KR20120049039A - Preparation method for adefovir dipivoxil - Google Patents

Abstract

PURPOSE: A method for preparing adefovir dipivoxil(9-[2-[bis[(pivaloyloxy)methoxy]phosphynyl]methoxy]ethyl]adenine) is provided to easily obtain a large amount of products of high purity. CONSTITUTION: A method for preparing adefovir dipivoxil comprises: a step of reaction of adefovir of chemical formula 2 with chloromethyl pivalate of chemical formula 3 to prepare non-purified adefovir dipivoxil; a step of dissolving the adefovir dipivoxil in organic solvent and adding organic acid(HA) to crystallize adefovir dipivoxil acid salt of chemical formula 5; a step of dissolving the compound of chemical formula 5 in water and adding organic salt to form precipitate of adefovir dipivoxil of chemical formula 1; and a step of washing and drying the precipitate. The organic solvent includes ethyl acetate, isopropyl acetate, propyl acetate, isopropanol, 1-propanol, or 1-butanol.

Description

Adefovir difficile manufacturing method {PREPARATION METHOD FOR ADEFOVIR DIPIVOXIL}

The present invention relates to adefovir dipivoxil, 9- [2- [bis [(pivaloyloxy) methoxy] phosphinyl] methoxy] ethyl] adenine (9- [2- [Bis [(pivaloyloxy) methoxy] phosphinyl] methoxy] ethyl] adenine)), more specifically, iii) preparing a crude adefovir difficile by reacting adefovir of Formula 2 with chloromethylpivalate of Formula 3; Ii) dissolving the crude adefovir difficile acid in an organic solvent and then adding an organic acid (HA) to crystallize in the form of adefovir difficyl acid salt of Formula 5; Iii) dissolving the crystallized adefovir difficile acid salt of Formula 5 in water and then adding inorganic salts to form an adefovir difficile precipitate of Chemical Formula 1; Iii) a method for producing adefovir difficile, comprising the step of washing and drying the adefovir difficile precipitate of Formula 1;

[Formula 1]

[Formula 2]

(3)

[Chemical Formula 5]

9- [2- [bis [(pivaloyloxy) methoxy] phosphinyl] methoxy] ethyl] adenine is a compound of formula 1, also referred to as Adefovir dipivoxil, a drug useful as an antiviral therapeutic It is used as a nucleotide reverse transcriptase inhibitor and is an agent showing excellent therapeutic effect.

[Formula 1]

The compound of Formula 1, Adefovir difficile is Inst. Org. Chem. Biochem. Acad. Sci. Is a registered patent under the name of Prodrugs of phosphonates ( U.S. Pat.No.5663159), A compound developed by Galide Science Incorporated, which is a registered patent under the name of nucleotide homolog (Korean Patent 10-0619298), and a patent on the preparation method is used for nucleotide homologous composition (Korean Patent 10-0618663, Process for preparing Adefovir). Dipivoxil European Patent EP 1256584,) is registered under the name. In addition, CJ has filed a patent under the name of improved manufacturing method of adefovir difficile (Korean Publication No. 10-2010-0032839). This adefovir difficile is a nucleotide reverse transcriptase inhibitor and shows excellent in vivo antiviral activity against HIV and hepatitis B (HBV). As prior art for the preparation of adefovir difficile, U.S. Pat.

Scheme 1 US Pat. No. 5,566,359, Inst. Org. Chem. Biochem. Acad. Sci.

In N, N- dicyclohexyl-4-morpholin the adefovir of Formula 2 with chloromethyl pivalate blood (Chloromethyl pivalate) phosphorylation reagent (Phosphorylating Agents) - carboxamidine (N, N'-Dicylcohexyl- A process for preparing adefovir difficile acid of Chemical Formula 1 in the presence of 4-morpholinecarboxamidine (32% ). After reaction for 36 hours using -4-morpholine-carboxamidine (N, N'-Dicylcohexyl-4-morpholinecarboxamidine), the reaction mixture was obtained by a conventional method, and then silica gel chromatography was used. It describes a method for purifying and separating a product to obtain adefovir difficile, using silica gel chromatography, which is very difficult to apply in industrial mass production. have. In addition, Korean Patent No. 10-0618663 discloses adefovir difficile compound of Formula 1 in the presence of adefovir and chloromethyl pivalate as organic solvent 1-methyl-2-pyrrolidinone and triethylamine as organic base. A method of making 48.8% is disclosed. However, the above patent excessively generates the compound of formula 6 due to a long reaction time (reaction time 18.5 hours), a long time of crystallization and aging time (crystallization time 16 hours) as a purification process to remove this. This results in a low production yield and a patent as described in a high performance liquid chromatography HPLC, which obtains 98.7 ~ 99.8% purity products, but the sequential purification process is required to produce high purity products. It implies

Another patent, a patent on an improved method for preparing adefovir difficile (Korean Publication No. 10-2010-0032839), is represented by Scheme 3 below.

[Reaction Scheme 3] Republic of Korea Patent Publication No. 10-2010-0032839, CJ ,

As a reaction solvent, dimethyl sulfoxide was reacted with adefovir of Formula 2 with chloromethylpivalate at 30 to 50 ^° C. for 3 to 7 hours under a solvent of triethylamine, whereby the by-product of Formula 6 was less than 15%. Adefovir difficile acid of Formula 1 is prepared in an impure state. After adding acid to the containing organic solvent layer of the reaction mixture and extracting with aqueous layer, the aqueous solution (mobile phase) contains a polymeric material which is not soluble in water such as C1 to C18 alkyl or HP20, and preferably an octadecyl column having 18 carbon atoms. The purity of adefovir difficile after use and passage through an inverted column is said to recover 95% or more, preferably 99% or more of the product.

