CN103819472A - Acidic added salt of 2-amino-8-[(1S, 3R, 4S)-4-hydroxyl-2-methylene cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-L-valinate and preparation method thereof - Google Patents
Acidic added salt of 2-amino-8-[(1S, 3R, 4S)-4-hydroxyl-2-methylene cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-L-valinate and preparation method thereof Download PDFInfo
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- 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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Abstract
The invention discloses acidic added salt of 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-L-valinate and a preparation method thereof as well as a pharmaceutical mixture taking the salt as an effective medicine. The preparation method comprises the following steps: firstly, preparing 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-L-valinate; and then, carrying out a reaction with an inorganic acid (preferably concentrated hydrochloric acid) or an organic acid (preferably maleic acid) to obtain the acidic added salt of 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-L-valinate. The acidic added salt of 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-L-valinate prepared by the invention has the characteristics of good stability, high solubility in water, HBV resistance and good effect in treating hepatitis B.
Description
Technical field
The present invention relates to anti-HBV effect, can be used as treating the medicine 2-amino-9-[(1S of hepatitis B, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester (being called for short figured silk fabrics Entecavir), is specifically related to figured silk fabrics Entecavir acid salt and preparation method thereof.
Background technology
Entecavir is cyclohexanedione hydroxyphenylpyruvate dioxygenase carbon pancreatic desoxyribonuclease, is a kind of pancreatic desoxyribonuclease analogue that can effectively suppress hepatitis B virus duplication, has stronger anti-HBV effect.In in vitro tests, Entecavir extremely low concentration can suppress copying of HBV, and its cytotoxicity is very low, has very good selective therapy index.
The treatment of chronic viral hepatitis B is a long-term process, can not accomplish in one move, and for a long time, the resistance of virus to medicine, has become a difficult problem of puzzlement treating chronic hepatitis B.Nucleosides is just controlled the patient that YMDD virus variation do not occur and is accepted Bo Luding (Entecavir sheet) treatment, and resistance phenomenon does not appear in the data presentation of 144 weeks.These data declarations Bo Luding (Entecavir sheet) is as the first-line drug for the treatment of hepatitis B, there is high " drug resistant gene barrier ", make the long-term objective that realizes " long term inhibition hepatitis B virus duplication or thoroughly remove hepatitis B virus " this treating hepatitis B become possibility.
Entecavir poorly water-soluble, bioavailability is lower, needs to add a large amount of solubility promoters to absorb to strengthen it in preparation prescription, in this part degree, has increased security concern.
Figured silk fabrics Entecavir is the L-valine ester prodrug of Entecavir, absorbs and enters after human body, in enteron aisle and liver cell, is hydrolyzed rapidly by esterase dissociate Entecavir and α-amino-isovaleric acid, and oral administration biaavailability improves greatly.But valine entecavir has the following disadvantages: the one, valine entecavir belong to ester compound easily hydrolysis cause preserving and Treatment Stability poor, the 2nd, although solubleness increases compared with Entecavir in figured silk fabrics Entecavir water, but still poor, affect the treatment.
Summary of the invention
The object of this invention is to provide that solubleness in a kind of good stability, water is high, hepatitis B virus resisting and the effective figured silk fabrics Entecavir acid addition salt for the treatment of hepatitis B and preparation method thereof and the medicinal mixture take them as active drug.
For realizing above object, figured silk fabrics Entecavir acid addition salt of the present invention is 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the acid salt of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester, its structural formula is as follows:
Wherein H
ax
bthe mineral acid that represents to comprise sulfuric acid or hydrochloric acid or nitric acid or phosphoric acid can be also the organic acid that comprises trifluoroacetic acid or toxilic acid or methylsulfonic acid or tosic acid; A represents hydrogen atom number, span 1-10; B represents acid group number, span 1-5; N represents mineral acid or organic acid number, span 0.1-5.
Preferably 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the hydrochloride of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester, this compound has following formula structure:
Preferably 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the maleate of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester, this compound has following formula structure:
Described 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the acid salt of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester is placed in air or passes through recrystallization, easily absorb moisture and produce planar water formation hydrate, the acid salt that contains such moisture is also contained in the present invention.
Pharmaceutical pack of the present invention contains using figured silk fabrics Entecavir acid addition salt as active drug composition, and the preferably figured silk fabrics Entecavir acid addition salt mixture of one or more vehicle or carrier is used for the treatment of viral and pharmaceutical composition relative disease.
