CN105622631A - Crystal form VI of free alkali and preparation method and application of crystal form VI - Google Patents
Crystal form VI of free alkali and preparation method and application of crystal form VI Download PDFInfo
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- CN105622631A CN105622631A CN201610117597.7A CN201610117597A CN105622631A CN 105622631 A CN105622631 A CN 105622631A CN 201610117597 A CN201610117597 A CN 201610117597A CN 105622631 A CN105622631 A CN 105622631A
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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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- 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 medicament and particularly provides a crystal form VI of (5-(2-nitrile benzyl)-4, 5, 6, 7-tetrahydrothiophene and [3, 2-c] pyridine-2-base) acetic acid ester. The invention further provides a preparation method of the crystal form and application of the crystal form to preparation of a medicine composition for resisting to platelet aggregation.
Description
Technical field
The invention belongs to medical art, more properly say, relate to a kind of (5-(2-itrile group benzyl)-4 with platelet aggregation-against effect, 5,6,7-tetramethylene sulfide is [3,2-c] pyridine-2-base also) the brilliant type VI 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.
Causing a lot of because have of thrombosis, 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 the required material of thrombosis, therefore suppresses the gathering of thrombocyte to be one of the important means of prevention and therapy thrombus disease.
The present inventor once have submitted Chinese invention patent application (publication number: CN102241690) with regard to " the thienopyridine ester derivative of a class nitrile group-containing, Preparation Method And The Use ". 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 sulfide 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 treatment disease that causes because of platelet aggregation of the mankind, such as thrombotic diseases.
Above-mentioned patent " the thienopyridine ester 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 acetic ester:
The reaction flask that stirring, condenser, thermometer are housed adds 2.7g intermediate 1, is dissolved with 10mL methylene dichloride, under stirring, add 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 (display of plate layer reacts completely). With 3 �� 15mL water washing reaction solution, divide and get dichloromethane layer, fully dry by anhydrous sodium sulphate, to filter, methylene dichloride to the greatest extent is 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) ��: 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-powdery diffractometry, such as accompanying drawing 1 (hereinafter referred to as the brilliant type of patent CN102241690).
Contriver finds in research process, obtains a kind of new crystal being different from above-mentioned white solid product with refining methanol. This crystalline substance type has embodied the technical superiority being better than the brilliant type of prior art CN102241690, has therefore also applied for new crystal patent.
Patent " the brilliant type of (5-(2-itrile group benzyl)-4; 5; 6; 7-tetramethylene sulfide is [3_2-c] pyridine-2-base also) acetic ester " (CN104098586) discloses (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine-2-base also) a kind of brilliant type 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 with X-powdery diffractometry, such as accompanying drawing 3.
The preparation method of crystal, it is characterised in that: type I compound being added in the methyl alcohol of 8 times (weightmeasurement ratios), be stirred and heated to 60 DEG C, after dissolving completely, filter, filtrate room temperature is placed 20-24 hour, crystallization. Filter out this crystallization, obtain through indoor drying. Purity (HPLC:99.0%), fusing point: 91.1-91.8 DEG C.
It is called 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 brilliant types 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 thus it illustrates different physical propertiess when solid-state, 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 the crystal habit with excellent physico-chemical property, thus provide more material choice for medicine manufacture.
Summary of the invention
It is an object of the invention to overcome the defect of above two kinds of known brilliant type existence, provide a kind of new crystal of formula I compound, this crystalline substance type has stable apparent condition and good long-term storing stability, it is possible to stable ground the supply system is for bulk drug. Present invention also offers the preparation method and application of this crystalline substance type.
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 brilliant type of the compound of structure shown in formula I:
The i.e. brilliant type VI of (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic ester, it is characterised in that:
Measure with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, the diffraction angle (2 ��) that its collection of illustrative plates has, as shown in Figure 4, the error of 2 �� is �� 0.2 for spacing (d value) and intensity (%).
Brilliant type according to the present invention, wherein, the fusing point of this crystalline substance type can be 88.1-88.8 DEG C. In addition, the purity of this crystalline substance type can be 99.0% or more.
Brilliant type according to the present invention, wherein, the X powder diffraction of this crystalline substance type can be as shown in Figure 4.
Present invention also offers the method for the preparation of above-mentioned brilliant type, the method comprises the following steps:
The brilliant type VI of type I compound is that crystallization obtains in the mixed solution of sherwood oil ethyl acetate. The usage quantity of mixed solution is 2��10 times (volume-mass ratio, mL/g) of type I compound quality, wherein preferably 3 times.
Ethyl acetate accounts for the 10%��50% of mixed solution cumulative volume; Preferably 30%.
Temperature during dissolving is 30 DEG C��75 DEG C, it is preferable that 50 DEG C. Then Temperature fall is to room temperature, places 1��9 hour, it is preferable that place 5 hours; Namely new crystal VI type of type I compound is obtained.
Specific operation process is:
Get a certain amount of type I compound, add sherwood oil ethyl acetate mixtures, heated and stirred, after dissolving, naturally cool to room temperature. Precipitate out solid, filter, obtain the brilliant type VI of type I compound.
