CN110372637A - The preparation method of PAC-1 crystal form - Google Patents
The preparation method of PAC-1 crystal form Download PDFInfo
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- CN110372637A CN110372637A CN201910585127.7A CN201910585127A CN110372637A CN 110372637 A CN110372637 A CN 110372637A CN 201910585127 A CN201910585127 A CN 201910585127A CN 110372637 A CN110372637 A CN 110372637A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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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
Abstract
The present invention provides a kind of preparation methods of the crystal form of PAC-1, the crystal form A of PAC-1 provided by the invention, it is radiated using CuK α, the X-ray powder diffraction pattern indicated with the 2 θ angles of diffraction shows characteristic peak at 8.92 ± 0.2 °, 17.14 ± 0.2 °, 17.82 ± 0.2 °, 18.90 ± 0.2 °, 20.37 ± 0.2 ° and 26.06 ± 0.2 °.PAC-1 crystal form A of the invention can be using anti-solvent additive process, suspension paddling process, gas-liquid osmosis, gas-solid osmosis, slow cooling method, slow volatility process, high polymer revulsion, humidity revulsion or grinding rotating crystal method preparation.PAC-1 crystal form A of the invention is suitable for pharmaceuticals industry application, and crystal form dissolubility is good, and the drug effect of product can be improved, and preparation process is simple, stablizes, strong operability, is suitble to industrialized production, and stability of crystal form is high.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of crystal form of PAC-1 and preparation method thereof.
Background technique
Cancer is disease incidence and a kind of malignant disease that the death rate is high, therapeutic effect is relatively poor in world wide.?
In global range, antineoplastic has become the first big therapy field in medication market, and currently used antineoplastic includes cell
Malicious class drug, hormone drug, molecular targeted therapy medicine, biological response modifiers, Tumor Differentiation inducer, Tumor Angiongesis inhibit
Agent and the drug of adjuvant therapy of tumors etc..
Quinn P.Peterson professor in University of Illinois, the U.S. is carrying out in-vitro screening to 20000 multiple compounds
In, first of discovery can directly activate the small molecule compound of procaspase-3 (procaspasse-3), (E)-
N '-(3- allyl -2- phenol methylene) -2- (4- benzyl diethylenediamine -1- base) acethydrazide, is named as PAC-1, chemical formula is
C23H28N4O2, structure such as formula 1.Research has shown that, PAC-1 can selective induction tumour cell apoptosis occurs, and its is apoptosis-induced
Effect is positively correlated with intracellular procaspasse-3 level, and the procaspasse-3 content of normal cell is lower, right
Its killing ability is just smaller, has preferable selectivity, is mainly used for treating the malignant tumours such as lung cancer, breast cancer, human primary gastrointestinal cancers.
Studies have shown that it, which mainly passes through chelating, inhibits zinc ion, make procaspase-3 (procaspasse-3) autoactivation
For caspase-3 mRNA (caspase-3), induce cell apoptosis (Quinn P, et al., J Mol Biol, 2009,388 (1):
144-158.；Peterson Q P, etal.J Med Chem, 2009,52 (18): 5721-5731.), while it swells to a variety of
Oncocyte all has apoptosis-induced effect.Also there is the PAC-1 of studies have shown that high concentration can be from endoplasmic reticulum Apoptosis in the recent period
Approach induces cell apoptosis, show distinct cell apoptosis action character (West DC, et al.Mol Pharm.2012,9
(5):1425-1434)。
Chinese patent discloses CN101184491A and U.S. Patent Publication US2007/0049602A1 and discloses first to masses
A small molecule compound PAC-1 for directly activating procaspasse-3, and claimed PAC-1, PAC-1 derivative library
Object is closed, including with ZZ formula, ZZ2 formula, ZZ3 formula, the related compound of ZZ4 formula and its synthetic method；Simultaneously to it in cancer cell
The method of middle selective induction Apoptosis, external and directly screening can modify the chemical combination of procaspasse-3 molecule into the cell
Method, identification or the side for judging the potential sensitivity that cancer cell handles Caspase proenzyme activating compounds of object
Method, a kind of elevated levels by caspase original in identification candidate cancer patient's body are applicable to caspase to screen
The method of the candidate of former activator treatment is protected.International monopoly WO2010/091382A1 to PAC-1, without mind
It is protected through toxic chemical S-PAC-1 and the like.
Chinese patent, which discloses, discloses a kind of unbodied PAC-1 in CN104910100A, be named as ZYS-1, wherein also
Refer to that a kind of PAC-1 needle in the prior art, X-ray powder diffraction (XRPD) map are as shown in Figure 2.
Crystal form refers to that the spread pattern of molecule in crystalline material lattice, the difference between crystal form are substantially the microcosmic knot of structure cell
Difference on structure.The different crystal forms of same compound appearance, solubility, fusing point, dissolution rate, in terms of may
Have dramatically different, to affect the stability of drug, bioavilability and curative effect, the phenomenon is in terms of oral solid formulation
Show particularly evident.One of an important factor for polymorph in pharmaceuticals phenomenon is influence drug quality and clinical efficacy, therefore to crystalline substance
Type analysis, which is paid special attention to, to be just particularly important.
