CN107438595A - Crystal formation and preparation method thereof - Google Patents
Crystal formation and preparation method thereof Download PDFInfo
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- CN107438595A CN107438595A CN201680020018.5A CN201680020018A CN107438595A CN 107438595 A CN107438595 A CN 107438595A CN 201680020018 A CN201680020018 A CN 201680020018A CN 107438595 A CN107438595 A CN 107438595A
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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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- 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
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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
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- 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
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Preparation in accordance with the present invention, although cost is low, 4 (((base of oxinane 2) epoxide) methyl) aniline can be prepared with high yield and purity.In addition, the crystal formation of the present invention has significantly excellent stability, hygroscopicity and dissolubility.
Description
Technical field
The invention provides a kind of new method for preparing statin compound, and the novel crystal forms of statin compound and its
Preparation method.More specifically, the invention provides a kind of economic means of prepare compound, high-purity and high yield be may be used as
The reactant of statin compound is prepared to rate, and is largely produced in the case of without using any expensive catalyst, with
And have and be obviously improved statin compound novel crystal forms of physical property and preparation method thereof.
Background
(3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles
Cough up -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt is by serving as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase
Inhibitor suppress the synthesis of cholesterol in cell, be advantageously used as hypolipidemic or gemfibrozil.
In Registered Korean Patent No. 1329113, (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4-
[(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt preparation method it is as described below：
Wherein THP is dihydro pyranyl, and tBu is the tert-butyl group.
In above-mentioned patent, methods of the formula II as initiation material is described in embodiment 1, wherein also illustrating the party
Method according to [J.Med.Chem., 41,26, (1998), 5297-5309] and [Tetrahedron Lett., 43,30, (2002),
5353] prepared by the method described in document, that is to say, that this method is as follows：
Wherein THP is dihydro pyranyl, and PPTS is p-methyl benzenesulfonic acid pyridine.
, it is specified that the benzylalcohol of 4- nitrobenzyl alcohols ((4- nitrobenzophenones) methanol) is protected with 3,4- dihydro pyranyls in upper document
Shield, the compound shown in 2b is synthesized, then form amido with palladium/carbon (Pd/C) catalyst reduction nitro, therefore synthesize 3b institutes
The compound shown.
However, the Pd/C used in above-mentioned preparation method becomes highly inflammable when exposed to air, and at it
Containing becoming more inflammable in the state of hydrogen.Therefore, if carried out in atmosphere using the reaction of catalyst, used in reaction
Very high (the laboratory judicious exercise of risk that solvent is easy to light：Processing and disposal chemicals (1995,370p).In addition, even if
Catalyst is used in the reaction, and its reaction yield is not also high, and the purity for generating compound shown in 3b is not also high.In addition, Pd/C is too
It is expensive, therefore high cost is needed by reacting synthesis 3b compounds, this causes economy low and reaction time length.
Therefore, this method is not suitable for largely producing as the compound shown in 3b.Therefore, exploitation one kind is had increasing need for be used for
High-purity and yield ground novel methods of compound shown in a large amount of production 3b, so as to be used to largely producing as initiation material (3R,
5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,
5- dihydroxy-Semi-Heptanoic Acid Calcium Salt.
(3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyls according to prepared by existing Registered Korean Patent No. 1329113
Base -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt have it is excellent
Dissolubility, but do not have excellent stability and hygroscopicity, therefore, it is difficult to store for a long time, and as the raw material of active component
Decomposed during the preparation process of preparation or storage.Therefore, the uniformity of dosage units of gained preparation may decline.Therefore, it is necessary to
Develop a kind of method for improving compound physical performance, thus do not reduce it is deliquescent in the case of have it is more excellent steady
Qualitative and hygroscopicity.
[prior art references]
[patent document]
(patent document 1) Registered Korean Patent No. 1329113
[non-patent literature]
(non-patent literature 1) Goodman and Gilman,《Therapeutic pharmacological basis》841(MacMillan
Publ.Co.:The 7th edition, New York .1985).
(non-patent literature 2) laboratory judicious exercise：Processing and disposal chemicals (1995,370p.
(non-patent literature 3) J.Med.Chem., 41,26, (1998), 5297-5309.
(non-patent literature 4) Tetrahedron Lett., 43,30, (2002), 5353.
Detailed description of the invention
Technical problem
It is an object of the invention to provide a kind of a large amount of new methods for producing the initiation material for synthesizing statin compound.
Another mesh of the present invention is to provide one kind (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4-
[(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt hydrate crystal forms and its preparation
Method.
Technical scheme
The invention provides a kind of method of the compound shown in formula 2, this method includes：
In the presence of iron, zinc, tin, iron containing compoundses, zinc compound, sn-containing compound or its mixture, by the institute of following formula 1
The compound shown is reacted with ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine or its mixture.
[formula 1]
[formula 2]
Wherein in formula 1 and 2, R is acetyl group, benzoyl, THP trtrahydropyranyl, methoxy, methoxy ethoxy
Methyl or benzyl, preferably THP trtrahydropyranyl.
Therefore, compound or can be respectively preferably shown in following formula 1-1 or 2-1 as the compound shown in formula 2 as shown in formula 1
Compound.
[formula 1-1]
[formula 2-1]
According to this method, the compound shown in formula 2 can be obtained in a short time high-purity and yield.In addition, zinc,
Tin, iron and not only security is excellent containing their compound, and it is cheap.In addition, in zinc, tin or contains them at iron
Compound in the presence of carry out the reaction of compound shown in formula 2, the reaction yield and purity of gained compound be also high.Cause
This, this method economically can largely produce the compound shown in formula 2, therefore can largely produce by using shown in formula 2
Many compounds prepared by compound.For example, the method according to the present invention, can economic a large amount of production (3R, 5R) -7-
[2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxies
Base-Semi-Heptanoic Acid Calcium Salt, there is higher purity and yield than conventional method.
According to the present invention, compound and ammonium formate shown in formula 1, ammonium chloride, sodium dihydrogen phosphate, hydrazine or its mixture it is anti-
Should can be in iron or compound containing iron, zinc or the compound containing zinc, tin or containing being carried out in the presence of tin compound.Should
Material is cheap, can improve the compound shown in formula 1 and ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine or the reaction of its mixture
Reaction yield, so as to high-purity obtain the compound shown in formula 2.
Compared with Pd/C price, iron or the compound containing iron, zinc or the compound containing zinc or contain tin chemical combination at tin
1/300 to 1/60 of the price of thing equivalent to Pd/C prices.However, compared with Pd/C, iron or the compound containing iron or contain zinc
There is a compound of zinc, tin or reaction yield can be improved three times or more containing tin compound, and also improve purity
10% or higher.
