CN100471857C - Purine derivatives - Google Patents

Purine derivatives Download PDF

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CN100471857C
CN100471857C CNB2006800004415A CN200680000441A CN100471857C CN 100471857 C CN100471857 C CN 100471857C CN B2006800004415 A CNB2006800004415 A CN B2006800004415A CN 200680000441 A CN200680000441 A CN 200680000441A CN 100471857 C CN100471857 C CN 100471857C
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compound
acid
purine
methylol
dihydro
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CN101044142A (en
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李志兵
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BEIJING DIANFAN SCIENCE AND TECHNOLOGY Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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BEIJING DIANFAN SCIENCE AND TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Abstract

The invention discloses purine derivatives of formula (II), including pharmaceutically-acceptable solvate or hydrate thereof, wherein M<SUP>-</SUP> represents a pharmaceutically-acceptable acid anion. It also relates to the preparation of such compounds, pharmaceutical compositions containing them and the use of such compounds for the treatment of hepatitis B viral infections and/or concurrent infections in human being.

Description

Purine derivative
Invention field
The present invention relates to new purine derivative, its preparation method contains the pharmaceutical composition of these compounds and is used for the treatment of that the viruses of human hepatitis B infects and/or the purposes of accompanying infection.
Background technology
Publication number is 5206244 United States Patent (USP), has described the compound that contains formula (I) and the activity of antiviral particularly hepatitis B virus resisting thereof, and publication number is 1310999 Chinese patent application, has described the pharmaceutical composition that contains low dosage formula (I) compound.
Figure C200680000441D00031
Formula (I) compound [1S-(1 α; 3 α; 4 β)]-2-amino-1; 9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-solubleness of 6H-purine-6-one in room temperature water solution and neutral physiological buffer solution is less than 2.5 mg/ml; belong to insoluble chemical compound; insoluble chemical compound is because solubleness is low; usually can increase the difficulty of pharmaceutical preparation; influence the snap-out release of pharmaceutical active compounds; and the preparation of other preparation or non-oral formulation, for example in solid orally ingestible.Therefore improve the solubleness of insoluble drug.For better performance insoluble drug drug effect, expansion insoluble drug formulation, the cost that reduces pharmaceutical preparation has crucial meaning.
Summary of the invention
The objective of the invention is to seek new purine derivative and salt thereof, so that industrialization is a large amount of, convenient and effectively prepare its oral preparations with good water-soluble and Pickering.
Adopt the SARS drug design experimental technique that formula (I) compound is carried out computational analysis, on contriver's discoverable type (I) compound purine skeleton on 2 bit aminos electric density of nitrogen-atoms be-0.53, the pKb that this experimental result discloses nitrogen-atoms on purine skeleton 2 bit aminos of formula (I) compound is 4.31, discloses it and cannot add with any acid radical anion and be shaped as acid salt.
For this reason, the contriver has further studied mineral acid and has comprised Hydrogen bromide (pKa is-9), hydrochloric acid (pKa is-7), sulfuric acid (pKa is-7), nitric acid (pKa is-1.64), phosphoric acid (pKa is 2.12) and carbonic acid (pKa is 3.88), and find Hydrogen bromide, hydrochloric acid, sulfuric acid and nitric acid can react with formula (I) compound and generate stable acid salt.The phosphoric acid salt instability that forms under similarity condition, carbonic acid can not generate stable acid salt with formula (I) compound.The contriver has also studied organic acid and has comprised methylsulfonic acid (pKa is 0.50), toxilic acid (pKa is 1.92), tartrate (pKa is 2.98), fumaric acid (pKa is 3.02), Citric Acid (pKa is 3.13), oxysuccinic acid (pKa is 3.40), lactic acid (pKa is 3.86) and acetic acid (pKa is 4.75), and discovery methylsulfonic acid, toxilic acid, tartrate, fumaric acid and Citric Acid can react with formula (I) compound and generate stable acid salt, and under similarity condition oxysuccinic acid, lactic acid and acetic acid and formula (I) compound can not form stable acid salt.Obviously the acid salt of formula I compound forms and exists unpredictability.
Therefore, the invention provides the purine derivative of the stable general formula of a class (II):
Figure C200680000441D00051
M wherein -Represent pharmaceutically acceptable acid radical anion;
Acid radical anion M -Be selected from pKa for less than 2.0 mineral acid or pKa less than 3.5 organic acid.
