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    • 专利摘要:
    The method of obtaining derivatives of i-phenoxy alkylcarboxylic acid ob-,. common femory, “--- TE (eng) n - ©) - O - ciooH i. - (where R is hydrogen or lower alkyl | radical; RJ is a Skyl radical with 1-16 carbon atoms, a naphthyl radical, a non-hardened phenyl radical, or substituted by fluorine, chlorine,. lower alkyl, hydroxy, acetyl, lower alkenyl radical; or. lower alkenyl or alkylene pCHs {KALOM and CHLOXXg in the parapoledenyl diphenyl radical - the same or different and mean hydrogen or lower alkyl radical, as well as their salts, esters and amides of the acid, are distinguished by the fact that the amine General formula H |; MdH,) R. where R is a hydrogen or a lower alkyl radical, in which the amino or hydroxy group is protected,. , schena /. , / ::, - v - /, P has the indicated meanings, interact in any CO sequence with the sulfonyl chloride of the general formula C vtii) where R has the indicated values. in and with the compound of the general Formula ft) es d have the indicated values / where R, and Ri .... NIA; -.;,.;. . X is chlorine or bromine; Y is the group COOHD in which R is hydrogen or lower alkyl; in the presence of an acceptor of hydrofluoric acid and, if necessary, a compound of the general formula 1, in which R is hydrogen, is substituted with an alkyl or: radical. lower haloalkyl in pri-. the presence of sodium hydride and isolate the desired product in free form or as an ester or as an amide acid.
    公开号:SU1052157A3
    申请号:SU792739296
    申请日:1979-03-02
    公开日:1983-10-30
    发明作者:Витте Эрнст-Кристиан；Петер Вольфф Ханс；Тиль Макс；Роеш Эгон；Штегмайер Карлхайнц
    申请人:Берингер Маннхайм Гмбх (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a method for producing new phenox alkylcarboxylic acid derivatives that reduce lipid levels and also have a inhibitory effect on platelet aggregation.  The C13phenoxy alkylcarboxylic acid derivatives of the general formula A-L (dHz) n - (Q) -o-j-c are known: oz.   where R, is an alkyl radical; , 2; Z is a hydroxy or alkoxy group.  Derivatives of 2 7 feioxyalkyl carboxylic acids of the general formula / -l-dOlJH- (YIg) n - (-: Kch hydrogen or halo; hydrogen or methoxy group hydrogen or methyl; hydroxy, methoxy, ethoxy) are also known.  Group; , pg: 1-3.  .   These compounds. are structural analogs of the proposed and also lower the level of lipids in the blood, but do not exhibit an inhibitory effect on platelet aggregation: The purpose of the invention is to develop a method for producing Derivatives of phenols of alkylalkarboxylic acid, lowering the level of lipids and having a pronounced inhibitory effect on aggregation platelet count.  Delivered tsen. What is achieved is that according to the method of producing phenoxyalkyl carboxylic acid derivatives of the general formula OVo-d-cioo () pK where R is hydrogen or a lower alkyl radical; R, j-alkyl radical with carbon atoms, naphthyl radical, unsubstituted phenyl radical or substituted by fluorine, chlorine, lower alkyl, alkoxy, aceto syrup, lower alkenyl radical or lower alkenyl or alkyl radical and chlorine, in the phenyl radical radical; same or different and denote hydrogen, or lower alkyl; as well as their salts, esters and amidbv acid, based on the known reactions of condensation of an amine with sulfonyl chloride in an aqueous medium C3J and interaction of the hydroxy compounds with a halide-containing compound in an organic solvent medium C4 3, amine of the general formula H-iT- (dH) n- {O-one: (Hj in where E is hydrogen or a lower alkyl radical in which there is an amino or hydroxy group.  protected; P.  has the indicated values, is reacted in any sequence with the sulfonyl chloride of the general formula, where E has the indicated meanings, and the compound of the general formula R 3 where E, has the indicated meanings; : X is chlorine or bromine; Y is a group-eon. in which  H 4 hydrogen or a LOW alkyl radical or amide group, in the presence of a hydrohalic acid acceptor and, if necessary, a compound of the general formula (i) in which E is hydrogen, is alkylated with lower haloalkyl in the presence of sodium hydride and the desired product is isolated in free form or as an ester, or as an amide acid. ; The proposed method is expediently carried out in two stages.  