DK150851B - OXAZOLIDON- (2) COMPOUNDS FOR USING INTERMEDIATES FOR THE PREPARATION OF 4-AMINO-3,5-DIHALOGEN-PHENYLETHANOLAMINES - Google Patents

Description

150851

The invention relates to novel oxazolidone (2) compounds for use as intermediates in the preparation of 4-amino-3,5-dihalo-phenylethanolamines of the general formula I as claimed in which Hal is the same and represents a chlorine atom or a and R represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, preferably methyl, ethyl, propyl, tert. butyl or iso-pentyl, which compounds are characterized in that they have the general formula II as claimed, wherein Hal and R are as defined above.

The compounds of formula I are known compounds having pharmaceutically valuable properties. Thus, e.g. The N-alkyl-1- (4-amino-3,5-dihalo-phenyl) ethanolamines wherein the alkyl group is methyl or ethyl, analgesic properties, and the compounds in which the alkyl group is tert. butyl or iso-pentyl, has broneholytic properties.

The novel compounds of general formula II can be obtained by halo-

generating an oxazolidone of the general formula III

0

II

O N-R

HH2- ™ III

wherein R has the meaning given above, or acid addition salts thereof, in a solvent having at least 2 moles of bromine or chlorine.

The halogenation may be carried out in a solvent such as 50-100% acetic acid or in a halogenated hydrocarbon such as chloroform or in an alcohol such as ethanol, and preferably at temperatures between 0 and 50 ° C.

The compounds of general formula III used as starting materials may, for example, is obtained from the corresponding 4-nitrophenyl-ethanolamines by reaction with phosgene and subsequent reduction of the nitro group.

From the present intermediates, the ethanolamines of formula I are prepared by acidic or alkaline hydrolysis. This preparation is described in the specification for Danish Patent Application No. -5713/72.

Of course, from the specification of Danish Patent Application No. 4016/69, in particular Example 9 therein, it is known to prepare substituted phenyl-alkanolamines which are related to the end-products of formula I, by acidic or alkaline hydrolysis of the corresponding oxazolidone compounds. (2) compounds. In said Example 9, the preparation of (-) - erythro-α- (1-aminoethyl) -m- (p-chlorobenzyloxy) benzyl alcohol is described by alkaline hydrolysis of optically active cis-5- (m- [p-chlorobenzyloxy] -4 however, it could not be foreseen that the oxazolidones of formula II herein can be used as intermediates to produce 4-amino-3,5-dihalo by acid or alkaline hydrolysis. gene phenylethanolamines of formula I, and thus would achieve extremely good yields, as is the case, cf. Example 2 below. In chemistry, it is not possible simply to transfer a specific reaction, which is carried out in the course of a certain compound class, to another compound class, since other substituents, for example in aromatics, can completely change the reactivity of the total molecule. In said application No. 4016/69 there is the use of an aromatase which is in m position substituted with a p-chlorobenzyloxy group while they r in the present case is an intermediate substituted with an amino group at the 4-position and with halogen atoms at the 3- and 5-positions. However, from the literature it is known (see, for example, Fieser and Fieser, pages 625, 626 and 629) that at least 3 150851 by alkaline hydrolysis of aromatics substituted by halogen atoms a dehalogenation must be counted. Therefore, the person skilled in the art could not expect that the oxazolidones of this invention could be hydrolyzed in an almost quantitative yield to 1- (4-amino-3,5-dihalogenphenyl) ethanolamines,

The preparation of the intermediates of formula II and their use in the preparation of the final compounds of formula I are elucidated by the following Examples 1 and 2, respectively.

Example 1 5- (4-Amino-3,5-dibromo-phenyl) -3-tert. butyl oxazolidon- (2).

2.8 g of 5- (4-amino-phenyl) -3-tert. butyl-oxazolidone (2) (mp 102-104 ° C) is dissolved in 50 ml of glacial acetic acid and 2 ml of water and, with stirring, a solution of 3.9 g of bromine in 10 ml of glacial acetic acid is added dropwise within minutes. After 15 minutes, the reaction mixture is diluted with 250 ml of water extracted twice with chloroform and the organic phase is shaken with water, dried over sodium sulfate and evaporated. The residue is dissolved in a little vinegar ester and 5- (4-amino-3,5-dibromo-phenyl) -3-tert. butyl oxazolidone (2) is crystallized by the addition of petroleum ether.

