CN107915743A - A kind of prasugrel hydrogen sulfate crystal form IV and preparation method thereof - Google Patents
A kind of prasugrel hydrogen sulfate crystal form IV and preparation method thereof Download PDFInfo
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- CN107915743A CN107915743A CN201610882527.0A CN201610882527A CN107915743A CN 107915743 A CN107915743 A CN 107915743A CN 201610882527 A CN201610882527 A CN 201610882527A CN 107915743 A CN107915743 A CN 107915743A
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- prasugrel
- hydrogen sulfate
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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
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Abstract
The invention discloses a kind of crystallization of new prasugrel hydrogen sulfate crystal form IV (Formula II)；And the crystal or the preparation method of its crystallization.Prasugrel is dissolved in organic solvent, the concentrated sulfuric acid or the concentrated sulfuric acid and solvent mixed liquor are slowly added dropwise under stirring, prasugrel is 1: 1 1.1 with strong sulfuric acid response molar ratio, solution is heated with stirring to dissolved clarification, crystallisation by cooling can be obtained by prasugrel hydrogen sulfate crystal form IV to crystalline substance is gone out, with conventional method filtering drying.By XRD spectra it can be confirmed that product crystallinity is high, crystal size is larger, plane of crystal is bright and clean；Filtering and rate of drying are fast, improve preparation process efficiency, the application being more advantageous in prepared by pharmaceutical preparation.
Description
Technical field
The present invention relates to the novel crystal forms IV and preparation method of a kind of prasugrel hydrogen sulfate, belongs to drug crystallization technology neck
Domain.
Background technology
Prasugrel, English name (Prasugrel), its chemical name are：2- [2- (acetoxyl group) -6,7- dihydro thiophenes
Fen simultaneously [3,2-c] pyridine -5 (4H)-yl] -1- cyclopropyl -2- (2- fluorophenyls) ethyl ketone, structural formula such as following formula (I).Prasugrel
It is that pula is shown by a kind of platelet ADP receptor blocking agent of the common company's joint development of Lilly Co., Eli. and Japan three, research
Effect of the effect of the pre- preventing thrombosis of Gray than chlorine pyrroles's thunder is also eager to excel, in experiments it is found that prasugrel can faster work,
And having preferably effect, the thrombus after the patient medication of prasugrel group in blood is less than chlorine pyrroles's thunder group, prasugrel
The incidence of group ischemic event is reduced than chlorine pyrroles's thunder group, and the effect that prasugrel antiplatelet is built up is obvious and rapid.
Prasugrel hydrogen sulfate (such as Formula II) has a variety of crystal forms.
Patent WO2011127300A1 (crystal form of prasugrel salt) discloses 3 kinds of S1 types, S2 types and S3 types crystal forms, and gives
The specific preparation method of different crystal forms is gone out.
Patent WO2011027988A2 (novel crystal forms of prasugrel hydrogen sulfate) disclose two kinds of crystal forms of I types and II types and
Its preparation method.
Patent EP0542411 discloses a kind of preparation method of hydrogenated pyridine derivative and its dynamic isomer, described
Hydrogenated pyridine derivative is the parent nucleus of prasugrel, but is not directed to prasugrel hydrogen sulfate and preparation method thereof.
Patent CN102099361 and US20110124675 disclose prasugrel hydrogen sulfate and its pharmaceutical composition, and
Point out the disulfate with good stability, absorbability, hypotoxicity, metabolic activity and blood platelet inhibitory action.
Patent CN101456864A discloses a kind of prasugrel hydrogen sulfate, composition and preparation method thereof.Pass through this
Inventing the experiment, we have found a kind of new polymorphic IV of prasugrel hydrogen sulfate.
The content of the invention
It is an object of the invention to introduce the prasugrel hydrogen sulfate novel crystal forms and preparation method of research process discovery,
Poor for prasugrel hydrogen sulfate stability in the current technology of solution, crystal size is small, and magma is sticky, and bad adverse reaction is high
Defect provides new crystal form resource.Novel crystal forms IV and preparation the present invention provides a kind of prasugrel hydrogen sulfate do not reported
Method.
Novel crystal forms IV the invention discloses a kind of prasugrel hydrogen sulfate and preparation method thereof.
