WO2020103945A1 - Composé d'oxycodone, et intermédiaire et son procédé de préparation - Google Patents

Composé d'oxycodone, et intermédiaire et son procédé de préparation

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Publication number
WO2020103945A1
WO2020103945A1 PCT/CN2019/120322 CN2019120322W WO2020103945A1 WO 2020103945 A1 WO2020103945 A1 WO 2020103945A1 CN 2019120322 W CN2019120322 W CN 2019120322W WO 2020103945 A1 WO2020103945 A1 WO 2020103945A1
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formula
compound represented
reaction
solvent
organic solvent
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PCT/CN2019/120322
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English (en)
Chinese (zh)
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汤文军
徐斯尧
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中国科学院上海有机化学研究所
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Publication of WO2020103945A1 publication Critical patent/WO2020103945A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/28—Morphinans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • 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
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a oxycodone compound and its intermediate and preparation method.
  • Oxycodone (oxycodone), its chemical structural formula is It is a semi-synthetic opioid extracted from the alkaloid thebaine. Oxycodone has been used clinically as a powerful analgesic for more than 80 years. Due to its high bioavailability and many routes of administration, oxycodone is widely used in clinic.
  • the synthesis method of oxycodone compounds is mainly to extract morphine compounds from plants, and the morphine compounds are further modified.
  • the chemical synthesis method for preparing oxycodone from common compounds as starting materials has not been reported so far.
  • the invention provides a oxycodone compound and its intermediate and preparation method which are different from the prior art.
  • the preparation method uses common compounds as starting materials to prepare oxycodone compounds, with high yield and simple operation.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a method for preparing a compound represented by Formula A9, which includes the following steps:
  • the compound represented by formula A8b Under a protective gas, under the action of a palladium catalyst and a phosphine ligand, the compound represented by formula A8b is subjected to the dearomatization cyclization reaction shown below in an organic solvent to obtain the compound represented by formula A9, namely Yes; wherein, the phosphine ligand is a phosphine ligand represented by formula L1 and / or a phosphine ligand represented by formula L2;
  • R 1 and R 2 are independently H, C 1 ⁇ 10 alkyl group, C 1 ⁇ 10 alkoxy, C 3 ⁇ 10 cycloalkyl or C 6 ⁇ 20 aryl group, R 3 is C 1 ⁇ 4 alkyl base.
  • the protective gas may be a conventional protective gas in the art, preferably nitrogen and / or argon, and more preferably nitrogen.
  • the palladium catalyst may be a conventional palladium catalyst for such reactions in the art, preferably palladium chloride, palladium hydroxide, bis (acetonitrile) palladium chloride, palladium trifluoromethanesulfonate And one or more of palladium acetate, more preferably palladium chloride.
  • the phosphine ligand is preferably a phosphine ligand represented by formula L1.
  • the organic solvent may be an organic solvent conventional for such reactions in the art, preferably alcohol solvents, ether solvents, aromatic solvents, nitrile solvents, halogenated alkane solvents, One or more of sulfone-based solvents and amide-based solvents, preferably sulfoxide-based solvents and / or amide-based solvents, more preferably amide-based solvents.
  • the amide solvent may be N, N-dimethylformamide (DMF) and / or N, N-dimethylacetamide (DMA).
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the volume-to-mass ratio of the organic solvent to the compound represented by formula A8b may be the volume-to-mass ratio of such reactions in the art, preferably 5-20 ml / g, for example 10 ml / g.
  • the molar ratio of the palladium catalyst to the compound represented by Formula A8b may be a conventional molar ratio in this type of reaction in the art, preferably 0.01 to 0.5, more preferably 0.1 ⁇ 0.5.
  • the molar ratio of the phosphine ligand to the compound represented by Formula A8b may be 0.01 to 0.5, preferably 0.1 to 0.5.
  • the temperature of the dearomatization cyclization reaction may be 80 ° C to 180 ° C, or may be 100 ° C to 130 ° C, for example, 120 ° C.
  • the progress of the dearomatization cyclization reaction can be monitored using conventional monitoring methods in the art (eg, TLC or LCMS).
  • TLC time since it disappears, it serves as the end point of the reaction.
  • the reaction time may be 10-24 hours, for example 14 hours).
  • the R 1 and the R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • the compound represented by formula A8b is preferably
  • the following post-processing steps may be further included: extracting, drying, concentrating, and column chromatography the reaction solution after the reaction.
  • a mixture of "the compound represented by formula A8b and the organic solvent” is mixed with “the catalyst, the ligand and the base”.
  • the catalyst, the ligand and the base are added to the mixture of "the compound represented by formula A8b and the organic solvent”.
  • the method of addition is preferably added in batches.
  • the number of batch additions is preferably 2 to 5, more preferably 3 times.
  • the method for preparing the compound shown in Formula A9 may further include the method for preparing the compound shown in Formula A8b, which is Method 1 or Method 2;
  • Method 1 includes the following steps: under the action of a deprotection reagent, the compound represented by formula A8a-I is subjected to the deprotection reaction shown below in an organic solvent to obtain the compound represented by formula A8b;
  • R 4 is a hydroxy protecting group
  • R 1 , R 2 and R 3 are as defined above;
  • Method 2 includes the following steps: under the action of a base, the compound represented by formula A8a-II and the chloroformate in an organic solvent are acylated as shown below to obtain the compound represented by formula A8b;
  • R 1 , R 2 and R 3 are as defined above.
  • the conditions of the deprotection reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the deprotection reagent may be tetrabutylammonium fluoride.
  • the molar ratio of the deprotection reagent to the compound A8a-I is 1 to 5, for example, 1.1.
  • the organic solvent may be an ether solvent and / or a chlorinated hydrocarbon solvent, and more preferably an ether solvent.
  • the ether solvent may be one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether (MTBE), more preferably tetrahydrofuran.
  • R 1 and R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • the hydroxy protecting group when R 4 is a hydroxy protecting group, the hydroxy protecting group may be a conventional hydroxy protecting group in the art, preferably a silicon ether protecting group (such as a trimethyl silicon ether protecting group, Tert-butyl dimethyl silicon ether protecting group, tert-butyl diphenyl silicon ether protecting group (TBDPS)), more preferably tert-butyl diphenyl silicon protecting group
  • a silicon ether protecting group such as a trimethyl silicon ether protecting group, Tert-butyl dimethyl silicon ether protecting group, tert-butyl diphenyl silicon ether protecting group (TBDPS)
  • TDPS tert-butyl diphenyl silicon protecting group
  • the conditions of the acylation reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the organic solvent may be a chlorinated alkane solvent and / or an amide solvent, preferably a chlorinated alkane solvent.
