唑并[3,4-f]喹啉-7-羧酸的制备
Figure PCTCN2020077413-appb-000051
在25℃下，向反应瓶中加入7g 2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸乙酯(1.0eq)，14ml甲醇和28ml四氢呋喃，反应液降温至5±5℃，滴加12.5g 10％氢氧化钠水溶液(2.0eq)，在5±5℃下搅拌1h，滴加稀盐酸至pH值为3-5，升温至25±5℃，搅拌过滤反应液，滤饼用甲醇洗涤，真空干燥，得到6.23g黄色固体2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸，收率约95％。
质谱(M+1):421
1H-NMR(CDCl 3-d 3,400MHz):δ8.54(1H,d),8.12(1H,d),7.47(1H,d),7.33(1H,s),7.03(1H,d),4.72-4.76(1H,m),3.05-3.62(3H,m),1.23-2.43(11H,m).
实施例7 (3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四 氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1S,2S)-环己二胺盐的制备
Figure PCTCN2020077413-appb-000052
在25℃下，向反应釜中加入5.0g 2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1.0eq)和2.71g(1S,2S)-环己二胺(2.0eq)，加入500ml丙酮，反应液在25℃搅拌不低于10h，过滤，滤饼用丙酮洗涤，滤饼取样，HPLC测试PSC/1手性纯度不低于95％，真空干燥，得到2.3g黄色固体(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1S,2S)-环己二胺盐，收率约35％。产物做液相，与对照品一致。
质谱(M+1):421
1H-NMR(CDCl 3-d 3,400MHz):δ8.35(1H,d),8.04(1H,d),7.43(1H,d),7.27(1H,s),6.96(1H,d),4.60-4.64(1H,m),2.90-3.84(5H,m),1.01-2.41(23H,m).
实施例8 (3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四 氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1R,2R)-环己二胺盐的制备
Figure PCTCN2020077413-appb-000053
按照实施例7所述方法，过滤,收集母液后蒸馏制得(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1R,2R)-环己二胺盐，HPLC测试PSC/1手性纯度不低于95％。
实施例9 (3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四 氢-2H-吡唑并[3,4-f]喹啉-7-羧酸奎宁盐的制备
在25℃下，向反应釜中加入5.0g 2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1eq)和3.8g奎宁(1eq)，加入乙酸乙酯(300mL)，反应液在25℃搅拌不低于10h， 过滤，滤饼用乙酸乙酯洗涤，滤饼经过烘干后制得(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸奎宁盐，HPLC测试PSC/1手性纯度不低于75％。
实施例10 (3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四 氢-2H-吡唑并[3,4-f]喹啉-7-羧酸奎尼丁盐的制备
按照实施例9所述方法，过滤，收集母液后蒸馏制得(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸奎尼丁盐，HPLC测试PSC/1手性纯度不低于75％。
实施例11 (3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四 氢-2H-吡唑并[3,4-f]喹啉-7-羧酸的制备
Figure PCTCN2020077413-appb-000054
在25℃下，向反应瓶中加入5g(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1S,2S)-环己二胺盐(1.0eq)和30ml乙醇，加入10ml盐酸(1mol/L，1.07eq)，反应液在25℃搅拌2h，过滤，滤饼用乙醇洗涤，滤饼取样，真空干燥，得到3.7g黄色固体(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸，收率94％。
实施例12 2-氯-4-[(3S,3aR)-3-环戊基-7-(4-羟基哌啶-1-羰 基)-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-2-基]苯甲腈的制备
Figure PCTCN2020077413-appb-000055
在25℃下，向反应瓶中加入10g(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1.0eq)、10.8g 2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU) (1.2eq)、50ml二氯甲烷和10ml NMP，加入3.6g三乙胺(1.5eq)，反应液在25℃搅拌30min。先将2.9g 4-羟基哌啶(1.2eq)溶解在20ml二氯甲烷中，然后滴入反应瓶中，反应液25℃搅拌2h。取样，加入盐酸水溶液搅拌，静置分相，加入碳酸钠水溶液搅拌，静置分相，加入水溶液搅拌，静置分相，有机相蒸干得到18g黄棕色油状物，将该油状物和120g异丙醇溶液加入反应瓶中，加热至80℃溶液澄清，冷却至25℃后，搅拌3h以上，过滤，滤饼用异丙醇洗涤，真空干燥，得到8.4g黄色固体2-氯-4-[(3S,3aR)-3-环戊基-7-(4-羟基哌啶-1-羰基)-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-2-基]苯甲腈，收率约70％。产物做液相，与对照品一致。
实施例13 2-氯-4-[(3S,3aR)-3-环戊基-7-(4-羟基哌啶-1-羰 基)-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-2-基]苯甲腈的制备
Figure PCTCN2020077413-appb-000056
按照实施例12所述方法，(3S,3aR)-2-(3-氯-4-氰基-苯基)-3-环戊基-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-7-羧酸(1S,2S)-环己二胺盐与4-羟基哌啶反应，得到2-氯-4-[(3S,3aR)-3-环戊基-7-(4-羟基哌啶-1-羰基)-3,3a,4,5-四氢-2H-吡唑并[3,4-f]喹啉-2-基]苯甲腈。

