CN101085786A - Method for preparing adefovir monoesters and method of detecting content of the same - Google Patents

Method for preparing adefovir monoesters and method of detecting content of the same Download PDF

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CN101085786A
CN101085786A CN 200710009159 CN200710009159A CN101085786A CN 101085786 A CN101085786 A CN 101085786A CN 200710009159 CN200710009159 CN 200710009159 CN 200710009159 A CN200710009159 A CN 200710009159A CN 101085786 A CN101085786 A CN 101085786A
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acetonitrile
water
adefovir
volume ratio
monoester
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CN100560596C (en
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康惠燕
陈国华
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Fujian Cosunter Pharmaceutical Co Ltd
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Abstract

The invention provides a method for preparing adefovir dipivoxil monoesters. The adefovir dipivoxil monoesters is hydrolyzed in mixed medium of acetonitrile and water, and is stirred and heated if needed, the hydrolyzed solid product is washed and dried. The invention aslo provides a method for checking adefovir dipivoxil monoesters content, which is used for quality control and observation.

Description

A kind of preparation method of adefovir (AD) monoester and detection method of content thereof
Technical field
The invention belongs to medical technical field, relate to a kind of medical material intermediates preparation, and its quality control matter method, specifically be meant the preparation method and the detection method of content thereof of adefovir (AD) monoester.
Background technology
Adefovir ester is a kind of new oral broad-spectrum antiviral drug, by suppressing viral dna polymerase and cryotron transcriptase, suppress transcribing and duplicating of virus, hepatitis B virus and hiv virus etc. there is stronger restraining effect, lamivudine and the drug-fast hepatitis B virus of Famciclovir also there is stronger restraining effect, be the open loop efabirenz, be the prodrug of the double esterification thing form of Adefovir (PMEA) and pivaloyl oxygen base methyl alcohol, bioavailability is big than Adefovir.Adefovir ester is because its physics and chemistry poor stability, the monoester compound (structural formula is as shown in the formula I) that is easy to take off an esterified group and forms Adefovir, in the medicinal application of adefovir ester, in order to ensure quality product, usually need carry out the content monitoring to the pharmaceutical preparation or the adefovir (AD) monoester in its bulk drug of adefovir ester, therefore, reference substance material when often needing the higher adefovir (AD) monoester compound of purity as the content monitoring and detection, and adefovir (AD) monoester also has certain pharmacologically active effect.
Figure A20071000915900041
(formula I).
Common, adefovir (AD) monoester is to obtain by mole esterifications such as Adefovir and pivaloyl oxygen base methyl alcohol, but the purity of the adefovir (AD) monoester that this preparation method obtains is not ideal enough, and reaction yield is lower, and numerous rope of preparation process and operation control difficulty are bigger.
Summary of the invention
The purpose of this invention is to provide a kind of preparation method who prepares simple easy handling, yield height, adefovir (AD) monoester that purity is high, and its detection method of content.
Find that after deliberation adefovir ester is easy to hydrolysis, with the adefovir ester reaction that is hydrolyzed, control the environment and condition of its hydrolysis reaction in water-bearing media, can make adefovir ester remove an ester group and obtain adefovir (AD) monoester, its reaction principle is as follows:
Figure A20071000915900051
Should be understood that the selection of the environment and condition of its hydrolysis reaction is very important and requires circulation ratio good that because when the environment and condition of hydrolysis reaction is not suitable for, the situation that is easy to cause two ester groups all to remove takes place, and promptly complete hydrolysis can take place.
The invention provides a kind of preparation method of adefovir (AD) monoester, its adopts adefovir ester in the reaction that is hydrolyzed of the blending agent of acetonitrile and water, optionally reactant is stirred and heat, preferably 30 ℃ to the reflux temperature, further the solid product after the hydrolysis is washed and dry.The preferred methylene dichloride that adopts washs reaction product.
