CN109293508A - A kind of preparation method of entecavir midbodies - Google Patents
A kind of preparation method of entecavir midbodies Download PDFInfo
- Publication number
- CN109293508A CN109293508A CN201811277939.7A CN201811277939A CN109293508A CN 109293508 A CN109293508 A CN 109293508A CN 201811277939 A CN201811277939 A CN 201811277939A CN 109293508 A CN109293508 A CN 109293508A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- reaction
- solvent
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/39—Preparation of carboxylic acid esters by oxidation of groups which are precursors for the acid moiety of the ester
- C07C67/42—Preparation of carboxylic acid esters by oxidation of groups which are precursors for the acid moiety of the ester by oxidation of secondary alcohols or ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/21—Acetic acid esters of hydroxy compounds with more than three hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the preparation methods for synthesizing grace body card Wei key intermediate.Specifically, this method is with bis benzyl (+)-Coreylactone diol (I) for starting material, and by acylation, protected silane, grignard reaction obtains entecavir key intermediate shown as a formula V after B-V oxidation.
Description
Technical field
The present invention relates to a kind of preparation methods of chipal compounds, are specifically related to a kind of preparation of entecavir midbodies
Method.
Background technique
Entecavir (Entecavir) chemical name are as follows: (1S, 3R, 4S) -9- [4- hydroxyl-(3- methylol) -2- methylene
Cyclopentyl] -6H- purine-6-one.Molecular formula: C12H15O3N5, molecular weight: 277.3, structural formula is as follows:
Entecavir is developed by Bristol-Myers squibb company of the U.S., and in March, 2005 is by U.S.'s food medicine
The approval listing of product management board.It is a kind of NSC 22837 class of effective, selectivity inhibition hepatitis B replication
Like object, has the function of extremely strong inhibition hepatitis B virus duplication, reduces serum-virus DNA level.Compound selectivity simultaneously
Relatively high, cytotoxicity is the 1/8000 of anti-hepatitis B activity, can effectively treat chronic hepatitis B without interfering influenza disease
Poison and inhibition of HIV, use is safe, and tolerance is good.
United States Patent (USP) US5206244 and disclose within 1993 Entecavir preparation and its as HBV inhibitor purposes,
This method synthesizes to obtain Entecavir (process 1) by multi-section using cyclopentadiene as starting material.Subsequent numerous patents are in this base
Be somebody's turn to do on plinth into.But this route, because gradually introducing chiral centre, the control of optics impurity is more difficult.Reaction process center pillar layer
Analysis step is more, and yield is lower.
Process 1
In conclusion this field needs to develop a kind of new starting material of use, need not gradually introduce chiral centre, be produced into
This is low, processing efficient, easy to operate, optics impurity is easy to control, and is suitble to the preparation of the entecavir midbodies of industrialized production
Method, and it is used to prepare Entecavir new intermediate.
Summary of the invention
It is an object of the invention to provide a kind of using new starting material, need not gradually introduce chiral centre, production cost
Low, processing efficient, easy to operate, optics impurity is easy to control, and is suitble to the preparation side of the entecavir midbodies of industrialized production
Method, and it is used to prepare Entecavir new intermediate.
In the first aspect of the present invention, a kind of preparation method of intermediate shown as a formula V, the preparation method packet are provided
Include step:
(1) react double benzyl (+)-Ke Li lactones glycol (shown in formula I) with nafoxidine, to obtain Formula II
Compound
(2) react Formula II compound with hydroxy protecting agent, to obtain formula III compound
(3) react formula III compound with methyl Grignard, thus shape compound of formula IV
With
(4) formula IV compound is made to carry out B-V oxidation reaction, to obtain the intermediate
Wherein, R is hydroxyl protection base.
In another preferred example, the reaction of step (1) carried out in the first solvent or condition of no solvent under carry out.
In another preferred example, compound of formula I and the molar ratio of nafoxidine are 1:3~10.
