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WO2015032357A1 - Zanamivir, intermédiaire du zanamivir et procédé de synthèse - Google Patents

Zanamivir, intermédiaire du zanamivir et procédé de synthèse Download PDF

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Publication number
WO2015032357A1
WO2015032357A1 PCT/CN2014/086112 CN2014086112W WO2015032357A1 WO 2015032357 A1 WO2015032357 A1 WO 2015032357A1 CN 2014086112 W CN2014086112 W CN 2014086112W WO 2015032357 A1 WO2015032357 A1 WO 2015032357A1
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Prior art keywords
compound
preparing
solvent
producing
base
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English (en)
Chinese (zh)
Inventor
马大为
田峻山
钟建康
潘强彪
李运生
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LIANHE CHEMICAL TECHNOLOGY (TAIZHOU) Co Ltd
Shanghai Institute of Organic Chemistry of CAS
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LIANHE CHEMICAL TECHNOLOGY (TAIZHOU) Co Ltd
Shanghai Institute of Organic Chemistry of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
    • C07D317/36—Alkylene carbonates; Substituted alkylene carbonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

  • This invention relates to intermediates of zanamivir and ranamivir and methods for their synthesis.
  • Zanamivir (zanamivir) is the first type of neuraminidase inhibitor synthesized based on drug design. It and Oseltamivir (oseltamivir) are currently the only two approved on the market for the treatment of type A. And drugs of the influenza B virus. It was discovered by scientists at Biota in 1989 and was licensed to GlaxoSmithKline for clinical treatment in 1990. 1999 was approved by the FDA and listed in the US.
  • Laninamivir (Lanafinevir) is a neuraminidase inhibitor developed by Biota Pharmaceuticals and Daiichi Sankyo to treat influenza virus infections that are resistant to oseltamivir. People taking Laninamivir recovered more than 60 hours earlier than those who took Tamiflu. Laninamivir was approved in 2010 for listing under the name Inavir in Japan. Its octanoate CS-8958 was also launched in Japan in the same year.
  • the method the raw material N-acetylneuraminic acid, is not easy to obtain in large quantities and limits the application of the method.
  • the technical problem to be solved by the invention is to overcome the defects that the existing zanamivir synthesis route is long, the total yield is low, the atomic economy is poor, the operation is dangerous, the production cost is high, and it is not suitable for industrial production, and the like is provided.
  • Intermediates of amivir and lamamivir and methods for their synthesis The synthesis method of the invention has the advantages of low cost and easy availability, mild reaction conditions, short steps, high total yield, low production cost, good product purity, high chiral purity and good prospect of industrial production.
  • the invention provides a preparation method of the compound 2, which can adopt the method 1 or the method 2,
  • the method 1 includes the following steps: the compound 3 is subjected to a reaction for removing a protecting group to obtain a compound 2;
  • R is hydrogen or methyl
  • R 1 is trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilane Base (TIPS), methoxymethyl (MOM), methyl or hydrogen;
  • R 2 and R 5 are each independently methyl, ethyl or propyl;
  • R 4 is an amino protecting group such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or p-toluenesulfonyl (Ts).
  • the method 2 includes the following steps: subjecting the compound 35 to a hydrolysis reaction to obtain the compound 2;
  • R is hydrogen or methyl
  • the method 1 for preparing the compound 2 may employ a conventional method of the above-described reaction for removing a protecting group in the art, and particularly preferred in the present invention are the following reaction methods and conditions: in an aprotic solvent, in the presence of an acid, the compound is used. 3 to carry out the reaction of removing the protecting group to obtain the compound 2;
  • the aprotic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; and the chlorinated hydrocarbon solvent is preferably dichloromethane. .
  • the volume-mass ratio of the aprotic solvent to the compound 3 is preferably 0.1 mL/mg to 5 mL/mg, and more preferably 0.1 mL/mg to 1 mL/mg.
  • the acid is preferably a mineral acid and/or an organic acid; the inorganic acid is preferably hydrochloric acid; the organic acid is preferably trifluoroacetic acid; and the hydrochloric acid may be conventional in the art.
  • a commercially available hydrochloric acid reagent is preferably 10% to 37% by mass of hydrochloric acid, and the mass percentage means a percentage of the mass of hydrogen chloride to the total mass of the hydrochloric acid reagent.
  • the molar ratio of the compound 3 to the acid is preferably 1:1 to 1:100, further preferably 1:30 to 1:50.
  • the temperature of the reaction for removing the protecting group is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.
  • the progress of the reaction for removing the protecting group can be monitored by a conventional test method (such as TLC, HPLC or NMR) in the art, generally when the disappearance of the compound 3 is the end point of the reaction.
  • the reaction time is preferably from 1 h to 20 h, more preferably from 8 h to 10 h.
  • the method 1 for preparing the compound 2 further comprises the following steps, in the method 1 for preparing the compound 2, when R 1 is trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyl When diphenylsilyl (TBDPS), triisopropylsilyl (TIPS), methoxymethyl (MOM) or methyl, the compound 3 can be prepared by the following method 1; when R 1 is hydrogen When the compound 3 can be prepared by the following method 2; when R 1 is trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyl diphenyl silicon (TBDPS) , triisopropylsilyl (TIPS), methoxymethyl (MOM), methyl or hydrogen, the compound 3 can be prepared by the following method three;
  • Method 1 in a protic solvent, under acidic conditions, the compound 4 is oxidized with an oxidizing agent to obtain the compound 3;
  • Method 2 in aprotic solvent, the compound 12 and a reducing agent are reduced to obtain the compound 3;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the first method for preparing the compound 3 can employ a conventional method of the oxidation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the protic solvent is preferably an alcohol solvent and/or water; the alcohol solvent is preferably t-butanol; when a mixed solvent of t-butanol and water is used, the uncle
  • the volume ratio of t-butanol to water in the mixed solvent of butanol and water is preferably 10:1 to 1:1, further preferably 5:1 to 3:1.
  • the volume-mass ratio of the protic solvent to the compound 4 is preferably 20 mL/g to 300 mL/g, and more preferably 120 mL/g to 300 mL/g.
  • the oxidizing agent is preferably chlorous acid; and the chlorous acid is preferably obtained by reacting sodium chlorite with sodium dihydrogen phosphate.
  • the molar ratio of the compound 4 to the oxidizing agent is preferably 1:1 to 1:5, further preferably 1:3 to 1:4.
  • the acidic conditions are preferably achieved by the addition of a strong base weak acid salt.
  • the strong base weak acid salt is preferably sodium dihydrogen phosphate.
  • the molar ratio of the strong base weak acid salt to the compound 4 is preferably 1:1 to 20:1, further preferably 5:1 to 10:1.
  • the acidic condition is preferably pH 2-4.
  • the temperature of the oxidation reaction is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.
  • the progress of the oxidation reaction can be monitored by a conventional test method (such as TLC, HPLC or NMR) in the art, generally when the compound 4 disappears as the reaction end point, and the reaction time is preferably 1 h. ⁇ 24h, further preferably 2h-8h.
  • a conventional test method such as TLC, HPLC or NMR
  • the first method for preparing the compound 3 is preferably carried out in the presence of a radical scavenger, preferably 2-methylbutene or phenol.
  • a radical scavenger preferably 2-methylbutene or phenol.
  • the molar ratio of the radical scavenger to the compound 4 is preferably from 0.5:1 to 3:1, more preferably from 1:1 to 2:1.
  • the method 1 for preparing the compound 2 further comprises the following steps.
  • the compound 4 can be obtained by oxidizing the compound 5 with an oxidizing agent in an aprotic solvent. Reacting to obtain the compound 4;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the method for preparing the compound 4 can employ a conventional method of the oxidation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably 1,4-dioxane.
  • the volume-to-mass ratio of the aprotic solvent to the compound 5 is preferably 20 mL/g to 300 mL/g, and more preferably 150 mL/g to 300 mL/g.
  • the oxidizing agent is preferably selenium dioxide.
  • the molar ratio of the compound 5 to the oxidizing agent is preferably 1:1 to 1:5, more preferably 1:2 to 1:3.
  • the temperature of the oxidation reaction is preferably from 30 ° C to 100 ° C, more preferably from 60 ° C to 100 ° C, still more preferably from 35 ° C to 80 ° C, and most preferably from 40 ° C to 80 ° C.
  • the progress of the oxidation reaction can be monitored by a conventional test method (such as TLC, HPLC or NMR) in the art, and generally, when the compound 5 disappears, the reaction end time is preferably 1 h. 5h, further preferably 2h to 3h.
  • a conventional test method such as TLC, HPLC or NMR
  • the process for preparing the compound 4 is preferably carried out under the protection of an inert gas, preferably one or more of nitrogen, argon and helium.
  • the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 4, the compound 5 can be obtained by the method of: in a solvent, in the presence of a base, the compound 6 and acetyl The nucleophilic substitution reaction is carried out to obtain the compound 5;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the method for preparing the compound 5 can employ a conventional method of nucleophilic substitution reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the solvent is preferably a halogenated hydrocarbon solvent and/or an organic base;
  • the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; and
  • the chlorinated hydrocarbon solvent is preferably dichloromethane.
  • the organic base is preferably one or more of pyridine, piperidine and triethylamine.
  • the base is preferably an organic base, and the organic base is preferably one or more of pyridine, piperidine and triethylamine.
  • the molar ratio of the compound 6 to the base is preferably 1:3 to 1:6, more preferably 1:4 to 1:5.
  • the acetylating agent is an acetylating agent having an acetyl group commonly used in such a nucleophilic substitution reaction, preferably an acetyl halide and/or acetic anhydride; the acetyl halide is preferably B. Acid chloride or acetyl bromide.
  • the molar ratio of the compound 6 to the acetylating agent is preferably 1:1 to 1:20, further preferably 1:1 to 1:3, still more preferably 1:1 to 1 :1.1.
  • the temperature of the nucleophilic substitution reaction is preferably 0 ° C to 100 ° C, and more preferably 0 ° C to 60 ° C.
  • the progress of the nucleophilic substitution reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, generally when the compound 6 disappears as the reaction end point, the reaction
  • the time is preferably from 1 h to 24 h, more preferably from 2 h to 3 h.
  • the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 5, the compound 6 can be obtained by the following method: in an aprotic solvent, under the action of an acid and a reducing agent , the compound 7 is subjected to a reduction reaction to obtain the compound 6;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the aprotic solvent is preferably an ester solvent; and the ester solvent is preferably ethyl acetate.
  • the volume-to-mass ratio of the aprotic solvent to the compound 7 is preferably 20 mL/g to 200 mL/g, and more preferably 90 mL/g to 120 mL/g.
  • the acid is preferably an organic acid; and the organic acid is preferably glacial acetic acid.
  • the molar ratio of the acid to the compound 7 is preferably from 10:1 to 100:1, further preferably from 60:1 to 100:1.
