CN104610191A - Crystal form, preparation method and application of Rhodanine chiral cyclohexane spiro-compound - Google Patents
Crystal form, preparation method and application of Rhodanine chiral cyclohexane spiro-compound Download PDFInfo
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- 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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Abstract
The invention discloses a crystal form of a Rhodanine chiral cyclohexane spiro-compound shown in formula 1 in the specification. The crystal form is an orthorhombic system, a space group is P212121, cell parameters are as follows: a=10.8961(3) angstrom, b=12.0000(3) angstrom, c=19.3611(4) angstrom, alpha=90.00 degrees, beta=90.00 degrees, gamma=90.00 degrees, Z=4, and the unit-cell volume is 2531.52(10) cubic angstrom. The crystal form of the compound shown in the formula 1 disclosed by the invention has inhibiting effect on one or more of maltophilia monad, Nofuel acinetobacter, staphylococcus aureus and staphylococcus epidermidis; meanwhile, stability of crystal drugs is improved by the crystal form disclosed by the invention, moisture absorption and air-slake can be effectively avoided, quality of the drugs can be conveniently controlled, and a new choice is provided for clinically screening antibiosis, bacteriostasis and sterilization drugs and other crystal drugs.
Description
Technical field
The present invention relates to crystal formation of rhodanine chirality hexanaphthene spirocyclic compound and preparation method thereof and purposes.
Background technology
Spirocyclic compound refers to that two monocycles share the polynuclear compound of a carbon atom, may be used for photochromic material, electroluminescent material, agricultural chemicals, medicine etc.
The structure of spirocyclic compound is different, its physico-chemical property is not identical yet, also all there is different purposes respectively, such as: there is the spirocyclic compound (a) except mite effect, anxiolytic Travin (b), delay arteriosclerotic spiro indole derivative (c), NSAID (non-steroidal anti-inflammatory drug) spiro indole derivative (d), there is pharmaceutical intermediate azaspiro compounds, their (e) of physiologically active, there is the spirocyclic compound (f) of antioxidant cyclic bacillus, there is broad spectrum antibiotic activity spiroheterocyclic derivatives (g), there is the spirocyclic compound (h) of the active inhibit feature of AP-1, volution antibacterials (i), have spirocyclic compound (j) of Activated By Acetylcholine effect etc. (" spirocyclic compound chemistry ". Wei Rongbao writes, Chemical Industry Press, 2007.7).
Rhodanine, chemistry 2-sulfo--2,4-thiazolidinedione by name, may be used for calibrating and weight analysis determining silver, spectrometry gallic acid, organic synthesis etc.
For same compound; usually have the crystalline state that two or more are different, different crystal formations then can show different bioavailabilities, dissolution rate, dissolution rate, stability, fusing point, color, filtrability, density and mobility etc. usually.For medicine, develop solvability and the better crystal formation of stability has very important significance.
At present, there are no the report of the hexanaphthene of rhodanine chirality shown in formula I spirocyclic compound; Also there are no the crystal formation and preparation method thereof of the hexanaphthene of rhodanine chirality shown in formula I spirocyclic compound and the report of purposes.
Summary of the invention
The object of the present invention is to provide a kind of crystal formation of rhodanine chirality hexanaphthene spirocyclic compound.
The crystal formation of the spirocyclic compound of rhodanine chirality hexanaphthene shown in formula I provided by the invention,
This crystal formation is rhombic system, and spacer is P2
12
12
1, unit cell parameters is
α=90.00 °, β=90.00 °, γ=90.00 °, Z=4, unit cell volume is
Preferably, the ee value >90% of the hexanaphthene of rhodanine chirality shown in formula I spirocyclic compound; Fusing point is 211 DEG C ~ 213 DEG C; Specific rotatory power is [α]
d 20+ 162.
Preferably, the ee value >90% of described crystal formation; Fusing point is 203 DEG C ~ 205 DEG C.
