FI64591B - FRUIT PROCESSING FOR THERAPEUTIC THERAPY 4- (2-BENZOFURYL) -1-PYRROLINDERIVAT - Google Patents

Description

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Patent ooJ'ii'lnt '(51) Kv.lk. ^ nt-CI.3 C 07 D 405/04 SUOH I FI N LAND (21) P »t *« ttlh * kemu * - PatcntaraBknlng 79 ^ 002 (22 ) H * k «mltpllvt - AmSknlngtdaf 27-12.79 (23) Alkupitvi — Glltlghetidag 27-12-79 (41) Become Public - Bllvlt ofTentllg 28.06.8l

National Board of Patents and Registration / 44) Date of Publication and Publication—

Patent and registration authorities Ara5k »n utlagd ech utl-skrlft ·» published 31-08.83 (32) (33) (31) Privilege requested — Begird prlorltet (71) Laboratoires Jacques Logeais, 71 Avenue du General de Gaulle, 9213Ο Issy-les -Moulineaux, France-France (FR) (72) Jacques Georges Maillard, Versailles, Jacky Legeai, Palaiseau, France-France (FR) (74) Oy Kolster Ab (54) Method for the development of new therapeutically useful U- (2-benzofuryl) The present invention relates to a process for the preparation of novel 4- (2-benzofuryl) -1-pyrroline derivatives and their pharmaceutically acceptable acid addition salts. These compounds are useful in the treatment of cardiovascular disease.

The formula for the new compounds is

On '^ 0 L — I m

WkN / Ri ··.

K

wherein the group -N; is R 2 '2 / ¾ 64591 1) -N, which is hydrogen and is hydrogen, C 1-8 alkyl, R 2 C 2-8 alkenyl, C 2-8 alkynyl, phenyl, phenyl-C 1-8 alkyl, mono-, di- or trimethoxyphenyl-C 1-8 alkyl, C 1-8 alkoxy, benzyloxy, di-C 1-8 alkylamino-C 1-8 alkyl, C 1-8 hydroxyalkyl or C 1-8 alkyloxycarbonyl-C 1-8 alkyl / 2 ) -N, where and R 1j represent C 1-6 alkyl, p "R 2 3) CH 2) n / where n is 4, 5 or 6, 4) -N 0 or 5) -N-N-CH-.

The compounds of formula I and their acid addition salts may be prepared by:

Na) an acrylate of the formula \ J ~ 1 11111 ^ Χ0 SCH = CH-COOC2H5 is reacted with nitromethane in the presence of a strong base to give a nitroester of the formula f> sir “ii 'N: h-ch2cooc2h5 dv) ch2no2 b) the resulting nitroester is reduced by hydrogenation in the presence of a catalyst to give an amino ester which is cyclized by heating to pyrrolidin-2-one of the formula ^ -------.

I! C) The pyrrolMin-2-ane obtained is reacted with triethyloxonium tetrafluoroborate in an inert solvent to give 2-ethoxy-pyrroline of the formula f-yl]-! M) The 2-ethoxy-pyrroline obtained by d) is reacted with an amine of the formula HNR 1 R 2 'wherein R 1 and R 2 are as defined above to give the compound of formula (I) and e) if desired, converting the resulting compound into a salt.

The salts may typically be those formed with hydrochloric, sulfuric, phosphoric, methanesulfonic, maleic, succinic, acetic, fumaric, lactic, aspartic or citric acid.

The preparation of the compounds of formula (I) can be illustrated by the following reaction scheme: ^ jr — n, m ®> CH = ai ^ OOC2H5 (II) (III) ΚΗ, ΝΟ, -Π h -.

+ OTäs> XX jl ^ C

0 CH-CH-OOOCpHe I

(IV) CV) 101 ° + HN ^ g>: <C2H5) 3j XXj-j] -2-> XX] -f> -1, / R1 * · oc2h5 x: (VI) (I) * 2 ·· · 4 64591

The first step comprises 2-formylbenzofuran (Bull.

Soc. Chim. France 1962, p. 1875) with carbetoxymethylidene-triphenylphosphorane under the conditions used in the conventional Wittig reaction in an inert solvent such as benzene or toluene.

This reaction gives ethyl 3- (2-benzofuran) acrylate (III) as described in J. Chinese Chem. Soc. 1961, Series II, 8, 274-9.