Concrete, a kind of preparation method of adefovir (AD) monoester, it comprises following:
In the mixed solution of acetonitrile and water, add adefovir ester, stir and in 30 ℃ to the reflux temperature, make the adefovir ester partial hydrolysis, concentrating under reduced pressure, add methylene dichloride, suction filtration, washed with dichloromethane, be drying to obtain, the mixed solution of optionally available acetonitrile and water gets the adefovir (AD) monoester white crystals to products therefrom recrystallization secondary.
In the above-mentioned preparation, be used for the acetonitrile of hydrolysis adefovir ester and the mixed solution of water, wherein the volume ratio of acetonitrile and water is 1: 0.5～5, and promptly the water mixed liquid of the acetonitrile of 1 volume and 0.5～5 volume is as the reaction solution of hydrolysis adefovir ester, and the volume ratio of preferred acetonitrile and water is 1: 0.7～3;
The volume ratio of preferred acetonitrile and water is 1: 1～2;
The volume ratio of preferred acetonitrile and water is 1: 1～1.5;
The volume ratio of preferred acetonitrile and water is 1: 1～1.2;
The volume ratio of preferred acetonitrile and water is 1: 1～1.15.
In the above-mentioned preparation, be used for the acetonitrile of recrystallization and the mixed solution of water, wherein the volume ratio of acetonitrile and water is 1: 0.5～3, and promptly the water mixed liquid of the acetonitrile of 1 volume and 0.5～3 volume is as the reaction solution of hydrolysis adefovir ester, and the volume ratio of preferred acetonitrile and water is 1: 0.7～2;
The volume ratio of preferred acetonitrile and water is 1: 1～1.5;
The volume ratio of preferred acetonitrile and water is 1: 1.
The adefovir (AD) monoester that obtains with preparation method of the present invention be white in color pressed powder or crystalline powder, content can be used as standard substance or reference substance fully and is used for demarcating medicine adefovir (AD) monoester content greater than 99%.
On the other hand, the present invention also provides a kind of method that detects adefovir (AD) monoester content, and the quality control quality supervision that is used for adefovir (AD) monoester is surveyed.
The invention provides the method that detects adefovir (AD) monoester content with high-efficient liquid phase technique, it is characterized in that with octadecylsilane chemically bonded silica be weighting agent; 0.1mol/L potassium dihydrogen phosphate-acetonitrile is a moving phase; Detect wavelength: 255～265nm, wherein the volume proportion of 0.1mol/L potassium dihydrogen phosphate and acetonitrile is (30: 70)～(70: 30) in the moving phase, and being preferably volume proportion is 60: 40 or 50: 50; Flow velocity during test and sample size are selected according to the model of high performance liquid chromatograph, for example can adopt the flow velocity of 1.0ml/min usually, the sample size of 20 μ l.
Adefovir (AD) monoester is in above-mentioned detection method, can observe and two bigger absorption peaks near 260nm and 210nm, occur, but during transformation system suitability condition, have only near the absorption peak the 260nm can stable existence, so the specific detection wavelength when near the absorption peak of preferred 260nm detects as present method.
Adefovir (AD) monoester and its content detecting method with the inventive method preparation prepare simple easy handling, and product cost is low, and the control of system amount can be guaranteed.
Description of drawings
Accompanying drawing 1: the high-efficient liquid phase chromatogram of adefovir (AD) monoester (purity test figure);
Accompanying drawing 2: the infrared absorpting light spectra of adefovir (AD) monoester;
Accompanying drawing 3: the uv absorption spectra of adefovir (AD) monoester (in ethanol);
Accompanying drawing 4: the nmr spectrum of adefovir (AD) monoester ( 1HNMR);
Accompanying drawing 5: the nmr spectrum of adefovir (AD) monoester ( 1HNMR+D 2O);
Accompanying drawing 6: the mass spectrum of adefovir (AD) monoester.
Embodiment is come the present invention done further by the following examples and is specified, but does not represent the embodiment limitation of the present invention.
The preparation of embodiment 1. adefovir (AD) monoesters
In a 250ml eggplant-shape bottle, add adefovir ester 10.0g, acetonitrile 48.0ml, water 55.0ml stirs reflux 8h, concentrating under reduced pressure adds methylene dichloride 100.0ml, and 45 ℃ are stirred 2h, suction filtration, washed with dichloromethane, the dry 3.6g off-white color solid that gets, acetonitrile/water (1: 1) recrystallization secondary gets adefovir (AD) monoester white crystals 2.5g, yield 32.0%, mp228～230 ℃ (decomposition).
