TW201215612A - Synthetic method of entecavir and intermediate compounds thereof - Google Patents

Abstract

The present invention relates to preparation method of drugs and intermediate compounds thereof, in particular, to preparation method of entecavir, intermediate compounds thereof and synthetic method of said intermediate compounds.

Description

201215612 VI. Description of the Invention: [Technical Field] 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. [Prior Art] Entecavir, a compound represented by the following formula (1), 2-amino-1,9-dihydro-9-[(lS,3R,4S)-4-hydroxy-3-(hydroxyl decyl) -2-Methylenecyclopentyl]-6H-11, phenoxy-6-one, is a new nuclear 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 effect is 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 ZL91 1 10831. 9 and International Application W098/09964. The method uses cyclopentadiene 8 as a raw material, and sequentially reacts with chloromercaptobenzyl ether and dioxene borane prepared by O-α-pinene 3 95335 201215612 (the chiral intermediate 9 is obtained by reacting IPC2BI0) It is epoxidized with tert-butyl alcohol peroxide under the catalysis of acetonitrile oxidation [v〇(·)2] to obtain 1 〇. 1 〇 in the hydrogenation of sodium (tetra) tetramethylene sulphate and the reaction to obtain 1W1 in gasification Under the action of 6-hydroxyl group; aminoguanidine 12 reaction to obtain 13. After a single pair of decyloxy trisyl group gas to protect the amino group to obtain hydrazine, (4) under the action of Dess-Martin reagent to oxidize the base group to obtain (5) The methyleneation reaction is carried out under the action of _ed reagent and titanium tetrachloride to obtain 16. Subsequently, the reaction with hydrochloric acid removes the MMT on the amino group and the benzyl group on the anthracene ring to obtain 17'. The county carbon ring is fed to the base to obtain entecavir. The method is shown in the following scheme.

fcHa〇H The problem with the preparation method is that the starting material requires expensive 4 95335 201215612 chiral boron reagent, and the final debenzylation is highly toxic boron trichloride. The intermediate synthesis is difficult and the reaction conditions are harsh. The equipment requirements are high and the cost of some reagents is high. In addition, a synthesis method using Compound 2' as a raw material is disclosed in the patent application of Serco, Inc. (Publication No. 2004/052310 A2), as shown in the following scheme.

2' CHO I .OH Ο 〆 TsCI/Py] ’·'"Ch^OTBS OTBS 21 19 CHO ^〇Ts

1. NalQ4^

2. NaBH4 • '〃CH2OTBS

HO

Q

1 丄 il/DBU

2.K2C〇3/MeOH w"CH2OTBS

TBSO <Ah2 H 23 -►

Ph3P/DEADE

CH2〇TBS OTBS 22

4,

1 Applicants 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 is not only the yield of 5 95335 201215612, the yield is low. The coupling product 24 which is unstable and the obtained amino group is unprotected is similar to the polarity of the triphenylphosphine oxide formed by the reagent trisuccinyl phosphine, which is difficult to be separated from the purification, and the coupling product 24 is subsequently dehydroxylated. The intermediate 25 obtained by the base has high water solubility, is difficult to be purified by simple extraction and is low in yield, and the method of the patent is disadvantageous for industrial production. In addition, although in the above method, it is also mentioned that the above compound 2 can be used as a raw material, photochemical method can be used, iodide can be formed under the action of iodophenyl acetate and iodine, and then an intermediate can be 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: Phl(〇Ac)2/I2, hv (Tetrahedron Letters, 1987, 28, 3397-3400) when preparing the intermediate 4 using the above method described in WO 2004/052310 A2 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. 6 95335 201215612 Ο Ο

27 28

OH

29

30 ΒηΟ

31 ΟΒη

ΟΒη

33 ΟΒη

34 Ο

However, the above preparation method has a long synthetic route and 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. SUMMARY OF THE INVENTION In the present invention, the following terms have the meanings described below: The term "alkyl", alone or in combination with other groups, means a straight or branched monovalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. "C!-6 alkyl" means a branched or straight-chain alkyl group having 1 to 6 carbon atoms, such as anthracenyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl Base, Zhengji 7 95335 201215612 base. "Halogen" means fluorine, gas, desert or hydrazine. "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. The group ', denotes a group R - 〇-, wherein R' is an alkyl group as described above. "Cie alkoxy, a watch, R-〇-, wherein R' is a C16 alkyl group as defined above. "Alkyloxy" means a radical as defined above substituted by one or more halogens. Alkoxy group, for example, trifluoromethoxy group. The aryl group may be phenyl or naphthyl π aryl group means a monocyclic or slightly bicyclic aromatic ring containing a carbon atom. "CH.Aryl," refers to an aryl group having 5 to 10 carbon atoms. For example, an alkyl group of an arylalkyl group. It means that the "aryl alkoxy group" as described above is substituted with an aryl group as described above. An alkoxy group substituted by an aryl group as described above. "Rowry group" means a group -C0-R' wherein R is an aryl group or an aralkyl group as described above. As the group itself, or as a part of another group such as an aralkyl group or an aralkyloxy group, one or more substituents may be optionally substituted. When the aryl group is substituted, the household is more preferably selected. From methoxy, ethoxy, «, benzene, the present invention provides a novel method for synthesizing entecavir, which has fewer reaction steps of 95335 201215612, is simple to operate, can improve yield and reduce cost. On the one hand, the present invention relates to the use of 2-is A method for synthesizing entecavir (compound of formula 1) using a protected amino-6-substituted indole compound as a starting material, the method comprising the steps of: c) performing a Mitsunobu reaction of compound 4 with a 2-protected amino-6-substituted indole compound 5 Coupling product 6

NRR' -CHzOR!

I where:

Ri and R2 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) Ri and R2 are each independently selected from an alkyl group, a halo group, Benzyl, t-BuMe2Si, t-BuPh2Si, (i_pr)3Si or Et3Si, preferably t-BuMe2Si; or (ii) Ri and R2 are each independently selected from the group consisting of t_BuMe2Si, t-BuPh2Si, benzoyl, tetrahydrogen ratio a benzyl group with a substituent on the benzene ring, a benzamidine group with a substituent on the benzene ring, a biphenyl fluorenyl group, and a triphenyl fluorenyl group, but 匕 and ^ are not t-BuMe2Si at the same time; or (1U) 1 and Rz forms a system such as a fused ring with the connected five-member carbon ring: 95335 9 201215612 *

\ p

Si. R4 r5 wherein R3 is an argon atom, a Ch alkyl group, a stupid group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a decyloxy group, an ethoxy group, a halogen group, a benzene group, and an exact group. ; 1 and R 5 may be the same or the same, respectively, representing Gi e or aryl, preferably t-butyl or phenyl; wherein * indicates the point of attachment of the fused ring to other parts of the molecule;

The fused ring formed above is preferably a fused ring system as described below

"R and R may be the same or different and each represent a nitrogen, a 6-oxyl alkoxy group or an aryloxyalkyl group, such as a Cl_6 alkoxylated silk or a C5M. an aromatic oxyl group, preferably a tert-butoxycarbonyl group, conditions Is R and R, and at the same time 2 hydrogen. χ is a south, alkoxy, alkoxy or aryloxy group, such as G 6 alkoxy, halogenated G-6 alkoxy or L. An oxy group, preferably a chlorine, a methoxy group, a benzyloxy group, a tert-butoxy group, particularly preferably a gas; d) when R>R2 is a aryl protecting group or neither is a compound of 6 Compound 7, soil 95335 10 201215612

Wherein X, Ri, R2, R and R' are as defined above; e) hydrolysis of compound 7 to give a compound of formula 1 (entecavir)

Μ

Wherein X, R and R' are as defined above; or d') when neither Ri nor R2 is a thiol protecting group, compound 6 is simultaneously deprotected and hydrolyzed to directly obtain a compound of formula 1

Wherein X, Ri, R2, R and R' are as defined above, or (d") when one of 1 and R2 is a fluorenyl protecting group, for example, phenylhydrazine 11 95335 201215612, substituted on the phenyl ring When the phenylhydrazine group or the biphenyl fluorenyl 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,

Deprotection

hydrolysis

Deprotection deprotection hydrolysis

Wherein X, Ri, R2, 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 Ph3P/Et〇2CN=NC〇2Et or Ph3P/i-Pr〇2CN=NC〇2 i -Pr in an aprotic The solvent is carried out, for example, in 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 h 12 95335 201215612 mouth 2 = stone lysine) or a test (for example, when both lanthanum and cerium are protected by a base): In the presence of hydrogen dentate acid such as hydrochloric acid, hydrogen, formic acid or fluoride containing Φ (tetra), such as tetraradyl fluorinated (Lic) or =.: salt such as sodium alcohol, preferably under tetrabutyl ic: . The reaction is carried out in a suitable organic solvent or in the following:::::: into the hydrogen--, methanol or ethanol or below, 隹ί上, step e) 'the hydrolysis of the compound 7 in acidic or test conditions: The ship or the time is carried out in a mixed solvent of τ, water or water and its machine, for example, in a tetrahydrogen or a mixture of ethanol and water: More preferably, it is carried out in a tetrahydrogen feed in the presence of hydrochloric acid. In the above step d'), in the presence of 'deprotection of compound 6, for example, dilute hydrochloric acid' such as dilute hydrochloric acid, in a suitable organic solvent or a mixture thereof with water, such as methanol = hydrogen furan or It is carried out in a mixture of water. - or four in the above step d"), the compound i can be directly obtained from the compound, or by humanization. The substance 8 9 = depends on the woman's shot, the first is removed first: for example, in the carbon-hydrogen oxide Salt =: is synthesized by the following method: c) Compound 4 and 2-amino are protected = ί: Γ 的 的 的 的 ' ' ' 式 式 式 ' 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 953 /Et〇2CN=NC〇2Et or Ph3P/i-pr〇2CN=NC〇2i-Pr is reacted in an aprotic solvent such as an aromatic hydrocarbon, a toothed aromatic hydrocarbon, a toothed hydrocarbon or an ether such as THF. Coupling product 6; d) Deprotecting compound 6 in the presence of tetrabutylammonium fluoride (TBAF) or hydrochloric acid to give compound 7; e) hydrolyzing compound 7 in the presence of hydrochloric acid in tetrahydrofuran 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 3 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, 〇. 〇 to 15〇〇c, especially room temperature to the reflux temperature of the solvent. Now, 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 Mitsun〇bu reaction can be accelerated and the reaction yield is greatly increased, thereby preparing entecavir. The overall yield is greatly increased. It is not intended to be bound by any theory. It is believed that the above reaction rate is accelerated and the yield is increased because the 2-amino protected -6-substituted fluorene compound 5 overcomes the amino hydrazine compound in the reaction solvent. The problem of poor solubility in the solution, and the physical and chemical properties of the obtained coupling product intermediate are improved, and the subsequent reaction and purification of the intermediate are easy to handle. The 2-amino protected -6-substituted anthracene compound of the present invention can be The synthesis method described in the literature (/. This §*. 2000, not 5,7697-7699) for 2-tert-butoxycarbonylamino-6-aminated guanine is based on 2-amino-6-substituted guanine. In the above process, the intermediate compounds of the formulae 6 and 7 are novel compounds. 14 95335 201215612 Thus, in one aspect, the invention also relates to compounds of the formula:

Or2 where,

Ri and R2 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): (1) Ri and R2 are each independently selected from an alkyl group, a dentate Base, benzyl, t BuMe2Si, t-BuPh2Si, (i-Pr)3Si or Et3Si, preferably t-BuM&Si; or (li) 匕 and R2 are each independently selected from t_BuMe2Si, t_BuPh2Si, benzoinyl, tetra Hydrogen η is a nonyl-2-yl group, a phenyl fluorenyl group having a substituent on a benzene ring, a biphenyl-4-methyl fluorenyl group, a triphenyl fluorenyl group, but hydrazine and Rz are not simultaneously t-BuMe2Si; or (iii)匕 and R2 together with the attached five-membered carbon ring form one of the fused ring systems described below:

Wherein R3 is a hydrogen atom, a Cl-radical group, a stupid group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a decyloxy group, an ethoxy group, a phenyl group, a benzene 95335 15 201215612 group, and a nitrate And I and Rs may be the same or different ocaryl, preferably t-butyl or stupid; which is the connection point of the Cm alkyl group or the moiety thereof; and the copper ring and the molecule formed by the two: ring preference It is one of the following (four) ring systems: Bu...1' 0, 乂〇CH,

>'»11 0, S[, ^CH3 Ch3><^Γ〇η3 CH3 CH3^n3 , and R' may be the same or different and represent nitrogen, alkoxycarbonyl or aryloxy, respectively, such as G1_6 The condition of the oxygen-sintered or aryloxyl group 'preferably t-butoxycarbonyl' is R*R, and is also nitrogen; x is dentate, alkoxy, dentate or aryloxy The group is, for example, Ci 6 alkoxy, dentate G-6 alkoxy or 〇5_1()aralkyloxy, preferably chloro, decyloxy, benzyloxy or tert-butoxy, particularly preferably chlorine. Among the compounds of the above formula, the compounds of the following formula are preferred: compound structure L, 丄UIV, 〇 〇 一 斗 一 漆 又 丁 - - - - - - - - - - - - - - - - - - - ) mercapto-2-indenyl-cyclopentyl]-6-gas-9H-indole-2-aminodecanoic acid & tert-butyl ester; 9-[(1S,3R,4S)-4-tert-butyl Dimethyl oxaxo-3-(tert-butyldimethyl oxalyl) fluorenyl-2-arylene-cyclopentyl]-6-aero-9H-indole-2-aminodicarboxylic acid Tert-butyl ester;

NHBoc

TBSO CH20TBS π

N(Boc)2

TBSO CH2OTBS 16 95335 201215612 9-[(lS,3R,4S)-4-tert-Butyldimethylindenyloxy-3-(tert-butyldimethylsilyloxy)methyl-2-indenyl -cyclopentyl]-6-decyloxy-9H-indole-2-aminodecanoic acid tert-butyl ester; OMe <Xl N NHBoc TBSO^^^ ch2otbs 6-benzyloxy-9-[(lS,3R, 4S)-4-tert-butyldidecyloxyl_3-(tert-butyldidecyloxy)indol-2-indenyl-cyclopentyl]-9H-indol-2-aminoindole Tert-butyl acid ester; OCH2Ph N NHBoc ch2otbs 6-tert-butoxy-9_[(1S, 3R, 4S)_4_tert-butyldimethylaminooxy-3-(tert-butyldimethylfluorenyloxy)anthracene Tert-butyl 2-benzylidene-cyclopentyl]-9H-indole-2-carbamate; QC(Me)3 gas. TBSO CH2OTBS 9-[(13,3 ft,43)-4-benzyloxy-3-(benzyloxymethyl)-2-indenyl-cyclopentyl]-6-gas-9H-嘌呤-2 - tert-butyl aminoguanate; Cl h: BnO CH2OBn 6-chloro-9-[(lS,3R, 4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]-9H -tert-butyl-2-aminodecanoate; Cl -^NHBoc h: HO CH2〇H 6-gas-9[(1S,3R, 4S)-4-hydroxy-3-hydroxyindol-2-Afluorene --cyclopentyl] -9H-indole-2-aminodidecanoic acid di-tert-butyl ester; Cl ""3-i^n(b〇c)2 hr HO CH2〇H 9-[(lS,3R, 4S)-4-hydroxy-3-hydroxymethyl-2-indenyl-cyclopentyl]-6-decyloxy-9H-indole-2-aminodecanoic acid tert-butyl ester; OMe NN NHBoc ch2oh 17 95335 201215612 4-Benzyloxy-9-[(lS,3R,4S)-4-hydroxy-3-hydroxyindol-2-methylene-cyclopentyl]-9H-indole-2-carbamic acid tert-butyl ester; OCH2Ph becomes B. . HO^ ch2oh 6-tert-butoxy-9-[(lS,3R,4S)-4-hydroxy-3-hydroxyindol-2-indenyl-cyclopentyl]-9H-indol-2-aminoindole Tert-butyl acid. QC(Me)3 <VNHB〇c HO^ ch2oh and 9-[(lS,3R,4S)-3-tert-butyldifluorenyloxycarbonyl]_4_(tetrazoline 0 to _2_2_yloxy Tert-]methylene-cyclopentyl]-6-chloro-9H-indole-2-aminodecanoic acid tert-butyl ester <^χ N^N^NHBoc 〒H3 ch3 Si—<-ch3 〇- 〇6h3 CH3 9-[(lS,3R,4S)-3-tert-butyldidecyloxymethyl-4-tert-butyldiphenyloxy-2-methylene-cyclopentyl] -6-Chloro-9H-indole-2-aminodecanoic acid tert-butyl ester; y^V^NHBoc h3c 0 <cy^ ?Hs /cH3 \ T Si-^ch3 h3c-^-s. 0 ch3 H3C0 9- [(lS,3R, 4S)-3-tert-Butyldiindenyloxymethyl-4-(biphenyl-4-methylindoleoxy)_2-methylene-cyclopentyl]-6-gas tert-butyl-9H-indole-2-carbamate; y^N^NHBoc <CT f3 /CHa O^-r0"-.❻ 0 9-[(lS,3R,4S)-3-tert-butyl Tert-butyl methoxycarbonyl-4-phenylhydroxy-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamic acid tert-butyl ester; ^^N^NHBoc 〒H3 /CH3 0 18 95335 201215612 9-[(lS,3R,4S)-3-tert-Butyldiphenylphosphonyloxy-4--4-(tetrahydrofuran-2-yloxy)-2-indenylene Tert-butyl group of cyclo-cyclopentyl]-6-chloro-9H-indole-2-carbamate Jx octa-P 9-[(lS,3R,4S)-4-tert-butyldidecyloxyl-3-tert-butyldiphenylanthoxymethyl-2-indenyl-cyclopentyl ]-6-Chloro-9H-indole-2-aminodecanoic acid tert-butyl ester; into B. ?H3 H3C CH3 9-[(lS,3R,4S)-4-(biphenyl-4-decyloxy) ) tert-butyl 3-tert-butyldiphenyl decyloxyindenyl-2-arylene-cyclopentyl]-6-chloro-9H-indole-2-carbamate; <<XNHB〇c 9-[(lS,3R,4S)-4-tert-butyldiphenyl-homooxy-3-tert-butyldiphenyloxyoxy-2-yl-cyclopentyl] -6-Chloro-9H-indole-2-aminodecanoic acid tert-butyl ester; <<XNHB〇c η/Γ° ^SVCH3 3 6 卜 9-[(lS,3R,4S)-4-benzoquinone醯oxy-3-tert-butyldiphenyl-oxymethyl-2-indenyl-cyclopentyl]-6-chloro-9H-indole-2-aminodecanoic acid tert-butyl ester; c6NHB.. p cH3 0 d 9-[(lS,3R,4S)-4-benzofluorenyl-3-benzoyloxyindol-2-indenyl-cyclopentyl]-6-gas-9H-indole- Tert-butyl 2-aminodecanoate; Qin. . 19 95335 201215612 9-[(lS,3R,4S)-4-(tetrahydro-β-pyran-2-yloxy)-3-phenylindoleoxyindol-2-methylene-cyclopentyl]- 6-Gas-9H-indole-2-carbamic acid tert-butyl ester; CI human NHBoc __0Ρζ-〇-"—0 9-[(lS,3R,4S)-4-tert-butyldimethyloxyl- 3-phenylindoleoxy-2-methylene-cyclopentyl]-6-chloro-9Η-σ 呤 呤 呤 叔 ; ;; A 皇 入 NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH (lS,3R,4S)-4-tert-butyldiphenylphosphoniumoxy-3-phenylindoleoxymethyl-2-indenyl-cyclopentyl]-6-gas-9H-°Ticket _ 2-aminodecanoic acid tert-butyl vinegar; into B〇C Η;^ίΡ^〇-ϊ-〇h/6 9-[(lS,3R,4S)-4-(biphenyl-4·'曱醯oxy )-3-benzylideneoxymethyl-2-methylene-cyclopentyl]-6-chloro-9H-indole-2-carbamic acid tert-butyl ester; 〇-〇-r〇^〇-^- 〇9-[(1S,3R,4S)-4-Benzylmethoxy-3-(biphenyl-4-oxooxymethyl)-2-methylene-cyclopentyl]-6-gas- 9Η-β 呤-2-aminodecanoic acid tert-butyl ester; Cl <NT^|N leads N people NHBoc ^0~0 9-[(lS,3R,4S)-4-(tetrahydro"喃-2-yloxy)-3-(biphenyl-4-methylindoleoxymethyl)-2-methylene-cyclopentyl]-6-gas-9H-oxime Tert-butyl-2-carbamic acid; hexa-NHBoc 〇, 〇-o Cr 9-[(lS,3R, 4S)-4-tert-butyldimethyl oxalyl-3-(biphenyl-4-yl)醯Oxymethyl)-2-indenyl-cyclopentyl]-6 mono--9H-indole-2-carbamic acid tert-butyl ester; Cl into NHBoc H3° CHa 20 95335 201215612

