CN105524064B - The synthetic method of Entecavir - Google Patents

Abstract

The invention discloses a kind of synthetic method of Entecavir, belong to pharmaceutical synthesis method and technology field.This method is with 1; 3 propane diols are initiation material; beta-unsaturated esters are generated after being oxidized to aldehyde, then Entecavir has been synthesized through the reaction such as reduction, asymmetric Epoxidation, open loop, desiliconization alkane protection group, hydroxyl protection, deprotection, oxidation, cyclization, oxidation, reduction, condensation, deprotection.The present invention is raw materials used cheap and easy to get, and reaction condition is gently easily-controllable, it is easy to industrialized production.

Description

The synthetic method of Entecavir

Technical field

The present invention relates to a kind of synthetic method of medicine, more particularly to a kind of synthetic method of Entecavir.

Background technology

Entecavir is a kind of guanosine analog, for treating hepatitis B.It is by U.S.'s Bristol Myers Squibb Company develops, and is ratified to list by FDA in March, 2005.Entecavir has extremely strong suppression hepatitis B replication, The effect of serum-virus DNA level is reduced, the mutant strain to resistance to Lamivudine is still effective, and have no obvious bad anti- Should and mitochondrial toxicity.Compared with other similar medicines, Entecavir is a kind of higher treatment hepatitis B of security Active drug.

The synthetic method about Entecavir has much at present, such as following synthetic route disclosed in Shi Guibao companies:

But there is initiation material in above-mentioned synthetic method to be not easy to obtain, the high defect of cost.

Also researcher provides following Entecavir synthesis technique:

But in above-mentioned synthetic method, the 2nd step reaction condition requires harshness, it is necessary to less than -70 DEG C of low temperature and strict nothing Water, industrialization difficulty is higher.

For the synthetic method of Entecavir, researchers have carried out substantial amounts of research, have obtained different synthetic methods, But synthetic method disclosed at present has that initiation material is not easy to obtain, partial reaction condition requires that harshness, cost height etc. are a variety of Defect, industrialization difficulty is higher.

The content of the invention

Based on this, for process route cost in the industrialized production of current Entecavir is high, raw material is rare, partial reaction The problems such as condition requires harsh, it is an object of the invention to the defect for overcoming prior art, there is provided a kind of synthesis of Entecavir Method, this method has the advantages that cost is low, reaction condition is gentle, synthetic route is brief.

To achieve the above object, the present invention takes following technical scheme：

A kind of synthetic method of Entecavir, comprises the following steps：

(1) by one of hydroxyl of Formula X IV compound 1,3- propane diols with hydroxyl protecting group R₁Protection, production XVization Compound；

(2) hydroxyl in Formula X V compounds and oxidant reaction are into aldehyde, production XVI compounds；

(3) Formula X VI compounds generate α, the Formula X VII compounds of beta-unsaturated esters with horner-emmons reagent reactings；

(4) Formula X VII compounds obtain Formula II compound through reducing agent reduction；

(5) Formula II compound is carried out in the presence of titanium compound and chiral esters part in the presence of oxidant Asymmetric oxidation reaction, production III compounds；

(6) formula III compound carries out ring-opening reaction, production IV compounds, the open loop in the presence of Ring Opening Reagent Reagent includes：Lithium alkylide and alkyl silicon ether protection group R₃Replaced acetylene；Or alkyl silicon ether protection group R₃The form examination of replaced acetylene Agent；

(7) by the hydroxyl of formula IV compound with protection group R₂Protection, and slough silicon ether protection group R₃Production VI compounds；

(8) Formula IV compound sloughs R₁Hydroxyl protecting group production VII compounds；

(9) Formula VII compound is aoxidized, and makes to slough R₁Hydroxyl be oxidized to aldehyde, production VIII compounds；

(10) ring closure reaction, production IX compounds occur in the presence of cyclization reagent for Formula VIII compound；

(11) Formula IX compound is aoxidized to production X compounds in the presence of oxidant；

(12) Formula X compound is reduced to production XI compounds in the presence of reducing agent；

(13) Formula X I is entered with Formula X II compounds under the conditions of mitsunobu reaction conditions or substitution reaction Row condensation reaction, production XIII compounds；

(14) Formula X III compounds slough protection group R under the action of an acid₂And R₄, production I Entecavir；

Reaction scheme is as follows：

Wherein：R₁, R₂For hydroxyl protecting group, and R₂R is sloughed for that can be resistant to₁Hydroxyl protecting group；

R₃For alkyl silicon ether protection group；

R₄For hydrogen, C1-C6 alkyl, the substitution of C1-C6 alkyl or not substituted aryl, the substitution of C1-C6 alkyl or not substituted benzyl.

In the reaction scheme, compound II obtains compound III by asymmetric Epoxidation, then with alkynes in alkyl lithium reagents In the presence of, alkynes obtains compound IV from 2 carbon open loop oxygen, then uses R₂Two hydroxyls are protected, and slough R₃Changed Compound VI, is then oxidized to aldehyde by compound VII hydroxyl and obtains compound VIII, acts on aldehyde radical and alkynyl, cyclization is obtained Compound IX, reoxidizes hydroxyl and obtains compound X for carbonyl, asymmetric reduction obtains compound XI, then is coupled with compound XII Compound XIII is obtained, R is finally sloughed under the action of an acid₂And R₄, obtain compound I.

