WO2019080686A1 - Entecavir intermediate and synthesis method therefor, and method for synthesizing entecavir - Google Patents

Abstract

The present invention discloses entecavir intermediates and methods of preparing the intermediates and methods of preparing entecavir using the intermediates. The method for synthesizing entecavir and its intermediates has the advantages of chiral controllability, high yield and high product purity, and has wide sources of raw materials, cheap and easy reagents, simple reaction, simple operation, green environmental protection, and is suitable for industrial scale production. .

Description

Entecavir intermediate and synthesis method thereof, and synthesis method of entecavir Technical field

The invention relates to the technical field of pharmaceutical synthesis, in particular to an intermediate of entecavir and a synthetic method thereof, and a method for synthesizing entecavir.

Background technique

Entecavir (a compound of formula 1) having the chemical name 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylene The base cyclopentyl]-6H-indol-6-one was first approved by the original research company Bristol-Myers Squibb in March 2005 for the treatment of chronic hepatitis B. Currently, it is one of the most important drugs for the treatment of hepatitis B.

The structure of entecavir contains a chiral five-membered carbon ring and a guanine mother nucleus. The five-membered carbon ring has three chiral centers and one outer double bond structure, and the chemical structure is relatively complicated. Although some synthetic methods have been reported, when these methods are used to synthesize chiral five-membered carbon rings, the establishment of chiral centers is mostly carried out by achiral cleavage or asymmetric synthesis. The original research route uses cyclopentadiene as a raw material for asymmetric synthesis. This route uses hazardous reagents such as sodium hydride and lithium hydride many times, while Dess-Martin reagent and Nysted reagent are very expensive, and more anhydrous water is involved in the synthesis process. The operation reaction has high requirements on equipment and is not conducive to industrial production. The synthetic route is as follows:

The other method still uses cyclopentadiene as a raw material, introduces the desired functional group by [2+2] reaction, chiralizes the carboxylic acid intermediate to obtain a single enantiomer compound, and synthesizes entecavir through other steps. . In this method, the raw material is wasted by the splitting method, and the splitting efficiency is not high, and the synthetic route is as follows.

In addition, the reverse synthesis analysis of entecavir involves the coupling of an important carbocyclic intermediate through the Mitsunobu reaction. There are many synthetic methods for the preparation of the carbocyclic intermediate, but there are steps in these synthetic methods. Longer, or the source of chiral raw materials is not easy, or the asymmetric method is difficult to control the adverse aspects such as chiral centers. The synthesis methods of key intermediates of carbon rings are as follows:

Therefore, the existing entecavir preparation methods have disadvantages, and it is necessary to develop a preparation method of entecavir which has wide sources of raw materials, low cost and easy availability, simple operation, environmental protection, high optical purity and suitable for industrial scale production.

Summary of the invention

Based on this, the present invention provides novel intermediates for the preparation of entecavir.

The specific technical solutions are as follows:

An entecavir intermediate or intermediate composition for the preparation of entecavir, the entecavir intermediate or intermediate composition being selected from at least one of the following compounds:

Wherein R is a methyl group or an ethyl group.

The invention also provides a method of synthesizing entecavir intermediates.

The specific technical solutions are as follows:

A method for synthesizing an entecavir intermediate having the structure shown in Formula 10, comprising the steps of:

(c) a compound of formula 3 is reacted with an esterification reagent in the presence of a base to form a compound of formula 4;

(d) a compound of formula 4 is epoxidized in the presence of an epoxidizing reagent to form a compound of formula 5;

(e) a compound of formula 5 undergoes an epoxy ring opening reaction under the action of an acid to form a compound of formula 6;

(f) a compound of formula 6 is subjected to an acetone reaction of a hydroxy group with an acetonide protecting reagent under the action of an acid catalyst to form a compound of formula 7;

(g) a compound of formula 7 undergoes a Favorskii rearrangement reaction under the action of a base to form a compound of formula 8;

(h) a compound of formula 8 is subjected to a reduction reaction under the action of a reducing agent to form a compound of formula 9;

(i) a compound of formula 9 is deprotected by acid catalysis, and then an oxidation reaction is carried out under the action of an oxidizing agent to form a compound of formula 10;

The reaction formula is as follows:

Wherein R is a methyl group or an ethyl group.

In some of the embodiments, the method for synthesizing the entecavir intermediate having the structure represented by Formula 10 further comprises the steps of:

(a) dextro-carvone is epoxidized by the action of a base and an oxidizing agent to form a compound of formula 2;

(b) a compound of formula 2 undergoes a chloro ring opening reaction under the action of an acid and a chlorinating reagent to form a compound of formula 3;

The reaction formula is as follows:

In some of the embodiments, the reaction solvent of the step (a) is methanol, the base is sodium hydroxide, the oxidant is hydrogen peroxide, and the reaction temperature of the epoxidation reaction is -5 to 10 ° C, the right The molar ratio of carvone, base and oxidizing agent is 1:0.1 to 0.3:0.8 to 1.4; and/or,

The reaction solvent of the step (b) is tetrahydrofuran, the acid is trifluoroacetic acid, the chlorinating reagent is anhydrous lithium chloride, and the reaction temperature of the chloro ring opening reaction is 0 to 35 ° C. The molar ratio of the compound, the acid and the chlorinating agent is from 1:0.8 to 2:0.8 to 2.

In some of the embodiments, the reaction solvent of step (c) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, water, ethyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran. In at least one of the above, the base is selected from the group consisting of 4-dimethylaminopyridine, or a combination of 4-dimethylaminopyridine and another base, the esterification reagent is p-toluenesulfonyl chloride, and the reaction temperature of the reaction is 0 to The molar ratio of the compound of the formula 3, 4-dimethylaminopyridine, other base and p-toluenesulfonyl chloride is from 1:0.5 to 10:0 to 3:1 to 3 at 50 ° C; and/or

The reaction solvent in the step (d) is dichloromethane, the temperature of the epoxidation reaction is 0 to 40 ° C, and the epoxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, peracetic acid, and trifluoroperoxygen. a molar ratio of the compound of the formula 4 to the epoxidizing agent of at least one of acetic acid: 1:1 to 2; and/or

The reaction solvent in the step (e) is a combination of water and an organic solvent, which is tetrahydrofuran and/or 1,4-dioxane, and the volume ratio of water to the organic solvent is 1:1 to 10, The acid is sulfuric acid, the temperature of the epoxy ring opening reaction is 0 to 50 ° C, and the molar ratio of the compound of the formula 5 to the acid is 1:0.5 to 2; and/or

The reaction in the step (f) is carried out in the absence of a solvent, or the reaction solvent in the step (f) is dichloromethane, and the acetone-protecting reagent of the hydroxyl group is selected from 2,2-dimethoxypropane or acetone. The acid catalyst is selected from at least one of p-toluenesulfonic acid, camphorsulfonic acid and sulfuric acid, and the reaction temperature of the bishydroxyl group is 0 to 50 ° C. The compound of the formula 6 and the acetone of the hydroxyl group The molar ratio of the reagent to the acid catalyst is 1:1 to 5: 0.01 to 0.2; and/or

The reaction solvent in the step (g) is an alcohol solvent or a combination of an alcohol solvent selected from the group consisting of methanol and ethanol, and the ether solvent is selected from the group consisting of diethyl ether and methyl tert-butyl ether. Tetrahydrofuran, 1,4-dioxane, the base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, and the reaction temperature of the Favorskii rearrangement reaction -20 to 50 ° C, the molar ratio of the compound of the formula 7 to the base is 1:2 to 5; and / or,

The reaction solvent in the step (h) is selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, toluene, and 1,4-dioxane, and the reducing agent is selected from the group consisting of lithium aluminum hydride and dihydro bis (2-methoxy ethoxy). Sodium oxy)aluminate, diisobutylaluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, lithium triethylborohydride, the reaction temperature of the reduction reaction is -20 to 60 ° C, the formula The molar ratio of the compound of 8 to the reducing agent is 1:1 to 3; and/or

The reaction solvent in the step (i) is selected from the group consisting of methanol, ethanol, tetrahydrofuran, 1,4 dioxane, water, and the acid is selected from the group consisting of p-toluenesulfonic acid, dilute hydrochloric acid, dilute sulfuric acid, and acetic acid, and the oxidizing agent is selected from the group consisting of The sodium iodate, periodic acid, lead tetraacetate, and potassium permanganate have a reaction temperature of 0 to 80 ° C, and the molar ratio of the compound of the formula 9 to the acid to the oxidizing agent is 1:0.1 to 2:0.8 to 3.

In some of the embodiments, the reaction temperature of the reaction in the step (c) is 10 to 30 ° C, the base is selected from the group consisting of 4-dimethylaminopyridine, the compound of the formula 3, 4-dimethylaminopyridine, and The molar ratio of p-toluenesulfonyl chloride is 1:1.5 to 2:1.2 to 1.8.

In some of the embodiments, the temperature of the epoxidation reaction in the step (d) is 20 to 30 ° C, and the molar ratio of the compound of the formula 4 to the epoxidizing agent is 1:1 to 1.2.

In some of the embodiments, the temperature of the epoxy ring-opening reaction in the step (e) is 20 to 30 ° C, and the molar ratio of the compound of the formula 5 to the acid is 1:0.8 to 1.

In some of the embodiments, the reaction temperature of the bishydroxyl group in the step (f) is 20 to 30 ° C, and the molar ratio of the compound of the formula 6, the acetonide reagent of the hydroxyl group and the acid catalyst is 1: 1 to 1.5: 0.02 to 0.06.

In some of these embodiments, the reaction temperature of the Favorskii rearrangement reaction in step (g) is from -5 to 30 ° C, and the molar ratio of the compound of formula 7 to base is from 1:2.5 to 3.5.

In some of the embodiments, the reaction temperature of the reaction solvent in the step (h) is from -5 to 15 ° C, and the molar ratio of the compound of the formula 8 to the reducing agent is from 1:1 to 1.3.

In some of these embodiments, the temperature of the reaction in step (i) is from 20 to 30 ° C, and the molar ratio of the compound of the formula 9, acid to oxidizing agent is from 1:0.8 to 1.5:0.8 to 1.5.

A method for synthesizing an entecavir intermediate having the structure shown in Formula 12, comprising the steps of:

(j) a compound of formula 10 undergoes a Baeyer-Villiger oxidative rearrangement reaction under the action of a base and a peroxide to form a compound of formula 11;

(k) a compound of formula 11 undergoes an epoxidation reaction under the action of a catalyst and an oxidizing agent to form a compound of formula 12;

The reaction formula is as follows:

In some of these embodiments, the method of synthesizing the entecavir intermediate having the structure of Formula 12, comprising the steps of:

(c) a compound of formula 3 is reacted with an esterification reagent in the presence of a base to form a compound of formula 4;

(d) a compound of formula 4 is epoxidized in the presence of an epoxidizing reagent to form a compound of formula 5;

(e) a compound of formula 5 undergoes an epoxy ring opening reaction under the action of an acid to form a compound of formula 6;

(f) a compound of formula 6 is subjected to an acetone reaction of a hydroxy group with an acetonide protecting reagent under the action of an acid catalyst to form a compound of formula 7;

(g) a compound of formula 7 undergoes a Favorskii rearrangement reaction under the action of a base to form a compound of formula 8;

(h) a compound of formula 8 is subjected to a reduction reaction under the action of a reducing agent to form a compound of formula 9;

(i) a compound of formula 9 is deprotected by acid catalysis, and then an oxidation reaction is carried out under the action of an oxidizing agent to form a compound of formula 10;

(j) a compound of formula 10 undergoes a Baeyer-Villiger oxidative rearrangement reaction under the action of a base and a peroxide to form a compound of formula 11;

(k) a compound of formula 11 undergoes an epoxidation reaction under the action of a catalyst and an oxidizing agent to form a compound of formula 12;

The reaction formula is as follows:

Wherein R is a methyl group or an ethyl group.

