CS237741B1 - Ethylene-N, N'-bis-leucine and its method of preparation - Google Patents

Abstract

Ethylene-N,N'-bis-leucine, of the general formula I CH, CHí CH-CH2-CH-C00H NH Wn (I) CH, NH I CH-CH2-CH-C00H where n = 2, is prepared by condensation of leucine with ethylene dibromide in an alkaline environment from reflux and a pressure of 105 to 5.10° Pa in a molar ratio of leucine to ethylene dibromide of 2:1 to 5:1 θ the product is isolated by acidifying the reaction mixture with an inorganic acid. Ethylene-Ν,Ν -bis-leuoin can be used as a selective detoxifying agent in healthcare.

Description

The invention aa relates to ethylene-N,N'-bis-leucine and its preparation.

Ethylene-N,N'-bis-leuines are new complexones based on the natural amino acid leuine. They are newly synthesized substances, not yet described in the literature. Although there are data in the patent literature on the condensation of some lower amino acids, for example British patent No. 732 316, this procedure has the disadvantage that it is a pressure process and the reaction yields are considerably low.

Previously known derivatives of this type have lower selectivity and stereospecificity. The above-mentioned shortcomings are eliminated by the invention, the essence of which is the new ethylene-H,N'-bis-leucine complexones of the general formula I

where n = 2.

The essence of the method for preparing ethylene N,N'-bis-leuines is that in an aqueous solution or in an aqueous-alcoholic medium, leucine is allowed to condense with ethylene dibromide in an alkaline medium under reflux and a pressure of ItP to 5.10^ Pa in a molar ratio of leucine to ethylene dibromide of 2:1 to 5:'1, preferably 2:1 to 3:2. The condensation of leucine with ethylene dibromide proceeds according to the equation:

CH, 'CH.

CHI

3CHCH ₂ jHCOOH + X(CH ₂ ) _n X

NH, /

6^3

3 1

CH-CH,-CH=COOH + 2ΗΧ (I), w _n

CH ₃ \

from

CH,

CHNH

I ch ₂ -ch-cooh where

X = bromine and n = 2.

The reaction produces ethylene N,N'-bis-leuine and hydrogen bromide, which is advantageously bound by the addition of alkali in the form of the appropriate alkali metal halide, thereby shifting the reaction course to the right, which is favorable for the formation of ethylene-N,N'-bis-leucines.

The aqueous condensation is carried out by mixing an aqueous suspension of leucine with ethylene dibromide with an aqueous, aqueous-alcoholic or alcoholic solution of an alkali metal hydroxide. It is also preferred to use a solid carbonate or bicarbonate of an alkali metal or alkaline earth metal.

The solution is refluxed with stirring for several hours. After cooling the solution and acidifying with an inorganic acid, for example concentrated hydrochloric acid, crude ethylene N,N'-bis-leucine is separated, which is recrystallized several times from hot water or a mixture of water and ethanol, or purified by conversion back to an alkali metal or alkaline earth metal salt and reprecipitation with an inorganic acid.

The advantage of preparing ethylene N,N*-bis-leucines according to the invention is that the condensations proceed sufficiently rapidly even at atmospheric pressure and with higher yields than in the processes described in the above-mentioned patent.

Example

In a 250 ml three-necked flask equipped with a stirrer, reflux condenser and dropping funnel, 65.6 g (0.5 mol) of L-leuine are added to 20 g (0.5 mol) of sodium hydroxide in 40 ml of water. The solution is heated to reflux with stirring and 47 g (0.25 mol) of ethylene dibromide together with 34.5 g (0.25 mol) of potassium carbonate are slowly added so that the pH of the solution is 11 to 12. After the entire amount of ethylene dibromide has been added, the solution is allowed to reflux with stirring for another 30 hours.

After cooling and filtering off the unreacted potassium carbonate and the cured potassium bromide, the solution is acidified with concentrated hydrochloric acid. At pH 9, a white crude product is separated, which, after washing with distilled water, is purified by recrystallization from a mixture of ethanol and water (1 + 1) or by conversion to sodium sol’ra by careful precipitation with concentrated hydrochloric acid at Ph 9. ”

This gives 45.5 g of ethylene N,N'-bis-L-leucine, which represents a 63% yield. The melting point is 280 °C. The molecular formula is C^H^gN^O^. The molecular weight is 288.38. Elemental analysis by calculation: C = 58.31%, H = 9.78%, N = 9.71%. Found: C = 57.93%,

H = 9.64%, N = 9.55%. The newly synthesized substance obtained was characterized by IR and 13C-13C IR spectroscopy. The IR spectra were measured by KBr technique in the range of 4000 to 400 cm. The characteristic absorption bands of ethylene-Ν,Ν-bis-L-leucine are given in Table 1.