  • the reducing agent is preferably one or more of zinc, iron and aluminum.
  • the molar ratio of the reducing agent to the compound 7 is preferably 10:1 to 100:1, further preferably 60:1 to 100:1.
  • the temperature of the reduction reaction is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.
  • the progress of the reduction reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, and the reaction time is preferably 1 h to 20 h when the compound 7 disappears. Further, it is preferably 10 h to 15 h.
  • a conventional test method such as TLC, NMR or HPLC
  • the method for producing the compound 6 is preferably carried out by the following steps: a solution of the compound 7 and an aprotic solvent is added to the reducing agent and the acid in order to carry out a reduction reaction to obtain a compound 6.
  • the method for preparing the compound 6 preferably includes the following post-treatment step: after the end of the reaction, the base is adjusted to pH about 7, the extract is concentrated, and the column chromatography is carried out to obtain the compound 6.
  • the alkali is preferably an organic base, and the organic base is preferably aqueous ammonia; the aqueous ammonia may be a conventional commercially available aqueous ammonia reagent, and the aqueous ammonia reagent preferably has a mass percentage of 5% to 50%, more preferably 15%. 40%, the mass percentage refers to the mass of ammonia gas as a percentage of the total mass of the aqueous ammonia solution.
  • the solvent used for the extraction is preferably an ester solvent, and the ester solvent is preferably ethyl acetate.
  • the column chromatography separation method can employ a conventional method of such operation in the art.
  • the method 1 for preparing the compound 2 further comprises the following steps.
  • the compound 7 can be obtained by the following method: in an organic solvent, in the presence of a base, the compound 8 is Dehydrating agent is subjected to a dehydration reaction to obtain the compound 7;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the method for preparing the compound 7 can employ a conventional method of dehydration reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the organic solvent is preferably one or more of an ether solvent, a halogenated hydrocarbon solvent, and an aromatic hydrocarbon solvent; further preferably an ether solvent and/or a halogenated hydrocarbon solvent;
  • the ether solvent is preferably tetrahydrofuran;
  • the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent;
  • the chlorinated hydrocarbon solvent is preferably dichloromethane;
  • the aromatic hydrocarbon solvent is preferably toluene.
  • the volume-to-mass ratio of the organic solvent to the compound 8 is preferably 20 mL/g to 200 mL/g, and more preferably 100 mL/g to 150 mL/g.
  • the base is preferably an organic base; the organic base is preferably triethylamine and/or pyridine.
  • the molar ratio of the base to the compound 8 is preferably from 100:1 to 1:1, further preferably from 50:1 to 1:1.
  • the dehydrating agent is preferably dichlorosulfoxide, methanesulfonyl chloride and Burgess reagent (Burgess reagent means methyl N-(triethylammoniumsulfonylcarbamate, ie N-(triethylammoniumsulfonyl)carbamate)
  • Burgess reagent means methyl N-(triethylammoniumsulfonylcarbamate, ie N-(triethylammoniumsulfonyl)carbamate
  • the molar ratio of the compound 8 to the dehydrating agent is preferably 1:1 to 1:5, more preferably 1:2 to 1:3.
  • the temperature of the dehydration reaction is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.
  • the progress of the dehydration reaction can be carried out by a conventional tester in the art.
  • the method is monitored by a method such as TLC, NMR or HPLC.
  • the reaction time is preferably 1 h to 5 h, more preferably 1 h to 3 h.
  • the process for preparing the compound 7 is preferably carried out in the presence of a catalyst, preferably 4-dimethylaminopyridine (DMAP).
  • a catalyst preferably 4-dimethylaminopyridine (DMAP).
  • DMAP 4-dimethylaminopyridine
  • the molar ratio of the catalyst to the compound 8 is preferably 1:1 to 1:10, more preferably 1:1 to 1:5.
  • the method for producing the compound 7 preferably employs the step of sequentially adding a catalyst and a dehydrating agent to a solution of the compound 8, a base and an organic solvent, followed by dehydration to obtain the compound 7.
  • the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 7, the compound 8 can be obtained by the following method: in an aprotic solvent, a base, a catalyst and a catalyst ligand are present. Under the conditions, the compound 10 and the compound 9 are reacted to obtain the compound 8;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the method for preparing the compound 8 can employ a conventional method of the reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.
  • the volume-to-mass ratio of the aprotic solvent to the compound 9 is preferably 1 mL/g to 50 mL/g, and more preferably 1 mL/g to 10 mL/g.
  • the base is preferably an inorganic base; and the inorganic base is preferably one or more of cesium carbonate, sodium carbonate, potassium carbonate and potassium t-butoxide.
  • the molar ratio of the compound 9 to the base is preferably 1:1 to 10:1, further preferably 1:1 to 3:1.
  • the catalyst is preferably an inorganic copper salt and/or an organic copper salt;
  • the inorganic copper salt refers to a salt formed by reacting copper with an inorganic acid;
  • the organic copper salt refers to copper and A salt formed by the reaction of an organic acid.
  • the inorganic copper salt is preferably one or more of copper chloride, cuprous chloride, cuprous bromide, copper bromide and cuprous iodide, further preferably copper bromide and/or copper chloride;
  • the organic copper salt is preferably copper acetate.
  • the molar ratio of the compound 9 to the catalyst is preferably 1:1 to 10:1. More preferably, it is 3:1 - 10:1.
  • the molar ratio of the compound 10 to the compound 9 is preferably 1:1 to 5:1, further preferably 2:1 to 5:1.
  • the catalyst ligand is preferably a pyrrolidine-phenol catalyst; the pyrrolidine-phenol catalyst is preferably
  • the molar ratio of the catalyst ligand to the compound 9 is preferably from 1:10 to 3:10, further preferably from 2:10 to 3:10.
  • the temperature of the reaction is preferably -20 ° C to 40 ° C, more preferably -20 ° C to 30 ° C.
  • the progress of the reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, generally when the disappearance of the compound 9 is the end of the reaction, and the reaction time is preferably 24 h to 96 h. Further, it is preferably 24h to 48h.
  • a conventional test method such as TLC, NMR or HPLC
  • the catalyst ligand It can be synthesized by the method reported in the literature Chem. Eur. J. 2012, 18, 12357.
  • the compound 9 can be synthesized by the method reported in Tetrahedron: Asymmetry. 1998, 9, 1359 - 1367.
  • the second method for preparing the compound 3 can employ a conventional method of the reduction reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.
  • the volume-to-mass ratio of the aprotic solvent to the compound 12 is preferably from 10 mL/g to 500 mL/g, more preferably from 400 mL/g to 500 mL/g.
  • the reducing agent is preferably zinc borohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride or lithium borohydride.
  • the molar ratio of the compound 12 to the reducing agent is preferably 1:1. 1:5, further preferably 1:1 to 1:3.
  • the temperature of the reduction reaction is preferably -78 ° C to 40 ° C, and more preferably 20 ° C to 30 ° C.
  • the progress of the reduction reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, generally when the compound 12 disappears as the reaction end point, and the reaction time is preferably 1 h. ⁇ 12h, further preferably 4h to 10h.
  • a conventional test method such as TLC, NMR or HPLC
  • the method 1 for preparing the compound 2 further comprises the following steps.
  • the compound 12 can be produced by the following method: in a protic solvent, under the acidic condition, the compound 13 and the oxidizing agent Performing an oxidation reaction to obtain the compound 12;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the method for preparing the compound 12 can employ a conventional method of the oxidation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the protic solvent is preferably an alcohol solvent and/or water; the alcohol solvent is preferably t-butanol; when a mixed solvent of t-butanol and water is used, the tert-butyl
  • the volume ratio of t-butanol to water in the mixed solvent of alcohol and water is preferably 10:1 to 1:1, further preferably 5:1 to 3:1.
  • the volume-to-mass ratio of the protic solvent to the compound 13 is preferably 20 mL/g to 300 mL/g, and more preferably 200 mL/g to 300 mL/g.
  • the oxidizing agent is preferably chlorous acid; the chlorous acid is preferably obtained by reacting sodium chlorite with sodium dihydrogen phosphate.
  • the molar ratio of the compound 13 to the oxidizing agent is preferably 1:1 to 1:5, more preferably 1:2 to 1:3.
  • the acidic conditions are preferably achieved by the addition of a strong base weak acid salt, preferably sodium dihydrogen phosphate.
  • a strong base weak acid salt preferably sodium dihydrogen phosphate.
  • the molar ratio of the strong base weak acid salt to the compound 13 is preferably 1:1 to 20:1, further preferably 5:1 to 10:1.
  • the acidic condition is preferably pH 2-4.
  • the temperature of the oxidation reaction is preferably from 10 ° C to 40 ° C, further preferably 20 ° C ⁇ 30 ° C.
  • the progress of the oxidation reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, and generally, when the compound 13 disappears, the reaction end is preferably 1 h. 24h, further preferably 2h-8h.
  • the method of preparing the compound 12 is preferably carried out in the presence of a radical scavenger, preferably 2-methylbutene or phenol.
  • a radical scavenger preferably 2-methylbutene or phenol.
  • the molar ratio of the radical scavenger to the compound 13 is preferably from 0.5:1 to 3:1, more preferably from 1:1 to 2:1.
  • the method 1 for preparing the compound 2 further comprises the following steps.
  • the compound 13 can be produced by oxidizing the compound 14 with an oxidizing agent in an aprotic solvent. Obtaining the compound 13;
  • R 2 , R 4 and R 5 are as defined above.
  • the method for producing the compound 13 can employ a conventional method of the oxidation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably 1,4-dioxane.
  • the volume-to-mass ratio of the aprotic solvent to the compound 14 is preferably 20 mL/g to 300 mL/g, and more preferably 150 mL/g to 300 mL/g.
  • the oxidizing agent is preferably selenium dioxide.
  • the molar ratio of the compound 14 to the oxidizing agent is preferably 1:1 to 1:5, more preferably 1:2 to 1:3.
  • the temperature of the oxidation reaction is preferably from 80 ° C to 150 ° C, more preferably from 100 ° C to 140 ° C.
  • the progress of the oxidation reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, and the reaction time is preferably 1 h to 5 h when the compound 14 disappears. Further, it is preferably 2h to 4h.
  • the process for preparing compound 13 is preferably carried out under the protection of an inert gas, preferably nitrogen or argon.
  • an inert gas preferably nitrogen or argon.
  • One or more of the suffocating gases are preferably carried out under the protection of an inert gas, preferably nitrogen or argon.
  • the method 1 for preparing the compound 2 further comprises the following steps, in the method for preparing the compound 13, the compound 14 can be obtained by the following method: the compound 15 is subjected to an oxidation reaction to obtain the compound 14;
  • R 2 , R 4 and R 5 are as defined above.
  • the method for preparing the compound 14 may employ a conventional method of the oxidation reaction in the art.
