TWI588146B - Synthetic method of entecavir and intermediate compounds thereof - Google Patents

Description

Synthetic method of entecavir and its intermediate compounds

The present invention relates to a method for preparing a pharmaceutical and an intermediate compound thereof, and more particularly to a method for producing entecavir, an intermediate compound thereof, and a method for synthesizing the intermediate compound.

Entecavir, a compound represented by the following formula (1), 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2- Methylcyclopentyl]-6H-indol-6-one is a new nucleoside antiviral drug.

Entecavir is the third anti-hepatitis B virus (HBV) drug listed after lamivudine and adefovir dipivoxil, and is the most potent anti-HBV drug currently on the market. The anti-HBV effect of entecavir is 100 times that of lamivudine and more than 30 times that of adefovir dipivoxil; its side effects are extremely low, the selection index is greater than 8000, and the HBV virus resistant to lamivudine is also very Good curative effect, in theory, provides a possibility for the cure of hepatitis B.

At present, there are mainly the following synthetic routes for the preparation of entecavir.

The preparation method of entecavir is disclosed in Chinese patent ZL91110831.9 and international application WO98/09964. The method comprises the following steps: reacting cyclopentadiene 8 with chloromethylbenzyl ether and dioxene borane complex (Ipc ₂ BH) prepared from (+)-α-pinene to obtain chiral intermediate 9 And epoxidized with t-butanol peroxide to catalyze the oxidation of vanadium oxyhydroxide [VO(acac) ₂ ] to obtain 10.10 which is reacted with benzyl bromide under the action of sodium hydride and tetrabutylammonium iodide to obtain 11.11 in hydrogenation. Reaction with 6-benzyloxy-2-aminoindole 12 under lithium affords 13. The amino group is protected by mono-p-methoxytriphenylchloromethane (MMTC1) to obtain 14 and then oxidized to a keto group by Dess-Martin reagent to obtain 15.15 under the action of Nysted reagent and titanium tetrachloride. The methyleneation reaction gave 16. Subsequent reaction with hydrochloric acid removes the MMT on the amino group and the benzyl group on the anthracene ring to obtain 17, and finally removes the benzyl group on the carbocyclic hydroxyl group under the action of boron trichloride to obtain entecavir. This method is shown in the following flow.

The preparation method has the problem that the starting material requires expensive chiral boron reagent, and the final debenzylation adopts highly toxic boron trichloride. The intermediate synthesis is difficult, the reaction conditions are harsh, and the equipment requirements are high, and some reagents are required. The cost is higher.

In addition, a synthesis method using Compound 2' as a raw material is disclosed in the patent application of the company (Publication No. WO 2004/052310 A2), as shown in the following scheme.

The Applicant has attempted to synthesize entecavir by the above method of WO2004/052310A2, and found that the Mitsunobu reaction of the amino-protected 2-aminoindole compound 23 and the intermediate 4 provided by the method has low yield and unstable yield, and The obtained unprotected coupling product 24 of the amino group is similar to the polarity of the triphenylphosphine oxide formed by the reagent triphenylphosphine in the reaction, and is difficult to be separated and purified; and the intermediate obtained by coupling the product 24 and then removing the hydroxy protecting group The water solubility of 25 is strong, and it is difficult to separate and purify by simple extraction, and the yield is low. The method of the patent is not conducive to industrial production.

In addition, in the above method, although it is also mentioned that the above compound 2' can be used as a raw material, a photochemical method can be used to form an iodo compound under the action of iodophenyl acetate and iodine, and then an intermediate is prepared by elimination reaction and alcoholysis reaction. 4, but the patent does not provide specific experimental examples and experimental data to confirm the feasibility of the method.

We have attempted to use the literature conditions of the relevant reaction: PhI(OAc) ₂ /I ₂ , hv (Tetrahedron Letters, 1987, 28, 3397-3400) using the above method described in WO 2004/052310 A2 to prepare the intermediate 4 It was found that the method has low yield and is difficult to be applied to industrial production.

The following method is also disclosed in Chinese Chemical Letters, 2006, 17(7) 907-910 and Chinese Patent Application Publication No. CN 1861602A, as shown in the following scheme.

However, the above preparation method has a long synthetic route, complicated experimental operation, and is difficult to be applied to industrial production.

Therefore, there is a need to develop a new preparation method that overcomes the above problems and is convenient for industrial production.

In the present invention, the following terms have the meanings described below:

The term "alkyl", alone or in combination with other groups, denotes a straight or branched monovalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. "C _1-6 alkyl" means a branched or straight-chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl Base, n-hexyl.

"Halogen" means fluoro, chloro, bromo or iodo.

"Haloalkyl" means an alkyl group, as defined above, substituted by one or more halogens, such as trifluoromethyl.

The term "alkoxy", alone or in combination with other groups, denotes a group R'-O-, wherein R' is alkyl as described above. "C _1-6 alkoxy" denotes a group R'-O-, wherein R' is C _1-6 alkyl as described above.

"Haloalkoxy" means an alkoxy group as defined above substituted by one or more halogens, for example trifluoromethoxy.

"Aryl" means a monocyclic or fused bicyclic aromatic ring containing a carbon atom. "C _5-10 aryl" means an aryl group having 5 to 10 carbon atoms. For example, the C _5-10 aryl group can be phenyl or naphthyl.

"Aralkyl" means an alkyl group as described above substituted with an aryl group as described above.

"Aralkoxy" refers to an alkoxy group as described above which is substituted with an aryl group as described above.

"Amidino" refers to the group -CO-R, wherein R is alkyl, aryl, aralkyl as described above.

The aryl groups described above, whether as a group itself or as part of other groups such as aralkyl groups, aralkyloxy groups, may be optionally substituted with one or more substituents. When the aryl group is substituted, the substituent is preferably selected from a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen, an aryl group and a nitro group, more preferably selected from the group consisting of a methoxy group and an ethoxy group. Base, halogen, phenyl and nitro.

The present invention provides a novel method for synthesizing entecavir, which has fewer reaction steps, is simple to operate, and can improve yield and reduce cost.

In one aspect, the invention relates to a method of synthesizing entecavir (compound of formula 1) using a 2-protected amino-6-substituted indole compound as a starting material, the method comprising the steps of:

c) Compound 4 is reacted with 2-protected amino-6-substituted indole compound 5 by Mitsunobu to obtain a coupled product 6

among them:

R ₁ and R ₂ may be the same or different and are each independently selected from the hydroxy protecting groups described in the following groups (i) to (iii):

(i) R ₁ and R ₂ are each independently selected from alkyl, haloalkyl, benzyl, t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si, preferably t-BuMe ₂ Si; or

(ii) R ₁ and R ₂ are each independently selected from the group consisting of t-BuMe ₂ Si, t-BuPh ₂ Si, benzamyl, tetrahydropyran-2-yl, and benzamidine with a substituent on the benzene ring. a base, a biphenyl-4-methylindenyl group, a trityl group, but R ₁ and R _{2 are} not simultaneously t-BuMe ₂ Si;

(iii) R ₁ and R ₂ together with the attached five-membered carbocyclic ring form one of the fused ring systems described below:

Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group. And R ₄ and R ₅ may be the same or different and each represents a C _1-6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates a point of attachment of the fused ring to other moieties of the molecule; The fused ring is preferably one of the fused ring systems described below:

R and R' may be the same or different and each represent hydrogen, an alkoxycarbonyl or an aralkoxycarbonyl group, for example a _C1-6 alkoxycarbonyl group or a _C5-10 aralkoxycarbonyl group, preferably a tert-butoxycarbonyl group. with the proviso that R and R 'are not simultaneously hydrogen; X is halogen, alkoxy, haloalkoxy or aralkyl group, for example C _1-6 alkoxy, halo C _1-6 alkoxy, or C _{5 a -10} aralkyloxy group, preferably chlorine, methoxy, benzyloxy, tert-butoxy, particularly preferably chlorine;

d) when both R ₁ and R ₂ are a thiol protecting group or neither are a thiol protecting group, the compound 6 is deprotected from the hydroxy protecting group to give the compound 7

Wherein X, R ₁ , R ₂ , R and R' are as defined above;

e) hydrolysis of compound 7 to give the compound of formula 1 (entecavir)

Wherein X, R and R' are as defined above; or

d') when neither R ₁ nor R ₂ is a thiol protecting group, compound 6 is simultaneously deprotected and hydrolyzed to directly obtain a compound of formula 1

Wherein X, R ₁ , R ₂ , R and R' are as defined above, or

(d") When one of R ₁ and R ₂ is a mercapto protecting group such as a benzamidine group, a benzamidine group having a substituent on a benzene ring, or a benzamidine group, the compound 6 is subjected to Deprotection gives 8 or 9, which is hydrolyzed or hydrolyzed by compound 7 to give compound 1

Wherein X, R ₁ , R ₂ , R and R' are as defined above.

In the above step c), the reaction of the compound 4 with the compound 5 is carried out in the presence of a Mitsunobu reaction reagent such as Ph ₃ P/EtO ₂ CN=NCO ₂ Et or Ph ₃ P/i-PrO ₂ CN=NCO ₂ i-Pr. It is carried out in an aprotic solvent such as an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, a halogenated hydrocarbon or an ether such as THF.

In the above step d), the deprotection of compound 6 is in the presence of an acid (for example, when both R ₁ and R ₂ are a hydrazine protecting group) or a base (for example, when both R ₁ and R ₂ are a thiol protecting group) For example, in the presence of a quaternary ammonium salt such as hydrochloric acid, hydrogen fluoride, formic acid or a fluoride ion such as tetrabutylammonium fluoride (TBAF) or pyridine hydrofluoride or potassium carbonate, an alkoxide such as sodium alkoxide, preferably It is carried out in the presence of tetrabutylammonium fluoride (TBAF) or hydrochloric acid. The reaction is carried out in a suitable organic solvent or a mixture thereof with water, such as tetrahydrofuran, dichloromethane, methanol or ethanol or any combination thereof.

In the above step e), the hydrolysis of the compound 7 is carried out under acidic or basic conditions, preferably in the presence of hydrochloric acid or formic acid, in water or a mixed solvent of water and other organic solvents, for example in tetrahydrofuran or ethanol and water. In the mixture. More preferably, it is carried out in tetrahydrofuran in the presence of hydrochloric acid.

In the above step d'), the deprotection and hydrolysis of the compound 6 may be carried out in the presence of a hydrohalic acid such as dilute hydrochloric acid such as 0.1 N to 3 N of dilute hydrochloric acid in a suitable organic solvent or a mixture thereof with water, for example It is carried out in methanol, ethanol or tetrahydrofuran or a mixture thereof with water.

In the above step d"), the compound 8, 9 obtained from the compound 6 can be directly obtained as the compound 1, or the compound 1 can be further obtained through the compound 7, depending on whether the first deprotection group or the first deprotection group is protected in this step. The sulfhydryl protecting group is removed by alkaline hydrolysis, for example, in the presence of a base, for example, in the presence of potassium carbonate, an alkali metal hydroxide, an alkoxide such as sodium alkoxide.

Thus, in a preferred embodiment, entecavir of formula (1) is synthesized by the following method:

c) compound 4 and 2-amino protected -6-substituted indole compound 5 in the presence of Ph ₃ P/EtO ₂ CN=NCO ₂ Et or Ph ₃ P/i-PrO ₂ CN=NCO ₂ i-Pr, The reaction is carried out in an aprotic solvent such as an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, a halogenated hydrocarbon or an ether such as THF to obtain a coupled product 6;

d) removing the hydroxy protecting group from compound 6 in the presence of tetrabutylammonium fluoride (TBAF) or hydrochloric acid to give compound 7;

e) Hydrolysis of compound 7 in the presence of hydrochloric acid in tetrahydrofuran affords the compound of formula 1.

In the above steps c) to e), the reaction time may be from several minutes to several days, for example, from 30 minutes to 14 days, depending on the conditions used; the reaction temperature is from about -78 ° C to the reflux temperature of the solvent, for example, from 0 ° C to 150 ° C. Especially at room temperature to the reflux temperature of the solvent.

Applicants have found that in the above step c), when a 2-protected amino-6-substituted anthracene compound is used as a raw material, the reaction rate of the above Mitsunobu reaction can be accelerated and the reaction yield can be greatly increased, thereby preparing entecavir. The overall yield is greatly improved. Without wishing to be bound by any theory, it is believed that the above reaction rate is increased and the yield is increased because the 2-amino protected -6-substituted fluorene compound 5 overcomes the problem of poor solubility of the amino hydrazine compound in the reaction solvent, and The physicochemical properties of the obtained coupled product intermediate are improved, and the subsequent reaction and purification of the intermediate are easy to handle. The 2-amino protected -6-substituted fluorene compound of the present invention can be used according to the literature ( J. Org. Chem. 2000, 65 , 7697-7699) for 2-tert-butoxycarbonylamino-6-chloroguanine. The synthetic method described is prepared by using 2-amino-6-substituted guanine as a raw material.

In the above process, the intermediate compounds of the formulae 6 and 7 are novel compounds.

