CN105254669A - Ceftaroline fosamil aspartate and crystal thereof - Google Patents
Ceftaroline fosamil aspartate and crystal thereof Download PDFInfo
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- CN105254669A CN105254669A CN201410334599.2A CN201410334599A CN105254669A CN 105254669 A CN105254669 A CN 105254669A CN 201410334599 A CN201410334599 A CN 201410334599A CN 105254669 A CN105254669 A CN 105254669A
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- phosphine
- aspartate
- sieve
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- aspartic acid
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Abstract
The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a ceftaroline fosamil aspartate and a crystal thereof. A purpose of the present invention is to provide the ceftaroline fosamil aspartate, wherein the ceftaroline fosamil aspartate has better stability compared with ceftaroline fosamil acetate, and further has good solubility. In addition, the preparation is simple and easy to operate, and particularly the requirements of the pharmaceutical preparation are met.
Description
Technical field
The present invention relates to medicinal chemistry art, in particular to cephalo sieve phosphine aspartate and crystallization thereof.
Technical background
Cephalo sieve phosphine (CeftarolineFosamil; formula I); chemical name is: (6R; 7R)-7-{ (2Z)-2-(ethoxy imino)-2-[5-(phosphono)-1; 2; 4-thiadiazoles-3-base] kharophen }-3-{ [4-(1-picoline-1--4-base)-1,3-thiazoles-2-base] sulfanyl }-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.
Cephalo sieve phosphine is by Japan's military field pharmacy Development of New Generation cynnematin, in October, 2010, obtains U.S. FDA license and is used for the treatment of Community-acquired bacterial pneumonia and acute bacterial skin and skin structure infection.
CN1282335A discloses cephalo sieve phosphine and preparation method thereof, and CN1462275A discloses cephalo sieve PHOSPHONACETIC salt, propionic salt, acetonitrile compound and hydrate thereof.According to the study, cephalo sieve phosphine less stable, and the stability of cephalo sieve phosphonium salt is better than cephalo sieve phosphine, what FDA approval was gone on the market is cephalo sieve PHOSPHONACETIC salt.
General, wish that pharmaceutical preparation has excellent character in the following areas: bioavailability, stability, solvability, purity, easily preparation etc.The applicant is through a large amount of experimental studies, and discovery cephalo sieve phosphine aspartate beyond expectation has stability more better than cephalo sieve PHOSPHONACETIC salt, and has good solvability, prepares simple to operation, meets the demand of pharmaceutical preparation especially.
Summary of the invention
The present invention relates to cephalo sieve phosphine aspartate.Cephalo sieve phosphine aspartate of the present invention, can be easy to crystallize out from solvent (such as acetic acid/water mixed solvent), form stable salt, and product characteristics are good, meet the demand of pharmaceutical preparation especially.
The object of the present invention is to provide a kind of stable cephalo sieve phosphonium salt, described cephalo sieve phosphonium salt is the aspartate of cephalo sieve phosphine.
Aspartic acid, also known as amino-succinic acid, it has following structure:
Due to its chiral carbon, there are two kinds of enantiomers, L-Aspartic acid and D-Asps in aspartic acid.
L-Aspartic acid has following structure:
D-Asp has following structure:
In an embodiment of the invention, described cephalo sieve phosphine aspartate is cephalo sieve phosphine L-Aspartic acid salt.
In an embodiment of the invention, described cephalo sieve phosphine aspartate is cephalo sieve phosphine D-Asp salt.
Another object of the present invention is the crystallization providing cephalo sieve phosphine aspartate, it is characterized in that, powder x-ray diffraction collection of illustrative plates is shown in 17.46 with 2 θ angle measuring gauges, 19.10, 19.94, 21.04, 21.73, 23.30, 28.21, 31.13 degree has characteristic peak, preferred 9.58, 11.62, 13.95, 16.39, 17.46, 19.10, 19.94, 21.04, 21.73, 23.30, 28.21, 31.13 degree has characteristic peak, more preferably 6.91, 9.58, 11.62, 12.28, 13.95, 16.39, 17.46, 19.10, 19.94, 21.04, 21.73, 23.30, 25.56, 26.19, 28.21, 31.13, 37.26 degree has characteristic peak.