Preferably, the ρ of described crystal formation
calcfor 1.324mg/mm
3; 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 hexanaphthene of rhodanine chirality shown in formula I spirocyclic compound, slowly to volatilize in the mixed solvent of n-hexane/ethyl acetate crystallization, obtain the crystal formation of the hexanaphthene of rhodanine chirality shown in formula I spirocyclic compound; In the mixed solvent of described n-hexane/ethyl acetate, the volume ratio of normal hexane and ethyl acetate is (90:10) ~ (95:5);
The spirocyclic compound of rhodanine chirality hexanaphthene 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 reaction solution of compound 3;
Described organic catalyst is selected from
in any one or multiple, R
5for trialkyl silyl, R
6, R
7independently be selected from aromatic base or heterocycle, R
8for alkyl or hydrogen atom, R
9for alkyl or heterocycle, R
11for benzyl or hydrogen; Described nitrile solvents be selected from acetonitrile, propionitrile, butyronitrile, isopropyl cyanide, benzyl cyanide any one or multiple;
B, in the reaction solution of step a compound 3, add compound 4, mineral alkali, quaternary ammonium salt catalyzer, stirring reaction at 60 ~ 65 DEG C, thin-layer chromatography monitoring reacts completely, and obtains reaction solution; By reaction solution except desolventizing, obtain crude product; Separation and purification is carried out to crude product, obtains the rhodanine chirality hexanaphthene spirocyclic compound shown in formula I;
Described mineral alkali be selected from salt of wormwood, sodium carbonate any one or multiple; Described quaternary ammonium salt catalyzer be selected from tetrabutyl ammonium fluoride, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide any one or multiple;
The mol ratio of described compound 1, compound 2, organic catalyst, Glacial acetic acid, compound 4, mineral alkali, quaternary ammonium salt catalyzer is 1:(0.1 ~ 1): (0.02 ~ 0.1): (0.05 ~ 0.5): (0.1 ~ 1): (0.1 ~ 0.5): (0.01 ~ 0.05); Described compound 1 is 1:(1 ~ 10 with the molecular volume ratio of nitrile solvents) mol/L.
Preferably,
In step a, described organic catalyst is (2R)-2-[phenylbenzene [trimethylsiloxy group] methyl]-tetramethyleneimine; Described nitrile solvents is acetonitrile;
In step b, described mineral alkali is salt of wormwood; Described quaternary ammonium salt catalyzer is Tetrabutyl amonium bromide;
The mol ratio of described compound 1, compound 2, organic catalyst, Glacial acetic acid, compound 4, mineral alkali, quaternary ammonium salt catalyzer is 1:0.75:0.1:0.1:0.5:0.25:0.025; Described compound 1 is 1:10mol/L with the molecular volume ratio of nitrile solvents.
Present invention also offers the purposes of above-mentioned crystal formation 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, the luxuriant and rich with fragrance acinetobacter calcoaceticus of promise, streptococcus aureus, staphylococcus epidermidis or the multiple antibacterials with anti-microbial activity.
Further again, described is addicted to Fructus Hordei Germinatus Zymomonas mobilis S1 addicted to Fructus Hordei Germinatus Zymomonas mobilis; The luxuriant and rich with fragrance acinetobacter calcoaceticus of described promise is the luxuriant and rich with fragrance acinetobacter calcoaceticus N2 of promise or the luxuriant and rich with fragrance acinetobacter calcoaceticus N3 of promise; Described streptococcus aureus is streptococcus aureus J4; Described staphylococcus epidermidis is staphylococcus epidermidis BP8 or staphylococcus epidermidis BP4.
Preferably, the formulation of described antibacterials is solid preparation.
Preferred again, 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 luxuriant and rich with fragrance acinetobacter calcoaceticus, streptococcus aureus, staphylococcus epidermidis etc.; Simultaneously, invention increases the stability of crystal formation medicine, the activity of crystal formation medicine, the bioavailability of crystal formation medicine, reduce the toxic side effect of crystal formation medicine, and can effectively avoid moisture absorption deliquescence, being convenient to control drug quality, providing a kind of selection newly for screening the crystal formation medicines such as antibacterial, antibacterial, sterilization clinically.
