KR102379965B1 - Efficient preparation method of Tenofovir - Google Patents

Abstract

The present invention reacts (R)-9-[2-(hydroxy)propyl]adenine (HPA) with diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) using a magnesium catalyst to produce (R)- 9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) is synthesized and then dealkylated to prepare a high yield and high purity tenofovir (PMPA).

Description

Efficient preparation method of Tenofovir

The present invention relates to a method for preparing tenofovir ((R)-9-[2-(Phosphonomethoxy)propyl]adenine, PMPA) in high yield and high purity using a magnesium catalyst.

Tenofovir disoproxil (TD) has the IUPAC name (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)phosphoryl)bis A compound of (oxy)bis(methylene)isopropyl dicarbonate, a phosphonomethoxy nucleotide analogue useful for the treatment of HIV-1 infection and hepatitis B. When administered orally as a prodrug, this drug is metabolized to tenofovir ((R)-9-[2-(phosphonomethoxy)propyl]adenine, hereinafter PMPA) in the form of phosphonic acid in which disoproxyl group is hydrolyzed. It becomes active and is currently sold in the form of fumarate (Viread, Viread, TDF).

Korean Patent Application Laid-Open No. 2000-29705 discloses (R)-9-[2-(hydroxy)propyl]adenine (HPA) in dimethylformamide with diethyl p-toluenesulfonyloxymethyl as shown in Scheme 1 below. (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) was prepared by reaction with phosphonate (DESMP) and lithium t-butoxide, which was then prepared by bromotrimethyl in acetonitrile A method for dealkylation using a silane is presented.

[Scheme 1]

In addition, Korean Patent Application Laid-Open No. 2006-105807 discloses (R)-9-[2-(hydroxy)propyl]adenine (HPA) and diethyl p-toluenesulfonyloxymethylphosphonate as shown in Scheme 2 below. (DESMP) was reacted with magnesium t-butoxide in dimethylformamide to prepare (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA), followed by use of bromotrimethylsilane Thus, a method for dealkylation was proposed.

[Scheme 2]

The above methods use lithium or magnesium alkoxide (C1-C6) with (R)-9-[2-(hydroxy)propyl]adenine (HPA) and diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) ), but there is a problem with the risk due to the process of injecting the solid reagent at high temperature and the non-uniformity of the reaction.

Accordingly, the present inventors prepared a magnesium base catalyst in-situ , followed by (R)-9-[2-(hydroxy)propyl]adenine (HPA) and diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) reacted to synthesize (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) in high yield and high purity, and using this, tenofovir (PMPA) can be effectively prepared. As a result, the present invention was completed.

In the present invention, (R)-9-[2-(hydroxy)propyl]adenine (HPA) and diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) are reacted using a magnesium catalyst to react (R)- An object of the present invention is to provide a method for preparing high yield and high purity tenofovir (PMPA) by synthesizing 9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) and dealkylating it.

The present invention relates to (a) reacting (R)-9-[2-(hydroxy)propyl]adenine (HPA) and diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) using a magnesium catalyst ( preparing R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA), (b) (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine Provided is a method for the preparation of tenofovir ((R)-9-[2-(phosphonomethoxy)propyl]adenine, PMPA) comprising the step of dealkylating (DPPA).

The magnesium catalyst used in the present invention is in the form of magnesium alkoxide, and magnesium octan-1-oleate, magnesium octan-2-oleate, magnesium 3-ethyl-3-pentanolate, and the like may be used.

In addition, the magnesium catalyst used in the present invention may be used as a magnesium catalyst system by reacting methyl magnesium chloride or di-n-butyl magnesium with 1-octanol, 2-octanol, 3-ethyl-3-pentanol, and the like.

The method for preparing tenofovir ((R)-9-[2-(phosphonomethoxy)propyl]adenine, PMPA) according to the present invention is performed by using a catalyst composed of magnesium metal and C7~C8 alcohol in-situ . , (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) can be synthesized with high yield and purity compared to conventionally known lithium alkoxide or magnesium alkoxide (C1-C6), This has the advantage of being able to mass-produce tenofovir (PMPA).

