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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- adefovir
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- mother liquor
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- methylene dichloride
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- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 229960003205 adefovir dipivoxil Drugs 0.000 title abstract 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 72
- 229960001997 adefovir Drugs 0.000 claims abstract description 59
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000001914 filtration Methods 0.000 claims abstract description 39
- 239000000706 filtrate Substances 0.000 claims abstract description 38
- 239000000047 product Substances 0.000 claims abstract description 38
- 239000012452 mother liquor Substances 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000007599 discharging Methods 0.000 claims abstract description 26
- 239000003480 eluent Substances 0.000 claims abstract description 25
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229940011051 isopropyl acetate Drugs 0.000 claims abstract description 25
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 25
- 238000003756 stirring Methods 0.000 claims abstract description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000005406 washing Methods 0.000 claims abstract description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims abstract description 14
- 238000001035 drying Methods 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- 230000006837 decompression Effects 0.000 claims description 35
- -1 adefovir ester Chemical class 0.000 claims description 25
- 238000004042 decolorization Methods 0.000 claims description 22
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 19
- 239000000463 material Substances 0.000 claims description 18
- 230000001681 protective effect Effects 0.000 claims description 18
- 239000012065 filter cake Substances 0.000 claims description 14
- 239000002994 raw material Substances 0.000 claims description 11
- 238000010792 warming Methods 0.000 claims description 11
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 9
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 7
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 7
- 235000010265 sodium sulphite Nutrition 0.000 claims description 7
- 235000019154 vitamin C Nutrition 0.000 claims description 7
- 239000011718 vitamin C Substances 0.000 claims description 7
- XOUQAVYLRNOXDO-UHFFFAOYSA-N 2-tert-butyl-5-methylphenol Chemical compound CC1=CC=C(C(C)(C)C)C(O)=C1 XOUQAVYLRNOXDO-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 208000012839 conversion disease Diseases 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 2
- 238000001816 cooling Methods 0.000 abstract 2
- 239000012043 crude product Substances 0.000 abstract 2
- 238000000643 oven drying Methods 0.000 abstract 2
- 239000000126 substance Substances 0.000 abstract 2
- 239000012467 final product Substances 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000003223 protective agent Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract 1
- 238000000034 method Methods 0.000 description 3
- 239000007806 chemical reaction intermediate Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- WHBYZUNNYCCANS-UHFFFAOYSA-N C(C(C)(C)C)(=O)O.[O] Chemical compound C(C(C)(C)C)(=O)O.[O] WHBYZUNNYCCANS-UHFFFAOYSA-N 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of adefovir dipivoxil, which comprises the steps of sequentially adding a solvent, a protective agent and adefovir under the protection of nitrogen, stirring and cooling; dropwise adding triethylamine and chloromethyl pivalate, and slowly heating until the reaction is complete; cooling to room temperature, adding isopropyl acetate, and filtering to obtain mother liquor; washing the mother liquor twice with water, drying with anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain oily substance; performing silica gel column chromatography on the oily substance, collecting eluent containing the product, and concentrating under reduced pressure until a small amount of the product remains; adding activated carbon, decolorizing, filtering, concentrating the filtrate under reduced pressure to dry, discharging, and oven drying to obtain crude product; performing silica gel column chromatography on the crude product, collecting eluent containing the product, and concentrating under reduced pressure until a small amount of the eluent remains; adding activated carbon, decolorizing, filtering, concentrating the filtrate under reduced pressure to dry, discharging, and oven drying to obtain the final product. The invention can reduce the side reaction generated in the reaction of adefovir dipivoxil, thereby improving the reaction conversion rate and reducing the 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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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 |
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