KR102013157B1 - Crystalline form and Method of preparing the same - Google Patents

Abstract

According to the preparation method of the present invention, 4-(((tetrahydro-pyran-2-yl) oxy) methyl) aniline can be produced in high yield and purity despite low cost. In addition, the crystalline form of the present invention is remarkably excellent in stability, hygroscopicity and solubility.

Description

Crystalline form and method of preparing the same

The present invention provides a novel method for preparing a statin compound, a novel crystalline form of the statin compound and a method for preparing the same. More specifically, the present invention provides an economical method and physical properties of the statin compound which can be prepared in large quantities in high purity and yield without using expensive catalysts, which can be used as a reactant in preparing a statin compound. Novel crystalline forms and methods for their preparation are provided.

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] The -3,5-dihydroxy-heptanoic hemicalcium salt acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, preventing the synthesis of cholesterol in cells Inhibitors are useful as hypolipidemic agents or hypocholesterolemic agents.

Korean Patent No. 1329113 discloses (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]- A method for preparing pyrrole-1-yl] -3,5-dihydroxy-heptanoic hemicalcium salt is described as follows.

THP is a dihydropyranyl group and tBu is a tert butyl group in a said formula.

The patent describes a method for preparing the starting formula II according to Example 1, which is described in J. Med. Chem., 41, 26, (1998), 5297-5309 and Tetrahedron Lett., 43 , 30, (2002), 5353, which is stated to have been prepared according to the method described in the following.

Wherein THP is a dihydropyranyl group and PPTS is pyridinium para-toluenesulfonate.

In this paper, the benzyl alcohol of 4-nitrobenzyl alcohol ((4-nitrophenyl) methanol) is protected by 3,4-dihydropyranyl group to synthesize a compound represented by 2b, and then palladium / carbon (Pd / C) It is specified that the compound represented by 3b above was synthesized by reducing the nitro group with an amine group as a catalyst.

However, Pd / C used in the preparation method is highly flammable when exposed to air, and more flammable in a hydrogen-containing state, so that the solvent used in the reaction may ignite when the reaction proceeds using the catalyst in air. Very large (Prudent Practices in the Laboratory: Handling and Disposal of Chemicals (1995), 370 p). In addition, even when the catalyst is used, the reaction yield is not high, and the purity of the resulting 3b compound is not high. In addition, the Pd / C in the case of high price is expensive to synthesize the compound 3b through the reaction is uneconomical and somewhat longer reaction time.

Therefore, this method is not suitable for mass production of the compound represented by the formula (3b). Therefore (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl ] 3,5-dihydroxy-heptanoic acid Hemicalcium salts in mass production requires a new method for mass production of higher purity and yield of the compound represented by the starting material 3b.

Also, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino prepared by the method of the prior art Patent No. 1329113 Carbonyl] -pyrrole-1-yl] -3,5-dihydroxy-heptanoic acid hemicalcium salts have excellent solubility, but do not have good stability and hygroscopicity, making them difficult to store for long periods of time. The material may decompose to lower the content uniformity of the formulation. Therefore, there is a demand for a method capable of improving the physical properties of the compound to exhibit more excellent stability and hygroscopicity without falling solubility.

Republic of Korea Patent No. 1329113

Goodman and Gilman, The Pharmacological Basis of Therapeutics 841 (MacMillan Publ. Co .: New York 7th ed. 1985) Prudent Practices in the Laboratory: Handling and Disposal of Chemicals (1995), 370 p J. Med. Chem., 41, 26, (1998), 5297-5309 Tetrahedron Lett., 43, 30, (2002), 5353

It is an object of the present invention to provide a novel method for mass production of starting materials used for the synthesis of statin compounds.

The object of the invention is (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole It is to provide a hydrate crystal form of -1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt and a method for producing the same.

The present invention is a compound represented by the following formula (1) in the presence of iron, zinc, tin, a compound containing iron, a compound containing zinc, a compound containing tin or a mixture thereof, ammonium formate, ammonium chloride, sodium di It provides a method for preparing a compound represented by the formula (2) comprising the step of reacting with hydrogen phosphate, hydrazine or a mixture thereof.

[Formula 1]

[Formula 2]

R in Formulas 1 and 2 is acetyl, benzoyl, tetrahydropyranyl, methoxy methyl, methoxy ethoxymethyl or benzyl, preferably tetrahydropyranyl.

Therefore, the compound represented by Chemical Formula 1 or the compound represented by Chemical Formula 2 may be a compound represented by Chemical Formula 1-1 or Chemical Formula 2-1, respectively.

[Formula 1-1]

[Formula 2-1]

According to the above method, the compound represented by Formula 2 can be obtained in high yield and purity within a short time. In addition, zinc, tin, iron and compounds containing them are not only excellent in safety but also inexpensive. In addition, the reaction yield and purity of the obtained compound is also high when the reaction of preparing the compound represented by Formula 2 in the presence of zinc, tin, iron or a compound containing them. Therefore, the method can economically mass-produce the compound represented by Chemical Formula 2, and as a result, it is possible to mass-produce many compounds prepared using the compound represented by Chemical Formula 2. For example, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) via the process of the present invention Carbonyl] -pyrrole-1-yl] -3,5-dihydroxy-heptanoic hemicalcium salts can be mass produced in higher yield and purity more economically than in the prior art.

In the present invention, the reaction of the compound represented by Formula 1 with ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine or a mixture thereof is iron or iron-containing compound, zinc or zinc-containing compound, Or in the presence of tin or a compound comprising tin. The materials are low cost and can increase the reaction yield in the reaction of Formula 1 with ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine or mixtures thereof. Makes it possible.