1 is a nuclear magnetic resonance analysis ( ¹ H NMR) results of tenofovir (PMPA) synthesized in Examples 2 to 5.
2 is a nuclear magnetic resonance analysis ( ¹ H NMR) result of tenofovir disoproxil fumarate (TDF) synthesized in Example 6.

The present invention provides a method for preparing Chemical Formula 4 by reacting Chemical Formulas 1 and 2 under a magnesium catalyst to prepare Chemical Formula 3, and then dealkylating it.

[Formula 1]

(HPA)

(HPA)

[Formula 2]

(DESMP)

(DESMP)

[Formula 3]

(DPPA)

(DPPA)

[Formula 4]

(PMPA)

(PMPA)

Specifically, the preparation method of tenofovir (PMPA) of the present invention is shown in Scheme 3 below.

[Scheme 3]

(wherein R ₁ is 1-octyl, 2-octyl or 3-ethyl-3-pentyl)

Specifically,

[Step 1] Under a magnesium catalyst, (R)-9-[2-(hydroxy)propyl]adenine (HPA, Formula 1) was reacted with diethyl p-toluenesulfonyl oxymethylphosphonate (DESMP, Formula 2) with reacting to prepare (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA, Formula 3);

[Step 2] Dealkylation of (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA, Formula 3) to (R)-9-[2-(phosphonomethoxy)propyl ] including the step of preparing adenine (PMPA, Formula 4).

In this case, the magnesium catalyst may be magnesium alkoxide or methyl magnesium chloride, but is not limited thereto.

The manufacturing method of the present invention will be described in more detail as follows.

[Step 1]

DPPA Manufacturing method

Manufacturing method 1

(R)-9-[2-(hydroxy)propyl]adenine (HPA, Formula 1) and diethyl p-toluenesulfonyloxymethylphosphonate (DESMP, Formula 2) are reacted with magnesium alkoxide represented by Formula 5 below (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA, Formula 3) is prepared by reacting in an organic solvent under

[Formula 5]

(Here, R ₁ is 1-octyl, 2-octyl or 3-ethyl-3-pentyl, etc.)

In this case, as the organic solvent, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, and a solvent composed of single or mixed solvents thereof may be used, but not limited thereto. does not

In addition, 1 to 4 equivalents of diethyl p-toluenesulfonyloxymethylphosphonate (DESMP, Formula 2) based on (R)-9-[2-(hydroxy)propyl]adenine (HPA, Formula 1) It can be used in the range of, and preferably can be used in the range of 2 equivalents to 3 equivalents.

In addition, the magnesium alkoxide (Formula 5) may be used in the range of 2 to 8 equivalents, preferably in the range of 3 to 4 equivalents.

The reaction temperature may be in the range of 60 °C to 100 °C, preferably in the range of 70 °C to 80 °C.

In addition, the reaction time may be in the range of 2 to 6 hours, preferably 3 to 4 hours.

The magnesium alkoxide represented by Formula 5 may be prepared by reacting di-n-butyl magnesium with an alkyl alcohol as shown in Scheme 4 below.

[Scheme 4]

More specifically, a magnesium alkoxide may be prepared by cooling a C7 to C8 alkyl alcohol to 0° C. and then injecting di-n-butyl magnesium. Here, the C7~C8 alcohol may preferably be 1-octanol, 2-octanol or 3-ethyl-3-pentane, but is not limited thereto.

In this case, di-n-butyl magnesium may be used in an amount of 0.5 to 5 equivalents based on 1 equivalent of alcohol, and preferably in an amount of 0.5 to 1 equivalent.

The reaction temperature may be in the range of 0 °C to 40 °C, preferably in the range of 20 °C to 40 °C.

In addition, the reaction time may be in the range of 1 to 4 hours, preferably in the range of 1 to 2 hours.

The magnesium alkoxide of the present invention may be selected from the group consisting of the following Chemical Formulas 6 to 8, but is not limited thereto.

[Formula 6]

(magnesium 3-ethyl-3-pentanolate)

[Formula 7]

(magnesium 1-octanolate)

[Formula 8]

(magnesium 2-octanolate)

Manufacturing method 2

(R)-9-[2-(hydroxy)propyl]adenine (HPA, formula 1) with diethyl p-toluenesulfonyloxymethylphosphonate (DESMP, formula 2), methyl magnesium chloride and an alkyl alcohol (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA, Formula 3) is prepared by reaction in a solvent.

