CN103570741A - Prasugrel novel crystals and preparation method thereof - Google Patents

Prasugrel novel crystals and preparation method thereof Download PDF

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Publication number
CN103570741A
CN103570741A CN201210260168.7A CN201210260168A CN103570741A CN 103570741 A CN103570741 A CN 103570741A CN 201210260168 A CN201210260168 A CN 201210260168A CN 103570741 A CN103570741 A CN 103570741A
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prasugrel
crystal formation
new
places
radiation
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CN201210260168.7A
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CN103570741B (en
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张雅然
李蒙
道硕
刘磊娜
何晓燕
李少华
金晓利
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石药集团中奇制药技术(石家庄)有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic 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
    • C07D495/04Ortho-condensed systems

Abstract

The invention discloses prasugrel novel crystals and a preparation method thereof. The prasugrel novel crystals solve the problem that the existing prasugrel crystal is not conducive to drug preparation. The preparation method provides a plurality of the prasugrel novel crystals. The prasugrel novel crystals have the advantages of good stability and high rate of dissolution from drugs.

Description

Prasugrel new crystal and preparation method thereof
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to new crystal of antithrombotic reagent prasugrel and preparation method thereof.
Background technology
Chemistry 2-acetoxyl group-5-(a-cyclopropyl carbonyl-2-luorobenzyl by name of prasugrel (prasugrel))-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine also, and structural formula is suc as formula shown in I.Prasugrel is the oral antiplatelet drug of and affiliate first pharmacy San Gong company joint development next by gift,
Formula I.
Prasugrel is a kind of adenosine diphosphate (ADP) (ADP) receptor antagonist, belongs to prodrug, effectively changes in vivo its active metabolite R-138727.R-138727 has reduced the dependency to cytochrome P-450 enzyme, and special, the irreversible purine bases acceptor that is attached to thrombocyte P2Y12 rapidly,, suppress ADP and regulate hematoblastic activity and gathering, thus the activity of performance anti-platelet aggregation.Clinical study proves, takes after prasugrel that integrated risk is low, good effect.Therefore the good prospect of prasugrel receives much attention.
Prasugrel is with the form listing of hydrochloride at present; hydrochloride and the maleate of prasugrel in the patent of the CN0185108.6 of Sankyo Co., Ltd's application, have been protected; claim prasugrel to make after these two kinds of salt; possess oral absorptivity, metabolic activity and platelet aggregation restraining effect well; toxicity is low, easily preservation, good stability.
The CN201010141713.1 of in April, 2010 08 Shanghai Institute of Pharmaceutical Industry application has disclosed the problem that prasugrel hydrochloride having and maleate exist poorly water-soluble.So invented prasugrel hydrochloride having solvate.Other contrivers by goal displacement in the invention of other salt, as CN102342921, WO2011127300, WO2011016686, WO2011004392, GB2469883, WO2009130289 disclose the salt such as prasugrel hydrobromide, but prasugrel salify step can increase industry cost in industrial production undoubtedly.
Some contrivers start to pay close attention to the one-tenth property of medicine of prasugrel free alkali.The patent that relates to the crystal formation of prasugrel free alkali in prior art is respectively CN200910170675.X, WO2009066326, WO2009062044, WO2011057592.
In August, 2009, the CN200910170675.X of 26, Huahai Pharmaceutical Co., Ltd., Zhejiang application disclosed preparation method and the recrystallization method of prasugrel, and provided its XRD figure spectrum, and its fusing point is 121.3 ~ 125.2 ℃.Its recrystallization method carries out recrystallization with alcoholic solvent.The preparation method of WO2009062044 prasugrel and salt thereof, comprising recrystallization method is: prasugrel crude product methyl alcohol reflux, stir 30min, and cooling, filters, and uses washed with methanol filter cake, dries.Above-mentioned two patents are similar to the crystallization method of prasugrel, compare the XRD figure spectrum that it provides, and find that the prasugrel crystal formation that two patents are reported is same crystal formation.The solvability of this crystal formation is undesirable, becomes the property of medicine poor, is not suitable for directly as bulk drug.
