Vitamins №27
Vitamins of the aromatic and hyterocyclic
row: derivatives of chromane,
phenylchromane, pyridine,
oxymethylpyridine. Antivitamines.
prepared as. Medvid I.I.
Aromatic vitamins
2-methyl-1,4-naphthoquinone (vitamin of К group)
derivatives belong to the aromatic vitamin’s raw. They
have antihemorragic action and participate in the
formation of prothrombin.
Vitamin К1 (phylloquinone) present in the plants (lucerne ,
spinach , cabbage), vitamin К2 (pharnoquinone) is in
animal products and is produced by intestinal
microflora. Vitamin К3 (menadione) is called 2-methyl1,4-naphtoquinone.
In medical practice, using a synthetic analogue of
vitamin K - vikasol.
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.
Vikasol (Vikasolum)
(Menadione of sodium bisulfite)
O
CH3
SO3Na * 3 H2O
O
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.
Vikasol obtaining
Precursor for the synthesis of the drug is a βmethylnaphthalene, 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.
Identification of vikasol
1.
2.
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 ,4naphthoquinone, 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
3.
At the interaction of vikasol with a concentrated
sulfuric acid there is sulfurdioxide small:
Substance + ethanol + HCl conc.  red colour.
5. Aqua solution of the substance + sodium ethylate 
Red-brown color, according to the formation of 2-oxi-3-methylnaphthoquinone (phtyoxol).
4.
Impurities
Sodium bisulfite and 2-methyl-1,4-naphthohydroquinone-3sulfonate are the specific impurities in vikasol.
Sodium bisulfite NaHSO3 is determined by iodometric titration
method (less than 2 %).
2-methyl-1,4-naphthohydroquinone-3-sulfonate is determined
by the adding of о-phenanthroline - hould not form the
precipitate (the impurity is not allowed.
Assay
1.
Cerimetri. Direct titration, the indicator is o-phenanthroline.
By the interaction with a sodium hydroxide solution 2-methyl1 ,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:
2. Gravimetry. (Precipitation form – 2-methyl-1,4-
naphthoquinone).
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.
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.
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.
Obtaining of α-tocopherol
Tocopherol acetate is synthetically extracted by the
condensation of trimethylhydroquiinone with
phythilbromide and subsequent acetylation of αtocopherol:
Phythilbromide is extracted from phytol
containing in the nettles. From 1 ton of nettles get
about 3 kg of phytol.
Tocopherol acetate
(Tocopheroli acetas) Vitamin Е
(±)-2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6acetoxichromane
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.
Identification of Tocopherol acetate
1.
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 ophenylenediamine, then forming a phenazine dye of red-orange
color with a yellow-green fluorescence
2. 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.
3. At the oxidation of tocopherol by a potassium
ferricyanide in an alkaline medium there is formed
colored di-α-tocopherol:
Assay
1.
2.
3.
4.
Cerimetry. Direct titration after 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.
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, dysfunction of 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.
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.
Rutin (Rutinum)
3-Rutinoside quercetin or 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).
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
1. The reaction wth iron (III) chloride - there is a dark
green color (the presence of phenolic groups).
2. 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.
3. Glucose residue is detected after acidic hydrolysis by
the reaction with copper-tartrate reagent (Feling).
4.
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.
6. Reactions on the keto group (formation of oxime,
phenylhydrazone, semicarbazone).
5.
7.
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
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).
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.
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:
Nicotinic acid (Acidum nicotinicum),
Vitamin РР, Vitamin В5, Niacyn (ДФУ)
N
COOH
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.
Identification
1. Substance at the interaction with the cyanobromide
(cyanochloride) solution and aniline solution forms
a yellow color:
COOH
+
HC
BrSCN
Br
N
HBr
+
+
C
CHOH
OH
O
SCN
COOH
C
C
H
C
H
C
CHOH
2H2O
2 H2N
+
COOH
+
O
C
C
H
NH2SCN
O
H
-
+
N
+
H
C
COOH
N
C
H
C
H
C
H
C
C
H
N
H
+
2. Melting point, ІR-spectroscopy.
3. Un pharmacopoeia reaction :
а) Reaction of pyridine cycle with 2,4-dinitrochlorbenzene
(Cink reaction)
b) formation of copper nicotinate blue color:
COOH
2
COO
-
Cu2+
CuSO4
+
N
+
H2SO4
2
N
c) With copper sulfate and ammonium thiocyanide solutions green color:
COOH
4
+
COOH
Cu
CuSO4
N
N
4
COOH
Cu
N
4
(SCN)2
+ (NH4)2SO4
SO4 + 2NH4SCN
d) At the heating of the substance with anhydrous
sodium carbonate, there is a smell of pyridine:
Assay
1. Alkalimetry, direct titration, the indicator phenolphthalein. Parallel to conduct a blind test.
Е = М.м
COOH
+
N
COONa
+
NaOH
N
H2O .
