CN104230992A - Preparation method of high-purity fumaric acid tenofovir disoproxil fumarate - Google Patents
Preparation method of high-purity fumaric acid tenofovir disoproxil fumarate Download PDFInfo
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Abstract
The invention discloses a preparation method of high-purity fumaric acid tenofovir disoproxil fumarate. The method comprises the following steps: (1) preparing tenofovir; (2) preparing tenofovir disoproxil fumarate, carrying out condensation reaction between tenofovir and chloromethyl isopropyl carbonate in an organic solvent under the action of a catalyst, purifying the product to obtain the tenofovir disoproxil fumarate, wherein the catalyst is a mixture of triethylamine and tetrabutylammonium bromide which are in the molar ratio of (22-30) to (1.5-3.0); the ratio of the triethylamine to the organic solvent is (22-30mol) to (150L-200L); and (3) preparing fumaric acid tenofovir disoproxil fumarate, salifying tenofovir disoproxil fumarate and fumaric acid which are obtained in the step (2), carrying out suction filtration, and drying to obtain the fumaric acid tenofovir disoproxil fumarate. According to the preparation method, dual catalysts are adopted in the process of preparing the tenofovir disoproxil fumarate, so that the yield and the efficiency of the tenofovir disoproxil fumarate are effectively increased, and the reaction process of the whole reaction is greatly shortened.
Description
Technical field
The present invention relates to a kind of preparation method of high purity TDF, belong to the technical field of pharmaceutical compound preparation method.
Background technology
TDF (I) (Tenofovir disoproxil fumarate; TDF); chemical name: 9-[(R)-2-[[two [[(butyloxycarbonyl) oxygen base] methoxyl group] phosphoryl] methoxyl group] propyl group] adenine fumarate; be researched and developed by Glead Sciences company of the U.S., October calendar year 2001 goes on the market in the U.S. first.It has the acyclic nucleotide phosphate compounds of AntiHIV1 RT activity and Anti-HBV effect, it is the prodrug of tenofovir (II) (chemical name: (R)-9-(2-phosphatidyl methoxy propyl group) VITAMIN B4), after entering human body, hydrolysis discharges tenofovir very soon, produces antivirus action.
The chemical structure of TDF and tenofovir is as follows:
Compound US Patent No. 5922695 makes public for the first time the preparation method of TDF, is that triethylamine is catalyzer, carries out condensation reaction with chloromethyl butylperoxyisopropyl carbonate with tenofovir (formula (II)) for raw material.Reaction terminates, and dilutes and lower the temperature with isopropyl acetate, filters, washing layering, obtains tenofovir disoproxil oily matter after organic layer is concentrated.The molten clear and fumaric acid salify of oily matter Virahol obtains TDF.
Although the aftertreatment method of above-mentioned technique is simple, the dopant species produced in the reaction process of this technique is more, and the method just washed with water in above-mentioned technique processes organic layer, then by salify direct after organic layer evaporate to dryness.But found by great many of experiments, utilize this processing method to be difficult to obtain the higher TDF of purity; And also find in a large amount of experimentations, some impurity are still difficult to removing in salify and treating process, such as tenofovir list pyrrole furan ester (chemical name: [[2-(6-amino-9H-purine-9-base)-1-methyl ethoxy] methyl] p isopropylbenzoic acid oxygen base carbonyloxymethyl ester (chemical structural formula: as Suo Shi (III)).
Patent CN101870713A also discloses a kind of TDF preparation technology, and with tenofovir (formula (II)) for raw material, triethylamine is catalyzer, carries out condensation reaction with chloromethyl butylperoxyisopropyl carbonate.Reaction terminates, and cooling, adds water, add methylene chloride extraction, and organic layer 10% sodium hydrogen carbonate solution washs, then washes with water, drying, concentrates and obtains tenofovir disoproxil oily matter, adds ethyl acetate precipitation tenofovir disoproxil free alkali solid and dry to obtain TDF with fumaric acid salify.