The condensation of compounds of general formula (c) with a compound of general formula (111) and compounds of general formula - (iv) is preferably carried out in such a way that one of the two is first blocked. reactive groups of compound (11) with an easily cleavable protective group, the resulting compound is reacted with compound (III) or one of its derivatives, or with a compound of general formula (II), the protective group is removed again, and then the reactive agent is subjected to interaction with a yet unused compound, the general Formula (ill) OR (IV).  . Such a process is preferred,. In Which amino-protected compound (iv) is first reacted with compound (IVJ.  Then, after cleavage of the protecting group, the reaction is carried out with the compound (ill) or with one of its derivatives.  Instead of free amines, their salts can also be used.  Halides are used in particular as reactive derivatives of the compound (y).  Halobenic acid sulfide reactions with compounds o. a general formula (II) is carried out with the addition of an acid binding agent, for example, an alkali metal acetate, sodium bicarbonate, sodium carbonate I, sodium phosphate, an oxide; qi, calcium carbonate or magnesium carbonate.  However, these functions may also take organic: bases, for example pyridine or triethylamine, with the inert solvent used being ether, benzene, methylene chloride, d-oxane or an excess of tertiary amine.  When using inorganic acid-binding substances, water, aqueous ethanol or aqueous dirxane are used as the reactive medium.  For the reaction of the compound (IT) with the compound (IV amino group of the compound til), it is first transferred to a protecting group, for example, to the ft imide group, which, after carrying out the reaction, can again be easily split in a known manner, for example, using an amino group. introduce other groups known from the chemistry of peptides and, after carrying out the reaction, split again.  Preferred is the blocking of amino groups by an acyl group, for example pho.  After the reaction, you can easily remove it again with strong bases, for example sodium or xoxide, as well as with aqueous mineral acids, for example hydrochloric acid.  .  As a reactive compound (IV), in particular, such is used in which X is anionyl type, for example, hydroxy hydrogen and sulfonic acid.  In addition / favorable impact on the reaction. renders the conversion of the feiolic hydroxyl group of the compound (II) to phenol t, for example, by reaction with sodium alkoxide.  The reaction of the two components is preferably carried out in warm solvents, impremer, toluene or xylene, metlethyl ketone or dimethylformamide.  As Seed substituent (111), the compounds of general formula (iv).  which can be converted into the group - COOR, use, for example, nitrile, carbaldehyde, hydroxymethyl, aminomethyl and phoryl groups.  If necessary, additional alkylation of a compound of the general formula (17}, where P is hydrogen, can be carried out by known methods, preferably a compound is introduced into the reaction, where and is hydrogen.  With basyl halide or dialkyl sulfate in the presence of an acidic solvent, for example sodium hydroxide.  The transformation of the substituent P, carried out, if necessary, directly after condensation, for example, by saponification of carboxylic esters ("4-alkyl) into the corresponding carboxylic acids (yd-hydrogen) with mineral acids or alkali metal hydroxides in a polar solvent (water, methanol, ethanol, dioxane or acetone).  Saponification is preferably carried out with a strong base (sodium or potassium hydroxide) in a mixture of methanol and water at room temperature or at moderately elevated temperatures.  Conversely, carboxylic acids can also be esterified in the usual way, or an ester with a specific residue can be converted into an ester with another residue by transesterification.  The esterification of the carboxylic acids is preferably carried out in the presence of an ACID catalyst, for example hydrogen chloride, sulfuric acid, p-toluenesulfonic acid or a strongly acidic ion exchange resin.  In contrast, area esterification requires the addition of a small amount of base, for example, hydroxy alkali or alkaline earth metals, or an alkali metal alcohol.  