CN103848868B - method for preparing tenofovir - Google Patents
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- CN103848868B CN103848868B CN201210514647.7A CN201210514647A CN103848868B CN 103848868 B CN103848868 B CN 103848868B CN 201210514647 A CN201210514647 A CN 201210514647A CN 103848868 B CN103848868 B CN 103848868B
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Abstract
The invention provides a method for preparing tenofovir. The method is characterized by comprising the following steps: 1) reacting 9-(2-hydroxy propyl) adenine with a compound as shown in the formula (1) in the specification in the presence of magnesium alkoxide to prepare tenofovir ethyl ester, wherein Y is selected from methyl, trifluoromethyl, phenyl or 4-trifluoromethylphenyl; 2) hydrolyzing the tenofovir ethyl ester in the presence of a dealkylation reagent to prepare tenofovir. The method for preparing tenofovir provided by the invention has the advantages of safe process, good product quality, high yield and suitability for industrialization.
Description
Technical field
The present invention relates to it is a kind of prepare anti-hepatitis virus and HIV (human immunodeficiency virus) compound tenofovir (Tenofovir,
PMPA method).
Background technology
Tenofovir disoproxil fumarate (tenofovir disoproxil fumarate, TDF), its structure such as formula (5) institute
Show, be to be researched and developed by Glead Scierices companies of the U.S., be a kind of novel nucleoside acids reverse transcriptase inhibitors, in calendar year 2001
October is ratified to list in the U.S. first by FDA, in the countries and regions listing such as Europe, Australia and Canada.2008
Ratify its treatment Adult chronic's hepatitis B year FDA again.TDF obtains medicinal ingredient tenofovir such as formula (3) after hydrolyzing in vivo
Shown, it can significantly inhibit the activity of hbv replication in vitro, and effective to most of HBV persisters, therefore controlling in infection
Have broad application prospects in treatment.
Shown in the formula (3) of existing document report, the synthetic route of compound has summed up 4 kinds, specific as follows.
Synthetic route 1
Protection and deprotection are used repeatedly in whole route, synthetic route is longer, cumbersome, is not suitable for industrial metaplasia
Produce, total recovery only 14.3% (referring to, Holy A, Maso jidkova M., CollectCzechChem Commun, 1995,
60：1196～1212).
Synthetic route 2
Use protection and deprotection reaction in whole route twice, though shortened with respect to synthetic route 1, but still seem compared with
Long, total recovery 2.3% is (referring to Holy A, Maso jidkova M., CollectCzechChem Commun, 1995,60
(8)：1390～1490；Holy A, Dvorakova H, DeClerq E, et al., US6653296B1,2003-11-25)).
Synthetic route 3
The route uses expensive chiral auxiliary (S, S)-SalenCr, is unsuitable for industrialized production, and yield is relatively low
(referring to, Jay F.Larrow, Scott E.Schaus, Eric N.Jacobsen, J.Am.Chem.Soc, 1996,118 (31)：
7420-7421)。
Synthetic route 4
The route is more brief, makees catalyst using tert-butyl alcohol lithium, and two step yield of (7) → (2) → (3) is 30% or so
(referring to, Schultze LM, Chapman HH, Dubree NJP, et al.Tetrahedron Letters, 1998,39
(14)：1853～1856；Munger J D, Rohloff J C, Schultze L M., US5935946A1,1999-08-
10)).Patent (Becker.Mark.W, Chapman.Harlan.H, et al, CN100402539,2001-07-20) is with tertiary fourth
Magnesium alkoxide is catalyst, and (7) are obtained (2) with the reaction of tolysulfonyl oxygen methylphosphonic acid diethylester, then take off ethyl, two steps with TMSBr
Total recovery 50.4%.
Therefore, need exist for synthesizing the new method of tenofovir, to overcome the shortcomings of existing method.
The content of the invention
The invention aims to overcome weak point of the prior art, there is provided a kind of process safety, product quality
Tenofovir preparation method that is good, simple to operate, being suitable to industrialization.
