CN102250146A - Method for synthesizing adefovir serving as anti-hepatitis B virus medicine - Google Patents
Method for synthesizing adefovir serving as anti-hepatitis B virus medicine Download PDFInfo
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Abstract
The invention discloses a method for synthesizing adefovir serving as anti-hepatitis B virus medicine, which belongs to the field of antiviral chemical medicines. In the method, adefovir is obtained by using adenine as a starting raw material and by three nucleophilic substitution reactions. In the invention, the reaction conditions are mild, the method is simple, easy to implement, efficient and high in selectivity, fewer byproducts are produced, and the yield and purity of the product are high.
Description
Technical field
The invention belongs to antiviral chemicals field, be specifically related to a kind of anti-hepatitis B virus (HBV) medicine Adefovir (9-(2-(phosphatidyl methoxy) ethyl) VITAMIN B4) the preparation method.
Background technology
Hepatitis B is a kind of worldwide disease that is caused by hepatitis B virus (HBV).Developing country's sickness rate height, according to statistics, the asymptomatic hepatitis B virus carriers in the whole world surpasses 3.5 hundred million, and China accounts for 1.3 hundred million.Most asymptomatic, wherein 1/3 clinical manifestation that hepatic injury occurs.There are about 3,000 ten thousand people of hepatitis B patient in China at present.
Adefovir is the nucleotide analog of single adenosine phosphate, is phosphorylated to the bisphosphate Adefovir with active function by the cell kinase effect in vivo.The bisphosphate Adefovir suppresses NDA polymerase or the reversed transcriptive enzyme effect of HBV.Adefovir be by adefovir ester oral after, be converted into Adefovir performance antivirus action in vivo.Adefovir is the key core of synthetic adefovir ester.The chemical name of adefovir ester is two (pivaloyl oxygen methoxyl group) the phosphono methoxyl groups of 9-[2-[] ethyl] VITAMIN B4, drugs approved by FDA can be respectively applied for the positive and negative hepatitis B patient of treatment hepatitis B virus carriers (HBeAg) in 2002.In March, 2005, He Weili (Hepser adefovir ester) medicine that SFDA official approval GlaxoSmithKline PLC company produces is used for the treatment of chronic viral hepatitis B.This is second antiviral oral hepatitis B medicine of domestic listing after its Hepuding that continues.The home-made adefovir ester is then released by Hainan Kang Lian pharmaceutcal corporation, Ltd, and commodity are called " Dai Ding ", by the national new drug of Taipu Medicine Science ﹠ Technology Development Co., Ltd., Tianjin's research and development, Tianjin Medicine Research Academy Pharmaceutical Co., Ltd's production.
Several main method of at present synthetic Adefovir all are to be initial feed with the VITAMIN B4, mainly are to the synthetic improvement of carrying out of side chain.
Collect Czech Chem Commun, 1987,52,2801 ~ 2809 disclose a kind of synthesis technique:
This route amino that needs protection, and use bromotrimethylsilane and sodium hydride makes cost and dangerous sharp increase, but also needs column chromatography and ion exchange column, is unfavorable for industrial production.
Collect Czech Chem Commun, 1989,52,2190 ~ 2195; Acta Pharmaceutica Sinica, 1996,31,112 ~ 117 and Org. Proc. Res. Dev. 1999,3:53-55 improves synthetic method:
This synthesis step is shortened, but still use bromotrimethylsilane and sodium hydride, but also need ion exchange column, and use sodium hydride that the side reaction of this reaction is increased, still unfavorable to industrial production.
Subsequently, W09904774, US56451340 improve once more to synthetic having carried out of Adefovir:
After the improvement, NSC 11801, sodium tert-butoxide all are easy to get very much, and when synthetic Adefovir diethyl ester, use washed with dichloromethane, obtain Adefovir with the bromotrimethylsilane reaction more afterwards.Than previous method, raw material is comparatively cheap, does not also need column chromatography and ion exchange column, but the bromotrimethylsilane price is still very high, and methylene dichloride is volatile, and washing time is longer.
