CN107438595B - Crystal form and preparation method thereof - Google Patents
Crystal form and preparation method thereof Download PDFInfo
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- CN107438595B CN107438595B CN201680020018.5A CN201680020018A CN107438595B CN 107438595 B CN107438595 B CN 107438595B CN 201680020018 A CN201680020018 A CN 201680020018A CN 107438595 B CN107438595 B CN 107438595B
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- 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
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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
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- 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
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- 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
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Abstract
According to the production method of the present invention, 4- (((tetrahydro-pyran-2-yl) oxy) methyl) aniline can be produced in high yield and purity, despite low cost. In addition, the crystal form of the present invention has remarkably excellent stability, hygroscopicity and solubility.
Description
Technical Field
The invention provides a novel method for preparing a statin compound, a novel crystal form of the statin compound and a preparation method thereof. More particularly, the present invention provides an economical process for preparing a compound, which can be used as a reactant for preparing a statin compound with high purity and high yield and can be mass-produced without using any expensive catalyst, and a novel crystalline form of the statin compound having significantly improved physical properties and a method for preparing the same.
Background
(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt inhibits the synthesis of cholesterol in cells by acting as an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, useful as a hypolipidemic or hypocholesterolemic agent.
In korean patent registration No. 1329113, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid, hemi calcium salt, was prepared as follows:
wherein THP is dihydropyranyl and tBu is tert-butyl.
In the above-mentioned patent, a process for preparing the compound of formula II as a starting material is described in example 1, which is also described to be prepared according to the processes described in the documents [ J.Med.Chem.,41,26, (1998), 5297-:
wherein THP is dihydropyranyl and PPTS is pyridinium p-toluenesulfonate.
In the above document, benzyl alcohol of 4-nitrobenzyl alcohol ((4-nitrophenyl) methanol) is protected with 3, 4-dihydropyranyl group to synthesize a compound represented by 2b, and then the nitro group is reduced with a palladium/carbon (Pd/C) catalyst to form an amine group, thereby synthesizing a compound represented by 3 b.
However, the Pd/C used in the above preparation method becomes highly flammable when exposed to air, and becomes more flammable in its hydrogen-containing state. Therefore, if the reaction using the catalyst is carried out in air, the risk of easy ignition of the solvent used in the reaction is very high (laboratory judicious practice: handling and disposing of the chemical (1995,370 p). furthermore, even if the catalyst is used in the reaction, the reaction yield is not high, and the purity of the compound represented by 3b is not high.
Therefore, this method is not suitable for mass production of the compound represented by 3 b. Therefore, there is an increasing need to develop a novel method for mass-producing a compound represented by 3b in high purity and yield for mass-producing (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt as a starting material.
The (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt prepared according to the prior korean patent registration No. 1329113 has excellent solubility, but does not have excellent stability and hygroscopicity, and thus is difficult to store for a long period of time, and the raw material as an active ingredient is decomposed during the preparation process or during storage of the formulation. Therefore, content uniformity of the resulting formulation may be reduced. Therefore, it is required to develop a method for improving physical properties of a compound, and thus more excellent stability and hygroscopicity without lowering solubility.
[ Prior art reference ]
[ patent document ]
(patent document 1) Korean patent registration No. 1329113
[ non-patent document ]
(non-patent document 1) Goodman and Gilman, pharmacological basis of therapeutics 841(MacMillan publ. Co., 7 th edition, New York, 1985).
(non-patent document 2) judicious practice in the laboratory: treatment and disposal chemicals (1995,370 p.
(non-patent document 3) j.med.chem.,41,26, (1998), 5297-.
(non-patent document 4) Tetrahedron lett, 43,30, (2002), 5353.
Detailed description of the invention
Technical problem
The object of the present invention is to provide a novel process for the mass production of starting materials for the synthesis of statins.
The invention also aims to provide a hydrate crystal form of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethyl phenyl amino) carbonyl ] -pyrrole-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt and a preparation method thereof.
Technical scheme
The present invention provides a method for preparing a compound represented by formula 2, comprising:
reacting a compound represented by the following formula 1 with ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine, or a mixture thereof in the presence of iron, zinc, tin, an iron-containing compound, a zinc-containing compound, a tin-containing compound, or a mixture thereof.
[ formula 1]
[ formula 2]
Wherein in formulae 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 preferably be a compound represented by the following formula 1-1 or 2-1, respectively.
[ formula 1-1]
[ formula 2-1]
According to this method, the compound represented by formula 2 can be obtained in a short time with high purity and yield. In addition, zinc, tin, iron, and compounds containing them are not only excellent in safety but also inexpensive. In addition, the reaction for preparing the compound represented by formula 2 is carried out in the presence of zinc, tin, iron or a compound containing them, and the obtained compound is also high in reaction yield and purity. Therefore, the method can economically mass-produce the compound represented by formula 2, and thus can mass-produce many compounds prepared by using the compound represented by formula 2. For example, according to the method of the present invention, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt can be produced in large quantities economically and with higher purity and yield than conventional methods.
According to 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 performed in the presence of iron or an iron-containing compound, zinc or a zinc-containing compound, tin or a tin-containing compound. The material is inexpensive, and can improve the reaction yield of the reaction of the compound represented by formula 1 with ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine, or a mixture thereof, so that the compound represented by formula 2 can be obtained with high purity.