This technique adopts first separates out solid by tenofovir disoproxil free alkali, go the method for purification of salify again, no doubt the slightly high TDF of purity can be obtained, but its aftertreatment is still too simple to the treatment process of organic layer, sodium bicarbonate aqueous solution with 10% and washing organic layer, although sub-fraction slant acidity impurity can be removed, but it is still quite so tired for removing as this kind of impurity of tenofovir monoesters, and this impurity together can be separated out with tenofovir disoproxil, brings the finished product into.This technique also has a defect, and can lose a part of tenofovir disoproxil in the process with ethyl acetate crystallization, product yield reduces greatly.
Above two kinds of methods preparing TDF, all exist that product impurity number is many and impurities left is comparatively large, of low quality, and the drawback that yield is on the low side, further industrial amplification production is limited.
Summary of the invention
Technical problem to be solved by this invention is the preparation method providing the TDF that a kind of purity is high, output is excellent for the state of the art.
The present invention solves the problems of the technologies described above adopted technical scheme: a kind of preparation method of high purity TDF, comprises the steps:
(1) tenofovir is prepared;
(2) tenofovir disoproxil is prepared, by tenofovir and chloromethyl propylene carbonate under catalyst action, carry out condensation reaction in organic solvent, purification of products, obtain tenofovir disoproxil, described catalyzer is triethylamine is the mixture that 22 ~ 30:1.5 ~ 3.0 mix with Tetrabutyl amonium bromide with mol ratio, and the ratio of triethylamine and organic solvent is 22 ~ 30 moles: 150L ~ 200L;
(3) prepare TDF, the tenofovir disoproxil obtain step (2) and fumaric acid salify, filter, dry, obtain TDF.
In described step (2), the mol ratio of triethylamine and Tetrabutyl amonium bromide is 24.73:2.48.
In described step (2), organic solvent is methylene dichloride, and the ratio of described triethylamine and methylene dichloride is 24.73 moles: 180L.
In described step (1), the preparation of tenofovir comprises the steps:
1a. prepares R-9-(2-hydroxypropyl) VITAMIN B4, VITAMIN B4, R-propylene carbonate, dimethyl formamide and sodium hydroxide is added in reaction vessel, the mol ratio of VITAMIN B4, R-propylene carbonate and sodium hydroxide is 140 ~ 155:188 ~ 196:8 ~ 13, the ratio of sodium hydroxide and dimethyl formamide is 8 ~ 13 moles: 80L ~ 100L, stir, after reacting completely, purification, drying, obtain R-9-(2-hydroxypropyl) VITAMIN B4;
1b. prepares R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4;
1c. prepares tenofovir.
In step 1b, the preparation process of R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4 is, R-9-(2-hydroxypropyl) VITAMIN B4 is added in reaction vessel, tert-butyl alcohol magnesium and Virahol, tert-butyl alcohol magnesium, the ratio of Virahol and VITAMIN B4 is 160 ~ 170 moles: 200L ~ 250L:140 ~ 155 mole, be warming up to 50 DEG C ~ 90 DEG C, in this reaction vessel, dropping ratio is the N-Methyl pyrrolidone solution of the p-benzenesulfonyloxymethyl phosphoric acid diethylester of 125 ~ 133 moles: 100L ~ 150L, the mol ratio of p-benzenesulfonyloxymethyl phosphoric acid diethylester and tert-butyl alcohol magnesium is 125 ~ 135:160 ~ 170, decompression steams Virahol, stirs, and separates out solid, filters, dry, obtains R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4.
Wherein, the water content of described N-Methyl pyrrolidone is less than 0.1%.
Wherein, in step 1c, the preparation process of tenofovir is, R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4 is added in reaction vessel, ethyl acetate and anhydrous acetic acid, ethyl acetate, the volume ratio of anhydrous acetic acid and dimethyl formamide is 500 ~ 600:2 ~ 8:80 ~ 100, be warming up to 90 ~ 95 DEG C, room temperature is down to after 5 ~ 7 hours, add acetone, the volume ratio of acetone and anhydrous acetic acid is 100 ~ 150:2 ~ 8, be stirred to layering, water intaking layer, adjust ph to 3 ~ 3.3, separate out solid, stirring at room temperature 0.5 ~ 1 hour, continue to be cooled to 0 ~ 5 DEG C, filter, obtain tenofovir.