Technical solution provided by the invention is as follows：
The invention discloses a kind of prasugrel hydrogen sulfate crystal, it is characterized in that the powder X-ray of prasugrel hydrogen sulfate-
X ray diffraction angle (2 θ °) is respectively 7.5 ± 0.1,8.3 ± 0.1,8.6 ± 0.1,10.7 ± 0.1,12.7 ± 0.1,13.2 ±
0.1,13.5 ± 0.1,14.5 ± 0.1,15.3 ± 0.1,16.3 ± 0.1,17.4 ± 0.1,18.2 ± 0.1,19.1 ± 0.1,
20.0 ± 0.1,20.6 ± 0.1,21.4 ± 0.1,22.7 ± 0.1,23.2 ± 0.1,23.6 ± 0.1,24.2 ± 0.1,24.7 ±
0.1,25.0 ± 0.1,25.8 ± 0.1,26.7 ± 0.1,27.5 ± 0.1,28.5 ± 0.1,29.5 ± 0.1,29.7 ± 0.1,
There is characteristic peak at 31.7 ± 0.1, and 38.9 ± 0.1 degree.
The prasugrel hydrogen sulfate crystal, it is characterized in that the infrared spectrum of prasugrel hydrogen sulfate 428 ±
2,470 ± 2,509 ± 2,536 ± 2,586 ± 2,603 ± 2,651 ± 2,673 ± 2,731 ± 2,763 ± 2,798 ± 2,821 ±
2,848 ± 2,879 ± 2,910 ± 2,945 ± 2,977 ± 2,1006 ± 2,1029 ± 2,1064 ± 2,1083 ± 2,1163 ± 2,
1197 ± 2,1228 ± 2,1375 ± 2,1392 ± 2,1444 ± 2,1463 ± 2,1498 ± 2,1589 ± 2,1614 ± 2,1706
± 2,1765 ± 2m-1There is characteristic peak at place.
The prasugrel hydrogen sulfate crystal, it is characterized in that differential scanning calorimetric curve has a suction at 232 ± 2 DEG C
Thermal spike
The preparation method of the prasugrel hydrogen sulfate crystal form IV, comprises the following steps：Prasugrel is dissolved in
In organic solvent, the concentrated sulfuric acid or the concentrated sulfuric acid and solvent mixed liquor are slowly added dropwise under stirring, solution is heated with stirring to dissolved clarification, cools down
Crystal precipitation is crystallized to, target product is can be obtained by with conventional method filtering drying, being separated out if any crystal to pass through
Filter is evaporated under reduced pressure solvent after obtaining product, or reaction, and cooling crystallization obtains target product, can also pass through the method for recrystallization
Refined target product.
In above-mentioned preparation reaction process：
(1) reaction dissolvent can be aromatic hydrocarbon, aliphatic hydrocarbon, halogenated hydrocarbons, esters, ketone, alcohols, the one of nitrile organic solvent
Kind or more than one, can select benzene,toluene,xylene, ethane, hexamethylene, n-hexane, dichloromethane, chloroform, ethanol,
Sec-butyl alcohol, normal propyl alcohol, ethyl acetate, methyl acetate, Ethyl formate, ether, petroleum ether, acetone, butanone, one kind of DMF or one
More than kind.As long as solvent for use can dissolve reactant and not hinder reaction to carry out.Quantity of solvent is different with solvent species and becomes
Change, but to ensure reaction mass dissolved clarification.
(2) reaction temperature changes, -40 DEG C~0 DEG C of General reactions temperature range selected as solvent species is different, excellent
- 35 DEG C~5 DEG C of choosing, more preferably -20 DEG C~0 DEG C, the reactive crystallization time changes also with solvent species difference or with anti-
Answer temperature different and change, the General reactions time be 10 minutes to 24 it is small when, preferably 1 it is small when to 12 it is small when.
(3) to ensure that the reaction was complete during the reaction, i.e., the concentrated sulfuric acid is excessive, first choice reaction relative to prasugrel
Molar ratio is 1: 1-1.1.
(4) dropwise addition of the concentrated sulfuric acid can be added disposably under agitation, can also be added in batches, concentrated sulfuric acid feed postition
The concentrated sulfuric acid can directly be added dropwise, added after can also being diluted with reaction dissolvent, the concentrated sulfuric acid after being diluted with solvent can also be added
Enter to in the dissolved Prasugrel solution of solvent.
