HK1172033B

HK1172033B - Novel method for preparing entecavir and intermediate used therein

Info

Publication number: HK1172033B
Application number: HK12112982.1A
Authority: HK
Inventors: 李在宪; 朴柯胜; 金进喜; 崔泰镇; 李智垠; 韩定希; 方孝正; 郑善英; 张永佶; 李宽淳; 金孟燮
Original assignee: 韩美科学株式会社
Priority date: 2009-10-12
Filing date: 2010-09-15
Publication date: 2015-08-07

Description

Novel preparation method of entecavir and intermediate used therein

Technical Field

The present invention relates to a novel process for the preparation of entecavir and intermediates used therein.

Background

Entecavir ([1-S- (1 α,3 α, 4 β) ] -2-amino-1, 9-dihydro-9- [ 4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentyl ] -6H-purin-6-one), the structure of which comprises a cyclopentane ring having purines, exocyclic methylene (ethylene), hydroxymethyl, and hydroxy substituents at the 1S-, 2-, 3R-, and 4S-positions of the cyclopentane ring, respectively, is currently used for the treatment of hepatitis b virus infection.

Much research has been conducted in order to develop processes for preparing entecavir. For example, U.S. Pat. No. 5,206,244 and WO 98/09964 disclose a process for preparing entecavir as shown in reaction scheme 1.

Reaction scheme 1

Wherein P is₁Is trityl or substituted trityl, Bn is benzyl, BOMCP is benzyloxymethylcyclopentadiene, IpcBH is diisopinocampheylborane (diisopinocampheylborane), DMAP is N, N-dimethyl-4-aminopyridine, DMF is dimethylformamide, MC is dichloromethane, MMTr-Cl is 4-monomethoxytrityl chloride, TBAI is tetrabutylammonium iodide, TEA is triethylamine and THF is tetrahydrofuran.

However, the above method has disadvantages in that: i) the cyclopentadiene monomer must be maintained at a temperature below-30 ℃ to prevent its conversion to dicyclopentadiene; ii) sodium remaining after the reaction and sensitivity of the reaction to moisture cause problems; iii) the process to obtain the intermediate of formula (1a) must be carried out at very low temperatures below-70 ℃ to prevent the production of isomers; iv) use of (-) -Ipc₂When BH (diisopinocampheylkenyl borane) is subjected to hydroboration reaction, a decantation method is required; v) preparation of the intermediate of formula (1e)Can be smoothly carried out; and vi) the need to use MCI GEL^TMThe CHP-20P resin (Sigma-Aldrich) was purified by column chromatography for entecavir.

WO 2004/52310 and U.S. patent publication No.2005/0272932 disclose methods of preparing entecavir using intermediates of formula (2f) prepared as shown in reaction scheme 2:

reaction scheme 2

Wherein Me is methyl, t-Bu is t-butyl, Et is ethyl, n-Hex is n-hexane, and Ph is phenyl.

The above-mentioned process for producing the intermediate of formula (2b) must be carried out at an extremely low temperature of-70 ℃ or less, and the yield of the desired product (2f) in the optical resolution step is less than 50%.

Various methods have been developed for the preparation of enol triflates (triflates). For example, the document [ Preparation of allosilane 12 ", J.Am.chem.Soc., 1998, 120, 12980-]A process for preparing an enol triflate is disclosed, comprising performing a reaction between potassium hexamethyldisilazane (KHMDS) and N-phenyltrifluoromethanesulfonimide (PhNTf) as described in scheme 3₂) A step of carrying out a regioselective reaction. U.S. Pat. No.7,381,746B2 discloses a process for preparing enol triflate as described in reaction scheme 4. Document [ J.chem.Soc., Perkis trans.1, 2000, 345-]A process for preparing the enol triflate is also disclosed.

Reaction scheme 3

Reaction scheme 4

Wherein R is a hydroxy protecting group, X is halogen or benzyloxy, MOP is 2-methoxy-2-propyl ether, TBS is tert-butyldimethylsilyl, Tf is trifluoromethanesulfonyl, and TMS is trimethylsilyl.

In the above-mentioned process for producing an enol trifluoromethanesulfonate, the process for obtaining the enol trifluoromethanesulfonate must be carried out at an extremely low temperature for a long period of time, and the process for obtaining the enol trifluoromethanesulfonate disclosed in U.S. Pat. No.7,381,746B2 is also carried out at a temperature of from-63 ℃ to-45 ℃. However, the starting material for the preparation of enol triflate is liable to decompose at a temperature higher than-30 ℃, which is not suitable for mass production of enol triflate.

Summary of The Invention

Accordingly, it is an object of the present invention to provide a novel process for the preparation of entecavir in high yield and novel intermediates used therein.

According to one aspect of the present invention, there is provided a process for preparing entecavir of formula (I), comprising the steps of:

(a) hydrolyzing the α -exomethylene derivative of formula (II) to obtain a compound of formula (III);

(b) carrying out a Mitsunobu reaction of the compound of formula (III) with a purine derivative of formula (IV) to obtain a nucleoside compound of formula (V);

(c) reacting the nucleoside compound of formula (V) with tetrabutylammonium fluoride to obtain a compound of formula (VI); and

(d) hydrolyzing a compound of formula (VI):

wherein:

R₁and R₂Each independently is a hydroxy protecting group, or R₁And R₂Condensed together to form a cyclic hydroxyl protecting group;

R₃is benzoyl or arylbenzoyl, preferably benzoyl or 4-phenylbenzoyl;

tf is trifluoromethanesulfonyl; and

x is halogen or benzyloxy.

According to another aspect of the present invention, there are provided α -exocyclic methylene derivatives of formula (II), β -exocyclic methylene derivatives of formula (VII), epoxide derivatives of formula (VIII), compounds of formula (IX), enol triflate derivatives of formula (X) and compounds of formula (XIII) which are useful as intermediates for the preparation of entecavir of formula (I) or a solvate thereof.

Wherein:

R₁、R₂and Tf is as defined above, and Y is an alkylsilyl or arylsilyl group.

According to still another aspect of the present invention, there is provided a solvate of crystalline entecavir dimethylformamide of formula (XIV) and a method for preparing the same, wherein an X-ray diffraction (hereinafter, referred to as XRD) spectrum of the solvate obtained using Cu-K α radiation shows peaks having a peak intensity of 10% or more at the following diffraction angles (2 θ ± 0.2): 10.2, 14.4, 14.5, 16.6, 17.9, 18.8, 19.3, 19.8, 21.4, 21.9, 24.5, 25.5, 25.8, 26.7, 29.3 and 30.2:

wherein DMF is dimethylformamide.

Brief Description of Drawings

The above and other objects and features of the present invention will become apparent from the following description of the invention taken in conjunction with the accompanying drawings, which respectively show:

FIG. 1: an XRD spectrum of the compound of formula (IX) of the present invention;

FIG. 2: an XRD spectrum of the compound of formula (XIII) of the present invention; and

FIG. 3: XRD patterns of the compounds of formula (XIV) of the present invention.

