CN109748944B

CN109748944B - 5 '-deoxy-5' -isopropyl substituted amino nucleoside compound, and preparation method and application thereof

Info

Publication number: CN109748944B
Application number: CN201711071717.5A
Authority: CN
Inventors: 沈竞康; 陈越磊; 熊兵; 刘同超; 任焕明
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: 2021-12-10
Anticipated expiration: 2037-11-03
Also published as: CN109748944A

Abstract

The invention discloses a 5 '-deoxy-5' -isopropyl substituted amino nucleoside compound shown in a general formula 7, a preparation method of the compound 7 and application of the compound 7 as an intermediate in preparation of a 5 '-deoxy-5' -polysubstituted amino nucleoside compound 1.

Description

5 '-deoxy-5' -isopropyl substituted amino nucleoside compound, and preparation method and application thereof

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a 5 '-deoxy-5' -polysubstituted amino nucleoside compound, and a preparation method and application thereof.

Background

There are several references [ 1) Olhava, E.J.methods of synthesizing substistuted purine nucleosides, WO2014152566A2, 2014; 2) klaus, c.; raimondi, m.a.; daigle, s.r.; pollock, R.M. combination of store methyl transfer enzymes DOTIL inhibitors and anti agents for the purpose of the treatment of cancer. WO2014153001A1, 2014; 3) yu, w.; smil, d.; li, F.; tempel, w.; fedorov, o.; nguyen, k.t.; bolshan, y.; Al-Awar, R.; knapp, s.; arrowsmith, C.H.; vedadi, m.; brown, p.j.; schapira, M., Bromo-deaza-SAH A patent and selective DOT1L inhibitor, bioorganic & Medicinal Chemistry2013,21(7), 1787-; 4) anglin, j.l.; deng, l.; yao, y.; cai, g.; liu, z.; jiang, h.; cheng, g.; chen, p.; dong, s.; song, Y., Synthesis and Structure-Activity Relationship Investigation of Adenosine-containment Inhibitors of tissue metabolism factor DOT1L. journal of medical Chemistry2012,55(18),8066 and 8074; 5) yu, w.; chord, e.j.; wernimont, a.k.; tempel, w.; scopton, a.; federation, A.; marineau, j.j.; qi, j.; Barsyte-Lovejoy, d.; yi, j.; marcellus, r.; iacobs, r.e.; engen, j.r.; griffin, c.; aman, a.; wienholds, e.; li, F.; pineda, j.; estiu, g.; shatseva, t.; hajian, t.; al-aware, R.; dick, j.e.; vedadi, m.; brown, p.j.; arrowsmith, C.H.; bradner, j.e.; schapira, m., Catalytic site modifying soft he DOT1L methyl transfer enzyme by selective inhibitors nat Commun 2012,3,1288, describes a process for the preparation of nucleoside DOT1L inhibitors. DOT1L inhibitors generally have the structure shown in 1:

the synthesis of representative compound EPZ-5676 is as follows [ 1) Olhava, e.j. methods of synthesizing substitedpuranine nucleosides, wo2014152566a2,2014 ]:

disclosure of Invention

The invention aims to provide an intermediate compound 5 '-deoxy-5' -isopropyl substituted aminonucleoside compound and a salt thereof, which are shown in a general formula 7 and used for preparing a 5 '-deoxy-5' -polysubstituted aminonucleoside compound 1.

Another object of the present invention is to provide a process for producing the 5 '-deoxy-5' -isopropyl substituted aminonucleosides represented by the general formula 7 and salts thereof.

The invention also aims to provide the application of the 5 '-deoxy-5' -isopropyl substituted amino nucleoside compound shown in the general formula 7 and the salt thereof in preparing the 5 '-deoxy-5' -polysubstituted amino nucleoside compound 1.

In a first aspect of the present invention, there is provided a 5 '-deoxy-5' -isopropyl substituted aminonucleoside compound represented by the following general formula 7:

wherein X, Y are each independently selected from carbon or nitrogen;

z is selected from carbon, nitrogen, CR⁰Wherein R is⁰Is halogen or cyano;

preferably, X and Z are both nitrogen and Y is carbon; or, Y and Z are both nitrogen, X is carbon; or, X and Z are both carbon, Y is nitrogen; or, X is nitrogen, Y is carbon, and Z is carbon; or, X is nitrogen, Y is carbon, Z is CR⁰Wherein R is⁰Is cyano;

r is selected from H or methyl;

R²selected from H, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), tert-butyryl (Piv), acetyl, isobutyryl, benzoyl, halogen, or substituted with C₁-C₆Alkyl-substituted benzoyl.

It is further preferred that the first and second liquid crystal compositions,

x and Z are both nitrogen and Y is carbon;

r is selected from H or methyl.

In a second aspect of the present invention, there is also provided a method for preparing a 5 '-deoxy-5' -isopropyl substituted aminonucleoside compound represented by the general formula 7, which comprises one or more steps of:

(a) reacting the amino group of the heterocyclic compound 2 with R¹Cl or R¹OR¹Carrying out protection reaction to obtain a compound 2-1;

(a1) reacting-OH and Pg of sugar Compound 3¹Cl or Pg¹Br is subjected to protection reaction to obtain a lactone compound 3-1;

(b) removing proton from the compound 2-1 after amino protection, performing Br-metal exchange, performing addition reaction with a lactone compound 3-1, and reducing to obtain a nucleoside compound 4;

(c) deprotecting nucleoside compound 4 to give compound 5 or compound 5';

(d) chlorinating compound 5 or compound 5' to give compound 6;

(e) substituting the amido of the compound shown in the general formula 6 to obtain a compound 7;

(f) reacting a compound represented by the general formula 6 with Pg²Amino substitution of NH to obtain compound 8, deamination of protecting group Pg²Is compound 9;

(g) mixing Compound 5 with Pg²NH is substituted by amido to obtain a compound 8;

(h) reductive amination of compound 9 to give compound 7;

wherein the content of the first and second substances,

x and Y are independently selected from carbon or nitrogen, Z is selected from carbon, nitrogen, CR⁰Wherein R is⁰Is halogen or cyano; preferably, X and Z are both nitrogen and Y is carbon; or, Y and Z are both nitrogen, X is carbon; or, X and Z are both carbon, Y is nitrogen; or, X is nitrogen, Y is carbon, and Z is carbon; or, X is nitrogen, Y is carbon, Z is CR⁰Wherein R is⁰Is cyano;

r is selected from H or methyl;

R¹selected from tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), tert-butyryl (Piv), acetyl, isobutyryl, benzoyl, halogen or substituted by C₁-C₆An alkyl-substituted benzoyl group; preferably, it is tert-butoxycarbonyl, benzyloxycarbonyl or tert-butyryl;

R²selected from H, tert-butoxycarbonyl, benzyloxycarbonyl, tert-butyryl, acetyl, isobutyryl, benzoyl, halogen, or by C₁-C₆An alkyl-substituted benzoyl group; preferably, it is H, tert-butoxycarbonyl, benzyloxycarbonyl or tert-butyryl;

Pg¹selected from 2-naphthylmethyl, 1-naphthylmethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, substituted by halogen or C₁-C₆An alkyl-substituted benzyl group; preferably, it is 2-naphthylmethyl or p-methoxybenzyl;

Pg²is phthaloyl.

In a preferred embodiment of the present invention,

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

the amino protection reaction is carried out in two steps;

the first step is as follows: reacting with an amino protection reagent in the presence of a solvent a1, a base a1 and a catalyst to obtain an intermediate 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; 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), benzyloxyformic anhydride (Cbz)₂O), benzyl chloroformate (CbzCl), pivaloyl chloride, acetic anhydride, acetyl chloride, isobutyric anhydride, isobutyryl chloride, benzoyl chloride, benzoic anhydride, substituted by halogen or C₁-C₆Alkyl-substituted benzoyl chlorides, by halogen or C₁-C₆Alkyl substituted benzoic anhydride, said 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 is between-30 ℃ and +60 ℃, and the reaction time is between 0.5 and 24 hours;

the second step is that: reacting the intermediate a1 prepared in the first step in the presence of a solvent a2 and a base a2 to prepare a compound 2-1;

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 diethyl 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;

after the alkali a2 and the solvent a2 are mixed, the concentration of the alkali is selected from 1M to 20M, preferably 2M to 4M;

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

In the step (a1),

said hydroxyl groupThe radical protection reaction is carried out with a hydroxyl protecting reagent Pg¹Br or Pg¹Cl in the presence of a solvent a3 and a base a3 to obtain a lactone compound 3-1;

the solvent a3 can be a mixed solvent of one or more of ethers and amide solvents; the ethers are selected from one or more of diethyl ether, TBME, isopropyl ether, 2-methyl tetrahydrofuran and tetrahydrofuran; the amide is selected from N, N-dimethylformamide, N, N-dimethylacetamide and formamide; the solvent a3 is preferably tetrahydrofuran and N, N-dimethylformamide.

The hydroxyl protecting reagent Pg¹Br or Pg¹Cl is selected from brominating agent Pg¹Br and chlorinated reagent Pg¹Cl; the hydroxyl protecting reagent is preferably 2-naphthylmethyl bromide and p-methoxybenzyl chloride.

The base a3 is selected from pyridine, triethylamine, diisopropylethylamine, dimethylaminopyridine, NaH and sodium hexamethyldisilazide; the base a3 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 (b), the step (c),

the deprotonation reaction is carried out with a metal organic reagent b1 in the presence of a solvent b 1;

r in the deprotonated substrate Compound 2-1¹Preferably selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, tert-butyryl, more preferably tert-butoxycarbonyl.

The solvent b1 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 metal organic reagent b1 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 alkyl lithium, n-butyl lithium, isobutyl lithium, tert-butyl lithium, methyl lithium and phenyl lithium; preferably isopropyl magnesium chloride, lithium diisopropylamide;

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

The Br-metal exchange reaction is carried out with a metal organic reagent b2 in the presence of a solvent b 2;

the solvent b2 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 b2 is preferably tetrahydrofuran.

The metal organic reagent b2 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 alkyl lithium, n-butyl lithium, isobutyl lithium, tert-butyl lithium, methyl lithium and phenyl lithium; preferably an isopropylmagnesium chloride-LiCl mixture (Turbo-Grignard reagent), n-butyllithium.

The temperature of the Br-metal exchange reaction 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 b 3;

pg in Compound 3-1, a substrate of the reaction¹Selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, triisopropylsilyl, trimethylsilyl, benzyl, p-methoxybenzyl, substituted by halogen or C₁-C₆Alkyl-substituted benzyl, 1-naphthylmethyl, 2-naphthylmethyl, preferably 2-naphthylmethyl and p-methoxybenzyl;

the solvent b3 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 b3 is preferably tetrahydrofuran;

it is further preferred that the first and second liquid crystal compositions,

the addition reaction is carried out in the presence of a Lewis acid catalyst b4, wherein the Lewis acid catalyst b4 is selected from CuI, cuprous trifluoromethanesulfonate (CuOTf), CuCN, LiCl, CuBr dimethyl sulfide complex, boron trifluoride diethyl etherate or TMSCl and the like;

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

the above deprotonation reaction, Br-metal exchange reaction and addition reaction are preferably carried out in a "one-pot" manner;

the reduction reaction is to react with a reducing agent in the presence of a solvent b5 and a Lewis acid catalyst b5 to obtain a nucleoside compound 4;

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

the Lewis acid catalyst b5 is selected from boron trifluoride diethyl etherate or trimethylsilyl trifluoromethanesulfonate (TMSOTf) and the like; the lewis acid catalyst b5 is preferably trimethylsilyl trifluoromethanesulfonate (TMSOTf);

the solvent b5 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 selected from one or more of dichloromethane, 1, 2-dichloroethane, 1, 1-dichloroethane and trichloromethane; the solvent b5 is preferably dichloromethane;

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

in the step (c),

the deprotection reaction is carried out under the condition selected from the reaction in the presence of a fluorine-containing reagent, in the presence of an oxidant and a solvent c2 or in the presence of a catalyst containing Pd, Pt or Ni, a hydrogen donor and a solvent c3 to obtain a compound 5 or a compound 5';

when the deprotection reaction is carried out in the presence of a fluorine-containing reagent, the fluorine-containing reagent is selected from tetrabutylammonium fluoride Trihydrate (TBAF), KHF₂Or KF, etc.;

when the deprotection reaction is carried out in the presence of an oxidizing agent selected from dichlorodicyanoquinone (DDQ) and the like and a solvent c 2; the solvent c2 is one or more of dichloromethane, trichloromethane, methanol, ethanol and water; the solvent c2 is preferably a mixture of dichloromethane and methanol.

