DD210031A5 - METHOD FOR PREPARING 1-ARYL-2-AMINOAETHANOL (1) - 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

AP C07G / 252 756 -i 62 556-12 / 37

16/11/83

Process for the preparation of 1-aryl-2-aminoethanol (1) Field of application of the invention

The invention relates to a process for the preparation of i-aryl-2-aminoethanol (1) having the general formula I.

Z-Ar-C-GH ₀ -K _v (I),

OH ^K

in which mean:

Ar is a phenyl group, a haphthyl group and another aromatic or heterocyclic system such as pyridyl, thienyl or ffuryl; X is one or more substituents such as "a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group, an alcohol group , an alkoxyalkyl group, an aralkyl group, a hitro group, an isonitrile group and a dialkylamino group, H is a hydrogen atom, an alkyl group and an aralkyl group, H and Ή 'are the same or different hydrogen atom, an alkyl, an aralkyl and an aryl group ,

Compounds of general formula I have pharmacologically valuable properties, some of which are used as medicaments.

Characteristic of the known technical solutions

By a known method, compounds of general formula I are prepared by the addition of ammonia or

[general formula II

Amin to oxirane of the general formula ^TT

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C ₂ (II),

wherein Ar, X and E have the meanings indicated. The known method. However, due to the lack of suitable and Kirksamer methods for the preparation of the not very stable oxirane derivatives, especially of compounds in which Σ denotes a higher number of substituents, found no widespread use *

Processes for the preparation of oxirane are also known. Each oxirane is prepared by oxidation of a suitable alkene, alkenes which are derivatives of styrene are difficult to synthesize and tend to polymerize easily.

Another method for obtaining oxirane by reaction of arylocarbonyne compounds with Tliden has also found no practical application. This is due to the fact that the known process for obtaining a vinylidene sulfoxide or sulfoxonium iodide oxide is technically unsuitable since it requires the preservation of an anhydrous sea-diving medium and the use of alkali metal hydrides and also an unpleasant and strong odor of both the substrate and The ylides, which are prepared from dimethylalkyisulfonium iodides and from aqueous solutions of alkali metal hydroxides, do not yield pure products when reacted with aryl carbonyl compounds Introduction of iodine into the aromatic ring, that they are not used for further synthesis.

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can be. Their isolation and purification is not possible in the Hegel because of the polymerizability of these compounds. In addition, the initial methyl alkyl sulfide is unsuitable for regeneration from the post-reaction mixture, which is related to the side reactions that occur in this process *

Object of the invention

The aim of the invention is to provide an improved process with which i-aryl-2-aminoethanol (1) can be obtained in good yield and high purity.

Explanation of the essence of the invention

The invention is based on the object ^: to find easily accessible starting compounds and suitable reaction conditions *

ISrfindungsgemäßungsgemäßen 1-aryl-2-aminoethanol (1) of the general Pormel I _P 1 _o

OH

1 2 Ί

wherein Ar, X, R, R and R ^ have the meaning given, without isolation and purification of the intermediates prepared in such a way that sulfonium, which from; the reaction of methyl alkyl sulfide with dimethyl sulfate was recovered in the medium of an organic, not water-miscible solvent, and further the Dimethylalkylsulfoniummethylsulfat obtained under the conditions of a Grenzfla-

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The catalysis is deprotonated by the action of alkali metal hydroxide or its concentrated aqueous solutions, exposed to a reaction with arylocarbony compounds, and the oxirane obtained is then reacted with ammonia or amine.

Subject of the invention is methyl alkyl sulfide having the general formula ESCHo, wherein E. denotes a primary alkyl group having at least 4 carbon atoms, reacted with dimethyl sulfate in the medium of an organic, water-insoluble solvent. »Subsequently, the obtained Hachreaktions- · mixture in the presence of a catalyst with alkali metal hydroxide or its concentrated aqueous solution and then with a compound of general formula III

implemented, p

X-Ar-C = O (III),

where Ar, X and B are as defined. Then, after removal of water and / or a portion of the organic solvent, the best of a reaction is subjected to ammonia or amine of general formula H - M-L-E- E and B have the abovementioned meaning, and the product obtained is isolated and purified using the known process,

As the water-immiscible organic solvent, methylene chloride or benzene is used, Quaternary ammonium salt such as CDetrabutylammonium chloride or bromide is used as the catalyst. The alkali metal hydroxides used are IT atrium or potassium hydroxide. Their concentrated aqueous solutions are saturated solutions in the sail.

