The method of obtaining the acid-additive insoluble salts of carboxylic acids and amines or amino acids

 

(57) Abstract:

Usage: in medicine, chemistry and agriculture. Entity: receiving acid-additive insoluble salts of carboxylic acids and amines or amino acids f-ly I with certain values radicals by adding to an aqueous or alcoholic suspension of the corresponding carboxylic acid of triethylamine, followed by the interaction of the obtained water-soluble complex with a pre-prepared aqueous or alcoholic solution of the mineral salt of the corresponding amine or amino acid, as obtained by crystallization of the target product is washed with water. table 1.

The invention relates to the field of synthesis of potential biologically active compounds and intermediates for their production, in particular derivatives of benzoic, orotovoy, salicylic, pyridinedicarboxylic acids, which can find application in medicine, chemistry and agriculture.

The most famous and obvious method of obtaining salts of organic carboxylic acids with amines or amino acids is the direct interaction of the acid with the amine on the classic salt formation reactions of acids and bases. Eats the NTA reaction or at least one of them. Most often used for this purpose water, alcohol or water-alcohol mixture /1 7/. However, this method is not suitable in cases where one or both components of the mixture are slightly soluble in water and alcohols, as well as upon receipt of the adducts based on unstable under normal conditions amines or heterocyclic nitrogen bases. In such cases, the yield and quality of the target product is low, the process have to carry out in very dilute solutions or in a heterogeneous environment, which reduces the yield and complicates the process of isolation and purification of target products.

A method of obtaining a new salt dichlorsilane acid of the benzene series and oxyamine /1/ by reacting 3,6-dichloro-2-methoxybenzoic acid with 2-(2-hydroxyethoxy)ethylamine, which we have chosen for the prototype. In /1/ the reaction is carried out in the aquatic environment and consists in mixing the source of the acid and amine with stirring until complete dissolution of the solid compounds with subsequent processing and secretion of the target product known techniques. There are many similar examples of implementation of the salt formation reaction by direct interaction of organic carboxylic acid with an amine or amino acid in vodnikova method is the unsuitability of the method for obtaining the acid-additive insoluble salts of acids and amines or amino acids, i.e. when one or both components of the reaction mixture is poorly soluble in water, alcohols and other organic solvents, as well as when using unstable in water nitrogenous bases.

Sometimes to obtain the acid additive salts instead of organic acids come from their mineral salts (for example, in the patent /8/ of the silver salt orotovoy acid, and patent /5/ of the calcium salt of Pantothenic acid), which react with chloride or sulfate oxyamine. However, this variant of the process of salt formation is limited, more complicated and unsuitable when used sparingly soluble acids and to prepare their mineral salts.

The aim of the invention is to increase the output and simplify the process of obtaining soluble acid additive salts. This goal is achieved by the proposed method of obtaining new acid-additive insoluble salts of carboxylic acids and amines or amino acids of General formula:

< / BR>
consisting in the addition of water or alcohol suspensions of poorly soluble carboxylic acid triethylamine, followed by the interaction of the resulting vodorastvorimogo amino acids. After aging at room temperature or under heating and crystallization upon cooling, the desired product precipitated, the latter is washed on the filter with water from the resulting exchange reactions of triethylamine hydrochloride.

The process proceeds according to the following equations:

< / BR>
In accordance with this chemical scheme the essence of the method consists in carrying out an exchange reaction between a water-soluble complex of a carboxylic acid with triethylamine (I) and hydrochloride (or other mineral salt) amine or amino acid (II). The formation of complexes of type I greatly improves the solubility of the organic acid in water, which provides the possibility of further entry into the double exchange reaction with a separately prepared solution of hydrochloride nitrogenous bases (II) in aqueous or alcoholic medium with the formation of the target product (III), which after cooling, precipitates and hydrochloride of triethylamine, which remains in the aqueous solution, and a small amount of the latter in the crystalline product is then easily washed on the filter with water.

The proposed method was obtained over 20 new chemical connection of Alloway and acetylsalicylic acid, pyridinedicarboxylic acid (see table).

