Post-treatment method for tenofovir production

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a synthesis post-treatment method of tenofovir. The preparation method comprises the following steps: carrying out nucleophilic substitution reaction on (R)-9-(2-hydroxy propyl) adenine and p-toluenesulfonyloxy diethyl methylphosphonate under the condition that magnesium tert-butoxide is used as alkali, hydrolyzing under the action of strong acid to obtain tenofovir, and concentrating to remove acid; washing off other impurities after passing through an activated cation exchange resin column; then, the tenofovir is eluted with alkali; and adjusting the pH value to separate out a product, thereby obtaining qualified tenofovir. According to the technical scheme, the synthesis post-treatment method of tenofovir is less in three industrial wastes, the resin column can be repeatedly used, meanwhile, the product yield can be improved, and industrial production of tenofovir is facilitated.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a post-synthesis treatment method of tenofovir. Background Art

[0002] Tenofovir is an acyclic nucleoside antiviral drug that inhibits HBV polymerase and HIV reverse transcriptase. The active ingredient of tenofovir, tenofovir bisphosphonate, can inhibit viral polymerase by directly competing with natural deoxyribose substrates and terminate the chain by inserting into DNA. It is the first nucleotide analog approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 infection. Tenofovir is a drug in the AIDS cocktail therapy. Studies have shown that it can effectively improve the ability of monkeys to prevent immunodeficiency virus (similar to human AIDS virus).

[0003]

[0004] In addition, Tenofovir is a key intermediate of two raw materials, Tenofovir Disoproxil Fumarate (abbreviated as: TDF) and Tenofovir Alafenamide Fumarate (abbreviated as: TAF). Both are currently the first-line antiviral treatment drugs for HIV and HBV.

[0005]

[0006] It can be seen from the structural formulas of the two raw materials that tenofovir is the key main fragment of the two drugs. Therefore, developing a tenofovir synthesis method with low cost, simple operation and good product quality can help provide the society, the country and the community with TDF and TAF drugs with good product quality and low price.

[0007] At present, the mainstream synthesis route of tenofovir is to use adenine and R-propylene carbonate as starting materials, and react under alkaline catalysis to obtain (R)-(+)-9-(2-hydroxypropyl) adenine (abbreviated as: HPA), which is then reacted with another key material diethyl p-toluenesulfonyloxymethylphosphonate (abbreviated as: DESMP) to obtain tenofovir diethyl ester (abbreviated as: DEP), and then the phosphate ester is hydrolyzed and the pH value is adjusted to obtain tenofovir:

[0008]

[0009] In the preparation of PMPA according to patent WO9804569A1, when preparing the intermediate DEP, DMF is used as a solvent and lithium tert-butoxide is used as a base (acidifying agent) to prepare DEP by a nucleophilic substitution reaction by heating. After the reaction is completed, a weak acid is used to neutralize N,N-dimethylformamide (DMF for short, the same below) and then concentrated under reduced pressure and then hydrolyzed to prepare PMPA:

[0010]

[0011] The original synthesis used tert-butyl lithium as a base, and trimethylsilyl bromide as a hydrolysis agent during the hydrolysis of phosphate esters. After completion, the acid and base were adjusted once and the recrystallization and slurrying were performed twice, which ultimately increased the production cost of the product and greatly reduced the yield.

[0012] The synthesis process reported in patent US5733788A uses lithium hydride as an acidifying agent and DMF as a reaction solvent when preparing DEP. Similarly, after the reaction is completed, the acid is used for neutralization and the solvent is concentrated under reduced pressure before the next reaction.

[0013]

[0014] The nucleophilic substitution reaction used lithium hydride as a base for the nucleophilic substitution reaction, and then was hydrolyzed with trimethylsilyl bromide. The yield of the first step reaction was 50%, the yield of the second step was 79%, and the total yield of the two steps was 39.5%, and the reaction yield was relatively low.

