FI70209C - PROCEDURE FOR FRAMSTAELLNING AV PYRROLIDIN-2-ONER OCH 3-PYRROLIN-2-ONER - Google Patents

Description

rBl ADVERTISEMENT 70209 «| §Γ® [BJ 1 UTLÄGGNINGSSKRIFT '(45):, t -: t,. ; '. . nf ib. :: '"o (51) Kv.ik.4 / lnt.ci. * C 07 D 207/26, 207/38 FINLAND —FINLAND <21) Patent application - Patentansökning 791866 (22) Application date - Ansökningsdag 12.06. 79 (23) Start date - Giltighetsdag 1 2.06.79 (41) Become public - Blivit offentlig 13-12.79

National Board of Patents and Registration Date of publication and publication. - 28.02.86

Patent- and Register-Register ν 'Ansökan utlagd och utl.skriften publicerad (32) (33) (31) Privilege claimed - Begärd priority 1 2.06.78 15.02.79 USA (US) 914682, 12496 (71) Mundipharma AG, St. AIban -Vorstadt 94, Postfach, 4006 Basel,

Switzerland-Schweiz (CH) (72) Peter Hofer, Liestal, Switzerland-Schweiz (CH) (74) Oy Kolster Ab (54) Method for the preparation of pyrrolidin-2-ones and 3-pyrrolin-2-ones - Förfarande för f ramstä11 Both pyrrolidin-2-one and 3-pyrrolin-2-one

Pyrrolidin-2-ones of formula I <R3

r5 A

rai Ao ™

A

l · and the corresponding pyrrolidines of formula II R4, R3 *% / Vh (ii) R5 '/ \ / 2

R

2,70209 wherein hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl or aroyl; R 3 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; R is aryl, substituted aryl, alkyl or substituted alkyl; RD is hydrogen, 5 · alkyl, substituted alkyl, aryl or substituted aryl; R is hydrogen, alkyl or substituted alkyl; includes compounds that have an effect on the central nervous system (Archivum Immunologiae et Therapiae Experimentalis 1975, 23, 733-751). The potency of many of the compounds of formula (I) is of the prostaglandin type (DE application 2,527,989).

The pyrrolidin-2-ones of formula (I) are usually prepared in the ring form of the corresponding r5r4 r3 R'NH-C-1H-1H-CO R (III) A * · 4-aminobutyric acid or ester and 4-halobutyramide of formula (III). by reaction with lactones and amines or by hydrolysis of iminopyrrolidines (GB Patent 1,350,582 and U.S. Patent 4,012,495).

These processes for the preparation of the compounds of formulas (I) and (II) were deficient in their potency as well as in the preparation of the substituent types at different positions and the pure stereo- and optically active isomers.

In general, in accordance with the present invention, 3-4-cis-substituted, optionally optically active pyrrolidin-2-ones of formula (I) are prepared from V 3 R 3 - p \ o (I-cis) R 5 / l · or isomerization. after

II

70209 3

R4 H

Η · / '\; r3 r5 "^ 7 \ / ^ <j-trans)

R5 N

by hydrogenation of 3-pyrrolin-2-ones of formula (V) R4 R3 A A) lv) R5 ^ TA '

V

R is hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, an acyl group or an aroyl group., 3 R is hydrogen, an optionally substituted alkyl group or an optionally substituted aryl group, 4 R is an optionally substituted aryl group, R * * is hydrogen, an optionally substituted alkyl group or an optionally substituted aryl group and 5 · R is hydrogen or an optionally substituted alkyl group, the above-mentioned groups being optionally substituted with up to five identical or different groups, which may be alkyl, haloalkyl. For example, F 1 -C 4), O-alkyl, N-dialkyl (same or different alkyl) ), S-alkyl, halogen, O-benzyl, N-dibenzyl, N-alkyl / benzyl, S-benzyl, O-aryl, S-aryl, N-diaryl, N-alkyl / benzyl / aryl, OH- , NH 2 and / or SH group, using a suitable catalyst which may, if desired, be optically active (Angew. Chem. 83, 956 (1971)) or contain in its structure the asymmetry of a compound of formula (V) Center.

