CN105646526A - Crystal form VII of (5-2(2-cyanobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)acetate and preparation method and application thereof - Google Patents
Crystal form VII of (5-2(2-cyanobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)acetate and preparation method and application thereof Download PDFInfo
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- 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
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Abstract
The invention belongs to the technical field of medicine and particularly provides a following crystal form VII of (5-2(2-cyanobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)acetate. The invention further provides a preparation method of the above-mentioned crystal form and application of the crystal form in the preparation of pharmaceutical compositions for resisting platelet aggregation.
Description
Technical field
The invention belongs to pharmaceutical technology field, more precisely, relate to a kind of (5-(2-itrile group benzyl)-4 with antiplatelet aggregative activity, 5,6,7-Tetramethylene sulfides are [3,2-c] pyridine-2-base also) crystal form VII of acetas and its preparation method and application.
Background technology
The formation of thrombosis may result in 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, for instance platelet adhesion on the blood vessel wall surface of damage and gathering, blood stream stasis, thrombin activation promote the formation of thrombin, antiplasmin activity low inferior. In above-mentioned factor, platelet is thrombotic required material, and therefore suppressing hematoblastic gathering is one of prevention and the important means treating thrombus disease.
The present inventor once have submitted Chinese invention patent application (publication number: CN102241690) with regard to " the thienopyridine esters derivative of a class nitrile group-containing, Preparation Method And The Use ". This disclosure of the invention a kind of chemical structural formula such as compound shown in formula I: (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas (hereinafter referred to as type I compound).
Above invention discloses compound (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfides also [3,2-c] pyridine-2-base) acetas is effective for the treatment disease that causes because of platelet aggregation of the mankind, for instance thrombotic disease.
Above-mentioned patent " the thienopyridine esters derivative of a class nitrile group-containing, Preparation Method And The Use " 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 acetas:
Equipped with stirring, condenser, thermometer reaction bulb in add 2.7g intermediate1, to be dissolved with 10mL dichloromethane, stirring is lower adds sodium hydroxide 1.2g. Reaction system is cooled to-20 DEG C, 1.02g acetic anhydride is dividedly in some parts reaction system. Add, under room temperature, continue stirring reaction 1h (flaggy show react completely). With 3 �� 15mL water washing reactant liquor, divide and take dichloromethane layer, fully dry with anhydrous sodium sulfate, to filter, dichloromethane to the greatest extent, post separation are steamed in decompression, obtain white solid product (HPLC:99.6%). Rf=0.58 [single-point, developing solvent: v (petroleum ether): v (ethyl acetate)=4:1].1HNMR (DMSO-d6,400MHz) ��: 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, repeating above-mentioned preparation method, the product fusing point obtained is 85 DEG C-85.5 DEG C, and it characterizes with X-powder diffraction, such as accompanying drawing 1 (hereinafter referred to as patent CN102241690 crystal formation).
Inventor finds in research process, obtains a kind of novel crystal forms being different from above-mentioned white solid product with refining methanol. This crystal formation has embodied the technical advantage being better than prior art CN102241690 crystal formation, has therefore also applied for novel crystal forms patent.
(5-(2-itrile group benzyl)-4 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) acetas " (CN104098586), 5,6,7-Tetramethylene sulfides are [3,2-c] pyridine-2-base also) a kind of crystal formation of acetas:
Monoclinic system, P21/n space group, the molecular 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
Packing of molecules in structure cell is shown in accompanying drawing 2.
It characterizes with X-powder diffraction, such as accompanying drawing 3.
The preparation method of crystal, it is characterised in that: type I compound being added in the methanol of 8 times (w/vs), be stirred and heated to 60 DEG C, after being completely dissolved, filter, filtrate room temperature is placed 20-24 hour, crystallization. Leach this crystallization, obtain through indoor seasoning. Purity (HPLC:99.0%), fusing point: 91.1-91.8 DEG C.
It is referred to as polytropism, it is known that it is present in many organic compound with the ability that different crystal forms compound structure exists. These different crystal formations are referred to as " polymorph ", and different in the accumulation mode of its crystalline solid state, geometry arrangement and other descriptive nature. Different polymorphs has different lattice energies, and thus it illustrates different physical propertys when solid-state, for instance shape, color density, hardness, deformability, stability and dissolubility etc.
For this, present inventors studied 5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfides are [3,2-c] pyridine-2-base also) polymorphism of acetas, and wish to find the crystal habit with excellent physicochemical property, thus provide more material choice for medicine manufacture.
