CS214147B1 - Process for preparing 3-iodo-4- (4-methoxyphenoxy) -βC-benzoylamino-cinnamic acid ethyl ester - Google Patents

Abstract

The invention relates to a method for preparing ethyl ester of 3-iodo-4-(4-methoxyphenoxy)-</>- benzoylaminocinnamic acid, which is a suitable intermediate for the synthesis of 3-iodothyronine, 3,3^-O1-iodothyronine and 3,3,5/-triiodothyronine. The essence of the invention lies in the fact that ethyl ester of 3-nitro-4-(4-methoxyphenoxy)- ¢6 - benzoylaminocinnamic acid is reduced with hydrogen at a temperature of 20 to 50 °C in the presence of a palladium catalyst, the resulting amino ester is diazotized in a mineral acetic acid environment. The resulting diazonium salt is substituted with iodine and the reaction product of the substitution is extracted. The substances prepared by the method according to the invention can be used in the investigation of the biological activity of thyroid hormones and their analogues.

Description

The present invention relates to a process for the preparation of 3-joc-4- (4-methoxyphenoxy) -β, p-benzoylamino-cinnamic acid ethyl ester of formula I below, which is a preferred intermediate for the synthesis of 3-iodo-thyronine, 3,3'-diiodo-thyronine and 3,3 ^, 5'-triiodothyronine. These substances are intensively investigated for biological activity of thyroid hormones and their analogs. Ethyl ester of formula I

R.

ω, ο

CH 'C.-C006A fl) where R jejod can be prepared from the nitroester of formula II, σι,

wherein R 10 O, ^{NH (MC} 6 ^{H 1} whose three-step synthesis from 4-chloro-3-nitrobenzaldehyde, 4-methoxyphenol and benzoylamino acetic acid (hippuric acid) is described (Block., P.Jr., J. Med. Chem.) 10, (1967)) The substitution of nitro-iodine for iodine in a compound of formula II, which can be schematically represented by the order of conversions of compounds of formulas II -> III (compound of formula I, wherein R = N 1 · 4 - IV) wherein R 'Ng X') —-> I is not described in more detail, only with reference to elsewhere described (Chalmers JR, Dickson GT, Elks J., Hems BA, J. Chem. Soc, 1949, 3424). Its constitution was confirmed by comparison with the product of esterification of the acid in question. When attempting to reproduce the recommended reaction conditions and purification method of the product was inconvenient, the disadvantage was the difficulty to control the initial catalytic reduction of the nitro group. to an amino group Also, purification of the ester of Formula I on alumina and repeated crystallization from aqueous ethanol were lossy and poorly effective.

These drawbacks are eliminated by a method of preparation of 3-iodo-4- (4-methoxyphenoxy) - _{0 (/} benzoylamlndískořicové .; acids of the invention The invention consists in that the ethyl ester of 3-nitro-4 (4-methoxyphenoxy) - -benzoylaminoskořicové of the acid is reduced with hydrogen at 20 DEG-50 DEG C. in the presence of a palladium catalyst, preferably 10% palladium chloride on carbon, and the resulting 3-aminoester is diazotized in a strong mineral acid and acetic acid medium. purified by preparative column chromatography.

It is preferred that sulfuric acid is used as the mineral acid in diazotization.

The reaction product is purified by preparative column chromatography on a column of 30 to 40 times the amount of silica gel for column chromatography with a grain size of 100 to 10 µm using an elution mixture of benzene-ethyl acetate, preferably in a ratio of 9sl or chloroform-methanol, preferably in a ratio of 200: 1. .

According to the process of the invention, the conversion of the nitro compound of formula II into the iodo derivative of formula 1 can be carried out by a simple technique without isolation and purification of intermediates, with chromatographic control of the process and with chromatographic method. The ester of formula (X) is obtained in satisfactory purity and in a higher yield than that known from the prior art.

The invention is illustrated by the following examples;

