CN105085593A - Regadenoson crystal form and preparation method thereof - Google Patents
Regadenoson crystal form and preparation method thereof Download PDFInfo
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- CN105085593A CN105085593A CN201410164386.XA CN201410164386A CN105085593A CN 105085593 A CN105085593 A CN 105085593A CN 201410164386 A CN201410164386 A CN 201410164386A CN 105085593 A CN105085593 A CN 105085593A
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Abstract
The present invention relates to the field of pharmaceutical chemistry, and discloses a new regadenoson crystal form, ie., regadenoson crystal form E, and a preparation method of the new regadenoson crystal form. According to the present invention, the regadenoson crystal form E has excellent performances in the field of radionuclide myocardial perfusion imaging, has characteristics of weak toxicity and good storage stability, and can be used for preparing drugs for radionuclide myocardial perfusion imaging stress agents.
Description
Technical field
The present invention relates to medicinal chemistry art, new crystal E being specifically related to Rui Jiadesong and preparation method thereof.
Background technology
Rui Jiadesong, chemistry is called (1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylol) oxygen Polymorphs-2-base]-adenine-2-base } pyrazoles-4-base)-N-METHYLFORMAMIDE, structural formula is as follows:
Publication number is disclose Rui Jiadesong and preparation method thereof and purposes first in the United States Patent (USP) of US6403567B1.Rui Jiadesong is a kind of adenosine A 2 A receptor agonist with high selectivity, and for radionuclide scheming Perfusion Imaging stress agent medicine, its cardiovascular diastole agent as cardiac imaging carries out clinical application in the U.S..
Polymorph in pharmaceuticals is the common phenomenon in drug research and development, is the important factor affecting drug quality.Polymorphism, refers to same compound, by controlling its different formation condition, can form two or more molecule space arrangement mode, thus producing the phenomenon of different solid crystals.The different crystal forms of same compound, its chemical constitution is identical, but microcosmic crystalline structure is different, thus causes them to there are differences in mode of appearance, physico-chemical property and biological activity.The different crystal forms of medicine often has different solvabilities, stability in storage, water-absorbent, density and bioavailability.The crystal formation of medicine directly affects the quality of the medicinal preparations of medicine, the absorption behavior at human body, and finally affects the benefit ratio of result for the treatment of that said preparation produces in human body and side effect.Therefore, the polytropism of drugs and the preparation method of different crystal forms have great importance.
At present, Rui Jiadesong is known exists multiple crystal formation.US7732595 U.S. patents discloses the multiple crystal formation of Rui Jiadesong, comprises crystal form A, crystal form B, crystal C, and unformed.
Crystal form A (as Fig. 1) carries out crystalline by protonic solvent or polar solvent.As the mixed solvent of ethanol, second alcohol and water, or the mixed solution of N, N-dimethyl sulfoxide (DMSO) (DMSO) and water.Rui Jiadesong crystal form A is single crystalline hydrate, and be the most stable in multiple Rui Jiadesong crystal formation, it is heated to its fusing point under relative humidity stress, is all stable.But due to Rui Jiadesong solubleness extreme difference, most of insoluble in general solvent, slightly soluble in water, be difficult to dissolve by the mitigation solvent of protonic solvent alcohols and water, therefore crystal form A is not suitable for large-scale production preparation.And when utilizing the mitigation liquid of DMSO and water to prepare crystal form A, because the fusing point of DMSO is high, reach 189 DEG C, be difficult to remove totally, therefore cannot obtain highly purified crystal form A.
Crystal form B (as Fig. 2) is that Rui Jiadesong is dissolved in trifluoroethanol solvent under normal temperature condition, through the crystal formation that concentrating under reduced pressure obtains.This crystal formation feature is totally different in other crystal formations, presents rambling wide cutting edge of a knife or a sword in the analysis collection of illustrative plates of its X-Ray diffraction, and containing the crystal water that number does not wait in this crystal formation, its preparation technology is difficult to repeat.