In some of the embodiments, the method for synthesizing the entecavir intermediate having the structure of Formula 12 further comprises the steps of:

(a) dextro-carvone is epoxidized by the action of a base and an oxidizing agent to form a compound of formula 2;

(b) a compound of formula 2 undergoes a chloro ring opening reaction under the action of an acid and a chlorinating reagent to form a compound of formula 3;

The reaction formula is as follows:

In some of the embodiments, the reaction solvent of the step (a) is methanol, the base is sodium hydroxide, the oxidant is hydrogen peroxide, and the reaction temperature of the epoxidation reaction is -5 to 10 ° C, the right The molar ratio of carvone, base and oxidizing agent is 1:0.1 to 0.3:0.8 to 1.4; and/or,

The reaction solvent of the step (b) is tetrahydrofuran, the acid is trifluoroacetic acid, the chlorinating reagent is anhydrous lithium chloride, and the reaction temperature of the chloro ring opening reaction is 0 to 35 ° C. The molar ratio of the compound, the acid and the chlorinating agent is from 1:0.8 to 2:0.8 to 2.

In some of the embodiments, the reaction solvent in step (j) is selected from the group consisting of methanol, ethanol, tert-butanol, isopropanol, the base is sodium hydroxide and/or potassium hydroxide, and the peroxide is selected from the group consisting of sodium hydroxide and/or potassium hydroxide. Hydrogen peroxide, hydrogen peroxide complex, peroxybutanol, the temperature of the Baeyer-Villiger oxidative rearrangement reaction is 0 to 100 ° C, and the molar ratio of the compound of the formula 10, the base and the peroxide is 1 :1～20:1～20; and/or,

The reaction solvent in the step (k) is selected from the group consisting of dichloromethane, toluene, 1,2-dichloroethane, the catalyst is bis(acetylacetone) vanadium oxide, and the oxidizing agent is t-butanol peroxide, the ring The reaction temperature of the oxidation reaction is -25 to 25 ° C, and the molar ratio of the compound of the formula 11 and the catalyst to the oxidizing agent is 1:0.001 to 0.2:1 to 2.

In some of the embodiments, the temperature of the Baeyer-Villiger oxidative rearrangement reaction in the step (j) is 55 to 75 ° C, and the molar ratio of the compound, the base and the peroxide of the formula 10 is 1:2 to 3.5. : 5 to 8.

In some of the embodiments, the reaction temperature of the epoxidation reaction in the step (k) is -10 to 10 ° C, and the molar ratio of the compound of the formula 11 to the catalyst and the oxidizing agent is 1:0.03 to 0.06:1 to 1.5. .

In some of the embodiments, the reaction solvent of step (c) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, water, ethyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran. In at least one of the above, the base is selected from the group consisting of 4-dimethylaminopyridine, or a combination of 4-dimethylaminopyridine and another base, the esterification reagent is p-toluenesulfonyl chloride, and the reaction temperature of the reaction is 0 to The molar ratio of the compound of the formula 3, 4-dimethylaminopyridine, other base and p-toluenesulfonyl chloride is from 1:0.5 to 10:0 to 3:1 to 3 at 50 ° C; and/or

The reaction solvent in the step (d) is dichloromethane, the temperature of the epoxidation reaction is 0 to 40 ° C, and the epoxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, peracetic acid, and trifluoroperoxygen. a molar ratio of the compound of the formula 4 to the epoxidizing agent of at least one of acetic acid: 1:1 to 2; and/or

The reaction solvent in the step (e) is a combination of water and an organic solvent, which is tetrahydrofuran and/or 1,4-dioxane, and the volume ratio of water to the organic solvent is 1:1 to 10, The acid is sulfuric acid, the temperature of the epoxy ring opening reaction is 0 to 50 ° C, and the molar ratio of the compound of the formula 5 to the acid is 1:0.5 to 2; and/or

The reaction in the step (f) is carried out in the absence of a solvent, or the reaction solvent in the step (f) is dichloromethane, and the acetone-protecting reagent of the hydroxyl group is selected from 2,2-dimethoxypropane or acetone. The acid catalyst is selected from at least one of p-toluenesulfonic acid, camphorsulfonic acid and sulfuric acid, and the reaction temperature of the bishydroxyl group is 0 to 50 ° C. The compound of the formula 6 and the acetone of the hydroxyl group The molar ratio of the reagent to the acid catalyst is 1:1 to 5: 0.01 to 0.2; and/or

The reaction solvent in the step (g) is an alcohol solvent or a combination of an alcohol solvent selected from the group consisting of methanol and ethanol, and the ether solvent is selected from the group consisting of diethyl ether and methyl tert-butyl ether. Tetrahydrofuran, 1,4-dioxane, the base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, and the reaction temperature of the Favorskii rearrangement reaction -20 to 50 ° C, the molar ratio of the compound of the formula 7 to the base is 1:2 to 5; and / or,

The reaction solvent in the step (h) is selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, toluene, and 1,4-dioxane, and the reducing agent is selected from the group consisting of lithium aluminum hydride and dihydro bis (2-methoxy ethoxy). Sodium oxy)aluminate, diisobutylaluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, lithium triethylborohydride, the reaction temperature of the reduction reaction is -20 to 60 ° C, the formula The molar ratio of the compound of 8 to the reducing agent is 1:1 to 3; and/or

The reaction solvent in the step (i) is selected from the group consisting of methanol, ethanol, tetrahydrofuran, 1,4 dioxane, water, and the acid is selected from the group consisting of p-toluenesulfonic acid, dilute hydrochloric acid, dilute sulfuric acid, and acetic acid, and the oxidizing agent is selected from the group consisting of The sodium iodate, periodic acid, lead tetraacetate, and potassium permanganate have a reaction temperature of 0 to 80 ° C, and the molar ratio of the compound of the formula 9 to the acid to the oxidizing agent is 1:0.1 to 2:0.8 to 3.

In some of the embodiments, the reaction temperature of the reaction in the step (c) is 10 to 30 ° C, the base is selected from the group consisting of 4-dimethylaminopyridine, the compound of the formula 3, 4-dimethylaminopyridine, and The molar ratio of p-toluenesulfonyl chloride is 1:1.5 to 2:1.2 to 1.8.

In some of the embodiments, the temperature of the epoxidation reaction in the step (d) is 20 to 30 ° C, and the molar ratio of the compound of the formula 4 to the epoxidizing agent is 1:1 to 1.2.

In some of the embodiments, the temperature of the epoxy ring-opening reaction in the step (e) is 20 to 30 ° C, and the molar ratio of the compound of the formula 5 to the acid is 1:0.8 to 1.

In some of the embodiments, the reaction temperature of the bishydroxyl group in the step (f) is 20 to 30 ° C, and the molar ratio of the compound of the formula 6, the acetonide reagent of the hydroxyl group and the acid catalyst is 1: 1 to 1.5: 0.02 to 0.06.

In some of these embodiments, the reaction temperature of the Favorskii rearrangement reaction in step (g) is from -5 to 30 ° C, and the molar ratio of the compound of formula 7 to base is from 1:2.5 to 3.5.

In some of the embodiments, the reaction temperature of the reaction solvent in the step (h) is from -5 to 15 ° C, and the molar ratio of the compound of the formula 8 to the reducing agent is from 1:1 to 1.3.

In some of these embodiments, the temperature of the reaction in step (i) is from 20 to 30 ° C, and the molar ratio of the compound of the formula 9, acid to oxidizing agent is from 1:0.8 to 1.5:0.8 to 1.5.

The invention also provides a method for synthesizing entecavir.

The specific technical solutions are as follows:

A method for synthesizing entecavir, comprising the steps of:

(l) protecting a hydroxyl group in the compound of formula 12 to form a compound of formula 13;

(m) a compound of formula 13 is subjected to an epoxy isomerization reaction with an epoxy isomerization reagent to form a compound of formula 14;

(n) a compound of formula 14 is reacted with a compound of formula 16 under Mitsunobu reaction conditions to form a compound of formula 15;

(o) a compound of formula 15 undergoes a hydrolysis reaction to remove a hydroxy protecting group and an amino protecting group to form a compound of formula 1, ie, entecavir;

The reaction formula is as follows:

Wherein R1 and R2 are protecting groups for a hydroxy group, and R1 and R2 are each independently selected from the group consisting of: (1) silane group, (2) alkyl group, (3) alkoxymethyl group, (4) benzyl group. Oxymethyl and substituted benzyloxymethyl, (5) alkoxyethyl, (6) benzyl and phenyl ring substituted benzyl, (7) acyl, (8) alkoxy acyl, (9 ) siloxymethyl.

In some of the embodiments, the method for synthesizing entecavir further comprises the steps of:

(c) a compound of formula 3 is reacted with an esterification reagent in the presence of a base to form a compound of formula 4;

(d) a compound of formula 4 is epoxidized in the presence of an epoxidizing reagent to form a compound of formula 5;

(e) a compound of formula 5 undergoes an epoxy ring opening reaction under the action of an acid to form a compound of formula 6;

(f) a compound of formula 6 is subjected to an acetone reaction of a hydroxy group with an acetonide protecting reagent under the action of an acid catalyst to form a compound of formula 7;

(g) a compound of formula 7 undergoes a Favorskii rearrangement reaction under the action of a base to form a compound of formula 8;

(h) a compound of formula 8 is subjected to a reduction reaction under the action of a reducing agent to form a compound of formula 9;

(i) a compound of formula 9 is deprotected by acid catalysis, and then an oxidation reaction is carried out under the action of an oxidizing agent to form a compound of formula 10;

(j) a compound of formula 10 undergoes a Baeyer-Villiger oxidative rearrangement reaction under the action of a base and a peroxide to form a compound of formula 11;

(k) a compound of formula 11 undergoes an epoxidation reaction under the action of a catalyst and an oxidizing agent to form a compound of formula 12;

The reaction formula is as follows:

Wherein R is a methyl group or an ethyl group.

In some of these embodiments, R1 and R2 are each independently selected from the group consisting of: trimethylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, triethylsilyl, triisopropyl Silyl, methyl, methoxymethyl, 2-methoxyethoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, p-nitrobenzyloxymethyl, o-Nitrobenzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl-2-yl, 1-ethoxyethyl, benzyl, p-methoxy Benzyl, 3,4-dimethoxybenzyl, trityl, formyl, acetyl, benzoyl, p-phenylbenzoyl, methoxyacyl, ethoxylated, 9-indenyl Oxyacyl, tert-butoxy acyl.

