59-67-6 Usage
Description
Nicotinic acid, also known as niacin or vitamin B3, is a water-soluble vitamin that plays a crucial role in various biological processes. It is an essential nutrient for the formation of coenzymes NAD and NADP, which are involved in numerous cellular redox reactions. Nicotinic acid is widely distributed in nature and can be found in liver, fish, yeast, and cereal grains. It is an odorless white crystalline powder with a slightly acidic taste and is amphoteric, forming salts with both acids and bases.
Uses
1. Used in Pharmaceutical Applications:
Nicotinic acid is used as a precursor of the coenzymes NAD and NADP, which are essential for various cellular redox reactions. It is also used as an antidote, an antilipemic drug, a vasodilator agent, and an inhibitor of EC 3.5.1.19 (nicotinamidase).
2. Used in Nutritional Supplements:
Nicotinic acid is used as a nutrient and dietary supplement to prevent pellagra, a disease caused by niacin deficiency. It is also used to treat and prevent high cholesterol levels, as it can help reduce VLDL synthesis and lower cholesterol levels.
3. Used in Food Fortification:
Niacin USP granular is used for food fortification, as a dietary supplement, and as an intermediate in the production of pharmaceuticals.
4. Used in Animal Feed:
Nicotinic acid feed grade is used as a vitamin for poultry, swines, ruminants, fish, dogs, and cats. It is also used as an intermediate for nicotinic acid derivatives and technical applications.
5. Used in Skin Care and Hair Care:
Nicotinic acid, in the form of niacinamide, is used in the formulation of skin care products to improve the appearance of dry or damaged skin by reducing flaking and restoring suppleness. It also enhances the appearance and feel of hair by increasing body, suppleness, or sheen, or by improving the texture of hair that has been damaged physically or by chemical treatment.
6. Used in Chemical Synthesis:
Nicotinic acid is used as a starting material for the synthesis of various nicotinic acid derivatives, which have applications in different industries.
Preparation
Nicotinic acid exists naturally in grain germs, meats and peanuts. It can also be synthesized artificially through the liquid phase method (potassium permanganate oxidation and nitric acid oxidation) and gas phase method (ozone oxidation, ammonia oxidation and air oxidation).
3-methyl pyridine method
In the gas phase ammonia oxidation process, add 3-methyl pyridine, air and ammonia into the fluidized bed reactor and catalyze the reaction at 290~360℃,V2O5 to produce nicotinonitrile; then hydrolyze in sodium hydroxide aqueous solution at 160℃ to produce sodium nicotinate; finally, add hydrochloric acid to acidify, creating nicotinic acid. In the potassium permanganate oxidation method, add potassium permanganate gradually at 80℃ to a mixture of 3-methyl pyridine and water, and then continue to mix for 30min at 85~90℃. Distill to collect and reuse the unreacted 3-methyl pyridine and filter away the produced manganese dioxide. Adjust the PH of the resulting nicotinic acid solution to 3.8~4.0 using hydrochloric acid, cool to 30℃ crystals, and filter to obtain crude nicotinic acid. Dissolve the crude nicotinic acid in hot water, add activated charcoal to eliminate the color, filter, cool, and obtain the crystalline end product. Yield is approximately 86%.
6- hydroxyquinoline method
Add sulfuric acid and quinoline into a reaction kettle and mix while maintaining heat at 150~160℃ for 5h. Then with the temperature maintained at 180~220℃, slowly drop in nitric acid and the sulfuric acid mixture over the course of 36~40h. While maintaining the temperature, mix for 2~3h to obtain a nicotinic acid solution and add water to dilute the solution. Use 30%~33% NaOH solution to neutralize the PH to 8~9. Cool and filter away the sodium sulfate and sodium nitrate crystals, add copper sulfate solution to the filtered liquid, and mix and heat to yield copper nicotinate precipitation. Cool, filter and add the copper nicotinate to an adequate amount of water, drop in NaOH solution until PH>9 and the liquid is no longer blue, and filter away the produced cupric oxide. Add a small amount of sodium sulfide solution to remove traces of copper and iron until the solution no longer produces black precipitate, and then filter. Use hydrochloric acid to adjust the PH of the filtered liquid to 3.5~3.9, filter to yield crystals as crude nicotinic acid. Dissolve the crude product in 12 times the amount of distilled water, add activated charcoal to eliminate the color, filter, cool, and obtain the crystalline end product. Yield is 35%~39%.
2-methyl-5-ethyl pyridine method
With 2-methyl-5-ethyl pyridine as the raw ingredient, oxidize with nitic acid under high pressure and high temperatures, then decarboxylate to yield nicotinic acid.
Identifying tests
Add 2 portions of 2, 4-Dinitrochlorobenzene to the sample and process into powder. Place 10mg of the powder in a test tube, gently heat until melted, and continue to heat for a couple of seconds. Cool and add 3ml potassium hydroxide ethanol solution (TS-190). The solution should be dark red.
