CN103848869B - The method preparing tenofovir - Google Patents
The method preparing tenofovir Download PDFInfo
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- CN103848869B CN103848869B CN201210514649.6A CN201210514649A CN103848869B CN 103848869 B CN103848869 B CN 103848869B CN 201210514649 A CN201210514649 A CN 201210514649A CN 103848869 B CN103848869 B CN 103848869B
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- tenofovir
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Abstract
The present invention provides a kind of method preparing tenofovir, it is characterized in that, comprise the steps: 1) make 9 (2 hydroxypropyl) adenine react with to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester in the presence of magnesium alkoxide, prepare tenofovir ethyl ester；2) hydrolysis of tenofovir ethyl ester is made to obtain tenofovir in the presence of de-alkyl reagent.The present invention prepares that the method for tenofovir has process safety, good product quality, yield is high, the advantage that is suitable to industrialization.
Description
Technical field
The present invention relates to 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 company 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 such as European, Australian and Canadian listing.2008
Ratify again its treatment Adult chronic's hepatitis B year FDA.TDF obtains medicinal ingredient tenofovir such as formula (3) after hydrolyzing in vivo
Shown in, it can significantly inhibit the activity of hbv replication in vitro, and effective to most of HBV persisters, therefore controlling of infecting
Treatment has broad application prospects.
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
Repeatedly using protection and deprotection in whole route, synthetic route is longer, complex operation, is not suitable for industry metaplasia
Produce, total recovery only 14.3% (see, Holy A, Maso jidkova M., Collect CzechChem Commun, 1995,
60:1196～1212).
Synthetic route 2
Whole route is used for twice protection and deprotection reaction, though relative synthetic route 1 has shortened, but still seems relatively
Long, total recovery 2.3% (sees, Holy A, Maso jidkova M., Collect CzechChem Commun, 1995,60
(8): 1390～1490；Holy A, Dvorakova H, DeClerq E, et al., US6653296B1,2003-11-25)).
Synthetic route 3
This route uses expensive chiral auxiliary (S, S)-SalenCr, is unsuitable for industrialized production, and productivity is relatively low
(see, Jay F.Larrow, Scott E.Schaus, Eric N.Jacobsen, J.Am.Chem.Soc, 1996,118 (31):
7420-7421)。
Synthetic route 4
This route is more brief, uses tert-butyl alcohol lithium to make catalyst, and (7) → (2) → (3) two step yield is about 30%
(see, 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) and tolysulfonyl oxygen methylphosphonic acid diethylester react and prepare (2), then take off ethyl with TMSBr, two steps
Total recovery 50.4%.
Therefore, need exist for synthesizing the new method of tenofovir, in order to overcome the most methodical deficiency.
Summary of the invention
The invention aims to overcome weak point of the prior art, it is provided that a kind of process safety, product quality
Good, simple to operate, be suitable to the tenofovir preparation method of industrialization.
The inventors discovered that, under the effect of magnesium alkoxide, with to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester and (R)-9-
The condensation of [2-(hydroxyl) propyl group] adenine prepares tenofovir diethylester, and reactant liquor is the most treated, in the presence of de-alkyl reagent
Carrying out de-ethyl reaction, cooling separates out tenofovir crystal, it is achieved " one kettle way " operates, and two step yields can reach more than 60%,
Higher than document above report yield, and related process produce product have related substance (see Fig. 1) conformance with standard.
Therefore, the present invention provides a kind of method preparing tenofovir, it is characterised in that comprise the steps:
1) in the presence of magnesium alkoxide, 9-(2-hydroxypropyl) adenine is made and to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester
Reaction, prepares the tenofovir ethyl ester shown in formula (2)；
2) hydrolysis of tenofovir ethyl ester is made to obtain the tenofovir shown in formula (3) in the presence of de-alkyl reagent.
According to one preferred embodiment of the invention, described step 1) in magnesium alkoxide in hydrocarbon can be C1-C6?
Chain or straight chained alkyl, the particularly preferred tert-butyl group and isopropyl.
According to one preferred embodiment of the invention, described step 1) carry out under inert gas shielding.
According to one preferred embodiment of the invention, described step 1) in 9-(2-hydroxypropyl) 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, described step 1) reaction with 1-Methyl-2-Pyrrolidone, N, N-
Dimethylformamide or oxolane are solvent, preferably with 1-Methyl-2-Pyrrolidone as solvent.
According to one preferred embodiment of the invention, described step 1) reaction temperature be 70～80 DEG C.
According to one preferred embodiment of the invention, described step 2) in de-alkyl reagent selected from bromotrimethylsilane
Or hydrobromic acid.
According to one preferred embodiment of the invention, described step 2) described in tenofovir ethyl ester and de-alkyl try
The mol ratio of agent is 1: 4～10.
According to one preferred embodiment of the invention, described step 2) response time 5～8h.
The present invention is prepared the raw material of tenofovir to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester and 9-(2-hydroxypropyl)
Adenine is known compound, can be purchased, and the present invention synthesizes both reactants with following steps A and B respectively.
A. following compound is madeReact with compound as shown in formula (4)
Obtain shown in formula (1) to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester:
B. make adenine and (R)-Allyl carbonate carry out condensation reaction, obtain the 9-(2-hydroxypropyl) shown in formula (6)
Adenine:
In above-mentioned steps A, described hydroxymethyl phosphonic acid diethylester reacts with to fluorophenylsulfonyl chloride, can be with dichloromethane, chlorine
Imitative, carbon tetrachloride or dichloroethanes are reaction dissolvent, with one or more in triethylamine, tripropyl amine (TPA), tri-n-butylamine and pyridine are
Acid binding agent.
In above-mentioned steps B, described adenine and (R)-Allyl carbonate carry out condensation reaction with N, N-dimethyl formyl
Amine (DMF) or oxolane (THF) are reaction dissolvent, with NaOH, KOH, NaCO3Or the one in triethylamine is catalyst, gland
The mol ratio of purine and catalyst is 10～40: 1, and reaction temperature controls at 120～140 DEG C.
The present invention prepares the method for tenofovir and has the advantage that
(1) present invention does not uses costliness or special reagent, and raw material is easy to get, beneficially large-scale production.
(2) present invention uses magnesium alkoxide to be catalyst, compares sodium hydrogen, tert-butyl alcohol lithium and potassium tert-butoxide, decreases amino
Replace the generation of by-product, improve the safety of reaction yield and operation.
(3) present invention uses and fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester is substituted tolysulfonyl oxygen methylphosphonic acid diethyl
Ester, improves yield.
(4) present invention uses 1-Methyl-2-Pyrrolidone to make solvent, and prepared tenofovir reactant liquor is the most treated can be straight
Connecing next step reaction of input, the tenofovir solid of generation separates out, and this " one kettle way " operation is easily achieved industrialized production.
Accompanying drawing explanation
Fig. 1 is the HPLC collection of illustrative plates of the tenofovir that embodiment 1 prepares.
Detailed description of the invention
The present invention is further illustrated below by concrete 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 being used, and are not to be construed as limiting in any form this
Bright.
The present invention to test used in material and test method carry out generality and/or concrete description.Though
It is so to it is known in the art that still the present invention is still at this for realizing many materials that the object of the invention used and operational approach
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.；R-Allyl carbonate, 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 from the buying of Sa En chemical technology (Shanghai) Co., Ltd.；Remaining reagent is by traditional Chinese medicines
Reagent Company of group provides.
Embodiment 1
The preparation of hydroxymethyl phosphonic acid diethylester
In a reactor containing inert atmosphere (such as nitrogen), addition diethyl phosphite (81.0g,
0.586mol, 1.0eq.), triethylamine (63.2g, 0.625mol, 1.1eq.), paraformaldehyde (22.4g, 0.746mol,
1.3eq.), stirring.At 90 DEG C, backflow 8h is until having reacted, according to the diethyl phosphite of TLC monitoring display only trace
Or can't detect diethyl phosphite, decompression distillation obtains 59.2g product, yield 60%.ESI-MS (m/z): 169.06M+。
(R) preparation of-9-[2-(hydroxyl) propyl group] adenine
The DMF (DMF) of 200ml, N is added in reaction bulb2Protection, addition adenine (30.0g,
0.222mol, 1eq.), stirring, add NaOH (0.45g, 0.011mol) and R-Allyl carbonate (28.5g, 0.279mol,
1.26eq.), 130～140 DEG C it are warming up to.Sample detection after 12 hours, when adenine content is below 1%, can stop anti-
Should.Temperature is slowly down to less than 90 DEG C, adds 200ml toluene, continues to be cooled to 0～5 DEG C, stir 2 hours.Sucking filtration, is dried,
To white solid 38.13g, yield 87%, fusing point 192～194 DEG C.ESI-MS (m/z): 194.11 [M+H]+。
Preparation to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester
Hydroxymethyl phosphonic acid diethylester (18.48g, 0.11mol) is dissolved in 40ml dichloromethane, adds fluorophenylsulfonyl chloride
(19.4g, 0.10mol), be then slowly added into add triethylamine (11.1g, 0.11mol) keep simultaneously temperature less than 10 DEG C,
The mixture of gained is warming to 22 DEG C and stirs at least about 5 hours, until TLC display reaction completes.Solids removed by filtration, uses
Dichloromethane washs.In filtrate, add 80ml water, add 100ml dichloromethane and extract at least twice.The anhydrous sulfur of organic layer
Acid sodium is dried, and solvent is evaporated off, 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
Adding 1-Methyl-2-Pyrrolidone (NMP) 20ml in reaction bulb, stirring is lower adds (R)-9-[2-(hydroxyl) third
Base] adenine (4.0g, 21.0mmol, 1.0eq.), it is heated to 65 DEG C.In mixture, tert-butyl alcohol magnesium is added in 1 hour
(3.0g, 17.3mmol, 0.8eq.), keeps temperature 78 DEG C, is 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, and ice bath cools down
To 0～5 DEG C, dropping bromotrimethylsilane (12.9g, 84.3mmol, 4.0eq.), then reacting by heating mixture 8 at 77 DEG C
Hour.Stopped reaction, adds 20ml water in reactant liquor, and 50mol ethyl acetate is extracted twice.Water intaking layer, stirs under ice bath,
NaOH solution with 50% adjusts PH to 2.5～3.1, and pale solid separates out, and stirs at least 3 hours.Sucking filtration, is dried, must replace 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 executing the tenofovir that example prepares is shown in Fig. 1.
Embodiment 2:
Wherein hydroxymethyl phosphonic acid diethylester, (R)-9-[2-(hydroxyl) propyl group] adenine and to fluorobenzene sulphonyl oxygen methylphosphonic acid
Diethylester such as embodiment 1 is prepared.
The preparation of tenofovir
Adding 1-Methyl-2-Pyrrolidone (NMP) 40ml in reaction bulb, stirring is lower adds (R)-9-[2-(hydroxyl) third
Base] adenine (8.0g, 42.0mmol, 1.0eq.), it is heated to 60 DEG C, addition tert-butyl alcohol magnesium (6.0g, 34.6mmol,
0.8eq.), keep temperature 75 DEG C, be slowly added into fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester (20.28g, about 62.2mmol,
1.5eq.).Reaction stirred 2 hours at 75～80 DEG C, are cooled to room temperature, dropping bromotrimethylsilane (67.7g,
0.42mol, 10eq.), then reacting by heating mixture 8 hours at 77 DEG C.Stopped reaction, adds 20ml water in reactant liquor,
60mol ethyl acetate is extracted twice.Water intaking layer, stirs under ice bath, and the NaOH solution with 50% adjusts PH to 2.5～3.1, greyish white
Color solid separates out, and stirs at least 3 hours.Sucking filtration, is dried, obtains tenofovir crude product 12.6g.
Embodiment 3:
Wherein hydroxymethyl phosphonic acid diethylester, (R)-9-[2-(hydroxyl) propyl group] adenine and to fluorobenzene sulphonyl oxygen methylphosphonic acid
Diethylester such as embodiment 1 is prepared.
The preparation of tenofovir
Adding 1-Methyl-2-Pyrrolidone (NMP) 40ml in reaction bulb, stirring is lower adds (R)-9-[2-(hydroxyl) third
Base] adenine (8.0g, 42.0mmol, 1.0eq.), it is heated to 60 DEG C, addition tert-butyl alcohol magnesium (7.3g, 42.7mmol,
1.0eq.), keep temperature 75 DEG C, be slowly added into fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester (20.28g, about 62.2mmol,
1.5eq.).Reaction stirred 2 hours at 75～80 DEG C, are cooled to room temperature, dropping bromotrimethylsilane (52.1g,
0.34mol, 8.1eq.), then reacting by heating mixture 8 hours at 78 DEG C.Stopped reaction, adds 20ml in reactant liquor
Water, 60mol ethyl acetate is extracted twice.Water intaking layer, stirs under ice bath, and the NaOH solution with 50% adjusts PH to 3.1, canescence
Solid separates out, and stirs at least 3 hours.Sucking filtration, is dried, obtains tenofovir crude product 11.8g.
Embodiment 4:
Wherein hydroxymethyl phosphonic acid diethylester, (R)-9-[2-(hydroxyl) propyl group] adenine and to fluorobenzene sulphonyl oxygen methylphosphonic acid
Diethylester such as embodiment 1 is prepared.
The preparation of tenofovir
Adding DMF (DMF) 45ml in reaction bulb, stirring is lower adds (R)-9-[2-(hydroxyl) third
Base] adenine (12.0g, 63.0mmol, 1.0eq.), it is heated to 65 DEG C.In mixture, tert-butyl alcohol magnesium is added in 1 hour
(9.0g, 51.9mmol, 0.8eq.), keeps temperature 75 DEG C, is slowly added into fluorobenzene sulphonyl oxygen methylphosphonic acid diethyl in 2 hours
Ester (30.42g, about 93.3mmol, 1.5eq.).Reacting 2 hours, be cooled to room temperature, ice bath is cooled to 0～5 DEG C, drips trimethyl
Bromo-silicane (38.7g, 0.25mol, 4.0eq.), then reacting by heating mixture 7 hours at 74 DEG C.Stopped reaction, to reaction
Adding 20ml water in liquid, 80mol ethyl acetate is extracted twice.Water intaking layer, stirs under ice bath, and the NaOH solution with 50% adjusts PH
To 2.5～3.1, pale solid separates out, and stirs at least 3 hours.Sucking filtration, is dried, obtains tenofovir crude product 18.05g.
Embodiment 5:
Wherein hydroxymethyl phosphonic acid diethylester, (R)-9-[2-(hydroxyl) propyl group] adenine and to fluorobenzene sulphonyl oxygen methylphosphonic acid
Diethylester such as embodiment 1 is prepared.
The preparation of tenofovir
Adding DMF (DMF) 60ml in reaction bulb, stirring is lower adds (R)-9-[2-(hydroxyl) third
Base] adenine (20.0g, 0.104mol, 1.0eq.), it is heated to 65 DEG C.In mixture, tert-butyl alcohol magnesium is added in 1 hour
(17.7g, 0.104mol, 1.0eq.), keeps temperature 75 DEG C, is slowly added into fluorobenzene sulphonyl oxygen methylphosphonic acid two in 2 hours
Ethyl ester (30.42g, about 93.3mmol, 1.5eq.).Reaction 24, time, be cooled to room temperature, ice bath is cooled to 0～5 DEG C, drip front three
Bromide silane (127.4g, 0.832mol, 8.0eq.), then reacting by heating mixture 7 hours at 74 DEG C.Stopped reaction, to
Adding 40ml water in reactant liquor, 100mol ethyl acetate is extracted twice.Water intaking layer, stirs under ice bath, and the NaOH with 50% is molten
Liquid adjusts PH to 3.1, and pale solid separates out, and stirs at least 3 hours.Sucking filtration, is dried, obtains tenofovir crude product 22.9g.
Claims (10)
1. the method preparing tenofovir, it is characterised in that comprise the steps:
1) 9-(2-hydroxypropyl) adenine is made to react with to fluorobenzene sulphonyl oxygen methylphosphonic acid diethylester in the presence of magnesium alkoxide,
Prepare tenofovir ethyl ester, described step 1) carry out under inert gas shielding；
2) hydrolysis of tenofovir ethyl ester is made to obtain tenofovir, wherein said tenofovir ethyl ester in the presence of de-alkyl reagent
It is 1: 4～10 with the mol ratio of de-alkyl reagent.
Method the most according to claim 1, it is characterised in that described step 1) in magnesium alkoxide in hydrocarbon be C1-C6?
Chain or straight chained alkyl.
Method the most according to claim 2, it is characterised in that described step 1) in magnesium alkoxide in hydrocarbon be the tert-butyl group
Or isopropyl.
Method the most according to claim 1, it is characterised in that described step 1) in 9-(2-hydroxypropyl) adenine and hydrocarbon
The molar ratio of epoxide magnesium is 1: 0.5～3.
Method the most according to claim 4, it is characterised in that described step 1) in 9-(2-hydroxypropyl) adenine and hydrocarbon
The molar ratio of epoxide magnesium is preferably 1: 0.8～1.
Method the most according to claim 1, it is characterised in that described step 1) reaction with 1-Methyl-2-Pyrrolidone,
One or more in DMF and oxolane are solvent.
Method the most according to claim 6, it is characterised in that described step 1) reaction with 1-methyl-2-pyrrolidine
Ketone is solvent.
Method the most according to claim 1, it is characterised in that described step 1) reaction temperature be 70～80 DEG C.
Method the most according to claim 1, it is characterised in that described step 2) in de-alkyl reagent selected from front three bromide
Silane or hydrobromic acid.
Method the most according to claim 1, it is characterised in that described step 2) response time 5～8h.
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| CN110179767A (en) * | 2019-05-17 | 2019-08-30 | 南京望知星医药科技有限公司 | A kind of tenofovir micro-capsule and preparation method thereof |
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 |
| 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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| ES2532502T3 (en) * | 2006-07-12 | 2015-03-27 | Mylan Laboratories Limited | Tenofovir preparation process |
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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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