The resulting acrylate (III) is then reacted with nitromethane (generally used as a solvent in the reaction) in the presence of a strong base such as Triton B (benzyltrimethylammonium hydroxide) or a metal alkoxide such as sodium methoxide or methoxide to give the nitroester (IV). The reaction can also be performed in another solvent such as dimethylformamide.

The nitroester (IV) is reduced by hydrogenation under ordinary pressure in the presence of a catalyst such as Raney nickel in a solvent such as ethanol. The intermediate amino ester is cyclized by heating to pyrrolidin-2-one (V).

Pyrrolidinone (V) is treated with triethyloxonium tetrafluoroborate in an inert solvent such as methylidene chloride and converted to 2-ethoxy-pyrroline (VI).

The latter is reacted with the amine HNR 2 in a solvent such as ethanol to give 2-aminopyrroline (I) # which is then, if desired, converted into a salt in a manner known per se. Volatile amines can be used as hydrochlorides to give directly the hydrochlorides of 2-aminopyrrolines (I).

The compounds of formula (I) have useful pharmacological properties, especially in the treatment of cardiovascular diseases. They have an arterial circulation-increasing and antidysrhythmic effect. -They are toxic only at doses significantly higher than pharmacologically active doses. They are therefore therapeutically useful as drugs in the treatment of dysrhythmias and in the improvement of blood circulation.

The results of toxicological and pharmacological studies are presented below.

a) Acute toxicity in mice

Each compound was administered orally, intraperitoneally or intravenously in a single dose. The behavior and mortality of the animals were monitored for several hours after treatment and then daily for at least one week. The results obtained are shown in Table I.

Table I

Eg LD50 'P * ° * LD50' LD50 'i, v * Remarks 1 115 mg / kg 58 mg / kg 46 mg / kg Vasodilation 2> 200 mg / kg 58 mg / kg Convulsions 3 200 mg / kg 58 mg / kg Convulsions, anxiety 4 240 mg / kg 38.5 mg / kg Convulsions 5 180 mg / kg 58 mg / kg Central nervous system excitation 6 110 mg / kg 58 mg / kg Sensory hypersensitivity 7> 200 mg / kg 98 mg / kg Seizures 8,200 mg / kg 76 mg / kg Restlessness, convulsions 9> 200 mg / kg 142 mg / kg Seizures, cyanosis 10> 200 mg / kg 142 mg / kg Restlessness, convulsions b) Effect on the central nervous system

The effect of different compounds on the central nervous system was studied in mice using a series of experiments: - traction test; - interaction with the hypnotic effect of barbiturates; - octotremorine test; - reserpine test (ptosis).

\ The above series of experiments did not show a significant effect on the central nervous system.

c) Effect on the cardiovascular system

The effect of each compound on cardiovascular disease was studied in anesthetized dogs.

A strong arterial dilating effect was observed with a number of compounds.

d) Antidyshythmic effect

The antidysrhythmic activity of the compounds of formula (I) was evaluated on the basis of the following pharmacological experiments: - heart rate by maximal stimulation (FMS).

FMS. determined in vivo in rabbits by stimulating the heart with a stimulation probe placed in the left ear cavity to determine the duration of the period of uptake of the conductive pathways and connective tissues of the myocardium.

- dysrhythmia when stimulating the central nervous system of rabbits: electrical stimulation of the posterior part of the hypothalamus causes strong activation of the sympathetic nervous system and dysrhythmias; - aconitine-induced dysrhythmias in rats: this substance causes a severe disturbance in the ionic permeability of the membranes; - ouabain-induced dysrhythmias in guinea pigs: at toxic doses, ouabain causes ion exchange in membranes; on the other hand, it at the same time causes the activation of the sympathetic nervous system; - anoxia-induced dysrhythmias in rats with a sublimation dose of aconitine after pretreatment (sympathetic combination of effects of stimulation and ion-conducting disorders); - method according to Harris, in dogs: coronary ligation and dysrhythmias caused by local anemia.

The results obtained are shown in Table II. The results show that the compounds of formula (I) have a strong anti-arrhythmic effect.

The compounds of formula (I) are very useful therapeutically in the treatment of various circulatory or cardiac diseases (circulatory failure; vascular obstruction; angina pectoris; dysrhythmia and the like).

The compounds may be administered to a human orally or rectally as bases or salts (formed into tablets, capsules, drops or suppositories) or parenterally, as aqueous solutions of water-soluble salts or in another excipient which provides a delay in resorption.

The preparations may contain 10 to 1000 mg of active substance per unit dose for oral or rectal administration and 5 to 500 mg of active substance for other administration.

