Method for producing mixture of chelating agents

FIELD: chemistry.

SUBSTANCE: invention refers to a method for producing a mixture of aspartic acid diethoxysuccinate and an amino acid derivative of general formula , which can find application as a chelating agent. In formula I, n is equal to 1-10, m is equal to 0 or 1, whereas R represents a hydrogen atom or an alkali or alkali earth metal ion. The method involves carrying out a reaction of maleate and diethanolamine in the alkali medium in the presence of a lanthanide catalyst element to form aspartic acid diethoxysuccinate. That is followed by adding aspartic acid, which reacts with unreacted maleate to form iminodisuccinic acid, i.e. an amino acid derivative of formula I, wherein m is equal to 0, or adding a diamine derivative of general formula NH2(CH2)nNH2 II, wherein n is such as described above, which reacts to unreacted maleate to form the amino acid derivative of formula I, wherein m is equal to 1, whereas n is such as specified above.

EFFECT: method enables producing the mixtures of chelating agents with the use of unreacted maleate from the process of producing aspartic acid diethoxysuccinate that makes the presented method more cost-efficient.

11 cl, 2 tbl, 2 ex

 

The present invention relates to a method for producing a mixture of deoxycytidine aspartic acid and iminodiethanol acid or mixture of deoxycytidine aspartic acid and ethylenediaminetetra acids that can be used as a chelating agent.

PRIOR art

In patent document WO 97/45396 discloses derivatives of N-bis - and N-Tris-[(1,2-dicarboxylate)ethyl]amine including N-bis-[(1,2-dicarboxylate)ethyl]aspartic acid (also called diethoxybenzene aspartic acid or AES), and the use of such derivatives as chelating agents for metals, particularly in the bleaching of pulp. Such derivatives can be obtained by reacting di - or triethanolamine salt of maleic acid, and alkali or alkaline earth metal in the presence of a catalyst such as compounds of the lanthanides, Nickel compounds or compounds of alkaline earth metals such as calcium hydroxide or magnesium hydroxide.

The disadvantage of the above-mentioned synthesis, such as AES, is that the reaction is quite slow - reaction time is from about 12 to 16 hours and that the reaction does not go to the end. Achieved in most cases, the degree of conversion of diethanolamine in AES is approximately �t 60 to 70%. A considerable amount of quite expensive maleic acid, usually to about 40%, remains unreacted.

The aim of the present invention is an improved method of producing AES and cost-effective method of obtaining AES. Another objective of the present invention is to provide a method of obtaining in situ mixtures of complexing agents.

BRIEF DESCRIPTION of the INVENTION

In accordance with the present invention it was unexpectedly found that the unreacted maleic acid may be easily and efficiently converted into another reactive ingredient by the addition to the reaction of the amine with the formation of a derivative of aspartic acid, resulting in the use of unreacted maleic acid. When adding aspartic acid or ethylene diamine are formed respectively iminediately acid (ISA) or ethylenediaminetetra acid (EDDS), giving as a result a mixture of AES and ISA or a mixture of AES and EDDS.

DETAILED description of the INVENTION

Thus, the present invention provides a method of producing a mixture of deoxycytidine aspartic acid and derived amino acid of the General formula:

where n is 1-10, m is 0 or 1, R represents a hydrogen atom or ion or alkaline shch�lachnosterna metal, including interaction maleate with diethanolamine in alkaline conditions in the presence lantanoides catalyst with the formation of deoxycytidine aspartic acid, then the addition of aspartic acid, which reacts with unreacted with the formation of malate iminodiethanol acid, is a derivative of the amino acid of formula I, where m is 0, or the addition of a diamine derivative of the General formula

NH2(CH2)nNH2II

where n is as defined above, which reacts with unreacted malate with the formation of the derived amino acid of formula I, where m is I and n is as defined above.

A mixture of deoxycytidine aspartic acid and iminodiethanol acid or mixture of deoxycytidine aspartic acid and ethylenediaminetetra acid prepared by reacting maleate with diethanolamine in alkaline conditions in the presence lantanoides catalyst with the formation of deoxycytidine aspartic acid followed by the addition of aspartic acid, which will react with unreacted small�inovas acid with the formation of iminodiethanol acid, or with the subsequent addition of ethylene diamine to react with unreacted with the formation of malate ethylenediaminetetra acid.

