CN114907409A - Preparation method of propofol tenofovir - Google Patents

Preparation method of propofol tenofovir Download PDF

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CN114907409A
CN114907409A CN202210706308.2A CN202210706308A CN114907409A CN 114907409 A CN114907409 A CN 114907409A CN 202210706308 A CN202210706308 A CN 202210706308A CN 114907409 A CN114907409 A CN 114907409A
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tenofovir
reaction
propofol
stirring
dichloromethane
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许应玉
李中井
杜丙柱
鞠金军
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Cisen Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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Abstract

The invention relates to the technical field of drug synthesis, and provides a preparation method of prophenoltenofovir, which solves the problems of high cost and low yield of the existing prophenoltenofovir synthesis method and comprises the following steps: (1) preparing a dichloromethane solution of isopropyl L-alanine; (2) generating chloride of tenofovir monophenyl ester by tenofovir monophenyl ester and thionyl chloride, and then stirring and reacting the chloride of tenofovir monophenyl ester and dichloromethane solution of L-isopropyl alanine to obtain a crude product of the prophenoltenofovir; (3) stirring and reacting the crude product of the prophenoltenofovir with a resolving agent to obtain prophenoltenofovir salt; (4) extracting and layering the benofovir salt, carrying out alkali washing, drying, filtering and vacuum concentration on an organic phase to obtain the benofovir, and treating a water phase to recover a resolving agent for next resolving.

Description

Preparation method of propofol tenofovir
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of propofol, namely tenofovir.
Background
Tenofovir Alafenamide Fumarate (TAF) is a novel nucleoside reverse transcriptase inhibitor for treating chronic hepatitis B, is a new drug approved by the U.S. food and drug administration for treating adult chronic hepatitis B again in the last decade, TAF is degraded into an active substance tenofovir in blood, then enters liver cells to be converted into tenofovir diphosphate which is an active metabolite, inhibits viral polymerase by directly and competitively combining with a natural deoxyribose substrate, and inhibits the activity of HIV-1 reverse transcriptase by inserting a chain termination in DNA, thereby exerting the curative effects of resisting hepatitis B virus infection (HBV) and acquired immune syndrome (HIV). Tenofovir alafenamide fumarate, marketed under the tradename Vemlidy, is the 2 nd approved tenofovir prodrug for both anti-hepatitis B virus and human immunodeficiency virus, following Tenofovir Disoproxil Fumarate (TDF). The TAF is an upgraded version of TDF, and can effectively reach liver cells due to higher blood stability, so that the TAF can exert a curative effect similar to that of TDF under the condition that the dosage is less than one tenth of TDF, the concentration in blood plasma is reduced by 90%, and the concentration in cells is 4 times higher, so that the over-high concentration of tenofovir in blood is avoided, the curative effect is enhanced, the safety is improved, the renal function and bone safety parameters can be improved, the TAF is more favorable for developing compound preparations, and the TAF has great clinical value and market.
The chemical name of the tenofovir alafenamide fumarate is as follows: propan-2-yl N- [ (S) - ({ [ (2R) -1- (6-amino-9H-purin-9-yl) propan-2 yl ] -oxy } methyl) (phenoxy) phosphoryl ] -1-alaninate, but-2-enedioic acid (2: 1). The chemical structural formula is as follows:
Figure BDA0003705190350000021
the compound is hemifumarate, and the free state of the compound is propiophenol tenofovir, and the chemical name is as follows: prop-2-yl N- [ (S) - ({ [ (2R) -1- (6-amino-9H-purin-9-yl) prop-2-yl ] -oxy } methyl) (phenoxy) phosphoryl ] -1-alaninate. The chemical structural formula of the prophenoltenofovir is as follows:
Figure BDA0003705190350000022
the molecular structure of the Propofovir has a plurality of chiral centers, which relates to the isomer impurities of up to 7, in particular to the isomerization of the position of a phosphoramide group.
Gilidd scientific company for the first time disclosed a preparation method of propofol tenofovir in patent CN1291994C, which uses adenine as a starting material, and performs condensation, substitution, hydrolysis and esterification reactions in the middle to firstly synthesize tenofovir monophenyl ester, and then performs chlorination, amination and resolution steps to finally obtain the propofol tenofovir. The preparation method of the patent has the following defects: (1) dicyclohexylcarbodiimide is used in the esterification reaction step, so that the raw material cost is high, the product yield is low, a large amount of toxic and harmful substances are generated in the reaction process, and the environment-friendly cost is high. (2) The chlorination and amination steps have poor selectivity, and the single-configuration propiophenol tenofovir can be prepared only by liquid phase, so that the production cost is high, and the method is not suitable for large-scale production.