When the deprotection reaction is carried out in the presence of a catalyst containing Pd, Pt or Ni, a hydrogen donor, and a solvent c3, the catalyst containing Pd, Pt or Ni includes, but is not limited to, palladium on carbon, palladium black, palladium oxide, palladium acetate, platinum on carbon, platinum oxide, raney nickel, etc.;

the hydrogen donor comprises hydrogen, transfer hydrogenation hydrogen donor or a combination of an active metal and a proton solvent as the hydrogen donor; the transfer hydrogenation hydrogen donor is selected from ammonium formate, cyclohexene, tetrahydronaphthalene, cyclohexadiene, methylcyclohexadiene, or diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate (Hantzsch ester), etc.; the method adopts the combination of active metal and proton solvent as a hydrogen donor, wherein the active metal is selected from zinc, zinc amalgam, sodium amalgam or magnesium, and the proton solvent is selected from methanol, ethanol, isopropanol or water;

the solvent c3 is selected from one or more of methanol, ethanol, isopropanol, dichloromethane, trichloromethane, acetonitrile, acetone, water, TBME, DMF and THF;

the reaction temperature of the deprotection reaction is between-20 ℃ and +70 ℃, and the reaction time is between 0.5 and 24 hours.

Preferably, the deprotection reaction is such that after one deprotection reaction is completed, the product is reacted again in a reaction selected from the group consisting of the presence of a fluorine-containing reagent, the presence of an oxidizing agent and a solvent c2, or the presence of a catalyst containing Pd, Pt or Ni, a hydrogen donor, and a solvent c 3.

In step (d), the chlorination reaction is carried out in two steps, d1 and d 2.

Step d 1:

in the step d1, in a solvent d1, the compound 5 or the compound 5' is reacted with thionyl chloride and a base d1 to obtain an intermediate d 1;

the solvent d1 is selected from acetonitrile, acetone, tetrahydrofuran, preferably acetonitrile.

The base d1 is selected from pyridine, dimethylaminopyridine, triethylamine and DBU, and is preferably pyridine.

The reaction temperature of the step d1 is between-20 ℃ and +70 ℃, and the reaction time is between 0.5 and 48 hours.

Step d 2:

step d2 is that the intermediate d1 prepared in step d1 is reacted with a base d2 in a solvent d2 to obtain a compound 6;

the solvent d2 is selected from water, methanol, ethanol, acetonitrile, dioxane and tetrahydrofuran, and is preferably methanol.

The alkali d2 is selected from pyridine, dimethylaminopyridine, triethylamine, DBU, ammonia water, ammonia gas, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and lithium carbonate, and preferably is selected from ammonia water and ammonia gas;

the reaction temperature of the step d2 is between-20 ℃ and +120 ℃, and the reaction time is between 0.5 and 48 hours.

In the step (e), the amino substitution reaction is carried out on a compound 6 and an amination reagent in a solvent to obtain a compound 7;

the amination reagent is selected from isopropylamine and potassium isopropylamine;

the solvent is selected from one or more of dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethanol, methanol, water, dichloromethane, trichloromethane, acetonitrile and TBME, or is not existed; the solvent is preferably ethanol or absent;

the temperature of the amino substitution reaction is between 0 ℃ and +150 ℃, and the reaction time is between 1 hour and 48 hours.

In the step (f),

the amido substitution reaction is carried out on a compound 6 and an amination reagent in a solvent f1 to obtain a compound 8;

the amination reagent is selected from phthalimide and phthalimide potassium salt;

the solvent f1 is selected from one or more of dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethanol, methanol, water, dichloromethane, trichloromethane, acetonitrile and TBME;

the temperature of the amino substitution reaction is between 0 ℃ and +150 ℃, and the reaction time is between 1 hour and 24 hours;

the deprotection reaction is carried out on a compound 8 and hydrazine hydrate in a solvent f2 to obtain a compound 9;

the solvent f2 is selected from one or more of dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethanol, methanol, water, dichloromethane, trichloromethane, acetonitrile and TBME; the solvent f2 is preferably ethanol;

the deprotection reaction temperature is between 0 ℃ and +150 ℃, and the reaction time is between 1 hour and 24 hours.

In the step (g), the step (c),

the amido substitution reaction is a compound 5 and an amination reagent Pg²NH, in the presence of a solvent g1, triphenylphosphine, and a condensing agent to obtain a compound 8;

the amination reagent Pg²NH is phthalimide;

the condensing agent is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate (DIAD);

the solvent g1 is selected from one or more of dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethanol, methanol, water, dichloromethane, trichloromethane, acetonitrile and TBME, and the solvent g1 is preferably THF;

the reaction temperature is between-20 ℃ and +100 ℃, and the reaction time is between 1 hour and 24 hours.

In the step (h), the step (c),

the reductive amination reaction is carried out on a compound 9 in an alkylating reagent h1, a reducing agent h1, an acid catalyst h1 and a solvent h1 to obtain a compound 7;

the alkylating agent h1 is selected from acetone, dimethoxyacetone ketal, preferably acetone;

the reducing agent h1 is selected from sodium cyanoborohydride or sodium triacetoxyborohydride, preferably sodium triacetoxyborohydride;

the acid catalyst h1 is selected from trifluoroacetic acid, hydrochloric acid, formic acid or acetic acid, preferably acetic acid;

controlling the pH of the reaction solution to be between 2 and 10 in the reductive amination reaction process;

the solvent h1 is selected from one or more of dichloromethane, trichloromethane, acetonitrile, TBME, methanol, ethanol, acetone, water and THF, and is preferably methanol;

the temperature of the reductive amination reaction is between-20 ℃ and +100 ℃, and the reaction time is 1 hour to 24 hours.

Preferably, the method for preparing the 5 '-deoxy-5' -isopropyl substituted aminonucleosides represented by the general formula 7 is selected from one of the following preparation methods:

the method comprises the following steps:

reacting the compound 5 or the compound 5' with thionyl chloride and pyridine, then reacting with ammonia water, and chlorinating to obtain a compound 6;

then, the compound shown in the general formula 6 and isopropylamine are subjected to amino substitution to obtain a compound 7;

the second method comprises the following steps:

then, the compound represented by the formula 6 is reacted with Pg²NH is substituted by amido in the presence of triphenylphosphine and diisopropyl azodicarboxylate to obtain compound 8, and deamination protecting group Pg is added in the presence of hydrazine hydrate²Is compound 9;

then, carrying out reductive amination on the compound 9 in the presence of acetone and sodium triacetoxyborohydride to obtain a compound 7;

the third method comprises the following steps:

mixing Compound 5 or Compound 5' with Pg²NH is substituted by amido under the existence of triphenylphosphine and diisopropyl azodicarboxylate to obtain a compound 8;

then, compound 8 is further deprotected to protect group Pg in the presence of hydrazine hydrate²Is compound 9;

wherein, R, R¹、R²、Pg¹、Pg²The definition of X, Y and Z groups are as described above, and the methods and conditions for each step of the above process can be performed with reference to steps (a), (a1), (b), (c), (d), (e), (f), (g) and (h) or conventional methods.

The compound shown in the general formula 5 can be prepared by the following method:

the compound represented by the formula 5 can also be prepared from compounds represented by the following references (1) C.McGuigan, P.perrone, K.Madela, J.Neyts, Bioorg.Med.chem.Lett.2009,19, 4316-4320; 2) S.E.Metobo, J.xu, O.L.Saunders, T.Butler, E.Aktoudanaikis, A.Cho, C.U.Kim, Tetrahedron Lett.2012,53, 484-.

In a third aspect of the present invention, there is provided a method for preparing the compound 1 from the 5 '-deoxy-5' -isopropyl substituted aminonucleoside compound represented by the general formula 7, wherein the method further comprises the following steps after preparing the compound represented by the general formula 7:

(j) carrying out reductive amination on the compound shown in the general formula 7 and an alkylating reagent M ═ O to obtain a compound 1;

wherein X and Y are independently selected from carbon or nitrogen, Z is selected from carbon, nitrogen, CR⁰Wherein R is⁰Is halogen or cyano; preferably, X and Z are both nitrogen and Y is carbon; or, X is nitrogen, Y is carbon, and Z is carbon;

m is

Ar is unsubstituted or substituted by C₁-C₆Alkyl or halogen substituted C₆-C₁₂Aryl, ring A being unsubstituted or substituted by C, condensed with imidazole ring₁-C₆Alkyl or halogen substituted C₆-C₁₂An aryl group;

said L is C₂-C₂₉The carbon chain of (a) is selected from substituted or unsubstituted C₂-C₆Straight or branched alkylene, substituted or unsubstituted C₂-C₆Straight or branched alkenylene, substituted or unsubstituted C₂-C₆Straight or branched alkynyl or substituted or unsubstituted C₃-C₆A cycloalkylene group, the substituted substituent being selected from halogen, C₁-C₆Alkoxy radical, said C₃-C₆The cycloalkylene group is preferably a cycloalkylene group

The R is⁴Is selected from C₁-C₆Acyl or H;

m is preferably

R is selected from H or methyl;

R²selected from H, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), tert-butyryl (Piv), acetyl, isobutyryl, benzoyl, substituted by halogen or C₁-C₆An alkyl-substituted benzoyl group;

preferably, the first and second electrodes are formed of a metal,

in the step (j),

the reductive amination reaction is carried out on a compound 7 in an alkylating agent M ═ O, a reducing agent j, an acid catalyst j, and a solvent j;

the alkylating reagent M ═ O is selected from ketone reagents

Or aldehyde reagents

Preferably, it is

The reducing agent j is selected from sodium cyanoborohydride or sodium triacetoxyborohydride; preferably sodium triacetoxyborohydride;

the acid catalyst j is selected from trifluoroacetic acid, hydrochloric acid, formic acid or acetic acid, preferably acetic acid;

the solvent j is selected from one or more of dichloromethane, trichloromethane, acetonitrile, TBME, methanol, ethanol, water and THF, and is preferably methanol or acetonitrile;

the temperature of the reductive amination reaction is between 0 ℃ and +100 ℃, and the reaction time is between 12 hours and 36 hours.

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 1-and 5-position substituents of ribose on both sides of ribose, and specifically, when the substituents at the 1-and 5-positions of ribose are on opposite sides of ribose, the configuration of nucleoside is defined as alpha-type; 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., EPZ-5676;

in the terminology used in the present invention, "C₁-C₆Alkyl "refers to a straight or branched chain alkyl group 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.

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

“C₆-C₁₂Aryl "means a monocyclic aromatic radical or a fused or non-fused polycyclic aromatic radical having 6 to 12 carbon atoms, in the case of a polycyclic one as long as one of the carbocyclic rings is aromatic, for example phenyl, naphthyl.

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

Taking the synthesis example of EPZ5676, starting from adenosine 5e starting material, the EPZ-5676 can be obtained by the reaction of the intermediate 7e through the first method provided by the invention in only 3 steps; according to the second method provided by the invention, EPZ-5676 can be obtained only by 4 steps of reaction; according to the third method provided by the invention, EPZ-5676 can be obtained only by 5 steps of reaction; according to the literature methods, 6 steps are required to obtain EPZ-5676. Therefore, the invention can obviously simplify the synthesis difficulty of EPZ-5676; the method can also take the structure 7 as a common intermediate, and conveniently prepare various 5 '-deoxy-5' -polysubstituted aminonucleoside compounds 1.