  • the chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the base may be a conventional base for such reactions in the art, preferably an organic weak base, and further preferably triethylamine.
  • the molar ratio of the base to the compound represented by Formula A8a-II may be 1 to 3, for example, 1.41.
  • the chloroformate may be one or more of methyl chloroformate, ethyl chloroformate, propyl chloroformate and butyl chloroformate, preferably methyl chloroformate.
  • the molar ratio of the chloroformate to the compound represented by formula A8a-II may be 0.9-1.1, such as 0.96.
  • R 1 and R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • the compound represented by formula A8a-II is preferably
  • the temperature of the reaction may be 10-50 ° C, for example 20 ° C, for example 40 ° C.
  • the method for preparing the compound shown in Formula A8a-I may include the following steps:
  • the compound represented by formula A7 and H 2 are subjected to an asymmetric hydrogenation reaction as shown below in an organic solvent to obtain the compound represented by formula A8a-I;
  • the ligand is a ligand represented by formula L3 and / or a ligand represented by formula L4;
  • R 4 , R 1 , R 2 and R 3 are as defined above.
  • the rhodium catalyst may be a conventional rhodium catalyst for such reactions in the art, preferably bis (norbornene) rhodium (I) tetrafluoroborate, (acetylpyruvate) dicarbonyl rhodium , One or more of rhodium trifluoroacetate dimer, tris (acetonitrile) trichlororhodium and acetylacetone dicarbonyl rhodium, more preferably bis (norbornene) rhodium (I) tetrafluoroborate.
  • a conventional rhodium catalyst for such reactions in the art preferably bis (norbornene) rhodium (I) tetrafluoroborate, (acetylpyruvate) dicarbonyl rhodium , One or more of rhodium trifluoroacetate dimer, tris (acetonitrile) trichlororhodium and
  • the ligand is preferably a ligand represented by Formula L4.
  • the asymmetric hydrogenation reaction is preferably carried out under a certain pressure.
  • the pressure of the asymmetric hydrogenation reaction may be a conventional pressure for such reactions in the art, preferably 1 atm to 50 atm, for example 300 psi.
  • the asymmetric hydrogenation reaction is preferably carried out in a reactor (for example, a high-pressure reactor).
  • the organic solvent may be an organic solvent commonly used in this type of reaction in the art, preferably alcohol solvents, ether solvents, aromatic hydrocarbon solvents, nitrile solvents, halogenated alkane solvents, sulfoxides One or more of solvents and amide solvents, preferably alcohol solvents.
  • the alcohol solvent may be one or more of methanol, ethanol, n-propanol, and isopropanol, preferably methanol.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the volume-to-mass ratio of the organic solvent to the compound represented by Formula A7 may be a conventional volume-to-mass ratio for such reactions in the art, and is preferably 5-20 ml / g, for example, 10 ml / g.
  • the molar ratio of the rhodium catalyst to the compound represented by Formula A7 may be a conventional molar ratio in this type of reaction in the art, preferably 0.00005 to 0.0005, such as 0.00015.
  • the molar ratio of the ligand to the compound represented by Formula A7 may be 0.00005 to 0.0005, for example, 0.00015.
  • the temperature of the asymmetric hydrogenation reaction may be a conventional temperature for such reactions in the art, preferably 10 ° C to 50 ° C, such as 25 ° C.
  • the R 1 and the R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • the compound represented by formula A7 is preferably
  • the progress of the asymmetric hydrogenation reaction can be monitored using conventional monitoring methods in the art (for example, TLC or HPLC), and the end point of the reaction is generally taken when the compound represented by Formula A7 disappears.
  • the reaction time may be 10-24 hours, for example 12 hours.
  • the following post-processing steps may also be included: extracting, drying, concentrating and column chromatography the reaction solution after the reaction.
  • the method for preparing the compound shown in formula A7 may include the following steps: under the action of POCl 3 , the compound shown in formula A6 The compound undergoes ring closure reaction in an organic solvent to obtain a ring closure product; then, under the action of a base, the ring closure compound and chloroformate are subjected to an acylation reaction of the following formula in an organic solvent to obtain the formula The compound shown;
  • R 4 , R 1 , R 2 and R 3 are as defined above.
  • the conditions of the ring-closing reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the molar ratio of the POCl 3 to the compound represented by Formula A6 may be 1.0 to 1.5, for example, 1.01.
  • the organic solvent may be a chlorinated alkane solvent and / or an amide solvent, preferably a chlorinated alkane solvent.
  • the chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the conditions of the acylation reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the base may be a conventional base for such reactions in the art, preferably an organic weak base, and further preferably triethylamine.
  • the molar ratio of the base to the compound represented by Formula A6 may be 1 to 3, for example, 1.41.
  • the chloroformate may be one or more of methyl chloroformate, ethyl chloroformate, propyl chloroformate and butyl chloroformate, preferably methyl chloroformate.
  • the molar ratio of the chloroformate to the compound represented by formula A6 may be 0.9-1.1, for example 0.96.
  • the R 1 and the R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • the compound represented by formula A6 is preferably
  • the temperature of the reaction may be 10-50 ° C, for example 20 ° C, for example 40 ° C.
  • the following post-processing steps may be further included: extracting, drying, and column chromatography the reaction solution after the reaction.
  • the method for preparing the compound represented by formula A8a-II may include the following steps: under the action of a deprotection reagent, the compound of formula A8a-III Carry out the deprotection reaction shown below in an organic solvent to obtain the compound represented by formula A8a-II;
  • R 4 , R 1 and R 4 are the same as described above.
  • the conditions of the deprotection reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the deprotection reagent may be tetrabutylammonium fluoride.
  • the molar ratio of the deprotection reagent to the compound A8a-III may be 1 to 5, for example, 1.1.
  • the organic solvent may be an ether solvent and / or a chlorinated hydrocarbon solvent, preferably an ether solvent.
  • the ether solvent may be one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether (MTBE), more preferably tetrahydrofuran.
  • the R 1 and the R 2 are independently preferably H.
