CN118063463A - Preparation method of entecavir - Google Patents

Abstract

The present invention relates to a method for preparing entecavir, belonging to the technical field of drug synthesis. The preparation method of the present invention comprises the following steps: (1) adding the aldehyde group of furfural by Grignard reaction to generate compound 1 (2) Compound 1 undergoes an asymmetric Piancatelli reaction under the action of a chiral Lewis acid catalyst to generate compound 2 (3) Compound 2 first undergoes Sharpless epoxidation reaction in the presence of an oxidant and a catalyst to generate an epoxide intermediate, and then the hydroxyl group is protected to generate compound 3 (4) Compound 3 undergoes an epoxide ring-opening reaction under the action of a Pd/C catalyst and a boron reagent to generate compound 4 (5) Compound 4 undergoes a substitution reaction with a purine compound under the action of a phosphine catalyst to generate compound 5 (6) Compound 5 undergoes carbonyl olefination reaction to generate compound 6 (7) Compound 6 is deprotected to generate the entecavir. The method has cheap raw materials, convenient process, short reaction route, and meets the requirements of large-scale industrial production.

Description

A method for preparing entecavir

Technical Field

The invention belongs to the technical field of drug synthesis, and in particular relates to a method for preparing entecavir.

Background technique

Hepatitis B is a chronic infectious disease caused by the hepatitis B virus (HBV). Currently, there are an estimated 90 million chronic hepatitis B patients, of which 28 million require treatment and 7 million require emergency treatment due to the risk of severe liver disease and cancer. Entecavir is a guanine nucleoside analog. Its chemical name is 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purine-6-one, and its CAS number is 142217-69-4. It is currently mainly used for antiviral treatment of hepatitis B. It has the characteristics of rapid onset, strong resistance to hepatitis B virus, and low drug resistance. It is the first choice for antiviral treatment of chronic hepatitis B patients.

There are several main synthetic routes for synthesizing entecavir in the prior art:

Patent CN 102924454A discloses a method using chiral corilactone diol as a starting material, which is subjected to hydroxyl protection, _LiAlH4 reduction, hydroxyl protection with dimethyl tert-butyl chlorosilane, condensation with guanine through Mitsunobu reaction, removal of silicon-based protecting groups, elimination to olefins, ozone oxidation and cutting and reduction, and then elimination to olefins through hydroxyl elimination, and finally removal of protecting groups. Entecavir is obtained through 11 steps of reaction.

Patent CN 105524064A discloses a method of using 1,3-propylene glycol as a starting material, which is oxidized to form an aldehyde to generate an unsaturated ester, and then undergoes 16 steps of reduction, asymmetric epoxidation, ring opening, desilylation, hydroxyl protecting group, deprotection, oxidation, ring closure, oxidation, reduction, Mitsunobu reaction, and deprotection to obtain entecavir.

The method for preparing entecavir disclosed in ZL 91110831.9 and WO 98/09964 uses cyclopentadiene as a raw material, which is sequentially reacted with a dipinene borane complex (Ipc ₂ BH) prepared from chloromethyl benzyl methyl ether and (+)-a-pinene, and then epoxidized with tert-butyl peroxide under the catalysis of acetylacetonato vanadium oxide [VO(acac) ₂ ], and then reacted with benzyl bromide under the action of sodium hydride and tetrabutylammonium iodide, and propylene oxide reacted with 6-benzyloxy-2-aminopurine to open the ring under the action of lithium hydride, and then the amino group was protected by p-methoxytriphenylmethane chloride (MMTCl), and then the hydroxyl group was oxidized to a ketone by Dess-Martin oxidation, the ketone carbonyl group was subjected to a methylenization reaction under the action of Nysted reagent and titanium tetrachloride, and then reacted with hydrochloric acid to remove the MMT on the amino group and the benzyl group on the purine ring, and finally the benzyl group on the carbon ring hydroxyl group was removed under the action of boron trichloride to obtain entecavir. Patent CN 106928227 A and Patent CN 106565769 A optimized some reactions based on this route, and the method involves 11 steps of reaction.

Patent CN 101838207 A and Patent CN 101863842A disclose a method for synthesizing entecavir using a cyclopentane epoxypropane compound having four chiral centers as a starting material, which undergoes epoxy ring opening, hydroxyl oxidation to ketone, olefination, and removal of diimide to obtain an amino compound, which is then coupled with nitroaminochloropyrimidine, the nitro group is reduced to an amine group, and then the two amino groups undergo a cyclization reaction with an orthoformate triester, and then all protecting groups on the molecule are removed to obtain entecavir. The method undergoes eight reaction steps.

