HU192958B - Process for preparing 1-aryl-2-amino-ethanol derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of 1-aryl-2-aminoaethanol (1) with pharmacological activity for use as a medicament. The aim of the invention is to provide an improved method. According to the invention, compounds of the general formula I in which, for example: Ar phenyl, naphthyl, etc., X is one or a large number of substituents such as hydrogen, fluorine, chlorine, bromine, alkyl, alkoxyl, alkoxyalkyl, R 2 and R 3 are hydrogen , Alkyl, aralkyl and aryl, without isolation of intermediates, by reacting methyl alkyl sulfide, wherein alkyl is a primary group containing at least 4 carbon atoms, with dimethyl sulfate in a water-immiscible solvent, the post-reaction mixture recovered in the presence of a catalyst with alkali metal hydroxide and then reacted with an aryl carbonyl compound. The residue is treated with ammonia or an amine.

Description

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

Ar is phenyl, naphthyl, benzo (1,3) dioxanyl, pyridyl or thienyl,

X is one or more, the same or different, selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, and nitro;

R ¹ is hydrogen, C 1-4 alkyl,

R ² and R ³ are the same or different and are hydrogen, C 1-6 alkyl or phenyl,

R ^! and R ³ together are C 4 -C 6 alkylene.

Compounds of formula (I) are prepared by reacting methylalkylsulfide of formula RSCHs wherein R is a primary alkyl group of at least four carbon atoms with dimethylsulfate in an organic, water-immiscible solvent to give the product thus obtained in the presence of a catalyst. hydroxide or a concentrated aqueous solution thereof, the product thus obtained is reacted with an arylcarbonyl compound of formula (III) wherein Ar, X and R ¹ are as defined above, removing water and / or a portion of the organic solvent from the reaction mixture. , the residue is treated with ammonia or an amine of the formula R ² NHR - wherein R ² and R ³ are as defined above, and the product thus obtained is isolated and purified in a known manner.

The compounds of formula I are biologically active and some of them are used as medicaments. The most well-known of these are adrenaline, bamethanesulfate and salbutamol? L- (3,4-dihydroxyphenyl) -2-methylaminoethanol, 2-n-butylamino-1- (4-hydroxyphenyl) ethanol, 2-tert-butylamino-1- [4-hydroxy-3- (hydroxymethyl) phenyl] ethanol).

One known method of preparing compounds of formula I is by adding ammonia or an amine to oxirane of formula II, wherein Ar, X and R ¹ are as defined above (see U.S. Patent No. 2,310,141). However, this method has not gained widespread application because there is no method by which relatively degradable oxirane derivatives can be prepared, especially for compounds wherein X represents multiple substituents.

The compounds of formula (I) may also be prepared by reaction of amines with halide hydrides (U.S. Patent No. 2,603,417) or by reaction of amines with .alpha.-halo ketones (British Patent No. 1,200,886).

Generation of the oxiranes of formula II by oxidation of the corresponding alkenes is generally not possible because the preparation of the corresponding styrene derivatives is difficult and is readily polymerized.

Another method for preparing oxiranes is by reacting arylcarbonyl compounds with ylides. This method is also not widespread in practice because a well-known method for the preparation of ylides starting from trimethylsulfonium or trimethylsulfoxonium iodide is not practicable on an industrial scale because it requires the use of an anhydrous reaction medium and alkali metal hydrides, and all of the reaction products have an unpleasant odor. [J. Chem. Soc. 87, 1353 (1965)]. Conversely, when ylides of dimethylalkylsulfonium iodides in aqueous alkali metal hydroxide solutions are reacted with arylcarbonyl compounds, they do not yield pure products. The oxiranes resulting from such a reaction are so contaminated, for example due to the formation of an aromatic iodine compound, that they cannot be used in further steps because they are generally not possible to be isolated and purified because of their propensity for polyolysis. In addition, the starting alkylmethylsulfide cannot be recovered from the mixture obtained after the reaction due to side reactions of the process.