According to the present invention, pKa has said for example less than 2.0 mineral acid: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid and nitric acid;
According to the present invention, pKa has said for example less than 3.5 organic acid: methylsulfonic acid, toxilic acid, tartrate, fumaric acid, Citric Acid and oxalic acid;
Preferred formula (II) compound is according to the present invention: hydrochloric acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the 6H-purine-6-one;
Methylsulfonic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the 6H-purine-6-one; With
Toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the 6H-purine-6-one.
Should be appreciated that formula of the present invention (II) compound also comprises pharmaceutically acceptable solvate and/or hydrate that it is suitable.
The present invention shows that formula (II) compound compares with formula (I) compound, has remarkable enhanced solubleness under similarity condition.For example, hydrochloric acid [1S-(1 α at room temperature water solution and neutral physiological buffer solution Chinese style (II) compound, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-solubleness of 6H-purine-6-one is greater than 165 mg/ml, toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-solubleness of 6H-purine-6-one monohydrate is 14.1 mg/ml, and be 2.4 mg/ml in the solubleness of similarity condition following formula (I) compound, formula II compound of the present invention compare with formula I compound solubleness significantly improve 5-68 doubly more than.The water solubility that formula (II) compound significantly improves, for formula II compound provides good pharmaceutically acceptable characteristic, as the quick stripping from solid preparation, but or bioavailability, thereby make things convenient for it to prepare various oral preparations or other preparation in a large number and effectively.
Further, formula (II) compound has the stability in excellent solid and the stability of solution, the particularly aqueous solution.For example, toxilic acid [1S-(1 α of formula (II) compound, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-6H-purine-6-one or its monohydrate, under high temperature and destructive test concrete conditions in the establishment of a specific crime, for example: in 100 degrees centigrade of aqueous solution of high temperature, in 100 degree centigrade of 0.1 normal aqueous hydrochloric acid and the 100 degree centigrade of 0.1 normal aqueous sodium hydroxide solution, destroyed 24 hours, it is stable that sample keeps in 100 degrees centigrade of aqueous solution of high temperature, do not surpass 2% with the high-performance liquid chromatogram determination degraded product.This excellent stability of solution is that industrialization prepares its various oral preparations, the particularly preparation of oral liquid formulation in a large number and effectively advantage is provided.
Say that further formula (II) compound also has excellent processability, they are stable high-melting-point crystal materials, and its solid is loose and have a good flowability.Therefore, be suitable for large-scale industrialization preparation and processing, particularly in the medicine course of processing of needs heat or generation heat, for example grind, heat drying vulcanizes the bed drying, spraying drying, and autoclave sterilization.Therefore, the compound of formula (II) structure can be enough effectively, economical and easily method process, be particularly conducive to the preparation of large-scale industrialization production technique.
Formula (II) compound is the acid salt of formula (I) compound, the present invention relates to the acid salt that nitrogen-atoms and acid group associate and form on form of ownership, particularly formula (I) compound purine skeleton 2 bit aminos of this salt.
In addition, the present invention also provides the preparation method of formula (II) compound and/or its pharmaceutically acceptable solvate and/or its hydrate.Formula (I) compound can prepare (Bisacchi, et al, Bioorganic ﹠amp according to the method that document provides; Medicinal Chemistry Letters, Vo17, No2, pp127-132,1997).Formula (I) compound and negatively charged ion M -Reaction between the source is to carry out under acidic conditions, for example, is generally C in solvent 1-6Carry out in low-grade alkane alcohol solvent such as methyl alcohol or the aqueous solution, under the arbitrary temp that the suitable speed that generates required compound can be provided, usually in room temperature or high temperature reaction down, as under the reflux temperature of solvent, carrying out, conveniently with excessive slightly but preferred negatively charged ion M with about equimolar amount -Under the situation in source with formula (I) compound and suitable acid group reaction, then can from suitable solvent such as lower alkyl ketone for example the acetone crystallization separate out required product, can promote crystalline separate out by cooling usually.The pharmaceutically acceptable solvate of formula (II) compound and/or its hydrate can prepare with common chemical process.