Patent CN 109705063 A discloses a method for synthesizing entecavir using dextrorotatory carvone as a starting material. Entecavir is produced by epoxidation, chlorination, hydroxyl protection, re-epoxidation, hydrolysis ring opening, diol protection, Favorskii rearrangement reaction under the action of a base, ester reduction, deprotection and re-oxidation of the hydroxyl group, Baeyer-Villiger oxidation rearrangement reaction of the aldehyde group, re-epoxidation, hydroxyl protection, epoxidation intermediate and epoxide isomerization agent, Mitsunobu reaction with guanine compound, hydrolysis and removal of hydroxyl and amine protecting groups. The method undergoes 16 steps of reaction.

Patents CN 101891741 A, CN 101531660A and CN 102952156A disclose a method for synthesizing entecavir using cyclopentadiene as a starting material. Sodium cyclopentadiene is first silylated to generate silylcyclopentadiene, then reacts with dichloroacetyl chloride to undergo a 2+2 cyclization reaction, then hydrolyzes, and then uses optically pure amine CA to chirally resolve it, and then uses acid washing to obtain an optically pure silylcyclopentane-substituted alcohol carboxylic acid intermediate. The yield of this step is very low, and then the diol compound is obtained by protecting the carboxylic acid, epoxidizing the double bond, and reducing the ester, and then reacting with a chloropurine compound, and then dehydrating the diol to generate an olefin, and then oxidizing the silicon group to an alcohol, and hydrolyzing the chloropurine to finally obtain entecavir. This method undergoes 11 steps of reaction.

Patent CN 105037363 A discloses a method for synthesizing entecavir using (S)-3-hydroxyadipate dimethyl ester as a starting material. First, the alcohol hydroxyl group is protected by TBS, and then an intramolecular cyclization reaction occurs under the action of a base to generate cyclopentanone. After the carbonyl group is protected, the ester group is reduced to an alcohol and protected by TBS, and then hydrolyzed to obtain a ketone. Under the action of a strong base, hydrogen is removed to generate an alkenyl silyl ether, and then oxidized and hydrolyzed using a peroxide to obtain a carbonyl a-position alcohol. The ketone carbonyl is then alkenylated, and then a Mitsunobu reaction is performed with chloroguanine, followed by hydrolysis and removal of the hydroxyl protecting group and the amino protecting group to generate entecavir. The method undergoes 11 steps of reaction.

The above existing technologies basically have several common problems, such as: (1) the raw materials are expensive, especially when non-natural chiral compounds are used as starting materials; (2) the reaction route is relatively long, resulting in a low total yield of the final product, and a large amount of three wastes are generated in the entire process route; (3) if guanine is to be used in the route for Mitsunobu reaction, all existing technologies currently use the traditional equivalent reaction, that is, using excess PPh ₃ and diisopropyl azodicarboxylate (DIAD), which generates a large amount of waste in this step and makes it difficult to purify the target product; (4) if non-chiral raw materials are used as starting materials, chiral separation is often required in the process, which results in a yield of less than 50%, thereby greatly reducing the final yield of the entire process and increasing the various costs of the process; (5) most existing technical processes require multiple steps of protecting group and deprotecting group reactions, and the operation is complicated. Etc., all these problems lead to large amounts of three wastes, high costs, difficulty in product purification, and even the need for special production equipment in industrial large-scale production.

In view of the defects in the existing entecavir synthesis technology and process, the present invention provides a new synthesis route, which can greatly improve the shortcomings of the existing synthesis process.

Summary of the invention

In order to solve the above technical problems, the present invention provides a method for preparing entecavir, which uses cheap and easily available furfural as a starting material, overcomes the shortcomings of the prior art as much as possible through very few reaction steps and asymmetric catalytic reactions, and provides a synthetic route with cheap raw materials, simple equipment, convenient process, and short reaction route, which meets the requirements of large-scale industrial production.