Melting point 118.5-120 ° C.

Similarly, the following additional compounds are obtained by chlorination or bromination: a) 5- (4-Amino-3,5-dichloro-phenyl) -3-tert. buty1-oxazolidon- (2).

Prepared by chlorination of 5- (4-amino-phenyl) -3-tert. butyl-oxazolidinone and jacking points (2).

Mp 109-111 ° C.

b) 3-Ethyl-5- (4-amino-3,5-dibromo-phenyl) -oxazolidone- (2).

Prepared by bromination of 3-ethyl-5- (4-amino-phenyl) -oxazolidone- (2), mp 112-113 ° C.

c) 5- (4-Amino-3,5-dibromo-phenyl) -3-methyl-oxazolidone- (2).

Prepared by bromination of 5- (4-amino-phenyl) -3-methyl-oxazolidone- (2). Melting point 95-97 ° C.

d) 5- (4-Amino-3,5-dibromo-phenyl) -oxazolidone- (2).

Prepared by bromination of 5- (4-amino-phenyl) -oxazolidone- (2). Melting point 167-169.5 ° C.

e) 5- (4-Amino-3,5-dichloro-phenyl) -oxazolidone- (2).

Prepared by chlorination of 5- (4-amino-phenyl) -oxazolidone- (2). Melting point 157-159¾.

150851 4

Example 2 1- (4-Amino-3,5-dichloro-phenyl) -2-tert. butylamino-ethanol.

1 g (0.0033 mol) 5- (4-amino-3,5-dichloro-phenyl) -3-tert. butyl 1-oxazolidone (2) is dissolved in 20 ml of 2-propanol and 2 ml of water and 2 g of potassium hydroxide are added. The resulting two-phase solution is refluxed for 24 hours, and then 1- (4-amino-3,5-dichloro-phenyl) -2-tert is brought. butylamino-ethanol. for crystallization by the addition of some ethanol and water.

Yield: 0.80 g (87.4% of theory).

Melting point 116-119 ° C.

Molecular Weight: 277.20 (C

Calculated: G 52.01 H 6.55 N 10.10 Cl 25.57

Found: 51.70 6.40 9.85 25.00 Similarly, the following compounds of general formula I were prepared by acidic or alkaline hydrolysis of the corresponding oxazolidones: a) 1- (4-Amino-3,5- dibromo-phenyl) -2-tert.-butylamino-ethanol.

Melting point of hydrochloride 219.5-220 ° C (decomposition).

Prepared by alkaline hydrolysis of 5- (4-amino-3,5-dibromo-phenyl) -3-tert. butyl oxazolidon- (2).

v b) 2-Ethylamino-1- (4-amino-3,5-dibromo-phenyl) -ethanol.

Melting point of the hydrochloride 174-175 ° C (dec.).

Prepared by acidic hydrolysis of 3-ethyl-5- (4-amino-3,5-dibromo-phenyl) -oxazo-lidone- (2).

c) 1- (4-Amino-3,5-dibromo-phenyl) -2-methylamino-ethanol.

Melting point of hydrochloride 210-216 ° C (decomposition).

Prepared by acidic hydrolysis of 5- (4-amino-3,5-dibromo-phenyl) -3-methyl-oxazo-lidone- (2).

d) 2-Amino-1- (4-amino-3,5-dibromo-phenyl) -ethanol.

Melting point of hydrochloride 214-216 ° C (dec.).

Prepared by alkaline hydrolysis of 5- (4-amino-3,5-dibromo-phenyl) -oxazolone- (2).

e) 2-Amino-1- (4-amino-3,5-dichloro-phenyl) -ethanol.

Melting point of the hydrochloride 199-204 ° C (dec.).

Prepared by alkaline hydrolysis of 5- (4-amino-3,5-dichloro-phenyl) -oxazoli-don- (2).

Claims (2)

Oxazolidone (2) Compounds for Use as Intermediates for Preparation of 4-Amino-3,5-Dihalo-phenylethanolamines of the General Formula I ° H η I - Hal CH-CHO-N I Hal and represents a chlorine atom or a bromine atom and R represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, characterized in that they have the general formula II / II 0 N -R Hal CH-CH2 11 Hal wherein Hal and R have the meaning given above.