9-[(lS, 3R,4S)-4-tert-Butyldiphenylphosphonyloxy-3-(phenyl)-4-methylene-cyclopentyl]-6 - gas-9H-indole-2-aminodecanoic acid tert-butyl ester; into NHBoc H3C ό 9-[(lS,3R,4S)-4-(biphenyl-4-anthraceneoxy)-3-(tetrahydrogen) °-Butyl-2-yloxy)decyl-2-arylene-cyclopentyl]-6-chloro-9H-indole-2-aminodecanoic acid tert-butyl ester; οά with NHBoc 0-<yr ^°X) 0 9-[(lS,3R,4S)-4-tert-Butyldifluorenyloxy-3-(tetrahydropyran-2-yloxy)decyl-2-methylene Tert-butyl-cyclopentyl]-6-gas-9H-indole-2-aminodecanoate; soap^'n^NHBoc^fHs pC〇-r^i H3hc^~〇〇h3c CH3 9-[(lS ,3R,4S)-4-(biphenyl-4-decyloxy)-3-(biphenyl-4-indolyl)-2-methylene-cyclopentyl]-6-chloro- Tert-butyl 9H-indole-2-aminodecanoate; ^^N^NHBoc 0 (4aR,6S,7aS)-[6_chloro_9_(2,2-di-tert-butyl-5-anthracenyl-six氲-cyclopentadieno[1,3,2]dioxanthenehexene-6-yl)-9H-indole-2-carbamic acid tert-butyl ester Cl <Νώ N^^N^^NHBoc ςH^SiY〇H; h3c 'Ch3 ch3 (2S,4aR,6S,7aS)_[6_氯_9_(2_ 曱--5-methylene-hexahydro) -cyclopenta[1,3]dioxine-6-yl)-9H-indole-2-aminodecanoic acid tert-butyl ester Cl Mee^!V^NHBoc v° (2R, 4aR, 6S ,7aS)_[6_Chloro_9_(2-mercapto-5-methylene-hexahydro-cyclopenta[1,3]dioxan-6-yl)-9H-indole tert-Butyl -2-carbamate a N^^N^NHBoc V 21 95335 201215612 (4aR, 6S,7aS)_[6-chloro-(2-methyl-5-arylene-hexahydro-cyclopentane妇和[1,3]一氧摩尔辰稀-6-yl)-9Η-嘌呤-2-aminodecanoic acid tert-butyl ester CI k 丫0 9-[(lS,3R,4S)-4-tertidine Diphenyl phenyloxy-3-(triphenylphosphonium fluorenyl) 2 - fluorenyl-cyclopentyl] _ 6 gas-9H-° 吟-2-amino decanoic acid hr hr 9 In one aspect, the invention also relates to a process for the preparation of a compound of formula 6, which comprises reacting compound 4 with a 2-amino protected -6-substituted hydrazine compound 5 in the presence of a Mitsunobu reagent to obtain a coupled product 6

among them,

Ri and R2 may be the same or different and are each independently selected from the group consisting of the group of protecting groups described in the following groups (i) to (iii): (i) R and R2 are each independently selected from the group consisting of an alkyl group. Alkyl, benzyl, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si or Et3Si, preferably t-BuMe2Si; or 22 95335 201215612 (li) 匕 and R2 are each independently selected from t_BuMe2Si, Benzopyridinyl, tetrahydrofuran-2-yl, benzhydryl group with a substituent on the phenyl ring, biphenyl-4-methylindenyl, trityl, but 匕 and 匕 are not t- BuMe2Si; or (iii) 1^ and R2 together with the attached five-membered carbocyclic ring form one of the following fused ring systems:

Wherein R3 is a hydrogen atom, a Ci-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 dentate, a phenyl group and a nitro group; And Rs may be the same or different and each represents a 匕6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates the point of attachment of the fused ring to other parts of the molecule; the fused ring formed above is preferably as follows One of the fused ring systems:

R and R' may be the same or different and each represent hydrogen, an alkoxy drum group or an aralkoxycarbonyl group, such as a Ch alkoxycarbonyl group. The aryloxy group is preferably a tert-butoxycarbonyl group, provided that R and R are not nitrogen at the same time; χ is a halogen, alkoxy, haloalkoxy or aralkyloxy group, for example, ruthenium 6 is burned with oxygen 95335 23 201215612 Base, halogenated G-6 alkoxy or C5-!. The aralkyloxy group is preferably chlorine, decyloxy, benzyloxy or t-butoxy, and particularly preferably chlorine. The reaction conditions of this reaction are as described above. In another aspect, the 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,

Wherein, 匕 and R 2 may be the same or different and are each independently selected from the group consisting of the following hydroxy protecting groups of (i) to (iii): (i) Ri and R2 are each independently selected from the group consisting of a burnt group and a halogenated institute. Base, benzyl, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si or Et3Si, preferably t-BuMe2Si; or (ii) Ri and R2 are each independently selected from t-BuMe2Si, t-BuPh2Si, 24 95335 201215612 The present indenyl group, the tetrahydropyridinium-2-yl group, the abbreviated group having a substituent on the benzene ring, the hydrazine-4-methyl aryl group, the triphenyl fluorenyl group, but the L and R2 are not the same -BuMe2Si; or (iii) 仏 and R2 together with the attached five-membered carbon ring form one of the fused ring systems:

R3 r3 r3

Wherein 'R3 is a hydrogen atom, a Ci-e 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 decyloxy group, an ethoxy group, a phenyl group, a phenyl group and a nitro group; R4 and Rs may be the same or different and each represents a Ci 6 alkyl group or a '' 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; It is one of the fused ring systems as follows:

R and R' may be the same or different and each represent hydrogen, an alkoxycarbonyl or an aralkoxycarbonyl group, for example a C,-e alkoxycarbonyl group or a (V,.alkoxycarbonyl group, preferably a tert-butoxy group) a group, the condition is that R and not simultaneously hydrogen; X is halogen, alkoxy, _alkoxy or aralkyloxy, for example Ci 6 alkoxy self-made Cl-6 alkoxy or alkoxy 'Preferable gas, methoxy, 95335 25 201215612 benzyloxy, tert-butoxy, particularly preferred gas. The reaction conditions of the reaction are as described above. In another aspect, the invention relates to a compound of formula 4:

4 where,

Ri and R2 may be the same or different and are each independently selected from the hydroxy protecting groups described in the following (earth) to (iii) groups: (i) hydrazine and hydrazine are each independently selected from alkyl, dentate alkyl, Benzyl, t-BuMedi, t-BuPhdi, (i-Pr)3Si or Et3Si, preferably t-BuMezSi; or: ii) Rl*R2 are each independently selected from t-BuMe2Si « t-DUMe2^i > t- BuPh2Si benzhydryl group, tetrahydrobi-2-pyryl, benzoyl group with a substituent on the benzene ring, biphenyl-4-methylindenyl, trityl group, but hydrazine and hydrazine are not simultaneously t-BuMe2Si; or a carbocyclic ring together form one of the following (iii) 匕 and 匕 and the connected five-member fused ring system:

Wherein R3 is a hydrogen atom, a Cl-6 alkylphenyl group or a substituted benzene 95335 26 201215612 group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, an iS element, a phenyl group and a nitrate匕 and R5 may be the same or different and each represent an ind-6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates the point of attachment of the fused ring to other parts of the molecule; The ring is preferably one of the fused ring systems described below:

Among the above compounds of the formula 4, the following compounds are preferred: 4a: (1R, 3R, 4S)-4-(tert-butyldimethylfluorenyloxy)-3-[(tert-butyldimethylamyloxy)anthracene ]]-2-indenyl-cyclopentanol OH k TBSO CH2〇TBS 4b : (lR,3R,4S)-4-benzyloxy-3-(benzyloxyindenyl)-2-methylene- Cyclopentanol OH BnO CH2OBn 4c : (1R,3R,4S)-4-tert-butyldiphenylsuccinyloxy-3-yl-tert-butyldiphenyldecyloxyindenyl-2-methylene-1- Cyclopentanol OH V? P H3C 0 ^h?CH3 4d : (lR,3R,4S)-4-tert-butyldiphenyloxy-3-(tert-butyldimethyloxycarbonyl) -2-indolyl-1-cyclopentanol OH h3c P <V ?H3/H3 \ 甲一^*CH3 ^-f-ψ 0 iH3 ch3 H3C〇4e : (lR,3R,4S)-4 -tert-Butyldidecyloxy-3-tert-butyldiphenylphosphonyloxymethyl-2-methylene-1-cyclopentanol OH <y H3c CH3 V__/V/〇_si_Z_cH3 0 A CH3 h3c ch3 27 95335 201215612 4f : (1R,3R,4S)-4-tert-butyldiindenyloxy-3-(biphenyl-4-indolyl)-2-indenyl- 1-cyclopentanol OH ' strict pC〇CH3-7-Si-0 CH3 CH3 4g : (4aR,6R,7aS)-2,2_di-tert-butyl-5-indenyl-6-hydroxyl -6H-cyclopenta[1,3,2]dioxanthene OH °\/° H3C^/S'\-CH3 ch3^ch3 ch^3 4h : (1R,3R,4S) 4-tert-Butyldiphenylphosphoniumoxy-3-(biphenyl-4-methylindoleoxymethyl)-2-methylene-1-cyclopentanol OH η ? H3C—*7—Si 〇H3C ό 4i : (1R,3R,4S)-4-(biphenyl-4-anthraceneoxy)_3_tert-butyldiindenyloxyindenyl-2-methylene-1-cyclopentanol OH ?H3 〇4j : (1R,3R,4S)-4-Benzenyloxy-3-tert-butyldidecyloxymethyl-2-indenyl-1-cyclopentanol OH 1 H3 / CH3 0 4k : (2R,4aR,6S,7aS)-2-mercapto-5-indenyl-6-ylamino-6H-cyclopenta[1,3]dioxane HO 〇\ / 41 : (1R,3R,4S)-4-(® Hydrogen~pyran-2-yloxy)-3-tert-butyldidecyloxycarbonyl-2-methyl-1-one Pentanol OH bf ?Hs λ Plant 0, Si-^-CH3 ΟTM〇Ah3 CH3 28 95335 201215612 4m . (1R,3R,4S)-4-tert-Butyldiphenylphosphonium-3-(triphenyl) Mercaptooxyalkyl)-2-methylene-1-cyclopentanol

Compound 4 can be synthesized by a similar method as described in the literature, or 'Compound 4 can also be synthesized by using Compound 2 as a raw material by the following method: a) Opening Compound 2 directly to obtain cyclopentene intermediate 3

Or2 2 where,

Ri and R2 may be the same or different and are each independently selected from the group consisting of the following hydroxy protecting groups of (丄) to (iii): (i) Ri and R2 are each independently selected from alkyl, dentate alkyl, Benzyl, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si or Et3Si, preferably t-BuMe2Si; or (ii) 匕 and 1 are each independently selected from t-BuMe2Si, t-BuPh2Si, benzoinyl, Tetrahydron-pyranyl-2-yl, benzinyl, biphenyl-4-carboxamyl, trityl with a substituent on the phenyl ring, but l and oxime are not t-BuMe2Si at the same time; or 29 95335 201215612 (iii) 匕 and R2 together with the connected five-member carbon ring form one of the following fused ring systems:

Wherein R 3 is a hydrogen atom, a G-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 hydroxyl group, a phenyl group and a nitro group; R4 and R5 may be the same or different and each represents a Cl-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; It is one of the fused ring systems as follows:

b) Compounds of formula 3 are obtained by alcoholysis or hydrolysis to give compounds

CHO

Or2 alcoholysis or hydrolysis

'"/CH2ORi or 2 30 95335 201215612 The method described in the examples or a similar method is prepared. In the above step a), a suitable reagent for catalyzing and initiating a radical cleavage reaction of the compound 2 in the copper (1) salt, for example, phI(GAc)2, K〇Ac)3 or PbCOAcV, preferably Pb(GAe), is directly opened. The ring can be obtained as a cyclopentane intermediate 3 13⁄4 reaction in a solvent such as benzene, toluene, cyclohexene, petroleum or n-glycol or in a non-f-polar solvent such as acetonitrile, ethyl acetate or halogen L or tooth It is preferably carried out in the presence of an organic test such as triethylamine or hydrazine. In the above step b) 'the compound of the formula 3 is tested in the presence of, for example, triethylamine, Km or an alkoxide, in an organic solvent such as ▼ alcohol, ethanol or a mixture thereof or in a mixed solvent of water or water with other organic solvents, For example, a mixture of water and water is subjected to alcoholysis or hydrolysis to give compound 4. The reaction in this step is preferably carried out using 〇?3 and methanol. Thus, in a preferred embodiment, the compound of formula 4 is synthesized by: a) catalyzing compound 2 under the action of copper (π) salt and pb(〇Ac)4, preferably in an organic base such as triethyl The cyclopentane intermediate 3 is obtained directly in the presence of an amine or ntb bite; b) the compound of formula 3 is subjected to alcoholysis in methanol in the presence of IGC03 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, to 150 Torr, especially From room temperature to the reflux temperature of the solvent. 31 95335 201215612 The compound of formula 3 produced in step a) above is a novel compound. Thus the 'one aspect' of the invention also relates to the compound of formula 3:

, CHO

Ο Among them,

Ri and R2 may be the same or different and are each independently selected from the group consisting of the group-protecting groups described in the following groups (i) to (iii): (I) Rdo R2 is each independently selected from an alkyl group, a toothed alkyl group, Benzyl, t-BuMe2Si, t-BuPh2Si, (i-pr)3Si or Et3Si, preferably ΐ-BuMe2Si; or (II) Ri and R2 are each independently selected from t-BuMe2si, t-BuPh2Si, benzamidine, Tetrahydro D is a nonyl-2-yl group, a benzamidine group having a substituent on a benzene ring, a biphenyl-4-methylindenyl group, a trityl group, but ruthenium and osmium are not simultaneously t-BuMe2Si; or Iii) 匕 and I together with the attached five-membered carbon ring form one of the fused ring systems described below:

Wherein 'K3 is hydrogen, (:, _6 minus, stupid or stupid with a substituent, the substituent on the phenyl is preferably methoxy, ethoxy, arginine, benzene 95335 32 201215612 base and nitrate R4 and R5 may be the same or different and each represent a Cl-6 alkyl group or an aryl group, preferably a tert-butyl group or a stupid group; wherein * indicates the point of attachment of the fused ring to other parts of the molecule; The ring is preferably one of the fused ring systems described below:

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

OCHO

Further, it is particularly preferable that the compound of the formula 3 is a compound having the following structure: (1R, 3R, 4S) 4-(tetrazoπpyran-2-yloxy)-3-tert-butyldidecyloxycarbonyl group -2-indenyl-cyclopentanol phthalate OCHO 〒h3 ch3 Si-^-ch3 CH3 CH3 (1R,3R,4S)-4-tert-butyldiphenyl oxalyl-3-tert-butyl Mercaptomethoxymethyl-2-indenyl-cyclopentanolcarboxylate OCHO h3〇o hr ?hvch3 ^-f-ψ 0 iH3 ch3 H3C0 (1R,3R,4S)-4-(biphenyl- 4-曱 oxy)_3-tert-butyldimethylammonyl-2-indenyl-cyclopentanol phthalate OCHO bf ?H3 0 33 95335 201215612

