SU451237A3 - The method of obtaining 3 - (/ - carbamoyl-2,4,6triodophenoxy) -alkoxy-2-alkylpropionic acid or its salt - Google Patents

Description

one

I The invention relates to the preparation of new derivatives of triiodobenzoic acid, in particular to a method for producing 3- | 3-carbamoyl-2, 4,6-triyodophenoxy) -alkoxy -2-alkylpropionic acid, which can be used in the pharmaceutical industry.

A known method for the preparation of 3-1 (3-aikpamino-2, 4,6-triiodophenoxy-alkoxy -2-alkylpropionic acid or its salt by esterification of 3-acetylamino-2,4,6-triiodophenol with a reactive derivative of Z-alkoxy-2-alkylpropionic acids, followed by saponification of the ester thus obtained, and isolation of the desired product or salting it by known methods.

Using instead of 3-acetyl-amino-2, 4,6-triiodo-phenol 3-carbamoyl-2,4,6-triodo-phenol, a new compound 3- (3-carbamoyl-2.4, b-triiodo-phenoxy) -alkoxy -2-alkylpropionic was obtained compared to the known analogous compound, the acid, which has a cotorub, has an increased biological activity ...

I A method is proposed for the preparation of 3-G (3-carbamo and l-2,4,6-triiodophenoxy) alkoxyT-2-alkylpropionic acid of the general formula

