KR101703257B1 - Preparation method for (r)-9-[2-(phosphonomethoxy)propyl]adenine with high purity - Google Patents

Abstract

The present invention relates to a process for producing (R) -9- [2- (phosphonomethoxy) propyl] adenine (PMPA) of high purity and which has a high purity (Phosphoryl) methylnaphthalene-1-sulfonate or (diethoxyphosphoryl) methylnaphthalene-2-sulfonate is used as an intermediate, PMPA having high purity can be produced. Particularly, (diethoxyphosphoryl) methylnaphthalene-1-sulfonate is a solid material, which is easy to handle when used in the production of PMPA, and is suitable for mass production and can be produced in homogeneous and constant quality, It has advantages. In addition, it does not use reagents sensitive to moisture and air contact, so it is safe, reproducible and suitable for mass production. Also, since PMPA prepared by the method of the present invention has a very high purity, it can be advantageously used to produce a high-quality raw material medicine because it can produce telopoxil and its acid addition salt in high purity.

Description

METHOD FOR PREPARING (R) -9- [2- (PHOSPHONOMETHOXY) PROPYL] ADENINE WITH HIGH PURITY} The present invention relates to a process for producing (R) -9- [2- (phosphonomethoxy)

The present invention relates to a process for preparing high purity (R) -9- [2- (phosphonomethoxy) propyl] adenine (PMPA).

(TDF, tenofovir disoproxil fumarate, chemical name: 9 - [ (R) -2 - [[Bis [[(isopropoxycarbonyl) oxy] methoxy] phosphinyl] methoxy] propyl ] Adenine fumarate) is a kind of prodrug which is usefully used as a raw material for medicines in the treatment of hepatitis B disease or acquired immune deficiency diseases. When administered orally, the phospholipid form (R) -9- [2- (phosphonomethoxy) propyl] adenine, PMPA).

TDF has been sold in a variety of trade names currently in the world, for example, AIDS true ocean as a deficiency disease treatment (Truvada ^®), art ripple LA (Atripla ^®), comb player called (Complera ^®) and registry building (Stribild ^® ), And Viread ( ^R ) is being marketed as a treatment for hepatitis B disease.

Various methods for manufacturing TDF are known as follows.

Korean Patent Laid-Open Publication No. 2000-29705 discloses a process for producing (R) -9- [2- (hydroxy) propyl] adenine (HPA) in diethyl p -toluenesulfonyloxymethyl Phosphonate (DESMP) and lithium t -butoxide to produce an intermediate, which is then dealkylated in acetonitrile using bromotrimethylsilane.

[Reaction Scheme 1]

Korean Patent Laid-Open Publication No. 2006-105807 discloses a process for producing an intermediate by reacting HPA and DESMP with magnesium t -butoxide in dimethylformamide as shown in Reaction Scheme 2 below, dealkylating the intermediate using bromotrimethylsilane A method is disclosed.

[Reaction Scheme 2]

In addition, International Patent Publication No. WO 2014/033688 discloses a process for the preparation of 2,2,6,6-trichloro- p -toluenesulfonyloxymethylphosphonate or dialkylmethylsulfonyloxymethylphosphonate in an organic solvent containing an alcohol, , 6-tetramethylpiperidinyl magnesium to produce an intermediate, followed by dealkylation.

The above methods all involve the production of (R) -9- [2- (phosphonomethoxy) propyl] adenine (PMPA) which is a key intermediate used for the preparation of tenofovir disoproxyl and its acid addition salts , Wherein the leaving group of the starting material used in the reaction has a structure containing a p -toluenesulfonyl group. Since this raw material is present in a liquid phase, purification and handling are difficult, and it is very difficult to produce the raw material with high purity. Therefore, the production of PMPA of high purity by minimizing the generation of impurities in the intermediate production step is essential for producing high purity cannabisidicloxyl and its acid addition salt meeting the needs of the pharmaceutical industry.

Accordingly, the present inventors have conducted a series of studies to produce high purity PMPA It has been found that when HPA is reacted with (diethoxyphosphoryl) methylnaphthalene-1-sulfonate or (diethoxyphosphoryl) methylnaphthalene-2-sulfonate and magnesium alkoxide, PMPA of high purity can be produced, It was completed.