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

4 70209

For the above reason, the present invention also relates to general processes for the preparation of compounds of formula (V) using the ring-forming reaction of N-aroylmethylacetamides of formula (IV), 3 * r4 / r3 r5>? ^ Uv.

R

»R1 1 3 4 5 5 '3 i

wherein R, R, R, R and R are as defined above and R

means hydrogen or triphenylphosphonium bromide, provided that when R and R are each hydrogen then R must not be hydrogen or alkyl to form the corresponding compound of formula (V). This ring-forming reaction according to the invention is carried out under a nitrogen atmosphere in a basic solution, e.g. t-butanol with t-potassium butoxide as a base, after which the reaction mixture is acidified with a mineral acid, e.g. hydrochloric acid and diluted with water. The following definitions of terms have been used in the text:

Aroyl = Aryl-CO

Acyl = Alkyl (minus 1 C) -CO

Aryl = phenyl, pyridinyl, furyl, thienyl, N-alkyl or N-arylpyrrolyl, and the corresponding benzene derivatives, i.e. naphthyl, quinolyl, etc.

Alkyl = hydrocarbons C 1 -C 4 g Substituents (1-5 identical or different): alkyl, haloalkyl (e.g. F 1 -C 4), O-alkyl, N-dialkyl (identical or different), S-alkyl, halogen, O -benzyl, N-dibenzyl, N-alkyl / benzyl, S-benzyl, O-aryl, S-aryl, N-diaryl, N-alkyl / benzyl / aryl, OH, NH2 / SH (the last three are protected in a basic ring-forming reaction ).

U.S. Patent 3,272,842 claims certain 3-pyrrolin-2-ones of formula (V) prepared by the following method:

II

70209 5 r4 r4 r3 Λ / '^, X> R1 (IV) (V) 5 51 4 However, R and R cannot be hydrogen and R is always S-CH9- (S = substituent). This ring formation reaction of compound (IV), when R = aryl or substituted aryl and R and / or R = hydrogen, according to the examples of U.S. Patent 3,272,842, does not proceed or yields yellow compounds (possibly dimers) due to the difference in substituents, i. these methods were not suitable for use in the preparation of the compounds disclosed in this application.

3-Pyrrolin-2-ones (V) have been prepared by G. Stork and R. Matthews,

Chemical Communications 1970, 445-6) with the following reaction chain: 4 3 <s ° * R ^ PO: rOEt

„5 f <-OR ♦ f 0ET

l υ dcc 5y 's'' 2) H +

R 'NH, HO O

(VI) (VII) 4 3 R *, R, OEt <) = 0 \ PO-OEt NaH r

5X / V DME

R \ n /!

(VIII) H

\ / R

'N' H (V) 6 70209

However, in the preparation of larger amounts, dicyclohexylcarbodiimide (DCC) is unsuitable for condensation of aminoketone derivatives (VI) with unstable phosphonoacetic acid (VII). In addition, the price of DCC is quite high, and the by-product N, N'-dicyclohexylurea is difficult to remove, which makes the process economically unprofitable.

A similar ring-forming reaction according to the following scheme has also been proposed (TWGuntert et atl. Helv. Chim. Acta 60, 334-9 (1977)): R4 4 \ / / P® (Ph) 3> \> - vO · - · - NN * / (IX) H li (X)

_ H

H (V), however, which requires several chromatographic separations in order to obtain a 10% yield for 4 3-pyrrolin-2-one (V), where R = 1Ίβ -steroidyl, so that this method is also not suitable for the preparation of large quantities, taking into account , it was not possible to prepare the starting bromine compound of formula (IX) until formula (XII) of this application.

