CS266316B2 - Process for preparing 1-aryl-2-amino-1-ethanoles - Google Patents

Description

The invention relates to a process for the preparation of 1-aryl-2-amino-1-ethanol derivatives of the general formula I:

OH í

X - Ar - C - CH - N

I ²

(I) where

Ar is naphthyl, thienyl or furyl,

is at least one of hydrogen, fluorine, chlorine, bromine, straight or branched chain alkylene of 1 to 6 carbon atoms, straight or branched chain alkoxy of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms , straight-chain or branched phenylalkyl of up to 3 carbon atoms, nitro, isonitrile or dialkylamino of 1 to 5 carbon atoms in the alkyl portion means a hydrogen atom, a straight or branched chain alkyl radical of 1 to 4 carbon atoms or straight chained or branched phenylalkyl of up to 3 carbon atoms, the same or different denoting a hydrogen atom, straight chained or branched alkyl of 1 to 4 carbon atoms or straight chained or branched phenylalkyl of 1 to 3 or aryl.

The compounds of formula (I) have biological activity, and some of them may be used in medicine, for example 2-n-butylamine-1- (p-hydroxyphenyl) ethanol (Bamhanesulfate), 2-tert-butylamine-1- (4-hydroxy) -3-hydroxymethylphenyl) ethanol (Salbutamol), 1- (4-amino-3,5-dichlorophenyl) -2-tert-butylaminethanol (Clenbuterol hydrochloride), L- (3,4-dihydroxyphenol) -2-methylaminethanol (Adrenaline).

A known process for the preparation of the compounds of the formula I consists in carrying out the addition reaction of ammonia or an amine to the oxirane of the formula II (II):

Ar, X and r! are as defined above.

However, this method is not widely used, since there is no truly effective method of producing oxirane derivatives, since they are not stable enough, especially when they are substances in which X represents a higher number of substituents.

Obtaining the oxirane by oxidation of the corresponding alkene is usually not possible because alkenes as styrene derivatives are difficult to manufacture and readily polymerize.

Another method for obtaining oxiranes is to react the arylcarbonyl compound with a ylide, but this method is not commonly used. A process for obtaining an ylide from trimethyl- sulfonium iodide or sulfoxonium iodide is difficult to carry out on a technical scale because it requires an anhydrous reaction medium and the use of alkali metal hydrides and, moreover, the starting and reaction products have an infusible and unpleasant odor. Ylides obtained from dimethylalkylsulfonium-I iodide and aqueous alkali metal hydroxide solutions do not give a reaction with arylcarbonyloxy

CS 266 316 B2 pure products. The oxiranes obtained by these reactions are so contaminated, for example, by incorporating iodine into the aromatic nucleus, that they cannot be used for further synthesis and their isolation and purification is usually impossible due to the easy formation of polymers. Furthermore, the starting methyl alkyl sulfides cannot be regenerated from the reaction mixture, so side reactions are formed.

Prod / higher 1 »6) Ozitech jo způr.ob production Ethiopian obočného formula I in which Ar, X, R, R ⁵ and K ³ are as hereinbefore defined, without isolation and purification of intermediates. The process is based on the sulfonium ylide obtained by the reaction of methylalkyl sulfide with dimethyl sulphate in an organic, water-immiscible solvent and the dimethylalkylsulfonium methyl sulfate obtained further by deprotonation in the presence of a catalyst with an alkali metal hydroxide or a concentrated aqueous solution thereof and then reacted with arylcarbonyl compounds. and reacting the obtained oxirane with ammonia or an amine.

The process according to the invention is carried out by reacting a methyl alkyl sulfide of the formula

RSCH ₃ where

R is a primary alkyl radical of at least 4 carbon atoms, i.e. a radical in which the carbon adjacent to the sulfur is of a primary nature, reacted with dimethyl sulphate in a water-immiscible organic solvent and reacted with alkali hydroxide in the presence of a catalyst metal or a concentrated aqueous solution thereof and then with a compound of formula III

AND

X - Ar - C = O (III) where

Ar, X and R ¹ are as hereinbefore defined, and, after removal of water and / or parts of organic solvent, the reaction mixture is reacted with ammonia or an amine of formula wherein

R ² and R ³ are as defined above, and the product obtained is isolated and purified in known manner.

Methylene chloride or benzene is usually used as an organic solvent immiscible with water. The catalyst used is a quaternary ammonium salt, for example tetrabutylammonium chloride or tetrabutylammonium bromide. The alkali metal hydroxide is usually sodium or potassium hydroxide; when a concentrated aqueous solution is used, it is usually a saturated solution.