Korean Patent Publication No. 2000-29705 Korean Patent Publication No. 2006-105807 International Patent Publication No. WO 2014/033688

Accordingly, an object of the present invention is to provide a process for preparing high purity (R) -9- [2- (phosphonomethoxy) propyl] adenine.

According to the above object, the present invention provides a process for preparing a compound represented by the formula (1): (1) reacting a compound represented by the following formula 3 with a compound represented by the following formula 4-1 or a compound represented by the formula 4-2 and magnesium alkoxide; And (2) the compound of formula (5) obtained in step (1) The compound is dealkylated to give a compound of formula (R) -9- [2- (phosphonomethoxy) propyl] adenine, comprising the step of:

(3)

[Formula 4-1]

[Formula 4-2]

[Chemical Formula 5]

[Chemical Formula 6]

In the general formulas (4-1), (4-2) and (5), R ₁ is C _1-6 alkyl.

The process for producing (R) -9- [2- (phosphonomethoxy) propyl] adenine (PMPA) according to the present invention is advantageous in that the reaction process is easy, Since methylnaphthalene-1-sulfonate or (diethoxyphosphoryl) methylnaphthalene-2-sulfonate is used as an intermediate, PMPA having high purity can be produced.

Particularly, (diethoxyphosphoryl) methylnaphthalene-1-sulfonate is a solid substance, which is easier to handle in the production of PMPA than diethyl p -toluenesulfonyloxymethylphosphonate, which is already known oil, and is suitable for mass production Since it is a solid substance, it is possible to produce a homogeneous and uniform quality than the oil phase material, so that it is possible to input the exact equivalent amount during the reaction.

In addition, since it does not use water and air-sensitive reagents like Grignard reagent, it is safe, reproducible production, easy handling of magnesium alkoxide used in reaction, Have.

In addition, since the PMPA prepared by the method of the present invention has a very high purity, the acid addition salt of terfenoviride sofferoxyl (TD) and terfenoviride sofferoxyl (TD) can be produced with high purity It is very advantageous to produce high quality raw medicine.

Hereinafter, the present invention will be described more specifically.

The process for producing (R) -9- [2- (phosphonomethoxy) propyl] adenine (PMPA) according to the present invention comprises: (1 ) (Diethoxyphosphoryl) methylnaphthalene-1-sulfonate (Compound 4-1) or (diethoxyphosphoryl) methylnaphthalene-2-sulfo (Compound 4-2) and magnesium alkoxide to prepare (R) -9- [2- (dialkylphosphonomethoxy) propyl] adenine (Compound 5); And (2) (R) -9- [ 2- ( dialkyl phosphono-methoxy) propyl] adenine by de-alkylation (Compound 5) (R) -9- [2- ( phosphono-methoxy) propyl] adenine (Compound 6).

[Reaction Scheme 3-1]

[Reaction Scheme 3-2]

In the above Reaction Schemes 3-1 and 3-2, R ₁ is C _1-6 alkyl.

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

The procedure of step (1)

First, in step (1), (diethoxyphosphoryl) methylnaphthalene-1-sulfonate or (diethoxyphosphoryl) methylnaphthalene-2-sulfonate is reacted with (R) -9- [2- ) Propyl] adenine and magnesium alkoxide to produce (R) -9- [2- (dialkylphosphonomethoxy) propyl] adenine.

More specifically, after adding (R) -9- [2- (hydroxy) propyl] adenine and a magnesium alkoxide to an organic solvent and stirring the solution, (diethoxyphosphoryl) methylnaphthalene-1-sulfonate or (diethoxyphosphine) Methyl-naphthalene-2-sulfonate is added and stirred. The reaction product is cooled and concentrated, an organic solvent is added to precipitate a solid, the reaction product is filtered, and the filtrate is concentrated again to obtain (R) -9- [2- (dialkylphosphonomethoxy) propyl] adenine .

Examples of the magnesium alkoxide include magnesium methoxide, magnesium ethoxide, magnesium propoxide, magnesium butoxide, and magnesium t -butoxide.

The magnesium alkoxide may be used in an amount of 0.9 to 3 equivalents based on 1 equivalent of (R) -9- [2- (hydroxy) propyl] adenine, preferably 1 to 2 equivalents .

Examples of the organic solvent used in the reaction include organic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, Can be used.

Examples of the organic solvent used for separation (solid precipitation) include dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, hexane, heptane, cyclohexane, etc. Or may be used in combination.

