CS214689B2 - Method of making the phenylethanolamines - Google Patents

Description

The present invention relates to novel processes for the preparation of phenylethanolamines of formula (I)

in which

R 1 represents a chlorine or bromine atom,

R ₂ represents trifluoromethyl, fluorine or chlorine and

R 3 represents a branched alkyl or cycloalkyl group containing from 3 to 5 carbon atoms and their physiologically tolerable addition salts with inorganic or organic acids, the compounds having valuable pharmacological properties, in particular broncholytic activity.

Within the meaning of the above-mentioned R3, in particular, isopropyl, isobutyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, cyclopropyl, cyclobutyl or cyclopentyl groups are suitable for this symbol.

In accordance with the invention, the phenylethanolamines of the above general formula (I) are prepared by ss 4-aminobenzaldehyde of the general formula II

in which

Ri and R ₂ have the above meanings, is reacted with an isonitrile of the formula III

NC — R3 (ΠΙ) in which

R ₃ has the abovementioned meaning, with carboxylic acid. with an acid of formula IV

R 1 -OH (IV) in which

R4 represents an acyl radical of the carboxylic acid, and the thus obtained .alpha.-acyloxyacetamide of formula (V)

in which

Rj to. . R4. have the above. the meaning is reduced by a hydride, for example a metal hydride or a complex metal hydride.

Within . . In particular, any of the acyl radicals of aliphatic or aromatic carboxylic acids such as acetic acid, propionic acid, trimethylacetic acid, valeric acid, benzoic acid, nitrobenzoic acid or 2-naphthalenecarboxylic acid are suitable for this symbol.

The reaction of the 4-aminobenzaldehyde II with the isonitrile III and the carboxylic acid IV is conveniently carried out in a suitable solvent such as methylene chloride, chloroform, benzene, ether, tetrahydrofuran or dioxane. at lower temperatures, for example at -20 to 75 ° C, conveniently at room temperature. However, the reaction is preferably carried out by adding a compound of the formula III and a carboxylic acid of the formula II simultaneously from individual dropping funnels while stirring at room temperature for several hours, for example 5 to 10 hours. IV, or to a solution of the isonitrile III and the aldehyde II, the carboxylic acid IV, and the reaction mixture is stirred for a further 10 to 165 hours.

The reduction of the obtained α-acyloxyacetamide of the formula (V) with hydride is preferably carried out in a suitable solvent such as ether, tetrahydrofuran or dixane at a low to slightly elevated temperature, for example at 0 to 100 ° C, conveniently boiling the reaction mixture. However, a reduction with borane in tetrahydrofuran carried out under boiling of tetrahydrofuran as a solvent is particularly preferred.

Isolation of the desired final product of formula (I) is conveniently carried out using aqueous bases, for example a mixture of water and ammonia, whereupon any a-acyloxy group still present is cleaved.

The phenylethanolamine (I) thus obtained can then optionally be converted by treatment with an inorganic or organic acid into a physiologically compatible acid addition salt. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, tartaric acid, citric acid, fumaric acid or maleic acid.

The compounds III and IV used as starting materials are known from the literature.

The aldehyde II used as the starting material is obtained, for example, by reduction of the corresponding 4-aminobenzoic acid halide or ester and subsequent oxidation of the optionally obtained benzyl alcohol with manganese dioxide.

From literature. A process for the preparation of phenylethanolamines of the formula I is already known, characterized in that the glycolic acid amide of the formula VI

in which

R b R ₂ and R 3 are as defined above, reduced by a complex metal hydride.

However, this process has the disadvantage that the glycolic acid amides used as starting materials are difficult to prepare.

The good yields obtained with the novel process of the invention could not have been expected in advance, as it is known from the literature [see J. Am. Chem. Soc. 67, 1499-1500 (1945)] that Passerini reaction with sterically hindered and N-unsaturated carbonyl compounds cannot be accomplished. The inactivity of α-unsaturated carbonyl compounds, for example crotonaldehyde, against the Passerini reaction is explained by the neutralization of the electron center of the carbonyl function on the basis of mesomeric boundary structures. ® <? Θ

Thus, R-CH -CH-C-R-> R-CH-CH-C-R is due to the presence of an adjacent electron donating group.