In some of these embodiments, protecting the hydroxyl group in the compound of Formula 12 as described in Step (1) comprises: reacting a compound of Formula 12 with a hydroxy protecting reagent; R1 and R2 are each independently selected from: trimethylsilyl , tert-butyldiphenylsilyl, tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl, methyl, methoxymethyl, 2-methoxyethoxymethyl , benzyloxymethyl, p-methoxybenzyloxymethyl, p-nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, 2-(trimethylsilyl)ethoxylate Methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, formyl, acetyl, benzoyl, p-phenylbenzoyl, methoxy An acyl group, an ethoxyl group, a 9-fluorenyl methoxy group, a tert-butoxy group, the hydroxy protecting agent is R1X and R2X, wherein X is a leaving group and X is selected from a halogen or a trifluoromethanesulfonate group. The compound of formula 12 is reacted with a hydroxy protecting reagent to react a compound of formula 12 with R1X and R2X in the presence of a base and/or a catalyst selected from the group consisting of triethylamine, diisopropylethylamine, imidazole Pyridine, At least one of sodium oxide, potassium hydroxide, sodium hydride, lithium hydride, sodium bis(trimethylsilyl)amide, and lithium bis(trimethylsilyl)amide, the catalyst being selected from the group consisting of 4-dimethylamino At least one of pyridine, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, and tetrabutylammonium iodide; or

R1 and R2 are each independently selected from tetrahydropyranyl-2-yl, the hydroxy protecting reagent is dihydropyran, and the compound of formula 12 is reacted with a hydroxy protecting reagent to form a compound of formula 12 under acid catalysis Reacting with dihydropyran, the acid is selected from p-toluenesulfonic acid, pyridine p-toluenesulfonate; or

R1 and R2 are each independently selected from the group consisting of 1-ethoxyethyl, the hydroxy protecting reagent is ethyl vinyl ether, and the compound of formula 12 is reacted with a hydroxy protecting reagent to form a compound of formula 12 under acid catalysis. Reaction with ethyl vinyl ether selected from p-toluenesulfonic acid, pyridine p-toluenesulfonate; or

In some of the embodiments, the hydroxy protecting reagent described in the step (1) is tert-butyldimethylchlorosilane, and the compound of the formula 12 is reacted with a hydroxy protecting reagent under the action of a base and a catalyst, and the reaction is carried out. The solvent is selected from the group consisting of dichloromethane, N,N-dimethylformamide, the base is selected from the group consisting of triethylamine and imidazole, the catalyst is 4-dimethylaminopyridine, and the reaction temperature is 0-50 ° C. The molar ratio of the compound of the formula 12, the base, the catalyst and the tert-butyldimethylsilyl chloride is from 1:2 to 3:0.05 to 0.2:2 to 3.

In some of the embodiments, the temperature of the reaction in the step (1) is 5 to 30 ° C, the base is imidazole, the catalyst is 4-dimethylaminopyridine, the compound of the formula 12, tert-butyl The molar ratio of dimethylchlorosilane, imidazole and 4-dimethylaminopyridine is from 1:2 to 2.5:2.2 to 2.5:0.1 to 0.2.

In some of the embodiments, the reaction solvent in the step (m) is selected from the group consisting of toluene, xylene, tetrahydrofuran, methyl tert-butyl ether, and diethyl ether, and the epoxy isomerization reagent is selected from lithium diisopropylamide. In-situ aluminum complex of lithium 2,2,6,6-tetramethylpiperidine, lithium diisopropylamide and diethylaluminum chloride, lithium 2,2,6,6-tetramethylpiperidine The reaction temperature of the epoxy isomerization reaction is -25 to 110 ° C with an aluminum complex formed in situ with diethylaluminum chloride, aluminum isopropoxide, camphorsulfonic acid or p-toluenesulfonic acid.

In some of the embodiments, the reaction solvent in step (m) is toluene, and the epoxy isomerization reagent is lithium 2,2,6,6-tetramethylpiperidine and diethylaluminum chloride in situ. The resulting aluminum complex has a reaction temperature of -10 to 5 ° C for the epoxy isomerization reaction, and a molar ratio of the compound of the formula 13 to the epoxy isomerization reagent is 1:1 to 3.

In some of these embodiments, the molar ratio of the compound of Formula 14 to the compound of Formula 16 as described in Step (n) is from 1:1 to 2.

In some of these embodiments, the molar ratio of the compound of Formula 14 to the compound of Formula 16 as described in Step (n) is from 1:1.3 to 1.6.

In some of the embodiments, R1 and R2 are each a tert-butyldimethylsilyl group, and the reaction solvent of the hydrolysis reaction in the step (o) is tetrahydrofuran and water, and the hydrolysis reaction is carried out under the action of dilute hydrochloric acid. The reaction temperature is 10 to 70 °C.

In some of the embodiments, the reaction solvent of the hydrolysis reaction in the step (o) is tetrahydrofuran and water, and the hydrolysis reaction is carried out under the action of dilute hydrochloric acid at a reaction temperature of 50 to 60 °C.

In some of the embodiments, the reaction solvent of step (c) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, water, ethyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran. In at least one of the above, the base is selected from the group consisting of 4-dimethylaminopyridine, or a combination of 4-dimethylaminopyridine and another base, the esterification reagent is p-toluenesulfonyl chloride, and the reaction temperature of the reaction is 0 to The molar ratio of the compound of the formula 3, 4-dimethylaminopyridine, other base and p-toluenesulfonyl chloride is from 1:0.5 to 10:0 to 3:1 to 3 at 50 ° C; and/or

The reaction solvent in the step (d) is dichloromethane, the temperature of the epoxidation reaction is 0 to 40 ° C, and the epoxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, peracetic acid, and trifluoroperoxygen. a molar ratio of the compound of the formula 4 to the epoxidizing agent of at least one of acetic acid: 1:1 to 2; and/or

The reaction solvent in the step (e) is a combination of water and an organic solvent, which is tetrahydrofuran and/or 1,4-dioxane, and the volume ratio of water to the organic solvent is 1:1 to 10, The acid is sulfuric acid, the temperature of the epoxy ring opening reaction is 0 to 50 ° C, and the molar ratio of the compound of the formula 5 to the acid is 1:0.5 to 2; and/or

The reaction in the step (f) is carried out in the absence of a solvent, or the reaction solvent in the step (f) is dichloromethane, and the acetone-protecting reagent of the hydroxyl group is selected from 2,2-dimethoxypropane or acetone. The acid catalyst is selected from at least one of p-toluenesulfonic acid, camphorsulfonic acid and sulfuric acid, and the reaction temperature of the bishydroxyl group is 0 to 50 ° C. The compound of the formula 6 and the acetone of the hydroxyl group The molar ratio of the reagent to the acid catalyst is 1:1 to 5: 0.01 to 0.2; and/or

The reaction solvent in the step (g) is an alcohol solvent or a combination of an alcohol solvent selected from the group consisting of methanol and ethanol, and the ether solvent is selected from the group consisting of diethyl ether and methyl tert-butyl ether. Tetrahydrofuran, 1,4-dioxane, the base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, and the reaction temperature of the Favorskii rearrangement reaction -20 to 50 ° C, the molar ratio of the compound of the formula 7 to the base is 1:2 to 5; and / or,

The reaction solvent in the step (h) is selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, toluene, and 1,4-dioxane, and the reducing agent is selected from the group consisting of lithium aluminum hydride and dihydro bis (2-methoxy ethoxy). Sodium oxy)aluminate, diisobutylaluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, lithium triethylborohydride, the reaction temperature of the reduction reaction is -20 to 60 ° C, the formula The molar ratio of the compound of 8 to the reducing agent is 1:1 to 3; and/or

The reaction solvent in the step (i) is selected from the group consisting of methanol, ethanol, tetrahydrofuran, 1,4 dioxane, water, and the acid is selected from the group consisting of p-toluenesulfonic acid, dilute hydrochloric acid, dilute sulfuric acid, and acetic acid, and the oxidizing agent is selected from the group consisting of Sodium iodate, periodic acid, lead tetraacetate, potassium permanganate, the reaction temperature is 0-80 ° C, the molar ratio of the compound of the formula 9, acid and oxidant is 1: 0.1 ~ 2: 0.8 ~ 3; And / or,

The reaction solvent in the step (j) is selected from the group consisting of methanol, ethanol, tert-butanol, isopropanol, the base is sodium hydroxide and/or potassium hydroxide, and the peroxide is selected from the group consisting of hydrogen peroxide and hydrogen peroxide. The compound, peroxytert-butanol, the Baeyer-Villiger oxidative rearrangement reaction temperature is 0 to 100 ° C, and the molar ratio of the compound of the formula 10, the base and the peroxide is 1:1 to 20:1 20; and / or,

The reaction solvent in the step (k) is selected from the group consisting of dichloromethane, toluene, 1,2-dichloroethane, the catalyst is bis(acetylacetone) vanadium oxide, and the oxidizing agent is t-butanol peroxide, the ring The reaction temperature of the oxidation reaction is -25 to 25 ° C, and the molar ratio of the compound of the formula 11 and the catalyst to the oxidizing agent is 1:0.001 to 0.2:1 to 2.

In some of the embodiments, the reaction temperature of the reaction in the step (c) is 10 to 30 ° C, the base is selected from the group consisting of 4-dimethylaminopyridine, the compound of the formula 3, 4-dimethylaminopyridine, and The molar ratio of p-toluenesulfonyl chloride is 1:1.5 to 2:1.2 to 1.8.

In some of the embodiments, the temperature of the epoxidation reaction in the step (d) is 20 to 30 ° C, and the molar ratio of the compound of the formula 4 to the epoxidizing agent is 1:1 to 1.2.

In some of the embodiments, the temperature of the epoxy ring-opening reaction in the step (e) is 20 to 30 ° C, and the molar ratio of the compound of the formula 5 to the acid is 1:0.8 to 1.

In some of the embodiments, the reaction temperature of the bishydroxyl group in the step (f) is 20 to 30 ° C, and the molar ratio of the compound of the formula 6, the acetonide reagent of the hydroxyl group and the acid catalyst is 1: 1 to 1.5: 0.02 to 0.06.

In some of these embodiments, the reaction temperature of the Favorskii rearrangement reaction in step (g) is from -5 to 30 ° C, and the molar ratio of the compound of formula 7 to base is from 1:2.5 to 3.5.

In some of the embodiments, the reaction temperature of the reaction solvent in the step (h) is from -5 to 15 ° C, and the molar ratio of the compound of the formula 8 to the reducing agent is from 1:1 to 1.3.

In some of these embodiments, the temperature of the reaction in step (i) is from 20 to 30 ° C, and the molar ratio of the compound of the formula 9, acid to oxidizing agent is from 1:0.8 to 1.5:0.8 to 1.5.

In some of the embodiments, the temperature of the Baeyer-Villiger oxidative rearrangement reaction in the step (j) is 55 to 75 ° C, and the molar ratio of the compound, the base and the peroxide of the formula 10 is 1:2 to 3.5. : 5 to 8.

In some of the embodiments, the reaction temperature of the epoxidation reaction in the step (k) is -10 to 10 ° C, and the molar ratio of the compound of the formula 11 to the catalyst and the oxidizing agent is 1:0.03 to 0.06:1 to 1.5. .

It can be understood that, in the above method for synthesizing entecavir, entecavir can be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any one of steps (a) to (n) as a raw material. For example, entecavir can be prepared using the compound of formula 7 as a starting material and carrying out steps (g) to (o) as described above, or using the compound of formula 8 as a starting material and carrying out steps (h) to (o) as described above. To prepare entecavir.