The (diethoxyphosphoryl) methylnaphthalene-1-sulfonate or (diethoxyphosphoryl) methylnaphthalene-2-sulfonate is added in an amount of 0.9 to 1 equivalent of (R) -9- [2- (hydroxy) To 3 equivalents, preferably 1 to 2 equivalents.

According to one embodiment, step (1) may be performed as follows. First, (R) -9- [2- (hydroxy) propyl] adenine and magnesium t -butoxide were added to a vessel, dimethylformamide was added, the temperature was raised to about 55-65 ° C, Lt; / RTI > The mixture is heated again to about 70 to 80 DEG C, and (diethoxyphosphoryl) methylnaphthalene-1-sulfonate or (diethoxyphosphoryl) methylnaphthalene-2-sulfonate is added and stirred for about 2 hours. The reaction solution is cooled to room temperature, and acetic acid is added thereto. The mixture is stirred at room temperature for 30 to 60 minutes, concentrated under reduced pressure, and dichloromethane is added. The reaction solution is stirred at room temperature for 30 to 60 minutes, filtered, and the filtrate is concentrated under reduced pressure to obtain (R) -9- [2- (diethylphosphonomethoxy) propyl] adenine in oil phase.

The procedure of step (2)

In step (2) of the method of the present invention, (R) -9- [2- (dialkyl phosphono-methoxy) propyl] adenine by de-alkylation (R) -9- [2- (phosphono-methoxy) Propyl] adenine, which can be carried out using any of the known methods, for example, the method disclosed in Korean Patent Laid-Open Publication No. 2000-29705.

In one embodiment of the present invention, (R) -9- [2- (dialkyl phosphono-methoxy) propyl] adenine by de-alkylation by reacting with bromo-trimethylsilane in an organic solvent, (R) -9- [2- (Phosphonomethoxy) propyl] adenine.

More specifically, (R) -9- [2- (dialkylphosphonomethoxy) propyl] adenine is added to an organic solvent, bromotrimethylsilane is added and stirred. The reaction solution is concentrated, crystallized with an organic solvent and water, and the precipitated solid is filtered to produce (R) -9- [2- (phosphonomethoxy) propyl] adenine.

The bromotrimethylsilane may be used in an amount of 1 to 5 equivalents based on 1 equivalent of (R) -9- [2- (dialkylphosphonomethoxy) propyl] adenine, preferably 3 to 4 equivalents Can be used.

Examples of the organic solvent used in the reaction include organic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, Can be used.

Examples of the organic solvent used for the crystallization include methanol, ethanol, propanol, butanol, t -butanol, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, May be used singly or in combination.

Preparation of starting material

(Diethoxyphosphoryl) methylnaphthalene-1-sulfonate (compound 4-1) or (diethoxyphosphoryl) methylnaphthalene-2-sulfonate (compound 4-2) used as a starting material in the method of the present invention ) Can be produced by reacting dialkyl hydroxymethylphosphonate (Compound 1) with 1-naphthalenesulfonyl chloride (Compound 2-1) or 2-naphthalenesulfonyl chloride (Compound 2-2), respectively.

[Reaction Scheme 4-1]

[Reaction Scheme 4-2]

In the above Reaction Schemes 4-1 and 4-2, R ₁ is C _1-6 alkyl.

More specifically, the dialkyl hydroxymethylphosphonate (Compound 1) is added to an organic solvent, the base is added, followed by cooling, and then 1-naphthalenesulfonyl chloride (compound 2-2) or 2- naphthalenesulfonyl chloride Compound 2-2) was added and stirred to precipitate a solid. The reaction product was filtered to separate the filtrate, which was then extracted and concentrated to obtain a solid (diethoxyphosphoryl) methylnaphthalene-1-sulfonate (Compound 4-1) (Diethoxyphosphoryl) methylnaphthalene-2-sulfonate (Compound 4-2) can be produced.

Here, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, toluene, etc. may be used alone or in combination as the organic solvent.

As the base, organic bases such as trimethylamine, triethylamine, tributylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, and inorganic bases may be used alone or in combination. The base may be used in an amount of 0.5 to 5 equivalents based on 1 equivalent of dialkyl hydroxymethylphosphonate, preferably 1 to 2 equivalents.

