CN104945417A - Children sulbenicillin sodium compound entity and pharmaceutical preparation thereof - Google Patents
Children sulbenicillin sodium compound entity and pharmaceutical preparation thereof Download PDFInfo
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- CN104945417A CN104945417A CN201510283121.6A CN201510283121A CN104945417A CN 104945417 A CN104945417 A CN 104945417A CN 201510283121 A CN201510283121 A CN 201510283121A CN 104945417 A CN104945417 A CN 104945417A
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- Prior art keywords
- sulfocillin
- children
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- sulbenicillin sodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/62—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
Abstract
The present invention discloses a children sulbenicillin sodium compound entity, wherein the original research tradename is Lilacillin, and the chemical structural formula of the compound entity is defined in the specification. The preparation steps comprise: (1) dissolving a sulbenicillin sodium crude product in purified water, adding active carbon, carrying out stirring decolorizing, and filtering; (2) adding an extractant to the filtrate under the stirring, transferring and filling into a pressure resistance container, removing air bubbles, carrying out sealing oscillation, carrying out temperature control freezing, and taking out; and (3) carrying out liquid-solid separation, discarding the extractant, adding acetone in a dropwise manner at a temperature of 5 DEG C after the solid melts, stirring at a slow speed, growing the grain, filtering, washing, and carrying out vacuum drying to obtain the sulbenicillin sodium finished product. The children sulbenicillin sodium compound entity of the present invention has advantages of good solubility, good clarity, low related substance content, good stability, low toxic-side effect, and the like.
Description
Technical field
The present invention relates to a kind of children's with Sulfocillin chemical entities and pharmaceutical preparation thereof, belong to medical compounds field.
Background technology
Sulfocillin, English name: Sulbenicillin Sodium, former development trade(brand)name: Sulbenicillin Lilacillin, its chemistry (2S by name, 5R, 6R)-3,3-dimethyl-6-(2-phenyl-2-sulfo group kharophen)-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid disodium salt.Molecular formula: C
16h
16n
2na
2o
7s
2, molecular weight: 458.42.
Sulfocillin belongs to semi-synthetic penicillins microbiotic, to enterobacteriaceae lactobacteriaceaes such as escherichia coli, proteus, enterobacter, citric acid bacterium genus, Salmonella and Shigellas, and other gram-negative bacteria such as Pseudomonas aeruginosa, hemophilus influenzae, neisseria has anti-microbial effect.This product also has an anti-microbial activity to Hemolytic streptococcus, streptococcus pneumoniae and the staphylococcus that do not produce penicillinase.This product to peptostreptococcus, clostridium interior anerobe also to there being certain effect.The mechanism of action of sulbenicillin is play germicidal action by anti-bacteria Cell wall synthesis.
Chinese patent 201010255035.1 provides a kind of preparation method of Sulfocillin, comprises the steps: to prepare α-sulphur phenyllacetyl chloride by α-sulphur toluylic acid; By α-sulphur phenyllacetyl chloride and 6-APA in the mixed solvent of water, ethanol and 2-methyltetrahydrofuran between pH to 5.6-7.0, temperature 15-25 DEG C room temperature reaction 20-40 minute obtain Sulfocillin crude product; Obtain sulbenicillin sodium water solution through aftertreatment, afterwards lyophilize again, namely obtain final product Sulfocillin.But show less stable by Sulfocillin prepared by aforesaid method, all unstable to heat, meta-acid environment, meta-alkali environment, show that outward appearance is easy to change, content reduces, occurs the problems such as degraded product, the reason of appearance may be the partial impurities cannot removed by the crystallization impact in Sulfocillin finished product.Therefore, high purity is prepared and stable Sulfocillin is those skilled in the art always makes great efforts.
Summary of the invention
The object of this invention is to provide a kind of children's and use Sulfocillin chemical entities, make children's have the advantages such as solvability is good, clarity is good, its related substances is low, good stability, toxic side effect are little with Sulfocillin chemical entities.