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After the product has been isolated from the post-reaction mixture, the starting material methyl alkyl sulfide can be completely recovered. Methyl alkyl sulfides have the general formula ESGH-, where E has the meaning given above, and are relatively low-odor compounds or odor-free if E contains more than 7 carbon atoms .

Indirectly obtained dimethylalkylsulfonium methylsulfates having the general formula SS / CHV 2 SO 4 CH 2 -, where E has the meaning given, are new compounds which have hitherto not been used in the synthesis with ylides.

As substrates are aryl carbonyl compounds of the general formula III _ß 1

X-Ar-C = O (III)

where Ar, I and E have the meaning given

Compounds of the general formula IH are stable and readily available. There are numerous processes known for their preparation which are based in particular on the introduction of the carbonyl function into the substituted aromatic system and on the introduction of substituents into the aromatic carbonyl system.

The yield of 1-aryl-2-aminoethanol (1) of the general formula I in relation to the aryl carbonyl compounds of the general formula III exceeds 60% »

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embodiment

The invention will be explained in more detail nach.s-teh.end by some examples.

example 1

Dimethylsulfate 8 g (0.05 mol) of methyl octyl sulfate and 7 S (0.055 mol) are mixed in 25 onr methylene chloride and allowed to stand for 48 hours at room temperature. 'Dimethyloctyl sulfonium' solution obtained is 0.15 S 2 -tetrabutylammonium bromide and 25 cm ^ added to a 50% aqueous solution of sodium hydroxide, then allowed with constant stirring 9.8 g (0.05 mol) of 3.4.5 ^l l imetho: xybenzaldehyd in 25 cm ^J methylene chloride dropwise, - The reaction mixture is The mixture is heated to boiling for 4 hours, then the organic layer is separated off, from which the solvent is evaporated, and 50 ml of isopropanol and 18 g (0.25 mol) of tert-butylamine are added. The mixture is heated to boiling for 8 hours, then the excess of tert-butylamine and the solvent are removed by steaming. From the residue, the recovered 1- (3 »4,5- ⁱ 3} i'imethoxyphenol) -2-tert-butylaminoethanol (1) is isolated in 5 mol of hydrochloride with a yield of 70% after crystallization from ethanol, the melting point -at 203 to 205 ⁰ C. Methyloktylsulfid is distilled from the residue. The structure of 1- (3,4 _t 5-trimethosymethyl) -2-tert-butylaminoethanol (1) was confirmed by the spectrum of proton magnetic resonance (PME).

Example 2

Following the same procedure as in Example 1 and using acetophenone, 1-phenyl-1-methyl-2-tert-butyl

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Aminoeth of oil (1) in the form of the hydrochloride having a melting point of 191 to 192 ⁰ C obtained »the structure of which was confirmed by the PMR method. The yield was 65%.

Example 3 .

According to a method as specified in Example 1, using p-ülitrobenzaldehyde for the reaction, 1- (4-nitrophenol) -2-tert-butylaminoethanol (1) was isolated in the form of a base in a yield of 73 % ; the melting point was 145 to 147 ⁰ Cj the structure was confirmed by the PME spectrum,

Example 4

In the procedure specified in Example 1 and using 1-STaphthaldehyde for the reaction, 1- (1-Uaphtho-7l) -2-tert-butylaminoethanol (1) in the form of: a _t base was obtained in 60 % yield. won; the melting point was at 125 to 126 ⁰ G, the structure was confirmed by the PMR spectrum »

