CN104610191A - Crystal form, preparation method and application of Rhodanine chiral cyclohexane spiro-compound - Google Patents

Abstract

The invention discloses the crystal form of rhodanine chiral cyclohexane spiro compound shown in formula I, The crystal form is orthorhombic, the space group is P2 ₁ 2 ₁ 2 ₁ , and the unit cell parameters are α=90.00°, β=90.00°, γ=90.00°, Z=4, the unit cell volume is 2531.52(10) . The crystal form of the compound shown in formula I disclosed by the present invention has inhibitory effect on one or more of Maltophilia, Acinetobacter nofi, Staphylococcus aureus, Staphylococcus epidermidis, etc.; meanwhile, the present invention The stability of crystal-form drugs is improved, and moisture absorption and deliquescence can be effectively avoided, which is convenient for drug quality control, and provides a new option for clinical screening of crystal-form drugs such as antibacterial, bacteriostatic, and bactericidal.

Description

Crystal form of rhodanine chiral cyclohexane spiro compound and its preparation method and use

technical field

The invention relates to a crystal form of rhodanine chiral cyclohexane spiro compound, a preparation method and application thereof.

Background technique

A spiro compound refers to a polycyclic compound in which two monocyclic rings share one carbon atom, and can be used in photochromic materials, electroluminescent materials, pesticides, medicines, etc.

The structures of spiro compounds are different, and their physical and chemical properties are also different, and they all have different uses, such as: spiro compound (a) with anti-mite effect, anti-anxiety drug buspirone hydrochloride (b), delaying arteriosclerosis Hardened spirocyclic indole derivatives (c), non-steroidal anti-inflammatory drug spirocyclic indole derivatives (d), physiologically active drug intermediate azaspirocyclic compound (e), anti-ring bacillus Spiro compounds (f), spiro heterocyclic derivatives with broad-spectrum antibacterial activity (g), spiro compounds with AP-1 activity inhibitory function (h), spiro antibacterial drugs (i), and spiro compounds with acetylcholine activation Cyclic compound (j) and so on ("Spiral Compound Chemistry". Edited by Wei Rongbao, Chemical Industry Press, 2007.7).

Rhodanine, whose chemical name is 2-thio-2,4-thiazolidinedione, can be used for verification and gravimetric determination of silver, spectroscopic determination of gallic acid, and organic synthesis.

For the same compound, there are usually two or more different crystal states, and different crystal forms usually show different bioavailability, dissolution rate, dissolution rate, stability, melting point, color, Filterability, density and fluidity, etc. For drugs, it is of great significance to develop crystal forms with better solubility and stability.

At present, there is no report of rhodanine chiral cyclohexane spiro compound shown in formula I of the present invention; there is no crystal form of rhodanine chiral cyclohexane spiro compound shown in formula I and its preparation method and use reports.

Contents of the invention

The object of the present invention is to provide a crystal form of rhodanine chiral cyclohexane spiro compound.

The crystal form of rhodanine chiral cyclohexane spiro compound shown in formula I provided by the invention,

The crystal form is orthorhombic, the space group is P2 ₁ 2 ₁ 2 ₁ , and the unit cell parameters are α=90.00°, β=90.00°, γ=90.00°, Z=4, the unit cell volume is

Preferably, the ee value of the rhodanine chiral cyclohexane spiro compound shown in formula I is >90%; the melting point is 211° C. to 213° C.; the specific rotation is [α] _D ²⁰ +162.

Preferably, the ee value of the crystal form is >90%; the melting point is 203°C-205°C.

Preferably, the ρ _calc of the crystal form is 1.324 mg/mm ³ ; F(000) is 1056.0.

Another object of the present invention is to provide a preparation method of the above-mentioned crystal form.

