KR101640504B1 - Novel process of Entecavir monohydrate - Google Patents
Novel process of Entecavir monohydrate Download PDFInfo
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- KR101640504B1 KR101640504B1 KR1020150053004A KR20150053004A KR101640504B1 KR 101640504 B1 KR101640504 B1 KR 101640504B1 KR 1020150053004 A KR1020150053004 A KR 1020150053004A KR 20150053004 A KR20150053004 A KR 20150053004A KR 101640504 B1 KR101640504 B1 KR 101640504B1
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- dimethylacetamide
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- QZXCVYHKNTUNCU-IEAUDRPASA-N C=C([C@@H](CN(C1N=C(N)N2)C=NC1C2=O)C1)[C@H](CO)[C@H]1O Chemical compound C=C([C@@H](CN(C1N=C(N)N2)C=NC1C2=O)C1)[C@H](CO)[C@H]1O QZXCVYHKNTUNCU-IEAUDRPASA-N 0.000 description 1
- NLKWEGSVEJMGLY-GSDWIKKDSA-N C=C([C@H](COCc1ccccc1)[C@H](C1)OCc2ccccc2)[C@H]1N(C1N=C(N)N2)C=NC1C2=O Chemical compound C=C([C@H](COCc1ccccc1)[C@H](C1)OCc2ccccc2)[C@H]1N(C1N=C(N)N2)C=NC1C2=O NLKWEGSVEJMGLY-GSDWIKKDSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
Abstract
The present invention relates to an improved process for the production of entecavir monohydrate which is useful for mass production since it can be obtained as a high purity product under milder conditions and without special equipment.
Description
The present invention relates to an improved process for the production of entecavir monohydrate, which can be obtained as a high purity product under milder conditions and without special equipment.
Entecavir is a hepatitis B treatment agent and its chemical name is 2-amino-9 - ((1S, 3R, 4S) -4-hydroxy-3- (hydroxymethyl) -2- methylcyclopentyl) Purin-6 (9H) -one. ≪ / RTI >
[Chemical Formula 1]
Various production methods of entecavir are known. As a typical preparation method thereof, there is a method of synthesizing entecavir using a compound represented by the following formula (2) as an intermediate.
(2)
The compound represented by Formula 2 is a compound having a benzyl group as a hydroxy-protecting group at the C3 and C4 positions of the cyclopentyl group, which is chemically stable and easy to remove impurities, and has a small side reaction.
United States Patent No. 5,206,244 (hereinafter referred to as Patent Document 1) discloses a method for directly producing entecavir from a compound represented by the following formula (2) as shown in
[Reaction Scheme 1]
According to
In addition, International Patent Publication No. WO 2004/052310 (hereinafter referred to as Patent Document 2) discloses a method for adsorbing an entecavir using a column filled with SP207 resin as a purification method of entecavir. However, this method is also ineffective for industrial application as a column separation method.
As described above, Entecavir is commercialized as a hepatitis B treatment agent, but it is highly urged to develop a manufacturing method and a purification method suitable for industrially mass production of entecavir.
The object of the present invention is to provide a process for preparing entecavir monohydrate from the compound of formula (2) under mild conditions and without any special equipment.
It is another object of the present invention to provide a method for purifying entecavir monohydrate via synthesis of an entecavir dimethylacetamide solvate.
In order to solve the above-mentioned problems, the present invention is characterized by a process for producing entecavir monohydrate comprising steps (i), (ii) and (iii) as shown in
(I) acetylating a compound represented by the following formula (2) using a Lewis acid and an acetylating reagent to prepare a compound represented by the following formula (3);
Ii) deacetylating the compound represented by the
Iii) subjecting the compound represented by the following formula (4) to debenzylation under acidic conditions to produce an entecavir monohydrate represented by the following formula (1).