Detailed Description

The term "alkyl" as used herein refers to a straight or branched chain saturated C₁-C₆A hydrocarbyl group. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and hexyl.

The term "alkoxy" as used herein refers to the group-OR_aWherein R is_aIs an alkyl group as defined above. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

The term "aryl" as used herein means C₆-C₁₈An aromatic hydrocarbon group. Aromatic hydrocarbon groups include optionally substituted monocyclic or bicyclic aromatic ring systems (e.g., phenyl or substituted phenyl) and fused ring systems (e.g., naphthyl or phenanthryl). Examples of "aryl" include, but are not limited to, phenyl, toluyl, xylyl, biphenyl, and naphthyl.

The term "hydroxy protecting group" as used herein refers to, for example, a methyl group having one, two or three phenyl substituents (e.g., benzyl, trityl or benzhydryl); benzyl substituted with alkoxy or nitro (e.g., methoxybenzyl or p-nitrobenzyl); benzoyl optionally substituted with alkoxy or nitro (e.g., benzoyl, methoxybenzoyl or p-nitrobenzoyl); a silyl group optionally substituted with at least one selected from an alkyl group and an aryl group (e.g., a trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, or a hexyldimethylsilyl group); an allyl group; alkoxyalkyl (e.g., methoxymethyl or (2-methoxyethoxy) methyl); and a tetrahydropyranyl group; preferably trityl, benzoyl and tert-butyldiphenylsilyl; most preferred is trityl or tert-butyldiphenylsilyl.

The term "cyclic hydroxy protecting group" as used herein refers to, for example, benzylidene (phenylene), naphthylidene (naphthylidene), 4-phenylbenzylidene (4-phenylbenzidene), cyclic acetal, cyclic ketal, cyclic carbonate, cyclic orthoester (cyclic orthoester), and cyclic 1,3- (1, 1,3, 3-tetraisopropyl) disiloxane diyl.

A process for preparing entecavir of formula (I) according to the present invention is shown in reaction scheme 5, but is not limited thereto:

reaction scheme 5

Wherein R is₁To R₃Tf, X and Y are the same as defined above.

Hereinafter, a description will be given in detail of each step of the production method shown in reaction scheme 5.

< step 1>

The enol triflate derivative of formula (X) is prepared by reacting a compound of formula (XI) with a triflating agent in the presence of a base.

Examples of the base used in this reaction include lithium hexamethyldisilazane (LiHMDS), potassium hexamethyldisilazane (KHMDS), sodium hexamethyldisilazane (NaHMDS), Lithium Diisopropylamide (LDA), n- (C)_1-6Alkyl) lithium (e.g., n-butyllithium), tetramethyllithium piperidine (LiTMP), potassium butoxide, potassium pentoxide, potassium amylate, and mixtures thereof. The base is preferably used in an amount of 0.8 to 3 molar equivalents based on the compound of formula (XI).

Examples of the trifluoromethanesulfonizing agent used in this reaction include trihalomethanesulfonic anhydride (e.g., trifluoromethanesulfonic anhydride), compounds having C₁～C₆Alkyl or C₆～C₁₈Aryl N-substituted trifluoromethanesulfonimides (e.g. N-phenyltrifluoromethanesulfonimide (PhNTf)₂) ) and mixtures thereof. The above triflating agent is preferably used in an amount of 1 to 1.5 molar equivalents based on the compound of formula (XI).

The reaction may proceed as follows: dissolving the compound of formula (XI) and a base in an organic solvent, followed by adding thereto a trifluoromethanesulfonizing agent (method 1); or the compound of formula (XI) is added dropwise to a mixture of triflating agent and base (method 2). Examples of the organic solvent used in the reaction include, but are not limited to, ethers (e.g., tetrahydrofuran); chlorinated alkanes (e.g., dichloromethane), or mixtures thereof.

The reaction according to method 1 may be carried out at a temperature of-30 ℃ to-80 ℃, preferably by raising the temperature from-50 ℃ to-73 ℃ to-30 ℃ for 1 to 2 hours. The reaction according to the method 2 may be carried out in an organic solvent at 20 ℃ to-29 ℃ (preferably 0 ℃ to 20 ℃) for 1 to 2 hours.

Method 2 allows the enol triflate derivative of formula (X) to be easily prepared at-29 ℃ and higher without using column chromatography to obtain entecavir in high yield and in large amounts.

In order to evaluate the influence of the reaction conditions, each of the enol trifluoromethanesulfonate derivatives of the formula (X) prepared under the reaction conditions described in table 1 was used in step 2 to prepare the cyclic olefin compound of the formula (IX). The analysis results of the compound of formula (IX) are shown in table 1.

< Table 1>

As shown in table 1, the yield of the compound of formula (IX) prepared according to method 2 is higher than the yield of the compound of formula (IX) prepared according to method 1.

< step 2>

The compound of formula (IX) is prepared by reacting the enol triflate derivative of formula (X) obtained in step 1 with an alkylsilylmethylmagnesium chloride or arylsilylmethylmagnesium chloride in the presence of a metal catalyst.

Examples of the metal catalyst used in this reaction include tetrakis (triphenylphosphine) palladium (palladium) [ Pd (PPh)₃)₄]The metal catalyst is preferably used in an amount of 0.01 to 0.1 molar equivalent based on the enol trifluoromethanesulfonate derivative of the formula (X).

Examples of the alkylsilylmethylmagnesium chloride include (C)₁～C₆Alkyl) silylmethylmagnesium chloride (e.g., trimethylsilylmethylmagnesium chloride), and the like. Examples of arylsilylmethylmagnesium chloride include t-butyldiphenylsilylmethylmagnesium chloride and the like. The above alkylsilylmethylmagnesium chloride or arylsilylmethylmagnesium chloride is preferably used in an amount of 1 to 2 molar equivalents based on the enol trifluoromethanesulfonate derivative of the formula (X). The alkylsilylmethylmagnesium chloride or arylsilylmethylmagnesium chloride can be prepared by one of the conventional methods including the step of treating magnesium with (chloromethyl) alkylsilane or (chloromethyl) arylsilane.

The reaction may be carried out at 0 ℃ to 20 ℃ (preferably 5 ℃ to 10 ℃) for 1 to 3 hours in an organic solvent, examples of which include, but are not limited to, ethers (such as diethyl ether or tetrahydrofuran); chlorinated alkanes (e.g., dichloromethane); and mixtures thereof.

In order to obtain a crystalline form of the cyclic olefin compound of formula (IX), the inventive process for preparing entecavir may further comprise a step of crystallizing the compound of formula (IX) using a mixture of isopropanol and water.

According to the above method, the compound of formula (IX) can be prepared in a high yield of 86% or more.

< step 3>

The epoxide derivative of formula (VIII) is prepared by treating the compound of formula (IX) obtained in step 2 with a peroxide.