Compared with the price of Pd/C, the price of iron or compounds containing iron, zinc or compounds containing zinc, and tin or compounds containing tin is 1/300 to 1/60 which is equivalent to the price of Pd/C. However, iron or iron-containing compounds, zinc or zinc-containing compounds, tin or tin-containing compounds can improve the reaction yield by three times or more and also improve the purity by 10% or more, as compared with Pd/C.
According to the invention, iron or iron-containing compounds, zinc or zinc-containing compounds, tin or tin-containing compounds may preferably be iron, zinc or tin chloride (SnCl)2)。
According to the present invention, a method of preparing the compound represented by formula 2 may further include 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.
According to the present invention, the step of reacting the compound represented by formula 1 with ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine, or a mixture thereof may be adding ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine, or a mixture thereof to a solution containing the compound represented by formula 1.
The compound represented by formula 2 may be prepared by adding iron or an iron-containing compound, zinc or a zinc-containing compound, tin or a tin-containing compound to a solution containing the compound represented by formula 1, and then adding ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine, or a mixture thereof.
According to the invention, in
To a solution containing the compound represented by formula 1, ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine, or a mixture thereof is added.
According to the present invention, the compound represented by 1 may be prepared from the compound represented by formula 3.
[ formula 3]
According to the present invention, if R in formula 1 represents tetrahydropyranyl, the compound represented by formula 2 may be prepared by reacting the compound represented by formula 3 with 3, 4-dihydropyran.
According to the present invention, the reaction of the compound represented by formula 3 may be carried out in the presence of a pyridine-p-toluenesulfonate compound as a catalyst.
The present invention provides a method for preparing a compound represented by the following formula 2, which comprises:
preparing a solution containing a compound represented by the following formula 1; and
the reactants are prepared by adding to the solution iron, zinc, tin, an iron-containing compound, a zinc-containing compound, tin, or a mixture thereof, and ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine, or a mixture thereof.
[ formula 1]
[ formula 2]
Wherein formula 1 and 2, R is acetyl, benzoyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl or benzyl, preferably tetrahydropyranyl.
According to the invention, at a temperature of about 5 to 30 ℃, preferably about
Ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine, or a mixture thereof may be added to the solution containing the compound of formula 1 at a temperature of about 20 c, which is more preferred.
According to the invention, the reactants may be in the range of about
Preferably about
More preferably at a temperature of about 65 c.
The present invention provides a method for preparing a compound represented by the following formula a or an isomer thereof or a salt thereof, the method comprising:
a compound represented by the following formula 1 is reacted with ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine, or a mixture thereof in the presence of iron, zinc, tin, an iron-containing compound, a zinc-containing compound, a tin-containing compound, or a mixture thereof to prepare a compound represented by the following formula 2.
[ formula 1]
[ formula 2]
[ formula A ]
Wherein R is acetyl, benzoyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl or benzyl, preferably tetrahydropyranyl.
The present invention enables mass production of a compound represented by the following formula 2 with high purity and yield economically, and thus a compound represented by the formula a, an isomer thereof or a salt thereof prepared by using the compound represented by the formula 2 as a reactant can be obtained with high purity and high yield and economically mass-produced at low cost.
The method for preparing the compound represented by formula a, its isomer, or its salt based on formula 2 is as described in korean patent registration No. 1329113.
According to the invention, the salt is a metal salt or a salt prepared from an organic base. For example, the metal salt may be lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, and aluminum salt, but is not limited thereto. For example, the salt prepared by using the organic base may be a salt prepared by using an amino acid, an amine, monoalkylammonium, dialkylammonium, trialkylammonium, N-methylglucamine, or the like, specifically, a salt prepared by using glycine, arginine, lysine, trimethylamine, ammonia, pyridine, picoline, or the like, but is not limited thereto.
Preferably, the salt may be a hemi-calcium salt of the compound represented by formula a, and the salt may be (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemi-calcium salt, i.e., a compound represented by the following formula B.
[ formula B ]
Wherein the method for preparing the compound represented by formula B based on formula 2 is as described in korean patent registration No. 1329113.
The present invention provides a method for preparing a compound represented by the following formula a or an isomer thereof or a salt thereof, the method comprising:
preparing a solution containing a compound represented by the following formula 1; and
preparing a compound represented by the following formula 2 by adding iron, zinc, tin, an iron-containing compound, a zinc-containing compound or a tin-containing compound or a mixture thereof, and ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine or a mixture thereof to the solution:
[ formula 1]
[ formula 2]
[ formula A ]
Wherein R is acetyl, benzoyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl or benzyl, preferably tetrahydropyranyl.
According to the invention, the salt of the compound of formula a is as described above, preferably the hemicalcium salt of the compound of formula (a), which may be (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt.
The invention provides a novel crystal form of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethyl phenyl amino) carbonyl ] -pyrrole-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt, which is a compound shown in a formula B below.
[ formula B ]
The novel crystal form can be (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethyl phenyl amino) carbonyl ] -pyrrole-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt, a hydrate of the compound shown as a formula B, and preferably a trihydrate thereof.
According to the present invention, the novel trihydrate crystal form of the compound represented by formula B has more excellent stability and hygroscopicity than the compound prepared by the conventional case described in korean patent registration No. 1329113, and thus can be stably maintained for a long time without absorbing moisture after preparation. Therefore, the preparation can keep the moisture content constant for a long time when the preparation is prepared or stored by using the component as an active ingredient. In addition, according to the present invention, the novel crystal form of the compound represented by formula B is shown to have high solubility, thus showing excellent pharmacological effects.
