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Vitamins №27

Vitamins №27. Vitamins of the aromatic and hyterocyclic row: derivatives of chromane, phenylchromane, pyridine, oxymethylpyridine. Antivitamines. prepared as. Medvid I.I. Aromatic vitamins.

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Vitamins №27

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  1. Vitamins №27 Vitamins of the aromatic and hyterocyclic row: derivatives of chromane, phenylchromane, pyridine, oxymethylpyridine. Antivitamines. prepared as. Medvid I.I.

  2. Aromatic vitamins • 2-methyl-1,4-naphthoquinone(vitamin of К group)derivativesbelong to the aromatic vitamin’s raw. They have antihemorragic actionand participate in the formation of prothrombin. • Vitamin К1 (phylloquinone) present in the plants (lucerne , spinach , cabbage), vitamin К2 (pharnoquinone) isin animal products and is produced by intestinal microflora. Vitamin К3 (menadione) is called 2-methyl-1,4-naphtoquinone. • In medical practice, using a synthetic analogue of vitamin K - vikasol.

  3. Coagulation effect of vitamin K is very specific, since the small changes in their molecule lead to a significant change in their activity. The discovery of Ansbaher and Ferngolts (1939) was a great achievement, that the 2-methylnaphthoquinone (it was called vitamin K3) is by three times more active than vitamin K1. Insolubility in water of 3-methylnaphthoquinone has led to the synthesis of a number of its water-soluble derivatives (by O.V. Palladin), including vikasol.

  4. Vikasol(Vikasolum) (Menadione of sodium bisulfite) Sodium 2,3-dihydro-2-methyl-1,4-naphthoquinone-2-sulfonate threehydrate • CHARACTERS. A pale-yellow, crystalline powder, freely soluble in water, very slightly soluble in ether, hard soluble in alcohol.

  5. Vikasol obtaining Precursor for the synthesis of the drug is a β-methylnaphthalene, which is extracted from the waste cokecoal industry. Methylnaphthalene is oxidized in acetate acid by chromic anhydride to methylnaphthoquinone, which is heated with an aqueous solution of sodium hydrosulfite: Identification reaction of vikasol is based on its lability in alkaline and acid solutions.

  6. Identification of vikasol • It gives reaction of a sodium. • At the interaction with a sodium hydroxide solution there is settled down a yellow crystalline precipitate of 2-methyl-1 ,4-naphthoquinone, which is extracted by chloroform, purified from impurities and determine the melting point (104-107 ° C): Sodium sulfite is determined after the removal of the excess of alkali solution by a iodine solution according to the iodine discoloration reaction. Vikasol itself does not react with iodine. Na2SO3 + I2 + H2O → Na2SO4 + 2HI

  7. At the interaction of vikasol with a concentrated sulfuric acid there is sulfurdioxide small: • Substance + ethanol + HClconc.  red colour. • Aqua solution of the substance + sodium ethylate Red-brown color, according to the formation of 2-oxi-3-methyl-naphthoquinone (phtyoxol).

  8. Impurities • Sodium bisulfite and 2-methyl-1,4-naphthohydroquinone-3-sulfonate are the specific impurities in vikasol. • Sodium bisulfiteNaHSO3 is determined by iodometric titration method (less than 2 %). • 2-methyl-1,4-naphthohydroquinone-3-sulfonateis determined by the adding of о-phenanthroline- hould not form the precipitate (the impurity is not allowed. Assay • Cerimetri. Direct titration, the indicator is o-phenanthroline. By the interaction with a sodium hydroxide solution 2-methyl-1 ,4-naphthoquinone is precipitated, which is extracted with chloroform. After removal of chloroform, it is reduced in an acidic medium to 2-methyl-1 ,4-dioxinaphthalene, then it is titrated by a solution of cerium (IV) sulfate until the green color:

  9. Gravimetry. (Precipitation form – 2-methyl-1,4-naphthoquinone).

  10. Storage • Store protected from light. Application To increase the clotting of blood at various bleedings. Water-soluble synthetic substitute of K group vitamins, which take part in the formation of liver prothrombin and promotes the normal blood coagulation. At Haemophilia it does not act. It acts during 12-18 hours after injection. Produced: powder, tablets. оn 0,015 g, 1% solution for injection. • Per oral: the highest day dose – 60 mg,intra/muscular – 30 mg.

