DD150198A5 - PROCESS FOR PREPARING NEW ALPHA-ACYLOXY-ACETAMIDES - Google Patents

Abstract

New alpha-acyloxy-acetamides of the general formula (I) in which R & ind1! a chlorine or bromine atom; R & ind2! the trifluoromethyl group, a fluorine or chlorine atom; R & IND3! a branched alkyl group or a cycloalkyl group each having 3 to 5 carbon atoms and the like; R & IND4! an acyl radical of a carboxylic acid. These new intermediates can be reduced to the corresponding phenyl-ethanolamines, which have valuable pharmacological properties, in particular broncholytic effects. The new intermediates are obtained by reacting a corresponding benzaldehyde with a corresponding isonitrile and a corresponding carboxylic acid.

Description

56 685 11

AP C07C / 218

Process for the preparation of novel o ^ -acyloxy-acetamides. Application of the invention

The invention relates to a process for the preparation of new oC-acyloxy-acetamides,.

The compounds prepared according to the invention are valuable intermediates for the preparation of phenylethanolamines which have valuable pharmacological properties, in particular bronchiolytic action. They are used as medicaments.

Characteristics of the known technical solutions

From the literature, a process for the preparation of Phenyläthanolamine the general formula II is already known, which is characterized in that a glycolic acid amide of the general formula

, rvnr

• H

(VI)

in the

K ^, R ₂ ¹ ^ K3 ^ i ^{e are} initially defined, is reduced with a complex Metallhydxid.

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

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It is also known from the literature (see J. Amerhern, ^Soc ., Pp. 1, 99 - W0 (1945)) that the Passerini reaction with sterically hindered and with ^, p-unsaturated carbonyl! can not make connections. Here, the inroactivity of e, ß, -unsaturated carbonyl compounds, z. B * of crotonaldehyde, compared to the Passerini reaction by the neutralization of the electronic center of the carbonyl functionality due to the mesomeric boundary structures _o

E-CH =: CH-C-R "> R-CH-CH = C-E

explained, so because of the electron-delivering effect of an adjacent group.

It is also known that the amino group in the o- or p-position of a phenyl nucleus has a strong electron-donating effect. ·

The expert would therefore have to expect that the electronic center of CarbonyIfunkt ion of a 4-amino-benzaldehyde of the general formula III due to its mesomeric limit structure of the general formula

, (11 ia)

deactivated and thus the Passerini reaction is not accessible. Surprisingly, this is not the case

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Object of the invention

The aim of the invention is to provide a simple and economical process by means of which the pharmacologically four-fold phenylthanolamines known from the literature can be prepared in good yield,

Explanation of the invention of the invention

The invention is based on the object of producing readily available starting materials new oxyacetylamides as intermediates,

According to the invention, new ^ C-acyloxy-acetamides of the general formula

CH-CO-N

prepared for use as intermediates for the preparation of phenylethanolamines of the general formula

OH H

CH - CH ₀ - N, (II)

which have valuable pharmacological properties, in particular bronchiolytic effects

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In the above general formulas I and II ", IL means a chlorine or bromine atom,.

the trifluoromethyl group, a fluorine or chlorine atom, a branched alkyl radical or a cycloalkyl group each having 3 to 5 carbon atoms and an acyl radical of a carboxylic acid,

Among the above-mentioned in the definition of Eeste Eo and B ^ meanings replacing IU particular the importance of isopropyl, isobutyl, tert-butyl, isopentyl, Heopentyl-, tert _e pentyl, cyclopropyl, cyclobutyl or cyclopentyl group and for E 1, those of an acyl radical of an aliphatic or aromatic carboxylic acid, such as acetic acid, propionic acid, trimethylacetic acid, valeric acid, benzoic acid, nitrobenzoic acid or naphthalene-2-carboxylic acid.