The inventors discovered that, with adenine and (R)-Allyl carbonate as initiation material, (R) -9- [2- (hydroxyl) third are obtained
Base] adenine；In the presence of magnesium alkoxide, (R) -9- [2- (hydroxyl) propyl group] adenine terminal hydroxyls and sulphonyl oxygen methylphosphine
Diethyl phthalate class compound condensation is obtained tenofovir diethylester, and reactant liquor adds TMSBr without process, carries out de- ethyl anti-
Should, cooling separates out tenofovir crystal, realizes " one kettle way " operation.Two step yields can reach 56-67%, higher than document above report
Road yield, and relevant material (see Fig. 1-3) conformance with standard of the product of related process production.
Therefore, the present invention provides a kind of method for preparing tenofovir, it is characterised in that comprise the steps：
1) in the presence of magnesium alkoxide 9- (2- hydroxypropyls) adenine is reacted with such as following formula (1) compound, formula is obtained
(2) the tenofovir ethyl ester shown in；
Wherein Y is selected from methyl, trifluoromethyl, phenyl or 4- trifluoromethyls；
2) in the presence of de- alkyl reagent the hydrolysis of tenofovir ethyl ester is made to obtain the tenofovir shown in formula (3)：
According to one preferred embodiment of the invention, Y is methyl.
According to one preferred embodiment of the invention, the step 1) in magnesium alkoxide in hydrocarbon can be C1-C6
Chain or straight chained alkyl, the particularly preferred tert-butyl group or isopropyl.
According to one preferred embodiment of the invention, the step 1) carry out under inert gas shielding.
According to one preferred embodiment of the invention, the step 1) in 9- (2- hydroxypropyls) adenine and oxyl
The molar ratio of magnesium is 1: 0.5～3, preferably 1: 0.8～1.
According to one preferred embodiment of the invention, the step 1) reaction with 1-Methyl-2-Pyrrolidone, N, N-
One or more in dimethylformamide and tetrahydrofuran is solvent, preferably with 1-Methyl-2-Pyrrolidone as solvent.
According to one preferred embodiment of the invention, the step 1) reaction temperature be 70～80 DEG C.
According to one preferred embodiment of the invention, the step 2) in de- alkyl reagent be selected from bromotrimethylsilane
Or hydrobromic acid.
According to one preferred embodiment of the invention, the step 2) described in tenofovir ethyl ester try with de- alkyl
The mol ratio of agent is 1: 4～10.
According to one preferred embodiment of the invention, the step 2) 5～8h of response time.
Starting materials of formulae (1) compound and 9- (2- hydroxypropyls) adenine of tenofovir are prepared in the present invention respectively with following
Step A and B are synthesizing.
A. make following compoundReact with the compound as shown in formula (4)
YSO2Cl (4)；
Wherein Y is as defined above.
Obtain compound shown in formula (1)：
B. make adenine condensation reaction be carried out with (R)-Allyl carbonate, obtain the 9- (2- hydroxypropyls) shown in formula (6)
Adenine：
In above-mentioned steps A, described hydroxymethyl phosphonic acid diethylester with fluorophenylsulfonyl chloride is reacted, can be with dichloromethane, chlorine
Imitative, carbon tetrachloride or dichloroethanes are reaction dissolvent, with triethylamine, tripropyl amine (TPA), tri-n-butylamine or pyridine as acid binding agent.
In above-mentioned steps B, described adenine carries out condensation reaction with N, N- dimethyl formyls with (R)-Allyl carbonate
Amine (DMF) or tetrahydrofuran (THF) are reaction dissolvent, with NaOH, KOH, NaCO3Or the one kind in triethylamine be catalyst, gland
The mol ratio of purine and catalyst is 10～40: 1, and reaction temperature is controlled at 120～140 DEG C.
The present invention prepares the method for tenofovir and has the advantage that：
(1) present invention is not used expensive or special reagent, and raw material is easy to get, and is conducive to large-scale production.
(2) present invention is catalyst using magnesium alkoxide, compares sodium hydrogen, tert-butyl alcohol lithium and potassium tert-butoxide, reduces amino
Replace the generation of by-product, improve the safety of reaction yield and operation.
(3) present invention substitutes tolysulfonyl oxygen methylphosphonic acid diethyl using to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester
Ester, improves yield.
(4) present invention makees solvent using 1-Methyl-2-Pyrrolidone, and obtained tenofovir reactant liquor can be straight without process
Input next step reaction is connect, the tenofovir solid of generation is separated out, and this " one kettle way " operation is easily achieved industrialized production.