Pulled an oar for a long time in acetonitrile at 60 DEG C by Rui Jiadesong, the solid after filtration presents the crystal habit made new advances, i.e. crystal C (as Fig. 3).This crystal formation also contains uncertain crystal water content, the instability that it becomes after losing crystal water at high operating temperatures.
Namely form the unformed crystalline substance of Rui Jiadesong after crystal form A being heated to 200 DEG C, but it is unstable under atmospheric moisture, can form various crystalline hydrate.
International monopoly WO2012149196 crystal formation D (as Fig. 4) reporting Rui Jiadesong and preparation method thereof.Rui Jiade loose warp is crossed reverse-phase chromatography and is dissolved in the mixed solution of first alcohol and water, and after concentrated, form glutinous shape thing, after being decompressed to 20mmHg, be heated to 150 DEG C in oil bath, 6 hours, obtain white solid, i.e. crystal formation D, crystal formation D contains the crystal water of 0.8 to 1.7%.But the method described in this patent, technique is too complicated, harsh, is difficult to repetition and amplification, and needs to be heated to 150 DEG C of high temperature, be easy to cause compound decomposition.
Summary of the invention
In view of this, the present invention seeks to by crystallographic method, study, find and new crystal formation that Rui Jiadesong is provided and preparation method thereof.
The present invention, by crystallographic method, research, finds and provides the crystallized form of Rui Jiadesongxin, i.e. Rui Jiadesong crystal formation E.
The present invention adopts the x-ray powder diffraction (XRPD) of generally acknowledging in the world to study and characterize the new crystallized form of Rui Jiadesong.Plant and instrument: D/MAX-1200 type X-ray powder diffractometer.Condition determination and method: Cu/K-alpha1 (target), 40KV-40mA (operating voltage and electric current), I (max)=2244,2 θ=5-60 degree (sweep limit), 0.005/0.06sec. (sweep velocity), λ=1.54056.
Substantially pure Rui Jiadesong crystal formation E provided by the invention, its X-ray powder diffraction pattern as shown in Figure 5.
The present invention also adopts infrared spectroscopy (IR) to study and characterize Rui Jiadesong crystal formation E.Instrument: BRUKERTENSOR27 Fourier transform mid-infrared light spectrometer (German Brooker company).Measuring method: KBr pressed disc method, spectral range 400cm
-1-4000cm
-1, resolving power is 4cm
-1.
Rui Jiadesong crystal formation E provided by the invention, its infrared spectrogram as shown in Figure 6, it is characterized in that, infrared spectrogram has absorption peak in 3331.71,3215.54,2927.97,1648.75,1604.99,1577.42,1530.74,1492.24,1447.33,1409.03,1380.47,1343.48,1286.87,1234.77,1205.30,1188.55,1125.28,1092.61,1060.80,1025.93,983.13,910.61,866.49,810.21,791.76,725.68,663.00,632.69,511.09 and 410.05cm-1 place.
It should be noted that, for the infrared spectra peak of the above crystal formation, between a machine and another machine and between a sample and another sample, the absorption peak of infrared spectra collection of illustrative plates may slightly change, and its numerical value may differ about 1 unit, or differs about 0.8 unit, or differ about 0.5 unit, or differ about 0.3 unit, or differ about 0.1 unit, therefore given numerical value can not be considered as absolute.
Crystal formation also can use technically other analytical technologies known to characterize.Such as dsc (DSC).Substantially pure Rui Jiadesong crystal formation E provided by the invention, as shown in Figure 7, it has following characteristic to its differential scanning calorimetric analysis curve: its differential scanning calorimetric analysis curve has endotherm(ic)peak at about 221.02 DEG C of places.
Present invention also offers purity high and not containing the Rui Jiadesong crystal formation E preparation method of residual solvent.
The preparation method of Rui Jiadesong crystal formation E provided by the invention, for be dissolved in DMF by Rui Jiadesong, adds appropriate polar solvent, concentrating under reduced pressure and get final product.