The existing synthesis methods of the propofol tenofovir all have the defects of high material cost, low yield, long reaction time and the like, so that a process which is simple and convenient to operate, low in cost and more suitable for industrial production needs to be designed urgently.
Disclosure of Invention
Therefore, aiming at the technical defects, the invention provides the preparation method of the propofol tenofovir, which has the advantages of low cost, simple operation and high yield and is very suitable for large-scale industrial production.
In order to achieve the purpose, the invention is realized by the following technical scheme:
a preparation method of propofol tenofovir is characterized in that: the method comprises the following steps:
(1) adding L-alanine isopropyl ester hydrochloride and a dichloromethane solvent into a reaction kettle, adding inorganic base under the atmosphere of inert gas, stirring for reaction, filtering after the reaction is finished, carrying out reduced pressure concentration, then adding dichloromethane again, carrying out reduced pressure concentration until no liquid flows out basically, and repeating the operation until the water content of the system is less than 0.2% to obtain a dichloromethane solution of L-alanine isopropyl ester;
(2) adding tenofovir monophenyl ester into a toluene solvent, adding thionyl chloride for chlorination reaction, concentrating under reduced pressure after the reaction is finished, and removing toluene and redundant thionyl chloride to obtain chlorinated substance of tenofovir monophenyl ester;
dissolving chloride of tenofovir monophenyl ester in dichloromethane, adding organic base, controlling the temperature of the system to be below 10 ℃, then adding dichloromethane solution of L-isopropyl alanine, reacting for 1-6 h, adding deionized water after the reaction is finished, collecting organic phases in a layered mode, and concentrating under reduced pressure to obtain a crude product of the tenofovir prophenolate;
(3) adding the crude product of the prophenoltenofovir into an organic solvent, heating, stirring and dissolving, adding a resolving agent, stirring and reacting, and filtering after the reaction is finished to obtain prophenoltenofovir salt;
(4) adding the Propofol tenofovir disoproxil into a mixed solution of dichloromethane and water, adjusting the pH value to 8-10, stirring and layering at room temperature, and respectively collecting organic phases
And mixing with water phase, washing organic phase with alkali solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain tenofovir disoproxil hydrochloride;
and adjusting the pH value of the collected water phase to 1-3 by using hydrochloric acid, stirring for 1-2 h, filtering and drying the precipitated solid to obtain a recovered resolving agent, wherein the resolving agent can be used for next resolving.
The further improvement is that: the reaction temperature in the step (1) is 10-20 ℃, and the reaction time is 15-25 h.
The further improvement is that: the molar ratio of the L-alanine isopropyl ester hydrochloride to the inorganic base is 0.8-2: 1.
the further improvement is that: in the step (2), the chlorination reaction temperature is 70-80 ℃, and the reaction time is 10-15 h.
The further improvement is that: the mol ratio of the tenofovir monophenyl ester to the thionyl chloride to the organic base is 1: 1.2-1.8: 2 to 4.
The further improvement is that: the reaction temperature in the step (3) is 50-90 ℃, and the reaction time is 1-6 h.
The further improvement is that: the resolving agent is formed by mixing any one or more than two of D-tartaric acid, D- (+) -dibenzoyl tartaric acid, D- (+) -di-p-methylbenzoyl tartaric acid and D- (+) -di-p-methoxyl benzoyl tartaric acid in any ratio.
The further improvement is that: the inorganic base is any one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
The further improvement is that: the organic base is any one of triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine and morpholine.
The further improvement is that: the organic solvent is any one of isopropanol, tetrahydrofuran, acetonitrile and methyl ethyl ketone.
By adopting the technical scheme, the invention has the beneficial effects that:
the method takes tenofovir monophenyl ester and L-alanine isopropyl ester hydrochloride as raw materials to prepare the prophenoltenofovir, has wide raw material sources, is a reagent with high accessibility in the market, is safe and easy to obtain, and has low price.
The method has the advantages of short reaction time and simple operation, and the used solvents are conventional low-toxicity reagents, and a single solvent system can be recycled;
the yield of the target product of the first resolution is more than 75 percent, the content of the isomer (phosphoramide) is less than 0.1 percent, and the selectivity is high. The adopted resolving agent (tartaric acid and derivatives thereof) can be recycled, and the recycling process is simple.
In a word, the preparation route of the application has high economical efficiency, the materials can be recycled, the generated three wastes are few, the operation is simple, the cost is low, and the preparation method is very suitable for large-scale industrial production.
