CN102491960A - Intermediate compound for synthesis of entecavir, and preparation method and application of intermediate compound - Google Patents
Intermediate compound for synthesis of entecavir, and preparation method and application of intermediate compound Download PDFInfo
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- 0 COc1cc(-c2c*(C(CC[C@]([C@](*)C[C@@]3[n]4c(nc(N)nc5OCc6ccccc6)c5nc4)[C@@]3O)=O)ccc2OC)ccc1 Chemical compound COc1cc(-c2c*(C(CC[C@]([C@](*)C[C@@]3[n]4c(nc(N)nc5OCc6ccccc6)c5nc4)[C@@]3O)=O)ccc2OC)ccc1 0.000 description 1
- PNVSBVRZIIJGJZ-MBDNFAEBSA-N COc1ccc(COC[C@@H]([C@@H]2O[C@@H]2C2)[C@H]2OCc(cc2)ccc2OC)cc1 Chemical compound COc1ccc(COC[C@@H]([C@@H]2O[C@@H]2C2)[C@H]2OCc(cc2)ccc2OC)cc1 PNVSBVRZIIJGJZ-MBDNFAEBSA-N 0.000 description 1
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Abstract
The invention relates to an intermediate compound for synthesis of entecavir. The preparation method of the intermediate compound comprises the steps as follows: 1, preparation of cyclopentadienyl sodium; 2, preparation of (1S, 2R)-2-((4-methoxyl benzyloxy) methyl)-3-cyclopentene-1-alcohol; 3, preparation of (1S, 2R, 3S, 5R)-2-((4-methoxyl benzyloxy) methyl)-6-oxabicyclo (3. 1. 1)-hexanenitrile-3-alcohol; and 4, preparation of (1S, 2R, 3S, 5R)-3-benzyloxy-2-((4-methoxyl benzyloxy) methyl)-6-oxabicyclo (3. 1. 1)-hexane.
Description
Technical field:
The present invention relates to a kind of medicine compound method, particularly a kind of midbody of Entecavir.
Background technology:
A kind of 2 '-penta ring NSC 22837 analogues of Entecavir (Entecavir), chemical name be 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-3-methylol-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one monohydrate.
Its molecular structural formula is following:
Molecular formula: C
12H
15N
5O
3H
2O
Molecular weight: 295.30
Entecavir is a kind of medicine of hepatitis B virus resisting.II/III phase clinical study shows, oral 0.5mg can effectively suppress HBV-DNA and duplicated adult's every day, and curative effect is superior to lamivudine; III phase clinical study shows, dosage is increased to every day 1mg can effectively suppresses the HBV dna replication dna YMDD variation person is taken place.To just controlling the resistance incidence of patient treatment in the time of 1 year is 0, but is 5.8% to the resistance incidence of YMDD variation patient treatment in the time of 1 year takes place.For synthesizing of Entecavir several different methods being arranged at present; But adopt purine and cyclopentyl group bonded route more; And need use midbody (1S, 2R, 3S; 5R)-3-benzyloxy-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] hexane, so this midbody becomes the important intermediate of preparation Entecavir.
The invention reside in provides a kind of above-mentioned intermediates preparation, the difficulty in synthesizing with the solution Entecavir.
Summary of the invention:
The present invention provides a kind of midbody of synthetic Entecavir.
Midbody of the present invention, its chemical structure is following:
This midbody, chemical name is following: (1S, 2R, 3S, 5R)-3-benzyloxy-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] hexane
Its synthetic route of midbody of the present invention is following:
Synthetic route of the present invention, step is following:
One, the preparation of cyclopentadiene sodium
Two, (1S, 2R)-the pure preparation of 2-[(4-methoxyl group benzyloxy base) methyl]-3-cyclopentenes-1-
Three, (1S, 2R, 3S, 5R)-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] oneself-preparation of 3-alcohol
Four, (1S, 2R, 3S, 5R)-preparation of 3-benzyloxy-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] hexane
Wherein, the preparation of cyclopentadiene sodium, step is following: use cycle pentadiene dimer to be raw material, cracking obtains cyclopentadiene, prepares cyclopentadiene sodium with sodium sand, or prepares cyclopentadiene sodium with sodium hydride.
