CN105566346A - (5-(2-cyanobenzyl)-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine-2-yl)acetate crystal form I and preparation method and application thereof - Google Patents
(5-(2-cyanobenzyl)-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine-2-yl)acetate crystal form I and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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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 invention belongs to the technical field of medicine, in particular provides a (5-(2-cyanobenzyl)-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine-2-yl)acetate crystal form I. The invention further provides a preparation method of the crystal form and application of the crystal form in the preparation of a medicine composition for inhibiting platelet aggregation. The formula of the crystal form is shown in the description.
Description
Technical field
The invention belongs to medical art, or rather, relate to a kind of (5-(2-itrile group benzyl)-4 with antiplatelet aggregative activity, 5,6,7-tetramethylene sulfide is [3,2-c] pyridine-2-base also) crystalline form I of acetic ester and its preparation method and application.
Background technology
The formation of thrombus can cause the heart, brain, the pulmonary circulation illness such as Acute Myocardial Infarction, apoplexy, pulmonary infarction, the health and lives of the serious threat mankind, is also one of factor inaccessible again after complication common in surgical operation and interventional angioplasty.
Cause thrombotic a lot because have, the activation of the adhesion of such as thrombocyte on the vessel wall surface of damage and gathering, blood stream stasis, thrombin impels the formation of zymoplasm, antiplasmin activity low inferior.In above-mentioned factor, thrombocyte is thrombotic required material, therefore suppresses hematoblastic gathering to be one of important means of prevention and therapy thrombus disease.
The present inventor once have submitted Chinese invention patent application (publication number: CN102241690) with regard to " thienopyridine ester derivative, the Preparation Method And The Use of a class nitrile group-containing ".A kind of chemical structural formula of this disclosure of the invention is such as formula the compound shown in I: (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-base) acetic ester (hereinafter referred to as type I compound).
Above invention discloses compound (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic ester is effective for the disease that causes because of platelet aggregation of the treatment mankind, such as thrombotic diseases.
Above-mentioned patent " thienopyridine ester derivative, the Preparation Method And The Use of a class nitrile group-containing " also discloses (5-(2-itrile group benzyl)-4 simultaneously, 5,6,7-tetramethylene sulfide is [3,2-c] pyridine-2-base also) preparation method of acetic ester:
2.7g intermediate is added in the reaction flask that stirring, condenser, thermometer are housed
1, dissolved with 10mL methylene dichloride, under stirring, added sodium hydroxide 1.2g.Reaction system is cooled to-20 DEG C, 1.02g diacetyl oxide is added reaction system in batches.Add, under room temperature, continue stirring reaction 1h (flaggy display reacts completely).With 3 × 15mL water washing reaction solution, divide and get dichloromethane layer, fully dry by anhydrous sodium sulphate, filter, methylene dichloride is to the greatest extent steamed in decompression, and post separation, obtains white solid product (HPLC:99.6%).Rf=0.58 [single-point, developping agent: v (sherwood oil): v (ethyl acetate)=4:1].
1HNMR(DMSO-d6，400MHz)δ：2.253(s，3H)，2.700(s，2H)，2.767～2.780(d，2H)，3.402(s，2H)，3.816(s，2H)，6.421(s，1H)，7.452～7.489(t，1H)，7.606～7.625(d,1H)，7.660～7.697(t,1H)，7.803～7.822(d，1H)。MS，m/Z：312.0(M)。
In research afterwards, repeat above-mentioned preparation method, the product fusing point obtained is 85 DEG C-85.5 DEG C, and it characterizes, as accompanying drawing 1 (hereinafter referred to as patent CN102241690 crystal formation) with X-powdery diffractometry.
Contriver finds in research process, obtains a kind of new crystal being different from above-mentioned white solid product with refining methanol.This crystal formation has embodied the technical superiority being better than prior art CN102241690 crystal formation, has therefore also applied for new crystal patent.
