KR20160117843A - Crystalline form and Method of preparing the same - Google Patents

Abstract

The present invention relates to a crystal and a production method thereof. According to the present invention, the production method enables production of 4-(((tetrahydro-pyran-2-yl)oxy)methyl)aniline in high yield and purity even with low costs. In addition, the crystal of the present invention exhibits remarkably excellent stability, hygroscopicity, and solubility.

Description

Crystalline Form and Method of Preparing the Same [

The present invention provides a novel process for preparing a statin compound, a novel crystalline form of the statin compound, and a process for producing the same. More specifically, the present invention relates to an economical method capable of mass-producing a compound which can be used as a reactant in the production of a statin compound at a high purity and yield without using expensive catalyst, and a method for producing the statin compound A novel crystal form and a process for producing them.

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid hemicalcium salt acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase to inhibit the synthesis of cholesterol in cells And is useful as a hypolipidemic agent or a hypocholesterolemic agent.

Korean Patent Registration No. 1329113 discloses a process for producing (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Pyrrol-1-yl] -3,5-dihydroxy-heptanoic acid hemicalcium salt is described as follows.

Wherein THP is a dihydropyranyl group, and tBu is a tert-butyl group.

In the above patent, the starting material of the formula (II) is described in Example 1, which is described in J. Med. Chem., 41, 26 (1998), 5297-5309 and Tetrahedron Lett., 43 , 30, (2002), 5353), and the method is as follows.

Wherein THP is a dihydropyranyl group and the PPTS is pyridinium para-toluene sulfonate.

(Pd / C) is obtained by synthesizing a compound represented by 2b by protecting the benzyl alcohol of 4-nitrobenzyl alcohol ((4-nitrophenyl) methanol) with a 3,4-dihydropyranyl group, It is stated that the compound represented by the above-mentioned 3b is synthesized by reducing the nitro group to an amine group with a catalyst.

However, the Pd / C used in the above production method has a high flammability when exposed to air and has a higher flammability in a state containing hydrogen, and there is a risk that the solvent used in the reaction will ignite when the reaction is performed using the catalyst in air (Prudent Practices in the Laboratory: Handling and Disposal of Chemicals (1995), 370 p). Also, the reaction yield is not high even when the catalyst is used, and the purity of the produced 3b compound is not high. In addition, the cost of Pd / C is high, so that it takes a lot of time to synthesize 3b compound through the reaction, which is uneconomical and the reaction time is rather long.

Therefore, this method is not suitable for mass production of the compound represented by the formula (3b). Thus, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- ] -3,5-dihydroxy-heptanoic acid hemicalcium salt, there is a need for a new method capable of mass-producing the starting material, 3b, at a higher purity and yield.

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4 - [(4-hydroxymethylphenylamino) ) Carbonyl] -pyrrol-1-yl] -3,5-dihydroxy-heptanoic acid hemicalcium salt is excellent in solubility but is not excellent in stability and hygroscopicity and is difficult to be stored for a long period of time. The substance may be decomposed to lower the uniformity of the content of the preparation. Therefore, there is a demand for a method capable of improving the physical properties of the compound to exhibit better stability and hygroscopicity without lowering the solubility.

Korean Registered 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 Disposition 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 in the synthesis of statins.

The object of the present invention is to provide a process for the preparation of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- -1-yl] -3,5-dihydroxyheptanoic acid hemicalcium salt and a process for their preparation.

The present invention relates to a process for the preparation of a compound represented by the 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, With hydrazine, hydrazine, hydrazine, or a mixture thereof.

[Chemical Formula 1]

(2)

In the above general formulas (1) and (2), R is acetyl, benzoyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl or benzyl, preferably tetrahydropyranyl.

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

[Formula 1-1]

[Formula 2-1]

According to the above method, the compound represented by the general formula (2) can be obtained with 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. The reaction yield and the purity of the obtained compound are also high when the reaction for producing the compound represented by the general formula (2) is carried out in the presence of zinc, tin, iron or a compound containing them. Accordingly, the method can economically mass-produce the compound represented by the formula (2), and as a result, it is possible to mass-produce many compounds produced using the compound represented by the formula (2). For example, by the method of the present invention, (3R, 5R) -7- [2- (4-fluorophenyl) -5- Carbonyl] -pyrrol-1-yl] -3,5-dihydroxy-heptanoic acid hemicalcium salt can be mass-produced at a higher yield and purity 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 may be carried out by using a compound containing iron or iron, a compound containing zinc or zinc, Or in the presence of a compound comprising tin or tin. These materials can increase the reaction yield in the reaction of the compound of formula (I) with ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine or a mixture thereof, and can be obtained by reacting the compound represented by the formula (2) Lt; / RTI >

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 of the price of Pd / C. However, the compound containing iron or iron, the compound containing zinc or zinc, or the compound containing tin or tin may have a purity higher by at least 10% while improving the reaction yield by three times or more as compared with Pd / C.

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

In the present invention, the method for preparing the compound represented by Formula 2 may further include a step for preparing a solution containing the compound represented by 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 linear or branched C1 to C4 alcohol, preferably methanol.

