CS203996B2 - Method of producing n-substituted amides of 2-oxopyrrolidine - Google Patents

Description

The present invention relates to novel N-suhstituovaných amides ^and 2-oxo-pyrrolidine of general formula I, ·,

AND

CO- (NH-CH 2 CO) 4 NH _Z 10 where

X is C 1 -C 5 alkyl or C 6 H 5 CH and n is an integer of 0 or 1.

These compounds are prepared according to the invention by the formation of 4-halobutyric acid amides of the general formula II, hal-CH2CH2CH2-CONH-X-CO- (NH- -CHa-CO) n-NH2 (II) wherein:

X, n are as defined above, and hal represents a chlorine, bromine or iodine atom, cyclizes intramolecularly.

It is known that compounds of formula I wherein X is C 1 -C 2 alkyl and n is 0 can be obtained by reacting 2-oxo-pyrrolidinnatria with ω-haloalkylamides according to British Patent 1,039,113, by treating with esters of ammonia or ammonia; the chlorides of 2-oxo-pyrrolidinalcanic acids according to British patent specification 1039113 or by thermal decomposition of the ammonium salts of these 2-oxo-pyrrolidinalcanic acids according to British patent specification 1 309 692.

It is further known that according to U.S. Pat. No. 3,250,784, 2-oxo-pyrrolidin-N-γ-butyramide can be obtained at elevated temperatures and high vacuum by liquid / ammonia treatment on β-butyrolactone. It is further known that the above compounds can be prepared by electrolytic reduction of 2,5-dioxopyrrolidine-N-alkyl amides according to Yugoslav patent application P 77/76. Partial hydrolysis of 2-oxo-1-pyrrolidineacetonitrile according to German patent 2,507,576 gives 2-oxo-pyrrolidineacetamide.

Some of the above compounds have a therapeutic effect in the treatment of disorders of physical activity, hypertonia, hyperkinesia and memory.

The best known of these compounds is 2-oxo203996

-pyrrolidinacetamide, commonly known as Piracetam.

Furthermore, it is known that 4-chlorobutyrylderivatives of amino acid esters undergo cyclization reaction under certain conditions and in the presence of silver tetrafluoroborate to form the imino-lactones which are used to prepare N-substituted amino acid derivatives [H. Peter, M. Brugger, J. Schreiber, and A. Eschenmoser, Helv. Chem. Acta 46, 577 (1963).

4-Chlorobutyryl derivatives of amino acids are usually prepared by treatment. 4-chlorobutyryl chloride to amino acid esters or amides in the presence of a tertiary amine or with a molar excess of amino acid.

It is also known to prepare peptides by reacting activated esters or corresponding acid chlorides to Ν, dis-disilyl amino acid derivatives [L. Birkhofer, W. Konkol and A. Ritter, Chem. Ber. 94 pp. 1263 (1961)]. The advantage of this process over other processes is that after the reaction is possible; The silyl group can be easily removed under mild conditions with water or alcohol.

The general process for the preparation of the 2-oxo-pyrrolidine N-substituted amides of formula I has not been described hitherto. Only various processes are known for the preparation of the individual compounds of formula (I) wherein n is zero. Compounds of formula (I) wherein n is zero and X is methylene or ethylene may be prepared according to British Patent Specification 1,038,111 from 2-oxo-pyrrolidinonium and ω-haloalkylamides. However, the preparation of a compound of formula I, wherein n is zero and X is n-propyl, from pyrrolidinonitrile and β-chlorobutyric acid amide according to U.S. Pat. No. 3,250,784 cannot be successfully performed. Surprisingly, it has been found that the action of pyrrolidinnatrium bases quantitatively the intramolecular cyclization of chlorobutyramide into pyrrolidone.

