CN105524064A - Method for synthesizing Entecavir - Google Patents

Method for synthesizing Entecavir Download PDF

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CN105524064A
CN105524064A CN201410522567.5A CN201410522567A CN105524064A CN 105524064 A CN105524064 A CN 105524064A CN 201410522567 A CN201410522567 A CN 201410522567A CN 105524064 A CN105524064 A CN 105524064A
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compound
formula
reaction
protecting group
production
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CN105524064B (en
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张健存
姚国强
叶康志
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Guangzhou Institute of Biomedicine and Health of CAS
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Guangzhou Institute of Biomedicine and Health of CAS
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a method for synthesizing Entecavir and belongs to the technical field of medicine synthesis methods. According to the method, Entecavir is synthesized through taking 1,3-propanediol as a starting raw material, carrying out oxidation so as to form an aldehyde, then, producing an unsaturated ester, and then, carrying out reactions such as reduction, asymmetric epoxidation, ring opening, silane protecting group removing, hydroxyl protection, deprotection, oxidation, ring closing, oxidation, reduction, condensation and deprotection. According to the method, the used raw material is cheap and readily available, and the reaction conditions are mild and are easy in control, so that the industrial production is facilitated.

Description

The synthetic method of Entecavir
Technical field
The present invention relates to a kind of synthetic method of medicine, particularly relate to a kind of synthetic method of Entecavir.
Background technology
Entecavir is a kind of guanosine-analogue, is used for the treatment of hepatitis B.It is developed by Bristol-Myers Squibb Co. of the U.S., ratifies listing in March, 2005 by FDA.Entecavir has extremely strong suppression hepatitis B replication, reduces the effect of serum-virus DNA level, still effective to the mutated viruses strain of resistance to lamivudine, and has no obvious untoward reaction and mitochondrial toxicity.Compared with other similar medicines, Entecavir is the active drug of the higher treatment hepatitis B of a kind of security.
At present about the synthetic method of Entecavir has a lot, the disclosed following synthetic route of such as Shi Guibao company:
But there is starting raw material in above-mentioned synthetic method to be not easy to obtain, the defect that cost is high.
Investigator is also had to provide following Entecavir synthesis technique:
But in above-mentioned synthetic method, the 2nd step reaction conditions requires harsh, need the low temperature of less than-70 DEG C and strictly anhydrous, industrialization difficulty is higher.
For the synthetic method of Entecavir, investigators have carried out large quantifier elimination, obtain different synthetic methods, but synthetic method disclosed at present all exists, and starting raw material is not easy to obtain, partial reaction conditional request harsh, high in cost of production number of drawbacks, industrialization difficulty is all higher.
Summary of the invention
Based on this, the problems such as, raw material high for operational path cost in the suitability for industrialized production of current Entecavir is rare, partial reaction conditional request is harsh, the object of the invention is to the defect overcoming prior art, there is provided a kind of synthetic method of Entecavir, the method has the advantages such as cost is low, reaction conditions is gentle, synthetic route is brief.
For achieving the above object, the present invention takes following technical scheme:
A synthetic method for Entecavir, comprises the following steps:
(1) by one of them hydroxyl of formula XIV compound 1,3-PD with hydroxyl protecting group R 1protection, production XV compound;
(2) hydroxyl in formula XV compound becomes aldehyde with oxidant reaction, production XVI compound;
(3) formula XVI compound and horner-emmons reagent react generate the formula XVII compound of alpha, beta-unsaturated esters;
(4) formula XVII compound obtains formula II compound through reductive agent reduction;
(5) formula II compound is under the existence of titanium compound and chiral ester class part, under the effect of oxygenant, carry out asymmetric oxidation reaction, generates formula III compound;
(6) formula III compound carries out ring-opening reaction under the effect of Ring Opening Reagent, production IV compound, and described Ring Opening Reagent comprises: lithium alkylide and alkyl silicon ether protecting group R 3replaced acetylene; Or alkyl silicon ether protecting group R 3the grignard reagent of replaced acetylene;
(7) by the hydroxyl of formula IV compound with protecting group R 2protection, and slough silicon ether protecting group R 3production VI compound;
(8) formula VI compound sloughs R 1hydroxyl protecting group production VII compound;
(9) formula VII compound is oxidized, and makes to slough R 1hydroxyl oxidize be aldehyde, production VIII compound;
(10) there is ring closure reaction, production IX compound in formula VIII compound under the effect of closing cyclization reagent;
(11) formula IX compound is oxidized production X compound under the effect of oxygenant;
(12) formula X compound is reduced under the effect of reductive agent production XI compound;
(13) formula XI compound and formula XII compound are carried out condensation reaction, production XIII compound under mitsunobu reaction conditions or substitution reaction condition;
(14) formula XIII compound sloughs protecting group R under the action of an acid 2and R 4, the Entecavir of production I;
Reaction scheme is as follows:
Wherein: R 1, R 2for hydroxyl protecting group, and R 2r is sloughed for tolerating 1hydroxyl protecting group;
R 3for alkyl silicon ether protecting group;
R 4for hydrogen, C1-C6 alkyl, C1-C6 alkyl replaces or substituted aryl, C1-C6 alkyl do not replace or not substituted benzyl.
