CN104610191B - Crystal formation of rhodanine chirality hexamethylene spiro-compound and preparation method thereof and purposes - Google Patents
Crystal formation of rhodanine chirality hexamethylene spiro-compound and preparation method thereof and purposes Download PDFInfo
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- CN104610191B CN104610191B CN201510072781.XA CN201510072781A CN104610191B CN 104610191 B CN104610191 B CN 104610191B CN 201510072781 A CN201510072781 A CN 201510072781A CN 104610191 B CN104610191 B CN 104610191B
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- 0 CCCC(*)(*)N(*)N Chemical compound CCCC(*)(*)N(*)N 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N CCC[C@@H](C(O)=O)N Chemical compound CCC[C@@H](C(O)=O)N SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- WFRGKTODASDIQD-JHEVNIALSA-N C[C@H](C[C@H]([C@@H](C=[O]=C1N2c3ccccc3)SC2=S)[N+]([O-])=O)[C@@H]1O Chemical compound C[C@H](C[C@H]([C@@H](C=[O]=C1N2c3ccccc3)SC2=S)[N+]([O-])=O)[C@@H]1O WFRGKTODASDIQD-JHEVNIALSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Cc1ccccc1 Chemical compound Cc1ccccc1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
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Abstract
The invention discloses the crystal formation of the hexamethylene spiro-compound of rhodanine chirality shown in formula I,This crystal formation is rhombic system, and space group is P212121, cell parameter is ��=90.00 ��, ��=90.00 ��, ��=90.00 ��, Z=4, unit cell volume is The crystal formation of compound shown in formula I disclosed by the invention, to inhibited addicted to one or more in Fructus Hordei Germinatus Zymomonas mobilis, promise phenanthrene acinetobacter calcoaceticus, staphylococcus aureus, staphylococcus epidermidis etc.; Meanwhile, the present invention improves the stability of crystal formation medicine, and can be prevented effectively from moisture absorption deliquescence, it is simple to controls drug quality, provides a kind of new selection for screening the crystal formation medicines such as antibacterial, antibacterial, sterilization clinically.
Description
Technical field
The present invention relates to crystal formation of rhodanine chirality hexamethylene spiro-compound and preparation method thereof and purposes.
Background technology
Spiro-compound refers to that two monocycles share the polycyclic compound of a carbon atom, it is possible to for photochromic material, electroluminescent material, pesticide, medicine etc.
The structure of spiro-compound is different, its physicochemical property also differs, also all there is different purposes respectively, such as: there is the spiro-compound (a) of acaricide effect, antianxiety drugs buspirone hydrochloride (b), delay spiro indole derivant (c) of arteriosclerosis, NSAID (non-steroidal anti-inflammatory drug) spiro indole derivant (d), there is pharmaceutical intermediate azaspiro compounds, their (e) of physiologically active, there is the spiro-compound (f) of antioxidant cyclic bacillus, there is broad spectrum antibiotic activity spiroheterocyclic derivatives (g), there is AP-1 activity and suppress the spiro-compound (h) of function, volution antibacterials (i), spiro-compound (j) with acetylcholine activation etc. (" spiro-compound chemistry ". Wei Rongbao writes, Chemical Industry Press, 2007.7).
Rhodanine, chemistry 2-sulfo--2 by name, 4-thiazolidinedione, it is possible to for calibrating and weight analysis determining silver, spectroscopic assay gallic acid, organic synthesis etc.
For same compound; generally having two or more different crystalline states, different crystal formations then would generally show different bioavailability, dissolution, rate of dissolution, stability, fusing point, color, filtrability, density and mobility etc. For medicine, develop dissolubility and the better crystal formation of stability has very important significance.
At present, there are no the report of the hexamethylene spiro-compound of rhodanine chirality shown in formula I of the present invention; Also there are no the report of crystal formation of the hexamethylene spiro-compound of rhodanine chirality shown in formula I and preparation method thereof with purposes.