Thus, in one aspect, the invention also relates to a compound of the formula:

among them,

R ₁ and R ₂ may be the same or different and are each independently selected from hydrogen or a hydroxy protecting group as described in the following groups (i) to (iii):

(i) R ₁ and R ₂ are each independently selected from alkyl, haloalkyl, benzyl, t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si, preferably t-BuMe ₂ Si; or

(ii) R ₁ and R ₂ are each independently selected from the group consisting of t-BuMe ₂ Si, t-BuPh ₂ Si, benzamyl, tetrahydropyran-2-yl, and benzamidine with a substituent on the benzene ring. a base, a biphenyl-4-methylindenyl group, a trityl group, but R ₁ and R _{2 are} not simultaneously t-BuMe ₂ Si;

(iii) R ₁ and R ₂ together with the attached five-membered carbocyclic ring form one of the fused ring systems described below:

Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group. And R ₄ and R ₅ may be the same or different and each represents a C _1-6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates a point of attachment of the fused ring to other moieties of the molecule; The fused ring is preferably one of the fused ring systems described below:

R and R' may be the same or different and each represent hydrogen, an alkoxycarbonyl or an aralkoxycarbonyl group, for example a _C1-6 alkoxycarbonyl group or a _C5-10 aralkoxycarbonyl group, preferably a tert-butoxycarbonyl group. with the proviso that R and R 'are not simultaneously hydrogen; X is halogen, alkoxy, haloalkoxy or aralkyl group, for example C _1-6 alkoxy, halo C _1-6 alkoxy, or C _{5 A -10} aralkoxy group, preferably chlorine, methoxy, benzyloxy or tert-butoxy, particularly preferably chlorine.

Among the compounds of the above formula, the compounds of the following table are particularly preferred:

In another aspect, the present invention is also directed to a process for the preparation of a compound of formula 6, which comprises reacting compound 4 with a 2-amino protected -6-substituted indole compound 5 in the presence of a Mitsunobu reagent to obtain a coupled product 6

among them,

R ₁ and R ₂ may be the same or different and are each independently selected from the hydroxy protecting groups described in the following groups (i) to (iii):

(i) R ₁ and R ₂ are each independently selected from alkyl, haloalkyl, benzyl, t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si, preferably t-BuMe ₂ Si; or

(ii) R ₁ and R ₂ are each independently selected from the group consisting of t-BuMe ₂ Si, t-BuPh ₂ Si, benzamyl, tetrahydropyran-2-yl, and benzamidine with a substituent on the benzene ring. a base, a biphenyl-4-methylindenyl group, a trityl group, but R ₁ and R _{2 are} not simultaneously t-BuMe ₂ Si;

(iii) R ₁ and R ₂ together with the attached five-membered carbocyclic ring form one of the fused ring systems described below:

Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group. And R ₄ and R ₅ may be the same or different and each represents a C _1-6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates a point of attachment of the fused ring to other moieties of the molecule; The fused ring is preferably one of the fused ring systems described below:

R and R' may be the same or different and each represent hydrogen, an alkoxycarbonyl or an aralkoxycarbonyl group, for example a _C1-6 alkoxycarbonyl group or a _C5-10 aralkoxycarbonyl group, preferably a tert-butoxycarbonyl group. with the proviso that R and R 'are not simultaneously hydrogen; X is halogen, alkoxy, haloalkoxy or aralkyl group, for example C _1-6 alkoxy, halo C _1-6 alkoxy, or C _{5 A -10} aralkoxy group, preferably chlorine, methoxy, benzyloxy or tert-butoxy, particularly preferably chlorine. The reaction conditions of this reaction are as described above.

In another aspect, the present invention is also directed to a process for the preparation of a compound of formula 7, which comprises deprotecting compound 6 from a hydroxy protecting group to provide compound 7,

among them,

R ₁ and R ₂ may be the same or different and are each independently selected from the hydroxy protecting groups described in the following groups (i) to (iii):

(i) R ₁ and R ₂ are each independently selected from alkyl, haloalkyl, benzyl, t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si, preferably t-BuMe ₂ Si; or

(ii) R ₁ and R ₂ are each independently selected from the group consisting of t-BuMe ₂ Si, t-BuPh ₂ Si, benzamyl, tetrahydropyran-2-yl, and benzamidine with a substituent on the benzene ring. a base, a biphenyl-4-methylindenyl group, a trityl group, but R ₁ and R _{2 are} not simultaneously t-BuMe ₂ Si;

(iii) R ₁ and R ₂ together with the attached five-membered carbocyclic ring form one of the fused ring systems described below:

Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group. And R ₄ and R ₅ may be the same or different and each represents a C _1-6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates a point of attachment of the fused ring to other moieties of the molecule; The fused ring is preferably one of the fused ring systems described below:

R and R' may be the same or different and each represent hydrogen, an alkoxycarbonyl or an aralkoxycarbonyl group, for example a _C1-6 alkoxycarbonyl group or a _C5-10 aralkoxycarbonyl group, preferably a tert-butoxycarbonyl group. with the proviso that R and R 'are not simultaneously hydrogen; X is halogen, alkoxy, haloalkoxy or aralkyl group, for example C _1-6 alkoxy, halo C _1-6 alkoxy, or C _{5 A -10} aralkoxy group, preferably chlorine, methoxy, benzyloxy or tert-butoxy, particularly preferably chlorine. The reaction conditions of the reaction are as described above.

In another aspect, the invention relates to a compound of formula 4:

among them,

R ₁ and R ₂ may be the same or different and are each independently selected from the hydroxy protecting groups described in the following groups (i) to (iii):

(i) R ₁ and R ₂ are each independently selected from alkyl, haloalkyl, benzyl, t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si, preferably t-BuMe ₂ Si; or

(ii) R ₁ and R ₂ are each independently selected from the group consisting of t-BuMe ₂ Si, t-BuPh ₂ Si, benzamyl, tetrahydropyran-2-yl, and benzamidine with a substituent on the benzene ring. a base, a biphenyl-4-methylindenyl group, a trityl group, but R ₁ and R _{2 are} not simultaneously t-BuMe ₂ Si;

(iii) R ₁ and R ₂ together with the attached five-membered carbocyclic ring form one of the fused ring systems described below:

Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group. And R ₄ and R ₅ may be the same or different and each represents a C _1-6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates a point of attachment of the fused ring to other moieties of the molecule; The fused ring is preferably one of the fused ring systems described below:

Among the above compounds of the formula 4, the following compounds are preferred:

Compound 4 can be synthesized by a similar method as described in the literature, or Compound 4 can also be synthesized using Compound 2 as a raw material by the following method:

a) ring opening of compound 2 directly to obtain cyclopentane intermediate 3

among them,

R ₁ and R ₂ may be the same or different and are each independently selected from the hydroxy protecting groups described in the following groups (i) to (iii):

(i) R ₁ and R ₂ are each independently selected from alkyl, haloalkyl, benzyl, t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si, preferably t-BuMe ₂ Si; or

(ii) R ₁ and R ₂ are each independently selected from the group consisting of t-BuMe ₂ Si, t-BuPh ₂ Si, benzamyl, tetrahydropyran-2-yl, and benzamidine with a substituent on the benzene ring. a base, a biphenyl-4-methylindenyl group, a trityl group, but R ₁ and R _{2 are} not simultaneously t-BuMe ₂ Si;

(iii) R ₁ and R ₂ together with the attached five-membered carbocyclic ring form one of the fused ring systems described below:

Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group. And R ₄ and R ₅ may be the same or different and each represents a C _1-6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates a point of attachment of the fused ring to other moieties of the molecule; The fused ring is preferably one of the fused ring systems described below:

b) Compound of formula 3 is subjected to alcoholysis or hydrolysis to give compound 4

Wherein R ₁ and R ₂ are as defined above.

Compound 2 can be produced according to a method known in the literature, for example, according to the method disclosed in EP134153 or a method analogous thereto, or the method as described in the examples or the like.

In the above step a), a suitable reagent for catalyzing and initiating a free radical cleavage reaction of the compound 2 in the copper (II) salt, such as PhI(OAc) ₂ , Mn(OAc) ₃ or Pb(OAc) ₄ , preferably Pb (OAc Directly ring-opening under the action of ₄ gives cyclopentane intermediate 3. The reaction can be carried out in a hydrocarbon solvent such as benzene, toluene, cyclohexane, petroleum ether or n-heptane or in an aprotic polar solvent such as acetonitrile, ethyl acetate or a halogenated hydrocarbon or a halogenated aromatic hydrocarbon such as trifluorotoluene or a mixture thereof. This is carried out, preferably in the presence of an organic base such as triethylamine or pyridine.

In the above step b), the compound of the formula 3 is present in the presence of a base such as ammonia, triethylamine, K ₂ CO ₃ or an alkoxide in an organic solvent such as methanol, ethanol or a mixture thereof or in water or water and other organic solvents. A mixed solvent such as a mixture of EtOH and water is subjected to alcoholysis or hydrolysis to give Compound 4. The reaction in this step is preferably carried out using K ₂ CO ₃ and methanol.

Thus, in a preferred embodiment, the compound of formula 4 is synthesized by the following method:

a) the compound 2 is catalyzed by a copper (II) salt and Pb(OAc) ₄ , preferably in the presence of an organic base such as triethylamine or pyridine to directly give a cyclopentane intermediate 3;

b) The compound of formula 3 is subjected to alcoholysis in methanol in the presence of K ₂ CO ₃ to give compound 4.

In each step of the above method, the reaction time may be from several minutes to several days, for example, from 30 minutes to 14 days, depending on the conditions used; the reaction temperature is from about -78 ° C to the reflux temperature of the solvent, for example, from 0 ° C to 150 ° C, In particular, from room temperature to the reflux temperature of the solvent.

The compound of formula 3 produced in the above step a) is a novel compound.

Thus, in one aspect, the invention also relates to a compound of formula 3:

among them,

R ₁ and R ₂ may be the same or different and are each independently selected from the hydroxy protecting groups described in the following groups (i) to (iii):

(i) R ₁ and R ₂ are each independently selected from alkyl, haloalkyl, benzyl, t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si, preferably t-BuMe ₂ Si; or

(ii) R ₁ and R ₂ are each independently selected from the group consisting of t-BuMe ₂ Si, t-BuPh ₂ Si, benzamyl, tetrahydropyran-2-yl, and benzamidine with a substituent on the benzene ring. a base, a biphenyl-4-methylindenyl group, a trityl group, but R ₁ and R _{2 are} not simultaneously t-BuMe ₂ Si;

(iii) R ₁ and R ₂ together with the attached five-membered carbocyclic ring form one of the fused ring systems described below:

Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group. And R ₄ and R ₅ may be the same or different and each represents a C _1-6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates a point of attachment of the fused ring to other moieties of the molecule; The fused ring is preferably one of the fused ring systems described below:

A particularly preferred compound of formula 3 is (1R,3R,4S)-4-(tert-butyldimethylamyloxy)-3-[(tert-butyldimethylamyloxy)methyl]-2-a Methyl-cyclopentanol formate having the following structural formula:

Further, it is particularly preferable that the compound of the formula 3 is a compound having the following structure:

In another aspect, the invention is also directed to a method of preparing a compound of formula 3, the method comprising the steps of:

a) ring opening of compound 2 directly to obtain cyclopentane intermediate 3

among them,

R ₁ and R ₂ may be the same or different and are each independently selected from the hydroxy protecting groups described in the following groups (i) to (iii):

(i) R ₁ and R ₂ are each independently selected from alkyl, haloalkyl, benzyl, t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si, preferably t-BuMe ₂ Si; or

(ii) R ₁ and R ₂ are each independently selected from the group consisting of t-BuMe ₂ Si, t-BuPh ₂ Si, benzamyl, tetrahydropyran-2-yl, and benzamidine with a substituent on the benzene ring. a base, a biphenyl-4-methylindenyl group, a trityl group, but R ₁ and R _{2 are} not simultaneously t-BuMe ₂ Si;

(iii) R ₁ and R ₂ together with the attached five-membered carbocyclic ring form one of the fused ring systems described below:

Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group. And R ₄ and R ₅ may be the same or different and each represents a C _1-6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates a point of attachment of the fused ring to other moieties of the molecule; The fused ring is preferably one of the fused ring systems described below:

The reaction conditions of step a) are as described above.

In another aspect, the invention also relates to a process for the preparation of a compound of formula (1) using compound 2 as a starting material, the process comprising the steps of:

a) ring opening of compound 2 directly to obtain cyclopentane intermediate 3

among them,

R ₁ and R ₂ may be the same or different and are each independently selected from the hydroxy protecting groups described in the following groups (i) to (iii):

(i) R ₁ and R ₂ are each independently selected from alkyl, haloalkyl, benzyl, t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si, preferably t-BuMe ₂ Si; or

(ii) R ₁ and R ₂ are each independently selected from the group consisting of t-BuMe ₂ Si, t-BuPh ₂ Si, benzamyl, tetrahydropyran-2-yl, and benzamidine with a substituent on the benzene ring. a base, a biphenyl-4-methylindenyl group, a trityl group, but R ₁ and R _{2 are} not simultaneously t-BuMe ₂ Si;

(iii) R ₁ and R ₂ together with the attached five-membered carbocyclic ring form one of the fused ring systems described below:

Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group. And R ₄ and R ₅ may be the same or different and each represents a C _1-6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates a point of attachment of the fused ring to other moieties of the molecule; The fused ring is preferably one of the fused ring systems described below:

b) Compound of formula 3 is subjected to alcoholysis or hydrolysis to give compound 4

Wherein R ₁ and R ₂ are as defined above;

c) Mitsunobu reaction of compound 4 with 2-protected amino-6-substituted indole compound 5 to obtain coupled product 6

Wherein R ₁ and R ₂ are as defined above; R and R' may be the same or different and each represent hydrogen, alkoxycarbonyl or aralkyloxycarbonyl, for example C _1-6 alkoxycarbonyl or C _5-10 aryl. Alkoxycarbonyl, preferably tert-butoxycarbonyl, provided that R and R' are not hydrogen at the same time; X is halogen, alkoxy, haloalkoxy or aralkyloxy, for example _C1-6 alkoxy, halo a C _1-6 alkoxy group or a C _5-10 aralkyloxy group, preferably chlorine, methoxy, benzyloxy, tert-butoxy, particularly preferably chlorine;

d) when both R ₁ and R ₂ are a thiol protecting group or neither are a thiol protecting group, the compound 6 is deprotected from the hydroxy protecting group to give the compound 7

Wherein X, R ₁ , R ₂ , R and R' are as defined above;

e) hydrolysis of compound 7 to give the compound of formula 1 (entecavir)

Wherein X, R and R' are as defined above; or

d') when neither R ₁ nor R ₂ is a thiol protecting group, compound 6 is simultaneously deprotected and hydrolyzed to directly obtain a compound of formula 1

Wherein X, R ₁ , R ₂ , R and R' are as defined above; or

(d") When one of R ₁ and R ₂ is a mercapto protecting group such as a benzamidine group, a benzamidine group having a substituent on a benzene ring, or a benzamidine group, the compound 6 is subjected to Deprotection gives 8 or 9, which is hydrolyzed or hydrolyzed by compound 7 to give compound 1

Wherein X, R ₁ , R ₂ , R and R' are as defined above.

