KR20150025993A - Acid Salt of Tenofovir Disoproxil and Preparation method thereof - Google Patents

Abstract

The present invention relates to a novel tenofovir disoproxil acid addition salt, which is bound to an organic acid selected from a group consisting of tenofovir disoproxil gentisic acid, suberic acid, hippuric acid, urosodeoxycholic acid, myristic acid, pamoic acid, 4-chlorosalicylic acid, ethane-1,2-disulfonic acid, 5-sulfosalicylic acid, stearic acid, 4-methyl-3-nitrobenzoic acid and 4-(methylthio)benzoic acid, and a manufacturing method thereof. According to the present invention, the tenofovir disoproxil acid addition salt is anhydride and has outstanding physical and chemical properties, thereby resolving problems caused by physical and chemical properties of tenofovir disoproxil fumarate, and is not harmful to human body and is safety when manufactured, thereby leading to ease of management and mass-production.

Description

≪ Desc / Clms Page number 2 > Tenofovir Disoproxil and Preparation Method thereof < RTI ID = 0.0 &

The present invention relates to novel tenofovir disoproxil acid addition salts and processes for their preparation.

Hepatitis B virus (HBV) is recognized as an important pathogen causing liver cancer in many people. HBV infection also causes fulminant hepatitis, a fatal disease that destroys the liver. Chronic hepatitis infections lead to chronic persistent infections, fatigue, cirrhosis, liver cancer, and death. Currently, HBV drugs approved for clinical use require the presence of drugs that can sustain the medical effect and reduce toxicity because of the problems of rapid emergence resistance and the limited toxicity problems associated with the treatment of HBV do. Drugs approved for clinical use include alpha interferon, genetically engineered proteins and nucleoside analogs such as lamivudine, clevudine, telbivudine, and entecavir. Other approved anti-HBV drugs include athevobia and tenofovir, which are considered mononucleotide phosphonate analogs.

The tenofovir disoproxil has the chemical structure of the following formula (2).

(2)

Tenofoviridisoproxyl is a prodrug of bis-ester of tenofovir and is a prodrug of 9- [2- (R) - [[bis [[(isopropoxycarbonyl) oxy] methoxy] Yl] methoxy] propyl] adenine. One of its salts, tenofovir disoproxil fumarate, has a rapid, sustained, low tolerance antiviral effect and has a structure and mechanism similar to that of atefovir but is a drug that significantly improves renal toxicity. It is also recommended as the first line treatment in the American Liver Association and European Liver Association Guidelines and is a prescriptionable medicine for pregnant women and has strong activity for the treatment of human immunodeficiency virus infection in humans.

The conventional technique is as follows.

U.S. Patent No. 5,922,695 discloses a process for the preparation of (R) -9- [2- (hydroxy) propyl] adenyl by condensation reaction with diethyl p-toluenesulfonyloxymethylphosphonate followed by dealkylation, Discloses a pathway for synthesis of beadisofroxyl. Also disclosed is a method for converting a fumaric acid having a low molecular weight into a fumarate salt by reacting the resulting terpolvar base with a fumaric acid having a melting point of about 116 ° C.

WO99 / 05150, EP-A-998480 and US-A-5,935,946 disclose XRD Peak of crystalline tepofovir disoproxil fumarate. Ray diffraction angles of 4.9, 10.2, 10.5, 18.2, 20.0, 21.9, 24.0, 25.0, 25.5, 27.8, 30.1 and 30.4 and an Onset temperature of 116.98 ° C in thermogravimetric analysis.

US Published Patent Publication No. 2009/0286981 discloses the XRD Peak of crystalline terpovoid disoproxil hemifumarate. 11.9, 14.2, 14.6, 16.7, 21.1, and 24.2 + -0.2, and has an Onset temperature of 116.93 DEG C in thermogravimetric analysis.

U.S. Patent Application Publication No. 2011/009368 discloses solid forms of tenofovir disoproxil succinate, oxalate, saccharate, L-tartrate, citrate salts and their physical properties, These are examples of syntheses and most of them have low melting point.

The tenofovir disoproxil fumarate has a problem in thermal stability and light stability, and when the finished product is manufactured or stored for a long period of time, careful attention must be paid to the weather and there is a disadvantage that it is difficult or difficult to control the process due to moisture absorption. In order to solve the above problems, it is necessary to study the pharmaceutical salts of the novel tenofovir disoproxil with physicochemical properties.

