CN105037363A - Novel synthetic method for entecavir compound - Google Patents
Novel synthetic method for entecavir compound Download PDFInfo
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- CN105037363A CN105037363A CN201510406573.9A CN201510406573A CN105037363A CN 105037363 A CN105037363 A CN 105037363A CN 201510406573 A CN201510406573 A CN 201510406573A CN 105037363 A CN105037363 A CN 105037363A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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- C—CHEMISTRY; METALLURGY
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Abstract
The invention belongs to the field of drug synthesis and relates to an entecavir compound and a synthetic method of an intermediate of the entecavir compound. The novel synthetic method comprises: by taking (S)-3-hydroxyl dimethyl adipate as an initial raw material, preparing an intermediate 9 through hydroxyl TBS protection, Dieckmann condensation reaction, ketone protection to ketal, ester group reduction to hydroxyl, hydroxyl protection, deprotection, ketone to silyl enol ether and Rubottom oxidizing reaction; and preparing entecavir from the intermediate 9 through wittig reaction, Mitsunobu reaction, silicon preventing radical group removal and basic hydrolysis. The novel synthetic method provided by the invention is mild and easily controllable in reaction condition, simple to operate, high in product yield, high in purity and suitable for industrialized mass production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, relate to a kind of entecavir compound prepared novel synthesis.
Background technology
Entecavir (Entecavir), chemical name is: [1-S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylenecyclopentyl]-6H-purine-6-one, it is a kind of deoxyguanosine analog of effective, Selective depression hepatitis B replication, inhibited to hepatitis B virus (HBV) polymerase, researched and developed by U.S. Bristol-MyersSquibb (Bristol Myers Squibb) company, in April, 2005 goes on the market in the U.S., and its structural formula is as follows:
In vitro tests shows, Entecavir is more effective than other nucleoside analogs.Animal model and the display of human clinical's result of study, Entecavir has extremely strong suppression hepatitis B replication, reduce the effect of serum-virus DNA level, still effective to the mutated viruses strain of resistance to lamivudine, and have no obvious untoward reaction and mitochondrial toxicity.A large amount of clinical experiment shows, it has direct restraining effect to reversed transcriptive enzyme in liver cell and hepatitis B virus DNA polymerase, there is very strong anti-virus ability, the selectivity ratios of this compound is higher simultaneously, its cytotoxicity is 1/8000 of anti-hepatitis B virus activities, effectively can treat chronic viral hepatitis B and not disturb influenza virus and HIV virus.And due to its mechanism of action difference, the resistance that life-time service produces is low.Because it has rapid-action, strong, the low resistance of resistance hepatitis B virus, be the first-selection of Chronic Hepatitis B antiviral therapy, the market requirement is larger.
There are a lot of document and the synthetic method that patent describes Entecavir and intermediate thereof at present, such as:
1, two kinds of novel methods of synthesizing Entecavir respectively using 16 and 17 as key intermediate are reported in patent WO2004052310.
The synthetic method being wherein key intermediate with intermediate 16 first builds the chirality five-membered ring intermediate 16 containing exocyclic double bond by asymmetric synthesis, then be combined with purine compound, and obtain Entecavir through three-step reaction, reaction scheme is as follows:
The synthetic route of this intermediate (16) is short, and productive rate is higher, but reagent price is very expensive, and cost is too high, severe reaction conditions, and the reagent environmental pollutions such as methylsulfonyl chloride are comparatively large, are not suitable for suitability for industrialized production.
The synthetic method being key intermediate with intermediate 17 is first with chain type silane (-SiR
2 br
a) as configuration blocking group; build five-ring racemic compound (24); chirality five-membered ring is obtained again by the method for chemical resolution; thus synthesis obtains key intermediate 17 further; and then be combined with purine compound; obtain Entecavir through three-step reaction, reaction scheme is as follows:
At present, the defect that the synthesis of such intermediate (17) also exists is exactly generate a large amount of tar in reaction, makes product purification difficult, also affects yield simultaneously.In order to solve this difficult problem, 2005, MaotangX.Zhou carries out further base group modification to 17, devise the method (US20050272932) of synthesizing Entecavir using intermediate 30 and 31 as key intermediate, the use of these two intermediates decreases the coal-tar middle oil generation of late phase reaction, and productive rate is higher, but its synthesis step is oversize, and whole economic efficiency is not high.
Above method Problems existing have impact on the industrialization development of Entecavir all greatly.For current Problems existing, explore the gentle easily control of a kind of reaction conditions, synthesis step is simple, suitability for industrialized production is purified easily, is applicable to product key intermediate and synthetic method thereof significant.
2, Entecavir is Carbocyclic nucleoside analogues, and its synthetic method is very complicated.In prior art, the chiral starting materials that Chinese patent ZL03135304.5 discloses a kind of use is [1S-(1 α, 2 α, 3 β, 5 α)] own-3-alcohol of-2-[(benzyloxy) methyl]-6-oxabicyclo [3.1.0], this compound is not easy to obtain, expensive; And in reduction reaction, use palladium-carbon catalyst, expensive.Chinese patent application 200610088464.8 discloses and employs chiral starting materials [1S-(1 α, 2 α, 3 β, 5 α)]-3-(benzyloxy)-2-[(benzyloxy) methyl]-6-oxabicyclo [3.1.0] hexane, expensive and be difficult to obtain; Expensive methylenation reagents NYSTED reagent is used in methylenation.
