CN109748921B

CN109748921B - N-tert-butyloxycarbonyl protected heterocyclic compound, preparation method thereof and method for preparing C-nucleoside analogue by using N-tert-butyloxycarbonyl protected heterocyclic compound

Info

Publication number: CN109748921B
Application number: CN201711071763.5A
Authority: CN
Inventors: 沈竞康; 陈越磊; 熊兵; 刘同超
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2017-11-03
Filing date: 2017-11-03
Publication date: 2022-03-22
Anticipated expiration: 2037-11-03
Also published as: CN109748921A

Abstract

The invention belongs to the field of chemical synthesis, and particularly discloses a N-tert-butyloxycarbonyl protected heterocyclic compound shown in a general formula 5, a preparation method thereof and a method for preparing a C-nucleoside analogue by using the N-tert-butyloxycarbonyl protected heterocyclic compound. In the compound 5, Hal is selected from chlorine, bromine and iodine; z is selected from CR⁰Or nitrogen, R⁰Is H, halogen, cyano, C₁‑C₆Straight or branched alkyl, C₂‑C₆Straight or branched alkenyl or C₂‑C₆Straight or branched alkynyl. In the prior literature, the synthesized C-nucleosides are mainly beta-C-nucleoside products, but beta: alpha has unsatisfactory stereoselectivity, and has the problems of separation and purification of products and consumption of expensive synthetic raw materials. The method provided by the invention starts from the compound 5 which is easy to prepare and low in cost, and can be used for controllably synthesizing the alpha-C-nucleoside product 8 or the beta-C-nucleoside product 3, and has the advantages of good stereoselectivity, high yield and good repeatability.

Description

N-tert-butyloxycarbonyl protected heterocyclic compound, preparation method thereof and method for preparing C-nucleoside analogue by using N-tert-butyloxycarbonyl protected heterocyclic compound

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to N-tert-butyloxycarbonyl (Boc) protected heterocyclic compounds (compounds shown in a general formula 5), a preparation method thereof and a method for preparing C-nucleoside analogues by using the same.

Background

C-nucleosides have gained extensive research interest due to their superior druggability, and the C-nucleoside structures shown in the following documents all show superior antiviral or antitumor pharmacological activity. There are many reports on methods for the synthesis of C-nucleoside analogues, but the synthesis of some specific C-nucleosides, as shown in the following documents, is still difficult.

Gilead company reported in 2012 that bases 1-1a and 1-2a can be added and reduced with ribolactone 2-1a after being temporarily protected by silicon to obtain C-nucleoside analogs 3a and 3b [ 1) Cho, A.; zhang, l.; xu, j.; babusis, d.; butler, t.; lee, r.; saunders, o.l.; wang, t.; parrish, J.; perry, j.; feng, j.y.; ray, a.s.; kim, c.u., Synthesis and catalysis of 2' -C-Me branched C-nucleotides as HCV polymerase inhibitors bioorganic & Medicinal Chemistry Letters 2012,22(12), 4127-4132.2) Cho, a; zhang, l.; xu, j.; lee, r.; butler, t.; metobo, s.; aktoutianakis, v.; lew, w.; ye, h.; clarke, m.; doerfler, e.; byun, d.; wang, t.; babusis, d.; carey, a.c.; german, p.; sauer, d.; zhong, w.; rossi, s.; finaux, m.; McHutchison, j.g.; perry, j.; feng, j.; ray, a, s.; kim, C.U., Discovery of the First C-nucleotide HCV Polymerase Inhibitor (GS-6620) with a purified antibiotic Response in HCV Infected Patients. journal of Medicinal Chemistry 2014,57(5), 1812. 1825.

The Gilead company in 2017 reported an improvement of this method: starting from bases 1-1b, the C-nucleoside analog 4a [ Siegel, d.; hui, h.c.; doerfler, e.; clarke, m.o.; chun, k.; zhang, l.; neville, s.; carra, e.; lew, w.; ross, b.; wang, q.; wolfe, l.; jordan, r.; soloveva, v.; knox, j.; perry, j.; perron, m.; stray, k.m.; barauskas, o.; feng, j.y.; xu, y.; lee, g.; rheingold, a, l.; ray, a.s.; banister, r.; strickley, r.; swaminathan, s.; lee, w.a.; bavari, s.; cihler, t.; lo, m.k.; warren, t.k.; mackman, R.L., Discovery and Synthesis of phosphate Prodrug of a Pyrrolo [2,1-f ] [ triazin-4-amino ] Adenine C-nucleotide (GS-5734) for the Treatment of Ebola and ignition viruses journal of medical Chemistry 2017,60(5),1648-1661 ].

More complicated synthetic methods for the C-nucleoside analogs 3-1a and 3-1b were reported in 2014 by the company Biota Scientific Management and Boehringer Ingelheim [ Draffan, a.g.; frey, b.; pool, b.; gannon, c.; tyndall, e.m.; lilly, m.; francom, p.; hufton, r.; halim, r.; jahangiri, s.; bond, s.; nguyen, v.t.t.; jeynes, t.p.; wirth, v.; luttick, a.; timanis, d.; thomas, j.d.; pryor, M.; porter, k.; morton, c.j.; lin, B.; duan, j.; kukolj, g.; simoneau, b.; McKercher, g.; langac é, l.; amad, m.a.; bethell, r.c.; tucker, S.P., Discovery and Synthesis of C-nucleotides as Potential New Anti-HCV Agents. ACS Medicinal Chemistry Letters 2014,5(6), 679-.

The above methods for synthesizing C-nucleoside analogs all have problems of long route, low yield, or poor repeatability, etc.

Meanwhile, according to literature reports, a variety of alpha-nucleosides have important biological activity or structural research values [ 1) Brown, k.l.; cheng, s.; zuo, x.; li, J.; chen, g.; valente, e.j.; zukkowski, j.d.; marques, H.M., Structural and Enzymic students of a New Analog of Coenzyme B12with an α -Adenosyl Upper Axial ligand, biochemistry 1998,37(27), 9704-; (2) gosselin, g.; bergogne, m.c.; imbach, J.L., Stereospermic synthesis and biological evaluation of 9-alpha-D-ribofuranosylguanine (alpha-guanosine). Nucleotides 1990,9(1), 81-7; (3) reitz, a.b.; rebarchak, m.c., Expeditious and stereoselective synthesis of α -guanosine, Nucleotides 1992,11(5), 1115-21; (4) secreist, j.a., III; parker, w.b.; allan, P.W.; bennett, l.l., jr.; roud, w.r.; truss, j.w.; fowler, a.t.; montgomery, j.a.; ealick, S.E.; wells, a.h.; gillespie, g.y.; gadi, v.k.; sorscher, E.J., Gene therapy of cancer: activation of nucleotide precursors with E.coli Gene protease Nucleotides 1999,18(4&5),745-757, the alpha-C-nucleoside analogs of which are of corresponding research interest. However, since the synthesis of alpha-C-nucleoside analogs is more difficult than the synthesis of C-nucleosides in general, studies on their application have been greatly limited.

Disclosure of Invention

The invention aims to provide N-tert-butyloxycarbonyl protected heterocyclic compounds which are intermediate compounds shown as a general formula 5 and are used for preparing C-nucleoside analogues.

Another object of the present invention is to provide a method for preparing the compound represented by the general formula 5.

Another object of the present invention is to provide the use of the compound represented by the general formula 5 for the preparation of C-nucleoside analogues.

In a first aspect of the present invention, there is provided a compound having the following formula 5:

wherein the content of the first and second substances,

hal is selected from chlorine, bromine and iodine;

z is selected from CR⁰Or nitrogen, R⁰Is H, halogen, cyano, C₁-C₆Straight or branched alkyl, C₂-C₆Straight or branched alkenyl or C₂-C₆Straight or branched alkynyl.

Preferably, the compound represented by the formula 5 is a compound having one of the following formulae:

wherein the content of the first and second substances,

r is selected from H, halogen, cyano, C₁-C₆Straight or branched alkyl, C₂-C₆Straight or branched alkenyl or C₂-C₆Straight or branched alkynyl; hal is as defined in formula 5.

In the second aspect of the present invention, there is also provided a process for producing a compound represented by the general formula 5, which comprises subjecting an amino group of the heterocyclic compound 1 to an amino group protection reaction to obtain a compound represented by the general formula 5,

wherein the content of the first and second substances,

hal is selected from chlorine, bromine and iodine;

In a third aspect of the present invention, there is also provided a process for preparing a C-nucleoside analogue from a compound represented by the general formula 5, which comprises the steps of:

(c) removing N from the compound shown in the general formula 5⁶-proton, performing halogen-metal exchange, performing addition reaction with lactone compound 2 to obtain compound 7, and reducing compound 7 to obtain alpha-C-nucleoside analogue 8;

or the like, or, alternatively,

(d) removal of Compound 5 from N⁶Proton, performing halogen-metal exchange, performing addition reaction with lactone compound 2-1 to obtain compound 9, reducing compound 9, and removing N⁶-tert-butoxycarbonyl protection to give beta-C-nucleoside analogue 3;

wherein the content of the first and second substances,

hal is selected from chlorine, bromine and iodine;

z is selected from CR⁰Or nitrogen, R⁰Is H, halogen, cyano, C₁-C₆Straight or branched alkyl, C₂-C₆Straight or branched alkenyl or C₂-C₆Straight or branched chain alkynyl;

R¹selected from H or methyl;

R²selected from H or Boc;

pg is selected from 2-naphthylmethyl, 1-naphthylmethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, substituted by halogen or C₁-C₆The benzyl group substituted with a linear or branched alkyl group is preferably a 2-naphthylmethyl group, a p-methoxybenzyl group.

In a preferred embodiment, the compound of formula 5 is prepared by the following method:

(a) the amino group of the heterocyclic compound 1 is subjected to amino protection reaction to obtain the compound shown as the general formula 5

Wherein the content of the first and second substances,

hal is selected from chlorine, bromine and iodine;

z is selected from CR⁰Or nitrogen, R⁰Is H, halogen, cyano or vinyl.

In a preferred embodiment, the lactone compound 2 or the lactone compound 2-1 is prepared by the following method:

(b) hydroxyl of the sugar compound 6 and PgBr or PgCl are subjected to hydroxyl protection reaction to obtain a lactone compound 2; or hydroxyl of the sugar compound 6-1 and PgBr or PgCl are subjected to hydroxyl protection reaction to obtain a lactone compound 2-1;

R¹selected from H or methyl;

pg is selected from 2-naphthylmethyl, 1-naphthylmethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, substituted by halogen or C₁-C₆The linear or branched alkyl-substituted benzyl group is preferably a benzyl group, a 2-naphthylmethyl group or a p-methoxybenzyl group.

In a preferred embodiment, the beta-C-nucleoside analog 3 or alpha-C-nucleoside analog 8 is prepared by the following method:

(a) carrying out amino protection reaction on the amino of the heterocyclic compound 1 to obtain a compound shown as a general formula 5;

(b) hydroxyl of the sugar compound 6 and PgBr or PgCl are subjected to hydroxyl protection reaction to obtain a lactone compound 2;

or hydroxyl of the sugar compound 6-1 and PgBr or PgCl are subjected to hydroxyl protection reaction to obtain a lactone compound 2-1;

or the like, or, alternatively,

(d) removing N from the general formula 5⁶Protons, halogen-metal exchange, with lactone compounds 2-1Carrying out addition reaction to obtain a compound 9, reducing the compound 9, and removing N⁶-tert-butoxycarbonyl protection to give beta-C-nucleoside analogue 3;

wherein the content of the first and second substances,

hal is selected from bromine and iodine;

z is selected from CR⁰Or nitrogen, R⁰Is H, cyano or vinyl;

R¹selected from H or methyl;

R²selected from H or Boc;

pg is benzyl, 2-naphthylmethyl or p-methoxybenzyl.

In a preferred embodiment of the present invention,

the step (c) is one selected from the following steps:

(c-a) removing N from Compound 5-1a⁶-proton, performing halogen-metal exchange, and performing addition reaction with lactone compound 2 to obtain compound 7-1, and reducing compound 7-1 to obtain alpha-C-nucleoside analogue 8-1;

or the like, or, alternatively,

(c-b) removing N from the compound 5-2a⁶-proton, performing halogen-metal exchange, performing addition reaction with lactone compound 2 to obtain compound 7-2, and reducing compound 7-2 to obtain alpha-C-nucleoside analogue 8-2;

wherein the content of the first and second substances,

R¹selected from H or methyl;

R²selected from H or tert-butyloxycarbonyl;

pg is 2-naphthylmethyl or benzyl.

In a preferred embodiment of the present invention,

step (d) is one selected from the following steps:

(d-a) removing N from Compound 5-1a⁶Proton, performing halogen-metal exchange, performing addition reaction with lactone compound 2-1 to obtain compound 9-3, reducing compound 9-3, and removing N⁶-tert-butoxycarbonyl protection to give beta-C-nucleoside analogue 3-3;

or the like, or, alternatively,

(d-b) removing N from Compound 5-2a⁶Proton, performing halogen-metal exchange, performing addition reaction with lactone compound 2-1 to obtain compound 9-4, reducing compound 9-4, and removing N⁶-tert-butoxycarbonyl protection to give beta-C-nucleoside analogue 3-4;

wherein the content of the first and second substances,

R¹selected from H or methyl;

R²selected from H or tert-butyloxycarbonyl;

pg is p-methoxybenzyl or benzyl.

More preferably still, the first and second liquid crystal compositions are,

in the step (a), the first step of the method,

the amino protection reaction is carried out in two steps of a1 and a 2;

step a 1: the compound 1 is used as a raw material to react with an amino protection reagent in the presence of a solvent a1, an alkali a1 and a catalyst to obtain a product a 1.

The solvent a1 can be a mixed solvent of one or more of ethers, toluene, hexane and dichloromethane; the ethers are selected from one or more of diethyl ether, tert-butyl methyl ether (TBME), isopropyl ether, dioxane, 2-methyltetrahydrofuran and Tetrahydrofuran (THF); the solvent a1 is preferably tetrahydrofuran and dichloromethane;

the amino protecting reagent is selected from di-tert-butyl dicarbonate (Boc)₂O), tert-butyl chloroformate (Boc-Cl), the amino protecting reagent preferably being Boc₂O；

The base a1 is selected from pyridine, triethylamine, diisopropylethylamine and dimethylaminopyridine; the base a1 is preferably triethylamine;

the catalyst is dimethylamino pyridine;

the reaction temperature in the step a1 is between-30 ℃ and +60 ℃, and the reaction time is between 0.5 and 24 hours;

step a 2: taking the product a1 prepared in the step a1 as a raw material, and reacting the raw material with a solvent a2 in the presence of a base a2 to obtain a compound 5;

the solvent a2 can be a mixed solvent of one or more of ethers, alcohols and water; the ethers are selected from one or more of ethyl ether, TBME, isopropyl ether, dioxane, 2-methyltetrahydrofuran and tetrahydrofuran; the alcohol is selected from one or more of methanol, ethanol and isopropanol; the solvent a2 is preferably water;

the alkali a2 is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, triethylamine, diisopropylethylamine and calcium hydroxide;

the concentration of the alkali a2 and the solvent a2 after mixing is selected from 1M to 20M, preferably 2M to 4M.

The reaction temperature in the step a2 is between 0 ℃ and +100 ℃, and the reaction time is between 0.5 hours and 24 hours.

In the step (b), the step (c),

the hydroxyl protection reaction is to take a sugar compound 6 or a sugar compound 6-1 as a raw material to react with a hydroxyl protection reagent PgBr or PgCl in the presence of a solvent b and alkali b to obtain a lactone compound 2 or a lactone compound 2-1;

the solvent b can be a mixed solvent of one or more of ethers and amides; the ethers are selected from one or more of ethyl ether, TBME, isopropyl ether, 2-methyltetrahydrofuran and tetrahydrofuran; the amide is selected from N, N-Dimethylformamide (DMF), N, N-Dimethylacetamide (DMF), and formamide; the solvent b is preferably tetrahydrofuran and N, N-dimethylformamide;

the hydroxyl protecting reagent PgBr or PgCl is selected from a bromization reagent PgBr and a chlorination reagent PgCl; the hydroxyl protecting reagent is preferably 2-naphthylmethyl bromide and p-methoxybenzyl chloride;

the base b is selected from pyridine, triethylamine, diisopropylethylamine, dimethylaminopyridine, sodium hydride NaH and sodium hexamethyldisilazide, and is preferably NaH;

the temperature of the hydroxyl protection reaction is between-30 ℃ and +150 ℃, and the reaction time is between 0.5 and 12 hours.