The structural identification of new formula (II) compound can pass through NMR (Nuclear Magnetic Resonance) spectrum, mass spectrum, and UV spectrum, infrared spectra, TGA, monocrystalline X-ray diffractions etc. are determined, particularly can be passed through nucleus magnetic resonance 1H spectrum and infrared spectra are clearly accused of.For example, the infrared spectra experimental result shows, the eigen vibration of its functional group behind formula (I) the compound salify, particularly tangible displacement takes place in the eigen vibration of 2 bit aminos on its purine skeleton, and Fig. 1 has provided the infrared spectrogram of hydrochloride and mesylate in formula (I) compound and formula (II) compound respectively to Fig. 3.Nucleus magnetic resonance 1H spectrum experimental result shows, hydrogen behind formula (I) the compound salify on its purine skeleton 2 bit aminos and the hydrogen on 1 nitrogen of purine skeleton are obviously to the high field displacement of nuclear-magnetism, behind hydrogen evolution hydrochloride and mesylate on (I) compound purine skeleton 2 bit aminos, its chemical shift is by 6.4ppm, be displaced to 7.2ppm and 7.04ppm respectively, behind the hydrogen evolution hydrochloride and mesylate on 1 nitrogen of formula (I) compound purine skeleton, its chemical shift is by 10.5ppm, be displaced to 11.7ppm and 11.4ppm respectively, Fig. 4 has provided the nucleus magnetic resonance of hydrochloride and mesylate in formula (I) compound and formula (II) compound respectively to Fig. 6 1The H spectrogram.
Description of drawings
Fig. 1 is [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-infrared spectrogram of 6H-purine-6-one;
Fig. 2 is hydrochloric acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-infrared spectrogram of 6H-purine-6-one;
Fig. 3 is methylsulfonic acid acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-infrared spectrogram of 6H-purine-6-one;
Fig. 4 is [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-nucleus magnetic resonance of 6H-purine-6-one 1The H spectrogram;
Fig. 5 is hydrochloric acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-nucleus magnetic resonance of 6H-purine-6-one 1The H spectrogram;
Fig. 6 is methylsulfonic acid acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-nucleus magnetic resonance of 6H-purine-6-one 1The H spectrogram;
Fig. 7 is toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the monocrystalline X-ray diffraction structure of 6H-purine-6-one monohydrate.
Suitable anion M-source is known commercially obtainable, hydrochloric acid for example, and hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, methanesulfonic acid, maleic acid, tartaric acid, fumaric acid, citric acid and oxalic acid perhaps can prepare required anion M according to known method-The source.
According to the present invention, the solubility of the compounds of this invention can be measured with the solubility test method of standard, for example, in 25 ± 0.5 degrees centigrade of saturated aqueous solutions of room temperature, the solubility of hydrochloride is greater than 165 mg/ml in formula (II) compound, the solubility of mesylate is greater than 200 mg/ml, and under similarity condition, the solubility of formula (I) compound is 2.4 mg/ml. Therefore, formula (II) compound and formula (I) Compound Phase have the solubility that significantly improves than in the aqueous solution and neutral physiological buffer solution, this character is the bioavailable degree of formula (II) compound, and a large amount of the use with effective its oral formulations of preparation provides advantage.
According to the present invention, formula of the present invention (II) compound has good stability and this stability can be measured with conventional quantitative analysis method, for example formula (II) compound stability can be measured with accelerated stability test, as at 40 degrees centigrade, and 75% relative humidity; 40 degrees centigrade, 92.5% relative humidity; And 80 degrees centigrade, the stability of mensuration formula (II) compound. Analysis can be used high performance liquid chromatography, thin-layer chromatography, and differential scanning calorimetry, the isothermal experiment under TGA and the intensification carries out, and the quantitative analysis of test compound is before shelf time, takes a sample between the shelf time and after the shelf time and carries out.
The present invention also provides formula (II) compound and/or its pharmaceutically acceptable solvate or its hydrate that is used for the treatment of hepatitis B and/or accompanying infection.
The invention still further relates to the pharmaceutical composition that contains formula (II) compound and/or its pharmaceutically acceptable solvate or its hydrate and pharmaceutically acceptable carrier. This pharmaceutical composition can be used through number of ways, for example oral tablet, capsule, pulvis, oral liquid, injection and preparation capable of permeating skin. According to the convention on the medicine of routine, pharmaceutically acceptable carrier comprises diluent, filler, disintegrant, wetting agent, lubricant, colouring agent, flavor enhancement or other conventional additives. Typical pharmaceutically acceptable carrier comprises for example microcrystalline cellulose, starch, commissure PVP, PVP, polyethylene pyrrolidone, maltitol, citric acid, dodecyl sodium sulfate or dolomol.
