3-Acetylpyridine

Identification

Description

A colorless liquid with sweet, nutty, popcorn-like aroma.

Regulatory Status

CoE: Used provisionally. Bev.: 2 ppm; Food: 3 ppm
FDA: n/a
FDA (other): n/a
JECFA: ADI: Acceptable. No safety concern at current levels of intake when used as a flavoring agent (2004).

Usage

Reported uses (ppm): (FEMA, 1994)

Natural occurrence

Reported found in roasted filberts, beer, brandy, coffee, malt and wheaten bread.

Aroma

Powerful, almost choking, Cigar-tobaccotype odor, which becomes pleasant only at extreme dilution, then also more typical tobacco-like. In certain types of flower bases, substitutes for flower absolutes, etc. this chemical can produce interesting and desirable effects, Lily, Jasmin, Tuberose, etc. are types of floral fragrances that may benefit from this effect.

Chemical Properties

A colorless liquid with sweet, nutty, popcorn-like aroma

Occurrence

Reported found in roasted filberts, beer, brandy, coffee, malt and wheaten bread.

Uses

Used in the fragrance industry and as an intermediate in the synthesis of a number of clinical drugs, including Imatinib, Mesylate, Metyrapone, Telithromycin, and Ridogrel. An analog of nicotinamide that competes for incorporation into NAD. It has been used to chemically lesion the inferior olive nucleus, thereby eliminating climbing fibers within the cerebellar cortex.

Uses

3-Acetylpyridine used as an intermediate for the synthesis of risedronate sodium, inhibitor of bone resorption. It is also used in perfumery.

Preparation

Dry distillation of calcium nicotinate with calcium acetate.

Definition

It is a nicotinic acidantagonist.

Production Methods

Produced from Ethyl nicotinate and Ethyl acetoacetate, in principle by hydrolysis of Aceto acetylpyridine.

Safety Profile

Poison by ingestion. Moderately toxic by intraperitoneal routeMutation data reported. A flammable liquid. When heated to decomposition emits toxic fumes of NOx,. See also KETONES

Synthesis

A mixture of 22 g/h of methyl nicotinate, 57 g/h of acetic acid and 20 g/h of water was evaporated in an evaporator and passed, together with 10 l/h of nitrogen, at 400° C., over 100 ml of catalyst, which contained 2% by weight of sodium oxide, the remainder being anatase. The catalyst was prepared by impregnating 980 g of TiO2 carrier I with a solution which contained 20 g of Na2O (as aqueous NaOH). The reaction gases were then cooled and were collected in a receiver. From the discharged two-phase mixture, the organic phase was analyzed by gas chromatography. The selectivity with respect to 3-acetylpyridine was 60%.

Purification Methods

It is purified by dissolving in HCl, extracting with Et2O to remove the possible impurity of nicotinic acid, basified with NaOH and extracted with Et2O. The dried extract is filtered, evaporated and the residual oil is distilled. If the NMR spectrum indicates further impurities, then convert it to the phenylhydrazone (m 137o, yellow needles from EtOH). This is hydrolysed with HCl [Engler & Kiby Chem Ber 22 597 1889], the phenylhydrazine HCl is removed by filtration, NaNO2 is added, the solution is basified with aqueous NaOH and extracted with Et2O as before and distilled at atmospheric pressure to give 3-acetylpyridine as a colourless oil. Purification can also be achieved by shaking with 50% aqueous KOH, extracting with Et2O, drying the extract and distilling it at atmospheric pressure or in vacuo. [Kloetzel & Chubb J Am Chem Soc 79 4226 1957.] The hydrochloride has m 180-181o (from MeOH/EtOH), the picrate has m 133.8-134.8o (from H2O), and the phenylhydrazone has m 137o (129-130o)(needles, from EtOH) [Webb & Webb J Am Chem Soc 71 2285 1949]. The ketoxime has m 112o (from EtOH or *C6H6). [Strong & McElvain J Am Chem Soc 55 816 1933, Kolloff & Hunter J Am Chem Soc 63 490 1941, Beilstein 21/7 V 394.]