Summary of the invention
It is an object of the invention to the defect overcoming the known crystal formation of both the above to exist, provide a kind of novel crystal forms of formula I compound, this crystal formation has stable apparent condition and good long-term storing stability, it is possible to is stably supplied and prepares crude drug. Present invention also offers the preparation method and application of this crystal formation.
A further object of the invention is in that, provide the application as antiplatelet drug aspect of the formula I compound, particularly for preparing prevention or treating the coronary syndrome caused because of platelet aggregation, myocardial infarction, the purposes of the cardiovascular and cerebrovascular diseases medicament aspects such as myocardial ischemia.
Present invention relates particularly to the crystal formation of the compound of structure shown in formula I:
The i.e. crystal form VII of (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfides also [3,2-c] pyridine-2-base) acetas, it is characterised in that:
Measure with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, the angle of diffraction (2 ��) that its collection of illustrative plates has, as shown in Figure 4, the error of 2 �� is �� 0.2 for interplanar distance (d value) and intensity (%).
Crystal formation according to the present invention, wherein, the fusing point of this crystal formation can be 88.5-89.0 DEG C.It addition, the purity of this crystal formation can be 99.0% or more than.
Crystal formation according to 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 preparing above-mentioned crystal formation, the method comprises the following steps:
The crystal form VII of type I compound is that crystallization obtains in the mixed liquor of petroleum ether chloroform. Make consumption be type I compound quality 2��8 times (volume-mass ratio, mL/g) of mixed liquor, wherein preferably 6 times.
Chloroform accounts for the 10%��40% of mixed liquor cumulative volume; Preferably 20%.
Temperature during dissolving is 30 DEG C��60 DEG C, it is preferable that 45 DEG C. Then it is naturally cooling to room temperature, places 3��15 hours, it is preferable that place 8 hours; Namely novel crystal forms VII type of type I compound is obtained.
Specific operation process is:
Take a certain amount of type I compound, add petroleum ether chloroform mixed liquor, heated and stirred, after dissolving, naturally cool to room temperature. Precipitate out solid, filter, obtain type I compound crystal form VII.
Purity (HPLC:99.7%), fusing point: 88.5-89.0 DEG C.
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition comprises above-mentioned crystal formation and one or more pharmaceutically acceptable adjuvants of effective dose. Described pharmaceutically acceptable adjuvant can be to maintain substrate or the adjuvant of pharmaceutical dosage form, by selecting according to different medicaments or combining use, it is optionally included with carrier, excipient, diluent, filler, binding agent, disintegrating agent, lubricant, fluidizer, effervescent, correctives, preservative, coating material etc. Excipient includes the compositions of one or more in such as microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, dextran, mannitol, sorbitol, glucose, fructose, water, Polyethylene Glycol, propylene glycol, glycerol, cyclodextrin, cyclodextrin derivative. Filler includes the compositions of one or more of such as lactose, sucrose, dextrin, starch, pregelatinized Starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, microcrystalline Cellulose. Binding agent includes the compositions of one or more of such as sucrose, starch, polyvidone, sodium carboxymethyl cellulose, carboxylic the third methylcellulose, carboxylic the third cellulose, methylcellulose, Polyethylene Glycol, medicinal alcohol, water. Disintegrating agent includes the compositions of one or more of such as starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
Pharmaceutical composition according to the present invention, wherein, described pharmaceutical composition can be solid orally ingestible, liquid oral medicine or injection. Preferably, described solid orally ingestible includes dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, capsule or granule; Described liquid oral medicine includes oral solution; Described injection includes injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
Present invention also offers above-mentioned crystal formation or the crystal formation prepared according to the said method of the present invention is being prepared for the purposes in the pharmaceutical composition of antiplatelet aggregation. It addition, present invention also offers above-mentioned crystal formation or the crystal formation prepared according to the said method of the present invention preparation for treat cause because of antiplatelet aggregation coronary syndrome, myocardial infarction, myocardial ischemia, cardiovascular and cerebrovascular disease pharmaceutical composition in purposes. The present inventor has passed through and mouse platelets is assembled inhibitory action experiment confirmation, the crystal formation of the formula I compound of the present invention has the obvious anti-ADP platelet aggregation induced, coronary syndrome that therefore it can be used to prevention or treatment causes because of platelet aggregation, myocardial infarction, the cardiovascular and cerebrovascular disease such as myocardial ischemia.
The crystal formation of the present invention is effective in comparatively wide dosage range. The dosage that such as every day takes, within the scope of 10mg-500mg, is divided into once or is administered for several times. The actual dosage taking crystal formation of the present invention can be determined according to relevant situation by doctor. These situations include: the condition of patient, route of administration, age, body weight, individual reaction to medicine, the order of severity etc. of symptom.