The compound containing iron or iron, the compound containing zinc or zinc, or the compound containing tin or tin is only about 1/300 to 1/60 compared to Pd / C. However, the compound containing iron or iron, a compound containing zinc or zinc, or a compound containing tin or tin may increase the reaction yield by three times or more compared with Pd / C, and also increase the purity by 10% or more.

In the present invention, the compound containing iron or iron, the compound containing zinc or zinc or the compound containing tin or tin, preferably, may be iron, zinc or tin chloride (SnCl ₂ ).

In the present invention, the method for preparing the compound represented by Chemical Formula 2 may further include preparing a solution containing the compound represented by Chemical Formula 1.

The solution containing the compound represented by Formula 1 may be prepared by dissolving the compound represented by Formula 1 in a solvent. The solvent may be a straight or branched C1 to C4 alcohol, preferably methanol.

In the present invention, the step of reacting the compound represented by the formula (I) with ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine or a mixture thereof, the ammonium in a solution containing the compound represented by the formula (I) Formate, ammonium chloride, sodium dihydrogenphosphate, hydrazine or mixtures thereof.

After adding the iron or iron-containing compound, the zinc-containing compound or the compound containing tin or tin to the solution containing the compound represented by the formula (1), ammonium formate, ammonium chloride, sodium Dihydrogen phosphate, hydrazine or a mixture thereof may be added to prepare a compound represented by Chemical Formula 2.

In the present invention, ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine or mixtures thereof may be added to a solution containing the compound represented by the formula (I) at a temperature of 5 to 30 ° C.

In the present invention, the compound represented by Formula 1 may be prepared from a compound represented by the following Formula 3.

[Formula 3]

In the present invention, when R in the formula (1) is tetrahydropyranyl, the compound represented by the formula (1) can be prepared by reacting the compound represented by the formula (3) with 3,4-dihydropyran.

In the present invention, the compound represented by Chemical Formula 3 may be performed in the presence of the pyridinium-para-toluenesulfonate compound as the catalyst.

The present invention comprises the steps of preparing a solution containing a compound represented by the formula (1); And

Iron, zinc, tin, compounds containing iron, compounds containing zinc, compounds containing tin or mixtures thereof, and ammonium formate, ammonium chloride, sodium dihydrogenphosphate, hydrazine or mixtures thereof in the solution It provides a method for producing a compound represented by the following formula (2) comprising the step of preparing a reactant by the addition.

[Formula 1]

[Formula 2]

R in Formulas 1 and 2 is acetyl, benzoyl, tetrahydropyranyl, methoxy methyl, methoxy ethoxymethyl or benzyl, preferably tetrahydropyranyl.

In the present invention, the ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine or a mixture thereof may be added to a solution containing the compound represented by Formula 1 at a temperature of about 5 to 30 ℃, Preferably it may be added at a temperature of about 10 to 25 ℃, more preferably at a temperature of about 20 ℃.

In the present invention, the reactant may be refluxed at a temperature of about 40 to 80 ℃, preferably at a temperature of about 45 to 75 ℃, more preferably at a temperature of about 65 ℃ have.

The present invention is a compound represented by the following formula (1) in the presence of iron, zinc, tin, a compound containing iron, a compound containing zinc, a compound containing tin or a mixture thereof, ammonium formate, ammonium chloride, sodium di Provided is a method of preparing a compound represented by Formula A, an isomer thereof, or a salt thereof including reacting with hydrogen phosphate, hydrazine or a mixture thereof to prepare a compound represented by Formula 2.

[Formula 1]

[Formula 2]

[Formula A]

R in Formulas 1 and 2 is acetyl, benzoyl, tetrahydropyranyl, methoxy methyl, methoxy ethoxymethyl or benzyl, preferably tetrahydropyranyl.

The present invention can economically mass-produce the compound represented by the following Chemical Formula 2 in high purity and yield, and as a result, the compound represented by the Chemical Formula A prepared using the compound represented by the Chemical Formula 2 as a reactant, an isomer thereof Or salts thereof can also be obtained in high purity and yield, and can be mass produced economically at low cost.

Method for producing a compound represented by the formula (A), an isomer thereof or a salt thereof from the formula (2) is as described in Korean Patent No. 1329113.

In the present invention, the salts refer to salts prepared from metal salts or organic bases. Examples of the metal salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, aluminum salts. Examples of the salt prepared using the organic base include salts prepared using a base such as amino acid, amine, mono-alkyl ammonium, dialkyl ammonium, trialkyl ammonium or N-methyl glucamine, and specifically, Salts prepared using glycine, arginine, lysine, trimethylamine, ammonia, pyridine or picoline and the like, but are not limited thereto.

The salt may preferably be hemi calcium salt of the compound represented by Formula A, and the salt is (3R, 5R) -7- [2- (4-fluorophenyl)-which is a compound represented by Formula B below. Hemi calcium salt of 5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxy heptanoic acid.

[Formula B]

The method for preparing the compound represented by Formula B from Formula 2 is as described in Korean Patent No. 1329113.

The present invention comprises the steps of preparing a solution containing a compound represented by the formula (1); And

In the solution, iron, zinc, tin, a compound containing iron, a compound containing zinc, a compound containing tin or mixtures thereof and ammonium formate, ammonium chloride, sodium dihydrogenphosphate, hydrazine or mixtures thereof Provided is a method of preparing a compound represented by the following Formula A, an isomer thereof, or a salt thereof, which comprises the step of adding a compound represented by the following Formula 2.

[Formula 1]

[Formula 2]

[Formula A]

R in Formulas 1 and 2 is acetyl, benzoyl, tetrahydropyranyl, methoxy methyl, methoxy ethoxymethyl or benzyl, preferably tetrahydropyranyl.