Patent WO2009066326 discloses the preparation method of prasugrel and salt thereof, recrystallization method and prasugrel XRD figure spectrum comprising prasugrel, its recrystallization method is for to be heated to 60 ~ 65 ℃ of dissolvings by prasugrel crude product by ethyl acetate, keep this temperature to stir 1h, add hexanaphthene to stir again 1h, be cooled to 0-5 ℃ and stir 1h, filtration drying.Preparation method's technique of the disclosed prasugrel crystal formation of this patent is comparatively loaded down with trivial details, and gained crystal formation is still identical with crystal form X RD collection of illustrative plates in above-mentioned patent WO2009062044.
Patent WO2011057592 discloses the preparation method of prasugrel and salt thereof, and wherein recrystallization method is: by prasugrel crude product acetone solution, add gac, filter, filter cake acetone rinsing, filtrate is cooled to-15 ~-10 ℃, add water, stir 2h, filter.Regrettably, the crystal formation that patent relates to is also consistent with disclosed crystal formation in WO2009062044.
For the polymorphic of medicine, the polymorphic of medicine directly affects physico-chemical property (as fusing point, solubleness, dissolution rate and stability etc.) and the clinical efficacy (absorptivity and efficacy) of medicine.Different polymorphics can directly affect processing or the production of bulk drug and preparation, and can affect stability, solubleness and the bioavailability of preparation.For prasugrel, the crystal formation existing at present cannot reach medicinal requirements well, so its listing raw material is only prasugrel hydrochloride having.The shorter operational path of the selection schemer of should trying one's best in the industrial production of bulk drug, prasugrel salify step has increased industrial cost undoubtedly.Therefore research and develop the new crystal of new prasugrel, to improve its dissolution rate, improve bioavailability to improve drug quality, guarantee that clinical drug effect becomes issue to be resolved that current those skilled in the art endeavour.
Summary of the invention
In order to solve existing prasugrel free alkali, be not suitable for the technical problem of patent medicine, inventor, through a large amount of research, provides three kinds of good stabilities, and solubleness is high, prasugrel new crystal that dissolution rate is high and preparation method thereof.
The object of this invention is to provide new prasugrel crystal formation thing.
Specifically, the invention provides a kind of new prasugrel M crystal formation, use Cu-Ka radiation, its x-ray diffraction pattern, 2 θ that show with kilsyth basalt have diffraction peak at 8.6 ± 0.2 and 20.1 ± 0.2 places.
Further, new prasugrel M crystal formation provided by the present invention, is used Cu-Ka radiation, its x-ray diffraction pattern, and 2 θ that show with kilsyth basalt also have diffraction peak at 16.4 ± 0.2,17.3 ± 0.2,30.9 ± 0.2 places.
Further, new prasugrel M crystal formation provided by the present invention, use Cu-Ka radiation, its x-ray diffraction pattern, 2 θ that show with kilsyth basalt also have diffraction peak at 13.2 ± 0.2,13.6 ± 0.2,19.0 ± 0.2,19.3 ± 0.2,19.5 ± 0.2,20.0 ± 0.2,21.7 ± 0.2,23.7 ± 0.2,24.2 ± 0.2,24.4 ± 0.2 places.
The present invention also provides a kind of new prasugrel N crystal formation, uses Cu-Ka radiation, its x-ray diffraction pattern, and 2 θ that show with kilsyth basalt have highest peak at 19.5 ± 0.2 places.
Further, new prasugrel N crystal formation provided by the present invention, use Cu-Ka radiation, its x-ray diffraction pattern, 2 θ that show with kilsyth basalt have strong diffraction peak at 7.9 ± 0.2,11.4 ± 0.2,14.6 ± 0.2,15.6 ± 0.2,31.5 ± 0.2 places, and the relative intensity of described strong diffraction peak is greater than 80%.
Further, new prasugrel N crystal formation provided by the present invention, use Cu-Ka radiation, its x-ray diffraction pattern, 2 θ that show with kilsyth basalt have strong diffraction peak at 7.9 ± 0.2,11.4 ± 0.2,14.6 ± 0.2,14.9 ± 0.2,15.6 ± 0.2,19.0 ± 0.2,21.6 ± 0.2,31.5 ± 0.2 places, and the relative intensity of described strong diffraction peak is greater than 70%.
