CN102267996A - Crystal form of carbapenem derivative or hydrate of the carbapenem derivative, and preparation method thereof - Google Patents
Crystal form of carbapenem derivative or hydrate of the carbapenem derivative, and preparation method thereof Download PDFInfo
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- CN102267996A CN102267996A CN 201010190636 CN201010190636A CN102267996A CN 102267996 A CN102267996 A CN 102267996A CN 201010190636 CN201010190636 CN 201010190636 CN 201010190636 A CN201010190636 A CN 201010190636A CN 102267996 A CN102267996 A CN 102267996A
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- 239000013078 crystal Substances 0.000 title claims abstract description 95
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
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- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 8
- 229910002483 Cu Ka Inorganic materials 0.000 claims abstract description 7
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- 230000015572 biosynthetic process Effects 0.000 claims description 46
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- 238000004440 column chromatography Methods 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 20
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical class OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 claims description 17
- 239000003513 alkali Substances 0.000 claims description 17
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- 238000000354 decomposition reaction Methods 0.000 claims description 13
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Abstract
The invention belongs to the medical technical field and specifically relates to a crystal form of a carbapenem derivative (4R, 5S, 6S)-3-[(3S, 5S)-5-[(4-aminosulfonylphenyl-1-ylmethyl)carbamoyl]-3-pyrrolidine]thio-6-[(R)-1-ethoxyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid or a hydrate of the carbapenem derivative, and a preparation method of the crystal form. As shown in the structural formula I, the crystal form of the carbapenem derivative or the hydrate of the carbapenem derivative is characterized in that through Cu-Ka radiation, an X-ray powder diffraction pattern expressed in 2 theta angles has characteristic peaks at 18.9+/-0.2, 19.4+/-0.2, 21.0+/-0.2, 21.7+/-0.2, and 23.4+/-0.2.
Description
1, technical field
The invention belongs to medical technical field; be specifically related to Carbpenem derivants (4R; 5S; 6S)-3-[(3S, 5S)-5-[(4-sulfahydantoin phenmethyl) carbamyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-1-hydroxyethyl]-crystal formation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid or its hydrate and preparation method thereof.
2, background technology
Carbapenems (Carbapenems) microbiotic is the novel β-Nei Xiananleikangshengsu that grows up the seventies in 20th century, because it has characteristics such as super wide spectrum, superpower effect, anti-enzyme, the status in clinical application is more and more outstanding.The carbapenem antibiotic of listing has imipenum-cilastatin, panipenem-Betamipron, meropenem, ertapenem sodium, biapenem, S-4661 at present.
Carbpenem derivants (4R shown in the structural formula (I); 5S; 6S)-3-[(3S; 5S)-and 5-[(4-amino-sulfonyl benzene-1-ylmethyl) amine formyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being called for short following compd A in this manual), the existing description in CN200810127480.2.Mainly by combining with penicillin-binding protein (PBPs) on the bacterial cell membrane, it is synthetic and produce germicidal action to suppress bacteria cell wall, and Gram-positive, negative bacterium are all had anti-microbial effect preferably.
Formula (I)
Crystal formation research and development are extremely important in medicament research and development, the crystal formation difference of compound, its different in kind.Crystal formation difference for example, the bioavailability of medicament difference, the solution degree is not equal.Simultaneously, different crystal formation also has considerable influence to the stability of compound, processing property etc.Therefore the inventor has carried out a large amount of research to the crystal formation of compd A, confirms and invented the crystal formation of compd A thus.
Wherein described the crystal formation I of compd A in CN201010178970.2 in detail, it has characteristic peak 10.3 ± 0.2,14.5 ± 0.2,16.3 ± 0.2,17.1 ± 0.2,18.0 ± 0.2,20.8 ± 0.2,21.3 ± 0.2,22.0 ± 0.2,23.3 ± 0.2.Though the crystal formation I of compd A has improved the stability of compd A to a certain extent, still need the stability and the processing property of further improvement and raising compd A.
3, summary of the invention
The objective of the invention is to solve the problem of above-mentioned existence, provide stability better, operability is better, bioavailability and solubleness good the new crystal formation and preparation method thereof of compd A.