  • Ley's oxidation is particularly preferably used; the Ley's oxidation may be in the art.
  • the conventional method of Ley's oxidation in the present invention, the following reaction methods and conditions are particularly preferred: the compound 15 and the oxidizing agent are subjected to a Lewis oxidation reaction in the presence of a catalyst in an organic solvent to obtain a compound 14 .
  • the organic solvent is preferably a halogenated hydrocarbon solvent and/or a nitrile solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; and the chlorinated hydrocarbon solvent is preferably used.
  • the volume ratio of dichloromethane to acetonitrile in the mixed solvent is preferably 20:1 to 1:1, further preferably 15:1 to 10:1.
  • the volume-to-mass ratio of the organic solvent to the compound 15 is preferably 20 mL/g to 200 mL/g, and more preferably 150 mL/g to 200 mL/g.
  • the oxidizing agent is preferably N-methylmorpholine oxide (CAS: 7529-22-8, English name is 4-Methylmorpholine N-oxide).
  • the molar ratio of the compound 15 to the oxidizing agent is preferably 1:1 to 1:5, further preferably 1:1 to 1:2.
  • the catalyst is preferably tetra-n-propylammonium perruthenate (TPAP).
  • the molar ratio of the compound 15 to the catalyst is preferably from 20:1 to 5:1, further preferably from 10:1 to 15:1.
  • the temperature of the Leyd oxidation reaction is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.
  • the progress of the oxidation reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, generally when the compound 15 disappears as the reaction end point.
  • the reaction time is preferably 5 h to 20 h, and more preferably 8 h to 12 h.
  • the method for preparing the compound 14 is preferably carried out in the presence of a molecular sieve; the molecular sieve is preferably Molecular sieves.
  • the mass molar ratio of the molecular sieve to the compound 15 is preferably from 1 g/mol to 5 g/mol, further preferably from 1 g/mol to 2 g/mol.
  • the method 1 for preparing the compound 2 further comprises the following steps.
  • the compound 15 can be produced by removing the hydroxyl group from the compound 16 and the fluorinating reagent in a solvent. a reaction of the group to obtain the compound 15;
  • R 3 is a hydroxy protecting group such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyl Phenylsilyl (TBDPS), triisopropylsilyl (TIPS) or methoxymethyl (MOM).
  • TMS trimethylsilyl
  • TBS tert-butyldimethylsilyl
  • TDPS tert-butyl Phenylsilyl
  • TIPS triisopropylsilyl
  • MOM methoxymethyl
  • the method for producing the compound 15 can employ a conventional method of the reaction for removing a hydroxy protecting group in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.
  • the volume-to-mass ratio of the solvent to the compound 15 is preferably from 1 mL/g to 100 mL/g, and more preferably from 50 mL/g to 100 mL/g.
  • the fluorinating agent is preferably tetrabutylammonium fluoride and/or potassium fluoride.
  • the molar ratio of the compound 16 to the fluorinating agent is preferably 1:1 to 1:5, more preferably 1:1 to 1:2.
  • the temperature of the reaction for removing the hydroxy protecting group is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.
  • the progress of the reaction for removing the hydroxy protecting group can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, generally when the compound 16 disappears as the reaction end point.
  • the reaction time is preferably from 1 h to 5 h, more preferably from 2 h to 3 h.
  • the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 15, the compound 16 can be produced by subjecting the compound 17 to acetylation in a solvent in the presence of a base.
  • the reagent is subjected to a nucleophilic substitution reaction to obtain the compound 16;
  • R 2 , R 3 , R 4 and R 5 are as defined above.
  • the solvent is preferably a halogenated hydrocarbon solvent and/or an organic base;
  • the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; and
  • the chlorinated hydrocarbon solvent is preferably dichloromethane.
  • the organic base is preferably one or more of pyridine, piperidine and triethylamine.
  • the base is preferably an organic base, and the organic base is preferably one or more of pyridine, piperidine and triethylamine.
  • the molar ratio of the compound 17 to the base is preferably 1:1 to 1:5, further preferably 1:1 to 1:4.
  • the acetylating agent is an acetylating agent having an acetyl group commonly used in such a nucleophilic substitution reaction, preferably an acetyl halide and/or acetic anhydride, further preferably acetic anhydride;
  • the acetyl halide is preferably acetyl chloride or acetyl bromide.
  • the molar ratio of the compound 17 to the acetylating agent is preferably 1:1 to 1:20; when the acetylating agent is an acetyl halide, the compound 17 is as described
  • the molar ratio of the acetylating agent is preferably 1:1 to 1:3, further preferably 1:1 to 1:1.5.
  • the temperature of the nucleophilic substitution reaction is preferably 0 ° C to 100 ° C, and more preferably 0 ° C to 60 ° C.
  • the progress of the nucleophilic substitution reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, generally when the disappearance of the compound 17 is the end point of the reaction, and the reaction time is preferably 1h to 24h, further preferably 8h to 12h.
  • a conventional test method such as TLC, NMR or HPLC
  • the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 16, the compound 17 can be obtained by the following method: in an aprotic solvent, under the action of an acid and a reducing agent , the compound 18 is subjected to a reduction reaction to obtain the compound 17;
  • R 2 , R 3 , R 4 and R 5 are as defined above.
  • the aprotic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; and the chlorinated hydrocarbon solvent is preferably dichloromethane.
  • the volume-to-mass ratio of the aprotic solvent to the compound 18 is preferably from 1 mL/g to 200 mL/g, and more preferably from 30 mL/g to 50 mL/g.
  • the acid is preferably an organic acid; and the organic acid is preferably glacial acetic acid.
  • the molar ratio of the acid to the compound 18 is preferably from 10:1 to 100:1, further preferably from 40:1 to 100:1.
  • the reducing agent is preferably one or more of zinc, iron and aluminum.
  • the molar ratio of the reducing agent to the compound 18 is preferably from 10:1 to 100:1, further preferably from 40:1 to 100:1.
  • the temperature of the reduction reaction is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.
  • the progress of the reduction reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, and generally, when the compound 18 disappears, the reaction end is preferably 1 h. 20h, further preferably 12h to 18h.
  • a conventional test method such as TLC, NMR or HPLC
  • the method for producing the compound 17 is preferably carried out by the following steps: a solution of the compound 18 and an aprotic solvent, followed by a reducing agent and an acid, followed by a reduction reaction to obtain the compound 17.
  • the method for preparing the compound 17 preferably includes the following post-treatment step: after the end of the reaction, the base is adjusted to pH about 7, the extract is concentrated, and the column chromatography is carried out to obtain the compound 17.
  • the alkali is preferably an organic base, and the organic base is preferably aqueous ammonia; the aqueous ammonia may be a conventional commercially available aqueous ammonia reagent, and the aqueous ammonia reagent preferably has a mass percentage of 5% to 50%, further preferably 15%. ⁇ 40%, the mass percentage refers to the percentage of the mass of ammonia gas to the total mass of the aqueous ammonia solution.
  • the solvent used for the extraction is preferably an ester solvent, and the ester solvent is preferably ethyl acetate.
  • the column chromatography separation method can employ a conventional method of such operation in the art.
  • the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 17, the compound 18 can be obtained by the following method: in an organic solvent, in the presence of a base, the compound 19 Dehydrating with a dehydrating agent to obtain the compound 18;
  • R 2 , R 3 , R 4 and R 5 are as defined above.
  • the method for producing the compound 18 can employ a conventional method of dehydration reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the organic solvent is preferably one or more of an ether solvent, a halogenated hydrocarbon solvent, and an aromatic hydrocarbon solvent; further preferably an ether solvent and/or a halogenated hydrocarbon solvent;
  • the ether solvent is preferably tetrahydrofuran;
  • the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent;
  • the chlorinated hydrocarbon solvent is preferably dichloromethane;
  • the aromatic hydrocarbon solvent is preferably toluene.
  • the volume-mass ratio of the organic solvent to the compound 19 is preferably 20 mL/g to 200 mL/g, and more preferably 100 mL/g to 150 mL/g.
  • the dehydrating agent is preferably dichlorosulfoxide, methanesulfonyl chloride and Burgess reagent (Burgess reagent means methyl N-(triethylammoniumsulfonylcarbamate, N-(triethylammoniumsulfonyl)carbamate)
  • Burgess reagent means methyl N-(triethylammoniumsulfonylcarbamate, N-(triethylammoniumsulfonyl)carbamate
  • the molar ratio of the compound 19 to the dehydrating agent is preferably 1:1 to 1:5, more preferably 1:2 to 1:3.
  • the base is preferably an organic base; and the organic base is preferably triethylamine and/or pyridine.
  • the molar ratio of the base to the compound 19 is preferably 1:1 to 50:1; for example, 1:1 to 10:1, and further, for example, 3:1 to 6:1.
  • the temperature of the dehydration reaction is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.
  • the progress of the dehydration reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, and generally, when the compound 19 disappears, the reaction end is preferably 1 h. 20h, further preferably 8h to 15h.
  • a conventional test method such as TLC, NMR or HPLC
  • the process for the preparation of the compound 18 is preferably carried out in the presence of a catalyst, preferably 4-dimethylaminopyridine (DMAP, CAS: 1122-58-3, English name 4-Dimethylaminopyridine).
  • a catalyst preferably 4-dimethylaminopyridine (DMAP, CAS: 1122-58-3, English name 4-Dimethylaminopyridine).
  • DMAP 4-dimethylaminopyridine
  • CAS CAS: 1122-58-3
  • English name 4-Dimethylaminopyridine 4-dimethylaminopyridine
  • the method for preparing the compound 18 preferably comprises the steps of: sequentially adding 4-dimethylaminopyridine (DMAP) and methanesulfonyl chloride to a solution of the compound 19, triethylamine and an organic solvent, followed by dehydration to obtain the compound.
  • DMAP 4-dimethylaminopyridine
  • methanesulfonyl chloride a solution of the compound 19, triethylamine and an organic solvent
  • the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 18, the compound 19 can be obtained by the following method: in an aprotic solvent, in the presence of a basic substance, Compound 10 is reacted with compound 20 to obtain the compound 19;
  • R 2 , R 3 , R 4 and R 5 are as defined above.
  • the method for producing the compound 19 can employ a conventional method of the reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the aprotic solvent is preferably an ether solvent solvent; and the ether solvent is preferably tetrahydrofuran.
  • the volume-to-mass ratio of the aprotic solvent to the compound 10 is preferably from 1 mL/g to 50 mL/g, and more preferably from 30 mL/g to 50 mL/g.
  • the basic substance may be a basic substance conventionally known in the art (ie, a substance having a pH greater than 7); preferably an inorganic base, an organic base, a basic oxide, or a strong base is weak.