The compound provided in the present invention and derivative can according to IUPAC (International Union of Pure and Applied Chemistry(IUPAC)) or the names of CAS (chemical abstracts service, Columbus, OH) naming system.
Definition about use term of 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 be not specifically defined, according to disclosure and context, the implication that those skilled in the art can give them should be provided herein.
" replacement " refer to hydrogen atom in molecule by other different atom or molecule replace.
In hydrocarbon group, the minimum value of carbon content and maximum value are represented by prefix, such as, prefix (Ca ~ b) alkyl show any containing " a " to alkyl of " b " individual carbon atom.Therefore, such as, C
1~ C
4alkyl refers to the alkyl comprising 1 ~ 4 carbon atom.
Term " pharmaceutically acceptable " refers to certain carrier, load, thinner, auxiliary material, and/or the salt formed usually chemically or physically with form certain pharmaceutical dosage form other becomes phase-splitting compatibility, and mutually compatible with acceptor on physiology.
Term " salt " and " pharmaceutically useful salt " refer to above-claimed cpd or its steric isomer, and the acid formed with inorganic and/or organic bronsted lowry acids and bases bronsted lowry and/or subsalt also comprise zwitter-ion salt (inner salt), also comprise quaternary ammonium salt, such as alkylammonium salt.These salt can be directly obtain in the last abstraction and purification of compound.Also can be by by above-claimed cpd, or its steric isomer, with the acid of some amount or alkali suitably (such as equivalent) be obtained by mixing.These salt may form precipitation in the solution and collect with filter method, or reclaim after the solvent evaporates and obtain, or in water medium, react postlyophilization obtain.Salt described in the present invention can be the hydrochloride of compound, vitriol, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphoric acid salt, acetate, propionic salt, succinate, oxalate, 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 listed Compound Phase is same herein, but one or more atom is replaced by another atom, the atomic mass of this atom or total mass number are different from the common atomic mass of occurring in nature or total mass number.Hydrogen, carbon, nitrogen, oxygen, sulphur can be comprised by isotropic substance in drawing-in system (I) compound, namely
2h,
3h,
13c,
14c,
15n,
17o,
18o,
35s.The compound of the formula (I) containing above-mentioned isotropic substance and/or other atom isotope and steric isomer thereof, and this compound, steric isomer pharmaceutically useful salt all should be included within the scope of the invention.
Key intermediate in the present invention and compound carry out abstraction and purification, and the mode used is Isolation and purification method conventional in organic chemistry and the example of described method comprises filtration, extraction, drying, is spin-dried for and various types of chromatogram.Selectively, can 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 compound of the present invention can be selected to be combined with other active agent any, for the preparation of medicine or the pharmaceutical composition of regulating cell function or disease therapy.If use one group of compound, then can by these compounds simultaneously, respectively or in an orderly manner administration be carried out 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 comprises (but being not limited to): oral, parenteral (intravenously, intramuscular or subcutaneous) and topical.
Solid dosage for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, active compound mixes with at least one conventional inert excipients (or carrier), as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or mix with following compositions: (a) filler or expanding material, such as, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, such as, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, such as, glycerine; (d) disintegrating agent, such as, agar, calcium carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, such as paraffin; F () absorbs accelerator, such as, and quaternary ammonium compound; (g) wetting agent, such as hexadecanol and glyceryl monostearate; (h) sorbent material, such as, kaolin; (i) lubricant, such as, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and pill, formulation also can comprise buffer reagent.
Solid dosage such as tablet, sugar-pill, capsule, pill and granule can adopt dressing and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and in this composition, the release of active compound or compound can discharge in certain part in a delayed fashion in digestive tube.The example of adoptable embedding component is polymeric material and Wax.If desired, active compound also can form microencapsulation form with one or more in above-mentioned vehicle.