  • the hydroxy protecting group may be a silicon ether protecting group (such as trimethyl silicon ether protecting group, tert-butyl dimethyl silicone protecting group, tert-butyl group)
  • the diphenylsilyl protecting group (TBDPS-) is more preferably a tert-butyldiphenylsilyl protecting group.
  • the compound represented by formula A8a-III is preferably
  • the method for preparing the compound shown in formula A8a-II may include the following steps: under the action of a metal complex, in a solvent , The compound represented by formula A8a-IV is subjected to an asymmetric hydrogenation reaction as shown below to obtain a compound represented by formula A8a-III; the metal complex is a complex represented by formula L5;
  • R 1 , R 2 and R 4 are the same as described above.
  • the organic solvent may be an organic solvent commonly used in this type of reaction in the art, preferably alcohol solvents, ether solvents, aromatic hydrocarbon solvents, nitrile solvents, halogenated alkane solvents, sulfoxide
  • solvent-based and amide-based solvents are preferably halogenated solvents, more preferably dichloromethane.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the molar ratio of the metal complex to the compound represented by Formula A8a-IV may be a conventional molar ratio in this type of reaction in the art, preferably 0.005 to 0.05, for example 0.02.
  • the asymmetric hydrogenation reaction is preferably carried out in the presence of a reducing agent.
  • the reducing agent is preferably an organic weak base and an organic weak acid.
  • the weak organic base may be triethylamine.
  • the organic weak acid may be formic acid.
  • the molar ratio of the organic weak base to the compound represented by Formula A8a-IV is preferably 1.5-3.0, for example 1.8.
  • the molar ratio of the organic weak acid to the compound represented by formula A8a-IV is preferably 15-30, for example 21.
  • the volume ratio of the organic weak acid to the organic weak base is preferably 2 to 5, for example 3.
  • the temperature of the asymmetric hydrogenation reaction may be a conventional temperature for such reactions in the art, preferably 10 ° C to 50 ° C, such as 25 ° C.
  • the R 1 and the R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • the post-processing step of the asymmetric hydrogenation reaction may be a post-processing step of conventional organic reactions in the art, which may include the following steps: after the reaction is completed, the pH value of the reaction solution is adjusted to 8-9, extraction, drying, and filtration , Concentration and column chromatography.
  • the reagent used for adjusting the pH of the reaction solution may be a carbonate salt, and sodium bicarbonate is further preferred.
  • the solvent used for the extraction may be ethyl acetate.
  • the method for preparing the compound shown in formula A8a-IV may include the following steps: under the action of POCl 3 , the formula shown in formula A6 The compound undergoes a ring closure reaction in an organic solvent to obtain the compound represented by formula A8a-IV;
  • R 1 , R 2 and R 4 are the same as described above.
  • the conditions of the ring-closing reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the molar ratio of the POCl 3 to the compound represented by Formula A6 may be 1.0 to 1.5, such as 1.01.
  • the organic solvent may be a chlorinated alkane solvent and / or an amide solvent, preferably a chlorinated alkane solvent.
  • the chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the temperature of the ring closure reaction may be 30-50 ° C, for example 40 ° C.
  • the method for preparing the compound represented by formula A8a-IV and the formula A7, and the method for preparing the compound represented by formula A6 may include the following steps:
  • R 1 , R 2 and R 4 are the same as described above.
  • the conditions of the condensation reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the catalyst may be "dicyclohexylcarbodiimide (DCC) and 4-diaminopyridine (DMAP)", 2- (7-benzotriazole) -N, N, N ', N One or more of '-tetramethylurea hexafluorophosphate (HATU) and carbonyldiimidazole (CDI), preferably “dicyclohexylcarbodiimide and 4-diaminopyridine".
  • the molar ratio of the dicyclohexylcarbodiimide to the 4-diaminopyridine may be 1.0-2.
  • the molar ratio of the catalyst to the compound represented by Formula A5 may be 1.0 to 3, for example, 1.17.
  • the molar ratio of the compound represented by Formula A2 to the compound represented by Formula A5 may be 1.0 to 3, for example, 1.15.
  • the organic solvent may be chloroalkanes and / or amides, preferably chloroalkanes.
  • the chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the temperature of the condensation reaction may be 10-30 ° C, for example 20 ° C.
  • the progress of the condensation reaction can be monitored by conventional monitoring methods in the art (for example, TLC or LCMS), and generally the end point of the reaction is when the compound represented by Formula A5 disappears.
  • the time of the condensation reaction may be 12-36h, for example 30h.
  • the R 1 and the R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • the compound represented by formula A5 is preferably
  • condensation reaction After the condensation reaction is completed, it may further include the following post-processing steps: extracting, drying, and column chromatography the reaction solution after the reaction is completed.
  • the invention also provides a method for preparing the compound represented by formula A8a-I, which comprises the following steps: under the action of a rhodium catalyst and a ligand, the compound represented by formula A7 and H 2 are carried out in an organic solvent
  • the asymmetric hydrogenation reaction shown below is sufficient to obtain the compound represented by formula A8a;
  • the ligand is a ligand represented by formula L3 and / or a ligand represented by formula L4;
  • R 1 , R 2 , R 3 and R 4 are the same as described above.
  • the present invention also provides a method for preparing a compound represented by formula A8a-III, which includes the following steps: under the action of a metal complex, in a solvent, the compound represented by formula A8a-IV is carried out as follows An asymmetric hydrogenation reaction of the formula to obtain a compound represented by formula A8a-III; the metal complex is a complex represented by formula L5;
  • R 1 , R 2 and R 4 are the same as described above.
  • the asymmetric hydrogenation method of the present invention is used to obtain hydrogenated products with high optical purity and / or high yield.
  • the present invention also provides a method for preparing a compound represented by Formula A, which includes the following steps:
  • R 1 , R 2 and R 3 are the same as described above.
  • step S1 the conditions of the condensation reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the catalyst may be "dicyclohexylcarbodiimide (DCC) and 4-diaminopyridine (DMAP)", 2- (7-oxybenzotriazole) -N, N, N ' , N'-tetramethylurea hexafluorophosphate (HATU) and carbonyl diimidazole (CDI) one or more, preferably "dicyclohexylcarbodiimide and 4-diaminopyridine".
  • the molar ratio of the dicyclohexylcarbodiimide to the 4-diaminopyridine may be 1.0-2.