It will be appreciated that the corresponding entecavir intermediate described above can be synthesized using the corresponding steps in the above synthetic entecavir process. For example, the intermediate 4 can be synthesized by the step (c), and the intermediate 8 can be synthesized by using the steps (c) to (g), and the intermediate 10 can be synthesized by the steps (c) to (i), and the step (c)- can be employed. j) Synthesis of intermediate 11 and the like. It is also understood that the above entecavir intermediate can be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any of the steps (a) to (j) as a raw material. For example, the intermediate 11 can be prepared by using the compound of the formula 7 as a raw material and carrying out the steps (g) to (j) as described above, or using the compound of the formula 8 as a raw material and carrying out the steps (h) to (as described above). j) to prepare intermediate 11.

The entecavir intermediate of the present invention and its synthesis method and the synthesis method of entecavir have the following advantages and beneficial effects:

The present invention produces a series of new entecavir intermediates, and provides an optimized synthesis method for intermediates. These intermediates can be used to prepare entecavir in high yield. The method for synthesizing entecavir and its intermediate of the invention has the advantages of chiral controllability, high yield and high product purity, and the obtained intermediate and entecavir finished product have high optical purity (100% ee), and the raw material source Wide range, reagents are cheap and easy to obtain, simple to react, easy to operate, green and environmentally friendly, suitable for industrial scale production.

Detailed ways

The entecavir intermediate of the present invention, a method for synthesizing the same, and a method for synthesizing entecavir are further illustrated by the following specific examples. The following examples are provided for the purpose of better understanding of the invention and are not intended to limit the scope of the invention in any way.

Example 1 Preparation of Intermediate Compound 4

Step (a): To a 50 L autoclave, dextrocarvone [(+)-carvone] (3.00 kg, 19.97 mol, 1.00 eq) and methanol (15 L) were added, stirred for 8 minutes, and cooled to 0 °C. Hydrogen peroxide solution (2.49 kg, 30% wt, 21.97 mol, 1.10 eq) was added dropwise with NaOH solution (1 L, 4 mol/L, 3.99 mol, 0.20 eq), and the internal temperature of the dropwise addition process did not exceed 5 °C. After the completion of the dropwise addition, the mixture was further stirred at 0 to 5 ° C for about 10 hours. After TLC monitoring, anhydrous sodium sulfite solid (0.60 kg) was added and the mixture was stirred for 0.5 hour. After testing the non-oxidizing property with the starch potassium iodide test paper, the reaction liquid was concentrated under reduced pressure and methanol was recovered, and the remaining liquid was added with water (5 L) and dichloromethane (15 L), stirred for 20 minutes, and then separated, and the aqueous layer was extracted with dichloromethane (10L) ×2), the organic layer was combined, washed with a saturated sodium chloride solution (5 L), and the organic layer was concentrated under reduced pressure and dichloromethane was evaporated, and the residue was dissolved in petroleum ether (16 L). (0.50 kg)] The mixture was filtered under reduced pressure and washed with EtOAc EtOAc EtOAc (EtOAc (EtOAc) ), R _f = 0.54 (petroleum ether / ethyl acetate = 10:1).

[α] _D = -60.7° (c = 1.03, MeOH);

_{^{1 H NMR (500MHz, CDCl 3}} ) δ4.78 (s, 1H), 4.71 (s, 1H), 3.43 (d, J = 2.6Hz, 1H), 2.71 (td, J = 11.2,5.3Hz, 1H) , 2.58 (dd, J = 17.6, 4.5 Hz, 1H), 2.36 (d, J = 14.8 Hz, 1H), 2.02 (dd, J = 17.6, 11.6 Hz, 1H), 1.93 - 1.84 (m, 1H), 1.70(s,3H), 1.40(s,3H);

¹³ C NMR (126 MHz, CDCl ₃ ) δ 205.5, 146.5, 110.6, 61.5, 58.9, 41.9, 35.2, 28.9, 20.7, 15.4.

Step (b): Compound 2 (4.10 kg, 24.67 mol, 1 eq) and tetrahydrofuran (20 L) were added to a 50 L reactor, stirred for 8 minutes, and cooled to 2 °C. Anhydrous lithium chloride (0.93 kg, 21.97 mol, 0.89 eq) was added, followed by dropwise addition of trifluoroacetic acid (2.51 kg, 21.97 mol, 0.89 eq), and the internal temperature of the dropwise addition was 0 to 10 °C. After the dropwise addition, the temperature was gradually raised to room temperature and stirring was continued for about 8 hours, and sodium bicarbonate solution (1.8 kg of sodium hydrogencarbonate dissolved in 10 L of water) was added to neutralize, and after stirring at pH 7-8, stirring was continued for 0.5 hour. The tetrahydrofuran was recovered under reduced pressure, and the residue was evaporated to ethyl acetate (20L). The organic layers were combined and washed with a saturated sodium chloride solution (10L×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. R _f = 0.23 (petroleum ether / ethyl acetate = 10:1).

[α] _D = -123.2 ° (c = 1.95, MeOH);

_{^{1 H NMR (500MHz, CDCl 3}} ) δ4.84-4.81 (m, 1H), 4.79 (s, 1H), 4.29-4.24 (m, 1H), 3.04 (t, J = 13.4Hz, 1H), 2.83 ( Tt, J = 12.8, 3.7 Hz, 1H), 2.49 - 2.35 (m, 2H), 1.92 (ddd, J = 14.2, 5.5, 3.5 Hz, 1H), 1.76 (s, 3H), 1.67 (s, 3H) ;

¹³ C NMR (126 MHz, CDCl ₃ ) δ 204.8, 146.6, 110.8, 77.2, 68.2, 41.3, 39.2, 33.1, 22.2, 20.5.

Step (c): To a 50 L reactor was added compound 3 (4.50 kg, 22.22 mol, 1 eq) and dichloromethane (12 L), stirred for 8 minutes, cooled to 18 ° C, and added 4-dimethylaminopyridine (4.39 kg, 35.97 mol, 1.61 eq). P-toluenesulfonyl chloride (5.71 kg, 29.97 mol, 1.35 eq) was dissolved in dichloromethane (12 L) and added dropwise to the reaction vessel. The internal temperature of the dropwise addition process was 15 to 25 °C. After the completion of the dropwise addition, the mixture was moved to room temperature and stirring was continued for about 12 hours. To the reaction vessel, tap water (15 L) was added to the mixture, and the organic layer was washed with dilute hydrochloric acid (2 to 3%, 15 L) and tap water (15 L), and the organic layer was dried over anhydrous sodium sulfate. weight. The residue was added to methanol (20 L) and stirred and crystallized at 0 to 5 ° C for about 8 hours. Filtration under reduced pressure, the crystals were washed with cold methanol and dried in vacuo to give a white solid, Compound 4 (4.25 kg, yield: 53.6%), and a three-step yield of 59.6%, purity 98% and 100%. %ee[HPLC purity detection chromatographic conditions: C18 column, 5 μm, 4.6 × 250 mm, mobile phase water - acetonitrile = 10:90, flow rate 0.5 mL / min, detection wavelength 227 nm, t _R = 9.64 min; enantiomeric detection conditions: OD column, 5 μm, 4.6×250 mm, mobile phase water-methanol = 15:85, flow rate 0.2 mL/min, detection wavelength 227 nm, t _R (enantiomer 4) = 37.4 min, t _R (4) = 40.6 min] . R _f = 0.54 (petroleum ether / ethyl acetate = 10:1).

[α] _D = -75.15° (c = 0.83, CH ₂ Cl ₂ );

_{^{1 H NMR (500MHz, CDCl 3}} ) δ7.77 (d, J = 8.3Hz, 2H), 7.35 (d, J = 8.0Hz, 2H), 5.03 (dd, J = 3.0,2.1Hz, 1H), 4.79 (s, 1H), 4.69 (s, 1H), 2.97 (t, J = 13.8 Hz, 1H), 2.66 (tt, J = 13.1, 3.4 Hz, 1H), 2.45 (s, 3H), 2.42 - 2.34 ( m, 2H), 2.03 (ddd, J = 14.8, 5.5, 3.3 Hz, 1H), 1.65 (s, 3H), 1.47 (s, 3H);

¹³ C NMR (126 MHz, CDCl ₃ ) δ 201.8, 145.62, 145.58, 133.8, 130.2, 127.9, 111.1, 85.3, 65.7, 40.8, 38.8, 31.2, 22.2, 21.8, 20.3.

Example 2 Preparation of Intermediate Compound 7

Step (d): Compound 4 (4.20 kg, 11.77 mol, 1.00 eq) and dichloromethane (21 L) were added to a 50 L reactor, and the mixture was cooled to 18 ° C with stirring. m-Chloroperoxybenzoic acid (2.63 kg, 85%, 12.95 mol, 1.10 eq) was added to the reaction vessel at intervals of four times for 30 minutes. After the addition, the mixture was allowed to warm to room temperature and stirred for 5 hours. The reaction solution was cooled to 0 to 5 ° C, stirred for 1.5 hours, and the reaction mixture was filtered under reduced pressure. The filter cake was washed with cold dichloromethane (5 L), and the filtrate was slowly added to saturated sodium hydrogen carbonate solution (5 L), and stirred for 30 minutes. The aqueous layer was extracted with dichloromethane (10 L). EtOAc (EtOAc) The white solid compound 5 (4.61 kg, yield: 105.1%), _Rf = 0.14 ( petroleum ether / ethyl acetate = 10:1).

[α] _D = -56.9° (c = 0.68, MeOH);

¹ H NMR (500MHz, CDCl ₃ ) δ 7.76 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 5.05 - 4.99 (m, 1H), 2.86 (td, J = 13.9, 9.9 Hz, 1H), 2.63 (d, J = 4.4 Hz, 0.5H), 2.54 (d, J = 4.4 Hz, 0.5H), 2.53 (s, 1H), 2.45 (s, 3H), 2.44 - 2.27 (m, 2H), 2.16 - 1.96 (m, 2H), 1.45 (s, 3H), 1.25 (s, 1.5H), 1.24 (s, 1.5H);

¹³ C NMR (126MHz, CDCl ₃ ) δ 201.1, 201.0, 145.70, 145.68, 133.6, 133.5, 130.2, 127.94, 127.89,84.9,84.8,65.61,65.55,57.65,57.60,52.7,52.6,37.7,37.6,37.6,37.5 , 28.4, 28.0, 22.2, 21.8, 18.6, 18.3.

Step (e): To a 50 L reactor, add compound 5 (4.61 kg, 12.36 mol, 1 eq) and tetrahydrofuran (23 L), stir, and add sulfuric acid solution at room temperature (1.15 kg concentrated sulfuric acid diluted with 4.6 L water, 11.78 mol, 0.95 Eq), after completion, was stirred at room temperature for 12 hours. The reaction mixture was slowly neutralized by adding sodium hydrogencarbonate solid (2.1 kg) to a pH of 7 to 8, and stirred for 30 minutes. Filtration under reduced pressure, the filter cake was washed with THF, EtOAc (EtOAc) The organic layer was washed with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to afford compound 6 (5.10 kg, yield: 105.6%). .