Detailed Description

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

In the following preparation examples, the following examples were conducted,¹H-NMRmeasured with a Varian Mercury AMX300 model instrument, a Varian Mercury-300High Performance Digital FT-NMR model instrument, a Bruker Ultrashield 500NMR model instrument, a Varian Mercury-400High Performance Digital FT-NMR model instrument, an Agilent 1260Prospekt 2Bruker Assicend 600NMR model instrument, deuterated chloroform (CDCl)₃) Deuterated methanol (MeOD-d)₄) Tetramethylsilane (TMS) was used as an internal standard. . Mass spectra were measured on a ThermoFinnigan MAT-95 type instrument, a Waters Q-TofUltima Global spectrometer type instrument. Melting points were determined on an SGWX-4 melting point apparatus.

In the following preparation examples, reagents such as petroleum ether, ethanol, ethyl acetate and the like with a boiling range of 60 to 90 ℃ are analytically pure and are provided by chemical reagents of the national drug group, ltd, and the used reagents and solvents are not specially treated except for special instructions. All solvents were redistilled before use and the anhydrous solvents used were dried according to standard procedures. All reactions were carried out under nitrogen and followed by TLC, all work-up was carried out with a saturated saline wash and anhydrous magnesium sulfate drying, except as indicated. The purification of the product was performed by column chromatography using silica gel (200-300 mesh) including 200-300 mesh, GF₂₅₄Produced by Qingdao oceanic plant or tobacco terrace edge Bo silica gel company. General reagents are available from Shanghai Biao medicine science and technology, Inc., Shanghai book sub-medicine science and technology, Shanghai Tatanke technology, Inc., Annagi chemical or national drug group chemical reagents, Inc., unless otherwise specified.

All temperatures are expressed in degrees Celsius (C), and room temperature is 20-25 ℃.

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), ultraviolet detection band 214 and 280nm, elution conditions 0-90% acetonitrile (containing 0.1% V/VTFA) gradient wash for 30 minutes. Preparing high performance liquid chromatography conditions: c18 column (5 μm,19X 250mm), ultraviolet detection band 214 and 280nm, elution conditions 0-90% acetonitrile (containing 0.1% V/VTFA) gradient wash for 30 minutes.

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;

TMSOTf is trimethylsilyl trifluoromethanesulfonate;

DDQ is dichlorodicyanobenzoquinone.

Example 1

Preparation of Compound 2-1b

Compound 2b (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), reacting overnight under stirring at room temperature, adding 3M sodium hydroxide aqueous solution (100mL) after reaction, heating to 60 deg.C, reacting under stirring for 6 hr, recovering to room temperature, separating organic layer, extracting water layer with ethyl acetate (20mLx 3), combining organic phases, saturatingThe organic phase was washed with 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 2-1b as a white solid (6.6g, 21.12mmol), 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(CH ₃)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 2-1 a:

compound 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 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 (20mLx 3), combining the organic layers, washing the organic layer by saturated saline (100mL), drying by anhydrous sodium sulfate, concentrating, separating by silica gel column (10:1, V/V, petroleum ether: EtOAc), and obtaining a white solid product 2-1a (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(CH ₃)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 3

Preparation of Compound 3-1 a:

dissolving raw material 3(5.0g,30.84mmol) [ prepared according to the Tetrahedron: Asymmetry 2007,18,500-512 method ] in anhydrous DMF (200mL), cooling to-10 ℃, 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, then adding 60% NaH (1.6g, 40.09mmol) and 2-bromomethylnaphthalene (10.2g, 46.26mmol), repeating twice, stirring at-10 ℃ for reaction for 48 hours, quenching the reaction liquid in 500mL of ice water, extracting with ethyl acetate (100mLx 4), combining organic phases, washing with 200mL of saturated common salt organic layer, drying over anhydrous sodium sulfate, concentrating, separating (10:1, V/V, petroleum ether: 3-12 g) to obtain white product (3.12 a), 21.59mmol), yield: 70 percent.

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

Example 4

Preparation of Compound 3-1 b:

dissolving raw material 3(5.0g,33.76mmol) [ prepared according to the method of org. Synth.2005,82,75-79 ] in anhydrous DMF (200mL), cooling to-10 deg.C under nitrogen protection, 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, quenching the reaction mixture in 500mL ice water, extracting with ethyl acetate (100 mL. times.4), combining the organic phases, washing with 200mL saturated brine, drying with anhydrous sodium sulfate, concentrating, separating with EtOAc (10:1, V/V, petroleum ether: 3-1 g-1 b (13.8 g), 24.31mmol), yield: 72 percent.

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

Example 5

Preparation of compound 4 a:

cooling THF (20mL) solution of 2-1b (1.0g, 3.19mmol) to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamino lithium THF solution (2.1mL, 4.15mmol, 2M tetrahydrofuran solution) dropwise, controlling the temperature at-30 deg.C, stirring for reaction for 50min, cooling to-78 deg.C, adding n-BuLi (5.0mL, 7.98mmol, 1.6M hexane solution dropwise), stirring for reaction for 5min, adding THF (20mL) solution of 3-1a (5.6g, 9.58mmol), maintaining the temperature at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄Quenching the reaction with a Cl aqueous solution (50mL), returning to room temperature, extracting with ethyl acetate (40mL × 4) for 4 times, combining the organic layers, drying with anhydrous sodium sulfate, and concentrating to obtain a crude intermediate product; the crude product 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) to quench the reaction, and adding CH to the aqueous layer₂Cl₂(15 mL. times.3) 3 times with combined extractsThe organic layer was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column separation (4:1, V/V, petroleum ether: EtOAc) to give product 4a (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 6

Cooling THF (10mL) solution of 2-1a (0.5g, 1.59mmol) 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 for 50min, cooling to-78 deg.C, adding n-BuLi (2.5mL, 3.98mmol, 1.6M hexane solution dropwise), stirring for 5min, adding THF (20mL) solution of 3-1a (2.8g, 4.77mmol), maintaining at-78 deg.C, reacting for 2 hr, and adding saturated NH after TLC detection₄Quenching 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 an intermediate crude product; dissolving the crude product 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 isolated and purified by silica gel column (25:1, V/V, dichloromethane: methanol) to give amorphous white solid product 4b (726mg,1.03mmol), yield: 65 percent.

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

Example 7

Preparation of compound 4 c:

cooling THF (20mL) solution of 2-1b (1.0g, 3.19mmol) 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 for 50min, cooling to-78 deg.C, adding n-BuLi (5.0mL, 7.98mmol, 1.6M hexane solution), stirring for 5min, adding THF (20mL) solution of 3-1b (5.4g, 9.58mmol), maintaining at-78 deg.C, reacting for 2 hr, detecting by TLC, adding saturated NH₄Quenching the reaction with a Cl aqueous solution (50mL), returning to room temperature, extracting with ethyl acetate (40mL × 4) for 4 times, combining the organic layers, drying with anhydrous sodium sulfate, and concentrating to obtain a crude intermediate product; the crude product 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) to quench the reaction, and adding CH to the aqueous layer₂Cl₂Extraction (15 mL. times.3) 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 product 4c (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 8

Preparation of compound 4 d:

cooling THF (10mL) solution of 2-1a (0.5g, 1.59mmol) 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 for 50min, cooling to-78 deg.C, adding n-BuLi (2.5mL, 3.98mmol, 1.6M hexane solution dropwise), stirring for 5min, adding THF (20mL) solution of 3-1b (2.7g, 4.77mmol), maintaining at-78 deg.C, reacting for 2 hr, and adding saturated NH after TLC detection₄Quenching the reaction with a Cl aqueous solution (10mL), returning to room temperature, extracting with ethyl acetate (20 mL. times.4) for 4 times, combining the organic layers, drying with anhydrous sodium sulfate, and concentrating to obtain a crude intermediate product; dissolving the crude product 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 isolated and purified by silica gel column (25:1, V/V, dichloromethane: methanol) to give amorphous white solid product 4d (712mg,1.03mmol), 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 9

Preparation of compound 5 a:

intermediate 4a (1.5g,1.87mmol) was dissolved in 40mL of dichloromethane/methanol (4:1) at room temperature, 10 drops of water were added, DDQ (2.6g, 11.24mmol) was added, the reaction was stirred at room temperature for 72 hours, after the reaction was completed, 50mL of saturated sodium bicarbonate solution was added to quench the reaction, the organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column separation (8:1, V/V, dichloromethane: methanol) to give a slightly reddish brown amorphous solid 5a (584mg, 1.54mmol), yield: 82 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₇H₂₅N₄O₆ ⁺Theoretical value is 381.1769, found 381.1762.

Example 10

Preparation of compound 5 b:

dissolving intermediate 4b (0.7g,1.00mmol) in 20mL dichloromethane/methanol (4:1, V/V) at room temperature, adding 10 drops of water, adding DDQ (1.4g, 5.98mmol), stirring at room temperature for reaction for 72 hours, adding 20mL saturated sodium bicarbonate solution after the reaction is finished to quench the reaction, separating an organic layer, drying over anhydrous sodium sulfate, concentrating, and separating and purifying with silica gel column (8:1, V/V, dichloromethane: methanol) to obtain a reddish brown amorphous solid 5a (224mg, 0.80mmol), yield: 80 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₁H₁₆N₅O₄ ⁺Theoretical value is 282.1197, found 282.1190.

Example 11

Preparation of compound 5 c:

dissolving intermediate 4c (1.3g,1.65mmol) in 40mL dichloromethane/methanol (4:1, V/V) at room temperature, adding 10 drops of water, adding DDQ (2.3g, 9.91mmol), stirring at room temperature for reaction for 72 hours, adding 100mL saturated sodium bicarbonate solution after the reaction is finished to quench the reaction, separating an organic layer, drying over anhydrous sodium sulfate, concentrating, separating and purifying by silica gel column to obtain a reddish brown amorphous solid 5c (514mg, 1.40mmol), yield: 85 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₆H₂₃N₄O₆ ⁺Theoretical value is 367.1612, found 367.1605.

Example 12

Preparation of compound 5 d:

dissolving intermediate 4d (0.7g,1.02mmol) in 20mL of dichloromethane/methanol (4:1, V/V) at room temperature, adding 10 drops of water, adding DDQ (1.4g, 6.11mmol), stirring at room temperature for reaction for 72 hours, adding 20mL of saturated sodium bicarbonate solution after the reaction is finished, quenching the reaction, separating an organic layer, drying over anhydrous sodium sulfate, concentrating, separating and purifying by silica gel column to obtain a reddish brown amorphous solid 5d (226mg, 0.84mmol), wherein the yield is as follows: 83 percent.

High resolution mass spectrometry (ESI)⁺)C₁₀H₁₄N₅O₄ ⁺Theoretical value is 268.1040, found 268.1025.

Example 13

Preparation of compound 4 e:

the method comprises the following steps: cooling 2-1b (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamine 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 3-1c THF (10mL) solution (830mg, 1.92mmol) from Shanghai Farmer Biotech Co., Ltd., maintaining temperature at-78 deg.CReacting for 2 hours, adding saturated NH after TLC detection reaction₄Quenching 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 a saturated sodium bicarbonate solution and a saturated salt solution, drying over anhydrous sodium sulfate, and concentrating to obtain a crude product; the crude product 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 saturated brine, dried over anhydrous sodium sulfate, concentrated, and isolated and purified on silica gel (4:1, V/V, petroleum ether: EtOAc) to give the product 4e (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＝0.155CHCl₃)；HPLC t_R4.10min；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-CH ₂-),4.69–4.57(m,4H,2x Bn-C ₂H-),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(CH ₃)₃),1.01(s,3H,2-C ₃H) (ii) a Selected fractions NOESY (600MHz, CDCl)₃):δ(¹H)/δ(¹H)＝7.10/3.91,3.72,4.06(H-1/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 2-1b (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamine 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 3-1c THF (10mL) solution (830mg, 1.92mmol) from Shanghai Farmer Biotech, Inc.), maintaining temperature at-78 deg.C, reacting for 2 hr, and adding saturated NH after TLC detection reaction₄Quenching 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 a saturated sodium bicarbonate solution and a saturated salt solution, drying over anhydrous sodium sulfate, and concentrating to obtain a crude product; the crude product 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 (5mL) to quench the 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 isolated and purified with silica gel column (4:1, V/V, petroleum ether: EtOAc) to give the product 4e (333mg,0.51mmol) as a white amorphous solid in yield: 80 percent.

