WO2015032357A1

WO2015032357A1 - Zanamivir, zanamivir intermediate, and synthesis method

Info

Publication number: WO2015032357A1
Application number: PCT/CN2014/086112
Authority: WO
Inventors: 马大为; 田峻山; 钟建康; 潘强彪; 李运生
Original assignee: 中国科学院上海有机化学研究所; 联化科技（台州）有限公司
Priority date: 2013-09-09
Filing date: 2014-09-09
Publication date: 2015-03-12
Also published as: CN111116567B; CN104418876B; CN104418876A; CN111018901B; CN111116533A; CN111116567A; CN111116533B; CN111018901A

Abstract

Zanamivir, a Zanamivir intermediate compound (formula 2), and a preparation method therefor. The preparation method is method 1 or 2. Method 1 comprises the following steps: compound 3 undergoes a reaction to remove a protecting group so as to obtain compound 2; method 2 comprises the following steps: compound 35 undergoes a hydrolysis reaction so as to obtain compound 2; R is hydrogen or methyl; R¹ is trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl silicon, silicon-triisopropylsilyl, methoxymethyl, methyl, or hydrogen; R² and R⁵ are independently methyl, ethyl, or propyl; R⁴ is an amino protecting group; the amino protecting group is a tert-butoxycarbonyl group, benzyloxycarbonyl group, or p-toluenesulfonyl chloride.

Description

Intermediates of zanamivir and lamamivir and synthesis methods thereof

The present application claims priority to Chinese Patent Application No. CN201310408033.5, filed on Sep. 9, 2013. This application cites the entire text of the above-mentioned Chinese patent application.

Technical field

This invention relates to intermediates of zanamivir and ranamivir and methods for their synthesis.

Background technique

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.

In 1994, M.V. Itzstein of Monash University in Australia completed the first synthesis of zanamivir (Carbohydr. Res., 1994, 259, 301-305). Starting from N-acetylneuraminic acid, the aziridine ring is opened by an azide to introduce the desired nitrogen atom, and the azide is hydrogenated and converted into zanamivir in several steps.

This method can only provide milligrams of product for clinical studies. The danger of explosion due to the use of azides, reagents and intermediates poses a risk to large-scale industrial production. In addition, the raw material N-acetylneuraminic acid is not readily available, which also limits the application of the method.

In 1995, J. Scheigetz et al. of Merck, Canada, found that the above reaction was not reproducible. They used the same raw materials and similar strategies to optimize the synthesis of zanamivir to improve yield and repeatability (Org. Prep. Proc. Int., 1995, 27, 637-644). DPPA is substituted for reagents with explosive properties such as lithium azide. Although they only synthesized milligrams of products, they laid the foundation for later research.

In 1995, M. Chandler et al. of GlaxoSmithKline, UK, reported for the first time a gram-level synthesis of zanamivir (J. Chem. Soc., Perkin Trans. I, 1995, 1173-1180). They also used N-acetylneuraminic acid as a starting material, and the key oxazoline intermediates were obtained very efficiently in 3 steps. The product can be obtained after 5 steps of conversion using TMSN ₃ as a nitrogen source.

Although they obtained 1.28 grams of zanamivir, their multi-step reactions required preparation on a few hundred grams scale, including a 600 gram scale azide substitution reaction, and required multiple steps of ion exchange resin desalting. The total yield of the 9-step reaction was 8.3%, and there are still many areas where improvement is needed.

The work of the predecessors was to reconstruct the structure of N-acetylneuraminic acid. In 2004, Professor Yao Zhujun of the Shanghai Institute of Organic Chemistry in China also reported the synthesis of zanamivir (Org. Lett., 2004, 6, 2269-2272). ). Different from the predecessors, they use cheap gluconolactone as raw material, and adopt a step-by-step key azide compound to open a ring of aziridine to introduce the nitrogen atom needed in zanamivir to hydrogenate azide. Subsequent subsequent conversions can complete their synthesis.

However, although its starting materials are very inexpensive, its 24 step reaction, a total yield of 0.2%, makes industrialization of the process very difficult.

In 2012, Professor M. Shibasaki of the University of Tokyo in Japan also reported their group's synthesis of zanamivir (Angew. Chem. Int. Ed., 2012, 51, 1644-1647). They constructed two key chiral centers using the asymmetric Henry reaction developed by their group and synthesized key oxazoline intermediates using novel 3,3-σ rearrangement reactions. Like Professor Yao Zhujun, they also completed the synthesis in 24 steps with a total yield of 1.2%. Although the reaction is quite novel, too long linear steps and lower yields make the process difficult to industrialize.

However, with the emergence of resistant strains, the development of some new NA inhibitors has accelerated. 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.

In 2002, T. Honda et al. of Daiichi Sankyo Corporation of Japan took the lead in completing the synthesis of laninamivir (US6340702). They started from the benzyl-protected sugar and obtained the Aldol reaction precursor by literature. After the core skeleton was constructed by Aldol reaction enzyme, the laninamivir was obtained through 11 steps.

In the same year, T. Honda et al., Daiichi Sankyo, Japan, improved the synthesis of laninamivir (Bioorg. Med. Chem. Lett., 2002, 12, 1921-1924). They start from the cheaper pyranose compounds known to pass through The step is simple transformation to obtain the Aldol reaction precursor, and then the core skeleton is constructed by Aldol reaction enzyme, and laninamivir is obtained through 8 steps of transformation.

The method, the raw material N-acetylneuraminic acid, is not easy to obtain in large quantities and limits the application of the method.

In 2002, Y. Kawaoka et al., Daiichi Sankyo, Japan, reported improved synthesis of lamamivir (Bioorg. Med. Chem. Lett., 2002, 12, 1925-1928). Starting from N-acetylneuraminic acid, they first protected the two hydroxyl groups near the terminal with an acetone fork and methylated the desired hydroxyl group. After converting the hydroxyl group to the amine group, it was converted into lanamivir in several steps.

In 2008, Y. Nakamura et al. of Daiichi Sankyo Corporation of Japan perfected the synthesis of lamamivir and applied for a world patent (WO 2008/126943). They also used N-acetylneuraminic acid as a starting material, and the key oxazoline intermediates were obtained very efficiently in 3 steps. The product can be obtained after 5 steps of conversion using TMSN ₃ as a nitrogen source.

It is expected to develop more efficient synthetic methods for the synthesis of important intermediates of zanamivir in order to make the entire synthetic route more economical and easier to operate.

Summary of the invention

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;

Wherein 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;

In the method 1 for preparing 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. .

In the method 1 for preparing the compound 2, 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.

In the method 1 for preparing the compound 2, 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.

In the method 1 for producing the compound 2, the molar ratio of the compound 3 to the acid is preferably 1:1 to 1:100, further preferably 1:30 to 1:50.

In the method 1 for producing the compound 2, 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.

In the method 1 for preparing the compound 2, 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;

Method 3: Compound 34 is subjected to a hydrolysis reaction to obtain Compound 3;

Wherein, 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:

In the first method for preparing the compound 3, 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.

In the first method for producing the compound 3, 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.

In the first method for producing the compound 3, the oxidizing agent is preferably chlorous acid; and the chlorous acid is preferably obtained by reacting sodium chlorite with sodium dihydrogen phosphate.

In the first method for producing the compound 3, 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.

In Process 1 for the preparation of Compound 3, 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. When a strong base weak acid salt is used to achieve acidic conditions, 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.

In the first method for producing the compound 3, the acidic condition is preferably pH 2-4.

In the first method for producing the compound 3, the temperature of the oxidation reaction is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.

In the first method for preparing the compound 3, 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.

The first method for preparing the compound 3 is preferably carried out in the presence of 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. In the first method for preparing the compound 3, 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;

Wherein, 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:

In the method of preparing the compound 4, the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably 1,4-dioxane.

In the method for producing the compound 4, 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.

In the method of preparing the compound 4, the oxidizing agent is preferably selenium dioxide.

In the method of producing the compound 4, 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.

In the method for producing the compound 4, 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.

In the method for preparing the compound 4, 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.

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;

Wherein, 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:

In the method for preparing the compound 5, 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.

In the process for preparing the compound 5, the base is preferably an organic base, and the organic base is preferably one or more of pyridine, piperidine and triethylamine.

In the method for producing the compound 5, the molar ratio of the compound 6 to the base is preferably 1:3 to 1:6, more preferably 1:4 to 1:5.

In the process for the preparation of the compound 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.

In the method for producing the compound 5, 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.

In the method for producing the compound 5, the temperature of the nucleophilic substitution reaction is preferably 0 ° C to 100 ° C, and more preferably 0 ° C to 60 ° C.

In the method of preparing the compound 5, 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;

Wherein, R ¹ , R ² , R ⁴ and R ⁵ are as defined above.

In the method of preparing the compound 6, the aprotic solvent is preferably an ester solvent; and the ester solvent is preferably ethyl acetate.

In the method for producing the compound 6, 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.

In the process for preparing the compound 6, the acid is preferably an organic acid; and the organic acid is preferably glacial acetic acid.

In the process for producing the compound 6, 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.

In the method of preparing the compound 6, the reducing agent is preferably one or more of zinc, iron and aluminum.

In the method of preparing the compound 6, 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.

In the method for producing the compound 6, the temperature of the reduction reaction is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.

In the method for preparing the compound 6, 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.

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. In the method for producing the compound 6, 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;

Wherein, 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:

In the method of preparing the compound 7, 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; and the aromatic hydrocarbon solvent is preferably toluene.

In the method for producing the compound 7, 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.

In the process for the preparation of the compound 7, the base is preferably an organic base; the organic base is preferably triethylamine and/or pyridine.

In the method of producing the compound 7, 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.

In the process for preparing the compound 7, the dehydrating agent is preferably dichlorosulfoxide, methanesulfonyl chloride and Burgess reagent (Burgess reagent means methyl N-(triethylammoniumsulfonylcarbamate, ie N-(triethylammoniumsulfonyl)carbamate) One or more of esters, CAS: 29684-56-8).

In the method of producing the compound 7, 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.

In the method for producing the compound 7, the temperature of the dehydration reaction is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.

In the method of preparing the compound 7, 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. Generally, when the compound 8 disappears, 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). 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;

Wherein, 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:

In the method of preparing the compound 8, the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.

In the method for producing the compound 8, 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.

In the process for producing the compound 8, 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.

In the method of producing the compound 8, the molar ratio of the compound 9 to the base is preferably 1:1 to 10:1, further preferably 1:1 to 3:1.

In the method for preparing the compound 8, 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; and 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.

In the method of preparing the compound 8, 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.

In the method of producing the compound 8, 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.

In the process for preparing compound 8, the catalyst ligand is preferably a pyrrolidine-phenol catalyst; the pyrrolidine-phenol catalyst is preferably

In the process for producing the compound 8, 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.

In the process for producing the compound 8, the temperature of the reaction is preferably -20 ° C to 40 ° C, more preferably -20 ° C to 30 ° C.

In the method for preparing the compound 8, 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.

In the method of preparing compound 8, the catalyst ligand

It can be synthesized by the method reported in the literature Chem. Eur. J. 2012, 18, 12357.

In the process for the preparation of compound 8, 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:

In the second method of preparing the compound 3, the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.

In the second method for producing the compound 3, 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.

In the second method of preparing the compound 3, the reducing agent is preferably zinc borohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride or lithium borohydride.

In the second method for preparing the compound 3, the molar ratio of the compound 12 to the reducing agent is preferably 1:1. 1:5, further preferably 1:1 to 1:3.

In the second method of producing the compound 3, the temperature of the reduction reaction is preferably -78 ° C to 40 ° C, and more preferably 20 ° C to 30 ° C.

In the second method for preparing the compound 3, 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.

The method 1 for preparing the compound 2 further comprises the following steps. In the second method for preparing the compound 3, 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;

Wherein, 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:

In the method of preparing the compound 12, 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.

In the method for producing the compound 12, 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.

In the process for the preparation of the compound 12, the oxidizing agent is preferably chlorous acid; the chlorous acid is preferably obtained by reacting sodium chlorite with sodium dihydrogen phosphate.

In the method of producing the compound 12, 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.

In the process for preparing compound 12, the acidic conditions are preferably achieved by the addition of a strong base weak acid salt, preferably sodium dihydrogen phosphate. When a strong base weak acid salt is used to achieve acidic conditions, 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.

In the process for the preparation of the compound 12, the acidic condition is preferably pH 2-4.

In the method for producing the compound 12, the temperature of the oxidation reaction is preferably from 10 ° C to 40 ° C, further preferably 20 ° C ~ 30 ° C.

In the method of preparing the compound 12, 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. 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. In the method for producing the compound 12, the compound 13 can be produced by oxidizing the compound 14 with an oxidizing agent in an aprotic solvent. Obtaining the compound 13;

Wherein 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:

In the method of producing the compound 13, the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably 1,4-dioxane.

In the method for producing the compound 13, 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.

In the method of preparing the compound 13, the oxidizing agent is preferably selenium dioxide.

In the method of producing the compound 13, 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.

In the method for producing the compound 13, the temperature of the oxidation reaction is preferably from 80 ° C to 150 ° C, more preferably from 100 ° C to 140 ° C.

In the method of preparing the compound 13, 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. One or more of the suffocating gases.

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;

Wherein 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. In the present invention, Ley's oxidation is particularly preferably used; the Ley's oxidation may be in the art. In 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 .

In the method for preparing the 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. Methylene chloride; the nitrile solvent is preferably acetonitrile; the organic solvent is further preferably a mixed solvent of dichloromethane and acetonitrile; when a mixed solvent of dichloromethane and acetonitrile is used, the dichloromethane and acetonitrile are 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.

In the method for producing the compound 14, 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.

In the process for the preparation of the compound 14, the oxidizing agent is preferably N-methylmorpholine oxide (CAS: 7529-22-8, English name is 4-Methylmorpholine N-oxide).

In the method of producing the compound 14, 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.

In the process for preparing compound 14, the catalyst is preferably tetra-n-propylammonium perruthenate (TPAP).

In the process for producing the compound 14, 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.

In the method for producing the compound 14, the temperature of the Leyd oxidation reaction is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.

In the method of preparing the compound 14, 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. In the method for preparing the compound 14, 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;

Wherein R ² , R ⁴ and R ⁵ are as defined above; R ³ is a hydroxy protecting group such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyl Phenylsilyl (TBDPS), triisopropylsilyl (TIPS) or methoxymethyl (MOM).

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:

In the process for producing the compound 15, the solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.

In the method for producing the compound 15, 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.

In the process for producing the compound 15, the fluorinating agent is preferably tetrabutylammonium fluoride and/or potassium fluoride.

In the method of producing the compound 15, 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.

In the method for producing the compound 15, 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.

In the method of preparing the compound 15, 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;

Wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above.

In the method for preparing the compound 16, 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.

In the process for producing the compound 16, the base is preferably an organic base, and the organic base is preferably one or more of pyridine, piperidine and triethylamine.

In the process for producing the compound 16, the molar ratio of the compound 17 to the base is preferably 1:1 to 1:5, further preferably 1:1 to 1:4.

In the method of preparing compound 16, 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.

In the method of preparing the compound 16, 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.

In the method for producing the compound 16, the temperature of the nucleophilic substitution reaction is preferably 0 ° C to 100 ° C, and more preferably 0 ° C to 60 ° C.

In the method of preparing the compound 16, 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.

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;

Wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above.

In the method of preparing the compound 17, 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.

In the method for producing the compound 17, 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.

In the process for the preparation of the compound 17, the acid is preferably an organic acid; and the organic acid is preferably glacial acetic acid.

In the process for producing the compound 17, 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.

In the method of preparing the compound 17, the reducing agent is preferably one or more of zinc, iron and aluminum.

In the process for producing the compound 17, 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.

In the method of producing the compound 17, the temperature of the reduction reaction is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.

In the method for preparing the compound 17, 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.

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;

Wherein 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:

In the method of preparing the compound 18, 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; and the aromatic hydrocarbon solvent is preferably toluene.

In the method for producing the compound 18, 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.

In the process for preparing the compound 18, the dehydrating agent is preferably dichlorosulfoxide, methanesulfonyl chloride and Burgess reagent (Burgess reagent means methyl N-(triethylammoniumsulfonylcarbamate, N-(triethylammoniumsulfonyl)carbamate) One or more of esters, CAS: 29684-56-8).

In the method of producing the compound 18, 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.

In the process for the preparation of the compound 18, the base is preferably an organic base; and the organic base is preferably triethylamine and/or pyridine.

In the process for the preparation of the compound 18, 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.

In the method for producing the compound 18, the temperature of the dehydration reaction is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.

In the method for preparing the compound 18, 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.

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). Said catalyst The molar ratio to the compound 19 is preferably 1:1 to 1:5, more preferably 1:3 to 1:4.

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. 18.

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;

Wherein 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:

In the method for producing the compound 19, the aprotic solvent is preferably an ether solvent solvent; and the ether solvent is preferably tetrahydrofuran.

In the method for producing the compound 19, 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.

In the method for preparing the compound 19, 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. One or more of an acid salt and an ion exchange resin; the inorganic base is preferably sodium methoxide and/or potassium t-butoxide; and the organic base is preferably tetrabutylammonium hydroxide or 1,8-diazabicyclo ring. [5.4.0] 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.

In the method of producing the compound 19, 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.

In the method for producing the compound 19, the temperature of the reaction is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.

In the method for preparing the compound 19, 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.

In the method of preparing the compound 8 or 19, 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;

Wherein 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:

In the method of preparing the compound 10, 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.

In the method for producing the compound 10, 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.

In the method of preparing the compound 10, 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.

In the method of producing the compound 10, 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.

In the process for producing the compound 10, the molar ratio of the acetone to the compound 11 is preferably 5:1 to 20:1, further preferably 5:1 to 10:1.

In the method of preparing the compound 10, the catalyst is preferably any of the catalysts represented by the following formula, and more preferably a Jacobsen catalyst;

In the process for producing the compound 10, 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.

In the method of producing the compound 10, the temperature of the Michael addition reaction is preferably 0 ° C to 40 ° C, more preferably 20 ° C to 30 ° C.

In the method of preparing the compound 10, 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.

In the process for preparing compound 10, 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;

Wherein, 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:

In the method for preparing the compound 20, 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.

In the method for producing the compound 20, 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.

In the process for the preparation of the compound 20, 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).

In the method of producing the compound 20, 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.

In the method of producing the compound 20, the temperature of the oxidation reaction is preferably 0 ° C to 40 ° C, and more preferably 20 ° C to 30 ° C.

In the method of preparing the compound 20, 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. Kind. 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. In the method for preparing the compound 20, 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;

Wherein, 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:

In the process for producing the compound 21, the catalyst is preferably montmorillonite; the montmorillonite is preferably a conventional commercially available montmorillonite, further preferably K-10 montmorillonite.

In the method of producing the compound 21, 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.

In the process for the preparation of the compound 21, the ketone is preferably acetone, methyl ethyl ketone, 2-pentanone or 3-pentanone.

In the method for producing the compound 21, 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.

In the method for producing the compound 21, the temperature of the condensation reaction is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.

In the method for preparing the compound 21, 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.

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. In the method for producing the compound 21, 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;

Wherein R ^{3 is} as defined above.

In the method of preparing the compound 22, 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.

In the method of preparing the compound 22, the reducing agent is preferably one or more of lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride.

In the method of producing the compound 22, 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.

In the method for producing the compound 22, the temperature of the reduction reaction is preferably 0 ° C to 40 ° C, more preferably 10 ° C to 30 ° C.

In the method for preparing the compound 22, 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.

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;

Wherein 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:

In the method of preparing the compound 23, the organic solvent is preferably an amide solvent; and the amide solvent is preferably N,N-dimethylformamide.

In the method for producing the compound 23, 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.

In the method of preparing compound 23, 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.

In the process for preparing the compound 23, the molar ratio of the base to the D-(-)-divinyl tartrate 24 is preferably 1:1.

In the method of preparing compound 23, the hydroxy protecting agent is preferably tert-butyldimethylchlorosilane, trimethylchlorosilane, tert-butyldiphenylchlorosilane, triisopropylchlorosilane, and chloromethyl group. One or more of the ethers.

In the method for producing the compound 23, 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.

In the process for preparing compound 23, 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 When the ester 24 disappears, it is the reaction end point, and the reaction time is preferably 1 h to 24 h, and more preferably 8 h to 15 h.

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.

In the present invention, 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. In the present invention, 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;

In the method 2 for preparing the compound 2, the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.

In the method 2 for preparing the compound 2, 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.

In the method 2 for preparing the compound 2, 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.

In the method 2 for preparing the compound 2, the molar ratio of the compound 35 to the base is preferably 1:1 to 1:100, further preferably 1:40 to 1:100.

In the method 2 for producing the compound 2, the temperature of the hydrolysis reaction is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.