In addition, 1-naphthalenesulfonyl chloride or 2-naphthalenesulfonyl chloride can be used in an amount of 0.5 to 3.0 equivalents based on 1 equivalent of dialkyl hydroxymethylphosphonate, preferably in an amount of 0.5 to 1.5 equivalents .

The reaction may be carried out at a temperature ranging from 0 ° C to 80 ° C, preferably from 20 ° C to 40 ° C. In addition, the reaction time can be from 2 to 48 hours, preferably from 2 to 20 hours.

Effects of the Invention

The process for producing (R) -9- [2- (phosphonomethoxy) propyl] adenine (PMPA) of the present invention is advantageous in that the reaction process is easy and the purity is high (diethoxyphosphoryl) methyl Naphthalene-1-sulfonate or (diethoxyphosphoryl) methylnaphthalene-2-sulfonate is used as an intermediate, PMPA having high purity can be produced.

Particularly, (diethoxyphosphoryl) methylnaphthalene-1-sulfonate is easier to handle when used in the production of PMPA than diethyl p- toluenesulfonyloxymethylphosphonate, which is already known as a solid phase material, and is suitable for mass production Since it is a solid substance, it is more homogeneous than the oil phase and can be produced with a constant quality.

In addition, since it does not use water and air-sensitive reagents like Grignard reagent, it is safe, reproducible production, easy handling of magnesium alkoxide used in reaction, Have.

Also, since PMPA prepared by the method of the present invention has a very high purity, it can be advantageously used to produce a high-quality raw material medicine because it can produce telopoxil and its acid addition salt in high purity.

Preparation of terfenoviridisoproxyl and its acid addition salts

(R) -9- [2- (phosphonomethoxy) propyl] adenine prepared by the method of the present invention was used to prepare high purity cannabisidiproxyl and its acid addition salt can do.

[Reaction Scheme 5]

Such acid addition salts include, but are not limited to, fumarate, succinate, oxalate, saccharate, tartrate, citrate, salicylate, Oxalate, oleanolate, coumalate, orotate, and the like may be exemplified.

In the above production process, the specific reaction can be carried out with reference to known prior arts, for example, those described in International Patent Publications WO 1999/005150, WO 2009/074351, WO 2010/142761, and the like.

The PMPA and tenofovir disoproxylic acid addition salts prepared in the present invention can be purified to a desired level through purification if necessary.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Reference example: Equipment used and measurement conditions

Methods for the determination of tenofovir disoproxil fumarate include a high performance liquid chromatography (HPLC) assay and a control standard for impurities in a monograph registered in the US Pharmacopoeia (2011, Authorized USP pending Monograph Ver. . One).

In the following examples, the purity of the compounds was determined by high performance liquid chromatography (HPLC) using a stationary phase (Capcell pak MGII column, 250 x 4.6 mm), mobile phase A (methanol: t- butyl alcohol: And the mobile phase B (methanol: t -butyl alcohol: buffer = 27: 1: 12 (v / v / v)) at a flow rate of 1.0 ml / , And a wavelength of 260 nm. Optical purity of the compound was also measured by chiral high performance liquid chromatography (Chromtech Chiral AGP column, 150 x 4.0 mm) and mobile phase (methanol: buffer = 15:85 (v / v)) And measured at a flow rate of 0.8 ml / min, an oven temperature of 15 캜, and a wavelength of 260 nm. The buffer was prepared by adding phosphoric acid to 0.01 M aqueous solution of disodium hydrogen phosphate to adjust the pH to 5.5.

The nuclear magnetic resonance spectrum (NMR) was also measured using a 300 MHz FT-NMR spectrometer (Bruker, Germany).

(R) -9- [2- (hydroxy) propyl] adenine (Jingmen ShuaiBang Chem Sci. & Tech. Co., Ltd., China), diethyl (hydroxymethyl) phosphonate (LEAPChem, China), 1-naphthalene sulfonyl chloride (TCI, Japan), and 2-naphthalene sulfonyl chloride (Alfa Aesar, UK) were purchased commercially.

Production Example 1: Preparation of (diethoxyphosphoryl) methylnaphthalene-1-sulfonate (1-DENMP)

(Diethoxyphosphoryl) methylnaphthalene-1-sulfonate (1-DENMP) was prepared according to the procedure of any one of Production Examples 1-1 to 1-3 below.

