WO2013135165A1

WO2013135165A1 - Synthetic intermediate of entecavir and method for preparing same

Info

Publication number: WO2013135165A1
Application number: PCT/CN2013/072458
Authority: WO
Inventors: 郑志国
Original assignee: 浙江奥翔药业有限公司
Priority date: 2012-03-12
Filing date: 2013-03-12
Publication date: 2013-09-19
Also published as: CN103304375A; CN103304375B

Abstract

The present invention is related to a synthetic intermediate of entecavir and a method for preparing same, and particularly, related to a synthetic intermediate of Formula II for preparing entecavir, a method for preparing the intermediate, and a method for preparing entecavir by using the intermediate of Formula II, wherein R and R' are defined in the specification.

Description

Synthetic intermediate of entecavir and preparation method thereof

The present invention relates to a synthetic intermediate for a medicament and a process for the preparation thereof, and in particular to a novel synthetic intermediate for the preparation of entecavir and a process for the preparation of the intermediate.

Entecavir, a compound of the formula I below, 2-amino-1,9-dihydro-9-[(lS,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylene Cyclopentyl]-6H-indol-6-one is a new nucleoside antiviral drug.

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

The structure of entecavir contains a chiral five-membered ring and a guanine nucleus. The chiral five-membered carbocyclic ring has three chiral centers and one methylene ring outside the ring. The structure is more complicated, although it has been reported that There are few synthetic methods, but existing synthetic methods have difficulties in preparation. At present, there are mainly the following methods for preparing entecavir.

The preparation method of entecavir is disclosed in Chinese patent ZL91110831.9 and international application WO98/09964. The method comprises the steps of: reacting cyclopentadiene as a raw material, and sequentially reacting with chloromethylbenzyl ether and a di-enyl borane complex (Ipc ₂ BH) prepared from (+)-α-olefin to obtain a chiral intermediate iii. Acetylacetone Oxidation of oxidized t-butanol to give iv under the catalysis of vanadium oxide [VO(acac) ₂ ]. Iv reacted with benzyl bromide under the action of sodium hydride and tetrabutylammonium iodide to give v. V is reacted with 6-benzyloxy-2-aminopurine under the action of lithium hydride to give vi. Vi is protected by a single p-methoxytriphenylchloromethane (MMTC1) protecting group, and then oxidized to a keto group by the Dess-Martin reagent to give viii. Viii is subjected to a methyleneation reaction under the action of Nysted reagent and titanium tetrachloride to obtain ix. Ix is reacted with hydrochloric acid to remove the MMT from the amino group and the benzyl group on the anthracene ring to obtain X. Finally, the benzyl entecavir (the compound of the formula I) on the carbocyclic hydroxyl group is removed by the action of boron trichloride. This method is shown in the following flow.

The problems in the preparation method should be complicated, and some reagents are expensive. For example, the starting materials require expensive chiral boron reagents, and some intermediates are difficult to synthesize, the reaction conditions are harsh, and the final debenzylation is highly toxic. The boron trichloride is highly polluting to the environment and requires high equipment.

In addition, the key intermediate II is synthesized first, and then reacted with the guanine ring by Mitsunobu. The method of entecavir, but the preparation of intermediate II in the existing method is costly, complicated, and lacks application value. For example, a synthetic method using expensive Corey lactone as a raw material is disclosed in the patent application of the company (Publication No. WO 2004/052310 A2), as shown in the following scheme.

Further, WO2010/074534 uses the following reaction to prepare entecavir via Intermediate II, but the reaction conditions are harsh, the reagents used are expensive, and it is difficult to apply to industrial production.

Therefore, there is a need to develop a new method for preparing a key intermediate II which overcomes the problems of the prior art methods, has a high yield, is low, and has less environmental pollution. 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, denotes a straight or branched monovalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. "Cw alkyl" means a branched or straight-chain alkyl group having 1 to 6 ^, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, Is the base.

The term "alkylene", alone or in combination with other groups, denotes a straight or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. "d_ ₆ alkylene" denotes a ^ 1-6, child Branched or linear alkylene, such as methylene, ethylene, and the like.

The term "alkane, alone or in combination with other groups, denotes a radical R,-0-, wherein R is an alkyl radical as defined above. "d- ₆ alkoxy" denotes a radical R,-0-, wherein R, Is as described above

Ci-6 base.

"Halogen" means fluorine, chlorine, bromine or iodine.

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

"Aryl" means a monocyclic or fused bicyclic aromatic ring containing a carbon atom. "C ₅ _ _1Q aryl" means an aryl group having 5 to 10 carbon atoms. For example, the C ₅ _ ₁₍₎ aryl group can be phenyl or naphthyl.

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

"Aralkyloxy" means an alkoxy group as described above substituted with an aryl group as described above.

"Grubbs catalyst" refers to a Grubbs catalyst that catalyzes the metathesis of olefins.

The first generation of Grubbs catalyst is, for example, benzylidene-bis(tricyclohexylphosphine) dichloro ruthenium, and the second generation catalyst of Grubbs is, for example, benzylidene-[1,3-di(2,4,6-three) Methylphenyl)-2-imidazolinium iododi-(tricyclohexylphosphine) ruthenium.

"Dioxane wire" means "compound _2, wherein R" are each independently of formula NR ₆ alkyl or C ₃ _ ₇ cycloalkyl is selected D_, e.g. N, N- diisopropylamine, N, N- Dicyclohexylamine. Herein, the case where "the dioxane further includes two R" together with the N atom to which they are attached forms an optionally substituted heterocyclic ring, for example, 2,2,6,6-tetramethylhexahydropyridine.

The present invention provides a novel process for the preparation of intermediate II in the entecavir synthesis of formula I which has a higher yield, lower cost and less environmental pollution than existing processes.

R,

In one aspect, the invention provides a novel method of synthesizing intermediate II, characterized by Asymmetric catalytic reaction The chiral five-membered carbocyclic intermediate II of entecavir was prepared in high yield.

In one embodiment, a method is provided:

R is a hydroxy protecting group selected from the group consisting of: (i) an alkyl group, (ii) an aralkyl group such as a benzyl group, (iii) an alkoxyalkylene group such as an alkoxymethylene group such as MeOCH ₂ -, (iv An aralkoxyalkylene group, such as an aralkylmethyl group, such as a BnOCH ₂ -, or a (V) silane group, such as a triphenyl 3⁄4, a triisopropylsilyl group, a tert-butyldimethyl group, a tertiary Butyl diphenyl ^ ^ group;

R, is a hydroxy protecting group, selected from: (i) an aralkyl group such as a trityl group, or (ii) a silane group, such as a triphenyl group, a triisopropyl group, a t-butyl dimethyl group: Uncle Ding ^! Benzene: base; the method comprises the following steps:

c) the compound 3 is subjected to olefin metathesis reaction in the presence of a Grubbs catalyst to obtain a cyclic compound 4,

Where R, as defined above,

d) stereoselectively obtaining an epoxidation intermediate 5 by catalyzing the compound 4 with an epoxidation reagent under a metal vanadium reagent,

e) protecting the secondary alcohol of compound 5 to give compound 6,

Wherein X is halogen, R and R, as defined above,

f) compound 6 is epoxy-opened to form intermediate II under the action of a dialkylaluminum chloride reagent and lithium N,N-dialkylamine,

Where R and R are as defined above.

In the above reaction, the reaction solvent may be a polar or non-polar aprotic solvent, and preferred solvents include, but are not limited to, tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dioxane, diethyl ether.

In the step c, the reaction solvent may be dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, benzene or toluene. The catalyst for the reaction may be Grubbs first or second generation catalyst in an amount of from 0.1 to 20 eq%, and the reaction temperature is from room temperature to 120 * €.

In step d, a coordination reagent of metal vanadium is used as a catalyst, such as VO(acac) ₂ , and the epoxidizing reagent may be t-butyl hydroperoxide, hydrogen peroxide, m-chloroperoxybenzoic acid, peroxybenzoic acid. , peroxyformic acid, peracetic acid, the reaction solvent can be dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, benzene, toluene and other solvents; reaction temperature is 0" € ~ room temperature, reaction time is 1 ~ 48 hours.