(lR,3R,4S)-4-benzylideneoxy-3-tert-butyldimethylsilyloxynonyl-2-methylene-cyclopentanol phthalate OCHO 〒h3 ch3 \=/ II CH3 CH3 o (1R,3R,4S)-4-(tetrazoliumpyran-2-yloxy)-3~tert-butyldiphenylphosphonyloxyindol-2-indenyl-cyclopentyl Alcohol formate OCHO. Pc. , p (1R,3R, 4S)-4-tert-butyldimethylfluorenyloxy-3-(tert-butyl-diphenylphosphonyloxymethyl)-2-methylene-cyclopentanol decanoic acid Ester OCHO HsCv |H3 ^C〇NP H3c-^-& 〇SI ch3 HsC cHa dH/cH3 (lR,3R,4S)-4-(biphenyl-4-methoxyl)_3-tert-butyl Phenyloxymethyl-2-methylene-cyclopentanol phthalate OCHO. 〇(lR,3R,4S)-4-tert-Butyldiphenyl-homooxy-3((tert-butyldiphenylphosphonyloxy)-2-methylene-cyclopentanolcarboxylate OCHO &amp ; , P HaC ^ ^Η3ΓεΗ3 (lR,3R,4S)-4-benzylideneoxy-3-tert-butyldiphenyl oxalylhydrazino-2-indenyl-cyclopentanol phthalate OCHO h : p 0 d t3 (lR,3R,4S)-4_benzylideneoxy-3-phenylindoleoxy-2-methylene-cyclopentanolcarboxylate OCHO 34 95335 201215612 (1R,3R , 4S)_4-(tetrazo.pyran-2-yloxy)-3-phenylindoleoxymethyl-2-indenyl-cyclopentanyl phthalate OCHO (1R,3R, 4S)-4 -tert-Butyldidecyloxy-3-phenylindoleoxy-2-ylindenyl-cyclopentanyl phthalate OCHO η3η03^-Γ3 0fc°-"-O H3C CH3 (1R, 3R ,4S)-4-tert-butyldiphenylphosphoniumoxy-3-benzhydryloxyindenyl-2-indenyl-cyclopentanol phthalate OCHO H3Cx9 h3c-4—Si—J ^ H3C ό ( 1R,3R,4S)-4-(biphenyl-4-decyloxy)-3-phenylindoleoxymethyl-2-indenyl-cyclopentanyl phthalate OCHO (y^y-crP^ -〇-"0 0 (1R,3R,4S)-4-Benzenyloxy-3-(biphenyl-4-methylindoleoxy)-2-indenyl-cyclopentanolcarboxylate OCHO 0 (1R,3R,4S)_4_(tetrazoππ比南-2-yloxy)-3-(biphenyl-4-methylindoleoxy)-2-indenyl-cyclopentanol Acid ester OCHO (1R 3R,4S)-4-tert-butyldidecyloxyl_3_(biphenyl-4-indoleoxymethyl)-2-indenyl-cyclopentanol phthalate OCHO H3C-4—Si— 0 H3C CH3 (1R,3R,4S)-4-tert-butyldiphenylphosphonium-3-(biphenyl-4-indolyl)-2-indenyl-cyclopentanyl decanoate OCHO H3C-4—Si—0 ^ w H3C 0 35 95335 201215612 (1R, 3R, 4S)-4-(biphenyl-4-decyloxy)-3-(tetrahydro-β-pyran-2-yloxy) Methyl-2-indenyl-cyclopentanol formate OCHO (IK, 3R, 4S)~4-tert-butyldimethylanthryloxy-3-(tetrahydron-pyran-2-yl) Oxy) indenyl-2-indenyl-cyclopentanol phthalate UCHO Η3\ ίΗ3 >-C〇-r^i H3c-V-si- H3c ch3 (lk,3Κ, 4S)-4-( Biphenyl-4-decyloxy)-3-(biphenyl-4-methylindoleoxymethyl)-2-methylene-cyclopentanolcarboxylate 〇CH〇0 (4aR,6R,7aS)- 2,2-di-tert-butyl-5-methylene-6H-cyclopenta[1,3,2]dioxanthene-6-formate 〇CH〇: XVY〇H; H3C CH3 CH3 (2S,4aR,6S,7aS)-2-methyl-5-methylene-6H-cyclopenta[1,3]dioxane_6 monodecanoate OCHO (2R , 4aR, 6S, 7aS)-2-methyl-5-Asia -6H-cyclopenta[1,3]monoxanthene-6-decanoate-ester OCHO V (1R,3R,4S)-4-tert-butyldiphenylphosphonium-3- (triphenylsulfonyloxyindenyl)-2-indenyl-cyclopentanol phthalate T°\. Υ-Λύ° 〇-|-〇 In another aspect, the invention also relates to the preparation of a compound of formula 3 Method, the 95335 36 201215612 method comprises the steps of: a) ring opening of compound 2 directly to give cyclopentane intermediate 3 OH ____

Or2 2 where,

Ri and Rz may be the same or different and are each independently selected from the group consisting of the following hydroxy protecting groups as described in (iii): (i) Ri and I are each independently selected from alkyl, haloalkyl, benzyl, t- BuMe2Si, t-BuPh2Si, (i-Pr)3Si or EtsSi, preferably t~BuMe2Si; or (ii) Ri and r2 are each independently selected from the group consisting of t-BuMe2Si, t-BuPh2Si, benzoyl, tetrahydropyran _ a 2-benzyl group, a benzamidine group having a substituent on a benzene ring, a biphenyl-4-methyl fluorenyl group, a trityl group, but ruthenium and osmium are not simultaneously t-BuMedi; or (111) 匕 and R 2 are The connected five-membered carbon rings together form one of the ring-ring systems:

95335 37 201215612 base and nitro; R4 and R5 may be the same or different and each represents a G 6 alkyl or aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates the point of attachment of the fused ring to other parts of the molecule; The fused ring formed above is preferably one of the following slightly ring systems:

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 give cyclopentane intermediate 3

Or2 2 where,

Ri and R2 may be the same or different and are each independently selected from the hydroxy protecting groups described in the following groups (i) to (iii): (Ο Ri and R2 are each independently selected from alkyl, dentate alkyl, benzyl Base, t-BnMe2Si, t-BuPh2Si, (i-Pr)3Si or Et3Si, preferably t-BuMe2Si; or (ii) 匕 and 1 are each independently selected from t-Bu|je2Si, t-BuPh2Si, 38 95335 201215612 benzene Sulfhydryl, tetrahydro"pyran-2-yl, abbreviated with a substituent on the phenyl ring, biphenyl-4-mercapto, trityl, but 1 and R2 are not t- BuMe2Si; or (iii) 1 and R2 together with the attached five-membered carbocyclic ring form one of the fused ring systems described below:

Wherein R3 is a halogen atom, a G-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the stupid group is preferably selected from the group consisting of a decyloxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group; And R5 may be the same or different and each represents a Cl-6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates the point of attachment of the fused ring to other moieties; the fused ring formed above is preferably One of the fused ring systems as follows:

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

Wherein Ri and R2 are as defined above; 39 95335 201215612 C) Compound 4 is reacted with 2-protected amino-6-substituted indole compound 5 by Mi tsunobu reaction to obtain a coupled product 6

Wherein Ri and R2 are as defined above; R and R' may be the same or different 'representing hydrogen, alkoxycarbonyl or aromatic oxycarbonyl, for example Cw alkoxycarbonyl or c5-iearkoxycarbonyl'. Preferred is tert-butoxycarbonyl, provided that R and R are not hydrogen at the same time; X is a south alkoxy group, a methoxy group or an alkoxy group, for example, a C 6 alkoxy group, a C alkoxy group Or a c5_1()aralkyloxy group, preferably a gas, a methoxy group, a methoxy group, a tert-butoxy group, particularly preferably a gas; a cleavage group 6 is deprotected to give a compound 7 d) when hydrazine and R 2 When both are sulfhydryl protecting groups or none of them are sulfhydryl protecting groups,

R and R' are as defined above; e) hydrolysis of compound 7 to give a compound of formula 1 (entecavir) 40 95335 201215612

OH 〇H 7 1 wherein X, R and R' are as defined above; or d') when neither 1 nor R2 is a thiol protecting group, compound 6 is simultaneously deprotected and hydrolyzed to directly obtain a compound of formula 1

Wherein X, Ri, R2, R and R' are as defined above; or (d") when one of hydrazine and R2 is a fluorenyl protecting group, for example a benzylidene group or a benzene having a substituent on the benzene ring Compounds 6 are deprotected to give 8 or 9, which are hydrolyzed or hydrolyzed by compound 7 to give compound 1, 41 95335 201215612

Deprotection

N

Deprotection

OH 1 deprotection / hydrolysis

NRR1 ORa 9

Vf

Y^CHzOH wherein X, Ri, R2, 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 process for the preparation of a compound of formula (1) comprises the steps of: a) ring opening of compound 2 directly to give the cyclopentane intermediate 3 42 95335 201215612

2 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-protected amino-6-substituted anthracene compound 5 to obtain a coupled product 6

Or2 4

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

e) Hydrolysis of compound 7 to give compound of formula 1 43 95335 201215612

Or d') simultaneously deprotecting and hydrolyzing compound 6 to obtain the compound of formula 1 directly

In each of the above steps, 1 and R2 may be the same or different and each represents a hydroxy protecting group, such as an alkyl group, a halogenated group, a benzyl group, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si or Et3Si, Preferred is t-BuMe2Si; R and R' may be the same or different and each represent hydrogen, an alkoxycarbonyl or an aralkoxycarbonyl group, for example, a Cl-6 alkoxycarbonyl group or a C5-1D aryloxycarboxy group, preferably a tertiary Butoxycarbonyl, provided that R and R' are not hydrogen at the same time; X is halogen, alkoxy, halooxy or aryloxy, such as Cl-6 alkoxy, _Cl-6 Base or C5-!. The aralkyloxy group is preferably a gas, a decyloxy group, a benzyloxy group or a tert-butoxy group, and particularly preferably chlorine. The reaction conditions of the above steps a) to e) are as described above. 44 95335 201215612 In a particularly preferred embodiment, entecavir of formula (1) is synthesized by a process comprising the steps of: a) catalyzing compound 2 under copper (II) salt catalysis and Pb(0Ac)4 Preferably, the cyclopentane intermediate 3 is obtained directly by ring opening in the presence of an organic base such as triethylamine or pyridine; b) the compound of formula 3 is subjected to alcoholysis in decyl alcohol in the presence of K2C〇3 to give compound 4 c) Compound 4 and 2-protected amino-6-substituted indole compound 5 in the presence of Ph3P/Et〇2CN=NC〇2Et or Ph3P/i-Pr〇2CN=NC〇2i-Pr in aprotic Solvents such as aromatic hydrocarbons, dentate aromatic hydrocarbons, halogenated alkanes or ethers, such as THF, are reacted to give the coupled product 6; 'd) Compound 6 is deprotected in the presence of tetrabutyl vaporized (TBAF) or hydrochloric acid. The compound is obtained as a compound of the formula 1; e) the compound 7 is hydrolyzed to the compound of the formula 1 in the presence of a solution. ^ In the method, the step can be adopted: the reaction of the subsequent anti-two (4) is directly carried out in the form of the compound, and the compound of the formula (3) can be used as the compound of the formula (1). You b) to e) to prepare the compound of formula (1) and to carry out the ij starting material as described above and carry out the second step as described above: 'or the compound of formula (8), or formula (7) / ) e) To prepare a compound of formula (1) to prepare a compound of formula (1). The material is directly subjected to the step f as a raw material. [Embodiment] 95335 45 201215612 The method of the present invention will be further described by the following examples. It is to be understood that the following examples are provided for the purpose of better understanding of the invention and are not intended to limit the scope of the invention. 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-BuMe2Si Preparation of tert-butyl dimercaptoyl base material: Raw material for the synthesis of compound 2 And methods are known and can be synthesized by the following methods or the like. (1) When [^ and R2 in the compound 2 together with the attached five-membered carbocyclic ring form a fused ring system, the synthesis of the starting materials is as follows. Synthesis of a compound of the formula: (4aR, 4bS, 7aR, 8aS) _2-mercapto-hexahydro-furo[3',2':3,4]cyclopenta[1,2-d][l, 3, 2]dioxaindene heterocyclic-6(7a^〇-ketone 46 95335 201215612

Under a nitrogen atmosphere, Corey Diol (172 g, 1 mol), 2,6-dimercaptopyridine (257 ml, 2.2 mol), DMF (1700 g) was added to the reaction flask, and di-tert-butylfluorene was added dropwise with stirring at room temperature. Base bis(trifluorosulfonane sulfonate) ester (400 ml, 1. lmol), after completion of the reaction, the reaction was completed at room temperature until the material was slowly poured into water, the solid was precipitated, the mash was dried, and the cake was dried to give the desired product. NMR (CDC13, 500MHz) NMR: (5 = 0.98 (s, 9H), 1.03 (s, 9H), 1.83 (m, 2H), 2.29 (m, 1H), 2.39 (m, 1H, ), 2.70 (in , 2H), 3.86(m, 1H), 2. 01 (m, 1H), 4. 24 (m, 1H), 4.83 (m, 1H); 13C Li R: <5 = 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-mercapto-hexahydro-furo[3', 2':3,4]cyclopentadienyl[l,2-d][l,3]dioxacyclo-6(7a^〇-ketone

47 95335 201215612 Under the protection of nitrogen, 'In the reaction flask, add C〇rey acetonitrile diol (172g, 1mol) 'anhydro-p-benzenesulfonic acid (π. gg), two gas smoldering (1720ml), acetal acid &quot ; (354g, 3mol). After stirring at room temperature for 1 hour, the temperature was refluxed until the reaction was completed, and the crystal was concentrated to give the desired product 9 g. NMR (CDC13, 500MHz) 丨HNMR: (5 = 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, ih), 4. 85 (m, 1H); 13CNMR: (5 = 20.70, 32.56, 36.70, 37.07, 45.40, 70.52, 79.84, 80.68, 99.80, 176. 18. (2) When 1 and R2 in compound 2 are each independently a protecting group or a thiol protecting group, the synthesis of the starting materials is as follows First, a compound of the formula (TC0D) is synthesized: (3aS, 4R, 5S, 6aR)-hexahydro-5-hydroxy-4-tert-butyldimethylammoniomethyl-2H-cyclopentane and [b ° °-2-one

The TBDMCU 150. 5g, lmol) was added to the reaction flask, and the mixture was added to the TBDMCU 150. 5g, 1mol). Add the heat to the reaction and complete the reaction. After workup, 220 g of the desired product was obtained. The following starting materials were synthesized starting from TC0D. 48 95335 201215612 Synthesis of a compound of the formula: (335,4155,631〇-hexahydro-5-tert-butyldiphenylsuccinyl-4-tert-butyldimethylpyromethyl-2H-cyclopentan And [b]biting-2-one

Under the protection of nitrogen, TCOD (286 g, 1 mol) was added to the reaction flask, and the mixture was stirred (95. 2g, 1.4 mol), DMF (1144 g), and the mixture was dissolved at room temperature, and t-butyldiphenyl was added in portions. Chlorodecane (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. R (CDC13, 500MHz) (5 = -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 (ra, 2H), 2.80 (m, 1H), 3.3. (m, 1H), 3. 44 (m, 1H), 4. 15 (m, 1H), 4. 84 ( m, 1H) 7. 39 (ra, 6H) 7. 69 (m, 4H); 13CNMR: 5 = -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: (333,4153,68[〇-hexahydro-5-(biphenyl-4-decyloxy)-4- uncle Butyl dimethyl fluorenyl 2H-cyclopenta[b] alpha pentan-2-one 49 95335 201215612

CH3lrCH3 3 H3-CH-H3 Under the protection of nitrogen, add TCOD (286g, 1mol), imiprazole (95. 2g '1.4mol) 'DMF (1144g) in the reaction flask, stir and dissolve at room temperature, and add in batches. Biphenyl hydrazine chloride (239 g ' 1. lmol) 'filled with heat until the reaction was complete. After workup, 343 g of the desired product was obtained. NMR (CDCh, 500MHz) • HNMR: δ = 0.08 (s) (6H)) 〇91 (s 9H), 2.35 (m, 2H), 2.49 (m, 1H), 2.59 (m, iH, ), 2.92 (m , 2H), 3. 70 (m, 1H), 3. 76 (in, 1H), 5. H 1H), 5 38 (m, 19H), 7.74 (m, 9H); 丨3CNMR: (5 =- 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,Π7. i〇. Compound (3aS, 4R, 5S, 6aR)-hexanitro-5-benzylideneoxy-4-tert-butyldimethyloxyloxymethyl-2H-cyclopenta[b]furan-2_嗣

95335 50 201215612 Under the protection of nitrogen, add TC0D (286g, 1mol), sodium β (95. 2g, 1.4 mol), DMF (1144g) in the reaction flask, mix and dissolve at room temperature, add benzoquinone chloride (239 g, 1. lmol) 'Additional heat to complete reaction. After work-up and column chromatography, 3 g of the desired product was obtained.匪R (CDC13,500MHz) WNMR: (5 = 〇.〇2 (s,6H), 0.86 (s, 9H), 2.28 (in, 2H), 2.43(m, 1H), 2.51 (m, 1H, ) , 2.87 (in, 2H), 3. 64 (m, 1H), 3.70 (m, 1H), 5.03 (m, 1H), 5.28 (m, 1H) 7. 67 (m, 5H); 13CNMR: 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 hydrazine or R2 in 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-butyldiphenylphosphonyl-4-(triphenylphosphonyloxymethyl)-2H -cyclopenta[b]furan-2-

Step 1: Synthesis of TrCOD In a clean reaction flask, 138 g of lactone diol, 950 g of pyridyl and 300 g of triphenylsulfonyl chloride (TrCl) were added, and the reaction was incubated until tlc showed that the starting material had been reacted 51 95335 201215612. Then, the reaction mixture was extracted into an organic solvent of k octahydrate, washed, dried, and then transferred, and the filtrate was concentrated to give a white solid TrCOD (265 g), yield 80%. Step 2: Synthesis of hexahydro-tert-butyldiphenyl-glycidyltrityloxymethylcyclopentanfuranone in a clean reaction flask with force π Λ, 1 τ τ Add 41.4 g TrCOD, 20 g imidazole ( ΙΜΙ) and 300ml DMF 'mixed' and then add 3〇g of tert-butyl diphenyl gas oxalate (TBDPSC1)' after about 1 hour, the reaction is kept until the raw material is completely reacted, then post-treated, after crystal drying A white solid of 45 g was obtained. HNMR. 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); CKiMR: δ-19.16, 27.G2, 36.Gl, 4G.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-butyldimethylsilyloxy-methyl)-hexahydro-cyclopentane Preparation of the dilute [b]nonan-2-ol (Compound 2a; RpRet-BuMeJi). The title compound was obtained as a white solid, 7.55 g (94%). MS 402. 3. In a similar manner, using the starting materials for the preparation of compound 2 described above, compounds having different protecting group types, such as a cycloether protecting group, a hydrazine protecting group, a tripentate protecting group or a thiol protecting group, were prepared. 2. Example 2: (lR,3R,4S)-4-(tert-butyldimethylfluorenyloxy)_3—[(ter 95335 52 201215612 butyldimethylamyloxy)methyl]-2-methylene Preparation of keto-cyclopentanol phthalate (compound 3a; Ri = R2 = t-BuMe2Si);