Above-mentioned preparation method, the consumption of used adefovir ester, acetonitrile, water, methylene dichloride can amplify or dwindle in proportion.
In addition, the adefovir (AD) monoester of above-mentioned preparation is carried out structural analysis, to confirm as the structure of adefovir (AD) monoester:
1. infrared absorption spectrum detects
1.1 instrument model: Nicolet Nexus 670 type FT-IR infrared absorption spectrometers.Proofread and correct and examine and determine by two appendix IVC of Chinese Pharmacopoeia version in 2005 relevant regulations.
1.2 the preparation of sample: solid K Br compressing tablet
1.3 infrared absorpting light spectra: see accompanying drawing 2
1.4 infrared absorption spectrometry data: see Table 1
Table 1 sample infrared absorption spectrum data and parsing
Figure A20071000915900081
Figure A20071000915900091
1.5 resolve
(1) 3500～3200cm -1: be the N-H stretching vibration of 6 bit aminos on the purine skeleton; 1697cm -1Be 6-NH 2Flexural vibration; 1282cm -1Be the C-N stretching vibration of 6 aminopurine rings, proving has the primary amine structure that links to each other with purine skeleton in the molecular structure.
(2) 3062cm -1: for purine skeleton=the C-H stretching vibration; 1590cm -1, 1514cm -1, 1480cm -1Be purine skeleton skeleton carbon-carbon double bond, carbon-to-nitrogen double bon stretching vibration; 878cm -1, 801cm -1Be the C-H out-of-plane deformation vibration of purine skeleton, therefore, proving has purine skeleton to exist in the molecule.
(3) 2975cm -1: methyl, methylene radical C-H stretching vibration; 1417cm -1, 1393cm -1, 1366cm -1, 1355cm -1Be the C-H out-of-plane deformation vibration of methyl, methylene radical, prove methyl is arranged in the molecule, the methylene radical structure exists.
(4) 1743cm -1: be the carbonylic stretching vibration of pivalate; 1147cm -1Be the C-O stretching vibration of pivalate, conform to there being the pivalate structure in the molecule.
(5) 3500～3200cm -1: for
Figure A20071000915900092
The hydroxyl stretching vibration; 1230cm -1For The P=O stretching vibration; 1028cm -1For
Figure A20071000915900094
The P-O-C stretching vibration; 721cm -1For
Figure A20071000915900095
The P-C stretching vibration, exist with molecular structure
Figure A20071000915900096
Structure conforms to.
(6) 1059cm -1: be the C-O stretching vibration of ether (C-O-C), with existence-CH in the molecule 2CH 2O-CH 2-structure conforms to.
(7) 972cm -1: be methylene-dioxy (O-CH 2-O-) C-O stretching vibration and exists in the molecule
Figure A20071000915900101
Structure conforms to.
1.6. conclusion
Learn from infrared spectra, contain in the molecular structure: primary amine groups, purine skeleton, ester, ether,
Figure A20071000915900102
Functional groups such as methylene-dioxy, methyl, methylene radical conform to molecular structure.
2. ultra-violet absorption spectrum detects
2.1 instrument model: PERKIN-ELMER LAMBDA 17 UV/VIS type UV, visible light photothermal spectroscopic analyzers
2.2 solvent: ethanol
2.3 uv absorption spectra: see accompanying drawing 3
2.4 ultra-violet absorption spectrum determination data: see Table 2
Table 2 sample ultra-violet absorption spectrum data
Solvent Concentration λ max(nm) ε λ max(nm) ε
Ethanol 25.9μg/ml 209 10389 261 7369
2.5 resolve
Sample in ethanol at λ Max(nm) 209, λ Max(nm) there is maximum absorption at 261 places, and E band and the absorption of B band for female ring gland purine skeleton contain the female ring of VITAMIN B4 in the interpret sample molecule, conform to compound structure.