As preferably, described polar solvent is low boiling-point and polarity solvent.The i.e. polar solvent of boiling point below 100 DEG C.
Further, as preferably, described polar solvent is methylene dichloride, tetrahydrofuran (THF), ethanol or acetonitrile.
Rui Jiadesong crystal formation E preparation method of the present invention obtains crystal formation E content >90%.
Carry out thermogravimetric analysis to Rui Jiadesong crystal formation E of the present invention, result shows Rui Jiadesong crystal formation E of the present invention and keeps original crystal formation constant, and obvious change does not also occur for content and total impurities, just starts to decompose, good stability, be applicable to standing storage at 237 DEG C.
Rui Jiadesong crystal formation E of the present invention excellent performance in radionuclide scheming Perfusion Imaging, and its toxicity is weak, has good preservation stability, can be used for the medicine preparing radionuclide scheming Perfusion Imaging stress agent.Therefore the invention provides the described application of Rui Jiadesong crystal formation E in the medicine for the preparation of radionuclide scheming Perfusion Imaging stress agent.
Further, the invention provides the described pharmaceutical preparation for radionuclide scheming Perfusion Imaging stress agent, comprise described Rui Jiadesong crystal formation E.
Accompanying drawing explanation
Fig. 1 shows the X-ray powder diffraction pattern of the Rui Jiadesong crystal form A described in patent US7732595;
Fig. 2 shows the X-ray powder diffraction pattern of the Rui Jiadesong crystal form B described in patent US7732595;
Fig. 3 shows the X-ray powder diffraction pattern of the Rui Jiadesong crystal C described in patent US7732595;
Fig. 4 shows the X-ray powder diffraction pattern of the Rui Jiadesong crystal formation D described in patent WO2012149196;
Fig. 5 shows the X-ray powder diffraction pattern of the Rui Jiadesong crystal formation E that the embodiment of the present invention 1 provides, it is by obtaining with copper K alpha-irradiation, in X-ray powder diffraction pattern, ordinate zou represents the diffracted intensity with counting/second, (cps) represented, X-coordinate represents diffraction angle 2 θ that expenditure represents;
The infrared spectrogram of the Rui Jiadesong crystal formation E that Fig. 6 embodiment of the present invention 1 provides, ordinate zou is transmittance (T), and unit is percentage (%); X-coordinate is wave number, and unit is cm
-1;
Fig. 7 shows dsc (DSC) graphic representation of the Rui Jiadesong crystal formation E that the embodiment of the present invention 1 provides, and ordinate zou is rate of heat flow, and unit is card/second; X-coordinate is temperature, and unit is DEG C;
Fig. 8 shows the thermogram of the Rui Jiadesong crystal formation E that the embodiment of the present invention 1 provides, and its cathetus is thermal gravimetric analysis curve figure, and ordinate zou is that weight keeps percentage, and X-coordinate is temperature, and unit is DEG C; Dotted line is the differential curve figure of thermogravimetric analysis, and ordinate zou is weight rate, and unit is %/min, and X-coordinate is temperature, and unit is DEG C.
Embodiment
Crystal formation that the embodiment of the invention discloses Rui Jiadesong and preparation method thereof and application.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Method of the present invention is described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope method as herein described is changed or suitably change with combination, realize and apply the technology of the present invention.
In order to understand the present invention further, below in conjunction with embodiment, the present invention is described in detail.Numerical range described in specification sheets, as measure unit, reaction conditions, compound physical state or per-cent, is all to provide undoubted desk reference.Those skilled in the art when putting into practice this patent,
Be used in outside this scope or be different from the temperature, concentration, quantity etc. of single numerical value, still can obtain expected result.
The preparation of embodiment 1: Rui Jiadesong crystal formation E
1g Rui Jiadesong is dissolved in 10mLDMF, adds 10mL methylene dichloride, concentrating under reduced pressure at 50 DEG C, obtain 1g Rui Jiadesong crystal formation E, content 92%.The X-ray powder diffraction pattern of this crystal formation and infrared spectrogram are respectively as shown in Figure 5, Figure 6.