According to the present invention, formula (II) compound has the stability in the water solubility that significantly improves and the excellent stability of solution, the particularly aqueous solution. Pharmaceutical composition of the present invention can be mixed with oral unit dosage form. This unit dosage forms contains 0.001-50mg usually, is preferably 0.01-10mg, more preferably the formula of 0.05-1mg (II) compound. Oral liquid formulation can be solution, syrup or emulsion, and perhaps it can provide with dry product, and the before use water dissolving of this dry product is taken. Oral liquid formulation can contain for example maltitol of common additives, sorbierite, and syrup, gelatin, carboxymethyl cellulose, citrate and phosphate also can contain general aromatic or colouring agent if need.
The present invention also provides the method for a kind of viruses of human hepatitis B's for the treatment of infection and/or accompanying infection medicine, the method comprises hepatitis b virus infected and/or formula (II) compound of accompanying infection person's administering therapeutic effective dose and/or the pharmaceutical composition of its pharmaceutically acceptable solvate or its hydrate to the needs treatment, said composition is administered once every day, pharmaceutical composition preferably contains formula (II) compound of 0.1-1mg, more preferably contains formula (II) compound of 0.5mg. But pharmaceutical composition of the present invention is administered once and is used for the treatment of the hepatitis b virus infected and/or accompanying infection of adult patient every day.
Embodiment
The following examples are used to illustrate the present invention, but to the present invention without any restriction.
Embodiment 1
Hydrochloric acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the 6H-purine-6-one
With 2.77 gram (0.01mol) [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the 6H-purine-6-one places the 500ml round-bottomed flask, adds 150ml methyl alcohol and makes the solid dissolving, filter.Hydrochloric acid-the methanol solution from equimolar amount to above-mentioned filtrate (12.0M hydrochloric acid, 0.83ml, the 0.01mol that add, be dissolved in the 10ml methyl alcohol), stir, make solution even, most methyl alcohol are revolved in decompression, add 150ml acetone then, place crystallization, filter, wash solid with small amount of acetone, 40 ℃ of vacuum-dryings get title compound 2.85 grams, yield 90.2%.
IRvcm -1(KBr)：3365.0，3164.1，3126.6，3062.2，3015.6，2916.0，2876.4，1701.2，1638.7，1595.2，1468.0，1360.1，1169.3，1049.8，1028.9，778.0，670.7。
1HNMR(600MHz，DMSO-d 6)δppm：11.70(s，1H)，8.96(s，1H)，7.26(br，2H)，5.49～5.46(q，1H)，5.22(s，1H)，4.83(s，1H)，4.26～4.25(t，1H)，3.59～3.53(m，2H)，2.55(t，1H)，2.33～2.29(m，1H)，2.16～2.12(m，1H)，2.09～1.99(m，1H)。
MS m/e：277.1[M] +，260.1，246.1[100]，229.1，216.1，204.1，151.1，152.1，135.0，109.0，95.1，81.1，67.1。
Embodiment 2
Methylsulfonic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the 6H-purine-6-one
With 2.77 gram (0.01mol) [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the 6H-purine-6-one places the 500ml round-bottomed flask, adds 150ml methyl alcohol and makes the solid dissolving, filter.Methylsulfonic acid-the methanol solution (0.98 gram methylsulfonic acid, 0.01mol is dissolved in the 10ml methyl alcohol) that adds equimolar amount to above-mentioned filtrate, stir, make solution even, most methyl alcohol are revolved in decompression, add 150ml acetone then, place crystallization, filter, wash solid, 40 ℃ of vacuum-dryings with small amount of acetone, get title compound 3.20 grams, yield 85.6%.
IRvcm -1(KBr)：3396.07，1573.65，1407.8，1342.23，1209.16，1051.03，1018.24，921.82，649.90。
1HNMR(600MHz，DMSO-d 6)δppm：11.42(s，1H)，8.93(s，1H)，7.04(br，2H)，5.49～5.46(q，1H)，5.22(s，1H)，4.82(s，1H)，4.25(br，1H)，3.59～3.54(m，2H)，2.54(t，1H)，2.37(s，3H)，2.32～2.28(m，1H)，2.15～2.12(m，1H)。
MS m/e：277.1[M+]，260.1，246.1，229.1，216.1，204.1，151.1[100]，152.0，146.0，135.0，109.0，96.0，91.0，81.0，69.0。
Embodiment 3
Toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the 6H-purine-6-one
Toxilic acid 1.21 grams (0.011mol) are placed the 100ml round-bottomed flask, add 30ml water and make the solid dissolving.In above-mentioned bottle, add 2.77 gram (0.01mol) [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the 6H-purine-6-one, stir, heating makes the solid dissolving become the homogeneous phase colourless transparent liquid, adds 15ml acetone then, place crystallization, filter, wash solid, 40 ℃ of vacuum-dryings with small amount of acetone, get title compound 3.19 grams, yield 82.3%.