In one of the embodiments, in step (5), the titanium compound is selected from：Titanium tetrachloride or the isopropyl of metatitanic acid four Ester；The hand-type esters part is selected from：L- (+)-ethyl tartrate or L- (+)-tartaric acid diisopropyl ester；The oxidant choosing From：TBHP or isopropyl benzene hydroperoxide, reaction temperature is：0~-50 DEG C, preferably -20~-40 DEG C.The step is reacted Also it can be carried out under the conditions of Vo (acac) 2, shi and Jacobson asymmetric Epoxidations.

In one of the embodiments, in step (6), R₃It is selected from：Trimethyl silicon substrate, triethyl group silicon substrate；Lithium alkylide is selected from： Lithium methide, n-BuLi, tert-butyl lithium；Reaction condition is：0~-50 DEG C, preferably 0~-30 DEG C.

In one of the embodiments, in step (6), the Ring Opening Reagent also includes dimethylaluminum chloride or diethyl chlorine Change aluminium.The dimethylaluminum chloride or diethyl aluminum chloride can be generated with alkynes after alkynyl aluminon, aluminium and the complexing of alcohol negative oxygen ion, alkynes Base is more likely to from 2 carbon open loop oxygen, so as to aid in the regioselectivity for improving open loop.

In one of the embodiments, in step (10), the cyclization reagent is Ni (COD)₂, PBu₃With Zn (Et)₂；Or SmI₂；Or Na and naphthalene；Or Li and naphthalene；Or Na and NH₃；Or Li and NH₃；Or CrCl₂, NiCl₂And PPh₃, reaction temperature is：0~- 50 DEG C, preferably 0~-10 DEG C.

In one of the embodiments, in step (7), first in the presence of a base, by the hydroxyl of formula IV compound with Protection group R₂Protection, obtains Formula V compound, then is reacted with fluoride or alkali under the conditions of 0-40 DEG C, sloughs in Formula V compound Alkyl silicon ether protection group R₃Production VI compounds；

Or first reacted with fluoride or alkali under the conditions of 0-40 DEG C, slough the silicon ether protection group R in formula IV compound₃, The hydroxyl of ' compound, then in the presence of a base by the Formula V ' compound that obtains Formula V is with protection group R₂Protection, production VIization Compound；

In one of the embodiments, R₁, R₂, R₄It is respectively and independently selected from：Benzyl, C1-C6 alkyl or alkoxy substitution benzyl Base, trityl, trialkyl silyl or tert-butyl diphenyl silicon substrate.In view of R₂R is sloughed for that can be resistant to₁Hydroxyl protecting group, Then one skilled in the art will appreciate that such as R₁For alkoxy substituted benzyl, then R₂For benzyl, trityl or substitution trityl, three Alkyl silyl or tert-butyl diphenyl silicon substrate；Such as R₁For trialkyl silyl, then R₂For tert-butyl diphenyl silicon substrate, benzyl, C1-C6 Alkyl or alkoxy substituted benzyl, trityl or substitution trityl, such as tert-butyl diphenyl silicon substrate, R₁For trialkyl silyl Or tert-butyl diphenyl silicon substrate, then R₂For benzyl, C1-C6 alkyl or alkoxy substituted benzyl, trityl or substitution triphen first Base, such as R₁For trityl or substitution trityl, then R₂For benzyl, C1-C6 alkyl or alkoxy substituted benzyl.

In one of the embodiments, R is worked as₁For to methoxy-benzyl, R₂During for t-Butyldimethylsilyl, step (8) In, using dichloro dicyan 1,4-benzoquinone, or ammonium ceric nitrate, at 0-40 DEG C, reacted under the conditions of preferably 0-25 DEG C, slough R₁Hydroxyl is protected Protect base.

In one of the embodiments, in step (13), mitsunobu (light the prolongs reaction) reaction condition is：Three In the presence of Phenylphosphine and aliphatic azo compound (DEAD), in 0~40 DEG C of reaction, preferably 0~25 DEG C.The aliphatic is even Nitrogen compound (DEAD) preferably azo dicarbonic acid diethyl ester or the diisopropyl carbonate of azo two.

In one of the embodiments, in step (3), the horner-emmons reagents are selected from：The second of phosphonoacetic acid three Ester, or phosphonoacetic acid trimethyl；The step reaction temperature is 0~40 DEG C, preferably 0~25 DEG C.

In one of the embodiments, in step (2), the oxidant is selected from：Sodium hypochlorite, pyridinium chloro-chromate, weight Chromic acid pyridine, dimethyl sulfoxide, 2- iodosobenzoic acids, or Dai Si-Martin's oxidant, reaction temperature is：- 10~40 DEG C, preferably 0 ~25 DEG C；

In step (4), the reducing agent is selected from：Diisobutyl aluminum hydrogen (DIBAL-H), or lithium aluminium hydride reduction and tri-chlorination Aluminium, reaction temperature is：0~-50 DEG C, preferably 0~-20 DEG C.

In step (9), at -10~40 DEG C, preferably 0-25 DEG C, using sodium hypochlorite, pyridinium chloro-chromate, dichromic acid pyrrole Pyridine, dimethyl sulfoxide, 2- iodosobenzoic acids, or Dai Si-Martin's oxidant (Dess-Martin reagents) are aoxidized；

In step (11), at -10~40 DEG C, preferably 0-25 DEG C, using 2- iodosobenzoic acids, pyridinium chloro-chromate, Sodium hypochlorite, Pyridinium dichromate, dimethyl sulfoxide, or Dai Si-Martin's oxidant (Dess-Martin reagents) are aoxidized；

In step (12), at -50~0 DEG C, at preferably -20~-40 DEG C, using lithium triethylborohydride, or cerous chloride Reduced with sodium borohydride；

In step (14), at 20~80 DEG C, using hydrochloric acid, protection group R is sloughed₂And R₄。

In one of the embodiments, the Entecavir of generation is purified by recrystallizing in step (14), the recrystallization Method is：Recrystallized with water as solvent.

