Patent GB-656273-A (GB)
Title: A process for the production of thiophane derivatives
Filed: 1948-07-20
Abstract: In a process for the production of optically-active or racemic biotin or nor-biotin, a thiolactone of the general formula <FORM:0656273/IV (b)/1> wherein R and R1 each represent hydrogen or an aralkyl, substituted aralkyl, or an acyl radical, and at most one of R and R1 is hydrogen, is reacted with a 3-alkoxy-propyl magnesium halide, the 3,4-(21-keto-imidazolido)-2-hydroxy-2-(o -alkoxy-propyl) -thiophane obtained is dehydrated, the substituted 3,4-(21-keto-imidazolido) - 2 - (o  - alkoxy - propylidene) - thiophane obtained is catalytically hydrogenated, the substituted 3,4 - (21 - keto - imidazolido) - 2 - (o  - alkoxy-propyl)-thiophane is converted by means of a hydrogen halide into the substituted 3,4 - (21 - keto - imidazolido) - 1,2 - trimethylene-thiophanium halide of the general formula <FORM:0656273/IV (b)/2> the latter, if desired, after having been reacted with a salt of D-camphor sulphonic acid to produce the corresponding substituted 3,4-(21-keto - imidazolido) - 1,2 - trimethylene - thiophanium D-camphor sulphonate, which may in turn be separated into its optical isomers, is reacted with a metal salt or a salt of a malonic acid ester, the reaction product is saponified and, if the reaction leading to it involved a salt of a malonic acid ester, decarboxylated, and the N-substituent or substituents in the compound obtained is or are replaced by hydrogen, in the case of an acyl substituent by means of hydrolysis and in the case of an aralkyl substituent by means of an alkali metal in liquid ammonia.  The thiolactone may be obtained by the process of Specification 628,902. In examples: (1) 3-ethoxypropyl magnesium bromide is reacted with 3,4-(11.31-dibenzyl-21-keto-imidazolido)-2-keto - thiophane.  The 3.4 - (11,31 - dibenzyl - 21 - keto - imidazolido) - 2 - hydroxy - 2 - (o - ethoxypropyl) - thiophane produced is dehydrated by boiling in acetic acid, catalytically hydrogenated, and reacted with hydrogen bromide in acetic acid.  The 3,4-(11.31-dibenzyl-21 - keto - imidazolido) - 1,2 - trimethylene thiophanium bromide obtained is converted to the D-camphorsulphonate and resolved by fractional crystallization into its optical isomers.  The laevo-rotatory isomer is reacted with sodium in diethyl malonate, and the D( - )-3,4-(11.31 - dibenzyl - 21 - keto - imidazolido) - 2 - (o ,o  - dicarboxy - butyl) - thiophane obtained is decarboxylated by heating in xylene, to give D( - )-dibenzyl biotin which by reaction with sodium in ethylene glycol diethyl ether and liquid ammonia is converted to D(+)-monobenzyl biotin.  Further treatment with sodium in liquid ammonia gives D-biotin.  (2) L-biotin is obtained by the same series of reactions as in (1), but employing for reaction with the sodiodiethyl malonate the mother liquors after the separation of the laevo-rotatory D-camphor-sulphonate crystals used in (1); (3) DL-biotin is obtained by a process as in (1), omitting the formation and resolution of the D-camphor-sulphonates; (4) DL-nor-biotin is formed by the same series of reactions as in (3), using sodium cyanide in place of sodio-diethyl-malonate, and omitting the de-carboxylation; (5) one benzyl group is removed from 3,4-(11,31-di-benzyl - 21 - keto - imidazolido) - 2 - (o  - ethoxy-propyl thiophane (prepared as in (1)) by treatment with sodium in liquid ammonia.  The mono-benzyl compound is formed into its chloride by reaction with HCl in formic acid and this is formed into the D-camphor sulphonate.  By reaction with sodio-diethyl malonate followed by saponification and de-carboxylation, DL - monobenzyl - biotin is obtained which can be converted to DL-biotin as in (1).