Individual components of the mixture is preferably obtained in the form of salts of alkali metals or alkaline earth salts of metals, however, components can also be obtained in the acid form or can be converted from salts in acid. Preferred salts of alkali metals are sodium or potassium, and the preferred salts of alkaline earth metals are calcium salts or magnesium.

A preferred embodiment of the invention relates to the preparation of a mixture of deoxycytidine aspartic acid and iminodiethanol acid, where the method includes the interaction maleate with diethanolamine in alkaline conditions in the presence lantanoides catalyst with the formation of deoxycytidine aspartic acid, then the addition of aspartic acid, which reacts with unreacted with the formation of malate iminodiethanol acid.

This method of obtaining the following diagram illustrates the reaction:

Another preferred embodiment of the invention relates to the preparation of a mixture of deoxycytidine aspartic acid and ethylenediaminetetra acid, wherein the method VC�uchet maleate interaction with diethanolamine in alkaline conditions in the presence lantanoides catalyst with the formation of deoxycytidine aspartic acid, then adding a diamine which reacts with unreacted with the formation of malate ethylenediaminetetra acid.

This illustrates obtaining the following reaction scheme:

Preferably, the amount of diethanolamine was stoichiometric with the amount of maleate. By changing this ratio, it is possible to obtain the required number of ISA or EDDS in the final mix.

The molar ratio of diethanolamine and maleate can be from 1:3.1 to 1:10, preferably from 1:3.5 to 1:4.

However, you can use, for example, a stoichiometric amount of diethanolamine in relation to the amount of maleate and add Ethylenediamine or aspartic acid after or before the reaction AES reaches equilibrium.

It is preferable to maleate and diethanolamine reacted in such a period of time sufficient for conversion of at least 30 mol.% diethanolamine in detoxicant aspartic acid.

The molar ratio lantanoides catalyst and maleate is preferably from 0.1:2.5 to 1:5, more preferably from 1:3 to 1:6.

The group of lanthanides (formerly known as the lanthanides) includes fifteen elements with atomic numbers from 57 to 71. Preferred lanthanoide catalysts are lanthanum (La), praseodymium (WG) neodymium (Nd), europium (EU), dysprosium (Dy), erbium (Er) and ytterbium (Yb)

The elements of the lanthanide group can be used in the form of oxides or salts, including carbonates, nitrates, chlorides, maleate and Octanate.

Especially preferred lantanoides catalyst is lanthanum catalyst including an oxide of lanthanum (III) and salts of lanthanum (III), such as lanthanum carbonate, maleate lanthanum, lanthanum nitrate, lanthanum chloride or octanoate lanthanum.

In accordance with the invention, the alkaline conditions can be obtained by dissolving maleic anhydride in water with the addition compounds of alkali metal or alkaline earth metal compound such as a hydroxide or carbonate of an alkali metal or the oxide, carbonate, hydroxide of an alkaline earth metal.

The main advantage of the present invention is that the unreacted maleate in obtaining AES can be used to obtain ISA or EDDS, preferably in the same reactor, making the process more cost effective. The resulting mixture can be used as a chelating agent, for example, in the bleaching of pulp.

The invention will be described in more detail with the following non-limiting examples.

DESCRIPTION of embodiments of the INVENTION

Example 1

Preparation of a mixture of AES and ISA

98,06 g (1,000 mol) of Malinovo� anhydride was dissolved in 258,40 g of water using a magnetic stirrer while heating to a temperature of approximately 70°C. The aqueous solution of maleic acid was transferred into a three-neck flask, placed in a pre-heated oil bath. To a solution of maleic acid was added La2(CO3)3(To 0.263 mol). The addition was carried out slowly for about 5 minutes to regulate the foaming caused by carbon dioxide. After this reaction mixture was added 31,14 g (0,252 mol) of diethanolamine. The temperature of the mixture was increased to about 90°C. the pH Value was adjusted by adding 77,61 g (0,931 mol) of NaOH solution (water. 48 wt.%). The alkalinity of the reaction mixture for the second sample was adjusted by adding 4,47 g (0,054 mol) of NaOH solution (water. 48 wt.%), whereby the pH value was increased to 8.55, and for the third sample is the addition of 7.35 g (0,088 mol) of NaOH solution (water. 48 wt.%), whereby the pH value was increased to 9,16.