2.
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.
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”
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.
Identification
Melting point.
2. IR-spectroscopy.
3. Ammonia evolving at the heating of the substance
with a sodium hydroxide solution:
1.
4.
Reaction of the formation of Schiff bases at the
interaction with cyanobromide reagent and aniline
(see nicotinic acid).
Un pharmacopoeia reaction.
а) At the heating with crystalline Na2CO3 – appearance
pyridine small:
5.
b) With CuSO4 and NH4SCN solutions appearance emeraldgreen color.
c) With 2,4-dinitrochlorbenzene and NaOH solution – redviolet color (on the pyridine cycle).
d) Dragendorff’s reagent (on the heterocyclic nitrogen atom).
Assay
Acidimetry in nonaqueous medium of the mixture of
anhydrous acetic acid and acetic anhydride , a direct
titration at 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.
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.
Oxymethylpyridine vitamins (vitamins of
В6 group)
Vitamins of В6 group are represented by the related
substances: pyridoxol (pyridoxine), pyridoxal and
pyridoxamine, consistently converted into each other:
Pyridoxine hydrochloride (UP)
(Pyridoxini hydrochloridum) viyamin В6
(5-hydroxy-6-methylpyridine-3,4-diyl)-dimethanol h/ch оr
3,4-di (oximethyl)-5-oxi-6-methylpyridine h/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.
Storage
Store in tightly closed container of a dark
glasses, in a cool place.
Obtaining of Pyridoxine hydrochloride
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.
Identification
1. According to the physico-chemical constants: IR and
UV spectroscopy, TLC (as a developer using 2,6dichlorquinonechlorimide):
2. It giver reaction of chlorides.
3. Un pharmacopoeia reaction :
а) With silicontungstenic and phosphorustungstenic
acids it is formed sediments (on the presence of
pyridine bases).
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:
Assay
1. 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)
2.
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.
3.
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%.
1) Acidimetry in nonaqueous medium, a direct
titration at the present of mercury (II) acetate, the
indicator - crystal violet (Е=М.м).
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.
Application
Pyridoxine is in codecarboxilase. Daily requirement
for healthy humans is 2 mg. When hypo-and
avitaminosis there is observed characteristic
dermatosis (erythredema), swelling, degenerative
changes in the nervous system, etc.
Applied in various forms of Parkinson's disease,
chorea, acute and chronic hepatitis, toxicosis during
pregnancy, anemia, radiculitis, neuritis, neuralgia and
other nervous diseases.
producing: tab оn 0,01 g №10; аmp 1% - 1,0 №10; 2,5%1,0 №10; 5% - 1,2 №10.
You can not mix in the same syringe В1 and В12.
Included in the medicines of B vitamins: magne-B6,
Neyrorubin, Neurobex, Neurovitan, neuron, multi-tabs
B-complex.
Antivitamins
Investigation of the relationship between chemical
structure and vitamin activity allowed to establish for
each vitamin, one or more antivitamin. They tend to
differ from vitamins structure of a single functional
group.
In some antivitamin structure differs significantly from
the vitamins. For example, antivitamin
naphthoquinones (neodicoumarin, phenyline).
Antivitamin in biocatalytic reactions behave as
competitive inhibitors. The essence of their actions
that they form a kind of psevdoenzymes that suppress
the action of these enzymes or displace vitamins from
enzymatic systems. This leads to the using of
antivitamin as drugs for the treatment of many
Vitamins
Antivitamins
L-Ascorbic acid
D-Ascorbic acid
Pantothenic acid
ω-methylpantothenic acid
Naphthoquinones
Neodicoumarin
Nicitinamide
Pyridine-β-sulfoacid
β-acetopyridine
Pyridoxine
5-desoxipyridoxal
Thiamin
oxithiamine
Folic acid
Aminopterine
Riboflavin – 6,7-dimethyl-9-(1’- 7-methyl-8-chlor-10-(1’-DD-ribithyl)-isoaloxasine
ribithyl)-isoaloxasine
7- methyl -8-аmino-10-(1’-Dribithyl)-isoaloxasine
Cyanocobalamin
2,5-dimethylbenzimidazole
Thanks for attention!