(1S, 2R)-the pure preparation of 2-[(4-methoxyl group benzyloxy base) methyl]-3-cyclopentenes-1-, step is following: 1-chloromethyl-(4-methoxyl group) phenmethyl ether and the reaction of cyclopentadiene sodium add (-)-diisopinocampheylchloroborane thiazolinyl borane, sodium hydroxide and hydrogen peroxide again.
(1S; 2R, 3S, 5R)-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] oneself-preparation of 3-alcohol; Step is following: (1S, 2R)-2-[(4-methoxyl group benzyloxy base) methyl]-3-cyclopentenes-1-alcohol in the presence of the methyl ethyl diketone vanadyl with tertbutyl peroxide reaction.
(1S, 2R, 3S; 5R)-preparation of 3-benzyloxy-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] hexane; Step is following: in the presence of 4-methoxyl group bromobenzyl and tetrabutylammonium iodide, and sodium hydride and (1S, 2R; 3S, 5R)-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] oneself-3-alcohol reaction.
Midbody of the present invention is used to prepare Entecavir, and the preparation process is following:
1, midbody of the present invention; Promptly
and
is in the presence of lithium hydride; In polar aprotic solvent, like DMF, DMSO.Reaction obtains midbody 6 under the guard mode of rare gas element; Promptly
wherein reaction solvent be preferably DMF, reaction finishes the back and collects and purify intermediates 6.
be by 2-amino-6-chlorine guanine and benzylalcohol, sodium hydride in THF, under protection of inert gas, react and make.
2, midbody 6 obtains midbody 7 with 4-methoxyl group-phenyl-chloride ditan in reaction in the presence of TEA and the 4-dimethylaminopyridine, under protection of inert gas; Promptly
wherein reaction solvent be preferably methylene dichloride, reaction finishes the back and collects and purify intermediates 7.
3, midbody 7 tries like potassium permanganate, sodium bromate, chromic acid reagent, DMSO/DCC, DMSO/SOCl in oxidation
2, DMSO/TFA or Dess-Marting reagent existence under, under the protection of rare gas element, carry out oxidizing reaction, obtain midbody 8, promptly
Wherein oxidising agent preferentially adopts DMSO/DCC reagent from the angle of environmental protection more, and reaction finishes the back and collects midbody 8.
4, midbody 8 is in the presence of Nysted reagent; With the methylene dichloride is solvent; Reaction obtains midbody 9 under protection of inert gas, i.e.
reaction finishes the back and collects and purify intermediates 9.
5, midbody 9 is dissolved in and is fit in the solvent; Under 20 ℃～55 ℃ acidic conditionss, slough blocking group; Obtain midbody 10; Promptly
wherein; Solvent can be selected the mixed solvent of THF, methyl alcohol or their arbitrary proportions, and employed souring agent is hydrochloric acid or phosphoric acid, and the best is the hydrochloric acid of 3mol/L.
6, under protection of inert gas, midbody 10 and boron trichloride are sloughed blocking group in methylene dichloride, and reactant obtains Entecavir under the methyl alcohol effect, promptly get the Entecavir bullion after revolving dried solvent.
7, purifying: the Entecavir bullion with after the suitable quantity of water reflux dissolving, is added an amount of gac and refluxed 10 minutes, and filtered while hot is filtrated and is left standstill crystallization, promptly obtains the pure article of Entecavir, and wherein the mass ratio of Entecavir and water is 1: (0.5～20).
In the above-mentioned preparation process, the mode of collection and each step products therefrom of purifying is preferably collected and purifying with the mode of column chromatography.It preferably is the protection of inert gas reaction process with nitrogen.