CN 1421451A has announced the improvement of carrying out alkali to above:
This route has used cheap sodium methylate and has reduced danger, but needs a large amount of comparatively expensive iodide to make catalyzer, and yield neither be very desirable simultaneously, and cost is increased greatly.
CN1560059 discloses a kind of with salt of wormwood, and 18-hat-6 is the synthetic method of catalyzer:
This method is used expensive 18-hat-6, and can not recycle, and the side chain raw material is difficult for obtaining, and the utilization of fluorochemical also makes reactivity hazard and cost increase greatly.
In view of Adefovir in the comparatively superior therapeutic action of clinical application, it is high and economical and practical again to seek a kind of productive rate, is easy to control, dangerous little synthetic method is present comparatively urgent demand with technology.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of yield height, strong, the lower-cost Adefovir formula of controllability,, side reaction many etc. low with the synthesis technique yield that solves Adefovir in the prior art and intermediate thereof is unsuitable for the problems of suitability for industrialized production.
Technical solution of the present invention may further comprise the steps:
1) in nitrogen atmosphere, under alkaline condition, react by VITAMIN B4 and oxyethane, obtain compound 9-(2-hydroxyethyl through heat washing or recrystallization) VITAMIN B4;
2) with the 9-(2-hydroxyethyl) VITAMIN B4 is dissolved in behind the solvent to mix with tert-butyl alcohol magnesium and tolysulfonyl oxygen methyl phosphonous acid diethyl ester nucleophilic substitution reaction takes place, with the mixed solution after the sour neutralization reaction, with behind the solvent wash, obtain 9-(2-(diethyl phosphatidyl methoxy again) ethyl) VITAMIN B4;
3) with 9-(2-(diethyl phosphatidyl methoxy) ethyl) reactant aqueous solution of VITAMIN B4 and HCl or HBr or HI is to reaction bundle knot, the pH to 2 of conditioned reaction liquid～4 then, separate out solid, get solid solubilizing agent recrystallization, obtain the 9-(2-(phosphatidyl methoxy) ethyl) VITAMIN B4.
Superiority of the present invention is embodied in following several respects:
1, the present invention replaces NSC 11801 with oxyethane when preparation Adefovir intermediate, and advantage is: (1) selectivity is good, and side reaction reduces greatly, is 9 exclusive reactions substantially, and yield increases substantially; (2) reactive behavior height, room temperature reaction, temperature is low, save energy; (3) regeneration carbonic acid gas has not reduced emission of carbon-dioxide; (4) raising of reaction preference has reduced by product, has reduced the discharging of solid waste, the cleaner environmental protection of technology.
2, the present invention is at preparation Adefovir intermediate 9-(2-hydroxyethyl) during VITAMIN B4, can adopt the heat washing, also can adopt the method for recrystallization.As adopt the heat washing, and can not only go out decon well, more reduced solvent load and product losses.
3, the present invention is an alkali with the tert-butyl alcohol magnesium when preparation Adefovir intermediate, has replaced sodium tert-butoxide in the past, and hydride etc. greatly reduce side reaction, thereby productive rate is improved.Reaction can be carried out under the safe mild conditions, is more suitable for industrial production.
4, the present invention with HCl or HBr or HI acid substitution bromotrimethylsilane, greatly reduces cost when the preparation Adefovir.Also reduced simultaneously the use of organic solvent, more safety and environmental protection.
In the step 1) of the present invention, used alkali is the oxyhydroxide of basic metal or alkaline-earth metal; The molar ratio of described VITAMIN B4 and alkali is 1 ︰ 0.01～0.1; The temperature condition of reaction is 0～50 ℃; Reaction solvent is N, dinethylformamide, methyl-sulphoxide or dioxane at least a; The solvent that adopts during the heat washing is to be the alcohols of liquid under 0～50 ℃ of envrionment temperature under the normal pressure.Described alcohols is at least a arbitrarily in methyl alcohol, ethanol or the propyl alcohol.