In this reaction scheme, Compound II per obtains compound III by asymmetric Epoxidation, then with alkynes under the effect of alkyl lithium reagents, alkynes obtains compound IV from 2 carbon open loop oxygen, then uses R 2two hydroxyls are protected, and sloughs R 3obtain compound VI, be that aldehyde obtains compound VI II subsequently by the hydroxyl oxidize of compound VI I, make aldehyde radical and alkynyl effect, Guan Huan obtains Compound I X, reoxidizing hydroxyl is that carbonyl obtains compounds X, asymmetric reduction obtains compounds X I, then obtains compounds X III with compounds X II coupling, finally sloughs R under the action of an acid 2and R 4, obtain Compound I.
Wherein in an embodiment, in step (5), described titanium compound is selected from: titanium tetrachloride or titanium isopropylate; Described hand-type ester class part is selected from: L-(+)-diethyl tartrate or L-(+)-tartrate diisopropyl ester; Described oxygenant is selected from: tertbutyl peroxide or isopropyl benzene hydroperoxide, and temperature of reaction is: 0 ~-50 DEG C, preferably-20 ~-40 DEG C.The reaction of this step also can be carried out under Vo (acac) 2, shi and Jacobson asymmetric Epoxidation condition.
Wherein in an embodiment, in step (6), R 3be selected from: trimethyl silicon based, triethyl is silica-based; Lithium alkylide is selected from: lithium methide, n-Butyl Lithium, tert-butyl lithium; Reaction conditions is: 0 ~-50 DEG C, preferably 0 ~-30 DEG C.
Wherein in an embodiment, in step (6), described Ring Opening Reagent also comprises dimethylaluminum chloride or diethyl aluminum chloride.This dimethylaluminum chloride or diethyl aluminum chloride can generate alkynyl aurin tricarboxylic acid with alkynes, and after aluminium and the complexing of alcohol negative oxygen ion, alkynyl is more prone to from 2 carbon open loop oxygen, thus can assist the regioselectivity improving open loop.
Wherein in an embodiment, in step (10), described pass cyclization reagent is Ni (COD) 2, PBu 3with Zn (Et) 2; Or SmI 2; Or Na and naphthalene; Or Li and naphthalene; Or Na and NH 3; Or Li and NH 3; Or CrCl 2, NiCl 2and PPh 3, temperature of reaction is: 0 ~-50 DEG C, preferably 0 ~-10 DEG C.
Wherein in an embodiment, in step (7), first in the presence of a base, by the hydroxyl of formula IV compound with protecting group R 2protection, obtains formula V compound, then reacts under 0-40 DEG C of condition with fluorochemical or alkali, slough the alkyl silicon ether protecting group R on formula V compound 3production VI compound;
Or first react under 0-40 DEG C of condition with fluorochemical or alkali, slough the silicon ether protecting group R on formula IV compound 3, obtain formula V ' compound, more in the presence of a base by the hydroxyl of formula V ' compound with protecting group R 2protection, production VI compound;
Wherein in an embodiment, R 1, R 2, R 4independently be selected from: benzyl, C1-C6 alkyl or alkoxyl group substituted benzyl, trityl, trialkyl silyl or tert-butyl diphenyl are silica-based.Consider R 2r is sloughed for tolerating 1hydroxyl protecting group, then one skilled in the art will appreciate that as R 1for alkoxyl group substituted benzyl, then R 2for benzyl, trityl or replacement trityl, trialkyl silyl or tert-butyl diphenyl are silica-based; As R 1for trialkyl silyl, then R 2for tert-butyl diphenyl is silica-based, benzyl, C1-C6 alkyl or alkoxyl group substituted benzyl, trityl or replace trityl, tert-butyl diphenyl is silica-based, as R 1for trialkyl silyl or tert-butyl diphenyl silica-based, then R 2for benzyl, C1-C6 alkyl or alkoxyl group substituted benzyl, trityl or replacement trityl, as R 1for trityl or replacement trityl, then R 2for benzyl, C1-C6 alkyl or alkoxyl group substituted benzyl.
Wherein in an embodiment, work as R 1for to methoxy-benzyl, R 2during for t-Butyldimethylsilyl, in step (8), use dichloro dicyan para benzoquinone, or ceric ammonium nitrate, at 0-40 DEG C, react under preferred 0-25 DEG C condition, slough R 1hydroxyl protecting group.
Wherein in an embodiment, in step (13), described mitsunobu (light prolongs reaction) reaction conditions is: under the effect of triphenylphosphine and aliphatic azo compound (DEAD), in 0 ~ 40 DEG C of reaction, preferably 0 ~ 25 DEG C.Described aliphatic azo compound (DEAD) is azo Ue-5908 or azo two diisopropyl carbonate preferably.
