A method for preparing entecavir

Abstract

The present application relates to a preparation method of entecavir, and belongs to the technical field of drug synthesis. The preparation method comprises the following steps: (1) addition is carried out on the aldehyde group of furfural through a Grignard reaction to generate compound 1; (2) asymmetric Piancatelli reaction occurs to compound 1 under the action of a chiral Lewis acid catalyst to generate compound 2; (3) compound 2 first undergoes a Sharpless epoxidation reaction under the action of an oxidizing agent and a catalyst to generate an epoxy 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) substitution reaction occurs between compound 4 and a purine compound under the action of a phosphine catalyst to generate compound 5; (6) carbonyl olefination reaction occurs to compound 5 to generate compound 6; and (7) the protecting group of compound 6 is removed to generate the entecavir. The method has the advantages of cheap raw materials, convenient process, short reaction route and meeting the requirements of large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, and particularly relates to a method for preparing entecavir. Background Technology

[0002] Hepatitis B is a chronic infectious disease caused by the hepatitis B virus (HBV). Entecavir is a guanine nucleoside analogue with the chemical name 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purine-6-one and CAS number 142217-69-4. It is currently mainly used for antiviral treatment of hepatitis B, characterized by rapid onset of action, strong inhibition of the hepatitis B virus, and low drug resistance, making it the first-line treatment for chronic hepatitis B patients.

[0003] The main synthetic routes for entecavir in existing technologies are as follows:

[0004] Patent CN 102924454A discloses a method for obtaining entecavir by using chiral cyclohexyl lactone diol as a starting material, followed by hydroxyl protection, LiAlH4 reduction, hydroxyl protection with dimethyl tert-butylchlorosilane, condensation with guanine via the Mitsunobu reaction, removal of the silyl protecting group, elimination to form an alkene, cleavage by ozone oxidation and reduction, hydroxyl elimination to form an alkene again, and finally removal of the protecting group, through 11 steps.

[0005] Patent CN 105524064A discloses a method for obtaining entecavir by starting with 1,3-propanediol, oxidizing it to an aldehyde to generate an unsaturated ester, and then proceeding through 16 steps including reduction, asymmetric epoxidation, ring opening, desilane protecting group removal, hydroxyl protecting group removal, deprotection, oxidation, ring closure, oxidation, reduction, Mitsunobu reaction, and deprotection.

[0006] The methods for preparing entecavir disclosed in ZL 91110831.9 and WO 98 / 09964 use cyclopentadiene as a raw material, which is reacted sequentially with chloromethylbenzyl methyl ether and (+)-α-pinene to prepare a pinene borane complex (Ipc2BH), then epoxidized with tert-butanol peroxide under the catalysis of vanadium acetylacetone oxide [VO(acac)2], then reacted with benzyl bromide in the presence of sodium hydride and tetrabutylammonium iodide, and propylene oxide was ring-opened with 6-benzyloxy-2-aminopurine in the presence of lithium hydride. The amino group was then protected with p-methoxytriphenylchloromethane (MMTCl), and the hydroxyl group was oxidized to a ketone by Dess-Martin oxidation. The ketone carbonyl group was methyleneized in the presence of Nysted reagent and titanium tetrachloride, then reacted with hydrochloric acid to remove MMT from the amino group and benzyl group from the purine ring, and finally the benzyl group on the carbocyclic hydroxyl group was removed in the presence of boron trichloride to obtain entecavir. Patents CN 106928227 A and CN 106565769 A optimize part of the reaction based on this route, and the method involves 11 reaction steps.

[0007] Patents CN 101838207 A and CN 101863842A disclose a method for synthesizing entecavir from a cyclopentane-propylene oxide compound with four chiral centers. The method involves epoxide ring opening, hydroxyl oxidation to ketone, alkenylation, removal of diimide to obtain an amino compound, coupling with nitroaminochloropyrimidine to reduce the nitro group to an amino group, then cyclizing the two amino groups with orthoformate triester, and finally removing all protecting groups on the molecule to obtain entecavir. The method involves eight steps.