0- (CH2 g-0-CH2-CH-COOH,

where a Ik - lower alkyl containing 1-4 carbon atoms, the radical

 i

AlK. Morpholino-, piperidino- or pyrrolidino, group; A is methyl, ethyl, propyl or butyl,. e salt ..-. „,. The method consists in the fact that 3- “arbamoyl-2, 4,6 - triiodophenol of the general form / w (H) h IKr g: de Alk has the indicated value, is subjected to esterification with a reactive derivative of 3-alkoxy-2-alkylpropioic acid in total formulas X- (fcHaj -O-CW, A where X is halogen, sulphate or sulphonate residue; COOR is a carboxylic ester group or a carboxylate group; A, n have the indicated values by saponification of the resulting B ester and of the Neutral product or by transferring it to salt, are known by their methods. carried out in the presence of a basic condensing agent, alkali metal or alkali metal carbonate or 3-carbamoyl-2,4,6. triiodoethanol alkali metal, 1 As a cancer-capable 3-alkoxy-2-alkylpropionic derivative lots use 3- (halogen ethoxy) -2-alkylproduct 10 noic ester or 3-alkyl (aryl) sulfoxyloxy ethoxy-2-alkylpropionic ester. Example 1. Preparation of (3-M-methylcarbamoyl-2,4,6-triyodophenoxy-ethoxy-2-ethylpropionic acid. A. Preparation of ethyl ester To a solution of 27.5 g of 3-N-methylcarbamoyl -2,4,6- triiodo phenol sodium (0.05 mol in 5O ml dimethylformamide) was added | l6,5 g of ethyl ester 3- (2-odetoxy) -2-tylpropionic acid (0.055 mol), stirring for 1020 min at 70 ° С, Reactivity The mixture is stirred for 16 hours at 110 ° C, cooled, and poured into 500 ml of water. An oily product separates out and gradually hardens. It is dissolved in ethyl acetate. The solution is washed with water, sodium carbonate solution, water, sodium bisulfite solution and again with water, dissolved over sodium sulfate and evaporated. The crystalline residue is suspended in isopropyl ether, filtered under suction and washed with pure isopropyl ether. The yield of the product is 27.45 g (78 , 5% of theoretical). T. paragraphs 88-89 C. Calculated,%: C 29.12; 3 54.31. 7 223z "% Found,%: C 29.27; J 54.55. Thin layer chromatogram pa of silica gel using benzene (chloroform) glacial acetic acid 7: 3: 2 RO, 7O. B. Stirring for 3 hours at 5 ° C, add 170 ml of sodium hydroxide to 36 g of ethyl ester in 14O ml of ethanol, and wash the ester group. The ethanol is distilled off in vacuo, the residue is diluted with water and extracted with ethylacetate. Next, separate the aqueous phase from the dissolved traces of ethyl acetate, acidify it with 18% hydrochloric acid, and precipitate the product. product 26.9 g (78% of theoretical). T. pl. 77-78 ° C. Suspension of this product in boiling ethyl acetate (4 O ml) converts it into a more кристалли mobile, melting at a higher temperature, crystalline form with m.p. 138 C. Calculated,% C 26.77; 3 56.57. . Found,%: C 26.77; 3 56.31. Silica gel thin layer chromatogram using benzene (chloroform) glacial acetic acid 7: 3: 2 fJ, 0.65. The product is practically insoluble in water, in lower alcohols and aqueous base, or x (NaOH, ethanolamine, N-methylglucamine, etc.). PRI m e. P 2. Getting 3 .- (3-etilk and rbamoyl-2, 4,6-triyodophenoxy) I-ethoxy-2-ethylpropionic acid. A. Preparation of ethyl ester A solution of 11.3 g (0.02 mol) of 3-N-ethylcarbamyl-2, 4,6-triiodoethyl sodium, sodium compound H-hydroxy-2,4,6-triiodo-N-ethylbenzamide in 200 ml of dimethylformamide is reacted with 6.6 g (0.022 mol); 3- (2-iodoethoxy) -2-ethylpropionic acid ester or 4.6 g of 3- (2-chloroethoxy) -2-ethylpropionic ester acids in the presence of 3-4 g of sodium iodide with 15-hour heating to. The yield of the product is 10.5 g (73.5% of the theoretical). T. pl. (after recrystallization from aqueous ethanol) 80-820 Calculated,%: C 30.23; D 53.24. Found,%: C 30.04; 353.01. Silica gel thin-layer chromatogram using chloroform / glacial acetic acid 19: Ij Rf 0.65. B. Getting free, acid. According to the method described in Example 1B, 5 g of ethyl ester in ethanol is washed with an aqueous solution of sodium alkali and the saponified product is converted into lithium acid. Yield 2.5 g (52% of theoretical T. pl. (After recrystallization from ethyl acetate) 114-116 ° C. Calculated,%: C 27.97; 055.42. Found,%: C 27.89; 1 55 , 52. Silica gel thin layer chromatogram using ethyl acetate / isopropanol / ammonia: 55:35:20; Rf 0.415. The product is practically insoluble in water, soluble in lower alcohols and aqueous bases and x (NaOH, N-methylglucamine, ethanolamine and etc.). / Example 3. Preparation of (3-f -methylcarbamoyl-2,4,6-triiodo-phenoxy-ethoxy-2-methylpropionic acid. To 22 g of 3-N-methylcarbamoyl-2,4,6-triiodoxydate of sodium 3 -CH NHCO-2,4 6-triyodophenyl-O-Na) in 40 ml dimethyl forms Yes, 7.9 g of 3- (2-chloroethoxy) -2-methy propionic acid methyl ester was added and the resulting mixture was stirred at 11 ° C for 20 hours to form an ester (3-K-methylcarbamoyl-2 , 4,6-triyodophenoxy) -ethoxy1 g-2 methylpropioEvic acid. After recrystallization, from a small amount of ethyl acetate, it melts at 74-75 ° C. Calculated,%: C 26.77; 3 56.57. S5 l8bN05 Found, %: C, 26.73; 1 56,43. Thin-layer chromatogram on silica gel using chloroform / glacial acetic acid 19: 1 F 0.56. | According to the method described in Example 1, this methyl ester was washed and converted into free crystalline acid. Output 75.5% of theoretical. T. pl. 110-112 ° C. Calculated,%: C 25.51; 57.77. Found,%: C 25.47; 3 57.73. Thin-layer chromatogram on silica gel using 19: 1 chloroform / glacial acetic acid; F about 0.26. The product is practically insoluble in water, soluble in 1O of cold and 2 parts of boiling ethanol, soluble in 50 parts of Ho; -: i solid, and 10 parts of boiling of chloroform. Sodium salt: 50/100 ml of water at 20 ° C. Salt N -methylglucamine: 50 g / 100 ml of water at 20 ° C. Example 4. Obtaining (3- -ethylcarbamoyl-2, 4,6-triiodophenoxy) -ethoxy -2-methylpropionic acid. 13.4 g of 3-N-9-tricarbamoyl-2,4,6-triiodo-phenol sodium in 30 ml of dimethylformamide in an SO are reacted with 7.65 g of 3- (2-iodoethoxy) ethyl ether. -2-methylpropionic acid or from 5.16 g of 3- (2-chloroethoxy) -2-methylpropionic acid ethyl ester in the presence of; -, VII 4.5 g of sodium iodide at 9O C. Reac-: qi lasts 15 hours. The ethyl ester of (3-M-ethylcarbamoyl-2, 4,6-triiodophenoxy) -ethoxyT -2-methylpropionic acid is obtained. T. pl. 99-1OO C. Thin-layer chromatogram using, chloroform / glacial acetic acid 19:; 19: 1; 1 0.69. : C 29.12; 3 54.31. Calculated, 3 ° 5 C. Found,%: C 29.17; 54.33. By washing this ester with a rastro or sodium alkali in ethanol and by sub-acidification, free acid is obtained. Yield 89% of theoretical. T. pl. 142-.143 ° C. Thin-layer chromatogram using ethyl etat / isopropanol / ammonia 55: 35: 20; -R 0.41. Calculated,%: C 26.77; 3 56.57. Found,%: C 26.86; 3 56,53. The free acid is practically insoluble in Rome, but readily soluble in aqueous bases (NaOH, N-methyl glucamine, this Nolami, etc.). Example 5. Preparation of (3-N-morpholinocarbonyl-2,4,6-triyodfenok si) - ethoxy -1 -2-methylpropionic acid. 30.15 g of 3-N-morpholinocarbonyl-2,4 6-triiodoethanol sodium in 50 ml of dimethyl formamide is reacted with 9.9 g of 3- (2-chloroethoxy) -2-methyl propionic acid ester by 2O-hour heating is neither up to 110 ° C, and methyl (3-N-morpholin-carbonyl-2, 4,6-triyne phenoxy) -ethoxy-2 -methyl lpr o pionic acid methyl ester is obtained. According to the method described in Example 1, the last method is washed in the last one and converted into free acid. Yield 28.7 g. The crude acid is dissolved in isopropane containing 4 ml of cyclohexylamine. The salt of cyclohexyl on which is developed with it is liberated. The reaction product is isolated overnight, filtered under suction, washed with isopropanol, and dissolved in about 300 ml of warm water. This solution is slowly mixed into 3% hydrochloric acid, and 3- p1 O (3-M-morpholine carbonic acid-2,4,6-tri-dihydrogen-2-methylpropionic acid) precipitates. Yield 23.9 g (66.7% of the theoretical) T. pl. 75-780С. Calculated,%: C, 28.55; 353.25. . Found,%: C 28.54; 3 53.22. Thin-layer chromatogram on silica gel using chloroform / glacial acetic acid 19: 1; Hf 0.51. The resulting acid is practically insoluble in water, readily soluble in methanol, ethanol and chloroform. Sodium salt: 100 g / 100 ml of water at 20 ° C. Salt N-methylg manholes per 100g / / UOml water at 20 C. In the same way as described example receive

