CS254868B1 - Method of cyclic dipeptides production - Google Patents

Abstract

The present invention relates to a process for producing cyclic compounds dipeptides by cyclization of linear esters dipeptides in an organic solvent environment, preferably toluene, forming azeotropic mixture, by gradual distillation volatile fractions. Cyclization is catalyzed an alkancarboxylic acid, preferably acetic acid.

Description

The invention relates to a process for the preparation of cyclic dipeptides of the general formula I

R ²

(I) in which it 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, hydroxyalkyl of 1 to 3 carbon atoms, benzyl or phenyl.

R '

R '

R '

2 is hydrogen, alkyl of 1 to 3 carbon atoms, wherein R and R are optionally joined together to form an alkylene chain - wherein n = 2 to 4, alkyl of 1 to 5 carbon atoms, hydroxyalkyl of 1 to 3 carbon atoms, aminoalkyl of 1 R 5 and optionally joined together form a three to six-membered spirocycle, optionally substituted with C 1 -C 5 alkyl, hydrogen, or C 1 -C 3 alkyl.

The cyclodipeptide derivatives of the formula I (2,5-piperazinediones) are important biologically active substances useful in human and veterinary medicine (J. Vanzura et al., Proc., VlXIth Int. Symp. Med. Chem., Uppsala 1984 (R. Dahlbom). JLG Nilsson, Eds., Swed Pharm.

Press. Stockholm 1985, Vol. 2, s. 461-463; J. Vanžura et al. ibid. Vol. 1, pp. 245-247; čs. author's certificate No 210 383; čs. author's certificate 231 227).

Dipeptide esters are relatively reactive compounds which in some cases cyclize to stable cyclodipeptides (2,5-piperazinediones). Dipeptides containing proline as the C-terminal amino acid appear to have a strong tendency to cyclization, often even spontaneously. On the other hand, esters of dipeptides cyclizing extremely difficult are known even when using a targeted cyclization reaction, e.g., Pro-Ile-OMe, or other esters of linear dipeptides sterically shielded at the N-terminus of the chain.

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

J. Org. Chem. 33, 862 (1968)) or in beta-naphthol at 135-140 [deg.] C. (N. Lichtenstein, J. Am. Chem. Soc. 60, 560 (1938)), yielding yields in the range of 20-60% of theory. and obtaining a pure product is technologically difficult. For better results, heating the linear dipeptide methyl ester formates in 2-butanol / 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 conventional cyclodipeptides are reported to be in the range of 50 to 90%.

From a technological point of view, heating at 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 resulting cyclodipeptides are well soluble, so the mother liquors need to be thickened or transferred to another solvents. A review of cyclization methods is given in P. G. Sammes, In. Fortschritte der Chemie Organischer Naturstoffe, pp. 51-113, Springer-Verlag, Vienna 1975.

All of the above cyclizations are time-consuming and product isolation difficult, often racemizing. Using any cyclization method, yields of cyclodipeptides and reaction time are highly dependent on steric shielding of the carboxyl group at the C-terminus and nitrogen at the N-terminus of the dipeptide.

The above disadvantages are overcome by a process for the preparation of derivatives of the formula X in which the substituents R and R are as defined above by cyclizing the linear ester of the dipeptides of the formula II

R

AND

HN i \

Jh co

R ³ R ⁴ \ /

C COO (II),

Wherein R to R is the same as in Formula I and R is methyl or ethyl, in an inert inert solvent such as an aromatic hydrocarbon type, especially toluene, under acid catalysis at the boiling point of the reaction mixture of the present invention characterized in that the linear ester of the dipeptide of the formula (II) is cyclized in an amount of 1 to 3 times by volume excess of inert inert solvent capable of forming a ternary azeotropic mixture, preferably toluene, in the presence of an acidic alkanecarboxylic acid catalyst of 1 to 3 carbon atoms, preferably acetic acid, distilling 85 to 95% by volume of volatiles, after which the desired product is isolated from the residue.

The process according to the invention is time-consuming and inexpensive, economically advantageous and leads to optically pure products. Using organic solvents forming ternary azeotropic mixtures, preferably toluene and under acid catalysis, preferably again with acetic acid, without the requirement of substrate and solvent anhydrity, often required in other processes, surprisingly good results are obtained.