An advantage of the process of the invention is that sodium hydroxide or an aqueous solution thereof may be used instead of sodium hydride; the normally unstable oxirane derivative can be reacted directly with the amine without isolation; furthermore, the methyl alkyl sulfide used in the process is almost completely recovered from the reaction mixture at the end of the process; which positively affects the cost of the procedure.

It has now been found that 1-aryl-2-amino-1-ethanols can be prepared without reacting the isolation of the intermediates by reacting the methyl alkyl sulfide derivative with dimethyl sulfate in an organic, water-immiscible solvent. Methylsulfate is deprotonated with alkali metal hydroxide or a concentrated aqueous solution thereof under interfacial catalysis conditions, the resulting azulfonium ylide is reacted with an arylcarbonyl compound, and the resulting oxirane derivative is reacted with ammonia or the corresponding amine.

As a water immiscible organic solvent, it is preferable to use dichloromethane or benzene. The catalyst used is a quaternary ammonium salt such as tetrabutylammonium chloride or bromide. Suitable alkali metal hydroxides are, for example, sodium or potassium hydroxide; their concentrated aqueous solutions are usually their saturated aqueous solutions.

After isolation of the product from the mixture obtained after completion of the production process, the methyl alkyl sulfide used as starting material can be completely recovered. They are

The methyl alkyl sulfides of the formula RSCH3 wherein R is as defined above are substantially odorless or, when R is alkyl having more than 7 carbon atoms, are completely odorless.

The dimethylalkylsulfonium (methylsulfate) dimethylalkylsulfonium [RS <CH3hrCH3SO-] formed as an intermediate in the production process, wherein R is as defined above, is a novel compound which has not yet been used for the preparation of ylides.

The arylcarbonyl compounds of formula (III) are stable, readily available materials for which many methods are known. In one embodiment, carbonyl groups are introduced into substituted aromatic compounds; alternatively, the substituents are subsequently introduced into the aromatic carbonyl compound.

By the process of the invention, the 1-aryl-2-amino-1-ethanol of formula (I) can be prepared in a yield of greater than 60% relative to the arylcarbonyl compound of formula (III).

The following examples illustrate the process of the invention in more detail.

Example 1

1- (3,4,5-Trimethoxyphenyl) -2- (tertiary-butyl)

Preparation of -amino) -1-ethanol A solution of methyl octyl sulfide (0.05 mol), dimethyl sulfate (7 g, 0.055 mol) and dichloroethane (25 ml) was allowed to stand at room temperature for 48 hours. To the resulting dimethyl octylsulfonium (methylsulfate) solution was added 0.15 g of tetrabutylammonium bromide and 25 ml of 5054 aqueous solution of ethyl acetate and added dropwise with constant stirring.

A solution of 3,4,5-trimethoxybenzaldehyde (9.8 g, 0.05 mol) in dichloromethane (25 mL) was added. The reaction mixture was refluxed for 4 hours, then the organic phase was separated, the solvent was evaporated and to the residue was added isopropanol (50 ml) and tert-butylamine (18 g, 0.25 mol). The mixture was refluxed for 8 hours and the excess amine was distilled off. From the distillation residue, the title compound is isolated as its hydrochloride. After recrystallization from ethanol, the yield is 70%, m.p. 203-205 ° C. From the residue, methyl octyl sulfide is distilled off.

The structure of the title compound was confirmed by ¹ H NMR.

Example 2 Preparation of 1-Phenyl-1-methyl-2- (tert-butylamino) -1-ethanol

The procedure is the same as in Example 1, but using acetophenone instead of 3,4,5-trimethoxybenzaldehyde. The title compound was isolated as its hydrochloride in 65% yield, m.p. 191-192 ° C.

The structure of the title compound was confirmed by Ή-NMR.