For solving the problems of the technologies described above, a kind of children's of the present invention uses Sulfocillin chemical entities, its structure as shown in formula I,
As preferably, described sulbenicillin sodium compound is prepared by following steps:
(1) Sulfocillin crude product is dissolved in purified water, adds gac, stir decolouring, filter;
(2) under agitation add extraction agent in filtrate, be transferred to and be full of in pressure vessel, remove sealing vibration after bubble, the freezing rear taking-up of temperature control;
(3) by solid-liquor separation, discard extraction agent, solid drips acetone at 5 DEG C, low rate mixing, growing the grain after melting, and filters, and washing, vacuum-drying, obtains Sulfocillin finished product.
As preferably, in described step (1), Sulfocillin strength of solution is 0.1 ~ 0.3g/ml, and activated carbon dosage is 3 ~ 10% of Sulfocillin crude product.
As preferably, in described step (2), extraction agent is several mixture of ethyl acetate, chloroform, ether or more.
As preferably, in described step (2), extraction agent is 1:100 ~ 200 with the volume ratio of the middle purified water of step (2).
As preferably, in described step (2), temperature control freezing temp is-20 ~-10 DEG C, and freezing time is 2 ~ 8 hours.
As preferably, in described step (3), the dripping quantity of acetone is 3 ~ 5 times of purified water consumption, and the low rate mixing time is 30 minutes, and rearing crystal time is 1 hour, and vacuum-drying temperature is 40 ~ 50 DEG C.
Present invention also offers and a kind ofly comprise the pharmaceutical preparation of above-mentioned children's with Sulfocillin chemical entities, described preparation is freeze-dried preparation.
A kind of children's of the present invention with the beneficial effect of Sulfocillin chemical entities and pharmaceutical preparation thereof is:
(1) Sulfocillin crude product is dissolved in purified water, with activated carbon decolorizing, can remove portion impurity.
(2) sulbenicillin sodium solution under agitation extracts with immiscible with it and also immiscible with water extraction agent, dissolve organic contaminants can be removed in extraction agent, improves the purity of Sulfocillin.
(3) mixing solutions be transferred to and be full of in pressure vessel, after removing bubble, sealing is vibrated, carry out temperature control freezing, in refrigerating process, aqueous solvent is frozen into ice, and volumetric expansion increases, and the internal pressure in airtight pressure vessel is increased, thus the solubleness of the organic impurity that improve in Sulfocillin in extraction agent, reduce the foreign matter content in Sulfocillin finished product.
(4) aqueous solvent is frozen in the process of ice, and organic impurity is extruded from ice, further increases extraction efficiency, reduces foreign matter content.
(5) powder injection prepared with Sulfocillin chemical entities of children's provided by the invention, has solvability good, clarity good (without small particles phenomenon), good stability, the advantages such as impurity is low, and toxic side effect is little.
Embodiment
Below in conjunction with specific embodiment, embodiment of the present invention are described in detail.Should be appreciated that enforcement of the present invention is not limited to the following examples, any pro forma accommodation make the present invention and/or change all will fall into protection scope of the present invention.
Embodiment 1
Take Sulfocillin crude product 100g, add purified water 1000ml, being warming up to 30 DEG C to all dissolving, adding 10g gac, stir decolouring, filter and obtain filtrate.
Under agitation in above-mentioned filtrate, add 5ml ethyl acetate, be transferred in 1000ml pressure vessel, guarantee to be full of and bubble removal, sealed vessel, vibration, takes out after the freezing 2h of temperature control-20 DEG C.
By solid-liquor separation, discard ethyl acetate solution, after ice-out, be transferred to crystallizer, within at 5 DEG C about 1 hour, drip 5000ml acetone, low rate mixing 30min, continue growing the grain 1h, suction filtration, with washing with acetone, obtain Sulfocillin finished product after 40 DEG C of vacuum-dryings, purity is 99.4%.
Embodiment 2
Take Sulfocillin crude product 100g, add purified water 500ml, being warming up to 30 DEG C to all dissolving, adding 7g gac, stir decolouring, filter and obtain filtrate.
Under agitation in above-mentioned filtrate, add 5ml chloroform, be transferred in 500ml pressure vessel, guarantee to be full of and bubble removal, sealed vessel, vibration, takes out after the freezing 5h of temperature control-15 DEG C.