OCHO

1. 2 g (3 mmol) of compound 2a (Ri = R2 = t-BuMe2Si), 2. 65 g of Pb (0Ac) 4 (6 mmol) and 0.1 g of anhydrous Cu (OAcM 〇. 2 mmol) were added to 100 ml of benzene and 0. 5 ml 〇 咬 (6. lmmol), heated and stirred under reflux for 1 hour, cooled to room temperature, and filtered through celite. The residue was washed with petroleum ether / ethyl acetate (50/1), and the filtrate was washed with water and then dried. And the title compound is 0. 74 g (yield of the title compound (yield: EtOAc (EtOAc) 62%). j^RCCDCh, 300MHz): 5=0.02, 0.03, 0.05, 0.058 (s, each 3H, 4XCH3-), 0.87 (s, 18H), 1.7 (m, 1H), 2.4 (m, 1H), 2.58 (m , 1H), 3. 68 (d, J=4. 5Hz, 2H, -CH2-O), 4.12 (in, 1H), 5. 19(t, 1H, J=1.8Hz), 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: Compound name structure MS data 53 95335 201215612 3c: (lR, 3R, 4S)-4-tertidine Diphenylphenyloxy 3-(tert-butyldiphenylphosphonium)-2-indenyl-cyclopentanyl phthalate OCHO & , P % 6 ^ηΓ〇Η3 648.31 3d: (lR, 3R, 4S)-4-tert-butyldiphenyl decyloxy_3_tert-butyl fluorenyl fluorenyl-2-indenyl -cyclopentanyl phthalate OCHO H3C P bf ?H3/CH3 h3C_|_T 〇iH3 ch3 H3C0 524·28 3e: (lR,3R,4S)-4-tert-butyl fluorenyl oxetyl - 3_(uncle Butyl-diphenylphosphoniumoxymethyl)-2-indenyl-cyclopentanol phthalate OCHO H3cx |H3 ^C〇xP H3C 今一〒 '/'v^CHa HaC ch3 \ 524.28 3f: ( lR,3R,4S)-4-tert-butyldimethylamyloxy-3-(biphenyl-4-indoxymethyl)-2-indenyl-cyclopentanol phthalate OCHO η3ϊ^_Γ Ρ^-ό-^—0~0 H3c ch3 466. 22 3g: (4aR,6R,7aS)-2,2-di-tert-butyl-5-indenyl-6H-cyclopentane[1,3 , 2] Dioxaindole Heterocyclohexane-6-decanoate OCHO 〇, I) siC°/CH3 H3X YcH3 h3c 'Ch3 ch3 312. 18 3h: (lR, 3R, 4S)-4-tert-butyl Diphenyl decyloxy-3-(biphenyl-4-methyl-methoxymethyl)-2-indenyl-cyclopentanyl phthalate OCHO J6 590. 25 54 95335 201215612 3i: (lR, 3R, 4S )-4-(biphenyl-4-methyloxy)-3-tert-butyldiindenyloxyindenyl-2-indenyl-cyclopentanol decanoic acid OCHO hr ?Ha 3 0 466. 22 3j: (lR,3R,4S)-4-Benzenyloxy-3-tert-butyldimethylammoniomethyl-2-indenyl-cyclopentanol Phthalate OCHO 〒h3 ch3 0 390. 19 3k: (2R,4aR,6S,7aS)-2-mercapto-5-indenyl-6H-cyclopenta[1,3]dioxine Alk-6-phthalate OCHO 〇/ r 198. 09 31: (1R,3R, 4S)-4-(tetrahydropi-pyran-2-yloxy)-3_tert-butyldifluorenyloxyl Methyl-2-indenyl-cyclopentanol phthalate OCHO 〒h3 ch3 si—^-ch3 ^y° U ch3 370. 22 3m: (1R, 3R, 4S) -4- (tetra argon α ratio σ南-2-yloxy)-3-tert-butyldiphenylphosphoniumoxy-2-ylindolyl-cyclopentanolcarboxylate OCHO 494. 25 3n: (1R,3R, 4S)- 4-(Biphenyl-4-decyloxy)_3_tert-butyldiphenylphosphonyloxymethyl-2-indenyl-cyclopentanyl phthalate OCHO (y^y-〇-^\P dHK: 590.25 55 95335 201215612 3o: (lR,3R,4S)-4-Benzyloxy-3-tert-butyldiphenylphosphoniumoxy-2-ylindenyl-cyclopentanolate OCHO & p wide. Ch3 0 3 under CH3 \J ch3 514.22 3p: (lR,3R,4S)-4-benzoquinone-3-phenylindoleoxy-2-ylindenyl-cyclopentanol phthalate OCHO 380.13 3q: (1R,3R,4S)-4-(tetrazine π than 2-aminooxy)-3-phenylindoleoxy-2-ylindenyl-cyclopentanol phthalate OCHO 360.16 3r : (lR,3R,4S)-4-tert-butyl bis-indenyl oxalyl-3-phenylindoleoxy-2-ylindenyl-cyclopentanol phthalate OCHO H3C\ ?H3 Q h3c- ^—Si—0 ^ H3C CH3 390. 19 3s: (lR,3R,4S)-4-tert-Butyldiphenyloxyoxy-3_benzoquinoneoxyindol-2-indenyl-cyclopentanol Phthalate OCHO H3Cv? h3c-4—si—J ^ H3C 514 514.22 3t: (1R,3R,4S)-4-(biphenyl-4-methyl methoxy)-3-benzenemethyl oxime oxime- 2-indenyl-cyclopentanol phthalate OCHO Ο〇-?Γ^〇Λ<} 0 456. 16 3u: (lR, 3R, 4S)-4-phenylindoleoxy-3-(biphenyl -4-曱醯Oxymethyl)-2-indenyl-cyclopentanol phthalate OCHO 0_C_-〇^^〇_"-O_O 0 456. 16 56 95335 201215612 3v: (1R,3R,4S) 4-(tetrahydrofuran-2-yloxy)-3-(biphenyl-4-oxoindenyl)-2-indenyl-cyclopentanolcarboxylate OCHO 436. 19 3w: ( 1R, 3R, 4S) -4- (Linked 4-A)醯oxy)-3-(tetrahydroηpyran-2-yloxy)methyl-2_indenyl-cyclopentanolcarboxylate ff 0-^r〇y"〇X) 0 436.19 (lR ,3R,4S)-4-tert-butyl-monomethyloxy-3-(tetrahydropyran-2-yloxy)indol-2-methylene-cyclopentanol phthalate OCHO h3\ i Ha H3c ch3 370.22 3y: (1R,3R,4S)-4-(biphenyl-4-methyloxy)-3-(biphenyl-4-methylindoleoxy)-2-indenyl- Cyclopentyl decanoate OCHO 0-Q— 0 532.19 (2S, 4aR, 6S, 7aS) OCHO -2-mercapto-5-methylene-6H-cyclopentane[1,3] {x 198.09 II Oxeane-6-曱4 o / ___ acid ester \^0 where NMR of 'compound 3k' is as follows:

r 57 95335 201215612 NMR (CDC13, 500MHz): 1HNMR: 5 = 1.34 (d, 3H), 1.76 (m, iH)' 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), 5.5 〇 (t, 1H), 8.03 ( s, 1H); 13C NMR: 6 = 20.78, 36.04, 45.16, 68.64, 71.75, 78.59, 100.02, 113.04, 144.77, 160.79. 3aa . (1R,3R,4S)-4-tert-Butyldiphenyl oxalyl-3-(trimethyleneoxymethyl)_2_arylene-cyclopentanol phthalate Example 2 is similar to compound 3aa:

The NMR data are as follows: !ΗΝΜΚ: <5=1.03 (d, 9H), 1.26 (m, 1H), i.78(ln, 1H), 2.12 (m, 1H, ), 2.86 (m, 1H), 2.98 (m, 1H), 3.12 (m, 1H), 4. 07 (m, 1H), 5.21 (s, ih), 5·45 (s, 1H), 7·37^25H), 8.03(s, 1H);»3CNMR: ^l9.22, 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.实列列列篇名 (10)3R,4S)+(tert-Butyldimethylglycine)_3_[(tert-butylf-dimethyl oxalyl)methyl]-2-methylene, pentanol (Compound & R! Preparation of -R2=t-BuMe2Si) · 95335 58 201215612

OH

CHo0TBS TBSO CHj To 490 mg (1.22 mmol) of compound 3a (Ri=R2=t-BuMe2Si) was added 15 ml of methanol and 250 mg of anhydrous K2C〇3' at room temperature for 1 hour, and dried under salt pressure, and the residue was added with 20 ml of petroleum ether. The title compound 440 mg (96%) was obtained as a white solid. Mp 64_66. /'.匕!HNMR (CDCh, 300MHz): (5=0.02(s, 3H), 〇. 〇4 (s 3R) 0. 09(s, 6H), 0.88(s, 18H), 1.8(dd, Ji 〇, 9U ?, ' Α·〇> 12Hz, 1H), 1. 99 (m,1H), 2.75 (m, 1H), 3.30 (dd, 1H,j=8 7 1〇H ) 3.56(dd,1H, J=5.1, 10 Hz), 4.36 (m, 2H), 5. i2 '(dj ' J=lHz), 5.38 (d, 1H, J=lHz). ' ' Example 4b: (1R, 3R, 4S) Preparation of -4-benzyloxy-3-(benzyloxyindenyl)_2-methylene-cyclopentanol (Compound 4b; Ri=R2=Benzyl).

Preparation 0 The title compound was obtained by a method similar to the procedure of Example 4 to 4a (CD Ch, 300 MHz): 5=1.92 (m, 1H), 2 〇-2 1 (m 1H), 3· 07 (m, 1H) ), 3. 30 (t, > 9Hz, 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, 1〇H) o 95335 59 201215612 The following compounds were obtained in a similar manner to the examples 4a and 4b: Compound 4c : (lR,3R,4S)-4-tert-Butyldiphenylphosphonium __3 tert-butyl '-propenyloxyoxyindenyl-2-methylene-1-cyclopentanol

OH

1HNMR: 5=1.03 (s, 9H), 1. 17(s, 9H), !.94 (m, 1H), 2.〇5(m, 1Η), 2.93(m, 1H, ), 3. 02 (m, lH), 3. 51 (m, 2H) 4. 43 (m, 1H), 4.49 0η, 1H), 5.22 (m, 1H), 5 48 (m, 1H) 7. 49 (m, 20H NMR (CDCh, 13C NMR: <5 = 19.20, 19.29, 26.88, 27.19, 42 99 54 65 - ο, n, 43, 12, 75, 12, 879\; 9; 76; 129.94, 133.44, 133.70, 135.74, 135.47, 154 66 Compound 4d: (1R,3R,4S)-4_tert-Butyldiphenylmethoxy_3_(tert-butyldimethyloxycarbonyl)-2-methylene-i -cyclopentanol

OH

?Ha /η3 S-^-CHa ch3 ch3 NMR (CDCh, 500MHz) 1HNMR: 5=-0.01 (S, 6H), 0.85(s, 9H), 1. i8 (s, 9H), 95335 60 201215612 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); 13CNMR: 6 = -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-butyldimethylsilyloxy-3-tert-butyldiphenylfluorenyloxy-yl- 2-methylene-1-cyclopentanol

NMR (CDCh, 500MHz) • HNMR: (5 = 0.20 (s, 6H), 0.97 (s, 9H), 1.18 (s, 9H), 1.89 (ra, 1H), 2.09 (m, 1H, ), 2. 92 (m, 1H), 3. 20(m, 1H), 3. 56 (m, 1H), 3. 75 (in, Η), 4. 45 (m, 1H), 4. 52 (m, 1H ), 5.16 (m, 1H), 5.46 (in, 1H), 7.61 (m, 10H); 13CNMR: (5=-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: (11?,3匕45)-4-tert-butyldidecyloxy-3-(biphenyl-4-oxofluorenyl)-2 -indolyl-i-cyclopentanol 61 95335 201215612

!~~Ο-Ο NMR (CDCh, 500MHz), =0.11 (s, 6H), 〇.92u 9H)> 1 88 (m> 1HX 2· 22(m' 1H)' 3. 07 (m' 1H ,),3·1〇(m, 1H), 4. 3〇(m,3H), 4.48(m,1H),5·29(ιη,1H),5.49(m,1H),7 73 (m , 9H); Μ. 5 = _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' Na 2, 2 di-tert-butyl + fluorenylene- 6-hydroxy-6H-cyclopenta[1,3,2]dioxanthene

OH

Ch3 CH-, NMR (CDCh, 500MHz) • HNMR: ^=0.99 (s, 18H), 1. 6〇(s> 1H), 2.11 (m, iH)> 2. 59(m, 1H), 2 80 (m, 1H, ), 3. 86 (m, 2H), 4. 48 (m, 2H), 4.84 (m, 1H), 5. 18 (m, 1H); ' CNMR: (5=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-butyldiphenyl sulphate_3_(biphenyl-4 -曱醢曱醢曱))-2-indolyl-1-cyclopentanol 95335 62 201215612

R (CDC13, 500MHz) 'HNMR: (5-1.13 (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(ra, 1H), 5. 23 (m, 1H), 5. 44 (m, 1H), 7. 59 (m, 19H); 13C Li R: (5=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 : (lR,3R,4S)-4-(biphenyl-4-decyloxy)-3-tert-butyldimethyloxoxime Gentyl-2-indenyl-1-cyclopentanol

丽R (CDC13,500MHz) ^NMR: 5=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 (in, 1H), 3.88 (m, 1H), 4. 58(m, 1H), 5.21(m, 1H), 5.41(m, 2H ), 7. 69(m, 9H); 13OiMR: 5=-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 63 95335 201215612 Compound 4j: (lR,3R,4S)-4-Astyloxy-3-tert-butyldidecyloxyindenyl-2-indenyl-1-cyclopentanol

iMMR: 5=0.04 (s,6H), 〇.87(s,9H),1·89 (m,1H), 2.22(m, 1H), 2.58(m, 1H, ), 2. 96 ( 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); 'NMR (CDCh, 500MHz) 13C NMR: 5 = -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 (CDCh, 500MHz)^NMR: 5=1.25 (s, 3H), 1.58 (m, 1H), 2.46 (m, 2H), 3. 12 (m,1H,), 3.39 (m,1H), 3.52 (ra, 1H), 4.29 (m, 2H), 4.61 (m, 1H), 4.77 (m, 1H), 5.09 (m, 1H); 13CNMR: (5=20.71, 38.76, 45.04, 68.77, 70.59, 78.44 95335 64 201215612 99.87, 109.99, 148.22 oxy)-3-tert-butyl compound 41 : (1R,3R,4S)-4-(tetrahydropyridyl.Nan~yldidecyloxycarbonyl-2-a Mercapto-1-cyclopentanol

〇- NMR (CDCh, 500 MHz) NMR: mp.: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (m, ih) 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); 13C NMR: 5 = - 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-butyldiphenyl oxalyl-3-3(diphenylphosphonyloxymethyl)-2-indenyl-1-cyclopentanol

^NMR: &lt;5=1.03 (s, 9H), 1.79 (s, 2H), 2.72 (s, 1H), 2. 85 (in, 2H), 2.99 (s, 1H), 4. 30 ( s, 2H), 5. 11 (s, 1H), 5.35 (s, 1H), 7.40 (m, 25H); 13CNMR: ά=19.22, 27.22, 65 95335 201215612 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 described above, compound 5 has the following formula:

Wherein compound 5a: X = C1, R = H, R' = Boc; compound 5b: X = 0Me, R = H, R' = Boc; compound 5c: X = 0Bn, R = H, R' = Boc; 5d: X=C1, R=Boc, R' = Boc; Compound 5e: X=0Bu-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 similar manner to compound 5a, and compound 5e was prepared according to the procedure in the literature of Org. Lett., 2009, 11, 2465. 66 95335 201215612

, NH〇 23; (X=CI) 35; (X=OMe) 12; (X=OBn)

Boc20, DMAP

N(Boc)2 NaHC03/Me0H

K2C03/Me0H &quot;N&quot; 'N(Boc)2 5d; (X=CI) ΝΛΛ N N NHBoc 5a; (X=C1) 5b; (X=OMe) 5c; (X=OBn)

Boc20/TEA, CH.CN OBu-t

DMAP

, N(Boc)2

OBu-t K2C03/Me0H

N&quot; W 'NHBoc 5e boc Org_ Lett·, 2009, 11, 2465 The spectral data of the obtained compounds 5b, 5c and 5e are as follows: Compound 5b: OMe

NHBoc iMMR (d6-DMS0, 300MHz): (5= 1.45 (s, 9H), 4.03 (s, 3H), 8.1 (bs, NH), 9.7 (s, 1H), 13.08 (bs, NH).

OCH2Ph H 'NHBoc ^NMRCCDCK 300MHz): 5 = 1.58 (s, 9H), 5.61 (s, 2H), 67 95335 201215612 7.32-7.53 (m, 5H), 8.28 (s, 1H). Compound 5e OC(Me).