The present invention is carrying out all the year round Entecavir, deep structure of modification, show that Entecavir L-valine ester can improve the distribution of Entecavir in target organ liver, under same dose, reduce the distribution in other organs thereby improved drug effect and reduced on the basis of conclusion of the untoward reaction that relates to widely whole body of Entecavir, develop 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the acid salt (particularly hydrochloric acid or maleate) of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester, it not only has good oral absorptivity, a little less than metabolic activity and anti-HBV effect and toxicity, and because of its good preservation and Treatment Stability and water-soluble, hepatitis B virus resisting and the ideal medicament for the treatment of hepatitis B.In addition, said medicine also can be used for warm-blooded animal.
2-amino-9-[(1S of the present invention, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the preparation method of the acid addition salt of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester is as follows:
The first step: first make 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester, is called for short figured silk fabrics Entecavir, for subsequent use;
Second step: the figured silk fabrics Entecavir preparing is mixed and carries out chemical reaction with acid, 0 ℃～70 ℃ of temperature of reaction, reaction times 10min～5h, generate 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the acid addition salt of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester;
The 3rd step: after reaction finishes, by ordinary method 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the acid addition salt of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester is separated from reaction mixture.For example: reaction finishes the crystallization that rear filtration obtains separating out, or obtains target compound by heating up in a steamer desolventizing; The target compound obtaining, can further purify by ordinary methods such as recrystallization, redeposition or chromatographies if necessary.
Described figured silk fabrics Entecavir mixes in inert solvent and carries out with acid, and the ratio of this solvent and reaction raw materials medicine is solvent (volume ml): reaction raw materials medicine (weight g)=(5-30): 1, preferred (10-20): 1.
Described inert solvent is acetone.
Described second step operation is: figured silk fabrics Entecavir is dissolved in acetone, get concentrated hydrochloric acid ready by the equimolar quantity of figured silk fabrics Entecavir, at 40 ℃ to 55 ℃ temperature, drip 40%～60% of concentrated hydrochloric acid total amount, time for adding is 2 minutes to 10 minutes, and add as required crystal seed, react at the same temperature 30 minutes to 2 hours, and then residue concentrated hydrochloric acid was splashed in 2 hours at 30 minutes, react again at the same temperature 1 hour to 3 hours, obtain figured silk fabrics Entecavir hydrochloride.
Described second step operation is: toxilic acid is dissolved in acetone, at 0 ℃ to 70 ℃, add 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester, makes its reaction 1 to 3 hour at the same temperature.
The preferred hydrochloric acid of above-mentioned acid or toxilic acid, most preferably concentrated hydrochloric acid, hybrid mode can join figured silk fabrics Entecavir in acid, also acid can be divided into once or secondary and even for several times drip or add in figured silk fabrics Entecavir, and it is reacted, and is prepared.Can also add as required crystal seed.
Above-mentioned solvent, only otherwise hinder reaction, raw material is had outside certain solubleness, do not have anything to limit especially, it can be any in following solvent: hexane, hexanaphthene, heptane, the aliphatic hydrocarbon such as volatile oil or sherwood oil, benzene, toluene or dimethylbenzene etc. are aromatic hydrocarbon based, methylene dichloride, chloroform, tetracol phenixin, 1, 2-ethylene dichloride, the halogenated hydrocarbon such as chlorobenzene or dichlorobenzene, diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, the ethers such as glycol dimethyl ether or diethylene glycol dimethyl ether, acetone, the ketone such as butanone or diethyl ketone, ethyl acetate, the ester such as propyl acetate or butylacetate class, the carboxylic-acid such as acetic acid or propionic acid, or the nitrile such as acetonitrile or propionitrile, the in the situation that of hydrochloride, preferably ethers, ketone, ester class, carboxylic-acid or nitrile, more preferably tetrahydrofuran (THF), diox, acetone, butanone, ethyl acetate, acetic acid or acetonitrile, particularly preferably tetrahydrofuran (THF), diox, acetic acid or acetone, most preferably acetone, the in the situation that of maleate, preferably ethers, ketone, ester class or nitrile, more preferably tetrahydrofuran (THF), diox, acetone, butanone, ethyl acetate or acetonitrile, particularly preferably tetrahydrofuran (THF), diox or acetone, most preferably acetone.
2-amino-9-[(1S of the present invention, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the acid salt of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester, in the time that the medicine as above-mentioned disease uses, can mix by itself or with acceptable vehicle, thinner etc. on suitable pharmacology, with oral administrations such as tablet, capsule, granule, powder or syrups or with injection or the parenteral mode administration of suppository.