A method for preparing the above-mentioned crystal form provided by the present invention comprises the following steps: at room temperature, the rhodanine chiral cyclohexane spiro compound shown in formula I is slowly mixed in a mixed solvent of n-hexane/ethyl acetate Volatile crystallization obtains the crystal form of rhodanine chiral cyclohexane spiro compound shown in formula I; in the mixed solvent of n-hexane/ethyl acetate, the volume ratio of n-hexane and ethyl acetate is (90:10) ~(95:5);

The rhodanine chiral cyclohexane spiro compound shown in the formula I, its synthetic route is:

It includes the following steps:

a. Compound 1, compound 2, organic catalyst and glacial acetic acid were stirred and reacted at 25°C to 30°C for 3 to 4 hours in a nitrile solvent to obtain a reaction solution of compound 3;

The organic catalyst is selected from Any one or more of them, R ₅ is a trialkylsilyl group, R ₆ and R ₇ are independently selected from aromatic groups or heterocycles, R ₈ is an alkyl group or a hydrogen atom, R ₉ is an alkyl group or a heterocycle , R ₁₁ is benzyl or hydrogen; The nitrile solvent is selected from any one or more of acetonitrile, propionitrile, butyronitrile, isobutyronitrile, benzyl nitrile;

b. Add compound 4, inorganic base and quaternary ammonium salt catalyst to the reaction solution of compound 3 in step a, stir and react at 60-65° C., monitor the reaction by thin-layer chromatography to obtain the reaction solution; remove the solvent from the reaction solution, The crude product is obtained; the crude product is separated and purified to obtain the rhodanine chiral cyclohexane spiro compound shown in formula I;

The inorganic base is selected from any one or more of potassium carbonate and sodium carbonate; the quaternary ammonium salt catalyst is selected from tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, Any one or more of tetrabutylammonium iodide;

The molar ratio of compound 1, compound 2, organic catalyst, glacial acetic acid, compound 4, inorganic base and quaternary ammonium salt catalyst is 1: (0.1～1): (0.02～0.1): (0.05～0.5): ( 0.1-1): (0.1-0.5): (0.01-0.05); the molar volume ratio of the compound 1 to the nitrile solvent is 1: (1-10) mol/L.

preferred,

In step a, the organic catalyst is (2R)-2-[diphenyl[trimethylsiloxy]methyl]-pyrrolidine; the nitrile solvent is acetonitrile;

In step b, the inorganic base is potassium carbonate; the quaternary ammonium salt catalyst is tetrabutylammonium bromide;

The molar ratio of the compound 1, compound 2, organic catalyst, glacial acetic acid, compound 4, inorganic base, and quaternary ammonium salt catalyst is 1:0.75:0.1:0.1:0.5:0.25:0.025; the compound 1 and nitriles The molar volume ratio of the solvent is 1:10mol/L.

The present invention also provides the use of the above crystal form in the preparation of antibacterial drugs.

Use of the above-mentioned crystal form in the preparation of antibacterial drugs.

Further, the antibacterial drug refers to an antibacterial drug that has antibacterial activity against any one or more of Maltophilia, Acinetobacter nooffi, Staphylococcus aureus, and Staphylococcus epidermidis.

Still further, the maltophilia is maltophilia S1; the Acinetobacter noferi is Acinetobacter noferi N2 or Acinetobacter noferi N3; the Staphylococcus aureus is Staphylococcus aureus coccus J4; the Staphylococcus epidermidis is Staphylococcus epidermidis BP8 or Staphylococcus epidermidis BP4.

Preferably, the dosage form of the antibacterial drug is a solid preparation.

More preferably, the solid preparation is capsule, powder injection, tablet, pill, powder and/or granule.

The crystal form of the compound shown in formula I disclosed by the present invention has inhibitory effect on one or more of Maltophilia, Acinetobacter nofi, Staphylococcus aureus, Staphylococcus epidermidis, etc.; meanwhile, the present invention It improves the stability, activity, and bioavailability of crystal-form drugs, reduces the toxic and side effects of crystal-form drugs, and can effectively avoid moisture absorption and deliquescence, which is convenient for drug quality control. Antibacterial, bactericidal and other crystalline drugs provide a new choice.

The compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

Definition of terms used in the present invention: Unless otherwise stated, the initial definition provided by a group or term herein applies to the group or term throughout the specification; for terms that are not specifically defined herein, they should be based on the disclosure and context , giving the meanings a person skilled in the art can assign to them.