In the method 2 for preparing the compound 2, 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.

The third method for preparing the compound 3 may be a conventional method of the hydrolysis reaction in the art. In the present invention, 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;

In the third method for producing the compound 3, the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.

In the third method for producing the compound 3, 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.

In the third method for preparing the compound 3, 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.

In the third method for producing the compound 3, the molar ratio of the compound 34 to the base is preferably 1:1 to 1:100, more preferably 1:40 to 1:100.

In the third method for producing the compound 3, the temperature of the hydrolysis reaction is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.

In the third method for preparing the compound 3, 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.

In the present invention, 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. In the method 2 for preparing the compound 2, 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;

Wherein, 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. In the present invention, 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.

In the method of preparing the compound 35, the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.

In the method for producing the compound 35, 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.

In the method of preparing the compound 35, 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.

In the method of producing the compound 35, the molar ratio of the compound 34 to the acid is preferably 1:1 to 1:100, further preferably 1:30 to 1:50.

In the method for producing the compound 35, 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.

In the method of preparing the compound 35, 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;

Wherein, 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:

In the method of preparing the compound 34, 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.

In the process for producing the compound 34, 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.

In the method for producing the compound 34, the molar ratio of the compound 33 to the base is preferably 1:3 to 1:6, more preferably 1:4 to 1:5.

In the method of preparing compound 34, 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.

In the method of producing the compound 34, 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.

In the method for producing the compound 34, the temperature of the nucleophilic substitution reaction is preferably 0 ° C to 100 ° C, and more preferably 0 ° C to 30 ° C.

In the method of preparing the compound 34, 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. In the method for preparing the compound 34, 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;

Wherein, R ¹ , R ² , R ⁴ and R ⁵ are as defined above.

In the method of producing the compound 33, the aprotic solvent is preferably an ester solvent; and the ester solvent is preferably ethyl acetate.

In the method for producing the compound 33, 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.

In the process for preparing compound 33, the acid is preferably an organic acid; and the organic acid is preferably glacial acetic acid.

In the process for producing the compound 33, 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.

In the method of preparing the compound 33, the reducing agent is preferably one or more of zinc, iron and aluminum.

In the method of producing the compound 33, 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.

In the method of producing the compound 33, the temperature of the reduction reaction is preferably -10 to 40 °C, more preferably 0 to 30 °C.

In the method for preparing the compound 33, 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.

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;

Wherein, 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:

In the method of preparing the compound 32, 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; and the aromatic hydrocarbon solvent is preferably toluene.

In the method for producing the compound 32, 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.

In the process for preparing the compound 32, the base is preferably an organic base; and the organic base is preferably triethylamine and/or pyridine.

In the method of producing the compound 32, the molar ratio of the base to the compound 31 is preferably 10:1 to 1:1, further preferably 8:1 to 5:1.

In the process for preparing compound 32, the dehydrating agent is preferably thionyl chloride and/or methanesulfonyl chloride.

In the method of producing the compound 32, 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.

In the process for producing the compound 32, the temperature of the dehydration reaction is preferably -78 ° C to 30 ° C, and more preferably -78 ° C to 0 ° C.

In the method of preparing the compound 32, 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.

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;

Wherein, 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:

In the method of preparing the compound 31, 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.

In the method for producing the compound 31, 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.

In the process for preparing compound 31, 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.

In the method of producing the compound 31, 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.

In the method of producing the compound 31, the temperature of the oxidation reaction is preferably -30 ° C to 30 ° C, more preferably -20 ° C to 30 ° C.

In the method for preparing the compound 31, 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.

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;

Wherein, 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:

In the method of producing the compound 30, the protic solvent is preferably an alcohol solvent; and the alcohol solvent is preferably methanol.

In the method for producing the compound 30, 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.

In the process for producing the compound 30, the base is preferably potassium carbonate and/or sodium methoxide, further preferably sodium methoxide.

In the method of producing the compound 30, 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.

In the method for producing the compound 30, the temperature of the hydrolysis reaction is preferably 0 ° C to 50 ° C, more preferably 20 ° C to 30 ° C.

In the method of preparing the compound 30, 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.

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;

Wherein, 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:

In the method of preparing the compound 29, the aprotic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.

In the method for producing the compound 29, 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.

In the process for the preparation of the compound 29, the base is preferably an inorganic base; and the inorganic base is preferably cesium carbonate.

In the process for producing the compound 29, the molar ratio of the compound 9 to the base is preferably 1:1 to 5:1, further preferably 2:1 to 4:1.

In the method of preparing the compound 29, 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.

In the process for producing the compound 29, the molar ratio of the compound 28 to the catalyst is preferably 1:1 to 10:1, further preferably 2:1 to 10:1.

In the process for producing the compound 29, 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.

In the process for preparing compound 29, the catalyst ligand is preferably a pyrrolidine-phenol catalyst; the pyrrolidine-phenol catalyst is preferably

In the process for producing the compound 29, 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.

In the process for producing the compound 29, the temperature of the reaction is preferably -20 ° C to 40 ° C, more preferably -20 ° C to 30 ° C.

In the method of preparing the compound 29, 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.

In the method of preparing compound 29, the catalyst ligand

In the process for the preparation of compound 29, 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;

Among them, the definition of 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:

In the method of preparing the compound 28, the organic solvent is preferably an ether solvent; and the ether solvent is preferably tetrahydrofuran.

In the method for producing the compound 28, 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.

In the process for preparing the compound 28, the base is preferably an organic base; and the organic is preferably triethylamine.

In the method of producing the compound 28, the molar ratio of the base to the compound 27 is preferably 1:1 to 3:1.

In the process for preparing compound 28, the catalyst is preferably 4-dimethylaminopyridine.

In the process for producing the compound 28, 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.

In the process for the preparation of the compound 28, 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.

In the process for producing the compound 28, 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.

In the method of preparing the compound 28, 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;

Among them, the definition of 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:

In the method of preparing the compound 27, the protic solvent is preferably an alcohol solvent; and the alcohol solvent is preferably methanol.

In the method for producing the compound 27, 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.

In the process for preparing the compound 27, the reducing agent is preferably an alkali metal borohydride, and the alkali metal borohydride refers to a salt of an alkali metal with BH ₄ ^- , preferably sodium borohydride, potassium borohydride and boron. One or more of lithium hydride, the sodium borohydride, potassium borohydride or lithium borohydride is a conventionally commercially available reagent.

In the method of producing the compound 27, 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.

In the method for producing the compound 27, the temperature of the reduction reaction is preferably 0 ° C to 40 ° C, and more preferably 20 ° C to 30 ° C.

In the method of preparing the compound 27, 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. In the method for producing the compound 27, 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;

Wherein 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:

In the method of preparing the compound 26, 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; and the ether solvent Preference is given to diethyl ether and/or anisole; the alkane-based solvent is preferably n-hexane.

In the method for producing the compound 26, 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.

In the method of producing the compound 26, 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.

In the method of producing the compound 26, the catalyst is preferably any of the catalysts represented by the following formulas, and further preferably a Jacobsen catalyst:

In the process for producing the compound 26, 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.

In the method for producing the compound 26, 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.

In the process for the preparation of compound 26, 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.

In the process for the preparation of compound 26, 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:

Route 1:

Route 2:

Route 3:

Route four

Compound 20 is preferably prepared by the following route:

Compound 10 was prepared using the following route:

In the present invention, 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;

Wherein 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:

In the process for preparing the compound 1, the solvent is preferably water.

In the method for producing the compound 1, 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.

In the process for preparing the compound 1, 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)

In the method of producing the compound 1, 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.

In the method for producing the compound 1, the temperature of the nucleophilic substitution reaction is preferably from 10 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.

In the method of preparing the compound 1, 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.

The process for preparing the compound 1 is preferably carried out in the presence of a base.

When the method for preparing the compound 1 is 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.

When R in the compound 1 is a methyl group, it is lamivicil. After the lanamivir is obtained, the patent can also be referred to (WO). Method of 2008/126943) Preparation of octyl octanoate CS-8958.

The invention also provides a method for synthesizing compound 3, when R ¹ is trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), triiso When propylsilyl (TIPS), methoxymethyl (MOM) or methyl group, the compound 3 can be prepared by the following method 1; when R ¹ is hydrogen, the compound 3 can be the following method. Preparation; when R ¹ is trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), When methoxymethyl (MOM), methyl or hydrogen, the compound 3 can be prepared by the following method three;

Method 2: reducing the compound 12 and the reducing agent in an aprotic solvent to obtain the compound 3;

Wherein, 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;

Wherein, 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;

Wherein, 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;

Wherein 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;

Wherein 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;

Wherein 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;

Wherein, the definition of R ⁴ is the same as described above; each reaction condition is as described in the previous method for preparing 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;

Wherein R ² , R ⁴ and R ⁵ are as defined above; each reaction condition is as described in the previous method for preparing 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;

Wherein R ² , R ⁴ and R ⁵ are as defined above; each reaction condition is as described in the previous method for preparing 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;

Wherein R ² , R ⁴ and R ⁵ are as defined above; each reaction condition is as described above for the preparation of 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;

Wherein R ² , R ⁴ and R ⁵ are as defined above; each reaction condition is as described in the previous method for preparing 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;

Wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above; each reaction condition is as described in the previous method for preparing 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;

Wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above; each reaction condition is as described in the previous method for preparing 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;

Wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above; each reaction condition is as described in the previous method for preparing 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;

Wherein R ² , R ³ and R ⁵ are as defined above; each reaction condition is as described in the previous method for preparing 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;

The definition of 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;

The definition of 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;

Wherein 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;

Wherein 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;

Wherein 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;

Wherein 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;

Wherein 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 ;

Wherein 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; ;

Wherein 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;

Wherein 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;

Wherein 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:

Wherein 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.

Preferably, 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; or R ³ is hydrogen, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl.

The above preferred conditions can be arbitrarily combined without departing from the ordinary knowledge in the art, that is, preferred embodiments of the present invention.

In the present invention, 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.

detailed description

The invention is further illustrated by the following examples, which are not intended to limit the invention. The experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications.

In the present invention, "dr" 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. The chemical shift value of hydrogen or carbon at the same position in the body.

Synthesis of Compound 10 of Example 1

The nitro compound 11 (R ⁴ is tert-butoxycarbonyl) (38.72 g, 205.76 mmol) was dissolved in anhydrous toluene (13 mL). EtOAc (4.01 g, 10.27 mmol) benzoic acid (5.02 g, 41.11 After adding acetone (152.3 mL, 2056 mmol), it was reacted at room temperature for 4 d. After completion of the spin solvent directly by column chromatography, petroleum ether / ethyl acetate = 4: 1 to give compound 10 (R ⁴ is a tert-butoxycarbonyl group) (42.6g, 84%, 84 % ee). The product was recrystallized from petroleum ether / ethyl acetate = 20:1 to give compound 10 (R ⁴ as tert-butoxycarbonyl) (37.1 g, yield 73%, 93% ee). [α] _D ²⁰ = +1.83° (c 1.0, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.28 (d, J = 5.6 Hz, 1H), 4.72 (dd, J = 12.4, 5.6 Hz , 1H), 4.55 (dd, J = 12.4, 5.2 Hz, 1H), 4.48 (m, 1H), 2.17 (s, 3H), 1.41 (s, 9H); ¹³ CNMR (100 MHz, CDCl ₃ ): δ 216. 17,154.87,80.47,76.94,45.28,44.08,30.38,28.25; ESI-MS (m / z): 269 ([m + Na] +); ESI-HRMS (m / z): Calcd: C ₁₀ H ₁₈ N ₂ NaO ₅ ([M+Na] ⁺ ): 269.11052, experimental value: 269.11079.

The nitro compound 11 (R ⁴ is tert-butoxycarbonyl) (170 mg, 0.90 mmol) was dissolved in anhydrous toluene (30 uL), followed by Jacobsen catalyst (3.5 mg, 0.009 mmol), benzoic acid (1.1 mg, 0.009 mmol) After adding acetone (670 uL, 9.034 mmol), it was reacted at room temperature for 4 d. After completion of the spin solvent directly by column chromatography, petroleum ether / ethyl acetate = 4: 1 to give compound 10 (R ⁴ is a tert-butoxycarbonyl group) (205mg, yield 92%, 70% ee). [α] _D ²⁰ = +0.75° (c 1.0, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.28 (d, J = 5.6 Hz, 1H), 4.72 (dd, J = 12.4, 5.6 Hz , 1H), 4.55 (dd, J = 12.4, 5.2 Hz, 1H), 4.48 (m, 1H), 2.17 (s, 3H), 1.41 (s, 9H); ¹³ CNMR (100 MHz, CDCl ₃ ): δ 216. 17,154.87,80.47,76.94,45.28,44.08,30.38,28.25; ESI-MS (m / z): 269 ([m + Na] +); ESI-HRMS (m / z): Calcd: C ₁₀ H ₁₈ N ₂ NaO ₅ ([M+Na] ⁺ ): 269.11052, experimental value: 269.11079.

The preparation of compound 10 under different catalyst catalysis, the reaction conditions were optimized as shown in Table 1; the preparation of compound 10 under the catalysis of catalyst 12 (Cat. 12), under different organic solvent conditions, the reaction conditions were optimized as shown in Table 2; Preparation of compound 10 under the catalysis of Catalyst 12 (Cat. 12), under different additive conditions, the reaction conditions were optimized as shown in Table 3; Cat.1, Cat.2, and Cat.3 are commercially available items. Cat. 4 can be found in the literature: J. Am. Chem. Soc. 2012, 134, 20197; Cat. 5 can be found in the literature: Angew. Chem. Int. Ed. 2012, 51, 8838; Cat. 6 can be found in the literature: Chem. Commun. 2012, 48, 5193; reported methods of synthesis. 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;

Table 1 Synthesis of Compound 10 Catalysts

Brosm (Based on Recovered Starting Materials) = calculated yield based on recovered raw materials

Table 2 Compound 10 synthetic organic solvent screening (Cat. 12)

实验编号Experiment number	添加剂additive	有机溶剂Organic solvents	温度temperature	时间time	收率(％)Yield (%)	ee(％)Ee(%)
实验编号Experiment number	添加剂additive	有机溶剂Organic solvents	温度temperature	时间time	收率(％)Yield (%)	ee(％)Ee(%)	11	苯甲酸benzoic acid	苯benzene	室温Room temperature	4d4d	7878	8383
22	苯甲酸benzoic acid	均三甲苯Mesitylene	室温Room temperature	4d4d	8484	8484	11	苯甲酸benzoic acid	苯benzene	室温Room temperature	4d4d	7878	8383
22	苯甲酸benzoic acid	均三甲苯Mesitylene	室温Room temperature	4d4d	8484	8484	33	苯甲酸benzoic acid	氯苯chlorobenzene	室温Room temperature	4d4d	7171	8484
44	苯甲酸benzoic acid	三氟甲苯Trifluorotoluene	室温Room temperature	4d4d	6969	8484	33	苯甲酸benzoic acid	氯苯chlorobenzene	室温Room temperature	4d4d	7171	8484
44	苯甲酸benzoic acid	三氟甲苯Trifluorotoluene	室温Room temperature	4d4d	6969	8484	55	苯甲酸benzoic acid	苯甲醚Anisole	室温Room temperature	4d4d	7777	8484
66	苯甲酸benzoic acid	正己烷Hexane	室温Room temperature	4d4d	8181	7878	55	苯甲酸benzoic acid	苯甲醚Anisole	室温Room temperature	4d4d	7777	8484
66	苯甲酸benzoic acid	正己烷Hexane	室温Room temperature	4d4d	8181	7878	77	苯甲酸benzoic acid	乙醚Ether	室温Room temperature	4d4d	8181	8282
88	苯甲酸benzoic acid	二氯甲烷Dichloromethane	室温Room temperature	4d4d	7171	8383	77	苯甲酸benzoic acid	乙醚Ether	室温Room temperature	4d4d	8181	8282
88	苯甲酸benzoic acid	二氯甲烷Dichloromethane	室温Room temperature	4d4d	7171	8383	99	苯甲酸benzoic acid	四氯化碳Carbon tetrachloride	室温Room temperature	4d4d	4747	8383

Table 3 Compound 10 Synthetic Additive Screening (Cat. 12)

实验编号Experiment number	添加剂additive	有机溶剂Organic solvents	温度temperature	时间time	收率(％)Yield (%)	ee(％)Ee(%)
实验编号Experiment number	添加剂additive	有机溶剂Organic solvents	温度temperature	时间time	收率(％)Yield (%)	ee(％)Ee(%)	11	乙酸Acetic acid	甲苯Toluene	室温Room temperature	4天4 days	9292	7575
22	对二苯甲酸Dibenzoic acid	甲苯Toluene	室温Room temperature	4天4 days	8484	7373	11	乙酸Acetic acid	甲苯Toluene	室温Room temperature	4天4 days	9292	7575
22	对二苯甲酸Dibenzoic acid	甲苯Toluene	室温Room temperature	4天4 days	8484	7373	33	对羟基苯甲酸Hydroxybenzoic acid	甲苯Toluene	室温Room temperature	4天4 days	8989	7979
44	对硝基苯甲酸P-nitrobenzoic acid	甲苯Toluene	室温Room temperature	4天4 days	8787	7979	33	对羟基苯甲酸Hydroxybenzoic acid	甲苯Toluene	室温Room temperature	4天4 days	8989	7979
44	对硝基苯甲酸P-nitrobenzoic acid	甲苯Toluene	室温Room temperature	4天4 days	8787	7979	55	(+)-樟脑磺酸(+)-camphorsulfonic acid	甲苯Toluene	室温Room temperature	4天4 days	7777	8484
66	对甲苯磺酸p-Toluenesulfonic acid	甲苯Toluene	室温Room temperature	4天4 days	6464	8484	55	(+)-樟脑磺酸(+)-camphorsulfonic acid	甲苯Toluene	室温Room temperature	4天4 days	7777	8484

The structure of the catalyst is as follows:

The structure of the Jacobsen catalyst (Cat. 12) is as follows:

Synthesis of the compound of Example 2 (R ¹ is a methoxymethyl group, and R ² and R ⁵ are each independently a methyl group)

Compound 9 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl) (32.00 g, 121.82 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL). Compound 10 (R ⁴ is tert-butoxycarbonyl) (90.00 g, 365.50 mmol), copper bromide (8.16 g, 36.55 mmol), cesium carbonate (18.00 g, 54.82 mmol), catalyst ligand

(15.60g, 36.55mmol) was placed in an egg-shaped flask, and added to anhydrous tetrahydrofuran (1500 mL) at room temperature for 4 h to give a small amount of white solid. Then, compound 9 was added at 0 ° C (R ¹ was methoxymethyl, R ² and R ^{5 )} The reaction was carried out separately in methyl tetrahydrofuran solution, and the reaction was continued at 0 ° C for 36 hours. The saturated ammonium chloride solution was quenched and extracted with ethyl acetate. After the solvent was evaporated, the mixture was purified by column chromatography, petroleum ether / ethyl acetate = 4: 1, a compound 8 is obtained (R ¹ is a methoxymethyl group, R ² and R ⁵ are each independently a methyl group, and R ⁴ is a tert-butoxycarbonyl group) (56.50 g, yield 80%), and a catalyst ligand is recovered.

(12.10 g, yield 78%) and compound 10 (R ⁴ is tert-butoxycarbonyl) (62.50 g, yield 69%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.45 - 4.80 (m, 7H), 4.17 - 4.22 (m, 1H), 4.00 - 4.05 (m, 2H), 3.67 (m, 1H), 3.40 (m, 3H) ), 2.17 to 2.23 (m, 1H), 1.75 to 1.85 (m, 1H), 1.50 (m, 3H), 1.42 (m, 9H), 1.39 (m, 3H) 1.33 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 155.23, 109.60, 98.36, 96.26, 82.74, 81.50, 76.82, 73.19, 67.19, 65.36, 56.09, 48.75, 38.30, 28.13, 27.57, 25.97, 25.23; ESI-MS (m/z): ^{473.3 ([m + Na] +} ); ESI-HRMS (m / z): _{_{_{Calcd: C 19 H 34 N 2 NaO}}} 10 ([m + Na] +): 473.21057, found: 473.21034.

The conditions for the types and equivalents of the catalysts synthesized for the compound 8 are shown in Tables 4 and 5, and the substrate equivalents for the reaction are shown in Table 6.