[0015] Patent WO2008007392A2 (Process for the preparation of Tenofovir) reports the use of magnesium tert-butoxide as an acidifying agent to prepare PMPA in the process for preparing TDF.

[0016]

[0017] The literature uses magnesium butoxide as a base for the reaction, and then uses concentrated hydrochloric acid or concentrated bromic acid as a hydrolysis reagent. The hydrolysis reagent no longer uses trimethylsilyl bromide, which saves material costs. However, the total yield of the two-step reaction (substitution reaction and acidolysis reaction) is at most 70%, which is low.

[0018] Patent WO0208241 reported the production of TAF, using magnesium isopropoxide as the acidifying agent and DMF as the reaction solvent to prepare PMPA:

[0019]

[0020] The synthetic route uses magnesium isopropoxide as a base reaction, and trimethylsilyl bromide is used to hydrolyze the ester. The reaction uses relatively expensive trimethylsilyl bromide as an acid hydrolysis reagent. The total yield of the other two steps is only 65.4%, and the reaction yield is low.

[0021] Most of the literatures reported above used the relatively expensive acid hydrolysis reagent trimethylsilyl bromide, and the yields of both steps were not high, thus increasing the production cost of PMPA.

[0022] In addition, the equivalent ratio of HPA and diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) in all literatures is basically 1.00:1.20, and DESMP is in liquid state. Due to its high boiling point, it cannot be distilled off. Therefore, impurities such as p-toluenesulfonic acid, hydroxymethylphosphonic acid, and p-toluenesulfonyloxymethylphosphonic acid are generated during the hydrolysis process. Therefore, the above impurities need to be removed and controlled during post-treatment:

[0023]

[0024] It can be seen from the above patents that optimizing the use of cheaper reagents and optimizing the post-processing methods to increase product yields can reduce PMPA production costs and improve product competitiveness. Summary of the invention

[0025] The purpose of the present invention is to develop a post-processing method that is simple to use, low in cost, reusable, has a high product yield and good quality, and can achieve industrial production of products.

[0026] In order to achieve the above object, the technical solution adopted by the present invention is:

[0027] A tenofovir post-production processing method comprises the following process steps:

[0028] (R)-9-(2-hydroxypropyl)adenine reacts with diethyl p-toluenesulfonyloxymethylphosphonate in the presence of magnesium tert-butoxide as a base, and then undergoes a nucleophilic substitution reaction. The reaction is then hydrolyzed under the action of a strong acid to obtain tenofovir, which is then concentrated and deacidified. Other impurities are then washed off through an activated cation exchange resin column.

[0029] Tenofovir is then eluted with alkali, and the eluate is concentrated under reduced pressure;

[0030] Then adjust the pH value to precipitate the product and obtain qualified tenofovir.

[0031] The further improvement of the technical solution of the present invention lies in that: the cation exchange resin is a strongly acidic cation exchange resin; the strongly acidic cation exchange resin is a gel-type ion exchange resin or a macroporous ion exchange resin; the ion exchange groups of the cation exchange resin include -SO3H, -SO3NH4, -SO3Na, -SO3K, these ion groups.

[0032] The further improvement of the technical solution of the present invention is that after the tenofovir mother solution is activated, the resin column is rinsed with purified water to remove impurities with excess hydrochloric acid, and finally the pH value is rinsed to 3-7; when the tenofovir mother solution is activated, the resin column is rinsed at a temperature of 10-80°C.

[0033] A further improvement of the technical solution of the present invention is that when eluting the tenofovir resin column, the mobile phase is a 2-10% ammonia solution.

[0034] A further improvement of the technical solution of the present invention is that when eluting a tenofovir resin column, the mobile phase solution is a purified water-ammonia solution, or purified water-methanol; or a purified water-ethanol solution; or a purified water-isopropanol solution; or a mixed solution of purified water and other organic solvents.

[0035] The further improvement of the technical solution of the present invention is that when eluting the tenofovir resin column, the molar ratio of ammonia to tenofovir in the eluent is (1.0-15.0):1.00; and the ammonia solution content of the eluent is 2%-16%.