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

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

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

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

(3)

In the present invention, when R is tetrahydropyranyl in the general formula (1), the compound represented by the general formula (2) can be prepared by reacting the compound represented by the general formula (3) with 3,4-dihydropyran.

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

The present invention relates to a process for preparing a compound represented by the formula (I) And

Wherein the solution contains a compound selected from the group consisting of iron, zinc, tin, iron, a zinc-containing compound, a tin-containing compound or mixtures thereof, and ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine, To produce a reaction product. ≪ Desc / Clms Page number 2 >

[Chemical Formula 1]

(2)

In the above general formulas (1) and (2), R is acetyl, benzoyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl 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 ° C, Preferably at a temperature of about 10 to 25 占 폚, and more preferably at a temperature of about 20 占 폚.

In the present invention, the reactants may be refluxed at a temperature of about 40 to 80 ° C, preferably at a temperature of about 45 to 75 ° C, more preferably at a reflux temperature of about 65 ° C have.

The present invention relates to a process for the preparation of a compound represented by the 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, Hydrazine, hydrazine or a mixture thereof to prepare a compound represented by the following formula (2), an isomer thereof, or a salt thereof.

[Chemical Formula 1]

(2)

(A)

In the above general formulas (1) and (2), R is acetyl, benzoyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl or benzyl, preferably tetrahydropyranyl.

The present invention can economically mass-produce a compound represented by the following formula (2) with high purity and yield, and as a result, the compound represented by the above formula (A) prepared using the compound represented by the above formula (2) Or their salts can also be obtained at high purity and yield, and can be economically mass produced at low cost.

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

In the present invention, the salt represents a salt prepared from a metal salt or an organic base. Examples of the metal salt include, but are not limited to, a lithium salt, a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt, and an aluminum salt. Examples of the salt prepared using the organic base include salts prepared by using bases such as amino acid, amine, mono-alkylammonium, dialkylammonium, trialkylammonium or N-methylglucamine, and specifically, But are not limited to, salts prepared using glycine, arginine, lysine, trimethylamine, ammonia, pyridine or picoline.

The salt may preferably be a hemicalcium salt of the compound represented by the formula (A), wherein the salt is a compound represented by the following formula (B): (3R, 5R) -7- [2- (4-fluorophenyl) 3-phenyl-4 - [(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid.

[Chemical 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 relates to a process for preparing a compound represented by the formula (I) And

Wherein the solution contains a compound selected from the group consisting of iron, zinc, tin, a compound containing iron, a compound containing zinc, a compound containing tin or a mixture thereof and an organic solvent such as ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine, To prepare a compound represented by the following formula (A), an isomer thereof, or a salt thereof, which comprises the step of preparing a compound represented by the following formula (2).

[Chemical Formula 1]

(2)

(A)

In the above general formulas (1) and (2), R is acetyl, benzoyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl or benzyl, preferably tetrahydropyranyl.

In the present invention, the salt of the compound represented by the above formula (A) is as described above, preferably a hemicalcium salt of a compound represented by the formula (A), wherein (3R, 5R) -7- [2- 3-phenyl-4 - [(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid .

The present invention relates to a process for the preparation of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- ) Carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid.

[Chemical Formula B]

The novel crystal form is prepared by reacting a compound represented by the formula (B), (3R, 5R) -7- [2- (4-fluorophenyl) Amino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid, preferably a trihydrate.

The novel crystal form of the trihydrate of the compound represented by the formula (B) according to the present invention shows superior stability and hygroscopicity to the compound prepared only by the method disclosed in Korean Patent No. 1329113, and is stably maintained for a long period after the preparation, It does not absorb moisture and can be retained as an active ingredient without changing the moisture content for a long period of time in preparation or storage. In addition, the novel crystalline form of the compound represented by the formula (B) according to the present invention shows a high solubility, and can exhibit excellent pharmacological effect.

The present invention relates to a process for the preparation of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- -Yl] -3,5-dihydroxyheptanoic acid hemicalcium salt trihydrate.

According to the present invention, the crystal form I is characterized in that the X-ray powder diffraction pattern using Cu-Ka radiation has an X-ray powder diffraction pattern of 5.38 DEG +/- 0.2 DEG, 9.46 DEG +/- 0.2 DEG, 11.22 DEG +/- 0.2 DEG, 18.84 DEG +/- 0.2 DEG, 20.70 DEG. + -. 0.2 DEG and 22.68 DEG. + -. 0.2 DEG, preferably the crystal form I shows a peak at an X-ray powder diffraction pattern using Cu-Ka radiation of 11.86 DEG. + -. 0.2 DEG, 22.00 DEG ± 0.2 °, 23.86 ° ± 0.2 ° and 24.48 ° ± 0.2 ° and at least one selected from the group consisting of 5.38 ° ± 0.2 °, 9.46 ° ± 0.2 °, 11.22 ° ± 0.2 °, 18.84 ° ± 0.2 °, 19.18 ° ± 0.2 °, 20.70 ° ± 0.2 ° and 22.68 ° ± 0.2 °, and more preferably the crystal form I shows a peak at an X-ray powder diffraction pattern using Cu-Ka radiation of 11.86 ° ± 0.2 °, 22.00 DEG +/- 0.2 DEG, 23.86 DEG +/- 0.2 DEG, 24.48 DEG +/- 0.2 DEG, 5.38 DEG +/- 0.2 DEG, 9.46 DEG +/- 0.2 DEG, 11.22 DEG +/- 0.2 DEG, 18.84 DEG +/- 0.2 DEG, 19.18 DEG +/- 0.2 DEG, And shows peaks at a diffraction angle 2 &thetas; of 0.2 deg. And 22.68 deg. 0.2 deg.