The object of the present invention is to provide a method for preparing entecavir, comprising the following steps:

(1) adding the aldehyde group of furfural through a Grignard reaction to generate compound 1;

(2) Compound 1 described in step (1) undergoes an asymmetric Piancatelli reaction under the action of a chiral Lewis acid catalyst to generate compound 2;

(3) Compound 2 described in step (2) first undergoes a Sharpless epoxidation reaction in the presence of an oxidant and a catalyst to generate an epoxy intermediate, and then the hydroxyl group is protected to generate compound 3;

(4) Compound 3 described in step (3) undergoes an epoxide ring-opening reaction under the action of a Pd/C catalyst and a boron reagent to generate compound 4;

(5) Compound 4 described in step (4) undergoes a substitution reaction with a purine compound in the presence of a phosphine catalyst, and the stereo configuration of the hydroxyl group is reversed to generate compound 5;

(6) Compound 5 described in step (5) undergoes a carbonyl olefination reaction to convert the keto carbonyl group into an olefin to generate compound 6;

(7) removing the protecting group of the compound 6 described in step (6) to generate the entecavir;

The reaction route is as follows:

wherein R ₁ and R ₂ are independently selected from TBS, TMS, Boc or TBDPS;

_R3 is selected from OBn or Cl;

_R4 is selected from Boc or MMT.

In one embodiment of the present invention, in step (1), the molecular formula of the Grignard reagent used in the Grignard reaction is R ₁ OCH ₂ MgX;

wherein R ₁ is selected from TBS, TMS, Boc or TBDPS;

X is selected from Br or I.

In one embodiment of the present invention, in step (1), the solvent used in the Grignard reaction is selected from tetrahydrofuran and/or toluene; the temperature of the Grignard reaction is 25° C.-60° C., and the time of the Grignard reaction is 1 h-6 h.

In one embodiment of the present invention, in step (2), the chiral Lewis acid catalyst is selected from Al(Salen)Cl or Co(Salen)Cl;

Wherein, Salen is a Schiff base ligand prepared from chiral o-diamine and o-hydroxybenzaldehyde.

In one embodiment of the present invention, the chiral o-diamine is selected from cyclohexanediamine, and the o-hydroxybenzaldehyde is selected from 1,3-di-tert-butyl-substituted o-hydroxybenzaldehyde.

In one embodiment of the present invention, in step (2), the solvent used in the asymmetric Piancatelli reaction is selected from tetrahydrofuran and/or toluene; the temperature of the asymmetric Piancatelli reaction is 60° C.-100° C., and the time of the asymmetric Piancatelli reaction is 2 h-4 h.

In one embodiment of the present invention, in step (3), the oxidant is selected from tert-butyl peroxide (t-BuOOH), hydrogen peroxide or meta-chloroperbenzoic acid (m-CPBA).

In one embodiment of the present invention, in step (3), the catalyst is tetraisopropyl titanate and tartaric acid.

In one embodiment of the present invention, in step (3), the protecting agent used to protect the hydroxyl group has the molecular formula of R ₂ -Cl;

wherein R ₂ is selected from TBS, TMS, Boc or TBDPS;

X is selected from Cl.

In one embodiment of the present invention, in step (4), the boron reagent is selected from boron hydroxide B(OH) ₃ or boron trichloride BCl ₃ .

In one embodiment of the present invention, in step (4), the solvent used in the epoxy ring-opening reaction is selected from one or more of methanol, acetonitrile, tetrahydrofuran, dichloromethane and toluene.

In one embodiment of the present invention, in step (5), the phosphine catalyst is selected from (2-hydroxybenzyl)diphenylphosphine oxide.

In one embodiment of the present invention, in step (5), the structure of the purine compound is as follows:

Wherein, R ₃ is selected from OBn or Cl;

_R4 is selected from Boc or MMT.

The technical solution of the present invention has the following advantages over the prior art:

(1) The preparation method of the present invention uses a chiral Lewis acid catalyst to catalyze an asymmetric Piancatelli reaction to generate compound 2. Boron reagent is used as an oxygen-philic auxiliary reagent to generate a hydroxyl group at the a position of the carbonyl group when Pd/C hydrogenates the ortho-carbonyl epoxy ring; in this process, the boron reagent interacts with the carbonyl oxygen and the oxygen atom of propylene oxide to form a five-membered ring transition state, so that the selectivity of the Pd/C catalyst hydrogenation is guaranteed to generate compound 4. Using a phosphine catalyst, the alcohol hydroxyl group and the purine compound are reacted to achieve a catalytic Mitsunobu reaction to generate compound 5, avoiding the need to use excessive triphenylphosphine and diisopropyl azodicarboxylate in the prior art, avoiding the formation of a large number of waste by-products, and simplifying the post-processing; the reaction principle of this process is that the phosphine catalyst first reacts with the hydroxyl group to remove a portion of water to form a phosphine salt, and then accepts the nucleophilic attack of the purine compound on the back, the original hydroxyl group leaves, and the stereo configuration of the site is reversed.