Furthermore, the amino group at the o- or β-position of the phenyl core is known to act as a strong electron donor.

The expert had to. thus, the electron center of the carbonyl function of the 4-aminobenzaldehyde of formula II is expected to be due to its mesomeric boundary structure of formula IIa

deactivated, e - that the Passerini reaction is therefore inaccessible. Surprisingly, however, it has been found that in the process according to FIG. This is not the case.

The invention is illustrated by the following non-limiting examples.

Ex.

α-Acetoxy-α- (4-amino-3,5-dichlorophenyl) -N-tert-butyiacetamide

To a solution of 3.8 g (0.02 mol) -4-amino-3,5-dichlorobenzaldehyde in - 50 ml of absolute methylene chloride - was added dropwise at room temperature from 8 separate dropping funnels at the same rate at room temperature over 3 hours. 32 g (0.04 mol) of tert-butylisonitrile and 4.8 g (0.08 mol) of glacial acetic acid were then evaporated to half volume and cooled. The 4-amino-3,5-dichlorobenzaldehyde is filtered off with suction and the filtrate is again concentrated to half volume.A equal volume of diisopropyl ether is added to the residue, crystallizing the desired product, which is filtered off with suction and washed with diisopropyl ether.

The product melts at 175-176 ° C.

Example 2 N-Acetoxy-α- (4-amino-3,5-dichlorophenyl) -N-tert-butylacetamide

To a solution of 4-amino-3,5-dichlorobenzaldehyde (30 g, 0.16 mol) in methylene chloride (280 ml) was added tert-butyl isocyanide (45 ml), and 40 ml of glacial acid was added dropwise with stirring at room temperature over 16 hours. acetic. The reaction mixture is stirred for a further 4 hours and then evaporated in vacuo until crystallization begins. After cooling to 0 ° C, the unreacted 4-amino-3,5-dichlorobenzaldehyde precipitated is filtered off. This material can be directly reused. N-Hexane is added to the filtrate to precipitate the desired product. The precipitate is filtered off with suction and dried after washing with n-hexane.

The product melts at 175-176 ° C.

Example 3

1- (4-Aminophenol-2-yl) -2-tert-butylaminoethanol

To a solution of 4.01 g of .alpha.-acetoxy-.alpha .- (4-amino-3,5-dichlorophenyl) -N-tert-butylacetamide in 50 ml of absolute. tetrahydrofuran was added 100 mL of a 1 M solution of borane in tetrahydrofuran. After heating at reflux for 2 hours, the reaction mixture is evaporated, 100 ml of water are added to the residue and the mixture is acidified to pH 2 with hydrochloric acid. The aqueous phase is washed with ethyl acetate. then basified with ammonia and extracted with methylene chloride. After evaporation of the organic phase, isopropyl alcohol is obtained by adding ethereal hydrogen chloride; the corresponding hydrochloride.

The hydrochloride melts at 174-175 ° C.

Example 4

- (N-Acetoxy-α- (4-amino-3-chloro-5-trifluoromethylphenyl) acetic acid tert-amide) To a solution of 4.47 g (20 mmol) of 4-amino-3-chloro-5-trifluoromethylbenzaldehyde in 50 mL 3.32 g (40 mmol) of t-butylisonitrile and 4.8 g (80 mmol) of glacial acetic acid are added dropwise over 5 hours at room temperature with stirring, and the reaction mixture is stirred at room temperature for 65 hours. The residue was dissolved in ether, washed successively with water and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated to dryness in vacuo, and the residue was chromatographed on a silica gel column using methylene chloride as eluent. The fractions containing the desired compound were combined, evaporated and the residue crystallized from ether.

The product melts at 155-156 ° C.