  • a basic substance conventionally known in the art ie, a substance having a pH greater than 7
  • an inorganic base preferably sodium methoxide and/or potassium t-butoxide
  • the organic base is preferably tetrabutylammonium hydroxide or 1,8-diazabicyclo ring.
  • Undec-7-ene (DBU, CAS: 6674-22-2, English name is 1,8-Diazabicyclo [5.4.0]undec-7-ene), tetramethylguanidine (TMG, CAS: 80-70-6, English name is Tetramethylguanidine) and lithium diisopropylamide (LDA, CAS: 4111-44-0, English name is Lithium diisopropylamide).
  • the basic oxide is preferably basic alumina; the strong base weak acid salt is preferably potassium acetate; and the ion exchange resin is preferably Amberlite A-21.
  • the molar ratio of the basic substance to the compound 10 is preferably 1:1 to 1:10, more preferably 1:1 to 1:5.
  • the temperature of the reaction is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.
  • the progress of the reaction can be monitored by a conventional test method (such as TLC or HPLC) in the art, generally when the compound 20 disappears as the reaction end point, and the reaction time is preferably 1 h to 10 h, further. It is preferably 5h to 8h.
  • a conventional test method such as TLC or HPLC
  • the compound 10 can be synthesized by the method reported in Angew. Chem. Int. Ed., 2010, 49, 4656-4660, and the following reaction methods and conditions can also be employed:
  • the method 1 for preparing the compound 2 further comprises the steps of: performing a Michael addition reaction of the compound 11 with acetone in the presence of an additive and a catalyst in an organic solvent to obtain the compound 10;
  • R 4 is as defined above.
  • the method for preparing the compound 10 can employ a conventional method of the Michael addition reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the organic solvent is preferably one or more of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether solvent, an alkane solvent, and a halogenated aromatic hydrocarbon solvent;
  • the aromatic hydrocarbon The solvent is preferably toluene and/or mesitylene;
  • the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent;
  • the chlorinated hydrocarbon solvent is preferably dichloromethane and/or carbon tetrachloride;
  • the solvent is preferably diethyl ether and/or anisole;
  • the alkane solvent is preferably n-hexane; and the halogenated arene solvent is preferably chlorobenzene and/or trifluorotoluene.
  • the volume-to-mass ratio of the organic solvent to the compound 11 is preferably 0.1 mL/g to 10 mL/g, and more preferably 0.1 mL/g to 1 mL/g.
  • the additive is preferably an organic acid; the organic acid is preferably benzoic acid, acetic acid, p-dibenzoic acid, p-hydroxybenzoic acid, p-nitrobenzoic acid, (+)-camphorsulfonic acid. And one or more of p-toluenesulfonic acid.
  • the molar ratio of the additive to the compound 11 is preferably 0.1:1 to 1:1, further preferably 0.1:1 to 0.5:1.
  • the molar ratio of the acetone to the compound 11 is preferably 5:1 to 20:1, further preferably 5:1 to 10:1.
  • the catalyst is preferably any of the catalysts represented by the following formula, and more preferably a Jacobsen catalyst;
  • the molar ratio of the catalyst to the compound 11 is preferably 0.01 to 0.1:1, more preferably 0.01 to 0.05:1.
  • the temperature of the Michael addition reaction is preferably 0 ° C to 40 ° C, more preferably 20 ° C to 30 ° C.
  • the progress of the Michael addition reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, and the reaction is terminated when the compound 11 disappears.
  • the time is preferably from 1 d to 5 d, and more preferably from 3 d to 4 d.
  • the Jacobsen catalyst can be synthesized by the method reported in J. Am. Chem. Soc., 2006, 128, 7170-7171.
  • the method for producing the compound 10 preferably comprises the steps of: sequentially adding a catalyst, an additive and acetone to a solution of the compound 11 and an organic solvent to carry out a Michael addition reaction to obtain the compound 10.
  • the method 1 for preparing the compound 2 further comprises the following steps, in the method for preparing the compound 19, Compound 20 can be synthesized by the method reported in Bioorg. Med. Chem., 2003, 11, 827-841. In the present invention, particularly preferred is the following reaction method and conditions: in an aprotic solvent, the compound 21 and an oxidizing agent oxidation reaction to obtain the compound 20;
  • R 2 , R 3 and R 5 are as defined above.
  • the method for producing the compound 20 can employ a conventional method of the oxidation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the aprotic solvent is preferably an ether solvent and/or a halogenated hydrocarbon solvent; the ether solvent is preferably tetrahydrofuran; and the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon.
  • the solvent, the chlorinated hydrocarbon solvent is preferably dichloromethane.
  • the volume-to-mass ratio of the aprotic solvent to the compound 21 is preferably from 1 mL/g to 50 mL/g, and more preferably from 10 mL/g to 30 mL/g.
  • the oxidizing agent is preferably a Dess-Martin periodinane (CAS: 87413-09-0, English name is 1,1,1-Triacetoxy-1, 1-dihydro-1, 2-benziodoxol- One or more of 3(1H)-one), pyridinium chlorochromate (PCC) and pyridinium dichromate (PDC).
  • a Dess-Martin periodinane CAS: 87413-09-0
  • English name is 1,1,1-Triacetoxy-1, 1-dihydro-1, 2-benziodoxol- One or more of 3(1H)-one
  • PCC pyridinium chlorochromate
  • PDC pyridinium dichromate
  • the molar ratio of the compound 21 to the oxidizing agent is preferably 1:1 to 1:5, further preferably 1:1 to 1:2.
  • the temperature of the oxidation reaction is preferably 0 ° C to 40 ° C, and more preferably 20 ° C to 30 ° C.
  • the progress of the oxidation reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, generally when the compound 21 disappears as the reaction end point, the reaction time. It is preferably 1 h to 10 h, further preferably 1 h to 3 h.
  • the method for preparing the compound 20 is preferably carried out in the presence of a base; the base is preferably an inorganic base; and the inorganic base is preferably one or more of sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate and cesium carbonate.
  • the molar ratio of the compound 21 to the base is preferably 1:1 to 1:5, and more preferably 1:2 to 1:4.
  • the method 1 for preparing the compound 2 further comprises the following steps.
  • the compound 21 can be produced by subjecting the compound 22 to a condensation reaction with a ketone in the presence of a catalyst. Obtaining the compound 21;
  • R 2 , R 3 and R 5 are as defined above.
  • the method for preparing the compound 21 can employ a conventional method of the condensation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the catalyst is preferably montmorillonite; the montmorillonite is preferably a conventional commercially available montmorillonite, further preferably K-10 montmorillonite.
  • the mass molar ratio of the catalyst to the compound 22 is preferably from 100 g/mol to 1000 g/mol, further preferably from 400 g/mol to 600 g/mol.
  • the ketone is preferably acetone, methyl ethyl ketone, 2-pentanone or 3-pentanone.
  • the volume-mass ratio of the ketone to the compound 22 is preferably 30 mL/g to 100 mL/g, and more preferably 30 mL/g to 50 mL/g.
  • the temperature of the condensation reaction is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.
  • the progress of the condensation reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, and generally, when the compound 22 disappears, the reaction end is preferably 5 h. 20h, further preferably 8h to 15h.
  • a conventional test method such as TLC, NMR or HPLC
  • the method for preparing the compound 21 is preferably carried out in the presence of a molecular sieve; the molecular sieve is preferably a conventional commercially available molecular sieve, further preferably Molecular sieves.
  • the method 1 for preparing the compound 2 further comprises the following steps.
  • the compound 22 is preferably produced by a method of reducing a compound 23 with a reducing agent in an aprotic solvent. Obtaining the compound 22;
  • R 3 is as defined above.
  • the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.
  • the mass-to-mass ratio of the aprotic solvent to the compound 23 in the method of preparing the compound 22 It is preferably 1 mL/g to 50 mL/g, and more preferably 1 mL/g to 10 mL/g.
  • the reducing agent is preferably one or more of lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride.
  • the molar ratio of the reducing agent to the compound 23 is preferably 1:1 to 5:1, further preferably 1:1 to 3:1.
  • the temperature of the reduction reaction is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.
  • the progress of the reduction reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, and generally, when the compound 23 disappears, the reaction end is preferably 1 h. 20h, further preferably 10h to 15h.
  • a conventional test method such as TLC, NMR or HPLC
  • the method for producing the compound 22 preferably employs the step of dropwise adding a solution of the compound 23 and an aprotic solvent to a solution of an aprotic solvent and a reducing agent to carry out a reduction reaction to obtain a compound 22.
  • the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 22, the compound 23 can be obtained by the following method: in an organic solvent, in the presence of a base, D-( -) - diethyl tartrate 24 and a hydroxyl protecting reagent to carry out the reaction of the upper hydroxyl protecting group to obtain the compound 23;
  • R 3 is as defined above.
  • the method for producing the compound 23 can employ a conventional method of nucleophilic substitution reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the organic solvent is preferably an amide solvent; and the amide solvent is preferably N,N-dimethylformamide.
  • the volume-to-mass ratio of the organic solvent to the compound 6 is preferably 1 mL/g to 50 mL/g, and more preferably 1 mL/g to 10 mL/g.
  • the base is preferably an inorganic base; the inorganic base is preferably sodium hydride; the sodium hydride is preferably a conventional commercially available sodium hydride reagent; and the sodium hydride reagent is preferably 20% by mass. ⁇ 95%, further preferably 50% to 85%; the mass percentage refers to the mass of sodium hydride as a percentage of the total mass of the sodium hydride reagent.
  • the molar ratio of the base to the D-(-)-divinyl tartrate 24 is preferably 1:1.
  • the hydroxy protecting agent is preferably tert-butyldimethylchlorosilane, trimethylchlorosilane, tert-butyldiphenylchlorosilane, triisopropylchlorosilane, and chloromethyl group.
  • the ethers One or more of the ethers.
  • the temperature of the reaction of the upper hydroxy protecting group is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.
  • the progress of the reaction of the upper hydroxy protecting group can be monitored by conventional test methods in the art (such as TLC, NMR or HPLC), generally D-(-)-divinyl tartaric acid
  • TLC time-(-)-divinyl tartaric acid
  • the method for preparing the compound 23 preferably comprises the steps of: adding a solution of D-(-)-diethyl tartrate 24 and an organic solvent to a solution formed of sodium hydride and an organic solvent, and further adding a hydroxy protecting reagent and an organic solvent.
  • the resulting solution is subjected to a nucleophilic substitution reaction to give the compound 23.
  • the compound 11 can be prepared by the method reported in the literature, Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew. Chem., Int. Ed. 2010, 49, 4656. get.
  • the method 2 for preparing the compound 2 may employ a conventional method of the hydrolysis reaction in the art.
  • the following reaction methods and conditions are particularly preferred: the compound 35 is hydrolyzed with a base in an aprotic solvent to obtain Compound 2 can be described;
  • the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.
