NO791943L - PROCEDURES FOR THE PREPARATION OF PYRROLIDIN-2-ONES FROM 3-PYRROLIN-2-ONES, AND PROCEDURES OF 3-PYRROLIN-2-ONES - Google Patents

Description

Pyrrolidin-2-ones (I) of formula: and their corresponding pyrrolidines (II) of formula:

wherein R = hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl or aroyl; R 3 = hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; R 4 = aryl, substituted aryl, alkyl or substituted alkyl; R 5 = hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; and R 5 1 = hydrogen, alkyl or substituted alkyl; includes many known compounds exhibiting 'interesting CNS activity (Archivum Immunologiae et Therapies Experimentalis 1975, 23, 733-751). Many of the compounds of formula I exhibit prostaglandin-like activity (Cer. Offen. 2,527,989).

The pyrrolidin-2-ones (I) have generally been prepared by cyclization of the corresponding 4-aminobutyric acid or ester (III) of formula:

and 4-halogeno-butyramide, by reaction of lactones with amines, or hydrolysis of 2-imino-pyrrolidines (British patent no. 1,350,582 and US patent no. 4,012,495).

These methods for preparing compounds of formula I and II are limited in terms of efficiency, type of substituents in the different positions and difficulty in preparing pure stereo- and optically active isomers.

According to the invention, 3-4-cis-substituted, possibly optically active, pyrrolidin-2-ones of formula I are produced, namely:

or after isomerization by hydrogenation of 3-pyrrolin-2-ones (V) of formula:

rhvori R 1 , R 3 , R 4 , R 5 and R 5' have the meanings given above, using the suitable catalyst, optionally optically active [Angew. Chem. 8_3 , 956 (1971)] or a built-in asymmetric center in C-5 of (V), during hydrogenation.

One of the main difficulties in preparing pyrrolidin-2-ones (I) by hydrogenating 3-pyrrolin-2-ones (V) is the difficulty in preparing 3-pyrrolin-2-ones (V).

The present invention therefore also relates to general methods for the production of compounds of formula V, and this is carried out according to the invention by cyclization of N-aroylmethylacetamides (IV) of formula: while forming the corresponding compound of formula V. This cyclization is carried out according to the invention under basic conditions, e.g. in t-butanol with potassium t-butoxide as base under nitrogen followed by acidification with an inorganic acid such as HCl and dilution with water or by cyclization of the corresponding phosphonium bromide (XIII) of formula:

where the cyclization is carried out in basic medium to the corresponding compound of formula V.

The following definitions and expressions are used:

Aroyl = Aryl-CO-

Acyl = Alkyl(minus 1 C)-C0-

Aryl = phenyl, pyridyl, furyl, thienyl, N-alkyl- or N-aryl-pyrrolyl, and the corresponding benzo derivatives, i.e. naphthyl,

quinolyl, etc.

Alkyl = to C16 hydrocarbons

Substituents (up to 5, equal or mixed) =

alkyl, haloalkyl (e.g. F3C), O-alkyl, N-dialkyl (same and different), S-alkyl, halogen, O-benzyl, N-dibenzyl, N-alkyl/benzyl, S-benzyl, O- aryl, S-aryl, N-diaryl, N-alkyl/

benzyl/aryl>OH, NI-^, SH (the latter three are protected during the basic cyclization).

Certain 3-pyrrolin-2-ones (V) are claimed in US Patent No. 3,272,842, and are prepared according to the following reaction equation:

5 5' 4 However, R and R exclude hydrogen, and R is always S-CH-- (S = substituent). This cyclization of VI with R 4 = aryl or substituted aryl and R 5 and/or R 51 = hydrogen, according to the examples in US Patent No. 3,272,842 either does not proceed, or gives yellow compounds (probably dimers), which is the result that the difference in substituents, i.e. that the specified methods were not applicable to the present compounds. 3-pyrrolin-2-ones (V) have been prepared (G. Stork and R. Matthews, Chemical Communications 1970, 445-6) according to the following reaction scheme:

However, the application of dicyclohexylcarbodiimide. (DCC) for the condensation of the aminoketone derivative (VI) with unstable phosphonium acetic acid (VII) unsuitable for large-scale synthesis. In addition, the price of DCC is quite high, and N,N<1->dicyclohexylurea is a by-product that is difficult to remove, making the process even more uneconomical.