The invention provides the crystal formation of compd A shown in the structural formula (I) or its hydrate: use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles has characteristic peak at 18.9 ± 0.2,19.4 ± 0.2,21.0 ± 0.2,21.7 ± 0.2,23.4 ± 0.2 places.
The crystal formation of described compd A or its hydrate uses the Cu-Ka radiation, and the X-ray powder diffraction so that 2 θ angles are represented except that characteristic peak mentioned above, also has characteristic peak at 10.8 ± 0.2,11.8 ± 0.2,12.0 ± 0.2,23.7 ± 0.2 places.
The crystal formation of described compd A or its hydrate, its DSC absorb heat deflection at 105-117 ℃, and maximum decomposition temperature is about 170-179 ℃.
The crystal formation of described compd A or its hydrate, its water content are 6%-10%.
The inventor has done a large amount of research to the preparation method of the crystal formation of compd A or its hydrate, because the molecular structure of compd A has determined that compd A is an amphiprotic substance, be acidity be again alkaline, so compound not only can be dissolved in sour environment but also can be dissolved in the alkaline environment.The present invention also provides the preparation method of the crystal formation of compd A or its hydrate.
The crystal formation of compd A (hereinafter to be referred as crystal form II) can make by following four kinds of methods.
Method 1
After adding alkali or basic solution adjusting pH value is dissolved extremely fully in the aqueous suspension of compd A, use acid for adjusting pH value, reduce to low temperature, obtain crystal, filter, drying, promptly.
Method 2
After the adding acid for adjusting pH value dissolves extremely fully in the aqueous suspension of compd A, regulate the pH value, reduce to low temperature, obtain crystal, filter with alkali or basic solution, drying, promptly.
Method 3
After adding alkali or basic solution adjusting pH value is dissolved extremely fully in the aqueous suspension of compd A, this solution is passed through the column chromatography adsorption and enrichment, use the mixed solvent wash-out of organic solvent and water then, decompression steams organic solvent, uses acid for adjusting pH value, reduces to low temperature, obtain crystal, filter, drying, promptly.
Method 4
After the adding acid for adjusting pH value dissolves extremely fully in the aqueous suspension of compd A, this solution is passed through the column chromatography adsorption and enrichment, use the mixed solvent wash-out of organic solvent and water then, decompression steams organic solvent, regulates the pH value with alkali or basic solution, reduces to low temperature, obtain crystal, filter, drying, promptly.
Above-mentioned preparation method 1-4 is described, and described acid is mineral acid or organic acid with in the step of acid for adjusting pH value, and wherein mineral acid is selected from Hydrogen bromide, hydrochloric acid, sulfuric acid, sulfurous acid, nitric acid or phosphoric acid, preferred hydrochloric acid; Organic acid is selected from methylsulfonic acid, dodecyl sulphate, 2-naphthene sulfonic acid, Phenylsulfonic acid, oxalic acid, 2,2-dichloro acetic acid, Phosphoric acid glycerol esters, 2-ethylenehydrinsulfonic acid, L-aspartic acid, toxilic acid, ethyl sulfonic acid, 1,5-disulfonic acid naphthalene, ethane-1,2-disulfonic acid, cyclohexyl thionamic acid or tosic acid.
Above-mentioned preparation method 1-4 is described to be regulated with alkali or basic solution in the step of pH value, and described alkali is organic bases or mineral alkali, and described basic solution is the solution that organic bases or mineral alkali are made into after water-soluble; Wherein mineral alkali is selected from potassium hydroxide, sodium hydroxide, zinc hydroxide, calcium hydroxide, salt of wormwood, saleratus, yellow soda ash or sodium bicarbonate, preferred sodium bicarbonate; Organic bases is selected from left-handed spermine acid, trimethyl-glycine, choline, diethylamine, Methionin, N, N '-two benzyl Edamines, 2-(diethylamino) ethanol, 2-monoethanolamine, 1-(2-hydroxyethyl) pyrroles, diethanolamine, dimethylethanolamine, N-methyl glucoside amine, Trometamol, trolamine, 4-(2-hydroxyethyl) morpholine, imidazoles or quadrol.