[0008] Patent CN 109705063 A discloses a method for synthesizing entecavir using dextrorotatory carvone as a starting material. The method involves epoxidation, chlorination, hydroxyl protection, re-epoxidation, hydrolysis ring-opening, diol protection, a Favorskii rearrangement reaction under alkaline conditions, reduction of the ester group, deprotection and reoxidation of the hydroxyl group, a Baeyer-Villiger oxidative rearrangement reaction of the aldehyde group, re-epoxidation, hydroxyl protection, an epoxidation intermediate undergoing an epoxidation isomerization reaction with an epoxide isomerizing reagent, a Mitsunobu reaction with a guanine compound, and further hydrolysis and removal of the hydroxyl and amino protecting groups to generate entecavir. This method comprises 16 steps.

[0009] 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 silanized to generate silyl cyclopentadiene, which then undergoes a 2+2 cyclization reaction with dichloroacetyl chloride, followed by hydrolysis. The cyclopentadiene is then chirally resolved using optically pure amine CA, and acid washing yields an optically pure silyl cyclopentane-substituted alcohol-carboxylic acid intermediate. This step has a very low yield. The carboxylic acid is then protected, the double bond is epoxidized, and the ester is reduced to obtain a diol compound. This diol compound is then reacted with a chloropurine compound, followed by dehydration of the diol to generate an olefin. The silyl group is then oxidized to an alcohol, and the chloropurine is hydrolyzed to finally obtain entecavir. This method involves 11 steps.

[0010] Patent CN 105037363 A discloses a method for synthesizing entecavir using (S)-3-hydroxyadipic acid dimethyl ester as a starting material. First, TBS protects the hydroxyl group of the alcohol. Then, an intramolecular cyclization reaction occurs under the action of a base to generate cyclopentanone. After protecting the carbonyl group, the ester group is reduced to an alcohol and protected by TBS again. Hydrolysis yields a ketone, which is then dehydrogenated under a strong base to generate an alkenyl silyl ether. This ether is then oxidized with a peroxide compound and hydrolyzed to obtain a carbonyl α-ol. The ketone carbonyl group is then alkenylated, followed by a Mitsunobu reaction with chloroguanine. Hydrolysis and removal of the hydroxyl and amino protecting groups further yield entecavir. This method involves 11 steps.

[0011] The above-mentioned existing technologies all have several common problems, such as: (1) expensive raw materials, especially when using non-natural chiral compounds as starting materials; (2) long reaction routes, resulting in low overall yield of the final product and generating a large amount of waste throughout the process; (3) if guanine is used in the Mitsunobu reaction, all existing technologies currently use the traditional equivalence reaction, i.e., using excess PPh3 and diisopropyl azodicarboxylate (DIAD), which generates a large amount of waste and makes it difficult to purify the target product; (4) if non-chiral raw materials are used as starting materials, chiral resolution is often required in the process, which results in a yield of less than 50%, thus greatly reducing the final yield of the entire process and increasing the cost of various processes; (5) most existing technologies require multiple steps of protecting and deprotecting reactions, making the operation complicated. All these problems lead to a large amount of waste, high cost, and difficulty in product purification in large-scale industrial production, and even require special production equipment.

[0012] In view of the shortcomings of existing entecavir synthesis technology and processes, this invention provides a novel synthesis route that can significantly improve the deficiencies of existing synthesis processes. Summary of the Invention

[0013] To address the aforementioned technical problems, this invention provides a method for preparing entecavir, utilizing inexpensive and readily available furfural as a starting material. By employing minimal reaction steps and asymmetric catalytic reactions, it overcomes the shortcomings of existing technologies as much as possible, providing a synthetic route that is inexpensive to produce, uses simple equipment, is convenient to process, and has a short reaction route, thus meeting the requirements for large-scale industrial production.

[0014] The purpose of this invention is to provide a method for preparing entecavir, comprising the following steps:

[0015] (1) The aldehyde group of furfural is added via Grignard reaction to generate compound 1;

[0016] (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;

[0017] (3) Compound 2 described in step (2) first undergoes a sharpless epoxidation reaction under the action of an oxidant and a catalyst to generate an epoxy intermediate, and then the hydroxyl group is protected to generate compound 3;

[0018] (4) Compound 3 described in step (3) undergoes an epoxy ring-opening reaction under the action of Pd / C catalyst and boron reagent to generate compound 4;

[0019] (5) Compound 4 described in step (4) undergoes a substitution reaction with a purine compound under the action of a phosphine catalyst, and the stereoconfiguration of the hydroxyl group is reversed to generate compound 5;

[0020] (6) Compound 5 described in step (5) undergoes a carbonyl olefination reaction, converting the ketone carbonyl group into an olefin to generate compound 6;

[0021] (7) The protecting group of compound 6 described in step (6) is removed to generate the entecavir;

[0022] The reaction route is as follows:

[0023]

[0024] R1 and R2 are selected independently from TBS, TMS, Boc or TBDPS;

[0025] R3 is selected from OBn or Cl;

[0026] R4 is selected from Boc or MMT.

