DD156179A5 - PROCESS FOR THE PRODUCTION OF PHENYLETHANOLAMINES - Google Patents

Abstract

The invention relates to a process for the preparation of phenylethanolamines having valuable pharmacological properties, in particular broncholytic action. The aim of the invention is to provide a simple and economical process by means of which phenylethanolamines can be prepared in good yield. According to the invention, phenylethanolamines of the general formula I in which R is 1, a chlorine or bromine atom, R 2 is the trifluoromethyl group, a fluorine or chlorine atom and R 3 is a branched alkyl radical or a cycloalkyl radical, and their physiologically acceptable acid addition salts are prepared by Reaction of a 4-amino-benzaldehyde with an isonitrile and with a carboxylic acid and subsequent reduction with a hydride, eg a metal hydride or a complex metal hydride.

Description

Berlin, January 23, 1981 58 325/11

Process for the preparation of Pheuylethanolaminen

Field of application of the invention

The present invention is a new process for the preparation of phenylethanolamines of the general. formula

- N-

(D,

which have valuable pharmacological properties, in particular broncholytic effects.

In the above general formula I mean:

R _{1 is} a chlorine or bromine atom,

R _{2 is} the trifluoromethyl group, a fluorine or chlorine atom and

R ~ is a branched alkyl radical or a cycloalkyl group each having 3 to 5 carbon atoms.

Among the meanings mentioned in the definition of the radical R-entry is in particular the meaning of isopropyl, isobutyl, tert-butyl, isopentyl, ITeopentyl, tert-pentyl, cyclopropyl, cyclobutyl or cyclopentyl

group into consideration.

23. 1 .. 1931 58 325/11

CHARACTERI stik that be known en te chni s ch eii Lo sunk en

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

OH

CHCO

(VI)

in the

R ₁ , R, -, and R ~ are as defined above, reduced with a complex metal hydride ·

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

Y / eiterhin is known from the literature (see J. Amer ehern "Soc, 67, 1499 to 1500 (1945)) that the Passerini reaction with sterically hindered and with c (, ß-unsaturated carbonyl compounds can not perform. Here, the inreactivity of the α, ß-unsaturated carbonyl compounds, ζ " B" of crotonaldehyde, to the Passerini reaction by the neutralization of the electronic center of the carbonyl function due to the mesomeric boundary structures

R-CH = CH-C-R

R-CH-CK = C-R

23 «1. 1981 58 325/11

explained, that is due to the electron-supplying 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 skilled person would therefore have to expect that the electronic center of the carbonyl function of a 4-amino-benzaldehyde of the general formula II due to its mesomeric limit structure of the general formula

(IIa)

deactivated and thus the Passerini reaction is not accessible.

Aim of the invention

The aim of the invention is to provide a simple and economical process by which phenylethanolamines having valuable pharmacological properties can be produced in good quality.

Explanation of the essence of the invention

The invention has for its object to find readily available starting compounds and suitable reaction conditions for the preparation of Phenylethanolaminen.

23 · 1. 1981 58 325/11

According to the invention, the phenylethanolamines of the above general formula I are obtained by reacting a 4-aminobenzaldehyos of the general formula

(II)

in the

R .. and R _{2 are} as defined above, with an isonitrile

the general formula

HC -

(III)

in the

R_ is as defined above, and with a carboxylic acid of

general formula

R ₄ - OH

(IV),

in the

R. represents an acyl radical of a carboxylic acid, and reduction of a thus obtained W-acyloxy-acetamide of the general

formula

0R _y

.H

CH-CO- I

23. 1. 1981 58 325/11

in the

IL. to R. as defined above, with a hydride, ζ «B. with a metal hydride or a complex metal hydride«

Among the meanings mentioned in the definition of the radical R, in particular, is the meaning 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 ITaphthalene-2-carboxylic acid in consideration

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

The reduction of a resulting cx-acyloxy-acetamide of the general formula V 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.

23. 1. 1981 58 325/11

at temperatures between 0 and 100 ⁰ C, but advantageously at the boiling temperature of the reaction mixture, carried out. However, the reduction with borane / tetrahydrofuran is particularly advantageously carried out at the boiling point of the tetrahydrofuran used as solvent.

The isolation of the desired end product of general formula I is conveniently carried out over aqueous bases, for. B. on V. ^r aERER / ammonia, wherein an optionally still existing oC-acyloxy group is cleaved.

A phenylethanolamine of the general formula I thus obtained can if desired subsequently be converted with an inorganic or organic acid into its physiologically tolerated acid addition salt with the relevant acid. Suitable acids for this example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, tartaric acid, citric acid, fumaric acid or maleic acid into consideration.

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

An aldehyde of the general formula II 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.

The good yields obtained according to the novel process of the invention could not be foreseen by a person skilled in the art. Rather, the person skilled in the art had to assume in the known state of the art that the invention

23. 1. 1981 58 325/11

_ 7 -

would not be feasible according to the reactions carried out. Surprisingly, this is not the case.