The analytical data were consistent with 4e obtained in method one.

Example 14

Preparation of compound 4 f:

2-1b (200mg, 0.64mmol) of THF (THF) under anhydrous and oxygen-free conditions5mL) solution is cooled to-30 ℃, diisopropylamino lithium THF solution (415 mu L, 0.83mmol, 2M tetrahydrofuran solution) is dripped, the temperature is controlled at-30 ℃, after stirring reaction is carried out for 50min, the temperature is continuously reduced to-78 ℃, n-BuLi (100 mu L, 1.60mmol, 1.6M hexane solution) is dripped, after the dripping is finished, the stirring reaction is carried out for 5min, 3-1d THF (10mL) solution which is 803mg, 1.92mmol and is purchased from Shanghai Biaode medicine science and technology Limited company is dripped, the temperature is kept at-78 ℃, the reaction is carried out for 2h, after TLC detection is finished, saturated NH is added₄Quenching 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 a saturated sodium bicarbonate solution and a saturated salt solution, drying over anhydrous sodium sulfate, and concentrating to obtain a crude product; the crude product 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 saturated brine, dried over anhydrous sodium sulfate, concentrated, and isolated and purified with silica gel column (4:1, V/V, petroleum ether: EtOAc) to give product 4f (355mg,0.56mmol) as a white amorphous solid in yield: 87 percent.

R_f0.32(4:1,60-90 ℃ petroleum ether-EtOAc); [ alpha ] to]_D ²⁰＝69.49(c＝0.495CHCl₃)；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＝3.6Hz，1H,H-1),4.73(t,J＝10.2Hz,2H,Bn-C ₂H-),4.62–4.51(m,3H,Bn-C ₂H-,Bn-CH ₂-),4.43–4.39(m,2H,H-4,Bn-CH ₂-),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(CH ₃)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 15

Preparation of compound 4 g:

cooling 2-1a (200mg, 0.64mmol) THF (5mL) solution to-30 deg.C under anhydrous and oxygen-free conditions, adding diisopropylamine 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 3-1c THF (10mL) solution (830mg, 1.92mmol) from Shanghai Farmer Biotech, Inc.), maintaining temperature at-78 deg.C, reacting for 2 hr, and adding saturated NH after TLC detection reaction₄Quenching 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 a saturated sodium bicarbonate solution and a saturated salt solution, drying over anhydrous sodium sulfate, and concentrating to obtain a crude product; the crude product obtained above was dissolved in 10mL dry MeCN under nitrogen, 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), naturally heating to room temperature, reacting for 2h, after TLC detection reaction, adding saturated carbonic acidThe reaction was quenched with aqueous sodium hydrogen (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, dichloromethane: methanol) to give 4g (212mg,0.38mmol) of the product as a white amorphous solid, yield: 60 percent.

¹H-NMR(500MHz,CDCl₃) δ 8.08(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). Data and literature [ CHO, Aesop; KIM, chong; PARRISH, Jay; XU, jie, caroa-nucleotide analogs for anti viral stream, wo2009132123a1,2009. High resolution mass spectrometry (ESI)⁺)：C₃₂H₃₄N₅O₄ ⁺Theoretical value is 552.2605, found 552.2600.

Example 16

Preparation of compound 4 h:

cooling 2-1a (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) dropwise, stirring for reaction for 5min, adding 3-1d THF (10mL) solution (803mg, 1.92mmol) from Shanghai Bijie pharmaceutical and technology Limited, maintaining temperature at-78 deg.C, reacting for 2 hr, and adding saturated NH after TLC detection reaction₄Quenching 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 a saturated sodium bicarbonate solution and a saturated salt solution, drying over anhydrous sodium sulfate, and concentrating to obtain a crude product; the crude product obtained above was dissolved in 10mL dry MeCN under nitrogen, cooled to-40 ℃ and Et was added₃SiH(408μL,256mmol), stirring for 5min, and dropwise adding BF₃·Et₂O (162 μ L,1.28mmol), naturally warmed to room temperature, reacted for 2h, after TLC detection reaction was completed, quenched with saturated aqueous sodium bicarbonate solution (10mL), the aqueous layer was extracted 3 times with dichloromethane (10mL × 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, dichloromethane: methanol) to give a white amorphous solid product for 4h (203mg,0.38mmol), yield: 59 percent.

¹H-NMR(400MHz,MeOD-d₄) δ 7.97(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,1H),3.62(dd, J ═ 10.7, 3.8, 10.2 Hz, 1H). Data and 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 17

Preparation of compound 5 a:

compound 4e (1.0g, 1.54mmol), 10% palladium on carbon (100mg) and HCl (1mL, 2M in methanol) were added to 30mL of anhydrous methanol, and after introducing hydrogen gas, the mixture was stirred at room temperature for 4 hours, and after completion of the reaction, the mixture was filtered through celite, the filtrate was concentrated, and the resulting filtrate was separated and purified by silica gel column to obtain compound 5a (497mg, 1.31mmol), yield: 85 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₇H₂₅N₄O₆ ⁺Theoretical value is 381.1769, found 381.1760.

Example 18

Preparation of compound 5 c:

compound 4f (1.0g, 1.57mmol), 10% palladium on carbon (100mg) and HCl (1mL, 2M in methanol) were added to 30mL of anhydrous methanol, and after introducing hydrogen gas, the mixture was stirred at room temperature for 4 hours, and after completion of the reaction, the mixture was filtered through celite, the filtrate was concentrated, and the resulting filtrate was isolated and purified by silica gel column to give compound 5c (506mg, 1.38mmol), yield: 88 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₆H₂₃N₄O₆ ⁺Theoretical value is 367.1612, found 367.1603.

Example 19

Preparation of compound 5' b:

method one compound 4g (1.0g, 1.81mmol), 10% palladium on carbon (100mg) and HCl (1mL, 2M in methanol) were added to 30mL of anhydrous methanol, and after introducing hydrogen gas, stirred at room temperature for 4 hours, after completion of the reaction, filtered through celite, the filtrate was concentrated, and isolated and purified by silica gel column to give compound 5' b (428mg, 1.52mmol), yield: 84 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₁H₁₆N₅O₄ ⁺Theoretical value is 282.1197, found 282.1193.

Method two under the protection of nitrogen, dissolving 4g (1.0g, 1.81mmol) of the compound in 20mL of anhydrous dichloromethane, cooling to-78 ℃, and slowly dropping BCl₃(1.3mL, 12.69mmol, 1.0M dichloromethane solution), after the dropwise addition, the reaction was stirred at-78 ℃ for 3 hours, 5mL methanol was added to quench the reaction, the reaction was warmed to room temperature, the reaction was concentrated, and the reaction was separated and purified by silica gel column to give compound 5' b (408mg, 1.45mmol), yield: 80 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₁H₁₆N₅O₄ ⁺Theoretical value is 282.1197, found 282.1191.

Example 20

Preparation of compound 5 d:

method one compound 4h (1.0g, 1.86mmol), 10% palladium on carbon (100mg) and HCl (1mL, 2M in methanol) were added to 30mL of anhydrous methanol, stirred at room temperature for 4 hours after hydrogen gas was introduced, after the reaction was completed, filtered through celite, the filtrate was concentrated, and isolated and purified by silica gel column to give compound 5'd (413mg, 1.54mmol), yield: 83 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₀H₁₄N₅O₄ ⁺Theoretical value is 268.1040, found 268.1035.

Method II under the protection of nitrogen, dissolving the compound 4h (1.0g, 1.86mmol) in 20mL of anhydrous dichloromethane, cooling to-78 ℃, and slowly dropping BCl₃(1.3mL, 13.02mmol, 1.0M dichloromethane solution), after the dropwise addition, the reaction was stirred at-78 ℃ for 3 hours, 5mL methanol was added to quench the reaction, the reaction was warmed to room temperature, the reaction was concentrated, and the reaction was separated and purified by silica gel column to give compound 5'd (403mg, 1.45mmol), yield: 81 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₀H₁₄N₅O₄ ⁺Theoretical value is 268.1040, found 268.1034.

Example 21

Preparation of compound 4 e:

suspending compound 5a (1.0g,2.63mmol) in acetonitrile (10mL), adding pyridine (846 uL, 10.52mmol) to the suspension under nitrogen protection, cooling to 0 ℃, stirring for 10 minutes, slowly dropping thionyl chloride (1.9mL, 26.29mmol), keeping the temperature at 0 ℃, stirring for reaction for 4 hours, then heating to room temperature, stirring for reaction overnight, spin-drying the reaction solution, adding methanol (20mL), filling methanol (20mL), and stirringStirring, clarifying, adding ammonia water (5mL), stirring for 30 min, checking by TLC for reaction completion, spin-drying to obtain yellow oil, adding mixed solution of dichloromethane and methanol (20mL, 4:1), stirring, filtering, concentrating, and purifying with silica gel column (DCM: MeOH: NH)₄OH 15:1:0.01, V/V) to give the product 6a (668mg, 2.23mmol) as an amorphous white solid in 85% yield.

High resolution mass spectrometry (ESI)⁺)C₁₂H₁₆ClN₄O₃ ⁺Theoretical value is 299.0905, found 299.0891.

Example 22

Preparation of compound 6 b:

suspending compound 5' b (prepared according to the methods of documents c.mcguigan, p.perrone, k.madela, j.neyts, bioorg.med.chem.lett.2009,19,4316-4320, 3.0g, 10.67mmol) in acetonitrile (50mL), adding pyridine (3.4mL,42.66mmol) to the suspension under nitrogen protection, cooling to 0 ℃, stirring for 10 minutes, slowly adding thionyl chloride (7.7mL, 106.66mmol), stirring at 0 ℃ for 4 hours, subsequently heating to room temperature, stirring overnight, drying the reaction solution, adding methanol (50mL), clarifying the solution after stirring sufficiently, adding ammonia water (10mL), stirring for 30 minutes, checking the completion of the reaction by TLC, drying the reaction solution to obtain a yellow oily substance, adding a mixed solution of DCM and MeOH (50mL, 4:1), stirring sufficiently, filtering, concentrating the filtrate, and purifying by silica gel column separation (DCM: NH: MeOH)₄OH 15:1:0.01, V/V) to give white solid 6b (2.6g, 8.75mmol), yield: 82 percent.

High resolution mass spectrometry (ESI)⁺)C₁₁H₁₅ClN₅O₃ ⁺Theoretical value is 300.0858, found 300.0849.

Example 23

Preparation of compound 6 c:

suspending compound 5c (4.0g,10.92mmol) in acetonitrile (50mL), adding pyridine (3.5mL,43.67mmol) to the suspension under the protection of nitrogen, cooling to 0 ℃, stirring for 10 min, slowly dropping thionyl chloride (7.9mL, 109.18mmol), stirring and reacting for 4h while maintaining the temperature at 0 ℃, then heating to room temperature, stirring and reacting overnight, adding methanol (50mL), stirring thoroughly, clarifying the solution, adding ammonia water (10mL), stirring for 30 min, checking the reaction completion by TLC, drying the reaction solution to obtain yellow oil, adding a mixed solution of DCM and MeOH (50mL, 4:1), stirring thoroughly, filtering, concentrating the filtrate, and separating and purifying by silica gel column (DCM: MeOH: NH)₄OH 15:1:0.01, V/V) to give 6c as a white solid (2.5g, 8.73mmol), yield: 80 percent.

