Patent GB-496726-A (GB)
Title: Improvements in or relating to the manufacture of pyrimidine thiazolium compounds
Filed: 1937-06-02
Abstract: Vitamin B1 is prepared by condensing 2-methyl - 5 - bromomethyl - 6 - aminopyrimidine hydrobromide with 4-methyl-5-b -hydroxyethylthiazole. The resulting bromide hydrobromide may be converted into the chloride hydrochloride of the vitamin by treatment with silver chloride. Examples are given of both the condensation and the conversion.  The general formula of the products is stated.  The Specification as open to inspection under Sect. 91 also describes the condensation of the thiazole with other esters than the above bromide of 2-methyl-6-aminopyrimethyl alcohol, these esters being obtained by heating 2-methyl-6-aminopyrimethyl methylether or ethylether with the corresponding acid or the pyrimethyl bromide with the appropriate silver salt.  Examples are given of (1) the interaction of the ethylether with alkyl and aryl sulphonic acids such as p-toluenesulphonic acid, benzenesulphonic acid, b -naphthalenesulphonic acid or methylsulphonic acid and condensation of the resulting sulphonic ester with 4-methyl-5-b -hydroxyethyl-thiazole to form the corresponding sulphonate of Vitamin B1; (2) the treatment of 2-methyl-6-aminopyrimethyl bromide with silver acetate, lactate, benzoate, chloride, sulphate, phosphate or nitrate, followed by condensation with 4-methyl-5-b -hydroxyethylthiazole to give the corresponding Vitamin B1 ester; if desired, hydrobromic acid may be added at the intermediate stage to replace the acid molecule attached to the 6-amino group by hydrogen bromide.  Instead of first forming a pyrimethyl ester, a mixture of pyrimethyl alcohol or ether or amine with an acid may be reacted with the thiazole. The Specification also adverts to the formation of products of analogous composition to that of Vitamin B1, but in which the 2-methyl group in the pyrimidine nucleus is replaced by 2-ethyl or propyl and the 4-methyl group of the thiazole nucleus similarly replaced by ethyl and propyl radicles; also of products in which the group in the 6-position is a functional derivative of an amino group, e.g. halogen or hydroxyl, or in which the hydroxy group of the 5-hydroxyethyl residue is replaced by a functional derivative, e.g. amino, halogen or an acid radicle, the products being treated with appropriate reagents to form the 6-amino and 5-hydroxyethyl groups. The Specification further includes the matter described in Specification 496,738, together with the following modifications: (1) the preparation of compounds similar to b -ethoxy-propionic acid ethylester in which the ethyl groups are replaced by aralkyl or other alkyl groups; (2) the condensation of the products with alkyl or aralkyl formates to form the sodio-formyl derivatives, or similar derivatives containing other alkali metals or no metal at all; (3) the interaction of the said derivatives with acetamidine and other amidines such as propamidine and butamidine, if desired in the presence of caustic soda instead of sodium alcoholate; and finally (4) the condensation of the resulting pyrimethyl ethers, via their 6-chloro compounds, into the 2-alkyl or aralkyl-5-alkyl- or aralkyl-oxymethyl-6-aminopyrimidines.  The conversion of the low-melting Vitamin B1 chloride hydrochloride and bromide hydrobromide into the high-melting compounds by crystallizing from isopropyl alcohol or precipitating them with ethyl alcohol from their solutions in methylalcohol is also described.  This subject-matter does not appear in the Specification as accepted.  Reference has been directed by the Comptroller to Specification 471,416.