Background technology
Ertapenem list sodium salt (Ertapenem Sodium) is to be invented by Britain AstraZeneca company; After transfer Merck & Co., Inc. and do further research and development; It is the new injection broad-spectrum long-acting carbapenem antibiotic that has 4 (R) methyl; 2002 in U.S.'s Initial Public Offering; Have has a broad antifungal spectrum, stable to dehydropeptidase of kidney-1 (DHP-1), pharmacokinetic parameters is good, clinical therapeutic efficacy good, better tolerance, untoward reaction are few, long half time, characteristics such as can be administered once in a day, is used for the responsive microbial infection of treatment adult moderate to severe clinically, can obtain satisfactory effect to the acquired polyinfection of community.The structural formula of ertapenem list sodium salt is as follows:
Disclose unformed ertapenem list sodium salt among the patent documentation WO2008062279, this unformed material is unstable, and variable color and purity are low easily.
Patent documentation WO03026572 discloses ertapenem list sodium salt A type and Type B crystallization; A type crystalline preparation method joins the part n-propyl alcohol in the ertapenem list sodium-salt aqueous solution earlier; Be cooled to-5 ℃; With acid for adjusting pH value=5~6, add 0.5~3 times of amount methyl alcohol (volume of water relatively) and the crystallization of 0.5~3 times of amount n-propyl alcohol subsequently.Type B crystalline preparation method gets the crystallization of A type with containing the washed with isopropyl alcohol of 5~25% moisture.
Patent documentation CN1821248 discloses the crystallization of ertapenem list sodium salt C type, and the preparation method gets with the organic solvent washing A type or the Type B crystallization that are selected from methyl acetate, acetonitrile, THF, acetone or its aqueous mixture.This patent also discloses a kind of reduction crystal form A, and the method for residual solvent among B and the C is about to nitrogen gas stream at low temperatures through wet crystal, obtains meeting the product of medicinal standard.
Patent documentation WO2009150630 discloses the crystallization of ertapenem list sodium salt D type; The preparation method joins part methyl alcohol in the ertapenem list sodium-salt aqueous solution earlier, with acid for adjusting pH value=5~6, adds an amount of methyl alcohol and n-propyl alcohol crystallization subsequently; Filtration is also used washing with acetone, and vacuum-drying obtains.
All contain residual organic solvent in the A of the ertapenem list sodium salt of having reported, B, C and four kinds of crystal formations of D; Wherein crystal form A, B and C can be reduced to residual solvent through the nitrogen gas stream drying and meet medicinal standard, but do not report whether crystal formation keeps and consequent stability problem.And amorphous ertapenem list sodium salt poor stability.Therefore be necessary still to study that the preparation method is simple, residual solvent is low, good stability, the new crystal of the ertapenem list sodium salt of suitability for industrialized production smoothly; To guarantee bulk drug and preparation thereof the stability in preparation and storage, to improve the drug quality and the clinical effectiveness of ertapenem list sodium salt.
Summary of the invention
To existing in prior technology the problems referred to above and defective, the purpose of this invention is to provide that a kind of residual solvent is low, the novel ertapenem list sodium salt crystal body of good stability and provide that a kind of technology is simple, preparation cost is cheap, be fit to the preparation method of this xln of suitability for industrialized production.
For realizing the foregoing invention purpose, the technical scheme that the present invention adopts is following:
Ertapenem list sodium salt crystal body of the present invention has powder x-ray diffraction spectrogram shown in Figure 1.
Furtherly, ertapenem list sodium salt crystal body of the present invention also has FT-IR spectrogram shown in Figure 2.
Furtherly, ertapenem list sodium salt crystal body of the present invention under powder x-ray diffraction, is 4.4 ° ± 0.1 ° at angle of diffraction 2 θ; 5.2 ° ± 0.1 °, 7.4 ° ± 0.1 °, 8.1 ° ± 0.1 °; 10.9 ° ± 0.1 °, 12.6 ° ± 0.1 °, 14.7 ° ± 0.1 °; 15.5 ° ± 0.1 °, 17.3 ° ± 0.1 °, located main peak for 19.3 ° ± 0.1 °.