A similar ring closure reaction [T.W. Guntert et al. Hooray. Chim. Acta 60, 334-9 (1977)] has been proposed as follows:

however, this process requires repeated chromatographic separations for the isolation of 3-pyrrolin-2-one (V) with R 4 = 170-steroidyl in a 10% yield, so that this process is unsuitable for large-scale synthesis, and one was unable to prepare the bromine parent compound of formula IX (corresponding to the present compound of formula XII).

According to the invention, direct cyclization of compounds of formula IV can be effective, even for the synthesis of substituted 3-pyrrolin-2-ones (V) most appropriately where the substituents R 1 and - R 3 in compounds of formula (IV) fulfill the following two criteria: (1) that either rVh, i.e., R"*" = alkyl, substituted alkyl, aryl, substituted aryl, acyl, or aroyl, or (2) if R = H, that R^ is a group that stabilizes anions at C-3 and are stable to bases, ie aryl, substituted aryl, ;.carbonyl etc, but not alkyl or hydrogen. ;For the preparation of compounds of formula V by ring- ;1 3 conclusion in the case where R = hydrogen and R = hydrogen, alkyl or substituted alkyl, it has been found best to proceed according to the following reaction equation. Thus where R 4 = .aryl substituted 5 5' aryl, R = hydrogen, alkyl or substituted alkyl and R = hydro gene, alkyl or substituted alkyl, it is possible to react 2-amino-acetophenone (XI) of formula: ;with a 2-bromo-acyl chloride or bromide to form the corresponding bromine compound (XII) of formula: ;in practically quantitative dividend. The bromine compound of formula XII reacts in contrast to the chlorine compound of formula IX between room temperature and 50°C with triphenylphosphine, e.g. in benzene or chlorobenzene solution, without cleavage, to form the corresponding phosphonium bromide (XIII) of formula: ; which is sufficiently soluble in alcohols and water for ring closure reactions. the ion of the corresponding compound of formula V, e.g. with 2N NaOH solution. ;According to this method, the starting aminoketones (XI) in which R 4= aryl, substituted aryl, alkyl or substituted alkyl, ;5 51 ;R = hydrogen, alkyl or substituted alkyl, and R = hydrogen or alkyl, are generally readily available compounds which can is acyl-erized in practically quantitative yield in weakly basic media, e.g. sodium bicarbonate in a water-ether mixture, with 2-bromoacyl chlorides or bromides to the corresponding N-(2-bromoacyl)-amino ketone (XII) in which R 3 = hydrogen, aryl, substituted aryl, alkyl or substituted alkyl. The ketones of formula XII as indicated above react at room temperature with triphenylphosphine, e.g. in benzene solution, forming the corresponding phosphonium bromide XIII which precipitates and can be collected by simple filtration. The dissolution of the compound of formula XIII in alcohol (preferably methanol) or water, and treatment with more than one equivalent base (preferably 2N NaOH solution) at room temperature rapidly gives the desired 3-pyrrolin-2-one (V) and triphenylphosphine oxide in practically quantitative yield, which is precipitated from the solution. After dilution with water and evaporation of the alcohol, the mixture is collected and separated by extraction, e.g. with methylene chloride, which removes the triphenylphosphine oxide. ;3-pyrrolin-2-one (V) prepared in any of the above ways can be easily hydrogenated with e.g. Pd/C, Pt, or chiral rhodium complexes as catalyst in alcohol (preferably methanol) solution to the CNS-active substituted pyrrolidin-2-ones (I-cis). This reaction has the advantage that the derivatives are obtained in which R 3 and R 4 are formed exclusively as cis-substituents. The I-cis compounds can be converted into the corresponding I-traris compounds by base or acid treatment. ;The pyrrolidin-2-ones of formula (I) can be hydrolyzed by strong acid or base treatment to the corresponding 4-aminobutyric acid derivatives of formula III accompanied by partial isomerization of the R 3 substituent, resulting in a diastereoisomeric mixture which can be isolated as salts (e.g. HC1 or sodium and magnesium etc.) or as free amino acids. The hydrolysis with R"^ = alkyl is incomplete due to the formation of an equilibrium between I and III which can be separated by extraction. A further advantage of the invention is that the reduction of the new pyrrolidin-2-ones (I), e.g. . with B9H, or LiAlH. leads to the formation of new pyrrolidines (II-cis (R 3 and R 4 = cis) or II-trans (R 3 and R 4 = trans) depending on the starting material. ;The reduction of C= The C double bond in V is easily carried out with hydrogen and about 5 - 15% 10% palladium on carbon as catalyst. Asymmetric hydrogenation is obtained with chiral rhodium catalysts (eg J. Am. Chem. -Soc. 1977, 99 , 5946-52). Filtration and evaporation of the solvent, preferably methanol, gives directly the desired lactams I-cis in quantitative yield. In the case where R"'" = benzyl in formula V, the compound of I-cis where R"< *>"= hydrogen, obtained by hydrogenolysis, i.e. that the N-benzyl group has a function as a protecting group in the case where R 3 = hydrogen, alkyl, or subs titrated alkyl.