It has now been found that compounds of formula I wherein X is as defined above! and n is zero, can be prepared according to the following reaction scheme:

_2-F-X-φ CONHf ClCH--CH-CH-COCl ----->

Cl-CH 2 CH 2 CONH-X-CONH 2

X'CONH _Z

A preferred embodiment of this process is characterized in that the amino acid amide is converted to 4-chlorobutyrylamino acid amide by condensation with 4-chlorobutyric acid chloride, which is then cyclized to 2-oxo-pyrrolidinecarboxylic acid amide under basic reaction conditions. In the process of the invention, for example, glycinamide is dissolved in Ν, Ν-dimethylacetamide and gradually added to a cooled solution of 4-chlorobutyric acid chloride in an aprotic organic solvent. The resulting precipitate of glycinamide hydrochloride is filtered off to regenerate the glycinamide and the readily volatile solvent is removed from the filtrate under reduced pressure. The product is eliminated from the residue by addition of a suitable solvent in which the product is insoluble. The alcohol is then added to the 4-chlorobutyrylglycinamide obtained and then converted by treatment with inorganic bases such as sodium hydroxide, potassium hydroxide, etc., or organic bases such as alcoholates, alkali metal salts of secondary amides or basic anionic resins such as Dowex-1. in 2-oxo-1-pyrrolidineacetamide, which is isolated from the reaction mixture after removal of the solvent. The advantage of the process according to the invention is that it is not necessary to use sodium metal or sodium hydride and that the product is obtained in very good yield.

The preparation of the compounds of formula (II) in which X, R and hal are as defined above and n is an integer of 1 or 2 cannot be carried out with the 4-chlorobutyryl chloride peptidamides as starting material, since chain polymerization or by the presence of free amino groups, dipeptidamides can be cyclized to diketopiperazines. Surprisingly, it has been found that cyclization or chain polymerization can be avoided by reacting the amino acid or peptide in activated silyl form with chlorobutyric acid chloride. The product obtained is converted to the 4-halobutyryl derivatives of the general formula (II) by known methods.

It has been found that the compounds of the formula I are very easily and in good yields obtained by intramolecular cyclization under basic conditions from the N-4-halobutyryl derivatives of the amine carboxylic acid amides of the formula II.

The method is characterized in that compounds of formula II are prepared by converting an amino acid or peptide of formula III,

H 2 N - X - CO (NH - CHS - CO) _{n -} OH (III j where

X and n are as defined above, by known silylation procedures to silyl derivatives, which are then converted to a compound of formula IV by reaction with 4-halobutyric acid chloride and hydrolysis, hal — CH2 — CH2 — CH2 — CONH — X— —CO (NH-) CH ₂ -CO _{3 n} -OH (IV) wherein

X, n and hal are as defined above.

The process is further characterized by the subsequent conversion of compounds of formula IV by known methods using inorganic acid chlorides, such as phosphorus pentachloride, into the corresponding organic acid chlorides, which are then converted to compounds of formula II by treatment with ammonia. The process is further characterized in that the obtained compounds of formula II are converted by intramolecular cyclization in a basic reaction medium into the N-substituted carboxylic acid amides of 2-oxo-pyrrolidine of formula I.

According to a preferred embodiment of the method of the invention, the amino acid or peptide is first converted to an activated silyl derivative by conventional means of a silylaonic reaction (trimethylchlorosilane, dimethyldichlorosilane, hexamethyldisalazane, etc.) in an aprotic organic solvent. To this mixture is then added 4-butyric acid chloride. After about 1 hour reaction time, the mixture is hydrolyzed with water. The dried organic solution was chlorinated with phosphorus pentachloride for about 1 hour. The resulting solid reaction product is filtered off and dissolved in an aprotic organic solvent, and ammonia is added to the obtained solution. The solid reaction product is recrystallized from ethyl acetate to give the pure 4-halobutyryl derivative of formula II. Treatment with inorganic bases such as sodium hydroxide or potassium hydroxide, or organic bases such as alcoholates or alkali salts of secondary amides, or an anion exchange resin in the OH-cycle such as Dowex-1, Amberlite IRA-410 gives N-substituted carboxylic acid amides 2 -oxo-pyrrolidine of formula I.

The process according to the invention is illustrated by the following examples, but the invention is not limited thereto.

Preparation of Compounds of Formula IV

Example 1

N- (4-chlorobutyryl) -α-aminobutyric acid (of formula IV wherein R = H, X = (CH3Js, hal = Cl, n = 0))

6.18 g (0.06 mol) of χ-aminobutyric acid was suspended in 60 ml of methylene chloride, 8.04 ml (0.06 mol) of trimethylchlorosilane was added thereto, and a solution of 8.4 ml (0.1 ml) was added dropwise with stirring. The mixture was stirred at room temperature for 1 hour, cooled to 0 ° C, and an additional 8.4 mL (0.06 mol) of triethylamine was added with stirring. solution of 8.46 g (0.06 mol) of 4-chlorobutyric acid chloride in 20 ml of methylene chloride After stirring for 1 hour at room temperature, the precipitated triethylamine hydrochloride precipitate is filtered off and the filtrate is washed with 10 ml of water. completely distilled off to give the product as an anhydrous oil.