12 hours after the start of the measurements was added 61,71 g (0,459 mol) of DL-aspartic acid. Alkalinity was reduced by adding 74,00 g (0,888 mol) of NaOH solution (water. 48 wt.%) to pH 9,98 (T=93°C). After adding aspartic acid and NaOH control samples carried out at intervals of half an hour for six hours. The reason for this was the rapid synthesis of ISA from aspartic acid and maleate, especially during the catalytic reaction. In each case, was collected on two samples. In one of the samples immediately well� added warm 30 wt.% a solution of Na 2CO3to stop reaction, catalyzed by lanthanum, at the time of sampling. Another sample was retained and frozen. Analyses were performed for samples treated with a solution of carbonate. During the synthesis, the samples were taken 23 times. The total duration of the synthesis was 60 hours, of which the first 12 were pure synthesis AES.

More accurate information concerning the conditions of synthesis and concentration of the reaction mixture, are presented in the following Table 1.

Table 1
SampleReaction time (HH:mm:SS)ISA (mol.%)AES (mol.%)Maleic acid (%)pHT°C
10:00:002,69100,008,1397
24:00:005,6492,378,2690
3800:00 18,0378,90To 8.4292
412:15:0037,1469,909,5393
512:35:002,1534,3862,829,9893
613:05:00To 6.88To 34.0459,049,9892
713:35:0010,7236,1357,419,9891
814:05:0013,1537,1257,13To 10.0691
914:35:0018,56 38,8055,98Of 10.0591
1015:05:0019,7835,7948,5110,0791
1115:35:0022,5838,1551,4210,1291
1216:05:0024,9936,2950,3610,1791
1316:35:0027,4836,4247,0610,1291
1417:05:0029,5336,2946,2010,1091
1517:35:0031,4737,06 45,67Of 10.0991
1618:05:00To 33.5236,1543,9010,1291
1719:05:0037,0236,2141,27To 10.0692
1820:05:0040,2036,2240,7210,1393
1922:05:0045,9336,16Thus 37.6410,1592
2024:05:0050,5934,8435,4810,1591
2136:05:0067,7833,1924,15 10,2192
2248:05:0075,9031,6218,1310,0793
2360:05:0010,1692

The results presented in Table 1 show that when added to the reaction mixture of aspartic acid it begins to react with the unreacted malate present in the reaction mixture, whereas the formation of additional quantities of AES essentially stops. 5 the Results further show that after about 24 hours of reaction, the AES output is approximately 35 mol.%,and ISA is approximately 50 mol.% (based on the original aspartic acid).

Example 2

Preparation of a mixture of AES and EDDS

Of 98.1 g (1,000 mol) of maleic anhydride was dissolved in 258,28 g of water using a magnetic stirrer while heating to a temperature of approximately 70°C. an Aqueous solution of maleic acid was transferred into a three-neck flask, placed in a pre-heated oil bath. To a solution of maleic acid(T=70°C) was added La 2(CO3)3(0,255 mol) in aqueous suspension. The addition was carried out slowly for about 5 minutes to regulate the foaming caused by carbon dioxide. Then the reaction mixture was added diethanolamine (30,96 g, 0,252 mol). The temperature of the mixture was increased to about 90°C. the pH Value was adjusted by adding 70,68 g (0,848 mol) of NaOH solution (water. 48 wt.%).

After approximately 12 hours after the start of measurement was added 14,27 g (0,235 mol) of Ethylenediamine. After adding Ethylenediamine control samples carried out at intervals of half an hour for six hours. After that, the interval of sampling was increased. The reason for this was the rapid synthesis of EDDS from diamine and maleate, especially during the catalytic reaction. In each case, was collected on two samples. In one of the samples immediately added warm 30 wt.% a solution of Na2CO3to stop reaction, catalyzed by lanthanum, at the time of sampling. Another sample was retained and frozen. Analyses were performed for samples treated with a solution of carbonate. During the synthesis, the samples were taken 23 times. The total duration of the synthesis was 60 hours, of which the first 12 were pure synthesis AES.

More accurate information concerning the conditions of synthesis and concentration of the reaction mixture, are presented in the following� Table 2.

