CN102010423B - Crystal form II of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-yl)]-N'-(dimethyl) methylene) acethydrazide and preparation method - Google Patents
Crystal form II of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-yl)]-N'-(dimethyl) methylene) acethydrazide and preparation method Download PDFInfo
- Publication number
- CN102010423B CN102010423B CN2010105465149A CN201010546514A CN102010423B CN 102010423 B CN102010423 B CN 102010423B CN 2010105465149 A CN2010105465149 A CN 2010105465149A CN 201010546514 A CN201010546514 A CN 201010546514A CN 102010423 B CN102010423 B CN 102010423B
- Authority
- CN
- China
- Prior art keywords
- crystal form
- formula
- compound
- preparation
- mixed solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a crystal form II of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-yl)]-N'-(dimethyl) methylene) acethydrazide and a preparation method, and also relates to a medicinal composition prepared by the new crystal form II and application. The crystal form II is characterized by a powder X-ray diffraction pattern and melting point data of the crystal form II.
Description
Technical field
The invention belongs to the medicament for resisting platelet aggregation field, more particularly, relate to (S)-α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-N '-(dimethyl-) methene base) crystal form II of acethydrazide and preparation method thereof.
Background technology
Thrombosis can cause the heart, brain, pulmonary circulation illness such as Acute Myocardial Infarction, apoplexy, pulmonary infarction, is threatening human beings'health and life, also is common complication and the inaccessible again factor of intervention property postangioplasty in the surgical operation.Though the thromboembolism treatment of carrying out in recent years, PCI even operative treatment make acute myocardial infarction and treatment of cerebral obtain the progress that attracts people's attention; Patient's salvage success rate improves greatly; Quality of life has also had tangible improvement, but the cardiovascular and cerebrovascular disease disability rate is after all up to 30%.Therefore the drug development of prevention and treatment cardiovascular and cerebrovascular disease becomes the focus of paying close attention in recent years and studying.
Cause thrombotic factor a lot, as thrombocyte stagnate in the lip-deep adhesion of vessel wall and gathering, the blood flow stasis of blood of damage, the activation of thrombin impels the formation of zymoplasm, antiplasmin activity is low inferior, can both impel thrombosis.Thrombocyte is thrombotic essential material in these factors, thus suppress hematoblastic accumulate in the prevention of thrombus disease and treat in play an important role.ADP (ADP) is the important agonist that platelet activation, buildup effect amplify, and suppressing the thrombocyte effect through the blocking-up adp receptor has become the important means that stops pathologic thrombosis (coronary heart disease, cerebro-vascular diseases, pulmonary infarction, thrombophlebitis etc.) and myocardial infarction, unstable angina pectoris, peripheral vascular disease, congestive heart failure etc.
Patent ZL200510016205.X provides a kind of new adp receptor retarding agent class antiplatelet compound I, has the good bioactive while, has more superior physico-chemical property compared to traditional adp receptor retarding agent class antiplatelet drug clopidogrel.
Chemical structure:
Chemistry is by name:
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-N '-(dimethyl-) methene base) acethydrazide.
The compound method of this compound of putting down in writing among the patent ZL200510016205.X is following:
In the reaction flask that stirring, condensing surface, TM are housed, add clopidogrel 38g, absolute ethyl alcohol 30mL, stir down slowly heating; Make the reaction raw materials dissolving, add 45.6g Hydrazine Hydrate 80 (80%), continue to be heated to backflow; Insulation reaction 4 hours, (the flaggy demonstration reacts completely).Solvent is to the greatest extent steamed in decompression then, steams and finishes, and in resistates, adds 50mL zero(ppm) water and 30mL methylene dichloride, fully stirs, and tells organic layer, and water layer merges organic layer with 3 * 30mL dichloromethane extraction, uses the SODIUM SULPHATE ANHYDROUS 99PCT thorough drying.Methylene dichloride is to the greatest extent steamed in decompression, gets white solid 23.4g.(HPLC：97.16)，m.p.139.0～139.3℃。
In the reaction flask that stirring, condensing surface, TM are housed, add hydrazides thing 4g, anhydrous methanol 40mL, start stirring, heating makes its dissolving.Continue to be heated to 40 ℃, drip 0.79g acetone, finish, insulation reaction 3 hours (the flaggy demonstration reacts completely).Stopped reaction, cooling has solid to generate.Filter, anhydrous methanol 3 * 2mL washing, drying gets solid product (HPLC:99.8%).M.p.169.1～170.8 ℃, Rf=0.3 [single-point, developping agent: sherwood oil (60-90 ℃): ETHYLE ACETATE=1: 1].