Example 1. Obtaining an acid additive salt orotovoy and aspartic acid.

3-necked flask equipped with forsteo with stirrer, dropping funnel, reflux condenser and thermometer load 105 ml of water and 45 ml of methyl alcohol and 5.42 g of aspartic acid, and then poured 3.4 ml of concentrated hydrochloric acid. The mass is heated with stirring to 80oC and incubated until complete dissolution of aspartic acid.

In the conical flask is charged with 38 ml of water, 6,35 g dry orotovoy acid and 5.7 ml of triethylamine and stirred until complete dissolution orotovoy acid. Then to a hot solution of the hydrochloride aspartic acid is gradually added to the solution prepared as described above, the water-soluble salts orotovoy acid and triethylamine. When this begins to fall precipitate the desired product. The reaction mass is stirred for further 2 h, then cooled to a temperature of 2 5oC and the next day dropped a white precipitate of the desired product is filtered off, press under vacuum, washed 4 to 5 times with 10 ml of cold water until no odor of triethylamine in the wash water when handling caustic soda. Pressed to salt orotovoy and aspartic acid (82,5% of theoretical) with so pl. above 300oC (with decomp.). IR spectrum (cm-1): 3085, 1700 1685.

Example 2. Getting salt orotovoy acid and 2-(3,4-dioksifenil)ethylamine.

3-necked flask is charged with 3.12 g orotovoy acid, 30 ml of water and 2,79 ml of triethylamine and stirred until complete dissolution orotovoy acid. The resulting solution was added dropwise to the prepared in another flask solution 4,06 g of the hydrochloride of 2-(3,4-dioksifenil)ethylamine in 30 ml of water.

After some time begins to fall a white precipitate of the desired product. After holding the reaction mass at a temperature of from -2 to -7oC for 2 h, the product is filtered, washed on the filter 3 times with 10 ml of cold water and 4 to 5 times in 6 ml of cold alcohol to the lack of the smell of triethylamine in the wash water and dried at a temperature of 105oC to constant weight.

Get 4,16 g (68% of theoretical) of an acid additive salt orotovoy acid and 2-(3,4-dioksifenil)ethylamine with so pl. 285 290oC (with decomp.). IR-spectrum (in cm-1): 3490, 3155, 1695, 1645, 1580, 1430.

Example 3. Obtaining an acid additive salt of 4-chloro-N-(2-furylmethyl)-5-sulfamoylanthranilic acid and glutamic acid.

1.98 g of 4-chloro-N-(2-furylmethyl)-5-sulfamoylanthranilic acid is treated with a solution of bleaching charcoal and filtered from coal. Then in the hot filtrate to a temperature of 90oC gradually added separately prepared solution of 0.88 g of glutamic acid in 6 ml of water and 0.5 ml of concentrated hydrochloric acid. Then the reaction mass is stirred without heating for 4 h, cooled to 5 of the 7oC and incubated for 16 hours the precipitation of the desired product is filtered off and washed several times with cold water from the hydrochloride of triethylamine to the lack of the smell of triethylamine in the wash water.

The crystalline product is dried at a temperature of 70oC to constant weight. Gain of 2.23 g (78% of theoretical) of salt furosemide and glutamic acid in the form of crystals with white shade with so pl. 226 229oC (with decomp.). IR spectrum ( cm-1): 3410, 3360, 3280, 1675, 1570, 750.

Example 4. Getting acid additive salts of salicylic acid and p-aminometilbensana acid.

In a three-neck flask was dissolved with stirring 2,33 g p-aminometilbensana acid in 15 ml of water from 1.32 ml of concentrated hydrochloric acid at a temperature of 50oC. In another flask dissolve 2,13 g of salicylic acid in 6 ml of water with 2,16 ml of triethylamine at a temperature of 50oC and add it dropwise to a solution of the hydrochloride of p-aminomethyl the 15 16 h at 5-7oC.