Compound according to the present invention, iron or containing iron, zinc or the compound containing zinc, tin or can be excellent containing tin compound
Elect iron, zinc or stannic chloride (SnCl as2)。
According to the present invention, a kind of method of the compound shown in formula 2 may further include preparation containing shown in formula 1
Compound solution.
Solution containing the compound shown in formula 1 can be prepared in a solvent by the compound dissolving for representing formula 1.
Solvent can be straight or branched C1 to C4 alcohol, preferably methanol.
It is according to the present invention, the compound shown in formula 1 and ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine or its mixture is anti-
Should the step of can be ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine or its mixture are added to containing formula 1 shown in chemical combination
In the solution of thing.
Compound shown in formula 2 can be by by iron or compound containing iron, zinc or the compound containing zinc, tin or contains
There is tin compound to be added in the solution containing the compound shown in formula 1, then add ammonium formate, ammonium chloride, sodium dihydrogen phosphate,
It is prepared by hydrazine or its mixture.
According to the present invention,Temperature conditionss under, add first into the solution containing the compound shown in formula 1
Sour ammonium, ammonium chloride, sodium dihydrogen phosphate, hydrazine or its mixture.
According to the present invention, can be prepared as the compound shown in 1 as the compound shown in formula 3.
[formula 3]
According to the present invention, if the R in formula 1 represents THP trtrahydropyranyl, the compound shown in formula 2 can be by by formula 3
Shown compound is reacted with 3,4- dihydropyran to prepare.
According to the present invention, the reaction of compound shown in formula 3 can be in the pyridine as catalyst-p- tosylated
Carried out in the presence of compound.
The present invention provides a kind of method for preparing the compound as shown in following formula 2, and this method includes：
Prepare the solution containing the compound represented such as following formula 1；With
By adding iron, zinc, tin, iron containing compoundses, zinc compound, stanniferous or its mixture and formic acid into the solution
Ammonium, ammonium chloride, sodium dihydrogen phosphate, hydrazine or its mixture prepare reactant.
[formula 1]
[formula 2]
Wherein formula 1 and 2, R is acetyl group, benzoyl, THP trtrahydropyranyl, methoxy, methoxvethoxvmethvl
Or benzyl, preferred THP trtrahydropyranyl.
According to the present invention, in about 5 to 30 DEG C of temperature, preferably from aboutAt a temperature of, more preferably from about 20 DEG C of temperature
Under the conditions of degree, ammonium formate, ammonium chloride, dihydrogen phosphoric acid sodium, hydrazine or its mixture can be added to the solution containing the compound of formula 1
In.
According to the present invention, reactant can be aboutPreferably from aboutEven more preferably about 65 DEG C
At a temperature of flow back.
The invention provides a kind of compound prepared as shown in following formula A or the method for its isomers or its salt, this method
Including：
, will under the existence condition of iron, zinc, tin, iron containing compoundses, zinc compound, sn-containing compound or its mixture
Compound as shown in following formula 1 is reacted with ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine or its mixture, is prepared such as the institute of following formula 2
The compound shown.
[formula 1]
[formula 2]
[formula A]
Wherein R is acetyl group, benzoyl, THP trtrahydropyranyl, methoxy, methoxvethoxvmethvl or benzyl,
It is preferred that THP trtrahydropyranyl.
The present invention can compound of high-purity and the yield ground shown in economic lot size production following formula 2, therefore can be high
Purity and high yield are obtained and economically produced in batches using low cost is used as reactant preparation by using the compound shown in formula 2
Formula A shown in compound, its isomers or its salt.
Method based on compound, its isomers or its salt shown in the formula A of formula 2 is such as in Registered Korean Patent No.
Method described in 1329113.
According to the present invention, salt is salt prepared by metal salt or organic base.For example, metal salt can be lithium salts, sodium salt, potassium
Salt, calcium salt, magnesium salts, zinc salt and aluminium salt, but not limited to this.For example, by using organic base prepare salt can be by using
Amino acid, amine, monoalkyl ammonium, dialkyl ammonium, the salt of the preparation such as trialkyl ammonium, N-METHYL-ALPHA-L-GLUCOSAMINE, specifically, by using
The salt of the preparations such as glycine, arginine, lysine, trimethylamine, ammonia, pyridine, picoline, but not limited to this.
Preferably, salt can be half calcium of the compound shown in formula A, and the salt can be (3R, 5R) -7- [2- (4- fluorine
Phenyl) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-enanthic acid half
Calcium, i.e., the compound represented by following formula B.
[formula B]
That as described in Registered Korean Patent No. 1329113 of method wherein based on the compound shown in the formula B of formula 2
Sample.
The invention provides a kind of compound prepared as shown in following formula A or the method for its isomers or its salt, this method
Including：
Prepare containing the solution by such as compound that following formula 1 represents；With
By by iron, zinc, tin, iron containing compoundses, zinc compound or sn-containing compound or its mixture, and ammonium formate,
Ammonium chloride, sodium dihydrogen phosphate, hydrazine or its mixture are added to the compound prepared in the solution as shown in following formula 2：
[formula 1]
[formula 2]
[formula A]
Wherein R is acetyl group, benzoyl, THP trtrahydropyranyl, methoxy, methoxvethoxvmethvl or benzyl,
It is preferred that THP trtrahydropyranyl.
According to the present invention, the salt of the compound shown in formula A is described above, half calcium of the compound shown in preferred formula (A)
Salt, it can be (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyls
Base]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt.
The invention provides one kind (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- methylols
Phenyl amino) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt, the novel crystal forms of the compound as shown in following formula B.
[formula B]
Novel crystal forms can be (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethyl phenyls
Amino) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt, the hydrate of the compound as shown in formula B, preferably its
Trihydrate.
According to the present invention, with the compound phase prepared by the regular situation described in Registered Korean Patent No. 1329113
Than there is more excellent stability and hygroscopicity as the new trihydrate crystal formation of the compound shown in formula B, so as to prepare
Stably keep for a long time, not absorbing moisture afterwards.Therefore, preparation is being prepared or stored as active component by using the component
When, said preparation can be constant in long time retaining water content content.In addition, according to the present invention, as the new crystalline substance of the compound shown in formula B
Type shows with high-dissolvability, thus it is shown that good pharmacological action.
The invention provides (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethyl phenyls
Amino) carbonyl]-pyrroles -1- bases] and -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation I.