The daily dose may range from 10 mg to 3 g, depending on the route of administration and the intended therapeutic uses.

7 64591

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The compounds of formula I have been compared to two compounds, namely quinidine sulphate and lidocaine, which are well known antidysrhythmic compounds. Tables III and IV show the acute toxicity and antidysrhythmic activity of the compounds. Toxicity of the compounds of Examples 1 and 4 i.v. is approximately the same as for known compounds. When administered orally, the LD50 of the compounds of formula I is slightly lower than the LD50 of the known compounds.

The pharmacological methods described above were used to compare antidyshythmic activities. It should be emphasized that almost all compounds of formula I were active in all experiments. Of the compounds, mention may be made in particular of the compound of Example 4. Quinidine sulfate, on the other hand, is hardly active at all in the coronary ligation test, which is a very important test. In this experiment, lidocaine has a weak effect but is very short-lived.

It should also be noted that lidocaine has no effect in the aconitine test nor in the oubaine test. The results show that the compounds of formula I have a better antidysrhythmic effect than the known compounds.

Table III

Acute toxicity

Example LD50 P '° * LD50 · * - * ν · mg / kg mg / kg 1 115 46 2> 200 3 200 4 240 39 5 180 6 110 7> 200 8 200 9> 200 10> 200

Quinidine sulphate 505 49 ^ 2)

Lidocaine 445 ^ ^ 45 ^ (1) Capra et al. II Farmaco 1980, 35, 49 (2) Luduena et al. J.Pharmacol, exp. Therap. 1958, 123, 269

Table IV

64591

Antidyshythmic activity (active dose mg / kg)

Example Aconitine Anoxia Oubaine Coronary ligation dog 2 + (10) 30+ (10) 4 ++ (10-20) ++ (10-20) + (10-20) ++ (10) 5 ++ (10- 20) 7 + (5) 8 + (10) + (10) 9 - (10) 0 10 0 + (10)

Quinidine Sulfate + (20) + (20) + (20) - 0 (10)

Lidocaine 0 - (10) 0 + (10)

The following examples illustrate the invention.

Example 1 (I) Rx * R2 = h a) Ethyl 3- (2-benzofuryl) acrylate (III)

A mixture of 35 g (0.24 mol) of 2-formyl-benzofuran (II) and 83.5 g (0.24 mol) of carboxymethylidene-triphenylphosphorane in 300 ml of benzene is refluxed under nitrogen for seven hours. I drive. After evaporation to dryness under reduced pressure, the residue is triturated with ether, filtered off with suction and recrystallized from isopropyl ether.

Sp. (dec.) = 78 ° C. Yield: 100%.

The product obtained may contain some triphenylphosphine oxide formed during the reaction. It can be removed from the mixture by distillation (Kp.g 2 = 126 ° C or Kp.Q = 140 ° C (yield = 80%).

b) Ethyl 4-nitro-3- (2-benzofuryl) butyrate (IV) 51.8 g (0.24 mol) of the derivative (III) obtained in a), 61 g (1 mol) of nitromethane and 10 ml of Triton B (40 "> solution in methanol) is heated at 70-90 [deg.] C. for 16-24 hours. After cooling and slow acidification with normal hydrochloric acid, the nitroester is extracted with ether, washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily nitro ester. purified by equilibrium distillation Kp.Q ^ = 150 ° C or Kp.Q 6 = 178 ° C.

The main fractions containing unreacted ester (III) can be recycled for processing (average yield of 3 successive treatments: 60%).

c) The ester (IV) obtained in 4- (2-benzofuryl) pyrrolin-2-one (V) b) (81.5 g; 0.297 mol) is dissolved in 500 ml of ethanol and hydrogenated under normal pressure at 55 ° C. g in the presence of Raney nickel. The hydrogen required for the reaction (14.8 L) is consumed in seven hours. After filtration of the catalyst and evaporation of the ethanol, the oily residue is heated to 100 [deg.] C. in a water pump vacuum for two hours. Upon trituration with isopropyl ether, the product crystallizes. Sp. (dec.) = 142 ° C. Yield = 47.9 g (80%).