91
Table 2
SampleReaction time (HH:mm:SS)EDDS (mol.%)AES (mol.%)Maleic acid (%)pHT°C
10:00:002,76100,008,0496
24:00:004,8990,437,9790
38:00:0010,9084,038,3091
412:00:0037,9057,36The 9.2590
512:15:000,00 For 38.6859,5910,3385
612:55:00To 10.3841,00For 46.71Of 10.3293
713:30:0040,7839,1210,5792
814:00:0035,8940,8334,4010,6292
914:30:0042,3434,1910,7092
1015:00:0058,0040,98Of 32.08Is 10.6892
1115:30:0038,55Of 30.5 Is 10.6892
1216:00:0073,42Measuring 38.7628,99Is 10.6892
1316:30:0038,1126,9010,5892
1417:00:0038,4626,6110,5992
1517:30:0038,7526,3110,5992
1618:00:0084,7738,7824,5610,5992
1719:00:0039,15Of 22.7610,52
1820:00:0036,8720,5410,5291
1922:00:0038,7819,4210,4491
2024:00:0094,8436,6617,5410,3790
2136:00:00100,0032,9012,1710,1990
2248:00:0033,269,8110,0491
2360:00:00Of 9.8991

Results, performance�introduced in Table 2, show that when added to the reaction mixture of ethylene diamine he begins to react with the unreacted malate present in the reaction mixture, whereas the formation of additional quantities of AES essentially stops.

The results also show that the content of EDDS increased by more than 50% of theoretical maximum after 2-3 hours after the addition of Ethylenediamine.

The results further show that after approximately 36 hours of reaction, the AES output is about 33 mol.%, and the output of EDDS is 100 mol.% (based on the initial Ethylenediamine).

1. Method of producing a mixture of deoxycytidine aspartic acid and derived amino acid of the General formula

where n is 1-10, m is 0 or 1, R represents a hydrogen atom or an ion of an alkaline or alkaline earth metal, comprising the maleate interaction with diethanolamine in alkaline conditions in the presence lantanoides catalyst with the formation of deoxycytidine aspartic acid, then the addition of aspartic acid, which reacts with unreacted with the formation of malate iminodiethanol acid, is a derivative of the amino acid of formula I, where m is 0, or the addition of a diamine derivative of the General formula

where n is as defined above, which reacts with unreacted malate with the formation of the derived amino acid of formula I, where m is 1 and n is as defined above.

2. A method according to claim 1, characterized in that the amount of diethanolamine is stoichiometric with the amount of maleate.

3. A method according to claim 2, characterized in that the molar ratio of diethanolamine and maleate is from 1:3.1 to 1:5, preferably from 1:3.5 to 1:4.

4. A method according to claim 1, characterized in that the maleate and the diethanolamine to react in such a period of time sufficient for conversion of at least 30 mol.% diethanolamine in detoxicant aspartic acid.

5. A method according to claim 1, characterized in that the molar ratio lantanoides catalyst and maleate is between 1:2.5 to 1:5, preferably from 1:3 to 1:4.

6. A method according to claim 1, characterized in that lantanoides the lanthanum catalyst is a catalyst comprising an oxide of lanthanum (III) and salts of lanthanum (III).

7. A method according to claim 6, where the salt of lanthanum (III) is selected from the group including lanthanum carbonate, maleate lanthanum, lanthanum nitrate, lanthanum chloride or octanoate lanthanum.

8. A method according to claim 1, characterized in that the alkaline conditions are produced by dissolving maleic anhydride in water with the addition compounds of alkali or alkaline earth�on metal.

9. A method according to claim 8, wherein the alkaline compound or an alkaline earth metal chosen from the group comprising a hydroxide or carbonate of an alkali metal or the oxide, carbonate, hydroxide of an alkaline earth metal.

10. A method according to claim 1, wherein a mixture of deoxycytidine aspartic acid and iminodiethanol acid, where the method includes the interaction maleate with diethanolamine in alkaline conditions in the presence lantanoides catalyst with the formation of deoxycytidine aspartic acid, then the addition of aspartic acid, which reacts with unreacted with the formation of malate iminodiethanol acid.

11. A method according to claim 1, wherein a mixture of deoxycytidine aspartic acid and ethylenediaminetetra acid, where the method includes the interaction maleate with diethanolamine in alkaline conditions in the presence lantanoides catalyst with the formation of deoxycytidine aspartic acid, then adding a diamine which reacts with unreacted with the formation of malate ethylenediaminetetra acid.



 

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FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing a compound of formula (I) or its salt, wherein R1 and R1' are independently hydrogen or a protective group for amino group, while R2 is carboxyl or ester group. The method involves a reaction of the compound of formula (II) or its salt wherein R1, R1' and R2 are specified above, and hydrogen in the presence of a catalyst on the basis of transition metal and chiral ligand. Transition metal is specified in group 8 or 9 of the periodic system, while chiral ligand is chiral phosphine.

