CN102295660A - Synthetic technology of PMPA - Google Patents

Abstract

The invention relates to a synthesis process of tenofovir, and relates to the field of medicinal chemistry. Using natural (R)-lactate as the starting material, chiral R-1,2-propanediol is obtained through reduction, and then reacted with diethyl carbonate under the action of alkali to obtain the key reaction intermediate R-propylene carbonate ester. Use adenine and R-propylene carbonate to prepare R-9-(2-hydroxypropyl)adenine; the resulting R-9-(2-hydroxypropyl)adenine and p-toluenesulfonyloxy phosphate diethyl ester Under the catalysis of magnesium tert-butoxide, the condensation reaction is carried out to obtain R-9[(diethylphosphorylmethoxy)propyl]purine; the obtained R-9[2-(diethylphosphorylmethoxy) Propyl]purine is hydrolyzed to obtain Tenofovir. The process has short reaction steps, short required reaction time, high quality yield and good product quality, and is suitable for industrialized production.

Description

Synthetic process of tenofovir

technical field

The invention relates to the field of medicinal chemistry, and relates to a synthesis process for preparing tenofovir, an anti-AIDS and anti-hepatitis B drug.

Background technique

Tenofovir disoproxil fumarate (tenofovir disoproxil fumarate), chemical name (R)-[[2-(6-amino-9H-purine-9- Base)-1-methylethoxy]methyl]phosphonic acid bis(isopropionyloxymethyl) fumarate, whose structure is shown in Figure 1, is a first-line treatment against hepatitis B The drug is quickly transformed into tenofovir (PMPA) after being absorbed by the human body to produce antiviral effects. PMPA has been confirmed to have broad-spectrum antiviral activity against human immunodeficiency virus HIV and HBV, and has been approved by the US FDA in 2001 as a drug for clinical treatment of AIDS.

Structural formula 1 Tenofovir disoproxil

Tenofovir is the key intermediate of tenofovir dipivoxil, and there are mainly two kinds of synthetic methods of tenofovir reported in the literature.

Synthetic method one

Holy A., Masojidkova M., Collect Czech. Chem Commun. , 1995 , 60, 1192-1212.

The synthetic route of this route is long, the operation is cumbersome, and the total yield of the whole route is low.

Synthetic method two

Munger J. D., Rohloff J. C., Schultze L. M., US5935946A1, 1999-08-10 .

    This route is shorter and the yield is higher, but the optical purity of the final product is only 90-94%, which does not meet the clinical requirements and needs to be purified by other means, which will inevitably lead to an increase in production costs.

Contents of the invention

In the present invention, a major reform has been carried out on the synthesis process of tenofovir disoproxil, the key intermediate for the synthesis of tenofovir disoproxil, and the specific synthesis route is as follows:

The chiral R-1,2-propanediol (I) is obtained by reducing natural (R)-lactate as the starting material, and then reacted with diethyl carbonate under the action of a base to obtain the key reaction intermediate R - Propylene carbonate (II). Use adenine and R-propylene carbonate to prepare R-9-(2-hydroxypropyl)adenine (III); the resulting R-9-(2-hydroxypropyl)adenine and p-toluenesulfonyloxyphosphate Diethyl ester is condensed under the catalysis of magnesium tert-butoxide to obtain R-9 [(diethylphosphorylmethoxy) propyl] purine (IV); the resulting R-9 [2-(diethyl Phosphorylmethoxy)propyl]purine is hydrolyzed to obtain tenofovir (V). The specific technical scheme is as follows:

The synthetic technique of tenofovir is carried out according to the following steps:

(1) Add (R)-lactate, reducing agent and solvent into the reaction bottle, the molar ratio of reducing agent to lactate is 1:1-2:1, stir at room temperature for 2 hours, then slowly add methanol dropwise, Cool to room temperature and use hydrochloric acid to adjust the pH value to neutral, filter out the insoluble matter, evaporate the solvent to obtain R-1,2-propanediol, and directly use it in the next step without purification;