In the step (c),

the removal of N⁶The protonic reaction is carried out by reacting compound 5 with a metal-organic reagent c1 in the presence of a solvent c 1;

the solvent c1 can be a mixed solvent of one or more of ethers, toluene, hexane and dichloromethane; the ethers are selected from one or more of diethyl ether, TBME, isopropyl ether, 2-methyl tetrahydrofuran and tetrahydrofuran; the solvent b1 is preferably tetrahydrofuran.

The organometallic reagent c1 is characterized by sufficient alkalinity to remove N⁶Protons, but not so much as to produce a halogen-metal exchange reaction. The metal organic reagent c1 is selected from one or more of isopropyl magnesium chloride, methyl magnesium bromide, methyl magnesium chloride, isopropyl magnesium chloride-LiCl mixture (Turbo-Grignard reagent), isobutyl magnesium chloride-LiCl mixture, phenyl magnesium chloride, phenyl magnesium bromide, o-tolyl magnesium chloride, o-tolyl magnesium bromide, magnesium dichloride (2,2,6, 6-tetramethylpiperidine) lithium salt, diisopropylaminolithium, hexamethyldisilazane lithium, n-butyllithium, isobutyl lithium, tert-butyllithium, methyllithium, phenyllithium, sodium hydride, potassium hydride; when Hal in compound 5 is Br, the organometallic reagent c1 is preferably isopropylmagnesium chloride, lithium diisopropylamide. When Hal in compound 5 is I, the metal-organic reagent c1 is preferably sodium hydride, phenylmagnesium chloride.

The temperature of the deprotonation reaction is between-78 ℃ and +30 ℃, and the reaction time is between 0.5 and 12 hours.

The halogen-metal exchange reaction is carried out in the presence of a solvent c2 and a metal organic reagent c 2;

the solvent can be a mixed solvent of one or more of ethers, toluene, hexane and dichloromethane; the ethers are selected from one or more of diethyl ether, TBME, isopropyl ether, 2-methyltetrahydrofuran and tetrahydrofuran; the solvent is preferably tetrahydrofuran.

The metal organic reagent c2 is selected from one or more of isopropyl magnesium chloride, methyl magnesium bromide, isopropyl magnesium chloride-LiCl mixture (Turbo-Grignard reagent), isobutyl magnesium chloride-LiCl mixture, lithium dichloride (2,2,6, 6-tetramethylpiperidine) salt, lithium diisopropylamide, hexamethyldisilazane lithium alkyl, n-butyl lithium, isobutyl lithium, tert-butyl lithium, methyl lithium and phenyl lithium; when Hal in compound 5 is Br, the organometallic reagent c2 is preferably an isopropylmagnesium chloride-LiCl mixture (Turbo-Grignard reagent), n-butyllithium. When Hal in compound 5 is I, the organometallic reagent c2 is preferably an isopropylmagnesium chloride-LiCl mixture (Turbo-Grignard reagent).

The temperature of the halogen-metal exchange reaction c2 is between-100 ℃ and-40 ℃, and the reaction time is between 0.5 and 12 hours.

The addition reaction is carried out in the presence of a solvent c3 and a lactone compound 2;

pg in the substrate 2 of the reaction is selected from 2-naphthylmethyl, 1-naphthylmethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, substituted by halogen or C₁-C₆The benzyl group substituted with a linear or branched alkyl group is preferably a 2-naphthylmethyl group, a p-methoxybenzyl group.

The solvent c3 can be a mixed solvent of one or more of ethers, toluene, hexane and dichloromethane; the ethers are selected from one or more of diethyl ether, TBME, isopropyl ether, 2-methyl tetrahydrofuran and tetrahydrofuran; the solvent is preferably tetrahydrofuran.

Preferably, the addition reaction involving the metal organic reagent is carried out in the presence of a lewis acid catalyst selected from CuI, cuprous triflate (CuOTf), CuCN, LiCl, CuBr-dimethylsulfide complex, boron trifluoride etherate, TMSCl, or the like.

The temperature of the addition reaction c3 is between-100 ℃ and-10 ℃, and the reaction time is between 0.5 and 12 hours.

The above removal of N⁶The proton reaction, halogen-metal exchange reaction, addition reaction are preferably carried out in a "one-pot" manner to give compound 7.

The reduction reaction is carried out by reacting compound 7 raw material with reducing agent C4 and Lewis acid C4 in the presence of solvent C4 to obtain alpha-C-nucleoside analogue 8;

the reducing agent c4 is selected from silicon hydride derivatives, such as triethylsilane and polymethylhydrosiloxane, preferably triethylsilane and polymethylhydrosiloxane;

the reductive reaction is carried out in the presence of a Lewis acid catalyst c4, wherein the Lewis acid catalyst c4 is selected from boron trifluoride diethyl etherate or trimethylsilyl trifluoromethanesulfonate (TMSOTf) and the like; the lewis acid catalyst is preferably trimethylsilyl trifluoromethanesulfonate (TMSOTf).

The solvent c4 can be a mixed solvent of one or more of ethers, toluene, hexane and halogenated alkanes; the ethers are selected from one or more of diethyl ether, TBME, isopropyl ether, 2-methyl tetrahydrofuran and tetrahydrofuran; the halogenated alkane is one or more of dichloromethane, 1, 2-dichloroethane, 1, 1-dichloroethane and chloroform. The solvent is preferably dichloromethane.

The temperature of the reductive reaction is between-100 ℃ and-40 ℃, and the reaction time is between 0.5 and 12 hours;

the reagents, conditions and steps described in step (c) can be used in step (c) or (c-b);

in the step (d), the step (c),

the removal of N⁶The proton reaction is in the solvent d1, taking a compound 5 as a raw material to react with a metal organic reagent d1 in the presence of a catalyst;

the solvent d1 can be a mixed solvent of one or more of ethers, toluene, hexane and dichloromethane; the ethers are selected from one or more of diethyl ether, TBME, isopropyl ether, 2-methyl tetrahydrofuran and tetrahydrofuran; the solvent d1 is preferably tetrahydrofuran.

The metal-organic reagent d1 is characterized by sufficient alkalinity to remove N⁶Protons, but not so much as to produce a halogen-metal exchange reaction. The metal organic reagent c1 is selected from one or more of isopropyl magnesium chloride, methyl magnesium bromide, methyl magnesium chloride, isopropyl magnesium chloride-LiCl mixture (Turbo-Grignard reagent), isobutyl magnesium chloride-LiCl mixture, phenyl magnesium chloride, phenyl magnesium bromide, o-tolyl magnesium chloride, o-tolyl magnesium bromide, magnesium dichloride (2,2,6, 6-tetramethylpiperidine) lithium salt, diisopropylaminolithium, hexamethyldisilazane lithium, n-butyllithium, isobutyl lithium, tert-butyllithium, methyllithium, phenyllithium, sodium hydride, potassium hydride; when Hal in compound 5 is Br, the organometallic reagent c1 is preferably isopropylmagnesium chloride, lithium diisopropylamide. When Hal in compound 5 is I, the metal-organic reagent c1 is preferably sodium hydride, phenylmagnesium chloride.

The halogen-metal exchange reaction is carried out with a metal organic reagent d2 in the presence of a solvent d 2;

the solvent d2 can be a mixed solvent of one or more of ethers, toluene, hexane and dichloromethane; the ethers are selected from one or more of diethyl ether, TBME, isopropyl ether, 2-methyl tetrahydrofuran and tetrahydrofuran; the solvent is preferably tetrahydrofuran.

The metal organic reagent d2 is selected from one or more of isopropyl magnesium chloride, methyl magnesium bromide, isopropyl magnesium chloride-LiCl mixture (Turbo-Grignard reagent), isobutyl magnesium chloride-LiCl mixture, lithium dichloride (2,2,6, 6-tetramethylpiperidine) salt, lithium diisopropylamide, hexamethyldisilazane lithium alkyl, n-butyl lithium, isobutyl lithium, tert-butyl lithium, methyl lithium and phenyl lithium;

when Hal in compound 5 is Br, the organometallic reagent d2 is preferably an isopropylmagnesium chloride-LiCl mixture (Turbo-Grignard reagent), n-butyllithium. When Hal in compound 5 is I, the organometallic reagent d2 is preferably an isopropylmagnesium chloride-LiCl mixture (Turbo-Grignard reagent).

The temperature of the halogen-metal exchange reaction is between-100 ℃ and-40 ℃, and the reaction time is between 0.5 hour and 12 hours.

The addition reaction is carried out with a lactone compound 2 in the presence of a solvent d 3;

pg in the lactone compound 2 in the reaction is selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, triisopropylsilyl, trimethylsilyl, benzyl, p-methoxybenzyl, halogen or C₁-C₆Linear or branched alkyl-substituted benzyl, 1-naphthylmethyl, 2-naphthylmethyl, preferably 2-naphthylmethyl and p-methoxybenzyl.

The solvent d3 can be a mixed solvent of one or more of ethers, toluene, hexane and dichloromethane; the ethers are selected from one or more of diethyl ether, TBME, isopropyl ether, 2-methyl tetrahydrofuran and tetrahydrofuran; the solvent is preferably tetrahydrofuran.

Preferably, the addition reaction is carried out in the presence of a lewis acid catalyst d3, the lewis acid catalyst d3 being selected from CuI, cuprous triflate (CuOTf), CuCN, LiCl, CuBr-dimethyl sulfide complex, boron trifluoride diethyl etherate or TMSCl, etc.

The temperature of the addition reaction is between-100 ℃ and-10 ℃, and the reaction time is between 0.5 and 12 hours.

The above removal of N⁶The proton reaction, halogen-metal exchange reaction, addition reaction are preferably carried out in a "one-pot" manner to give compound 9.

The reduction reaction is to react a compound 9 with a reducing agent d4 and Lewis acid d4 in the presence of a solvent d4 to obtain beta-C-nucleoside analogue 3;

the reducing agent d4 is selected from silicon hydride derivatives, such as triethylsilane and polymethylhydrosiloxane, preferably triethylsilane and polymethylhydrosiloxane;

the Lewis acid catalyst d4 is selected from boron trifluoride diethyl etherate or trimethylsilyl trifluoromethanesulfonate (TMSOTf) and the like; the Lewis acid catalyst d4 is preferably boron trifluoride diethyl etherate.

The solvent d4 can be a mixed solvent of one or more of ethers, toluene, hexane, acetonitrile and halogenated alkanes; the ethers are selected from one or more of diethyl ether, TBME, isopropyl ether, 2-methyl tetrahydrofuran and tetrahydrofuran; the halogenated alkane is one or more of dichloromethane, 1, 2-dichloroethane, 1, 1-dichloroethane and chloroform. The solvent is preferably acetonitrile.

the reagents, conditions and procedures described in step (d) may be employed in step (d-a) or (d-b).

Among the terms used in the present invention, C-nucleoside analogs can be classified into alpha-C-nucleoside analogs and beta-C-nucleoside analogs according to the relative positions of the substituents at the 1-and 5-positions of the ribose on both sides of the ribose, specifically, when the substituents at the 1-and 5-positions of the ribose are on opposite sides of the ribose, the configuration of the nucleoside is defined as alpha-form, such as alpha-C-nucleoside analog 8; when the substituents at the 1-and 5-positions of the ribose are on the same side of the ribose, the configuration of the nucleoside is defined as beta-type, e.g., beta-C-nucleoside analog 3;

in the terminology used in the present invention, "C₁-C₆Straight or branched alkyl "refers to straight or branched chain alkyl groups containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and the like.

“C₂-C₆Straight-chain or branched alkenyl "means straight-chain or branched alkenyl having 1 to 6 carbon atomsIncluding, but not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, n-pentenyl, and the like.

“C₂-C₆Straight or branched alkynyl "means straight or branched alkynyl containing 1 to 6 carbon atoms and includes, but is not limited to, ethynyl, n-propynyl, isopropynyl, n-butynyl, n-pentynyl, and the like.

"halogen" means fluorine, chlorine, bromine or iodine.

The term "one-pot" as used in the present invention means that the reaction product of the respective stages of the reaction is carried out in one step without isolation and purification.

Advantageous effects

Starting from a N-tert-butyloxycarbonyl protected heterocycle 5, the C-nucleoside analogue can be simply synthesized.

The inventors have found that when the method of the document [ Journal of Medicinal Chemistry 2014,57(5), 1812-; recent documents [ Journal of Medicinal Chemistry 2017,60(5),1648-1661 ] provide the same information as the applicants' findings, and synthesize the C-nucleoside 4a using 1-1b as a starting material; however, 1-1b itself is more difficult to synthesize and is much more expensive than 1-1 a. Meanwhile, other documents [ ACS Medicinal Chemistry Letters 2014,5(6), 679-. Meanwhile, the C-nucleosides synthesized in the above documents all have a predominant beta-C-nucleoside product, but the documents show that the beta: alpha is not ideal in stereoselectivity, not only causing the problems of separation and purification of products, but also consuming expensive synthetic raw materials.

The method can controllably synthesize the alpha-C-nucleoside product 8 or the beta-C-nucleoside product 3 from the compound 5 which is easy to prepare and has lower cost, has good stereoselectivity, higher yield and good repeatability, and shows remarkable advantages compared with the literature method.

Detailed Description

The invention will now be further illustrated, but is not limited, by the following specific examples.

Sample data were determined by the following instrument: the melting point is measured by an SGW X-4B melting point apparatus, and the temperature is not corrected; nuclear magnetic resonance hydrogen spectrum (¹H NMR) by means of a Bruker Avance III 400, 500 or 600 NMR spectrometer, carbon NMR spectrum: (¹³C NMR) was measured on a Bruker Avance III 600 or 500 nuclear magnetic resonance apparatus with TMS as internal standard and chemical shift in ppm; mass spectra were determined on a Finnigan LCQ/DECA and Micromass Ultra Q-TOF (ESI) mass spectrometer; the liquid phase model used for purity analysis is Agilent 1260 definition; the developing WFH-203B three-purpose ultraviolet analyzer is used in the department of science, and the wavelength is 254nm and 365 nm.

Column chromatography silica gel (100-; the TLC silica gel plate is an HSGF-254 thin-layer chromatography silica gel plate produced by a tobacco chemical plant, the thickness of the chromatography plate used for thin-layer chromatography is 0.2 +/-0.03 mm, and the thickness of the thin-layer chromatography prefabricated plate used for prefabricated preparation is 0.4-0.5 mm; petroleum ether (boiling range 60-90 deg.C), dichloromethane, ethyl acetate, and methanol are analytically pure and provided by Shanghai Tantake technology, Inc. or national drug group chemical reagent, Inc., and the reagents and solvents used are not specially treated except for special description.

Compounds 1-1a were obtained from Shanghai Bigdi pharmaceutical science and technology, Inc., 1-1c, 1-1d, 1-2a and 1-2b were obtained from Shanghai Farmer Biotechnology, Inc.,

1-1b was prepared according to the Journal of Medicinal Chemistry 2017,60(5), 1648-1661;

6a and 6-1c were prepared according to the method in Tetrahedron: Asymmetry 2007,18, 500-;

6b and 6-1d were prepared according to the method in org. Synth.2005,82, 75-79.

The optical rotation (+/-) was measured by an OR-2090 chiral detector (Hg-Xe lamp, 150W) manufactured by Japan chemical Co., Ltd. (JASCO).

High Performance Liquid Chromatography (HPLC) assay conditions: agilent 1260 analytical high performance liquid chromatography system (Agilent Inc.) and LC3000 preparative high performance liquid chromatography system (Beijing Innovation technology, Inc.).