According to the present invention, crystal formation I is with the X-ray powder diffraction figure for radiating to obtain using Cu-Ka, and it is in the following angle of diffraction
Peak value is shown at 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 °, it is preferable that crystal formation I is with the x-ray powder for radiating to obtain using Cu-Ka
Diffraction pattern, peak value is shown at least one θ of the angle of diffraction 2 being selected from the group：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 °, radiated it is highly preferred that crystal formation I has using Cu-Ka
The X-ray powder diffraction figure arrived, the peak value display at the following θ of the angle of diffraction 2：11.86°±0.2°、22.00±0.2°、23.86±
0.2°、24.48°±0.2°、5.38°±0.2°、9.46°±0.2°、11.22°±0.2°、18.84°±0.2°、19.18°±
0.2 °, 20.70 ° ± 0.2 ° and 22.68 ° ± 0 0.2 °.
According to the present invention, (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethyl phenyl ammonia
Base) carbonyl]-pyrroles -1- bases] the trihydrate crystal formation I ratios of -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt pass through Registered Korean Patent No.
Compound prepared by existing method described in 1329113 has more excellent stability and hygroscopicity, and has and the latter
Identical solubility.
Because novel crystal forms I hardly picks up moisture, so it can keep identical hydrated state for a long time, and i.e.
Long-term storage is set also can stably to hold without decomposing or becoming another material.Therefore, stored or with crystal formation I in crystal formation I
Preparation of preparation, or after preparing containing crystal formation I preparations, crystal formation I can keep identical state, so as to keep system steadily in the long term
The content uniformity of agent, and condition of storage also without hell and high water and preparation process thereof keep stability, therefore
It is especially suitable for producing greatly.
In addition, novel crystal forms I shows high-dissolvability.Therefore, if administration, crystal formation I can show excellent therapeutic effect.
The invention provides (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethyl phenyls
Amino) carbonyl]-pyrroles -1- bases] and -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation II.
According to the present invention, crystal formation II is with the X-ray powder diffraction figure for radiating to obtain using Cu-Ka, and it is in following diffraction
Peak value is presented at the θ of angle 2：5.46 ° ± 0.2 °, 9.50 ° ± 0.2 ° and 19.30 ° ± 0.2 °, it is preferable that crystal formation II, which has, uses Cu-
Ka radiates obtained X-ray powder diffraction figure, and peak value is shown at least one θ of the angle of diffraction 2 being selected from the group：5.78°±
It is 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 excellent
Selection of land, the X-ray powder diffraction figure that crystal formation II radiates to obtain using Cu-Ka, peak value is presented in it at the following θ of the angle of diffraction 2：
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 (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethyl phenyl ammonia
Base) carbonyl]-pyrroles -1- bases] and -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation III.
According to the present invention, crystal formation III is with the X-ray powder diffraction figure for radiating to obtain using Cu-Ka, and it is in following diffraction
Peak value is presented at the θ of angle 2：21.90 ° ± 0.2 °, 8.04 ° ± 0.2 °, 8.11 ° ± 0.2 ° and 13.07 ° ± 0.2 °, it is preferable that crystal formation
III is shown with the X-ray powder diffraction figure for radiating to obtain using Cu-Ka at least one θ of the angle of diffraction 2 being selected from the group
Peak value：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 °, it is highly preferred that crystal formation III is penetrated using the Cu-Ka X for radiating to obtain
Line powder diagram, peak value is presented in it at the following θ of the angle of diffraction 2：21.90°±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, (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethyl phenyl ammonia
Base) carbonyl]-pyrroles -1- bases] trihydrate the crystal formation II and III of -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt shown than passing through Korea Spro
Compound prepared by the existing method described in state's Patent Publication No 1329113 has more excellent stability and hygroscopicity, and
And have and the latter's identical solubility.
The invention provides prepare one kind to prepare (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4-
[(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation side
Method, this method include：
Preparation contains (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos)
Carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt reactant and include water and ethyl acetate, dichloromethane, first
The mixed solvent of at least one of alcohol and tetrahydrofuran.
According to above-mentioned preparation method, (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyls can be obtained with high-purity and yield
Base -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt three hydrations
Thing crystal formation, its preparation method is simple, therefore is adapted to a large amount of productions.
The invention provides one kind to prepare (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxyls
MethYlphenylamino) carbonyl]-pyrroles -1- bases] and -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation I method, the party
Method includes：
Preparation contains (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos)
Carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt, ethyl acetate and water reaction solution；With
Stir the reaction solution.
According to above-mentioned preparation method, (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyls can be obtained with high-purity and yield
Base -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt three hydrations
Thing crystal formation I, its preparation method is simple, therefore is adapted to a large amount of productions.
In the method for preparing the crystal formation I of the present invention, the step of preparing reaction solution, includes：
By adding water to (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- methylol benzene
Base amino) carbonyl]-pyrroles -1- bases] mixture is prepared in -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt；
Stir the mixture；With
Reaction solution is prepared by adding ethyl acetate in the mixture to stirring.
In the method for preparing the crystal form I of the present invention, the volume ratio of ethyl acetate and water can be in reaction solution
3:1 to 1:3 (V/V), preferably 2:1 to 1:2(V/V).
, can be about in the present invention prepares crystal formation I methodUnder the conditions of stir mixture
Hour, the stir about preferably at about 25 DEG CHour.
Crystal formation I method is prepared in the present invention, reaction solution can be made about 65 to 80 the step of stirring reaction solution
Backflow stir about 1 to 3 hour, stir about 1.5 to 2 hours preferably at about 70 DEG C to 75 DEG C at DEG C.
Crystal formation I method is prepared in the present invention, the step of this method can also include the reaction solution of cooling and stirring.It is logical
The reaction solution of supercooling stirring can produce solid.
Cooling can make reaction solution be cooled to about 30 to 50 DEG C about 1 to 3 hour, more preferably be cooled to about 40 DEG C about 2
Hour.
In the present invention prepares crystal formation I method, (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4-
[(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt (it is initiation material) can be
Amorphous, crystal form or its mixture.For example, parent material can be amorphous or trihydrate crystal formation I and unbodied
Mixture.
Preparing crystal formation I of the present invention method can also include what is filtered, obtain the solid of generation and washed with ethyl acetate
Step.
The step of preparing the crystal formation I of present invention method can also include drying gained solid.Drying can about 50 to
Carried out about 10 to 20 hours at a temperature of 800mmHg pressure and 40 to 70 DEG C, preferably about 100 to 600mmHg peace treatiesAt a temperature of carry out about 14 to 17 hours.
The invention provides one kind to prepare (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxyls
MethYlphenylamino) carbonyl]-pyrroles -1- bases] and -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation II method.
This method includes：
Preparation contains (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos)
Carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt, the reaction solution of first alcohol and water；With
Stir the reaction solution.