Essentially all alcohols are suitable for the esterification of a carboxyl group or for transesterification, preferably nastie monohydric alcohols, for example methanol, ethanol or propanol, as well as polyhydric alcohols, for example glycol or alcohols with other functional groups, for example etaiolamine or glycol ether.  Amides of carboxylic acids of the general form; ch (1), are preferably obtained by methods known from carboxylic acids or their reactive derivatives, for example halides; esters, azides and carboxylic anhydrides.  acids, in reaction with chlorine.   Ammonia, alkylamines, dialkylamines and amino alcohols, for example ethanolamine and 2-aminopropanol, as well as amino acids, are used as the amino component, for example.  p-aminobenzoic acid -alanine and others.  Other valuable ammonium components are alkyl-, aral-kil and arylpiperazine.  For the preparation of salts with pharmacologically acceptable organic or inorganic bases, for example sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methyl glucamine, morpholine or ethanolamine, it is possible to carry out the reaction of carboxylic acids with appropriate bases. corresponding carbonato or. bicarbonate alkali metal.  P p and m (E p 1.  4-C2- (Benzenesulfylamino) ethyl 3-phenoxyacetic acid.  .  Method I.  BUT.  A mixture of 240 g (1.34 mol of N-acetylthiramine, 370 g (2.68 mol) of anhydrous -powered potassium carbonate, and 2.5 l of 2-butanone is heated to boiling point for 2 hours with stirring, then 266 g ( 1.47 mol of bromoacetic acid ethyl ester and 1.5 g of potassium iodide are again heated to the boiling point.  After about 6 hours, the reaction is terminated.  The reaction mixture is filtered, the filter cake is washed with acetone and the combined filtrates are evaporated in vacuo.  The residue is dissolved in 1.75 L of methylene chloride.  The methylene chloride solution is washed three times with 300 ml of 0.5N.  a solution of sodium hydroxide each time and once with 300 ml of water, dried with sodium sulfate and evaporated in vacuo.  As a result, 321 g (98% of theory) of ethyl 4- (2-acetylaminoethyl-phenoxyacetic acid) with m are obtained. square bb In the same way, it is possible to obtain 4- | 2-acetylamino-9tyl) -phenoxyacetic acid etheral ester from N-acetylthyramine and chloroacetic acid ethyl ester.  The reaction is continued for 9 hours, the yield is quantitative,.  t. front  83-84,5 ° C.  B.  A mixture of FROM 498.6 g (1,845. mol of 4- {2-acetylaminoethyl) -phenoxy-acetic acid ethyl ester and 2.77 l (5.54 mol) of 2 n.  The salt pans are stirred for 8 hours at boiling point, then it is cooled and from about 460 ml of Yun.  The caustic soda solution is adjusted to pH 6.  After cooling in an ice bath (suction is carried out.  The filter cake is treated twice with 250 ml of water, quickly sucked off and dried in vacuum at 50 ° C.  The result is 299.5 g (83% of theory) of 4- (2-amino-methyl) -phenoxyacetic acid with t. square   (decomposed).  B, 280 g (1,435 mol of 4- (2-aminoethyl) -: phenoxyacetic acid) are suspended in a solution of 2.85 l of water and 436 g (3.157 mol G of anhydrous potassium carbonate and 266 g (1.507 mole benzenesulfonyl chloride.  Then stirring is carried out for 2.5 hours at 80 ° C.  After cooling, 1 l of ethyl acetate was added to the reaction mixture and the mixture was acidified with 800 ml of 6N with stirring.  hydrochloric acid.  Then the organic phase is separated, the aqueous phase is extracted with 1 l of ethyl. The acetic acid ester is combined and the organic phases are extracted to a sufficient amount for the salt formation of a saturated sodium bicarbonate solution.  Filter the aqueous phase and 6 n.  The hydrochloric acid is adjusted to pH 1 with stirring, and the product precipitates as a brownish granulate. The latter is sucked off, washed with a small amount of water and dried on air-: he.  This substance is then dissolved in approximately 3 liters of warm ether.  At the same time, an oily dark brown precipitate remains undissolved.  A clear solution of the ether is poured off and evaporated, and 312 g (b5% of theory) of colorless 4-C2- (benzenesulfonicyl7-ethyl-phenoxyacetic acid with t. square  117-118 ° C.  T. square  after recrystallization from toluene 1191200. A: The following two methods can be used to obtain the N-acetylthiramine used as the starting material.  one. 64.0 g (0.466 mol) of tyramine are mixed with 200 ml of acetic anhydride at ets (a clear solution is formed upon spontaneous heating.  