Chiral OD or OJ columns were purchased from xylonite drug chiral technology (shanghai) ltd, column size 2cm Φ X25 cm.

Analytical high performance liquid chromatography conditions: c18 column (5 μm,4.6X 250mm), UV detection band 214 and 280nm, elution conditions 0-90% acetonitrile (containing 0.1% v/v TFA) gradient for 30 min. Preparing high performance liquid chromatography conditions: c18 column (5 μm,19X 250mm), UV detection band 214 and 280nm, elution conditions 0-90% acetonitrile (containing 0.1% v/v TFA) gradient 30 min.

In the above discussion and in the examples below, the following abbreviations have the following meanings. An abbreviation has a generally accepted meaning if it is not defined.

TLC is thin layer chromatography;

DMF is N, N-dimethylformamide;

EtOAc is ethyl acetate;

THF is tetrahydrofuran;

DMSO is dimethyl sulfoxide;

DCM is dichloromethane;

Et₃n is triethylamine;

TBME is tert-butyl methyl ether;

Boc₂o is di-tert-butyl dicarbonate;

Cbz₂o is benzyloxy formic anhydride;

CbzCl is benzyl chloroformate;

PMB is p-methoxybenzyl;

TMSOTf is trimethylsilyl trifluoromethanesulfonate.

Example 1

Preparation of Compound 5-1 a:

compound 1-1a (5.0g,23.47mmol) was suspended in THF (100mL), triethylamine (16.3mL, 0.12mol) and dimethylaminopyridine (287mg,2.35mmol) were added, and Boc was added slowly in portions₂O (15.4g,70.42mmol), stirred at room temperature overnight, after completion of the reaction, 3M aqueous sodium hydroxide (100mL) was added and the mixture was heated to room temperatureAfter stirring at 60 ℃ for 6 hours, the reaction mixture was allowed to return to room temperature, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column (10:1, V/V, petroleum ether: EtOAc) to give the product 5-1a (6.6g, 21.12mmol) as a white solid in yield: 90 percent.

M.p.180.0 ℃ (decomposition); r_f0.21(10:1, V/V, petroleum ether: EtOAc); HPLC t_R＝2.79min；¹H NMR(400MHz,CDCl₃)δ8.28(s,1H,ArH),8.24(s,1H,NH),7.39(d,J＝4.8Hz,1H,ArH), 6.90(d,J＝4.8Hz,1H,ArH),1.58(s,9H,C(CH₃)₃)；¹³C-NMR(126MHz,CDCl₃)δ151.52 (C＝O),150.60,147.00,116.57,115.34,108.71,103.35,83.13(C(CH₃)₃),28.29(C(CH₃)₃) (ii) a High resolution mass spectrometry (ESI)⁺)：C₁₁H₁₃BrN₄NaO₂ ⁺Theoretical value is 335.0114, found 335.0119.

Example 2

Preparation of Compound 5-1 b:

compound 1-1b (0.5g, 1.92mmol) was suspended in THF (10mL), triethylamine (1.3mL, 9.61mmol) and dimethylaminopyridine (23mg, 0.19mmol) were added, and Boc was added slowly in portions₂O (1.3g, 5.77mmol), stirring at room temperature for reaction overnight, after the reaction is finished, adding 3M aqueous sodium hydroxide (10mL), heating to 60 ℃, stirring for reaction for 6 hours, returning to room temperature, separating an organic layer, extracting an aqueous layer by ethyl acetate (15mL x 3), combining the organic layers, washing the organic layer by saturated saline (30mL), drying by anhydrous sodium sulfate, concentrating, separating by silica gel column (10:1, V/V, petroleum ether: EtOAc), obtaining a product 5-1b (582mg, 1.62mmol), wherein the yield: 84 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₁H₁₄IN₄O₂ ⁺Theoretical value is 361.0156, found 361.0144.

Example 3

Preparation of Compounds 5-1 c:

compound 1-1c (0.5g, 2.10mmol) was suspended in THF (10mL), triethylamine (1.5mL, 10.50mmol) and dimethylaminopyridine (26mg, 0.21mmol) were added, and Boc was added slowly in portions₂O (1.4g, 6.30 mmol), stirring at room temperature overnight, after the reaction is finished, adding 3M aqueous sodium hydroxide (10mL), heating to 60 ℃, stirring for reaction for 6 hours, returning to room temperature, separating an organic layer, extracting an aqueous layer with ethyl acetate (15mL x 3), combining the organic layers, washing the organic layer with saturated saline (30mL), drying with anhydrous sodium sulfate, concentrating, separating with silica gel column (10:1, V/V, petroleum ether: EtOAc), obtaining a product 5-1c (554mg, 1.64mmol), yield: 78 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₂H₁₃BrN₅O₂ ⁺Theoretical value is 338.0247, found 338.0234.

Example 4

Preparation of Compounds 5-1 d:

compound 1-1d (0.5g, 2.09mmol) was suspended in THF (10mL), triethylamine (1.5mL, 10.46mmol) and dimethylaminopyridine (26mg, 0.21mmol) were added, and Boc was added slowly in portions₂O (1.4g, 6.27 mmol), stirring at room temperature for reaction overnight, after the reaction is finished, adding 3M aqueous sodium hydroxide solution (10mL), heating to 60 ℃, stirring for reaction for 6 hours, returning to room temperature, separating an organic layer, extracting an aqueous layer by ethyl acetate (15mL x 3), combining the organic layers, washing the organic layer by saturated saline (30mL), drying by anhydrous sodium sulfate, concentrating, separating by a silica gel column (10:1, V/V, petroleum ether: EtOAc), obtaining a product 5-1d (583mg, 1.71mmol), wherein the yield: 82 percent.

High resolutionMass spectrometry (ESI)⁺)：C₁₃H₁₆BrN₄O₂ ⁺Theoretical value is 339.0451, found 339.0440.

Example 5

Preparation of Compound 5-2 a:

compound 1-2a (5.0g, 23.36mmol) was suspended in THF (100mL), triethylamine (16.3mL, 0.12mol) and dimethylaminopyridine (287mg,2.35mmol) were added, and Boc was added slowly in portions₂O (15.4g,70.42mmol), stirring at room temperature for reaction overnight, after the reaction is finished, adding 3M aqueous sodium hydroxide solution (100mL), heating to 60 ℃, stirring for reaction for 6 hours, returning to room temperature, separating an organic layer, extracting an aqueous layer by ethyl acetate (20mL x 3), combining the organic layers, washing the organic layer by saturated saline (100mL), drying by anhydrous sodium sulfate, concentrating, separating by a silica gel column (10:1, V/V, petroleum ether: EtOAc), obtaining a white solid product 5-2a (6.3g, 20.09mmol), yield: 86 percent.

M.p. 160.5-163.8 deg.C (petroleum ether: EtOAc); r_f0.29(5:1, V/V, petroleum ether: EtOAc); HPLC t_R＝2.72min；¹H-NMR(400MHz,CDCl₃)δ8.62(s,1H,ArH),8.58(s,1H,NH),7.70(s,1H, ArH),1.57(s,9H,C(CH₃)₃)；¹³C-NMR(126MHz,CDCl₃)δ149.51(C＝O),149.41,148.68, 133.48,129.16,103.44,83.87(C(CH₃)₃),28.14(C(CH₃)₃) (ii) a High resolution mass spectrometry (ESI)⁺)： C₁₀H₁₂BrN₅NaO₂ ⁺Theoretical value is 336.0067, found 336.0058.

Example 6

Preparation of Compound 5-2 b:

compound 1-2b (0.2g, 0.77mmol) was suspendedTo THF (10mL) was added triethylamine (0.5mL, 3.83mmol) and dimethylaminopyridine (9mg, 0.08mmol) and the Boc was added slowly in portions₂O (0.5g, 2.30mmol), stirring at room temperature for reaction overnight, after the reaction is finished, adding 3M aqueous sodium hydroxide solution (10mL), heating to 60 ℃, stirring for reaction for 6 hours, returning to room temperature, separating an organic layer, extracting an aqueous layer by ethyl acetate (15mL x 3), combining the organic layers, washing the organic layer by saturated saline (30mL), drying by anhydrous sodium sulfate, concentrating, separating by silica gel column (10:1, V/V, petroleum ether: EtOAc), obtaining a product 5-2b (194mg, 0.54mmol), wherein the yield: 70 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₀H₁₃IN₅O₂ ⁺Theoretical value is 362.0108, found 362.0103.

Example 7

Preparation of compound 2 a:

dissolving a raw material 6a (10.0g,49.46mmol) in anhydrous DMF (100mL), cooling to 0 ℃ in an ice bath, slowly adding 60% NaH (3.0g, 74.18mmol) in portions under the protection of nitrogen, stirring at 0 ℃ for reaction for 30 minutes, slowly adding 2-bromomethylnaphthalene (16.4g, 74.18mmol) in portions, removing the ice bath, heating to room temperature for stirring for reaction for 3 hours, after the reaction is completed, adding 200mL of ice water to quench the reaction, extracting with ethyl acetate (100mL x 4), combining organic phases, washing an organic layer by 100mL of saturated saline water, drying with anhydrous sodium sulfate, concentrating, separating by a silica gel column (4:1, V/V, petroleum ether: EtOAc) to obtain a white solid product 2a (15.1g, 44.10mmol), wherein the yield: 89 percent.

M.p. 68.8-70.2 deg.C (petroleum ether: EtOAc); r_f0.27(5:1, V/V, petroleum ether: EtOAc); [ alpha ] to]_D ²⁰＝-15.46 (c＝0.705,CHCl₃)；HPLC t_R＝3.81min；¹H-NMR(500MHz,CDCl₃)δ7.87–7.80(m,3H, ArH),7.72(s,1H,ArH),7.53–7.45(m,2H,ArH),7.40(dd,J＝8.4,1.6Hz,1H,ArH),4.72 (d,J＝11.9Hz,1H,OCH₂-),4.65(d,J＝11.9Hz,1H,OCH₂-),4.57(t,J＝2.6Hz,1H,H-4), 4.51(s,1H,H-3),3.76(dd,J＝10.9,3.0Hz,1H,H-5),3.73(dd,J＝10.9,2.6Hz,1H,H-5’), 1.58(s,3H,2-CH₃),1.43(s,3H,OC(CH₃)₂O),1.40(s,3H,OC(CH₃)₂O)；¹³C-NMR(126 MHz,CDCl₃)δ176.43(C＝O),134.41(ArC),133.27(2x ArC),128.63(ArC),128.02(ArC), 127.86(ArC),127.14(ArC),126.47(ArC),126.35(ArC),125.80(ArC),112.90 (OC(CH₃)₂O),82.98(C-2),82.84(C-3),82.02(C-4),74.13(OCH₂-),69.33(C-5),26.98 (OC(CH₃)₂O),26.88(OC(CH₃)₂O),19.95(2-CH₃) (ii) a High resolution mass spectrometry (ESI)⁺)：C₂₀H₂₂NaO₅ ⁺Theoretical value is 365.1359, found 365.1366.

Example 8

Preparation of compound 2 b:

dissolving the raw material 6b (10.0g,53.14mmol) in anhydrous DMF (100mL), cooling to 0 ℃ in ice bath, slowly adding 60% NaH (3.2g, 79.71mmol) in portions under the protection of nitrogen, stirring at 0 ℃ for reaction for 30 minutes, slowly adding 2-bromomethylnaphthalene (17.6g, 79.71mmol) in portions, removing the ice bath, heating to room temperature, stirring for reaction for 3 hours, after the reaction is completed, adding 200mL of ice water to quench the reaction, extracting with ethyl acetate (100mL x 4), combining organic phases, washing an organic layer with 100mL of saturated saline water, drying with anhydrous sodium sulfate, concentrating, separating with a silica gel column (4:1, V/V, petroleum ether: to obtain a white solid product 2b (15.9g, 48.42mmol) with the yield: 91 percent.

M.p. 105.4-106.8 deg.C (petroleum ether: EtOAc); r_f0.22(5:1, V/V, petroleum ether: EtOAc); [ alpha ] to]_D ²⁰＝-41.67(c＝0.240,CHCl₃)；HPLC t_R＝3.65min；¹H NMR(500MHz,CDCl₃)δ7.86– 7.81(m,3H,ArH),7.69(s,1H,ArH),7.51–7.47(m,2H,ArH),7.37(dd,J＝8.4,1.4Hz,1H, ArH),4.81(d,J＝5.5Hz,1H,H-2),4.73(d,J＝2.2Hz,1H,H-3),4.71(d,J＝4.0Hz,1H, OCH₂-),4.65(t,J＝1.8Hz,1H,H-4),4.62(d,J＝11.9Hz,1H,OCH₂-),3.75(dd,J＝10.7, 2.3Hz,1H,H-5),3.70(dd,J＝10.7,1.8Hz,1H,H-5’),1.47(s,3H,OC(CH₃)₂O),1.36(s,3H, OC(CH₃)₂O)；¹³C NMR(126MHz,CDCl₃)δ174.47(1-C＝O),134.46(ArC),133.29(ArC), 133.28(ArC),128.72(ArC),128.04(ArC),127.87(ArC),126.93(ArC),126.50(ArC), 126.37(ArC),125.58(ArC),113.31((OC(CH₃)₂O),81.23(C-4),78.54(C-3),75.87(C-2), 74.19(OCH₂-),69.17(C-5),26.95(OC(CH₃)₂O),25.76(OC(CH₃)₂O); high resolution mass spectrometry (ESI)⁺)： C₁₉H₂₀NaO₅ ⁺Theoretical value is 351.1203, found 351.1209.

Example 9

Preparation of compound 2 c:

dissolving a raw material 6a (1.0g,4.95mmol) in anhydrous DMF (20mL), cooling to 0 ℃ in an ice bath, slowly adding 60% NaH (0.3g, 7.42mmol) in portions under the protection of nitrogen, stirring at 0 ℃ for reaction for 30 minutes, slowly adding 4-methoxybenzyl chloride (1.0mL, 7.42mmol) in portions, removing the ice bath, heating to room temperature, stirring for reaction for 3 hours, adding 50mL of ice water to quench the reaction after the reaction is completed, extracting with ethyl acetate (20mL x 4), combining organic phases, washing an organic layer by 50mL of saturated saline, drying with anhydrous sodium sulfate, concentrating, separating by a silica gel column (2:1, V/V, petroleum ether: EtOAc) to obtain a product 2c (1.1g, 3.56mmol), wherein the yield: 72 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₇H₂₃O₆ ⁺Theoretical value is 323.1489, found 323.1483.

Example 10

Preparation of compound 2 d:

dissolving the raw material 6b (1.0g,5.31mmol) in anhydrous DMF (20mL), cooling to 0 ℃ in an ice bath, slowly adding 60% NaH (0.3g, 7.97mmol) in portions under the protection of nitrogen, stirring at 0 ℃ for reaction for 30 minutes, slowly adding 4-methoxy benzyl chloride (1.1mL, 7.97mmol) in portions, removing the ice bath, heating to room temperature, stirring for reaction for 3 hours, adding 50mL of ice water to quench the reaction after the reaction is completed, extracting with ethyl acetate (20mL x 4), combining organic phases, washing an organic layer by 50mL of saturated saline water, drying with anhydrous sodium sulfate, concentrating, separating by a silica gel column (2:1, V/V, petroleum ether: EtOAc) to obtain a product 2d (1.2g, 3.99mmol), wherein the yield: 75 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₆H₂₁O₆ ⁺Theoretical value is 309.1333, found 309.1328.

Example 11

Preparation of Compounds 2-1 c:

dissolving 6-1c (5.0g,30.84mmol) of raw material in anhydrous DMF (200mL), cooling to-10 ℃ under the protection of nitrogen, slowly adding 60% NaH (1.6g, 40.09mmol), stirring at-10 ℃ for reaction for 1 hour, slowly adding 2-bromomethylnaphthalene (10.2g, 46.26mmol), stirring for 30 minutes, adding 60% NaH (1.6g, 40.09mmol) and 2-bromomethylnaphthalene (10.2g, 46.26mmol) according to the above operation, repeating twice, stirring at-10 ℃ for reaction for 48 hours, pouring the reaction liquid into 500mL of ice water to quench the reaction, extracting with ethyl acetate (100mL x 4), combining organic phases, washing the organic layer with 200mL of saturated saline, drying with sodium sulfate, concentrating, separating with silica gel column (10:1, V/V, petroleum ether: EtOAc) to obtain colorless oily product 2-1c (12.6g, 21.59mmol), yield: 70 percent.