In the present invention, the salt of the compound represented by the formula (A) is as described above, preferably hemi calcium salt of the compound represented by the formula (A), (3R, 5R) -7- [2- (4- Fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxy heptanoic acid Can be.

The present invention relates to (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) Hemicalcium salts of carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid provide a novel crystalline form.

[Formula B]

The novel crystalline form is (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl), a compound of formula B Amino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxy heptanoic acid. It may be a hydrate of the hemi calcium salt, preferably trihydrate.

The novel trihydrate crystalline form of the compound represented by the formula (B) according to the present invention exhibits better stability and hygroscopicity than the compound prepared only by the method described in the existing Korean Patent No. 1329113, and thus remains stable for a long time after preparation, It does not absorb moisture and can be maintained without changing the water content for a long time when the preparation or storage of the formulation as an active ingredient. In addition, the novel crystalline form of the compound represented by the formula (B) according to the present invention exhibits high solubility and may exhibit excellent pharmacological effects.

The invention relates to (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole-1 -Yl] -3,5-dihydroxy heptanoic acid hemi calcium salt trihydrate.

In the present invention, the crystalline Form I is X-ray powder diffraction pattern using Cu-Ka radiation is 5.38 ° ± 0.2 °, 9.46 ° ± 0.2 °, 11.22 ° ± 0.2 °, 18.84 ° ± 0.2 °, 19.18 ° ± 0.2 A peak at diffraction angles 2θ of 20, 70 ° ± 0.2 ° and 22.68 ° ± 0.2 °, preferably Crystalline Form I has an X-ray powder diffraction pattern of 11.86 ° ± 0.2 °, 22.00 ° using Cu-Ka radiation. 5.38 ° ± 0.2 °, 9.46 ° ± 0.2 °, 11.22 ° ± 0.2 °, 18.84 ° ± 0.2 °, 19.18 ° ± and at least one selected from the group consisting of ± 0.2 °, 23.86 ° ± 0.2 ° and 24.48 ° ± 0.2 ° Peaks at diffraction angles 2θ of 0.2 °, 20.70 ° ± 0.2 ° and 22.68 ° ± 0.2 °, more preferably the crystalline Form I has an X-ray powder diffraction pattern using Cu-Ka radiation of 11.86 ° ± 0.2 °, 22.00 ° ± 0.2 °, 23.86 ° ± 0.2 °, 24.48 ° ± 0.2 °, 5.38 ° ± 0.2 °, 9.46 ° ± 0.2 °, 11.22 ° ± 0.2 °, 18.84 ° ± 0.2 °, 19.18 ° ± 0.2 °, 20.70 ° Peaks are shown at diffraction angles 2θ of ± 0.2 ° and 22.68 ° ± 0.2 °.

Said (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole- of the present invention Hemi calcium salt crystalline Form I of 1-yl] -3,5-dihydroxy heptanoic acid exhibits significantly better stability, hygroscopicity and equivalent solubility than the compounds prepared only by the methods described in the prior art.

The novel crystalline Form I absorbs little water so that the same hydrate state can be maintained for long periods of time, and remains stable without prolonged storage or degradation into other substances. Therefore, the same state is maintained during the storage of Form I or when the formulation is prepared using the Form I or after the preparation of the formulation including the Form I, so that the content uniformity of the formulation is stably maintained for a long time. It does not require demanding storage conditions and formulation manufacturing processes and is therefore advantageous for mass production.

In addition, the novel crystalline Form I exhibits high solubility. Thus, administration of Form I may result in an excellent therapeutic effect.

The invention relates to (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole-1 -Yl] -3,5-dihydroxy heptanoic acid hemi calcium salt trihydrate.

In the present invention, the crystalline Form II is the X-ray powder diffraction pattern using Cu-Ka radiation shows a peak at diffraction angles 2θ of 5.46 ° ± 0.2 °, 9.50 ° ± 0.2 ° and 19.30 ° ± 0.2 °, more preferred Preferably, the crystalline Form II has at least one selected from the group consisting of 5.78 ° ± 0.2 °, 11.16 ° ± 0.2 ° and 20.84 ° ± 0.2 °, wherein the X-ray powder diffraction pattern using Cu-Ka radiation is 5.46 ° ± 0.2 °, Peaks at diffraction angles 2θ of 9.50 ° ± 0.2 ° and 19.30 ° ± 0.2 °, more preferably, Form II has an X-ray powder diffraction pattern using Cu-Ka radiation of 5.78 ° ± 0.2 °, 11.16 ° ± Peaks are shown at diffraction angles 2θ of 0.2 °, 20.84 ° ± 0.2 °, 5.46 ° ± 0.2 °, 9.50 ° ± 0.2 ° and 19.30 ° ± 0.2 °.

The invention relates to (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole-1 -Yl] -3,5-dihydroxy heptanoic acid hemi calcium salt trihydrate.

In the present invention, the crystal form III has an X-ray powder diffraction pattern using Cu-Ka radiation at diffraction angles 2θ of 21.90 ° ± 0.2 °, 8.04 ° ± 0.2 °, 8.11 ° ± 0.2 °, and 13.07 ° ± 0.2 ° Peaks, more preferably, Form III has an X-ray powder diffraction pattern using Cu-Ka radiation consisting of 14.02 ° ± 0.2 °, 17.23 ° ± 0.2 °, 18.98 ° ± 0.2 ° and 23.46 ° ± 0.2 ° Peaks at diffraction angles 2θ of at least one selected from the group, 21.90 ° ± 0.2 °, 8.04 ° ± 0.2 °, 8.11 ° ± 0.2 °, and 13.07 ° ± 0.2 °, more preferably Form III is Cu-Ka radiation X-ray powder diffraction pattern using the 21.90 ° ± 0.2 °, 8.04 ° ± 0.2 °, 8.11 ° ± 0.2 °, 13.07 ° ± 0.2 °, 14.02 ° ± 0.2 °, 17.23 ° ± 0.2 °, 18.98 ° ± 0.2 ° And a diffraction angle 2θ of 23.46 ° ± 0.2 °.