Step (f): Compound 6 was dissolved in dichloromethane (15 L) and transferred to a 50 L reactor and stirred at room temperature. p-Toluenesulfonic acid monohydrate (0.10 kg, 0.53 mol, 0.043 eq) and 2,2-dimethoxypropane (1.49 kg, 14.36 mol, 1.16 eq) were added, and the mixture was stirred at room temperature for 1 hour. Saturated sodium carbonate solution (2 L) was slowly added and stirred for 30 minutes. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The concentrate was added to methanol (12 L) and stirred at 0 to 5 ° C for 5 hours. Filtration under reduced pressure, the filter cake was washed with cold methanol (5L), and dried in vacuo to give white solid compound 7 (3.40 kg, yield: 95.7%). (HPLC purity check chromatographic conditions: C18 column, 5 μm, 4.6 × 250 mm, mobile phase water - acetonitrile = 10:90, flow rate 0.5 mL / min, detection wavelength 227 nm, t _R = 9.14 min), R _f = 0.21 (petroleum ether) /ethyl acetate = 10:1).

[α] _D = -61.2 ° (c = 1.22, CH ₂ Cl ₂ );

¹ H NMR (500MHz, CDCl ₃ ) δ 7.80 - 7.73 (m, 2H), 7.39 - 7.32 (m, 2H), 5.07 (s, 0.6H), 5.03 (s, 0.4H), 3.76 (d, J) = 8.8 Hz, 0.6H), 3.64 (d, J = 8.4 Hz, 0.4H), 3.69 - 3.59 (m, 1H), 2.88 (t, J = 13.8 Hz, 0.4H), 2.87 (t, J = 13.7) Hz, 0.6H), 2.50 (d, J = 14.3 Hz, 0.4H), 2.45 (s, 3H), 2.39 - 2.09 (m, 3.2H), 1.87 (d, J = 14.4 Hz, 0.4H), 1.50 (s, 1.2H), 1.48 (s, 1.8H), 1.36 (s, 3H), 1.33 (s, 1.8H), 1.31 (s, 1.2H), 1.21 (s, 1.8), 1.19 (s, 1.2) );

¹³ C NMR (126MHz, CDCl ₃ ) δ 202.0, 201.7, 145.64, 145.56, 133.78, 133.76, 130.23, 130.18,127.9,109.89,109.85,85.2,85.1,81.6,72.8,72.6,65.7,65.6,40.2,40.1,37.9 , 37.2, 27.9, 27.3, 26.9, 26.83, 26.78, 22.5, 22.4, 22.21, 22.19, 21.8.

Example 3 Preparation of Intermediate Compound 10 (R is methyl)

Step (g): Compound 7 (3.4 kg, 7.88 mol, 1.00 eq) and methyl tert-butyl ether (34 L) and methanol (6.8 L) were added to a 100 L reactor, stirred, and cooled to 0 to 5 °C. A methanol solution of sodium methoxide (4.55 kg, 30% by weight, 25.25 mol, 3.20 eq) was added dropwise, and the internal temperature was controlled to not exceed 5 °C. After the dropwise addition, the mixture was slowly warmed to room temperature and stirred for 20 hours. The reaction solution was cooled to 5 to 10 ° C, and ice water (17.5 L) was slowly added dropwise. The mixture was separated, and the aqueous layer was extracted with EtOAc (EtOAc). The filtrate was concentrated under reduced pressure. The concentrate was dissolved in petroleum ether (8 L), EtOAc (EtOAc m.) Compound 8 (2.08 kg, yield: 100%), R _f = 0.41 ( petroleum ether / ethyl acetate = 10:1).

[α] _D = +127.7° (c = 0.69, MeOH);

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.47 - 5.39 (m, 1H), 3.81 (t, J = 8.7 Hz, 1H), 3.705 (s, 1.8H), 3.700 (s, 1.2H), 3.70 - 3.66 (m, 1H), 3.43–3.36 (m, 0.4H), 3.36–3.29 (m, 0.6H), 3.00–2.88 (m, 1H), 2.60–2.44 (m, 1H), 2.22–2.06 (m) , 1H), 1.67 (s, 1.2H), 1.65 (s, 1.8H), 1.38 (s, 1.8H), 1.37 (s, 1.8H), 1.36 (s, 1.2H), 1.35 (s, 1.2H) ), 1.26 (s, 1.8H), 1.22 (s, 1.2H);

¹³ C NMR (126 MHz, CDCl ₃ ) δ 175.7, 175.5, 137.5, 137.3, 127.5, 127.4, 109.54, 109.47, 82.9, 73.3, 72.3, 56.5, 56.1, 51.93, 51.91, 50.3, 50.2, 34.5, 34.3, 27.2, 27.1 , 27.0, 26.9, 24.5, 22.4, 15.31, 15.27.

Step (h): A 50 L reactor was charged with tetrahydrofuran (18 L), stirred, cooled to 5 ° C, and lithium aluminum hydride (0.33 kg, 8.67 mol, 1.10 eq) was slowly added under a nitrogen stream. An intermediate compound 8 (2.08 kg, 7.88 mol, 1 eq) in tetrahydrofuran (2 L) was added dropwise to the reaction vessel, and the internal temperature of the dropping process was 5 to 10 °C. After the dropwise addition, stirring was continued at 5 to 10 ° C for 2 hours. A saturated sodium sulfate solution (1.32 L) was slowly added dropwise, and the mixture was stirred at room temperature for 0.5 hour. Filtration under reduced pressure, the filter cake was washed with tetrahydrofuran (6L×3), and the filtrate was concentrated under reduced pressure to a total volume of about 18 L to obtain a solution of the compound 9 in tetrahydrofuran, which was directly used for the next reaction.

Step (i): The tetrahydrofuran solution of the compound 9 was transferred to a 50 L reactor, stirred at room temperature, and a sulfuric acid solution (3.86 L, 20%, 7.88 mol, 1.00 eq) was added thereto, and the mixture was stirred at room temperature for 5 hours. Water (15 L) was added, and the pH was adjusted to 7-8 with sodium bicarbonate solid (1.3-1.5 kg). Sodium periodate (1.68 kg, 7.88 mol, 1.00 eq) was added slowly in portions, and after completion, stirring was continued at room temperature for 2 hours. Filter under reduced pressure and the filter cake was washed with tetrahydrofuran (3L). The filtrate was transferred to a reaction kettle, stirred, and anhydrous sodium sulfite (1.49 kg) was added and stirred for 0.5 hours (starch KI test paper tested for no oxidation). The organic layer was washed with saturated sodium chloride (10 L). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. Purification by chromatography (petroleum ether: ethyl acetate = 10:1 to 5:1) to afford compound 10 (yield: 91.8%) as a pale yellow oil. . R _f = 0.57 (petroleum ether / ethyl acetate = 1:1).

[α] _D = +105.7° (c = 1.42, MeOH);

_{^{1 H NMR (500MHz, CDCl 3}} ) δ5.35 (s, 1H), 3.80-3.71 (m, 1H), 3.65-3.57 (m, 1H), 3.18 (dt, J = 9.7,6.2Hz, 1H), 2.98(s,1H), 2.62 (ddd, J=11.7, 10.8, 1.8 Hz, 1H), 2.50–2.39 (m, 1H), 2.19 (s, 3H), 1.68 (s, 3H);

¹³ C NMR (126 MHz, CDCl ₃ ) δ 210.4, 138.3, 124.8, 63.9, 54.4, 52.5, 34.3, 28.4, 14.7.

Example 4 Preparation of Intermediate Compound 11

Step (j): In a 50 L reactor equipped with a reflux condenser, a compound 10 (1.12 kg, 7.26 mol, 1.00 eq) and methanol (40 L) were added, and stirred at room temperature, and a hydrogen peroxide solution (1.86 kg, 30) was slowly added. %wt, 16.41mol, 2.26eq), added in about 30 minutes, heated to an internal temperature of 60 ° C, then added sodium hydroxide solution (2.53L, 2.5mol / L, 6.25mol, 0.86eq) to the reactor After 80 minutes, the internal temperature was maintained at 65-70 ° C and stirred for 0.5 hours. At this temperature, hydrogen peroxide solution (1.87 kg, 30% wt, 16.41 mol, 2.26 eq) and sodium hydroxide were separately added. The solution (2.53 L, 2.5 mol/L, 6.25 mol, 0.86 eq) was repeated three times and the reaction was monitored by TLC. After the disappearance of the starting material 10, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. Filtration under reduced pressure, the filtrate was added triphenylphosphine (0.70 kg), stirred for 2 hr, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl ether: ethyl acetate = 10:1 to 1:2) Light yellow solid compound 11 (0.42 kg), yield 45%. R _f =0.19 (petroleum ether / ethyl acetate = 1:1).

[α] _D = +98.1° (c = 2.63, MeOH);

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.41 - 5.32 (m, 1H), 4.38 (dt, J = 7.1, 3.7 Hz, 1H), 3.84 (dd, J = 10.7, 3.9 Hz, 1H), 3.50 ( Dd, J = 10.7, 7.6 Hz, 1H), 2.83 (brs, 2H), 2.69 - 2.59 (m, 1H), 2.59 - 2.51 (m, 1H), 2.26 - 2.14 (m, 1H), 1.69 (s, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 137.6, 124.5, 76.6, 63.2, 59.8, 41.1, 15.3.

Example 5 Synthesis of Intermediate Compound 12

Step (k): A 10 L reactor was charged with compound 11 (0.42 kg, 3.28 mol, 1.00 eq) and dichloromethane (4.20 L), stirred, cooled to -5 to 0 ° C, and added with bis(acetylacetone) vanadium oxide ( 40 g, 0.15 mol, 0.046 eq). A solution of m-tert-butanol in dichloromethane [0.52 kg of a 70% wt aqueous solution of t-butanol (4.0 mol, 1.22 eq) was extracted with dichloromethane (0.8 L). , Filtration] was added dropwise to the reaction vessel, and the internal temperature of the dropping process was controlled to not exceed 5 ° C, and the mixture was continuously stirred at 0 to 5 ° C for 5 hours. Anhydrous sodium sulfite (0.3 kg) was added, and the mixture was stirred for 3 hr. EtOAc (EtOAc m. 12 (0.45 kg, yield: 95.7%), R _f = 0.11 ( petroleum ether / ethyl acetate = 1:1).

[α] _D = +38.9° (c = 1.81, MeOH);

_{^{1 H NMR (500MHz, CDCl 3}} ) δ4.00 (dd, J = 11.6,6.0Hz, 1H), 3.76 (d, J = 10.6Hz, 1H), 3.58-3.51 (m, 1H), 3.45 (s, 1H), 2.57 (d, J = 11.8 Hz, 1H), 2.17 - 2.11 (m, 2H), 2.00 (d, J = 15.2 Hz, 1H), 1.48 (s, 3H);

¹³ C NMR (126 MHz, CDCl ₃ ) δ 74.0, 66.2, 64.3, 61.6, 54.8, 37.6, 15.6.

