CN103896936A - (5S, 6R) cloxacillin penicilloate as well as preparation method and application thereof - Google Patents
(5S, 6R) cloxacillin penicilloate as well as preparation method and application thereof Download PDFInfo
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- CN103896936A CN103896936A CN201410105329.4A CN201410105329A CN103896936A CN 103896936 A CN103896936 A CN 103896936A CN 201410105329 A CN201410105329 A CN 201410105329A CN 103896936 A CN103896936 A CN 103896936A
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- Prior art keywords
- cloxacillin
- acid salt
- solution
- penicilloic
- penicilloic acid
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- 229960003326 cloxacillin Drugs 0.000 title claims abstract description 135
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 title claims abstract description 83
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- HCYWNSXLUZRKJX-UHFFFAOYSA-N penicilloic acid Chemical compound N1C(C(O)=O)C(C)(C)SC1C(C(O)=O)NC(=O)CC1=CC=CC=C1 HCYWNSXLUZRKJX-UHFFFAOYSA-N 0.000 title abstract 5
- 239000003513 alkali Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 8
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 8
- -1 cloxacillin penicilloic acid salt Chemical class 0.000 claims description 52
- 239000000243 solution Substances 0.000 claims description 39
- OPEGYZAATHKDEM-HCWXCVPCSA-N (2r,4s)-2-[(r)-carboxy(formamido)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid Chemical compound CC1(C)S[C@H]([C@H](NC=O)C(O)=O)N[C@H]1C(O)=O OPEGYZAATHKDEM-HCWXCVPCSA-N 0.000 claims description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 230000006378 damage Effects 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003637 basic solution Substances 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000012535 impurity Substances 0.000 claims description 6
- 239000013558 reference substance Substances 0.000 claims description 6
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000013019 agitation Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 238000001514 detection method Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 238000004108 freeze drying Methods 0.000 abstract 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 19
- 229910052708 sodium Inorganic materials 0.000 description 19
- 239000011734 sodium Substances 0.000 description 19
- 239000000843 powder Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000005352 clarification Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000003760 magnetic stirring Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 150000003952 β-lactams Chemical class 0.000 description 3
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical class [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- SCLZRKVZRBKZCR-SLINCCQESA-M cloxacillin sodium Chemical compound [Na+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl SCLZRKVZRBKZCR-SLINCCQESA-M 0.000 description 2
- 229960003026 cloxacillin sodium Drugs 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 0 CC(C1(C)C)N[C@]([C@](CC(C2=C(C)ON[C@@]2C(C(Cl)=*)=CC=C)=O)C(O)=O)*1=C Chemical compound CC(C1(C)C)N[C@]([C@](CC(C2=C(C)ON[C@@]2C(C(Cl)=*)=CC=C)=O)C(O)=O)*1=C 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 244000005709 gut microbiome Species 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/3563—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light for analysing solids; Preparation of samples therefor
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/90—Plate chromatography, e.g. thin layer or paper chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/025—Gas chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/20—Screening for compounds of potential therapeutic value cell-free systems
Abstract
The invention provides a (5S, 6R) cloxacillin penicilloate as well as a preparation method and application thereof. The preparation method comprises the steps of adding an alkali solution into cloxacillin serving as a raw agent to perform alkali destroy on the cloxacillin, wherein the molar ratio of the cloxacillin to the solute in the alkali solution is 1: (1-10); adding an acid solution to adjust the pH value of the solution to be 6-10.2, then reacting, and freeze-drying the solution obtained by the reaction to obtain the (5S, 6R) cloxacillin penicilloate. The preparation method is simple, convenient, feasible, simple in operation, mild in reaction conditions, low in equipment requirement, cheap and readily available in raw materials, low in cost, high in yield and high in product purity and is an economic and efficient method for preparing the (5S, 6R) cloxacillin penicilloate, and the prepared (5S, 6R) cloxacillin penicilloate can be applied to the detection of cloxacillin antibiotics.
Description
Technical field
The invention belongs to impurity of the drug preparation field, be specifically related to (5S, 6R) cloxacillin penicilloic acid salt and its preparation method and application.