Hydrolysis of compounds of formula I in refluxing concentrated (15-35%) inorganic acids (e.g. hydrochloric acid) followed by evaporation leads directly to the formation of corresponding 4-amino-butyric acid hydrochlorides of formula III in the case of HCl . With sulfuric acid, sulfates can be removed with barium hydroxide solution to form the free amino acids of form] III which can be converted to a desired carboxylic acid salt (eg magnesium) or to an ammonium salt with a therapeutically acceptable acid. On the other hand, hydrolysis with base leads to the corresponding carboxylic acid salts (e.g. sodium, potassium).

Reduction of the carbonyl group in lactams of formula I with e.g. lithium aluminum hydride or borohydride leads to the formation of . of the corresponding pyrrolidines of formula II which can be converted to an ammonium salt with a therapeutically acceptable acid.

The following examples illustrate the invention.

EXAMPLE. In 3, 4- diphenyl- 3- pyrrolin- 2- one (Va)

A solution of 12.6 g (50 mmol) of 2-phenylacetamido-aceto-phenone in 200 ml of t-butanol was added to a refluxing solution of potassium t-butoxide prepared from 6.5 g of potassium (166 mmol) and 200 ml of t -butanol under nitrogen. After refluxing for 40 minutes, the solution was cooled to 40°C and acidified with 2N HCl (ca. 120 ml) to pH 6 to 5. The resulting suspension was poured into 3 liters of ice water. The precipitate was collected and washed with water. After drying, 9.85 g (84.1%) of Va with melting point 183 - 90°C were obtained. Extraction of the water with chloroform gave an additional 1.3 g (11.1%) of Va. A recrystallized sample from benzene showed a melting point of 177 - 9°C. The following compounds of formula V were prepared in an analogous manner: 3-phenyl-4-(4'-chlorophenyl)-3-pyrrolin-2-one (Vb), m.p. '204- 10°C 3-(2<1->carboxyphenyl)-4-phenyl-3-pyrrolin-2-one (Vc), m.p. 238- 41°C 3-phenyl-4-(4'-fluorophenyl)-3-pyrrolin-2-one (Vd), m.p. 200- 2°C 3-(4'-fluorophenyl)-4-phenyl-3-pyrrolin-2-one (Ve), m.p. 199-209°C 3-phenyl-4-(4<1->methylphenyl)-3-pyrrolin-2-one (Vf), m.p. 210- 20°C 3-phenyl-4-(4'-trifluoromethylphenyl)-3-pyrrolin-2-one (Vg), m.p. 195- 8°C 3-(21-fluorophenyl)-4-(4'-trifluoromethylphenyl)-3- pyrrolin-2-one (Vh), m.p. 165- 6 C 1,3,5-trimethyl-4-phenyl-3-pyrrolin-2-one (Vi), m.p. 79- 81°C 1-benzyl-4-(4<1->trifluoromethylphenyl)-3-pyrrolin-2-one (Vk), gum 1-benzyl-3-methyl-4-(4'-trifluoromethylphenyl) -3-pyrrolin-2-one (VI),

gum 1,5-dimethyl-3,4-diphenyl-3-pyrrolin-2-one (Vm), m.p. 95-103°C 1,5-dimethyl-4-phenyl-3-pyrrolin-2-one (Vn), m.p. 130-5°C 1-methyl-3-phenyl-4-(4'-methylphenyl)-3-pyrrolin-2-one (Vo), m.p. 123- 4°C 3-phenyl-4-(4'-methoxyphenyl)-3-pyrrolin-2-one (Vp), m.p. 179- 81°C 3-phenyl-4-(31,4'-dimethoxyphenyl)-3-pyrrolin-2-one (Vq), m.p. 202- 4°C 3-(4'-fluorophenyl)-4-(4'-trifluoromethylphenyl)-3-pyrrolin-2-one (Vu), m.p. 212-3C