The present invention provides crystalline form I trihydrate of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt.
According to the invention, form I has an X-ray powder diffraction pattern obtained using Cu-Ka radiation, which shows peaks at the following diffraction angles 2 θ: 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 °, preferably, form I has an X-ray powder diffraction pattern obtained using Cu-Ka radiation showing a peak at least one diffraction angle 2 θ selected from the group consisting of: 11.86 ° ± 0.2 °, 22.00 ° ± 0.2 °, 23.86 ° ± 0.2 ° and 24.48 ± 0.2 ° and 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 °, more preferably, form I has an X-ray powder diffraction pattern obtained using Cu-Ka radiation showing peaks at the following diffraction angles 2 θ: 11.86 degrees +/-0.2 degrees, 22.00 +/-0.2 degrees, 23.86 +/-0.2 degrees, 24.48 degrees +/-0.2 degrees, 5.38 degrees +/-0.2 degrees, 9.46 degrees +/-0.2 degrees, 11.22 degrees +/-0.2 degrees, 18.84 degrees +/-0.2 degrees, 19.18 degrees +/-0.2 degrees, 20.70 degrees +/-0.2 degrees and 22.68 degrees +/-00.2 degrees.
According to the present invention, the trihydrate crystal form I of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt has more excellent stability and hygroscopicity than the compound prepared by the prior method described in korean patent registration No. 1329113, and has the same solubility as the latter.
Since the new form I hardly absorbs moisture, it can maintain the same hydrate state for a long time and stably maintain without being decomposed or changed into another material even if it is stored for a long time. Therefore, the crystal form I can keep the same state after the crystal form I is stored or used for preparing a preparation, or after a preparation containing the crystal form I is prepared, so that the content uniformity of the preparation is stably kept for a long time, and any difficult storage condition and preparation process of the preparation are not needed for keeping the stability, so that the preparation method is very suitable for large-scale production.
In addition, the new form I shows high solubility. Thus, form I can exhibit excellent therapeutic effects if administered.
The present invention provides crystalline form II trihydrate of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt.
According to the invention, form II has an X-ray powder diffraction pattern obtained using Cu-Ka radiation, which exhibits peaks at the following diffraction angles 2 θ: 5.46 ° ± 0.2 °, 9.50 ° ± 0.2 ° and 19.30 ° ± 0.2 °, preferably, form II has an X-ray powder diffraction pattern obtained using Cu-Ka radiation showing a peak at least one diffraction angle 2 θ selected from the group consisting of: 5.78 ° ± 0.2 °, 11.16 ° ± 0.2 ° and 20.84 ° ± 0.2 ° and 5.46 ° ± 0.2 °, 9.50 ° ± 0.2 ° and 19.30 ° ± 0.2 °, more preferably, form II exhibits an X-ray powder diffraction pattern obtained using Cu-Ka radiation that exhibits peaks at the following diffraction angles 2 θ: 5.78 ° ± 0.2 °, 11.16 ° ± 0.2 °, 20.84 ° ± 0.2 °, 5.46 ° ± 0.2 °, 9.50 ° ± 0.2 ° and 19.30 ° ± 0.2 °.
The present invention provides crystalline form III trihydrate of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt.
According to the invention, form III has an X-ray powder diffraction pattern obtained using Cu-Ka radiation, which exhibits peaks at the following diffraction angles 2 θ: 21.90 ° ± 0.2 °, 8.04 ° ± 0.2 °, 8.11 ° ± 0.2 ° and 13.07 ° ± 0.2 °, preferably, form III has an X-ray powder diffraction pattern obtained using Cu-Ka radiation, exhibiting a peak at least one diffraction angle 2 θ selected from the group consisting of: 14.02 ° ± 0.2 °, 17.23 ° ± 0.2 °, 18.98 ° ± 0.2 ° and 23.46 ° ± 0.2 ° and 21.90 ° ± 0.2 °, 8.04 ° ± 0.2 °, 8.11 ° ± 0.2 ° and 13.07 ° ± 0.2 °, more preferably, form III exhibits an X-ray powder diffraction pattern obtained using Cu-Ka radiation that peaks at the following diffraction angles 2 Θ: 21.90 ° ± 0.2 °, 8.04 ° ± 0.2 °, 8.11 ° ± 0.2 °, 13.07 ° ± 0.2 °, 14.02 ° ± 0.2 °, 17.23 ° ± 0.2 °, 18.98 ° ± 0.2 ° and 23.46 ° ± 0.2 °.
According to the present invention, the trihydrate crystal forms II and III of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt show more excellent stability and hygroscopicity than the compound prepared by the prior method described in korean patent registration No. 1329113, and have the same solubility as the latter.
The present invention provides a process for preparing a crystalline trihydrate form of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt comprising:
a reactant containing (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt and a mixed solvent comprising water and at least one of ethyl acetate, dichloromethane, methanol and tetrahydrofuran were prepared.
According to the above preparation method, the trihydrate crystal form of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt can be obtained in high purity and yield, the preparation method is simple, and therefore, the preparation method is suitable for mass production.
The present invention provides a process for preparing crystalline trihydrate form I of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt comprising:
preparing a reaction solution containing (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt, ethyl acetate and water; and
the reaction solution was stirred.
According to the above preparation method, the trihydrate crystal form I of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt can be obtained in high purity and yield, and the preparation method is simple and therefore suitable for mass production.