IRvcm -1(KBr)：3380.07，3141.5，1691.29，1571.72，1405.87，1307.52，1052.96，1018.24，8，63.96，649.90。
1HNMR(600MHz，DMSO-d 6)δppm：13.25(br，1H)，10.68(s，1H)，7.83(s，1H)，7.04(br，2H)，6.50(s，2H)，6.25(s，2H)5.40～5.35(q，1H)，5.12(s，1H)，4.93(br，1H)，4.83(s，1H)，4.59(s，1H)，4.23(s，1H)，3.54～3.52(m，2H)，2.52(t，1H)，2.26～2.19(m，1H)，2.07～2.02(m，1H)。
MS m/e：277.2[M +]，259.1，246.1[100]，229.1，216.1，204.1，152.0，151.1，135.1，109.1，95.1，81.1，69.1。
Embodiment 4
Toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-6H-purine-6-one monohydrate
Toxilic acid [1S-(1 α, 3 α, 4 β)]-and 2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-6H-purine-6-one (according to embodiment 3 preparations) 1.44g, place triangular flask, add entry 5.0ml, heating for dissolving is cooled to room temperature, separates out white crystals, 0 ℃～5 ℃ placements are spent the night, abundant crystallization, suction filtration is dried to constant weight, get toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-6H-purine-6-one monohydrate, white crystals 1.38g, yield 93.2%.Ultimate analysis: theoretical value (C 12H 15N 5O 3C 4H 4O 4H 2O): C (%), 48.81, H (%), 5.80, N (%), 23.72; Measured value: C (%), 49.09, H (%) 5.76, N (%), 23.77.
IRvcm -1(KBr)：3446.5，3366.3，3294.9，2949.2，2856.6，2704.2，1724.3，1630.1，1599.5，1539.5，1485.7，1396.5，1061.2，1014.6.
1HNMR(600MHz，DMSO-d 6)δppm：10.56(s，1H)，7.66(s，1H)，6.41(br，2H)，5.38～5.35(s，1H)，5.11～5.10(t，1H)，4.87(d，1H)，4.84～4.82(t，1H)，4.57～4.56(t，1H)，4.239～4.236(m，1H)，3.55～3.53(q，1H)，2.54～2.52(t，1H)，2.25～2.20(m，1H)，2.06～2.03(m，1H)。
MS m/e:277.2[[1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-6H-purine-6-one quasi-molecular ions], 259.2,246.2[100], 242.0,229.2,151.1,135.1,109.1,95.1,69.1.
TGA analyzes :～110 ℃ of weightlessness, rate of weight loss is 6.07% (with respect to C 12H 15N 5O 3H 2O, its theoretical rate of weight loss is 6.10%), amount to a crystal water.
Embodiment 5
Toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-stability of 6H-purine-6-one monohydrate
With compound toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-6H-purine-6-one monohydrate sample puts into 80 degrees centigrade of baking ovens, respectively the 0th, 15, quantitative analysis is carried out in sampling in 45 days, detect and adopt U.S. HP1100 high performance liquid chromatograph, chromatographic column is YMC-Pack ODS-A 3 μ 4.6 * 150mm, and moving phase is 0.01M KH 2PO 4: acetonitrile equals 94.5:5.5, flow velocity 1ml/min, and the detection wavelength is 254nm, and all samples calculates content with area normalization method, and detected result all samples content is all greater than 99%, and degraded product does not surpass 1%, and sample has good stability under accelerated tests.
Embodiment 6
Toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-sucting wet stability of 6H-purine-6-one monohydrate
With compound toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-6H-purine-6-one monohydrate sample puts into 40 degrees centigrade of constant temperature respectively, be equipped with in the moisture eliminator of saturated KNO3 solution (relative humidity 92.5%) and saturated NaCl solution (relative humidity 75%), respectively the 0th, 15, sampling in 30 days, detect and adopt U.S. HP1100 high performance liquid chromatograph, chromatographic column is YMC-Pack ODS-A 3 μ 4.6 * 150mm, and moving phase is 0.01M KH 2PO 4: acetonitrile equals 94.5:5.5, flow velocity 1ml/min, and the detection wavelength is 254nm, and all samples calculates content with area normalization method, and detected result all samples content is all greater than 99%, and degraded product does not surpass 1%, and sample has good stability under super-humid conditions.