According to the invention, the new o-acyloxyacetamides of the above general formula I are obtained by reaction of a 4-amino

benzaldehyde of the general formula

CHO

, (III)

E ₂

in the

R ₁ and E _{2 are} as defined above, with an isonitrile of the general formula

NC - E ₃ , (17)

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in the

E ^ as defined above, and with a carboxylic acid of the general formula

V - ^0H

in the

E ^ as defined above.

For the preparation of a phenylethanolamine of the general formula II, a thus obtained o ^ -Acyloxy-acetamide of the general formula I, which can also be further reacted as a crude product, with a hydride, for. B * with a metal hydride or a complex metal hydride such as borane / tetrahydrofuran or lithium aluminum hydride, reduced »

The reaction of a 4-amino-benzaldehyde of the general formula III with an isonitrile of the general formula IY and with a carboxylic acid of the general formula V is conveniently carried out in a suitable solvent such as methylene chloride, chloroform, benzene, ither, tetrahydrofuran or dioxane at low temperatures, eg at temperatures between -20 and 75 ⁰ C, but expediently carried out at Eaumtemperatur. However, the reaction is preferably carried out in such a way that under Eühren and at room temperature either simultaneously from a dropping funnel, a compound of general formula I? and a carboxylic acid of general formula V to a solution of an aldehyde of general formula III or to a solution of an isonitrile of general formula IV and an aldehyde of general formula III a carboxylic acid of general formula V within several hours, for. B. 5 to 10 hours, added dropwise and then stirred for 10 to 165 hours.

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The reduction of an obtained ^ -acyloxy-acetamide of general formula I with a hydride is preferably carried out in a suitable solvent such as ether, tetrahydrofuran or dioxane at low to slightly elevated temperatures, e.g. B "at temperatures between 0 and 100 ⁰ C, more conveniently ~

However, carried out at the boiling temperature of the reaction mixture. However, the reduction with borane / tetrahydrofuran is carried out particularly advantageously at the boiling point of the tetrahydrofuran used as solvent.

The isolation of the desired end product of the general formula II is conveniently carried out via aqueous bases, z, B, via water / ammonia, wherein an optionally still existing C-acyloxy group is cleaved.

If desired, a phenylethanolamine of the general formula II thus obtained can then be converted with an inorganic or organic acid into its physiologically tolerated acid addition salt with the acid in question. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, Y / acid, citric acid. Fumaric acid or maleic acid into consideration.

The compounds of the general formulas IV and V used as starting materials are known from the literature.

An aldehyde of the general formula III used as starting material is obtained, for. B. by reduction of a corresponding 4-amino-benzoic acid halide or ester and subsequent oxidation of the optionally obtained benzyl alcohol with manganese dioxide.

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The good yields obtained by the process according to the invention could not be foreseen by a person skilled in the art; The inventive method thus represents an enrichment of the prior art.

Exemplary embodiment

The invention will be explained in more detail below on some embodiments.

example 1

O-acetoxy- ['' - '' - amino-, 5-dichloro-p- yl) -N-tert-butylacetamide

To a solution of 3.8 g (0.02 mol) of benzaldehyde A in 50 ml of absolute methylene chloride is added dropwise at room temperature 3 x 32 g (0.04 mol) of tert-butylisonitrile and 4.8 g (0.08 g) Moles) of glacial acetic acid from two separate dropping funnels at the same speed for 8 hours. Subsequently, the resulting solution is concentrated by half and cooled. The resulting unreacted 4-amino-3,5-dichlorobenzaldehyde is filtered off with suction and the PiItrat again concentrated by half. The same volume of diisopropyl ether is added to the resulting mixture to crystallize the desired product, which is filtered off with suction and washed with diisopropyl ether. Melting point: 175 to 176 ⁰ C

