CN107163025A - It is a kind of to treat medical compounds of disease of digestive system and preparation method thereof - Google Patents
It is a kind of to treat medical compounds of disease of digestive system and preparation method thereof Download PDFInfo
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- CN107163025A CN107163025A CN201710410953.9A CN201710410953A CN107163025A CN 107163025 A CN107163025 A CN 107163025A CN 201710410953 A CN201710410953 A CN 201710410953A CN 107163025 A CN107163025 A CN 107163025A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention belongs to pharmaceutical technology field, disclose and a kind of treat medical compounds of disease of digestive system and preparation method thereof, the Vonoprazan fumarate dihydrate purity of offer is high, stability is good, the X ray powder diffractions that it is represented with the 2 θ ± 0.2 ° angles of diffraction are at 6.742 °, 7.036 °, 9.157 °, 10.528 °, 15.194 °, 17.457 °, 20.679 °, 22.223 °, 27.426 °, 28.621 °, 29.298 °, 35.227 °, 37.136 characteristic diffraction peak is shown at °, the X ray powder diffractograms obtained using Cu K alpha ray measurements are as shown in Figure 1, it is entirely different with prior art, surprisingly find that the Vonoprazan fumarate dihydrate dissolubility that the present invention is obtained is significantly improved through experiment.The composition tablet dissolution rate and stability that the Vonoprazan fumarate dihydrate of the present invention is made are significantly improved, and are especially suitable for clinical practice.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of medical compounds for treating disease of digestive system and its preparation side
A kind of method, and in particular to Vonoprazan fumarate dihydrate and preparation method thereof.
Background technology
Vonoprazan fumarate, chemical entitled 1- [5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3-
Base]-N- methyl methylamine fumarates, its molecular formula is：C17H16FN3O2S·C4H4O4, molecular weight：461.46, chemical constitution is such as
Shown in Formulas I.Vonoprazan fumarate is a kind of new proton pump inhibitor, can be used as acid secretion inhibitors, neoplastic disease or from
The medicine of body immunity disease.Omeprazole etc. can effectively gastric acid secretion inhibiting, but in acidity as proton pump inhibitor
Under the conditions of unstability and because metabolism enzyme polymorphism and drug interaction caused by effect disperse, Vonoprazan fumarate
Excellent in stability in acid condition, to show more excellent therapeutic effect to peptic ulcer, reflux esophagitis etc..
The different crystal forms of one bulk drug can have different chemically and physically characteristics, including fusing point, chemical reactivity, table
See solubility, optically and mechanically rate of dissolution, property, vapour pressure and density.These characteristics can directly affect bulk drug and system
The processing and/or production of agent, and the stability, solubility and bioavilability of preparation can be influenceed.When compound has polycrystalline
During type, because specific polymorph has specific macroscopic property and stability, therefore during preparation, understand
The crystal formation for the compound applied in each formulation is important, to ensure the pharmaceutical activity chemical combination of process application same modality
Thing.Therefore, it is that the known mixtures of single crystal formation or some crystal formations is necessary to keep pharmaceutical active compounds.
The A of patent CN 105315258 disclose Vonoprazan fumarate new crystal formation A, B and suitable industrialized production
Preparation method, the present invention prepares crystal formation preparation technology simply, and stability is good, meets medicinal requirements.Crystal formation A its preparation methods are：
Vonoprazan fumarate free alkali is dissolved in ethyl acetate, fumaric acid methanol solution is added, reaction is stirred at room temperature, is filtered,
Obtain Vonoprazan fumarate A crystal formations after filter cake drying, crystal formation A is 15.290,20.403,20.704,21.572,25.182,
There is characteristic diffraction peak at 25.559, differential scanning calorimetric collection of illustrative plates has absworption peak at 204.8 DEG C.Crystal formation B its preparation methods are：By richness
Horse acid Wo Nuolazan A crystal formations are dissolved in the aqueous solution of C1~C4 alkylol or below C4 the ketone aqueous solution, heating stirring
Dissolving, stirring is let cool；Filtering, Vonoprazan fumarate B crystal form is obtained after filter cake drying, crystal formation B is 12.253,13.559,
15.259th, there is characteristic diffraction peak at 16.889,17.422,20.399,20.764,22.478,25.198,28.077.Differential thermal is swept
Retouch calorimetric collection of illustrative plates has absworption peak at 209.0 DEG C.Two kinds of crystal formations are anhydrous compound after testing.