TLC (silica gel, TLC): _Rf = 0.77 (n-butanol / acetic acid / water 4):

: 1: 1, iodine detection).

Neutralization equivalent:

calculated: 207 found: 211

Analysis for C 8 H 14 ClNO 3 (molecular mass 207.5) calculated:

C 46.26, H 6.75, N 6.75% found:

C 45.60, H 6.30, N 6.50%.

IR spectrum (cm ¹ ):

3400-3140 (OH, NH), 1710 (COOH), 1630 (CONH), 1540 (CONH).

Example 2

N- (4-Chlorobutyryl) -glycylglycine (Formula IV wherein R = Η, X = CH 2, n - = 1, hal = Cl

4.8 g (0.036 mol) of glycylglycine are suspended in 60 ml of methylene chloride, then 8.58 g (0.079 mol) of trimethylchlorosilane are added and 8.0 g (0.079 mol) of triethylamine in 20 ml of methylene chloride are added dropwise with stirring. The resulting mixture was stirred at room temperature for 1 hour, then cooled to 0 ° C, then 3.69 g (0.036 mol) of triethylamine was added, and 5.12 g (0.036 mol) of 4-chlorobutyric acid chloride in 10 mL were gradually added dropwise. ml of methylene chloride. The reaction mixture was then stirred for 1 hour at 25 ° C and the resulting triethylamine hydrochloride was filtered off. Water (10 ml) was added to the filtrate and the organic layer was separated. Upon standing of the aqueous layer, a product crystallized which was recrystallized from ethyl acetate to give colorless leaves having a melting point of 134-136 ° C.

Chromatography on silica gel thin layer appears product spot at R _f = 0.57 (ethyl acetate / acetic acid / water 3: 1: 1, detection with iodine).

Neutralization equivalent:

calculated: 237 found: 243

Analysis for C 6 H 6 ClN 2 Cl 2 (molecular mass 236.65) calculated:

C 40.58, H 5.54, N 11.84%, found:

C 40.77, H 5.55, N 12.05%. IR spectrum (cm ^-1 ):

3320 - 3060 (OH, NH), 1710 (COOH), 1640,

1540 (CONH).

Example 3

N- (4-Chlorobutyryl) -, 3-alanine (of formula IV wherein R = Η, X = (CH 2) 2, n = O, hal = Cl.)

Following the procedure of Example 1, _(0-alanine N- (4-chlorobutyryl) - / 3-alanine as an oil, R _f = 0.70 (conditions as in Example 2)

Neutralization equivalent:

Calcd .: 193

Found: 190

Analysis for C 7 H 12 ClNO 3 (molecular mass 193.5)

Calculated:

C 43.41, H 6.20, N 7.24%,

Found:

C 43.05, H 6.40, N 6.60%.

IR spectrum (cm ¹ ):

3400-3100 (OH, NH), 1725 (COOH), 1635,

1550

Example 4

N- (4-Chlorobutyryl} -glycine (of formula IV wherein R = Η, X = CH 2, n-O, hal = Cl)

Following the procedure of Example 1, N- (4-chlorobutyryl) -glycine was prepared from glycine as an oil liquid having an Rf ₌ 0.70 (conditions as in Example 2).

Neutralization equivalent:

Calcd .: 179

Found: 173

Analysis for CeHioCINOs (molecular mass 179.5)

Calculated:

C 40.11, H 5.57, N 7.80 ° / o,

Found:

C 39.80, H 5.15, N 7.40%.

IR spectrum (cm ¹ ):

3360-3320 (OH, NH), 1740 (COOH), 1655,

1540 (CONH).

Preparation of compounds of formula II EXAMPLE 1 a d 5

N- (4-Chlorobutyryl) glycinamide (Formula II wherein R = Η, X = CH 2, n -O, hal = Cl).