In the process according to the invention, the starting linear ester of the dipeptide of the formula II, dissolved, for example, in toluene, with the addition of 0.1 to 1.5 moles of acetic acid as catalyst, is heated to a temperature at which the solvent slowly distills off. the mixture absolutizes. Cyclization proceeds in this arrangement even at difficult cycling esters of linear dipeptides at an unprecedented rate in other cyclizations, resulting in a high purity chemical and optical product in high yield. A further advantage of the process according to the invention is the very low solubility of the starting cyclodipeptide derivative of the formula I in the reaction medium, which, together with the reduction of the reaction medium volume during cyclization, leads to a quantitative and technologically easy separation of the product. There is no need to isolate the product from the mother liquor, in which mainly the residues of the starting material remain dissolved.

The process of the invention provides yields for commonly cyclizing dipeptides ranging from 85 to 95% over a reaction time of 20 to 30 minutes. In the case of the poorly cyclizing L-Pro-L-Ile-OMe, whose synthesis was based on Z-Pro-Ile-OMe, a yield of 47% optically pure cyclodipeptide was obtained after 120 minutes of cyclization.

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

Example 1

Cycles (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 were heated at an external bath temperature of 130-140 ° C to 150 ml of solvent was distilled off over 120 minutes. Petroleum ether was added to the residue and the precipitated crystals were aspirated. 0.49 g (51%) of the product with mp 123-127 ° C was obtained, which after crystallization from ethyl acetate-petroleum ether gave 0.45 g (47%) of colorless crystals of mp 126-128 ° C, ⁼ -139.6 (c = (5.2, methanol) _Rf 0.86 (S ^) = chloroform-methanol-acetic acid mixture 14: 2: 1st

Cyclization of the L-Pro-L-Ile-OMe procedure (K. Suzuki et al., Chem. Pharm. Bull. 29, 233 (1981)) yielded a 28% yield of a crude product with identical properties after a reaction time of 300 minutes. thin layer chromatography results 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 was converted to HBr.D-Ala-L-Leu-OMe, which was a solution, in a conventional manner, 8.7 g of a 37% solution of hydrogen bromide in acetic acid. of anhydrous ammonia in absolute chloroform converted to the free methyl ester of the linear dipeptide D-Ala-L-Leu-OMe. 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 were distilled off from the solution with external heating at about 140 ° C over a period of 30 minutes. The reaction was monitored at 5 minute intervals by thin layer chromatography.

Retrospective evaluation showed that cyclization was completed between 20 and 25 minutes. 1.6 g (87%) of cyclo (D-Ala-L-Leu), m.p. 258-260 ° C (sealed capillary) from methanol after previous sublimation. = + 28.3 ° (c = 0.8; methanol). The reaction in the same configuration with the addition of 0.9 g (50 mmol) of water was performed at the same time in a yield of 81%.

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

The abbreviations used conform to the IDPAC-IUB standard (Biochemistry 2 445 (1966); 6 362 (1967); 7, 2 703 (1968), the other symbols having the following meanings:

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. ° C M ^{20 LJ} D in ° (L-Ala-L-Val) 89 260-262 -29.8 (c = 1; AcOH) (Gly-L-Leu) 91 253-254 + 29.0 (C = 1; water) (Gly-D-Phg) 95 232-233 dec. - 1,6 (c = 2.6, DMSO) (L-Pro-L-Val) 87 180-190 -161.0 (c = 0.5, MeOH). (L-Pro-L-Leu) 88 157-158 -133.7 (c = 1 MeOH) (L-Ala-L-Leu) 94 257-259 -35.2 (c = 1.2; MeOH) c (L-Val-D) 85 165-166 dec. -83.5 (c = 1.2; AcOH) c (Val-L-Ser) 88 232-234 dec. -83.0 (0.5; MeOH)

continued table

Substance Yield in% M.p. ° C ze ° C (L-Leu-L-Phe) 93 266-267 -15.6 (0.1; water) c (L-lle-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) .HCl 86 255-257 dec. -53.8 (1.5; water) (L-MeAla-L-MeLeu) 68 52-54 -51.7 (1.0; MeOH) c (Acb-Gly) 92 277-278 c (Ac-L-Ala) 90. 280-281 - 8,3 (1.2; AcOH) c (Ac-L-Ser) 88 267-269 + 24.4 (1.3; AcOH) c (Acp-D-Leu) 90 277-278 + 17.3 (1.0; DMSO) c (Ac-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 (2MeAch-Gly) 88 333-334

object 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.