After studying the novel salts of tenofovir disoproxil for solving the pharmaceutical disadvantages caused by the physico-chemical properties of the tenofovir disoproxyl fumarate, The present inventors have developed a novel salt of tenofovir disoproxil having chemically excellent properties and completed the present invention.

In order to solve the disadvantages caused by the physico-chemical properties of tenofovir disoproxil fumarate, the present invention provides a tenofovir disoproxil acid addition salt having physicochemical properties and a process for producing the same, do.

In order to solve the above problems, the present invention provides a novel acid addition salt of tenofovir disoproxil represented by the following general formula (1).

≪ Formula 1 >

The acid addition salt used in the present invention is an organic acid. Examples of the organic acid include organic acid salts such as acetate, dichloroacetate, adipate, alginate, ascorbate, camphorate, caprate, caproate, caprylate, cyclamate, But are not limited to, lactose, glutarate, lactate, glueceptate, glucuronate, glutamate, oxoglutarate, lactobionate, thiocyanate, malonate, uronate, propionate, decanoate, caprylate, Mica, isobutyrate, heptanoate, propiolate, malonate, succinate, suberate, sebacate, maleate, orotate, myristate, butyne-1,4-dioate, hexyne- Citrate, lactate, betahydroxybutyrate, glycolate, maleate, tartrate; Methanesulfonate, propanesulfonate, camphorsulfonate, camsylate, eddylate, escitalate, isethionate, which are aliphatic sulfone organic acid salts; Aromatic organic acid salts such as benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, phenylacetate, phenylpropionate, phenylbutyrate, mandelate, salicylate, para - aminosalicylates, tannates, cinnamates; Aromatic sulfonic organic acid salts such as benzene sulfonate, toluene sulfonate, xylene sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and the like.

Preferably, the present invention relates to the use of tenofovir disoproxil as gentisic acid, suberic acid, hippuric acid, ursodeoxycholic acid, Myristic acid, pamoic acid, 4-chlorosalicylic acid, ethane-1,2-disulfonic acid, 5-sulfosalicylic acid, 5-sulfosalicylic acid, stearic acid, 4-methyl-3-nitrobenzoic acid and 4- (methylthio) benzoic acid. Wherein the at least one organic acid is selected from the group consisting of:

The preferred tenofovir disoproxil acid addition salt according to the present invention may be represented by the following general formula (1).

≪ Formula 1 >

,

,

,

,

,

,

,

,

,

,

, 또는

를 나타낸다.
In the above formula, A represents

,

,

,

,

,

,

,

,

,

,

, or

.

The tenofovir disoproxylic acid addition salt according to the present invention is an anhydrous and has excellent physicochemical properties capable of solving the pharmaceutical shortcomings caused by the physico-chemical properties of tenofovir disoproxil fumarate. In particular, DSC (Oneset) confirmed that pamoate, chlorosalicylate, and ethanesulfonate have better physico-chemical properties than fumarate salt, and thus are excellent in formulation stability. As can be seen from the following examples, it is easy to handle because of its stability in production, which is very useful for mass production.

The present invention also relates to the use of terfenoviridisoproxyl as an antioxidant selected from the group consisting of gentic acid, suberic acid, hifric acid, ursodeoxycholic acid, myristic acid, pamoic acid, 4-chlorosalicylic acid, - reacting with a single organic acid selected from the group consisting of sulfosalicylic acid, stearic acid, 4-methyl-3-nitrobenzoic acid and 4- (methylthio) benzoic acid. .

At this time, the reaction between the above-mentioned cannabisisoproxyl and the organic acid can be carried out in any organic solvent capable of dissolving these reactants and carrying out an acid-base reaction. However, in order to allow the acid-base reaction to proceed appropriately and to produce an acid addition salt in which an equivalent ratio of the tenofovir disoproxil and the organic acid is increased, the reaction of gentianophobia diisoproxyl and the organic acid is performed by using C 1 -C 4 It is preferably carried out in at least one organic solvent selected from the group consisting of an alcohol, N, N-dimethylformamide, dimethylsulfoxide, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, hexane and isopropyl ether. The reaction can be carried out in the above-mentioned solvent at a reaction temperature of from -5 to 100 ° C, preferably from 0 to 80 ° C, for 30 minutes to 48 hours, preferably from 30 minutes to 16 hours.

In addition, for the reaction of such an organophosphorous acid with an organic acid, the organic acid may be used in an amount of 0.9 to 2 equivalents, preferably 0.95 to 1.2 equivalents, relative to tenofovir disoproxil. With such an amount of use, a preferred tenofovir dysoproxylic acid addition salt in which the tenofovir disoproxil and the organic acid are combined in an equivalent ratio can be prepared.