That is, the method described in the patent uses the dimethyl sulfoxide instead of 1-methyl-3-pyrrolidinone used in the Republic of Korea Patent 10-0618663 reaction time and by-products of formula 6 containing less than 15% Purifying the aqueous solution layer containing the adefovir difficile compound of Formula 1 in an impure state into a reversed phase column using an octadecyl having 18 carbon atoms as shown in the HPLC chart of FIG. It can be seen that the column retention time of the adefovir difficile acid of Formula 1 is very close to 10.106 minutes and 10.917 minutes, respectively. In other words, the separation yield is very low (25%) because a long time separation operation that requires passage through a mobile phase at a very slow flow rate for separation and purification using a column, and the mixed solution is abandoned to separate only a pure product. .

To summarize the above three patents, the manufacturing process listed in the above patent example is simple, but in order to prepare a high-purity adefovir difficile from an organic solvent layer containing the formula 1 adefovir difficile in an impure state containing substantially by-products Several steps of purification process from above i). Recrystallization ii). There is also the hassle of preparing the final compound by proceeding with silica gel column separation. In addition, it is economically disadvantageous in mass production because the adefovir of Formula 2, which is a very expensive raw material, is used to induce a reaction to separate the Formula 1 adefovir difficile with low production yield.

Therefore, there is a need for a new manufacturing method that can maximize the industrial applicability by supplementing the above-described problems of the present invention and at the same time simplifying the separation and purification conditions.

Accordingly, the technical problem of the present invention is a drug useful as an antiviral therapeutic agent, and adefovir difficile compound of Formula 1, which is used as a nucleotide reverse transcriptase inhibitor and exhibits an excellent therapeutic effect, i). It is to provide a new manufacturing method that is simple, ii) easy to mass production, iii) recovery of high purity products, and iv) economically synthesized, such as yield improvement.

In order to achieve the above technical problem, the present invention is to prepare a crude adefovir difficile by iii) reacting adefovir of Formula 2 with chloromethylpivalate of Formula 3; Ii) dissolving the crude adefovir difficile acid in an organic solvent and then adding an organic acid (HA) to crystallize in the form of adefovir difficyl acid salt of Formula 5; Iii) dissolving the crystallized adefovir difficile acid salt of Formula 5 in water and then adding inorganic salts to form an adefovir difficile precipitate of Chemical Formula 1; Iii) adefovir difficile preparation comprising the steps of washing and drying the adefovir difficile precipitate of formula (1).

[Formula 1]

[Formula 2]

(3)

[Chemical Formula 5]

The present invention also provides a method for producing adefovir difficile, wherein the organic acid is at least one selected from the group consisting of oxalic acid, maleic acid and succinic acid.

In addition, the present invention is a method for producing adefovir difficile, characterized in that the inorganic salt is added to at least one selected from the group consisting of sodium carbonate and potassium carbonate in a ratio of 0.97 to 1.03 equivalents based on the equivalent of the adefovir difficile. To provide.

The present invention also provides a method for producing adefovir difficile, characterized in that the organic solvent is at least one selected from the group consisting of ethyl acetate, isopropyl acetate, propyl acetate, isopropanol, 1-propanol and 1-butanol.

In addition, the present invention provides a method for producing adefovir difficile, characterized in that the step iii) is carried out in the pH 6 to 10 range.

Adefovir difficile manufacturing method according to the present invention is simple, it is possible to manufacture a high-purity product easily for mass production, and to enable economic production, such as yield improvement.

1 is a HPLC analysis data of the composite carried out in Example 1
2 is HPLC analysis data of the composition carried out by Example 2
3 is HPLC analysis data of the composition carried out by Example 8
4 is HPLC analysis data of the composition carried out in Example 9
5 is HPLC analysis data of the composition carried out in Example 10.

Adefovir dipivoxil (Adefovir dipivoxil) manufacturing method of the present invention comprises the steps of iii) preparing a crude adefovir difficile by reacting adefovir of formula 2 and chloromethyl pivalate of formula (3); Ii) dissolving the crude adefovir difficile acid in an organic solvent and then adding an organic acid (HA) to crystallize in the form of adefovir difficyl acid salt of Formula 5; Iii) dissolving the crystallized adefovir difficile acid salt of Formula 5 in water and then adding inorganic salts to form an adefovir difficile precipitate of Chemical Formula 1; Iii) washing and drying the adefovir difficile precipitate of Formula 1;

[Formula 1]

[Formula 2]

(3)

[Chemical Formula 5]

In the present invention, the preparation of the crude adefovir difficile by reacting the adefovir of Formula 2 with the chloromethyl pivalate of Formula 3 of step (iii) is a known chemical reaction, in the embodiment of the present invention adefovir of Formula 2 The temperature of the reaction with the chloromethyl pivalate of formula (3) is in the range of 50 to 55 ℃, the reaction time takes about 4.5 to 5.5 hours. As the reaction solvent, a single solvent selected from ethers such as 1,4-dioxane, a polar solvent such as dimethylformamide or dimethylformacetamide, or a mixed solvent of 1: 1 is used, and the weight ratio of the reaction solvent is represented by Chemical Formula 2 A weight ratio of 7 to 20.0 times with respect to the weight of can be used, especially 7 to 12 weight ratio is preferred. In addition, triethylamine was used as a base, and the amount of base was used in the amount of 4.5 to 5.5 equivalents based on adefovir of formula (2). After diluting by adding ethyl acetate to an organic solvent layer containing an adefovir difficile in an impure state containing the by-products prepared under the above-mentioned manufacturing conditions, washing with water three times, and then separating the organic layer containing the product separately After storage, the salt was added to the aqueous washing solution in which the product was partially dissolved, and the ethyl acetate layer obtained by back extraction with ethyl acetate was mixed with the organic layer obtained before. After washing with an aqueous solution of salt dissolved in the mixed organic layer of the product, the separated organic solution layer was treated with anhydrous sodium sulfate, filtered and concentrated to give an impure adefovir difficile containing light yellow by-products. Obtain the contained oil phase. Removal of the organic solvent is carried out under vacuum at 45-50 ° C. (not to exceed 50 ° C.) and typically contains 71-83% of adefovir difficile in the oil phase.