CN 106478597A disclose a kind of Vonoprazan fumarate monocrystalline and its production and use, and the present invention is rich
Horse acid Wo Nuolazan is easy to separate with other impurities, and obtained Vonoprazan fumarate single crystal forms are good, and HPLC purity can be high
Up to more than 99.5%, and the reappearance of this method is very good.In addition, the fumaric acid prepared using the method for the present invention is irrigated
Nola praises monocrystalline, it is easy to the absolute structure of product is determined by the X-ray diffraction analysis of monocrystalline, and then, using when ensure that
The accuracy of medicine containing Vonoprazan fumarate monocrystalline.The preparation method of this monocrystalline is：To Vonoprazan fumarate crude product
Middle addition recrystallisation solvent first alcohol and water (0.25-4:1, preferably 1:1)；And under predetermined temperature (20-30 degrees Celsius), slowly
Volatilize recrystallisation solvent, and carries out culture 5-10 days, and to obtain crystalline product, the crystalline product constitutes the fumaric acid and irrigates promise
Monocrystalline is praised in drawing.Monocrystalline of the present invention is in the θ=11.4,12.3 of the angle of diffraction 2, and 13.5,15.1,15.3,16.9,18.6,20.4,20.7,
There is characteristic peak at 22.4 and 25.1.It is detected as anhydrous compound.
The A of CN 106317020 disclose a kind of Vonoprazan fumarate crystal formation α and preparation method thereof, and the crystal form purity is high,
And with good chemical stability and stability of crystal form, it is easy to prepare with scale, simple to operate, cost is low, with wide
Application prospect.Crystal formation α preparation method is：Vonoprazan fumarate crude product is added in glycol monoethyl ether, 60 DEG C of heating~
Backflow dissolving, then adds purified water, reaction is stirred at room temperature 1~2 hour, filters, and purifies water washing filter cake, dries, obtain richness
Horse acid Wo Nuolazan crystal formations α.Determined through differential scanning calorimetric analysis (DSC), Vonoprazan fumarate crystal formation α of the invention, with 2
The X-ray powder diffraction (X-RPD) that θ angles are represented at 8.6 ± 0.2 °, 10.2 ± 0.2 °, 12.7 ± 0.2 °, 17.4 ± 0.2 °,
There is diffraction maximum at 18.1 ± 0.2 °, 19.6 ± 0.2 °, 20.3 ± 0.2 °, 23.2 ± 0.2 °, 24.5 ± 0.2 °, 27.8 ± 0.2 °；
There is endothermic peak in the range of 166~204 DEG C in its DSC collection of illustrative plates；Preferably, the peak value of the endothermic peak of its DSC collection of illustrative plates appears in 194
At ± 2 DEG C.It is detected as anhydrous compound.
CN106478601A discloses a kind of Vonoprazan fumarate novel crystal forms, its preparation method with ethyl acetate, methanol,
Purified water is mixed crystallization solvent, obtains the new crystal formation of Vonoprazan fumarate.In its powder x-ray diffraction collection of illustrative plates, spreading out
The θ of firing angle 2 is to have characteristic peak at 12.18 ± 0.5,13.43 ± 0.5,22.35 ± 0.5,37.06 ± 0.5,38.25 ± 0.5.This hair
Bright described novel crystal forms have good stability, and can be prevented effectively from the increase of impurity of the drug, reduce the high cost that storage is brought, for production
The security of product and ensure that clinical efficacy brings effective guarantee.It is detected as anhydrous compound.
The A of CN 104327051 disclose a kind of crystal form of the fumarate of azole derivatives, crystal form A purity
Height, stability is good, is adapted to preparation technical process and long term storage, also has superiority in industrial production.Its preparation method is：
1) by 1- [base of 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3]-N- methyl methylamine list fumarates, or
Person adds 1- [base of 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3]-N- methyl methylamines and fumaric acid respectively
Heat of solution is in appropriate organic solvent, cooling, crystallization, and the organic solvent is selected from alcohols, the ketone that carbon number is less than or equal to 3
Any one or a few mixed solvent of class, esters；Or their mixed solvents with water；Described organic solvent may be selected from
Methanol, ethanol, isopropanol, isobutanol, tert-pentyl alcohol, acetone, butanone, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2- methyl
Tetrahydrofuran, isopropyl ether, methyl tertiary butyl ether(MTBE), methylcyclopentyl ether, acetonitrile, N,N-dimethylformamide, N, N- dimethyl second
Acid amides.2) filtering for crystallizing and wash, dry.Wherein in about 5.1 (17.3), 10.1 (8.7), 11.4 (7.7), 11.5 (7.6),
12.2 (7.3), 13.4 (6.6), 13.9 (6.4), 15.2 (5.8), 16.1 (5.5), 16.6 (5.3), 16.9 (5.3) 17.3
(5.1), 17.8 (5.0), 18.5 (4.8), 19.1 (4.7), 20.0 (4.4), 20.3 (4.4), 20.6 (4.3), 21.0 (4.2),
21.5 (4.1), 22.4 (4.0), 23.0 (3.9), 23.5 (3.8), 24.3 (3.7), 25.1 (3.5), 25.5 (3.5) 26.0
(3.4) there is feature at, 26.7 (3.3), 27.6 (3.2), 27.9 (3.2), 28.8 (3.1), 29.1 (3.1), and 29.9 (3.0) places
Peak.Its fusing point is about 203 DEG C.It is detected as anhydrous compound.
