CN109776539A - Entecavir long-chain ester and its preparation method and application - Google Patents
Entecavir long-chain ester and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of Entecavir derivatives and combinations thereof, and the invention further relates to a kind of preparation methods of Entecavir derivative.Entecavir derivative provided by the invention has the pharmaceutical usage for the treatment of hepatitis B, and blood concentration fluctuation is small in vivo, and effective blood drug concentration is held time length, and bioavilability is high, can achieve the long-acting effect steadily discharged.
Description
Technical field
The present invention relates to a kind of Entecavir derivatives and its preparation method and application, and in particular to a kind of Entecavir is long
Chain ester and its preparation method and application.
Background technique
Entecavir (Entecavir) is a kind of oral antiviral medicament, is initially developed and is opened by Bristol-Myers Squibb Co.
Hair, entecavir tablets are approved to list in China within 2 months 2006, entitled [1S- (1 α, 3 α, 4 β)] -2- amino -1,9- of chemistry
Dihydro -9- [4- hydroxyl -3- (methylol) -2- methylenecyclopentyl] -6H- purine-6-one has following structural formula:
In the therapeutic process of hepatitis B, need effectively to inhibit hepatitis B, once virus obtains effectively
Inhibit, then can be used low dosage to carry out maintenance therapy, blocks or persistently inhibit the duplication of hepatitis B in vivo to reach, it should
Treatment is a long-term, lasting therapeutic process, once stopping anti-hepatitis B treatment, then may cause the exacerbation of serious acute hepatitis.
Existing frequently-used entecavir tablets, which exist, to be absorbed fast, and blood drug concentration peak valley phenomenon is serious, half-life short, when cannot be long
Between maintain stablize therapeutic drug level the problem of.Therefore, it is simple to develop a kind of preparation process, it is at low cost, and release steady in a long-term
Entecavir formulation have important clinical meaning.
A kind of Entecavir multivesicular liposome is disclosed in CN105534905A, release in vitro the result shows that on day 4 when,
Drug discharges completely substantially, although the purpose of sustained release may be implemented in the multivesicular liposome, it is complicated that there are the preparation processes of preparation,
The problems such as product cost is high, sustained release release time is short.
Entecavir derivative provided by the invention, solves the problems, such as above-mentioned, has reached effective blood drug concentration dimension
Hold the effect that the time is long, bioavilability is high and long-acting stabilization discharges.
Summary of the invention
The present invention provides a kind of Entecavir long-chain esters and its preparation method and application.
Entecavir long-chain ester provided by the invention, structural formula is as shown in formula I:
Wherein RCO- is selected from the linear or branched alkyl group carbonyl of 18 carbon and 18 carbon or more；It is preferred that C18~C28 straight chain or
Branched alkyl carbonyl；It is preferred that C18~C26 linear or branched alkyl group carbonyl；More preferable C18~C24 linear or branched alkyl group carbonyl；
Further preferred C18~C22 linear or branched alkyl group carbonyl；Most preferably stearyl or peanut acyl group.
In segmentation scheme of the invention, the structural formula of formula I -1 is as follows:
In segmentation scheme of the invention, the structural formula of formula I -2 is as follows:
The present invention provides the preparation methods of type I compound, it is characterised in that: Entecavir is in condensing agent, condensation activation
It is reacted in the presence of agent and solvent with RCOOH, the compound of formula I is made；
Wherein RCOOH is selected from the linear chain or branched chain fatty acid of 18 carbon and 18 carbon or more；It is preferred that C18~C28 straight chain or branch
Chain fatty acid；It is preferred that C18~C26 linear chain or branched chain fatty acid；More preferable C18~C24 linear chain or branched chain fatty acid；It is further excellent
Select C18~C22 linear chain or branched chain fatty acid；Most preferably stearic acid or arachidic acid.
In certain embodiments of the invention, condensing agent is selected from diisopropylcarbodiimide (DIC), two cyclohexyl carbon, two Asia
Amine (DCC), 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide (EDCI)；It is condensed activator and is selected from 4-dimethylaminopyridine
(DMAP), I-hydroxybenzotriazole (HOBT), 1- hydroxyl -7- azo benzotriazole (HOAT), O- (three nitrogen of 7- azepine benzo
Azoles -1- base)-two (dimethylamino) carbon hexafluorophosphates (HATU).
