Preparation nicotinic acid

Pyridine carboxamide [98-92-0] (nicotinamide) (1) and 3-pyridine carboxylic acid [59-67-6] (nicotinic acid) (2) have a rich history and their early significance stems not from their importance as a vitamin but rather as products derived from the oxidation of nicotine. In 1867, Huber prepared nicotinic acid from the potassium dichromate oxidation of nicotine. Many years later, Engler prepared nicotinamide. Workers at the turn of the twentieth century isolated nicotinic acid from several natural sources. In 1894, Su2uki isolated nicotinic acid from rice bran, and in 1912 Funk isolated the same substance from yeast (1). 

Both nicotinic acid and nicotinamide have been used in the enrichment of bread, flour, and other grain-derived products. Animal feed is routinely supplemented with nicotinic acid and nicotinamide. Nicotinamide is also used in multivitamin preparations. Nicotinic acid is rarely used in this appHcation. The amide and carboxyHc acid have been used as a hrightener in electroplating baths and as stabili2er for pigmentation in cured meats. 

A new route to prepare nicotinic acid starts from 2-methylglutaronitrile, a major side-product in the adiponitrile process and, as such, a readily available starting-material. It is easily hydrogenated to 2-methylpentanediamine, which is then condensed to methyl piperidine and dehydrogenated to 3-picoline. The gas-phase ammoxidation of the latter to cyanopyridine is followed by hydrolysis to either nicotinamide or nicotinic acid (Scheme 20.4). The cyanopyridine route for the production of nicotinic acid has the advantage of a significantly better selectivity with respect to the direct oxidation route from 3-picoline owing to the easy decar-... 

The classic method of preparing nicotinic acid was by oxidizing nicotine with potassium dichromate (Scheme 15.1). This was discovered over 100 years ago. 

The actual location of the —COOH group at carbon 3 was established by Skraup and CobenzD by physical and chemical criteria. Through a series of steps 3 phenylpyridine is prepared from j >-naphthylamine and glycerine, and upon oxidation it yields nicotinic acid. Skraup and Vortmanni, also prepared nicotinic acid from synthetic dipyridyl of known w-structure. The three position isomers have very different melting points picolinic acid (0-, or 1,2) around 136° nicotinic acid m- or 1,3-) around 236° and isonicotinic acidi p- or 1,4-) iiround 319°. 

By halogen-metal interconversion, Murray et al. prepared nicotinic acid labeled with i C (82% yield) or (62% yield) on the carboxyhc radical. Using M-butyl lithium and 3-bromopyridine, 3-pyridyl hthium was prepared and carbonation of this compound was carried out with i C02 or COa generated from the respective labeled barium carbonates with acid. 

In pharmaceutical preparations, nicotinic acid can be separated from nicotinamide by TLC on silica gel, aluminum oxide, and ion-exchange resins detection of the spots can be made by examination of the plates under UV light or by specific detection reagents. For a table listing the values of water-soluble vitamins, consult Hengen and deVries (1985). Nicotinic acid can be separated from nicotinamide and other water-soluble vitamins by TLC on silica gel using the mobile phase acetic acid-acetone-methanol-benzene (5 5 20 70). Expected Rp values of water-soluble vitamins in this system are as follows B2, 0.3 nicotinic acid, 0.75 nicotinamide, 0.55 65, 0.13 C, 0.27 (Hengen and deVries. 1985). 

Nitric acid is a useful, cheaper oxidizing agent for the preparation of pyridine-carboxylic acids but has to be used at high temperatures and pressures284, It has been employed to oxidize a number of alkylpyridines 2786, 284 especially for preparing nicotinic acid. It also provides a useful way to isonicotinic acid28S. 

Nicotinic acid is prepared in good tdeld by the oxidation of p picollne with potassium permanganate ... 

P-Picoline may serve as an important source of nicotinic acid [59-67-6] for dietary supplements. A variety of substituted pyridines may be prepared from acrolein (75—83). 

