CN104130288A - Tenofovir disoproxil salt preparation method - Google Patents
Tenofovir disoproxil salt preparation method Download PDFInfo
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Abstract
The invention relates to a tenofovir disoproxil salt preparation method; first tenofovir or tenofovir monohydrate is used as a starting material for condensation reaction with chloromethyl isopropyl carbonate in a strong polar organic solvent in the presence of a phase transfer catalyst to prepare tenofovir disoproxil, then the tenofovir disoproxil is salified with succinic acid and fumaric acid to prepare a tenofovir disoproxil salt; in the stage of esterification reaction for removing the organic solvent, a thin film evaporator is used for distillation for removing rapidly the solvent at low temperature, the material flows through the evaporator in a very short time about 10 seconds, the problems of reactant decomposition caused by too high distillation temperature and long heating time in the prior art can be avoided, and the product purity and yield are greatly improved. The final finished product HPLC (high performance liquid chromatography) is more than or equal to 99.85%, the single impurity content is less than 0.1%, and the yield is 62%-67%.
Description
Technical field
The present invention relates to a kind of preparation method of tenofovir disoproxil salt.
Background technology
Tenofovir disoproxil is a kind of ucleotides antiviral drug of lucky Leadd B.V of U.S. exploitation, and calendar year 2001 is used for the treatment of the infection of HIV (human immunodeficiency virus) through U.S. FDA approval.Because result for the treatment of is definite, suitability is good, dosage is suitable, tenofovir disoproxil has become a line HIV medicine of multiple treatment guide recommendations, tenofovir disoproxil and compound preparation thereof are the anti-AIDS drugs of current sales volume maximum, and, be the antiviral first-line drug of acquired immune deficiency syndrome (AIDS) that the WHO of World Health Organization treating AIDS guide is recommended, be listed at home the free AIDS antiretroviral therapy Second line Drug of country.
Synthesising process research report for tenofovir disoproxil or its salt is more, publication number is Chinese invention patent application " tenofovir disoproxil the new synthetic process " (application number: 201310281153.3) disclosed a kind of processing method of utilizing the synthetic following formula I of following formula IV of CN103304601A, the be weight percentage ammonia methyl alcohol of concentration 26% of the ammonia solution reagent adopting in this technique, ammonia methanol usage is 10～20 times (W/V) of formula IV compound amount, temperature of reaction is 50～100 DEG C, owing to having used ammonia methyl alcohol and temperature of reaction at 50～100 DEG C in this technique, this will inevitably cause the increase of impurity monoesters (Tenofovir isoproxil monoester), and then cause finished product impurity to exceed standard and yield obviously declines.
Publication number is Chinese invention patent application " a kind of industrialized manufacturing technique of the tenofovir disoproxil " (application number: 201010185710.8) also disclosed a kind of method of CN101870713A, in order to make product up to standard, it is by the first recrystallization purification in ethyl acetate of synthetic tenofovir disoproxil, and then in Virahol salify, be that the method has increased by a post-processing step compared with existing production technique, although the increase of this step can improve the purity of product, but inevitably, the setting of this step is reduced in the yield that has reduced to a great extent product, product yield can only reach 36.5%, there is no market competition advantage.
In addition, application number is 200480002190.5,200510099916.8,200610056926.8 and 200710014625.3 Chinese invention patent or patent application have also proposed respectively oneself viewpoint to the synthesis technique of tenofovir disoproxil salt, but substantially be all adopt purification tenofovir disoproxil then the mode of salify or the direct salify of not purifying produce, such production technique tends to cause the single contaminant content overproof of the finished product, cause product cost price high, and also brought other a series of uncertain factors in the environmental protection of producing and safety.Therefore,, for the production technique of current tenofovir disoproxil salt, await doing further improvement.
Summary of the invention
Technical problem to be solved by this invention is the present situation for prior art, and the preparation method of the tenofovir disoproxil salt that a kind of technique is simple, production cost is low is provided, and the Nuo Fuwei ester salt that the method prepares has higher purity and yield.