Examples of the peroxides include m-chloroperoxybenzoic acid, hydrogen peroxide, t-butyl hydroperoxide (TBHP), osmium tetroxide (OsO)₄) Sodium periodate and mixtures thereof. The peroxide is preferably used in an amount of 1 to 3 molar equivalents based on the compound of formula (IX).

The reaction may be carried out at 0 ℃ to 25 ℃ (preferably 10 ℃ to 25 ℃) for 1 to 3 hours in an organic solvent, examples of which include, but are not limited to, C₁～C₆Alcohols, e.g. methanolAlcohol, ethanol, isopropanol or tert-butanol; nitriles such as acetonitrile; chlorinated alkanes, such as dichloromethane; and mixtures thereof.

According to the above process, the epoxide derivative of formula (VIII) can be prepared in the form of a crystalline solid.

< step 4>

The β -exomethylene compound of formula (VII) is prepared by hydrolysis of the epoxide derivative of formula (VIII) obtained in step 3.

The hydrolysis may be carried out at 0 ℃ to 30 ℃ in an organic solvent, examples of which include, but are not limited to, chlorinated alkanes such as dichloromethane; c₁To C₆Alcohols such as methanol; and mixtures thereof.

According to the above process, the β -exomethylene compound of the formula (VII) can be prepared from the cyclopentanol compound of the formula (VIII) in a high yield of 75% via 5 steps.

< step 5>

By reacting the beta-exocyclic methylene compound of the formula (VII) obtained in step 4 with triphenylphosphine and bis (C) azodicarboxylate₁～C₆Alkyl) esters (di (C)₁ to C₆alkyl) azodicarbonylates) to produce the α -exomethylene derivative of formula (II).

The triphenylphosphine is preferably used in an amount of 1 to 2 molar equivalents based on the β -exocyclic methylene compound of formula (VII).

Azobis (C) azodicarboxylate₁～C₆Examples of alkyl) esters include diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD), and mixtures thereof, the above-mentioned bis (C) azodicarboxylate₁～C₆Alkyl) esters are preferably used in an amount of 1 to 2 molar equivalents based on the β -exomethylene compound of formula (VII).

An additive selected from the group consisting of benzoic acid, 4-phenylbenzoic acid, p-nitrobenzoic acid, p-methoxybenzoic acid and mixtures thereof may be used in the above reaction, preferably in an amount of 1 to 2 molar equivalents based on the β -exocyclic methylene compound of formula (VII).

The reaction may be carried out at 0 ℃ to 25 ℃ (preferably 0 ℃ to 5 ℃) for 30 minutes to 2 hours in an organic solvent, examples of which include, but are not limited to, tetrahydrofuran, dichloromethane, and mixtures thereof.

The reaction may be carried out according to method 1 or method 2, said method 1 comprising the steps of adding DIAD to an organic solvent solution of triphenylphosphine to obtain a suspension and adding a mixed solution of a β -exocyclic methylene compound of formula (VII) and tetrahydrofuran of benzoic acid to the suspension; the method 2 comprises the step of dropwise adding a DIAD to a mixture of a β -exomethylene compound of formula (VII), triphenylphosphine, and benzoic acid.

The yield of the compound of formula (II) prepared according to method 2 was 70%, which was higher than the yield of the compound of formula (II) prepared according to method 1 (yield: 68.6%). In addition, process 2 requires one reactor for the mass production of entecavir.

< step 6>

The compound of formula (III) is prepared by hydrolyzing the compound of formula (II) obtained in step 5 in an alkaline solution to remove the benzoyl group of the compound of formula (II).

Examples of the base used to form the base solution include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, and mixtures thereof, and the amount of the above base is preferably 1 to 2 molar equivalents based on the compound of formula (II).

The hydrolysis may be carried out at-5 ℃ to room temperature (preferably 0 ℃ to 5 ℃) for 30 minutes to 5 hours in an organic solvent, examples of which include, but are not limited to, tetrahydrofuran, dichloromethane, and mixtures thereof.

< step 7>

The nucleoside compound of formula (V) is prepared by Mitsunobu reaction of the compound of formula (III) obtained in step 6 with a purine derivative of formula (IV).

Examples of purine derivatives of formula (IV) include 2-amino-6-halopurines, such as 2-amino-6-chloropurine; and 6-O-benzylguanine, the purine derivative of formula (IV) above being used in an amount of preferably 1 to 2 molar equivalents based on the compound of formula (III).

The Mitsunobu reaction can be carried out on triphenylphosphine and azodicarboxylic acid di (C)₁～C₆Alkyl) esters in an organic solvent at 0 ℃ to 25 ℃ (preferably 0 ℃ to 5 ℃) for 30 minutes to 2 hours.

The amount of triphenylphosphine is preferably from 1 to 2 molar equivalents, based on the compound of the formula (III).

Azobis (C) azodicarboxylate₁～C₆Examples of alkyl) esters include diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD), and mixtures thereof, bis (C) azodicarboxylate₁～C₆The amount of alkyl) ester is preferably 1 to 2 molar equivalents based on the compound of formula (III).

Examples of organic solvents include, but are not limited to, tetrahydrofuran, dichloromethane, and mixtures thereof.

The nucleoside compound of formula (V) according to the above-mentioned method can be prepared as a solid in a high yield of 64.7%.

< step 8>

Removing the protecting group R by reacting the nucleoside compound of formula (V) obtained in step 7 with tetrabutylammonium fluoride (TBAF)₂To prepare the compound of formula (VI).

The tetrabutylammonium fluoride is preferably used in an amount of 1 to 2 molar equivalents based on the nucleoside compound of formula (V).

The reaction may be carried out at 20 to 30 deg.C (preferably 20 to 25 deg.C) for 1 to 5 hours in an organic solvent, examples of which include tetrahydrofuran, dichloromethane and a mixture thereof.

< step 9>

The entecavir compound of formula (I) is prepared by hydrolyzing the compound of formula (VI) obtained in step 8.

The hydrolysis is carried out by heating the compound of formula (VI) in an acidic solution to remove the protecting group R₁And X.

The acidic solution used above may be prepared by dissolving an acid selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid and mixtures thereof in water. Preference is given to using 2N hydrochloric acid solution as the acidic solution in an amount of from 10 to 20 times based on the weight of the compound of the formula (VI).

The reaction may be carried out at 60 ℃ to 90 ℃ (preferably 80 ℃ to 85 ℃) for 3 to 6 hours.

After deprotection of the compound of formula (VI) in acidic solution, the resulting solution may be further neutralized to pH 6 to 8 with sodium hydroxide solution.

The compound of formula (XI) used as a starting material for the process of the present invention can be prepared by one of conventional methods well known in the art (see korean patent publication No. 2010-0076640), preferably by the preparation method as shown in reaction scheme 6:

reaction scheme 6

Wherein R is₁And R₂As defined above.