Liquid dosage form for oral administration comprises 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, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture etc. of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials.
Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and spices.
Except active ingredient beyond the region of objective existence, suspension can comprise suspension agent, such as, and the mixture etc. of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials.
Composition for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or emulsion, and for being again dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
Formulation for the compounds of this invention of topical comprises ointment, powder, patch, propellant and inhalation.Activeconstituents aseptically with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need if desired is mixed together.
Pharmaceutically acceptable auxiliary material of the present invention, refers to the material be included in addition to the active ingredient (s in formulation.
Pharmaceutically acceptable complementary composition of the present invention, it has certain physiologically active, but adding of this composition can not change the dominant position of aforementioned pharmaceutical compositions in treatment of diseases, and only play auxiliary effect, these auxiliary effects are only the utilizations 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, according to foregoing of the present invention, according to ordinary technical knowledge and the customary means of this area, not departing under the present invention's above-mentioned basic fundamental thought prerequisite, the amendment of other various ways, replacement or change can also be made.
The embodiment of form by the following examples, is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
Accompanying drawing explanation
Compound shown in Fig. 1 formula I
1h NMR spectrogram
Compound shown in Fig. 2 formula I
13c NMR spectrogram
Compound shown in Fig. 3 formula I
1h NMR 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, its three-dimensional arrangement sciagraph
Definition and abbreviation:
" ee " representative " enantiomeric excess ", is measure excessive relative to racemize sample of a kind of enantiomorph of chipal compounds, with regard to given sample, represents with per-cent.
Some flow process and embodiment can omit the details of common reactant (comprising oxidation, reduction etc.), isolation technique and analytic 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, comprise Richard larock, Comprehensive Organic Transformations (1999) and multireel series Compendium of Organic Synthetic Methods (1974 ~ 2005) edited by Michael B.Smith and others.Some reaction process can omit secondary product from chemical conversion (such as from esterolytic alcohol, CO from diprotic acid glutamic acid
2deng).In addition, in some cases, namely reaction intermediate can be used in step subsequently without the need to 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 also may be used for the physical properties improving solvability or otherwise change compound.About the discussion of blocking group strategy; install and remove the explanation of the materials and methods of blocking group; with the compilation etc. of blocking group that can be used for common functional groups; see T.W.Greene and P.G.Wuts; ProtectingGroups in Organic Chemistry (1999) and P.Kocienski; Protective Groups (2000), they are complete is referenced herein by reference.
Generally speaking, the reaction reagent being essentially stoichiometry can be used to carry out throughout the chemical conversion described in specification sheets, but some reaction can benefit from one or more excessive reaction reagents of use.In addition, much can carry out under about RT (room temperature) and envrionment temperature throughout the reaction disclosed in specification sheets, but depend on reaction kinetics, yield etc., some reaction can under high pressure or adopt the temperature of higher (such as reflux conditions) or lower (such as-70 DEG C ~ 0 DEG C) to carry out.A lot of chemical conversion also can adopt one or more compatible solvent, and they can affect speed of reaction and yield.Depend on the attribute of reaction reagent, one or more solvents can be polar aprotic solvent (comprising water), polar proton inert solvent, non-polar solvent or some combinations.No matter whether any open description for stoichiometric range, temperature range, pH scope etc. herein clearly use term " scope ", also all comprises shown end points.
Embodiment
The raw material used in the specific embodiment of the invention, equipment are known product, obtain by buying commercially available prod.
Compound shown in preparation formula I
With propionic aldehyde (23.20mg, 0.4mmol) with compound 2 (44.74mg, 0.3mmol, commercially available, CAS 102-96-5) be raw material, add (2R)-2-[phenylbenzene [trimethylsiloxy group] methyl]-tetramethyleneimine (13.00mg, 0.04mmol) as catalyzer and Glacial acetic acid (2.4mg, 0.04mmol), acetonitrile (4ml) is as solvent, stirring at room temperature reaction 3 ~ 4 hours, obtains compound 3.