Table 4 Screening of Catalysts for Compound 8 Synthesis

Experiment number

Catalyst ^a

9 equivalent

10 equivalent

Ligand equivalent

Alkali equivalent

Yield(%)

11	乙酸铜Copper acetate	11	55	0.20.2	0.30.3	3333
11	乙酸铜Copper acetate	11	55	0.20.2	0.30.3	3333	22	氯化亚铜Cuprous chloride	11	55	0.20.2	0.30.3	1616
33	氯化铜Copper chloride	11	55	0.20.2	0.30.3	5555	22	氯化亚铜Cuprous chloride	11	55	0.20.2	0.30.3	1616
33	氯化铜Copper chloride	11	55	0.20.2	0.30.3	5555	44	溴化亚铜Cuprous bromide	11	55	0.20.2	0.30.3	23twenty three
55	溴化铜Copper bromide	11	55	0.20.2	0.30.3	7878	44	溴化亚铜Cuprous bromide	11	55	0.20.2	0.30.3	23twenty three
55	溴化铜Copper bromide	11	55	0.20.2	0.30.3	7878	66	碘化亚铜Cuprous iodide	11	55	0.20.2	0.30.3	1717

^a (The ratio of the molar amount of the catalyst to the molar amount of the compound 9 is 0.2)

Table 5 Screening of Catalyst Equivalents for Compound 8 Synthesis

Table 6 Screening of Reaction Substrate Equivalents for Compound 8 Synthesis 10

Synthesis of the compound of Example 3 (R ¹ is a methoxymethyl group, R ² and R ⁵ are each independently a methyl group, and R ⁴ is a tert-butoxycarbonyl group)

Compound 8 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl) (20 g, 44.40 mmol) is dissolved in anhydrous dichloromethane (3.0 L). Pyridine (71.5 mL, 888.00 mmol) and chlorosulfoxide (6.5 mL, 88.80 mmol) were sequentially added at 0 ° C, and the mixture was reacted at 0 ° C for 2 h. The filtrate was concentrated and subjected to column chromatography, petroleum ether / ethyl acetate = 8:1 to give compound 7 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (13.44 g, yield 70%) (dr = 8:1). [α] _D ²⁰ = +27.95° (c 0.75, CHCl ₃ ); ¹ H NMR (Pyridine-d ₅ , 400 MHz) (major isomer): δ 8.24 (d, J = 8.0 Hz, 1H), 5.14 (t, J = 7.6 Hz, 1H), 5.04 (t, J = 9.6, 1H), 4.69 (br, 1H), 4.62 (d, J = 10.8 Hz, 1H), 4.65 (dd, J = 6.4, 2.4 Hz, 2H), 4.58 (d, J = 6.4 Hz, 1H), 4.51 (d, J = 6.4 Hz, 1H), 4.43 (s, 1H), 4.26 (q, J = 5.6, 1H), 4.02 ( Dd, J = 8.4, 6.0 Hz, 1H), 3.94 (dd, J = 8.4, 6.4 Hz, 1H), 3.79 (d, J = 4.8 Hz, 1H), 3.00 (s, 3H), 1.45 (s, 3H) ), 1.22 (s, 9H), 1.19 (s, 3H), 1.12 (s, 3H); ¹³ C NMR (100 MHz, Pyridine-d ₅ ) (major isomer): δ 156.85, 153.21, 109.42, 99.08, 98.91, 85.11, 79.64, 76.84, 76.61, 76.39, 66.91, 56.53, 51.20, 28.84, 27.21, 25.84, 19.34; ESI-MS (m/z): 455.4 ([M+Na] ⁺ ); ESI-HRMS (m/z ): Calculated value: C ₁₉ H ₃₂ N ₂ NaO ₉ ([M+Na] ⁺ ): 455.20000, Experimental value: 455.20090.

Compound 8 (R ¹ is a methoxymethyl group, R ² and R ⁵ are each independently a methyl group, and R ⁴ is a tert-butoxycarbonyl group) (100 mg, 0.22 mmol) dissolved in anhydrous tetrahydrofuran (15 mL), followed by three Ethylamine (92 μL, 0.66 mmol), DMAP (6 mg, 0.04 mmol) and methanesulfonyl chloride (49 μL, 0.22 mmol) were reacted at room temperature for 8 h, supplemented with triethylamine (61 μL, 0.44 mmol), DMAP (4 mg, 0.03 mmol) With methanesulfonyl chloride (28 μL, 0.13 mmol), the reaction was continued for 4 h. The reaction was quenched with saturated aq. The filtrate was concentrated and subjected to column chromatography, petroleum ether / ethyl acetate = 8:1 to give compound 7 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (56 mg, yield 58%).

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. (Burgess reagent means methyl N-(triethylammoniumsulfonylcarbamate, methyl N-(triethylammoniumsulfonyl)carbamate, CAS: 29684-56-8) (79 mg, 0.33 mmol) for 8 h at room temperature. Saturated ammonium chloride solution the reaction was quenched, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated by column chromatography, petroleum ether / ethyl acetate = 8: 1 to give compound 7 (R ¹ is methoxymethyl, R ^2, and R ^{5 is} independently methyl and R ⁴ is tert-butoxycarbonyl) (41 mg, yield 43%).

Synthesis of the compound of Example 4 (R ¹ is a methoxymethyl group, R ² and R ⁵ are each independently a methyl group, and R ⁴ is a tert-butoxycarbonyl group)

Compound 7 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (10 g, 23.12 mmol) dissolved in ethyl acetate (1.10 L), cooled to After 0 ° C, zinc powder (151 g, 2312.00 mmol) and glacial acetic acid (133 mL, 2312.00 mmol) were sequentially added, and the reaction was continued at this temperature overnight. The excess zinc powder was removed by filtration, and the excess ammonia water was added to the filtrate, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated, and then purified by column chromatography, petroleum ether / ethyl acetate = 2:1 to obtain compound 6 (R ¹ Methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (7.91 g, yield 85%). [α] _D ²⁰ = -15.58° (c 1.0, CHCl ₃ ); ¹ H NMR (CDCl ₃ , 400 MHz): δ 4.96 (d, J = 6.8 Hz, 1H), 4.74 (d, J = 6.8 Hz, 1H), 4.42 (br, 1H), 4.39 (s, 1H), 4.30 (br, 1H), 4.24 (m, 1H), 4.00 to 4.30 (m, 3H), 3.67 (d, J = 10.0 Hz, 1H) ), 2.85 (t, J = 9.6 Hz, 1H), 1.71 (s, 3H), 1.45 (s, 9H), 1.39 (s, 3H), 1.35 (s, 3H); ¹³ C NMR (100 MHz, CDCl _{3 )} ): δ 156.45, 152.96, 108.00, 98.77, 98.13, 80.37, 79.67, 77.78, 75.02, 65.40, 56.24, 51.80, 51.04, 28.39, 26.40, 25.43, 19.21; ESI-MS (m/z): 403.4 ([M+ H] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₉ H ₃₅ N ₂ O ₇ ([M+H] ⁺ ): 403.24388, Experimental value: 403.24551.

Compound 7 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (1 g, 2.31 mmol) dissolved in ethyl acetate (110 mL), cooled to 0 After °C, iron powder (12.95 g, 231.20 mmol) and glacial acetic acid (13.3 mL, 231.20 mmol) were sequentially added, and the reaction was continued at this temperature overnight. Excess iron powder was removed by filtration, the filtrate was added excess of aqueous ammonia, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated by column chromatography, petroleum ether / ethyl acetate = 2: 1 to give compound 6 (R ¹ is Methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (510 mg, yield 55%).

Compound 7 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (1 g, 2.31 mmol) dissolved in ethyl acetate (110 mL), cooled to 0 After °C, aluminum powder (6.24 g, 231.20 mmol) and glacial acetic acid (13.3 mL, 231.20 mmol) were sequentially added, and the reaction was continued at this temperature overnight. Excess aluminum was removed by filtration, the filtrate was added excess of aqueous ammonia, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated by column chromatography, petroleum ether / ethyl acetate = 2: 1 to give compound 6 (R ¹ is Methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (316 mg, yield 34%).

Synthesis of Compound 5 of Example 5 (R ¹ is a methoxymethyl group, R ² and R ⁵ are each independently a methyl group, and R ⁴ is a tert-butoxycarbonyl group)

Compound 6 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (10 g, 24.85 mmol) dissolved in dichloromethane (1 L), cooled to 0 After °C, triethylamine (14.0 mL, 99.40 mmol) and acetyl chloride (1.77 mL, 25.10 mmol) were sequentially added and reacted at 0 ° C for 2 h. After completion of solvent chromatography, direct column chromatography, petroleum ether / ethyl acetate = 4:1 to give compound 5 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxy Carbonyl) (9.94 g, yield 90%). [α] _D ²⁰ =+11.14° (c 1.1, CHCl ₃ ); ¹ H NMR (CD ₃ CN, 400 MHz): δ 6.40 (d, J = 8.4 Hz, 1H), 5.29 (d, J = 6.8 Hz) , 1H), 4.63 to 4.68 (m, 2H), 4.45 (s, 1H), 4.18 to 4.25 (m, 3H), 4.08 (dd, J = 8.8, 6.0 Hz, 1H), 4.04 (dd, J = 8.8 , 6.0 Hz, 1H), 3.86 (t, J = 9.6 Hz, 1H), 3.80 (dd, J = 6.0, 1.2 Hz, 1H), 3.35 (s, 3H), 1.88 (s, 3H), 1.73 (br) , 3H), 1.42 (s, 9H), 1.39 (s, 3H), 1.33 (s, 3H); ¹³ CNMR (100 MHz, CD ₃ CN): δ 170.17, 155.64, 151.44, 107.97, 98.17, 97.46, 78.13, 76.13 , 76.00, 75.24, 65.79, 55.17, 49.94, 48.19, 27.35, 25.71, 24.21, 22.21, 18.08; ESI-MS (m/z): 467.5 ([M+Na] ⁺ ), 483.6 ([M+K] ⁺ ); ESI-HRMS (m / z): _{_{_{Calcd: C 21 H 36 N 2 NaO}}} 8 ([m + Na] +): 467.23639, found: 467.23778.

Compound 6 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (1 g, 2.49 mmol) dissolved in pyridine (120 mL), acetic anhydride (5 mL) ), the temperature was raised to 60 ° C for 12 h. After completion of the solvent, the residue was purified by chromatography.

Compound 6 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (1 g, 2.49 mmol) is dissolved in piperidine (120 mL), and acetic anhydride is added ( 5 mL), the temperature was raised to 60 ° C for 12 h. After the solvent was swirled, the residue was purified by column chromatography eluting elut elut elut

Synthesis of the compound of Example 6 (R ¹ is a methoxymethyl group, R ² and R ⁵ are each independently a methyl group, and R ⁴ is a tert-butoxycarbonyl group)

Compound 5 (R ¹ is a methoxymethyl group, R ² and R ⁵ are each independently a methyl group, and 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. The mixture was filtered with a funnel of celite, and the filtrate was concentrated and then directly subjected to column chromatography, petroleum ether / ethyl acetate = 1:1 to obtain compound 4 (R ¹ is methoxymethyl, and R ² and R ⁵ are each independent. It is a methyl group, and R ⁴ is a tert-butoxycarbonyl group (515 mg, yield 50%). [α] _D ²⁰ = +54.55° (c 0.9, CHCl ₃ ); ¹ H NMR (400MHz, CDCl ₃ ): δ 9.17 (s, 1H), 6.08 (d, J = 6.8 Hz, 1H), 5.72 ( d, J=2.5 Hz, 1H), 5.14 (d, J=7.2 Hz, 1H), 4.65 to 4.75 (m, 3H), 4.28 to 4.38 (m, 2H), 4.07 to 4.19 (m, 3H), 3.83 (d, J = 5.5 Hz, 1H), 3.35 (s, 3H), 1.98 (s, 3H), 1.43 (m, 9H), 1.39 (s, 3H), 1.34 (s, 3H); ¹³ C NMR ( 100 MHz, CDCl ₃ ): δ 185.28, 170.98, 156.00, 151.70, 118.87, 108.82, 98.98, 80.32, 77.08, 75.35, 66.49, 56.24, 49.48, 48.53, 29.67, 28.27, 26.67, 25.16, 23.40; ESI-MS (m/) z): 481.5 ([M+Na] ⁺ ), 513.6 ([M+MeOH+Na] ⁺ ); ESI-HRMS (m/z): Calculated: C ₂₁ H ₃₄ N ₂ NaO ₉ ([M+Na ] ⁺ ): 481.21565, experimental value: 481.21434.

Compound 5 (R ¹ is a methoxymethyl group, R ² and R ⁵ are each independently a methyl group, and 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. The mixture was filtered with a funnel of celite, and the filtrate was concentrated and then directly subjected to column chromatography, petroleum ether / ethyl acetate = 1:1 to obtain compound 4 (R ¹ is methoxymethyl, and R ² and R ⁵ are each independent. It is a methyl group, and R ⁴ is a tert-butoxycarbonyl group (309 mg, yield 30%).

Synthesis of Compound 3 of Example 7 (R ¹ is a methoxymethyl group, R ² and R ⁵ are each independently a methyl group, and R ⁴ is a tert-butoxycarbonyl group)

Compound 4 (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. The filtrate is concentrated and subjected to column chromatography, methylene chloride / methanol = 8:1 to give compound 3 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) 827 mg, yield 80%). [α] _D ²⁰ = +10.12 ° (c 0.43 MeOH); ¹ H NMR (CD ₃ OD, 500 MHz): δ 5.71 (d, J = 2.0 Hz, 1H), 4.73 (d, J = 6.5 Hz, 1H) ), 4.68 (d, J = 7.0, 1H), 4.37 to 4.46 (m, 2H), 4.29 (d, J = 8.4 Hz, 1H), 4.20 (dd, J = 6.4, 4.8 Hz, 1H), 4.07 ( Dd, J = 7.2, 4.8 Hz, 1H), 3.99 (t, J = 8.0 Hz, 1H), 3.86 (d, J = 5.5 Hz, 1H), 3.38 (s, 3H), 1.97 (s, 3H), 1.44(s,9H), 1.40(s,3H), 1.34(s,3H); ¹³ C NMR (125MHz, DMSO-d ₆ ): δ169.91,162.77,156.09,134.05,128.27,108.20,98.21,78.21,76.94 , 76.07, 75.39, 65.91, 56.12, 50.02, 47.71, 28.65, 26.94, 25.64, 23.31; ESI-MS (m/z): 473.4 ([MH] ⁺ ). ESI-HRMS (m/z): Calculated: C ₂₁ H ₃₃ N ₂ O ₁₀ ([MH] ⁺ ): 473.21407, found: 473.21467.

Synthesis of Compound 2 of Example 8 (R is hydrogen)

Compound 3 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (100 mg, 0.211 mmol) dissolved in dichloromethane (100 mL), trifluorobenzene Acetic acid (10 mL) was reacted at room temperature for 8 h. The system was concentrated to give the trifluoroacetic acid salt of Compound 2 (R is hydrogen) (85 mg, yield 90%). [α] _D ²⁰ = +20.13° (c 0.01, DMSO); ¹ H NMR (D ₂ O, 500 MHz): δ 5.85 (d, J = 2.5 Hz, 1H), 4.35 (d, J = 11.0 Hz, 1H), 4.26 (dd, J = 10.5, 9.5 Hz, 1H), 4.10 (dd, J = 9.5, 2.5 Hz, 1H), 3.88 (ddd, J = 9.0, 5.5, 3.0 Hz, 1H), 3.76 (dd , J = 12.0, 3.0 Hz, 1H), 3.57 (dd, J = 12.0, 5.5 Hz, 1H), 3.46 (dd, J = 9.0, 1 Hz, 1H), 3.30 (s, 1H), 1.98 (s, 1H) ¹³ C NMR (125 MHz, D ₂ O): δ 174.55, 164.72, 144.61, 104.12, 77.23, 75.73, 69.52, 62.27, 60.32, 50.44, 45.43, 22.13; ESI-MS (m/z): 289.2 ([MH. ^{] +) .ESI-HRMS (m} / z): _{_{_{Calcd: C 11 H 17 N 2 O}}} 7 ([MH] +): 289.10412, found: 289.10520.

Synthesis of Compound 23 of Example 10 (R ³ is tert-butyldimethylsilyl)

Weigh 24g NaH (24g, 0.4mmol, 60% by mass, the mass percentage refers to the mass of sodium hydride as a percentage of the total mass of sodium hydride reagent) in a 2L three-necked flask, add 600mL After N,N-dimethylformamide (DMF, CAS: 68-12-2), it was cooled to 0 ° C, and 82.5 g of D-(-)-diethyl tartrate 24 (82.5 g, 0.4 mmol) was dissolved. The solution was slowly added dropwise to 200 ml of N,N-dimethylformamide (DMF, CAS: 68-12-2), and the reaction was clarified by adding the reaction for about half an hour. TBSCl (tert-butyldimethylsilyl chloride) (60.3 g, 0.4 mmol) was added to the above solution, and the reaction was allowed to warm to room temperature overnight. After being added to a saturated NH ₄ Cl solution, the mixture was extracted with EtOAc EtOAc (EtOAc)EtOAc. Compound 23 (R ³ is tert-butyldimethylsilyl) (128.2 g, yield 80%). [α] _D ²⁰ = -29.17° (c 1.0, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.50 (d, J = 1.6 Hz, 1H), 4.45 (dd, J = 10.0, 1.6 Hz) , 1H), 4.00 to 4.24 (m, 4H), 3.04 (d, J = 10.0 Hz, 1H), 1.20 (q, J = 6.8 Hz, 6H), 0.77 (s, 9H), 0.01 (s, 3H) , -1.0 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 171.30, 170.36, 73.59, 73.16, 61.77, 61.34, 25.41, 18.08, 14.05, 13.96, -4.84, -5.92; ESI-MS (m/) z): 343 ([M+Na] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₄ H ₂₈ NaO ₆ Si ([M+Na] ⁺ ): 343.1546, Experimental value: 343.15474.

Synthesis of Compound 22 of Example 11 (R ³ is tert-butyldimethylsilyl)

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. After rotary evaporation column chromatography, dichloromethane / methanol = 15: 1, to give compound 22 (R ³ is tert-butyldimethylsilyl) (63.8 g, yield 90%). [α] _D ²⁰ = -3.60° (c 1.0, CHCl ₃ ); ¹ H NMR (400 MHz, CD ₃ CN): δ 3.62 (m, 1H), 3.44 to 3.50 (m, 2H), 3.38 to 3.41 (m) , 3H), 2.77 (t, J = 6.0 Hz, 1H), 2.73 (t, J = 5.6 Hz, 1H), 2.68 (d, J = 6.8 Hz, 1H), 0.81 (s, 9H), 0.01 (s) , 3H), 0.00(s, 3H); ¹³ CNMR (100MHz, CDCl ₃ ): δ 72.21, 72.10, 63.33, 62.49, 25.73, 17.93, -4.62, -5.02. ESI-MS (m/z): 259 ^{([m + Na] +)} ; ESI-HRMS (m / z): _{_{_{Calcd: C 10 H 24 NaO 4 (}}} [m + Na] +) Si: 259.13361, found: 259.13304.

Synthesis of the compound of Example 12 (R ³ is tert-butyldimethylsilyl, and R ² and R ⁵ are each independently methyl)

Compound 22 (R ³ is tert-butyldimethylsilyl) (31 g, 0.131 mol) was weighed into an egg-shaped flask, and 78.6 g of montmorillonite K-10, 31 g were sequentially added.

Molecular sieves and 1500 mL of acetone were reacted overnight at room temperature. The mixture was filtered with celite, and the residue was washed twice with ethyl acetate. The solvent was evaporated to give the crude compound 21 ( R ³ is tert-butyldimethylsilyl, and R ² and R ⁵ are each independently methyl) (36 g, yield 100%). [α] _D ²⁰ =+13.65° (c 1.0, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.19 (q, J = 6.8 Hz, 1H), 3.98 (dd, J = 8.0, 6.8 Hz) , 1H), 3.83 (dd, J = 8.4, 6.8 Hz, 1H), 3.81 (t, J = 5.6 Hz, 1H), 3.63 to 3.67 (m, 1H), 3.50 to 3.56 (m, 1H), 2.18 ( t, J = 6.4 Hz, 1H), 1.42 (s, 3H), 1.34 (s, 3H), 0.89 (s, 9H), 0.10 (s, 6H); ¹³ CNMR (100 MHz, CDCl ₃ ): δ 109. , 77.12, 72.85, 65.30, 63.64, 26.28, 25.81, 25.11, 18.09, -4.68, - 4.78. ESI-MS (m/z): 299 ([M+Na] ⁺ ); ESI-HRMS (m/z) : Calculated for C ₁₃ H ₂₈ NaO ₄ Si ([M+Na] ⁺ ): 299.16491, calc.: 299.16474.