Wherein in an embodiment, in step (3), described horner-emmons reagent is selected from: triethyl phosphonoacetate, or phosphonoacetic acid trimethyl; This step temperature of reaction is 0 ~ 40 DEG C, preferably 0 ~ 25 DEG C.
Wherein in an embodiment, in step (2), described oxygenant is selected from: clorox, pyridinium chloro-chromate, Pyridinium dichromate, methyl-sulphoxide, 2-iodosobenzoic acid, or Dai Si-Martin's oxygenant, temperature of reaction is :-10 ~ 40 DEG C, preferably 0 ~ 25 DEG C;
In step (4), described reductive agent is selected from: diisobutyl aluminum hydrogen (DIBAL-H), or lithium aluminum hydride and aluminum chloride, and temperature of reaction is: 0 ~-50 DEG C, preferably 0 ~-20 DEG C.
In step (9), at-10 ~ 40 DEG C, at preferred 0-25 DEG C, adopt clorox, pyridinium chloro-chromate, Pyridinium dichromate, methyl-sulphoxide, 2-iodosobenzoic acid, or Dai Si-Martin's oxygenant (Dess-Martin reagent) is oxidized;
In step (11), at-10 ~ 40 DEG C, at preferred 0-25 DEG C, adopt 2-iodosobenzoic acid, pyridinium chloro-chromate, clorox, Pyridinium dichromate, methyl-sulphoxide, or Dai Si-Martin's oxygenant (Dess-Martin reagent) is oxidized;
In step (12), at-50 ~ 0 DEG C, preferably at-20 ~-40 DEG C, adopt lithium triethylborohydride, or cerous compounds and sodium borohydride reduce;
In step (14), at 20 ~ 80 DEG C, adopt hydrochloric acid, slough protecting group R 2and R 4.
Wherein in an embodiment, the Entecavir generated in step (14) is purified by recrystallization, and the method for this recrystallization is: use water as solvent and carry out recrystallization.
Compared with prior art, the present invention has following beneficial effect:
The invention discloses a kind of synthetic method of Entecavir; the method is with 1; ammediol is starting raw material; unsaturated ester is generated after being oxidized to aldehyde; restore into vinyl carbinol, the Entecavir through Reactive Synthesis such as asymmetric Epoxidation, open loop, desiliconization alkane protecting group, hydroxyl protection, deprotection, oxidation, Guan Huan, oxidation, reduction, condensation, deprotections.
In this synthetic method, raw materials used 1,3-PD is cheap and easy to get, and as large batch of volume production, its cost also will reduce.
And contriver also to respond and be optimized, obtain and can complete at ambient pressure, and without the need to the mild reaction conditions of the extreme conditions such as high temperature, there is the feature of gentle easily control, be easy to suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but these embodiments should as limitation of the scope of the invention.
Embodiment 1
A synthetic method for Entecavir, comprises the following steps:
(1) preparation of compounds X V
1 is added in temperature control, churned mechanically 20L reactor, ammediol (1457.6g, 19.15mol), DMF (dimethyl formamide) (5L), DCM (methylene dichloride) (1L), then mechanical stirring is when system is lower than 10 DEG C, 60%NaH (281g is slowly added in still, 7.024mol), about 2h, control reactor temperature not higher than 15 DEG C, 70min. adds, and maintains temperature in the kettle and continues to stir 30min. lower than 10 DEG C; Then add TBAI (tetrabutylammonium iodide) (23.6g, 0.064mol), 15min adds; Dilute PMBCl (to mehtoxybenzyl) (1000g, 6.385mol) with the DCM of 1.5L, slowly drip in still, 4h.Dropwise; Then system is risen to stirred overnight at room temperature .TLC display raw material consumption complete.Then, system is cooled to less than 10 DEG C, in reaction system, slowly adds the water of 10L, then add the DCM of 2L, stir 15min, leave standstill separatory, organic phase washed with water, saturated common salt water washing, anhydrous Na 2sO 4drying, obtains 1085g yellow liquid after concentrating under reduced pressure, productive rate 86.6%. 1HNMR(400MHz,CDCl 3)δ7.24(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) preparation of compounds X VI
Compounds X V (500g is added in band temperature control and churned mechanically 20L reactor, 2.5mol), TEMPO (2,2,6,6-tetramethyl piperidine oxide compound) (3.98g, 25.479mmol), TBAB (Tetrabutyl amonium bromide) (7.5g), saturated NaHCO 3the aqueous solution (2000ml), DCM (4000ml), violent stirring at being placed in-5 DEG C; Then slowly join in reaction system with 4000ml water dilution clorox (2.36kg, the reactive chlorine of 13%), keep being stabilized in less than 5 DEG C, about 2h dropwises.Maintain 5 DEG C to continue to stir, TLC follows the tracks of 1h again, and raw material consumption is complete.After raw material consumption, leave standstill separatory, aqueous phase DCM washes, and merges organic phase, successively with the HCl of 10%, hypo solution, the H of 10% that are dissolved with KI 2o, saturated common salt water washing washing, anhydrous Na 2sO 4drying, filter, concentrating under reduced pressure obtains 414g tawny liquid, yield: 83.7%. 1HNMR(400MHz,CDCl 3)δ9.78(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) preparation of compounds X VII