Said (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole- of the present invention Trihydrate crystalline forms II and III of hemicalcium salts of 1-yl] -3,5-dihydroxy heptanoic acid exhibit significantly better stability and hygroscopicity than the compounds prepared only by the methods described in Korean Patent No. 1329113. Indicates.

The present invention

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] Preparing a reactant comprising a mixed solvent containing -3,5-dihydroxy heptanoic hemicalcium salt and at least one or more of ethyl acetate, methylene chloride, methanol and tetrahydrofuran and water;

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] Provided are methods for preparing the crystalline form of hemi calcium salt trihydrate of -3,5-dihydroxy heptanoic acid.

According to the above preparation method, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]- Hemi calcium salt trihydrate crystal forms of pyrrole-1-yl] -3,5-dihydroxy heptanoic acid can be obtained with high purity and high yield, and the manufacturing process is simple and suitable for mass production.

The invention relates to (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole-1 -Yl] -3,5-dihydroxy heptanoic acid provides a method for preparing hemi calcium salt trihydrate Form I.

The method is

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] Preparing a reaction solution comprising -3,5-dihydroxy heptanoic acid hemi calcium salt, ethyl acetate and water; And

Agitation of the reaction solution.

According to the above preparation method, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]- Hemi calcium salt trihydrate crystalline form I of pyrrole-1-yl] -3,5-dihydroxy heptanoic acid can be obtained in high purity and in high yield, and the manufacturing process is simple and suitable for mass production.

In the method for preparing Form I of the present invention, the step of preparing the reaction solution,

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl ] -3,5-dihydroxy heptanoic acid hemicalcium salt to add water to prepare a mixture;

Stirring the mixture; And

Adding ethyl acetate to the stirred mixture to prepare a reaction solution.

In the method for preparing Form I of the present invention, the volume ratio of ethyl acetate and water in the reaction solution may be 3: 1 to 1: 3 (V / V), preferably 2: 1 to 1: 2 (V / V).

In the process for preparing Form I of the present invention, the mixture may be stirred at about 20 ° C. to 30 ° C. for 10 hours to 20 hours, preferably the mixture is stirred at about 25 ° C. for about 16 to 18 hours. Can be.

In the method for preparing Form I of the present invention, the step of stirring the reaction solution,

The reaction solution may be stirred under reflux at about 65 ° C. to 80 ° C. for about 1 hour to 3 hours, and more preferably at about 70 ° C. to 75 ° C. under reflux for about 1.5 hours to 2 hours.

In the method for preparing Form I of the present invention, the method may further comprise cooling the stirred reaction solution. Solids may be produced by cooling the reaction solution.

The cooling may cool the reaction solution to about 30 ° C. to 50 ° C. for about 1 to 3 hours, and more preferably to about 40 ° C. for about 2 hours.

Process for preparing Form I of the present invention, the starting material (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydride) Hemicalcium salts of oxy methyl phenyl amino) carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid may be amorphous, crystalline or mixtures thereof. For example, the starting material may be amorphous, or may be a mixture of Form I of amorphous and trihydrate.

In the method for preparing Form I of the present invention, the obtained solid may be further obtained by filtration and washing with ethyl acetate.

In the process for preparing Form I of the present invention, the method may further comprise drying the obtained solid. The drying may be performed for about 10 hours to 20 hours at a pressure of about 50 to 800mmHg and a temperature of 40 to 70 ℃, preferably about 14 to 17 hours at about 50 to 60 ℃ under about 100 to 600mmHg Can be.

The invention relates to (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole-1 -Yl] -3,5-dihydroxy heptanoic acid Hemi calcium salt provides a method for preparing trihydrate Form II.

The method is

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] Preparing a reaction solution including -3,5-dihydroxy heptanoic hemicalcium salt, methanol, and water; And

Agitation of the reaction solution.

According to the above preparation method, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]- Form II of pyrrole-1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt can be obtained with high purity and high yield, and the manufacturing process is simple and suitable for mass production.

In the method for preparing Form II of the present invention, the step of preparing the reaction solution,

Preparing a mixed solvent comprising methanol and water; And

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole was added to the mixed solvent. -1-yl] -3,5-dihydroxy heptanoic acid hemi calcium salt is added.

In the method for preparing Form II of the present invention, the mixed solvent may include methanol and water in a volume ratio of 3: 1 to 1: 3 (V / V), preferably 2: 1 to 1: 2 It may be included in the volume ratio of (V / V).

Process for preparing Form II of the present invention, the starting material (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydride) Hemicalcium salts of oxy methyl phenyl amino) carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid may be amorphous, crystalline or mixtures thereof. For example, the starting material may be amorphous or may be a mixture of crystalline Form II of amorphous and trihydrate.

In the method for preparing Form II of the present invention, the stirring of the reaction solution may be performed at room temperature for about 2 to 4 days, preferably about 3 days.

In the process for preparing Form II of the present invention, after stirring of the reaction solution, a solid can be filtered and obtained from the reaction solution.

In the method for preparing Form II of the present invention, the method may further comprise drying the obtained solid. The drying may be performed at a pressure of about 50 to 800mmHg and about 40 to 70 ° C, preferably about 100 to 600mmHg and about 50 to 60 ° C.