Described step 2) in, be used to dissolve the 9-(2-hydroxyethyl) solvent of VITAMIN B4 is N, in dinethylformamide, dioxane or the methyl-sulphoxide at least any one; The temperature condition of nucleophilic substitution reaction is 20～120 ℃; Washer solvent be with in methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, ethyl propionate, tetrahydrofuran (THF), methylene dichloride or the chloroform at least any one.The 9-(2-hydroxyethyl) molar ratio of VITAMIN B4 and tert-butyl alcohol magnesium is 1 ︰ 0.5～2.
In the described step 3), the concentration of volume percent of employed HCl or HBr or the HI aqueous solution is 10～80%; The temperature of reaction condition is 20～120 ℃; The recrystallization solvent is to be the alcohols of liquid under 0～50 ℃ of envrionment temperature under the normal pressure.
Preferably: with 9-(2-(diethyl phosphatidyl methoxy) ethyl) VITAMIN B4 and HI reactant aqueous solution, the concentration of the HI aqueous solution is 40～80%.
In addition, in the described step 3), described recrystallization is specifically as follows water, methyl alcohol or ethanol with solvent.
Preferably: in the step 3), pH to 2.9～3.3 of reaction bundle knot back conditioned reaction liquid.
Preferably: in the described step 3), the temperature of reaction condition is 50～100 ℃.
Embodiment
Following example just illustrates technical conceive of the present invention and characteristics, and its purpose is to allow the people who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.
Embodiment 1:
Synthetic 9-(2-hydroxyethyl) VITAMIN B4:
Room temperature and under nitrogen protection in 250 mL reaction flasks, drops into 27 g (0.200 mol) VITAMIN B4, DMF 100 mL, sodium hydroxide 0.3 g.A straight-through ethylene oxide gas in system then, and detect by TLC and HPLC, till VITAMIN B4 disappears.Decompression steams DMF, adds dehydrated alcohol 80 mL, and 2 h that reflux filter, and get white solid 9-(2-hydroxyethyl) VITAMIN B4 33.3 g, productive rate 94%, and HPLC purity is greater than 99%.
Synthetic 9-(2-(diethyl phosphono methoxyl group) VITAMIN B4 ethyl):
Under 80 ℃ of conditions, with 9-(2-hydroxyethyl) VITAMIN B4 10.0 g(0.056 mol) join among the 50 mL DMF, drop into tert-butyl alcohol magnesium 4.8 g (0.028 mol) again, behind the reaction 0.5-1 h, add tolysulfonyl oxygen methyl phosphonous acid diethyl ester 18.0 g(0.056 mol), reaction 7 ~ 8 h, add in the acetic acid extremely neutral with excess base, steam DMF, with ethyl acetate (200 mL * 3) washing, combined ethyl acetate phase, concentrate, get white solid 9-(2-(diethyl phosphono methoxyl group) ethyl) VITAMIN B4 16.3 g, productive rate 90%, HPLC purity is greater than 95%.
Synthetic 9-(2-(phosphono methoxyl group) VITAMIN B4 ethyl):
With 9-(2-(diethyl phosphono methoxyl group) ethyl) VITAMIN B4 10.0 g(0.030 mol) put into and contain 5.8 g(0.045 mol) in the hydroiodic acid HI solution of hydrogen iodide, behind the backflow 4-5 h, add sodium hydroxide and regulate pH between 3 ~ 3.1, filter, with water-ethanol system (V:V=7:3) recrystallization, get white solid 9-(2-(phosphono methoxyl group) ethyl) VITAMIN B4 7.2 g, productive rate 85%, HPLC purity is greater than 99%.
Embodiment 2:
Synthetic 9-(2-hydroxyethyl) VITAMIN B4:
Room temperature and under nitrogen protection, disposable input 54.0 g (0.400 mol) VITAMIN B4, DMF 150 mL, sodium hydroxide 0.6 g.A straight-through ethylene oxide gas in system then, and detect by TLC and HPLC, till VITAMIN B4 disappears.Decompression steams DMF, uses ethanol-water system recrystallization (V:V=2:8) to get white solid 9-(2-hydroxyethyl) VITAMIN B4 62.3 g, productive rate 87%, and HPLC purity is greater than 99%.