In the step e, in the protective reagent RX of the secondary alcohol of the compound 4, R is selected from the group consisting of BnOCH ₂ -, MeOCH ₂ -, t-Bu(Me) ₂ Si -, i-Pr ₃ Si- and t-BuPh ₂ Si - X is a halogen, such as C1; the base used in the reaction may be triethylamine, diisopropylethylamine, DBU, imidazole, etc.; the reaction solvent may be dichloromethane, 1,2-dichloroethane, Chloroform, tetrahydrofuran, benzene, toluene, dimethylformamide; The temperature should be -10*C~45X.

In step f, the dialkyl aluminum chloride reagent is, for example, diethylaluminum chloride, and the N,N-dialkyllithium is prepared in situ from the corresponding dialkylamine by reaction with butyllithium, wherein the dialkyl group The amine is selected from the group consisting of N,N-diisopropylamine, N,N-dicyclohexylamine and 2,2,6,6-tetramethylhexahydropyridine, preferably 2,2,6,6-tetramethyl-6 Hydropyridine; reaction temperature is -20" € ~ room temperature, reaction time is 1 ~ 48 hours.

It will be understood by those skilled in the art that in the above method of synthesizing the intermediate II, the intermediate product can be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any of the steps c) to e) as a raw material. For example, the compound of the formula (4) can be used as a raw material and the steps d) to f) as described above can be used to prepare the intermediate II, or the compound of the formula (5) can be used as a raw material and the step e) as described above can be carried out. f) to prepare intermediate II, and the like.

In another embodiment, a method of synthesizing Intermediate II is provided:

CH ₂ 〇R'

II where

R is a hydroxy protecting group selected from the group consisting of: (i) an alkyl group, (ii) an aralkyl group such as a benzyl group, (iii) an alkoxyalkylene group such as an alkoxymethylene group such as MeOCH ₂ -, (iv ) aralkyloxy alkylene, e.g. methylene aralkyl * ^, as BnOCH ₂ -, or (V) silyl, such as triphenyl silicon, triisopropylsilyl, tert-butyldimethyl , tert-butyl diphenyl ^ ^ group;

R, is a hydroxy protecting group, selected from: (i) an aralkyl group such as a trityl group, or (ii) a silane group, such as a triphenyl group, a triisopropyl J3⁄4 group, a t-butyl dimethyl group , tert-butyl benzene ^ ^ base; the method comprises the following steps:

a) Intermediate compound 1 is reacted with an isopropenol Grignard reagent in the presence of a cuprous halide to obtain compound 2

Wherein X is a halogen or a cyano group,

b) selectively protecting the primary hydroxyl group of compound 2 to give compound 3,

Where R, as defined above, X is a halogen,

Where R, as defined above,

e) protecting the secondary alcohol of compound 5 to give compound 6,

Wherein X is halogen, R and R, as defined above,

Where R and R are as defined above.

In the step a, the reaction solvent may be tetrahydrofuran, diethyl ether, dibutyl ether or dioxane. A preferred solvent may be tetrahydrofuran. The reaction time is from 1 to 48 hours, and the reaction temperature is from -78 to room temperature. The cuprous halide reagent can be Cul, CuBr or CuBr.Me ₂ S. Compound 1 can be produced according to the method of the literature (Angew. Chem. Int. Ed. 2010, 49, 881).

In step b, the primary hydroxyl protecting agent R, X is selected from the group consisting of triphenylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride, three Phenylchloromethane. The reaction solvent may be dimethylformamide, dichloromethane, chloroform or toluene. The base includes an organic base such as triethylamine,

DBU, imidazole, diisopropylethylamine.

The reaction conditions of steps c, d, e, and f are as described above.

It will be understood by those skilled in the art that in the above process for the synthesis of intermediate II, the intermediate product can be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any of steps a) to e) as a raw material. For example, a compound of the formula (4) can be used as a raw material and carried out as described above. The intermediates II are prepared by the steps d) to f), or the intermediates of the formula (2) are used as starting materials and the steps b) to f) as described above are carried out to prepare the intermediate II, and the like.

In another aspect, the invention provides a compound of the formula V:

RO Ί

R'O v

among them

R is a hydrogen or hydroxy protecting group selected from: (i) an alkyl group, (ii) an aralkyl group such as a benzyl group, (iii) an alkoxyalkylene group such as an alkylene group such as MeOCH ₂ -, (iv An aralkoxyalkylene group, such as an aralkyloxymethylene group, such as a BnOCH ₂ -, or a (V) silane group, such as triphenyl&, triisopropylsilyl, tert-butylmethyl, tert-butyl ^phenyl;

R, which is a hydroxy protecting group, is selected from the group consisting of: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as a triphenyl group, a triisopropyl group, a tert-butyl group; Base, tert-butyl benzene ^ ^ base.

In a preferred embodiment, the compound of formula V is selected from the group consisting of:

In another aspect, the invention provides a method of preparing a compound of formula V,

R is a hydrogen or hydroxy protecting group selected from the group consisting of: (i) an alkyl group, (ii) an aralkyl group such as a benzyl group, (iii) an alkoxyalkylene group such as an alkoxymethylene group such as MeOCH ₂ -, (iv) an aralkoxyalkylene group, such as an aralkyloxymethylene group, such as a BnOCH ₂ -, or a (V) silane group, such as a triphenylsilyl group, a triisopropylsilyl group, a tert-butyl group ^^基, 叔丁^苯^^基;

R, which is a hydroxy protecting group, is selected from the group consisting of: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as triphenyl, triisopropyl, tert-butyldimethyl, and tert-butylbenzene.

The method includes the following steps:

a) Intermediate compound 1 is reacted with isopropenol Grignard reagent in the presence of cuprous halide to obtain compound 2

Where X is a halogen or an aryl group,

b) selective compounding of the compound 3,

Where R, as defined above, X is a halogen,

Where R, as defined above,

d) stereoselectively obtaining compound 4 with an epoxidizing reagent catalyzed by a metal vanadium reagent, wherein R is hydrogen

Wherein R is hydrogen, R, as defined above,

Or

e) protecting a secondary alcohol of a compound of formula V wherein R is hydrogen to give a compound of formula V wherein R is not hydrogen,

Wherein is 3⁄4, R and R, as defined above, and R is not hydrogen.

In a preferred embodiment, the reaction conditions of steps a), b), c), d) and e) are as described above.

It will be understood by those skilled in the art that in the above process for synthesizing the compound V, the intermediate product can be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any of the steps a) to d) as a raw material. For example, the compound of the formula (4) can be used as a raw material and the steps d) to e) as described above can be carried out to prepare the compound V, or the compound of the formula (2) can be used as a raw material and the steps b) to e as described above can be carried out. To prepare compound V, or to use compound of formula (3) as a starting material and to carry out steps c) to e) as described above to prepare compound V, and the like. In another aspect, the invention provides a compound of formula 4:

Wherein R is a hydroxy protecting group selected from the group consisting of: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as triphenyl & triisopropyl, tert-butyl & tert-butyldiphenyl ^ ^ 基.

In another aspect, the invention provides a method of preparing a compound of formula 4,

Wherein R is a hydroxy protecting group selected from the group consisting of: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as a triphenyl group: a trisyl group, a triisopropyl group, a tert-butyl group! M ^: base, tert-butyl diphenyl ^ J3⁄4 base, the method comprises the following steps:

Where X is a halogen or an aryl group,

Where R, as defined above, X is a halogen,

Where R is as defined above.

In a preferred embodiment, the reaction conditions of steps a), b), c) are as described above. It will be understood by those skilled in the art that in the above method of synthesizing the compound 4, the reaction product obtained in any of the steps a) to b) can be directly used as a starting material to carry out the subsequent reaction to prepare the intermediate II. For example, compound 4 can be prepared by using the compound of formula (3) as a starting material and carrying out step c) as described above, or using the compound of formula (2) as a starting material and carrying out steps b) to c) as described above. Compound 4, and so on.