The invention relates to (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole-1 -Yl] -3,5-dihydroxy heptanoic acid Hemi calcium salt provides a method for preparing trihydrate Form III.

The method is

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] Preparing a reaction solution comprising -3,5-dihydroxy heptanoic hemicalcium salt, one of tetrahydrofuran and methylene chloride, and a solvent of methanol;

Concentrating the reaction solution to prepare a concentrate; And

Adding water to the concentrate to produce a solid.

According to the above preparation method, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]- Trihydrate Form III of pyrrole-1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt can be obtained in high purity and high yield, and the manufacturing process is simple and suitable for mass production.

In the method for preparing Form III of the present invention, the step of preparing the reaction solution,

Preparing a mixed solvent including one of the tetrahydrofuran and methylene chloride and methanol; And

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole was added to the mixed solvent. -1-yl] -3,5-dihydroxy heptanoic acid hemi calcium salt is added.

In the method for preparing Form III of the present invention, the mixed solvent may include one of tetrahydrofuran and methylene chloride and methanol in a volume ratio of 1:10 to 4: 5 (V / V), preferably It may be included in the volume ratio of 1: 5 to 3: 5 (V / V).

In the method for preparing Form III of the present invention, the method may further include stirring the reaction solution before concentration after preparation of the reaction solution.

In the process for preparing Form III of the present invention, the step of adding water may be added dropwise for about 20 minutes to 1 hour at a temperature of about 0 to 5 ℃.

In the method for preparing Form III of the present invention, the method may further include adding water and then stirring. The stirring step may be performed at a temperature of about 0 to 5 ° C. for about 30 minutes to 3 hours, preferably about 2 hours.

In the process for preparing Form III of the present invention, the step of drying the solid may be further performed. The drying may be carried out at a temperature of about 40 to 70 ℃, preferably at a temperature of about 60 ℃.

The present invention relates to (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-as an active ingredient. It provides a pharmaceutical composition for the prevention or treatment of cardiovascular diseases comprising a trihydrate crystalline form of hemi calcium salt of pyrrole-1-yl] -3,5-dihydroxy heptanoic acid and a pharmaceutically acceptable additive.

In the present invention, the pharmaceutical composition comprises (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethyl) as an active ingredient. Phenyl amino) carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid and at least one selected from trihydrate Form I, Trihydrate Form II and Trihydrate Form III of the hemicalcium salt, preferably Preferably (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole-1- Trihydrate crystalline Form I of hemi calcium salt of general] -3,5-dihydroxy heptanoic acid.

The pharmaceutically acceptable additive is particularly limited as long as it is an physiologically acceptable additive and is an additive commonly used in the medical field which, when administered to humans, does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness or the like. It doesn't work. Examples of such additives include carriers, excipients and diluents. Examples of such carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The pharmaceutical composition may further include an antioxidant, a buffer, a filler, an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, and a preservative.

In the pharmaceutical composition of the present invention, the cardiovascular disease is hypertension, stroke, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, complex lipidosis, arteriosclerosis, atherosclerosis, angina pectoris, myocardial infarction, arterial obstructive disease , Cerebral infarction, myocardial microvascular disease, diabetic angiopathy or coronary arteriosclerosis, preferably hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia or complex hyperlipidemia.

The pharmaceutical compositions of the present invention may be formulated according to conventional methods and may be used in various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions or parenterals such as intramuscular, intravenous or subcutaneous administration. It may be prepared in a dosage form.

When the pharmaceutical composition of the present invention is prepared in the form of an oral preparation, examples of the additives used are cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, stearic acid Calcium, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents and the like.

When the pharmaceutical composition is formulated as a liquid preparation, such as oral suspensions, liquid solutions, emulsions or syrups, in the pharmaceutical composition, simple diluents such as water and liquid paraffin, wetting agents, sweeteners, fragrances, preservatives, preservatives, Various additives, such as a coloring agent, can be added and formulated. For example, the pharmaceutical composition may be formulated by further adding a sweetener such as peppermint oil, eucalyptus oil, or saccharin.

When the pharmaceutical composition of the present invention is prepared in the form of an injection, the additives include water, saline solution, aqueous glucose solution, pseudo-aqueous solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid, fatty acid ester, glycerol Ride, surfactant, a suspending agent, an emulsifier, etc. are mentioned.

In the pharmaceutical composition of the present invention, the content of the additive is not particularly limited and may be appropriately adjusted within the content range used for conventional formulation.

The pharmaceutical compositions of the invention may be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically), and the dosage may be determined by the weight, age, sex, health status, diet of the patient. The range may vary depending on the administration time, administration method, administration period or interval, excretion rate, constitution specificity, the nature of the preparation, the severity of the disease, and the like.

The pharmaceutical composition of the present invention is an active ingredient (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) Carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid so that the amount of the crystalline form of hemicalcium salt is about 0.01 to 100 mg / kg / day, preferably 0.1 to 30 mg / kg / day It may be administered, may be administered once to several times a day as needed.

The present invention provides a new process for preparing 4-(((tetrahydro-pyran-2-yl) oxy) methyl) aniline. According to the present invention, the compound can be economically produced in high purity and yield so that the yield of reactions using the compound as a reactant can also be improved.

In addition, the novel crystalline forms of the present invention has excellent stability, hygroscopicity and solubility, which is advantageous for mass production, and can exhibit excellent therapeutic effect even in a small amount.