In the method of preparing form I of the present invention, the step of preparing the reaction solution comprises:
preparing a mixture by adding water to (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid, hemi calcium salt;
stirring the mixture; and
the reaction solution was prepared by adding ethyl acetate to the stirred mixture.
In the method for preparing crystalline form I of the present invention, the volume ratio of ethyl acetate to water in the reaction solution may be 3:1 to 1:3(V/V), preferably 2:1 to 1:2 (V/V).
In the process of the present invention for preparing form I, can be at about
Stirring the mixture under conditions
For hours, preferably about 25 deg.C, with stirring
And (4) hours.
In the method of the present invention for preparing form I, the step of stirring the reaction solution may be performed by stirring the reaction solution at reflux at about 65 to 80 ℃ for about 1 to 3 hours, preferably at about 70 to 75 ℃ for about 1.5 to 2 hours.
In the method of the present invention for preparing form I, the method may further comprise the step of cooling the stirred reaction solution. A solid may be produced by cooling the stirred reaction solution.
The cooling may be effected by cooling the reaction solution to about 30 to 50 ℃ for about 1 to 3 hours, more preferably to about 40 ℃ for about 2 hours.
In the process of the present invention for preparing crystalline form I, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt, which is the starting material, may be in amorphous, crystalline form or a mixture thereof. For example, the starting material may be a mixture of amorphous or trihydrate form I and amorphous.
The process for preparing form I of the present invention may further comprise the steps of filtration, obtaining the resulting solid and washing with ethyl acetate.
The process for preparing form I of the present invention may further comprise the step of drying the obtained solid. The drying may be carried out at a pressure of about 50 to 800mmHg and a temperature of 40 to 70 ℃ for about 10 to 20 hours, preferably at about 100 to 600mmHg and about
At temperature for about 14 to 17 hours.
The invention provides a method for preparing a trihydrate crystal form II of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethyl phenyl amino) carbonyl ] -pyrrole-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt.
The method comprises the following steps:
preparing a reaction solution containing (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt, methanol and water; and
the reaction solution was stirred.
According to the above preparation method, the crystalline form II of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt can be obtained in high purity and yield, and the preparation method thereof is simple and therefore suitable for mass production.
In the method of preparing the crystalline form II of the present invention, the step of preparing the reaction solution includes:
preparing a mixed solvent containing methanol and water; and
the hemicalcium salt of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid is added to the mixed solvent.
In the method of preparing the crystalline form II of the present invention, the mixed solvent may contain methanol and water in a volume ratio of 3:1 to 1:3(V/V), preferably 2:1 to 1:2 (V/V).
In the process of the present invention for preparing crystalline form II, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt, which is the starting material, may be in amorphous, crystalline form or a mixture thereof. For example, the starting material may be a mixture of amorphous or trihydrate form II and amorphous.
In the method of preparing form II of the present invention, the stirring of the reaction solution may be performed at room temperature for about 2 to 4 days, preferably for about 3 days.
In the method of preparing form II of the present invention, after stirring the reaction solution, a solid may be filtered and obtained from the reaction solution.
In the method of preparing form II of the present invention, a step of drying the obtained solid may be further included. The drying may be performed under a pressure of about 50 to 800mmHg and a pressure of 40 to 70 ℃, preferably under a pressure of about 100 to 600mmHg and a temperature of about 50 to 60 ℃.
The present invention provides a process for the preparation of crystalline form III trihydrate of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt;
the method comprises the following steps:
preparing a reaction solution containing (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt and a solvent comprising methanol and one of tetrahydrofuran and dichloromethane;
preparing a concentrate by concentrating the reaction solution; and
solids were produced by adding water to the concentrate.
According to the preparation method, the trihydrate crystal form III of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt can be obtained in high purity and yield, the preparation method is simple, and therefore, the preparation method is suitable for mass production.
In the method of preparing form III of the present invention, the step of preparing the reaction solution comprises:
preparing a mixed solvent containing methanol and one of tetrahydrofuran and dichloromethane; and
(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 added to the mixed solvent.
In the method for preparing the crystalline form III of the present invention, the mixed solvent may comprise one of tetrahydrofuran and dichloromethane in a volume ratio of 1:10 or 4:5(V/V) to methanol, preferably 1:5 to 3: 5 (V/V).
In the method of preparing form III of the present invention, a step of stirring the reaction solution may be further included after preparing the reaction solution and before concentrating the reaction solution.
In the process of the present invention for preparing form III, the step of adding water may be carried out in such a way that: in the range of
Is added dropwise at a temperature of about 20 minutes to 1 hour.
In the method of the present invention for producing form III, a step of stirring the reaction solution may be further included after adding water. The step of stirring the reaction solution may be at about
Is carried out at a temperature of from about 30 minutes to 3 hours, preferably 2 hours.
In the process of the present invention for preparing form III, the step of drying the solid may be further carried out, and the drying may be carried out at a temperature of about 40 to 70 ℃, preferably at a temperature of about 60 ℃.
The present invention provides a pharmaceutical composition for preventing and treating cardiovascular diseases, wherein the pharmaceutical composition contains a trihydrate crystal form of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt and pharmaceutically acceptable additives as active ingredients.
According to the present invention, the pharmaceutical composition may contain at least one of the trihydrate crystal form I, trihydrate crystal form II and trihydrate crystal form III of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt as an active ingredient, preference is given to crystalline trihydrate form I of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt.