EXAMPLE II cis-3,4-diphenyl-pyrrolidin-2-one (cis-Ia)

A solution of 9.00 g of 3,4-diphenyl-3-pyrrolin-2-one (Va) in 200 ml of methanol and 0.90 g of 10% palladium on carbon was placed in a 500 ml hydrogenation flask, and hydrogenated 16 hours at room temperature. The catalyst was filtered off, and the methanol was evaporated in vacuo. Crystallization from benzene-petroleum ether (1:1) gave crystals with melting point 154 - 5°C. The following compounds were prepared in a similar manner.

3-phenyl-4-(4<1->fluorophenyl)-pyrrolidin-2-one (cis-Id), m.p. 198-200°C 3-(4'-fluorophenyl)-4-phenyl-pyrrolidin-2-one (cis-Ie), m.p. 167- 8°C 3-phenyl-4-(4'-methylphenyl)-pyrrolidin-2-one (cis-If), m.p. 190- 1°C 3-phenyl-4-(4'-trifluoromethylphenyl)-pyrrolidin-2-one

(cis-Ig), m.p. 149- 51°C 3-(2'-fluorophenyl)-4-(41-trifluoromethylphenyl)-

pyrrolidin-2-one (cis-Ih), m.p. 154- 6°C 1,3,5-trimethyl-4-phenyl-pyrrolidin-2-one ( cis- Ii ), gum 4-(4'-trifluoromethylphenyl)-pyrrolidin-2-one ( Ik ), m.p. 121- 22°C 3-methyl-4-(4'-trifluoromethylphenyl)-pyrro-

1id in-2-one (cis-Il), 1,5-dimethyl-4-phenyl-pyrrolidin-2-one (In), gum l-methyl-3-phenyl-4-(4'-methylphenyl)-pyrrolidine -2-one (cis-Io), m.p. 113- 4 C 3-phenyl-4-(4<1->methoxyphenyl)-

pyrrolidin-2-one (cis-Ip), m.p. 156- 9°C 3-phenyl-4-(31,4'-dimethoxyphenyl)-pyrrolidin-2-one ( cis - Iq ), m.p. 144- 6 C 3-(4'-fluorophenyl)-4-(41-trifluoromethyl-phenyl)-pyrrolidin-2-one ( cis - Iu ), m.p. 203-4°C

EXAMPLE III 1,5-dimethyl-4-(4'-nitrophenyl)-pyrrolidin-2-one (Ir)

4.32 gin was gradually added to 30 ml of fuming nitric acid at -5 to 0°C. After 1 hour at -10°C, the solution was poured into 300 ml of water. Extraction with ethyl acetate and washing with

bicarbonate solution and water leave after evaporation of the solvent 4.89 g (91.6%) Ir. Crystallization from acetone ether (1:3) gave crystals with a melting point of 94 - 5°C.

EXAMPLE IV 1,5-dimethyl-4-(4'-chlorophenyl)-pyrrolidin-2-one (It)

A solution of 4.89 g (20.9 mmol) I_r in 50 ml of methanol and 0.49 g of 10% palladium on carbon was placed in a 250 ml hydrogenation flask and hydrogenated at room temperature for 30 hours. The catalyst was filtered off, and the methanol was evaporated in vacuo.

The resulting 1,5-dimethyl-4-(4'-aminophenyl)-pyrrolidin-2-one ( Is ), isolated in 100% yield, was dissolved in 12 ml of 18% hydrochloric acid in a 250 ml beaker and treated dropwise with 5.23 ml of 4N sodium nitrite solution at 0 - 5°C. After 5 minutes at 0°C, the excess nitrite was destroyed with urea. After 10 minutes at 0-5°C, the diazonium solution was added dropwise to a freshly prepared solution of CuCl (20.9 mmol) in 8 ml of 37% hydrochloric acid at 0°C. A brown precipitate immediately formed, which was heated to 60°C for 1 hour. Extraction with chloroform and washing with water gave 4.30 g of impure reaction product after evaporation. After filtration through 130 g of silica gel, 3.80 g (81%) of It were obtained as a gum.