Compared with the white solid product of the formula I compound obtained by direct solvent evaporated (such as dichloromethane) mode, the crystal formation prepared by the present invention batch between there is good appearance stability and repeatability. Such as, the present inventor is found through experiments, this crystal formation continuously preparation 7 batches batch within the scope of, its outward appearance is stable, is all normally white solid, and after measured every batch be all stable crystal formation (test result is as shown in table 1).
Table 1 stability of crystal form is tested
Additionally, the 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, thus has more good long term storage stability.
Based on features described above, the crystal formation of the present invention as the stable supplying source of formula I raw materials of compound medicine, can be more suitable for industrialized production.
Meanwhile, in view of the crystal formation of the present invention has good long-time stability, it is possible to certainly, should have the longer limited time limit with the preparation that it prepares for raw material, simultaneously that the requirement of preservation condition is also lower.
Accompanying drawing explanation
Hereinafter, describe embodiment of the present invention in detail in conjunction with accompanying drawing, wherein:
Fig. 1 illustrates the X-ray powder diffraction pattern being prepared crystal formation by patent CN102241690 method;
Fig. 2 illustrates the structure cell packing of molecules figure being prepared crystal formation by patent CN104098586 method;
Fig. 3 illustrates the X-ray powder diffraction pattern being prepared crystal formation by patent CN104098586 method;
Fig. 4 illustrates the X-ray powder diffraction pattern of crystal form VII.
Detailed description of the invention
The present invention is further illustrated below by specific embodiment, it should be understood, however, that, these embodiments are only used for the use specifically described in more detail, and are not to be construed as limiting in any form the present invention.
Material and test method that this part is used during the present invention is tested carry out general description. Although for realize many materials that the object of the invention uses and operational approach is to it is known in the art that but the present invention remains in this to be described in detail as far as possible. It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and operational approach are well known in the art.
With the following Examples, the present invention is as follows to the condition determination of crystal formation:
Measure with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, the angle of diffraction (2 ��) that its collection of illustrative plates has, as shown in Figure 3, the error of 2 �� is �� 0.2 for interplanar distance (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: C18, 150mm �� 4.6mm, 5um
Mobile phase: methanol: water: acetic acid=70:30:0.25
Wavelength: 230nm
Flow velocity: 0.8ml/min
Sample size: 10uL
Column temperature: 35 DEG C
Instrument:
The general L6 chromatograph of liquid of general analysis
Hitachi's L-7250 automatic sampler
The general LCWin chromatographic work station of general analysis
Embodiment 1
The present embodiment is for illustrating crystal formation and the preparation process thereof of (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas of the present invention.
Preparation (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas is as raw material. Its preparation process is referred in the open CN102241690 of Chinese invention patent the reaction process recorded. Such as, its reaction process can be:
Intermediate1Preparation:
Equipped with stirring, condenser, thermometer reaction bulb in add 5,6,7,7a-Tetramethylene sulfides also [3,2-c] pyridine-2 (4H)-one 19.2g, is dissolved with 70mL acetonitrile, under stirring, is cooled to-10 DEG C, addition Anhydrous potassium carbonate 41.5g. 2-cyano-benzyl bromide 19.6g is dividedly in some parts in reaction system, finishes and be warming up to 45 DEG C and continue reaction 4h (flaggy show react completely). Filter, filtrate solvent evaporated acetonitrile, add 50mL dichloromethane, with 3 �� 50mL water washing reactant liquor, divide and take dichloromethane layer, fully dry with anhydrous sodium sulfate, filtering, dichloromethane to the greatest extent is steamed in decompression, obtains yellow oil product 22.6g (HPLC:97.2%). Rf=0.47 [single-point, developing solvent: v (petroleum ether): 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 sulfide also [3,2-c] pyridine-2-base) acetas):
Equipped with stirring, condenser, thermometer reaction bulb in add the above-mentioned prepared intermediate 1 of 2.7g, is dissolved with 10mL dichloromethane, stirring lower addition sodium hydroxide 1.2g. Reaction system is cooled to-20 DEG C, 1.02g acetic anhydride is dividedly in some parts reaction system. Add, under room temperature, continue stirring reaction 1h (flaggy show react completely). With 3 �� 15mL water washing reactant liquor, divide and take dichloromethane layer, fully dry with anhydrous sodium sulfate, to filter, dichloromethane to the greatest extent, post separation are steamed in decompression, obtain white solid product (HPLC:99.6%). Rf=0.58 [single-point, developing solvent: v (petroleum ether): v (ethyl acetate)=4:1].1HNMR (DMSO-d6,400MHz) ��: 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).