High resolution mass spectrometry (ESI)⁺)C₁₁H₁₄ClN₄O₃ ⁺Theoretical value is 285.0749, found 285.0735.

Example 24

Preparation of compound 6 d:

suspending compound 5'd (2.8g,10.48mmol) in acetonitrile (50mL), adding pyridine (3.4mL,41.91mmol) to the suspension under the protection of nitrogen, cooling to 0 ℃, stirring for 10 min, slowly dropping thionyl chloride (7.6mL, 104.77mmol), stirring and reacting for 4h while maintaining the temperature at 0 ℃, then heating to room temperature, stirring and reacting overnight, spinning dry the reaction solution, adding methanol (50mL), stirring thoroughly, clarifying the solution, adding ammonia water (10mL), stirring for 30 min, checking the reaction completion by TLC, spinning dry the reaction solution to obtain yellow oil, adding a mixed solution of DCM and MeOH (50mL, 4:1), stirring thoroughly, filtering, concentrating the filtrate, and separating and purifying by silica gel column (DCM: MeOH: NH)₄OH 15:1:0.01, V/V) to give 6d (2.6g, 9.01mmol) as a white solid, yield: 86 percent.

High resolution mass spectrometry(ESI⁺)：C₁₀H₁₃ClN₅O₃ ⁺Theoretical value is 286.0701, found 286.0693.

Example 25

Preparation of compound 6 e:

suspending adenosine 5' e [ available from Shanghai Biao pharmaceutical science Co., Ltd. ] (5.0g,18.71mmol) in acetonitrile (50mL), adding pyridine (6.02mL,74.84mmol) to the suspension under the protection of nitrogen, cooling to 0 ℃, stirring for 10 minutes, slowly dropping thionyl chloride (13.6mL, 187.10mmol), maintaining the temperature at 0 ℃ for stirring reaction for 4 hours, then heating to room temperature for stirring reaction overnight, spin-drying the reaction liquid, adding methanol (100mL), after sufficient stirring, clarifying the solution, adding ammonia (20mL), stirring for 30 minutes, checking the reaction by TLC, spin-drying the reaction liquid to obtain a yellow or red oily substance, adding water (100mL) to the oily substance, stirring at room temperature for 5 minutes, precipitating a white solid, filtering, vacuum-drying the filter cake to constant weight to obtain an amorphous white solid product 6e (4.8g,16.80mmol), yield: 90 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₀H₁₃ClN₅O₃ ⁺Theoretical value is 286.0701, found 286.0699.

Example 26

Preparation of compound 6 f:

suspending compound 5' f (5.0g,17.78mmol) from Shanghai Eisen chemical technology Co., Ltd in acetonitrile (50mL), adding pyridine (5.7mL,71.11mmol) to the suspension under nitrogen protection, cooling the reaction solution to 0 ℃ in an ice bath, stirring for 10 minutes, slowly adding thionyl chloride (12.9mL, 177.77mmol), keeping the temperature at 0 ℃ after the addition is completed, stirring for reaction for 4 hours, and then heating to room temperatureStirring at room temperature overnight, spin-drying the reaction mixture, adding methanol (100mL), stirring thoroughly to clarify the solution, adding ammonia (20mL), stirring for 30 min, checking by TLC that the reaction is complete, spin-drying the reaction mixture to obtain a pale yellow residue, adding a mixed solution of DCM and MeOH (150mL, 4:1, V/V), stirring thoroughly, filtering, concentrating the filtrate, and purifying by silica gel column separation (DCM: MeOH: NH)₄OH 15:1:0.01, V/V) to give amorphous white solid product 6f (4.7g, 15.68mmol) in 88% yield.

R_f＝0.46(8:1:0.01，V/V/V，DCM:MeOH:NH₄OH)；[α]_D ²⁰＝-3.33(c＝0.150,CH₃OH)；HPLC t_R＝1.60min；¹H-NMR(500MHz,MeOD-d₄) δ 8.30(s,1H, purine-H), 8.23(s,1H, purine-H), 6.12(s,1H, H-1),4.27(ddd, J ═ 8.7,5.0,2.7Hz,1H, H-4),4.21(d, J ═ 8.8Hz,1H, H-3),4.08(dd, J ═ 12.3,2.7Hz,1H, H-5),4.02(dd, J ═ 12.3,5.0Hz,1H, H-5'), 0.95(s,3H, 2-C)H ₃) OH and NH₂Removing the defect;¹³C-NMR(126MHz,MeOD-d₄) Delta 157.41 (purine-C), 154.00 (purine-C), 150.35 (purine-C), 140.49 (purine-C), 120.26 (purine-C), 93.21(C-1),82.54(C-4),80.02(C-2),75.79(C-3),45.49(C-5),20.28 (2-)CH₃) (ii) a High resolution mass spectrometry (ESI)⁺)：C₁₁H₁₅ClN₅O₃ ⁺Theoretical value is 300.0858, found 300.0857.

Example 27

Preparation of compound 6 g:

suspension of 5' g of compound (prepared according to the methods of J.D. Anderson, R.J. Bontems, S.Geary, H.B. Cottam, S.B. Larson, S.S. Matsumoto, D.F. Smee, R.K. Robins, Nucleosides 1989,8,1201-1216, 1.0g, 3.76mmol) in acetonitrile (10mL), addition of pyridine (1.2mL,15.02mmol) to the suspension under nitrogen protection, cooling to 0 deg.C, stirring for 10 min, slow addition of thionyl chloride (2.7mL, 37.56mmol), stirring at 0 deg.C for 4h, and subsequent rise in volume of thionyl chlorideStirring at room temperature for reaction overnight, spin-drying the reaction solution, adding methanol (20mL), stirring thoroughly to clarify the solution, adding ammonia (5mL), stirring for 30 min, checking by TLC for completion of the reaction, spin-drying the reaction solution to obtain a yellow oil, adding a mixed solution of dichloromethane and methanol (20mL, 4:1), stirring thoroughly, filtering, concentrating the filtrate, and purifying with silica gel column (DCM: MeOH: NH)₄OH 15:1:0.01, V/V) to give 6g (909mg, 3.19mmol) of amorphous white solid product in 85% yield.

High resolution mass spectrometry (ESI)⁺)：C₁₁H₁₄ClN₄O₃ ⁺Theoretical value is 285.0749, found 285.0743.

Example 28

Preparation of compound 6 h:

suspending compound 5' h (prepared according to the methods of S.S. Spurr, E.D.Bayle, W.Yu, F.Li, W.Tempel, M.Vedadi, M.Schapira, P.V.Fish, bioorg.Med.Chem.Lett.2016,26,4518-4522, 1.0g, 3.43mmol) in acetonitrile (10mL), adding pyridine (1.1mL,13.73mmol) to the suspension under nitrogen, cooling to 0 deg.C, stirring for 10 minutes, slowly dropping thionyl chloride (2.5mL, 34.33mmol), maintaining the temperature at 0 deg.C, stirring for 4 hours, subsequently heating to room temperature, stirring overnight, drying the reaction solution, adding methanol (20mL), stirring thoroughly, clarifying the solution, adding ammonia (5mL), stirring for 30 minutes, checking the completion of the reaction by TLC, obtaining a yellow oily reaction solution, adding a mixed solution of dichloromethane and methanol (20mL), filtering thoroughly, concentrating the filtrate, filtering, and purifying by using silica gel column (NH: 1 mL)₄OH 15:1:0.01, V/V) to give the product as an amorphous white solid for 6h (904mg, 2.92mmol), 85% yield.

High resolution mass spectrometry (ESI)⁺)：C₁₂H₁₃ClN₅O₃ ⁺Theoretical value is 310.0701, found 310.0693.

Example 29

Preparation of compound 7 d:

dissolving compound 6d (2.6g,9.10mmol) in isopropylamine (20mL), placing the solution in a pressure-resistant reaction tube, heating to 100 ℃ in an oil bath, stirring for reaction for 48 hours, evaporating the solvent after the reaction is finished, and separating and purifying the residue by a silica gel column (DCM: MeOH: NH)₄OH 8:1:0.01, V/V) to give a brown oil which solidified gradually as a bubble under vacuum drying to give compound 7d (2.4g, 7.83mmol), yield: 86 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₃H₂₁N₆O₃ ⁺Theoretical value is 309.1670, found 309.1660.

Example 30

Preparation of compound 7 e:

compound 6e (4.8g,16.80mmol) was dissolved in isopropylamine (50mL), the solution was placed in a pressure-resistant reaction tube, heated to 100 ℃ in an oil bath, stirred for reaction for 48 hours, after completion of the reaction, the solvent was evaporated to dryness, and the residue was isolated and purified by silica gel column (DCM: MeOH: NH)₄OH 8:1:0.01, V/V) to give a brown oil which solidified gradually as a bubble under vacuum drying to give compound 7e (4.3g, 13.95mmol), yield: 83 percent.

R_f＝0.15(8:1:0.01，V/V/V，DCM:MeOH:NH₄OH)；[α]_D ²⁰＝-6.25(c＝0.240,CH₃OH)；HPLC t_R＝0.50min；¹H-NMR(600MHz,MeOD-d₄) δ 8.26(s,1H, purine-H), 8.19(s,1H, purine-H), 5.97(d, J ═ 5.4Hz,1H, H-1),4.86(t, J ═ 5.4Hz,1H, H-2), 4.32-4.29 (m,1H, H-3),4.21(dt, J ═ 7.9,3.9Hz,1H, H-4),3.06(dd, J ═ 12.4,8.1Hz,1H, H-5),3.00(dd, J ═ 12.5,3.6Hz,1H, H-5 '), 2.93(p, J ═ 6.3Hz,1H, isopropyl-C), 1.97 (d, J ═ 12.5,3.6Hz,1H, H-5')H) 1.11(t, J ═ 6.2Hz,6H, isopropyl-C ₃H) NH, OH and NH₂Removing the defect;¹³C-NMR(151MHz,MeOD-d₄) Delta 157.38 (purine-C), 153.80 (purine-C), 150.52 (purine-C), 142.11 (purine-C), 120.91 (purine-C), 90.96(C-1),84.55(C-4),74.54(C-2),73.46(C-3),50.25 (isopropyl-CH) 49.99(C-5),22.01(2x isopropyl-CH₃) (ii) a High resolution mass spectrometry (ESI)⁺)：C₁₃H₂₁N₆O₃ ⁺Theoretical value is 309.1670, found 309.1660.

Example 31

Preparation of compound 7 f:

dissolving compound 6f (4.7g, 15.68mmol) in isopropylamine (50mL), placing the solution in a pressure-resistant reaction tube, heating to 100 ℃ in an oil bath, stirring for reaction for 48 hours, evaporating the solvent after the reaction of the raw materials is finished, and separating and purifying the residue by a silica gel column (DCM: MeOH: NH)₄OH 8:1:0.01, V/V) to give a brown oil which solidified gradually as a bubble under vacuum drying to give compound 7f (4.3g, 13.34mmol), yield: 85 percent.