In another preferred example, the reaction temperature of step (1) is under 40 DEG C to reflux temperature.
In another preferred example, the reaction time of step (1) is 1-3 hours.
In another preferred example, in step (1), first solvent is non-protonic solvent.
In another preferred example, when the reaction of step (1) carries out in the first solvent, compound of formula I and nafoxidine
Molar ratio is 1:3~5；Or
When the reaction of step (1) carries out under solvent-free conditions, compound of formula I and nafoxidine molar ratio are 1:6~10.
In another preferred example, the solvent-free progress of the reaction of step (1).
In another preferred example, compound of formula I and nafoxidine molar ratio are 1:6.
In another preferred example, in step (2), the hydroxy protecting agent is tert-butyl chloro-silicane (TBSCl)
Or chlorotriethyl silane (TESCl).
In another preferred example, step (2) be in the second solvent, in the presence of acid binding agent, make Formula II compound with
Hydroxy protecting agent is reacted, to obtain Formula II compound.
In another preferred example, in step (2), second solvent is polar aprotic solvent.
In another preferred example, in step (2), the acid binding agent is imidazoles.
In another preferred example, in step (2), the molar ratio of Formula II compound and hydroxy protecting agent is 1:1~5；More
It preferably, is 1:1.2.
In another preferred example, in step (2), the reaction temperature of the reaction is 0 DEG C to reflux temperature.
In another preferred example, in step (2), the reaction time of the reaction is 1~10 hour.
In another preferred example, step (3) carries out in third solvent；
In another preferred example, in step (3), the molar ratio of formula III compound and methyl Grignard is 1:1.2~2；
In another preferred example, in step (3), the methyl Grignard is that bromomethane or chloromethanes are formed with magnesium chips
Grignard Reagent；
In another preferred example, in step (3), the reaction time of the reaction is 3-5 hours；And/or
In another preferred example, in step (3), the reaction temperature of the reaction is 0 DEG C to reflux temperature.
In another preferred example, in step (3), the third solvent is non-protonic solvent.
It in another preferred example, is that chloromethanes and magnesium chips are formed by Grignard Reagent in step (3).
In another preferred example, in step (3), the molar ratio of formula III compound and methyl Grignard is 1:1.2.
In another preferred example, step (4) is to carry out formula IV compound and peroxy trifluoroacetic acid anti-in the 4th solvent
It answers, to obtain the intermediate.
In another preferred example, in step (4), the 4th solvent is non-protonic solvent.
In another preferred example, in step (4), the molar ratio of formula IV compound and peroxy trifluoroacetic acid is 1:3~5；More
It preferably, is 1:3.
In another preferred example, in step (4), the reaction temperature of the reaction is 0-30 DEG C.
In another preferred example, in step (4), the reaction time of the reaction is 1~10 hour.
In another preferred example, in step (4), the molar ratio of the formula IV compound and peroxy trifluoroacetic acid is 1:3.
In another preferred example, in step (4), the reaction temperature of the reaction is 20~30 DEG C.
In another preferred example, the non-protonic solvent is selected from the group: methylene chloride, 1,2- dichloroethanes, chloroform, second
Acetoacetic ester, tetrahydrofuran, ether, toluene, or combinations thereof.
In another preferred example, the polar aprotic solvent is selected from the group: n,N-Dimethylformamide, N, N- diformazan
Yl acetamide, or combinations thereof.
The second aspect of the present invention provides a kind of intermediate for being used to prepare Entecavir, the intermediate such as Formula V institute
Show
The third aspect of the present invention provides a kind of purposes of intermediate as described in second aspect, which is characterized in that uses
In preparing Entecavir.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
Inventor is after extensive and in-depth study, it was found that a kind of new intermediate for being used to prepare Entecavir, in this
Chiral centre needed for mesosome itself has Entecavir, so that preparing Entecavir using the intermediate avoids traditional preparation
Method needs gradually to introduce chiral centre, and is difficult to control optics impurity, and preparation process needs multistep column to chromatograph, and yield is low to be lacked
It falls into.In addition, the present invention additionally uses the by-product generated when a kind of starting material for preparing prostaglandin as new intermediate
The starting material of preparation, reduces production cost.The present invention is completed based on this.