Wherein, the mol ratio of described fumaric acid and VITAMIN B4 is 75 ~ 80:140 ~ 155.
Wherein, the moisture of described chloromethyl propylene carbonate is lower than 0.1%, and described Tetrabutyl amonium bromide first dries up pre-treatment through air blast before using.
Wherein, in described step (2), the method for purification of tenofovir disoproxil is, after reaction terminates, add water and organic solvent extraction, be layered as organic layer and water layer, organic layer adds water extremely acid with acidic substance tune pH, and the extraction of tenofovir disoproxil free alkali is entered water layer; Water layer adds organic solvent sodium carbonate solution pH to neutral or alkaline, and the extraction of tenofovir disoproxil free alkali is entered organic layer, dry organic layer, and 0.07MPa-0.1MPa vacuum concentration obtains highly purified tenofovir disoproxil.
Compared with prior art, the invention has the advantages that: this preparation method have employed dual catalyst in the process preparing tenofovir disoproxil, effectively increase output and the efficiency of tenofovir disoproxil, greatly reduce the reaction process of whole reaction; In addition, in the step 1b of this preparation method, alkali used does not adopt the catalyzer such as sodium hydrogen, improves the security of production; In addition, in whole preparation method, most of solvent can reclaim, and three wastes generation is few, can be considered as process for cleanly preparing; The production technique of a kind of highly purified tenofovir disoproxil that this preparation method provides, solves the problem of by product mono ethyl ester, list (POC) ester and chiral isomer impurity too high levels in the product.The TDF purity prepared by this tenofovir disoproxil is high, output is excellent.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
Embodiment 1
The preparation method of the TDF of the present embodiment, comprises the steps:
(1) prepare tenofovir, specifically comprise the steps:
1a. prepares R-9-(2-hydroxypropyl) VITAMIN B4, VITAMIN B4, R-propylene carbonate, dimethyl formamide and sodium hydroxide is added in reaction vessel, the mol ratio of VITAMIN B4, R-propylene carbonate and sodium hydroxide is 140:188:8, the ratio of sodium hydroxide and dimethyl formamide is 8 moles: 80L, stir, after reacting completely, purification, drying, obtain R-9-(2-hydroxypropyl) VITAMIN B4;
1b. prepares R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4, R-9-(2-hydroxypropyl) VITAMIN B4 is added in reaction vessel, tert-butyl alcohol magnesium and Virahol, tert-butyl alcohol magnesium, the ratio of Virahol and VITAMIN B4 is 160 moles: 200L:140 mole, be warming up to 50 DEG C, in this reaction vessel, dropping ratio is the N-Methyl pyrrolidone solution of the p-benzenesulfonyloxymethyl phosphoric acid diethylester of 125 moles: 100L, the water content of N-Methyl pyrrolidone is less than 0.1%, the mol ratio of p-benzenesulfonyloxymethyl phosphoric acid diethylester and tert-butyl alcohol magnesium is 125:160, decompression steams Virahol, stirs, and separates out solid, filters, dry, obtains R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4,
1c. prepares tenofovir; R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4, ethyl acetate and anhydrous acetic acid is added in reaction vessel; the volume ratio of ethyl acetate, anhydrous acetic acid and dimethyl formamide is 500:2:80; be warming up to 90 DEG C; room temperature is down to after 5 hours; add acetone; the volume ratio of acetone and anhydrous acetic acid is 100:2, is stirred to layering, water intaking layer; adjust ph to 3; separate out solid, stirring at room temperature 0.5 hour, continues to be cooled to 0 DEG C; filter, obtain tenofovir.
(2) tenofovir disoproxil is prepared, by tenofovir and chloromethyl propylene carbonate under catalyzer, condensation reaction is carried out in methylene dichloride, purification of products, obtain tenofovir disoproxil, described catalyzer is triethylamine is the mixture that 22:1.5 mixes with Tetrabutyl amonium bromide with mol ratio, and the ratio of triethylamine and methylene dichloride is 22 moles: 150L, and namely the concentration of triethylamine is 0.15mol/L.