Example 1

A mixture of 12 g (26 mol) of nitroester of formula II and 3 g of catalyst, 10% palladium chloride on carbon in 200 ml of acetic acid was shaken under a hydrogen atmosphere at atmospheric pressure and a room temperature of 20 ° C. After five hours, hydrogen uptake began, and after another three hours, the uptake was stopped at $ 90 ml, the calculated theoretical consumption per substance and catalyst under the conditions used was 1,936 ml. The reaction mixture, analyzed by thin layer chromatography silikagelutmeleného gypsum with developing solvent of benzene-ethyl acetate 9: 1, showed the presence of a single substance, the spot having _Rf 0.16 in detecting the UV light shines on a dark background, unlike the starting nitro ester of the formula II, the spot of which by the same chromatography has an Rp of 0.34 and a UV light. Also when using carbonization detection (1% cerium sulphate in 10% sulfuric acid), both substances differ in the color of the burned spots: nitroester of formula II brown, aminoester of formula III gray-green. After filtering off the catalyst, the filtrate was concentrated to a weight of 36 g, cooled to 0-5 ° C and combined with 10 ml of cold concentrated 98% sulfuric acid while stirring slowly. The resulting solution was added dropwise with stirring over 30 minutes to a cooled mixture of 2.3 g of sodium nitrite, 32 ml of conc. sulfuric acid and 65 ml acetic acid at 0 ° C. The diazotization mixture was stirred for 1 hour at 0 ° C before being added over 25 minutes to a solution of 9.75 g (65 mmol) of sodium iodide, 8.25 g of iodine, 2.6 g of urea in 100 ml of water and 65 ml of chloroform. The reaction mixture was stirred at room temperature for 1 hour, then extracted three times with 125 mL of chloroform. Excess iodine was removed with sulfur dioxide gas in chloroform extract, overlaid with 200 ml of a 30% aqueous solution of sodium sulfite. The disappearance of free iodine appears to be a clear lightening of the chloroform phase. The chloroform extract was dried and filtered through a pad of alumina to remove the mineral acid residue. Evaporation of the solvent gave a syrupy residue (13.5 g), showing a gypsum-coated silica gel thin layer of 9: 1 ethyl acetate: an Rp of 0.36 (intense yellow-brown spot on carbon dioxide detection) next to it. several other substances of higher and lower Rp, providing less pronounced stains. The material was purified by preparative column chromatography on a 55 x 400 mm column containing 500 g of silica gel for column chromatography with a particle size of 100-160 (µm, developed with a 9: 1 benzene-ethyl acetate mixture). 700 to 1,400 ml of volume gave 9 g (64% of theory) of the chromatographically pure compound of formula I. After recrystallization from 120 ml of ethanol water 3: 1, the crystalline ethyl ester of formula I had a melting point of 126 ° C and elemental analysis consistent with theory. 2

A mixture of 12 g of the nitroester of formula II and 3 g of catalyst in 200 ml of acetic acid was shaken under a hydrogen atmosphere at atmospheric pressure. The flask with the reaction mixture was externally heated by infrared to maintain the temperature of the reaction mixture between 40 and 50 ° C. The theoretical amount of hydrogen was consumed within 110 min. Further processing of the reaction mixture is the same as in Example 1.

Example 3

Mixture 1? g of the nitroester of formula II and 3 g of catalyst, 10% palladium on carbon, in 200 ml of acetic acid were shaken under a hydrogen atmosphere at atmospheric pressure and a room temperature of 22 ° C. Hydrogen uptake occurred after 10 min and was stopped after absorption of 2050 ml. The reaction mixture analyzed by thin layer chromatography under the conditions of Example 1 showed the presence of Rp 0.16 and less Rp 0.27. After working up according to the procedure of Example 1, the ester of formula I was obtained in a yield of 55%.

Example 4

The amino ester of formula III, prepared according to the procedure of Example 1 and dissolved in 25 ml of acetic acid, was mixed at 0-5 ° C with 25 ml of 37% hydrochloric acid. The resulting inhomogeneous mixture was slowly added dropwise to a cooled mixture of 2.3 g of sodium nitrite, 75 ml of 37% hydrochloric acid and 65 ml of acetic acid at 0 ° C. The diazotization mixture was stirred at 0 ° C for 1.5 h and then worked up as described in Example 1. After the preparative chromatography of the much more varied mixture, 22% of theory was obtained. yield of ethyl ester of formula I.

Example 5

The crude ethyl ester of formula I, prepared according to the procedure of Example 1 (9g), was purified by preparative silica gel column chromatography for grain size 100-160 µm (450 g) eluting with 0.5% chloroform-methanol. After collecting 550 ml of the impurity-containing eluent, a 50% yield of the chromatographically pure desired compound of formula I was obtained in an elution volume of 550 to 1450 ml. In other fractions, this substance was accompanied by impurities of lower Rp.

Claims (1)

A process for the preparation of 3-iodo-4- (4-methoxyphenoxy) -? 50 ° C in the presence of a palladium catalyst, preferably 10% palladium chloride on carbon, the resulting 3-aminoester is diazotized in a strong mineral acid and acetic acid medium, the resulting diazonium salt is substituted with iodine and the substitution product is purified by preparative column chromatography.