According to the present invention, the direct ring-forming reaction of the compounds of formula (IV) can be well used even in the preparation of substituted 1,3-pyrrolin-2-ones (V) when R and R in formula (IV) satisfy the following two conditions: (1) either R f H , i.e. R = alkyl, substituted alkyl, aryl, substituted aryl, acyl or aroyl, or 11 7 70209 • 1 3 (2) 3os R = H, then R is a group which stabilizes the anions in C-3 and is stable against bases, i.e. aryl, substituted aryl, carbonyl, etc., but not alkyl or hydrogen.

In the preparation of compounds of formula (V) by a ring-forming reaction in the case where R is hydrogen and R is hydrogen, alkyl, or substituted alkyl, it has been found best to follow the following reaction chain. Thus, when R = aryl or substituted aryl, R = hydrogen, alkyl or substituted alkyl and R = hydrogen, alkyl or substituted alkyl, it is possible to give 2-aminoacetophenone of formula (XI) R 4 5 / = ° (XI) R 1 / R NH 2 'hci to react with 2-bromoacyl chloride or bromide to form the corresponding bromine compound of formula (XII): R 4 Br »A / °' n7»

B

almost quantitatively. Unlike the chlorine compound (IX), the bromine compound (XII) reacts without decomposition with triphenylphosphine at room temperature to 50 ° C, e.g. in benzene or chlorobenzene solution, to form the corresponding phosphonium bromide of formula (XIII): R4 Λη, βγ9 O "0 ^» 3> <V (XIII) Λ k 70209 8 which is sufficiently soluble in alcohols and water to effect a ring-forming reaction in which a compound of formula (V) is formed, e.g. in 2N NaOH solution.

Thus, according to this method, the starting amino ketones (XI) in which R = aryl, substituted aryl, alkyl or substituted alkyl, R 5 = hydrogen, alkyl or substituted alkyl 5 'and R = hydrogen or alkyl are easy to obtain, and can be practically acylated quantitatively in a weakly basic solution, e.g. sodium bicarbonate in aqueous ether, with 2-bromoacyl chlorides or bromides to the corresponding N- (2-bromoacyl) -3-aminoketone (XII), where R = hydrogen, aryl, substituted aryl , alkyl or substituted alkyl.

As indicated above, the ketones of formula (XII) react with triphenylphosphine at room temperature, e.g. in benzene solution, to form the corresponding phosphonium bromide (XIII), which crystallizes and can be recovered by simple filtration. When an alcoholic (preferably methanol) or aqueous solution of a compound of formula (XIII) is treated with more than an equivalent amount of base (preferably 2N NaOH solution), the desired 3-pyrrolin-2-one and triphenylphosphine oxide, which crystallize from solution, rapidly form at room temperature. in virtually quantitative yields. After dilution with water and evaporation of the alcohol, the mixture is collected and separated by extraction, e.g. with methylene chloride, which removes triphenylphosphine oxide.

The 3-pyrrolin-2-one (V) prepared by some of the above methods can be readily hydrogenated, e.g., with Pd / C, Pt, or a chiral rhodium complex as a catalyst in an alcoholic solution (preferably in methanol) to a CNS-substituted substituted pyrrolidin-2-one (I-cis). This reaction chain has the advantage of obtaining derivatives,. . 3 4 where R and R are exclusively in the cis position. The I-cis compounds can be converted to the corresponding I-trans compounds by acid or base treatment.

Pyrrolidin-2-ones (I) can be hydrolyzed with a strong acid or base to the corresponding 4-amino-butyric acid derivatives (III), 3 after which the R substituent can be partially isomerized to give a diastereoisomeric mixture which can be isolated as salts.

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70209 9 (e.g. HCl or sodium and magnesium, etc.) or as free amino acids.

When R = alkyl, the hydrolysis is not complete because an equilibrium is formed between the products (I) and (III). Products (I) and (III) can be separated by extraction.

A further advantage of the present invention is that the reduction of the new pyrrolidin-2-ones (I), e.g. with 3 H 6 or LiAlH. 3 g 6 4, gives new pyrrolidines (II-cis (R and R cis)). or II-trans 3 4 (R and R trans)) depends on the starting material.