In one embodiment of the present invention, after the reaction of the tenofovir disoproxil and the organic acid in an organic solvent, water or tert-butyl methyl ether may be added to obtain a salt. The amount of water or tert-butyl methyl ether to be added in the present reaction may be 1 to 10 times larger than the volume of the organic solvent used in the previous step reaction. The amount of water or tert-butyl methyl ether may be 10 v / w to 30 v / w relative to tenofovir disoproxil But is not limited thereto. Water or tert-butyl methyl ether is added to a reaction solution in which terpovoid disulfoxyl and organic acid are dissolved, and the mixture is stirred at a reaction temperature of 0 to 80 ° C for 30 minutes to 48 hours, preferably 30 minutes to 16 hours The precipitated terpovaporidosulfoacylic acid addition salt can be obtained.

The tenofovir disoproxylic acid addition salt according to the present invention is an anhydrous and has excellent physicochemical properties capable of solving the pharmaceutical disadvantages arising from the problem of physico-chemical properties of tenofovir disoproxyl fumarate. It is not harmful to the human body and is easy to handle because of its stability in production, which is very useful for mass production.

Fig. 1 shows X-ray powder diffraction (XRD) results of the tenofovir disoproxil gentisate prepared in Example 1. Fig.
2 is a differential scanning calorimetry (DSC) result of the tenofovir disoproxil gentisate prepared in Example 1. Fig.
FIG. 3 shows X-ray powder diffraction (XRD) results of the cannabisis isopropyl hydroxylated beverages prepared in Example 2. FIG.
4 is a differential scanning calorimetry (DSC) result of Tenofovir disoproxylsuversate prepared in Example 2. Fig.
5 is the X-ray powder diffraction (XRD) results of the tenofovir disoproxil hydrate prepared in Example 3. Fig.
6 is a differential scanning calorimetry (DSC) result of the tenofovir disoproxil hippurate prepared in Example 3. Fig.
Fig. 7 shows the X-ray powder diffraction (XRD) results of the tenofovir disoproxilusodeoxycholinate prepared in Example 4. Fig.
8 is a differential scanning calorimetry (DSC) result of tenofovir disoproxilusodeoxycholinate prepared in Example 4. Fig.
9 is an X-ray powder diffraction (XRD) result of the Tenofovir disoproxil myristate prepared in Example 5
10 is a differential scanning calorimetry (DSC) result of the Tenofovir disoproxil myristate prepared in Example 5. Fig.
11 is the X-ray powder diffraction (XRD) result of the tenofovir disoproxil pamoate prepared in Example 6
12 is a differential scanning calorimetry (DSC) result of tenofovir disoproxil pamoate prepared in Example 6. Fig.
13 is the result of X-ray powder diffraction (XRD) of the tenofovir disoproxyl 4-chlorosalicylate prepared in Example 7
14 is a differential scanning calorimetry (DSC) result of tenofovir disoproxyl 4-chlorosalicylate prepared in Example 7. Fig.
15 is the X-ray powder diffraction (XRD) result of the tenofovir disoproxilethane-1,2-disulfonate prepared in Example 8
16 is a differential scanning calorimetry (DSC) result of the tenofovir disoproxilethane-1,2-disulfonate prepared in Example 8. Fig.
17 is the X-ray powder diffraction (XRD) result of the tenofovir disoproxyl 5-sulfosalicylate prepared in Example 9
18 is a differential scanning calorimetry (DSC) result of tenofovir disoproxil 5-sulfosalicylate prepared in Example 9. Fig.
19 is the X-ray powder diffraction (XRD) result of the tenofovir disoproxyl stearate prepared in Example 10
20 is a differential scanning calorimetry (DSC) result of the tenofovir disoproxil stearate prepared in Example 10. Fig.
21 is the X-ray powder diffraction (XRD) result of the tenofovir disoproxil hemipamoate prepared in Example 11
22 is a differential scanning calorimetry (DSC) result of the tenofovir disoproxil hemipamoate prepared in Example 11. Fig.
23 is the X-ray powder diffraction (XRD) result of the tenofovir disoproxil 4-methyl-3-nitrobenzoate prepared in Example 12
24 is a differential scanning calorimetry (DSC) result of the tenofovir disoproxil 4-methyl-3-nitrobenzoate prepared in Example 12. Fig.
25 is an X-ray powder diffraction (XRD) result of the tenofovir disoproxil 4- (methylthio) benzoate prepared in Example 13
26 is a differential scanning calorimetry (DSC) result of the tenofovir disoproxil 4- (methylthio) benzoate prepared in Example 13. Fig.
FIG. 27 shows the X-ray powder diffraction (XRD) results of the prepared tenofovir disoproxyl fumarate of Comparative Example 1. FIG.
28 is a differential scanning calorimetry (DSC) result of the prepared tepofovir disoproxyl fumarate of Comparative Example 1. Fig.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