The present invention solves the problems of the technologies described above adopted technical scheme: a kind of preparation method of tenofovir disoproxil salt, and chemical equation is as follows:
It is characterized in that comprising the following steps:
(1) preparation of tenofovir disoproxil:
In organic solvent, adding successively mol ratio is chloromethyl sec.-propyl carbonic ether, triethylamine, phase-transfer catalyst, tynofovir or the tynofovir monohydrate of 1～10:1～10:0.1～1:1, adjust the temperature to 40 DEG C～60 DEG C reaction 2h～5h, react rear filtration, after filtrate washing, add desiccant dryness, remove after filtration again siccative, gained filtrate thin membrane distillation desolvation, to dry, obtains the tenofovir disoproxil crude product of oily;
(2) preparation of tenofovir disoproxil salt:
In the tenofovir disoproxil crude product of described oily, add organic solvent, stir molten clear after washing completely, the solution after washing adds desiccant dryness, then filters and removes siccative, gained filtrate removes organic solvent to dry through thin film distillation, obtains the tenofovir disoproxil of oily; In the tenofovir disoproxil of this oily, add organic solvent, stir and moltenly add succinate or fumarate after clear, adjust the temperature to 40 DEG C～60 DEG C reaction 1h～2h, after having reacted, be cooled to 0 DEG C～30 DEG C crystallizatioies, filtration obtains tenofovir disoproxil salt wet product, and this tenofovir disoproxil salt wet product decompression drying at 40 DEG C～60 DEG C is obtained to tenofovir disoproxil salt finished product.
In order to accelerate the speed that removes of organic solvent, reduce the residence time of tenofovir disoproxil in the distillation stage, reduce the rate of decomposition of tenofovir disoproxil, thereby the purity of improving product and yield to greatest extent, in described step (1), step (2), the boiling point of the organic solvent that needs thin film distillation that uses reduces successively, further to guarantee that the tenofovir disoproxil in step (2) does not decompose in still-process.
In step (1), reacted the organic solvent drip washing of rear filtration gained filter cake, suction filtration is to the dry solid wet product that obtains, and this solid wet product is triethylamine hydrochloride.
Described organic solvent is dimethyl sulfoxide (DMSO), N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methylene dichloride, trichloromethane, ethyl acetate, 2-methyltetrahydrofuran, 1, the one in 2-monochloroethane, acetone, hexanaphthene, isopropyl acetate, Virahol, methyl alcohol, ethanol, sherwood oil, normal hexane.
Described phase-transfer catalyst is the one in tetraethylammonium bromide, Tetrabutyl amonium bromide, crown ether, sodium lauryl sulphate.
Described siccative is the one in anhydrous sodium sulphate, anhydrous magnesium sulfate, calcium chloride, calcium oxide, molecular sieve.
Described in step (1), the envelope-bulk to weight ratio of organic solvent and tynofovir or tynofovir monohydrate is 2～10:1.
Described in step (2), the envelope-bulk to weight ratio of organic solvent and tenofovir disoproxil is 2～10:1.
Compared with prior art, the invention has the advantages that:
1) the present invention is first taking tynofovir or tynofovir monohydrate as starting raw material, in strong polar organic solvent with under the existence of chloromethyl sec.-propyl carbonic ether at phase-transfer catalyst, there is condensation reaction and make tenofovir disoproxil, and then tenofovir disoproxil and succsinic acid or fumaric acid salify are made to tenofovir disoproxil salt; Remove the organic solvent stage in esterification, the distillation of employing thin-film evaporator, rapid at low temperatures desolvation, material flushing time in vaporizer is very short, approximately 10 seconds, has avoided in prior art because distillation temperature is too high, the long reactant resolution problem causing of heated time, purity and the yield of product are all greatly improved, HPLC >=99.8% of final finished of the present invention, individual event foreign matter content < 0.1%, yield 62%～67%;
2) in prior art, for the purity that makes the tenofovir disoproxil salt of preparing reaches more than 99.8%, before by tenofovir disoproxil salify, generally first add alkali product is carried out to purifying, but so just directly cause the yield of product low, preparation cost is high; The present invention has given up the above-mentioned process that adds alkali purifying, adopt physical method to purify to tenofovir disoproxil, and adopt thin-film evaporator distillation to remove organic solvent, and in preparation process boiling point with an organic solvent reduce successively, be conducive to accelerate the speed that removes of organic solvent, reduce tenofovir disoproxil in the residence time in distillation stage, thus the purity of improving product and yield to greatest extent, reduce production costs, improve the competitiveness of product in market.