In the preparation method, preferably depressurized to obtain high quality prasugrel hydrogen sulfate product at 30~60 DEG C
Dry, decompression drying at more preferably 40~50 DEG C.
The prasugrel hydrogen sulfate crystal is to suppressing caused by ADP and collagen as the purposes of drug regimen
Platelet aggregation.
The present invention prasugrel hydrogen sulfate crystal form preparation method the advantages of be：Easy to operate, reaction condition is easily-controllable, leads to
XRD spectra confirmation is crossed, crystal structure degree is high；Filtering and rate of drying are fast, improve preparation process efficiency.
Brief description of the drawings
Fig. 1：The X-ray diffracting spectrum of prasugrel hydrogen sulfate crystal form IV；
Fig. 2：The infared spectrum of prasugrel hydrogen sulfate crystal form IV；
Fig. 3：Means of differential scanning calorimetry (DSC) curve of prasugrel hydrogen sulfate crystal form IV；
Embodiment
Below by by the embodiment of embodiment form, the above of the present invention is explained, but should not incite somebody to action
This scope for being interpreted as the above-mentioned theme of the present invention is only limitted to following embodiments.In every case the skill realized based on the above of the present invention
Art belongs to scope of the invention.
Embodiment 1
5g prasugrels are dissolved in 30ml xylene solvents, stir 30min at room temperature.Start to be added dropwise under continuously stirring
Concentrated sulfuric acid 1.36g, is continuously stirring to dissolved clarification, is then cooled to 5 DEG C with 5 DEG C/min, continues stirring until there is a large amount of crystal to separate out,
The crystal separated out is filtered, is dried in vacuo at 40 DEG C, obtains 3.75g prasugrel hydrogen sulfate IV crystal forms.
The powder x-ray diffraction collection of illustrative plates of product is consistent with Fig. 1, and infrared spectrum is consistent with Fig. 2, its means of differential scanning calorimetry is bent
Line has an endothermic peak at 232 DEG C.
Embodiment 2
3g prasugrels are dissolved in 15ml ethyl acetate solvents, stir 30min at room temperature.Start to drip under continuously stirring
Enriching sulfuric acid 0.79g, is continuously stirring to dissolved clarification, is then cooled to 0 DEG C with 1 DEG C/min, continues stirring until there is a large amount of crystal to analyse
Go out, filter the crystal of precipitation, filter cake is washed with the ethyl acetate of frost, will be dried in vacuo at 50 DEG C of filter cake, obtain 2.46g whites
Prasugrel hydrogen sulfate IV crystal forms.
The powder x-ray diffraction collection of illustrative plates of product is consistent with Fig. 1, and infrared spectrum is consistent with Fig. 2, its means of differential scanning calorimetry is bent
Line has an endothermic peak at 232.5 DEG C.
Embodiment 3
5g prasugrels are dissolved in 20ml dichloromethane solvents, stir 1h at room temperature, start to be added dropwise under continuously stirring
Concentrated sulfuric acid 1.36g, is continuously stirring to dissolved clarification, is cooled to -10 DEG C with 10 DEG C/min, then proceedes to stir, filters the crystal of precipitation,
Washed with 30ml frost acetone, be dried in vacuo at 60 DEG C, obtain 4.3g white prasugrel hydrogen sulfate IV crystal forms.
The powder x-ray diffraction collection of illustrative plates of product is consistent with Fig. 1, and infrared spectrum is consistent with Fig. 2, its means of differential scanning calorimetry is bent
Line has an endothermic peak at 233 DEG C.
Embodiment 4
10g prasugrels are dissolved in 40ml Ethyl formate solvents, the 2.68g concentrated sulfuric acids, heating are added dropwise under stirring condition
Complete dissolved clarification is allowed to when to 55 DEG C and stirring 2 is small, heat filtering removes insoluble impurity, starts to cool down under continuously stirring, be cooled to 5-
10 DEG C go out crystalline substance, keep the temperature 1-2h, then are cooled to 0 DEG C, after having a large amount of crystal to separate out, filter cake are washed with ice-cold ethanol 50ml, by filter cake
It is dried in vacuo at 40 DEG C, obtains 7.68g prasugrel hydrogen sulfate IV crystal forms.