Vonoprazan fumarate is in crystallization, if using different solvent and process conditions, its molecule is in each crystal formation
The number of permutations of structure cell and position and latticed form are different, form different crystal structures, Vonoprazan fumarate polymorphic
Change can change its property, quality and drug effect.Therefore, the stable crystalline of Vonoprazan fumarate, should for further research
The physicochemical properties of compound, study its drug regimen and clinical practice, and tool is of great significance.
Vonoprazan fumarate belongs to insoluble drug, typically applies in solid form in the formulation, the biology of its preparation
Availability quality directly affects its curative effect, and it is more sensitive to illumination, therefore has highly important meaning to the research of its crystal formation
Justice.In addition, impurity present in medicine influences larger thus appropriate impurity-removing method very necessary the quality of product.Due to
Troublesome impurity is more in Vonoprazan fumarate, and prior art does not provide efficient Vonoprazan fumarate purification process,
It is difficult to take into account yield and purity.The special physicochemical property of Vonoprazan fumarate brings greatly tired to the preparation of hydrate
It is difficult.The present invention has carried out substantial amounts of experiment to existing literature technology and has found that obtained Vonoprazan fumarate is equal in the prior art
For anhydrous compound, it is present, and dissolubility is poor, the low problem of purity, the people's drug safety problem having a strong impact on.
The present invention passes through substantial amounts of experimental study, using new method for crystallising, has not only obtained a kind of new fumaric acid and has irrigated
Nola praises crystal formation and contains dimolecular water after measured, the Vonoprazan fumarate dihydrate purity height of the invention provided,
Stability is good, surprisingly finds that the Vonoprazan fumarate dihydrate dissolubility that the present invention is obtained is significantly improved through experiment.This
Invention also discloses the preparation method of Vonoprazan fumarate dihydrate, and the preparation method is simple to operation, reaction condition temperature
With suitable large-scale production.The composition tablet dissolution rate that is made of Vonoprazan fumarate dihydrate of the present invention and stably
Property is significantly improved, and is especially suitable for clinical practice.
The content of the invention
The present invention is intended to provide a kind of Vonoprazan fumarate dihydrate and preparation method thereof, technology to be solved is asked
Topic is the dissolubility and purity for improving Vonoprazan fumarate in water, so as to improve the dissolution rate and biological utilisation of its preparation
Degree, to overcome prior art defect.
In order to realize the purpose of the present invention, the technical scheme used for：
A kind of medical compounds for treating disease of digestive system, the compound is Vonoprazan fumarate dihydrate, its
Molecular formula is：C17H16FN3O2S·C4H4O4·2H2O, structural formula is following (Formula II), its X- represented with the 2 θ ± 0.2 ° angles of diffraction
Ray powder diffraction 6.742 °, 7.036 °, 9.157 °, 10.528 °, 15.194 °, 17.457 °, 20.679 °,
Characteristic diffraction peak is shown at 22.223 °, 27.426 °, 28.621 °, 29.298 °, 35.227 °, 37.136 °.
The X-ray powder that the Vonoprazan fumarate dihydrate that the present invention is provided is obtained using Cu-K alpha ray measurements spreads out
Penetrate figure as shown in Figure 1.
Present invention also offers a kind of preparation method of Vonoprazan fumarate dihydrate, concretely comprise the following steps：
1) Vonoprazan fumarate crude product is dissolved in the mixed solvent, with 220~250 revs/min of speed agitating and heating
It is completely dissolved crude product, to solution clarification, filtering；
2) by solution slow cooling obtained above, when being down to -5~0 DEG C into solution by 2.0~3.0mL/min's
Flow velocity adds the purified water of precooling to crystalline substance is gone out, and continues to be cooled to -20 DEG C~-10 DEG C crystallizations, insulated and stirred to crystallization completely, is supported
It is brilliant；
3) suction filtration, collects crystal, water washing is purified on a small quantity, is dried in vacuo, obtains white crystalline powder.