≪ Production Example 1-1 >

10 g of diethyl (hydroxymethyl) phosphonate (DEHP) and 50 ml of ethyl acetate were added to the vessel, and 9.1 ml of triethylamine was added. 13.5 g of 1-naphthalenesulfonyl chloride was slowly added thereto at 25 DEG C, and the mixture was stirred for 2 hours. The resulting crystals of the reaction solution were filtered, washed with 20 ml of ethyl acetate, and extracted with 50 ml of water to the filtrate. After layer separation, the aqueous layer was extracted once more with 50 mL of ethyl acetate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 18.1 g of solid (diethoxyphosphoryl) methylnaphthalene-1-sulfonate (1-DENMP).

_{^{1 H-NMR (CDCl 3,}} 400 MHz) δ 8.57 (d, 1H, J = 8.6 Hz), 8.23 (dd, 1H, J = 1.2 Hz), 8.10 (d, 1H, J = 8.4 Hz), 7.91 ( d, 1H, J = 8.4 Hz ), 7.66 (t, 1H, J = 7.8 Hz), 7.58 (t, 1H, J = 8.2 Hz), 7.52 (t, 1H, J = 7.8 Hz), 4.11 (d, 2H, J = 10.0 Hz), 3.89-4.06 (m, 4H), 1.15 (t, 6H, J = 7.1 Hz).

≪ Production example 1-2 >

10 g of diethyl (hydroxymethyl) phosphonate (DEHP) and 20 ml of tetrahydrofuran were added to the vessel, 9.1 ml of triethylamine was added, and the mixture was cooled to about 5 캜. While maintaining the reaction solution at 10 ° C or lower, a mixed solution of 13.5 g of 1-naphthalenesulfonyl chloride and 30 ml of tetrahydrofuran was added slowly, the temperature was raised to room temperature, and the mixture was stirred for 60 minutes. The resulting crystals of the reaction solution were filtered, washed with 20 ml of tetrahydrofuran, filtered and the filtrate was concentrated under reduced pressure. 50 ml of water and 50 ml of dichloromethane were added to extract, the layers were separated, and the aqueous layer was extracted once more with 50 ml of dichloromethane. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 19.8 g of solid (diethoxyphosphoryl) methylnaphthalene-1-sulfonate (1-DENMP).

≪ Production Example 1-3 >

10 g of diethyl (hydroxymethyl) phosphonate (DEHP) and 50 ml of toluene were added to the vessel, and 9.1 ml of triethylamine was added. 13.5 g of 1-naphthalenesulfonyl chloride was slowly added thereto at 25 DEG C, and the mixture was stirred for 2 hours. The resulting crystals of the reaction solution were filtered, washed with 20 ml of toluene, and then 50 ml of water and 50 ml of ethyl acetate were added to the filtrate. After layer separation, the aqueous layer was extracted once more with 50 mL of ethyl acetate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 18.1 g of solid (diethoxyphosphoryl) methylnaphthalene-1-sulfonate (1-DENMP).

Production Example 2: Preparation of (diethoxyphosphoryl) methylnaphthalene-2-sulfonate (2-DENMP)

(Diethoxyphosphoryl) methylnaphthalene-2-sulfonate (2-DENMP) was prepared according to the procedure of any one of Production Examples 2-1 to 2-3 below.

≪ Production example 2-1 >

10 g of diethyl (hydroxymethyl) phosphonate (DEHP) and 50 ml of ethyl acetate were added to the vessel, and 9.1 ml of triethylamine was added. After slowly adding 13.5 g of 2-naphthalenesulfonyl chloride at 25 DEG C, the mixture was stirred for 2 hours. The resulting crystals of the reaction solution were filtered, washed with 20 ml of ethyl acetate, and extracted with 50 ml of water to the filtrate. After layer separation, the aqueous layer was extracted once more with 50 mL of ethyl acetate. The organic layer was dried with magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 17.9 g of (diethoxyphosphoryl) methylnaphthalene-2-sulfonate (2-DENMP) as an oil phase.

_{^{1 H-NMR (CDCl 3,}} 400 MHz) δ 8.50 (s, 1H), 8.00 (t, 2H, J = 8.4 Hz), 7.94 (d, 1H, J = 8.0 Hz), 7.86 (dd, 1H, J = 1.8 Hz), 7.68 (m, 2H), 4.24 (d, 2H, J = 9.8 Hz), 4.08-4.17 (m, 4H), 1.28 (t, 6H, J = 7.2 Hz).