(2) Add alkali and R-1,2-propanediol in the reaction bottle, the molar ratio of alkali and R-1,2-propanediol is 1:100-1:10, heat to reflux for 30 minutes, slowly drop dicarbonate Ethyl ester; reflux after the dropwise addition, white insoluble matter is produced, continue to heat to 120 oC, react for 2 hours, the reaction is terminated, distill the unreacted diethyl carbonate under reduced pressure, cool to room temperature, and dichloromethane Dilution; filter out insolubles, obtain product R-propylene carbonate after the filtrate is evaporated to remove solvent;

(3) Add adenine, R-propylene carbonate, solvent and NaOH into the reaction bottle, stir at room temperature for 10 minutes, after the system is uniform, start to heat up to 120-130 oC, keep warm for reaction, TLC detection every 1 hour; when the reaction Complete, the reaction can be stopped; slowly lowered to below 90 oC, began to add toluene, and a large amount of white solids precipitated; after cooling down to room temperature, continued to drop to 0-5 oC, kept stirring for 2 hours; suction filtered, soaked in ice toluene The filter cake is dried to obtain R-9-(2-hydroxypropyl) adenine; the obtained R-9-(2-hydroxypropyl) adenine product is added to ethanol and toluene, heated to dissolve, and gac is added. After refluxing for half an hour, remove gac by suction filtration while hot, the filtrate is down to room temperature, further cooled to 0 o C, suction filtration after insulation for 1 hour, and obtain product R-9-(2-hydroxypropyl)adenine after drying;

(4) Add R-9-(2-hydroxypropyl) adenine, magnesium tert-butoxide and solvent DMF into the reaction flask, then raise the temperature to 60-80 oC, and start to add p-toluenesulfonyloxy diethyl phosphate dropwise Ester; control the rate of addition, and drop it in about 1 hour; detect it after 2 hours of dropping, and stop the reaction when the adenine is completely consumed; slowly drop to room temperature, add anhydrous acetic acid dropwise; after dropping, stir at room temperature for 30 Minutes; DMF was evaporated under reduced pressure, and the maximum internal temperature was controlled below 100 oC; after the evaporation was completed, dichloromethane was added, naturally cooled to 25-30 oC, and stirred for 30 minutes; water was added, a large amount of white solids were precipitated, and the temperature was kept Stir for 1 hour; suction filter to remove the solid; stand to separate the layers, and concentrate the dichloromethane layer to dryness to obtain the product R-9-[2-(diethylphosphorylmethoxy)propyl]adenine;

(5) Add R-9-[2-(diethylphosphorylmethoxy)propyl]adenine and hydrobromic acid aqueous solution into the reaction flask, heat up to 90-95 oC, and react for 6 hours to detect the reaction by HPLC The by-product in the solution, the content of monoethyl ester should be below 1%, cool down to room temperature, add methylene chloride, layer after stirring for half an hour, take the water layer, adjust the pH value of the solution to 3.2 with sodium hydroxide solution Around, a large amount of white solid precipitated, stirred at room temperature for half an hour, continued to cool to 0-5 oC, filtered with suction, and purified the obtained white solid with water to obtain Tenofovir.

Wherein the reducing agent described in the step (1) is sodium borohydride, lithium aluminum hydride, etc.; the solvent is toluene, cyclohexane or tetrahydrofuran, etc.

The innovation of this process:

[1] The production process described in this process is easy to operate, and all raw materials are cheap and easy to get.

[2] The reduction of methyl lactate in the first step of this process uses a cheap, stable and easy-to-operate reducing agent such as sodium borohydride. The reduction yield is high, the post-treatment is simple, and the optical purity of the obtained product can reach more than 99%.

[3] The alkali used in the fourth step of this process does not use catalysts such as sodium hydrogen, which improves the safety of production;

[4] The reaction conditions are mild, avoiding the reaction conditions of high temperature, high pressure and ultra-low temperature, which is very suitable for industrial processing;

[5] Most of the solvents in the whole process can be recycled, and the three wastes are produced in a small amount, which can be regarded as a clean production process;

[6] The process provides a high-purity tenofovir dipivoxil production process, which solves the problem that the by-product monoethyl ester, mono (POC) ester and chiral isomer impurities are too high in the product.

In a word, the economic benefit and social benefit are very remarkable by adopting the production process of this process.

The present invention can be explained more specifically by the following examples. However, the scope of the present invention is not limited to the following examples.