As an embodiment of the invention, in the powder x-ray diffraction collection of illustrative plates of cephalo sieve phosphine aspartic acid salt-pepper noise of the present invention, the peak position of characteristic peak and intensity are represented by following table:
| Numbering | 2 θ (degree) | Relative intensity (I/I 0) |
| 1 | 6.91 | 15 |
| 2 | 9.58 | 17 |
| 3 | 11.62 | 34 |
| 4 | 12.28 | 26 |
| 5 | 13.95 | 19 |
| 6 | 16.39 | 32 |
| 7 | 17.46 | 41 |
| 8 | 19.10 | 80 |
| 9 | 19.94 | 61 |
| 10 | 21.04 | 66 |
| 11 | 21.73 | 100 |
| 12 | 23.30 | 84 |
| 13 | 25.56 | 46 |
| 14 | 26.19 | 40 |
| 15 | 28.21 | 53 |
| 16 | 31.13 | 45 |
| 17 | 37.26 | 30 |
In an embodiment of the invention, described cephalo sieve phosphine aspartic acid salt-pepper noise is cephalo sieve phosphine L-Aspartic acid salt-pepper noise.
The X-ray diffraction condition determination that the present invention adopts is: CuK α line, tube voltage 40kV, tube current 50mA.For any given crystallized form, due to the preferred orientation that the factors such as such as crystal habit cause, the relative intensity of diffraction peak can change, and this is known in crystallography art.There is the place of preferred orientation impact, peak intensity changes, but the characteristic peak positions of crystal formation cannot change.In addition, for any given crystal formation, may there is slight errors in the position at peak, and this is also known in crystallography art.Such as, because the change of temperature during analytic sample, sample move or the demarcation etc. of instrument, the position at peak can be moved, and the error at measurment of 2 θ values is about sometimes ± and 0.2 degree.Therefore, when determining often kind of crystalline texture, this error should be taken into account.
Another object of the present invention is the preparation method providing cephalo sieve phosphine aspartate, comprises the steps:
(1) cephalo sieve phosphine is joined in acetic acid/water mixing solutions, stirring and dissolving;
(2) add aspartic acid, stir;
(3) crystallization, optionally adds acetic acid/water mixing solutions;
(4) filter, dry.
In above-mentioned steps (1) and (3), in acetic acid/water mixing solutions, the volume ratio of acetic acid and water is 1:0.1-10, is preferably 1:0.5-5, most preferably is 1:1; Wet concentration is from distilled water, D/W, mannose aqueous solution etc.
In above-mentioned steps (2), the mol ratio of cephalo sieve phosphine and aspartic acid is 1:1-10, is preferably 1:1-5, most preferably is 1:1.
In above-mentioned steps (3), recrystallization temperature is 0 ~ 50 DEG C, is preferably 10 ~ 30 DEG C, most preferably is 25 DEG C; Crystallization state can be standing, also can under agitation carry out; Adding described mixing solutions with the volume mass ratio (mL/g) of cephalo sieve phosphine is 1-20:1, is preferably 2-10:1, most preferably is 3-5:1.
In above-mentioned steps (4), drying temperature 0 ~ 50 DEG C, is preferably 10 ~ 30 DEG C, most preferably is 25 DEG C; Drying can be carried out under decompression or normal pressure.
Another aspect of the present invention provides the crystal composition of cephalo sieve phosphine aspartic acid salt-pepper noise of the present invention, wherein cephalo sieve phosphine aspartic acid salt-pepper noise accounts for more than 50% of crystal composition weight, be better more than 80%, be more preferably more than 90%, preferably more than 95%.
The present invention provides the pharmaceutical composition comprising cephalo sieve phosphine aspartate, cephalo sieve phosphine aspartic acid salt-pepper noise or cephalo sieve phosphine aspartate crystal composition on the other hand, comprises above-mentioned cephalo sieve phosphine aspartate for the treatment of significant quantity, cephalo sieve phosphine aspartic acid salt-pepper noise or cephalo sieve phosphine aspartate crystal composition in this pharmaceutical composition.In addition, can also contain in this pharmaceutical composition or not contain pharmaceutically acceptable auxiliary material.
Another aspect of the invention provides cephalo sieve phosphine aspartate, cephalo sieve phosphine aspartic acid salt-pepper noise, cephalo sieve phosphine aspartate crystal composition or the purposes of its pharmaceutical composition in the medicine preparing bacterial-infection resisting.
Accompanying drawing explanation
Fig. 1 is cephalo sieve phosphine L-Aspartic acid salt powder x-ray diffraction collection of illustrative plates prepared by embodiment 1.
Embodiment
The present invention is by following examples, and they are only embodiments, do not limit the present invention, and every technology realized based on the present invention, all belongs to scope of the present invention.
The preparation of embodiment 1 cephalo sieve phosphine L-Aspartic acid salt
5.00g cephalo sieve phosphine (7.3mmol) is joined in the mixed solution of 25ml distilled water and 25ml acetic acid, stirring and dissolving.Add 0.97gL-aspartic acid (7.3mmol), stir.Stirred at ambient temperature crystallization, has solid to separate out after 4h, continue crystallization 14h (spending the night); Add the mixed solution of 15ml distilled water and acetic acid (1:1), stir 2h.Filtration gained precipitates, with the mixed solution washing leaching cake 3 times of 15ml distilled water and acetic acid (1:1), and with 10ml distilled water wash 5 times.With 3A molecular sieve as siccative, by this crystallization drying under reduced pressure, until reach constant weight.