EXAMPLE V 4-Amino-2-phenyl-3-(4'-trifluoromethylphenyl)-butyric acid hydrochloride (IIIg-HCl)

9.15 g of cis-Ig was suspended in 300 ml of 25% HCl solution in a 500 ml flask and refluxed for 13 hours. Dilution with 300 ml of water and evaporation in vacuo to dryness gave a crystalline white residue which was suspended in ether overnight to remove any lactam. Filtration and washing with ether gave 9.65 g (89.4%) IIIg-HCl with melting point 182 - 3°C.

Analysis calculated for C17H17ClF3N02-0.5 H20 (368.8)

Found: C 55.84%, H 4.96%, N 3.79%

Calculated: C 55.37%, H 4.85%, N 3.80%

The following acid hydrochlorides were prepared in a similar way: 4-amino-2, 3-diphenyl-butyric acid - HCl (IIIa-1-ICl), m.p. 210- 22°C 4-amino-3-(4'-fluorophenyl)-2-phenyl-butyric acid-

HC1 (IIId-HCl), m.p. 190-5°C 4-amino-2-(41-fluorophenyl)-3-phenyl-butyric acid-HC1 ( IIIe - HCl ), m.p. 170- 5°C 4-amino-3-(4'-methylphenyl)-2-phenyl-butyric acid-HC1 ( IIIf - HCl ), m.p.- 210- 6°C 4-amino-2-(21-fluorophenyl) -3-(4'-trifluoro-'

methylphenyl)-butyric acid HC1 ( IIIh - HCl ), m.p. 182-5°C

4-amino-2-(41-fluorophenyl)-3-, (4'-trifluoromethyl-phenyl)-butyric acid-HCl (IIIu-HCl)., m.p. 200-3°C 4-amino-3-(4'-trifluoromethylphenyl)-butyric acid HCl (IIIk-HCl), m.p. 175- 77°C 4-amino-2-methyl-3-(4'-trifluoromethylphenyl)-

butyric acid-HCl (III- HC1)

4-methylamino-4-methyl-3-phenyl-butyric acid-HCl (IIIn-HCl), m.p. 165-75°C 4-amino-3-(4'-methoxyphenyl-2-phenyl)-butyric acid-HCl (IIIp-HCl), m.p. 190-210°C 4-amino-3-(3<1>,4<1->dimethoxyphenyl)-2-phenyl-

butyric acid-HCl (IIIq-HCl), m.p. 230-3°C.

EXAMPLE VI 3,4-diphenylpyrrolidine (IIa)

A solution of 1.185 g of cis-3,4-diphenyl-pyrrolidin-2-one (Ia) in 30 ml of tetrahydrofuran (THF) was slowly added to a suspension of 0.950 g of lithium aluminum hydride (LAH) and refluxed for 7 hours. After cooling, 5 ml of ethyl acetate was added to destroy the excess of LAH, and 7 ml of water to form hydroxides. The suspension was filtered and washed with THF. The THF was removed in vacuo, and the residue was taken up in chloroform and extracted twice with 50 ml of 2N sulfuric acid. The water phase was treated with 2N NaOH solution until it became alkaline and extracted with chloroform. Crystallization of the residue from methylene chloride gave crystals with m.p. 169-72°C. 0.05 m of 37% hydrochloric acid solution was added to a solution of 0.100 g of Ila dissolved in 3 ml of methanol. Evaporation and suspension in ether gave 0.111 g of Ila-HCl with m.p. 74-84°C.

EXAMPLE VII N-[(4'-trifluoromethylbenzoyl)methyl]-2-bromoacetamide (Xllk)

A solution of 51.16 g (0.609 mol) of sodium bicarbonate in 550 mL of water was added under nitrogen at 0 to 10°C to a two-phase solution of 48.5 g (0.203 mol) of 2-amino-4'-trifluoromethyl-acetophenone hydrochloride (Xlk) in 250 ml of water and 250 ml of ether. Another solution of 18.41 ml (0.223 mol) of bromoacetyl chloride in 200 ml of dry ether was added at 0 to 5°C within 15 minutes to the above stirred suspension. The immediately thick suspension became thinner. After stirring for 2 hours, ethyl acetate was added until a clear two-phase solution was obtained. The water was separated and the ethyl acetate-ether solution was washed with water until neutral. Evaporation in vacuo gave 62.3 g (95%) of Xllk. A recrystallized sample had m.p. at 201 - 11°C.