Execution ia game

The following examples are intended to explain the invention in more detail:

example 1

<X ~ acetoxy <^ - (4-amino-3> 5 ~ dichloro-phenyl) ~ lT-tert, -butylace tamid

To a solution of 3.8 g (0.02 mol) of 4-amino-3J5 "-dichlorobenzaldehyde in 50 ml of absolute methylene chloride is added dropwise with stirring at room temperature 3 * 32 g (0.04 mol) of tert-butylisonitrile and 4, 8 g (0.08 mol) of glacial acetic acid from two separate dropping funnels at the same speed for 8 hours, then half of the resulting solution is concentrated and cooled, the resulting unreacted 4 ~ amino-3,5-dichloro-benzaldehyde is filtered off with suction and the same amount of diisopropyl ether is added to the resulting mixture, whereby the desired product crystallizes out, which is filtered off with suction and washed with diisopropyl ether

Melting point: 175 to 176 ⁰ G,

Example 2

cC-acetoxy- <X- (4-amino-3,5-dichloro-phenyl) ~ lT ~ tert. butylacetamide _;

To a Lösimg of 30 g (0.16 mol) of 4-amino-3 »5-dichlorobenzaldehyde in 280 ml of methylene chloride 45 ml tert.-

23. 1. 1981 58 325/11

- 8th

Butyl isocyanide and then added dropwise with stirring and at Räumteraperatür about 40 ml of glacial acetic acid for 1β hours. Then it is stirred for a further 4 hours and concentrated in vacuo until the first crystals precipitate, after cooling to 0 ⁰ C, the precipitated unreacted 4-amino-3,5-dic.hlorbenzaldehyd is filtered off with suction. This can be implemented directly again. The filtrate is mixed 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 ^° C.

Example 3

1 ^ (4 ^ amino - 3 5 -? D.ichlor ° phenyl) -2- "te rt .-- but ylamino - ethanojL

To a solution of 4> 01 g of iX-acetoxy - <- (- (4-araino-3,5-dichlorophenyl) ~ N-tert-butyl-acetamide in 50 ml of absolute tetrahydrofuran is added 100 ml of a After stirring for 2 hours under reflux, it is concentrated, 100 ml of water are added and the mixture is acidified with hydrochloric acid to pH 2. The aqueous phase is washed with ethyl acetate, then made alkaline with ammonia and extracted with methylene chloride Concentration of the organic phase gives the hydrochloride from tsopropanol by addition of ethereal hydrochloric acid

Melting point of the hydrochlorides: 174 to 175 ⁰ CV

23. 1. 1981 58-325 / 11

2274 54 O - ⁹ -

Step Example l 4

<X-Acetoxy-c <- (4-amino-3-chloro-5-trifluoromethylphenyl) -sulfite tert. butylamide

To a solution of 4.47 g (0.02 mol) of 4-amino-3-chloro-5-trifluoromethyl-benzaldehyde in 50 ml of methylene chloride at room temperature with stirring 3> 32 g (0.04 mol) of tert. Butyl isonitrile and 4.8 g (0.08 mol) of glacial acetic acid simultaneously during. After stirring for 5 hours at room temperature, the solvent is removed in vacuo and the residue is dissolved in ether, washed successively with water and a saturated solution of sodium bicarbonate, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue chromatography is rt over a silica gel column with methylene chloride as eluent. The fractions containing the desired compound are combined, evaporated and the residue is crystallized from ether. Melting point: 155 ⁰ C. bit 156

Example 5

1 ~ (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butyl- amino-ethanol-hydrochloride

Dissolve 2 g (5%) of methyl acetate (4-amino-3-chloro-5-trifluoromethylphenyl) -acetic acid tert -butylamide in 15 ml of absolute tetrahydrofuran and bring to -27 under nitrogen ml of a 1M solution of borane in tetrahydrofuran added all at once. After refluxing for 4 hours, another 15 ml of 1M 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

23. 1. 1981 58 325/11

closing the solvent evaporated in vacuo. The aqueous distillation residue is acidified with 2 η hydrochloric acid to pH 1, made alkaline again with ammonia and extracted with ether. The ether extract is extracted with 0.5 N hydrochloric acid, the acidic solution is washed with ether, alkalized with ammonia and extracted again with ether. The ether extract is washed with water, dried with magnesium sulfate and evaporated in vacuo. The oily evaporation 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 to 193 ⁰ C

Example 6

~ C ^ - (4-amino-3 , 5-dicyclo-ph-enyl) ~ B-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-butylisonitrile. The reaction mixture is then refluxed for 3 hours. After the above operation (addition of acetic acid, tert-butylisonitrile under reflux) is repeated 4 times, pour the reaction mixture into cold 2N sodium hydroxide solution and separate the organic phase , Each washing with water and drying of the organic phase over sodium sulfate v / ird concentrated in vacuo and the residue crystallized from methylene chloride / hexane, m.p .: 175 to 176 ⁰ C.

January 23, 1981. 58 325/11

227 4 54 O -1- · -

Example 7.