Summary of the invention
The object of the present invention is to provide the preparation methods of PAC-1 crystal form A.
Technical scheme is as follows:
1. a kind of method for preparing PAC-1 crystal form A using anti-solvent additive process, wherein comprising: by PAC-1 compound
It is dissolved in positive solvent, then anti-solvent is added dropwise, collect obtained solid and obtain PAC-1 crystal form A.
2. preparing the method for PAC-1 crystal form A according to item 1, wherein the positive solvent is selected from methanol, acetone, tetrahydro
Furans, dioxanes, acetonitrile, ethyl alcohol, methyl ethyl ketone, ethyl acetate, 2- methyltetrahydrofuran, methyl phenyl ethers anisole, methylene chloride, first
Benzene, acetone, any one in dimethyl acetamide are any several combination.
3. preparing the method for PAC-1 crystal form A according to item 1 or 2, wherein the anti-solvent be selected from water, normal heptane,
In cyclopentyl methyl ether any one or be any several combination.
4. preparing the method for PAC-1 crystal form A according to item 1, wherein be precipitated described in solid preparation at room temperature
PAC-1 crystal form A.
5. preparing the method for PAC-1 crystal form A according to any one of item 1~3, wherein
When the positive solvent is toluene, and anti-solvent is normal heptane, solid is precipitated under the conditions of -20 DEG C and obtains PAC-1 crystalline substance
Type A；Or
When the positive solvent is acetone or dimethyl acetamide, and anti-solvent is cyclopentyl methyl ether, volatilize at room temperature
To PAC-1 crystal form A.
6. a kind of method that application suspension paddling process prepares PAC-1 crystal form A, wherein comprising: in PAC-1 compound
Solvent is added and obtains suspension, stirs the suspension, obtained solid is collected by centrifugation and obtains PAC-1 crystal form A.
7. preparing the method for PAC-1 crystal form A according to item 6, wherein the solvent is selected from ethyl alcohol, isopropanol, acetic acid
Ethyl ester, methyl tertiary butyl ether(MTBE), acetonitrile, water, methanol and the mixed solvent of water, the mixed solvent of acetone and water, tetrahydrofuran and water
Mixed solvent, the mixed solvent of normal propyl alcohol and water, the mixed solvent of dimethylformamide and water, the mixing of ethyl alcohol and water it is molten
Agent, the mixed solvent of acetonitrile and water, the mixed solvent of methyl iso-butyl ketone (MIBK) and normal heptane, the mixing of dioxanes and normal heptane are molten
Agent, the mixed solvent of chloroform and normal heptane, isobutanol, isobutyl acetate, cyclopentyl methyl ether, methyl tertiary butyl ether(MTBE), acetone with just
The in the mixed solvent of the mixed solvent of heptane, the mixed solvent of isopropanol and normal heptane, dioxanes and water any one or be
Any several combination.
8. preparing the method for PAC-1 crystal form A according to item 6 or 7, wherein under the conditions of 25~100 DEG C described in stirring
Suspension 0.1~10 day.
9. preparing the method for PAC-1 crystal form A according to any one of item 6~8, wherein stirred at room temperature or 50 DEG C
Mix the suspension 6 days.
10. preparing the method for PAC-1 crystal form A according to any one of item 7~9, wherein the solvent be methanol with
The mixed solvent of water, and the volume ratio of the mixed solvent of the methanol and water is methanol: water is 1:1.3~1:14.
11. preparing the method for PAC-1 crystal form A according to any one of item 7~9, wherein the solvent is selected from acetone
With the mixed solvent of the mixed solvent of water, the mixed solvent of tetrahydrofuran and water, normal propyl alcohol and water, dimethylformamide and water
Mixed solvent, the mixed solvent of ethyl alcohol and water, the mixed solvent of acetonitrile and water, the mixing of methyl iso-butyl ketone (MIBK) and normal heptane are molten
Agent, the mixed solvent of dioxanes and normal heptane, the mixed solvent of chloroform and normal heptane, acetone and normal heptane mixed solvent, different
When any mixed solvent in the mixed solvent of the mixed solvent of propyl alcohol and normal heptane, dioxanes and water, it is used to form mixing
The volume ratio of two kinds of solvents of solvent is 1:1.
12. a kind of method for preparing PAC-1 crystal form A using gas-liquid osmosis, wherein comprising: which PAC-1 compound is molten
In Xie Zheng solvent, clear solution is made, and the container opening equipped with clear solution is placed on the sealing equipped with anti-solvent and is held
It is stood in device, the solid for collecting precipitation obtains PAC-1 crystal form A.
13. preparing the method for PAC-1 crystal form A according to item 12, wherein the positive solvent is selected from ethyl alcohol, methyl second
Base ketone, 2- methyltetrahydrofuran, N-Methyl pyrrolidone, normal propyl alcohol, dioxanes, toluene, isopropyl acetate, methylene chloride, third
Ketone, tetrahydrofuran, in acetonitrile any one or be any several combination.
14. preparing the method for PAC-1 crystal form A according to item 12 or 13, wherein the anti-solvent is selected from water, positive heptan
In alkane any one or be any several combination.