Output: 4.21g (yield: 71%).
IR(KBr)cm
-1：1755，1696，1684，1668，1646，1540，1395，1273，1040
The preparation of embodiment 2 cephalo sieve phosphine L-Aspartic acid salt
5.00g cephalo sieve phosphine (7.3mmol) is joined in the glucose injection of 25ml5% and the mixed solution of 25ml acetic acid, stirring and dissolving.Add 0.97gL-aspartic acid (7.3mmol), stir.Stirred at ambient temperature crystallization 18h (spending the night); Add the mixed solution of 15ml distilled water and acetic acid (1:1), stir.Filtration gained precipitates, with the mixed solution washing leaching cake 3 times of 15ml distilled water and acetic acid (1:1), and with 10ml distilled water wash 5 times.With 3A molecular sieve as siccative, by this crystallization drying under reduced pressure, until reach constant weight.
Output: 4.06g (yield: 68%).
The preparation of embodiment 3 cephalo sieve phosphine L-Aspartic acid salt
D-mannose alcohol injection with 20% substitutes the glucose injection of 5%, obtains title compound with the operation identical with embodiment 2.
Output: 3.88g (yield: 65%).
The preparation of embodiment 4 cephalo sieve phosphine L-Aspartic acid salt
5.00g cephalo sieve phosphine (7.3mmol) is joined in the mixed solution of 50ml distilled water and 50ml acetic acid, stirring and dissolving.Add 0.97gL-aspartic acid (7.3mmol), stir.Stirring at room temperature, crystallization 18h (spending the night), filters gained precipitation, with the mixed solution washing leaching cake 3 times of 15ml distilled water and acetic acid (1:1), and with 10ml distilled water wash 5 times.With 3A molecular sieve as siccative, by this crystallization drying under reduced pressure, until reach constant weight.
Output: 3.10g (yield: 52%).
The preparation of embodiment 5 cephalo sieve phosphine L-Aspartic acid salt
5.00g cephalo sieve phosphine (7.3mmol) is joined in the mixed solution of 25ml distilled water and 25ml acetic acid, stirring and dissolving.Add 0.97gL-aspartic acid (7.3mmol), stir.0 DEG C of standing crystallization 18h (spending the night); Add the mixed solution of 15ml distilled water and acetic acid (1:1), stir.Filtration gained precipitates, with the mixed solution washing leaching cake 3 times of 15ml distilled water and acetic acid (1:1), and with 10ml distilled water wash 5 times.With 3A molecular sieve as siccative, by this crystallization drying under reduced pressure, until reach constant weight.
Output: 3.90g (yield: 65%).
The preparation of embodiment 5 cephalo sieve phosphine L-Aspartic acid salt
5.00g cephalo sieve phosphine (7.3mmol) is joined in the mixed solution of 25ml distilled water and 25ml acetic acid, stirring and dissolving.Add 0.97gL-aspartic acid (7.3mmol), stir.Stirring at room temperature crystallization 18h (spending the night); Add the mixed solution of 15ml distilled water and acetic acid (1:1), stir, continue crystallization 30h.Filtration gained precipitates, with the mixed solution washing leaching cake 3 times of 15ml distilled water and acetic acid (1:1), and with 10ml distilled water wash 5 times.With 3A molecular sieve as siccative, by this crystallization drying under reduced pressure, until reach constant weight.
Output: 4.48g (yield: 75%).
The preparation of embodiment 8 cephalo sieve phosphine D-Asp salt
5.0g cephalo sieve phosphine is joined in the mixed solution of 25ml distilled water and 25ml acetic acid, stirring and dissolving.Add 0.93gD-aspartic acid, stir.Stirring at room temperature crystallization 18h (spending the night); Add the mixed solution of 15ml distilled water and acetic acid (1:1), stir, continue crystallization 32h.Filtration gained precipitates, and with the mixed solution washing leaching cake of 15ml distilled water and acetic acid (1:1), and uses 10ml distilled water wash.With 3A molecular sieve as siccative, by this crystallization drying under reduced pressure, until reach constant weight.
Output: 3.9g (yield: 66%).