Adefovir difficile preparation method of the present invention comprises the steps of ii) dissolving the crude adefovir difficile in an organic solvent and then adding an organic acid to crystallize in the form of adefovir difficyl acid salt of the formula (5). The organic solvent is added to the oil obtained after the step iii), and then heated to 40 to 45 ° C., stirred to a clear solution. The organic acid solution is prepared in advance and contains adefovir difficile. The reaction solution was slowly added dropwise while maintaining at 40 to 45 ° C. After the dropwise addition, the mixture was slowly cooled to form crystals. The mixture was further stirred and filtered to obtain adefovir dipivoxil acid salt having a purity of 99.30 to 99.88%. In preparing Adefovir dipivoxil acid salt, the organic solvent used includes at least one selected from the group consisting of ethyl acetate, isopropyl acetate, propyl acetate, isopropanol, 1-propanol and 1-butanol. Preferably, a single or mixed solvent selected from these solvents is used, preferably a mixed solvent of ethyl acetate and isopropanol.

In addition, the organic acid to be used is preferably added 0.71 to 0.83 equivalents to the adefovir of formula (2). The type of the organic acid is not particularly limited and may be crystallized by forming an acid salt with adefovir difficile, but preferably at least one selected from the group consisting of oxalic acid, maleic acid and succinic acid, and considering the purity of the obtained acid salt. Maleic acid is most preferred. The adefovir dipoxylate thus obtained is at least 99% high purity.

After the above steps, the method for preparing adefovir difficile compound of the present invention is iii) dissolving the crystallized adefovir difficyl acid salt of Formula 5 in water and then adding inorganic salts to form the adefovir difficile precipitate of Formula 1. The high-purity adefovir dipivoxil maleic acid salt obtained in step ii) was added to water, followed by warming and stirring at 50 to 55 ° C. to obtain a clear solution. When slowly added, white crystals form. After dropping, the pH of the aqueous solution of the aqueous solution is maintained at 6 to 10, preferably 7.5 to 8.5, and the crystallized reaction solution is cooled to 15 to 20 ° C, further stirred and filtered to prepare 9% of Adefovir dipivoxil. Obtain a product of ~ 99.8% purity. As the inorganic base used, at least one selected from the group consisting of sodium carbonate and potassium carbonate is preferable, and sodium carbonate is more preferable. The amount used is preferably 0.97 to 1.0 equivalents to difficile adefovir maleic acid salt.

Thus obtained adefovir difficile precipitate of Formula 1 can be washed and dried to finally obtain a high purity adefovir difficile. Washing and drying are well known to those skilled in the art and will not be described further.

Hereinafter, the present invention will be described in more detail based on the following examples.

However, this is only to help understand the configuration and operation of the present invention and the scope of the present invention is not limited to these embodiments.

Example 1 Synthesis of Adefovir dipivoxil maleic acid salt

Adefovir compound of formula 2 (30 g, 109.8 mmol) was suspended in N, N'-dimethylacetamide (360 g), triethylamine (55.5 g, 5.0 equiv) was added at room temperature (˜25 ° C.), and then room temperature. Stir at (~ 25 ° C) for 15 minutes. Chloromethyl pivalate (84 g, 5.1 equivalents) was added to the reaction mixture at once, and then heated to maintain an internal temperature of 50 to 55 ° C. and stirred for 5.5 hours. When analyzed by HPLC, when the adefovir of Chemical Formula 2 becomes 2.0% or less, in order to terminate the reaction, the reaction temperature is cooled to 20-25 ° C., ethyl acetate (360 gr) is added at a time, and the internal temperature is maintained at 10 to 15 ° C. . The reaction mixture in which the crystals were precipitated was stirred at 10 to 15 ° C. for 30 minutes to remove the precipitated triethylamine hydrochloride by filtration. Water (360 g) was added to the filtered solution, stirred for 20 minutes, then left to stand, separated and separated. The aqueous solution layer was stored separately (primary aqueous solution layer). Water (180g) was added to the separated organic solution layer, and the same washing process was performed twice consecutively, and then the organic solution was separated separately (primary organic layer). Combine, add salt (45g), dissolve, add ethyl acetate (180g), back extract some products, and separate the organic solution, which is then combined with the previously separated organic layer (primary organic layer). 10% brine (250g) was added to the combined organic solution layers, stirred for 20 minutes, and left to stand. The separated organic solution layer was treated with anhydrous sodium sulfate, anhydrous and filtered. The organic solvent was distilled off under reduced pressure at 45 to 50 ° C. to obtain an oil phase (64.2 g). The obtained compound was analyzed via HPLC. The analysis conditions were analyzed according to the disclosure law set out in the Korean Pharmacopoeia, and the conditions are as follows.

Column type-Alltech Mixed Mode ExchangeTM C8 (7u, 100Å),

Flow rate-1.2 ml / min,

Detector-UV absorption photometer (wavelength: 260 nm),

Column temperature-25 ° C,

Mobile Phase A-Phosphate Buffer (pH 6.0): Mixture of acetonitrile in 70:30 ratio,

Mobile phase B-Phosphoric acid buffer solution (pH 6.0): acetonitrile 50:50 ratio mixed solution,

Diluent-Phosphate Buffer (pH 3.0): Mixture of acetonitrile in 20:30 ratio,

The column operating conditions are shown below as gradients.