(2) The raw materials used in the preparation method of the present invention are cheap and readily available. Inexpensive and readily available furfural is used as the starting material, the synthesis route is short, the cost of the entire synthesis process is low, the yield is high, the reaction conditions of the preparation method are mild, strong acid and strong base and high temperature and high pressure reaction conditions are not required, the equipment requirements are low, and the requirements of green chemistry and sustainable development are met, and it has good prospects for large-scale industrial production applications.

Detailed ways

The present invention is further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

The present invention is further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention and implement it. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. It should be understood that the specific embodiments are only used to explain the present invention, but the embodiments are not intended to limit the present invention.

In the present invention, unless otherwise defined, technical and scientific terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which the present invention belongs.

In the present invention, unless otherwise stated, the term "and/or" used in the present invention includes any and all combinations of one or more of the associated listed items.

In the present invention, unless otherwise stated, the experimental methods used in the embodiments of the present invention are conventional methods unless otherwise stated, and the materials, reagents, etc. used are all commercially available unless otherwise stated.

Example 1 Preparation of Compound 1

Scheme 1: At room temperature, furfural (28.8 g, 0.3 mol) was dissolved in 200 mL of tetrahydrofuran, and 300 mL of tetrahydrofuran containing TBSOCH ₂ MgBr (75 g, 0.3 mol) was slowly added dropwise while stirring. After the addition was completed, the mixture was slowly heated to 60°C, reacted for 6 h, cooled to room temperature, and 20 mL of deionized water was added to the reaction system to quench the reaction. The organic phase was separated and washed twice with 200 mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid compound 1 (69.1 g, yield 95%).

Scheme 2: At room temperature, furfural (28.8 g, 0.3 mol) was dissolved in 200 mL of tetrahydrofuran, and 300 mL of tetrahydrofuran containing TBSOCH ₂ MgI (89 g, 0.3 mol) was slowly added dropwise while stirring. After the addition was completed, the mixture was slowly heated to 60°C, reacted for 6 h, cooled to room temperature, and 20 mL of deionized water was added to the reaction system to quench the reaction. The organic phase was separated, washed twice with 200 mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid compound 1 (62.3 g, yield 86%).

The analytical data of compound 1 are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.60 (d, 1H), 6.39-6.43 (m, 2H), 5.21 (s, 1H), 5.06 (m, 1H), 4.21-4.36 (m, 2H), 1.05 (s, 9H), 0.24 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ156.2, 142.1, 110.5, 108.3, 74.2, 70.3, 31.6, 27.7, -1.9.

Example 2 Preparation of Compound 2

Scheme 1: At room temperature, compound 1 (24.2 g, 0.1 mol) was dissolved in tetrahydrofuran (150 mL), Al(Salen)Cl catalyst (3.0 g, 5.0 mol%) was added under stirring, the temperature was gradually raised to 60°C, the reaction was allowed to proceed for 4 h, 10 mL of deionized water was added to quench the reaction, the liquids were separated, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phases were combined, and the mixture was washed twice with 100 mL of saturated brine and deionized water, dried over anhydrous sodium sulfate, and filtered to obtain compound 2 as an oily liquid (23.1 g, 95%).

Scheme 2: At room temperature, compound 1 (24.2 g, 0.1 mol) was dissolved in toluene (150 mL), Al(Salen)Cl catalyst (3.0 g, 5.0 mol%) was added under stirring, the temperature was gradually raised to 100 ° C, the reaction was allowed to proceed for 2 h, 10 mL of deionized water was added to quench the reaction, the liquids were separated, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phases were combined, and the mixture was washed twice with 100 mL of saturated brine and deionized water, dried over anhydrous sodium sulfate, and filtered to obtain an oily liquid compound 2 (22.4 g, 93%).

Scheme 3: At room temperature, compound 1 (24.2 g, 0.1 mol) was dissolved in tetrahydrofuran (150 mL), Co(Salen)Cl catalyst (3.2 g, 5.0 mol%) was added under stirring, the temperature was gradually raised to 60°C, the reaction was allowed to proceed for 4 h, 10 mL of deionized water was added to quench the reaction, the liquids were separated, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phases were combined, and the mixture was washed twice with 100 mL of saturated brine and deionized water, dried over anhydrous sodium sulfate, and filtered to obtain an oily liquid compound 2 (16.9 g, 70%).