According to above-mentioned preparation method, (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyls can be obtained with high-purity and yield
Base -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt crystal formation
II, its preparation method is simple, therefore is adapted to a large amount of productions.
In the method for preparing the crystal formation II of the present invention, the step of preparing reaction solution, includes：
Prepare the mixed solvent containing first alcohol and water；With
By (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl] -
Pyrroles -1- bases] half calcium salt of -3,5- dihydroxy-enanthic acid is added in the mixed solvent.
In the present invention prepares crystal formation II method, it is 3 that mixed solvent, which can contain volume ratio,:1 to 1:3 (V/V) first
Alcohol and water, preferably 2:1 to 1:2(V/V).
In the present invention prepares crystal formation II method, (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4-
[(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt (it is initiation material) can be
Amorphous, crystal form or its mixture.For example, parent material can be amorphous or trihydrate crystal formation II and unbodied
Mixture.
In the present invention prepares crystal formation II method, the stirring of reaction solution can be carried out about 2 to 4 days at room temperature, excellent
Choosing about 3 days.
In the present invention prepares crystal formation II method, after stirring reaction solution, it can filter and obtain from reaction solution
Solid.
In the present invention prepares crystal formation II method, the step of drying gained solid may further include.Drying can be with
Carried out under about 50 to 800mmHg pressure and 40 to 70 DEG C of pressure, preferably in about 100 to 600mmHg pressure and about 50
To carrying out at a temperature of 60 DEG C.
The invention provides one kind to prepare (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxyls
MethYlphenylamino) carbonyl]-pyrroles -1- bases] and -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation III method；
This method includes：
Preparation contains (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos)
Carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt and the solvent containing one of methanol and tetrahydrofuran, dichloromethane
Reaction solution；
Concentrate is prepared by concentrated reaction solution；With
Solid is produced by adding water into concentrate.
According to preparation method, can be obtained with high-purity and yield (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyls -
3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate
Crystal formation III, its preparation method is simple, therefore is adapted to a large amount of productions.
Include the step of the present invention prepares crystal formation III method, prepares reaction solution：
Prepare the mixed solvent containing one of methanol and tetrahydrofuran, dichloromethane；With
By (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl] -
Pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt is added in the mixed solvent.
In the present invention prepares crystal formation III method, mixed solvent can include one in tetrahydrofuran and dichloromethane
Kind, the volume ratio with methanol is 1:10 or 4:5 (V/V), preferably 1:5 to 3：5(V/V).
In the present invention prepares crystal formation III method, after reaction solution is prepared, before concentrated reaction solution, may be used also
The step of with including stirring reaction solution.
The step of preparing crystal formation III method in the present invention, adding water can be carried out by this way：AboutAt a temperature of be added dropwise about 20 minutes to 1 hour.
In the present invention prepares crystal formation III method, the step of stirring reaction solution can be further comprised after addition of water
Suddenly.The step of stirring reaction solution, can be aboutAt a temperature of carry out about 30 minutes to 3 hours, preferably 2 hours.
The present invention prepares crystal formation III method, can further be dried solid the step of, drying can be about
Carry out at a temperature of 40 to 70 DEG C, preferably carried out at a temperature of about 60 DEG C.
The invention provides a kind of medicinal composition for preventing and treating cardiovascular diseases, wherein pharmaceutical composition contains
There are (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1-
Base] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation and pharmaceutically acceptable additive as active component.
According to the present invention, pharmaceutical composition can contain (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -
4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation I, three
At least one of hydrate crystal forms II and trihydrate crystal formation III are used as active component, preferably (3R, 5R) -7- [2- (4- fluorine
Phenyl) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-enanthic acid half
The trihydrate crystal formation I of calcium salt.
The conventional use of additive in pharmaceutically acceptable additive is physiologically acceptable and medical field,
When it is individual give human body when do not cause any allergic reaction, such as gastrointestinal disease, dizziness or other analogues, type be not special
Limit.The example of additive can be carrier, excipient and diluent.The example of carrier, excipient and diluent can be breast
Sugar, glucose, sucrose, D-sorbite, mannitol, xylitol, antierythrite, maltitol, starch, gum arabic, alginic acid
Salt, gelatin, calcium phosphate, calcium silicates, cellulose, methylcellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, hydroxyl
Propyl benzoate, talcum powder, magnesium stearate and mineral oil.
Pharmaceutical composition can also include antioxidant, cushioning liquid, filler, anti-coagulants, lubricant, NMF, perfume (or spice)
Material, emulsifying agent, preservative etc..
In the pharmaceutical composition of the present invention, angiocardiopathy can be hypertension, headstroke, hyperlipidemia, high fat egg
White mass formed by blood stasis, hypercholesterolemia, hypertriglyceridemia, joint hyperlipidemia, artery sclerosis, atherosclerosis, angina pectoris,
Miocardial infarction, arterial occlusive disease, cerebral infarction, myocardial microvascular disease, diabetic vascular complications or coronary sclerosis,
It is preferred that hyperlipidemia, hyperlipoprotememia, hypercholesterolemia, hypertriglyceridemia or joint hyperlipidemia.
The pharmaceutical composition of the present invention can be prepared according to conventional methods, and various types of oral administrations can be made
Form, such as tablet, pill, pulvis, capsule, syrup, emulsion and microemulsion or various types of parenteral administration forms such as muscle
It is interior, be intravenously or subcutaneously administered.
If the pharmaceutical composition of the present invention is made into oral formulations, the example of additive can be cellulose, silicic acid
Calcium, cornstarch, lactose, sucrose, glucose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talcum powder, surface
Activating agent, suspension, emulsifying agent, diluent etc..
If pharmaceutical composition is pharmaceutically configured to liquid preparation, such as oral suspension, liquid for oral administration
Medicine, emulsion, syrup etc., pharmaceutical composition can be by adding simple diluent such as water and atoleine, and various additions
It is prepared by agent such as wetting agent, sweetener, air freshener, preservative, antiseptic, colouring agent etc..For example, pharmaceutical composition can
Pharmaceutically to be prepared by further adding sweetener such as peppermint oil, eucalyptus oil or saccharin.
If the pharmaceutical composition of the present invention is pharmaceutically configured to injection, additive can be water, saline solution, Portugal
It is grape sugar aqueous solution, similar sugar aqueous solution, alcohol, ethylene glycol, ether (such as polyethylene glycol 400), oil, aliphatic acid, fatty acid ester, sweet
Grease, surfactant, suspension, emulsifying agent etc.
In the pharmaceutical composition of the present invention, the content of additive is not particularly limited, and can be used in conventional formulation
Content range in suitably adjusted.