Description of the drawings
Fig. 1 is with to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester and (R) -9- [2- (hydroxyl) propyl group] gland described in embodiment 1
HPLC collection of illustrative plates of the purine for tenofovir obtained in raw material；
Fig. 2 is with methylsulfonyl oxygen methylphosphonic acid diethylester and (R) -9- [2- (hydroxyl) propyl group] adenine described in embodiment 2
The HPLC collection of illustrative plates of tenofovir obtained in raw material；
Fig. 3 is with trifluoro methylsulfonyl oxygen methylphosphonic acid diethylester and (R) -9- [2- (hydroxyl) propyl group] gland described in embodiment 3
HPLC collection of illustrative plates of the purine for tenofovir obtained in raw material.
Specific embodiment
The present invention is further illustrated below by specific intermediate and embodiment, it should be understood, however, that, in the middle of these
Body and embodiment are only used for specifically describing in more detail and are used, and are not to be construed as limiting this in any form
It is bright.
The present invention to used in test to material and test method carry out generality and/or specific describe.Though
So to realize that but many materials that the object of the invention used and operational approach are it is known in the art that the present invention still here
Describe in detail as far as possible.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and
Operational approach is well known in the art.Wherein adenine is purchased from Shanghai Hai Qu Chemical Co., Ltd.s；R- Allyl carbonaties, trifluoro
Mesyl chloride, to trifluoromethyl benzene sulfonyl chloride, to fluorophenylsulfonyl chloride from Shanghai De Mo Pharmaceutical Technology Co., Ltd purchase；The tert-butyl alcohol
Magnesium, bromotrimethylsilane, phosphonous acid diethylester are purchased from Sa En chemical technologies (Shanghai) Co., Ltd.；Remaining reagent is by traditional Chinese medicines
Reagent Company of group provides.
Embodiment 1：With to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester and (R) -9- [2- (hydroxyl) propyl group] adenine for original
Material prepares tenofovir
The preparation of hydroxymethyl phosphonic acid diethylester
To in a reactor containing inert atmosphere (such as nitrogen), addition diethyl phosphite (81.0g,
0.586mol, 1eq.), triethylamine (63.2g, 0.625mol, 1.1eq.), paraformaldehyde (22.4g, 0.746mol, 1.3eq.),
Stirring.The 8h that flows back at 90 DEG C is completed up to reaction, is monitored according to TLC and is shown the diethyl phosphite for there was only trace or detect not
To diethyl phosphite, vacuum distillation obtains 59.2g products, yield 60%.ESI-MS(m/z)：169.06M+。
(R) preparation of -9- [2- (hydroxyl) propyl group] adenine
The DMF (DMF) of 200ml, N are added in reaction bulb2Protection, addition adenine (30.0g,
0.222mol, 1eq.), stirring, add NaOH (0.45g, 0.011mol) and R- Allyl carbonaties (28.5g, 0.279mol,
1.3eq.), 130～140 DEG C are warming up to.Sampling detection later in 12 hours, when adenine content is below 1%, can stopped reaction.
Temperature is slowly down to less than 90 DEG C, adds 200ml toluene, continues to be cooled to 0～5 DEG C, stirs 2 hours.Sucking filtration, is dried, obtains
White solid 38.13g, yield 87%, 192～194 DEG C of fusing point.ESI-MS(m/z)：194.11[M+H]+。
Preparation to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester
Hydroxymethyl phosphonic acid diethylester (18.48g, 0.11mol, 1.1eq.) is dissolved in 40ml dichloromethane, is added to fluorine
Benzene sulfonyl chloride (19.4g, 0.10mol, 1eq.), is then slowly added into plus triethylamine (11.1g, 0.11mol, 1.1eq.) is while protect
Temperature is held less than 10 DEG C, the mixture of gained is warming to 22 DEG C and is stirred at least about 5 hours, reacted until TLC shows
Complete.Solids removed by filtration, is washed with dichloromethane.80ml water is added in filtrate, adds 100ml dichloromethane to extract at least
Twice.Organic layer anhydrous sodium sulfate drying, is evaporated off solvent, obtains pale yellow oil 20.64g.Crude product is directly used in reaction.
