CN1506370A - Prepn process of Adefovir dipivalate - Google Patents
Prepn process of Adefovir dipivalate Download PDFInfo
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- CN1506370A CN1506370A CNA021510172A CN02151017A CN1506370A CN 1506370 A CN1506370 A CN 1506370A CN A021510172 A CNA021510172 A CN A021510172A CN 02151017 A CN02151017 A CN 02151017A CN 1506370 A CN1506370 A CN 1506370A
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- adefovir
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- trimethylchlorosilane
- potassiumiodide
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Abstract
The present invention discloses one improved preparation process of Adefovir dipivalate. In the synthesis of the mother compound 9-[2-(phosphinocarboxyl methoxy) ethyl adenine, trimethyl chlorsilane, rather than expensive trimethyl bromosilane, as material and potassium iodide as nucleophilic reagentare used to reduce cost while the product yield and quality is maintained. The production process of the present invention may be used in industrial production.
Description
Technical field
The present invention relates to a kind of two (pivaloyl oxygen base) methoxyl groups of nucleotide analog 9-[(2-[[that prepare] phosphinyl] methoxyl group) ethyl] method of VITAMIN B4, specifically relevant its prepare its parent compound matter 9-[2-(the phosphono methoxy ethyl] the improving one's methods of VITAMIN B4.
Background technology
Two (the pivaloyl oxygen base) methoxyl groups of nucleotide analog 9-[(2-[[] phosphinyl] methoxyl group) ethyl] VITAMIN B4, the two special pentyl esters of general Adefovir by name, English name adefovirdipivoxil (hereinafter to be referred as AD), be parent compound matter 9-[2-(phosphono methoxyl group) ethyl] the two special pentyl ester of VITAMIN B4 (hereinafter to be referred as PMEA), the animal and human is had antiviral activity, retrovirus, poxvirus, sore exanthema virus and hepatitis B virus are all had very strong restraining effect.Clinical trial shows, short-term oral administration chronic hepatitis B can make virus obviously descend, and can heighten the effect of a treatment with the other medicines drug combination.
AD synthetic and open by people such as U.S. Starrott the earliest (patent No. EP481214, on April 22nd, 1992 bulletin, 14 days September nineteen ninety of priority date).World patent Nucleotideanalog compositions (patent No. WO9904774, on February 4th, 1999 is open) also discloses the method for a kind of AD of preparation, and it is with VITAMIN B4, and dimethylphosphite is the synthetic AD of starting raw material, and main synthesis step is:
Its step C by the synthetic PMEA of 9-(2,2-diethoxy phosphonium mesitoyl base) VITAMIN B4 (hereinafter to be referred as diethyl PMEA), has used bromotrimethylsilane to make nucleophilic reagent.Because bromotrimethylsilane costs an arm and a leg (about 1480 yuan of per 100 grams), the preparation cost height; And the present domestic manufacturer production bromotrimethylsilane that still do not have, the buying difficulty causes being difficult to suitability for industrialized production.
Summary of the invention
The present invention is by the improvement to its preparation technology, specifically to the improvement of step C, promptly the reagent trimethylchlorosilane with production domesticization replaces bromotrimethylsilane to make raw material, and make nucleophilic reagent with potassiumiodide, it is expensive and need the drawback of import well to have solved the reagent price, make AD the production domesticization of production reagent and adapt to industrial big production.
Preparation AD provided by the invention improves one's methods, and may further comprise the steps:
Wherein trimethylchlorosilane, potassiumiodide, acetonitrile are respectively 3 with the molar weight ratio of diethyl PMEA among the step C: 1--20: 1,3: 1--0: 1,10: 1--60: 1, back flow reaction is adopted in described reaction, reflux temperature is 40--90 ℃, and return time is 3--72 hour.
Trimethylchlorosilane, potassiumiodide, acetonitrile were respectively 4.5: 1 with the molar weight ratio of diethyl PMEA among the step C, and 4.5: 1,22: 1; Described back flow reaction makes two bites at a cherry, and primary temperature is than for the second time low.
The reflux temperature first time in the back flow reaction among the step C is 55 ℃, and return time is 2 hours, and reflux temperature is 75 ℃ for the second time, and return time is 3 hours.
The concrete operations of steps A and B are described as disclosed patent, the reaction process of step C is: in the three-necked bottle that prolong, drying tube are housed, drop into diethyl PMEA, acetonitrile with rare gas element such as nitrogen replacement air, potassiumiodide and trimethylchlorosilane, charging capacity is according to molar ratio computing, and trimethylchlorosilane, potassiumiodide, acetonitrile are respectively 3 with the ratio of diethyl PMEA: 1--20: 1,3: 1--20: 1,10: 1--60: 1, preferred proportion is 4.5: 1,4.5: 1, and 22: 1; Stir down and be warming up to 40--60 ℃, because the boiling point of trimethylchlorosilane is at 55--57 ℃, so temperature is good with its boiling point when refluxing the first time, backflow 1--24 hour was good with 2 hours; And then be warming up to 55--90 ℃, and its temperature is good than corresponding reflux temperature height for the first time with 75 ℃, backflow 2--48 hour was good with 3 hours.Later step is as operation as described in the publication.
The price of trimethylchlorosilane is 35 yuan/100 grams, and the price of potassiumiodide is 120 yuan/500 grams, by 89 gram PEMA, can economize in raw materials more than 3000 yuan of cost of every batch reaction.
The AD that produces with preparation technology of the present invention compares with the disclosed technology of WO9904774, and production cost obviously reduces, and quality product and yield are unaffected.Make the production of AD be suitable for industrialization.