Summary of the invention
It is an object of the invention to provide the crystal formation of a kind of rhodanine chirality hexamethylene spiro-compound.
The crystal formation of rhodanine chirality hexamethylene spiro-compound shown in formula I provided by the invention,
This crystal formation is rhombic system, and space group is P212121, cell parameter is ��=90.00 ��, ��=90.00 ��, ��=90.00 ��, Z=4, unit cell volume is
Preferably, the ee value of the hexamethylene spiro-compound of rhodanine chirality shown in formula I > 90%;Fusing point is 211 DEG C��213 DEG C; Specific rotatory power is [��]D 20+162��
Preferably, the ee value of described crystal formation > 90%; Fusing point is 203 DEG C��205 DEG C.
Preferably, the �� of described crystal formationcalcFor 1.324mg/mm3; F (000) is 1056.0.
Another object of the present invention is to the preparation method that above-mentioned crystal formation is provided.
A kind of method preparing above-mentioned crystal formation provided by the invention, it comprises the following steps: at normal temperatures, by the hexamethylene spiro-compound of rhodanine chirality shown in formula I, slowly volatilize in the mixed solvent of n-hexane/ethyl acetate crystallization, obtain the crystal formation of the hexamethylene spiro-compound of rhodanine chirality shown in formula I; In the mixed solvent of described n-hexane/ethyl acetate, the volume ratio of normal hexane and ethyl acetate is (90:10)��(95:5);
Rhodanine chirality hexamethylene spiro-compound shown in described formula I, its synthetic route is:
It comprises the following steps:
A, compound 1, compound 2, organic catalyst and glacial acetic acid are in nitrile solvents, and at 25 DEG C��30 DEG C, stirring reaction 3��4 hours, obtains the reactant liquor of compound 3;
Described organic catalyst is selected from In any one or multiple, R5For trialkyl silyl, R6��R7It is respectively and independently selected from aromatic radical or heterocycle, R8For alkyl or hydrogen atom, R9For alkyl or heterocycle, R11For benzyl or hydrogen; Described nitrile solvents in acetonitrile, propionitrile, butyronitrile, isopropyl cyanide, the benzene acetonitrile any one or multiple;
B, in the reactant liquor of step a compound 3 add compound 4, inorganic base, quaternary ammonium salt catalyst, stirring reaction at 60��65 DEG C, thin layer chromatography monitoring react completely, obtain reactant liquor; Reactant liquor is removed solvent, obtains crude product; Crude product is easily separated purification, obtains the rhodanine chirality hexamethylene spiro-compound shown in formula I;
Described inorganic base in potassium carbonate, the sodium carbonate any one or multiple; Described quaternary ammonium salt catalyst in tetrabutyl ammonium fluoride, tetrabutylammonium chloride, tetrabutyl ammonium bromide, the tetrabutylammonium iodide any one or multiple;
Described compound 1, compound 2, organic catalyst, glacial acetic acid, compound 4, inorganic base, quaternary ammonium salt catalyst mol ratio be 1:(0.1��1): (0.02��0.1): (0.05��0.5): (0.1��1): (0.1��0.5): (0.01��0.05); The molal volume of described compound 1 and nitrile solvents is than for 1:(1��10) mol/L.
Preferably,
In step a, described organic catalyst is (2R)-2-[diphenyl [trimethylsiloxy group] methyl]-pyrrolidine; Described nitrile solvents is acetonitrile;
In step b, described inorganic base is potassium carbonate; Described quaternary ammonium salt catalyst is tetrabutyl ammonium bromide;
Described compound 1, compound 2, organic catalyst, glacial acetic acid, compound 4, inorganic base, quaternary ammonium salt catalyst mol ratio be 1:0.75:0.1:0.1:0.5:0.25:0.025; The molal volume of described compound 1 and nitrile solvents is than for 1:10mol/L.
Present invention also offers above-mentioned crystal formation purposes in preparation antibacterials.