In another aspect, the invention provides

Wherein R is a hydrogen or hydroxy protecting group selected from: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as a triphenyl JJ3⁄4 group, a triisopropyl group, a tert-butyl group JJ3⁄4 base, tert-butyldiphenyl group.

In a preferred embodiment, the compound of formula III is selected from the group consisting of:

In another aspect, the invention provides a method,

Wherein R is a hydrogen or hydroxy protecting group selected from the group consisting of: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as a triphenyl group, a triisopropyl group: a tert-butyl group M ^ 3⁄4 base, tert-butyl diphenyl silicon,

The method includes the following steps:

a) intermediate compound 1 is reacted with isopropenol Grignard reagent in the presence of cuprous halide to obtain a compound of formula III wherein R is hydrogen

Wherein X is a halogen or a cyano group,

Or

b) selectively protecting a primary hydroxyl group of a compound of formula III wherein R is hydrogen, to give a compound of formula III wherein R is not hydrogen,

Wherein R is as defined above, and R is not hydrogen and X is halogen.

In a preferred embodiment, the reaction conditions of steps a), b) are as described above.

It will be understood by those skilled in the art that in the above process for synthesizing a compound of formula III, a compound of formula III wherein R, which is hydrogen, can be employed as starting material and step b) as described above can be used to prepare formula III wherein R is not hydrogen. Compound.

In another aspect, the invention provides a method of synthesizing entecavir of formula I via intermediate II as described above, characterized in that entecavir is obtained by the Mitsunobu reaction of the intermediate II with a guanine derivative.

In one embodiment, the method for synthesizing entecavir of formula I comprises the steps of: c) subjecting compound 3 to the cyclic compound 4 via olefin metathesis in the presence of a Grubbs catalyst,

Wherein R is as defined by the compound of formula II above,

e) protecting the secondary alcohol of compound 5 to give compound ⁶

Wherein X is a compound, R and R, as defined by the compound of formula II above,

Wherein R and R are as defined by the compound of formula II above,

g) coupling intermediate II with 2-J^-6-chloro-guanine by Mitsunobu reaction to obtain compound 8;

h) Compound 8 is hydrolyzed under acidic frfr to give a compound of formula I

In the step C, the reaction solvent may be dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, benzene or toluene. The catalyst for the reaction may be Grubbs first or second generation catalyst in an amount of from 0.1 to 20 eq%, and the reaction temperature is from room temperature to 120 "€.

In step d, a coordination reagent of metal vanadium is used as a catalyst, such as VO(acac) ₂ , and the epoxidizing reagent may be t-butyl hydroperoxide, hydrogen peroxide, m-chloroperoxybenzoic acid, peroxybenzoic acid. , peroxyformic acid, peracetic acid, the reaction solvent can be dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, benzene, toluene and other solvents; reaction temperature is 0X~ room temperature, reaction time is 1~48 hours .

In the step e, in the protective reagent RX of the secondary alcohol of the compound 4, R is selected from the group consisting of BnOCH ₂ -, MeOCH ₂ -, t-Bu(Me) ₂ Si -, i-Pr ₃ Si- and t-BuPh ₂ Si - X is a halogen, such as C1; the base used in the reaction may be triethylamine, diisopropylethylamine, DBU, imidazole, etc.; the reaction solvent may be dichloromethane, 1,2-dichloroethane, chloroform , tetrahydrofuran, benzene, toluene, dimethylformamide; reaction temperature is -10*C~45X.

In step g, the Mitsunobu reaction reagent is a phosphine catalyst such as triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate, and the reaction solvent may be an aprotic solvent such as tetrahydrofuran, dichloromethane, or Oxycyclohexane, diethyl ether, toluene, etc.; tetrahydrofuran is preferred. The reaction temperature is -23 "C~ room temperature. The reaction time is 1 to 48 hours.

In the step h, the reaction solvent is an aprotic or protic solvent such as tetrahydrofuran, dioxane, methanol, ethanol or the like, and the acid used is a mineral acid such as hydrochloric acid, sulfuric acid or the like. The reaction temperature is room temperature ~ 120" €. The reaction time is 3 to 48 hours.

It will be understood by those skilled in the art that in the above process for synthesizing entecavir, the reaction product obtained in any of the steps c) to _g ) can be directly used as a raw material to carry out the subsequent reaction to prepare entecavir of the formula (I). For example, a compound of the formula (4) can be used as a raw material and carried out as described above. Steps d) to h) to prepare entecavir of formula (I), or to use the compound of formula (5) as a starting material and to carry out steps e) to h) as described above to prepare entecavir of formula (I), etc. .

In another embodiment, the method of synthesizing entecavir of Formula I comprises the steps of: a) intermediate compound 1 being reacted with an isopropenol Grignard reagent in the presence of a cuprous halide to provide a compound 2

Where X is a halogen or an aryl group,

b) compounding the compounds to the compound 3,

Where R, as defined above, X is a halogen,

Where R, as defined above,

d) stereoselectively obtaining epoxidation intermediate 5 with compound 4 and an epoxidation reagent catalyzed by a metal vanadium reagent,

e) Compound 5

Wherein X is halogen, R and R, as defined above,

Where R and R are as defined above,

g) coupling intermediate II with 2-J^-6-chloro-guanine using Mitsunobu reaction to give compound 8;

h) Compound 8 is hydrolyzed under acidic conditions to give a compound of formula I

In the above reaction, the reaction solvent is a polar or non-polar solvent, and preferred solvents are tetrahydrofuran, dichloromethane, chloroform, methanol, ethanol, dimethylformamide, dioxane, diethyl ether.

DBU, imidazole, diisopropylethylamine.

The reaction conditions of the steps c, d, e, f, g, h are as described above.

In a more preferred embodiment, the synthetic route of entecavir is as follows,

b;

Wherein the reaction conditions and group definitions of steps a) to h) are as described above, and Compound 1 can be produced by the method of (Angew. Chem. Int. Ed. 2010, 49, 881).

In a particularly preferred embodiment, the synthetic route of entecavir is as follows,

Powder form

Br

b;

Wherein the reaction conditions and group definitions of steps a) to h) are as described above, compound 1 is prepared according to the method of Angew. Chem. Int. Ed. 2010, 49, 881, and the first step is in powder form.

It will be understood by those skilled in the art that in the above process for synthesizing entecavir, the reaction product obtained in any of steps a) to _g ) can be used as a raw material to directly carry out the subsequent reaction to prepare entecavir of the formula (I). For example, the compound of the formula (4) can be used as a raw material and the steps d) to h) as described above can be carried out to prepare entecavir of the formula (I), or the compound of the formula (2) can be used as a raw material and the steps as described above can be carried out. b) to h) to prepare entecavir of formula (I), and the like. Detailed ways

The method of the present invention is further illustrated by the following examples. It is to be understood that the following examples are provided only for a better understanding of the invention, and not in any way. The scope of the invention is defined.

The abbreviations used in this application have the following meanings,

Abbreviation:

Boc Tert

DEAD diethyl azodicarboxylate

DIPEA diisopropylethylamine

EtOAc ethyl acetate

MOMC1 methyl chloride

MOMO methyl methoxy

TBAF tetrabutylammonium fluoride

THF tetrahydrofuran

t-Bu(Me) ₂ Si tert-butyl ^ ^甲 ^ ^ base

TBS tert-butyl dimethyl group: base

TBSC1 tert-butyldimethylsilyl chloride solid alcohol (compound 2)

Fw 1 14 145/191 156

Wt 1 .6 100ml/1 .0

Mmmol 14.2 50/5.0

The l.Og Cul (5 mmol) was suspended in 50 ml of anhydrous diethyl ether, cooled to -20*C, and a solution of isopropene Grignard reagent 0.5 M in 100 ml of THF (50 mmol) was added dropwise under argon atmosphere. Stir for 25 min, cool to -78" €, add a solution of 1.6 g (14.2 mmol) of compound 1 in 15 ml of THF, add the temperature to -20", stir the reaction for 16 hours, then add saturated NH ₄ C1 200 ml, separate The organic layer was extracted with EtOAc EtOAc (EtOAc)EtOAc. 2.63 g. 20 ml of THF and 30 ml of H ₂ 0 were added to the above oil, and 3.0 g of NaI0 ₄ was added under stirring, and the mixture was stirred at room temperature for 3 h. Saturated Na ₂ S0 _3, the organic layer was separated, the aqueous layer was washed with saturated EtOAc 20ml X 2 extraction with NaCl extracts were combined, washed dried over anhydrous Na ₂ S0 _4, filtered and the filtrate evaporated to dryness to give 1.83 g of the product ( Yield 83%).