The invention has the advantages that:
1, raw material sources are wider, and cost is lower;
2, the synthetic of this midbody controlled the selectivity and the stereospecificity that react at the very start from reaction, can effectively suppress the generation of chiral isomer, and the product purification method is simple and yield is higher;
3, (1S, 2R)-2-[(4-methoxyl group benzyloxy base) methyl]-3-cyclopentenes-1-pure and mild (1S, 2R; 3S; 5R)-the preparation process of 3-benzyloxy-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] hexane in, 2 and 3 s' protection base is to methoxy-benzyl, because space steric effect and the more unsubstituted benzylic ether of the substituted benzylic ether of methoxyl group go protection more easily; This protection base can not only effectively be protected the target group; And removing when base protection, and also easy handling, target product yield is high;
4, this midbody can obtain the anti-hepatic-B virus medicine Entecavir through reaction of 6 steps and simple crystallization purifying of a step, each go on foot reaction temperature with and yield higher, be fit to amplify and produce.
Embodiment:
Below further specify the present invention through embodiment, but not as limitation of the present invention.
Embodiment 1
The preparation of cyclopentadiene sodium
In 100mL single port flask, add the 50mL cycle pentadiene dimer, slowly be warmed up to about 180 ℃.Normal pressure distillation down then makes the fractionation post make the temperature on the fractionation capital remain on 41～42 ℃, bathes the cooling distillate with cryosel, collects and obtains about 30mL water white transparency cyclopentadiene, and is subsequent use.
(1) prepares cyclopentadiene sodium with sodium sand
Get dried 100mL there-necked flask, (0.55gNa 23.9mmol), washs sodium sand three times with anhydrous tetrahydro furan in right amount under protection of nitrogen gas, to add the sodium sand sodium sand.Add the 25mL anhydrous tetrahydro furan then, cryosel is bathed cooling reaction liquid to about-10 ℃, stirs the cyclopentadiene 3.0g (the dropping time must not be lower than 30 minutes) that drips above-prepared down, stirs 1 hour down at-10 ℃, obtains red cyclopentadiene sodium, and is subsequent use.
(2) prepare cyclopentadiene sodium with sodium hydride
Get dried 100mL there-necked flask, under protection of nitrogen gas, add sodium hydride (60%, be scattered in Liquid Paraffin) 0.96g (24.0mmol); Add the 25mL anhydrous tetrahydro furan; Cryosel is bathed cooling reaction liquid to about-10 ℃, stirs the cyclopentadiene 3.0g (the dropping time must not be lower than 30 minutes) that drips above-prepared down, stirs 1 hour down at-10 ℃; Obtain red cyclopentadiene sodium, subsequent use.
(1S, 2R)-the pure preparation of 2-[(4-methoxyl group benzyloxy base) methyl]-3-cyclopentenes-1-
Get dry 500mL there-necked flask later under protection of nitrogen gas, add 4.5g (24.1mmol) 1-chloromethyl-(4-methoxyl group) phenmethyl ether, 40ml anhydrous tetrahydro furan, magnetic agitation;-78 ℃ approximately of cooling reaction liquid temps, the cyclopentadiene sodium of drawing above-prepared with disposable syringe slowly is added drop-wise in the reaction flask in constant pressure funnel; The dropping process is kept the temperature of reaction system all the time at-65 ℃～-78 ℃, dropwises continued reaction 1 hour, stopped reaction; Reaction solution is poured in 160mL pentane and the 80mL mixture of ice and water; Constantly stir back solution layering, separatory, collected organic layer is also used the mixture of ice and water washed twice.Organic layer is stirring drying with anhydrous magnesium sulfate below 0 ℃, filters rapidly, and filtrating is at concentrating under reduced pressure below 0 ℃, and the yellow oil that obtains adds the cold anhydrous tetrahydro furan of 40mL; Cooling reaction liquid is to-78 ℃, treat temperature-stable after, drip the suspension liquid of 7.40g (25mmol) (-)-diisopinocampheylchloroborane thiazolinyl borane and the formation of 40ml anhydrous