Specifically, the cyclopentanol compound is prepared as a crystalline solid by a preparation method comprising the steps of: with (+) -diisopinocampheylborane ((+) -Ipc₂BH) and H₂O₂Treating a cyclopentene derivative of formula (XII); extracting the resulting mixture, which contains the cyclopentanol compound of formula (XIII) and isopinocamphenol as a by-product, with a hydrocarbon-based solvent such as heptane, hexane or octane to separate an organic layer; washing with a mixture of water and an alcohol (e.g., methanol)Washing the separated organic layer to selectively remove isopinocamphene; and crystallizing the compound of formula (XIII) by adding a solvent as a crystallization aid.

(+)-Ipc₂BH and H₂O₂The amounts are preferably 1 to 3 molar equivalents and 1 to 7 molar equivalents, respectively, based on the cyclopentene derivative of the formula (XII).

The washing process may be performed two or more times, preferably three or more times, using a mixture of water and alcohol in a mixing weight ratio of 1: 1 to 1: 3. More preferably, the washing process may be carried out five times using any mixture of water and alcohol mixed in a weight ratio of 1: 1, 1: 1.5, 1: 2, 1: 2.5 and 1: 3.

Examples of the solvent used for the crystallization include hydrocarbon-based solvents such as hexane, heptane or octane; alcohols, such as methanol, ethanol or isopropanol; water; and mixtures thereof.

The reaction can be carried out in an organic solvent at 0 ℃ to 40 ℃.

Then, by using pyridine SO₃Oxidation of cyclopentanol compound of formula (XIII) with a mixture of the complex, trialkylamine and dimethylsulfoxide to prepare the compound of formula (XI) wherein pyridine SO₃The complexes are superior to dess-martin oxidizer (DMP) due to their low price and stability. The compound of formula (XI) thus obtained can be used without further purification.

Pyridine SO₃The amounts of the complex, trialkylamine and dimethylsulfoxide are 1 to 3 molar equivalents, 1 to 4 molar equivalents and 1 to 10 molar equivalents, respectively, of the cyclopentanol compound of formula (XIII).

The reaction can be carried out in an organic solvent at 0 ℃ to room temperature.

According to another aspect of the present invention, there are provided α -exocyclic methylene derivatives of formula (II), β -exocyclic methylene derivatives of formula (VII), epoxide derivatives of formula (VIII), cyclic olefin compounds of formula (IX), enol triflate derivatives of formula (X) and crystalline cyclopentanol compounds of formula (XIII) which are useful as intermediates for preparing entecavir of formula (I) or a solvate thereof.

According to another aspect of the present invention, there is provided a process for preparing crystalline entecavir dimethylformamide solvate of formula (XIV) and crystalline entecavir dimethylformamide solvate of formula (XIV) prepared by the process:

wherein, DMF is dimethyl formamide,

the method comprises the following steps: dissolving an entecavir compound of formula (I) in a solvent comprising dimethylformamide; and allowing the compound of formula (XIV) to crystallize therefrom; and optionally filtering and drying.

DMF makes up 10 to 40 wt% of the total weight of the solvate.

Preferably, the drying process may be performed under a nitrogen atmosphere to obtain a stable DMF mono-solvate.

As shown in fig. 1, the solvate exhibits peaks having a peak intensity of 10% or more at diffraction angles (2 θ ± 0.2) of 10.2, 14.4, 14.5, 16.6, 17.9, 18.8, 19.3, 19.8, 21.4, 21.9, 24.5, 25.5, 25.8, 26.7, 29.3, and 30.2 in an X-ray diffraction spectrum obtained using Cu — K α radiation.

In addition, the solvate can be used as an intermediate for preparing the entecavir of the invention. Specifically, entecavir of the present invention is prepared by a conventional recrystallization process comprising the steps of: dissolving the solvate in a solvent (e.g., water); and cooling the resulting solution to precipitate entecavir.

According to the method for preparing entecavir using the novel intermediate of the present invention, highly pure entecavir can be economically prepared with high yield.

The following examples illustrate some embodiments of the invention in more detail. However, the following embodiments of the present invention are merely examples, and the present invention is not limited thereto.

Example 1-1: preparation of 4- (tert-butyl-diphenyl-siloxy) -5-trityloxymethyl-1-cyclopentenyl trifluoromethanesulfonate (Compound of formula (X))

3- (tert-butyl-diphenyl-siloxy) -2-trityloxymethyl-cyclopentanone (31g, 50.7mmol) was dissolved in anhydrous tetrahydrofuran (310ml) and cooled to-78 ℃. Lithium hexamethyldisilazane (17.0g, 101.5mmol) was added thereto and stirred at-78 ℃ for 1 hour. To the mixture thus obtained was added N-phenyltrifluoromethanesulfonimide (23.6g, 66mmol) and warmed to room temperature, followed by stirring at room temperature overnight. After completion of the reaction, saturated sodium bicarbonate (310ml) was added thereto. The resulting solution was extracted with ethyl acetate (310ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The thus-obtained substance was purified by column chromatography to obtain the title compound (33.5g, yield: 88.9%).

NMR(300MHz，CDCl₃)：δ7.36(m，4H)，7.09-6.99(m，21H)，5.50(s，1H)，4.14(d，1H)，2.89(dd，1H)，2.68(s，1H)，2.59(dd，1H)，2.37-2.34(m，1H)，2.15(d，1H)，0.80(s，9H)

Examples 1 to 2: preparation of tert-butyl-diphenyl- (3-trimethylsilylmethyl-2-trityloxymethyl-cyclopenten-3-yloxy) -silane (compound of formula (IX))

The enol compound (X) obtained in example 1-1 (33.5g, 45.1mmol) was dissolved in diethyl ether (335 ml). Tetrakis (triphenylphosphine) palladium (2.6g, 2.25mmol) was added thereto at room temperature and cooled to 0 ℃. To the resulting mixture was added 1M trimethylsilylmagnesium chloride (90.2ml, 90.2mmol) and stirred at room temperature for 1 hour. After completion of the reaction, the resulting mixture was cooled to 0 ℃. The cooled mixture was quenched with saturated sodium bicarbonate (335ml) and filtered through celite. The resulting solid was washed with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The thus-obtained substance was purified by column chromatography to obtain the title compound (26.99g, yield: 87.4%).

NMR(300MHz，CDCl₃)：δ7.59(dd，4H)，7.33-7.14(m，21H)，5.06(s，1H)，4.33(d，1H)，2.90(dd，1H)，2.78-2.73(m，1H)，2.64-2.62(m，1H)，2.26-2.24(m，1H)，2.09(d，1H)，1.50(d，1H)，1.23(d，1H)，1.00(s，9H)，0.01(s，9H)

Examples 1 to 3: preparation of 3- (tert-butyl-diphenyl-siloxy) -1-trimethylsilylmethyl-2-trityloxymethyl-6-oxa-bicyclo [3.1.0] hexane (compound of formula (VIII))

The compound of the formula (IX) (708g, 1.03mol) obtained in example 1-2 was dissolved in isopropanol (16L) and cooled to 0 ℃. To the resulting solution was added sodium phosphate (2214g, 15.59mol) and 77% m-chloroperoxybenzoic acid (699g, 3.11mol) in that order. The resulting solution was stirred at 0 ℃ for 2 hours. The solid was filtered to obtain a solid mixture of the title compound and sodium phosphate (724 g).