This solution is contaminated with several crystals of N-acetylthiramine, after which immediate crystallization begins.  Rapid cooling, suction, washing with water and ether and drying are carried out.  Output 59 g (71% of theory of N-acetylthiramine with t. square  .  By evaporating the mother liquor, dissolving the precipitate in dilute sodium hydroxide solution, filtering and acidifying the filtrate, the following 5.5 g (6% of theory) are obtained with t. square  122-124 s.  Recrystallized from ethyl acetate A-acetylthiramine melts at 129-G51 C.  2 To a solution of 54.9.  g (0.4 mol) of tyramine and 200 ml of pyridine with stirring and at 30-35 0 is added dropwise g (0.84 mol) of acetyl chloride.  Then it is heated to a boiling water bath for 15 minutes, then cooled and poured into a mixture of water and ice.  By the addition of concentrated hydrochloric acid, a marked acidification is carried out and then extracted with chloroform.  The chloroform solution is washed with water, dried with HC1D calcium chloride and then evaporated. .  A residue of 88.5 g (quantitative yield) of diacetyl thiramine remains. square  EE-YuO S (recrystallization from benzene).  The diacetylthiramine is then dissolved in 500 ml of methanol.  Dropwise add nzt 800 MP (0.8 mol 1 n.  solution of potassium hydroxide (at the same time i increases the temperature Pj / and close to) and then it is kept at.  Putting 1 h of this cool.  weakly acidified with concentrated hydrochloric acid and methanol is evaporated in vacuo.  The product of crystallization of suction, washed well with water and dried.  Output 58.3 g (81% of theory), t. square  131 s (crystallization from ethyl acetate ;.  Method II  To a mixture of 15.0 g (0.11 mol) of thiram, 18.0 g (0.22 mol) of anhydrous sodium acetate and 250 ml of 97% ethanol was added dropwise 19.3 g (0.11 mol ) Benzenesulfonylchloride and then heated to boiling point for 2 hours.  Then ethanol is removed in a vacuum, the precipitate is dissolved with water and the aqueous solution is acidified with 2N.  hydrochloric acid.  The precipitated product is placed in ether, extracted once more with ether, and the combined solutions of the ethers are dried with sodium sulfate.  The ether is then distilled off and the residue is triturated with ligroin.  Dissolve in 2N for purification.  sodium hydroxide solution, the solution is treated with activated carbon and phenol is again extracted using dilute hydrochloric acid.  After drying with water and drying, 23.5 g (77% of theory) are obtained (benaene sulfonylamino-ethyl-phenol, t. silt  .  To a mixture of 18.0 g (65 mmol) of 4-C2- (benzenesulfonylamino) ethyl phenol 5 g (65 mmol} of anhydrous powdered Kssi carbonate and 250 ml of ethanol at the boiling point and with stirring, add dropwise 11.9% g (71.5 mmol I of bromoacetic acid ethyl ester and keep boiling for 2.5 h.  Then the reaction mixture is evaporated in vacuo, the precipitate is extracted three times with efrom and the ether extracts are evaporated. The remaining product is recrystallized from a mixture of ethyl acetate and ligroin.  As a result, 9.8 g (42% of theory) of 4-C2- (benzenesulfonyl amino-ethyl phenoxyacetic acid) ethyl ester are obtained. square  b8-70 s.  A mixture of 22.1 gSb1 mmol} ethyl ester 4 -2-benzenesulfonylamide-methyl j-phenoxyacetic acid, 183 ml (183 mmol 1 n.  solution of potassium hydroxide and 250 ml of methanol for 2 h, maintained at 35 ° C.  Then acidified with 2N.  hydrochloric acid.  Methanol is evaporated and the remaining aqueous solution is extracted several times with methylene chloride.  The combined methylene chloride solution is washed with water, dried over sodium sulfate and evaporated.  The residue obtained by evaporation was triturated with ligroin and sucked off, resulting in 17.6 g (86% of theory (benzenesulfonylaminoethyl J-phenoxyacetic acid). with t. kip  116-118 C.  Method 1117 To an ice-cooled solution of 19.5 g (75 mmol) of 4- (2-amino-ethyl-phenoxyacetic acid ethyl ester hydrochloride in 250 ml abs.  pyridine is added over 1 hour while stirring. 1 dropwise 13.3 g (75 mmol) of benzenesulfonyl chloride is added.  The cooling bath is then removed and stirring is carried out for 2 hours at-commin. Temperature.  It is then poured into ice water and acidified with concentrated hydrochloric acid, in which case the oil is separated, which dissolves in the ether.  