tetrahydro furan, slowly be warmed up to-10 ℃ after dropwising; Stirring reaction 48h under this temperature, stopped reaction adds 10mL methyl alcohol, slowly adds the aqueous sodium hydroxide solution of 10ml (0.03mol) 3mol/L; Guarantee to drip the process reaction liquid temp and be no more than 5 ℃, slowly drip the aqueous hydrogen peroxide solution of 10ml (0.03mol) 30% then, guarantee to drip the process reaction liquid temp and be no more than 12 ℃; Reaction solution continues reaction 1 hour, and the maintenance system temperature is at 0 ℃～10 ℃, TLC (sherwood oil: after ETHYLE ACETATE=4: 1) the detection reaction raw material disappears basically; Add the saturated unnecessary hydrogen peroxide of sodium sulfite solution cancellation of 50ml, stir after 30 minutes, add the saturated nacl aqueous solution of 50ml and the ether of 50ml; Stirred 10 minutes, and told organic layer, water layer is with an amount of extracted with diethyl ether 3 times; Merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying; Concentrating under reduced pressure obtains bullion, and the silicagel column purifying (gradient elution, eluent is sherwood oil before this; Sherwood oil then: ethyl acetate=3: 1), obtain yellow oil 3.58g, yield 63.5%.
(1S, 2R, 3S, 5R)-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] oneself-preparation of 3-alcohol
The preparation of tertbutyl peroxide anhydrous solution: the tertbutyl peroxide solution of getting 20ml 70% mixes with the 34mL methylene dichloride, and careful shaking flasks makes mixes fully, and standing demix is isolated organic layer, uses anhydrous sodium sulfate drying, filters filtrate for later use.
Get exsiccant 100mL there-necked flask, under nitrogen protection, adding 1.1g (4.69mmol) (1S, 2R)-2-[(4-methoxyl group benzyloxy base) methyl]-3-cyclopentenes-1-alcohol; 1.2g (4.69mmol) methyl ethyl diketone vanadyl and 30mL anhydrous methylene chloride, magnetic agitation drips off the dichloromethane solution of the 3.2mL 3mol/L tertbutyl peroxide of above-prepared in the 30min, and the control reacting liquid temperature is no more than 20 ℃; Stirred 15 hours, TLC (sherwood oil: ETHYLE ACETATE=3: 1) detect the basic disappearance of raw material point after, cooling reaction liquid to 0 ℃; Slowly drip the 10mL saturated sodium sulfite aqueous solution, temperature at room temperature stirred after dropwising 2 hours below 20 ℃ in the control reaction solution; Tell organic layer, water layer merges organic layer with an amount of dichloromethane extraction three times; The saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains bullion; Silicagel column purifying (eluent: sherwood oil: ethyl acetate=4: 1), obtain faint yellow oily thing 0.82g, yield: 70.0%.
(1S, 2R, 3S, 5R)-preparation of 3-benzyloxy-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] hexane
Get dried 100mL there-necked flask, under protection of nitrogen gas, add 3.5g (88mmol) sodium hydride (60%, be dispersed in the MO) and 20mL anhydrous tetrahydro furan, magnetic agitation; Slowly drip 11g (44mmol) (1S, 2R, 3S, 5R)-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] oneself-the 10mL anhydrous tetrahydrofuran solution of 3-alcohol; After dropwising, stirred 2 hours under the room temperature, be warming up to 40 ℃ again and stirred 3 hours, cooling reaction liquid is after room temperature; Add 13ml (88mmol) 4-methoxyl group bromobenzyl and 4mg (10.8mmol) tetrabutylammonium iodide, continued stirring at room 6 hours, (sherwood oil: ETHYLE ACETATE=4: 1) the detection reaction raw material disappears TLC basically; Add the 10mL absolute ethyl alcohol then and destroy reaction solution, stirred 15 minutes, decompression steams solvent; Add each 20mL of ETHYLE ACETATE and water washing respectively, tell organic layer, water layer is with an amount of ethyl acetate extraction three times; Merge organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains bullion; Silicagel column purifying (eluent: sherwood oil: ethyl acetate=5: 1), obtain white or off-white color solid 12.3g, yield 75.6%.