But the crystal formation that does not relate to formula I compound among the patent ZL200510016205.X.In view of the pharmacy value of this compound, it is very important obtaining purity compound high, that have very definite crystal formation and favorable reproducibility.
The contriver is according to the compound method of this compound of putting down in writing among the patent ZL200510016205.X, and repeatedly revision test is attempted, and all obtains single crystal X-powder diffraction data, and characteristic (is seen accompanying drawing 1) as follows:
Measure with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, its collection of illustrative plates have following diffraction angle (2 θ), spacing (d value) and intensity (%), the error of 2 θ is 0.2.
Through a plurality of batches fusing point test, fusing point is between 169.1～170.8 ℃.
Summary of the invention
An object of the present invention is to provide (S)-α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-N '-(dimethyl-) methene base) a kind of new crystal II of acethydrazide.
Another object of the present invention provides (S)-α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-N '-(dimethyl-) methene base) preparation method of the new crystal II of acethydrazide.
A further object of the invention provides (S)-α; α-[(2-chloro-phenyl-)-(4,5,6; 7-THTP also [3; 2-c] pyridine-5-yl)]-N '-(dimethyl-) methene base) crystal form II of acethydrazide is as effective constituent, and the medicinal compsns that contains one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect medicament for resisting platelet aggregation.
Combine the object of the invention that content of the present invention is specifically described at present.
(S)-and α, α-[(2-chloro-phenyl-)-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-N '-(dimethyl-) methene base) crystal form II of acethydrazide has following characteristic:
Measure with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, its collection of illustrative plates have following diffraction angle (2 θ), and spacing (d value) and intensity (%), the error of 2 θ are 0.2 (seeing accompanying drawing 2).
Through fusing point test, its melting range is 151.5～153.0 ℃.Measure condition determination with Japanese PTC-10A TG-DTA analyser of science: temperature rise rate: 10 ℃/min, DTA range: ± 25 μ V, TG range: 5.0mg, TR: room temperature～400 ℃, no crystal water crystallization solvent (seeing accompanying drawing 3).
(S)-α that the present invention uses, α-[(2-chloro-phenyl-)-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-N '-(dimethyl-) methene base) acethydrazide has adopted the compound method of introducing among the patent ZL200510016205.X.
The crystal that former technology obtains, warp is revision test repeatedly, and the fluctuation ratio of its yield and purity is bigger, and quality is unstable, does not especially meet people's medication requirement (seeing accompanying drawing 4).
The former technology of table 1. formula I compound is investigated experimental result
But above-mentioned product carries out crystallization with mixed solvent ETHYLE ACETATE-DMF and can obtain favorable reproducibility, yield steady quality and purity better products (seeing accompanying drawing 5).The usage quantity of mixed solvent be 3～9 times of formula I compound quality (volume-mass ratio, mL/g), wherein preferred 5～8 times.
DMF accounts for 5%～15% of mixed solution TV.
Temperature during dissolving is 50 ℃～70 ℃.Be incubated 2～7 hours, slowly be cooled to room temperature then and place, promptly obtain the new crystal II type of formula I compound.
Specific operation process is:
Get a certain amount of formula I compound, and add ETHYLE ACETATE-DMF mixed solution, heated and stirred, to its dissolving, insulation for some time, the control cooling rate makes it slowly cool to room temperature.Solid to be separated out filters, and promptly gets formula I compound crystal form II.
Through the X-powder diffraction method, thermogravimetry is measured its characteristic then.
The crystal form II purity that this method makes is high, does not contain crystal water and recrystallisation solvent.In the described process parameters range of this method, repeat a plurality of batches simultaneously, circulation ratio is fabulous.To the monitoring energetically of drug safety, while GMP strictly regulates pharmacy corporation in view of at present, and the method that makes the high-quality feedstocks medicine seems very important.
The present invention (S)-α; α-[(2-chloro-phenyl-)-(4,5,6; 7-THTP also [3; 2-c] pyridine-5-yl)]-N '-(dimethyl-) methene base) acethydrazide crystal form II preparation of drug combination method is following: use standard and conventional technology, acceptable solid or liquid vehicle are combined, and make it at random with technology of pharmaceutics on acceptable auxiliary and vehicle combine to be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, Ucar 35, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension-s for example injection, pulvis or the like.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form can specifically be applied according to patient's the state of an illness, the situation of diagnosis; The amount of used compound or concentration are regulated in the scope of a broad; Usually, the weight range of active compound is 0.5%～90% (weight) of compsn.Another preferred range is 0.5%～70%.