Among the above-mentioned preparation method 3-4, described column chromatography is reverse column chromatography, is selected from C
4Column chromatography, C
8Column chromatography, C
18Column chromatography or resin column chromatography, preferred C
18Column chromatography.
Among the above-mentioned preparation method 3-4, the organic solvent of organic solvent for dissolving each other with water is selected from the lower alcohol that contains 1-4 carbon atom, as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol etc. in the mixed solvent of described organic solvent and water; The lower ketones that contains 1-6 carbon atom is as acetone, butanone etc.; Acetonitrile; Propionitrile or tetrahydrofuran (THF) etc.; Particular methanol, acetone, acetonitrile.
Among the above-mentioned preparation method 3-4, in the mixed solvent of described organic solvent and water, the ratio of organic solvent and water is 1: 0.2～1: 4, and preferred 1: 0.5～1: 2, optimum was 1: 1.
Among the above-mentioned preparation method 1-4, the described low temperature of reducing to is meant when reducing to 0～10 ℃.
To the crystal form II that makes by aforesaid method, measure:
(1) powder x-ray diffraction
The condition that the X diffraction is measured: the Cu-Ka line,
(monochromator), record by D/MAX-RB type X-ray diffractometer.
Use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles has stronger characteristic peak at 18.9 ± 0.2,19.4 ± 0.2,21.0 ± 0.2,21.7 ± 0.2,23.4 ± 0.2 places; Also characteristic peak is arranged at 10.8 ± 0.2,11.8 ± 0.2,12.0 ± 0.2,23.7 ± 0.2 places.
When measuring crystal formation of the present invention with the X diffraction, sometimes because the instrument of measuring or the condition of mensuration, for the peak that records, error at measurment can be arranged slightly, therefore when determining crystalline texture, this error should be taken into account, so the applicant has considered limit of error (± 0.2) when determining 2 θ angles.
(2) the DSC heat absorption is measured
DSC condition determination: DZ 3335 differential scanning calorimeter, nitrogen protection, temperature rise rate 5 degree/minute.
DSC absorbs heat deflection at 105-117 ℃, and maximum decomposition temperature is about 170-179 ℃.
(3) single crystal diffraction is measured
The condition determination of single crystal diffraction: Mo/K α-wire harness, Bruker CCD APEX-II single crystal diffractometer
Obtain the molecular structure of crystal form II according to single crystal diffraction, its cell parameter is as follows,
(4) moisture determination
Measure according to Ka Er Fischer aquametry (being called for short the K-F method), the water content of The compounds of this invention A or its hydrate is at 6%-10%.
The crystal formation that the present invention also provides compd A or its hydrate treats and/or prevents application in the infectious disease medicament in preparation.
The present invention also provides the crystal formation of compd A or its hydrate and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner, is pharmaceutically acceptable arbitrary formulation, for example oral preparations and injection.When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.
Description of drawings
Fig. 1 is a compd A crystal form II powder x-ray diffraction collection of illustrative plates, and ordinate zou is represented diffracted intensity (CPS), and X-coordinate is represented angle of diffraction (2 θ).
Fig. 2 is the DSC collection of illustrative plates of compd A crystal form II, and ordinate zou is represented power (mW), X-coordinate represent temperature (℃).
Fig. 3 is the molecular structure that the compd A crystal form II obtains through single crystal diffraction.
4. embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But the scope that should not be construed as the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The preparation example one of embodiment 1 compd A crystal form II
Get 2.03 and digest compound A adding 50mL deionized water, stir and make suspension liquid, after dissolving extremely fully with sodium bicarbonate solid adjusting pH value then, this solution C
18The mixing solutions wash-out of 1: 1 acetonitrile/water is used in the column chromatography enrichment then, and decompression steams acetonitrile, is 6 with 2N salt acid for adjusting pH value, leave standstill in 0-5 ℃, obtain crystal, filter cold wash, vacuum-drying gets compd A crystal form II 1.37 grams, purity 99.1%, yield 67%.
