KR20180105450A - A Method of preparing Fimarsartan choline salt and hydrate thereof - Google Patents

Abstract

The present invention relates to a preparation method of fimarsartan choline salt and a hydrate thereof. The preparation method of the present invention uses an inexpensive starting material takes shorter processing time to prepare fimarsartan choline salt at a high yield. Therefore, the preparation method can remarkably reduce the production unit cost, thereby being economical and suitable for mass production.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a method for preparing phimacartan choline salt and hydrate thereof,

The present invention relates to a method for preparing a castor oil chalcine salt and a hydrate thereof.

Fimasartan has reported that (2-n-butyl-5-dimethylamino thiocarbonyl methyl-6-methyl-3 - [[ 3H) -one}, and has the following structure.

(I)

Pimassartan is known as an angiotensin II receptor antagonist and is marketed in three doses, 30, 60 and 120 mg, under the trade name Kanab®, approved as a hypertensive drug.

Pimassartan is a pyrimidinone compound having a structure different from that of a drug having an antagonistic action to the conventional angiotensin II receptor and is described in International Application No. PCT / KR1999 / 00198, Korean Patent No. 10-0617953 A manufacturing method is disclosed.

Korean Patent Registration No. 10-0521980 discloses a method for producing a trihydrate of a pimecartan potassium salt, and Korean Patent No. 10-1490329 discloses a method for producing a monohydrate of a pimecartan potassium salt .

The Pimassartan has excellent pharmacological activity but has low solubility and has been used in the form of Pimassa potassium salt for its improvement. Although excellent physico-chemical properties such as solubility have various advantages such as an increase in bioavailability, new salts have not been developed except for the present Pimacartan potassium salt.

Therefore, there is a need to develop a new method for producing castor oil, and a new method for producing castor oil and salt thereof efficiently and economically.

International Patent Publication No. PCT / KR9999 / 00198 Korean Patent No. 10-0617953 Korean Patent No. 10-0521980 Korean Patent No. 10-1490329

It is an object of the present invention to provide a process for preparing a castor oil chalcine salt.

It is another object of the present invention to provide a process for preparing a castor oil chalcine salt hydrate.

It is still another object of the present invention to provide a castor oil chalcine salt or a hydrate thereof produced by the process for producing a castor oil chalcine salt or a hydrate thereof.

The present invention provides a method for preparing a castor oil chalcine salt and a hydrate thereof.

Pima Saltan Choline salt  Manufacturing method

The present invention provides a process for preparing a piramassa cholinic salt represented by the following general formula (1).

[Chemical Formula 1]

The process for the preparation of the < RTI ID = 0.0 >

(1) preparing a reactant comprising a solvent and an aqueous choline hydroxide solution;

(2) preparing a mixture by adding to the reactant a filmassalant; And

(3) obtaining a castaxol salt of the palmitic acid from the mixture

.

In the present invention, step (1) means mixing a solution of choline hydroxide and a solvent.

In the present invention, the concentration of aqueous solution of choline hydroxide in step (1) may be 40% to 60%, preferably 48% to 50%.

In the present invention, the solvent in the step (1) may be an organic solvent and may be, for example, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, methanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, Ethanol, 1,4-dioxane, methyl acetate or a mixture thereof, preferably isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, ethanol or a mixture thereof, more preferably isopropanol, ethyl Acetate or a mixture thereof. Further, when the solvent is a solvent which is miscible with water, the solvent may further comprise water.

In the present invention, the step (2) is preferably a step of freezing the parmesan free base.

In the present invention, the mixture of step (2) may be heated, and the heating temperature may preferably be 50 ° C to 90 ° C, more preferably 60 ° C to 80 ° C.

In the present invention, the step (3) is usually a method applicable to obtain an organic compound from a solvent. Examples of the method include filtration, drying, vacuum drying, vacuum drying and vacuum drying under reduced pressure.

The method for producing the castor oil chalcine salt of the present invention comprises:

(4) The step of dissolving the resulting castazate cholinic salt in a solvent, heating, and then lowering the temperature may further comprise the step of purifying.

In the step (4), the heating temperature may be 50 캜 to 80 캜, preferably 65 캜 to 75 캜.

In the step (4), the temperature may be lowered to 0 ° C to 20 ° C, preferably to 0 ° C to 10 ° C.

In the above step (4), the solvent is as described in the above step (1), preferably, acetonitrile, tetrahydrofuran or a mixture thereof.

Pima Saltan Choline salt  Method of manufacturing hydrate

The present invention provides a process for preparing a castor oil chalcine salt hydrate.

In one aspect of the present invention, a process for preparing a castor oil,

(A) dissolving a castor salt of picasaltan in a solvent and adding water to prepare a mixture;

(B) heating the mixture produced in step (A) to form crystals; And

(C) drying the formed crystals

.