Example 6 Synthesis of Entecavir

1. Preparation of intermediate compound 14 (R1=R2=TBS)

Step (l): Compound 12 (0.45 kg, 3.12 mol) and N,N-dimethylformamide (4 L), imidazole (0.49 kg, 7.21 mol, 2.31 eq), 4-dimethyl group were sequentially added to a 50 L reactor. Aminopyridine (40 g, 0.33 mol, 0.11 eq), stirred, cooled to an internal temperature of 10 to 15 ° C, tert-butyldimethylsilyl chloride (1.04 kg, 6.88 mol, 2.21 eq) was added to the reaction in 4 minute intervals for 20 minutes. The kettle was added and the mixture was stirred at room temperature for 12 hours. Methyl tert-butyl ether (8 L) and water (8 L) were added, and the mixture was evaporated. Filtration under reduced pressure, the filtrate was evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj wash. The filtrate was concentrated under reduced pressure. EtOAc _m . 0.69 (petroleum ether / ethyl acetate = 10:1).

[α] _D = +31.5° (c = 1.31, MeOH);

_{^{1 H NMR (500MHz, CDCl 3}} ) δ4.27 (d, J = 7.6Hz, 1H), 3.68 (d, J = 3.6Hz, 2H), 3.25 (s, 1H), 2.10 (ddd, J = 14.6, 7.6, 1.4 Hz, 1H), 2.02 (s, 1H), 1.83 (d, J = 14.6 Hz, 1H), 1.41 (s, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.050 ( s, 3H), 0.054 (s, 3H), 0.03 (s, 6H);

¹³ C NMR (126 MHz, CDCl ₃ ) δ 76.5, 66.0, 64.8, 62.6, 55.3, 39.0, 26.0, 25.8, 18.2, 18.1, 16.1, -4.4, -4.5, -5.6, -5.7.

Step (m): In a 20 L four-neck reaction flask, 2,2,6,6-tetramethylpiperidine (0.48 kg, 3.42 mol, 1.30 eq) and toluene (8 L) were added under nitrogen, stirred, and cooled to - 8 ° C. A n-hexane solution of n-butyllithium (1.37 L, 2.5 mol/L, 3.42 mol, 1.30 eq) was added dropwise, and the internal temperature during the dropwise addition did not exceed 0 ° C. After about 2 hours, the dropwise addition was completed, and the temperature was maintained at -10 to 0. Stir at °C for 1 hour. A solution of diethylaluminum chloride in n-hexane (1.71 L, 2.0 mol/L, 3.42 mol, 1.30 eq) was added dropwise, and the internal temperature during the dropwise addition did not exceed 0 ° C. After about 2 hours, the mixture was dripped, and the mixture was maintained at -10. Stir at ~0 °C for 1.5 hours. A solution of the compound 13 (0.98 kg, 2.63 mol, 1.0 eq) in toluene (2 L) was added dropwise to the reaction flask, and the mixture was dropped over 2 hours, and the mixture was stirred at -5 to 0 ° C for 3 hours. Saturated sodium potassium tartrate solution (0.6 L) was slowly added dropwise, and the mixture was stirred for 1 hour, filtered under reduced pressure, and the filtered cake was washed with ethyl acetate (5 L), and the combined filtrate was washed with water (3L×3). The organic layer was concentrated under reduced pressure. EtOAcjjjjjjjjj %ee)[Enantiomeric detection conditions: OD column, 5 μm, 4.6×250 mm, mobile phase water-acetonitrile=20:80, flow rate 0.3 mL/min, detection wavelength 211 nm, t _R (enantiomer-14)=16.27 Min, t _R (14) = 18.46 min], the intermediate step 11 was used to calculate a yield of 74.5%. R _f = 0.43 (petroleum ether / ethyl acetate = 10:1).

[α] _D = -51.9° (c = 1.07, MeOH);

_{^{1 H NMR (500MHz, CDCl 3}} ) δ5.38 (s, 1H), 5.13 (s, 1H), 4.38-4.30 (m, 2H), 3.57 (dd, J = 10.2,5.1Hz, 1H), 3.32 ( t, J = 9.3 Hz, 1H), 2.88 (d, J = 10.5 Hz, 1H), 2.80 - 2.71 (m, 1H), 1.99 (dt, J = 13.5, 4.9 Hz, 1H), 1.82 (d, J) =13.6 Hz, 1H), 0.89 (s, 18H), 0.09 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H);

¹³ C NMR (126 MHz, CDCl ₃ ) δ 154.6, 111.8, 75.7, 75.5, 64.9, 55.2, 42.3, 26.1, 26.0, 18.5, 18.1, -4.6, -4.7, -5.3, -5.4.

2. Preparation of intermediate compound 15

Step (n): In a 2 L four-neck reaction flask, compound 14 (180 g, 0.483 mol, 1.00 eq), compound 16 (169 g, 0.700 mol, 1.45 eq), triphenylphosphine (253 g, 0.966 mol, 2.00 eq) and dry tetrahydrofuran (1.8 L), stirred, and the internal temperature dropped to 0 to 5 °C. Diisopropyl azodicarboxylate (169 g, 0.966 mol, 2.00 eq) was added dropwise, the internal temperature was controlled to not exceed 5 ° C, and the mixture was stirred at 0 to 5 ° C for 2 to 3 hours. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc) (EtOAc) 1. 2 L), the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (ethyl ether-ethyl acetate=20:1 to 10:1) to give pale yellow foamy compound 15 (235 g) ), the yield was 81.6%. R _f =0.68 (petroleum ether / ethyl acetate = 2:1).

[α] _D = +17.6° (c = 1.00, MeOH);

^{1 H NMR (400MHz, Chloroform-} d) δ7.65 (s, 1H), 7.51 (d, J = 7.36Hz, 2H), 7.39-7.27 (m, 3H), 5.56 (s, 2H), 5.51 (t , J = 8.08 Hz, 2H), 5.16 (s, 1H), 4.84 (s, 2H), 4.83 (d, J = 2.6 Hz, 1H), 4.47 - 4.38 (m, 1H), 3.84 - 3.71 (m, 2H), 2.66 (s, 1H), 2.28 (td, J = 11.38, 9.24, 4.84 Hz, 1H), 2.21 - 2.12 (m, 1H), 0.92 (s, 9H), 0.90 (s, 9H), 0.11 –0.04(m,12H).

¹³ C NMR (126 MHz, Chloroform-d) δ 161.1, 159.1, 154.5, 149.4, 138.9, 136.7, 128.49, 128.45, 128.1, 115.8, 111.2, 72.5, 68.1, 64.2, 56.0, 54.9, 40.6, 26.2, 26.0, 18.6, 18.2, -4.4, -4.6, -5.2, -5.3.

3. Preparation of entecavir 1

Step (o): In a 2L three-neck reaction flask equipped with a reflux condenser, compound 15 (200 g, 0.335 mol, 1.00 eq) and tetrahydrofuran (1.34 L) were added, and the mixture was stirred at room temperature, and diluted hydrochloric acid (1.34 L, 2.5) was added. Mol/L, 3.360 mol, 10.00 eq), heated to an internal temperature of 55 ° C and stirred for 6 hours. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and the aqueous mixture was extracted with ethyl acetate (0.5L×3). The water layer was cooled to 5-10 ° C, neutralized with sodium hydroxide solution (6 mol / L, about 0.6 L), adjusted to pH 7 ~ 7.5, stirred for 5 hours, crystallized, filtered under reduced pressure, and filtered cake with cold water (300 ml) and 95 respectively. Wash with % ethanol (200 ml) and collect the solid. The filtrate was concentrated under reduced pressure at 70-75 ° C to a volume of 300-400 ml. The mixture was stirred for 10 hours, crystallized, filtered under reduced pressure, and the filter cake was rinsed with cold water (150 ml) and 95% ethanol (100 ml), and the solids were collected and combined, vacuum at 45 ° C Drying for 5 hours gave entecavir crude (86 g), purity 98%, 100% ee. The crude product was recrystallized from pure water to give entecavir monohydrate (72 g), HPLC purity >99.7%, single <0.1%, yield 77.3%. [HPLC chromatographic conditions: C18 column, 5 μm, 4.6 × 250 mm, mobile phase A is acetonitrile-water (3:97), mobile phase B is acetonitrile, gradient is 0-8 min, 100% A; 8-25 min, 100→70 %A; 25-30 min, 70→20% A; 30-32 min, 20→10% A; 32-55 min, 10% A; 55-56 min, 10→100% A; 56-65 min, 100% A. Flow rate 1.0 mL/min, detection wavelength 254 nm, t _R (entecavir) = 15.8 min; enantiomeric detection conditions: AD column, 5 μm, 4.6 × 250 mm, mobile phase: n-hexane: ethanol: methanol: triethylamine (60: 20:20:0.1), flow rate 1.0 mL/min, detection wavelength 254 nm, t _R (enantiomer) = 8.1 min, t _R (entecavir) = 12.9 min].

^{1 H NMR (500MHz, DMSO)} δ10.55 (s, 1H), 7.65 (s, 1H), 6.40 (s, 2H), 5.36 (dd, J = 10.3,8.0Hz, 1H), 5.10 (s, 1H ), 4.85 (d, J = 3.1 Hz, 1H), 4.81 (t, J = 5.3 Hz, 1H), 4.56 (s, 1H), 4.23 (s, 1H), 3.54 (t, J = 6.1 Hz, 2H) ), 2.55–2.50 (m, 1H), 2.26–2.17 (m, 1H), 2.04 (dd, J=12.5, 7.8 Hz, 1H);

¹³ C NMR (126 MHz, DMSO) δ 156.8, 153.4, 151.4, 151.3, 135.9, 116.2, 109.2, 70.4, 63.0, 55.1, 54.1, 39.2.

The technical features of the above-described embodiments may be arbitrarily combined. For the sake of brevity of description, all possible combinations of the technical features in the above embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be considered as the scope of this manual.

The above-described embodiments are merely illustrative of several embodiments of the present invention, and the description thereof is more specific and detailed, but is not to be construed as limiting the scope of the invention. It should be noted that a number of variations and modifications may be made by those skilled in the art without departing from the spirit and scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.