Starting material: (+)-Ke Li lactones glycol ((+)-Coreylactone diol)
Starting material (+)-Ke Li lactones glycol is prostaglandin starting material (-)-Ke Li lactones glycol ((-)-
Coreylactone diol) split after enantiomer, and the enantiomer is without other usages.It can be reduced into using enantiomer
This, reduces offal treatment cost, protects environment.And (+)-Ke Li lactones glycol makes in starting material as starting material
There are the chiral centres that product needs.And the optical purity of raw material itself is fine, and optical isomer is extremely low.
Entecavir key intermediate
The present invention provides a kind of key intermediates for being used to synthesize Entecavir shown as a formula V.
The preparation method of entecavir key intermediate
The present invention provides a kind of for synthesizing the preparation method of entecavir key intermediate (shown as a formula V).
Specifically, shown preparation method comprising steps of
Step (1): make double benzyl (+)-Ke Li lactones glycol (bis benzyl (+)-Coreylactone diol) and four
Hydrogen pyrroles is at reacting, to obtain Formula II compound.
Preferably, the reaction of step (1) carried out in the first solvent or condition of no solvent under carry out.
Preferably, first solvent is non-protonic solvent.
Preferably, the molar ratio of step (1) compounds of formula I and nafoxidine is 1:3~10.
Preferably, when the reaction of step (1) carries out in non-protonic solvent, mole of compound of formula I and nafoxidine
When than carrying out under solvent-free conditions for the reaction of 1:3~5 or step (1), compound of formula I is with nafoxidine molar ratio
1:6~10.
Preferably, the solvent-free progress of the reaction of step (1).
Preferably, compound of formula I and nafoxidine molar ratio are 1:6.
Preferably, the reaction temperature of step (1) is under 40 DEG C to reflux temperature.
Preferably, the reaction time of step (1) is 1-3 hours.
Step (2): react Formula II compound with hydroxy protecting agent (for example, TBSCl or TESCl), to make
The hydroxyl in Formula II compound is obtained by protection shape compound of Formula III.
Preferably, step (2) is in the presence of acid binding agent, to make Formula II compound and hydroxyl protection in the second solvent
Reagent is reacted, to obtain Formula II compound.
Preferably, in step (2), the hydroxy protecting agent is tert-butyl chloro-silicane (TBSCl) or triethyl group
Chlorosilane (TESCl).
Preferably, in step (2), the acid binding agent is imidazoles.
Preferably, in step (2), second solvent is polar aprotic solvent；It is highly preferred that being DMF.
Preferably, in step (2), the molar ratio of Formula II compound and hydroxy protecting agent is 1:1~5；It is highly preferred that being
1:1.2.
Preferably, the reaction temperature of step (2) reaction is 0 DEG C to reflux temperature；It is highly preferred that being room temperature (10~30
℃)。
Preferably, the reaction time of step (2) reaction is 1~10 hour.
Step (3): reacting formula III compound with methyl Grignard, thus shape compound of formula IV.
Preferably, step (3) be in third solvent, react formula III compound with methyl Grignard, thus
Shape compound of formula IV.
Preferably, in step (3), the molar ratio of formula III compound and methyl Grignard is 1:1.2~2；More preferably
Ground, molar ratio 1:1.2.
Preferably, in step (3), the methyl Grignard is that bromomethane or chloromethanes and magnesium chips are formed by grignard examination
Agent, it is highly preferred that being that chloromethanes and magnesium chips are formed by Grignard Reagent.
Preferably, the third solvent is non-protonic solvent；It is highly preferred that being THF.
Preferably, the reaction time of step (3) reaction is 3-5 hours.
