CN104447868B - A kind of preparation method of tenofovir disoproxil fumarate - Google Patents
A kind of preparation method of tenofovir disoproxil fumarate Download PDFInfo
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- CN104447868B CN104447868B CN201410734426.XA CN201410734426A CN104447868B CN 104447868 B CN104447868 B CN 104447868B CN 201410734426 A CN201410734426 A CN 201410734426A CN 104447868 B CN104447868 B CN 104447868B
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Abstract
A preparation method for tenofovir disoproxil fumarate, belongs to tenofovir disoproxil fumarate synthesis technical field. Comprise the following steps: prepare tenofovir two pyrrole furan esters, prepare tenofovir disoproxil fumarate crude product, refine tenofovir disoproxil fumarate. Wherein refining tenofovir disoproxil fumarate step adopts 65% ethanolic solution as tenofovir disoproxil fumarate recrystallization solvent, places 3 ~ 6 hours natural crystallization in 5 ~ 10 degrees Celsius of environment of low temperature. Preparation method of the present invention has overcome organic residue and the too high problem of side reaction thing in tenofovir disoproxil fumarate preparation process, total recovery can reach more than 40%, and in end product, tenofovir disoproxil fumarate content is high, recrystallization process is easy and simple to handle, cost is low, without poisonous and harmful side reaction and product.
Description
Technical field
A preparation method for tenofovir disoproxil fumarate, belongs to the synthetic skill of tenofovir disoproxil fumarateArt field.
Background technology
Tenofovir disoproxil fumarate, molecular weight 635.51. Molecular formula C19H30N5O10P·C4H4O4. Fumaric acid is for promiseIn good fortune Wei two pyrrole furan ester molecules, having 1 chiral centre, is R-enantiomer. Tenofovir disoproxil fumarate structural formula:
First, in prior art, tenofovir disoproxil fumarate yield after synthetic is lower, and synthetic method is comparatively multipleAssorted. Secondly, in the tenofovir disoproxil fumarate that existing synthetic method obtains, contain more organic residue more, need be to richnessHorse acid tenofovir two pyrrole furan esters are refined, but existing process for purification yield is low, and process for purification cost is higher, easily producesSide reaction product.
Summary of the invention
The technical problem to be solved in the present invention is: overcome the deficiencies in the prior art, a kind of fumaric acid tenofovir two is providedThe preparation method of pyrrole furan ester, the method has overcome organic residue and too high the asking of accessory substance in the refining recrystallization process of step 3Topic, total recovery can reach more than 40%, and in end product, tenofovir disoproxil fumarate content is high, recrystallization processEasy and simple to handle, cost is low, without poisonous and harmful side reaction and product.
The technical solution adopted for the present invention to solve the technical problems is: the preparation of this tenofovir disoproxil fumarateMethod, by preparing tenofovir two pyrrole furan esters, prepare tenofovir disoproxil fumarate crude product, refining fumaric acid tenofovirTwo three of pyrrole furan esters steps realize, and it is characterized in that, described refining tenofovir disoproxil fumarate step is followed successively by isopropylAlcohol recrystallization, ethyl alcohol recrystallization, solution salt and salify.
Described refining tenofovir disoproxil fumarate is made up of following steps:
1) isopropyl alcohol recrystallization: the tenofovir disoproxil fumarate crude product preparing is added in reaction bulb, addEnter isopropyl alcohol, be heated with stirring to 50 ~ 55 DEG C, molten clear rear continuation of question response liquid stirs 20 ~ 30 minutes, stops heating, naturally coolingTo room temperature, use instead and be cooled to 5 ~ 10 DEG C with ice-water bath, keep constant temperature stirring and crystallizing 1 ~ 2 hour, suction filtration obtains filter cake; Filter cake is usedA small amount of isopropyl alcohol drip washing, centrifugal rejection filter obtains tenofovir disoproxil fumarate isopropyl alcohol recrystallized product;
2) ethyl alcohol recrystallization: tenofovir disoproxil fumarate isopropyl alcohol recrystallized product is added in reaction bulb, toIn reaction bulb, adding volume fraction is 60 ~ 75% ethanol water, is heated with stirring to 50 ~ 55 DEG C, continues to stir 20 ~ 30 minutesQuestion response liquid dissolves after clarification; Stop heating, naturally cool to room temperature, use instead and be cooled to 5 ~ 10 DEG C with ice-water bath, keep constant temperatureStirring and crystallizing 1 ~ 2 hour; Suction filtration obtains filter cake; By filter cake ethanol drip washing, centrifugal rejection filter obtains fumaric acid tenofovir two pyrrolesFuran ester ethyl alcohol recrystallization product;
3) separate salt: tenofovir disoproxil fumarate ethyl alcohol recrystallization product is added in reaction bulb, add water, acetic acidEthyl ester stirs, and then adds saturated sodium bicarbonate to adjust Ph to 7 ~ 8, stirring reaction 1 ~ 2 hour; In reaction bulb, add ethyl acetateExtract 2 ~ 4 times, merge the ethyl acetate phase that extraction obtains, by saturated common salt water washing ethyl acetate phase, obtain extract; Xiang CuiGet in liquid and add anhydrous sodium sulfate to stir evenly, filter and obtain filtrate, by 40 ~ 45 DEG C of reduced pressure concentrations of filtrate, centrifugal rejection filter obtains rich horseAcid tenofovir two pyrrole furan esterlysis salt products;
4) salify: tenofovir disoproxil fumarate solution salt product is transferred in reaction bulb with isopropyl alcohol, adds richnessHorse acid, reactant liquor is heated to 50 ~ 55 DEG C, keeps 50 ~ 55 DEG C of constant temperature after 1 ~ 2 hour, to stop heating; In reaction bulb, liquid cools extremelyWhen 30 DEG C of left and right, change ice bath and be cooled to 5 ~ 10 DEG C, continue crystallization 1 ~ 2 hour, suction filtration obtains filter cake, by true at 35 ~ 45 DEG C of filter cakesEmpty dry 10 ~ 20 hours, to obtain final product.