3, Chinese patent application ZL200610003451.6, ZL200610130565.7 disclose that to employ these method stepss of chiral starting materials long, complex operation, the chipal compounds that all employ similar costliness is starting raw material and catalyzer, reaction yield is low, reaction process isomerization is serious, and a lot of intermediate needs to use column chromatography to purify.CN91110831, CN1747959, WO2004052310 have had significant improvement in these synthetic methods.Have employed cyclopentadiene sodium is raw material, obtains the finished product by series reaction.Its shortcoming is to have employed expensive 3,5-dimethylphenyl chlorosilane as protecting group.
In order to solve problems of the prior art, applicant is through large quantity research, and spy proposes the present invention.
Summary of the invention
The object of the invention is to provide a kind of synthetic method of entecavir compound prepared and intermediate, to solve the problems such as operational path cost intensive in prior art, raw material is rare, method and technology requirement is high.
Technical scheme provided by the invention is:
An entecavir compound prepared synthetic method, is characterized in that, the method with compound 9 for starting raw material
comprise the following steps:
A) compound 9 is through wittig reacting generating compound 10;
B) compound 10 and compound 11 mix, through Mitsunobu reacting generating compound 12;
C) compound 12 desiliconization protecting group generates compound 13;
D) compound 13 hydrolyzed under basic conditions generates Entecavir,
Preferably, described entecavir compound prepared synthetic method, is characterized in that, comprise the steps:
A) by compound 9 in a solvent, with Witting reagent effect, compound 10 is obtained through aftertreatment;
B) compound 10 is reacted with compound 11 under the existence of triphenylphosphine, diethyl azodiformate or diisopropyl azodiformate, obtain compound 12 through aftertreatment;
C) by compound 12 in a solvent, add tetrabutyl ammonium fluoride and carry out the reaction of desiliconization protecting group, reaction terminates, through aftertreatment compound 13;
D) compound 13 is joined in basic solution, reaction solution is heated to 70 DEG C, stirring reaction, after reaction terminates, obtain Entecavir through aftertreatment.
Preferred, described entecavir compound prepared synthetic method:
Step a) being prepared as of described Witting reagent: under nitrogen protection, triphen ylmethyl phosphonium bromide is joined in solvent, at being cooled to 0 DEG C, adds basic catalyst, finish, rise to room temperature reaction, thus obtained Witting reagent; Described solvent be methylene dichloride, tetrahydrofuran (THF), toluene, ether one or more; Described basic catalyst is sodium methylate, sodium ethylate, potassium tert.-butoxide or n-Butyl Lithium; Described aftertreatment is: cancellation, concentrating under reduced pressure, extraction into ethyl acetate, washing organic phase, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure, and crude product to be purified to obtain compound 10 through silica gel column chromatography;
Step b) described reaction carries out in solvents tetrahydrofurane, the described temperature adding the suspension of triphenylphosphine and DEAD is wherein 0 DEG C, the temperature of described stirring reaction is 0 DEG C, the time is 1-5 hour, described aftertreatment is: after having reacted, ethyl acetate is added in reaction solution, with the washing of 0.5M sodium hydroxide solution, anhydrous sodium sulfate drying organic phase, filtration, concentrating under reduced pressure, crude product to be purified to obtain compound 11 through silica gel column chromatography;
Step c) described reaction carries out in solvents tetrahydrofurane, described stirring reaction temperature is room temperature, and the stirring reaction time is 12 hours, described aftertreatment is: after reaction terminates, cancellation, extraction into ethyl acetate, water washing organic phase, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure;
Steps d) described in basic solution be 2M sodium hydroxide solution, the described stirring reaction time is 4 hours, and described aftertreatment is: reaction terminate after, reaction solution is cooled to 0 DEG C, adjust pH to 6.8 with 1M hydrochloric acid soln, and stir 2h at 0 DEG C, filter to obtain Entecavir.
Further preferred:
Step a) middle compound 9 is 1:1.4-1.6:1.4-1.6 with the mol ratio of triphen ylmethyl phosphonium bromide, basic catalyst;
Step b) in compound 10 be 1:1.5-2.5:1.5-2.5:1.5-2.5 with the mol ratio of compound 11, triphenylphosphine, diethyl azodiformate or diisopropyl azodiformate;
Step c) in compound 12 be 1:1.5-3 with the mol ratio of tetrabutyl ammonium fluoride;
Step a) in the eluting solvent of silica gel column chromatography be petrol ether/ethyl acetate=50:1-10:1.
Present invention also offers a kind of synthetic method of entecavir midbodies compound.
