WO2016159666A2 - Forme cristalline et procédé de préparation de celui-ci - Google Patents

Forme cristalline et procédé de préparation de celui-ci Download PDF

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WO2016159666A2
WO2016159666A2 PCT/KR2016/003285 KR2016003285W WO2016159666A2 WO 2016159666 A2 WO2016159666 A2 WO 2016159666A2 KR 2016003285 W KR2016003285 W KR 2016003285W WO 2016159666 A2 WO2016159666 A2 WO 2016159666A2
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preparing
formula
trihydrate
carbonyl
isopropyl
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PCT/KR2016/003285
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WO2016159666A3 (fr
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박상욱
임종재
김철우
송세현
손세일
이홍우
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대원제약주식회사
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Priority to CN201680020018.5A priority Critical patent/CN107438595B/zh
Publication of WO2016159666A2 publication Critical patent/WO2016159666A2/fr
Publication of WO2016159666A3 publication Critical patent/WO2016159666A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • 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.
  • 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.
  • THP is a dihydropyranyl group and PPTS is pyridinium para-toluenesulfonate.
  • 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.
  • Patent Document 1 Republic of Korea Registered Patent 1329113
  • Non-Patent Document 1 Goodman and Gilman, The Pharmacological Basis of Therapeutics 841 (MacMillan Publ. Co .: New York 7th ed. 1985)
  • Non-Patent Document 2 Prudent Practices in the Laboratory: Handling and Disposal of Chemicals (1995), 370 p
  • Non-Patent Document 3 J. Med. Chem., 41, 26, (1998), 5297-5309
  • Non-Patent Document 4 Tetrahedron Lett., 43, 30, (2002), 5353
  • 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.
  • R in Formulas 1 and 2 is acetyl, benzoyl, tetrahydropyranyl, methoxy methyl, methoxy ethoxymethyl or benzyl, preferably tetrahydropyranyl.
  • 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.
  • the compound represented by Formula 2 can be obtained in high yield and purity within a short time.
  • zinc, tin, iron and compounds containing them are not only excellent in safety but also inexpensive.
  • 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.
  • 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.
  • 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.
  • 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 ).
  • 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.
  • 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.
  • 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 5 to 30 ° C.
  • the compound represented by Chemical Formula 1 may be prepared from the compound represented by Chemical Formula 3.
  • R in the formula (1) is tetrahydropyranyl
  • the compound represented by the formula (3) can be prepared by reacting the compound represented by the formula (3) with 3,4-dihydropyran.
  • 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);
  • 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.
  • R in Formulas 1 and 2 is acetyl, benzoyl, tetrahydropyranyl, methoxy methyl, methoxy ethoxymethyl or benzyl, preferably tetrahydropyranyl.
  • 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 it may be added at a temperature of about 10 to 25 °C, more preferably at a temperature of about 20 °C.
  • the reactant 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 temperature of about 65 °C 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
  • 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.
  • 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.
  • the salts refer to salts prepared from metal salts or organic bases.
  • the metal salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, aluminum salts.
  • 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.
  • 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);
  • 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.
  • R in Formulas 1 and 2 is acetyl, benzoyl, tetrahydropyranyl, methoxy methyl, methoxy ethoxymethyl or benzyl, preferably tetrahydropyranyl.
  • 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) ) Provides a novel crystalline form of the hemi calcium salt of carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid.
  • 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 by the method described in the existing Korean Patent No. 1329113, so that it is stably maintained for a long time after preparation, and the surrounding moisture It does not absorb and can be maintained without changing the moisture content for a long time when the preparation or storage of the formulation as an active ingredient.
  • 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.
  • 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
  • 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 ° ⁇ 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 2 ⁇ 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
  • 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.
  • novel crystalline Form I exhibits high solubility.
  • 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.
  • the crystalline Form II is the X-ray powder diffraction pattern using Cu-Ka radiation shows a peak at diffraction angles 2 ⁇ of 5.46 ° ⁇ 0.2 °, 9.50 ° ⁇ 0.2 ° and 19.30 ° ⁇ 0.2 °, more preferred
  • 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 2 ⁇ 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 2 ⁇ of 0.2 °, 20
  • 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.