WNMR (CDCI3, 300MHz): 5 = 1.56 (s, 9H), 1.71 (s, 9H) 7. 29 (bs, 1H), 8. 19 (s, 1H). Example 6. 9-[ (1S,3R,4S)-4-tert-Butyl dimethyl oxalyl-3-(tert-butyl dimethyl fluorenyloxy) fluorenyl-2-arylene-ring Preparation of pentyl]- 6-gas- 9H-indole-2-aminodecanoic acid tert-butyl ester (Compound 6a; Ri=R2=t-BuMe2Si, R=H, R' = Boc);

TBSO CH, OTBS

186 mg (0.5 mmol) of compound 4a (Ri=R2=t-BuMe2Si), 200 mg (0.75 mmol) of compound 5a (R=H 'R' = Boc) and 156 mg of Ph3P (0.75 mmol) in 50 ml round bottom In a 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, at -23. 〇 〇 反应 3 3 3 3 3 3 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' The insoluble material was removed by filtration, and the filtrate was purified by column chromatography eluting with petroleum ether/EtOAc (10/l, v/v) to give a colorless syrup. ^NMR (CDCh, 300MHz): 5 = 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=5.4Hz), 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-[(15,3148)-4-tert-butyldimethylamyloxy-3-(tert-butyldimethylfluorenyloxy)fluorenyl-2-indenyl-cyclopentyl [6-Chloro-9H-indole-2-aminodidecanoic acid di-tert-butyl] [Preparation of compound 6d; Ri=R2=t-BuMe2Si, R=Boc 'R' = Boc];

TBSO ChUOTBS 640 mg (1.72 mmol) of compound 4a (Ri=R2=t-BuMe2Si), 888 mg (2.4 mmol) of compound 5d [R=Boc, R' =Boc] and 607 mg Ph3P (2.32 mmol) in 50 ml round bottom flask Add 20 ml of anhydrous THF, cool to -23 ° C, and add 〇. 5 ml (2.75 mmol) of DEAD. After the addition, stir the reaction at -23 ° C for 2 hours, stir the reaction at room temperature for 12 hours, then evaporate under reduced pressure. The THF was removed, and 150 ml of n-hexane was added, and 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 EtOAc (10/1, v/v). (87°/.).

WfiMRCCDCh, 300MHz) K 07 (s, 3H), 0.08 (s, 3H), 69 95335 201215612 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, IS), 5.70 ( t, 1H), 8.24 (s, 1H). Example 8: In a similar manner to Example 6, the compounds 5b, 5c and 5e were respectively conjugated with the compound 4a to obtain the compounds 6b, 6c and 6e. In a similar manner to the example 6, the compound 5a was used. Compound 4b is coupled to give compound 6f. Compound 6b: 9-[(lS,3R,4S)-4-tert-butyldimethylamyloxy-3-(tert-butyldimethylammoniooxy)methyl-2-indenyl-cyclopentyl Tert-butyl- 6-decyloxy-9H-indole-2-aminodecanoate;

'MMRCCDCh, 300MHz): 5=0. 001 (s,12H), 0.11 (s,3H), 〇. 19(s, 6H), 0.90(s, 6H), 0. 92 (s, 6H), 1.54 (s, 6H), 2. 27 (in, 2H), 2. 65 (m, 1H), 3. 81 (d, J=6Hz » 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-[(15,3匕43)-4-tert-butyldimethyloxaxo-3-(tert-butyldimethylamyloxy)indenyl-2 -methylene-cyclopentyl]-9H-indole-2-aminodecanoic acid tert-butyl ester; 70 95335 201215612 OCH2Ph

'HNMR (CDCh, 300MHz): δ = Q (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 (in, 2H), 2.68 (m, 1H), 3.8 (d, J=4. 8Hz, 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-butyldimethylfluorenyloxy-3-(tert-butyldimethylanthryloxy)indolyl-2-indenyl-cyclopentyl] -9H-indole-2-carbamic acid tert-butyl ester;

!HNMR (CDCh, 300MHz): (5=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) 71 95335 201215612 Compound 6f: 9-[(lS,3R,4S)-4-benzyloxy-3-(benzyloxymethyl)-2-indenyl-cyclopentyl] -6-chloro-9H-indole-2-carbamic acid tert-butyl ester

'HNMRCCDCh, 300MHz): 5=1.53 (s, 9H), 2.52 (m, 2H), 3.0 (bs, 1H), 3.74 (m, 2H), 4.22 (dd, 2H), 4.35 (in, 1H), 4.56 (d, J=6Hz, 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 compound was 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-[(lS, 3R, 4S)-4-tert-butyl Tert-Butyl phenyloxy-3-tert-butyldiphenyl decyloxyindenyl-2-indenyl-cyclopentyl]-6-aero-9H-indole-2-carbamic acid tert-butyl ester

NMR (CDCh, 500MHz) 72 95335 201215612 •HNMR: 5-0.99 (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 (in, 1H), 5. 17 (m, 1H), 5 83 (m, 1H), 7.49 (m, 21H), 7.81 (s, 1H); 13C Li R: 5 = 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-[( 13,3匕43)-3-tert-butyldidecyloxyindolyl-4-tert-butyldiphenyloxy-2-indenyl-cyclopentyl]-6-gas-9H- Tert-butyl 2-aminodecanoate

NMR (CDC13,500MHz) !MMR: 5=-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 (in, 1H), 4. 40 (m, 1H), 4. 84 (m , 1H), 5.22(m, 1H), 5.77(ra, 1H), 7.48(m, 1H), 7.92(s, 1H); 13OiMR: 5=-5.31, 18.58,19.38,26. 16, 27.23,28.46 , 73 95335 201215612 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-[(lS, 3R,4S)-4-tert-butyldimethylammoniooxy-3-tert-butyl-based syloxycarbonyl-2-methylene-cyclopentyl]-β-gas-9H-indole Tert-butyl 2-aminodecanoate

NMR (CDCh, 500MHz) • HNMR: ^=0.08 (s, 6H), 0.90 (s, 9H), 1. i〇(Sj 9Η)&gt; 1.53(m, 9H), 2. 25(ra, 2H, ), 2. 77 (m, 1H), 3. 80(m, 2H), 4. 52(m, 1H), 4. 72 (in, 1H), 5. 12 (m, 1H), 5. 67 (m, 1H), 7.49 (m, 11H), 7.87 (s, 1H); 13CNMR: 5 = -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-[(lS,3R,4S)-4-tert-butyldimethyloxy-3- (Biphenyl-4-oxooxymethyl)-2-indenyl-cyclopentyl]-6-gas-9H-indole-2-carbamic acid tert-butylate 74 95335 201215612

—〇—Ο R (CDC13,500ΜΗζ) WNMR: (5=0. ll(s,6H), 0.91(s,9H), 1.52 (s,9H), 2. 22(m, 1H), 2. 76(m, 1H, ), 3. 08(ra, 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); 13C匪R: (5=-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_gas_9_(2,2_di-tert-butyl-5-fluorenylene-hexahydro-cyclopenta[1, 3, 2]dioxaindole heterocyclohex-6-yl)-9H-indole-2-aminodecanoic acid tert-butyl ester

75 95335 201215612 NMR (CDCh, 500MHz) !HNMR: (5=1.04(s, 9H), 1. 08(s, 9H), 1.54 (s, 9H), 2.37(m, 2H), 2. 72(m , 1H, ), 4. 12(m, lH), 4. 50(m, 2Ή), 4. 69(m, 1H), 4. 89(m, 1H), 5. 64 (m, 1H), 7. 53 (m, 1H), 7. 88(s, 1H); 13C Li R: 5=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-[(lS,3R,4S)-4-tert-butyldiphenylphosphonyloxy-3-(biphenyl-4 -nonanoyloxymethyl)-2-indolyl-cyclodecyl]-6-chloro-9Η-β ° 令-2-aminodecanoate tert-butyl ester

NMR (CDCh, 500MHz) NMR: d=\A\(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); 13C Li R: (5=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, 76 95335 201215612 147.59, 150.28, 151.37, 152.27, 152.51 Compound 6m: 9-[(15,3匕43)-3-tert-butyl Methyl nonyloxyindenyl-4-(biphenyl-4-decyloxy)-2-indenyl-cyclopentyl]-6-gas-9H-indole-2-aminodecanoic acid tert-butyl ester

R (CDC13, 500MHz) !HNMR: (5=0.14(s, 6H), 0. 95(s, 9H), 1.54 (s, 9H), 2.63(m, 1H), 3. 02(m, 1H ), 3. 99(ra, 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); 13CNMR: 6=-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. 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-[(13,3^43)-3-tert-butyldidecylfluorene Oxidyl-4-benzylideneoxy-2-indenyl-cyclopentyl]-6-chloro-9H-indole-2-aminodecanoic acid tert-butyl ester 77 95335 201215612

R (CDC13, 500MHz) !HNMR: 5=-0.05(s, 6H), 0.75(s, 9H), 1.34 (s, 9H), 2.47(ra, 2H), 2. 84(m, 1H, ) , 3. 82(m, 1H), 3. 92(m, 1H), 4. 73(ra, 1H), 5. 15(m, 1H), 5. 42(m, 1H), 5. 66 ( m, 1H), 7. 58(m, 6H), 7. 98(s, 1H); 13CNMR: 5=-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-indenyl) -5-Methylene-hexahydro-cyclopenta[1,3]dioxine-6-yl)-9H-indole-2-aminodecanoate tert-butyl ester

1.52 (s, 9H), 2.33 (m, 1H), NMR (CDCh, 500MHz) NMR: 5 = 1.41 (d, 3H), 78 95335 201215612 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); 13C Li R: 5=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-Butyldiphenyl-decyloxy_3_(trityloxyindenyl)-2-methylene-cyclopentyl]-6 - gas-9H-indole-2-aminodecanoate tert-butyl ester

WNMR: (5 = 1.12 (s, 9H), 1.55 (s, 9H), 1.99 (m, 1H), 2.22 (in, 1H, ), 2.97 (m, 1H), 3.11 (m, 2H), 4.45 ( In, 1H), 4. 70(s, 1H), 5. 06(s, 1H), 5. 77 (m, 1H) , 7. 46(m, 26H); 13C Li R: (5=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-[(lS,3R,4S)-4-hydroxy-3-hydroxyindol-2-yl 79 95335 201215612 Mercapto-cyclopentyl]-9H-嘌呤一Preparation of 2-aminobutyl phthalate (compound 7a; R = H, R' = Boc);

312 mg (0.5 mm 〇l) of compound 6a (Ri=R2=t-BuMe2Si, R=H, R' = Boc) was dissolved in i〇ml THf, and 78 〇mg TBAF (tetrabutylammonium fluoride) was added ( 3mmol) 'Stirring at room temperature for 2 hours, TLC showed the disappearance of the starting material spot. The residue was evaporated under reduced pressure. THF residue was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc The gum was dried <RTI ID=0.0>: </RTI> </RTI> <RTIgt; !HNMR (CDCh, 300MHz): &lt;5=1.53 (s, 9H), 2.29 (m, 1H), 2.66(m, 1), 2.75 (m, 1H), 4. 03 (dd, 2H»J= 1.8, 3. 3Hz), 4.75 (m, 1H), 4.87 (s, 1H), 5.27 (s, 1H), 5.60 (t, 1H, J=8Hz), 7.41 (s, 1H), 8.16 (s, 1H). Example 10: 6-Gas-9-[(lS,3R,4S)-4-hydroxy-3-hydroxyindol-2-methylene-cyclopentyl]-9H-indole-2-aminodecanoic acid Preparation of butyl ester (compound 7a; R = H, R' = Boc);

312 mg (0-5 mmol) of compound 6a (Ri=R2=t-BuMe2Si, R=H, 80 95335 201215612 R' =Boc) was dissolved in 10 ml of THF, 3 ml of decyl alcohol was added, and hydrochloric acid (3 匪ol) was added at room temperature. After stirring for 2 hours, TLC showed the disappearance of the starting material, the THF was evaporated, and the residue was evaporated, evaporated, evaporated, evaporated, evaporated. 95.7%. 4丽R(CDCh, 300MHz): (5=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=8Hz), 7.41 (s, 1H) , 8. 16 (s, 1H). Example 11: 6-chloro-9-[(lS,3R,4S)-4-hydroxy-3-hydroxyindol-2-indenyl-cyclopentyl]- Preparation of 9H-indole-2-aminodidecanoic acid di-tert-butyl ester [Compound 7d; R=Boc, R' = Boc];

2.16 g (3 mmol) of compound 6d [Ri=R2=t-BuMe2Si, 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. After stirring for 2 h, TLC showed the disappearance of the starting material, and the THF was evaporated under reduced pressure. EtOAc was evaporated. EtOAc EtOAc EtOAc EtOAc EtOAc The title compound was 1.47 g (~100%). j^RCCDCh, 300MHz): 6 = 1.43 (s, 18H), 2.34 (m, 1H), 2.61 (m, 1H), 2.77 (m, 1H), 3.90 (dd, 1H, J=5.4, 81 95335 201215612 10.8Hz), 4.01 (dd, 1H, J 2. 5, 10.8Hz), 4.58 (bs, 1H), 4. 84(s, 1H), 5.26(s, 1H), 5. 65 (t, 1H , J=8. 1Hz), 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-[(lS,3R,4S)-4-hydroxy-3-hydroxymethyl-2-indenyl-cyclopentyl]-6-decyloxy-9H-indole-2-aminodecanoic acid Tert-butyl ester;

HNMR (CDCh, 300MHz): (5=1.53 (s, 9H), 2.25 (m, 1H), 2.26-2.80 (m, 2H), 3.39 (in, 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). : 6-Benzyloxy-9-[(lS,3R,4S)-4-hydroxy-3-hydroxyindol-2-indenyl-cyclopentyl]-9H-indole-2-aminodecanoic acid Butyl ester

!HNMR (CDCh, 300MHz): (5=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), 82 95335 201215612 7. 29-7. 35 (m, 3H), 7.48- 7. 50 (m, 2H), 8.05 (s, 1H). Compound 7e: 6-tert-butoxy-9-[(lS,3R,4S)-4-yl-3-ylaminomethyl-2 -methylene-cyclopentyl]-9H-°-tert-butyl-2-aminodecanoate;

WfiMRCCDCh, 300MHz): (5=1.52 (s,9Η), 1.73 (s,9Η), 2. 25 (in, 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 -[(lS,3R,4S)-4-carbyl-3-tert-butyldimethylsilyloxymethyl-2-indenyl-cyclopentyl]-6-chloro-9Η-β ticket Preparation of tert-butyl-2-aminodecanoate (Compound 8a).

Llg of compound 6m was dissolved in 155 ml of anhydrous decyl alcohol, 2 g of potassium carbonate was added, and the reaction was stirred until the reaction of the starting material was completely filtered. After concentration, the compound 8a was obtained in a yield of 95%. Surface R (CDCK 500MHz): jNMR: 6=0.07 (s,6H), 0.86 (s,9H), ι· 5〇(s,9H), 2·28(ιη,1H),2.43 (m,1H) , 2· 71 (s, 1H), 3.81 (m, 1H), 95335 83 201215612 3. 95 (m, 1H), 4. 47 (m, 1Η), 4· 79 (m, 1H), 5. 11 (m,1H)' 5.87 (m, 1H), 7.4 (m, 1H), 7.82 (s, 1H); 13CNMR: (5=-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-[(18,3 ft, 45)-4-tert-butyl Preparation of methyl oxalyl-3-carboxymethyl-2-indenyl-cyclopentyl]-6-chloro-9H-indole-2-carbamic acid tert-butyl ester (Compound 9a). c-n« ^nhboc

OTBS 1 g of compound 6 j was dissolved in 155 ml of anhydrous decyl alcohol, 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 (CDCh, 500MHz): 'HNMR: (5=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); 13CNMR: 5 = -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, 161.46 Example 15: Preparation of compound 7a (using compound 8a as starting material) 84 95335 201215612 9 g of compound 8a was dissolved in 100 ml of THF, and 25 g of tetrabutylammonium fluoride was added at room temperature overnight. The residue was concentrated to dryness. EtOAc was evaporated. The W-NMR data was consistent with the data of the compound 7a obtained in Example 10. Example 16: Preparation of the compound 7a (using the compound 9a as a starting material) 9 g of the compound 9a was dissolved in 100 ml of THF, and 25 g of tetrabutyl was added at room temperature. The reaction was carried out overnight, and concentrated under reduced pressure to near dryness. 10 〇ml 酉 充分 乙 充分 充分 充分 充分 充分 充分 充分 充分 充分 充分 充分 充分 充分 充分 充分 充分 充分 充分 充分 充分 充分 5% 5% 5% 5% 5% 5% 5% 5% 5% It is in agreement with the data of the compound 7a obtained in Example 10. Example 17: 2-Amino-1,9-dihydro-9-[(lS,3R,4S)-4-hydroxy-3-(methyl) -2-indenylcyclopentyl-6H-indol-6-one (preparation of compound n;

(1) Preparation of Compound 1 from Compound 7a: 150 mg (0·38 mmol) of Compound 7a (R=H, R, = B〇c) was added 3 ml of 2N HCl and 3 ml of THF, and the mixture was stirred under reflux for 6 hours under reduced pressure. A portion of THF was distilled off, and the residual aqueous solution was adjusted to pH 7 with 2.5N NaOH. The crystals were allowed to stand at room temperature at 95335 85 201215612 20 min, and allowed to stand overnight at room temperature, filtered, and washed with a small amount of water to give an off-white solid. The above product was recrystallized from about 2 ml of water to give white crystals (yield: 73 mg (69). (2) Preparation of Compound 1 from Compound 7d: 1.2 g (2.42 mmol) of compound 7d (R = Boc, R' = Boc) was added 20 ml of 2NHC1 and 20 ml of THF, and the mixture was stirred under reflux with stirring for 8 hours. The THF, residual aqueous solution was extracted with 20 ml of diethyl ether. The aqueous layer was adjusted to pH 7 with 2.5N NaOH, and allowed to stand overnight at room temperature, filtered, and washed with a small amount of water to give an off-white solid. The above product was recrystallized from about 2 ml of water to give 360 mg (54%) of white crystals. ^NMR (d6-DMSO, 300MHz): 5 = 2. 03 (m, 1H), 2.20 (m, 1H), 3.51 (t, 2H, J=6Hz), 4.21 (bs, 1H), 4.54 (s, 1H), 4. 80-4. 86 (m, 2H, can be exchanged by D2〇), 5. 08 (s, 1), 7. 64 (s, 1H, can be widened by D2〇), 10.54 ( s, 1H). Example 18: 2-Amino-1,9-diar Argon-9-[(lS,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl-6H-indole Preparation of -6-ketone (Compound 1);