The pharmaceutical composition of the present invention can administered orally or parenterally (it is such as intravenous, subcutaneous, intraperitoneal or part
Using), when dosage can be according to the body weight of patient, age, sex, health status, diet, administration time, administering mode, administration
Between or interval, excretion rate, individual specificity, preparation nature, disease severity etc. change.
The pharmaceutical composition of the present invention, (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- can be applied
[(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt crystal formation gives as active component
Dose can be about 0.01 to 100mg/kg/ days, preferably 0.1 to 30mg/kg/ days, or if desired, can once all
Or fraction time administration daily.
The invention provides one kind by administering to the human containing (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- benzene
Base -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation
And the pharmaceutical composition of pharmaceutically acceptable additive is prevented or treats angiocardiopathy method method.
The invention provides one kind to contain (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxyls
MethYlphenylamino) carbonyl]-pyrroles -1- bases] and -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation and pharmaceutically may be used
The pharmaceutical composition of the additive of receiving is used to prevent or treat treating cardiovascular disease purposes.
According to the present invention, angiocardiopathy can be that hypertension, headstroke, hyperlipidemia, hyperlipoprotememia, high courage are consolidated
Alcoholemia, hypertriglyceridemia, joint hyperlipidemia, artery sclerosis, atherosclerosis, angina pectoris, miocardial infarction, artery
Obliteran, cerebral infarction, myocardial microvascular disease, diabetic vascular complications or coronary sclerosis, preferably hyperlipidemia,
Hyperlipoprotememia, hypercholesterolemia, hypertriglyceridemia or joint hyperlipidemia.
Beneficial effect
The invention provides one kind to prepare the 4- (new methods of (((ttetrahydro-pyran -2- bases) epoxide) methyl) aniline.According to
The present invention, reactant can be used as so as to improve using the compound with high-purity and the high productivity economical production compound
Reaction yield.
In addition, the novel crystal forms of the present invention have excellent stability, hygroscopicity and dissolubility, therefore be advantageous to a large amount of lifes
Production, and show excellent therapeutic effect using a small amount of medicine.
The brief description of accompanying drawing
(3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxyls in Fig. 1 to Fig. 3 display present invention
MethYlphenylamino) carbonyl]-pyrroles -1- bases] and -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation I to III each X
Ray powder diffraction (XRD).In figure, transverse axis represents 2 θ (degree), and vertical direction represents intensity (CPS).
Inventive embodiments
Hereinafter, for a better understanding of the present invention, preferred embodiment and experimental example are prompted.However, following examples and
Experimental example provides only for the mesh of the explanation present invention, therefore the invention is not restricted to this.
In addition, unless illustrating otherwise herein, otherwise reagent and solvent mentioned below are purchased from Sigma-
Aldrich, and use the purity of HPLC (1200 series, An Jielun) measurement product.
Prepare embodiment 1)
Prepare 2- ((4- nitrobenzyls) epoxide) ttetrahydro-pyran compound (compound shown in formula 1)
(being prepared according to the synthetic method of [J.Med.Chem., 41,26, (1998), 5297-5309])
4- nitrobenzyl alcohols (1.6g, 10.45mmol) are dissolved in ethanol (52ml) to prepare solution, are added dropwise into the solution
3,4- dihydropyran (1.32g, 1.43ml, 15.68mmol) and dropwise addition p-methyl benzenesulfonic acid pyridine (262.6mg, 1.05mmol),
Mixture is made.Stir the mixture for 1.5 hours, solvent, concentration is evaporated under reduced pressure.Concentrate is extracted with ethyl acetate (25ml),
Washed with water (50ml × 3), with salt water washing, with anhydrous sodium sulfate drying, concentration, obtain the compounds of this invention, it is oily
Product.
Yield：2.82g (98.8%), purity：99.8%
Embodiment 1)
Prepare 4- (((ttetrahydro-pyran -2- bases) epoxide) methyl) aniline (compound shown in formula 2-1) and (be used as catalysis by the use of zinc
Agent)
The 2- prepared in embodiment 1 is prepared ((4- nitrobenzyls) epoxide) ttetrahydro-pyran (1g, 3.66mmol) is dissolved in
To prepare solution in methanol (100ml), zinc powder (1.4g) is added drop-wise in solution, ammonium formate (0.9g), system are added at 20 DEG C
Obtain mixture.Mixture flows back at 65 DEG C.After backflow terminates 10 minutes, the zinc powder of removing residual in the mixture obtains molten
Liquid, removes solvent from obtained solution at reduced pressure conditions, and extract is therefrom obtained with ethyl acetate.Extract is washed with water
Wash, with anhydrous sodium sulfate drying, concentration, obtain the compound of title of the present invention, it is oil product.
Yield：0.71g (93%), purity：75%
Embodiment 2)
4- (((ttetrahydro-pyran -2- bases) epoxide) methyl) aniline (compound shown in formula 2-1) is prepared (using iron as urging
Agent)
The 2- prepared in embodiment 1 is prepared ((4- nitrobenzyls) epoxide) ttetrahydro-pyran (1g, 3.66mmol) is dissolved in
To prepare solution in methanol (100ml), iron powder (1.4g) is added drop-wise in solution, it is lower under the conditions of 20 DEG C to add ammonium formate
(0.9g), mixture is made.Mixture flows back at 65 DEG C.Behind after backflow terminates 1.5 hours, residual is removed in the mixture
Iron powder, obtain solution, remove solvent from obtained solution under reduced pressure, extract is obtained therefrom with ethyl acetate.Extraction
Take liquid to be washed with water, with anhydrous sodium sulfate drying and concentrate, obtain the compounds of this invention, it is oil product.
Yield：0.72g (95%), purity：80%
Embodiment 3)
Prepare 4- (((ttetrahydro-pyran -2- bases) epoxide) methyl) aniline (compound shown in formula 2-1) and (use tin compound
As catalyst)
The 2- prepared in embodiment 1 is prepared ((4- nitrobenzyls) epoxide) ttetrahydro-pyran (1g, 3.66mmol) is dissolved in
To prepare solution in methanol (100ml), and by stannic chloride (II) (SnCl2, 3.5g) it is added drop-wise in solution, prepare mixture.It is mixed
Compound flows back at 65 DEG C.20 minutes 1 hour after backflow terminates, the tin of residual in the mixture is removed, solution is obtained, is subtracting
Solvent is removed under the conditions of pressure from resulting solution, extract is obtained therefrom with ethyl acetate.Extract 2M potassium hydroxide waters
Solution washs, and with salt water washing, with anhydrous sodium sulfate drying, concentration, obtains the compounds of this invention, it is oil product.
