Patent GB-441692-A (GB)
Title: Process for the manufacture of isoalloxazine compounds
IPC: A61K31/525
Filed: 1934-07-20
Abstract: Isoalloxazine compounds of the general formula <FORM:0441692/IV/1> wherein B stands for an aromatic ring system and R for a substituent such as alkyl, cycloalkyl, or aryl, are prepared by condensing N-monosubstituted aromatic o-diamines with alloxan or its monosubstitution products or its derivatives.  Condensation is effected in acid solution or by using the o-diamines in the form of their salts and/or by heating in a higher boiling solvent. Alternatively, instead of the N-monosubstituted aromatic o-diamines there may be used the N-monosubstituted aromatic o-nitroamines, a reducing agent being present (tin, stannous chloride, iron and trivalent titanium compounds), and the leuco compound formed being further treated with a dehydrogenating agent (oxygen, potassium permanganate, halogens and quinoid dyestuffs).  Suitable derivatives of alloxan are hydroxypyrimidones and their condensation products, dialuric acid, isodialuric acid and alloxantin being specified; these may be used in either of the foregoing processes.  The latter may often be advantageously performed in presence of boric acid and of a non-aqueous solvent such as glacial acetic acid.  The utility of boric acid is presumed to be connected with the formation of complex compounds, in the case of those diamines containing an oxyalkyl substituent the formation of intermediate ester-like compounds being probable.  When these latter substances are involved as starting materials in the above processes they can also advantageously be employed in the form of their esters with mineral acids and any ester-like groups subsequently saponified. The products are a class of which vitamin B2 is a member, and while primarily of pharmacological interest they are also capable of use as vat dyes. In examples: (1) N - methyl - o - phenylenediamine dissolved in hydrochloric acid is condensed with alloxan hydrate to give 9-methyl-isoalloxazine; N-ethyl-o-phenylenediamine and alloxan similarly yield 9-ethyl-isoalloxazine; hydrochloric acid may be replaced by sulphuric, nitric phosphoric, oxalic or acetic acids, or less favourably the free bases may be used and heating effected in presence of a high-boiling solvent such as nitrobenzene pyridine; (2) N-methyl-o-phenylenediamine dissolved in hydrochloric acid is condensed with monomethylalloxan-sodium bisulphite to give 3.9-dimethylisoalloxazine; (3) 1 . 3 - dimethyl - 5 - amino - 6 - methylaminobenzene hydrochloride (prepared by heating 1 . 3 - dimethyl - 5 - nitro - 6 - aminobenzene with methyl iodide and reducing with stannous chloride) is condensed with alloxan to give 6 . 8 . 9 - trimethylisoalloxazine; (4) 1 - (2<1> . 3<1> . 4<1> . 5<1> - tetrahydroxy - 1<1> - amylamino) - 2 - amino - 4 . 5 - dimethylbenzene hydrochloride (prepared from the o-nitrohalogenxylene and the polyoxyamylamine followed by reduction) is condensed with alloxan to give 6.7-dimethyl-9 - (2<1> . 3<1> . 4<1> . 5<1> - tetrahydroxy - 1<1> - amyl) - isoalloxazine (Vitamin B2 is stated to have the same composition); the hydrochloride of 2<1> . 3<1> - dihydroxy - 1<1> - propylamino - 2 - aminobenzene (prepared analogously to the above diamine) condensed with alloxan similarly yields 9 - (2<1> . 3<1> - dihydroxy - 1<1> - propyl) - isoalloxazine; (5) the hydrochloride of 1 . 2 - dimethyl - 4 - amino - 5 - n - amylaminobenzene (prepared by heating 1 . 2 - dimethyl - 4 - nitro - 5 - aminobenzene with n - amyliodide in a bomb tube at 140 DEG  C. followed by reduction) is heated with alloxan in glacial acetic acid to give 6 . 7 - dimethyl - 9 - n - amyl - isoalloxazine; similarly 6 . 7 - dimethyl - 9 - allyl - isoalloxazine and 9-phenyl-isoalloxazine are derived from the hydrochlorides of 1.2-dimethyl-4-amino-5-allylaminobenzene and 2 - aminodiphenylamine respectively; (6) 1 - (2<1> . 3<1> . 4<1> . 5<1> - tetrahydroxy - 1<1> - amylamino - 2 - nitrobenzene (derived by heating o-bromnitrobenzene with 1-arabinamine in pyridine at 130 DEG  C.) in hydrochloric acid and in presence of alloxan is reduced with stannous chloride and then carefully treated with potassium permanganate to give an isoalloxazine compound; (7) 1-methylamino - 2 - amino - 4 . 5 - dimethylbenzene (prepared by heating 1 - amino - 2 - nitro - 4 . 5 - dimethylbenzene with toluene sulphochloride, methylating, saponifying and reducing) in hydrochloric acid is condensed with alloxantin to give 6.7.9-trimethylisoalloxazine; (8) 1.2-dimethyl - 4 - nitro - 5 - tetrahydroxyamylaminobenzene (prepared by boiling 4-nitro-5-iodoxylol(-1.2-) with arabinamine in pyridine) is reduced with stannous chloride and hydrochloric acid in presence of dialuric acid and the leuco compound dehydrogenated with permanganate to give the product of (4); (9) 1.2-dimethyl - 4 - nitro - 5 - l - arabitylaminobenzene (prepared by heating 1 . 2 - dimethyl - 4 . 5 - dinitrobenzene with l-arabinamine in alcohol to about 130 DEG  C.) is boiled in acetic acid in presence of boric acid, cooled, reduced with zinc dust, and condensed with alloxan to give 6.7-dimethyl-9-l-arabitylisoalloxazine; using 1 . 2 - dimethyl - 4 - nitro - 5 - d - ribitylaminobenzene as starting material the 6.7-dimethyl-9-a -ribitylisoalloxazine is similarly obtained, and by starting from o-aminodiphenylamine and excluding the reduction with zinc dust the 9-phenylisoalloxazine is similarly derived.  A sample has been furnished under Sect. 2 (5) of 5.6-benzo-9-methylisoalloxazine prepared by reducing 1-nitro-2-methylaminonaphthalene and condensing the product with alloxan in presence of hydrochloric, acetic or boric acids.