Example 1 (1) Preparation of R-1,2-propanediol (I)

Take a 250 mL three-necked flask, add sodium borohydride (5.7 g, 0.15 mol), methyl lactate (10.4 g, 0.10 mol) and toluene (60 mL), stir at room temperature for 2 hours, then add 5 mL of methanol (note: the reaction violently emits After 10 minutes, continue to add 5 mL of methanol, and then carefully add 5 mL of methanol for the third time after 10 minutes to stop the reaction. After cooling to room temperature, adjust the pH value to neutral with 5 mol/L hydrochloric acid (Note: It also releases gas violently and needs to be added carefully), the system produces a large amount of insoluble matter, which is filtered out, and the diol product is obtained after distilling off the solvent. It was directly used in the next reaction without purification.

(2) Preparation of R-propylene carbonate (II)

Take a 50 mL three-neck flask with a spherical condenser, add a stirring magnet, and then measure 2 mL of absolute ethanol into the bottle. Weigh metal sodium block (0.23 g, 0.01 mol), and carefully pour into absolute ethanol in portions. After the metal sodium is consumed, add diol (6.61 g, 89.7 mmol), heat to reflux for 30 minutes, slowly drop dicarbonate Ethyl ester (12.98 g, 0.11 mol), the rate of addition was controlled, and the system released heat. Reflux after the dropwise addition, white insoluble matter is produced, continue heating to 120 oC, and react for 2 hours, during which ethanol is continuously distilled out, the reaction is terminated, and unreacted diethyl carbonate is distilled out by vacuum distillation. Cool to room temperature and dilute with 20 mL of dichloromethane. The insoluble matter was filtered off, and the filtrate was evaporated to remove the solvent to obtain 8.0 g of the product with a yield of 90.4%. ¹ H NMR (500MHz, CDCl ₃ ): δ 4.87-4.86 (m, 1H), 4.58-4.55 (m, J = 8.5 Hz, 1H), 4.05-4.02 (m, J = 8.5 Hz, 1H), 1.50- 1.49 (d, J = 6.5 Hz, 3H).

(3) Preparation of R-9-(2-hydroxypropyl)adenine (III)

Add adenine (10.0 g, 0.074 mol) into a 250 mL three-neck flask, fill with N ₂ for protection, then add 50 mL of DMF, add R-propylene carbonate (9.5 g, 0.092 mol), add NaOH (0.3 g, 0.0075 mol), stir at room temperature for 10 minutes, after the system is uniform, start to heat up to 120-130 oC, keep warm for reaction, TLC detection every 1 hour; when the reaction is complete, stop the reaction; slowly drop to 90 Below oC, start to add 60 mL of toluene, a large amount of white solids precipitate; after cooling down to room temperature, continue to drop to 0-5 oC, keep stirring for 2 hours; suction filter, wash the filter cake with 20 mL ice toluene to obtain a wet filter cake About 18 g, after drying, about 13-14 g of R-9- (2-hydroxypropyl) adenine, HPLC purity 80% -90%, melting point 185-195 oC; the obtained R-9- (2- Add 60 mL of ethanol and 10 mL of toluene to 13 g of hydroxypropyl) adenine product, heat up to dissolve, add 1.0 g of activated carbon, reflux for half an hour and remove the activated carbon by suction filtration while the filtrate is cooled to room temperature, and further cooled to 0 oC , vacuum filtration after heat preservation for 1 hour, and about 10.5 g of product R-9-(2-hydroxypropyl)adenine was obtained after drying, with an HPLC purity of over 98% and a molar yield of about 73%.

(4) Preparation of R-9-[2-(diethylphosphorylmethoxy)propyl]adenine (IV)

