Saccharin, discovery

In 1969, a chronic toxicity study on a cyclamate saccharin (10 1) blend indicated bladder cancer problems in rats. Cyclamate was soon banned by the FDA, but saccharin remained an approved sweetener. In 1977, the FDA proposed a ban on saccharin because of the discovery of bladder tumors in some male rats fed with high doses of saccharin. Because no other nonnutritive sweetener was available at that time, the proposed ban faced strong opposition. 

Many analogues of saccharin have been synthesized since its discovery. With the exception of one compound, thieno[3,4-i/ isothiazolone dioxide [59337-79-0] lOOOX, this effort has not generated more potent compounds. Acesulfame-K could be considered a ring-modification derivative of saccharin, however. 

Saccharin is the generic name for l,2-benzisothiazolin-3-one-1,1-dioxide and has been used for over 100 years, since its discovery by Fahlberg and Remsen in 1879 and the first production patent granted in 1885. Saccharin is a white crystalline product the sodium salt of saccharin is the commonly used form in the soft drinks industry. Solubility is excellent and stability under food and drink processing conditions is also excellent. 

Because of this difficulty in predicting what features are necessary for a compound to taste sweet, most of the discoveries of artificial sweeteners have been serendipitous. In fact, many of the early discoveries resulted from dangerous laboratory practices that we would not condone today. For example, the sweetness of saccharin was discovered in 1879 by a chemist who spilled some of the compound on his hand. Later, while eating lunch in the laboratory, he noticed the extremely sweet taste. The sweetness of cy-clamate was discovered in 1937 by a chemist who tasted it on a cigarette that he had set on the lab bench. And aspartame was found to be sweet by a chemist who got some on his hand and later licked his Finger before picking up a piece of paper. This resulted in a billion-dollar-per-year product ... 

The history of saccharin (1)B since its discovery by Remsen and Fahlberg in 1879,6> 7 is reflected in a host of names e.g., 2,3-dihydro-3-oxo-benzisosulfonazole 1,2-benzoisothiazolin-3-one-1,1 -dioxide o-sul-fobenzimide o-benzosulfimide benzoic sulfimide benzoic sulfon-imide benzoic sulfinide l-benzosulfonazol-2(l)-one besides clearly... 

Within five years after its discovery in 1879, 7 saccharin (1) became an industrial product as the first non carbohydrate sweetener,5 and it is still holding an important position in the market.29-31 Substantial quantities are used as additives in the electroplating industry.32 Numerous synthetic approaches are known.4,29-31 More recent synthesis of 1 and derivatives substituted in the phenyl ring are based essentially on the following procedures. 

Three structurally isomeric forms have been established for the six-carbon saccharinic acids. In the order of their discovery, these are the sac-charinic or 2-C -methylpentonic acids, the isosaccharinic or 3-deoxy-2-C -(hydroxymethyl)-pentonic acids, and the metasaccharinic or 3-deoxy-hexonic acids. Although none of these six-carbon, deoxyaldonic acids has been crystallized, six are known in the form of crystalline lactones (saccharins). All the possible metasaccharinic acids of less than six-carbon content have been obtained, in the form of crystalline derivatives, by the sugar-alkali reaction. Only one example of a branched-chain deoxyaldonic acid (the racemic, five-carbon isosaccharinic acid) of other than six-carbon content has been so obtained. The formation of saccharinic acids containing more than six carbon atoms remains to be explored. 

Shortly after the discovery of Peligot s a -D-glucosaccharin, Dubrun-faut reported that the calcium salt of a monobasic acid resulted from the action of lime-water on maltose. Cuisinier named the acid isosaccharinic acid, after he had prepared from it a crystalline lactone (CeHioOt) isomeric with Peligot s a -D-glucosaccharin. The name was expanded to a -D-iso-saccharinic acid after Nef obtained evidence of the concurrent formation of its epimer, /3 -D-isosaccharinic acid, in the hexose-alkali reaction. 

The discovery of the A-cumyl directed metalation group (DMG) for amides, 0-carbamates, and sulfonamides helps to broaden the scope of new DoM strategies. Synthetic utility is demonstrated by establishing viable routes to 4- and 4,7-substituted saccharin derivatives (eq 50). Thus, BuLi/TMEDA metalation of selected biaryl A -cumylsulfonamides followed by M(Y-diethylcarbamoyl chloride quench results in a regioselective functionalization (eq51). 

The real-time in situ synchrotron PXRD technique found its next application in the mechanistic study of mechanochemically promoted co-crystallization of carbamazepine and nicotinamide as representatives of active pharmaceutical ingredients (API) [62], In the case of carbamazepine saccharin co-crystal, in situ analysis confirmed previous studies by cryomiUing that neat grinding led to amorphization while LAG synthesis rapidly produced the co-crystal. The other investigated system involved two-step neat grinding synthesis of nicotinamide suberic acid 2 1 co-crystal. The ex situ PXRD analysis had revealed a stepwise mechanism with the 1 1 cocrystal as the intermediate. Whereas LAG synthesis was too fast for ex situ approach, in situ monitoring enabled the discovery of an unknown phase that preceded the rapid formation of the 1 1 intermediate (Fig. 1.28). However, the authors were not successful at full characterization of the new phase due to its pronounced instability. 

Among the food science developments helpful to diabetics have been the discovery and commercial distribution of several synthetic noncarbohydrate sweetening agents. Three that have been approved by the American Diabetes Association are saccharin, acesulfame-K, and aspartame ... 

The first artificial sweetener to be used extensively was saccharine, which is used commonly as its more soluble sodium salt. Saccharine is about 300 times sweeter than sucrose. The discovery of saccharine was hailed as a great benefit for diabetics because it could be used as an alternative to sugar. As a pure substance, the sodium salt of saccharine has a very intense sweet taste, with a somewhat bitter aftertaste. Because it has such an intense taste, it can be used in very small amounts to achieve the desired effect. In some preparations, sorbitol is added to ameliorate the bitter aftertaste. Prolonged studies on laboratory animals have shown that saccharine is a possible carcinogen. In spite of this health risk, the government has permitted saccharine to be used in foods that are primarily intended to be used by diabetics. 

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