23774.4 a b u Ϊ k a 1

Characteristic absorption bands of ethylene-N,N'-bis-L-leucine

Belt position, cm ^- ' Character!pike Assignment 3,050 s, w \ + Vnh ₂ valence vibrations 2,960 seconds, 2 874 sec t Y CH valence vibrations 1,607 sec + d * deformationally degenerate v. 1 5Θ0 s 0 coo• as valence antisym. v. 1,515 seconds Í^NH, ⁺ s 2 deformationally symmetric vib. 1,470 pages From _{dn 3} deformationally degenerate v. 1,406 sec P coo with valence symmetry v. 1,387 pages '< ^Honors 3 deformationally symmetric vibr. 1,362 pages, 1,344 page, OřCH+P CH, + w 2 CH bending + CHg wagging + CH ₂ twisting 1,317 pages, 1,298 page, A ^CH 2 1,241 pages, 1 .91 page, 1 117 pages, ?CH _3+> P _w NH ₂ ⁺ CKjrocking + NHg wa- 1,135 pages, 1,087 sl, ^νη ₂ ⁺ ,ί)οο _{3 +} gging + twisting, 1,068 sl, 1 031 sl, pííCCCN sym.CC^ + CCCII mi- 1,006 sentences 946 sl, 920 page with seaweed vibration 849 sec í CC, + P CCN valence sym. CC ₃ + valence CCH vibr. 836 pages COO ^- scissors vibration 604 sl, 771 page IC ₂ rocking vibrations 706 sl, 672 with coo ^- w wagging vibration 537 sec ^coo ^- rocking vibrations 456 years, 444 page ï cc, s 3 deformationally symmetric v. 403 pages </CCCN deformation skeleton, v.

s = strong, ś = broad, str = medium, sl = weak, r = arm The structure of the newly synthesized compound was confirmed by 13C-IR spectroscopy. A solution of ethylene-N,N ^x -bis-L-leucine was prepared with a concentration of 10 wt. % in NaOD (pD = 13). Sodium 4,4-dimethyl-4 silapentanesulfonate (D3S) was used as an internal standard. The spectrum was measured on a pulse spectrometer at a working frequency of 25.047 MHz and a range of 6,000 Hz. The resonance frequencies of the individual signals together with their assignments are given in Table 2.

Table 2 '^C-NMR spectral data of ethylene-N,N'-bis-L-leucines

, Hz (f, ppm Assignment 4,646.56 185,518 °1 1,632.37 65,174 cZ 1,229.41 49,085 C/9 1,131.23 45,165 ^C 3 684.31 27,321 ^C 4 611.04 24,396 ^C 5 600.78 23,986 ^C 6

Transition metal complexes and complexones of this type themselves can be used as selective detoxification agents in healthcare.

Claims (4)

BEFORE THE INVENTION An ethylene-N, N'-bis-leucine of the general formula I Wn; i) NH CHCH 8 CHCOOH where n = 2. 237741 6 2. A process for the preparation of ethylene-N, N ^from -bis-leucine of formula (I) according to claim 1, characterized in that in aqueous solution, if appropriate, aqueous-alcoholic: pressure range * 56 5 5 10 to 5.10 Fa, preferably 10 to 5.10 Pa, in a molar ratio of leucine to ethylenedihalogen of 2: 1 to 5: 1, preferably 2: 1 to 3: 2, wherein the product is isolated by acidifying the reaction mixture with an inorganic acid, preferably concentrated acid hydrochloric acid and cleans. 3. The process according to claim 2, wherein the product precipitated from the aqueous solution is purified by recrystallization from an aqueous ethanol solution of 1: 1 at a temperature of 50-75 [deg.] C. 4. The process of claim 2, wherein the aqueous solution precipitated from the aqueous solution is purified by repeated conversion to an alkali metal salt, preferably sodium or potassium salt, and reprecipitated with an acidic inorganic acid, preferably hydrochloric acid.