Above-mentioned crystal formation, the purposes in preparation antibacterials.
Further, described antibacterials refer to addicted to any one in Fructus Hordei Germinatus Zymomonas mobilis, promise phenanthrene acinetobacter calcoaceticus, staphylococcus aureus, staphylococcus epidermidis or the multiple antibacterials with antibacterial activity.
Further, described is addicted to Fructus Hordei Germinatus Zymomonas mobilis S1 addicted to Fructus Hordei Germinatus Zymomonas mobilis; Described promise phenanthrene acinetobacter calcoaceticus is promise phenanthrene acinetobacter calcoaceticus N2 or promise phenanthrene acinetobacter calcoaceticus N3;Described staphylococcus aureus is staphylococcus aureus J4; Described staphylococcus epidermidis is staphylococcus epidermidis BP8 or staphylococcus epidermidis BP4.
Preferably, the dosage form of described antibacterials is solid preparation.
Further preferably, described solid preparation is capsule, powder pin, tablet, pill, powder and/or granule.
The crystal formation of compound shown in formula I disclosed by the invention, to inhibited addicted to one or more in Fructus Hordei Germinatus Zymomonas mobilis, promise phenanthrene acinetobacter calcoaceticus, staphylococcus aureus, staphylococcus epidermidis etc.; Simultaneously, the present invention improves the bioavailability of the stability of crystal formation medicine, the activity of crystal formation medicine, crystal formation medicine, reduce the toxic and side effects of crystal formation medicine, and moisture absorption deliquescence can be prevented effectively from, it is easy to control drug quality, provides a kind of new selection for screening the crystal formation medicines such as antibacterial, antibacterial, sterilization clinically.
The compound and the derivant that there is provided in the present invention can be named according to IUPAC (IUPAC) or CAS (chemical abstracts service, Columbus, OH) nomenclature.
The definition using term about the present invention: except as otherwise noted, the original definition that group or term provide herein is applicable to this group or the term of entire description; For the term being not specifically defined herein, it should according to disclosure and context, provide those skilled in the art and can give their implication.
The hydrogen atom that " replacement " refers in molecule is replaced by other different atom or molecule.
In hydrocarbon group, the minima of carbon content and maximum are represented by prefix, for instance, prefix (Ca��b) alkyl shows any alkyl containing " a " to " b " individual carbon atom. It is therefoie, for example, C1��C4Alkyl refers to the alkyl comprising 1��4 carbon atom.
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, adjuvant, and/or the salt formed is generally chemically or physically mutually compatible and mutually compatible with receptor on physiology with other composition constituting certain pharmaceutical dosage form.
Term " salt " and " pharmaceutically useful salt " refer to above-claimed cpd or its stereoisomer, with inorganic and/or organic bronsted lowry acids and bases bronsted lowry formed acid and/or basic salt, also include amphion salt (inner salt), also include quaternary ammonium salt, for instance alkylammonium salt. These salt can be compound be finally separating with purification in directly obtain. Can also be by by above-claimed cpd, or its stereoisomer, it is obtained by mixing with a number of acid or alkali suitably (such as equivalent). These salt are likely to form precipitation in the solution and collect with filter method, or reclaim after the solvent evaporates and obtain, or it is prepared to react postlyophilization in aqueous medium. Heretofore described salt can be the hydrochlorate of compound, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphate, acetate, propionate, succinate, oxalates, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
In some embodiment of the present invention, present invention comprises isotope-labeled compound, described compound isotopically labelled refers to same with listed Compound Phase herein, but one or more atom is replaced by another atom, the atomic mass of this atom or mass number are different from nature common atomic mass or mass number. Hydrogen, carbon, nitrogen, oxygen, sulfur can be included by isotope in introduction-type (I) compound, namely2H,3H��13C��14C��15N��17O��18O��35S.The compound of the formula (I) containing above-mentioned isotope and/or other atom isotope and stereoisomer thereof, and the pharmaceutically useful salt of this compound, stereoisomer should be included within the scope of the invention.