The reaction conditions of the respective steps described above are as described above.

In a preferred embodiment, the method of preparing a compound of formula (1) comprises the steps of:

a) ring opening of compound 2 directly to obtain cyclopentane intermediate 3

b) Compound of formula 3 is subjected to alcoholysis or hydrolysis to give compound 4

c) Mitsunobu reaction of compound 4 with 2-protected amino-6-substituted indole compound 5 to obtain coupled product 6

d) Deprotecting compound 6 from the hydroxy protecting group to give compound 7

e) hydrolysis of compound 7 to give a compound of formula 1

or

d') Compound 6 is simultaneously deprotected and hydrolyzed to directly obtain the compound of formula 1

In each of the above steps, R ₁ and R ₂ may be the same or different and each represents a hydroxy protecting group, for example, an alkyl group, a halogenated alkyl group, a benzyl group, t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr). ₃ Si or Et ₃ Si, preferably t-BuMe ₂ Si; R and R' may be the same or different and each represent hydrogen, an alkoxycarbonyl or an aralkoxycarbonyl group, for example a C _1-6 alkoxycarbonyl group or a C _{5 a -10} aralkyloxycarbonyl group, preferably a tert-butoxycarbonyl group, provided that R and R' are not hydrogen at the same time; X is a halogen, an alkoxy group, a halogenated alkoxy group or an aralkyloxy group, for example a C _1-6 alkoxy group The group is a halogenated C _1-6 alkoxy group or a C _5-10 aralkyloxy group, preferably chlorine, methoxy, benzyloxy or tert-butoxy, particularly preferably chlorine.

The reaction conditions of the above steps a) to e) are as described above.

In a particularly preferred embodiment, entecavir of formula (1) is synthesized by a method comprising the steps of:

a) the compound 2 is catalyzed by a copper (II) salt and Pb(OAc) ₄ , preferably in the presence of an organic base such as triethylamine or pyridine to directly give a cyclopentane intermediate 3;

b) the compound of formula 3 is subjected to alcoholysis in methanol in the presence of K ₂ CO ₃ to give compound 4;

c) compound 4 and 2-protected amino-6-substituted indole compound 5 in the presence of Ph ₃ P/EtO ₂ CN=NCO ₂ Et or Ph ₃ P/i-PrO ₂ CN=NCO ₂ i-Pr, The reaction is carried out in an aprotic solvent such as an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, a halogenated alkane or an ether such as THF to obtain a coupled product 6;

d) removing the hydroxy protecting group from compound 6 in the presence of tetrabutylammonium fluoride (TBAF) or hydrochloric acid to give compound 7;

e) Hydrolysis of compound 7 in the presence of hydrochloric acid in tetrahydrofuran affords the compound of formula 1.

It will be understood by those skilled in the art that in the above process for synthesizing entecavir, the compound of formula (1) can be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any of steps a) to e) as a starting material. For example, a compound of the formula (3) can be used as a raw material and the steps b) to e) as described above can be carried out to prepare a compound of the formula (1), or a compound of the formula (6) can be used as a raw material and the steps as described above can be carried out. d) and e) to prepare the compound of the formula (1), and the compound of the formula (1) can also be directly subjected to the step e) using the compound of the formula (7) as a raw material.

The method of the present invention is further illustrated by the following examples. It is to be understood that the following examples are provided for the purpose of providing a better understanding of the invention.

The abbreviations used in this application have the following meanings.

abbreviation:

Boc tert-butoxycarbonyl

DEAD diethyl azodicarboxylate

EtOAc ethyl acetate

TBAF tetrabutylammonium fluoride

THF tetrahydrofuran

t-BuMe ₂ Si tert-butyldimethylmethyl

Preparation of raw materials:

The starting materials and methods for synthesizing the compound 2 are known and can be synthesized by the following methods or the like.

(1) When the compound 2 R ₁ and R ₂ five ring carbon of attachment to form a fused ring system, as for example the synthesis of the raw material thereof.

Synthesis of a compound of the formula: (4aR, 4bS, 7aR, 8aS)-2-methyl-hexahydro-furo[3',2':3,4]cyclopenta[1,2-d][1 ,3,2]dioxanthene-6(7a H )-one

Under a nitrogen atmosphere, Corey Diol (172 g, 1 mol), 2,6-lutidine (257 ml, 2.2 mol), DMF (1700 g) were added to the reaction flask, and di-tert-butylfluorenyl group was added dropwise with stirring at room temperature. Bis(trifluoromethanesulfonate) ester (400 ml, 1.1 mol), after completion of the reaction, the reaction was completed at room temperature until the material was slowly poured into water to precipitate a solid, which was filtered and dried to give the desired product.

^{_{NMR (CDCl 3, 500MHz) 1}} H NMR: δ = 0.98 (s, 9H), 1.03 (s, 9H), 1.83 (m, 2H), 2.29 (m, 1H), 2.39 (m, 1H,), 2.70 (m, 2H), 3.86 (m, 1H), 2.01 (m, 1H), 4.24 (m, 1H), 4.83 (m, 1H); ¹³ CNMR: δ = 20.04, 22.92, 27.30, 27.62, 33.20, 37.80 , 40.25, 50.52, 68.25, 78.83.

Synthesis of a compound of the formula: (2R, 4aR, 4bS, 7aR, 8aS)-2-methyl-hexahydro-furo[3',2':3,4]cyclopenta[1,2-d ][1,3]dioxine-6(7a H )-one

Under a nitrogen atmosphere, Corey lactone diol (172 g, 1 mol), anhydrous p-toluenesulfonic acid (17.2 g), dichloromethane (1720 ml), acetal (354 g, 3 mol) were added to the reaction flask. After stirring at room temperature for 1 hour, the temperature was refluxed until the reaction was completed, and the crystals were concentrated to give the desired product (90 g).

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 1.32 (d, 3H), 1.63 (m, 1H), 1.82 (m, 1H), 2.27 (m, 2H), 2.63 (m, 2H,), 3.36 ( m, 1H), 3.53 (m, 1H), 4.23 (m, 1H), 4.64 (m, 1H), 4.85 (m, 1H); ¹³ CNMR: δ = 20.70, 32.56, 36.70, 37.07, 45.40, 70.52, 79.84, 80.68, 99.80, 176.18.

(2) when the compound 2 R ₁ and R ₂ are each independently a silicon protecting group or acyl protective groups, for example following synthesis of the raw material.

First, a compound of the formula (TCOD) is synthesized: (3aS, 4R, 5S, 6aR)-hexahydro-5-hydroxy-4-tert-butyldimethylammoniomethyl-2H-cyclopentane[b] Furan-2-one

Under the protection of nitrogen, Corey lactone diol (172 g, 1 mol), imidazole (95.2 g, 1.4 mol), DMF (1000 g) were added to the reaction flask, stirred, and TBDMCl (150.5 g, 1 mol) was added in portions at a controlled temperature. Stir until the reaction is complete. After workup, 220 g of the desired product was obtained.

The following starting materials were synthesized starting from TCOD.

Synthesis of a compound of the formula: (3aS, 4R, 5S, 6aR)-hexahydro-5-tert-butyldiphenylphosphonium-4-tert-butyldimethylammoniomethyl-2H-cyclopentane [b]furan-2-one

Under a nitrogen atmosphere, TCOD (286 g, 1 mol), imidazole (95.2 g, 1.4 mol), DMF (1144 g) were added to the reaction flask, and the mixture was stirred at room temperature, and tert-butyldiphenylchloromethane (330 g, 1.2 mol). The mixture was kept warm until the reaction was completed, and after workup, it was separated by column chromatography to give 515 g of desired product.

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = -0.02 (s, 6H), 0.87 (s, 9H), 1.09 (s, 9H), 2.01 (m, 1H), 2.05 (m, 1H,), 2.14 (m, 1H), 2.64 (m, 2H), 2.80 (m, 1H), 3.3. (m, 1H), 3.44 (m, 1H), 4.15 (m, 1H), 4.84 (m, 1H) 7.39 ( m, 6H) 7.69 (m, 4H); ¹³ C NMR: δ = -5.61, 18.10, 18.97, 25.83, 26.75, 35.89, 39.90, 41.05, 57.24, 63.34, 76.36, 84.52, 127.57, 129.72, 133.58, 135.83, 177.08.

Synthesis of a compound of the formula: (3aS, 4R, 5S, 6aR)-hexahydro-5-(biphenyl-4-methyloxy)-4-tert-butyldimethylammoniomethyl-2H-cyclopentyl Alkano[b]furan-2-one

Under nitrogen protection, TCOD (286 g, 1 mol), imidazole (95.2 g, 1.4 mol), DMF (1144 g) were added to the reaction flask, and the mixture was stirred at room temperature, and biphenylformamidine chloride (239 g, 1.1 mol) was added in portions. ), add heat to the reaction. After workup, 343 g of the desired product was obtained.

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 0.08 (s, 6H), 0.91 (s, 9H), 2.35 (m, 2H), 2.49 (m, 1H), 2.59 (m, 1H,), 2.92 ( m, 2H), 3.70 (m, 1H), 3.76 (m, 1H), 5.11 (m, 1H), 5.38 (m, 19H), 7.74 (m, 9H); ¹³ CNMR: δ=-5.35, 18.37, 26.05, 36.45, 39.28, 40.74, 55.37, 63.64, 78.99, 85.65, 127.40, 128.34, 128.72, 129.11, 130.36, 140.15, 146.08, 166.10, 177.10.

Synthesis of a compound of the formula: (3aS, 4R, 5S, 6aR)-hexahydro-5-benzylideneoxy-4-tert-butyldimethyloxymethyl-2H-cyclopenta[b]furan 2-ketone

Under nitrogen protection, TCOD (286 g, 1 mol), imidazole (95.2 g, 1.4 mol), DMF (1144 g) were added to the reaction flask, and the mixture was stirred at room temperature, and benzamidine chloride (239 g, 1.1 mol) was added dropwise. Keep warm until the reaction is complete. After work-up and column chromatography, 300 g of the desired product was obtained.

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 0.02 (s, 6H), 0.86 (s, 9H), 2.28 (m, 2H), 2.43 (m, 1H), 2.51 (m, 1H,), 2.87 ( m, 2H), 3.64 (m, 1H), 3.70 (m, 1H), 5.03 (m, 1H), 5.28 (m, 1H) 7.67 (m, 5H); ¹³ CNMR: δ = -5.53, 18.18, 25.88 , 36.21, 39.05, 40.55, 55.12, 63.45, 78.78, 85.38, 128.43, 129.72, 133.05, 165.96, 176.85.

When R ₁ or R ₂ in the compound 2 is protected with a trityl protecting group, the synthesis of the starting materials is exemplified below.

Synthesis of Compound (3aS, 4R, 5S, 6aR)-Hexahydro-5-tert-butyldiphenylphosphonium-4-(trityloxymethyl)-2H-cyclopenta[b]furan -2-ketone:

Step 1: Synthesis of TrCOD

In a clean reaction flask, 138 g of lactone diol, 950 g of pyridine, and 300 g of trityl chloride (TrCl) were added, and the reaction was kept until TLC showed that the starting material was completely reacted. Then, the reaction mixture was poured into water, extracted with an organic solvent, washed, dried, and then filtered, and the filtrate was concentrated to dryness to give white solid TrCOD 265 g.

Step 2: Synthesis of hexahydrotert-butyl diphenyl decyloxytrityloxymethylcyclopentanefuranone

41.4g of TrCOD, 20g of imidazole (IMI) and 300ml of DMF were added to the clean reaction flask, stirred, and then 30g of t-butyldiphenylchlorodecane (TBDPSC1) was added dropwise. After about 1 hour, the reaction was kept until the reaction was completed. Then, it was worked up, and after crystal drying, 45 g of a white solid was obtained.

¹ H NMR: δ = 1.00 (s, 9H), 1.83 (m, 1H), 1.94 (m, 1H), 2.25 (m, 1H,), 2.45 (m, 1H), 2.70 (m, 2H), 2.86 ( m,1H), 3.01 (m, 1H), 4.05 (m, 1H), 4.71 (m, 1H), 7.38 (m, 25H); ¹³ CNMR: δ = 19.16, 27.02, 36.01, 40.48, 40.76, 60.12, 64.20, 76.19, 84.10, 86.98, 127.25, 127.83, 127.97, 129.90, 133.68, 136.04, 143.90, 177.46.

Example 1: (3aS, 4R, 5S, 6aR)-5-(tert-butyldimethylamyloxy)-4-(tert-butyldimethylamyloxy-methyl)-hexahydro-cyclopentane Preparation of dienyl[b]furan-2-ol (Compound 2a; R ₁ =R ₂ =t-BuMe ₂ Si);

The title compound was obtained as a white solid, mp. MS 402.3.