High resolution mass spectrometry (ESI)⁺)：C₃₉H₃₅O₅ ⁺Theoretical value is 583.2479, found 583.2471.

Example 12

Preparation of Compounds 2-1 d:

dissolving 6-1d (5.0g,33.76mmol) of raw material in anhydrous DMF (200mL), cooling to-10 deg.C under the protection of nitrogen, slowly adding 60% NaH (1.8g, 43.89mmol), stirring at-10 deg.C for 1 hr, slowly adding 2-bromomethylnaphthalene (11.2g, 50.64mmol), stirring for 30 min, adding 60% NaH (1.8g, 43.89mmol) and 2-bromomethylnaphthalene (11.2g, 50.64mmol), repeating twice, stirring at-10 deg.C for 48 hr, pouring the reaction solution into 500mL of ice water to quench the reaction, extracting with ethyl acetate (100 mL. times.4), combining the organic phase, washing the organic layer with 200mL of saturated saline, drying over anhydrous sodium sulfate, concentrating, separating with silica gel column (10:1, V/V, petroleum ether: EtOAc) to obtain white oily product 2-1d (13.8g, 24.31mmol), yield: 72 percent.

High resolution mass spectrometry (ESI)⁺)：C₃₈H₃₃O₅ ⁺Theoretical value is 569.2323, found 569.2315.

Example 13

Preparation of Compound 8-1 a:

the method comprises the following steps: cooling 5-1a (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (415 μ L, 0.83mmol, 2M tetrahydrofuran solution) dropwise, controlling temperature at-30 deg.C, stirring for reaction for 50min, further cooling to-78 deg.C, adding n-BuLi (100 μ L, 1.60mmol, 1.6M hexane solution), stirring for reaction for 5min, adding 2a (656mg, 1.92mmol) THF (10mL), maintaining temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (10mL), brought to room temperature, extracted 4 times with ethyl acetate (10 mL. times.4), and combinedThe organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give crude product 7-1 a. High resolution mass spectrometry (ESI)⁺)：C₃₁H₃₇N₄O₇ ⁺Theoretical value is 577.2657, found 577.2651.

The crude 7-1a obtained above was dissolved in 10mL of dry MeCN under nitrogen protection, cooled to-40 ℃ and Et was added₃SiH (408. mu.L, 2.56mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (162. mu.L, 1.28mmol), reaction at-40 ℃ for 2h, TLC detection, quenching with saturated aqueous sodium bicarbonate (5mL), extraction of the aqueous layer with dichloromethane (10 mL. times.3) for 3 times, combining the organic layers, washing with saturated brine, drying over anhydrous sodium sulfate, concentration, and purification by silica gel column separation (4:1, V/V, petroleum ether: EtOAc) to give the product 8-1a (183mg,0.33mmol) as a white amorphous solid in yield: 51 percent.

R_f0.71(1:1, V/V, petroleum ether: EtOAc); [ alpha ] to]_D ²⁰＝-100.48(c＝0.210,CHCl₃)；HPLC t_R＝3.74 min；¹H-NMR(500MHz,CDCl₃)δ8.16(s,1H,ArH),7.85–7.82(m,4H,ArH),7.54–7.47 (m,3H,ArH),7.21(d,J＝4.2Hz,1H,ArH),7.05(d,J＝3.7Hz,1H,ArH),5.86(s,1H,H-1), 4.80(d,J＝12.3Hz,1H,OCH₂-),4.75(d,J＝12.2Hz,1H,OCH₂-),4.64(s,1H,H-3),4.40(t, J＝4.1Hz,1H,H-4),3.79–3.76(m,2H,H-5,H-5’),1.59(s,3H,2-CH₃),1.57(s,9H, C(CH₃)₃),1.47(s,3H,OC(CH₃)₂O),1.38(s,3H,OC(CH₃)₂O), NH is absent; selected fractions NOESY (500MHz, CDCl)₃):δ(¹H)/δ(¹H)＝5.86/3.79–3.76(H-1/H-5,H-5’)；¹³C-NMR (126MHz,CDCl₃)δ151.24(C＝O),150.25(ArC),146.05(ArC),135.40(ArC),133.39(ArC), 133.15(ArC),129.26(ArC),128.37(ArC),127.98(ArC),127.83(ArC),126.64(ArC), 126.28(ArC),126.08(ArC),125.76(ArC),115.10(ArC),114.08(ArC),113.06 (OC(CH₃)₂O),105.22(ArC),91.13(C-2),89.49(C-3),83.31(C-4),82.67(C(CH₃)₃),80.48 (C-1),73.93(OCH₂-),71.41(C-5),28.27(C(CH₃)₃),27.76(OC(CH₃)₂O),27.52 (OC(CH₃)₂O),23.08(2-CH₃) (ii) a High resolution mass spectrometry (ESI)⁺)：C₃₁H₃₇N₄O₆ ⁺The theoretical value was 561.2708, and the measured value was 561.2701.

The second method comprises the following steps: cooling 5-1a (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (415 μ L, 0.83mmol, 2M tetrahydrofuran solution) dropwise, controlling temperature at-30 deg.C, stirring for reaction for 50min, further cooling to-78 deg.C, adding n-BuLi (100 μ L, 1.60mmol, 1.6M hexane solution), stirring for reaction for 5min, adding 2a (656mg, 1.92mmol) THF (10mL), maintaining temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (10mL), returned to room temperature, extracted 4 times with ethyl acetate (10mL × 4), the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 7-1 a. High resolution mass spectrometry (ESI)⁺)：C₃₁H₃₇N₄O₇ ⁺Theoretical value is 577.2657, found 577.2651.

The crude product 7-1a obtained above was dissolved in 10mL of dry CH under nitrogen protection₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (408. mu.L, 2.56mmol), stirring for 5min, adding TMSOTf (247. mu.L, 1.28mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated aqueous sodium bicarbonate solution (5mL), quenching, and adding CH to water layer₂Cl₂(10 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (4:1, V/V, petroleum ether: EtOAc) to give the product 8-1a (269mg,0.48mmol) as a white amorphous solid in yield: 75 percent.

The analytical data were consistent with 8-1a obtained in method one.

Example 14

Preparation of Compound 8-1 b:

cooling 5-1a (0.5g, 1.60mmol) THF (10mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (1.04mL, 2.08mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C for 50min, cooling to-78 deg.C, adding n-BuLi (2.5mL, 3.99mmol, 1.6M hexane solution dropwise), stirring for 5min, adding 2c (1.5g, 4.79mmol) THF (20mL), maintaining at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (40mL), allowed to return to room temperature, and then extracted 4 times with ethyl acetate (20mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 7-1 b. High resolution mass spectrometry (ESI)⁺): theoretical value of C₂₈H₃₇N₄O₈ ⁺557.2606, found 557.2659.

The crude product 7-1b obtained above was dissolved in 20mL of dry CH under nitrogen protection₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (1.02mL,6.39mmol), stirring for 5min, adding TMSOTf (0.6mL,3.19mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated aqueous sodium bicarbonate solution (20mL), quenching, and adding CH to the water layer₂Cl₂(20 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (1:1, V/V, petroleum ether: EtOAc) to give the product 8-1b (518mg,0.96mmol) as a white amorphous solid in yield: 60 percent.

¹H-NMR(500MHz,CDCl₃) alpha-configuration characteristic peak delta 5.7(s,1H, H-1); high resolution mass spectrometry (ESI)⁺)： C₂₈H₃₇N₄O₇ ⁺Theoretical value is 541.2657, found 541.2648.

Example 15

Preparation of Compound 8-1 a:

cooling 5-1b (0.2g, 0.56mmol) THF (10mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (0.36mL, 0.72mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (0.87mL, 1.39mmol, 1.6M hexane solution), stirring for 5min, adding 2a (570mg, 1.67mmol) THF (10mL), reacting for 2 hr at-78 deg.C, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (20mL), returned to room temperature, and then extracted 4 times with ethyl acetate (20mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 7-1 a. High resolution mass spectrometry (ESI)⁺)：C₃₁H₃₇N₄O₇ ⁺Theoretical value is 577.2657, found 577.2651.

The crude product 7-1a obtained above was dissolved in 20mL of dry CH under nitrogen protection₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (0.35mL,2.22mmol), stirring for 5min, adding TMSOTf (0.21mL,1.11mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated sodium bicarbonate water solution (20mL), quenching, and adding CH to water layer₂Cl₂(20 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (2:1, V/V, petroleum ether: EtOAc) to give the product 8-1a (249mg,0.44mmol) as a white amorphous solid in yield: 80 percent.

The analytical data agree with the product 8-1a of example 13.

Example 16

Preparation of compound 8 c:

under the anhydrous and anaerobic condition, the mixture is prepared5-1c (0.5g, 1.48mmol) of THF (20mL) solution is cooled to-30 ℃, diisopropylaminolithium THF solution (0.96mL, 1.92mmol, 2M tetrahydrofuran solution) is added dropwise, the temperature is controlled at-30 ℃, after stirring reaction for 50min, the temperature is continuously reduced to-78 ℃, n-BuLi (2.3mL, 3.70mmol, 1.6M hexane solution) is added dropwise, after the dropwise addition, the stirring reaction is carried out for 5min, 2a (1.52g, 4.44mmol) of THF (20mL) solution is added dropwise, the temperature is kept at-78 ℃, the reaction is carried out for 2h, after TLC detection reaction, saturated NH is added₄The reaction was quenched with aqueous Cl (40mL), allowed to return to room temperature, and then extracted 4 times with ethyl acetate (30mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 7 c. High resolution mass spectrometry (ESI)⁺): theoretical value of C₃₂H₃₆N₅O₇ ⁺602.2609, found 602.2604.

The crude product 7c obtained above was dissolved in 20mL of dry CH under nitrogen protection₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (0.94mL,5.91mmol), stirring for 5min, adding TMSOTf (0.57mL,2.96mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated sodium bicarbonate water solution (20mL), quenching, and adding CH to water layer₂Cl₂(20 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (2:1, V/V, petroleum ether: EtOAc) to give product 8c (554mg,0.95mmol) as a white amorphous solid in yield: and 64 percent.

¹H-NMR(500MHz,CDCl₃) alpha-configuration characteristic peak delta 5.4(s,1H, H-1); high resolution mass spectrometry (ESI)⁺)： C₃₂H₃₆N₅O₆ ⁺Theoretical value is 586.2660, found 586.2652.

Example 17

Preparation of compound 8 d:

under the anhydrous and oxygen-free conditions, 5-1d (0) is added.5g, 1.47mmol) of THF (20mL) to-30 deg.C, dropwise adding lithium diisopropylamide THF solution (0.96mL, 1.92mmol, 2M tetrahydrofuran solution), controlling the temperature at-30 deg.C, stirring for 50min, further cooling to-78 deg.C, dropwise adding n-BuLi (2.3mL, 3.69mmol, 1.6M hexane solution), stirring for 5min after dropwise addition, dropwise adding 2a (1.5g, 4.42mmol) of THF (20mL), maintaining the temperature at-78 deg.C, reacting for 2 hr, and after TLC detection, adding saturated NH₄The reaction was quenched with aqueous Cl (40mL), allowed to return to room temperature, and then extracted 4 times with ethyl acetate (30mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude product 7 d. High resolution mass spectrometry (ESI)⁺): theoretical value of C₃₃H₃₉N₄O₇ ⁺603.2813, found 603.2808.

The crude product 7d obtained above was dissolved in 20mL of dry CH under nitrogen protection₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (0.94mL,5.90mmol), stirring for 5min, adding TMSOTf (0.57mL,2.95mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated sodium bicarbonate water solution (20mL), quenching, and adding CH to water layer₂Cl₂(20 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (2:1, V/V, petroleum ether: EtOAc) to give the product 8d (519mg,0.88mmol) as a white amorphous solid in yield: 60 percent.

¹H-NMR(500MHz,CDCl₃) alpha-configuration characteristic peak delta 5.9(s,1H, H-1); high resolution mass spectrometry (ESI)⁺)： C₃₃H₃₉N₄O₆ ⁺Theoretical value is 587.2864, found 587.2859.

Example 18

Preparation of Compounds 8-1 e:

under anhydrous and oxygen-free conditions, 5-1a (200mg,0.64mmol) of THF (5mL) to-30 deg.C, adding diisopropylamino lithium THF solution (415 μ L, 0.83mmol, 2M tetrahydrofuran solution) dropwise, controlling the temperature at-30 deg.C, stirring for reaction for 50min, cooling to-78 deg.C, adding n-BuLi (100 μ L, 1.60mmol, 1.6M hexane solution) dropwise, stirring for reaction for 5min, adding 2b (629mg, 1.92mmol) of THF (10mL), keeping the temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (10mL), allowed to return to room temperature, and then extracted 4 times with ethyl acetate (10mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 7-1 e. High resolution mass spectrometry (ESI)⁺)：C₃₀H₃₅N₄O₇ ⁺Theoretical value is 563.2500, found 563.2488.

The crude 7-1e from above was dissolved in 10mL dry CH under nitrogen₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (408. mu.L, 2.56mmol), stirring for 5min, adding TMSOTf (247. mu.L, 1.28mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated aqueous sodium bicarbonate solution (5mL), quenching, and adding CH to water layer₂Cl₂(10 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (4:1, V/V, petroleum ether: EtOAc) to give the product 8-1e (287mg,0.52mmol) as a white amorphous solid in yield: 82 percent.

R_f0.46(2:1, V/V, petroleum ether: EtOAc); [ alpha ] to]_D ²⁰＝-131.30(c＝0.115,CHCl₃)；HPLC t_R＝3.62 min；¹H-NMR(500MHz,CDCl₃)δ8.16(s,1H,ArH),7.85–7.81(m,4H,ArH),7.50–7.45 (m,3H,ArH),7.19(d,J＝3.6Hz,1H,ArH),7.02(s,1H,ArH),5.89(s,1H,H-1),5.11(s,1H, H-2),4.96(d,J＝5.9Hz,1H,H-3),4.78(d,J＝12.3Hz,1H,OCH₂-),4.72(d,J＝12.3Hz, 1H,OCH₂-),4.42(t,J＝3.5Hz,1H,H-4),3.75(dd,J＝10.2,3.8Hz,1H,H-5),3.71(dd,J＝ 10.2,4.2Hz,1H,H-5’),1.56(s,9H,C(CH₃)₃),1.40(s,3H,OC(CH₃)₂O),1.28(s,3H, OC(CH₃)₂O), NH is absent; selected fractions NOESY (500MHz, CDCl)₃):δ(¹H)/δ(¹H)＝5.89/ 3.75,3.71(H-1/H-5,H-5’)；¹³C-NMR(126MHz,CDCl₃)δ151.08(C＝O),150.20(ArC), 146.26(ArC),135.42(ArC),133.40(ArC),133.16(ArC),129.05(ArC),128.42(ArC), 128.01(ArC),127.84(ArC),126.57(ArC),126.31(ArC),126.10(ArC),125.67(ArC), 115.00(ArC),113.33(ArC),112.79(OC(CH₃)₂O),105.03(ArC),83.58(C-3),82.97(C-4), 82.71(C(CH₃)₃),81.57(C-2),77.25(C-1),73.88(OCH₂-),71.44(C-5),28.28(C(CH₃)₃), 26.38(OC(CH₃)₂O),25.18(OC(CH₃)₂O); high resolution mass spectrometry (ESI)⁺)：C₃₀H₃₅N₄O₆ ⁺Theoretical value is 547.2551, found 547.2565.