(5-(2-itrile group benzyl)-4 is disclosed in patent " crystal formation of (5-(2-itrile group benzyl)-4; 5; 6; 7-tetramethylene sulfide is [3_2-c] pyridine-2-base also) acetic ester " (CN104098586), 5,6,7-tetramethylene sulfide is [3,2-c] pyridine-2-base also) a kind of crystal formation of acetic ester:
Oblique system, P21/n spacer, the molecule number in structure cell is 4,
a＝14.174(3)A，alpha＝90deg.，
b＝5.9321(12)A，beta＝99.06(3)deg.，
c＝18.796(4)A，gamma＝90deg.，
Unit cell volume 1560.7 (5)
Packing of molecules in structure cell is shown in accompanying drawing 2.
It characterizes, as accompanying drawing 3 with X-powdery diffractometry.
The preparation method of crystal, is characterized in that: type I compound added in the methyl alcohol of 8 times (weight or measurement (WM) ratios), be stirred and heated to 60 DEG C, after dissolving completely, filter, filtrate room temperature places 20-24 hour, crystallization.Leach this crystallization, obtain through indoor seasoning.Purity (HPLC:99.0%), fusing point: 91.1-91.8 DEG C.
Be called as polytropism with the ability that different crystal forms compound structure exists, known its is present in many organic compound.These different crystal formations are referred to as " polymorphic form ", and different in the accumulation mode of its crystalline solid state, geometry arrangement and other descriptive nature.Different polymorphic forms has different lattice energies, and it illustrates different physical propertiess when solid-state thus, such as shape, color density, hardness, deformability, stability and solvability etc.
For this reason, present inventors studied 5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-2-base also) heteromorphism of acetic ester, and wish to find there is the crystal habit of excellent physico-chemical property, thus provide more material choice for medicine manufacture.
Summary of the invention
The object of the invention is to the defect overcoming above two kinds of known crystal formation existence, provide a kind of new crystal of formula I compound, this crystal formation has stable apparent condition and good long-term storing stability, can stably the supply system for bulk drug.Present invention also offers the preparation method and application of this crystal formation.
A further object of the invention is, provide the application of formula I compound as antiplatelet drug aspect, particularly at the coronary syndrome caused because of platelet aggregation for the preparation of prevention or treatment, myocardial infarction, the purposes of the cardiovascular and cerebrovascular diseases medicament aspects such as myocardial ischemia.
The present invention is specifically related to the crystal formation of the compound of structure shown in formula I:
The i.e. crystalline form I of (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-base) acetic ester, is characterized in that:
Measure with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, the diffraction angle (2 θ) that its collection of illustrative plates has, as shown in Figure 4, the error of 2 θ is ± 0.2 for spacing (d value) and intensity (%).
According to crystal formation of the present invention, wherein, the fusing point of this crystal formation can be 87.2-87.9 DEG C.In addition, the purity of this crystal formation can be 99.0% or more.
According to crystal formation of the present invention, wherein, the X powder diffraction of this crystal formation can be as shown in Figure 4.
Present invention also offers the method for the preparation of above-mentioned crystal formation, the method comprises the following steps:
The crystalline form I of type I compound is that crystallization obtains in the mixed solution of acetonitrile-water.The usage quantity of mixed solution is 2 ~ 8 times (volume-mass ratio, mL/g) of type I compound quality, wherein preferably 6 times.
Water accounts for 10% ~ 20% of mixed solution cumulative volume; Preferably 15%.
Temperature during dissolving is 30 DEG C ~ 65 DEG C, preferably 50 DEG C.Then Temperature fall is to room temperature, places 3 ~ 7 hours, preferably places 5 hours; Namely the New crystal form I type of type I compound is obtained.
Specific operation process is:
Get a certain amount of type I compound, add acetonitrile-water mixed liquid, heated and stirred, after dissolving, naturally cool to room temperature.Separate out solid, filter, obtain type I compound crystalline form I.
Purity (HPLC:99.8%), fusing point: 87.2-87.9 DEG C.
