CS254868B1 - Process for producing cyclic dipeptides - Google Patents

Abstract

The solution relates to a method for producing cyclic dipeptides by cyclizing linear dipeptide esters in an organic solvent, preferably toluene, forming an azeotropic mixture, with gradual distillation of volatile components. The cyclization is catalyzed by an alkanecarboxylic acid, preferably acetic acid.

Description

The invention relates to a method for producing cyclic dipeptides of general formula I

R ²

(I) in which represents a hydrogen atom, alkyl with 1 to 5 carbon atoms, carbamoylalkyl with 1 to 5 carbon atoms, guanidinoalkyl with 1 to 5 carbon atoms, aminoalkyl with 1 to 5 carbon atoms, hydroxyalkyl with 1 to 3 carbon atoms, benzyl or phenyl.

R'

R'

R'

2 hydrogen atom, alkyl with 1 to 3 carbon atoms, wherein R and R together optionally form an alkylene chain - , where n = 2 to 4, alkyl with 1 to 5 carbon atoms, hydroxyalkyl with 1 to 3 carbon atoms, aminoalkyl with 1 to 5 carbon atoms, phenyl or benzyl, hydrogen atom, wherein R^ and optionally form a three- to six-membered spirocycle, optionally substituted with alkyl with 1 to 5 carbon atoms, hydrogen atom or alkyl with 1 to 3 carbon atoms.

Derivatives of cyclodipeptides of general formula I (2,5-piperazindiones) are significantly biologically active substances, useful in human and veterinary medicine (J. Vanžura et al., Proc, VlXIth Int. Symp. Med. Chem., Uppsala 1984 (R. Dahlbom, J. L. G. Nilsson, Eds.), Swed. Pharm.

Press. Stockholm 1985, Vol. 2, pp. 461-463; J. Vanžura with the same work. Vol. 1, pp, 245-247; Czechoslovak author's certificate No. 210 383; Czechoslovak author's certificate 231 227).

Dipeptide esters are relatively reactive compounds that in some cases cyclize to stable cyclodipeptides (2,5-piperazindiones). Dipeptides containing proline as the C-terminal amino acid show a strong tendency to cyclize, often spontaneously. In contrast, dipeptide esters are known that cyclize extremely difficultly even when using a targeted cyclization reaction, e.g. Pro-Ile-OMe, or other esters of linear dipeptides sterically hindered at the N-terminus of the chain.

During the cyclization of linear dipeptide esters under the catalysis of anhydrous ammonia in methanol (E. Fischer, Ber. 39, 2 893 /1906/) partial racemization may occur even after modification (K. Bláha, Coll. Czech. Chem. Commun. 34, ⁴ θθ ¹ /1969/). The cyclization of dipeptides in a phenol environment at a temperature of 140 to 150 °C is equally disadvantageous (KD Kopple, HG Ghazarian,

J. Org. Chem. 33, 862 /1968/) or in beta-naphthol at a temperature of 135 to 140 ° C (N. Lichtenstein, J. Am. Chem. Soc. 60, 560 /1938/), which give yields in the range of 20 to 60% of theory, while obtaining a pure product is technologically difficult. Better results are provided by heating the methyl ester formates of linear dipeptides in a mixture of 2-butanol with toluene {D. E. Nitecki et al.,

J. Org. Chem. 33, 864 /1968/), or their acetates in refluxing butanol under acetic catalysis (K. Suzuki et al., Chem. Pharm. Bull. 29./ 233 /1981/). The yields of common cyclodipeptides are reported to be in the range of 50 to 90%.

From a technological point of view, heating to a temperature of 120 to 130 °C for at least 2 to 3 hours is disadvantageous, as is the use of expensive 2-butanol, in which most of the cyclodipeptides formed are readily soluble, so that the mother liquors must be concentrated or transferred to another solvent. An overview of cyclization methods is provided by P. G. Sammes, In. Fortschrítte der Chemie Organischer Naturstoffe, pp. 51 to 113, Springer-Verlag, Vienna 1975.

All of the above cyclizations are time-consuming and the isolation of the products is difficult, racemization often occurs. When using any cyclization method, the yields of cyclodipeptides and the reaction time are highly dependent on the steric shielding of the carboxyl group at the C-terminus and the nitrogen at the N-terminus of the dipeptide.