[a] _D ²⁰ = -4.9 (c 1.1, CHC1 ₃ );

^J H匪R (300M, CDC1 ₃ , ppm) δ 5.82 (m, 1H), 5.21 (s, 1H), 5.16 (d, 1H, J=9.3Hz), 4.92 (s, 1H), 4.82(s, 1H), 3.92-3.81 (m, 2H), 3.71 (dd, 1H, J=ll.l, 5.4Hz), 2.39 (m, 1H), 2.29-2.27 (m, 1H), 2.09 (m, 1H) , 1.73 (s, 3H);

¹³ C NMR (100M, CDCI3, ppm) δ 143.4, 134.4, 118.8, 113.7, 73.0, 65.0, 54.0, 40.2, 21.6 Example 2: Preparation of (3R,4S)-3- ((tert-butyldimethylsilyl) Oxy)methyl)-2-methylhepta-1,6-diene_4- (Compound 3, wherein R,=t-Bu(Me) ₂ Si-)

S

Fw 156 150/68

Wt(mg) 232 245/202

m mol 1 .48 1 .63/2.97

Mol/mol 1 1 .1 /2

Add 232 mg of 2 plus 7.5 ml of CH ₂ Cl ₂ il to 202 mg of Mi Jun, cool to 0*C, add 245 mg of TBSCl with stirring, add 0"C to room temperature for 10 hours. Add 10 ml of water, separate the organic layer, and wash with water. dried over anhydrous Na ₂ S0 _4, filtered and purified by a short column of silica gel, petroleum ether / EtOAc (50/1) to give the product 290mg (72.3%), Rf = 0.75 ( petroleum ether / EtOAc (20 / l)) .

[a] _D ²⁰ = -25 (c 0.5, CHC1 ₃ );

^J H NMR (300M, CDC1 ₃ , ppm) δ 5.98-5.86 (m, 1H), 5.12 (d, 1H, J=6.3Hz), 5.07 (s, 1H), 4.86 (s, 1H), 4.76 (s , IH), 3.94-3.77 (m, 3H), 2.09-2.35 (m, 3H), 1.71 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H); ¹³ C NMR (100M, CDCI3, ppm) δ 143.6, 135.5, 116.9, 113.4, 74.0, 66.9, 53.3, 39.8, 25.8, 22.0, 18.1.

HR-MS (ESI) calcd for _{_{_{C 15 H 31 0 2 Si (}}} M + H) + 271.2088, found 271.2087 Example 3: Preparation of (lS, 2R) -2- ((tert-butyl-dimethoxy J¾ group) Methyl)-3-methylcyclopent-3-en-1-ol ( ,=t-Bu(Me) ₂ Si-)

S

Fw 270 848

Wt(mg) 820 50

m mol 3 2% X3

820 mg of compound 3, dissolved in 20 ml of dichloromethane, 50 mg of Grubbs second-generation catalyst (2%) was added in an argon atmosphere, and the mixture was stirred under reflux for 2 hours under argon atmosphere, and concentrated under reduced pressure. Elution with EtOAc (20/1) gave EtOAc (EtOAc:EtOAc)

[a] _D ²⁰ = +34 (c 0.25, CHC1 ₃ );

^{_{! H NMR (300M, CDC1 3}} , ppm) δ 5.32 (s, 1H), 4.34-4.29 (m, 1H), 3.85 (dd, 1H, J = 9.9, 4.8Hz) 3.46 (t, J = 8.4Hz) , 2.64-2.56 (m, 2H), 2.21-2.16 (m, 1H), 1.66 (s, 3H), 0.9 (s, 9H), 0.10 (s, 6H).

¹³ C NMR (125M, CDC1 ₃ , ppm ) δ 138.1, 123.4, 64.1, 59.2, 39.9, 25.9,

18.2, 15.3, -5.5, -5.5.

HR-MS (ESI) calcd for _{_{_{C 13 H 27 0 2 Si (}}} M + H) +: 243.1775, found 243.1772 Example 4: Preparation of (lS, 2R, 3S, 5R ) -2- (( tert- Methoxycarbonyl)methyl-1-methyl-6-oxa-bicyclo[3.1.0]hexan-3-ol (Compound 5, wherein R,=t-Bu(Me) ₂ Si-)

Fw 242 90/265

Wt(mg) 700 0.83ml/56

m mol 2.89 6/cat

700 mg (2.89 mmol) of compound 4 was dissolved in 15 ml of 1,2-dichloroethane, 50 mg of VO(acac) _{2 was added} , the water salt was cooled to -5*C, and 0.83 of 70% of t-BuOOH was added dropwise. 5 ml of 2-dichloroethane, stirred for 5 hours at -5 to room temperature, TLC showed disappearance of the starting material spots, the reaction solution was cooled to 0" €, saturated Na ₂ SO ₃ 10 ml was added, stirred for 30 minutes, and organic layer, washed with water, dried over anhydrous Na ₂ S0 _4, filtered, and the filtrate was purified by a short column of silica gel, eluting with petroleum ether / EtOAc (10 / l), to give the product 703mg (94%).

[a] _D ²⁰ = +25.6 (c 0.285, CHC1 ₃ );

^J H匪R (300M, CDC1 ₃ , ppm) δ 3.92 (d, 1H, J=6.3Hz), 3.75-3.63 (m, 2H), 3.43 (s, 1H), 2.19-2.09 (m, 2H), 1.99-1.94 (m, 1H), 1.48 (s, 3H), 0.87 (s, 9H), 0.04 (s, 6H);

¹³ C NMR (125M, CDC1 ₃ , ppm ) δ 75.1, 66.5, 64.8, 62.3, 54.7, 38.4, 25.8, 18.1, 15.5, -5.6, -5.8.

HR-MS (ESI) calcd for _{_{_{C 13 H 27 0 3 Si (}}} M + H) +: 259.1724, found 259.1717 Example 5: Preparation of (lS, 2R, 3S, 5R ) -3- ( tert-A <S ^|LS -2-((tert-Butyldimethylsilyloxy)methyl)-1-methyl-6-oxa-bicyclo[3.1.0]hexane (Compound 6, wherein R=R' =t-Bu(Me) ₂ Si-)

Fw 258 150/68

Wt(mg) 700 749/430

Mmmol 2.7 4.9/6.2

700 mg (2.7 mmol) of compound 5 was dissolved in 8 ml of DMF, and 749 mg of TBSC1 and 430 mg of imidazole were added in sequence. After the addition, the mixture was stirred at room temperature for 4 hours, diluted with 50 ml of petroleum ether, washed with water, dried over anhydrous Na ₂ SO ₄ , filtered and filtered. Column purification, elution with petroleum ether /EtOAc (EtOAc /EtOAc) (EtOAc)

[a] _D ²⁰ = +35 (c 0.15, CHC1 ₃ );

^J H匪R (300M, CDC1 ₃ , ppm) δ 4.27 (d, 1H, J=7.5Hz), 3.68 (d, 2H, J=3.3Hz), 3.26 (s,lH), 2.14-2.07 (m, lH), 2.03 (s, 1H), 1.86-1.81 (m, 1H), 1.41 (s, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.05 (s, 6H), 0.03 (s , 6H);

¹³ C匪R (125M, CDCI3, ppm ) δ 76.4, 66.1, 64.9, 62.6, 55.3, 39.0, 26.0, 25.8, 18.2, 18.1, 16.0, -5.7, -5.7, -4.5, -4.5;