Yield：0.57g (76%), purity：83%
Comparative example 1)
Prepare 4- (((ttetrahydro-pyran -2- bases) epoxide) methyl) aniline (compound shown in formula 2) (according to
Prepared by the synthetic method of [J.Med.Chem., 41,26 (1998), 5297-5309])
The 2- prepared in embodiment 1 is prepared ((4- nitrobenzyls) epoxide) ttetrahydro-pyran (1g, 3.66mmol) is dissolved
To prepare solution in ethanol (100ml), 10% (w/w) palladium/carbon (0.3g) is added drop-wise in solution, and first is added under the conditions of 20 DEG C
Sour ammonium (0.9g), prepares mixture.After 1.5 hour, the palladium/carbon of residual in the mixture is removed, obtains solution, in decompression bar
Solvent is removed under part from resulting solution, extract is obtained therefrom with ethyl acetate.Extract is washed with water, and uses anhydrous slufuric acid
Sodium is dried and concentrated, and obtains the compounds of this invention, and it is oil type product.
Yield：0.19g (25%), purity：68%
Embodiment 4)
Trihydrate crystal formation I preparation
By compound ((3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxyls shown in 20g formulas B
MethYlphenylamino) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt) it is added to preparation mixing in 200ml water
Thing, and mixture is stirred 17 hours at about 25 DEG C.200ml ethyl acetate is added in mixture and prepares reaction solution,
By reaction solution, return stirring 1.5 hours to 2 hours, reaction solution are cooled to 40 DEG C at 70 to 75 DEG C, 2 hours, at 40 DEG C
Lower stirring 1 hour, generates solid.Generated solid is filtered, obtains solid, solid is washed twice with 250ml ethyl acetate,
100 to 600mmHg, dry 16 hours at 55 DEG C, obtain 17.1g (purity 99.82%) (3R, 5R) -7- [2- (4- fluorophenyls) -
5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt
Trihydrate crystal formation I, it is white solid.
Embodiment 5)
Prepare trihydrate crystal formation I
By compound ((3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxyls shown in 19g formulas B
MethYlphenylamino) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt) and 1g embodiments 4 in three hydrations that prepare
Thing crystal formation I, which is added in 200ml water, prepares mixture, and mixture is stirred 17 hours at about 25 DEG C.By 200ml ethyl acetate
It is added in mixture and prepares reaction solution, reaction solution return stirring 1.5 hours to 2 hours at 70 to 75 DEG C, reacts molten
Liquid is cooled to 40 DEG C, 2 hours, is stirred 1 hour at 40 DEG C, generates solid.The solid of generation is filtered, obtains solid, solid
Washed 2 times with 250ml ethyl acetate, dried 16 hours at 100 to 600mmHg, 55 DEG C, obtain 17.8g (purity 99.89%)
(3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1-
Base] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation I, be white solid.
Embodiment 6)
Prepare trihydrate crystal formation II
Compound ((3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxyl first shown in 20g formulas B
Base phenyl amino) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt) it is suspended in 200ml methanol and 200ml water
In the mixed solvent, reaction solution is prepared, reaction solution is stirred into three days generation solids.The solid generated is filtrated to get solid
Body, solid are dried at 100-600mmHg, 70 DEG C, obtain 17.4g (purity 99.74%) (3R, 5R) -7- [2- (4- fluorobenzene
Base) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-the calcium of enanthic acid half
The trihydrate crystal formation II of salt, it is white solid.
Embodiment 7)
Prepare trihydrate crystal formation II
By compound ((3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxyls shown in 19g formulas B
MethYlphenylamino) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt) and 1g embodiments 6 in three hydrations that prepare
Thing crystal formation II is suspended in 200ml methanol and the in the mixed solvent of 200ml methanol prepares reaction solution, and reaction solution is stirred 3 days
Produce solid.The solid generated is filtrated to get solid, solid is dried at 100-600mmHg, 70 DEG C, and it is (pure to obtain 17.9g
(3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyls of degree 99.83%)
Base]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation II, be white solid.
Embodiment 8)
Prepare trihydrate crystal formation III
Compound ((3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxyl first shown in 20g formulas B
Base phenyl amino) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt) it is added to 200ml methanol and 60ml tetrahydrochysene furans
The in the mixed solvent muttered, prepares reaction solution, and reaction solution is stirred at room temperature into a hour dissolving.Solution is filtered to remove
Insoluble matter, resulting solution is concentrated under reduced pressure into its volume to the (v/v, to prepare concentrate of initial volume 50%.Concentrate is moved to
In single reactor, and under the conditions of 0 DEG C to 5 DEG C, 800ml water is slowly added to thereto, 30 minutes, stirring 2 hours and simultaneously
Keeping temperature.Then, dry the filtering of the white solid of generation and at 60 DEG C, obtain 17.2g (purity 99.69%) (3R,
5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,
The trihydrate crystal formation III of 5- dihydroxy-Semi-Heptanoic Acid Calcium Salt, it is white solid.
Embodiment 9)
Prepare trihydrate crystal formation III
Compound ((3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxyl first shown in 20g formulas B
Base phenyl amino) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt) it is added to 200ml methanol and 80ml dichloromethanes
The in the mixed solvent of alkane, reaction solution is prepared, and reaction solution is stirred at room temperature 1 hour and dissolved.Solution is filtered to remove
Insoluble matter, it is initial volume 50% (v/v) that resulting solution is concentrated under reduced pressure into its volume, prepares concentrate.Concentrate is moved to
In single reactor, and under the conditions of 0 DEG C to 5 DEG C, 800ml water is slowly added to thereto 30 minutes, stirring is simultaneously protected for 2 hours simultaneously
Hold temperature.Then, dry the filtering of the white solid of generation and at 60 DEG C, obtain 17.3g (purity 99.73%) (3R, 5R)-
7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- two
The trihydrate crystal formation III of hydroxyl-Semi-Heptanoic Acid Calcium Salt, it is white solid.
Comparative example 2)
Prepare (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyls
Base]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt (compound shown in formula B).
Using the compound of the method preparation according to embodiment 1 as initiation material, pass through Registered Korean Patent No.：1329113
The method that middle embodiment 2 to 6 describes prepares (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4-
Hydroxymethylphenylarnino) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt (compound shown in formula B).
EXPERIMENTAL EXAMPLE 1)
Identify crystal formation I, II and III X-ray powder diffraction (XRD) figure
The crystal formation I to III prepared in embodiment 4 to 9 x-ray powder is identified by the CuKa radiation of solid phase detector
Diffraction (XRD) figure.X-ray powder diffraction (XRD) figure is measured by following equipment and under following measuring condition.