The above disadvantages are eliminated by the method of producing derivatives of the general formula X, in which the substituents R and R have the above-mentioned meaning, cyclization of a linear ester of dipeptides of the general formula II

R

AND

HN i\

South what

R ³ R ⁴ \ /

CCOO(II),

6 in which R to R denote the same as in formula I and R denotes methyl or ethyl, in the environment of an inert organic solvent, e.g. of the aromatic hydrocarbon type, especially toluene, under acid catalysis, at the boiling temperature of the reaction mixture, according to the invention, the essence of which consists in the fact that the linear ester of the dipeptide of the general formula II in a mass amount of 1 mol is cyclized in the environment of a ten- to fifty-fold volume excess of an inert organic solvent, capable of forming a ternary azeotropic mixture, preferably toluene, in the presence of an acidic catalyst of the alkanecarboxylic acid type with 1 to 3 carbon atoms, preferably acetic acid, with distillation of 85 to 95% by volume of volatile components, after which the desired product is isolated from the residue.

The method according to the invention is time- and production-saving, economically advantageous and leads to optically pure products. Using organic solvents forming ternary azeotropic mixtures, preferably toluene and under acid catalysis, preferably again acetic acid, without the requirements for anhydrous substrate and solvent, often required in other methods, surprisingly good results are achieved.

In carrying out the method according to the invention, the starting linear ester of the dipeptide of the general formula II, dissolved for example in toluene, with the addition of 0.1 to 1.5 mol of acetic acid as a catalyst, is heated to a temperature at which the solvent is slowly distilled off, while in the first phase the reaction mixture is made absolute. In this arrangement, even for difficult-to-cyclize linear dipeptide esters, the cyclization proceeds at a rate not seen in other cyclizations, and the reaction results in a product of high chemical and optical purity with a high yield. Another advantage of the method according to the invention is the very low solubility of the resulting cyclodipeptide derivative of the general formula I in the reaction medium, which, together with the reduction in the volume of the reaction medium during the cyclization, leads to quantitative and technologically easy separation of the product. There is no need to isolate the product from the mother liquors, in which mainly the residues of the starting substance remain dissolved.

The method according to the invention provides yields for commonly cyclizing dipeptides in the range of 85 to 95% with a reaction time of 20 to 30 minutes. In the case of the difficultly cyclizing L-Pro-L-Ile-OMe, the synthesis of which was based on Z-Pro-Ile-OMe, a yield of 47% of optically pure cyclodipeptide was achieved after 120 minutes of cyclization.

The method according to the invention is illustrated in more detail, but is not limited to, the following examples.

Example 1

Cycle (L-prolyl-L-isoleucyl)

1.1 g (4.54 mmol) of L-Pro-L-Ile-OMe dissolved in 160 ml of toluene containing 0.6 ml (9 mmol) of acetic acid was heated at an external bath temperature of 130-140 °C so that 150 ml of solvent was distilled off within 120 minutes. Petroleum ether was added to the residue and the precipitated crystals were filtered off with suction. 0.49 g (51%) of product with mp 123-127 °C was obtained, which after crystallization from ethyl acetate-petroleum ether gave 0.45 g (47%) of colorless crystals with mp 126-128 °C, ⁼ -139.6 (c = (5.2; methanol), R _f 0.86 (S^) ; = chloroform-methanol-acetic acid 14:2:1.

By cyclization of L-Pro-L-Ile-OMe by the procedure (K. Suzuki et al., Chem. Pharm. Bull. 29, 233 /1981/) a 28% yield of crude product with identical properties was obtained after a reaction time of 300 minutes, while the results of thin-layer chromatography indicated that the reaction mixture contained a significant amount of the starting substrate.

Example 2

Cyclo(D-alanyl-L-leucyl)

3.5 g (10 mmol) of Ζ-D-Ala-L-Leu-OMe were converted in the usual manner to HBr.D-Ala-L-Leu-OMe in 8.7 g of a 37% solution of hydrogen bromide in acetic acid, which was converted to the free methyl ester of the linear dipeptide D-Ala-L-Leu-OMe with a solution of anhydrous ammonia in absolute chloroform. The precipitated ammonium bromide was filtered off, the filtrate was concentrated and the non-crystalline residue was diluted with 180 ml of toluene containing 20 mmol of acetic acid. 160 ml of toluene was distilled off from the solution during 30 minutes while heating it externally to about 140 °C. The reaction was monitored at five-minute intervals by thin-layer chromatography.

Retrospective evaluation showed that the cyclization was complete between 20 and 25 minutes. 1.6 g (87%) of cyclo(D-Ala-L—Leu) was obtained, mp 258-260 °C (sealed capillary) from methanol after prior sublimation. = +28.3°’ (c = 0.8; methanol). The reaction in the same setup with the addition of 0.9 g (50 mmol) of water proceeded in the same time with a yield of 81%.

The following cyclodipeptides were prepared from the corresponding methyl and ethyl esters of linear dipeptides of general formula II using the same procedure, using a reaction time of maximum 50 minutes. Their overview is given in the table. The identity of the substances was confirmed by elemental analysis, melting point, optical rotation and IR spectra.