Claims (20)

An entecavir intermediate or intermediate composition for the preparation of entecavir, characterized in that the entecavir intermediate or intermediate composition is selected from at least one of the following compounds:

Wherein R is a methyl group or an ethyl group. A method for synthesizing an entecavir intermediate having the structure shown in Formula 10, comprising the steps of: (c) a compound of formula 3 is reacted with an esterification reagent in the presence of a base to form a compound of formula 4; (d) a compound of formula 4 is epoxidized in the presence of an epoxidizing reagent to form a compound of formula 5; (e) a compound of formula 5 undergoes an epoxy ring opening reaction under the action of an acid to form a compound of formula 6; (f) a compound of formula 6 is subjected to an acetone reaction of a hydroxy group with an acetonide protecting reagent under the action of an acid catalyst to form a compound of formula 7; (g) a compound of formula 7 undergoes a Favorskii rearrangement reaction under the action of a base to form a compound of formula 8; (h) a compound of formula 8 is subjected to a reduction reaction under the action of a reducing agent to form a compound of formula 9; (i) a compound of formula 9 is deprotected by acid catalysis, and then an oxidation reaction is carried out under the action of an oxidizing agent to form a compound of formula 10; The reaction formula is as follows:

Wherein R is a methyl group or an ethyl group. The method for synthesizing entecavir intermediates having the structure of formula 10 according to claim 2, further comprising the steps of: (a) dextro-carvone is epoxidized by the action of a base and an oxidizing agent to form a compound of formula 2; (b) a compound of formula 2 undergoes a chloro ring opening reaction under the action of an acid and a chlorinating reagent to form a compound of formula 3; The reaction formula is as follows:

The method for synthesizing entecavir intermediate having the structure of formula 10 according to claim 3, wherein the reaction solvent of the step (a) is methanol, the alkali is sodium hydroxide, and the oxidizing agent is hydrogen peroxide. The reaction temperature of the epoxidation reaction is -5 to 10 ° C, and the molar ratio of the dextrorotatory ketone, the alkali and the oxidizing agent is 1:0.1 to 0.3:0.8 to 1.4; and/or The reaction solvent of the step (b) is tetrahydrofuran, the acid is trifluoroacetic acid, the chlorinating reagent is anhydrous lithium chloride, and the reaction temperature of the chloro ring opening reaction is 0 to 35 ° C. The molar ratio of the compound, the acid and the chlorinating agent is from 1:0.8 to 2:0.8 to 2. The method for synthesizing the entecavir intermediate having the structure of the formula 10 according to any one of claims 2 to 4, wherein the reaction solvent of the step (c) is selected from the group consisting of dichloromethane and 1,2-dichloroethane. At least one of alkane, chloroform, water, ethyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, the base being selected from 4-dimethylaminopyridine, or 4-dimethylaminopyridine and other bases a combination of the esterification reagent is p-toluenesulfonyl chloride, the reaction temperature of the reaction is 0-50 ° C, the molar ratio of the compound of the formula 3, 4-dimethylaminopyridine, other base and p-toluenesulfonyl chloride It is 1:0.5~10:0~3:1~3; and/or, The reaction solvent in the step (d) is dichloromethane, the temperature of the epoxidation reaction is 0 to 40 ° C, and the epoxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, peracetic acid, and trifluoroperoxygen. a molar ratio of the compound of the formula 4 to the epoxidizing agent of at least one of acetic acid: 1:1 to 2; and/or The reaction solvent in the step (e) is a combination of water and an organic solvent, which is tetrahydrofuran and/or 1,4-dioxane, and the volume ratio of water to the organic solvent is 1:1 to 10, The acid is sulfuric acid, the temperature of the epoxy ring opening reaction is 0 to 50 ° C, and the molar ratio of the compound of the formula 5 to the acid is 1:0.5 to 2; and/or The reaction in the step (f) is carried out in the absence of a solvent, or the reaction solvent in the step (f) is dichloromethane, and the acetone-protecting reagent of the hydroxyl group is selected from 2,2-dimethoxypropane or acetone. The acid catalyst is selected from at least one of p-toluenesulfonic acid, camphorsulfonic acid and sulfuric acid, and the reaction temperature of the bishydroxyl group is 0 to 50 ° C. The compound of the formula 6 and the acetone of the hydroxyl group The molar ratio of the reagent to the acid catalyst is 1:1 to 5: 0.01 to 0.2; and/or The reaction solvent in the step (g) is an alcohol solvent or a combination of an alcohol solvent selected from the group consisting of methanol and ethanol, and the ether solvent is selected from the group consisting of diethyl ether and methyl tert-butyl ether. Tetrahydrofuran, 1,4-dioxane, the base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, and the reaction temperature of the Favorskii rearrangement reaction -20 to 50 ° C, the molar ratio of the compound of the formula 7 to the base is 1:2 to 5; and / or, The reaction solvent in the step (h) is selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, toluene, and 1,4-dioxane, and the reducing agent is selected from the group consisting of lithium aluminum hydride and dihydro bis (2-methoxy ethoxy). Sodium oxy)aluminate, diisobutylaluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, lithium triethylborohydride, the reaction temperature of the reduction reaction is -20 to 60 ° C, the formula The molar ratio of the compound of 8 to the reducing agent is 1:1 to 3; and/or The reaction solvent in the step (i) is selected from the group consisting of methanol, ethanol, tetrahydrofuran, 1,4 dioxane, water, and the acid is selected from the group consisting of p-toluenesulfonic acid, dilute hydrochloric acid, dilute sulfuric acid, and acetic acid, and the oxidizing agent is selected from the group consisting of The sodium iodate, periodic acid, lead tetraacetate, and potassium permanganate have a reaction temperature of 0 to 80 ° C, and the molar ratio of the compound of the formula 9 to the acid to the oxidizing agent is 1:0.1 to 2:0.8 to 3. A method for synthesizing an entecavir intermediate having the structure shown in Formula 12, which comprises the steps of: (j) a compound of formula 10 undergoes a Baeyer-Villiger oxidative rearrangement reaction under the action of a base and a peroxide to form a compound of formula 11; (k) a compound of formula 11 undergoes an epoxidation reaction under the action of a catalyst and an oxidizing agent to form a compound of formula 12; The reaction formula is as follows:

The method for synthesizing entecavir intermediates having the structure of formula 12 according to claim 6, comprising the steps of: (c) a compound of formula 3 is reacted with an esterification reagent in the presence of a base to form a compound of formula 4; (d) a compound of formula 4 is epoxidized in the presence of an epoxidizing reagent to form a compound of formula 5; (e) a compound of formula 5 undergoes an epoxy ring opening reaction under the action of an acid to form a compound of formula 6; (f) a compound of formula 6 is subjected to an acetone reaction of a hydroxy group with an acetonide protecting reagent under the action of an acid catalyst to form a compound of formula 7; (g) a compound of formula 7 undergoes a Favorskii rearrangement reaction under the action of a base to form a compound of formula 8; (h) a compound of formula 8 is subjected to a reduction reaction under the action of a reducing agent to form a compound of formula 9; (i) a compound of formula 9 is deprotected by acid catalysis, and then an oxidation reaction is carried out under the action of an oxidizing agent to form a compound of formula 10; (j) a compound of formula 10 undergoes a Baeyer-Villiger oxidative rearrangement reaction under the action of a base and a peroxide to form a compound of formula 11; (k) a compound of formula 11 undergoes an epoxidation reaction under the action of a catalyst and an oxidizing agent to form a compound of formula 12; The reaction formula is as follows:

Wherein R is a methyl group or an ethyl group. The method for synthesizing entecavir intermediates having the structure of formula 12 according to claim 7, further comprising the steps of: (a) dextro-carvone is epoxidized by the action of a base and an oxidizing agent to form a compound of formula 2; (b) a compound of formula 2 undergoes a chloro ring opening reaction under the action of an acid and a chlorinating reagent to form a compound of formula 3; The reaction formula is as follows:

The method for synthesizing entecavir intermediate having the structure of formula 12 according to claim 8, wherein the reaction solvent of the step (a) is methanol, the alkali is sodium hydroxide, and the oxidizing agent is hydrogen peroxide. The reaction temperature of the epoxidation reaction is -5 to 10 ° C, and the molar ratio of the dextrorotatory ketone, the alkali and the oxidizing agent is 1:0.1 to 0.3:0.8 to 1.4; and/or The reaction solvent of the step (b) is tetrahydrofuran, the acid is trifluoroacetic acid, the chlorinating reagent is anhydrous lithium chloride, and the reaction temperature of the chloro ring opening reaction is 0 to 35 ° C. The molar ratio of the compound, the acid and the chlorinating agent is from 1:0.8 to 2:0.8 to 2. The method for synthesizing the entecavir intermediate having the structure of the formula 12 according to any one of claims 6 to 9, wherein the reaction solvent in the step (j) is selected from the group consisting of methanol, ethanol, tert-butanol and isopropyl alcohol. An alcohol, the base being sodium hydroxide and/or potassium hydroxide, the peroxide being selected from the group consisting of hydrogen peroxide, a hydrogen peroxide complex, and peroxybutanol, the temperature of the Baeyer-Villiger oxidation rearrangement reaction 0 to 100 ° C, the molar ratio of the compound of the formula 10, the base and the peroxide is 1:1 to 20:1 to 20; and/or The reaction solvent in the step (k) is selected from the group consisting of dichloromethane, toluene, 1,2-dichloroethane, the catalyst is bis(acetylacetone) vanadium oxide, and the oxidizing agent is t-butanol peroxide, the ring The reaction temperature of the oxidation reaction is -25 to 25 ° C, and the molar ratio of the compound of the formula 11 and the catalyst to the oxidizing agent is 1:0.001 to 0.2:1 to 2. The method for synthesizing the entecavir intermediate having the structure of the formula 12 according to any one of claims 7 to 9, wherein the reaction solvent of the step (c) is selected from the group consisting of dichloromethane and 1,2-dichloroethane. At least one of alkane, chloroform, water, ethyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, the base being selected from 4-dimethylaminopyridine, or 4-dimethylaminopyridine and other bases a combination of the esterification reagent is p-toluenesulfonyl chloride, the reaction temperature of the reaction is 0-50 ° C, the molar ratio of the compound of the formula 3, 4-dimethylaminopyridine, other base and p-toluenesulfonyl chloride It is 1:0.5~10:0~3:1~3; and/or, The reaction solvent in the step (d) is dichloromethane, the temperature of the epoxidation reaction is 0 to 40 ° C, and the epoxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, peracetic acid, and trifluoroperoxygen. a molar ratio of the compound of the formula 4 to the epoxidizing agent of at least one of acetic acid: 1:1 to 2; and/or The reaction solvent in the step (e) is a combination of water and an organic solvent, which is tetrahydrofuran and/or 1,4-dioxane, and the volume ratio of water to the organic solvent is 1:1 to 10, The acid is sulfuric acid, the temperature of the epoxy ring opening reaction is 0 to 50 ° C, and the molar ratio of the compound of the formula 5 to the acid is 1:0.5 to 2; and/or The reaction in the step (f) is carried out in the absence of a solvent, or the reaction solvent in the step (f) is dichloromethane, and the acetone-protecting reagent of the hydroxyl group is selected from 2,2-dimethoxypropane or acetone. The acid catalyst is selected from at least one of p-toluenesulfonic acid, camphorsulfonic acid and sulfuric acid, and the reaction temperature of the bishydroxyl group is 0 to 50 ° C. The compound of the formula 6 and the acetone of the hydroxyl group The molar ratio of the reagent to the acid catalyst is 1:1 to 5: 0.01 to 0.2; and/or The reaction solvent in the step (g) is an alcohol solvent or a combination of an alcohol solvent selected from the group consisting of methanol and ethanol, and the ether solvent is selected from the group consisting of diethyl ether and methyl tert-butyl ether. Tetrahydrofuran, 1,4-dioxane, the base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, and the reaction temperature of the Favorskii rearrangement reaction -20 to 50 ° C, the molar ratio of the compound of the formula 7 to the base is 1:2 to 5; and / or, The reaction solvent in the step (h) is selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, toluene, and 1,4-dioxane, and the reducing agent is selected from the group consisting of lithium aluminum hydride and dihydro bis (2-methoxy ethoxy). Sodium oxy)aluminate, diisobutylaluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, lithium triethylborohydride, the reaction temperature of the reduction reaction is -20 to 60 ° C, the formula The molar ratio of the compound of 8 to the reducing agent is 1:1 to 3; and/or The reaction solvent in the step (i) is selected from the group consisting of methanol, ethanol, tetrahydrofuran, 1,4 dioxane, water, and the acid is selected from the group consisting of p-toluenesulfonic acid, dilute hydrochloric acid, dilute sulfuric acid, and acetic acid, and the oxidizing agent is selected from the group consisting of The sodium iodate, periodic acid, lead tetraacetate, and potassium permanganate have a reaction temperature of 0 to 80 ° C, and the molar ratio of the compound of the formula 9 to the acid to the oxidizing agent is 1:0.1 to 2:0.8 to 3. A method for synthesizing entecavir, comprising the steps of: (l) protecting a hydroxyl group in the compound of formula 12 to form a compound of formula 13; (m) a compound of formula 13 is subjected to an epoxy isomerization reaction with an epoxy isomerization reagent to form a compound of formula 14; (n) a compound of formula 14 is reacted with a compound of formula 16 under Mitsunobu reaction conditions to form a compound of formula 15; (o) a compound of formula 15 undergoes a hydrolysis reaction to remove a hydroxy protecting group and an amino protecting group to form a compound of formula 1, ie, entecavir; The reaction formula is as follows:

Wherein R1 and R2 are protecting groups for a hydroxy group, and R1 and R2 are each independently selected from the group consisting of: (1) silane group, (2) alkyl group, (3) alkoxymethyl group, (4) benzyl group. Oxymethyl and substituted benzyloxymethyl, (5) alkoxyethyl, (6) benzyl and phenyl ring substituted benzyl, (7) acyl, (8) alkoxy acyl, (9 ) siloxymethyl. The method for synthesizing entecavir according to claim 12, further comprising the steps of: (c) a compound of formula 3 is reacted with an esterification reagent in the presence of a base to form a compound of formula 4; (d) a compound of formula 4 is epoxidized in the presence of an epoxidizing reagent to form a compound of formula 5; (e) a compound of formula 5 undergoes an epoxy ring opening reaction under the action of an acid to form a compound of formula 6; (f) a compound of formula 6 is subjected to an acetone reaction of a hydroxy group with an acetonide protecting reagent under the action of an acid catalyst to form a compound of formula 7; (g) a compound of formula 7 undergoes a Favorskii rearrangement reaction under the action of a base to form a compound of formula 8; (h) a compound of formula 8 is subjected to a reduction reaction under the action of a reducing agent to form a compound of formula 9; (i) a compound of formula 9 is deprotected by acid catalysis, and then an oxidation reaction is carried out under the action of an oxidizing agent to form a compound of formula 10; (j) a compound of formula 10 undergoes a Baeyer-Villiger oxidative rearrangement reaction under the action of a base and a peroxide to form a compound of formula 11; (k) a compound of formula 11 undergoes an epoxidation reaction under the action of a catalyst and an oxidizing agent to form a compound of formula 12; The reaction formula is as follows:

Wherein R is a methyl group or an ethyl group. The method for synthesizing entecavir according to claim 12 or 13, wherein R1 and R2 are each independently selected from the group consisting of: trimethylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl , triethylsilyl, triisopropylsilyl, methyl, methoxymethyl, 2-methoxyethoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl , p-Nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl-2-yl, 1-ethoxy Ethyl ethyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, formyl, acetyl, benzoyl, p-phenylbenzoyl, methoxy An acyl group, an ethoxy group, a 9-fluorenyl methoxy group, a tert-butoxy group. The method for synthesizing entecavir according to claim 12 or 13, wherein the protecting the hydroxyl group in the compound of the formula 12 in the step (1) comprises: reacting the compound of the formula 12 with a hydroxy protecting reagent; R1 and R2 They are independently selected from the group consisting of: trimethylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl, methyl, methoxy , 2-methoxyethoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, p-nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, 2-(Trimethylsilyl)ethoxymethyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, formyl, acetyl, benzoyl , p-phenylbenzoyl, methoxy acyl, ethoxy acyl, 9-fluorenyl methoxy acyl, tert-butoxy acyl, the hydroxy protecting reagent is R 1 X and R 2 X, wherein X is a leaving group, X is selected from halogen or trifluoromethanesulfonate, and the compound of formula 12 is reacted with a hydroxy protecting reagent to react a compound of formula 12 with R1X and R2X in the presence of a base and/or a catalyst selected from three Ethylamine, diisopropylethylamine, imidazole, pyridine, sodium hydroxide, potassium hydroxide, sodium hydride, lithium hydride, sodium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide In at least one of the catalysts, the catalyst is selected from at least one of 4-dimethylaminopyridine, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, and tetrabutylammonium iodide; or R1 and R2 are each independently selected from tetrahydropyranyl-2-yl, the hydroxy protecting reagent is dihydropyran, and the compound of formula 12 is reacted with a hydroxy protecting reagent to form a compound of formula 12 under acid catalysis Reacting with dihydropyran, the acid is selected from p-toluenesulfonic acid, pyridine p-toluenesulfonate; or R1 and R2 are each independently selected from the group consisting of 1-ethoxyethyl, the hydroxy protecting reagent is ethyl vinyl ether, and the compound of formula 12 is reacted with a hydroxy protecting reagent to form a compound of formula 12 under acid catalysis. Reaction with ethyl vinyl ether selected from p-toluenesulfonic acid, pyridine p-toluenesulfonate; or The method for synthesizing entecavir according to claim 15, wherein the hydroxy protecting reagent in the step (1) is tert-butyldimethylchlorosilane, and the compound of the formula 12 is reacted with a hydroxy protecting reagent in a base. And the catalyst is carried out, the solvent of the reaction is selected from the group consisting of dichloromethane, N,N-dimethylformamide, the base is selected from the group consisting of triethylamine and imidazole, and the catalyst is 4-dimethylaminopyridine, and the reaction is carried out. The temperature is from 0 to 50 ° C, and the molar ratio of the compound of the formula 12, the base, the catalyst and the tert-butyldimethylsilyl chloride is from 1:2 to 3:0.05 to 0.2:2 to 3. The method for synthesizing entecavir according to claim 12 or 13, wherein the reaction solvent in the step (m) is selected from the group consisting of toluene, xylene, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, and the epoxy isomerism. The reagent is selected from lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, lithium complex of lithium diisopropylamide and diethylaluminum chloride in situ, 2,2 , an aluminum complex formed by lithium 6,6-tetramethylpiperidine and diethyl aluminum chloride in situ, aluminum isopropoxide, camphorsulfonic acid, p-toluenesulfonic acid, the epoxy isomerization reaction The reaction temperature is -25 to 110 °C. The method for synthesizing entecavir according to claim 17, wherein the reaction solvent in the step (m) is toluene, and the epoxy isomerization reagent is lithium 2,2,6,6-tetramethylpiperidine. The aluminum complex formed in situ with diethylaluminum chloride, the reaction temperature of the epoxy isomerization reaction is -10 to 5 ° C, and the molar ratio of the compound of the formula 13 to the epoxy isomerization reagent is 1:1~3. The method for synthesizing entecavir according to claim 12 or 13, wherein the molar ratio of the compound of the formula 14 to the compound of the formula 16 in the step (n) is 1:1 to 2; and/or; And R2 is a tert-butyldimethylsilyl group, and the reaction solvent of the hydrolysis reaction in the step (o) is tetrahydrofuran and water, and the hydrolysis reaction is carried out under the action of dilute hydrochloric acid at a reaction temperature of 10 to 70 ° C. . The method for synthesizing entecavir according to claim 12 or 13, wherein the reaction solvent of the step (c) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, water, and ethyl acetate. At least one of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, the base is selected from 4-dimethylaminopyridine, or a combination of 4-dimethylaminopyridine and another base, and the esterification reagent is p-toluene The acid chloride, the reaction temperature of the reaction is 0 to 50 ° C, and the molar ratio of the compound of the formula 3, 4-dimethylaminopyridine, other base and p-toluenesulfonyl chloride is 1:0.5 to 10:0 to 3:1. ～3; and/or, The reaction solvent in the step (d) is dichloromethane, the temperature of the epoxidation reaction is 0 to 40 ° C, and the epoxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, peracetic acid, and trifluoroperoxygen. a molar ratio of the compound of the formula 4 to the epoxidizing agent of at least one of acetic acid: 1:1 to 2; and/or The reaction solvent in the step (e) is a combination of water and an organic solvent, which is tetrahydrofuran and/or 1,4-dioxane, and the volume ratio of water to the organic solvent is 1:1 to 10, The acid is sulfuric acid, the temperature of the epoxy ring opening reaction is 0 to 50 ° C, and the molar ratio of the compound of the formula 5 to the acid is 1:0.5 to 2; and/or The reaction in the step (f) is carried out in the absence of a solvent, or the reaction solvent in the step (f) is dichloromethane, and the acetone-protecting reagent of the hydroxyl group is selected from 2,2-dimethoxypropane or acetone. The acid catalyst is selected from at least one of p-toluenesulfonic acid, camphorsulfonic acid and sulfuric acid, and the reaction temperature of the bishydroxyl group is 0 to 50 ° C. The compound of the formula 6 and the acetone of the hydroxyl group The molar ratio of the reagent to the acid catalyst is 1:1 to 5: 0.01 to 0.2; and/or The reaction solvent in the step (g) is an alcohol solvent or a combination of an alcohol solvent selected from the group consisting of methanol and ethanol, and the ether solvent is selected from the group consisting of diethyl ether and methyl tert-butyl ether. Tetrahydrofuran, 1,4-dioxane, the base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, and the reaction temperature of the Favorskii rearrangement reaction -20 to 50 ° C, the molar ratio of the compound of the formula 7 to the base is 1:2 to 5; and / or, The reaction solvent in the step (h) is selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, toluene, and 1,4-dioxane, and the reducing agent is selected from the group consisting of lithium aluminum hydride and dihydro bis (2-methoxy ethoxy). Sodium oxy)aluminate, diisobutylaluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, lithium triethylborohydride, the reaction temperature of the reduction reaction is -20 to 60 ° C, the formula The molar ratio of the compound of 8 to the reducing agent is 1:1 to 3; and/or The reaction solvent in the step (i) is selected from the group consisting of methanol, ethanol, tetrahydrofuran, 1,4 dioxane, water, and the acid is selected from the group consisting of p-toluenesulfonic acid, dilute hydrochloric acid, dilute sulfuric acid, and acetic acid, and the oxidizing agent is selected from the group consisting of Sodium iodate, periodic acid, lead tetraacetate, potassium permanganate, the reaction temperature is 0-80 ° C, the molar ratio of the compound of the formula 9, acid and oxidant is 1: 0.1 ~ 2: 0.8 ~ 3; And / or, The reaction solvent in the step (j) is selected from the group consisting of methanol, ethanol, tert-butanol, isopropanol, the base is sodium hydroxide and/or potassium hydroxide, and the peroxide is selected from the group consisting of hydrogen peroxide and hydrogen peroxide. The compound, peroxytert-butanol, the Baeyer-Villiger oxidative rearrangement reaction temperature is 0 to 100 ° C, and the molar ratio of the compound of the formula 10, the base and the peroxide is 1:1 to 20:1 20; and / or, The reaction solvent in the step (k) is selected from the group consisting of dichloromethane, toluene, 1,2-dichloroethane, the catalyst is bis(acetylacetone) vanadium oxide, and the oxidizing agent is t-butanol peroxide, the ring The reaction temperature of the oxidation reaction is -25 to 25 ° C, and the molar ratio of the compound of the formula 11 and the catalyst to the oxidizing agent is 1:0.001 to 0.2:1 to 2.