CN101812090B - Preparation method of adefovir monoester - Google Patents
Preparation method of adefovir monoester Download PDFInfo
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- CN101812090B CN101812090B CN 201010165903 CN201010165903A CN101812090B CN 101812090 B CN101812090 B CN 101812090B CN 201010165903 CN201010165903 CN 201010165903 CN 201010165903 A CN201010165903 A CN 201010165903A CN 101812090 B CN101812090 B CN 101812090B
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Abstract
The invention discloses a preparation method of adefovir monoester, which comprises the following steps that: adefovir dipivoxil is added into the mixture of alcohol and water for alcoholysis and hydrolysis, and the adefovir monoester is prepared after treatment. The preparation method has the main advantages that the solvent is clean and environmental-friendly, the preparation process is simple, and the high-content adefovir monoester can be prepared at one step.
Description
Technical field
The present invention relates to a kind of preparation method of nucleoside compound adefovir (AD) monoester.
Background technology
Adefovir ester is a kind of novel HBV-DNA AG14361, a kind of novel antiviral, and it has antiviral activity to the animal and human.Adefovir ester is the prodrug of Adefovir, and hydrolysis reaction easily takes place, and generates adefovir (AD) monoester and Adefovir, has reduced oral administration biaavailability.Adefovir (AD) monoester is as the major impurity in the adefovir ester, needs control its content for ensuring drug quality, and the adefovir (AD) monoester that therefore prepares a kind of high-content product in contrast is extremely necessary.And adefovir (AD) monoester has certain pharmacologically active, and the preparation high purity product can be offered help in the research aspect the treatment to it.
Chinese patent CN101085786 discloses a kind of preparation method of adefovir (AD) monoester, it adopts adefovir ester to be hydrolyzed in the blending agent of acetonitrile and water, solid product washed with dichloromethane after the hydrolysis, the dry adefovir (AD) monoester crude product that gets carries out recrystallization then and gets the pure product of adefovir (AD) monoester in the mixed solution of acetonitrile and water.This method steps is more, and has used inflammable reagent acetonitrile.
Chinese patent CN101190987 then discloses adefovir ester and has been hydrolyzed in the presence of mineral alkali, and product demand pole chromatography purification just can obtain the adefovir (AD) monoester of required purity.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of adefovir (AD) monoester, this method solvent for use clean environment firendly, and preparation technology is simple, can disposablely make the high-content adefovir (AD) monoester.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
A kind of preparation method of adefovir (AD) monoester, described method comprises: in the mixing solutions of alcohol and water, add adefovir ester, carry out alcoholysis and hydrolysis, handle adefovir (AD) monoester.
In technique scheme, alcoholysis at first takes place in adefovir ester in alcohol and water solution, hydrolysis takes place then, gets adefovir (AD) monoester, and its synthetic route is as follows:
Further, the volume ratio of alcohol and water is 100: 0.1～10 in the preferred described mixing solutions of the present invention.More preferably volume ratio is 100: 0.1～1.
Further, the volumetric usage of the mixing solutions of alcohol and water of the present invention is counted 5～20ml/g with the quality of adefovir ester; Be preferably 8～12ml/g.
Further, the preferred described alcoholysis of the present invention and hydrolysis are carried out to the reflux temperature at 50 ℃.More preferably under the reflux temperature, carry out.
Further, the reaction times of the preferred described alcoholysis of the present invention and hydrolysis is 3～10 hours.
Further, alcohol of the present invention is preferably following a kind of or several mixing by arbitrary proportion arbitrarily: methyl alcohol, ethanol, propyl alcohol or Virahol.
The concrete preparation method of described adefovir (AD) monoester that recommends of the present invention carries out according to following steps: be to add adefovir ester in 100: 0.1～10 the mixing solutions at the volume ratio of alcohol and water, wherein alcohol is following a kind of or several mixing of pressing arbitrary proportion arbitrarily: methyl alcohol, ethanol, propyl alcohol or Virahol, and carried out alcoholysis and hydrolysis to the reflux temperature 3～10 hours in 50 ℃, being cooled to room temperature places, no longer separate out to material, filter, dry adefovir (AD) monoester; The volumetric usage of the mixing solutions of described alcohol and water is counted 5～20ml/g with the quality of adefovir ester.
Further, the concrete preparation method of described adefovir (AD) monoester that recommends of the present invention carries out according to following steps: be to add adefovir ester in 100: 0.1～1 the mixing solutions at the volume ratio of alcohol and water, wherein alcohol is following a kind of or several mixing of pressing arbitrary proportion arbitrarily: methyl alcohol, ethanol, propyl alcohol or Virahol, and under the reflux temperature, carried out alcoholysis and hydrolysis 3～10 hours, being cooled to room temperature places, no longer separate out to material, filter, dry adefovir (AD) monoester; The volumetric usage of the mixing solutions of described alcohol and water is counted 8～12ml/g with the quality of adefovir ester.
Compared with prior art, preparation method's major advantage of adefovir (AD) monoester provided by the invention has: adopt the mixed solvent of alcohol and water, and the solvent for use clean environment firendly, preparation technology is simple, can disposablely make content at the adefovir (AD) monoester more than 99.5%.
Description of drawings
The infrared absorpting light spectra of the adefovir (AD) monoester that Fig. 1 makes for the present invention.
Embodiment
Below with concrete exemplifying embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Embodiment 1
10g adefovir ester crude product is dissolved in 100ml ethanol and the 10ml water mixed solution, and reflux 4 hours, room temperature are placed to and no longer include material and separate out, filter, dry adefovir (AD) monoester 2.5g, yield 32.4%, adopting the HPLC detection level is 99.8%.Fig. 1 is the infared spectrum of gained adefovir (AD) monoester.
Embodiment 2
10g adefovir ester crude product is dissolved in 190.5ml methyl alcohol and the 9.5ml water mixed solution, and reflux 3 hours is placed the nature cooling, analysis of material.Filter, dry the about 2.1g of adefovir (AD) monoester, yield 27.2%, employing HPLC detection level is 99.5%.Infared spectrum is identical with Fig. 1.
Embodiment 3
10g adefovir ester crude product is dissolved in 119.4ml ethanol and the 0.6ml water mixed solution, and 50 ℃ were heated 10 hours, placed the nature cooling, analysis of material.Filter, dry the about 2.7g of adefovir (AD) monoester, yield 35.0%, employing HPLC detection level is 99.6%.Infared spectrum is identical with Fig. 1.
Embodiment 4
10g adefovir ester crude product is dissolved in 100ml methyl alcohol and the 0.1ml water mixed solution, and reflux 4 hours is placed the nature cooling, analysis of material.Filter, dry the about 2.4g of adefovir (AD) monoester, yield 31.1%, employing HPLC detection level is 99.6%.Infared spectrum is identical with Fig. 1.
Embodiment 5
10g adefovir ester crude product is dissolved in 100ml ethanol and the 1ml water mixed solution, and reflux 8 hours is placed the nature cooling, analysis of material.Filter, dry the about 2.6g of adefovir (AD) monoester, yield 33.7%, employing HPLC detection level is 99.7%.Infared spectrum is identical with Fig. 1.
Embodiment 6
10g adefovir ester crude product is dissolved in 100ml Virahol and the 2ml water mixed solution, and 50 ℃ were heated 6 hours, placed the nature cooling, analysis of material.Filter, dry the about 2.3g of adefovir (AD) monoester, yield 29.8%, employing HPLC detection level is 99.8%.Infared spectrum is identical with Fig. 1.
Embodiment 7
10g adefovir ester crude product is dissolved in 100ml propyl alcohol and the 1ml water mixed solution, and reflux 5 hours is placed the nature cooling, analysis of material.Filter, dry the about 2.2g of adefovir (AD) monoester, yield 28.5%, employing HPLC detection level is 99.6%.Infared spectrum is identical with Fig. 1.
Embodiment 8
10g adefovir ester crude product is dissolved in 50ml propyl alcohol and the 2.5ml water mixed solution, and reflux 7 hours is placed the nature cooling, analysis of material.Filter, dry the about 2.1g of adefovir (AD) monoester, yield 27.2%, employing HPLC detection level is 99.6%.Infared spectrum is identical with Fig. 1.
