CN105418682A - Method for preparing tenofovir disoproxil fumarate through two-step method - Google Patents
Method for preparing tenofovir disoproxil fumarate through two-step method Download PDFInfo
- Publication number
- CN105418682A CN105418682A CN201511013838.5A CN201511013838A CN105418682A CN 105418682 A CN105418682 A CN 105418682A CN 201511013838 A CN201511013838 A CN 201511013838A CN 105418682 A CN105418682 A CN 105418682A
- Authority
- CN
- China
- Prior art keywords
- tenofovir disoproxil
- disoproxil fumarate
- prepares
- approach according
- step approach
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The invention provides a method for preparing tenofovir disoproxil fumarate through a two-step method. The reaction conditions are mild, the production cost is low, the product yield is high, the quality is good, and the method is convenient for industrial production.
Description
Technical field
The invention belongs to organic compound synthesis technical field, particularly, relate to a kind of method that two-step approach prepares tenofovir disoproxil fumarate.
Background technology
A kind of novel nucleoside acids of tenofovir disoproxil fumarate reverse transcriptase inhibitors.Suppress reversed transcriptive enzyme with the method similar with efabirenz, thus there is potential Anti-HIV-1 Active.The activeconstituents tynofovir Diphosphonate of tynofovir combines with natural ribodesose substrate by direct competitive and suppresses varial polymerases, and by inserting terminating chain in people DNA.Tynofovir, hardly through gastrointestinal absorption, therefore carries out esterification, salify, becomes tenofovir disoproxil fumarate.Tenofovir disoproxil has water-soluble, can be rapidly absorbed and be degraded into active substance tynofovir, and then tynofovir changes active metabolite tynofovir Diphosphonate again into.Tenofovir disoproxil has the effect suppressing hepatitis B virus duplication and the stable state of an illness, and to a certain degree can reduce transaminase, can play liver-protective effect, have reasonable effect to the treatment of hepatitis B.Although although the ratio that current China patients infected hiv accounts for total population is very low, number of the infected has occupied the 2nd in Asia, and has rising tendency year by year, so the demand of AIDS medicine can increase gradually.Tenofovir disoproxil fumarate is as the free AIDS antiretroviral therapy first-line drug of country, and demand can obviously increase.So to the improvement of tenofovir disoproxil fumarate synthesis technique and optimize to society and enterprise self all significant.
The existing production technique of tenofovir disoproxil fumarate after esterification, synthesizes tenofovir disoproxil as starting raw material and chloromethyl propylene carbonate from tynofovir monohydrate or anhydride, then tenofovir disoproxil fumarate is obtained with fumaric acid salify, but reaction conversion ratio is on the low side in existing synthetic technology, its major cause is because tynofovir first carries out mono-esterification when esterification, then continue to be reacted into dibasic acid esters, but because steric hindrance increases after mono-esterification, reactive behavior reduces, double esterification difficulty strengthens, and cause has monoesters exist and affect reaction yield always in reaction.And because mono-substituted products exists in a large number, post-reaction treatment is also more difficult, and quality product is comparatively difficult to ensure card.Although promote that the forward reacted carries out by increasing raw material charging capacity, this can improve production cost greatly, and when raw material is increased to a certain amount of, reaction forward carries out reaching a balance, does not transform in continuation.In addition, in existing synthetic technology, esterification all uses high boiling solvent, and tenofovir disoproxil is at high temperature unstable, cannot directly reclaim, so generally all adopt a large amount of frozen water to carry out saltouing or a large amount of water washings during aftertreatment, cause a large amount of solvent to enter Sewage treatment systems, not only increase the pressure of environmental protection, and cannot recycle due to solvent and cause product cost too high.
Summary of the invention
Goal of the invention: for the deficiencies in the prior art, the invention provides a kind of method that two-step approach prepares tenofovir disoproxil fumarate, and reaction conditions is gentle, and production cost is low, and product yield is high, quality good, is convenient to the advantages such as suitability for industrialized production.