In 20L reactor, add NaH (93g, 60% content, 2.3mol), THF (4000ml, AR), stir at 0 DEG C, then in system, slowly add triethyl phosphonoacetate (519g, 2.3mol), stir 30min.; Then use the THF diluted compounds XVI (500g, 2.6mol) of 5000ml to drip in system, 50min. dropwises, and then rises to stirring at room temperature 1h. raw material consumption complete.Add 500ml saturated aqueous ammonium chloride cancellation reaction, removing THF, then toward wherein adding EA (6000ml), water washing, saturated common salt water washing, anhydrous Na 2sO 4drying, filter, concentrating under reduced pressure, obtains 526g yellow liquid.Yield: 85.9%. 1HNMR(400MHz,CDCl 3)δ7.25(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) preparation of compounds X VIII
Under argon shield, in the there-necked flask of 10L, add compounds X VII (249g, 0.94mol), anhydrous THF (1800ml), the cryostat, being placed in-20 DEG C stirs; After system maintenance-20 DEG C is stable, in system, slowly drip DIBAL-H (1180g, 25%intoluene, 2.07mol), 2.0h. dropwises; Maintain-20 DEG C of stirrings, TLC follows the tracks of 30min., and raw material consumption is complete.After having reacted, add 1000g diatomite, then slowly in system, drip 4000ml saturated aqueous ammonium chloride, suction filtration, filter cake EA washs, and filtrate leaves standstill separatory, and inorganic phase EA extracts, and merges organic phase saturated common salt water washing, anhydrous Na 2sO 4drying, filter, concentrating under reduced pressure obtains 191.2g light yellow liquid, productive rate 91.5%. 1HNMR(400MHz,CDCl 3)δ7.26(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) preparation (R of compound III 1=to methoxy-benzyl)
Under argon shield, add activation in the reactor of 20L after molecular sieve (200g); add in anhydrous DCM (methylene dichloride) (4000ml);-25 DEG C of stirrings; by L-DET (L-(+)-diethyl tartrate) (80g; after 388.4mmol) adding under argon shield, more slowly add Ti (i-PrO) 4(titanium isopropylate) (88g, 310.8mmol), stir 30min, then by t-BuOOH (tertbutyl peroxide) (1.13L, 4.6Mintoluene, 5.18mol) slowly add, stir 30min again, Compound II per (575.2g, 2.59mol) is dissolved in anhydrous DCM (1100ml), slowly add again in reaction solution, stir at-25 DEG C and spend the night.It is complete that TLC observes raw material consumption, slowly adds monohydrate potassium (600g) and FeSO in system 47H 2the aqueous solution (6000ml) the cancellation reaction of O (790g); Then add suction filtered through kieselguhr, filter cake DCM washs, and filtrate leaves standstill separatory, and inorganic phase DCM extracts; Merge the NaOH aqueous solution (1200ml) that organic phase adds 30% at 0 DEG C, stir 10min.; Filtrate leaves standstill separatory, organic phase saturated common salt water washing, anhydrous Na 2sO 4drying, filter, concentrating under reduced pressure, obtaining 587.6g yellow liquid is compound III.Productive rate: 95.3%.
The characterization data of this compound III is: 1hNMR (400MHz, CDCl 3) 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) preparation (R of compound IV 3=trimethyl silicon based)
Under argon shield, trimethylsilyl acetylene (380ml is added in the reactor of 20L, 2.68mol), anhydrous DCM (5000ml), stirs at 0 DEG C, toward wherein adding n-BuLi (n-Butyl Lithium) (1120ml, 2.4Minhexanes, 2.68mol), 100min dropwises, and stirs 30min; Again toward wherein adding Et 2alCl (2688ml, 1M, 2.68mol), 80min dropwises, and continues to stir 30min; Then system is cooled to-30 DEG C of stirrings; above obtained compound III (160g is added in the 5000ml two-mouth bottle of another one with argon shield; 672mmol), anhydrous DCM (800ml); the cryostat, being placed in 0 DEG C stirs; toward wherein adding n-BuLi (308ml; 2.4Minhexanes; 740mmol); 30min dropwises, and stirs 30min, is then added in above-mentioned-30 DEG C of reactors; 10min dropwises; stir 30min, then system is risen to stirred overnight at room temperature (18h.), raw material consumption is complete.Reaction system is cooled to 0 DEG C, adds the saturated NH of 1000ml 4the cancellation of the Cl aqueous solution is reacted; Add suction filtered through kieselguhr, filter cake DCM washs, and filtrate directly uses saturated common salt water washing, anhydrous Na 2sO 4drying, filter, concentrating under reduced pressure, obtaining 139.2g yellow liquid through separation and purification is compound IV.Productive rate: 61.6%.