Purity (HPLC:99.9%), fusing point: 88.1-88.8 DEG C.
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition includes above-mentioned brilliant type 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.
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 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 brilliant type that present invention also offers above-mentioned brilliant type or prepare according to the 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 the brilliant type that present invention also offers above-mentioned brilliant type or prepare according to the aforesaid method of the present invention 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. The present inventor confirms by mouse platelets is assembled restraining effect experiment, the brilliant type of the formula I compound of the present invention has the platelet aggregation effect that obvious anti-ADP induces, therefore its can be used for preventing or treat cause because of platelet aggregation coronary syndrome, myocardial infarction, the cardiovascular and cerebrovascular diseases such as myocardial ischemia.
The brilliant type 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 dosage of the brilliant type of the actual the present invention of taking can be determined 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 (such as methylene dichloride) mode, the brilliant type prepared by the present invention batch between there is good appearance stability and circulation ratio. Such as, the present inventor found through experiments, this crystalline substance type continuous production 7 batches batch within the scope of, its outward appearance is stable, is all normal white solid, and often to criticize after measured be all stable brilliant type (test result is as shown in table 1).
Table 1 stability of crystal form is tested
In addition, the brilliant type of the present invention also has good long-term storing stability. Such as, the present inventor verifies by experiment, this crystalline substance type three months by a definite date to, in light, heat, wet stability experiment, its impurity is not significantly increased, and thus has more good long term storage stability.
Based on above-mentioned feature, the brilliant type 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 the brilliant type of the present invention has good permanent stability, it is possible to certainly, the preparation obtained taking it as raw material should have the longer limited time limit, simultaneously that the requirement of preservation condition is also lower.
Accompanying drawing explanation
Hereinafter, come by reference to the accompanying drawings embodiment of the present invention are described in detail, wherein:
Fig. 1 shows the X-ray powder diffraction pattern by the obtained brilliant type of patent CN102241690 method;
Fig. 2 shows the structure cell packing of molecules figure by the obtained brilliant type of patent CN104098586 method;
Fig. 3 shows the X-ray powder diffraction pattern by the obtained brilliant type of patent CN104098586 method;
Fig. 4 shows the X-ray powder diffraction pattern of brilliant type VI.
Embodiment
Below by specific embodiment, the present invention being described further, however, it should be understood that be, 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.
The material that this part uses in the present invention being tested and test method carry out general description. Although being well known in the art for realizing many materials that the object of the invention uses and working method, but the present invention still describes as far as possible in detail at this work. Those skilled in the art know 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 present invention is as follows to the condition determination of brilliant type:
Measuring with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, the diffraction angle (2 ��) that its collection of illustrative plates has, as shown in Figure 3, the error of 2 �� is 0.2 for spacing (d value) and intensity (%).
Fusing point test:
Instrument: YTR-3 type melting point apparatus (purchased from precision instrument factory of University Of Tianjin)
High performance liquid chromatography (HPLC) condition:
Chromatographic column: C18, 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
Post temperature: 35 DEG C
Instrument:
The general L6 liquid chromatograph of general analysis
Hitachi's L-7250 automatic sampler
The general LCWin chromatographic working station of general analysis
Embodiment 1
The present embodiment is for illustration of the brilliant type of (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic ester of the present invention and preparation process thereof.
Preparation (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic ester is as raw material. Its preparation process can with reference to the reaction flow process recorded in the open CN102241690 of Chinese invention patent. Such as, its reaction flow process can be:
Intermediate1Preparation:
The reaction flask that stirring, condenser, thermometer are housed adds 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2 (4H)-one 19.2g, is 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 (display of plate layer reacts completely). Filtering, 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, filtering, methylene dichloride to the greatest extent is 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 sulfide also [3,2-c] pyridine-2-base) acetic ester:
The reaction flask that stirring, condenser, thermometer are housed adds the above-mentioned obtained intermediate 1 of 2.7g, is dissolved with 10mL methylene dichloride, under stirring, add 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 (display of plate layer reacts completely). With 3 �� 15mL water washing reaction solution, divide and get dichloromethane layer, fully dry by anhydrous sodium sulphate, to filter, methylene dichloride to the greatest extent is 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) ��: 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. Repeating above-mentioned preparation method, the fusing point of the white solid product measuring gained is 85-85.5 DEG C.
The preparation of the brilliant type 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 (ethyl acetate accounts for the 50% of mixed solution cumulative volume) of the petroleum ether-ethyl acetate of 6ml, under agitation it is heated to 75 DEG C, make it all dissolve, filter, get filtrate; Gained filtrate is at room temperature placed 1h analysis brilliant, filter and collect crystallization, dry, obtain the crystal 2.95g of the present invention.
The fusing point recording this crystalline substance type is 88.2-88.5 DEG C, it may also be useful to it is 99.9% that HPLC records the purity of this crystalline substance type.