R_f＝0.20(8:1:0.01，V/V/V，DCM:MeOH:NH₄OH)；[α]_D ²⁰＝4.62(c＝0.130,CH₃OH)；HPLC t_R＝0.59min；¹H-NMR(600MHz,MeOD-d₄) δ 8.27(s,1H, purine-H), 8.23(s,1H, purine-H), 6.07(s,1H, H-1),4.37(d, J ═ 8.9Hz,1H, H-3),4.23(td, J ═ 8.8,2.7Hz,1H, H-4),3.45(dd, J ═ 13.1,7.8Hz,1H, H-5), 3.31-3.28 (m,1H, H-5'), 3.23(hept, J ═ 6.4Hz,1H, isopropyl-C), and 3.23(hept, J ═ 6.4Hz,1H, isopropyl-C)H) 1.23(dd, J ═ 8.3,6.6Hz,6H, isopropyl-C ₃H),0.95(s,3H,2-CH ₃) NH, OH and NH₂Removing the defect;¹³C-NMR(151MHz,MeOD-d₄) Delta 157.48 (purine-C), 153.85 (purine-C), 150.00 (purine-C), 141.68 (purine-C), 120.73 (purine-C), 94.51(C-1),80.65(C-2),80.02(C-4),76.83(C-3),51.36 (isopropyl-CH) 48.21(C-5),20.62 (isopropyl-CH₃) 20.51 (isopropyl-CH₃),20.23(2-CH₃) (ii) a High resolution mass spectrometry (ESI)⁺)：C₁₄H₂₃N₆O₃ ⁺Theoretical value is 323.1826, found 323.1828.

Example 32

Preparation of compound 7 g:

6g (0.5g,1.76mmol) of the compound is dissolved in isopropylamine (5mL), the solution is placed in a pressure-resistant reaction tube, the temperature is raised to 100 ℃ by oil bath, the reaction is stirred for 48 hours, after the reaction is finished, the solvent is evaporated to dryness, and the residue is separated and purified by a silica gel column (DCM: MeOH: NH)₄OH 8:1:0.01, V/V) to give a brown oil which solidified gradually as a bubble under vacuum drying to give compound 7g (464mg, 1.51mmol), yield: 86 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₄H₂₂N₅O₃ ⁺Theoretical value is 308.1717, found 308.1712.

Example 33

Preparation of compound 7 h:

dissolving compound 6h (0.5g,1.61mmol) in isopropylamine (5mL), placing the solution in a pressure-resistant reaction tube, heating to 100 ℃ in an oil bath, stirring for 48 hours, evaporating the solvent after the reaction is finished, and separating and purifying the residue by a silica gel column (DCM: MeOH: NH)₄OH 8:1:0.01, V/V) to give a brown oil which solidified gradually as a bubble under vacuum drying to give compound 7h (472mg, 1.42mmol), yield: 88 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₅H₂₁N₆O₃ ⁺Theoretical value is 333.1670, found 333.1663.

Example 34

Preparation of compound 7 a:

dissolving compound 6a (0.5g,1.67mmol) in isopropylamine (5mL), placing the solution in a pressure-resistant reaction tube, heating to 100 ℃ in an oil bath, stirring for 48 hours, evaporating the solvent after the reaction is finished, and separating and purifying the residue by a silica gel column (DCM: MeOH: NH)₄OH 8:1:0.01, V/V) to give a brown oil which solidified gradually in a bubble under vacuum drying to give compound 7a (463mg, 1.44mmol), yield: 86 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₅H₂₄N₅O₃ ⁺Theoretical value is 322.1874, found 322.1869.

Example 35

Preparation of compound 7 c:

dissolving compound 6c (0.5g,1.76mmol) in isopropylamine (5mL), placing the solution in a pressure-resistant reaction tube, heating to 100 ℃ in an oil bath, stirring for 48 hours, evaporating the solvent after the reaction is finished, and separating and purifying the residue by a silica gel column (DCM: MeOH: NH)₄OH 8:1:0.01, V/V) to give a brown oil which solidified gradually in a bubble under vacuum drying to give compound 7c (453mg, 1.48mmol), yield: 84 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₄H₂₂N₅O₃ ⁺Theoretical value is 308.1717, found 308.1713.

Example 36

Preparation of compound 9 e:

compound 6e (5.0g, 17.50mmol) was suspended in 50mL tetrahydrofuran,adding phthalimide (5.1g, 35.00mmol) and triphenylphosphine (9.2g, 35.00mmol), cooling to 0 ℃ in an ice bath, slowly dropping DIAD (6.9mL, 35.00mmol), returning to room temperature after dropping, stirring for reacting overnight, evaporating the solvent, and separating and purifying by a silica gel column to obtain a compound 8 e; high resolution mass spectrometry (ESI)⁺)：C₁₈H₁₇N₆O₅ ⁺Theoretical value is 397.1255, found 397.1242. Dissolving the compound 8e in 50mL ethanol, adding hydrazine monohydrate (5.1mL, 105.01mmol), refluxing for 2 hours, evaporating the reaction solution to dryness, and separating and purifying the residue with silica gel column to obtain the compound 9e (3.5g, 13.13mmol) yield: 75 percent. High resolution mass spectrometry (ESI)⁺)：C₁₀H₁₅N₆O₃ ⁺Theoretical value is 267.1200, found 267.1184.

Example 37

Preparation of compound 9 f:

suspending the compound 6f (5.0g, 16.68mmol) in 50mL tetrahydrofuran, adding phthalimide (4.9g, 33.37mmol) and triphenylphosphine (8.8g, 33.37mmol), cooling to 0 ℃ in an ice bath, slowly dropping DIAD (6.6mL, 33.37mmol), returning to room temperature after dropping, stirring for reaction overnight, evaporating the solvent, and separating and purifying by a silica gel column to obtain a compound 8 f; high resolution mass spectrometry (ESI)⁺)：C₁₉H₁₉N₆O₅ ⁺Theoretical value is 411.1411, found 411.1400. Dissolving the compound 8f in 50mL ethanol, adding hydrazine monohydrate (4.9mL, 100.10mmol), refluxing for 2 hours, evaporating the reaction solution, and separating and purifying the residue by a silica gel column to obtain the yield of the compound 9f (3.3g, 11.68 mmol): 70 percent.

High resolution mass spectrometry (ESI)⁺)：C₁₁H₁₇N₆O₃ ⁺Theoretical value is 281.1357, found 281.1342.

Example 38

Preparation of compound 7 e:

dissolving compound 9e (3.0g, 11.27mmol) in 50mL of anhydrous methanol under nitrogen protection, adding acetone (20mL) and acetic acid (1.3mL,22.53mmol) with stirring, stirring at room temperature for 10 minutes, adding sodium triacetoxyborohydride (4.8g, 22.53mmol) in portions, continuing to react at room temperature for 5 hours, adjusting pH to 7 with saturated aqueous sodium bicarbonate solution after completion of the reaction, extracting the reaction solution (50mLx 4) with dichloromethane/methanol (10:1, V/V), combining organic phases, washing with saturated saline (200mL), drying with anhydrous sodium sulfate, concentrating, separating and purifying white bubble solid (2.6g, 8.56mmol) with silica gel column, yield: 76 percent.

Example 39

Preparation of compound 7 f:

dissolving compound 9f (3.0g, 10.70mmol) in 50mL of anhydrous methanol under nitrogen protection, adding acetone (20mL) and acetic acid (1.2mL,21.41mmol) with stirring, stirring at room temperature for 10 minutes, adding sodium triacetoxyborohydride (4.5g, 21.41mmol) in portions, continuing to react at room temperature for 5 hours, adjusting pH to 7 with saturated aqueous sodium bicarbonate solution after completion of the reaction, extracting the reaction solution (50mLx 4) with dichloromethane/methanol (10:1, V/V), combining organic phases, washing with saturated saline (200mL), drying with anhydrous sodium sulfate, concentrating, separating and purifying white bubble solid (2.5g, 7.71mmol) with silica gel column, yield: 72 percent.

Example 40

Preparation of compound 1 d:

compound 7d (500mg, 1.55mmol) was suspended in anhydrous acetonitrile (10mL), heated to 60 deg.C, stirred for 30 minutes, and AcOH (0.177mL, 3.1) was added under nitrogen protection0mmol), side chain 1 (prepared according to the methods in w.yu, e.j.chord, a.k.wernimont, w.tempel, a.scopton, a.federation, j.j.marineau, j.qi, d.barsyte-Lovejoy, j.yi, r.marcellus, r.e.iacobo, j.r.engen, c.griffin, a.aman, e.wisholds, f.li, j.pineda, g.estiu, t.shaeva, t.hajian, r.al-aware, j.e.dick, m.vedadi, p.j.brown, c.h.artowsh, j.e.bradk, m.aptirara, Nat, 3, 1288; 578mg, 2.33mmol) and sodium triacetoxyborohydride (1.3g, 6.20mmol) were stirred overnight and after completion of the TLC monitoring, methanol (10mL) was added and after stirring at room temperature for 30 minutes, sodium bicarbonate solid (652mg,7.76mmol) was added and stirred at room temperature for 2 hours, the solvent was evaporated directly and purified by silica gel column separation (DCM: MeOH: NH)₄OH 15:1:0.01, V/V) to give product 1d (671mg, 1.21mmol), yield: 78 percent.

High resolution mass spectrometry (ESI)⁺)C₂₈H₄₃N₈O₄ ⁺Theoretical value is 555.3402, found 555.3385.

EXAMPLE 41

Preparation of compound 1 dd:

compound 7d (1.0g,3.10mmol) was added to anhydrous acetonitrile (20mL) under nitrogen, acetic acid (0.355mL, 6.20mmol) was added, side chain 2 (prepared according to the procedure in E.J. Olhova, US20160024134A 1; 1.7g, 6.20mmol) was added and the reaction heated to 60-70 deg.C and stirred for 10 min, sodium triacetoxyborohydride (2.6g, 12.41mmol) was added and allowed to react overnight. After completion of the reaction was monitored by TLC, methanol (10mL) was added, and after stirring at room temperature for 30 minutes, a solid sodium hydrogencarbonate (1.3g,15.51mmol) was added, and the mixture was stirred at room temperature for 2 hours, the solvent was directly evaporated to dryness, and the mixture was purified by silica gel column separation (DCM: MeOH: NH)₄OH 15:1:0.01, V/V) to give the product 1dd (1.34g, 2.32mmol) as a brown solid in yield: 75 percent.

High resolution mass spectrometry (ESI)⁺)：C₃₁H₄₅N₈O₃ ⁺Theoretical value is 577.3609, found 577.3591.

Example 42

Preparation of the compounds cis-1dd and trans-1 dd:

column chromatography of compound 1dd (100mg, 0.17mmol) gave cis-1dd (70mg, 0.12mmol) and trans-1dd (20mg, 0.03 mmol).

Compound cis-1 dd: high resolution mass spectrometry (ESI)⁺)：C₃₁H₄₅N₈O₃ ⁺Theoretical value is 577.3609, found 577.3601.

The compound trans-1 dd: high resolution mass spectrometry (ESI)⁺)：C₃₁H₄₅N₈O₃ ⁺Theoretical value is 577.3609, found 577.3598.

Example 43

Preparation of compound 1 e:

suspending compound 7e (100mg, 0.32mmol) in anhydrous acetonitrile (10mL), heating to 50 deg.C, adding AcOH (37. mu.L, 0.64mmol), side chain 1 (according to W.Yu, E.J.Chory, A.K.Werniont, W.Tempel, A.Scopton, A.Federation, J.J.Marineau, J.Qi, D.Barsyte-Lovejoy, J.Yi, R.Marcellus, R.E.Iacob, J.R.Engen, C.Griffin, A.Aman, E.Wienholds, F.Li, J.Pineda, G.Estimu, T.Shatseva, T.Hajian, R.Al-Diawar, J.E.Vedak.P.P.Pidadi, G.E.Pimenta, C.H.S.P.H.P.H.H.P.H.H.P.H.H.H.C.C.C.C.S.C.C.H.C.S. Gerniader.C.C.C.C.C.C.C.H.C.C.H.C.C.H.C.C.H.C.C.C.H.C.C.C.C.C.H.C.C.H.H.C.C.C.C.C.H.C.C.H.C.C.C.H.C.C.C.C.C.H.C.C.C.C.C.C.C.C.H.H.C.C.C.C.C.C.H.H.H.C.C.H.C.C.C.H.C.C.C.C.C.C.C.C.H.H.C.C.C.C.H.H.C.H.C.C.C.H.H.C.C.H.C.C.H.H.C.C.H.C.C.H.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.H.H.S.C.C.C.S.C.H.C.C.C.C.C.H.H.H.C.C.C.C.C.C.C.C.H.H.C.C.C.C.C.C.C.C.C.C.C.C.C.C.H.H.H.C.C.C.C.C.C.C.C.C.C.C.C.C.C.H.C.C.C.C.H.H.H.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.H.H.C.C.H.H.H.H.C.C.H.H.C.C.H.H.H.H.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.₄OH 15:1:0.01, V/V) to give the product 1e (140mg, 0.26mmol) as a solid, yield: 80 percent.