≪ Example 1 > Preparation of tenofovir disoproxil gentisate

(5 g) and gentisic acid (1.41 g) were added to the reaction part and dissolved by adding N, N-methylformamide (20 ml). Purified water (150 ml) was slowly added dropwise and stirred at room temperature overnight. The resulting solid was filtered and washed with purified water (200 ml). Vacuum drying overnight at room temperature yielded 3 g of terpovoid disulfroxylatedisite (yield: 49%).

The XRD measurement results are shown in Fig. 1, and the DSC measurement results are shown in Fig.

≪ Example 2 > Preparation of Tenofovir Distemorosilv.

To the reaction part, a reaction solution was prepared by adding terbinafiorisofroxyl (2 g), dimethylsulfoxide (8 ml) and purified water (60 ml). Suberic acid (0.65 g) was added to the reaction solution, and the mixture was stirred overnight at room temperature. The resulting solid was filtered and washed with purified water (20 ml). Vacuum drying overnight at 50 DEG C afforded 1.6 g of terfenoviride soaproxyl satvate (yield: 60%).

The XRD measurement results are shown in Fig. 3, and the DSC measurement results are shown in Fig.

≪ Example 3 > Preparation of terpovoid disoproxil hippurate

(25 g) and methanol (50 ml) were charged into the reaction part and dissolved therein by heating (65 ° C). To the reaction solution was added tert-butyl methyl ether (250 ml) and hippuric acid (8.62 g), and the mixture was stirred at the same temperature for 1 hour and then cooled to room temperature. Thereafter, the reaction was carried out at an internal temperature of 0-5 占 폚 for 24 hours to obtain crystals. The resulting crystals were filtered off under reduced pressure, washed with tert-butyl methyl ether (750 ml) and dehydrated. The dehydrated crystals were vacuum-dried at an internal temperature of 60 DEG C for 15 hours to obtain 27.7 g of terpovobiadisopropyl hydroxylase (yield: 82.3%).

The XRD measurement results are shown in Fig. 5, and the DSC measurement results are shown in Fig.

<Example 4> Preparation of Tenofovir disesoproxylurusodeoxycholinate

Tenofovir disoproxil (5 g) and ursodeoxycholic acid (3.78 g) were added to the reaction part and dissolved in N, N-dimethylformamide (20 ml). Purified water (200 ml) was slowly added to the dissolved reaction solution and stirred at an internal temperature of 0-5 占 폚 for 14 hours. The resulting crystals were filtered off under reduced pressure, washed with purified water (50 ml) and dehydrated. The dehydrated crystals were vacuum-dried at an internal temperature of 60 占 폚 for 15 hours to obtain 6.27 g of terpovoid disoproxilusodeoxycholineate (yield: 71.5%).

The XRD measurement results are shown in Fig. 7, and the DSC measurement results are shown in Fig.

&Lt; Example 5 > Preparation of tenofovir disoproxil myristate

To the reaction part, 5 g of terfenoviridisoproxyl and myristic acid (2.09 g) were added and dissolved in N, N-dimethylformamide (20 ml). Purified water (150 ml) was slowly added to the dissolved reaction solution and stirred at room temperature for 15 hours. The resulting crystals were filtered off under reduced pressure, washed with purified water (50 ml) and dehydrated. The dehydrated crystals were vacuum dried at an internal temperature of 60 占 폚 for 15 hours to obtain 4.1 g of terbinafide dissoloxyl myristate (yield: 60%).

The XRD measurement results are shown in Fig. 9, and the DSC measurement results are shown in Fig.

&Lt; Example 6 > Preparation of tenofovir disoproxil pamoate

Tenofovir disoproxyl (5 g) and pamoic acid (3.55 g) were added to the reaction part, followed by addition of N, N-dimethylformamide (20 ml) and dissolution at 50 ° C. Purified water (150 ml) was slowly added to the dissolved reaction solution and stirred at room temperature for 15 hours. The resulting crystals were filtered off under reduced pressure, washed with purified water (50 ml) and dehydrated. The dehydrated crystals were vacuum-dried at an internal temperature of 60 캜 for 15 hours to obtain 4.6 g of terbinafide disoproxil pamoate (yield: 70%).