Key intermediate in the present invention and compound is easily separated and purification, the mode used is that the example of Isolation and purification method conventional in organic chemistry and described method includes filtering, extracts, dries, is spin-dried for and various types of chromatographs. Selectively, it is possible to make intermediate not purified namely carry out next step reaction.
In some embodiments, one or more compounds of the present invention can combine with one another use. Also optional the compound of the present invention is combined use with other active agent any, is used for preparing regulating cell function or treating medicine or the pharmaceutical composition of disease. If using one group of compound, then can by these compounds simultaneously, be administered respectively or in an orderly manner to study subject.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representational method of application includes (but being not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous) and topical.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule. In these solid dosage formss, reactive compound mixes with at least one conventional inert excipients (or carrier), such as sodium citrate or dicalcium phosphate, or mix with following compositions: (a) filler or bulking agent, such as, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binding agent, for instance, hydroxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and arabic gum; (c) wetting agent, for instance, glycerol; (d) disintegrating agent, for instance, agar, calcium carbonate, potato starch or tapioca, alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, for instance paraffin; F () absorbs accelerator, for instance, quaternary ammonium compound; (g) wetting agent, for instance spermol and glyceryl monostearate; (h) adsorbent, for instance, Kaolin; (i) lubricant, for instance, Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture. In capsule, tablet and pill, dosage form also can comprise buffer agent.
Solid dosage forms such as tablet, sugar pill, capsule, pill and granule can adopt coating and shell material to prepare, such as casing and other material well known in the art. They can comprise opacifying agent, and, in this compositions, the release of reactive compound or compound can release in the part of certain in digestive tract in a delayed fashion. The example of adoptable embedding component is polymeric material and Wax. If desired, reactive compound also can with one or more formation microencapsulation form in above-mentioned excipient.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture. Except active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent adopted in this area, such as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture etc. of ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethylformamide and oil, particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, maize embryo oil, olive oil, Oleum Ricini and Oleum sesami or these materials.
Except these inert diluents, compositions also can comprise auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives and spice.
Except active ingredient beyond the region of objective existence, suspension can comprise suspending agent, for instance, the mixture etc. of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline Cellulose, aluminium methoxide and agar or these materials.
Compositions for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or emulsion, and for being again dissolved into the sterilized powder of aseptic Injectable solution or dispersion liquid. Moisture and the nonaqueous carrier, diluent, solvent or the excipient that are suitable for include water, ethanol, polyhydric alcohol and suitable mixture thereof.
Dosage form for the compounds of this invention of topical includes ointment, powder, patch, propellant and inhalant. Active component aseptically with physiologically acceptable carrier and any preservative, buffer agent, or if desired be likely to need propellant be mixed together.
Pharmaceutically acceptable adjuvant of the present invention, refers to the material being included in dosage form in addition to the active ingredient (s.
Pharmaceutically acceptable complementary composition of the present invention, it has certain physiologically active, but the addition of this composition will not change aforementioned pharmaceutical compositions leading position in treatment of diseases, and only play auxiliary effect, these auxiliary effects are only utilization to this composition known activity, are the usual adjuvant treatment modality of field of medicaments. If by above-mentioned complementary composition and pharmaceutical composition of the present invention with the use of, still should belong to the scope of protection of the invention.
Obviously, the foregoing according to the present invention, according to ordinary technical knowledge and the customary means of this area, without departing under the above-mentioned basic fundamental thought premise of the present invention, it is also possible to make the amendment of other various ways, replacement or change.
The detailed description of the invention of form by the following examples, is described in further detail the foregoing of the present invention again. But this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to Examples below. All technology realized based on foregoing of the present invention belong to the scope of the present invention.