Figure of description
Fig. 1 is the X-powder diagram of control sample.
Fig. 2 is the X-powder diagram of crystal form II.
Fig. 3 is the TG-DTA spectrogram of crystal form II.
Fig. 4 is the HPLC spectrogram of contrast formula I compound.
Fig. 5 is the HPLC spectrogram of crystal form II.
Embodiment
Below in conjunction with embodiment the present invention is done further explanation, it is indicative that embodiment is merely, and means that never it limits scope of the present invention by any way.
Embodiment 1:
Take by weighing formula I compound 5.0g, add 15mL ETHYLE ACETATE-DMF mixed solution (volume ratio 85: 15), be heated to 70 ℃, after the stirring and dissolving, be incubated 2 hours, filtered while hot, the control cooling rate makes it slowly cool to room temperature, places.Separate out solid, filter, about 24 hours of vacuum-drying gets colourless crystallization property powder.
Embodiment 2:
Take by weighing formula I compound 5.0g, add 30mL ETHYLE ACETATE-DMF mixed solution (volume ratio 90: 10), be heated to 60 ℃, after the stirring and dissolving, be incubated 4 hours, filtered while hot, the control cooling rate makes it slowly cool to room temperature, places.Separate out solid, filter, about 24 hours of vacuum-drying gets colourless crystallization property powder.
Embodiment 3:
Take by weighing formula I compound 5.0g, add 45mL acetoacetic ester-DMF mixed solution (volume ratio 90: 10), be heated to 50 ℃, after the stirring and dissolving, be incubated 7 hours, filtered while hot, the control cooling rate makes it slowly cool to room temperature, places.Separate out solid, filter, about 24 hours of vacuum-drying gets colourless crystallization property powder.
Embodiment 4:
Prepare hard gelatin capsule with following compositions:
Consumption/capsule weight concentration (%)
Formula I compound crystal form II 20mg 8.7
Dry starch 200mg 87.0
Magnesium Stearate 10mg 4.3
After the mentioned component mixing, be packed in the hard gelatin capsule with 460mg.
Embodiment 5:
Prepare tablet with following compositions:
Consumption/sheet weight concentration (%)
Formula I compound crystal form II 10mg 16.4
Starch 45mg 73.8
CMS sodium salt 4.5mg 7.4
Magnesium Stearate 0.5mg 0.8
Talcum powder 1mg 1.6
Supplementary material is dry in advance, and it is subsequent use to cross 100 mesh sieves.Earlier with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in the auxiliary material to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of auxiliary material; Cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dried particle cross the whole grain of 16 mesh sieves; Measure midbody content, mix compressing tablet on tabletting machine.
Claims (10)
1. one kind suc as formula (the S)-α shown in the I, α-[(2-chloro-phenyl-)-(4,5; 6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-crystal form II of N '-[(dimethyl-) methene base] acethydrazide; Have following physical behavior: its powder x-ray diffraction collection of illustrative plates has following diffraction angle (2 θ angle), spacing (d value) and relative intensity; Said 2 θ angular units are degree, and error is 0.2
2. the preparation method of a formula I compound crystal form II as claimed in claim 1 is characterized in that: in a certain amount of formula I compound, add ETHYLE ACETATE-DMF mixed solution, heated and stirred; To its dissolving; Insulation for some time, the control cooling rate makes it slowly cool to room temperature, solid to be separated out; Filter, promptly get formula I compound crystal form II.
3. the preparation method of a formula I compound crystal form II as claimed in claim 2, said ETHYLE ACETATE-DMF mixed solution, the TV of mixed solution are 3～9 times of corresponding formula I compound quality, and this multiple is volume-mass ratio, and its unit is mL/g.
4. the preparation method of formula I compound crystal form II as claimed in claim 3, said ETHYLE ACETATE-DMF mixed solution, the TV of mixed solution are 5～8 times of corresponding formula I compound quality, and this multiple is volume-mass ratio, and its unit is mL/g.
5. the preparation method of a formula I compound crystal form II as claimed in claim 2, said ETHYLE ACETATE-DMF mixed solution, wherein the volume of DMF accounts for 5%～15% of mixed solution TV.
6. the preparation method of a formula I compound crystal form II as claimed in claim 2, said ETHYLE ACETATE-DMF mixed solution, temperature is 50 ℃～70 ℃.
7. the preparation method of a formula I compound crystal form II as claimed in claim 2, said insulation for some time is 2～7 hours.
8. the preparation method of formula I compound crystal form II as claimed in claim 7, said insulation for some time is 3～5 hours.