The precipitation of the desired product is filtered off, washed several times with cold water until the total absence of the hydrochloride of triethylamine in the filtrate. Pressed under vacuum, the crystalline product is dried at 70oTo Get 2,47 g (55% of theoretical) salt of salicylic acid and p-aminometilbensana acid so pl. above 250oC (wash.)

IR spectrum (cm-1): 3200, 1620, 1580, 1340, 1250, 760.

Example 5. Obtaining an acid additive salt of 2,6-pyridinedicarboxylic acid and glutamic acid.

3-necked flask is charged with 2 g of 2,6-pyridinedicarboxylic acid, 8 ml of water and 1.67 ml of triethylamine and intensively stirred at a temperature of 40 45oC to dissolve and the resulting solution was added dropwise prepared in another flask a solution of 1.76 g of glutamic acid in 12 ml of water of 1.02 ml of concentrated hydrochloric acid. Then the reaction mass is gradually cooled to 20oC and stirred for further 5 hours the Crystalline target product is filtered off, press under vacuum, washed several times with cold water from the hydrochloride of triethylamine, air-dried, and then at 100oC to constant weight. Get only 2.91 g of salt pyridinedicarboxylic acid and g, 1570, 700 to 750.

Obtained by the proposed method acid additive salts are adducts of structure 1 1, the structure and composition of which is confirmed by elemental analysis, IR and PMR spectroscopy.

Some of the new synthesized salts possess biological activity.

Thus, the positive effect of technical and scientific applicability of the proposed method lies in the possibility of obtaining new acid additive salts trudnorastvorimykh carboxylic acids and amines or amino acids, which in some cases impossible to obtain by other means due to the poor solubility of the parent compounds in water and in organic solvents, or they can be obtained in a known manner with direct exposure to the components in the solvent in very dilute solutions, which reduces output and makes difficult the separation and purification of target products.

The method may find application in organic synthesis of biologically active compounds and their products.

The method of obtaining the acid-additive insoluble salts of carboxylic acids and amines or amino acids of General formula

< / BR>
if X X1N, Y, Y1mean C=O group or Hikimi radicals, selected from the group: halogen, sulfamoyl, carboxy, hydroxy, lower alkoxycarbonyl, two of R1, R2, R3can denote hydrogen, and one of the remainder of the aliphatic amino acid, or its amide, or a lower alkyl ester, or a salt thereof with orotovoy acid, or guanidinium or balance aminoester alkylbenzene in which the alkyl part may be branched and substituted hydroxy groups and the benzene nucleus may be substituted by hydroxy or nitro groups, or the remainder of

< / BR>
either one of R1, R2, R3H, other sulfamoyl, and the third residue of aliphatic aminocarbonyl acid or one of R1, R2, R3H, and the other two C5H11-alkyl, wherein the aqueous or alcoholic suspension of the corresponding carboxylic acid is added triethylamine with subsequent interaction of the obtained water-soluble complex with a pre-prepared aqueous or alcoholic solution of the mineral salt of the corresponding amine or amino acid, as obtained by crystallization of the target product is washed with water from the resulting exchange reactions mineral salt of triethylamine.

 

Same patents:

The invention relates to new biologically active compounds, in particular to derive orotovoy acid, and can be used in medicine, chemistry and agriculture

The invention relates to the synthesis of biologically active compounds, namely, salts of nitrogen-containing heterocyclic derivatives and 5-hydroxynicotinic acid of General formula:

< / BR>
where X 0(1a), CH2(1B), NH(1B)

The invention relates to a derivative of quinone f-ly Ior its pharmacologically acceptable salts, where R1heteroalkyl group, in which heteroalkyl is a five - or six-membered cycle, containing as the heteroatom nitrogen and the alkyl portion contains 1 to 10 carbon atoms, B is carboxyl or protected carboxyl group, R3,R4,R5the same or different from each other and each represents a hydrogen atom, a hydroxyl group, a C1-C8alkyl, C1-C8alkoxy, C1-C8alkoxy, C1-C10alkyl, C1-C8alkoxy, C1-C8alkoxy, C3-C7cycloalkyl C1-C8alkoxy, thio C1-C8alkyl, thio C1-C8alkyl, except when R3and R4each is simultaneously the lowest C1-C8alkoxygroup, or a group represented by the formula IIwhere R3,R4,R5have the meanings specified above, X and Y are the same or different and each represents a hydroxyl or C1-C8alkoxy