[Reaction Scheme 2]
In order to solve the above-mentioned problems, the present invention also features a process for producing entecavir monohydrate, which further comprises the following step (iv-1) of purification after steps (i), (ii) and (iii):
(Iv-1) The entecavir monohydrate represented by the formula (1) is dissolved in N, N-dimethylacetamide (DMAc) or an aqueous solution thereof and then crystallized to obtain an entecavir dimethylacetamide solvate,
Dissolving the entecavir dimethylacetamide solvate in a solvent selected from the group consisting of water, an alcohol and an aqueous solution of alcohol, and then recrystallizing to obtain entecavir monohydrate.
Further, in order to solve the above-mentioned problems, the present invention is characterized by further comprising a purification step of entecavir monohydrate, further comprising the following step (iv-2) of purification after steps (i), (ii) and (iii):
Iv-2) The entecavir monohydrate represented by the formula (1) is dissolved in N, N-dimethylacetamide (DMAc) or an aqueous solution thereof and then crystallized to obtain an entecavir dimethylacetamide solvate,
Dissolving the entecavir dimethylacetamide solvate in an aqueous acid solution and then recrystallizing the solution with an aqueous alkaline solution adjusted to a pH in the range of 6.90 to 7.1 to obtain entecavir monohydrate.
In order to solve the above-mentioned problems, the present invention is characterized by an entecavir dimethylacetamide solvate as an intermediate compound produced in the purification step iv-1) or iv-2).
The present invention is a method for producing entecavir monohydrate from the compound represented by the above formula (2), and does not use expensive palladium catalyst or titanium trichloride (TiCl 3 ) or boron trichloride (BCl 3 ) Is high.
In addition, the production method of the present invention uses a reaction reagent having a price competitiveness and is also useful as a mass production process because the reaction conditions are mild.
1 is a liquid chromatogram (HPLC) chart showing the purity of crude entecavir monohydrate.
2 is a liquid chromatogram (HPLC) chart showing the purity of high purity entecavir monohydrate.
3 is a nuclear magnetic resonance (NMR) chart of an entecavir dimethylacetamide solvate.
4 is an X-ray diffraction (XRD) chart of an entecavir dimethylacetamide solvate.
The compound represented by Formula 2 used as a starting material in the method for producing entecavir monohydrate according to the present invention is a compound in which a benzyl group is substituted as a hydroxy protecting group at the C3 position and the C4 position of the cyclopentyl group.
The objective entecavir monohydrate of the present invention is a compound represented by the above formula (1) wherein the C3 position of the cyclopentyl group and the benzyl group at the C4 position are deprotected.
In the present invention, in order to deprotect two benzyl groups from the starting material represented by the above formula (2), a method of deprotecting the C3 benzyl group of the cyclopentyl group and then deprotecting the C5 benzyl group of the cyclopentyl group was adopted.
As described above, the compound represented by Formula 2 has a chemically stable structure, and it is not easy to selectively deprotect the hydroxy protecting group only at positions C3 and C4 of the cyclopentyl group. In a conventional way the two benzyl groups at the same time, titanium trichloride (TiCl 3), or boron trichloride to the reaction with Pd / C catalyst and hydrogen pressure conditions in order to deprotection or -70 ℃ at a low temperature from a compound of the formula 2 (BCl 3 ) Was used as the reaction system. However, the reaction conditions are too severe and the yield of the product is too low to be applied in a mass production method. Particularly, the compound represented by the following formula (A), which is produced as a byproduct, is chemically structurally similar to entecavir, so that it is not easy to purify and entarvir can not be produced with high purity.
(A)
Accordingly, in order to solve the problems of the conventional method, in the present invention, benzyl groups bound to the C3 position of the cyclopentyl group are deprotected under mild reaction conditions, benzyl group deprotection sequentially bonded to the C5 position of the cyclopentyl group It is a way of thinking.