1-3 show (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) according to the invention A diagram showing each of the X-ray powder rotation patterns (XPRD) of hemi calcium salt trihydrate crystalline forms I to III of carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid. In the figure, the horizontal axis represents 2θ (degree) value and the vertical axis represents intensity (CPS).

Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following Examples and Experimental Examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the Examples and Experimental Examples.

In addition, the reagents and solvents mentioned below were purchased from Sigma-Aldrich, unless otherwise noted, and the purity of the product was measured using HPLC (1200 series, Agilent).

Preparation Example 1

Preparation of 2-((4-nitrobenzyl) oxy) tetrahydro-pyran compound (compound of formula 1)

(Prepared according to the synthetic process of J. Med. Chem., 41, 26, (1998), 5297-5309)

After dissolving 4-nitrobenzyl alcohol (1.6 g, 10.45 mmol) in ethanol (52 ml) to prepare a solution, 3,4-dihydropyran (1.32 g, 1.43 ml, 15.68 mmol) was added dropwise to the solution, Pyridinium para-toluenesulfonate (262.6 mg, 1.05 mmol) was added dropwise to prepare a mixture. The mixture was stirred for 1 hour 30 minutes and then concentrated by evaporation of the solvent under reduced pressure. The concentrate was extracted with ethyl acetate (25 ml), washed with water (50 ml x 3), washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as an oil.

Yield: 2.82 g (98.8%), purity: 99.8%

Example 1

Preparation of 4-(((tetrahydro-pyran-2-yl) oxy) methyl) aniline (compound of formula 2-1) (using zinc as catalyst)

A solution was prepared by dissolving 2-((4-nitrobenzyl) oxy) tetrahydro-pyran (1 g, 3.66 mmol) prepared in Preparation Example 1 in methanol (100 ml), and zinc dust (1.4) in the solution. After dropping g) dropwise, ammonium formate (0.9 g) was added at 20 ° C. to prepare a mixture. The mixture was refluxed at 65 ° C. 10 minutes after the end of reflux, the zinc powder remaining in the mixture was removed, and the solvent was removed from the obtained solution under reduced pressure and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to afford the title compound as an oil. Yield: 0.71 g (93%), purity: 75%

Example 2)

Preparation of 4-(((tetrahydro-pyran-2-yl) oxy) methyl) aniline (compound of formula 2-1) (using iron as catalyst)

To prepare a solution by dissolving 2-((4-nitrobenzyl) oxy) tetrahydro-pyran (1 g, 3.66 mmol) prepared in Preparation Example 1 in methanol (100 ml) and iron powder (1.4 g) was added to the solution. After dropwise addition, ammonium formate (0.9 g) was added at 20 ° C. to prepare a mixture. The mixture was refluxed at 65 ° C. 1 hour and 30 minutes after the end of reflux, the iron powder remaining in the mixture was removed, and the solvent was removed from the obtained solution under reduced pressure and extracted with ethyl acetate. The extract was washed with water, then dried over anhydrous sodium sulfate and concentrated to afford the title compound as an oil.

Yield: 0.72 g (95%), purity: 80%

Example 3

Preparation of 4-(((tetrahydro-pyran-2-yl) oxy) methyl) aniline (compound of formula 2-1) (using tin compound as catalyst)

A solution was prepared by dissolving 2-((4-nitrobenzyl) oxy) tetrahydro-pyran (1 g, 3.66 mmol) prepared in Preparation Example 1 in methanol (100 ml) and preparing tin tin (SnCl ₂ , 3.5 g) was added dropwise to prepare a mixture. The mixture was refluxed at 65 ° C. One hour and 20 minutes after the end of reflux, the tin remaining in the mixture was removed, the solvent was removed under reduced pressure, and extracted with ethyl acetate. The extract was washed with 2 M aqueous potassium hydroxide solution, washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as an oil.

Yield: 0.57 g (76%), purity: 83%

Comparative Example 1)

Preparation of 4-(((tetrahydro-pyran-2-yl) oxy) methyl) aniline (compound of formula 2) (synthesis of [J. Med. Chem., 41, 26, (1998), 5297-5309] Manufactured according to the process)

A solution was prepared by dissolving 2-((4-nitrobenzyl) oxy) tetrahydro-pyran (1 g, 3.66 mmol) prepared in Preparation Example 1 in ethanol (100 ml) and 10% (w / w) in the solution. After palladium / carbon (0.3 g) was added dropwise, ammonium formate (0.9 g) was added at 20 ° C. to prepare a mixture. After 1 hour and 30 minutes the palladium / carbon residue was filtered off from the mixture, then the solvent was removed under reduced pressure and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to afford the title compound as an oil.

Yield: 0.19 g (25%), purity: 68%

Example 4

Preparation of Trihydrate Form I

((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] represented by the formula (B)- 20 g of pyrrole-1-yl] -3,5-dihydroxy heptanoic acid) was added to 200 ml of water to prepare a mixture, which was then stirred at about 25 ° C. for a total of 17 hours. 200 ml of ethyl acetate was added to the mixture to prepare a reaction solution, and the reaction solution was stirred under reflux at 70 to 75 ° C. for 1.5 to 2 hours, then cooled to 40 ° C. for 2 hours, and then at 40 for 1 hour. Stirring at 占 폚 produced a solid. The resulting solid was filtered to give a solid, which was washed twice with 250 ml of ethyl acetate, and then dried at 55 ° C. under 100 to 600 mmHg for 16 hours to give (3R, 5R) -7- [2- (4-fluoro Hemicalcium salt trihydrate of rophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxy heptanoic acid 17.1 g (99.82% purity) of cargo crystalline Form I were obtained as a white solid.