The XRD diffraction: in the XRD diffractogram, crystallization has been located characteristic peak in following angle of diffraction (2 θ):
10.82、11.80、12.10、18.88、19.46、21.08、21.74、23.44、23.76；
The DSC decomposition point: maximum decomposition temperature is about 172 ℃;
Water content (K-F method): 7.69%.
The preparation example two of embodiment 2 compd A crystal form IIs
Get 2.01 and digest compound A adding 50mL deionized water, stir and make suspension liquid, after dissolving extremely fully with saturated aqueous solution of sodium bicarbonate adjusting pH value then, this solution C
18The mixing solutions wash-out of 1: 1 acetone is used in the column chromatography enrichment then, and decompression steams acetone, is 6 with 2N salt acid for adjusting pH value, leave standstill in 0-5 ℃, obtain crystal, filter cold wash, vacuum-drying gets compd A crystal form II 1.10 grams, purity 98.8%, yield 55%.
The XRD diffraction: XRD diffraction measurement result is shown among Fig. 1;
The DSC decomposition point: maximum decomposition temperature is about 172 ℃;
Water content (K-F method): 7.60%.
The preparation example three of embodiment 3 compd A crystal form IIs
Get 2.05 and digest compound A adding 50mL deionized water, stir and make suspension liquid, after dissolving extremely fully with 1N salt acid for adjusting pH value, this solution C
18The mixing solutions wash-out of 1: 1 methanol is used in the column chromatography enrichment then, and decompression steams methyl alcohol, is 6 with the saturated sodium bicarbonate aqueous solution adjust pH, leave standstill in 0-5 ℃, obtain crystal, filter cold wash, vacuum-drying gets compd A crystal form II 0.92 gram, purity 98.8%, yield 45%.
The XRD diffraction: in the XRD diffractogram, crystallization has been located characteristic peak in following angle of diffraction (2 θ):
10.76、11.74、12.06、18.90、19.40、21.02、21.68、23.38、23.70；
The DSC decomposition point: maximum decomposition temperature is about 173 ℃;
Water content (K-F method): 7.67%.
The preparation example four of embodiment 4 compd A crystal form IIs
Get 2.08 and digest compound A adding 50mL deionized water, stir and make suspension liquid, after dissolving extremely fully with saturated aqueous solution of sodium bicarbonate adjusting pH value, this solution C
18The mixing solutions wash-out of 1: 1 methanol is used in the column chromatography enrichment then, and decompression steams methyl alcohol, is 6 with 2N hydrochloric acid adjust pH, leave standstill in 0-5 ℃, obtain crystal, filter cold wash, vacuum-drying gets compd A crystal form II 0.97 gram, purity 99.0%, yield 46.6%.
The cultivation of monocrystalline after usefulness 2N hydrochloric acid has been transferred pH, places 0-10 ℃ to deposit the sample that obtained being suitable for the monocrystalline test in 2 days with reference to the foregoing description method.
The XRD diffraction: in the XRD diffractogram, crystallization has been located characteristic peak in following angle of diffraction (2 θ):
10.88、11.84、12.16、18.98、19.52、21.12、21.80、23.48、23.84；
The DSC measurement result: maximum decomposition temperature is about 172 ℃, and the extrapolation initial decomposition temperature is about 163 ℃, the results are shown among Fig. 2;
Gained monocrystalline X ray single crystal diffraction measurement result is shown among Fig. 3, and cell parameter is as follows,
Water content (K-F method): 7.57%;
Ultimate analysis: with regard to C
22H
28N
4O
7S
22H
2O
Theoretical value: C 47.13%, H 5.75%, N 9.99%
Measured value: C 47.20%, H 6.06%, N 10.11%.
The preparation example five of embodiment 5 compd A crystal form IIs
Get 2.02 and digest compound A adding 20mL deionized water, suspension liquid is made in stirring, after dissolving extremely fully with saturated aqueous solution of sodium bicarbonate adjusting pH, filters, filtrate is 6 with 2N hydrochloric acid adjust pH, leave standstill in 0-5 ℃, obtain crystal, filter, cold wash, vacuum-drying gets compd A crystal form II 1.27 grams, purity 98.0%, yield 62.9%.