  • the volume-mass ratio of the aprotic solvent to the compound 35 is preferably 0.1 mL/mg to 5 mL/mg, and more preferably 0.1 mL/mg to 1 mL/mg.
  • the base is preferably an inorganic base, and the inorganic base is preferably one or more selected from the group consisting of sodium hydroxide, potassium hydroxide and lithium hydroxide; Potassium oxide or lithium hydroxide can be a conventional commercially available reagent in the art.
  • the inorganic base may participate in the reaction in the form of an aqueous solution thereof, and when the inorganic base participates in the reaction in the form of an aqueous solution thereof, the molar concentration of the aqueous solution of the inorganic alkali is preferably from 1 mol/L to 10 mol/L, further preferably 5 mol. /L ⁇ 10mol / L, the molar ratio refers to the ratio of the number of moles of the inorganic base to the volume of the aqueous solution of the inorganic base.
  • the molar ratio of the compound 35 to the base is preferably 1:1 to 1:100, further preferably 1:40 to 1:100.
  • the temperature of the hydrolysis reaction is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.
  • the progress of the hydrolysis reaction can be monitored by a conventional test method (such as TLC, HPLC or NMR) in the art, generally when the compound 35 disappears as the reaction end point, and the reaction time is preferably 1 h. ⁇ 20h, further preferably 1h to 5h.
  • a conventional test method such as TLC, HPLC or NMR
  • the third method for preparing the compound 3 may be a conventional method of the hydrolysis reaction in the art.
  • the following reaction methods and conditions are particularly preferred: the compound 34 is hydrolyzed with a base in an aprotic solvent to obtain Compound 3 can be described;
  • the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.
  • the volume-mass ratio of the aprotic solvent to the compound 34 is preferably 0.1 mL/mg to 5 mL/mg, and more preferably 0.1 mL/mg to 1 mL/mg.
  • the base is preferably an inorganic base, and the inorganic base is preferably one or more selected from the group consisting of sodium hydroxide, potassium hydroxide and lithium hydroxide; Potassium oxide or lithium hydroxide can be a conventional commercially available reagent in the art.
  • the inorganic base may participate in the reaction in the form of an aqueous solution thereof, and when the inorganic base participates in the reaction in the form of an aqueous solution thereof, the molar concentration of the aqueous solution of the inorganic alkali is preferably from 1 mol/L to 10 mol/L, further preferably 5 mol. /L ⁇ 10mol / L, the molar ratio refers to the ratio of the number of moles of the inorganic base to the volume of the aqueous solution of the inorganic base.
  • the molar ratio of the compound 34 to the base is preferably 1:1 to 1:100, more preferably 1:40 to 1:100.
  • the temperature of the hydrolysis reaction is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.
  • the progress of the hydrolysis reaction can be monitored by a conventional test method (such as TLC, HPLC or NMR) in the art, generally when the compound 34 disappears as the reaction end point, and the reaction time is preferably 10 Minutes to 20 hours, further preferably 30 minutes to 10 hours.
  • a conventional test method such as TLC, HPLC or NMR
  • the method 1 for preparing the compound 2 further preferably comprises the steps of: hydrolyzing the compound 34 with a base in an aprotic solvent to obtain the compound 3 without post-treatment, and then in the acid. In the presence of the reaction, the reaction for removing the protecting group is carried out to obtain the compound 2 as described above.
  • the method 2 for preparing the compound 2 further comprises the following steps.
  • the compound 35 can be produced by the following method: the compound 34 is subjected to a reaction for removing a protecting group to obtain the Compound 35;
  • R, R 1 , R 2 , R 4 and R 5 are as defined above.
  • the method for preparing the compound 35 can employ a conventional method for the reaction for removing the protecting group in the art.
  • the following reaction methods and conditions are particularly preferred: in the aprotic solvent, in the presence of an acid, the compound 34
  • the reaction of removing the protecting group can be carried out to obtain the compound 35.
  • the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.
  • the volume-mass ratio of the aprotic solvent to the compound 34 is preferably 0.1 mL/mg to 5 mL/mg, and more preferably 0.1 mL/mg to 1 mL/mg.
  • the acid is preferably a mineral acid; the inorganic acid is preferably hydrochloric acid; the hydrochloric acid may be a commercially available hydrochloric acid reagent conventionally used in the art, preferably 1% to 10% by mass of hydrochloric acid.
  • the mass percentage refers to the percentage of the mass of hydrogen chloride to the total mass of the hydrochloric acid reagent.
  • the molar ratio of the compound 34 to the acid is preferably 1:1 to 1:100, further preferably 1:30 to 1:50.
  • the temperature of the reaction for removing the protecting group is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.
  • the progress of the reaction for removing the protecting group can be monitored by a conventional test method (such as TLC, HPLC or NMR) in the art, generally when the compound 34 disappears as the reaction end point, the reaction
  • the time is preferably from 1 h to 20 h, further preferably from 1 h to 8 h.
  • the method 2 for preparing the compound 2 preferably comprises the steps of: removing the protecting group from the compound 34 in an aprotic solvent in the presence of an acid, and preparing the compound 35 without post-treatment, and then The hydrolysis reaction may be carried out in the presence of a base to obtain the compound 2 as described above.
  • the method 1 or the method 2 for preparing the compound 2 further comprises the following steps, in the method for producing the compound 35 or the method 3 for preparing the compound 3, the compound 34 can be produced by the following method: in a solvent, a base The compound 33 is subjected to a nucleophilic substitution reaction with an acetylating reagent to obtain the compound 34;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the method for preparing the compound 34 can employ a conventional method of nucleophilic substitution reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the solvent is preferably a halogenated hydrocarbon solvent and/or an organic base;
  • the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; and
  • the chlorinated hydrocarbon solvent is preferably dichloro Methane.
  • the organic base is preferably one or more of pyridine, diisopropylethylamine, piperidine and triethylamine.
  • the base is preferably an organic base, and the organic base is preferably one or more selected from the group consisting of pyridine, diisopropylethylamine, piperidine and triethylamine.
  • the molar ratio of the compound 33 to the base is preferably 1:3 to 1:6, more preferably 1:4 to 1:5.
  • the acetylating agent is an acetylating agent having an acetyl group commonly used in such a nucleophilic substitution reaction, preferably an acetyl halide and/or acetic anhydride; and the acetyl halide is preferably B. Acid chloride or acetyl bromide.
  • the molar ratio of the acetylating agent to the compound 33 is preferably 1:1 to 1:3, further preferably 1:1 to 1:1.1.
  • the temperature of the nucleophilic substitution reaction is preferably 0 ° C to 100 ° C, and more preferably 0 ° C to 30 ° C.
  • the progress of the nucleophilic substitution reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, generally when the compound 33 disappears as the reaction end point, and the reaction time is preferred. 10 min to 2 h, further preferably 10 min to 1 h.
  • the method 2 for preparing the compound 2 further comprises the following steps.
  • the compound 33 can be produced by the following method: in an aprotic solvent, under the action of an acid and a reducing agent, The compound 32 is subjected to a reduction reaction to obtain the compound 33;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the aprotic solvent is preferably an ester solvent; and the ester solvent is preferably ethyl acetate.
  • the volume-to-mass ratio of the aprotic solvent to the compound 32 is preferably 20 mL/g to 200 mL/g, and more preferably 90 mL/g to 120 mL/g.
  • the acid is preferably an organic acid; and the organic acid is preferably glacial acetic acid.
  • the molar ratio of the acid to the compound 32 is preferably from 10:1 to 100:1, further preferably from 60:1 to 100:1.
  • the reducing agent is preferably one or more of zinc, iron and aluminum.
  • the molar ratio of the reducing agent to the compound 32 is preferably from 10:1 to 100:1, further preferably from 60:1 to 100:1.
  • the temperature of the reduction reaction is preferably -10 to 40 °C, more preferably 0 to 30 °C.
  • the progress of the reduction reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, and the reaction time is preferably 1 h to 24 h when the compound 32 disappears. Further, it is preferably 4h to 10h.
  • a conventional test method such as TLC, NMR or HPLC
  • the method for producing the compound 33 is preferably carried out by the following steps: a solution of the compound 32 and an aprotic solvent is sequentially added with a reducing agent and an acid to carry out a reduction reaction to obtain the compound 33.
  • the method for preparing the compound 33 preferably includes the following post-treatment step: after completion of the reaction, filtration, extraction, concentration, and column chromatography to give the compound 33.
  • the filtration is preferably filtered using diatomaceous earth.
  • the extraction is preferably carried out using an ester solvent, and the ester solvent is preferably ethyl acetate.
  • the column chromatography separation method can employ a conventional method of such operation in the art.
  • the method 2 for preparing the compound 2 further comprises the step of, in the method for producing the compound 33, the compound 32 can be obtained by the following method: in an organic solvent, in the presence of a base, the compound 31 is Dehydrating agent is subjected to a dehydration reaction to obtain the compound 32;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the method for preparing the compound 32 can employ a conventional method of dehydration reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the organic solvent is preferably one or more of an ether solvent, a halogenated hydrocarbon solvent, and an aromatic hydrocarbon solvent; further preferably an ether solvent and/or a halogenated hydrocarbon solvent;
  • the ether solvent is preferably tetrahydrofuran;
  • the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent;
  • the chlorinated hydrocarbon solvent is preferably dichloromethane;
  • the aromatic hydrocarbon solvent is preferably toluene.
  • the volume-to-mass ratio of the organic solvent to the compound 31 is preferably from 1 mL/g to 200 mL/g, and more preferably from 20 mL/g to 100 mL/g.
  • the base is preferably an organic base; and the organic base is preferably triethylamine and/or pyridine.
  • the molar ratio of the base to the compound 31 is preferably 10:1 to 1:1, further preferably 8:1 to 5:1.
  • the dehydrating agent is preferably thionyl chloride and/or methanesulfonyl chloride.
  • the molar ratio of the compound 31 to the dehydrating agent is preferably 1:1 to 1:5, more preferably 1:2 to 1:3.
  • the temperature of the dehydration reaction is preferably -78 ° C to 30 ° C, and more preferably -78 ° C to 0 ° C.
  • the progress of the dehydration reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, generally when the compound 31 disappears as the reaction end point, and the reaction time is preferably 0.1 h. ⁇ 5h, further preferably 0.5h to 2h.
  • a conventional test method such as TLC, NMR or HPLC
  • the method for producing the compound 32 preferably comprises the steps of: adding a dehydrating agent to a solution of the compound 31, a base and an organic solvent, and performing a dehydration reaction to obtain the compound 32.
  • the method 2 for preparing the compound 2 further comprises the step of, in the method for producing the compound 32, the compound 31 can be produced by the following method: in an aprotic solvent, in the presence of an oxidizing agent, the compound 30 Performing an oxidation reaction to obtain the compound 31;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the method for producing the compound 31 can employ a conventional method of the oxidation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the aprotic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent, and the chlorinated hydrocarbon solvent is preferably dichloromethane.