Preferably, step 1) described in mixed solvent be dimethyl sulfoxide and water mixed solvent；Vonoprazan fumarate is thick
The mass volume ratio of product and mixed solvent is 1g:15~20ml.
Preferably, step 1) described in the mixed solvent, the volume ratio of dimethyl sulfoxide and water is 2~4:1.
Preferably, step 1) described in mixed solvent and step 2) described in the volume ratio of purified water be 1:3~4.
Preferably, step 2) described in cooling extent be every 10 minutes 1 DEG C~3 DEG C, rearing crystal time be 2~4h.
Preferably, step 3) described in vacuum drying refer at 40~50 DEG C be dried in vacuo 4~6h.
In the present invention, described Vonoprazan fumarate crude product can be that Vonoprazan fumarate to be further purified is consolidated
Body mixture Vonoprazan fumarate crude product can also be marketable material or be prepared by art methods, the crystalline substance of gained
Type result is novel crystal forms of the present invention in error range.
The formation mechenism of crystal is very complicated, and the acquisition of a new crystal also has very big contingency, and sometimes different is molten
Agent, identical crystal structure can be produced under different crystallization conditions.Some specific crystal formations also can not necessarily obtain more added with
The physicochemical property of profit.The properties such as stability, hygroscopicity, dissolubility, bioactivity, the toxicity of medicine can be produced because of the difference of crystal formation
Raw huge difference.
The present invention passes through substantial amounts of experiment sieving, by selecting different solvents to dissolve and different solvent crystallizations, obtains
The preparation method of the present invention, by the control to mixing speed, solvent load, temperature and rearing crystal time, is unexpectedly obtained
A kind of Vonoprazan fumarate novel crystal forms, are detected as dihydrate.The Vonoprazan fumarate purity that the present invention is provided is high, steady
It is qualitative good, surprisingly find that the Vonoprazan fumarate dihydrate dissolubility that the present invention is obtained is significantly improved through experiment.This hair
The bright preparation method for also disclosing Vonoprazan fumarate dihydrate, the preparation method is simple to operation, and reaction condition is gentle,
It is adapted to large-scale production.The composition tablet dissolution rate and stability that the Vonoprazan fumarate dihydrate of the present invention is made are aobvious
Write and improve, be especially suitable for clinical practice.
Research shows that in the X-ray powder diffraction pattern, the diffraction spectrogram obtained by novel crystal forms is for specific crystal formation
Often characteristic, the wherein relative intensities of bands of a spectrum (especially in low angle) may because of crystallization condition, particle diameter and its
The difference of its condition determination and the advantage orientation effect that produces and change.Therefore, the relative intensity of diffraction maximum is to targeted crystalline substance
Type is not characteristic, when judging whether identical with known crystal formation, it should be noted that the relative position at peak rather than
Their relative intensity.
Vonoprazan fumarate dihydrate crystallization provided by the present invention confirms that, containing 2 crystallizations water, its character is white
Crystalline powder, the loss that the crystallization water will not occur under the conditions of air drying.And its powder x-ray diffraction collection of illustrative plates with it is existing
Technology has the relative position at visibly different peak, it is seen that it is a kind of novel crystal forms unlike the prior art.
Carry out explanation and illustration below by being studied the Vonoprazan fumarate dihydrate crystal formation that the present invention is provided
Technical solution of the present invention：
1st, elementary analysis C17H16FN3O2S·C4H4O4·2H2O
Instrument：VarioELcube elemental analysers；It is C, H, O, N, S to measure element；
DIOENXDX-500 type ion chromatographs；Measurement element is F.
Elementary analysis (%) theoretical value：H (4.86), C (50.70), N (8.45), O (25.73), S (6.44), F
(3.82)。
Elementary analysis (%) measured value is：H (4.86), C (50.69), N (8.44), O (25.72), S (6.46), F
(3.83)。
It is consistent substantially with the theoretical value of elementary analysis.
2nd, crystal formation is detected
Take the Vonoprazan fumarate crystallization that the present invention is prepared, the X-ray powder obtained using Cu-K alpha ray measurements
Last diffraction pattern as shown in figure 1, its X-ray powder diffraction figure for being represented with the angles of diffraction of 2 θ ± 0.2 6.742 °, 7.036 °,
9.157°、10.528°、15.194°、17.457°、20.679°、22.223°、27.426°、28.621°、29.298°、
Characteristic peak is shown at 35.227 °, 37.136 °.
3rd, differential thermal analysis and thermogravimetric analysis
Differential thermal and thermogravimetric analysis are carried out to Vonoprazan fumarate crystal prepared by the present invention, as a result such as the institute of accompanying drawing 2 and 3
Show；As a result show, this product is in 110 DEG C or so the quick weight for losing about 2 hydrones；This product has heat absorption at about 213.5 DEG C
Peak, it is demonstrated for a kind of different crystal formation from side.