Synthesis of the compound of Example 13 (R ³ is tert-butyldimethylsilyl, and R ² and R ⁵ are each independently methyl)

Compound 21 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl) (45 g, 0.163 mmol) in an egg-shaped flask, and 800 mL of anhydrous tetrahydrofuran is added and cooled to 0. °C, sodium bicarbonate (49.3g, 0.587mmol) was added, followed by Dess-Martin oxidant (CAS:87413-09-0, English name is 1,1,1-Triacetoxy-1, 1-dihydro-1,2 -benziodoxol-3(1H)-one) (82.96g, 0.196mmol), after natural addition to room temperature, after about 2 hours of reaction, the TLC plate was traced to the end of the reaction, the pad was filtered with silica gel and the residue was washed with dichloromethane. After concentration, direct column chromatography, petroleum ether / ethyl acetate = 20:1 to give compound 20 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl) (41.15 g, Yield 92%). [α] _D ²⁰ = -22.59° (c 1.0, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.68 (d, J = 1.2 Hz, 1H), 4.31 (m, 1H), 4.06 (dd , J=8.4, 6.8 Hz, 1H), 4.04 (dd, J=4.8, 1.2 Hz, 1H), 3.93 (dd, J=8.4, 6.0 Hz, 1H), 1.41 (s, 3H), 1.33 (s, 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); ¹³ CNMR (100 MHz, CDCl ₃ ): δ 201.88, 109.42, 77.45, 76.11, 64.79, 25.72, 25.38, 24.81, 17.93 , -5.06, -5.40. ESI-MS (m/z): 297 ([M+Na] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₃ H ₂₆ NaO ₄ Si ([M+Na ] ⁺ ): 297.14926, experimental value: 297.1500.

Compound 21 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl) (45 g, 0.163 mmol) in an egg-shaped flask, and 800 mL of anhydrous dichloromethane is added and cooled. To 0 ° C, sodium bicarbonate (49.3 g, 0.587 mmol) was added, followed by Dess-Martin oxidant (CAS: 87413-09-0, English name 1,1,1-Triacetoxy-1, 1-dihydro-1 , 2-benziodoxol-3(1H)-one) (82.96g, 0.196mmol), after natural addition to room temperature, after about 2 hours of reaction, the TLC plate was traced to the end of the reaction, and the pad was filtered with silica gel and washed with dichloromethane. The residue was filtered, concentrated and purified by column chromatography, petroleum ether / ethyl acetate = 20:1 to give compound 20 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl) (42.94 g, yield 96%).

Synthesis of the compound of Example 15 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl)

Compound 10 (R ⁴ is tert-butoxycarbonyl) (17.93 g, 72.9 mmol) was dissolved in anhydrous tetrahydrofuran (600 mL). A solution of 20 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl) (20.01 g, 72.9 mmol) in tetrahydrofuran solution was added, and the mixture was reacted at room temperature for 8 h. After the solvent was swirled, it was directly subjected to column chromatography, petroleum ether / ethyl acetate = 4:1, and starting material 10 (R ⁴ was tert-butoxycarbonyl) (3.5 g, yield 19%) to obtain compound 19 (R ³ is uncle butyldimethylsilyl group, R ² and R ⁵ each independently are methyl, R ⁴ is tert-butoxycarbonyl) (29.3g, yield recovered starting material (brsm: based on recovered Starting Materials ). 96% 1 H NMR (400 MHz, CDCl ₃ ): δ 5.12 (m, 1H), 4.83 (m, 1H), 4.27 (m, 1H), 4.08 (m, 1H), 4.00 (m, 1H), 3.93 (m, 1H) ), 3.72 (m, 1H), 3.61 (m, 1H), 2.73 to 2.89 (m, 1H), 1.85 to 2.05 (m, 1H), 1.30 to 1.44 (m, 18H), 0.87 (m, 9H), 0.08 (m, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 154.91, 109.14, 95.75, 84.63, 81.68, 80.24, 73.92, 71.40, 65.81, 48.84, 40.50, 28.71, 26.60, 26.23, 25.20, 18.31, -4.63 ESI-MS (m/z): 543 ([M+Na] ⁺ ), 559 ([M+K] ⁺ ); ESI-HRMS (m/z): Calculated: C ₂₃ H ₄₄ N ₂ NaO ₉ Si ([M+Na] ⁺ ): 534.2719, experimental value: 534.27083.

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.

Table 7 Synthesis of Compound 19 in the presence of different bases

碱Alkali	DBUDBU	Bu₄NOHBu ₄ NOH	TMGTMG	KOBuKOBu	Al₂O₃ Al ₂ O ₃	NaOHNaOH	KOAcKOAc	LDALDA
碱Alkali	DBUDBU	Bu₄NOHBu ₄ NOH	TMGTMG	KOBuKOBu	Al₂O₃ Al ₂ O ₃	NaOHNaOH	KOAcKOAc	LDALDA	时间time	10h10h	10h10h	10h10h	10h10h	10h10h	10h10h	10h10h	2h2h
产率(％)Yield(%)	6565	8282	7878	5656	3232	1616	1414	1010	时间time	10h10h	10h10h	10h10h	10h10h	10h10h	10h10h	10h10h	2h2h

Synthesis of the compound of Example 16 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl)

Compound 19 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (130 mg, 0.25 mmol) dissolved in anhydrous tetrahydrofuran (15 mL) Add triethylamine (174 μL, 0.75 mmol), 4-dimethylaminopyridine (DMAP) (7 mg, 0.05 mmol) and methanesulfonyl chloride (56 μL, 0.25 mmol), and react at room temperature for 8 h, add triethylamine (90 μL) , 0.63 mmol), 4-dimethylaminopyridine (DMAP) (4 mg, 0.03 mmol) and methanesulfonyl chloride (28 μL, 0.13 mmol). The reaction was quenched with a saturated aqueous solution of ammonium chloride. The filtrate was concentrated and subjected to column chromatography, petroleum ether / ethyl acetate = 8:1 to give compound 18 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl and R ⁴ is un Butoxycarbonyl) (89 mg, yield 71%). [α] _D ²⁰ = +9.13° (c 1.0, CHCl ₃ ); ¹ H NMR (CDCl ₃ , 400 MHz): δ 4.89 (br, 1H), 4.35 (m, 2H), 4.56 to 4.70 (m, 2H) ), 4.50 (s, 1H), 4.20 (d, J = 7.2 Hz, 1H), 4.03 (dd, J = 8.0, 6.8 Hz, 1H), 3.95 (dd, J = 8.4, 5.2 Hz, 1H), 4.50 (s, 1H), 3.81 (m, 3H), 3.66 (t, J = 8.0 Hz, 1H), 1.76 (s, 3H), 1.42 (s, 9H), 1.40 (s, 3H), 1.30 (s, 3H), 0.90 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H); ¹³ CNMR (100 MHz, CDCl ₃ ): δ 154.89, 152.88, 109.41, 96.64, 83.12, 80.48, 77.23, 65.83, 49.28 , 26.20, 26.63, 25.88, 25.23, 19.15, 18.35, -4.51, -4.80; ESI-MS (m/z): 503 ([M+H] ⁺ ), 525 ([M+Na] ⁺ ), 541 ( ^{[m + K] +);} ESI-HRMS (m / z): _{_{_{Calcd: C 23 H 42 N 2 NaO}}} 8 ([m + Na] +) Si: 525.2619, Found: 525.26027.

Compound 19 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (28.6 g, 54.9 mmol) dissolved in anhydrous dichloromethane ( In 1.1 L), pyridine (221 mL, 2746.4 mmol) was added after cooling to 0 ° C and stirred for 30 min. After adding thionyl chloride (20 mL, 274.6 mmol) at this temperature, it was naturally warmed to room temperature for 2 h. The reaction was quenched by the addition of a small amount of sodium hydroxide and filtered over Celite. After concentration and column chromatography, petroleum ether / ethyl acetate = 10:1 to give compound 18 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butyl Oxycarbonyl) (22.4 g, yield 81%).

Compound 19 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl) (130 mg, 0.25 mmol) dissolved in anhydrous toluene (15 mL) Add Burgess reagent (Burgess reagent means methyl N-(triethylammoniumsulfonylcarbamate, methyl N-(triethylammoniumsulfonyl)carbamate, CAS: 29684-56-8) (91mg, 0.38mmol) for 8h at room temperature. the reaction was quenched with ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated by column chromatography, petroleum ether / ethyl acetate = 8: 1 to give compound 18 (R ³ is tert- Methylsilyl group, R ² and R ⁵ are each independently a methyl group, and R ⁴ is a tert-butoxycarbonyl group (53 mg, yield 43%).

Synthesis of Compound 17 of Example 17 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl)

Compound 18 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (1.22 g, 2.43 mmol) dissolved in dichloromethane (50 mL) Zinc powder (6.35 g, 97.10 mmol) and glacial acetic acid (5.55 mL, 97.10 mmol) were sequentially added and reacted at room temperature for 18 h. Excess zinc powder was removed by filtration, and the filtrate was concentrated and subjected to column chromatography, petroleum ether / ethyl acetate = 2:1 to obtain compound 17 (R ³ is tert-butyldimethylsilyl, and R ² and R ⁵ are each independently The group, R ⁴ is a tert-butoxycarbonyl group (1.00 g, yield 87%). [α] _D ²⁰ =+11.96° (c 1.0, CHCl ₃ ); ¹ H NMR (CDCl ₃ , 400 MHz): δ 4.50 (d, J = 7.6 Hz, 1H), 4.35 (m, 2H), 4.07 ( m, 2H), 3.94 (d, J = 8.0 Hz, 1H), 3.65 (t, J = 8.0 Hz, 1H), 3.40 (d, J = 8.4 Hz, 1H), 2.93 (t, J = 8.8 Hz, 1H), 1.68 (s, 3H), 1.45 (s, 9H), 1.40 (s, 3H), 1.33 (s, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H) ¹³ C NMR (100 MHz, CDCl ₃ ): δ 156.41, 152.60, 109.05, 97.39, 81.21, 79.49, 78.24, 77.93, 66.21, 51.39, 28.36, 26.67, 25.92, 25.50, 19.25, 18.36, -4.55, -4.74; - MS (m/z): 473 ([M+H] ⁺ ); ESI-HRMS (m/z): Calculated: C ₂₃ H ₄₅ N ₂ O ₆ Si ([M+H] ⁺ ): 473.3056, Experimental value: 473.30414.

Compound 18 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (1.22 g, 2.43 mmol) dissolved in dichloromethane (50 mL) Zinc powder (159.8 mg, 2.43 mmol) and glacial acetic acid (148 uL, 2.43 mmol) were sequentially added and reacted at room temperature for 24 h. Excess zinc powder was removed by filtration, and the filtrate was concentrated and subjected to column chromatography, petroleum ether / ethyl acetate = 2:1 to obtain compound 17 (R ³ is tert-butyldimethylsilyl, and R ² and R ⁵ are each independently The group, R ⁴ is tert-butoxycarbonyl) (0.52 g, yield 45%).

Compound 18 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (1.22 g, 2.43 mmol) dissolved in dichloromethane (50 mL) Iron powder (117.2 mg, 2.09 mmol) and glacial acetic acid (148 uL, 2.43 mmol) were sequentially added and reacted at room temperature for 24 h. Excess iron powder was removed by filtration, and the filtrate was concentrated and subjected to column chromatography, petroleum ether / ethyl acetate = 2:1 to obtain compound 17 (R ³ was tert-butyldimethylsilyl, and R ² and R ^{5 were} each independently The group, R ⁴ is tert-butoxycarbonyl) (0.64 g, yield 55%).

Compound 18 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (1.22 g, 2.43 mmol) dissolved in dichloromethane (50 mL) Among them, aluminum powder (27.2 mg, 1.01 mmol) and glacial acetic acid (148 uL, 2.43 mmol) were successively added and reacted at room temperature for 24 h. Excess iron powder was removed by filtration, and the filtrate was concentrated and subjected to column chromatography, petroleum ether / ethyl acetate = 2:1 to obtain compound 17 (R ³ was tert-butyldimethylsilyl, and R ² and R ^{5 were} each independently The group, R ⁴ is tert-butoxycarbonyl) (0.64 g, yield 55%).

Synthesis of Compound 16 of Example 18 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl)

Compound 17 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (1.24 g, 2.62 mmol) dissolved in pyridine (120 mL) Acetic anhydride (5 mL) was added, and the mixture was heated to 60 ° C for 12 h. After completion of solvent chromatography, petroleum column / ethyl acetate = 4:1 to give compound 16 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, R ⁴ Is tert-butoxycarbonyl) (1.20 g, yield 89%). [α] _D ²⁰ = +4.4 ° (c 1.0, CHCl ₃ ); ¹ H NMR (CDCl ₃ , 400 MHz): δ 6.06 (d, J) = 7.6 Hz, 1H), 5.35 (d, J = 8.0 Hz, 1H), 4.47 (d, J = 1.6 Hz, 1H), 4.04 to 4.21 (m, 3H), 3.91 to 3.99 (m, 3H), 3.72 (t, J = 8.0 Hz, 1H), 1.96 (s, 3H), 1.73 (s, 3H), 1.42 (s, 12H), 1.36 (s, 3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 170.45, 156.24, 152.34, 108.85, 96.62, 79.76, 79.42, 78.03, 75.16, 65.86, 49.43, 49.14, 28.34, 26.69, 25.97, 25.80 , 23.38, 19.43, 18.30, - 4.479; ESI-MS (m/z): 537 ([M+Na] ⁺ ), 553 ([M+K] ⁺ ); ESI-HRMS (m/z): Calculated :C ₂₅ H ₄₆ N ₂ NaO ₇ Si([M+Na] ⁺ ): 537.2976, calc.: 537.29665.

Compound 17 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (1.24 g, 2.62 mmol) dissolved in pyridine (120 mL) Acetic anhydride (5 mL) was added and reacted at 25 ° C for 12 h. After completion of solvent chromatography, petroleum column / ethyl acetate = 4:1 to give compound 16 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, R ⁴ Is tert-butoxycarbonyl) (0.43 g, yield 32%).

Compound 17 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (1.24 g, 2.62 mmol) dissolved in piperidine (120 mL) Acetic anhydride (5 mL) was added, and the mixture was heated to 60 ° C for 12 h. After completion of solvent chromatography, petroleum column / ethyl acetate = 4:1 to give compound 16 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, R ⁴ Is tert-butoxycarbonyl) (0.74 g, yield 74%).

Compound 17 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (1.24 g, 2.62 mmol) dissolved in dichloromethane (120 mL) Triethylamine (1.82 mL, 13.10 mmol) and acetyl chloride (0.28 mL, 3.92 mmol) were added and the mixture was warmed to 25 ° C for 12 h. After completion of solvent chromatography, petroleum column / ethyl acetate = 4:1 to give compound 16 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, R ⁴ Is tert-butoxycarbonyl) (0.84 g, yield 64%).

Synthesis of Compound 15 of Example 19 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl)

Compound 16 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl) (1.20 g, 2.33 mmol) dissolved in anhydrous tetrahydrofuran (100 mL) A solution of tetrabutylammonium fluoride (1 M/L) in tetrahydrofuran (3.5 mL) was added, and the mixture was reacted at room temperature for 3 h. The reaction was quenched with saturated aq. The filtrate was concentrated and column chromatography, petroleum ether / ethyl acetate = 4:1 to give compound 15 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl and R ⁴ is un Butoxycarbonyl) (813 mg, yield 87%). [α] _D ²⁰ =+15.96° (c 1.0, CHCl ₃ ); ¹ H NMR (CD ₃ OD, 400 MHz): δ 6.32 (br, 1H), 5.08 (br, 1H), 4.49 (s, 1H) , 4.00 to 4.21 (m, 3H), 3.82 (m, 1H), 3.75 (t, J = 8.0 Hz, 1H), 3.68 (m, 1H), 3.46 (br, 1H), 1.94 (s, 3H), 1.70(s,3H), 1.38(s,12H), 1.33(s,3H); ¹³ CNMR(100MHz, CD ₃ OD): δ173.43,158.06,153.18,110.18,98.10,80.23,79.41,77.76,72.20,67.41 , 50.64, 28.84, 26.77, 26.00, 22.92, 19.80; ESI-MS (m/z): 423 ([M+Na] ⁺ ), 439 ([M+K] ⁺ ); ESI-HRMS (m/z) Calcd for C ₁₉ H ₃₂ N ₂ NaO ₇ ([M+Na] ⁺ ): 423.2106, found: 423.21017.

Compound 16 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl) (1.20 g, 2.33 mmol) dissolved in anhydrous tetrahydrofuran (100 mL) Potassium fluoride (1.35 g, 2.66 mmol) was added and reacted at room temperature for 12 h. The reaction was quenched with saturated aq. The filtrate was concentrated and column chromatography, petroleum ether / ethyl acetate = 4:1 to give compound 15 (R ³ is tert-butyldimethylsilyl, R ² and R ⁵ are each independently methyl and R ⁴ is un Butoxycarbonyl) (387 mg, yield 41%).

Synthesis of Example 14 Compound 14 (R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl)

Compound 15 (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. The filtrate was concentrated and column chromatography, petroleum ether / ethyl acetate = 1: 1, to give compound 14 (R ² and R ⁵ each independently are methyl, R ⁴ is tert-butoxycarbonyl) (238 mg, 64% yield) . [α] _D ²⁰ = -11.84° (c 1.0, CHCl ₃ ); ¹ H NMR (CDCl ₃ , 400 MHz): δ 5.92 (d, J = 6.4 Hz, 1H), 4.79 (t, J = 6.8 Hz, 1H), 4.67 (d, J = 4.8 Hz, 1H), 4.99 (d, J = 3.2 Hz, 1H), 4.45 (br, 2H), 4.28 (t, J = 8.4 Hz, 1H), 4.28 (t, J=8.4 Hz, 1H), 4.08 (dd, J=8.4, 6.8 Hz, 1H), 4.05 (br, 1H), 1.94 (s, 3H), 1.84 (s, 3H), 1.49 (s, 3H), 1.39(s,12H), 1.38(s,3H); ¹³ CNMR (100MHz, CDCl ₃ ): δ202.86,170.23,155.58,153.60,112.13,95.29,80.19,78.32,66.17,49.59,47.10,29.67,28.25,25.62 , 25.22, 23.10, 19.62; ESI-MS (m/z): 399 ([M+H] ⁺ ), 421 ([M+Na] ⁺ ), 437 ([M+K] ⁺ ) ESI-HRMS (m /z): Calculated: C ₁₉ H ₃₀ N ₂ NaO ₇ ([M+Na] ⁺ ): 421.1962, Experimental value: 421.19452.

Compound 15 (R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (400 mg, 1.00 mmol) is dissolved in anhydrous dichloromethane (60 mL), and Dess-Martin oxidant (CAS: 87413- 09-0, English name is 1,1,1-Triacetoxy-1, 1-dihydro-1,2-benziodoxol-3(1H)-one) (636 mg, 1.5 mmol), stirred at room temperature for 3 h. The reaction was quenched with saturated aqueous ammonium chloride. The filtrate was concentrated and column chromatography, petroleum ether / ethyl acetate = 1: 1, to give compound 14 (R ² and R ⁵ each independently are methyl, R ⁴ is tert-butoxycarbonyl) (130 mg of, 35% yield) .

Synthesis of Compound 13 of Example 21 (R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl)

Compound 14 (R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (160 mg, 0.40 mmol) dissolved in anhydrous 1,4-dioxane (30 mL), added with selenium dioxide (90 mg, 0.80 mmol). Argon gas was bubbled through the solution for 5 min to remove oxygen from the solution, and reacted at 130 ° C for 4 h under argon protection. After concentration of the system, direct column chromatography, petroleum ether / ethyl acetate = 1:1 gave compound 13 (R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (74 mg, yield 45%) ). [α] _D ²⁰ = +32.93° (c 1.0, CHCl ₃ ); ¹ H NMR (CDCl ₃ , 400 MHz): δ 9.24 (d, J = 7.6 Hz, 1H), 6.10 (d, J = 8.4 Hz, 1H), 5.82 (d, J = 4.0 Hz, 1H), 4.79 to 4.94 (m, 3H), 4.63 (m, 1H), 4.43 (br, 1H), 4.27 (t, J = 8.4 Hz, 1H), 4.07 (dd, J=8.4, 6.4 Hz, 1H), 1.96 (s, 3H), 1.49 (s, 3H), 1.42 (s, 9H), 1.38 (s, 3H); ¹³ CNMR (100 MHz, CDCl ₃ ) : δ203.01,185.39,170.51,155.50,151.34,118.43,111.28,80.60,79.42,78.58,65.93,48.84,47.33,28.24,25.62,24.99,22.96;ESI-MS(m/z):413 ([M+H ] ⁺ ), 435 ([M+Na] ⁺ ), 467 ([M+MeOH+Na] ⁺ ), 483 ([M+MeOH+K] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₉ H ₂₈ N ₂ NaO ₈ ([M+Na] ⁺ ): 435.1738, found: 435.1754.