A synthetic method for entecavir midbodies, is characterized in that as claimed in claim 1, the method with (S)-3-hydroxyl dimethyl adipate (compound 1) for starting raw material
comprise the following steps:
(1) compound 1 protects to obtain compound 2 through hydroxyl TBS;
(2) compound 2 generates compound 3 through Dieckmann condensation reaction;
(3) compound 3 protects into ketal through ketone, generates compound 4;
(4) compound 4 is reduced into hydroxyl through ester group, generates compound 5;
(5) compound 5 is through hydroxyl protection, generates compound 6;
(6) compound 6 deprotection generates compound 7;
(7) compound 7 becomes silyl enol ether through ketone, generates compound 8;
(8) compound 8 metachloroperbenzoic acid is oxidized to obtain compound 9;
Preferably, the synthetic method of described entecavir midbodies, is characterized in that comprising the steps:
1) compound 1 is generated compound 2 at organic solvent, acid binding agent under existing with TBSCl;
2) by step 1) in gained compound 2 in a solvent, cyclization under alkaline matter catalysis; Compound 3 is obtained through aftertreatment;
3) under the existence of organic solvent and catalyzer, by step 2) in gained compound 3 obtain compound 4 with glycol reaction;
4) by step 3) in gained compound 4 be dissolved in anhydrous tetrahydro furan, react under the effect of sodium borohydride and lithium chloride, obtain compound 5 through aftertreatment;
5) by step 4) gained compound 5 generates compound 6 at organic solvent, acid binding agent under existing with TBSCl;
6) by step 5) gained compound 6 is dissolved in methyl alcohol, and add hydrochloric acid and carry out ketal deprotection reaction, obtain compound 7 through aftertreatment;
7) by step 6) gained compound 7 in organic solvent, the obtained compound 8 of reaction under the existence of organic bases and TMSOTf;
8) by step 7) gained compound 8 through metachloroperbenzoic acid oxidizing reaction, obtain compound 9 through aftertreatment;
Further preferred, the synthetic method of described entecavir midbodies, concrete steps are as follows:
1) compound 1 is dissolved in organic solvent, adds acid binding agent, TBSCl successively, stirred at ambient temperature reaction 3-5 hour, add shrend and go out, separatory, organic phase washed with water, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, obtains compound 2; Described organic solvent be selected from methylene dichloride, dimethyl formamide, chloroform, tetrahydrofuran (THF) one or more; Described acid binding agent is imidazoles or pyridine;
2) by step 1) in gained compound 2 be dissolved in solvent, add alkaline matter, reflux 2-5 hour, question response terminates, concentrating under reduced pressure; Resistates adds 0.5M hydrochloric acid soln, with dichloromethane extraction, and organic phase washed with water twice, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, and crude product to be purified to obtain compound 3 through silica gel column chromatography; Described solvent is methyl alcohol, ethanol, the trimethyl carbinol, tetrahydrofuran (THF), dimethyl formamide; Described alkaline matter is sodium alkoxide or potassium alcoholate, sodium amide, sodium hydride, potassium hydride KH or hydrolith;
3) by step 2) in gained compound 3 be dissolved in organic solvent, add ethylene glycol and catalyzer, reflux divides water, reaction 4-10 hour, after not having moisture to produce, stop heating, be cooled to room temperature, add saturated sodium bicarbonate solution and stir 10 minutes, separatory, organic phase washed with water twice, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains compound 4; Described catalyzer is tosic acid, pyridine hydrochloride or pyridine hydrogen bromide salt; Described organic solvent is toluene, benzene, methylene dichloride, trichloromethane or tetrahydrofuran (THF).
4) sodium borohydride and lithium chloride are joined in anhydrous tetrahydro furan, stir 30 minutes under nitrogen protection, stop stirring allow deposition of solids, be added dropwise to by supernatant liquid in the round-bottomed flask of the anhydrous tetrahydro furan that compound 4 is housed, stirring at room temperature, until reactionless thing, adds shrend and to go out reaction, reaction solution concentrating under reduced pressure removes tetrahydrofuran (THF), residue from dichloromethane extracts, organic phase washed with water twice, merges, dry, filter, concentrating under reduced pressure, crude product column chromatography is purified to obtain compound 5;
5) by step 4) gained compound 5 is dissolved in organic solvent, adds acid binding agent, TBSCl successively, stirred at ambient temperature reaction 3-5 hour, and add shrend and go out, separatory, organic phase washed with water, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, obtains compound 2; Described organic solvent be selected from methylene dichloride, dimethyl formamide, chloroform, tetrahydrofuran (THF) one or more; Described acid binding agent is imidazoles or pyridine;
6) by step 5) gained compound 6 is dissolved in methyl alcohol, 3N hydrochloric acid is added under room temperature, stirring reaction 2-4 hour at 50 DEG C, until reactionless thing, is cooled to room temperature, adjust pH to neutral with saturated sodium bicarbonate solution, with dichloromethane extraction, organic phase, through anhydrous sodium sulfate drying, is filtered, concentrating under reduced pressure, crude product to be purified to obtain compound 7 through column chromatography;
7) by step 6) compound 7 is dissolved in organic solvent, is cooled to 0 DEG C, drips organic bases and TMSOTf wherein successively, stirs the mixture 1 hour of gained at 5 DEG C; After having reacted, add shrend and to go out reaction, be separated organic phase, wash with water, through anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains target compound 8; Described organic bases is one or more of pyridine, triethylamine, imidazoles or DBU; Described organic solvent is methylene dichloride;
8) by step 7) gained compound 8 is dissolved in methylene dichloride, and be cooled to-25 DEG C, add the metachloroperbenzoic acid of Sodium phosphate dibasic and 70% successively, stirring reaction 2-4 hour at-25 DEG C, add sodium sulfite solution and sodium bisulfate, reaction solution is heated to room temperature, stir 1-2 hour, after having reacted, be separated organic phase, wash twice with water, through anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, crude product to be purified to obtain compound 9 through silica gel column chromatography.
Further:
Step 1) in compound 1 be 1:1.1-1.3:1.0-1.2 with the mol ratio of acid binding agent, TBSCl;
Step 2) in compound 2 be 1:1-3 with the mol ratio of alkaline matter;
Step 3) in compound 3 be 1:2-4:0.05-0.10 with the mol ratio of ethylene glycol, catalyzer;
Step 4) in compound 4 be 1:1.1-1.2:1.1-1.2 with the mol ratio of sodium borohydride, lithium chloride;
Step 5) in compound 5 be 1:1.1-1.3:1.1-1.2 with the mol ratio of acid binding agent, TBSCl;
Step 7) in compound 7 be 1:3-5:1-2 with the mol ratio of organic bases, TMSOTf;
Step 8) in compound 8 be 1:4-6:2-3 with the mol ratio of Sodium phosphate dibasic, metachloroperbenzoic acid.
