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 PDFInfo
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- 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
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- 0 **c(cc1)nc(CC[C@@]2[C@@]3C4CCCC4)c1C2=NN3c(cc1Cl)ccc1C#N Chemical compound **c(cc1)nc(CC[C@@]2[C@@]3C4CCCC4)c1C2=NN3c(cc1Cl)ccc1C#N 0.000 description 10
- BMTYDFBITNBXBO-UHFFFAOYSA-N CC(CCc1nc(Cl)ccc11)C1=O Chemical compound CC(CCc1nc(Cl)ccc11)C1=O BMTYDFBITNBXBO-UHFFFAOYSA-N 0.000 description 1
- IALAJANFQUXTJS-VQLLRRGWSA-N N#Cc(c(Cl)c1)ccc1N1N=C2c3ccc(C(N(CC4)CCC4O)=O)nc3CC[C@@H]2[C@@H]1C(CC1)CC1C(C1)NCCC1O Chemical compound N#Cc(c(Cl)c1)ccc1N1N=C2c3ccc(C(N(CC4)CCC4O)=O)nc3CC[C@@H]2[C@@H]1C(CC1)CC1C(C1)NCCC1O IALAJANFQUXTJS-VQLLRRGWSA-N 0.000 description 1
- AUMQUQJTKCJMPA-UHFFFAOYSA-N O=C(CCC1)C(C=C2)=C1NC2=O Chemical compound O=C(CCC1)C(C=C2)=C1NC2=O AUMQUQJTKCJMPA-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
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- 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.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Claims (13)
- 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。
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US17/435,181 US20220144824A1 (en) | 2019-03-01 | 2020-03-02 | Method for preparing tricyclic compound, and intermediate thereof |
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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 |
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IL286015A IL286015B1 (en) | 2019-03-01 | 2021-08-31 | A process for the preparation of tricyclic substances and intermediates obtained in this process |
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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 |
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