Detailed Description
The following detailed description will be provided for the embodiments of the present invention with reference to specific embodiments, so that how to apply the technical means to solve the technical problems and achieve the technical effects can be fully understood and implemented.
Unless otherwise indicated, the techniques employed in the examples are conventional and well known to those skilled in the art, and the reagents and products employed are also commercially available. The source, trade name and if necessary the constituents of the reagents used are indicated at the first appearance.
Example 1
(1) Adding 20g of L-alanine isopropyl ester hydrochloride and 150ml of dichloromethane into a reaction bottle, adding 13.6g of potassium bicarbonate under the nitrogen atmosphere, stirring and reacting for 20 hours, wherein the reaction temperature is 15 ℃, filtering and concentrating under reduced pressure after the reaction is finished until no liquid flows out basically, then adding 60ml of dichloromethane, concentrating under reduced pressure until no liquid flows out basically, and repeating the operations until the water content of the system is within 0.2% to obtain an L-alanine isopropyl ester dichloromethane solution;
(2) dissolving 12.3g of tenofovir monophenyl ester in a toluene solvent, slowly dropwise adding 6.5g of a toluene solution of thionyl chloride, carrying out reflux reaction for 13 hours at the temperature of 75 ℃, carrying out reduced pressure concentration after the reaction is finished, and removing redundant thionyl chloride and the toluene solvent to obtain chloride of tenofovir monophenyl ester;
dissolving chloride of tenofovir monophenyl ester in dichloromethane, adding 12.8g of triethylamine, controlling the temperature of the system to be below 10 ℃ in the nitrogen atmosphere, adding an L-isopropyl alanine dichloromethane solution, stirring and reacting for 3 hours, adding 50ml of deionized water after the reaction is finished, stirring and layering, collecting an organic phase, and concentrating under reduced pressure to obtain a crude product of the tenofovir;
(3) heating and dissolving the crude product of the prophenoltenofovir disoproxil fumarate in isopropanol, adding 4.5g of D-tartaric acid, stirring and reacting for 4 hours at 70 ℃, and filtering to obtain prophenoltenofovir disoproxil tartrate after the reaction is finished;
(4) adding the propofol tenofovir tartrate obtained in the step (3) into a dichloromethane/water mixed solvent (volume ratio is 1:1), adjusting the pH value to be within 8-10, stirring and layering at room temperature, collecting an organic phase, washing the organic phase with a 3% sodium carbonate solution, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 12.1g of the propofol tenofovir with yield of 75% and content of isomer (phosphoramide) of 0.04%;
and adjusting the pH value of the collected water phase to be within 8-10 by using concentrated hydrochloric acid, stirring for 2 hours, filtering and drying the precipitated solid to obtain 4.3g of D-tartaric acid, wherein the recovery rate is 95.5%, and the D-tartaric acid can be continuously used for next resolution.
Example 2
(1) Adding 20g of L-alanine isopropyl ester hydrochloride and 150ml of dichloromethane into a reaction bottle, adding 8.1g of sodium carbonate under the nitrogen atmosphere, stirring and reacting for 25 hours, wherein the reaction temperature is 10 ℃, filtering and concentrating under reduced pressure after the reaction is finished until no liquid flows out basically, then adding 60ml of dichloromethane, concentrating under reduced pressure until no liquid flows out basically, and repeating the operation until the water content of the system is within 0.2% to obtain an L-alanine isopropyl ester dichloromethane solution;
(2) dissolving 12.3g of tenofovir monophenyl ester in a toluene solvent, slowly dropwise adding a toluene solution of 5.0g of thionyl chloride, carrying out reflux reaction for 15 hours at the temperature of 70 ℃, carrying out reduced pressure concentration after the reaction is finished, and removing redundant thionyl chloride and the toluene solvent to obtain chloride of tenofovir monophenyl ester;
dissolving chloride of tenofovir monophenyl ester in dichloromethane, adding 7.0g of triethylamine, controlling the temperature of the system to be below 10 ℃ in the nitrogen atmosphere, adding an L-isopropyl alanine dichloromethane solution, stirring and reacting for 1h, adding 50ml of deionized water after the reaction is finished, stirring and layering, collecting an organic phase, and concentrating under reduced pressure to obtain a crude product of the tenofovir;
(3) heating and dissolving the crude product of the prophenoltenofovir disoproxil in isopropanol, adding 3.8g of D-tartaric acid, stirring and reacting for 6 hours at 50 ℃, and filtering to obtain prophenoltenofovir disoproxil tartrate after the reaction is finished;
(4) adding the Propofol tenofovir tartrate obtained in the step (3) into a dichloromethane/water mixed solvent (volume ratio is 1:1), adjusting the pH value to be within 8-10, stirring at room temperature for layering, collecting an organic phase, washing with a 3% sodium carbonate solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 12.7g of Propofol tenofovir, wherein the yield is 78.9%, and the content of an isomer (phosphoramide) is 0.04%;
and adjusting the pH value of the collected water phase to be within 8-10 by using concentrated hydrochloric acid, stirring for 1h, filtering and drying the precipitated solid to obtain 3.6g of D-tartaric acid, wherein the recovery rate is 94.7%, and the D-tartaric acid can be continuously used for next resolution.