Further: the developping agent that silica gel column chromatography described in reaction process uses is petrol ether/ethyl acetate:
Step 2) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=90:1-70:1;
Step 4) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=60:1-40:1;
Step 6) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=90:1-70:1;
Step 8) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=50:1-10:1.
Compared to prior art, technical solution of the present invention has following significant advantage:
1) technical solution of the present invention provides the route that a kind of applicable domestic industryization is produced, and this route for starting raw material, solves the problem that prior art Raw is rare with (S)-3-hydroxyl dimethyl adipate (compound 1);
2) technical solution of the present invention is carried out all the time within the scope of comparatively constant temp, and step is few, simple and easy to control, the consumption of reactant is easy to control, and reaction conditions is gentle, and reaction process is stablized, side reaction is few, solves the problem topic that the technical requirements of prior art processes route methods is high;
3) reagent that uses of technical solution of the present invention is cheap, and environmental pollution is little, solves the problem of prior art processes route cost intensive;
4) technical solution of the present invention gained Entecavir yield is high, and purity is high, and dopant species is few, the large production of suitability for industrialized.
Embodiment
Following content is in conjunction with concrete preferred implementation further description made for the present invention, can not assert that specific embodiment of the invention is confined to these explanations.For general technical staff of the technical field of the invention; without departing from the inventive concept of the premise; some simple deduction or replace can also be made; all should be considered as belonging to protection scope of the present invention; the present invention uses but the technology be not described and indexing section, is prior art.
Embodiment 1:
1) synthesis of compound 2
By (S)-3-hydroxyl dimethyl adipate (190.2g, 1mol) be dissolved in 2000ml methylene dichloride, add imidazoles (81.7g, 1.2mol) and TBSCl (165.8g successively, 1.1mol), reaction solution at room temperature stirs 4 hours.Add 1500ml shrend to go out reaction, separatory, organic phase 2000ml water washing twice, anhydrous sodium sulfate drying, filter, after concentrating under reduced pressure compound 2 (289.25g, productive rate 95%).
2) synthesis of compound 2
By (S)-3-hydroxyl dimethyl adipate (190.2g, 1mol) be dissolved in 2000ml tetrahydrofuran (THF), add pyridine (103.1g, 1.3mol) and TBSCl (180.9g successively, 1.2mol), reaction solution at room temperature stirs 3 hours.Add 1500ml shrend to go out reaction, separatory, organic phase 2000ml water washing twice, anhydrous sodium sulfate drying, filter, after concentrating under reduced pressure compound 2 (287.8g, productive rate 94.5%).
Embodiment 2:
1) synthesis of compound 3
Compound 2 (228.35g, 750mmol) is dissolved in 12500ml methyl alcohol, adds the methanol solution of sodium methylate (486g, 2250mmol) of 25%, reflux 3 hours.After reaction terminates, concentrating under reduced pressure removes methyl alcohol.Resistates adds 5000ml0.5M hydrochloric acid soln, use 2500ml dichloromethane extraction, organic phase 2500ml washing twice, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=80:1) is purified to obtain compound 3 (147.1g, productive rate 72%).
2) synthesis of compound 3
Compound 2 (243.6g, 0.8mol) is dissolved in the 12500ml trimethyl carbinol, adds the t-butanol solution (179.5g, 1.6mol) of the potassium tert.-butoxide (t-BuOK) of 25%, reflux 2 hours.After reaction terminates, the concentrating under reduced pressure trimethyl carbinol.Resistates adds 5000ml0.5M hydrochloric acid soln, use 2500ml dichloromethane extraction, organic phase 2500ml washing twice, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=80:1) is purified to obtain compound 3 (169.0g, productive rate 73%).
Embodiment 3:
1) synthesis of compound 4
By compound 3 (136.2g, 500mmol) be dissolved in 280ml toluene, add ethylene glycol (93.1g, 1500mmol) with tosic acid monohydrate (7.6g, 40mmol), reflux divides water, react 8 hours, after not having moisture to produce, stop heating, be cooled to room temperature.Add 750ml saturated sodium bicarbonate solution and stir 10 minutes, separate organic phase, with 1000ml water washing twice, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains compound 4 (145.6g, productive rate 92%).
2) synthesis of compound 4
By compound 3 (136.2g, 500mmol) be dissolved in 280ml methylene dichloride, add ethylene glycol (62.1g, 1000mmol) with pyridine hydrochloride (5.8g, 50mmol), reflux divides water, react 9 hours, after not having moisture to produce, stop heating, be cooled to room temperature.Add 750ml saturated sodium bicarbonate solution and stir 10 minutes, separate organic phase, with 1000ml water washing twice, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains compound 4 (147.2g, productive rate 93%).
Embodiment 4:
The synthesis of compound 5
1) sodium borohydride (18.9g, 500mmol) and lithium chloride (21.2g, 500mol) are joined in 250ml anhydrous tetrahydro furan, stir after 30 minutes under nitrogen protection, stop stirring allow deposition of solids.Supernatant liquid is added dropwise to compound 4 (142.4g is housed, in the round-bottomed flask of 1400ml anhydrous tetrahydro furan 450mmol), stirring at room temperature is until reactionless thing, add 450ml shrend to go out reaction, reaction solution concentrating under reduced pressure removes tetrahydrofuran (THF), resistates 750ml dichloromethane extraction, organic phase 150ml water washing twice, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=50:1) is purified to obtain compound 5 (109.05g, productive rate 84%).