The analytical data of compound 2 are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.70-6.76 (m, 1H), 6.36 (d, 1H), 5.26 (s, 1H), 4.41 (d, 2H), 3.70-3.88 (m, 2H), 2.41 (m, 1H), 1.04 (s, 9H), 0.25 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 210.5, 152.2, 135.3, 71.4, 67.1, 56.7, 26.8, -2.1.

Example 3 Preparation of Compound 3

Scheme 1: At 0°C, compound 2 (24.2 g, 0.1 mol) was dissolved in CH ₂ Cl ₂ (150 mL), and tartaric acid (-)-DET (1.5 g, 10 mol%) and catalyst Ti(O ^i- Pr) ₄ (1.4 g, 5.0 mol%) were added under stirring, and then tert-butyl peroxide (t-BuOOH) (10 g, 0.11 mol, 1.1 eq.) was added dropwise. The mixture was reacted at 0°C for 6 h. After TLC detection until the reaction was complete, 50 mL of deionized water was added to quench the reaction, the liquids were separated, and the organic phase was washed twice with saturated brine (100 mL of deionized water), dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried to obtain the epoxide intermediate as an oily liquid. Then the intermediate was dissolved in CH ₂ Cl ₂ (150 mL) at room temperature, Et ₃ N (12 g, 0.12 mol, 1.2 eq.) and TBS-Cl (18 g, 0.12 mol, 1.2 eq.) were added under stirring, the temperature was gradually raised to 60° C., the reaction was continued for 2 h, the mixture was cooled to room temperature, the precipitate was removed by filtration, the organic phase was spin-dried and purified by flash column chromatography with PE/EA=20:1 as the mobile phase, to obtain compound 3 (30.2 g, yield 81%) as a colorless oily liquid.

Scheme 2: At 0°C, compound 2 (24.2 g, 0.1 mol) was dissolved in CH ₂ Cl ₂ (150 mL), and tartaric acid (-)-DET (1.5 g, 10 mol%) and catalyst Ti(O ^i- Pr) ₄ (1.4 g, 5.0 mol%) were added under stirring, and then 30% hydrogen peroxide (12.6 g, 0.11 mol, 1.1 eq.) was added dropwise. The mixture was reacted at 0°C for 6 h. After TLC detection until the reaction was complete, 50 mL of deionized water was added to quench the reaction, and the liquids were separated. The organic phase was washed twice with saturated brine (100 mL of deionized water), dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried to obtain the epoxide intermediate as an oily liquid. Then the intermediate was dissolved in CH ₂ Cl ₂ (150 mL) at room temperature, Et ₃ N (12 g, 0.12 mol, 1.2 eq.) and TBS-Cl (18 g, 0.12 mol, 1.2 eq.) were added under stirring, the temperature was gradually raised to 60° C., the reaction was continued for 2 h, the mixture was cooled to room temperature, the precipitate was removed by filtration, the organic phase was spin-dried and purified by flash column chromatography with PE/EA=20:1 as the mobile phase, to obtain compound 3 (17.6 g, yield 57%) as a colorless oily liquid.

Scheme 3: At 0°C, compound 2 (24.2 g, 0.1 mol) was dissolved in CH ₂ Cl ₂ (150 mL), and tartaric acid (-)-DET (1.5 g, 10 mol%) and catalyst Ti(O ^i- Pr) ₄ (1.4 g, 5.0 mol%) were added under stirring, and then meta-chloroperbenzoic acid (m-CPBA) (16.1 g, 0.11 mol, 1.1 eq.) was added gradually and several times, and the reaction was carried out at 0°C for 6 h. After TLC detection until the reaction was complete, 50 mL of deionized water was added to quench the reaction, and the liquids were separated. The organic phase was washed twice with saturated brine (100 mL of deionized water), dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried to obtain the epoxide intermediate as an oily liquid. Then the intermediate was dissolved in CH ₂ Cl ₂ (150 mL) at room temperature, Et ₃ N (12 g, 0.12 mol, 1.2 eq.) and TBS-Cl (18 g, 0.12 mol, 1.2 eq.) were added under stirring, the temperature was gradually raised to 60° C., the reaction was continued for 2 h, the mixture was cooled to room temperature, the precipitate was removed by filtration, the organic phase was spin-dried and purified by flash column chromatography with PE/EA=20:1 as the mobile phase, to obtain compound 3 (22.5 g, yield 73%) as a colorless oily liquid.