Time (minutes) Mobile phase A (%) Mobile phase B (%)

0 to 19 100 → 0 19 0 → 100

19 to 36 0 0

36 to 46 0 → 100 100 → 0

Analysis of the composition under these conditions contained 82.7% of adefovir difficile.

Ethyl acetate (417 g) was added to the obtained oil to dissolve it at room temperature (˜25 ° C.), and then maleic acid (maleic acid, 10.54 g, 0.827 equivalents to adefovir) was added to isopropanol (289 g) in another reactor. Warm to C and stir to a clear solution. The solution in which the maleic acid is dissolved is slowly added dropwise to the reaction solution containing adefovir difficile above while maintaining at 40 to 45 ° C. The dropping time takes 30 minutes, after which the reaction mixture is cooled slowly. Crystals form inside the reaction from 13 ℃, which is further cooled to 5 ~ 8 ℃ and further precipitated crystals at the same temperature for 1 hour, filtered and washed with isopropanol. The filtrate was vacuum dried at 60 ° C. for 8 hours to give the title compound Adefovir dipivoxil maleic acid salt. Yield is 42.9 g (yield 63.3%) and purity is 99.73%. The obtained compound was analyzed via HPLC in the same manner as before, and the results are shown in FIG. 1.

The following scheme summarizes the reaction of Example 1.

¹ H NMR (400 MHz, DMSO d ₆ )

8.195 (1H, s, H-8), 8.139 (1H, s, H-2), 7.653 (2H, brs, -NH2),

6.194 (2H, s, maleic acid -CH = CH-) 5.526 (4H, d, -CH ₂ OP (= O)-),

4.335 ((2H, t, J = 4.8 Hz, H-1 '), 3.943 (2H, d, J = 7.6 Hz, H-4'),

3.884 (2H, t, J = 5.2 Hz, H-2 '), 1.116 (18H, s)

¹³ C NMR (400 MHz, DMSO d ₆ ) 175.954 (-C (= O)-), 166.781 (-C (= O)-, maleic acid), 154.151 (C-6), 150.175 (C-2), 149.152 (C-4), 141.835 (C-8), 131.614 (-CH = CH-, maleic acid), 118.340 (C-5), 81.589 (-CH ₂ OP-, d, J = 26.4 Hz), 70.576 ( C-2 ', d, J = 42.8 Hz, 65.016 (C-4'), 63.399 (C-4 '), 42.684 (C-1'), 38.213 (-C- (CH ₃ ) ₃ ), 26.499 (-CH ₃ ).

Melting Point: 280 ~ 283 ℃

Example 2: Synthesis of 2 Adefovir dipivoxil maleic acid salt

Adefovir compound of Formula 2 (30 g, 109.8 mmol) was suspended in N, N'-dimethylacetamide (210 g), triethylamine (55.5 g, 5.0 equiv) was added at room temperature (~ 25 ° C), and then room temperature. Stir at (~ 25 ° C) for 15 minutes. Chloromethyl pivalate (84 g, 5.1 equivalents) was added to the reaction mixture at once, and then heated to maintain an internal temperature of 50 to 55 ° C. and stirred for 5.5 hours. When analyzed by HPLC, when the adefovir of formula 2 became 2.0% or less, in order to terminate the reaction, the reaction temperature was cooled to 20-25 ° C., ethyl acetate (210gr) was added at a time, and the internal temperature was maintained at 10-15 ° C. . The reaction mixture in which the crystals were precipitated was stirred at 10 to 15 ° C. for 30 minutes to remove the precipitated triethylamine hydrochloride by filtration. Water (210 g) was added to the filtered solution, stirred for 20 minutes, left to stand, separated, and the separated aqueous layer was stored separately (primary aqueous layer). The separated organic solution layer was washed with water (120 g) in the same manner for two successive washing operations, and then the organic solution was separated separately (first organic layer), and the second and third aqueous solution layers were washed with the first aqueous layer. Combine, add salt (30g), dissolve, add ethyl acetate (120g), back extract some products, and separate the organic solution, which is combined with the previously separated organic layer (primary organic layer). 10% brine (150g) was added to the combined organic solution layers, stirred for 20 minutes, and left to stand. The separated organic solution layer was treated with anhydrous sodium sulfate, anhydrous treated and filtered, and then the organic solvent was distilled off under reduced pressure at 45 to 50 ° C. to obtain an oil phase (65.4 g). The obtained compound was analyzed by HPLC to contain 78.0% of adefovir difficile.

Ethyl acetate (425 g) was added to the obtained oil to dissolve it at room temperature (˜25 ° C.), and then maleic acid (maleic acid, 9.92 g, 0.780 equivalents to adefovir) was added to isopropanol (294 g) in another reactor. Warm to C and stir to a clear solution. The solution in which the maleic acid is dissolved is slowly added dropwise to the reaction solution containing adefovir difficile above while maintaining at 40 to 45 ° C. The dropping time takes 30 minutes, after which the reaction mixture is cooled slowly. Crystals form inside the reaction from 13 ℃, which is further cooled to 5 ~ 8 ℃ and further precipitated crystals at the same temperature for 1 hour, filtered and washed with isopropanol. The filtrate was vacuum dried at 60 ° C. for 8 hours to give the title compound Adefovir dipivoxil maleic acid salt. The yield is 38.9 g (58.3% yield) and the purity is 99.59%.

The following scheme summarizes the reaction of Example 2.