Synthetic 9-(2-(diethoxy phosphonium mesitoyl methoxyl group) ethyl) VITAMIN B4:
Under 80 ℃ of conditions, with 9-(2-hydroxyethyl) VITAMIN B4 17.9 g(0.100 mol) join among the 50 mL DMF, drop into tert-butyl alcohol magnesium 8.5g (0.050 mol) again, behind the reaction 0.5-1 h, add tolysulfonyl oxygen methyl phosphonous acid diethyl ester 32.2 g(0.100 mol), reaction 7 ~ 8 h, add in the tosic acid extremely neutral with excess base, steam DMF, with ethyl acetate (300 mL * 3) washing, combined ethyl acetate phase, concentrate, get white solid 29.3 g, yield 89%, HPLC purity is greater than 95%.
Synthetic 9-(2-(phosphono methoxyl group) VITAMIN B4 ethyl):
With 9-(2-(diethoxy phosphonium mesitoyl methoxyl group) ethyl) VITAMIN B4 32.9 g(0.100 mol) put into and contain 19.2 g(0.150 mol) in the hydroiodic acid HI solution of hydrogen iodide, behind the backflow 4-5 h, add sodium hydroxide and regulate pH between 3 ~ 3.2, filter, with water-ethanol system (V:V=8:2) recrystallization, get white solid 9-(2-(phosphono methoxyl group) ethyl) VITAMIN B4 24.0 g, productive rate 88%, HPLC purity is greater than 99%.
The concrete synthetic route of the present invention is as follows:
Claims (10)
1. a kind of synthetic method of anti-hbv drug Adefovir is characterized in that may further comprise the steps:
1) in nitrogen atmosphere, under alkaline condition, react by VITAMIN B4 and oxyethane, obtain compound 9-(2-hydroxyethyl through heat washing or recrystallization) VITAMIN B4;
2) with the 9-(2-hydroxyethyl) VITAMIN B4 is dissolved in behind the solvent to mix with tert-butyl alcohol magnesium and tolysulfonyl oxygen methyl phosphonous acid diethyl ester nucleophilic substitution reaction takes place, with the mixed solution after the sour neutralization reaction, with behind the solvent wash, obtain 9-(2-(diethyl phosphatidyl methoxy again) ethyl) VITAMIN B4;
3) with 9-(2-(diethyl phosphatidyl methoxy) ethyl) reactant aqueous solution of VITAMIN B4 and HCl or HBr or HI is to reaction bundle knot, the pH to 2 of conditioned reaction liquid～4 then, separate out solid, get solid solubilizing agent recrystallization, obtain the 9-(2-(phosphatidyl methoxy) ethyl) VITAMIN B4.
2. according to a kind of synthetic method of the described anti-hbv drug Adefovir of claim 1, it is characterized in that in described step 1) that used alkali is the oxyhydroxide of basic metal or alkaline-earth metal; The molar ratio of described VITAMIN B4 and alkali is 1 ︰ 0.01～0.1; The temperature condition of reaction is 0～50 ℃; Reaction solvent is N, dinethylformamide, methyl-sulphoxide or dioxane at least a; The solvent that adopts during the heat washing is to be the alcohols of liquid under 0～50 ℃ of envrionment temperature under the normal pressure.
3. according to a kind of synthetic method of the described anti-hbv drug Adefovir of claim 2, it is characterized in that described alcohols is at least a arbitrarily in methyl alcohol, ethanol or the propyl alcohol.
4. according to a kind of synthetic method of the described anti-hbv drug Adefovir of claim 1, it is characterized in that described step 2) in, be used to dissolve the 9-(2-hydroxyethyl) solvent of VITAMIN B4 is N, in dinethylformamide, dioxane or the methyl-sulphoxide at least any one; The temperature condition of nucleophilic substitution reaction is 20～120 ℃; Washer solvent be with in methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, ethyl propionate, tetrahydrofuran (THF), methylene dichloride or the chloroform at least any one.
5. according to a kind of synthetic method of claim 1 or 4 described anti-hbv drug Adefovirs, it is characterized in that described step 2) in, the 9-(2-hydroxyethyl) molar ratio of VITAMIN B4 and tert-butyl alcohol magnesium is 1 ︰ 0.5～2.