The aqueous solution is extracted several times with ether, the combined solutions of ethanol are added to sodium sulfate 4 and finally evaporated. 22.5 g (82% of theory) of ethyl ether remains.  (benzenesulfonyl) -g EthylD-.  - phenoxyacetic acid with t. square  7677 ° C.  Saponification of this ethyl ester to 4- 2- (benzenesulfonylamino-ethyl-J-phenoxyacetic acid is carried out as described above.  BUT.  Isopropyl ether (benz zolsulfonylamino J-ethyl 3-phenoxyacetic acid.   A mixture of FROM 7.28 g (20) of ethyl ester (benzenesulfonylaminoethyl J-phenoxyacetic acid, 75 ml of isopropanol and approximately 50 mg of sodium isopropylate is heated to boiling point for 12 hours and then isopropanol is distilled off.  The remainder of processing from 0.5 n.  hydrochloric acid and ether, the ether phase is dried and evaporated. The remaining oil is triturated with ligroin and 4.5 g (67% of theory) of 4- {2- (benzenesulf-.) isopropyl ester are obtained.  fonilamino) -ethyl} -phenoxyacetic acid with t. square  56-57 C.  Example 2  4-2- (4-Methoxybei-; zolsulfonylsimino) -ethyl-phenoxy-acec. .  on acid.  To a solution of 11.2 g (50 Mmol) ethyl 4- (2-aminoethyl) phenoxy succinic acid in 125 ml abs.  a mixture of 10.35 g (5Q mmol of 4-methoxybenzenesulfonyl chloride and 50 ml of pyridine) was added dropwise to the room temperature and then incubated for 45 minutes at.  The mixture is then evaporated in vacuo to half the volume, poured into water in water and acidified with hydrochloric acid.  The precipitated viscous mass is dissolved in toluene and this solution in toluene is successively extracted with dilute hydrochloric acid, sodium bicarbonate solution and water. After drying over chloride to: the alci is evaporated under vacuum and the residue is triturated 4, the product is sucked off and recrystallized from a very small amount of ether.  The result is 13.0 g (66% of theory) of ethyl 4-C2-C4-methoxybenzrlsulfonylamino) ethyl j-phenoxy-acetic acid with t. square  82-83 C,
    In the presence of 4-C2- (4-methoxy-benzenesulfonyl-amine) -ethyl 3-phenoxy-acetic acid, its ethyl ester can also be synthesized as follows.
    The acid is dissolved in a 20-fold weight amount of abs. ethanol and from the surface are treated with dry hydrogen chloride, while the temperature of the BO-B C is maintained almost to saturation. Then the temperature of 50-60 ° C is maintained for the next 30 minutes, then evaporated in vacuo, and the yellowish oily residue is first recrystallized from ether. The yield is approximately 90%, from theory. .
    To a solution of 11.8 g (30 mmol) of 4-t2- (4-methoxybenzenesulfonylamino) ethyl-phenoxyacetic acid ethyl ester and 70 ml of ethanol was added dropwise to 70 ml (70 mmol) of 1N. potassium hydroxide solution and then kept for 5 hours at 35-40 ° C. Then ethanol was distilled off in vacuo and the aqueous pacTjaop was extracted with ether. Addition of 35 mp 2 n. hydrochloric acid leads to the separation of a colorless precipitate, which is sucked off) and recrystallized from dilute acetic acid. The yield is 8.66 g (79% of theory) of 4- 2- (4-labels, Sibenzenesulfonylamino) -ethyl-3-phenoxyacetic acid, mp 103 ° C.
    The preparation of 4- (2-aminoethyl) -floxyoxyacetic acid ethyl ester or its hydrochloride required for the reaction can be carried out in two ways.
    A. From 4- (2-aminoethyl) -phenoxycyclic acid and ethanol.
    To a cooled () solution of 67.2 g of 4- (2-aminoethyl) -phenoxyacetic acid and 672 ml of abs. Ethanol, with stirring, inject the dry HC1 gas to saturation. After, just overnight, the solution is evaporated at .30 ° C. The crystalline precipitate is first dried in air and then dried over potassium hydroxide. The yield was 85.6 g (96% of theory) of 4- (2-amNoethyl) -phenoxyacetic acid ethyl ester hydrochloride, m.p. 158-160 with (isopropanol). The free base in the form of a viscous oil condenses very quickly. .B. Through 4-C2- (phthalimido) -ethyl-phenol.
    A mixture of 137.1 g (1 mol) of tyramine, 148.1 g (1 mol) of phthalic anhydride, 13 MP of triethylamine and 2 l of toluene is heated at the boil in a water separator until it is separated from the theoretical amount of water. . Then cool and filter the precipitate. 259 g (97% of theory) of 4-2- (phthalimido) ethyl phenol are obtained with a melting point of 223-226 ° C. After recrystallization from isopropanol, this substance melts at 228-230 s.