Compound 14 (R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (160 mg, 0.40 mmol) dissolved in anhydrous 1,4-dioxane (30 mL), added with selenium dioxide (90 mg, 0.80 mmol). Argon gas was bubbled through the solution for 5 min to remove oxygen from the solution, and reacted at 100 ° C for 4 h under argon protection. The system was concentrated and directly subjected to column chromatography, petroleum ether / ethyl acetate = 1:1 to obtain compound 13 (R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (102 mg, yield 62%) ).

Synthesis of Compound 12 of Example 22 (R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl)

Compound 13 (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. The filtrate was concentrated and column chromatography, petroleum ether / ethyl acetate = 1: 1, to give compound 12 (R ² and R ⁵ each independently are methyl, R ⁴ is tert-butoxycarbonyl) (48mg, 63% yield) . [α] _D ²⁰ = +24.52° (c 1.0, Acetone); ¹ H NMR (Acetone-d ₆ , 400 MHz): δ 7.18 (d, J = 7.6 Hz, 1H), 5.75 (br, 1H), 4.78 (dd, J = 7.6, 6.8 Hz, 1H), 4.76 (d, J = 7.6 Hz, 1H), 4.35 (q, J = 7.2 Hz, 1H), 4.23 (m, 1H), 4.18 (t, J = 8.4 Hz, 1H), 3.99 (dd, J = 8.4, 6.4 Hz, 1H), 1.76 (s, 3H), 1.29 (s, 12H), 1.22 (s, 3H); ¹³ CNMR (Acetone-d ₆ , 100 MHz ): δ201.72,169.06,161.70,154.92,143.77,110.01,109.05,79.30,78.27,77.56,65.27,47.75,46.80,27.13,24.60,24.29,21.52;ESI-MS(m/z):427 ([MH] ^{-) .ESI-HRMS (m /} z): _{_{_{Calcd: C 19 H 28 N 2 NaO}}} 9 ([m + Na] +): 451.1687, Found: 451.1670.

Synthesis of Compound 3 of Example 23 (R ¹ is hydrogen, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl)

Compound 12 (R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (12 mg, 0.028 mmol) is dissolved in anhydrous tetrahydrofuran (5 mL), and a solution of zinc borohydride in tetrahydrofuran (0.5 M) is added. (100 uL), reacted at room temperature for 4 h. The reaction was quenched with saturated aq. The filtrate was concentrated and column chromatography, petroleum ether / ethyl acetate = 1: 1, to give compound 3 (R ¹ is hydrogen, R ² and R ⁵ each independently are methyl, R ⁴ is tert-butoxycarbonyl) (9 mg of, 75%).

Compound 12 (R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (12 mg, 0.028 mmol) is dissolved in anhydrous tetrahydrofuran (5 mL), and placed in a cold bath at -78 ° C, slowly The solution of lithium aluminum hydride (0.21 mmol) in tetrahydrofuran was added dropwise and the reaction was continued at this temperature for 1 h. The reaction was quenched with saturated aq. The filtrate is concentrated and subjected to column chromatography (dichloromethane / methanol / water = 100: 20:1) to give compound 3 (R ¹ is hydrogen, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl (9.6 mg, yield 80%).

[α] _D ²⁰ = +22.56° (c 0.03, CHCl ₃ ); ¹ H NMR (CD ₃ OD, 400 MHz): δ 5.58 (s, 1H), 4.32 (d, J = 10.0 Hz, 1H), 4.24 (m, 1H), 4.01 to 4.05 (m, 2H), 3.86 to 3.94 (m, 2H), 3.44 (d, J = 8.4 Hz, 1H), 1.87 (s, 3H), 1.33 (s, 9H), 1.26(s,3H), 1.22(s,3H); ¹³ CNMR(100MHz, CD ₃ OD): δ174.14,169.50,157.74,148.50,110.52,106.26,81.15,75.72,74.18,69.17,66.64,49.11,48.32, 27.56, 25.88, 24.20, 22.03; ESI-MS (m/z): 429 ([MH] ⁺ ). ESI-HRMS (m/z): Calculated: C ₁₉ H ₃₀ N ₂ NaO ₉ ([M+Na ] ⁺ ): 453.1844, experimental value: 453.1843.

Synthesis of Compound 3 under Different Reductant Conditions

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:

Table 8 Synthesis of Compound 3 under Different Reductant Conditions

还原剂reducing agent	NaBH₄ NaBH ₄	KBH₄ KBH ₄	LiBH₄ LiBH ₄	Mg(BH₄)₂ Mg(BH ₄ ) ₂
还原剂reducing agent	NaBH₄ NaBH ₄	KBH₄ KBH ₄	LiBH₄ LiBH ₄	Mg(BH₄)₂ Mg(BH ₄ ) ₂	时间time	4h4h	4h4h	4h4h	4h4h
产率(％)Yield(%)	5252	4545	3232	6363	时间time	4h4h	4h4h	4h4h	4h4h

Synthesis of Compound 2 of Example 24 (R is hydrogen)

Compound 3 (R ¹ is hydrogen, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (9 mg, 0.007 mmol) is dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid is added. 0.1 mL), reacted at room temperature for 8 h. Water (10 uL) was added and reacted at room temperature for 1 h. The system was concentrated to give the trifluoroacetic acid salt of Compound 2 (R is hydrogen) (10 mg, yield 90%). [α] _D ²⁰ = +20.13° (c0.01, DMSO). A heavy aqueous solution of sodium hydroxide was added to adjust the pH to be weakly basic to obtain Compound 2 (R is hydrogen). ¹ H NMR (D ₂ O, 400 MHz): δ 5.71 (d, J = 2.4 Hz, 1H), 4.38 (m, 2H), 4.20 (d, J = 8.0 Hz, 1H), 3.99 (ddd, J = 9.6, 6.0, 2.4 Hz, 1H), 3.93 (dd, J = 12.0, 2.4 Hz, 1H), 3.71 (d, J = 9.6 Hz, 1H), 3.69 (dd, J = 11.6, 6.0 Hz, 1H), 2.12(s,3H); ¹³ CNMR (100MHz, D ₂ O): δ174.9,168.8,150.2,101.8,75.2,69.8,68.0,62.2,50.1,46.8,22.2; ESI-MS(m/z):291 [M+H] ⁺ ), 313 ([M+Na] ⁺ ), 329 ([M+K] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₁ H ₁₈ N ₂ NaO ₇ ([ M+Na] ⁺ ): 313.1006, experimental value: 313.1012.

Example 25 Synthesis of Zanamivir

Compound 2 (R is hydrogen) (19 mg, 0.056 mmol) was dissolved in water (1.5 mL), and then potassium carbonate (4.5 mg, 0.056 mmol) and thiourea trioxide (4.1 mg, 0.056 mmol) were added sequentially at 0.5 h. A total of 12 times. The reaction was carried out for 36 h at room temperature. After concentration and filtration, the filtrate was separated by HPLC to yield (10 mg, yield 50%). ¹ H NMR (D ₂ O, 500 MHz): δ 5.65 (d, J = 2.5 Hz, 1H), 4.47 (dd, J = 9.5, 2.5 Hz, 1H), 4.40 (dd, J = 10, 1.5 Hz, 1H), 4.25 (t, J = 10.0 Hz, 1H), 3.97 (ddd, J = 9.5, 6.5, 3.0 Hz, 1H), 3.91 (dd, J = 11.5, 2.5 Hz, 1H), 3.70 (dd, J = 9.0 Hz, 1H), 3.67 (dd, J = 12.0, 6.5 Hz, 1H), 2.06 (s, 3H); ESI-MS (m/z): 333.3 ([M+H] ⁺ ). C ₁₂ H ₂₁ N ₄ NaO ₇ ([M+Na] ⁺ ): 333.14048, Experimental value: 333.14077.

Synthesis of Compound 8 of Example 26 (R ¹ is methyl)

Compound 9 (R ¹ is methyl, R ² and R ⁵ are each independently methyl) (7.00 g, 40.19 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Compound 10 (R ⁴ is tert-butoxycarbonyl) (49.20 g, 199.79 mmol), copper bromide (2.68 g, 12.00 mmol), cesium carbonate (5.86 g, 12.00 mmol), catalyst ligand

(5.13g, 12.00mmol) was placed in an egg-shaped flask, added to anhydrous tetrahydrofuran (500mL) and stirred at room temperature for 4h to give a small amount of white solid, then added to the compound 10 (R ⁴ is tert-butoxycarbonyl) tetrahydrofuran solution at 0 ° C, 0 ° C The reaction was continued for 36 hours. After quenching with saturated ammonium chloride solution, the mixture was extracted with ethyl acetate. After solvent was applied, the solvent was applied to column chromatography, petroleum ether / ethyl acetate = 4:1 to obtain compound 8 (R ¹ is methyl group, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (14.12 g, 78%), and the catalyst ligand is recovered.

(4.10 g, 80%) and Compound 10 (R ⁴ is tert-butoxycarbonyl) (41.50 g, yield 84%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.55 to 4.80 (m, 4H), 3.94 to 4.18 (m, 4H), 3.41 to 3.55 (m, 3H), 3.37 (br, 1H), 2.65 to 2.80 (m) , 1H), 2.17 to 2.24 (m, 1H), 1.48 (m, 3H), 1.35 to 1.46 (m, 12H), 1.33 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 155.04, 108.16, 96.03, 86.00, 80.23, 78.29, 77.09, 70.70, 65.14, 61.75, 48.17, 40.33, 28.53, 28.07, 26.36, 25.20; ESI-MS (m/z): 443.4 ([M+Na] ⁺ ); ESI-HRMS (m/z): Calculated for C ₁₈ H ₃₂ N ₂ NaO ₉ ([M+Na] ⁺ ): 443.2000, Experimental value: 443.19987.

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.

Table 9 Screening of Catalysts for Compound 8 Synthesis

实验编号Experiment number	催化剂^b Catalyst ^b	9的当量9 equivalent	10的当量10 equivalent	配体当量Ligand equivalent	碱的当量Alkali equivalent	产率(％)Yield(%)
实验编号Experiment number	催化剂^b Catalyst ^b	9的当量9 equivalent	10的当量10 equivalent	配体当量Ligand equivalent	碱的当量Alkali equivalent	产率(％)Yield(%)	11	乙酸铜Copper acetate	11	55	0.20.2	0.30.3	4545
22	氯化亚铜Cuprous chloride	11	55	0.20.2	0.30.3	1212	11	乙酸铜Copper acetate	11	55	0.20.2	0.30.3	4545
22	氯化亚铜Cuprous chloride	11	55	0.20.2	0.30.3	1212	33	氯化铜Copper chloride	11	55	0.20.2	0.30.3	5454
44	溴化亚铜Cuprous bromide	11	55	0.20.2	0.30.3	21twenty one	33	氯化铜Copper chloride	11	55	0.20.2	0.30.3	5454
44	溴化亚铜Cuprous bromide	11	55	0.20.2	0.30.3	21twenty one	55	溴化铜Copper bromide	11	55	0.20.2	0.30.3	7474
66	碘化亚铜Cuprous iodide	11	55	0.20.2	0.30.3	1515	55	溴化铜Copper bromide	11	55	0.20.2	0.30.3	7474

(The molar percentage of the catalyst is 20%)

Table 10 Screening of Catalyst Equivalents for Compound 8 Synthesis

Table 11 Screening of Equivalents of Compound 10 in Compound 8 Synthesis

Experiment number

10 equivalent

9 equivalent

Ligand equivalent

Copper bromide

Alkali equivalent

Yield(%)

				量the amount
				量the amount			11	1.051.05	11	0.20.2	0.20.2	0.30.3	1616
22	22	11	0.20.2	0.20.2	0.30.3	6363	11	1.051.05	11	0.20.2	0.20.2	0.30.3	1616
22	22	11	0.20.2	0.20.2	0.30.3	6363	33	55	11	0.20.2	0.20.2	0.30.3	7474

Synthesis of Compound 7 of Example 27 (R ¹ is methyl)

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. The filtrate was concentrated and subjected to column chromatography, petroleum ether / ethyl acetate = 8:1 to give compound 7 (R ¹ is methyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (8.36 g, yield 76%) (d: r = 8:1). [α] _D ²⁰ = +31.20° (c 0.2, CHCl ₃ ); ¹ H NMR (Pyridine-d ₅ , 400 MHz): δ 8.52 (d, J = 8.4 Hz, 1H), 5.45 (dd, J = 9.6 , 8.0 Hz, 1H), 5.31 (t, J = 9.6, 1H), 4.75 (d, J = 10.0 Hz, 1H), 4.70 (s, 1H), 4.48 (m, 1H), 4.20 (dd, J = 6.4, 2.4 Hz, 1H), 3.74 (d, J = 3.6, 1H), 3.50 (s, 3H), 1.69 (s, 3H), 1.50 (s, 9H), 1.48 (s, 3H), 1.41 (s) , 3H); ¹³ C NMR (100 MHz, Pyridine-d ₅ ): δ 156.85, 153.24, 109.04, 98.89, 85.74, 79.66, 79.08, 77.23, 77.16, 66.43, 61.79, 51.00, 28.83, 27.18, 25.80, 19.27; ESI-MS (m/z): 425.5 ([M+Na] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₈ H ₃₀ N ₂ NaO ₈ ([M+Na]+): 425.1894, 425.1900.

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 (100μL, 0.72mmol), DMAP (7mg, 0.04mmol) and methanesulfonyl chloride (53μL, 0.24mmol), reacted for 8h at room temperature, add triethylamine (66μL, 0.48mmol), DMAP (4mg, 0.03mmol) and methane Sulfonyl chloride (31 μL, 0.14 mmol) was continued for 4 h. The reaction was quenched with saturated aq. The filtrate was concentrated and subjected to column chromatography, petroleum ether / ethyl acetate = 8:1 to give compound 7 (R ¹ is methyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (44 mg) , yield 46%).

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. the reaction extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated by column chromatography, petroleum ether / ethyl acetate = 8: 1 to give compound 7 (R ¹ is methyl, R ² and R ⁵ are each independently It is a methyl group, and R ⁴ is a tert-butoxycarbonyl group (41 mg, yield 43%).

Synthesis of the compound of Example 28 (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)

Compound 7 (R ¹ is methyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl) (8.36 g, 20.773 mmol) dissolved in ethyl acetate (1 L), cooled to 0 ° C Then, zinc powder (135.80 g, 2077.30 mmol) and glacial acetic acid (118.80 mL, 2077.30 mmol) were added in this order, and the mixture was reacted at room temperature for 18 h. Excess zinc powder was removed by filtration, and the filtrate was concentrated and subjected to column chromatography, petroleum ether / ethyl acetate = 2:1 to give compound 6 (R ¹ is methyl, R ² and R ⁵ are each independently methyl, R ⁴ is uncle Butoxycarbonyl) (5.91 g, yield 76%). [α] _D ²⁰ = +29.63° (c 2.0, CHCl ₃ ); ¹ H NMR (CDCl ₃ , 400 MHz): δ 4.47 (d, J = 8.8 Hz, 1H), 4.31 (s, 1H), 4.21. 4.26 (m, 2H), 3.95 to 4.05 (m, 4H), 3.70 (d, J = 10.0 Hz, 1H), 2.81 (t, J = 9.6 Hz, 1H), 1.67 (s, 3H), 1.42 (s) , 9H), 1.41 (s, 3H), 1.33 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 156.53, 153.15, 108.15, 97.72, 80.17, 79.64, 77.87, 77.23, 65.70, 61.42, 52.75, 51.44, 28.37, 26.52, 25.29, 19.24; ESI-MS (m/z): 373.3 ([M+H] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₈ H ₃₃ N ₂ O ₆ ( [M+H]+): 373.2335, experimental value: 373.2333.

Compound 7 (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) (1 g, 2.48 mmol) dissolved in ethyl acetate (110 mL), cooled to 0 ° C Iron powder (13.88 g, 247.71 mmol) and glacial acetic acid (14.2 mL, 248 mmol) were added in that order, and the reaction was continued at this temperature overnight. Excess iron powder was removed by filtration, the filtrate was added excess of aqueous ammonia, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated by column chromatography, petroleum ether / ethyl acetate = 2: 1 to give compound 6 (R ¹ is Methyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl) (622 mg, yield 65%).

Compound 7 (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) (1 g, 2.48 mmol) dissolved in ethyl acetate (110 mL), cooled to 0 ° C Aluminum powder (6.70 g, 248 mmol) and glacial acetic acid (14.2 mL, 248 mmol) were successively added, and the reaction was continued at this temperature overnight. Excess aluminum was removed by filtration, the filtrate was added excess of aqueous ammonia, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated by column chromatography, petroleum ether / ethyl acetate = 2: 1 to give compound 6 (R ¹ is Methyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (412 mg, yield 43%).

Synthesis of the compound of Example 29 (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)

Compound 6 (R ¹ is methyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (5.91 g, 15.87 mmol) dissolved in dichloromethane (1 L), cooled to 0 ° C Then triethylamine (8.82 mL, 62.83 mmol) was added sequentially with acetyl chloride (1.11 mL, 15.87 mmol) and reacted at 0 ° C for 2 h. After completion of the solvent, the column chromatography was carried out, and petroleum ether / ethyl acetate = 4:1 to give compound 5 (R ¹ is methyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (5.81 g, yield 88%). [α] _D ²⁰ =-1.43° (c 1.0, CHCl ₃ ); ¹ H NMR (CD ₃ CN, 400 MHz): δ 6.55 (d, J = 7.6 Hz, 1H), 5.32 (d, J = 8.4 Hz) , 1H), 4.42 (s, J = 1.6 Hz, 1H), 4.20 (m, 2H), 4.02 to 4.07 (m, 2H), 3.93 to 3.99 (m, 2H), 3.61 (d, J = 4.0 Hz, 1H), 3.43 (s, 3H), 1.90 (s, 3H), 1.70 (s, 3H), 1.42 (s, 9H), 1.40 (s, 3H), 1.32 (s, 3H); ¹³ C NMR (100 MHz , CD ₃ CN): δ171.06, 156.88, 152.75, 108.71, 98.75, 79.34, 78.91, 77.98, 77.91, 66.29, 61.63, 51.17, 49.33, 28.56, 26.77, 25.51, 23.39, 19.24; ESI-MS (m/z) : 437.4 ([M+Na] ⁺ ), 453.5 ([M+K] ⁺ ); ESI-HRMS (m/z): Calculated: C ₂₀ H ₃₄ N ₂ NaO ₇ ([M+Na] ⁺ ): 437.2269, experimental value: 437.2264.

Compound 6 (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) (1 g, 2.67 mmol) is dissolved in pyridine (120 mL), and acetic anhydride (5 mL) is added. The temperature was raised to 60 ° C for 12 h. After completion of the solvent, the residue was purified by column chromatography eluting elut elut

Compound 6 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (1 g, 2.67 mmol) is dissolved in piperidine (120 mL), and acetic anhydride is added ( 5 mL), the temperature was raised to 60 ° C for 12 h. After completion of the solvent, the residue was purified by EtOAcjjjjjjj

Synthesis of Compound 4 of Example 30 (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)

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. The system is concentrated and directly subjected to column chromatography, petroleum ether / ethyl acetate = 1:1 to give compound 4 (R ¹ is methyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) 3.12 g, yield 52%). [α] _D ²⁰ = +48.01° (c 1.0, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.15 (s, 1H), 6.09 (d, J = 9.6 Hz, 1H), 5.68 ( d, J = 2.0 Hz, 1H), 5.15 (d, J = 9.2 Hz, 1H), 4.56 (td, J = 9.6, 2.0 Hz, 1H), 4.27 to 4.37 (m, 2H), 4.19 (dd, J = 8.8, 6.0 Hz, 1H), 4.13 (d, J = 10.4 Hz, 1H), 4.02 (dd, J = 8.8, 6.0 Hz, 1H), 3.60 (d, J = 4.4 Hz, 1H), 3.49 (s) , 3H), 2.01 (s, 3H), 1.43 (m, 12H), 1.34 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 185.16, 170.66, 156.34, 151.89, 118.76, 108.43, 80.28, 78.12 , 78.04, 65.93, 61.47, 50.13, 48.02, 28.32, 26.56, 25.26, 23.31; ESI-MS (m/z): 451.4 ([M+Na] ⁺ ), 467.4 ([M+K] ⁺ ), 483.3 ( ^{[m + MeOH + Na] +} ); ESI-HRMS (m / z): _{_{_{Calcd: C 20 H 32 N 2 NaO}}} 8 ([m + Na] +): 451.2051, Found: 451.20509.

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. The system is concentrated and directly subjected to column chromatography, petroleum ether / ethyl acetate = 1:1 to give compound 4 (R ¹ is methyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) 1.32 g, yield 22%).