4th, water analysis
Determined using cassette moisture teller, the water content of fumaric acid Wo Nuola dihydrates of the invention is 7.25-
7.27%, it is consistent with the theoretical water content 7.24% of dihydrate, it was demonstrated that the present invention contains the crystallization water of 2 molecules.
5th, purity detecting
Through HPLC purity detectings, the purity of the Vonoprazan fumarate crystallization that the present invention is prepared can reach 99.97~
99.99%.
6th, fusing point is detected
The Vonoprazan fumarate dihydrate for taking the present invention to prepare is detected that fusing point is 212~214 DEG C.
Compared with prior art, the invention has the advantages that：
(1) Vonoprazan fumarate provided by the present invention is a kind of novel crystal forms different from prior art, is detected as
Dihydrate；The preparation method of Vonoprazan fumarate dihydrate provided by the present invention is simple to operation, reaction condition temperature
With suitable large-scale production.
(2) the Vonoprazan fumarate dihydrate purity height of the invention provided, stability are good, are surprisingly found through experiment
The Vonoprazan fumarate dihydrate dissolubility that the present invention is obtained is significantly improved.The Vonoprazan fumarate two of the present invention is hydrated
The composition tablet dissolution rate and stability that thing is made are significantly improved, and are especially suitable for clinical practice.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction collection of Vonoprazan fumarate dihydrate prepared by the embodiment of the present invention 1.
Fig. 2 is the thermogravimetric analysis TGA collection of illustrative plates of Vonoprazan fumarate dihydrate prepared by the embodiment of the present invention 1.
Fig. 3 is the DSC collection of illustrative plates of Vonoprazan fumarate dihydrate prepared by the embodiment of the present invention 1.
Specific embodiment
Technical scheme is described in detail with embodiment below, it will help to technical scheme
Advantage, effect have and further understand, embodiment does not limit protection scope of the present invention, and protection scope of the present invention is by weighing
Profit requires to determine.
The preparation of embodiment 1, Vonoprazan fumarate dihydrate
1) Vonoprazan fumarate crude product 100g is dissolved in the dimethyl sulfoxide and water (dimethyl sulfoxide of (1500ml)：Water=2:
1) in the mixed solvent, crude product is completely dissolved with 220 revs/min of speed agitating and heating, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 3 DEG C of speed slow coolings, when being down to 0 DEG C into solution by
2.0mL/min flow velocity adds the purified water 6000ml of precooling to crystalline substance is gone out, and continues to be cooled to -20 DEG C of crystallizations, insulated and stirred to analysis
It is brilliant complete, growing the grain 2h；
3) suction filtration, collects crystal, purifies be dried in vacuo 4h at water washing, 50 DEG C on a small quantity, obtain white crystalline powder
99.90g, yield 99.90%, purity 99.98%.
The X-ray powder diffraction spectrogram that obtained white crystalline powder is obtained using Cu-K alpha ray measurements is shown in Fig. 1.
The preparation of embodiment 2, Vonoprazan fumarate dihydrate
1) Vonoprazan fumarate crude product 100g is dissolved in 2000ml dimethyl sulfoxide and water (dimethyl sulfoxide：Water=3:1)
In the mixed solvent, be completely dissolved crude product with 250 revs/min of speed agitating and heating, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 1 DEG C of speed slow coolings, when being down to -5 DEG C into solution by
2.2mL/min flow velocity adds the purified water 6000ml of precooling to crystalline substance is gone out, and continues to be cooled to -15 DEG C of crystallizations, insulated and stirred to analysis
It is brilliant complete, growing the grain 4h；
3) suction filtration, collects crystal, purifies be dried in vacuo 5h at water washing, 45 DEG C on a small quantity, obtain white crystalline powder
99.91g, yield 99.91%, purity 99.99%.
The X-ray powder diffraction spectrogram that obtained white crystalline powder is obtained using Cu-K alpha ray measurements is with implementing
Example 1 is similar.
The preparation of embodiment 3, Vonoprazan fumarate dihydrate
1) Vonoprazan fumarate crude product 100g is dissolved in 1800ml dimethyl sulfoxide and water (dimethyl sulfoxide：Water=3:1)
In the mixed solvent, be completely dissolved crude product with 240 revs/min of speed agitating and heating, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 2 DEG C of speed slow coolings, when being down to -3 DEG C into solution by
2.5mL/min flow velocity adds the purified water 6300ml of precooling to crystalline substance is gone out, and continues to be cooled to -15 DEG C of crystallizations, insulated and stirred to analysis
It is brilliant complete, growing the grain 3h；
3) suction filtration, collects crystal, purifies be dried in vacuo 5h at water washing, 45 DEG C on a small quantity, obtain white crystalline powder
99.94g, yield 99.94%, purity 99.99%.