A kind of preparation method of ertapenem list sodium salt crystal body of the present invention comprises the steps:
A) at 0~5 ℃, with ertapenem list sodium salt raw material with to contain the sodium mineral alkali soluble in water;
B) be cooled to-2~10 ℃, regulate pH=5~6 (preferred pH=5.4~5.6), add activated carbon decolorizing, filtration again with acidic solution;
C) add methyl alcohol, be cooled to 0~-40 ℃ (preferred-5~-20 ℃); The methyl alcohol volume that wherein adds is 0.5~3 times of volume of step a) institute water;
D) drip n-propyl alcohol, stirring and crystallizing; The n-propyl alcohol volume that wherein drips is 0.5~3 times of volume of step a) institute water;
E) filter, use the organic solvent washing filter cake, oil pump is drained solvent, promptly gets described ertapenem list sodium salt crystal body.
As preferred version, the preparation method of described ertapenem list sodium salt crystal body comprises the steps:
A) at 0~5 ℃, with ertapenem list sodium salt raw material with to contain the sodium mineral alkali soluble in water;
B) be cooled to-2~10 ℃, regulate pH=5~6, add activated carbon decolorizing, filtration again with acidic solution;
C) add methyl alcohol, be cooled to 0~-40 ℃; The methyl alcohol volume that wherein adds is 0.5~3 times of volume of step a) institute water;
D) add crystal seed, drip n-propyl alcohol then, stirring and crystallizing; The n-propyl alcohol volume that wherein drips is 0.5~3 times of volume of step a) institute water;
E) filter, use the organic solvent washing filter cake, oil pump is drained solvent, and logical at last dew point is moisture inert gas 4~48h of 0~30 ℃, promptly obtains described ertapenem list sodium salt crystal body.
Crystal formation or unformed ertapenem list sodium salt or their mixture that described ertapenem list sodium salt raw material is an any known.
The described sodium mineral alkali that contains is recommended as yellow soda ash, sodium hydrogencarbonate or sodium hydroxide, preferred sodium hydrogencarbonate or yellow soda ash.
Described ertapenem list sodium salt raw material is 1: 1~1: 4 with the mol ratio that contains the sodium mineral alkali.
The quality of step a) institute water is 6~12 times of ertapenem list sodium salt raw materials quality, preferred 8~10 times.
Described acidic solution is selected from any one in the organic alcoholic solution of C1~C4 of formic acid, acetate, propionic acid, hydrochloric acid or formic acid, acetate, propionic acid, hydrochloric acid, the methanol solution of preferable formic acid or acetate.
The volumetric molar concentration of described acidic solution is recommended as 1~25mol/L, is preferably 3~10mol/L.
Described organic solvent is selected from any one or a few the mixed solvent in acetone, ETHYLE ACETATE, THF, ether, MTBE, methylene dichloride, methyl alcohol, the ethanol.
Compared with prior art, ertapenem list sodium salt crystal body provided by the invention has advantages such as the low and good stability of residual solvent amount.In addition, the preparation method of ertapenem list sodium salt crystal body provided by the invention has advantages such as technology is simple, preparation cost is cheap, suitable suitability for industrialized production.
Embodiment
Below in conjunction with accompanying drawing and embodiment the present invention is done further detailed explanation.
Ertapenem list sodium salt raw material used among the embodiment can be the ertapenem list sodium salt of unformed or known arbitrary crystal formation or their mixture; Its preparation method can be with reference to US6504027, WO2002057266, WO2008062279, CN200510030660, CN200710045327, " China Medicine University's journal "; Described in 2007,38 (4): 305~310 documents such as grade.
Analytical instrument model and condition determination used among the embodiment are following:
1. powder x-ray diffraction analysis
Instrument: Dedye-Scherrer INEL CPS-120 powder x-ray diffraction.
The condition of scanning: source of radiation α
1(wavelength
), α
2(wavelength
), strength ratio α
1/ α
2Be 0.5, and Cu (40KV, 30mA).
2.FT-IR analyze
Instrument: Perkin-Elmer, the Spectrum type.
Condition determination: KBr compressing tablet.
3.
1H-NMR analyzes
Instrument: Brooker,Switzerland AV400,400MHz nmr analysis appearance.
Measure solvent: D
2O.
4.MS analyze
Instrument: the UPLC-TQD of Waters company type liquid chromatography mass combined instrument.
Mass spectrum condition: positive ion full scan pattern (ESI ion source), molecular weight ranges: 100~1500amu.Capillary voltage :+3.5/-3.0 (KV); Taper hole voltage :+20/-25 (V); Secondary taper hole voltage: ± 3 (V); Six grades of bar voltages: ± 0.3 (V); Source temperature: 150 ℃; Desolventizing temperature: 350 ℃; Desolventizing air-flow: 800L/Hr; Taper hole air-flow: 50L/Hr.