3. proton nmr spectra detects
3.1 instrument model: Bruker ACF-300 type NMR spectrometer with superconducting magnet
3.2 condition determination: solvent DMSO-d 6, interior mark TMS
3.3 hydrogen nuclear magnetic resonance spectrogram: 1HNMR (accompanying drawing 4), 1HNMR+D 2O (accompanying drawing 5)
Figure A20071000915900111
3.4 1HNMR determination data: see Table 3
Table 3 sample nuclear magnetic resonance hydrogen spectrum data
Chemical shift (ppm) Multiplicity The hydrogen number Coupling constant The hydrogen atom ownership
1.12 s 9 H 17，H 18，H 19
3.68 d 2 J＝6.0Hz H 12
3.88 m 2 H 11′
4.33 m 2 H 10′
5.44 m 2 H 14′
7.62 brs 2 D 2O exchanges disappearance H 20
8.16 s 2 H 2，H 8
3.5 resolve
(1) δ 1.12ppm is unimodal, and 9H is classified as 3 methyl hydrogen H of the tertiary butyl 17, H 18, H 19
(2) δ 3.68ppm, doublet, J=6.0Hz, 2H is classified as the methylene radical hydrogen H that links to each other with phosphorus atom 12 '
(3) δ 3.88ppm, multiplet, 2H is classified as the methylene radical hydrogen H that links to each other with Sauerstoffatom 11 '
(4) δ 4.33ppm, multiplet, 2H is classified as the methylene radical hydrogen H that links to each other with nitrogen-atoms 10 '
(5) δ 5.44ppm, multiplet, 1H is classified as the methylene radical hydrogen H of methylene-dioxy 14 '
(6) δ 7.62ppm, wide unimodal, 2H, D 2O exchange back disappears, and is classified as 20 primary amino hydrogen-NH 2
(7) δ 8.16ppm is unimodal, and 2H is classified as the alkene hydrogen H of purine skeleton 2, H 8
3.6 conclusion
From 1The HNMR spectrum learns that the corresponding proton of sample conforms to fully with molecular structure.
4. mass spectrometric detection
4.1 instrument model: Agilent 1100 type mass spectrographs
4.2 condition: electron spray(ES), ESI (-) 70V
4.3 mass spectrum: see accompanying drawing 6
4.4 resolve
M/z 386 (base peak) is (M-H) -The peak is with the molecular formula C of adefovir (AD) monoester 14H 22N 5O 6P conforms to.
In sum, the IR of sample, UV, 1HNMR, 1HNMR+D 2O, MS spectrum can rationally be made ownership to molecular structure, and the product that conclusive evidence makes is an adefovir (AD) monoester.
The preparation of embodiment 2. adefovir (AD) monoesters
In a 250ml eggplant-shape bottle, add adefovir ester 10.0g, acetonitrile 35ml, water 70ml, heat 60 ℃ and stir 12h, concentrating under reduced pressure adds methylene dichloride 110ml, and 45 ℃ are stirred 2h, suction filtration, washed with dichloromethane, the dry 3.1g off-white color solid that gets, acetonitrile/water (1: 1.5) recrystallization secondary gets the adefovir (AD) monoester white crystals.
Same, usefulness IR, UV, 1HNMR, 1HNMR+D 2The molecular structure of the sample that O, MS spectrum can be rationally makes aforesaid method is made ownership, and proving conclusively the product that makes is adefovir (AD) monoester.
Embodiment 3. adefovir (AD) monoester content detecting method
Get the adefovir (AD) monoester content of embodiment 1 preparation, adopt high performance liquid phase to detect, method is as follows:
Chromatographic instrument: LC-10A type high performance liquid chromatograph, SPD-10AV UV-detector, N2000 chromatographic working station, chromatographic column: Lichrospher-C 18, 5 μ, 250 * 4.6mm, moving phase: 0.1mol/L potassium dihydrogen phosphate-acetonitrile (60: 40), flow velocity: 1.0ml/min detects wavelength: 260nm, sample size: 20 μ l.
