CN108178772A - A kind of tenofovir disoproxil new intermediate and preparation method thereof - Google Patents
A kind of tenofovir disoproxil new intermediate and preparation method thereof Download PDFInfo
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- CN108178772A CN108178772A CN201710990974.2A CN201710990974A CN108178772A CN 108178772 A CN108178772 A CN 108178772A CN 201710990974 A CN201710990974 A CN 201710990974A CN 108178772 A CN108178772 A CN 108178772A
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- tenofovir disoproxil
- new intermediate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
Abstract
The invention discloses a kind of tenofovir disoproxil new intermediates, have following formula（Ⅱ）Structure：；The invention also discloses the preparation methods of the tenofovir disoproxil new intermediate.Tenofovir disoproxil new intermediate disclosed by the invention is to prepare tenofovir disoproxil to open new preparation path, need not move through the purifying of subsequent step, tenofovir disoproxil related substances related with phosphonate moiety in pharmacopeia can effectively be controlled, high income, impurity is few, is conducive to prepare the tenofovir disoproxil of higher degree.
Description
Technical field
The present invention relates to medicinal chemistry art, specifically a kind of tenofovir disoproxil new intermediate and preparation method thereof.
Background technology
Tenofovir disoproxil fumarate（Tenofovir Disoproxil Fumarate, TDF）, entitled (the R)-[[2- of chemistry
(6- amino -9H- purine -9- bases) -1- methyl ethoxies] methyl] phosphonic acids diisopropyl oxygen carbonyloxy group methyl ester fumarate is beautiful
A kind of novel nucleoside acids reverse transcriptase inhibitor of Gilead Sciences companies of state research and development, mainly by inhibiting HIV-1 inverse
The activity of transcriptase and the duplication for inhibiting inhibition of HIV.Said preparation lists for 2001 in the U.S. for the first time, at present in Canada, Europe
Multiple countries and regions listings such as continent, as the first-line drug for the treatment of HIV, have good application prospect.Although at present I
Although the ratio that state's patients infected hiv accounts for total population is very low, number of the infected has occupied the 2nd in Asia, and has year by year
Growth trend, so the demand of Fight against AIDS drug can gradually increase.Tenofovir disoproxil fumarate is as the free AIDS of country
Sick antiviral therapy first-line drug, demand can significantly increase.In addition to this, tenofovir disoproxil, which has, inhibits hepatitis B virus duplication
With the effect for stablizing the state of an illness, and transaminase can be being reduced to a certain degree, can play liver-protective effect, the treatment to hepatitis B
Play the role of relatively good.The good market demand based on tenofovir disoproxil fumarate, to tenofovir disoproxil fumarate synthesis technology
Improvement and optimization to society and enterprise itself be all of great significance.
The existing production technology of tenofovir disoproxil fumarate is as intermediate from tenofovir monohydrate or anhydride
Tenofovir disoproxil is synthesized after esterification with chloromethyl propylene carbonate, then obtains fumaric acid tenofovir into salt with fumaric acid
Ester, but reaction conversion ratio is relatively low in existing synthetic technology, is also easy to produce impurity.It is first in esterification to be primarily due to tenofovir
Mono-esterification is carried out, then proceedes to reaction into dibasic acid esters, but because steric hindrance increases after mono-esterification, reactivity reduces, double esterification is difficult
Degree increases, and causes to influence reaction yield with the presence of monoesters always in reaction.And because mono-substituted products largely exist, after reaction
Processing is also relatively difficult, and product quality is relatively difficult to guarantee.Although the positive of reaction is promoted to carry out by increasing raw material inventory,
It is that this can greatly improve production cost, and the related impurities of the progress tenofovir disoproxil with reaction（As schemed impurity shown in I）
Start to occur.In short, there are the disadvantages such as yield is low, of high cost, impurity is more for the existing method for preparing tenofovir disoproxil.
In order to overcome the shortcomings of tenofovir monohydrate or anhydride utilized above as intermediate, it is necessary to develop
A kind of new intermediate is used to efficiently prepare the tenofovir disoproxil of higher degree.
Invention content
The purpose of the present invention is to provide a kind of tenofovir disoproxil new intermediate and preparation method thereof, to solve above-mentioned background
The problem of being proposed in technology.
To achieve the above object, the present invention provides following technical solution：
A kind of tenofovir disoproxil new intermediate has following formula（Ⅱ）Structure：
The preparation method of the tenofovir disoproxil new intermediate, using synthetic route as follows：
；
Specifically include following steps：1）Tolysulfonyl oxygroup methylphosphonic acid diethylester is anti-through hydrolyzing under hydrolysing agent effect
It should be made such as formula（Ⅲ）Compound represented tolysulfonyl oxygroup methylphosphonic acid；2）By step 1）Obtained such as formula（Ⅲ）Institute
The compound tolysulfonyl oxygroup methylphosphonic acid shown is condensed with chloromethyl butylperoxyisopropyl carbonate under alkali effect, is made such as formula
（Ⅱ）Shown tenofovir disoproxil new intermediate, formula（Ⅱ）Shown tenofovir disoproxil new intermediate is entitled（（It is double（（Isopropyl oxygen
Base carbonyl）Oxygroup）Methoxyl group）Phosphoryl）Methyl 4- toluenesulfonic acid esters.
As further scheme of the invention：Step 1）In, the hydrolysing agent is bromotrimethylsilane, 48% bromination
The combination of one or both of aqueous solution of hydrogen；Step 2）In, the alkali is pyridine, 4-dimethylaminopyridine, N, N- diisopropyls
Ethamine, 2,6- lutidines, sodium carbonate, potassium carbonate, triethylamine or diethylamine.
As further scheme of the invention：Step 1）In, the hydrolysing agent is bromotrimethylsilane；Step 2）
In, the alkali is triethylamine.
As further scheme of the invention：Step 1）In, the tolysulfonyl oxygroup methylphosphonic acid diethylester with
The molar ratio of hydrolysing agent is 1:3-10；Step 2）In, formula（Ⅲ）Compound represented, alkali, chloromethyl butylperoxyisopropyl carbonate
Molar ratio is 1:3-5:2.5-5.
As further scheme of the invention：Step 1）In, the tolysulfonyl oxygroup methylphosphonic acid diethylester with
The molar ratio of hydrolysing agent is 1:8；Step 2）In, formula（Ⅲ）Compound represented, alkali, chloromethyl butylperoxyisopropyl carbonate mole
Than being 1:3:5.
As further scheme of the invention：Step 1）In, the hydrolysis temperature is 10-80 DEG C；Step 2）In, it is described
The temperature of condensation reaction is 30-80 DEG C.
As further scheme of the invention：Step 1）In, the hydrolysis temperature is 30 DEG C；Step 2）In, the contracting
The temperature for closing reaction is 60 DEG C.
As further scheme of the invention：Step 1）In, solvent for use is n,N-Dimethylformamide, N, N- diformazans
Yl acetamide, dimethyl sulfoxide, acetonitrile or N-Methyl pyrrolidone；Step 2）In, solvent for use is acetonitrile, N, N- dimethyl formyls
Amine, n,N-dimethylacetamide, dimethyl sulfoxide or N-Methyl pyrrolidone；Step 1）In, it is counted according to W/V, the use of the solvent
Measure 5-40 times for tolysulfonyl oxygroup methylphosphonic acid diethylester dosage；Step 2）In, it is counted according to W/V, the use of the solvent
It measures as formula（Ⅲ）5-10 times of shown compound amount.
As further scheme of the invention：Step 1）In, solvent for use is acetonitrile；Step 2）In, solvent for use is
N,N-Dimethylformamide.
Compared with prior art, the beneficial effects of the invention are as follows：
1st, tenofovir disoproxil new intermediate disclosed by the invention is to prepare tenofovir disoproxil to open new preparation path, due to elder generation
It is double to synthesize phosphonic acids（Isopropenoxy methyl）Ester moiety needs not move through the purifying of subsequent step, can effectively control in pharmacopeia
The tenofovir disoproxil related substances related with phosphonate moiety, high income, impurity is few, be conducive to prepare higher degree for promise good fortune
Wei ester；
2nd, the preparation method of tenofovir disoproxil new intermediate disclosed by the invention, due to not using n-BuLi, sodium hydride contour
Dangerous material, thus production technology is safer, and technological operation is simple, reaction condition is mild, is suitble to industrialized production, realizes and replaces
Nuo Fuwei esters new intermediate more preferably synthesis mode.
Description of the drawings
Fig. 1 is the nuclear magnetic resonance spectroscopy of tenofovir disoproxil new intermediate.
Fig. 2 is the LCMS spectrograms of tenofovir disoproxil new intermediate.
Specific embodiment
Technical scheme of the present invention is described in more detail With reference to embodiment.
A kind of tenofovir disoproxil new intermediate has following formula（Ⅱ）Structure：
The preparation method of the tenofovir disoproxil new intermediate, using synthetic route as follows：
。
Embodiment 1
Such as formula（Ⅲ）The preparation of compound represented tolysulfonyl oxygroup methylphosphonic acid：
Tolysulfonyl oxygroup methylphosphonic acid diethylester 15g is added in 1L reaction bulbs（0.046mol）, 450ml acetonitriles, stirring,
Bromotrimethylsilane 56.4g is slowly added dropwise under ice bath（0.37mol）, it is added dropwise, is warming up to 30 DEG C, keeps the temperature and react 24 at 30 DEG C
Hour, reaction terminates, and removal acetonitrile is concentrated under reduced pressure, and 100ml toluene is added in into concentrate and is transferred in 500ml there-necked flasks, ice
Bath is cooled to 10~20 DEG C, adds the pre- cold water of 100ml, keeps the temperature 10~20 DEG C of stirring 10min, stands, layering, removal is organic
Layer.Water layer is washed 3 times with 100ml ethyl acetate, is kept the temperature 10~20 DEG C, is removed water layer after washing, combined ethyl acetate layer,
Then 100ml saturated brines are added in into ethyl acetate layer, 10~20 DEG C of 5~10min of stirring is kept the temperature, stands, layering goes to remove water
Layer.Anhydrous magnesium sulfate drying is added in into ethyl acetate layer again, keeps the temperature 10~20 DEG C of stirring 10min, filtering is concentrated in vacuo dry second
Acetoacetic ester obtains 12.3g compounds（Ⅲ）Colourless transparent oil liquid, yield 98%, 1H-NMR（DMSO-d6,δppm）：2.40（S,
3H）, 3.90 (d, 2H), 7.46 (d, 2H), 7.77（d, 2H）.
Embodiment 2
Such as formula（Ⅲ）The preparation of compound represented tolysulfonyl oxygroup methylphosphonic acid：
Tolysulfonyl oxygroup methylphosphonic acid diethylester 20g is added in 1L reaction bulbs（0.06mol）, n,N-Dimethylformamide
500ml, sodium bromide 21.7g（0.882mol）, stir, trim,ethylchlorosilane 32.6g be slowly added dropwise under ice bath（1.26mol）, drop
Add it is complete, be warming up to 60 DEG C react 16 hours, reaction terminates, and reaction solution is down to room temperature, filtering, filtrate high vacuum distillation remove
Solvent n,N-Dimethylformamide adds in 100ml toluene into concentrate and is transferred in 500ml there-necked flasks, and ice bath is cooled to 10
~20 DEG C, the pre- cold water of 100ml is added, 10~20 DEG C of stirring 10min is kept the temperature, stands, layering removes organic layer.Water layer is used
100ml ethyl acetate washs 3 times, keeps the temperature 10~20 DEG C, water layer, combined ethyl acetate layer, then to second are removed after washing
100ml saturated brines are added in ethyl acetate layer, 10~20 DEG C of 5~10min of stirring is kept the temperature, stands, layering removes water layer.Again to
Anhydrous magnesium sulfate drying is added in ethyl acetate layer, keeps the temperature 10~20 DEG C of stirring 10min, filtering is concentrated in vacuo dry ethyl acetate,
Obtain 15.3g compounds（Ⅲ）Colourless transparent oil liquid, yield 91%.
Embodiment 3
Such as formula（Ⅱ）The preparation of compound represented tenofovir disoproxil new intermediate：
20g compounds are added in 500mL reaction bulbs（Ⅲ）（0.075mol）, 200ml n,N-Dimethylformamide is added,
It stirs and evenly mixs at room temperature.It is slowly dropped into 23.2g triethylamines again（0.228mol）, drop is complete, stir about 1h；Then again to reaction solution
Middle addition 57.2g chloromethyl butylperoxyisopropyl carbonates（0.38mol）, reaction solution is warming up to 60 DEG C, insulation reaction 5h.Reaction knot
Beam, is cooled to 10~20 DEG C by reaction solution, adds in 75ml hexamethylenes, stir, stand, and layering removes hexamethylene layer, N, N- diformazans
Base formyl amine layer is washed once again as stated above.Then 450ml ethyl acetate, stirring 0.5 are added in n,N-Dimethylformamide
Hour, filtering, with 150ml water washings three times, 150ml saturated salt solutions washed once filtrate, anhydrous magnesium sulfate drying, mistake
Filter, filtrate are evaporated, and obtain 28g compounds（Ⅱ）Pale yellow oily liquid, yield 75%, 1H-NMR（DMSO-d6,δppm）：1.22
（M, 12H）, 2.42（S, 3H）, 4.49（D, 2H）, 4.80（M, 2H）, 5.57（D, 4H）, 7.48（D, 2H）, 7.80（D, 2H）.
Embodiment 4
Such as formula（Ⅱ）The preparation of compound represented tenofovir disoproxil new intermediate：
50g compounds are added in 1L reaction bulbs（Ⅲ）（0.18mol）, 500ml N-Methyl pyrrolidones are added, at room temperature
It stirs and evenly mixs.It is slowly dropped into 29.4g n,N-diisopropylethylamine again（0.54mol）, drop is complete, stir about 1h；Then again to reaction
137.4g chloromethyl butylperoxyisopropyl carbonates are added in liquid（0.90mol）, reaction solution is warming up to 60 DEG C, insulation reaction 5h.Reaction
Terminate, reaction solution is cooled to 10~20 DEG C, adds in 75ml hexamethylenes, is stirred, is stood, layering removes hexamethylene layer, N- methyl
Pyrrolidones layer is washed once again as stated above.Then 450ml ethyl acetate is added in N-Methyl pyrrolidone, stirring 0.5 is small
When, filtering, with 150ml water washings three times, 150ml saturated salt solutions washed once filtrate, anhydrous magnesium sulfate drying, filtering,
Filtrate is evaporated, and obtains 64g compounds（Ⅱ）Pale yellow oily liquid, yield 68%.
Tenofovir disoproxil new intermediate disclosed by the invention is to prepare tenofovir disoproxil to open new preparation path, due to
First synthesis phosphonic acids is double（Isopropenoxy methyl）Ester moiety needs not move through the purifying of subsequent step, can effectively control pharmacopeia
In tenofovir disoproxil related substances related with phosphonate moiety, high income, impurity is few, be conducive to prepare higher degree for promise
Good fortune Wei ester；The preparation method of tenofovir disoproxil new intermediate disclosed by the invention, due to not using n-BuLi, sodium hydride contour
Dangerous material, thus production technology is safer, and technological operation is simple, reaction condition is mild, is suitble to industrialized production, realizes and replaces
Nuo Fuwei esters new intermediate more preferably synthesis mode.
The better embodiment of the present invention is explained in detail above, but the present invention is not limited to above-mentioned embodiment party
Formula, can also be under the premise of present inventive concept not be departed from the knowledge that one skilled in the relevant art has
Various changes can be made.
Claims (10)
1. a kind of tenofovir disoproxil new intermediate, which is characterized in that there is following formula（Ⅱ）Structure：
。
2. a kind of preparation method of tenofovir disoproxil new intermediate as described in claim 1, which is characterized in that use following institute
The synthetic route shown：
；
Specifically include following steps：
1）Tolysulfonyl oxygroup methylphosphonic acid diethylester is made through hydrolysis such as formula under hydrolysing agent effect（Ⅲ）It is shown
Compound tolysulfonyl oxygroup methylphosphonic acid；
2）By step 1）Obtained such as formula（Ⅲ）Compound represented tolysulfonyl oxygroup methylphosphonic acid and chloromethyl isopropyl
Base carbonic ester is condensed under alkali effect, is made such as formula（Ⅱ）Shown tenofovir disoproxil new intermediate, formula（Ⅱ）Shown replaces promise
Good fortune Wei ester new intermediate is entitled（（It is double（（Isopropoxy carbonyl）Oxygroup）Methoxyl group）Phosphoryl）Methyl 4- toluenesulfonic acid esters.
3. the preparation method of tenofovir disoproxil new intermediate according to claim 2, which is characterized in that step 1）In, institute
Hydrolysing agent is stated as the combination of one or both of bromotrimethylsilane, 48% aqueous solution of hydrogen bromide；Step 2）In, the alkali is
Pyridine, 4-dimethylaminopyridine, n,N-diisopropylethylamine, 2,6- lutidines, sodium carbonate, potassium carbonate, triethylamine or two
Ethamine.
4. the preparation method of tenofovir disoproxil new intermediate according to claim 3, which is characterized in that step 1）In, institute
Hydrolysing agent is stated as bromotrimethylsilane；Step 2）In, the alkali is triethylamine.
5. the preparation method of tenofovir disoproxil new intermediate according to claim 2, which is characterized in that step 1）In, institute
The molar ratio for stating tolysulfonyl oxygroup methylphosphonic acid diethylester and hydrolysing agent is 1:3-10；Step 2）In, formula（Ⅲ）It is shown
Compound, alkali, chloromethyl butylperoxyisopropyl carbonate molar ratio be 1:3-5:2.5-5.
6. the preparation method of tenofovir disoproxil new intermediate according to claim 5, which is characterized in that step 1）In, institute
The molar ratio for stating tolysulfonyl oxygroup methylphosphonic acid diethylester and hydrolysing agent is 1:8；Step 2）In, formula（Ⅲ）Shown change
Close object, alkali, chloromethyl butylperoxyisopropyl carbonate molar ratio be 1:3:5.
7. the preparation method of tenofovir disoproxil new intermediate according to claim 2, which is characterized in that step 1）In, institute
It is 10-80 DEG C to state hydrolysis temperature；Step 2）In, the temperature of the condensation reaction is 30-80 DEG C.
8. the preparation method of tenofovir disoproxil new intermediate according to claim 7, which is characterized in that step 1）In, institute
It is 30 DEG C to state hydrolysis temperature；Step 2）In, the temperature of the condensation reaction is 60 DEG C.
9. the preparation method of tenofovir disoproxil new intermediate according to claim 2, which is characterized in that step 1）In, institute
It is n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile or N-Methyl pyrrolidone with solvent；Step
2）In, solvent for use is acetonitrile, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide or N- crassitudes
Ketone；Step 1）In, it is counted according to W/V, the dosage of the solvent is the 5-40 of tolysulfonyl oxygroup methylphosphonic acid diethylester dosage
Times；Step 2）In, it is counted according to W/V, the dosage of the solvent is formula（Ⅲ）5-10 times of shown compound amount.
10. the preparation method of tenofovir disoproxil new intermediate according to claim 9, which is characterized in that step 1）In, institute
It is acetonitrile with solvent；Step 2）In, solvent for use is n,N-Dimethylformamide.
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| CN201710990974.2A CN108178772B (en) | 2017-10-23 | 2017-10-23 | Preparation method of tenofovir disoproxil fumarate intermediate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103641858A (en) * | 2013-12-31 | 2014-03-19 | 湖南千金湘江药业股份有限公司 | Tenofovir disoproxil fumarate and preparation method thereof |
| WO2015085256A1 (en) * | 2013-12-05 | 2015-06-11 | Chimerix, Inc. | Branched chain acyclic nucleoside phosphonate esters and methods of synthesis and uses thereof |
-
2017
- 2017-10-23 CN CN201710990974.2A patent/CN108178772B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015085256A1 (en) * | 2013-12-05 | 2015-06-11 | Chimerix, Inc. | Branched chain acyclic nucleoside phosphonate esters and methods of synthesis and uses thereof |
| CN106061982A (en) * | 2013-12-05 | 2016-10-26 | 奇默里克斯公司 | Branched chain acyclic nucleoside phosphonate esters and methods of synthesis and uses thereof |
| CN103641858A (en) * | 2013-12-31 | 2014-03-19 | 湖南千金湘江药业股份有限公司 | Tenofovir disoproxil fumarate and preparation method thereof |
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