(3) TDF is prepared, the tenofovir disoproxil that step (2) is obtained and fumaric acid salify, filter, dry, obtain TDF, the mol ratio of fumaric acid and VITAMIN B4 is 75:140, and the weight of final product TDF is 7.66kg.
In step (1), Tetrabutyl amonium bromide first dries up pre-treatment through air blast before using, and in step (2), the moisture of chloromethyl propylene carbonate is lower than 0.1%.
In described step (2), the method of purification of tenofovir disoproxil is, after reaction terminates, add water and dichloromethane extraction, be layered as organic layer and water layer, organic layer adds water and adjusts pH to acid (as pH is adjusted to 3.0) with acidic substance (example hydrochloric acid), and the extraction of tenofovir disoproxil free alkali is entered water layer; Water layer adds methylene chloride (as ethyl acetate) adjusts pH to neutral or alkalescence (as pH is adjusted to 7.5) with sodium carbonate solution, the extraction of tenofovir disoproxil free alkali is entered organic layer, dry organic layer, 0.07MPa vacuum concentration obtains highly purified tenofovir disoproxil.
In the present embodiment, VITAMIN B4 amount used is 140mol, and quality is about 18.92kg, and the quality of other components or volume are according to this quality and convert in conjunction with above-mentioned ratio.
Embodiment 2
The preparation method of the TDF of the present embodiment, comprises the steps:
(1) prepare tenofovir, specifically comprise the steps:
1a. prepares R-9-(2-hydroxypropyl) VITAMIN B4,148mol VITAMIN B4,192molR-propylene carbonate, 90L dimethyl formamide and 11.75mol sodium hydroxide is added in reaction vessel, stir, after reacting completely, purification, drying, obtain R-9-(2-hydroxypropyl) VITAMIN B4;
1b. prepares R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4, hydroxypropyl prepared by step 1a is added in reaction vessel) VITAMIN B4,165.4mol tert-butyl alcohol magnesium and 220L Virahol, be warming up to 70 DEG C, the N-Methyl pyrrolidone solution of p-benzenesulfonyloxymethyl phosphoric acid diethylester is dripped in this reaction vessel, p-benzenesulfonyloxymethyl phosphoric acid diethylester addition is 130.3mol, the water content of N-Methyl pyrrolidone is less than 0.1%, and its addition is 120L; Decompression steams Virahol, stirs, and separates out solid, filters, dry, obtains R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4;
1c. prepares tenofovir, adds R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4,550L ethyl acetate and 5L anhydrous acetic acid prepared by step 1b, be warming up to 95 DEG C in reaction vessel; room temperature is down to after 6 hours; add 130L acetone, be stirred to layering, water intaking layer; adjust ph to 3; separate out solid, stirring at room temperature 0.5 hour, continues to be cooled to 3 DEG C; filter, obtain tenofovir.
(2) tenofovir disoproxil is prepared, by tenofovir and 254mol chloromethyl propylene carbonate under catalyzer, condensation reaction is carried out in the methylene dichloride of 180L, purification of products, obtain tenofovir disoproxil, catalyzer is the mixture that 24.73mol triethylamine mixes with 2.48mol Tetrabutyl amonium bromide.
(3) prepare TDF, the tenofovir disoproxil obtain step (2) and 77.6mol fumaric acid salify, filter, dry, obtain TDF, the weight of final product TDF is 8.1kg.
In step (1), Tetrabutyl amonium bromide first dries up pre-treatment through air blast before using, and in step (2), the moisture of chloromethyl propylene carbonate is lower than 0.1%.
In described step (2), the method of purification of tenofovir disoproxil is, after reaction terminates, add water and dichloromethane extraction, be layered as organic layer and water layer, organic layer adds water and adjusts pH to acid (as pH is adjusted to 3.0) with acidic substance (example hydrochloric acid), and the extraction of tenofovir disoproxil free alkali is entered water layer; Water layer adds methylene chloride (as ethyl acetate) adjusts pH to neutral or alkalescence (as pH is adjusted to 7.5) with sodium carbonate solution, the extraction of tenofovir disoproxil free alkali is entered organic layer, dry organic layer, 0.07MPa-0.1MPa vacuum concentration obtains highly purified tenofovir disoproxil.