NMR(300MHz，CD₂Cl₂+D₂O)：δ7.65-7.22(m，25H)，4.74(t，2H)，3.44(q，1H)，3.27(dd，1H)，3.13(s，1H)，2.88(t，1H)，2.42-2.41(m，1H)，1.99-1.88(m，2H)，1.02-0.93(m，9H)，0.15-0.13(m，9H)

Examples 1 to 4: preparation of 1- (S) -4- (tert-butyl-diphenyl-siloxy) -2-methylene-3-trityloxymethylcyclopentanol (compound of formula (VII))

A solid mixture (724g) of the compound of the formula (VIII) obtained in example 1-3 and sodium phosphate was added to methanol (10L) and stirred at room temperature. To this was added 77% m-chloroperoxybenzoic acid (350g, 1.56mol) and methylene chloride (5L) to complete the reaction. The resulting mixture was quenched by the addition of a mixture of 20% aqueous sodium bisulfate (1.5L) and 12% aqueous sodium bicarbonate (1.5L). The thus-obtained reaction mixture was extracted twice with dichloromethane (1.6L) and dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (494g, yield of the title compound from the compound of formula (XI): 60.5%).

NMR(300MHz，CDCl₃)：δ7.84-7.58(m，5H)，7.33-7.18(m，39H)，5.40(s，0.2H)，5.18(s，1H)，5.11(s，0.2H)，4.99(s，1H)，4.65(d，1H)，4.13(q，2H)，3.02(m，3H)，2.87(m，2H)，1.88(d，1H)，1.00(s，17H)

Examples 1 to 5: 1-benzoyl-4- (tert-butyl-diphenyl-siloxy) -2-methylene-3-trityloxymethyl-cyclopentane (compound of formula (II))

Triphenylphosphine (311g, 1.18mol) was dissolved in tetrahydrofuran (4.9L) and cooled to 0 ℃. To the thus obtained solution was added diisopropyl azodicarboxylate (DIAD) (233ml, 1.18mol) and stirred at 0 ℃ for 1 hour to obtain a suspension. Tetrahydrofuran (4.9L) was added to a mixture of the compound of the formula (VII) (494g, 0.79mol) obtained in examples 1-4 and benzoic acid (145g, 1.18 mol). A suspension of triphenylphosphine and DIAD was added thereto at 0 ℃ and stirred at the same temperature for 0.5 hour. The thus-obtained mixture was concentrated under reduced pressure to remove the solvent and ethyl acetate (4.9L) was added thereto, followed by washing with a 0.5N aqueous sodium hydroxide solution. To the resulting material was added sodium sulfate, filtered and concentrated under reduced pressure. The resulting substance was crystallized by adding methanol (4.9L) and filtered to obtain the title compound (369g, yield: 68.6%).

NMR(300MHz，CDCl₃)：δ8.09(dd，2H)，7.56(dd，5H)，7.33-7.20(m，23H)，5.60(t，1H)，5.26(d，2H)，4.11(q，1H)，3.13-3.08(m，1H)，3.02(d，1H)，2.85(q，1H)，2.24-2.18(m，1H)，1.94-1.88(m，1H)，1.54(s，3H)，0.99(s，9H)

Examples 1 to 6: preparation of 1- (R) -4- (tert-butyl-diphenyl-siloxy) -2-methylene-3-trityloxymethylcyclopentanol (compound of formula (III))

The compound of formula (II) (367g, 0.5mol) obtained in examples 1 to 5 was mixed with a 1% sodium hydroxide solution in methanol (7.34L) and dichloromethane (3.7L) at room temperature for 5 hours. After completion of the reaction, water (7.3L) was added to the resulting mixture to separate an aqueous layer. The separated aqueous layer was extracted with dichloromethane (7.3L). To the resultant was added sodium sulfate, dried and filtered to obtain the title compound (404g, yield: > 100%).

NMR(300MHz，CDCl₃)：δ7.65-7.60(m，4H)，7.39-7.17(m，21H)，5.35(s，1H)，5.10(s，1H)，4.30(d，1H)，2.97(s，1H)，2.88-2.79(m，2H)，2.73(d，1H)，1.78(t，2H)，1.02(s，9H)

Examples 1 to 7: preparation of 9- [4- (tert-butyl-diphenyl-siloxy) -2-methylene-3-trityloxymethyl-cyclopentyl ] -6-chloro-9H-purin-2-ylamine (compound of formula (V))

Triphenylphosphine (13.37g, 50.88mmol) was dissolved in tetrahydrofuran (240ml) and cooled to 0 ℃. Diethyl azodicarboxylate (DEAD) (8.3ml, 50.88mmol) was added thereto and stirred at 0 ℃ for 1 hour to give a suspension. Tetrahydrofuran (160ml) was added to a mixture of the compound of the formula (III) obtained in examples 1 to 6 (15.93g, 25.44mmol) and 2-amino-6-chloropurine (8.64g, 50.88mmol), and a suspension of triphenylphosphine and DEAD was added thereto at 0 ℃ followed by stirring at the same temperature for 1 hour. After completion of the reaction, ethyl acetate (400ml) was added to the resulting mixture and washed three times with 0.5N aqueous sodium hydroxide solution (400ml) at 0 ℃. The resultant was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound (12.8g, yield: 64.7%).

NMR(300MHz，DMSO-d₆)：δ7.82(s，1H)，7.61(d，4H)，7.49-7.20(m，21H)，6.69(br s，2H)，5.53(t，1H)，4.91(s，1H)，4.57(s，1H)，4.40(s，1H)，3.19-3.13(m，1H)，3.08-3.03(m，1H)，2.83(s，1H)，2.13-2.10(m，2H)，1.03(s，9H)

Examples 1 to 8: preparation of 4- (2-amino-6-chloro-4, 5-dihydropurin-9-yl) -3-methylene-2-trityloxymethyl-cyclopentanol (compound of formula (VI))

The compound of the formula (V) obtained in examples 1 to 7 (3.2g, 4.12mmol) was dissolved in anhydrous tetrahydrofuran (32 ml). To the resulting solution was added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (8.24mL, 8.24mmol), and stirred at room temperature for 13 hours. After completion of the reaction, the resulting mixture was quenched by addition of distilled water (30 ml). The thus-obtained solution was extracted with ethyl acetate (30ml), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting material was stirred in methanol (32ml) to obtain the title compound (1.6g, yield: 71.6%).

