FI66846C - OIL MILLAN PRODUCTS FOR FRAMSTATION OF AV N-ALKYLAMIDER AV 2-OXOPYRROLIDINE - Google Patents

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M ANNOUNCEMENT

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Patent-OCh reglstantyralMn 1; Af »6kan och ucUkrifc ·· pttMcarwi 31.08.84 (32) (33) (31) ^ yr4« ** r ***** 14.01.76 11.08.76 Yugoslavia and Yugoslavia (YU) P 77/76, P 1983/76 (71) PLIVA Pharmaceutical and Chemical Works, Ive Lole Ribara 89, Zagreb, Yugoslavia-Yugoslavia (YU), Karl 0. Helm, Nordkana1 str. 28, D-2 Hamburg 1, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Slobodan Djokid, Zagreb, Branimir Gaspert, Zagreb,

Branimir Simunid, Zagreb, Mirjana Tomid, Zagreb,

Yugoslavia-Yugoslavia (YU)

Alfred Maasbol, Hamburg, Federal Republic of Germany Förbundsrepubliken Tyskland (DE) (74) Berggren Oy Ab (54) Process and intermediate for the preparation of 2-oxo-pyrrolidine in N-alkylamides - Preparation of N-alkylamides in the form of N-alkylamides This invention relates to a process for the preparation of N-alkylamides of 2-oxo-pyrrolidine of the formula 1 = O, X-CO- (NH-CH-CO) n -NH2 (I)

R

wherein X is a C 1 -C 4 alkylene group, R is a hydrogen atom or a benzyl group, and n is 0 or 1.

It is known that compounds of general formula I in which X represents alkyl having 1 to 2 carbon atoms and n is 0 can be prepared by reacting 2-oxo-pyrrolidine sodium and omega-haloalkylamides according to GB Patent No. 1,039,113 by reacting ammonia With esters or acid chlorides of 2-oxo-pyrrolidine-alkanoic acids according to GB Patent No. 1,039,113 or by thermal decomposition of the ammonium salts of these 2-oxo-pyrrolidin-alkanoic acids according to GB Patent No. 1,309,692 2 6 6 8 4 6.

In addition, it is known that when liquid ammonia reacts with gamma-butyrolactone at higher temperatures and under supernatant vacuum, 2-oxo-pyrrolidine-N-gamma-butyramide can be formed according to U.S. Patent No. 3,250,784. It is also known that the above-mentioned products can be prepared by electrolytically reducing 2,5-dioxopyrrolidine-N-alkylamides according to FI patent no. 63,750. Partial hydrolysis of 2-oxo-1-pyrrolidine-acetonitrile according to DE No. 2,507,576 gives 2-oxo-pyrrolidine-acetamide.

A few of these compounds are known to have therapeutic activity in the treatment of exercise disorders, hypertension, hyperkinesia, and memory disorders. In particular, the compound 2-oxo-pyrrolidine-acetamide, commonly known as "Piracetam", has such effects.

It is further known that 4-chlorobutyryl derivatives of amino acid esters under special conditions and in the presence of silver tetrafluoroborate cyclize to iminolactones, which are used for the preparation of N-substituted derivatives of amino acids (H. Peter, M. Brugger, J. Schreiber and A. Eschenmoser, Helv. Acta 46 (1963) 577).

4-Chlorobutyryl derivatives of amino acids are generally prepared by reacting 4-chlorobutyryl chloride with esters or amides of amino acids in the presence of a tertiary amine or in a molar excess of amino acid.

Also known is a process for the preparation of peptides by reacting activated esters or corresponding acid chlorides with N, O-disilyl derivatives of amino acids (L. Birkhofer, W. Konkol and A. Ritter, Chem. Ber. 9 (1961) 1263). The advantage of this process over other processes is that after completion of the reaction, the silyl group can be removed very gently with water or alcohol.

To date, no general method has been published for the preparation of N-substituted amides of 2-oxo-pyrrolidine of general formula I.

II

3,66846. Only various methods for the preparation of individual compounds of general formula I are known, in which n is zero. Compounds of general formula I wherein n is zero and X is methylene or ethylene can be prepared from 2-oxo-pyrrolidine sodium and omega-haloalkylamides according to GB Patent No. 1,039,111. U.S. Patent 3,250,784 discloses that the formula. The compound of formula I wherein n is zero and X is an n-propyl radical can be prepared from pyrrolidine sodium and gamma-chlorobutyric acid amide, but experiments have shown that this is not the case. the preparation of the compound as described in U.S. Patent 3,250,784 is successful.