Synthesis of Compound 3 of Example 31 (R ¹ is a methoxymethyl group, R ² and R ⁵ are each independently a methyl group, and R ⁴ is a tert-butoxycarbonyl group)

Compound 4 (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. The filtrate was concentrated and subjected to column chromatography, petroleum ether / ethyl acetate = 1:1 to give compound 3 (R ¹ is methyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (2.13) g, yield 95%). [α] _D ²⁰ = +42.60° (c 0.25, DMSO); ¹ H NMR (CD ₃ OD, 500 MHz): δ 5.57 (d, J = 2.5 Hz, 1H), 4.35 to 4.45 (m, 2H), 4.23 (dd, J=9.0, 6.0 Hz, 1H), 4.16 (d, J=9.5 Hz, 1H), 4.06 (t, J=9.5 Hz, 1H), 4.04 (dd, J=9.0, 7.5 Hz, 1H) , 3.67 (d, J = 2.5 Hz, 1H), 3.49 (s, 3H), 1.98 (s, 3H), 1.44 (s, 9H), 1.41 (s, 3H), 1.34 (s, 3H); ¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 169.57, 163.57, 156.11, 145.00, 111.10, 107.72, 78.31, 77.93, 77.65, 77.48, 65.35, 61.26, 49.46, 47.50, 28.63, 26.81, 25.80, 23.29. ESI-MS ( m/z): 443.7 ([MH] ^- ). ESI-HRMS (m/z): Calculated: C ₂₀ H ₃₂ N ₂ NaO ₉ ([M+Na] ⁺ ): 467.2000, Experimental value: 467.2004.

Synthesis of Compound 2 of Example 32 (R is a methyl group)

Compound 3 (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, 0.225 mmol) is dissolved in dichloromethane (20 mL), and trifluoroacetic acid is added. 2 mL), reacted at room temperature for 2 h. Water (0.1 mL) was added and the mixture was reacted at room temperature for 1 h. The system was concentrated to give the trifluoroacetic acid salt of Compound 2 (R is methyl) (129 mg, yield 100%). [α] _D ²⁰ = +0.33° (c 1.3, MeOH); ¹ H NMR (D ₂ O, 500 MHz): δ 5.85 (d, J = 2.5 Hz, 1H), 4.35 (d, J = 11.0 Hz, 1H), 4.26 (dd, J = 10.5, 9.5 Hz, 1H), 4.10 (dd, J = 9.5, 2.5 Hz, 1H), 3.88 (ddd, J = 9.0, 5.5, 3.0 Hz, 1H), 3.76 (dd , J = 12.0, 3.0 Hz, 1H), 3.57 (dd, J = 12.0, 5.5 Hz, 1H), 3.46 (dd, J = 9.0, 1 Hz, 1H), 3.30 (s, 1H), 1.98 (s, 3H) ¹³ C NMR (125 MHz, D ₂ O): δ 174.55, 164.72, 144.61, 104.12, 77.23, 75.73, 69.52, 62.27, 60.32, 50.44, 45.43, 22.13; ESI-MS (m/z): 305.2 ([M ^{+ H] +) .ESI-HRMS} (m / z): _{_{_{Calcd: C 12 H 21 N 2 O}}} 7 ([m + H] +): 305.1343, Found: 305.1342.

Example 33 Synthesis of Compound 26 (R ⁴ is a tert-butoxycarbonyl group)

The 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. The reaction system was washed with saturated sodium bicarbonate solution twice, once with saturated sodium chloride solution, the solvent was spin-finished column chromatography, petroleum ether / ethyl acetate = 4: 1, to give a pale yellow solid 26 (R ⁴ is tert-butyl Oxycarbonyl) (63.25 g, yield 74%, 81% ee). The product was recrystallized from tetrahydrofuran / n-hexane = 1:2 to give a white solid 26 ( R ⁴ as tert-butoxycarbonyl) (51 g, yield 81%, 94% ee)

[α] _D ²⁰ =-0.8480° (c 1.0, CHCl ₃ )

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.15 (s, 1H), 4.85 to 4.68 (m, 1H), 4.68 to 4.52 (m, 2H), 3.90 (s, 3H), 3.40 to 3.20 (m, 2H) ), 1.43 (s, 9H);

¹³ C NMR (126 MHz, CDCl ₃ ): δ 190.92, 160.43, 154.85, 80.86, 76.90, 53.46, 45.12, 41.05, 28.31 (3C);

ESI-MS (m/z): 313.4 ([M+Na] ⁺ ), 345.3 ([M+MeOH+Na] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₂ H ₂₂ N ₂ NaO ₈ ([M+Na+MeOH] ⁺ ): 345.1268, found: 345.127.

The preparation of compound 26 under different catalyst catalysis, the reaction conditions were optimized as shown in Table 1; the preparation of compound 26 under the catalysis of catalyst 12 (Cat. 12), under different organic solvent conditions, the reaction conditions were optimized as shown in Table 2; Preparation of compound 26 under the catalysis of Catalyst 12 (Cat. 12), under different additive conditions, the reaction conditions were optimized as shown in Table 3; Cat.1, Cat.2, and Cat.3 are commercially available items. Cat. 4 can be found in the literature: J. Am. Chem. Soc. 2012, 134, 20197; Cat. 5 can be found in the literature: Angew. Chem. Int. Ed. 2012, 51, 8838; Cat. 6 can be found in the literature: Chem. Commun. 2012, 48, 5193; reported methods of synthesis. 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;

Table 1 Synthesis of Compound 26 Catalysts

Table 2 Compound 26 synthetic organic solvent screening (Cat. 12)

实验编号Experiment number	添加剂additive	有机溶剂Organic solvents	温度temperature	时间time	收率(％)Yield (%)	ee(％)Ee(%)
实验编号Experiment number	添加剂additive	有机溶剂Organic solvents	温度temperature	时间time	收率(％)Yield (%)	ee(％)Ee(%)	11	--	氯仿Chloroform	室温Room temperature	2d2d	7474	8181
22	--	均三甲苯Mesitylene	室温Room temperature	2d2d	23twenty three	7878	11	--	氯仿Chloroform	室温Room temperature	2d2d	7474	8181
22	--	均三甲苯Mesitylene	室温Room temperature	2d2d	23twenty three	7878	33	--	氯苯chlorobenzene	室温Room temperature	2d2d	5252	7676
44	--	三氟甲苯Trifluorotoluene	室温Room temperature	2d2d	3939	6565	33	--	氯苯chlorobenzene	室温Room temperature	2d2d	5252	7676
44	--	三氟甲苯Trifluorotoluene	室温Room temperature	2d2d	3939	6565	55	--	苯甲醚Anisole	室温Room temperature	2d2d	5959	6868
66	--	正己烷Hexane	室温Room temperature	2d2d	3434	7474	55	--	苯甲醚Anisole	室温Room temperature	2d2d	5959	6868
66	--	正己烷Hexane	室温Room temperature	2d2d	3434	7474	77	--	乙醚Ether	室温Room temperature	2d2d	3131	7272
88	--	二氯甲烷Dichloromethane	室温Room temperature	2d2d	6464	7070	77	--	乙醚Ether	室温Room temperature	2d2d	3131	7272
88	--	二氯甲烷Dichloromethane	室温Room temperature	2d2d	6464	7070	99	--	四氯化碳Carbon tetrachloride	室温Room temperature	2d2d	4747	7373

Table 3 Compound 26 synthetic additive screening (Cat. 12)

实验编号Experiment number	添加剂additive	有机溶剂Organic solvents	温度temperature	时间time	收率(％)Yield (%)	ee(％)Ee(%)
实验编号Experiment number	添加剂additive	有机溶剂Organic solvents	温度temperature	时间time	收率(％)Yield (%)	ee(％)Ee(%)	11	乙酸Acetic acid	氯仿Chloroform	室温Room temperature	2d2d	5858	7575
22	对二苯甲酸Dibenzoic acid	氯仿Chloroform	室温Room temperature	2d2d	24twenty four	7373	11	乙酸Acetic acid	氯仿Chloroform	室温Room temperature	2d2d	5858	7575
22	对二苯甲酸Dibenzoic acid	氯仿Chloroform	室温Room temperature	2d2d	24twenty four	7373	33	对羟基苯甲酸Hydroxybenzoic acid	氯仿Chloroform	室温Room temperature	2d2d	5656	7979
44	对硝基苯甲酸P-nitrobenzoic acid	氯仿Chloroform	室温Room temperature	2d2d	4747	7979	33	对羟基苯甲酸Hydroxybenzoic acid	氯仿Chloroform	室温Room temperature	2d2d	5656	7979
44	对硝基苯甲酸P-nitrobenzoic acid	氯仿Chloroform	室温Room temperature	2d2d	4747	7979	55	(+)-樟脑磺酸(+)-camphorsulfonic acid	氯仿Chloroform	室温Room temperature	2d2d	6767	6464
66	对甲苯磺酸p-Toluenesulfonic acid	氯仿Chloroform	室温Room temperature	2d2d	3434	6868	55	(+)-樟脑磺酸(+)-camphorsulfonic acid	氯仿Chloroform	室温Room temperature	2d2d	6767	6464

7

-

Chloroform

Room temperature

2d

74

81

The structure of the catalyst is as follows:

The structure of the Jacobsen catalyst (Cat. 12) is as follows:

Synthesis of Compound 27 of Example 34 (R ⁴ is tert-butoxycarbonyl)

Compound 26 (5g, 17.2mmol) was dissolved in methanol (200mL) was added NaBH ₄ (260mg, 6.87mmol), stirred at rt for 10min, quenched with saturated ammonium chloride was added, methanol was removed by rotary evaporation, dissolved in water, extracted with ethyl acetate two times, dried over anhydrous sodium sulfate, and spin dry column chromatography to give a white solid 27 (R ⁴ is tert-butoxycarbonyl) (4.95 g, yield 98%).

¹ H NMR (500 MHz, CDCl ₃ ) (a pair of diastereomers, ratio 1:1) δ 5.28 (d, J = 7.3 Hz, 1H) & 5.03 (d, J = 6.7 Hz, 1H ), 4.73 to 4.51 (m, 4H), 4.48 to 4.37 (m, 2H), 4.31 (dd, J = 13.3, 8.0 Hz, 2H), 3.80 (s, 3H) & 3.79 (s, 3H) 3.09 ( Br, 2H), 2.24 to 2.04 (m, 3H), 1.91 to 1.78 (m, 1H), 1.44 (s, 18H);

^{_{13 C NMR (126MHz, CDCl 3}} ) ( diastereomer thereof a pair ratio of 1: 1) δ174.59 & 174.38,155.54 & 155.05,80.53 & 80.41,78.09,67.53,52.80 & 52.73,46.57 & 45 .84,36.05&35.34,28.27(3C)&28.24(3C);

ESI-MS (m/z): 315.2 ([M+Na] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₁ H ₂₀ N ₂ NaO ₇ ([M+Na] ⁺ ): 315.1163, Experimental value: 315.1166.

Compound 26 (2.9 g, 17.2 mmol) was dissolved in tetrahydrofuran (100 mL), ZnCl ₂ (1.36 g, 10 mmol) was added, and stirred at -78 ° C for 0.5 h, and a solution of lithium tri-sec-butylborohydride in tetrahydrofuran (1.0 mol/L) was added. , 11mL), the reaction was continued at -78 ° C for 10 min, quenched with saturated NH ₄ Cl solution, warmed to room temperature, a small amount of 1 mol / L hydrochloric acid, diluted with water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated , spin dry column chromatography to give a white solid 27 (R ⁴ is tert-butoxycarbonyl) (2.9 g of, yield 99%, dr = 1: 2.7 ).

¹ H NMR (500MHz, CDCl ₃ ) δ 5.28 (d, J = 7.3 Hz, 1H) & 5.03 (d, J = 6.7 Hz, 1H), 4.73 to 4.51 (m, 4H), 4.48 to 4.37 (m) , 2H), 4.31 (dd, J = 13.3, 8.0 Hz, 2H), 3.80 (s, 3H) & 3.79 (s, 3H) 3.09 (br, 2H), 2.24 to 2.04 (m, 3H), 1.91 - 1.78 (m, 1H), 1.44 (s, 18H);

¹³ C NMR (126 MHz, CDCl ₃ ) δ 174.59 & 174.38, 155.54 & 155.05, 80.53 & 80.41, 78.09, 67.53, 52.80&52.73, 46.57 & 45.84, 36.05 & 35.34, 28.27 &28.24;

Synthesis of Compound 28 of Example 35 (R ⁴ is tert-butoxycarbonyl)

Compound 27 (R ⁴ is tert-butoxycarbonyl) (1.8 g, 6.16 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), 4-dimethylaminopyridine (75 mg, 0.62 mmol) was added, and acetic anhydride (0.7 mL, 7.39) was added. Methyl acetate (2.6 mL, 18.18 mmol) was added, and the mixture was stirred at room temperature for 10 min.

¹ H NMR (400 MHz, CDCl ₃ ) (a pair of diastereomers, ratio 1:1) δ 5.17 (t, J = 5.5 Hz, 1H), 5.08 (dd, J = 10.7, 2.7 Hz, 1H), 5.06 to 4.96 (m, 2H), 4.68 (dd, J = 13.1, 5.1 Hz, 1H), 4.61 to 4.50 (m, 3H), 4.39 to 4.19 (m, 2H), 3.76 (s, 3H) & 3.74(s,3H)2.29(m,1H), 2.15(s,3H)&2.14(s,3H),2.05(m,1H),1.42(s,9H)&1.41(s,9H );

¹³ C NMR (126 MHz, CDCl ₃ ) (a pair of diastereomers, ratio 1:1) δ 170.26 & 170.15, 170.10&169.71, 154.96 & 154.74, 80.78 & 80.68, 78.29 & 77.59, 69.17 & 68. 66,52.84&52.78,46.26&45.69,33.22&32.84,28.36(3C)&28.30(3C),20.70&20.63;

ESI-MS (m/z): 357.3 ([M+Na] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₃ H ₂₂ N ₂ NaO ₈ ([M+Na] ⁺ ): 357.1268, Experimental value: 357.1273.

Compound 27 (R ⁴ is tert-butoxycarbonyl) (117 mg, 0.4 mmol) was dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.223 mL, 1.6 mmol) was added, and acetyl chloride (0.057 mL, 0.8 mmol) was added. The reaction was carried out at room temperature for 24 h, and the residue was purified by chromatography.

Synthesis of the compound of Example 36 (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)

Weigh copper bromide (254 mg, 1.14 mmol), cesium carbonate (555 mg, 1.70 mmol), catalyst ligand

(486 mg, 1.14 mmol) was placed in an egg-shaped flask, and added to anhydrous tetrahydrofuran (50 mL), stirred at room temperature for 2 h to give a small white solid, then placed in a 0 ° C circulating cold bath, and added 28 (1.9 g, 5.68 mmol) A solution of water (tetrahydrofuran (25 mL) was added, and a solution of 9 ( 1.19 g, 6.83 mmol) in anhydrous tetrahydrofuran was added, and the reaction was continued at 0 ° C for 48 h. After quenching the saturated ammonium chloride solution, ethyl acetate is extracted, and the solvent is directly subjected to column chromatography to obtain compound 29 (R ¹ is a methyl group, R ² and R ⁵ are each independently a methyl group, and R ⁴ is a tert-butyl group. Oxycarbonyl) (1.92 g, yield 66%).

^{_{1 H NMR (500MHz, CDCl 3}} ) δ5.20 (t, J = 5.3Hz, 1H), 5.12 (dd, J = 11.3,2.8Hz, 1H), 4.99 (d, J = 10.3Hz, 1H), 4.87 ~4.81 (m, 4H), 4.57 (d, J = 5.4 Hz, 1H), 4.54 to 4.47 (m, 1H), 4.47 to 4.40 (m, 1H), 4.25 to 4.19 (m, 2H), 4.13 to 4.05 (m, 4H), 4.01 to 3.95 (m, 2H), 3.75 (s, 3H) & 3.74 (s, 3H), 3.53 (s, 3H) & 3.52 (s, 3H), 3.29 (m, 2H) ), 2.21 to 2.15 (m, 1H), 2.14 (s, 3H) & 2.12 (s, 3H), 2.07 to 1.99 (m, 2H), 1.90 (m, 1H), 1.47 (s, 9H) & 1. 46(s,9H), 1.40(s,3H)&1.39(s,3H), 1.33(s,3H)&1.32(s,3H);

¹³ C NMR (126 MHz, CDCl ₃ ) δ 170.14, 170.04, 169.79, 169.44, 157.35 & 157.14, 108.49 & 108.36, 90.07 & 89.99, 82.06, 82.04, 79.44 & 79.40, 77.02, 69.92, 69.64, 68.71, 68.35, 66.09 &66.06,61.50&61.42,52.81&52.77,46.04&46.03,33.36,28.37,28.27,28.21,26.62,25.38&25.36,20.70&20.51;

ESI-MS (m / z) : 531.6 ([M + Na] +); ESI-HRMS (m / z): _{_{_{Calcd: C 21 H 36 N 2 NaO}}} 12 ([M + Na] +): 531.2160, Experimental value: 531.2162.

Synthesis of the compound of Example 37 (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)

Compound 29 (155 mg, 0.305 mmol) was dissolved in anhydrous methanol (5 mL), sodium MeOH (16 mg, 0.305 mmol) was added, and the mixture was reacted for 4h at room temperature. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. Drying on sodium, concentration column chromatography to give compound 30 (R ¹ is methyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (70 mg, yield 50%), and compound 29 is recovered ( 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) 35 mg.

^{_{1 H NMR (500MHz, CDCl 3}} ) δ4.85 (dd, J = 9.8,2.6Hz, 1H), 4.79 (d, J = 10.2Hz, 1H), 4.71 (d, J = 4.9Hz, 1H), 4.65 –4.57 (m, 1H), 4.33 (dd, J=9.2, 4.5 Hz, 1H), 4.22 (td, J=6.4, 4.7 Hz, 1H), 4.11–4.05 (m, 2H), 3.99 (dd, J = 8.5, 6.8 Hz, 1H), 3.80 (s, 3H), 3.51 (s, 3H), 3.29 (d, J = 4.5 Hz, 1H), 3.13 (d, J = 4.0 Hz, 1H), 2.19 - 2.14 (m, 1H), 1.89 (ddd, J = 14.7, 10.5, 4.5 Hz, 1H), 1.47 (d, J = 4.7 Hz, 9H), 1.39 (s, 3H), 1.33 (s, 3H);

¹³ C NMR (126 MHz, CDCl ₃ ) δ 174.59 & 174.41, 157.13 & 155.08, 109.17 & 109.05, 108.42 & 108.28, 90.39 & 89.81, 81.65, 80.55 & 80.44, 79.51 & 79.43, 78.09, 69.67, 69.60, 67.54, 52.79 &52.73,45.82,45.36,36.04,35.34,28.26&28.18,26.48&26.38,25.21&25.14.

ESI-MS (m/z): 489.5 ([M+Na] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₉ H ₃₄ N ₂ NaO ₁₁ ([M+Na] ⁺ ): 489.2055, Experimental value: 489.2058.

Compound 29 (1.2 g, 2.36 mmol) was dissolved in anhydrous tetrahydrofuran (120 mL), EtOAc (EtOAc, EtOAc (EtOAc) the reaction was quenched, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound 30 (824mg, yield 75%) (R ¹ is methyl, R ² and R ⁵ each independently are methyl , R ⁴ is tert-butoxycarbonyl)

Synthesis of Compound 31 of Example 38 (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)

Compound 30 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (500 mg, 1.07 mmol) dissolved in anhydrous dichloromethane (25 mL), Add Dess-Martin oxidant (500 mg, 1.18 mmol) at 20 ° C, react at -20 ° C for 4 h, add saturated NaHCO ₃ solution to quench the reaction, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate The compound 31 was obtained (R ¹ is a methoxymethyl group, R ² and R ⁵ are each independently a methyl group, and R ⁴ is a tert-butoxycarbonyl group) (433 mg, yield 86%).

^{_{1 H NMR (500MHz, CDCl 3}} ) δ4.87-4.83 (m, 1H), 4.74-4.72 (m, 1H), 4.65-4.63 (m, 2H), 4.43 (br, 1H), 4.14-4.11 (m , 1H), 3.96-3.88 (m, 2H), 3.82 (s, 3H), 3.53 (s, 3H), 3.47 (s, 1H), 2.22-2.21 (m, 2H), 1.42 (s, 9H), 1.39(s,3H), 1.32(s,3H);

¹³ C NMR (126 MHz, CHCl ₃ ) δ 169.11, 154.65, 125.64, 108.60, 94.43, 85.49, 80.79, 78.34, 76.61, 71.47, 62.05, 53.93, 30.46, 28.29 (3C), 26.65, 25.40.

ESI-MS (m/z): 487.5 ([M+Na] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₉ H ₃₂ N ₂ NaO ₁₁ ([M+Na] ⁺ ): 487.1898, Experimental value: 487.1896.