Example 5

1- (4-Amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylaminoethanol hydrochloride g (5.4 mmol) α-acetoxy-α- (4-amino-3-chloro-5-trifluoromethylphenyl) tert-butylamide The acetic acid is dissolved in 15 ml of absolute tetrahydrofuran and the solution is added in a single portion under nitrogen to 27 ml of a 1 M solution of borane in tetrahydrofuran. After refluxing for 4 hours, an additional 15 ml of 1M borane solution is added, the reaction mixture is refluxed for 2 hours, then excess borane is quenched with acetone, the boron complex is quenched with water and the solvent is evaporated off under vacuum. The aqueous distillation residue was acidified to pH 1 with 2N hydrochloric acid, basified again with ammonia, and extracted with ether. The ethereal solution was extracted with 0.5 N hydrochloric acid, and the acidic solution was filtered. Wash with ether, basify with ammonia and extract again with ether. The ethereal extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The oily residue was. dissolved in ether and acidified with ethereal hydrogen chloride. The precipitated crystals are filtered off with suction and washed with ether.

The product melts at 192-193 ° C.

Example 6 a) Acethoxy-α- (4-amino-3,5-dichlorophenyl) -N-tert-butylacetamide

To a solution of 14.1 g (0.08 mol) of 4-amino-3,5-dichlorobenzaldehyde in 60 ml of methylene chloride was added 3.6 g (0.06 mol) of acetic acid and 2.5 g at room temperature with stirring. (0.03 mol) of tert-butylisonitrile was then heated to reflux for 3 hours. The above operation (addition of acetic acid and tert-butylisonitrile, and refluxing) is repeated four times, then the reaction mixture is poured into cold. 2 N sodium hydroxide solution and the organic phase are separated. After washing with water and drying over sodium sulfate, the organic phase is evaporated in vacuo and the residue is crystallized from a mixture of methylene chloride and hexane.

The product obtained melts at '175' to 176 ° C

Example 7.

ai- (4-Ainino-3,5-dichlorophenyl) -α-benzoyloxy-N-tert-butylacetamide

The above product was prepared in an analogous manner to Example 4 from 4 amino-3,5-dichloro-benzaldehyde, tert-butylisonitrile and benzoic acid in chloroform at reflux.

The product melts at 189-192 ° C (sinters from 185 ° C).

Example 8 o- (4-Amino-3,5-dichlorophenyl) -α-valeroyloxy-N-tert-butylacetamide

Above mentioned. The product was prepared in analogy to Example 4 from 4-amino-3,5-dichlorobenzaldehyde, tert-butylisonitrile and valeric acid.

The product melts at 95-98 ° C.

Example 1 and 9

1- (4-Amino-d, 5-dichlorophenyll- --- εгс.lamи)

The product was prepared in analogy to Example 3 from α- (4-amino-3,5-dichlorophenyl) -α-benzoyloxy-N-tert-butylacetamide and lithium aluminum hydride in tetrahydrofuran.

The hydrochloride melts at 174-175 ° C.

Example 10

1- (4-Amino-d, 5-dichlorophenyl-2-det. Butyl) aminomethanate

The above product was prepared from 4-amino-3,5-dichiophobenzaidehyde, tert-butylisnitrile and valeric acid in an analogous manner to Examples 2 and 5 without isolation of the resulting α- (4-amino-3,5-dichloro-phenyl) - N-tert-butyl-α-valeroyloxyacetamide.

The hydrochloride melts at 174-173 ° C.

The following compounds were prepared in an analogous manner to the previous examples:

1- (4-Amino-3-bromo-5-fluorophenyl) -2-tert-butylamino-ethanol-ethanol hydrochloride. mp 207-208 ° C,

1- (1-Amino-3-chloro-5-fluorophenyl-2-cyclopropylamino-ethanol-hydrochloride), m.p. 175-177 ° C;

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butyl-4-amino-ethanol-chlorochloride, m.p. 206-208 ° C;

1- (4 (amino) (3-chloro (5-trifluoromethylphenyl)) -2-cyclobutylaminoethanol hydrochloride, m.p. 177-178 ° C,

1- (4 (aminr (3 (bfrm (5 (fluorophenyl) -2-cyclobutyl) 4-aminoethanol hydrochloride), m.p. 164-166 ° C),

1- (4 (amino (3-chloro-5 (trifluoromethylphenyl) -2-t-pentylaminoethoxyphenoxy) chloride) melting at 176-178 ° C with decomposition,

1- (4-Amino (3-chloro-5-fluorophenyl) -Z-isopropylaminethanol hydrofluoride melting with decomposition at 152 to 154 ° C and 1- (4-4mino-3-bromo-5-trifluoromethylphenyl) (2-cyclopentylaminoethanol) melting with decomposition at 100 to 102.5 ° C.

