DE1170961B - Process for the preparation of N- (N'-methyl-N'-ª ‰ -phenaethylamino-tert-butyl) -propionanilides - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school KL: C 07 c

German KL: 12 q- 1/02

Number: 1170961

File number: R 32520IV b / 12 q

Filing date: April 19, 1962

Opening day: May 27, 1964

It has been found that compounds of the general formula

CO

/ CH ₃
^ CH ₂ -

CH ₂ -

C ₂ H ₅
a tertiary butyl radical in the C4H8

CH ₃ CH ₃

-C-CH ₂ - or -CH ₂ -C-

CH ₃ CH ₃

and X denotes a hydrogen or halogen atom or the trifluoromethyl radical, valuable therapeutic ones Possess properties. Compounds similar in their chemical structure are already known. So have WB W right and coworkers (vgL Journal of Organic Chemistry, Vol. 26 [1961], p. 485) N- [2-Methyl-2- (N'-methyl-N'-jS-phenethyl) -aminoethyl] - propionanilide manufactured. In determining the analgesic effect of this compound, it was found that said propionanilide only shows an effect at 140 mg / kg, the known Tail clamping method according to H a f f η e r (German Medical Weekly [1929], p. 731) applied became. In contrast, the compounds prepared according to the invention are already sufficient about 10 mg / kg for an analgesia of several hours To evoke duration. Thus, with N- [2,2-dimethyl-2- (N '* methyl-N' ^ /? - phenethyl) aminoethyl] propionanilide produced painlessness for 4 hours in the mouse at a dose of 7 mg / kg.

The inventive method is characterized in that compounds of the general formula

CH ₃
Ri-CO-CR ₂

CH ₃

or the formula

CH ₃

Ri-C-CO-R ₂
OH ₃

Process for the production of

N- (N'-methyl-N'-ß-phenethylamino-tert-butyI) propionanilides

Register ,

Rohm & Haas G. m. B. H-,

Darmstadt, Mainzer Str. 42

Named as inventor:

Dr. Franz Wenzel,

Dr. Klaus Lehmann, Darmstadt

in the Ri the aniline radical which is optionally substituted in the above sense

NH-

means reduced to the corresponding diamines and these propionylated in a manner known per se will. As a reducing agent are, for. B. metal hydrides are suitable, with particular advantage Lithium aluminum hydride is used. The introduction of the propionic acid residue happens through Implementation of the diamine obtained in each case with propionic acid or its derivatives, in particular with propionic anhydride or propionic acid chloride. All compounds prepared according to the invention has an analgesic effect, albeit to a different extent. By varying the or the substituents denoted by X in the formulaic representation become compounds obtained that have additional therapeutic properties compared to the analgesic Effect can withdraw. Substituting a chlorine atom in the meta position gives a Compound with a central excitatory effect, while the corresponding trifluoromethyl compound is a has pronounced sedative effects.

The compounds prepared by the process according to the invention smd liquid bases with

409597/431

Acids form water-soluble salts and are advantageously applied in this form.

As already shown in the formula, the quaternary carbon atom of the tertiary butyl radical can either be bound to the nitrogen atom of the aniline residue or the phenethylamine residue. Connections of both Types can be produced within the meaning of the described invention and are therapeutically effective.

The new compounds are prepared in a manner known per se: starting from isobutyric acid one first produces a-bromoisobutyric acid bromide. By gradually replacing the Bromine atoms against the N-methyl-zS-phenethylamine residue on the one hand and against the optionally ring-substituted aniline residue on the other hand, one obtains a substituted aminoisobutyric acid amide, which according to the invention with z. B. LiAlHU to the corresponding Diamine is reduced. By propionylation with z. B. propionic anhydride, you get the desired End product. To the starting products, ao for the purposes of the invention by reduction and subsequent propionylation can be converted into the therapeutically effective end products, you can also come in the following way, for example:

Acetone cyanohydrin produced by the addition of hydrogen cyanide to acetone is mixed with an amine, z. B. aniline, converted to α-anilino-isobutyric acid nitrile; the reaction proceeds in a simple manner by bringing together approximately equimolar amounts of the starting products. By saponifying the CN group in the reaction product mentioned a-anilino-isobutyric acid obtained by reaction with N-methyl-yS-phenethylamine in the presence of phosphorus pentoxide into one of the formula

CH ₃

Ri - C - CO - R ₂ CH ₃

corresponding compound is converted, where Ri is the aniline and R2 is the N-methyl-ß-phenethylamine radical means.

Protection is not sought in the context of the invention for the preparation of these starting compounds.

The process according to the invention is illustrated in the examples below.

For example, 1 1

a) 23 g of a- (N-methyl-N-jS-phenäthylamino) -isobutyric anilide (prepared from a-bromoisobutyric acid bromide by reaction with aniline and N-methyl-ß-phenethylamine) are in 40 ml of n-dibutyl ether dissolved and to a suspension of 6.15 g of lithium aluminum hydride in 30 ml of n-dibutyl ether given. The mixture is heated to boiling for 15 hours with stirring, then the dibutyl ether is largely distilled off, diethyl ether is added and, after dropping in, the mixture is added the alkaline ether extract is distilled from sodium hydroxide solution.

