Patent GB-637923-A (GB)
Title: Manufacture of thiophene derivatives
Filed: 1946-12-10
Abstract: Thiophene derivatives are manufactured by hydrogenating reducible bonds or groupings in thiophene, in substituted thiophenes, and in substituted tetrahydrothiophene compounds containing at least one reducible non-aromatic substituent, without affecting the sulphur linkages, by treating such compounds with hydrogen in the presence of a metal of the platinum group, especially palladium (but excluding the process of Specification 606,194).  The hydrogenation is preferably carried out at a moderately low hydrogen pressure, and with the catalyst distributed on a carrier (e.g. charcoal, diatomaceous silica or barium sulphate) suspended in a reaction medium (e.g. a hydroxylated solvent such as water, methanol or ethanol).  The process is applicable to the hydrogenolysis of nuclear halogen atoms (normally accompanied in the case of halogenated thiophenes by reduction to the tetrahydro derivatives, except when the product also contains amino substituents), and to the reduction of ketone or aldehyde groups and nitrogen derivatives thereof such as oximes, arylhydrazones and semicarbazones, of nitro groups and intermediate reduction products thereof such as nitroso, azo and azoxy groups (nitrothiophenes yielding aminothiophenes without hydrogenation of the nucleus), and of unsaturated carbon-carbon linkages (i.e. side-chain olefinic or acetylenic bonds or nuclear double bonds), and especially to the reduction of compounds of the general formul  <FORM:0637923/IV (b)/1> (wherein R and R1 represent alkyl, aryl or aralkyl groups and Z represents a ketonic oxygen atom or an oximino, arylhydrazino or semicarbazido group) to compounds of the general formula <FORM:0637923/IV (b)/2> (wherein A represents a hydroxy or amino group).  The compounds in which A is NH2 (into which those in which A is OH may be converted by treating them with a thionyl or phosphorus halide and reacting the resulting halo compound with ammonia) may be hydrolysed to 2-(41-carboxybutyl)-3 : 4-diaminotetrahydrothiophene, which is an intermediate in the synthesis of biotin.  Examples describe the reduction of: (1) thiophene to tetrahydrothiophene; (2) 2-(41-carboxybutyl)-thiophene in the presence of methanol and sulphuric acid 2-(41-carbomethoxybutyl)-tetrahydrothiophene; (3) 2 : 5 - dibromo - 3 : 4 - dinitrothiophene to 3 : 4 - diaminothiophene (which may be identified by acetylation with acetic anhydride, benzoylation with benzoyl chloride or conversion into 3 : 4-ureidothiophene by the action of phosgene); (4) 2-bromothiophene to tetrahydrothiophene; (5) 2 - (41 - carbomethoxybutylidene) - 3 - oximino - 4 - benzamidotetrahydrothiophene to 2 - (41 - carbomethoxybutyl - 3 - amino - 4 - benzamidotetrahydrothiophene (which may be hydrolysed and treated with phosgene to form biotin, or may be acetylated to give a mixture of isomers from which dl - cis - 2 - (41 - carbomethoxybutyl) - 3 - acetamido - 4 - benzamidotetrahydrothiophene may be isolated); (6) and (7) 2-(41-carbomethoxybutylidene) - 3 - keto - 4 - benzamidotetrahydrothiophene to 2-(41-carbomethoxybutyl)-3 - keto - 4 - benzamidotetrahydrothiophene or (with excess hydrogen) the corresponding 3-hydroxy compound (which may be separated into its stereoisomers by fractional crystallization).  Lists of additional starting materials are given.  The Specification as open to inspection under Sect. 91 comprises also the hydrogenation of reducible bonds or groupings in other organic compounds containing divalent sulphur, including the starting materials of Specification 606,194, and also compounds in which the sulphur atom is not part of a ring, e.g. substituted dialkyl sulphides, such as p-nitrobenzoyl methionine, and substituted diaryl sulphides, such as 2-nitro- and 2 : 21-dinitro-diphenyl sulphide.  This subject-matter does not appear in the Specification as accepted.