R_f＝0.35(8:1:0.01，V/V/V，DCM:MeOH:NH₄OH)；[α]_D ²⁰＝13.33(c＝0.060,CH₃OH)；HPLC t_R＝2.50min；¹H-NMR(600MHz,MeOD-d₄) δ 8.21(s,1H, ArH),8.19(s,1H, ArH),7.26(d, J ═ 8.7Hz,2H, ArH),7.21(d, J ═ 8.7Hz,2H, ArH),5.98(d, J ═ 4.2Hz,1H, H-1),4.75(t, J ═ 4.8Hz,1H, H-2),4.40(t, J ═ 5.2Hz,1H, H-3),4.33 to 4.23(m,1H, H-4),3.53 to 3.34(m,1H, isopropyl-C)H),3.29–3.10(m,4H,H-5,H-5’,-C ₂H-),3.04–2.75(m,2H,-C ₂H-),1.85–1.76(m,2H,-C ₂H-),1.28(s,9H,C(CH ₃)₃) 1.21(d, J ═ 5.3Hz,3H, isopropyl-C) ₃H) 1.14(d, J ═ 5.4Hz,3H, isopropyl-C ₃H),NH,NH₂OH is absent;¹³C-NMR(151MHz,MeOD-d₄) δ 158.79(C ═ O),157.38(ArC),153.89(ArC),150.37(ArC),146.60(ArC),141.71(ArC),137.96(ArC),126.58(2x ArC),120.80(ArC),120.33(2x ArC),91.19(C-1),82.68(C-4),74.50(C-2),73.54(C-3),54.51 (isopropyl-CH),53.51(C-5),49.86(-CH₂-),38.55(-CH₂-),35.02(C(CH₃)₃),31.85(C(CH₃)₃),28.18(-CH₂-, 17.61 (isopropyl-)CH₃) 17.12 (isopropyl-CH₃) (ii) a High resolution mass spectrometry (ESI)⁺)：C₂₇H₄₁N₈O₄ ⁺Theoretical value is 541.3245, found 541.3234.

Example 44

Preparation of compound 1 g:

suspension of 7g (200mg,0.65mmol) of compound in dry acetonitrile (10mL), heating to 60 ℃ and adding AcOH (74. mu.L, 1.30mmol), side chain 1 (according to W.Yu, E.J.Chory, A.K.Werniont, W.Tempel, A.Scopton, A.Federation, J.J.Marineau, J.Qi, D.Barsyte-Lovejoy, J.Yi, R.Marcellus, R.E.Iacob, J.R.Engen, C.Gri.) under nitrogen protectionffin, a.aman, e.wineholds, f.li, j.pineda, g.estau, t.sharseva, t.hajian, r.al-awar, j.e.dick, m.vedadi, p.j.brown, c.h.arrowsmith, j.e.bradner, m.schapira, Nat commu 2012,3,1288; 242mg, 0.98mmol) and sodium triacetoxyborohydride (276mg, 1.30mmol) were stirred overnight and after completion of the reaction monitored by TLC, methanol (10mL) was added and stirred at room temperature for 30 minutes, solid sodium bicarbonate (218mg,2.60mmol) was added and stirred at room temperature for 2 hours, the solvent was evaporated directly and purified by silica gel column separation (DCM: MeOH: NH)₄OH 15:1:0.01, V/V) to give 1g (253mg, 0.47mmol) of amorphous white solid product, yield: 72 percent.

High resolution mass spectrometry (ESI)⁺)：C₂₈H₄₂N₇O₄ ⁺Theoretical value is 540.3293, found 540.3287.

Example 45

Preparation of compound 1 h:

suspending compound 7h (200mg, 0.60mmol) in anhydrous acetonitrile (10mL), heating to 60 deg.C, adding AcOH (69. mu.L, 1.20mmol), side chain 1 (according to W.Yu, E.J.Chory, A.K.Werniont, W.Tempel, A.Scopton, A.Federation, J.J.Marineau, J.Qi, D.Barsyte-Lovejoy, J.Yi, R.Marcellus, R.E.Iacob, J.R.Engen, C.Griffin, A.Aman, E.Wienholds, F.Li, J.Pineda, G.Estilu, T.Shatseva, T.Hajian, R.Al-Diawar, J.E.Vedak.P.255.Pidadi, G.Eastueda, T.Shatseva, T.Hajijn, R.Al-Schwann, R.Al-Diwar, J.E.E.Vedak.P.K.K.P.255, C.M.H.M.K.H.M.M.H.M.M.H.N, C.H.M.M.M.H.M.M.H.M.H.M.M.M.M.M.M.K.M.M.H.K.M.M.K.M.M.H.M.M.M.M.M.M.K.M.M.M.M.M.H.M.M.M.M.M.M.K.M.K.M.M.M.M.K.M.H.K.K.K.K.K.H.M.M.M.H.M.M.K.M.M.M.M.K.M.H.M.M.H.M.M.M.K.M.K.K.M.M.M.M.M.H.K.M.H.M.M.M.H.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.K.K.K.K.K.M.M.M.K.K.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.K.M.M.M.M.M.M.M.M.M.M.K.M.M.M.M.M.M.M.K.K.K.K.K.M.K.K.K.K.K.K.K.K.K.M.M.K.M.M.M.M.M.M.M.M.M.M.M.K.K.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.₄OH 15:1:0.01, V/V) to give the product as an amorphous white solid 1h (238mg, 0.42mmol), yield: 70 percent.

High resolution mass spectrometry (ESI)⁺)：C₂₉H₄₁N₈O₄ ⁺Theoretical value is 565.3245, found 565.3235.

Example 46

Preparation of compound 1 f:

suspending compound 7f (100mg, 0.31mmol) in anhydrous acetonitrile (10mL), heating to 50 deg.C, adding AcOH (35. mu.L, 0.62mmol), side chain 1 (according to W.Yu, E.J.Chory, A.K.Werniont, W.Tempel, A.Scopton, A.Federation, J.J.Marineau, J.Qi, D.Barsyte-Lovejoy, J.Yi, R.Marcellus, R.E.Iacob, J.R.Engen, C.Griffin, A.Aman, E.Wienholds, F.Li, J.Pineda, G.Estilu, T.Shatseva, T.Hajian, R.Al-Diawar, J.E.Vedak.P.P.P.Pidadi, G.E.P.P.Pineda, G.S.S.S.P.S.S.S.P.P.H.H.P.H.P.H.P.H.H.P.H.H.H.M.M.H.H.M.H.M.M.H.H.P.H.H.M.M.M.H.H.H.M.H.H.M.M.M.M.M.M.M.M.H.H.H.M.H.M.M.M.H.M.M.M.M.H.H.M.M.M.M.M.H.H.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.H.H.M.H.H.M.M.M.M.M.H.H.M.M.M.M.M.H.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.H.M.M.H.H.M.M.H.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M.M₄OH 15:1:0.01, V/V) to give the product 1f (146mg, 0.26mmol) as a solid, yield: 85 percent.

R_f＝0.53(8:1:0.01，V/V/V，DCM:MeOH:NH₄OH)；[α]_D ²⁰＝17.00(c＝0.100,CH₃OH)；HPLC t_R＝2.47min；¹H-NMR(500MHz,MeOD-d₄) Δ 8.23(s,1H, ArH),8.21(s,1H, ArH), 7.26-7.23 (m,2H, ArH), 7.21-7.17 (m,2H, ArH),6.04(s,1H, H-1),4.31-4.28(m,2H, H-3, H-4), 3.61-3.37 (m,2H, H-5, isopropyl-C)H),3.30–3.17(m,3H,H-5’,-C ₂H-),3.09–2.83(m,2H,-C ₂H-),1.84(p,J＝6.6Hz,2H,-C ₂H-),1.28(s,9H,C(CH ₃)₃) 1.23(d, J ═ 5.9Hz,3H, isopropyl-C ₃H) 1.19(d, J ═ 6.5Hz,3H, isopropyl-C) ₃H),0.92(s,3H,2-C ₃H),NH,NH₂OH is absent;¹³C-NMR(126MHz,MeOD-d₄) δ 158.76(C ═ O),157.43(ArC),153.88(ArC),150.00(ArC),146.57(ArC),141.41(ArC),137.93(ArC),126.54(2xArC),120.69(ArC),120.31(2xArC),94.29(C-1),80.64(C-4),79.73(C-2),77.32(C-3),54.83 (isopropyl-CH),53.01(C-5),50.26(-CH₂-),38.66(-CH₂-),35.00(C(CH₃)₃),31.85(C(CH₃)₃),28.10(-CH₂-),20.14(2-CH₃) 17.42 (isopropyl-CH₃) 17.39 (isopropyl-CH₃) (ii) a High resolution mass spectrometry (ESI)⁺)：C₂₈H₄₃N₈O₄ ⁺Theoretical value is 555.3402, found 555.3390.

Example 47

Preparation of compound 1 ee:

compound 7e (200mg,0.65mmol) was added to anhydrous acetonitrile (10mL) under nitrogen, acetic acid (74. mu.L, 1.30mmol) was added to the above suspension, side chain 2 (prepared according to the method in E.J. Olhova, US20160024134A 1; 175mg,0.65mmol) was added further, the reaction was heated to 60 ℃ and stirred for 10 min, sodium triacetoxyborohydride (137mg, 0.65mmol) was added and reacted for 72 h. Side chain 2(175mg,0.65mmol) was added in three portions over a 48 hour period and sodium triacetoxyborohydride (412mg,1.95mmol) was added in 5 portions. After cooling to room temperature, methanol (10mL) was added, and after stirring at room temperature for 30 minutes, a solid sodium bicarbonate (218mg, 2.59mmol) was added, and the mixture was stirred at room temperature for 2 hours, directly evaporated to dryness, and purified by silica gel column separation (DCM: MeOH: NH)₄OH 15:1:0.01, V/V) to give the product as a brown solid, 1ee (274mg, 0.49mmol), yield: 75 percent.

High resolution mass spectrometry (ESI)⁺)：C₃₀H₄₃N₈O₃ ⁺Theoretical value is 563.3453, found 563.3446.

Example 48

Preparation of the Compounds cis-1ee and trans-1 ee:

column chromatography of compound 1ee (274mg, 0.49mmol) gave cis-1ee (230mg, 0.41mmol) and trans-1ee (44mg, 0.08 mmol).

Compound cis-1 ee: high resolution mass spectrometry (ESI)⁺)：C₃₀H₄₃N₈O₃ ⁺Theoretical value is 563.3453, found 563.3449.

The compound trans-1 ee: high resolution mass spectrometry (ESI)⁺)：C₃₀H₄₃N₈O₃ ⁺Theoretical value is 563.3453, found 563.3445.

Example 49

Preparation of compound 1 ff:

compound 7e (200mg,0.62mmol) was added to anhydrous acetonitrile (10mL) under nitrogen, acetic acid (71. mu.L, 1.24mmol) was added to the above suspension, side chain 2 (prepared according to the method in E.J. Olhova, US20160024134A 1; 168mg,0.62mmol) was added, the reaction heated to 60 ℃ and stirred for 10 min, sodium triacetoxyborohydride (131mg, 0.62mmol) was added and reacted for 72 h. Side chain 2(168mg,0.62mmol) was added in three portions over a 48 hour period and sodium triacetoxyborohydride (394mg,1.86mmol) was added in 5 portions. After cooling to room temperature, methanol (10mL) was added, and after stirring at room temperature for 30 minutes, a solid sodium bicarbonate (208mg, 2.48mmol) was added, and the mixture was stirred at room temperature for 2 hours, directly evaporated to dryness, and purified by silica gel column separation (DCM: MeOH: NH)₄OH 15:1:0.01, V/V) to give the product 1ff (280mg, 0.49mmol) as a brown solid, yield: 78 percent.