In a dry 100 mL four-neck flask, add R-9-(2-hydroxypropyl) adenine (10.0 g 0.052 mol), fill with N ₂ for protection, add DMF 20 mL; add magnesium tert-butoxide (9.0 g , 0.053 mol ), then heated up to 60-80 oC, and started to drop diethyl p-toluenesulfonyloxyphosphate (25 g, 0.077 mol ); control the rate of addition, and drop it in about 1 hour; Detect after 2 hours, when the R-9-(2-hydroxypropyl) adenine in the raw material is completely consumed, the reaction can be stopped; slowly cool down to room temperature, add (7.5 g, 0.124 mol) anhydrous acetic acid dropwise, about The dropwise addition was completed in 15 minutes; after the dropwise addition, stirred at room temperature for 30 minutes; the DMF was evaporated under reduced pressure, the maximum internal temperature was controlled below 100 oC, and evaporated to dryness in about 2 hours; after the evaporation was completed, 100 mL of dichloromethane was added, Cool to 25-30 oC, stir for 30 minutes; add 10 mL of water, a large amount of white solid precipitates out, keep stirring for 1 hour; remove the solid by suction filtration; stand to separate layers, and concentrate the dichloromethane layer to dryness to obtain the The four-step product R-9-[2-(diethylphosphorylmethoxy)propyl]adenine is 18 g, which is a light yellow oily substance with a purity of over 98% and a molar yield of about 95%.

(5) Preparation of tenofovir (V)

Add R-9-[2-(diethylphosphorylmethoxy)propyl]adenine to 65 g of hydrobromic acid solution, heat up to 90-95 oC, and react for 6 hours to detect by-products in the reaction solution by HPLC. Product, the content of monoethyl ester should be below 1%, be cooled to room temperature, add 10 mL dichloromethane, layer after stirring for half an hour, get water layer, adjust the pH value of solution to 3.0% with 40% sodium hydroxide solution. 2 or so, a large amount of white solids were precipitated, stirred at room temperature for half an hour, continued to cool to 0-5 oC, and filtered with suction, the obtained white solids were refined with 15 times the amount of water to obtain about 8.0 g of the key intermediate tenofovir, Purity above 99%, molar yield 55%. [α] ^D ₂₅ = +22.3 (c 0.55, 0.1M HCl), Mp: 278-281 oC, ¹ H NMR (500MHz, D ₂ O): δ 8.24 (s , 2H), 4.31-4.14 (m, 2H), 4.10-3.94 (m, 1H), 3.72-3.45 (m, 2H), 1.10-1.07 (d, 3H).

Example 2 (1) Preparation of R-1,2-propanediol (I)

Take a 250 mL three-necked flask, add lithium aluminum hydride (5.7 g, 0.15 mol) and THF (100 mL), add methyl lactate (10.4 g, 0.10 mol) in batches, stir at room temperature for 2 hours, then slowly add 50 mL THF dropwise The mixture with water was cooled to room temperature and then filtered, the filter cake was washed several times with THF, the filtrates were combined, and the diol product was obtained after distilling off the solvent. It was directly used in the next reaction without purification.

(2) Preparation of R-propylene carbonate (II)

Take a 50 mL three-neck flask with a spherical condenser, add a stirring magnet, and then measure 2 mL of absolute ethanol into the bottle. Weigh sodium methoxide (0.50 g, 0.009 mol), add diol (6.61 g, 89.7 mmol), heat to reflux for 30 minutes, slowly drop diethyl carbonate (12.98 g, 0.11 mol), control the rate of addition, the system releases hot. Reflux after the dropwise addition, white insoluble matter is produced, continue to heat to 120 oC, react for 2 hours, during which ethanol is continuously distilled out, the reaction is terminated, and unreacted diethyl carbonate is distilled out by vacuum distillation. Cool to room temperature and dilute with 20 mL of dichloromethane. The insoluble matter was filtered off, and the filtrate was evaporated to remove the solvent to obtain 6.9 g of the product, with a yield of 61.1%.

(3) Preparation of R-9-(2-hydroxypropyl)adenine (III)

Add adenine (10.0 g, 0.074 mol) into a 250 mL three-neck flask, fill with N ₂ for protection, then add 50 mL of DMF, add R-propylene carbonate (9.5 g, 0.092 mol), add NaOH (0.3 g, 0.0075 mol), stir at room temperature for 10 minutes, after the system is uniform, start to heat up to 120-130 oC, keep warm for reaction, TLC detection every 1 hour; when the reaction is complete, stop the reaction; slowly drop to 90 Below oC, start to add 60 mL of toluene, a large amount of white solids precipitate; after cooling down to room temperature, continue to drop to 0-5 oC, keep stirring for 2 hours; suction filter, wash the filter cake with 20 mL ice toluene to obtain a wet filter cake About 18 g, after drying, about 13-14 g of R-9- (2-hydroxypropyl) adenine, HPLC purity 80% -90%, melting point 185-195 oC; the obtained R-9- (2- Add 60 mL of ethanol and 10 mL of toluene to 13 g of hydroxypropyl) adenine product, heat up to dissolve, add 1.0 g of activated carbon, reflux for half an hour and remove the activated carbon by suction filtration while the filtrate is cooled to room temperature, and further cooled to 0 oC , vacuum filtration after heat preservation for 1 hour, and about 10.5 g of product R-9-(2-hydroxypropyl)adenine was obtained after drying, with an HPLC purity of over 98% and a molar yield of about 73%.