ESI-MS(m/z)：327.10[M+H]+。
The preparation of tenofovir
1-Methyl-2-Pyrrolidone (NMP) 20ml is added in reaction bulb, stirring is lower to add (R) -9- [2- (hydroxyl) third
Base] adenine (4.0g, 21.0mmol, 1eq.), it is heated to 65 DEG C.Tert-butyl alcohol magnesium is added in mixture in 1 hour
(3.0g, 17.3mmol, 0.8eq.), 78 DEG C of keeping temperature were slowly added into fluorobenzene sulphonyl oxygen methylphosphonic acid diethyl in 2 hours
Ester (10.14g, about 31.1mmol, 1.5eq.).Reaction stirred 7 hours at 75～80 DEG C, are cooled to room temperature, ice bath cooling
To 0～5 DEG C, Deca bromotrimethylsilane (12.9g, 84.3mmol, 4.0eq.), the then reacting by heating mixture 8 at 77 DEG C
Hour.Stopped reaction, adds 20ml water, 50mol ethyl acetate to be extracted twice in reactant liquor.Water intaking layer, stirs under ice bath,
Adjust PH to 2.5～3.1, pale solid to separate out with 50% NaOH solution, stir at least 3 hours.Sucking filtration, is dried, obtains for promise
Good fortune Wei 5.95g, yield 64%.ESI-MS(m/z)：288.05[M+H]+, 310.03 [M+Na]+, 597.07 [2M+Na]+.This reality
The HPLC for applying the tenofovir that example is prepared is shown in Fig. 1.
Embodiment 2：With methylsulfonyl oxygen methylphosphonic acid diethylester and (R) -9- [2- (hydroxyl) propyl group] adenine as raw material system
Standby tenofovir
The preparation of methylsulfonyl oxygen methylphosphonic acid diethylester
Hydroxymethyl phosphonic acid diethylester (59.2g, 0.352mol, 1eq.) is dissolved in 70ml dichloromethane, solution is cooled to 1
DEG C (typically about -2～4 DEG C), slowly Deca mesyl chloride (43.63g, 0.381mol, 1.1eq.), is then slowly added into three
Ethamine (57.6g, 0.540mol, 1.5eq.) at the same keeping temperature be less than 10 DEG C, be stirred at room temperature at least about 5 hours, until
Till TLC shows that reaction is completed (only detect the mesyl chloride of trace or can't detect mesyl chloride).Solids removed by filtration, uses
Dichloromethane is washed.100ml water is added in filtrate, adds 150ml dichloromethane to extract at least twice.The anhydrous sulfur of organic layer
Sour sodium is dried, and solvent is evaporated off, pale yellow oil 72.4g is obtained.Crude product is directly used in reaction.ESI-MS(m/z)：246.98M+。
The preparation of tenofovir
1-Methyl-2-Pyrrolidone (NMP) 40ml is added in reaction bulb, adds (R) -9- [2- (hydroxyl) propyl group] gland fast
Purine (20.0g, 0.104mol, 1eq.), is heated to 65 DEG C.In 1 hour in mixture add tert-butyl alcohol magnesium (15g,
0.088mol, 0.8eq.) or magnesium isopropoxide, 78 DEG C of keeping temperature, methylsulfonyl oxygen methylphosphonic acid diethyl is slowly added in 2 hours
Ester crude product (47.65g, about 0.155mol).Reaction stirred 7 hours at 75～80 DEG C, until (R) -9- [2- (hydroxyl) third
Base] adenine content be less than 10%.Room temperature is cooled to, ice bath is cooled to 0～5 DEG C, Deca bromotrimethylsilane (156.6g,
1.02mol, 10eq.), then reacting by heating mixture 8 hours at 77 DEG C.Stopped reaction, adds 100ml in reactant liquor
Water, 100mol ethyl acetate are extracted twice.Water intaking layer, stirs under ice bath, adjusts PH to 2.5～3.1 with 50% NaOH solution,
Pale solid is separated out, and is stirred at least 3 hours.Sucking filtration, is dried, obtains tenofovir 21.8g, yield 56%.This scheme is prepared and is replaced
The HPLC of Nuo Fuwei is shown in Fig. 2.