Synthesis of the compound of Example 39 (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)

Compound 31 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl) (392 mg, 0.84 mmol) dissolved in anhydrous dichloromethane (8 mL), Add pyridine (0.55 mL, 6.85 mmol) at 10 ° C, add thionyl chloride (1.4 mL, 1.96 mmol), continue the reaction at -10 ° C for 2 h, add water to quench the reaction, wash once with a small amount of 1 mol / L hydrochloric acid, two Methyl chloride extraction, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate and column chromatography to give compound 32 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl (200 mg, yield 53%).

[α] _D ²⁰ = +39.6880° (c 1.0, CHCl ₃ )

¹ H NMR (500 MHz, CD ₃ CN) δ 5.88 (d, J = 2.2 Hz, 1H), 5.74 (s, 1H), 5.05 - 4.96 (m, 1H), 4.93 (t, J = 9.7 Hz, 1H) ), 4.56 (d, J = 9.6 Hz, 1H), 4.29 - 4.23 (m, 1H), 4.14 (dd, J = 8.8, 6.3 Hz, 1H), 3.96 (dd, J = 8.8, 6.5 Hz, 1H) , 3.76 (d, J = 2.8 Hz, 3H), 3.47 (s, 3H), 3.43 (dd, J = 4.8, 1.6 Hz, 1H), 1.39 (s, 9H), 1.36 (s, 3H), 1.30 ( s, 3H).

¹³ C NMR (126 MHz, CD 3 CN) δ 162.20, 156.02, 145.04, 111.60, 109.15, 83.66, 80.78, 78.78, 77.85, 76.89, 66.33, 61.99, 53.11, 50.47, 28.34 (3C), 26.74, 25.45;

ESI-MS (m/z): 469.5 ([M+Na] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₉ H ₃₀ N ₂ NaO ₁₀ ([M+Na] ⁺ ): 469.1793, Experimental value: 469.1797.

Compound 31 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (20 mg, 0.043 mmol) dissolved in anhydrous dichloromethane (1 mL), Triethylamine (30 μL, 0.21 mmol), was added with methanesulfonyl chloride (12 μL, 0.17 mmol), and the reaction was continued at -10 ° C for 2 h. The reaction was quenched with saturated sodium hydrogen carbonate and extracted with dichloromethane. Drying, filtration, concentration of the filtrate and column chromatography gave compound 32 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (5 mg, yield 26%) ).

Synthesis of the compound of Example 40 (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)

Compound 32 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl, R ⁴ is tert-butoxycarbonyl) (38 mg, 0.085 mmol) is dissolved in 2 mL of anhydrous ethyl acetate, and zinc powder is added. (556 mg, 8.5 mmol), glacial acetic acid (487 μL, 8.5 mmol) was added, and the mixture was reacted at room temperature overnight, filtered over Celite, washed with ethyl acetate and concentrated to afford compound 33 (28 mg, yield 81%) ¹ is a methoxymethyl group, R ² and R ⁵ are each independently a methyl group, and R ⁴ is a tert-butoxycarbonyl group).

[α] _D ²⁰ = +32.8100° (c 1.0, CHCl ₃ )

¹ H NMR (500MHz, CDCl ₃ ) δ 5.82 (d, J = 2.5 Hz, 1H), 4.53 (d, J = 8.6 Hz, 1H), 4.33 - 4.25 (m, 2H), 4.21 (dd, J = 8.8, 6.3 Hz, 1H), 4.07 (dd, J = 8.7, 7.2 Hz, 2H), 3.83 (dd, J = 10.1, 1.3 Hz, 1H), 3.75 (s, 3H), 3.63 (s, 3H), 2.96 (t, J = 9.7 Hz, 1H), 1.55 (br, 2H), 1.46 (s, 9H), 1.45 (s, 3H), 1.37 (s, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 162.44, 156.41, 145.16, 110.82, 108.27, 81.48, 77.69, 77.56, 65.69, 61.60, 52.35, 52.23, 50.53, 29.82, 28.47 (3C), 26.61, 25.44.

ESI-MS (m/z): 417.5 ([M+H] ⁺ ); 439.5 ([M+Na] ⁺ ); ESI-HRMS (m/z): Calculated: C ₁₉ H ₃₃ N ₂ O ₈ ( [M+H] ⁺ ): 417.2235, experimental value: 417.2231.

Synthesis of Compound 34 of Example 41 (R ¹ is methyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl)

Compound 33 (R ¹ is methoxymethyl, R ² and R ⁵ are each independently methyl, and R ⁴ is tert-butoxycarbonyl) (27 mg, 0.064 mmol) dissolved in anhydrous dichloromethane (3 mL). Triethylamine (38 μL, 0.26 mmol) was added to an ice water bath, and then acetyl chloride (5 μL, 0.077 mmol) was added thereto, and the mixture was reacted in an ice water bath for 30 minutes, and subjected to spin-drying column chromatography to obtain compound 34 (R ¹ is methoxymethyl group, R ² and R ⁵ are each independently methyl and R ⁴ is tert-butoxycarbonyl) (27 mg, yield 91%);

[α] _D ²⁰ = +17.5969° (c0.65, CHCl ₃ )

^{_{1 H NMR (500MHz, CDCl 3}} ) δ5.99 (br, 1H), 5.84 (d, J = 1.8Hz, 1H), 4.99 (br, 1H), 4.47-4.45 (m, 1H), 4.31-4.24 ( m, 2H), 4.18 (dd, J = 8.7, 6.2 Hz, 1H), 4.08-4.04 (m, 2H), 3.75 (s, 3H), 3.66 (d, J = 3.3 Hz, 1H), 3.52 (s) , 3H), 1.99 (s, 3H), 1.43 (s, 3H), 1.42 (s, 9H), 1.35 (s, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 170.63, 162.14, 156.44, 144.81, 110.18, 108.44, 80.34, 78.61, 77.83, 65.87, 61.81, 52.45, 49.99, 48.38, 29.83, 28.43 (3C), 26.65, 25.51, 23.50.

ESI-MS (m/z): 481.6 ([M+Na] ⁺ ). ESI-HRMS (m/z): Calculated: C ₂₁ H ₃₄ N ₂ NaO ₉ ([M+Na] ⁺ ): 481.2157, Experimental value: 481.2157

Synthesis of Compound 2 of Example 42 (R ¹ is a methyl group)

Compound 34 (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) (20 mg, 0.044 mmol) is dissolved in 1 mL of tetrahydrofuran, and a sodium hydroxide solution (3 mol/) is added. L, 0.44 mL), reacted at room temperature overnight to obtain intermediate compound 3, without post-treatment, then add hydrochloric acid (3 mol/L, 0.9 mL) to the system, continue the reaction for 0.5 h, and concentrate the system to obtain compound 2 (R ¹ is A Base) (13 mg, yield 97.2%).

[α] _D ²⁰ = +0.33° (c 1.3, MeOH)

¹ H NMR (500 MHz, D ₂ O) δ 6.09 (d, J = 2.2 Hz, 1H), 4.61 (d, J = 10.7 Hz, 1H), 4.49 (t, J = 10.0 Hz, 1H), 4.39 ( Dd, J=9.5, 2.2 Hz, 1H), 4.14-4.11 (m, 1H), 4.00 (dd, J=12.0, 2.8 Hz, 1H), 3.81 (dd, J=12.0, 5.7 Hz, 1H), 3.71 (d, J = 8.3 Hz, 1H), 3.54 (s, 3H), 2.23 (s, 3H).

¹³ C NMR (126 MHz, D ₂ O) δ 174.46, 163.98, 145.90, 104.75, 77.16, 75.72, 69.52, 62.21, 60.22, 50.26, 45.35, 22.03.

ESI-MS (m/z): 305.2 ([M+H] ⁺ ). ESI-HRMS (m/z): Calculated: C ₁₂ H ₂₀ N ₂ NaO ₇ ([M+Na] ⁺ ):327.1163, Experimental value: 327.1160.

Compound 34 (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) (20 mg, 0.044 mmol) is dissolved in 1 mL of tetrahydrofuran, and hydrochloric acid (3 mol/L, 0.44) is added. (mL), reaction at room temperature for 1h, to obtain intermediate 35, without post-treatment, then add sodium hydroxide solution (3mol / L, 0.9mL) to the system, continue the reaction for 8h, add 3mol / L hydrochloric acid to adjust the pH of 2 ~ 3 , the system concentrated to give compound 2 (R ¹ is methyl) (13.2 mg, 98.7% yield).

Compound 35 data

[α] _D ²⁰ = +1.3240° (c 0.5, MeOH)

¹ H NMR (500 MHz, D ₂ O) δ 6.01 (d, J = 2.3 Hz, 1H), 4.48 (d, J = 10.7 Hz, 1H), 4.38 (t, J = 10.1 Hz, 1H), 4.23 ( Dd, J=9.4, 2.4 Hz, 1H), 3.98 (m, 1H), 3.88 (dd, J = 12.0, 2.5 Hz, 1H), 3.82 (s, 3H), 3.69 (dd, J = 12.0, 5.4 Hz) , 1H), 3.58 (d, J = 8.5 Hz, 1H), 3.41 (s, 3H), 2.09 (s, 3H).

^{_{13 C NMR (126MHz, D 2}} O) δ174.53,163.07,145.81,104.71,77.17,75.88,69.57,62.22,60.34,53.10,50.33,45.35,22.14.

ESI-MS (m/z): 319.4 ([M+H] ⁺ ); 341.3 ([M+Na] ⁺ ).

Example 43 Synthesis of Laninamivir

Compound 2 (R is a methyl group) (19 mg, 0.056 mmol) was dissolved in water (1.5 mL), and potassium carbonate (4.5 mg, 0.056 mmol) and thiourea trioxide (4.1 mg, 0.056 mmol) were added sequentially every 0.5 h. , a total of 12 times. The reaction was carried out for 36 h at room temperature. After concentration and filtration, the filtrate was separated by HPLC to yield (10 mg, yield 50%). [α] _D ²⁰ = +8.44° (c0.5, H ₂ O); ¹ H NMR (D ₂ O, 500 MHz): δ 5.52 (d, J = 2.5 Hz, 1H), 4.30 (dd, J = 10.0, 2.0 Hz, 2H), 4.10 (t, J = 9.5 Hz, 1H), 3.88 (ddd, J = 8.5, 5.5, 3.0 Hz, 1H), 3.78 (dd, J = 12.0, 3.0 Hz, 1H), 3.57 (dd, J = 12.0, 5.5 Hz, 1H), 3.45 (dd, J = 8.5, 1.5 Hz, 1H), 3.31 (s, 3H), 1.94 (s, 3H); ¹³ C NMR (125 MHz, D ₂₎ O): δ 174.20, 168.97, 157.03, 149.22, 104.13, 77.72, 75.76, 69.61, 62.42, 60.37, 51.65, 48.97, 47.76, 22.13; ESI-MS (m/z): 347.8 ([M+H] ⁺ ). ESI-HRMS (m / z) : _{_{_{Calcd: C 13 H 23 N 4 O}}} 7 ([m + H] +): 347.15613, Found: 347.1565.

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. After adding water, it was washed three times with ethyl acetate, three times with dichloromethane, and then recrystallized three times with methanol/ethyl acetate = 1:8. The product was obtained (1.12 g, yield 100%).

Laninamivir's octanoate CS-8958 can be esterified to Lannamivir by reference to a patent (WO 2008/126943).

Although specific embodiments of the invention have been described above, those skilled in the art will appreciate that these are only It is to be understood that various changes and modifications may be made to these embodiments without departing from the spirit and scope of the invention. Accordingly, the scope of the invention is defined by the appended claims.

Claims

A method for preparing compound 2, which is characterized by method 1 or 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;

Wherein R is hydrogen or methyl; R 1 is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl Or hydrogen; R 2 and R 5 are each independently methyl, ethyl or propyl; R 4 is an amino protecting group; the amino protecting group is t-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl;

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 for preparing a compound 2 according to claim 1, wherein the method 1 for preparing the compound 2 comprises the steps of: removing the compound 3 in an aprotic solvent in the presence of an acid. The reaction of the group can obtain the compound 2;

and / or,

The method 2 for preparing the compound 2 comprises the steps of: hydrolyzing the compound 35 with a base in an aprotic solvent to obtain the compound 2.
The method for producing a compound 2 according to claim 2, wherein in the method 1 for preparing the compound 2, the aprotic solvent is a halogenated hydrocarbon solvent; and the acid is a mineral acid. And/or an organic acid; the inorganic acid is hydrochloric acid; the organic acid is trifluoroacetic acid; and the molar ratio of the compound 3 to the acid is 1:1 to 1:100; The temperature of the reaction of the protecting group is from 10 ° C to 40 ° C;

and / or,

In the method 2 for preparing the compound 2, the aprotic solvent is an ether solvent; the base is an inorganic base; and the molar ratio of the compound 35 to the base is 1:1. 1:100; The temperature of the hydrolysis reaction is from 10 ° C to 40 ° C.
The method for preparing a compound 2 according to claim 3, wherein:

The method 1 for preparing the compound 2 further comprises the following steps, when R 1 is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, A In the case of oxymethyl or methyl, the compound 3 is prepared by the following method 1; when R 1 is hydrogen, the compound 3 is prepared by the following method 2; when R 1 is trimethylsilyl, uncle When butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl or hydrogen, the compound 3 is prepared by the following method three;

Method 1: in a protic solvent, under acidic conditions, the compound 4 and an oxidizing agent are oxidized to obtain a compound 3;

Method 2: in aprotic solvent, the compound 12 and a reducing agent are reduced to obtain a compound 3;

Method 3: Compound 34 is subjected to a hydrolysis reaction to obtain Compound 3;

Wherein R 1 , R 2 , R 4 and R 5 are as defined in claim 1;

and / or,

The method 2 for preparing the compound 2 further comprises the following steps, the compound 35 is prepared by the following method: the compound 34 is subjected to a reaction for removing a protecting group to obtain the compound 35;

Wherein R, R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
The method for preparing compound 2 according to claim 4, wherein:

In the first method for preparing the compound 3, the protic solvent is an alcohol solvent and/or water; the oxidizing agent is chlorous acid; and the molar ratio of the compound 4 to the oxidizing agent is 1:1~1:5; the acidic condition is achieved by adding a strong base weak acid salt; when a strong base weak acid salt is used to achieve acidic conditions, the strong base weak acid salt and the compound are 4 molar ratio is 1:1 ~ 20:1; said acidic conditions, pH is 2 ~ 5; the temperature of the oxidation reaction is 10 ° C ~ 40 ° C;

and / or,

The method 1 for preparing the compound 3 is carried out in the presence of a radical scavenger; the radical scavenger is 2-methylbutene or phenol; and the molar ratio of the radical scavenger to the compound 4 0.5:1 to 3:1;

and / or,

The third method for preparing the compound 3 comprises the following steps: hydrolyzing the compound 34 with a base in an aprotic solvent to obtain the compound 3;

and / or,

The method for producing the compound 35 comprises the step of subjecting the compound 34 to removal of a protecting group in an aprotic solvent in the presence of an acid to obtain a compound 35.
The method for preparing a compound 2 according to claim 5, wherein:

The method 1 for preparing the compound 2 further comprises the step of, in the method 1 of the preparation of the compound 3, the compound 4 is obtained by the method of: in the aprotic solvent, the compound 5 and the oxidizing agent Performing an oxidation reaction to obtain a compound 4;

Wherein R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
The method for preparing compound 2 according to claim 6, wherein in the method for preparing compound 4, the aprotic solvent is an ether solvent; the oxidizing agent is selenium dioxide; the compound 5 molar ratio of the oxidizing agent is 1:1 ~ 1:5; the temperature of the oxidation reaction is 30 ° C ~ 100 ° C;

and / or,

The method of preparing the compound 4 is carried out under the protection of an inert gas; the inert gas is one or more of nitrogen, argon and helium.
The method for producing a compound 2 according to claim 7, wherein the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 4, the compound 5 is obtained by the following method. : nucleophilic substitution reaction of compound 6 with an acetylating reagent in a solvent, in the presence of a base, to obtain a compound 5;

Wherein R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
The method for preparing the compound 2 according to claim 8, wherein in the method for preparing the compound 5, the solvent is a halogenated hydrocarbon solvent and/or an organic base; the base is an organic base; The organic base is one or more of pyridine, piperidine and triethylamine; the molar ratio of the compound 6 to the base is 1:3 to 1:6; the acetylating reagent is acetyl The halogen and/or acetic anhydride; the molar ratio of the compound 6 to the acetylating agent is 1:1 to 1:20; and the temperature of the nucleophilic substitution reaction is 0 ° C to 100 ° C.
The method for producing a compound 2 according to claim 9, wherein the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 5, the compound 6 is obtained by the following method. : in aprotic solvent, under the conditions of acid and reducing agent, the compound 7 is subjected to a reduction reaction to obtain a compound 6;

Wherein R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
The method for preparing compound 2 according to claim 10, wherein in the method for preparing compound 6, the aprotic solvent is an ester solvent; the acid is an organic acid; and the organic acid Is glacial acetic acid; the molar ratio of the acid to the compound 7 is 10:1 to 100:1; the reducing agent is one or more of zinc, iron and aluminum; the reducing agent The molar ratio to the compound 7 is from 10:1 to 100:1; and the temperature of the reduction reaction is from 0 °C to 40 °C.
The method for producing a compound 2 according to claim 11, wherein the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 6, the compound 7 is obtained by the following method. : in an organic solvent, in the presence of a base, the compound 8 and a dehydrating agent are dehydrated to obtain a compound 7;

Wherein R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
The method for producing compound 2 according to claim 12, wherein in the method for producing compound 7, the organic solvent is one or more of a halogenated hydrocarbon solvent, an ether solvent, and an aromatic hydrocarbon solvent. The base is an organic base; the organic base is triethylamine and/or pyridine; the molar ratio of the base to the compound 8 is 100:1 to 1:1, the dehydration The agent is one or more of thionyl chloride, methanesulfonyl chloride and Burgess reagent; the molar ratio of the compound 8 to the dehydrating agent is 1:1 to 1:5; The temperature is from 0 ° C to 40 ° C;

and / or,

The method for preparing the compound 7 is carried out in the presence of a catalyst; the catalyst is 4-dimethylaminopyridine; and the molar ratio of the catalyst to the compound 8 is 1:1 to 1:10.
The method for producing a compound 2 according to claim 13, wherein the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 7, the compound 8 is obtained by the following method. : reacting compound 10 with compound 9 in an aprotic solvent in the presence of a base, a catalyst and a catalyst ligand to obtain compound 8;

Wherein R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
The method for preparing compound 2 according to claim 14, wherein in the method for preparing compound 8, the aprotic solvent is an ether solvent; the base is an inorganic base; and the inorganic base is Is 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 1:1 to 10:1; the catalyst is inorganic a copper salt and/or an organic copper salt; the inorganic copper salt being one or more of copper chloride, cuprous chloride, cuprous bromide, copper bromide and cuprous iodide; The copper salt is copper acetate; the molar ratio of the compound 9 to the catalyst is 1:1 to 10:1; and the molar ratio of the compound 10 to the compound 9 is 1:1 to 5:1. The catalyst ligand is a pyrrolidine-phenol catalyst; the pyrrolidine-phenol catalyst is
The molar ratio of the catalyst ligand to the compound 9 is 1:10 to 3:10; and the temperature of the reaction is preferably -20 to 40 °C.
The method for preparing compound 2 according to claim 4, wherein in the second method for preparing compound 3, the aprotic solvent is an ether solvent; and the reducing agent is zinc borohydride or hydroboration. Sodium, potassium borohydride, lithium aluminum hydride or lithium borohydride; the molar ratio of the compound 12 to the reducing agent is 1:1 to 1:5; the temperature of the reduction reaction is -78 ° C - 40 ° C;

and / or,

In the third method for preparing the compound 3, the aprotic solvent is an ether solvent, the base is an inorganic base, and the molar ratio of the compound 34 to the base is 1:1 to 1:100. The temperature of the hydrolysis reaction is from 10 ° C to 40 ° C.
The method for producing a compound 2 according to claim 16, wherein the method 1 for preparing the compound 2 further comprises the following steps. In the second method for preparing the compound 3, the compound 12 is prepared by the following method. : in an aprotic solvent, under acidic conditions, the compound 13 is oxidized with an oxidizing agent to obtain a compound 12;