Example 3: Synthesis of 2 adefovir dipivoxil maleic acid salt

Adefovir compound of Formula 2 (30 g, 109.8 mmol) was suspended in N, N'-dimethylacetamide (480 g), triethylamine (55.5 g, 5.0 equiv) was added at room temperature (˜25 ° C.), and then room temperature. Stir at (~ 25 ° C) for 15 minutes. Chloromethyl pivalate (84 g, 5.1 equivalents) was added to the reaction mixture at once, and then heated to maintain an internal temperature of 50 to 55 ° C. and stirred for 5.5 hours. When analyzed by HPLC, when the adefovir of Chemical Formula 2 became 2.0% or less, in order to terminate the reaction, the reaction temperature was cooled to 20 to 25 ° C., ethyl acetate (480 gr) was added at a time, and the internal temperature was maintained at 10 to 15 ° C. . The reaction mixture in which the crystals were precipitated was stirred at 10 to 15 ° C. for 30 minutes to remove the precipitated triethylamine hydrochloride by filtration. Water (480 g) was added to the filtered solution, stirred for 20 minutes, left to stand, separated, and the separated aqueous layer was stored separately (primary aqueous layer). Water (240 g) was added to the separated organic solution layer to perform the same washing process twice consecutively, and then the organic solution was separated separately (the first organic layer), and the second and third aqueous solution layers were washed with the primary aqueous layer. Combine and add salt (60g), dissolve and add ethyl acetate (240g) to back extract some products, and separate the organic solution, which is combined with the previously separated organic layer (primary organic layer). 10% brine (320g) was added to the combined organic solution layers, stirred for 20 minutes, and left to stand. The separated organic solution layer was treated with anhydrous sodium sulfate, anhydrous and filtered. The organic solvent was distilled off under reduced pressure at 45 to 50 ° C. to obtain an oil phase (65.3 g). The obtained compound was analyzed by HPLC containing 76.0% of adefovir difficile.

Ethyl acetate (424 g) was added to the obtained oil to dissolve it at room temperature (~ 25 ° C), and then maleic acid (maleic acid, 9.69 g, 0.760 equivalents to adefovir) was added to isopropanol (294 g) in another reactor. Warm to C and stir to a clear solution. The solution in which the maleic acid is dissolved is slowly added dropwise to the reaction solution containing adefovir difficile above while maintaining at 40 to 45 ° C. The dropping time takes 30 minutes, after which the reaction mixture is cooled slowly. Crystals form inside the reaction from 13 ℃, which is further cooled to 5 ~ 8 ℃ and further precipitated crystals at the same temperature for 1 hour, filtered and washed with isopropanol. The filtrate was vacuum dried at 60 ° C. for 8 hours to give the title compound Adefovir dipivoxil maleic acid salt. Yield is 36.1 g (53.2% yield) and purity is 99.60%.

The following scheme summarizes the reaction of Example 3.

Example 4 Synthesis of Adefovir dipivoxil maleic acid salt

Adefovir compound of Formula 2 (30 g, 109.8 mmol) was added to N, N'-dimethylformamide.

It is suspended in (210 g), triethylamine (55.5 g, 5.0 equivalents) is added at room temperature (-25 DEG C), followed by stirring at room temperature (-25 DEG C) for 15 minutes. Chloromethyl pivalate (84 g, 5.1 equivalents) was added to the reaction mixture at once, and then heated to maintain an internal temperature of 50 to 55 ° C. and stirred for 5.5 hours. When analyzed by HPLC, when the adefovir of formula 2 became 2.0% or less, in order to terminate the reaction, the reaction temperature was cooled to 20-25 ° C., ethyl acetate (210gr) was added at a time, and the internal temperature was maintained at 10-15 ° C. . The reaction mixture in which the crystals were precipitated was stirred at 10 to 15 ° C. for 30 minutes to remove the precipitated triethylamine hydrochloride by filtration. Water (210 g) was added to the filtered solution, stirred for 20 minutes, left to stand, separated, and the separated aqueous layer was stored separately (primary aqueous layer). Water (150g) was added to the separated organic solution layer to perform the same washing process twice in succession, and then the organic solution was separated separately (first organic layer), and the second and third aqueous solution layers were washed with the first aqueous layer. Combine, add salt (30g), dissolve, add ethyl acetate (150g), back extract some products, and separate the organic solution, which is combined with the previously separated organic layer (primary organic layer). 10% brine (150g) was added to the combined organic solution layers, stirred for 20 minutes, and left to stand. The separated organic solution layer was treated with anhydrous sodium sulfate, anhydrous and filtered. The organic solvent was distilled off under reduced pressure at 45 to 50 ° C. to obtain an oil phase (63.2 g). The resulting compound was analyzed by HPLC containing 77.0% of adefovir difficile. Ethyl acetate (411 g) was added to the obtained oil to dissolve it at room temperature (˜25 ° C.), and then maleic acid (maleic acid, 9.80 g, 0.77 equivalents to adefovir) was added to isopropanol (284 g) in another reactor. Warm to C and stir to a clear solution. The solution in which the maleic acid is dissolved is slowly added dropwise to the reaction solution containing adefovir difficile above while maintaining at 40 to 45 ° C. The dropping time takes 30 minutes, after which the reaction mixture is cooled slowly. Crystals form inside the reaction from 13 ℃, which is further cooled to 5 ~ 8 ℃ and further precipitated crystals at the same temperature for 1 hour, filtered and washed with isopropanol. The filtrate was vacuum dried at 60 ° C. for 8 hours to give the title compound Adefovir dipivoxil maleic acid salt. The yield is 37.9 g (yield 55.9%) and the purity is 99.58%.

The following scheme summarizes the reaction of Example 4.