Embodiment 3
The preparation method of the TDF of the present embodiment, comprises the steps:
(1) prepare tenofovir, specifically comprise the steps:
1a. prepares R-9-(2-hydroxypropyl) VITAMIN B4, VITAMIN B4, R-propylene carbonate, dimethyl formamide and sodium hydroxide is added in reaction vessel, the mol ratio of VITAMIN B4, R-propylene carbonate and sodium hydroxide is 155:196:13, the ratio of sodium hydroxide and dimethyl formamide is 13 moles: 100L, stir, after reacting completely, purification, drying, obtain R-9-(2-hydroxypropyl) VITAMIN B4;
1b. prepares R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4, R-9-(2-hydroxypropyl) VITAMIN B4 is added in reaction vessel, tert-butyl alcohol magnesium and Virahol, tert-butyl alcohol magnesium, the ratio of Virahol and VITAMIN B4 is 170 moles: 250L:155 mole, be warming up to 90 DEG C, in this reaction vessel, dropping ratio is the N-Methyl pyrrolidone solution of the p-benzenesulfonyloxymethyl phosphoric acid diethylester of 133 moles: 150L, the water content of N-Methyl pyrrolidone is less than 0.1%, the mol ratio of p-benzenesulfonyloxymethyl phosphoric acid diethylester and tert-butyl alcohol magnesium is 135:170, decompression steams Virahol, stirs, and separates out solid, filters, dry, obtains R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4,
1c. prepares tenofovir; R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4, ethyl acetate and anhydrous acetic acid is added in reaction vessel; the volume ratio of ethyl acetate, anhydrous acetic acid and dimethyl formamide is 600:8:100; be warming up to 95 DEG C; room temperature is down to after 7 hours; add acetone; the volume ratio of acetone and anhydrous acetic acid is 150:8, is stirred to layering, water intaking layer; adjust ph to 3.3; separate out solid, stirring at room temperature 1 hour, continues to be cooled to 5 DEG C; filter, obtain tenofovir.
(2) tenofovir disoproxil is prepared, by tenofovir and chloromethyl propylene carbonate under catalyzer, condensation reaction is carried out in methylene dichloride, purification of products, obtain tenofovir disoproxil, described catalyzer is triethylamine is the mixture that 30:3.0 mixes with Tetrabutyl amonium bromide with mol ratio, and the ratio of triethylamine and methylene dichloride is 30 moles: 200L.
(3) TDF is prepared, the tenofovir disoproxil that step (2) is obtained and fumaric acid salify, filter, dry, obtain TDF, the mol ratio of fumaric acid and VITAMIN B4 is 80:155, and the weight of final product TDF is 8.48kg.
In step (1), Tetrabutyl amonium bromide first dries up pre-treatment through air blast before using, and in step (2), the moisture of chloromethyl propylene carbonate is lower than 0.1%.
In described step (2), the method of purification of tenofovir disoproxil is, after reaction terminates, add water and dichloromethane extraction, be layered as organic layer and water layer, organic layer adds water and adjusts pH to acid (as pH is adjusted to 3.0) with acidic substance (example hydrochloric acid), and the extraction of tenofovir disoproxil free alkali is entered water layer; Water layer adds methylene chloride (as ethyl acetate) adjusts pH to neutral or alkalescence (as pH is adjusted to 7.5) with sodium carbonate solution, the extraction of tenofovir disoproxil free alkali is entered organic layer, dry organic layer, 0.1MPa vacuum concentration obtains highly purified tenofovir disoproxil.
In the present embodiment, VITAMIN B4 amount used is 155mol, and quality is about 20.95kg, and the quality of other components or volume are according to this quality and convert in conjunction with above-mentioned ratio.
The process to product mentioned in above-described embodiment, as purification, drying, filters, belongs to the ordinary method in TDF preparation field, therefore repeat no more in the above-described embodiments.
Above content is only preferred embodiment of the present invention, and for those of ordinary skill in the art, according to thought of the present invention, all will change in specific embodiments and applications, this description should not be construed as limitation of the present invention.