Surprisingly, it has been found that the intramolecular cyclization of chlorobutyrylamide to pyrrolidone occurs quantitatively by pyrrolidine sodium base.

The process according to the invention for the preparation of the compounds of the formula I is characterized in that the compound of the formula

Hal-CH2CH2CH2-CONH-X-CO (NH-CH-CO) n ~ NH2 (II)

R

wherein R, X and n are as defined above and Kai is a chlorine, bromine or iodine atom, subjected to intramolecular cyclization.

Compounds of formula I wherein X is as defined above and n is zero may be prepared according to the following reaction formula: 2 h2n-x-conh2 + cich2-ch2-ch2-coci ------> C1-CH - CH9- CH9-CONH-X-CONH ~ ------> \ N> -0 X-CONH2

The compounds of formula I can be advantageously prepared by condensing the amino acid amide with 4-chlorobutyric acid chloride to give the amide of 4-chlorobutyrylamino acid, which is then cyclized under basic reaction conditions to the amide of 2-oxo-pyrrolidinecarboxylic acid. According to the process of the present invention, for example, glycinamide is dissolved in N, N-dimethylacetamide and gradually added to a cooled solution of 4-chlorobutyric acid chloride 4,66846 in an aprotic organic solvent (unable to donate or receive protons). The precipitate of glycinamide formed is filtered to regenerate glycinamide and the light volatile solvent is removed from the filtrate in vacuo. The product is precipitated from the residue by adding a conventional solvent in which the product is insoluble. The resulting 4-chlorobutyrylglycinamide is then added with alcohol and then reacted with inorganic bases such as sodium hydroxide, potassium hydroxide, etc. or organic bases such as alcoholates, alkali metal salts of secondary amides or basic anion exchange resins such as Dowex-1 , which is separated from the reaction mixture after removal of the solvent. The advantage of the process according to the invention is that the use of metallic sodium or sodium hydride is avoided and the product is obtained in good yields.

The preparation of products of formula II in which X, R and Hal are as defined above and n is 1 cannot be carried out with peptidamides using 4-chlorobutyryl chloride as starting material, since chain polymerization may occur or, in the presence of free amino groups, dipeptide amides may e.g. cyclized to diketo-piperazines. Surprisingly, it has been found that cyclization or chain polymerization can be avoided if the amino acid or peptide in activated silyl form is reacted with chlorobutyric acid chloride. The product obtained is converted into a 4-halobutyryl derivative of the general formula II by known methods.

Compounds of formula II may be prepared by reacting an amino acid or peptide of formula H9N-X-CO (NH-CH-CO) -OH (III)

R

wherein X, R and n are as defined above, to be reacted by known silylation methods to give a silyl derivative which is then reacted with 4-halobutyric acid chloride and hydrolysed to convert it to a compound of formula IV

Hal-CHo-CH „CH0-CONH-X-CO (NH-CH-CO) -OH (IV) ^ z δ j n

R

II

5,668 4 6 wherein X, R, n and Hai have the same meaning as above. The compound of the formula IV is then converted into the corresponding organic acid chloride by means of inorganic acid chlorides, e.g. phosphorus pentachloride, by methods known per se, which is then converted into the compound of the formula II with ammonia.

According to a preferred embodiment of the process according to the invention, the amino acid or peptide is first converted into an activated silyl derivative in a conventional manner by silylation (trimethylchlorosilane, dimethyldichlorosilane, hexamethyldisalazane, etc.) in an aprotic organic solvent. To this mixture is then added 4-halobutyric acid chloride. After a reaction time of about one hour, it is hydrolyzed with water. The dried organic solution is then chlorinated with phosphorus pentachloride for about an hour. The solid reaction product formed is filtered and, after dissolution in an aprotic organic solvent, ammonia is added thereto. The solid reaction product is recrystallized from ethyl acetate to give the pure 4-halobutyryl derivative of general formula II. Inorganic bases, e.g. sodium hydroxide, potassium hydroxide or organic bases, e.g. alcoholates or secondary salts of secondary amides or anion exchange resins in OH form, such as Dowex-1, Amberlite IRA-410, give the carboxyl of 2-oxo-pyrrolidine of the general formula I 2-oxo-pyrrolidine. amides.

The invention is described in more detail below by means of examples.