Claims (13)

  1. 一种制备式(III)化合物的方法，其特征在于，所述式(III)化合物是通过下述步骤(g)获得的：
    (g)将式(IV)化合物与手性碱Y反应得式(III)化合物，
    Figure PCTCN2020077413-appb-100001
    所述手性碱Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物。
  2. 如权利要求1所述的方法，其特征在于，所述步骤(g)是在酮类溶剂、酯类溶剂或四氢呋喃中反应。
  3. 如权利要求1或2所述的方法，其特征在于，所述式(IV)化合物是通过下述步骤(f)获得的：
    (f)将式(V)化合物通过水解反应得式(IV)化合物
    Figure PCTCN2020077413-appb-100002
    其中R是C 1-6烷基。
  4. 如权利要求3所述的方法，其特征在于，所述式(V)化合物是通过下述步骤(e)获得的：
    (e)将式(VII)化合物与式(VI)化合物反应得式(V)化合物
    Figure PCTCN2020077413-appb-100003
    其中R是C 1-6烷基。
  5. 如权利要求4所述的方法，其特征在于，所述式(VI)化合物是通过下述步骤(d)获得的：
    (d)将2-氯-4-氟苯甲腈与水合肼反应得式(VI)化合物
    Figure PCTCN2020077413-appb-100004
  6. 如权利要求4所述的方法，其特征在于，所述式(VII)化合物是通过下述步骤(c)获得的：
    (c)将式(VIII)化合物与环戊基甲醛反应得式(VII)化合物
    Figure PCTCN2020077413-appb-100005
    其中R是C 1-6烷基。
  7. 如权利要求6所述的方法，其特征在于，所述式(VIII)化合物是通过下述步骤(b)获得的：
    (b)式(IX)化合物与ROH制备得式(VIII)化合物，优选地式(IX)化合物与ROH在CO的存在下制备得式(VIII)化合物
    Figure PCTCN2020077413-appb-100006
    其中R是C 1-6烷基。
  8. 如权利要求7所述的方法，其特征在于，所述式(IX)化合物是通过下述步骤(a)获得的：
    (a)通过式(X)化合物制备得式(IX)化合物，优选地通过式(X)化合物与酰氯类化合物制备得式(IX)化合物，
    Figure PCTCN2020077413-appb-100007
    其中酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯。
  9. 如权利要求6所述的方法，其特征在于，所述式(VIII)化合物是通过下述步骤(a)和(b)获得的：
    (a)通过式(X)化合物制备得式(IX)化合物，优选地通过式(X)化合物与酰氯类化合物制备得式(IX)化合物，其中酰氯类化合物选自磷酰氯、碳酰氯、硫酰氯；
    (b)式(IX)化合物与ROH制备得式(VIII)化合物，优选地式(IX)化合物与ROH在CO的存在下制备得式(VIII)化合物，
    Figure PCTCN2020077413-appb-100008
    其中R是C 1-6烷基。
  10. 如权利要求1-8中任一项所述的方法，其特征在于，所述方法还包括使用式(III)化合物制备式(II)化合物，其包括以下步骤：
    (h)将式(III)化合物加入酸溶液反应得式(II)化合物，
    Figure PCTCN2020077413-appb-100009
    其中Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物。
  11. 如权利要求1-8中任一项所述的方法，其特征在于，所述方法还包括使用式(III)化合物制备式(I)化合物，其包括以下步骤：
    Figure PCTCN2020077413-appb-100010
    (h)将式(III)化合物加入酸溶液反应得式(II)化合物，
    (i)将式(II)化合物和4-羟基哌啶反应得式(I)化合物，其中Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物。
  12. 如权利要求1-8中任一项所述的方法，其特征在于，所述方法还包括使用式(III)化合物制备式(I)化合物，其包括以下步骤：
    将式(III)化合物和4-羟基哌啶反应得式(I)化合物，
    Figure PCTCN2020077413-appb-100011
    其中Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物。
  13. 式(III)化合物，其特征在于，具有下式结构
    Figure PCTCN2020077413-appb-100012
    其中Y选自(1S,2S)-环己二胺、(1R,2R)-环己二胺、奎宁、奎尼丁或其氘代衍生物。
PCT/CN2020/077413 2019-03-01 2020-03-02 一种三并环化合物的制备方法及其中间体 WO2020177658A1 (zh)