Claims (10)
1. a preparation method for high purity TDF, is characterized in that, comprises the steps:
(1) tenofovir is prepared;
(2) tenofovir disoproxil is prepared, by tenofovir and chloromethyl propylene carbonate under catalyst action, carry out condensation reaction in organic solvent, purification of products, obtain tenofovir disoproxil, described catalyzer is triethylamine is the mixture that 22 ~ 30:1.5 ~ 3.0 mix with Tetrabutyl amonium bromide with mol ratio, and the ratio of triethylamine and organic solvent is 22 ~ 30 moles: 150L ~ 200L;
(3) prepare TDF, the tenofovir disoproxil obtain step (2) and fumaric acid salify, filter, dry, obtain TDF.
2. preparation method according to claim 1, is characterized in that: in described step (2), and the mol ratio of triethylamine and Tetrabutyl amonium bromide is 24.73:2.48.
3. preparation method according to claim 1, is characterized in that: in described step (2), and organic solvent is methylene dichloride, and the ratio of described triethylamine and methylene dichloride is 24.73 moles: 180L.
4. preparation method according to claim 1, is characterized in that, in described step (1), the preparation process of tenofovir is:
1a. prepares R-9-(2-hydroxypropyl) VITAMIN B4, VITAMIN B4, R-propylene carbonate, dimethyl formamide and sodium hydroxide is added in reaction vessel, the mol ratio of VITAMIN B4, R-propylene carbonate and sodium hydroxide is 140 ~ 155:188 ~ 196:8 ~ 13, the ratio of sodium hydroxide and dimethyl formamide is 8 ~ 13 moles: 80L ~ 100L, stir, after reacting completely, purification, drying, obtain R-9-(2-hydroxypropyl) VITAMIN B4;
1b. prepares R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4;
1c. prepares tenofovir.
5. preparation method according to claim 4, it is characterized in that: in step 1b, the preparation process of R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4 is, R-9-(2-hydroxypropyl) VITAMIN B4 is added in reaction vessel, tert-butyl alcohol magnesium and Virahol, tert-butyl alcohol magnesium, the ratio of Virahol and VITAMIN B4 is 160 ~ 170 moles: 200L ~ 250L:140 ~ 155 mole, be warming up to 50 DEG C ~ 90 DEG C, in this reaction vessel, dropping ratio is the N-Methyl pyrrolidone solution of the p-benzenesulfonyloxymethyl phosphoric acid diethylester of 125 ~ 133 moles: 100L ~ 150L, the mol ratio of p-benzenesulfonyloxymethyl phosphoric acid diethylester and tert-butyl alcohol magnesium is 125 ~ 135:160 ~ 170, decompression steams Virahol, stirs, and separates out solid, filters, dry, obtains R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4.
6. preparation method according to claim 5, is characterized in that: the water content of described N-Methyl pyrrolidone is less than 0.1%.
7. preparation method according to claim 4, it is characterized in that: in step 1c, the preparation process of tenofovir is, R-9-[2-(diethylphosphoryl ylmethoxy) propyl group] VITAMIN B4 is added in reaction vessel, ethyl acetate and anhydrous acetic acid, ethyl acetate, the volume ratio of anhydrous acetic acid and dimethyl formamide is 500 ~ 600:2 ~ 8:80 ~ 100, be warming up to 90 ~ 95 DEG C, room temperature is down to after 5 ~ 7 hours, add acetone, the volume ratio of acetone and anhydrous acetic acid is 100 ~ 150:2 ~ 8, be stirred to layering, water intaking layer, adjust ph to 3 ~ 3.3, separate out solid, stirring at room temperature 0.5 ~ 1 hour, continue to be cooled to 0 ~ 5 DEG C, filter, obtain tenofovir.
8. preparation method according to claim 4, is characterized in that: the mol ratio of described fumaric acid and VITAMIN B4 is 75 ~ 80:140 ~ 155.
9. preparation method according to claim 1, is characterized in that: the moisture of described chloromethyl propylene carbonate is lower than 0.1%.