In this case, as the organic solvent, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, and a solvent composed of single or mixed solvents thereof may be used, but not limited thereto. does not

In addition, methyl magnesium chloride and C7-C8 alcohol may be used in the range of 1 to 4 equivalents, respectively, based on (R)-9-[2-(hydroxy)propyl]adenine (HPA, Formula 1), preferably may be in the range of 2 equivalents to 3 equivalents.

The reaction temperature may be in the range of 60 °C to 100 °C, preferably in the range of 70 °C to 80 °C.

In addition, the reaction time may be 2 to 6 hours, preferably 3 to 4 hours.

More specifically, methyl magnesium chloride may be reacted with C7~C8 alkyl alcohol to prepare DPPA. Here, the C7~C8 alkyl alcohol may preferably be 3-ethyl-3-pentanol, 1-octanol or 2-octanol, but is not limited thereto.

[Step 2]

PMPA Manufacturing method

(R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA, Formula 3) may be prepared by any known dealkylation method. For example, (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA, Chemical Formula 4) may be synthesized through the method disclosed in Korean Patent Application Laid-Open No. 2000-29705.

In an embodiment of the present invention, (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) is reacted with bromotrimethylsilane in an organic solvent to dealkylate (R)-9- [2-(phosphonomethoxy)propyl]adenine (PMPA, Formula 4) can be prepared.

More specifically, (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA, Formula 3) was dissolved in an organic solvent, bromotrimethylsilane was injected and stirred, and the reaction solution was Concentration and crystallization with an organic solvent and water can prepare (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA, Chemical Formula 4).

In this case, bromotrimethylsilane may be used in an amount of 1 to 5 equivalents, and preferably 3 to 4 equivalents.

As the organic solvent, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, etc. may be used alone or in combination. not limited

In addition, methanol, ethanol, propanol, butanol, t-butanol, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, water, etc. are used as the organic solvent used for the crystallization. It may be used alone or in combination, but is not limited thereto.

Preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the content of the present invention is not limited by the examples.

The reagents and solvents mentioned below were purchased from Sigma-Aldrich and TCI unless otherwise specified, 1H NMR data were measured using a Buruker DPX 400, and HLPC was measured using Agilent Technoliges' 1200 Series.

The HPLC conditions used in the present invention were as follows, and the purity was measured after the reaction or in the reaction mixture.

- Detector: Ultraviolet absorbance spectrometer (measurement wavelength: 260 nm)

- Column : Hypersil ODS (4.6 mm X 250 mm, 5 μm)

- Mobile phase A: After dissolving 11.94 g of potassium dihydrogen phosphate and 2.14 g of potassium monohydrogen phosphate in 2 L of water, titrate pH 6.0 with dilute phosphoric acid.

- Mobile phase B: Mobile phase A and acetonitrile 7: 3 mixed solution

- Flow rate: 0.5 mL / min

- Sample: 25 mg / 10 mL of mobile phase A

- Injection volume: 20 μl

Magnesium Octane-2- oleate Produce

57.2 mL (0.36 mol) of 2-octanol was placed in a 500 mL-three round flask, cooled to 0°C, 180 mL (0.18 mol) of a 1.0M dibutylmagnesium n-heptane solution was injected, and stirred at 25°C for 2 hours. Then, it was used in-situ for the reaction.

of tenofovir (PMPA) synthesis

1) (R)-9-[2-(hydroxy)propyl]adenine (HPA) 7.25g (0.0375mol), 73mL of dimethylformamide were placed in a 250mL-samguround flask, and the temperature was raised to 75℃ while stirring, and then 75 Magnesium octan-2-oleate (0.15 mol) synthesized in Example 1 was added while maintaining ℃, and stirred at 75 ℃ for 1 hour.

2) At the same temperature, 30.2 g (0.0938 mol) of diethyl ρ-toluenesulfonyloxymethyl phosphonate (DESMP) was added, and the mixture was stirred at 80° C. for 3 hours.

3) After cooling to 25° C. and standing to separate the layers, the upper layer was discarded, and 108 mL of saturated sodium chloride aqueous solution was added to the lower layer and stirred for 10 minutes.