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl- 1-yl] -3,5-dihydroxyheptanoic acid has a remarkably excellent stability, hygroscopicity and an equivalent solubility in comparison with a compound prepared only by the method described in Korean Patent Registration No. 1329113.

The novel crystalline Form I absorbs little water and can maintain the same hydrate state for a long period of time and remains stable without being decomposed or changed into another material even when stored for a long period of time. Therefore, the same uniformity is maintained during the storage of the crystalline form I, or during the preparation of the product using the crystalline Form I or after the preparation containing the crystalline Form I, so that the uniformity of the contents of the preparation is stably maintained for a long period of time. It is remarkably advantageous for mass production since it does not require strict storage conditions and manufacturing process.

In addition, the novel crystalline Form I shows a high solubility. Therefore, when the crystalline Form I is administered, an excellent therapeutic effect can be exhibited.

The present invention relates to a process for the preparation of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- -Yl] -3,5-dihydroxyheptanoic acid hemicalcium salt trihydrate.

In the present invention, the crystal form II shows a peak at a diffraction angle 2? Of 5.46 占 .2 占 and 9.50 占 .2 占 and 19.30 占 占 占 with an X-ray powder diffraction pattern using Cu-Ka radiation, , Said crystal type II is at least one selected from the group consisting of 5.78 DEG. + -. 0.2 DEG, 11.16 DEG. + -. 0.2 DEG and 20.84 DEG. + -. 0.2 DEG in the X-ray powder diffraction pattern using Cu- 9.50 DEG. + -. 0.2 DEG and 19.30 DEG. + -. 0.2 DEG, and more preferably the crystal type II shows a peak at an X-ray powder diffraction pattern using Cu-Ka radiation at 5.78 DEG. + -. 0.2 DEG, 11.16 DEG. 0.2 °, 20.84 ° ± 0.2 °, 5.46 ° ± 0.2 °, 9.50 ° ± 0.2 ° and 19.30 ° ± 0.2 °.

The present invention relates to a process for the preparation of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- -Yl] -3,5-dihydroxyheptanoic acid hemicalcium salt trihydrate.

According to the present invention, the crystal form III is characterized in that the X-ray powder diffraction pattern using Cu-Ka radiation has a diffraction angle of 2.90 DEG +/- 0.2 DEG, 8.04 DEG +/- 0.2 DEG, 8.11 DEG +/- 0.2 DEG and 13.07 DEG +/- 0.2 DEG X-ray powder diffraction pattern using Cu-Ka radiation is 14.02 deg. 0.2 deg., 17.23 deg. 0.2 deg., 18.98 deg. 0.2 deg. And 23.46 deg. 0.2 deg. And at least one selected from the group consisting of the crystal form III, the peak at diffraction angle 2 &thetas; 21.90 DEG +/- 0.2 DEG, 8.04 DEG +/- 0.2 DEG, 8.11 DEG +/- 0.2 DEG and 13.07 DEG +/- 0.2 DEG, Wherein the X-ray powder diffraction pattern using the X-ray powder diffraction pattern has a diffraction angle of 2190 占 쏙옙 0.2 占 8.04 占 占 0, 8.11 占 쏙옙 0.2 占 13.07 占 0.2 占 14.02 占 0.2 占 17.23 占 0.2 占 18.98 占 占 0.2 And a diffraction angle 2 &thetas; of 23.46 DEG +/- 0.2 DEG.

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl- 1-yl] -3,5-dihydroxyheptanoic acid showed significantly superior stability and hygroscopicity than the compound prepared only by the method described in Korean Patent Registration No. 1329113, and had the same solubility .

The present invention

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid hemicalcium salt and a mixed solvent containing at least one of ethyl acetate, methylene chloride, methanol and tetrahydrofuran and water.

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid in the form of a crystal of a hemicalcium salt trihydrate.

According to the above production method, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Pyrrol-1-yl] -3,5-dihydroxyheptanoic acid can be obtained in high purity and high yield, and the production process is simple and suitable for mass production.

The present invention relates to a process for the preparation of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- -Yl] -3,5-dihydroxyheptanoic acid of the formula (I).

The method

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid hemi-calcium salt, ethyl acetate and water; And

And stirring the reaction solution.

According to the above production method, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Pyrrol-1-yl] -3,5-dihydroxyheptanoic acid can be obtained with high purity and high yield, and the production process is simple and suitable for mass production.

