KR20100098037A - New salt of lamivudine and the preparation method thereof - Google Patents

Abstract

PURPOSE: A novel lamivudine orotate, cinnamate, cyclamate, are nicotinate are provided to obtain pure lamivudine with antiviral activity against retroviruses. CONSTITUTION: A lamivudine organic acid addition salt of chemical formula 1 contains orotic acid. A lamivudine organic acid addition salt of chemical formula 2 contains cinnamic acid. A lamivudine organic acid addition salt of chemical formula 3 contains cyclamic acid. A lamivudine organic acid addition salt of chemical formula 4 contains napadisilate. A lamivudine organic acid addition salt of chemical formula 5 contains nicotinic acid.

Description

New salt of Lamivudine and the preparation method

The present invention relates to novel salts of lamivudine and methods for their preparation.

Lamivudine is (2R-cis) -4-amino-1- [2- (hydroxymethyl) -1,3-oxathiolan-5-yl) -2 (1H), a compound used in antiviral active agents As a pyrimidinone, it has a mechanism of action that inhibits the activity of viral DNA polymerase and acts as a chain terminator to inhibit the maturation of DNA and the proliferation of virus. In particular, it is known to exhibit effective antiviral activity against retroviruses such as hepatitis B virus (HBV) and human immunodeficiency virus (HIV) which is the cause of AIDS.

In Laid-Open Patent Publication No. 1991 / 017,159 and the like, lamivudine is present as four stereoisomers, and among these isomers, particularly, a compound having a cis- (2R, 5S) structure is known to exhibit excellent antiviral activity.

Thus, many studies on the preparation of lamivudine have been conducted. For example, in EP 382,526, condensation reaction of benzoyloxyacetaldehyde and mercaptoacetaldehyde dialkyl acetal, 1,3, which is a major intermediate of lamivudine -Oxathiola derivatives are synthesized, and then a method for preparing lamivudine is obtained by sequentially glycosylation reaction with cytosine. In addition, International Patent Publication No. 1999 / 111,186 discloses a process for preparing lamivudine, which comprises a step of reacting silylated glycoaldehyde and thioglycolic acid followed by reduction in the presence of DIBAL-H.

However, in several known methods, intermediate compounds are not stereoselectively prepared so that lamivudine is obtained as a mixture of cis / trans. Therefore, there is a disadvantage in that the yield is low and expensive because it is necessary to use HPLC or an enzyme to separate and obtain the lamivudine of the cis-isomer structure with high purity therefrom.

In order to overcome this problem, International Patent Publication No. 1992 / 020,669 discloses a method for separating an isomer using a chromatographic method and then separating the optical isomer from a chiral assistant, but the process is long and complicated. However, the yield is low, there is a disadvantage that is not suitable for applying to the bulk process.

Thus, the present inventors completed the present invention by synthesizing lamivudine acid addition salt having superior physicochemical properties and using a pharmaceutically acceptable organic acid.

It is an object of the present invention to provide high purity novel lamivudine acid addition salts and methods for their preparation.

The present invention is alginic acid (alginic acid), aspartic acid (aspartic acid), caprylic acid (Caprylic acid), dodecyl sulfonic acid, 1,2-ethanedisulfonic acid, music acid, methanesulfonic acid, malic acid, napadi silicic acid, 2 , 5-dihydroxybenzene acid, gluconic acid, glucuronic acid, glutamic acid, hypofuric acid, orotic acid, thiocyanic acid, 4-acetamidobenzene acid, caproic acid, glucoheptonic acid, lactose One organic acid selected from bionic acid, lauric acid, oleic acid, palmitic acid, pyroglutamic acid, sebacic acid and stearic acid, cinnamic acid, cyclamic acid and nicotinic acid was added. Lamivudine organic acid addition salt is provided.