15. preparing the method for PAC-1 crystal form A according to any one of item 12~14, wherein at room temperature, will fill
There is the container opening of clear solution to be placed in the sealing device equipped with anti-solvent to stand.
16. a kind of method for preparing PAC-1 crystal form A using gas-solid osmosis, wherein comprising: which PAC-1 chemical combination will be equipped with
The open-top receptacle of object is placed in the sealing container equipped with positive solvent, is stood, and is taken out solid and is obtained PAC-1 crystal form A.
17. preparing the method for PAC-1 crystal form A according to item 16, wherein the positive solvent is selected from methanol, ethyl alcohol, different
Propyl alcohol, acetone, acetonitrile, methylene chloride, chloroform, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, ethyl acetate, toluene, dimethyl are sub-
Any one in sulfone, N,N-dimethylformamide is any several combination.
18. preparing the method for PAC-1 crystal form A according to item 16 or 17, wherein will be spacious equipped with PAC-1 compound
Mouth container is placed in the sealing container equipped with positive solvent, is stood at room temperature.
19. a kind of method for preparing PAC-1 crystal form A using slow cooling method, wherein comprising: which PAC-1 compound is molten
Solution in a solvent, heats at 30~140 DEG C, and solution filters after becoming clarification, by filtrate from 30~140 DEG C of slow coolings to 0~
25 DEG C, and placed 0.1~10 day in 0~25 DEG C of constant temperature, filtrate is then transferred to -20~-5 DEG C of conditions, places 0.1~10h,
It collects obtained solid and obtains PAC-1 crystal form A.
20. preparing the method for PAC-1 crystal form A according to item 19, wherein comprising: which PAC-1 compound is dissolved in
It in solvent, is heated at 50 DEG C, solution filters after becoming clarification, by filtrate from 50 DEG C of slow coolings to 5 DEG C, and puts in 5 DEG C of constant temperature
It sets 5 days, filtrate is then transferred to -20 DEG C, place 1h, collect obtained solid and obtain PAC-1 crystal form A.
21. preparing the method for PAC-1 crystal form A according to item 19 or 20, wherein the rate of the slow cooling is
0.1~20 DEG C/min, preferably 0.1 DEG C/min.
22. preparing the method for PAC-1 crystal form A according to any one of item 19~21, wherein the slow cooling
Rate is 0.1 DEG C/min.
23. preparing the method for PAC-1 crystal form A according to any one of item 19~22, wherein the solvent is selected from different
Propyl alcohol, methyl tertiary butyl ether(MTBE), butyl acetate, alcohol and the mixed solvent of water, the mixed solvent of tetrahydrofuran and water, methyl phenyl ethers anisole with
The mixed solvent of normal heptane, the in the mixed solvent of acetonitrile and normal heptane any one or be any several combination.
24. a kind of method for applying slow volatility process to prepare PAC-1 crystal form A, wherein comprising: which PAC-1 compound is set
In container, and solvent, which is added, dissolves PAC-1 compound in a solvent, is configured to clear solution, and then slowly volatilization, is collected
Obtained solid obtains PAC-1 crystal form A.
25. preparing the method for PAC-1 crystal form A according to item 24, wherein the solvent is selected from methanol, ethyl alcohol, acetic acid
Ethyl ester, acetone, methyl ethyl ketone, tetrahydrofuran, toluene, acetonitrile, methylene chloride, chloroform, methyl tertiary butyl ether(MTBE), appointing in acetic acid
One kind of anticipating is any several combination.
26. preparing the method for PAC-1 crystal form A according to item 24 or 25, wherein after being configured to clear solution, in room
The lower slowly volatilization of temperature.
27. preparing the method for PAC-1 crystal form A according to any one of item 24~26, wherein using sealed membrane to dress
There is the container of PAC-1 compound to be sealed, and has aperture on sealed membrane.
28. a kind of method for preparing PAC-1 crystal form A using high polymer revulsion, wherein comprising: by PAC-1 compound
It is dissolved in positive solvent, and high polymer is added, switch to volatilize after stirring, collect obtained solid and obtain PAC-1 crystal form A.
29. preparing the method for PAC-1 crystal form A according to item 28, wherein the positive solvent is selected from methanol, ethyl alcohol, third
In ketone, tetrahydrofuran any one or be any several combination.
30. preparing the method for PAC-1 crystal form A according to item 28 or 29, wherein the high polymer is selected from hydroxypropyl first
Base cellulose, polyvinylpyrrolidone, methylcellulose, polyvinyl acetate, polyvinyl alcohol, any one in polyvinyl chloride
It or is any several combination.
31. preparing the method for PAC-1 crystal form A according to any one of item 28~30, wherein after being stirred at room temperature
Switch to volatilize.
32. a kind of method for preparing PAC-1 crystal form A using humidity revulsion, wherein comprising: which PAC-1 chemical combination will be equipped with
The container of object is placed in the drier that humidity is 5~100%, and solid is collected after 0.1~10 day and obtains PAC-1 crystal form A.
