Patent GB-659087-A (GB)
Title: A process for the production of thiophane derivatives
Filed: 1948-07-20
Abstract: Homo-biotin, bis-homo-biotin, tris-homo-biotin, and tetrio-homo-biotin, are produced by reacting a thiolactone of the formula <FORM:0659087/IV (b)/1> wherein R and R1 represent hydrogen or an aralkyl, substituted aralkyl or an acyl radical and at most one of R and R1 is hydrogen, with an w-alkoxy-alkyl magnesium halide in which the alkyl radical contains from 5 to 7 carbon atoms, the substituted 3,4-(21-keto-imidazolido)-2-hydroxy-2-(w-alkoxy-alkyl) -thiophane formed is dehydrated, the substituted 3,4-(21-ketoimidazolido) - 2 - (w - alkoxy - alkylidene) - thiophane obtained is catalytically hydrogenated, the substituted 3,4-(21-keto-imidazolido)-2-(w-alkoxy-alkyl)-thiophane obtained is if desired converted into the N-monosubstituted compound, acyl substituents being removed by hydrolysis and aralkyl substituents by means of an alkali metal in liquid ammonia, the reaction product is reacted with a hydrogen halide to form the substituted 3,4-(21-ketoimidazolido) - 2 - (w - halogeno - alkyl) - thiophane, the latter compound is reacted with a salt of a malonic acid ester or a metal cyanide, 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 remaining in the compound is or are replaced by hydrogen, in the case of acyl substituents by means of hydrolysis and in the case of an aralkyl substituent by means of an alkali metal in liquid ammonia. Homo-biotin is also prepared by a similar series of reactions in which the thiolactone of the above general formula is reacted with an w-alkoxy-butyl magnesium halide in which the alkoxy group contains at least two carbon atoms, and, at the appropriate stage (N - benzyl - 21 - keto - imidazolido) - 2 - (w-halogeno-butyl)-thiophane is reacted with a salt of a malonic acid ester.  The thiolactone starting material may be produced by the process of Specification 628,902.  In examples: (1) 4 - ethoxy - butyl 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 - (w - ethoxy - butyl) - thiophane obtained is dehydrated and the resulting 3,4-(11,31-dibenzyl - 21 - keto - imidazolido) - 2 - (w - ethoxybutylidene thiophane is hydrogenated, e.g. using a Raney nickel or palladium catalyst.  One benzyl substituent is removed by treatment with sodium in liquid ammonia and the product reacted with hydrogen bromide in aretic acid to give 3,4-(N-monobenzyl-21-ketoimidazolido) - 2 - (w - bromo - butyl) - thiophane, which is reacted with sodio-malonic ester and saponified.  The 3,4-(N-monobenzyl-21 - keto - imidazolido) - 2 - (w,w - dicarboxypentyl)-thiophane obtained is dicarboxylated and the benzyl group removed with sodium in liquid ammonia to give D.L-homo-biotin; (2) bis-homo-biotin is prepared in a similar manner to (1), using however 6-ethoxy-hexyl magnesium bromide as starting material and potassium cyanide in place of sodio-malonic ester; (3) trio-homo-biotin is prepared by a similar process to (2), but with sodio-diethyl malonate in place of potassium cyanide.  The N-monobenzyl-homo-biotin and D,L-monobenzyl-trio-homo-biotin obtained respectively in the course of examples 2 and 3 may be oxidized with potassium permanganate and debenzylated to yield bis- and trio-homo-biotin sulphones respectively.  The 6-ethoxy-hexyl bromide employed in example 2 is prepared by reacting ethyl bromide with 1,6-hexane diol and sodium. 6-Ethoxy-hexanol-1 is distilled out of the resulting mixture with 1,6-die-hoxy-ethane, and is reacted with phosphorus tribromide.  The Specification as open to inspection under Sect. 91 comprises also the preparation of norbiotin by a similar series of reactions to the above, using 3-ethoxy-propyl magnesium bromide as starting material.  It also refers to the oxidation with the preparation of homo-biotin sulphone by the oxidation of monobenzyl homo-biotin with potassium permanganate followed by debenzylation.  This subject-matter does not appear in the Specification as accepted.