The XRD diffraction: in the XRD diffractogram, crystallization has been located characteristic peak in following angle of diffraction (2 θ):
10.88、11.86、12.18、18.92、19.52、21.12、21.78、23.50、23.80；
The DSC decomposition point: maximum decomposition temperature is about 172 ℃;
Water content (K-F method): 7.71%;
The study on the stability of embodiment 6 compd A crystal form IIs
The inventor investigates the stability of the crystal form II of gained compd A, by its result as can be known, compares the excellent in stability of crystal form II of the present invention with the crystal formation I of the compd A of describing among the CN201010178970.2.Have advantages such as stability is high, degree of crystallinity is high, the dynamics distribution is concentrated, good product mobility, any surface finish.
Trial-product:
Crystal formation I: the method with reference to embodiment among the CN201010178970.2 1 makes, and lot number is 20100315-4;
Crystal form II: made by this specification sheets embodiment 1, lot number is 040805.
The investigation condition, 60 ℃ of high temperature are placed sampling after 5 days, 10 days, compare with placing 0 day sample, measure moisture, related substance, content.Between probation, sample is packed with plastics bag overcoat foil sealing.
Moisture determination is measured according to 2010 editions appendix VIII of Chinese Pharmacopoeia M, first method (Ka Erfeixiushi method).
Assay according to 2010 editions appendix V of Chinese Pharmacopoeia D high performance liquid chromatography, adopts reference substance to measure as external standard.
Operational condition
Instrument: high-efficient liquid phase chromatogram discuss (Agilent 1200series)
Chromatographic column: Agilent C
18, filler is the octadecylsilane silica gel of 5 μ m, internal diameter 4.6mm, column length 150mm
Column temperature: 30 ℃
Moving phase: 0.02M Secondary ammonium phosphate (phosphoric acid is transferred pH=5.2): acetonitrile=100: 7
Flow velocity: 1.0mL/min
Sample size: 10 μ l
Determination of related substances according to 2010 editions appendix V of Chinese Pharmacopoeia D high performance liquid chromatography, adopts area normalization method to measure.
Operational condition
Instrument: high-efficient liquid phase chromatogram discuss (Agilent 1200series)
Chromatographic column: Agilent C
18, filler is the octadecylsilane silica gel of 5 μ m, internal diameter 4.6mm, column length 150mm
Column temperature: 30 ℃
Moving phase: A:0.02M Secondary ammonium phosphate (phosphoric acid is transferred pH=5.2): acetonitrile=95: 5
B:0.02M Secondary ammonium phosphate (phosphoric acid is transferred pH=5.2): acetonitrile=30: 70
Gradient condition: see the following form 1.
Table 1 determination of related substances chromatogram gradient condition
| T(min) | 0 | 5 | 15 | 18 | 25 | 30 | 35 | 40 | 42 | 47 |
| B％ | 0 | 3 | 4 | 15 | 30 | 65 | 100 | 100 | 0 | 0 |
Flow velocity: 1.0mL/min
Sample size: 10 μ l
Gained test-results: see the following form 2.
Table 2 study on the stability result
Remarks: because the compd A facile hydrolysis, the beta-lactam ring is opened after the hydrolysis, is major impurity, so the inventor is called for short ring-opening product with the content of a ring-opening product factor as study on the stability; Open loop %, compare the amount of increase when increasing content that % is meant that 60 ℃ of high temperature place ring-opening product and related substance after 5 days, 10 days and placing 0 day.
As can be seen from Table 2, high temperature is placed after 5 days, 10 days for 60 ℃, and the amount that the crystal form II ring-opening product increases is little than the amount that crystal formation I ring-opening product increases, and the amount that crystal form II total impurities content increases is little than the amount that crystal formation I total impurities content increases; The amount that the crystal form II moisture content reduces is little than the amount that crystal formation I moisture content reduces; The amount that crystal form II content reduces is little than the amount that crystal formation I content reduces; Therefore the crystal form II of compd A is compared with crystal formation I, and what foreign matter content increased lacks, and what moisture reduced lacks, and what content reduced lacks, and the character of each side is all good than crystal formation I, illustrates that the crystal form II of compd A is better than the stability of crystal formation I.