Example 19

Cooling 5-1a (0.5g, 1.60mmol) THF (10mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (1.04mL, 2.08mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (2.5mL, 3.99mmol, 1.6M hexane solution dropwise), stirring for 5min, adding 2d (1.57g, 4.79mmol) THF (20mL), reacting for 2 hr at-78 deg.C, detecting by TLC, adding saturated NH₄Quenching the reaction with a Cl aqueous solution (40mL), returning to room temperature, extracting with ethyl acetate (20mL × 4) for 4 times, combining the organic layers, washing with saturated sodium bicarbonate solution and saturated salt water, drying with anhydrous sodium sulfate, and concentrating to obtain crude product 7-1 f; high resolution mass spectrometry (ESI)⁺): theoretical value of C₂₇H₃₅N₄O₈ ⁺543.2449, found 543.2595.

Under the protection of nitrogen, the crude product 7-1f obtained above is dissolved in 20mL of dryCH (A) of₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (1.02mL,6.39mmol), stirring for 5min, adding TMSOTf (0.6mL,3.19mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated aqueous sodium bicarbonate solution (20mL), quenching, and adding CH to the water layer₂Cl₂(20 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (1:1, V/V, petroleum ether: EtOAc) to give the product 8-1f (589mg,1.12mmol) as a white amorphous solid in yield: 70 percent.

High resolution mass spectrometry (ESI)⁺)：C₂₇H₃₅N₄O₇ ⁺Theoretical value is 527.2500, found 527.2492.

Example 20

Preparation of compound 8 g:

cooling 5-1c (0.5g, 1.48mmol) THF (20mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (0.96mL, 1.92mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (2.3mL, 3.70mmol, 1.6M hexane solution), stirring for 5min, adding 2b (1.46g, 4.44mmol) THF (20mL), reacting for 2 hr at-78 deg.C, detecting by TLC, adding saturated NH₄Quenching the reaction with a Cl aqueous solution (40mL), returning to room temperature, extracting with ethyl acetate (30 mL. times.4) for 4 times, combining the organic layers, washing with saturated sodium bicarbonate solution and saturated salt water, drying with anhydrous sodium sulfate, and concentrating to obtain crude product 7 g; high resolution mass spectrometry (ESI)⁺)：C₃₁H₃₄N₅O₇ ⁺Theoretical value is 588.2453, found 588.2538.

Under the protection of nitrogen, 7g of the crude product obtained above is dissolved in 20mL of dry CH₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH(0.94mL,5.91mmol)Stirring for 5min, adding TMSOTf (0.57mL,2.96mmol) dropwise, reacting at-78 deg.C for 2h, detecting by TLC, adding saturated sodium bicarbonate water solution (20mL), quenching, and adding CH to water layer₂Cl₂(20 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (2:1, V/V, petroleum ether: EtOAc) to give 8g (609mg,1.06mmol) of a white amorphous solid product, yield: 72 percent.

¹H-NMR(500MHz,CDCl₃) alpha-configuration characteristic peak δ 5.4(d, J ═ 4.0Hz,1H, H-1); high resolution mass spectrometry (ESI)⁺)：C₃₁H₃₄N₅O₆ ⁺Theoretical value is 572.2504, found 572.2493.

Example 21

Preparation of compound 8 h:

cooling 5-1d (0.5g, 1.47mmol) of THF (20mL) under anhydrous and oxygen-free conditions to-30 deg.C, adding diisopropylamino lithium THF solution (0.96mL, 1.92mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C for 50min, cooling to-78 deg.C, adding n-BuLi (2.3mL, 3.69mmol, 1.6M hexane solution dropwise), stirring for 5min, adding 2b (1.45g, 4.42mmol) of THF (20mL), maintaining at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄Quenching the reaction with a Cl aqueous solution (40mL), returning to room temperature, extracting with ethyl acetate (30mL × 4) for 4 times, combining the organic layers, washing with saturated sodium bicarbonate solution and saturated salt water, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product for 7 h; high resolution mass spectrometry (ESI)⁺)：C₃₂H₃₇N₄O₇ ⁺Theoretical value is 589.2657, found 589.2701. The crude product obtained above is dissolved for 7h in 20mL of dry CH under nitrogen protection₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (0.94mL,5.90mmol), stirred for 5min, and TMSOTf (R) (b)0.57mL,2.95mmol), reacting at-78 deg.C for 2h, detecting by TLC, adding saturated sodium bicarbonate water solution (20mL), quenching, and adding CH to water layer₂Cl₂(20 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated, and isolated and purified on silica gel (2:1, V/V, petroleum ether: EtOAc) to give the product as a white amorphous solid for 8h (540mg,0.94 mmol), yield: and 64 percent.

¹H-NMR(500MHz,CDCl₃) alpha-configuration characteristic peak δ 5.9(d, J ═ 4.0Hz,1H, H-1); high resolution mass spectrometry (ESI)⁺)：C₃₂H₃₇N₄O₆ ⁺Theoretical value is 573.2708, found 573.2856.

Example 22

Preparation of Compounds 8-1 e:

cooling 5-1b (0.2g, 0.56mmol) THF (10mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (0.36mL, 0.72mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (0.87mL, 1.39mmol, 1.6M hexane solution), stirring for 5min, adding 2b (547mg, 1.67mmol) THF (10mL), reacting for 2 hr at-78 deg.C, detecting by TLC, adding saturated NH₄Quenching the reaction with aqueous Cl (20mL), returning to room temperature, extracting with ethyl acetate (20 mL. times.4) for 4 times, combining the organic layers, washing with saturated sodium bicarbonate solution and saturated brine, drying over anhydrous sodium sulfate, and concentrating to obtain crude product 7-1 e; high resolution mass spectrometry (ESI)⁺)：C₃₀H₃₅N₄O₇ ⁺Theoretical value is 563.2500, found 563.2488.

The crude 7-1e from above was dissolved in 20mL dry CH under nitrogen₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (0.35mL,2.22mmol), stirred for 5min, and then added dropwiseAdding TMSOTf (0.21mL,1.11mmol), reacting at-78 deg.C for 2h, after TLC detection, adding saturated sodium bicarbonate water solution (20mL), quenching the reaction, and adding CH to the water layer₂Cl₂(20 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (2:1, V/V, petroleum ether: EtOAc) to give the product 8-1e (219mg,0.40mmol) as a white amorphous solid in yield: 72 percent.

The analytical data agree with the products 8-1e of example 18.

Example 23

Preparation of compound 8 i:

cooling 5-2a (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (415 μ L, 0.83mmol, 2M tetrahydrofuran solution) dropwise, controlling temperature at-30 deg.C, stirring for reaction for 50min, further cooling to-78 deg.C, adding n-BuLi (100 μ L, 1.60mmol, 1.6M hexane solution), stirring for reaction for 5min, adding 2a (656mg, 1.92mmol) THF (10mL), maintaining temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄Quenching the reaction with a Cl aqueous solution (10mL), returning to room temperature, extracting with ethyl acetate (10 mL. times.4) for 4 times, combining the organic layers, washing with saturated sodium bicarbonate solution and saturated salt water, drying over anhydrous sodium sulfate, and concentrating to obtain crude product 7-2 i; high resolution mass spectrometry (ESI)⁺)：C₃₀H₃₆N₅O₇ ⁺Theoretical value is 578.2609, found 578.2600.

Dissolving the crude product 7-2i obtained above in 10mL dry MeCN under nitrogen protection, cooling to-40 deg.C, adding Et₃SiH (408. mu.L, 2.56mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (162. mu.L, 1.28mmol), naturally warmed to room temperature, reacted for 2h, after TLC detection, quenched with saturated aqueous sodium bicarbonate (10mL), the aqueous layer extracted 3 times with dichloromethane (10 mL. times.3), and combinedAnd the organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column separation (25:1, V/V, DCM: MeOH) to give the product 8-2i (162mg,0.35mmol) as a white amorphous solid in yield: and 55 percent.

R_f＝0.63(15:1，V/V，DCM:MeOH)；[α]_D ²⁰＝-92.00(c＝0.125,CHCl₃)；HPLC t_R＝3.36 min；¹H-NMR(500MHz,CDCl₃)δ8.10(s,1H,ArH),7.87–7.81(m,4H,ArH),7.77(s,1H, ArH),7.56–7.51(m,1H,ArH),7.50–7.45(m,2H,ArH),5.68(s,1H,H-1),4.80(d,J＝ 12.1Hz,1H,OCH₂-),4.75(d,J＝12.1Hz,1H,OCH₂-),4.67(s,1H,H-3),4.37(t,J＝3.8Hz, 1H,H-4),3.80(dd,J＝10.3,3.8Hz,1H,H-5),3.76(dd,J＝10.3,4.1Hz,1H,H-5’),1.57(s, 3H,2-CH₃),1.50(s,3H,OC(CH₃)₂O),1.40(s,3H,OC(CH₃)₂O)，NH₂Removing the defect; selected fractions NOESY (500MHz, CDCl)₃):δ(¹H)/δ(¹H)＝5.68/3.80,3.76(H-1/H-5,H-5’)；¹³C-NMR (126MHz,CDCl₃)δ153.84(ArC),148.80(ArC),135.34(ArC),133.41(ArC),133.19(ArC), 132.74(ArC),128.48(ArC),128.44(ArC),128.01(ArC),127.86(ArC),126.97(ArC), 126.73(ArC),126.32(ArC),126.13(ArC),125.80(ArC),113.24(OC(CH₃)₂O),90.84(C-2), 89.47(C-3),83.54(C-4),79.74(C-1),74.01(OCH₂-),71.60(C-5),27.90(OC(CH₃)₂O), 27.62(OC(CH₃)₂O),22.77(2-CH₃) (ii) a High resolution mass spectrometry (ESI)⁺)：C₂₅H₂₈N₅O₄ ⁺Theoretical value is 462.2136, found 462.2133.

Example 24

Preparation of Compounds 8-2 j:

a solution of 5-2a (0.5g, 1.59mmol) in THF (10mL) was cooled to-30 deg.C under anhydrous and oxygen-free conditions, and lithium diisopropylamide THF solution (1.03mL, 2.07mmol, 2M tetra-N-ethyl-N-isopropylamide) was added dropwiseTetrahydrofuran solution), controlling the temperature at-30 ℃, stirring for reaction for 50min, then continuously cooling to-78 ℃, dropwise adding n-BuLi (2.5mL, 3.98mmol, 1.6M hexane solution), stirring for reaction for 5min after dropwise adding, dropwise adding 2c (1.54g, 4.77mmol) THF (20mL), keeping the temperature at-78 ℃, reacting for 2h, after TLC detection reaction, adding saturated NH₄The reaction was quenched with aqueous Cl (40mL), allowed to return to room temperature, and then extracted 4 times with ethyl acetate (20mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 7-2 j. High resolution mass spectrometry (ESI)⁺)：C₂₇H₃₆N₅O₈ ⁺Theoretical value is 558.2558, found 558.2550.

Dissolving the crude product 7-2j obtained above in 10mL of dried MeCN under nitrogen protection, cooling to-40 deg.C, adding Et₃SiH (1.5mL,9.55mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (0.4mL,3.18mmol), naturally heating to room temperature, reacting for 2h, after TLC detection reaction is finished, adding saturated sodium bicarbonate aqueous solution (10mL) to quench the reaction, extracting the water layer with ethyl acetate (10mL × 3) for 3 times, combining the organic layers, washing with saturated common salt water, drying with anhydrous sodium sulfate, concentrating, and separating and purifying with silica gel column (25:1, V/V, DCM: MeOH) to obtain white amorphous solid product 8-2j (386mg,0.87mmol), yield: and 55 percent.

¹H-NMR(500MHz,CDCl₃) alpha-configuration characteristic peak delta 5.6(s,1H, H-1); high resolution mass spectrometry (ESI)⁺)： C₂₂H₂₈N₅O₅ ⁺Theoretical value is 442.2085, found 442.2077.

Example 25

Preparation of Compound 8-2 k:

a solution of 5-2b (0.2g, 0.55mmol) in THF (10mL) was cooled to-30 deg.C under anhydrous and oxygen-free conditions, and lithium diisopropylamide THF solution (0.36mL, 0.72mmol, 2M in tetrahydrofuran) was added dropwiseControlling the temperature at-30 ℃, stirring for reaction for 50min, then continuously cooling to-78 ℃, dropwise adding n-BuLi (0.87mL, 1.38mmol and 1.6M hexane solution), stirring for reaction for 5min after dropwise adding, dropwise adding 2a (569mg and 1.66mmol) THF (10mL) solution, keeping the temperature at-78 ℃, reacting for 2h, and adding saturated NH after TLC detection reaction₄The reaction was quenched with aqueous Cl (20mL), returned to room temperature, and then extracted 4 times with ethyl acetate (20mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 7-2 i. High resolution mass spectrometry (ESI)⁺)：C₃₀H₃₆N₅O₇ ⁺Theoretical value is 578.2609, found 578.2600.

Dissolving the crude product 7-2i obtained above in 10mL dry MeCN under nitrogen protection, cooling to-40 deg.C, adding Et₃SiH (0.35mL,2.22mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (0.14mL,1.11mmol), naturally warmed to room temperature, reacted for 2h, after TLC detection reaction, added saturated sodium bicarbonate aqueous solution (10mL) to quench the reaction, the aqueous layer was extracted with ethyl acetate (10 mL. times.3) for 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (25:1, V/V, DCM: MeOH) to give 8-2i (133mg,0.29mmol) as a white amorphous solid product, yield: 52 percent.

The analytical data agree with the products 8-2i of example 23.

Example 26

Preparation of Compound 8-2 k:

cooling 5-2a (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (415 μ L, 0.83mmol, 2M tetrahydrofuran solution) dropwise, controlling temperature at-30 deg.C, stirring for reaction for 50min, cooling to-78 deg.C, adding n-BuLi (100 μ L, 1.60mmol, 1.6M hexane solution), stirring for reaction for 5min, adding 2b (629mg, 1.92mmol) THF dropwise(10mL) solution, keeping the temperature at-78 ℃, reacting for 2 hours, adding saturated NH after TLC detection reaction₄The reaction was quenched with aqueous Cl (10mL), allowed to return to room temperature, and then extracted 4 times with ethyl acetate (10mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 7-2 k. High resolution mass spectrometry (ESI)⁺)：C₂₉H₃₄N₅O₇ ⁺Theoretical value is 564.2453, found 564.2446.

Dissolving the crude product 7-2k in 10mL dry MeCN under nitrogen, cooling to-40 deg.C, adding Et₃SiH (408. mu.L, 2.56mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (162. mu.L, 1.28mmol), naturally warmed to room temperature, reacted for 2h, after TLC detection reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate (10mL), the aqueous layer was extracted 3 times with dichloromethane (10 mL. times.3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (25:1, V/V, DCM: MeOH) to give 8-2k (155 mg,0.35mmol) as a white solid, yield: 54 percent.

R_f＝0.60(15:1，V/V，DCM:MeOH)；[α]_D ²⁰＝-62.14(c＝0.140,CHCl₃)；HPLC t_R＝3.29min； ¹H-NMR(600MHz,CDCl₃)δ8.10(s,1H,ArH),7.83(dd,J＝15.5,8.4Hz,4H,ArH),7.74(s, 1H,ArH),7.51–7.45(m,3H,ArH),5.79(d,J＝4.1Hz,1H,H-1),5.07(dd,J＝5.8,4.2Hz, 1H,H-2),4.98(d,J＝6.0Hz,1H,H-3),4.78(d,J＝12.3Hz,1H,OCH₂-),4.72(d,J＝12.3 Hz,1H,OCH₂-),4.41(t,J＝3.7Hz,1H,H-4),3.76(dd,J＝10.3,3.6Hz,1H,H-5),3.71(dd, J＝10.3,4.0Hz,1H,H-5’),2.17(s,2H,NH₂),1.45(s,3H,OC(CH₃)₂O),1.31(s,3H, OC(CH₃)₂O)；，NH₂Removing the defect; selected fractions NOESY (500MHz, CDCl)₃):δ(¹H)/δ(¹H)＝5.79/ 3.76,3.71(H-1/H-5,H-5’)；¹³C NMR(151MHz,CDCl₃)δ153.85(ArC),148.84(ArC), 135.32(ArC),133.37(ArC),133.15(ArC),131.92(ArC),128.46(ArC),128.41(ArC), 127.99(ArC),127.83(ArC),126.75(ArC),126.63(ArC),126.32(ArC),126.13(ArC), 125.69(ArC),112.97(OC(CH₃)₂O),83.63(C-3),83.08(C-4),81.64(C-2),76.02(C-1),73.90 (OCH₂-),71.54(C-5),26.39(OC(CH₃)₂O),25.13(OC(CH₃)₂O); high resolution mass spectrometry (ESI)⁺)： C₂₄H₂₅N₅NaO₄ ⁺Theoretical value is 470.1799, found 470.1806.

