CN114292297B - Method for preparing antiviral drug tenofovir alafenamide fumarate - Google Patents
Method for preparing antiviral drug tenofovir alafenamide fumarate Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 20
- 229960003560 tenofovir alafenamide fumarate Drugs 0.000 title claims abstract description 10
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 title claims abstract description 10
- 239000003443 antiviral agent Substances 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 18
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 17
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 14
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 14
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 13
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims abstract description 11
- 229960004556 tenofovir Drugs 0.000 claims abstract description 10
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims abstract description 10
- KTVKQTNGWVJHFL-UHFFFAOYSA-N 2-ethylchromen-4-one Chemical compound C1=CC=C2OC(CC)=CC(=O)C2=C1 KTVKQTNGWVJHFL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000001530 fumaric acid Substances 0.000 claims abstract description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 7
- RUOJZAUFBMNUDX-GSVOUGTGSA-N (4r)-4-methyl-1,3-dioxolan-2-one Chemical compound C[C@@H]1COC(=O)O1 RUOJZAUFBMNUDX-GSVOUGTGSA-N 0.000 claims abstract description 5
- KDUWXMIHHIVXER-UHFFFAOYSA-N 2'-hydroxypropiophenone Chemical compound CCC(=O)C1=CC=CC=C1O KDUWXMIHHIVXER-UHFFFAOYSA-N 0.000 claims abstract description 5
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229930024421 Adenine Natural products 0.000 claims abstract description 5
- 229960000643 adenine Drugs 0.000 claims abstract description 5
- QDQVXVRZVCTVHE-YFKPBYRVSA-N propan-2-yl (2s)-2-aminopropanoate Chemical compound CC(C)OC(=O)[C@H](C)N QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 238000005815 base catalysis Methods 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000012467 final product Substances 0.000 abstract description 3
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- CDOMXXVCZQOOMT-UHFFFAOYSA-N [phenoxy(phenyl)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(C=1C=CC=CC=1)(=O)OC1=CC=CC=C1 CDOMXXVCZQOOMT-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Abstract
The invention discloses a method for preparing an antiviral drug tenofovir alafenamide fumarate, which comprises the following steps: (1) Adenine and (R) -propylene carbonate react to generate a compound I; (2) The compound I is treated by magnesium tert-butoxide and then is added with phosphonate S for reaction to obtain a compound II; (3) The compound III is obtained by hydrolyzing the compound II in hydrobromic acid; (4) The phosphono chloride obtained by the reaction of the compound III and thionyl chloride is directly reacted with L-alanine isopropyl ester without purification to generate a compound IV; (5) The final product, propionyl phenol tenofovir fumarate, is prepared by salifying compound IV with fumaric acid. The method has the advantages of few steps of the synthetic route, mild reaction conditions, saving principles and improving the yield of the final product.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing an antiviral drug tenofovir alafenamide fumarate.
Background
The current method for preparing tenofovir alafenamide fumarate from tenofovir is characterized by using tenofovir as a starting material, and the route is as follows:
wherein the monoester intermediate A is prepared from triphenyl phosphonate and tenofovir.
Since the crude drug registration of tenofovir alafenamide fumarate declares that the starting materials of tenofovir Wei Zuowei tenofovir alafenamide fumarate cannot be used, the synthetic route must be extended forward. The usual method for preparing tenofovir is as follows:
From the above synthetic route, TF is obtained by hydrolysis of intermediate B. It was found that when only one ethyl group was hydrolyzed, this was done at room temperature, whereas the second ethyl group was hydrolyzed at a very slow rate, requiring reflux to completely hydrolyze in a few hours. That is, if desired, the reaction conditions may be controlled to selectively provide monoester intermediates.
Disclosure of Invention
Aiming at the technical problems, the invention provides a synthetic route of tenofovir alafenamide fumarate, which has fewer steps, mild hydrolysis reaction conditions, half reduction of hydrobromic acid consumption and fewer side reactions compared with the existing synthetic route.
The technical scheme provided by the invention is as follows:
A novel method for preparing antiviral drug tenofovir alafenamide fumarate, which comprises the following steps:
(1) Dissolving adenine and (R) -propylene carbonate in a first organic solvent for reaction to obtain a compound I;
Compound I is
(2) Dissolving the compound I and magnesium tert-butoxide in a second organic solvent, dropwise adding phosphonate S, and carrying out heat preservation reaction to obtain a compound II;
The phosphonate S is Compound II is/>
(3) Adding the compound II into hydrobromic acid for hydrolysis, and purifying to obtain a compound III;
Compound III is
(4) Reacting the compound III with thionyl chloride, and dissolving the reaction product in a third organic solvent to obtain a solution A;
(5) Dissolving L-alanine isopropyl ester in a third organic solvent, dropwise adding the solution A for reaction, and purifying to obtain a compound IV;
(6) And (3) dissolving the compound IV in a fourth organic solvent, and adding fumaric acid to react to obtain propionyl phenol tenofovir fumarate.
In the step (1), the first organic solvent is DMF, and the reaction is performed by heating and refluxing, and by base catalysis.