Priority Applications (16)

Application Number Priority Date Filing Date Title
AU2020230627A AU2020230627B2 (en) 2019-03-01 2020-03-02 Method for preparing tricyclic compound, and intermediate thereof
CN202080018246.5A CN113874371B (zh) 2019-03-01 2020-03-02 一种三并环化合物的制备方法及其中间体
BR112021017276A BR112021017276A2 (pt) 2019-03-01 2020-03-02 Método para preparar composto tricíclico e intermediário do mesmo
NZ779681A NZ779681A (en) 2019-03-01 2020-03-02 Process for preparing a fused tricyclic compound, and intermediate thereof
CA3132075A CA3132075A1 (en) 2019-03-01 2020-03-02 Process for preparing a fused tricyclic compound, and intermediate thereof
JP2021551807A JP7291426B2 (ja) 2019-03-01 2020-03-02 縮合三環式化合物を調製するための方法、及びその中間体
SG11202109564U SG11202109564UA (en) 2019-03-01 2020-03-02 Process for preparing a fused tricyclic compound, and intermediate thereof
MX2021010511A MX2021010511A (es) 2019-03-01 2020-03-02 Procedimiento para preparar un compuesto tricíclico fusionado, e intermedio del mismo.
PE2021001428A PE20212179A1 (es) 2019-03-01 2020-03-02 Procedimiento para preparar un compuesto triciclico fusionado, e intermedio del mismo
US17/435,181 US20220144824A1 (en) 2019-03-01 2020-03-02 Method for preparing tricyclic compound, and intermediate thereof
KR1020217031105A KR102704291B1 (ko) 2019-03-01 2020-03-02 융합 3환 화합물의 제조 방법, 및 그의 중간체
EP20765627.3A EP3932920A4 (en) 2019-03-01 2020-03-02 METHOD FOR PREPARING A TRICYCLIC COMPOUND, AND INTERMEDIATE THEREOF
UAA202105530A UA127368C2 (uk) 2019-03-01 2020-03-02 Спосіб одержання трициклічної сполуки і її проміжного продукту
IL286015A IL286015B1 (en) 2019-03-01 2020-03-02 A process for the preparation of tricyclic substances and intermediates obtained in this process
ZA2021/06376A ZA202106376B (en) 2019-03-01 2021-09-01 Process for preparing a fused tricyclic compound, and intermediate thereof
CONC2021/0012061A CO2021012061A2 (es) 2019-03-01 2021-09-15 Procedimiento para preparar un compuesto tricíclico fusionado, e intermedio del mismo

