FI73973C - FOERFARANDE FOER FRAMSTAELLNING AV -ACYLOXI- - (4-AMINO-PHENYL) -ACETAMIDER. ADDITIONAL PATENT 59396 - TILLAEGG TILL PATENT 59396. - Google Patents

Description

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SUOMI FINLAND

(Fl) (21) Patent application-Patentansökning 79380A

(22) Date of application - Ansökningsdeg 0A.12.79

National Board of Patents and Registration (23) Starting date - Giltighetsdag o A. 12.79

Patent-och ragisterstyrelsen (41) Published public - Biivit offentiig 2A.0A.8i (44) Date of dispatch and of publication 08 87

Ansökan utlagd och utl.skriften publicerad -5 4 4 '(86) Kv. Application-Int. ansökan (32) (33) (31) Privilege claimed - Begärd priority 23.10.79

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 29A2723.A

(71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, Biberach an der Rlss, Federal Republic of Germany-FörbundsrepublΪken Tyskland (DE) (72) Jarkko Ruohonen, Vanhalinna, Kauko Nieminen, Masku, Finland-Finland (FI), Johannes Keck, Biberach, Gerd Kruger, Biberach, Federal Republic of Germany Förbundsrepubl iken Tyskland (DE) (7A) Lei tzinger Oy (5A) Methods for the preparation of acyloxy-o (- (A-amino-phenyl) -acetamides -Förfarande för framstäl lning avo <-acyloxi -b (- (A-amino-phen 1) -acetamider (61) Addition to patent 59396 - Tillägg till patent 59396

The present invention relates to a process for the preparation of α-acyloxy-of- (4-amino-phenyl) -acetamides of formula (I) O - R 4 R 1

K1 n ... CH - CO - N

| Il X * 3 tl) R2 where

R1 is a chlorine or bromine atom, R2 is a fluorine atom, a trifluoromethyl group, or also a chlorine atom if R3 is an isopropyl or isobutyl group, a branched alkyl group having 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms or R4 is a benzoyl group.

2,73973 R3 is a branched alkyl group or a cycloalkyl group each having 3 to 5 carbon atoms and R4 is an alkanoyl group having 1 to 5 carbon atoms or a benzoyl group.

Of the acyloxyacetamides of general formula (I) according to the invention are obtained by reacting 4-amino-benzaldehyde of general formula (III)

Rj; ___ CHO

(III) H2N '^ p R2 wherein

R1 and R2 are as defined above, to react an isonitrile of general formula (IV) CN to R3 (IV) wherein R3 is as defined above and with a carboxylic acid of general formula (V) R4 to OH (V) wherein R4 is as defined above.

To prepare 1- (4-aminophenyl) -2-aminoethanol derivatives, the cis-acyloxyacetamide of general formula (I), which can also be further reacted as a crude product, is reduced with a hydride, for example a metal hydride or a complex metal hydride such as borane / tetrahydrofuran or lithium aluminum hydride.

The reaction of a 4-amino-benzaldehyde of general formula (III) with an isonitrile of general formula (IV) and a carboxylic acid of general formula (V) is conveniently carried out in a suitable solvent such as methylene chloride, chloroform, 3,73973 benzene, ether, tetrahydrofuran or dioxane -20 and 75 ° C, but suitably at room temperature.

However, the reaction is best carried out by stirring at room temperature, either simultaneously, a compound of general formula (IV) and a carboxylic acid of general formula (V) into a solution of an aldehyde of general formula (III) or an isonitrile of general formula (IV) and an aldehyde of general formula (III). the carboxylic acid of general formula (V) over a period of several hours, for example over 5 to 10 hours and then stirred for a further 10 to 165 hours.

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

The aldehyde of the general formula (III) used as a starting material is obtained, for example, by reduction of the corresponding 4-amino-benzoic acid halide or ester and then oxidation of the benzyl alcohol optionally obtained with lignite.

A process for the preparation of 1- (4-aminophenyl) -2-aminoethanol derivatives is already known from the literature, which is characterized in that the glycolic acid amide of the general formula (VI)

OH H

R - CO - N

X jj? '3 H2N ^ Y (VI) R2 where

R1, r2 and r3 have the same meaning as above, are reduced with a complex metal hydride.

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

4,73973

The good yields obtained by the new process according to the invention were unexpected for a person skilled in the art, since it is known from the literature (see J. Amer. Chem. Soc. 67, 1499-1500 (1945)) that the Passerini reaction cannot be carried out with sterically hindered and ctf, / S- with unsaturated carbonyl compounds. a (.0-unsaturated carbonyl compounds, for example crotonaldehyde, in the case of the Passerini reaction is explained by the neutralization of the electron center of the carbonyl function in the mesomeric boundary structure O © O Θ

Il I

R-CH = CH-C-R R-CH-CH = C-R

i.e., the electron-producing effect of the adjacent group.

It is further known that the amino group in the o- or p-position of the phenyl group has a strong electron-producing effect.

Thus, one skilled in the art would expect that the electron center of the carbonyl function of 4-amino-benzaldehyde of general formula (III) is deactivated by the electronic center of general formula (IIIa).

RlW-o0 ^ (Ula)

H R

R2 due to its mesomeric boundary structure, in which case the Passerini reaction is not possible. Surprisingly, however, this is not the case.

The following examples further illustrate the invention: 5,73973

Example 1 o (-acetoxy) - (- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -acetic acid tert-butylamide)

A solution of 4.47 g (20 mmol) of 4-amino-3-chloro-5-trifluoromethylbenzaldehyde in 50 ml of methylene chloride is added dropwise at room temperature with stirring over a period of 5 hours to 3.32 g (40 mmol) of tert. butyl isonitrile and 4.8 g (80 mmol) of glacial acetic acid, followed by stirring for 65 hours at room temperature. The solvent is removed in vacuo, then the residue is dissolved in ether, washed successively with water and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue is chromatographed on a silica gel column using methylene chloride as eluent. The fractions containing the desired compound are combined, evaporated and the residue is crystallized from ether. Melting point: 155-156 ° C.

Example 2 of- (4-Amino-3,5-dichloro-phenyl) -of-benzoyloxy-N-tert-butyl-acetamide_

Prepared according to Example 1 from 4-amino-3,5-dichlorobenzaldehyde, tert-butyl isonitrile and benzoic acid in chloroform at reflux temperature.

Melting point: 189-192 ° C (sintered from 195 ° C).

Claims (2)

Process for the preparation of o (-acyloxy-o (- (4-amino-phenyl) -acetamides of formula (I)) according to patent 59 396 0. R4 h R1 CH - CO - N .Xf ..... in which R2 R1 is a chlorine or bromine atom, R2 is a fluorine atom, a trifluoromethyl group, or also a chlorine atom if R3 is an isopropyl or isobutyl group, a branched alkyl group, having 5 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms or R4 being a benzoyl group, R3 being a branched alkyl group or a cycloalkyl group each having 3 to 5 carbon atoms and R4 being an alkanoyl group having 1 to 5 carbon atoms or a benzoyl group, characterized therein that the 4-amino-benzaldehyde R2 of the general formula (III) is CHO with isonitrile CN - r3 (IV) wherein R3 is as defined above, and with carboxylic acid of formula (V) R4 - OH (V) wherein R4 is as defined above.