The XRD measurement results are shown in Fig. 11, and the DSC measurement results are shown in Fig.

&Lt; Example 7 > Preparation of terpovoiddisofroxyl 4-chlorosalicylate

4-Chlorosalicylic acid (1.66 g) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. After the reaction, tert-butyl dicarbonate (5 g), acetone (25 ml) or dimethyl sulfoxide Butyl methyl ether (250 ml) or purified water (150 ml) was added dropwise. The reaction was carried out at room temperature for 1 hour to 5 hours, and the resulting crystals were filtered under reduced pressure, washed with tert-butyl methyl ether (50 ml) or purified water (50 ml) and dehydrated. The dehydrated crystals were dried under vacuum at an internal temperature of 50 캜 for 15 hours to obtain 6.6 g of terbinafide disoproxil 4-chlorosalicylic acid (Yield: 84.8%).

The XRD measurement result is shown in Fig. 13, and the DSC measurement result is shown in Fig.

&Lt; Example 8 > Preparation of terpovoiddisopropylsilane-1,2-disulfonate

Ethanol-1,2-disulfonic acid (1.04 g) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. Tert (tert-Butyldisopropyl) -Butyl methyl ether (60 ml) was added dropwise. The resulting crystals were heated to 50 &lt; 0 &gt; C for 30 minutes, then cooled to room temperature, filtered under reduced pressure, washed with tert-butyl methyl ether (50 ml) and dehydrated. The dehydrated crystals were vacuum-dried at an internal temperature of 50 캜 for 15 hours to obtain 3.55 g of terpovoid disoproxilethane-1,2-disulfonate (yield: 86.6%).

The XRD measurement results are shown in Fig. 15, and the DSC measurement results are shown in Fig.

&Lt; Example 9 > Preparation of 5-sulfosalicylate

To the reaction part was added terfenovirisofroxyl (3 g) and 5-sulfosalicylic acid (1.2 g), followed by dissolving in tetrahydrofuran (12 ml), followed by the addition of tert-butyl methyl ether And the mixture was stirred at room temperature for 18.5 hours. The resulting crystals were filtered off under reduced pressure, washed with tert-butyl methyl ether (30 ml) and dehydrated. The dehydrated crystals were vacuum-dried at room temperature for 24 hours to obtain 2.65 g of terpovoid disulfoxyl 5-sulfosalicylate (yield: 65%).

The XRD measurement result is shown in Fig. 17, and the DSC measurement result is shown in Fig.

&Lt; Example 10 > Preparation of terfenoviridisoproxyl stearate

Tenofovir disoproxyl (3 g) and stearic acid (1.56 g) were added to the reaction part, followed by addition of N, N-dimethylformamide (12 ml) and stirring. 2N-sodium hydroxide solution (2 ml) and purified water (90 ml) were added and stirred. 2N-hydrochloric acid solution (1 ml) was added dropwise thereto, followed by stirring at room temperature for 18 hours. The resulting crystals were filtered under reduced pressure, washed with purified water (30 ml) and dehydrated. The dehydrated crystals were vacuum-dried at room temperature for 24 hours to obtain 2.81 g of terpovoid disoproxyl stearate (yield: 64%).

The XRD measurement results are shown in Fig. 19, and the DSC measurement results are shown in Fig.

&Lt; Example 11 > Preparation of tenofovir disoproxil hemipamoate

Tenofovir disoproxil (3 g) and pamoic acid (0.65 g) were added to the reaction part, and then acetone (12 ml) and N, N-dimethylformamide (12 ml) were added to dissolve. Tert-Butyl methyl ether (180 ml) was slowly added thereto, followed by stirring at room temperature for 18 hours to obtain crystals. The resulting crystals were filtered under reduced pressure, washed with purified water (30 ml) and dehydrated. The dehydrated crystals were vacuum-dried at room temperature for 24 hours to obtain 2.9 g of terpovoid disoproxil hemipamoate (yield: 70%).

The XRD measurement result is shown in Fig. 21, and the DSC measurement result is shown in Fig.

