Patent GB-927964-A (GB)
Title: Novel gammagalactonolactones and a process for the manufacture thereof
IPC: C07D309/12
Filed: 1961-09-11
Abstract: The invention comprises 2-(O lower alkyl)-3,5,6-tri (O benzyl)-D-gammagalactonolactones and their preparation by solvolysing, preferably between 25 DEG  and 100 DEG C., a 2-(O loweralkyl)-3,5,6-tri (O benzyl)-D-gluconic acid for a functional derivative thereof), which is esterified in the 4-position with a sulphonic acid moiety, in a water-miscible organic solvent, e.g. acetic acid, acetonitrile, nitromethane, N,N-dimethylformamide and dimethyl sulphoxide, which contains at least one mol of water per mol of said substituted gluconic acid (or functional derivative thereof). (The term "lower-alkyl" used herein represents an alkyl group containing up to four carbon atoms.) The solvolysis may take place in the presence of an alkali metal salt of a lower aliphatic or monocyclic aromatic carboxylic acid. The functional derivative of said gluconic acid may be a substituted or unsubstituted amide, e.g. an N-mono (lower-alkyl)- or N,N-di (lower-alkyl)-amide, or a lower-alkyl ester or nitrile.  These gluconic acid compounds can be prepared from an alkyl 2-(O lower-alkyl)-3,5,6-tri (O benzyl)-D-glucofuranoside which itself may be obtained, as an anomeric mixture, from the 1,2-monoacetone derivative of D-glucose by tribenzylation, hydrolysis at the 1- and 2-positions, and then alkylation.  To obtain said gluconic acid functional derivatives, said alkyl glucofuranoside is subjected to acid-catalysed hydrolysis to form the corresponding D-glucofuranose which is then oxidised to the corresponding D-gammagluconolactone; the latter compound is converted to a corresponding gluconic acid amide or ester by ammonlysis with ammonia or a primary or secondary lower-alkyl amine, or by esterification with a lower alkanol.  The corresponding nitrile is obtained by reaction of the previously mentioned 2-(O lower-alkyl)-3,5,6-tri (O benzyl)-D-glucofuranose with hydroxylamine, and dehydrating the oxime so formed.  The required starting materials are then obtained by esterifying these gluconic acid derivatives in the 4-position with a sulphonic acid or sulphonyl halide, e.g. methanesulphonyl, p-toluenesulphonyl or p-bromobenzenesulphonyl chloride.  The galactonolactones of the invention can be reacted with a 2 mol proportion of a Grignard reagent to form an addition product which on hydrolysis gives a 1,1-di (lower-alkyl)-2-(O lower-alkyl)-3,5,6-tri (O benzyl)-dulcitol.  The free hydroxy groups in the 1- and 4-positions of this product can be etherified by the addition of dihydropyran in the presence of an acid agent to form the 1,4-di (O tetrahydropyranyl)-derivative; alternatively, by use of a molar amount of a lower alkanoic or monocyclic aromatic carboxylic acid (or suitable functional derivative thereof, e.g. benzoyl, p-methoxybenzoyl or p-nitrobenzoyl chloride), an acidic phosphate ester, or a nitrosyl halide, only the hydroxy group in the 4-position will be esterified.  Such a 4-(O acyl) derivative can be reductively debenzylated to yield a 1,1-di (lower-alkyl)-2 (O lower-alkyl)-4-(O acyl)-dulcitol which on oxidation (glycol-splitting reaction) produces a 5,5-di (lower-alkyl)-4-(O lower alkyl)-2 (O acyl)-L-lyxopyranose.  This product can be acetalised with a lower alkyl or monocyclic aralkyl alcohol to form a corresponding lyxopyranoside.  The 2-(O acyl) group of the abovementioned lyxopyranoses and lyxopyranosides can be removed by saponification. In an example, methyl 2(O methyl)-3,5,6-tri (O benzyl)-D-glucofuranoside is hydrolysed with 66% acetic acid to the corresponding D-glucofuranose which on oxidation with urea/bromine or N-bromoacetamide yields 2-(O methyl)-3,5,6-tri (O benzyl)-D-gammagluconolactone; this when treated with methylamine at 0 DEG  gives the corresponding gluconic acid N-methyl amide which on esterification with mesyl chloride yields the 4-(O mesyl) derivative; 2-(O methyl)-3,5,6-tri (O benzyl)-D-gammagalactonolactone is then obtained by heating the mesyl ester with 66% acetic acid; reaction of the galactonolactone with ethereal megnesium/methyl iodide and subsequent treatment with 3N sulphuric acid gives 1,1-dimethyl-2 (O methyl)-3,5,6-tri (O benzyl)-dulcitol which (a) with dihydropyran in the presence of p-toluenesulphonic yields the 1,4-di (O-tetrahydropyranyl)-derivative and (b) with benzoyl chloride in pyridine yields 1,1-dimethyl-2 (O methyl)-3,5,6-tri (O benzyl-4-(O benzoyl)-dulcitol; the latter compound is hydrogenated in the presence of palladium/charcoal and carbon dioxide to give 1,1-dimethyl-2-(O methyl)-4-(O benzoyl)-dulcitol which is oxidised with lead tetraacetate to 5,5-dimethyl-4-(O methyl)-2-(O benzoyl)-L-lyxopyranose which is then converted, by boiling in methanol containing a little acetyl chloride, to methyl 5,5-dimethyl-4-(O methyl)-2-(O benzyl)-L-lyxopyranoside.  The lyxopyranose and lyxopyranoside are debenzoylated by alcoholic sodium hydroxide to yield noviose and methyl novioside respectively.  In part (9) of the example, the preparation of crystalline 5,5-dimethyl-4-(O methyl)-2-[O (p-benzoylamino-benzoyl)]-L-lyxopyranose is described; this is obtained by treating 1,1-dimethyl-2-(O methyl)-3,5,6-tri (O benzyl-dulcitol with p-nitrobenzoyl chloride to produce the 4-(O p-nitrobenzoyl) derivative which is catalytically reduced in the presence of Raney nickel to the 4-(O p-aminobenzoyl)-derivative which is then benzoylated, debenzylated and subjected to glycol-splitting oxidation according to the procedure described above for the corresponding 4-(O benzoyl)-derivative.