By gentle heating, 11.1 g (0.15 mol) of glycinamide are dissolved in 50 ml of N, N-dimethylacetamide and, while cooling with ice, 10.55 g (0.075 mol) of 4-chlorobutyric acid chloride in 50 ml of anhydrous dioxane are gradually added. The reaction solution was then stirred at room temperature for 10 minutes and the resulting precipitate was filtered off. 8 g of glycinamide hydrochloride are obtained. The dioxane used as solvent was distilled off under reduced pressure and the product was separated from the residue with ether. 10.5 g (78% of theory) of the product with a melting point of 123 DEG -125 DEG C. are obtained.

Chromatography on silica gel thin layer appears product spot at R _f = 0.43 (methylene chloride), acetone / methanol, 5: 5: 1, detection with iodine.

For analysis, the product was recrystallized from acetone / hexane / ethyl acetate to give colorless melting points 128-130 ° C.

Analysis for C6HuN2O2Cl (molecular mass 178, 62)

Calculated:

C 40.34, H 6.21, N 15.68%,

Found:

C 40.46, H 5.97, N 15.54%.

Example 6

N- (4-Chlorobutyryl) -y-aminobutyrylamide (Formula II wherein R = Η, X = = (CH 2) 3, hal = Cl, n = O) g (0.048 mol) of N- (4-chlorobutyryl) The .alpha.-aminobutyric acid is dissolved in 30 ml of methylene chloride and cooled to -15 DEG C., and 10 g (0.048) of phosphorus pentachloride are added in portions with stirring. Stirring is continued for 1 hour, then the crystalline precipitate is filtered off and dissolved in 80 ml of a 1: 1 mixture of methylene chloride and benzene, and the resulting solution is cooled to 0 ° C. Ammonia gas is then introduced into the solution for approximately 1 hour, the precipitate formed is filtered off and then extracted with hot ethyl acetate. Upon cooling, the product with a melting point of 110 DEG-112 DEG C. crystallizes from ethyl acetate.

When chroimatografii gel TLC appear product spot at R _f = 0.60 (conditions as in Example 1).

Analysis for C8H15N2O2Cl (molecular mass 206.7)

Calculated:

C 46.49, H 7.32, N 13.56%,

Found:

C 46.48, H 7.39, N 13.34%.

IR spectra (cm ^-1 ): 3380, 3310 (NHz), 3180 (NH), 1650-1610 (CONH, CONHz), 1530 (CONH)

Example 7

N- (4-Chlorobutyryl) -glycylglycinamide (Formula II wherein R = Η, X-CH 2, n = 1, hal = Cl).

2.1 g (0.008 mol) of N- (4-chlorobutyryl) glycylglycine was suspended in 60 ml of methylene chloride and then cooled to 4-5 ° C. 1.84 g (0.008 mol) of phosphorus pentachloride are gradually added to the suspension. The reaction mixture was stirred for 1 hour and then added gradually to a mixture of benzene and methylene chloride (1: 1).

The mixture was cooled to 0 ° C and ammonia was introduced into the cooled solution for about an hour. The precipitate obtained is filtered off. Recrystallization from ethyl acetate or acetonitrile gave the product in 70% yield.

Recrystallization from dioxane gave the product with a melting point of 178-180 ° C.

When tlc appears silicic product spot at R _f = 0.19 (methylene chloride / acetone / methanol 5: 1:

: 1, iodine detection).

Analysis for C8H14ClN3O3 (molecular mass 235.67)

Calculated:

C 40.77, H 5.99, N 17.83%,

Found:

C 40.96, H 5.99, N 18.00%.

IR spectrum (cm ¹ ):

3390, 3300, 3200 (NH 2, NH), 1660 (CONH),

1650, 1540 (CONH2)

Example 8

N- (4-Chlorobutyryl) -3-aminopropionamide of formula II wherein R = Η, X = (CH 2, N = O, and hal = Cl)

Following the procedure of Example 6, N- (4-chlorobutyryl-5S-aminopropionamide) is obtained from N- (4-chlorobutyryl) -. Beta.-alanine, m.p. 124 DEG-126 DEG C. (after recrystallization from dioxane), _Rf = 0.76 (conditions as in Example 2).

Analysis for C7H13ClN2O0 molecular mass 192.6)

Calculated:

C 43.64, H 6.80, N 14.54%,

Found:

C 43.86, H 6.66, N 14.61%.