After isolation of the resulting product, the starting methylalkyl sulfide can be fully recovered from the remaining mixture. Methyl alkyl sulfides of formula

RSCH ₃

CS 266 316 B2 where

R is as hereinbefore defined, are non-volatile which have no odor or find a relatively faint odor if R contains more than 7 carbon atoms.

Indirectly obtained dimethylalkylsulfonium methyl sulfates of general formula rs (ch ₃ j ₂ ⁺ so ₄ ch ₃ where

R is as hereinbefore defined, are new substances which have not been used in the synthesis with ylides.

The arylcarbonyl compounds of the formula III in which Ar, X and R ¹ are as defined above and which are the starting materials for carrying out the process according to the invention are stable and readily obtainable compounds and a number of methods are known which essentially consist of introducing carbonyl functions into a substituted aromatic system.

The yield of the 1-aryl-2-amino-1-ethanol derivatives of formula I is greater than 60% based on the compounds of formula III.

The invention will be illustrated by the following examples.

EXAMPLE 1 g (0.05 mol) of methyl octyl sulfate and 7 g (0.055 mol) of dimethyl sulfate were mixed in 25 ml of methylene chloride and the mixture was allowed to stand at room temperature for 48 hours. 0.15 g of tetrabutylammonium bromide and 25 ml of a 50% aqueous solution of sodium hydroxide are added to the dimethyloctylsulphonium solution obtained, followed by dropwise stirring of 9.8 g (0.05 mol) of 3,4,5-trimethoxybenzaldehyde in 25 ml of methylene chloride. The reaction mixture is heated at reflux for 4 hours, then the organic layer is separated, the solvent is evaporated and 50 ml of isopropanol and 18 g (0.25 mol) of tert-butylamine are added. The mixture was heated at reflux for 8 hours, whereupon the excess of t-butylamine and the solvent were evaporated. The resulting 1- (3,4,5-trimethoxyphenyl) -2-tert-butylamino-1-ethanol is isolated as the hydrochloride in a yield of 70% after recrystallization from ethanol. Mp 203-205 ° C. Methyl octyl sulfide was distilled off from the remaining mixture. The structure of 1- (3,4,5-trimethoxymethyl) -2-tert-butylamino-1-ethanol was confirmed by 1 H-nuclear magnetic spectrum (PMR).

Example 2

In a manner analogous to that of Example 1, acetophenone was obtained in a yield of 65% of 1-phenyl-1-methyl-2-tert-butylamino-1-ethanol as the hydrochloride, m.p. 191-192 ° C. Resulting structure)) »? The product was confirmed by PMR spectrum.

Example 3

The procedure of Example 1 was followed, but using 2,2-dimethyl-6-formylbenzo-1,3-dioxane to give 2,2-dimethyl-6- (2-tert-butylamino-1-ethanol) -benzo -1,3-dioxane as oxalate in 60% yield, melting point of the free product 91-92 ° C, structure confirmed by PMR spectrum.

CS 266 316 B2

Example 4

The procedure was analogous to Example 1 except that p-nitrobenzaldehyde was used to afford 1- (4-nitrophenyl) -2-tert-butylamino-1-ethanol in 73% yield, m.p. mp 145-147 ° C. The structure was confirmed by PMR spectrum.

Example 5

The procedure was analogous to Example 1 except that 1-naphthaldehyde was used to give 1- (1-naphthyl) -2-tert-butylamino-1-ethanol in the free form in 60% yield, m.p. to 126 ° C. The structure was confirmed by PMR spectrum.

Example 6

To a suspension of powdered sodium hydroxide (16.4 g) and potassium carbonate (2.5 g) in methylene chloride (50 ml) was added dropwise a solution of 32.5 g (0.11 mol) of dimethyloctylsulfonium methyl sulfate obtained by the method of Example 1, 22.0 g. (0.1 mol) of 3,5-dichloro-4-nitrobenzaldehyde and 0.33 g of tetrabutylammonium bromide in 50 ml of methylene chloride so that the temperature of the reaction mixture does not exceed 25 ° C. The reaction mixture is heated at reflux for 2 hours. After cooling, the mixture is diluted with 20 ml of methylene chloride and filtered. The solution was washed twice with 50 ml of water and, after drying over anhydrous magnesium sulfate, the methylene chloride was evaporated. The residue is dissolved in 110 ml of isopropanol, 20 ml of 0.40 mol of tert-butylamine are added and the mixture is heated at reflux for 6 hours. Then isopropanol and unreacted t-butylamine are evaporated under reduced pressure. The dark brown crystalline residue is dissolved in 200 ml of ethanol and 25 ml of saturated ethanolic hydrogen chloride solution are added. After 10 minutes the ethanol was evaporated and the residue was treated with 100 ml of benzene, cooled to 0 ° C and the cream colored crystalline residue was collected by filtration and washed with benzene. 21 g of 1- (3,5-dichloro-4-nitrophenyl) -2-tert-butylamino-1-ethanol hydrochloride are obtained in a yield of 61.4%, m.p. the structure of the free substance was confirmed by PMR spectrum.