&Lt; Example 12 > Preparation of terpovoiddiopsoproxyl 4-methyl-3-nitrobenzoate

To the reaction part, 5 g of terbinoviedisofroxyl and dimethyl sulfoxide (20 ml) were added, followed by 4-methyl-3-nitrobenzoic acid (1.74 g). Then, purified water (150 ml) was added dropwise at room temperature, reacted at 0-55 ° C for 2 hours, and reacted at room temperature for 15 hours. The resulting crystals were filtered under reduced pressure, washed with purified water (100 ml) and dehydrated. The dehydrated crystals were vacuum-dried at an internal temperature of 50 占 폚 for 15 hours to obtain 5.89 g of terpovovir disoproxil 4-methyl-3-nitrobenzoate (yield: 87.3%).

The XRD measurement results thereof are shown in Fig. 23, and the DSC measurement results are shown in Fig.

Example 13 Preparation of terfenoviridisopropylxyl 4- (methylthio) benzoate

(5 g) and dimethylsulfoxide (20 ml) were added to the reaction portion, and then 4- (methylthio) benzoic acid (1.45 g) was added thereto. After reacting at room temperature for 1 hour, purified water (150 ml) was added dropwise, reacted at 60-65 ° C for 4 hours, and reacted at room temperature for 15 hours. The resulting crystals were filtered under reduced pressure, washed with purified water (50 ml) and dehydrated. The dehydrated crystals were vacuum-dried at an internal temperature of 50 占 폚 for 15 hours to obtain 4.99 g (yield: 75%) of terbinafide disoproxil 4- (methylthio) benzoate.

The XRD measurement result is shown in Fig. 25, and the DSC measurement result is shown in Fig.

&Lt; Comparative Example 1 & Preparation of terfenoviride disoproxil fumarate

(Purity (HPLC): 99.1%, yield: 84%) was prepared according to the method described in Korean Patent Publication No. 10-0619298.

The XRD measurement results are shown in Fig. 27, and the DSC measurement results are shown in Fig.

<Experimental Example 1> XRD measurement

XRD measurement tests were carried out on the tenofovir disoproxylate prepared in Examples 1 to 13 and the tenofovir disoproxyl fumarate prepared in Comparative Example 1, and the results are shown in the respective figures.

<XRD Meter>

 Device name: Bruker D8ADVAN

 Output: 40mA to 40mA

Measuring angle: 3.5 to 40 at 6 deg / min

<Experimental Example 2> DSC measurement (differential scanning calorie)

DSC was measured on the tenofovir disoproxilate prepared in Examples 1 to 13 and the tenofovir disoproxyl fumarate prepared in Comparative Example 1, and the results are shown in the respective figures.

<DSC measuring instrument>

 Manufacturer: METTLER

Model: DSC1 STAR System

Heating rate: 10 C / min

Referring to the crystalline diffraction X-ray peak graph of the tenofovir disoproxyl salt according to Examples 1 to 13 of the present invention, it can be seen that the diffraction X-ray peak of the tenofovir disoproxyl fumarate shown in Fig. Of the total.

Claims (6)

It has been reported that tenofovir disoproxil and gentisic acid, suberic acid, hippuric acid, ursodeoxycholic acid, myristic acid Pamoic acid, 4-chlorosalicylic acid, ethane-1,2-disulfonic acid, 5-sulfosalicylic acid, Wherein the organic acid is selected from the group consisting of stearic acid, 4-methyl-3-nitrobenzoic acid and 4- (methylthio) benzoic acid. Lt; RTI ID = 0.0 &gt; of &lt; / RTI &gt;
[Claim 2] The method according to claim 1, wherein the terpovoid diphosphonic acid addition salt represented by the following formula (1)
&Lt; Formula 1 >

In the above formula, A represents

,

,

,

,

,

,

,

,

,

,

, or

.
It is also possible to use terfenoviridisoproxyl as an antioxidant in combination with at least one selected from the group consisting of gentilic acid, suberic acid, hippuric acid, ursodeoxycholic acid, myristic acid, pamoic acid, 4-chlorosalicylic acid, With an organic acid selected from the group consisting of stearic acid, 4-methyl-3-nitrobenzoic acid and 4- (methylthio) benzoic acid.
The method of claim 3, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of C 1 -C 4 alcohols, N, N-dimethylformamide, dimethylsulfoxide, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, hexane, &Lt; / RTI &gt; or more in a solvent.
4. The method of claim 3, wherein the organic acid is used in an amount of 0.9 to 2 equivalents based on tenofovir disoproxil.
4. The process according to claim 3, further comprising the step of adding water or tert-butyl methyl ether after the reaction of the tenofovir disoproxil and the organic acid in an organic solvent to afford a salt of tenofovir disoproxil acid addition salt Gt;

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