HR-MS (ESI) calcd for _{_{_{_{C 19 H 41 0 3 Si 2}}}} (M + H) +: 373.2589, Found 373.2592 Example 6: Preparation of tert-butyl (((18,211,38,511) -3- (methoxymethoxy)-1-methyl-6-oxa-bicyclo[3·1·0]hex-2-yl)methoxy)dimethylsilane (Compound 6, wherein R=CH ₃ OCH ₂ -, R'=tB

Fw 258 80/129

Wt(mg) 370 0.94ml/2.16ml

Mmmol 1 .55 12.4/12.4

370 mg (1.55 mmol) of compound 5 was dissolved in 15 ml of CH ₂ C1 ₂ and 2.16 ml of DIPEA was added. (12.2 mmol), cooled with water dropwise 0.94ml MOMCl, plus complete 0 "C to room temperature and stir overnight fall, the solvent was distilled off under reduced pressure, the residue was diluted with EtOAc, washed with water, dried over anhydrous Na ₂ S0 _4, filtered and the filtrate Purification by silica gel EtOAc (EtOAc/EtOAc)

[a] _D ²⁰ = +33.1 (c 0.175, CHC1 ₃ );

^J H匪R (300M, CDC1 ₃ , ppm) δ 4.59 (s, 2H), 4.12 (d, 1H, J=7.2Hz), 3.70 (m, 2H), 3.33 (s, 4H), 2.20 (m, 1H), 2.11-2.00 (m, 2H), 1.44 (s, 3H), 0.88 (s, 9H), 0.05 (s, 6H);

¹³ C NMR (125M, CDC1 ₃ , ppm) δ 95.3, 80.4, 65.7, 36.0, 25.8, 18.0, 15.7, -5.6, -5.8;

HR-MS (ESI) calcd for _{_{_{C 15 H 3 () 0 4}}} SiNa (M + Na) +:. 325.18110; found 325.18037 Example 7: Preparation of (lR, 3R, 4S) -3- (( tert-butyl Dimethyl^*J^)methyl)-4-(methoxymethyl3⁄4J-methylene-cyclopentanol (Compound II, where R=CH ₃ OCH ₂ -, R'=t-Bu(Me) ₂ Si-)

Fw 302 141/2.5M/0.9M

Wt(mg) 70 131 /0.37ml/1 m l

Mmmol 0.232 0.927/0.927/0.927

Mol/mol 1 4/4/4

Add 131mg of 2,2,6,6-tetramethylhexahydropyridine to 1.5ml of anhydrous toluene, cool to 0*€, add 0.37ml of 2.5M BuLi, add to the stirring reaction for 30min, then add 1ml A 0.9 M Et ₂ AlCl (toluene) solution was added and stirred for 5 min to 5", then a solution of 70 mg (0.232 mmol) of the compound of Example 6 in 1.5 ml of toluene was added dropwise, and the reaction was stirred for 20 hours. The spot of the raw material disappears, carefully add methanol to stop the reaction, add saturated NH ₄ C1, Extracted with ether, and the combined extracts were washed with water, dried over anhydrous Na ₂ S0 _4, filtered, and the filtrate was purified by a short column of silica gel, eluting with petroleum ether / EtOAc (10 / l), to give the product 50mg (71.4%), Rf = 0.35 (Petroleum ether / EtOAc = 4 / l).

[a] _D ²⁰ = -60 (c 0.33, CHC1 ₃ );

^J H NMR (300M, CDC1 ₃ , ppm) δ 5.35 (s, 1H), 5.14 (s, 1H), 4.67 (s, 2H), 4.39 (s, 1H), 4.18 (s, 1H), 3.68-3.63 (m, 1H), 3.50-3.44 (m, 1H), 3.37 (s, 3H), 2.82 (s, 1H), 2.24-2.16 (m, 1H), 1.88-1.83 (m, 1H), 0.89 (s , 9H), 0.05 (s, 3H), 0.04 (s, 3H);

¹³ C NMR (125M, CDC1 ₃ , ppm) δ 110.6, 95.1, 78.4, 74.6, 64.5, 55.4, 52.1, 40.4, 29.7, 25.8, 18.2, -5.5, -5.5.

HR-MS (ESI) calcd for _{_{_{C 15 H 31 0 4 SiNa (}}} M + Na) +: 325.18351, found 325.18398 Example 8: Preparation of (lR, 3R, 4S) -4- ( t-butyldimethyl Silyloxy)-3-((tert-butyldimethylsilylmethyl)-2-methylene-cyclopentanol (Compound II, where R=R, = t-Bu(Me) ₂ Si-)

According to the similar method of the above Example 7, the secondary hydroxysilicon-protected compound prepared in Example 5 was used to obtain the following product in a yield of 92.5%.

II

[a] _D = -34 (c 0.44, CHC1 ₃ ); mp63-65"C

^J H NMR (300M, CDC1 ₃ , ppm) δ 5.39 (s, 1H), 5.13 (s, 1H), 4.36 (m, 2H) 3.56 (dd, 1H, J=10.5, 5.1Hz), 3.31 (dd, 1H, J=10.2, 8.7Hz), 2.76 (m, 1H) 1.99 (ddd, 1H, J=13.2, 5.4, 4.5Hz), 1.82 (dq, 1H, J=13.2, 1.1Hz), 0.88 (s 18H) ), 0.09 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H);

¹³ C NMR (75M, CDC1 ₃ , ppm ) δ 154.2, 111.7, 75.4, 75.3, 64.6, 54.9, 42.0 25.9, 25.8, 25.6, 18.2, 17.8, -4.8, -4.9, -5.5, -5.6. HR-MS (ESI) calcd for _{_{_{_{C 19 H 41 0 3 Si 2}}}} (M + H) +: 373.2589, Found 373.2585 Example 9: Preparation of 9 - ((lS, 3R, 4S) -3- (( tert-butoxy Dimethyl(methyl)-4-(methoxymethoxy)-2-methylenecyclopentyl)-6-chloro-9H-indol-2-amine (Compound 8, wherein R=CH ₃ OCH ₂ -, R'=t-Bu(Me) ₂ Si-)

Fw 302 169/262/174 453

Wt(mg) 150 210/262/175

Mmol 0.5 1 .25/1 .0/1 .0

Mol/mol 1 2.5/2/2

150 mg (0.5 mmol) of compound II prepared in Example 7 (R = MOM, R, = t-BuMe ₂ Si), 210 mg (1.25 mmol) 2-amino-6-chloro-guanine and 262 mg Ph ₃ P (1.0 mmol Place a 25 ml round bottom flask, add 10 ml of anhydrous THF, cool to -23*€, add 175 mg (1.0 mmol) of DEAD, add the reaction at -23"C to 0"C for 8 hours, then decompress. The THF was evaporated, and EtOAc (EtOAc) (EtOAc)EtOAc.

[a] _D ²⁰ = +30 (c 0.105, CHC1 ₃ ); mp 157-160 °C

^J H匪R (300M, CDC1 ₃ , ppm) δ 7.87 (s, 1H), 6.63 (s, 1H), 5.54 (m, 1H), 5.25 (s, 1H), 4.88 (s, 1H), 4.69 ( s, 2H), 4.32 (m, 1H), 3.88-3.81 (m, 2H), 3.39 (s, 3H), 2.84 (s, 1H), 2.38-2.29 (s, 2H), 0.93 (s, 9H) , 0.11 (s, 6H);

¹³ C匪R (100M, CDCI3, ppm )δ 158.9, 153.9, 151.2, 148.5, 141.5, 111.5 95.1, 76.8, 64.3, 56.3, 55.5, 51.7, 38.0, 30.5, 25.9, 18.4, -5.4.

HR-MS (ESI) calcd for C _{2 ()} H ₃₃ ClN ₅ 0 ₃ Si (M+H)+: 454.2036, measured value 454.2027 Example 10: 9-((lS,3R,4S)-4-(tert-Butyldimethoxy)-3-((tert-butyldimethyl 3 methoxy)methyl)-2-methyl Preparation of cyclopentyl)-6-chloro-9H-indol-2-amine (Compound 8, wherein R=R, = t-Bu(Me) ₂ Si-)

According to the similar method of the above Example 9, the secondary hydroxysilicon-protected compound II prepared in Example 8 gave the following product in a yield of 61.3%.