Preferably, the reaction temperature of step (3) reaction is 0 DEG C to reflux temperature；It is highly preferred that being 60~65 DEG C.
Step (4): formula IV compound is made to carry out B-V oxidation reaction, to obtain intermediate shown as a formula V.
Preferably, step (4) be in the 4th solvent, react formula IV compound with peroxy trifluoroacetic acid, thus
Obtain the intermediate.
Preferably, in step (4), the molar ratio of formula IV compound and peroxy trifluoroacetic acid is 1:3~5；It is highly preferred that being
1:3.
Preferably, the reaction temperature of step (4) reaction is 0-30 DEG C；It is highly preferred that being 20~30 DEG C.
Preferably, the reaction time of step (4) reaction is 1~10 hour.
Preferably, in step (4), the 4th solvent is non-protonic solvent；It is highly preferred that being methylene chloride.
Main advantages of the present invention include:
(a) chiral purity of Entecavir can be improved in the intermediate prepared by the method for the invention, reduces optics impurity,
Combined coefficient is improved, production cost is reduced.
(b) starting material for preparing intermediate of the invention commonly uses the by-product that starting materials generate from other are prepared,
Therefore cost can be reduced using preparation method of the invention, reduce offal treatment cost and protects environment.
(c) it is easy to control suitable chiral centre, optics impurity need not gradually to be introduced during preparing intermediate of the invention
Industrialized production.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, or according to manufacturer
Proposed condition.Unless otherwise stated, otherwise percentage and number are weight percent and parts by weight.
The preparation of 1 compound of formula I of embodiment
(+)-Coreylactone diol (172.0g, 0.1mol) is dissolved in DMF (1720.0ml), bromobenzyl is added in stirring
(599.0g, 3.5mol), 60%NaH (160.0g, 4.0mol), room temperature reaction to TLC detect fully reacting.Post-processing.It will be anti-
Liquid is answered to pour in ice water, ethyl acetate extracts, and organic layer is successively washed with 1% hydrochloric acid solution, washes, and saturated salt washing, layering has
Machine layer anhydrous magnesium sulfate dries, filters, and filtrate is concentrated to give grease.Target product, decompression are collected in silicagel column on grease, elution
It is concentrated to give product: 252.0g (yield 71.6%).
The preparation of 2 Formula II compound of embodiment
Under argon gas protection, compound of formula I (35.24g, 0.1mol) is dissolved in nafoxidine (42.66g, 0.6mol), is stirred
It is warming up to 80-85 DEG C, is reacted 5 hours, TLC detects fully reacting.Post-processing: it after reaction solution is cooled to room temperature, is concentrated under reduced pressure into
Do to obtain grease, (quantitative yield).
The preparation of 3 formula III compound of embodiment
Formula II compound (42.4g, 0.1mol) is dissolved in DMF (212.0ml), stirring addition imidazoles (17.0g,
0.25mol), tert-butyl chloro-silicane (18.09g, 0.12mol), room temperature reaction to TLC detect fully reacting.Post-processing:
Reaction solution is poured in ice water, ethyl acetate extracts, and organic layer is successively washed with 10% citric acid solution, it washes, saturated salt washing,
Layering, organic layer anhydrous magnesium sulfate dry, filter, and filtrate is concentrated to give grease: 48.0g (yield 89.3%).
The preparation of 4 formula III compound of embodiment
Formula II compound (42.4g, 0.1mol) is dissolved in DMF (212.0ml), stirring addition imidazoles (17.0g,
0.25mol), chlorotriethyl silane (18.09g, 0.12mol), room temperature reaction to TLC detect fully reacting.Post-processing: it will react
Liquid pours in ice water, and ethyl acetate extracts, and organic layer is successively washed with 10% citric acid solution, washes, saturated salt washing, layering,
Organic layer anhydrous magnesium sulfate dries, filters, and filtrate is concentrated to give grease: 44.0g (yield 81.8%).