Preparation of compounds of general formula IV Example 1 N- (4-chlorobutyryl) -gamma-aminobutyric acid (IV; X =. ((^ 2) 3,

Hai = Cl, n = 0___

Gamma aminobutyric acid (6.18 g, 0.06 mol) was suspended in methylene chloride (60 mL). To the suspension was added trimethylchlorosilane (8.04 mL, 0.06 mol) and a stirred solution of triethylamine (8.4 mL, 0.06 mol) in methylene chloride (20 mL) dropwise. The solution was stirred for 1 hour at room temperature, then cooled to 0 ° C and more triethylamine (8.4 ml, 0.06 mol) was added with stirring. To the cooled solution was added dropwise a solution of 4-chlorobutyric acid chloride (8.46 g, 0.06 mol) in methylene chloride (20 mL). After stirring for 1 hour at room temperature, the resulting precipitate of triethylamine hydrochloride was filtered off and the filtrate was washed with water (10 ml). After drying the organic layer, the methylene chloride was completely removed by distillation to give the product as a colorless oil.

On the silica gel thin layer, the product showed a spot with Rf = 0.77 (n-butanol / acetic acid / water 4: 1: 1, expressed as iodine).

Neutralization equivalent: Calculated: 207

Found: 211

Analysis: C 9 H 18 ClNO 2 (molecular weight 207.5)

Calculated: C 46.26; H 6.75; N 6.75%

Found: C, 45.60; H 6.30; N 6.50% IR spectrum (cm -1): 3400-3140 (OH, NH), 1710 (COOH), 1630 (CONH), 1540 (CONH).

Example 2 N- (4-chloro-butyryl) -glycylglycine (IV; R = H, X = Cl 2 = n = 1, Hal = Cl)

Glycylglycine (4.8 g, 0.036 mol) was suspended in methylene chloride (60 ml), then trimethylchlorosilane (8.58 g, 0.079 mol) was added and triethylamine (8.0 g, 0.079 mol) in methylene chloride (20 ml) was added dropwise with stirring. . After stirring for 1 hour at room temperature, the solution was cooled to 0 ° C and then triethylamine (3.69 g, 0.036 mol) and 4-chlorobutyric acid chloride (5.12 g, 0.036 mol) in methylene chloride (10 ml) were gradually added dropwise. The reaction mixture was stirred for 1 hour at 25 ° C, and then the triethylamine hydrochloride formed was filtered. Water (10 ml) was added to the filtrate, and the organic layer was separated. By allowing the aqueous layer to stand, the product crystallized, which was recrystallized from ethyl acetate to give colorless plates, m.p. was 134-136 ° C.

Il 7 66846

The product showed a spot on the silica gel thin layer with Rf = 0.57 (ethyl acetate / acetic acid / water 3: 1: 1, expressed as iodine).

Neutralization equivalent: Calculated: 237

Found: 243

Analysis: C 9 H 18 Cl 2 O 2 (molecular weight 236.65)

Calculated: C 40.58; H 5.54; N 11.84%

Found: C, 40.77; H 5.55; N 12.05% IR spectrum (cm-1): 3320-3060 (OH, NH), 1710 (COOH), 1640, 1540 (CONH).

Example 3 N- (4-chlorobutyryl) -beta-alanine (IV; X = (CH2) 2, n = 0, Hal = Cl)

In analogy to Example 1, N- (4-chlorobutyryl) -beta-alanine was prepared from beta-alanine.

oil, Rf = 0.70 (conditions as in Example 2).

Neutralization equivalent: Calculated: 193

Found: 190

Analysis: C 18 H 11 ClNO 3 (molecular weight 193.5)

Calculated: C 43.41; H 6.20; N 7.24%

Found: C, 43.05; H 6.40; N 6.90% IR spectrum (cm-1): 3400-3100 (OH, NH), 1725 (COOH), 1635, 1550 (CONH).

Example 4 N- (4-chlorobutyryl) glycine (IV; X = CH 2, n = 0, Hal = Cl) In analogy to Example 1, N- (4-chlorobutyryl) glycine was prepared from glycine.

oil, Rf = 0.70 (conditions as in Example 2)

Neutralization equivalent: Calculated: 179

Found: 173

Analysis: C 9 H 11 ClNO 3 (molecular weight 179.5)

Calculated: C 40.11; H 5.57; N 7.80%

Found: C, 39.80; H 5.15; N 7.40% IR spectrum (cm-1): 3360-3320 (OH, NH), 1740 (COOH), 1655, 1540 (CONH).