[a] _D = +33 (c 0.13, CHC1 ₃ ); Melting point 37-39 "C

^J H匪R (300M, CDC1 ₃ , ppm) δ 7.83 (s, 1H), 5.55-5.50 (m, 1H), 5.19 (s, 1H), 4.83 (s, 1H), 4.35-4.42 (m, 1H) ), 3.84-3.74 (m, 2H), 2.67 (br s, 1H), 2.33-2.15 (m, 2H), 0.92 (s, 9H), 0.90 (s, 9H), 0.10 (s, 6H), 0.08 (s, 6H);

¹³ C匪R (125M, CDCI3, ppm )δ 158.8, 153.9, 151.1, 148.9, 141.8, 125.4 111.4, 72.4, 64.1, 56.3, 54.7, 40.4, 26.0, 25.8, 18.4, 18.0, -4.6, -4.7, - 5.4, -5.4.

HR-MS (ESI) calcd for _{_{_{_{C 24 H 43 ClN 5 0 2}}}} Si 2 (M + H) +: 524.2638, found 524.2635 Example 11: Preparation of abacavir entecavir

Fw 453 277

Wt(mg) 450

450 mg (1 mmol) of the compound 8 prepared in Example 9 [R = MOM, R, = t-BuMe ₂ Si], 20 ml of 2N HCl and 20 ml of THF were added, and the mixture was stirred under reflux for 8 hours, and a portion of THF was evaporated under reduced pressure. It 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 172 mg (62%) of white crystals.

^NMR (d ⁶ -DMSO, 300 ΜΗζ): δ = 2.03 (m, lH), 2.20 (m, lH), 3.51 (t, 2H, J = 6 Hz), 4.21 (bs, lH), 4.54 (s, lH) ), 4.80-4.86 (m, 2H, can be exchanged by D ₂ 0), 5.08 (s,l), 7.64 (s,lH, can be widened by D ₂ 0 exchange), 10.54 (s,lH)„

Compared with the prior art, the novel preparation method provided by the invention is easy to purify, the quality is controllable, and the raw materials are easy to obtain, the price is cheap, and the production cost is better reduced.

The embodiments of the present invention and the specific examples thereof are provided above, but those skilled in the art can understand that the embodiments and examples are merely illustrative of the present invention, and without departing from the gist of the present invention, They make other modifications and transformations.

Claims

right

1. A method of preparing a compound of formula II,

CH ₂ 〇R'

II where

R is a hydroxy protecting group selected from the group consisting of: (i) an alkyl group, (ii) an aralkyl group such as a benzyl group, (iii) an alkoxyalkylene group such as an alkoxymethylene group such as MeOCH ₂ -, (iv An aralkoxyalkylene group, such as an aralkyl*^methylene group, such as BnOCH ₂ -, or a (V) silane group, such as triphenylsilyl, triisopropylsilyl, tert-butyldimethyl ^Based, tert-butyldiphenyl ^ ^ group;

The method includes the following steps:

Where R, as defined above,

5 e) the substance 6 of compound 5,

Wherein X is halogen, R and R, as defined above,

Where R and R are as defined above.

The method of claim 1, wherein in step c, the catalyst for the reaction is Grubbs first or second generation catalyst in an amount of from 0.1 to 20 eq%.

3. The method of claim 1 or 2, wherein in step d, a coordination reagent of a metal vanadium is used as a catalyst, such as VO(acac) ₂ , and the epoxidizing agent is selected from the group consisting of t-butyl hydroperoxide and hydrogen peroxide. , m-chloroperoxybenzoic acid, peroxybenzoic acid, peroxycarboxylic acid, peracetic acid.

The method according to any one of claims 1 to 3, wherein, in the step e, in the protective reagent RX of the secondary alcohol of the compound 4, R is selected from the group consisting of BnOCH ₂ -, MeOCH ₂ -, t-Bu (Me ₂ Si -, i-Pr ₃ Si- and t-BuPh ₂ Si-; X is a halogen such as C1; the base used in the reaction is selected from the group consisting of triethylamine, diisopropylethylamine, DBU, imidazole and the like.

The method according to any one of claims 1 to 4, wherein, in the step f, the dialkylaluminum chloride reagent is, for example, diethylaluminum chloride, N,N-dialkylamine lithium from the corresponding The dialkylamine is prepared in situ by reaction with butyllithium, wherein the dialkylamine is selected from the group consisting of N,N-diisopropylamine, N,N-dicyclohexylamine, and 2,2,6,6-tetra Methyl hexahydropyridine.

6. The method of any one of claims 1 to 5, wherein: In step c, the catalyst for the reaction is Grubbs first or second generation catalyst, and the amount is 0.120 eq%;

In step d, a coordination reagent of metal vanadium is used as a catalyst, such as VO(acac) ₂ , and the epoxidizing agent is selected from the group consisting of t-butyl hydroperoxide, hydrogen peroxide, m-chloroperoxybenzoic acid, and peroxybenzoic acid. , peroxyformic acid, peracetic acid;

In the step e, in the protective reagent RX of the secondary alcohol of the compound 4, R is selected from the group consisting of BnOCH ₂ -, MeOCH ₂ -, t-Bu(Me) ₂ Si -, i-Pr ₃ Si- and t-BuPh ₂ Si - X is a halogen, such as C1; the base used in the reaction is selected from the group consisting of triethylamine, diisopropylethylamine, DBU, imi, and the like;

In step f, the dialkyl aluminum chloride reagent is, for example, diethylaluminum chloride, and the N,N-dialkyllithium is prepared in situ from the corresponding dialkylamine by reaction with butyllithium, wherein the dialkyl group The amine is selected from the group consisting of N,N-diisopropylamine, N,N-dicyclohexylamine and 2,2,6,6-tetramethylhexahydropyridine.

The method according to any one of claims 1 to 6, wherein the compound 4 is used as a raw material and the steps d) to f) described therein are carried out.

The method according to any one of claims 1 to 6, wherein the compound 5 is used as a raw material and the steps e) to f) described therein are carried out.

The method according to any one of claims 1 to 6, wherein the step f) is directly carried out using the compound 6 as a raw material.

10. The method of synthesizing II according to claim 1,

R is a hydroxy protecting group selected from the group consisting of: (i) an alkyl group, (ii) an aralkyl group such as a benzyl group, (iii) an alkoxyalkylene group such as an alkoxymethylene group such as MeOCH ₂ -, (iv An aralkoxyalkylene group, such as an aralkylmethylene group, such as a BnOCH ₂ -, or a (V) silane group, such as triphenyl 3⁄4, triisopropylsilyl, tert-butyldimethyl, tert-butyl Diphenylene ^ ^ group; R, is a hydroxy protecting group, selected from: (i) an aralkyl group such as a trityl group, or (ii) a silane group, such as a triphenyl group, a triisopropyl group, a t-butyl dimethyl group: Uncle Ding ^! Benzene: base; the method comprises the following steps:

Wherein X is a halogen or a cyano group,

b) selective compounding of the compound 3,

Where R, as defined above, X is a halogen,

Where R, as defined above,

5 e) the substance 6 of compound 5,

Wherein X is halogen, R and R, as defined above,

Where R and R are as defined above.

11. The method of claim 10 wherein in step a the cuprous halide agent is selected from the group consisting of Cul, CuBr or CuBr.Me ₂ S.

12. The method of claim 10 or 11, wherein in step b, the primary hydroxyl protecting agent R, X is selected from the group consisting of triphenylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride , tert-butyl diphenyl silicon chloride, triphenylchloromethane, and the base is, for example, triethylamine, DBU, imidazole, diisopropylethylamine.

The process according to any one of claims 10 to 12, wherein, in the step c, the catalyst for the reaction is a Grubbs first or second generation catalyst in an amount of from 0.1 to 20 eq%.