2) sodium borohydride (20.4g, 540mmol) and lithium chloride (22.9g, 540mol) are joined in 250ml anhydrous tetrahydro furan, stir after 30 minutes under nitrogen protection, stop stirring allow deposition of solids.Supernatant liquid is added dropwise to compound 4 (142.4g is housed, in the round-bottomed flask of 1400ml anhydrous tetrahydro furan 450mmol), stirring at room temperature is until reactionless thing, add 450ml shrend to go out reaction, reaction solution concentrating under reduced pressure removes tetrahydrofuran (THF), resistates 750ml dichloromethane extraction, organic phase 150ml water washing twice, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=50:1) is purified to obtain compound 5 (119.2g, productive rate 85%).
Embodiment 5:
1) synthesis of compound 6
Compound 5 (108.15g, 375mmol) is dissolved in 1000ml methylene dichloride, adds imidazoles (30.65g successively, 450mmol) with TBSCl (62.15g, 415mmol), reaction solution at room temperature stirs 5 hours, until reactionless thing.Add 750ml shrend to go out reaction, separatory, organic phase 1000ml water washing twice, anhydrous sodium sulfate drying, filter, after concentrating under reduced pressure compound 6 (137.45g, productive rate 91%).
2) synthesis of compound 6
Compound 5 (115.36g, 400mmol) is dissolved in 1000 tetrahydrofuran (THF)s, adds pyridine (41.1g successively, 520mmol) with TBSCl (72.3g, 480mmol), reaction solution at room temperature stirs 5 hours, until reactionless thing.Add 750ml shrend to go out reaction, separatory, organic phase 1000ml water washing twice, anhydrous sodium sulfate drying, filter, after concentrating under reduced pressure compound 6 (149.8g, productive rate 93%).
Embodiment 6: the synthesis of compound 7
1) be dissolved in 600ml methyl alcohol by compound 6 (125.00g, 310mmol), add 100ml3N hydrochloric acid under room temperature, stirring reaction 3 hours at 50 DEG C, until reactionless thing.Be cooled to room temperature, adjust pH to neutral with saturated sodium bicarbonate solution, use 1000ml dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=80:1) is purified to obtain compound 7 (90.05g, productive rate 81%).
2) be dissolved in 800ml methyl alcohol by compound 6 (141.1g, 350mmol), add 120ml3N hydrochloric acid under room temperature, stirring reaction 2 hours at 50 DEG C, until reactionless thing.Be cooled to room temperature, adjust pH to neutral with saturated sodium bicarbonate solution, use 1000ml dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=80:1) is purified to obtain compound 7 (104.2g, productive rate 83%).
Embodiment 7:
1) synthesis of compound 8
Compound 7 (89.65g, 250mmol) is dissolved in 900ml methylene dichloride, is cooled to 0 DEG C, drip triethylamine (101.2g wherein successively, 1000mmol) and TMSOTf (83.4g, 375mmol), the mixture 1 hour of gained is stirred at 5 DEG C.After having reacted, add 750ml shrend and to go out reaction.Be separated organic phase, use 750ml water washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains compound 8 (93.7g, productive rate 87%).
2) synthesis of compound 8
Compound 7 (89.65g, 250mmol) is dissolved in 900ml methylene dichloride, is cooled to 0 DEG C, drip pyridine (79.1g wherein successively, 1000mmol) and TMSOTf (111g, 500mmol), the mixture 1 hour of gained is stirred at 5 DEG C.After having reacted, add 750ml shrend and to go out reaction.Be separated organic phase, use 750ml water washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains compound 8 (94.8g, productive rate 88%).
Embodiment 8: the synthesis of compound 9
1) by compound 8 (75.00g, 175mmol) be dissolved in 1000ml methylene dichloride, be cooled to-25 DEG C, add the metachloroperbenzoic acid (94.9g, 385mmol) of Sodium phosphate dibasic (124.2,875mmol) and 70% successively, stirring reaction 3 hours at-25 DEG C, add 200ml sodium sulfite solution and 400ml sodium bisulfate, reaction solution is heated to room temperature, stirs 1 hour.After having reacted, separate organic phase, with 1000ml water washing twice, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=40:1 ~ 20:1) is purified to obtain compound 9 (47.85g, productive rate 73%).
2) by compound 8 (75.00g, 175mmol) be dissolved in 1000ml methylene dichloride, be cooled to-25 DEG C, add the metachloroperbenzoic acid (129.4g, 525mmol) of Sodium phosphate dibasic (141.9g, 875mmol) and 70% successively, stirring reaction 4 hours at-25 DEG C, add 200ml sodium sulfite solution and 400ml sodium bisulfate, reaction solution is heated to room temperature, stirs 2 hours.After having reacted, separate organic phase, with 1000ml water washing twice, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=40:1 ~ 20:1) is purified to obtain compound 9 (48.5g, productive rate 74%).