Example 7

The procedure was analogous to Example 6, but using 2-nitrobenzaldehyde and aniline to give 1- (2-nitrophenyl) -2-phenylaminoethanol as the hydrochloride in 65% yield.

Elementary analysis:

calculated: C: 57.10%, H: 5.10%, N: 9.53%, found: C: 56.90%, H: 5.20%, N: 9.46%.

The structure was confirmed by PMR spectrum.

Example

The procedure was analogous to Example 1 except that 3-bromobenzaldehyde and alpha-phenylethylamine were used as starting materials to give 1- (3-bromophenyl) -2- [N- (alpha-phenylethyl) amino] as the product. -1-ethanol as hydrochloride, m.p. 203-205 ° C. Yield 72%.

Example 9

The procedure was analogous to Example 1 except that butyrphenone and morpholine were used as starting material to give 1-phenyl-1-propyl-2- (N-morpholine) ethanol as the hydrochloride, m.p. 220-223 ° C with decomposition. The reaction yield is 64%.

CS 266 316 B2

Example 10

The procedure is analogous to Example 1 except that the starting material is used

2-thienylaldehyd and di-isopropylamine, to give the final product afforded l- (2-thienyl) -2-diisopropylethyl | »i-propylamino Ι.Ίΐηίηο Ι« fm llianol in me <, ||. »É кар _in II. -Waves. Piodukl. neclinous clil ohm Log t а II cky. The structure of the resulting compound was confirmed by II-nuclear magnetic resonance. The yield is

Claims (5)

A process for the preparation of 1-aryl-2-amino-1-ethanol derivatives of the general formula I X-Ar-C-CH--N. (I) where Ar is naphthyl, thienyl or furyl, at least bromine, alkyl carbon, straight or branched chain alkoxy of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, phenylalkyl with 1 to 3 carbon atoms of straight or branched chain, nitro, isonitrile having an alkyl moiety of 1 to 5 carbon atoms, one substituent selected from hydrogen, fluorine, chlorine, a straight or branched chain moiety of 1 to 6 atoms, or a dialkylamino group R ¹ carbon atom a straight alkyl radical having portions R ² and R ³ wherein the reaction and the metal mixture obtained or where it represents a hydrogen atom, a C1-4 or branched chain alkyl radical or a straight chain or branched phenylalkyl group having 1 to 3 carbon atoms, the same or different denoting a hydrogen atom, straight or branched chain alkyl group having from 1 to 4 carbon atoms or phenylalkyl having a straight or branched chain alkyl group having from 1 to 3 carbon atoms or an aryl group, characterized in that the methylalkylsulfide of the formula RSCH ₃ represents a primary alkyl radical of at least 4 carbon atoms, with dimethylsulfate in an organic solvent, immiscible with water, in the presence of a catalyst, reacted with an alkaline hydroxide with a concentrated aqueous solution and then with a compound of formula III R ¹ AND X - Ar - C = O (III) Ar, X and R ¹ have the abovementioned meanings, CS 266 316 B2 and after removal of water and / or part of the organic solvent, the reaction mixture is reacted with ammonia or ammonium of the formula 2 3 R-NH-R kdr 2 3 R and R are as defined above, the product obtained is isolated and purified. 2. The process according to claim 1, wherein the water-immiscible organic solvent is methyl chloride or benzene. 3. The process according to claim 1, wherein the catalyst is a quaternary ammonium salt of at least 16 carbon atoms, for example tetrabutylammonium bromide, triethylbenzylammonium chloride and tricaprylmethylammonium chloride. 4. The process according to claim 1, wherein the alkali metal hydroxide is sodium or potassium hydroxide. 5. The process of claim 1 wherein the concentrated aqueous solution is a saturated solution.