33. preparing the method for PAC-1 crystal form A according to item 32, wherein comprising: which PAC-1 compound will be equipped with
Container is placed in the drier that humidity is 45%~100%, and solid is collected after 7 days and obtains PAC-1 crystal form A.
34. preparing the method for PAC-1 crystal form A according to item 32 or 33, wherein using sealed membrane to equipped with PAC-1
The container of compound is sealed, and has aperture on sealed membrane, and the container equipped with PAC-1 compound is then placed in drier again
In.
35. a kind of method that application grinding rotating crystal method prepares PAC-1 crystal form A, wherein comprising: which PAC-1 compound is existed
It is ground 1~80 minute under conditions of 5~50 DEG C, obtains PAC-1 crystal form A.
The effect of invention
The preparation method of PAC-1 crystal form A provided by the invention is simple, stablizes, strong operability, is suitble to industrialized production,
Obtained PAC-1 crystal form A stability is high.
Detailed description of the invention
X-ray powder diffraction (XRPD) map of Fig. 1 PAC-1 crystal form A
Thermogravimetric analysis/differential scanning calorimetric analysis (TGA/DSC) map of Fig. 2 PAC-1 crystal form A
Specific embodiment
In the case where not clashing with the definition in this specification, the term in this specification has art technology
The normally understood meaning of personnel, but if any conflict, then the definition in this specification shall prevail.
PAC-1
In the present specification, PAC-1 refers to that one kind can directly activate procaspase-3 (Procaspase-3)
Small molecule compound, chemical name is 1-Piperazineacetic acid, 4- (phenylmethyl) -2- [[2-
Hydroxy-3- (2-propen-1-yl) phenyl] methylene] ((E)-N '-(3- allyl -2- phenol methylene) -
2- (4- benzyl diethylenediamine -1- base) acethydrazide), structure such as formula 1 is believed to selective induction tumour cell and apoptosis occurs,
Anti-tumor drug can be thus used as.
Thermogravimetric analysis
Thermogravimetric analysis (Thermogravimetric Analysis, TGA) refer to measured under programed temperature it is to be measured
The quality of sample and a kind of thermoanalysis technology of temperature change relationship, for the thermal stability and component of research material.TGA is being ground
Hair and quality control aspect are all more commonly used detection means.Thermogravimetric analysis in actual material analysis often with other points
The combination of analysis method carries out Thermal Synthetic Analysis, comprehensive accurate analysis of material.The curve that thermogravimetric analyzer is recorded claims TGA curve.
Differential scanning calorimetric analysis
Differential scanning calorimetric analysis (differential scanning calorimetry, DSC), in temperature program(me) control
Under system, sample is measured relative to the heat flow rate of reference substance with temperature or a kind of technology of time change.Differential scanning calorimeter
The curve being recorded claims DSC curve, generally with W/g or mW/mg (flowing to the power of every gram of sample) for ordinate, with temperature T
Or time t is abscissa, can measure a variety of thermodynamics and kinetics parameters, such as specific heat capacity, reaction heat, the heat of transformation, phasor,
Reaction rate, crystalline rate, superpolymer crystal degree, sample purity etc..The method use temperature range wide (- 175~725 DEG C) is divided
Resolution is high, sample dosage is few.Suitable for inorganic matter, organic compound and Pharmaceutical Analysis.
PAC-1 crystal form of the invention is named as PAC-1 crystal form A, and X-ray powder diffraction (XRPD) map is as shown in Figure 1.
In a specific embodiment, the PAC-1 crystal form A obtained by the present invention is anhydrous crystal forms.
Anti-solvent additive process, suspension paddling process, gas-liquid osmosis, gas-solid osmosis, slow cooling can be used in the present invention
Method, slow volatility process, high polymer revulsion, humidity revulsion, grinding rotating crystal method prepare PAC-1 crystal form A.
In a specific embodiment, PAC-1 crystal form A is prepared in present invention application anti-solvent additive process.Anti-solvent
Additive process is that positive solvent is used in combination with anti-solvent, to reduce the dissolubility of object to be crystallized in a solvent.It is dissolved to
Crystal is to mix near transition temperature with anti-solvent.Since anti-solvent is in conjunction with water, the dissolution of object to be crystallized is reduced
Property, so that crystal be made to be precipitated, crystal is obtained by filtration.Specifically, preparing PAC-1 using anti-solvent additive process in the present invention
The method of crystal form A, comprising: PAC-1 compound is dissolved in positive solvent, then anti-solvent is added dropwise, obtained solid is collected, obtains
To PAC-1 crystal form.
In one preferred embodiment, PAC-1 crystal form A is prepared using anti-solvent additive process, the positive solvent is selected from
Methanol, acetone, tetrahydrofuran, dioxanes, acetonitrile, ethyl alcohol, methyl ethyl ketone, ethyl acetate, 2- methyltetrahydrofuran, benzene first
Ether, methylene chloride, toluene, acetone, any one in dimethyl acetamide are any several combination, and the anti-solvent is selected from
Water, normal heptane, in cyclopentyl methyl ether any one or be any several combination.