≪ Production example 2-2 >

10 g of diethyl (hydroxymethyl) phosphonate (DEHP) and 20 ml of tetrahydrofuran were added to the vessel, 9.1 ml of triethylamine was added, and the mixture was cooled to about 5 캜. While maintaining the reaction solution at 10 ° C or lower, a mixed solution of 13.5 g of 2-naphthalenesulfonyl chloride and 30 ml of tetrahydrofuran was added slowly, the temperature was raised to room temperature, and the mixture was stirred for 60 minutes. The resulting crystals of the reaction solution were filtered, washed with 20 ml of tetrahydrofuran, filtered and the filtrate was concentrated under reduced pressure. 50 ml of water and 50 ml of dichloromethane were added to extract, the layers were separated, and the aqueous layer was extracted once more with 50 ml of dichloromethane. The organic layer was dried with magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 19.3 g of an oil phase (diethoxyphosphoryl) methylnaphthalene-2-sulfonate (2-DENMP).

≪ Production Example 2-3 >

10 g of diethyl (hydroxymethyl) phosphonate (DEHP) and 50 ml of toluene were added to the vessel, and 9.1 ml of triethylamine was added. After slowly adding 13.5 g of 2-naphthalenesulfonyl chloride at 25 DEG C, the mixture was stirred for 2 hours. The resulting crystals of the reaction solution were filtered, washed with 20 ml of toluene, and then 50 ml of water and 50 ml of ethyl acetate were added to the filtrate. After layer separation, the aqueous layer was extracted once more with 50 mL of ethyl acetate. The organic layer was dried with magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 18.0 g of an oil phase (diethoxyphosphoryl) methylnaphthalene-2-sulfonate (2-DENMP).

Example 1: Preparation of Tenofovir (PMPA)

5.0 g of (R) -9- [2- (hydroxy) propyl] adenine (HPA) and 4.5 g of magnesium t -butoxide were added to a vessel, 10 ml of dimethylformamide was added, Stir for 60 min. The reaction solution was heated to about 78 캜 and a mixed solution of 13.3 g of solid (diethoxyphosphoryl) methylnaphthalene-1-sulfonate (1-DENMP) and 2.0 ml of dimethylformamide prepared in Preparation Example 1 was added to the reaction solution And the mixture was stirred for 2 hours. The reaction solution was cooled to room temperature, and 3.6 ml of acetic acid was added thereto. The mixture was stirred at the above temperature for 60 minutes and then concentrated under reduced pressure to remove dimethylformamide. 5.0 ml of water and 75 ml of dichloromethane were added to the concentrate, and the mixture was stirred at room temperature for about 60 minutes. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain (R) -9- [2- (diethylphosphonomethoxy) propyl] adenine (DPPA) as an intermediate oil.

5 ml of acetonitrile and 14 ml of bromotrimethylsilane were added to (R) -9- [2- (diethylphosphonomethoxy) propyl] adenine (DPPA) on an oil phase and stirred at 65 ° C for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and completely dissolved by adding 5 ml of water and 50 ml of methanol. The mixture was adjusted to pH 3.0 using a 20% sodium hydroxide aqueous solution and stirred at room temperature for 2 hours. The crystals were filtered, washed with 25 ml of water and 10 ml of acetone, and then dried under nitrogen at room temperature to obtain 5.0 g (yield: 67%) of the desired compound, Tenofovir (PMPA).

90.9 ml of water was added to 4.9 g of the obtained tenofovir (PMPA), and the temperature was raised to about 95 DEG C and completely dissolved for 30 minutes. The dissolved reaction solution was slowly cooled to about 25 캜, cooled again to 3 캜, and maintained at the above temperature for 3 hours. The crystals were filtered, washed with 25 ml of water and 10 ml of acetone, and dried under nitrogen at room temperature to obtain 4.2 g (yield: 86%) of terpovapor (PMPA).

Purity determination: 98.7% by HPLC

¹ H-NMR (D ₂ O, 300 MHz) ? 8.25 (s, IH), 8.09 (s, IH), 4.35 (dd, IH), 4.22 dd, 1 H), 3.46 (dd, 1 H), 1.11 (d, 3 H).