Embodiment 3：With trifluoro methylsulfonyl oxygen methylphosphonic acid diethylester and (R) -9- [2- (hydroxyl) propyl group] adenine as former
Material prepares tenofovir
The preparation of trifluoro methylsulfonyl oxygen methylphosphonic acid diethylester
Hydroxymethyl phosphonic acid diethylester (59.2g, 0.352mol, 1eq.) is dissolved in 70ml dichloromethane, fluoroform is added
Sulfonic acid chloride (114.3g, 0.381mol, 1.1eq.), is then slowly added into plus triethylamine (57.6g, 0.540mol, 1.5eq.) is same
When keeping temperature be less than 10 DEG C, the mixture of gained be warming to 22 DEG C and stirring at least about 5 hours, until TLC shows
Reaction is completed.Solids removed by filtration, is washed with dichloromethane.100ml water is added in filtrate, 150ml dichloromethane extraction is added
Take at least twice.Organic layer anhydrous sodium sulfate drying, is evaporated off solvent, obtains pale yellow oil 102.4g.Crude product is directly used
In reaction.ESI-MS(m/z)：300.19M+。
The preparation of tenofovir
1-Methyl-2-Pyrrolidone (NMP) 40ml is added in reaction bulb, stirring is opened, (R) -9- [2- (hydroxyl) are added
Propyl group] adenine (20.0g, 0.104mol, 1eq.), it is heated to 65 DEG C.Tert-butyl alcohol magnesium is added in mixture in 1 hour
(15g, 0.088mol, 0.8eq.), be slowly added in 2 hours methylsulfonyl oxygen methylphosphonic acid diethylester crude product (58.1g, about
0.155mol, 1.5eq.).Reaction stirred 7 hours at 75～80 DEG C.It is cooled to room temperature, Deca bromotrimethylsilane
(156.6g, 1.02mol, 9.8eq.), then reacting by heating mixture 8 hours at 77 DEG C.Stopped reaction, adds in reactant liquor
Enter 100ml water, 100mol ethyl acetate is extracted twice.Water intaking layer, stirs under ice bath, adjusts PH extremely with 50% NaOH solution
2.5～3.1, pale solid is separated out, and is stirred at least 3 hours.Sucking filtration, is dried, obtains tenofovir 23.3g, yield 60%.This side
Case prepares the HPLC of tenofovir and sees Fig. 3.
Embodiment 4：With fast to trifluoromethyl benzene sulfonyl oxygen methylphosphonic acid diethylester and (R) -9- [2- (hydroxyl) propyl group] gland
Purine prepares tenofovir for raw material
Preparation to trifluoromethyl benzene sulfonyl oxygen methylphosphonic acid diethylester
Hydroxymethyl phosphonic acid diethylester (6.38g, 38.0mmol, 1eq.) is dissolved in 20ml dichloromethane, is added to trifluoro
Toluene sulfonyl chloride (10.0g, 41.0mmol, 1.1eq.), is then slowly added into plus triethylamine 8.5ml is not while keeping temperature surpasses
10 DEG C are crossed, the mixture of gained is warming to 22 DEG C and is stirred at least about 5 hours, until TLC shows that reaction is completed.Cross and filter
Solid is removed, is washed with dichloromethane.50ml water is added in filtrate, adds 50ml dichloromethane to extract at least twice.Organic layer
With anhydrous sodium sulfate drying, solvent is evaporated off, obtains pale yellow oil 11.7g.Crude product is directly used in reaction.ESI-MS(m/z)：
399.06[M+Na]+。
The preparation of tenofovir
1-Methyl-2-Pyrrolidone (NMP) 15ml is added in reaction bulb, stirring is lower to add (R) -9- [2- (hydroxyl) third
Base] adenine (3.0g, 15.5mmol, 1eq.), it is heated to 65 DEG C.Tert-butyl alcohol magnesium is added in mixture in 1 hour
(2.32g, 13.0mmol, 0.8eq.), be slowly added in 2 hours to trifluoro benzene sulfonyl oxygen methylphosphonic acid diethylester (8.74g,
23.2mmol, 1.5eq.).Reaction stirred 7 hours at 75～80 DEG C, are cooled to room temperature, Deca bromotrimethylsilane 20ml,
Then reacting by heating mixture 8 hours at 77 DEG C.Stopped reaction, adds 25ml water, 50mol ethyl acetate extraction in reactant liquor
Take twice.Water intaking layer, stirs under ice bath, adjusts PH to 2.5～3.1, pale solid to separate out with 50% NaOH solution, stirring
At least 3 hours.Sucking filtration, is dried, obtains tenofovir 3.0g, yield 67%.