Example 27

Preparation of Compound 8-2 l:

cooling 5-2a (0.5g, 1.59mmol) THF (10mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (1.03mL, 2.07mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (2.5mL, 3.98mmol, 1.6M hexane solution dropwise), stirring for 5min, adding 2d (1.47g, 4.77mmol) THF (20mL), reacting for 2 hr at-78 deg.C, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (40mL), allowed to return to room temperature, and then extracted 4 times with ethyl acetate (20 mL. times.4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 7-2l of crude product. High resolution mass spectrometry (ESI)⁺)：C₂₆H₃₄N₅O₈ ⁺Theoretical value is 544.2402, found 544.2445.

Dissolving 7-2l of crude product obtained above in 20mL of dried MeCN under nitrogen protection, cooling to-40 deg.C, and adding Et₃SiH (1.02mL,6.37mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (0.4mL,3.18mmol), naturally heating to room temperature, reacting for 2h, after TLC detection reaction, adding saturated sodium bicarbonate water solution (20mL) to quench reaction, extracting water layer with ethyl acetate (10 mL. times.3) for 3 times, combining organic layers, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and performing silica gel columnPurification by isolation (25:1, V/V, DCM: MeOH) afforded 8-2l (381mg,0.89mmol) of the product as a white amorphous solid in yield: 56 percent.

¹H-NMR(500MHz,CDCl₃) alpha-configuration characteristic peak δ 5.7(d, J ═ 4.0Hz,1H, H-1); high resolution mass spectrometry (ESI)⁺)：C₂₁H₂₆N₅O₅ ⁺Theoretical value is 428.1928, found 428.1922.

Example 28

Preparation of Compound 8-2 k:

cooling 5-2b (0.2g, 0.55mmol) THF (10mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (0.36mL, 0.72mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (0.87mL, 1.38mmol, 1.6M hexane solution), stirring for 5min, adding 2b (546mg, 1.66mmol) THF (10mL), reacting for 2 hr at-78 deg.C, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (20mL), allowed to return to room temperature, and then extracted 4 times with ethyl acetate (20mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 7-2 k.

Dissolving the crude product 7-2k in 10mL dry MeCN under nitrogen, cooling to-40 deg.C, adding Et₃SiH (0.35mL,2.22mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (0.14mL,1.11mmol), naturally warmed to room temperature, reacted for 2h, after TLC detection reaction, added saturated sodium bicarbonate aqueous solution (10mL) to quench the reaction, the aqueous layer was extracted with ethyl acetate (10 mL. times.3) for 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (25:1, V/V, DCM: MeOH) to give 8-2k (149mg,0.33mmol) as a white amorphous solid product, yield: 60 percent.

The analytical data agree with the products 8-2k of example 26.

Example 29

Preparation of compound 3 c:

the method comprises the following steps: cooling 5-1a (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (415 μ L, 0.83mmol, 2M tetrahydrofuran solution) dropwise, controlling temperature at-30 deg.C, stirring for reaction for 50min, further cooling to-78 deg.C, adding n-BuLi (100 μ L, 1.60mmol, 1.6M hexane solution), stirring for reaction for 5min, adding 2-1a (830mg, 1.92mmol) THF (10mL), maintaining temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (10mL), returned to room temperature, and then extracted 4 times with ethyl acetate (10mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 9 a. High resolution mass spectrometry (ESI)⁺)：C₃₈H₄₃N₄O₇ ⁺Theoretical value is 667.3126, found 667.3121.

The crude product 9a obtained above was dissolved in 10mL of dry CH under nitrogen protection₂Cl₂In (b), cooling to-10 ℃, and adding Et₃SiH (408. mu.L, 2.56mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (162. mu.L, 1.28mmol), reacting at-10 deg.C for 2h, after TLC detection, adding saturated sodium bicarbonate water solution (5mL) to quench the reaction, and adding CH to the water layer₂Cl₂(10 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated, and isolated and purified by silica gel column (4:1, V/V, petroleum ether: EtOAc) to give product 3c (337mg,0.52mmol) as a white amorphous solid in yield: 81 percent.

R_f0.44(4:1,60-90 ℃ petroleum ether-EtOAc); [ alpha ] to]_D ²⁰＝24.52(c＝0.155，CHCl₃)；HPLC t_R＝4.10min；¹H NMR(600MHz,CDCl₃)δ8.15(s,2H,ArH,NH),7.43–7.25(m,15H, Bn-H),7.10(dd,J＝21.6,4.0Hz,2H,ArH),5.94(s,1H,H-1),4.86(dd,J＝55.4,12.0Hz, 2H,Bn-CH₂-),4.69–4.57(m,4H,2x Bn-CH₂-),4.42(d,J＝8.3Hz,1H,H-4),4.06(d,J＝ 8.7Hz,1H,H-3),3.91(d,J＝10.5Hz,1H,H-5),3.72(dd,J＝10.9,3.2Hz,1H,H-5’),1.57 (s,9H,C(CH₃)₃),1.01(s,3H,2-CH₃) (ii) a Selected fractions NOESY (600MHz, CDCl)₃):δ(¹H)/δ (¹H)＝7.10/3.91,3.72,4.06(ArH/H-5,H-5’,H-3)；¹³C NMR(151MHz,CDCl₃)δ151.20 (ArC),150.35(C＝O),146.02(ArC),139.76(Bn-C),138.30(Bn-C),138.26(Bn-C),132.14 (ArC),128.55(2x Bn-C),128.42(2x Bn-C),128.32(3x Bn-C),127.97(2x Bn-C),127.95 (2x Bn-C),127.81(Bn-C),127.26(2x Bn-C),127.21(Bn-C),115.10(ArC),112.41(ArC), 105.63(ArC),85.18(C-2),82.81(C(CH₃)₃),82.17(C-3),79.39(C-4),77.97(C-1),73.59(2x Bn-CH₂-),69.17(C-5),65.91(Bn-CH₂-),28.26(C(CH₃)₃),17.47(2-CH₃). High resolution mass spectrometry (ESI)⁺)：C₃₈H₄₂N₄NaO₆ ⁺Theoretical value is 673.2997, found 673.3004.

The second method comprises the following steps: cooling 5-1a (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (415 μ L, 0.83mmol, 2M tetrahydrofuran solution) dropwise, controlling temperature at-30 deg.C, stirring for reaction for 50min, further cooling to-78 deg.C, adding n-BuLi (100 μ L, 1.60mmol, 1.6M hexane solution), stirring for reaction for 5min, adding 2-1a (830mg, 1.92mmol) THF (10mL), maintaining temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (10mL), returned to room temperature, and then extracted 4 times with ethyl acetate (10mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 9 a. High resolution mass spectrometry (ESI)⁺)：C₃₈H₄₃N₄O₇ ⁺Theoretical value of 667.3126, found value of 667.3121。

The crude product 9a obtained above was dissolved in 10mL of dry CH under nitrogen protection₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (408. mu.L, 2.56mmol), stirring for 5min, adding TMSOTf (247. mu.L, 1.28mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated aqueous sodium bicarbonate solution (5mL), quenching, and adding CH to water layer₂Cl₂(10 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (4:1, V/V, petroleum ether: EtOAc) to give product 3c (333mg,0.51mmol) as a white amorphous solid in yield: 80 percent.

The analytical data were consistent with 3c obtained in method one.

Example 30

Preparation of compound 3 a:

cooling 5-1a (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (415 μ L, 0.83mmol, 2M tetrahydrofuran solution) dropwise, controlling temperature at-30 deg.C, stirring for reaction for 50min, further cooling to-78 deg.C, adding n-BuLi (100 μ L, 1.60mmol, 1.6M hexane solution), stirring for reaction for 5min, adding 2-1a (830mg, 1.92mmol) THF (10mL), maintaining temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (10mL), returned to room temperature, and then extracted 4 times with ethyl acetate (10mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 9 a. High resolution mass spectrometry (ESI)⁺)：C₃₈H₄₃N₄O₇ ⁺Theoretical value is 667.3126, found 667.3120.

The crude product 9a obtained above was dissolved in 10mL of dry CH under nitrogen protection₂Cl₂In (1), cooling to 0 ℃ and adding Et₃SiH (408. mu.L, 2.56mmol), stirring 5After min, BF was added dropwise₃·Et₂O (162. mu.L, 1.28mmol), returning to room temperature after completion of dropwise addition reaction for 1h, adding saturated sodium bicarbonate aqueous solution (5mL) to quench the reaction after completion of TLC detection reaction, and adding CH to the aqueous layer₂Cl₂(10 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (25:1, V/V, dichloromethane: methanol) to give product 3a (229mg,0.42mmol) as a white amorphous solid in yield: 65 percent.

¹H-NMR(400MHz,CDCl₃)δ7.89(s,1H),7.51–7.20(m,15H),6.90(d,J＝4.5

Hz,1H),6.53(d,J＝4.5Hz,1H),5.91(s,1H),5.65(br s,2H),4.92(d,J＝12.1Hz,1H),4.81 (d,J＝12.1Hz,1H),4.76–4.54(m,4H),4.41(dt,J＝8.4,2.4Hz,1H),4.08(d,J＝8.7Hz,

1H) 3.91(dd, J ═ 10.9,2.4Hz,1H),3.72(dd, J ═ 10.3,4.2Hz,1H),1.03(s, 3H). Data were analyzed against literature [ yarlagada, s.babu; pooran, Chand; pravin, Kotian; minwan, Wu; v. Satish, Kumar, Antiviral therapeutic agents, U.S. 20090227524A1, 2009).

High resolution mass spectrometry (ESI)⁺)：C₃₃H₃₅N₄O₄ ⁺Theoretical value is 551.2653, found 551.2645.

Example 31

Preparation of Compounds 3-3 d:

cooling 5-1a (1.0g, 3.19mmol) THF (20mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (2.1mL, 4.15mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (5.0mL, 7.98mmol, 1.6M hexane solution), stirring for 5min, adding 2-1c (5.6g, 9.58mmol) THF (20mL), reacting for 2 hr at-78 deg.C, detecting by TLC, and adding saturated NH₄Aqueous Cl solution (50mL)After quenching the reaction and returning to room temperature, extraction was performed 4 times with ethyl acetate (40 mL. times.4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 9-3 b. High resolution mass spectrometry (ESI)⁺)：C₅₀H₄₉N₄O₇ ⁺Theoretical value is 817.3596, found 817.3592.

The crude product 9-3b obtained above was dissolved in 20mL of dry CH under nitrogen protection₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (2.0mL,12.77mmol), stirring for 5min, adding TMSOTf (1.2mL,6.39mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated aqueous sodium bicarbonate solution (40mL), quenching, and adding CH to the water layer₂Cl₂(15 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (4:1, V/V, petroleum ether: EtOAc) to give the product 3-3d (1.9g,2.40mmol) as a white amorphous solid in yield: 75 percent.

¹H-NMR(400MHz,CDCl₃) beta-configuration characteristic peak δ 6.0(s,1H, H-1); high resolution mass spectrometry (ESI)⁺)： C₅₀H₄₉N₄O₆ ⁺Theoretical value is 801.3647, found 801.3643.

Example 32

Preparation of Compounds 3-3 e:

cooling 5-1a (1.0g, 3.19mmol) THF (20mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (2.1mL, 4.15mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (5.0mL, 7.98mmol, 1.6M hexane solution), stirring for 5min, adding 2-1c (5.6g, 9.58mmol) THF (20mL), reacting for 2 hr at-78 deg.C, detecting by TLC, and adding saturated NH₄Aqueous Cl solution (50mL)After the reaction was quenched and returned to room temperature, the mixture was extracted with ethyl acetate (40 mL. times.4) 4 times, and the organic layers were combined, washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give crude 9-3 b. High resolution mass spectrometry (ESI)⁺)：C₅₀H₄₉N₄O₇ ⁺Theoretical value is 817.3596, found 817.3591.

The crude product 9-3b obtained above was dissolved in 20mL of dry CH under nitrogen protection₂Cl₂In (1), cooling to 0 ℃ and adding Et₃SiH (2.0mL,12.77mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (0.8mL,6.39mmol), returning to room temperature after dropwise addition for 1h, adding saturated sodium bicarbonate aqueous solution (40mL) to quench the reaction after TLC detection, and adding CH to the water layer₂Cl₂(15 mL. times.3) extraction was performed 3 times, organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (25:1, V/V, dichloromethane: methanol) to give the product 3-3e (1.5g,2.08mmol) as a white amorphous solid in yield: 65 percent.

¹H-NMR(400MHz,CDCl₃) beta-configuration characteristic peak δ 5.9(s,1H, H-1); high resolution mass spectrometry (ESI)⁺)： C₄₅H₄₁N₄O₄ ⁺Theoretical value is 701.3122, found 701.3117.

Example 33

Preparation of compound 3 c:

cooling 5-1b (1.0g, 2.78mmol) THF (20mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (1.8mL, 3.61mmol, 2M tetrahydrofuran solution) dropwise, controlling temperature at-30 deg.C, stirring for reaction at-30 deg.C for 50min, further cooling to-78 deg.C, adding n-BuLi (4.3mL, 6.94mmol, 1.6M hexane solution dropwise), stirring for reaction for 5min, adding 2-1a (3.6g, 8.33mmol) THF (20mL) solution dropwise, maintaining temperature at-78 deg.C, reacting for 2 hr, TLC detecting reaction, adding saturated and saturated THF (20mL)NH₄The reaction was quenched with aqueous Cl (50mL), allowed to return to room temperature, and then extracted 4 times with ethyl acetate (40mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude product 9 a. High resolution mass spectrometry (ESI)⁺)：C₃₈H₄₃N₄O₇ ⁺Theoretical value is 667.3126, found 667.3118.

The crude product 9a obtained above was dissolved in 20mL of dry CH under nitrogen protection₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (1.8mL,11.11mmol), stirring for 5min, adding TMSOTf (1.1mL,5.55mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated aqueous sodium bicarbonate solution (40mL), quenching, and adding CH to the water layer₂Cl₂(15 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (4:1, V/V, petroleum ether: EtOAc) to give product 3c (1.3g,1.94mmol) as a white amorphous solid in yield: 70 percent.

The analytical data agree with product 3c from example 29.

Example 34

Preparation of compound 3 a:

cooling 5-1b (1.0g, 2.78mmol) THF (20mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (1.8mL, 3.61mmol, 2M tetrahydrofuran solution) dropwise, controlling the temperature at-30 deg.C, stirring for reaction at-30 deg.C for 50min, further cooling to-78 deg.C, adding n-BuLi (4.3mL, 6.94mmol, 1.6M hexane solution) dropwise, stirring for reaction for 5min, adding 2-1a (3.6g, 8.33mmol) THF (20mL) solution dropwise, maintaining the temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, and adding saturated NH₄The reaction was quenched with an aqueous solution of Cl (50mL), and after returning to room temperature, it was extracted 4 times with ethyl acetate (40 mL. times.4), the organic layers were combined, washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate,concentration gave crude 9 a. High resolution mass spectrometry (ESI)⁺)：C₃₈H₄₃N₄O₇ ⁺Theoretical value is 667.3126, found 667.3121.