Background technology
Cloxacillin (is called again Cloxacillin Sodium, cloxacillin) be the semi-synthetic penem antibiotic of a kind of acidproof of resistance to enzyme isoxazole, it is the derivative of 6-amino-penicillanic acid (6-APA), the ability of its antiacid resistance to penicillin enzyme is obviously better than other class microbiotic, can not destroyed by penicillinase in vivo.Treat insensitive patient for those penicillin Gs, cloxacillin sodium plays an important role.Its fungicidal activity is stronger, and mechanism of action is mainly to synthesize to reach curative effect by suppressing copying of cell walls.Cloxacillin is more because it is cheap, easy to use, anti-microbial effect is obviously widely used in treating mastadenitis of cow and other diseases, but improper due to what this antibiotic unreasonable use and milk sample were collected, cause the residual phenomena of this microbiotic in animal-derived food serious.
But cloxacillin is unstable to alkali, under the alkaline condition of low concentration, can degrade, not only make drug effect reduce, anti-microbial activity weakens, and sometimes even causes serious anaphylaxis.But existing detection method cannot detect impurity such as cloxacillin penicilloic acids, this is mainly immature owing to lacking cloxacillin penicilloic acid reference substance and existing preparation method.This has encouraged the abuse of cloxacillin in the industries such as livestock industry more, also serious threat the long-run development of animal derived food industry, brought harm also to the mankind healthy, as destroyed human intestinal microflora balance and strengthening the resistance of bacterium.At present detecting required reference substance about cloxacillin penicilloic acid, be mainly the preparation with reference to penicilloic acid or the acid of Oxazacillin thiazole, but products therefrom foreign matter content is high, large on final product quality impact, is unfavorable for application.Therefore the preparation to cloxacillin degraded product cloxacillin penicilloic acid and detection are also one of current scientific research focus.
Summary of the invention
The object of the present invention is to provide one (5S, 6R) cloxacillin penicilloic acid salt and its preparation method and application, the method is simple to operate, yield is high, products obtained therefrom purity is high, and (5S, 6R) cloxacillin penicilloic acid salt making can be applied aspect detect antibiotics cloxacillin.
In order to achieve the above object, the technical solution used in the present invention is:
(5S, 6R) cloxacillin penicilloic acid salt, its chemical structural formula is:
The preparation method of (5S, 6R) cloxacillin penicilloic acid salt, comprises the following steps:
1) in reaction vessel, add bulk drug cloxacillin, then add basic solution to carry out alkali destruction to cloxacillin, obtain cloxacillin penicilloic acid salt intermediate; Wherein in cloxacillin and basic solution, the mol ratio of solute is 1:(1～10);
2) in cloxacillin penicilloic acid salt intermediate, adding acid solution, is 6～10.2 until regulate its pH value, then react, then the solution lyophilize that reaction is obtained, obtain (5S, 6R) cloxacillin penicilloic acid salt.
The concentration of described basic solution is 0.02～2.0mol/L, and wherein the solute of basic solution is sodium hydroxide, potassium hydroxide, sodium carbonate or sodium phosphate, and solvent is the mixed solution of water, dehydrated alcohol or water and dehydrated alcohol.
In described step 1), cloxacillin is carried out to alkali destruction and carry out under constant temperature agitation condition, the temperature that wherein constant temperature stirs is 20～60 ℃, and rotating speed is 400～600r/min, and churning time is 5～90min.
Described acid solution is one or more the mixing solutions in hydrochloric acid soln, sulphuric acid soln, salpeter solution, phosphoric acid solution.
The concentration of described acid solution is 0.01～1.0mol/L.
Described step 2) in reaction be to carry out under the constant temperature of 4～60 ℃, the reaction times is 24～56h.
Described cryodesiccated concrete operations are first to freeze 12～24h-80 ℃～-70 ℃ refrigerator and cooled, are then transferred in freeze drier lyophilize 12～16h at the temperature of the vacuum tightness of 0.90～1.01MPa and-80 ℃～-70 ℃.
The application of described (5S, 6R) cloxacillin penicilloic acid salt aspect detect antibiotics cloxacillin.
In the process of detect antibiotics cloxacillin, (5S, 6R) cloxacillin penicilloic acid salt is detected as the reference substance of impurity cloxacillin penicilloic acid.
With respect to prior art, beneficial effect of the present invention is:
(5S provided by the invention, 6R) the preparation method of cloxacillin penicilloic acid salt, take cloxacillin as bulk drug, first add wherein basic solution to carry out alkali destruction, and then add acid solution regulate pH value and react, finally reaction product lyophilize is obtained to (5S, 6R) cloxacillin penicilloic acid salt.The method preparation technology is simple and easy to do, simple to operate, reaction conditions gentleness, equipment requirements is low, raw material is cheap and easy to get, with low cost, yield is high, product purity is high, and the purity that obtains (5S, 6R) cloxacillin penicilloic acid salt in synthetic sample by high performance liquid chromatography area normalization method reaches 98%, use indirect iodometric determination (5S, 6R) cloxacillin penicilloic acid purity salt is greater than 85%, and therefore the method is a kind of method of preparation (5S, 6R) cloxacillin penicilloic acid salt of economical and efficient.