(4) Preparation of R-9-[2-(diethylphosphorylmethoxy)propyl]adenine (IV)

In a dry 100 mL four-neck flask, add R-9-(2-hydroxypropyl) adenine (10.0 g 0.052 mol), fill with N ₂ for protection, add DMF 20 mL; add magnesium tert-butoxide (9.0 g , 0.053 mol ), then heated up to 60-80 oC, and started to drop diethyl p-toluenesulfonyloxyphosphate (25 g, 0.077 mol ); control the rate of addition, and drop it in about 1 hour; Detect after 2 hours, when the R-9-(2-hydroxypropyl) adenine in the raw material is completely consumed, the reaction can be stopped; slowly cool down to room temperature, add (7.5 g, 0.124 mol) anhydrous acetic acid dropwise, about The dropwise addition was completed in 15 minutes; after the dropwise addition, stirred at room temperature for 30 minutes; the DMF was evaporated under reduced pressure, the maximum internal temperature was controlled below 100 oC, and evaporated to dryness in about 2 hours; after the evaporation was completed, 100 mL of dichloromethane was added, Cool to 25-30 oC, stir for 30 minutes; add 10 mL of water, a large amount of white solid precipitates out, keep stirring for 1 hour; remove the solid by suction filtration; stand to separate layers, and concentrate the dichloromethane layer to dryness to obtain the The four-step product R-9-[2-(diethylphosphorylmethoxy)propyl]adenine is 18 g, which is a light yellow oily substance with a purity of over 98% and a molar yield of about 95%.

(5) Preparation of Tenofovir (V)

Add R-9-[2-(diethylphosphorylmethoxy)propyl]adenine to 65 g of hydrobromic acid solution, heat up to 90-95 oC, and react for 6 hours to detect by-products in the reaction solution by HPLC. Product, the content of monoethyl ester should be below 1%, be cooled to room temperature, add 10 mL dichloromethane, layer after stirring for half an hour, get water layer, adjust the pH value of solution to 3.0% with 40% sodium hydroxide solution. 2 or so, a large amount of white solids were precipitated, stirred at room temperature for half an hour, continued to cool to 0-5 oC, and filtered with suction, the obtained white solids were refined with 15 times the amount of water to obtain about 8.0 g of the key intermediate tenofovir, Purity above 99%, molar yield 55%. [α] ^D ₂₅ = +22.3 (c 0.55, 0.1M HCl), Mp: 278-281 oC, ¹ H NMR (500MHz, D ₂ O): δ 8.24 (s , 2H), 4.31-4.14 (m, 2H), 4.10-3.94 (m, 1H), 3.72-3.45 (m, 2H), 1.10-1.07 (d, 3H).

Example 3 (1) Preparation of R-1,2-propanediol (I)

Take a 250 mL three-necked flask, add sodium borohydride (7.6 g, 0.20 mol), tert-butyl lactate (14.6 g, 0.10 mol) and cyclohexane (100 mL), stir at room temperature for 2 hours, then add 15 mL of methanol to stop the reaction , after cooling to room temperature, adjust the pH value to neutral with 5 mol/L hydrochloric acid, the system produces a large amount of insoluble matter, filter out the insoluble matter, and obtain the diol product after distilling off the solvent. It was directly used in the next reaction without purification.