Embodiment 9:
1) synthesis of compound 10
Under room temperature, triphenylmethylphosphonium bromide phosphine (56.25g, 155mmol) is joined in 500ml anhydrous tetrahydro furan.Under nitrogen protection, be cooled to 0 DEG C, add potassium tert.-butoxide (17.65,155mmol), finish in reaction solution, rise to room temperature reaction 2 hours, reaction solution is from oyster white yellowing.Be dissolved in 250ml anhydrous tetrahydro furan by compound 9 (40g, 105mmol), add in reaction solution, stirring at room temperature reacts 24 hours.In reaction solution, add 500ml shrend to go out reaction, concentrating under reduced pressure removes tetrahydrofuran (THF), resistates 500ml extraction into ethyl acetate twice, merges organic phase, washes once successively with 500ml, the water washing of 500ml saturated common salt successively, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=50:1 ~ 30:1) is purified to obtain target compound 10 (25.45g, productive rate 65%).
2) synthesis of compound 10
Under room temperature, triphenylmethylphosphonium bromide phosphine (56.25g, 155mmol) is joined in 500ml anhydrous methylene chloride.Under nitrogen protection, be cooled to 0 DEG C, in reaction solution, add the sodium methoxide solution (248mmol) of 25%, finish, rise to room temperature reaction 2 hours, reaction solution is from oyster white yellowing.Be dissolved in 250ml anhydrous tetrahydro furan by compound 9 (40g, 105mmol), add in reaction solution, stirring at room temperature reacts 24 hours.In reaction solution, add 500ml shrend to go out reaction, concentrating under reduced pressure removes tetrahydrofuran (THF), resistates 500ml extraction into ethyl acetate twice, merges organic phase, washes once successively with 500ml, the water washing of 500ml saturated common salt successively, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=50:1 ~ 30:1) is purified to obtain target compound 10 (25.8g, productive rate 66%).
Embodiment 10: the synthesis of compound 12
1) by triphenylphosphine (31.5g, 120mmol) be dissolved in 500ml tetrahydrofuran (THF), be cooled to 0 DEG C, add diethyl azodiformate (DEAD) (20.9g wherein, 120mmol), at 0 DEG C, stirring obtains suspension in 1 hour.The mixture of compound 10 (22.5g, 60mmol) and 11 (20.35g, 120mmol) is dissolved with 450ml tetrahydrofuran (THF), at 0 DEG C, adds the suspension of triphenylphosphine and DEAD wherein, stirring reaction 1 hour at 0 DEG C.After having reacted, 1000ml ethyl acetate is added in reaction solution, three times are washed with 1000ml0.5M sodium hydroxide solution, organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=40:1 ~ 20:1) is purified to obtain target compound 12 (22.65g, productive rate 72%).
2) by triphenylphosphine (39.4g, 150mmol) be dissolved in 500ml tetrahydrofuran (THF), be cooled to 0 DEG C, add diethyl azodiformate (DEAD) (20.9g wherein, 120mmol), at 0 DEG C, stirring obtains suspension in 1 hour.The mixture of compound 10 (22.5g, 60mmol) and 11 (25.4g, 150mmol) is dissolved with 450ml tetrahydrofuran (THF), at 0 DEG C, adds the suspension of triphenylphosphine and DEAD wherein, stirring reaction 3 hours at 0 DEG C.After having reacted, 1000ml ethyl acetate is added in reaction solution, three times are washed with 1000ml0.5M sodium hydroxide solution, organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=40:1 ~ 20:1) is purified to obtain target compound 12 (23.3g, productive rate 74%).
Embodiment 11: the synthesis of compound 13
1) be dissolved in 200ml anhydrous tetrahydro furan by compound 12 (20g, 38mmol), add the tetrahydrofuran solution (114ml, 114mmol) of the tetrabutyl ammonium fluoride of 1M, stirred at ambient temperature reacts 12 hours.After reaction terminates, add 200ml shrend and to go out reaction, use 200ml extraction into ethyl acetate, organic phase with 200ml water washing once, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure obtains target compound 13 (9.87g, productive rate 88%).
2) be dissolved in 200ml anhydrous tetrahydro furan by compound 12 (20g, 38mmol), add the tetrahydrofuran solution (76ml, 76mmol) of the tetrabutyl ammonium fluoride of 1M, stirred at ambient temperature reacts 12 hours.After reaction terminates, add 200ml shrend and to go out reaction, use 200ml extraction into ethyl acetate, organic phase with 200ml water washing once, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure obtains target compound 13 (9.65g, productive rate 86%).
Embodiment 12: the synthesis of Entecavir
1) compound 13 (5g, 17mmol) is joined in 100ml2M sodium hydroxide solution, reaction solution is heated to 70 DEG C, stirring reaction 4 hours.After reaction terminates, reaction solution is cooled to 0 DEG C, adjusts pH to 6.8 with 1M hydrochloric acid soln, and stir 2h at 0 DEG C, filter to obtain Entecavir (3.3g, productive rate 71%).
2) compound 13 (5g, 17mmol) is joined in 100ml2M sodium hydroxide solution, reaction solution is heated to 70 DEG C, stirring reaction 4 hours.After reaction terminates, reaction solution is cooled to 0 DEG C, adjusts pH to 6.8 with 1M hydrochloric acid soln, and stir 2h at 0 DEG C, filter to obtain Entecavir (3.4g, productive rate 73%).