When the pharmaceutically acceptable additive is a physiologically acceptable additive which is conventionally used in the medical field and does not cause any allergic reaction when administered to a human body, such as gastrointestinal diseases, vertigo or the like, the type is not particularly limited. Examples of additives may be carriers, excipients and diluents. Examples of carriers, excipients and diluents may be lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.
The pharmaceutical composition may further comprise antioxidants, buffer solutions, fillers, anticoagulants, lubricants, humectants, fragrances, emulsifiers, preservatives, and the like.
In the pharmaceutical composition of the present invention, the cardiovascular disease may be hypertension, cerebral stroke, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, arteriosclerosis, atherosclerosis, angina pectoris, myocardial infarction, arterial occlusive disease, cerebral infarction, myocardial microvascular disease, diabetic vascular complication or coronary arteriosclerosis, preferably hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia or combined hyperlipidemia.
The pharmaceutical composition of the present invention can be prepared according to conventional methods, and can be prepared in various types of oral administration forms such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions or various types of parenteral administration forms such as intramuscular, intravenous or subcutaneous administration.
If the pharmaceutical composition of the present invention is formulated into oral preparations, examples of the additives may be cellulose, calcium silicate, corn starch, lactose, sucrose, glucose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspensions, emulsifiers, diluents, and the like.
If the pharmaceutical composition is pharmaceutically formulated into a liquid preparation such as a suspension for oral administration, a liquid medicine for oral administration, an emulsion, a syrup, etc., the pharmaceutical composition can be prepared by adding a simple diluent such as water and liquid paraffin, and various additives such as a wetting agent, a sweetener, an air freshener, a preservative, an antibacterial agent, a coloring agent, etc. For example, the pharmaceutical composition may be prepared pharmaceutically by further adding a sweetening agent such as peppermint, eucalyptus, or saccharin.
If the pharmaceutical composition of the present invention is pharmaceutically formulated as an injection, the additive may be water, saline solution, aqueous glucose solution, similar aqueous sugar solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid ester, glyceride, surfactant, suspension, emulsifier, etc
In the pharmaceutical composition of the present invention, the content of the additive is not particularly limited, and may be appropriately adjusted within the content range used in conventional preparations.
The pharmaceutical composition of the present invention may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and the dosage may vary depending on the body weight, age, sex, health condition, diet, administration time, administration mode, administration time or interval, excretion rate, individual specificity, formulation property, disease severity, and the like of the patient.
The pharmaceutical composition of the present invention may be administered in an amount of about 0.01 to 100 mg/kg/day, preferably 0.1 to 30 mg/kg/day, or if desired, all at once or several times per day, of the crystalline form of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt as active ingredient.
The present invention provides a method for preventing or treating cardiovascular disease by administering to a human a pharmaceutical composition comprising a crystalline trihydrate form of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt and pharmaceutically acceptable additives.
The invention provides a pharmaceutical composition containing a trihydrate crystal form of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethyl phenyl amino) carbonyl ] -pyrrole-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt and pharmaceutically acceptable additives, and the pharmaceutical composition is used for preventing or treating cardiovascular diseases.
According to the present invention, the cardiovascular disease may be hypertension, cerebral stroke, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, arteriosclerosis, atherosclerosis, angina pectoris, myocardial infarction, arterial occlusive disease, cerebral infarction, myocardial microvascular disease, diabetic vascular complications or coronary arteriosclerosis, preferably hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia or combined hyperlipidemia.
Advantageous effects
The present invention provides a novel process for the preparation of 4- (((tetrahydro-pyran-2-yl) oxy) methyl) aniline. According to the present invention, the compound can be economically produced in high purity and high yield, thereby increasing the reaction yield using the compound as a reactant.
In addition, the novel crystalline form of the present invention has excellent stability, hygroscopicity and solubility, and thus facilitates mass production, and exhibits excellent therapeutic effects with a small amount of drug.
Brief description of the drawings
Figures 1 to 3 show the respective X-ray powder diffraction (XRD) of the trihydrate crystalline forms I to III of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid, hemi calcium salt in accordance with the present invention. In the figure, the horizontal axis represents 2 θ (degrees), and the vertical direction represents intensity (CPS).
Examples of the invention
Hereinafter, preferred examples and experimental examples are shown for better understanding of the present invention. However, the following examples and experimental examples are provided only for the purpose of illustrating the present invention, and thus the present invention is not limited thereto.
In addition, the reagents and solvents mentioned below were purchased from Sigma-Aldrich and the purity of the product was measured using HPLC (1200 series, agilent), unless otherwise specifically indicated herein.
Preparation example 1)
Preparation of 2- ((4-nitrobenzyl) oxy) tetrahydro-pyran compound (compound represented by formula 1)
(prepared according to the synthetic method of [ J.Med.chem.,41,26, (1998),5297-
4-Nitro-benzyl alcohol (1.6g, 10.45mmol) was dissolved in ethanol (52ml) to prepare a solution, and 3, 4-dihydropyran (1.32g, 1.43ml, 15.68mmol) and pyridinium p-toluenesulfonate (262.6mg, 1.05mmol) were added dropwise to the solution to prepare a mixture. The mixture was stirred for 1.5 hours, the solvent was evaporated under reduced pressure and concentrated. The concentrate was extracted with ethyl acetate (25ml), washed with water (50 ml. times.3), washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the compound of the present invention as an oily product.