Trifluoromethylpyridine can be prepared ia 25—65% yield from nicotinic acid and sulfur tetrafluoride (434,439). An alternative method is the passage of chlorine iato a mixture of ( -picoline and hydrogen fluoride ia an autoclave (190°C, 3 MPa) (440). 4-Trifluoromethylpyridine is prepared ia 57% yield from isonicotinic acid and sulfur tetrafluoride. 

Oxidation. The synthesis of quinolinic acid and its subsequent decarboxylation to nicotinic acid [59-67-6] (7) has been accompHshed direcdy in 79% yield using a nitric—sulfuric acid mixture above 220°C (25). A wide variety of oxidants have been used in the preparation of quinoline N-oxide. This substrate has proved to be useful in the preparation of 2-chloroquinoline [612-62-4] and 4-chloroquinoline [611 -35-8] using sulfuryl chloride (26). The oxidized nitrogen is readily reduced with DMSO (27) (see Amine oxides). 

Key intermediates in the industrial preparation of both nicotinamide and nicotinic acid are alkyl pyridines (Fig. 1). 2-Meth5l-5-ethylpyridine (6) is prepared in ahquid-phase process from acetaldehyde. Also, a synthesis starting from ethylene has been reported. Alternatively, 3-methylpyridine (7) can be used as starting material for the synthesis of nicotinamide and nicotinic acid and it is derived industrially from acetaldehyde, formaldehyde (qv), and ammonia. Pyridine is the principal product from this route and 3-methylpyridine is obtained as a by-product. Despite this and largely due to the large amount of pyridine produced by this technology, the majority of the 3-methylpyridine feedstock is prepared in this fashion. 

From a bioavailabihty standpoint, the fact that a significant amount of nicotinic acid is in a bound form has important biological consequences. Poor bioavailabihty stems from the fact that the ester linkage is resistance to digestive enzymes. In the case of com, this condition can be alleviated if com is pretreated with alkah. This food preparation method is frequently practiced in Mexico for the preparation of tortillas. 

Hantzsch prepared this betaine by treating nicotinic acid methiodide with silver hydroxide and. lahns subsequently identified trigonelline with Hantzsch s synthetic base. 

Preparation of the first of these antiinflammatory prodrugs starts with the displacement of halogen on bromophthal ide 2 by the anion of the nicotinic acid derivative 1. Reaction of the intermediate 3 with aniline 4 leads to formation of talniflumate (5). ... 

Aluminum nicotinate is prepared by dissolving nicotinic acid in hot water and adding a slurry of aluminum hydroxide to it. A slight excess of aluminum hydroxide is used in order that the final product would be free of nicotinic acid. The precipitate is collected on a filter and dried. The final product contains a mixture of aluminum nicotinate and a small but acceptable amount of aluminum hydroxide. 

To a solution of 93.8 g of the monoglycol ester in 500 ml of benzene, there are added 55 g of nicotinic acid chloride and 25 g of trimethylemine dissolved in 200 ml of benzene. The solution is stirred gently at a temperature of 60°C for two hours. After this time, the solution is cooled and washed successively with water, dilute hydrochloric acid, dilute ammonia and water until neutrality, it is dried over anhydrous sodium sulfate, and the sol vent Is evaporated under vacuum In this wey llOg of glycol 2-(p-chlorophenoxy)-2-methylpropionate nico-tlnate Is prepared, which represents a yield of 84%. The product is a sllghly yellow oil having a refraction index of no = 1.5422 and which is distilled with decomposition et 214°C at a pressure of 0.3 mm. 

Niflumic acid is prepared as follows Nicotinic acid, m-trifluoromethylaniline, and potassium iodide are intimately mixed and heated on an oil bath at 140°C. The mixture melts... 

Nicotinic acid, HC6H402N (JCa = 1.4 X 1CT5) is another name for niacin, an important member of the vitamin B group. Determine [H+] in a solution prepared by dissolving 3.0 g of nicotinic acid (MM = 123.11 g/mol), HNic, in enough water to form 245 mL of solution. 