The X-ray powder diffraction spectrogram that obtained white crystalline powder is obtained using Cu-K alpha ray measurements is with implementing
Example 1 is similar.
The preparation of embodiment 4, Vonoprazan fumarate dihydrate
1) Vonoprazan fumarate crude product 100g is dissolved in the dimethyl sulfoxide and water (dimethyl sulfoxide of (1700ml)：Water=4:
1) in the mixed solvent, crude product is completely dissolved with 230 revs/min of speed agitating and heating, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 3 DEG C of speed slow coolings, when being down to -2 DEG C into solution by
2.7mL/min flow velocity adds the purified water 5950ml of precooling to crystalline substance is gone out, and continues to be cooled to -10 DEG C of crystallizations, insulated and stirred to analysis
It is brilliant complete, growing the grain 2h；
3) suction filtration, collects crystal, purifies be dried in vacuo 6h at water washing, 40 DEG C on a small quantity, obtain white crystalline powder
99.89g, yield 99.89%, purity 99.97%.
The X-ray powder diffraction spectrogram that obtained white crystalline powder is obtained using Cu-K alpha ray measurements is with implementing
Example 1 is similar.
The preparation of embodiment 5, Vonoprazan fumarate dihydrate
1) Vonoprazan fumarate crude product 100g is dissolved in the dimethyl sulfoxide and water (dimethyl sulfoxide of (1900ml)：Water=3:
1) in the mixed solvent, crude product is completely dissolved with 250 revs/min of speed agitating and heating, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 2 DEG C of speed slow coolings, when being down to -1 DEG C into solution by
2.9mL/min flow velocity adds the purified water 7600ml of precooling to crystalline substance is gone out, and continues to be cooled to -18 DEG C of crystallizations, insulated and stirred to analysis
It is brilliant complete, growing the grain 3h；
3) suction filtration, collects crystal, purifies be dried in vacuo 5h at water washing, 50 DEG C on a small quantity, obtain white crystalline powder
99.93g, yield 99.93%, purity 99.99%.
The X-ray powder diffraction spectrogram that obtained white crystalline powder is obtained using Cu-K alpha ray measurements is with implementing
Example 1 is similar.
The preparation of embodiment 6, Vonoprazan fumarate dihydrate
1) Vonoprazan fumarate crude product 100g is dissolved in the dimethyl sulfoxide and water (dimethyl sulfoxide of (1600ml)：Water=2:
1) in the mixed solvent, crude product is completely dissolved with 220 revs/min of speed agitating and heating, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 1 DEG C of speed slow coolings, when being down to -4 DEG C into solution by
3.0mL/min flow velocity adds the purified water 4800ml of precooling to crystalline substance is gone out, and continues to be cooled to -12 DEG C of crystallizations, insulated and stirred to analysis
It is brilliant complete, growing the grain 4h；
3) suction filtration, collects crystal, purifies be dried in vacuo 6h at water washing, 40 DEG C on a small quantity, obtain white crystalline powder
99.90g, yield 99.90%, purity 99.97%.
The X-ray powder diffraction spectrogram that obtained white crystalline powder is obtained using Cu-K alpha ray measurements is with implementing
Example 1 is similar.
The present invention is further illustrated below by experimental example：
Experimental example 1：Solvent screening is tested
Operated using the preparation method of the present invention, it is specific as follows：
1) Vonoprazan fumarate crude product 100g is dissolved in 1500ml solvent orange 2 A and solvent B in the mixed solvent, with 240
Rev/min speed agitating and heating be completely dissolved crude product, to solution clarification, filtering；
2) by solution obtained above with every 10 minutes 1 DEG C of speed slow coolings, when being down to -5 DEG C into solution by
3.0mL/min flow velocity adds the solvent C of precooling to crystalline substance is gone out, and continues to be cooled to -15 DEG C of crystallizations, insulated and stirred is complete to crystallization,
Growing the grain 3h；
3) suction filtration, collects crystal, purifies be dried in vacuo 5h at water washing, 45 DEG C on a small quantity, obtain white crystalline powder.
The solvent screening experimental result of table 1
Inventor is screened during solvent screening to most of organic solvents, different combination crystallization effects
Difference, only enumerates the data of part screening test herein.