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition includes above-mentioned crystal formation and one or more pharmaceutically acceptable auxiliary materials of effective amount.Described pharmaceutically acceptable auxiliary material can be the matrix or the auxiliary material that keep pharmaceutical dosage form, by selecting according to different medicaments or combinationally use, optionally comprise carrier, vehicle, thinner, weighting agent, tackiness agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material etc.Vehicle comprises the composition of one or more in such as Microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, dextran, N.F,USP MANNITOL, sorbyl alcohol, glucose, fructose, water, polyoxyethylene glycol, propylene glycol, glycerine, cyclodextrin, cyclodextrin derivative.Weighting agent comprises the composition of one or more of such as lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium carbonate, Microcrystalline Cellulose.Tackiness agent comprises the composition of one or more of such as sucrose, starch, polyvidone, Xylo-Mucine, carboxylic third methylcellulose, carboxylic third Mierocrystalline cellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water.Disintegrating agent comprises the composition of one or more of such as starch, polyvinylpolypyrrolidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
According to pharmaceutical composition of the present invention, wherein, described pharmaceutical composition can be solid orally ingestible, liquid oral medicine or injection.Preferably, described solid orally ingestible comprises dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule or granule; Described liquid oral medicine comprises oral solution; Described injection comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
The crystal formation that present invention also offers above-mentioned crystal formation or prepare according to aforesaid method of the present invention is for the preparation of the purposes in the pharmaceutical composition of platelet aggregation-against.In addition, the purposes of crystal formation in the pharmaceutical composition of the coronary syndrome caused because of platelet aggregation-against for the preparation for the treatment of, myocardial infarction, myocardial ischemia, cardiovascular and cerebrovascular diseases that present invention also offers above-mentioned crystal formation or prepare according to aforesaid method of the present invention.The present inventor confirms by assembling restraining effect experiment to mouse platelets, the crystal formation of formula I compound of the present invention has the platelet aggregation of obvious anti-ADP induction, and therefore it can be used for preventing or treating the cardiovascular and cerebrovascular diseases such as coronary syndrome, myocardial infarction, myocardial ischemia caused because of platelet aggregation.
Crystal formation of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 10mg-500mg, is divided into once or administration for several times.The actual dosage taking crystal formation of the present invention can be decided according to relevant situation by doctor.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
Compared with the white solid product of the formula I compound obtained by direct solvent evaporated (as methylene dichloride) mode, the crystal formation prepared by the present invention batch between there is good appearance stability and circulation ratio.Such as, the present inventor found through experiments, this crystal formation continuous production 7 batches batch within the scope of, its outward appearance is stable, is all normal white solids, and often to criticize after measured are all stable crystal formations (test result is as shown in table 1).
Table 1 stability of crystal form is tested
In addition, crystal formation of the present invention also has good long-term storing stability.Such as, the present inventor verifies by experiment, and this crystal formation schedules to last trimestral in light, heat, wet stability experiment, and its impurity is not significantly increased, and thus has more good long term storage stability.
Based on above-mentioned feature, crystal formation of the present invention as the stable supplying source of formula I raw materials of compound medicine, can be more suitable for suitability for industrialized production.
Meanwhile, in view of crystal formation of the present invention has good permanent stability, can affirm, with it for the preparation that raw material obtains should have the longer limited time limit, simultaneously also lower to the requirement of preservation condition.
Accompanying drawing explanation
Below, describe embodiment of the present invention in detail by reference to the accompanying drawings, wherein:
Fig. 1 shows the X-ray powder diffraction pattern being obtained crystal formation by patent CN102241690 method;
Fig. 2 shows the structure cell packing of molecules figure being obtained crystal formation by patent CN104098586 method;
Fig. 3 shows the X-ray powder diffraction pattern being obtained crystal formation by patent CN104098586 method;
Fig. 4 shows the X-ray powder diffraction pattern of crystalline form I.
Embodiment
Further illustrate the present invention below by specific embodiment, but should be understood to, these embodiments are only used for the use specifically described more in detail, and should not be construed as limiting the present invention in any form.