IR spectrum (cm ¹ ):

3380, 3310 (NH2), 3190 (NH2), 1660-1630 (CONH2, CONH), 1540 (CONH)

Example 9

N- (4-Chlorobutyryl) glycinamide (Formula II wherein R = H, X = CH 2, n = O, hal = Cl)

Following the procedure of Example 6, N- (4-chlorobutyryl) glycinamide is obtained from N- (4-chlorobutyryl) glycine, m.p. 128-130 ° C (after recrystallization from ethyl acetate).

Chromatography on silica gel thin layer appears product spot at R _f = 0.43 (methylene chloride / acetone / methanol 5: 5:

: 1, iodine detection).

Analysis for C6H11N2O2Cl (molecular mass 178.62)

Calculated:

C 40.34, H 6.21, N 15.68%,

Found:

C 40.46, H 5.97, N 15.54%. IR spectrum (cm ^-1 ):

3400, 3310, 3200, 1680-1620, 1550, 1530 Preparation of compounds of Formula I

Example 10

2-Oxo-1-pyrrolidine-acetamide by cyclization of 4-chlorobutyrylglycinamide with sodium hydroxide

While heating to 50 ° C, 100 ml of anhydrous ethanol was added to 10 g (0.056 mol) of 4-chlorobutyrylglycinamide, and 5.9 ml (0.056 mol) of 1N sodium hydroxide in ethanol was added dropwise with stirring. The reaction mixture was then heated to reflux for 10 minutes. After cooling, the resulting 2.9 g (89% of theory) of sodium chloride was filtered off. Removal of the solvent after addition of isopropanol afforded 6.9 g (86%) of white crystalline ^{1 product,} m.p. 145-147 ° C.

Example 11

2-Oxo-1-pyrrolidine-acetamide by cyclization using sodium tert-butylate.

4 g (0.022 mol) of 4-chlorobutyrylglycinamide are dissolved in 80 ml of dioxane with heating. A suspension of 0.022 mol of sodium tert-butoxide in 20 ml of anhydrous dioxane was added to the resulting solution with stirring. The reaction mixture was stirred at room temperature for 1 hour and the residue was filtered off to give

1.2 g (94% of theory) of sodium chloride. The mother liquor was evaporated to dryness and the crude product was recrystallized from isopropanol to give 2.55 g (81%) of product, m.p. 146-149 ° C.

Similarly, cyclization of 4-chlorobutyrylgly203996 cinamide can be accomplished using sodium methylate or sodium ethylate. Example 12

2-Oxo-1-pyrrolidine-acetamide by cyclization of 4-chlorobutyrylglycinamide using pyrrolidinnatrium

8.9 g (0.05 mol) of 4-chlorobutyrylglycinamide are heated in 200 ml of dloxane and the resulting solution is added to a suspension of 0.05 mol of pyrrolidinonitrile in 200 ml of anhydrous toluene. The resulting mixture was cooled to room temperature and stirred for 1 hour. The resulting precipitate was filtered off. Removal of the solvent under reduced pressure and addition of isopropanol / ether gave 4.5 g (63%) of a white crystalline product, m.p. 145-147 ° C. Example 13

2-oxo-1-pyrrolidine acetamide by cyclization with 4-chlorobutyrylglycinamides using anionic ion exchanger

2.2 g (0.0124 mol) of 4-chlorobutyrylglycinamide are dissolved in 15 ml of anhydrous ethanol and added to a suspension of Dowex-1 ion exchange resin in ethanol. The suspension contains 20 ml of Dowex-1 dry ion exchanger in an OH-cycle in 30 ml of anhydrous ethanol. The reaction mixture was stirred at 20-25 ° C for 1 hour. Then the solution is decanted, the residue is washed with an additional 20 ml of ethanol and the solvent of the combined ethanol solutions is removed under reduced pressure. From the solid residue, crystallization from isopropanol gave 1.25 g (71% of theory) of a white crystalline product, m.p. 145-147 ° C.

By analogy, a substantially purer product is obtained by recrystallization from isopropanol in a yield of 85% and a melting point of 148-150 ° C by passing a solution of 4-chlorobutyrylglycinamide in ethanol through a column packed with an ion exchange resin.