Accompanying drawing explanation
Compound shown in Fig. 1 formula I1HNMR spectrogram
Compound shown in Fig. 2 formula I13CNMR spectrogram
Compound shown in Fig. 3 formula I1HNMR spectrogram, belongs to corresponding hydrogen
The NOE spectrogram of compound shown in Fig. 4 formula I, for verifying chirality hydrogen dependency spatially
The crystal formation of compound shown in Fig. 5 formula I of the present invention, its stereochemical structure projection
Definition and abbreviation:
" ee " representative " enantiomeric excess ", is measure excessive relative to raceme sample of a kind of enantiomer of chipal compounds, for given sample, as a percentage.
Some flow process and embodiment can omit the details of common reactant (including oxidation, reduction etc.), isolation technics and analysis process below, and they are that organic chemistry filed those of ordinary skill is known. The details of this kind of reaction and technology can find in some monographs, including Richardlarock, ComprehensiveOrganicTransformations (1999) and the multireel series CompendiumofOrganicSyntheticMethods (1974��2005) that edited by MichaelB.Smithandothers. Some reaction process can omit secondary product from chemical conversion (such as from esterolytic alcohol, from the CO of binary acid glutamic acid2Deng). It addition, in some cases, namely reaction intermediate can be used in step subsequently without isolated or purified.
Below in some reaction process and embodiment, some compound can use blocking group to prepare, and they prevent from, in other reactive moieties, unwanted chemical reaction occurs. Blocking group can be used for improving dissolubility or otherwise changing the physical property of compound. Discussion about blocking group strategy; install and remove the material of blocking group and the explanation of method; compilation etc. with the blocking group that can be used for common functional groups; referring to T.W.GreeneandP.G.Wuts; ProtectingGroupsinOrganicChemistry (1999) and P.Kocienski; ProtectiveGroups (2000), they are completely referenced herein by reference.
It is said that in general, the reaction reagent of substantially stoichiometry can be used to carry out throughout the chemical conversion described in description, but some reaction can benefit from using one or more excessive reaction reagents. Additionally, much can carry out under about RT (room temperature) and ambient temperature throughout the reaction disclosed in description, but being to rely on kinetics, yield etc., some reaction can under high pressure or adopt the temperature of higher (such as counterflow condition) or lower (such as-70 DEG C��0 DEG C) to carry out. A lot of chemical conversions can also adopt one or more compatible solvent, and they can affect reaction rate and yield. Depending on the attribute of reaction reagent, one or more solvents can be polar aprotic solvent (including water), polar proton inert solvent, non-polar solven or some combinations. Any open description for stoichiometric range, temperature range, pH scope etc. is regardless of whether clearly use term " scope " herein, also all includes shown end points.
Detailed description of the invention
The raw material, the equipment that use in the specific embodiment of the invention are known product, obtain by buying commercially available prod.
Prepare compound shown in formula I
With propionic aldehyde (23.20mg, 0.4mmol) with compound 2 (44.74mg, 0.3mmol, commercially available, CAS 102-96-5) for raw material, add (2R)-2-[diphenyl [trimethylsiloxy group] methyl]-pyrrolidine (13.00mg, 0.04mmol) as catalyst and glacial acetic acid (2.4mg, 0.04mmol), acetonitrile (4ml) is as solvent, reaction is stirred at room temperature 3��4 hours, obtains compound 3.
After completing, direct one kettle way adds compound 4 (45.26mg, 0.2mmol), (13.82mg, 0.1mmol use 0.1mlH to potassium carbonate in this reaction2O dissolves) and TBAB (3.22mg, 0.01mmol; Tetrabutyl ammonium bromide), stirring reaction at 60 DEG C, react completely to TLC (thin layer chromatography) monitoring, obtain reactant liquor; Reactant liquor is spin-dried for solvent, through silica gel column chromatography separating purification, obtains compound shown in formula I, ee value 90%.