[0027] In one embodiment of the present invention, in step (1), the Grignard reagent used in the Grignard reaction has the molecular formula R1OCH2MgX;

[0028] R1 is selected from TBS, TMS, Boc or TBDPS;

[0029] X is selected from Br or I.

[0030] 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℃-60℃, and the time of the Grignard reaction is 1h-6h.

[0031] 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;

[0032] Salen is a Schiff base ligand prepared from chiral o-diamine and o-hydroxybenzaldehyde.

[0033] 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.

[0034] 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℃-100℃, and the time of the asymmetric Piancatelli reaction is 2h-4h.

[0035] In one embodiment of the present invention, in step (3), the oxidant is selected from tert-butanol peroxide (t-BuOOH), hydrogen peroxide or m-chloroperoxybenzoic acid (m-CPBA).

[0036] In one embodiment of the present invention, in step (3), the catalyst is tetraisopropyl titanate and tartaric acid.

[0037] In one embodiment of the present invention, in step (3), the molecular formula of the protective reagent used to protect the hydroxyl group is R2-Cl;

[0038] R2 is selected from TBS, TMS, Boc, or TBDPS;

[0039] X is selected from Cl.

[0040] In one embodiment of the present invention, in step (4), the boron reagent is selected from boron hydroxide B(OH)3 or boron trichloride BCl3.

[0041] 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.

[0042] In one embodiment of the present invention, in step (5), the phosphine catalyst is selected from (2-hydroxybenzyl)diphenylphosphine oxide.

[0043] In one embodiment of the present invention, in step (5), the structure of the purine compound is as follows:

[0044]

[0045] R3 is selected from OBn or Cl;

[0046] R4 is selected from Boc or MMT.

[0047] The technical solution of the present invention has the following advantages compared with the prior art:

[0048] (1) The preparation method described in this invention uses a chiral Lewis acid catalyst to catalyze an asymmetric Piancatelli reaction to generate compound 2. Boron reagent is used as an oxophilic auxiliary reagent to generate a hydroxyl group at the a-position of the carbonyl group during the hydrogenation of the ortho-carbonyl epoxy group by Pd / C. 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, which ensures the selectivity of the Pd / C catalyst hydrogenation and generates compound 4. Using a phosphine catalyst, the alcohol hydroxyl group and purine compound are reacted to achieve a catalytic Mitsunobu reaction to generate compound 5. This avoids the need to use excess triphenylphosphine and diisopropyl azodicarboxylic acid ester in the prior art, avoids the formation of a large amount of waste by-products, and simplifies the post-processing. The reaction principle of this process is that the phosphine catalyst first reacts with the hydroxyl group to remove a molar water to form a phosphine salt, and then accepts the nucleophilic attack of the purine compound on the back side, the original hydroxyl group leaves, and the stereoconfiguration of this site is flipped.

[0049] (2) The raw materials used in the preparation method described in this invention are inexpensive and readily available. Using inexpensive and readily available furfural as the starting material, the synthesis route is short, the overall synthesis process is low in cost and high in yield. The preparation method has mild reaction conditions, does not require strong acids, strong bases and high temperature and high pressure reaction conditions, has low equipment requirements, meets the requirements of green chemistry and sustainable development, and has good prospects for large-scale industrial production applications. Detailed Implementation

[0050] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand and implement the present invention, but the embodiments are not intended to limit the present invention.

[0051] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand and implement the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. 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.

[0052] In this invention, unless otherwise stated, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0053] In this invention, unless otherwise stated, the term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0054] In this invention, unless otherwise specified, the experimental methods used in the embodiments of this invention are conventional methods, and the materials and reagents used are commercially available unless otherwise specified.

[0055] Example 1: Preparation of Compound 1

[0056]

[0057] Option 1: At room temperature, furfural (28.8 g, 0.3 mol) was dissolved in 200 mL of tetrahydrofuran. While stirring, 300 mL of tetrahydrofuran containing TBSOCH2MgBr (75 g, 0.3 mol) was slowly added dropwise. After the addition was complete, the mixture was slowly heated to 60 °C and reacted for 6 h. After cooling to room temperature, 20 mL of deionized water was added to the reaction system to quench the reaction. The mixture was separated, and the organic phase was 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, 95% yield).