Target compound
1H NMR data parsing is following:
1H?NMR(CDCl
3，400MHz)δ：7.18～7.24(m，4H，ArH)，6.81～6.89(m，4H，ArH)，4.40(s，2H，PhCH
2OH)，4.38～4.39(d，J＝3.6Hz，2H，PhCH
2OH)，3.83～3.85(m，1H，3-H)，3.80(s，3H，OCH
3)，3.78(s，3H，OCH
3)，3.32～3.51(m，4H，1-H，5-H?and?OCH
2)，2.55～2.58(m，1H，2-H)，1.96～2.13(m，2H，4-H
2)。
Claims (6)
1. the midbody compound of a synthetic Entecavir, its chemical structure is following:
2. the midbody compound of claim 1, its preparation methods steps is following:
One, the preparation of cyclopentadiene sodium
Two, (1S, 2R)-the pure preparation of 2-[(4-methoxyl group benzyloxy base) methyl]-3-cyclopentenes-1-
Three, (1S, 2R, 3S, 5R)-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] oneself-preparation of 3-alcohol
Four, (1S, 2R, 3S, 5R)-preparation of 3-benzyloxy-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] hexane.
3. the midbody compound of claim 1, its preparation methods steps is following:
4. the midbody compound of claim 1, its preparation methods steps is following:
Wherein, the preparation of cyclopentadiene sodium, step is following: use cycle pentadiene dimer to be raw material, cracking obtains cyclopentadiene, prepares cyclopentadiene sodium with sodium sand, or prepares cyclopentadiene sodium with sodium hydride;
(1S, 2R)-the pure preparation of 2-[(4-methoxyl group benzyloxy base) methyl]-3-cyclopentenes-1-, step is following: 1-chloromethyl-(4-methoxyl group) phenmethyl ether and the reaction of cyclopentadiene sodium add (-)-diisopinocampheylchloroborane thiazolinyl borane, sodium hydroxide and hydrogen peroxide again;
(1S; 2R, 3S, 5R)-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] oneself-preparation of 3-alcohol; Step is following: (1S, 2R)-2-[(4-methoxyl group benzyloxy base) methyl]-3-cyclopentenes-1-alcohol in the presence of the methyl ethyl diketone vanadyl with tertbutyl peroxide reaction;
(1S, 2R, 3S; 5R)-preparation of 3-benzyloxy-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] hexane; Step is following: in the presence of 4-methoxyl group bromobenzyl and tetrabutylammonium iodide, and sodium hydride and (1S, 2R; 3S, 5R)-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] oneself-3-alcohol reaction.
5. the midbody compound of claim 1, its preparation methods steps is following:
The preparation of cyclopentadiene sodium
In 100mL single port flask, add the 50mL cycle pentadiene dimer, slowly be warmed up to about 180 ℃.Normal pressure distillation down then makes the fractionation post make the temperature on the fractionation capital remain on 41～42 ℃, bathes the cooling distillate with cryosel, collects and obtains about 30mL water white transparency cyclopentadiene, and is subsequent use;
(1) prepares cyclopentadiene sodium with sodium sand
Get dried 100mL there-necked flask, under protection of nitrogen gas, add sodium sand an amount of (0.55gNa, 23.9mmol); Wash sodium sand three times with anhydrous tetrahydro furan, add the 25mL anhydrous tetrahydro furan then, cryosel is bathed cooling reaction liquid to about-10 ℃; Stir the cyclopentadiene 3.0g (the dropping time must not be lower than 30 minutes) that drips above-prepared down; Stirred 1 hour down at-10 ℃, obtain red cyclopentadiene sodium, subsequent use;
(2) prepare cyclopentadiene sodium with sodium hydride
Get dried 100mL there-necked flask, under protection of nitrogen gas, add sodium hydride (60%, be scattered in Liquid Paraffin) 0.96g (24.0mmol); Add the 25mL anhydrous tetrahydro furan; Cryosel is bathed cooling reaction liquid to about-10 ℃, stirs the cyclopentadiene 3.0g (the dropping time must not be lower than 30 minutes) that drips above-prepared down, stirs 1 hour down at-10 ℃; Obtain red cyclopentadiene sodium, subsequent use;