Brief description of the drawings
Fig. 1 is the HPLC collection of illustrative plates of the embodiment of the present invention 1 products therefrom;
Fig. 2 is the HPLC collection of illustrative plates of the embodiment of the present invention 3 products therefroms.
Embodiment
Below in conjunction with accompanying drawing, embodiment is described in further detail the present invention.
Embodiment 1:
(1) control temperature at 25 DEG C～35 DEG C, N
2under protection, in 5L four-hole boiling flask, add successively N-Methyl pyrrolidone 1000mL and chloromethyl sec.-propyl carbonic ether 950g, then slowly drip triethylamine 700mL, add again tetraethylammonium bromide 40g, be warming up to 40 DEG C～45 DEG C, add tynofovir or tynofovir monohydrate 400g, react 3h after continuing to be warming up to 50 DEG C;
After having reacted, be cooled to 25 DEG C～30 DEG C, reactant is carried out to suction filtration, and filter cake carries out drip washing by 4000mL ethyl acetate, and filtrate is transferred in the four-hole boiling flask of 20L, in this four-hole boiling flask, add tap water 4800mL, temperature is controlled at 25 DEG C～30 DEG C, stirs 5min, leaves standstill 10min layering, upper strata is ethyl acetate layer A1, and lower floor is water layer B1;
Water layer B1 is extracted with ethyl acetate four times again, uses ethyl acetate 1000mL at every turn, stir 5min at every turn, leave standstill 10min, temperature is controlled at 25 DEG C～30 DEG C, obtains ethyl acetate layer A2, water layer B2;
After ethyl acetate layer A1, A2 are merged, with tap water washing three times, each tap water consumption 2400ml stirs 5min at every turn, leaves standstill 10min, and temperature is controlled at 25 DEG C～30 DEG C, obtains ethyl acetate layer A3, water layer B3;
Combining water layer B2, B3, be extracted with ethyl acetate secondary, and each ethyl acetate consumption 1000mL stirs 5min at every turn, leaves standstill 10min, and temperature is controlled at 25 DEG C～30 DEG C, obtains ethyl acetate layer A4, water layer B4;
Combined ethyl acetate layer A3, A4, and use 1000g anhydrous sodium sulfate drying, suction filtration is to dry, by 350ml ethyl acetate drip washing anhydrous sodium sulphate, gained filtrate thin membrane distillation is to till distillating without cut, is cooled to 25 DEG C～30 DEG C after steamed, obtains light yellow viscous liquid 851.04g;
(2) in above-mentioned light yellow viscous liquid, add 1600mL trichloromethane, after stirring, tap water washing three times for organic layer, each tap water consumption 1600ml stirs 5min at every turn, leaves standstill 10min layering, obtains trichloromethane layer C1, water layer D1;
By water layer D1 chloroform extraction three times, each trichloromethane consumption 200ml stirs 5min at every turn, leaves standstill 10min layering again, and temperature is controlled at 25 DEG C～30 DEG C, obtains trichloromethane layer C2, water layer D2;
By tap water washing three times for trichloromethane layer C2, each tap water consumption is 200ml, obtains trichloromethane C3, by trichloromethane C3 400g anhydrous sodium sulfate drying, till after suction filtration, gained filtrate thin membrane distillation extremely distillates without cut, the steamed thickness raffinate 860.72g that obtains;
(3) above-mentioned thickness raffinate is transferred in the four-hole boiling flask of 10L, in this four-hole boiling flask, adds Virahol 2400mL, after stirring, add fumaric acid 164g, N
2the lower stirring of protection is warming up to 50 DEG C, and insulation 1h is stirred to completely molten clear; In above-mentioned four-hole boiling flask, drip normal hexane 6200mL, continue insulated and stirred 15min, temperature is controlled at 50 DEG C; Resultant of reaction is cooled to 0 DEG C～10 DEG C crystallizatioies, suction filtration after crystallization completes, the mixed solution drip washing of Virahol and normal hexane for gained filter cake, gained white solid, in 40 DEG C～45 DEG C drying under reduced pressure 12h, obtains 594g target product, after testing, as shown in Figure 1, the present embodiment products therefrom HPLC>=99.85%, single contaminant < 0.1%, molar yield is 67%.