  11. Heterocyclic row vitamins Chromane derivatives • Heterocyclic vitamins, chromane derivatives (vitamins of Е group - tocopherols), are in (Corn, cotton, flax, peanuts, sea buckthorn, etc.) oils, and in the green parts of plants, especially in the young shoots of cereals. They are also available in small quantities in milk, butter, egg yolks, meat, fats.Source of tocopherols extraction is wheat germ oil, or corn.In industry, the vitamin E extracted from natural sources or by synthesis.

  12. The basis of the structure of E vitamin group is a tocol molecule - 6-oxy-2-methyl-2 (4 ', 8', 12'-trimethyltridecyl) chromane: • Different tocopherols by the number of methyl groups in the core of chromane, there are seven natural vitamins of E group. The most active-α-tocopherol. In clinical practice using tocopherol acetate.

  13. Obtaining of α-tocopherol Tocopherol acetate is synthetically extracted by the condensation of trimethylhydroquiinone with phythilbromide and subsequent acetylation of α-tocopherol:         Phythilbromide is extracted from phytol containing in the nettles. From 1 ton of nettles get about 3 kg of phytol.

  14. Tocopherol acetate(Tocopheroli acetas)Vitamin Е (±)-2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-acetoxichromane • CHARACTERS.Light yellow, transparent, thick, oily liquid with low odor. Practically insoluble in water, soluble in 95% alcohol and very easily soluble in ether, acetone, chloroform, and oils. Under the influence of light tocopherol acetate is oxidized and darkened.

  15. Identification of Tocopherol acetate • Oxidation of the fuming nitric acid, at the heating in a water bathe – appearance a red-orange color (o-tocopherylquinone). If we continue the condensation of o-tocopherylquinone with o-phenylenediamine, then forming a phenazine dye of red-orange color with a yellow-green fluorescence

  16. Tocopherol acetate is hydrolyzed by a solution of potassium hydroxide in absolute alcohol (at the heating), then to add the concentrated sulfuric acid – feeling the smell of ethyl acetate. • At the oxidation of tocopherol by a potassium ferricyanide in an alkaline medium there is formed colored di-α-tocopherol:

  17. Assay • Cerimetry. Direct titrationafter hydrolysis, indicator – diphenilamine. Е = ½ М.m. Firstly tocopherol is hydrolyzed by boiling with H2SO4, and then extracted tocopherol is titrated with cerium (IV) sulfate to the blue-violet color. • Photocolorimetry • Liquid chromatography • Spectrophotometry. Storage • Store protected from light in a cold place.

  18. Application • An important antioxidant. It participates in the biosynthesis of proteins and other important metabolic processes in cells. At its insufficient amount appearance the degenerative changes in nerve cells, skeletal muscle, cardiac muscle, increased fragility and permeability of capillaries.  Apply for nervous diseases, muscular dystrophy, sclerosis, menstrual irregularities and the threat of termination of pregnancy, dysfunctionof the sexual men glands, to improve vision, with radiation sickness, etc. Using 50-100 mg / day (sometimes up to 400 mg) as oil solutions of 5%, 10%, 30% α-tocopherol; intra/muscular - 5%, 10%, 30% oil solutions; inside - Capsules 100 , 200, 400 mg.

  19. Heterocyclic vitamins Phenylchromane derivatives (flavan) Flavans derivatives are naturally in a free state, or in conjunction with sugars (glycosides) - flavonoids. Flavonoids are a group of Vitamins P. They are able to reduce the fragility and permeability of capillaries, take part in the ox-red processes and have specific antioxidant properties. They are in green tea, rose hips, citrus fruit, unripe walnuts, mountain ash. How drugs they are used as - quercetin, rutin, and their natural (katergen) and semisynthetic (troxevasin) analogues.

  20. Rutin (Rutinum) 3-Rutinoside quercetinor 3-ramnoglycosyl-3,5,7,3',4'-pentaoxiflavone • Belongs to a glycosides class: quercetin aglycone is 3,5,7,3 ', 4'-pentaoxiflavon; sugar molecule part - rutenoza is a disaccharide consisting of D-glucose and L-rhamnose.Rutin is found in the leaves and fragrant flowers of rue (Ruta graveolens), buckwheat (Fagopyrum esculentum).