The crude product 9a obtained above was dissolved in 20mL of dry CH under nitrogen protection₂Cl₂In (1), cooling to 0 ℃ and adding Et₃SiH (1.8mL,11.11mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (0.7mL,5.55mmol), returning to room temperature after dropwise addition for 1h, adding saturated sodium bicarbonate water solution (40mL) to quench the reaction after TLC detection, and adding CH to the water layer₂Cl₂(15 mL. times.3) extraction was performed 3 times, organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (25:1, V/V, dichloromethane: methanol) to give product 3a (0.9g,1.72mmol) as a white amorphous solid in yield: 62 percent.

The analytical data agree with product 3a from example 30.

Example 35

Preparation of compound 3 f:

cooling 5-1c (0.5g, 1.48mmol) THF (20mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (0.96mL, 1.92mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (2.3mL, 3.70mmol, 1.6M hexane solution), stirring for 5min, adding 2-1a (1.9g, 4.44mmol) THF (20mL), reacting for 2 hr at-78 deg.C, detecting by TLC, and adding saturated NH₄Quenching the reaction with a Cl aqueous solution (40mL), returning to room temperature, extracting with ethyl acetate (30 mL. times.4) for 4 times, combining the organic layers, washing with saturated sodium bicarbonate solution and saturated salt water, drying with anhydrous sodium sulfate, and concentrating to obtain crude product 9 c; high resolution mass spectrometry (ESI)⁺)：C₃₉H₄₂N₅O₇ ⁺Theoretical value of 692.3079, found valueIs 692.3071.

The crude product 9c obtained above was dissolved in 20mL dry CH under nitrogen protection₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (0.94mL,5.91mmol), stirring for 5min, adding TMSOTf (0.57mL,2.96mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated sodium bicarbonate water solution (20mL), quenching, and adding CH to water layer₂Cl₂(20 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (2:1, V/V, petroleum ether: EtOAc) to give product 3f (699mg,1.04mmol) as a white amorphous solid in yield: 70 percent.

¹H-NMR(400MHz,CDCl₃) beta-configuration characteristic peak δ 5.8(s,1H, H-1); high resolution mass spectrometry (ESI)⁺)： C₃₉H₄₂N₅O₆ ⁺Theoretical value is 676.3130, found 676.3121.

Example 36

Preparation of Compounds 3-3 g:

cooling 5-1a (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (415 μ L, 0.83mmol, 2M tetrahydrofuran solution) dropwise, controlling temperature at-30 deg.C, stirring for reaction for 50min, further cooling to-78 deg.C, adding n-BuLi (100 μ L, 1.60mmol, 1.6M hexane solution), stirring for reaction for 5min, adding 2-1b (803mg, 1.92mmol) THF (10mL) solution dropwise, maintaining temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (10mL), brought to room temperature, extracted 4 times with ethyl acetate (10mL × 4), the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 9-3 d. High resolution mass spectrometry (ESI)⁺)：C₃₇H₄₁N₄O₇ ⁺Theoretical value of 653.2970, found value of 653.2964。

Under the protection of nitrogen, the crude product 9-3d obtained above is dissolved in 10mL of dry CH₂Cl₂In (b), cooling to-10 ℃, and adding Et₃SiH (408. mu.L, 2.56mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (162. mu.L, 1.28mmol), reacting at-10 deg.C for 2h, after TLC detection, adding saturated sodium bicarbonate water solution (5mL) to quench the reaction, and adding CH to the water layer₂Cl₂(10 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated, and isolated and purified with silica gel column (4:1, V/V, petroleum ether: EtOAc) to give 3-3g (355mg,0.56mmol) of a white amorphous solid product, yield: 87 percent.

R_f0.32(4:1,60-90 ℃ petroleum ether-EtOAc); [ alpha ] to]_D ²⁰＝69.49(c＝0.495，CHCl₃)；HPLC t_R＝3.97min；¹H NMR(400MHz,CDCl₃)δ8.77(s,1H,NH),8.20(s,1H,ArH),7.33–7.25 (m,15H,Bn-H),7.15(d,J＝4.7Hz,1H,ArH),6.93–6.81(m,1H,ArH),5.74(d,J＝3.6 Hz，1H,H-1),4.73(t,J＝10.2Hz,2H,Bn-CH₂-),4.62–4.51(m,3H,Bn-CH₂-,Bn-CH₂-), 4.43–4.39(m,2H,H-4,Bn-CH₂-),4.23–4.20(m,1H,H-2),4.11(dd,J＝6.7,4.9Hz,1H, H-3),3.82–3.76(m,1H,H-5),3.66(dd,J＝10.8,3.9Hz,1H,H-5’),1.57(s,9H,C(CH₃)₃) (ii) a Selected fractions NOESY (500MHz, CDCl)₃):δ(¹H)/δ(¹H)＝6.93–6.81/3.82–3.76,3.66 (ArH/H-5,H-5’)；¹³C NMR(126MHz,CDCl₃)δ151.45(ArC),150.55(C＝O),145.98 (ArC),138.34(Bn-C),137.97(Bn-C),137.95(Bn-C),131.06(ArC),128.45(2x Bn-C), 128.42(2x Bn-C),128.37(2x Bn-C),128.22(2x Bn-C),127.96(2x Bn-C),127.83(2x Bn-C),127.71(2x Bn-C),127.67(Bn-C),115.71(ArC),112.24(ArC),106.04(ArC),82.76 (C(CH₃)₃),80.63(C-4),79.12(C-2),77.23(C-3),76.36(C-1),73.48(Bn-CH₂-),72.13 (Bn-CH₂-),71.70(Bn-CH₂-),69.70(C-5),28.27(C(CH₃)₃). High resolution mass spectrometry (ESI)⁺)： C₃₇H₄₀N₄NaO₆ ⁺Theoretical value is 659.2840, found 659.2854.

Example 37

Preparation of compound 3-3 h:

cooling 5-1a (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (415 μ L, 0.83mmol, 2M tetrahydrofuran solution) dropwise, controlling temperature at-30 deg.C, stirring for reaction for 50min, further cooling to-78 deg.C, adding n-BuLi (100 μ L, 1.60mmol, 1.6M hexane solution), stirring for reaction for 5min, adding 2-1b (803mg, 1.92mmol) THF (10mL) solution dropwise, maintaining temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (10mL), brought to room temperature, extracted 4 times with ethyl acetate (10mL × 4), the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 9-3 d. High resolution mass spectrometry (ESI)⁺)：C₃₇H₄₁N₄O₇ ⁺Theoretical value is 653.2970, found 653.2963.

Under the protection of nitrogen, the crude product 9-3d obtained above is dissolved in 20mL of dry CH₂Cl₂In (1), cooling to 0 ℃ and adding Et₃SiH (408. mu.L, 2.56mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (162. mu.L, 1.28mmol), returning to room temperature after completion of dropwise addition reaction for 1h, adding saturated sodium bicarbonate aqueous solution (5mL) to quench the reaction after completion of TLC detection reaction, and adding CH to the aqueous layer₂Cl₂(10 mL. times.3) extraction was performed 3 times, organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (25:1, V/V, dichloromethane: methanol) to give the product as a white amorphous solid for 3-3h (209mg,0.39mmol), yield: 61 percent.

¹H-NMR(600MHz,CDCl₃)δ7.90(s,1H),7.34–7.24(m,15H),6.68(d,J＝4.5 Hz,1H),6.50(d,J＝4.5Hz,1H),5.72(br s,2H)5.68(d,J＝42Hz,1H),4.73(q, J ═ 12.3 Hz,2H),4.60(d, J ═ 12.0Hz,1H), 4.58-4.49 (m,2H),4.44(d, J ═ 11.9Hz,1H),4.40(dt, J ═ 6.9,3.8Hz,1H),4.27(t, J ═ 4.6Hz,1H),4.12(dd, J ═ 6.4,5.1Hz,1H),3.78(dd, J ═ 10.7, 3.4Hz,1H),3.66(dd, J ═ 10.7,4.1Hz, 1H). Data were analyzed against literature [ LEE, Jae Moon; CHOI, Min Jeong, Compounds and compositions for modulating histone methyl transferase activity, WO2014035140A2,2014.

Example 38

Preparation of Compounds 3-3 i:

cooling 5-1a (1.0g, 3.19mmol) THF (20mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (2.1mL, 4.15mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (5.0mL, 7.98mmol, 1.6M hexane solution), stirring for 5min, adding 2-1d (5.4g, 9.58mmol) THF (20mL), reacting for 2 hr at-78 deg.C, detecting by TLC, and adding saturated NH₄The reaction was quenched with aqueous Cl (50mL), brought to room temperature, extracted 4 times with ethyl acetate (40mL × 4), the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 9-3 e. High resolution mass spectrometry (ESI)⁺)：C₄₉H₄₇N₄O₇ ⁺Theoretical value is 803.3439, found 803.3432.

The crude 9-3e obtained above was dissolved in 20mL dry CH under nitrogen protection₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (2.0mL,12.77mmol), stirring for 5min, adding TMSOTf (1.2mL,6.39mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated aqueous sodium bicarbonate solution (20mL), quenching, and adding CH to the water layer₂Cl₂Extracting (15 mL. times.3) for 3 times, mixing organic layers, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and making into silica gel columnIsolation purification (4:1, V/V, petroleum ether: EtOAc) afforded the product 3-3i (1.9g,2.36mmol) as a white amorphous solid, in yield: 74 percent.

¹H-NMR(400MHz,CDCl₃) beta-configuration characteristic peak δ 5.8(d, J ═ 4.0Hz,1H, H-1); high resolution mass spectrometry (ESI)⁺)：C₄₉H₄₇N₄O₆ ⁺Theoretical value is 787.3490, found 787.3485.

Example 39

Preparation of Compounds 3-3 j:

The crude 9-3e obtained above was dissolved in 20mL dry CH under nitrogen protection₂Cl₂In (1), cooling to 0 ℃ and adding Et₃SiH (2.0mL,12.77mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (0.8mL,6.39mmol), returning to room temperature after dropwise addition for 1h, adding saturated sodium bicarbonate water solution (20mL) to quench the reaction after TLC detection, and adding CH to the water layer₂Cl₂(15 mL. times.3) was extracted 3 times, the organic layers were combined, washed with saturated brine,drying with anhydrous sodium sulfate, concentrating, and purifying with silica gel column (25:1, V/V, dichloromethane: methanol) to obtain white amorphous solid product 3-3j (1.3g,1.92mmol), yield: 60 percent.

¹H-NMR(400MHz,CDCl₃) beta-configuration characteristic peak δ 5.7(d, J ═ 4.0Hz,1H, H-1); high resolution mass spectrometry (ESI)⁺)：C₄₄H₃₉N₄O₄ ⁺Theoretical value is 687.2966, found 687.2961.

Example 40

Preparation of Compounds 3-3 g:

cooling 5-1b (1.0g, 2.78mmol) THF (20mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (1.8mL, 3.61mmol, 2M tetrahydrofuran solution) dropwise, controlling the temperature at-30 deg.C, stirring for reaction at-30 deg.C for 50min, further cooling to-78 deg.C, adding n-BuLi (4.3mL, 6.94mmol, 1.6M hexane solution dropwise), stirring for reaction for 5min, adding 2-1b (3.5g, 8.33mmol) THF (20mL) solution dropwise, maintaining the temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, and adding saturated NH₄The reaction was quenched with aqueous Cl (20mL), allowed to return to room temperature, extracted 4 times with ethyl acetate (40mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude product 9-3 d. High resolution mass spectrometry (ESI)⁺)：C₃₇H₄₁N₄O₇ ⁺Theoretical value is 653.2970, found 653.2964.

Under the protection of nitrogen, the crude product 9-3d obtained above is dissolved in 20mL of dry CH₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (1.8mL,11.11mmol), stirring for 5min, adding TMSOTf (1.1mL,5.55mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated aqueous sodium bicarbonate solution (40mL), quenching, and adding CH to the water layer₂Cl₂(15 mL. times.3) extraction was performed 3 times, and the organic layers were combined and saturatedWashing with brine, drying with anhydrous sodium sulfate, concentrating, separating and purifying with silica gel column (4:1, V/V, petroleum ether: EtOAc) to obtain 3-3g (1.1g,1.80mmol) of a white amorphous solid product, yield: 65 percent.

The analytical data agree with 3-3g for the product of example 36.

EXAMPLE 41

Preparation of compound 3-3 h:

cooling 5-1b (1.0g, 2.78mmol) THF (20mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (1.8mL, 3.61mmol, 2M tetrahydrofuran solution) dropwise, controlling the temperature at-30 deg.C, stirring for reaction at-30 deg.C for 50min, further cooling to-78 deg.C, adding n-BuLi (4.3mL, 6.94mmol, 1.6M hexane solution dropwise), stirring for reaction for 5min, adding 2-1b (3.5g, 8.33mmol) THF (20mL) solution dropwise, maintaining the temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, and adding saturated NH₄The reaction was quenched with aqueous Cl (50mL), brought to room temperature, extracted 4 times with ethyl acetate (40mL × 4), the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 9-3 d. High resolution mass spectrometry (ESI)⁺)：C₃₇H₄₁N₄O₇ ⁺Theoretical value is 653.2970, found 653.2965.

Under the protection of nitrogen, the crude product 9-3d obtained above is dissolved in 20mL of dry CH₂Cl₂In (1), cooling to 0 ℃ and adding Et₃SiH (1.8mL,11.11mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (0.7mL,5.55mmol), returning to room temperature after dropwise addition for 1h, adding saturated sodium bicarbonate water solution (40mL) to quench the reaction after TLC detection, and adding CH to the water layer₂Cl₂(15 mL. times.3) extraction was performed 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (25:1, V/V, dichloromethane: methanol) to give the product as a white amorphous solid for 3h (894mg,1.67 mmol)) Yield, yield: 60 percent.

The analytical data are in agreement with the products of example 37 from 3 to 3 h.

Example 42

Preparation of compound 3 k:

cooling 5-1c (0.5g, 1.48mmol) THF (20mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (0.96mL, 1.92mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (2.3mL, 3.70mmol, 1.6M hexane solution dropwise), stirring for 5min, adding 2-1b (1.9g, 4.44mmol) THF (20mL), maintaining at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄Quenching the reaction with a Cl aqueous solution (10mL), returning to room temperature, extracting with ethyl acetate (30 mL. times.3) for 3 times, combining the organic layers, drying with anhydrous sodium sulfate, and concentrating to obtain crude product 9 f; high resolution mass spectrometry (ESI)⁺)：C₃₈H₄₀N₅O₇ ⁺Theoretical value is 678.2922, found 678.2916.

The crude 9f obtained above was dissolved in 20mL of dry CH under nitrogen₂Cl₂In (b), cooled to-78 ℃, Et is added₃SiH (0.94mL,5.91mmol), stirring for 5min, adding TMSOTf (0.57mL,2.96mmol) dropwise, reacting at-78 deg.C for 2h, after TLC detection, adding saturated sodium bicarbonate water solution (20mL), quenching, and adding CH to water layer₂Cl₂(20 mL. times.3) extraction was performed 3 times, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (4:1, V/V, petroleum ether: EtOAc) to give the product 3k (665mg,1.01 mmol) as a white amorphous solid in yield: 68 percent.

¹H-NMR(400MHz,CDCl₃) beta-configuration characteristic peak delta 5.7(s,1H, H-1); high resolution mass spectrometry (ESI)⁺)： C₃₈H₄₀N₅O₆ ⁺Theoretical value of 662.2973Found 662.2965.

Example 43

Preparation of Compounds 3-4 b:

cooling 5-2a (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (415 μ L, 0.83mmol, 2M tetrahydrofuran solution) dropwise, controlling temperature at-30 deg.C, stirring for reaction for 50min, further cooling to-78 deg.C, adding n-BuLi (100 μ L, 1.60mmol, 1.6M hexane solution), stirring for reaction for 5min, adding 2-1a (830mg, 1.92mmol) THF (10mL), maintaining temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (10mL), returned to room temperature, and then extracted 4 times with ethyl acetate (10mL × 4), and the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 9-4g of crude product. High resolution mass spectrometry (ESI)⁺)：C₃₇H₄₂N₅O₇ ⁺Theoretical value is 668.3079, found 668.3072.