Pharmaceutically preferred lamivudine organic acid addition salt of the present invention is lamivudine orotate of formula (I):

[Formula 1]

Pharmaceutically preferred lamivudine organic acid addition salts of the present invention are lamivudine cinamate of Formula 2:

[Formula 2]

Pharmaceutically preferred lamivudine organic acid addition salts of the present invention are cyclamides of lamivudine of Formula 3:

(3)

Pharmaceutically preferred lamivudine organic acid addition salt of the present invention is lamivudine nafadisylate of formula (4):

[Formula 4]

Pharmaceutically preferred lamivudine organic acid addition salts of the present invention are lamivudine nicotinate of Formula 5:

[Chemical Formula 5]

In addition, the present invention provides alginic acid, aspartic acid, caprylic acid, dodecylsulfonic acid, 1,2-ethanedisulfonic acid, music acid, methanesulfonic acid, malic acid, napadisilic acid, 2,5-dihydroxybenzene acid, glue Cholic acid, glucuronic acid, glutamic acid, hypofuric acid, orotic acid, thiocyanic acid, 4-acetamidobenzene acid, caproic acid, glucoheptonic acid, lactobionic acid, lauric acid, oleic acid, palmitic acid, fatigue Provided is a method for preparing lamivudine acid addition salt in which lamivudine acid addition salt is prepared by reacting lamivudine free salt with one organic acid selected from glutamic acid, sebacic acid, stearic acid, cinnamic acid, cyclic acid and nicotinic acid.

Schematic of this is shown in [Scheme 1].

Scheme 1

In Scheme 1, HX is alginic acid, aspartic acid, caprylic acid, dodecylsulfonic acid, 1,2-ethanedisulfonic acid, music acid, methanesulfonic acid, malic acid, napadisic acid, 2,5-dihydroxybenzene acid , Gluconic acid, glucuronic acid, glutamic acid, hypofuric acid, orotic acid, thiocyanic acid, 4-acetamidobenzene acid, caproic acid, glucoheptonic acid, lactobionic acid, lauric acid, oleic acid, palmitic acid Means an acid selected from pyroglutamic acid, sebacic acid, stearic acid, cinnamic acid, cyclic acid and nicotinic acid.

The present invention also comprises the steps of: 1) mixing the lamivudine free base into the reaction solvent to mix; 2) preparing an organic acid addition salt of lamivudine by adding an organic acid to the resultant of the first step and heating and stirring; And 3) cooling the resultant of the second step to room temperature or below room temperature to crystallize to obtain lamivudine organic acid addition salt, thereby preparing a lamivudine organic acid addition salt.

In the production method of the present invention, lamivudine free base may be prepared directly or purchased by a known method.

In the production method of the present invention, the organic acid is as mentioned above, and orotic acid, cinnamic acid, cyclic acid, napadi silic acid or nicotinic acid are more preferable.

In the production method of the present invention, the reaction solvent may be a polar organic solvent or water. Polar organic solvents include methanol, ethanol, isopropanol, acetone, tetrahydrofuran, dimethylacetamide, 1,4-dioxane and the like, with water being most preferred.

The organic acid used in the production method of the present invention is preferably used in the amount of 1 to 3 equivalents, more preferably 1.1 to 1.5 equivalents based on lamivudine free base.

In the production method of the present invention, the reaction solvent is preferably used in an amount of 5 to 100 ml with respect to 1 g of lamivudine free base, and more preferably in an amount of 10 to 50 ml with respect to 1 g of lamivudine free base.

In the production method of the present invention, the reaction temperature is preferably a temperature below room temperature to the boiling point of the reaction solvent, more preferably 40 to 100 ° C. The preferred reaction temperature may vary depending on the type of reaction solvent, and when the reaction solvent is water, 80 to 90 ° C is preferred.

In the production method of the present invention, the reaction time may vary depending on the reaction temperature and the reaction solvent, preferably 30 minutes to 4 hours.

In the present invention, the crystallization method means a known crystallization method. For example, after cooling to room temperature (20-30 ° C.) or below room temperature, the mixture is stirred or left as it is to crystallize. Alternatively, the reaction product is concentrated under reduced pressure to obtain an oil residue, and then crystallized by adding a crystalline solvent and stirring at room temperature or below room temperature. The crystallization solvent here may be methanol, ethanol, isopropanol, acetone, water, with water, ethanol and methanol being preferred.

Lamivudine acid addition salt of the present invention has a simple manufacturing process, it is possible to obtain a more pure lamivudine in the process of synthesizing acid addition salt, and has a physicochemically superior properties compared to the lamivudine free base and conventional acid salt addition salts An antivirally active branch effective against retroviruses with an acceptable carrier can be used as an active ingredient in pharmaceutical compositions.