These preparations can adopt following additive to manufacture by existing technology of preparing: vehicle is (as lactose, sucrose, glucose, N.F,USP MANNITOL, the sugar derivativess such as sorbyl alcohol, W-Gum, yam starch, Alpha-starch, the starch derivative such as dextrin, the derivatived celluloses such as crystalline cellulose, Sudan Gum-arabic, dextran, the organic excipients such as Propiram, and light silicon anhydride, synthetic aluminium silicate, Calucium Silicate powder, the silicate derivatives such as magnesium aluminum silicate, the phosphoric acid salt such as secondary calcium phosphate, the carbonate such as calcium carbonate, the inorganic excipients of the vitriol such as calcium sulfate etc.), lubricant is (as stearic acid, calcium stearate, the Metallic stearates such as Magnesium Stearate, talcum, beeswax, the wax classes such as spermaceti, boric acid, hexanodioic acid, the vitriol such as sodium sulfate, ethylene glycol, FUMARIC ACID TECH GRADE, Sodium Benzoate, DL-leucine, sodium lauryl sulphate, the dodecyl sulfates such as Stepanol MG, silicic anhydride, the silicic acid classes such as hydrate of silicic acid, and above-mentioned starch derivative), tackiness agent is (as hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, polyoxyethylene glycol and the compound same with above-mentioned vehicle), disintegrating agent is (as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, internal crosslinking Xylo-Mucine lamp derivatived cellulose, carboxymethyl starch, sodium starch glycolate, cross-linked polyvinylpyrrolidones etc. are through the starch of chemical modification, cellulose family, above-mentioned starch derivative), emulsifying agent is (as wilkinite, the colloidal clays such as V word glue, magnesium hydroxide, the metal hydroxidess such as aluminium hydroxide, sodium lauryl sulphate, the anion surfactants such as calcium stearate, the cats products such as benzalkonium chloride, and Voranol EP 2001, polyoxyethylene sorbitan fatty acid esters, the nonionogenic tensides such as sucrose fatty ester), stablizer is (as para methyl paraben, the parabenses such as propylparaben, trichloro-butyl alcohol, phenylcarbinol, the alcohols such as phenylethyl alcohol, benzalkonium chloride, phenol, the phenols such as cresols, thimerosal, dehydroacetic acid (DHA), and Sorbic Acid), correctives is (as normally used sweetening material, acid flavoring, spices) and thinner etc.
Although the usage quantity of medicine is different and different with symptom, age etc., but with respect to grownup, can every 1-7 day according to symptom administration 1-7 time, in the time of oral administration, the lower limit of single administration amount is the preferred 0.5mg of 0.05mg(), the upper limit is the preferred 2mg of 500mg(), in the time of intravenously administrable, single administration amount lower limit is the preferred 0.2mg of 0.01mg(), the upper limit is the preferred 1mg of 200mg().
Embodiment
By specific embodiment, test example and formulation example, illustrate in greater detail the present invention once, and and non-limiting scope of the present invention.
First prepare 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester, is undertaken by following two steps:
(1) preparation of (S)-2-(tert-butoxycarbonyl-amino)-3 Methylbutanoic acid-Entecavir
Get Entecavir: 60.9g, add dimethyl formamide 1250mL, jolting makes to dissolve.
Get (S)-2-(tert-butoxycarbonyl-amino)-3 Methylbutanoic acid: 104.2g, dicyclohexyl carbodiimide: 69.6g, DMAP: 8.2g, add dimethyl formamide 1250mL, stir 60min, add above-mentioned Entecavir solution, 100 ℃ of stirring reaction 24h, HPLC monitors reaction.
After having reacted, suction filtration, filtrate adds silica gel 650g, to fried dry in 90 ℃ of water-baths.
Get silica gel 2900g, dress post, is loaded on fried dry silica gel on post, washes by methyl alcohol-ethyl acetate (10:90), and every 12L is a collection.TLC monitors flow point, merges the flow point that contains target product, and evaporated under reduced pressure, obtains (S)-2-(tert-butoxycarbonyl-amino)-3 Methylbutanoic acid-Entecavir.
(2) 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the preparation of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester
Get (S)-2-(tert-butoxycarbonyl-amino)-3 Methylbutanoic acid-Entecavir: 54g, add ethyl acetate 1100mL, add 3M hydrochloric acid 270mL, stirring reaction 24h at 60 ℃, HPLC monitors reaction.
