Alpha-crystalline form of substituted selenoxanthenes and method of producing said form

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, particularly to the technology of producing selenoxanthenes and can be used in producing food additives, medicinal agents and cosmetic agents, which exhibit broad biological activity. An agent is described, which is an α-crystalline form of 9-phenyl-sym-octahydroselenoxanthene, which has antixodant, detoxication, immunomodulating, antiatherogenic, antisclerotic, anabolic, hypolipid action, and the corresponding structural formula with powder X-ray pattern obtained on Cu-K radiation sources with characteristic reflection indices expressed in degrees of the diffraction angle 2θ: 6.0 12.0 15.0 17.0 19.0 20.0 21.5, 21.7, 20.9 25.0 27.0 28.0 29.0 37.0 and melting temperature 96.8°C, as well as to a method of producing said agent, involving crystallisation of the corresponding 9-R-sym-hydroselenoxanthene from low-polar or non-polar solvent, preferably hexane, chloroform or isopropyl alcohol.

EFFECT: design of an efficient method of producing selenoxanthenes.

3 cl, 1 dwg, 1 tbl

 

The invention relates to organic chemistry, medicine, pharmacology, food and cosmetic industries, in particular to a technology for production of selenocysteine, and can be used in the production of food additives, drugs and cosmetics exhibiting biological activity, a wide spectrum of action.

Substituted selenocysteine known (RU 2213092, EN 2239632). Their structural formula looks

So far replaced selenocysteine received mainly in the amorphous form. The disadvantage of amorphous form is unstable during storage. The substance has a low flowability, prone to caking.

Selenolate and the methods of its production are disclosed, for example, in patent RU 2213092, EN 2239632, EN 2281007. In these publications indicate that the received selenolate can be recrystallized from ethanol or acetone.

The use and activity of the compounds disclosed in these publications, in particular in EN 2281007. According to this patent, 9-phenyl-s-octahydrophenanthrene has antioxidant, detoxifying, gipolipidemiceski, immunomodulatory, immunocorrection, antiatherogenic, antiateroskleroticescoe and anabolic effects. According to the data obtained from the report on determination of toxicologica the fir characteristics of selenocysteine /Laboratory BAS Belgorod agricultural Academy, K. wetney. Overall, 1996/, is replaced by selenolate has acute toxicity after intragastric administration at the level of LD50=725+75 mg/kg All this limits the scope of substituted selenocysteine, including as substances for dietary supplements and pharmaceuticals.

The authors have solved the problem of obtaining non-toxic substituted selenocysteine, stable during storage and has good flowability.

To solve this problem is proposed remedy represents selenolate α-crystal modification with a powder x-ray obtained at the Cu-K a radiation source with parameters characteristic of reflection expressed in degrees of diffraction angle 2θ: 6,0 12,0 15,0 17,0 19,0 20,0 21,5, 21,7, 20,9 25,0 27,0 28,0 29,0 37,0, below the drawing.

Powder diffraction pattern was obtained on a diffractometer "Bruker D8 Advance" (T=298 K, λCu Kα-radiation, mirror Goebel, θ/2θ scans with a step of 0.02°).

Description of the experiment

X-ray diffraction study. Crystal connection N (C19H22Se1M=329.33), tetragonal, space group P 421c, at T=100 To a=b=19.5515(15)Å, C=8.0074(6)Å, V=3060.9(4)Å3Z(Z')=8(1), F(000)=1360, dcalc=1.429 g•cm-3, µ=at 24.42 mm-1. Intensity 12199 reflections measured on an automatic diffractometer "Bruker SMART APEX II CCD" (T=100 K, The Mo-α-radiation, graphite monochromator φ - and ω-scans, θmax=58°) and further calculations were carried out on 4063 independent reflections (Rint=0.0444). Accounting for the absorption of x-rays was performed according to the program SADABS1. The structure is defined by the direct method and refined by full-fabric by the least squares method in the anisotropic approximation for non-hydrogen atoms. Position of hydrogen atoms calculated geometrically and they are all refined in isotropic approximation with fixed position (model "rider") and thermal parameters. The final factors of divergence equal to R1=0.0306 for 3506 independent reflections with I > 2σ(I) and wR2=0.0614 and GOF=0.999 for all independent reflections. All calculations were performed using complex programs SHELXTL PLUS (Version 5.10)2.

The product is obtained in the following way. The amorphous powder obtained by known techniques, crystallized either from a polar solvent selected from the group consisting of methanol, isopropanol, any of the aprotic solvent selected from the group consisting of chloroform, and hexane.

To prove the achievement of the technical result, it is possible to provide data for evaluation of acute toxicity of the proposed substance. In the course of its General toxic studies have not found toxic effects at once the rats intragastrically, at a dose of 1000 mg/kg animal body weight, which is more than 1000 times the average therapeutic dose.

Results on the determination of physico-chemical data of amorphous and crystalline forms are presented in the table:

The angle of repose, °Melting point,°CShelf life, monthsAppearance
The substance of the patent RU 2281007 (acetone)52°95-96°6Beige, powder
Crystalline form (hexane)43°96.8°24Yellow needle crystals

The method is as follows.

To obtain 9-(o-oxyphenyl)-SIMM-octahydrophenanthrene took 12.5 g of 9-(o-oxyphenyl)-octahydro-10-oaxacana and were placed in a three-neck flask with a magnetic stirrer and with a supply of gas. Then added 30 ml of a mixture of acetic acid:acetic anhydride (4:1). With stirring, the reaction mixture was purged with nitrogen for 30 minutes, then a stream of nitrogen was stopped and missed in the reactions is nnow mixture and hydrogen selenide. 30 minutes after the start of transmission of the selenide in the reaction mixture at intervals of 1 hour twice was added 1.0 ml of concentrated hydrochloric acid. The bandwidth of the selenide was 2-3 bubble per second. The total time of transmission of the selenide was 6 hours, after its completion, the reaction mixture was purged with nitrogen for 40 minutae the reaction mixture was placed in a refrigerator and the next day the precipitation was filtered, washed with acetic acid and alcohol. The product yield was 11.5,

Example 1

For recrystallization took 10 g of amorphous product was placed in a flask with a capacity of 250 ml, was added 85 ml of hexane, brought to the boil, filtered hot solution. After the loss of their crystals filtered off, washed with cold alcohol and dried at 40°C. Yield is 8.7, Tpl.- 96.8°C.

Example 2

For recrystallization took 10 g of amorphous product was placed in a flask with a capacity of 500 ml, was added 250 ml of isopropanol, brought to the boil, filtered hot solution. After the loss of their crystals filtered off, washed with cold alcohol and dried at 40°C. Output - 9.2, Tpl.- 96.6°C.

1. The tool, which represents the α-crystalline form of 9-phenyl-s-octahydrophenanthrene with antioxidant, detoxifying, immune-modulating, anti-atherogenic, antic is erotic, anabolic, gipolipidemiceski action and the corresponding structural formula

with a powder x-ray obtained on Cu-K a radiation source with parameters characteristic of reflection, expressed in degrees of diffraction angle 2θ: 6,0 12,0 15,0 17,0 19,0 20,0 21,5, 21,7, 20,9 25,0 27, 0 28, 0 29,0 37,0 and melting temperature 96,8°C.

2. A method of obtaining a crystalline form of substituted 9-R-SIMM-hydroselenoquinolinate consists in the fact that the corresponding 9-R-SIMM-hydrosilicate crystallized from malopolyarnoi or non-polar solvent.

3. The method according to claim 2, characterized in that monopolarly or non-polar solvent is chosen from the series: hexane, chloroform, isopropyl alcohol.



 

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