Preferably, described refining tenofovir disoproxil fumarate is made up of following steps:
1) isopropyl alcohol recrystallization: the tenofovir disoproxil fumarate crude product preparing is added in reaction bulb, addEnter isopropyl alcohol, be heated with stirring to 52 DEG C, molten clear rear continuation of question response liquid stirs 25 minutes, stops heating, naturally cools to room temperature,Use instead and be cooled to 7 DEG C with ice-water bath, keep constant temperature stirring and crystallizing 1.5 hours, suction filtration obtains filter cake; By a small amount of isopropyl alcohol of filter cakeDrip washing, 40 DEG C, vacuum is dry, and centrifugal rejection filter obtains tenofovir disoproxil fumarate isopropyl alcohol recrystallized product;
2) ethyl alcohol recrystallization: tenofovir disoproxil fumarate isopropyl alcohol recrystallized product is added in reaction bulb, toIn reaction bulb, adding volume fraction is 65% ethanol water, is heated with stirring to 52 DEG C, continues to stir 25 minutes question response liquid moltenSeparate after clarification; Stop heating, naturally cool to room temperature, use instead and be cooled to 5 DEG C with ice-water bath, keep constant temperature stirring and crystallizing 1.5 littleTime; Suction filtration obtains filter cake; By filter cake ethanol drip washing, dry 7 hours of 45 DEG C, vacuum, centrifugal rejection filter obtains fumaric acid tenofovirTwo pyrrole furan ester ethyl alcohol recrystallization products;
3) separate salt: tenofovir disoproxil fumarate ethyl alcohol recrystallization product is added in reaction bulb, add water, acetic acidEthyl ester stirs, and then adds saturated sodium bicarbonate to adjust Ph to 7.5, stirring reaction 1 hour; In reaction bulb, add ethyl acetate extractionGet 3 times, merge the ethyl acetate phase that extraction obtains, by saturated common salt water washing ethyl acetate phase, obtain extract; To extractIn add anhydrous sodium sulfate drying 40 minutes, filter and obtain filtrate, by 40 DEG C of reduced pressure concentrations of filtrate, centrifugal rejection filter obtains fumaric acidTenofovir two pyrrole furan esterlysis salt products;
4) salify: tenofovir disoproxil fumarate solution salt product is transferred in reaction bulb with isopropyl alcohol, adds richnessHorse acid, reactant liquor is heated to 50 ~ 55 DEG C, keeps 50 ~ 55 DEG C of constant temperature after 1 ~ 2 hour, to stop heating; In reaction bulb, liquid cools extremelyWhen 30 DEG C of left and right, change ice bath and be cooled to 5 ~ 10 DEG C, continue crystallization 1 ~ 2 hour, suction filtration obtains filter cake, to obtain final product.
The described concrete operations of preparing tenofovir two pyrrole furan ester steps are:
1) 1-METHYLPYRROLIDONE is added in reaction bulb, first in reaction, add tenofovir to stir evenly, then add three secondAmine and TBAB stir evenly, and under nitrogen protection condition, heat reaction bulb; When the heating liquid to 45 in reaction bulb ~ 50 DEG C,Add chloromethyl isobutyl carbonate propyl ester, and continue to stir 3 ~ 5 hours, stop heating, when liquid is cooled to 25 ~ 35 DEG C in question response bottleAdd cyclohexane washing, remove cyclohexane phase, retain the rear liquid of washing;
2) in liquid after the washing of 30 ~ 35 DEG C, add water and ethyl acetate to extract, extract three times, merge organic phaseLiquid;
3) by step 2) obtain organic phase liquid, the sodium acid carbonate of first service property (quality) percentage 2 ~ 7% washs oneTime, re-use the ammonia scrubbing three times of mass percent 0.005 ~ 0.02%, finally wash twice with saturated sodium-chloride again;Organic phase liquid after washing obtains filtrate through anhydrous sodium sulfate drying, filtration; In filtrate, add cyclohexane, after decompression distillationObtain tenofovir two pyrrole furan esters.
Preferably, while adding chloromethyl isobutyl carbonate propyl ester described in step 1), stir 3.5 hours simultaneously, reach reaction end.
Preferably, step 2) described in the sodium acid carbonate of service property (quality) percentage 5% wash one time, re-use qualityThe ammonia scrubbing of percentage 0.01% three times, finally washs twice with saturated sodium-chloride again.
The described concrete operations of preparing tenofovir disoproxil fumarate crude product step are:
1) make tenofovir two pyrrole furan ester isopropyl alcohols and be transferred in reaction bulb, be stirred to solution clarification, add rich horseAcid, is heated to 50 ~ 55 DEG C of reactions 1 ~ 2 hour;
2) stop heating, while being cooled to 25 ~ 35 DEG C, changing ice bath and be cooled to 5 ~ 10 DEG C of crystallizatioies after 1 ~ 2 hour, suction filtration obtains filterCake, with isopropyl alcohol drip washing filter cake, and carries out centrifugal to the filter cake after drip washing; At 40 ~ 45 DEG C of temperature of the filter cake vacuum after centrifugalDry 10 ~ 15 hours, obtain tenofovir disoproxil fumarate crude product.
Preferably, step 2) in stop heating, while being cooled to 30 DEG C, changing ice bath and be cooled to 7 DEG C of crystallizatioies after 1.5 hours, take outFilter obtains filter cake, with isopropyl alcohol drip washing filter cake, and carries out centrifugal to the filter cake after drip washing; To 40 DEG C of temperature of the filter cake vacuum after centrifugalLower dry 15 hours of degree, obtains tenofovir disoproxil fumarate crude product.