NMR(300MHz，DMSO-d₆)：δ8.19(s，1H)，7.98-7.25(m，15H)，6.84(s，2H)，5.44(t，1H)，5.07(d，1H)，4.88(s，1H)，4.54(s，1H)，4.25(s，1H)，3.30-3.17(m，2H)，2.64(s，1H)，2.26-2.08(m，2H)

Examples 1 to 9: preparation of 2-amino-9- (4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl) -1, 9-dihydropurin-6-one (entecavir of formula (I))

Acetonitrile (30ml) and 2N aqueous hydrochloric acid (23.3ml) were added to the compound of the formula (VI) (1.38g, 2.56mmol) obtained in examples 1 to 8, and stirred under heating at 82 ℃ for 12 hours. After completion of the reaction, the resulting mixture was cooled to room temperature and washed with ethyl acetate to remove trityl methanol. The material thus obtained was neutralized to pH 6.8 with 3N aqueous sodium hydroxide solution (13.6ml), and stirred at 90 ℃ for 1 hour. The resulting solution was slowly cooled to room temperature with stirring, and further stirred at room temperature for 1 hour to obtain crystals. The resultant was cooled to 6 ℃ and stirred for 1 hour to obtain the title compound (0.554g, yield: 73.1%).

NMR(300MHz，MeOH-d₄)：10.6(s，1H)，7.78(s，1H)，5.53(t，1H)，5.26(t，1H)，4.82(t，1H)，4.43-4.40(m，1H)，3.81(d，2H)，2.70(s，1H)，2.47-2.38(m，1H)，2.27-2.20(m，1H)

Examples 1 to 10: preparation of N, N-dimethylformamide solvate of 2-amino-9- (4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl) -1, 9-dihydropurin-6-one (compound of formula (XIV))

The compound (1g) obtained in example 1-9 was added to N, N-dimethylformamide (5ml), and stirred at room temperature for 2 hours and further at 0 ℃ for 1 hour. The resulting solution was filtered to obtain the title compound (0.95g, yield: 85.6%) as a white solid.

NMR(300MHz，MeOH-d₄)：10.6(s，1H)，7.95(s，1H)，7.67(s，1H)，5.36(t，1H)，5.10(t，1H)，4.87(d，1H)，4.83(t，1H)，4.56(t，1H)，4.24(s，1H)，3.54(t，2H)，2.89(s，3H)，2.72(s，3H)，2.50(m，1H)，2.21(m，1H)，2.04(m，1H)

Examples 1 to 11: preparation of high purity monohydrate of 2-amino-9- (4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl) -1, 9-dihydropurin-6-one (compound of formula (I))

The compound of the formula (XIV) obtained in examples 1 to 10 (1.1g) was mixed with distilled water (16.5ml) and stirred at 95 ℃ for 1 hour. The resulting solution was cooled to room temperature to crystallize, and stirred at 10 ℃ for 1 hour. The resultant solid was filtered and dried under a nitrogen atmosphere to obtain the title compound (0.9g, yield: 96.9%) as a white solid with a purity of 99.8% or more.

Example 2-1: preparation of 3- (tert-butyl-diphenyl-siloxy) -2-trityloxymethyl-cyclopentanol (compound of formula (XIII))

Under a nitrogen stream, 2M BH₃DMS in tetrahydrofuran (210ml, 0.924mol) was mixed with dry tetrahydrofuran (300ml) in a reactor and cooled to 5 ℃. (-) - α -pinene (155ml, 0.924mol) was added dropwise thereto over 0.5 hour. Mixing the obtained solid phase (+) -Ipc₂BH was heated to 35 ℃ and tert-butyl-diphenyl- (2-trityloxymethyl-cyclo-2-pentenyloxy) -silane of the formula (II) (100g) was added thereto. The resulting mixture was stirred for 3 hours and 3N aqueous sodium hydroxide solution (196ml) was added dropwise thereto for 1 hour while maintaining the temperature at 0 ℃ to 10 ℃. To the resulting mixture was added dropwise hydrogen peroxide (105ml) for 1 hour or more and stirred for 1 hour. To the resulting reaction mixture was added dropwise 10% NaHSO₃(250ml) and 8% NaHCO₃(250ml) of the mixed solution to remove excess hydrogen peroxide. The resultant was extracted with heptane (500ml) to separate an organic layer. The separated organic layer was washed five times with a mixture of water and methanol in a weight ratio of 1: 1, 1: 1.5, 1: 2, 1: 2.5 or 1: 3 to remove isopinocampheol. The resulting solution was concentrated under reduced pressure, crystallized from heptane (300ml), and filtered at 0 ℃ to obtain the title compound (67g, yield: 65%) as crystals.

NMR(300MHz，CDCl₃)：δ7.57-7.21(m，25H)，3.91-3.81(m，2H)，3.12(dd，1H)，2.74(br，1H)，2.68(t，1H)，2.34(m，1H)，1.77-1.72(m，3H)，1.53-1.48(m，1H)，1.01(s，9H)

m.p.: 95.6 ℃ to 97 DEG C

Example 2-2: preparation of 3- (tert-butyl-diphenyl-siloxy) -2-trityloxymethyl-cyclopentanone (compound of formula (XI))

The compound of the formula (XIII) obtained in example 2-1 (60g, 97.9mmol) was mixed with DMSO (36ml) and dichloromethane (300 ml). The resulting solution was cooled to 0 ℃ and N, N-diisopropylethyl was added theretoAmine (DIPEA) (59.7ml, 0.343mol), followed by pyridine SO₃Complex (31.2g), pyridine (15.9ml) and DMSO (36 ml). The mixture thus obtained was stirred for 30 minutes. After completion of the reaction, the thus-obtained organic layer was washed with saturated ammonium chloride (300ml), 2M hydrochloric acid solution (300ml), sodium hydrogencarbonate solution (300ml) and brine (300ml), respectively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (60g, yield: 99%).

NMR(300MHz，CDCl₃)：δ7.62-7.18(m，25H)，4.53(q，1H)，3.34(dd，1H)，3.02(dd，1H)，2.53(m，1H)，2.32(q，1H)，2.18(m，1H)，1.99-1.88(m，2H)，0.89(9H)

Examples 2 to 3: preparation of 4- (tert-butyl-diphenyl-siloxy) -5-trityloxymethyl-1-cyclopentenyl trifluoromethanesulfonate (Compound of formula (X))

A1M solution of lithium hexamethyldisilazane in tetrahydrofuran (2.62L, 2.62mol) was cooled to 0 ℃ in the reactor. To this solution was added a mixed solution of N-phenyltrifluoromethanesulfonimide (608.4g, 1.70mol) and anhydrous tetrahydrofuran (2.4L) over 1 hour, followed by addition of a mixture of the compound of formula (XI) obtained in example 2-2 (800g, 1.31mol) and anhydrous tetrahydrofuran (2.4L) over 1 to 1.5 hours. The resulting mixture was stirred at 0 ℃ for 1 hour. After completion of the reaction, a 3% aqueous sodium hydrogencarbonate solution (8L) was added to the mixture and extracted with ethyl acetate (8L). The organic layer thus separated was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was mixed with heptane (6L) and celite (800g) and stirred at room temperature for 2 hours. The resulting mixture was filtered through celite to remove impurities. The thus-obtained organic layer was washed twice with a mixture (5.6L) of methanol and water at a mixed weight ratio of 6: 1, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (892 g).

