Alkylation saccharin

Alcohol B.P. M.P. 3 S-Dlnltro benzoate benzoate Phenyl urethane a-Naphthyl- urethane Hydrogen i-nltro- phthalate O-Alkyl saccharin Other Derivatives... 

N-Acyl saccharins (13) in part resemble iV-alkyl saccharins in their reactions. From the hydrolysis of 3-oxo-2-acetyl-6-chloro-2,3-dihydro-benz[d]isothiazole-1,1-dioxide (64) with a base/alcohol mixture one obtains iV-acetyl-4-chloro-2-sulfamoylbenzoic acid (65). On heating with base the acetyl group is hydrolyzed off.180... 

Alkylation of an imide eliminates sweet taste N-alkyl saccharins are tasteless... 

Pseudo-saccharin ethers. Pseudo-saccharin chloride (Section VII,26) reacts with alcohols to give ethers (0 alkyl derivatives of saccharin) ... 

Moncrief summarized the work of Cohn and the information in the early literature. As early as 1923, it was known that rupture of the heterocyclic ring, as well as substitution of the imino hydrogen atom, results in the loss of sweetness. Thus, o-carboxybenzenesulfonamide and N-alkyl derivatives of saccharin are tasteless. This loss of sweetness would be expected, as the NH group is the only proton-donor function available in the molecule. 

Bode and co-workers have used NHCs to form y-butyrolactams 34 from enals 27 and saccharin-derived cyclic sulfonylimines 32. A range of [3-alkyl and [3-aryl substituted enals, and a variety of substituted imines, are tolerated in this reaction,... 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

Rapid N-alkylation of saccharin (Eq. 24) by a series of halides was performed on silica gel via its sodium salt in a microwave oven. TEBA was shown to have a useful co-catalytic effect (Tab. 5.11). 

Tab. 5.11 N-Alkylation of saccharin with bromides under MW + PTC conditions (750 W).

In a similar manner, saccharin has been A-alkylated and A-acylated (Table 5.17) [31, 32], There is good evidence that the kinetic O-alkylated product is initially formed and it is converted into the thermodynamically more stable A-alkyl derivative upon prolonged heating [31, 32], The reaction fails with secondary haloalkanes and is most successful with primary bromoalkanes [31, 32]. 

Indeed, the choice of a nitrogen compound to be used as carrier in such O-alkyl prodrugs is not restricted to benzamides. Other amides were examined, e.g., phthalimide, succinimide, and saccharin. Thus, the saccharin prodrug of estradiol (11.50, R = 17/J-estradiol) underwent rapid nonenzymatic hydrolysis in rat and human plasma [85]. Administration of the prodrug to rats led to an impressive fivefold increase in the oral bioavailability of estradiol, and it was approximately nine times more potent orally, based on the 50% effective dose. 

The standard means for preparing oxicams 285, initially developed by Lombardino, is through the base-promoted rearrangement reaction of isothiazole dioxides 286, which in turn are prepared from saccharin derivatives such as 287 (Scheme 40) <1981AHC(28)73>. The oxicam core can be further derivatized by N-alkylation of oxicam 285 and amidation of the C-3 ester functionality of 288 to form the common drug scaffold 289. 

The use of chiral A-acylated sultams 1 as auxiliaries for diastereoselective alkylation and related reactions has emerged as a useful and versatile method for the construction of chiral compounds. Both enantiomers of 10.10-dimethyl-4-a2a-3-thiatricyclo[S.2.1,0 -5]decane 3,3-dioxide (bomane-10,2-sultam) have been employed1-6 and are now commercially available. A chiral sultam prepared from saccharin has also been used for a variety of asymmetric transformations8,9. 

R = Bul e = H from Saccharin Scheme 7. Some electrophilic substitution reactions of alkyl fulleride anions. 

Side-chain oxidations of alkyl aromatic compounds to aromatic carboxylic acids by electrogenerated and regenerated chromic acid have been studied extensively in the case of saccharin formation from o-toluene sulfonamide This... 

An improved procedure using 2-methoxyethyl 2-chloroacetate in place of methyl 2-chloroacetate for the alkylation of sodium saccharin has been described. The resulting 2-methoxyethyl saccharin-2-acetate is treated with sodium 2-methoxyethoxide in dimethyl sulfoxide, then acidified to give 2-methoxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, which is N-alkylated with methyl iodide in acetone-aqueous sodium hydroxide. The resulting 2-methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide is heated with 2-aminopyridine in xylene to give piroxicam. 

Nitro- benzoate °C Phenyl- urethan °C 1- Hydrogen Naphthyl- 3-nitro-urethan phthalate °C °C O-Alkyl Other saccharin derivatives °C °C ... 

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