  • the volume-to-mass ratio of the aprotic solvent to the compound 30 is preferably 20 mL/g to 300 mL/g, and more preferably 50 mL/g to 150 mL/g.
  • the oxidizing agent is preferably Dess Martin oxidizing agent (CAS: 87413-09-0).
  • the Dess Martin oxidizing agent can be a conventional commercially available reagent in the art.
  • the molar ratio of the compound 30 to the oxidizing agent is preferably 1:1 to 1:3, further preferably 1:1 to 1:2.
  • the temperature of the oxidation reaction is preferably -30 ° C to 30 ° C, more preferably -20 ° C to 30 ° C.
  • the progress of the hydrolysis reaction can be monitored by a conventional test method (such as TLC, HPLC or NMR) in the art, and generally, when the compound 30 disappears, the reaction end is preferably 1 h. 10h, further preferably 1h to 5h.
  • a conventional test method such as TLC, HPLC or NMR
  • the method 2 for preparing the compound 2 further comprises the step of, in the method of preparing the compound 31, the compound 30 can be produced by the following method: in a protic solvent, in the presence of a base, Compound 29 is subjected to a hydrolysis reaction to obtain the compound 30;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the method for preparing the compound 30 can employ a conventional method of the hydrolysis reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the protic solvent is preferably an alcohol solvent; and the alcohol solvent is preferably methanol.
  • the volume-to-mass ratio of the protic solvent to the compound 29 is preferably 20 mL/g to 300 mL/g, and more preferably 30 mL/g to 100 mL/g.
  • the base is preferably potassium carbonate and/or sodium methoxide, further preferably sodium methoxide.
  • the molar ratio of the compound 29 to the base is preferably from 3:1 to 1:1, further preferably from 2:1 to 1:1.
  • the temperature of the hydrolysis reaction is preferably 0 ° C to 50 ° C, more preferably 20 ° C to 30 ° C.
  • the progress of the hydrolysis reaction can be monitored by a conventional test method (such as TLC, HPLC or NMR) in the art, generally when the compound 29 disappears as the reaction end point, and the reaction time is preferably 1 hour. ⁇ 1 day, further preferably 3 hours to 10 hours.
  • a conventional test method such as TLC, HPLC or NMR
  • the method 2 for preparing the compound 2 further comprises the step of, in the method of producing the compound 30, the compound 29 can be produced by the following method: in an aprotic solvent, a base, a catalyst and a catalyst ligand are present. Under the conditions, the compound 28 and the compound 9 are reacted to obtain the compound 29;
  • R 1 , R 2 , R 4 and R 5 are as defined above.
  • the method for preparing the compound 29 can employ a conventional method of the reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.
  • the volume-to-mass ratio of the aprotic solvent to the compound 9 is preferably 1 mL/g to 50 mL/g, and more preferably 10 mL/g to 30 mL/g.
  • the base is preferably an inorganic base; and the inorganic base is preferably cesium carbonate.
  • the molar ratio of the compound 9 to the base is preferably 1:1 to 5:1, further preferably 2:1 to 4:1.
  • the catalyst is preferably an inorganic copper salt; and the inorganic copper salt is a salt formed by reacting copper with an inorganic acid.
  • the inorganic copper salt is preferably one or more of copper chloride, cuprous chloride, cuprous bromide, copper bromide and cuprous iodide, and further preferably copper bromide.
  • the molar ratio of the compound 28 to the catalyst is preferably 1:1 to 10:1, further preferably 2:1 to 10:1.
  • the molar ratio of the compound 28 to the compound 9 is preferably 1:1 to 1:5, further preferably 1:1 to 1:2.
  • the catalyst ligand is preferably a pyrrolidine-phenol catalyst; the pyrrolidine-phenol catalyst is preferably
  • the molar ratio of the catalyst ligand to the compound 28 is preferably from 1:10 to 3:10, further preferably from 1:5 to 3:10.
  • the temperature of the reaction is preferably -20 ° C to 40 ° C, more preferably -20 ° C to 30 ° C.
  • the progress of the reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, generally when the compound 28 disappears as the reaction end point, and the reaction time is preferably 24 h to 96 h. Further, it is preferably 24h to 48h.
  • a conventional test method such as TLC, NMR or HPLC
  • the compound 9 can be synthesized by the method reported in Tetrahedron: Asymmetry. 1998, 9, 1359 - 1367.
  • the method 2 for preparing the compound 2 further comprises the step of, in the method of preparing the compound 29, the compound 28 can be produced by the following method: in an organic solvent, in the presence of a base and a catalyst, the compound 27 The reaction with the hydroxy protecting reagent is carried out on the upper hydroxyl protecting group to obtain the compound 28;
  • R 4 is the same as described above.
  • the method for preparing the compound 28 can employ a conventional method of the reaction of the above-mentioned hydroxy protecting group in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the organic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.
  • the volume-to-mass ratio of the organic solvent to the compound 27 is preferably from 1 mL/g to 100 mL/g, and more preferably from 10 mL/g to 50 mL/g.
  • the base is preferably an organic base; and the organic is preferably triethylamine.
  • the molar ratio of the base to the compound 27 is preferably 1:1 to 3:1.
  • the catalyst is preferably 4-dimethylaminopyridine.
  • the molar ratio of the catalyst to the compound 27 is preferably from 0.01:1 to 0.5:1, further preferably from 0.05:1 to 0.2:1.
  • the hydroxy protecting agent is preferably acetic anhydride, acetyl chloride, acetyl bromide, trifluoroacetyl chloride, trifluoroacetyl bromide, trimethylchlorosilane, trimethylbromosilane, tert-butyl group Methylchlorosilane, tert-butyldimethylbromosilane, triethylchlorosilane, triethylbromosilane, benzyl chloride or benzyl bromide is further preferably acetic anhydride.
  • the temperature of the reaction of the upper hydroxy protecting group is preferably from 0 ° C to 40 ° C, more preferably from 10 ° C to 30 ° C.
  • the progress of the reaction of the upper hydroxyl protecting group can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, and the reaction time is generally when the compound 27 disappears. It is preferably 1 minute to 1 hour, further preferably 10 minutes to 30 minutes.
  • the method for preparing the compound 28 preferably employs the following steps: a solution of the compound 27 and an organic solvent, a catalyst, a base and a hydroxy protecting reagent, and a reaction of an upper hydroxy protecting group to obtain the compound 28.
  • the method for producing the compound 28 is further preferably carried out by the following steps: a solution of the compound 27 and an organic solvent, a catalyst, a base and a hydroxy protecting reagent, and a reaction of an upper hydroxy protecting group are carried out to obtain the compound 28.
  • the method 2 for preparing the compound 2 further comprises the step of, in the method of preparing the compound 28, the compound 27 can be produced by subjecting the compound 26 to a reducing agent in a protic solvent. Reduction reaction to obtain the compound 27;
  • R 4 is the same as described above.
  • the method for producing the compound 27 can employ a conventional method of the reduction reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the protic solvent is preferably an alcohol solvent; and the alcohol solvent is preferably methanol.
  • the volume-to-mass ratio of the protic solvent to the compound 26 is preferably from 1 mL/g to 100 mL/g, and more preferably from 20 mL/g to 40 mL/g.
  • the reducing agent is preferably an alkali metal borohydride
  • the alkali metal borohydride refers to a salt of an alkali metal with BH 4 - , preferably sodium borohydride, potassium borohydride and boron.
  • BH 4 - preferably sodium borohydride, potassium borohydride and boron.
  • lithium hydride, the sodium borohydride, potassium borohydride or lithium borohydride is a conventionally commercially available reagent.
  • the molar ratio of the reducing agent to the compound 26 is preferably from 0.4:1 to 10:1, more preferably from 0.4:1 to 1:1.
  • the temperature of the reduction reaction is preferably 0 ° C to 40 ° C, and more preferably 20 ° C to 30 ° C.
  • the progress of the reduction reaction can be monitored by a conventional test method (such as TLC, NMR or HPLC) in the art, and the reaction time is preferred when the compound 26 disappears. 10 minutes to 1 hour, further preferably 10 minutes to 30 minutes.
  • the method for producing the compound 27 preferably comprises the steps of: adding a sodium borohydride to a solution of the compound 26 and a protic solvent to carry out a reduction reaction to obtain the compound 27.
  • the method 2 for preparing the compound 2 further comprises the following steps.
  • the compound 26 can be produced by the following method: in the presence of a catalyst, the compound 11 and acetone are present in an organic solvent. The methyl ester is subjected to a Michael addition reaction to obtain the compound 26;
  • R 4 is as defined above.
  • the method for preparing the compound 26 can employ a conventional method of the Michael addition reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the organic solvent is preferably one or more of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether solvent, an alkane solvent, and a halogenated aromatic hydrocarbon solvent;
  • the aromatic hydrocarbon The solvent is preferably toluene and/or mesitylene;
  • the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent;
  • the chlorinated hydrocarbon solvent is preferably dichloromethane and/or chloroform;
  • the ether solvent Preference is given to diethyl ether and/or anisole;
  • the alkane-based solvent is preferably n-hexane.
  • the volume-to-mass ratio of the organic solvent to the compound 11 is preferably from 1 mL/g to 100 mL/g, and more preferably from 1 mL/g to 10 mL/g.
  • the molar ratio of the methyl pyruvate to the compound 11 is preferably 1:1 to 1:10, more preferably 1:3 to 1:10.
  • the catalyst is preferably any of the catalysts represented by the following formulas, and further preferably a Jacobsen catalyst:
  • the molar ratio of the catalyst to the compound 11 is preferably from 0.01:1 to 0.2:1, more preferably from 0.03:1 to 0.1:1.
  • the temperature of the Michael addition reaction is preferably -10 to 40 ° C, more preferably 0 to 30 ° C, still more preferably 20 to 30 ° C.
  • the progress of the Michael addition reaction can be monitored by conventional test methods in the art (such as TLC, NMR or HPLC), generally when the compound methyl pyruvate disappears.
  • the reaction time is preferably from 12 hours to 5 days, more preferably from 12 hours to 48 hours.
  • the Jacobsen catalyst can be synthesized by the method reported in J. Am. Chem. Soc., 2006, 128, 7170-7171.
  • the method for producing the compound 26 preferably comprises the steps of: sequentially adding a catalyst and methyl pyruvate to a solution formed of the compound 11 and an organic solvent, and performing a Michael addition reaction to obtain the compound 26.
  • the compound 2 described in the present invention is preferably prepared by any of the following routes:
  • Compound 20 is preferably prepared by the following route:
  • the compound 1 after the preparation of the compound 2, the compound 1 can also be prepared, which comprises the steps of: in a solvent, The compound 2 is subjected to a nucleophilic substitution reaction with a hydrazine reagent to obtain a compound 1;
  • R is methyl or hydrogen; when R is hydrogen, compound 1 is Zanamivir; and when R is methyl, compound 1 is Laninamivir.