General description is carried out to the material used in the present invention's test and test method in this part.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and working method are well known in the art.
With the following Examples, the condition determination of the present invention to crystal formation is as follows:
Measure with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, the diffraction angle (2 θ) that its collection of illustrative plates has, as shown in Figure 3, the error of 2 θ is ± 0.2 for spacing (d value) and intensity (%).
Fusing point test:
Instrument: YTR-3 type melting point apparatus (purchased from Precision Instrument Factory, Tianjin Univ.)
High performance liquid chromatography (HPLC) condition:
Chromatographic column: C
18, 150mm × 4.6mm, 5um
Moving phase: methyl alcohol: water: acetic acid=70:30:0.25
Wavelength: 230nm
Flow velocity: 0.8ml/min
Sample size: 10uL
Column temperature: 35 DEG C
Instrument:
Generally analyse general L6 liquid chromatograph
Hitachi L-7250 automatic sampler
Generally analyse general LCWin chromatographic working station
embodiment 1
The present embodiment is for illustration of the crystal formation of (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-base) of the present invention acetic ester and preparation process thereof.
Preparation (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-base) acetic ester is as raw material.Its preparation process can with reference to the reaction process recorded in the open CN102241690 of Chinese invention patent.Such as, its reaction process can be:
Intermediate
1preparation:
In the reaction flask that stirring, condenser, thermometer are housed, add 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2 (4H)-one 19.2g, dissolved with 70mL acetonitrile, under stirring, be cooled to-10 DEG C, add Anhydrous potassium carbonate 41.5g.2-cyano-benzyl bromide 19.6g is added in reaction system in batches, finishes and be warming up to 45 DEG C of continuation reaction 4h (flaggy display reacts completely).Filter, filtrate solvent evaporated acetonitrile, adds 50mL methylene dichloride, with 3 × 50mL water washing reaction solution, divide and get dichloromethane layer, fully dry by anhydrous sodium sulphate, filter, methylene dichloride is to the greatest extent steamed in decompression, obtains yellow oil product 22.6g (HPLC:97.2%).Rf=0.47 [single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 2].MS，m/Z：270.0(M)。
The preparation of formula (I) compound ((5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-base) acetic ester):
The above-mentioned obtained intermediate of 2.7g is added in the reaction flask that stirring, condenser, thermometer are housed
1, dissolved with 10mL methylene dichloride, under stirring, added sodium hydroxide 1.2g.Reaction system is cooled to-20 DEG C, 1.02g diacetyl oxide is added reaction system in batches.Add, under room temperature, continue stirring reaction 1h (flaggy display reacts completely).With 3 × 15mL water washing reaction solution, divide and get dichloromethane layer, fully dry by anhydrous sodium sulphate, filter, methylene dichloride is to the greatest extent steamed in decompression, and post separation, obtains white solid product (HPLC:99.6%).Rf=0.58 [single-point, developping agent: v (sherwood oil): v (ethyl acetate)=4:1].
1HNMR(DMSO-d6，400MHz)δ：2.253(s，3H)，2.700(s，2H)，2.767～2.780(d，2H)，3.402(s，2H)，3.816(s，2H)，6.421(s，1H)，7.452～7.489(t，1H)，7.606～7.625(d,1H)，7.660～7.697(t,1H)，7.803～7.822(d，1H)。MS，m/Z：312.0(M)。
To the white solid product (5-(2-itrile group benzyl)-4 of above-mentioned gained, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic ester carry out X-ray powder diffraction (PXRD) characterize, its PXRD collection of illustrative plates is as shown in Figure 1.Repeat above-mentioned preparation method, the fusing point measuring the white solid product of gained is 85-85.5 DEG C.
The preparation of crystal formation of the present invention:
Get the white solid ((5-(2-itrile group benzyl)-4 that 3g aforesaid method is obtained, 5,6,7-tetramethylene sulfide is [3,2-c] pyridine-2-base also) acetic ester), add the mixed solution (water accounts for 10% of mixed solution cumulative volume) of the acetonitrile-water of 6ml, under agitation be heated to 65 DEG C, make it all dissolve, filter, get filtrate; Gained filtrate is at room temperature placed 3h crystallization, collected by filtration, dry, obtain crystal 2.83g of the present invention.