Example 5 Synthesis of Adefovir dipivoxil maleic acid salt

Adefovir compound of formula 2 (30 g, 109.8 mmol) was suspended in N, N'-dimethylformamide (105 g) and 1,4-dioxane (105 g) and triethylamine (55.5) at room temperature (-25 DEG C). g, 5.0 equivalents) were added and stirred at room temperature (~ 25 ° C) for 15 minutes. Chloromethyl pivalate (84 g, 5.1 equivalents) was added to the reaction mixture at once, and then heated to maintain an internal temperature of 50 to 55 ° C. and stirred for 5.5 hours. When analyzed by HPLC, when the adefovir of formula 2 became 2.0% or less, in order to terminate the reaction, the reaction temperature was cooled to 20-25 ° C., ethyl acetate (210gr) was added at a time, and the internal temperature was maintained at 10-15 ° C. . The reaction mixture in which the crystals were precipitated was stirred at 10 to 15 ° C. for 30 minutes to remove the precipitated triethylamine hydrochloride by filtration. Water (210 g) was added to the filtered solution, stirred for 20 minutes, left to stand, separated, and the separated aqueous layer was stored separately (primary aqueous layer). Water (150g) was added to the separated organic solution layer to perform the same washing process twice in succession, and then the organic solution was separated separately (first organic layer), and the second and third aqueous solution layers were washed with the first aqueous layer. Combine, add salt (30g), dissolve, add ethyl acetate (150g), back extract some products, and separate the organic solution, which is combined with the previously separated organic layer (primary organic layer). 10% brine (150g) was added to the combined organic solution layers, stirred for 20 minutes, and left to stand. The separated organic solution layer was treated with anhydrous sodium sulfate, anhydrous treated, filtered, and the organic solvent was distilled off under reduced pressure at 45 to 50 ° C. to obtain an oil phase (65.7 g). The obtained compound was analyzed by HPLC to contain 78.0% of adefovir difficile. Ethyl acetate (427 g) was added to the obtained oil to dissolve it at room temperature (˜25 ° C.), and then maleic acid (maleic acid, 10.0 g, 0.78 equivalents to adefovir) was added to isopropanol (289 g) in another reactor. Warm to C and stir to a clear solution. The solution in which the maleic acid is dissolved is slowly added dropwise to the reaction solution containing adefovir difficile above while maintaining at 40 to 45 ° C. The dropping time takes 30 minutes, after which the reaction mixture is cooled slowly. Crystals form inside the reaction from 13 ℃, which is further cooled to 5 ~ 8 ℃ and further precipitated crystals at the same temperature for 1 hour, filtered and washed with isopropanol. The filtrate was vacuum dried at 60 ° C. for 8 hours to give the title compound Adefovir dipivoxil maleic acid salt. The yield is 35.9 g (yield 52.9%) and the purity is 99.40%.

The following scheme summarizes the reaction of Example 5.

Example 6 Synthesis of Adefovir dipivoxil maleic acid salt

Preparation of the crude Adefovir dipivoxil proceeds in the same manner as in Example 1. Isopropanol (121.3 g) was added to the obtained oil to dissolve it at room temperature (˜25 ° C.), and then maleic acid (0.83 equivalent to 10.54 g adefovir) was added to isopropanol (289 g) in another reactor. Warm to and stir until clear solution. The solution in which the maleic acid is dissolved is slowly added dropwise to the reaction solution containing adefovir difficile above while maintaining it at 50 to 55 ° C. The dropping time takes 30 minutes, after which the reaction mixture is cooled slowly. Crystals form inside the reaction from 18 ℃, it is further cooled to 5 ~ 8 ℃, and further stirred crystals precipitated at the same temperature for 1 hour, filtered and washed with isopropanol to vacuum at 60 ℃ for 8 hours vacuum Drying affords the title compound Adefovir dipivoxil maleic acid salt. The yield is 38.6 g (yield 56.9%) and the purity is 99.86%.

The following scheme summarizes the reaction of Example 6.

Example 7: Synthesis of Adefovir dipivoxil maleic acid salt

Preparation of the crude Adefovir dipivoxil proceeds in the same manner as in Example 1. Isopropanol (243 g) was added to the obtained oil to dissolve at room temperature (~ 25 ° C), and then maleic acid (0.83 equivalent to 10.54g adefovir) was added to isopropanol (289g) in another reactor to 50 to 55 ° C. Warm and stir to the clear solution. The solution in which the maleic acid is dissolved is slowly added dropwise to the reaction solution containing adefovir difficile above while maintaining it at 50 to 55 ° C. The dropping time takes 30 minutes, after which the reaction mixture is cooled slowly. Crystals form inside the reaction from 18 ℃, it is further cooled to 5 ~ 8 ℃, and further stirred crystals precipitated at the same temperature for 1 hour, filtered and washed with isopropanol to vacuum at 60 ℃ for 8 hours vacuum Drying affords the title compound Adefovir dipivoxil maleic acid salt. The yield is 35.8 g (yield 52.8%) and the purity is 99.88%.

The following scheme summarizes the reaction of Example 7.

Example 8 Synthesis of Adefovir dipivoxil oxaic acid salt

Ethyl acetate (417 g) was added to an oil containing 82.7% adefovir difficile obtained in Example 1, dissolved at room temperature (˜25 ° C.), and oxalic acid (8.2 g, 0.827 equivalents to adefovir) was added to another reactor. It is added to isopropanol (289g) and warmed to 50 to 55 ℃ and stirred until the conversion point to a clear solution. The solution in which the maleic acid is dissolved is slowly added dropwise to the reaction solution containing adefovir difficile above while maintaining at 40 to 45 ° C. The dropping time takes 30 minutes, after which the reaction mixture is cooled slowly. Crystals form inside the reaction from 13 ° C, which is further cooled to 3 to 5 ° C and further precipitated crystals at the same temperature for 2 hours, filtered and washed with isopropanol. The filtrate was vacuum dried at 60 ° C. for 8 hours to afford the title compound Adefovir dipivoxil oxalic acid salt. The yield is 39.7 g (yield 61.1%) and the purity is 99.60%. The obtained composite was analyzed via HPLC in the same manner as before and described in FIG. 3.