  • the method for preparing the compound 1 can be synthesized by referring to the method reported in J. Chem. Soc., Perkin Trans. I, 1995, 1173-1180, or a conventional method of nucleophilic substitution reaction in the art, in the present invention.
  • the following reaction methods and conditions are particularly preferred:
  • the solvent is preferably water.
  • the volume-to-mass ratio of the solvent to the compound 2 is preferably from 1 mL/g to 100 mL/g, and more preferably from 60 mL/g to 90 mL/g.
  • the hydrazine reagent is preferably thiourea trioxide, N, N'-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (N, N'-bis (tert) -butoxycarbonyl)-1H-pyrazole-1-carboxamidine, CAS: 152120-54-2), 1H-pyrazole-1-carboximidinehydrochloride, CAS: 4023-02-3 Or N,N'-di-tert-butoxycarbonylthiourea (N,N'-Di-Boc-thiourea, CAS: 145013-05-04)
  • the molar ratio of the compound 2 to the hydrazine reagent is preferably 1:1 to 1:30, further preferably 1:10 to 1:15.
  • the temperature of the nucleophilic substitution reaction is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.
  • the progress of the nucleophilic substitution reaction can be monitored by a conventional test method (such as TLC, HPLC or NMR) in the art, generally when the compound 2 disappears as the reaction end point, and the reaction time is preferably 18h to 36h, further preferably 30h to 36h.
  • a conventional test method such as TLC, HPLC or NMR
  • the process for preparing the compound 1 is preferably carried out in the presence of a base.
  • the base is preferably an inorganic base; the inorganic base is preferably potassium carbonate and/or sodium carbonate; the molar ratio of the inorganic base to the compound 2 The ratio is preferably 1:1 to 3:1, further preferably 1:1 to 2:1.
  • the method for preparing the compound 1 preferably employs the step of sequentially adding a base and a hydrazine reagent in a solution of the compound 2 and a solvent in a batchwise manner to carry out a nucleophilic substitution reaction to obtain a compound 1.
  • the invention also provides a method for synthesizing compound 3, when R 1 is trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), triiso
  • R 1 is trimethylsilyl
  • TIPS tert-butyldimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • TIPS propylsilyl
  • MOM methoxymethyl
  • the compound 3 can be prepared by the following method 1; when R 1 is hydrogen, the compound 3 can be the following method.
  • R 1 is trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS),
  • TMS trimethylsilyl
  • TBS tert-butyldimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • TIPS triisopropylsilyl
  • MOM methoxymethyl
  • methyl or hydrogen the compound 3 can be prepared by the following method three;
  • Method 1 in a protic solvent, under acidic conditions, the compound 4 is oxidized with an oxidizing agent to obtain the compound 3;
  • Method 2 reducing the compound 12 and the reducing agent in an aprotic solvent to obtain the compound 3;
  • R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described in the previous method for preparing compound 3.
  • the present invention also provides a method for synthesizing the compound 4, which comprises the steps of: oxidizing the compound 5 with an oxidizing agent in an aprotic solvent to obtain the compound 4;
  • R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described in the previous method for preparing compound 4.
  • the present invention also provides a method for synthesizing the compound 5, which comprises the steps of: subjecting the compound 6 to an nucleophilic substitution reaction with an acetylating reagent in a solvent in the presence of a base to obtain a compound 5;
  • R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described in the previous method for preparing compound 5.
  • the present invention also provides a method for synthesizing the compound 6, which comprises the steps of: subjecting the compound 7 to a reduction reaction in an aprotic solvent under the action of an acid and a reducing agent to obtain a compound 6;
  • R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described in the previous method for preparing compound 6.
  • the present invention also provides a method for synthesizing the compound 7, which comprises the steps of: dehydrating the compound 8 and the dehydrating agent in an organic solvent in the presence of a base to obtain the compound 7;
  • R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described in the previous method for preparing compound 7.
  • the present invention also provides a method for synthesizing the compound 8, which comprises the steps of: reacting the compound 10 with the compound 9 in an aprotic solvent in the presence of a base, a catalyst and a catalyst ligand to obtain a compound 8;
  • R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described in the previous method for preparing compound 8.
  • the present invention also provides a method for synthesizing the compound 10, which comprises the steps of: subjecting the compound 11 and acetone to a Michael addition reaction in an organic solvent, in the presence of an additive and a catalyst, to obtain a compound 10;
  • the present invention also provides a method for synthesizing the compound 12, which comprises the steps of: oxidizing the compound 13 with an oxidizing agent under acidic conditions in an aprotic solvent to obtain the compound 12;
  • the present invention also provides a method for synthesizing the compound 13, which comprises the steps of: oxidizing the compound 14 with an oxidizing agent in an aprotic solvent to obtain the compound 13;
  • the present invention also provides a method for synthesizing the compound 14, which comprises the steps of: subjecting the compound 15 to an oxidation reaction to obtain the compound 14;
  • the present invention also provides a method for synthesizing the compound 15, which comprises the steps of: removing the hydroxy protecting group from the compound 16 and the fluorinating reagent in a solvent to obtain the compound 15;
  • the present invention also provides a method for synthesizing the compound 16, which comprises the steps of: subjecting the compound 17 to an nucleophilic substitution reaction with an acetylating reagent in a solvent in the presence of a base to obtain a compound 16;
  • the present invention also provides a method for synthesizing the compound 17, which comprises the steps of: subjecting the compound 18 to a reduction reaction in an aprotic solvent under the action of an acid and a reducing agent to obtain a compound 17;
  • the present invention also provides a method for synthesizing the compound 18, which comprises the steps of: dehydrating the compound 19 with a dehydrating agent in an organic solvent in the presence of a base to obtain a compound 18;
  • the present invention also provides a method for synthesizing the compound 21, which comprises the steps of: subjecting the compound 22 to a condensation reaction with a ketone in the presence of a catalyst to obtain a compound 21;
  • the present invention also provides a method for synthesizing the compound 22, which comprises the steps of: reducing the compound 23 and the reducing agent in an aprotic solvent to obtain the compound 22;
  • R 3 is the same as above; each reaction condition is as described in the previous method for preparing compound 22.
  • the invention also provides a method for synthesizing the compound 23, which comprises the steps of: reacting D-(-)-diethyl tartrate 24 with a hydroxy protecting reagent in an organic solvent in the presence of a base; , obtaining compound 23;
  • R 3 is as defined above; each reaction condition is as described in the previous method for preparing compound 23.
  • the present invention also provides a preparation method of the compound 35, which comprises the following steps: the compound 34 is subjected to a reaction for removing a protecting group to obtain the compound 35;
  • R, R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described above for the preparation of compound 35.
  • the present invention also provides a method for preparing the compound 34, which comprises the steps of: nucleophilic substitution reaction of the compound 33 with an acetylating reagent in a solvent in the presence of a base to obtain the compound 34;
  • R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described above for the method of preparing compound 34 as described above.
  • the present invention also provides a method for preparing the compound 33, which comprises the steps of: reducing the compound 32 in an aprotic solvent under the action of an acid and a reducing agent to obtain a compound 33;
  • R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described above for the method of preparing compound 33 as described above.
  • the present invention also provides a method for preparing the compound 32, which comprises the steps of: dehydrating the compound 31 with a dehydrating agent in an organic solvent in the presence of a base to obtain the compound 32;
  • R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described above for the method of preparing compound 32 as described above.
  • the present invention also provides a method for preparing the compound 31, which comprises the steps of: oxidizing the compound 30 in an aprotic solvent in the presence of an oxidizing agent to obtain the compound 31;
  • R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described above for the method of preparing compound 31 as described above.
  • the present invention also provides a method for preparing the compound 30, which comprises the steps of: hydrolyzing the compound 29 in a protic solvent in the presence of a base to obtain the compound 30;
  • R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described above for the method of preparing the compound 30 described above.
  • the present invention also provides a process for the preparation of the compound 29, which comprises the steps of reacting the compound 28 with the compound 9 in an aprotic solvent in the presence of a base, a catalyst and a catalyst ligand to obtain the compound 29 ;
  • R 1 , R 2 , R 4 and R 5 are as defined above; each reaction condition is as described above for the method of preparing compound 29 as described above.
  • the invention also provides a preparation method of the compound 28, which comprises the steps of: reacting the compound 27 with a hydroxy protecting reagent in an organic solvent, in the presence of a base and a catalyst, to obtain the compound 28; ;
  • R 4 is as defined above; each reaction condition is as described above for the method of preparing compound 28 as described above.
  • the present invention also provides a method for preparing the compound 27, which comprises the steps of: reducing the compound 26 with a reducing agent in a protic solvent to obtain the compound 27;
  • R 4 is a tert-butoxycarbonyl group; and each reaction condition is as described above for the method of preparing the compound 27 described above.
  • the present invention also provides a method for preparing compound 26, which comprises the steps of: Michael addition reaction of compound 11 with methyl pyruvate in an organic solvent in the presence of a catalyst to obtain the compound 26;
  • R 4 is as defined above; each reaction condition is as described above for the method of preparing compound 26 as described above.
  • the invention also provides compounds 3, 4, 5, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35, the structural formula is as follows:
  • R 1 is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl or hydrogen;
  • R 2 and R 5 is independently methyl, ethyl or propyl;
  • R 4 is an amino protecting group; the amino protecting group is t-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl;
  • R 3 is a hydroxy protecting group, The hydroxy protecting group is a trimethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a triisopropylsilyl group or a methoxymethyl group.
  • R 1 is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl or hydrogen
  • R 2 and R 5 is independently methyl
  • R 4 is tert-butoxycarbonyl
  • R 3 is hydrogen
  • R 2 and R 5 are each independently methyl
  • R 4 is tert-butoxycarbonyl.
  • the room temperature refers to an ambient temperature of -20 ° C to 40 ° C.
  • the reagents and starting materials used in the present invention are commercially available.
  • the positive progress of the invention is that the synthesis method of the invention has the advantages of low cost and easy availability, mild reaction conditions, short steps, high total yield, low production cost, good product purity, high chiral purity and good industrial production. prospect.
  • diastereoisomer ratio is an abbreviation of English diastereoisomer ratio, indicating the ratio of diastereomers; when the product is a pair of diastereomers, two data before and after "&" indicate these two isoforms.
  • Cat. 7 can be found in the literature: Org. Lett. 2007, 9, 599; reported methods of synthesis.
  • Cat. 8 can be found in the literature: J. Am. Chem. Soc. 2006, 128, 9624;
  • Cat. 9 can be found in the literature: Eur. J. Org. Chem. 2010, 1849; reported methods of synthesis.
  • Cat. 10 can be found in the literature: Tetrahedron. Lett. 2010, 51, 209; reported method synthesis.