Further, condensing agent DIC, condensation activator are DMAP.
The present invention also provides another preparation methods of type I compound, it is characterised in that: Entecavir is in catalyst and molten
It is reacted in the presence of agent with RCOCl, the compound of formula I is made；
Wherein RCO- is selected from the linear or branched alkyl group carbonyl of 18 carbon and 18 carbon or more；It is preferred that C18~C28 straight chain or
Branched alkyl carbonyl；It is preferred that C18~C26 linear or branched alkyl group carbonyl；More preferable C18~C24 linear or branched alkyl group carbonyl；
Further preferred C18~C22 linear or branched alkyl group carbonyl；Most preferably stearyl or peanut acyl group.
The present invention provides a kind of pharmaceutical compositions, it is characterised in that the compound of formula I containing therapeutically effective amount and medicinal
Auxiliary material.
Further, described pharmaceutical composition is administered with parenteral form.
The present invention also provides purposes of the type I compound in the drug that preparation treatment has related disorders with hepatitis B.
Entecavir derivative provided by the invention, preparation process is simple, at low cost, when internal effective blood drug concentration maintains
Between it is long, bioavilability is high, realize the technical effect of long-acting stable release.
Detailed description of the invention
Fig. 1: the different Entecavir long-chain ester conversion ratios in hepatomicrosome of test example 1
Fig. 2: 2 rat 3 '-Entecavir of intramuscular injection stearate of test example, 3 '-Entecavir Arachidates and Entecavir
The average Drug-time curve of monohydrate preparation
Specific embodiment
Following embodiment is to be described in more detail the present invention, but the invention is not limited in any way.
Entecavir compound as shown in structure above, we are on the basis of the structure, to the hydroxyl on 3 ' positions
Base and long chain fatty acids carry out condensation reaction, a series of long-chain fatty acid ester of 3 '-Entecavirs have been prepared, subsequent
It is indicated in embodiment with 3 '-Entecavir aliphatic esters.This is reacted at ester using DMF as solvent, and DCC or DIC are condensing agent,
Under DMAP catalysis, make Entecavir and long chain fatty acids at ester.Specific composite signal is as follows
Embodiment 1:3 '-Entecavir stearate
1, embodiment 1- I
DMF300ml, entecavir-monohydrate (30.0g, 101.66mmol), stearic acid (31.8g, 101.66mmol),
DMAP (3.73g, 30.5mmol) and DIC (51.3g, 406.64mmol) reacts at room temperature 48h.It filters, washs filter with appropriate DMF
Cake, filtrate decompression concentration, is added 900ml ethyl acetate and petroleum ether mixed liquor, filters, white solid is obtained, by above-mentioned preparation
Obtained white solid is added in 400ml methanol, is heated to boiling, and the cooling 16h of room temperature has Precipitation, white is obtained by filtration
Solid 7.26g, yield 13.1%, 183.0-184.2 DEG C of fusing point.
1H NMR (400MHz, CD3OD): 7.731 (s, 1H, H-8), 5.507 (t, 1H, J=8.68Hz, H-1 '), 5.277
(brs, 1H, C=CH2), and 4.847 (brs, 1H ,-C=CH2), 4.322-4.377 (m, 3H ,-CH2OCO+H-4 '), 2.877
(brs, 1H, H-3 '), and 2.464-2.534 (m, 1H, H-5 '), 2.374 (t, 2H, J=7.36Hz ,-CH2COO), 2.201-
2.259 (m, 1H, H-5 '), 1.627 (t, 2H, J=7.12Hz ,-CH2CH2COO), 1.273 (s, 28H ,-CH2CH2CH2COO),
0.898 (t, 3H, J=7.04Hz ,-CH3)
2, embodiment 1- II
The product can also react as follows obtained: addition 10ml pyridine, entecavir-monohydrate (1.5g,
5.082mmol) with stearic acid chloride (5.13ml, 15.249mmol), 16h is reacted at room temperature, water is added, precipitating is precipitated, is filtered, filter cake
Through silica gel column chromatography, faint yellow solid is obtained.