The following scheme summarizes the reaction of Example 8.

¹ H NMR (400 MHz, DMSO d ₆ )

11.870 (1H, brs, oxalic acid), 8.205 (1H, s, H-8), 8.120 (1H, s, H-2),

7.530 (2H, brs, -NH2), 5.585 (4H, d, -CH ₂ OP (= O)-),

4.348 ((2H, t, J = 4.8 Hz, H-1 '), 3.970 (2H, d, J = 8.0 Hz, H-4'),

3.912 (2H, t, J = 5.2 Hz, H-2 '), 1.143 (18H, s)

¹³ C NMR (400 MHz, DMSO d ₆ ) 175.697 (-C (= O)-), 161.343 (-C (= O)-, oxalic acid), 154.834 (C-6), 150.916 (C-2), 149.109 (C-4), 141.148 (C-8), 118.264 (C-5), 81.360 (-CH ₂ OP-, d, J = 23.2 Hz), 70.356 (C-2 ', d, J = 42.8 Hz) , 64.841 (C-4 '), 63.224 (C-4'), 42.353 (C-1 '), 38.022 (-C- (CH ₃ ) ₃ ), 26.308 (-CH ₃ ).

Melting Point: 172 ~ 175 ℃

Example 9 Synthesis of Adefovir dipivoxil succinic acid salt

Ethyl acetate (417 g) was added to an oil containing 82.7% adefovir difficile obtained in Example 1, dissolved at room temperature (~ 25 ° C), and succinic acid (10.8 g, 0.827 equivalents to adefovir) was added to another reactor. It is added to isopropanol (289g) and warmed to 50 to 55 ℃ and stirred until the conversion point to a clear solution. The solution in which the maleic acid is dissolved is slowly added dropwise to the reaction solution containing adefovir difficile above while maintaining at 40 to 45 ° C. The dropping time takes 30 minutes, after which the reaction mixture is cooled slowly. Crystals form inside the reaction from 9 ℃, it is further cooled to 0 ~ 1 ℃ and further precipitated crystals at the same temperature for 2 hours, filtered and washed with isopropanol. The filtrate was vacuum dried at 60 ° C. for 8 hours to give the title compound Adefovir dipivoxil succinic acid salt. The yield is 44.0 g (yield 64.6%) and the purity is 99.58%. The obtained compound was analyzed via HPLC under the same conditions as before. 4 is the result.

The following scheme summarizes the reaction of Example 9.

¹ H NMR (400 MHz, DMSO d ₆ )

12.02 (1H, brs, succinic acid), 8.145 (1H, s, H-8), 8.056 (1H, s, H-2),

7.075 (2H, brs, -NH 2), 5.423 (4H, d, -CH ₂ OP (= 0)-),

4.339 ((2H, t, J = 4.8 Hz, H-1 '), 3.980 (2H, d, J = 7.6 Hz, H-4'),

3.925 (2H, t, J = 5.2 Hz, H-2 '),

2.443 (4H, t, J = 4.0 Hz, -C (= 0) CH ₂ CH ₂ C (= 0)-, siccnic acid), 1.151 (18H, s)

¹³ C NMR (400 MHz, DMSO d ₆ ) 175.798 (-C (= O)-), 173.364 (-C (= O)-, succinic acid), 155.727 (C-6), 152.138 (C-2), 149.342 (C-4), 140.795 (C-8), 118.456 (-C (= 0) CH ₂ CH ₂ C (= 0)-, siccnic acid), 81.490 (-CH ₂ OP-, d, J = 24.0 Hz ), 70.559 (C-2 ', d, J = 42.8 Hz), 64.958 (C-4'), 63.341 (C-4 '), 42.330 (C-1'), 28.792 (-C- (CH ₃ ) ₃ ), 26.557 (-CH ₃ ).

Melting Point: 118 ~ 123 ℃

Example 10 Synthesis of Adefovir dipivoxil Formula 1

Adefovir difficile maleic acid salt (30 g) prepared in Example 1 was added to water (300 g), followed by warming and stirring at 40 to 45 ° C. to obtain a clear solution. After dissolving sodium carbonate (10 g) in water (80 g) in another reactor, the solution is slowly added dropwise to a solution of adefovir difficyl maleic acid salts to form white crystals. After dropping, the pH of the aqueous solution of the aqueous solution is maintained at 7.5 to 8.5. The solution in which the crystals are precipitated is cooled to 20 to 25 ° C, stirred for an additional 1 hour, filtered, and washed with water sufficiently. The filtrate was vacuum dried at 60 ° C. for 12 hours to afford the title compound Adefovir dipivoxil. Yield was 23.5 g (yield 96.4%), purity was 99.88%, and the result is shown in FIG.

The following scheme summarizes the reaction of Example 8.

Example 11: Synthesis of Adefovir dipivoxil Formula 1

Adefovir difficile maleic acid salt (30 g) prepared in Example 3 was added to water (300 g), followed by warming and stirring at 40 to 45 ° C. to obtain a clear solution. After dissolving sodium carbonate (10 g) in water (80 g) in another reactor, the solution is slowly added dropwise to a solution of adefovir difficyl maleic acid salts to form white crystals. After dropping, the pH of the aqueous solution of the aqueous solution is maintained at 7.5 to 8.5. The solution in which the crystals are precipitated is cooled to 20 to 25 ° C, stirred for an additional 1 hour, filtered, and washed with water sufficiently. The filtrate was vacuum dried at 60 ° C. for 12 hours to afford the title compound Adefovir dipivoxil. Yield is 23.2 g (yield 95.2%) and purity is 99.81%.