10. preparation method according to claim 1, it is characterized in that: in described step (2), the method of purification of tenofovir disoproxil is, after reaction terminates, add water and organic solvent extraction, be layered as organic layer and water layer, organic layer adds water extremely acid with acidic substance tune pH, and the extraction of tenofovir disoproxil free alkali is entered water layer; Water layer adds organic solvent sodium carbonate solution and adjusts pH to neutral or alkaline, and the extraction of tenofovir disoproxil free alkali is entered organic layer, dry organic layer, and 0.07MPa-0.1MPa vacuum concentration obtains highly purified tenofovir disoproxil.
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| 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 |
| CN111116655A (en) * | 2019-12-30 | 2020-05-08 | 天津天士力圣特制药有限公司 | Preparation method of high-optical-purity tenofovir benzyl ester phosphonamide prodrug |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090286981A1 (en) * | 2006-07-12 | 2009-11-19 | Uma Maheswer Rao Vasireddy | Process for the prepartion of tenofovir |
| US20130005969A1 (en) * | 2010-03-11 | 2013-01-03 | Debashish Datta | Process for the preparation of tenofovir disoproxil fumarate |
| WO2014033688A1 (en) * | 2012-09-03 | 2014-03-06 | Ithemba Pharmaceuticals (Proprietary) Limited | A process for the preparation of (r)-9-[2-(phosphonometh-oxy)propyl]adenine (pmpa) |
| CN103880884A (en) * | 2014-03-21 | 2014-06-25 | 浙江苏泊尔制药有限公司 | Method for preparing high-purity tenofovir disoproxil fumarate |
-
2014
- 2014-08-27 CN CN201410427427.XA patent/CN104230992A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090286981A1 (en) * | 2006-07-12 | 2009-11-19 | Uma Maheswer Rao Vasireddy | Process for the prepartion of tenofovir |
| US20130005969A1 (en) * | 2010-03-11 | 2013-01-03 | Debashish Datta | Process for the preparation of tenofovir disoproxil fumarate |
| WO2014033688A1 (en) * | 2012-09-03 | 2014-03-06 | Ithemba Pharmaceuticals (Proprietary) Limited | A process for the preparation of (r)-9-[2-(phosphonometh-oxy)propyl]adenine (pmpa) |
| CN103880884A (en) * | 2014-03-21 | 2014-06-25 | 浙江苏泊尔制药有限公司 | Method for preparing high-purity tenofovir disoproxil fumarate |
Non-Patent Citations (1)
| Title |
|---|
| MA SHUAI ET AL: "Improved synthesis of tenofovir disoproxil fumarate", 《CHINESE JOURNAL OF MEDICINAL CHEMISTRY》, vol. 23, no. 5, 20 October 2013 (2013-10-20), pages 372 - 376 * |
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| CN105481897A (en) * | 2015-12-31 | 2016-04-13 | 苏州弘森药业有限公司 | New method for preparing 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 |
| 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 |
| CN105440076A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for preparing tenofovir disoproxil fumarate |
| CN105440077A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for synthesizing tenofovir disoproxil fumarate |
| CN105440078A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for synthesizing tenofovir disoproxil fumarate conveniently |
| 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 |
| CN105481898A (en) * | 2015-12-31 | 2016-04-13 | 苏州弘森药业有限公司 | Method for synthesizing tenofovir fumarate by two-step process |
| CN105566393A (en) * | 2015-12-31 | 2016-05-11 | 苏州弘森药业有限公司 | Synthetic method of tenofovir disoproxil fumarate |
| CN105566394A (en) * | 2016-03-16 | 2016-05-11 | 荆门市帅邦化学科技有限公司 | Production technique of tenofovir disoproxil fumarate |
| CN106349289A (en) * | 2016-08-03 | 2017-01-25 | 上海延安药业有限公司 | Tenofovir disoproxil fumarate crude medicine and tenofovir disoproxil fumarate tablet |
| 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 |
| CN111116655A (en) * | 2019-12-30 | 2020-05-08 | 天津天士力圣特制药有限公司 | Preparation method of high-optical-purity tenofovir benzyl ester phosphonamide prodrug |
| CN111116655B (en) * | 2019-12-30 | 2022-10-25 | 天津天士力圣特制药有限公司 | Preparation method of high-optical-purity tenofovir benzyl ester phosphonamide prodrug |
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