Scheme 4: At 0°C, compound 2 (24.2 g, 0.1 mol) was dissolved in CH ₂ Cl ₂ (150 mL), and tartaric acid (-)-DET (1.5 g, 10 mol%) and catalyst Ti(O ^i- Pr) ₄ (1.4 g, 5.0 mol%) were added under stirring, and then tert-butyl peroxide (t-BuOOH) (10 g, 0.11 mol, 1.1 eq.) was added dropwise. The mixture was reacted at 0°C for 6 h. After TLC detection until the reaction was complete, 50 mL of deionized water was added to quench the reaction, the liquids were separated, and the organic phase was washed twice with saturated brine (100 mL of deionized water), dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried to obtain the epoxide intermediate as an oily liquid. Then the intermediate was dissolved in CH ₂ Cl ₂ (150 mL) at room temperature, Et ₃ N (12 g, 0.12 mol, 1.2 eq.) and TMS-Cl (13 g, 0.12 mol, 1.2 eq.) were added under stirring, the temperature was gradually raised to 60° C., the reaction was continued for 2 h, the mixture was cooled to room temperature, the precipitate was removed by filtration, the organic phase was spin-dried and purified by flash column chromatography with PE/EA=20:1 as the mobile phase, to obtain compound 3 (22.8 g, yield 69%) as a colorless oily liquid.

Scheme 5: At 0°C, compound 2 (24.2 g, 0.1 mol) was dissolved in CH ₂ Cl ₂ (150 mL), and tartaric acid (-)-DET (1.5 g, 10 mol%) and catalyst Ti(O ^i- Pr) ₄ (1.4 g, 5.0 mol%) were added under stirring, and then tert-butyl peroxide (t-BuOOH) (10 g, 0.11 mol, 1.1 eq.) was added dropwise. The mixture was reacted at 0°C for 6 h. After TLC detection until the reaction was complete, 50 mL of deionized water was added to quench the reaction, and the liquids were separated. The organic phase was washed twice with saturated brine (100 mL of deionized water), dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried to obtain the epoxide intermediate as an oily liquid. Then the intermediate was dissolved in CH ₂ Cl ₂ (150 mL) at room temperature, Et ₃ N (12 g, 0.12 mol, 1.2 eq.) and TBDPS-Cl (32.9 g, 0.12 mol, 1.2 eq.) were added under stirring, the temperature was gradually raised to 60° C., the reaction was continued for 2 h, the mixture was cooled to room temperature, the precipitate was removed by filtration, the organic phase was spin-dried and purified by flash column chromatography with PE/EA=20:1 as the mobile phase, to obtain compound 3 (45.3 g, yield 76%) as a colorless oily liquid.

The analytical data of compound 3 are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ4.12-4.24 (m, 2H), 3.76-3.88 (m, 1H), 3.28 (d, 1H), 2.87 (m, 1H), 2.04 (m, 1H), 1.01 (s, 18H), 0.24 (s, 12H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ212.2, 70.2, 69.7, 62.0, 60.2, 55.4, 51.6, 30.8, 26.6, -2.2; HRMS (ESI) calcd. for C18H37O4Si2 [M+H]: 373.6616, found: 373.6617.

Example 4 Preparation of Compound 4

Scheme 1: Compound 3 (18.6 g, 0.05 mol) was dissolved in a methanol/acetonitrile (150 mL, v/v = 2:1) mixed solvent under 1 atm of hydrogen and room temperature, Pd/C (0.36 g, 2%) and boric acid B(OH) ₃ (3.01 g, 0.05 mol) were added under stirring, hydrogen was bubbled for 15 min, and then reacted under 1 atm of hydrogen pressure for 12 h. After TLC detection until the reaction was complete, palladium carbon was filtered out, and 10 mL of 15% sodium bicarbonate aqueous solution was added. The reaction solution was spin-dried to about 1/5, and 200 mL of ethyl acetate was added for extraction. The organic phase was washed three times with saturated brine, and then dried over countless sodium sulfate, filtered, and the organic phase was spin-dried and separated and purified by flash column chromatography. The mobile phase was PE/EA = 10:1 to obtain a colorless oily liquid compound 4 (14.7 g, yield 79%).