Yield 13 g, corresponding to 60% of theory, N-P ^ -dimethyl-1 ^ N'-methyl-N '- ^ - phenethylamino) ethyl] aniline. Kp.005 = 155 to 156 ° C, n? = 1.5594.

b) 9.4 g of N- [2,2-dimethyl-2- (N'-methyl-N '- ^ - phenethylamino) ethyl] aniline are mixed with 13 g propionic anhydride and 4 hours under re-

40 river heated to the boil. Then dilute HCl is added, etherified, made alkaline, and again extracted with ether, and this ether extract is distilled.

Yield 9.5 g, corresponding to 85% of theory, of N- [2,2-dimethyl-2- (N'-methyl-N '- / S-phenethylamino) ~ ethyl] propionanilide. Bp 0.25 = 185 to 186 ° C, nl ° = 1.5423.

Analysis for C22H30N2O:

Found ... C 77.8%, H 9.0%, N 8.2%; calculated ... C 78.0%, H 9.0%, N 8.3%.

Example 2

a) 7.3 g of a- (N-methyl-N- / f-phenethylamino) -isobutyric acid-m-chloroanilide (prepared from a-bromoisobutyric acid bromide by reaction with m-chloroaniline and N-methyl-ß-phenethylamine) are with 1.55 g of L1AIH4 as in Example 1, but in tetrahydrofuran as a solvent and with a heating time of 5 hours to N- [2,2-dimethyl ~ 2- (N'-methyl-N '- /? - phenethylamino) ethyl] -m-chloroaniline reduced.

Yield 4.9 g, corresponding to 70% of theory. Bp 0.5 = 187 to 189 ° C, nl ° = 1.5672.

b) 7.35 g of N- [2,2-dimethyl-2- (N'-methyl-N- _j S-phenethylamino) ethyl] -m-chloroaniline are boiled as in Example 1 with 9.1 g of propionic anhydride and worked up.

Yield 7.1 g, corresponding to 82% of theory, of N- [2,2-dimethyl-2- (N'-methyl-N'- | 8-phenethylamino) ethyl] -m-chloropropionanilide. Bp o, oe = 177 to 179 ° C, nf = 1.5507.

Analysis for C ₂₂ H ₂₉ ClN ₂ O:

Found C 70.6%, H 8.2%, Cl 9.5%, N 7.8%; calculated C 70.8%, H 7.85%, Cl 9.5%, N 7.55%.

Example 3

a) 25.5 g of a- (N-methyl-N- / S-phenethylamino) -isobutyric acid-m-trifluoromethylanilide (prepared from a-bromoisobutyric acid bromide by reaction with m-trifluoromethylaniline and N-methyl-ß-phenethylamine) are with 5.55 g L1AIH4 as in example 2

reduced.
Yield 18.2 g, corresponding to 75% of theory,

N- [2,2-dimethyl-2- (N'-methyl-N '- / S-phenethylamino) ethyl] -m-trifluoromethylaniline. Kp. ₀ , i5 = 153 to 155 ⁰ C, n? = 1.5234. Monohydrochloride: M.p. = 134 to 135 ° C.

b) 11.6 g of N- [2,2-dimethyl-2- (N'-methyl-N'- | S-phenethylamino) ethyl] -m-trifluoromethylaniline are boiled as in Example 1 with 11.7g propionic anhydride and worked up.

Yield 9.1 g, corresponding to 75% of theory, of N- [2,2-dimethyl-2- (N'-methyl-N '- /? - phenethylamino) ethyl] -m-trifluoromethylpropionanilide. Bp 1 = 166 ° C,

nf = 1.5122.
Analysis for

Found
calculated

C 68.3%, H 7.4%, N 7.2%, F 13.7%; C 68.0%, H 7.2%, N 6.9%, F 14.0%.

Claims (3)

Patent claims: 1. Process for the production of N- (N'-methyl - N '- β - phenäthylamino - tert. - butyl) - propion- CH ₂ -CH ₂ ^> anilides of the general formula —C ₄ h ₈ -n CO C ₂ H ₅
in the C ₄ Hs a tertiary butyl radical CH ₃ CH ₃ -C-CH ₂ - or -CH ₂ -C-CH ₃ CH ₃ and X denotes a hydrogen or halogen atom or the trifluoromethyl radical, thereby characterized in that compounds of the general formula CH ₃ Ri- -c -
ι R ₂ I.
CH ₃ or the formula Ri- CO- R ₂ -CO- CH ₃ -c -
I. CH ₃ in the Ri the aniline radical which is optionally substituted in the above sense NH- and R ₂ the rest
CH ₃ -N-CH ₂ - means reduced and the substituted diamines formed are then propionylated will. 2. The method according to claim 1, characterized in that the reduction is carried out by means of lithium aluminum hydride.
3. The method according to claims 1 and 2, characterized in that such starting compounds can be used in which the substituent in the aniline residue is in the meta position is located. Considered publications:
German Auslegeschrift No. 1 118 212;
Journal of the American Chemical Society, 81, 1518 and 1519 (1959);
"Journal of Organic Chemistry", Vol. 26 (1961), pp. 476 to 490.