Claims (9)
1. an entecavir compound prepared synthetic method, is characterized in that, the method with compound 9 for starting raw material
comprise the following steps:
A) compound 9 is through wittig reacting generating compound 10;
B) compound 10 and compound 11 mix, through Mitsunobu reacting generating compound 12;
C) compound 12 desiliconization protecting group generates compound 13;
D) compound 13 hydrolyzed under basic conditions generates Entecavir,
2. synthetic method entecavir compound prepared as claimed in claim 1, is characterized in that, comprises the steps:
A) by compound 9 in a solvent, with Witting reagent effect, compound 10 is obtained through aftertreatment;
B) compound 10 is reacted with compound 11 under the existence of triphenylphosphine, diethyl azodiformate or diisopropyl azodiformate, obtain compound 12 through aftertreatment;
C) by compound 12 in a solvent, add tetrabutyl ammonium fluoride and carry out the reaction of desiliconization protecting group, reaction terminates, through aftertreatment compound 13;
D) compound 13 is joined in basic solution, reaction solution is heated to 70 DEG C, stirring reaction, after reaction terminates, obtain Entecavir through aftertreatment.
3. synthetic method entecavir compound prepared as claimed in claim 2, is characterized in that:
Step a) being prepared as of described Witting reagent: under nitrogen protection, triphen ylmethyl phosphonium bromide is joined in solvent, at being cooled to 0 DEG C, adds basic catalyst, finish, rise to room temperature reaction, thus obtained Witting reagent; Described solvent be methylene dichloride, tetrahydrofuran (THF), toluene, ether one or more; Described basic catalyst is sodium methylate, sodium ethylate, potassium tert.-butoxide or n-Butyl Lithium; Described aftertreatment is: cancellation, concentrating under reduced pressure, extraction into ethyl acetate, washing organic phase, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure, and crude product to be purified to obtain compound 10 through silica gel column chromatography;
Step b) described reaction carries out in solvents tetrahydrofurane, the described temperature adding the suspension of triphenylphosphine and DEAD is wherein 0 DEG C, the temperature of described stirring reaction is 0 DEG C, the time is 1-5 hour, described aftertreatment is: after having reacted, ethyl acetate is added in reaction solution, with the washing of 0.5M sodium hydroxide solution, anhydrous sodium sulfate drying organic phase, filtration, concentrating under reduced pressure, crude product to be purified to obtain compound 11 through silica gel column chromatography;
Step c) described reaction carries out in solvents tetrahydrofurane, described stirring reaction temperature is room temperature, and the stirring reaction time is 12 hours, described aftertreatment is: after reaction terminates, cancellation, extraction into ethyl acetate, water washing organic phase, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure;
Steps d) described in basic solution be 2M sodium hydroxide solution, the described stirring reaction time is 4 hours, and described aftertreatment is: reaction terminate after, reaction solution is cooled to 0 DEG C, adjust pH to 6.8 with 1M hydrochloric acid soln, and stir 2h at 0 DEG C, filter to obtain Entecavir.
4. synthetic method entecavir compound prepared as claimed in claim 3, is characterized in that:
Step a) middle compound 9 is 1:1.4-1.6:1.4-1.6 with the mol ratio of triphen ylmethyl phosphonium bromide, basic catalyst;
Step b) in compound 10 be 1:1.5-2.5:1.5-2.5:1.5-2.5 with the mol ratio of compound 11, triphenylphosphine, diethyl azodiformate or diisopropyl azodiformate;
Step c) in compound 12 be 1:1.5-3 with the mol ratio of tetrabutyl ammonium fluoride;
Step a) in the eluting solvent of silica gel column chromatography be petrol ether/ethyl acetate=50:1-10:1.
5. a synthetic method for entecavir midbodies as claimed in claim 1, is characterized in that, the method with (S)-3-hydroxyl dimethyl adipate (compound 1) for starting raw material
comprise the following steps:
(1) compound 1 protects to obtain compound 2 through hydroxyl TBS;
(2) compound 2 generates compound 3 through Dieckmann condensation reaction;
(3) compound 3 protects into ketal through ketone, generates compound 4;
(4) compound 4 is reduced into hydroxyl through ester group, generates compound 5;
(5) compound 5 is through hydroxyl protection, generates compound 6;
(6) compound 6 deprotection generates compound 7;
(7) compound 7 becomes silyl enol ether through ketone, generates compound 8;
(8) compound 8 metachloroperbenzoic acid is oxidized to obtain compound 9;
6. the synthetic method of entecavir midbodies as claimed in claim 5, is characterized in that, comprise the steps:
1) compound 1 is generated compound 2 at organic solvent, acid binding agent under existing with TBSCl;
2) by step 1) in gained compound 2 in a solvent, cyclization under alkaline matter catalysis; Compound 3 is obtained through aftertreatment;
3) under the existence of organic solvent and catalyzer, by step 2) in gained compound 3 obtain compound 4 with glycol reaction;
4) by step 3) in gained compound 4 be dissolved in anhydrous tetrahydro furan, react under the effect of sodium borohydride and lithium chloride, obtain compound 5 through aftertreatment;
5) by step 4) gained compound 5 generates compound 6 at organic solvent, acid binding agent under existing with TBSCl;
6) by step 5) gained compound 6 is dissolved in methyl alcohol, and add hydrochloric acid and carry out ketal deprotection reaction, obtain compound 7 through aftertreatment;
7) by step 6) gained compound 7 in organic solvent, the obtained compound 8 of reaction under the existence of organic bases and TMSOTf;
8) by step 7) gained compound 8 through metachloroperbenzoic acid oxidizing reaction, obtain compound 9 through aftertreatment.