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Example 2

c ^ ~ acetoxy-c ^ - (4-amino-3,5-dichlo; r-phenyl) -N-tert-butyl acetamide ₀

To a solution of 30 g (0.16 mol) of 4-amino-3, ~ 5-dichlorobenzaldehyde in 280 ml of methylene chloride are added 4-5 ml of tert-butyl isocyanate and then with stirring and at room temperature ca, 40 ml of glacial acetic acid dripped for 16 hours. The mixture is then stirred for 4 hours and concentrated in vacuo until the first crystals precipitate. After cooling to 0 ⁰ C, the precipitated unreacted 4-amino-3 »5-dichlorobenzaldehyde is filtered off with suction. This can be implemented directly again. The filtrate is treated with η-hexane to precipitate the desired product. The precipitate is filtered off with suction, washed with η-hexane and dried

Melting point: 175 to 176 ⁰ C

Example 3 1- (4-amino-3 <5-dichloro-phenyl) -2-tert-butylaminoethanol

To a solution of 4.01 ga-acetoxy-4- (4-amino-3, 5-dichlorophenyl) -N-tert-butyl-acetamide in 50 ml of absolute tetrahydrofuran is added 100 ml of a 1 molar solution of borane in Given tetrahydrofuran. After refluxing for 2 hours, it is concentrated by evaporation, 100 ml of water are added and the mixture is acidified to pH 2 with hydrochloric acid. The aqueous phase is washed with ethyl acetate, then made alkaline with ammonia and extracted with methylene chloride. After concentrating the organic phase, the hydrochloride is obtained from isopropanol by addition of ethereal hydrochloric acid. Melting point of the hydrochloride: 174 - 175 ° C

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Example 4

acetic acid tert.butylamid

To a solution of 4.47 g (2OmMoI) of 4-amino-3-chloro-5-trifluoromethyl-benzaldehyde in 50 ml of methylene chloride at room temperature with stirring 3 * 32 g (40 nMol) tert * Butyliso nitril and 4.8 g (80 mmol) glacial acetic acid added dropwise simultaneously over 5 hours and then stirred for 65 hours at room temperature. After removal of the solvents in vacuo, the residue is dissolved in ether, washed successively with water and a saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo Damped dry. The residue is chromatographed over an egg-gel column with methylene chloride as a bluing agent. The fractions containing the desired compound are combined, concentrated and the residue is crystallized from ether

Melting point: 155-156 ⁰ C,

Example 5

^. (4-Amino-3 -chloro-5-trifluoromethyl-phenyl) -2-tert-butyl-amino-ethanol-hydrochloride

2 g (5 nmol * 4) ^ acetoxy- _<5 <;-( 4-amino ~ 3-chloro-5 - 'tetrahydrofuran dissolved trifluoromethylphenyl) -acetic acid tert butylamide _# v / ground in 15 ml of absolute and Nitrogen added to 27 ml of an i-molar solution of borane in tetrahydrofuran all at once. After refluxing for 4 hours, another 15 ml of 1 molar borane solution are added and the mixture is refluxed for a further 2 hours. Thereafter, the excess of borane is destroyed with acetone, the boron complex is decomposed with water and

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then the solvent was evaporated in vacuo. The aqueous distillation residue is acidified to pH 1 with 2N hydrochloric acid, made alkaline with ammonia, and extracted with ether. The ether extract vdrd with 0.5 η hydrochloric acid extracts the acidic solution with ether, alkalized with ammonia and extracted again with ither. The ether extract is washed with water, dried with magnesium sulphate and evaporated in vacuo. The oily argon residue is dissolved in ether and acidified with ethereal hydrochloric acid. The precipitated crystals are filtered off with suction and washed with ether

Melting point: 192-193 ⁰ C.