4) Celite was filtered to remove suspended solids, and the organic layer obtained by extraction with 73 mL of dichloromethane three times was dried over 7.3 g of anhydrous magnesium sulfate and concentrated under reduced pressure to form (R)-9-[2-(diethylphosphono) in the form of an oil. Methoxy)propyl]adenine (DPPA) was obtained.

5) To the obtained residue, 7.3 mL of acetonitrile and 19.4 mL of bromotrimethylsilane were injected, and the mixture was stirred at 65° C. for 1 hour.

6) The reaction solution was cooled to 25° C., concentrated under reduced pressure, and completely dissolved by adding 7.3 mL of water and 73 mL of methanol. Then, titrated to pH 3.0 using 20% aqueous sodium hydroxide solution, stirred at 25° C. for 2 hours, the resulting crystals were filtered, washed with 36.3 mL of water and 14.5 mL of acetone, and 6.7 g of crude tenofovir (yield 62.2%) ) was obtained.

7) 124 mL of water was added to 6.7 g of the crude tenofovir (PMPA), the temperature was raised to 95° C., and completely dissolved, then slowly cooled to 0-5° C. and stirred for 3 hours.

8) The resulting crystals were filtered and washed with 34 mL of water and 13 mL of acetone to obtain 6.0 g of tenofovir (PMPA) (yield 90%).

Purity : 99.4% by HPLC

¹ H NMR (D ₂ O, 400 MHz): δ 1.16 (d, 3H), 3.49 (dd, 1H), 3.68 (dd, 1H), 3.99 (m, 1H), 4.28 (dd, 1H), 4.47 ( dd, 1H), 8.38 (d, 2H).

of tenofovir (PMPA) synthesis

1) (R)-9-[2-(hydroxy)propyl]adenine (HPA) 3.3g (0.017mol) and cyclohexane 20mL were placed in a 100mL-three-round flask and stirred while stirring, 3-ethyl-3-pentanol 3.65 mL (0.0259 mol) was added.

2) The reaction mixture was cooled to 0-5° C., and 8.65 mL (0.0259 mol) of 3M methyl magnesium chloride was slowly added dropwise, followed by stirring at the same temperature for 30 minutes.

3) 13.7 g (0.0425 mol) of diethyl p-toluenesulfonyloxymethyl phosphonate (DESMP) was added while maintaining the temperature at 5° C. or less, and after stirring at 75° C. for 3 hours, the reaction solution was concentrated under reduced pressure.

4) The obtained residue was dissolved in 33 mL of water, and extracted twice with 33 mL of chloroform.

5) 10.0 mL of 2N hydrochloric acid solution was added to the obtained organic layer, stirred for 10 minutes, the aqueous layer was separated, and 25% aqueous ammonia was added thereto, followed by titration to pH 11.

6) The organic layer was extracted twice with 33 mL of dichloromethane, dried over 3.5 g of anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.9 g of (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) It was obtained (yield 66%).

7) To the obtained (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) 3.9g (0.0099mol), 4mL of acetonitrile and 5.5mL (0.0455mol) of bromotrimethylsilane were added After stirring at 65° C. for 1 hour, it was concentrated under reduced pressure.

8) 4 mL of water and 40 mL of methanol were added to the obtained residue to completely dissolve, and the pH was adjusted to 3.0 using 20% sodium hydroxide aqueous solution, followed by stirring at 25° C. for 2 hours.

9) The resulting crystals were filtered and washed with 8 mL of water and 6 mL of acetone to obtain 3.0 g of zotenofovir (yield 93%).

10) 56 mL of water was added to 3.0 g of the crude tenofovir (PMPA), the temperature was raised to 95° C., and completely dissolved, then slowly cooled to 0-5° C. and stirred for 3 hours.

11) The resulting crystals were filtered and washed with 45 mL of water and 18 mL of acetone to obtain 2.7 g of tenofovir (PMPA) (yield 90%).

Purity : 99.3% by HPLC

of tenofovir (PMPA) synthesis

1) (R)-9-[2-(hydroxy)propyl]adenine (HPA) 2.9g (0.015mol) and 17.4mL cyclohexane were put in a 100mL-samgu round flask, stirred, and then 1-octanol 3.54mL (0.0225 mol) was added.