In a specific embodiment, present invention application suspension paddling process prepares PAC-1 crystal form A.Specifically, to raw material
Solvent is added in sample and obtains suspension, the suspension is placed at room temperature or 25~100 DEG C after stirring 0.1~10 day, from
The heart collects obtained solid, obtains PAC-1 crystal form A.
In one preferred embodiment, PAC-1 crystal form A is prepared using suspension paddling process, is added in material sample
Solvent obtains suspension, and the solvent is selected from ethyl alcohol, isopropanol, ethyl acetate, methyl tertiary butyl ether(MTBE), acetonitrile, water, methanol and water
Mixed solvent, the mixed solvent of acetone and water, the mixed solvent of tetrahydrofuran and water, the mixed solvent of normal propyl alcohol and water, two
The mixed solvent of methylformamide and water, the mixed solvent of ethyl alcohol and water, the mixed solvent of acetonitrile and water, methyl iso-butyl ketone (MIBK) with
The mixed solvent of normal heptane, the mixed solvent of dioxanes and normal heptane, chloroform and normal heptane in the mixed solvent any one or
For any several combination, obtained suspension is placed in and is stirred at room temperature 0.1~10 day, preferably 6 days, it is solid that gained is collected by centrifugation
Body obtains PAC-1 crystal form A.Preferably, the solvent is the mixed solvent of methanol and water, and the mixing of the methanol and water is molten
The volume ratio of agent is methanol: water is 1:1.3~1:14；Any one other in the mixed solvent, the volume ratio of two kinds of solvents are
1:1.
In one preferred embodiment, PAC-1 crystal form A is prepared using suspension paddling process, is added in material sample
Solvent obtains suspension, and the solvent is selected from the mixed solvent, different of the mixed solvent of dioxanes and normal heptane, chloroform and normal heptane
Butanol, isobutyl acetate, cyclopentyl methyl ether, methyl tertiary butyl ether(MTBE), acetone and normal heptane mixed solvent, isopropanol and normal heptane
Mixed solvent, the mixed solvent of acetonitrile and water, dioxanes and water in the mixed solvent any one or be any several group
It closes, the suspension is placed at 50 DEG C and stirs 0.1~10 day, preferably 6 days, obtained solid and drying is collected by centrifugation, obtains
PAC-1 crystal form A.
In a specific embodiment, present invention application gas-liquid osmosis prepares PAC-1 crystal form A.Specifically, by raw material
Sample is dissolved in positive solvent, clear solution is made, and the container opening equipped with clear solution is placed on equipped with anti-solvent
It in sealing container, stands at room temperature, collects the solid of precipitation, obtain PAC-1 crystal form A.
In one preferred embodiment, PAC-1 crystal form A is prepared using gas-liquid osmosis, the positive solvent is selected from second
Alcohol, methyl ethyl ketone, 2- methyltetrahydrofuran, N-Methyl pyrrolidone, normal propyl alcohol, dioxanes, toluene, isopropyl acetate, two
Chloromethanes, acetone, tetrahydrofuran, any one in acetonitrile are any several combination, and the anti-solvent is selected from water and positive heptan
Any one in alkane.
In a specific embodiment, PAC-1 crystal form A is prepared in present invention application gas-solid osmosis.Specifically, will
Container equipped with material sample is placed in the sealing container equipped with positive solvent, is stood at room temperature, is taken out solid and is obtained PAC-1 crystalline substance
Type A.
In one preferred embodiment, PAC-1 crystal form A, the positive preferred second of solvent are prepared using gas-solid osmosis
Pure and mild acetone.
In a specific embodiment, PAC-1 crystal form A is prepared in present invention application slow cooling method.Specifically, will
Material sample dissolves in a solvent, and at 30~140 DEG C, preferably 50 DEG C are heated, and heated solution filters after becoming clarification, then
By filtrate slow cooling to 0~25 DEG C, preferably 5 DEG C, control rate of temperature fall be 0.1~20 DEG C/min, preferably 0.1 DEG C/min,
And constant temperature is placed 0.1~10 day at such a temperature, and preferably 5 days, filtrate is then transferred to -20~-5 DEG C, preferably -20 DEG C again,
1h is placed, obtained solid is collected, obtains PAC-1 crystal form A.
In one preferred embodiment, PAC-1 crystal form A is prepared using slow cooling method, the solvent is selected from isopropyl
Alcohol, methyl tertiary butyl ether(MTBE), butyl acetate, alcohol and the mixed solvent of water, the mixed solvent of tetrahydrofuran and water, methyl phenyl ethers anisole with just
The in the mixed solvent of the mixed solvent of heptane, acetonitrile and normal heptane any one or be any several combination.
In a specific embodiment, the present invention prepares PAC-1 crystal form A using slow volatility process.Specifically, by raw material
Sample is placed in container, and solvent is added and makes it dissolve, is configured to clear solution, is placed at room temperature slowly volatilization, is collected gained
Solid obtains PAC-1 crystal form A.In one preferred embodiment, the container equipped with clear solution is carried out using sealed membrane
Sealing, and have aperture on sealed membrane.
In one preferred embodiment, using slow volatility process prepare PAC-1 crystal form A, the solvent be selected from methanol,
Ethyl alcohol, ethyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, toluene, acetonitrile, methylene chloride, chloroform, methyl tertiary butyl ether(MTBE),
Any one in acetic acid is any several combination.