[0036] A further improvement of the technical solution of the present invention is that when the eluted tenofovir solution is concentrated, it is concentrated under reduced pressure until the tenofovir content is 5-50%.

[0037] A further improvement of the technical solution of the present invention is that after the tenofovir solution is concentrated and eluted, the pH value is adjusted to between 2.5 and 3.5 using hydrochloric acid.

[0038] The further improvement of the technical solution of the present invention is that after adjusting the pH value with hydrochloric acid, the crystallization temperature is -10 to 30° C. and the crystallization time is 1 to 10 hours.

[0039] A further improvement of the technical solution of the present invention is that after elution of the tenofovir resin column, the cation exchange resin column is activated using sulfuric acid, nitric acid, and hydrochloric acid.

[0040] Due to the adoption of the above technical solution, the technical effects achieved by the present invention are as follows:

[0041] The post-synthesis treatment method of tenofovir of this technical solution reduces the three industrial wastes, and the resin column can be reused. At the same time, the product yield can be improved, which is conducive to the industrial production of tenofovir. DETAILED DESCRIPTION

[0042] In order to make the technical means, creative features, objectives and effects achieved by the present invention easy to understand, the present invention is further explained below in conjunction with specific implementation methods.

[0043] The technical solution of the present invention is a tenofovir production post-processing method, which improves the product yield and product quality by improving the processing technology while reducing the cost.

[0044] The method comprises the following process steps:

[0045] Step 1: (R)-9-(2-Hydroxypropyl)adenine reacts with diethyl p-toluenesulfonyloxymethylphosphonate in the presence of magnesium tert-butoxide as a base, and then undergoes a nucleophilic substitution reaction. The reaction is then hydrolyzed under the action of a strong acid to obtain tenofovir, which is then concentrated and deacidified. Other impurities are then washed off using an activated cation exchange resin column.

[0046] Step 2: Tenofovir is then eluted with alkali and the eluate is concentrated under reduced pressure.

[0047] Step 3: Then adjust the pH value to precipitate the product and obtain qualified tenofovir.

[0048] Specifically, it is necessary to further optimize the process parameters in each of the above steps. The details are as follows:

[0049] The mass total exchange capacity of the cation exchange resin used in step 1 is ≥4mmol / g, and the volume total exchange capacity is ≥2mmol / ml.

[0050] The cation exchange resin is a strongly acidic cation exchange resin; the strongly acidic cation exchange resin is a gel-type ion exchange resin, such as a styrene-based gel-type ion exchange resin; or a macroporous ion exchange resin, such as a styrene-based macroporous ion exchange resin.

[0051] The ion exchange groups of the cation exchange resin include -SO3H, -SO3NH4, -SO3Na, -SO3K.

[0052] When the tenofovir mother solution is overactivated on the resin column, the ratio of the actual weight of tenofovir to the weight of the cation exchange resin is 1:(0.50-15.00).

[0053] In step 1, after the tenofovir mother solution is activated, the resin column is rinsed with purified water to remove impurities with excess hydrochloric acid, and finally the pH value is rinsed to 3-7; when the tenofovir mother solution is activated, the resin column is rinsed at a temperature of 10-80°C.

[0054] In step 2, when eluting a tenofovir resin column, the mobile phase is a 2-10% ammonia solution. When eluting a tenofovir resin column, the mobile phase solution is a purified water ammonia solution, or purified water-methanol; or purified water-ethanol solution; or purified water-isopropanol solution; or a mixed solution of purified water and other organic solvents. When eluting a tenofovir resin column, the molar ratio of ammonia to tenofovir in the eluent is (1.0-15.0):1.00; the ammonia solution content of the eluent is 2%-16%.

[0055] When the eluted tenofovir solution needs to be concentrated in step 2, it is concentrated under reduced pressure until the tenofovir content is 5-50%.