S. (3-α-morpholinocarbosh1l-2,4,6triodophenoxy) -ethoxy | -2-ethylpropionic acid. Example 6. A. Use in Examples 1-5 instead of 3- (2-halogentoxy) -2-methyl-yl-ethylpropionic acid ethyl ethyl ester, the corresponding methyl, propyl, isopropyl, butyl ether or other available ethyl ester, other acids with similar properties are obtained. B. Using 3- (2-haloethoxy) -2-methyl- or ethylpropionic acid ester instead of alkyl, 3- (2-alkyl- or arylsulfonyloxyethoxy) -2-methyl- or ethylpropionic acid esters, preferably ethyl ester 3- (2-benzosulphonyloxyethoxy) -2-ethylpropionic acid, purposefully | {the product is obtained with an increased yield. B. The condensation reaction can be carried out in an alcohol, for example ethanol or methoxyethanol, or in a ketone, for example methyl ethyl ketone. In the first case, an appropriate alkali metal alcoholate (hJa-OC H or Na-O-CH-CH-O-CH) is used as a condensing agent. During the reaction in the ketone, an alkali metal carbonate, usually carbonate, is used as the condensing agent. Kali. Example 7. Obtaining (3- -metiparb moyl-2,4,6-triyodophenoxy) - -propoxy -2 | -ethylpropionic acid. 42.5 g of sodium 43-N-methylcarbamoyl-2, 4,6-triiodo-phenol are reacted in 90 ml of dimethylformamide with 26.7 g of 3- (3-iodopropoxy) -2-ethylpropionic acid ethyl ester at 75 s. An ethyl ester of 3- | 3- (3-methylcaprobamoyl-2,4,6-tri-diodoxy) -propoxy -2-ethylpropionic acid is obtained. M.p. 85-87 ° С yield 46.7 g (84.8% of theoretical). A thin layer chromatogram with benzene / chloroform / glacial acetic acid 7: 3: 2; R Oh, 48. Calculated,%: C 30.23; 3 53.24. Found,%: C 30.24; 3 53.46. Sodium salt is readily soluble in water (100 g / 100 ml), menthol and ethanol. Analogously to Examples T-7 of gyu; the following compounds are prepared: 1 / (3-N-ethylcarbamoyl-2,4,6-tri- | iodophenoxy) -ethoxy-2-proxy-1-1 1 -shonic acid; (3-N-MeTHnKap6aMOHn-2,4,6-TpHy one-phenoxy) -ethoxy} -2-butylpropionic acid; (3-N-Prosh1carbamoyl-2,4,6-three iodophenoxy) -ethoxy -2-ethylpropionic acid; (3-N-butylcarbamoyl-2,4,6-triyodophenoxy) -ethoxy -2-ethylpropionic acid; (3-β-pyrrolidinocarbonyl-2,4,6-triyodophenoxy) -ethoxy 2-ethylpropanoic acid.; I (3-N-piperidinocarbonyl-2,4,6-triyodophenoxy-) -Etoxy -2-ethylpropionic acid, acid; O- (dHg) E-AlK