Claims (1)
1. the method for preparing tenofovir, it is characterised in that comprise the steps：
Preparation to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester：
Hydroxymethyl phosphonic acid diethylester 18.48g is dissolved in 40ml dichloromethane, is added to fluorophenylsulfonyl chloride 19.4g, then slowly
Keeping temperature is less than 10 DEG C simultaneously to add triethylamine 11.1g, the mixture of gained is warming to 22 DEG C and is stirred at least big
About 5 hours, until TLC shows that reaction is completed；Solids removed by filtration, is washed with dichloromethane；80ml water is added in filtrate, plus
Enter 100ml dichloromethane to extract at least twice；Organic layer anhydrous sodium sulfate drying, is evaporated off solvent, obtains pale yellow oil
20.64g；Crude product is directly used in reaction；ESI-MS(m/z)：327.10[M+H]+；
The preparation of tenofovir：
1-Methyl-2-Pyrrolidone 20ml is added in reaction bulb, stirring is lower to add (R) -9- [2- (hydroxyl) propyl group] adenine
4.0g, is heated to 65 DEG C；Tert-butyl alcohol magnesium 3.0g is added in 1 hour in mixture, 78 DEG C of keeping temperature is slow in 2 hours
Slowly add to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester 10.14g；At 75～80 DEG C, reaction stirred 7 hours, are cooled to room
Temperature, ice bath are cooled to 0～5 DEG C, Deca bromotrimethylsilane 12.9g, then reacting by heating mixture 8 hours at 77 DEG C；Stop
Only react, in reactant liquor, add 20ml water, 50mol ethyl acetate to be extracted twice；Water intaking layer, stirs under ice bath, uses 50%
NaOH solution adjust PH to 2.5～3.1, pale solid separate out, stir at least 3 hours；Sucking filtration, is dried, obtains tenofovir
5.95g, yield 64%；ESI-MS(m/z)：288.05[M+H]+, 310.03 [M+Na]+, 597.07 [2M+Na]+。
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| KR101677433B1 (en) | 2014-10-29 | 2016-11-21 | 주식회사 퍼슨 | Ion exchanging process method for Tenofovir disoproxil fumarate in manufacturing synthesis and a preparation method of the Fast Dissolving Films for Oral Dosage of Tenofovir disoproxil fumarate |
| CN106140298B (en) * | 2015-04-10 | 2020-06-30 | 浙江九洲药业股份有限公司 | Magnesium-based catalyst and application thereof |
| CN106146561A (en) * | 2015-04-19 | 2016-11-23 | 浙江九洲药业股份有限公司 | A kind of synthetic method of tenofovir |
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|---|---|---|---|---|
| CN1706855A (en) * | 2000-07-21 | 2005-12-14 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| CN101870713A (en) * | 2010-05-28 | 2010-10-27 | 杭州和素化学技术有限公司 | Industrial production process for tenofovir disoproxil fumarate |
| WO2011111074A2 (en) * | 2010-03-11 | 2011-09-15 | Matrix Laboratories Ltd | An improved process for the preparation of tenofovir disoproxil fumarate |
| CN102219805A (en) * | 2011-03-10 | 2011-10-19 | 苏州腾龙生物医药技术有限公司 | Novel production process of tenofovir |
| CN102295660A (en) * | 2011-07-04 | 2011-12-28 | 常州大学 | Synthetic technology of PMPA |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2046792B1 (en) * | 2006-07-12 | 2015-02-25 | Mylan Laboratories Limited | Process for the preparation of tenofovir |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1706855A (en) * | 2000-07-21 | 2005-12-14 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| WO2011111074A2 (en) * | 2010-03-11 | 2011-09-15 | Matrix Laboratories Ltd | An improved process for the preparation of tenofovir disoproxil fumarate |
| CN101870713A (en) * | 2010-05-28 | 2010-10-27 | 杭州和素化学技术有限公司 | Industrial production process for tenofovir disoproxil fumarate |
| CN102219805A (en) * | 2011-03-10 | 2011-10-19 | 苏州腾龙生物医药技术有限公司 | Novel production process of tenofovir |
| CN102295660A (en) * | 2011-07-04 | 2011-12-28 | 常州大学 | Synthetic technology of PMPA |
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