Example 5

Preparation of Trihydrate Form I

Compound represented by formula B ((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -Pyrrole-1-yl] -3 g of hemi calcium salt of 3,5-dihydroxy heptanoic acid) and 1 g of trihydrate Form I prepared in Example 4 were added to 200 ml of water to prepare a mixture, and then the mixture was prepared. Stir at about 25 ° C. for a total of 17 hours. 200 ml of ethyl acetate was added to the mixture to prepare a reaction solution, and the mixture was stirred under reflux at 70 to 75 ° C. for 1.5 to 2 hours. Generated. The resulting solid was filtered to give a solid, which was washed twice with 250 ml of ethyl acetate, and then dried at 55 ° C. under 100 to 600 mmHg for 16 hours to give (3R, 5R) -7- [2- (4-fluoro Hemicalcium salt trihydrate of rophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxy heptanoic acid 17.8 g (99.89% purity) of cargo crystalline Form I were obtained as a white solid.

Example 6

Preparation of Trihydrate Crystal Form II

Compound represented by formula B ((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] 20 g of hemicalcium salts of pyrrole-1-yl] -3,5-dihydroxy heptanoic acid were suspended in a mixed solvent of 200 ml of methanol and 200 ml of water to prepare a reaction solution, and the reaction solution was stirred for 3 days to obtain a solid. Generated. The solid was collected by filtration from the reaction solution, which was then dried at 70 ° C. under 100 to 600 mmHg to give (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-. 17.4 g (purity 99.74%) of hemicalcium salt trihydrate Form II of 4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid was obtained as a white solid. Obtained.

Example 7

Preparation of Trihydrate Crystal Form II

Compound represented by formula B ((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] 19 g of hemicalcium salt of -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid and 1 g of trihydrate crystalline form II prepared in Example 6 were suspended in a mixed solvent of 200 ml of methanol and 200 ml of water. It was prepared and the reaction solution was stirred for 3 days to produce a solid. The solid was collected by filtration from the reaction solution, which was then dried at 70 ° C. under 100 to 600 mmHg to give (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-. 17.9 g (purity 99.83%) of hemicalcium salt trihydrate Form II of 4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid was obtained as a white solid. Obtained.

Example 8

Preparation of Trihydrate Crystal Form III

Compound represented by formula B ((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] 20 g of -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid) was added to a mixed solvent of 200 ml of methanol and 60 ml of tetrahydrofuran to prepare a reaction solution. Stir for 1 hour to dissolve. The solution was filtered to remove insoluble materials, and then concentrated under reduced pressure until 50% (v / v) was used as the initial volume to prepare a concentrate. After transferring the concentrate to a separate reactor, 800 ml of water at 0 to 5 ° C. was slowly added for 30 minutes, followed by stirring for 2 hours while maintaining the temperature. The resulting white solid was filtered and dried at 60 ° C. to give (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy 17.2 g of hemi calcium salt trihydrate crystalline Form III (purity 99.69%) of methyl phenyl amino) carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid were obtained as a white solid.

Example 9

Preparation of Trihydrate Crystal Form III

Compound represented by formula B ((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -Pyrrole-1-yl] 20 g of hemi calcium salt of 3,5-dihydroxy heptanoic acid) was added to a mixed solvent of 200 ml of methanol and 80 ml of methylene chloride to prepare a reaction solution. Stirred to dissolve. The solution was filtered to remove insoluble materials, and then concentrated under reduced pressure until 50% (v / v) was used as the initial volume to prepare a concentrate. After transferring the concentrate to a separate reactor, 800 ml of water at 0 to 5 ° C. was slowly added for 30 minutes, followed by stirring for 2 hours while maintaining the temperature. The resulting white solid was filtered and dried at 60 ° C. to give (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy 17.3 g (purity 99.73%) of hemi calcium salt trihydrate Form III of methyl phenyl amino) carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid was obtained as a white solid.

Comparative Example 2)

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] Preparation of -3,5-dihydroxy heptanoic hemicalcium salt (compound of formula B)

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4- Hydroxy methyl phenyl amino) carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic hemicalcium salt (compound of formula B) was prepared as described in Examples 2 to 6 of Korean Patent No. 1329113. Obtained by

Experimental Example 1)

Identification of X-ray powder diffraction (XRD) patterns of crystalline forms I, II, and III

The X-ray powder diffraction pattern of the crystalline forms I to III prepared in Examples 4 to 9 was confirmed by irradiating CuKa radiation with a solid phase detector. The powder X-ray diffraction pattern was measured under the following apparatus and measurement conditions.

Powder X-ray diffraction spectrum measurement method

Manufacturer: RIGAKU

Device: Ultima IV

Voltage: 40 kV

Current: 40 mA

-scan range: 3 ~ 40deg.

scan rate: 0.5deg / min

increment: 0.02 deg.

Detector: D / teX Ultra

X-ray powder diffraction patterns of the crystalline forms prepared in Examples 4 and 5 are shown in Table 1 and FIG. 1.

Table 1. X-ray powder diffraction (XPRD) pattern of trihydrate Form I

X-ray powder diffraction patterns of the crystalline forms prepared in Examples 6 and 7 are shown in Table 2 and FIG. 2.

Table 2. X-ray Powder Diffraction (XPRD) Patterns of Trihydrate Crystal Form II

X-ray powder diffraction patterns of the crystalline forms prepared in Examples 8 and 9 are shown in Table 3 and FIG. 3.

Table 3. X-ray Powder Diffraction (XPRD) Patterns of Trihydrate Crystal Form III

As can be seen from Tables 1 to 3 powder diffraction patterns, the compounds prepared in Examples 4 and 5, Examples 6 and 7, and Examples 8 and 9 show different peaks in the X-ray powder diffraction pattern. It was found that the crystal form was different from each other.