Embodiment 2:3 '-Entecavir Arachidate
Using DMF as solvent, using DIC as condensing agent, Entecavir (1.0g) and arachidic acid (2.118g) react at room temperature 16h,
There is white solid precipitation, filter, filtrate decompression concentration dissolves residue with proper amount of methanol, and through silica gel column chromatography, it is solid to obtain white
Body obtains white solid 0.532g with recrystallizing methanol, fusing point: 185.7-188.6 DEG C, yield 27.0%.
1H NMR(400MHz,CD3OD): 7.741 (s, 1H, H-8), 5.522 (t, 1H, J=8.68Hz, H-1 '), 5.286
(brs, 1H, C=CH2), 4.863 (brs, 1H ,-C=CH2),4.336-4.412(m,3H,-CH2OCO+H-4’),2.894
(brs, 1H, H-3 '), and 2.478-2.548 (m, 1H, H-5 '), 2.389 (t, 2H, J=7.32Hz ,-CH2COO),2.216-
2.275 (m, 1H, H-5 '), 1.643 (t, 2H, J=7.12Hz ,-CH2CH2COO),1.297(s,32H,-CH2CH2CH2COO),
0.913 (t, 3H, J=6.64Hz ,-CH3).
Embodiment 3:3 '-Entecavir behenate
Anhydrous DMF (40ml) be solvent, be added DIC (2.053g, 16.266mmol), DMAP (149.1mg,
1.22mmol), entecavir-monohydrate (1.2g, 4.067mmol) and behenic acid (2.772g, 8.133mmol), room temperature reaction
16h has white solid precipitation, filters, and filtrate decompression concentration through silica gel column chromatography, finally obtains white solid 0.240g, melts
Point: 129.7-132.9 DEG C, yield 12.6%.
Reference examples 1:3 '-Entecavir dodecanoate and 3 ', the double dodecanoates of 4 '-Entecavirs
Anhydrous DMF (30ml) be solvent, be added DIC (1.28g, 10.166mmol), entecavir-monohydrate (1.0g,
3.389mmol) with lauric acid/dodecanoic acid (1.4g, 6.779mmol), 16h, filtering, filtrate decompression concentration, through silica gel column layer are reacted at room temperature
Analysis, obtains the double dodecanoate 880mg of 3 ', 4 '-Entecavirs, white solid, and 118.0-119.7 DEG C of fusing point, yield 45.5%；
1HNMR (400MHz, CD3OD): 7.757 (s, 1H, H-8), 5.501 (t, 2H, J=9.6Hz, H-1 '), 5.329
(t, 1H, J=2.56Hz, H-4 '), 5.289 (brs, 1H, C=CH2), 4.840 (brs, 1H, C=CH2), 4.404 (d, 2H, J
=7.08Hz ,-CH2OCO), 3.048 (brs, 1H, H-3 '), 2.683-2.757 (m, 1H, H-5 '), 2.333-2.410 (m,
3H ,-CH2COO+H-5 '), 1.631 (t, 2H, J=6.84Hz ,-CH2CH2COO), 1.302 (s, 32H ,-CH2CH2CH2COO),
0.895 (t, 6H, J=6.24Hz ,-CH3)
While 3 '-Entecavir dodecanoate 500mg are obtained, and white solid, 211.6-213.6 DEG C of fusing point, yield
31.2%
1HNMR (400MHz, CD3OD): 7.724 (s, 1H, H-8), 5.507 (t, 1H, J=8.48Hz, H-1 '), 5.277
(brs, 1H, C=CH2), 4.864 (s, 1H ,-C=CH2), 4.333-4.370 (m, 3H ,-CH2OCO+H-4 '), 2.877 (s,
1H, H-3 '), 2.463-2.532 (m, 1H, H-5 '), 2.384 (t, 2H, J=7.32Hz ,-CH2COO), 2.207-2.357 (m,
1H, H-5 '), 1.620 (t, 2H, J=7.00Hz ,-CH2CH2COO), 1.289 (s, 16H ,-CH2CH2CH2COO), 0.893 (t,
3H, J=6.48Hz ,-CH3)
Reference examples 2:3 '-Entecavir myristate and 3 ', the double myristates of 4 '-Entecavirs
Anhydrous DMF (30ml) be solvent, be added DIC (125.0g, 1.107mmol), entecavir-monohydrate (1.0g,
3.389mmol) with myristic acid (1.5g, 6.778mmol), 16h, filtering, filtrate decompression concentration, through silica gel column layer are reacted at room temperature
Analysis, obtains the double myristate 230mg of 3 ', 4 '-Entecavirs, white solid, fusing point: 203.0-205.1 DEG C, yield 13.4%；
While 3 '-Entecavir myristate 500mg are obtained, and white solid, fusing point: 142.4-144.5 DEG C, yield
30.2%.