Example 3

Preparation of 1- (2,2-Dimethyl) -benzo) -1,3-dioxan-6-yl-2- (tert-butylamino) -1-ethanol

The procedure was the same as in Example 1, except that 2,2,5-dimethyl-6-formybenzene (1,3) dioxane was used instead of 3,4,5-trimethoxybenzaldehyde. The title compound is isolated as its oxalate, 60%, m.p. 91-92 ° C.

The structure of the title compound was confirmed by ¹ H NMR.

Example 4

- Preparation of (4-Nitrophenyl) -2- (tertiary-butylamino) -1-ethanol

The procedure was the same as in Example 1, but using 4-nitrobenzaldehyde instead of 3,4,5-trimethoxybenzaldehyde. The title compound was isolated in basic form, yield 73%, mp 145-147 ° C.

The structure of the title compound was confirmed by1H NMR.

Example 5

- Preparation of (I-Naphthyl) -2- (tertiary butylamino) -1 ethanol

The procedure is the same as in Example 1, except that 1-naphthalaldehyde is used instead of 3,4,5-trimethoxybenzaldehyde. The title compound was isolated in basic form, yield 60%, mp 125-126 ° C.

The structure of the title compound was confirmed by 1 H-NMR.

EXAMPLE 6 PREPARATION OF 1- (3,5-Dichloro-4-nitrophenyl) -2- (tertiary-butylamino) -1-ee

To a suspension of 16.4 g of powdered sodium hydroxide and 2.5 g of potassium carbonate in 50 ml of dichloromethane was stirred 32.5 g (0.11 mol) of Example 1 Dimethyl octylsulfonium (methyl sulfate), 22.0 g (0.1 mol) of 3,5-dichloro-4-nitrobenz-37 aldehyde, 0.33 g of tetrabutylammonium bromide and 50 ml of dichloromethane are added dropwise at a rate such that do not rise above 25 ° C and reflux for 2 hours. After cooling, it is diluted with 50 ml of dichloromethane and filtered. The resulting solution was washed with water (2 x 50 mL), dried over anhydrous magnesium sulfate, and dichloromethane was distilled off. The residue was dissolved in isopropanol (110 ml), tert-butylamine (20 ml, 0.40 mol) was added and the solution was refluxed for 6 hours, then the isopropanol and unreacted tert-butylamine were distilled off in vacuo. The dark brown crystalline residue was dissolved in 200 ml of ethanol, 25 ml of saturated ethanolic hydrogen chloride solution were added and allowed to stand for 10 minutes. Ethanol ledeeztilláljuk, the resulting residue was added 100 ml of benzene, and the mixture was cooled to 0 ^4, the cream-colored crystalline product was filtered, washed with benzene to give the hydrochloride of the title compound, yield 21 g (61.4%), mp. : 150-255 ° C (with decomposition).

The title compound was confirmed by ¹ H NMR.

Example 7

- Preparation of (2-Ni-trophenyl) -2- (phenylamino) -1-ee

The procedure was the same as in Example 6, except that 2-chitro-benzaldehyde was used instead of 3,5-dichloro-4-nitrobenzaldehyde and aniline was used instead of tert-butylamine. The title compound was isolated as its hydrochloride in 65% yield. Analysis:

ANALYSIS:

Calculated: C, 57.10; H, 5.10; N, 9.53. Found: C, 56.90; H, 5.20; N, 9.46%.

The structure of the title compound was confirmed by 1 H NMR.

(60 MHz, CDCl 3, TMS) ppm: 3.1-3.7 (M), 5.0-5.2 (M), 6.4-8.2 (M).

Example 8 Preparation of 1- (3-bromophenyl) - [2-N- (x-phenylethyl) amino] ethanol

The procedure of Example 1 is followed. The starting material for the reaction is 3-bromobenzaldehyde and phenylethylamine. The hydrochloride salt of the title compound is obtained. Mp: 203-205 ° C.

Yield: 72%.

Example 9

Preparation of -phenyl-1-propyl-2- (N-piperidinyl) -eol

The procedure of Example 1 is followed. Butyrofencin and piperidine were used as starting materials. The title compound is obtained as the hydrochloride salt.