The present invention is described as follows: shown in accompanying drawing 1 technological process, and the fumaric acid tenofovir two pyrrole furans that the present invention sets forthIn the preparation method of ester, first step reaction is under the catalysis of TBAB and triethylamine, tenofovir and chloromethyl carbonic acidIsopropyl ester generation esterification, obtains tenofovir two pyrrole furan esters; Second step reaction is in isopropyl alcohol, tenofovir two pyrrole furansEster and fumaric acid salify, obtain tenofovir disoproxil fumarate crude product. The 3rd reaction is that salify obtains finished product. SalifyBe isopropyl alcohol recrystallization, ethyl alcohol recrystallization, once separate salt and a salify.
Prepare in the step 3) of tenofovir two pyrrole furan esters and add cyclohexane in filtrate, after decompression distillation, obtain for promise good fortuneWei two pyrrole furan esters, cyclohexane solvent role is to reduce the boiling point of filtrate, reaches the object of removing fast organic solvent.
What compared with prior art, the preparation method of a kind of tenofovir disoproxil fumarate of the present invention had hasBeneficial effect fruit is:
1, in preparation method of the present invention, the yield of tenofovir disoproxil fumarate is high. The present invention taking tenofovir asInitiation material, adds in 1-METHYLPYRROLIDONE solution and replaces promise through condensation, hydrolysis, esterification preparation with chloromethyl isobutyl carbonate propyl esterAfter good fortune Wei two pyrrole furan esters; Be dissolved in isopropyl alcohol, at a certain temperature, tenofovir two pyrrole furan esters and fumaric acid salify; Rich horseAcid tenofovir two pyrrole furan esters add the dissolve with ethanol solution of 3 times of volumes at a certain temperature, and crystallization obtains at low temperatures. HaveTechnique is the higher feature of row, environmental protection, purity and yield easily.
2, preparation method of the present invention can effectively remove the organic residue in tenofovir disoproxil fumarate crude product, andAnd in course of reaction, side reaction product is few. The present invention adopts 65% ethanolic solution heavily to tie as tenofovir disoproxil fumarateBrilliant solvent is placed 3 ~ 6 hours in 5 ~ 10 degrees Celsius of environment of low temperature, and natural crystallization, obtains white crystals through suction filtration, has overcomeIn the refining recrystallization process of step 3, organic residue and side reaction thing are too high, make product quality controlled.
Brief description of the drawings
Fig. 1 is the process chart of tenofovir disoproxil fumarate.
Detailed description of the invention
Embodiment 1 ~ 3rd, the specific embodiment of the present invention, wherein embodiment 1 is optimum embodiment.
Embodiment 1
The preparation method of the present embodiment, comprises the following steps: prepare tenofovir two pyrrole furan esters, prepare fumaric acid for promiseGood fortune Wei two pyrrole furan ester crude products, refining tenofovir disoproxil fumarate;
First the concrete operations of, preparing tenofovir two pyrrole furan ester steps are:
1) 1-METHYLPYRROLIDONE 49.25kg is added in reactor, then add tenofovir 12kg to stir in reactorEven, then add triethylamine 17.2kg and TBAB 12kg to stir evenly, under nitrogen protection condition, heat reactor and be heated to46 DEG C time, drip chloromethyl isobutyl carbonate propyl ester 30.3kg, control reaction temperature and be no more than 55 DEG C, and it is little to continue stirring reaction to 4Time, cooling, when liquid is cooled to 40 DEG C in question response still, adds respectively the washing of 50kg cyclohexane for twice, stirs 30 minutes, quietPut layering in 15 minutes, discard cyclohexane phase, retain the rear liquid of washing;
2) after washing, add 50kg water and 110kg ethyl acetate to extract in liquid, layering, retains ethyl acetatePhase. Use respectively 55kg ethyl acetate wash water phase twice for twice, combined ethyl acetate phase;
3) by step 2) obtain organic phase liquid, first use the sodium acid carbonate of 55kg5% mass percent to wash oneTime, then use respectively the ammonia scrubbing three times of 55kg0.02% mass percent, finally wash one with 55k saturated sodium-chloride againTime; Organic phase liquid after washing obtains filtrate through 26.25kg anhydrous sodium sulfate drying 2 hours, filtration; Filtrate 40 ~ DEG C decompressionAfter distillation, obtain tenofovir two pyrrole furan ester 21.64kg.
Then the concrete operations of, preparing tenofovir disoproxil fumarate crude product step are:
1) make tenofovir two pyrrole furan ester 47kg isopropyl alcohols and be transferred in reactor, be stirred to solution clarification, addFumaric acid 4.735kg, is heated to 50 ~ 55 DEG C of reactions 2 hours;
2) stop heating, while being cooled to 30 DEG C, changing ice bath and be cooled to 5 ~ 10 DEG C of crystallizatioies after 1 hour, carry out centrifugal rejection filter1500r/min; Obtain tenofovir disoproxil fumarate crude product 10.27kg.