7. the synthetic method of entecavir midbodies as claimed in claim 6, is characterized in that concrete steps are as follows:
1) compound 1 is dissolved in organic solvent, adds acid binding agent, TBSCl successively, stirred at ambient temperature reaction 3-5 hour, add shrend and go out, separatory, organic phase washed with water, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, obtains compound 2; Described organic solvent be selected from methylene dichloride, dimethyl formamide, chloroform, tetrahydrofuran (THF) one or more; Described acid binding agent is imidazoles or pyridine;
2) by step 1) in gained compound 2 be dissolved in solvent, add alkaline matter, reflux 2-5 hour, question response terminates, concentrating under reduced pressure; Resistates adds 0.5M hydrochloric acid soln, with dichloromethane extraction, and organic phase washed with water twice, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, and crude product to be purified to obtain compound 3 through silica gel column chromatography; Described solvent is methyl alcohol, ethanol, the trimethyl carbinol, tetrahydrofuran (THF), dimethyl formamide; Described alkaline matter is sodium alkoxide or potassium alcoholate, sodium amide, sodium hydride, potassium hydride KH or hydrolith;
3) by step 2) in gained compound 3 be dissolved in organic solvent, add ethylene glycol and catalyzer, reflux divides water, reaction 4-10 hour, after not having moisture to produce, stop heating, be cooled to room temperature, add saturated sodium bicarbonate solution and stir 10 minutes, separatory, organic phase washed with water twice, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains compound 4; Described catalyzer is tosic acid, pyridine hydrochloride or pyridine hydrogen bromide salt; Described organic solvent is toluene, benzene, methylene dichloride, trichloromethane or tetrahydrofuran (THF).
4) sodium borohydride and lithium chloride are joined in anhydrous tetrahydro furan, stir 30 minutes under nitrogen protection, stop stirring allow deposition of solids, be added dropwise to by supernatant liquid in the round-bottomed flask of the anhydrous tetrahydro furan that compound 4 is housed, stirring at room temperature, until reactionless thing, adds shrend and to go out reaction, reaction solution concentrating under reduced pressure removes tetrahydrofuran (THF), residue from dichloromethane extracts, organic phase washed with water twice, merges, dry, filter, concentrating under reduced pressure, crude product column chromatography is purified to obtain compound 5;
5) by step 4) gained compound 5 is dissolved in organic solvent, adds acid binding agent, TBSCl successively, stirred at ambient temperature reaction 3-5 hour, and add shrend and go out, separatory, organic phase washed with water, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, obtains compound 2; Described organic solvent be selected from methylene dichloride, dimethyl formamide, chloroform, tetrahydrofuran (THF) one or more; Described acid binding agent is imidazoles or pyridine;
6) by step 5) gained compound 6 is dissolved in methyl alcohol, 3N hydrochloric acid is added under room temperature, stirring reaction 2-4 hour at 50 DEG C, until reactionless thing, is cooled to room temperature, adjust pH to neutral with saturated sodium bicarbonate solution, with dichloromethane extraction, organic phase, through anhydrous sodium sulfate drying, is filtered, concentrating under reduced pressure, crude product to be purified to obtain compound 7 through column chromatography;
7) by step 6) compound 7 is dissolved in organic solvent, is cooled to 0 DEG C, drips organic bases and TMSOTf wherein successively, stirs the mixture 1 hour of gained at 5 DEG C; After having reacted, add shrend and to go out reaction, be separated organic phase, wash with water, through anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains target compound 8; Described organic bases is one or more of pyridine, triethylamine, imidazoles or DBU; Described organic solvent is methylene dichloride;
8) by step 7) gained compound 8 is dissolved in methylene dichloride, and be cooled to-25 DEG C, add the metachloroperbenzoic acid of Sodium phosphate dibasic and 70% successively, stirring reaction 2-4 hour at-25 DEG C, add sodium sulfite solution and sodium bisulfate, reaction solution is heated to room temperature, stir 1-2 hour, after having reacted, be separated organic phase, wash twice with water, through anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, crude product to be purified to obtain compound 9 through silica gel column chromatography.
8. the synthetic method of entecavir midbodies as claimed in claim 6, is characterized in that:
Step 1) in compound 1 be 1:1.1-1.3:1.0-1.2 with the mol ratio of acid binding agent, TBSCl;
Step 2) in compound 2 be 1:1-3 with the mol ratio of alkaline matter;
Step 3) in compound 3 be 1:2-4:0.05-0.10 with the mol ratio of ethylene glycol, catalyzer;
Step 4) in compound 4 be 1:1.1-1.2:1.1-1.2 with the mol ratio of sodium borohydride, lithium chloride;
Step 5) in compound 5 be 1:1.1-1.3:1.1-1.2 with the mol ratio of acid binding agent, TBSCl;
Step 7) in compound 7 be 1:3-5:1-2 with the mol ratio of organic bases, TMSOTf;
Step 8) in compound 8 be 1:4-6:2-3 with the mol ratio of Sodium phosphate dibasic, metachloroperbenzoic acid.
9. the synthetic method of entecavir midbodies as claimed in claim 5, is characterized in that, the developping agent that silica gel column chromatography described in reaction process uses is petrol ether/ethyl acetate:
Step 2) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=90:1-70:1;
Step 4) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=60:1-40:1;
Step 6) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=90:1-70:1;
Step 8) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=50:1-10:1.
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| CN109705063B (en) * | 2017-10-26 | 2021-01-01 | 广州市朗启医药科技有限责任公司 | Entecavir intermediate and synthetic method thereof, and synthetic method of entecavir |
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| CN108976231B (en) * | 2018-10-26 | 2019-12-24 | 东莞理工学院 | Method for synthesizing entecavir as hepatitis B treating medicine |
| CN109593090A (en) * | 2019-01-25 | 2019-04-09 | 连云港贵科药业有限公司 | A kind of synthetic method of Entecavir |
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