The characterization data of this compound IV is: 1hNMR (400MHz, CDCl 3) 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). 13cNMR (101MHz, CDCl 3) δ 159.63,129.52,114.14,104.09,89.31,74.95,73.32,69.29,64.89,55.44,41.97,34.63,0.19.
(7) preparation (R of compound VI 2=t-Butyldimethylsilyl)
One, in the single port bottle of 5000ml, above obtained compound IV (139.2g, 413.6mmol), TBAF-3H is added 2o (4-butyl ammonium fluoride trihydrate) (261.3g, 827.2mmol), THF (tetrahydrofuran (THF)) (2000ml), is placed in stirred at ambient temperature, and TLC detects 30min., and raw material consumption is complete.Then, vacuum rotary steam removing THF, then toward wherein adding DCM, washes with water; Saturated common salt water washing, anhydrous Na 2sO 4drying, filters, concentrating under reduced pressure 110.4g brownish black liquid.
Two, in the single port bottle of 5000ml, step reaction gained brownish black liquid (110.4g), TBSCl (tert-butyldimethylsilyl chloride silicon) (188.8g is added, 1.25mol, 3.0eq), Imidazole (imidazoles) (85.2g, 1.25mmol, 3.0eq), DCM (3000ml), be placed in stirred at ambient temperature, TLC detects 30min., and raw material consumption is complete.Maintain room temperature continuation stirring to spend the night (48h), TLC detection reaction is complete.Wash with water; Saturated common salt water washing, anhydrous Na 2sO 4drying, filter, concentrating under reduced pressure, obtaining 170.8g yellow liquid is compound VI.Two step productive rates: 82.9%.
The characterization data of this compound VI is: 1hNMR (400MHz, CDCl 3) 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) preparation of compound VI I
Step reaction gained compound VI (170.8g, 346.8mmol), DCM (1200ml), H is added in the single port bottle of 2000ml 2o (300ml), the cryostat, being placed in 0 DEG C stirs, then toward wherein adding DDQ (dichloro dicyan para benzoquinone) (93.4g, 416.4mmol), maintain 0 DEG C of stirring, it is complete that TLC follows the tracks of reaction 100min. raw material consumption, toward wherein adding 800ml saturated sodium bicarbonate aqueous solution cancellation reaction, leave standstill separatory, then add saturated NaHSO 3, suction filtration removing aubepine after stirring, inorganic phase adds DCM extraction, merges organic phase saturated common salt water washing, anhydrous Na 2sO 4drying, filter, it is compound VI I that concentrating under reduced pressure obtains 110.2g light yellow liquid.Productive rate: 85.1%.
The characterization data of this compound VI I is: 1hNMR (400MHz, CDCl 3) 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) preparation of compound VI II
Compound VI I (178.8g is added in the there-necked flask of 5000ml, 480.0mmol), the cryostat, that DCM (1800ml) is placed in-5 DEG C stirs, then toward wherein adding TEMPO (2,2,6,6-tetramethyl piperidine oxide compound) (960mg, 5.76mmol), TBAB (Tetrabutyl amonium bromide) (1.92g, 5.76mmol); Until system maintain-5 DEG C stable after, add sodium bicarbonate make it be saturated solution with 960ml water dilution clorox (612g, the reactive chlorine of 13%), dripped in reaction system by this saturated solution, 10min dropwises.Maintain-5 DEG C to continue to stir, TLC monitors reaction, 30min, and raw material consumption is complete.Leave standstill separatory, organic phase adds water washing, saturated common salt water washing, anhydrous Na 2sO 4drying, filters, and concentrated, obtaining 156.3g light yellow liquid through separation and purification is compound VI II.Productive rate: 88.0%.
The characterization data of this compound VI II is: 1hNMR (400MHz, CDCl 3) 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) preparation of Compound I X
Under argon shield, in the two-mouth bottle of 2000ml, add Ni (COD) 2(two (1,5-cyclooctadiene) nickel) (1003.4mg, 3.51mmol), THF (12000ml, under argon shield) and PBu 3(tributylphosphine) (1.42g, 7.0mmol), stirring at room temperature 5min, then ZnEt is added 2(zinc ethyl) (176ml, 2M toluene solution, stir at 35.08mol) being placed in 0 DEG C, again by previous step gained compound VI II (130g, 350.8mmol) add with THF (500ml), stir at 0 DEG C, TLC monitors, after raw material consumption, toward wherein slowly adding 200ml saturated aqueous ammonium chloride cancellation reaction, add 100g diatomite and mix sample suction filtration, vacuum rotary steam removing THF, add the EA (ethyl acetate) of 1000ml, water washing, saturated common salt water washing, anhydrous sodium sulfate drying, filter, vacuum concentration, obtaining 94.2g white solid is Compound I X.Productive rate: 72.5%.