Embodiment 2
The present embodiment is for illustration of the brilliant type of (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic ester of the present invention 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 (ethyl acetate accounts for the 30% of mixed solution cumulative volume) of the petroleum ether-ethyl acetate of 9ml, under agitation it is heated to 50 DEG C, make it all dissolve, filter, get filtrate; Gained filtrate is at room temperature placed 5h analysis brilliant, filter and collect crystallization, dry, obtain the crystal 2.92g of the present invention.
The fusing point recording this crystalline substance type is 88.5-88.8 DEG C, it may also be useful to it is 99.9% that HPLC records the purity of this crystalline substance type.
Embodiment 3
The present embodiment is for illustration of the brilliant type of (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic ester of the present invention 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 (ethyl acetate accounts for the 10% of mixed solution cumulative volume) of the petroleum ether-ethyl acetate of 30ml, under agitation it is heated to 30 DEG C, make it all dissolve, filter, get filtrate; Gained filtrate is at room temperature placed 9h analysis brilliant, filter and collect crystallization, dry, obtain the crystal 2.93g of the present invention.
The fusing point recording this crystalline substance type is 88.3-88.6 DEG C, it may also be useful to it is 99.9% that HPLC records the purity of this crystalline substance type.
Embodiment 4
The present embodiment is for illustration of the preparation of the tablet containing the brilliant type of the present invention.
The embodiment 1 brilliant type of obtained sample, pregelatinized Starch and Microcrystalline Cellulose being sieved, fully mix with recipe quantity, add the solution containing recipe quantity polyvinylpyrrolidone, 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, obtain the tablet of the brilliant type containing the present invention.
Embodiment 5
This test example for illustration of the brilliant type of the present invention to the restraining effect of rat platelet aggregation.
1, Experimental agents and reagent:
Brilliant type prepared by embodiment 1;
ADP:SIGMA company product;
Xylo-Mucine 800-1200: Chemical Reagent Co., Ltd., Sinopharm Group, lot number: F20051103.
2, laboratory animal:
Wistar rat: SPF level, male, institute of lab animals of the 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 brilliant type administration group. The dosage of brilliant type 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, abdominal injection 40mg/kg vetanarcol (1mL/kg) is 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 ��Ms) 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, the brilliant type (30mg/kg) of the present invention has the platelet aggregation effect that obvious anti-ADP induces. Therefore its may be used for preventing or treat cause because of platelet aggregation coronary syndrome, myocardial infarction, the cardiovascular and cerebrovascular diseases such as myocardial ischemia.
Embodiment 6
The brilliant type of the present invention obtained for embodiment 1 and the brilliant type of patent CN102241690 and patent CN104098586 crystalline substance type are carried out influence factor test, place three months when illumination (4500 �� 500Lx), high temperature (60 DEG C) and height wet (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
The wet stability test data of table 5 height
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 the brilliant type of the present invention are better, it is better than the brilliant type of CN102241690 and the brilliant type of CN104098586 especially, measured by HPLC simultaneously, the increase speed of its impurity number and total impurities is also considerably slower than the brilliant type of CN102241690 and the brilliant type of CN104098586, the brilliant type of visible the 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 description to a certain degree, it is evident that when not departing from the spirit and scope of the present invention, can carry out the suitable change of each condition. It can be appreciated that the invention is not restricted to described embodiment, and being attributed to the scope of claim, it comprises the equivalent replacement of each factor described.
Claims (9)
1. the brilliant type VI of one kind (5-(2-itrile group benzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic ester, it is characterised in that, the X-ray powder diffraction of described brilliant type is as shown in Figure of description 4.
2. brilliant type VI according to claim 1, it is characterised in that, the fusing point of this crystalline substance type is 88.1-88.8 DEG C.
3. the preparation method of brilliant type VI according to claim 1 and 2, it is characterised in that, the method comprises the following steps:
(1) according to the weightmeasurement ratio of 1:2-10 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 sherwood oil ethyl acetate, wherein ethyl acetate accounts for the 10%��50% of mixed solution cumulative volume, under agitation 30 DEG C��75 DEG C heating for dissolving, filters;
(2) filtrate that step (1) is filtered gained at room temperature places 1-9h analysis crystalline substance, filters and collects crystallization, dry, obtains described brilliant type VI.
4. preparation method according to claim 3, it is characterised in that, in step (1), described weightmeasurement ratio is 1:3; In the mixed solution of sherwood oil ethyl acetate, ethyl acetate accounts for the 30% of mixed solution cumulative volume; Preferably, under agitation it is heated to 50 DEG C, the brilliant 5h of analysis.
5. a pharmaceutical composition, it is characterised in that, described pharmaceutical composition includes the brilliant type VI described in the claim 1 or 2 of effective amount and one or more pharmaceutically acceptable auxiliary materials.
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 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 brilliant type VI described in claim 1 or 2 or the brilliant type VI 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. purposes 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 of brilliant type VI described in claim 1 or 2 or the brilliant type VI prepared according to the method described in claim 3 or 4.
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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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2016
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