In a similar manner, using the starting materials for the preparation of compound 2 described above, R ₁ and R ₂ are prepared as different protecting group types such as a cyclic ether protecting group, a guanidine protecting group, a trityl protecting group or a thiol protecting group. Compound 2.

Example 2: (1R,3R,4S)-4-(tert-Butyldimethylamyloxy)-3-[(tert-butyldimethylamyloxy)methyl]-2-methylene- Preparation of cyclopentanol formate (compound 3a; R ₁ = R ₂ = t-BuMe ₂ Si);

1.23 g (3 mmol) of compound 2a (R ₁ =R ₂ =t-BuMe ₂ Si), 2.65 g of Pb(OAc) ₄ (6 mmol) and 0.1 g of anhydrous Cu(OAc) ₂ (0.2 mmol) were added to 100 ml of toluene and 0.5. The mixture was stirred under reflux with heating for 1 hour, cooled to room temperature and filtered over Celite. The residue was washed with petroleum ether / ethyl acetate (50/1), and the filtrate was washed with water and dried Na ₂ SO ₄ . The residue was evaporated to dryness eluted elut elut elut elut elut elut elut elut elut elut elut elut

¹ H NMR (CDCl ₃ , 300 MHz): δ = 0.02, 0.03, 0.05, 0.058 (s, each 3H, 4XCH ₃ -), 0.87 (s, 18H), 1.7 (m, 1H), 2.4 (m, 1H), 2.58 (m, 1H), 3.68 (d, J = 4.5 Hz, 2H, -CH ₂ -O), 4.12 (m, 1H), 5.19 (t, 1H, J = 1.8 Hz), 5.21 (t, 1H, J = 1.8 Hz), 5.47 (t, 1H, J = 7.5 Hz), 8.11 (s, 1H).

Example 3: In the same manner as in Example 2, the following compounds were obtained by using the above different compound 2 starting materials:

Among them, the NMR data of the compound 3k are as follows:

_{NMR (CDCl 3, 500MHz):} 1HNMR: δ = 1.34 (d, 3H), 1.76 (m, 1H), 2.51 (m, 1H), 2.63 (m, 1H,), 3.23 (m, 1H), 3.59 ( m, 1H), 4.36 (m, 1H), 4.67 (m, 1H), 4.90 (s, 1H), 5.22 (d, 1H), 5.50 (t, 1H), 8.03 (s, 1H); = 20.78, 36.04, 45.16, 68.64, 71.75, 78.59, 100.02, 113.04, 144.77, 160.79.

Further, in a similar manner to Example 2, compound 3aa was also synthesized:

The NMR data is as follows:

¹ H NMR: δ = 1.03 (d, 9H), 1.26 (m, 1H), 1.78 (m, 1H), 2.12 (m, 1H,), 2.86 (m, 1H), 2.98 (m, 1H), 3.12 ( m, 1H), 4.07 (m, 1H), 5.21 (s, 1H), 5.45 (s, 1H), 7.37 (m, 25H), 8.03 (s, 1H); ¹³ CNMR: δ = 19.22, 27.12, 40.62 , 52.02, 64.67, 73.89, 74.44, 86.51, 112.62, 127.08, 127.82, 128.14, 128.90, 129.16, 129.84, 135.98, 144.13, 149.38, 160.97.

Example 4a: (1R,3R,4S)-4-(tert-Butyldimethylmethyloxy)-3-[(tert-butyldimethylamyloxy)methyl]-2-methylene- Preparation of cyclopentanol (compound 4a; R ₁ = R ₂ = t-BuMe ₂ Si);

To 490 mg (1.22 mmol) of compound 3a (R ₁ = R ₂ = t-BuMe ₂ Si), 15 ml of methanol and 250 mg of anhydrous K ₂ CO _{3 were added} , stirred at room temperature for 1 hour, and evaporated to dryness. 15ml of water and stirred for 15min, the organic layer was separated, washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and the filtrate evaporated to dryness to give the title compound as a white solid 440mg (96%). Mp 64-66 ° C.

¹ H NMR (CDCl ₃ , 300 MHz): δ = 0.02 (s, 3H), 0.04 (s, 3H), 0.09 (s, 6H), 0.88 (s, 18H), 1.8 (dd, J = 1.8, 12 Hz, 1H), 1.99 (m, 1H), 2.75 (m, 1H), 3.30 (dd, 1H, J = 8, 7, 10 Hz), 3.56 (dd, 1H, J = 5.1, 10 Hz), 4.36 (m, 2H) ), 5.12 (d, 1H, J = 1 Hz), 5.38 (d, 1H, J = 1 Hz).

Example 4b: (1R,3R,4S)-4-benzyloxy-3-(benzyloxymethyl)-2-methylene-cyclopentanol (Compound 4b; R ₁ =R ₂ =benzyl) Preparation

The title compound was prepared in a similar manner to that of Examples 1 to 4a.

¹ H NMR (CDCl ₃ , 300 MHz): δ = 1.92 (m, 1H), 2.0-2.1 (m, 1H), 3.07 (m, 1H), 3.30 (t, J = 9 Hz, 1H), 3.45 (m, 1H) ), 4.06 (m, 1H), 4.4 (m, 1H), 4.48 (dd, 2H), 4.53 (s, 2H), 5.14 (s, 1H), 5.37 (s, 1H), 7.29-7.36 (m, 10H).

The following compounds were also prepared in a similar manner to Examples 4a and 4b:

Compound 4c: (1R,3R,4S)-4-tert-butyldiphenylphosphonyloxy-3-tert-butyldiphenylphosphonyloxymethyl-2-methylene-1-cyclopentanol

NMR (CDCl ₃ , 500 MHz) 1H NMR: δ = 1.03 (s, 9H), 1.17 (s, 9H), 1.94 (m, 1H), 2.05 (m, 1H), 2.93 (m, 1H,), 3.02 (m) , 1H), 3.51 (m, 2H), 4.43 (m, 1H), 4.49 (m, 1H), 5.22 (m, 1H), 5.48 (m, 1H), 7.49 (m, 20H); 13CNMR: δ = 19.20,19.29,26.88,27.19,42.99,54.65,65.24,74.96,76.04,111.43,127.75,127.87,129.76,129.94,133.44,133.70,135.74,135.47,154.66

Compound 4d: (1R,3R,4S)-4-tert-butyldiphenylphosphonyloxy-3-(tert-butyldimethylmethoxymethyl)-2-methylene-1-cyclopentanol alcohol

NMR (CDCl ₃ , 500 MHz) 1H NMR: δ = -0.01 (s, 6H), 0.85 (s, 9H), 1.18 (s, 9H), 1.92 (m, 1H), 2.05 (m, 1H,), 2.91 ( m, 1H), 3.06 (m, 1H), 3.45 (m, 2H), 4.39 (m, 2H), 5.21 (m, 1H), 5.43 (m, 1H), 7.60 (m, 10H); =-5.44,18.32,19.18,26.00,27.17,42.95,54.68,64.42,74.67,75.48,110.73,127.72,129.87,133.78,135.93,154.65

Compound 4e: (1R,3R,4S)-4-tert-butyldimethylammoniooxy-3-tert-butyldiphenylphosphonyloxymethyl-2-methylene-1-cyclopentanol

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 0.20 (s, 6H), 0.97 (s, 9H), 1.18 (s, 9H), 1.89 (m, 1H), 2.09 (m, 1H,), 2.92 ( m, 1H), 3.20 (m, 1H), 3.56 (m, 1H), 3.75 (m, 1H), 4.45 (m, 1H), 4.52 (m, 1H), 5.16 (m, 1H), 5.46 (m) , 1H), 7.61 (m, 10H); ¹³ C NMR: δ = -4.57, 18.01, 19.32, 25.95, 26.81, 42.56, 54.95, 65.28, 74.76, 77.27, 111.63, 127.80, 129.85, 133.43, 135.72, 154.11

Compound 4f: (1R,3R,4S)-4-tert-butyldimethylamyloxy-3-(biphenyl-4-methylindoleoxymethyl)-2-methylene-1-cyclopentanol

^{_{NMR (CDCl 3, 500MHz) 1}} HNMR: δ = 0.11 (s, 6H), 0.92 (s, 9H), 1.88 (m, 1H), 2.22 (m, 1H), 3.07 (m, 1H,), 3.10 ( m, 1H), 4.30 (m, 3H), 4.48 (m, 1H), 5.29 (m, 1H), 5.49 (m, 1H), 7.73 (m, 9H); ¹³ CNMR: δ = -4.75, 17.91, 25.79,42.58,51.43,65.22,74.12,112.27,127.15,127.23,128.21,128.72,128.94,130.08,139.80,145.75,152.68,166.32

Compound 4g: (4aR,6R,7aS)-2,2-di-tert-butyl-5-methylene-6-hydroxy-6H-cyclopentacyclo[1,3,2]dioxanthene heterocycle Hexane

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 0.99 (s, 18H), 1.60 (s, 1H), 2.11 (m, 1H), 2.59 (m, 1H), 2.80 (m, 1H,), 3.86 ( m, 2H), 4.48 (m, 2H), 4.84 (m, 1H), 5.18 (m, 1H); ¹³ CNMR: δ = 20.17, 22.87, 27.42, 27.65, 42.25, 49.65, 67.68, 71.04, 75.03, 110.26 , 150.75

Compound 4h: (1R,3R,4S)-4-tert-butyldiphenylphosphonyloxy-3-(biphenyl-4-carbomethoxymethyl)-2-methylene-1-cyclopentanol

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 1.13 (s, 9H), 1.93 (s, 2H), 2.20 (m, 1H), 3.17 (m, 1H), 3.61 (m, 1H,), 4.04 ( m, 1H), 4.19 (m, 1H), 4.35 (m, 1H), 5.23 (m, 1H), 5.44 (m, 1H), 7.59 (m, 19H); ¹³ CNMR: δ = 18.75, 26.71, 42.59 , 51.04, 64.23, 72.62, 73.35, 110.73, 126.74, 127.51, 127.90, 128.57, 129.73, 133.10, 135.48, 139.51, 145.19, 152.34, 165.73, 170.57

Compound 4i: (1R,3R,4S)-4-(biphenyl-4-methyloxy)-3-tert-butyldimethylammoniomethyl-2-methylene-1-cyclopentyl Alcohol

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 0.05 (s, 6H), 0.07 (s, 6H), 0.90 (s, 9H), 1.94 (m, 2H), 2.61 (m, 1H,), 3.01 ( m, 1H), 3.71 (m , 1H), 3.88 (m, 1H), 4.58 (m, 1H), 5.21 (m, 1H), 5.41 (m, 2H), 7.69 (m, 9H); 13 CNMR: δ=-5.26,18.48,26.10,41.11,51.70,64.97,74.11,110.40,127.28,127.51,128.38,129.16,129.26,130.34,140.22,145.94,154.04,166.27

Compound 4j: (1R,3R,4S)-4-Benzylmethoxy-3-tert-butyldimethylammoniomethyl-2-methylene-1-cyclopentanol

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 0.04 (s, 6H), 0.87 (s, 9H), 1.89 (m, 1H), 2.22 (m, 1H), 2.58 (m, 1H,), 2. m,1H), 3.67 (m, 1H), 3.84 (m, 1H), 4.55 (m, 1H), 5.17 (m, 1H), 5.35 (m, 2H), 7.71 (m, 5H); ¹³ CNMR: δ=-5.33,18.40,26.03,40.98,51.55,64.88,73.84,76.25,110.18,128.52,129.76,130.47,133.13,153.83,166.36

Compound 4k: (2R, 4aR, 6S, 7aS)-2-methyl-5-methylene-6-hydroxy-6H-cyclopenta[1,3]dioxane

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 1.25 (s, 3H), 1.58 (m, 1H), 2.46 (m, 2H), 3.12 (m, 1H,), 3.39 (m, 1H), 3.52 ( m,1H), 4.29 (m, 2H), 4.61 (m, 1H), 4.77 (m, 1H), 5.09 (m, 1H); ¹³ CNMR: δ = 20.71, 38.76, 45.04, 68.77, 70.59, 78.44, 99.87,109.99,148.22

Compound 41: (1R,3R,4S)-4-(tetrahydropyran-2-yloxy)-3-tert-butyldimethylammoniomethyl-2-methylene-1-cyclopentyl alcohol

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ=0.01 (m, 6H), 0.84 (s, 9H), 1.48 (m, 3H), 1.51 (m, 1H,), 1.70 (m, 2H), 1.88 ( m, 1H), 2.13 (m, 1H), 2.77 (m, 1H), 3.60 (m, 5H), 4.24 (m, 2H), 4.65 (m, 2H), 5.06 (m, 1H), 5.28 (d) , 2H); ¹³ CNMR: δ=-5.36, 18.36, 19.62, 25.71, 31.05, 38.46, 41.17, 52.09, 65.16, 62.88, 64.75, 74.62, 78.76, 96.66, 110.44, 154.16

Compound 4m: (1R,3R,4S)-4-tert-butyldiphenyloximeoxy-3-(trityloxymethyl)-2-methylene-1-cyclopentanol

¹ H NMR: δ = 1.03 (s, 9H), 1.79 (s, 2H), 2.72 (s, 1H), 2.85 (m, 2H), 2.99 (s, 1H), 4.30 (s, 2H), 5.11 (s) , 1H), 5.35 (s, 1H), 7.40 (m, 25H); ¹³ CNMR: δ = 19.22, 27.22, 42.68, 63.03, 66.09, 74.98, 77.62, 86.82, 112.16, 127.07, 127.88, 127.90, 128.89, 129.98 , 133.68, 136.05, 144.14, 164.79

Example 5: Preparation of Compounds 5a-5e

As stated above, compound 5 has the following general formula:

Wherein compound 5a: X = Cl, R = H, R' = Boc; compound 5b: X = OMe, R = H, R' = Boc; compound 5c: X = OBn, R = H, R' = Boc; 5d: X = Cl, R = Boc, R' = Boc; Compound 5e: X = OBu-t, R = H, R' = Boc.