Chapter 10 is devoted to the preparation and purification of hydrophilic vitamins (C, Bj, Bj, Bg, B[2, nicotinic acid and nicotinamide, pantothenic acid, biotin, and folic acid) in pharmaceutical preparations, food products, and biological samples. 

A TLC method was developed for the estimation of nieotinie aeid and nicotinamide (Fignre 10.7) in phatmacentical preparations containing other vitamins, enzymes, herbs, and drugs, etc. [16]. The percentage recoveries for nicotinic acid and nicotinamide were 100.1 + 1.9 and 100.2 1.5, respectively, with this system. Each alcohol extract of samples or standard was pnt on sihca gel TLC plates, which were developed with distilled water. Each silica gel spot visualized under UV lamp was collected and extracted with 0.1 mol/1 HCl. The optical density of each clear extract was measured at 262 run. 

The method described is essentially that of La Forge.2 Nicotinonitrile has also been prepared from nicotinic acid by heating with ammonium acetate and acetic acid,3 from 3-pyridinesulfonic acid by fusion of the sodium salt with sodium cyanide,4 and from 3-bromopyridine and cuprous cyanide.6... 

Early investigators assumed that human erythrocytes could convert nicotinic acid, but not the amide, into NAD (H3, H8). There are later reports to the contrary, i.e., that nicotinamide, but not the acid, produced increased synthesis of NAD-active material (L3). To resolve these discrepancies, standards for assaying nicotinic acid activity were prepared by mixing equal weights of the acid and amide, because these... 

The reagent is prepared in 85% yield in a reaction of nicotinic acid with 2 equiv. of CrO, in water. 

In view of the biological importance of nicotinic acid, it was decided to prepare a quaternary salt from the acid or ester and bromofluoroethane. S Carbethoxy- N-2-fluoroethylpyridinium bromide (XIX) was therefore prepared and examined. The l.d. 50 for subcutaneous injection into mice was 200 mg. /kg., i.e. it was relatively non-toxic compared with methyl fluoroacetate. 

An examination of some of the factors influencing the chemical and enzymatic hydrolysis of nicotinic acid esters was undertaken [45-48]. Twenty-five esters of nicotinic acid were prepared whose pro-moiety was a simple alkyl (unbranched, sec-, or /er/-alkyl), a chloroalkyl, a hydroxyalkyl, an alkoxyalkyl, a carbamoylmethyl, an aminoalkyl, a cycloalkyl, an arylalkyl, or an aryl group (Table 8.5). 

Prepare a solution of 5 m 3-cyanopyridine (320 mL) to be used as substrate for nicotinic acid preparation in 0.1 m potassium phosphate buffer pH 8.0. 

Stock solution 4. 100 x stock solution of vitamins was prepared by dissolving biotin (20 mg), folic acid (20 mg), pyrodoxine hydrochloride (100 mg), riboflavin (50 mg), thiamine hydrochloride (50 mg), nicotinic acid (50 mg), pantothenic acid (50 mg), vitamin B12 (1 mg), 4-aminobenzoic acid (50 mg) and thioctic acid (50 mg) in deionized water. The volume was adjusted to 1.0 L. The solution was filtered, sterilized and stored as 10 mL aliquots at —20 °C. 

The first biochemical analysis of a selenium-containing XDH was reported in 1999 by Andreesen s group. This preparation was specific for xanthine and did not hydroxylate nicotinic acid. Moreover, the enzyme contained FAD, acid-labile sulfur, iron, and a dinucleotide molybdenum cofactor. Most intriguing was the near-equimolar presence of tungsten and molybdenum. It should be noted that the culture medium contained nearly equimolar levels of these metals, making one wonder whether the specificity of this enzyme for metal may be relaxed (i.e., can use Mo or W). Selenium was also found in the preparation and could be released by treatment with cyanide indicating it was also a labile cofactor. This further confirmed the chemical nature of the cofactor from the NAH enzyme from the same strain. ... 

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