In a specific embodiment, present invention application high polymer revulsion prepares PAC-1 crystal form A.Specifically, by former
Expect sample dissolution in a solvent, and high polymer is added, after being stirred at room temperature 0.1~12 hour, switch to volatilize after preferably 2 hours, receives
Collect the solid being precipitated, obtains PAC-1 crystal form A.
In one preferred embodiment, PAC-1 crystal form A is prepared using high polymer revulsion, the high polymer is selected from
Polyvinyl chloride, polyvinyl alcohol, polyvinyl acetate, methylcellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose etc.；
The solvent in methanol, ethyl alcohol, acetone, tetrahydrofuran any one or be any several combination.
In a specific embodiment, PAC-1 crystal form A is prepared in present invention application humidity revulsion.Specifically, will
Material sample is placed in the drier that humidity is 45%~100%, and after 0.1~10 day, after preferably 7 days, collection obtains PAC-1 crystalline substance
Type A.
In one preferred embodiment, PAC-1 crystal form A is prepared using humidity revulsion, first using sealed membrane to dress
There is the container of material sample to be sealed, and have aperture on sealed membrane, the container equipped with material sample is then placed in drying again
In device.
In a specific embodiment, PAC-1 crystal form A is prepared in application grinding rotating crystal method of the present invention.Specifically, will
Material sample is ground 1~80 minute under conditions of 5~50 DEG C, obtains PAC-1 crystal form A.
In a specific embodiment, anti-solvent additive process of the invention, suspension paddling process, gas-liquid osmosis, gas-solid
Osmosis, slow cooling method, slow volatility process, high polymer revulsion, humidity revulsion, grinding rotating crystal method prepare PAC-1 crystal form A
Method in, it is dried after obtained PAC-1 crystal form A.
Embodiment
What is be exemplified below is only several specific embodiments of the invention.The present invention is not limited to the above embodiments, may be used also
With there are many deformations.All deformations that those skilled in the art directly can export or associate from present disclosure,
It is considered as protection scope of the present invention.
Embodiment 1
Anti-solvent additive process: weighing about 20 milligrams every part of sample in 20 milliliters of bottles, molten with a certain amount of positive solvent
Corresponding anti-solvent in following table is added dropwise into the clear solution by Xie Hou, stirs when being added dropwise to there is solid precipitation, by gained
Solid is dry.The finally obtained solid of embodiment is respectively labeled as solid 1-1 to 1-14 in table 1, and the solid of precipitation is carried out
XRPD detection, is crystal form A.
Table 1
Note: *: -20 DEG C of solids are precipitated to obtain；*: room temperature volatilizees to obtain.
Embodiment 2
Suspension paddling process: the sample for weighing about 15 milligrams every part into bottle, be separately added into 0.3 milliliter it is listed in Table molten
Agent, obtained suspension is respectively placed in stirred 6 days at room temperature and 50 DEG C after, be collected by centrifugation to obtain solid and drying.It will be real in table 2
It applies the finally obtained solid of example and is respectively labeled as solid 2-1 to 2-27, solid will be obtained and carry out XRPD detection, be crystal form A.
Table 2
Embodiment 3
Gas-liquid osmosis: weighing about 20 milligrams every part of sample and be dissolved in a certain amount of solvent, be placed in 3 milliliters of bottles,
The another anti-solvent for taking 20 milliliters of bottles and about 3 milliliters are added thereto, 3 milliliters of bottle openings are placed in 20 milliliters of bottles, close
It closes and stands at room temperature, be precipitated to solid, obtained solid is dry.The finally obtained solid of embodiment in table 3 is marked respectively
It is denoted as solid 3-1 to 3-12, XRPD detection is carried out, is crystal form A.
Table 3
Embodiment 4
Slow cooling method: the sample for weighing about 20 milligrams every part is separately added into 0.8 milliliter of following table in 3 milliliters of bottles
Solvent, sample is placed in 50 DEG C of baking ovens and is balanced 1 hour, if becoming limpid after heating for dissolving, is then filtered.By clear solution from
50 DEG C are cooled to 5 DEG C, 0.1 DEG C/min of rate, and 5 DEG C constant temperature 5 days, clarification sample is then transferred to -20 DEG C, places 1h,
Collect obtained solid and drying.The finally obtained solid of the present embodiment in table 4 is respectively labeled as solid 4-1 to 4-7, into
Row test, is crystal form A.
Table 4
Embodiment 5
Slow volatility process: weighing about 20 milligrams every part of sample into bottle, the solvent being separately added into 1 milliliter of following table,
It is configured to clear solution, then 4 aperture postpositions is pricked with sealed membrane and places volatilization at room temperature, collection obtains solid and drying.
The finally obtained solid of the present embodiment in table 5 is respectively labeled as solid 5-1 to 5-12, and is tested, is crystal form A.