The preparation of 5 formula IV compound of embodiment
Under argon gas protection, magnesium rod (8.7g, 0.36mol) is dissolved in anhydrous THF (130.0ml), a small amount of chlorine of agitation and dropping
Methane Grignard Reagent after illumination causes, is passed through methyl chloride gas, natural exotherm, and control gas is passed through speed, keeps pico-
Reflux state to magnesium rod completely disappears, and is cooled to the 0-5 DEG C of Grignard Reagent for obtaining chloromethyl magnesium.
Under argon gas protection, intermediate (III) (53.8g, 0.1mol) is dissolved in anhydrous THF (269.0ml), stirring and dissolving room
The Grignard Reagent of chloromethyl magnesium is added dropwise in temperature, is added dropwise, and after being warming up to 60-65 DEG C of reaction 3 hours, TLC detects fully reacting.Afterwards
Processing: reaction solution is poured into saturated ammonium chloride solution, and ethyl acetate extracts, and organic layer is successively washed with water, saturated salt washing, point
Layer, organic layer anhydrous magnesium sulfate dry, filter, and filtrate decompression is concentrated to give grease: 47.3g (yield 98.0%).
The preparation of 6 formula IV compound of embodiment
Under argon gas protection, magnesium rod (8.7g, 0.36mol) is dissolved in anhydrous THF (130.0ml), a small amount of chlorine of agitation and dropping
Methane Grignard Reagent after illumination causes, is passed through methyl chloride gas, natural exotherm, and control gas is passed through speed, keeps pico-
Reflux state to magnesium rod completely disappears, and is cooled to the 0-5 DEG C of Grignard Reagent for obtaining chloromethyl magnesium.
Under argon gas protection, intermediate (III) (53.8g, 0.1mol) is dissolved in anhydrous THF (269.0ml), stirring and dissolving room
The Grignard Reagent of chloromethyl magnesium is added dropwise in temperature, is added dropwise, and after being warming up to 60-65 DEG C of reaction 3 hours, TLC detects fully reacting.Afterwards
Processing: reaction solution is poured into saturated ammonium chloride solution, and ethyl acetate extracts, and organic layer is successively washed with water, saturated salt washing, point
Layer, organic layer anhydrous magnesium sulfate dry, filter, and filtrate decompression is concentrated to give grease: 45.8g (yield 94.9%).
The preparation of the intermediate shown as a formula V of embodiment 7
Trifluoroacetic anhydride (63.0g, 0.3mol) is dissolved in methylene chloride (1260.0ml), stirring is cooled to 0 degree, is added dropwise
30% hydrogen peroxide (34.0g, 0.3mol), is added dropwise, and after being warming up to 20-30 DEG C of stirring 30 minutes, is added dropwise intermediate (IV)
Methylene chloride (242.0ml) solution of (48.3g, 0.1mol) detects fully reacting in 20-30 DEG C of reaction to TLC, by reaction solution
It being poured into after being stirred 15 minutes in saturated sodium bisulfite solution, water layer methylene chloride extracts, and merge organic layer and successively washes, saturated salt
Washing, organic layer dry, filter, silica gel column purification on filtrate, and target product is collected in elution, and product: 24.8g is concentrated under reduced pressure to obtain
(yield 64.6%).
1H-NMR(CDCl3)δ1.782-1.793(dm,2H),δ2.080-2.092(s,3H),δ2.121-2.194(m,
2H),δ2.830-2.847(dm,1H),δ3.198-3.211(m,3H),δ4.404-4.538(m,4H),δ7.194-7.208(m,
10H)。
The preparation of the intermediate shown as a formula V of embodiment 8
Trifluoroacetic anhydride (63.0g, 0.3mol) is dissolved in methylene chloride (1260.0ml), stirring is cooled to 0 degree, is added dropwise
30% hydrogen peroxide (34.0g, 0.3mol), is added dropwise, and after being warming up to 20-30 DEG C of stirring 30 minutes, is added dropwise intermediate (IV)
Methylene chloride (242.0ml) solution of (48.3g, 0.1mol) detects fully reacting in 20-30 DEG C of reaction to TLC, by reaction solution
It being poured into after being stirred 15 minutes in saturated sodium bisulfite solution, water layer methylene chloride extracts, and merge organic layer and successively washes, saturated salt
Washing, organic layer dry, filter, silica gel column purification on filtrate, and target product is collected in elution, and product: 21.0g is concentrated under reduced pressure to obtain
(yield 54.7%).