Preparation of compounds of general formula II ττ- __ 8 66846

Example 5 N- (4-chlorobutyryl) -glycinamide (II; X. = CH2, n = O,

Hai = Cl) _

With gentle heating, glycinamide (11.1 g, 0.15 mol) was dissolved in N, N-dimethylacetamide (50 ml) and 4-chlorobutyric acid chloride (10.55 g, 0.075 mol) in anhydrous dioxane (50 ml) was gradually added under ice-cooling. The reaction solution was then stirred for 10 minutes at room temperature and the precipitate formed was filtered. Glycinamide hydrochloride (8 g) was obtained. The dioxane solvent was removed by distillation in vacuo and the product was separated from the residue with ether. The product was obtained (10.5 g, 78%), m.p. was 123-125 ° C.

The product showed a spot on the silica gel thin layer of 0.43 (methylene chloride / acetone / methanol 5: 5: 1, expressed as iodine).

For analysis, the product was recrystallized from a mixture of acetone and hexane or ethyl acetate to give colorless plates, m.p. 128-130 ° C.

j! Analysis: C 9 H 18 Cl 2 Cl (molecular weight 178.62)

Calculated: C 40.34; H 6.21; N 15.68%

Found: C, 40.46; H 5.97; N 15.54%

Example 6 N- (4-Chlorobutyryl) -gamma-aminobutyrylamide (II; X = (CHq 2, Hai = Cl, n = O) - N- (4-chlorobutyryl) -gamma-aminobutyric acid (10 g, 0.048 mol) was dissolved methylene chloride (30 mL) and cooled to -15 ° C, then phosphorus pentachloride (10 g, 0.048 mol) was added portionwise with stirring, stirring was continued for 1 hour, after which the crystallized precipitate was filtered and dissolved in methylene chloride and benzene. to mixture 1 (80 ml), cooled to 0. Gaseous ammonia was introduced into the solution for about an hour, the precipitate formed was filtered and then extracted with hot ethyl acetate, cooling to 110-112 ° C, the product crystallized from ethyl acetate.

The product had a spot on the silica gel thin layer with an Rf of 0.60 (conditions as in Example 1).

9

Analysis: C 9 H 11 Cl 2 Cl 2 (molecular weight 206.7) 668 4 6

Calculated: C 46.49; H 7.32; N 13.56%

Found: C, 46.68; H 7.39; N 13.34% IR spectrum (cm-1): 3380, 3310 (NH 2), 3180 (NH), 1650-1610 (CONH, CONH 2), 1530 (CONH).

Example 7 N- (4-Chlorobutyryl) -glycylglycinamide (II; R = H, X = CH 2, n = 1, Hal = Cl) - N- (4-chlorobutyryl) -glycylglycine (2.1 g, 0.008 mol) was added to methylene chloride (60 ml) and then cooled to + 5 ° C. Phosphorus pentachloride (1.84 g, 0.008 mol) was gradually added to the suspension. After stirring for 1 hour, the reaction solution was gradually added to a mixture of benzene and methylene chloride (1: 1), frozen at 0 ° C, and ammonia was added to the solution over about an hour, after which the resulting precipitate was filtered off. After crystallization from ethyl acetate or acetonitrile, the product was obtained in 70% yield.

Recrystallization from dioxane gave the product, m.p. was 178-180 ° C.

The product had a spot on the silica gel thin layer with Rf = 0.19 (methylene chloride / acetone / methanol 5: 1: 1, expressed as iodine).

Analysis: CgH- ^ ClNgOg (MW 235.67)

Calculated: C 40.77; H 5.99; N 17.83%

Found: C, 40.96; H 5.99; N 18.00% IR spectrum (cm-1): 3390, 3300, 3200 (NH 2, NH), 1660 (CONH), 1650, 1540 (CONH 2).

Example 8 N- (4-Chlorobutyryl) -beta-aminopropionamide (II; X = (CH2) 2, n = O, Hal = Cl)

In analogy to Example 6, N- (4-chlorobutyryl) -beta-alanine was prepared from N- (4-chlorobutyryl) -beta-aminopropionamide, m.p. was 124-126 ° C (from dioxane), R f = 0.76 (conditions as in Example 2).