  • Form III has an X-ray powder diffraction pattern using Cu-Ka radiation at diffraction angles 2 ⁇ 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 2 ⁇ 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 ° ⁇
  • the present invention is a.
  • (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 a
  • (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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the starting material may be amorphous, or may be a mixture of Form I of amorphous and trihydrate.
  • the obtained solid may be further obtained by filtration and washing with ethyl acetate.
  • 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 °C, preferably about 14 to 17 hours at about 50 to 60 °C 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 a
  • (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.
  • 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).
  • 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.
  • the starting material may be amorphous or may be a mixture of crystalline Form II of amorphous and trihydrate.
  • the stirring of the reaction solution may be performed at room temperature for about 2 to 4 days, preferably about 3 days.
  • 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 a
  • (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.
  • 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).
  • the method may further include stirring the reaction solution before concentration after preparation of the reaction solution.
  • the step of adding water may be added dropwise for about 20 minutes to 1 hour at a temperature of about 0 to 5 °C.
  • 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.
  • the step of drying the solid may be further performed.
  • the drying may be carried out at a temperature of about 40 to 70 °C, preferably at a temperature of about 60 °C.
  • 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.
  • the pharmaceutical composition comprises (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethyl) as an active ingredient.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition 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.
  • the pharmaceutical composition may be formulated by further adding a sweetener such as peppermint oil, eucalyptus oil, or saccharin.
  • 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.
  • the content of the additive is not particularly limited and may be appropriately adjusted within the content range used for conventional formulation.
  • 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 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 trihydrate of the hemicalcium salt form and a pharmaceutically acceptable additive comprising a pharmaceutical composition for the prevention or treatment of cardiovascular diseases, the method of treating cardiovascular disease to a human To provide.
  • 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 therapeutic use for the cardiovascular disease of a pharmaceutical composition for the prevention or treatment of cardiovascular diseases comprising a trihydrate crystalline form of a hemicalcium salt and a pharmaceutically acceptable additive.
  • the cardiovascular disease is hypertension, stroke, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, complex lipidosis, arteriosclerosis, atherosclerosis, angina pectoris, myocardial infarction, arterial obstructive disease, cerebral infarction, myocardial disease Microvascular disease, diabetic angiopathy or coronary atherosclerosis, preferably hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia or complex hyperlipidemia.
  • 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.
  • 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.
  • 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%
  • 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.
  • 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.
  • 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.
  • 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%
  • 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.
  • 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.
  • the crystalline Forms I to III was found to be less than 3% change in moisture content when exposed to air for 24 hours.
  • 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.
  • the water content was increased by almost 10 times.
  • 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.
  • the 4-(((tetrahydro-pyran-2-yl) oxy) methyl) aniline can be economically produced in high purity and yield to improve the yield of reactions using the compound as a reactant. Can be.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Un procédé de préparation de la présente invention peut produire de la 4- (( (tétrahydro-pyran-2-yl) oxy) méthyl) aniline avec un rendement et une pureté élevés, en dépit d'un faible coût. En outre, une forme cristalline de la présente invention est remarquablement une excellente stabilité, une hygroscopicité et la solubilité.
PCT/KR2016/003285 2015-03-31 2016-03-30 Forme cristalline et procédé de préparation de celui-ci WO2016159666A2 (fr)

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KR102218320B1 (ko) * 2019-07-12 2021-02-23 대원제약주식회사 (3r,5r)-7-(2-(4-플루오로페닐)-5-이소프로필-3-페닐-4-((4-히드록시메틸페닐아미노)카보닐)-피롤-1-일)-3,5-디히드록시 헵탄산 헤미칼슘염의 제조방법, 및 이에 사용되는 중간체의 제조방법

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CA2753318A1 (fr) * 2003-05-30 2004-12-09 Ranbaxy Laboratories Limited Derives pyrroliques substitues
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WO2016159666A3 (fr) 2017-01-26

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