In the present invention, in order to deprotect the benzyl group at the C3 position of the cyclopentyl group of the starting material represented by the formula (2), a two-step process consisting of i) acetylation and ii) deacetylation is carried out. This avoids the use of strong reducing agents such as Pd / C to prevent the reduction of the double bonds at the C2 position and induce the debenzylation at the C3 position under mild conditions. In the present invention, the purity of the final object can be improved by passing the compound represented by the formula (3) through an acetylation reaction as an intermediate and separating the purified compound of the formula (3).
In addition, the compound represented by Formula 4, prepared through the above acetylation and deacetylation reaction, is synthesized as a high purity compound, so that the debenzylation reaction at the C4 position proceeds easily under mild acid conditions to obtain the desired entecavir It became possible to obtain the hydrate at a high purity and a high yield.
The process for preparing entecavir monohydrate according to the present invention will be described in more detail as follows.
The step i) may be carried out by subjecting a compound represented by the following
The acetylation reaction is carried out using a Lewis acid and an acetylation reagent. As the Lewis acid, at least one selected from the group consisting of zinc (II) chloride, iron (II) chloride and tin (II) chloride can be used. The Lewis acid may be used in a range of 5 to 15 molar ratio based on 1 mol of the compound represented by the formula (2) used as a starting material. The acetylation reagent may be at least one selected from the group consisting of acetic acid, acetic anhydride and acetyl halide, preferably acetyl halide, or a mixture of 60 to 70% by weight of acetic anhydride and 30 to 40% By weight based on the total weight of the composition. The acetylation reagent may be used in a range of 30 to 70 molar equivalents based on 1 mol of the compound represented by the formula (2) used as a starting material. The acetylation reaction temperature may be maintained at a mild condition of -10 ° C to 30 ° C, preferably 0 ° C to 20 ° C. When the reaction is carried out under the above-mentioned conditions, the acetylation reaction can be selectively performed only for the C3 position of the cyclopentyl group and the C2 position of the purine-9-one.
The step (ii) is a step of deacetylating the compound represented by the following formula (3) to obtain a compound represented by the following formula (4) wherein the acetyl group bonded to the C3 position of the cyclopentyl group and the C2 position of the purine- It is a manufacturing step.
The deacetylation reaction is carried out under the conditions using a base and a polar solvent. As the base, an alkali metal salt or an alkaline earth metal salt compound may be used. Specifically, at least one selected from the group consisting of a hydroxide of an alkali metal or an alkaline earth metal or a C 1 -C 6 alkoxide may be included. More specifically, the base may be at least one selected from the group consisting of LiOH, NaOH, KOH, Ca (OH) 2 , sodium methoxide, and sodium ethoxide, and preferably sodium hydroxide or sodium methoxide Can be used. The base may be used in an amount of 10 to 30 molar ratio based on 1 mol of the compound represented by the formula (3). As the polar solvent, at least one selected from the group consisting of water and C 1 -C 6 alcohols can be used. As the polar solvent, at least one selected from the group consisting of water, methanol, ethanol and isopropanol may be used, and methanol may be preferably used. The polar solvent may be used in an amount of 5 to 30 parts by volume based on the compound represented by the formula (3). The deacetylation reaction temperature is maintained in the range of 30 ° C to 50 ° C. When the reaction is carried out under the above-described conditions, the deacetylation reaction can be selectively performed only on the C3 position of the cyclopentyl group and the C2 position of the purine-9-one.
The step iii) is a step for preparing an entecavir hydrate represented by the following
The debenzylation reaction is carried out at a temperature of 40 to 70 DEG C using an aqueous hydrochloric acid solution or concentrated hydrochloric acid. It is best to use concentrated hydrochloric acid. The aqueous hydrochloric acid solution or concentrated hydrochloric acid may be used in an amount of 10 to 50 molar ratio based on the compound represented by the formula (4).
The entecavir monohydrate represented by
On the other hand, the present invention proposes a method of crystallizing entecavir monohydrate with a solvate to purify it.
