Patent GB-915487-A (GB)
Title: A process for the manufacture of vitamins of the b-group and analogues thereof
IPC: C07H23/00
Filed: 1960-12-15
Abstract: Vitamins of the B12 group and analogues which contain the divalent cation of the skeletal general formula:-wherein R is the group:- <FORM:0915487/IV (b)/1> or <FORM:0915487/IV (b)/2> in which R1 is an alkyl, aralkyl or aryl group, R2 and R3 are each an alkyl or aryl group, R4 is an alkyl or aryl or alkoxycarboxyl group, R5 and R6 are each a halogen atom or an alkyl, alkoxy, hydroxy, alkyl-mercapto, or mercapto group and the broken lines denote that the groups attached thereby are optional, and the asterisks denote the point of attachment of the dative bond or covalent line to the main structure, are manufactured by condensing a compound containing a cobyrinic acid a, b, c, d, e.g. hexamide cation of the formula:-  <FORM:0915487/IV (b)/3> referred to as factor V1a, with an amine of the formula R-H, R having the designation as above.  Factor V1a may be isolated from sewage sludge by the method described in Specification 891,916. Amines which may be used as starting materials are 1-[5,6-dimethyl-benzimidazolyl-(1)] - D - alpha - ribofuranosyl-(3 or 2)-DL-2-amino-1-methyl-ethyl hydrogen phosphate, 1-[5,6-dimethyl-benzimidazolyl-(1)]-D-alpha-ribofuranosyl-(3 or 2) D-2-amino-1-methyl-ethyl hydrogen phosphate, 1-[5,6-dimethyl-benzimidazolyl-(1)] - D - alpha - ribofuranosyl-(3 or 2) L-2-amino-1-methyl-ethyl hydrogen phosphate, 1-[5,6-dimethyl-benzimidazolyl-(1)]-D-alpha-ribofuranosyl-(3 or 2) 1-methyl - 1 - methoxycarbonyl - 2 - amino ethyl hydrogen phosphate, 1-[5,6-dimethyl-benzimidazolyl-(1)]-D-alpha-ribofuranosyl-(3 or 2)-2-amino-ethyl hydrogen phosphate, 1-[5-methyl-benzimidazolyl-(1)] - D - alpha - ribofuranosyl-(3 or 2) D-2-amino-1-methyl ethyl hydrogen phosphate, 1-[6-methyl-benzimidazolyl-(1)]-D-alpha-ribofuranosyl (3 or 2) D-2-amino-1-methyl ethyl hydrogen phosphate, 1-[5-methoxy-benzimidazolyl-(1)] - D-alpha - ribofuranosyl (3 or 2) D-2-amino-1-methyl ethyl hydrogen phosphate, 1-[5-hydroxy-benzimidazolyl-(1)]-D-alpha-ribofuranosyl (3 or 2) D-2-amino-1-methyl ethyl hydrogen phosphate, 1-[5,6-dichloro-benzimidazolyl-(1)] D - alpha-ribofuranosyl D-2-amino-1-methyl-ethyl hydrogen phosphate, 1-[5,6-dimethyl-benzimidazolyl-(1)]-D-alpha-ribofuranosyl (3 or 2) - DL-1-phenyl 2-amino-ethyl hydrogen phosphate, 1-[5,6-dimethyl-benzimidazolyl-(1)] D - alpha-ribofuranosyl (3 or 2) DL - 1 - cetyl-2-amino-ethyl hydrogen phosphate.  The amine is advantageously stored as the calcium salt.  Reaction may be p effected in water, acetone, dioxan, tetrahydro-furan, formamide, methanol, ethanol, isopropanol, methylene chloride, chloroform, benzene, toluene, pyridine or butidine.  The process may be carried out at air temperatures or slightly higher in the presence of hydrochloric acid, para toluenesulphonic acid or sodium methylate as catalyst, and acetic acid anhydride, calcium chloride or sodium sulphate to take up the water produced. Isolation and purification of the products may be effected by chromatography or electrophoresis or by fractional pecipitation with the aid of solvent mixtures of water and acetone, and finally by recrystallization.  The amine starting materials may be prepared by reacting a cyclic phosphate of the skeletal general formula:-  <FORM:0915487/IV (b)/4> wherein R5 and R6 have the above significance with the appropriate amine alcohol in which the amino group is protected by conversion into a suitable derivative which is subsequently removed.  In a typical example, 1-[5,6-dimethyl-benzimidazolyl-(1)] - D-alpha - ribofuranosyl - (3) DL - 2 - amino-1-methyl-ethyl hydrogen phosphate can be prepared by converting 1-[5,6-dimethyl-benzimidazolyl-(1)]-D-alpha -ribofuranosyl-(3) dihydrogen phosphate into its cyclic phosphate by treatment with dicyclohexyl-carbodimide the cyclic phosphate then being treated with CL-1-benzyloxycarboxylamino-2-hydroxypropane and the protecting group is removed by hydrolysis or hydrogenolysis.