Example 14

2-oxo-1-pyrrolidinebutyramide (of formula I wherein R - Η, X - (CH 2) 3, n = O)

1.03 g (0.05 mol) of N- (4-chlorobutyryl) -ylaminobutyramide was dissolved in 5 ml of anhydrous ethanol, 5 ml of 1N sodium hydroxide solution in anhydrous ethanol was added and the resulting mixture was stirred at room temperature for 5 hours. . The resulting precipitate was filtered off and the solvent was removed from the filtrate by distillation. An oily liquid is obtained which is crystallized by addition of isopropanol and ether.

Recrystallization from isopropanol / ether gave the product with a melting point of 98-100 ° C (99.8-100.5 ° C according to literature).

Example 15

2-oxo; -1-pyrrolidineacetylglycinamide of formula I wherein R = Η, X-CH2, n = 1) g (0.008 mol) of N- (4-chlorobutyryl) glycylglycinamide are suspended in 50 ml of anhydrous ethanol and then 20 ml of Dowex-1 ion exchanger are added in the OH-cycle. The mixture was stirred at 25 ° C for 3 hours, during which time the substance dissolved. After removal of the ion exchanger and distillation of the solvent, a product which readily crystallizes first, having a melting point in the range of 134-136 ° C in a yield of 75% of theory. After recrystallization from ethanol, the melting point is increased to 138-139 <.

When chromatographed on a thin layer according to Example 2 appears to be a product spot at R _f = 0.30.

Analysis for CaH13N3O3 (molecular mass 199.29)

Calculated:

C 48.23, H 6.58, N 21.10%,

Found:

C 48.02, H 6.58, N 20.98%. IR spectrum (cm ^-1 ):

3360, 3320, 3190 (NHz, NH), 1690-1660 (CON, CONH, CONHz), 1550 (CONH)

Example 16

2-oxo-1-pyrrolidinepropionamide (Formula I wherein R = Η, X = (CH 2) 2, n = O)

Following the procedure of Example 14, N- (4-chlorobutyryl) -3-aminopropionamide gave 2-oxo-1-pyrrolidinopropamide having a melting point of 141-142 ° C (142-143 ° C according to literature), which by thin layer chromatography. Silica gel shows a spot of Rf ₌ 0.53 (conditions as in Example 1). Example 17

2-oxo-pyrrolidin-1- (η-benzyl) acetamide (of formula I wherein R = Η, X = C 6 H 5 CH 2 CH, n = O)

Following the procedure of Examples 1 to 6, N- (4-chlorobutyryl) phenylalaninamide of melting point 178-179 ° C was prepared.

Analysis for C 13 H 17 N 2 O 2 Cl (molecular mass 268.75)

Calculated:

C 58.09, H 6.38, N 10.43%, Found:

C 58.09, H 6.38, N 10.43%, IR spectrum (cm ^-1 ):

3370, 3310, 3180 (NH 2, NH), 1660, 1640 (CONH, CONH 2), 1530 (CONH), 740, 700 (C-C6H5)

In a similar manner to that described in Example 14, this compound was converted to 20o-pyrrolidine-1- (α-benzyl) acetamide, m.p. 138-139 ° C.

Analysis for C 13 H 16 N 2 O 2 (molecular mass 232.28)

Calculated:

C 67.22, H 6.94, N 12.06%,

Found:

C 67.45, H 6.95, N 12.07%. IR spectrum (cm ¹ ):

3300, 3160 (CH 2, NH), 1680, 1665 (CON, CONH, CONH 2). 700, 755 (C — CeHs).

Claims (3)

SUBJECT A process for the preparation of 2-oxopyrrolidine N-alkylamides of the general formula I, X - CO - (NH - CH 2 CO) - NH _Z (O where X is C 1 -C 5 alkyl or C 5 H 5 CH and n is an integer of 0 or 1, characterized in that the compound of formula (II), YNALEZU hal — CH2CH2CH2 — CONH — X — CO (NH — —CH2 — CO) _{n —} NH ₂ (II) where X and n are as defined above, and hal represents a chlorine, bromine or iodine atom, cyclizes intramolecularly. Process according to claim 1, characterized in that the cyclization is carried out using basic agents such as inorganic bases, preferably sodium hydroxide or potassium hydroxide, or organic bases, preferably alkali metal alcoholates or alkali metal salts of secondary amides, in particular pyrrolidone sodium. . 3. The process according to claim 1, wherein the cyclization is carried out using basic ion exchangers in organic solvents.