Compound 5a was prepared according to the procedure described in J. Org. Chem. 2000, 65, 7697-7699.

Compound 5a:

Compounds 5b, 5c and 5d were prepared in a manner analogous to compound 5a, which was prepared according to the procedure in the literature of Org. Lett., 2009, 11, 2465.

The spectral data of the obtained compounds 5b, 5c and 5e are as follows:

Compound 5b:

¹ H NMR (d ⁶ -DMSO, 300 MHz): δ = 1.45 (s, 9H), 4.03 (s, 3H), 8.1 (bs, NH), 9.7 (s, 1H), 13.08 (bs, NH).

Compound 5c

¹ H NMR (CDCl ₃ , 300 MHz): δ = 1.58 (s, 9H), 5.61 (s, 2H), 7.32 - 7.53 (m, 5H), 8.28 (s, 1H).

Compound 5e

¹ H NMR (CDCl ₃ , 300 MHz): δ = 1.56 (s, 9H), 1.71 (s, 9H), 7.29 (bs, 1H), 8.19 (s, 1H).

Example 6: 9-[(1S,3R,4S)-4-tert-butyldimethylamyloxy-3-(tert-butyldimethylamyloxy)methyl-2-methylene-cyclo Preparation of tert-butyl amyl]-6-chloro-9H-indole- ₂ -carbamate (compound 6a; R ₁ =R ₂ =t-BuMe ₂ Si, R=H, R'=Boc);

186 mg (0.5 mmol) of compound 4a (R ₁ =R ₂ =t-BuMe ₂ Si), 200 mg (0.75 mmol) of compound 5a (R=H, R'=Boc) and 156 mg of Ph ₃ P (0.75 mmol) were placed In a 50 ml round bottom flask, 8 ml of anhydrous THF was added, and the mixture was cooled to -23 ° C, and 0.17 ml of DEAD (1.0 mmol) was added dropwise. After the addition, the reaction was stirred at -23 ° C for 3.5 hours. TLC showed the disappearance of the material A spot, and 3 drops of water were added. The mixture was warmed to room temperature, then THF was evaporated under reduced pressure. 5 ml of t-BuOMe was stirred for 5 min, and 15 ml of n-hexane was added and allowed to stand for 5 hours. The insoluble material was removed by filtration, and the filtrate was purified by column chromatography, petroleum ether / EtOAc (10/1, v/v) eluted to give the title compound 320 mg (~100%).

¹ H NMR (CDCl ₃ , 300 MHz): δ = 0.08 (s, 3H), 0.09 (s, 3H), 0.10 (s, 6H), 0.90 (s, 9H), 0.92 (s, 9H), 1.54 (s, 9H), 2.23 (m, 1H), 2.33 (m, 1H), 2.66 (m, 1H), 3.83 (d, 2H, J = 5.4 Hz), 4.45 (m, 1H), 4.82 (s, 1H), 5.22 (s, 1H), 5.64 (t, 1H, J = 8.1), 7.38 (s, 1H), 8.03 (s, 1H).

Example 7: 9-[(1S,3R,4S)-4-tert-butyldimethylamyloxy-3-(tert-butyldimethylamyloxy)methyl-2-methylene-cyclo Preparation of di-tert-butyl amyl]-6-chloro-9H-indole- ₂ -aminodicarboxylate [Compound 6d; R ₁ =R ₂ =t-BuMe ₂ Si, R=Boc, R'=Boc];

640 mg (1.72 mmol) of compound 4a (R ₁ =R ₂ =t-BuMe ₂ Si), 888 mg (2.4 mmol) of compound 5d [R=Boc, R'=Boc] and 607 mg of Ph ₃ P (2.32 mmol) in 50 ml round In a bottom flask, 20 ml of anhydrous THF was added, and the mixture was cooled to -23 ° C, and 0.5 ml (2.75 mmol) of DEAD was added dropwise. After the addition, the reaction was stirred at -23 ° C for 2 hours, and the reaction was stirred at room temperature for 12 hours, then evaporated under reduced pressure. After adding 150 ml of n-hexane, the mixture was allowed to stand for 5 hours, and the insoluble material was removed by filtration. The filtrate was purified by column chromatography eluting with petroleum ether /EtOAc (10/1, v/v) to give the title compound 1.08 g (87%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ = 0.07 (s, 3H), 0.08 (s, 3H), 0.10 (s, 6H), -0.89 - (s, 9H), 0.93 (s, 9H), 1.43 ( s, 18H), 2.30 (m, 2H), 2.70 (m, 1H), 3.83 (m, 2H), 4.50 (m, 1H), 4.85 (s, 1H), 5.25 (s, 1S), 5.70 (t , 1H), 8.24 (s, 1H).

Example 8: Compounds 6b, 6c and 6e were obtained by coupling compounds 5b, 5c and 5e to compound 4a, respectively, in a similar manner to Example 6. In a similar manner to Example 6, compound 5a was coupled with compound 4b to give compound 6f. Compound 6b: 9-[(1S,3R,4S)-4-tert-butyldimethylamyloxy-3-(tert-butyldimethylamyloxy)methyl-2-methylene-cyclopentyl tert-butyl-6-methoxy-9H-indole-2-carbamate;

¹ H NMR (CDCl ₃ , 300 MHz): δ = 0.001 (s, 12H), 0.11 (s, 3H), 0.19 (s, 6H), 0.90 (s, 6H), 0.92 (s, 6H), 1.54 (s, 6H), 2.27 (m, 2H), 2.65 (m, 1H), 3.81 (d, J = 6 Hz, 2H), 4.16 (s, 3H), 4.45 (m, 1H), 4.84 (s, 1H), 5.21. (s, 1H), 5.63 (t, 1H), 7.97 (s, 1H).

Compound 6c: 6-Benzyloxy-9-[(1S,3R,4S)-4-tert-butyldimethylamyloxy-3-(tert-butyldimethylamyloxy)methyl-2- Methylene-cyclopentyl]-9H-indole-2-carbamic acid tert-butyl ester;

¹ H NMR (CDCl ₃ , 300 MHz): δ = 0 (s, 9H), 0.067 (s, 3H), 0.078 (s, 3H), 0.195 (s, 3H), 0.89 (s, 6H), 0.92 (s, 6H), 1.40 (s, 9H), 2.0-2.26 (m, 2H), 2.68 (m, 1H), 3.8 (d, J = 4.8 Hz, 2H), 4.44 (bs, 1H), 4.84 (s, 1H) ), 5.22 (s, 1H), 5.64 (s, 2H), 7.32 - 7.35 (m, 3H), 7.51 - 7.53 (m, 2H), 8.1 (s, 1H)

Compound 6e: 6-tert-Butoxy-9-[(1S,3R,4S)-4-tert-butyldimethylamyloxy-3-(tert-butyldimethylamyloxy)methyl-2 -methylene-cyclopentyl]-9H-indole-2-carbamic acid tert-butyl ester;

¹ H NMR (CDCl ₃ , 300 MHz): δ = 0.01 (s, 6H), 0.09 (s, 6H) 0.86 (s, 12H), 0.88 (s, 12H), 1.54 (s, 6H), 1.63 (s, 6H) ), 2.19 (m, 2H), 2.68 (m, 1H), 3.77 (m, 2H), 4.43 (bs, 1H), 4.81 (s, 1H), 5.18 (s, 1H), 5.41 (m, 1H) , 7.68 (s, 1H)

Compound 6f: 9-[(1S,3R,4S)-4-benzyloxy-3-(benzyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-indole-2 - tert-butyl carbamate

¹ H NMR (CDCl ₃ , 300 MHz): δ = 1.53 (s, 9H), 2.52 (m, 2H), 3.0 (bs, 1H), 3.74 (m, 2H), 4.22 (dd, 2H), 4.35 (m, 1H), 4.56 (d, J = 6 Hz, 2H), 4.81 (s, 1H), 5.23 (s, 1H), 5.66 (t, 1H), 7.18-7.42 (m, 10H), 8.0 (s, 1H) .

The following compounds were obtained by a similar method to that of Example 6 and using the corresponding compound 4c to 4m as a starting material to react with Compound 5a:

Compound 6g: 9-[(1S,3R,4S)-4-tert-butyldiphenylphosphonyloxy-3-tert-butyldiphenylphosphonyloxymethyl-2-methylene-cyclopentyl] -6-chloro-9H-indole-2-carbamic acid tert-butyl ester

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 0.99 (s, 9H), 1.12 (s, 9H), 1.55 (s, 9H), 2.04 (m, 1H), 2.10 (m, 1H,), 2.91 ( m,1H), 3.61 (m, 2H), 4.51 (m, 1H), 4.78 (m, 1H), 5.17 (m, 1H), 5.83 (m, 1H), 7.49 (m, 21H), 7.81 (s) , 1H); ¹³ CNMR: δ = 19.23, 19.30, 27.01, 27.14, 28.34, 40.39, 54.47, 56.84, 65.18, 73.86, 81.57, 111.54, 127.88, 127.99, 129.95, 133.02, 133.17, 133.68, 133.80, 133.65, 135.87 , 143.47, 149.18, 150.29, 151.23, 152.39, 153.15

Compound 6h: 9-[(1S,3R,4S)-3-tert-butyldimethylammoniomethyl-4-tert-butyldiphenyloxy-2-methylene-cyclopentyl" -6-chloro-9H-indole-2-carbamic acid tert-butyl ester

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = -0.04 (s, 6H), 0.83 (s, 9H), 1.11 (s, 9H), 1.55 (m, 9H), 2.12 (m, 1H,), 2.28 (m, 1H), 2.77 (m, 1H), 3.55 (m, 1H), 3.66 (m, 1H), 4.40 (m, 1H), 4.84 (m, 1H), 5.22 (m, 1H), 5.77 ( m,1H), 7.48 (m, 1H), 7.92 (s, 1H); ¹³ C NMR: δ = -5.31, 18.58, 19.38, 26.16, 27.23, 28.46, 41.13, 84.60, 56.90, 64.62, 74.39, 84.75, 111.88 , 127.96, 130.05, 133.87, 133.98, 135.97, 143.87, 149.68, 150.39, 151.25, 152.42, 153.26

Compound 6i: 9-[(1S,3R,4S)-4-tert-butyldimethylamyloxy-3-tert-butyldiphenylphosphonyloxymethyl-2-methylene-cyclopentyl] -6-chloro-9H-indole-2-carbamic acid tert-butyl ester

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 0.08 (s, 6H), 0.90 (s, 9H), 1.10 (s, 9H), 1.53 (m, 9H), 2.25 (m, 2H,), 2.77 ( m,1H), 3.80 (m, 2H), 4.52 (m, 1H), 4.72 (m, 1H), 5.12 (m, 1H), 5.67 (m, 1H), 7.49 (m, 11H), 7.87 (s) , 1H); ¹³ CNMR: δ=-4.43, 18.21, 19.48, 26.04, 27.20, 28.43, 40.43, 54.99, 56.98, 65.16, 72.47, 81.75, 111.68, 128.13, 130.14, 133.32, 135.81, 135.93, 143.75, 148.98, 150.32, 151.41, 152.40, 153.16

Compound 6j: 9-[(1S,3R,4S)-4-tert-butyldimethylamyloxy-3-(biphenyl-4-methylindoleoxymethyl)-2-methylene-cyclopentyl ]-6-Chloro-9H-indole-2-carbamic acid tert-butyl ester

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 0.11 (s, 6H), 0.91 (s, 9H), 1.52 (s, 9H), 2.22 (m, 1H), 2.76 (m, 1H,), 3.08 ( m,1H), 4.60 (m, 2H), 4.72 (m, 1H), 4.83 (m, 1H), 5.33 (m, 1H), 5.63 (m, 1H), 7.49 (m, 8H), 8.01 (s) , 1H), 8.12 (m, 2H); ¹³ CNMR: δ=-4.52, 18.24, 26.01, 28.40, 39.34, 52.16, 57.68, 65.16, 72.63, 81.65, 112.72, 127.38, 127.50, 128.46, 128.63, 128.83, 129.16 , 130.28, 140.06, 144.28, 146.16, 147.82, 150.30, 151.58, 152.35, 152.61, 166.67

Compound 6k: (4aR, 6S, 7aS)-[6-chloro-9-(2,2-di-tert-butyl-5-methylene-hexahydro-cyclopenta[1,3,2] Oxanthene heterocyclohexene-6-yl)-9H-indole-2-carbamic acid tert-butyl ester

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 1.04 (s, 9H), 1.08 (s, 9H), 1.54 (s, 9H), 2.37 (m, 2H), 2.72 (m, 1H,), 4.12 ( m,1H), 4.50 (m, 2H), 4.69 (m, 1H), 4.89 (m, 1H), 5.64 (m, 1H), 7.53 (m, 1H), 7.88 (s, 1H); ¹³ CNMR: δ=20.16,22.95,27.39,27.66,28.45,40.01,50.38,53.81,67.19,76.73,81.87,110.65,127.96,143.36,146.27,150.22,151.57,152.64,153.03

Compound 61: 9-[(1S,3R,4S)-4-tert-butyldiphenyloximeoxy-3-(biphenyl-4-methylindoleoxymethyl)-2-methylene-cyclopentyl -6-Chloro-9H-indole-2-carbamic acid tert-butyl ester