(5S provided by the invention, 6R) cloxacillin penicilloic acid salt is the new configuration of one in cloxacillin penicilloic acid, in the process of detect antibiotics cloxacillin, can be by (5S, 6R) cloxacillin penicilloic acid salt detects as the reference substance of impurity cloxacillin penicilloic acid, for the detection of microbiotic cloxacillin provides a new direction.
Accompanying drawing explanation
Fig. 1 is the uv scan figure of (5S, 6R) cloxacillin penicilloic acid salt;
Fig. 2 is the thin-layer chromatogram of (5S, 6R) cloxacillin penicilloic acid salt;
Fig. 3 is the mass spectrum of (5S, 6R) cloxacillin penicilloic acid salt;
Fig. 4 is the interpretation of mass spectra figure of (5S, 6R) cloxacillin penicilloic acid salt;
Fig. 5 is the infrared spectrogram of (5S, 6R) cloxacillin penicilloic acid salt.
Embodiment
Below in conjunction with accompanying drawing, the present invention is described in further detail.
(5S, 6R) cloxacillin penicilloic acid salt is the main configuration that cloxacillin degraded product cloxacillin penicilloic acid exists, and the chemical structural formula of (5S, 6R) cloxacillin penicilloic acid is:
The preparation method of (5S, 6R) provided by the invention cloxacillin penicilloic acid salt, its chemical equation is:
Below in conjunction with preferred embodiment of the present invention, the preparation method of (5S, 6R) provided by the invention cloxacillin penicilloic acid salt is elaborated.
Embodiment 1
1) in the ground Erlenmeyer flask with stopper, add 0.2mmol cloxacillin to 50mL, adding 10mL concentration is the aqueous sodium hydroxide solution (amount of substance of solute sodium hydroxide is 2mmol) of 0.2mol/L again, obtain achromaticity and clarification clear solution, then Erlenmeyer flask is put into heat-collecting magnetic stirring device, under the water bath with thermostatic control of 25 ℃, stir 60min with the rotating speed of 500r/min and carry out alkali destruction, obtain cloxacillin penicilloic acid sodium intermediate;
2) being the hydrochloric acid of 0.1mol/L to obtaining adding concentration in cloxacillin penicilloic acid sodium intermediate, is 8.12 until regulate its pH value, by after airtight this Erlenmeyer flask in 4 ℃ refrigeration 48h, obtain micro-yellow settled solution; This solution is taken out to lyophilize immediately, wherein cryodesiccated concrete operations are first to freeze 12h-80 ℃ of refrigerator and cooled, then be transferred in freeze drier, lyophilize 12h at the temperature of the vacuum tightness of 1.01MPa and-80 ℃, the white solid powder obtaining is (5S, 6R) cloxacillin penicilloic acid sodium.Get after part (5S, 6R) cloxacillin penicilloic acid sodium tri-distilled water dissolves and adopt HPLC chromatography to detect, area percentage can reach 98%.
Embodiment 2
1) in the ground Erlenmeyer flask with stopper, add 0.2mmol cloxacillin to 50mL, adding 1mL concentration is the aqueous sodium carbonate (amount of substance of solute sodium hydroxide is 2mmol) of 2mol/L again, obtain achromaticity and clarification clear solution, then Erlenmeyer flask is put into heat-collecting magnetic stirring device, under the water bath with thermostatic control of 60 ℃, stir 5min with the rotating speed of 600r/min and carry out alkali destruction, obtain cloxacillin penicilloic acid sodium intermediate;
2) being the hydrochloric acid of 1mol/L to obtaining adding concentration in cloxacillin penicilloic acid sodium intermediate, is 6 until regulate its pH value, by putting into 30 ℃ of water-bath reacting by heating 24h after airtight this Erlenmeyer flask, obtains micro-yellow settled solution; This solution is taken out to lyophilize immediately, wherein cryodesiccated concrete operations are first to freeze 24h-70 ℃ of refrigerator and cooled, then be transferred in freeze drier, lyophilize 16h at the temperature of the vacuum tightness of 0.90MPa and-70 ℃, the white solid powder obtaining is (5S, 6R) cloxacillin penicilloic acid sodium.Get after part (5S, 6R) cloxacillin penicilloic acid sodium tri-distilled water dissolves and adopt HPLC chromatography to detect, area percentage can reach 96%.