Finally, refining tenofovir disoproxil fumarate is made up of following steps:
1) isopropyl alcohol recrystallization: the tenofovir disoproxil fumarate crude product preparing is added in reactor, addEnter 51.35L isopropyl alcohol, be heated with stirring to 50 ~ 55 DEG C, molten clear rear continuation of question response liquid stirs 30 minutes, stops heating, is cooled toRoom temperature, uses instead and is cooled to 5 ~ 10 DEG C with ice-water bath, keeps constant temperature stirring and crystallizing 1 hour, and centrifugal rejection filter obtains fumaric acid for promise good fortuneWei two pyrrole furan ester isopropyl alcohol recrystallized product 8.54kg;
2) ethyl alcohol recrystallization: tenofovir disoproxil fumarate isopropyl alcohol recrystallized product is added in reactor, toIn reaction bulb, adding volume fraction is 65% ethanol water 34.16L, is heated to 50 ~ 55 DEG C of stirrings, continues to stir 30 minutesQuestion response liquid stops heating after dissolving clarification, is cooled to room temperature, uses ice-water bath instead and is cooled to 5 ~ 10 DEG C, keeps constant temperature stirring and crystallizing1 hour; Centrifugal rejection filter obtains tenofovir disoproxil fumarate ethyl alcohol recrystallization product 6.832kg;
3) separate salt: tenofovir disoproxil fumarate ethyl alcohol recrystallization product is added in reactor, add 27.33LWater and 27.33L ethyl acetate stir, and then add 57kg saturated sodium bicarbonate to adjust Ph to 7 ~ 8, and stirring reaction 1 hour, leaves standstillLayering in 30 minutes, retains ethyl acetate phase; Use respectively again 17.1L ethyl acetate wash water 3 times mutually, merge the acetic acid second that extraction obtainsEster phase; Use respectively 27.33L saturated common salt water washing ethyl acetate 2 times mutually, obtain ethyl acetate phase; Add in mutually to ethyl acetateEnter anhydrous sodium sulfate 10.25kg dry 60 minutes, filter and obtain filtrate, by 40 ~ 45 DEG C of reduced pressure concentrations of filtrate, obtain fumaric acid and replaceNuo Fuwei bis-pyrrole furan esterlysis salt product 5.708kg;
4) salify: tenofovir disoproxil fumarate solution salt product is transferred in reactor with 23L isopropyl alcohol, adds1.299kg fumaric acid, reactant liquor is heated to 55 DEG C, keeps stopping heating after constant temperature 1; Liquid cools to 30 DEG C left and right in reaction bulbTime, change ice bath and be cooled to 5 ~ 10 DEG C, continue crystallization 1 hour, centrifugal rejection filter obtains tenofovir disoproxil fumarate wet product. To filterCake 35 ~ 45 DEG C of vacuum drying 12 hours again, obtain tenofovir disoproxil fumarate finished product 5.22kg.
Embodiment 2
The preparation method of the present embodiment, comprises the following steps: prepare tenofovir two pyrrole furan esters, prepare fumaric acid for promiseGood fortune Wei two pyrrole furan ester crude products, refining tenofovir disoproxil fumarate;
First the concrete operations of, preparing tenofovir two pyrrole furan ester steps are:
1) 1-METHYLPYRROLIDONE 49.25kg is added in reactor, then add tenofovir 12kg to stir in reactorEven, then add triethylamine 17.2kg and TBAB 12kg to stir evenly, under nitrogen protection condition, heat reactor and be heated to46 DEG C time, drip chloromethyl isobutyl carbonate propyl ester 30.3kg, control reaction temperature and be no more than 55 DEG C, and it is little to continue stirring reaction to 4Time, cooling, when liquid is cooled to 40 DEG C in question response still, adds respectively the washing of 50kg cyclohexane for twice, stirs 30 minutes, quietPut layering in 15 minutes, discard cyclohexane phase, retain the rear liquid of washing;
2) after washing, add 50kg water and 110kg ethyl acetate to extract in liquid, layering, retains ethyl acetatePhase. Use respectively 55kg ethyl acetate wash water phase twice for twice, combined ethyl acetate phase;
3) by step 2) obtain organic phase liquid, first use the sodium acid carbonate of 55kg5% mass percent to wash oneTime, then use respectively the ammonia scrubbing three times of 55kg0.02% mass percent, finally wash one with 55k saturated sodium-chloride againTime; Organic phase liquid after washing obtains filtrate through 26.25kg anhydrous sodium sulfate drying 2 hours, filtration; 40 ~ 45 DEG C of filtrates subtractAfter pressing distillation, obtain tenofovir two pyrrole furan ester 21.76kg.
Then the concrete operations of, preparing tenofovir disoproxil fumarate crude product step are:
1) make tenofovir two pyrrole furan ester 47kg isopropyl alcohols and be transferred in reactor, be stirred to solution clarification, addFumaric acid 4.747kg, is heated to 50 ~ 55 DEG C of reactions 2 hours;
2) stop heating, while being cooled to 30 DEG C, changing ice bath and be cooled to 5 ~ 10 DEG C of crystallizatioies after 1 hour, carry out centrifugal rejection filter1500r/min; Obtain tenofovir disoproxil fumarate crude product 9.899kg.