    34.7 g (0.13 mol) (phthalimido) ethyl 3-phenol and 35.9 g (0.26 mol) of anhydrous powdered potassium carbonate in 300 ml of dry acetone are heated to boiling point for 2 hours with stirring. Then, 31.8 g (0.19 mol) of bromoacetic acid ethyl ester and 0.2 g of potassium iodide are added and the boiling point is maintained again for 8 hours. The inorganic precipitate is filtered off, washed with acetone and the combined filtrates are evaporated in vacuo. The residue is dissolved in chloroform, the solution is washed with 0.5N. a solution of caustic soda and water, dried and evaporated. The residue is recrystallized from isopropanol. The yield is 38.8 g (83% of theory) of 4-C2- (phthalimido) ethyl ethyl phenoxyacetic acid ethyl ester with a pour point of 104-106 ° C.

    35.3 g (0.1 mol) of this ether are dissolved in 1 l of boiling ethanol and mixed with 7.5 g (0.15 mol) of hydra3 INH hydrate in a hot state. The solution was left overnight, acidified with a small amount of concentrated hydrochloric acid and evaporated. The cage is stirred in 1 l of water, the insoluble is filtered off and the aqueous filtrate is evaporated. The residue obtained by evaporation, when added, recrystallized from isopropanol. 17.2 g (66% of the theory) of 4- (2-aminoethyl) -phenoxyacetic acid ethyl ester hydrochloride are obtained with a yield temperature of 157160 ° C. Example 3 .4-C2- (4-Fluoro-6-ene-sulfonylamino) -ethyl} -phenoxyacetic acid. In a mixture of 160 ml abs. pyridine, 11.1 g (70 mmol) of porous anhydrous potassium carbonate and 20.3 g (80 mmol) of 4- (2-amino-ethyl) -phenoxyacetic acid ethyl ester hydrochloride are added dropwise, at lO-l C C g (84 mmol ) 4-fluorobenylssulfonyl chloride. After that, they are stirred for 30 minutes at 30 / C, and then for 5 minutes at, after which they are cooled and poured out, they are poured into ice-water. The acidic acid is acidified with concentrated hydrochloric acid and the oxidized substance is extracted with methylene chloride. After drying over; sodium sulfate solution in methylene chloride vaporized and the residue after evaporation is recrystallized from a mixture of methanol and water. Obtain 25.5 g (84% of theory) of ethyl 4-C2- (4-fluorobenzenesulfonyl amiyo) ethyl} phenoxyacetic acid, m.p. 75-78 ° C. Hydrolysis of ethyl ester according to ayalogy with Example 2 yields 87% (from theory) (4-fluorobenzenesulfonylamino) -ethyl phenoxyacetic acid, p. 206-208 ° C. To obtain the sodium salt, 7.46 g (21.1 mol) of the acid is suspended in 150 ml of methanol, heated to approximately 21.1 ml of 1 and sodium hydroxide solution. After this, the mixture is evaporated in vacuo, the residue is triturated with acetone, and the BACUOT is filtered off and washed with HN. The yield is 7.8 g, m.p. 260-270 ° C (decomposed). Similarly, the reaction of 4- (2 aminoethyl) -phenoxyacetic acid hydrochloride with the corresponding sulfonyl chlorides in the presence of pyridine and potassium carbonate gives the following compounds: ;. .:. . -, BUT . E, methyl ester (methanesul fonilamino) ethyl 3-phenoxyacetic acid as a viscous oil, yield 65% - (from theory) maximum X-ray: 3290, 1750, 1608 from which its hydrolysis produces (metanzul fonylamino) ethyl phenoxy acetic acid, t .pl. 142-143 s, yield 77% (from). Sodium salt: mp. (decomposed). B. Ethyl ester 4 - (; 2- (p-toluolefonylamino) -ethyl} -phenoxyacetic acid; mp. 66-67 C (from ethanol); 74% (from theory), and from this substance by hydrolysis, 4- Sz- (p -toluenesulfonylamio) -ethyl-phenoxyacetic acid, mp.119120 ° C, yield 93% (from theory),. Salt S3O sodium as monohydrate: mp.245247 s. V. Ethyl ester 4-C2 ( 1-naphthalenesulfonylamino-ethyl 3-phenoxyacetic acid, mp lOS-loe C (from ethanol, 65% yield (from theory), and 4- 