Yield: 75%.

¹ H-NMR ppm: 0.6-2.7 (M), 7.27 (S).

Example 10 - (2-Thienyl) -2-diisopropylaminoethanol

The procedure of Example 1 is followed. The starting material was 2-thienyl aldehyde and diisopropylamine. The title compound is obtained as a brown oily product. Purification by chromatography afforded a colorless, air-darkening product. Yield: 42%. The structure of the resulting compound was monitored by NMR.

1 H-NMR ppm: 1.0 (D, J = 6.5 Hz), 2.4-3.3 (M),

4.9 (M), 6.8-7.7 (2M).

Example 11 Preparation of 1- (4-pyridyl) -2-n-butylaminoethanol

The procedure of Example 1 is followed. Starting material is 4-piperidylsildehyde and n-butylamine. The title compound is obtained as a hygroscopic oily product. Yield: 52%. The identity of the product obtained is confirmed by NMR spectroscopy.

1 H-NMR, ppm: 0.7-1.6 (M), 2.5-3.3 (M), 4.9 (M), 7.15-7.40 (M), 8.25-. 8.40 (M).

Example 12 Preparation of 1- (4-methoxy / enyl) -2-methylamino-ethanol

23.8 g of methyl dodecyl sulfide, 13.5 g of dimethyl sulfate and 50 ml of benzene are heated at 90 ° C for 3 hours. The mixture was cooled to room temperature (20 ° C) and 13.6 g of 4-meloxybenzaldehyde, 0.6 g of tetrabutylammonium bromide and 30 ml of 50% aqueous sodium hydroxide solution were added.

The mixture was stirred vigorously for 12 hours under a stream of nitrogen at 20 ° C. The layers were then separated and the benzene was distilled off. The residue was dissolved in ethanol (50 mL). To this solution was added 120 ml of a 30% solution of methylamine in ethanol and the whole was refluxed for 6 hours. The solvent was then distilled off and the residue was distilled under reduced pressure. 22.0 g of methyl dodecyl sulfide (boiling point 122 ° C / 1.1 kPa) are obtained, and 12.3 g of the expected product are obtained; (boiling point 150 ° C / 1.1 kPa) m.p. 103-104 ° C.

Claims (6)

PATENT CLAIMS A process for the preparation of 1-aryl-2-amino-1-ethanol of formula (I): Ar is phenyl, naphthyl, benzo (1,3) dioxanyl, pyridyl or thienyl, X is one or more identical or different substituents selected from the group consisting of hydrogen and halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro, R ¹ is hydrogen, C 1-4 alkyl, R ³ and R ³ are the same or different and are hydrogen, (C 1 -C 6) -alkyl or phenyl, R 'and R ³ together are C 4 -C 6 alkylene groups characterized in that a methyl alkyl sulfide of the formula RSCH 5 - wherein R is a primary alkyl group of at least 4 carbon atoms - is reacted with dimethylsulfate in an organic, water-immiscible solvent. in the presence of an alkali metal hydroxide or a concentrated aqueous solution thereof, the product thus obtained is reacted with an arithcarbonyl compound of formula III wherein Ar, X and R ¹ are as defined above, from the reaction mixture to water and / or organic a portion of the solvent is removed, and the residue is reacted with ammonia or an amine of formula R'NHR ³ where R ^{3 and} R ³ are as defined above, and the product thus obtained is isolated and purified in a known manner. The method of claim 1, wherein Characterized in that dichloromethane or benzene is used as the organic, water immiscible solvent. The process according to claim 1, wherein the catalyst is quaternary 20 ammonium salts were used. 4. The process of claim 3 wherein the quaternary ammonium metal is tetrabutylammonium chloride or bromide. 25 5. A process according to claim 1, wherein the alkali metal hydroxide is sodium or potassium hydroxide. 6. The process of claim 1, wherein the alkali metal hydroxide is concentrated A solution of 30 is a saturated aqueous solution thereof.