  • step S1 the molar ratio of the catalyst to the compound represented by Formula A5 may be 1.0 to 3, for example, 1.17.
  • step S1 the molar ratio of the compound represented by Formula A2 to the compound represented by Formula A5 may be 1.0 to 3, for example, 1.15.
  • the organic solvent may be chloroalkanes and / or amides, preferably chloroalkanes.
  • the chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the temperature of the condensation reaction may be 10-30 ° C, for example 20 ° C.
  • step S1 the progress of the condensation reaction may be monitored by using conventional monitoring methods in the art (for example, TLC or LCMS), and generally the end point of the reaction is when the compound represented by Formula A5 disappears.
  • the time of the condensation reaction may be 12-36h, for example 30h.
  • R 1 and R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • step S1 the compound represented by formula A5 is preferably
  • condensation reaction After the condensation reaction is completed, it may further include the following post-processing steps: extracting, drying, and column chromatography the reaction solution after the reaction is completed.
  • the conditions of the ring-closing reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • step S2 the molar ratio of the POCl 3 to the compound represented by Formula A6 may be 1.0 to 1.5, for example, 1.01.
  • the organic solvent may be a chloroalkane solvent and / or an amide solvent, preferably a chloroalkane solvent.
  • the chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the base may be a conventional base for such reactions in the art, preferably an organic weak base, and further preferably triethylamine.
  • step S2 the molar ratio of the base to the compound represented by Formula A6 may be 1 to 3, for example, 1.41.
  • the chloroformate may be one or more of methyl chloroformate, ethyl chloroformate, propyl chloroformate and butyl chloroformate, preferably methyl chloroformate.
  • the temperature of the reaction may be 10-50 ° C, for example 20 ° C, for example 40 ° C.
  • step S2 the molar ratio of the chloroformate to the compound represented by Formula A6 may be 0.9-1.1, such as 0.96.
  • R 1 and R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • the compound represented by formula A6 is preferably
  • step S2 may further include the following post-processing steps: extracting, drying, and column chromatography the reaction solution after the reaction.
  • step S3 the conditions of the asymmetric hydrogenation reaction are the same as described above.
  • step S4 the conditions of the deprotection reaction are the same as described above.
  • step S5 the conditions of the dearomatization cyclization reaction are the same as described above.
  • step S6 the conditions of the deprotection reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the deprotection reagent may be one or more of boron trichloride, boron tribromide, and Pd / hydrogen, preferably boron trichloride.
  • step S6 the molar ratio of the deprotection reagent to the compound A9 may be 2-5, such as 4.
  • the organic solvent may be chloroalkanes.
  • the chlorinated hydrocarbon solvent is preferably dichloromethane.
  • step S6 the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • step S6 the temperature of the deprotection reaction may be -78 to -50 ° C, for example, -60 ° C.
  • step S6 the progress of the deprotection reaction can be monitored using conventional monitoring methods in the art (for example, TLC or LCMS), and generally the end point of the reaction is when the compound represented by Formula A9 disappears.
  • the deprotection reaction time may be 1 to 3 hours, for example 1.5 hours.
  • R 1 and R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • the compound represented by formula A9 is preferably
  • the following post-processing steps may also be included: extracting, drying, concentrating, and column chromatography the reaction solution after the reaction.
  • the conditions of the reduction reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the reducing agent may be alkali metal borohydride and / or lithium aluminum hydride, preferably alkali metal borohydride.
  • the alkali metal borohydride may be sodium borohydride and / or lithium borohydride, preferably sodium borohydride.
  • step S7 the molar ratio of the reducing agent to the compound A10 may be 3-6.
  • the organic solvent may be an alcohol solvent and / or a chloroalkane solvent, preferably an alcohol solvent.
  • the alcohol solvent may be methanol and / or ethanol, preferably methanol.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the temperature of the reduction reaction may be -5 to 5 ° C, for example, 0 ° C.
  • step S7 the progress of the reduction reaction may be monitored by using conventional monitoring methods in the art (for example, TLC or LCMS), and generally the end point of the reaction is when the compound represented by Formula A10 disappears.
  • the time of the reduction reaction may be 1 to 3 hours, for example 1.5 hours.
  • step S7 the R 1 and the R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • step S7 the compound represented by formula A10 is preferably
  • the reduction reaction may further include the following post-processing steps: extracting, drying, concentrating, and column chromatography the reaction solution after the reaction.
  • step S8 the conditions of the cyclization reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the cyclization reagent may be one or more of N, N-dimethylformamide dimethyl acetal, p-toluic acid, sodium methoxide and sodium ethoxide, preferably N, N- Dimethylformamide dimethyl acetal.
  • step S8 the molar ratio of the cyclization reagent to the compound represented by Formula A11 may be 10-15.
  • the organic solvent may be a chlorinated alkane solvent.
  • the chloroalkane solvent may be one or more of dichloromethane, 1,2 dichloroethane and chloroform, preferably dichloromethane.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the temperature of the cyclization reaction may be -5 to 5 ° C, for example, 0 ° C.
  • step S8 the progress of the cyclization reaction may be monitored by using conventional monitoring methods in the art (for example, TLC or LCMS), and generally the end point of the reaction is when the compound represented by Formula A11 disappears.
  • the time of the reduction reaction may be 5-12 hours, for example 8 hours.
  • step S8 the R 1 and the R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • step S8 the compound represented by formula A11 is preferably
  • the cyclization reaction After the cyclization reaction is completed, it also includes the following post-treatment steps: extracting, drying, concentrating, and column chromatography the reaction solution.
  • step S9 the conditions of the oxidation reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the oxidant may be m-chloroperoxybenzoic acid (mCPBA).
  • the molar ratio of the oxidant to the compound A12 may be 1 to 2, such as 1.1.
  • the organic solvent may be a chloroalkane solvent.
  • the chloroalkane solvent may be one or more of dichloromethane, 1,2 dichloroethane and chloroform, preferably dichloromethane.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the temperature of the oxidation reaction may be 30-60 ° C, for example 40 ° C.
  • step S9 the progress of the oxidation reaction may be monitored by using conventional monitoring methods in the art (for example, TLC or LCMS), and generally the end point of the reaction is when the compound represented by Formula A12 disappears.
  • the reduction reaction time may be 3-8 hours, for example 5 hours.