Example 2: Preparation of Tenofovir (PMPA)

5.0 g of (R) -9- [2- (hydroxy) propyl] adenine (HPA) and 4.5 g of magnesium t -butoxide were added to a vessel, 10 ml of dimethylformamide was added, Stir for 60 min. The reaction solution was heated to about 78 캜 and a mixed solution of 13.3 g of (diethoxyphosphoryl) methylnaphthalene-2-sulfonate (2-DENMP) and 2.0 ml of dimethylformamide prepared in Preparation Example 2 was added to the reaction solution And the mixture was stirred for 2 hours. The reaction solution was cooled to room temperature, and 3.6 ml of acetic acid was added thereto. The mixture was stirred at the above temperature for 60 minutes and then concentrated under reduced pressure to remove dimethylformamide. 5.0 ml of water and 75 ml of dichloromethane were added to the concentrate, and the mixture was stirred at room temperature for about 60 minutes. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain (R) -9- [2- (diethylphosphonomethoxy) propyl] adenine (DPPA) as an intermediate oil.

5 ml of acetonitrile and 14 ml of bromotrimethylsilane were added to (R) -9- [2- (diethylphosphonomethoxy) propyl] adenine (DPPA) on an oil phase and stirred at 65 ° C for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and completely dissolved by adding 5 ml of water and 50 ml of methanol. The mixture was adjusted to pH 3.0 using a 20% sodium hydroxide aqueous solution and stirred at room temperature for 2 hours. The crystals were filtered, washed with 25 ml of water and 10 ml of acetone, and then dried under nitrogen at room temperature to obtain 4.4 g (yield: 59%) of the desired compound, Tenofovir (PMPA).

To 4.3 g of the obtained prepolymer (PMPA) was added 80 ml of water, and the temperature was raised to about 95 캜 and completely dissolved for 30 minutes. The dissolved reaction solution was slowly cooled to about 25 캜, cooled again to 3 캜, and maintained at the above temperature for 3 hours. The crystals were filtered, washed with 25 ml of water and 10 ml of acetone, and dried under nitrogen at room temperature to obtain 3.5 g of terpovapor (PMPA) (yield: 82%).

Purity measurement: 98.8% by HPLC

¹ H-NMR (D ₂ O, 300 MHz) ? 8.25 (s, IH), 8.09 (s, IH), 4.35 (dd, IH), 4.22 dd, 1 H), 3.46 (dd, 1 H), 1.11 (d, 3 H).

REFERENCE EXAMPLE 1 Preparation of Tenofovir Dysorofoxyl Fumarate (TDF)

To the container was added 4.0 g of the tenofovir (PMPA) prepared in Example 1, and 15 ml of N-methylpyrrolidone and 5.8 ml of triethylamine were added. The reaction solution was heated to about 63 캜, stirred for 30 minutes, added with 10 g of chloromethyl isopropyl carbonate, and stirred at that temperature for 4 hours. The reaction solution was cooled to room temperature, cooled again to 5 deg. C and kept at 15 deg. C or lower, and 25 ml of cold water was added thereto. The mixture was stirred at 15 DEG C for 1 hour and extracted twice with 15 mL of methylene chloride. After the layer separation, the organic layer was washed twice with 10 ml of water, and the organic layer was dried with magnesium sulfate and filtered. The remaining filtrate was concentrated under reduced pressure to give terpovavir disoproxyl (TD) in oil.

35 ml of isopropyl alcohol and 1.6 g of fumaric acid were added to terpovapor discosyl (TD) on an oil phase, and the temperature was raised to about 50 캜 and completely dissolved for 30 minutes. The dissolved reaction solution was gradually cooled to about 25 캜, cooled again to 3 캜, and maintained at the above temperature and stirred for 4 hours. The crystals were filtered, washed with 10 ml of isopropyl alcohol, and then vacuum-dried at about 40 ° C to obtain 4.7 g (yield: 53%) of the desired compound, tenofovir dysoproxyl fumarate (TDF).

40 ml of isopropyl alcohol was added to 4.7 g of the above-obtained tepofibaredisopropyl fumarate (TDF), and the temperature was raised to about 50 캜 and completely dissolved for 30 minutes. The dissolved reaction solution was slowly cooled to about 25 캜, cooled again to 3 캜, and maintained at the above temperature for 4 hours. The crystals were filtered, washed with 100 ml of isopropyl alcohol, and vacuum-dried at about 40 ° C to obtain 4.3 g (yield: 90%) of crystalline type terfenoviridisopropyl fumarate (TDF).