Technical scheme: the invention provides a kind of method that two-step approach prepares tenofovir disoproxil fumarate, comprise the following steps:
(1) tynofovir, acetonitrile and dimethyl formamide mixed solvent are joined reaction unit, control temperature, at 20-25 DEG C, successively drips acid binding agent and chloromethyl propylene carbonate under agitation condition;
(2) 55-60 DEG C of insulation reaction 8-10 hour is warming up to;
(3) step (2) reaction solution is evaporated to below 40 DEG C absence of liquid to flow out;
(4) in concentrated raffinate, extraction liquid is added, layering extraction after stirring;
(5) step (4) gained organic phase purified water washing 2-3 time; Be evaporated to dry more after drying;
(6) in the concentrated raffinate of step (5), add solvent, be stirred under 45-55 DEG C of condition and dissolve completely;
(7) in step (6) reaction solution, add fumaric acid, be cooled to 10-15 DEG C of insulated and stirred crystallization 2-6 hour;
(8) filter; Extremely dry through 40-45 DEG C of vacuum-drying after filter cake solvent wash, obtain described tenofovir disoproxil fumarate.
Two-step approach of the present invention prepares the method for tenofovir disoproxil fumarate, method is succinct, reaction conditions is gentle, wherein the mol ratio of tynofovir, chloromethyl propylene carbonate, fumaric acid and acid binding agent is about 1:0.5:1:0.5, production cost is low, and it is high to react overall yield, and quality product is also relatively stable.In addition, make mixed solvent with acetonitrile and dimethyl formamide and carry out esterification, use lower boiling acetonitrile as primary solvent, can by recycled solvent under the condition that temperature is lower, under the prerequisite not affecting quality product, solve the high expensive problem because solvent loss causes, also mitigate the pressure of environmental protection.
Further, above-mentioned two-step approach prepares the method for tenofovir disoproxil fumarate, and described tynofovir is tynofovir monohydrate or tynofovir anhydride.Raw material is easy to get, and application cost is low.
Further, above-mentioned two-step approach prepares the method for tenofovir disoproxil fumarate, and described acid binding agent is DIPEA.DIPEA, as acid binding agent, promotes that reaction is carried out, and effective.
Further, above-mentioned two-step approach prepares the method for tenofovir disoproxil fumarate, and the volume ratio of described dimethyl formamide and acetonitrile is 1:8-10.Ratio is reasonable, uses lower boiling acetonitrile as primary solvent.
Further, above-mentioned two-step approach prepares the method for tenofovir disoproxil fumarate, and described step (4) described extraction liquid is the mixing solutions of ethyl acetate and sodium bicarbonate.Raw material sources are wide, and application cost is low.
Preferred as one of the present invention, above-mentioned two-step approach prepares the method for tenofovir disoproxil fumarate, and the volume ratio of described sodium bicarbonate and ethyl acetate is 1:1.25-2.5.Ratio is reasonable.
Further, above-mentioned two-step approach prepares the method for tenofovir disoproxil fumarate, and described sodium bicarbonate is 6% sodium hydrogen carbonate solution.Application cost is low.
Further, above-mentioned two-step approach prepares the method for tenofovir disoproxil fumarate, and described step (5) uses anhydrous sodium sulfate drying.Raw material sources are wide, and application cost is low.
Further, above-mentioned two-step approach prepares the method for tenofovir disoproxil fumarate, and described step (6) and the middle solvent of step (8) are Virahol.Virahol, as solvent, makes follow-up salting-out condition gentle.And only use a small amount of washed with isopropyl alcohol, three-protection design burden is little, reaches the requirement of cleaner production, is conducive to suitability for industrialized production.
Beneficial effect: compared with prior art, the present invention has the following advantages: two-step approach of the present invention prepares the method for tenofovir disoproxil fumarate, and method is succinct, raw material sources are wide, and reaction conditions is gentle, and production cost is low, and it is high to react overall yield, and quality product is also relatively stable.In addition, make mixed solvent with acetonitrile and dimethyl formamide and carry out esterification, use lower boiling acetonitrile as primary solvent, can by recycled solvent under the condition that temperature is lower, under the prerequisite not affecting quality product, solve the high expensive problem because solvent loss causes, also mitigate the pressure of environmental protection.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of tenofovir disoproxil fumarate of the present invention.