Entecavir is a poorly soluble compound and can not be easily purified by washing and purification methods using common organic solvents. Further, in the synthesis process of entecavir, it is required to develop an improved purification method for synthesizing entecavir of high purity, since a chemically structurally flexible substance is produced as a by-product (for example, the compound of the above formula A).
The present invention is characterized by a method for purifying entecavir monohydrate according to the following (iv-1) or (iv-2).
As the first purification method, iv-1) can be obtained by dissolving the entecavir monohydrate represented by the above formula (1) in N, N-dimethylacetamide (DMAc) or an aqueous solution thereof and then crystallizing to obtain an entecavir dimethylacetamide solvate after,
Dissolving the entecavir dimethylacetamide solvate in a solvent selected from the group consisting of water, an alcohol and an aqueous solution of alcohol, and then recrystallizing to obtain entecavir hydrate; .
As a second purification method, iv-2) can be prepared by dissolving the entecavir monohydrate represented by the above formula (1) in N, N-dimethylacetamide (DMAc) or an aqueous solution thereof and then crystallizing the entecavir dimethylacetamide solvate After obtaining,
Dissolving the entecavir dimethylacetamide solvate in an aqueous acid solution and then recrystallizing the solution with an aqueous alkali solution to adjust the pH to 6.90 to 7.1 to obtain entecavir hydrate; .
In order to synthesize an entecavir dimethylacetamide (DMAc) solvate, the entecavir monohydrate represented by the above formula (1) is dissolved in N, N-dimethylacetamide (DMAc) or N , And N-dimethylacetamide (DMAc), followed by crystallization.
Then, in the step (iv-1), the entecavir dimethylacetamide solvate is dissolved in a solvent selected from the group consisting of water, an alcohol and an aqueous alcohol solution, and then crystallized by cooling to precipitate entecavir monohydrate ≪ / RTI >
In the purification step (iv-2), the solvate of entecavir dimethylacetamide is dissolved in an aqueous solution of an acid, and then crystals are precipitated by adjusting the pH to 6.90 to 7.1 with an aqueous alkaline solution. Of entecavir monohydrate is obtained.
The entecavir monohydrate prepared through the above-described purification method can be used as a medicine with a purity of 99.9% or more.
Meanwhile, the method for purifying entecavir monohydrate according to the present invention generally comprises synthesizing an entecavir dimethylacetamide (DMAc) solvate represented by the following formula (5) as an intermediate.
[Chemical Formula 5]
The entecavir dimethylacetamide (DMAc) solvate represented by
The entecavir dimethylacetamide (DMAc) solvate represented by
The present invention will now be described in more detail with reference to the following examples, but the present invention is not limited thereto.
[Example]
Example 1 (1S, 2R, 4S) -4- (2-Acetamido-6-oxo-1,6-dihydropurin-9-yl) -2- (benzyloxymethyl) -3- Preparation of pentyl acetate (compound of formula 3).
The reaction part was charged with 2-amino-9 - ((1S, 3R, 4S) -4- (benzyloxy) -3- (benzyloxymethyl) -2- methylcyclo- -6 (5H) -one (compound of formula 2) (10 g), acetic acid (33 g) and acetic anhydride (67 g) were added and the temperature was adjusted to 0 ° C. 30 g of zinc chloride (II) was subdivided and warmed, and the mixture was heated at 15 DEG C for 8 hours. When the reaction was completed, the temperature was cooled to 0 ° C, 300 mL of ethyl acetate and 300 g of purified water were added to the reaction solution and stirred for 1 hour. The supernatant was layered and washed with 5% aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure until the volume of the solvent became about 1/10, stirred at 0 ° C for 1 hour, filtered and dried to obtain 8.99 g (yield: 91.08%) of the title compound as a solid .