[0056] In step 3, the pH value of the concentrated eluted tenofovir solution is adjusted to between 2.5 and 3.5 using hydrochloric acid. Specifically, after adjusting the pH value using hydrochloric acid, the crystallization temperature is between -10 and 30° C., and the crystallization time is between 1 and 10 hours.

[0057] After elution of the tenofovir resin column was completed, the cation exchange resin column was activated using sulfuric acid, nitric acid, and hydrochloric acid.

[0058] Example 1: Preparation of Tenofovir (PMPA)

[0059] Tenofovir was prepared with reference to Example 3 of WO2008007392A2 (Process for the preparation of Tenofovir), which specifically comprises the following steps: (R)-9-[2-(Hydroxy)propyl]adenine (HPA) (100.00 g, 0.52 mol) was weighed and added to 200 ml of N,N-dimethylformamide (DMF) and stirred evenly; 70.61 g (0.41 mol) of magnesium tert-butoxide was slowly added at 25-35° C. under a temperature control system; then the temperature was raised to 60-65° C. and stirred for 1 hour; after 1 hour, the temperature was raised to 74-78° C.; p-toluenesulfonyloxymethyl was slowly added under a temperature control system; 200.19 g (0.62 mol) of diethyl phosphonate (DESMP) was added over 1-2 hours. After the addition, the temperature was kept at 74-78°C and stirred for 5 hours. Then the temperature was lowered to 25-35°C. 60.00 g (1.00 mol) of glacial acetic acid was added dropwise with stirring. After the addition was completed, the solvent was concentrated under reduced pressure (80-85°C). Then the temperature was lowered to 25-35°C. 600 ml of dichloromethane and 100 ml of purified water were added to the system. After stirring for 1 hour, the generated salt was filtered out. Then the water layer was separated and the dichloromethane was evaporated under reduced pressure. 655g (3.88mol) of concentrated hydrobromic acid was added to the concentrate, and then the temperature was raised to 90-95°C, and the reaction was kept warm for 5 hours. After the reaction was completed, the temperature was lowered and the sample was sent for detection to find that the tenofovir content was 120.56g (the total conversion rate of the two steps was 81.10%). 300ml of purified water and 300ml of dichloromethane were added to the system, and then the pH value was adjusted to 2.50-3.00 with 30% sodium hydroxide solution, and then the temperature was controlled at 0-5°C and stirred for 4 hours while maintaining the pH value, and the solid was filtered out. The filter cake was refluxed and slurried in 200ml of purified water for 1 hour, and then the temperature was lowered to 0-5°C and stirred for 4 hours, and the solid was filtered out. The filter cake was rinsed with purified water and then dried, and then dried to obtain 103.04g of tenofovir, with a yield of 69.31%, and the product purity (HPLC): 97.89%. The product yield is consistent with that reported in the patent literature.

[0060] Example 2: Preparation of Tenofovir (PMPA)

[0061] Tenofovir was prepared with reference to Example 3 of WO2008007392A2 (Process for the preparation of Tenofovir), specifically comprising the following steps: 2.0 L of N,N-dimethylformamide was added to a 10 L glass reactor, 1.00 kg (5.18 mol) of (R)-9-[2-(hydroxy)propyl]adenine (HPA) was weighed and added to the reactor and stirred evenly, nitrogen was replaced 3 times, 0.71 kg (4.14 mol) was slowly added at a temperature of 25 to 35 ° C, the temperature was raised to 60 to 65 ° C and stirred for 1 hour, and the temperature was raised to 74 to 78 ° C after 1 hour, and the mixture was added dropwise under temperature control and stirring. 2.00 kg (6.21 mol) of diethyl tosyloxymethylphosphonate (DESMP) was added dropwise over 1 to 2 hours, and then the temperature was controlled at 74 to 78°C and stirred for 5 hours. The system was cooled to 20 to 25°C, and 0.60 kg (10.00 mol) of glacial acetic acid was added dropwise with stirring. After the addition was completed, the solvent was concentrated under reduced pressure (interlayer temperature 80 to 85°C), and then the temperature was cooled to 25 to 35°C. 6 L of dichloromethane and 1 L of purified water were added to the system. After stirring for 1 hour, the generated salt was filtered out, and then the water layer was separated and the dichloromethane was evaporated under reduced pressure. To the concentrate, 6.55 kg (38.8 mol) of concentrated hydrobromic acid was added, the temperature was raised to 90-100 ° C, and the reaction was refluxed for 5 hours. After the reaction was completed, the temperature was lowered and the sample was sent for detection to find that the tenofovir content was 1.22 kg (the total conversion rate of the two steps was 81.91%). The temperature of the reactor interlayer was raised to 80-85% and the hydrobromic acid was concentrated under reduced pressure (the hydrobromic acid was recovered and activated with resin) to obtain a light yellow oily PMPA hydrobromide for stand-alone use.