Further, in the step (2), the second organic solvent is DMF, and the reaction temperature is 70-80 ℃.
Further, in the step (2), the molar usage ratio of the compound I, the magnesium tert-butoxide and the phosphonate S is 1: 0.6-1:1.1-1.5.
Further, in the step (3), the reaction temperature is room temperature and the reaction time is 6-10 hours.
Further, in the step (4) and the step (5), the third organic solvent is DCM.
Further, in the step (4), the dosage ratio of the compound III to the thionyl chloride is 1 g:1.0-10 ml.
Further, in the step (4), the reaction temperature is-30 ℃ to-20 ℃.
Further, in the step (6), the fourth organic solvent is acetone.
Further, in the step (6), the molar use ratio of the compound IV to the fumaric acid is 1:0.5-1.
The beneficial effects of the invention are as follows:
the invention synthesizes the phosphonic acid mixed ester through reactant screening and route optimization As an intermediate, the method has few steps of a synthetic route, mild hydrolysis reaction conditions and half of hydrobromic acid consumption. In addition, the temperature of the strong acid hydrolysis reaction is reduced to room temperature from reflux, so that the occurrence of side reactions is reduced, and the yield of the final product is improved.
Drawings
FIG. 1 is a synthetic route diagram of the present invention.
Detailed Description
The invention is further illustrated below in connection with specific examples, the content of which is not limited at all.
The synthetic route provided by the invention is shown in figure 1, and the specific steps are as follows:
The method comprises the following steps:
(1) Dissolving adenine and (R) -propylene carbonate in a first organic solvent for reaction to obtain a compound I;
Compound I is
(2) Dissolving the compound I and magnesium tert-butoxide in a second organic solvent, dropwise adding phosphonate S, and carrying out heat preservation reaction to obtain a compound II;
The phosphonate S is Compound II is/>
(3) Adding the compound II into hydrobromic acid for hydrolysis, and purifying to obtain a compound III;
Compound III is
(4) Reacting the compound III with thionyl chloride, and dissolving the reaction product in a third organic solvent to obtain a solution A;
(5) Dissolving L-alanine isopropyl ester in a third organic solvent, dropwise adding the solution A for reaction, and purifying to obtain a compound IV;
(6) And (3) dissolving the compound IV in a fourth organic solvent, and adding fumaric acid to react to obtain propionyl phenol tenofovir fumarate.
In the step (1), the first organic solvent is DMF, and the reaction is performed by heating and refluxing, and by base catalysis.
Further, in the step (2), the second organic solvent is DMF, and the reaction temperature is 70-80 ℃.
Further, in the step (2), the molar usage ratio of the compound I, the magnesium tert-butoxide and the phosphonate S is as follows: 1: 0.6-1:1.1-1.5.
Further, in the step (3), the reaction temperature is room temperature and the reaction time is 6-10 hours.
Further, in the step (4) and the step (5), the third organic solvent is DCM.
Further, in the step (4), the dosage ratio of the compound III to the thionyl chloride is 1 g:1.0-10 ml.
Further, in the step (4), the reaction temperature is-30 ℃ to-20 ℃.
Further, in the step (6), the fourth organic solvent is acetone.
Further, in the step (6), the molar use ratio of the compound IV to the fumaric acid is 1:0.5-1.
Examples
The synthesis steps are as follows:
(1) Synthesis of Compound I
Into the reaction flask were added 100g adenine and 0.9g sodium hydroxide, 120mL DMF, and stirring was turned on. After 91g of (R) -propylene carbonate was added, the mixture was refluxed for 6 hours. Cooling to 70 ℃, dropwise adding an aqueous solution of acetic acid, and adjusting the pH to be between 6 and 7. 150mL of ethanol was added. After the addition, the temperature is reduced to 0-10 ℃ for crystallization. Filtration, rinsing the filter cake with ethanol, and drying to obtain 115g of compound I with a yield of 80%.
(2) Synthesis of Compound II
200ML of DMF, 100g of Compound I and 68g of magnesium tert-butoxide were each added with stirring to the flask, and stirred at 70-80℃for 1 hour. Then, 230g of phosphonate S was started to be added dropwiseAfter the completion of the dropwise addition, the reaction was continued for 3 hours at a constant temperature. After the reaction solution was cooled to 30.+ -. 5 ℃, 600g of glacial acetic acid was added dropwise. Concentrating under reduced pressure until no liquid flows out. 800mL of methylene chloride, and 150mL of water were added. The aqueous phase was extracted 2 more times with 150mL of dichloromethane and the organic phases were combined and concentrated under reduced pressure until no solvent was present to give crude compound II which was used directly in the next step.
(3) Synthesis of Compound III
300ML of 48wt% hydrobromic acid was added to the crude compound II in the above step, and the reaction was stirred at room temperature for 8 hours. 300mL of water was added and extracted with 400mL of dichloromethane. The pH of the water phase is regulated to 2.5-3 by using strong ammonia water. Filtering, leaching the filter cake with water, and drying to obtain 185.8g of compound III, wherein the yield of the two steps is 85%.