"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix (Ca-b)alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, C ₁ -C ₄ alkyl refers to an alkyl group comprising 1 to 4 carbon atoms.

The term "pharmaceutically acceptable" means that a certain carrier, carrier, diluent, excipient, and/or formed salt are generally chemically or physically compatible with other ingredients that constitute a pharmaceutical dosage form, and are physiologically compatible Compatible with receptors.

The terms "salt" and "pharmaceutically acceptable salt" refer to the above-mentioned compounds or their stereoisomers, acidic and/or basic salts formed with inorganic and/or organic acids and bases, and also include zwitterionic salts (internal salts), also include quaternary ammonium salts, such as alkyl ammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base as appropriate (for example, equivalent). These salts may form precipitates in solution and be collected by filtration, or may be recovered after evaporation of the solvent, or may be obtained by freeze-drying after reaction in an aqueous medium. Said salt in the present invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, dibutyl salt, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate.

In some embodiments of the present invention, the present invention includes isotope-labeled compounds, said isotope-labeled compounds are the same as the compounds listed herein, but wherein one or more atoms are replaced by another atom, the atom's The atomic mass or mass number is different from the atomic mass or mass number commonly found in nature. Isotopes that may be introduced into compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, sulfur, ie ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³⁵ S. Compounds of formula (I) containing the above-mentioned isotopes and/or other atomic isotopes and their stereoisomers, as well as pharmaceutically acceptable salts of the compounds and stereoisomers are all within the scope of the present invention.

Key intermediates and compounds in the present invention are isolated and purified in a manner commonly used in organic chemistry and examples of such methods include filtration, extraction, drying, spin-drying, and various types of chromatography. Alternatively, the intermediate can be carried on to the next step without purification.

In certain embodiments, one or more compounds of the invention may be used in combination with each other. Alternatively, the compound of the present invention may be used in combination with any other active agents for the preparation of drugs or pharmaceutical compositions for regulating cell functions or treating diseases. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.

The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.

The pharmaceutically acceptable adjuvant in the present invention refers to the substances contained in the dosage form except the active ingredient.

The pharmaceutically acceptable auxiliary component of the present invention has certain physiological activity, but the addition of this component will not change the leading position of the above-mentioned pharmaceutical composition in the disease treatment process, but only play an auxiliary effect, and these auxiliary effects are only It is the utilization of the known activity of the ingredient, and it is a commonly used adjuvant therapy in the field of medicine. If the above-mentioned auxiliary components are used in conjunction with the pharmaceutical composition of the present invention, it should still belong to the protection scope of the present invention.

Apparently, according to the above content of the present invention, according to common technical knowledge and conventional means in this field, without departing from the above basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.

The above-mentioned content of the present invention will be further described in detail below through specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Description of drawings

¹ H NMR spectrum of the compound shown in Fig. 1 formula Ⅰ

¹³ C NMR spectrum of the compound shown in Fig. 2 formula Ⅰ

The ¹ H NMR spectrum of the compound shown in Fig. 3 Formula I, and the assignment of the corresponding hydrogen

The NOE spectrum of the compound shown in Figure 4 Formula I is used to verify the spatial correlation of chiral hydrogen

The crystalline form of the compound shown in Fig. 5 formula I of the present invention, its three-dimensional structure projection view

Definitions and Abbreviations:

"ee" stands for "enantiomeric excess" and is a measure of the excess of one enantiomer of a chiral compound relative to a racemic sample, expressed as a percentage for a given sample.

Some of the schemes and examples below may omit details of common reactions (including oxidations, reductions, etc.), separation techniques, and analytical procedures, which are known to those of ordinary skill in the art of organic chemistry. Details of such reactions and techniques can be found in several monographs, including Richard Larock, Comprehensive Organic Transformations (1999) and the multi-volume series Compendium of Organic Synthetic Methods edited by Michael B. Smith and others (1974-2005). Some reaction schemes can omit minor products from chemical transformations (e.g. alcohols from ester hydrolysis, _CO2 from dibasic acid decarboxylation, etc.). Also, in some cases, reaction intermediates can be used in subsequent steps without isolation or purification.