Embodiment 3
1) in the ground Erlenmeyer flask with stopper, add 0.2mmol cloxacillin to 50mL, adding 10mL concentration is the ethanol solution (amount of substance of solute sodium hydroxide is 0.2mmol) of the sodium hydroxide of 0.02mol/L again, obtain achromaticity and clarification clear solution, then Erlenmeyer flask is put into heat-collecting magnetic stirring device, under the water bath with thermostatic control of 40 ℃, stir 30min with the rotating speed of 550r/min and carry out alkali destruction, obtain cloxacillin penicilloic acid sodium intermediate;
2) being the nitric acid of 0.01mol/L to obtaining adding concentration in cloxacillin penicilloic acid sodium intermediate, is 10.2 until regulate its pH value, by putting into 40 ℃ of water-bath reacting by heating 56h after airtight this Erlenmeyer flask, obtains micro-yellow settled solution; This solution is taken out to lyophilize immediately, wherein cryodesiccated concrete operations are first to freeze 18h-75 ℃ of refrigerator and cooled, then be transferred in freeze drier, lyophilize 14h at the temperature of the vacuum tightness of 0.95MPa and-75 ℃, the white solid powder obtaining is (5S, 6R) cloxacillin penicilloic acid sodium.Get after part (5S, 6R) cloxacillin penicilloic acid sodium tri-distilled water dissolves and adopt HPLC chromatography to detect, area percentage can reach 94%.
Embodiment 4
1) in the ground Erlenmeyer flask with stopper, add 0.2mmol cloxacillin to 50mL, adding 1mL concentration is the water of sodium phosphate and the mixing solutions (amount of substance of solute sodium hydroxide is 2mmol) of dehydrated alcohol (volume ratio is 1:1) of 2mol/L again, obtain achromaticity and clarification clear solution, then Erlenmeyer flask is put into heat-collecting magnetic stirring device, under the water bath with thermostatic control of 20 ℃, stir 90min with the rotating speed of 400r/min and carry out alkali destruction, obtain cloxacillin penicilloic acid sodium intermediate;
2) being the phosphoric acid of 0.1mol/L to obtaining adding concentration in cloxacillin penicilloic acid sodium intermediate, is 7.2 until regulate its pH value, by putting into 60 ℃ of water-bath reacting by heating 32h after airtight this Erlenmeyer flask, obtains micro-yellow settled solution; This solution is taken out to lyophilize immediately, wherein cryodesiccated concrete operations are first to freeze 12h-80 ℃ of refrigerator and cooled, then be transferred in freeze drier, lyophilize 14h at the temperature of the vacuum tightness of 1.01MPa and-75 ℃, the white solid powder obtaining is (5S, 6R) cloxacillin penicilloic acid sodium.Get after part (5S, 6R) cloxacillin penicilloic acid sodium tri-distilled water dissolves and adopt HPLC chromatography to detect, area percentage can reach 92%.
Embodiment 5
1) in the ground Erlenmeyer flask with stopper, add 0.2mmol cloxacillin to 50mL, adding 1mL concentration is the ethanol solution (amount of substance of solute potassium hydroxide is 1mmol) of the potassium hydroxide of 1mol/L again, obtain achromaticity and clarification clear solution, then Erlenmeyer flask is put into heat-collecting magnetic stirring device, under the water bath with thermostatic control of 30 ℃, stir 75min with the rotating speed of 450r/min and carry out alkali destruction, obtain cloxacillin penicilloic acid potassium intermediate;
2) being the hydrochloric acid of 0.5mol/L and the mixture of sulfuric acid to obtaining adding concentration in cloxacillin penicilloic acid potassium intermediate, is 9.2 until regulate its pH value, reacts 38h by after airtight this Erlenmeyer flask at 15 ℃, obtains micro-yellow settled solution; This solution is taken out to lyophilize immediately, wherein cryodesiccated concrete operations are first to freeze 24h-70 ℃ of refrigerator and cooled, then be transferred in freeze drier, lyophilize 12h at the temperature of the vacuum tightness of 0.90MPa and-75 ℃, the white solid powder obtaining is (5S, 6R) cloxacillin penicilloic acid potassium.
