CN114292297A - 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 18
- 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 37
- 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
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 16
- 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
- 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 9
- 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- -1 phosphonate ester Chemical class 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
- 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
- 235000004279 alanine Nutrition 0.000 claims abstract description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 4
- 239000003960 organic solvent Substances 0.000 claims description 27
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 229960004556 tenofovir Drugs 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 239000012467 final product Substances 0.000 abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 8
- 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
- 238000003756 stirring Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 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
- 239000000203 mixture Substances 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
- 239000007864 aqueous solution Substances 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
- 238000002386 leaching Methods 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
- 239000002253 acid Substances 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
- 238000005815 base catalysis Methods 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
- 150000002148 esters Chemical class 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 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
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Abstract
The invention discloses a method for preparing antiviral drug tenofovir alafenamide fumarate, which comprises the following steps: (1) adenine reacts with (R) -propylene carbonate to generate a compound I; (2) treating the compound I with magnesium tert-butoxide, and then adding phosphonate ester S to react to obtain a compound II; (3) compound III is obtained by hydrolyzing compound II in hydrobromic acid; (4) reacting the compound III with thionyl chloride to obtain phosphonyl chloride, and directly reacting with L-isopropyl alanine without purification to obtain a compound IV; (5) the final product, tenofovir disoproxil fumarate, is prepared by salifying compound IV with fumaric acid. The invention has the advantages of few steps of synthetic route, mild reaction condition, saving principle 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 existing method for preparing tenofovir alafenamide fumarate takes 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 registration of raw material medicaments of tenofovir alafenamide fumarate states that tenofovir cannot be used as a starting material of tenofovir alafenamide fumarate, the synthetic route must be extended forward. The general process for preparing tenofovir follows:
from the above synthetic route, TF is obtained via hydrolysis of intermediate B. It was found that when only one ethyl group was hydrolyzed, it could be completed at room temperature, while the reaction rate for hydrolyzing the second ethyl group was very slow, requiring reflux to completely hydrolyze for several hours. That is, the reaction conditions can be controlled to selectively obtain the monoester intermediate, if desired.
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 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 an antiviral drug tenofovir alafenamide fumarate comprises the following steps:
(1) dissolving adenine and (R) -propylene carbonate in a first organic solvent for reaction to obtain a compound I;
the compound I is
(2) Dissolving a 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
The compound II is
(3) Adding the compound II into hydrobromic acid for hydrolysis, and purifying to obtain a compound III;
the compound III is
(4) Reacting the compound III with thionyl chloride, and dissolving a reaction product in a third organic solvent to obtain a solution A;
(5) dissolving L-isopropyl alanine in a third organic solvent, dropwise adding the solution A for reaction, and purifying to obtain a compound IV;
(6) and dissolving the compound IV in a fourth organic solvent, and adding fumaric acid for reaction to obtain the propionylphenol fumarate tenofovir.
Further, in the step (1), the first organic solvent is DMF, and the reaction is performed by heating, refluxing and alkali-catalyzed reaction.
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 ratio of the compound I, magnesium tert-butoxide and 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 1g: 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 ratio of the compound IV to fumaric acid is 1: 0.5-1.
The invention has the following beneficial effects:
the invention synthesizes the phosphonic acid mixed ester by screening reactants and optimizing a route
As an intermediate, the synthetic route has few steps, the hydrolysis reaction condition is mild, and the consumption of hydrobromic acid is saved by half. In addition, the temperature of the strong acid hydrolysis reaction is reduced to room temperature from reflux, so that the occurrence of some side reactions is reduced, and the yield of the final product is improved.
Drawings
FIG. 1 is a diagram of the synthetic route of the present invention.
Detailed Description
The invention will be further illustrated with reference to specific examples, to which the present invention is not at all restricted.
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;
the compound I is
(2) Dissolving a 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
The compound II is
(3) Adding the compound II into hydrobromic acid for hydrolysis, and purifying to obtain a compound III;
the compound III is
(4) Reacting the compound III with thionyl chloride, and dissolving a reaction product in a third organic solvent to obtain a solution A;
(5) dissolving L-isopropyl alanine in a third organic solvent, dropwise adding the solution A for reaction, and purifying to obtain a compound IV;
(6) and dissolving the compound IV in a fourth organic solvent, and adding fumaric acid for reaction to obtain the propionylphenol fumarate tenofovir.
Further, in the step (1), the first organic solvent is DMF, and the reaction is performed by heating reflux and base catalysis reaction.