Embodiment
Below in conjunction with embodiment the present invention is done a concrete description.
Embodiment 1:
The concrete operations of steps A and B are described as disclosed patent, step C is embodied as: be equipped with in the three-necked bottle of prolong, drying tube at 1000ml, dropping into 130g with the nitrogen replacement air is the diethyl PMEA of 0.395mol, 350g is the 8.54mol acetonitrile, 289g is that 1.74mol potassiumiodide and 192.5g are the 1.77mol trimethylchlorosilane, is warming up to 55 ℃ under stirring, and refluxes 2 hours, be warming up to 75 ℃ again and refluxed 3 hours, sampling detects (TLC).Take off the second eyeball under the negative pressure of qualified back to doing (temperature is no more than 80 ℃ in the bottle).Be cooled to room temperature and add water 260ml and fully dissolve, be warming up to 55 ℃ again and stir insulation 1 hour, be cooled to room temperature, be neutralized to PH=3.0--3.5 with 20% (W/W) sodium hydroxide solution.Be warming up to 75 ℃ of insulations 1 hour, be cooled to 0--3 ℃ of insulation 3 hours, suction filtration is to doing.Filter cake is changed in the bottle, add water 487.5ml, be warming up to 75 ℃, be incubated 2 hours, be cooled to 0--3 ℃ of insulation 2 hours, suction filtration adds water 65ml washing 2 times to doing, and drains.Adding acetone 130ml washing drains 2 times.Filter cake is 80 ℃ of following negative pressure dryings 12 hours, 89gPMEA.Back one step D and disclosed patented technology same operation.
Below provide three embodiment again, its working method is identical with embodiment 1, and wherein the unit of charging capacity is g/mol, and its temperature unit is ℃, and return time unit is hour.
| Diethyl PMEA | Trimethylchlorosilane | Potassiumiodide | Acetonitrile | Reflux temperature for the first time/for the second time | Return time for the first time/for the second time | PMEA must measure | |
| Embodiment 2 | ??130/0.395 | ??150/1.38 | ??231/1.39 | ??194/4.74 | ??40/70 | ??1/3 | ??60 |
| Embodiment 3 | ??130/0.395 | ??429/3.95 | ??656/3.95 | ??567/13.83 | ??50/80 | ??2/5 | ??90 |
| Embodiment 4 | ??130/0.395 | ??770/7.10 | ??1189/7.16 | ??891/21.73 | ??60/90 | ??3/60 | ??91 |
Claims (4)
1. method that changes for preparing the two special pentyl esters of Adefovir may further comprise the steps:
2. preparation method according to claim 1, it is characterized in that trimethylchlorosilane among the described step C, potassiumiodide, acetonitrile and 9-(2,2-dihydroxyl phosphonoethyl) the molar weight ratio of VITAMIN B4 is respectively 3: 1--20: 1,3: 1--0: 1,10: 1--60: 1; The reaction of described step C is adopted and is refluxed, and reflux temperature is 40--90 ℃, and return time is 3--72 hour.
3. preparation method according to claim 1 and 2 is characterized in that the molar weight ratio of trimethylchlorosilane, potassiumiodide, acetonitrile and 9-among the described step C (2,2-dihydroxyl phosphonoethyl) VITAMIN B4 was respectively 4.5: 1,4.5: 1, and 22: 1; Described back flow reaction makes two bites at a cherry, and primary temperature is than for the second time low.
4. preparation method according to claim 3 is characterized in that the reflux temperature first time in the back flow reaction of described step C is 55 ℃, and return time is 2 hours, and reflux temperature is 75 ℃ for the second time, and return time is 3 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021510172A CN1506370A (en) | 2002-12-05 | 2002-12-05 | Prepn process of Adefovir dipivalate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021510172A CN1506370A (en) | 2002-12-05 | 2002-12-05 | Prepn process of Adefovir dipivalate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1506370A true CN1506370A (en) | 2004-06-23 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CNA021510172A Pending CN1506370A (en) | 2002-12-05 | 2002-12-05 | Prepn process of Adefovir dipivalate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101633672B (en) * | 2009-08-07 | 2012-01-25 | 中国药科大学 | Novel nucleoside compound as well as preparation method and application thereof |
| CN104628773A (en) * | 2013-11-06 | 2015-05-20 | 杭州和泽医药科技有限公司 | Preparation method of (R)-9-[2-(phosphoryl phenol methoxy)propyl]adenine |
| CN109438514A (en) * | 2018-10-10 | 2019-03-08 | 湖南方盛制药股份有限公司 | The preparation method of Aldoforwe ester |
-
2002
- 2002-12-05 CN CNA021510172A patent/CN1506370A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101633672B (en) * | 2009-08-07 | 2012-01-25 | 中国药科大学 | Novel nucleoside compound as well as preparation method and application thereof |
| CN104628773A (en) * | 2013-11-06 | 2015-05-20 | 杭州和泽医药科技有限公司 | Preparation method of (R)-9-[2-(phosphoryl phenol methoxy)propyl]adenine |
| CN104628773B (en) * | 2013-11-06 | 2018-10-23 | 杭州和泽医药科技有限公司 | (R)-9-[2- (phosphinylidyne phenol ylmethoxy) propyl;The preparation method of adenine |
| CN109438514A (en) * | 2018-10-10 | 2019-03-08 | 湖南方盛制药股份有限公司 | The preparation method of Aldoforwe ester |
| CN109438514B (en) * | 2018-10-10 | 2020-12-18 | 湖南方盛制药股份有限公司 | Preparation method of adefovir dipivoxil |
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