The following scheme summarizes the reaction of Example 9.

Example 12 Synthesis of Adefovir dipivoxil Formula 1

Adefovir difficile maleic acid salt (30 g) prepared in Example 4 was added to water (300 g), followed by warming and stirring at 40 to 45 ° C. to obtain a clear solution. After dissolving sodium carbonate (10 g) in water (80 g) in another reactor, the solution is slowly added dropwise to a solution of adefovir difficyl maleic acid salts to form white crystals. After dropping, the pH of the aqueous solution of the aqueous solution is maintained at 7.5 to 8.5. The solution in which the crystals are precipitated is cooled to 20 to 25 ° C, stirred for an additional 1 hour, filtered, and washed with water sufficiently. The filtrate was vacuum dried at 60 ° C. for 12 hours to afford the title compound Adefovir dipivoxil. Yield is 23.3 g (yield 95.6%) and purity is 99.79%.

The following scheme summarizes the reaction of Example 10.

Example 13: Synthesis of Adefovir dipivoxil Formula 1

Adefovir difficile maleic acid salt (30 g) prepared in Example 5 was added to water (300 g), followed by warming and stirring at 40 to 45 ° C. to obtain a clear solution. After dissolving sodium carbonate (10 g) in water (80 g) in another reactor, the solution is slowly added dropwise to a solution of adefovir difficyl maleic acid salts to form white crystals. After dropping, the pH of the aqueous solution of the aqueous solution is maintained at 7.5 to 8.5. The solution in which the crystals are precipitated is cooled to 20 to 25 ° C, stirred for an additional 1 hour, filtered, and washed with water sufficiently. The filtrate was vacuum dried at 60 ° C. for 12 hours to afford the title compound Adefovir dipivoxil. Yield is 23.5 g (yield 96.4%) and purity is 99.84%.

The following scheme summarizes the reaction of Example 11.

Example 14 Synthesis of Adefovir dipivoxil Formula 1

The adefovir difficyl oxalate (30 g) prepared in Example 8 was added to water (300 g), followed by warming and stirring to 40 to 45 ° C. to obtain a clear solution. After dissolving sodium carbonate (10.5 g) in water (80 g) in another reactor, the solution is slowly added dropwise to a solution of adefovir difficyl oxalate to form white crystals. After dropping, the pH of the aqueous solution of the aqueous solution is maintained at 7.5 to 8.5. The solution in which the crystals are precipitated is cooled to 20 to 25 ° C, stirred for an additional 1 hour, filtered, and washed with water sufficiently. The filtrate was vacuum dried at 60 ° C. for 12 hours to afford the title compound Adefovir dipivoxil. Yield is 24.0 g (yield 94.5%) and purity is 99.79%.

The following scheme summarizes the reaction of Example 14.

Example 15 Synthesis of Adefovir dipivoxil Formula 1

Adefovir difficile succinic acid salt (30 g) prepared in Example 9 was added to water (300 g), followed by warming and stirring at 40 to 45 ° C. to obtain a clear solution. After dissolving sodium carbonate (9.8 g) in water (80 g) in another reactor, the solution is slowly added dropwise to the solution of adefovir difficyl succinate salt to form white crystals. After dropping, the pH of the aqueous solution of the aqueous solution is maintained at 7.5 to 8.5. The solution in which the crystals are precipitated is cooled to 20 to 25 ° C, stirred for an additional 1 hour, filtered, and washed with water sufficiently. The filtrate was vacuum dried at 60 ° C. for 12 hours to afford the title compound Adefovir dipivoxil. Yield is 23.3 g (yield 95.8%) and purity is 99.81%.

The following scheme summarizes the reaction of Example 15.

The embodiments of the present invention described above should not be construed as limiting the technical idea of the present invention. The scope of protection of the present invention is limited only by the matters described in the claims, and those skilled in the art will be able to modify the technical idea of the present invention in various forms. Therefore, such improvements and modifications will fall within the protection scope of the present invention, as will be apparent to those skilled in the art.

Claims (5)

Iii) reacting adefovir of Formula 2 with chloromethylpivalate of Formula 3 to produce crude adefovir difficile;
Ii) dissolving the crude adefovir difficile acid in an organic solvent and then adding an organic acid (HA) to crystallize in the form of adefovir difficyl acid salt of Formula 5;
Iii) dissolving the crystallized adefovir difficile acid salt of Formula 5 in water and then adding inorganic salts to form an adefovir difficile precipitate of Chemical Formula 1;
Iii) adefovir difficile manufacturing method comprising the step of washing and drying the adefovir difficile precipitate of formula (1).
[Formula 1]

(2)

(3)

[Chemical Formula 5]

The method of claim 1,
The organic acid is adefovir difficile manufacturing method, characterized in that at least one selected from the group consisting of oxalic acid, maleic acid and succinic acid. The method of claim 1,
The inorganic salt is one or more selected from the group consisting of sodium carbonate and potassium carbonate, the adefovir difficile manufacturing method, characterized in that added in a ratio of 0.97 to 1.03 equivalents based on the equivalent of the adefovir difficile. The method of claim 1,
Wherein said organic solvent is at least one member selected from the group consisting of ethyl acetate, isopropyl acetate, propyl acetate, isopropanol, 1-propanol and 1-butanol. The method of claim 1,
The step iii) is adefovir difficile manufacturing method, characterized in that carried out in the pH 6 to 10 range.

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