  • step S9 the R 1 and the R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • step S9 the compound represented by formula A12 is preferably
  • the following post-processing steps may be further included: extracting, drying, concentrating, and column chromatography the reaction solution after the reaction.
  • the conditions of the hydrogenation reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the catalyst may be Raney nickel and / or palladium catalyst, preferably palladium catalyst, further preferably palladium / carbon, still more preferably 10% palladium / carbon, the "%" is the mass of palladium accounting for palladium and carbon The mass percentage of the total mass.
  • the mass percentage of the catalyst and the compound A13 may be 30-50%, such as 36%.
  • the organic solvent may be an alcohol solvent.
  • the alcohol solvent may be methanol and / or ethanol, preferably methanol.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • step S10 the pressure of the hydrogenation reaction may be 1 to 1.5 atm.
  • the temperature of the hydrogenation reaction may be 30-60 ° C, for example 40 ° C.
  • step S10 the progress of the hydrogenation reaction may be monitored by using conventional monitoring methods in the art (for example, TLC or LCMS), and generally the end point of the reaction is when the compound represented by Formula A13 disappears.
  • the time of the hydrogenation reaction may be 3-8 hours, for example 5 hours.
  • step S10 the R 1 and the R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • step S10 the compound represented by formula A13 is preferably
  • the hydrogenation reaction may further include the following post-treatment steps: extracting, drying, concentrating, and column chromatography the reaction solution after the reaction.
  • the conditions of the reduction reaction may be conventional conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the reducing agent may be lithium aluminum hydride and / or alkali metal borohydride, preferably sodium lithium aluminum hydride.
  • step S11 the molar ratio of the reducing agent to the compound represented by formula A14 may be 3-8, such as 6.
  • the organic solvent may be an ether solvent.
  • the ether solvent may be one or more of tetrahydrofuran, dioxane, diethyl ether, and methyl tert-butyl ether (MTBE), preferably tetrahydrofuran.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the temperature of the reduction reaction may be 10-40 ° C, for example 20 ° C.
  • step S11 the progress of the reduction reaction may be monitored by using conventional monitoring methods in the art (for example, TLC or LCMS), and generally the end point of the reaction is when the compound represented by Formula A14 disappears.
  • the time of the reduction reaction may be 1 to 4 hours, for example 2 hours.
  • step S11 the R 1 and the R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • step S11 the compound represented by formula A14 is preferably
  • the reduction reaction After the reduction reaction is completed, it also includes the following post-processing steps: extracting, drying, concentrating, and column chromatography the reaction solution.
  • step S12 the operation and conditions of the oxidation reaction may be conventional operations and conditions of this type of reaction in the art, and the following conditions are preferred in the present invention:
  • the oxidant may be Dess-Martin oxidant (Dess-Martin) and / or hydrogen peroxide, preferably Dess-Martin oxidant.
  • step S12 the molar ratio of the oxidant to the compound represented by Formula A15 may be 1 to 3, for example, 1.5.
  • the organic solvent may be an ether solvent and / or a halogenated alkane solvent, preferably a halogenated alkane solvent.
  • the halogenated alkane solvent may be one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane.
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the progress of the reaction.
  • the temperature of the oxidation reaction may be 10-40 ° C, for example 20 ° C.
  • step S12 the progress of the oxidation reaction may be monitored by using conventional monitoring methods in the art (for example, TLC or LCMS), and generally the end point of the reaction is when the compound represented by Formula A15 disappears.
  • the time of the reduction reaction may be 1 to 4 hours, for example 2 hours.
  • step S12 the R 1 and the R 2 are independently preferably H.
  • the C 1-4 alkyl group is preferably a C 1-2 alkyl group, and more preferably a methyl group.
  • the compound represented by formula A15 is preferably
  • the following post-processing steps may be further included: extracting, drying, concentrating, and column chromatography the reaction solution after the reaction.
  • the present invention also provides a method for preparing a compound represented by Formula A, which includes the following steps:
  • the compound represented by formula A9 is prepared according to any of the above methods; the conditions and operations in steps S6 'to S12' are the same as those in steps S6 to S12; R 1 , R 2 and R 3 The definitions are the same as mentioned above.
  • the present invention also provides a method for preparing a compound represented by Formula A6, which includes the following steps:
  • R 1 , R 2 and R 4 are as defined above (R 1 and R 2 are independently H, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl or C 6 ⁇ 20 aryl group, R 4 is a hydroxy protecting group).
  • the present invention also provides a method for preparing a compound represented by Formula A7, which includes the following steps: Under the action of POCl 3 , the compound represented by Formula A6 is subjected to a ring closure reaction in an organic solvent to obtain a ring closure product ;
  • R 1 , R 2 , R 3 and R 4 are the same as described above.
  • the present invention also provides a method for preparing a compound represented by formula A8b, which includes the following steps: under the action of a deprotection reagent, the deprotection reaction as shown in formula A8a-I in an organic solvent is obtained as The compound represented by formula A8b is sufficient;
  • R 1 , R 2 , R 3 and R 4 are the same as described above.
  • the present invention also provides a method for preparing a compound represented by Formula A10, which includes the following steps: Under the action of a deprotection reagent, the compound represented by Formula A9 is subjected to a deprotection reaction as shown below in an organic solvent To obtain the compound represented by formula A10,
  • R 1 , R 2 and R 3 are the same as described above.
  • the present invention also provides a method for preparing a compound represented by Formula A11, which includes the following steps: under the action of a reducing agent, the compound represented by Formula A10 is subjected to the reduction reaction shown below in an organic solvent to obtain The compound represented by formula A11 is sufficient;
  • R 1 , R 2 and R 3 are as defined above (R 1 and R 2 are independently H, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl or C 6 ⁇ 20 aryl group, R 3 is C 1 ⁇ 4 alkyl group).
  • the present invention also provides a method for preparing a compound represented by Formula A12, which includes the following steps: Under the action of a cyclization reagent, the compound represented by Formula A11 is subjected to the cyclization reaction shown below in an organic solvent To obtain the compound represented by formula A12,
  • R 1 , R 2 and R 3 are the same as described above.
  • the present invention also provides a method for preparing a compound represented by Formula A13, which includes the following steps: using an oxidizing agent, oxidizing the compound represented by Formula A12 in an organic solvent to obtain a compound represented by Formula A13 Compound, just;
  • R 1 , R 2 and R 3 are the same as described above.