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201910155700 2019-03-01
CN201910155700.0 2019-03-01
CN201910187667 2019-03-13
CN201910187667.X 2019-03-13

Publications (1)

Publication Number Publication Date
WO2020177658A1 true WO2020177658A1 (zh) 2020-09-10

Family

ID=72337678

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/077413 WO2020177658A1 (zh) 2019-03-01 2020-03-02 一种三并环化合物的制备方法及其中间体

Country Status (19)

Country Link
US (1) US20220144824A1 (zh)
EP (1) EP3932920A4 (zh)
JP (1) JP7291426B2 (zh)
KR (1) KR102704291B1 (zh)
CN (1) CN113874371B (zh)
AU (1) AU2020230627B2 (zh)
BR (1) BR112021017276A2 (zh)
CA (1) CA3132075A1 (zh)
CL (1) CL2021002287A1 (zh)
CO (1) CO2021012061A2 (zh)
IL (1) IL286015B1 (zh)
MX (1) MX2021010511A (zh)
NZ (1) NZ779681A (zh)
PE (1) PE20212179A1 (zh)
SG (1) SG11202109564UA (zh)
TW (1) TWI728727B (zh)
UA (1) UA127368C2 (zh)
WO (1) WO2020177658A1 (zh)
ZA (1) ZA202106376B (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012022121A1 (zh) 2010-08-18 2012-02-23 山东轩竹医药科技有限公司 作为盐皮质激素受体拮抗剂的并环类化合物
WO2014094664A1 (zh) 2012-12-22 2014-06-26 山东亨利医药科技有限责任公司 作为盐皮质激素受体拮抗剂的化合物的晶型及其制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08301850A (ja) * 1995-05-01 1996-11-19 Sagami Chem Res Center 光学活性５，９−メタノシクロオクタ［ｂ］ピリジン誘導体の製造方法
JPH11322635A (ja) * 1998-05-07 1999-11-24 Kankyo Kagaku Center:Kk 光学活性化合物及び光学分割剤からなる分子化合物の生成方法
JP5212740B2 (ja) * 2009-10-29 2013-06-19 東レ・ファインケミカル株式会社 １，２−ジアミノシクロヘキサンの製造法
CN103694253A (zh) * 2013-11-04 2014-04-02 湖南华腾制药有限公司 一种噻吩并三唑并[4,3-a][1,4]二氮杂卓类化合物的制备方法
WO2017063307A1 (zh) * 2015-10-13 2017-04-20 山东轩竹医药科技有限公司 1，4-二氢吡啶-3，5-二羧酸酯衍生物的制备方法及中间体
PL3519416T3 (pl) * 2016-09-27 2021-09-06 Merck Sharp & Dohme Corp. Pochodne chromanu, izochromanu i dihydroizobenzofuranu jako ujemne allosteryczne modulatory mglur2, ich kompozycje i zastosowanie

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012022121A1 (zh) 2010-08-18 2012-02-23 山东轩竹医药科技有限公司 作为盐皮质激素受体拮抗剂的并环类化合物
WO2014094664A1 (zh) 2012-12-22 2014-06-26 山东亨利医药科技有限责任公司 作为盐皮质激素受体拮抗剂的化合物的晶型及其制备方法