Yield: 2.82g (98.8%), purity: 99.8 percent
Example 1)
Preparation of 4- (((tetrahydro-pyran-2-yl) oxy) methyl) aniline (compound represented by the formula 2-1) (Using Zinc as a catalyst)
2- ((4-nitrobenzyl) oxy) tetrahydro-pyran (1g, 3.66mmol) prepared in preparation example 1 was dissolved in methanol (100ml) to prepare a solution, zinc powder (1.4g) was added dropwise to the solution, and ammonium formate (0.9g) was added at 20 ℃ to prepare a mixture. The mixture was refluxed at 65 ℃. After 10 minutes from the end of the reflux, the zinc powder remaining in the mixture was removed to give a solution, the solvent was removed from the obtained solution under reduced pressure, and an extract was obtained therefrom with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated to give the title compound of the present invention as an oily product.
Yield: 0.71g (93%), purity: 75 percent of
Example 2)
Preparation of 4- (((tetrahydro-pyran-2-yl) oxy) methyl) aniline (compound represented by formula 2-1) (using iron as a catalyst)
2- ((4-nitrobenzyl) oxy) tetrahydro-pyran (1g, 3.66mmol) prepared in preparation example 1 was dissolved in methanol (100ml) to prepare a solution, iron powder (1.4g) was added dropwise to the solution, and ammonium formate (0.9g) was added under a condition of 20 ℃ to prepare a mixture. The mixture was refluxed at 65 ℃. After 1.5 hours after the end of the reflux, iron powder remaining in the mixture was removed to obtain a solution, the solvent was removed from the obtained solution under reduced pressure, and an extract was obtained therefrom with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to give the compound of the present invention as an oily product.
Yield: 0.72g (95%), purity: 80 percent of
Example 3)
Preparation of 4- (((tetrahydro-pyran-2-yl) oxy) methyl) aniline (compound represented by the formula 2-1) (Using tin compound as catalyst)
2- ((4-Nitrobenzyl) oxy) tetrahydro-pyran (1g, 3.66mmol) prepared in preparation example 1 was dissolved in methanol (100ml) to prepare a solution, and tin (II) chloride (SnCl) was added23.5g) was added dropwise to the solution to prepare a mixture. The mixture was refluxed at 65 ℃. After 1 hour and 20 minutes from the end of the reflux, tin remaining in the mixture was removed to obtain a solution, the solvent was removed from the obtained solution under reduced pressure, and an extract was obtained therefrom with ethyl acetate. Extract (Cuiyu)The extract was washed with 2M aqueous potassium hydroxide, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the compound of the present invention as an oily product.
Yield: 0.57g (76%), purity: 83 percent
Comparative example 1)
Preparation of 4- (((tetrahydro-pyran-2-yl) oxy) methyl) aniline (compound represented by the formula 2) (prepared according to the synthetic method of [ J.Med.chem.,41,26(1998),5297-
2- ((4-nitrobenzyl) oxy) tetrahydro-pyran (1g, 3.66mmol) prepared in preparation example 1 was dissolved in ethanol (100ml) to prepare a solution, 10% (w/w) palladium on carbon (0.3g) was added dropwise to the solution, and ammonium formate (0.9g) was added at 20 ℃ to prepare a mixture. After 1.5 hours, the palladium/carbon remaining in the mixture was removed to obtain a solution, the solvent was removed from the obtained solution under reduced pressure, and an extract was obtained therefrom with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to give the compound of the present invention as an oil-type product.
Yield: 0.19g (25%), purity: 68 percent of
Example 4)
Preparation of trihydrate crystalline form I
A mixture was prepared by adding 20g of the compound represented by formula B ((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt) to 200ml of water, and the mixture was stirred at about 25 ℃ for 17 hours. A reaction solution was prepared by adding 200ml of ethyl acetate to the mixture, and the reaction solution was stirred under reflux at 70 to 75 ℃ for 1.5 to 2 hours, cooled to 40 ℃ for 2 hours, and stirred at 40 ℃ for 1 hour to give a solid. The resulting solid was filtered to give a solid which was washed twice with 250ml of ethyl acetate and dried at 55 ℃ for 16 hours at 100 to 600mmHg to give 17.1g (purity 99.82%) of crystalline form I trihydrate of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt as a white solid.
Example 5)
Preparation of trihydrate form I
A mixture was prepared by adding 19g of the compound represented by formula B ((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid, hemi calcium salt) and 1g of the trihydrate form I prepared in example 4 to 200ml of water and the mixture was stirred at about 25 ℃ for 17 hours. A reaction solution was prepared by adding 200ml of ethyl acetate to the mixture, the reaction solution was stirred under reflux at 70 to 75 ℃ for 1.5 to 2 hours, the reaction solution was cooled to 40 ℃ for 2 hours, and stirred at 40 ℃ for 1 hour to give a solid. The resulting solid was filtered to give a solid which was washed 2 times with 250ml ethyl acetate and dried at 55 ℃ for 16 h at 100 to 600mmHg to give 17.8g (purity 99.89%) of crystalline form I trihydrate of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt as a white solid.
Example 6)
Preparation of trihydrate crystalline form II
20g of the compound represented by the formula B ((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt) was suspended in a mixed solvent of 200ml of methanol and 200ml of water to prepare a reaction solution, and the reaction solution was stirred for three days to give a solid. The resulting solid was filtered to give a solid, which was dried at 70 ℃ under 100 mmHg to 600mmHg to give 17.4g (purity 99.74%) of crystalline form II trihydrate of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt as a white solid.