[0062] Example 3: Tenofovir (PMPA) post-processing method

[0063] The concentrated PMPA mother solution in Example 2 (PMPA content: 100.5 g) was weighed and added to 200 ml of purified water to stir and dissolve. The solution was passed through 1.0 kg of activated cation exchange resin and then the resin column was rinsed with purified water to about neutral (6.0-7.0 according to a broad pH test paper). The resin column was then rinsed and eluted with 100 g of 6.00% ammonia water, and an eluent with a pH value of about 7.5-12 was collected (PMPA began to flow out of the TLC monitoring until PMPA no longer showed color). First, the excess ammonia is concentrated at 50-55° C. (the concentrated solution can be prepared with ammonia water to reduce wastewater discharge), then the temperature is raised to 75-80° C., and the PMPA content is concentrated to 25-35%. Then the concentrated solution is cooled to 0-10° C., and the pH value is adjusted to 2.8-3.0 with hydrobromic acid recovered from the previous concentration. Then, the solution is stirred at low temperature for 6 hours, filtered, rinsed with cooled purified water, and dried to obtain PMPA weighing 97.41 g, with a yield of 79.79% and a product quality of 99.53% (HPLC).

[0064] The cation exchange resin is first rinsed with purified water to neutrality, then rinsed with recovered hydrobromic acid to a pH value of about 1.0 to 3.0, and then rinsed with purified water to neutrality (pH about 6.5 to 7.5). The resin activation is completed and it is used.

[0065] Example 4: Tenofovir (PMPA) post-processing method

[0066] The concentrated PMPA mother solution in Example 2 (PMPA content: 102 g) was measured and added to 100 ml of purified water to stir and dissolve. After the solution passed through 1.0 kg of the activated cation exchange resin in Example 3, the resin column was rinsed with purified water until it was approximately neutral (6.0 to 7.0 according to a broad pH test paper), and then the resin column was rinsed with 100 g of 6.00% ammonia water to elute the resin column. The eluent with a pH value of about 7.5 to 12 was collected (PMPA began to flow out of the TLC monitoring until PMPA no longer showed color). The eluent was first The excess ammonia was concentrated at 50-55°C, and then the temperature was raised to 75-80°C to concentrate until the PMPA content was 25-35% (the concentrated liquid was recovered for the preparation of ammonia water to reduce wastewater discharge), and then the concentrated liquid was cooled to 0-10°C, and the pH value was adjusted to 2.8-3.0 with hydrobromic acid recovered from the previous concentration, and then stirred at low temperature for 6 hours, filtered, rinsed with pre-cooled purified water, and dried to obtain PMPA weighing 98.30g, with a yield of 78.93% and a product quality of 99.74% (HPLC). The resin column was activated according to the method of Example 3 and then used.