By solid-liquor separation, discard chloroformic solution, after ice-out, be transferred to crystallizer, within at 5 DEG C about 1 hour, drip 2000ml acetone, low rate mixing 30min, continue growing the grain 1h, suction filtration, with washing with acetone, obtain Sulfocillin finished product after 45 DEG C of vacuum-dryings, purity is 99.5%.
Embodiment 3
Take Sulfocillin crude product 100g, add purified water 350ml, being warming up to 30 DEG C to all dissolving, adding 3g gac, stir decolouring, filter and obtain filtrate.
Under agitation in above-mentioned filtrate, add 2.3ml ethyl acetate and 2.3ml chloroform mixed solvent, be transferred in 350ml pressure vessel, guarantee to be full of and bubble removal, sealed vessel, vibration, takes out after the freezing 8h of temperature control-10 DEG C.
By solid-liquor separation, discard the mixing solutions of ethyl acetate and chloroform, after ice-out, be transferred to crystallizer, within at 5 DEG C about 1 hour, drip 1050ml acetone, low rate mixing 30min, continue growing the grain 1h, suction filtration, with washing with acetone, obtain Sulfocillin finished product after 50 DEG C of vacuum-dryings, purity is 99.4%.
Embodiment 4 (comparative example)
Being stirred by the α of 52.4g-sulphur toluylic acid is dissolved in 100ml ether, sulfur oxychloride 89ml is dripped in-3 DEG C, drip 1.2mlN, N-diisopropylethylamine, then stirring reaction 2.5 hours under the condition of temperature 20 DEG C, after completion of the reaction, underpressure distillation is to dry, and repeats the washing that to be added diethyl ether by the residue after distillation for 2 times, then underpressure distillation is extremely done, namely 61.2g α-sulphur phenyllacetyl chloride is obtained, yield 85.4%.
20.5g6-APA is joined in the mixed solvent of 50ml water, 25ml ethanol and 12.5ml2-methyltetrahydrofuran, maintain the temperature at 25 DEG C, dripping concentration is again that 15% sodium hydroxide solution regulates pH to 6.0, be stirred to solid at 25 DEG C to dissolve completely, drip the butylacetate solution containing 34.0g α-sulphur phenyllacetyl chloride under keeping this temperature, dropwise, maintain reaction solution pH6.0, room temperature reaction 40 minutes, obtains Sulfocillin crude product.
At ambient temperature, drip dilute hydrochloric acid by the solution of Sulfocillin crude product obtained above, regulate pH to 1.5, and then add propyl carbinol, wherein the volume ratio of propyl carbinol and Sulfocillin crude product solution is 3:1.2, layering, get organic phase extracting solution, obtain sulbenicillin organic solution; Be under the condition of 2 DEG C in temperature, in the organic solution of sulbenicillin, drip mass percent concentration is 25% sodium hydrogen carbonate solution, and wherein 1:1.8 is compared with the amount of substance of sodium bicarbonate in sulbenicillin, insulated and stirred 20 minutes, stratification, point water-yielding stratum, then washes 3 times to water layer ether extraction, charcoal absorption is being added 15 minutes at water layer, filter carbon removal, filtrate obtains 29.8g Sulfocillin through lyophilize, yield 68.5%, total recovery 58.0%, purity is 98.7%.
Embodiment 5
By the Sulfocillin that above-described embodiment 1-3 prepares, be dissolved in water for injection, former medicine is divided in sterile vial according to 1.0g/ bottle, through lyophilize, obtain sulbenicillin sodium for injection freeze-dried preparation.
Accelerated test
Get the sulbenicillin sodium freeze-dried preparation that the freeze-dried preparation be made up of the Sulfocillin of embodiment 1-3 and embodiment 4 traditional technology produce at random each a collection of, temperature 40 DEG C, place 6 months under relative humidity 75% condition, respectively at the 1st, 2,3, sampling in June, investigate the projects such as appearance character, look level, content, related substance, and with 0 month results contrast, test-results is in table 1.