The characterization data of this Compound I X is: 1hNMR (400MHz, CDCl 3) δ 5.39 (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).; 13cNMR (101MHz, CDCl 3) δ 154.46,153.76,111.91,110.06,76.85,75.72,75.60,74.16,72.80,64.84,64.43,55.11,54.09,44.01,42.18,26.06,25.95,18.49,18.46,18.13,18.07 ,-4.40 ,-4.59 ,-4.63 ,-4.69 ,-5.29 ,-5.34 ,-5.38.
(11) preparation of compounds X
Under argon shield; previous step gained Compound I X (95.0g is added in the two-mouth bottle of 2000ml; 255.0mmol), stir at DCM (500ml), DMSO (dimethyl sulfoxide (DMSO)) (500ml) are placed in 0 DEG C; then IBX (2-iodosobenzoic acid) (39.27g is added; 140.3mmol); 15min adds, and is then raised to stirring at room temperature 2h., and raw material consumption is complete.Suction filtration removing solid, add 800mlDCM, water washing, saturated sodium bicarbonate aqueous solution washs, saturated common salt water washing, anhydrous Na 2sO 4drying, filter, it is compounds X that vacuum concentration obtains 91.8g yellow liquid.Yield: 97.1%.
(12) preparation of compounds X I
Under argon shield; previous step gained compounds X (91.8g is added in the two-mouth bottle of 2000ml;, 247.6mmol), anhydrous THF (800ml), the cryostat, that is then placed in-40 DEG C stir, until system maintain-40 DEG C stable after; lithium triethylborohydride (272.2ml is dripped in system; 1M tetrahydrofuran solution, 272.2mmol), 30min. dropwises; TLC monitors, and 15min. raw material consumption is complete.In system, slowly drip 20ml shrend to go out reaction, then add the 1MNaOH aqueous solution (150ml), 30%H 2o 2(56ml) stir 30min., then add the 10%Na of 500ml 2s 2o 3solution washing, adds 30g suction filtered through kieselguhr, the EA washing leaching cake of 500ml, leaves standstill separatory, and saturated aqueous ammonium chloride washs, saturated common salt water washing, anhydrous sodium sulfate drying, and filter, it is compounds X I that vacuum concentration obtains 75.7g light yellow solid.Yield: 82.0%.
The characterization data of this Compound I X is: 1hNMR (400MHz, CDCl 3) δ 5.39 (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).; 13cNMR (101MHz, CDCl 3) δ 154.46,153.76,111.91,110.06,76.85,75.72,75.60,74.16,72.80,64.84,64.43,55.11,54.09,44.01,42.18,26.06,25.95,18.49,18.46,18.13,18.07 ,-4.40 ,-4.59 ,-4.63 ,-4.69 ,-5.29 ,-5.34 ,-5.38.
(13) preparation (R of compounds X III 4=benzyl)
Under the protection of Ar gas, by previous step gained compounds X I (75.7g, 203.1mmol), 6-benzyl guanine (compounds X II) (58.8g, 243.7mmol, 1.2 equivalents) and triphenylphosphine (106.4g, 406.2mmol, 2 equivalents) add in two mouthfuls of bottles of 2000ml, vacuumize and change Ar gas shielded, the anhydrous THF of 1200ml is injected with syringe, reactant is put into the low-temp reaction device of 0 DEG C, when question response thing is down to 0 DEG C, with syringe by DIAD (diisopropyl azodiformate) (82.1g, 406.2mol, 2eq) slowly drop in reactor, maintain 0 DEG C of 1h, then stirring at room temperature 24h is placed on.TLC display reaction is complete.Add saturated aqueous common salt cancellation reaction, add EA extraction, with anhydrous sodium sulfate drying, concentrating under reduced pressure, obtaining 75.9g colourless liquid through separation and purification is compounds X III.Productive rate: 62.1%.
The characterization data of this compounds X III is: 1hNMR (400MHz, CDCl 3) 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). 13cNMR (101MHz, CDCl 3) δ 161.09,159.12,154.36,149.35,138.91,136.64,128.49,128.45,128.08,115.72,111.32,72.41,68.13,64.11,56.01,54.86,40.58,26.13,26.06,25.98,18.57,18.19 ,-4.46 ,-4.58 ,-5.24 ,-5.30.
(14) preparation of Compound I Entecavir
By previous step gained compounds X III (75.9g, 127.3mmol) add THF-MeOH (800ml, the v/v=1:1 of tetrahydrofuran (THF)/methyl alcohol) mixing solutions in, the HCl aqueous solution (260ml) of instillation 4N, at 55 DEG C, stir 5h, TLC display reaction is complete.Decompression removing THF and MeOH, washes with DCM, separatory, and aqueous phase under agitation regulates PH=7.0, suction filtration with the NaOH of 2N, and solid water and cold EA wash, and obtains 28.3g white solid, be Entecavir with water recrystallization is dry.Productive rate: 75.3%.