The reduction of the C = C double bond of the compound of formula (V) can be readily carried out with hydrogen using about 5-15% of a 10% palladium / carbon catalyst as catalyst. Asymmetric hydrogenation is achieved with chiral rhodium catalysts (e.g. J. Am. Chem. Soc. 1977, 99, 5946-52). The desired lactams are obtained quantitatively directly by filtration and evaporation of the solvent, preferably methanol. If in the formula V R 1 = benzyl, hydrogenolysis gives the product I-cis in which R is hydrogen, i.e.

3 The N-benzyl group acts as a protecting group if R = hydrogen, alkyl or substituted alkyl.

Hydrolysis of a compound of formula (I) by refluxing in concentrated (15-35%) mineral acid (e.g. HCl) followed by evaporation directly leads to the corresponding 4-aminobutyric acid hydrochlorides of formula (III) when HCl is used. If sulfuric acid is used, the sulfates can be removed with barium hydroxide solution to give the free amino acids of formula (III) which can be converted to the desired carbonic acid salts (e.g. magnesium) or ammonium salts with a therapeutically acceptable acid. On the other hand, hydrolysis with a base gives the corresponding carbonic acid salts (e.g. sodium, potassium).

Reduction of the carbonyl group in lactams of formula (I), e.g. with lithium aluminum hydride or borohydride, affords the corresponding pyrrolidines of formula (II) which can be converted to the ammonium salts with a therapeutically acceptable acid.

The invention is further illustrated by the following examples.

Example 1 70-Diphenyl-3-pyrrolin-2-one (Va)

A solution of 12.6 g (50 mmol) of 2-phenylacetamidoacetophenone in 200 ml of t-butanol is added to a refluxing solution of t-potassium butoxide prepared from 6.5 g of potassium (166 mmol) and 200 ml of t-butanol. -butanol in a nitrogen atmosphere. The mixture is refluxed for 40 min after which it is cooled to 40 ° C and the pH is adjusted to approximately 5-6 with 2N HCl (ca. 120 mL). The resulting suspension is poured into 3 l of ice water. The crystals are collected and washed with water. After drying, 9.85 g (84.1%) of compound Va with a melting point of 183-190 ° C are obtained. When water is extracted with chloroform, a further 1.3 g (11.1%) of compound Va are obtained. The sample recrystallized from benzene m.p. was 177-179 ° C. The following compounds of formula (V) were prepared by a similar method: 3-phenyl-4- (4'-chlorophenyl) -3-pyrrolin-2-one (Vb), m.p. 204-210 ° C.

3- (2'-carboxyphenyl) -4-phenyl-3-pyrrolin-2-one (Vc), m.p. 238-241 ° C.

3-phenyl-4- (4'-fluorophenyl) -3-pyrrolin-2-one (Vd), m.p. 200-202 ° C.

3- (4-fluorophenyl) -4-phenyl-3-pyrrolin-2-one (Ve), m.p. 199-209 ° C.

3-phenyl-4- (4'-methylphenyl) -3-pyrrolin-2-one (Vf), m.p. 210-220 ° C.

3-phenyl-4- (4'-trifluoromethylphenyl) -3-pyrrolin-2-one (Vg), m.p.

195-198 ° C.

3- (2'-fluorophenyl) -4- (4'-trifluoromethylphenyl) -3-pyrrolin-2-one (Vh), m.p. 165-166 ° C, 1,3,5-trimethyl-4-phenyl-3-pyrrolin-2-one (Vi), mp 79-81 ° C 1-benzyl-4- (4'-trifluoromethylphenyl) -3-pyrroline- 2-one (Vk) when 1-benzyl-3-methyl-4- (4'-trifluoromethylphenyl) -3-pyrrolin-2-one (VI), rubber 1,5-dimethyl-3,4-diphenyl-3-pyrrole -2-one (Vm), m.p. 95-103 ° C

1,5-dimethyl-4-phenyl-3-pyrrolin-2-one (Vn), m.p. 130-135 ° C

1-methyl-3-phenyl-4- (4'-methylphenyl) -3-pyrrolin-2-one (Vo), m.p. 1 2 3-1 2 4 ° C,

3-phenyl-4- (4'-methoxyphenyl) -3-pyrrolin-2-one (Vp), m.p. 179-181 ° C

3-phenyl-4- (3 ', 4'-dimethoxyphenyl) -3-pyrrolin-2-one (Vq), m.p.