After this reaction completes, direct one kettle way adds compound 4 (45.26mg, 0.2mmol), (13.82mg, 0.1mmol use 0.1ml H to salt of wormwood
2o dissolves) and TBAB (3.22mg, 0.01mmol; Tetrabutyl amonium bromide), stirring reaction at 60 DEG C, reacts completely to TLC (thin-layer chromatography) monitoring, obtains reaction solution; Reaction solution 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;
[α]
d 20+ 162 (c=0.18, at CH
2cl
2in);
ESI HRMS:C
27h
24n
2o
4s
2na
+, detected value is 527.1077;
1h NMR (400MHz, CDCl
3): δ=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, J
1=4.4Hz, J
2=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;
13c NMR (100MHz, CDCl
3): δ=201.44,176.51,134.56,133.85,131.53,128.81,128.65,128.46,128.27,128.03,127.40,126.92,89.35,78.37,70.38,50.98,49.10,33.28,14.73ppm; As shown in Figure 2.
Embodiment 1
Compound shown in the formula I of getting preparation, at n-hexane-ethyl acetate (90%:10%, v/v) slowly to volatilize under normal 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 is by 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
Compound shown in the formula I of getting preparation, crystallization of slowly volatilizing under normal temperature in n-hexane-ethyl acetate (95%:5%, v/v), obtains the crystal formation of compound shown in formula I.
In order to beneficial effect of the present invention is described, the invention provides following test example:
Test example 1 anti-microbial activity is tested
The present invention adopts equimultiple dilution method (also referred to as coubling dilution) to measure the anti-microbial activity of the crystal formation of compound shown in formula I.
The acquisition of experimental strain:
Experimental strain of the present invention is all for being collected the Clinical isolate bacterial of qualification by People's Hospital, Sichuan Prov., healthcare hospital for women & children of Sichuan Province.Sample is mainly derived from blood, phlegm, urine etc., identify through French Mei Liai (BioMeriruk) VITEK-32, VITEK-60 automatic microbe identification and analysis instrument in collection unit, and again identify through Sichuan Industrial Institute of Antibiotics Biolog Bacteria analyzer (U.S.) API 20E, 20NE, Staph series and ordinary method, called after respectively: addicted to Fructus Hordei Germinatus Zymomonas mobilis S1, the luxuriant and rich with fragrance acinetobacter calcoaceticus N2 of promise, the luxuriant and rich with fragrance acinetobacter calcoaceticus N3 of promise, streptococcus 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 2ml DMSO (dimethyl sulfoxide (DMSO)) is dissolved, 10 concentration gradients are done respectively by equimultiple dilution method, each gradient adds 1ml containing drug solns in MH culture dish, and with 14mlMH solid medium (caseinhydrolysate (Mueller-Hinton) substratum) mixing, make the culture dish that pastille is different.Then be 10 with the punch tool in 27 holes by bacteria containing amount
6bacterium liquid be inoculated on culture dish, put into the constant incubator of 37 DEG C, cultivate 18h ~ 24h, observe inoculation position whether have bacterial growth, to judge its fungistatic effect, the results are shown in Table 2; Using levofloxacin as reference.
Anti-microbial activity refers to the ability of antimicrobial drug suppression or pathogenic microbe killing; Available extracorporeal bacteria inhibitor test and experiment in vivo therapeutics measure; Antibacterial experiment in vitro has important references meaning to clinical application.The minimum concentration of bacterial growth in substratum can be suppressed to be minimal inhibitory concentration (minimal inhibitory concentration, MIC).Bacteriostatic action and the germicidal action of antimicrobial drug are relative, and some antimicrobial drug is bacteriostatic action when lower concentration, and high density is germicidal action.
The anti-microbial activity MIC (mg/ml) of the crystal formation of compound shown in table 2 formula I
Note: the bacterial strain of above-mentioned use, except reference culture, all the other are all clinical separation strains.