1 H NMR (400 MHz, DMSO-d 6 )? 11.97 (s, IH), 11.60 (s, IH), 8.02 (s, IH), 7.13-7.36 (m, 5H), 5.38-5.49 2H), 4.18-4.22 (m, 1H), 4.09-4.14 (m, 1H), 4.01-4.02 (d, 2H), 5.18 (s, 3.01 (m, 1 H), 2.28-2.37 (m, 2 H) 2.33 - 2.36 (m, 6 H)
The following Table 1 summarizes the yield changes of the compound represented by
(Molar ratio)
(weight%)
(Molar ratio)
Table 2 summarizes the yield and purity change of the compound represented by the formula (3) produced by conducting the acetylation reaction according to the method of Example 1 but setting different kinds of Lewis acid.
- Lewis acid: 10 mole ratio based on 1 mole of starting material of formula (2)
- acetylation reagent: a mixture of 55:45 wt% of acetic anhydride and acetic acid
30 mole ratio based on 1 mole of the starting material of formula (2)
- Reaction temperature: 10 ~ 15 ℃
- Reaction time: 9 hours
Example 2. (1S, 2R, 4S) -4- (2-Acetamido-6-oxo-1,6-dihydropurin-9-yl) -2- (benzyloxymethyl) -3- Preparation of pentyl acetate (compound of formula 3).
The reaction part was charged with 2-amino-9 - ((1S, 3R, 4S) -4- (benzyloxy) -3- (benzyloxymethyl) -2- methylcyclo- -6 (5H) -one (compound of formula 2) (10 g) was added to 100 mL of dichloromethane and the temperature was adjusted to 0 < 0 > C. 23 mL of acetyl chloride was slowly added dropwise, and the mixture was warmed and stirred at 40 DEG C for 6 hours. The temperature was gradually lowered to room temperature, 300 g of purified water was slowly added dropwise to the reaction solution, and the mixture was stirred at the same temperature for 1 hour. The mixture was layered and washed with 5% aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure until the volume of the solvent became about 1/10, stirred at 0 ° C for 1 hour, filtered and dried to obtain 8.84 g (yield 89.56%) of the title compound as a solid .
Example 3. Synthesis of 2-amino-9 - ((lS, 3R, 4S) -3- (benzyloxymethyl) -4- hydroxy-2- methylenecyclopentyl) -4,9-dihydro- 6 (5H) -one (compound of formula 4).
The reaction was carried out in the same manner as in (1S, 2R, 4S) -4- (2-acetamido-6-oxo-1,6-dihydropurin-9-yl) -2- (benzyloxymethyl) -3- 10 g of pentyl acetate (compound of formula (III)) and 250 mL of methanol were added and the temperature was adjusted to 10 DEG C. 100 g of 30% sodium methoxide was added dropwise and the mixture was stirred at 40 DEG C for 3 hours. 150 g of purified water was added dropwise and the mixture was stirred for 1 hour at 25 DEG C. The reaction product was concentrated under reduced pressure to remove methanol and washed with 150 mL of ethyl acetate. The aqueous layer was separated, washed with 5N hydrochloric acid to pH 6.90 The temperature of the reaction solution was lowered to 0 캜 and stirred for 1 hour, followed by filtration and drying to obtain 7.88 g (yield: 96.81%) of the title compound as a solid.
1 H NMR (400 MHz, DMSO -d 6) 1H), 5.08 (m, IH), 4.91-4.94 (m, IH), 7.27-7.33 (m, IH), 4.49-4.50 (s, IH), 4.48 (s, 2H), 4.08 (s, IH), 3.45-3.58 2H)
The following Table 3 summarizes the yield changes of the compound represented by
(Molar ratio)
(Volume ratio)
The following Table 4 summarizes the yield and purity of the compounds represented by
- 25 parts by volume of methanol, 25 parts by mol of base,
-
-
Example 4. Preparation of entecavir monohydrate (compound of formula 1).