(1S, 2R)-the pure preparation of 2-[(4-methoxyl group benzyloxy base) methyl]-3-cyclopentenes-1-
Get dry 500mL there-necked flask later under protection of nitrogen gas, add 4.5g (24.1mmol) 1-chloromethyl-(4-methoxyl group) phenmethyl ether, 40ml anhydrous tetrahydro furan, magnetic agitation;-78 ℃ approximately of cooling reaction liquid temps, the cyclopentadiene sodium of drawing above-prepared with disposable syringe slowly is added drop-wise in the reaction flask in constant pressure funnel; The dropping process is kept the temperature of reaction system all the time at-65 ℃～-78 ℃, dropwises continued reaction 1 hour, stopped reaction; Reaction solution is poured in 160mL pentane and the 80mL mixture of ice and water; Constantly stir back solution layering, separatory, collected organic layer is also used the mixture of ice and water washed twice.Organic layer is stirring drying with anhydrous magnesium sulfate below 0 ℃, filters rapidly, and filtrating is at concentrating under reduced pressure below 0 ℃, and the yellow oil that obtains adds the cold anhydrous tetrahydro furan of 40mL; Cooling reaction liquid is to-78 ℃, treat temperature-stable after, drip the suspension liquid of 7.40g (25mmol) (-)-diisopinocampheylchloroborane thiazolinyl borane and the formation of 40ml anhydrous tetrahydro furan, slowly be warmed up to-10 ℃ after dropwising; Stirring reaction 48h under this temperature, stopped reaction adds 10mL methyl alcohol, slowly adds the aqueous sodium hydroxide solution of 10ml (0.03mol) 3mol/L; Guarantee to drip the process reaction liquid temp and be no more than 5 ℃, slowly drip the aqueous hydrogen peroxide solution of 10ml (0.03mol) 30% then, guarantee to drip the process reaction liquid temp and be no more than 12 ℃; Reaction solution continues reaction 1 hour, and the maintenance system temperature is at 0 ℃～10 ℃, TLC (sherwood oil: after ETHYLE ACETATE=4: 1) the detection reaction raw material disappears basically; Add the saturated unnecessary hydrogen peroxide of sodium sulfite solution cancellation of 50ml, stir after 30 minutes, add the saturated nacl aqueous solution of 50ml and the ether of 50ml; Stirred 10 minutes, and told organic layer, water layer is with an amount of extracted with diethyl ether 3 times; Merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying; Concentrating under reduced pressure obtains bullion, and the silicagel column purifying (gradient elution, eluent is sherwood oil before this; Sherwood oil then: ethyl acetate=3: 1), obtain yellow oil 3.58g, yield 63.5%;
(1S, 2R, 3S, 5R)-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] oneself-preparation of 3-alcohol
The preparation of tertbutyl peroxide anhydrous solution: the tertbutyl peroxide solution of getting 20ml 70% mixes with the 34mL methylene dichloride, and careful shaking flasks makes mixes fully, and standing demix is isolated organic layer, uses anhydrous sodium sulfate drying, filters filtrate for later use;