Example 5

In a suspension of 16.4 g of powdered sodium hydroxide and 2.5 g of potassium carbonate in 50 eier methylene chloride with constant stirring, a solution of 32.5 g (0.11 mol) Dimethyloktylsulfoniuinmethylsulfat, which was obtained according to Example 1, 22.0 g (0.1 mol) of 3j5-I> dichloro-4-nitrobenzaldeb.yd and 0.33 S of iTetrabutylammoniusbromid dripped in 50 ml of methylene chloride at a rate at which the temperature of the ReaktionsgeniisGhes 25 ⁰ C is not exceeded. The Seaktionsgemisch is then heated for 2 hours at boiling temperature Ή ach cooling, the mixture is diluted with 50 cm ⁵ methylene chloride and filtered The solution is treated with

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2 χ 50 OTOr of water, and after drying with anhydrous magnesium sulfate, the methylene chloride is evaporated. The residue is dissolved in 110 cm.sup.2 of isopropanol, 20 .mu.r. (0.40 mol) of ertbutylamine are added and the whole is left for six hours. isopropanol and unreacted (Eertbutylamine are evaporated under reduced pressure »The remaining dark brown, crystalline residue is dissolved in -200 ml of ethanol and 25 cnr of a saturated ethanolic solution of hydrogen chloride are added · Each 10 minutes, the ethanol is evaporated, and the pike stand are added 100 cur benzene, then the whole is cooled to 0 ⁰ g; the cream-colored crystalline pike stand is filtered and washed with benzene »lan 21 g of 1- (3,5-dichloro-4-nitrophenyl) - 2-tert-butylaminoethanol (1) hydrochloride with a yield of 61.4 % , the melting point was 250 fyis 255 ⁰ C (decomposition), the Str uktur was confirmed by the PMB-iest as the one base *

Example 6 "

In a method-in Example 5 using 2-nitrobenzaldehyde and aniline for the reaction, 1- (2-nitrophenyl) -2-phenylaminoethanol in the form of the hydrochloride was recovered, the yield being 65%.

Elemental analysis;

Calculated! G 57.10 % H 5.10 % Έ 9.53 % Determined: 0 56.90% H 5.20 % Ή 9.46%

The structure confirmed by the PME method,

ti 

ι / R

CCHN _x Formula N .. 1

H ₁ Formula N..2

CO Formula No.3

Claims (5)

- 9 - δ2 556 12/37 16.11.83 invention claim 1
wherein Ar, X and R have the meaning given, whereupon the residue after removal of the water and / or a Part of the organic solvent with ammonia or 1
Dialkylamine group, S is a hydrogen atom, an alkyl group 1, Process for the preparation of i-aryl-2-aminoethanol (1) having the general formula 1 E ¹ "" 2
^! / OH Vi or in mean: Ar is a phenyl group, a naphthyl group or another aromatic or heterocyclic system such as pyridyl, ihienyl or furyl, T is one or more substituents, for example a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group, a Alkoxy group, an alkoxyalkyl group, an aralkyl group, an i-tetro group, an isonitrile group and a 2. The method according to item 1, characterized in that methyl chloride or benzene are used as a water-immiscible organic solvent. 2 "V 2. an amine of the general formula H -NH-R-, where H ο · and IIr have the meaning mentioned, is reacted and the product obtained is isolated and purified by known methods. 2 3 pe and an aralkyl group, E and S ^ are the same or different and are each a hydrogen atom, an alkyl, aralkyl and aryl group, characterized in that methyl alkyl sulfide having the general formula ESCHo, wherein B denotes a primary alkyl group having at least 4 carbon atoms, is subjected to reaction with dimethyl sulfate in a medium of a water immiscible organic solvent such that the resulting reaction mixture is in the presence of a Catalyst is reacted with alkali metal hydroxide or its concentrated aqueous solution and then with a compound of general formula HI X-Ar-C = O (III) - 10 - 62 556 12/37 16 * 11 * 83 3. The method according to item 1, characterized in that a quaternary ammonium salt, for example tetrabutylammonium chloride or bromide, is used as catalyst · 4 »Method according to item 1, characterized in that sodium or potassium hydrosulfide are sent as alkali metal hydroxide» 5. The method according to item 1, characterized in that a saturated solution is used as a concentrated aqueous solution.