312 mg (0.5 mmol) of compound 6a (Ri=R2=t-BuMe2Si, R=H, R' = Boc) was dissolved in 15 ml of tetrahydrofuran, and 15 ml of dilute hydrochloric acid was added, and the mixture was heated to a TLC to show that the spot of the material disappeared. Evaporation of tetrahydrofuran under reduced pressure, residue 86 95335 201215612, EtOAc (30 mL, EtOAc, EtOAc, EtOAc (EtOAc) . The iH-NMR data of the title compound obtained was obtained from 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 hydrazine was added, and the mixture was heated to reflux until the reaction was completed. The j-NMR data of the title compound obtained was identical to the data of the compound 1 obtained in Example π. Example 20: Preparation of Compound 1 (using Compound 9a as a starting material) 9 g of Compound 9a was dissolved in 200 ml of THF and added; [〇〇mi 2N HC1 'heated to reflux until the reaction was completed, concentrated, the aqueous solution was made basic, and crystallized. Drying gave the title compound as a white solid. The iH-NMR data of the title compound obtained was identical to that of the compound 1 obtained in Example 17. . Reference Example: According to the method described in WO2004/052310A2, the Mitsunobu reaction was carried out using the intermediate 4 and the 2-amino group-protected compound which was not subjected to amino protection, and the obtained compound was deprotected by TBAF to finally hydrolyze 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 : 95335 87 201215612 9-[(1S,3R' 4S)-4_tert-Butyldimethylammonyloxy-3-(tert-butyldimethylsilyloxy)methyl~2-Asia Preparation of decyl-cyclopentyl]-6-chloro-9H-indol-2-amine (Compound 24);

Ch2otbs 24 370mg( 1. 〇mm〇i)(1 r,3R,4S)-4-(tert-butyldimethylfluorenyloxy)-3-[(tert-butyldimethylfluorenyloxy)methyl ]_2-indenyl-cyclopentanol (Compound 4a, Ri=R2=t-BuMe2Si), 338 mg (2.0 mmol) 6-Gas-2-aminoindole (Compound 23) and 524 mg of Ph3P (2.0 mmol) in a 20 ml circle The mixture was stirred at room temperature for 3-5 ° C. Then, the THF was evaporated under reduced pressure, and the mixture was stirred for 5 min with EtOAc (methanol), and then stirred for 5 min, and then added with 15 ml of n-hexane, and allowed to stand for 5 hours, and filtered to remove insolubles. The filtrate was purified by column chromatography, petroleum ether/Et〇Ac (3/l ( The title compound 305 mg (59 ° / 〇) was obtained as a pale yellow oil. Reference Example 2: 6-gas-9-[(lS,3R,4S)-4-hydroxy-3-(hydroxyl Preparation of methyl)-2-indenyl-cyclopentyl]-9H-indol-2-amine (Compound 25); 88 95335 201215612

200 mg (0.38 mmol) of compound 24 was dissolved in 10 ml of THF, and 720 mg of TBAF (tetrabutylammonium fluoride) (6mmo 1) was added, and the mixture was stirred at room temperature for 1 h. TLC showed disappearance of the starting material, and THF was evaporated under reduced pressure. 40 ml of EtOAc, EtOAc (EtOAc)EtOAc. Reference Example 3: 2-Amino-1,9-diar Argon-9-[(lS,3R,4S)-4-hydroxy-3-(hydroxyindenyl)-2-indenylcyclopentyl-6H-indole Preparation of -6-ketone (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 stirring for 6 hr. THF was evaporated under reduced pressure, and the aqueous mixture was adjusted to pH 7 with 2.5N NaOH and allowed to stand at room temperature for 20 min. Crystallize, leave at room temperature overnight, filter, and wash with a small amount of water to give a white solid. The above product was recrystallized from about 2 ml of water to give a white crystals of &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&&& Amino deuterated 89 95335 201215612 The compound was subjected to Mitsunobu reaction, and the obtained compound was deprotected by TBAF 'final hydrolysis to obtain entecavir. The total yield of the three-step reaction was only 17% (based on intermediate 4). Compared with the present invention, the Mitsunobu reaction is carried out using Intermediate 4 and 2-protected amino-6-substituted $7 to obtain a high yield (~1% by weight), and the obtained coupling product can purify the subsequent reaction. The process is simplified, and the yield is also greatly improved. Also, the total yield of the three-step reaction is more than 52% based on the intermediate 4. Therefore, the method of the present invention can make the preparation process simple and easy, and the yield is remarkably improved. And significantly reduce the production cost. [Simple diagram description] No [main component symbol description] No 95335 90

Claims (1)