Example 3
(1) Adding 20g of L-alanine isopropyl ester hydrochloride and 150ml of dichloromethane into a reaction bottle, adding 16.5g of sodium bicarbonate under the nitrogen atmosphere, stirring and reacting for 15 hours, wherein the reaction temperature is 20 ℃, filtering and concentrating under reduced pressure after the reaction is finished until no liquid flows out basically, then adding 60ml of dichloromethane, concentrating under reduced pressure until no liquid flows out basically, and repeating the operation until the water content of the system is within 0.2% to obtain an L-alanine isopropyl ester dichloromethane solution;
(2) dissolving 12.3g of tenofovir monophenyl ester in a toluene solvent, slowly dropwise adding a toluene solution of 7.2g of thionyl chloride, carrying out reflux reaction for 10 hours at the temperature of 80 ℃, carrying out reduced pressure concentration after the reaction is finished, and removing redundant thionyl chloride and the toluene solvent to obtain chloride of tenofovir monophenyl ester;
dissolving chloride of tenofovir monophenyl ester in dichloromethane, adding 10.2g of triethylamine, controlling the temperature of the system to be below 10 ℃ in the nitrogen atmosphere, adding an L-isopropyl alanine dichloromethane solution, stirring and reacting for 5 hours, adding 50ml of deionized water after the reaction is finished, stirring and layering, collecting an organic phase, and concentrating under reduced pressure to obtain a crude product of the tenofovir;
(3) heating and dissolving the crude product of the prophenoltenofovir disoproxil in isopropanol, adding 5.9g of D-tartaric acid, stirring and reacting for 1h at 90 ℃, and filtering to obtain prophenoltenofovir disoproxil tartrate after the reaction is finished;
(4) adding the Propofol tenofovir tartrate obtained in the step (3) into a dichloromethane/water mixed solvent (volume ratio is 1:1), adjusting the pH value to be within 8-10, stirring and layering at room temperature, collecting an organic phase, washing the organic phase with a 3% sodium carbonate solution, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 13.0g of Propofol tenofovir, wherein the yield is 80.7%, and the content of an isomer (phosphoramide) is 0.03%;
and adjusting the pH value of the collected water phase to be within 8-10 by using concentrated hydrochloric acid, stirring for 2 hours, filtering and drying the precipitated solid to obtain 5.5g of D-tartaric acid, wherein the recovery rate is 93.2%, and the D-tartaric acid can be continuously used for next resolution.
Example 4
The difference from example 3 is that: the resolving agent is D- (+) -dibenzoyl tartaric acid. As a result, 13.2g of Propofol tenofovir was obtained in a yield of 82.0%; drying to obtain 5.6g of D- (+) -dibenzoyl tartaric acid with recovery rate of 94.9%.
Example 5
The difference from example 3 is that: the resolving agent is D- (+) -di-p-methyl benzoyl tartaric acid. As a result, 12.2g of Propofol tenofovir was obtained in a yield of 75.8%; drying to obtain 5.7g of D- (+) -di-p-methylbenzoyl tartaric acid, and the recovery rate is 96.6%.
Example 6
The difference from example 3 is that: the resolving agent is D- (+) -di-p-methoxybenzoyl tartaric acid. As a result, 12.9g of Propofol tenofovir was obtained in a yield of 80.0%; drying to obtain 5.5g of D- (+) -di-p-methoxybenzoyl tartaric acid with a recovery rate of 93.2%.
The above description is only an embodiment utilizing the technical content of the present disclosure, and any modification and variation made by those skilled in the art can be covered by the claims of the present disclosure, and not limited to the embodiments disclosed.