In the method for producing the crystalline form I of the present invention,

Phenyl-4 - [(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl ] -3,5-dihydroxyheptanoic acid hemicalcium salt to prepare a mixture;

Stirring the mixture; And

And adding ethyl acetate to the stirred mixture to prepare a reaction solution.

In the method for producing the crystalline 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: / V).

In the process for preparing crystalline 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 hours to 18 hours .

In the method for producing the crystalline form I of the present invention,

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

In the method for producing crystalline Form I of the present invention, the method may further include cooling the stirred reaction solution. Solids may be produced through cooling of the reaction solution.

The cooling can be performed by cooling the reaction solution to about 30 ° C to 50 ° C for about 1 hour to 3 hours, and more preferably to about 40 ° C for about 2 hours.

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl- Hydroxy methyl] phenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid may be amorphous, crystalline, or a mixture thereof. For example, the starting material may be amorphous, or it may be a mixture of crystalline Form I of amorphous and trihydrate.

In the process for producing crystalline Form I of the present invention, the resulting solid may be obtained by filtration and washed with ethyl acetate.

In the method for producing crystalline Form I of the present invention, it may further include drying the obtained solid. The drying may be carried out at a pressure of about 50 to 800 mm Hg and a temperature of 40 to 70 캜 for about 10 to 20 hours, preferably about 100 to 600 mm Hg at about 50 to 60 캜 for about 14 to 17 hours .

The present invention relates to a process for the preparation of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- -Yl] -3,5-dihydroxyheptanoic acid hemi-calcium salt.

The method

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid hemicalcium salt, methanol and water; And

And stirring the reaction solution.

According to the above production method, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Pyrrol-1-yl] -3,5-dihydroxyheptanoic acid hemicalcium salt can be obtained in high purity and high yield, and the production process is simple and suitable for mass production.

In the method for producing the crystalline Form II of the present invention,

Preparing a mixed solvent comprising methanol and water; And

To the mixed solvent was added the above (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- -1-yl] -3,5-dihydroxyheptanoic acid hemicalcium salt.

In the method of producing the crystalline 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 (V / V).

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl- Hydroxy methyl] phenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid may be amorphous, crystalline, or a mixture thereof. For example, the starting material may be amorphous, or it may be a mixture of crystalline II of amorphous and trihydrate.

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

In the method for producing the crystalline Form II of the present invention, after stirring the reaction solution, a solid can be obtained from the reaction solution by filtration.

In the method for producing the crystalline Form II of the present invention, it may further include drying the obtained solid. The drying may be carried out at a pressure of about 50 to 800 mm Hg and at a temperature of about 40 to 70 ° C, preferably at about 100 to 600 mm Hg pressure and at about 50 to 60 ° C.

The present invention relates to a process for the preparation of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- -Yl] -3,5-dihydroxyheptanoic acid hemicalcium salt of the present invention.

The method

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid 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 production method, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Pyrrol-1-yl] -3,5-dihydroxyheptanoic acid hemicalcium salt can be obtained in high purity and high yield, and the production process is simple and suitable for mass production.

In the method for producing the crystalline Form III of the present invention,

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

To the mixed solvent was added the above (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- -1-yl] -3,5-dihydroxyheptanoic acid hemicalcium salt.

In the method for producing the crystalline 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) 1: 5 to 3: 5 (V / V).

In the method for producing the crystalline Form III of the present invention, it may further include a step of stirring the reaction solution before the concentration of the reaction solution and before the concentration.

In the process for producing crystalline Form III of the present invention, the step of adding water may be carried out at a temperature of about 0 to 5 占 폚 for about 20 minutes to 1 hour.

In the method for producing crystalline Form III of the present invention, it may further include stirring after adding the water. The stirring may be carried out at a temperature of about 0 to 5 DEG C for about 30 minutes to 3 hours, preferably about 2 hours.

In the method for producing crystalline 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 DEG C, preferably at a temperature of about 60 DEG C.

The present invention relates to a process for the preparation of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Pyrrol-1-yl] -3,5-dihydroxyheptanoic acid, and a pharmaceutically acceptable additive. The present invention also provides a pharmaceutical composition for preventing or treating cardiovascular diseases.

In the present invention, the pharmaceutical composition comprises (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Phenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid, at least one selected from the trihydrate crystal form I, the trihydrate crystal form II and the trihydrate crystalline form III of a hemicalcium salt of a Phenyl-4 - [(4-hydroxymethylphenylamino) carbonyl] -pyrrol-l- Dihydroxyheptanoic < / RTI > acid.

The pharmaceutically acceptable excipient is physiologically acceptable and, when administered to a human, is usually an additive commonly used in the field of medicine which does not cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like, It does not. Examples of the additives include carriers, excipients and diluents. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The pharmaceutical composition may further comprise an antioxidant, a buffer, a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.

In the pharmaceutical composition of the present invention, the cardiovascular disease is selected from the group consisting of hypertension, stroke, hyperlipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hyperlipidemia, arteriosclerosis, atherosclerosis, angina pectoris, myocardial infarction, , Cerebral infarction, myocardial microvascular disease, diabetic vascular complication or coronary atherosclerosis, preferably hyperlipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or hyperlipidemia.

