DE1620463A1 - Process for the preparation of basic substituted amides of alpha-acylaminoacrylic acids - Google Patents

Description

B _E S0HKEI _Bg K ₆ T620463 Process for the preparation of basic substituted amides of the

α-acylamino-acrylic acids .

In the patent application Sch 38 215 IVb / l2 ο a process for the preparation of the previously unknown basic substituted amides of Ot-. Acylamino-acrylic acids described, which consists in reacting the azlactones of the C-acylamino-acrylic acids with tert-amino-alkylamines in suitable solvents at tree temperature or with heating. The reaction products are characterized by special pharmacological properties.

According to this process, N- (ß-morpholine ethyl) -a-acetylaminoacrylic acid amides made of the general formula:

CH ■ = CC — NH. CH ₀ . CH ₀

. NHO

Ε NH 0

. ■■. ι- ...

C = O

^CH 3

E here denotes an alkyl, aryl or aralkyl radical. The substituents can themselves be substituted; mainly with halogens, lower ones Alkyl radicals, hydroxyl groups and with esterified and / or etherified Hydroxyl groups,

As starting materials for the preparation of the amides according to the invention Most useful azlactones of α-acetylamino-acrylic acids are used. These are umyj in suitable solvents such as benzene, toluene or xylene O at tree temperature or under warming with ß-aminoethyl-morpholine set. The amide formation can also be carried out in the pure without a solvent To make diamine.

cn - ■ .- .. ■■. . \ _%

^ Isolation of the reaction products is easy in most cases ί the substances crystallize when the solvent cools down ·*** the end. If this does not happen, either the solvent is concentrated or the reaction products precipitate through the addition of z, B »ether.

BADr ORIGINAL - 2 -

Process for the preparation of basic substituted amides of the - «βΓ-

q-acylamino-acrylic acids .

CH == CC = O CH = C C-NH. CH ₃ .CH ₃ . NHO

RN 0 + NH ₀ .CH ₀ .CH ₀ . NHO R NH 0

^CH 3 CH "

The preparation of the N- (ß-morpholine ethyl) -a-acetylaminoacrylic acid amides according to the invention can also be achieved by reacting esters of α-acetylaminoacrylic acids with ß-aminoethyl-morpholine. One can also use the ß-aminoethylmorpholine salts the a-AcetylaminQ ^ acrylic acids by heating in suitable Convert solvents into the amides with elimination of water. Usually comes however, this leads to cyclization with further elimination of water and formation of imidazolones- (5).

The products of the process are characterized by surprising pharmacological properties Properties. This is how the N- (ß-morpholine ethyl) -a-acetylaminocinnamic acid amide works after intravenous, intramuscular and oral administration in rats, rabbits and dogs a safe long-lasting increase. of blood pressure. After oral administration in dogs, there is a sharp increase in systolic blood pressure, while diastolic blood pressure increases Pressure is only increased slightly. There are no counter-regulations. At the same time, the substance leads to a considerable improvement in the coronary blood flow and increases spontaneous motility, without states of excitement trigger. The toxicity of the amide is extremely low.

These results obtained in animal experiments are also used in the clinic confirmed: The amide leads to a slow, especially after oral administration not abrupt rise in blood pressure with a long-lasting effect.

chewrlch Erk te.mbH 4;

009015/1852 'BAD

Process for the preparation of basic substituted amides of the

q-acylamino-acrylic acids.

EXAMPLE El E

Representation of R ^ (fl-Morpholineäthyl) -a-acetylaminocinnamic acid amide ;

In a 500 ml three-necked flask fitted with a stirrer, dropping funnel and reflux condenser is equipped, 18.7 g of pure α-acetylaminocinnamic acid azlactone dissolved in 300 ml of benzene with stirring and heating. In the on The solution cooled to room temperature is quickly added dropwise to 13.0 g of β-aminoethylmorpholine a; after a short time the reaction product crystallizes out.

The reaction mixture is left to stand overnight and the next suction Day the solids sharply off and wash intensively with acetone, then with little ether. The almost colorless product is then recrystallized from acetone, the substance is obtained as colorless, fine needles.

Yield: 22.1 g (70 # of theory) mp: 164-166 ° C.

Preparation of N- (ß-MorpholinäthylY-a-acetylamino-p-methoxycinnamic acid amide;

21.7 "g of a-acetylamino-p-methoxyzimtsätire-az Iac ton are in 300 ml of toluene dissolved by heating in a Bührapparat and with 13, Og ß-Aminoäthylmorpholin offset. On cooling, the amide falls in a finely crystalline form the end. The crystallizate is suctioned off on the suction filter and washed twice After ether and dries in the vacuum desiccator »The boh product will dry out Acetone / methanol (4: l) recrystallized, the substance is obtained in Form of colorless fine needles.

Yield? 24.1 g (£ 75 of theory) mp: 186-187 ° C.

Preparation of N-Cß-morpholethyl) -p-chlorocinnamic acid amide:

° In a 500 ml three-necked flask equipped with a Bührer, 22.2 g

cd (Ojl Mol) ä-Acetylamino-p-chlorocinamic acid-azlacton in 200 ml dry.

_ »Toluene dissolved with stirring and heating. The mixture is cooled to room

temperature and then carries 13.0 g of ß-aminoethylmorpholine. To - »The reaction product crystallizes out of the clear solution for a short time

oo ■ "- .." .- ■ "". "■■■ -." "-

cn off. The solid is separated off, washed intensively with ether and recrystallized from acetone. The amide is obtained in the form of colorless small needles. Yield: 25 g (71 % of theory) mp; 180-181 ° G.

■ "■ '· - ■■■' ■ '';'■;■■'' - / ν v -''- r -: * - ² -

Process for the preparation of basic substituted amides

α-acylamino-acrylic acids.

ide the - ,,

Representation of ^ (ß-Morpholinäthylj-a-acetylamino-p-acetoxycinnamic acid ainide

12.3 g of a-acetylamino-p-acetoxycinnamic acid-azlactoii are in 375 ml dissolved in dry benzene with warming. The solution is mixed with 6.5 g of β-aminoethylniorpholine while stirring at the same time. The reaction mixture 100 ml of ether are added and the mixture is left to stand overnight, iun a fine crystalline precipitate formed in the next few days, which is sucked off sharply and washed thoroughly with ether. The raw product is recrystallized from ethyl acetate after previous treatment with charcoal; the substance is obtained as colorless, fine needles.

Yield: 10 g (53 % of theory)

Fpi 160-161 C.

E. Scheu rieh / Pharmwerk G / m.b.H.j A ρ ρ e η w θ i e> // Ba d <

BATH

η 0'98 15/1852

Claims (1)

16204 Process for the preparation of basic substituted amides of the cc-acylamino-acrylic acids. PAIEITiN. S EBUC H ' Process for the preparation of basic substituted imides of α-acylaminoacrylic acids the general formula: CH = C II A NH C-NH _β CH ₂ , CH ₂ . NHO C-0 wherein B is alkyl, aryl or aralkyl radicals which may be substituted, primarily with halogens, lower alkyl radicals, hydroxyl groups and with esterified and / or etherified hydroxyl groups, means, characterized in that azlactones of a- ^ acetylamino-acrylic acids the general formula j. - .- · CH = C ^ C-0 I I in which B has the same meaning as the symbol of the amide, with ß-Aminoethyl-morpholine in suitable solvents such as toluene at room temperature or under warming. PK 0 098 1S / 18 52