The reaction was carried out in the same manner as in Example 1, except that 2-amino-9 - ((1S, 3R, 4S) -3- (benzyloxymethyl) -4-hydroxy-2-methylenecyclopentyl) -4,9-dihydro- (5H) -one (compound of formula (IV)) and 13 g of concentrated hydrochloric acid were added and stirred at 60 ° C for 5 hours. When the reaction was completed, the reaction solution was cooled to 0 ° C and washed with 50 ml of dichloromethane. The aqueous layer was separated and then adjusted to pH 6.90 to 7.1 using 5N aqueous sodium hydroxide solution. After stirring for 3 hours at room temperature, 9 mL of methanol was added and dissolved by heating to 80 to 90 ° C, and 0.15 g of activated carbon was added thereto. The mixture was stirred for 5 minutes and then filtered at the same temperature. The temperature of the reaction solution was lowered to 0 캜, stirred for 1 hour, filtered and dried at 60 캜 for 12 hours to give 2.18 g of the title compound (yield 90.5%, purity 99.72%, formula A impurity 0.04%).
1 H NMR (400 MHz, MeOH -d 4) δ 7.75 (s, 1H), 5.51-5.47 (t, 1H), 5.23-5.22 (t, 1H), 4.78-4.83 (t, 1H), 4.38-4.37 (m, 1H), 3.78-3.77 (d, 2H), 2.67 (s, 1H), 2.42-2. 35 (m, 1H), 2.23-2.18 (m, 1H); HPLC spectrum See FIG.
The following Table 5 summarizes the yield changes of the compound represented by the formula (1) produced by performing the debenzylation reaction in the method of Example 4 but setting the reaction conditions differently.
Example 5. Preparation of high purity entecavir monohydrate (compound of formula 1)
1) Preparation of entecavir dimethyl acetamide solvate (compound of formula 5)
25 g of N, N-dimethylacetamide and 25 ml of purified water were added to 5 g of the entecavir monohydrate prepared in Example 4, followed by stirring at 0 ° C for 2 hours, followed by filtration and drying to obtain 4.9 g of the title compound as a solid ≪ / RTI >
1 H NMR (400 MHz, DMSO -d 6) δ 10.54 (s, 1H), 7.63 (s, 1H), 6.39 (s, 2H), 5.34-5.29 (t, 1H), 5.06 (s, 1H), 2H), 2.90 (s, 2H), 4.90 (s, 2H), 4.86-4.85 2H), 2.18-2.16 (m, IH), 2.02-1.99 (m, IH), 1.92 (s, 2H)
2) Preparation of high purity entecavir monohydrate (compound of formula 1)
15 ml of methanol and 73.5 ml of distilled water were added to 4.9 g of the entecavir dimethylacetamide solvent prepared above, dissolved by heating at 90 ° C and cooled to room temperature. The resulting crystals were stirred at room temperature for 1 hour, filtered, and dried to obtain 4.57 g of the title compound (yield 91.4%, purity 99.93%, formula A: 0.01%) as a white solid.
HPLC spectral analysis of the prepared high purity entecavir monohydrate was attached as FIG. Nuclear magnetic resonance (NMR) and X-ray diffraction (XRD) analyzes of the entecavir dimethylacetamide solvent compound prepared in the above purification process were shown in FIGS. 3 and 4, respectively.
Example 6. Preparation of high purity entecavir monohydrate (compound of formula 1)
1) Preparation of entecavir dimethyl acetamide solvate (compound of formula 5)
25 g of N, N-dimethylacetamide and 25 ml of purified water were added to 5 g of the entecavir monohydrate prepared in Example 4, followed by stirring at 0 ° C for 2 hours, followed by filtration and drying to obtain 4.9 g of the title compound as a solid ≪ / RTI >
2) Preparation of high purity entecavir monohydrate (compound of formula 1)
To 4.9 g of the prepared entecavir dimethylacetamide solvent was added 25 mL of a 1 N aqueous hydrochloric acid solution and dissolved. After washing twice with 50 mL of dichloromethane, 0.25 g of activated carbon was added thereto, followed by stirring for 5 minutes, followed by filtration. The filtrate was adjusted to pH 6.90 to 7.1 with 1 N aqueous sodium hydroxide solution, stirred at room temperature for 1 hour, filtered and dried to obtain 4.63 g of the title compound (yield 92.6%, HPLC purity 99.97%, formula A impurity 0.01%) as a white solid .