Table 5
Embodiment 6
High polymer revulsion: the high polymer in about 2 milligrams of following tables is added in bottle in the sample for weighing about 20 milligrams every part
With 0.5 milliliter of solvent, switch to volatilize after being stirred at room temperature 2 hours, is collected after room temperature volatilization and solid and drying is precipitated to obtain.By table
The finally obtained solid of the present embodiment is respectively labeled as solid 6-1 to 6-6 in 6, and is tested, and is crystal form A.
Table 6
Embodiment 7
Humidity revulsion: weighing 15 milligrams of samples and be placed in bottle, then seals 4 apertures of bundle with sealed membrane and is placed on correspondence
In the drier of humidity, solid and drying are collected after 7 days.The finally obtained solid of the present embodiment in table 7 is respectively labeled as solid
Body 7-1 to 7-4, is tested, and crystal form A is obtained.
Table 7
Embodiment 8
Gas-solid osmosis
It weighs about 15 milligrams every part of sample to be placed in 3 milliliters of bottles, separately takes 20 milliliters of bottle and about 3 are added thereto
The correspondence solvent of milliliter, 3 milliliters of bottle openings are placed in 20 milliliters of bottle, are sealed and are stood 6~10 days at room temperature, receive
Collect solid and drying.The finally obtained solid of the present embodiment is respectively labeled as solid 8-1 to 8-9 in table 8, is tested,
To crystal form A.
Table 8
Embodiment 9
Grind rotating crystal method
It weighs 50 milligrams of samples to be placed in mortar, hand-ground about 10 minutes, 10 milliliters of coordinative solvents is added, then collect
Solid and drying.The finally obtained solid of the present embodiment is respectively labeled as solid 9-1 to 9-2 in table 9, is tested, is obtained
Crystal form A.
Table 9
Experimental example
Experimental example 1
For the preparation-obtained PAC-1 crystal form A of Examples 1 to 9 in the present invention, spread out respectively using XRERT-3X ray
Instrument and Empyream X-ray diffractometer are penetrated, under the test condition of table 10, obtained all PAC-1 crystal form A's is spread out with 2 θ
The X-ray powder diffraction pattern that firing angle indicates is identical, in 8.92 ± 0.2 °, 17.14 ± 0.2 °, 17.82 ± 0.2 °, 18.90
Characteristic peak is shown at ± 0.2 °, 20.37 ± 0.2 ° and 26.06 ± 0.2 °.
Table 10
Further, the X-ray powder diffraction pattern that PAC-1 crystal form A is indicated with the 2 θ angles of diffraction is in 5.46 ± 0.2 °, 8.92
±0.2°、10.14±0.2°、15.76±0.2°、17.14±0.2°、17.82±0.2°、18.27±0.2°、18.90±
Feature is shown at 0.2 °, 19.43 ± 0.2 °, 20.37 ± 0.2 °, 21.48 ± 0.2 °, 21.80 ± 0.2 ° and 26.06 ± 0.2 °
Peak.
Further, the X-ray powder diffraction pattern that PAC-1 crystal form A is indicated with the 2 θ angles of diffraction is in 5.46 ± 0.2 °, 8.92
±0.2°、10.14±0.2°、11.24±0.2°、11.91±0.2°、14.04±0.2°、14.53±0.2°、16.34±
0.2°、15.76±0.2°、17.14±0.2°、17.82±0.2°、18.27±0.2°、18.90±0.2°、19.43±0.2°、
20.37±0.2°、20.96±0.2°、21.48±0.2°、21.80±0.2°、22.52±0.2°、22.94±0.2°、23.47
±0.2°、24.00±0.2°、25.62±0.2°、26.06±0.2°、26.84±0.2°、27.16±0.2°、27.60±
0.2°、27.90±0.2°、28.99±0.2°、29.31±0.2°、29.98±0.2°、30.66±0.2°、32.09±0.2°、
It is shown at 32.35 ± 0.2 °, 34.28 ± 0.2 °, 36.09 ± 0.2 °, 37.07 ± 0.2 °, 37.93 ± 0.2 ° and 38.39 ± 0.2 °
Show characteristic peak.
Further, the X-ray powder diffraction pattern of PAC-1 crystal form A has data included in following table 11:
Table 11
In the present invention, the measurement accuracy at 2 angles θ is ± 0.2 °, thus each characteristic peaks of above-mentioned crystal form peak value ±
It is its allowable range of error within the scope of 0.2 °.
Further, the X-ray powder diffraction pattern of PAC-1 crystal form A of the invention is as shown in Figure 1.
Experimental example 2
Using thermogravimetric analyzer, under the test condition of the following table 12, to the PAC-1 crystal form being prepared in Examples 1 to 9
A carries out thermogravimetric analysis.
Table 12
Using differential scanning calorimetry (DSC), under the test condition of upper table 12, to the PAC-1 being prepared in Examples 1 to 9
Crystal form A carries out differential scanning calorimetric analysis, measures the endothermic process of crystal form.
According to the measurement parameter in upper table 9, the PAC-1 crystal form A's that is prepared in the Examples 1 to 9 that the present invention measures
TGA/DSC map is as shown in Figure 2.