Scheme 2: Compound 3 (18.6 g, 0.05 mol) was dissolved in a methanol/acetonitrile (150 mL, v/v = 2:1) mixed solvent under 1 atm of hydrogen and room temperature, Pd/C (0.36 g, 2%) and boric acid BCl ₃ (5.68 g, 0.05 mol) were added under stirring, hydrogen was bubbled for 15 min, and then reacted under 1 atm of hydrogen pressure for 12 h. After TLC detection until the reaction was complete, palladium carbon was filtered out, and 10 mL of 15% sodium bicarbonate aqueous solution was added. The reaction solution was spin-dried to about 1/5, and 200 mL of ethyl acetate was added for extraction. The organic phase was washed three times with saturated brine, and then dried over countless sodium sulfate, filtered, and the organic phase was spin-dried and separated and purified by flash column chromatography. The mobile phase was PE/EA = 10:1 to obtain a colorless oily liquid compound 4 (6.2 g, yield 33%).

The analytical data of compound 4 are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ5.22 (s, 1H), 4.00-4.21 (m, 3H), 3.80-3.86 (m, 1H), 2.41-2.52 (m, 2H), 2.06 (m, 1H), 0.98 (s, 18H), 0.22 (s, 12H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ211.5, 70.2, 62.2, 56.4, 54.6, 31.7, 31.0, 26.5, -2.3.

Example 5 Preparation of Compound 5

At room temperature, compound 4 (7.5 g, 0.02 mol) was dissolved in toluene (100 mL), and guanine raw material (11.3 g, 0.022 mol, 1.1 eq, R ₃ = OBn, R ₄ = MMT) and phosphine catalyst (2-hydroxybenzyl) diphenylphosphine oxide (3.01 g, 0.05 mol) were added under stirring, and then slowly heated to reflux, reacted for 16 h, and TLC was detected until compound 4 was completely reacted, cooled to room temperature, most of the toluene solvent was distilled off under reduced pressure, an appropriate amount of ethyl acetate was added, stirred to dissolve the solid, and then 150 mL of ether was added to produce a precipitate, and the precipitate was filtered to recover 2.8 g of phosphine catalyst (2-hydroxybenzyl) diphenylphosphine oxide (recovery rate 93%). The remaining organic solvent was purified by flash column chromatography, and the mobile phase was PE/EA = 5:1 to obtain a light grayish white foam solid compound 5 (14.45 g, yield 83%).

The analytical data of compound 5 are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.52-7.28 (m, 15H), 7.20 (d, 2H), 6.80 (d, 2H), 5.32 (br, 1H), 5.24 (s, 1H), 5.16 (s, 2H), 4.10-4.20 (m, 3H), 3.82-3.88 (m, 4H), 2.41-2.54 (m, 2H), 2.07 (m, 1H), 0.98 (s, 18H), 0.23 (s, 12H).

Example 6 Preparation of Entecavir

Under nitrogen protection, TiCl ₄ (11.0 g, 0.058 mol) was slowly added dropwise to a suspension of CH ₂ Br ₂ (13.9 g, 0.08 mol) and Zn powder (16.3 g, 0.25 mol) in tetrahydrofuran (150 mL) at about -50°C. After the addition was complete, the reaction temperature was raised to 0-5°C within 30 min, and the reaction system was stirred at this temperature for about 4 days. Then, tetrahydrofuran (100 mL) dissolved with compound 5 (8.7 g, 0.01 mol) was slowly added dropwise to the above-mentioned olefination reagent reaction bottle, and the reaction was carried out at this temperature for 4 h. The reaction progress was detected by TLC, and the temperature was gradually raised to 25°C. After compound 5 was fully reacted, the reaction system was poured into 400 mL of saturated sodium bicarbonate aqueous solution and stirred for 1-2 h to produce a large amount of precipitate. The precipitate was filtered and the filter cake was washed with _CH2Cl2 . The liquids were separated, the aqueous phase was washed with 100 mL of _{CH2Cl2 ,} and the organic phases _were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude intermediate 6 as a foamy solid, which was directly used in the next deprotection reaction.

At room temperature, under nitrogen protection, the crude intermediate 6 was dissolved in 50 mL of a tetrahydrofuran/methanol (1/1) mixed solvent, and 2M HCl (20 mL) was added thereto. Then the temperature was slowly raised to about 60°C, and the reaction was carried out for about 4 hours. The reaction was detected by TLC until compound 6 was completely converted. After cooling to room temperature, 50 mL of deionized water and 50 mL of ethyl acetate were added, and the pH value was adjusted to about 7.2 with a 2M NaOH aqueous solution under stirring. The liquids were separated, and the aqueous phase was extracted with 150 mL of ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated and purified by flash column chromatography to obtain a white product, entecavir (2.0 g, yield 74%), mp 247-249°C, [a] _D ²⁰ = +34.1° (literature mp 247-250°C, [a] _D ²⁰ = +34.0°).