The present invention also provides a kind of new prasugrel P crystal formation, uses Cu-Ka radiation, its x-ray diffraction pattern, and 2 θ that show with kilsyth basalt have highest peak at 18.9 ± 0.2 places.
Further, new prasugrel P crystal formation provided by the present invention, use Cu-Ka radiation, its x-ray diffraction pattern, 2 θ that show with kilsyth basalt have strong diffraction peak at 13.5 ± 0.2,14.8 ± 0.2,19.4 ± 0.2,21.5 ± 0.2,23.5 ± 0.2,24.4 ± 0.2 places, and the relative intensity of described strong diffraction peak is greater than 60%.
Another object of the present invention is to provide the preparation method of new prasugrel crystal formation.
Concrete, the invention provides the preparation method of described prasugrel M crystal formation:
(1) prasugrel crude product is joined in organic solvent;
(2) heating for dissolving;
(3) under stirring, be slowly down to room temperature, adularescent solid is separated out;
(4) growing the grain is 0.5 ~ 4 hour;
(5) filter, obtain white crystal, vacuum-drying;
Wherein, described organic solvent is one or more in Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF) and DMF.
The present invention also provides the preparation method of described prasugrel N crystal formation:
(1) prasugrel crude product is joined in the mixing solutions of organic solvent A and sherwood oil;
(2) heating for dissolving;
(3) the standing room temperature of being slowly down to, adularescent solid is separated out;
(4) growing the grain is 0.5 ~ 3 hour;
(5) filter, obtain white crystal, vacuum-drying;
Wherein, described organic solvent A is selected from a kind of in butanone, acetone, ethyl acetate, butylacetate, ethyl formate, mibk.
Further, the volume ratio of the organic solvent A described in the preparation method of prasugrel N crystal formation and sherwood oil is 1:0.5 ~ 3.
The present invention also provides a kind of preparation method of new prasugrel P crystal formation:
(1) prasugrel crude product is joined in organic solvent, dissolve;
(2) solution is poured in purified water;
(3) standing, adularescent solid is separated out;
(4) growing the grain is 0.5 ~ 1.5 hour;
(5) filter, obtain white crystal, vacuum-drying;
Wherein, described organic solvent is selected from one or more in acetonitrile, ethanol, methyl alcohol, Virahol, tetrahydrofuran (THF), DMF and dimethyl sulfoxide (DMSO).
New pula Cray crystal formation provided by the invention has overcome problems of the prior art, has embodied following useful technique effect:
1, new prasugrel crystal formation provided by the present invention is compared with original crystal formation, has improved the stability of medicine;
2, the preparation technology of prasugrel crystal formation provided by the invention is simple, compares with the prasugrel hydrochloride having of listing, has reduced salify step, reduces industrial cost, has shortened production line;
3, to adopt tablet prepared by the prasugrel new crystal provide and the hydrochloric acid prasugrel tablets of listing to compare dissolution rate suitable in the present invention.
Accompanying drawing explanation
Accompanying drawing 1 is for adopting the XRD figure spectrum of the prasugrel M crystal formation of embodiment 1 preparation.
Accompanying drawing 2 is for adopting the XRD figure spectrum of the prasugrel N crystal formation of embodiment 3 preparations.
Accompanying drawing 3 is for adopting the XRD figure spectrum of the prasugrel P crystal formation of embodiment 5 preparations.
Accompanying drawing 4 prasugrel tablets stripping curves.
embodiment
Following examples are to illustrate of the present invention, should not be construed as limiting scope of the present invention.
embodiment 1the preparation of prasugrel M crystal formation
2 grams of prasugrel crude products are joined in 6ml Isosorbide-5-Nitrae-dioxane, be heated to 30 degree and dissolve, under agitation condition, slow cooling is to room temperature, adularescent solid is separated out, and continues to stir 2 hours, filters, and obtains white crystal, vacuum drying, obtains 1.71 grams of products, yield 85.5%.
embodiment 2the preparation of prasugrel M crystal formation
2 grams of prasugrel crude products are joined in 6ml tetrahydrofuran (THF), be heated to 30 degree and dissolve, under agitation condition, slow cooling is to room temperature, and adularescent solid is separated out, continue to stir 0.5 hour, filter, obtain white crystal, vacuum drying, obtains 1.58 grams of products, yield 79.0%.