The castaxol cholinic salt of step (A) may be one prepared by the above-described method for producing a castor oil cholinic salt.

In the present invention, the solvent of step (A) may be an organic solvent and may be, for example, ethyl acetate, ethanol, acetonitrile, methanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, butanol, The solvent may be ethyl acetate, ethanol, isopropanol, acetonitrile, tetrahydrofuran, or a mixture thereof, more preferably ethyl acetate, ethanol, isopropanol, Acetate.

In the present invention, the volume of water added in the step (A) may be 1% to 100%, preferably 10% to 30%, with respect to the solvent.

In the present invention, water added in the step (A) may be, for example, distilled water, purified water, sterilized water, but is not limited thereto.

In the present invention, the step (B) may further include a step of heating the reactant, followed by the addition of a solvent. The solvent may be the same as that described in step (A) May be the same as or different from those used in step < RTI ID = 0.0 >

In the present invention, the drying temperature in step (C) may be 20 ° C to 60 ° C, preferably 30 ° C to 50 ° C.

In the present invention, the drying time of the step (C) may be 2 to 24 hours, preferably 4 to 6 hours.

In one embodiment of the present invention, the drying temperature of step (C) is 40 ° C to 50 ° C. In this case, the castor oil chalcine salt hydrate is specifically a castor oil chalcine salt monohydrate.

In one embodiment of the present invention, the drying temperature of step (C) is 30 ° C to 40 ° C. In this case, the castor oil chalcine salt hydrate is specifically a castaxol chalcone salt trihydrate.

In one aspect of the present invention, a process for preparing a castor oil,

(a) drying the castor oil salt under a humidity of 70% to 100%.

The castaxol cholinic salt of step (a) may be prepared according to the process for preparing the castor oil cholinic salt described above.

In the present invention, the drying temperature in the step (a) may be 15 ° C to 50 ° C, preferably 20 ° C to 40 ° C.

In one specific embodiment of the present invention, the drying temperature of step (a) is 30 ° C to 40 ° C, and in another specific embodiment of the present invention, the drying temperature of step (a) is 20 ° C to 30 ° C.

In the present invention, the drying time of the step (a) may be 2 hours to 48 hours, preferably 2 to 36 hours.

In one specific embodiment of the present invention, the drying time of step (a) is 4 hours to 6 hours, and in another specific embodiment of the present invention, the drying time of step (a) is 20 hours to 28 hours.

In one specific embodiment of the present invention, the humidity of step (a) is 75% to 90%, and in another specific embodiment of the present invention, the humidity of step (a) is 90% to 100%.

In one specific embodiment of the present invention, the castor oil is dried at a temperature of 30 ° C to 40 ° C under a humidity of 75% to 90% for 4 hours to 6 hours, wherein the castor oil is, Salten is choline salt trihydrate.

In one specific embodiment of the present invention, the castor oil is dried at 20 ° C to 30 ° C under a humidity of 95% for 24 hours, wherein the castor oil is in particular a castor oil chitin salt.

The present invention provides a method for producing a castor oil cholinic salt as described above or a castor oil cholinic salt or a hydrate thereof prepared by the method for producing a castor oil cholinic salt hydrate.

The Pima Sartan cholin salt and Pima Sartan choline salt hydrate are as described in detail above.

The process of the present invention makes it possible to prepare a castaxol cholinic salt and its hydrate in a high yield for a shorter process time using an inexpensive starting material.

Therefore, the production method of the present invention can economically reduce production cost, and is suitable for mass production.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited thereto.

Example  One : Pima Saltan Choline salt  Produce

36.23 g of a 48% to 50% aqueous solution of choline hydroxide was placed in a round flask, and the reaction product was concentrated under reduced pressure at an external temperature of 80 ° C so that the volume became 1/3 to 1/2. 70 ml of isopropanol and 105 ml of ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes, and then 70 g of Pimersartan free base was added. The mixture was heated so as to be in a transparent solution state, stirred further for 30 minutes, slowly cooled down, stirred for one day, and filtered under reduced pressure. And washed twice with 70 ml of isopropanol and ethyl acetate 1: 5 mixed solvent. The filtrate was vacuum dried at about 20 mmHg for at least 6 hours to yield 79.3 g of the castor oil chalcine salt.

Yield: 94%

^{1 H NMR (400MHz, DMSO-} d6): δ 7.48 (m, 1H), 7.38 (m, 2H), 7.29 (m, 1H), 7.02 (d, 2H), 6.94 (d, 2H), 5.60 (s 2H), 2.13 (s, 3H), 2.07 (s, 2H), 3.51 (m, 3H) 1H), 1.51 (m, 2H), 0.78 (t, 3H).