[0058] Option 2: At room temperature, furfural (28.8 g, 0.3 mol) was dissolved in 200 mL of tetrahydrofuran. While stirring, 300 mL of tetrahydrofuran containing TBSOCH2MgI (89 g, 0.3 mol) was slowly added dropwise. After the addition was complete, the mixture was slowly heated to 60 °C and reacted for 6 h. After cooling to room temperature, 20 mL of deionized water was added to the reaction system to quench the reaction. The mixture was separated, and the organic phase was 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%).

[0059] The analytical data for compound 1 are as follows: 1H NMR (400MHz, CDCl3) 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 (100MHz, CDCl3) δ156.2, 142.1, 110.5, 108.3, 74.2, 70.3, 31.6, 27.7, -1.9.

[0060] Example 2 Preparation of Compound 2

[0061]

[0062] Option 1: At room temperature, compound 1 (24.2 g, 0.1 mol) was dissolved in tetrahydrofuran (150 mL), and Al(Salen)Cl catalyst (3.0 g, 5.0 mol%) was added with stirring. The temperature was gradually increased to 60 °C and the reaction was carried out for 4 h. The reaction was quenched with 10 mL of deionized water. The mixture was separated, and the aqueous phase was extracted with 50 mL of ethyl acetate. The organic phases were combined and washed twice with 100 mL of saturated brine and deionized water. The mixture was dried with anhydrous sodium sulfate and filtered to obtain compound 2 as an oily liquid (23.1 g, 95%).

[0063] Option 2: At room temperature, compound 1 (24.2 g, 0.1 mol) was dissolved in toluene (150 mL), and Al(Salen)Cl catalyst (3.0 g, 5.0 mol%) was added with stirring. The temperature was gradually increased to 100 °C and the reaction was carried out for 2 h. The reaction was quenched with 10 mL of deionized water. The mixture was separated, and the aqueous phase was extracted with 50 mL of ethyl acetate. The organic phases were combined and washed twice with 100 mL of saturated brine and deionized water. The mixture was dried with anhydrous sodium sulfate and filtered to obtain an oily liquid compound 2 (22.4 g, 93%).

[0064] Option 3: At room temperature, compound 1 (24.2 g, 0.1 mol) was dissolved in tetrahydrofuran (150 mL), and Co(Salen)Cl catalyst (3.2 g, 5.0 mol%) was added with stirring. The temperature was gradually increased to 60 °C and the reaction was carried out for 4 h. The reaction was quenched with 10 mL of deionized water. The mixture was separated, and the aqueous phase was extracted with 50 mL of ethyl acetate. The organic phases were combined and washed twice with 100 mL of saturated brine and deionized water. The mixture was dried with anhydrous sodium sulfate and filtered to obtain an oily liquid compound 2 (16.9 g, 70%).

[0065] The analytical data for compound 2 are as follows: 1H NMR (400MHz, CDCl3) δ6.70-6.76(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 (100MHz, CDCl3) δ210.5,152.2,135.3,71.4,67.1,56.7,26.8,-2.1.

[0066] Example 3 Preparation of Compound 3

[0067]

[0068] Option 1: At 0℃, dissolve compound 2 (24.2 g, 0.1 mol) in CH2Cl2 (150 mL), and add tartaric acid (-)-DET (1.5 g, 10 mol%) with stirring, and catalyst Ti(O) i- Pr)4 (1.4 g, 5.0 mol%) was added dropwise, followed by the addition of tert-butanol peroxide (t-BuOOH) (10 g, 0.11 mol, 1.1 eq.). The reaction was carried out at 0 °C for 6 h, and TLC was used to detect the reaction until it was complete. Then, 50 mL of deionized water was added to quench the reaction. The mixture was separated, and the organic phase was washed twice with 100 mL of saturated brine and deionized water. The mixture was dried with anhydrous sodium sulfate, filtered, and the organic phase was evaporated to dryness to obtain an oily liquid intermediate of the epoxy compound. The intermediate was then dissolved in CH2Cl2 (150 mL) at room temperature. Et3N (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 increased to 60 °C, and the reaction was carried out for 2 h. The mixture was then cooled to room temperature, the precipitate was removed by filtration, and the organic phase was purified by rapid column chromatography with PE / EA = 20:1 as the mobile phase. This yielded a colorless oily liquid compound 3 (30.2 g, yield 81%).