14. The method of any of claims 10-13, wherein in step d, a coordination reagent of a metal vanadium is used as a catalyst, such as VO(acac) ₂ , and the epoxidizing agent is selected from the group consisting of t-butyl hydroperoxide, Hydrogen peroxide, m-chloroperoxybenzoic acid, peroxybenzoic acid, peroxycarboxylic acid, peracetic acid.

The method according to any one of claims 10 to 14, wherein, in the step e, in the protective reagent RX of the secondary alcohol of the compound 4, R is selected from the group consisting of BnOCH ₂ -, MeOCH ₂ -, t-Bu (Me ₂ Si -, i-Pr ₃ Si- and t-BuPh ₂ Si-; X is a halogen, such as C1; used in the reaction The base is selected from the group consisting of triethylamine, diisopropylethylamine, DBU, imidazole and the like.

The method according to any one of claims 10 to 15, wherein in the step f, the dialkylaluminum chloride reagent is, for example, diethylaluminum chloride, N,N-dialkylamine lithium by the corresponding The dialkylamine is prepared in situ by reaction with butyllithium, wherein the dialkylamine is selected from the group consisting of N,N-diisopropylamine, N,N-dicyclohexanyl and 2,2,6,6- Tetramethylhexahydropyridine.

17. The method of any of claims 10 to 16, wherein:

In step a, the cuprous halide reagent is selected from Cul, CuBr or CuBr.Me ₂ S;

In step b, the primary hydroxyl protecting agent R, X is selected from the group consisting of triphenylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride, three Phenylchloromethane, the base is organically called, such as triethylamine, DBU, imidazole, diisopropylethylamine;

In step c, the catalyst for the reaction is Grubbs first or second generation catalyst, and the amount is 0.120 eq%;

The method according to any one of claims 10 to 17, wherein the compound 2 is used as a raw material and the steps b) to f) described therein are carried out.

19. Compounds of formula V:

among them

R is a hydrogen or hydroxy protecting group selected from the group consisting of: (i) an alkyl group, (ii) an aralkyl group such as a benzyl group, (iii) an alkoxyalkylene group such as an alkoxymethylene group such as MeOCH ₂ -, (iv) an aralkoxyalkylene group, such as an aralkyloxymethylene group, such as a BnOCH ₂ -, or a (V) silane group, such as a triphenylene group, a triisopropylsilyl group, a tert-butyl group Base, tert-butyl phenyl;

R, is a hydroxy protecting group, selected from: (i) an aralkyl group such as a trityl group, or (ii) a silane group, such as a triphenyl group, a triisopropyl group, a t-butyl dimethyl group: Uncle Ding ^! Benzene ^: base.

20. A compound of claim 19 selected from the group consisting of:

tert-Butyl ((18,211,38,511)-3-(methoxymethoxy)-1-methyl-6-oxa-bicyclo[3.1.0]

-2-yl) A *J dimethyl burning,

(1S, ² R, ³ S, ⁵ R)_ ³ - (tert-Butyldimethylsilyloxy)-2-((tert-butyldimethylsilyloxy)methyl)-1-methyl- 6-oxa-bicyclo[3.1.0]hexane,

(lS, 2R, 3S, 5R)-2-((tert-butyldimethylsilyloxy)methyl)-1-methyl-6-oxa-bicyclo

[3丄0]hex-3-ol.

21. The method of claim 19,

Wherein R and R are as recited in claim 19,

The method includes the following steps:

Wherein X is a halogen or a cyano group,

Wherein R, as recited in claim 19, X is a halogen,

Where R, as recited in claim 19,

d) stereoselectively obtaining a compound of the formula V wherein R is hydrogen, by catalyzing the compound 4 with an epoxidizing reagent under the catalysis of a metal vanadium reagent,

Wherein R is hydrogen, R, as recited in claim 19,

Or

Wherein X is halogen, R and R, as recited in claim 19, and R is not hydrogen.

22. The method of claim 21 wherein in step a the cuprous halide reagent is selected from the group consisting of Cul, CuBr or CuBr.Me ₂ S.

23. The method of claim 21 or 22, wherein in step b, the primary hydroxyl protecting agent R, X is selected from the group consisting of triphenylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride , tert-butyldiphenylsilyl chloride, triphenylchloroformamidine, a base; M3⁄4, such as triethylamine, DBU, imidazole, diisopropylethylamine.

The method according to any one of claims 21 to 23, wherein, in the step c, the catalyst for the reaction is a Grubbs first or second generation catalyst in an amount of from 0.1 to 20 eq%.

The method according to any one of claims 21 to 24, wherein, in the step d, a coordination reagent of a metal ruthenium is used as a catalyst, for example, VO(acac) ₂ , and the epoxidizing agent is selected from t-butyl hydroperoxide, Hydrogen peroxide, m-chloroperoxybenzoic acid, peroxybenzoic acid, peroxycarboxylic acid, peracetic acid.

The method according to any one of claims 21 to 25, wherein, in the step e, in the protective reagent RX of the secondary alcohol of the compound 4, R is selected from the group consisting of BnOCH ₂ -, MeOCH ₂ -, t-Bu (Me ₂ Si -, i-Pr ₃ Si- and t-BuPh ₂ Si-; X is a halogen such as C1; the base used in the reaction is selected from the group consisting of triethylamine, diisopropylethylamine, DBU, imidazole and the like.

27. The method of any of claims 21 to 26, wherein:

In the step e, in the protective reagent RX of the secondary alcohol of the compound 4, R is selected from the group consisting of BnOCH ₂ -, MeOCH ₂ -, t-Bu(Me) ₂ Si -, i-Pr ₃ Si- and t-BuPh ₂ Si - X is a halogen, for example, C1; the base used in the reaction is selected from the group consisting of triethylamine, diisopropylethylamine, DBU, milidine, and the like.

The method according to any one of claims 21 to 27, wherein compound 2 is used as The raw materials are subjected to steps b) to e) described therein.

The method according to any one of claims 21 to 27, wherein the compound 3 is used as a raw material and the steps c) to e) described therein are carried out.

30. Compound of formula 4:

Wherein R is a hydroxy protecting group selected from the group consisting of: (i) an aralkyl group such as a trityl group, or (ii) a silane group, such as a triphenyl group, a triisopropyl group, a t-butyl group, a methyl group, Tert-butyldiphenyl^3⁄4 base.

31. The compound of claim 30 which is selected from the group consisting of:

^{^{(1S, 2 R) _ 2}} _ (( tert-butyl-dimethoxy J¾) methyl) ³ _ _ _ ³ _ methylcyclopentadienyl-1-ol.

32. A method of preparing the method of claim 30:

Where R is as recited in claim 30,

The method includes the following steps:

Wherein X is a halogen or a cyano group,

Wherein R, as recited in claim 30, X is a halogen,

Where R is as set forth in claim 30.

33. The method of claim 32 wherein in step a the cuprous halide agent is selected from the group consisting of Cul, CuBr or CuBr. Me ₂ S.

34. The method of claim 32 or 33, wherein in step b, the primary hydroxyl protecting agent R, X is selected from the group consisting of triphenylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride , tert-butyl diphenyl chloride, triphenylchloromethane, a base; M3⁄4, such as triethylamine, DBU, imidazole, diisopropylethylamine.

The method according to any one of claims 32 to 34, wherein in the step c, the catalyst for the reaction is Grubbs first or second generation catalyst in an amount of from 0.1 to 20 eq%.

36. The method of any of claims 32 to 35, wherein:

In step b, the primary hydroxyl protecting agent R, X is selected from the group consisting of triphenylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride, three Phenylchloromethane, the base is organically reduced, such as triethylamine, DBU, imidazole, diisopropylethylamine;

In step c, the catalyst for the reaction is Grubbs first or second generation catalyst in an amount of 0.120 eq%.

37. The method of any one of claims 32 to 36, wherein compound 2 is used as The raw materials are subjected to steps b) to C) described therein.

The method according to any one of claims 32 to 37, wherein the compound 3 is used as a raw material and the step c) described therein is carried out.

39. Compounds of formula III:

Wherein R is a hydrogen or hydroxy protecting group selected from the group consisting of: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as a triphenyl group, a triisopropyl group, a tert-butyl group A ^ ^ base, tert-butyl diphenyl silicon.