Finally, refining tenofovir disoproxil fumarate is made up of following steps:
1) isopropyl alcohol recrystallization: the tenofovir disoproxil fumarate crude product preparing is added in reactor, addEnter 39.6L isopropyl alcohol, be heated with stirring to 50 ~ 55 DEG C, molten clear rear continuation of question response liquid stirs 30 minutes, stops heating, is cooled toRoom temperature, uses instead and is cooled to 5 ~ 10 DEG C with ice-water bath, keeps constant temperature stirring and crystallizing 1 hour, and centrifugal rejection filter obtains fumaric acid for promise good fortuneWei two pyrrole furan ester isopropyl alcohol recrystallized product 8.374kg;
2) ethyl alcohol recrystallization: tenofovir disoproxil fumarate isopropyl alcohol recrystallized product is added in reactor, toIn reaction bulb, adding volume fraction is 65% ethanol water 35.5L, is heated to 50 DEG C of stirrings, continue to stir within 30 minutes, treat anti-After answering liquid to dissolve clarification, stop heating, be cooled to room temperature, use ice-water bath instead and be cooled to 5 ~ 10 DEG C, keep constant temperature stirring and crystallizing 1 littleTime; Centrifugal rejection filter obtains tenofovir disoproxil fumarate ethyl alcohol recrystallization product 6.697kg;
3) separate salt: tenofovir disoproxil fumarate ethyl alcohol recrystallization product is added in reactor, add 26.8L waterStir with 26.8L ethyl acetate, then add 60kg saturated sodium bicarbonate to adjust Ph to 7 ~ 8, stirring reaction 1 hour, leaves standstill 30 pointsClock layering, retains ethyl acetate phase; Use respectively again 16.7L ethyl acetate wash water 3 times mutually, merge the ethyl acetate that extraction obtainsPhase; Use respectively 26.8L saturated common salt water washing ethyl acetate 2 times mutually, obtain ethyl acetate phase; Add nothing to ethyl acetate in mutuallyDry 60 minutes of aqueous sodium persulfate 10kg, filters and obtains filtrate, by 40 DEG C of reduced pressure concentrations of filtrate, obtains fumaric acid tenofovir two pyrrolesFuran esterlysis salt product 5.583kg;
4) salify: tenofovir disoproxil fumarate solution salt product is transferred in reactor with 23L isopropyl alcohol, adds1.299kg fumaric acid, reactant liquor is heated to 55 DEG C, keeps stopping heating after constant temperature 1; Liquid cools to 30 DEG C left and right in reaction bulbTime, change ice bath and be cooled to 10 DEG C, continue crystallization 1 hour, centrifugal rejection filter obtains tenofovir disoproxil fumarate wet product, by filter cake45 DEG C of vacuum drying 12 hours, obtain tenofovir disoproxil fumarate finished product 5.18kg again.
Embodiment 3
1) 1-METHYLPYRROLIDONE 49.25kg is added in reactor, then add tenofovir 12kg to stir in reactorEven, then add triethylamine 17.2kg and TBAB 12kg to stir evenly, under nitrogen protection condition, heat reactor and be heated to46 DEG C time, drip chloromethyl isobutyl carbonate propyl ester 30.3kg, control reaction temperature and be no more than 55 DEG C, and it is little to continue stirring reaction to 4Time, cooling, when liquid is cooled to 40 DEG C in question response still, adds respectively the washing of 50kg cyclohexane for twice, stirs 30 minutes, quietPut layering in 15 minutes, discard cyclohexane phase, retain the rear liquid of washing;
2) after washing, add 50kg water and 110kg ethyl acetate to extract in liquid, layering, retains ethyl acetatePhase. Use respectively 55kg ethyl acetate wash water phase twice for twice, combined ethyl acetate phase;
3) by step 2) obtain organic phase liquid, first use the sodium acid carbonate of 55kg mass percent 5% to wash oneTime, then use respectively the ammonia scrubbing three times of 55kg mass percent 0.02%, finally wash one with 55k saturated sodium-chloride againTime; Organic phase liquid after washing obtains filtrate through 26.25kg anhydrous sodium sulfate drying 2 hours, filtration; 45 DEG C of decompressions of filtrateAfter distillation, obtain tenofovir two pyrrole furan ester 24.34kg.
Then the concrete operations of, preparing tenofovir disoproxil fumarate crude product step are:
1) make tenofovir two pyrrole furan ester 47kg isopropyl alcohols and be transferred in reactor, be stirred to solution clarification, addFumaric acid 4.735kg, is heated to 50 ~ 55 DEG C of reactions 2 hours;
2) stop heating, while being cooled to 30 DEG C, changing ice bath and be cooled to 5 ~ 10 DEG C of crystallizatioies after 1 hour, carry out centrifugal rejection filter1500r/min; Obtain tenofovir disoproxil fumarate crude product 9.767kg.
Finally, refining tenofovir disoproxil fumarate is made up of following steps:
1) isopropyl alcohol recrystallization: the tenofovir disoproxil fumarate crude product preparing is added in reactor, addEnter 48.8L isopropyl alcohol, be heated with stirring to 50 ~ 55 DEG C, molten clear rear continuation of question response liquid stirs 30 minutes, stops heating, is cooled toRoom temperature, uses instead and is cooled to 5 ~ 10 DEG C with ice-water bath, keeps constant temperature stirring and crystallizing 1 hour, and centrifugal rejection filter obtains fumaric acid for promise good fortuneWei two pyrrole furan ester isopropyl alcohol recrystallized product 8.073kg;
2) ethyl alcohol recrystallization: tenofovir disoproxil fumarate isopropyl alcohol recrystallized product is added in reactor, toIn reaction bulb, adding volume fraction is 65% ethanol water 32.3L, is heated to 55 DEG C of stirrings, continue to stir within 30 minutes, treat anti-After answering liquid to dissolve clarification, stop heating, be cooled to room temperature, use ice-water bath instead and be cooled to 10 DEG C, keep constant temperature stirring and crystallizing 1 hour;Centrifugal rejection filter obtains tenofovir disoproxil fumarate ethyl alcohol recrystallization product 6.636kg;
3) separate salt: tenofovir disoproxil fumarate ethyl alcohol recrystallization product is added in reactor, add 26.54LWater and 26.54L ethyl acetate stir, and then add 58kg saturated sodium bicarbonate to adjust Ph to 7 ~ 8, and stirring reaction 1 hour, leaves standstillLayering in 30 minutes, retains ethyl acetate phase; Use respectively again 16.6L ethyl acetate wash water 3 times mutually, merge the acetic acid second that extraction obtainsEster phase; Use respectively 26.54L saturated common salt water washing ethyl acetate 2 times mutually, obtain ethyl acetate phase; Add in mutually to ethyl acetateEnter anhydrous sodium sulfate 9.95kg dry 60 minutes, filter and obtain filtrate, by 45 DEG C of reduced pressure concentrations of filtrate, obtain fumaric acid for promise good fortuneWei two pyrrole furan esterlysis salt product 5.5kg;
4) salify: tenofovir disoproxil fumarate solution salt product is transferred in reactor with 23L isopropyl alcohol, adds1.287kg fumaric acid, reactant liquor is heated to 50 DEG C, keeps stopping heating after constant temperature 1; Liquid cools to 30 DEG C left and right in reaction bulbTime, change ice bath and be cooled to 5 ~ 10 DEG C, continue crystallization 1 hour, centrifugal rejection filter obtains tenofovir disoproxil fumarate wet product. Again 35~ 45 DEG C of vacuum drying 12 hours, obtain tenofovir disoproxil fumarate finished product 5.25kg.