After having reacted, add water 500ml, separate lower floor, with 4 times (4 × 500ml) of ethyl acetate washing, water intaking phase, regulates pH to approximately 10 with ammoniacal liquor, separate out a large amount of flockss, incline and supernatant liquor, centrifugal, by 50 ℃ of drying under reduced pressure of the precipitation obtaining, obtaining white solid, is 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester.
embodiment 1
2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the preparation of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester hydrochloride.
By the 2-amino-9-[(1S preparing, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester (10g) is dissolved in acetone (150ml), under room temperature (25 ℃) stirs, drip 36% concentrated hydrochloric acid (2.69g), then stir at the same temperature 90 minutes.The crystallization that filtration obtains separating out, after cleaning, 50 ℃ of drying under reduced pressure 4 hours, obtains the title compound hydrochloric acid figured silk fabrics Entecavir (7.8g, yield 71%) of white crystals with a small amount of acetone.
1H?NMR（H
2O）δppm：0.916-0.970（6H，m），2.277-2.345（2H，m），2.496-2.514（1H，m），2.955（1H，s），4.008-4.018（1H，d），4.359-4.364（1H，d），4.433-4.471（2H，t），5.032（1H，s），5.392（1H，s），5.543-5.584（1H，t），8.807（1H，s）。
Mass spectrum (MALDI-TOF, m/z): 399.2[M+Na]
+; 415.2[M+K]
+.
embodiment 2
2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the preparation of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester maleate.
Toxilic acid (4.43g) is dissolved in acetone (60ml), then add wherein 2-amino-9-[(1S that embodiment 1 obtains, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester (14.9g), at room temperature stirs 2 hours.The crystallization that filtration obtains separating out, after cleaning, 50 ℃ of drying under reduced pressure 4 hours, obtains white crystal title compound toxilic acid figured silk fabrics Entecavir (16.5g, 85%) with a small amount of acetone.
1H?NMR（H
2O）δppm：0.894-0.938（6H，m），2.241-2.318（2H，m），2.459-2.485（1H，m），2.920（1H，s），3.971-3.980（1H，d），4.312-4.333（1H，d），4.402-4.447（2H，t），5.001（1H，s），5.365（1H，s），5.509-5.557（1H，t），6.372（2H，s），8.763（1H，s）。
Mass spectrum (MALDI-TOF, m/z): 399.1[M+Na]
+; 415.1[M+K]
+.
test example 1
Metabolite concentration in dog plasma
Give after male beasle dog (the about 10kg of body weight) oral test compound, measure the metabolite concentration in blood plasma, measure the summation of figured silk fabrics Entecavir+Entecavir (interior metabolism product, activeconstituents).
Give dog feeding after 30 minutes, make the oral test compound (10mg/kg) that is loaded on capsule of dog.After administration 15,30,45,60,90 and 120 minutes, use the syringe of processing through heparin, take a blood sample by forearm saphena, 3ml takes a blood sample at every turn.The whole blood obtaining is carried out to centrifugation immediately, obtain blood plasma, the blood plasma obtaining carries out-30 ℃ of freezing preservations before test.In the blood plasma thawing (0.5ml), add 2-hydroxy acetophenone (0.25ml) and 10mM potassium phosphate buffer (pH 4.5,0.25ml) and the methyl alcohol (0.5ml) as 1 μ g/ml concentration of internal standard substance, 20 ± 3 ℃ of stirrings.Add wherein after isopropanol/chloroform (1:9) mixture (8ml), vibration, is extracted into solvent phase by figured silk fabrics Entecavir, Entecavir and internal standard substance.By low-speed centrifugal (1500g, 15 minutes), water is separated with solvent phase, with lower floor's solvent phase of nitrogen drying appropriate amount.Be dissolved in again in HPLC moving phase (0.25ml).In addition, the figured silk fabrics Entecavir of known quantity and Entecavir are added in dog blood contrast blood plasma, carry out same extracting operation.Take the Area Ratio of figured silk fabrics Entecavir+Entecavir and internal standard substance in sample as y axle, take figured silk fabrics Entecavir+Entecavir concentration of adding as x axle, make working curve.Calculated the concentration of figured silk fabrics Entecavir+Entecavir in sample by this working curve, thereby quantitatively.