embodiment 3the preparation of prasugrel N crystal formation
2 grams of prasugrel crude products are joined in the mixed solvent of 10ml butanone: sherwood oil=1:2, be heated to 80 degree and dissolve, standing slow cooling is to room temperature, and adularescent solid is separated out, growing the grain 2 hours, filters, and obtains white crystal, vacuum drying, obtains 1.66 grams of products, yield 83.1%.
embodiment 4the preparation of prasugrel N crystal formation
2 grams of prasugrel crude products are joined in the mixed solvent of 10ml ethyl acetate: sherwood oil=1:0.5, be heated to 80 degree and dissolve, standing slow cooling is to room temperature, and adularescent solid is separated out, growing the grain 2 hours, filters, and obtains white crystal, vacuum drying, obtains 1.57 grams of products, yield 78.5%.
embodiment 5the preparation of prasugrel P crystal formation
2 grams of prasugrel crude products are joined in 20ml DMF, stir, under room temperature, dissolve clarification, solution is poured in 100ml purified water, and adularescent solid is separated out, and growing the grain 1 hour filters, obtain white crystal, vacuum drying, obtains 1.64 grams of products, yield 82.0%.
embodiment 6the preparation of prasugrel P crystal formation
2 grams of prasugrel crude products are joined in 20ml ethanol, stir, dissolve clarification under room temperature, solution is poured in 100ml purified water, adularescent solid is separated out, and growing the grain 0.5 hour filters, and obtains white crystal, and vacuum drying, obtains 1.52 grams of products, yield 76.0%.
comparative example 1
According to the preparation method of embodiment in CN200910170675.X 8, under nitrogen protection, with Virahol, 2g prasugrel is carried out to recrystallization, room temperature reaction 12 hours, crystallization solid, obtains off-white color solid 0.63g, and yield is 31.5%.
comparative example 2
According to the preparation method of prasugrel in WO2009066326,2g prasugrel crude product is heated to 60-65 ℃ of dissolving by ethyl acetate, keep this temperature to stir 1h, add hexanaphthene to stir again 1h, be cooled to 0-5 ℃ and stir 1h, filtration drying.Obtain light yellow crystal.
comparative example 3
Patent WO2011057592 discloses the preparation method of prasugrel and salt thereof, and wherein recrystallization method is: by prasugrel crude product acetone solution, add gac, filter, filter cake acetone rinsing, filtrate is cooled to-15 ~-10 ℃, add water, stir 2h, filter.
embodiment 7stability test
1, exposure experiments to light
The crystal formation raw material of the prasugrel crystal formation ,Yuan Yan unit prasugrel hydrochloride having of prasugrel M, N, P crystal formation, comparative example 1-3 is evenly shared to uncovered culture dish, thickness≤5mm, adjustable range, making intensity of illumination is 4500 ± 500Lx, in sampling in 10 days, detect, and contrast with the result of 0 day.The results are shown in Table 1,
Table 1 exposure experiments to light (4500 ± 500Lx)
Note: 23 ~ 26 ℃ of temperature variation; Relative humidity variations 56 ~ 63%.
2, high temperature test
The crystal formation raw material of the prasugrel crystal formation of prasugrel M, N, P crystal formation, comparative example 1-3, prasugrel hydrochloride having is positioned over respectively in sealing clean vial, is placed in 60 ℃ of thermostatic drying chambers, in sampling in 10 days, detect, and contrast with the result of 0 day.The results are shown in Table 2,
Table 2 high temperature test (60 ℃)
Note: relative humidity variations 54%-62%.
3, high wet test
The crystal formation raw material of the prasugrel crystal formation of prasugrel M, N, P crystal formation, comparative example 1-3, prasugrel hydrochloride having is evenly shared to uncovered culture dish, thickness≤5mm, be placed in room temperature (25 ℃ of left and right), in the fixed temperature and humidity incubator of relative humidity 92.5 ± 5%, in sampling in 10 days, detect, and contrast with the result of 0 day.The results are shown in Table 3,
The high wet test of table 3 (92.5 ± 5%)
Note: temperature variation 23-26 ℃.