The powder x-ray diffraction collection of illustrative plates of product is consistent with Fig. 1, and infrared spectrum is consistent with Fig. 2, its means of differential scanning calorimetry is bent
Line has an endothermic peak at 231 DEG C.
Embodiment 5
5g prasugrels are dissolved in 30ml normal propyl alcohol solvents, stir 30min at room temperature, are slowly added to the dense sulphur of 1.35g
Acid, stirs to solution the homogeneous phase for clarification, starts to cool down under continuously stirring, 1 DEG C is cooled to 10 DEG C/min, then add real
Apply 0.1 gram of the crystal obtained in example 1 and make crystal seed, when insulated and stirred 2 is small, filter the crystal of precipitation, filter is washed with the ethanol of frost
Cake, is dried in vacuo at 40 DEG C of filter cake, obtains 4.15g prasugrel hydrogen sulfate IV crystal forms.
The powder x-ray diffraction collection of illustrative plates of product is consistent with Fig. 1, and infrared spectrum is consistent with Fig. 2, its means of differential scanning calorimetry is bent
Line has an endothermic peak at 232 DEG C.
Embodiment 6
3g prasugrels are dissolved in 10mlDMF solvents, stir 30min at room temperature, stir the lower dropwise addition dense sulphur of 0.79g
Acid, is allowed to complete dissolved clarification when being warming up to 50 DEG C and small stirring 1, heat filtering removes insoluble impurity, starts to cool down under continuously stirring, and drops
Warm to 5-10 DEG C goes out crystalline substance, keeps the temperature 1-2h, then is cooled to 0 DEG C, and after having a large amount of crystal to separate out, filter cake is washed with ice-cold ethanol 50ml,
It will be dried in vacuo at 40 DEG C of filter cake, obtain 2.15g prasugrel hydrogen sulfate IV crystal forms.
The powder x-ray diffraction collection of illustrative plates of product is consistent with Fig. 1, and infrared spectrum is consistent with Fig. 2, its means of differential scanning calorimetry is bent
Line has an endothermic peak at 232 DEG C.
Embodiment 7
The I crystal prasugrel hydrogen sulfate 10g that will be prepared in patent WO2011027988A2, it is molten with 25ml chloroforms
Solution, is heated to 50 DEG C of dissolved clarifications, and the insoluble impurity of heat filtering, then continuously stirs down and be cooled to 5 DEG C, continuously stirs 12 hours to a large amount of
Crystal occurs, and is washed with 50ml frost chloroforms, vacuum drying at 40 DEG C of filter cake, obtains 7.87g white prasugrel sulfuric acid
Hydrogen salt IV crystal forms.
The powder x-ray diffraction collection of illustrative plates of product is consistent with Fig. 1, and infrared spectrum is consistent with Fig. 2, its means of differential scanning calorimetry is bent
Line has an endothermic peak at 232 DEG C.
A kind of prasugrel hydrogen sulfate IV crystal forms that the present invention is disclosed and proposed and its preparation method and application, this area
Technical staff can be realized by using for reference the link such as present disclosure, appropriate feed change, technological parameter.The present invention is by preferable
Examples of implementation are described, related technical personnel substantially can not depart from present invention, in spirit and scope to this paper institutes
The method and product stated are modified and suitably change is with combining, to realize the technology of the present invention.In particular, own
Similar replacement and change is apparent to those skilled in the art, they are considered as in spirit of the invention, model
Enclose with content.
Claims (10)
- A kind of 1. prasugrel hydrogen sulfate crystal, it is characterized in that the powder x-ray diffraction angle (2 of prasugrel hydrogen sulfate θ °) it is respectively 7.5 ± 0.1,8.3 ± 0.1,8.6 ± 0.1,10.7 ± 0.1,12.7 ± 0.1,13.2 ± 0.1,13.5 ± 0.1, 14.5 ± 0.1,15.3 ± 0.1,16.3 ± 0.1,17.4 ± 0.1,18.2 ± 0.1,19.1 ± 0.1,20.0 ± 0.1,20.6 ± 0.1,21.4 ± 0.1,22.7 ± 0.1,23.2 ± 0.1,23.6 ± 0.1,24.2 ± 0.1,24.7 ± 0.1,25.0 ± 0.1, 25.8 ± 0.1,26.7 ± 0.1,27.5 ± 0.1,28.5 ± 0.1,29.5 ± 0.1,29.7 ± 0.1,31.7 ± 0.1, and 38.9 There is characteristic peak at ± 0.1 degree.