Embodiment
By several specific embodiment, will illustrate the present invention further below, these embodiments, just in order to describe the problem, are not a kind of restriction.
Embodiment 1
As shown in Figure 1, tenofovir disoproxil fumarate synthesis technique is totally 2 step reactions, is starting raw material by tynofovir, through esterification, becomes salt refining to obtain tenofovir disoproxil fumarate.
1. esterification:
400ml acetonitrile is added in 1000ml reaction flask, 50ml dimethyl formamide and 40g tynofovir monohydrate, open and stir, control temperature drips the N of 85g at 20 DEG C, N-diisopropylethylamine, drip off and continue to drip 100g chloromethyl propylene carbonate, reaction system is warming up to 57 DEG C of insulation reaction 8 hours after dripping off, in detection reaction, monoesters is less than 10%, reaction solution is evaporated to below 40 DEG C absence of liquid to flow out, 500ml ethyl acetate is added in concentrated raffinate, the sodium hydrogen carbonate solution of 200ml6%, layering extraction after stirring, organic phase continuation 200ml purified water washes twice, gained organic phase is evaporated to dry after anhydrous sodium sulfate drying, gained concentrates raffinate and is directly used in the next step.
2. salify
Upwards add 200ml Virahol in the concentrated raffinate of step, 50 DEG C are heated under stirring, in question response bottle molten clear after, add 15g fumaric acid, add and reaction solution is cooled to 10 DEG C of insulated and stirred crystallizatioies 4 hours, filter, filter cake to obtain 69g tenofovir disoproxil fumarate finished product with extremely doing through 40 DEG C of vacuum-dryings after a small amount of washed with isopropyl alcohol.Total recovery 83%, purity 99.4%.
Embodiment 2
As shown in Figure 1, tenofovir disoproxil fumarate synthesis technique is totally 2 step reactions, is starting raw material by tynofovir, through esterification, becomes salt refining to obtain tenofovir disoproxil fumarate.
1. esterification:
900ml acetonitrile is added in 2000ml reaction flask, 100ml dimethyl formamide and 100g tynofovir anhydride, open and stir, control temperature drips the N of 215g at 25 DEG C, N-diisopropylethylamine, drip off and continue to drip 250g chloromethyl propylene carbonate, reaction system is warming up to 60 DEG C of insulation reaction 10 hours after dripping off, in detection reaction, monoesters is less than 10%, reaction solution is evaporated to below 40 DEG C absence of liquid to flow out, 500ml ethyl acetate is added in concentrated raffinate, the sodium hydrogen carbonate solution of 400ml6%, layering extraction after stirring, organic phase continuation 400ml purified water washs three times, gained organic phase is evaporated to dry after anhydrous sodium sulfate drying, gained concentrates raffinate and is directly used in the next step.
2. salify
Upwards add 500ml Virahol in the concentrated raffinate of step, 55 DEG C are heated under stirring, in question response bottle molten clear after, add 38g fumaric acid, add and reaction solution is cooled to 15 DEG C of insulated and stirred crystallizatioies 2 hours, filter, filter cake to obtain 166g tenofovir disoproxil fumarate finished product with extremely doing through 45 DEG C of vacuum-dryings after a small amount of washed with isopropyl alcohol.Total recovery 80%, purity 99.2%.
Embodiment 3
As shown in Figure 1, tenofovir disoproxil fumarate synthesis technique is totally 2 step reactions, is starting raw material by tynofovir, through esterification, becomes salt refining to obtain tenofovir disoproxil fumarate.
1. esterification:
400ml acetonitrile is added in 1000ml reaction flask, 40ml dimethyl formamide and 40g tynofovir monohydrate, open and stir, control temperature drips the N of 85g at 22 DEG C, N-diisopropylethylamine, drip off and continue to drip 100g chloromethyl propylene carbonate, reaction system is warming up to 55 DEG C of insulation reaction 9 hours after dripping off, in detection reaction, monoesters is less than 10%, reaction solution is evaporated to below 40 DEG C absence of liquid to flow out, 500ml ethyl acetate is added in concentrated raffinate, the sodium hydrogen carbonate solution of 250ml6%, layering extraction after stirring, organic phase continuation 200ml purified water washes twice, gained organic phase is evaporated to dry after anhydrous sodium sulfate drying, gained concentrates raffinate and is directly used in the next step.
