Amines saccharine

Saccharine can be used to convert an alkyl halide into a primary amine. Saccharine is reacted with the alkyl halide followed by a mild acidic cleavage of the resulting benzenesulfonylcarboxy residue (Abe, 1955 Eckenroth and Koerppen, 1896, 1897). This reaction has been used in cyclizations by first treating the dichloride derivative of a di- or triethylene glycol with the sodium salt of saccharine in DMF in the presence of sodium iodide to form the bis-... 

Although benzenesulphonyl chloride has for simplicity been used in the above discussion, tolucne-/>- sulphonyl chloride, CHaCeH SO Cl, is more frequently used in the laboratory, owing to its much lower cost, the latter being due in turn to the fact that toluene-p-sulphonyl chloride is a by-product in the commercial preparation of saccharin. Toluene-p sulphonyl chloride is a crystalline substance, of m.p. 68° the finely powdered chloride will, however, usually react readily with amines in the Schotten-Baumann reaction it does not react so readily with alcohols, but the reaction may be promoted considerably by first dissolving the chloride in some inert water-soluble solvent such as acetone. 

When saccharin is treated with diethyl phosphorothiolothionate, the 3-ethylmercapto compound is obtained, rather than the expected organophosphorus compound (77 ACS(B)460). Treatment of saccharin with phosphorus pentoxide and amines gives 3-(substituted-amino)-1,2-benzisothiazole 1,1-dioxides, via an intermediate phosphate (81ZN(B)1640). Reduction of saccharin with zinc and hydrochloric acid gives 2,3-dihydro-l,2-benzisothiazole 1,1-dioxide, the method being used to estimate saccharin in foodstuffs (75MI41701). 

Stem nuclei. Morpholine, 5. Hydroxy compounds Scopolamine, 99. Carbonyl compoimds, 135 Saccharin, 169. Carboxylic acids, 313. Sulphonio acids, 355. Amines, 361 Meldola s blue, 383. 

Alitame [L- -aspartyl-/V-(2,2,4,4-tetramethyl-3-thioethanyl)-D-alaninamide] is an amino acid-based sweetener developed by Pfizer from L-aspartic acid, D-alanine, and an amine 2,2,4,4-tetraethylthioethanyl amine (Fig. 1). Its formula is CI4H2504N3S with a molecular weight of 331.06. It is produced under the brand name Aclame . It is a crystalline, odorless, nonhygro-scopic powder that is soluble in water (130 g/L at pH 5.6) and alcohol and significantly more stable than aspartame (Table 1). Alitame is 2000 times as sweet as sucrose and has a clean, sweet taste, with no unpleasant aftertaste. It blends with other sweeteners, such as acesulfame-K, saccharin, and cyclamate, to maximize the quality of sweetness (3,7-9). 

Saccharin in the Gabriel synthesis of primary amines 91ACR285. 

We are going to do a little more than simply give the reactions that eventually made up the synthesis of dofetilide. We are going to put ourselves in the place of the chemists who invented the synthesis and try to see what led them to the reactions they chose. First, we should inspect the structure of the molecule. There are two sulfonamides, one at each end. We have seen how to make sulfonamides earlier in this chapter when saccharin was being discussed. The usual way is to react the amine with a sulfonyl chloride. In this case we shall need to react methane sulfonyl chloride (MeS02Cl or MsCl) with the aromatic amines. This is a well-known reaction and should work well here. The other functional groups—tertiary amine and alkyl aryl ether—should not interfere so no protection is needed. 

A-Halogenoalkyl saccharins (56)103,153,200 are key intermediates for the preparation of symmetrically substituted ethylenediamines, ethanolamines, and homologs120 through direct exchange with an amine (57) or with acetate, in the latter case followed by Abe s procedure. (57) is also obtained from alkylation of 1 with alkyl or dialkylaminoalkyl halides.106,119. 

Practical syntheses of 5a or N-substituted 3-aminobenz[d]isothiazole-1,1 -dioxides are mostly based on the following procedures (iv) Refluxing saccharin with an excess of a monoalkyl or aryl amine above 130°, presumably via ring opening, by analogy with 75.161,189,248... 

True 3-imino-2,3-dihydrobenz[d]isothiazole-l,1-dioxides (82) are capable of existence provided they bear an alkyl or aryl substituent in 2-position as in saccharin anils (23). The free imino compound (82a R = Me, R =H) is obtained from isomerization of o-cyano-V-methyl-phenylsulfonamide in the presence of methylamine,256 or more generally preparation of 82 may start from o-cyanophenylsulfonyl chloride together with an excess of amine.3, 256 A straightforward approach uses cyclization of an o-sulfamylbenzamide monosubstituted at each amide function, like o-(iV-phenylsulfamyl)benzanilide (83)257 with phosphorus pentoxide, phosphorus pentachloride, or preferably phosphorus oxychloride.135,257 Similarly, 2-chlorocarbonylbenzene sulfonyl chloride... 

Kutlu. H Condensation products of saccharin with some amines. V., Istanbul Univ. Eczacilik Eak. Mecm., 5, il, 1975 Chem. Ahstr., 84, 30945, 1976 see also Chem. Ahstr., 79. 53220. 1973. 

Saccharin was discovered in 1879 by Remsen and Fahlberg. It is only slightly soluble in cold water, but is soluble in hot water, acetone, alcohol or ether. From acetone it crystallizes in beautiful crystals. It is a valuable medicinal substance as it can be used for its sweetening effect in food, by persons who have the disease known as diabetes and who are unable to use cane sugar, and only a minimum of any carbohydrate food. It does not possess any nutritive value, however. It is also used as a food preservative, but its use is restricted or prohibited by most pure food laws. It is interesting that only the or//fo-sulph-amine benzoic acid yields such a sulphinid anhydride. The para compound, on heating, yields other products. 

Notice the diversity in structure of lhe.se proton dunurs. They include the classical hydrochloric acid (reaction a). Ihc weakly acidic dihydrogen phosphate anion (reaction b). the ammonium cation as is found in ammonium chloride (reaction c), the carboxylic acetic acid (reaction d). Ihc cnolic form of phenobarbital (reaction e), Ihe carboxylic acid moiety of indomelhacin (reaction j), Ihc imidc of saccharin (reaction g). and the prolonaied amine of ephedrine (reaction h). Because all are proton donors, they mu.st be treated as acids when calculating the pH uf a solution or percent ionization of the drug. At the same lime, as nuted below, there are important differences in the pharmaceutical properties of ephedrine hydrochloride (an acid salt of an amine) and lho.se of indomelhacin. phenobarbital. or saccharin. 

Many initiator-accelerator systems that contain accelerators other than amine have been suggested for vinyl pol3rmerization, but only a few have been employed in dental resins. Substitution of p-toluenesulfinic acid, alpha-substituted sulfones and low concentrations of halide and cupric ions for tertiary amine accelerators, yields colorless products (43-48). Most of these compounds have poor shelf-life. They readily oxidize in air to sulfonic acids which do not activate polymerization. Lauroyl peroxide, in conjunction with a metal mercaptide (such as zinc hexadecyl mercaptide) and a trace of copper, has been used to cure monomer-pol3rmer slurries containing methacrylic acid (49-50). Addition of Na salts of saccharine to monomer containing an N,N-dialkylarylamine speeds up pol)rmerization (51). 

Further examples of the formation of 3-aminopseudosaccharin derivatives (46 R = NHR, NR R") from amines and saccharin have been reported.72... 

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