REFERENCE EXAMPLE 2 Preparation of Tenofovir disisopropyl fumarate (TDF)

To the container was added 3.5 g of the tenofovir (PMPA) prepared in Example 2, 15 ml of N-methylpyrrolidone and 5.1 ml of triethylamine were added. The reaction solution was heated to about 63 캜, stirred for 30 minutes, added with chloromethyl isopropyl carbonate (8.7 g), and stirred at this temperature for 4 hours. The reaction solution was cooled to room temperature, cooled again to 5 deg. C and kept at 15 deg. C or lower, and 25 ml of cold water was added thereto. The mixture was stirred at 15 DEG C for 1 hour and extracted twice with 15 mL of methylene chloride. After the layer separation, the organic layer was washed twice with 10 ml of water, and the organic layer was dried with magnesium sulfate and filtered. The remaining filtrate was concentrated under reduced pressure to give terpovavir disoproxyl (TD) in oil.

30 ml of isopropyl alcohol and 1.4 g of fumaric acid were added to terpovapordisopropyl (TD) in oil, and the temperature was raised to about 50 캜 and completely dissolved for 30 minutes. The dissolved reaction solution was gradually cooled to about 25 캜, cooled again to 3 캜, and maintained at the above temperature and stirred for 4 hours. The crystals were filtered, washed with 100 ml of isopropyl alcohol, and then vacuum-dried at about 40 ° C to obtain 4.0 g (yield: 52%) of the target compound, tenofovir dysoproxyl fumarate (TDF).

35 ml of isopropyl alcohol was added to 4.0 g of the obtained terpovoid dinofroxyl fumarate (TDF), and the temperature was raised to about 50 캜 and completely dissolved for 30 minutes. The dissolved reaction solution was slowly cooled to about 25 캜, cooled again to 3 캜, and maintained at the above temperature for 4 hours. The crystals were filtered, washed with 100 ml of isopropyl alcohol, and then vacuum-dried at about 40 ° C to obtain 3.6 g (yield: 90%) of crystalline type terfenoviridisopropyl fumarate (TDF).

Claims (9)

(1) reacting a compound of the following formula (3) with a compound of the formula (4-1) and magnesium alkoxide in the following solid to prepare a compound of the formula (5); And
(2) dealkylating the compound of the formula (5) obtained in the above step (1) to prepare a compound of the following formula (6)
The solid compound of formula (4-1) can be prepared by reacting a compound of formula (1) with a compound of formula (2-1) below in the presence of a base such as dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, (R) -9- [2- (phosphonomethoxy) propyl] adenine, which is produced by reacting a compound represented by the general formula (1) in an organic solvent selected from the group consisting of a mixed solvent thereof in the presence of a base,
[Chemical Formula 1]

[Formula 2-1]

(3)

[Formula 4-1]

[Chemical Formula 5]

[Chemical Formula 6]

In the above general formulas (1), (4-1) and (5), R ₁ is C _1-6 alkyl.
The method according to claim 1,
(R) -9- [2- (phosphonomethoxy) propyl] -propyl] -methanol, which is characterized in that the magnesium alkoxide is magnesium methoxide, magnesium ethoxide, magnesium propoxide, magnesium butoxide or magnesium t- ≪ / RTI >
3. The method of claim 2,
A process for producing (R) -9- [2- (phosphonomethoxy) propyl] adenine, wherein the magnesium alkoxide is magnesium t -butoxide.
The method according to claim 1,
Wherein the reaction of step (1) is carried out in a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, (R) -9- [2- (phosphonomethoxy) propyl] adenine, which is characterized in that it is carried out in an organic solvent selected from the group consisting of:
The method according to claim 1,
9. A process for the preparation of (R) -9- [2- (phosphonomethoxy) propyl] adenine wherein the dealkylation is carried out by reacting the compound of formula (5) with bromotrimethylsilane in an organic solvent.
6. The method of claim 5,
Wherein the organic solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, chloroform, methyl acetate, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, (R) -9- [2- (phosphonomethoxy) propyl] adenine.
delete delete The method according to claim 1,
It said base is trimethylamine, triethylamine, tributylamine, sodium hydroxide, characterized in that selected from potassium hydroxide, sodium carbonate, potassium carbonate and mixtures thereof, (R) -9- [2- (Force ≪ / RTI >< RTI ID = 0.0 > adenosine < / RTI >