Example 6

_| og '~ acetox y · -og ~ (4-amino-3 ^ 5-dichloro-phθn, γl) ^ - tert, butyl acetamide

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

Melting point: 175 --176 ⁰ C

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Example, ^. '

^ _T ( _| 4 ^ Amino ~ 3.5 ~ dichloro-phenyl) - »o <C.-benzoyloxy ~ N-tert-butylacetamide

Prepared from ^ -Amino ^^ - dichloro-benzaldehyde, tert-butyl isonitrile and benzoic acid in.Chloroform and Eickflußtemperatur analogously to Example 4 _# Melting point j 189 - 192 ⁰ C (sintering from I85 ⁰ C)

Example 8

~ 3 ₁ β-dichloro-phenol) ~ ° ^ -valeroyloxy-N-tert-butyl-

a ceja mid

Prepared from 4-amino ~ 3 '~ 5-dichloro-benzaldehyde, tert-butyl isonitrile and valeric acid analogously to Example 4. Melting point: 95-98 ⁰ C

Example 9

Prepared from o ^ - (4-Aniino "3,5-dichloro-phenyl) -u6-benzoyloxy-K-tert-butyl-acetamide and lithium aluminum hydride in tetrahydrofuran · analogously to Example 3. Melting point of the hydrochloride: 174-175 ⁰ C.

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Example 10 1 ~ (^ -amino-3 ^ 5 - <3ichlor-phenyl) "- 2-tert _a butylaiiiino - ethanol

Prepared from 4-amino-3 »5 * -dichloro-benzaldehyde, tert.-butyl-isonitrile and valeric acid analogously to Examples 2 and without isolation of the formed ε - (4-amino-3,5-dichloro-phenyl) -lT-tert. -butyl-oC-valeroyloxy-acetamide, melting point of the hydrochloride j 174 - 175 ⁰ C.

The following compounds were prepared analogously to the above examples:

1- (4 ~ amino-3-rom b-5-f luor-pheny 1) -2-te rt _β b uty laminoäthanol hydrochloride Melting point: 207-208 ⁰ C.

1- (4-amino-3-chloro-5-flaor ~ phenyl) -2-cyclopropylaminoäthanol hydrochloride Melting point: 175-177 ⁰ C.

1- (4-amino-3-chloro-5-ilu.or-phenyl) -2-tert.butylaminoäthanol hydrochloride Melting point: 206-208 ⁰ C.

. 1 - (if_Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride Melting point: 177-178 ⁰ C.

1- (4-amino-3-bromo-5-fluoro-phenyl) -2-cyclob utylaminoäthanol hydrochloride Melting point: 164-166 ⁰ C.

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1- (4-amino-3-chloro ~ 5-'ferifluoriiiethyl-phenyl) -2-1; ert "pentylaiaino Ethanol bydro chloride Melting point: 176-178 ⁰ C (dec.)

1- (4-amino-3-chloro-5-fluoro-3-phenyl) -2-isopropylaminoethanol hydrochloride.

Meltpurple: 152 - 154 ⁰ C (Zers.)

1- (4-amino ~ 3 ~ t 'rom-5-'trifluormethyl-pherLyl) -2-cyclopeiitylamino Ethanol

Melting point: 100 to 102.5 ⁰ C (dec.)

Claims (3)

18 350 - 14 - 56 685 11 T o v e n ts a tio n s * 1 »Process for the preparation of new oC-acyloxy-acetamides of the general formula O - E ^ * ϊ ^ \ CH-CO- <".CD in the IL is a chlorine or bromine atom, the trifluoromethyl group, a fluorine or chlorine atom, o a branched alkyl radical or a cycloalkyl radical having in each case 3 to 5 carbon atoms and an acyl radical of a carboxylic acid, characterized in that a 4-amino-benzaldehyde of the general formula CHO , (III) in the R- and E ₂ vjie are defined above, with an isonitrile of the general formula HC-E ₃ , (IV) in the Eo as defined above, and with a carboxylic acid of the general formula - OH *, (V) - 15 - 56 685 11 in the "R ₁ , as defined above, is implemented * 2 · Process according to item 1, characterized in that the reaction is carried out in a solvent and at temperatures between -20 and 75 ⁰ C. 3 ancestors according to the items 1 and 2, characterized in that the reaction at room temperature and for several hours, z. B. 5 to 175 hours.