202-204 ° C, 3- (4'-fluorophenyl) -4- (4'-trifluoromethylphenyl) -3-pyrrolin-2-one (Vu), m.p. 212-213 ° C #

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Example 2 70209 11 cis-3,4-diphenyl-pyrrolidin-2-one (cis-Ia) 9.00 g of 3,4-diphenyl-3-pyrrolin-2-one (Va) in 200 ml of methanol and 0, 90 g of a 10% palladium-on-charcoal mixture are placed in a 500 ml hydrogenation vessel and hydrogenated for 16 hours at room temperature. The catalyst is filtered off and the methanol is evaporated off under vacuum. Crystallization from benzene-petroleum ether (1: 1) gave crystals of m.p. was 154-155 ° C. The following compounds were prepared in a similar manner: 3-phenyl-4- (4'-fluorophenyl) -pyrrolidin-2-ones (cis-Id), m.p. 198-200 ° C.

3- (4'-fluorophenyl) -4-phenyl-pyrrolidin-2-one (cis-Ie), m.p. 167-168 ° C, 3-phenyl-4- (4'-methylphenyl) -pyrrolidin-2-one (cis-If), m.p. 190-191 ° C, 3-phenyl-4- (4'-trifluoromethylphenyl) -pyrrolidin-2-one (cis-Ig), m.p. 149-151 ° C.

3- (2'-fluorophenyl) -4- (4'-trifluoromethylphenyl) -pyrrolidin-2-one (cis-Ih), m.p. 154-156 ° C, 1,3,5-Trimethyl-4-phenyl-pyrrolidin-2-one (cis-II), gum 4- (4'-trifluoromethylphenyl) -pyrrolidin-2-one (Ik), m.p. 121-122 ° C 3-Methyl-4- (4'-trifluoromethyl-phenyl) -pyrrolidin-2-one (cis-II), 1,5-dimethyl-4-phenyl-pyrrolidin-2-one (In), rubber 1-methyl- 3-phenyl-4- (4'-methylphenyl) -pyrrolidin-2-one (cis-10), m.p. 133-134 ° C, 3-phenyl-4- (4'-methoxyphenyl) pyrrolidin-2-one (cis-Ip), m.p. 156 - 9

159 C

3-phenyl-4- (3 ', 4'-dimethoxyphenyl) -pyrrolidin-2-one (cis-Iq), m.p.

114-116 ° C, 3- (4'-fluorophenyl) -4- (4'-trifluoromethylphenyl) pyrrolidin-2-one (cis-Iu), m.p. 203-204 ° C.

Example 3 70209 12 1,5-Dimethyl-4- (4'-nitrophenyl) -pyrrolidin-2-one (Ir) 4.32 g of 1N are gradually added to 30 ml of fuming sulfuric acid at a temperature between -5 and 0 ° C. The solution was kept at -10 ° C for 1 hour, after which it was poured into 300 ml of water.

The mixture was extracted with ethyl acetate and washed with bicarbonate solution and water, and after evaporation of the solvent, 4.89 g (91, 6 &) lr were obtained. Crystallization from acetone-ether / 1: 3 gave crystals of m.p. was 94-95 ° C.