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. a kind of preparation method of intermediate shown as a formula V, which is characterized in that the preparation method comprising steps of
(1) react double benzyl (+)-Ke Li lactones glycol (shown in formula I) with nafoxidine, to obtain Formula II chemical combination
Object
(2) react Formula II compound with hydroxy protecting agent, to obtain formula III compound
(3) react formula III compound with methyl Grignard, thus shape compound of formula IV
With
(4) formula IV compound is made to carry out B-V oxidation reaction, to obtain the intermediate
Wherein, R is hydroxyl protection base.
2. preparation method as described in claim 1, which is characterized in that step (1) has following one or more features:
A. the reaction of step (1) carried out in the first solvent or condition of no solvent under carry out；
B. compound of formula I and the molar ratio of nafoxidine are 1:3~10；
C. the reaction temperature of step (1) is under 40 DEG C to reflux temperature；And/or
D. the reaction time of step (1) is 1-3 hours.
3. preparation method as claimed in claim 2, which is characterized in that when the reaction of step (1) carries out in the first solvent, formula
Compound I and the molar ratio of nafoxidine are 1:3~5；Or
When the reaction of step (1) carries out under solvent-free conditions, compound of formula I and nafoxidine molar ratio are 1:6~10.
4. preparation method as described in claim 1, which is characterized in that in step (2), the hydroxy protecting agent is tert-butyl
Dimethylchlorosilane (TBSCl) or chlorotriethyl silane (TESCl).
5. preparation method as described in claim 1, which is characterized in that step (2) is in the second solvent, in depositing for acid binding agent
Under, react Formula II compound with hydroxy protecting agent, to obtain Formula II compound.
6. preparation method as described in claim 1, which is characterized in that step (3) has following one or more features:
A. step (3) carries out in third solvent；
B. the molar ratio of formula III compound and methyl Grignard is 1:1.2~2；
C. the methyl Grignard is that bromomethane or chloromethanes and magnesium chips are formed by Grignard Reagent；
D. the reaction time of the reaction is 3-5 hours；And/or
E. the reaction temperature of the reaction is 0 DEG C to reflux temperature.
7. preparation method as described in claim 1, which is characterized in that step (4) is to make formula IV compound in the 4th solvent
It is reacted with peroxy trifluoroacetic acid, to obtain the intermediate.
8. preparation method as claimed in claim 7, which is characterized in that step (4) has following one or more features:
A. the 4th solvent is non-protonic solvent；
B. the molar ratio of formula IV compound and peroxy trifluoroacetic acid is 1:3~5；
C. the reaction temperature of the reaction is 0-30 DEG C；And/or
D. the reaction time of the reaction is 1~10 hour.
9. a kind of intermediate for being used to prepare Entecavir, which is characterized in that the intermediate is shown as a formula V
10. a kind of purposes of intermediate as claimed in claim 9, which is characterized in that be used to prepare Entecavir.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811277939.7A CN109293508B (en) | 2018-10-30 | 2018-10-30 | Preparation method of entecavir intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811277939.7A CN109293508B (en) | 2018-10-30 | 2018-10-30 | Preparation method of entecavir intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109293508A true CN109293508A (en) | 2019-02-01 |
| CN109293508B CN109293508B (en) | 2021-01-22 |
Family
ID=65145548
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811277939.7A Active CN109293508B (en) | 2018-10-30 | 2018-10-30 | Preparation method of entecavir intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109293508B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924454A (en) * | 2012-11-13 | 2013-02-13 | 苏州市玮琪生物科技有限公司 | Synthetic method of entecavir |
| WO2014000673A1 (en) * | 2012-06-29 | 2014-01-03 | Sunshine Lake Pharma Co., Ltd. | Process for preparation of entecavir |
| CN104177396A (en) * | 2013-05-23 | 2014-12-03 | 浙江星月药物科技股份有限公司 | Entecavir intermediates and preparation methods thereof |
| WO2015051900A1 (en) * | 2013-10-08 | 2015-04-16 | Pharmathen S.A. | Process for the preparation of entecavir through novel intermediates |
-
2018
- 2018-10-30 CN CN201811277939.7A patent/CN109293508B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014000673A1 (en) * | 2012-06-29 | 2014-01-03 | Sunshine Lake Pharma Co., Ltd. | Process for preparation of entecavir |
| CN102924454A (en) * | 2012-11-13 | 2013-02-13 | 苏州市玮琪生物科技有限公司 | Synthetic method of entecavir |
| CN104177396A (en) * | 2013-05-23 | 2014-12-03 | 浙江星月药物科技股份有限公司 | Entecavir intermediates and preparation methods thereof |
| WO2015051900A1 (en) * | 2013-10-08 | 2015-04-16 | Pharmathen S.A. | Process for the preparation of entecavir through novel intermediates |
Non-Patent Citations (1)
| Title |
|---|
| 胡小彤: "恩替卡韦中间体五元碳环的合成", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109293508B (en) | 2021-01-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109293508A (en) | A kind of preparation method of entecavir midbodies | |
| KR100980379B1 (en) | Process for the preparation of optically active 5-hydroxy-3-oxoheptanoate derivatives | |
| JPH0834768A (en) | New dimethacrylate | |
| CZ299193B6 (en) | Process for preparing HIV protease inhibitors | |
| JP2009518380A (en) | Preparation of 2-chloroethoxy-acetic acid-N, N-dimethylamide | |
| CN103467443B (en) | 2-alkyl-3-aminothiophene derivative and application thereof | |
| JP5265144B2 (en) | Novel process for producing 3-O-substituted-catechin derivatives | |
| JP2002179611A (en) | Method for producing dicarboxylic acid compound | |
| CN111556861A (en) | Preparation method of jasmonate compound | |
| JP2002037759A (en) | Method for producing acrylic acid ester or methacrylic acid ester | |
| JP4832019B2 (en) | Polycyclic ester containing cyclic carbonate skeleton | |
| KR100296737B1 (en) | The Process of Aceclofenac | |
| JPS5940158B2 (en) | Organosyrannoseizohouhou | |
| JP4049965B2 (en) | Novel (meth) acrylic acid esters and process for producing the same | |
| US20050059732A1 (en) | Synthesis of 8-membered carbocyclic compound having diexomethylene groups | |
| JP2681202B2 (en) | Tribasic acid ester | |
| KR100418327B1 (en) | New aziridine derivatives and their preparation methods | |
| JP2009256307A (en) | Adamantyl ester of unsaturated carboxylic acid and method for producing the same | |
| JP4659251B2 (en) | Process for producing hydroxy-4-oxatricyclo [4.3.1.13,8] undecan-5-one and (meth) acrylic acid ester thereof | |
| Lee et al. | Selective Reduction of Nitrocinnamoylfumagillols with α, β-Unsaturated Ester Using Borohydride Exchange Resin (BER)-Nickel Acetate | |
| JP3272340B2 (en) | Method for producing 1-[(cyclopent-3-en-1-yl) methyl] -5-ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione | |
| JP2001192379A (en) | 1,3-dioxan-2-on-5-yl(meth)acrylate and method for producing the same | |
| JP3758707B2 (en) | (-)-Trans-coumaucine production method and novel intermediate | |
| JP4747748B2 (en) | Preparation of imidazopyran derivatives | |
| CN112142710A (en) | Method for producing ester compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |