CN101891767B - Preparation method of adefovir dipivoxil - Google Patents
Preparation method of adefovir dipivoxil Download PDFInfo
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- CN101891767B CN101891767B CN2010102353052A CN201010235305A CN101891767B CN 101891767 B CN101891767 B CN 101891767B CN 2010102353052 A CN2010102353052 A CN 2010102353052A CN 201010235305 A CN201010235305 A CN 201010235305A CN 101891767 B CN101891767 B CN 101891767B
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Abstract
The invention relates to a preparation method of adefovir dipivoxil, which comprises the following steps: under the protection of nitrogen, adding a solvent, a protective agent and adefovir in sequence, stirring and lowering the temperature; dropwise adding triethylamine and chloromethyl pivalate, after that, slowly raising the temperature until complete reaction; lowering the temperature to roomtemperature, adding isopropylacetate for filtering to obtain mother liquor; washing the mother liquor twice, and then drying and filtering by anhydrous magnesium sulfate, concentrating the filtrate to oil matter under reduced pressure; carrying out silicagel column chromatography on the oil matter, collecting eluent containing the product, and concentrating under reduced pressure until a little amount of the eluent is left; adding active carbon, discoloring and filtering, concentrating the filtrate until dry under reduced pressure, discharging materials, and drying to obtain the finished product. In the invention, the side reaction generated during adefovir dipivoxil reaction can be reduced, thereby improving the reaction conversion rate and reducing production cost.
Description
Technical field
The present invention relates to a kind of preparation method of adefovir ester.
Background technology
9-[2-[[two [(trimethylacetic acid oxygen base) methoxyl group] phosphoryl] methoxyl group] ethyl] gland fast (the two ester of adefovir ester or Adefovir) is that it has significant inhibitory effect to hepatitis B virus by the efficient ucleosides antibacterials of a kind of low toxicity of U.S. Gilead company research and development; Its structural formula is following:
This medicine went through to go through to go on the market in China in 2005 in U.S.'s listing in 2002.Chinese patent document ZL02151028.8, ZL200410015562.X and foreign patent document EP 1256584, EP481214 have reported its compound method; Promptly pass through different methods; Obtain Adefovir, obtain adefovir ester with the chloromethyl pivalate reaction then.
But the preparation of the disclosed adefovir ester of above document exists reaction conversion ratio low (productive rate is low), problem that production cost is high.
Summary of the invention
The present invention is for addressing the above problem, and a kind of side reaction that produces when reducing the adefovir ester reaction is provided, thereby improves reaction conversion ratio, the preparation method of the adefovir ester that reduces production costs.
To achieve these goals, the technical scheme that the present invention adopted is:
A kind of preparation method of adefovir ester comprises the steps:
1) under nitrogen protection, add solvent 30-35ml, protective material 0.5-1.0g and Adefovir 5-10g successively, after stirring, be cooled to 0-10 ℃;
2) be added dropwise to triethylamine 12-16ml, stir;
3) be added dropwise to chloromethyl pivalate 28-32ml, drip off and slowly be warming up to 60 ℃, to reacting completely;
4) be cooled to room temperature, add isopropyl acetate 105-115ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing; (the filter cake composition is Adefovir and reaction intermediate adefovir (AD) monoester)
5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;
6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to residue on a small quantity;
7) add activated carbon, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;
8) after bullion dissolves with methylene dichloride, last silica gel column chromatography, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to residue on a small quantity;
9) add activated carbon, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is finished product;
Above-mentioned, be raw material with the Adefovir, in the presence of protective material and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:
Further preferred as aforesaid method, the preparation method of said a kind of adefovir ester comprises the steps:
1) under nitrogen protection, add solvent 32ml, protective material 0.8g and Adefovir 8g successively, after stirring, be cooled to 5 ℃;
2) be added dropwise to triethylamine 15ml, stir;
3) be added dropwise to chloromethyl pivalate 30ml, drip off and slowly be warming up to 60 ℃, to reacting completely;
4) be cooled to room temperature, add isopropyl acetate 110ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing; (the filter cake composition is Adefovir and reaction intermediate adefovir (AD) monoester)
5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;
6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to residue on a small quantity;
7) add activated carbon, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;
8) after bullion dissolves with methylene dichloride, last silica gel column chromatography, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to residue on a small quantity;
9) add activated carbon, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is finished product;
Above-mentioned, be raw material with the Adefovir, in the presence of protective material and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:
Said protective material be S-WAT, sodium sulfite anhy 96, vitamins C, 2,6 di tert butyl 4 methyl phenol, 4,4 '-a kind of in thiobis-(the 3-methyl 6-t-butyl phenol).
Said solvent is a kind of in N-Methyl pyrrolidone, the N-formyl n n dimetylaniline.
Theoretical foundation of the present invention does, when adefovir ester by Adefovir and chloromethyl pivalate prepared in reaction.The reaction structure formula is following:
Adefovir and adefovir ester all contain amido functional group, and it is at high temperature oxidized that this group is prone to, and produced by product, so crude reaction generally presents redness or yellow or incarnadine or faint yellow, thereby have reduced reaction yield.The present invention considers that protection is amino, generally has the protection of going up base to protect and go to protect (like the benzyloxycarbonyl protection, hydrogenation goes protection), or adds a small amount of effective antioxygen base and protect.After theoretical and experimental selection, we find to protect base to protect and go protection, and cost is too big, deficiency in economic performance.Therefore, we take to add a small amount of effectively antioxygen base according to qualifications through experiment and protect, and effect is obvious, and reaction yield is brought up to about 52% by 45%, reduces production costs about 20%.
Embodiment
Through specific embodiment the present invention is described further below, but the present invention is not limited by following examples.
The contrast experiment:
In reaction flask, add Adefovir (PMEA) 8g, N-Methyl pyrrolidone (NMP) 32ml stirs, and behind dropping triethylamine 15ml, the chloromethyl pivalate 30ml, slowly is heated to 60 ℃, reacts 4 hours, and (adopting TLC to analyze) reacts completely.Be cooled to room temperature and add the filtration of 110ml isopropyl acetate, filter cake washs with isopropyl acetate, and gained organic phase (mother liquor) is with twice of washing; Dry, the filtration of anhydrous MgSO4, filtrate decompression is concentrated into silica gel column chromatography on the oily matter, methyl alcohol: methylene dichloride (1: 19) wash-out; Elutriant is concentrated into about 30ml, adds gac and stirred 30 minutes, filter; Filtrating is concentrated into dried, and discharging is dried and is bullion.
With bullion 20g, with the dissolving of 40ml methylene dichloride, last silicagel column (400g) is used methyl alcohol: methylene dichloride (1: 19) wash-out; Collection contains the elutriant of product, is evaporated to about 100ml, adds gac 1g, stirs 0.5 hour; Filter, filtrate decompression is concentrated into dried, discharging; Oven dry gets finished product, productive rate 45%.
The embodiment of the invention 1:
1) under nitrogen protection, add N-Methyl pyrrolidone 32ml, 2,6 di tert butyl 4 methyl phenol 0.8g and Adefovir 8g successively, after stirring, be cooled to 5 ℃;
2) be added dropwise to triethylamine 15ml, stir;
3) be added dropwise to chloromethyl pivalate 30ml, drip off and slowly be warming up to 60 ℃, to react completely (adopting TLC to analyze);
4) be cooled to room temperature, add isopropyl acetate 110ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing;
5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;
6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 30ml;
7) add activated carbon and stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;
8) with bullion 20g, with the dissolving of 40ml methylene dichloride, last silica gel column chromatography (400g), wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 100ml;
9) add activated carbon 1g, stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is that finished product, productive rate are 52%.
Above-mentioned, be raw material with the Adefovir, in the presence of protective material 2,6 di tert butyl 4 methyl phenol and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:
The embodiment of the invention 2:
1) under nitrogen protection, add N-Methyl pyrrolidone 30ml, sodium sulfite anhy 96 0.5g and Adefovir 5g successively, after stirring, be cooled to 0 ℃;
2) be added dropwise to triethylamine 12ml, stir;
3) be added dropwise to chloromethyl pivalate 28ml, drip off and slowly be warming up to 60 ℃, to react completely (adopting TLC to analyze);
4) be cooled to room temperature, add isopropyl acetate 105ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing;
5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;
6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 30ml;
7) add activated carbon and stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;
8) with bullion 20g, with the dissolving of 40ml methylene dichloride, last silica gel column chromatography (400g), wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 100ml;
9) add activated carbon 1g, stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is that finished product, productive rate are 48%.
Above-mentioned, be raw material with the Adefovir, in the presence of protective material sodium sulfite anhy 96 and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:
The embodiment of the invention 3:
1) under nitrogen protection, add N-Methyl pyrrolidone 33ml, S-WAT 0.7g and Adefovir 6g successively, after stirring, be cooled to 3 ℃;
2) be added dropwise to triethylamine 14ml, stir;
3) be added dropwise to chloromethyl pivalate 29ml, drip off and slowly be warming up to 60 ℃, to react completely (adopting TLC to analyze);
4) be cooled to room temperature, add isopropyl acetate 108ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing;
5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;
6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 30ml;
7) add activated carbon and stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;
8) with bullion 20g, with the dissolving of 40ml methylene dichloride, last silica gel column chromatography (400g), wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 100ml;
9) add activated carbon 1g, stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is that finished product, productive rate are 50%.
Above-mentioned, be raw material with the Adefovir, in the presence of protective material S-WAT and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:
The embodiment of the invention 4:
1) under nitrogen protection, add N-Methyl pyrrolidone 34ml, vitamins C 0.9g and Adefovir 9g successively, after stirring, be cooled to 8 ℃;
2) be added dropwise to triethylamine 15ml, stir;
3) be added dropwise to chloromethyl pivalate 31ml, drip off and slowly be warming up to 60 ℃, to react completely (adopting TLC to analyze);
4) be cooled to room temperature, add isopropyl acetate 112ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing;
5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;
6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 30ml;
7) add activated carbon and stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;
8) with bullion 20g, with the dissolving of 40ml methylene dichloride, last silica gel column chromatography (400g), wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 100ml;
9) add activated carbon 1g, stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is that finished product, productive rate are 51%.
Above-mentioned, be raw material with the Adefovir, in the presence of protective material vitamins C and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:
The embodiment of the invention 5:
1) under nitrogen protection, add N-Methyl pyrrolidone 35ml, vitamins C 1.0g and Adefovir 10g successively, after stirring, be cooled to 10 ℃;
2) be added dropwise to triethylamine 16ml, stir;
3) be added dropwise to chloromethyl pivalate 32ml, drip off and slowly be warming up to 60 ℃, to react completely (adopting TLC to analyze);
4) be cooled to room temperature, add isopropyl acetate 115ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing;
5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;
6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 30ml;
7) add activated carbon and stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;
8) with bullion 20g, with the dissolving of 40ml methylene dichloride, last silica gel column chromatography (400g), wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 100ml;
9) add activated carbon 1g, stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is that finished product, productive rate are 50%.
Above-mentioned, be raw material with the Adefovir, in the presence of protective material vitamins C and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:
The embodiment of the invention 6:
1) under nitrogen protection, add N-formyl n n dimetylaniline 32ml, 2,6 di tert butyl 4 methyl phenol 0.8g and Adefovir 8g successively, after stirring, be cooled to 5 ℃;
2) be added dropwise to triethylamine 15ml, stir;
3) be added dropwise to chloromethyl pivalate 30ml, drip off and slowly be warming up to 60 ℃, to react completely (adopting TLC to analyze);
4) be cooled to room temperature, add isopropyl acetate 110ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing;
5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;
6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 30ml;
7) add activated carbon and stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;
8) with bullion 20g, with the dissolving of 40ml methylene dichloride, last silica gel column chromatography (400g), wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 100ml;
9) add activated carbon 1g, stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is that finished product, productive rate are 50%.
Above-mentioned, be raw material with the Adefovir, in the presence of protective material 2,6 di tert butyl 4 methyl phenol and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:
The embodiment of the invention 7:
1) under nitrogen protection, add N-formyl n n dimetylaniline 32ml, sodium sulfite anhy 96 0.8g and Adefovir 8g successively, after stirring, be cooled to 5 ℃;
2) be added dropwise to triethylamine 15ml, stir;
3) be added dropwise to chloromethyl pivalate 30ml, drip off and slowly be warming up to 60 ℃, to react completely (adopting TLC to analyze);
4) be cooled to room temperature, add isopropyl acetate 110ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing;
5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;
6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 30ml;
7) add activated carbon and stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;
8) with bullion 20g, with the dissolving of 40ml methylene dichloride, last silica gel column chromatography (400g), wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to 100ml;
9) add activated carbon 1g, stirred 30 minutes, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is that finished product, productive rate are 51%.
Above-mentioned, be raw material with the Adefovir, in the presence of protective material sodium sulfite anhy 96 and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:
Claims (3)
1. the preparation method of an adefovir ester is characterized in that comprising the steps:
1) under nitrogen protection, add solvent 30-35ml, protective material 0.5-1.0g and Adefovir 5-10g successively, after stirring, be cooled to 0-10 ℃; Wherein, protective material be S-WAT, sodium sulfite anhy 96, vitamins C, 2,6 di tert butyl 4 methyl phenol, 4,4 '-a kind of in thiobis-(the 3-methyl 6-t-butyl phenol);
2) be added dropwise to triethylamine 12-16ml, stir;
3) be added dropwise to chloromethyl pivalate 28-32ml, drip off and slowly be warming up to 60 ℃, to reacting completely;
4) be cooled to room temperature, add isopropyl acetate 105-115ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing;
5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;
6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to residue on a small quantity;
7) add activated carbon, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;
8) after bullion dissolves with methylene dichloride, last silica gel column chromatography, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to residue on a small quantity;
9) add activated carbon, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is finished product;
Above-mentioned, be raw material with the Adefovir, in the presence of protective material and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:
2. the preparation method of a kind of adefovir ester as claimed in claim 1 is characterized in that comprising the steps:
1) under nitrogen protection, add solvent 32ml, protective material 0.8g and Adefovir 8g successively, after stirring, be cooled to 5 ℃; Wherein, protective material be S-WAT, sodium sulfite anhy 96, vitamins C, 2,6 di tert butyl 4 methyl phenol, 4,4 '-a kind of in thiobis-(the 3-methyl 6-t-butyl phenol);
2) be added dropwise to triethylamine 15ml, stir;
3) be added dropwise to chloromethyl pivalate 30ml, drip off and slowly be warming up to 60 ℃, to reacting completely;
4) be cooled to room temperature, add isopropyl acetate 110ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing;
5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;
6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to residue on a small quantity;
7) add activated carbon, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;
8) after bullion dissolves with methylene dichloride, last silica gel column chromatography, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to residue on a small quantity;
9) add activated carbon, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is finished product;
Above-mentioned, be raw material with the Adefovir, in the presence of protective material and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:
3. according to claim 1 or claim 2 a kind of preparation method of adefovir ester is characterized in that: said solvent is a kind of in N-Methyl pyrrolidone, the N-formyl n n dimetylaniline.
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Denomination of invention: A kind of preparation method of adefovir dipivoxil Effective date of registration: 20220728 Granted publication date: 20120523 Pledgee: Zhejiang Shaoxing Ruifeng Rural Commercial Bank Co.,Ltd. Yuezhou sub branch Pledgor: ZHEJIANG BETTER PHARMACEUTICALS Co.,Ltd. Registration number: Y2022980011559 |
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Date of cancellation: 20230706 Granted publication date: 20120523 Pledgee: Zhejiang Shaoxing Ruifeng Rural Commercial Bank Co.,Ltd. Yuezhou sub branch Pledgor: ZHEJIANG BETTER PHARMACEUTICALS Co.,Ltd. Registration number: Y2022980011559 |
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Denomination of invention: A preparation method of Adefovir dipivoxil Effective date of registration: 20230713 Granted publication date: 20120523 Pledgee: Zhejiang Shaoxing Ruifeng Rural Commercial Bank Co.,Ltd. Yuezhou sub branch Pledgor: ZHEJIANG BETTER PHARMACEUTICALS Co.,Ltd. Registration number: Y2023980048372 |