Embodiment 6
1) in the ground Erlenmeyer flask with stopper, add 0.2mmol cloxacillin to 50mL, adding 1mL concentration is the sodium phosphate aqueous solution (amount of substance of solute sodium hydroxide is 0.5mmol) of 0.5mol/L again, obtain achromaticity and clarification clear solution, then Erlenmeyer flask is put into heat-collecting magnetic stirring device, under the water bath with thermostatic control of 50 ℃, stir 15min with the rotating speed of 500r/min and carry out alkali destruction, obtain cloxacillin penicilloic acid sodium intermediate;
2) be the mixture of sulfuric acid, nitric acid and the phosphoric acid of 0.05mol/L to obtaining adding concentration in cloxacillin penicilloic acid sodium intermediate, be 6.7 until regulate its pH value, by reacting by heating 50h in airtight this Erlenmeyer flask water-bath that is placed on 50 ℃, obtain micro-yellow settled solution; This solution is taken out to lyophilize immediately, wherein cryodesiccated concrete operations are first to freeze 14h-78 ℃ of refrigerator and cooled, then be transferred in freeze drier, lyophilize 13h at the temperature of the vacuum tightness of 0.98MPa and-72 ℃, the white solid powder obtaining is (5S, 6R) cloxacillin penicilloic acid sodium.
Preparation technology of the present invention is simple and easy to do, simple to operate, reaction conditions gentleness, equipment requirements is low, raw material is cheap and easy to get, with low cost, yield is high, product purity is high, and the purity that obtains (5S, 6R) cloxacillin penicilloic acid salt in synthetic sample by high performance liquid chromatography area normalization method reaches 98%, use indirect iodometric determination (5S, 6R) cloxacillin penicilloic acid purity salt is greater than 85%, and therefore the method is a kind of method of preparation (5S, 6R) cloxacillin penicilloic acid salt of economical and efficient.
(5S provided by the invention, 6R) cloxacillin penicilloic acid salt is the new configuration of one in cloxacillin penicilloic acid, in the process of detect antibiotics cloxacillin, can be by (5S, 6R) cloxacillin penicilloic acid salt detects as the reference substance of impurity cloxacillin penicilloic acid, for the detection of microbiotic cloxacillin provides a new direction.
Below in conjunction with accompanying drawing, the present invention is further elaborated:
Fig. 1 is the uv scan figure of (5S, 6R) cloxacillin penicilloic acid salt brine solution, and as can be seen from the figure, the maximum absorption wavelength of (5S, 6R) cloxacillin penicilloic acid salt is 228nm.
Take respectively cloxacillin and the each 0.0050g of (5S, 6R) cloxacillin penicilloic acid salt, dissolve respectively with tri-distilled water, make cloxacillin and (5S, 6R) cloxacillin penicilloic acid salt sample solution of concentration 2.50mg/mL; Respectively get 2 μ L and carry out point sample on the silica GF254 thin layer plate of activation 30min; By thin layer plate put into chromatography cylinder saturated, launch, developping agent is propyl carbinol: Glacial acetic acid: water=6:3:2(volume ratio); After expansion finishes, dry dry 30min under 80 ℃ of conditions in baking oven, rear employing iodine vapor and fluorescence developing method develop the color to sample, and as shown in Figure 2, wherein a is (5S to the thin-layer chromatogram obtaining, 6R) cloxacillin penicilloic acid salt, b is cloxacillin.As shown in Figure 2, with respect to cloxacillin, after synthetic (5S, 6R) cloxacillin penicilloic acid salt launches in chromatography cylinder, R
fbe worth differently from cloxacillin, and material is relatively single.
Adopt the method for gas chromatography-mass spectrography to synthetic (5S, 6R) cloxacillin penicilloic acid salt is analyzed, the mass spectrum obtaining as shown in Figure 3, wherein ionization condition is electric spray ion source, electron energy 70eV, 200 ℃ of ion source temperatures, 60 ℃ of interface temperature, detector voltage 1130V, mass range 50-500amu.The fragmention information providing according to gaseous mass spectrum figure, molecular ion peak is m/z435.1, peak (the m/z58 that other ion abundance are stronger, m/z100.1, m/z161.0, m/z188.0, m/z230.0) can make rational explanation, make thus reasonable supposition, confirm that the primary product of reaction is (5S, 6R) cloxacillin penicilloic acid salt.