Examples 2 to 4: preparation of tert-butyl-diphenyl- (3-trimethylsilylmethyl-2-trityloxymethyl-cyclopenten-3-yloxy) -silane (compound of formula (IX))

Magnesium (turning) (33g, 5.22mol) was mixed with anhydrous tetrahydrofuran (2L). 1, 2-dibromoethane (8ml) was added thereto and stirred for 15 minutes. To the resulting solution was added dropwise a mixture of chloromethyltrimethylsilane (364ml, 2.61mol) and anhydrous tetrahydrofuran (0.6L) over 10 minutes. The mixed solution thus obtained was heated to 40 ℃ and slowly cooled to precipitate trimethylsilylmethyl magnesium chloride. To the resulting solution was added dropwise a mixture of the compound of the formula (X) obtained in example 2-3 (892g), tetrakis (triphenylphosphine) palladium (37.7g, 0.033mmol) and anhydrous tetrahydrofuran (4.5L) over 20 minutes, and stirred at room temperature for 1 to 2 hours. After completion of the reaction, the resulting solution was cooled to 0 ℃ and 3% aqueous sodium hydrogen sulfonate (8L) was added thereto. The resulting mixture was filtered through celite, washing with ethyl acetate (4L). The organic layer thus separated was concentrated under reduced pressure. The residue thus obtained was mixed with heptane (6L) and celite (400g), stirred for 2 hours, filtered and washed with heptane (2L). The organic layer thus separated was washed twice with a mixture (5.6L) of methanol and water in a mixed weight ratio of 6: 1, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of isopropanol and water to obtain the title compound (786g) as a crystalline solid.

m.p.: 57.8 ℃ to 59.0 DEG C

Examples 2 to 5: preparation of 3- (tert-butyl-diphenyl-siloxy) -1-trimethylsilylmethyl-2-trityloxymethyl-6-oxa-bicyclo [3.1.0] hexane (compound of formula (XIII))

The compound of formula (IX) (786g, 1.14mol) obtained in examples 2-4 was dissolved in isopropanol (12L) and cooled to 0 ℃. To this was added sodium phosphate (2.78kg, 19.58mol) and 77% m-chloroperoxybenzoic acid (292.5g, 1.31mol) in this order and stirred for 2.5 hours. The solid thus obtained was filtered to obtain a mixture (3.25kg) of the title compound and sodium phosphate.

NMR(300MHz，CD₂C1₂+D₂O)：δ7.65-7.22(m，25H)，4.74(t，2H)，3.44(q，1H)，3.27(dd，1H)，3.13(s，1H)，2.88(t，1H)，2.42-2.41(m，1H)，1.99-1.88(m，2H)，1.02-0.93(m，9H)，0.15-0.13(m，9H)

Examples 2 to 6: preparation of 1- (S) -4- (tert-butyl-diphenyl-siloxy) -2-methylene-3-trityloxymethylcyclopentanol (compound of formula (VII))

A mixture of the compound of formula (XIII) obtained in examples 2 to 5 and sodium phosphate (3.25kg) was mixed with methanol (8L) and dichloromethane (4L). 77% m-chloroperoxybenzoic acid (292.5g) was added thereto and stirred for 1 to 1.5 hours. After completion of the reaction, the resulting mixture was filtered to remove sodium phosphate, and the solid thus obtained was washed with dichloromethane (4L). To the thus-obtained substance was added a mixed solution of a 20% aqueous solution of sodium hydrogensulfate (2.4L) and a 6% aqueous solution of sodium hydrogencarbonate (4.8L) and rapidly cooled. The organic layer thus obtained was separated and the aqueous layer was extracted with dichloromethane (4L). The thus-separated organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (587.3g, yield of the compound of formula (VII) from the compound of formula (III): 72%).

NMR(300MHz，CDCl₃)：δ7.84-7.58(m，5H)，7.33-7.18(m，39H)，5.40(s，9.2H)，5.18(s，1H)，5.11(s，0.2H)，4.99(s，1H)，4.65(d，1H)，4.13(q，2H)，3.02(m，3H)，2.87(m，2H)，1.88(d，1H)，1.00(s，17H)

Examples 2 to 7: preparation of 1-benzoyl-4- (tert-butyl-diphenyl-siloxy) -2-methylene-3-trityloxymethyl-cyclopentane, a compound of formula (II)

The compound of the formula (VII) obtained in examples 3-6 (500g, 0.8mol), triphenylphosphine (314.8g, 1.2mol) and benzoic acid (146.7g, 1.2mol) were mixed in tetrahydrofuran (10L) and cooled to 0 ℃. DIAD (242.7ml, 1.2mol) was added dropwise thereto and stirred at 0 ℃ for 1 hour. After completion of the reaction, the resulting mixture was concentrated under reduced pressure to remove the solvent. Ethyl acetate (5L) was added thereto and washed with 0.5N aqueous sodium hydroxide (5L). To the organic layer thus separated was added sodium sulfate, dried, filtered and concentrated. The resulting material was dissolved in ethyl acetate (1L), and methanol (4L) was added to crystallize the title compound. The thus-obtained solid was filtered to obtain the title compound (408.3g, yield: 70.0%) as a solid.

m.p.: 142.3 ℃ to 144 DEG C

Examples 2 to 8: preparation of 1- (R) -4- (tert-butyl-diphenyl-siloxy) -2-methylene-3-trityloxymethylcyclopentanol (compound of formula (III))

Sodium hydroxide (80g, 2mol) and methanol (4.0L) were mixed in the reactor. To this were added the compound of the formula (II) obtained in examples 2 to 7 (400g, 0.5487mol) and methylene chloride (2.0L) and reacted at room temperature for 5 hours. After completion of the reaction, the resulting mixture was washed with water (2L). To the thus-separated organic layer was added sodium sulfate, dried and filtered to obtain the title compound (341g, yield: 99%).

Examples 2 to 9: preparation of 9- [4- (tert-butyl-diphenyl-siloxy) -2-methylene-3-trityloxymethyl-cyclopentyl ] -6-chloro-9H-purin-2-ylamine (compound of formula (V))

Triphenylphosphine (216g, 0.823mol) was dissolved in tetrahydrofuran (3.43L) and cooled to 0 ℃. DEAD (130ml, 0.823mol) was added thereto and stirred at 0 ℃ for 1 hour to obtain a suspension. This suspension was added to a mixed solution of the compound of the formula (III) obtained in example 2-8 (341g, 0.5487mol) and a tetrahydrofuran solution (3.43L) of 2-amino-6-chloropurine (140g, 0.823mol) at 0 ℃ and stirred at the same temperature for 1 hour. After completion of the reaction mixture, ethyl acetate (3.43L) was added to the resulting mixture, and washed with 0.5N aqueous sodium hydroxide solution (3.43L) at 0 ℃. The thus-obtained substance was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (426g, yield: 99%).