In some of the reaction schemes and examples below, certain compounds can be prepared using protecting groups, which prevent undesired chemical reactions at otherwise reactive sites. Protecting groups can also be used to increase solubility or otherwise modify the physical properties of the compound. For a discussion of protecting group strategies, descriptions of materials and methods for installing and removing protecting groups, and a compilation of protecting groups available for common functional groups, see T.W. Greene and P.G. Wuts, Protecting Groups in Organic Chemistry (1999) and P . Kocienski, Protective Groups (2000), which are incorporated herein by reference in their entirety.

In general, the chemical transformations described throughout the specification can be performed using substantially stoichiometric amounts of the reactants, although certain reactions may benefit from using excesses of one or more reactants. Additionally, many of the reactions disclosed throughout the specification can be performed at about RT (room temperature) and ambient temperature, but depending on reaction kinetics, yields, etc., some reactions can be performed at elevated pressures or using higher (e.g., reflux conditions) or Lower (for example -70°C to 0°C) temperature. Many chemical transformations also employ one or more compatible solvents, which can affect reaction rates and yields. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination. Any disclosure herein of stoichiometric ranges, temperature ranges, pH ranges, etc., whether or not the term "range" is explicitly used, also includes the endpoints indicated.

Detailed ways

The raw materials and equipment used in the specific embodiment of the present invention are all known products, obtained by purchasing commercially available products.

Compound shown in the preparation formula I

Taking propionaldehyde (23.20mg, 0.4mmol) and compound 2 (44.74mg, 0.3mmol, commercially available, CAS No. 102-96-5) as raw materials, add (2R)-2-[diphenyl[trimethylsilyl Oxy]methyl]-pyrrolidine (13.00mg, 0.04mmol) as catalyst, glacial acetic acid (2.4mg, 0.04mmol) and acetonitrile (4ml) as solvent were stirred at room temperature for 3-4 hours to obtain compound 3.

After the completion of the reaction, compound 4 (45.26 mg, 0.2 mmol), potassium carbonate (13.82 mg, 0.1 mmol, dissolved in 0.1 ml H ₂ O) and TBAB (3.22 mg, 0.01 mmol; tetrabutyl bromide ammonium), stirred and reacted at 60°C, and the reaction was monitored by TLC (thin layer chromatography) to obtain a reaction solution; the reaction solution was spin-dried to solvent, separated and purified by silica gel column chromatography to obtain the compound shown in formula I, ee value> 90%.

The detection data of the compound shown in formula I is as follows:

The melting point is 211℃～213℃;

[α] _D ²⁰ +162 (c=0.18 in CH ₂ Cl ₂ );

ESI HRMS: C ₂₇ H ₂₄ N ₂ O ₄ S ₂ Na ⁺ , the detection value is 527.1077;

¹ H 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;

¹³ C 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, 33.1, 53.1, 5pp ;as shown in picture 2.

Example 1

Take the prepared compound shown in formula I, and slowly volatilize and crystallize it in n-hexane-ethyl acetate (90%:10%, v/v) at room temperature to obtain the crystal form of the compound shown in formula I, with ee value>90%, The melting point is 203°C-205°C. This crystal form is diffracted by single crystal, and its crystal structure data is shown in Table 1:

Table 1 The single crystal diffraction data of the crystal form of the present invention

Example 2

The prepared compound represented by formula I was slowly volatilized and crystallized in n-hexane-ethyl acetate (95%: 5%, v/v) at room temperature to obtain the crystal form of the compound represented by formula I.

In order to illustrate the beneficial effects of the present invention, the present invention provides following test example:

Test example 1 antibacterial activity test

The present invention uses an equal dilution method (also known as a doubling dilution method) to measure the antibacterial activity of the crystal form of the compound represented by formula I.