4, accelerated test
The crystal formation raw material of the prasugrel crystal formation of prasugrel M, N, P crystal formation, comparative example 1-3, prasugrel hydrochloride having is packed with polyethylene film plastic bag sealing, be placed in 40 ± 2 ℃, relative humidity is in 75 ± 5% fixed temperature and humidity incubator, place six months, respectively at 1,2,3 samplings at the end of month detect, and contrast with the result of 0 month.The results are shown in Table 4,
Table 4 accelerated test (40 ℃, relative humidity 75%)
Experimental result shows, in stability test, the detected result of prasugrel M provided by the invention, N, P crystal formation, is all better than the crystal formation of prasugrel in prior art and commercially available hydrochloric acid prasugrel.Prasugrel crystal formation provided by the invention possesses good stability.
embodiment 8
The preparation method of prasugrel tablets
Prescription (specification 5mg, 100)
Prasugrel and sodium lauryl sulphate are pre-mixed, and then mix dry method granulation with N.F,USP MANNITOL, Microcrystalline Cellulose, Vltra tears, croscarmellose sodium, Magnesium Stearate.After adding croscarmellose sodium, Magnesium Stearate to mix, particle is pressed into the tablet that 125-250mg is heavy at home and abroad.Then the tablet making is carried out to film coating.
The prasugrel crystal formation of prasugrel M, N, P crystal formation, comparative example 1-3 is prepared into 100, tablet as stated above.Investigate tablet appearance and content, the results are shown in Table 5,
The character comparison in blocks of table 5 product
Conclusion: from the above results, the resulting prasugrel crystal form M of the present invention, N, P are after being prepared into medicine, and outward appearance is qualified, and uniformity of dosage units meets the requirements, and are obviously better than the prepared tablet of comparative example 1 ~ 3 crystal formation.
embodiment 9
Embodiment 1, embodiment 3, embodiment 5, the prepared tablet of comparative example 1 ~ 3 and commercially available hydrochloric acid prasugrel are carried out to dissolution rate experiment, the results are shown in Table 6,
Table 6 dissolution rate detected result
Conclusion: the M of prasugrel provided by the present invention, N, the prepared tablet of P crystal formation, compare with the tablet that existing crystal formation is prepared, there is good dissolution rate.Suitable with commercially available hydrochloric acid prasugrel tablets result of extraction.

Claims (12)

1. a new prasugrel M crystal formation, is used Cu-Ka radiation, its x-ray diffraction pattern, and 2 θ that show with kilsyth basalt have diffraction peak at 8.6 ± 0.2 and 20.1 ± 0.2 places.
2. new prasugrel M crystal formation as claimed in claim 1, is used Cu-Ka radiation, its x-ray diffraction pattern, and 2 θ that show with kilsyth basalt also have diffraction peak at 16.4 ± 0.2,17.3 ± 0.2,30.9 ± 0.2 places.
3. new prasugrel M crystal formation as claimed in claim 2, use Cu-Ka radiation, its x-ray diffraction pattern, 2 θ that show with kilsyth basalt also have diffraction peak at 13.2 ± 0.2,13.6 ± 0.2,19.0 ± 0.2,19.3 ± 0.2,19.5 ± 0.2,20.0 ± 0.2,21.7 ± 0.2,23.7 ± 0.2,24.2 ± 0.2,24.4 ± 0.2 places.
4. a new prasugrel N crystal formation, is used Cu-Ka radiation, its x-ray diffraction pattern, and 2 θ that show with kilsyth basalt have highest peak at 19.5 ± 0.2 places.
5. new prasugrel N crystal formation as claimed in claim 4, use Cu-Ka radiation, its x-ray diffraction pattern, 2 θ that show with kilsyth basalt have strong diffraction peak at 7.9 ± 0.2,11.4 ± 0.2,14.6 ± 0.2,15.6 ± 0.2,31.5 ± 0.2 places, and the relative intensity of described strong diffraction peak is greater than 80%.