The pharmaceutical composition of the present invention may be formulated according to a conventional method and may be formulated into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions or parenteral administration such as intramuscular, intravenous or subcutaneous administration Can 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 to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, stearic acid Calcium, gelatin, talc, surfactants, suspending agents, emulsifying agents, diluents and the like.

When the pharmaceutical composition is formulated into a liquid preparation such as a suspension, solution, emulsion or syrup for oral administration, a simple diluent such as water, liquid paraffin, a wetting agent, a sweetener, a fragrance, a preservative, A coloring agent and the like may be added to formulate the composition. For example, the pharmaceutical composition may be formulated by further adding a sweetening agent 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 additive may include water, saline solution, glucose aqueous solution, pseudosugar solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, Rides, surfactants, suspending agents, and emulsifiers.

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

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intrathecally, or topically), and the dose may be determined depending on the patient's body weight, age, sex, , The administration time, the administration method, the administration period or interval, the excretion rate, the somatic specificity, the nature of the preparation, the severity of the disease, and the like.

The pharmaceutical composition of the present invention comprises (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid is about 0.01 to 100 mg / kg / day, preferably 0.1 to 30 mg / kg / day And may be administered once or several times per day as needed.

The present invention provides a novel process for preparing 4 - (((tetrahydro-pyran-2-yl) oxy) methyl) aniline. According to the present invention, the compounds can be produced economically at high purity and yield, and the yields of reactions using the compounds as a reaction material can also be improved.

In addition, the novel crystalline forms of the present invention have excellent stability, hygroscopicity and solubility, so they are advantageous for mass production and exhibit excellent therapeutic effects even in small amounts.

1 to 3 are schematic cross-sectional views illustrating a process for producing (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid (XRPD) of the hemicalcium salt trihydrate crystal forms I to III. In the figure, the abscissa represents the value of 2? (Degree) and the ordinate represents the intensity (CPS).

Hereinafter, preferred embodiments and experimental examples are provided to facilitate understanding of the present invention. However, the following examples and experimental examples are provided only for the purpose of easier understanding of the present invention, and the present invention is 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 determined using HPLC (1200 series, Agilent).

Production 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]

4-Nitrobenzyl alcohol (1.6 g, 10.45 mmol) was dissolved in ethanol (52 ml) to prepare a solution. 3,4-Dihydropyran (1.32 g, 1.43 ml, 15.68 mmol) 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, then the solvent was evaporated under reduced pressure and concentrated. The concentrate was extracted with ethyl acetate (25 ml), washed with water (50 ml x 3), brine, dried over anhydrous sodium sulfate and concentrated to give the title compound as an oil-like product.

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

Example 1)

Preparation of 4 - (((tetrahydro-pyran-2-yl) oxy) methyl) aniline (compound of formula (II-

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 g) was added dropwise, followed by addition of ammonium formate (0.9 g) at 20 占 폚 to prepare a mixture. The mixture was refluxed at 65 < 0 > C. After 10 minutes of refluxing, the zinc powder remaining in the mixture was removed and the solvent was removed from the resulting solution under reduced pressure and extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous sodium sulfate and concentrated to give the title compound as an oil-like product. Yield: 0.71 g (93%), purity: 75%

Example 2)

Preparation of 4 - (((tetrahydro-pyran-2-yl) oxy) methyl) aniline (compound of formula (II-

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 iron powder (1.4 g) After dropwise addition, ammonium formate (0.9 g) was added at 20 캜 to prepare a mixture. The mixture was refluxed at 65 < 0 > C. After 1 hour and 30 minutes of refluxing, the iron powder remaining in the mixture was removed, the solvent was removed from the resulting solution under reduced pressure, and extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous sodium sulfate and concentrated to give the title compound as an oil-like product.

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

Example 3)

Preparation of 4 - (((tetrahydro-pyran-2-yl) oxy) methyl) aniline (compound of formula (II-

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 adding tin chloride (SnCl ₂ , 3.5 g) was added dropwise to prepare a mixture. The mixture was refluxed at 65 < 0 > C. After 1 hour and 20 minutes of refluxing, the tin remaining in the mixture was removed, the solvent was removed under reduced pressure and extracted with ethyl acetate. The extracts were washed with 2M aqueous potassium hydroxide solution, washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound as an oil-like product.

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

Comparative Example 1)

Synthesis of 4 - ((tetrahydro-pyran-2-yl) oxy) methyl) aniline (Compound of Formula 2) (J. Med. Chem., 41, 26, (1998), 5297-5309] 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) Palladium / carbon (0.3 g) was added dropwise, followed by addition of ammonium formate (0.9 g) at 20 占 폚 to prepare a mixture. After 1 h 30 min, the palladium / carbon residue was filtered off from the mixture and the solvent was removed under reduced pressure and extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous sodium sulfate and concentrated to give the title compound as an oil-like product.