Hereinafter, the present invention will be described in more detail based on the following examples, which are intended to illustrate the present invention, but are not intended to limit the present invention.

Hereinafter, ¹ H NMR used in the examples was Bruker UltraShield ™ 400 (400 MHz), HPLC was used Agilent 1200 series and elemental analysis was used CE Instrument EA1110. Reagents and solvents not specifically mentioned by the manufacturer were used from Aldrich, Sigma and Acros.

Example 1 Preparation of Lamivudine Orotate

10.0 g of lamivudine free base (purity 99.62%) and 200 mL of water were added to a 500 mL reaction vessel, and the mixture was stirred at room temperature to dissolve. 7.6 g of orotic acid was added and stirred at 80 ° C to 90 ° C for 1 hour. After the reaction was cooled to room temperature (20 ~ 30 ℃) and stirred for 3 hours to crystallize. The precipitated solid was filtered and dried in vacuo to give 15.0 g of lamivudine orotate as a white title compound.

HPLC purity: 99.96%

Elemental analysis: Found N 17.8%, C 40.4%, H 4.2%, S 8.3% (Theory N 18.1%, C 40.5%, H 3.9%, S 8.3%)

¹ H NMR (400 MHz, DMSO- d ₆ ): 11.23 (s, 1H), 10.60 (s, 1H), 7.92 (d, 1H), 7.85 (s, 2H), 6.18 (t, 1H), 5.91 ( s, 1H), 5.80 (d, 1H), 5.17 (t, 1H), 3.74 (d, 2H), 3.42 (dd, 1H), 3.10 (dd, 1H) ppm

< Example  2> Lamivudine Cinnamate  Produce

10.0 g of lamivudine free base (purity 99.62%) and 200 mL of water were injected into a 500 mL reaction vessel, and the mixture was stirred at room temperature to dissolve. Cinnamic acid (cinnamic acid) 6.5 g was added and stirred for 1 hour at 80 ~ 90 ℃. The reaction was then cooled to room temperature (20-30 ° C.) and crystallized by stirring overnight. The precipitated solid was filtered and dried in vacuo to give 13.0 g of lamivudine cinamate as a white title compound.

HPLC purity: 99.91%

Elemental analysis: Found N 10.8%, C 54.0%, H 5.1%, S 8.3% (Theory N 11.1%, C 54.1%, H 5.1%, S 8.5%)

¹ H NMR (400 MHz, DMSO- d ₆ ): 7.81 (d, 1H), 7.66 (m, 2H), 7.57 (d, 1H), 7.39 (m, 3H), 7.27 (br, 2H), 6.52 ( d, 1H), 6.19 (t, 1H), 5.72 (d, 1H), 5.16 (t, 1H), 3.75 (m, 2H), 3.38 (dd, 1H), 3.02 (dd, 1H) ppm

< Example  3> Lamivudine Cyclate  Produce

10.0 g of lamivudine free base (purity 99.62%) and 200 mL of water were injected into a 500 mL reaction vessel, and the mixture was stirred at room temperature to dissolve. 7.8 g of cyclic acid was added and stirred at 80 ° C. to 90 ° C. for 1 hour. The reaction was then concentrated under reduced pressure at 50 ° C. and 50 mbar to obtain an oily residue. 50 mL of acetone was injected into the obtained residue, which was then crystallized by stirring at -10 to -5 ° C. The precipitated solid was filtered and dried in vacuo to give 13.0 g of lamivudine cyclate, the white title compound.

HPLC purity: 99.92%

Elemental Analysis: Found N 13.5%, C 40.1%, H 5.9%, S 15.5% (Theory N 13.7%, C 41.2%, H 5.9%, S 15.7%)

¹ H NMR (400 MHz, DMSO- d ₆ ): 7.88 (d, 1H), 7.48 (br, 2H), 6.20 (t, 1H), 5.77 (d, 1H), 5.34 (br, 1H), 5.18 ( t, 1H), 3.74 (m, 2H), 3.42 (dd, 1H), 3.13-2.98 (m, 2H), 2.10 (s, 2H), 1.69 (s, 2H), 1.54 (d, 1H), 1.21 (br, 4H), 1.05 (br, 1H) ppm