(4) Synthesis of Compound IV
15G of Compound III and 20mL of thionyl chloride were added to the reaction flask, respectively, and heated under reflux overnight. Excess thionyl chloride was removed under reduced pressure and the residue was dissolved in DCM to give a solution.
13G L-alanine isopropyl ester was dissolved in 100mL DCM and cooled to-30deg.C. Then, the solution A is dripped, and the temperature is controlled to be lower than-20 ℃ in the dripping process. After the dripping, stirring was continued for 2 hours. The reaction solution was washed with dilute hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give crude compound. The crude product is recrystallized and decolorized to obtain 15g of compound IV with a yield of 75%.
(5) Synthesis of propionyl phenol tenofovir fumarate
10G of Compound IV are dissolved in 100mL of acetone, 1.2g of fumaric acid are added with stirring, and the mixture is heated under reflux for 2 hours. Cooling to room temperature for crystallization, filtering and drying to obtain 10g of product with the yield of 90 percent.
The present invention is not limited to the above-mentioned embodiments, but any modifications, equivalents, improvements and modifications within the scope of the invention will be apparent to those skilled in the art.
Claims (9)
1. A novel method for preparing an antiviral drug tenofovir alafenamide fumarate, which is characterized by comprising the following steps:
(1) Dissolving adenine and (R) -propylene carbonate in a first organic solvent for reaction to obtain a compound I;
Compound I is
(2) Dissolving the compound I and magnesium tert-butoxide in a second organic solvent, dropwise adding phosphonate S, and carrying out heat preservation reaction to obtain a compound II;
The phosphonate S is Compound II is/>
(3) Adding the compound II into hydrobromic acid for reaction, and purifying to obtain a compound III;
Compound III is The reaction temperature is room temperature, and the reaction time is 6-10 hours;
(4) Reacting the compound III with thionyl chloride, and dissolving the reaction product in a third organic solvent to obtain a solution A;
(5) Dissolving L-alanine isopropyl ester in a third organic solvent, dropwise adding the solution A for reaction, and purifying to obtain a compound IV;
(6) And (3) dissolving the compound IV in a fourth organic solvent, and adding fumaric acid to react to obtain propionyl phenol tenofovir fumarate.
2. The method according to claim 1, characterized in that: in the step (1), the first organic solvent is DMF, and the reaction is performed in a heating reflux reaction and base catalysis mode.
3. The method according to claim 1, characterized in that: in the step (2), the second organic solvent is DMF, and the reaction temperature is 70-80 ℃.
4. The method according to claim 1, wherein in the step (2), the molar ratio of the compound I, the magnesium tert-butoxide to the phosphonate S is: 1:0.6-1:1.1-1.5.
5. The method of claim 1, wherein in step (4) and step (5), the third organic solvent is DCM.
6. The method according to claim 1, wherein in the step (4), the ratio of the compound III to the thionyl chloride is 1 g/1.0-10 ml.
7. The method according to claim 1, wherein in the step (4), the reaction temperature is-30 ℃ to-20 ℃.
8. The method according to claim 1, wherein in the step (6), the fourth organic solvent is acetone.
9. The method according to claim 1, wherein in the step (6), the molar ratio of the compound IV to fumaric acid is 1:0.5-1.
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CN104262397A (en) * | 2014-09-30 | 2015-01-07 | 浙江省天台县奥锐特药业有限公司 | Preparation method of high-purity tenofovir |
CN104817593A (en) * | 2015-04-27 | 2015-08-05 | 广州同隽医药科技有限公司 | Synthetic process of key intermediate of hemifumarate tenofovir alafenamide |
CN107021984A (en) * | 2017-04-28 | 2017-08-08 | 福建广生堂药业股份有限公司 | A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates |
CN107522743A (en) * | 2017-09-30 | 2017-12-29 | 深圳科兴生物工程有限公司 | A kind of half fumaric acid tenofovir Chinese mugwort draws phenol amine industrial continuous producing method |
CN110092803A (en) * | 2018-01-31 | 2019-08-06 | 北京睿创康泰医药研究院有限公司 | Tenofovir Chinese mugwort draws the preparation and its application of phenol amine fumarate process impurity |
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2021
- 2021-12-21 CN CN202111571502.6A patent/CN114292297B/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104262397A (en) * | 2014-09-30 | 2015-01-07 | 浙江省天台县奥锐特药业有限公司 | Preparation method of high-purity tenofovir |
CN104817593A (en) * | 2015-04-27 | 2015-08-05 | 广州同隽医药科技有限公司 | Synthetic process of key intermediate of hemifumarate tenofovir alafenamide |
CN107021984A (en) * | 2017-04-28 | 2017-08-08 | 福建广生堂药业股份有限公司 | A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates |
CN107522743A (en) * | 2017-09-30 | 2017-12-29 | 深圳科兴生物工程有限公司 | A kind of half fumaric acid tenofovir Chinese mugwort draws phenol amine industrial continuous producing method |
CN110092803A (en) * | 2018-01-31 | 2019-08-06 | 北京睿创康泰医药研究院有限公司 | Tenofovir Chinese mugwort draws the preparation and its application of phenol amine fumarate process impurity |
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