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

Example 4)

Preparation of Trihydrate Carrier Crystalline Form I

((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Pyrrol-1-yl] -3,5-dihydroxyheptanoic acid) was added to 200 ml of water to make a mixture, and the mixture was 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. The reaction solution was refluxed at 70 to 75 캜 for 1.5 to 2 hours, then cooled to 40 캜 for 2 hours, RTI ID = 0.0 > C < / RTI > to produce 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 < 0 > C for 16 hours under 100 to 600 mm Hg to give (3R, 5R) -7- [2- 3-phenyl-4 - [(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid Cargo Crystalline Form I (17.1 g, purity 99.82%) was obtained as a white solid.

Example 5)

Preparation of Trihydrate Carrier Crystalline Form I

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl- -1-yl] -3,5-dihydroxyheptanoic acid) and 1 g of the trihydrate crystal form I prepared in Example 4 were added to 200 ml of water to prepare a mixture, Lt; RTI ID = 0.0 > 25 C < / RTI > for a total of 17 hours. To the mixture was added 200 ml of ethyl acetate to prepare a reaction solution. The mixture was refluxed at 70 to 75 ° C for 1.5 to 2 hours, cooled to 40 ° C for 2 hours, cooled and stirred at 40 ° C for 1 hour to obtain a solid Respectively. The resulting solid was filtered to give a solid which was washed twice with 250 ml of ethyl acetate and then dried at 55 < 0 > C for 16 hours under 100 to 600 mm Hg to give (3R, 5R) -7- [2- 3-phenyl-4 - [(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid Cargo Crystalline Form I (17.8 g, purity 99.89%) was obtained as a white solid.

Example 6)

Preparation of Trihydrate Carbide Crystals II

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl- -Hexyl] -3,5-dihydroxyheptanoic acid) was suspended in a mixed solvent of 200 ml of methanol and 200 ml of water to prepare a reaction solution. The reaction solution was stirred for 3 days to obtain a solid Respectively. The solid was obtained from the reaction solution by filtration and dried at 70 ° C under 100 to 600 mmHg to obtain (3R, 5R) -7- [2- (4-fluorophenyl) 17.4 g (purity 99.74%) of the hemicalcium salt trihydrate II of 4 - [(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid as a white solid .

Example 7)

Preparation of Trihydrate Carbide Crystals II

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl- -1-yl] -3,5-dihydroxyheptanoic acid) and 1 g of the trihydrate crystal form II prepared in Example 6 were suspended in a mixed solvent of 200 ml of methanol and 200 ml of water, And the reaction solution was stirred for 3 days to produce a solid. The solid was obtained from the reaction solution by filtration and dried at 70 ° C under 100 to 600 mmHg to obtain (3R, 5R) -7- [2- (4-fluorophenyl) 17.9 g (purity 99.83%) of the hemicalcium salt trihydrate II of 4- [(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid as a white solid .

Example 8)

Preparation of Trihydrate Carbide Crystalline Form III

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl- -Hexyl] -3,5-dihydroxyheptanoic acid) was added to a mixed solvent of 200 ml of methanol and 60 ml of tetrahydrofuran to prepare a reaction solution, and then the reaction solution was stirred at room temperature And dissolved by stirring for 1 hour. The solution was filtered to remove insolubles, and the concentrate was concentrated under reduced pressure until the volume became 50% (v / v) based on the initial volume. The concentrate was transferred to a separate reactor, and then 800 ml of water at 0 to 5 ° C was gradually added thereto for 30 minutes, followed by stirring for 2 hours while maintaining the temperature. The resulting white solid was filtered and dried at 60 DEG C to give (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Methylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid as a white solid in the form of a hemicalcium salt trihydrate III (purity 99.69%).

Example 9)

Preparation of Trihydrate Carbide Crystalline Form III

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl- 3-yl] -3,5-dihydroxyheptanoic acid) was added to a mixed solvent of 200 ml of methanol and 80 ml of methylene chloride to prepare a reaction solution. The reaction solution was stirred at room temperature for 1 hour ≪ / RTI > The solution was filtered to remove insolubles, and the concentrate was concentrated under reduced pressure until the volume became 50% (v / v) based on the initial volume. The concentrate was transferred to a separate reactor, and then 800 ml of water at 0 to 5 ° C was gradually added thereto for 30 minutes, followed by stirring for 2 hours while maintaining the temperature. The resulting white solid was filtered and dried at 60 DEG C to give (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Methylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid as a white solid in 17.3 g (purity 99.73%) of the hemicalcium salt trihydrate III.

Comparative Example 2)

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid hemi-calcium salt (compound of formula B)

(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl- (Hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid hemicalcium salt (compound of Formula B) was prepared according to the method described in Examples 2 to 6 of Korean Patent No. 1329113 ≪ / RTI >

Experimental Example 1)

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

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

≪ Method of measuring powder X-ray diffraction spectrum >

- Manufacturer: RIGAKU

- Device: Ultima IV

- Voltage: 40kV

- Current: 40mA

- scan range: 3 ~ 40 deg.

- scan rate: 0.5 deg / min

- increment: 0.02 deg.