The characterization data of this Entecavir is: 1hNMR (400MHz, DMSO) δ 10.61 (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). 13cNMR (101MHz, DMSO) δ 156.94,153.56,151.52,151.32,136.10,116.25,109.35,70.43,63.08,55.19,54.13.
Embodiment 3
The preparation method of the present embodiment is substantially identical with the preparation method in embodiment 1, and difference is:
In step (10), the preparation method of Compound I X is as follows:
Under argon shield, in the two-mouth bottle of 2000ml, add SmI 2the cryostat, that (samarium diodide) (812ml, 0.1M tetrahydrofuran solution, 81.2mmol) is placed in-40 DEG C stirs; Previous step gained compound (VIII) (7.5g is added in the 25ml two-mouth bottle of another one with argon shield; 20.3mmol), anhydrous tertiary butanol (4.5g; 60.8mmol), anhydrous THF (50ml); the cryostat, being placed in-40 DEG C stirs; after system maintenance-40 DEG C is stable; be added dropwise in the reaction system of above-mentioned-40 DEG C, 5min. dropwises.TLC follows the tracks of reaction, and 15min. raw material consumption is complete.Toward wherein adding saturated aqueous ammonium chloride cancellation reaction, and toward wherein adding EA, leave standstill separatory, inorganic phase EA extracts, and merges organic phase saturated common salt water washing, anhydrous Na 2sO 4drying, filter, it is compound (IX) that concentrating under reduced pressure obtains 5.32g white solid.Productive rate: 70.9%.
Embodiment 4
The preparation method of the present embodiment is substantially identical with the preparation method in embodiment 1, and difference is:
In step (10), the preparation method of Compound I X is as follows:
Under argon shield, sodium Metal 99.5 (1.55g, 67.45mmol) is added in 100ml liquefied ammonia, with the anhydrous THF diluted compounds VIII (5.00g of 50ml under stirring at-50 DEG C, 13.49mmol) join in the middle of reaction system, stir 15min.; Then after placement room temperature treats that liquefied ammonia all volatilizees.Add 50ml saturated aqueous ammonium chloride cancellation reaction, add the EA of 100ml, saturated common salt water washing (3 × 50ml), anhydrous Na 2sO 4drying, filters, and concentrated, it is compound (IX) that separation and purification obtains 3.08g yellow liquid.Productive rate: 61.3%.
Embodiment 5
The preparation method of the present embodiment is substantially identical with the preparation method in embodiment 1, and difference is:
In step (10), the preparation method of Compound I X is as follows:
Under Ar protection, in the flask of a 250ml, add compound VI II substrate (2.95g, 7.95mmol); add 80mlDMF to dissolve; and then add chromium dichloride (4.39g, 35.7mmol) respectively, Nickel Chloride (258mg; 1.99mmol; 0.25eq) with triphenylphosphine (1.04g, 3.98mmol, 0.5eq); then be placed in stirred at ambient temperature, after 10min, in reaction system, slowly add H 2o (570mg, 31.8mmol), then at room temperature stirs 4h.TLC detection reaction, display reaction is complete.Add EA (150ml), then slowly add 300mlH 2o, uses H 2o, saturated nacl aqueous solution wash, anhydrous sodium sulfate drying, and pressurization is concentrated, and it is compound (IX) that separation and purification obtains 2.1g pale yellow oily liquid body, productive rate about 70.5%.
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.

Claims (10)

1. a synthetic method for Entecavir, is characterized in that, comprises the following steps:
(1) by one of them hydroxyl of formula XIV compound 1,3-PD with hydroxyl protecting group R 1protection, production XV compound;
(2) hydroxyl in formula XV compound becomes aldehyde with oxidant reaction, production XVI compound;
(3) formula XVI compound and horner-emmons reagent react generate the formula XVII compound of alpha, beta-unsaturated esters;
(4) formula XVII compound obtains formula II compound through reductive agent reduction;
(5) formula II compound is under the existence of titanium compound and chiral ester class part, under the effect of oxygenant, carry out asymmetric oxidation reaction, generates formula III compound;
(6) formula III compound carries out ring-opening reaction under the effect of Ring Opening Reagent, production IV compound, and described Ring Opening Reagent comprises: lithium alkylide and alkyl silicon ether protecting group R 3replaced acetylene; Or alkyl silicon ether protecting group R 3the grignard reagent of replaced acetylene;
(7) by the hydroxyl of formula IV compound with protecting group R 2protection, and slough silicon ether protecting group R 3production VI compound;
(8) formula VI compound sloughs R 1hydroxyl protecting group production VII compound;
(9) formula VII compound is oxidized, and makes to slough R 1hydroxyl oxidize be aldehyde, production VIII compound;
(10) there is ring closure reaction, production IX compound in formula VIII compound under the effect of closing cyclization reagent;
(11) formula IX compound is oxidized production X compound under the effect of oxygenant;
(12) formula X compound is reduced under the effect of reductive agent production XI compound;
(13) formula XI compound and formula XII compound are carried out condensation reaction, production XIII compound under mitsunobu reaction conditions or substitution reaction condition;
(14) formula XIII compound sloughs protecting group R under the action of an acid 2and R 4, the Entecavir of production I;
Reaction scheme is as follows:
Wherein: R 1, R 2for hydroxyl protecting group, and R 2r is sloughed for tolerating 1hydroxyl protecting group;
R 3for alkyl silicon ether protecting group;
R 4for hydrogen, C1-C6 alkyl, C1-C6 alkyl replaces or substituted aryl, C1-C6 alkyl do not replace or not substituted benzyl.