Analysis: CyH- ^ Cl ^^ (ra.ecyl weight 192.6) 66846 10 π

Calculated: C 43.64; H 6.80; N 14.54%

Found: C, 43.86; H 6.66; N 14.61% IR spectrum (cm-1): 3380, 3310 (NH 2), 3190 (NH), 1660-1630 (CONH 2, CONH), 1540 (CONH).

Example 9 N- (4-chlorobutyryl) -glycinamide (II; X = CH 2, n = O,

Hai = Cl) ___

In analogy to Example 6, N- (4-chlorobutyryl) glycine N- (4-chlorobutyryl) glycinamide was obtained, m.p. was 128-130 ° C (ethyl acetate).

The product showed a spot on the silica gel thin layer with = 0.43 (methylene chloride / acetone / methanol 5: 5: 1, expressed as iodine).

Analysis: C6H11N2 ° 2Cl (molecular weight 178.62)

Calculated: C 40.34; H 6.21; N 15.68%

Found: C, 40.46; H 5.97; N 15.54% IR spectrum (cm-1): 3400, 3310, 3200, 1680-1620, 1550, 1530.

Preparation of compounds of general formula I Example 10 2-Oxo-1-pyrrolidine-acetamide by cyclization of 4-chlorobutyrylglycinamide with sodium hydroxide____

With heating to 50 ° C, anhydrous ethanol (100 mL) was added to 4-chlorobutyrylglycinamide (10 g, 0.056 mol), and to the solution was added 1N sodium hydroxide in ethanol (5.9 mL, 0.056 mol) dropwise with stirring. The reaction solution was heated at reflux for 10 minutes. Sodium chloride formed after cooling (2.9 g, 89%) was filtered off. Removal of the solvent gave a white crystalline product (6.9 g, 86%) after addition of isopropanol, m.p. 145-147 ° C.

Example 11 2-Oxo-1-pyrrolidine acetamide by cyclization with sodium tert. - using butylate, _____ 4-chlorobutyrylglycinamide (4 g, 0.022 mol) was dissolved with heating in dioxane (80 ml). A stirred suspension of sodium tert-butylate (0.022 mol) in anhydrous 11 6 6 8 4 6 dioxane (20 ml) was added to the solution. The mixture was stirred for 1 hour at room temperature and the residue was filtered off to give sodium chloride (1.2 g, 94%). The mother liquor was concentrated to dryness and the crude product was crystallized from isopropanol to give the product (2.55 g, 81%), m.p. 146-149 ° C.

The ring closure of 4-chlorobutyrylglycinamide can be performed analogously using sodium methylate or sodium ethylate.

Example 12 2-Oxo-1-pyrrolidine-acetamide by cyclization of 4-chlorobutyrylglycinamide using pyrrolidine-sodium-4-chloro-butyryl-glycinamide (8.9 g, 0.05 mol) was heated in dioxane (200 ml) and pyrrolidine-sodium (0 ml) was added. .05 moles) to a suspension in absolute toluene (200 mL), cooled to room temperature. The solution was stirred for 1 hour at room temperature and the precipitate formed was removed by filtration. After removal of the solvent in vacuo and addition of a mixture of isopropanol and ether, a white crystalline product was obtained (4.5 g, 63%), m.p. 145-147 ° C.

Example 13 2-Oxo-1-pyrrolidine-acetamide by cyclization of 4-chlorobutyrylglycine amide using anion exchange resins 4-Chlorobutyrylglycinamide (2.2 g, 0.0124 mol) was dissolved in anhydrous ethanol (15 ml) and added to a suspension of the ion exchange resin Dow. . The suspension contained dry ion exchange resin in Dowex-1 OH form (20 mL) in anhydrous ethanol (30 mL). The reaction mixture was stirred for 1 hour at 20-25 ° C. The solution was then decanted, the residue washed further with ethanol (20 ml) and the combined ethanol solutions removed in vacuo. The solid residue was obtained by crystallization from isopropanol as a white crystalline product (1.25 g, 71%), m.p. 145-147 ° C.

Analogously, a substantially purer product was obtained by recrystallization from isopropanol in 85% yields and a melting point of 148-150 ° C if an ethanolic solution of 4-chlorobutyrylglycinamide was passed through a column packed with ion exchange resin.

12 66 84 6

Example 14 2-Oxo-1-pyrrolidine-butyramide (I; X = (CH 2) 4, n = O N- (4-chlorobutyryl)-gamma-aminobutyramide (1.03 g, 0.05 mol) was dissolved in absolute ethanol. (5 ml), 1N sodium hydroxide in absolute ethanol (5 ml) was added and the solution was stirred for 5 hours at room temperature, the precipitate formed was filtered off and the solvent was removed from the filtrate by distillation to give an oil which was crystallized by adding isopropanol and ether.