The detection data of compound shown in formula I are as follows:
Fusing point is 211 DEG C��213 DEG C;
[��]D 20+ 162 (c=0.18, at CH2Cl2In);
ESIHRMS:C27H24N2O4S2Na+, detected value is 527.1077;
1HNMR(400MHz,CDCl3): ��=7.38-7.28 (m, 11H), 7.14 (d, J=7.2Hz, 2H), 6.61 (brs, 1H), 4.95 (t, J=4.4Hz, 1H), 4.18 (t, J=7.2Hz, 1H), 4.13 (d, J=4.4Hz, 1H), 3.11 (dd, J1=4.4Hz, J2=11.6Hz, 1H), 2.99-2.93 (m, 1H), 2.48 (d, J=10.8Hz, 1H), 1.05 (d, J=6.4Hz, 3H) ppm; As shown in Figure 1;
13CNMR(100MHz,CDCl3): ��=201.44,176.51,134.56,133.85,131.53,128.81,128.65,128.46,128.27,128.03,127.40,126.92,89.35,78.37,70.38,50.98,49.1 0,33.28,14.73ppm;As shown in Figure 2.
Embodiment 1
Take compound shown in the formula I of preparation, at n-hexane-ethyl acetate (90%:10%, v/v) slowly volatilize under room temperature in crystallization, obtain the crystal formation of compound shown in formula I, ee value > 90%, fusing point is 203 DEG C��205 DEG C, and this crystal formation passes through single crystal diffraction, and its crystal structural data is in Table 1:
The single crystal diffraction data of table 1 crystal formation of the present invention
Embodiment 2
Take compound shown in the formula I of preparation, crystallization of slowly volatilizing under room temperature in n-hexane-ethyl acetate (95%:5%, v/v), obtain the crystal formation of compound shown in formula I.
In order to beneficial effects of the present invention is described, the present invention provides tests below example:
Test example 1 antibacterial activity is tested
The present invention adopts equimultiple dilution method (also referred to as coubling dilution) to measure the antibacterial activity of crystal formation of compound shown in formula I.
The acquisition of experimental strain:
Experimental strain of the present invention is all clinically separated pathogenic bacterium for what identified by People's Hospital, Sichuan Prov., the collection of healthcare hospital for women & children of Sichuan Province. Specimen is mainly derived from blood, expectorant, urine etc., identify through France's Mei Liai (BioMeriruk) VITEK-32, VITEK-60 automatic microbe identification and analysis instrument collecting unit, and again identify through Sichuan Industrial Institute of Antibiotics Biolog Bacteria analyzer (U.S.) API20E, 20NE, Staph series and conventional method, it is respectively designated as: addicted to Fructus Hordei Germinatus Zymomonas mobilis S1, promise phenanthrene acinetobacter calcoaceticus N2, promise phenanthrene acinetobacter calcoaceticus N3, staphylococcus aureus J4, staphylococcus epidermidis BP8, staphylococcus epidermidis BP4, for antibacterial tests.
The crystal formation 30mg of compound shown in the formula I of accurate weighing 2mlDMSO (dimethyl sulfoxide) is dissolved, 10 Concentraton gradient are done respectively by equimultiple dilution method, each gradient adds 1ml containing drug solns in MH culture dish, and mix with 14mlMH solid medium (caseinhydrolysate (Mueller-Hinton) culture medium), make the culture dish that pastille is different. Then it is 10 with the card punch in 27 holes by bacteria containing amount6Bacterium solution be inoculated on culture dish, put into the constant incubator of 37 DEG C, cultivate 18h��24h, observe whether inoculation position has bacterial growth, to judge its fungistatic effect, result is in Table 2; Using levofloxacin as reference.
Antibacterial activity refers to the ability of antimicrobial drug suppression or pathogenic microbe killing; Available extracorporeal bacteria inhibitor test and experiment in vivo therapy measure; Clinical application is had important references meaning by antibacterial experiment in vitro. Can suppress the least concentration of bacterial growth in culture medium is minimal inhibitory concentration (minimalinhibitoryconcentration, MIC). The bacteriostasis of antimicrobial drug is relative with bactericidal action, and some antimicrobial drug is bacteriostasis when low concentration, and high concentration is bactericidal action.