Claims (10)

1. A preparation method of propofol tenofovir is characterized in that: the method comprises the following steps:
(1) adding L-alanine isopropyl ester hydrochloride and a dichloromethane solvent into a reaction kettle, adding inorganic base under the atmosphere of inert gas, stirring for reaction, filtering after the reaction is finished, carrying out reduced pressure concentration, then adding dichloromethane again, carrying out reduced pressure concentration until no liquid flows out basically, and repeating the operation until the water content of the system is less than 0.2% to obtain a dichloromethane solution of L-alanine isopropyl ester;
(2) adding tenofovir monophenyl ester into a toluene solvent, adding thionyl chloride for chlorination reaction, after the reaction is finished, concentrating under reduced pressure, and removing toluene and redundant thionyl chloride to obtain chlorinated substance of tenofovir monophenyl ester;
dissolving chloride of tenofovir monophenyl ester in dichloromethane, adding organic base, controlling the temperature of the system to be below 10 ℃, then adding dichloromethane solution of L-isopropyl alanine, reacting for 1-6 h, adding deionized water after the reaction is finished, collecting organic phases in a layered mode, and concentrating under reduced pressure to obtain a crude product of the tenofovir prophenolate;
(3) adding the crude product of the prophenoltenofovir into an organic solvent, heating, stirring and dissolving, adding a resolving agent, stirring and reacting, and filtering after the reaction is finished to obtain prophenoltenofovir salt;
(4) adding the propofol tenofovir salt into a mixed solution of dichloromethane and water, adjusting the pH value to 8-10, stirring and layering at room temperature, respectively collecting an organic phase and a water phase, washing the organic phase with an alkali solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the propofol tenofovir;
and adjusting the pH value of the collected water phase to 1-3 by using hydrochloric acid, stirring for 1-2 h, filtering and drying the precipitated solid to obtain a recovered resolving agent, wherein the resolving agent can be used for next resolving.
2. The method for preparing propofol, tenofovir, according to claim 1, wherein: the reaction temperature in the step (1) is 10-20 ℃, and the reaction time is 15-25 h.
3. The method for preparing propofol, tenofovir, according to claim 1, wherein: the molar ratio of the L-alanine isopropyl ester hydrochloride to the inorganic base is 0.8-2: 1.
4. the method for preparing propofol, tenofovir, according to claim 1, wherein: step by step
In the step (2), the chlorination reaction temperature is 70-80 ℃, and the reaction time is 10-15 h.
5. The method for preparing propofol, tenofovir, according to claim 1, wherein: the mol ratio of the tenofovir monophenyl ester to the thionyl chloride to the organic base is 1: 1.2-1.8: 2 to 4.
6. The method for preparing propofol, tenofovir, according to claim 1, wherein: the reaction temperature in the step (3) is 50-90 ℃, and the reaction time is 1-6 h.
7. The method for preparing propofol, tenofovir, according to claim 1, wherein: the resolving agent is any one or more than two of D-tartaric acid, D- (+) -dibenzoyl tartaric acid, D- (+) -di-p-methylbenzoyl tartaric acid and D- (+) -di-p-methoxybenzoyl tartaric acid which are mixed in any ratio.
8. The method for preparing propofol, tenofovir, according to claim 1, wherein: the inorganic base is any one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
9. The method for preparing propofol, tenofovir, according to claim 1, wherein: the organic base is any one of triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine and morpholine.
10. The method for preparing propofol, tenofovir, according to claim 1, wherein: the organic solvent is any one of isopropanol, tetrahydrofuran, acetonitrile and methyl ethyl ketone.
CN202210706308.2A 2022-06-21 2022-06-21 Preparation method of propofol tenofovir Pending CN114907409A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015107451A2 (en) * 2014-01-14 2015-07-23 Mylan Laboratories Ltd. Purification of tenofovir alafenamide and its intermediates
CN106928277A (en) * 2017-03-16 2017-07-07 江苏诚信药业有限公司 A kind of tenofovir Chinese mugwort draws the process of phenol amine synthesis
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
CN110305163A (en) * 2018-03-27 2019-10-08 北京济美堂医药研究有限公司 Tenofovir Chinese mugwort draws the preparation method of phenol amine hemifumarate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015107451A2 (en) * 2014-01-14 2015-07-23 Mylan Laboratories Ltd. Purification of tenofovir alafenamide and its intermediates
CN106928277A (en) * 2017-03-16 2017-07-07 江苏诚信药业有限公司 A kind of tenofovir Chinese mugwort draws the process of phenol amine synthesis
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
CN110305163A (en) * 2018-03-27 2019-10-08 北京济美堂医药研究有限公司 Tenofovir Chinese mugwort draws the preparation method of phenol amine hemifumarate

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