- Detector: D / teX Ultra

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

Table 1. X-ray Powder Diffraction (XPRD) Pattern of Triple Carbon Crystal Type I

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

Table 2. X-ray Powder Diffraction (XPRD) Patterns of Trihydrate Carbide Type II

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

Table 3. X-ray Powder Diffraction (XPRD) Pattern of Triple Carbon Crystal Type III

As can be seen from the Tables 1 to 3 powder diffraction pattern, the compounds prepared in Examples 4 and 5, Examples 6 and 7, and Examples 8 and 9 showed different peaks in the X-ray powder diffraction pattern , And it was found that these crystals were different from each other.

Experimental Example 2)

Determination of water content of trihydrate cargo crystals I, II and III

Moisture contents of the crystalline compounds prepared in Examples 4 to 9 of the present invention were measured by KF (Karl Fisher) method. The moisture measurement of the crystalline Form I prepared in Examples 4 and 5 was about 4.24%, the moisture measurement of the crystalline Form II prepared in Examples 6 and 7 was about 4.28%, and the moisture of crystalline Form III prepared in Examples 8 and 9 The measured value was about 4.22%. From these, the crystalline forms prepared in Examples 4 to 9 were obtained by using (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Phenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid hemi-calcium salt.

Experimental Example 3)

Stability evaluation of trihydrate cargo crystalline forms I, II and III

The stability tests of the crystals 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 ° C., relative humidity 75%), and the remaining crystalline content after a certain period of time was expressed as a percentage of the area ratio of HPLC. The results are shown in Table 4 below.

Table 4. Results of stability test (Unit:%)

As can be seen from the above Table 4, each of the crystalline Forms I to III prepared in Examples 4, 6 and 8 was kept almost unchanged until 6 months. Particularly, in the case of crystalline type 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, the content was reduced to almost 10% after 6 months.

(3R, 5R) -7- [2- (4-Fluorophenyl) -5-isopropyl-3-phenyl-4 - [(4-hydroxymethylphenylamino) carbonyl] - Pyrrol-1-yl] -3,5-dihydroxyheptanoic acid hemicalcium salt of the present invention has excellent stability and can be stably maintained for a long period of time. In the case of crystalline form I, It can be easily applied to mass production, and it can be stably maintained without changing the content over the long term during manufacture and storage of the preparation.

Experimental Example 4)

Hygroscopicity evaluation of trihydrate cargo crystalline forms I, II and III

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

Table 5. Result of hygroscopicity confirmation test (Unit:%)

As can be seen in Table 5, the crystalline forms I to III showed a change in moisture content of 3% or less when exposed to air for 24 hours. Particularly, in the case of the crystalline Form I, the moisture content was only increased by about 0.2% even after exposure to air for 24 hours, and it was found that almost no moisture was absorbed. On the contrary, in the case of the compound prepared in Comparative Example 2, it was found that the water content increased nearly 10 times.

From this, it was confirmed that (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- Pyrrole-1-yl] -3,5-dihydroxyheptanoic acid hemicalcium salt of trihydrate was found to be excellent in hygroscopicity. Particularly, crystal form I of trihydrate was found to be almost It is possible to maintain the state of the hydrate during the preparation process without absorbing moisture and to maintain the same state of hydrate for a long period of time without maintaining a difficult storage environment at the time of storage.

Experimental Example 5)

Water solubility evaluation of trihydrate cargo crystals I, II and III

After dissolving the crystalline Forms I, II and III prepared in Examples 4, 6 and 8 of the present invention to saturation in non-ionized water or pH 6.8 phosphate buffer, the undissolved solute was filtered to collect the filtrate and dilute it . The diluted filtrate was analyzed by ultraviolet absorption spectroscopy at a wavelength of 247 nm using a spectrophotometer (JASCO, model: V-650) to measure its solubility.

Table 6. Solubility (unit, temperature: 占 퐂 / ml, 25 占 폚)

It can be seen from Table 6 that the crystalline Forms I to III are well dissolved in non-ionized water and a phosphate buffer solution of pH 6.8. In particular, crystalline Form I showed very high solubility in non-ionized water and pH 6.8 phosphate buffer. From this, a solution of the above (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl- -Yl] -3,5-dihydroxyheptanoic acid hemicalcium salt of the present invention can exhibit an excellent therapeutic effect even with a small dose.

Claims (21)

