The method of obtaining of symmetrical diamides of citric acid

<td rowspan="2">POLAND REPUBLIC CHINA</td><td>PATENT DESCRIPTION</td><td> 149145</td>

<td rowspan="2">Additional patent to patent No. -</td><td rowspan="2">I you ν I ''</td>

<td></td>

<td></td><td>Reported: '86 12 17 / ?. 263092 /</td><td>1 Patent Office | ^{hU 4} 1</td>

<td>in</td><td>Priority _________</td><td>Int. Cl.⁴ C07C 103/46</td>

<td>OFFICE PATENT</td><td>The application was announced: 88 09 Ol</td><td></td>

<td>PRL</td><td>Patent description published: 1990 03 31</td><td></td>

Creators of the invention: Mr ^ ia J. Milewska, Andrzej Chimiak

Patent holder: Politechnika Gdańska, Gdańsk / Polska /

HOW TO OBTAIN SYMMETRIC CITRIC ACID DIAMIDES

The present invention relates to a process for the preparation of symmetrical citric acid diamides of the general formula 1 in which R is hydrogen, an aliphatic or araliphatic residue, R 4 -hydrogen or alkyl, R₂ - hydrogen. The hitherto known method of obtaining symmetrical citric acid diamide consists in the condensation of the derivative of N-protected lysine with / 4-oxo-1,3-dioxolan-5-ylidane / diacetic acid dichloride followed by alkaline hydrolysis.

PJ Maurer, MJ Miller, J. Am. Chem. Soc., 104, 3096/1982 /. The disadvantage of the two-step process described is the formation of an amide-imide by-product. In addition, the second stage of synthesis, i.e. alkaline hydrolysis, causes the hydrolysis of the amides in question, and hence the ambiguity of the synthesis and the formation of symmetrical and asymmetrical diamides.

Method for the preparation of symmetrical citric acid diamides with general tongue 1, wherein R is hydrogen, an aliphatic or araliphatic residue, R1 - alkyl or hydrogen, R₂ - hydrogen, characterized by the fact that the amino group of esters of aliphatic or araliiic amino acids is subjected to an acylation reaction with an active citric acid ester of general formula 2, the reaction is carried out in the presence of a tertiary amine such as, for example, triethylemine or N-methytomerfilin, in an organic solvent dioxane or tetrahydroxyurane, at a temperature of 10 ♦ 30 ° C for several hours, and the obtained compound after washing the substrates and isolating by crystallization, is reacted with trifluoroacetic acid and the final product obtained is crystallized from a dry ethanol / ethyl ether or acetone / ethyl ether mixture.

The advantages of the process according to the invention consist in the unequivocal obtaining of chromatographically pure, symmetrical citric acid diamides in relatively short time, with a good yield of 69 - 87%. No irnido149 145 by-products are observed

149 145 amide Also acidisation of tert-butyl esters * with trifluoroacetic acid does not cause side reactions. This method can be successfully used for the synthesis of various symmetrical citric acid diamidóo, including 5,4-dihydroxyoxyl phenyl derivatives with 3 ... min / Dopa /, containing the so-called catechol system. The latter compounds are potential factors that can remove plutonium from living organisms. The process according to the invention is illustrated by the following examples.

EXAMPLE:. 1.6g / 2.5mmL · / 1,3-di-tert-butyl 2-tert-butyl-citrinate (2-tert-butyl) citrate is dissolved in 2.1 ml / 15 mmH / trifluoroacetic acid. After 30 'min. at room temperature, the solution is concentrated and the product is added with ethane ether in a yield of 89% / lg /. After crystallization from a dry acetone / ethyl ether mixture, the product has a melting point of 145 * 50 ° C. . '

For a compound of formula 1 in which R = benzyl, = R₂ = H / ^ / ^ ° + ²⁰° / c⁵, 5 acetone / ^ / 4: 1: 1 = n-butanol / ^ 0 /, acetic acid /0.16

1h - n, m, r, / D20 /

2.55 / d, 4H, -CH2CO- /: 5.1 '/ d, 4H - CH ^ H ^ /: 4.6 / m,

2H, -CH /: 7.5 / s. 1 OH, C._g^-/.

Example II: 1.7g /2.5 mmL · / 1.5-di- / teΓ - bu0oksy-L-tyryilll / citrate

2-tert-butyl is dissolved in 2.1 ml / 15 mmU / trifleroacic acid. After 45 min at room temperature, the product is isolated in the same way as in Example 1 with a yield of 1.19g / 92% /. The melting point of the product after crystallization from the dry ethanol / ethyl ether mixture is 104 ♦ 108 ° C.

For a compound of formula 1 in which R = p-hydelxybtnzyl

R₁ = R₂ = H / oC / 2 ° + 18 ° /^c1.2 acetone /

R, / 4: 1: 1 / 0.18

-n, mr / D₂0/

2.57 / m, 4H, -CH₂C &lt;0- / ί, 2.9 / m, 4H, -CH₂- /: 4.57 / m, 2H, -CH /:

6.67, 6.8, 6.97, 7.1 / dd, 8H, -CgH ^ /.

Example III: 1.04g / 2.5 1,3-di / ethoxyglycyll / 2-tert-butyl citrate is dissolved in 2.1 m / 15 mmol triflleloocoic acid.

After 50 min at room temperature the solution is concentrated and the product is precipitated with ethanol in a yield of 87% / 0.7g /. After crystallization from an ethyl acetate / ethyl ether mixture, the product had a melting point of 98-9 ° C.

For a compound of formula 1; R = R2 »H, R5 = ethyl

R_f / 4: 1: 1 / 0.5 H - n, mr / D₂0/

1.2 / t, 6H, CH 2 - /; 2.9 / s, 4H, CH₂C0 /; 4 / s, 4H, NHCH₂- / j

4.2 / q, 4H, -CH2CH3 /.

Other embodiments are summarized in the following table:

149 145

<td>1 At! Quad L _</td><td>and and R 1 1 1</td><td>! ri 1 1</td><td colspan="2"> ! _R '. issue and ! ^rR and%! 1 1 1 1 1 1</td><td> 0 ¹tt C dissolve to crystallize!</td><td>Rr J and 1 1</td><td>Si - nmr j</td>

<td>! iv</td><td>and / ho /₂c₆h₃analysis₂</td><td>L ! H</td><td> 1 1 1</td><td>H- J 9 «j</td><td>168-70 ° C</td><td> 1 1 1</td><td> ^₂0 / 2.55 / m, 4K, CH₂C0 / j J</td>

<td></td><td>AND 1</td><td> 1 1</td><td> 1 1 1</td><td> 1 1 1 1</td><td>acetone / ether j</td><td>O.O9J</td><td>2.95 / m, 4H, 0 ^ 0 ^ /, 4.5 / mj</td>

<td></td><td> 1</td><td>and 1 1</td><td> 1 1 1</td><td>And II 1 1</td><td>ethyl!</td><td> 1 1</td><td>2H, -CH /} 6.7 / m, 6H, -CgH ^ / · i</td>

<td> 1______</td><td> .1--------------</td><td> -4----</td><td>1 _L_</td><td>1 1 ---- ------ 1 μ.</td><td>1 ______ - ____- o_.</td><td>____jl.</td><td></td>

system: n-butanol-acetic acid-water / 4: 1: 1 /.