Compared with prior art, the invention has the advantages that：

The invention discloses a kind of synthetic method of Entecavir, this method is passed through using 1,3-PD as initiation material It is oxidized to after aldehyde generate beta-unsaturated esters, is then reduced into allyl alcohol, is protected through asymmetric Epoxidation, open loop, desiliconization alkane protection group, hydroxyl The reaction such as shield, deprotection, oxidation, cyclization, oxidation, reduction, condensation, deprotection has synthesized Entecavir.

Raw materials used 1,3-PD is cheap and easy to get in the synthetic method, such as large batch of volume production, and its cost will also reduction.

And also all reactions are optimized by inventor, have obtained completing at ambient pressure, and without poles such as high temperature The mild reaction conditions of end condition, with it is gentle easily-controllable the characteristics of, it is easy to industrialized production.

Embodiment

Below in conjunction with specific embodiment, the invention will be further described, however, these embodiments should not be used as to this hair The limitation of bright scope.

Embodiment 1

A kind of synthetic method of Entecavir, comprises the following steps：

(1) compound XV preparation

1,3- propane diols (1457.6g, 19.15mol), DMF are added in temperature control, churned mechanically 20L reactors (dimethylformamide) (5L), DCM (dichloromethane) (1L), then mechanical agitation is slow into kettle when system is less than 10 DEG C 60%NaH (281g, 7.024mol) is added, about 2h, control reactor temperature is not higher than 15 DEG C, and 70min. is added, and maintains kettle Interior temperature continues to stir 30min. less than 10 DEG C；Then TBAI (tetrabutylammonium iodide) (23.6g, 0.064mol), 15min are added Add；With 1.5L DCM dilution PMBCl (to mehtoxybenzyl) (1000g, 6.385mol), it is slowly added dropwise into kettle, 4h. Completion of dropping；Then system is warmed to room temperature be stirred overnight .TLC show consumption of raw materials finish.Then, system is cooled to 10 DEG C Hereinafter, toward the water that 10L is slowly added in reaction system, 2L DCM is then added, 15min is stirred, a point liquid is stood, organic phase is used Water washing, saturated common salt water washing, anhydrous Na₂SO₄Dry, 1085g yellow liquids, yield 86.6% are obtained after being concentrated under reduced pressure.¹H NMR(400MHz,CDCl₃) δ 7.24 (d, J=8.7Hz, 2H), 6.87 (d, J=8.7Hz, 2H), 4.44 (s, 2H), 3.79 (s, 3H), 3.75 (t, J=5.7Hz, 2H), 3.62 (t, J=5.8Hz, 2H), 2.44 (s, 1H), 1.87-1.80 (m, 2H).

(2) compound XVI preparation

Toward band temperature control and churned mechanically 20L reactors in add compound XV (500g, 2.5mol), TEMPO (2,2,6, 6- tetramethyl piperidine oxides) (3.98g, 25.479mmol), TBAB (TBAB) (7.5g), saturation NaHCO₃It is water-soluble Liquid (2000ml), DCM (4000ml), are placed in strong agitation at -5 DEG C；Then with 4000ml water dilution sodium hypochlorite (2.36kg, 13% Active Chlorine) it is slowly added into reaction system, it is kept stable at less than 5 DEG C, about 2h completion of dropping.Maintain 5 DEG C after Continuous stirring, TLC tracks 1h again, and consumption of raw materials is finished.After consumption of raw materials is finished, a point liquid is stood, aqueous phase is washed with DCM, merged organic Phase, successively with 10% HCl, 10% hypo solution, H dissolved with KI₂O, the washing of saturated common salt water washing, it is anhydrous Na₂SO₄Dry, filtering is concentrated under reduced pressure to give 414g yellowish-brown liquid, yield：83.7%.¹H NMR(400MHz,CDCl₃)δ 9.78 (s, 1H), 7.25 (d, J=9.2Hz, 2H), 6.88 (d, J=8.7Hz, 2H), 4.46 (s, 2H), 3.80 (s, 3H), 3.78 (t, J=6.2Hz, 2H), 2.68 (d, J=1.8Hz, 2H).

(3) compound XVII preparation

Add at NaH (93g, 60% content, 2.3mol), THF (4000ml, AR), 0 DEG C and stir in 20L reactors, connect And triethyl phosphonoacetate (519g, 2.3mol) is slowly added into system, stir 30min.；Then it is dilute with 5000ml THF Compound XVI (500g, 2.6mol) is released toward dropwise addition in system, then 50min. completion of dropping is warmed to room temperature stirring 1h. raw materials and disappears Consumption is finished.Add 500ml saturated aqueous ammonium chlorides and reaction is quenched, remove THF, be then charged with EA (6000ml), water Washing, saturated common salt water washing, anhydrous Na₂SO₄Dry, filtering is concentrated under reduced pressure, obtains 526g yellow liquids.Yield：85.9% 。¹H NMR(400MHz,CDCl₃) δ 7.25 (d, J=8.0Hz, 2H), 6.88 (d, J=8.6Hz, 2H), 5.88 (dt, J=15.7, 1.5Hz, 1H), 4.45 (s, 2H), 4.18 (dd, J=14.4,7.2Hz, 2H), 3.80 (s, 3H), 3.55 (dd, J=7.8, 5.2Hz, 2H), 2.49 (m, 2H), 1.28 (t, J=7.1Hz, 3H).