The analytical data of entecavir are as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 10.59 (s, 1H), 7.66 (s, 1H), 6.42 (bs, 2H), 5.36 (ddt, J=10.6, 7.8, 2.7 Hz, 1H), 5.10 (dd, J=2.7, 2.2 Hz, 1H), 4.87 (d, J=3.1 Hz, 1H), 4.84 (t, J=5.3 Hz, 1H), 4.56 (t, J=2.4 Hz, 1H), 4.23 (m, 1H), 3.53 (m, 2H), 2.52 (m, 1H), 2.22 (m, 1H), 2.04 (m, 1H); ¹³ C NMR (DMSO-d ₆ ,100MHz)δ:156.9,153.5,151.5,151.3,136.0,116.2,109.3,70.4,63.1,55.2,54.1,39.2;HRMS(ESI):m/z calcd forC ₁₂ H ₁₆ N ₅ O ₃ ⁺ /[M+H] ⁺ 278.1253;found 278.1262.

Obviously, the above embodiments are merely examples for clear explanation and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims (10)

1. A method for preparing entecavir, comprising the following steps: (1) adding the aldehyde group of furfural through a Grignard reaction to generate compound 1; (2) Compound 1 described in step (1) undergoes an asymmetric Piancatelli reaction under the action of a chiral Lewis acid catalyst to generate compound 2; (3) Compound 2 described in step (2) first undergoes a Sharpless epoxidation reaction in the presence of an oxidant and a catalyst to generate an epoxy intermediate, and then the hydroxyl group is protected to generate compound 3; (4) Compound 3 described in step (3) undergoes an epoxide ring-opening reaction under the action of a Pd/C catalyst and a boron reagent to generate compound 4; (5) Compound 4 described in step (4) undergoes a substitution reaction with a purine compound in the presence of a phosphine catalyst to generate compound 5; (6) Compound 5 described in step (5) undergoes carbonyl olefination reaction to generate compound 6; (7) removing the protecting group of the compound 6 described in step (6) to generate the entecavir; The reaction route is as follows: wherein R ₁ and R ₂ are independently selected from TBS, TMS, Boc or TBDPS; _R3 is selected from OBn or Cl; _R4 is selected from Boc or MMT. 2. The method for preparing entecavir according to claim 1, characterized in that, in step (1), the molecular formula of the Grignard reagent used in the Grignard reaction is R ₁ OCH ₂ MgX; wherein R ₁ is selected from TBS, TMS, Boc or TBDPS; X is selected from Br or I. 3. The method for preparing entecavir according to claim 1, characterized in that, in step (2), the chiral Lewis acid catalyst is selected from Al(Salen)Cl or Co(Salen)Cl; Wherein, Salen is a Schiff base ligand prepared from chiral o-diamine and o-hydroxybenzaldehyde. 4. The method for preparing entecavir according to claim 3, characterized in that the chiral o-diamine is selected from cyclohexanediamine, and the o-hydroxybenzaldehyde is selected from 1,3-di-tert-butyl-substituted o-hydroxybenzaldehyde. 5. The method for preparing entecavir according to claim 1, characterized in that in step (3), the oxidant is selected from tert-butyl peroxide, hydrogen peroxide or meta-chloroperbenzoic acid. 6. The method for preparing entecavir according to claim 1, characterized in that in step (3), the catalyst is tetraisopropyl titanate and tartaric acid. 7. The method for preparing entecavir according to claim 1, characterized in that, in step (3), the molecular formula of the protecting agent used to protect the hydroxyl group is R ₂ -Cl; wherein R ₂ is selected from TBS, TMS, Boc or TBDPS; X is selected from Cl. 8. The method for preparing entecavir according to claim 1, characterized in that in step (4), the boron reagent is selected from boron hydroxide or boron trichloride. 9. The method for preparing entecavir according to claim 1, characterized in that, in step (5), the phosphine catalyst is selected from (2-hydroxybenzyl) diphenyl phosphine oxide. 10. The method for preparing entecavir according to claim 1, characterized in that, in step (5), the structure of the purine compound is as follows: Wherein, R ₃ is selected from OBn or Cl; _R4 is selected from Boc or MMT.