Recrystallization from a mixture of isopropanol and ether gave the product, m.p. was 98-100 ° C (99.8-100.5 ° C according to the literature).

Example 15 2-Oxo-1-pyrrolidine-acetylglycinamide (I; R = H, X = CH 2, n = 1) - N- (4-chlorobutyryl) -glycylglycinamide (2 g, 0.008 mol) was suspended in absolute ethanol (50 ml). and then anion exchange resin (Dowex-1, 20 mL, OH form) was added. The mixture was stirred at 25 ° C for 3 hours during which time the material dissolved. After decanting the ion exchange resin and distilling off the solvent, a product was first obtained which crystallized easily. The yield was 75%, m.p. 134-136 ° C. After crystallization from ethanol, m.p. 138-139 ° C.

Thin layer chromatography according to Example 2 gave an Rf value of 0.30.

Analysis: C 9 H 11 N 2 O 2 (molecular weight 199.29)

Calculated: C 48.23; H 6.58; N 21.10%

Found: C, 48.02; H 6.58; N 20.98% IR spectrum (cm-1): 3360, 3320, 3190 (NH 2, NH), 1690-1660 (CON, CONH, CONH 2), 1550 (CONH).

Example 16 2-Oxo-1-pyrrolidine-propionamide (1; X = (CH 2) 2 / n = O In analogy to Example 14, 2-oxo-1-pyrrolidine-propionamide was obtained from N- (4-chlorobutyryl) -beta-aminopropionamide. having a mp of 141-142 ° C (142-143 ° C according to the literature), which on the silica gel thin layer gave a spot of = 0.53 (conditions as in Example 1).

Il 66846 13

Example 17 2-Oxo-pyrrolidine-1- (alpha-benzyl) -acetamide (I; X = C 6 H 5 CH 2 CH, n = O)

In analogy to Examples 1 and 6, N- (4-chloro-butyryl) -phenylalaninamide was prepared, m.p. was 178 ° C-179 ° C.

Analysis: c 13 H 17 N 2 O 2 Cl (molecular weight 268.75)

Calculated: C 58.09; H 6.38; N 10.43%

Found: C, 58.32; H 6.62; N 10.43% IR spectrum (cm-1): 3370, 3310, 3180 (NH 2, NH), 1660, 1640, CONH, CONH 2), 1530 (CONH), 740, 700 (C-C 9 H 5).

According to the procedure described in Example 14, this material was converted to 2-oxo-pyrrolidine-1- (alpha-benzyl) -acetamide, m.p. was 138-139 ° C.

Analysis: c 13 H 16 N 2 O 2 (m ° molecular weight 232.28)

Calculated: C 67.22; H 6.94; N 12.06%

Found: C, 67.45; H 6.95; N 12.07% IR spectrum (cnT1): 3300, 3160 (NH2, NH), 1680, 1665 (CON, CONH, CONH2), 700, 755 (C-CgHg)

Claims (4)

14 6 6 8 4 6 A process for the preparation of N-alkylamides of 2-oxo-pyrrolidine of the formula O- (I) X-CO (NH-CH-CO) -NH or a benzyl group and n is 0 or 1, characterized in that the compound of the formula Hal-CH "CH-, CHo-CONH-X-CO (NH-CH-CO) -NH" (II) | R ^ R where R, X and n have the same meaning as above and Hal is a chlorine, bromine or iodine atom, are subjected to intramolecular cyclization. Process according to Claim 1, characterized in that the cyclization is carried out with a basic substance, such as an inorganic base, preferably sodium hydroxide or potassium hydroxide, or an organic base, preferably sodium methylate 11a or ethylate 11a. Process according to Claim 1, characterized in that the cyclization is carried out with a basic ion exchange resin in an organic solvent. 4. N-4-halobutyryl derivatives of amino acid or peptide amides, known from the formula Hal-CH-CH 2 CH 2 -CO-NH-X-CO (NH-CH-CO) -NH 2 - (NH-CH-CO) -NH 2 (NH-CH) ) 2 2 2, n 2 R wherein X is a C 1 -C 4 alkylene group, R is a hydrogen atom or a benzyl group, n is 0 or 1 and Hal is a chlorine, bromine or iodine atom. Il 66846 15