9. pharmaceutical composition is characterized in that: comprise treat significant quantity crystal form II as claimed in claim 1 as activeconstituents and one or more pharmaceutically useful inert non-toxic carriers.
10. the purposes of the crystal form II of formula I compound as claimed in claim 1 in making medicament for resisting platelet aggregation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105465149A CN102010423B (en) | 2010-11-16 | 2010-11-16 | Crystal form II of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-yl)]-N'-(dimethyl) methylene) acethydrazide and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105465149A CN102010423B (en) | 2010-11-16 | 2010-11-16 | Crystal form II of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-yl)]-N'-(dimethyl) methylene) acethydrazide and preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102010423A CN102010423A (en) | 2011-04-13 |
| CN102010423B true CN102010423B (en) | 2012-06-27 |
Family
ID=43840771
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010105465149A Expired - Fee Related CN102010423B (en) | 2010-11-16 | 2010-11-16 | Crystal form II of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-yl)]-N'-(dimethyl) methylene) acethydrazide and preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102010423B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1683373A (en) * | 2005-02-23 | 2005-10-19 | 天津药物研究院 | Thiophenopyridine substituted acetyl hyarazine derivative |
| CN101781311A (en) * | 2010-03-12 | 2010-07-21 | 天津药物研究院 | Novel preparation method of platelet aggregation inhibition compound |
-
2010
- 2010-11-16 CN CN2010105465149A patent/CN102010423B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1683373A (en) * | 2005-02-23 | 2005-10-19 | 天津药物研究院 | Thiophenopyridine substituted acetyl hyarazine derivative |
| CN101781311A (en) * | 2010-03-12 | 2010-07-21 | 天津药物研究院 | Novel preparation method of platelet aggregation inhibition compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102010423A (en) | 2011-04-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106890147A (en) | Tablet containing 1 (β D glycopyranosyls) 3 (tolylthiophene ylmethyl) benzene compound | |
| KR102611445B1 (en) | Crystalline solid of salt of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Forms, methods for making them, and ways to use them | |
| CN102241690A (en) | Thienopyridine ester derivative containing nitrile group, its preparation method and its purpose | |
| TWI784276B (en) | New uses of complexes of metabolites of angiotensin II receptor antagonists and NEP inhibitors | |
| CN102219783A (en) | Vilazodone hydrochloride and composition thereof | |
| EP2002825B1 (en) | Pharmaceutical compositions comprising orlistat | |
| CN101774937B (en) | N-[2-(7-methoxyl-1-naphthyl)ethyl]acetamide and compound thereof | |
| CN102010423B (en) | Crystal form II of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-yl)]-N'-(dimethyl) methylene) acethydrazide and preparation method | |
| CN102010424B (en) | Crystal form III of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-thiophane[3,2-c]pyridine-5-yl)-N'-(dimethyl)methylene] acethydrazide and preparation method thereof | |
| CN101684108B (en) | 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid and composition thereof | |
| CN101781310B (en) | Thiofuran-pyridine [3, 2-c] contained acethydrazide derivative and preparation method and application thereof | |
| CN101735206B (en) | Crystalline form IV of azimilide dihydrochloride, preparation method and application thereof | |
| CN101735203B (en) | Azimilide dihydrochloride crystal form II as well as preparation method and application thereof | |
| CN101735204B (en) | Crystalline form III of azimilide dihydrochloride, preparation method and application thereof | |
| CN101735205B (en) | Crystalline form V of azimilide dihydrochloride, preparation method and application thereof | |
| CN101735202B (en) | Azimilide dihydrochloride crystal form I as well as preparation method and application thereof | |
| CN102120746B (en) | Clopidogrel hydrochloride crystal form II as well as preparation method and application thereof | |
| CN101817741B (en) | Crystal form IX of sofalcone, preparation method and use thereof | |
| CN101817742B (en) | Crystal form X of sofalcone, preparation method and use thereof | |
| CN102285996A (en) | Benzenesulfonic acid clopidogrel crystal form II, preparation method and application thereof | |
| CN102120745B (en) | Crystal form I of clopidogrel hydrochloride and preparation method and application thereof | |
| CN101781194B (en) | Crystal form V of sofalcone and preparation method and application thereof | |
| CN101735038B (en) | Crystal form I of sofalcone and preparation method and application thereof | |
| CN101781192B (en) | Crystal form VI of sofalcone and preparation method and application thereof | |
| CN101781195B (en) | Crystal form VII of sofalcone and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120627 Termination date: 20211116 |