Recording sample purity with high performance liquid chromatography is 99.8%, sees accompanying drawing 1.

Claims (10)

1. the preparation method of an adefovir (AD) monoester, its adopts adefovir ester in the reaction that is hydrolyzed of the blending agent of acetonitrile and water, optionally reactant is stirred and heats, and further the solid product after the hydrolysis is washed and drying.
2. the described preparation method of claim 1 preferably carries out stirring reaction at 30 ℃ to the reflux temperature, and preferred employing is gone into methylene dichloride reaction product is washed.
3. the preparation method of an adefovir (AD) monoester, it comprises following:
In the mixed solution of acetonitrile and water, add adefovir ester, stir and in 30 ℃ to the reflux temperature, make the adefovir ester partial hydrolysis, concentrating under reduced pressure, add methylene dichloride, suction filtration, washed with dichloromethane, be drying to obtain, the mixed solution of optionally available acetonitrile and water gets the adefovir (AD) monoester white crystals to products therefrom recrystallization secondary.
4. the described preparation method of claim 3 wherein is used for the acetonitrile of hydrolysis adefovir ester and the mixed solution of water, and the volume ratio of acetonitrile and water is 1: 0.5～5;
The volume ratio of preferred acetonitrile and water is 1: 0.7～3;
The volume ratio of preferred acetonitrile and water is 1: 1～2;
The volume ratio of preferred acetonitrile and water is 1: 1～1.5;
The volume ratio of preferred acetonitrile and water is 1: 1～1.2;
The volume ratio of preferred acetonitrile and water is 1: 1～1.15.
5. the described preparation method of claim 3 wherein is used for the acetonitrile of recrystallization and the mixed solution of water, and the volume ratio of acetonitrile and water is 1: 0.5～3;
The volume ratio of preferred acetonitrile and water is 1: 0.7～2;
The volume ratio of preferred acetonitrile and water is 1: 1～1.5;
The volume ratio of preferred acetonitrile and water is 1: 1.
6. the preparation method of an adefovir (AD) monoester, it comprises: get adefovir ester 10.0g, add acetonitrile 48.0ml, water 55.0ml, stir, reflux 8h, concentrating under reduced pressure adds methylene dichloride 100.0ml, 45 ℃ are stirred 2h, suction filtration, and washed with dichloromethane is drying to obtain.
7. the described preparation method of claim 6, the consumption of used adefovir ester, acetonitrile, water, methylene dichloride can amplify or dwindle in proportion.
8. the method with high-efficient liquid phase technique detection adefovir (AD) monoester content is characterized in that with octadecylsilane chemically bonded silica be weighting agent; 0.1mol/L potassium dihydrogen phosphate-acetonitrile is a moving phase; Detect wavelength: 255～265nm.
9. the described detection method of claim 8, wherein the volume proportion of 0.1mol/L potassium dihydrogen phosphate and acetonitrile is (30: 70)～(70: 30) in the moving phase, being preferably volume proportion is 60: 40 or 50: 50.
10. the described detection method of claim 8, wherein detecting wavelength is 260nm.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101812090A (en) * 2010-05-10 2010-08-25 浙江车头制药有限公司 Preparation method of adefovir monoester
CN102040626A (en) * 2010-11-05 2011-05-04 福建广生堂药业有限公司 Method for preparing tenofovir monoester and method for detecting content of tenofovir monoester
WO2013029199A1 (en) * 2011-08-29 2013-03-07 天津泰普药品科技发展有限公司 Adefovir monoester and preparation method thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101812090A (en) * 2010-05-10 2010-08-25 浙江车头制药有限公司 Preparation method of adefovir monoester
CN101812090B (en) * 2010-05-10 2013-08-14 浙江车头制药股份有限公司 Preparation method of adefovir monoester
CN102040626A (en) * 2010-11-05 2011-05-04 福建广生堂药业有限公司 Method for preparing tenofovir monoester and method for detecting content of tenofovir monoester
WO2013029199A1 (en) * 2011-08-29 2013-03-07 天津泰普药品科技发展有限公司 Adefovir monoester and preparation method thereof

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