Example 4 1,5-Dimethyl-4- (4'-chlorophenyl) -pyrrolidin-2-one (It)

A mixture of 4.89 g (20.9 mmol) of Ir, 50 ml of methanol and 0.49 g of 10% palladium on charcoal is placed in a 250 ml hydrogenation vessel and hydrogenated at room temperature for 30 hours. The catalyst is filtered off and the methanol is evaporated off under vacuum. The remaining 1,5-dimethyl-4- (4'-aminophenyl) -pyrrolidin-2-one (Is) in 100% yield is dissolved in 12 ml of 18% hydrochloric acid in a 250 ml beaker, and 5.23 ml of 4N sodium nitrite solution is added dropwise to the mixture at a temperature of 0-5 ° C. After the mixture has been at 0 ° C for 5 min. discard excess nitrite with urea. After the mixture has been at a temperature of 0-5 ° C for 10 min. a solution of diazonium is added dropwise to a freshly prepared solution of CuCl (20.9 mmol) in 8 ml of 37% hydrochloric acid at 0 ° C. This immediately produces brown crystals which are heated to 60 ° C for one hour. The mixture was extracted with chloroform and washed with water to give 4.30 g of a crude reaction product after evaporation. Filtration of the product through 130 g of silica gel gave 3.80 g (81%) of It gum.

Example 5 1 3 70209 4-Amino-2-phenyl-3- (4 * -trifluoromethyl-phenyl) -butyric acid hydrochloride (IIIg-HCl) 9/15 g of cis-Ig was slurried in 300 ml of 25% hydrochloric acid in 500 ml: n vessel and the mixture was refluxed for 13 hours. When the mixture was diluted with 300 ml of water and evaporated to dryness in vacuo, a crystalline white residue was obtained which was slurried in ether overnight to remove any lactam present. After filtration and washing with ether, 9.65 g (89.4%) of IIIg-HCl were obtained, m.p. 182-183 ° C.

Analysis: for C 7 H 7 ClF 3 NO 2 - 0.5 H 2 O (368.8)

Observed values: C 55.84%, H 4.96%, N 3.79%

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

The following acid hydrochlorides were prepared by a similar method:

4-amino-2,3-diphenylbutyric acid -HCl (IIIa-HCl), m.p. 210-222 ° C

4-amino-3- (4'-fluorophenyl) -2-phenylbutyric acid = HCl (IIId-HCl), m.p.

190-195 ° C.

4-amino-2- (4'-fluorophenyl) -3-phenylbutyric acid HCl (IIIe-HCl), m.p. 170-1 7 5 ° C,

4-amino-3- (4'-methylphenyl) -2-phenylbutyric acid HCl (IIIf-HCl), m.p. 210-216 ° C

4-amino-2- (2'-fluorophenyl) -3- (4'-trifluoromethylphenyl) butyric acid HCl (IIIh-HCl), m.p. 182-185 ° C, 4-amino-2- (4'-fluorophenyl) -3- (4'-trifluoromethylphenyl) butyric acid HCl (IIIu-HCl), m.p. 200-203 ° C, 4-amino-3- (4'-trifluoromethylphenyl) butyric acid HCl (IIIk-HCl), m.p. 175-177 ° C, 4-amino-2-methyl-3- (4'-trifluoromethylphenyl) butyric acid HCl (IIIl-HCl), 4-methylamino-4-methyl-3-phenylbutyric acid HCl (IIIn-HCl), mp.

165-175 ° C, 4-amino-3- (4'-methoxyphenyl-2-phenylbutyric acid HCl (IIIp-HCl), m.p.

1 90-210 ° C

4-amino-3- (3'-4'-dimethoxyphenyl) -2-phenylbutyric acid HCl (III-HCl), m.p. 230-233 ° C.

1 4

Example 6 70 2 0 9 3,4-Diphenyl-pyrrolidine (Ha)

A solution of 1.185 g of cis-3,4-diphenylpyrrolidin-2-one (Ia) in 30 ml of tetrahydrofuran (THF) is slowly added to a suspension of lithium aluminum hydride (0.950 g) (LiAH) and the mixture is refluxed. 7 hours. After cooling, 5 ml of ethyl acetate are added to the mixture to destroy LiAH and 7 ml of water to form hydroxides. The slurry is filtered and washed with THF. The THF is removed in vacuo and the residue is taken up in chloroform and extracted twice with 50 ml of 2N sulfuric acid. 2N Sulfuric acid is added to the aqueous phase. 2N NaOH is added to the aqueous phase until basic and extracted with chloroform. The residue is crystallized from methylene chloride to give crystals of m.p. was 169-172 ° C. 0.100 g of IIa is dissolved in 3 ml of methanol, and 0.05 ml of 37% hydrochloric acid is added to this mixture. After evaporation and slurrying in ether, 0.111 g of IIa-HCl was obtained, m.p. 74-84 ° C.