The antibacterial activity MIC (mg/ml) of the crystal formation of compound shown in table 2 formula I of the present invention
Note: the bacterial strain of above-mentioned use, except reference culture, all the other are all clinical separation strains.
By above-mentioned test it can be seen that the crystal formation of compound shown in formula I of the present invention has good antibacterial activity, to inhibited addicted to one or more in Fructus Hordei Germinatus Zymomonas mobilis, promise phenanthrene acinetobacter calcoaceticus, staphylococcus aureus, staphylococcus epidermidis.
Test example 2 stability of crystal form of the present invention and hygroscopicity are investigated
1, stability:
Being put into by the crystal formation of compound shown in formula I of the present invention and be accelerated test in stability test case, experimental condition is: temperature, 40 DEG C �� 2 DEG C; Humidity, RH75% �� 5%, the time is 3 months.
Adopt TLC (thin layer chromatography) and HPLC (high performance liquid chromatography) to measure, found that significant change does not occur this crystal formation, having good stability of crystal formation of the present invention is described.
2, hygroscopicity:
Adopting 2010 editions second annex XIXJ medicine of Pharmacopoeia of People's Republic of China to draw moist test direction principle, the crystal formation of compound shown in formula I of the present invention is carried out wettability test, its result is as follows:
Table 3 hygroscopicity test results
| Used time (my god) | 0 | 5 | 10 | 15 |
| Compound draws wet weightening finish | 0.0% | 1.2% | 1.2% | 1.2% |
It is shown that crystal formation of the present invention is placed 15 days in wet condition, it is inconspicuous that it draws wet weightening finish, illustrates that crystal formation of the present invention can be prevented effectively from moisture absorption deliquescence.
Owing to crystal formation of the present invention has good stability, and moisture absorption deliquescence can be prevented effectively from, it is possible to prepare into various dosage form easily, for instance: capsule, powder pin, tablet, pill, powder, granule etc.
In sum, the crystal formation of compound shown in formula I disclosed by the invention, to inhibited addicted to one or more in Fructus Hordei Germinatus Zymomonas mobilis, promise phenanthrene acinetobacter calcoaceticus, staphylococcus aureus, staphylococcus epidermidis etc.; Simultaneously, the present invention improves the bioavailability of the stability of crystal formation medicine, the activity of crystal formation medicine, crystal formation medicine, reduce the toxic and side effects of crystal formation medicine, and moisture absorption deliquescence can be prevented effectively from, it is easy to control drug quality, provides a kind of new selection for screening the crystal formation medicines such as antibacterial, antibacterial, sterilization clinically.
Claims (11)
1. the crystal formation of the hexamethylene spiro-compound of rhodanine chirality shown in formula I, it is characterised in that:
This crystal formation is rhombic system, and space group is P212121, cell parameter is ��=90.00 ��, ��=90.00 ��, ��=90.00 ��, Z=4, unit cell volume is
2. the crystal formation of the hexamethylene spiro-compound of rhodanine chirality shown in formula I according to claim 1, it is characterised in that: the ee value of the hexamethylene spiro-compound of rhodanine chirality shown in formula I > 90%; Fusing point is 211 DEG C��213 DEG C; C=0.18, at CH2Cl2The specific rotatory power of middle mensuration is [��]D 20+162��
3. the crystal formation of the hexamethylene spiro-compound of rhodanine chirality shown in formula I according to claim 1, it is characterised in that: the ee value of described crystal formation > 90%; Fusing point is 203 DEG C��205 DEG C.
4. the crystal formation of the hexamethylene spiro-compound of rhodanine chirality shown in formula I according to claim 1, it is characterised in that: the �� of described crystal formationcalcFor 1.324mg/mm3; F (000) is 1056.0.