HPLC condition
Chromatographic column: Waters Symetry C18(4.6 × 250mm)
Moving phase: acetonitrile/isopropanol/water/trifluoroacetic acid (10/12/78/0.01)
Flow velocity: 1.0ml/min
Detect wavelength: UV 240nm
Sample size: 30 μ l
Result is as shown in table 1.In table, as pharmacokinetic parameters, become concentration in area value under the Plasma-time curve of growing amount index in body and maximum plasma and indicate with AUC and Cmax abbreviation respectively.In addition, in table, " hydrochloride " represents 2-amino-9-[(1S of embodiment 1, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester hydrochloride, " maleate " represents 2-amino-9-[(1S of embodiment 2, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester maleate, " free body " represents the not free alkali of salify, be 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester.
Figured silk fabrics Entecavir+Entecavir in blood plasma after table 1 dog oral administration
Pharmacokinetic parameters (mean value ± standard deviation)
| Test compound | n | AUC（μg·min/ml） | Cmax（μg/ml） |
| Hydrochloride | 4 | 74.5±24.6 | 1.19±0.27 |
| Maleate | 4 | 72.3±23.1 | 1.15±0.30 |
| Free body | 4 | 35.8±8.0 | 0.613±0.138 |
The above results shows by by 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester becomes hydrochloride or maleate, and it is large that AUC and Cmax become.
test example 2
The stability of solid state
Get test compound (hydrochloride, maleate, free body), put in glass dish, the about 3mm thickness that tiles, puts under 60 ℃/75% RH condition and places 3 months, and sampling detects, and investigates the degraded situation of bulk drug.
HPLC condition:
Chromatographic column: Agilent C18(250 × 4.6mm, 5 μ m)
Mobile phase A: 0.02M SODIUM PHOSPHATE, MONOBASIC, with phosphorus acid for adjusting pH to 4.6
Mobile phase B: methyl alcohol
Gradient elution, gradient condition is as follows:
| Time | Mobile phase A | Mobile phase B |
| 0 | 90% | 10% |
| 10 | 90% | 10% |
| 20 | 20% | 80% |
| 30 | 20% | 80% |
| 35 | 90% | 10% |
| 40 | 90% | 10% |
Flow velocity: 1.0ml/min
Detect wavelength: 240nm
Column temperature: 40 ℃
Sampling volume: 10 μ L
Result is as shown in table 2.In table, " hydrochloride " represents 2-amino-9-[(1S of embodiment 1, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester hydrochloride, " maleate " represents 2-amino-9-[(1S of embodiment 2, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester maleate, " free body " represents the not free alkali of salify, be 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester.
The stability of table 2 solid state
The above results shows, by by 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester becomes hydrochloride or maleate, and stability obviously improves.
formulation example 1:hard capsule
Mix 0.5mg 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester hydrochloride, 179.2mg lactose, 70mg Microcrystalline Cellulose and 1.3mg Magnesium Stearate, after 60 mesh sieves, No. 3 gelatine capsules that these powder packed into 250mg are made capsule.
formulation example 2:tablet
Mix 0.5mg 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester hydrochloride, 174mg lactose, 25mg Microcrystalline Cellulose and 1mg Magnesium Stearate, by tabletting machine compressing tablet, make the tablet of 1 200mg.
Can carry out dressing to this tablet as required.
formulation example 3:hard capsule
Mix 0.5mg 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester maleate, 179.2mg lactose, 70mg Microcrystalline Cellulose and 1.3mg Magnesium Stearate, after 60 mesh sieves, No. 3 gelatine capsules that these powder packed into 250mg are made capsule.
formulation example 4:tablet
Mix 0.5mg 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester maleate, 174mg lactose, 25mg Microcrystalline Cellulose and 1mg Magnesium Stearate, by tabletting machine compressing tablet, make the tablet of 1 200mg.
Can carry out dressing to this tablet as required.
Claims (10)
1. a figured silk fabrics Entecavir acid addition salt, is characterized in that: this structural formula of compound is as follows:
Wherein H
ax
bthe mineral acid that represents to comprise sulfuric acid or hydrochloric acid or nitric acid or phosphoric acid can be also the organic acid that comprises trifluoroacetic acid or toxilic acid or methylsulfonic acid or tosic acid; A represents hydrogen atom number, span 1-10; B represents acid group number, span 1-5; N represents mineral acid or organic acid number, span 0.1-5.