Table 1
Result shows: the Sulfocillin that the present invention prepares is in accelerated test, and proterties, solution colour, related substance etc. are without considerable change, and its stability is good, significantly better than the Sulfocillin of comparative example.
Claims (8)
1. children's uses a Sulfocillin chemical entities, it is characterized in that, the structure of this Sulfocillin chemical entities as shown in formula I,
2. children's according to claim 1 uses Sulfocillin chemical entities, it is characterized in that, described sulbenicillin sodium compound is prepared by following steps:
(1) Sulfocillin crude product is dissolved in purified water, adds gac, stir decolouring, filter;
(2) under agitation add extraction agent in filtrate, be transferred to and be full of in pressure vessel, remove sealing vibration after bubble, the freezing rear taking-up of temperature control;
(3) by solid-liquor separation, discard extraction agent, solid drips acetone at 5 DEG C, low rate mixing, growing the grain after melting, and filters, and washing, vacuum-drying, obtains Sulfocillin finished product.
3. children's according to claim 2 uses Sulfocillin chemical entities, it is characterized in that, in described step (1), Sulfocillin strength of solution is 0.1 ~ 0.3g/ml, and activated carbon dosage is 3 ~ 10% of Sulfocillin crude product.
4. children's according to claim 2 uses Sulfocillin chemical entities, it is characterized in that, in described step (2), extraction agent is several mixture of ethyl acetate, chloroform, ether or more.
5. children's according to claim 2 uses Sulfocillin chemical entities, it is characterized in that, in described step (2), the volume ratio of extraction agent and the middle purified water of step (2) is 1:100 ~ 200.
6. children's according to claim 2 uses Sulfocillin chemical entities, it is characterized in that, in described step (2), temperature control freezing temp is-20 ~-10 DEG C, and freezing time is 2 ~ 8 hours.
7. children's according to claim 2 uses Sulfocillin chemical entities, it is characterized in that, in described step (3), the dripping quantity of acetone is 3 ~ 5 times of purified water consumption, and the low rate mixing time is 30 minutes, rearing crystal time is 1 hour, and vacuum-drying temperature is 40 ~ 50 DEG C.
8. comprise the pharmaceutical preparation of children's as claimed in any of claims 1 to 7 with Sulfocillin chemical entities, it is characterized in that, described preparation is freeze-dried preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201510283121.6A CN104945417A (en) | 2015-05-28 | 2015-05-28 | Children sulbenicillin sodium compound entity and pharmaceutical preparation thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510283121.6A CN104945417A (en) | 2015-05-28 | 2015-05-28 | Children sulbenicillin sodium compound entity and pharmaceutical preparation thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6025352A (en) * | 1997-09-29 | 2000-02-15 | Microcide Pharmaceuticals, Inc. | Cephalosporin antibiotics |
| CN102179063A (en) * | 2011-03-23 | 2011-09-14 | 苏州汇通色谱分离纯化有限公司 | High pressure liquid-liquid extraction method |
| CN103319502A (en) * | 2013-04-24 | 2013-09-25 | 济南康和医药科技有限公司 | Sulbenicillin sodium preparation method |
| CN104163822A (en) * | 2014-05-22 | 2014-11-26 | 杭州长典医药科技有限公司 | Special ultrafine cefmetazole sodium powder preparation and preparation method thereof |
-
2015
- 2015-05-28 CN CN201510283121.6A patent/CN104945417A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6025352A (en) * | 1997-09-29 | 2000-02-15 | Microcide Pharmaceuticals, Inc. | Cephalosporin antibiotics |
| CN102179063A (en) * | 2011-03-23 | 2011-09-14 | 苏州汇通色谱分离纯化有限公司 | High pressure liquid-liquid extraction method |
| CN103319502A (en) * | 2013-04-24 | 2013-09-25 | 济南康和医药科技有限公司 | Sulbenicillin sodium preparation method |
| CN104163822A (en) * | 2014-05-22 | 2014-11-26 | 杭州长典医药科技有限公司 | Special ultrafine cefmetazole sodium powder preparation and preparation method thereof |
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Application publication date: 20150930 |