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 ratio of the compound I, magnesium tert-butoxide and 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 1g: 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 ratio of the compound IV to fumaric acid is 1: 0.5-1.
Examples
The synthesis steps are as follows:
(1) synthesis of Compound I
100g adenine and 0.9g sodium hydroxide, 120mL DMF were added to the reaction flask and the stirring was turned on. After 91g of (R) -propylene carbonate was added, the mixture was refluxed for 6 hours. And cooling to 70 ℃, dropwise adding an acetic acid aqueous solution, and adjusting the pH value to 6-7. An additional 150mL of ethanol was added. After the addition, cooling to 0-10 ℃ for crystallization. Filtering, leaching the filter cake with ethanol, and drying to obtain 115g of the compound I with the yield of 80%.
(2) Synthesis of Compound II
200mL of DMF, 100g of Compound I and 68g of magnesium tert-butoxide were added to the reaction flask with stirring, and the mixture was stirred at 70 to 80 ℃ for 1 hour. Then, 230g of phosphonate S were added dropwise
After the dropwise addition, the reaction was carried out for 3 hours while maintaining the 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 dichloromethane, the organic phases were combined and concentrated under reduced pressure until no solvent flowed out to give the crude compound II which was used directly in the next step.
(3) Synthesis of Compound III
300mL of 48 wt% hydrobromic acid was added to the crude compound II obtained in the previous step, and the reaction was stirred at room temperature for 8 hours. 300mL of water was added and extracted with 400mL of dichloromethane. Adjusting the pH of the water phase to 2.5-3 by using concentrated ammonia water. Filtering, leaching filter cake with water, drying to obtain 185.8g of compound III with the yield of two steps of 85%.
(4) Synthesis of Compound IV
15g of Compound III and 20mL of thionyl chloride were added to the reaction flask, and the mixture was heated under reflux overnight. Excess thionyl chloride was removed under reduced pressure and the residue was dissolved in DCM to afford a solution.
Dissolve 13g L-Propanamic acid isopropyl ester in 100mL DCM, cool to-30 ℃. Then, the solution A is added dropwise, and the temperature is controlled to be lower than-20 ℃ in the process of adding dropwise. After dropping, stirring was continued for 2 hours. The reaction solution was washed with dilute hydrochloric acid, water, a saturated aqueous solution of sodium hydrogencarbonate and brine, respectively, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a crude compound. The crude product was recrystallized and decolorized to yield 15g of compound IV in 75% yield.
(5) Synthesis of propionylphenol fumarate tenofovir
10g of Compound IV is dissolved in 100mL of acetone, and 1.2g of fumaric acid is added thereto with stirring, followed by heating and refluxing for 2 hours. Cooling to room temperature for crystallization, filtering and drying to obtain 10g of product with yield of 90%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any modification, equivalent replacement, and improvement made by those skilled in the art within the technical scope of the present invention should be included in the scope of the present invention.
Claims (10)
1. A novel method for preparing an antiviral drug tenofovir alafenamide fumarate 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;
the compound I is
(2) Dissolving a 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
The compound II is
(3) Adding the compound II into hydrobromic acid for reaction, and purifying to obtain a compound III;
the compound III is
(4) Reacting the compound III with thionyl chloride, and dissolving a reaction product in a third organic solvent to obtain a solution A;
(5) dissolving L-isopropyl alanine in a third organic solvent, dropwise adding the solution A for reaction, and purifying to obtain a compound IV;
(6) and dissolving the compound IV in a fourth organic solvent, and adding fumaric acid for reaction to obtain the propionylphenol fumarate tenofovir.
2. The method of claim 1, wherein: in the step (1), the first organic solvent is DMF, and the reaction is carried out by heating reflux reaction and alkali catalysis.
3. The method of claim 1, wherein: 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 and the phosphonate S is as follows: 1: 0.6-1: 1.1-1.5.
5. The method according to claim 1, wherein in the step (3), the reaction temperature is room temperature, and the reaction time is 6 to 10 hours.
6. The method according to claim 1, wherein in the step (4) and the step (5), the third organic solvent is DCM.
7. The method according to claim 1, wherein in the step (4), the amount ratio of the compound III to the thionyl chloride is 1g: 1.0-10 ml.
8. The method of claim 1, wherein the reaction temperature in step (4) is-30 ℃ to-20 ℃.
9. The method according to claim 1, wherein in the step (6), the fourth organic solvent is acetone.
10. The method according to claim 1, wherein in the step (6), the molar ratio of the compound IV to the fumaric acid is 1: 0.5-1.
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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 |
-
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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