Example 7)
Preparation of trihydrate crystalline form II
A reaction solution was prepared by suspending 19g of the compound represented by formula B ((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt) and 1g of the trihydrate crystal form II prepared in example 6 in a mixed solvent of 200ml of methanol and 200ml of methanol, and the reaction solution was stirred for 3 days to give a solid. The resulting solid was filtered to give a solid, which was dried at 70 ℃ under 100 mmHg to 600mmHg to give 17.9g (purity 99.83%) of crystalline form II trihydrate of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt as a white solid.
Example 8)
Preparation of trihydrate form III
20g of the compound represented by the formula B ((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt) was added to a mixed solvent of 200ml of methanol and 60ml of tetrahydrofuran to prepare a reaction solution, and the reaction solution was dissolved by stirring at room temperature for one hour. The resulting solution was concentrated under reduced pressure to its volume of 50% of the initial volume (v/v to prepare a concentrate the concentrate was transferred to a separate reactor and under conditions of 0 ℃ to 5 ℃, 800ml of water was slowly added thereto, 30 minutes, stirred for 2 hours while maintaining the temperature, then the resulting white solid was filtered and dried at 60 ℃ to give 17.2g (purity 99.69%) (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt as a white solid in crystalline form III trihydrate.
Example 9)
Preparation of trihydrate form III
20g of the compound represented by the formula B ((3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt) was added to a mixed solvent of 200ml of methanol and 80ml of dichloromethane to prepare a reaction solution, and the reaction solution was stirred at room temperature for 1 hour to dissolve. The solution was filtered to remove insoluble matter, and the resulting solution was concentrated under reduced pressure to 50% (v/v) of its volume as the original volume to prepare a concentrate. The concentrate was transferred to a separate reactor, and 800ml of water was slowly added thereto at 0 ℃ to 5 ℃ for 30 minutes, stirred for 2 hours while maintaining the temperature. The resulting white solid was then filtered and dried at 60 ℃ to give 17.3g (purity 99.73%) of crystalline trihydrate form III of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid, hemi calcium salt as a white solid.
Comparative example 2)
Preparation of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt (compound of formula B).
Starting with the compound prepared according to the method of example 1, the compound was prepared by using korean patent registration No.: 1329113 prepared as described in examples 2 to 6 to give (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt (compound of formula B).
Experimental example 1)
X-ray powder diffraction (XRD) patterns for identifying crystalline forms I, II and III
The X-ray powder diffraction (XRD) patterns of crystalline forms I to III prepared in examples 4 to 9 were identified by CuKa irradiation of a solid phase detector. An X-ray powder diffraction (XRD) pattern was measured by the following apparatus and under the following measurement conditions.
< method for measuring X-ray powder diffraction Spectroscopy >
-the manufacturer: RIGAKU
-a device: ultima IV
-voltage: 40kV
-current: 40mA
-scan range:
degree of rotation
-scanning speed: 0.5 degree/min
-increment: 0.02 degree
-a detector: D/teX Ultra
The X-ray powder diffraction peaks of the crystalline forms prepared in examples 4 and 5 are shown in table 1 and fig. 1 below:
TABLE 1X-ray powder diffraction (XRD) peaks for trihydrate form I
X-ray powder diffraction peaks of the crystalline forms prepared in examples 6 and 7 are shown in table 2 and fig. 2 below.
TABLE 2X-ray powder diffraction (XRD) peaks for crystalline form II trihydrate
X-ray powder diffraction peaks of the crystalline forms prepared in examples 8 and 9 are shown in table 3 and fig. 3 below.
TABLE 3X-ray powder diffraction (XRD) peaks for trihydrate form III
As shown by the powder diffraction peaks of tables 1 to 3, the compounds prepared in examples 4 and 5, examples 6 and 7, and examples 8 and 9 showed different peaks in X-ray powder diffraction patterns, thus indicating that the compounds are different novel crystalline forms.
Experimental example 2)
Identification of Water content of trihydrate forms I, II and III
The water content of the crystalline form compounds prepared in examples 4 to 9 of the present invention was measured by Karl Fisher (KF) method. The moisture measurement for form I was about 4.24% as determined in examples 4 and 5, the moisture measurement for form II was about 4.28% as determined in examples 6 and 7, and the moisture measurement for form III was about 4.22% as determined in examples 8 and 9. Thus, it can be seen that the embodiments
The crystal form prepared in (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethyl phenylamino) carbonyl group]-pyrrol-1-yl]-trihydrate of 3, 5-dihydroxy-heptanoic acid hemicalcium salt.
Experimental example 3)
Stability evaluation of trihydrate crystalline forms I, II and III
Stability tests were performed on the trihydrate 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, respectively. The test was conducted under accelerated conditions (temperature 40 ℃ C., relative humidity 75%) and the residual crystal form content after a certain period of time was expressed as a percentage (%) based on the area ratio of HPLC, and the results are shown in Table 4 below.