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 1.11 (s, 9H), 1.51 (s, 9H), 2.15 (m, 1H), 2.58 (m, 1H), 3.22 (m, 1H,), 4.46 ( m,1H), 4.58 (m, 2H), 4.91 (m, 1H), 5.34 (m, 1H), 5.74 (m, 1H), 7.50 (m, 21H); ¹³ CNMR: δ = 19.23, 27.06, 28.27 , 38.86, 51.84, 57.49, 64.79, 73.59, 81.40, 113.08, 127.13, 127.34, 127.91, 128.31, 128.42, 128.59, 129.05, 130.02, 130.06, 130.18, 133.42, 135.76, 139.96, 144.06, 145.90, 147.59, 150.28, 151.37 , 152.27, 152.51

Compound 6m: 9-[(1S,3R,4S)-3-tert-butyldimethylammoniomethyl-4-(biphenyl-4-methyloxy)-2-methylene-cyclopentyl -6-chloro-9H-indole-2-carbamic acid tert-butyl ester

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 0.14 (s, 6H), 0.95 (s, 9H), 1.54 (s, 9H), 2.63 (m, 1H), 3.02 (m, 1H), 3.99 (m) , 1H), 4.14 (m, 1H), 4.91 (m, 1H), 5.33 (m, 1H), 5.60 (m, 1H), 5.84 (m, 1H), 7.71 (s, 11H); ¹³ CNMR: δ =-5.13,18.69,26.26,28.48,38.92,51.56,56.83,65.26,76.68,81.88,112.13,127.38,127.53,128.00,128.49,128.91,129.21,130.50,140.18,143.61,146.25,149.13,150.44,151.52, 152.60,153.43,166.15

Compound 6n: 9-[(1S,3R,4S)-3-tert-butyldimethylammoniomethyl-4-benzylideneoxy-2-methylene-cyclopentyl]-6-chloro -9H-indole-2-carbamic acid tert-butyl ester

^{_{NMR (CDCl 3, 500MHz) 1}} HNMR: δ = -0.05 (s, 6H), 0.75 (s, 9H), 1.34 (s, 9H), 2.47 (m, 2H), 2.84 (m, 1H,), 3.82 (m, 1H), 3.92 (m, 1H), 4.73 (m, 1H), 5.15 (m, 1H), 5.42 (m, 1H), 5.66 (m, 1H), 7.58 (m, 6H), 7.98 ( s,1H); ¹³ C NMR: δ=-5.53, 18.28, 25.88, 28.09, 38.27, 51.22, 56.56, 64.80, 76.20, 81.22, 111.73, 127.61, 128.30, 129.56, 129.95, 133.07, 143.35, 148.71, 150.30, 151.00 , 152.41, 153.03, 165.78

Compound 6o: (2R, 4aR, 6S, 7aS)-[6-chloro-9-(2-methyl-5-methylene-hexahydro-cyclopenta[1,3]dioxine Tert-butyl-6-yl)-9H-indole-2-carbamate

NMR (CDCl ₃ , 500 MHz) ¹ H NMR: δ = 1.41 (d, 3H), 1.52 (s, 9H), 2.33 (m, 1H), 2.46 (m, 2H,), 3.93 (m, 1H), 4.44 ( m,1H), 4.56 (m, 2H), 4.88 (s, 1H), 5.00 (m, 1H), 5.50 (d, 1H), 7.65 (s, 1H), 7.94 (s, 1H); ¹³ CNMR: δ=20.84,28.41,36.69,46.21,54.33,68.53,79.28,81.72,99.99,109.48,128.21,144.01,145.69,150.06,151.51,152.44,152.49

Compound 6p: 9-[(1S,3R,4S)-4-tert-butyldiphenylmethoxy-3-(trityloxymethyl)-2-methylene-cyclopentyl]- 6-chloro-9H-indole-2-carbamic acid tert-butyl ester

¹ H NMR: δ = 1.12 (s, 9H), 1.55 (s, 9H), 1.99 (m, 1H), 2.22 (m, 1H,), 2.97 (m, 1H), 3.11 (m, 2H), 4.45 ( m, 1H), 4.70 (s, 1H), 5.06 (s, 1H), 5.77 (m, 1H), 7.46 (m, 26H); ¹³ CNMR: δ = 19.26, 27.25, 28.47, 40.42, 52.86, 56.84, 64.75,74.16,81.79,87.26,111.96,127.33,127.98,128.06,128.86,130.06,133.77,133.87,136.00,142.63,143.92,149.17,150.34,151.29,152.42,153.22

Example 9: 6-Chloro-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]-9H-indole-2-carbamic acid tert-butyl Preparation of an ester (compound 7a; R = H, R' = Boc);

312 mg (0.5 mmol) of compound 6a (R ₁ =R ₂ =t-BuMe ₂ Si, R=H, R'=Boc) was dissolved in 10 ml of THF, and 780 mg of TBAF (tetrabutylammonium fluoride) (3 mmol) was added. was stirred room temperature for 2 h, TLC showed the starting material spot disappeared, drying of THF was distilled off under reduced pressure, the residue was added 30ml EtOAc, 20ml × 2 wash water, saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and the filtrate evaporated to dryness under reduced pressure to give a gum The title compound was 190 mg (96%).

¹ H NMR (CDCl ₃ , 300 MHz): δ = 1.53 (s, 9H), 2.29 (m, 1H), 2.66 (m, 1), 2.75 (m, 1H), 4.03 (dd, 2H, J = 1.8, 3.3 Hz), 4.75 (m, 1H), 4.87 (s, 1H), 5.27 (s, 1H), 5.60 (t, 1H, J = 8 Hz), 7.41 (s, 1H), 8.16 (s, 1H).

Example 10: 6-Chloro-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]-9H-indole-2-carbamic acid tert-butyl Preparation of an ester (compound 7a; R = H, R' = Boc);

312 mg (0.5 mmol) of compound 6a (R ₁ =R ₂ =t-BuMe ₂ Si, R=H, R'=Boc) was dissolved in 10 ml of THF, 3 ml of methanol was added, hydrochloric acid (3 mmol) was added, and stirred at room temperature 2 h, TLC showed the starting material spot disappeared, drying of THF was distilled off under reduced pressure, the residue was added 30ml EtOAc, 20ml × 2 wash water, saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and the filtrate evaporated to dryness under reduced pressure to give the title compound as a solid, yield The rate is 95.7%.

¹ H NMR (CDCl ₃ , 300 MHz): δ = 1.53 (s, 9H), 2.29 (m, 1H), 2.66 (m, 1), 2.75 (m, 1H), 4.03 (dd, J = 1.8, 3.3 Hz) , 4.75 (m, 1H), 4.87 (s, 1H), 5.27 (s, 1H), 5.60 (t, 1H, J = 8 Hz), 7.41 (s, 1H), 8.16 (s, 1H).

Example 11: 6-Chloro-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]-9H-indole-2-aminodicarboxylic acid Preparation of tert-butyl ester [Compound 7d; R = Boc, R' = Boc];

2.16 g (3 mmol) of compound 6d [R ₁ =R ₂ =t-BuMe ₂ Si, R=Boc, R'=Boc] was dissolved in 50 ml of THF, and 4.6 g of TBAF (tetrabutylammonium fluoride) (17 mmol) was added. at room temperature was stirred for 2h, TLC showed the starting material disappeared the spot, in addition to drying of THF was distilled off under reduced pressure, the residue was added 100ml EtOAc, washed 70ml × 2 of water, saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and the filtrate evaporated to dryness under reduced pressure to give a gum The title compound was dried (1.41 g (~100%).

¹ H NMR (CDCl ₃ , 300 MHz): δ = 1.43 (s, 18H), 2.34 (m, 1H), 2.61 (m, 1H), 2.77 (m, 1H), 3.90 (dd, 1H, J = 5.4, 10.8 Hz), 4.01 (dd, 1H, J=4.5, 10.8 Hz), 4.58 (bs, 1H), 4.84 (s, 1H), 5.26 (s, 1H), 5.65 (t, 1H, J = 8.1 Hz), 8.27 (s, 1H).

Example 12: Compounds 7b, 7c and 7e were obtained in the same manner as in Example 9 using the compounds 6b, 6c and 6e as starting materials. Compound 7b: 9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]-6-methoxy-9H-indole-2-carbamic acid Butyl ester

¹ H NMR (CDCl ₃ , 300 MHz): δ = 1.53 (s, 9H), 2.25 (m, 1H), 2.26-2.80 (m, 2H), 3.39 (m, 1H), 4.0 (dd, 2H), 4.15 ( s, 3H), 4.65 (m, 1H), 4.90 (s, 1H), 5.27 (s, 1H), 5.56 (t, 1H), 8.14 (s, 1H).

Compound 7c: 6-Benzyloxy-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]-9H-indole-2-carbamic acid Butyl ester

¹ H NMR (CDCl ₃ , 300 MHz): δ = 1.35 (s, 9H), 2.26 (m, 1H), 2.61-2.74 (m, 2H), 3.88 (dd, 1H), 3.93 (dd, 1H), 4.56 ( Bs, 1H), 4.80 (s, 1H), 5.21 (s, 1H), 5.60 (s, 2H), 7.29-7.35 (m, 3H), 7.48-7.50 (m, 2H), 8.05 (s, 1H) .

Compound 7e: 6-tert-Butoxy-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]-9H-indole-2-carbamic acid Tert-butyl ester;

¹ H NMR (CDCl ₃ , 300 MHz): δ = 1.52 (s, 9H), 1.73 (s, 9H), 2.25 (m, 1H), 2.6-2.8 (m, 2H), 4.0 (d, J = 6 Hz, 2H) ), 4.66 (bs, 1H), 4.83 (s, 1H) 5.29 (s, 1H), 5.45 (m, 1H), 7.83 (s, 1H).

Example 13: 9-[(1S,3R,4S)-4-hydroxy-3-tert-butyldimethylammoniomethyl-2-methylene-cyclopentyl]-6-chloro-9H- Preparation of tert-butyl carboxamide-2-carboxylate (compound 8a).

11 g of the compound 6m was dissolved in 155 ml of anhydrous methanol, 2 g of potassium carbonate was added, and the reaction was stirred until the starting material was completely reacted, filtered, and concentrated under reduced pressure to give compound 8a, yield 95%.

NMR (CDCl ₃ , 500 MHz): ¹ H NMR: δ = 0.07 (s, 6H), 0.86 (s, 9H), 1.50 (s, 9H), 2.28 (m, 1H), 2.43 (m, 1H), 2.71 ( s, 1H), 3.81 (m, 1H), 3.95 (m, 1H), 4.47 (m, 1H), 4.79 (m, 1H), 5.11 (m, 1H), 5.87 (m, 1H), 7.4 (m) , 1H), 7.82 (s, 1H); ¹³ CNMR: δ = -5.29, 18.53, 26.13, 28.46, 53.36, 54.39, 56.00, 65.36, 73.42, 81.35, 111.15, 117.85, 140.88, 150.18, 150.94, 152.32, 153.45 ,161.37

Example 14: 9-[(1S,3R,4S)-4-tert-butyldimethylammoniooxy-3-hydroxymethyl-2-methylene-cyclopentyl]-6-chloro-9H- Preparation of tert-butyl amidine-2-carbamate (Compound 9a).

11 g of the compound 6j was dissolved in 155 ml of anhydrous methanol, 2 g of potassium carbonate was added, and the reaction was stirred until the reaction of the starting material was completed, filtered, and concentrated under reduced pressure to give compound 9a, yield 94%.

NMR (CDCl ₃ , 500 MHz): ¹ H NMR: δ = 0.03 (s, 6H), 0.83 (s, 9H), 1.45 (s, 9H), 2.10 (m, 1H), 2.55 (m, 1H), 2.62 ( s, 1H), 3.89 (m, 2H), 4.00 (m, 1H), 4.53 (m, 1H), 4.70 (m, 1H), 5.14 (m, 1H), 5.43 (m, 1H), 7.38 (m) , 1H), 7.84 (s, 1H); ¹³ C NMR: δ = -4.66, 18.08, 25.90, 28.31, 54.36, 54.92, 58.26, 63.83, 73.76, 81.20, 111.33, 118.85, 141.99, 148.82, 150.72, 151.77, 152.04 , 161.66

Example 15: Preparation of Compound 7a (using Compound 8a as a starting material)

9 g of the compound 8a was dissolved in 100 ml of THF, and 25 g of tetrabutylammonium fluoride was added thereto at room temperature for reaction overnight, and concentrated under reduced pressure to dryness, dissolved in 100 ml of ethyl acetate, washed three times with 5% sodium chloride solution, and dried. Concentration to dryness afforded EtOAc m. The ¹ H-NMR data of the title compound obtained was consistent with the data of the compound 7a obtained in Example 10.

Example 16: Preparation of Compound 7a (using Compound 9a as a starting material)

9 g of the compound 9a was dissolved in 100 ml of THF, and 25 g of tetrabutylammonium fluoride was added thereto at room temperature to react overnight, and concentrated under reduced pressure to dryness, dissolved in 100 ml of ethyl acetate, washed three times with 5% sodium chloride solution, and dried. Concentration to dryness afforded EtOAc m. The ¹ H-NMR data of the title compound obtained was consistent with the data of the compound 7a obtained in Example 10.

Example 17: 2-Amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl-6H-indole Preparation of -6-ketone (Compound 1);

(1) Preparation of Compound 1 from Compound 7a:

150 mg (0.38 mmol) of compound 7a (R=H, R'=Boc) was added with 3 ml of 2N HCl and 3 ml of THF, and the mixture was stirred under reflux with stirring for 6 hr. THF was evaporated under reduced pressure and the residual aqueous solution was adjusted to pH 7 with 2.5 N NaOH. The crystals were precipitated at room temperature for 20 min, left at room temperature overnight, filtered, and washed with a small amount of water to give an off-white solid. The above product was recrystallized from ca. 2 ml of water to give white crystals (yield: 73%).