The fusing point recording this crystal formation is 87.3-87.5 DEG C, and the purity using HPLC to record this crystal formation is 99.9%.
embodiment 2
The present embodiment is for illustration of the crystal formation of (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-base) of the present invention acetic ester and preparation process thereof.
According to method preparation formula (I) compound in the same manner as in Example 1 as raw material.
Get the white solid (5-(2-itrile group benzyl)-4 that 3g aforesaid method is obtained, 5,6,7-tetramethylene sulfide is [3,2-c] pyridine-2-base also) acetic ester, add the mixed solution (water accounts for 15% of mixed solution cumulative volume) of the acetonitrile-water of 18ml, under agitation be heated to 50 DEG C, make it all dissolve, filter, get filtrate; Gained filtrate is at room temperature placed 5h crystallization, collected by filtration, dry, obtain crystal 2.76g of the present invention.
The fusing point recording this crystal formation is 87.2-87.5 DEG C, and the purity using HPLC to record this crystal formation is 99.8%.
embodiment 3
The present embodiment is for illustration of the crystal formation of (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-base) of the present invention acetic ester and preparation process thereof.
According to method preparation formula (I) compound in the same manner as in Example 1 as raw material.
Get the white solid (5-(2-itrile group benzyl)-4 that 3g aforesaid method is obtained, 5,6,7-tetramethylene sulfide is [3,2-c] pyridine-2-base also) acetic ester, add the mixed solution (water accounts for 20% of mixed solution cumulative volume) of the acetonitrile-water of 24ml, under agitation be heated to 30 DEG C, make it all dissolve, filter, get filtrate; Gained filtrate is at room temperature placed 7h crystallization, collected by filtration, dry, obtain crystal 2.92g of the present invention.
The fusing point recording this crystal formation is 87.4-87.6 DEG C, and the purity using HPLC to record this crystal formation is 99.9%.
embodiment 4
The present embodiment is for illustration of the preparation of the tablet containing crystal formation of the present invention.
Obtained for embodiment 1 sample crystal formation, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add the solution containing recipe quantity polyvinylpyrrolidone with recipe quantity, mixing, softwood processed, sieves, wet granular processed, in 50-60 DEG C of drying; Then Sodium carboxymethyl starch, Magnesium Stearate and talcum powder are sieved in advance, join in above-mentioned dried particle with recipe quantity, compressing tablet, obtains the tablet containing crystal formation of the present invention.
embodiment 5
This test example is for illustration of the restraining effect of crystal formation of the present invention to rat platelet aggregation.
1, Experimental agents and reagent:
Crystal formation prepared by embodiment 1;
ADP:SIGMA Products;
Xylo-Mucine 800-1200: Chemical Reagent Co., Ltd., Sinopharm Group, lot number: F20051103.
2, laboratory animal:
Wistar rat: SPF level, male, Institute of Experimental Animals, Chinese Academy of Medical Sciences provides, credit number SCXK (capital) 2005-0013.
3, laboratory apparatus:
PAM-3 type two channels platelet aggregation instrument: Danyang, Jiangsu Province radio factory product.
4, experimental technique and result:
Select healthy male Wistar rat, body weight 210-250g, random packet.Often criticize and all establish Normal group and crystal formation administration group.The dosage of crystal formation administration group is 30mg/kg.Adopt gastric infusion, administration volume is 10mL/kgbw, Normal group gives equivalent 0.5%CMC-Na, 2h after administration, abdominal injection 40mg/kg vetanarcol (1mL/kg) are anaesthetized, aorta abdominalis is taken a blood sample, with 3.8% Sodium Citrate anti-freezing, prepare platelet rich plasma (PRP) and platelet poor plasma (PPP) respectively, at the maximum gathering percentage of thrombocyte that PAM-3 type two channels platelet aggregation instrument mensuration ADP (final concentration: 1.08 μMs) is induced.The results are shown in Table 2.