(4) compound XVIII preparation

Under argon gas protection, compound XVII (249g, 0.94mol), anhydrous THF are added in 10L there-necked flask (1800ml), is placed in -20 DEG C of cryostat, and stirs；After system maintains -20 DEG C of stabilizations, DIBAL- is slowly added dropwise into system H (1180g, 25%in toluene, 2.07mol), 2.0h. completion of dropping；Maintain -20 DEG C of stirrings, TLC tracking 30min., original Material is exhausted.After the completion of reaction, 1000g diatomite is added, it is then slow toward dropwise addition 4000ml saturated ammonium chloride water in system Solution, suction filtration, filter cake is washed with EA, and filtrate stands a point liquid, and inorganic phase is extracted with EA, is merged organic phase and is washed with saturated common salt Wash, anhydrous Na₂SO₄Dry, filtering is concentrated under reduced pressure to give 191.2g light yellow liquids, yield 91.5%.¹H NMR(400MHz, CDCl₃) δ 7.26 (d, J=8.5Hz, 2H), 6.88 (d, J=8.6Hz, 2H), 5.71 (t, J=3.9Hz, 2H), 4.44 (s, 2H), 4.09 (d, J=2.7Hz, 2H), 3.80 (s, 3H), 3.49 (t, J=6.7Hz, 2H), 2.36 (dd, J=10.9,6.4Hz, 2H).

(5) compound III preparation (R₁=to methoxy-benzyl)

Under argon gas protection, added in 20L reactor after activationMolecular sieve (200g), adds anhydrous DCM (two Chloromethanes) in (4000ml), in -25 DEG C of stirrings, by L-DET (L- (+)-ethyl tartrate) (80g, 388.4mmol) in argon After being added under gas shielded, Ti (i-PrO) is slow added into₄(isopropyl titanate) (88g, 310.8mmol), stirs 30min, then will T-BuOOH (TBHP) (1.13L, 4.6M in toluene, 5.18mol) is slowly added to, and is stirred for 30min, will Compound II (575.2g, 2.59mol) is dissolved in anhydrous DCM (1100ml), is slow added into reaction solution, is stirred at -25 DEG C Mix overnight.TLC observations consumption of raw materials is finished, and monohydrate potassium (600g) and FeSO are slowly added into system₄·7H₂O Reaction is quenched in the aqueous solution (6000ml) of (790g)；Then plus suction filtered through kieselguhr, filter cake is washed with DCM, and filtrate stands a point liquid, nothing Machine is extracted with DCM；Merge the NaOH aqueous solution (1200ml) that organic phase adds 30% at 0 DEG C, stir 10min.；Filtrate is quiet Put a point liquid, organic phase saturated common salt water washing, anhydrous Na₂SO₄Dry, filtering is concentrated under reduced pressure, obtains 587.6g yellow liquids For compound III.Yield：95.3%.

Compound III characterize data is：¹H NMR(400MHz,CDCl₃) δ 7.26 (d, J=8.6Hz, 3H), 6.88 (d, J=8.6Hz, 2H), 4.45 (s, 2H), 3.89 (d, J=12.5Hz, 1H), 3.80 (s, 3H), 3.70-3.47 (m, 3H), 3.16-3.02 (m, 1H), 2.97 (dt, J=4.7,2.5Hz, 1H), 1.98-1.76 (m, 2H).

(6) compound IV preparation (R₃=trimethyl silicon substrate)

Under argon gas protection, trimethylsilyl acetylene (380ml, 2.68mol), anhydrous DCM are added into 20L reactor (5000ml), is stirred at 0 DEG C, be charged with n-BuLi (n-BuLi) (1120ml, 2.4M in hexanes, 2.68mol), 100min completion of dropping, stirs 30min；Et is charged with again₂AlCl (2688ml, 1M, 2.68mol), 80min completion of dropping, continues to stir 30min；Then system is cooled to -30 DEG C of stirrings, protected at another with argon gas 5000ml two-mouth bottles in add compound III (160g, 672mmol) produced above, anhydrous DCM (800ml), be placed in 0 DEG C Cryostat, in stir, be charged with n-BuLi (308ml, 2.4M in hexanes, 740mmol), 30min completion of dropping, 30min is stirred, is then added into -30 DEG C of above-mentioned reactors, 10min completion of dropping, 30min is stirred, then by system It is warmed to room temperature and is stirred overnight (18h.), consumption of raw materials is finished.Reaction system is cooled to 0 DEG C, 1000ml saturation NH is added₄Cl Reaction is quenched in the aqueous solution；Plus suction filtered through kieselguhr, filter cake washs with DCM, and filtrate directly uses saturated common salt water washing, anhydrous Na₂SO₄ Dry, filtering is concentrated under reduced pressure, 139.2g yellow liquids are obtained for compound IV through isolating and purifying.Yield：61.6%.

Compound IV characterize data is：¹H NMR(400MHz,CDCl₃) δ 7.24 (d, J=8.5Hz, 2H), 6.88 (d, J=8.6Hz, 2H), 4.46 (s, 2H), 3.93 (td, J=9.0,1.9Hz, 1H), 3.88-3.74 (m, 6H), 3.69 (td, J =9.1,3.5Hz, 1H), 2.65 (m, 1H), 2.11 (m, 1H), 1.87 (m, 1H)¹³C NMR(101MHz,CDCl₃)δ159.63, 129.52,114.14,104.09,89.31,74.95,73.32,69.29,64.89,55.44,41.97,34.63,0.19。

(7) compound VI preparation (R₂=t-Butyldimethylsilyl)

First, compound IV (139.2g, 413.6mmol), TBAF- produced above is added in 5000ml single port bottle 3H₂O (4-butyl ammonium fluoride trihydrate) (261.3g, 827.2mmol), THF (tetrahydrofuran) (2000ml), is placed at room temperature Stirring, TLC detection 30min., consumption of raw materials is finished.Then, vacuum rotary steam removes THF, is then charged with DCM, is washed with water Wash；Saturated common salt water washing, anhydrous Na₂SO₄Dry, filtering, be concentrated under reduced pressure 110.4g brownish black liquid.