Claims (17)
1. carbapenem derivative (4R shown in the formula (I); 5S; 6S)-3-[(3S; 5S)-and 5-[(4-amino-sulfonyl benzene-1-ylmethyl) amine formyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-1-hydroxyethyl]-crystal formation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid or its hydrate; it is characterized in that; use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles has characteristic peak at 18.9 ± 0.2,19.4 ± 0.2,21.0 ± 0.2,21.7 ± 0.2,23.4 ± 0.2 places.
2. the crystal formation of carbapenem derivative as claimed in claim 1 or its hydrate, it is characterized in that: use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles, except that right requires 1 characteristic peak of being explained, also characteristic peak is arranged at 10.8 ± 0.2,11.8 ± 0.2,12.0 ± 0.2,23.7 ± 0.2 places.
3. as the crystal formation of each described carbapenem derivative of claim 1-2 or its hydrate, it is characterized in that DSC absorbs heat deflection at 105-117 ℃, maximum decomposition temperature is at 170-179 ℃.
4. as the crystal formation of each described carbapenem derivative of claim 1-2 or its hydrate, it is characterized in that its water content is 6%-10%.
5. as the preparation method of the crystal formation of each described carbapenem derivative of claim 1-2 or its hydrate; it is characterized in that; at (4R; 5S; 6S)-3-[(3S; 5S)-and 5-[(4-amino-sulfonyl benzene-1-ylmethyl) amine formyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-1-hydroxyethyl]-add alkali or basic solution in the aqueous suspension of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid to regulate pH value after dissolve fully; use acid for adjusting pH value; reduce to low temperature; obtain crystal; filter, drying, promptly.
6. as the preparation method of the crystal formation of each described carbapenem derivative of claim 1-2 or its hydrate; it is characterized in that; at (4R; 5S; 6S)-3-[(3S; 5S)-and 5-[(4-amino-sulfonyl benzene-1-ylmethyl) amine formyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-1-hydroxyethyl]-add acid for adjusting pH value in the aqueous suspension of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid to dissolving fully; regulate the pH value with alkali or basic solution; reduce to low temperature; obtain crystal; filter, drying, promptly.
7. as the preparation method of the crystal formation of each described carbapenem derivative of claim 1-2 or its hydrate; it is characterized in that; at (4R; 5S; 6S)-3-[(3S; 5S)-and 5-[(4-amino-sulfonyl benzene-1-ylmethyl) amine formyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-1-hydroxyethyl]-add alkali or basic solution in the aqueous suspension of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid to regulate pH value after dissolve fully; this solution by the column chromatography adsorption and enrichment, is used the mixed solvent wash-out of organic solvent and water then, and decompression steams organic solvent; use acid for adjusting pH value; reduce to low temperature, obtain crystal, filter; drying, promptly.
8. as the preparation method of the crystal formation of each described carbapenem derivative of claim 1-2 or its hydrate; it is characterized in that; at (4R; 5S; 6S)-3-[(3S; 5S)-and 5-[(4-amino-sulfonyl benzene-1-ylmethyl) amine formyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-1-hydroxyethyl]-add acid for adjusting pH value in the aqueous suspension of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid to dissolving fully; this solution by the column chromatography adsorption and enrichment, is used the mixed solvent wash-out of organic solvent and water then, and decompression steams organic solvent; regulate the pH value with alkali or basic solution; reduce to low temperature, obtain crystal, filter; drying, promptly.
9. as the preparation method of the crystal formation of each described carbapenem derivative of claim 5-8 or its hydrate, it is characterized in that, described acid is mineral acid or organic acid, wherein mineral acid is selected from Hydrogen bromide, hydrochloric acid, sulfuric acid, sulfurous acid, nitric acid or phosphoric acid, organic acid is selected from methylsulfonic acid, dodecyl sulphate, the 2-naphthene sulfonic acid, Phenylsulfonic acid, oxalic acid, 2, the 2-dichloro acetic acid, Phosphoric acid glycerol esters, the 2-ethylenehydrinsulfonic acid, the L-aspartic acid, toxilic acid, ethyl sulfonic acid, 1,5-disulfonic acid naphthalene, ethane-1, the 2-disulfonic acid, cyclohexyl thionamic acid or tosic acid.