<X-ray powder diffraction spectrometric method>
- manufacturer：RIGAKU
- equipment：Ultima IV
- voltage：40kV
- electric current：40mA
- scanning range：Degree
- sweep speed：0.5 degree min
- increment：0.02 degree
- detector：D/teX Ultra
The X-ray powder diffraction figure of the crystal formation prepared in embodiment 4 and 5 is as shown in table 1 below and Fig. 1：
The trihydrate crystal formation I of table 1. X-ray powder diffraction (XRD) figure
The X-ray powder diffraction figure of the crystal formation prepared in embodiment 6 and 7 is shown as shown in table 2 below and Fig. 2.
The trihydrate crystal formation II of table 2. X-ray powder diffraction (XRD) figure
The X-ray powder diffraction figure of the crystal formation prepared in embodiment 8 and 9 is shown as shown in table 3 below and Fig. 3.
The trihydrate crystal formation III of table 3. X-ray powder diffraction (XRD) figure
As shown in the powder diagram of table 1 to 3, embodiment 4 and 5, prepare in embodiment 6 and 7 and embodiment 8 and 9
Compound shows different peaks in X-ray powder diffraction figure, therefore shows that compound is different novel crystal forms.
EXPERIMENTAL EXAMPLE 2)
Identify trihydrate crystal formation I, II and III water content
The aqueous of the crystal form compound prepared in the embodiment of the present invention 4 to 9 is determined by Karl Fisher (KF) method
Amount.The crystal formation I determined in embodiment 4 and 5 moisture measurement value is about 4.24%, the crystal formation II determined in embodiment 6 and 7
Moisture measurement value be about 4.28%, and the crystal formation III measured in embodiment 8 and 9 moisture measurement value is about 4.22%.
Thus, it will be seen that embodimentThe crystal formation of middle preparation is (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- benzene
Base -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate.
EXPERIMENTAL EXAMPLE 3)
Trihydrate crystal formation I, II and III stability assessment
To being prepared in trihydrate the crystal formation I, II and III and comparative example 2 that are prepared in embodiments of the invention 4,6 and 8
Compound each carry out stability test.Tested, certain time in acceleration environment (40 DEG C of temperature, relative humidity 75%)
Percentage (%) of the crystal formation content remained afterwards on the basis of HPLC area ratio represents, as a result to be as shown in table 4 below.
Stability test result (the unit of table 4.：%)
| Classification | Originally | January | 2 months | March | April | May | June |
| Crystal formation I | 99.89 | 99.87 | 99.85 | 99.81 | 99.77 | 99.72 | 99.69 |
| Crystal formation II | 99.74 | 99.68 | 99.53 | 99.49 | 99.41 | 99.31 | 99.22 |
| Crystal formation 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, until the every kind of crystal formation I to III prepared in 6 months, embodiment 4,6 and 8 content does not almost have
Any change.Particularly, to crystal formation I, even if after six months, the reduced rate of its content is also only 0.2%.By contrast, it is right
The compound prepared in comparative example 2, it is almost 10% that its content, which declines, after six months.
As can be seen that (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethyl phenyl ammonia
Base) carbonyl]-pyrroles -1- bases] trihydrate crystal formation I to the III of -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt shows excellent stabilization
Property, therefore can preserve steadily in the long term.Especially, it can also be seen that crystal formation I has excellent stability, so as to be easy to big
Amount production, and prepare and store preparation when, content also can keep constant in a long time.
EXPERIMENTAL EXAMPLE 4)
Trihydrate crystal formation I, II and III hygroscopicity are assessed
Crystal formation I, II and III for being prepared in embodiments of the invention 4,6 and 8 are determined in atmosphere and in comparative example 2
The hygroscopicity of the compound of middle preparation.It is 25 DEG C in temperature, under conditions of relative humidity is 45%, each crystal formation is exposed to air
In 24 hours, by determining each compound aqueous amount with Karl-Fisher methods identical method as described in Example 2, it is tied
Fruit is as shown in table 5 below.
The hygroscopicity validation test result (unit of table 5.：%)
| Classification | Crystal formation I | Crystal formation II | Crystal formation III | Comparative example 2 |
| Before air | 4.24 | 4.28 | 4.22 | 1.23 |
| After exposure 24 hours | 4.65 | 5.23 | 7.47 | 10.48 |
As shown in table 5, it can be seen that when 24 hours in air, crystal formation I to III moisture content change is
Less than 3%.Particularly, for crystal formation I, even if after exposing 24 hours in atmosphere, moisture also only increases by 0.2%, this table
Bright crystal formation I hardly picks up moisture.On the contrary, its water content, which almost adds, can be seen that to the compound prepared in comparative example 2
10 times.
Thus, it will be seen that (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- methylol benzene
Base amino) carbonyl]-pyrroles -1- bases] trihydrate crystal formation I to the III of -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt shown with excellent
Different hygroscopicity, though particularly for a long time be exposed to air in, trihydrate crystal formation I hardly picks up moisture, so as to
It can stably keep hydrated state in the preparation process of preparation, and also without the condition of storage of hell and high water, so as to
Identical hydrated state is kept long-term and stably.
EXPERIMENTAL EXAMPLE 5)
Trihydrate crystal formation I, II and III solubility are assessed
The crystal formation I, II and III that are prepared in the embodiment of the present invention 4,6 and 8 are dissolved in nonionic water or pH6.8 phosphate delays
To saturation in fliud flushing, insoluble solute is filtered out to collect filtrate, filtrate is diluted.Use light separator (JASCO, model V-
650) filtrate of dilution, is analyzed under 247nm wavelength by ultraviolet absorption spectrophotometry, to measure its solubility.
Table 6. solubility (unit, temperature:μ g/ml, 25 DEG C)
| Classification | Nonionic water | PH6.8 phosphate buffers (0.05M) |
| Crystal formation I | 325.4 | 485.1 |
| Crystal formation II | 218.5 | 325.4 |
| Crystal formation III | 219.6 | 327.3 |
As can be seen from Table 6, crystal formation I to III is easily dissolved in nonionic water and the phosphate buffers of pH 6.8.Especially
Ground, crystal formation I show very high solubility in nonionic water and pH6.8 phosphate buffers.Thus, it will be seen that only
With a small amount of (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles
Coughing up -1- bases] the trihydrate crystal formation I of -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt can show excellent therapeutic effect.
Industrial usability
According to the present invention it is possible to economically with high-purity and produced in yields 4- (((ttetrahydro-pyran -2- bases) oxygen) methyl) benzene
Amine, the compound is used as the reaction yield of reactant to improve.