[0069] Option 2: At 0℃, compound 2 (24.2 g, 0.1 mol) was dissolved in CH2Cl2 (150 mL), and tartaric acid (-)-DET (1.5 g, 10 mol%) was added with stirring, along with the catalyst Ti(O2). i-Pr)4 (1.4 g, 5.0 mol%) was added dropwise, followed by the addition of 30% hydrogen peroxide (12.6 g, 0.11 mol, 1.1 eq.). The reaction was carried out at 0 °C for 6 h, and TLC was used to detect the reaction until it was complete. Then, 50 mL of deionized water was added to quench the reaction. The mixture was separated, and the organic phase was washed twice with 100 mL of saturated brine and deionized water. The mixture was dried with anhydrous sodium sulfate, filtered, and the organic phase was evaporated to dryness to obtain an oily liquid intermediate of the epoxy compound. The intermediate was then dissolved in CH2Cl2 (150 mL) at room temperature. Et3N (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 increased to 60 °C, and the reaction was carried out for 2 h. The mixture was then cooled to room temperature, the precipitate was removed by filtration, and the organic phase was purified by rapid column chromatography with PE / EA = 20:1 as the mobile phase, yielding a colorless oily liquid compound 3 (17.6 g, yield 57%).

[0070] Option 3: At 0℃, compound 2 (24.2 g, 0.1 mol) was dissolved in CH2Cl2 (150 mL), and tartaric acid (-)-DET (1.5 g, 10 mol%) was added with stirring, along with the catalyst Ti(O2). i- Pr)4 (1.4 g, 5.0 mol%) was added, followed by the gradual addition of m-chloroperoxybenzoic acid (m-CPBA) (16.1 g, 0.11 mol, 1.1 eq.). The reaction was carried out at 0 °C for 6 h, and TLC was used to detect the reaction until it was complete. Then, 50 mL of deionized water was added to quench the reaction. The mixture was separated, and the organic phase was washed twice with 100 mL of saturated brine and deionized water. The mixture was dried with anhydrous sodium sulfate, filtered, and the organic phase was evaporated to dryness to obtain an oily liquid intermediate of epoxy compound. The intermediate was then dissolved in CH2Cl2 (150 mL) at room temperature. Et3N (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 increased to 60 °C, and the reaction was carried out for 2 h. The mixture was then cooled to room temperature, the precipitate was removed by filtration, and the organic phase was purified by rapid column chromatography with PE / EA = 20:1 as the mobile phase. This yielded a colorless oily liquid compound 3 (22.5 g, yield 73%).

[0071] Option 4: At 0℃, compound 2 (24.2 g, 0.1 mol) was dissolved in CH2Cl2 (150 mL), and tartaric acid (-)-DET (1.5 g, 10 mol%) was added with stirring, along with the catalyst Ti(O2). i-Pr)4 (1.4 g, 5.0 mol%) was added dropwise, followed by the addition of tert-butanol peroxide (t-BuOOH) (10 g, 0.11 mol, 1.1 eq.). The reaction was carried out at 0 °C for 6 h, and TLC was used to detect the reaction until it was complete. Then, 50 mL of deionized water was added to quench the reaction. The mixture was separated, and the organic phase was washed twice with 100 mL of saturated brine and deionized water. The mixture was dried with anhydrous sodium sulfate, filtered, and the organic phase was evaporated to dryness to obtain an oily liquid intermediate of the epoxy compound. The intermediate was then dissolved in CH2Cl2 (150 mL) at room temperature. Et3N (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 increased to 60 °C, and the reaction was carried out for 2 h. The mixture was then cooled to room temperature, the precipitate was removed by filtration, and the organic phase was purified by rapid column chromatography with PE / EA = 20:1 as the mobile phase. The result was a colorless oily liquid compound 3 (22.8 g, yield 69%).

