Patent GB-671070-A (GB)
Title: Improvements in or relating to the preparation of 2:6-diiododiphenyl ethers
Inventor: DICKSON GEORGE THOMSON
IPC: C07C43/29
Filed: 1949-09-08
Abstract: 2 : 6-Diidodiphenyl ethers of the general formula <FORM:0671070/IV (b)/1> are prepared by treating a diaminodiphenyl ether of the general formula <FORM:0671070/IV (b)/2> (where Z is hydrogen or an alkyl group containing not more than four carbon atoms, Y is hydrogen or a group used to protect an amino group such as an acetyl or benzoyl group and R is a hydroxyl group or a hydroxyl group protected by a group removable therefrom) in solution in glacial acetic acid and/or syrupy phosphoric acid with concentrated sulphuric acid and a suitable nitrite in the absence of water, and the resulting tetrazo compound is decomposed with an aqueous solution of an alkali metal iodide in the presence of a waterimmiscible organic solvent in which the 2 : 6-diiododiphenyl ether is soluble.  Suitable nitrites are an inorganic nitrite, preferably sodium nitrite, or an organic nitrite derived from an aliphatic alcohol having less than six carbon atoms, e.g. amyl nitrite.  Y may be an acetyl or benzoyl group and R may be protected by a methyl, ethyl, benzyl, acetyl or benzoyl group.  The method is said to give better yields than that of Specification 643,089.  Free iodine is preferably present during the decomposition of the tetrazo compound, e.g. an aqueous solution of sodium triiodide may be used.  Suitable solvents preferably have a boiling point not below 40 DEG CC., e.g. chloroform, tetrachlorethane, methylene dichloride, benzene, chlorobenzene and ethylene dichloride. Tetrazotization is carried out in the absence of water by adding a solution of the diamine in a mixture of sulphuric acid and acetic acid and/or syrupy phosphoric acid to a solution of sodium nitrite in those mixed acids.  The diaminodiphenyl ethers may be obtained by hydrogenation of dinitrodiphenylethers prepared according to Specification 642,159.  Optically active diaminodiphenyl ethers yield optically active diiododiphenyl ether.  In examples: (1) 3 : 5-diamino-4-(41-methoxyphenoxy) - N - acetyl - L - phenylalanine ethyl ester is diazotized in sulphuric acid solution with a solution of sodium nitrite in concentrated sulphuric acid diluted with acetic acid.  The product is reacted with a solution of sodium iodide, iodine and urea in water covering a layer of chloroform.  From the chloroform layer (after removing iodine with aqueous sodium sulphate to which sulphur dioxide is passed) is recovered 3 : 5-diiodo-4-(41-methoxyphenoxy) - N - acetyl - L - phenylalanine ethyl ester; (2) 3 : 5-diamino-4-(41-methoxyphenoxy) - L - phenylalamine is diazotized in sulphuric acid solution with a solution of nitrosyl-sulphuric acid obtained by adding sodium nitrite to concentrated sulphuric acid.  The product is reacted with a solution of sodium iodide, and iodine in water and chloroform and precipitates on adding sodium metabisulphite for the removal of excess iodine. Similarly are prepared from the corresponding 3 : 5-diamino compounds; (3) 3 : 5-diido-4-(41-methoxyphenoxy) - N - acetyl - L - phenylalanine; (4) 3 : 5-diido-4-(41-methoxyphenoxy)-L-phenylalanine ethyl ester; (5) 3 : 5-diiodo-4 - (41 - methoxyphenoxy) - N - benzoyl - L-phenylalanine ethyl ester; (6) 3 : 5-diiodo-4-(41 - benzoylphenoxy) - N - acetyl - L - phenylalanine ethyl ester (the use of phosphoric in place of acetic acid is also described); (7) 3 : 5 - diiodo - 4 - (41 - acetoxyphenoxy) - N-acetyl-L-phenylalamine ethyl ester.  The examples describe also the reduction of the corresponding nitro compounds to give the amines employed, hydrogenation with a palladized charcoal catalyst being specified. 3 : 5 - Dinitro - 4 - (41 - methoxyphenoxy) - L-phenylalanine is obtained by refluxing 3 : 5-dinitro - 4 - (41 - methoxyphenoxy) - N - acetyl-L-phenylalanine ethyl ester with concentrated hydrochloric and acetic acids.  3 : 5-Dinitro-4 - (41 - methoxyphenoxy) - N - acetyl - L - phenylalanine is obtained by hydrolysing the corresponding ethyl ester with sodium hydroxide in methylated spirit at 20 DEG  C.