White solid product (5-(2-itrile group benzyl)-4 to above-mentioned gained, 5,6,7-Tetramethylene sulfides also [3,2-c] pyridine-2-base) acetas carry out X-ray powder diffraction (PXRD) characterize, its PXRD collection of illustrative plates is as shown in Figure 1. Repeating above-mentioned preparation method, the fusing point of the white solid product measuring gained is 85-85.5 DEG C.
The preparation of crystal formation of the present invention:
Take the white solid (5-(2-itrile group benzyl)-4 that 3g said method prepares, 5,6,7-Tetramethylene sulfide is [3,2-c] pyridine-2-base also) acetas, add the mixed liquor (chloroform accounts for the 40% of mixed liquor cumulative volume) of the petroleum ether-chloroform of 6ml, under agitation heat to 60 DEG C, make it all dissolve, filter, take filtrate; Gained filtrate is at room temperature placed 3h crystallize, collected by filtration, dry, obtain the crystal 2.90g of the present invention.
The fusing point recording this crystal formation is 88.5-88.7 DEG C, and using the HPLC purity recording this crystal formation is 99.7%.
Embodiment 2
The present embodiment is for illustrating crystal formation and the preparation process thereof of (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas of the present invention.
Formula (I) compound is prepared as raw material according to method in the same manner as in Example 1.
Take the white solid (5-(2-itrile group benzyl)-4 that 3g said method prepares, 5,6,7-Tetramethylene sulfide is [3,2-c] pyridine-2-base also) acetas, add the mixed liquor (chloroform accounts for the 20% of mixed liquor cumulative volume) of the petroleum ether-chloroform of 18ml, under agitation heat to 45 DEG C, make it all dissolve, filter, take filtrate; Gained filtrate is at room temperature placed 8h crystallize, collected by filtration, dry, obtain the crystal 2.93g of the present invention.
The fusing point recording this crystal formation is 88.7-88.9 DEG C, and using the HPLC purity recording this crystal formation is 99.8%.
Embodiment 3
The present embodiment is for illustrating crystal formation and the preparation process thereof of (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas of the present invention.
Formula (I) compound is prepared as raw material according to method in the same manner as in Example 1.
Take the white solid (5-(2-itrile group benzyl)-4 that 3g said method prepares, 5,6,7-Tetramethylene sulfide is [3,2-c] pyridine-2-base also) acetas, add the mixed liquor (chloroform accounts for the 10% of mixed liquor cumulative volume) of the petroleum ether-chloroform of 24ml, under agitation heat to 30 DEG C, make it all dissolve, filter, take filtrate; Gained filtrate is at room temperature placed 15h crystallize, collected by filtration, dry, obtain the crystal 2.88g of the present invention.
The fusing point recording this crystal formation is 88.5-88.8 DEG C, and using the HPLC purity recording this crystal formation is 99.6%.
Embodiment 4
The present embodiment is for illustrating the preparation of the tablet containing crystal formation of the present invention.
Sample crystal formation, pregelatinized Starch and microcrystalline Cellulose that embodiment 1 prepares are sieved, is sufficiently mixed with recipe quantity, add the solution containing recipe quantity polyvinylpyrrolidone, mixing, soft material processed, sieve, wet granular processed, dry in 50-60 DEG C; Then Sodium carboxymethyl starch, magnesium stearate and Pulvis Talci are sieved in advance, join in above-mentioned dried granule with recipe quantity, tabletting, obtain the tablet of the crystal formation containing the present invention.
Embodiment 5
This test example is used for the crystal formation that the present invention the is described inhibitory action to rat platelet aggregation.
1, Experimental agents and reagent:
The crystal formation of embodiment 1 preparation;
ADP:SIGMA Products;
Sodium carboxymethyl cellulose 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, experimental apparatus:
PAM-3 type dual pathways 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. Every batch is all provided with Normal group and crystal formation administration group. The dosage of crystal formation administration group is 30mg/kg. Adopt gastric infusion, administration volume is 10mL/kg bw, Normal group gives equivalent 0.5%CMC-Na, 2h after administration, lumbar injection 40mg/kg pentobarbital sodium (1mL/kg) is anaesthetized, ventral aorta is taken a blood sample, with 3.8% sodium citrate anticoagulant, prepare platelet rich plasma (PRP) and platelet poor plasma (PPP) respectively, measure ADP (final concentration: 1.08 ��Ms) the maximum gathering percentage rate of platelet induced at PAM-3 type dual pathways platelet aggregation instrument. Result is in Table 2.