2. salify
Upwards add 200ml Virahol in the concentrated raffinate of step, 45 DEG C are heated under stirring, in question response bottle molten clear after, add 15g fumaric acid, add and reaction solution is cooled to 12 DEG C of insulated and stirred crystallizatioies 6 hours, filter, filter cake to obtain 67g tenofovir disoproxil finished product with extremely doing through 42 DEG C of vacuum-dryings after a small amount of washed with isopropyl alcohol.Total recovery 81%, purity 99.1%.
To sum up, use acetonitrile and dimethyl formamide to make mixed solvent and carry out esterification in the present invention, can control below 10% by the residual of monoesters in reaction, reaction conversion ratio promotes greatly, and total recovery brings up to more than 80%.
The above is only several embodiments of invention, and it should be pointed out that for those skilled in the art, under the prerequisite not departing from inventive principle, can also make some improvement, these improvement also should be considered as protection scope of the present invention.
Claims (9)
1. two-step approach prepares a method for tenofovir disoproxil fumarate, it is characterized in that: comprise the following steps:
(1) tynofovir, acetonitrile and dimethyl formamide mixed solvent are joined reaction unit, control temperature, at 20-25 DEG C, successively drips acid binding agent and chloromethyl propylene carbonate under agitation condition;
(2) 55-60 DEG C of insulation reaction 8-10 hour is warming up to;
(3) step (2) reaction solution is evaporated to below 40 DEG C absence of liquid to flow out;
(4) in concentrated raffinate, extraction liquid is added, layering extraction after stirring;
(5) step (4) gained organic phase purified water washing 2-3 time; Be evaporated to dry more after drying;
(6) in the concentrated raffinate of step (5), add solvent, be stirred under 45-55 DEG C of condition and dissolve completely;
(7) in step (6) reaction solution, add fumaric acid, be cooled to 10-15 DEG C of insulated and stirred crystallization 2-6 hour;
(8) filter; Extremely dry through 40-45 DEG C of vacuum-drying after filter cake solvent wash, obtain described tenofovir disoproxil fumarate.
2. two-step approach according to claim 1 prepares the method for tenofovir disoproxil fumarate, it is characterized in that: described tynofovir is tynofovir monohydrate or tynofovir anhydride.
3. two-step approach according to claim 1 prepares the method for tenofovir disoproxil fumarate, it is characterized in that: described acid binding agent is DIPEA.
4. two-step approach according to claim 1 prepares the method for tenofovir disoproxil fumarate, it is characterized in that: the volume ratio of described dimethyl formamide and acetonitrile is 1:8-10.
5. two-step approach according to claim 1 prepares the method for tenofovir disoproxil fumarate, it is characterized in that: described step (4) described extraction liquid is the mixing solutions of ethyl acetate and sodium bicarbonate.
6. two-step approach according to claim 5 prepares the method for tenofovir disoproxil fumarate, it is characterized in that: the volume ratio of described sodium bicarbonate and ethyl acetate is 1:1.25-2.5.
7. the two-step approach according to claim 5 or 6 prepares the method for tenofovir disoproxil fumarate, it is characterized in that: described sodium bicarbonate is 6% sodium hydrogen carbonate solution.
8. two-step approach according to claim 1 prepares the method for tenofovir disoproxil fumarate, it is characterized in that: described step (5) uses anhydrous sodium sulfate drying.