Dissolve 50mg of the sample solution in 20ml water, use 0.1mol/L sodium hydroxide to neutralize until a litmus paper reads neutral, and add 3ml copper sulfate solution (TS-78). Blue precipitate should begin forming slowly.
Dry the sample for 1h at 105℃ and collect its mineral oil dispersions. The peak wavelength of its infrared absorption spectrum should resemble the standard reference sample formulated using the same method.
Prepare an aqueous solution of the sample with a density of 20μg/ml, measure its absorbance at the wavelengths 237nm and 262nm in a 1cm pool, using water as a blank control. A237/A262 should be 0.35~0.39.
Content analysis
Precisely take a sample of 300mg and dissolve in 50ml water. Add a couple drops of phenolphthalein solution (TS-167) and titrate using 0.1mol/L sodium hydroxide. Conduct a control experiment at the same time. Every Ml0.1mol/L sodium hydroxide is equivalent to 12.31mg nicotinic acid (C6H5NO2).
Toxicity
LD50 7.0g/kg (Large mice, oral).
GRAS(FDA,§182.5530,2000)。
ADI has no special regulations (EEC, 1990).
History
Huber first synthesized nicotinic acid in 1867. In 1914, Funk isolated nicotinic acid from rice polishings. Goldberger, in 1915, demonstrated that pellagra is a nutritional deficiency. In 1917, Chittenden and Underhill demonstrated that canine blacktongue is similar to pellagra. In 1935, Warburg and Christian showed that niacinamide is essential in hydrogen transport as diphosphopyridine nucleotide (DPN). In the following year, Euler et al. isolated DPN and determined its structure. In 1937, Elvhehjem et al. cured blacktongue by administration of niacinamide derived from liver. In the same year, Fouts et al. cured pellagra with niacinamide. In 1947, Handley and Bond established conversion of tryptophan to niacin by animal tissues.
Air & Water Reactions
Water soluble.
Reactivity Profile
Nicotinic acid is incompatible with strong oxidizers. Nicotinic acid is also incompatible with sodium nitrite.
Fire Hazard
Flash point data for Nicotinic acid are not available; however, Nicotinic acid is probably combustible.
Biological Activity
Nicotinic acid can be converted to nicotinamide in the animal body and, in this form, is found as a component of two oxidation-reduction coenzymes, NAD and NADP.The nicotinamide portion of the coenzyme transfers hydrogens by alternating between an oxidized quaternary nitrogen and a reduced tertiary nitrogen. Enzymes that contain NAD or NADP are usually called dehydrogenases. They participate in many biochemical reactions of lipid, carbohydrate, and protein metabolism. An example of an NAD-requiring system is lactic dehydrogenase which catalyzes the conversion of lactic acid to pyruvic acid.
Biochem/physiol Actions
Nicotinic is an antioxidant and acts as a coenzyme in the form of nicotinamide adenine nucleotides(NAD). It modulates lipid metabolism and may be useful in treating dyslipidemia. Nicotinic acid reduces the low-density lipoprotein (LDL) synthesis and improves high-density lipoprotein (HDL) levels. Deficiency of niacin leads to enhanced lipid peroxidation and is implicated in Crohn′s disease Deficiency also impacts DNA repair and also leads to skin and gastrointestinal disorder pellagra.
Mechanism of action
Nicotinic acid decreases formation and secretion of
VLDL by the liver.This action
appears secondary to its ability to inhibit fatty acid
mobilization from adipose tissue. Circulating free fatty
acids provide the main source of fatty acids for hepatic triglyceride synthesis, and lowering triglyceride synthesis
lowers VLDL formation and secretion by the liver.
Since plasma VLDL is the source of LDL, lowering
VLDL can ultimately lower LDL. In addition, nicotinic
acid shifts LDL particles to larger (more buoyant) sizes.
The larger LDL particles are thought to be less atherogenic.
Nicotinic acid can also significantly increase
plasma HDL levels; the mechanism is unknown.
Pharmacokinetics
Nicotinic acid is readily absorbed. Peripheral vasodilation is seen within 20 minutes, and peak plasma concentrations occur within 45
minutes. The half-life of the compound is approximately one hour, thus necessitating frequent dosing or an extended-release
formulation. Extended release tablets produce peripheral vasodilation within 1 hour, reach peak plasma concentrations within 4 to 5
hours, and have a duration of 8 to 10 hours.
Dosing of nicotinic acid should be titrated to minimize adverse effects. An initial dose of 50 to 100 mg t.i.d. often is used with immediaterelease tablets. The dose then is gradually increased by 50 to 100 mg every 3 to 14 days, up to a maximum of 6 g/day, as tolerated.