Embodiment 2:
(1) control temperature at 25 DEG C～35 DEG C, N
2under protection, in 5L four-hole boiling flask, add successively N, dinethylformamide 1000mL and chloromethyl sec.-propyl carbonic ether 950g, then slowly drip triethylamine 700mL, add again sodium lauryl sulphate 38g, be warming up to 40 DEG C～45 DEG C, add tenofovir or tenofovir monohydrate 400g, continue insulation reaction 5h after 40 DEG C～45 DEG C;
After having reacted, be cooled to 25 DEG C～30 DEG C, reactant is carried out to suction filtration, and filter cake carries out drip washing with 3000mL isopropyl acetate, and filtrate is transferred in the four-hole boiling flask of 20L, in this four-hole boiling flask, add tap water 4500mL, temperature is controlled at 25 DEG C～30 DEG C, stirs 5min, leaves standstill 10min layering, upper strata is isopropyl acetate layer A1, and lower floor is water layer B1;
Water layer B1, again with isopropyl acetate extraction four times, is used to isopropyl acetate 8000mL at every turn, stir 5min at every turn, leave standstill 10min, temperature is controlled at 25 DEG C～30 DEG C, obtains isopropyl acetate layer A2, water layer B2;
After isopropyl acetate layer A1, A2 are merged, with tap water washing three times, each tap water consumption 2000ml stirs 5min at every turn, leaves standstill 10min, and temperature is controlled at 25 DEG C～30 DEG C, obtains isopropyl acetate layer A3, water layer B3;
Combining water layer B2, B3, extract secondary with isopropyl acetate, and each isopropyl acetate consumption 800mL stirs 5min at every turn, leaves standstill 10min, and temperature is controlled at 25 DEG C～30 DEG C, obtains isopropyl acetate layer A4, water layer B4;
Combined ethyl acetate layer A3, A4, and dry with 900g calcium chloride, suction filtration is to dry, and with 350ml isopropyl acetate drip washing calcium chloride, gained filtrate thin membrane distillation is to till distillating without cut, is cooled to 25 DEG C～30 DEG C after steamed, obtains light yellow viscous liquid 851g;
(2) in above-mentioned light yellow viscous liquid, add 1500mL trichloromethane, after stirring, tap water washing three times for organic layer, each tap water consumption 1200ml stirs 5min at every turn, leaves standstill 10min layering, obtains trichloromethane layer C1, water layer D1;
By water D1 chloroform extraction three times, each trichloromethane consumption 220ml stirs 5min at every turn, leaves standstill 10min layering again, and temperature is controlled at 25 DEG C～30 DEG C, obtains trichloromethane layer C2, water layer D2;
By tap water washing three times for trichloromethane layer C2, each tap water consumption is 200ml, obtains trichloromethane layer C3, and trichloromethane layer C3 is dry with 500g calcium chloride, till after suction filtration, gained filtrate thin membrane distillation extremely distillates without cut, the steamed thickness raffinate 860.2g that obtains;
(3) above-mentioned thickness raffinate is transferred in the four-hole boiling flask of 10L, in this four-hole boiling flask, adds ethanol 2000mL, after stirring, add fumaric acid 164g, N
2the lower stirring of protection is warming up to 40 DEG C, and insulation 1h is stirred to completely molten clear; In above-mentioned four-hole boiling flask, drip hexanaphthene 6000mL, continue insulated and stirred 15min, temperature is controlled at 53 DEG C; Resultant of reaction is cooled to 15 DEG C～20 DEG C crystallizatioies, suction filtration after crystallization completes, the mixed solution drip washing of ethanol and hexanaphthene for gained filter cake, gained white solid is in 40 DEG C～45 DEG C drying under reduced pressure 12h, obtain target product 538.2g, after testing, the present embodiment products therefrom HPLC>=99.85%, single contaminant < 0.1%, molar yield is 62%.