In addition, the novel crystal forms of the present invention show excellent stability, hygroscopicity and dissolubility, therefore be advantageous to a large amount of lifes
Production, and only use can show excellent therapeutic effect on a small quantity.
Claims (21)
- (1. 3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles Cough up -1- bases] the trihydrate crystal formation I of -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt, it is characterised in that the trihydrate crystal formation I tools Have and radiate obtained X-ray powder diffraction figure using Cu-Ka, it shows peak value at the following θ of the angle of diffraction 2：5.38°± 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°。
- 2. trihydrate crystal formation I as claimed in claim 1, it is characterised in that the trihydrate crystal formation I, which has, uses Cu- Ka radiates obtained X-ray powder diffraction figure, and peak value is shown at least one θ of the angle of diffraction 2 being selected from the group：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 °.
- (3. 3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles Cough up -1- bases] the trihydrate crystal formation II of -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt, it is characterised in that the trihydrate crystal formation II With the X-ray powder diffraction figure for radiating to obtain using Cu-Ka, peak value is presented in it at the following θ of the angle of diffraction 2：5.46°± 0.2 °, 9.50 ° ± 0.2 ° and 19.30 ° ± 0.2 °.
- 4. trihydrate crystal formation II as claimed in claim 3, it is characterised in that the trihydrate crystal formation II, which has, to be used Cu-Ka radiates obtained X-ray powder diffraction figure, and peak value is shown at least one θ of the angle of diffraction 2 being selected from the group：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 °.
- (5. 3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyl]-pyrroles Cough up -1- bases] the trihydrate crystal formation III of -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt, it is characterised in that the trihydrate crystal formation For III with the X-ray powder diffraction figure for radiating to obtain using Cu-Ka, peak value is presented in it at the following θ of the angle of diffraction 2：21.90°± 0.2 °, 8.04 ° ± 0.2 °, 8.11 ° ± 0.2 ° and 13.07 ° ± 0.2 °.
- 6. trihydrate crystal formation III as claimed in claim 5, it is characterised in that the trihydrate crystal formation III, which has, to be used Cu-Ka radiates obtained X-ray powder diffraction figure, and peak value is shown at least one θ of the angle of diffraction 2 being selected from the group：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 °.
- 7. one kind prepares (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyls Base]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation I method, this method includes：Preparation contains (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyls Base]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt, ethyl acetate and water reaction solution；WithStir the reaction solution.
- 8. the method as claimed in claim 7 for preparing trihydrate crystal formation I, it is characterised in that the reaction solution of the preparation Including：By to (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hidroxymethylphenylaminos) carbonyls Base]-pyrroles -1- bases] -3,5- dihydroxy enanthic acid half calcium salt in add water and prepare mixture；WithReaction solution is prepared by adding ethyl acetate into the mixture.
- 9. the method for preparing trihydrate crystal formation I as claimed in claim 7 or 8, it is characterised in that methods described also includes： The reaction solution of cooling and stirring.
- 10. trihydrate crystal formation I as claimed in claim 7 or 8 preparation method, it is characterised in that described ethyl acetate Volume ratio with water is 3:1 to 1:3(V/V).
- 11. one kind prepares (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) Carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation II method, this method includes：Preparation contains (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyls Base]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt, the reaction solution of first alcohol and water；WithStir the reaction solution.
- 12. the as claimed in claim 11 method for preparing trihydrate crystal formation II, it is characterised in that described first alcohol and water it Between volume ratio be 3:1 to 1:3(V/V).
- 13. one kind prepares (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) Carbonyl]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt trihydrate crystal formation III method；This method includes：Preparation contains (3R, 5R) -7- [2- (4- fluorophenyls) -5- isopropyl -3- phenyl -4- [(4- hydroxymethylphenylarninos) carbonyls Base]-pyrroles -1- bases] -3,5- dihydroxy-Semi-Heptanoic Acid Calcium Salt and the solvent containing one of methanol and tetrahydrofuran, dichloromethane Reaction solution；Concentrate is prepared by concentrating the reaction solution；WithSolid is produced by adding water into the concentrate.
- 14. the as claimed in claim 13 method for preparing trihydrate crystal formation III, it is characterised in that described tetrahydrofuran, Volume ratio between one of dichloromethane and methanol is 1:10 to 4:5(V/V).
- 15. a kind of method of the compound shown in formula 2, methods described include：In the presence of iron, zinc, tin, iron containing compoundses, zinc compound, sn-containing compound or its mixture, by shown in following formula 1 Compound and at least one reaction being selected from the group：Ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine；[formula 1][formula 2]Wherein R is acetyl group, benzoyl, THP trtrahydropyranyl, methoxy, methoxvethoxvmethvl or benzyl.
- 16. the method for the compound shown in formula 2 as claimed in claim 15, it is characterised in that methods described also includes：Prepare the solution containing the compound shown in formula 1.
- 17. the method for the compound shown in formula 2 as claimed in claim 16, it is characterised in that the compound shown in formula 1 With selected from least one of ammonium formate, ammonium chloride, sodium dihydrogen phosphate and hydrazine react the step of be by selected from ammonium formate, ammonium chloride, At least one of sodium dihydrogen phosphate and hydrazine are added in solution.
- 18. the method for the compound shown in formula 2 as claimed in claim 17, it is characterised in that in 5 to 30 DEG C of temperature It is lower to add selected from least one of ammonium formate, ammonium chloride, sodium dihydrogen phosphate and hydrazine.
- 19. the method for compound shown in formula 2 as claimed in claim 16, it is characterised in that the step of preparing solution be Compound shown in formula 1 is dissolved in the C1 of straight or branched into C4 alcohol.
- 20. as claimed in claim 15 prepare as the method for the compound shown in formula 2, it is characterised in that the chemical combination shown in formula 1 Thing and the reaction selected from least one of ammonium formate, ammonium chloride, sodium dihydrogen phosphate and hydrazine be have iron, zinc, stannic chloride and its Carried out in the presence of at least one of mixture.
- 21. a kind of compound prepared as shown in following formula A or the method for its isomers or its salt, it is characterised in that methods described Including：In the presence of iron, zinc, tin, the compound of iron content, zinc compound, sn-containing compound or its mixture, by such as following formula 1 Shown compound selected from the reaction of at least one of ammonium formate, ammonium chloride, sodium dihydrogen phosphate and hydrazine with preparing such as the institute of following formula 2 The compound shown：[formula 1][formula 2]Wherein R is acetyl group, benzoyl, THP trtrahydropyranyl, methoxy, methoxvethoxvmethvl or benzyl[formula A]
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