(2) Preparation of compound 1 from compound 7d:

1.2 g (2.42 mmol) of compound 7d (R=Boc, R'=Boc) was added to 20 ml of 2N HCl and 20 ml of THF, and the mixture was stirred under reflux with stirring for 8 hr. THF was evaporated and evaporated. The pH was adjusted to 7 with 2.5N NaOH and allowed to stand overnight at room temperature. The above product was recrystallized from about 2 ml of water to give 360 mg (54%) of white crystals.

¹ H NMR (d ⁶ -DMSO, 300 MHz): δ = 2.03 (m, 1H), 2.20 (m, 1H), 3.51 (t, 2H, J = 6 Hz), 4.21. (bs, 1H), 4.54 (s, 1H) ), 4.80-4.86 (m, 2H, can be exchanged by D ₂ O), 5.08 (s, 1), 7.64 (s, 1H, can be widened by D ₂ O exchange), 10.54 (s, 1H).

Example 18: 2-Amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl-6H-indole Preparation of -6-ketone (Compound 1);

312 mg (0.5 mmol) of compound 6a (R ₁ = R ₂ = t-BuMe ₂ Si, R = H, R' = Boc) was dissolved in 15 ml of tetrahydrofuran, and 15 ml of dilute hydrochloric acid was added thereto, and the mixture was stirred under heating until TLC showed that the material spots disappeared. The tetrahydrofuran was evaporated under reduced pressure. EtOAc was evaporated. The ¹ H-NMR data of the title compound obtained was consistent with the data of the compound 1 obtained in Example 17.

Example 19: Preparation of Compound 1 (using Compound 8a as a starting material)

9 g of the compound 8a was dissolved in 200 ml of THF, and 100 ml of 2N HCl was added, and the mixture was refluxed until the reaction was completed. The ¹ H-NMR data of the title compound obtained was consistent with the data of the compound 1 obtained in Example 17.

Example 20: Preparation of Compound 1 (using Compound 9a as a starting material)

9 g of the compound 9a was dissolved in 200 ml of THF, and then added to 100 ml of 2N HCl, and the mixture was evaporated to reflux. The ¹ H-NMR data of the title compound obtained was consistent with the data of the compound 1 obtained in Example 17. .

Reference example:

According to the method described in WO2004/052310A2, the Mitsunobu reaction is carried out using the intermediate 4 and the amino-protected 2-aminoindole compound as a starting material, and the obtained compound is deprotected by TBAF, and finally hydrolyzed to obtain entecavir. The reaction conditions used were essentially the same as those used in the process of the present invention except that the 2-aminoindole compound which was not protected with an amino group was substituted for the 2-protected amino-6-substituted anthracene in the process of the present invention.

Reference example 1: 9-[(1S,3R,4S)-4-tert-butyldimethylamyloxy-3-(tert-butyldimethylamyloxy)methyl-2-methylene-cyclopentyl]- Preparation of 6-chloro-9H-indol-2-amine (Compound 24);

370 mg (1.0 mmol) (1R,3R,4S)-4-(tert-butyldimethylamyloxy)-3-[(tert-butyldimethylamyloxy)methyl]-2-methylene -cyclopentanol (compound 4a, R ₁ =R ₂ =t-BuMe ₂ Si), 338 mg (2.0 mmol) of 6-chloro-2-aminoindole (compound 23) and 524 mg of Ph ₃ P (2.0 mmol) in 20 ml In a round bottom flask, add 5 ml of anhydrous THF, cool to -23 ° C, add 350 mg of DEAD (1.0 mmol) / 5 ml of THF solution, add the reaction after stirring at -23 ° C for 3.5 hours, stir to room temperature and stir overnight, then reduce The THF was distilled off, and 10 ml of t-BuOMe was added for 5 min, 15 ml of n-hexane was added, and the mixture was allowed to stand for 5 hours. The insoluble material was removed by filtration, and the filtrate was purified by column chromatography and washed with petroleum ether/EtOAc (3/1 (v/v)). The title compound (305 mg, 59%)

Reference Example 2: 6-Chloro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylene-cyclopentyl]-9H-indol-2-amine (Compound 25) preparation;

200 mg (0.38 mmol) of Compound 24 was dissolved in 10 ml of THF, 720 mg of TBAF (tetrabutylammonium fluoride) (6 mmol) was added, and the mixture was stirred at room temperature for 1 h. washed with water 20ml, saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and the filtrate evaporated to dryness under reduced pressure to give a pale yellow solid of the title compound 52mg (47%).

Reference Example 3: 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl-6H-indole-6-one Preparation of (Compound 1);

148 mg (0.5 mmol) of compound 25 was added with 5 ml of 2N HCl and 5 ml of THF, and the mixture was stirred under reflux with heating for 6 hours. Part of THF was evaporated under reduced pressure. The residual aqueous solution was adjusted to pH 7 with 2.5N NaOH and allowed to stand at room temperature for 20 min to initiate precipitation. It was left at room temperature overnight, filtered, and washed with a small amount of water to give a white solid. The above product was recrystallized from ca. 2 ml of water to give white crystals (yield: 85%).

As described in the above Reference Examples, the Mitsunobu reaction was carried out by using the intermediate 4 and the amino-protected 2-aminoindole compound as the starting material according to the method described in WO2004/052310A2, and the obtained compound was deprotected by TBAF, and finally hydrolyzed. With entecavir, the total yield of the three-step reaction was only 17% (based on Intermediate 4).

In contrast, the present invention uses the intermediate 4 and the 2-protected amino-6-substituted anthracene to carry out the Mitsunobu reaction to obtain a high yield (~100%), and the obtained coupling product can be used for the purification process of the subsequent reaction. It is simplified and the yield is greatly improved. Also based on Intermediate 4, the overall yield of the three-step reaction is greater than 52%. Therefore, the preparation process can be made simple and easy, the yield is remarkably improved, and the production cost is remarkably reduced.

Claims (34)