The preparation of embodiment 2: Rui Jiadesong crystal formation E
1g Rui Jiadesong is dissolved in 10mLDMF, adds 10mL tetrahydrofuran (THF), concentrating under reduced pressure at 50 DEG C, obtain 1g Rui Jiadesong crystal formation E, content 91%.The X-ray powder diffraction of this crystal formation is consistent with embodiment 1 with the results of FT-IR.
The preparation of embodiment 3: Rui Jiadesong crystal formation E
1g Rui Jiadesong is dissolved in 10mLDMF, adds 5mL ethanol, concentrating under reduced pressure at 50 DEG C, obtain 1g Rui Jiadesong crystal formation E, content 91%.The X-ray powder diffraction result of this crystal formation is consistent with embodiment 1 with infrared spectra.
The preparation of embodiment 4: Rui Jiadesong crystal formation E
1g Rui Jiadesong is dissolved in 10mLDMF, adds 5mL acetonitrile, concentrating under reduced pressure at 50 DEG C, obtain 1g Rui Jiadesong crystal formation E, content 93%.The X-ray powder diffraction result of this crystal formation is consistent with embodiment 1 with infrared spectra.
The differential scanning calorimetric analysis of embodiment 5: Rui Jiadesong crystal formation E
Dsc (DSC) is adopted to carry out research sign to Rui Jiadesong crystal formation E prepared by embodiment 1.Differential scanning calorimetric analysis test condition: instrument: DSC204F1 (Germany) differential scanning calorimeter; Example weight is 8.17mg; Temperature rise rate: 2 DEG C/min; The highest temperature 250 DEG C; Nitrogen flow rate: 20mL/min.The results are shown in Figure 7.
From Fig. 7 result, when temperature reaches 173.71 DEG C, have significant temperature absorption to react, when temperature reaches 221 DEG C, have minimal temperature to absorb, sample starts to decompose afterwards.The solvent of Rui Jiadesong crystal formation E of the present invention is low boiling point solvent, therefore 173.71 DEG C of thermotonuses that should be crystal water dehydration and cause.
The thermogravimetric analysis of embodiment 6: Rui Jiadesong crystal formation E
Thermogravimetry (TGA) is adopted to carry out research sign to Rui Jiadesong crystal formation E prepared by embodiment 1.Thermogravimetric analysis test condition: instrument: U.S. Pyris1TGA thermogravimetric analyzer; Sample size is 4.457mg; Under nitrogen protection, heat-up rate is 10 DEG C/min; Temperature range 30 DEG C to 600 DEG C; Nitrogen flow rate: 20mL/min.The results are shown in Figure 8.
From Fig. 8 result, weightlessness 5.3% 80 DEG C time, weight loss rate is 2.1%/min; Weightlessness 4.5% 182.21 DEG C time, weight loss rate is 0.39%/min; When temperature reaches 237 DEG C, occur continuing weightlessness, weightless ratio improves rapidly afterwards.Analytical results thinks that 80 DEG C should be low boiling-point and polarity dissolvent residual in sample, and 182.21 DEG C should be crystal water in sample, and 237 DEG C of weightlessness should be that sample starts to decompose.Result shows that Rui Jiadesong crystal formation E of the present invention heat is just decomposed at 237 DEG C, and good stability, is applicable to standing storage.
The explanation of above embodiment just understands method of the present invention and core concept thereof for helping.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improve and modify and also fall in the protection domain of the claims in the present invention.
Claims (7)
1. Rui Jiadesong crystal formation E, is characterized in that, it has X-ray powder diffraction substantially as shown in Figure 5.
2. crystal formation E according to claim 1, it is characterized in that, its infrared spectrogram is 3331.71,3215.54,2927.97,1648.75,1604.99,1577.42,1530.74,1492.24,1447.33,1409.03,1380.47,1343.48,1286.87,1234.77,1205.30,1188.55,1125.28,1092.61,1060.80,1025.93,983.13,910.61,866.49,810.21,791.76,725.68,663.00,632.69,511.09 and 410.05cm
-1there is absorption peak at place.