1H NMR(400MHz,CD3OD): 7.731 (s, 1H, H-8), 5.507 (t, 1H, J=8.68Hz, H-1 '), 5.277
(brs, 1H, C=CH2), 4.848 (brs, 1H ,-C=CH2),4.322-4.368(m,3H,-CH2OCO+H-4’),2.877
(brs, 1H, H-3 '), and 2.464-2.534 (m, 1H, H-5 '), 2.374 (t, 2H, J=7.36Hz ,-CH2COO),2.201-
2.260 (m, 1H, H-5 '), 1.626 (t, 2H, J=7.00Hz ,-CH2CH2COO),1.272(s,20H,-CH2CH2CH2COO),
0.895 (t, 3H, J=7.0Hz ,-CH3).
Reference examples 3:3 '-Entecavir pentadecanoic acid ester
Anhydrous DMF (45ml) be solvent, be added DIC (1.54g, 12.2mmol), entecavir-monohydrate (1.2g,
4.067mmol) with pentadecanoic acid (2.0g, 8.133mmol), 16h is reacted at room temperature, there is white solid precipitation, filtered, filtrate decompression is dense
Contracting finally obtains white solid 1.12g through silica gel column chromatography, and 196.2-196.4 DEG C of fusing point, yield 51.4%.
1HNMR(400MHz,CD3OD): 7.725 (s, 1H, H-8), 5.507 (t, 1H, J=8.96Hz, H-1 '), 5.724
(brs, 1H, C=CH2), 4.864 (brs, 1H ,-C=CH2),4.332-4.399(m,3H,-CH2OCO+H-4’),2.878
(brs, 1H, H-3 '), and 2.463-2.533 (m, 1H, H-5 '), 2.375 (t, 2H, J=7.32Hz ,-CH2COO),2.202-
2.261 (m, 1H, H-5 '), 1.629 (t, 2H, J=7.04Hz ,-CH2CH2COO),1.275(s,22H,-CH2CH2CH2COO),
0.897 (t, 3H, J=6.6Hz ,-CH3)
Reference examples 4:3 '-Entecavir palmitate
DMF (35ml) be solvent, be added DIC (1.069g, 8.472mmol), entecavir-monohydrate (1.0g,
3.389mmol), DMAP (62.0mg, 0.51mmol) and hexadecylic acid (1.738g, 6.778mmol) react at room temperature 16h, filter,
Filtrate decompression concentration, through silica gel column chromatography, finally obtains white solid 0.954g, fusing point: 170.2-172.5 DEG C, yield
53.1%.
1H NMR (400MHz, CD3OD): 7.723 (s, 1H, H-8), 5.507 (t, 1H, J=9.00Hz, H-1 '), 5.277
(brs, 1H, C=CH2), and 4.848 (brs, 1H ,-C=CH2), 4.320-4.398 (m, 3H ,-CH2OCO+H-4 '), 2.877
(brs, 1H, H-3 '), and 2.462-2.532 (m, 1H, H-5 '), 2.374 (t, 2H, J=7.32Hz ,-CH2COO), 2.201-
2.253 (m, 1H, H-5 '), 1.628 (t, 2H, J=7.00Hz ,-CH2CH2COO), 1.289 (s, 26H ,-CH2CH2CH2COO),
0.897 (t, 3H, J=7.04Hz ,-CH3)
Reference examples 5:3 '-Entecavir margarate
DMAP (0.149g, 1.22mmol), DIC (2.052g, 16.216mmol), entecavir is added in anhydrous DMF (40ml)
Wei monohydrate (1.2g, 4.067mmol) and heptadecanoic acid (2.200g, 8.133mmol), room temperature reaction are stayed overnight, after reaction,
There is more white solid to be precipitated, filter, filtrate decompression concentration through silica gel column chromatography, finally obtains white solid 1.450g, melts
Point: 183.3-185.4 DEG C, yield 65.1%.