40. The compound of claim 39 which is selected from the group consisting of:

(3R,4S)-3-((tert-Butyldimethyl J3⁄4oxy)methyl)-2-methylheptan-1,6-dien-4-ol,

(2R,3S)-2-(prop-1-en-2-yl)hex-5-ene-1,3-diol.

41. Preparation of a compound of formula III

Where R is as recited in claim 39,

The method includes the following steps:

a) intermediate compound 1 is reacted with isopropenol Grignard reagent in the presence of cuprous halide to obtain R, which is hydrogen

Wherein X is a halogen or a cyano group,

or b) selective protection of the primary hydroxyl group of the compound of formula III wherein R is hydrogen to give a compound of formula III wherein R is not hydrogen

Wherein R is as defined in claim 39, and R is not hydrogen and X is a halogen.

42. The method of claim 41 wherein in step a the cuprous halide reagent is selected from the group consisting of Cul, CuBr or CuBr. Me ₂ S.

43. The method of claim 41 or 42, wherein in step b, the primary hydroxyl protecting agent R, X is selected from the group consisting of triphenylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride , tert-butyldiphenylsilyl chloride, triphenylchloromethane, a base such as triethylamine, DBU, imidazole, diisopropylethylamine.

44. The method of any of claims 41 to 43, wherein:

In step b, the primary hydroxyl protecting agent R, X is selected from the group consisting of triphenylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride, three Phenylchloromethane, the base is organically reduced, such as triethylamine, DBU, imidazole, diisopropylethylamine.

The method of any one of claims 41 to 44, wherein R, a compound of formula III which is hydrogen is used as a starting material and step b) is carried out therein.

46. A method of preparing a compound of formula I,

The method includes the following steps: c) the compound 3 is subjected to olefin metathesis reaction in the presence of a Grubbs catalyst to obtain a cyclic compound 4,

Where R is as defined in claim 1

Where R is as defined in claim 1

e) the substance 6 of compound 5,

Wherein X is halogen, R and R, as defined in claim 1,

f) compound 6 is epoxy ring-opened to form intermediate II under the action of a dialkylaluminum chloride reagent and lithium N,N-dialkylamine,

Wherein R and R are as defined in claim 1. g) coupling intermediate II with 2-J^-6-chloro-guanine using Mitsunobu reaction to give compound 8,

Wherein R and R are as defined in claim 1;

h) compound 8 in acidic frfr

47. The method of claim 46, wherein in step c, the catalyst for the reaction is Grubbs first or second generation catalyst in an amount of from 0.1 to 20 eq%.

48. The method of claim 46 or 47, wherein in step d, a coordination reagent of a metal vanadium is used as a catalyst, such as VO(acac) ₂ , and the epoxidizing agent is selected from the group consisting of t-butyl hydroperoxide and hydrogen peroxide. , m-chloroperoxybenzoic acid, peroxybenzoic acid, peroxycarboxylic acid, peracetic acid.

The method according to any one of claims 46 to 48, wherein, in the step e, in the protective reagent RX of the secondary alcohol of the compound 4, R is selected from the group consisting of BnOCH ₂ -, MeOCH ₂ -, t-Bu (Me ₂ Si -, i-Pr ₃ Si- and t-BuPh ₂ Si-; X is a halogen such as C1; the base used in the reaction is selected from the group consisting of triethylamine, diisopropylethylamine, DBU, imidazole and the like.

50. The method of any one of claims 46 to 49, wherein in step f, the dialkylaluminum chloride reagent is, for example, diethylaluminum chloride, N,N-dialkylamine, by corresponding Dialkylamine Prepared in situ by reaction with butyllithium, wherein the dialkylamine is selected from the group consisting of N,N-diisopropylamine, N,N-dicyclohexylamine, and 2,2,6,6-tetramethylhexahydro Pyridine.

The method according to any one of claims 46 to 50, wherein, in the step g, the Mitsunobu reaction reagent is a phosphine catalyst such as triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate. .

The method according to any one of claims 46 to 51, wherein, in the step h, the acid used is a mineral acid such as hydrochloric acid or sulfuric acid.

53. The method of any of claims 46 to 52, wherein:

In step f, the dialkyl aluminum chloride reagent is, for example, diethylaluminum chloride, and the N,N-dialkyllithium is prepared in situ from the corresponding dialkylamine by reaction with butyllithium, wherein the dialkyl group The amine is selected from the group consisting of N,N-diisopropylamine, N,N-dicyclohexylamine, and 2,2,6,6-tetramethylhexahydropyridine;

In step g, the Mitsunobu reaction reagent is a phosphine catalyst such as triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate;

In step h, the acid used is a mineral acid such as hydrochloric acid or sulfuric acid.

The method according to any one of claims 46 to 53, wherein the compound 4 is used as a raw material and the steps d) to h) described therein are carried out.

The method according to any one of claims 46 to 53, wherein the compound 5 is used as a raw material and the steps e) to h) described therein are carried out.

The method according to any one of claims 46 to 53, wherein the compound 6 is used as a raw material and the steps f) to h) described therein are carried out.

57. A process for the preparation of a compound of formula I according to claim 46,

The method includes the following steps:

Wherein X is a halogen or a cyano group,

b) selective compounding of the compound 3,

Wherein R is as defined in claim 46, and X is a halogen,

Where R is as defined in claim 46,

Where R, as defined in claim 46, e) Compound 5

Wherein X is halogen, R and R, as defined in claim 46,

Wherein R and R are as defined in claim 46.

g) coupling intermediate II with 2-J^-6-chloro-guanine using Mitsunobu reaction to give compound 8,

Wherein R and R are as defined in claim 1;

h) Compound 8 is hydrolyzed under acidic frfr to give a compound of formula I

58. The method of claim 57, wherein in step a, the cuprous halide agent is selected from the group consisting of Cul, CuBr or CuBr.Me ₂ S;

59. The method of claim 57 or 58, wherein, in step b, the primary hydroxyl protecting agent R, X is selected from the group consisting of triphenylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride , tert-butyldiphenylsilyl chloride, triphenylchloromethane, a base such as triethylamine, DBU, imidazole, diisopropylethylamine.

60. The process of any of claims 57-59, wherein in step c, the catalyst for the reaction is a Grubbs first or second generation catalyst in an amount of from 0.1 to 20 eq%.

The method according to any one of claims 57 to 60, wherein, in the step d, a coordination reagent of a metal vanadium is used as a catalyst, for example, VO(acac) ₂ , and the epoxidizing agent is selected from t-butyl hydroperoxide, Hydrogen peroxide, m-chloroperoxybenzoic acid, peroxybenzoic acid, peroxycarboxylic acid, peracetic acid.

The method according to any one of claims 57 to 61, wherein, in the step e, in the protective reagent RX of the secondary alcohol of the compound 4, R is selected from the group consisting of BnOCH ₂ -, MeOCH ₂ -, t-Bu (Me ₂ Si -, i-Pr ₃ Si- and t-BuPh ₂ Si-; X is a halogen such as C1; the base used in the reaction is selected from the group consisting of triethylamine, diisopropylethylamine, DBU, imidazole and the like.

63. The method of any of claims 57-62, wherein in step f, the dialkylaluminum chloride reagent is, for example, diethylaluminum chloride, N,N-dialkylamine lithium from the corresponding The dialkylamine is prepared in situ by reaction with butyllithium, wherein the dialkylamine is selected from the group consisting of N,N-diisopropylamine, N,N-dicyclohexanyl and 2,2,6,6- Tetramethylhexahydropyridine.

64. The method of any of claims 57-63, wherein in step g, the Mitsunobu reagent is a phosphine catalyst such as triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate. .

The method according to any one of claims 57 to 64, wherein in the step h, the acid used is a mineral acid such as hydrochloric acid or sulfuric acid.

66. The method of any of claims 57-65, wherein:

The method according to any one of claims 57 to 66, wherein the compound 2 is used as a raw material and the steps b) to h) described therein are carried out.