  • the present invention also provides a method for preparing a compound represented by Formula A14, which includes the following steps: Under the action of a catalyst, the compound represented by Formula A13 is subjected to the hydrogenation reaction shown below in an organic solvent to obtain The compound represented by formula A14 may be sufficient;
  • R 1 , R 2 and R 3 are the same as described above.
  • the present invention also provides a method for preparing a compound represented by Formula A15, which includes the following steps: under the action of a reducing agent, the compound represented by Formula A14 is subjected to the reduction reaction shown below in an organic solvent to obtain The compound represented by formula A15 is sufficient;
  • R 1 , R 2 and R 3 are the same as described above.
  • the present invention also provides a method for preparing a compound represented by Formula A, which includes the following steps: under the action of an oxidizing agent, the compound represented by Formula A15 is subjected to the oxidation reaction shown below in an organic solvent to obtain The compound represented by formula A is sufficient;
  • R 1 and R 2 are the same as described above.
  • the present invention also provides a compound represented by formula A6:
  • R 1 , R 2 and R 4 are the same as described above.
  • the present invention also provides a compound represented by formula A7:
  • R 1 , R 2 , R 3 and R 4 are the same as described above.
  • the present invention also provides a compound represented by formula A8a-I:
  • R 1 , R 2 , R 3 and R 4 are the same as described above.
  • the present invention also provides a compound represented by formula A8b:
  • R 1 , R 2 and R 3 are the same as described above.
  • the present invention also provides a compound represented by formula A9:
  • R 1 , R 2 and R 3 are the same as described above.
  • the present invention also provides a compound represented by formula A10:
  • R 1 , R 2 and R 3 are the same as described above.
  • the invention also provides a compound represented by formula A11:
  • R 1 , R 2 and R 3 are the same as described above.
  • the present invention also provides a compound represented by formula A12:
  • R 1 , R 2 and R 3 are the same as described above.
  • the present invention also provides a compound represented by formula A13:
  • R 1 , R 2 and R 3 are the same as described above.
  • the present invention also provides a compound represented by formula A14:
  • R 1 , R 2 and R 3 are the same as described above.
  • the invention also provides a compound represented by formula A15:
  • R 1 and R 2 are the same as described above.
  • the present invention also provides a compound represented by formula A8a-IV:
  • R 1 , R 2 and R 4 are the same as described above.
  • the present invention also provides a compound represented by formula A8a-III:
  • R 1 , R 2 and R 4 are the same as described above.
  • the present invention also provides a compound represented by formula A8a-II:
  • R 1 and R 2 are the same as described above.
  • the present invention also provides a compound represented by formula A7:
  • R 1 , R 2 , R 3 and R 4 are the same as described above.
  • the compounds represented by formula A7, A8a-I, A8a-II, A8a-III, A8a-IV, A8b, A9, A10, A11, A12, A13, A14 or A15 are preferably the following compounds:
  • the chemical bond It means that the group connected to the chiral carbon atom can be above or below the plane, such as a compound Express or
  • the preparation methods of the above compounds can be combined arbitrarily to obtain the synthetic routes of the compounds represented by formulas A6, A7, A8a-I, A8a-III, A9, A10, A11, A12, A13, A14, A15, or A A5 ⁇ A6 ⁇ A7 ⁇ A8a-I, A6 ⁇ A7 ⁇ A8a-I, A6 ⁇ A8a-IV ⁇ A8a-III, A5 ⁇ A6 ⁇ A7 ⁇ A8a-I ⁇ A9, A6 ⁇ A8a-IV ⁇ A8a-III ⁇ A8a-II ⁇ A9, A9 ⁇ A10 ⁇ A11 ⁇ A12 ⁇ A13 ⁇ A14 ⁇ A15 ⁇ A, A5 ⁇ A6 ⁇ A8a-IV ⁇ A8a-III ⁇ A8a-II ⁇ A9 ⁇ A10 ⁇ A11 ⁇ A12 ⁇ A13 ⁇ A14 ⁇ A15 ⁇ A
  • both "C 1-10 alkyl” and “C 1-4 alkyl” include straight-chain alkyl and branched-chain alkyl.
  • alkoxy refers to the group -OR X , where R X is an alkyl group as defined above.
  • cycloalkyl refers to a monovalent saturated cyclic alkyl group, preferably a monovalent saturated cyclic alkyl group having 3 to 7 ring carbon atoms, more preferably 3 to 6 carbon atoms, such as cyclopropyl , Cyclobutyl, cyclopentyl or cyclohexyl.
  • aryl refers to a group having a 4n + 2 aromatic ring system (for example, 6, 10, or 14 shared p electrons in a cyclic array).
  • Aryl groups with 6 to 14 carbon atoms are preferred, such as phenyl, naphthyl, phenanthrenyl, or anthracenyl.
  • reagents of the present invention such as the phosphine ligands represented by formulas L1-2 and the ligands represented by formulas L3-4 are self-made, and other reagents and raw materials are commercially available.
  • the positive progress effect of the present invention is that the preparation method of the present invention uses common reagents as starting materials to prepare oxycodone compounds, which has high yield and simple operation.
  • Example 1 Compound represented by formula A2-1 (2- (4-((tert-butyldiphenylsilyl) oxy) -3-methoxyphenyl) ethan-1-amine)
  • ammonium acetate 9.1 g, 118 mmol was divided into three equal batches and slowly added to a solution of vanillin (15 g, 98.5 mmol) in nitromethane (1.0 g, 1.93 mmol, 1.0 equiv).
  • the reaction mixture was stirred at 100 ° C for 3 hours, then cooled down and spin-dried.
  • the resulting solution was extracted three times with a saturated solution of ammonium chloride and dichloromethane (300 mL), the organic phase was taken, the combined organic phase was dried over sodium sulfate, and methanol (30 mL) was recrystallized to obtain the product as a yellow solid. step.
  • tert-butyldiphenylchlorosilane (25.7g, 93.6mmol) was divided into three equal batches and slowly added to the product of the previous step and a solution of imidazole (6.4g, 93.6mmol) in dichloromethane (135mL) in.
  • the reaction mixture was stirred at 20 ° C for 6 hours.