Inventor surprisingly has found to irrigate promise in dimethyl sulfoxide and water mixed solvent system dissolving fumaric acid in process of the test
Crude product is praised in drawing, and brilliant with elutriation, and effect is more preferable relative to other alone dicyandiamide solutions.Then further to dimethyl sulfoxide and water
The ratio of mixed solvent is screened, and is found when the volume ratio of dimethyl sulfoxide and water is less than 2:1 or more than 4:When 1, its yield
It is a bit weaker with purity.When the volume ratio of dimethyl sulfoxide and water is 2~4:When 1, effect is best, and not only purity is high, yield
Height, and surprisingly find that its dissolubility is significantly improved by experiment.Therefore final determination selection is with dimethyl sulfoxide：Water 2~4:1 is
Dissolution solvent, add water crystallization, to do further screening.
Experimental example 2：Crystallization trial conditional filtering
1) Vonoprazan fumarate crude product 100g is dissolved in the in the mixed solvent of dimethyl sulfoxide and water, agitating and heating makes crude product
It is completely dissolved, to solution clarification, filtering；
2) by solution slow cooling obtained above, the purified water of precooling is added extremely into solution when being down to -5~0 DEG C
Go out crystalline substance, continue the crystallization that cools, insulated and stirred is complete to crystallization, growing the grain；
3) suction filtration, collects crystal, water washing is purified on a small quantity, is dried in vacuo, obtains white crystalline powder.
Table 2-1 crystallization trial conditional filtering results
Table 2-2 crystallization trial conditional filtering results
Table 2-3 crystallization trial conditional filtering results
Table 2-4 crystallization trial conditional filtering results
Screening test on crystallization trial condition is extremely complex, and we only enumerate A partial experiment knot therein herein
Really.There is too many variable, the change of each technological parameter in the crystallization process that can be seen that crystal from above-mentioned result of the test
May all influence be produced on result.Inventor passes through lot of experiments, the technique that technical solution of the present invention is finally determined.
Experimental example 3：Solubility test
Trial target：Sample prepared by 1-6 of the embodiment of the present invention；
Reference substance 1：The Vonoprazan fumarate crystal form A prepared with reference to the A embodiments 1 of patent CN 104327051.
Reference substance 2：The Vonoprazan fumarate crystal formation A prepared with reference to the A embodiments 1 of patent CN 105315258.
Reference substance 3：The Vonoprazan fumarate crystal formation B prepared with reference to the A embodiments 2 of patent CN 105315258.
Reference substance 4：The Vonoprazan fumarate crystal formation α prepared with reference to the A embodiments 1 of patent CN 106317020.
Reference substance 5：The Vonoprazan fumarate monocrystalline prepared with reference to patent CN 106478597A embodiments 2.
Reference substance 6：The Vonoprazan fumarate crystal formation prepared with reference to patent CN106478601A embodiments.
Reference substance 7：The Vonoprazan fumarate prepared with reference to the A embodiments 1 of patent CN 105085484.
Reference substance 8：The Vonoprazan fumarate crystal prepared with reference to the A embodiments one of patent CN 105130955.
Reference substance 9：The Vonoprazan fumarate crystal prepared with reference to the A embodiments 13 of patent CN 105294653.
Reference substance 10：The Vonoprazan fumarate crystal prepared with reference to patent CN106366071A embodiments 10.
Reference substance 11：The Vonoprazan fumarate crystal prepared with reference to the A embodiments 1 of patent CN 104860926.
Reference substance 12：The Vonoprazan fumarate crystal prepared with reference to patent 101300229A embodiments 8.
Its dissolubility, method are determined with reference to Chinese Pharmacopoeia two notes on the use of version in 2015：Take this product appropriate, be separately added into water,
Every strength shaking in 5 minutes 30 seconds, the dissolving situation in 30 minutes is observed, produces, the results are shown in Table 3.
Crystal formation and reference substance the dissolubility test result in water of the present invention of table 3
Above-described embodiment 1-6 aqueous samples dissolved are stirred 72 hours in 25 DEG C of constant temperature, 5ml is sampled.Sample is passed through
0.45 μm of filtering with microporous membrane, discards primary filtrate, and it is solubility (mg/ml) in water to take the μ L of subsequent filtrate 20 to determine medicament contg.
It the results are shown in Table 4：
Solubility of the crystal formation of the present invention of table 4 with prior art crystal formation in water is contrasted
As can be seen from the above table, at 25 DEG C, the solubility in water of Vonoprazan fumarate novel crystal forms of the present invention is with showing
There is technology to compare, be significantly increased, achieve unexpected technique effect.
Experimental example 4：Stability test
Experimental example investigates the stabilization for the Vonoprazan fumarate crystallization that the present invention is provided by accelerated test and long term test
Property.
