Patent GB-867918-A (GB)
Title: Improvements in and relating to amines
Inventor: EUGSTER CONRAD HANS
IPC: C07D307/22
Filed: 1957-06-13
Abstract: The invention comprises 3-tertiary-aminotetrahydrofurans of the formula:  <FORM:0867918/IV (b)/1> wherein Rn represents hydrogen or one or more identical or different alkyl, halogen alkenyl, hydroxyalkyl, alkanoyl, alkoxyalkyl, acetoxyalkyl, benzyloxyalkyl, cycloalkyl, aralkyl or aryl radicals, R1 represents a C1-4 alkyl, C1-4 alkenyl, aralkyl or aryl radical, R2 represents a C1-4 alkyl, C1-4 alkenyl or aralkyl radical, or R1 and R2 together with the nitrogen atom to which they are attached represent a 5 or 6-membered alkylenimino radical or the morpholino radical.  The compounds are prepared by the following methods:- (1) By reacting a compound of the formula:  <FORM:0867918/IV (b)/2> wherein An11 represents a halogen atom, with a secondary amine of the formula HNR1R2; (2) by reacting a 3-amino-tetrahydrofuran of the formula:  <FORM:0867918/IV (b)/3> wherein R1 represents hydrogen or the radical R1, in the presence of formic acid with at least two mols of a reactive ester of a C1-4 hydroxyalkyl or hydroxyalkenyl compound or of a hydroxyaralkyl compound, or with at least two mols of a C1-4 ketoalkane or ketoalkene or of an arylketoalkane when R1 represents hydrogen or, if it represents the radical R1, with at least one mol of either the reactive ester or the oxo-compound defined above; (3) by ring closing an N,N-disubstituted aminobutane diol of the formula: <FORM:0867918/IV (b)/4> with a ring closing agent such as a mineral acid or an acid halide (e.g. methane sulphochloride); (4) by reacting a 3-oxo-tetrahydrofuran of the formula:  <FORM:0867918/IV (b)/5> in the presence of formic acid with a secondary amine having C1-4 alkyl groups or with formamide N:N-disubstituted with C1-4 alkyl groups; (5) by reacting an N:N-disubstituted 3-amino-furan of the formula: <FORM:0867918/IV (b)/6> with catalytically activated hydrogen until twice the molecular amount of hydrogen has been taken up; and (6) by reacting a 3-acylamino-tetrahydrofuran of the formula: <FORM:0867918/IV (b)/7> wherein R12 represents the radical corresponding to R2 but having one CH2 group less, with an earth metal alkali metal hydride or with sodium borohydride.  When Rn represents an acetoxy alkyl, a benzyloxyalkyl or an alkanoyl radical, such radical may be converted to the corresponding hydroxy-alkyl radical by subsequent hydrolysis, hydrogenolysis or reduction, respectively.  When Rn represents a hydroxyl group, this may be subsequently acylated with acetic anhydride. The final products may be converted into acid addition salts with acids such as hydrochloric, hydroiodic and perchloric acids, or into quaternary ammonium salts in which the anion is, for example, iodide, chloride, methosulphate or tetrachloroaurate.  In some cases the final products may be fractionally crystallised into two optical isomers.  The lithium derivative of propargyl-tetrahydro-pyranyl ether is prepared by reacting propargyl-tetrahydropyranyl ether with phenyl lithium or butyl lithium.  This lithium derivative may be treated with propionic anhydride to give (g -propionyl-propargyl)-tetrahydropyranyl-ether. (g -Propionyl-b -dimethylamino-allyl)-tetrahydro-pyranyl ether is prepared by reacting (g -propianyl-propargyl)-tetrahydropyranyl ether with dimethylamine.  Subsequent reduction of the product with hydrogen and a platinum catalyst in glacial acetic acid yields a mixture of four products, viz:-(d -hydroxy-b -dimethylamino-n-hexyl)-tetrahydropyranyl ether, d -hydroxy-b -dimethylamino-n-hexanol and the acetyl derivatives thereof.  Vinyl allyl carbinol is prepared by reacting acrolein with allyl magnesium halide and may be subsequently treated with bromine to give 1, 2, 5, 6-tetrabromohexane-3-ol.  1,1-Diethoxy-3-butene is prepared by reacting ortho-formic acid ethyl ester with allyl magnesium bromide and may be subsequently treated with bromine to give 1,1-diethoxy-3,4-dibromobutane.  