Example 7 N - ['(4'-Trifluoromethylbenzoyl) methyl] -2-bromoacetamide (X11k)

A solution of 51.16 g (0.609 mol) of sodium bicarbonate in 550 ml of water is added to a biphasic solution of 48.5 g (0.203 mol) of 2-amino-4 in a nitrogen atmosphere at a temperature of 0-10 ° C. -trifluoromethylacetophenone hydrochloride (Xlk), 250 ml of water and 250 ml of ether. A second solution of 18.41 ml (0.223 mol) of bromoacetyl chloride in 200 ml of dry ether is added over 15 minutes, at a temperature between 0-5 ° C, to the previous stirred slurry. Initially, the thick slurry becomes thinner. After stirring for 2 hours, ethyl acetate is added to the mixture until a clear biphasic solution is formed. The water is separated and the ethyl acetate-ether solution is washed with water until neutral. After evaporation in vacuo, 62.3 g (95%) of XIIk were obtained. The m.p. of the recrystallized sample. was 201-211 ° C.

Il

Example 8 7 0 2 0 9 15 N- (4'-Trifluoromethylbenzoyl) methyl] -2- (triphenylphosphonium bromide) acetamide (XHIk) - 70.5 g (0.269 mol) of triphenylphosphine are added to a slurry of 62.36 g (0.192 mol). mol) XIIk in 600 ml of benzene. After stirring for four days at room temperature, the solid is collected and slurried in 250 ml of acetone for three hours. After filtration, 77.66 g (60%) of XIIIk were obtained, m.p. was 250-251 ° C.

Example 9 4- (4'-Trifluoromethylphenyl) -3-pyrrolin-2-one (Vk) 72.5 ml of a 2N NaOH solution are slowly added under nitrogen to a solution of 77.6 g (0.132 mol) of XIIIk in 780 ml of methanol. , at a temperature below 40 ° C. After stirring for 1 hour, 15 ml of 2N HCl solution are added to the mixture to bring the pH to approximately 6.5.

A portion of the methanol is evaporated in vacuo and 200 ml of water are added to the mixture, after which the rest of the methanol is removed. The precipitate is collected and washed with water. The dried residue (67.25 g) is slurried in 200 ml of methylene chloride for 2 hours. After filtration, 27.3 (91%) of Vk were obtained, m.p. 208-220 ° C (decomposition point).

Example 10 4- (4-Trifluoromethyl-phenyl) -pyrrolidin-2-one (Ik)

A solution of 27.2 g (0.12 mol) of Vk and 500 ml of methanol (partly as a slurry) is hydrogenated for 10 hours with 4.1 g of a 10% Pd-charcoal mixture acting as a catalyst. After filtration and evaporation in vacuo, 27.5 g (100%) of Ik were obtained. The melting point of the recrystallized (acetone ether / 1: 2) sample was 121-122 ° C.

Analysis (CH 2 Cl 2 / NO): calculated values: C 57.64%, H 4.40%, N 6.11% found values: C 57.65%, H 4.38%, N 6.35%

Example 11 70209 16 4-Amino-3- (4'-trifluoromethylphenyl) butyric acid HCl (Ulk-HCl) 11.45 g (50 mmol) of Ik are refluxed for 15 hours with 100 ml of 25% HCl solution. . The mixture is diluted with water and extracted, after which the aqueous phase is evaporated in vacuo. The residue is taken up in a small amount of ether and collected: 13.45 g (95%) of IIIk-HCl, m.p. 175-177 ° C.