-Araino-3> 5-di-chloro-phenyl) ~ CL-benzoylozy-N-tert-butyl

acetami d

Prepared from 4-amino-3 »5-dichloro-benzaldehyde, tert-butylisonitrile and benzoic acid in chloroform and at reflux temperature analogously to Example 4 # Melting point: 189 to 192 ⁰ G (sintering from 185 ⁰ C).

Example 8

(Xr- (4-amino-3) -5-dicb-lor ~ plienyl) - ^<:::> C -valeroyloxy-N-tert- butylacetamide

Prepared from 4-Aioino-3,5-dichloro-benzaldehyde, tert, -Butylisoiiitril and valeric acid analogously to Example 4. Melting point: 95 to 98 ⁰ C.

Example 9

1- (4 ~ ~ ß A mino, 5-dichloro-phenyl) ~ 2 -th t "-but-ylamino thanpj e.

Prepared from ^<X .- (4-Amino-3J5-dichloro-phenyl) -0 (_- benzoylox: yN-tert, butyl-acetamide and lithium aluminum hydride in tetrahydrofuran analogously to Example 3 "melting point of the hydrochloride: 174 to 175 ⁰ C,

Example 10 1- (4 - Am _i i no-3> 5 "dichloro-phgnyl) -2-tert _<, -butylariiino-ethanol

Prepared from 4-amino ~ 3> 5 ~ dichloro-benzaldehyde, tert-butylisonitrile and valeric acid analogously to Examples 2 and

23. 1. 1981 58 325 /

5 without isolation of the formed C <w- (4-amino-3 '5-dich.lorphenyl) ~ H-tert-butyl-O ^ -valeroyloxy-acetamide · Melting point of the hydrochloride: 174-175 ⁰ C ·

The following compounds were prepared analogously to the above examples:

1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylaminoet.hydanol hydrochloride Melting point: 207 to 208 ^° C

1 - (4-amino-3-ch.lor-5-fluoro ~ ph.enyl) -2-cyclopropylam.inoethaiiol hydrochloride Melting point: 175 to 177 ⁰ C.

1 - (4-amino-3-chloro-5-fluoro-phenyl) -2-te rt. Butylaminoethanol hydrochloride Melting point: 206 to 208 ⁰ C.

1- (4-Amino-3-chloro-5-trifluoromethylphenyl) -2-cyclobutylamino-e-ethanol hydrochloride Melting point: 177-178 ⁰

1- (4 ~ amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylaminoethanol hydrochloride Melting point: I64 to 166 ⁰ C.

1- (4-amino-3-chloro-5-trifluorniethyl-phenyl) -2-tert · - pentylamino-e.thanol hydrochloride Melting point: 176 to 178 ⁰ G (dec ·)

1- (4-amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino ethanol hydrochloride Melting point: 152 to 154 ⁰ G (dec.)

23. 1. 1981 58 325/11

1 ~ (4-Araino-3-bromo-5-trifluoromethylphenyl) -2-cyclopentylamino-ethanol -

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

Claims (7)

23. 1. 1981 58 325/11 1. A process for the preparation of phenylethanolamines of the general formula (D, in the R ^ is a chlorine or bromine atom, R "is the trifluoroethyl group, a fluorine or chlorine atom and R "is a branched alkyl radical or a cycloalkyl radical each having 3 to 5 carbon atoms, as well as their physiologically acceptable acid. Additionssalaen with inorganic or organic acids, characterized in that a 4-aminobenzaldehyde of the general formula CHO (ID, , January 23, 1981 58 325/11 2274 54 Ο- ¹⁵ - in the R. and Rp are as defined above, with an isonitrile of the general formula ITC - R ₃ (III), in the . R- is as defined above, and with a carboxylic acid of the general formula R ₄ - OH (IV), in the R. represents an acyl radical of a carboxylic acid is reacted and thus obtained oL- acyloxy-acetamide of the general formula ο - R ₄ CH - CO -: in the R ₁ to R, as defined above, with a hydride, for. B * a metal hydride or a complex metal hydride, is reduced and then, if desired, a resulting phenylethanolamine of the general formula I is converted with an inorganic or organic acid in its physiologically acceptable Sä'ureadditionssalz · 23. 1. 1981 58 325/11 • A II - 16 - 2. The method according to item 1, characterized in that the reaction is carried out in a solvent. Method according to points 1 and 2, characterized in that the 1 × reaction step is carried out at temperatures between -20 and 75 ^° C., but preferably at room temperature. 4. The method according to points 1 and 2, characterized in that the reduction at low to slightly elevated temperatures, z, B. at temperatures between 0 and 100 ⁰ C, is performed. 5c Process according to items 1, 2 and 4, characterized in that the reaction is carried out at the boiling point of the solvent used. 6. Process according to items 1, 2, 4 and 5 »characterized in that borane / tetrahydrofuran is used as hydride and tetrahydrofuran as solvent, 7 «method according to the points 1, 2 and 4 to 6, characterized in that in the reduction, a crude product of a © (acyloxy-acetamide of the general formula I is used. 8. The method according to points 1 and 4 to 7, characterized in that the workup via an aqueous base, ζ «Β« via water / ammonia, takes place.