Embodiment 1
With 1.86g NaHCO
3Be dissolved in the 60ml zero(ppm) water; Be cooled to 0~5 ℃, add ertapenem list sodium salt raw material 10.0g, dissolve clear; Regulate pH=5.5 at 0~5 ℃ of acetate-methanol solution with 3mol/L; Add 2g activated carbon decolorizing 20min, filtering gac under argon shield and ice-water bath; Add 100ml methyl alcohol, be cooled to-20~-15 ℃, Dropwise 5 0ml n-propyl alcohol stirs 40min at a slow speed, has a large amount of solids to separate out, and drips remaining 100ml n-propyl alcohol again, drips complete stirring and crystallizing 40min; Filter, use the small amount of acetone washing leaching cake, oil pump is drained solvent, gets the 7.4g white solid; The moisture argon gas stream 24h that logical at last dew point is 4~6 ℃ promptly obtains described ertapenem list sodium salt crystal body 7.2g.
Embodiment 2
0.88g NaOH is dissolved in the 120ml zero(ppm) water; Be cooled to 0~5 ℃, add ertapenem list sodium salt raw material 10.0g, dissolve clear; Regulate pH=5.5 at 0~5 ℃ of acetate-methanol solution with 3mol/L; Add 2g activated carbon decolorizing 20min, filtering gac under argon shield and ice-water bath; Add 100ml methyl alcohol, be cooled to-20~-15 ℃, add the 0.1g crystal seed, and drip the 150ml n-propyl alcohol, drip complete stirring and crystallizing 40min; Filter, use the small amount of acetone washing leaching cake, oil pump is drained solvent, gets the 7.2g white solid; Logical at last dew point is 0~4 ℃ moisture argon gas stream 24h, promptly obtains described ertapenem list sodium salt crystal body 7.0g (be designated as batch 1).
Repeat twice again according to above step, can obtain ertapenem list sodium salt crystal body 7.4g (be designated as batch 2) and 7.1g (be designated as batch 3) respectively.
The solvent residual amount of 3 batches the ertapenem list sodium salt crystal body that present embodiment is prepared is seen shown in the table 1.
Table 1 solvent residual amount (unit is ppm)
Sample |
Methyl alcohol |
Acetone |
N-propyl alcohol |
ETHYLE ACETATE | THF |
Batch |
1 |
213 |
390 |
993 |
ND | ND |
Batches |
2 |
206 |
153 |
ND |
ND |
ND |
Batches 3 |
240 |
238 |
ND |
ND |
ND |
Visible by table 1: the solvent residual amount of the ertapenem list sodium salt crystal body of present embodiment preparation is low, meets medicinal standard.
3 batches the ertapenem list sodium salt crystal body that present embodiment is prepared was deposited 6 months at-18 ℃ respectively, detected the purity of an ertapenem list sodium salt every other month, and detected result is seen shown in the table 2.
The purity of table 2 ertapenem list sodium salt
Sample |
0 month |
1 month |
2 months |
3 months |
6 months |
Batch |
1 |
98.3 |
98.2 |
98.2 |
98.1 |
98.0 |
Batches 2 |
98.5 |
98.4 |
98.4 |
98.3 |
98.2 |
Batches 3 |
98.6 |
98.5 |
98.4 |
98.3 |
98.3 |
Visible by table 2: the having good stability of the ertapenem list sodium salt crystal body of present embodiment preparation.
Embodiment 3
With 4.4g Na
2CO
3Be dissolved in the 60ml zero(ppm) water, be mixed with and contain the sodium inorganic base aqueous solution; Be cooled to 0~5 ℃, add ertapenem list sodium salt raw material 10.0g, dissolve clear; Regulate pH=5.6 at 0~5 ℃ of formic acid-methanol solution with 3mol/L; Add 2g activated carbon decolorizing 20min, filtering gac under argon shield and ice-water bath; Add 180ml methyl alcohol, be cooled to-10~-5 ℃, add the 0.1g crystal seed, drip the 180ml n-propyl alcohol, drip and finish stirring and crystallizing 40min at a slow speed; Filter, use the small amount of ethanol washing leaching cake, oil pump is drained solvent, gets the 6.9g white solid; Logical at last dew point is 10~14 ℃ moisture argon gas stream 6h, promptly obtains described ertapenem list sodium salt crystal body 6.8g (be designated as batch 4).