EFFECT: invention refers to the use of the catalyst on the basis of transition ligand and chiral ligand in the method for preparing the compound of formula (I) used in synthesis of neutral endopeptidase (NEP) inhibitor or its prodrug.

36 cl, 1 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing a fluorine-containing acylacetic acid derivative of formula (3) involving preparation of a mixture containing a base, a compound of formula (1) and a compound of formula (2) and adding a halogenating agent to the mixture, where Rf is an alkyl group having 1-6 carbon atoms which is substituted by at least one fluorine atom; where R1 and R2 each independently represents an alkyl group having 1-6 carbon atoms; R3 is a hydrogen atom; and R4 is an alkyl group having 1-6 carbon atoms; where Rf, R1, R2, R3 and R4 represent the same as given above. The invention also relates to a method of producing a fluorine-containing pyrazolecarboxylic acid ester derivative of formula (5), involving the following steps: - obtaining a mixture containing a base, a compound of formula (1) and a compound of formula (2), and adding a halogenating agent to the mixture, where Rf is an alkyl group having 1-6 carbon atoms which is substituted by at least one fluorine atom; where R1 and R2 each independently represents an alkyl group having 1-6 carbon atoms; R3 is a hydrogen atom; and R4 is an alkyl group having 1-6 carbon atoms; to obtain a fluorine-containing acylacetic acid derivative of formula (3), where Rf, R1, R2, R3 and R4 represent the same as given above; - reaction of the obtained compound of formula (3) with a compound of formula (4) where R5 is an alkyl group having 1-6 carbon atoms, to obtain a compound of formula (5) where Rf, R3, R4 and R5 represent the same as given above; and a method of producing a fluorine-containing pyrazolecarboxylic acid derivative of formula (6) involving the following steps: - obtaining a mixture containing a base, a compound of formula (1) and a compound of formula (2), and adding a halogenating agent to the mixture, where Rf is an alkyl group having 1-6 carbon atoms which is substituted by at least one fluorine atom; where R1 and R2 each independently represents an alkyl group having 1-6 carbon atoms; R3 is a hydrogen atom; and R4 is an alkyl group having 1-6 carbon atoms; to obtain a fluorine-containing acylacetic acid derivative of formula (3), where Rf, R1, R2, R3 and R4 represent the same as given above; - reaction of the obtained compound of formula (3) with a compound of formula (4), where R5 is an alkyl group having 1-6 carbon atoms, to obtain a compound of formula (5), where Rf, R3, R4 and R5 represent the same as given above; -hydrolysis of the compound of formula (5) to obtain a compound of formula (6), where Rf, R3 and R5 represent the same as given above. Addition of a halogenating agent at the last step facilitates the desired reaction with good output.

EFFECT: improved method of producing a fluorine-containing acylacetic acid derivative.

6 cl, 7 ex

FIELD: inorganic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing metal complex compounds, in particular, to iron complex (chelate) as its concentrated solution. Method is carried out by interaction of iron salt in an aqueous medium with a chelate-forming agent wherein N,N,N',N'-ethylenediaminetetraacetic acid is used as a chelating agent and citric acid that are added simultaneously or successively. The process is carried out at temperature 70-90°C and in the process of mixing iron salt or after mixing with chelate-forming agent an aqueous solution of ammonia or ammonium citrate is added for providing pH value of the end product 2.0-2.3. The complex-forming agent can comprise succinic acid additionally. Method provides preparing iron chelate as a concentrated solution with the content of iron 60-100 g/l. Invention can be used in agriculture for root and leaf feeding of plants.

EFFECT: improved preparing method.

4 cl, 6 ex

The invention relates to methods for obtaining optically active ester of Erythro - 3-amino-2-hydroxybutyric acid, which represents an important intermediary product pharmaceutical reagents, in particular inhibitor of HIV protease

FIELD: chemistry.

SUBSTANCE: invention concerns C1-symmetrical biophosphine ligands and respective catalysts and their application in asymmetrical syntheses, including enantioselective hydration of prochiral olefins for production of pharmaceutical compounds, including (S)-(+)-3-(aminomethyl)-5-methylhexane acid known as pregabaline and its structurally related compounds. The methods involve new prochiral catalysts or precatalysts for obtaining the catalysts, including chiral ligand, connected to rhodium by phosphor atoms, with chiral ligand structure represented by the formula 4 .

EFFECT: obtaining new catalysts for application in asymmetrical syntheses.

19 cl, 46 ex, 7 tbl,7 dwg

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