EXAMPLE VIII N-[4'-trifluoromethylbenzoyl)methyl]-2-triphenylphosphonium bromide)-acetamide (XHIk)

70.5 g (0.269 mol) of triphenylphosphine was added to a suspension of 62.36 g (0.192 mol) of XITk in 600 ml of benzene. After 4 days of stirring at room temperature, the solid material was collected and suspended in 250 ml of acetone for 3 hours. Filtration gave 77.66 g (69%) of XHIk with m.p. 250 - 1°C.

EXAMPLE IX 4-(4'-trifluoromethylphenyl)-3-pyrrolin-2-one (Vk)

72.5 ml of 2N NaOH solution was slowly added under nitrogen to a solution of 77.6 g (0.132 mol) XHIk in 780 ml of methanol. to keep the temperature below 40°C. After stirring for 1 hour, 15 ml of 2N HCl solution was added until a pH of 6.5. The methanol was partially evaporated in vacuo, and after the addition of 200 ml of water removed completely. The precipitate was collected and washed with water. After drying, the residue weighing 67.25 g was suspended in 200 ml of methylene chloride for 2 hours. Filtration yielded 27.3 g (91%) Vk with m.p. 208 - 20°C (decomposition).

EXAMPLE X 4-(4-trifluoromethylphenyl)-pyrrolidin-2-one (Ik)

A solution of 27.2 g (0.12 mol) Vk in 500 ml of methanol (partially suspended) was hydrogenated for 10 hours with 4.1 g of 10% Pd on carbon as catalyst. Filtration and evaporation in vacuo gave 27.5 g (100%) Ik. A recrystallized [acetone ether (1:2)] sample had m.p. 121. - 2°C.

Analysis (C,,H,nF.,N0): Calculated: C 57.64 % H 4.40 % N 6.11 %

Found: C 57.65% H 4.38% N 6.35%

EXAMPLE' XI 4-Amino-3-(4'-.trifluoromethylphenyl)-butyric acid-HCl (IIIk-HCl)

11.45 g (50 mmol) of Ik was refluxed for 15 hours in 100 ml of 25% HCl solution. After dilution with water and extraction with ether, the water phase was evaporated in vacuo. The residue was suspended in a little ether and collected: 13.45 g (95%) IIIk-HCl with m.p. 175 - 7°C.

Analysis (C, , H, -.CIF^NO-) : Calculated: C 46.57 % H 4.62 % N 4.94 %

Found: C 46.44% H 4.67% N 5.06%

Claims (8)

1. Process for the production of pyrrolidin-2-ones of the formula: wherein R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl or aroyl, R 3 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, R 4 is aryl, substituted aryl, alkyl or substituted alkyl, R~* is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, and R 5 'is hydrogen, alkyl or substituted alkyl, characterized in that a 3-pyrrolin-2-one of the formula: 3 4 5 5' in which R', R , R , R and R have the meanings given above, are subjected to hydrogenation. 2. Method according to claim 1, characterized in that the hydrogenation is carried out using a catalyst while forming the 3,4-cis isomer of the specified pyrrolidin-2-one. 3. Method according to claim 2, characterized in that the catalyst is palladium-carbon, platinum or rhodium, possibly in the form of an optically active complex forming the optically active isomer of specified cis-pyrrolidin-2-one. 4. Method according to claim 3, characterized in that the cis isomer is converted into the corresponding trans isomer by acid or base treatment. 5. Method for the preparation of a 3-pyrrolin-2-one of the formula: wherein R"*" is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl or aroyl, R 3 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, R 4 is aryl or substituted aryl, R 5 is hydrogen, alkyl, substituted alkyl, aryl or substituted 5 1 aryl, and R is hydrogen, alkyl or substituted alkyl, one of 5 51 the substituents R and R are hydrogen, k-.a;;r acted in that a compound of the formula: 1 3 4 5 51 wherein R , R , R , R , and R have the meanings given above, is subjected to cyclization under basic conditions. 6. Method according to claim 5, characterized in that the ring closure is carried out -with potassium t-butoxide in t-butanol. 7. Method according to claim 6, characterized in that the reaction medium is acidified and diluted with water after the ring closure. 8. Process for the production of a 3-pyrrolin-2-one according to claim 5, characterized in that a phosphonium bromide of the formula: 1 3 4 5 5 * in which R , R , R , R and R have the above meanings, is subjected to cyclization in basic medium.