Wherein R 2 , R 4 and R 5 are as defined in claim 1.
The method for preparing compound 2 according to claim 17, wherein in the method for preparing compound 12, the protic solvent is an alcohol solvent and/or water; and the oxidizing agent is chlorous acid; The molar ratio of the compound 13 to the oxidizing agent is 1:1 to 1:5; the acidic condition is achieved by adding a strong base weak acid salt; when a strong base weak acid salt is used to achieve acidic conditions, The molar ratio of the strong base weak acid salt to the compound 13 is 1:1 to 20:1; the acidic condition is pH 2 to 5; and the oxidation reaction temperature is 10 ° C to 40 °C;

and / or,

The method for preparing the compound 12 is carried out in the presence of a radical scavenger; the radical scavenger is 2-methylbutene or phenol; and the molar ratio of the radical scavenger to the compound 13 is 0.5:1 to 3:1.
The method for producing a compound 2 according to claim 18, wherein the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 12, the compound 13 is prepared by the following method: The compound 14 is oxidized with an oxidizing agent in an aprotic solvent to obtain a compound 13;

Wherein R 2 , R 4 and R 5 are as defined in claim 1.
The method for preparing compound 2 according to claim 19, wherein in the method for producing compound 13, the aprotic solvent is an ether solvent; the oxidizing agent is selenium dioxide; the compound The molar ratio of 14 to the oxidizing agent is 1:1 to 1:5; the temperature of the oxidation reaction is 80 ° C to 150 ° C;

and / or,

The method of preparing the compound 13 is carried out under the protection of an inert gas; the inert gas is one or more of nitrogen, argon and helium.
The method for producing a compound 2 according to claim 20, wherein the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 13, the compound 14 is as follows The method comprises the following steps: subjecting compound 15 to oxidation reaction to obtain compound 14;

Wherein R 2 , R 4 and R 5 are as defined in claim 1.
The method for producing a compound 2 according to claim 21, wherein the method for producing the compound 14 comprises the steps of: subjecting the compound 15 to an oxidizing agent to carry out a Lewis oxidation reaction in the presence of a catalyst in an organic solvent to obtain a compound. 14.
The method for preparing compound 2 according to claim 22, wherein in the method for preparing compound 14, the organic solvent is a halogenated hydrocarbon solvent and/or a nitrile solvent; and the oxidizing agent is N- Methylmorpholine oxide; the molar ratio of the compound 15 to the oxidizing agent is 1:1 to 1:5; the catalyst is tetra-n-propylammonium perruthenate; the compound 15 and The molar ratio of the catalyst is 20:1 to 5:1; the temperature of the Leyd oxidation reaction is 10 ° C to 40 ° C;

and / or,

The method for preparing the compound 14 is carried out in the presence of a molecular sieve; the molar ratio of the molecular sieve to the compound 15 is from 1 g/mol to 5 g/mol.
The process for producing the compound 2 according to claim 23, wherein the process 1 for preparing the compound 2 further comprises the step of preparing the compound 15 by the following method in the process for producing the compound 14: The compound 16 is reacted with a fluorinating reagent to remove a hydroxy protecting group in a solvent to obtain a compound 15;

Wherein R 2 , R 4 and R 5 are as defined in claim 1; R 3 is a hydroxy protecting group, said hydroxy protecting group being trimethylsilyl, tert-butyldimethylsilyl, uncle Butyl diphenylsilyl, triisopropylsilyl or methoxymethyl.
The method for preparing compound 2 according to claim 24, wherein in the method for preparing compound 15, the solvent is an ether solvent; and the fluorinating reagent is tetrabutylammonium fluoride and/or Potassium fluoride; said The molar ratio of the compound 16 to the fluorinating agent is from 1:1 to 1:5; and the temperature at which the hydroxy protecting group is removed is from 10 ° C to 40 ° C.
The process for producing the compound 2 according to claim 25, wherein the process 1 for preparing the compound 2 further comprises the step of preparing the compound 16 by the following method in the process for producing the compound 15: In a solvent, in the presence of a base, the compound 17 and the acetylation reagent are subjected to a nucleophilic substitution reaction to obtain a compound 16;

Wherein R 2 , R 4 and R 5 are as defined in claim 1; R 3 is as defined in claim 23.
The method for preparing compound 2 according to claim 26, wherein in the method for preparing compound 16, the solvent is a halogenated hydrocarbon solvent and/or an organic base; and the halogenated hydrocarbon solvent is chlorine. a hydrocarbon-based solvent; the base is an organic base; the organic base is one or more of pyridine, piperidine and triethylamine; the molar ratio of the compound 17 to the base is 1 The acetylating agent is acetyl halide and/or acetic anhydride; the molar ratio of the compound 17 to the acetylating agent is 1:1 to 1:20; The temperature of the nuclear substitution reaction is from 0 ° C to 100 ° C.
The method for producing a compound 2 according to claim 27, wherein the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 16, the compound 17 is obtained by the following method. : in aprotic solvent, under the conditions of acid and reducing agent, the compound 18 is subjected to a reduction reaction to obtain a compound 17;

Wherein R 2 , R 4 and R 5 are as defined in claim 1; R 3 is as defined in claim 23.
The method for preparing compound 2 according to claim 4, wherein in the method for preparing compound 17, the aprotic solvent is a halogenated hydrocarbon solvent; the acid is an organic acid; The organic acid is glacial acetic acid; the molar ratio of the acid to the compound 18 is 10:1 to 100:1; the reducing agent is zinc, iron and aluminum. One or more of the above; the molar ratio of the reducing agent to the compound 18 is from 10:1 to 100:1; and the temperature of the reduction reaction is from 0 °C to 40 °C.
The method for producing a compound 2 according to claim 29, wherein the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 17, the compound 18 is obtained by the following method. : in an organic solvent, in the presence of a base, the compound 19 and a dehydrating agent are dehydrated to obtain a compound 18;

Wherein R 2 , R 4 and R 5 are as defined in claim 1; R 3 is as defined in claim 23.
The method for producing compound 2 according to claim 30, wherein in the method for producing compound 18, the organic solvent is one or more of a halogenated hydrocarbon solvent, an ether solvent, and an aromatic hydrocarbon solvent. The dehydrating agent is one or more of thionyl chloride, methanesulfonyl chloride and Burgess reagent; the molar ratio of the compound 19 to the dehydrating agent is 1:1 to 1:5; The base is an organic base; the organic base is triethylamine and/or pyridine; the molar ratio of the base to the compound 19 is 1:1 to 50:1; The temperature is from 0 ° C to 40 ° C;

and / or,

The method for preparing the compound 18 is carried out in the presence of a catalyst; the catalyst is 4-dimethylaminopyridine; and the molar ratio of the catalyst to the compound 19 is 1:1 to 1:5.
The method for producing a compound 2 according to claim 31, wherein the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 18, the compound 19 is obtained by the following method. : reacting compound 10 with compound 20 in an aprotic solvent in the presence of a basic substance to obtain compound 19;

Wherein R 2 , R 4 and R 5 are as defined in claim 1; R 3 is as defined in claim 23.
The method for preparing compound 2 according to claim 32, wherein in the method for preparing compound 19, the aprotic solvent is an ether solvent solvent; the base is an inorganic base or an organic base; One or more of a basic oxide, a strong base weak acid salt, and an ion exchange resin; the inorganic base is sodium methoxide and/or potassium t-butoxide; and the organic base is tetrabutylammonium hydroxide, 1 One or more of 8-diazabicyclo[5.4.0]undec-7-ene, tetramethylphosphonium and lithium diisopropylamide; the basic oxide is alkaline The aluminum oxide; the strong base weak acid salt is potassium acetate; the ion exchange resin is Amberlite A-21; the molar ratio of the basic substance to the compound 10 is 1:1 to 1: 10; The temperature of the reaction is from 0 ° C to 40 ° C.
The method for producing a compound 2 according to claim 14 or claim 33, wherein the method 1 for preparing the compound 2 further comprises the step of: in the method for producing the compound 8 or 19, the compound 10 is used under Method preparation:

In an organic solvent, in the presence of an additive and a catalyst, the compound 11 and acetone are subjected to a Michael addition reaction to obtain a compound 10;

Wherein R 4 is as defined in claim 1.
The method for producing compound 2 according to claim 34, wherein in the method for producing compound 10, the organic solvent is an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether solvent, an alkane solvent, and a halogen. One or more of the aromatic hydrocarbon solvents; the additive is an organic acid; the organic acid is benzoic acid, acetic acid, p-dibenzoic acid, p-hydroxybenzoic acid, p-nitrobenzoic acid, (+) a molar ratio of the additive to the compound 11 of from 0.1:1 to 1:1; The molar ratio is from 5:1 to 20:1; the molar ratio of the catalyst to the compound 11 is from 0.01:1 to 0.1:1; and the temperature of the Michael addition reaction is from 0 °C to 40 °C; The catalyst described is any of the catalysts shown in the following formula:
The process for producing the compound 2 according to claim 32, wherein the process 1 for preparing the compound 2 further comprises the step of preparing the compound 20 by the following method in the process for producing the compound 19: The compound 21 is oxidized with an oxidizing agent in an aprotic solvent to obtain a compound 20;

Wherein R 2 and R 5 are as defined in claim 1; R 3 is as defined in claim 23.
The method for preparing compound 2 according to claim 36, wherein in the method for producing compound 20, the aprotic solvent is an ether solvent and/or a halogenated hydrocarbon solvent; One or more of a Dess-Martin periodinane, a pyridinium chlorochromate salt, and a pyridinium dichromate; the compound 21 and the oxygen The molar ratio of the chemical agent is 1:1 to 1:5; the temperature of the oxidation reaction is 0 ° C to 40 ° C;

and / or,

The method for preparing the compound 20 is carried out in the presence of a base; the base is an inorganic base; and the inorganic base is 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 1:1 to 1:5.
The method for producing a compound 2 according to claim 37, wherein the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 20, the compound 21 is prepared by the following method: The compound 22 is condensed with a ketone in the presence of a catalyst to obtain a compound 21;

Wherein R 2 and R 5 are as defined in claim 1; R 3 is as defined in claim 23.
The method for preparing compound 2 according to claim 38, wherein in the method for producing compound 21, the catalyst is montmorillonite; and the mass ratio of the catalyst to the compound 22 is 100 g. /mol ~ 1000g / mol; the ketone is acetone, methyl ethyl ketone, 2-pentanone or 3-pentanone; the volume ratio of the ketone to the compound 22 is 30mL / g ~ 100mL / g The temperature of the condensation reaction is 10 ° C ~ 40 ° C;

and / or,

The method of preparing compound 21 is carried out in the presence of a molecular sieve.
The method for producing a compound 2 according to claim 39, wherein the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 21, the compound 22 is produced by the following method: In a non-protic solvent, the compound 23 and a reducing agent are subjected to a reduction reaction to obtain a compound 22;

The definition of R 3 is as set forth in claim 23.
The method for preparing compound 2 according to claim 40, wherein in the method for preparing compound 22, the aprotic solvent is an ether solvent; and the reducing agent is lithium borohydride or sodium borohydride. And one or more of potassium borohydride and zinc borohydride; the molar ratio of the reducing agent to the compound 23 is 1:1 to 5:1; and the temperature of the reduction reaction is 0 ° C. 40 ° C.
The method for producing a compound 2 according to claim 41, wherein the method 1 for preparing the compound 2 further comprises the step of, in the method for producing the compound 22, the compound 23 is as follows The method comprises the steps of: reacting D-(-)-diethyl tartrate 24 with a hydroxy protecting reagent in an organic solvent in the presence of a base to obtain a compound 23;

The definition of R 3 is as set forth in claim 23.
The method for producing compound 2 according to claim 42, wherein in the method for producing compound 23, the organic solvent is an amide solvent; the base is an inorganic base; and the inorganic base is hydrogenated. Sodium; the molar ratio of the base to the D-(-)-divinyl tartrate 24 is 1:1; the hydroxy protecting reagent is tert-butyldimethylchlorosilane, trimethylchlorosilane One or more of tert-butyldiphenylchlorosilane, triisopropylchlorosilane and chloromethyl methyl ether; the reaction temperature of the upper hydroxyl protecting group is from 0 °C to 40 °C.
The method for preparing a compound 2 according to claim 5, wherein:

In the method of preparing the compound 35, the aprotic solvent is an ether solvent; the acid is a mineral acid; the molar ratio of the compound 34 to the acid is 1:1 ~ 1:100; The temperature of the reaction for removing the protecting group is from 10 ° C to 40 ° C.
The method for preparing compound 2 according to claim 4, wherein:

In the aprotic solvent, the compound 34 is subjected to a reaction for removing the protecting group in the presence of an acid, and the compound 35 is obtained without post-treatment, and then subjected to a hydrolysis reaction in the presence of a base to obtain a hydrolysis reaction. The compound 2 can be used;

and / or,

In the aprotic solvent, the compound 34 is subjected to a hydrolysis reaction with a base to obtain the compound 3, and then the reaction is carried out in the presence of an acid without post-treatment to obtain the compound. 2 can be.
The method for preparing the compound 2 according to claim 4, wherein the method 1 or the method 2 for preparing the compound 2 further comprises the following steps, in the method for preparing the compound 35 or the third method for preparing the compound 3, The compound 34 is prepared by the following method: in a solvent, in the presence of a base, the compound 33 and the acetylation reagent are subjected to nucleophilic substitution reaction to obtain the compound 34;

Wherein R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
A method of producing Compound 2 according to claim 46, wherein:

In the method for preparing compound 34, the solvent is a halogenated hydrocarbon solvent and/or an organic base; the base is an organic base; and the molar ratio of the compound 33 to the base is 1:3. 1:6; the acetylating agent is acetyl halide and/or acetic anhydride; the molar ratio of the compound 33 to the acetylating agent is 1:1 to 1:3; the nucleophilic substitution reaction The temperature is from 0 ° C to 100 ° C.
The process for producing the compound 2 according to claim 46, wherein the process 2 for preparing the compound 2 further comprises the step of preparing the compound 33 by the following method in the process for producing the compound 34: In aprotic solvent, under the conditions of acid and reducing agent, the compound 32 is subjected to a reduction reaction to obtain the compound 33;

Wherein R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
A method of producing Compound 2 according to claim 48, wherein:

The method for preparing the compound 33 comprises the following steps: a solution of the compound 32 and an aprotic solvent, followed by a reducing agent, an acid, followed by a reduction reaction to obtain the compound 33;

and / or,

In the method of preparing compound 33, the aprotic solvent is an ester solvent; the acid is an organic acid; the molar ratio of the acid to the compound 32 is 10:1 ~ 100:1; The reducing agent is one or more of zinc, iron and aluminum; the molar ratio of the reducing agent to the compound 32 is 10:1 to 100:1; the temperature of the reduction reaction is -10 ° C ~ 40 ° C.
The method of producing compound 2 according to claim 48, wherein the method 2 for preparing the compound 2 further comprises the step of, in the method for producing the compound 33, the compound 32 is obtained by the following method. : in an organic solvent, in the presence of a base, the compound 31 and a dehydrating agent are dehydrated to obtain the compound 32;

Wherein R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
A method of producing a compound 2 according to claim 50, wherein:

The method for preparing the compound 32 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;

and / or,

In the method of preparing compound 32, the organic solvent is one or more of an ether solvent, a halogenated hydrocarbon solvent, and an aromatic hydrocarbon solvent; the base is an organic base; the base and the The compound 31 has a molar ratio of 10:1 to 1:1; the dehydrating agent is dichlorosulfoxide and/or methanesulfonyl chloride; and the molar ratio of the compound 31 to the dehydrating agent is 1:1. ~1:5; The temperature of the dehydration reaction is -78 ° C to 30 ° C.
The process for producing the compound 2 according to claim 50, wherein the process 2 for preparing the compound 2 further comprises the step of preparing the compound 31 by the following method in the process for producing the compound 32: The compound 30 is subjected to an oxidation reaction in an aprotic solvent in the presence of an oxidizing agent to obtain the compound 31;

Wherein R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
The method for preparing compound 2 according to claim 52, wherein in the method for preparing compound 31, the aprotic solvent is a halogenated hydrocarbon solvent; and the oxidizing agent is a Dess Martin oxidizing agent; The molar ratio of the compound 30 to the oxidizing agent is 1:1 to 1:3; and the temperature of the oxidation reaction is -30 to 30 °C.
The method for producing a compound 2 according to claim 52, wherein the method 2 for preparing the compound 2 further comprises the step of, in the method for producing the compound 31, the compound 30 is as follows Method preparation: in a protic solvent, in the presence of a base, the compound 29 is hydrolyzed to obtain the compound 30;

Wherein R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
The method for preparing compound 2 according to claim 54, wherein in the method for preparing compound 30, the protic solvent is an alcohol solvent; and the base is potassium carbonate and/or sodium methoxide; The molar ratio of the compound 29 to the base is from 3:1 to 1:1; and the temperature of the hydrolysis reaction is from 0 °C to 50 °C.
The process for producing the compound 2 according to claim 54, wherein the process 2 for preparing the compound 2 further comprises the step of, in the process for producing the compound 30, the compound 29 is produced by the following method: The compound 28 is reacted 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;

Wherein R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
The method for producing compound 2 according to claim 56, wherein in the method for producing compound 29, the aprotic solvent is an ether solvent; the base is an inorganic base; and the compound 9 The molar ratio of the base to the base is 1:1 to 5:1; the catalyst is an inorganic copper salt; the molar ratio of the compound 28 to the catalyst is 1:1 to 10:1; The molar ratio of the compound 28 to the compound 9 is 1:1 to 1:5; the catalyst ligand is a pyrrolidine-phenol catalyst; the molar ratio of the catalyst ligand to the compound 28 It is 1:10 to 3:10; the temperature of the reaction is -20 ° C to 40 ° C.
The process for the preparation of the compound 2 according to claim 56, wherein the process 2 for preparing the compound 2 further comprises the following steps. In the process for producing the compound 29, the compound 28 is prepared by the following method: The compound 28 is obtained by reacting the compound 27 with a hydroxy protecting reagent in an organic solvent in the presence of a base and a catalyst;

Wherein R 4 is as defined in claim 1.
A method of producing a compound 2 according to claim 58, wherein:

The method for preparing the compound 28 comprises the following steps: a solution of the compound 27 and an organic solvent, adding a catalyst, adding a base and a hydroxyl protecting agent, and reacting the upper hydroxyl protecting group to obtain the compound 28;

and / or,

In the method of preparing the compound 28, the organic solvent is an ether solvent; the base is an organic base; the molar ratio of the base to the compound 27 is 1:1 to 3:1; The catalyst is 4-dimethylaminopyridine; the molar ratio of the catalyst to the compound 27 is 0.01:1 to 0.5:1; the hydroxy protecting reagent is acetic anhydride, acetyl chloride, acetyl bromide, trifluoro Acetyl chloride, trifluoroacetyl bromide, trimethylchlorosilane, trimethylbromosilane, tert-butyldimethylchlorosilane, tert-butyldimethylbromosilane, triethylchlorosilane, triethylbromosilane, Benzyl chloride or benzyl bromide; the reaction temperature of the upper hydroxy protecting group is from 0 ° C to 40 ° C.
The method of producing compound 2 according to claim 58, wherein said method 2 for preparing compound 2 further comprises the step of: in the method for producing said compound 28, said compound 27 is as follows Method preparation: in a protic solvent, the compound 26 and a reducing agent are reduced to obtain the compound 27;

Wherein R 4 is as defined in claim 1.
A method of producing Compound 2 according to claim 60, wherein:

The method for preparing the compound 27 includes the following steps: in the solution of the compound 26 and the protic solvent, sodium borohydride is added to carry out a reduction reaction to obtain the compound 27;

and / or,

In the method for preparing compound 27, the protic solvent is an alcohol solvent; the reducing agent is an alkali metal borohydride; and the molar ratio of the reducing agent to the compound 26 is 0.4:1. 10:1; The temperature of the reduction reaction is from 0 ° C to 40 ° C.
The process for producing the compound 2 according to claim 60, wherein the process 2 for preparing the compound 2 further comprises the step of preparing the compound 26 by the following method in the process for producing the compound 27: In the organic solvent, in the presence of a catalyst, the compound 11 and methyl pyruvate Michael addition reaction to obtain the compound 26;

Wherein R 4 is as defined in claim 1.
The method for producing compound 2 according to claim 62, wherein in the method for producing compound 26, the organic solvent is an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether solvent, an alkane solvent, and a halogen. One or more of the aromatic hydrocarbon solvents; the molar ratio of the methyl pyruvate to the compound 11 is 1:1 to 1:10; the molar ratio of the catalyst to the compound 11 The temperature of the Michael addition reaction is from -10 ° C to 40 ° C; the catalyst is any of the catalysts represented by the following formula:
a compound 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, its structural formula is as follows:

Wherein 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.
The compound according to claim 64, wherein R 1 is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl or methoxymethyl. a group, a methyl group or a hydrogen group, R 2 and R 5 are each independently a methyl group, and R 4 is a tert-butoxycarbonyl group;

Or R 3 is hydrogen, R 2 and R 5 are each independently a methyl group, and R 4 is a tert-butoxycarbonyl group.