201215612 VII. Patent application scope: 1. A method for preparing a compound of formula 1, The method comprises the steps of: c) subjecting compound 4 to 2-protected amino-6-substituted ruthenium compound 5 by Mitsunobu reaction to obtain a coupled product 6 Wherein: 匕 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) 匕 and R 2 are each independently selected from alkyl, haloalkyl, Benzyl, t-BuMe2Si, t-BuPh2Si, (i_Pr)3Si or Et3Si, preferably t_BuMe2Si; or (ii) Ri and 1 are each independently selected from t-BuMe2Si, t-BuPhzSi, benzamidine, tetrahydropyran _2_ base, benzene ring with 1 95335 201215612 generation of stupid gi base, Lian _4_ fluorenyl, triphenyl fluorenyl R2 is not t-BuMe2Si; or and (m) R And I co-form one of the fused ring systems with the connected five-member carbon ring: Wherein R 3 is a halogen atom, a G-6 alkyl group, a stupid 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 stupid group and a nitro group; And Rs may be the same or different, respectively representing Cw or aryl, preferably t-butyl or phenyl; wherein * indicates the point of attachment of the fused ring to other parts of the molecule; R and R' may be the same or different, respectively Represents hydrogen, alkoxy or aralkyloxycarbonyl, for example Ci-6 alkoxycarbonyl or Csm aralkoxy, preferably tert-butoxy, with the proviso that R and R' are not simultaneously 虱X is dentate, alkoxy, deuterated alkoxy or aryloxy, such as Cl-6 alkoxy, halo Cl-6 alkoxy or C5-10 aryloxy, preferably gas, hydrazine An oxy group, a benzyloxy group, a tert-butyloxy group, particularly preferably a gas; d) when both 1 and R 2 are a fluorenyl protecting group or none of a thiol protecting group, the compound 6 is deprotected from the hydroxy protecting group, Compound 7 2 95335 201215612 Wherein X, Ri, R2, R and p, and R are as defined above; e) hydrolyzing compound 7 to 钊a, ^ to a compound of formula 1 (entecavir) Hydrolysis ‘ci^oh wherein, X, R and R' are as defined above; or _d')tR々R2 is not a thiol protecting group, and compound 6 is simultaneously deprotected and hydrolyzed to directly obtain a compound of formula i 1 wherein 乂, 匕, 尺 2, 尺 and 尺, as defined above, or (d)) when one of r4R2: is a thio-protecting group, for example, benzene 95335 3 201215612 fluorenyl, substituted on the benzene ring When the phenylhydrazine group or 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, Ri, R2, R and R' are as defined above. 2. The method of claim 1, wherein hydrazine and R2 are the same or different and are each independently selected from the group consisting of alkyl, haloalkyl, benzyl, t-BuMe2Si, t-BuPh2Si, (i-Pr). 3Si or Et3Si, preferably t-BuMe2Si ° 3. The method of claim 1, wherein 仏 and R2 may be 4 95335 201215612, the same or different, and each independently selected from the group consisting of: Mercapto group, tetrahydro-w-yl group, benzamidine group with a substituent on the benzene ring, biphenyl-4-methyl fluorenyl group, trityl group as t-BuMe2Si lanthanum soil '^ and 匕 are not As described in the patent application, the t_R2 and the connected five-member carbon ring together form one of the following fused ring systems: 4. wherein R 3 is a hydrogen atom, a Cl 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 Rs may be the same or different and each represent a Cm alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein the * symbol indicates a point of attachment of the minor ring to other moieties of the molecule. The method of claim 4, wherein the ruthenium and osmium 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 a Mitsunobu reaction reagent, such as Ph3p/Et〇2CN=NC〇2El: or 5 95335 201215612 Ph3P/i-Pr〇2CN=NC〇2i-Pr 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. 7. The method of any one of claims 1 to 6, wherein in step d), the deprotection of compound 6 is in an acid or an assay such as a hydrohalic acid such as hydrochloric acid, cesium fluoride, citric acid or Fluorine-containing quaternary ammonium salts such as tetrabutylammonium fluoride (TBAF) or acridine hydrofluoride or potassium carbonate, alkoxides such as sodium alkoxide, preferably in tetrabutylammonium fluoride (TBAF) or hydrochloric acid Exist in the presence. 8. The method according to any one of the preceding claims, wherein in step e), the hydrolysis of compound 7 is carried out under acidic or inert conditions, preferably in the presence of hydrochloric acid or citric acid. Water or water is mixed with a mixture of other organic solvents, for example, in tetrahydrofuran or a mixture of EtOH and water. 9. The method of any one of claims 1 to 5, wherein in step d'), the deprotection and hydrolysis of compound 6 can be in the presence of a hydrohalic acid such as dilute hydrochloric acid, in a suitable organic The solvent or its mixture with water is carried out, for example, in methanol, ethanol or tetrahydrofuran or a mixture thereof with water. 10. The method of any one of claims 1 to 5, wherein in step d"), the thiol protecting group is present in the presence of, for example, potassium carbonate, an alkali metal hydroxide, an alkoxide 11. The method of any one of claims 1 to 10, which comprises the steps of: c) substituting compound 4 with a 2-amino protected -6-嘌呤化6 95335 201215612 体5 In the presence of Ph3P/Et〇2CN=NC〇2Et or Ph3P/i-Pr〇2CN=NC〇2i-Pr' in aprotic solvents such as aromatic hydrocarbons, halogenated aromatic hydrocarbons, halogenated hydrocarbons The reaction is carried out in an ether such as THF to obtain the coupled product 6; d) the compound 6 is removed in the presence of tetrabutylammonium fluoride (TBAF) or hydrochloric acid to give the compound 7; e) the compound 7 Hydrolysis in tetrahydrofuran in the presence of hydrochloric acid to give a compound of the formula 1. The method of any one of the preceding claims, wherein the compound of the formula 6 is used as a starting material and the Steps d) to e). 13. If you apply for the scope of patents The method according to any one of the preceding claims, wherein the compound of the formula 6 is used as a raw material, and the method of the formula 6 is used as a raw material. The method of any one of claims 1 to 11, wherein the method of the formula 4 is directly carried out using the compound of the formula 7 as a starting material. , Wherein, Ri and R2 may be the same or different and are each independently selected from the following hydroxy protecting groups as described in Groups 7 95335 201215612 (i) to (iii): (i) 匕 and R 2 are each independently selected from an alkyl group, An alkyl group, a nodal group, t-BuMezSi, t-BuPhdi, (i-pr)3Si or EbSi, preferably t_BuMe2Si; or (ii) R丨 and R2 are each independently selected from the group consisting of t-BuMe2Si, t-BuPhzSi, benzene A fluorenyl group, a tetrahydropyran-2-yl group, a benzamidine group with a substituent on a benzene ring, a biphenyl-4-methyl fluorenyl group, a trityl group, but fluorene and R2 are not simultaneously t-BuMe2Si Or (iii) 匕 and 匕 together with the connected five-member carbon ring form one of the following fused ring systems: Wherein R 3 is a hydrogen atom, a Ci-e 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 decyloxy group, an ethoxy group, a halogen group, a stupid group and a nitro group; And Rs may be the same or different and each represents a C1-6 alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates the point of attachment of the fused ring to other parts of the molecule; the method comprises the following steps: a) Ring-opening of compound 2 directly to give the cyclopentane intermediate 3 8 95335 201215612 OH Wherein Ri and R2 are as defined in the scope of the patent application; b) the compound of formula 3 is subjected to alcoholysis or hydrolysis to give compound 4 3 4 wherein Ri and R2 are as defined in the scope of the present patent application. 17. The method of claim 16, wherein L and r2 are each independently selected from the group consisting of t-BuMedi, t-BuPhdi, a phenylhydrazine group having a substituent on the benzene ring, and tetrahydrogen. Butyr-2-yl, phenylhydrazine, biphenyl_4_carboxylic acid, triphenyl fluorenyl; but hydrazine and hydrazine are not t-BuMe2Si at the same time. 18. The method of claim 16, wherein 1 and ! ^ Together with the connected five-member carbon ring to form one of the following fused ring systems: Wherein R3 is a hydrogen atom, a Ch 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; They may be the same or different and represent 9 95335 201215612 Cm alkyl or aryl, respectively, preferably t-butyl or phenyl; wherein the * indicates the point of attachment of the fused ring to the rest of the molecule. 19. The method of claim 18, wherein 匕 and R2 together with the attached five member carbon ring form one of the fused ring systems as follows: 20. The method of any one of claims 16 to 19, wherein in step a), a suitable reagent for catalyzing and initiating a free radical cleavage reaction of compound 2 in a copper (II) salt, such as PhI (OAc) 2, Mn(OAc)3 or Pb(0Ac)4, preferably Pb(OAc)4, preferably obtained by ring-opening directly in the presence of an organic base such as triethylamine or pyridine. 3. The method according to any one of claims 16 to 20, wherein in the step b), the compound of the formula 3 is in the presence of, for example, ammonia, triethylamine, K2C〇3 or an alkoxide. Alcohololysis or hydrolysis in an organic solvent such as decyl alcohol, ethanol or a mixture thereof or in a mixture of water or a mixed solvent of water and another organic solvent such as EtOH and water gives the compound 4. 22. The method of any one of claims 16 to 21, the method comprising the steps of: a) opening compound 2 directly under the action of copper (II) salt catalyzed by Pb(0Ac)4 The cyclopentane intermediate 3 is obtained; b) the compound of the formula 3 is subjected to alcoholysis in the presence of K2CO3 in decyl alcohol 10 95335 201215612 to give the compound 4. 23. 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 Or 2 2 wherein R! and R2 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) Ri and Rz are each independently selected from an alkyl group, Haloalkyl, benzyl, t-BuMe2Si, t-BuPh2Si, (i-pr)3Si or Et3Si, preferably t-BuMe2Si; or (ii) Ri and R2 are each independently selected from t-BuMe2Si, t-BuPhzSi, benzo a mercapto group, a tetrahydropyran-2-yl group, a benzamidine group having a substituent on a benzene ring, a biphenyl-4-mercapto group, a triphenylsulfonyl group, but the oxime and I are not t-BuMe2Si at the same time; Or 11 95335 201215612 (iii) 1 and 1 together with the connected five-member carbon ring form one of the following fused ring systems: 〇-~&lt; Wherein R3 is a halogen atom, a Ci-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 &gt; R4 and Rs may be the same or different and each represents a 0-6 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; b) a compound of formula 3 Obtaining compound 4 by alcoholysis or hydrolysis Wherein Ri and R2 are as defined above; c) the compound 4 is reacted with 2-protected amino-6-substituted ruthenium compound 5 by Mitsunobu reaction to obtain a coupled product 6 4 6 12 95335 201215612 wherein hydrazine and r2 are as defined above; R and R' may be the same or different and each represent hydrogen, alkoxycarbonyl or aralkoxycarbonyl, for example Cm alkoxycarbonyl or Cwo aralkyloxy a carbonyl 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, Ci-6 alkoxy, _Ci-e Alkoxy or C5-io aryloxy, preferably gas, decyloxy, benzyloxy, tert-butoxy, particularly preferably gas; d) when both Ri and R2 are sulfhydryl protecting groups or none of sulfhydryl groups In the case of a protecting group, the compound 6 is deprotected from the hydroxy protecting group to give the compound 7 As defined above; wherein X, Ri, R2, R and R, e) hydrolyze compound 7 to give a compound of formula μ (entecavir) Wherein X, R and R' d') are as defined above; or when both Ri and R2 are not a thiol protecting group, compound 6 95335 13 201215612 is simultaneously deprotected and hydrolyzed. Directly obtaining the compound of formula 1 Wherein X, Ri, R2, R and R' are as defined above; or (d") when one of 1 and hydrazine is a fluorenyl protecting group, for example a phenyl fluorenyl group, a benzene having a substituent on the benzene ring In the case of fluorenyl or biphenyl fluorenyl, compound 6 is deprotected to give 8 or 9, which is hydrolyzed or hydrolyzed by compound 7 to give compound 1, 14 95335 201215612 Or2 9 wherein X, Ri, R2, R and R' are as defined above. 24. As described in claim 23, Μ The method comprises the steps of: a) opening a ring of compound 2 directly to obtain a cyclopentane intermediate 3 15 95335 201215612 OH 2 CHO 3 b) Compound of formula 3 is subjected to alcoholysis or hydrolysis to give compound 4 3 4 c) Compound 4 is reacted with 2-amino protected -6-substituted ruthenium compound 5 by Mitsunobu reaction to obtain a coupled product 6 4 6 d) Deprotecting compound 6 from the hydroxy protecting group to give compound 7 16 95335 201215612 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 the above steps, X, Ri, R2, R and R' are as defined in claim 23 of the scope of the patent application. 25. The method of claim 23, wherein R! 17 95335 201215612 and R2 are each independently selected from the group consisting of t-BuMedi, t-BuPhdi, benzamidine, tetrahydropyran-2- a phenyl fluorenyl group having a substituent on the phenyl ring, a biphenyl-4-methyl fluorenyl group, or a triphenyl fluorenyl group; but ytterbium and ytterbium are not simultaneously t-BuMezSi ° 26. As claimed in claim 23 or 24 The method of the present invention, wherein, together with the attached five-membered carbon ring, form a fused ring system as described below Wherein R3 is a hydrogen atom, a Cw 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 transport group, a phenyl group and a nitro group; Rs may be the same or different and respectively represent a calcining group or a silk, and preferably a tert-based base group '·the towel* indicates the point of attachment of the fused ring to other parts of the molecule. &lt; The method of claim 26, wherein the connected five member carbon rings together form one of the fused ring systems as follows: The method of any one of claims 23 to 27, wherein in step a), the compound is compounded in the step a) 2 in the copper (1)) salt catalyzed and induced 95335 18 201215612 free radical cleavage reaction of appropriate reagents, such as phI (〇Ac) 2, Mn (0Ac) 3 or Pb (〇Ac) 4, preferably Pb (0Ac) 4 The cyclopentane intermediate 3 is obtained directly by ring opening in the presence of an organic base such as triethylamine or acridine. 29. The method of any one of clauses 23 to 28 wherein, in step b), the compound of formula 3 is in the presence of a base such as ammonia, triethylamine, K2C〇3 or an alkoxide Alcohololysis or hydrolysis in an organic solvent such as decyl alcohol, ethanol or a mixture thereof or in a mixture of water or a mixed solvent of water and another organic solvent such as EtOH and water gives the compound 4. The method according to any one of claims 23 to 29, wherein in the step c), the compound 4 and the 2-protected amino- 6-substituted hydrazine compound 5 are in a Mitsunobu reaction reagent such as Ph3P. /Et〇2CN=NC〇2Et or Ph3P/i-Pr〇2CN=NC〇2i-pr 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. Coupling product 6. The method according to any one of claims 23 to 30, wherein in the step d), the deprotection of the compound 6 is carried out in an acid or a base such as a hydrohalic acid such as hydrochloric acid, hydrogen fluoride, formic acid or fluorine. The quaternary ammonium salt of the ion, such as tetrabutyl fluorinated (TBAF) or in the presence of a bite or potassium carbonate, an alkoxide such as a sodium alcohol, preferably in the presence of tetrabutylammonium (TBAF) or hydrochloric acid Deprotection of the hydroxy group gives compound 7. The method of any one of claims 23 to 31, wherein 'in step e) 'compounding compound 7 under acidic or qualitative conditions, preferably in the presence of hydrochloric acid or citric acid, in water Alternatively, the compound of the formula 1 may be hydrolyzed in a mixed solvent of water and other organic solvent 95335 19 201215612, for example, in a tetrahydro alpha or a full mixture of EtOH and water. 33. The method according to any one of claims 23 to 30, wherein in step d'), the deprotection and hydrolysis of compound 6 can be carried out in the presence of a nitrogen halide such as dilute hydrochloric acid. The organic solvent or its mixture with water, such as methanol, ethanol or tetrahydrofurfuran or a mixture thereof with water. 34. The method of any one of claims 23 to 30, wherein in step d"), the base protecting group is present in the presence of, for example, potassium carbonate, an alkali metal cerium oxide, an alkoxide 35. The method of any one of claims 23 to 34, the method comprising the steps of: a) catalyzing compound 2 in copper (Π) salt and Pb (〇) Under the action of Ac) 4, it is preferred to open the ring directly to obtain the cyclopentane intermediate 3 in the presence of an organic base such as triethylamine or acridine; b) to give the compound of formula 3 in the presence of K2C〇3 in methanol Alcoholysis to give compound 4; c) Compound 4 and 2-protected amino-6-substituted indole compound 5 in Ph3p/Et〇2CN=NC〇2Et or Ph3P/i-Pr〇2CN=NC〇2i- In the presence of Pr, the reaction is carried out in an aprotic solvent such as a aryl group, a chiral aromatic hydrocarbon, a halogenated tobacco or an ether such as THF to obtain a coupling product 6; d) compound 6 in tetrabutylammonium fluoride (TBAF) Or deprotecting the hydroxy protecting group in the presence of hydrochloric acid to give compound 7; 20 95335 201215612 e) Compound 7 in the presence of hydrochloric acid in four The furan is hydrolyzed to give the compound of the formula 1. The method of any one of claims 23 to 35, wherein the compound of the formula 3 is used as a raw material and the steps b) to e) described therein are carried out. , or b) to d'), or b) to d"). 37. - Compounds of the following formula: Wherein Ri and R2 may be the same or different and are each independently selected from argon or a base protecting group as described in the following groups (i) to (iii): (i) Ri and R2 are each independently selected from an alkyl group, Haloalkyl, benzyl, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si or EtaSi, preferably t-BuMe2Si; or (ii) 匕 and R2 are each independently selected from t-BuMe2Si, t-BuPh2Si, benzo Sulfhydryl, tetrahydrogen. Butyr-2-yl, a benzoyl group with a substituent on the phenyl ring, a biphenyl-4-mercapto group, a trityl group, but 匕 and R2 are not t-BuMesSi at the same time; or (iii) 匕And 匕 and the connected five-member carbon ring together form one of the fused ring systems as described: 21 95335 201215612 Wherein, the substituent on the phenyl 'stupyl group wherein r3 is a hydrogen atom, an ind-6 alkyl group, a strepyl group or a substituent is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a present group and a nitro group; And R5 may be the same or different and represent Ci-6 alkyl or aryl, respectively, preferably tert-butyl or phenyl; wherein * indicates the point of attachment of the fused ring to other parts of the molecule; R and R' may be the same or different , respectively, represents hydrogen, an alkoxycarbonyl or an alkoxy group, for example, a C 6 alkoxy group or a Cs-IG araloxy group, preferably a tert-butoxycarbonyl group, provided that, at the same time, Hydrogen; X is _, alkoxy, haloalkoxy or aralkyloxy, such as Cl-6 alkoxy, dentate C, -6 alkoxy or Cs-1. Aralkoxy, preferably gas, methoxy, benzyloxy, tert-butoxy, particularly preferably gas. 38. The compound of claim 37, wherein 1 and r2 are each independently selected from the group consisting of t-BuMedi, t-BuPhzSi, benzamidine, tetrahydropyran-2-yl, benzene ring A phenyl fluorenyl group having a substituent, a biphenyl _4_ mercapto group, a trityl group; but 仏 and only 2 are not t_BuMe2Si. 39. The compound of claim 37, wherein l and r2 together with the attached five member carbon ring form one of the fused ring systems as follows: 22 95335 201215612 R3 , 9m And R3 is an oxygen atom, a Ci-e alkyl group, a stupid group or a stupid group having a substituent, 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 certain group; And Rs may be the same or different respectively representing a decyl or aryl group, preferably a tert-butyl group or a phenyl group; wherein the * symbol indicates the point of attachment of the fused ring to other moieties of the molecule. 