< Example  4> Lamivudine Nafadisylate  Produce

10.0 g of lamivudine free base (purity 99.62%) and 200 mL of water were injected into a 500 mL reaction vessel, and the mixture was stirred at room temperature to dissolve. 15.7 g of naphthalene-1,5-disulfonic acid tetrahydrate was added thereto, stirred at 80 to 90 ° C. for 1 hour, and the reaction mixture was concentrated under reduced pressure at 50 ° C. and 50 mbar to obtain an oily residue. 20 mL of methanol was added to the obtained residue to dissolve it, and 50 mL of acetone was added dropwise, followed by stirring for 3 hours at room temperature to crystallize. The precipitated solid was filtered and dried in vacuo to give 15.0 g of lamivudine nafadisylate, the white title compound.

HPLC purity: 99.87%

Elemental Analysis: Found N 10.7%, C 41.0%, H 4.1%, S 17.1% (Theory N 10.8%, C 40.1%, H 3.9%, S 16.5%)

¹ H NMR (400 MHz, DMSO- d ₆ ): 9.44 (s, 1H), 8.36 (d, 1H), 8.28 (d, 2H), 7.91 (d, 1H), 7.40 (dd, 1H), 6.18 ( t, 1H), 6.03 (d, 1H), 5.23 (t, 1H), 3.83 (m, 2H), 3.51 (dd, 1H), 3.31 (dd, 1H) ppm

< Example  5> Lamivudine Nicotinate  Produce

10.0 g of lamivudine free base (purity 99.62%) and 200 mL of water were injected into a 500 mL reaction vessel, and the mixture was stirred at room temperature to dissolve. 5.4 g of nicotinic acid were added and stirred for 1 hour at 80 to 90 ° C. The reaction was then concentrated under reduced pressure at 50 ° C. and 50 mbar to obtain an oily residue. 40 mL of methanol was added to the obtained residue, and the mixture was stirred at room temperature for 2 hours to crystallize and the precipitated solid was filtered. 100 mL of isopropanol was injected into the obtained solid, and the resulting mixture was heated to 50 ° C to dissolve and stirred for 15 minutes. The reaction was cooled to room temperature and crystallized by stirring overnight. The precipitated solid was filtered and dried in vacuo to give 12.0 g of lamivudine nicotinate as a white title compound.

HPLC purity: 99.83%

Elemental analysis: Found N 15.9%, C 47.4%, H 4.6%, S 9.2% (Theory N 15.9%, C 47.7%, H 4.6%, S 9.1%)

¹ H NMR (400 MHz, DMSO- d ₆ ): 9.05 (m, 1H), 8.76 (m, 1H), 8.24 (m, 1H), 7.80 (d, 1H), 7.52 (m, 1H), 7.24 ( br, 2H), 6.18 (t, 1H), 5.71 (d, 1H), 5.15 (t, 1H), 3.72 (m, 2H), 3.38 (dd, 1H), 3.02 (dd, 1H) ppm

Claims (8)

One organic acid selected from Naphthalene-1,5-disulfonic acid, orotic acid, cinnamic acid, cyclamic acid and nicotinic acid is added. Lamivudine organic acid addition salt. The organic acid addition salt of lamivudine of the formula (1) according to claim 1, wherein the organic acid is orotic acid. [Formula 1]

The organic acid addition salt of lamivudine of the formula (2) according to claim 1, wherein the organic acid is Cinnamic acid. [Formula 2]

The organic acid addition salt of lamivudine of the formula (3) according to claim 1, wherein the organic acid is Cyclamic acid. (3)

The organic acid addition salt of lamivudine of the formula (4) according to claim 1, wherein the organic acid is naphthalene-1,5-disulfonic acid. [Formula 4]

The organic acid addition salt of lamivudine of the formula (5) according to claim 1, wherein the organic acid is nicotinic acid. [Chemical Formula 5]

The lamivudine organic acid addition salt according to claim 1, wherein the organic acid addition salt of lamivudine is an anhydride or a hydrate. Lamivudine acid addition salt manufacturing method for producing lamivudine acid addition salt by reacting one of the organic acid selected from napadi silic acid, orotic acid, cinnamic acid, cyclic acid and nicotinic acid with lamivudine free base.