d) 2-Ethoxy-4- (2-benzofuryl) -4'-pyrroline-1 (VI) 8 g (0.04 mol) of 4- (2-benzofuryl) pyrrolin-2-one (V) and 12 g (O .6 moles) of triethyloxonium tetrafluoroborate is dissolved in 80 ml of methylene chloride and the mixture is stirred for one week at normal temperature. The mixture is then hydrolysed by adding 15 g of potassium hydroxide dissolved in 30 ml of water. The insoluble matter is filtered off and the organic phase is washed with water, dried over sodium sulfate and distilled. Mp = 128-130 ° C. Yield = 5.9 g (64%).

e) 2-Amino-4-benzofuryl-1-pyrroline hydrochloride

5.9 g (0.025 mol) of the derivative (VI) obtained in the previous reaction are dissolved in 50 ml of ethanol together with 1.36 g (0.025 mol) of ammonium hydrochloride. The desired hydrochloride of the amino derivative crystallizes on cooling. It is filtered off with suction and dried in vacuo. Sp. (dec.) = 253 ° C. Yield = 4 g (42%).

Example 2 (I) R 1 = N; R 0 = CH 2 X έ 3 7 \ 2-methylamino-4- (2-benzofuryl) '-1-pyrroline hydrochloride

The above compound is obtained in the same manner as the derivative (I) of Example 11 64591 1 by reacting methylamine hydrochloride

A

- 2-ethoxy-4- (2-benzofuryl) -N-1-pyrroline (VI) in boiling ethanol. The solution is then evaporated to dryness and the residue is taken up in hot ethanol. After addition of ethyl acetate and stirring at room temperature for 24 hours, the precipitate is filtered off with suction and dried. Sp. (dec.) = 151 ° C. Yield = 45%.

Example 3 (I) R = H; R2 = iC3H? 2-Isopropylamino-4- (2-benzofuryl) -N-1-pyrroline hydrochloride

To obtain the above compound in the same manner as the derivative (I) of Example 1 by reacting isopropylamine hydrochloride with the derivative (VI) in boiling ethanol. After evaporation of the solvent, the residue is taken up in hot isopropanol. The desired hydrochloride crystallizes by adding isopropyl ether and cooling. Sp. (dec.) = 186 ° C. Yield = 66%.

Example 4 (I) r1 = r2 = ch3 2-Dimethylamino-4- (2-benzofuryl) -4'-pyrroline hydrochloride

The above compound is obtained in the same manner as the derivative (I) of Example 1 by reacting dimethylamine hydrochloride with 2-ethoxy-4- (2-benzofuryl) -N-1-pyrroline (VI) in hot ethanol. After evaporation to dryness and addition of isopropanol, the hydrochloride crystallizes on addition of ether. Sp. (dec.) = 154 ° C. Yield = 84%.

Example 5 (I) R1 = R2 - c2h5 2-Diethylamino-4- (2-benzofuryl) -4'-pyrroline fumarate

The hydrochloride is obtained as described in the above examples by reacting diethylamine hydrochloride with the derivative (VI) in boiling ethanol (20 hours). After evaporation of the solvent, the residue is taken up in chloroform, after which the solution is washed with N sodium hydroxide and then with water. After evaporation of the chloroform, the oily residue remaining is distilled off under reduced pressure. Mp = 162-168 ° C.

The base obtained is dissolved in hot propanol together with a stoichiometric amount of fumaric acid. The fumarate crystallizes on cooling. Sp. (dec.) = 154 ° C. Yield = 35%.

Example 6 (I) Rx = H; R2 = CgH5 2-anilino-4- (2-benzofuryl) ZA-1-pyrroline hydrochloride

The base is prepared by the reaction between the excess of aniline and the derivative (VI) in refluxing ethanol (48 hours). After evaporation under reduced pressure, the residue is taken up in ethyl acetate, where the base crystallizes on stirring.

The above base is converted to the hydrochloride by adding an anhydrous solution of HCl in ethanol while hot to a solution of the base in isopropanol. The hydrochloride crystallizes on cooling. Sp. (dec.) = 203 ° C. Yield = 58%.

Example 7 (I) = H; R 2 = CH 2 CH 2 C 6 H 5 2-phenethylamino-4- (2-benzofuryl) A-1-pyrroline hydrochloride

The base is obtained in the same manner as the derivative of Example 6 from phenethylamine in ethanol and is then converted to the hydrochloride. Sp. (dec.) = 121 ° C. Yield = 62%.

Example 8 (i) r1-r2 = - (ch2) 4- 2-pyrrolidino-4- (2-benzofuryl) Δ-1 · -pyrroline hydrochloride

The above compound is obtained in the same manner as the derivative (I) of Example 1 by reacting pyrrolidine hydrochloride with the derivative (VI) in hot ethanol. After evaporation of the solvent and redissolution in hot isopropanol, the hydrochloride crystallizes on addition of isopropanyl ether and cooling. Sp. (dec.) = 260 ° C. Yield = 84%.