TABLE 4 stability test results (unit:%)
| Classification | At first, the method | 1 month | 2 month | 3 month | 4 | Month | 5 | 6 month |
| Crystal form I | 99.89 | 99.87 | 99.85 | 99.81 | 99.77 | 99.72 | 99.69 | |
| Crystal form II | 99.74 | 99.68 | 99.53 | 99.49 | 99.41 | 99.31 | 99.22 | |
| Crystal form III | 99.69 | 99.42 | 99.23 | 98.84 | 98.41 | 98.02 | 97.52 | |
| Comparative example 2 | 99.71 | 98.23 | 96.78 | 95.22 | 93.63 | 91.98 | 90.03 |
As shown in table 4, the contents of each of the crystalline forms I to III prepared in examples 4,6 and 8 hardly changed any more until 6 months. In particular, in the case of form I, the content reduction rate was only 0.2% even after six months. In contrast, the compound prepared in comparative example 2 had a content decrease of almost 10% after six months.
It can be seen that the trihydrate crystal forms I to III of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt show excellent stability and thus can be stably preserved for a long period of time. In particular, it can also be seen that form I has excellent stability, thus being easily mass-produced, and the content can be maintained for a long time while the formulation is prepared and stored.
Experimental example 4)
Hygroscopicity assessment of trihydrate crystalline forms I, II and III
The hygroscopicity of 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 was determined in air. The water content of each compound was measured by the same method as Karl-Fisher method as described in example 2 by exposing each crystal form to air at a temperature of 25 c and a relative humidity of 45% for 24 hours, and the results are shown in table 5 below.
TABLE 5 moisture absorption verification test results (unit:%)
| Classification | Crystal form I | Crystal form II | Crystal form III | Comparative example 2 |
| Before being exposed to air | 4.24 | 4.28 | 4.22 | 1.23 |
| After 24 hours of exposure | 4.65 | 5.23 | 7.47 | 10.48 |
As shown in table 5, it can be seen that the moisture content of forms I to III was changed to 3% or less when exposed to air for 24 hours. In particular, for form I, the moisture content increased only 0.2% even after 24 hours of exposure to air, indicating that form I absorbs little moisture. In contrast, the compound prepared in comparative example 2 was seen to have an almost 10-fold increase in water content.
Thus, it can be seen that the trihydrate crystalline forms I to III of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt exhibit excellent hygroscopicity, and particularly, the trihydrate crystalline form I hardly absorbs moisture even when exposed to air for a long time, so that the hydrate state can be stably maintained during the preparation of the formulation, and also does not require any difficult storage conditions, so that the same hydrate state is stably maintained for a long time.
Experimental example 5)
Solubility assessment of trihydrate crystalline forms I, II and III
The crystalline forms I, II and III prepared in examples 4,6 and 8 of the present invention were dissolved in non-ionic water or phosphate buffer ph6.8 until saturation, the insoluble solutes were filtered off to collect the filtrate, and the filtrate was diluted. The diluted filtrate was analyzed by ultraviolet absorption spectrophotometry at a wavelength of 247nm using a light separator (JASCO, model V-650) to measure its solubility.
TABLE 6 solubility (unit, temperature: μ g/ml, 25 ℃ C.)
| Classification | Nonionic water | pH6.8 phosphate buffer (0.05M) |
| Crystal form I | 325.4 | 485.1 |
| Crystal form II | 218.5 | 325.4 |
| Crystal form III | 219.6 | 327.3 |
As can be seen from table 6, forms I to III are readily soluble in non-ionic water and phosphate buffer pH 6.8. In particular, form I shows very high solubility in non-ionic water and phosphate buffer at ph 6.8. Thus, it can be seen that the trihydrate crystalline form I of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt can exhibit excellent therapeutic effects with only small amounts.
INDUSTRIAL APPLICABILITY
According to the present invention, 4- (((tetrahydro-pyran-2-yl) oxy) methyl) aniline can be economically produced in high purity and yield to improve the reaction yield using the compound as a reactant.
In addition, the novel crystalline form of the present invention exhibits excellent stability, hygroscopicity and solubility, and thus facilitates mass production, and can exhibit excellent therapeutic effects with only a small amount.
Claims (5)
- Crystalline trihydrate form I of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt, characterized in that said crystalline trihydrate form I has an X-ray powder diffraction pattern obtained using Cu-Ka radiation which shows peaks at the following diffraction angles 2 Θ: 5.38 degrees +/-0.2 degrees, 9.46 degrees +/-0.2 degrees, 11.22 degrees +/-0.2 degrees, 11.86 degrees +/-0.2 degrees, 18.84 degrees +/-0.2 degrees, 19.18 degrees +/-0.2 degrees, 20.70 degrees +/-0.2 degrees, 22.00 degrees +/-0.2 degrees, 22.68 degrees +/-0.2 degrees, 23.86 degrees +/-0.2 degrees and 24.48 degrees +/-0.2 degrees.
- 2. A process for preparing the trihydrate crystalline form I of claim 1, comprising:preparing a reaction solution containing (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt, ethyl acetate and water; andthe reaction solution was stirred.
- 3. The method of preparing trihydrate form I according to claim 2, wherein the reaction solution prepared comprises:preparing a mixture by adding water to the hemicalcium salt of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid; anda reaction solution was prepared by adding ethyl acetate to the mixture.
- 4. The process for preparing trihydrate crystalline form I according to claim 2 or 3, further comprising: the stirred reaction solution was cooled.
- 5. A process for the preparation of the trihydrate crystalline form I according to claim 2 or 3, characterized in that the volume ratio of ethyl acetate to water is from 3:1 to 1:3 (V/V).
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| CN107438595A (en) | 2017-12-05 |
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