The table 2 impact on the platelet aggregation that ADP induces
From table 2, compared with Normal group, the crystal formation (30mg/kg) of the present invention has the obvious anti-ADP platelet aggregation induced.Therefore it may be used for prevention or treatment causes because of platelet aggregation coronary syndrome, myocardial infarction, the cardiovascular and cerebrovascular disease such as myocardial ischemia.
Embodiment 6
The crystal formation of present invention embodiment 1 prepared carries out influence factor's test with patent CN102241690 crystal formation and patent CN104098586 crystal formation, place three months when 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. Result of the test is respectively in Table 3-5.
Table 3 light durability test 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 long-time stability of crystal formation of the present invention are better, it is especially better than CN102241690 crystal formation and CN104098586 crystal formation, measured by HPLC simultaneously, its impurity number and total impurities gather way also considerably slower than CN102241690 crystal formation and CN104098586 crystal formation, the crystal formation of the visible present invention has good long term storage stability, it is possible to as the stable source of formula (I) raw materials of compound medicine.
Although present invention has been a degree of description, it will be apparent that, without departing from the spirit and scope of the present invention when, can carry out the suitable change of each condition. Being appreciated that and the invention is not restricted to described embodiment, and be attributed to scope of the claims, it includes the equivalent replacement of described each factor.
Claims (9)
1. the crystal form VII of one kind (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfides also [3,2-c] pyridine-2-base) acetas, it is characterised in that the X-ray powder diffraction of described crystal formation is such as shown in Figure of description 4.
2. crystal form VII according to claim 1, it is characterised in that the fusing point of this crystal formation is 88.5-89.0 DEG C.
3. the preparation method of crystal form VII according to claim 1 and 2, it is characterised in that the method comprises the following steps:
(1) according to the w/v of 1:2-8 by (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas add petroleum ether chloroform mixed liquor in, wherein chloroform accounts for the 10%��40% of mixed liquor cumulative volume, under agitation 30 DEG C��60 DEG C heating for dissolving, filters;
(2) filtrate that step (1) filters gained at room temperature places 3-15h crystallize, collected by filtration, dry, obtains described crystal form VII.
4. preparation method according to claim 3, it is characterised in that in step (1), described w/v is 1:6; In the mixed liquor of petroleum ether chloroform, chloroform accounts for the 20% of mixed liquor cumulative volume; Preferably, under agitation heat to 45 DEG C, crystallize 8h.
5. a pharmaceutical composition, it is characterised in that described pharmaceutical composition comprises the crystal form VII described in the claim 1 or 2 of effective dose and one or more pharmaceutically acceptable adjuvants.
6. pharmaceutical composition according to claim 5, it is characterised in that described pharmaceutical composition is solid orally ingestible, liquid oral medicine or injection.
7. pharmaceutical composition according to claim 6, it is characterised in that described solid orally ingestible includes dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, capsule or granule; Described liquid oral medicine includes oral solution; Described injection includes injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
8. the crystal form VII that prepared by the crystal form VII described in claim 1 or 2 or the method described in claim 3 or 4 is being prepared for the purposes in the pharmaceutical composition of antiplatelet aggregation.
9. the crystal form VII that prepared by the crystal form VII described in claim 1 or 2 or the method described in claim 3 or 4 preparation for treat cause because of antiplatelet aggregation coronary syndrome, myocardial infarction, myocardial ischemia, cardiovascular and cerebrovascular disease pharmaceutical composition in purposes.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107474057A (en) * | 2016-06-07 | 2017-12-15 | 天津药物研究院有限公司 | Crystal formation of (5 (2 itrile group benzyl) 4,5,6,7 thiophanes simultaneously the base of [3,2 c] pyridine 2) acetic ester hydrochloride and its production and use |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101260112A (en) * | 2008-04-11 | 2008-09-10 | 天津药物研究院 | Acethydrazide derivatives containing thieno[3.2-c]pyridine, preparation method and use thereof |
| CN104098586A (en) * | 2013-04-03 | 2014-10-15 | 天津药物研究院 | Crystal form, preparation method and use of nitrile-group-containing thienopyridine lipid derivative |
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| CN104098586A (en) * | 2013-04-03 | 2014-10-15 | 天津药物研究院 | Crystal form, preparation method and use of nitrile-group-containing thienopyridine lipid derivative |
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| CN107474057A (en) * | 2016-06-07 | 2017-12-15 | 天津药物研究院有限公司 | Crystal formation of (5 (2 itrile group benzyl) 4,5,6,7 thiophanes simultaneously the base of [3,2 c] pyridine 2) acetic ester hydrochloride and its production and use |
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