(2) Preparation of R-propylene carbonate (II)

Take a 50 mL three-neck flask with a spherical condenser, add a stirring magnet, and then measure 2 mL of absolute ethanol into the bottle. Weigh sodium methoxide (0.50 g, 0.009 mol), add diol (6.61 g, 89.7 mmol), heat to reflux for 30 minutes, slowly drop diethyl carbonate (12.98 g, 0.11 mol), control the rate of addition, the system releases hot. Reflux after the dropwise addition, white insoluble matter is produced, continue to heat to 120 oC, react for 2 hours, during which ethanol is continuously distilled out, the reaction is terminated, and unreacted diethyl carbonate is distilled out by vacuum distillation. Cool to room temperature and dilute with 20 mL of dichloromethane. The insoluble matter was filtered off, and the filtrate was evaporated to remove the solvent to obtain 6.9 g of the product, with a yield of 61.1%.

(3) Preparation of R-9-(2-hydroxypropyl)adenine (III)

Add adenine (10.0 g, 0.074 mol) into a 250 mL three-neck flask, fill with N ₂ for protection, then add 50 mL of DMF, add R-propylene carbonate (9.5 g, 0.092 mol), add NaOH (0.3 g, 0.0075 mol), stir at room temperature for 10 minutes, after the system is uniform, start to heat up to 120-130 oC, keep warm for reaction, TLC detection every 1 hour; when the reaction is complete, stop the reaction; slowly drop to 90 Below oC, start to add 60 mL of toluene, a large amount of white solids precipitate; after cooling down to room temperature, continue to drop to 0-5 oC, keep stirring for 2 hours; suction filter, wash the filter cake with 20 mL ice toluene to obtain a wet filter cake About 18 g, after drying, about 13-14 g of R-9- (2-hydroxypropyl) adenine, HPLC purity 80% -90%, melting point 185-195 oC; the obtained R-9- (2- Add 60 mL of ethanol and 10 mL of toluene to 13 g of hydroxypropyl) adenine product, heat up to dissolve, add 1.0 g of activated carbon, reflux for half an hour and remove the activated carbon by suction filtration while the filtrate is cooled to room temperature, and further cooled to 0 oC , vacuum filtration after heat preservation for 1 hour, and about 10.5 g of product R-9-(2-hydroxypropyl)adenine was obtained after drying, with an HPLC purity of over 98% and a molar yield of about 73%.

(4) Preparation of R-9-[2-(diethylphosphorylmethoxy)propyl]adenine (IV)

In a dry 100 mL four-neck flask, add R-9-(2-hydroxypropyl) adenine (10.0 g 0.052 mol), fill with N ₂ for protection, add DMF 20 mL; add magnesium tert-butoxide (9.0 g , 0.053 mol ), then heated up to 60-80 oC, and started to drop diethyl p-toluenesulfonyloxyphosphate (25 g, 0.077 mol ); control the rate of addition, and drop it in about 1 hour; Detect after 2 hours, when the R-9-(2-hydroxypropyl) adenine in the raw material is completely consumed, the reaction can be stopped; slowly cool down to room temperature, add (7.5 g, 0.124 mol) anhydrous acetic acid dropwise, about The dropwise addition was completed in 15 minutes; after the dropwise addition, stirred at room temperature for 30 minutes; the DMF was evaporated under reduced pressure, the maximum internal temperature was controlled below 100 oC, and evaporated to dryness in about 2 hours; after the evaporation was completed, 100 mL of dichloromethane was added, Cool to 25-30 oC, stir for 30 minutes; add 10 mL of water, a large amount of white solid precipitates out, keep stirring for 1 hour; remove the solid by suction filtration; stand to separate layers, and concentrate the dichloromethane layer to dryness to obtain the The four-step product R-9-[2-(diethylphosphorylmethoxy)propyl]adenine is 18 g, which is a light yellow oily substance with a purity of over 98% and a molar yield of about 95%.

(5) Preparation of Tenofovir (V)

Add R-9-[2-(diethylphosphorylmethoxy)propyl]adenine to 65 g of hydrobromic acid solution, heat up to 90-95 oC, and react for 6 hours to detect by-products in the reaction solution by HPLC. Product, the content of monoethyl ester should be below 1%, be cooled to room temperature, add 10 mL dichloromethane, layer after stirring for half an hour, get water layer, adjust the pH value of solution to 3.0% with 40% sodium hydroxide solution. 2 or so, a large amount of white solids were precipitated, stirred at room temperature for half an hour, continued to cool to 0-5 oC, and filtered with suction, the obtained white solids were refined with 15 times the amount of water to obtain about 8.0 g of the key intermediate tenofovir, Purity above 99%, molar yield 55%. [α] ^D ₂₅ = +22.3 (c 0.55, 0.1M HCl), Mp: 278-281 oC, ¹ H NMR (500MHz, D ₂ O): δ 8.24 (s , 2H), 4.31-4.14 (m, 2H), 4.10-3.94 (m, 1H), 3.72-3.45 (m, 2H), 1.10-1.07 (d, 3H).