COMPARATIVE EXAMPLE 1 Preparation of entecavir monohydrate (compound of formula 1).
The reaction part was charged with 2-amino-9 - ((1S, 3R, 4S) -4- (benzyloxy) -3- (benzyloxymethyl) -2- methylcyclo- -6 (5H) -one (compound of formula 2) (5 g) was added under nitrogen to 100 mL of dichloromethane, the temperature was cooled to -78 ° C and 65 mL of 1 M boron trichloride in dichloromethane was slowly added dropwise. The reaction mixture was stirred at -78 ° C for 30 minutes and then at -20 ° C and stirred for 1 hour. When the reaction was complete, the reaction was cooled to -78 ° C and 150 mL of methanol was slowly added dropwise. The reaction mixture was warmed to room temperature, stirred for 30 minutes, concentrated under reduced pressure to remove methanol, and washed three times with 50 mL of dichloromethane. The aqueous layer was separated and then adjusted to pH 6.90 to 7.1 using 1N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 3 hours, dissolved by heating to 90 ° C, and 0.25 g of activated carbon was added thereto. The mixture was stirred for 5 minutes and then filtered at the same temperature. The temperature of the reaction solution was lowered to 0 캜 and stirred for 1 hour, followed by filtration and drying at 60 캜 for 12 hours to obtain 2.33 g of the title compound (yield: 72.3%, HPLC purity: 97.25%, formula A impurity: 0.24%).
Comparative Example 2 Purification of entecavir monohydrate (compound of formula 1).
1) Preparation of entecavir dimethyl acetamide solvate (compound of formula 5).
25 g of N, N-dimethylacetamide and 25 mL of purified water were added to 5 g of entecavir monohydrate prepared in Comparative Example 1, and the mixture was stirred at 0 ° C for 2 hours, followed by filtration and drying to obtain the title compound 4.71 g was obtained.
2) Purification of entecavir monohydrate (compound of formula 1).
To 4.71 g of the prepared entecavir dimethylacetamide solvent was added 23 mL of a 1 N aqueous hydrochloric acid solution and dissolved. After washing twice with 45 mL of dichloromethane, 0.23 g of activated carbon was added thereto, followed by stirring for 5 minutes, followed by filtration. The filtrate was adjusted to pH 6.90 to 7.1 with 1N aqueous sodium hydroxide solution, stirred at room temperature for 1 hour, filtered and dried to give 4.53 g (90.6%, HPLC purity 98.38%, formula A impurity 0.11%) of the title compound as a white solid Respectively.
[Reference Example]
In this Reference Example, the preparation of entecavir monohydrate (purity: 99.72%) prepared in Example 4 and the preparation of the solvent compound according to Example 5 and recrystallization were performed to prepare high purity entecavir monohydrate using a polar solvent To confirm the presence or absence of solvate formation and the change in purity after purification.
As suggested by the present invention, when the solid state entecavir dimethylacetamide solvate was prepared by the method of Example 5 and then purified by recrystallization with N, N-methylacetamide, the purity of entecavir monohydrate was 99.93% of ultra high purity product.
However, entecavir solvate was not formed when acetonitrile, methanol, or water was used as a polar solvent, and it was found that there was no significant difference in purity even when recrystallized using a polar solvent.
