Processes for producing highly pure nicotinamide

Details Processes for producing highly pure nicotinamide Processes for producing highly pure nicotinamide

1999-07-21

2001-04-17

Davis, Zinna Northington (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S286000

Reexamination Certificate

active

06218543

ABSTRACT:

BACKGROUND
The present invention relates generally to the preparation of nicotinamide. More particularly, the present invention relates to processes for the effective, economic, large-scale production of USP grade nicotinamide from crude nicotinamide employing both cation exchange and weak base resin treatment.
As further background, nicotinamide (also known as niacinamide and 3-pyridine carboxamide) and nicotinic acid (also known as niacin and 3-pyridine carboxylic acid), both commonly referred to as vitamin B
3
, are members of the B-vitamin complex and precursors of coenzymes I and II. As such, these compounds are important supplements to the diet of humans and animals. Pellegra related deaths in the United States caused by vitamin B
3
deficiency dropped from 7,358 in 1929, to 70 in 1956, primarily as a result of increased availability of vitamin B
3
. Higher growth rates occur in animals having diets supplemented with vitamin B
3
and in the case of ruminants, higher milk production also occurs.
In 1985, the U.S. market for niacinamide and niacin was estimated at 6,700 metric tons. See Kirk-Othmer,
Encyclopedia of Chemical Technology,
Third Edition, Vol. 24, pages 59-93 for a general discussion of the B
3
Vitamins.
These compounds have been prepared by hydrolysis of 3-cyanopyridine in batch and continuous processes with catalytic to stoichiometric excesses of a base. A majority of the methods reported have been batch processes. For example, the hydrolysis of 3-cyanopyridine with excess ammonia at 107°-109° C. for 12 hours was reported to give mixtures of nicotinamide and niacin. See J. Am Chem. Soc. 65, at pages 2256-7 (1943). In still another variation, the hydrolysis of 3-cyanopyridine has been reported with a polymeric base, Dowex 1X4 (in the hydroxide form), to yield nicotinamide. See Dutch Patent Application No. 7706612-A; CA:90:186814e. U.S. Pat. No. 4,314,064 describes the continuous hydrolysis of 3-cyanopyridine with 0.3 to 3.0 moles of an alkali metal hydroxide for each 100 moles of cyanopyridine at pressures of between 3 to 20 bars and with heating or cooling to maintain the prescribed reaction temperature. Similarly, 3-cyanopyridine is reported to react in a continuous process with aqueous ammonia at a molar ratio of 1:0.5 and a contact time of 40-50 minutes at 200°-260° C. to give nicotinamide. See Journal of Applied Chemistry of the USSR (English Translation: 45:2716-2718 (1972).
As an alternative to the hydration of cyanopyridines in the presence of bases, bacterial and enzymatic hydrolysis processes have been studied. U.S. Pat. No. 5,395,758, assigned to Sumitomo Chemical Company Ltd., describes the conversion of 3-cyanopyridine to nicotinamide using cultured broths of an Agrobacterium bacteria. Japanese Patent No. 9300770000, assigned to Nitto Chemical Ind. Co. Ltd., describes the hydration of 3-cyanopyridine using the action of Corynebacterium or Nocardia bacteria to selectively yield nicotinamide.
Because nicotinamide is commercially produced in very large scale, the recovery of the nicotinamide product, once formed, is a critical component of the overall process. This is especially true in the production of USP grade nicotinamide for human consumption, where the product must be recovered in highly pure form while nonetheless minimizing cost and technical difficulty in the workup. To date, commercial scale production of nicotinamide has involved its crystallization from crude nicotinamide product mediums. While crystallization has been demonstrated as a classic method for effectively recovering USP grade nicotinamide on a large scale, it does have drawbacks. First, crystallizations are generally time consuming, involve the use of large crystallization vessels, and necessitate a filtration step. In addition, the filtrate from the filtration step often contains significant amounts of unrecovered nicotinamide. This product either has to go to waste, or the filtrate must be recycled to subsequent crystallizations to generate additional isolated product. Such recycle process, when repeated several times, lead to a buildup of impurities in the filtrate, which makes subsequent recycles more and more difficult and eventually impracticable. Thus, a highly impure spent filtrate is eventually generated containing substantial nicotinamide, which must be stored or disposed as waste. These drawbacks are amplified when one considers the scale at which nicotinamide is produced. Nonetheless, alternative, commercially-practicable recovery strategies for USP grade nicotinamide remain to be discovered.
There are a few reports in the literature of attempts to treat certain crude nicotinamide mediums in other ways to recover nicotinamide. For example, British Patent Application 879,551 describes separating nicotinamide from a solution also containing ammonium nicotinate by passage over a column containing Amberlite IRA-400 resin, water wash, and elution with 2% nitric acid. French Patent No. 1335502 describes preparing a tasteless nicotinamide product by dissolving nicotinamide in water, mixing this medium with a non-toxic cation exchange resin to adsorb the nicotinamide onto the resin, and then washing and drying the resin. U.S. Pat. No. 3,143,465 describes the preparation of a similar style product by adsorbing nicotinamide and potentially other products onto polystyrene resins containing P(O)OH groups.
Japanese Kokai 72 18875 describes the purification of nicotinamide containing sodium or potassium nicotinate by passage through a strongly basic ion exchange resin such as Amberlite IRA 410 or IRC 50. Japanese Kokai 72 31983 describes heating 3-cyanopyridine with sodium or potassium hydroxide and water to prepare nicotinamide, diluting the resulting mixture with water to bring the nicotinamide concentration to less than 25%, and then passing the solution over a column of a strongly basic ion exchange resin. Ratajczak et al.,
Przem. Chem.
1981, 60(6), 335-7, report the use of a sulfonic acid cation exchanger, Wofatit KS-10, for the purification of the mother liquors resulting from the crystallization of nicotinamide. U.S. Pat. Nos. 4,447,614 and 4,447,615 describe a nicotinamide recovery process which involves adjusting the pH of a crude nicotinamide reaction mixture by adding acid or alkali and crystallizing the nicotinamide from 2-methylpropanol-1. The mother liquor from this crystallization is recycled and is treated from time to time either by distillation or by a sulfonated styrene-divinylbenzene copolymer and/or a strongly basic styrene-divinylbenzene copolymer quaternary ammonium resin. Atsuaki et al.,
Kogyo Kagaku Zasshi
60, 875-9 (1957), describe the treatment of a crude 30% nicotinamide solution with activated carbon for three hours, dilution with water to a final concentration of 10%, and passage through a double-bed column containing Amberlite IRA-410 and Amberlite IRC-50 at a rate of 1.8 cc/min. at 15° C.
In light of the above background there remain needs in the field of commercial nicotinamide production for efficient and economic processes for recovering highly pure forms of nicotinamide such as USP grade nicotinamide. The resent invention addresses these needs.
SUMMARY OF THE INVENTION
A feature of the present invention is the discovery of improved processes for producing nicotinamide which avoid relatively expensive recovery steps practiced in prior processes, and/or which enable maximal recovery of the produced nicotinamide and also of other useful substances such as nicotinic acid produced as byproducts. Accordingly, one preferred embodiment of the present invention provides a commercial process for producing nicotinamide which includes first reacting 3-cyanopyridine in an aqueous basic medium at a 3-cyanopyridine concentration of about 20 to about 85 weight percent to form a reacted medium containing about 20 to about 85 weight percent nicotinamide and a nicotinic acid salt. The reacted medium is treated with a cation exchange resin to remove cations and thereby convert the nicotinic acid salt to nicotinic acid, resulting in a cation-depleted aque

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