  • the system was extracted three times with a saturated solution of ammonium chloride and dichloromethane (200 mL), the organic phase was taken, the combined organic phase was dried over sodium sulfate, and methanol (40 mL) was recrystallized to obtain the product as a yellow solid (14.3 g , 75% yield).
  • lithium aluminum hydride (4 g, 105 mmol) was divided into three equal batches and slowly added to a solution of A-1 (15 g, 35 mmol) in anhydrous tetrahydrofuran (100 mL). The reaction mixture was stirred at 20 ° C for 50 minutes. The system was extracted three times with a saturated solution of potassium sodium tartrate and ethyl acetate (100 mL), the organic phase was taken, the combined organic phase was dried over sodium sulfate, concentrated and purified by column chromatography to obtain the product as a pale yellow oil (7.7g, 55% yield).
  • Example 2 The compound represented by formula A5-1 (2- (3- (benzyloxy) –2–bromo–4-methoxyphenyl) acetic acid)
  • potassium carbonate (10.8g, 77.4mmol) was divided into three equal batches and added to A-3 (12g, 51.6mmol) and benzyl bromide (6.7mL) in dimethylformamide (120mL) In solution.
  • the reaction mixture was stirred at 20 ° C for 8 hours.
  • the system was extracted three times with a saturated solution of sodium chloride and dichloromethane (150 mL), the organic phase was taken, the combined organic phase was dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a white solid (15.8 g, 95% yield).
  • ruthenium trichloride 830 mg, 4 mmol was divided into three equal batches and added to methylene chloride, A-4 (11.8 g, 33.6 mmol) and sodium periodate (14.6 g, 67.2 mmol), Water, acetonitrile (300mL, 1: 1: 1) solution.
  • the reaction mixture was stirred at 20 ° C for 0.5 hour.
  • the system was extracted three times with a saturated solution of sodium chloride and dichloromethane (250 mL), the organic phase was taken, the combined organic phase was dried over sodium sulfate, concentrated and purified by column chromatography to obtain the product as a white oil ( 10.7g, 87% yield).
  • Example 3 Compound represented by formula A6-1 (2- (3- (benzyloxy) -2-bromo-4-methoxyphenyl)-N- (4-((tert-butyldiphenylsilyl) oxy) -3-methoxyphenethyl) acetamide )
  • dicyclohexylcarbodiimide (3.2g, 15mmol) and 4-dimethylaminopyridine (1.4mg, 15mmol) were divided into three equal batches and added to A5 (4.52g, 12.8mmol) and A -2 (6g, 14.8mmol) in dichloromethane (60mL) solution.
  • the reaction mixture was stirred at 20 ° C for 30 hours.
  • the system was extracted three times with a saturated solution of sodium chloride and dichloromethane (150 mL), the organic phase was taken, the combined organic phase was dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a white solid (9.03 g, 95% yield).
  • Example 4 Compound represented by formula A7-1 (Methyl (Z) -1- (3- (benzyloxy) –2–bromo-4-methoxybenzylidene) -7-((tert-butyldiphenylsilyl) oxy) -6–methoxy -3,4-dihydroisoquinoline-2 (1H) -carboxylate)
  • methyl chloroformate (0.24 g, 2.6 mmol) was divided into three equal batches and added to the previous step product and triethylamine (0.39 g, 3.9 mmol) in dichloromethane (50 mL).
  • the reaction mixture was stirred at 20 ° C for 1 hour.
  • the system was extracted three times with a saturated solution of sodium chloride and dichloromethane (150 mL), the organic phase was taken, the combined organic phase was dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a white solid (9.03 g, 95% yield).
  • Example 5 The compound represented by formula A8a-I-1 (Methyl (R) –1- (3- (benzyloxy) –2–bromo–4-methoxybenzyl) -7-hydroxy-6-methoxy-3,4- Dihydroisoquinoline-2 (1H) -carboxylate)
  • Example 7 Compound represented by formula A9-1 (Methyl (4bS, 9R) -4- (benzyloxy) -3,6-dimethoxy-7--oxo-9,10--dihydro-7H-9,4b- (epiminoethano ) phenanthrene-11-carboxylate)
  • Example 8 Compound represented by formula A10-1 (Methyl (4bS, 9R) -4-hydroxy-3,6-dimethoxy-7-oxo-9,10-dihydro-7H-9,4b- (epiminoethano) Phenanthrene –11-carboxylate)
  • Example 9 Compound represented by formula A11-1 (Methyl (4bS, 9R) -4,7-dihydroxy-3,6-dimethoxy-9,10-dihydro-7H-9,4b- (epiminoethano) Phenanthrene-11 –Carboxylate)
  • Example 10 The compound represented by formula A12-1 (Methyl (4R, 7aR, 12bS) -7,9-dimethoxy-1,2,4,7a-tetrahydro-3H-4,12-methanobenzofuro [3,2- e] isoquinoline-3-carboxylate)
  • N, N-dimethylformamide dimethyl acetal (213.9 mg, 2 mmol) was divided into three equal batches and added to A11-1 (67 mg, 0.2 mmol) in anhydrous Methylene chloride (2 mL) in the mixture.
  • the reaction mixture was stirred at 0 ° C for 8 hours.
  • the system was extracted three times with a saturated solution of sodium chloride and dichloromethane (25 mL), the organic phase was taken, the combined organic phase was dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a white oil ( 55 mg, 86% yield).
  • Example 12 The compound represented by formula A14-1 (Methyl (4R, 4aS, 7aR, 12bS) -4a--hydroxyl-9-methoxy-7-oxo-1,2,4,4a, 5,6,7, 7a-octahydro-3H-4,12-Methanobenzofuro [3,2-e] isoquinoline-3-carboxylate)
  • Example 13 Compound represented by formula A15-1 ((4R, 4aS, 7aR, 12bS) -9-methoxy-3-methyl-1,2,3,4,5,6,7,7a-octahydro-4aH -4,12-methanobenzofuro [3,2-e] isoquinoline-4a, 7-diol)
  • lithium aluminum hydride (27.5 mg, 0.71 mmol) was divided into three equal batches and slowly added to a solution of A14-1 (43 mg, 0.12 mmol) in anhydrous tetrahydrofuran (5 mL). The reaction mixture was stirred at 20 ° C for 2 hours. The system was extracted three times with a saturated solution of potassium sodium tartrate and ethyl acetate (10 mL), the organic phase was taken, the combined organic phase was dried over sodium sulfate, concentrated and purified by column chromatography to obtain the product as a pale yellow oil (17 mg, 70% yield).