6. new prasugrel N crystal formation as claimed in claim 4, use Cu-Ka radiation, its x-ray diffraction pattern, 2 θ that show with kilsyth basalt 7.9 ± 0.2,11.4 ± 0.2,, there is strong diffraction peak at 14.6 ± 0.2,14.9 ± 0.2,15.6 ± 0.2,19.0 ± 0.2,21.6 ± 0.2,31.5 ± 0.2 places, the relative intensity of described strong diffraction peak is greater than 70%.
7. a new prasugrel P crystal formation, is used Cu-Ka radiation, its x-ray diffraction pattern, and 2 θ that show with kilsyth basalt have highest peak at 18.9 ± 0.2 places.
8. new prasugrel P crystal formation as claimed in claim 7, use Cu-Ka radiation, its x-ray diffraction pattern, 2 θ that show with kilsyth basalt have strong diffraction peak at 13.5 ± 0.2,14.8 ± 0.2,19.4 ± 0.2,21.5 ± 0.2,23.5 ± 0.2,24.4 ± 0.2 places, and the relative intensity of described strong diffraction peak is greater than 60%.
9. the preparation method of the new prasugrel M crystal formation as described in claim 1 ~ 3 any one:
(1) prasugrel crude product is joined in organic solvent;
(2) heating for dissolving;
(3) under stirring, be slowly down to room temperature, adularescent solid is separated out;
(4) growing the grain is 0.5 ~ 4 hour;
(5) filter, obtain white crystal, vacuum-drying;
Wherein, described organic solvent is one or more in Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF) and DMF.
10. the preparation method of the new prasugrel N crystal formation as described in claim 4 ~ 6 any one:
(1) prasugrel crude product is joined in the mixing solutions of organic solvent A and sherwood oil;
(2) heating for dissolving;
(3) the standing room temperature of being slowly down to, adularescent solid is separated out;
(4) growing the grain is 0.5 ~ 3 hour;
(5) filter, obtain white crystal, vacuum-drying;
Wherein, described organic solvent A is a kind of in butanone, acetone, ethyl acetate, butylacetate, ethyl formate, mibk.
The preparation method of 11. new prasugrel N crystal formations as claimed in claim 10, is characterized in that, described organic solvent A and the volume ratio of sherwood oil are 1:0.5 ~ 3.
12. preparation methods of new prasugrel P crystal formation as claimed in claim 7 or 8:
(1) prasugrel crude product is joined in organic solvent, dissolve;
(2) solution is poured in purified water;
(3) standing, adularescent solid is separated out;
(4) growing the grain is 0.5 ~ 1.5 hour;
(5) filter, obtain white crystal, vacuum-drying;
Wherein, described organic solvent is selected from one or more in acetonitrile, ethanol, methyl alcohol, Virahol, tetrahydrofuran (THF), DMF and dimethyl sulfoxide (DMSO).
CN201210260168.7A 2012-07-26 2012-07-26 Prasugrel novel crystal forms and preparation method thereof Active CN103570741B (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101343278A (en) * 2007-12-11 2009-01-14 鲁南制药集团股份有限公司 Preparation method for hydrogenated pyridine derivant and its salt
WO2009062044A2 (en) * 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Processes for the preparation of prasugrel, and its salts and polymorphs
WO2009066326A2 (en) * 2007-11-19 2009-05-28 Msn Laboratories Limited Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts
CN101993447A (en) * 2009-08-26 2011-03-30 浙江华海药业股份有限公司 Method for synthesizing Prasugrel artificially
CN102612519A (en) * 2009-11-16 2012-07-25 赞蒂瓦有限合伙公司 Method of producing highly pure prasugrel and pharmaceutically acceptable salts thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009062044A2 (en) * 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Processes for the preparation of prasugrel, and its salts and polymorphs
WO2009066326A2 (en) * 2007-11-19 2009-05-28 Msn Laboratories Limited Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts
CN101343278A (en) * 2007-12-11 2009-01-14 鲁南制药集团股份有限公司 Preparation method for hydrogenated pyridine derivant and its salt
CN101993447A (en) * 2009-08-26 2011-03-30 浙江华海药业股份有限公司 Method for synthesizing Prasugrel artificially
CN102612519A (en) * 2009-11-16 2012-07-25 赞蒂瓦有限合伙公司 Method of producing highly pure prasugrel and pharmaceutically acceptable salts thereof

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