Examples 2 to 10: preparation of 4- (2-amino-6-chloro-4, 5-dihydro-purin-9-yl) -3-methylene-2-trityloxymethyl-cyclopentanol (compound of formula (VI))

A solution was prepared by dissolving the compound of formula (V) obtained in examples 2 to 9 (426g, 0.5487mol) in anhydrous tetrahydrofuran (4L), to which 1M tetrahydrofuran solution of tetrabutylammonium fluoride (1.1L, 1.10mol) was added, and stirred at room temperature for 13 hours. After completion of the reaction, distilled water (2.0L) was added to the resultant mixture, and extracted twice with ethyl acetate (2.0L). The organic layer thus separated was dried over anhydrous sodium sulfate, filtered and concentrated. The resultant material was stirred in methanol (4.0L) to give the title compound (212.6g, yield: 72%).

Examples 2 to 11: preparation of 2-amino-9- (4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl) -1, 9-dihydro-purin-6-one (entecavir of formula (I))

The compound of formula (VI) obtained in examples 2-10 (200g, 0.372mol) was mixed with acetonitrile (3L) and 2N aqueous hydrochloric acid (3L) and stirred with heating at 82 ℃ for 12 hours. After completion of the reaction, the resulting solution was cooled to room temperature and washed with ethyl acetate (3L) to remove trityl methanol. The resultant was neutralized with 3N aqueous sodium hydroxide solution (1.2L) to pH 7 and stirred at 90 ℃ for 1 hour to give a solution. The resulting solution was slowly cooled to room temperature with stirring, and further stirred at room temperature for 1 hour to crystallize. The resultant was cooled to 6 ℃ and stirred for 1 hour to obtain the title compound (80.2g, yield: 73%) as a solid.

While the invention has been described in terms of the above specific embodiments, it will be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

1. A process for preparing entecavir of formula (I) comprising the steps of:

(d) hydrolyzing a compound of formula (VI):

wherein:

R₃is benzoyl or arylbenzoyl; and

x is halogen or benzyloxy.

2. The method of claim 1, wherein the hydroxyl protecting group is selected from methyl with one, two, or three phenyl substituents; benzyl substituted by alkoxy or nitro; a benzoyl group; benzoyl substituted with alkoxy or nitro; a silyl group; a silyl group substituted with at least one selected from an alkyl group and an aryl group; an allyl group; an alkoxyalkyl group; and a tetrahydropyranyl group.

3. The method of claim 1, wherein the cyclic hydroxyl protecting group is selected from the group consisting of benzylidene, naphthylidene, 4-phenylbenzylidene, cyclic acetal, cyclic ketal, cyclic carbonate, cyclic orthoester, and cyclic 1,3- (1, 1,3, 3-tetraisopropyl) disiloxanediyl.

4. The method according to claim 1, wherein X in the purine derivative of formula (IV) is chloro or benzyloxy.

5. The method of claim 1, wherein the Mitsunobu reaction is between triphenylphosphine and bis (C) azodicarboxylate₁～C₆Alkyl) esters.

6. The process of claim 1, wherein the α -exomethylene derivative of formula (II) is prepared by Mitsunobu reaction of a β -exomethylene derivative of formula (VII):

wherein R is₁And R₂As defined in claim 1.

7. The method of claim 6, wherein the Mitsunobu reaction is carried out by reacting a β -exomethylene derivative of formula (VII) with triphenylphosphine and bis (C) azodicarboxylate₁～C₆Alkyl) ester reaction.

8. The process of claim 6, wherein the β -exomethylene derivative of formula (VII) is prepared by hydrolysis of an epoxide derivative of formula (VIII):

wherein R is₁And R₂As defined in claim 1, Y is an alkylsilyl group or an arylsilyl group.

9. The method of claim 8, wherein the epoxide derivative of formula (VIII) is prepared by reacting a compound of formula (IX) with a peroxide, osmium tetroxide or sodium periodate:

the reaction is carried out to prepare the compound,

10. The process of claim 9, wherein the peroxide is selected from the group consisting of m-chloroperoxybenzoic acid, hydrogen peroxide, t-butyl hydroperoxide, and mixtures thereof.

11. The process of claim 9, wherein the compound of formula (IX) is a crystalline solid.

12. The process according to claim 9, wherein the enol triflate derivative of formula (X) is prepared by reacting in the presence of a metal catalyst:

(ii) with an alkylsilylmethylmagnesium chloride or arylsilylmethylmagnesium chloride to produce the compound of formula (IX),

wherein R is₁And R₂Tf is trifluoromethanesulfonyl, as defined in claim 1.

13. The method of claim 12, wherein the metal catalyst is tetrakis (triphenylphosphine) palladium.

14. The process according to claim 12, wherein the enol triflate derivative of formula (X) is prepared by reacting a compound of formula (XI) with a triflating agent in the presence of a base:

wherein R is₁And R₂As defined in claim 1.

15. The method of claim 14, wherein the reaction is carried out at a temperature in the range of 20 ℃ to-29 ℃.

16. The method of claim 14, wherein the base is selected from the group consisting of lithium hexamethyldisilazane, potassium hexamethyldisilazane, sodium hexamethyldisilazane, lithium diisopropylamide, n- (C)₁～C₆Alkyl) lithium, tetramethyllithium piperidine, potassium butoxide, potassium pentoxide, potassium amylate, and mixtures thereof.

17. The method of claim 14, wherein the triflating agent is selected from triflic anhydride; having a structure of C₁～C₆Alkyl or C6-C₁₈Aryl N-substituted trifluoromethanesulfonylimide; and mixtures thereof.

18. The process of claim 14, wherein the compound of formula (XI) is prepared by a process comprising the steps of:

by using (+) -diisopinocampheylborane and H₂O₂Treating the cyclopentene derivative of formula (XII), extracting the resulting mixture with a hydrocarbon-based solvent to separate an organic layer, washing the separated organic layer with a mixture of water and an alcohol, and crystallizing the compound of formula (XIII) by adding a solvent as a crystallization aid, thereby preparing the cyclopentanol compound of formula (XIII) as a crystalline solid; and

using pyridine SO₃Oxidizing the cyclopentanol compound of formula (XIII) with a mixture of the complex, trialkylamine and dimethylsulfoxide:

wherein R is₁And R₂As defined in claim 1The meanings are the same.

19. The method of claim 18, wherein the washing process uses a mixture of 1: 1 to 1: 3 of water and alcohol is carried out 3 times or more.

20. The method of claim 18, wherein the washing process is performed 5 times using any one of a mixture of water and alcohol mixed in a weight ratio of 1: 1, 1: 1.5, 1: 2, 1: 2.5, or 1: 3.

21. The process according to claim 18, wherein the solvent used as crystallization aid is selected from the group consisting of hexane, heptane, octane, methanol, ethanol, isopropanol, water and mixtures thereof.

22. A process for preparing a solvate of crystalline entecavir dimethylformamide of formula (XIV) comprising the steps of:

treating the compound obtained by the hydrolysis of step (d) in claim 1 with dimethylformamide to obtain the crystalline solvate form of entecavir dimethylformamide of formula (XIV); and

recrystallizing the solvate of entecavir dimethylformamide of formula (XIV) from water:

wherein DMF is dimethylformamide.