  • Cat. 11 can be found in the literature: Org. Lett. 2010, 12, 1756; reported methods of synthesis.
  • Cat. 12 can be found in the literature: J. Am. Chem. Soc. 2006, 128, 7170; reported method synthesis;
  • Cat. 13 can be found in the literature: Adv. Synth. Catal. 2012, 354, 740;
  • the structure of the catalyst is as follows:
  • Compound 8 (R 1 is methoxymethyl, R 2 and R 5 are each independently methyl, R 4 is tert-butoxycarbonyl) (100 mg, 0.22 mmol) is dissolved in anhydrous toluene (15 mL), and Burgess reagent is added.
  • Burges reagent means methyl N-(triethylammoniumsulfonylcarbamate, methyl N-(triethylammoniumsulfonyl)carbamate, CAS: 29684-56-8) (79 mg, 0.33 mmol) for 8 h at room temperature.
  • R 1 is a methoxymethyl group
  • R 2 and R 5 are each independently a methyl group
  • R 4 is a tert-butoxycarbonyl group
  • 1.0 g, 2.25 mmol dissolved in anhydrous 1,4-dioxane Selenium dioxide (500 mg, 4.50 mmol) was added to (300 mL).
  • Argon gas was bubbled through the solution for 5 min to remove oxygen from the solution, and reacted at 70 ° C for 2 h under argon protection.
  • R 1 is a methoxymethyl group
  • R 2 and R 5 are each independently a methyl group
  • R 4 is a tert-butoxycarbonyl group
  • 1.0 g, 2.25 mmol dissolved in anhydrous 1,4-dioxane Selenium dioxide (500 mg, 4.50 mmol) was added to (300 mL).
  • Argon gas was bubbled through the solution for 5 min to remove oxygen from the solution, and reacted at 100 ° C for 2 h under argon protection.
  • R 1 is methoxymethyl, R 2 and R 5 are each independently methyl, R 4 is tert-butoxycarbonyl) (1.0 g, 2.18 mmol) dissolved in tert-butanol (120 mL) and water (40 mL) 2, 2-methylbutene (40 mL) and sodium dihydrogen phosphate (2.10 mg, 17.44 mmol) were added in that order, and finally sodium chlorite (789 mg, 8.72 mmol) was added. The reaction was carried out at room temperature overnight. The reaction was quenched with saturated aq.
  • LiBH 4 (13.72 g, 0.63 mmol) was weighed into a three-necked flask, 630 mL of anhydrous tetrahydrofuran was added, and cooled to 0 ° C.
  • Compound 23 (R 3 was tert-butyldimethylsilyl) (96.13 g, 0.3 mmol) Dissolved in 200 mL, slowly added to the above solution, naturally added to room temperature after the addition, and allowed to react overnight. After quenching with a saturated NH 4 Cl solution, ethyl acetate was extracted three times, washed with brine and dried over anhydrous sodium sulfate.
  • Example 15 was repeated except that sodium methoxide was replaced with the following base, compound 19 in the presence of different bases (R 3 is tert-butyldimethylsilyl, and R 2 and R 5 are each independently methyl, R The synthesis optimization of 4 is tert-butoxycarbonyl) is shown in Table 7.
  • R 2 and R 5 are each independently methyl and R 4 is tert-butoxycarbonyl (400 mg, 1.00 mmol) dissolved in anhydrous dichloromethane (60 mL) and acetonitrile (6 mL) Molecular sieves (200 mg) and N-methylmorpholine oxide (203 mg, 1.50 mmol) were stirred for 3 min, and tetra-n-propylammonium perruthenate (TPAP) (35 mg, 0.10 mmol) was added and allowed to react at room temperature for 12 h. The reaction was quenched with saturated aqueous ammonium chloride.
  • TPAP tetra-n-propylammonium perruthenate
  • R 2 and R 5 are each independently methyl and R 4 is tert-butoxycarbonyl) (74 mg, 0.18 mmol) dissolved in tert-butanol (15 mL) and water (5 mL). Butene (0.3 mL) and sodium dihydrogen phosphate (223 mg, 1.43 mmol) were added, followed by sodium chlorite (65 mg, 0.72 mmol). The reaction was carried out for 2 h at room temperature. The reaction was quenched with saturated aq.
  • Example 23 was repeated except that the following reducing agent was used in place of the zinc borohydride, and the experimental results are shown in Table 8 below:
  • the catalyst type screening in the synthesis of compound 8 is shown in Table 9, the catalyst equivalent screening is shown in Table 10; and the equivalent screening of compound 10 is shown in Table 11.
  • Compound 8 (R 1 is a methyl group, R 2 and R 5 are each independently a methyl group, and R 4 is a tert-butoxycarbonyl group) (11.57 g, 27.53 mmol) dissolved in anhydrous dichloromethane (1.5 L), 0 Pyridine (110.82 mL, 1376.50 mmol) and chlorosulfoxide (10 mL, 137.65 mmol) were successively added, and the mixture was reacted at 0 ° C for 2 h.
  • Compound 8 (R 1 is a methyl group, R 2 and R 5 are each independently a methyl group, and R 4 is a tert-butoxycarbonyl group) (100 mg, 0.24 mmol) dissolved in anhydrous tetrahydrofuran (15 mL), followed by the addition of triethylamine (100 ⁇ L, 0.72mmol), DMAP (7mg, 0.04mmol) and methanesulfonyl chloride (53 ⁇ L, 0.24mmol), reacted for 8h at room temperature, add triethylamine (66 ⁇ L, 0.48mmol), DMAP (4mg, 0.03mmol) and methane Sulfonyl chloride (31 ⁇ L, 0.14 mmol) was continued for 4 h.
  • triethylamine 100 ⁇ L, 0.72mmol
  • DMAP 7mg, 0.04mmol
  • methanesulfonyl chloride 53 ⁇ L, 0.24mmol
  • Compound 8 (R 1 is methyl, R 2 and R 5 are each independently methyl, R 4 is tert-butoxycarbonyl) (100 mg, 0.24 mmol) is dissolved in anhydrous toluene (15 mL), and Burgess reagent (Burgess) Reagent means methyl N-(triethylammoniumsulfonylcarbamate, methyl N-(triethylammoniumsulfonyl)carbamate, CAS: 29684-56-8) (86 mg, 0.36 mmol) for 8 h at room temperature. Quenched with saturated ammonium chloride solution.
  • Compound 5 (R 1 is a methyl group, R 2 and R 5 are each independently a methyl group, and R 4 is a tert-butoxycarbonyl group) (5.81 g, 14.02 mmol) dissolved in anhydrous 1,4-dioxane (1 L) Selenium dioxide (3.11 g, 28.04 mmol) was added. Argon gas was bubbled through the solution for 5 min to remove oxygen from the solution, and reacted at 75 ° C for 2 h under argon protection.
  • Compound 5 (R 1 is a methyl group, R 2 and R 5 are each independently a methyl group, and R 4 is a tert-butoxycarbonyl group) (5.81 g, 14.02 mmol) dissolved in anhydrous 1,4-dioxane (1 L) Selenium dioxide (3.11 g, 28.04 mmol) was added. Argon gas was bubbled through the solution for 5 min to remove oxygen from the solution, and reacted at 100 ° C for 2 h under argon protection.
  • R 1 is methyl, R 2 and R 5 are each independently methyl and R 4 is tert-butoxycarbonyl) (2.33 g, 5.44 mmol) dissolved in tert-butanol (180 mL) and water (60 mL) 2-Methylbutene (20 mL) and sodium dihydrogen phosphate (5.25 g, 43.76 mmol) were sequentially added, and finally sodium chlorite (1.98 g, 21.89 mmol) was added. The reaction was carried out for 2 h at room temperature. The reaction was quenched with saturated aq.
  • nitro compound 11 (R 4 is tert-butoxycarbonyl) (165.41 g, 879 mmol) was dissolved in chloroform (1500 mL), then EtOAc (11.45 g, 29.31 mmol) was added sequentially, and methyl pyruvate (26.9 mL, 293 mmol) was added. After that, it was reacted at room temperature for 24 hours.
  • Cat. 7 can be found in the literature: Org. Lett. 2007, 9, 599; reported methods of synthesis.
  • Cat. 8 can be found in the literature: J. Am. Chem. Soc. 2006, 128, 9624;
  • Cat. 9 can be found in the literature: Eur. J. Org. Chem. 2010, 1849; reported methods of synthesis.
  • Cat. 10 can be found in the literature: Tetrahedron. Lett. 2010, 51, 209; reported method synthesis.
  • Cat. 11 can be found in the literature: Org. Lett. 2010, 12, 1756; reported methods of synthesis.
  • Cat. 12 can be found in the literature: J. Am. Chem. Soc. 2006, 128, 7170; reported method synthesis;
  • Cat. 13 can be found in the literature: Adv. Synth. Catal. 2012, 354, 740;
  • the structure of the catalyst is as follows:
  • the trifluoroacetate salt of Compound 2 (R is methyl) (1.35 g, 3.23 mmol) was dissolved in N,N-dimethylformamide (DMF, CAS: 68-12-2) (40 mL) 1d was added N,N-diisopropylethylamine DIPEA (CAS:7087-68-5, English name N,N-Diisopropylethylamine) (1.7 mL, 9.70 mmol) and 1H-pyrazole-1-carboxamidine salt. The acid salt (1.42 g, 9.70 mmol) was added a total of 3 times. The reaction was carried out for 5 days at room temperature.
  • DMF N,N-dimethylformamide
  • DIPEA CAS:7087-68-5, English name N,N-Diisopropylethylamine
  • Laninamivir's octanoate CS-8958 can be esterified to Lannamivir by reference to a patent (WO 2008/126943).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le zanamivir, un composé intermédiaire du zanamivir (formule 2) et un procédé de préparation associé. Le procédé de préparation est le procédé 1 ou 2. Le procédé 1 comprend les étapes suivantes : le composé 3 est soumis à une réaction pour éliminer un groupe protecteur afin d'obtenir le composé 2 ; le procédé 2 comprend les étapes suivantes : le composé 35 est soumis à une réaction d'hydrolyse afin d'obtenir le composé 2 ; R est un groupe hydrogène ou méthyle ; R1 est un groupe triméthylsilyle, t-butyldiméthylsilyle, t-butyldiphénylsilyle silicium, silicium-triisopropylsilyle, méthoxyméthyle, méthyle ou hydrogène ; R2 et R5 sont indépendamment un groupe méthyle, éthyle ou propyle ; R4 est un groupe protecteur amino ; le groupe protecteur amino est un groupe tert-butoxycarbonyle, benzyloxycarbonyle ou chlorure de p-toluènesulfonyle.
PCT/CN2014/086112 2013-09-09 2014-09-09 Zanamivir, intermédiaire du zanamivir et procédé de synthèse Ceased WO2015032357A1 (fr)

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