Embodiment 3:
(1) control temperature at 25 DEG C～35 DEG C, N
2under protection, in 5L four-hole boiling flask, add successively dimethyl sulfoxide (DMSO) 1000mL and chloromethyl sec.-propyl carbonic ether 950g, then slowly drip triethylamine 700mL, add again Tetrabutyl amonium bromide 40g, be warming up to 40 DEG C～45 DEG C, add tenofovir or tenofovir monohydrate 400g, at this temperature, continue insulation reaction 2h after continuing to be warming up to 60 DEG C;
After having reacted, be cooled to 25 DEG C～30 DEG C, reactant is carried out to suction filtration, filter cake 4500mL1,2-monochloroethane carries out drip washing, and filtrate is transferred in the four-hole boiling flask of 20L, in this four-hole boiling flask, adds tap water 5000mL, temperature is controlled at 25 DEG C～30 DEG C, stir 5min, leave standstill 10min layering, upper strata is 1,2-monochloroethane layer A1, lower floor is water layer B1;
Water layer B1 is used to 1,2-monochloroethane extraction four times again, use 1,2-monochloroethane 1200mL at every turn, stir 5min at every turn, leave standstill 10min, temperature is controlled at 25 DEG C～30 DEG C, obtains 1,2-monochloroethane layer A2, water layer B2;
After 1,2-monochloroethane layer A1, A2 are merged, with tap water washing three times, each tap water consumption 1800ml stirs 5min at every turn, leaves standstill 10min, and temperature is controlled at 25 DEG C～30 DEG C, obtains 1,2-monochloroethane layer A3, water layer B3;
Combining water layer B2, B3, with 1,2-monochloroethane extraction secondary, each 1,2-monochloroethane consumption 800mL stirs 5min at every turn, leaves standstill 10min, and temperature is controlled at 25 DEG C～30 DEG C, obtains 1,2-monochloroethane layer A4, water layer B4;
Merge 1,2-monochloroethane layer A3, A4, and use 1100g molecular sieve drying, suction filtration, to dry, is used 350ml1,2-monochloroethane drip washing molecular sieve, gained filtrate thin membrane distillation is to till distillating without cut, is cooled to 25 DEG C～30 DEG C after steamed, obtains light yellow viscous liquid 851.2g;
(2) in above-mentioned light yellow viscous liquid, add 1500mL methylene dichloride, after stirring, organic layer deionized water wash three times, each tap water consumption 1600ml stirs 5min at every turn, leaves standstill 10min layering, obtains dichloromethane layer C1, water layer D1;
By water layer D1 dichloromethane extraction three times, each methylene dichloride consumption 150ml stirs 5min at every turn, leaves standstill 10min layering again, and temperature is controlled at 25 DEG C～30 DEG C, obtains dichloromethane layer C2, water layer D2;
By tap water washing three times for dichloromethane layer C2, each tap water consumption is 300ml, obtains dichloromethane layer C3, by dichloromethane layer C3 400g molecular sieve drying, till after suction filtration, gained filtrate thin membrane distillation extremely distillates without cut, the steamed thickness raffinate 860.8g that obtains;
(3) above-mentioned thickness raffinate is transferred in the four-hole boiling flask of 10L, in this four-hole boiling flask, adds 2200mL methyl alcohol, after stirring, add succsinic acid 164g, N
2the lower stirring of protection is warming up to 60 DEG C, and insulation 2h is stirred to completely molten clear; In above-mentioned four-hole boiling flask, drip sherwood oil 5800mL, continue insulated and stirred 15min, temperature is controlled at 60 DEG C; Resultant of reaction is cooled to 20 DEG C～25 DEG C crystallizatioies, suction filtration after crystallization completes, the mixed solution drip washing of methyl alcohol and sherwood oil for gained filter cake, gained white solid, in 40 DEG C～45 DEG C drying under reduced pressure 12h, obtains 594g target product, after testing, as shown in Figure 2, the present embodiment products therefrom HPLC>=99.85%, single contaminant < 0.1%, molar yield is 67%.