A method of preparing a compound of formula 1, The method comprises the steps of: reacting compound 6 to obtain a compound of formula 1, Wherein: R ₁ and R ₂ may be the same or different and are each independently selected from the group consisting of the following hydroxy protecting groups (i) to (iii): (i) R ₁ and R ₂ are each independently selected from benzyl. , t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si; or (ii) R ₁ and R ₂ are each independently selected from t-BuMe ₂ Si, t-BuPh ₂ Si , benzhydryl, tetrahydropyran-2-yl, benzhydryl group with a substituent on the phenyl ring, biphenyl-4-methylindenyl, trityl, but when R ₁ and R _{2 are} different Is t-BuMe ₂ Si; or (iii) R ₁ and R ₂ together with the attached five-membered carbocyclic ring form one of the following fused ring systems: Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group, and a nitro group; R ₄ and R ₅ may be the same or different and each represents a C _1-6 alkyl group; wherein * indicates the point of attachment of the fused ring to other moieties; R and R' may be the same or different, respectively representing hydrogen, C _{1 -6} alkoxycarbonyl or C _5-10 aralkoxycarbonyl, provided that R and R' are not simultaneously hydrogen; X is halogen, C _1-6 alkoxy, halo C _1-6 alkoxy or C _5-10 aralkyloxy; d) when both R ₁ and R ₂ are a fluorenyl protecting group or are neither a fluorenyl protecting group, the compound 6 is deprotected from the hydroxy protecting group to give the compound 7 Wherein X, R ₁ , R ₂ , R and R' are as defined above; e) hydrolysis of compound 7 to give a compound of formula 1 (entecavir) Wherein X, R and R' are as defined above; or d') when neither R ₁ nor R ₂ is a thiol protecting group, compound 6 is simultaneously deprotected and hydrolyzed to directly obtain a compound of formula 1 Wherein X, R ₁ , R ₂ , R and R' are as defined above, or (d") when one of R ₁ and R ₂ is a benzamidine group, a benzamidine group having a substituent on the benzene ring When the base or the fluorenyl protecting group of the benzhydryl group is used, the compound 6 is deprotected to obtain 8 or 9, which is hydrolyzed or hydrolyzed by the compound 7 to obtain the compound 1, Wherein X, R ₁ , R ₂ , R and R' are as defined above. The method of claim 1, wherein R ₁ and R ₂ may be the same or different and are each independently selected from the group consisting of benzyl, t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si. The method of claim 1, wherein R ₁ and R ₂ may be the same or different and are each independently selected from the group consisting of t-BuMe ₂ Si, t-BuPh ₂ Si, benzamidine, tetrahydropyran. a benzyl group, a benzamidine group having a substituent on a benzene ring, a biphenyl-4-methyl fluorenyl group, or a trityl group; but R ₁ and R _{2 are} not simultaneously t-BuMe ₂ Si. The method of claim 1, wherein R ₁ and R ₂ together with the attached five member carbon ring form one of the fused ring systems as follows: Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group, and a nitro group; R ₄ and R ₅ may be the same or different and each represent a C _1-6 alkyl group; wherein the * sign indicates the point of attachment of the fused ring to the rest of the molecule. The method of claim 4, wherein R ₁ and R ₂ together with the attached five member carbon ring form one of the fused ring systems as follows: The method of any one of claims 1 to 5, wherein in step c), the reaction of compound 4 with compound 5 is in Ph ₃ P/EtO ₂ CN=NCO ₂ Et or Ph ₃ P/i -PrO ₂ CN=NCO _{2 In the} presence of i-Pr, it is carried out in an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, a halogenated hydrocarbon or an ether. The method of any one of claims 1 to 5, wherein in step d), the deprotection of compound 6 is in a hydrohalic acid, hydrogen fluoride, formic acid, a quaternary ammonium salt of a fluoride ion, potassium carbonate or It is carried out in the presence of an alkoxide. The method of any one of claims 1 to 5, wherein In the step e), the hydrolysis of the compound 7 is carried out in the presence of hydrochloric acid or formic acid in water or a mixed solvent of water and another organic solvent. The method of any one of claims 1 to 5, wherein in step d'), the deprotection and hydrolysis of compound 6 can be carried out in the presence of a hydrohalic acid in methanol, ethanol or tetrahydrofuran or It is carried out in a mixture of water. The method of any one of claims 1 to 5, wherein in the step d"), the thiol protecting group is removed in the presence of potassium carbonate, an alkali metal hydroxide, an alkoxide such as sodium alkoxide. The method of any one of claims 1 to 5, which comprises the steps of: c) compound 4 and a 2-amino protected -6-substituted anthracene compound 5 in Ph ₃ P/EtO ₂ CN=NCO ₂ Et or Ph ₃ P/i-PrO ₂ CN=NCO ₂ i-Pr is reacted in THF to obtain a coupling product 6; d) compound 6 is in tetrabutylammonium fluoride (TBAF) Or the hydroxy protecting group is removed in the presence of hydrochloric acid to give compound 7; e) hydrolysis of compound 7 in the presence of hydrochloric acid in tetrahydrofuran affords the compound of formula 1. The method of any one of claims 1 to 5, wherein the compound of the formula 6 is used as a raw material and the steps d) to e) described therein are carried out. The method of any one of claims 1 to 5, wherein the step d') is directly carried out using the compound of the formula 6 as a raw material. The method of any one of claims 1 to 5, wherein The step d") is carried out directly using the compound of the formula 6 as a raw material. The method according to any one of claims 1 to 5, wherein the step e) is directly carried out using the compound of the formula 7 as a raw material. A method of preparing a compound of formula 1, The method comprises the steps of: a) opening a ring of compound 2 directly to obtain a cyclopentane intermediate 3 Wherein R ₁ and R ₂ may be the same or different and are each independently selected from the hydroxy protecting groups described in the following groups (i) to (iii): (i) R ₁ and R ₂ are each independently selected from benzyl. , t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si; or (ii) R ₁ and R ₂ are each independently selected from t-BuMe ₂ Si, t-BuPh ₂ Si , benzhydryl, tetrahydropyran-2-yl, benzhydryl group with a substituent on the phenyl ring, biphenyl-4-methylindenyl, trityl, but when R ₁ and R _{2 are} different Is t-BuMe ₂ Si; or (iii) R ₁ and R ₂ together with the attached five-membered carbocyclic ring form one of the following fused ring systems: Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group, and a nitro group; R ₄ and R ₅ may be the same or different and each represent a C _1-6 alkyl group; wherein * indicates the point of attachment of the fused ring to the rest of the molecule; b) the compound of formula 3 is subjected to alcoholysis or hydrolysis to give compound 4 Wherein R ₁ and R ₂ are as defined above; c) the compound 4 is reacted with the 2-protected amino-6-substituted indole compound 5 by Mitsunobu to obtain a coupled product 6 Wherein R ₁ and R ₂ are as defined above; R and R' may be the same or different and each represent hydrogen, C _1-6 alkoxycarbonyl or C _5-10 aralkyloxycarbonyl, provided that R and R' are different When hydrogen; X is halogen, C _1-6 alkoxy, halo C _1-6 alkoxy or C _5-10 aralkyloxy; d) when R ₁ and R ₂ are fluorenyl protecting groups or When neither is a thiol protecting group, the compound 6 is deprotected from the hydroxy protecting group to give the compound 7 Wherein X, R ₁ , R ₂ , R and R' are as defined above; e) hydrolysis of compound 7 to give a compound of formula 1 (entecavir) Wherein X, R and R' are as defined above; or d') when neither R ₁ nor R ₂ is a thiol protecting group, compound 6 is simultaneously deprotected and hydrolyzed to directly obtain a compound of formula 1 Wherein X, R ₁ , R ₂ , R and R' are as defined above; or (d") when one of R ₁ and R ₂ is a benzamidine group, a benzamidine group having a substituent on the benzene ring When the base or the fluorenyl protecting group of the benzhydryl group is used, the compound 6 is deprotected to obtain 8 or 9, which is hydrolyzed or hydrolyzed by the compound 7 to obtain the compound 1, Wherein X, R ₁ , R ₂ , R and R' are as defined above. For example, the method described in claim 16 of the patent scope, The method comprises the steps of: a) opening a ring of compound 2 directly to obtain a cyclopentane intermediate 3 b) Compound of formula 3 is subjected to alcoholysis or hydrolysis to give compound 4 c) Performing a Mitsunobu reaction of compound 4 with a 2-amino protected -6-substituted fluorene compound 5 to obtain a coupled product 6 d) Deprotecting compound 6 from the hydroxy protecting group to give compound 7 e) hydrolysis of compound 7 to give a compound of formula 1 Or d') simultaneously deprotecting and hydrolyzing compound 6 to directly obtain the compound of formula 1 In the above steps, X, R ₁ , R ₂ , R and R' are as defined in claim 23 of the scope of the patent application. The method of claim 16 or 17, wherein R ₁ and R ₂ are each independently selected from the group consisting of t-BuMe ₂ Si, t-BuPh ₂ Si, benzamidine, tetrahydropyran-2- a benzylidene group having a substituent on the benzene ring, a biphenyl-4-methylindenyl group, a trityl group; but R ₁ and R _{2 are} not simultaneously t-BuMe ₂ Si. The method of claim 16 or 17, wherein R ₁ and R ₂ together with the attached five member carbon ring form one of the fused ring systems as follows: Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group, and a nitro group; R ₄ and R ₅ may be the same or different and each represent a C _1-6 alkyl group; wherein the * sign indicates the point of attachment of the fused ring to the rest of the molecule. The method of claim 19, wherein R ₁ and R ₂ together with the attached five member carbon ring form one of the fused ring systems as follows: The method of claim 16 or 17, wherein in step a), compound 2 is catalyzed by a copper (II) salt and PhI(OAc) ₂ , Mn(OAc) ₃ or Pb(OAc) ₄ The cyclopentane intermediate 3 is obtained directly by ring opening in the presence of triethylamine or pyridine. The method of claim 16 or 17, wherein in step b), the compound of formula 3 is in the presence of ammonia, triethylamine, K ₂ CO ₃ or an alkoxide in methanol, ethanol or The mixture is either subjected to alcoholysis or hydrolysis in water or a mixed solvent of water and another organic solvent to obtain a compound 4. The method of claim 16 or 17, wherein in step c), compound 4 and 2-protected amino-6-substituted anthracene compound 5 are in Ph ₃ P/EtO ₂ CN=NCO ₂ The coupling product 6 is obtained by reacting in an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, a halogenated hydrocarbon or an ether in the presence of Et or Ph ₃ P/i-PrO ₂ CN=NCO ₂ i-Pr. The method of claim 16 or 17, wherein in step d), the deprotection of compound 6 is present in a hydrohalic acid, hydrogen fluoride, formic acid, a quaternary ammonium salt of a fluoride ion, potassium carbonate or an alkoxide. The hydroxy protecting group is removed to give compound 7. The method of claim 16 or 17, wherein in step e), compound 7 is in the presence of hydrochloric acid or formic acid, in water or Hydrolysis is carried out in a mixed solvent of water and another organic solvent to obtain a compound of the formula 1. The method of claim 16 or 17, wherein in step d'), the deprotection and hydrolysis of compound 6 can be carried out in the presence of a hydrohalic acid in methanol, ethanol or tetrahydrofuran or a mixture thereof with water. In progress. The method of claim 16 or 17, wherein in step d"), the thiol protecting group is removed in the presence of potassium carbonate, an alkali metal hydroxide, an alkoxide such as sodium alkoxide. The method of claim 16 or 17, wherein the method comprises the steps of: a) catalyzing the compound 2 under the action of a copper (II) salt and Pb(OAc) ₄ in the presence of triethylamine or pyridine; The ring opening directly gives the cyclopentane intermediate 3; b) the compound of the formula 3 is subjected to alcoholysis in methanol in the presence of K ₂ CO ₃ to give the compound 4; c) the compound 4 and the 2-protected amino group-6 - a substituted oxime compound 5 is reacted in THF in the presence of Ph ₃ P/EtO ₂ CN=NCO ₂ Et or Ph ₃ P/i-PrO ₂ CN=NCO ₂ i-Pr to obtain a coupled product 6; d) Compound 6 is deprotected in the presence of tetrabutylammonium fluoride (TBAF) or hydrochloric acid to give compound 7; e) hydrolysis of compound 7 in the presence of hydrochloric acid in tetrahydrofuran affords the compound of formula 1. The method of claim 16 or 17, wherein the formula 3 is used The compound is used as a raw material and the steps b) to e), or b) to d'), or b) to d") described therein are carried out. a compound of formula 6, Wherein R ₁ and R ₂ may be the same or different and are each independently selected from hydrogen or a hydroxy protecting group as described in the following groups (i) to (iii): (i) R ₁ and R ₂ are each independently selected from Benzyl, t-BuMe ₂ Si, t-BuPh ₂ Si, (i-Pr) ₃ Si or Et ₃ Si; or (ii) R ₁ and R ₂ are each independently selected from t-BuMe ₂ Si, t-BuPh ₂ Si, benzhydryl, tetrahydropyran-2-yl, benzinyl with a substituent on the phenyl ring, biphenyl-4-methylindenyl, trityl, but R ₁ and R ₂ Not simultaneously t-BuMe ₂ Si; or (iii) R ₁ and R ₂ together with the attached five-membered carbocyclic ring form one of the fused ring systems described below: Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group, and a nitro group; R ₄ and R ₅ may be the same or different and each represent a C _1-6 alkyl group; wherein * indicates the point of attachment of the fused ring to other moieties; R and R' may be the same or different and represent hydrogen C _{1- 6} alkoxycarbonyl or C _5-10 aralkoxycarbonyl, provided that R and R' are not hydrogen at the same time; X is halogen, C _1-6 alkoxy, halo C _1-6 alkoxy or C _5-10 aralkyloxy. The compound according to claim 30, wherein R ₁ and R ₂ are each independently selected from the group consisting of t-BuMe ₂ Si, t-BuPh ₂ Si, benzamyl, tetrahydropyran-2-yl, a benzinyl group having a substituent on the benzene ring, a biphenyl-4-methylindenyl group, a trityl group; but R ₁ and R _{2 are} not simultaneously t-BuMe ₂ Si. The compound of claim 30, wherein R ₁ and R ₂ together with the attached five member carbon ring form one of the fused ring systems described below: Wherein R ₃ is a hydrogen atom, a C _1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group, and a nitro group; R ₄ and R ₅ may be the same or different and each represent a C _1-6 alkyl group; wherein the * sign indicates the point of attachment of the fused ring to the rest of the molecule. The compound of claim 32, wherein R ₁ and R ₂ together with the attached five member carbon ring form one of the fused ring systems described below: The compound of any one of claims 30 to 33, which is selected from the group consisting of: 9-[(1S,3R,4S)-4-tert-butyldimethylamoxy-3-(tert-butyl) Tert-butyl dimethyl methoxy)methyl-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamate; 9-[(1S,3R,4S)-4- tert-Butyldimethylamyloxy-3-(tert-butyldimethylamyloxy)methyl-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-aminodicarboxylic acid Di-tert-butyl ester; 9-[(1S,3R,4S)-4-tert-butyldimethylamyloxy-3-(tert-butyldimethylamyloxy)methyl-2-methylene- tert-Butyl cyclopentyl]-6-methoxy-9H-indole-2-carbamate; 6-benzyloxy-9-[(1S,3R,4S)-4-tert-butyldimethyloxoxime Tert-butyl 3-(tert-butyldimethylamyloxy)methyl-2-methylene-cyclopentyl]-9H-indole-2-carbamate; 6-tert-butoxy-9- [(1S,3R,4S)-4-tert-butyldimethylamyloxy-3-(tert-butyldimethylamyloxy)methyl-2-methylene-cyclopentyl]-9H- tert-Butyl-2-carbamic acid; 9-[(1S,3R,4S)-4-benzyloxy-3-(benzyloxymethyl)-2-methylene-cyclopentyl]-6- Tert-butyl chloro-9H-indole-2-carbamate; 6-chloro-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2- Armor Tert-butyl-cyclopentyl]-9H-indole-2-carbamate; 6-chloro-9[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclo Di-tert-butyl pentyl]-9H-indole-2-aminodicarboxylate; 9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]- 4-methoxy-9H-indole-2-carbamic acid tert-butyl ester; 6-benzyloxy-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene -cyclopentyl]-9H-indole-2-carbamic acid tert-butyl ester; 6-tert-butoxy-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene Tert-butyl-cyclopentyl]-9H-indole-2-carbamate; 9-[(1S,3R,4S)-3-tert-butyldimethylammoniomethyl-4-(tetrahydropyridyl) Tert-butyl ester of m--2-yloxy)-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamate; 9-[(1S,3R,4S)-3-tert Butyl dimethyl methoxyoxymethyl-4-tert-butyldiphenyl fluorenyl-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamic acid tert-butyl ester; 9-[(1S,3R,4S)-3-tert-butyldimethylammoniomethyl-4-(biphenyl-4-methyloxy)-2-methylene-cyclopentyl]- Tert-butyl 6-chloro-9H-indole-2-carbamate; 9-[(1S,3R,4S)-3-tert-butyldimethylammoniomethyl-4-benzylideneoxy-2 -methylene- Tert-butyl amyl]-6-chloro-9H-indole-2-carbamate; 9-[(1S,3R,4S)-3-tert-butyldiphenylphosphonyloxy-4--4-tetrahydro Tert-butyl pyran-2-yloxy)-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamate; 9-[(1S,3R,4S)-4-tert-butyldimethylammoniooxy-3-tert-butyldiphenylphosphonyloxymethyl-2-methylene-cyclopentyl]-6- tert-Butyl chloro-9H-indole-2-carbamate; 9-[(1S,3R,4S)-4-(biphenyl-4-methyloxy)-3-tert-butyldiphenylphosphoniumoxy Tert-butyl methyl-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamate; 9-[(1S,3R,4S)-4-tert-butyldiphenylfluorene Oxy-3-tert-butyldiphenylphosphonyloxymethyl-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamic acid tert-butyl ester; 9-[(1S, 3R,4S)-4-Benzylmethoxy-3-tert-butyldiphenylphosphonyloxymethyl-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamic acid Tert-butyl ester; 9-[(1S,3R,4S)-4-benzylideneoxy-3-benzhydryloxymethyl-2-methylene-cyclopentyl]-6-chloro-9H-indole tert-Butyl -2-carbamate; 9-[(1S,3R,4S)-4-(tetrahydropyran-2-yloxy)-3-benzylideneoxymethyl-2-methylene- Cyclopentyl]-6-chloro-9H-indole-2-carbamic acid tert-butyl ester; 9-[(1S,3R,4S)-4-tert-butyldimethylammoniumoxy-3-benzhydrazide Tert-butyl methyl-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamate; 9-[(1S,3R,4S)-4-tert-butyldiphenylfluorene Oxy-3-benzamide Tert-butyl 2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamate; 9-[(1S,3R,4S)-4-(biphenyl-4-carboindole Oxy)-3-benzamide Oxymethyl-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamic acid tert-butyl ester; 9-[(1S,3R,4S)-4-benzylideneoxy- 3-(Biphenyl-4-methylindoleoxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamic acid tert-butyl ester; 9-[(1S,3R, 4S)-4-(tetrahydropyran-2-yloxy)-3-(biphenyl-4-methylindoleoxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H- tert-Butyl-2-carbamic acid; 9-[(1S,3R,4S)-4-tert-butyldimethylamyloxy-3-(biphenyl-4-methylindoleoxymethyl)-2- Tert-butyl methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamate; 9-[(1S,3R,4S)-4-tert-butyldiphenylfluorenyl-3- (biphenyl-4-carbomethoxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamic acid tert-butyl ester; 9-[(1S,3R,4S) -4-(biphenyl-4-carbyloxy)-3-(tetrahydropyran-2-yloxy)methyl-2-methylene-cyclopentyl]-6-chloro-9H-indole Tert-butyl-2-carbamic acid; 9-[(1S,3R,4S)-4-tert-butyldimethylamyloxy-3-(tetrahydropyran-2-yloxy)methyl-2 -methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamic acid tert-butyl ester; 9-[(1S,3R,4S)-4-(biphenyl-4-methyloxy) -3-(biphenyl-4-carbomethoxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H- MTX -2- carbamate; (4aR, 6S, 7aS) - [6- chloro-9- (2,2-di-t-butyl-5-methylene - hexahydro-cyclopenta[1,3,2]dioxanthene-6-yl)-9H-indole-2-carbamic acid tert-butyl ester; (2S, 4aR, 6S, 7aS )-[6-Chloro-9-(2-methyl-5-methylene-hexahydro-cyclopenta[1,3]dioxan-6-yl)-9H-indole- tert-Butyl 2-carbamate; (2R, 4aR, 6S, 7aS)-[6-chloro-9-(2-methyl-5-methylene-hexahydro-cyclopenta[1,3] Tert-butyl dioxepipene-6-yl)-9H-indole-2-carbamate; (4aR,6S,7aS)-[6-chloro-9-(2-methyl-5-methylene - hexahydro-cyclopenta[1,3]dioxine-6-yl)-9H-indole-2-carbamic acid tert-butyl ester; 9-[(1S,3R,4S)-4 -tert-butyldiphenylphosphonyloxy-3-(trityloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamic acid tert-butyl ester .