2) The reaction mixture was cooled to 0-5° C., and 7.5 mL (0.0225 mol) of 3M methyl magnesium chloride was slowly added dropwise, followed by stirring at 0-5° C. for 30 minutes.

3) 12.09 g (0.0375 mol) of diethyl p-toluenesulfonyloxymethyl phosphonate (DESMP) was added while maintaining the temperature at 5° C. or less, and after stirring at 75° C. for 3 hours, the reaction solution was concentrated under reduced pressure.

4) The obtained residue was dissolved in 29 mL of water, and extracted twice with 29 mL of chloroform.

5) 8.7 mL of 2N hydrochloric acid solution was added to the obtained organic layer, stirred for 10 minutes to separate the aqueous layer, and then 25% aqueous ammonia was added thereto, followed by titration to pH 11.

6) The organic layer obtained by extraction twice with 29 mL of dichloromethane was dried over 3 g of anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 3.5 g of (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) (yield 68%).

7) (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) 3.5g (0.0102mol) was added with 4mL of acetonitrile and 4.98mL of bromotrimethylsilane (0.0377mol) at 65℃ After stirring for 1 hour, it was concentrated under reduced pressure.

8) 4 mL of water and 40 mL of methanol were added to the obtained residue to completely dissolve, and the pH was adjusted to 3.0 using 20% sodium hydroxide aqueous solution, followed by stirring at 25° C. for 2 hours.

9) The resulting crystals were filtered and washed with 8 mL of water and 6 mL of acetone to obtain 2.61 g of zotenofovir (yield 89%).

10) 49 mL of water was added to 2.61 g of the crude tenofovir (PMPA), the temperature was raised to 95° C., and completely dissolved, then slowly cooled to 0-5° C. and stirred for 3 hours.

11) The resulting crystals were filtered and washed with 40 mL of water and 16 mL of acetone to obtain 2.32 g of tenofovir (PMPA) (yield 89%).

Purity : 99.3% by HPLC

of tenofovir (PMPA) synthesis

1) (R)-9-[2-(hydroxy)propyl]adenine (HPA) 2.9g (0.015mol) and cyclohexane 17.4mL into a 100mL-samgu round flask, with stirring, 2-octanol 3.58mL (0.0225 mol) was added.

2) The reaction mixture was cooled to 0-5° C., and 7.5 mL (0.0225 mol) of 3M methyl magnesium chloride was slowly added dropwise, followed by stirring at the same temperature for 30 minutes.

3) 12.09 g (0.0375 mol) of diethyl p-toluenesulfonyloxymethyl phosphonate (DESMP) was added while maintaining the temperature at 5° C. or less, and after stirring at 75° C. for 3 hours, the reaction solution was concentrated under reduced pressure.

4) The obtained residue was dissolved in 29 mL of water, and extracted twice with 29 mL of chloroform.

5) 8.7 mL of a 2N hydrochloric acid solution was added to the obtained organic layer, stirred for 10 minutes, the aqueous layer was separated, and 25% aqueous ammonia was added thereto, followed by titration to pH 11.

6) The organic layer was extracted twice with 29 mL of dichloromethane, dried over 3 g of anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.3 g of (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) (yield 64%).

7) (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) 3.3g (0.0096mol), acetonitrile 4mL and bromotrimethylsilane 4.83mL (0.0355mol) were added, and 65℃ After stirring for 1 hour, it was concentrated under reduced pressure.

8) 4 mL of water and 40 mL of methanol were added to the obtained residue to completely dissolve, and the pH was adjusted to 3.0 using 20% sodium hydroxide aqueous solution, followed by stirring at 25° C. for 2 hours.

9) The resulting crystals were filtered and washed with 8 mL of water and 6 mL of acetone to obtain 2.58 g of zotenofovir (yield 93%).

10) 49 mL of water was added to 2.58 g of the crude tenofovir (PMPA), the temperature was raised to 95° C., and completely dissolved, then slowly cooled to 0-5° C. and stirred for 3 hours.