Embodiment 7
Toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-destructive test of 6H-purine-6-one monohydrate
With compound toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-6H-purine-6-one monohydrate sample respectively gets 10mg and places three to seal bottle, add 10 milliliters of 0.1N HCl respectively, 10 milliliters of 0.1N NaOH and 10 milliliters of neutral waters.Be placed in 100 ℃ the baking oven and heat sealing bottle sealing.In 0 hour and 24 hours sampling and measuring degradation production content.Detect and adopt U.S. HP1100 high performance liquid chromatograph, chromatographic column is YMC-Pack ODS-A 3 μ 4.6 * 150mm, and moving phase is 0.01M KH 2PO 4: acetonitrile equals 94.5:5.5, flow velocity 1ml/min, and the detection wavelength is 254nm, all samples calculates content with area normalization method.Measurement result shows that at 100 degrees centigrade of aqueous solution of high temperature, degraded product does not surpass 2%.Therefore title compound keeps stable under aqueous solution high temperature destructive test condition.
Embodiment 8
Toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-solubility test of 6H-purine-6-one monohydrate
Get 0.2 gram toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the pure product of 6H-purine-6-one monohydrate (〉 99.5%) place clean triangular flask, add entry, in 25 ℃ of stirrings, constantly add water and all dissolve until solid, add water 14.2ml altogether.Calculating solubleness is 14.1mg/ml.
Embodiment 9
Toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-test of 6H-purine-6-one monohydrate monocrystalline X-ray diffraction
Monocrystalline is cultivated: get 0.2 gram toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the pure product of 6H-purine-6-one monohydrate (〉 99.5%) place clean triangular flask, add entry, heating for dissolving is filtered, and adds less water and also do not separate out solid when being cooled to room temperature.Put solution and in clean vacuum drier, (leave ventilation mouth), occur needle-like crystal after a few days.Measuring method is as follows, and X-ray single crystal diffraction divides instrument RigakuRaxis Rapid IP, and MoK (0.71073 ) the monochromatic radiation device, measure temperature: 293K.
The toxilic acid of test determination [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the crystallography data of 6H-purine-6-one monohydrate are as follows
Solvent Water
Fusing point
65 ℃ of beginning dehydrations, 156 ℃ of dissolvings
Crystal formation Colourless prism
a 5.8947
b 25.097
c 7.0881
α 90.00
β 98.01
γ 90.00
Vc 1038.4 3
Spacer P2(1)
Molecular formula C12H15N503·C4H404·H20
Z
2
Dcalc，gcm—3 1.408
Toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the monocrystalline X-ray diffraction structure of 6H-purine-6-one monohydrate.

Claims (5)

1. toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-6H-purine-6-one monohydrate.
2. contain claim 1 compound, and the pharmaceutical composition of pharmaceutical carrier.
3. method for preparing claim 1 compound, this method comprises that with methyl alcohol or water be solvent, at room temperature, is M with equimolar amount or excessive slightly toxilic acid -Negative ion source and [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-reaction of 6H-purine-6-one, crystallization goes out [toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1 then, 9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the 6H-purine-6-one] compound, change the gained compound into its hydrate.
4. preparation claim 1 compound is as the method for the pharmaceutical composition of its activeconstituents, this method comprise with effective amount of actives with can in medicine, application carrier mix mutually.
5. toxilic acid [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-6H-purine-6-one monohydrate preparation be used for the treatment of that the viruses of human hepatitis B infects and/or the accompanying infection medicine in purposes.
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EP2488522B1 (en) * 2009-10-12 2017-02-15 Hanmi Science Co., Ltd. Novel method for preparing entecavir and intermediate used therein
CN109575026B (en) 2017-09-29 2020-12-01 广州市恒诺康医药科技有限公司 Long-acting entecavir prodrug and preparation method and application thereof
CN109053734B (en) * 2018-08-24 2020-12-15 浙江爱诺生物药业股份有限公司 Method for purifying entecavir crude product
KR102188965B1 (en) 2020-04-10 2020-12-09 강규영 Foam cushion and its manufacturing method
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