  21. CHARACTERS Greenish-yellow finely crystalline powder, odorless and tasteless. Practically insoluble in water, slightly soluble in alcohol, it is difficult to dissolve in boiling alcohol, practically insoluble in acid solution, ether, chloroform, acetone and benzene, soluble in dilute alkali. Identification The reaction wth iron (III) chloride - there is a dark green color (the presence of phenolic groups). Mineral acids at the heating hydrolyze rutin with the formation of quercetin, glucose and rhamnose. Quercetin + H2SO4 → oxonium salt is bright yellow color with a green fluorescence. Glucose residue is detected after acidic hydrolysis by the reaction with copper-tartrate reagent (Feling).

  22. When dissolved a substance in a sodium hydroxide solution appears yellow-orange color. According to the reaction flavonoid becomes into halcon: • The presence of two absorption maxima in the UV spectrum at 259 and 362.5 nm. • Reactions on the keto group (formation of oxime, phenylhydrazone, semicarbazone).

  23. Rutin is reduced by hydrogen in an acidic medium, and forming the perylene salts, which have red colors (cyanine reaction). For occurring of this reaction to the alcohol solution of substance to add concentrated chloric acid and magnesium powder: Assay UV-spectrophotometry

  24. Storage Store protected from light Application Vitamin P regulates vascular permeability, enhances the action of ascorbic acid. Used for the prevention and treatment of hypo-and avitaminosis of P vitamin, and for the treatment of diseases associated with the violation of vascular permeability and capillary lesions. Produced in powder and tablets on 20 mg. Included in the Table. "Ascorutin" (along with ascorbic acid and glucose) and vikalin (bismuth nitrate basic, basic magnesium carbonate, sodium bicarbonate, powders of sweet flag (calamus) root and buckthorn bark, rutin and Kelin).

  25. Heterocyclic vitamins Pyridine derivatives • the nicotinic acid, its amide (vitamin PP) and oximethylpyridine vitamins (group В6 )belong to the vitamins of pyridine derivatives. • Nicotinic or β-pyridinecarboxylic acid was firstly synthetically obtained by Huber in 1867-1870. Its vitamin properties were found in 1937-1938. In the natural materials nicotinic acid themselves does not occur but nicotinamide occures, which is a part of many enzymes. Thus, nicotinic acid is a pro-vitamin of nicotinamide. • Nicotinic acid is obtained only synthetically.

  26. Nicotinic acid obtaining The main source of the obtaining of nicotinic acid - an nicotine alkaloid, which is a by-product of the tobacco production and the anabasine alkaloid it is contained in anabazis - wild growing plant in Central Asia. These alkaloids are easily oxidized by various oxidants to nicotinic acid:

  27. Nicotinic acid (Acidum nicotinicum), Vitamin РР, Vitamin В5, Niacyn (ДФУ) Pyridine-3-carboxylic acid CHARACTERS. Crystalline white powder. Soluble in boiling water and boiling 96% alcohol, moderately soluble in water, practically insoluble in ether. Dissolves in dilute solutions of hydroxides and carbonates of alkali metals.

  28. Identification • Substance at the interaction with the cyanobromide (cyanochloride) solution and aniline solution forms a yellow color:

  29. Melting point, ІR-spectroscopy. • Un pharmacopoeia reaction : а) Reaction of pyridine cycle with 2,4-dinitrochlorbenzene(Cink reaction)

  30. b) formation of copper nicotinate blue color: c) With copper sulfate and ammonium thiocyanide solutions - green color:

  31. d) At the heating of the substance with anhydrous sodium carbonate, there is a smell of pyridine: Assay • Alkalimetry, direct titration, the indicator - phenolphthalein. Parallel to conduct a blind test. Е = М.м

  32. In the injection solutions (except nicotinic acid there is sodium bicarbonate), the quantitative content of the drug is determined by a coppermetry. In this case, to the solution of nicotinic acid to add a solution of Copper sulfate, the precipitate is filtered and in the filtrate there is determined the excess of CuSO4 by iodometric. Indicator - starch. Parallel to conduct the control test. Е = 2 М.м 3. UV-spectrophotometry in the injection solution. Storage Store protected from light.

  33. Application • Antipellagric medicine. Nicotinic acid has vasodilator and hypocholesterolemic action, so it is prescribed for liver disease, vascular spasm in the limbs, kidneys and brain, at the infectious diseases. • Side effects: flushing, feeling a rush of blood to the head. • H.d. – 0,1 g; h.d.d. – 0,5 g. • Producing: tablets оn 0,05 g №50; amp. 1% - 1,0 №10. • It is in the complex tablets “Nicoshpan”

  34. Nicotinamide (Nicotinamidum) (UP) Pyridine-3-carboxamide CHARACTERS. Crystalline white powder or colorless crystals. Easily soluble in water and ethanol. It has basic properties. It is obtained by the interaction of ammonia and ethylnicotinate.