From above-mentioned test, shown in formula I, the crystal formation of compound has good anti-microbial activity, to inhibited addicted to one or more in Fructus Hordei Germinatus Zymomonas mobilis, the luxuriant and rich with fragrance acinetobacter calcoaceticus of promise, streptococcus aureus, staphylococcus epidermidis.
Test example 2 stability of crystal form of the present invention and water absorbability are investigated
1, stability:
The crystal formation of compound shown in formula I is put into stability test case and carries out accelerated test, test conditions 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 considerable change does not occur this crystal formation, having good stability of crystal formation of the present invention is described.
2, water absorbability:
Adopt Pharmacopoeia of People's Republic of China 2010 editions second annex XIX J medicine to draw moist test direction principle, carry out wettability test to the crystal formation of compound shown in formula I, 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％ |
Result shows, crystal formation of the present invention places 15 days in wet condition, and it is not obvious that it draws wet weightening finish, illustrates that crystal formation of the present invention can effectively avoid moisture absorption deliquescence.
Because crystal formation of the present invention has satisfactory stability, and can effectively avoid moisture absorption deliquescence, various formulation can be prepared into easily, such as: 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 luxuriant and rich with fragrance acinetobacter calcoaceticus, streptococcus aureus, staphylococcus epidermidis etc.; Simultaneously, invention increases the stability of crystal formation medicine, the activity of crystal formation medicine, the bioavailability of crystal formation medicine, reduce the toxic side effect of crystal formation medicine, and can effectively avoid moisture absorption deliquescence, being convenient to control drug quality, providing a kind of selection newly for screening the crystal formation medicines such as antibacterial, antibacterial, sterilization clinically.
Claims (11)
1. the crystal formation of the hexanaphthene of rhodanine chirality shown in formula I spirocyclic compound, is characterized in that:
This crystal formation is rhombic system, and spacer is P2
12
12
1, unit cell parameters is
α=90.00 °, β=90.00 °, γ=90.00 °, Z=4, unit cell volume is
2. the crystal formation of the hexanaphthene of rhodanine chirality shown in formula I spirocyclic compound according to claim 1, is characterized in that: the ee value >90% of the hexanaphthene of rhodanine chirality shown in formula I spirocyclic compound; Fusing point is 211 DEG C ~ 213 DEG C; Specific rotatory power is [α]
d 20+ 162.
3. the crystal formation of the hexanaphthene of rhodanine chirality shown in formula I spirocyclic compound according to claim 1, is characterized in that: the ee value >90% of described crystal formation; Fusing point is 203 DEG C ~ 205 DEG C.
4. the crystal formation of the hexanaphthene of rhodanine chirality shown in formula I spirocyclic compound according to claim 1, is characterized in that: the ρ of described crystal formation
calcfor 1.324mg/mm
3; 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 hexanaphthene of rhodanine chirality shown in formula I spirocyclic compound, slowly to volatilize in the mixed solvent of n-hexane/ethyl acetate crystallization, obtain the crystal formation of the hexanaphthene of rhodanine chirality shown in formula I spirocyclic compound; In the mixed solvent of described n-hexane/ethyl acetate, the volume ratio of normal hexane and ethyl acetate is (90:10) ~ (95:5);
The spirocyclic compound of rhodanine chirality hexanaphthene 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 reaction solution of compound 3;
Described organic catalyst is selected from
in any one or multiple, R
5for trialkyl silyl, R
6, R
7independently be selected from aromatic base or heterocycle, R
8for alkyl or hydrogen atom, R
9for alkyl or heterocycle, R
11for benzyl or hydrogen; Described nitrile solvents be selected from acetonitrile, propionitrile, butyronitrile, isopropyl cyanide, benzyl cyanide any one or multiple;
B, in the reaction solution of step a compound 3, add compound 4, mineral alkali, quaternary ammonium salt catalyzer, stirring reaction at 60 ~ 65 DEG C, thin-layer chromatography monitoring reacts completely, and obtains reaction solution; By reaction solution except desolventizing, obtain crude product; Separation and purification is carried out to crude product, obtains the rhodanine chirality hexanaphthene spirocyclic compound shown in formula I;
Described mineral alkali be selected from salt of wormwood, sodium carbonate any one or multiple; Described quaternary ammonium salt catalyzer be selected from tetrabutyl ammonium fluoride, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide any one or multiple;
The mol ratio of described compound 1, compound 2, organic catalyst, Glacial acetic acid, compound 4, mineral alkali, quaternary ammonium salt catalyzer is 1:(0.1 ~ 1): (0.02 ~ 0.1): (0.05 ~ 0.5): (0.1 ~ 1): (0.1 ~ 0.5): (0.01 ~ 0.05); Described compound 1 is 1:(1 ~ 10 with the molecular volume ratio of nitrile solvents) mol/L.