Example 9 (i) r1-r2 = - (ch2) 2-o- (ch2) -2-morpholino-4- (2-benzofuryl) Δ-1 · -pyrroline hydrochloride

The above compound is obtained in the same manner as the derivative (I) of Example 1 by reacting morpholine hydrochloride with 64591 13 derivative (VI) in hot ethanol, followed by recrystallization from isopropanol. Sp. (dec.) = 195 ° C. Yield = 81%.

Example 10 ch3 (I) Rj-Rjj = - (CH2> 2 - N- (CH2> 2 - 2- (4-methyl-piperazino) -4- (2-benzofuryl) -A-1-pyrroline methanesulfonate

The above compound is obtained in the same manner as the derivative (I) of Example 1 by reacting N-methylpiperazine with the derivative (VI) in hot ethanol. After evaporation under reduced pressure, the residue is triturated with petroleum ether, filtered off with suction and dried. Sp. (dec.) = 124.5 ° C. Yield = 58%.

The base is converted to the methanesulfonate by adding a small deficit of methanesulfonic acid in ethyl acetate and stirring for three hours. The insoluble salt is filtered off with suction and dried. Sp. 146 ° C. Yield = 79.5%.

Example 11>. · Ι-ιι · .... I. ·., I.

(I) R 1 = H; R 2 = CH 2 CH 2 N (CH 3) 2 2- (2-dimethylaminoethyl) -4- (2-benzofuryl) -N-pyrrole-hydrochloride

The above compound is obtained in the same manner as the derivative of Example 6 by reacting 2-dimethylaminoethylamine with the derivative (VI) in hot ethanol, followed by conversion of the base to the dihydrochloride in isopropanol. The dihydrochloride crystallizes on cooling. Sp. (dec.) = 240 ° C. Yield = 52%.

Example 12 (I) = H; R2 = OCH2C6H5 2-Benzyloxyamino-4- (2-benzofuryl) -A-pyrroline hydrochloride

The above compound is obtained in the same manner as the derivative (I) of Example 1 by reacting benzyloxamine hydrochloride with the derivative (VI) in hot ethanol. After evaporation of the solvent and redissolution in hot isopropanol, the hydrochloride crystallizes on addition of isopropyl ether and cooling. Sp. (dec.) = 183 ° C. Yield = 39%.

64591 14

Example 13 (I) ^ = H; R 2 = OCH 3 2-methoxyamino-4- (2-benzofuryl) -N-1-pyrroline hydrochloride

The above compound is obtained in the same manner as the derivative (I) of Example 1 by reacting O-methylhydroxylamine hydrochloride with the derivative (VI) in hot ethanol. Sp. (dec.) = 184 ° C. Yield = 67%.

Example 14 (I) R 1 = H; R 2 = CH 2 CH = CH 2 2-allylamino-4- (2-benzofuryl) -4-1-pyrroline hydrochloride

The above compound is obtained in the same manner as the derivative (I) of Example 6 by reacting allylamine with compound (VI) in hot ethanol. After evaporation to dryness, the residue is converted into the hydrochloride by adding a solution of HCl in anhydrous ether. Sp. = 160 ° C. Yield = 98%.

Example 15

(I) = H; R2 = CH2-C = CH

2-Propargylamino-4- (2-benzofuryl) -1-pyrroline hydrochloride

The above compound is obtained in the same manner as the derivative (I) of Example 1 by reacting propargylamine hydrochloride with the compound (VI) in hot ethanol. After evaporation of the solvent, the residue is recrystallized from isopropanol.

Sp. = 196 ° C. Yield = 75%.

Example 16 - ULn-, R13 (I) Rx = H; R 2 = CH 2 CH 2 - (XVoCH 3 - Λ 2- (3,4-dimethoxy-phenethylamino) -4- (2-benzofuryl) -N-1-pyrroline hydrochloride

The above compound is obtained in the same manner as the derivative (I) of Example 1 by reacting 2- (3,4-dimethoxyphenyl) ethylamine hydrochloride with the compound (VI) in hot ethanol. After evaporation of the solvent, the residue is recrystallized from isopropanol. Sp. = 180 ° C. Yield = 75%.