[0067] Example 5: Post-treatment method of tenofovir (PMPA)

[0068] Weigh (R)-9-[2-(Hydroxy)propyl]adenine (HPA) (100.00 g, 0.52 mol) and add it to 200 ml of N,N-dimethylformamide (DMF), stir evenly to form a suspension, slowly add 70.61 g (0.41 mol) of magnesium tert-butoxide at 25-35 ° C, then heat to 60-65 ° C and stir for 1 hour, heat to 74-78 ° C and then slowly add 200.00 g (0.62 mol) of diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) dropwise after keeping warm for 1.3 hours, and then keep the temperature at 74-78 ° C and stir for 5 hours, then cool to 20-30 ° C and add 60.00 g (0.62 mol) of diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) dropwise. (1.00mol) glacial acetic acid, after the dropwise addition is completed, the solvent is concentrated under reduced pressure (external temperature: 80-85°C), then the temperature is lowered to 20-30°C, 600ml of dichloromethane and 100ml of purified water are added to the system, and the precipitated salt is filtered out after stirring for 1 hour, and then the water layer is separated, and the dichloromethane is concentrated and 655g (3.88mol) of concentrated hydrobromic acid is added, the temperature is raised to 90-95°C, and the reaction is kept warm for 5-7 hours. After the reaction is completed, the concentrated hydrobromic acid is concentrated under reduced pressure (the concentrated liquid retains the activated resin and the pH value is adjusted) until no liquid drips out, 284g of the concentrated liquid is weighed, and the PMPA content is 122.41g (the conversion rate of the two-step reaction is 82.34%).

[0069] 200 g of purified water was added to the concentrate, and after stirring to dissolve, the cation exchange resin activated in Example 4 was used, and the resin column was rinsed with purified water until it was neutral (6.0-7.0 according to a general pH test paper), and then the resin column was rinsed with 100 g of 6.00% ammonia water, and the eluent with a pH value of about 7.5-12 was collected (TLC monitoring PMPA began to flow out until PMPA no longer showed color), and the eluent was first concentrated at 50-55° C. to remove excess ammonia, and then heated to 40° C. to remove excess ammonia. The mixture was stirred at low temperature for 6 hours, filtered, rinsed with 50 ml of purified water cooled in advance, and dried to obtain PMPA weighing 119.72 g, with a two-step yield of 80.53% and a product quality of 99.61% (HPLC). The resin column was activated according to the method of Example 3 and then used.

[0070] Example 6: Post-treatment method of tenofovir (PMPA)

[0071] 12.0L of N,N-dimethylformamide was added to a 50L glass reactor, and 6.00kg (31.05mol) of HPA was added. The mixture was stirred to form a suspension. The nitrogen was replaced 3 times. The temperature of the system was controlled to 25-35℃, and 4.24kg (24.84mol) of magnesium tert-butylate was added under stirring. The mixture was kept warm and stirred for 1 hour. The temperature in the reactor was raised to 74-78℃, and 12.01kg (37.27mol) of DESMP was slowly added dropwise. The addition was completed within 1.5 hours. The temperature was controlled and the reaction was continued for 5 hours. After the reaction was completed, the temperature was lowered to 20-30℃, and 3. 6kg (60.00mol) of glacial acetic acid, after the addition is complete, the solvent is concentrated under reduced pressure (external temperature: 80-85°C), then the temperature is lowered to 20-30°C, 36.0L of dichloromethane and 6.0L of purified water are added to the system, stirred for 1 hour to precipitate salt, filtered, the filtrate layer is the water layer, the dichloromethane layer is concentrated, 39.3kg (232.80mol) of concentrated hydrobromic acid is added, the temperature is raised to 90-95°C, and the reaction is kept warm for 5-7 hours. After the reaction is completed, the concentrated hydrobromic acid is concentrated under reduced pressure (the concentrated liquid is retained to activate the resin and adjust the pH value) until no liquid drips out to obtain a light yellow viscous substance.