6. method according to claim 5, is characterized in that:
In step a, described organic catalyst is (2R)-2-[phenylbenzene [trimethylsiloxy group] methyl]-tetramethyleneimine; Described nitrile solvents is acetonitrile;
In step b, described mineral alkali is salt of wormwood; Described quaternary ammonium salt catalyzer is Tetrabutyl amonium bromide;
The mol ratio of described compound 1, compound 2, organic catalyst, Glacial acetic acid, compound 4, mineral alkali, quaternary ammonium salt catalyzer is 1:0.75:0.1:0.1:0.5:0.25:0.025; Described compound 1 is 1:10mol/L with the molecular volume ratio of nitrile solvents.
7. the crystal formation of the hexanaphthene of rhodanine chirality shown in Claims 1 to 4 any one formula I spirocyclic compound, the purposes in preparation antibacterials.
8. purposes according to claim 7, is characterized in that: described antibacterials refer to addicted to any one in Fructus Hordei Germinatus Zymomonas mobilis, the luxuriant and rich with fragrance acinetobacter calcoaceticus of promise, streptococcus aureus, staphylococcus epidermidis or the multiple antibacterials with anti-microbial activity.
9. purposes according to claim 8, is characterized in that: described is addicted to Fructus Hordei Germinatus Zymomonas mobilis S1 addicted to Fructus Hordei Germinatus Zymomonas mobilis; The luxuriant and rich with fragrance acinetobacter calcoaceticus of described promise is the luxuriant and rich with fragrance acinetobacter calcoaceticus N2 of promise or the luxuriant and rich with fragrance acinetobacter calcoaceticus N3 of promise; Described streptococcus aureus is streptococcus aureus J4; Described staphylococcus epidermidis is staphylococcus epidermidis BP8 or staphylococcus epidermidis BP4.
10. purposes according to claim 7, is characterized in that: the formulation of described antibacterials is solid preparation.
11. purposes according to claim 10, is characterized in that: described solid preparation is capsule, powder pin, tablet, pill, powder and/or granule.
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Non-Patent Citations (4)
| Title |
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| PANKAJ CHAUHAN ET AL.: "Asymmetric synthesis of functionalized cyclohexanes bearing five stereocenters via a one-pot organocatalytic Michael-Michael-1,2-addition sequence", 《CHEM. COMMUN.》, vol. 50, 15 May 2014 (2014-05-15) * |
| PANKAJ CHAUHAN ET AL.: "Streocontrolled Construction of Six Vicinal Stereogenic Centers on Spiropyrazolones via Organocascade Michael/Michael/1,2-Addition Reactions", 《ORGANIC LETTERS》, vol. 16, 19 May 2014 (2014-05-19) * |
| XIN XIE ET AL.: "Asymmetric synthesis of a structurally and stereochemically complex spirooxindole pyran scaffold through an organocatalytic multicomponent cascade reaction", 《CHEM. COMMUN.》, vol. 48, 4 September 2012 (2012-09-04) * |
| 谢欣等: "靛红3-位氧杂螺环化合物的合成", 《第四届中医药现代化国际科技大会论文集》, 26 September 2013 (2013-09-26) * |
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