Obtaining of experimental strains:

The experimental strains of the present invention are all clinically isolated pathogenic bacteria collected and identified by Sichuan Provincial People's Hospital and Sichuan Provincial Maternal and Child Health Hospital. The specimens mainly come from blood, sputum, urine, etc., and were identified by the French BioMeriruk VITEK-32 and VITEK-60 automatic microbial identification analyzers at the collection unit, and the Biolog bacterial identification instrument used by the Sichuan Antibiotic Industry Research Institute (USA) ) API 20E, 20NE, Staph series and conventional methods were re-identified and named respectively: Maltophilia S1, Acinetobacter nofi N2, Acinetobacter nofi N3, Staphylococcus aureus J4, Staphylococcus epidermidis BP8, Staphylococcus epidermidis BP4 for antibacterial tests.

Dissolve 30 mg of the precisely weighed crystal form of the compound represented by formula I in 2 ml of DMSO (dimethyl sulfoxide), and make 10 concentration gradients according to the equal dilution method, and add 1 ml of the drug-containing solution to the MH culture dish for each gradient. solution, and mixed with 14ml of MH solid medium (Mueller-Hinton hydrolyzed medium) to make petri dishes containing different medicines. Then use a 27-hole puncher to inoculate the bacterial solution with a bacterial content of 10 ⁶ on a petri dish, put it in a constant temperature incubator at 37°C, and incubate for 18h to 24h, and observe whether there is bacterial growth at the inoculation site to judge its inhibitory effect. Bacterial effect, the results are shown in Table 2; with levofloxacin as a reference.

Antibacterial activity refers to the ability of antibacterial drugs to inhibit or kill pathogenic microorganisms; it can be measured by in vitro antibacterial test and in vivo experimental treatment; in vitro antibacterial test has important reference significance for clinical medication. The lowest concentration that can inhibit the growth of bacteria in the medium is the minimum inhibitory concentration (MIC). The antibacterial and bactericidal effects of antibacterial drugs are relative. Some antibacterial drugs are bacteriostatic at low concentrations, but bactericidal at high concentrations.

The antibacterial activity MIC (mg/ml) of the crystal form of the compound shown in table 2 formula I of the present invention

Note: Except for the standard strains, the strains used above are all clinical isolates.

From the above tests, it can be seen that the crystal form of the compound shown in formula I of the present invention has good antibacterial activity, and has antimicrobial activity against one or more of the bacterium maltophilia, Acinetobacter nooffi, Staphylococcus aureus, and Staphylococcus epidermidis. inhibition.

Test example 2 crystal form stability and hygroscopicity investigation of the present invention

1. Stability:

The crystal form of the compound represented by formula I of the present invention is put into a stability test box for accelerated test. The test conditions are: temperature, 40°C±2°C; humidity, RH75%±5%, and the time is 3 months.

TLC (thin layer chromatography) and HPLC (high performance liquid chromatography) were used to measure, and it was found that the crystal form did not change significantly, indicating that the stability of the crystal form of the present invention is good.

2. Hygroscopicity:

Using the Pharmacopoeia of the People's Republic of China 2010 Edition Second Appendix XIX J Drug Hygroscopicity Test Guiding Principles, the crystal form of the compound shown in Formula I of the present invention was tested for hygroscopicity, and the results were as follows:

Table 3 Hygroscopicity test results

time (days) 0 5 10 15 compound weight gain 0.0% 1.2% 1.2% 1.2%

The results show that the crystal form of the present invention is placed in a humid environment for 15 days, and its weight gain due to moisture is not obvious, indicating that the crystal form of the present invention can effectively avoid moisture absorption and deliquescence.

Since the crystal form of the present invention has good stability and can effectively avoid moisture absorption and deliquescence, it can be conveniently prepared into various dosage forms, such as capsules, powder injections, tablets, pills, powders, granules and the like.

To sum up, the crystal form of the compound represented by formula I disclosed by the present invention has inhibitory effect on one or more of Maltophilia, Acinetobacter nofi, Staphylococcus aureus, Staphylococcus epidermidis, etc. ; Simultaneously, the present invention has improved the stability of crystalline drug, the activity of crystalline drug, the bioavailability of crystalline drug, has reduced the toxic side effect of crystalline drug, and can effectively avoid hygroscopic deliquescence, be convenient to control drug quality, for Clinical screening of antibacterial, bacteriostatic, bactericidal and other crystalline drugs provides a new option.

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.