Analysis calculated: C 46.57%, H 4.62%, N 4.94% Observed values: C 46.44%, H 4.67%, N 5.06%

Although the invention has been illustrated by methods of making certain products, it is to be understood that various modifications and variations are within the scope of the invention.

Il

Claims (6)

17 7 Π 9 Π Q Claims t ν 7 A process for the preparation of 3-pyrrolin-2-ones or pyrrolidin-2-ones of the general formula R4 R3 ** '> t * L R5' / ^ 7 ^ 0 (I), (V) L1 wherein the notation - ---- represents a double bond (formula V) or a single bond (formula I), R is hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, an acyl group or an aroyl group, 3 R is hydrogen, an optionally substituted alkyl group or an optionally substituted aryl group, 4 R is an optionally substituted aryl group, R 5 is hydrogen, an optionally substituted alkyl group or an optionally substituted aryl group, and 5 'R is hydrogen or an optionally substituted alkyl group, the above groups being optionally substituted with up to five identical or different groups which may be alkyl, haloalkyl ( for example FjC), O-alkyl, N-dialkyl (same or different alkyl), S-alkyl, halogen, O-benzyl, N-dibenzyl, N-alkyl / benzyl, S-benzyl, O-aryl, S-aryl, Nd aryl, N-alkyl / benzyl / aryl, OH, NH 2 and / or SH group, characterized in that the compound of general formula R 4 * 3: 5 V = 0 V ^ H (IV) s '\ / 18 70209 1 3 4 5 5' 3 'wherein R, R, R, R and R are as defined above and R is hydrogen or triphenylphosphonium bromide, provided that 13' 3 such that when R and R are each hydrogen then R must be neither hydrogen nor alkyl, a ring structure is formed under basic conditions and in the absence of oxygen, and the resulting 3-pyrrolin-2-one of the general formula R4 is (V) • A / 1 3 4 5 5 'wherein R, R, R, R and R have the same meaning as above, are hydrogenated, if desired, to the corresponding pyrrolidin-2-one (I), the hydrogenation being carried out using a noble metal catalyst of group VHIb with the corresponding pyrrolidine To obtain the 3,4-cis isomer of -2-one and, if an optically active isomer is desired, preferably using an optically active rhodium complex, and optionally converting the cis isomer to the corresponding trans isomer by treatment with an acid or a base. Process according to Claim 1, characterized in that the ring-forming reaction is carried out in the presence of potassium t-butoxide in t-butanol or also with a solution of sodium hydroxide-3 'in methanol when R is triphenylphosphonium bromide. Process according to Claim 1 or 2, characterized in that, after ring formation, the reaction mixture is acidified and diluted with water to separate the 3-pyrrolin-2-one (V). Il 70209 19 1. A process for the preparation of 3-pyrrole-2-oner eller pyrrolidin-2-oner raed the general formula R 3 R 4 R 5 V (v) ^ (i) l1 color symbol anger I dubbelbindning (Formel V) or a enkel- binding level ( Formula I) R is an optionally substituted alkyl group, an optionally substituted aryl group, an acyl group or an aroyl group, 3 R is an optionally substituted alkyl group or an optionally substituted aryl group, 4 R is an optionally substituted aryl group. 5 R är väte, en optionally substituted with an alkyl group or en optionally substituted with an aryl group, and 5 'R är väte, optionally substituted with an alkyl group, varvid det av de eventuella substituenterna i de ovannämnda grupperna kan fommekomma upp account flera lika eller olika grupper , haloalkyl (exempt F-jC), O-alkyl, N-dialkyl (same or alkyl), S-alkyl, halogen, O-benzyl, N-dibenzyl, N-alkyl / benzyl, S-benzyl, O- aryl, S-aryl, N-diaryl, N-alkyl1 / benzyl / aryl, OH-, NH2 and / or SH groups, inverted, for the purposes of formula 3 1 RV / R 3 R5 \ N / L4