Example  2 : Pima Saltan Choline salt  refine

73 g of the pima saccharan choline salt prepared in Example 1 was added to a mixed solvent of 182.5 ml of acetonitrile and 73 ml of tetrahydrofuran, and the mixture was heated to 65 ° C to 75 ° C and stirred under reduced pressure. After the filtration, the obtained solution was heated to 65 to 75 占 폚, 35 ml of tetrahydrofuran was added, and then the temperature was gradually lowered and stirred for about 3 hours to 5 hours at room temperature. Then, the solution was cooled to 0 ° C to 10 ° C, filtered under reduced pressure, and washed with 70 ml of a mixed solvent of acetonitrile and tetrahydrofuran (1: 1). And vacuum-dried at about 20 mmHg for 6 hours or more to obtain 68.0 g of pure castoracetic acid choline salt anhydride.

Yield: 93%

Example  3: Pima Satan Choline salt Monohydrate  Produce

5 g of the purified palmasaltan choline salt anhydride prepared in Example 2 was dissolved in 10 ml of ethyl acetate, followed by addition of 2.0 ml of purified water and heating. After heating for 30 minutes in a transparent dissolving state, 10 ml of ethyl acetate was further added. The temperature was gradually lowered to crystallize and stirred the next day. The resulting crystals were filtered, washed with ethyl acetate, and dried in a hot air drier at 40 ° C to 50 ° C for 4 hours to 6 hours to obtain 5.07 g of a castor oil monohydrate of chitosan.

Yield: 98.4%

Example  4 : Pimaanthan Choline salt Trihydrate  Produce

5 g of the purified palmasaltan choline salt anhydride prepared in Example 2 was dissolved in 10 ml of ethyl acetate, followed by addition of 2.0 ml of purified water and heating. After heating for 30 minutes in a transparent dissolving state, 10 ml of ethyl acetate was further added. The temperature was gradually lowered and crystallized and stirred for 16 hours. The resulting crystals were filtered, washed with ethyl acetate, and dried in a hot-air drier at 30 ° C to 40 ° C for 4 hours to 6 hours to obtain 5.07 g of the phimacetan cholorate salt trihydrate.

Yield: 97.8%

Example  5: Pima Saltan Choline salt Trihydrate  Produce

5 g of purified palmasalactan choline salt anhydride prepared in Example 2 was dried at 30 to 40 DEG C under a humidity of 75 to 90% for 24 hours to obtain 5.42 g of a palmasaltan salt trihydrate of 5.42 g

Example  6: Pima Saltan Choline salt Hexavalent  Produce

5 g of the purified Pima Sartan Cholinic Salt Anhydride prepared in Example 2 was dried at 20 ° C to 30 ° C under a humidity of 95% for 24 hours to obtain 5.75 g of PimaSaltan choline salt hexahydrate.

Claims (17)

(1) preparing a reactant comprising a solvent and an aqueous choline hydroxide solution;
(2) preparing a mixture by adding palmalactan to the reaction product; And
(3) obtaining a castaxol salt of the palmitic acid from the mixture
≪ / RTI > The method according to claim 1, wherein the concentration of the aqueous solution of choline hydroxide in step (1) is 48% to 50%. The method of claim 1, wherein the solvent of step (2) is selected from the group consisting of isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, methanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, butanol, ≪ / RTI > methyl acetate, or a mixture thereof. 2. The method according to claim 1, wherein the step (2) is a free base of Pimassartan. The method according to claim 1,
(4) A method for producing a castor oil, comprising dissolving the obtained castoracetic acid cholinic salt in a solvent, heating, and then lowering the temperature to purify the castor oil. (A) dissolving the castoracetic acid cholinic salt prepared according to any one of claims 1 to 5 in a solvent and adding water to prepare a mixture;
(B) heating the mixture prepared in the step (A) to form crystals; And
(C) drying the formed crystals
≪ / RTI > The method according to claim 6, wherein the drying temperature in step (C) is 40 to 50 ° C. 8. The method of claim 7, wherein the hydrate is a monohydrate. The process according to claim 6, wherein the drying temperature of step (C) is 30 to 40 占 폚. 10. The method of claim 9, wherein the hydrate is a trihydrate. (a) a step of drying the castor oil chalcine salt prepared according to any one of claims 1 to 5 under a humidity of 75% to 100%. 12. The method according to claim 11, wherein the humidity is 70% to 95%. 12. The method according to claim 11, wherein the drying temperature is 30 ° C to 40 ° C. 14. The method according to claim 12 or 13, wherein the hydrate is selected from the group consisting of a method for producing a hydrate of a < RTI ID = 0.0 > 12. The method according to claim 11, wherein the humidity is 90% to 100%. The method according to claim 11, wherein the drying temperature is 20 ° C to 30 ° C. 17. The method of claim 15 or 16, wherein the hydrate is a hexahydrate.