Embodiment 4:
(1) control temperature at 25 DEG C～35 DEG C, N
2under protection, in 5L four-hole boiling flask, add successively N, N-N,N-DIMETHYLACETAMIDE 1000ml and chloromethyl sec.-propyl carbonic ether 950g, then slowly drip triethylamine 700mL, add again crown ether 40g, be warming up to 40 DEG C～45 DEG C, add tenofovir or tenofovir monohydrate 400g, continue to be warming up to 55 DEG C and at this temperature, continue insulation reaction 4h;
After having reacted, be cooled to 25 DEG C～30 DEG C, reactant is carried out to suction filtration, and filter cake carries out drip washing with 4000mL2-methyltetrahydrofuran, and filtrate is transferred in the four-hole boiling flask of 20L, in this four-hole boiling flask, add tap water 4800mL, temperature is controlled at 25 DEG C～30 DEG C, stirs 5min, leaves standstill 10min layering, upper strata is 2-methyltetrahydrofuran layer A1, and lower floor is water layer B1;
Water layer B1 is extracted with ethyl acetate four times again, uses 2-methyltetrahydrofuran 1000mL at every turn, stir 5min at every turn, leave standstill 10min, temperature is controlled at 25 DEG C～30 DEG C, obtains 2-methyltetrahydrofuran layer A2, water layer B2;
After 2-methyltetrahydrofuran layer A1, A2 are merged, with tap water washing three times, each tap water consumption 2400ml stirs 5min at every turn, leaves standstill 10min, and temperature is controlled at 25 DEG C～30 DEG C, obtains 2-methyltetrahydrofuran layer A3, water layer B3;
Combining water layer B2, B3, with 2-methyltetrahydrofuran extraction secondary, each 2-methyltetrahydrofuran consumption 1000mL stirs 5min at every turn, leaves standstill 10min, and temperature is controlled at 25 DEG C～30 DEG C, obtains 2-methyltetrahydrofuran layer A4, water layer B4;
Merge 2-methyltetrahydrofuran layer A3, A4, and dry with 900g calcium oxide, and suction filtration is to dry, with 320ml2-methyltetrahydrofuran drip washing calcium oxide, gained filtrate thin membrane distillation is to till distillating without cut, is cooled to 25 DEG C～30 DEG C after steamed, obtains light yellow viscous liquid 851.04g;
(2) in above-mentioned light yellow viscous liquid, add 1500mL trichloromethane, after stirring, organic layer spends tap water washing three times, each tap water consumption 1600ml stirs 5min at every turn, leaves standstill 10min layering, obtain trichloromethane layer C1, from the beginning water layer D1;
By water layer D1 chloroform extraction three times, each trichloromethane consumption 200ml stirs 5min at every turn, leaves standstill 10min layering again, and temperature is controlled at 25 DEG C～30 DEG C, obtains trichloromethane layer C2, water layer D2;
By tap water washing three times for trichloromethane layer C2, each tap water consumption is 200ml, obtains trichloromethane layer C3, and trichloromethane layer C3 is dry with 400g calcium oxide, till after suction filtration, gained filtrate thin membrane distillation extremely distillates without cut, the steamed thickness raffinate 860.72g that obtains;
(3) above-mentioned thickness raffinate is transferred in the four-hole boiling flask of 10L, in this four-hole boiling flask, adds ethanol 2100mL, after stirring, add succsinic acid 164g, N
2the lower stirring of protection is warming up to 53 DEG C, and insulation 1h is stirred to completely molten clear; In above-mentioned four-hole boiling flask, drip hexanaphthene 6000mL, continue insulated and stirred 15min, temperature is controlled at 53 DEG C; Resultant of reaction is cooled to 25～30 DEG C of crystallizatioies, suction filtration after crystallization completes, the mixed solution drip washing of ethanol and hexanaphthene for gained filter cake, gained white solid is drying under reduced pressure 12h at 40～45 DEG C, obtain 538.4g target product, after testing, the present embodiment products therefrom HPLC>=99.85%, single contaminant < 0.1%, molar yield is 62%.