4. The compound of claim 39, wherein the five member carbon ring to which 仏 and R2 are joined together form one of the fused ring systems as follows: 〇 The compound of any one of claims 37 to 40, which is selected from the group consisting of: 9_[(lS,3R,4S)-4-tert-butyldifluorenyloxyl — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — 4-tert-Butyldifluorenyloxy_3_(tert-butylmethylsulfanyloxy)indol-2-methylene-cyclopentyl]~6_气_叩-1|票呤~ 2-tert-butyl 2-aminodidecanoate; 9-[(IS, 3R, 4S)-4-tert-butyldimethylfluorenyloxy__3-(tert-butyl 95335 23 201215612 dimethyl oxalate )methyl-2-indenyl-cyclopentyl]-6-decyloxy-9H-indole-2-carbamic acid tert-butyl ester; 6-benzyloxy-9-[(lS,3R,4S)- 4-tert-Butyldimethylamyloxy-3-(tert-butyldimethylamyloxy)methyl_2-methylene-cyclopentyl]-9H-indole-2-aminodecanoic acid tert-butyl Ester; 6 tert-butoxy-9-[(lS,3R,4S)_4-tert-butyldimethylmethoxy-3-(tert-butyldimethylfluorenyloxy)methyl-1-2 hydrazine Tert-butyl-cyclopentyl]-9H-indole-2-carbamate; 9-[(1S,3R,4S)-4-benzyloxy -3-(Benzyloxyindenyl)-2-methylene-cyclopentyl]-6-gas-9H-indole-2-carbamic acid tert-butyl ester; 6-gas-9-[(lS,3R, 4S)-4-hydroxy-3-hydroxyindol-2-methylene-cyclopentyl]-9H-indole-2-carbamic acid tert-butyl ester; 6-gas-9[(1S,3R,4S)- 4-tert-butyl 4-hydroxy-3-hydroxyindol-2-methylene-cyclopentyl]-9H-indole-2-aminodicarboxylate; 9-[ (1S,3R,4S)-4-hydroxy- Tert-butyl 3-hydroxymethyl-2-methylene-cyclopentyl]-6-decyloxy-9H-indole-2-carbamate; benzyloxy-9-[(lS, 3R,4S)- Tert-butyl 4-hydroxy-3-hydroxyindol-2-indenyl-cyclopentyl]-9H-indole-2-carbamate; 6-tert-butoxy_9~-[(lS,3R,4S) _4_Phenyl-3-transmethyl-2-indenyl-cyclopentyl]-9H-indole-2-carbamic acid tert-butyl ester; 9_[(1S,3R,4S)-3-tert-butyl Dimethyl decyloxymethyl-4-(tetrahydrofuran-2-yloxy)-2-methylene-cyclopentyl]-6-chloro-9H-mouth oxime-2-amino decanoic acid Butyl ester; 9_[(1S,3R,4S)-3-tert-butyldimethylmethyloxymethyl-4-tert 24 95335 201215612 Butyldiphenylphosphonium-2-methylene-cyclopentyl Tert-butyl-6-chloro-9H-indole-2-aminodecanoate; 9-[(IS, 3R,4S)-3-tert-butyldimethylammoniodecyl-4-(biphenyl-4-methyloxy)-2-indenyl-cyclopentyl]-6-gas-9H- tert-Butyl-2-aminodecanoate; 9-[(lS,3R,4S)-3-tert-butyldimethyloxycarbonyl-4-phenyloxy-2-methylene- Cyclopentyl]-6-chloro-9H-indole-2-aminodecanoic acid tert-butyl ester; 9_[(1S,3R,4S)_3_tert-butyldiphenylphosphonium hydrazino-4_(tetrahydroanthracene Tert-butyl ester of m--2-yloxy)-2-indenyl-cyclopentyl]-6-chloro-9H-indole-2-aminodecanoate; 9-[(lS,3R,4S)-4- tert-Butyldimethylaminooxy-3_tert-butyldiphenylphosphoniumoxy-2-ylindenyl-cyclopentyl]-6-chloro-9H-indole-2-aminodecanoic acid tert-butyl Ester; 9-[(lS,3R,4S)-4-(biphenyl-4-methyloxy)-3-tert-butyldiphenyl&gt;6-oxomethoxy-2-ylindenyl- Cyclopentyl]-6-chloro-9 H-°-tert-butyl-2-aminodecanoate tert-butyl ester; 9_[(1S,3R,4S)_4-tert-butyldiphenylpyroxy-3_tert-butyl Tert-butyl phenyl hydroxy decyl-2-ylidene-cyclopentyl]-6-chloro-9H-indole-2-aminodecanoate; 9-[(lS,3R,4S)-4 -Benzyloxy-3-tert-butyldiphenylphosphoniumoxy-2-methyl-cyclopentyl]-6 -Chloro-9H-indole-2-aminodecanoic acid tert-butyl ester; 9-[(lS, 3R,4S)-4-benzoquinoneoxy-3-benzoyloxycarbonyl 25 95335 201215612 -2-Asia Methyl-cyclopentyl]_6_chloro-9H-indole-2-aminodecanoic acid s-butyl ester; 9-[(IS, 3R,4S)-4-(tetrahydro D-pyran-2-yloxy) 3--3-phenylindoleoxy-2-ylidene-cyclopentyl]-6-chloro-9H-indole-2-aminodecanoic acid tert-butyl ester; 9-[(IS, 3R, 4S)-4 -tert-Butyl dimethyl oxa alkoxy _3 benzoquinone oxomethoxy-2-indenyl-cyclopentyl]-6-gas-9H-indole-2-aminodecanoic acid tert-butyl ester; 9-[(lS,3R,4S)-4-tert-butyldiphenylphosphonium_3-benzhydryloxymethyl-2-methylene-cyclopentyl]-6-gas-9H-n Tert-butyl-2-aminodecanoate; 9-[(1S,3R,4S)-4-(biphenyl-4-decyloxy)-3-phenylindoleoxymethyl-2-methylene Tert-butyl-cyclopentyl]-6-gas-9H-indole-2-aminodecanoate; 9-[(IS, 3R,4S)-4-benzoquinone-oxy-3-(biphenyl- 4-oxofluorenyl)-2-methylene-cyclopentyl]-6-gas-9H-indole-2-aminodecanoic acid tert-butyl ester; 9-[(lS,3R,4S)-4 -(tetrahydrogen ratio °Nan-2-yloxy)-3-(biphenyl-4-methylindoleoxy)- 2-indenyl-cyclopentyl]_6 1-Q-9H_嘌呤_2_ tert-butyl amino phthalate; 9-[(IS, 3R,4S)-4-tert-butyldidecyloxy-3-(biphenyl-4-oxofluorenyl) ) 2 - methylene-cyclopentyl]-6-gas-9H-indole-2-aminodecanoic acid tert-butyl ester; 9-[(1S,3R,4S)-4-tert-butyldiphenylphosphonium oxide Benzyl-3-(biphenyl 26 95335 201215612 -4-oxofluorenyl)- 2-methylene-cyclopentyl]_6_gas- 9H_嘌呤_2_ tert-butyl carbamate; 9-[(lS, 3R,4S)-4-(biphenyl-4-decyloxy)-3-(tetrahydrofuran-2-yloxy)indol-2-methylene-cyclopentyl]-6-gas a 9H_嘌呤-2-carbamic acid tert-butyl ester; 9-[(lS,3R,4S)-4-tert-butyldimethylfluorenyloxy-3-(tetrahydropyran-2-yloxy) Tert-butyl-2-methylene-cyclopentyl]+chloro- 9H-indole-2-aminodecanoic acid tert-butyl ester; 9_[(1S,3R,4S)-4-(biphenyl-4-oxo) Benzyl)-3-(biphenyl-4-methylindoleoxy)-2-indolyl·cyclopentyl]_6-chlorobenzyl-2-carbamic acid tert-butyl ester; (4aR,6S, 7aS)-[6 - gas-9-(2,2-di-tert-butyl-5-arylene-hexahydro-cyclopenta[1,3,2]dioxacyclohexene-6-yl) 9H-indole-2-aminodecanoic acid tert-butyl ester; (2S, 4aR , 6S, 7aS)-[6-lact-9-(2-methyl-5-methylene-hexahydro-cyclopenta[1,3]dioxine-6-yl)- 9H_嘌呤一2_ tert-butyl carbamate; (2R,4aR,6S,7aS)-[6-gas-9-(2-methyl-5-arylene-hexahydro-cyclopentadienyl[1 , 3]dioxine-6-yl)-9H-indole-2-carbamic acid tert-butyl ester; (4aR,6S,7aS)-[6-gas-9-(2-methyl-5- Ardenyl-hexafluoro-cyclopenta[1,3]dioxine-6-yl)-9H-indole-2-carbamic acid tert-butyl ester; 9-[(13,3145)- 4-tert-Butyldiphenylphosphoniumoxy_3_(triphenyl 27 95335 201215612 mercaptooxymethyl)-2-indenyl-cyclopentyl]_6_gas_9H_嘌呤2-aminocitric acid Tert-butyl vinegar. 42. A method of preparing a compound of formula 6 Wherein Ri and R2 may be the same or different and are each independently selected from the group consisting of the hydroxy protecting groups described in the following groups (i) to (iii): (i) 匕 and R2 are each independently selected from an alkyl group, a functional alkane Base, benzyl, t-BuMeaSi, t-BuPh2Si, (i-Pr)3Si or Et3Si, preferably t~BuMe2Si; or (ii) 1 and 1{2 are each independently selected from t-BuMe2Si, t-BuPhAi, stupid A fluorenyl group, a tetrahydropyran-2-yl group, a benzamidine group with a substituent on a benzene ring, a biphenyl-4-mercapto group, a trityl group, but the ruthenium and L are not t-BuMe2Si at the same time. Or (lii) 1 and 1^ together with the connected five-membered carbon ring form one of the condensed ring systems as described: 95335 28 201215612 * Wherein 'R3 is a hydrogen atom, an indole-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the stupid 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 may represent C,-6 alkyl or aryl, respectively, the same or different, preferably t-butyl or phenyl; wherein * indicates the point of attachment of the fused ring to the rest of the molecule; = may be the same or different, respectively Hydrogen, alkoxy group or alkoxy group, for example, 16 oxo or aryloxy group, preferred T-oxide, provided that hydrogen is different; X is halogen, alkoxy 1st silk or technical oxy group, such as k-yard oxy group, 4th generation α-oxy group or c-aryloxy group, decyloxy group, benzyloxy group, tert-butoxy group, particularly preferably gas; Including: Compound 4 and 2-protected amino group *Cut oxime compound for Mitsunobu reaction to obtain coupling product 6 95335 29 201215612 Its ^^, ^, (1) mouth ^ know the scope of this patent application. 43. The method of claim 42, wherein the oxime is independently selected from the group consisting of t-BuM&amp;Si, t-BuPhdi, benzamidine, tetrahydropyran-2-yl, benzene ring Benzyl fluorenyl group with a substituent, biphenyl _4_ mercapto group, trityl group; but 匕 and Rz are not simultaneously. 44. The method of claim 42, wherein ^ and 匕 together with the attached five member carbon ring form one of the fused ring systems as follows: /' Wherein R3 is a hydrogen atom, a Cm alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the stupid group is preferably selected from the group consisting of a decyloxy group, an ethoxy group, a halogen group and a nitro group, and R4 and R5 may be used. The same or different, respectively representing a Cm alkyl or aryl group, preferably a tert-butyl group or a phenyl group; wherein the * symbol indicates the point of attachment of the anthracene ring to the rest of the molecule. The method of claim 44, wherein 1 and 匕 together with the attached five member carbon ring form one of the following fused ring systems: 46. The method of any one of clauses 42 to 45, wherein the reaction of compound 4 with compound 5 is in a Mitsunobu reaction reagent, such as Ph3P/Et〇2CN=NC〇2Et or Ph3P/ In the presence of i-Pr〇2CN=NC〇2i-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. 47. A method of preparing a compound of formula 7, Wherein R and R' may be the same or different and each represent hydrogen, an alkoxycarbonyl or an aralkoxycarbonyl group, for example, a C!-6 alkoxycarbonyl group or a C5-1 aralkyloxycarbonyl group, preferably a tert-butoxy group. a carbonyl group, provided that R and R' are not simultaneously hydrogen; X is a halogen, alkoxy, haloalkoxy or aralkyloxy group, such as Cl-6 alkoxy, halogenated Cl-6, or C5- 1. The aryloxy group is preferably a chlorine, a decyloxy group, a benzyloxy group or a tert-butoxy group, and particularly preferably a gas. The method comprises: deprotecting the compound 6 to a hydroxy protecting group to obtain a compound 7 31 95335 201215612 R1 and R2 may be the same or different and are each independently selected from the hydroxy protecting groups described in the following groups (1) to (iii): (i) Ri and R2 are each independently selected from an alkyl group, a toothed alkyl group, Benzyl, t-BuMezSi, t_BuPh2Si, (i_pr)3si or 3, preferably t-BuMe2Si; or (ii) R丨 and R2 are each independently selected from the group consisting of pi test, Buruji, benzylidene, tetra Hydrogen terminal 2-yl, phenylf-decyl group with a substituent on the phenyl ring, biphenyl fluorenyl group, trityl group, only 2 is not t-BuMe2Si; or 1 _R2 and attached five-membered carbon The rings together form one of the fused ring systems such as τ: The battle is as follows 32 95335 201215612 Wherein R3 is a hydrogen atom, a Ch alkyl group, a phenyl group or a substituted benzene, and the substituent on the 'phenyl group is preferably selected from the group consisting of an foxy group, an ethoxy group, a dentate group and an exact group, R4 and Rs. They may be the same or different and each represent a deutero or aryl group, preferably a tert-butyl or phenyl group; wherein the * indicates the point of attachment of the fused ring to the rest of the molecule; R, R' and X are as in the scope of the present patent definition. 48. The method of claim 47, wherein l and hydrazine are each independently selected from the group consisting of t-BuMe2Si, t-BuPhaSi, benzamidine, tetrahydropyran-2-yl, and phenyl ring Substituted benzhydryl, biphenyl_4_methylindenyl, diphenylmethyl; but Ri and deuterium are not t-BuMe2Si at the same time. 49. The method of claim 47, wherein &amp; and 匕 together with the attached five member carbon ring form one of the fused ring systems as follows: Wherein R3 is a hydrogen atom, a Cl-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; They may be the same or different and each represent a Cm alkyl or aryl group, preferably a tert-butyl group or a phenyl group; wherein the * sign indicates the point of attachment of the 33 95335 201215612 fused ring to the rest of the molecule. 50. The method of claim 49, wherein Ri and 匕 together with the attached five member carbon ring form one of the fused ring systems described below: The method according to any one of claims 47 to 50, wherein the deprotection of the compound 6 is carried out in an acid or a quaternary ammonium salt such as hydrochloric acid, hydrogen fluoride, formic acid or a fluorine-containing ion. Tetrabutylammonium fluoride (TBAF) or ° is carried out in the presence of hydrazine hydrofluoride or carbonic acid clock, an alkoxide such as sodium alkoxide, preferably in the presence of tetrabutyl Ig (TBAF) or hydrochloric acid. 52. - Compound of formula 3: Ri and R2 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! and R2 are each independently selected from alkyl, haloalkyl , benzyl, t-BuMe2Si, i&gt;BuPh2Si, (i-Pr)3Si or Et3Si, preferably t-BuMe2Si; or (ii) Ri and R2 are each independently selected from t-BuMe2Si, t-BuPh2Si, benzoquinone , tetrahydropyran-2-yl, phenyl ring with 34 95335 201215612 alkenyl group, biphenyl-4-mercapto, triphenyl fluorenyl, but 匕 and I are not t- BuMezSi; or (iii) 1^ and ^ together with the connected five-membered carbon ring form one of the fused ring systems: Wherein R3 is a hydrogen atom, a Cw 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 stupid group and a nitro group; The oximes may be the same or different and each represent an alkyl or aryl group, preferably a tert-butyl group or a phenyl group; wherein the * symbol indicates the point of attachment of the fused ring to the rest of the molecule. The compound of claim 52, wherein l and r2 are each independently selected from the group consisting of t-BuMedi, t-BuPhzSi, benzamidine, tetrahydropyran-2-yl, and benzene ring. A substituted phenyl fluorenyl group, a biphenyl _4-methyl fluorenyl group, a dimercapto group; but Ri and fluorene are not simultaneously t-BuMe2Si. The compound of claim 52, wherein 匕 and r2 together with the attached five member carbon ring form one of the following slightly ring systems: R3 ^ Τ '&quot;5 wherein R3 is a hydrogen atom, a Cl_6 alkyl group, a phenyl group or a phenyl group having a substituent * 95335 35 201215612, and the substituent on the phenyl group is preferably selected from the group consisting of a decyloxy group, an ethoxy group, Halogen, phenyl and cleavage; R4 and Rs may be the same or different and each represent a Cw alkyl or aryl group, preferably a tert-butyl or phenyl group; wherein the * symbol indicates the point of attachment of the fused ring to the rest of the molecule. 55. The compound of claim 54, wherein Ri and R2 together with the attached five member carbon ring form one of the fused ring systems described below: make. The compound of any one of claims 52 to 55, which is: (1R, 3R, 4S)-4-(tert-butyldimethylamyloxy)-3-[ (tert-Butyldimethylammoniumoxy)methyl]-2-methylene-cyclopentanyl decanoate (1R,3R,4S)-4-(® Nitrogen-pyranyloxy)_3-Uncle Butyl dimethyl decyloxy decyl-2-ylidene-cyclopentanol formate (1R, 3R, 4S) 4-tert-butyldiphenyl decyloxy-3-tert-butyl dimethyl Hydroxypurin-2-ylidene-cyclopentanyl phthalate (1R,3R,4S)-4-(biphenyl-4-methyloxy)-3-tert-butyldimethylhydrazine Oxyfluorenyl-2-methylene-cyclopentanol formate (1R,3R,4S)-4-benzoinoxy-3-tert-butyldimethyloxycarbonyl-2-yl Mercapto-cyclopentanol formate (1R,3R,4S)-4-(tetrahydrofuran-2-yloxy)-3-tert-butyldiphenylfluorenyloxy-2-ylindole Base-cyclopentanyl phthalate 36 95335 201215612 (1R, 3R, 4S) 4-tert-butyl dimethyl fluorenyl-3-(tert-butyl-diphenyl fluorenyl fluorenyl)-2- N-decyl-cyclopentanol phthalate (1R,3R,4S)-4-(biphenyl-4-methyloxy)-3-tert-butyldiphenylphosphonium -2-indenyl-cyclopentanol decanoate (1R,3R,4S)-4-tert-butyldiphenylphosphonium_3_(tert-butyldiphenylphosphonyl)-2- N-decyl-cyclopentanyl decanoate (1R' 3R, 4S) 4-benzylideneoxy-3-tert-butyldiphenylphosphonyloxymethyl-2-indenyl-cyclopentanolcarboxylic acid酉((1R,3R,4S)-4-Benzyloxy-3-benzoyloxyindolyl-2-ylidene-cyclopentanol decanoate (1R,3R,4S)-4-( Tetrahydrofuran-2-yloxy)-3-phenylindoleoxyindol-2-methylene-cyclopentanol decanoate (1R,3R,4S)-4-tert-butyldimethylhydrazine Oxy_3_benzimidyloxymethyl-2-mercapto-cyclopentanol formate (1R' 3R,4S)-4-tert-butyldiphenylphosphonium oxy-3-phenyl benzoate Methyl-2-indenyl-cyclopentanol formate (1R,3R,4S)-4-(biphenyl-4-decyloxy)_3_benzhydryloxymethyl-2-methylene -cyclopentanol formate (1R,3R,4S)-4-benzylideneoxy-l-(biphenyl_&quot;醯oxymethyl)-2-methylene-cyclopentanolcarboxylate ( 1R,3R,4S)-4-(tetrahydrofuran-2-yloxy)_3_(Liandu-4_Methoxymethyl)-2-methylene-cyclopentanolcarboxylate (UUR, 4S )-4-tert-butyldimethyl-wei _3_(联笨+甲甲氧氧methylmethylene-cyclopentanol formate vinegar 95335 37 201215612 (1R,3R' 4S)-4-tert-butyldiphenyloxy-3-3_(biphenyl-4_methoxy Methyl)-2-methylene-cyclopentanolcarboxylic acid (1R' 3R,4S)-4-(biphenyl-4-methyl methoxy)-3-(tetrahydro-pyran-2-yl) Oxy)methyl-2-methylene-cyclopentanol formate (1R' 3R,4S)-4-tert-butyldimethyloxyl_3-(tetrahydro-pyran-2-yl) Oxy)methyl-2-methylene-cyclopentanol formate (1R,3R,4S)-4-(biphenyl-4-methyloxy)-3-(biphenyl-4-carboindole Oxymethyl)-2-methylene-cyclopentanol formate (4aR,6R,7aS)-2,2-di-tert-butyl-5-arylene-6H-cyclopentane[1,3 , 2] Dioxaindole Heterohexane-6-carboxylate (2S, 4aR, 6S, 7aS)-2-mercapto-5-methylene-6H-cyclopenta[1,3] Oxeane-6-formate (2R,4aR,6S,7aS)-2-methyl-5-indenyl-6H-cyclopentane U,3]dioxane-6 -Citrate (4aR,6R,7aS)-6H-2-mercapto-5-indenyl-cyclopenta[1,3]dioxane-6-decanoate (1R, 3R , 4S)-4-tert-butyldiphenyl oxaxo-3- ( Triphenylsulfonyloxyindenyl)-2-indenyl-cyclopentanyl phthalate. 57. Method for preparing a compound of the formula 3: /CH〇 38 95335 201215612 wherein Ri and R2 may be the same or different and are each independently selected from the group consisting of the following (i) to (ii i) groups: (Ο 1 and Rz are each independently selected from an alkyl group , haloalkyl, benzyl, t-BuMe2Si, t-BuPh2Si, (i-pr)3Si or Et3Si, preferably t-BuMe2Si; or (li) ruthenium and R2 are each independently selected from t-BuMe2Si, t-BuPhdi, benzoquinone a benzyl group, a tetrahydropyran-2-yl group, a benzamidine group having a substituent on a benzene ring, a biphenyl _4-methyl group, a triphenyl fluorenyl group, but fluorene and R 2 are not t-BuMedi at the same time; (111) 1 and 匕 together with the connected five-membered carbon ring form one of the fused ring systems described below: Wherein R3 is a hydrogen atom, a Cl_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 stupid group and a nitro group; They may be the same or different and each represent a Cm alkyl or aryl group, preferably a tert-butyl group or a phenyl group; wherein * indicates the point of attachment of the fused ring to the rest of the molecule; the method comprises the steps of: a) opening compound 2 The ring directly gives the cyclopentane intermediate 3 39 95335 201215612 OH 2 3 58 , ' R ' and R 2 are as defined in this patent scope. The method described in item 57, wherein - phenylhydrazine 1 has a substituent of phenyl fluorenyl, biphenyl-4 to 59 as a main quinodizyl group; ―. The method described in item 57, the Μ- and the five-membered stone anti-ring together form one of the following fused ring systems: Wherein R3 is a hydrogen atom, a Cl_6 alkyl group, a phenyl group or a substituted benzene, and the substituent on the phenyl group is preferably selected from the group consisting of an foxy group, an ethoxylated phenyl group and a nitro group, L and Rs. They may be the same or different and represent C»-channel or silk, (4) tertiary or phenyl, respectively; and the towel* indicates the point of attachment of the fused ring to the rest of the molecule. 60. The method of claim 59, wherein the joined five member carbon rings together form one of the fused ring systems as follows: 95335 40 201215612 61. The method of any one of clauses 57 to 60, wherein in step a), a suitable reagent for catalyzing and initiating a free radical cleavage reaction of compound 2 in a copper (II) salt, such as PhI ( 0Ac)2, Mn(0Ac)3 or Pb(0Ac)4' preferably under the action of Pb(OAc)4, preferably in the presence of an organic base such as triethylamine or alpha-pyridine, to directly give a cyclopentane intermediate 3 ° 62. — a compound of formula 4, Wherein Ri and R2 may be the same or different and are each independently selected from the group consisting of the hydroxy protecting groups described in the following groups (i) to (iii): (i) 仏 and R2 are each independently selected from an alkyl group, a dentate Base, benzyl, t-BuMe2Si, t-BuPh2Si, (i-pr)3Si or Et3Si, preferably t-BuMe2Si; or (ii) Ri and R2 are each independently selected from t-BuMe2Si, t-BuPhzSi, benzoquinone a tetrahydropyran-2-yl group, a presently substituted mercapto group having a substituent on a benzene ring, a biphenyl-4-mercapto group, a trityl group, but a ruthenium and a 41 95335 201215612 R2 are not simultaneously t- BuMezSi; or (ui) RjaR2 together with the connected five-member carbon ring form one of the following fused ring systems: Wherein R3 is a hydrogen atom, a Cm alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the stupid group is preferably selected from the group consisting of a decyloxy group, an ethoxy group, a halogen, a phenyl group and a nitro group; Rs may be the same or different and each represent a Cm alkyl or aryl group, preferably a tert-butyl group or a phenyl group; wherein the * symbol indicates the point of attachment of the fused ring to the rest of the molecule. 63. The compound according to claim 62, wherein the ruthenium and osmium are each independently selected from the group consisting of t-BuMe2Si, t-BuPh2Si, benzamidine, tetrahydropyran-2-yl, and benzene ring. A substituted phenyl fluorenyl group, a phenylene group, a trityl group; but 匕 and R 2 are not simultaneously t_BuMe2Si. 64. The compound of claim 62, wherein hydrazine and Rz together with the attached five member carbon ring form one of the fused ring systems described below: * wherein R3 is a hydrogen atom, a G-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the stupid group is preferably selected from the group consisting of a methoxy group, an ethoxy group, and a halogen 42 95335 201215612 The nitro group, R4 and R5, which may be the same or different, respectively represent a Cm alkyl group or an aryl group, preferably a tert-butyl group or a phenyl group; wherein the * symbol indicates the point of attachment of the fused ring to the rest of the molecule. 65. The compound of claim 64, wherein the core and R2 together with the attached five member carbon ring form one of the fused ring systems described below: 66. The compound of any one of claims 62 to 65, which is: UR, 3R, 4S)-4-(tert-butyldidecyloxy)-3-[(uncle Butyldimethylmethyloxy)methyl]-2-methylene-cyclopentanol (1R,3R,4S)-4-benzyloxy-3-(benzyloxymethyl)-2-methylene -cyclopentanol (1R,3R,4S)-4-(tetrahydrofuran-2-yloxy)-3-tert-butyldimethylammoniomethyl-2-indenyl-1- Cyclopentanol (1R,3R,4S)-4-tert-butyldiphenylphosphonyloxy-3-(tert-butyldimethylamyloxymethyl)-2-indenyl-1-cyclopentanol (1R,3R,4S)-4-(biphenyl-4-carbyloxy)-3-tert-butyldimethylamyloxy-f-yl-2-methylene-1-cyclopentanol (1R, 3R,4S)-4-Pyrylmethyloxy-3-tert-butyldimethylammoniomethyl-2-methylene-1-cyclopentanol (1R,3R,4S)-4-(four Hydroxan-2-yloxy)-3-tert-butyldi 43 95335 201215612 Stupyl fluorenyl-2-mercaptocyclopentanol (1R,3R' 4S)-4-tert-butyl Methyl decyloxy_3_tert-butyldiphenyl oxalylhydrazino-2-indenylcyclopentanol (1R,3R,4S)-4-(biphenyl-4-methoxyloxy)_3 _tert-butyldiphenyl Nonyloxy-2-phenylindol-1-cyclopentanol (1R,3R,4S)-4-tert-butyldiphenylcarbazyl-3-tert-butyldiphenylfluorenyloxy-yl- 2-indenyl-indole-cyclopentanol (lR'3R'4S)-4-phenylindoleoxyt-butyldiphenylphosphonyloxymethyl-2-methylene-1-cyclopentanol ( 1R,3R,4S)-4-Phenyloxy-3 - benzoyloxymethyl-2-methylene-1-cyclopentanol (1R,3R' 4S)-4-(tetrahydropyran _2_yloxy)_3-benzhydryloxymethyl-2-mercaptocyclopentanol (1R, 3R' 4S)-4-tert-butyldimethylamyloxy_3_phenylhydrazine Methyl-2-indenyl-p-cyclopentanol (1R,3R,4S)-4-tert-butyldiphenylphosphonium oxyhydrazino-oxymethyl-2-indolyl-monocyclopentanol (1R ,3R,4S)-4-(biphenyl-4-methyloxy)_3-benzylideneoxymethyl-2-indenyl-1-cyclopentanol (1R,3R,4S)-4-benzene曱醯oxy_3_(biphenyl_4_曱醯-oxymethyl)-2-methylene-indenyl-pentanol (1R,3R,4S)-4-(tetrahydro-11-pyran-2-yloxy) Benzyl-3-(biphenyl-4-methylindoleoxymethyl)-2-methylene+cyclopentanol UR, 3R, 4S)-4-tert-butyldiindenyloxy_3_(biphenyl _4_ 44 95335 201215612 Methionoxymethyl)-2-Methylene -i-cyclopentanol (1 ft, 3148)-4-tert-butyldiphenyl methoxy-3_(phenylene-4-yloxymethyl)-2-methylene-1-cyclopentanol (1R) ,3R,4S)-4-(biphenyl-4-methyloxy)_3_(tetrahydro 0-pyran-2-yloxy)indol-2-indenyl-1-cyclopentanol (1R, 3R , 4S)-4-tert-butyldimethyloxycarbonyl_3_(tetrahydrofurfurylpyran-2-yloxy)indol-2-indenylcyclopentanol (1R,3R' 4S)-4 -(biphenyl-4-decyloxy)-3_(biphenyl_4_methioninyl)-2-indolyl-1-cyclopentanol (4aR,6R,7aS)-2, 2- Di-tert-butyl-5-methylene-6-mono-yl-6H-cyclopenta[1,3,2]dioxanthene (2S, 4aR, 6S,7aS)-2-fluorenyl -5-fluorenylene-6-hydroxy-6H-cyclopenta[1,3]dioxane (2R,4aR,6S,7aS)-2-mercapto-5-methylene-6 monohydroxy-6H-cyclopenta[1,3]dioxane (4aR,6S,7aS)-2-methyl-5-methylene-6-hydroxy-6H-cyclopentane[ 1,3]dioxane (1R,3R,4S)-4-tert-butyldiphenyloxyl-3-(trimethyleneoxyindenyl)-2-indenyl-1- Cyclopentanol. 45 95335 201215612 IV. Designated representative map: (1) The representative representative of the case is: (). (There is no picture in this case) (2) The symbol of the symbol of this representative figure is simple: (none) 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: HO Nh2 1 Ch2oh 2 95335