where Alk is lower alkyl containing 1-4 carbon atoms, the radical

(LF

X

Alk morpholino, piperidino or pyrrolidino group; P - integer - 2, 3 or 4; A is methyl, ethyl, propyl and butyl or its salts, characterized in that the 3-carbamoyl-2,4,6-triiodophenol of the general formula gDe Aik has the indicated value, is subjected to esterification with the reaction

capable derivative of 3-alkoxy-2-alkylpropionic acid of General formula

X- (CHj,) - 0-CH2-CH-COOR,

A (3-M-ethylcarbamoyl-2,4,6-triyodophenoxy) -proxy-2-ethylpropionic acid; (3-N-methylcarbamoyl-2,4,6-triyodophenoxy) -butoxy -2-ethylpropionic. acid; (3-N-ethylcarbamoyl-2,4,6-triyodophenoxy) -butoxy} -2-methylpropionic acid ;; 3- {4- (3-M-morpholinocarbonyl-2,4,6-triiodophenoxy) - utox111-2-methylpropionic acid. The subject of the invention is a method for the preparation of 3- (3-carbamoyl-2, 4,6-triol odophenoxy) a-lkoxy 2-alkylpropionic acid of the general formula -CHg-CH-dooH A where X is a halogen, a sulfate residue or a sulfonate; -jCOOl is a carbonic acid ester group or a carboxylate group; A, ft have the indicated meanings, followed by saponification of the ester thus obtained, and isolation of the desired product or salt transfer by known methods. 2. A method according to claim 1, characterized in that the esterification is carried out in the presence of an alkali metal alcohol or carbonate of alkali metal or 3-carbamate-2,4,6-triyodophenol of alkali metal, which is the main condensing agent. 3, the Method according to PP. 1 and 2, characterized in that as a reactive derivative of Z-a coxy-2-alkylpropionic acid use I