11) The resulting crystals were filtered and washed with 40 mL of water and 16 mL of acetone to obtain 2.27 g of tenofovir (PMPA) (yield 88%).

Purity : 99.4% by HPLC

tenofovir disoproxil of fumarate (TDF) synthesis

1) To 8.0 g of tenofovir (PMPA), 30 mL of N-methylpyrrolidone and 11.6 mL of triethylamine were added, and the reaction solution was heated to 60° C. and stirred for 30 minutes.

2) At 60°C, 20 g of chloromethyl isopropyl carbonate was added, and after stirring at the same temperature for 4 hours, the mixture was cooled to 5°C, and 50 mL of water was slowly added thereto.

3) After stirring at 15°C for 1 hour, the organic layer obtained by extraction twice with 30 mL of dichloromethane was separated and washed twice with 20 mL of water.

4) The organic layer was dried with 5 g of anhydrous magnesium sulfate and concentrated under reduced pressure to obtain tenofovir disoproxil in the form of an oil.

5) 70 mL of isopropyl alcohol and 3.2 g of fumaric acid were added to the oily residue, and the temperature was raised to about 50° C. to completely dissolve it.

6) The reaction solution was cooled slowly to 5°C, stirred for 3 hours, and the resulting crystals were filtered and washed with 20 mL of isopropyl alcohol.

7) The obtained solid was vacuum dried at 40° C. to obtain 9.4 g (yield 53%) of crude tenofovir disoproxil fumarate (TDF).

8) 80 mL of isopropyl alcohol was injected into 9.4 g of tenofovir disoproxil fumarate (TDF), and the temperature was raised to about 50° C. to completely dissolve it.

9) The reaction solution was cooled slowly to 5°C, stirred at 5°C for 3 hours, the resulting crystals were filtered, washed with 100 mL of isopropyl alcohol, and vacuum dried at 40°C, tenofovir disoproxil fumarate (TDF) ) 8.6 g (yield 90%) was obtained.

¹ H NMR (D ₂ O, 400 MHz): δ 1.20 (m, 15H), 3.75 (dd, 1H), 3.90 (d, 1H), 4.02 (dd, 1H), 4.17 (dd, 1H), 4.37 ( d, 1H), 4.84 (m, 2H), 5.41 (m, 4H), 6.61 (s, 2H), 8.18 (s, 1H), 8.29 (s, 1H).

Claims (7)

(R)-9-[2-(hydroxy)propyl]adenine (HPA) of the following formula (1) and diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) of the following formula (2) were reacted under a magnesium catalyst to obtain the following A first step of preparing (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) of Formula 3; and
a second step of dealkylating (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) of Formula 3 obtained in the first step,
The magnesium catalyst is a magnesium alkoxide of formula 5 or methyl magnesium chloride,
The methyl magnesium chloride is (R)-9-[ of the following formula 4, characterized in that it is used together with an alkyl alcohol selected from the group consisting of 3-ethyl-3-pentanol, 1-octanol and 2-octanol. Method for preparing 2- (phosphonomethoxy) propyl] adenine (PMPA):

[Formula 1]

(HPA)

[Formula 2]

(DESMP)

[Formula 3]

(DPPA)

[Formula 4]

(PMPA)

[Formula 5]

(wherein R ₁ is 1-octyl, 2-octyl or 3-ethyl-3-pentyl)
delete (R)-9-[ according to claim 1 , wherein the magnesium alkoxide is selected from the group consisting of magnesium 3-ethyl-3-pentanolate, magnesium 1-octanolate and magnesium 2-octanolate. A process for the preparation of 2-(phosphonomethoxy)propyl]adenine (PMPA).
The preparation of (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA) according to claim 1, wherein the magnesium alkoxide is prepared by reacting di-n-butylmagnesium with an alkyl alcohol. method.
delete The method of claim 1, wherein the dealkylation in the second step is a reaction of (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (DPPA) of Formula 3 with bromotrimethylsilane in an organic solvent. (R)-9- [2- (phosphonomethoxy) propyl] adenine (PMPA) production method, characterized in that
The method according to claim 1, wherein the reaction of the first and second steps is dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, and mixed solvents thereof. A method for producing (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA), characterized in that it is carried out in an organic solvent selected from the group consisting of

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