9. two-step approach according to claim 1 prepares the method for tenofovir disoproxil fumarate, it is characterized in that: described step (6) and the middle solvent of step (8) are Virahol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511013838.5A CN105418682A (en) | 2015-12-31 | 2015-12-31 | Method for preparing tenofovir disoproxil fumarate through two-step method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511013838.5A CN105418682A (en) | 2015-12-31 | 2015-12-31 | Method for preparing tenofovir disoproxil fumarate through two-step method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105418682A true CN105418682A (en) | 2016-03-23 |
Family
ID=55497275
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201511013838.5A Pending CN105418682A (en) | 2015-12-31 | 2015-12-31 | Method for preparing tenofovir disoproxil fumarate through two-step method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105418682A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107400145A (en) * | 2017-08-03 | 2017-11-28 | 江苏汉斯通药业有限公司 | The synthetic method of high-purity tenofovir disoproxil fumarate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130005969A1 (en) * | 2010-03-11 | 2013-01-03 | Debashish Datta | Process for the preparation of tenofovir disoproxil fumarate |
| CN103360425A (en) * | 2012-04-01 | 2013-10-23 | 安徽贝克联合制药有限公司 | Synthesis method of tenofovir disoproxil and fumarate thereof |
| CN104130288A (en) * | 2014-06-27 | 2014-11-05 | 宁波美诺华药业股份有限公司 | Tenofovir disoproxil salt preparation method |
| CN104230992A (en) * | 2014-08-27 | 2014-12-24 | 太仓运通生物化工有限公司 | Preparation method of high-purity fumaric acid tenofovir disoproxil fumarate |
-
2015
- 2015-12-31 CN CN201511013838.5A patent/CN105418682A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130005969A1 (en) * | 2010-03-11 | 2013-01-03 | Debashish Datta | Process for the preparation of tenofovir disoproxil fumarate |
| CN103360425A (en) * | 2012-04-01 | 2013-10-23 | 安徽贝克联合制药有限公司 | Synthesis method of tenofovir disoproxil and fumarate thereof |
| CN104130288A (en) * | 2014-06-27 | 2014-11-05 | 宁波美诺华药业股份有限公司 | Tenofovir disoproxil salt preparation method |
| CN104230992A (en) * | 2014-08-27 | 2014-12-24 | 太仓运通生物化工有限公司 | Preparation method of high-purity fumaric acid tenofovir disoproxil fumarate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107400145A (en) * | 2017-08-03 | 2017-11-28 | 江苏汉斯通药业有限公司 | The synthetic method of high-purity tenofovir disoproxil fumarate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105418684A (en) | New method for synthesizing tenofovir disoproxil fumarate | |
| CN103570609A (en) | Preparation method for 2,3-dichloropyridine | |
| CN104974073A (en) | Preparation method of silodosin intermediate | |
| CN101486753A (en) | Novel method for synthesizing finasteroid | |
| CN105440076A (en) | Method for preparing tenofovir disoproxil fumarate | |
| CN102863408B (en) | Preparation method of andrographolide | |
| CN105418682A (en) | Method for preparing tenofovir disoproxil fumarate through two-step method | |
| CN105418683A (en) | Preparation method for tenofovir disoproxil fumarate | |
| CN105440078A (en) | Method for synthesizing tenofovir disoproxil fumarate conveniently | |
| CN102285937B (en) | Method for synthesizing febuxostat | |
| CN105218544A (en) | A kind of synthetic method of Eliquis intermediate | |
| CN105566393A (en) | Synthetic method of tenofovir disoproxil fumarate | |
| CN105481898A (en) | Method for synthesizing tenofovir fumarate by two-step process | |
| CN105481897A (en) | New method for preparing tenofovir disoproxil fumarate | |
| CN106349121B (en) | The preparation method of one kind 3,5- dichlorobenzoyl chlorides | |
| CN105440077A (en) | Method for synthesizing tenofovir disoproxil fumarate | |
| CN104072369B (en) | A kind of technique preparing Diisopropyl malonate | |
| CN105440012A (en) | Lenalidomide and lenalidomide intermediate preparation method | |
| CN103382193B (en) | Glycidyl methacrylate or the manufacture method of glycidyl acrylate | |
| CN106631777A (en) | Method for synthesizing methyl gamma-chlorobutyrate | |
| CN106916063A (en) | A kind of method that functionalized acidic ionic liquid catalysis prepares geranyl acetate | |
| CN102276508A (en) | Low-cost functional monomer containing polymerizable double bonds and mercapto chain transfer and preparation method thereof | |
| CN103265586B (en) | A kind of method being prepared Lauryl.beta.-maltoside by maltose | |
| CN106632483B (en) | A kind of preparation method of tenofovir dipivoxil | |
| CN106478402A (en) | The method that ethanol acid crystal is prepared by methyl glycollate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160323 |