3. crystal formation E according to claim 1, it is characterized in that, its differential scanning calorimetric analysis curve has endotherm(ic)peak at about 221.02 DEG C of places.
4. the preparation method of Rui Jiadesong crystal formation E according to claim 1, is characterized in that, be dissolved in by Rui Jiadesong in DMF, add appropriate polar solvent, concentrating under reduced pressure and get final product.
5. preparation method according to claim 4, it is characterized in that, described polar solvent is methylene dichloride, tetrahydrofuran (THF), ethanol or acetonitrile.
6. the application of Rui Jiadesong crystal formation E according to claim 1 in the medicine for the preparation of radionuclide scheming Perfusion Imaging stress agent.
7. for a pharmaceutical preparation for radionuclide scheming Perfusion Imaging stress agent, it is characterized in that, comprise Rui Jiadesong crystal formation E described in claim 1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410164386.XA CN105085593A (en) | 2014-04-21 | 2014-04-21 | Regadenoson crystal form and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110117305A (en) * | 2018-02-06 | 2019-08-13 | 上海键合医药科技有限公司 | A kind of Rui Jiadesong purification process and its novel crystal forms |
| US11535644B2 (en) | 2018-03-29 | 2022-12-27 | Macfarlan Smith Limited | Solid-state forms of Regadenoson, their use and preparation |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1358191A (en) * | 1999-06-22 | 2002-07-10 | Cv治疗公司 | N-pyrazole A2A receptor agonists |
| CN101379073A (en) * | 2006-02-03 | 2009-03-04 | Cv医药有限公司 | Process for preparing an a2a-adenosine receptor agonist and its polymorphs |
| CN101668768A (en) * | 2007-05-17 | 2010-03-10 | Cv医药有限公司 | Process for preparing an a2a-adenosine receptor agonist and its polymorphs |
| CN102260311A (en) * | 2006-02-03 | 2011-11-30 | 吉利德帕洛阿尔托股份有限公司 | Process for preparing an A2A-adenosine receptor agonist and its polymorphs |
| WO2012149196A1 (en) * | 2011-04-27 | 2012-11-01 | Reliable Biopharmaceutical Corporation | Improved processes for the preparation of regadenoson and a new crystalline form thereof |
-
2014
- 2014-04-21 CN CN201410164386.XA patent/CN105085593A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1358191A (en) * | 1999-06-22 | 2002-07-10 | Cv治疗公司 | N-pyrazole A2A receptor agonists |
| CN101379073A (en) * | 2006-02-03 | 2009-03-04 | Cv医药有限公司 | Process for preparing an a2a-adenosine receptor agonist and its polymorphs |
| CN102260311A (en) * | 2006-02-03 | 2011-11-30 | 吉利德帕洛阿尔托股份有限公司 | Process for preparing an A2A-adenosine receptor agonist and its polymorphs |
| CN101668768A (en) * | 2007-05-17 | 2010-03-10 | Cv医药有限公司 | Process for preparing an a2a-adenosine receptor agonist and its polymorphs |
| WO2012149196A1 (en) * | 2011-04-27 | 2012-11-01 | Reliable Biopharmaceutical Corporation | Improved processes for the preparation of regadenoson and a new crystalline form thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110117305A (en) * | 2018-02-06 | 2019-08-13 | 上海键合医药科技有限公司 | A kind of Rui Jiadesong purification process and its novel crystal forms |
| CN110117305B (en) * | 2018-02-06 | 2023-06-02 | 上海键合医药科技有限公司 | Method for purifying regadenoson and novel crystal form thereof |
| US11535644B2 (en) | 2018-03-29 | 2022-12-27 | Macfarlan Smith Limited | Solid-state forms of Regadenoson, their use and preparation |
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Application publication date: 20151125 |