Get exsiccant 100mL there-necked flask, under nitrogen protection, adding 1.1g (4.69mmol) (1S, 2R)-2-[(4-methoxyl group benzyloxy base) methyl]-3-cyclopentenes-1-alcohol; 1.2g (4.69mmol) methyl ethyl diketone vanadyl and 30mL anhydrous methylene chloride, magnetic agitation drips off the dichloromethane solution of the 3.2mL 3mol/L tertbutyl peroxide of above-prepared in the 30min, and the control reacting liquid temperature is no more than 20 ℃; Stirred 15 hours, TLC (sherwood oil: ETHYLE ACETATE=3: 1) detect the basic disappearance of raw material point after, cooling reaction liquid to 0 ℃; Slowly drip the 10mL saturated sodium sulfite aqueous solution, temperature at room temperature stirred after dropwising 2 hours below 20 ℃ in the control reaction solution; Tell organic layer, water layer merges organic layer with an amount of dichloromethane extraction three times; The saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains bullion; Silicagel column purifying (eluent: sherwood oil: ethyl acetate=4: 1), obtain faint yellow oily thing 0.82g, yield: 70.0%;
(1S, 2R, 3S, 5R)-preparation of 3-benzyloxy-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] hexane
Get dried 100mL there-necked flask, under protection of nitrogen gas, add 3.5g (88mmol) sodium hydride (60%, be dispersed in the MO) and 20mL anhydrous tetrahydro furan, magnetic agitation; Slowly drip 11g (44mmol) (1S, 2R, 3S, 5R)-2-[(4-methoxyl group benzyloxy base) methyl]-6-oxabicyclo [3.1.0] oneself-the 10mL anhydrous tetrahydrofuran solution of 3-alcohol; After dropwising, stirred 2 hours under the room temperature, be warming up to 40 ℃ again and stirred 3 hours, cooling reaction liquid is after room temperature; Add 13ml (88mmol) 4-methoxyl group bromobenzyl and 4mg (10.8mmol) tetrabutylammonium iodide, continued stirring at room 6 hours, (sherwood oil: ETHYLE ACETATE=4: 1) the detection reaction raw material disappears TLC basically, adds the 10mL absolute ethyl alcohol then and destroys reaction solution; Stirred 15 minutes, decompression steams solvent, adds each the 20mL washing of ETHYLE ACETATE and water respectively; Tell organic layer, water layer merges organic layer with an amount of ethyl acetate extraction three times; Anhydrous sodium sulfate drying, concentrating under reduced pressure obtains bullion, silicagel column purifying (eluent: sherwood oil: ethyl acetate=5: 1); Obtain white or off-white color solid 12.3g, i.e. target compound, yield 75.6%.
6. the application of the midbody compound of claim 1 in the preparation Entecavir.
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| CN107400135A (en) * | 2017-07-12 | 2017-11-28 | 浙江华圣生物药业有限公司 | A kind of processing method of entecavir midbodies |
| CN107652251A (en) * | 2017-08-09 | 2018-02-02 | 浙江华纳药业有限公司 | A kind of entecavir midbodies III preparation methods |
| CN111777556A (en) * | 2020-07-15 | 2020-10-16 | 遂成药业股份有限公司 | Method for preparing acridine 9-carboxylic acid by oxidation method |
| CN113024574A (en) * | 2019-12-25 | 2021-06-25 | 南通诺泰生物医药技术有限公司 | Preparation method of oxabicyclohexane compound |
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| CN107188786A (en) * | 2017-05-31 | 2017-09-22 | 湖北远大生命科学与技术有限责任公司 | A kind of preparation method of medicine intermediate optical voidness cyclopentenol |
| CN107188786B (en) * | 2017-05-31 | 2021-10-22 | 湖北远大生命科学与技术有限责任公司 | Preparation method of optically pure cyclopentenol as medical intermediate |
| CN107400135A (en) * | 2017-07-12 | 2017-11-28 | 浙江华圣生物药业有限公司 | A kind of processing method of entecavir midbodies |
| CN107652251A (en) * | 2017-08-09 | 2018-02-02 | 浙江华纳药业有限公司 | A kind of entecavir midbodies III preparation methods |
| CN113024574A (en) * | 2019-12-25 | 2021-06-25 | 南通诺泰生物医药技术有限公司 | Preparation method of oxabicyclohexane compound |
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| CN111777556A (en) * | 2020-07-15 | 2020-10-16 | 遂成药业股份有限公司 | Method for preparing acridine 9-carboxylic acid by oxidation method |
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