Performance test
One, applicant calculates respectively and in embodiment 1 ~ 3, prepares tenofovir two pyrrole furan ester step yields, prepares fumaric acid and replaceNuo Fuwei bis-pyrrole furan ester crude product step yields, refining tenofovir disoproxil fumarate step yield, and calculate and obtain respectivelyThe total recovery that obtains embodiment 1 ~ 3 technical scheme, the computing formula of each step yield and total recovery is as follows:
Product generates tenofovir disoproxil fumarate content in quality=end product gross mass × end product;
Each step yield=(product generates quality/reaction-ure feeding gross mass) × 100%;
Total recovery=prepare tenofovir two pyrrole furan ester step yields × prepare tenofovir disoproxil fumarate crude product stepRapid yield × refining tenofovir disoproxil fumarate step yield;
To in embodiment 1 ~ 3, prepare tenofovir two pyrrole furan esters, prepare tenofovir disoproxil fumarate crude product, refineIn three steps of tenofovir disoproxil fumarate, respectively the reaction-ure feeding gross mass of above three steps is carried out to record,And the product that weighs respectively above three steps generates quality, data typing table 1.
Two, applicant carries out fumaric acid for promise to the final product obtaining of refining tenofovir disoproxil fumarate stepGood fortune Wei two pyrrole furan ester contents are measured. Tenofovir disoproxil fumarate content is higher, shows organic residue in end productImpurity less, side reaction product is fewer. Tenofovir disoproxil fumarate content assaying method is as follows, and test result is in table 2Shown in.
1) reagent and test solution: acetonitrile, ammonium acetate, glacial acetic acid;
2) instrument and apparatus: electronic analytical balance, supersonic cleaning machine, pipette, volumetric flask, graduated cylinder, octadecylsilaneBonded silica gel post, high performance liquid chromatograph;
3) chromatographic condition:
Chromatographic column: month rising sun XB-C18250mm × 4.6mm, 5 μ m;
Detect wavelength: 260nm;
Mobile phase: acetonitrile-0.05mol/L ammonium acetate buffer (by glacial acetic acid adjusting pH value to 4.6) (35:65);
Ammonium acetate buffer (pH4.6): get ammonium acetate 3.854g, be dissolved in water and be diluted to 1000ml, adjust with glacial acetic acidJoint pH value puts 4.6;
Flow velocity: 1.0ml/min;
Column temperature: 35 DEG C;
Sampling volume: 10 μ l;
Sample solvent: mobile phase;
4) system suitability: theoretical cam curve should be not less than 3000 by tenofovir two pyrrole furan ester peaks;
5) need testing solution: get the about 10mg of this product, accurately weighed, put in 50ml measuring bottle, add mobile phase appropriate, the ultrasonic richness that makesHorse acid tenofovir two pyrrole furan esters dissolve, and put to room temperature, add mobile phase and are diluted to scale, shake up, as need testing solution;
6) reference substance solution: get the about 10mg of tenofovir disoproxil fumarate reference substance, accurately weighed, put 50ml measuring bottleIn, adding mobile phase appropriate, the ultrasonic tenofovir disoproxil fumarate that makes dissolves, and puts to room temperature, and add mobile phase and be diluted to scale,Shake up, in contrast product solution;
7) determination method: precision measures need testing solution and the each 10 μ l of reference substance solution, injection liquid chromatography respectively, recordChromatogram; By external standard method, with the content of calculated by peak area tenofovir disoproxil fumarate;
Formula: the content of tenofovir disoproxil fumarate=；
A in formulaSampleFor the two pyrrole furan ester peak areas of tenofovir in need testing solution;
CContrastFor reference substance solution concentration (C19H30N5O10P·C4H4O4）；
AContrastFor the two pyrrole furan ester peak areas of tenofovir in reference substance solution;
V is the extension rate of test sample; 50
WSample weighting amountFor the sample weighting amount (mg) of test sample.
Table 1 embodiment 1 ~ 3 the performance test results
Table 2 embodiment 1 ~ 3 liquid chromatograph test result
Conclusion is summed up: by preparing tenofovir two pyrrole furan ester step yields, preparing tenofovir disoproxil fumarateCrude product step yield and these 3 control point measured results of refining tenofovir disoproxil fumarate step yield, can find outIn embodiment 1 ~ 3, prepare tenofovir two pyrrole furan ester step yields and prepare tenofovir disoproxil fumarate crude product step and receiveRate changes little, and refining tenofovir disoproxil fumarate step yield data significant change. The refining rich horse of embodiment 1Acid tenofovir two pyrrole furan ester step yields are the highest, detect in this mother liquor that main ingredient is residual can not be calculated simultaneously, show this embodimentResult use 65% ethanol water to become positive relationship with the step of embodiment 1. Side reaction product in the embodiment of the present invention 1 ~ 3Become negative growth relation with product yield, produce so the present invention contributes to suppress side reaction. The total recovery of crossing embodiment 1 ~ 3 all existsMore than 50%. Be greater than in the synthetic field of 99% tenofovir disoproxil fumarate at content, be greater than 50% total recovery and compare existingThere is total recovery value to have outstanding progress. And can find out that by table 1 total recovery of embodiment 1 is 58%, and gained finally producesIn thing, tenofovir disoproxil fumarate content is that in 4 embodiment, yield is the highest.