The preparation of reference example 1 cephalo sieve PHOSPHONACETIC salt
Cephalo sieve PHOSPHONACETIC salt is prepared according to CN1462275A embodiment 1.100mg cephalo sieve phosphine (0.151mmol) is suspended in the mixed solution of 0.5ml distilled water for injection and 0.5ml acetic acid, is dissolved by ultrasonication, this solution is at room temperature placed and spends the night; With the crystal of spatula grinding precipitation, collecting by filtration.By this crystallization 1.2ml distilled water for injection washing, use 3A molecular sieve as siccative, through this crystallization drying under reduced pressure, until reach constant weight, obtain crystal seed.
Output 79mg (yield: 73%).
Embodiment 9 stability experiment
With reference to the Pharmacopoeia of the People's Republic of China 2010 editions two annex XIXC bulk drugs and pharmaceutical preparation stability test governing principle, cephalo sieve PHOSPHONACETIC salt, cephalo sieve phosphine L-Aspartic acid salt are carried out stability in 60 DEG C, and 5 days and 10 days are investigated, room temperature stability is investigated, and impurity (HPLC) changing conditions is in table 1.
HPLC testing conditions is as follows:
Chromatographic column: ThermoBDSC18 (5 μm, 4.6mm × 250mm)
Mobile phase A: the 0.05%H3PO4 aqueous solution
Mobile phase B: acetonitrile
Linear gradient elution, program is as follows:
Determined wavelength: 242nm detects
Flow velocity: 1.0ml/min
Column temperature: 25 DEG C
Sample size: 10 μ l
Solvent: water (pH6.5)-acetonitrile (4:1)
The preparation of need testing solution: get trial-product, precision takes in right amount, and solubilizing agent dissolves and dilutes the solution making 1mg/mL, as need testing solution.
Table 1 cephalo sieve phosphine L-Aspartic acid salt-stable is tested
Result shows, and cephalo sieve phosphine L-Aspartic acid salt has stability more better than cephalo sieve PHOSPHONACETIC salt.
Claims (10)
1. the aspartate of cephalo sieve phosphine shown in formula (I)
2. cephalo sieve phosphine aspartate according to claim 1, it is characterized in that, aspartic acid is L-Aspartic acid.
3. cephalo sieve phosphine aspartate according to claim 1, it is characterized in that, aspartic acid is D-Asp.
4. the crystallization of the cephalo sieve phosphine aspartate described in any one of claim 1-3, it is characterized in that, powder x-ray diffraction collection of illustrative plates is shown in 17.46,19.10,19.94,21.04,21.73,23.30,28.21,31.13 degree with 2 θ angle measuring gauges characteristic peak.
5. crystallization according to claim 4, is characterized in that, powder x-ray diffraction collection of illustrative plates is shown in 9.58,11.62,13.95,16.39,17.46,19.10,19.94,21.04,21.73,23.30,28.21,31.13 degree with 2 θ angle measuring gauges characteristic peak.
6. crystallization according to claim 5, it is characterized in that, powder x-ray diffraction collection of illustrative plates is shown in 6.91,9.58,11.62,12.28,13.95,16.39,17.46,19.10,19.94,21.04,21.73,23.30,25.56,26.19,28.21,31.13,37.26 degree with 2 θ angle measuring gauges characteristic peak.
7. the preparation method of cephalo sieve phosphine aspartate, comprises the steps:
(1) cephalo sieve phosphine is joined in acetic acid/water mixing solutions, stirring and dissolving;
(2) add aspartic acid, stir;
(3) crystallization, optionally adds acetic acid/water mixed solution;
(4) filter, dry.
8. crystal composition, the cephalo sieve phosphine aspartic acid salt-pepper noise wherein described in any one of claim 4-6 accounts for more than 50% of crystal composition weight, is better more than 80%, is more preferably more than 90%, and preferably more than 95%.
9. pharmaceutical composition, it comprises crystal composition described in cephalo sieve phosphine aspartic acid salt-pepper noise described in the treatment cephalo sieve phosphine aspartate described in any one of claim 1-3 of significant quantity, any one of claim 4-6 or claim 8.
10. the cephalo sieve phosphine aspartate described in any one of claim 1-3, the cephalo sieve phosphine aspartic acid salt-pepper noise described in any one of claim 4-6, crystal composition according to claim 8 or the purposes of pharmaceutical composition according to claim 9 in the medicine preparing bacterial-infection resisting.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410334599.2A CN105254669A (en) | 2014-07-14 | 2014-07-14 | Ceftaroline fosamil aspartate and crystal thereof |
| PCT/CN2015/083860 WO2016008393A1 (en) | 2014-07-14 | 2015-07-13 | Ceftaroline fosamil amino acid salt and crystal thereof |
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| CN201410334599.2A CN105254669A (en) | 2014-07-14 | 2014-07-14 | Ceftaroline fosamil aspartate and crystal thereof |
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