10. as the preparation method of the crystal formation of each described carbapenem derivative of claim 5-8 or its hydrate, it is characterized in that described alkali is organic bases or mineral alkali, described basic solution is the solution that organic bases or mineral alkali are made into after water-soluble; Wherein mineral alkali is selected from potassium hydroxide, sodium hydroxide, zinc hydroxide, calcium hydroxide, salt of wormwood, saleratus, yellow soda ash or sodium bicarbonate, organic bases is selected from left-handed spermine acid, trimethyl-glycine, choline, diethylamine, Methionin, N, N '-two benzyl Edamines, 2-(diethylamino) ethanol, 2-monoethanolamine, 1-(2-hydroxyethyl) pyrroles, diethanolamine, dimethylethanolamine, N-methyl glucoside amine, Trometamol, trolamine, 4-(2-hydroxyethyl) morpholine, imidazoles or quadrol.
11. the preparation method as the crystal formation of each described carbapenem derivative of claim 7-8 or its hydrate is characterized in that described column chromatography is reverse column chromatography, is selected from C
4Column chromatography, C
8Column chromatography, C
18Column chromatography or resin column chromatography.
12. preparation method as the crystal formation of each described carbapenem derivative of claim 7-8 or its hydrate, it is characterized in that, the organic solvent of organic solvent for dissolving each other with water is selected from the lower alcohol that contains 1-4 carbon atom, the lower ketones that contains 1-6 carbon atom, acetonitrile, propionitrile or tetrahydrofuran (THF) in the mixed solvent of described organic solvent and water.
13. the preparation method as the crystal formation of each described carbapenem derivative of claim 7-8 or its hydrate is characterized in that in the mixed solvent of described organic solvent and water, the ratio of organic solvent and water is 1: 0.2～1: 4.
14. the preparation method of the crystal formation of carbapenem derivative as claimed in claim 13 or its hydrate is characterized in that, in the mixed solvent of described organic solvent and water, the ratio of organic solvent and water is 1: 0.5～1: 2.
15., it is characterized in that the described low temperature of reducing to is meant when reducing to 0～10 ℃ as each described preparation method of claim 5-8.
16. treat and/or prevent application in the infectious disease medicament in preparation as the crystal formation of each described carbapenem derivative of claim 1-2 or its hydrate.
17. comprise the crystal formation of each described carbapenem derivative of claim 1-2 or its hydrate and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner, be pharmaceutically acceptable arbitrary formulation.
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| CN 201010190636 CN102267996A (en) | 2010-06-03 | 2010-06-03 | Crystal form of carbapenem derivative or hydrate of the carbapenem derivative, and preparation method thereof |
| PCT/CN2011/000925 WO2011150679A1 (en) | 2010-06-03 | 2011-06-01 | Crystalline form of carbapenem derivative or its hydrates and preparation methods and uses thereof |
| CN201180026651.2A CN103025733B (en) | 2010-06-03 | 2011-06-01 | Crystal formation of Carbpenem derivants or its hydrate and preparation method thereof and purposes |
| HK13106724.5A HK1179616B (en) | 2010-06-03 | 2011-06-01 | Crystalline form of carbapenem derivative or its hydrates and preparation methods and uses thereof |
| US13/701,704 US8822445B2 (en) | 2010-06-03 | 2011-06-01 | Crystalline form of carbapenem derivative or its hydrates and preparation methods and uses thereof |
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| CN101372489A (en) * | 2007-06-28 | 2009-02-25 | 山东轩竹医药科技有限公司 | Carbapenem derivatives containing benzyl mercaptopyrrolidine carboxamide |
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| CN101372489A (en) * | 2007-06-28 | 2009-02-25 | 山东轩竹医药科技有限公司 | Carbapenem derivatives containing benzyl mercaptopyrrolidine carboxamide |
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| CN112174965A (en) * | 2019-07-03 | 2021-01-05 | 轩竹生物科技有限公司 | Deuterium modified carbapenem derivative |
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