1H NMR(400MHz,CD3OD):1H NMR(400MHz,CD3OD):7.724(s,1H,H-8),5.506(t,1H,
J=8.64Hz, H-1 '), 5.270 (brs, 1H, C=CH2), 4.849 (brs, 1H ,-C=CH2), 4.316-4.398 (m, 3H ,-
CH2OCO+H-4 '), 2.878 (brs, 1H, H-3 '), 2.462-2.532 (m, 1H, H-5 '), 2.373 (t, 2H, J=7.36Hz ,-
), CH2COO 2.202-2.261 (m, 1H, H-5 '), 1.627 (t, 2H, J=7.12Hz ,-CH2CH2COO), 1.274 (s, 28H ,-
), CH2CH2CH2COO 0.897 (t, 3H, J=6.6Hz ,-CH3)
Test example 1: Entecavir long-chain ester rat liver microsomes incubated in vitro experiment
1, drug and reagent:
Rat liver microsomes: the auspicious moral in Shanghai (lot number: ASAN)
Sample:
Table 1: laboratory sample and source
2, experimental program
(1), 0.1mmol/L kaliumphosphate buffer (pH7.4) is prepared: weighing K2HPO417.418mg → 100ml pure water, takes
80.2ml；Weigh KH2PO413.609mg → 100ml pure water, takes 19.8ml；After the two mixing, it is diluted to 1000ml, phosphoric acid is adjusted
PH7.4.37 DEG C are incubated for for preparing following solution.
(2), rat hepatic microsome dilutes: rat hepatic microsome 20mg/mL is diluted with kaliumphosphate buffer, obtains 0.5mg/mL's
Rat hepatic microsome solution.
(3), long-chain ester is dissolved to 1mg/mL with DMSO, is diluted to 200 μM.
(4), liver microsomes incubation reacts: the hepatomicrosome solution 2ml of 0.5mg/mL is taken, 2 μ L of trial drug solution is added,
The concentration of Entecavir long-chain ester is 0.2 μM, is mixed, and every sample is 2 parts parallel, and 37 DEG C of water-bath concussion temperature are incubated, and concussion speed is
135r/min, in 0min, 30min, 1h, 2h, 4h, 6h, for 24 hours when sample 100 μ L, be added terminated into the ice acetonitrile of 200 μ L it is anti-
It answers, it is to be measured to be put into -80 DEG C of refrigerators.
(5), sample detection: the concentration of Entecavir in LC-MS/MS method test sample obtains conversion ratio.
3, experimental result
Different Entecavir long-chain ester conversion datas in hepatomicrosome are shown in Table 2, and different Entecavir long-chain esters are in liver
Conversion rate curve is shown in attached drawing 1 in microsome.
The different Entecavir long-chain esters of table 2. conversion ratio (%) in hepatomicrosome
Conclusion:
Dodecanoate, myristate, pentadecanoic acid ester, palmitate and margarate exist it can be seen from table 2 and attached drawing 1
For 8h up to balance, rate of release is very fast, and conversion ratio reaches 100%, cannot achieve the effect discharged steadily in the long term；Stearate and flower
For raw acid esters for 24 hours not yet up to balance, conversion ratio has the feature realized and discharged steadily in the long term between 40-70%.