6. according to a kind of synthetic method of the described anti-hbv drug Adefovir of claim 1, it is characterized in that in the described step 3) that the concentration of volume percent of employed HCl or HBr or the HI aqueous solution is 10～80%; The temperature of reaction condition is 20～120 ℃; The recrystallization solvent is to be the alcohols of liquid under 0～50 ℃ of envrionment temperature under the normal pressure.
7. according to a kind of synthetic method of the described anti-hbv drug Adefovir of claim 6, it is characterized in that in the described step 3), 9-(2-(diethyl phosphatidyl methoxy) ethyl) VITAMIN B4 and HI reactant aqueous solution, the concentration of the HI aqueous solution is 40～80%.
8. according to a kind of synthetic method of the described anti-hbv drug Adefovir of claim 6, it is characterized in that in the described step 3) that described recrystallization solvent is water, methyl alcohol or ethanol.
9. according to a kind of synthetic method of the described anti-hbv drug Adefovir of claim 1, it is characterized in that in the described step 3) pH to 2.9～3.3 of reaction bundle knot back conditioned reaction liquid.
10. according to a kind of synthetic method of the described anti-hbv drug Adefovir of claim 6, it is characterized in that in the described step 3) that the temperature of reaction condition is 50～100 ℃.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288878A (en) * | 2013-06-09 | 2013-09-11 | 江西师范大学 | Magnesium salt precipitator used for purifying (R)-9-[2-(diethyoxyl phosphorus acyl methoxyl) propyl] adenine and purifying method |
| CN103374039A (en) * | 2012-04-20 | 2013-10-30 | 上海益生源药业有限公司 | Synthesis method of tenofovir |
| CN104530130A (en) * | 2014-12-09 | 2015-04-22 | 河南师范大学 | Adefovir dipivoxil preparation method |
| CN106317115A (en) * | 2015-06-29 | 2017-01-11 | 天津市亨必达化学合成物有限公司 | Preparation method of adefovir |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999004774A2 (en) * | 1997-07-25 | 1999-02-04 | Gilead Sciences, Inc. | Nucleotide analog compositions |
| CN1560059A (en) * | 2004-03-05 | 2005-01-05 | 胡小侠 | Synthesis process for Adefovir ester of anti hepatitis type B virus medicine |
-
2011
- 2011-05-27 CN CN2011101398008A patent/CN102250146A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999004774A2 (en) * | 1997-07-25 | 1999-02-04 | Gilead Sciences, Inc. | Nucleotide analog compositions |
| CN1560059A (en) * | 2004-03-05 | 2005-01-05 | 胡小侠 | Synthesis process for Adefovir ester of anti hepatitis type B virus medicine |
Non-Patent Citations (1)
| Title |
|---|
| RENATA LUBCZAK: "Reactions of Adenine with Ethylene Oxide and Propylene Oxide", 《JOURNAL OF APPLIED POLYMER SCIENCE》, vol. 86, 31 December 2002 (2002-12-31), pages 489 - 497, XP002357688, DOI: doi:10.1002/app.11021 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103374039A (en) * | 2012-04-20 | 2013-10-30 | 上海益生源药业有限公司 | Synthesis method of tenofovir |
| CN103374039B (en) * | 2012-04-20 | 2015-11-18 | 上海益生源药业有限公司 | The synthetic method of tynofovir |
| CN103288878A (en) * | 2013-06-09 | 2013-09-11 | 江西师范大学 | Magnesium salt precipitator used for purifying (R)-9-[2-(diethyoxyl phosphorus acyl methoxyl) propyl] adenine and purifying method |
| CN103288878B (en) * | 2013-06-09 | 2015-12-02 | 江西师范大学 | For magnesium salts precipitation agent and the method for purification of (R)-9-[2-(diethoxy phosphatidyl methoxy) propyl group] VITAMIN B4 of purifying |
| CN104530130A (en) * | 2014-12-09 | 2015-04-22 | 河南师范大学 | Adefovir dipivoxil preparation method |
| CN106317115A (en) * | 2015-06-29 | 2017-01-11 | 天津市亨必达化学合成物有限公司 | Preparation method of adefovir |
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