The above, be only preferred embodiment of the present invention, is not the restriction of the present invention being made to other form, appointsWhat those skilled in the art may utilize the technology contents of above-mentioned announcement changed or be modified as equivalent variations etc.Effect embodiment. But every technical solution of the present invention content that do not depart from, according to technical spirit of the present invention to above embodiment instituteAny simple modification, equivalent variations and the remodeling done, still belong to the protection domain of technical solution of the present invention.
Claims (7)
1. a preparation method for tenofovir disoproxil fumarate, by preparing tenofovir two pyrrole furan esters, preparing fumaric acidTenofovir two pyrrole furan ester crude products, three steps of refining tenofovir disoproxil fumarate realize, and it is characterized in that described essenceTenofovir disoproxil fumarate step processed is followed successively by isopropyl alcohol recrystallization, ethyl alcohol recrystallization, solution salt and salify;
Described refining tenofovir disoproxil fumarate is made up of following steps:
1) isopropyl alcohol recrystallization: the tenofovir disoproxil fumarate crude product preparing is added in reaction bulb, add differentPropyl alcohol, is heated with stirring to 50 ~ 55 DEG C, and molten clear rear continuation of question response liquid stirs 20 ~ 30 minutes, stops heating, naturally cools to chamberTemperature, uses ice-water bath instead and is cooled to 5 ~ 10 DEG C, keeps constant temperature stirring and crystallizing 1 ~ 2 hour, and suction filtration obtains filter cake; Filter cake is used different on a small quantityPropyl alcohol drip washing, centrifugal rejection filter obtains tenofovir disoproxil fumarate isopropyl alcohol recrystallized product;
2) ethyl alcohol recrystallization: tenofovir disoproxil fumarate isopropyl alcohol recrystallized product is added in reaction bulb, to reactionIn bottle, adding volume fraction is 60 ~ 75% ethanol water, is heated with stirring to 50 ~ 55 DEG C, continue to stir within 20 ~ 30 minutes, treat anti-Answer liquid to dissolve after clarification; Stop heating, naturally cool to room temperature, use ice-water bath instead and be cooled to 5 ~ 10 DEG C, keep constant temperature to stir and analyseBrilliant 1 ~ 2 hour; Suction filtration obtains filter cake; By filter cake ethanol drip washing, centrifugal rejection filter obtains tenofovir disoproxil fumarate secondAlcohol recrystallized product;
3) separate salt: tenofovir disoproxil fumarate ethyl alcohol recrystallization product is added in reaction bulb, add water, ethyl acetateStir, then add saturated sodium bicarbonate to adjust pH to 7 ~ 8, stirring reaction 1 ~ 2 hour; In reaction bulb, add ethyl acetate extraction2 ~ 4 times, merge the ethyl acetate phase that extraction obtains, by saturated common salt water washing ethyl acetate phase, obtain extract; To extractIn add anhydrous sodium sulfate to stir evenly, filter and obtain filtrate, by 40 ~ 45 DEG C of reduced pressure concentrations of filtrate, centrifugal rejection filter obtains fumaric acid and replacesNuo Fuwei bis-pyrrole furan esterlysis salt products;
4) salify: tenofovir disoproxil fumarate solution salt product is transferred in reaction bulb with isopropyl alcohol, adds fumaric acid,Reactant liquor is heated to 50 ~ 55 DEG C, keeps 50 ~ 55 DEG C of constant temperature after 1 ~ 2 hour, to stop heating; Liquid cools to a 30 DEG C left side in reaction bulbWhen right, change ice bath and be cooled to 5 ~ 10 DEG C, continue crystallization 1 ~ 2 hour, suction filtration obtains filter cake, by vacuum drying at 35 ~ 45 DEG C of filter cakes10 ~ 20 hours, to obtain final product.