1st, accelerated test
Sample prepared by Example 1-3, is placed 6 months under conditions of 40 ± 2 DEG C of temperature, relative humidity 75 ± 5%,
Respectively at 0,1,2,3,6 the end of month character, relevant material, content is measured by sampling, the results are shown in Table 5.
Table 5：Accelerated test result (40 ± 2 DEG C of temperature, relative humidity 75 ± 5%)
As seen from Table 5, Vonoprazan fumarate crystallization of the present invention is in 40 ± 2 DEG C of temperature, the condition of relative humidity 75 ± 5%
Lower to place 6 months, relevant content of material does not have significantly raised, and each index has no significant change, and water content is stable (two molecular waters),
It is that the crystallization water is not absorption water to demonstrate the water in the compound from another point of view.
2nd, long term test
Sample prepared by Example 1-3, is placed 6 months under conditions of 25 ± 2 DEG C of temperature, relative humidity 60 ± 5%,
Respectively at 0,3,6,9,12,18,24 the end of month character, relevant material, content is measured by sampling, the results are shown in Table 6.
Table 6：Long-term test results (25 ± 2 DEG C of temperature, relative humidity 60 ± 5%)
As seen from Table 6, Vonoprazan fumarate crystallization of the present invention is in 25 ± 2 DEG C of temperature, the condition of relative humidity 60 ± 5%
Lower to place 24 months stabilizations, each index has no significant change, and water content is stable (two molecular waters), and the change is demonstrated from another point of view
Water in compound is that the crystallization water is not absorption water.
Other embodiment accelerates consistent with long term test testing result.
Claims (8)
1. a kind of medical compounds for treating disease of digestive system, it is characterised in that described compound is fumaric acid Wo Nuola
Dihydrate is praised, its molecular formula is：C17H16FN3O2S·C4H4O4·2H2O, its X-ray represented with the 2 θ ± 0.2 ° angles of diffraction
Powder diffraction spectrum 6.742 °, 7.036 °, 9.157 °, 10.528 °, 15.194 °, 17.457 °, 20.679 °, 22.223 °,
Characteristic diffraction peak is shown at 27.426 °, 28.621 °, 29.298 °, 35.227 °, 37.136 °.
2. a kind of medical compounds for treating disease of digestive system as claimed in claim 1, it is characterised in that use Cu-K α
The X-ray powder diffraction figure that radionetric survey is obtained is as shown in Figure 1.
3. a kind of preparation method for the medical compounds for treating disease of digestive system as claimed in claim 1 or 2, its feature exists
In comprising the following steps：
1) Vonoprazan fumarate crude product is dissolved in the mixed solvent, made slightly with 220~250 revs/min of speed agitating and heating
Product are completely dissolved, to solution clarification, filtering；
2) by solution slow cooling obtained above, the flow velocity when being down to -5~0 DEG C into solution by 2.0~3.0mL/min
The purified water of precooling is added to crystalline substance is gone out, continues to be cooled to -20 DEG C~-10 DEG C crystallizations, insulated and stirred is complete to crystallization, growing the grain；
3) suction filtration, collects crystal, water washing is purified on a small quantity, is dried in vacuo, obtains white crystalline powder.
4. a kind of preparation method for the medical compounds for treating disease of digestive system as claimed in claim 3, it is characterised in that：
Step 1) described in mixed solvent be dimethyl sulfoxide and water mixed solvent；The matter of Vonoprazan fumarate crude product and mixed solvent
Amount volume ratio is 1g:15~20ml.
5. a kind of preparation method for the medical compounds for treating disease of digestive system as claimed in claim 3, it is characterised in that：
Step 1) described in the mixed solvent, the volume ratio of dimethyl sulfoxide and water is 2~4:1.
6. a kind of preparation method for the medical compounds for treating disease of digestive system as claimed in claim 3, it is characterised in that：
Step 1) described in mixed solvent and step 2) described in the volume ratio of purified water be 1:3~4.
7. a kind of preparation method for the medical compounds for treating disease of digestive system as claimed in claim 3, it is characterised in that：
Step 2) described in cooling extent be every 10 minutes 1 DEG C~3 DEG C, rearing crystal time be 2~4h.
8. a kind of preparation method for the medical compounds for treating disease of digestive system as claimed in claim 3, it is characterised in that：
Step 3) described in vacuum drying refer at 40~50 DEG C be dried in vacuo 4~6h.
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| CN107098862A (en) * | 2017-06-05 | 2017-08-29 | 山东裕欣药业有限公司 | A kind of olaparib dihydrate and preparation method thereof |
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