Claims (8)
1. a preparation method for tenofovir disoproxil salt, is characterized in that comprising the following steps:
(1) preparation of tenofovir disoproxil:
In organic solvent, adding successively mol ratio is chloromethyl sec.-propyl carbonic ether, triethylamine, phase-transfer catalyst, tynofovir or the tynofovir monohydrate of 1～10:1～10:0.1～1:1, adjust the temperature to 40 DEG C～60 DEG C reaction 2h～5h, react rear filtration, after filtrate washing, add desiccant dryness, remove after filtration again siccative, gained filtrate thin membrane distillation desolvation, to dry, obtains the tenofovir disoproxil crude product of oily;
(2) preparation of tenofovir disoproxil salt:
In the tenofovir disoproxil crude product of described oily, add organic solvent, stir molten clear after washing completely, solution after washing adds desiccant dryness, then filter and remove siccative, gained filtrate removes organic solvent to dry through thin film distillation, obtain the tenofovir disoproxil of oily, in the tenofovir disoproxil of this oily, add organic solvent, stir and moltenly add succinate or fumarate after clear, adjust the temperature to 40 DEG C～60 DEG C reaction 1h～2h, after having reacted, be cooled to 0 DEG C～30 DEG C crystallizatioies, filtration obtains tenofovir disoproxil salt wet product, this tenofovir disoproxil salt wet product decompression drying at 40～45 DEG C is obtained to tenofovir disoproxil salt finished product.
2. the preparation method of tenofovir disoproxil salt according to claim 1, is characterized in that: in described step (1), step (2) boiling point with an organic solvent reduce successively.
3. the preparation method of tenofovir disoproxil salt according to claim 1, is characterized in that: in step (1), reacted the organic solvent drip washing of rear filtration gained filter cake, suction filtration is to the dry solid wet product that obtains, and this solid wet product is triethylamine hydrochloride.
4. the preparation method of tenofovir disoproxil salt according to claim 1 and 2, it is characterized in that: described organic solvent is dimethyl sulfoxide (DMSO), N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methylene dichloride, trichloromethane, ethyl acetate, 2-methyltetrahydrofuran, 1, the one in 2-monochloroethane, acetone, hexanaphthene, isopropyl acetate, Virahol, methyl alcohol, ethanol, sherwood oil, normal hexane.
5. the preparation method of tenofovir disoproxil salt according to claim 1 and 2, is characterized in that: described phase-transfer catalyst is the one in tetraethylammonium bromide, Tetrabutyl amonium bromide, crown ether, sodium lauryl sulphate.
6. the preparation method of tenofovir disoproxil salt according to claim 1 and 2, is characterized in that: described siccative is one or more in anhydrous sodium sulphate, anhydrous magnesium sulfate, calcium chloride, calcium oxide, molecular sieve.
7. the preparation method of tenofovir disoproxil salt according to claim 1 and 2, is characterized in that: described in step (1), the envelope-bulk to weight ratio of organic solvent and tynofovir or tynofovir monohydrate is 2～10:1.
8. the preparation method of tenofovir disoproxil salt according to claim 1 and 2, is characterized in that: described in step (2), the envelope-bulk to weight ratio of organic solvent and tenofovir disoproxil is 2～10:1.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105418684A (en) * | 2015-12-31 | 2016-03-23 | 苏州弘森药业有限公司 | New method for synthesizing tenofovir disoproxil fumarate |
| CN105418683A (en) * | 2015-12-31 | 2016-03-23 | 苏州弘森药业有限公司 | Preparation method for tenofovir disoproxil fumarate |
| CN105418682A (en) * | 2015-12-31 | 2016-03-23 | 苏州弘森药业有限公司 | Method for preparing tenofovir disoproxil fumarate through two-step method |
| CN108794531A (en) * | 2018-04-04 | 2018-11-13 | 盐城迪赛诺制药有限公司 | A kind of preparation method of high-purity tenofovir disoproxil fumarate |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418684A (en) * | 2015-12-31 | 2016-03-23 | 苏州弘森药业有限公司 | New method for synthesizing tenofovir disoproxil fumarate |
| CN105418683A (en) * | 2015-12-31 | 2016-03-23 | 苏州弘森药业有限公司 | Preparation method for tenofovir disoproxil fumarate |
| CN105418682A (en) * | 2015-12-31 | 2016-03-23 | 苏州弘森药业有限公司 | Method for preparing tenofovir disoproxil fumarate through two-step method |
| CN108794531A (en) * | 2018-04-04 | 2018-11-13 | 盐城迪赛诺制药有限公司 | A kind of preparation method of high-purity tenofovir disoproxil fumarate |
| CN110590842A (en) * | 2019-09-16 | 2019-12-20 | 奥锐特药业股份有限公司 | Synthesis method of tenofovir disoproxil fumarate |
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