Fig. 4 is cloxacillin penicilloic acid mass spectrum ion analysis diagram, and wherein (a) represents that fragmention molecular formula is C
10h
7clNO
+, its mass-to-charge ratio is 192.02, (b) represents that fragmention molecular formula is C
3h
3nO
+, its mass-to-charge ratio is 101.01, (c) represents that fragmention molecular formula is C
6h
10nO
2s
+, its mass-to-charge ratio is 160.04, (d) represents that fragmention molecular formula is C
11h
8clN
2o
+, its mass-to-charge ratio is 235.04, (e) represents that fragmention molecular formula is C
2h
2o
2 2+, its mass-to-charge ratio is 58.01, as can be seen from the figure, and the generation type that each main fragment is quasi-molecular ions.
Fig. 5 is by dried (5S, 6R) cloxacillin penicilloic acid salt powder and Potassium Bromide powder fully grind, in tabletting machine, carry out compressing tablet, scan respectively blank and (5S with infrared spectra detector, 6R) cloxacillin penicilloic acid salt compressing tablet, the infrared spectrogram obtaining.As can be seen from the figure, at 1500～2000cm
-1place is due to beta-lactam nucleus fracture, and the carbonyl on ring becomes carboxyl, merges into a peak so original carbonyl is bimodal; At 3300～3500cm
-1place is due to beta-lactam nucleus fracture, and the tertiary amino on ring becomes secondary amino group and environment of living in is different from original secondary amino group, so amino peak is cracked into two.It can be confirmed beta-lactam nucleus generation cracking in conversion process, for the analysis of cloxacillin penicilloic acid salt provides foundation.
Claims (10)
1. (5S, 6R) cloxacillin penicilloic acid salt, is characterized in that, its chemical structural formula is:
2. the preparation method of (5S, 6R) cloxacillin penicilloic acid salt, is characterized in that, comprises the following steps:
1) in reaction vessel, add bulk drug cloxacillin, then add basic solution to carry out alkali destruction to cloxacillin, obtain cloxacillin penicilloic acid salt intermediate; Wherein in cloxacillin and basic solution, the mol ratio of solute is 1:(1～10);
2) in cloxacillin penicilloic acid salt intermediate, adding acid solution, is 6～10.2 until regulate its pH value, then react, then the solution lyophilize that reaction is obtained, obtain (5S, 6R) cloxacillin penicilloic acid salt.
3. (5S according to claim 2,6R) the preparation method of cloxacillin penicilloic acid salt, it is characterized in that: the concentration of described basic solution is 0.02～2.0mol/L, wherein the solute of basic solution is sodium hydroxide, potassium hydroxide, sodium carbonate or sodium phosphate, and solvent is the mixed solution of water, dehydrated alcohol or water and dehydrated alcohol.
4. according to the (5S described in claim 2 or 3,6R) the preparation method of cloxacillin penicilloic acid salt, it is characterized in that: in described step 1), cloxacillin is carried out to alkali destruction and carry out under constant temperature agitation condition, the temperature that wherein constant temperature stirs is 20～60 ℃, rotating speed is 400～600r/min, and churning time is 5～90min.
5. according to the (5S described in claim 2 or 3,6R) the preparation method of cloxacillin penicilloic acid salt, is characterized in that: described acid solution is one or more the mixing solutions in hydrochloric acid soln, sulphuric acid soln, salpeter solution, phosphoric acid solution.
6. the preparation method of (5S, 6R) according to claim 5 cloxacillin penicilloic acid salt, is characterized in that: the concentration of described acid solution is 0.01～1.0mol/L.
7. according to the preparation method of (5S, 6R) cloxacillin penicilloic acid salt described in claim 2 or 3, it is characterized in that: described step 2) in reaction be to carry out under the constant temperature of 4～60 ℃, the reaction times is 24～56h.
8. according to the (5S described in claim 2 or 3,6R) the preparation method of cloxacillin penicilloic acid salt, it is characterized in that: described cryodesiccated concrete operations are first to freeze 12～24h-80 ℃～-70 ℃ refrigerator and cooled, then be transferred in freeze drier lyophilize 12～16h at the temperature of the vacuum tightness of 0.90～1.01MPa and-80 ℃～-70 ℃.
9. the application of (5S, 6R) as claimed in claim 1 cloxacillin penicilloic acid salt aspect detect antibiotics cloxacillin.
10. application as claimed in claim 9, is characterized in that, in the process of detect antibiotics cloxacillin, (5S, 6R) cloxacillin penicilloic acid salt is detected as the reference substance of impurity cloxacillin penicilloic acid.
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Cited By (1)
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| CN110143957A (en) * | 2019-06-20 | 2019-08-20 | 重庆医药高等专科学校 | The preparation method of Cefditoren pivoxil Cephalosporins ring-opening product |
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