The invention relates to new chemical compounds with biological activity, in particular derivatives pyridyl General formula I

_where And communication, cycloalkenes and cycloalkylcarbonyl groups, each with 3-4 carbon atoms in which one methylene group can be replaced dichloromethylene group, an unbranched Allenova group with 2 or 3 carbon atoms, which may be single or multiply unsaturated group-R7CR8-, -O-R7CR8- or-NR9where R7is a hydrogen atom, hydroxyl, phenyl or an alkyl group with 1-3 carbon atoms; R8is a hydrogen atom or an alkyl group with 1-3 carbon atoms and R9is a hydrogen atom, an alkyl group with 1-3 carbon atoms or phenyl; X is carbonyl, thiocarbonyl or sulfonylurea group;

R1is an alkyl group with 1-4 carbon atoms, unsubstituted or substituted phenyl group, cycloalkyl group with 5-7 carbon atoms, phenyl, naphthyl, biphenylyl, diphenylmethyl, indolyl, Tieni the group, in which the phenyl nucleus may be mono-, di - or tizamidine identical or different substituents from the group comprising fluorine, chlorine or bromine, alkoxy with 1-4 carbon atoms and an alkyl with 1-4 carbon atoms, and one of the substituents can also mean trifluoromethyl, carboxyl, amino - or nitro-group;

R2is a hydrogen atom or alkyl with 1-4 carbon atoms;

R3- pyridyl;

R4and R5is a hydrogen atom or together denote a further carbon-carbon bond;

R6is hydroxyl or alkoxygroup with 1-3 carbon atoms;

n = 2,3 or 4,

mixtures of their isomers or individual isomers and their physiologically tolerable additive salts (if R6means a hydroxyl group), which have valuable pharmacological properties, particularly an antithrombotic effect

The invention relates to substituted pyridine deoxyadenosyl acids, in particular to the new 3R,5S-(+)-7-[4-(4-forfinal)-2,6-aminobutiramida 5-methoxymethyl-PI - Reid-3-yl]-3,5-deoxyadenosine acid in Erythro-(E)-configuration in the form of a physiologically tolerable salt of the metal, which serves as an inhibitor of the biosynthesis of cholesterol

The invention relates to petrochemistry

The invention relates to organic chemistry, specifically to a method for producing 5-chlorosalicylic acid, which is used as an intermediate product in the synthesis of anthelminthic drugs

The invention relates to the synthesis of organic substances, chlorbenzoyl acid used as an intermediate product in the manufacture of dyes and pharmaceuticals

The invention relates to chemical-pharmaceutical industry, specifically to methods of producing 2-methoxy-5-chlorbenzoyl acid, used as an intermediate for the synthesis of the drug glibenclamide

The invention relates to the field of organic chemistry, more specifically to methods for solutions of cobalt salts and acids C7-C8

The invention relates to a method for producing salts of carboxylic acids or their mixtures, which can be used as stabilizers for polymers based on vinyl chloride (I)
The invention relates to organic chemistry, it is preferable to obtain the acid potassium salt of D-glucosami acid (CCF)

-diethylaminoethyl ester of p-aminobenzoic acid" target="_blank">

The invention relates to organic chemistry, in particular, to obtain the drug substance of novocaine, which is used for infiltration, wiring, epidural and spinal anaesthesia; for vagosympathetic and perirenal blockade, for potentiation of the principal narcotic drugs under General anesthesia; for pain relief with stomach ulcers, duodenal ulcers, hemorrhoids, etc

The invention relates to the field of organic chemistry, namely, the method of obtaining derivativesaminobutyric acid (GABA), used in various fields of medicine:

g Aminobutyric acid (acid) is used for treatment of vascular diseases of the brain (Mashkovsky M

The invention relates to medicine, namely to increase the resistance of tissues to the effects of cold
Up!