2. figured silk fabrics Entecavir acid addition salt according to claim 1, it is characterized in that: it is 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the hydrochloride of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester, this structural formula of compound is:
。
3. figured silk fabrics Entecavir acid addition salt according to claim 1, it is characterized in that: it is 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the maleate of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester, this structural formula of compound is:
4. figured silk fabrics Entecavir acid addition salt according to claim 1, it is characterized in that: using figured silk fabrics Entecavir acid addition salt as active drug composition, the preferably figured silk fabrics Entecavir acid addition salt mixture of one or more vehicle or carrier, is used for the treatment of viral and pharmaceutical composition relative disease.
5. a preparation method for figured silk fabrics Entecavir acid addition salt described in claim 1, is characterized in that: click step operation:
The first step: first make 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester, is called for short figured silk fabrics Entecavir, for subsequent use;
Second step: the figured silk fabrics Entecavir preparing is mixed and carries out chemical reaction with acid, 0 ℃～70 ℃ of temperature of reaction, reaction times 10min～5h, generate 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the acid addition salt of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester;
The 3rd step: after reaction finishes, by ordinary method 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1, the acid addition salt of 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester is separated from reaction mixture.
6. the preparation method of figured silk fabrics Entecavir acid addition salt according to claim 5, it is characterized in that: described figured silk fabrics Entecavir mixes in inert solvent and carries out with acid, and the ratio of this solvent and reaction raw materials medicine is solvent (volume ml): reaction raw materials medicine (weight g)=(5-30): 1.
7. the preparation method of figured silk fabrics Entecavir acid addition salt according to claim 6, is characterized in that: the ratio of described solvent and reaction raw materials medicine is solvent (volume ml): reaction raw materials medicine (weight g)=(10-20): 1.
8. according to the preparation method of figured silk fabrics Entecavir acid addition salt described in claim 5 or 6 or 7, it is characterized in that: described inert solvent is acetone.
9. the preparation method of figured silk fabrics Entecavir acid addition salt according to claim 5, it is characterized in that: described second step operation is that figured silk fabrics Entecavir is dissolved in acetone, get concentrated hydrochloric acid ready by the equimolar quantity of figured silk fabrics Entecavir, at 40 ℃ to 55 ℃ temperature, drip 40%～60% of concentrated hydrochloric acid total amount, time for adding is 2 minutes to 10 minutes, and add as required crystal seed, react at the same temperature 30 minutes to 2 hours, and then residue concentrated hydrochloric acid was splashed in 2 hours at 30 minutes, react again at the same temperature 1 hour to 3 hours, obtain figured silk fabrics Entecavir hydrochloride.
10. the preparation method of figured silk fabrics Entecavir acid addition salt according to claim 5, it is characterized in that: described second step operation is that toxilic acid is dissolved in acetone, at 0 ℃ to 70 ℃, add 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-2-methylene radical cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-Valine ester, makes its reaction 1 to 3 hour at the same temperature.
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| CN201410099880.2A CN103819472A (en) | 2014-03-18 | 2014-03-18 | Acidic added salt of 2-amino-8-[(1S, 3R, 4S)-4-hydroxyl-2-methylene cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-L-valinate and preparation method thereof |
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| CN201410099880.2A CN103819472A (en) | 2014-03-18 | 2014-03-18 | Acidic added salt of 2-amino-8-[(1S, 3R, 4S)-4-hydroxyl-2-methylene cyclopentyl]-1, 9-dihydro-6H-purine-6-one-3-methyl hydroxyl-L-valinate and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358481A (en) * | 2017-09-29 | 2021-02-12 | 广州市恒诺康医药科技有限公司 | Long-acting entecavir prodrug and preparation method and application thereof |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1106017A (en) * | 1993-06-29 | 1995-08-02 | 三菱化学株式会社 | Phosphonate-nucleotide ester derivatives |
| CN101096370A (en) * | 2006-06-29 | 2008-01-02 | 朱靖华 | Valine entecavir and preparation method and application |
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- 2014-03-18 CN CN201410099880.2A patent/CN103819472A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1106017A (en) * | 1993-06-29 | 1995-08-02 | 三菱化学株式会社 | Phosphonate-nucleotide ester derivatives |
| CN101096370A (en) * | 2006-06-29 | 2008-01-02 | 朱靖华 | Valine entecavir and preparation method and application |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358481A (en) * | 2017-09-29 | 2021-02-12 | 广州市恒诺康医药科技有限公司 | Long-acting entecavir prodrug and preparation method and application thereof |
| CN112358481B (en) * | 2017-09-29 | 2022-02-22 | 广州市恒诺康医药科技有限公司 | Long-acting entecavir prodrug and preparation method and application thereof |
| 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 |
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Application publication date: 20140528 |