High resolution mass spectrometry (ESI)⁺)：C₃₁H₄₅N₈O₃ ⁺Theoretical value is 577.3609, found 577.3599.

Example 50

Preparation of the Compounds cis-1ff and trans-1 ff:

column chromatography of compound 1ff (280mg, 0.49mmol) gave cis-1ff (233mg, 0.40mmol) and trans-1ff (47mg, 0.08 mmol).

Compound cis-1 ff: [ alpha ] to]_D ²⁰＝26.43(c＝0.140,CH₃OH)；¹H-NMR(500MHz,MeOD-d₄) δ 8.42(s,1H, purine-H), 8.22(s,1H, purine-H), 7.47(s,1H, ArH),7.37(d, J ═ 8.4Hz,1H, ArH),7.26(dd, J ═ 8.5,1.8Hz,1H, ArH),6.03(s,1H, H-1), 4.10-4.01 (m,2H, H-4, H-3),3.25(p, J ═ 9.1Hz,1H, N-cyclobutyl-C, H, C, g, CH-, 3.07(p, J ═ 6.6Hz,1H, isopropyl-CH),3.02–2.90(m,2H,H-5,H-5’),2.76(p,J＝7.6Hz,2H,-C ₂H-), 2.25-2.14 (m,2H, cyclobutyl-C ₂H-),1.86(t,J＝5.7Hz,3H，-C ₂H-, cyclobutyl-CH-, 1.64(p, J ═ 9.1Hz,2H, cyclobutyl-C ₂H-),1.36(s,9H,C(CH ₃)₃) 1.07(d, J ═ 6.7Hz,3H, isopropyl-C ₃H) 1.00(d, J ═ 6.6Hz,3H, isopropyl-C ₃H),0.92(s,3H,2-C ₃H),NH,NH₂OH is absent;¹³C-NMR(126MHz,MeOD-d₄) Delta 157.37 (purine-C), 156.48(ArC),153.90 (purine-C), 150.29 (purine-C), 146.63(ArC),146.63(ArC),146.62(ArC),146.61(ArC),141.34 (purine-C), 121.10(ArC),121.10(ArC),120.41 (purine-C), 93.39(C-1),82.68(C-4),79.79(C-2),77.13(C-3),53.48 (N-cyclobutyl-CH-),52.30 (isopropyl-CH) 49.72(C-5),36.29 (cyclobutyl-CH₂-),36.26(-CH₂-, 36.20 (cyclobutyl-CH₂-),35.58(C(CH₃)₃),32.29(C(CH₃)₃) 29.58 (cyclobutyl-CH-),27.73(-CH₂-),20.27(2-CH₃) 19.08 (isopropyl-CH₃) 18.57 (isopropyl-CH₃) (ii) a High resolution mass spectrometry (ESI)⁺)：C₃₁H₄₅N₈O₃ ⁺Theoretical value is 577.3609, found 577.3594.

The compound trans-1 ff: [ alpha ] to]_D ²⁰＝20.87(c＝0.115,CH₃OH)；¹H-NMR(600MHz,MeOD-d₄) δ 8.45(s,1H, purine-H), 8.22(s,1H, purine-H), 7.47(s,1H, ArH),7.38(d, J ═ 8.2Hz,1H, ArH),7.27(dd, J ═ 8.5,1.8Hz,1H, ArH),6.05(s,1H, H-1),4.08(ddd, J ═ 8.9,6.9,2.2Hz,1H, H-4),4.04(d, J ═ 9.0Hz,1H, H-3), 3.68-3.61 (m,1H, N-cyclobutyl-C, 1H), C, and a, C, and a, CH-, 3.07(p, J ═ 6.6Hz,1H, isopropyl-CH),3.02(dd,J＝14.9,2.0Hz,1H,H-5),2.96(dd,J＝14.9,6.7Hz,1H,H-5’),2.82–2.76(m,2H,-C ₂H-), 2.28-2.19 (m,2H, cyclobutyl-C ₂H-),2.01(dq,J＝14.3,7.2Hz,3H,-C ₂H-, cyclobutyl-CH-, 1.81(t, J ═ 9.4Hz,2H, cyclobutyl-C ₂H-),1.36(s,9H,C(CH ₃)₃) 1.07(d, J ═ 6.7Hz,3H, isopropyl-C ₃H) 1.00(d, J ═ 6.6Hz,3H, isopropyl-C ₃H),0.93(s,3H,2-C ₃H),NH,NH₂OH is absent;¹³C-NMR(151MHz,MeOD-d₄) Delta 157.36 (purine-C), 156.51(ArC),153.89 (purine-C), 150.28 (purine-C), 146.68(ArC),146.66(ArC),146.63(ArC),146.61(ArC),141.30 (purine-C), 121.12(2x ArC),120.36 (purine-C), 93.31(C-1),82.83(C-4),79.80(C-2),77.03(C-3),54.42 (N-cyclobutyl-CH-),52.42 (isopropyl-CH),49.35(C-5),35.57(C(CH₃)₃),35.33(-CH₂-) 33.90 (cyclobutyl-CH₂-, 33.77 (cyclobutyl-CH₂-),32.29(C(CH₃)₃) 29.12 (cyclobutyl-CH-),28.25(-CH₂-),20.27(2-CH₃) 19.33 (isopropyl-CH₃) 18.56 (isopropyl-CH₃) (ii) a High resolution mass spectrometry (ESI)⁺)：C₃₁H₄₅N₈O₃ ⁺Theoretical value is 577.3609, found 577.3594.

Claims

1. A5 '-deoxy-5' -isopropyl substituted aminonucleosides compound represented by the general formula 7:

wherein the content of the first and second substances,

x, Y are each independently selected from carbon or nitrogen;

z is selected from carbon, nitrogen, CR⁰Wherein R is⁰Is halogen or cyano;

r is selected from H or methyl;

R²selected from H, tert-butoxycarbonyl, benzyloxycarbonyl, tert-butyryl, acetyl, isobutyryl, benzoyl, halogen, or by C₁-C₆Alkyl-substituted benzoyl.

2. The 5 '-deoxy-5' -isopropyl substituted aminonucleosides of claim 1 represented by the general formula 7,

x and Z are both nitrogen and Y is carbon; or, Y and Z are both nitrogen, X is carbon; or, X and Z are both carbon, Y is nitrogen; or, X is nitrogen, Y is carbon, and Z is carbon; or, X is nitrogen, Y is carbon, Z is CR⁰Wherein R is⁰Is cyano;

r is H or methyl;

R²is H, tert-butyloxycarbonyl, benzyloxycarbonyl or tert-butyryl.

3. The 5 '-deoxy-5' -isopropyl substituted aminonucleosides of claim 1 represented by the general formula 7,

x and Z are both nitrogen and Y is carbon;

r is selected from H or methyl.

4. A method for preparing 5 '-deoxy-5' -isopropyl substituted aminoglycoside of formula 7 according to claim 1, which is one of the following methods:

the method comprises the following steps:

(a) reacting the amino group of the heterocyclic compound 2 with R¹Cl or R¹OR¹Generating amino groupsPerforming protection reaction to obtain a compound 2-1;

(c) deprotecting nucleoside compound 4 to give compound 5 or compound 5';

(d) chlorinating compound 5 or compound 5' to give compound 6;

or method two

(f) Mixing Compound 5 or Compound 5' with Pg²Substitution of NH with amino groupTo compound 8;

or a compound of the formula 6 with Pg²NH is substituted by amido to obtain a compound 8;

(g) removing the deaminating protecting group Pg from Compound 8²Is compound 9;

(h) reductive amination of compound 9 to give compound 7;

wherein the content of the first and second substances,

x and Y are each independently selected from carbon or nitrogen, Z is selected from carbon, nitrogen, CR⁰Wherein R is⁰Is halogen or cyano;

r is selected from H or methyl;

R¹selected from t-butyloxycarbonyl, benzyloxycarbonyl, t-butyryl, acetyl, isobutyryl, benzoyl, halogen or substituted by C₁-C₆An alkyl-substituted benzoyl group;

R²selected from H, tert-butoxycarbonyl, benzyloxycarbonyl, tert-butyryl, acetyl, isobutyryl, benzoyl, halogen or by C₁-C₆An alkyl-substituted benzoyl group;

Pg¹selected from 2-naphthylmethyl, 1-naphthylmethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, halogen or substituted C₁-C₆An alkyl-substituted benzyl group;

Pg²is phthaloyl.

5. The process for producing 5 '-deoxy-5' -isopropyl substituted aminonucleosides represented by the general formula 7 as claimed in claim 4, wherein,

x and Z are both nitrogen and Y is carbon; y and Z are both nitrogen, and X is carbon; or, X and Z are both carbon, Y is nitrogen;

R¹is tert-butoxycarbonyl, benzyloxycarbonyl or tert-butyryl;

R²is H, tert-butoxycarbonyl, benzyloxycarbonyl or tert-butyryl;

Pg¹is 2-naphthylmethyl, benzyl or p-methoxybenzyl.

6. The process for producing 5 '-deoxy-5' -isopropyl substituted aminonucleosides represented by the general formula 7 as claimed in claim 4, wherein,

x and Z are both nitrogen and Y is carbon;

R¹is tert-butyloxycarbonyl;

R²is H or tert-butoxycarbonyl;

Pg¹is 2-naphthylmethyl or benzyl.

7. The method for producing a 5 '-deoxy-5' -isopropyl substituted aminonucleoside compound represented by the general formula 7 according to claim 4, wherein the method is one selected from the following production methods:

the method comprises the following steps:

the second method comprises the following steps:

the third method comprises the following steps:

wherein, R, R¹、R²、Pg¹、Pg²X, Y and Z are as defined in claim 4.

8. The method according to claim 7, wherein the method comprises the steps of:

wherein the content of the first and second substances,

x and Z are both nitrogen and Y is carbon;

reacting the compound 5 or the compound 5' with thionyl chloride and pyridine, and then reacting with ammonia water to obtain a chlorination product compound 6;

then, the compound represented by the general formula 6 is substituted with isopropylamine to give a compound 7.

9. A method for producing a 5 '-deoxy-5' -polysubstituted aminonucleoside compound 1, which comprises the steps of, after producing a 5 '-deoxy-5' -isopropyl substituted aminonucleoside compound represented by the general formula 7 according to claim 4:

wherein X and Y are independently selected from carbon or nitrogen, Z is selected from carbon, nitrogen, CR⁰Wherein R is⁰Is halogen or cyano;

r is selected from H or methyl;

m is

Ar is unsubstituted or substituted by C₁-C₆Alkyl or halogen substituted C₆-C₁₂An aryl group, a heteroaryl group,

the ring A being unsubstituted or substituted by C and condensed with the imidazole ring₁-C₆Alkyl or halogen substituted C₆-C₁₂An aryl group;

said L is C₂-C₂₉The carbon chain of (a) is selected from substituted or unsubstituted C₂-C₆Straight-chain or branched alkylene, substituted orUnsubstituted C₂-C₆Straight or branched alkenylene, substituted or unsubstituted C₂-C₆Straight or branched alkynyl or substituted or unsubstituted C₃-C₆A cycloalkylene group, the substituted substituent being selected from halogen, C₁-C₆An alkoxy group;

R⁴is selected from C₁-C₆Acyl or H.

10. The method for producing a 5 '-deoxy-5' -polysubstituted amino nucleoside compound 1 according to claim 9,

said C is₃-C₆Cycloalkylene is

M is