Dissolving 9-4g of crude product obtained above in 10mL of dried MeCN under nitrogen protection, cooling to-40 deg.C, and adding Et₃SiH (408. mu.L, 2.56mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (162. mu.L, 1.28mmol), naturally warmed to room temperature, reacted for 2h, after TLC detection reaction, quenched with saturated aqueous sodium bicarbonate (10mL), the aqueous layer extracted 3 times with dichloromethane (10 mL. times.3), combined organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (25:1, V/V, dichloromethane: methanol) to give the product 3-4b (212mg,0.38mmol) as a white amorphous solid in yield: 60 percent.

¹H-NMR(500MHz,CDCl₃)δ8.08(s,1H),7.74(s,1H),7.50–7.22(m,15H),5.75 (s,1H),4.83(t,J＝8.3Hz,2H),4.69–4.62(m,3H),4.58(d,J＝11.9Hz,1H),4.44–4.38 (m,1H),4.08(d,J＝8.4Hz,1H),3.89(dd,J ═ 10.9,2.6Hz,1H),3.71(dd, J ═ 10.9,3.5Hz, 1H),1.10(s, 3H). Analytical data and literature [ CHO, Aesop; KIM, chong; PARRISH, Jay; XU, jie, Carba-nucleotide analogs for anti viral stream, wo2009132123a1,2009. High resolution mass spectrometry (ESI)⁺)：C₃₂H₃₄N₅O₄ ⁺Theoretical value is 552.2605, found 552.2600.

Example 44

Preparation of Compounds 3-4 l:

cooling 5-2a (0.5g, 1.59mmol) THF (10mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (1.03mL, 2.07mmol, 2M tetrahydrofuran solution) dropwise, controlling the temperature at-30 deg.C, stirring for reaction at-30 deg.C for 50min, further cooling to-78 deg.C, adding n-BuLi (2.5mL, 3.98mmol, 1.6M hexane solution dropwise), stirring for reaction for 5min, adding 2-1c (2.8g, 4.77mmol) THF (20mL) solution dropwise, maintaining the temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, and adding saturated NH₄The reaction was quenched with aqueous Cl (40mL), brought to room temperature, extracted 4 times with ethyl acetate (20mL × 4), the organic layers combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude product 9-4 h. High resolution mass spectrometry (ESI)⁺)：C₄₉H₄₈N₅O₇ ⁺Theoretical value is 818.3548, found 818.3543.

Dissolving the crude product in dry MeCN for 9-4h under nitrogen protection, cooling to-40 deg.C, adding Et₃SiH (1.02mL,6.37mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (402. mu.L, 3.18mmol), warmed up to room temperature, reacted for 2 hours, after completion of TLC detection, quenched with saturated aqueous sodium bicarbonate (10mL), and the aqueous layer with CH₂Cl₂Extracting (15 mL. times.3) for 3 times, mixing organic layers, washing with saturated salt solution, drying with anhydrous sodium sulfate, concentrating, and separating and purifying with silica gel column (25:1, V/V)Dichloromethane: methanol) gave 3-4l (726mg,1.03mmol) of a white foamy solid, yield: 65 percent.

¹H-NMR(400MHz,CDCl₃) beta-configuration characteristic peak δ 5.8(s,1H, H-1); high resolution mass spectrometry (ESI)⁺)： C₄₄H₄₀N₅O₄ ⁺Theoretical value is 702.3075, found 702.3070.

Example 45

Preparation of Compounds 3-4 b:

cooling 5-2b (0.2g, 0.55mmol) THF (10mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (0.36mL, 0.72mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (0.87mL, 1.38mmol, 1.6M hexane solution), stirring for 5min, adding 2-1a (719mg, 1.66mmol) THF (10mL), reacting for 2 hr at-78 deg.C, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (20mL), allowed to return to room temperature, extracted 4 times with ethyl acetate (20 mL. times.4), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give 9-4g of crude product. High resolution mass spectrometry (ESI)⁺)：C₃₇H₄₂N₅O₇ ⁺Theoretical value is 668.3079, found 668.3073.

Dissolving 9-4g of crude product obtained above in 10mL of dried MeCN under nitrogen protection, cooling to-40 deg.C, and adding Et₃SiH (0.4mL,2.22mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (0.1mL,1.11mmol), after the dropwise addition, the temperature is naturally raised to room temperature, the reaction is carried out for 2h, after the TLC detection reaction is finished, saturated sodium bicarbonate aqueous solution (10mL) is added for quenching reaction, and the water layer is treated with CH₂Cl₂Extracting (10 mL. times.3) for 3 times, mixing organic layers, washing with saturated saline, drying over anhydrous sodium sulfate, concentrating, and separating and purifying with silica gel column (25:1, V/V, dichloromethane: methanol) to obtain white pigmentProduct 3-4b (192mg,0.35mmol) as a colored amorphous solid, yield: and 63 percent.

The analytical data are in agreement with products 3-4b of example 43.

Example 46

Preparation of Compounds 3-4 m:

cooling 5-2a (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (415 μ L, 0.83mmol, 2M tetrahydrofuran solution) dropwise, controlling temperature at-30 deg.C, stirring for reaction for 50min, further cooling to-78 deg.C, adding n-BuLi (100 μ L, 1.60mmol, 1.6M hexane solution), stirring for reaction for 5min, adding 2-1b (803mg, 1.92mmol) THF (10mL) solution dropwise, maintaining temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄The reaction was quenched with aqueous Cl (10mL), returned to room temperature, extracted 4 times with ethyl acetate (10mL × 4), the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 9-4 i. High resolution mass spectrometry (ESI)⁺)：C₃₆H₄₀N₅O₇ ⁺Theoretical value is 654.2922, found 654.2918.

The crude 9-4i from above was dissolved in 10mL dry MeCN under nitrogen, cooled to-40 deg.C and Et was added₃SiH (408. mu.L, 2.56mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (162. mu.L, 1.28mmol), naturally warmed to room temperature, reacted for 2h, after TLC detection reaction, quenched with saturated aqueous sodium bicarbonate (10mL), the aqueous layer extracted 3 times with dichloromethane (10 mL. times.3), combined organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (25:1, V/V, dichloromethane: methanol) to give the product as a white amorphous solid 3-4m (203mg,0.38mmol), yield: 59 percent.

1H-NMR(400MHz,MeOD-d₄)δ7.97(s,1H),7.46(s,1H),7.33–7.26(m,10H),7.22 –7.18(m,5H) 5.45(d, J ═ 5.2Hz,1H),4.66(d, J ═ 12.1Hz,1H),4.61(d, J ═ 2.9Hz,1H), 4.58(d, J ═ 3.2Hz,1H),4.51(dd, J ═ 12.0,5.1Hz,3H),4.43(t, J ═ 5.1Hz,1H), 4.31-4.26 (m,1H),4.20(t, J ═ 5.2Hz,1H),3.71(dd, J ═ 10.7,3.7Hz,1 ddh), 3.62(dd, J ═ 10.8,4.2 Hz, 1H). Data were analyzed against literature [ LEE, Jae Moon; CHOI, MinJeong, Compounds and compositions for modulating tissue methyl Transferase activity, WO2014035140A2,2014. High resolution mass spectrometry (ESI)⁺)：C₃₁H₃₂N₅O₄ ⁺Theoretical value is 538.2449, found 538.2442.

Example 47

Preparation of Compounds 3-4 n:

cooling 5-2a (0.5g, 1.59mmol) THF (10mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (1.03mL, 2.07mmol, 2M tetrahydrofuran solution) dropwise, controlling the temperature at-30 deg.C, stirring for reaction at-30 deg.C for 50min, further cooling to-78 deg.C, adding n-BuLi (2.5mL, 3.98mmol, 1.6M hexane solution dropwise), stirring for reaction for 5min, adding 2-1d (2.7g, 4.77mmol) THF (20mL) solution dropwise, maintaining the temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, and adding saturated NH₄The reaction was quenched with aqueous Cl (10mL), allowed to return to room temperature, extracted 4 times with ethyl acetate (20 mL. times.4), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give crude 9-4 j. High resolution mass spectrometry (ESI)⁺)：C₄₈H₄₆N₅O₇ ⁺Theoretical value is 804.3392, found 804.3386.

Dissolving the crude product 9-4j in dry MeCN under nitrogen protection, cooling to-40 deg.C, adding Et₃SiH (1.02mL,6.37mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (402. mu.L, 3.18mmol), naturally warmed to room temperature, reacted for 2h, after TLC detection, quenched with saturated aqueous sodium bicarbonate (10mL), and the aqueous layer with CH₂Cl₂(15 mL. times.3) extraction was performed 3 times, organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column separation and purification (25:1, V/V, dichloromethane: methanol) to obtain 3 to 4n (712 mg,1.03mmol) as a white amorphous solid product, in terms of yield: 65 percent.

¹H-NMR(400MHz,CDCl₃) beta-configuration characteristic peak δ 5.6(d, J ═ 5.0Hz,1H, H-1); high resolution mass spectrometry (ESI)⁺)：C₄₃H₃₈N₅O₄ ⁺Theoretical value is 688.2918, found 688.2912.

Example 48

Preparation of Compounds 3-4 m:

cooling 5-2b (0.2g, 0.55mmol) THF (10mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (0.36mL, 0.72mmol, 2M tetrahydrofuran solution) dropwise, stirring at-30 deg.C, reacting for 50min, cooling to-78 deg.C, adding n-BuLi (0.87mL, 1.38mmol, 1.6M hexane solution), stirring for 5min, adding 2-1b (695mg, 1.66mmol) THF (10mL), reacting for 2 hr at-78 deg.C, detecting by TLC, and adding saturated NH₄The reaction was quenched with aqueous Cl (10mL), allowed to return to room temperature, extracted 4 times with ethyl acetate (20 mL. times.4), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give crude 9-4 i. High resolution mass spectrometry (ESI)⁺)：C₃₆H₄₀N₅O₇ ⁺Theoretical value is 654.2922, found 654.2918.

The crude 9-4i from above was dissolved in 10mL dry MeCN under nitrogen, cooled to-40 deg.C and Et was added₃SiH (0.4mL,2.22mmol), stirred for 5min, and then BF was added dropwise₃·Et₂O (0.1mL,1.11mmol), after the dropwise addition, the temperature is naturally raised to room temperature, the reaction is carried out for 2h, after the TLC detection reaction is finished, saturated sodium bicarbonate aqueous solution (10mL) is added for quenching reaction, and the water layer is treated with CH₂Cl₂(10 mL. times.3) extraction was performed 3 times, organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column separation and purification (25:1, V/V, dichloromethane: methanol) to obtain a white amorphous solid product 3-4m (214mg,0.40mmol), yield: 72 percent.

The analytical data agree with the products 3 to 4m of example 46.

Claims

1. A method for preparing a C-nucleoside analog, comprising the steps of:

(c) removing N from the compound shown in the general formula 5 in the presence of a metal organic reagent c1⁶-protons, which undergo halogen-metal exchange in the presence of a metal organic reagent C2, undergo an addition reaction with lactone compound 2 to give compound 7, compound 7 is reduced with a reducing agent C4 and lewis acid C4 to give alpha-C-nucleoside analogue 8;

or the like, or, alternatively,

(d) removing N from the compound shown in the general formula 5 in the presence of a metal organic reagent d1⁶-protons, which undergo halogen-metal exchange in the presence of a metal organic reagent d2, undergo an addition reaction with a lactone compound 2-1 to give a compound 9, the compound 9 being reduced to give beta-C-nucleoside analogue 3 by reaction with a reducing agent d4 and a lewis acid d 4;

wherein Hal is selected from chlorine, bromine, iodine;

z is selected from CR⁰Or nitrogen, R⁰Is H, halogen, cyano, C₁-C₆Straight or branched alkyl or C₂-C₆Straight or branched alkenyl;

R¹selected from H or methyl;

R²selected from H or tert-butyloxycarbonyl;

pg is selected from 2-naphthylmethyl, 1-naphthylmethyl, benzyl and p-methoxybenzyl;

the metal-organic reagent c1 and the metal-organic reagent d1 are respectively and independently lithium diisopropylamide;

the metal-organic reagent c2 and the metal-organic reagent d2 are respectively and independently n-butyl lithium;

the reducing agents c4 and d4 are independently triethylsilane;

the Lewis acid catalysts c4 and d4 are independently selected from boron trifluoride diethyl etherate or trimethylsilyl trifluoromethanesulfonate.

2. A process for the preparation of a C-nucleoside analogue according to claim 1, characterized by the steps of:

or the like, or, alternatively,

(d) removing N from compound 5 in the presence of metal organic reagent d1⁶Proton, halogen-metal exchange in the presence of a metal organic reagent d2, addition reaction with a lactone compound 2-1 to obtain a compound 9, reaction of the compound 9 with a reducing agent d4 and a Lewis acid d4, N removal⁶-tert-butoxycarbonyl protection to give beta-C-nucleoside analogue 3;

wherein the content of the first and second substances,

hal is selected from bromine and iodine;

z is selected from C R⁰Or nitrogen, R⁰Is H, cyano or vinyl;

R¹selected from H or methyl;

R²selected from H or tert-butyloxycarbonyl;

pg is benzyl, 2-naphthylmethyl or p-methoxybenzyl;

the reducing agents c4, d4 are each independently triethylsilane;

3. The method of preparing a C-nucleoside analog according to claim 1, wherein step (C) is one selected from the group consisting of:

(c-a) removal of N from Compound 5-1a in the Presence of a Metal-organic reagent c1⁶-protons, which undergo halogen-metal exchange in the presence of a metal-organic reagent C2, undergo an addition reaction with a lactone compound 2 to give a compound 7-1, the compound 7-1 is reacted with a reducing agent C4 and a Lewis acid C4 to give an alpha-C-nucleus by reduction8-1 parts of a glycoside analog;

or the like, or, alternatively,

(c-b) removing N from the compound 5-2a in the presence of a metal-organic reagent c1⁶-protons, which undergo halogen-metal exchange in the presence of a metal organic reagent C2, undergo an addition reaction with lactone compound 2 to give compound 7-2, compound 7-2 reacts with a reducing agent C4 and lewis acid C4, and is reduced to give alpha-C-nucleoside analogue 8-2;

wherein the content of the first and second substances,

R¹selected from H or methyl;

R²selected from H or tert-butyloxycarbonyl;

pg is 2-naphthylmethyl or benzyl;

the metal organic reagent c1 is lithium diisopropylamide;

the metal organic reagent c2 is n-butyl lithium;

the reducing agent c4 is triethylsilane;

the Lewis acid catalyst c4 is selected from boron trifluoride diethyl etherate or trimethylsilyl trifluoromethanesulfonate.

4. The method of preparing a C-nucleoside analog according to claim 1, wherein step (d) is one selected from the group consisting of:

(d-a) removal of N from Compound 5-1a in the Presence of a Metal-organic reagent d1⁶Proton, halogen-metal exchange in the presence of a metal organic reagent d2, addition reaction with a lactone compound 2-1 to obtain a compound 9-3, reaction of the compound 9-3 with a reducing agent d4 and a Lewis acid d4, N removal⁶-protection of tert-butyloxycarbonyl to give beta-C-nucleoside analogue 3-3;

or the like, or, alternatively,

(d-b) removal of N from Compound 5-2a in the Presence of a Metal-organic reagent d1⁶Proton, halogen-metal exchange in the presence of a metal organic reagent d2, addition reaction with a lactone compound 2-1 to obtain a compound 9-4, reaction of the compound 9-4 with a reducing agent d4 and a Lewis acid d4, N removal⁶-tert-butoxycarbonyl protection to give beta-C-nucleoside analogue 3-4;

wherein the content of the first and second substances,

R¹selected from H or methyl;

R²selected from H or tert-butyloxycarbonyl;

pg is p-methoxybenzyl or benzyl;

the metal organic reagent d1 is lithium diisopropylamide;

the metal organic reagent d2 is n-butyl lithium;

the reducing agent d4 is triethylsilane;

the Lewis acid catalyst d4 is selected from boron trifluoride diethyl etherate or trimethylsilyl trifluoromethanesulfonate.