Claims (2)

1. the synthesis technique of Tenofovir is characterized in that it is carried out according to the following steps: (1) Add (R)-lactate, reducing agent and solvent into the reaction bottle, the molar ratio of reducing agent to lactate is 1:1-2:1, stir at room temperature for 2 hours, then slowly add methanol dropwise, Cool to room temperature and use hydrochloric acid to adjust the pH value to neutral, filter out the insoluble matter, evaporate the solvent to obtain R-1,2-propanediol, and directly use it in the next step without purification; (2) Add alkali and R-1,2-propanediol in the reaction bottle, the molar ratio of alkali and R-1,2-propanediol is 1:100-1:10, heat to reflux for 30 minutes, slowly drop dicarbonate Ethyl ester; reflux after the dropwise addition, white insoluble matter is produced, continue to heat to 120 oC, react for 2 hours, the reaction is terminated, distill the unreacted diethyl carbonate under reduced pressure, cool to room temperature, and dichloromethane Dilution; filter out insolubles, obtain product R-propylene carbonate after the filtrate is evaporated to remove solvent; (3) Add adenine, R-propylene carbonate, DMF and NaOH into the reaction flask, stir at room temperature for 10 minutes, after the system is uniform, start to heat up to 120-130 oC, keep warm for reaction, TLC detection every 1 hour; when the reaction Complete, the reaction can be stopped; slowly lowered to below 90 oC, began to add toluene, and a large amount of white solids precipitated; after cooling down to room temperature, continued to drop to 0-5 oC, kept stirring for 2 hours; suction filtered, soaked in ice toluene The filter cake is dried to obtain R-9-(2-hydroxypropyl) adenine; the obtained R-9-(2-hydroxypropyl) adenine product is added to ethanol and toluene, heated to dissolve, and gac is added. After refluxing for half an hour, remove gac by suction filtration while hot, the filtrate is down to room temperature, further cooled to 0 o C, suction filtration after insulation for 1 hour, and obtain product R-9-(2-hydroxypropyl)adenine after drying; (4) Add R-9-(2-hydroxypropyl) adenine, magnesium tert-butoxide and solvent DMF into the reaction flask, then raise the temperature to 60-80 oC, and start to add p-toluenesulfonyloxy diethyl phosphate dropwise Ester; control the rate of addition, and drop it in about 1 hour; detect it after 2 hours of dropping, and stop the reaction when the adenine is completely consumed; slowly drop to room temperature, add anhydrous acetic acid dropwise; after dropping, stir at room temperature for 30 Minutes; DMF was evaporated under reduced pressure, and the maximum internal temperature was controlled below 100 oC; after the evaporation was completed, dichloromethane was added, naturally cooled to 25-30 oC, and stirred for 30 minutes; water was added, a large amount of white solids were precipitated, and the temperature was kept Stir for 1 hour; suction filter to remove the solid; stand to separate the layers, and concentrate the dichloromethane layer to dryness to obtain the product R-9-[2-(diethylphosphorylmethoxy)propyl]adenine; (5) Add R-9-[2-(diethylphosphorylmethoxy)propyl]adenine and hydrobromic acid aqueous solution into the reaction flask, heat up to 90-95 oC, and react for 6 hours to detect the reaction by HPLC The by-product in the solution, the content of monoethyl ester should be below 1%, cool down to room temperature, add methylene chloride, layer after stirring for half an hour, take the water layer, adjust the pH value of the solution to 3.2 with sodium hydroxide solution Around, a large amount of white solid precipitated, stirred at room temperature for half an hour, continued to cool to 0-5 oC, filtered with suction, and purified the obtained white solid with water to obtain Tenofovir. 2. The synthesis process of Tenofovir according to claim 1, characterized in that the reducing agent in the step (1) is sodium borohydride, lithium aluminum hydride; the solvent is toluene, cyclohexane or Tetrahydrofuran.