Claims (14)
Ii) reacting the compound represented by the following formula (3) with at least one base selected from the group consisting of hydroxides of an alkali metal or an alkaline earth metal and C 1 -C 6 alkoxide, and one kind selected from the group consisting of water and C 1 -C 6 alcohols Or more of a polar solvent to prepare a compound represented by the following formula (4); And
Iii) subjecting the compound represented by the formula (4) to debenzylation under hydrochloric acid to prepare an entecavir monohydrate represented by the following formula (1);
≪ / RTI >
(Iv-1) The entecavir monohydrate represented by the formula (1) is dissolved in N, N-dimethylacetamide (DMAc) or an aqueous solution thereof and then crystallized to obtain an entecavir dimethylacetamide solvate,
Purification step of the entecavir dimethylacetamide solvate of water, C 1 ~C 6 was then dissolved in the recrystallization solvent is selected from alcohols and C 1 ~C 6 the group consisting of aqueous alcohol, to give the entecavir monohydrate;
≪ / RTI >
Iv-2) The entecavir monohydrate represented by the formula (1) is dissolved in N, N-dimethylacetamide (DMAc) or an aqueous solution thereof and then crystallized to obtain an entecavir dimethylacetamide solvate,
Dissolving the solvate of entecavir dimethylacetamide in an aqueous hydrochloric acid solution and then recrystallizing the solution with adjusting the pH to 6.90 to 7.1 with an aqueous solution of sodium hydroxide to obtain entecavir hydrate;
≪ / RTI >
Wherein the Lewis acid is used in an amount of 5 to 15 molar equivalents based on 1 mol of the compound represented by the formula (2).
Wherein the acetylation reagent is a mixture of 60 to 70% by weight of acetic anhydride and 30 to 40% by weight of acetic acid.
Wherein the acetylating reagent is used in an amount of 30 to 70 molar equivalents based on 1 mol of the compound represented by the general formula (2).
Wherein the polar solvent in step (ii) is at least one selected from the group consisting of water, methanol, ethanol and isopropanol.
Wherein the debenzylation reaction in step (iii) is carried out using concentrated hydrochloric acid at a temperature of 40 to 70 占 폚.
Wherein said entecavir dimethylacetamide solvate is observed at 9.9, 14.3, 16.4, 18.8 degrees of diffraction angle 2 &thetas; characteristic peaks in powder X-ray diffraction analysis.
Wherein the entecavir dimethylacetamide solvate comprises dimethylacetamide in an amount of 10 to 40% by weight in the crystal.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020121123A3 (en) * | 2018-12-12 | 2020-07-30 | Janssen Biopharma, Inc. | Cyclopentyl nucleoside analogs as anti-virals |
| CN115433188A (en) * | 2022-09-29 | 2022-12-06 | 苏州东瑞制药有限公司 | Preparation method of entecavir |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5206244A (en) * | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
| WO2004052310A2 (en) | 2002-12-11 | 2004-06-24 | Bristol-Myers Squibb Company | Process and intermediates for synthesis entecavir |
| KR20110040671A (en) * | 2009-10-12 | 2011-04-20 | 한미홀딩스 주식회사 | Novel method for preparing entecavir and intermediate used therein |
| KR20130135411A (en) * | 2012-05-31 | 2013-12-11 | 일동제약주식회사 | Process for the preparation of highly pure entecavir monohydrate |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5206244A (en) * | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
| WO2004052310A2 (en) | 2002-12-11 | 2004-06-24 | Bristol-Myers Squibb Company | Process and intermediates for synthesis entecavir |
| KR20110040671A (en) * | 2009-10-12 | 2011-04-20 | 한미홀딩스 주식회사 | Novel method for preparing entecavir and intermediate used therein |
| KR20130135411A (en) * | 2012-05-31 | 2013-12-11 | 일동제약주식회사 | Process for the preparation of highly pure entecavir monohydrate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020121123A3 (en) * | 2018-12-12 | 2020-07-30 | Janssen Biopharma, Inc. | Cyclopentyl nucleoside analogs as anti-virals |
| CN115433188A (en) * | 2022-09-29 | 2022-12-06 | 苏州东瑞制药有限公司 | Preparation method of entecavir |
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