- 2. prasugrel hydrogen sulfate crystal as claimed in claim 1, it is characterized in that the infrared light of prasugrel hydrogen sulfate Spectrum is 428 ± 2,470 ± 2,509 ± 2,536 ± 2,586 ± 2,603 ± 2,651 ± 2,673 ± 2,731 ± 2,763 ± 2,798 ± 2,821 ± 2,848 ± 2,879 ± 2,910 ± 2,945 ± 2,977 ± 2,1006 ± 2,1029 ± 2,1064 ± 2,1083 ± 2,1163 ± 2,1197 ± 2,1228 ± 2,1375 ± 2,1392 ± 2,1444 ± 2,1463 ± 2,1498 ± 2,1589 ± 2, 1614 ± 2,1706 ± 2,1765 ± 2m-1There is characteristic peak at place.
- 3. prasugrel hydrogen sulfate crystal as claimed in claim 1, it is characterized in that differential scanning calorimetric curve is 232 ± 2 DEG C there is an endothermic peak.
- 4. the preparation method of the prasugrel hydrogen sulfate as described in claim 1,2 or 3 any one, its characterization step is will Prasugrel is dissolved in organic solvent, is slowly added dropwise the concentrated sulfuric acid, and solution is heated with stirring to dissolved clarification, and crystallisation by cooling is to there is crystal analysis Go out, product is obtained after magma is filtered, dried.
- 5. preparation method as claimed in claim 4, it is characterized in that the molar ratio of prasugrel and the concentrated sulfuric acid in the step For 1: 1-1.1.
- 6. preparation method as claimed in claim 4, it is characterized in that solvent is selected from aromatic hydrocarbon, aliphatic hydrocarbon, halogen in the step For hydrocarbon, alcohols, esters, ketone, nitrile, ethers organic reagent one or more.
- 7. preparation method as claimed in claim 4, it is characterized in that the solvent is benzene,toluene,xylene, ethane, hexamethylene, N-hexane, dichloromethane, chloroform, ethanol, sec-butyl alcohol, normal propyl alcohol, ethyl acetate, methyl acetate, Ethyl formate, ether, Petroleum ether, acetone, butanone, the one or more of DMF.
- 8. preparation method as claimed in claim 4, it is characterized in that the crystallisation by cooling temperature is 50 DEG C to -25 DEG C.
- 9. prasugrel hydrogen sulfate as claimed in claim 1 is used for the thrombosis or embolism for preventing or treating people in manufacture Purposes in the medicine of caused disease.
- 10. medicine as claimed in claim 9, it is characterised in that prasugrel hydrogen sulfate crystal accounts for composition gross mass 0.001-99.9wt%, surplus are the pharmaceutically material of acceptable carrier and other additives.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102076699A (en) * | 2008-04-25 | 2011-05-25 | 桑多斯股份公司 | Hydrogensulfate salt of 2-acetoxy-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and its preparation |
| CN102099361B (en) * | 2007-12-11 | 2012-07-04 | 鲁南制药集团股份有限公司 | The hydrosulfate of prasugrel, its pharmaceutical combination and uses thereof |
| CN102656175B (en) * | 2010-04-08 | 2015-08-26 | 特瓦制药工业有限公司 | The crystalline form of prasugrel salt |
-
2016
- 2016-10-10 CN CN201610882527.0A patent/CN107915743A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102099361B (en) * | 2007-12-11 | 2012-07-04 | 鲁南制药集团股份有限公司 | The hydrosulfate of prasugrel, its pharmaceutical combination and uses thereof |
| CN102076699A (en) * | 2008-04-25 | 2011-05-25 | 桑多斯股份公司 | Hydrogensulfate salt of 2-acetoxy-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and its preparation |
| CN102656175B (en) * | 2010-04-08 | 2015-08-26 | 特瓦制药工业有限公司 | The crystalline form of prasugrel salt |
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