Therapeutic monitoring to assess efficacy and prevent toxicity is essential until a stable and effective dose is reached. Similar dosing
escalations are available for extended-release products, with doses normally starting at 500 mg once daily at bedtime..
Clinical Use
Nicotinic acid has been esterified to prolong itshypolipidemic effect. Pentaerythritol tetranicotinate hasbeen more effective experimentally than niacin in reducingcholesterol levels in rabbits. Sorbitol and myo-inositolhexanicotinate polyesters have been used in the treatment ofpatients with atherosclerosis obliterans.The usual maintenance dose of niacin is 3 to 6 g/daygiven in three divided doses. The drug is usually given atmealtimes to reduce the gastric irritation that often accompanieslarge doses.
Side effects
Compliance with nicotinic acid therapy can be poor
because the drug can produce an intense cutaneous
flush. This can be reduced by beginning the drug in
stepped doses of 250 mg twice daily and increasing the
dose monthly by 500 to 1000 mg per day to a maximum
of 3000 mg per day.Taking nicotinic acid on a full stomach
(end of meal) and taking aspirin before dosage can
reduce the severity of flushing. Time-release forms of
nicotinic acid may also decrease cutaneous flushing.
Nicotinic acid can cause gastrointestinal (GI) distress,liver dysfunction (especially at high doses), decreased
glucose tolerance, hyperglycemia, and hyperuricemia.
Thus, it is contraindicated in patients with hepatic dysfunction,
peptic ulcer, hyperuricemia, or diabetes mellitus.
A paradox associated with nicotinic acid is that it is
the most widely available hypolipidemic drug (it is sold
over the counter), yet its use requires the closest management
by the physician.
Safety Profile
Poison by
intraperitoneal route. Moderately toxic by
ingestion, intravenous, and subcutaneous
routes. Human systemic effects: change in
clotting factors, changes in platelet count.
Questionable carcinogen with experimental
carcinogenic data. When heated to
decomposition it emits toxic fumes of NOx.
Synthesis
Nicotinic acid, pyridine-3-carboxylic acid (20.2.9) is synthesized industrially
by heating a paraldehyde trimer of acetaldehyde, under pressure with ammonia,
which leads to the formation of 2-methyl-5-ethylpyridine, followed by oxidation with
nitric acid which gives the desired product.
Metabolism
Nicotinic acid is a B-complex vitamin that is converted to nicotinamide, NAD+
, and NADP+
.The latter two compounds are coenzymes and
are required for oxidation/reduction reactions in a variety of biochemical pathways. Additionally, nicotinic acid is metabolized to a
number of inactive compounds, including nicotinuric acid and N-methylated derivatives. Normal biochemical regulation and feedback
prevent large doses of nicotinic acid from producing excess quantities of NAD+
and NADP+
.Thus, small doses of nicotinic acid, such as
those used for dietary supplementation, will be primarily excreted as metabolites, whereas large doses, such as those used for the
treatment of hyperlipoproteinemia, will be primarily excreted unchanged by the kidney.
Purification Methods
Crystallise the acid from *benzene, EtOH or H2O. It sublimes without decomposition. [McElvain Org Synth Coll Vol I 385 1941, Beilstein 22 III/IV 439, 22/2 V 57.]
Check Digit Verification of cas no
The CAS Registry Mumber 59-67-6 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 9 respectively; the second part has 2 digits, 6 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 59-67:
(4*5)+(3*9)+(2*6)+(1*7)=66
66 % 10 = 6
So 59-67-6 is a valid CAS Registry Number.
InChI:InChI=1/C6H5NO2/c8-6(9)5-2-1-3-7-4-5/h1-4H,(H,8,9)
59-67-6Relevant articles and documents
Analysis of simultaneous transport and metabolism of ethyl nicotinate in hairless rat skin
Sugibayashi, Kenji,Hayashi, Teruaki,Hatanaka, Tomio,Ogihara, Masahiko,Morimoto, Yasunori
, p. 855 - 860 (1996)
Purpose. Simultaneous skin transport and metabolism of ethyl nicotinate (EN), a model drug, were measured and theoretically analyzed. Methods. Several studies of EN or its metabolite nicotinic acid (NA) were done on full-thickness skin or stripped skin with and without an esterase inhibitor. Permeation parameters such as partion coefficient of EN from the donor solution to the stratum corneum and diffusion coefficients of EN and NA in the stratum corneum and the viable epidermis and dermis were determined by these studies. Enzymatic parameters (Michaelis constant K(m) and maximum metabolism rate V(max)) were obtained from the production rate of NA from different concentrations of EN in the skin homogenate. Obtained permeation data were then analyzed by numerical method based on differential equations showing Fick's second law of diffusion in the stratum corneum and the law with Michaelis-Menten metabolism in the viable epidermis and dermis. Results. Fairly good steady-state fluxes of EN and NA through the skin were obtained after a short lag time for all the concentrations of EN applied. These steady-state fluxes were not proportional to the initital donor concentration of EN: EN and NA curves were concave and convex, respectively, which suggests that metabolic saturation from EN to NA takes place in the viable skin at higher EN application. The steady-state fluxes of EN and NA calculated by the differential equations with resulting permeation and enzymatic parameters were very close to the obtained data. Conclusions. The present method is a useful tool to analyze simultaneous transport and metabolism of many drugs and prodrugs, especially those showing Michaelis-Menten type-metabolic saturation in skin.