[0072] Option 5: At 0℃, compound 2 (24.2 g, 0.1 mol) was dissolved in CH2Cl2 (150 mL), and tartaric acid (-)-DET (1.5 g, 10 mol%) was added with stirring, along with the catalyst Ti(O2). i- Pr)4 (1.4 g, 5.0 mol%) was added dropwise, followed by the addition of tert-butanol peroxide (t-BuOOH) (10 g, 0.11 mol, 1.1 eq.). The reaction was carried out at 0 °C for 6 h, and TLC was used to detect the reaction until it was complete. Then, 50 mL of deionized water was added to quench the reaction. The mixture was separated, and the organic phase was washed twice with 100 mL of saturated brine and deionized water. The mixture was dried with anhydrous sodium sulfate, filtered, and the organic phase was evaporated to dryness to obtain an oily liquid intermediate of the epoxy compound. The intermediate was then dissolved in CH2Cl2 (150 mL) at room temperature. Et3N (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 increased to 60 °C, and the reaction was carried out for 2 h. The mixture was then cooled to room temperature, the precipitate was removed by filtration, and the organic phase was purified by rapid column chromatography with PE / EA = 20:1 as the mobile phase. This yielded a colorless oily liquid compound 3 (45.3 g, yield 76%).

[0073] The analytical data for compound 3 are as follows: 1 H NMR (400MHz, CDCl3) 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); 13C NMR(100MHz, CDCl3)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.

[0074] Example 4: Preparation of Compound 4

[0075]

[0076] Option 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 hydrogen atmosphere and at room temperature. Pd / C (0.36 g, 2%) and boric acid B(OH)3 (3.01 g, 0.05 mol) were added with stirring. The mixture was bubbled with hydrogen for 15 min, and then reacted under 1 atm hydrogen atmosphere for 12 h. TLC was used to monitor the reaction until complete. Palladium on carbon was removed by filtration. 10 mL of 15% sodium bicarbonate aqueous solution was added, and the reaction solution was evaporated to about 1 / 5 dryness. 200 mL of ethyl acetate was added for extraction. The organic phase was washed three times with saturated brine, dried with sodium sulfate, filtered, and purified by rapid column chromatography with PE / EA = 10:1 as the mobile phase, yielding a colorless oily liquid compound 4 (14.7 g, yield 79%).

[0077] Option 2: In a hydrogen atmosphere at 1 atm and at room temperature, compound 3 (18.6 g, 0.05 mol) was dissolved in a methanol / acetonitrile (150 mL, v / v = 2:1) mixed solvent. Pd / C (0.36 g, 2%) and boric acid BCl3 (5.68 g, 0.05 mol) were added with stirring. The mixture was bubbled with hydrogen for 15 min, and then reacted under hydrogen at 1 atm for 12 h. TLC was used to monitor the reaction until complete. Palladium on carbon was removed by filtration, and 10 mL of 15% sodium bicarbonate aqueous solution was added. The reaction solution was evaporated to about 1 / 5 dryness, and extracted with 200 mL of ethyl acetate. The organic phase was washed three times with saturated brine, dried with sodium sulfate, filtered, and purified by rapid column chromatography with PE / EA = 10:1 as the mobile phase, yielding a colorless oily liquid compound 4 (6.2 g, yield 33%).

[0078] The analytical data for compound 4 are as follows: 1 H NMR (400MHz, CDCl3) 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 (100MHz, CDCl3) δ211.5,70.2,62.2,56.4,54.6,31.7,31.0,26.5,-2.3.

[0079] Example 5: Preparation of Compound 5

[0080]

[0081] At room temperature, compound 4 (7.5 g, 0.02 mol) was dissolved in toluene (100 mL). Guanine feedstock (11.3 g, 0.022 mol, 1.1 eq, R3 = OBn, R4 = MMT) and phosphine catalyst (2-hydroxybenzyl) diphenylphosphine oxide (3.01 g, 0.05 mol) were added with stirring. The mixture was then slowly heated to reflux and reacted for 16 h. TLC was used to monitor the reaction until compound 4 was completely reacted. After cooling to room temperature, most of the toluene solvent was distilled off under reduced pressure. A suitable amount of ethyl acetate was added, and the mixture was stirred to dissolve the solid. Then, 150 mL of diethyl ether was added to produce a precipitate. The precipitate was filtered to recover 2.8 g of the phosphine catalyst (2-hydroxybenzyl) diphenylphosphine oxide (93% recovery). The remaining organic solvent was purified by rapid column chromatography with a mobile phase of PE / EA = 5:1, yielding a light grayish-white foamy solid, compound 5 (14.45 g, 83% yield).

[0082] The analytical data for compound 5 are as follows: 1 H NMR(400MHz, CDCl3)δ7.88(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).