2nd, brownish black liquid (110.4g), the TBSCl (tert-butyl groups obtained by step reaction are added in 5000ml single port bottle Dimethyl chloride silicon) (188.8g, 1.25mol, 3.0eq), Imidazole (imidazoles) (85.2g, 1.25mmol, 3.0eq), DCM (3000ml), is placed in and stirs at room temperature, and TLC detection 30min., consumption of raw materials is finished.Room temperature is maintained to continue to be stirred overnight (48h), TLC detection reactions are finished.It is washed with water；Saturated common salt water washing, anhydrous Na₂SO₄Dry, filtering is concentrated under reduced pressure, obtained 170.8g yellow liquids are compound VI.Two step yields：82.9%.

Compound VI characterize data is：¹H NMR(400MHz,CDCl₃) δ 7.26 (d, J=8.6Hz, 2H), 6.87 (d, J=8.6Hz, 2H), 4.42 (s, 2H), 4.13-4.03 (m, 1H), 3.80 (s, 3H), 3.75-3.47 (m, 4H), 2.73 (qd, J=5.6,2.5Hz, 1H), 2.05 (d, J=2.5Hz, 1H), 2.03-1.93 (m, 1H), 1.88-1.84 (m, 1H), 0.90 (s,9H),0.88(s,9H),0.06(m,12H)。

(8) compound VII preparation

Compound VI (170.8g, 346.8mmol), DCM obtained by step reaction on being added in 2000ml single port bottle (1200ml)、H₂O (300ml), is placed in 0 DEG C of cryostat, and stirs, be then charged with DDQ (dichloro dicyan 1,4-benzoquinone) (93.4g, 416.4mmol), maintains 0 DEG C of stirring, and TLC tracking reaction 100min. consumption of raw materialss are finished, and are charged with 800ml Reaction is quenched in saturated sodium bicarbonate aqueous solution, stands a point liquid, adds saturation NaHSO₃, suction filtration removes anisaldehyde, nothing after stirring Machine is added to DCM extractions, merges organic phase saturated common salt water washing, anhydrous Na₂SO₄Dry, filtering is concentrated under reduced pressure to give 110.2g light yellow liquids are compound VII.Yield：85.1%.

Compound VII characterize data is：¹H NMR(400MHz,CDCl₃) δ 4.13 (td, J=6.5,4.0Hz, 1H), 3.88-3.62 (m, 4H), 2.80 (td, J=7.7,2.4Hz, 1H), 2.07 (d, J=2.4Hz, 1H), 2.06-1.94 (m, 2H), 1.88-1.82(m,1H),0.92(s,9H),0.90(s,9H),0.13–0.05(m,12H)。

(9) compound VIII preparation

Compound VII (178.8g, 480.0mmol), DCM (1800ml) are added in 5000ml there-necked flask and is placed in -5 DEG C Cryostat, in stir, be then charged with TEMPO (2,2,6,6- tetramethyl piperidine oxides) (960mg, 5.76mmol), TBAB (TBAB) (1.92g, 5.76mmol)；After system maintains -5 DEG C of stabilizations, sodium hypochlorite is diluted with 960ml water (612g, 13% Active Chlorine) and adding sodium acid carbonate makes it be in saturated solution, by the saturated solution toward dropwise addition in reaction system, 10min completion of dropping.- 5 DEG C are maintained to continue to stir, TLC monitoring reactions, 30min, consumption of raw materials is finished.Stand a point liquid, organic phase Add water washing, saturated common salt water washing, anhydrous Na₂SO₄Dry, filter, concentration, through isolating and purifying, to obtain 156.3g light yellow Liquid is compound VIII.Yield：88.0%.

Compound VIII characterize data is：¹H NMR(400MHz,CDCl₃) δ 9.86 (t, J=2.3Hz, 1H), 4.45 (td, J=6.3,4.4Hz, 1H), 3.76 (dd, J=10.1,4.9Hz, 1H), 3.63 (dd, J=10.1,7.0Hz, 1H), 2.83-2.76 (m, 2H), 2.64 (ddd, J=16.2,4.3,2.0Hz, 1H), 2.10 (d, J=2.5Hz, 1H), 1.03-0.77 (m, 18H), 0.09 (d, J=17.3Hz, 12H).

(10) compound IX preparation

Under argon gas protection, Ni (COD) is added in 2000ml two-mouth bottle₂(double (1,5- cyclo-octadiene) nickel) (1003.4mg, 3.51mmol), THF (12000ml, under argon gas protection) and PBu₃(tributylphosphine) (1.42g, 7.0mmol), room Temperature stirring 5min；Then ZnEt is added₂(diethyl zinc) (176ml, 2M toluene solution, 35.08mol) is placed at 0 DEG C and stirred, then Compound VIII (130g, 350.8mmol) and THF (500ml) obtained by previous step is added, stirred at 0 DEG C, TLC monitoring, raw material After being exhausted, 200ml saturated aqueous ammonium chlorides are slowly added to thereto reaction is quenched, addition 100g diatomite is mixed sample and taken out Filter, vacuum rotary steam removes THF, adds 1000ml EA (ethyl acetate), water washing, saturated common salt water washing, anhydrous sodium sulfate Dry, filter, be concentrated in vacuo, obtain 94.2g white solids for compound IX.Yield：72.5%.