2. a preparation method for tenofovir disoproxil fumarate, by preparing tenofovir two pyrrole furan esters, preparing fumaric acidTenofovir two pyrrole furan ester crude products, three steps of refining tenofovir disoproxil fumarate realize, and it is characterized in that described essenceTenofovir disoproxil fumarate step processed is followed successively by isopropyl alcohol recrystallization, ethyl alcohol recrystallization, solution salt and salify;
Described refining tenofovir disoproxil fumarate is made up of following steps:
1) isopropyl alcohol recrystallization: the tenofovir disoproxil fumarate crude product preparing is added in reaction bulb, add differentPropyl alcohol, is heated with stirring to 52 DEG C, and molten clear rear continuation of question response liquid stirs 25 minutes, stops heating, naturally cools to room temperature, uses insteadIce-water bath is cooled to 7 DEG C, keeps constant temperature stirring and crystallizing 1.5 hours, and suction filtration obtains filter cake; By a small amount of isopropyl alcohol drip washing for filter cake,40 DEG C, vacuum is dry, and centrifugal rejection filter obtains tenofovir disoproxil fumarate isopropyl alcohol recrystallized product;
2) ethyl alcohol recrystallization: tenofovir disoproxil fumarate isopropyl alcohol recrystallized product is added in reaction bulb, to reactionIn bottle, adding volume fraction is 65% ethanol water, is heated with stirring to 52 DEG C, continues to stir 25 minutes question response liquid and dissolves clearAfter clear; Stop heating, naturally cool to room temperature, use ice-water bath instead and be cooled to 5 DEG C, keep constant temperature stirring and crystallizing 1.5 hours; Suction filtrationObtain filter cake; By filter cake ethanol drip washing, dry 7 hours of 45 DEG C, vacuum, centrifugal rejection filter obtains fumaric acid tenofovir two pyrrole furansEster ethyl alcohol recrystallization product;
3) separate salt: tenofovir disoproxil fumarate ethyl alcohol recrystallization product is added in reaction bulb, add water, ethyl acetateStir, then add saturated sodium bicarbonate to adjust pH to 7.5, stirring reaction 1 hour; In reaction bulb, add ethyl acetate extraction 3Inferior, merge the ethyl acetate phase that extraction obtains, by saturated common salt water washing ethyl acetate phase, obtain extract; In extractAdd anhydrous sodium sulfate drying 40 minutes, filter and obtain filtrate, by 40 DEG C of reduced pressure concentrations of filtrate, centrifugal rejection filter obtains fumaric acid and replacesNuo Fuwei bis-pyrrole furan esterlysis salt products;
4) salify: tenofovir disoproxil fumarate solution salt product is transferred in reaction bulb with isopropyl alcohol, adds fumaric acid,Reactant liquor is heated to 50 ~ 55 DEG C, keeps 50 ~ 55 DEG C of constant temperature after 1 ~ 2 hour, to stop heating; Liquid cools to a 30 DEG C left side in reaction bulbWhen right, change ice bath and be cooled to 5 ~ 10 DEG C, continue crystallization 1 ~ 2 hour, suction filtration obtains filter cake, to obtain final product.
3. the preparation method of a kind of tenofovir disoproxil fumarate according to claim 1, is characterized in that: described inThe concrete operations of preparing tenofovir two pyrrole furan ester steps be:
1) 1-METHYLPYRROLIDONE is added in reaction bulb, first in reaction bulb, add tenofovir to stir evenly, then add triethylamineStir evenly with TBAB, under nitrogen protection condition, heat reaction bulb; , add when the heating liquid to 45 in reaction bulb ~ 50 DEG CEnter chloromethyl isobutyl carbonate propyl ester, and continue to stir 3 ~ 5 hours, stop heating, when liquid is cooled to 25 ~ 35 DEG C in question response bottle, addEnter cyclohexane washing, remove cyclohexane phase, retain the rear liquid of washing;
2) in liquid after the washing of 30 ~ 35 DEG C, add water and ethyl acetate to extract, extract three times, be associated with machine-phase liquidBody;
3) by step 2) obtain organic phase liquid, the sodium acid carbonate of first service property (quality) percentage 2 ~ 7% washs one time, thenThe ammonia scrubbing of service property (quality) percentage 0.005 ~ 0.02% three times, finally washs twice with saturated sodium-chloride again; After washingOrganic phase liquid through anhydrous sodium sulfate drying, filter obtain filtrate; In filtrate, add cyclohexane, after decompression distillation, obtain and replaceNuo Fuwei bis-pyrrole furan esters.
4. the preparation method of a kind of tenofovir disoproxil fumarate according to claim 3, is characterized in that, step1) while adding chloromethyl isobutyl carbonate propyl ester described in, stir 3.5 hours simultaneously, reach reaction end.
5. the preparation method of a kind of tenofovir disoproxil fumarate according to claim 3, is characterized in that, step2) sodium acid carbonate of the percentage of service property (quality) described in 5% washs one time, and the ammoniacal liquor that re-uses mass percent 0.01% is washedWash three times, finally wash twice with saturated sodium-chloride again.
6. the preparation method of a kind of tenofovir disoproxil fumarate according to claim 1, is characterized in that: described inThe concrete operations of preparing tenofovir disoproxil fumarate crude product step be:
1) make tenofovir two pyrrole furan ester isopropyl alcohols and be transferred in reaction bulb, be stirred to solution clarification, add fumaric acid, addHeat was to 50 ~ 55 DEG C of reactions 1 ~ 2 hour;
2) stop heating, while being cooled to 25 ~ 35 DEG C, changing ice bath and be cooled to 5 ~ 10 DEG C of crystallizatioies after 1 ~ 2 hour, suction filtration obtains filter cake,With isopropyl alcohol drip washing filter cake, and carry out centrifugal to the filter cake after drip washing; To dry at 40 ~ 45 DEG C of temperature of the filter cake vacuum after centrifugal10 ~ 15 hours, obtain tenofovir disoproxil fumarate crude product.
7. the preparation method of a kind of tenofovir disoproxil fumarate according to claim 6, is characterized in that, step2) in, stop heating, while being cooled to 30 DEG C, changing ice bath and be cooled to 7 DEG C of crystallizatioies after 1.5 hours, suction filtration obtains filter cake, uses isopropyl alcoholDrip washing filter cake, and carry out centrifugal to the filter cake after drip washing; To being dried 15 hours at 40 DEG C of temperature of the filter cake vacuum after centrifugal, to obtain final productTenofovir disoproxil fumarate crude product.
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| CN107417727B (en) * | 2017-04-25 | 2020-11-17 | 成都倍特药业股份有限公司 | Large-particle-size tenofovir disoproxil fumarate and preparation method thereof |
| 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 |
| CN110078765A (en) * | 2019-05-17 | 2019-08-02 | 南京望知星医药科技有限公司 | A kind of preparation method of tenofovir dipivoxil |
| CN110467639A (en) * | 2019-06-12 | 2019-11-19 | 北京鑫开元医药科技有限公司 | A kind of refining methd and purposes of tenofovir disoproxil fumarate |
| CN110283210B (en) * | 2019-08-12 | 2022-04-15 | 新乡双鹭药业有限公司 | Refining method of tenofovir disoproxil fumarate |
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