Test example 2:3 '-Entecavir stearate, 3 '-Entecavir Arachidates and entecavir-monohydrate are big
Medicine generation evaluation in mouse body
1, sample
3 '-Entecavir stearates: it is prepared according to embodiment 1- I；
3 '-Entecavir Arachidates: it is prepared according to embodiment 2；
Entecavir-monohydrate: Shandong greenery pharmacy provides；
2, prepared by sample formulation
(1), the preparation of the PBS of 10mM pH7.0:
Weigh 2.75gNaH2PO4·H2O is added 100ml water, is stirred with glass bar to dissolution, then surpass in 250ml beaker
Sound 5min.Weigh 2.83gNa2HPO4In 250ml beaker, 100ml water is added, is stirred with glass bar to dissolution, then ultrasound
5min.Take 64mlNaH2PO4·H2O aqueous solution is in above-mentioned 100mlNa2HPO4In aqueous solution, up to 0.2M phosphate buffer.It takes
In 250ml beaker 190ml deionized water is added to get 10mM phosphate buffer, surveying its PH is in 10ml0.2M phosphate buffer
7.01。
(2), the preparation of solvent:
| Solvent composition | It weighs |
| Polysorbas20 | 0.5g |
| NaCl | 0.6g |
| PEG4000 | 4.5g |
| PBS | 100g |
Solvent is prepared according to the prescription in above table, with 0.22 μ filtering with microporous membrane.
(3), the preparation of first suspension:
7mL solvent is measured in 10mL cillin bottle, the API of the amount of listing in above table is added, covers rubber stopper, sealed membrane is close
Envelope, vortex 1min, ultrasonic 1min, then the 1min that is vortexed promote mixing and incipient wetness.
(4), the preparation of suspension:
It for the first suspension of incipient wetness, is sheared with high speed shear dispersion machine, shearing rotating speed 17500rpm.It cuts
Sample need to remain condition of ice bath during cutting, to prevent local heat production in shear history.Effective shear time is 5min,
In every shearing 1min, stop 40s.
3, experimental program
(1), experimental animal
SD rat (Shandong Luye Pharmaceutical Co., Ltd.'s offer) 12 divides 3 groups, every group 4.
(2), dosage
By intramuscular injection, giving rat dose is 24mg/kg.
* dosage is in terms of Entecavir；
(3), the intramuscular injection group sampling time
Before administration (0 hour) and administration after 0.5h, 1h, 6h, 1d, 2d, 4d, 7d, 10d, 14d, 21d, 28d, 35d, 42d
Blood 0.5mL is taken in rat eye socket, is set in heparinised tubes, 3500rpm is centrifuged 10min, takes -35 DEG C of supernatant preservations.
4, test result:
Rat distinguishes intramuscular injection grace 3 '-and replaces card Wei stearate, 3 '-Entecavir Arachidates and entecavir-monohydrate
Entecavir concentration is shown in Table 3, table 4 and table 5 in blood plasma after preparation；Rat 3 '-Entecavir of intramuscular injection stearate, 3 '-entecavirs
The average Drug-time curve of Wei Arachidate and entecavir-monohydrate preparation is shown in attached drawing 2；3 '-Entecavir of rat intramuscular injection is stearic
The kinetic parameter of acid esters, 3 '-Entecavir Arachidates and entecavir-monohydrate preparation is relatively shown in Table 6.
3,4 rats of table give Entecavir concentration (ng/mL) in 3 '-Entecavir stearate preparation blood plasma
4,4 rats of table give Entecavir concentration (ng/mL) in 3 '-Entecavir Arachidate preparation blood plasma
5,4 rats of table give Entecavir concentration (ng/mL) in entecavir-monohydrate preparation blood plasma
Three kinds of table 6, Entecavir preparation kinetic parameters compare
Conclusion
Found out by table 3, table 4, table 5, table 6 and attached drawing 2, after rat muscle injects relative medicine, entecavir-monohydrate
Release is fast in vivo, and slow release effect is poor；The t of 3 '-Entecavir stearates and 3 '-Entecavir Arachidates1/2It is respectively
14.9d, 12.8d, Tmax are 5.00d, 8.00d respectively, and Cmax is 41.0ng/mL*h, 70.8ng/mL*h, AUC (0-t) respectively
Respectively 555ng/mL*h, 733ng/mL*h, absolute bioavailability are respectively 117%, 154%；3 '-Entecavir stearic acid
The effective blood drug concentration of ester and 3 '-Entecavir Arachidates is steady and internal blood concentration fluctuation is small, effective blood drug concentration dimension
It is long to hold the time, realizes reduction blood concentration fluctuation, improves the vivo biodistribution availability of drug, achievees the effect that steadily to discharge.