  35. Identification • Melting point. • IR-spectroscopy. • Ammonia evolving at the heating of the substance with a sodium hydroxide solution: • Reaction of the formation of Schiff bases at the interaction with cyanobromide reagent and aniline (see nicotinic acid).

  36. Un pharmacopoeia reaction. а) At the heating with crystallineNa2CO3– appearance pyridine small: b) With CuSO4 andNH4SCNsolutions appearance emerald-green color. c) With 2,4-dinitrochlorbenzene and NaOH solution –red-violetcolor (on the pyridine cycle). d) Dragendorff’s reagent (on the heterocyclic nitrogen atom).

  37. Assay • Acidimetryin nonaqueous medium of the mixture of anhydrous acetic acid and acetic anhydride, a direct titrationat the present of mercury(II) acetate, the indicator -crystal violet(Е=М.м).Parallel to conduct a blind test. • Modified Kjeldahl method (determination of ammonia after alkaline hydrolysis. Storage Store protected from light.

  38. Application • Antipellagric medicine. • It is included in the kodegidraz enzymes that transfer hydrogen, take part in ox-red reactions in the body. Daily requirement -   15 mg. • Assign at pellagra, liver disease, gastritis with low acidity, chronic colitis. Nicotinamide has no vasodilatory action. • producing: tab. оn 15 mg; amp. 1% - 1,0 №10. • It is in polyvitamins.

  39. Oxymethylpyridine vitamins (vitamins of В6group) Vitamins of В6group are represented by the related substances: pyridoxol (pyridoxine), pyridoxal and pyridoxamine, consistently converted into each other:

  40. Pyridoxinehydrochloride (UP) (Pyridoxini hydrochloridum) viyamin В6 (5-hydroxy-6-methylpyridine-3,4-diyl)-dimethanolh/ch оr 3,4-di (oximethyl)-5-oxi-6-methylpyridineh/ch CHARACTERS. Crystalline powder of white or nearly white color. Easily soluble in water, slightly soluble in 96% alcohol. Melts at about 205 ° C with decomposition.

  41. Storage Store in tightly closed container of a dark glasses, in a cool place. Obtaining of Pyridoxinehydrochloride Contained in the raw grain cereals, vegetables, meat, fish, cod liver oil and cattle, yeast, egg yolk, etc.             Now pyridoxine is obtained only by a synthetic way. Precursor for the synthesis of pyridoxine by the method of M.A. Preobragensky is monochloracetate acid.

  42. Identification • According to the physico-chemical constants: IR and UV spectroscopy, TLC (as a developer using 2,6-dichlorquinonechlorimide): • It giver reaction of chlorides. • Un pharmacopoeia reaction : а) With silicontungstenic and phosphorustungstenic acids it is formed sediments (on the presence of pyridine bases).

  43. b)At the interaction with FeCl3 solution it is formed a red coloration, which disappears when you add sulfuric acid (reaction to a phenolic hydroxyl group): c)Pyridoxine takes part in the azoconnection reacts with diazonium salts. Formed the azo dyes yield colored complexes with salts of heavy metals, particularly zinc:

  44. Assay • Acidimetry in non-aqueous medium in a mixture of formic acid and acetic anhydride. Equivalence point is determined by potentiometric method. E = М.м. Conduct a blind test. (UP, addition 1)

  45. Alkalimetry, direct titration in a mixture of 0.01 M hydrochloric acid solution and 96% alcohol. Equivalence point is determined by potentiometric method. (UP). Е = М.м. • Alkalimetry, direct titration. Indicator - bromothymol blue. E = A.m. Cl. Calculations are carried out on the chlorine content, which in terms of dry matter should be 17,1-17,35%.

  46. Acidimetryin nonaqueous medium, a direct titrationat the present of mercury(II) acetate, the indicator -crystal violet(Е=М.м).

  47. Purity test • Specific impurity: methyl ether of pyridoxine. It is determined by the using of a 2,4-dichlorquinonechlorimide - after binding of pyridoxine by a boric acid to a complex, which does not give the reaction of the dye: • An the presence of impurities appears a blue color layer of butyl alcohol.

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