[0072] Add 12L of purified water to the concentrate, stir to dissolve, and then elute the solution through a 60kg cation exchange resin column. Rinse the resin column with purified water until it is neutral (6.0-7.0 according to a broad pH test paper), then rinse the resin column with 60.0kg of 6.00% ammonia water, and accept an eluent with a pH value of about 7.5-12 (TLC monitors the outflow of PMPA until PMPA no longer shows color). First, concentrate the excess ammonia at 50-55°C, then heat to 7 5~80℃, concentrate to PMPA content of 30.59% (the concentrated liquid is recovered for preparing ammonia water to reduce wastewater discharge), reduce the temperature of the concentrated mother liquor to 0~10℃, adjust the pH value to 2.8~3.0 with hydrobromic acid recovered from the previous concentration, stir at low temperature for 6 hours, centrifuge and rinse with 3.0L of purified water cooled in advance, then centrifuge and filter at high speed, and dry the filter cake to obtain PMPA weighing 7.21kg, with a two-step yield of 80.87% and a product quality of 99.39% (HPLC).

[0073] According to the comparison between Examples 3-6 and Example 1 and the report in the patent (WO2008007392A2), it can be seen that the yield of PMPA obtained by the method for post-treatment of PMPA of the present invention is significantly improved, and the product purity is high. This shows that the method of the present invention can greatly improve the yield of PMPA. In addition, the hydrobromic acid, ammonia water, etc. recovered in the production of PMPA can be reused, reducing the discharge of three wastes, so industrial production can be carried out.

[0074] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A tenofovir post-production processing method, characterized in that: The process steps include: (R)-9-(2-hydroxypropyl)adenine reacts with diethyl p-toluenesulfonyloxymethylphosphonate in the presence of magnesium tert-butylate as a base, and then undergoes a nucleophilic substitution reaction. The reaction is then hydrolyzed under the action of a strong acid to obtain tenofovir, which is then concentrated and deacidified. Other impurities are then washed off using an activated cation exchange resin column. Tenofovir is then eluted with alkali, and the eluate is concentrated under reduced pressure; Then adjust the pH value to precipitate the product and obtain qualified tenofovir.

2. A tenofovir post-production processing method according to claim 1, characterized in that: The cation exchange resin is a strongly acidic cation exchange resin; the strongly acidic cation exchange resin is a gel-type ion exchange resin or a macroporous ion exchange resin; the ion exchange groups of the cation exchange resin include -SO3H, -SO3NH4, -SO3Na, -SO3K, and these ion groups.

3. A tenofovir post-production processing method according to claim 1, characterized in that: After the tenofovir mother solution is activated, the resin column is washed with purified water to remove excess hydrochloric acid, and finally the pH value is washed to 3-7; when the tenofovir mother solution is activated, the washing temperature of the resin column is 10-80°C.

4. A tenofovir post-production processing method according to claim 1, characterized in that: When eluting a tenofovir resin column, the mobile phase is a 2-10% ammonia solution.

5. A tenofovir post-production processing method according to claim 1, characterized in that: When eluting a tenofovir resin column, the mobile phase solution is a purified water-ammonia solution, or purified water-methanol; or purified water-ethanol solution; or purified water-isopropanol solution; or a mixed solution of purified water and other organic solvents.

6. A tenofovir post-production processing method according to claim 1, characterized in that: When eluting a tenofovir resin column, the molar ratio of ammonia to tenofovir in the eluent is (1.0-15.0):1.00; the ammonia solution content of the eluent is 2%-16%.

7. A tenofovir post-production processing method according to claim 1, characterized in that: When concentrating the eluted tenofovir solution, it is concentrated under reduced pressure until the tenofovir content is 5-50%.

8. A tenofovir post-production processing method according to claim 1, characterized in that: After the eluted tenofovir solution is concentrated, the pH value is adjusted to between 2.5 and 3.5 using hydrochloric acid.

9. A tenofovir post-production processing method according to claim 1, characterized in that: After adjusting the pH value with hydrochloric acid, the crystallization temperature is between -10 and 30°C, and the crystallization time is between 1 and 10 hours.

10. A tenofovir post-production processing method according to claim 1, characterized in that: After elution of the tenofovir resin column, the cation exchange resin column was activated using sulfuric acid, nitric acid, and hydrochloric acid.

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