Compound IX characterize data is：¹H NMR(400MHz,CDCl₃)δ5.39(s,1H),5.12(s,1H), 4.38-4.29 (m, 2H), 3.56 (dd, J=10.0,5.2Hz, 1H), 3.29 (dd, J=10.0,8.8Hz, 1H), 2.96 (dd, J =10.4Hz, 1H), 2.78-2.73 (m, 1H), 1.97 (ddd, J=13.6,5.6,4.4Hz, 1H), 1.83 (dq, J=13.6, 2.4Hz,1H),0.88(s,9H),0.87(s,9H),0.09(m,12H).；¹³C NMR(101MHz,CDCl₃)δ154.46, 153.76,111.91,110.06,76.85,75.72,75.60,74.16,72.80,64.84,64.43,55.11,54.09, 44.01,42.18,26.06,25.95,18.49,18.46,18.13,18.07,-4.40,-4.59,-4.63,-4.69,- 5.29,-5.34,-5.38。

(11) compound X preparation

Argon gas protection under, in 2000ml two-mouth bottle add previous step obtained by compound IX (95.0g, 255.0mmol), DCM (500ml), DMSO (dimethyl sulfoxide (DMSO)) (500ml) are placed at 0 DEG C and stirred, and are subsequently added into IBX (2- iodosobenzoic acids) (39.27g, 140.3mmol), 15min is added, and is then raised to and 2h. is stirred at room temperature, and consumption of raw materials is finished.Suction filtration removes solid, plus Enter 800ml DCM, water washing, saturated sodium bicarbonate aqueous solution washing, saturated common salt water washing, anhydrous Na₂SO₄Dry, filtering, Vacuum concentration obtains 91.8g yellow liquids for compound X.Yield：97.1%.

(12) compound XI preparation

Under argon gas protection, added into 2000ml two-mouth bottle previous step gained compound X (91.8g, 247.6mmol), Anhydrous THF (800ml), be subsequently placed in -40 DEG C of cryostat, stir, after system maintain -40 DEG C of stabilizations after, into system dropwise addition Lithium triethylborohydride (272.2ml, 1M tetrahydrofuran solution, 272.2mmol), 30min. completion of dropping, TLC monitoring, 15min. consumption of raw materialss are finished.20ml water quenchings are slowly added dropwise into system to go out reaction, the 1M NaOH aqueous solution is subsequently added into (150ml), 30%H₂O₂(56ml) stirs 30min., then adds 500ml 10%Na₂S₂O₃The aqueous solution is washed, and adds 30g silicon Diatomaceous earth suction filtration, 500ml EA washing filter cakes, stands a point liquid, and saturated aqueous ammonium chloride washing, saturated common salt water washing is anhydrous Sodium sulphate is dried, filtering, and vacuum concentration obtains 75.7g light yellow solids for compound XI.Yield：82.0%.

Compound IX characterize data is：¹H NMR(400MHz,CDCl₃)δ5.39(s,1H),5.12(s,1H), 4.38-4.29 (m, 2H), 3.56 (dd, J=10.0,5.2Hz, 1H), 3.29 (dd, J=10.0,8.8Hz, 1H), 2.96 (dd, J =10.4Hz, 1H), 2.78-2.73 (m, 1H), 20.2-1.95 (m, 1H), 1.83 (dd, J=13.6,1.6Hz, 1H), 0.88 (s,9H),0.87(s,9H),0.09(m,12H).；¹³C NMR(101MHz,CDCl₃)δ154.46,153.76,111.91, 110.06,76.85,75.72,75.60,74.16,72.80,64.84,64.43,55.11,54.09,44.01,42.18, 26.06,25.95,18.49,18.46,18.13,18.07,-4.40,-4.59,-4.63,-4.69,-5.29,-5.34,- 5.38。

(13) compound XIII preparation (R₄=benzyl)

Under the protection of Ar gas, by compound XI (75.7g, 203.1mmol) obtained by previous step, 6- benzyl guanines (are changed Compound XII) (58.8g, 243.7mmol, 1.2 equivalent) and triphenylphosphine (106.4g, 406.2mmol, 2 equivalent) addition 2000ml Two mouthfuls of bottles in, vacuumize and change Ar gas shieldeds, inject the anhydrous THF of 1200ml with syringe, the low temperature that reactant is put into 0 DEG C is anti- Answer in device, when question response thing is down to 0 DEG C, with syringe by DIAD (diisopropyl azodiformate) (82.1g, 406.2mol, 2eq) it is slowly added dropwise into reactor, maintains 0 DEG C of 1h, be then placed within and 24h is stirred at room temperature.TLC display reactions are complete.Add Reaction, plus EA extractions is quenched in saturated aqueous common salt, with anhydrous sodium sulfate drying, is concentrated under reduced pressure, through isolating and purifying to obtain the colourless liquid of 75.9g Body is compound XIII.Yield：62.1%.