Claims (7)

OBJECT OF THE INVENTION A process for the preparation of phenylethanolamines of the general formula I in which R 1 represents a chlorine or bromine atom, R ₂ represents trifluoromethyl, fluorine or chlorine and R ₃ represents a branched alkyl or cycloalkyl group which has 3 to 5 carbon atoms, and their physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that the 4-aminobenzaldehyde of the formula II Ri and R ₂ have the above meanings, is reacted with an isonitrile of the formula III NC-R ₃ (III) in which R ₃ is as defined above, and with a carboxylic acid of the general formula IV in which R _{@ 1} to R _{@ 4} as defined above are reduced with a hydride, for example a metal hydride or a complex metal hydride, in a solvent at 0 to 100 ° C, whereupon the optionally obtained phenylethanolamine of the formula I is converted into a physiologically tolerable an acid addition salt. 2. Process according to claim 1, characterized in that the reduction is carried out under the boiling of the solvent used. 3. The method of item 1 or. 2, characterized in that the reduction is carried out using a solution of borane in tetrahydrofuran. 4. A process according to any one of claims 1 to 3, wherein the reduction is carried out using crude a-acyloxyacetamide of the above-mentioned general formula V. 5. A process according to any one of claims 1 to 4, wherein the reaction mixture is treated with an aqueous base, e.g. aqueous ammonia, to isolate the resulting product of formula (I). 6. A process according to claim 1 for the preparation of 1- (4-amino-3,5-dlchlorophenyl) -2-tert-butylaminoethanol and its physiologically tolerable addition salts with inorganic or organic acids, characterized in that 5-dichlorobenzaldehyde is reacted with tert-butylisonitrile and a carboxylic acid of formula IVa R ₄ '- OH * (IVa) in which R ₄ 'represents an alkanoyl group, and the thus obtained α 1 -acyloxyacetamide of formula Va R ₄ —OH in which (IV), R ₄ represents an acyl radical of the carboxylic acid, in the presence of a solvent, at a temperature of -20 to> 75 ° C, preferably at room temperature, and the thus obtained ai-acyloxyacetamide of the general formula V R &lt; 1 &gt; is as defined above, is reduced with borane, and then optionally obtained 1- (4-amino-3,5-dichlorophenyl) -2-tert-butylaminoethanol is converted by treatment with an inorganic or organic acid to its physiologically tolerable acid addition salt. . 7. The process of item 1 for producing phenylethanolamines of formula Ib om _H 1 'CH-CH 2 N -tsjj H _Z N 1 3 CF ₃ (Ib) in which R1 represents a chlorine or bromine atom and R3 represents a branched alkyl or cycloalkyl group containing from 3 to 5 carbon atoms and their physiologically tolerable addition salts with organic or inorganic acids, characterized in that the 4-aminobenzaldehyde of the formula IIb is which Rt has from above. is reacted with an isonitrile of formula III NC - R3 (III). in which R 3 is as defined above, and with a carboxylic acid of formula IVb R4 '—OH (IVb) in which R4 'represents an acyl radical of the carboxylic acid, and the thus obtained ω-acyloxyacetamide of the general formula Vb in which: R _1, R 3 and R 4 are as defined above, are reduced with a hydride, for example a metal hydride or a complex metal hydride, and then the phenylethanolamine (Ib) thus obtained is converted by treatment with an inorganic or organic acid into its physiologically tolerable acid addition salt. sevarofraliA, a., · Plant 7, Mou