Claims (5)
1. the preparation method of an adefovir (AD) monoester, it is characterized in that described method is: in the mixing solutions of alcohol and water, add adefovir ester, carry out alcoholysis and hydrolysis, described alcoholysis and hydrolysis are carried out to the reflux temperature at 50 ℃, reaction times is 3～10 hours, handle adefovir (AD) monoester; The volume ratio of alcohol and water is 100:0.1～10 in the described mixing solutions, the volumetric usage of the mixing solutions of described alcohol and water is counted 5 ~ 20ml/g with the quality of adefovir ester, and described alcohol is following a kind of or several mixing by arbitrary proportion arbitrarily: methyl alcohol, ethanol, propyl alcohol or Virahol.
2. preparation method as claimed in claim 1, the volume ratio that it is characterized in that alcohol and water in the described mixing solutions is 100:0.1～1.
3. preparation method as claimed in claim 1 is characterized in that described alcoholysis and hydrolysis carry out under the reflux temperature.
4. preparation method as claimed in claim 1, it is characterized in that described method carries out according to following steps: be to add adefovir ester in the mixing solutions of 100:0.1～10 at the volume ratio of alcohol and water, wherein alcohol is following a kind of or several mixing of pressing arbitrary proportion arbitrarily: methyl alcohol, ethanol, propyl alcohol or Virahol, and carried out alcoholysis and hydrolysis to the reflux temperature 3～10 hours in 50 ℃, being cooled to room temperature places, no longer separate out to material, filter, dry adefovir (AD) monoester; The volumetric usage of the mixing solutions of described alcohol and water is counted 5 ~ 20ml/g with the quality of adefovir ester.
5. preparation method as claimed in claim 1, it is characterized in that described method carries out according to following steps: be to add adefovir ester in the mixing solutions of 100:0.1～1 at the volume ratio of alcohol and water, wherein alcohol is following a kind of or several mixing of pressing arbitrary proportion arbitrarily: methyl alcohol, ethanol, propyl alcohol or Virahol, and under the reflux temperature, carried out alcoholysis and hydrolysis 3～10 hours, being cooled to room temperature places, no longer separate out to material, filter, dry adefovir (AD) monoester; The volumetric usage of the mixing solutions of described alcohol and water is counted 8 ~ 12ml/g with the quality of adefovir ester.
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| CN 201010165903 CN101812090B (en) | 2010-05-10 | 2010-05-10 | Preparation method of adefovir monoester |
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| CN 201010165903 CN101812090B (en) | 2010-05-10 | 2010-05-10 | Preparation method of adefovir monoester |
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| CN101812090B true CN101812090B (en) | 2013-08-14 |
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| CN105294762A (en) * | 2015-11-13 | 2016-02-03 | 中国药科大学 | Preparation method of adefovir dipivoxil impurities |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5792756A (en) * | 1990-09-14 | 1998-08-11 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
| CN101085786A (en) * | 2007-06-28 | 2007-12-12 | 福建广生堂药业有限公司 | Method for preparing adefovir monoesters and method of detecting content of the same |
| CN101190927A (en) * | 2006-11-30 | 2008-06-04 | 天津天士力集团有限公司 | Method for preparing pivaloyloxymethyl 9-[2-(phosphonylmethoxy)ethyl]adenine |
| CN101504394A (en) * | 2007-06-28 | 2009-08-12 | 福建广生堂药业有限公司 | Content detection method for adefovir monoester |
-
2010
- 2010-05-10 CN CN 201010165903 patent/CN101812090B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5792756A (en) * | 1990-09-14 | 1998-08-11 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
| CN101190927A (en) * | 2006-11-30 | 2008-06-04 | 天津天士力集团有限公司 | Method for preparing pivaloyloxymethyl 9-[2-(phosphonylmethoxy)ethyl]adenine |
| CN101085786A (en) * | 2007-06-28 | 2007-12-12 | 福建广生堂药业有限公司 | Method for preparing adefovir monoesters and method of detecting content of the same |
| CN101504394A (en) * | 2007-06-28 | 2009-08-12 | 福建广生堂药业有限公司 | Content detection method for adefovir monoester |
Non-Patent Citations (2)
| Title |
|---|
| John E. Starrett, et al..Synthesis, Oral Bioavailability Determination, and in Vitro Evaluation of Prodrugs of the Antiviral Agent 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA).《J. Med. Chem.》.1994,第37卷第1857-1864页. * |
| JohnE.Starrett et al..Synthesis |
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