Also Published As

Publication number Publication date
MX2021010511A (es) 2021-11-17
CL2021002287A1 (es) 2022-04-22
US20220144824A1 (en) 2022-05-12
CN113874371B (zh) 2024-04-16
CN113874371A (zh) 2021-12-31
AU2020230627B2 (en) 2023-01-19
NZ779681A (en) 2024-08-30
JP7291426B2 (ja) 2023-06-15
ZA202106376B (en) 2022-07-27
IL286015B1 (en) 2024-07-01
TWI728727B (zh) 2021-05-21
AU2020230627A1 (en) 2021-09-30
JP2022522489A (ja) 2022-04-19
BR112021017276A2 (pt) 2021-11-09
CO2021012061A2 (es) 2021-09-30
EP3932920A4 (en) 2022-12-14
PE20212179A1 (es) 2021-11-09
IL286015A (en) 2021-10-31
KR20210136046A (ko) 2021-11-16
CA3132075A1 (en) 2020-09-10
SG11202109564UA (en) 2021-10-28
KR102704291B1 (ko) 2024-09-09
TW202039492A (zh) 2020-11-01
EP3932920A1 (en) 2022-01-05
UA127368C2 (uk) 2023-07-26

Similar Documents

Publication Publication Date Title
EP2027083A1 (en) Method of preparing chiral cyclic beta-aminocarboxamides
CN109734662A (zh) 一种三氟甲基取代二氢异喹啉酮衍生物及其制备方法
CN111018678B (zh) 一种高纯度3-苯氧基溴丙烷的制备方法
WO2020177658A1 (zh) 一种三并环化合物的制备方法及其中间体
CN105026370A (zh) 取代的吡咯烷-2-甲酰胺的不对称合成
CN113416162B (zh) 一种双手性联萘o-n-n三齿配体及其制备方法
CN108864084B (zh) 一组阿哌沙班有关物质及其制备方法
CN116041347A (zh) 非奈利酮中间体的制备方法
CN113754686B (zh) 一种生物素标记苦参碱探针的合成方法
CN112272665B (zh) 制备立他司特的方法
CN111100112B (zh) 苯并噻吩衍生物及其制备方法
WO2021238962A1 (zh) 一种制备glp-1受体激动剂的方法
WO2021242807A1 (en) Methods for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionate and hydrochloric acid salts thereof
RU2785963C1 (ru) Способ получения конденсированного трициклического соединения и соответствующего промежуточного соединения
CN103360343B (zh) 一种哌嗪酰胺类化合物的制备方法
CN101514201A (zh) (4,7-顺)-八氢-吡咯并[3,4-b]吡啶和莫西沙星的制备方法
CN104098556A (zh) 一种新的利伐沙班的合成工艺
CN115784941B (zh) 一种三官能度腈氧化物、制备方法及其应用
SU1034605A3 (ru) Способ получени молекул рного соединени @ -диэтиламиноэтиламида @ -хлорфеноксиуксусной кислоты с 4- @ -бутил-3,5-дикето-1,2-дифенилпиразолидином
CN108503583B (zh) 一种含氮氢类化合物的烷基化方法及其应用
JP4734975B2 (ja) ２−（テトラヒドロピラン−４−イル）−２−オキソ酢酸の製法
CN116082334A (zh) 非奈利酮及其中间体的制备方法
CN115703712A (zh) 5,8-二氨基-3,4-二氢-2h-1-萘酮的合成方法以及其中采用的中间体化合物
WO2023035571A1 (zh) 埃沙西林酮及其中间体的合成方法
CN112028827A (zh) 一种奈他地尔关键中间体的制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20765627

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021551807

Country of ref document: JP

Kind code of ref document: A

Ref document number: 3132075

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 286015

Country of ref document: IL

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112021017276

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 20217031105

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020230627

Country of ref document: AU

Date of ref document: 20200302

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2021128216

Country of ref document: RU

ENP Entry into the national phase

Ref document number: 2020765627

Country of ref document: EP

Effective date: 20211001

ENP Entry into the national phase

Ref document number: 112021017276

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20210831