Claims (8)
1. a kind of Entecavir derivative, it is characterised in that the structural formula with formula I:
Wherein RCO- is selected from the linear or branched alkyl group carbonyl of 18 carbon and 18 carbon or more；It is preferred that C18~C28 linear chain or branched chain
Alkyl-carbonyl；It is preferred that C18~C26 linear or branched alkyl group carbonyl；More preferable C18~C24 linear or branched alkyl group carbonyl；Into one
Walk preferred C18~C22 linear or branched alkyl group carbonyl；Most preferably stearyl or peanut acyl group.
2. the preparation method of type I compound, it is characterised in that: presence of the Entecavir in condensing agent, condensation activator and solvent
It is lower to be reacted with RCOOH, the compound of formula I is made；
Wherein RCOOH is selected from the linear chain or branched chain fatty acid of 18 carbon and 18 carbon or more；It is preferred that C18~C28 linear chain or branched chain rouge
Fat acid；It is preferred that C18~C26 linear chain or branched chain fatty acid；More preferable C18~C24 linear chain or branched chain fatty acid；Further preferably
C18~C22 linear chain or branched chain fatty acid；Most preferably stearic acid or arachidic acid.
3. preparation method according to claim 2, it is characterised in that: condensing agent be selected from diisopropylcarbodiimide (DIC),
Dicyclohexylcarbodiimide (DCC), 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide (EDCI)；Condensation activator is selected from
4-dimethylaminopyridine (DMAP), I-hydroxybenzotriazole (HOBT), 1- hydroxyl -7- azo benzotriazole (HOAT), O- (7-
Azepine benzotriazole -1- base)-two (dimethylamino) carbon hexafluorophosphates (HATU).
4. preparation method according to claim 3, it is characterised in that: condensing agent DIC, condensation activator are DMAP.
5. the preparation method of type I compound, it is characterised in that: Entecavir is anti-with RCOCl in the presence of catalysts and solvents
It answers, the compound of formula I is made；
Wherein RCO- is selected from the linear or branched alkyl group carbonyl of 18 carbon and 18 carbon or more；It is preferred that C18~C28 linear chain or branched chain
Alkyl-carbonyl；It is preferred that C18~C26 linear or branched alkyl group carbonyl；More preferable C18~C24 linear or branched alkyl group carbonyl；Into one
Walk preferred C18~C22 linear or branched alkyl group carbonyl；Most preferably stearyl or peanut acyl group.
6. a kind of pharmaceutical composition, it is characterised in that type I compound and pharmaceutic adjuvant containing therapeutically effective amount.
7. pharmaceutical composition according to claim 6, it is characterized in that: it is administered with parenteral form.
8. purposes of the type I compound in the drug that preparation treatment has related disorders with hepatitis B.
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| CN201711114221.1A CN109776539A (en) | 2017-11-13 | 2017-11-13 | Entecavir long-chain ester and its preparation method and application |
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| CN201711114221.1A CN109776539A (en) | 2017-11-13 | 2017-11-13 | Entecavir long-chain ester and its preparation method and application |
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| CN109776539A true CN109776539A (en) | 2019-05-21 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114105987A (en) * | 2020-08-26 | 2022-03-01 | 上海博志研新药物技术有限公司 | Entecavir medicinal salt and preparation method, pharmaceutical composition and application thereof |
| WO2022198195A1 (en) * | 2021-03-16 | 2022-09-22 | The Scripps Research Institute | Anitiviral prodrugs of entecavir (etv) and formulations thereof |
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2017
- 2017-11-13 CN CN201711114221.1A patent/CN109776539A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114105987A (en) * | 2020-08-26 | 2022-03-01 | 上海博志研新药物技术有限公司 | Entecavir medicinal salt and preparation method, pharmaceutical composition and application thereof |
| CN114105987B (en) * | 2020-08-26 | 2022-12-27 | 上海博志研新药物技术有限公司 | Entecavir medicinal salt, preparation method, pharmaceutical composition and application thereof |
| WO2022198195A1 (en) * | 2021-03-16 | 2022-09-22 | The Scripps Research Institute | Anitiviral prodrugs of entecavir (etv) and formulations thereof |
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