Wherein the X-ray powder diffraction pattern using Cu-Ka radiation is at least one of the following: 5.38 DEG +/- 0.2 DEG, 9.46 DEG +/- 0.2 DEG, 11.22 DEG +/- 0.2 DEG, 18.84 DEG +/- 0.2 DEG, 19.18 DEG +/- 0.2 DEG, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4 - [(4-hydroxymethylphenyl) Amino) carbonyl] - pyrrol-1-yl] -3,5-dihydroxyheptanoic acid. The method according to claim 1, wherein the trihydrate crystal form I is characterized in that the X-ray powder diffraction pattern using Cu-Ka radiation is 11.86 DEG +/- 0.2 DEG, 22.00 DEG +/- 0.2 DEG, 23.86 DEG +/- 0.2 DEG and 24.48 DEG +/- 0.2 DEG Diffraction angles of at least one selected from the group consisting of 5.38 DEG. + -. 0.2 DEG, 9.46 DEG. + -. 0.2 DEG, 11.22 DEG. + -. 0.2 DEG, 18.8 DEG. + -. 0.2 DEG, 19.18 DEG. Lt; RTI ID = 0.0 > II < / RTI > (3R, 5R) -7- [2- ((2R, 5R) -2,5-difluoro-4- < / RTI > 3-phenyl-4 - [(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxyheptanoic acid Crystalline Form of Trihydrate of Salts II. 4. The method according to claim 3, wherein the trihydroxydicarboxylic crystal type II is at least one selected from the group consisting of 5.78 DEG +/- 0.2 DEG, 11.16 DEG +/- 0.2 DEG and 20.84 DEG +/- 0.2 DEG in the X-ray powder diffraction pattern using Cu- 5.46 DEG. + -. 0.2 DEG, 9.50 DEG. + -. 0.2 DEG and 19.30 DEG. + -. 0.2 DEG. Wherein the X-ray powder diffraction pattern using Cu-Ka radiation shows a peak at diffraction angle 2? Of 21.90 ° ± 0.2 °, 8.04 ° ± 0.2 °, 8.11 ° ± 0.2 ° and 13.07 ° ± 0.2 °, 3-phenyl-4 - [(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-di Crystalline Form of Trihydrate of Hydroxyheptanoic Acid Hemicalcium Salt III. 6. The method according to claim 5, wherein the trihydroxydicarboxylic crystal type III is characterized in that the X-ray powder diffraction pattern using Cu-Ka radiation is 14.02 deg. 0.2 deg., 17.23 deg. 0.2 deg., 18.98 deg. 0.2 deg. And 23.46 deg. Crystal form III of trihydroxides wherein at least one selected from the group represents peaks at diffraction angles 2 &thetas; 21.90 DEG +/- 0.2 DEG, 8.04 DEG +/- 0.2 DEG, 8.11 DEG +/- 0.2 DEG and 13.07 DEG +/- 0.2 DEG. (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid hemi-calcium salt, ethyl acetate and water; And
And stirring the reaction solution.
(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid of the formula (I). 8. The method according to claim 7,
Phenyl-4 - [(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl ] -3,5-dihydroxyheptanoic acid hemicalcium salt to prepare a mixture;
And adding ethyl acetate to the mixture to prepare a reaction liquid. 8. The method according to claim 7 or 8, further comprising cooling the stirred reaction solution. The process according to claim 7 or 8, wherein the volume ratio of ethyl acetate to water is from 3: 1 to 1: 3 (v / v). (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid hemicalcium salt, methanol and water; And
And stirring the reaction solution.
(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid of the formula (II). 12. The process according to claim 11, wherein the volume ratio of methanol to water is from 3: 1 to 1: 3 (v / v). (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid 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. ≪ RTI ID = 0.0 >
(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3- -3,5-dihydroxyheptanoic acid of the formula (III). 14. The process according to claim 13, wherein the volume ratio of one of the tetrahydrofuran and the methylene chloride to the methanol is from 1:10 to 4: 5 (V / V). 1. A process for producing a silver halide photographic light-sensitive material, comprising: reacting a compound represented by the following formula (1) with at least one member selected from the group consisting of iron, zinc, tin and iron, a compound containing zinc, With at least one selected from the group consisting of chloride, sodium dihydrogen phosphate and hydrazine. 2. The process according to claim 1,
[Chemical Formula 1]

(2)

In the above Formulas 1 and 2, R is acetyl, benzoyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl or benzyl. 16. The method according to claim 15, further comprising the step of preparing a solution containing the compound represented by the formula (1). 17. The method of claim 16, wherein the step of reacting the compound of formula (I) with at least one selected from the group consisting of ammonium formate, ammonium chloride, sodium dihydrogen phosphate and hydrazine comprises reacting the ammonium formate, ammonium chloride, Wherein at least one selected from the group consisting of dihydrogen phosphate and hydrazine is added. 18. The method according to claim 17, wherein at least one selected from the group consisting of ammonium formate, ammonium chloride, sodium dihydrogen phosphate and hydrazine is added at a temperature of 5 to 30 占 폚. The method for producing a compound according to claim 16, wherein the step of preparing the solution comprises dissolving the compound represented by the formula (1) in a linear or branched C1 to C4 alcohol. 16. The process of claim 15, wherein the at least one reaction selected from the group consisting of the compound of formula (I) and ammonium formate, ammonium chloride, sodium dihydrogen phosphate and hydrazine comprises iron, zinc, tin chloride, Lt; RTI ID = 0.0 > (2) < / RTI > 1. A process for producing a silver halide photographic light-sensitive material, comprising: reacting a compound represented by the following formula (1) with at least one member selected from the group consisting of iron, zinc, tin and iron, a compound containing zinc, And reacting the resulting compound with at least one selected from the group consisting of chloride, sodium dihydrogen phosphate and hydrazine to produce a compound represented by the following formula (2), an isomer thereof, or a salt thereof.
[Chemical Formula 1]

(2)

In the above Formulas 1 and 2, R is acetyl, benzoyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl or benzyl.
(A)

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