Table 2 is on the impact of the platelet aggregation that ADP induces
From table 2, compared with Normal group, crystal formation of the present invention (30mg/kg) has the platelet aggregation of obvious anti-ADP induction.Therefore it may be used for preventing or treating the cardiovascular and cerebrovascular diseases such as coronary syndrome, myocardial infarction, myocardial ischemia caused because of platelet aggregation.
embodiment 6
The of the present invention crystal formation obtained by embodiment 1 and patent CN102241690 crystal formation and patent CN104098586 crystal formation carry out influence factor test, place three months under the condition of illumination (4500 ± 500Lx), high temperature (60 DEG C) and high humidity (92.5% relative humidity) respectively, compared outward appearance, impurity number and impurity level (measuring with HPLC) with the 0th day.Test-results is respectively in Table 3-5.
Table 3 light durability testing data
Table 4 thimble test data
Table 5 high humidity stability test data
From table 3-5, in stability test under the illumination of 3 months by a definite date, high temperature, super-humid conditions, the permanent stability of crystal formation of the present invention are better, be better than CN102241690 crystal formation and CN104098586 crystal formation especially, measured by HPLC simultaneously, its impurity number and gathering way of total impurities are also considerably slower than CN102241690 crystal formation and CN104098586 crystal formation, visible crystal formation of the present invention has good long term storage stability, can as the stable source of formula (I) raw materials of compound medicine.
Although present invention has been description to a certain degree, significantly, under the condition not departing from the spirit and scope of the present invention, can carry out the suitable change of each condition.Be appreciated that and the invention is not restricted to described embodiment, and be attributed to the scope of claim, it comprises the equivalent replacement of described each factor.
Claims (9)
1. the crystalline form I of one kind (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-base) acetic ester, it is characterized in that, the X-ray powder diffraction of described crystal formation is as shown in Figure of description 4.
2. crystalline form I according to claim 1, is characterized in that, the fusing point of this crystal formation is 87.2-87.9 DEG C.
3. the preparation method of crystalline form I according to claim 1 and 2, is characterized in that, the method comprises the following steps:
(1) according to the weightmeasurement ratio of 1:2-8 by (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic ester adds in the mixed solution of acetonitrile-water, wherein water accounts for 10% ~ 20% of mixed solution cumulative volume, under agitation 30 DEG C ~ 65 DEG C heating for dissolving, filters;
(2) filtrate of step (1) being filtered gained at room temperature places 3-7h crystallization, collected by filtration, dry, obtains described crystalline form I.
4. preparation method according to claim 3, is characterized in that, in step (1), described weightmeasurement ratio is 1:6; In the mixed solution of acetonitrile-water, water accounts for 15% of mixed solution cumulative volume; Preferably, be under agitation heated to 50 DEG C, crystallization 5h.
5. a pharmaceutical composition, is characterized in that, described pharmaceutical composition includes the crystalline form I described in claim 1 or 2 and one or more pharmaceutically acceptable auxiliary materials of effective amount.
6. pharmaceutical composition according to claim 5, is characterized in that, described pharmaceutical composition is solid orally ingestible, liquid oral medicine or injection.
7. pharmaceutical composition according to claim 6, is characterized in that, described solid orally ingestible comprises dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule or granule; Described liquid oral medicine comprises oral solution; Described injection comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
8. the crystalline form I described in claim 1 or 2 or the crystalline form I prepared according to the method described in claim 3 or 4 are for the preparation of the purposes in the pharmaceutical composition of platelet aggregation-against.
9. the crystalline form I described in claim 1 or 2 or the purposes of crystalline form I in the pharmaceutical composition of the coronary syndrome caused because of platelet aggregation-against for the preparation for the treatment of, myocardial infarction, myocardial ischemia, cardiovascular and cerebrovascular diseases prepared according to the method described in claim 3 or 4.
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