Compound XIII characterize data is：¹H NMR(400MHz,CDCl₃) δ 7.66 (s, 1H), 7.51 (d, J= 7.0Hz, 2H), 7.40-7.28 (m, 3H), 5.57 (s, 2H), 5.52 (t, J=8.4Hz, 1H), 5.17 (s, 1H), 4.89 (s, 2H), 4.84 (d, J=2.1Hz, 1H), 4.43 (dd, J=7.6,3.6Hz, 1H), 3.84-3.72 (m, 2H), 2.66 (s, 1H), 2.30-2.24(m,1H),2.20–2.14(m,1H),0.92(s,9H),0.90(s,9H),0.15–-0.00(m,12H).¹³C NMR(101MHz,CDCl₃)δ161.09,159.12,154.36,149.35,138.91,136.64,128.49,128.45, 128.08,115.72,111.32,72.41,68.13,64.11,56.01,54.86,40.58,26.13,26.06,25.98, 18.57,18.19,-4.46,-4.58,-5.24,-5.30。

(14) preparation of compound I Entecavirs

Compound XIII (75.9g, 127.3mmol) obtained by previous step is added into THF-MeOH (800ml, tetrahydrofuran/first The v/v=1 of alcohol:1) in mixed solution, 4N HCl/water solution (260ml) is instilled, 5h, TLC display reactions are stirred at 55 DEG C It is complete.THF and MeOH is removed under reduced pressure, is washed with DCM, point liquid, aqueous phase is under agitation with 2N NaOH regulation PH=7.0, suction filtration, Solid is washed with water and cold EA, with water recrystallization dry 28.3g white solids, as Entecavir.Yield：75.3%.

The characterize data of the Entecavir is：¹H NMR(400MHz,DMSO)δ10.61(s,1H),7.67(s,1H), 6.44 (s, 2H), 5.36 (dd, J=10.2,8.0Hz, 1H), 5.10 (s, 1H), 4.89 (d, J=3.0Hz, 1H), 4.85 (t, J =5.3Hz, 1H), 4.56 (s, 1H), 4.23 (s, 1H), 3.53 (t, J=5.9Hz, 2H), 2.53-2.46 (m, 1H), 2.22 (td, J=12.3,4.5Hz, 1H), 2.04 (dd, J=12.4,7.8Hz, 1H)¹³C NMR(101MHz,DMSO)δ156.94, 153.56,151.52,151.32,136.10,116.25,109.35,70.43,63.08,55.19,54.13。

Embodiment 3

The preparation method of the present embodiment is essentially identical with preparation method in embodiment 1, and difference is：

In step (10), compound IX preparation method is as follows：

Under argon gas protection, SmI is added in 2000ml two-mouth bottle₂(samarium diodide) (812ml, 0.1M tetrahydrofuran are molten Liquid, 81.2mmol) it is placed in -40 DEG C of cryostat, and stirs；Added in another 25ml two-mouth bottle protected with argon gas Compound (VIII) (7.5g, 20.3mmol), anhydrous tertiary butanol (4.5g, 60.8mmol), anhydrous THF obtained by previous step (50ml), is placed in -40 DEG C of cryostat, and stirs, and after system maintains -40 DEG C of stabilizations, is added dropwise to above-mentioned -40 DEG C In reaction system, 5min. completion of dropping.TLC tracking reactions, 15min. consumption of raw materialss are finished.It is charged with saturated ammonium chloride Reaction is quenched in the aqueous solution, and is charged with EA, stands a point liquid, inorganic phase is extracted with EA, merges organic phase saturated aqueous common salt Washing, anhydrous Na₂SO₄Dry, filtering, be concentrated under reduced pressure to give 5.32g white solids for compound (IX).Yield：70.9%.

Embodiment 4

The preparation method of the present embodiment is essentially identical with preparation method in embodiment 1, and difference is：

In step (10), compound IX preparation method is as follows：

Under argon gas protection, metallic sodium (1.55g, 67.45mmol) is added in 100ml liquefied ammonia under being stirred at -50 DEG C, used 50ml anhydrous THF diluted compounds VIII (5.00g, 13.49mmol) is added among reaction system, stirs 15min.；So Room temperature is placed afterwards after liquefied ammonia all volatilizees and finished.Add 50ml saturated aqueous ammonium chlorides and reaction is quenched, add 100ml's EA, saturated common salt water washing (3 × 50ml), anhydrous Na₂SO₄Dry, filter, concentration isolates and purifies and obtains 3.08g yellow liquids For compound (IX).Yield：61.3%.

Embodiment 5

The preparation method of the present embodiment is essentially identical with preparation method in embodiment 1, and difference is：

In step (10), compound IX preparation method is as follows：

Under Ar protections, compound VIII substrates (2.95g, 7.95mmol) are added in 250ml flask, are added 80ml DMF dissolve, and are then separately added into chromium dichloride (4.39g, 35.7mmol) again, Nickel Chloride (258mg, 1.99mmol, 0.25eq) with triphenylphosphine (1.04g, 3.98mmol, 0.5eq), it is subsequently placed in and stirs at room temperature, to reaction system after 10min In be slowly added into H₂O (570mg, 31.8mmol), is then stirred at room temperature 4h.TLC detection reactions, display reaction is complete. EA (150ml) is added, 300ml H are then slowly added into₂O, uses H₂O, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, plus Pressure concentration, isolate and purify 2.1g pale yellow oily liquids be compound (IX), yield about 70.5%.

Embodiment described above only expresses the several embodiments of the present invention, and it describes more specific and detailed, but simultaneously Therefore the limitation to the scope of the claims of the present invention can not be interpreted as.It should be pointed out that for one of ordinary skill in the art For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the guarantor of the present invention Protect scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.