The abbreviations used correspond to the IDPAC-IUB standard (Biochemistry 2» i 445 (1966); 6 362 (1967); 7_, 2 703 (1968), other symbols have the following meaning:

Acb = 1-aminocyclobutanecarboxylic acid

Acp = 1-aminocyclopentanecarboxylic acid

Ach = 1-aminocyclohexanecarboxylic acid

2MeAch = 1-amino-2-methylcyclohexanecarboxylic acid

Phg = 2-phenylglycine

MeAla = N-methyl-L-alanine

MeLeu = N-methyl-L-leucine

Table of prepared cyclodipeptides

Substance Yield in % M.p. in °C M ^{20 LJ} D in ° c (L-Ala-L-Val) 89 260-262 -29.8 (c=1; AcOH) c(Gly-L-Leu) 91 253-254 + 29.0 (C=1; water) c{Gly-D-Phg) 95 232-233 Dec. - 1.6 (c=2.6;DMSO) c (L-Pro-L-Val) 87 180-190 -161.0 (c=0.5; MeOH) c (L-Pro-L-Leu) 88 157-158 -133.7 (c=lí MeOH) c(L-Ala-L-Leu) 94 257-259 -35.2 (c=1.2; MeOH) c(L-Val-D-Phg) 85 165-166 Dec. -83.5 (c=1.2; AcOH) c(L-Val-L-Ser) 88 232-234 Dec. -83.0 (0.5; MeOH)

table continuation

Substance Yield in % M.p. in °C from ° C(L-Leu-L-Phe) 93 266-267 -15.6 (0.1; water) c(L-Ile-Phe) 90 166-168 Dec. + 11.9 (1.1; AcOH) c(L-Asn-L-Arg(NO ₂ )) 89 234-236 Dec. -106.8 (0.3; N-Me-2- -pyrrolidone) c(L-Val-L-Lys).HC1 86 255-257 Dec. -53.8 (1.5; water) c(L-MeAla-L-MeLeu) 68 52-54 -51.7 (1.0; MeOH) c(Acb-Gly) 92 277-278 c(Acp-L-Ala) 90. 280-281 - 8.3 (1,2; AcOH) c(Acp-L-Ser) 88 267-269 + 24.4 (1.3; AcOH) c(Acp-D-Leu) 90 277-278 + 17.3 (1.0; DMSO) c(Acp-D-Val) 91 318-320 Dec. - 5.2 (2;0; AcOH) c (Acp-D-Phe) 86 256-257 -66.0 (0.3; AcOH) c(Acp-L-Pro) 89 122-123 -122.8 (1.4; AcOH) c(Ach-Gly) 89 307-308 c (2MeAch-Gly) 88 333-334

Subject matter of the invention

Claims (2)

object of the invention Process for the preparation of cyclic dipeptides of the general formula I Π - CH CO and I OC R ³ R ⁴ (I) wherein: R ( ¹⁾ is hydrogen, alkyl of 1 to 5 carbon atoms, carbamoylalkyl of 1 to 5 carbon atoms, guanidinoalkyl of 1 to 5 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, hydroxy alkyl of 1 to 3 carbon atoms, benzyl or phenyl , 2 12 R is hydrogen, alkyl of 1 to 3 carbon atoms, wherein R and R are optionally joined together to form an alkylene chain ⁿ ' ⁴ ' R (C 1 -C 5) alkyl, (C 1 -C 3) hydroxyalkyl, (C 1 -C 5) aminoalkyl, phenyl or benzyl, hydrogen, wherein R 3 and optionally joined together form a three to six membered spirocycle optionally substituted with C 1-6 alkyl up to 5 carbon atoms, R is hydrogen or alkyl of 1 to 3 carbon atoms, by cyclization of the linear ester of the dipeptides of formula II R ² R ¹ R ⁵ R ³ R ⁴ II I \ 6 IIN ----- Chil ---- CO ----- N - C - C00 -R (II), in which up to R 1 denotes the same as in formula I and R 1 denotes methyl or ethyl, in an inert organic solvent, e.g. of the aromatic hydrocarbon type, in particular toluene, under acid catalysis at the boiling point of the reaction mixture, characterized in that the linear ester of the dipeptide of the formula II is cyclized in a volume of 10-50 an inert inert solvent capable of forming a ternary azeotropic mixture, preferably toluene, in the presence of an acid catalyst of the C 1 -C 3 alkanecarboxylic acid type, preferably acetic acid, distilling 85 to 95% by volume of volatiles, and recovering from the residue desired product.