  • Example 14 Compound represented by formula A-1 ((4R, 4aS, 7aR, 12bS) -9-methoxy-3-methyl-1,2,3,4,5,6,7,7a-octahydro-4aH -4,12-methanobenzofuro [3,2-e] isoquinoline-4a, 7-diol)
  • the Dess-Martin oxidant (20 mg, 0.045 mmol) was divided into three equal batches and slowly added to a solution of A15-1 (10 mg, 0.03 mmol) in anhydrous dichloromethane (1 mL). The reaction mixture was stirred at 20 ° C for two hours. The system was extracted three times with a saturated solution of ammonium chloride and ethyl acetate (10 mL), the organic phase was taken, the combined organic phase was dried over sodium sulfate, concentrated and purified by column chromatography to obtain the product as a pale yellow oil (7 mg, 60% yield).
  • the compound L1-1 (1.83 g, 4.47 mmol, 1.0 equiv) was placed in a Schlenk tube, and after evacuating nitrogen three times, THF (20 mL) was added. To this reaction system, Ti (OiPr) 4 (2.6 mL, 8.94 mmol, 2.0 equiv) and PMHS (3.0 mL) were added. The reaction solution was placed in an oil bath at 60 ° C for 12 hours. After 31P NMR detected the reaction, it was cooled to room temperature under the protection of nitrogen, and most of the THF solvent was removed by an oil pump. A degassed 30% aqueous sodium hydroxide solution (25 mL) was added dropwise to the reaction system.
  • the ligand of formula L3 is obtained according to the preparation method of compound 1 in Example 1 of CN103087105A.
  • the device was placed in an ice bath at -50 ° C, and 176.9 mL (176.9 mmol, 1 equivalent) of tert-butyl magnesium chloride was extracted with a syringe, injected into a constant pressure dropping funnel, and slowly added dropwise. After the dropwise addition is completed, the ice bath device is removed and the room temperature is restored. After the temperature stabilized, react for 2h. 31 P-NMR was used to detect the reaction, and if the reaction was completed, the reaction was directly carried to the next step without separation.
  • the device was placed in an ice bath at -50 ° C, and 154.9 mL (154.9 mmol, 1.1 equivalent) of vinyl magnesium bromide was extracted with a syringe, injected into a constant pressure dropping funnel, and slowly added dropwise. After the dropwise addition is completed, the ice bath device is removed and the room temperature is restored. After the temperature stabilized, react for 2h. 31 P-NMR was used to detect the reaction, and if the reaction was completed, the reaction was directly carried to the next step without separation.
  • the device was cooled to room temperature, and then the system pH was adjusted to 1 with 2 mol / L HCl solution. Extract several times with ethyl acetate and water and concentrate the organic phase. The organic phase was dried with saturated brine and anhydrous sodium sulfate. Spin the organic phase. The organic phase was added with silica gel powder (200-300 mesh) to mix the sample, packed with pure ethyl acetate, loaded with dry method, and subjected to column chromatography with an eluent of ethyl acetate and methanol volume ratio of 20: 1 to collect the product. A yellow viscous liquid was obtained with a yield of 5.502 g and a yield of 27.5%.
  • reaction proceed to the next step.
  • the reaction system was lowered to 0 ° C, and 3 g of sulfur powder (93.7 mmol, 1.5 equivalents) was slowly added dropwise, and the reaction was performed at an external temperature of 0 ° C for 1 h.
  • TLC developing agent: petroleum ether and ethyl acetate volume ratio 2: 1, potassium permanganate developer color development
  • the chiral preparative column AD-H column was used for separation.
  • the specific method is:
  • reaction system was lowered to 0 ° C, and 36.9 mL of a 1M borane tetrahydrofuran solution (36.9 mmol, 1.2 equiv) was slowly added dropwise, and the reaction was performed at an external temperature of 0 ° C for 1 h.
  • TLC developing agent: petroleum ether and ethyl acetate volume ratio 6: 1, potassium permanganate developer color development
  • the compound A8a-IV-1 was prepared by referring to the preparation method of step 1) in the compound represented by formula A7-1 in Example 4.
  • the compound A8a-II-1 was prepared according to the method for preparing the compound represented by formula A8b-1 in Example 6.
  • the compound A8b-1 was prepared by referring to the synthesis method in step 2) of the compound represented by formula A7-1 in Example 4.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un composé d'oxycodone, un intermédiaire et son procédé de préparation. L'invention concerne spécifiquement un procédé de préparation d'un composé représenté par la formule A9, comprenant les étapes suivantes : sous un gaz protecteur, et sous l'action d'un catalyseur au palladium et d'un ligand phosphine, la désaromatisation et la cyclisation comme indiqué ci-après est effectuée sur un composé représenté par la formule A8b dans un solvant organique pour obtenir le composé représenté par la formule A9. Le ligand phosphine est un ligand phosphine représenté par la formule L1 ou un ligand phosphine représenté par la formule L2. (I)
PCT/CN2019/120322 2018-11-22 2019-11-22 Composé d'oxycodone, et intermédiaire et son procédé de préparation WO2020103945A1 (fr)

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CN114573508B (zh) * 2020-12-01 2024-07-23 绍兴赜军生物医药科技有限公司 羟考酮类化合物、其中间体及制备方法
CN113845478B (zh) * 2020-12-18 2023-11-21 四川大学 一种中间体及其制备方法和应用
AU2021398814A1 (en) * 2020-12-18 2023-06-01 Sichuan University Novel intermediate, preparation method for same, and applications thereof
WO2022127320A1 (fr) * 2020-12-18 2022-06-23 四川大学 Intermédiaire, son procédé de préparation et son utilisation
CN114423764B (zh) * 2020-12-18 2023-03-17 四川大学 一种中间体及其制备方法和应用
CN113956263B (zh) * 2021-12-06 2023-06-20 四川大学 一种吗啡衍生物丁丙诺啡的合成方法
CN114105875B (zh) * 2021-12-06 2023-11-03 四川大学 一种吗啡衍生物二氢埃托啡的合成方法
CN114057642B (zh) * 2021-12-10 2023-03-28 广东嘉博制药有限公司 一种米库氯铵中间体的合成方法

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