Claims (8)

1. a kind of synthetic method of Entecavir, it is characterised in that comprise the following steps：

(1) by one of hydroxyl of Formula X IV compound 1,3- propane diols with hydroxyl protecting group R₁Protection, production XV compounds；

(2) hydroxyl in Formula X V compounds and oxidant reaction are into aldehyde, production XVI compounds；

(3) Formula X VI compounds generate α, the Formula X VII compounds of beta-unsaturated esters with horner-emmons reagent reactings；

(4) Formula X VII compounds obtain Formula II compound through reducing agent reduction；

(5) Formula II compound is in the presence of titanium compound and chiral esters part, and it is not right to be carried out in the presence of oxidant Claim oxidation reaction, production III compounds；

(6) formula III compound carries out ring-opening reaction, production IV compounds, the Ring Opening Reagent in the presence of Ring Opening Reagent For：Lithium alkylide and R₃Replaced acetylene and dimethylaluminum chloride, or the Ring Opening Reagent is：Lithium alkylide and R₃Replaced acetylene with And diethyl aluminum chloride；

(7) by the hydroxyl of formula IV compound with protection group R₂Protection, and slough protection group R₃Production VI compounds；

(8) Formula IV compound sloughs R₁Hydroxyl protecting group production VII compounds；

(9) Formula VII compound is aoxidized, and makes to slough R₁Hydroxyl be oxidized to aldehyde, production VIII compounds；

(10) ring closure reaction, production IX compounds occur in the presence of cyclization reagent for Formula VIII compound；

The cyclization reagent is Ni (COD)₂, PBu₃With Zn (Et)₂；Or SmI₂；Or Na and naphthalene；Or Li and naphthalene；Or Na and NH₃；Or Li and NH₃；Or CrCl₂, NiCl₂And PPh₃；

(11) Formula IX compound is aoxidized to production X compounds in the presence of oxidant；

(12) Formula X compound is reduced to production XI compounds in the presence of reducing agent；

(13) Formula X I and Formula X II compounds are subjected to condensation reaction, production XIII under mitsunobu reaction conditions Compound；

(14) Formula X III compounds slough protection group R under the action of an acid₂And R₄, production I Entecavir；

Reaction scheme is as follows：

Wherein：R₁, R₂For hydroxyl protecting group, and R₂R is sloughed for that can be resistant to₁Hydroxyl protecting group；

R₃For trimethyl silicon substrate or triethyl group silicon substrate；

R₄For hydrogen, C1-C6 alkyl, the not substitution of C1-C6 alkyl or substituted benzyl.

2. the synthetic method of Entecavir according to claim 1, it is characterised in that in step (5), the titanium class chemical combination Thing is selected from：Titanium tetrachloride or tetraisopropyl titanate；The hand-type esters part is selected from：L- (+)-ethyl tartrate or L- (+)- Tartaric acid diisopropyl ester；The oxidant is selected from：TBHP or isopropyl benzene hydroperoxide, reaction temperature is：0~- 50℃。

3. the synthetic method of Entecavir according to claim 1, it is characterised in that in step (6), lithium alkylide is selected from： Lithium methide, n-BuLi, tert-butyl lithium；Reaction condition is：0~-50 DEG C.

4. the synthetic method of Entecavir according to claim 1, it is characterised in that in step (10), reaction temperature is： 0~-50 DEG C.

5. the synthetic method of Entecavir according to claim 1, it is characterised in that in step (7), first exists in alkali Under the conditions of, by the hydroxyl of formula IV compound with protection group R₂Protection, obtains Formula V compound, then with fluoride or alkali at 0-40 DEG C Under the conditions of react, slough the protection group R in Formula V compound₃Production VI compounds；

Or first reacted with fluoride or alkali under the conditions of 0-40 DEG C, slough the protection group R in formula IV compound₃, obtain Formula V ' change Compound, then in the presence of a base by Formula V ' compound hydroxyl with protection group R₂Protection, production VI compounds；

6. the synthetic method of Entecavir according to claim 1, it is characterised in that described in step (13) Mitsunobu reaction conditions are：In the presence of triphenylphosphine and aliphatic azo compound, in 0~40 DEG C of reaction.

7. the synthetic method of Entecavir according to claim 1, it is characterised in that in step (3), the horner- Emmons reagents are selected from：Triethyl phosphonoacetate, or phosphonoacetic acid trimethyl；The step reaction temperature is 0-40 DEG C.

8. the synthetic method of Entecavir according to claim 1, it is characterised in that

In step (2), the oxidant is selected from：Sodium hypochlorite, pyridinium chloro-chromate, Pyridinium dichromate, dimethyl sulfoxide, 2- iodoxies Yl benzoic acid, or Dai Si-Martin's oxidant, reaction temperature is：- 10~40 DEG C；

In step (4), the reducing agent is selected from：Diisobutyl aluminium hydride, or lithium aluminium hydride reduction and alchlor, reaction temperature For：0~-50 DEG C；

In step (9), at -10~40 DEG C, using sodium hypochlorite, pyridinium chloro-chromate, Pyridinium dichromate, dimethyl sulfoxide, 2- Iodosobenzoic acid, or Dai Si-Martin's oxidant are aoxidized；

In step (11), at -10~40 DEG C, using 2- iodosobenzoic acids, pyridinium chloro-chromate, sodium hypochlorite, dichromic acid Pyridine, dimethyl sulfoxide, or Dai Si-Martin's oxidant are aoxidized；

In step (12), at -50~0 DEG C, reduced using lithium triethylborohydride, or sodium borohydride and cerous chloride；

In step (14), at 20~80 DEG C, using hydrochloric acid, protection group R is sloughed₂And R₄。