[0083] Example 6: Preparation of entecavir

[0084]

[0085] Under nitrogen protection, at approximately -50°C, TiCl4 (11.0 g, 0.058 mol) was slowly added dropwise to a suspension of tetrahydrofuran (150 mL) containing CH2Br2 (13.9 g, 0.08 mol) and Zn powder (16.3 g, 0.25 mol). After the addition was complete, the reaction temperature was raised to 0-5°C within 30 minutes and maintained at this temperature while the reaction system was stirred for about 4 days. Then, tetrahydrofuran (100 mL) containing 8.7 g (0.01 mol) of compound 5 was slowly added dropwise to the reaction flask containing the above-mentioned alkenylating reagent. The reaction was carried out at this temperature for 4 h, and the reaction progress was monitored by TLC. The temperature could be gradually increased to 25 °C. After compound 5 had fully reacted, the reaction system was poured into 400 mL of saturated sodium bicarbonate aqueous solution and stirred thoroughly for 1-2 h. A large amount of precipitate was produced. The precipitate was filtered, and the filter cake was washed with CH2Cl2. The liquid phase was separated, and the aqueous phase was washed with 100 mL of CH2Cl2. The organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to obtain intermediate 6 as a crude foamy solid, which was directly used in the next step of the deprotection reaction.

[0086] Under nitrogen protection at room temperature, crude intermediate 6 was dissolved in 50 mL of a tetrahydrofuran / methanol (1 / 1) mixed solvent, and 2 M HCl (20 mL) was added. The temperature was then slowly raised to about 60 °C, and the reaction was carried out for about 4 h. The reaction was monitored 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. The pH was adjusted to about 7.2 with 2 M NaOH aqueous solution while stirring. The aqueous phase was extracted three times with 150 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by rapid column chromatography to obtain the white product entecavir (2.0 g, yield 74%), mp 247-249 °C. [a] D 20 = +34.1° (reference mp 247-250°C, [a]) D 20 = +34.0°).

[0087] The analysis data for entecavir are as follows: 1 H NMR(DMSO-d6,400MHz)δ:10.59(s,1H),7.66(s,1H),6.42(bs,2H),5.36(ddt,J=10.6,7.8,2.7Hz,1H),5.10(dd,J=2.7,2.2Hz,1H),4 .87(d,J=3.1Hz,1H),4.84(t,J=5.3Hz,1H),4.56(t,J=2.4Hz,1H),4.23(m,1H),3.53(m,2H),2.52(m,1H),2.22(m,1H),2.04(m,1H); 13C NMR(DMSO-d6,100MHz)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 N5O3 + / [M+H] + 278.1253; found 278.1262.

[0088] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for preparing entecavir, characterized in that, Includes the following steps: (1) The aldehyde group of furfural is added via Grignard reaction to generate compound 1; (2) Compound 1 from step (1) undergoes an asymmetric Piancatelli reaction under the action of a chiral Lewis acid catalyst to generate compound 2; the structural formula of the chiral Lewis acid catalyst is as follows: ; (3) Compound 2 described in step (2) first undergoes a sharpless epoxidation reaction under the action 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 epoxy ring-opening reaction under the action of Pd / C catalyst and boron reagent to generate compound 4; (5) Compound 4 from step (4) undergoes a substitution reaction with a purine compound under the action of a phosphine catalyst to generate compound 5; the phosphine catalyst is selected from (2-hydroxybenzyl)diphenylphosphine oxide; the structural formula of the purine compound is as follows: ; (6) Compound 5 described in step (5) undergoes a carbonyl olefination reaction to generate compound 6; (7) The protecting group of compound 6 described in step (6) is removed to generate the entecavir; The reaction route is as follows: ； R1 and R2 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 Grignard reagent used in the Grignard reaction has the molecular formula R1OCH2MgX; R1 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 (3), the oxidant is selected from peroxytert-butanol, hydrogen peroxide or m-chloroperoxybenzoic acid.

4. The method for preparing entecavir according to claim 1, characterized in that, In step (3), the catalyst is tetraisopropyl titanate and tartaric acid.

5. The method for preparing entecavir according to claim 1, characterized in that, In step (3), the molecular formula of the protecting reagent used to protect the hydroxyl group is R2-Cl; R2 is selected from TBS, TMS, Boc, or TBDPS.

6. 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.

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