2. the synthetic method of Entecavir according to claim 1, is characterized in that, in step (5), described titanium compound is selected from: titanium tetrachloride or titanium isopropylate; Described hand-type ester class part is selected from: L-(+)-diethyl tartrate or L-(+)-tartrate diisopropyl ester; Described oxygenant is selected from: tertbutyl peroxide or isopropyl benzene hydroperoxide, and temperature of reaction is: 0 ~-50 DEG C.
3. the synthetic method of Entecavir according to claim 1, is characterized in that, in step (6), and R 3be selected from: trimethyl silicon based, triethyl is silica-based; Lithium alkylide is selected from: lithium methide, n-Butyl Lithium, tert-butyl lithium; Reaction conditions is: 0 ~-50 DEG C.
4. the synthetic method of Entecavir according to claim 1, is characterized in that, in step (6), described Ring Opening Reagent also comprises dimethylaluminum chloride or diethyl aluminum chloride.
5. the synthetic method of Entecavir according to claim 1, is characterized in that, in step (10), described pass cyclization reagent is Ni (COD) 2, PBu 3with Zn (Et) 2; Or SmI 2; Or Na and naphthalene; Or Li and naphthalene; Or Na and NH 3; Or Li and NH 3; Or CrCl 2, NiCl 2and PPh 3, temperature of reaction is: 0 ~-50 DEG C.
6. the synthetic method of Entecavir according to claim 1, is characterized in that, in step (7), first in the presence of a base, by the hydroxyl of formula IV compound with protecting group R 2protection, obtains formula V compound, then reacts under 0-40 DEG C of condition with fluorochemical or alkali, slough the alkyl silicon ether protecting group R on formula V compound 3production VI compound;
Or first react under 0-40 DEG C of condition with fluorochemical or alkali, slough the silicon ether protecting group R on formula IV compound 3, obtain formula V ' compound, more in the presence of a base by the hydroxyl of formula V ' compound with protecting group R 2protection, production VI compound;
7. the synthetic method of Entecavir according to claim 1, is characterized in that, R 1, R 2, R 4independently be selected from: benzyl, C1-C6 alkyl or alkoxyl group substituted benzyl, trityl, trialkyl silyl or tert-butyl diphenyl are silica-based.
8. the synthetic method of Entecavir according to claim 1, is characterized in that, in step (13), described mitsunobu reaction conditions is: under the effect of triphenylphosphine and aliphatic azo compound, in 0 ~ 40 DEG C of reaction.
9. the synthetic method of Entecavir according to claim 1, is characterized in that, in step (3), described horner-emmons reagent is selected from: triethyl phosphonoacetate, or phosphonoacetic acid trimethyl; This step temperature of reaction is 0-40 DEG C.
10. the synthetic method of Entecavir according to claim 1, is characterized in that,
In step (2), described oxygenant is selected from: clorox, pyridinium chloro-chromate, Pyridinium dichromate, methyl-sulphoxide, 2-iodosobenzoic acid, or Dai Si-Martin's oxygenant, and temperature of reaction is :-10 ~ 40 DEG C;
In step (4), described reductive agent is selected from: diisobutyl aluminium hydride, or lithium aluminum hydride and aluminum chloride, and temperature of reaction is: 0 ~-50 DEG C;
In step (9), at-10 ~ 40 DEG C, adopt clorox, pyridinium chloro-chromate, Pyridinium dichromate, methyl-sulphoxide, 2-iodosobenzoic acid, or Dai Si-Martin's oxygenant is oxidized;
In step (11), at-10 ~ 40 DEG C, adopt 2-iodosobenzoic acid, pyridinium chloro-chromate, clorox, Pyridinium dichromate, methyl-sulphoxide, or Dai Si-Martin's oxygenant is oxidized;
In step (12), at-50 ~ 0 DEG C, adopt lithium triethylborohydride, or sodium borohydride and cerous compounds reduce;
In step (14), at 20 ~ 80 DEG C, adopt hydrochloric acid, slough protecting group R 2and R 4.
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