Experimental Example 2)

Determination of Water Content of Trihydrate Crystal Forms I, II, and III

The water content of the crystalline compounds prepared in Examples 4 to 9 of the present invention was measured by KF (Karl Fisher) method. Moisture measurement of Form I prepared in Examples 4 and 5 was about 4.24%, Moisture measurement of Form II prepared in Examples 6 and 7 was about 4.28%, and moisture of Crystalline III prepared in Examples 8 and 9. The measurement was about 4.22%. The crystalline forms prepared in Examples 4 to 9 therefrom are (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl Phenyl amino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxy heptanoic acid hemi calcium salt.

Experimental Example 3)

Stability Assessment of Trihydrate Crystal Forms I, II, and III

The stability tests of crystalline forms I, II and III of each trihydrate prepared in Examples 4, 6 and 8 of the present invention and the compound prepared in Comparative Example 2 were carried out. The test was carried out under accelerated conditions (temperature 40 ℃, relative humidity 75%), the content of crystalline form remaining after a period of time was expressed in% through the area ratio of HPLC, the results are shown in Table 4 below.

Table 4. Stability Test Results (Unit:%)

As can be seen in Table 4 above, each of the crystalline forms I to III prepared in Examples 4, 6 and 8 remained almost unchanged until 6 months. In particular, in the case of Form I, the content reduction rate was only 0.2% after 6 months. On the contrary, in the case of the compound prepared in Comparative Example 2, it was found that the content was decreased by almost 10% after 6 months.

From this (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]- It was found that the trihydrate Forms I to III of pyrrole-1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salts are excellent in stability and can be stably maintained for a long time. It can be seen that it can be easily applied to mass production because it is excellent, and can be stably maintained without changing the content in the long term during preparation and storage of the preparation.

Experimental Example 4)

Hygroscopicity Evaluation of Trihydrate Crystal Forms I, II, and III

Hygroscopicity in air was measured for the crystalline forms I, II and III prepared in Examples 4, 6 and 8 of the present invention and the compound prepared in Comparative Example 2. After exposing each crystalline form in air at a temperature of 25 ° C. and a relative humidity of 45% for 24 hours, the amount of water contained in each compound was titrated by the same method as that described in Experimental Example 2 (Karl-Fisher measurement method). Is shown in Table 5 below.

Table 5. Hygroscopicity Test Results (Unit:%)

As can be seen in Table 5, the crystalline Forms I to III was found to be less than 3% change in moisture content when exposed to air for 24 hours. In particular, in the case of Form I, the moisture content increased only about 0.2% even after 24 hours of exposure to air, so that it was found that almost no moisture was absorbed. In contrast, in the case of the compound prepared in Comparative Example 2, it was found that the water content was increased by almost 10 times.

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]- It was found that Forms I to III of the trihydrate of pyrrole-1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salts were excellent in hygroscopicity, and in particular, Form I of the trihydrate was hardly exposed to prolonged exposure to air. It can be seen that the state of the hydrate can be stably maintained during the preparation process because it does not absorb moisture, and it is possible to stably maintain the state of the same hydrate for a long time without maintaining a demanding storage environment during storage.

Experimental Example 5)

Water Solubility Assessment of Trihydrate Forms I, II, and III

The crystalline forms I, II and III prepared in Examples 4, 6 and 8 of the present invention were dissolved in non-ionized water or pH 6.8 phosphate buffer solution, and then the undissolved solute was collected by filtration to dilute the filtrate. . The diluted filtrate was analyzed at 247 nm wavelength by ultraviolet absorption spectroscopy using a spectrometer (JASCO, Model: V-650) to measure the solubility.

Table 6. Solubility (unit, temperature: μg / ml, 25 ° C)

It can be seen from Table 6 that the crystalline Forms I to III are well dissolved in non-ionized water and phosphate buffer of pH 6.8. In particular, Form I showed very high solubility in non-ionized water and phosphate buffer at pH 6.8. From this (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrole-1 It can be seen that the trihydrate crystalline Form I of -yl] -3,5-dihydroxy heptanoic acid hemicalcium salt can exhibit an excellent therapeutic effect even at a small dose.

Claims (21)

X-ray powder diffraction pattern using Cu-Ka radiation shows 5.38 ° ± 0.2 °, 9.46 ° ± 0.2 °, 11.22 ° ± 0.2 °, 11.86 ° ± 0.2 °, 18.84 ° ± 0.2 °, 19.18 ° ± 0.2 °, 20.70 (3R, 5R) -7- [2- (4- showing peaks at diffraction angles 2θ of ° ± 0.2 °, 22.00 ° ± 0.2 °, 22.68 ° ± 0.2 °, 23.86 ° ± 0.2 ° and 24.48 ° ± 0.2 ° Fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxy heptanoic acid Trihydrate Form I. delete delete delete delete delete (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl] Preparing a reaction solution comprising -3,5-dihydroxy heptanoic acid hemi calcium salt, ethyl acetate and water;
Stirring the reaction solution; And
Cooling the stirred reaction solution; To include
A process for preparing trihydrate Form I of claim 1. The method of claim 7, wherein preparing the reaction solution,
(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl] -pyrrol-1-yl ] -3,5-dihydroxy heptanoic acid hemicalcium salt to add water to prepare a mixture;
Method for preparing trihydrate Form I comprising the step of preparing a reaction solution by adding ethyl acetate to the mixture. delete The process for preparing trihydrate crystalline Form I according to claim 7 or 8, wherein the volume ratio of ethyl acetate and water is 3: 1 to 1: 3 (v / v). delete delete delete delete delete delete delete delete delete delete delete

Images