The differential scanning calorimetric analysis DSC curve of the crystal form shows single dominant in 130 DEG C to 140 DEG C of temperature range
Heat absorption, the fusing point of sample are 136.2 DEG C, and endotherm peak is 137.3 DEG C ± 2 DEG C, and peak area is -94.54J/g.It should be appreciated that
There may be variation that there is similar situation with X-ray powder diffraction numerical value, numerical value cited in differential canning calorimetry can not
It is construed to absolute value, temperature measuring precision is ± 2 DEG C, therefore the endotherm peak of above-mentioned crystal form is within the scope of peak value ± 2 DEG C
Its allowable range of error.
The TGA curve of PAC-1 crystal form A shows that for crystal form A in 120 DEG C of weightlessness about 2.03%, thermal stability is high.
Experimental example 3
The present invention determines the solubility for the PAC-1 crystal form A being prepared in Examples 1 to 9.For each embodiment system
About 20 milligrams of solid of appropriate PAC-1 crystal form A, be placed in bottle by standby obtained PAC-1 crystal form A respectively, then divides four steps (respectively
Be 50,50,200,700 milliliters) be added coordinative solvent after shake, stop if solid dissolved clarification.What Examples 1 to 9 was prepared
The rough solubility of PAC-1 crystal form A at room temperature is as shown in the following table 10.
Table 10
Claims (10)
1. a kind of method for preparing PAC-1 crystal form A using anti-solvent additive process, wherein comprising: which PAC-1 compound is dissolved
In positive solvent, then anti-solvent is added dropwise, collects obtained solid and obtain PAC-1 crystal form A.
2. the method according to claim 1 for preparing PAC-1 crystal form A, wherein the positive solvent is selected from methanol, acetone, four
Hydrogen furans, dioxanes, acetonitrile, ethyl alcohol, methyl ethyl ketone, ethyl acetate, 2- methyltetrahydrofuran, methyl phenyl ethers anisole, methylene chloride, first
Benzene, acetone, any one in dimethyl acetamide are any several combination.
3. the method according to claim 1 or 2 for preparing PAC-1 crystal form A, wherein the anti-solvent is selected from water, positive heptan
In alkane, cyclopentyl methyl ether any one or be any several combination.
4. the method according to claim 1 for preparing PAC-1 crystal form A, wherein solid is precipitated at room temperature and prepares institute
State PAC-1 crystal form A.
5. the method described in any one of claim 1 to 3 for preparing PAC-1 crystal form A, wherein
When the positive solvent is toluene, and anti-solvent is normal heptane, solid is precipitated under the conditions of -20 DEG C and obtains PAC-1 crystal form A；
Or
When the positive solvent is acetone or dimethyl acetamide, and anti-solvent is cyclopentyl methyl ether, volatilization is obtained at room temperature
PAC-1 crystal form A.
6. a kind of method that application suspension paddling process prepares PAC-1 crystal form A, wherein comprising: be added in PAC-1 compound
Solvent obtains suspension, stirs the suspension, and obtained solid is collected by centrifugation and obtains PAC-1 crystal form A.
7. the method according to claim 6 for preparing PAC-1 crystal form A, wherein the solvent is selected from ethyl alcohol, isopropanol, second
Acetoacetic ester, methyl tertiary butyl ether(MTBE), acetonitrile, water, methanol and the mixed solvent of water, the mixed solvent of acetone and water, tetrahydrofuran with
The mixed solvent of water, the mixed solvent of normal propyl alcohol and water, the mixed solvent of dimethylformamide and water, the mixing of ethyl alcohol and water are molten
Agent, the mixed solvent of acetonitrile and water, the mixed solvent of methyl iso-butyl ketone (MIBK) and normal heptane, the mixing of dioxanes and normal heptane are molten
Agent, the mixed solvent of chloroform and normal heptane, isobutanol, isobutyl acetate, cyclopentyl methyl ether, methyl tertiary butyl ether(MTBE), acetone with just
The in the mixed solvent of the mixed solvent of heptane, the mixed solvent of isopropanol and normal heptane, dioxanes and water any one or be
Any several combination.
8. the method according to claim 6 or 7 for preparing PAC-1 crystal form A, wherein stir institute under the conditions of 25~100 DEG C
State suspension 0.1~10 day.
9. preparing the method for PAC-1 crystal form A according to any one of claim 6~8, wherein at room temperature or 50 DEG C
Stir the suspension 6 days.
10. preparing the method for PAC-1 crystal form A according to any one of claim 7~9, wherein the solvent is methanol
With the mixed solvent of water, and the volume ratio of the mixed solvent of the methanol and water is methanol: water is 1:1.3~1:14.
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| CN101307038A (en) * | 2008-02-02 | 2008-11-19 | 深圳市湘雅生物医药研究院 | 4- benzyl piperazi ethyliminumacyl (formimidoyl benzol)hydrazine compounds, preparation method thereof, pharmaceutical compositions and use |
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| CN104910100A (en) * | 2014-03-11 | 2015-09-16 | 王智民 | Compound PAC-1 or salt thereof, and medicinal composition containing compound or salt thereof |
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| US20130096133A1 (en) * | 2011-10-14 | 2013-04-18 | The Board of Trustees of the University lllinois | Procaspase-activating compounds and compositions |
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