5. prepare the method for crystal formation described in Claims 1 to 4 any one for one kind, it is characterized in that: it comprises the following steps: at normal temperatures, by the hexamethylene spiro-compound of rhodanine chirality shown in formula I, slowly volatilize in the mixed solvent of n-hexane/ethyl acetate crystallization, obtain the crystal formation of the hexamethylene spiro-compound of rhodanine chirality shown in formula I; In the mixed solvent of described n-hexane/ethyl acetate, the volume ratio of normal hexane and ethyl acetate is (90:10)��(95:5);
Rhodanine chirality hexamethylene spiro-compound shown in described formula I, its synthetic route is:
It comprises the following steps:
A, compound 1, compound 2, organic catalyst and glacial acetic acid are in nitrile solvents, and at 25 DEG C��30 DEG C, stirring reaction 3��4 hours, obtains the reactant liquor of compound 3;
Described organic catalyst is
Described nitrile solvents is acetonitrile;
B, in the reactant liquor of step a compound 3 add compound 4, inorganic base, quaternary ammonium salt catalyst, stirring reaction at 60��65 DEG C, thin layer chromatography monitoring react completely, obtain reactant liquor;Reactant liquor is removed solvent, obtains crude product; Crude product is easily separated purification, obtains the rhodanine chirality hexamethylene spiro-compound shown in formula I;
Described inorganic base in potassium carbonate, the sodium carbonate any one or multiple; Described quaternary ammonium salt catalyst in tetrabutyl ammonium fluoride, tetrabutylammonium chloride, tetrabutyl ammonium bromide, the tetrabutylammonium iodide any one or multiple;
Described compound 1, compound 2, organic catalyst, glacial acetic acid, compound 4, inorganic base, quaternary ammonium salt catalyst mol ratio be 1:(0.1��1): (0.02��0.1): (0.05��0.5): (0.1��1): (0.1��0.5): (0.01��0.05); The molal volume of described compound 1 and nitrile solvents is than for 1:(1��10) mol/L.
6. method according to claim 5, it is characterised in that:
In step a, described organic catalyst is (2R)-2-[diphenyl [trimethylsiloxy group] methyl]-pyrrolidine; Described nitrile solvents is acetonitrile;
In step b, described inorganic base is potassium carbonate; Described quaternary ammonium salt catalyst is tetrabutyl ammonium bromide;
Described compound 1, compound 2, organic catalyst, glacial acetic acid, compound 4, inorganic base, quaternary ammonium salt catalyst mol ratio be 1:0.75:0.1:0.1:0.5:0.25:0.025; The molal volume of described compound 1 and nitrile solvents is than for 1:10mol/L.
7. the crystal formation of rhodanine chirality hexamethylene spiro-compound shown in Claims 1 to 4 any one formula I purposes in preparation antibacterials.
8. purposes according to claim 7, it is characterised in that: described antibacterials refer to addicted to any one in Fructus Hordei Germinatus Zymomonas mobilis, promise phenanthrene acinetobacter calcoaceticus, staphylococcus aureus, staphylococcus epidermidis or the multiple antibacterials with antibacterial activity.
9. purposes according to claim 8, it is characterised in that: described is addicted to Fructus Hordei Germinatus Zymomonas mobilis S1 addicted to Fructus Hordei Germinatus Zymomonas mobilis; Described promise phenanthrene acinetobacter calcoaceticus is promise phenanthrene acinetobacter calcoaceticus N2 or promise phenanthrene acinetobacter calcoaceticus N3; Described staphylococcus aureus is staphylococcus aureus J4; Described staphylococcus epidermidis is staphylococcus epidermidis BP8 or staphylococcus epidermidis BP4.
10. purposes according to claim 7, it is characterised in that: the dosage form of described antibacterials is solid preparation.
11. purposes according to claim 10, it is characterised in that: described solid preparation is capsule, powder pin, tablet, pill, powder and/or granule.
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