Mechanism of the oxygen involvement in nicotinic acid formation under β-picoline oxidation on V-Ti-O catalyst
Chesalov, Yu. A.,Ovchinnikova,Chernobay,Popova, G.Ya.,Andrushkevich
, p. 39 - 43 (2010)
Mechanism of the oxygen involvement in nicotinic acid formation under β-picoline oxidation on vanadia-titania catalyst was studied by in situ FTIR spectroscopy and kinetic method in temperature range of 120-300 °C. The formation of nicotinic acid proceeds via a consecutive transformation of the surface carbonil-like and carboxylate complexes stabilized at reduced vanadium. Catalyst oxygen includes in formation of these complexes. Carboxylate is a direct precursor of nicotinic acid, it turns into nicotinic acid in the presence of the gas-phase oxygen in joint step of catalyst reoxidation-acid desorption. Significant concentration ratio of oxygen to β-picoline (C O2:CβP > 16:1) is necessary to effective running reaction. This factor can be explained by the reaction mechanism. The variety of oxygen functions and of oxygen species require the maximum oxidized state of the catalyst and explain the necessity of a high oxygen excess in the reaction mixture.
-
Rohrlich
, p. 122,126 (1950)
-
-
Rayburn et al.
, p. 115 (1941)
-
Oxidation of heterocyclic aldehydes by quinolinium dichromate: A kinetic study
Chaubey, Girija S.,Das, Simi,Mahanti, Mahendra K.
, p. 497 - 500 (2002)
Quinolinium dichromate in sulfuric acid, in 50% (v/v) acetic acid - water medium, oxidized heterocyclic aldehydes to the corresponding acids. The kinetic results supported a mechanistic pathway proceeding via a rate - determining oxidative decomposition of the chromate ester of the aldehyde hydrate.
-
Leete,Siegfried
, p. 4529 (1957)
-
THERMAL DECOMPOSITION OF AMMONIUM NICOTONATE
Guseinov, E. M.,Sokolovskii, A. A.,Kondrat'eva, N. M.,Zarutskii, V. V.,Oslyakov, G. V.
, p. 749 - 752 (1981)
-
Structural insights into the function of the nicotinate mononucleotide:phenol/p-cresol phosphoribosyltransferase (ArsAB) enzyme from Sporomusa ovata
Newmister, Sean A.,Chan, Chi Ho,Escalante-Semerena, Jorge C.,Rayment, Ivan
, p. 8571 - 8582 (2012)
Cobamides (Cbas) are cobalt (Co) containing tetrapyrrole-derivatives involved in enzyme-catalyzed carbon skeleton rearrangements, methyl-group transfers, and reductive dehalogenation. The biosynthesis of cobamides is complex and is only performed by some
One-Pot Direct Oxidation of Primary Amines to Carboxylic Acids through Tandem ortho-Naphthoquinone-Catalyzed and TBHP-Promoted Oxidation Sequence
Kim, Hun Young,Oh, Kyungsoo,Si, Tengda
supporting information, p. 18150 - 18155 (2021/12/09)
Biomimetic oxidation of primary amines to carboxylic acids has been developed where the copper-containing amine oxidase (CuAO)-like o-NQ-catalyzed aerobic oxidation was combined with the aldehyde dehydrogenase (ALDH)-like TBHP-mediated imine oxidation protocol. Notably, the current tandem oxidation strategy provides a new mechanistic insight into the imine intermediate and the seemingly simple TBHP-mediated oxidation pathways of imines. The developed metal-free amine oxidation protocol allows the use of molecular oxygen and TBHP, safe forms of oxidant that may appeal to the industrial application.
A Mild, General, Metal-Free Method for Desulfurization of Thiols and Disulfides Induced by Visible-Light
Qiu, Wenting,Shi, Shuai,Li, Ruining,Lin, Xianfeng,Rao, Liangming,Sun, Zhankui
supporting information, p. 1255 - 1258 (2021/05/05)
A visible-light-induced metal-free desulfurization method for thiols and disulfides has been explored. This radical desulfurization features mild conditions, robustness, and excellent functionality compatibility. It was successfully applied not only to the desulfurization of small molecules, but also to peptides.