64591 15

Example 17

(I) Rx = H; R2 = CH2CH2OH

2- (2-hydroxy-ethylamino) -4- (2-benzofuryl) 4 \ -l-pyrroline, hydrochloride

The above compound is obtained in the same manner as the derivative (I) of Example 6 by reacting ethanolamine with the compound (VI) in hot ethanol. After evaporation of the ethanol, the isolated base (m.p. = 130 [deg.] C., yield = 69%) is converted into the hydrochloride with a solution of HCl in anhydrous ether. Sp. = 171 ° C. Yield = 82%.

Example 18 (I) ^ = 11; R2 '= CH2COOC2H5 2- (2-ethoxycarbonylmethylamino) -4- (2-benzofuryl) -A-1-pyrroline hydrochloride

The above compound is obtained in the same manner as the derivative (I) of Example 1 by reacting ethyl 2-aminoacetate hydrochloride with the compound (VI) in hot ethanol. Sp. = 168 ° C.

Yield = 69%. / / / y \

Claims (1)

64591 16 A process for the preparation of novel therapeutically useful 4- (2-benzofuryl) -1-pyrroline derivatives of formula (I) and their pharmaceutically acceptable acid addition salts, '' |! ..........; i i .... ........ 1 (I) i! "NN" '"V - wherein the group -N 2 - is * 2' '' 1) -N, which is hydrogen and is hydrogen, C 1-6 alkyl, C 1-6 alkynyl-R 2 alkyl, C 1-6 alkynyl , phenyl, phenyl-C 1-6 alkyl, mono-, di- or trimethoxyphenyl-C 1-6 alkyl, C 1-6 alkoxy, benzyloxy, C 1-8 alkylamino-C 1-6 alkyl, C 1-6 alkyl hydroxyalkyl or C 1-8 alkyloxycarbonyl-C 1-6 alkyl, -R 12) -N 2, where R 1 and R 11 represent C 1-6 alkyl (R 2/3) -N (CH 2) n, where n is 4, 5 or 6 f 4) 9 or 3) ~ \ -CH3, characterized in that a) an acrylate of the formula 64591 17 M (III) v -. o ^ U CH = CH-OOOC2H5 is subjected to react with nitromethane in the presence of a strong base to give a nitroester of formula \ ________ L *! b) The nitroester obtained b) is reduced by hydrogenation in the presence of a catalyst to give an amino ester which is cyclized by heating to pyrrolidin-2-one with the formula CV \ ^> · ------ O j I (V) '-NH - x0 c) the pyrrolidin-2-one obtained is reacted with triethyloxonium tetrafluoroborate in an inert solvent to give 2-ethoxy-pyrroline of the formula > 1d) the obtained 2-ethoxy-pyrroline is reacted with an amine of formula HNR 1 R 2, wherein R 1 and R 2 have the same meaning as above, to give a compound of formula (I) and e) if desired, the compound obtained is converted into a salt. 64591 18 For the preparation of a therapeutically active compound 4- (2-benzofuryl) -1-pyrrole derivative with the formula I and a pharmaceutical form of a syringe addition, i il li Ί I! "O · --------- j (I ) -N "-NX, R2 ·· '^ Rr, van -N, ar R ·" 2 / i 1) -N, then R | aryl and aryl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, phenyl, phenyl-C 1-6 alkyl, mono-, di-trimeroxyphenyl-C 1-6 alkyl, C 1-6 alkoxy , benzyloxy, di-C 1-6 -alkylamino-C 1-6 -alkyl, C 1-6 -alkylalkyl or C 1-6 -alkyloxycarbanyl-C 1-6 -alkyl, R and R 1 is a C 1-6 alkyl group, R "R 2 / (3) 3) -N 2 (CH 2) n 'is 4, 5 or 6," () * - CH3 · \ _ / kännetecknat därav, att a) ett akrylat med formeln 64591 19, \ ___;. *! Li (ui) "'-O' xCH = CH-COOC2H5 omsätts med nitrometan i närvaro av en Stark bas, varvid erhälles en nitroester med formeln • __ I '! i! ^ dv) CH-CH2COOC2H5 CH2NO2 b) the nitroester reduction of the genome by hydration of the catalyst, the color of the amino ester, the cyclization of the genome up to the pyrrolidin-2-one with the form of ^ 11 \ / xo / Nj I (v ) (c) pyrrolidin-2-one with triethloxonium tetrafluoroborate and an inert solution, colored with 2-ethoxypyrrole in the form of fl (ii) I (vi>