Benzyloxymethyl-allyl carbinol is prepared by reacting benzyloxyacetaldehyde with allyl magnesium bromide and may be subsequently treated with bromine to give a dibromo-derivative, which may be ring closed with potassium hydroxide to give 3-bromo-5-benzyloxymethyl-tetrahydrofuran. 3,4-Dibromobutyraldehyde may be reacted with 2,4-dinitrophenylhydrazine to give the corresponding hydrazone or with sodium bisulphite to give the corresponding addition compound. This bisulphite addition compound may be further reacted with potassium cyanide, when ring closure occurs to give 3-bromo-5-cyano-tetrahydrofuran.  3-Hydroxy-4-benzyl-tetrahydrofuran is prepared by reacting benzyl magnesium chloride with epoxytetrahydrofuran and decomposing the product with water.  Further treatment with phosphorus tribromide gives 3-bromo-4-benzyl-tetrahydrofuran. 3-Bromo-5-(a ,b -dibromethyl)-tetrahydrofuran is obtained by ring closing 1, 2, 5, 6-tetrabromo-hexane-3-ol with alkali hydroxide. Removal of one molecule of hydrogen bromide from the product yields 3-bromo-5-bromo-vinyl-tetrahydrofuran. 2,5-Dimethyl-2,5-dihydroxy-3-dimethylamino-hexane is prepared by reacting 2,5-dimethyl-2,5-dihydroxy-3-aminohexane successively with formic acid and formaldehyde, hydrochloric acid, and sodium hydroxide.  Tetrahydrofuran-3-carboxylic acid methyl ester is prepared by hydrogenating 4,5-dihydro-furan-3-carboxylic acid methyl ester in presence of a palladium/barium sulphate catalyst. 5-Acetyl-furan-3-carboxylic acid methyl ester is prepared by reacting tetrahydrofuran-3-carboxylic acid methyl ester with acetic anhydride and a boron trifluoride-diethyl ether complex. The product may be hydrogenated in presence of a palladium/barium sulphate catalyst to give 5-(a -hydroxymethyl)-tetrahydrofuran-3-carboxylic acid methyl ester.  Tetrahydrofuran-3-carboxylic acid hydrazide and the 5-(a -hydroxyethyl)- and 2,5-dimethyl derivatives thereof are prepared by treating the corresponding 3-carboxylic acid methyl or ethyl esters with hydrazine hydrate.  The hydrazides may be converted to the corresponding 3-acid azide derivatives with nitrous acid and further subjected to the ourtius rearrangement with benzyl alcohol or formic acid to give (1) N-tetrahydro-furyl-3-carbamic acid benzyl ester, which may be hydrogenated to give 3-aminotetrahydrofuran; (2) 3-carbobenzyloxyamino-5-(a -hydroxyethyl) - tetrahydrofuran, which may be treated with hydrochloric acid to give 3-amino-5-(a -hydroxy-ethyl)-tetrahydrofuran (as the hydrochloride); and (3) 2,5-dimethyl-3-formylaminofuran, which may be reacted with sodamide and methyl iodide to give an N-methyl derivative, which is subsequently reduced with lithium aluminium hydride to give 2,5-dimethyl-3-dimethylamino-furan and then with hydrogen and palladium/barium sulphate to give the corresponding tetrahydrofuran. 3-Bromo-5-acetyl-tetrahydrofuran is prepared by reacting 3-bromo-5-cyano-tetrahydrofuran with methyl magnesium iodide. This product may be reduced with lithium aluminium hydride to give 3-bromo-5-(a -hydroxyethyl)-tetra-hydrofuran.  a -Acetyl-d -benzyloxy-g -valerolactane and a -acetyl-benzyloxy-g -caprolactane are prepared by condensing acetoacetic acid ethyl ester with benzylglycide ether and 3-benzyloxy-butane-1 : 2-epoxide respectively.  The products yield phenylhydrazones with benzene diazonium chloride and these hydrazones may be reduced with zinc and formic acid to give a -formylamino-d -benzyloxy-g -valerolactone and a -formylamino-d -benzyloxy-g -caprolactone respectively. Subsequent methylation with formaldehyde and formic acid gives a -dimethylamino-d -benzyloxy-g -valerolactone and a -dimethyl-d -benzyloxy-g -caprolactone respectively, which may be reduced with sodium borohydride to give 1,4-dihydroxy-2-dimethylamino-5-benzyl-oxy-pentane and 1,4-dihydroxy-2-dimethyl-amino-5-benzyloxy-hexane respectively. Specification 833,573 is referred to.