Repeat twice again according to above step, can obtain ertapenem list sodium salt crystal body 7.0g (be designated as batch 5) and 7.1g (be designated as batch 6) respectively.
The solvent residual amount of 3 batches the ertapenem list sodium salt crystal body that present embodiment is prepared is seen shown in the table 3.
Table 3 solvent residual amount (unit is ppm)
Sample |
Methyl alcohol |
Ethanol |
N-propyl alcohol |
ETHYLE ACETATE |
THF |
Batches 4 |
24 |
828 |
986 |
6 |
ND |
Batches 5 |
100 |
1600 |
1000 |
ND |
ND |
Batches 6 |
74 |
980 |
850 |
ND |
ND |
Visible by table 3: the solvent residual amount of the ertapenem list sodium salt crystal body of present embodiment preparation is low, meets medicinal standard.
3 batches the ertapenem list sodium salt crystal body that present embodiment is prepared was deposited 6 months at-18 ℃ respectively, detected the purity of an ertapenem list sodium salt every other month, and detected result is seen shown in the table 4.
The purity of table 4 ertapenem list sodium salt
Sample |
0 month |
1 month |
2 months |
3 months |
6 months |
Batches 4 |
98.4 |
98.2 |
98.1 |
98.0 |
97.9 |
Batches 5 |
98.6 |
98.4 |
98.3 |
98.2 |
98.0 |
Batches 6 |
98.7 |
98.5 |
98.4 |
98.3 |
98.2 |
Visible by table 4: the having good stability of the ertapenem list sodium salt crystal body of present embodiment preparation.
Ertapenem list sodium salt crystal body provided by the invention has powder x-ray diffraction spectrogram shown in Figure 1: at 2 θ is 4.43 °, 5.23 °, 7.37 °, 8.14 °, 10.97 °, 12.59 °, 14.74 °, 15.46 °, has located characteristic peak for 17.31 ° and 19.34 °.
Ertapenem list sodium salt crystal body provided by the invention has FT-IR spectrogram shown in Figure 2: have characteristic peak at (cm-1) 3422,2969,1751,1686,1560,1387 and 773 places.
Ertapenem list sodium salt crystal body provided by the invention have hydrogen nuclear magnetic resonance spectrogram shown in Figure 3: δ 1.03 (d, 3H, CH3, J=7.2); 1.13 (d, 3H, CH3, J=6.4); 2.04 (m, 1H, C4 '-H); 2.88 (m, 1H, C4 '-H); 3.18 (m, 1H, C3 '-H); (3.28 dd, 1H, C2 '-H, J=6.0,2.4); (3.33 dd, 1H, C5-H, J=12.0,5.2); (3.69 dd, 1H, C6-H, J=12.0,6.6); 3.92 (m, 1H, C4-H, J=6.4); (4.04 dd, 1H, C2 '-H, J=9.2,2.4); 4.08 (m, 1H, CH-OH); 4.49 (t, 1H, C5 '-H, J=8.1); 7.32 (t, 1H, C5 "-H, J=7.9); 7.49 (d, 1H, C4 "-H, J=8.1); 7.57 (d, 1H, C6 "-H, J=7.7); 7.74 (s, 1H, C2 "-H).
Ertapenem list sodium salt crystal body provided by the invention has mass spectrum shown in Figure 4 (MS, ESI) figure: 473.99 (M-H), 475.99 (M+H).
Fig. 5 is that ertapenem list sodium salt crystal body provided by the invention is in the x-ray diffractogram of powder spectrum of-18 ℃ of placements after 6 months; Comparison diagram 1 is visible with Fig. 5: ertapenem list sodium salt crystal body provided by the invention is composed basically in the x-ray diffractogram of powder of-18 ℃ of placements after 6 months and is not become, and has stability.
Fig. 6 is the x-ray diffractogram of powder spectrum of ertapenem list sodium salt crystal body provided by the invention before logical inert gas; Comparison diagram 1 is visible with Fig. 6: ertapenem list sodium salt crystal body provided by the invention is composed the basic change that do not have at the x-ray diffractogram of powder that leads to the inert gas front and back, has stability.
Should be noted that at last: above embodiment only is used for the present invention is further specified; Can not be interpreted as the restriction to protection domain of the present invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.