2-1-naphthapinsulfonyl lino-ethyl phenoxyacetic acid is obtained from it, mp 119-120 ° C (ethyl acetate + naphtha), yield 9 2% (from theory). Sodium salt: mp 238239 C. G. Ethyl ester (styrene sulfonylamino) -ethyl-phenoxyacetic acid, mp B2-63 s (acetic ester + ligroin), 71% yield (from theory ), and from this substance by hydrolysis, 4-C2- (styrenesulfonylamino) -ethyl-phenoxyacetic acid is obtained, mp. l4l-142c (acetone + water), yield 85% (from theory). D. Ethyl ester (4-chlorosteralocyllylamino ethyl 3-phenoxyacetic acid, m.p. 91-92 0 (acetic ester + ligroin), 76% yield (from theory), and from this substance by hydrolysis get 4-C2- (and-chlorostyrenesulfonylamino) -til -phenoxyacetic acid, so pl. 147-148 ° C (ethyl acetate + naphtha), yield 69% (from theory). E. Ethyl ester (lt-chlorobenzenesulfonylamino) ethyl 3-phenoxyacetic acid, m.p. 62-61 C (ether), yield 66% i (from Theoretical). From this substance, 4-C2- (-chlorobenzenesulfonylsino) -ethyl-phenoxyacetic acid is obtained by hydrolysis, so pl. 127-128 s (acetone -f water), yield 62% (from theory). EXAMPLE 4. 4- (BENOLSOLPHONYLINOMINOMETHL) PHENOXY ACID. To a solution of 15.9 g (0.1 mol) of 4-hydroxybenzylaminohydrochloride in 100 MP abs. pyridine cooling down 15.7 g (0.2 mol) of acetyl chloride while cooling. Then it is stirred for 1 hour at 20 ° C, after which it is heated for 15 minutes in a boiling water bath, in a warm condition, poured into ice-water and acidified with concentrated hydrochloric acid. Then, chlorofocum is extracted, chloroform solution is dried with sodium sulfate and evaporated. The product obtained is dissolved in ethyl acetate. After ligroin is added, the pure 4- (acetaminomethyl-fench1) ester of acetic acid is released. Output 18.86 g (91% of theory); m.p. 78-79 C. A mixture of 106.8 g (0.515 mol) of 4- (acetaminomethyl-phenyl) -fir of acetic acid, 800 ml of methanol and 1030 ml of 1 and. The solution of caustic potash is heated to 50 ° C for 2 hours, distilled under vacuum; g of methanol and acidified with hydrochloric acid. After concentration of the aqueous solution, it is sucked off and washed with ethanol. The result is 55.8 g (66% of theory) of 4- (acetaminomethyl) -phenol with so pl. 132-133 ° C. A mixture of 150.0 g (0.908 mol) of 4- (a g 1 minomethyl) phenol, 250.9 g (1.816 mol) of anhydrous powdered potassium carbonate and 3 liters of 2-bu tanol is heated to boiling point for 2 h. The mixture is cooled and 5 g of ydide potassium and 1 g (if 462 mol) of bromoacetic acid ethyl ester are added and added. Then, with stirring for 4 hours, the boiling point is maintained, then cooled, filtered, and the filter cake is washed with acetone. The combined filtrates are evaporated under vacuum. The residue obtained by evaporation is triturated with ether, sucked off and recrystallized and isopropanol. Yield 211.2 g (92% of theory) of ethyl ester of 4- (ace aminomethyl) -phenoxyacetic acid with m.p. 93-94 ° C. A mixture of 725 ml of ethanol, 125 g (0.5 mol) of ethyl 4- (acetylmethyl) -phenoxyacetic acid ethyl ester, 280 g (5.0 Moles of hydroxide kaln and € 00 ml of water for 14 hours is kept at boiling point, then cooled and concentrated hydrochloric acid is adjusted to pH 4. Sucked off, the precipitate is washed with water and recrystallized from aqueous ethanol. As a result, 73.4 g (81% of 4- (aminomethyl) - phenoxyacetic acid with a melting point of (decomposes). Hydrochloride has a melting point of 252-253 ° C. Allow for cooling in an ice bath, a mixture of 89.0 g (0.491 mol) of 4- (amino methyl) - phenoxyacetic acid and 890 ml of abs. ethanol were injected dry hydrogen chloride to saturation, and then stirred for 12 hours at room temperature, a clear solution was slowly but formed, and then evaporated in vacuo to give 115.3 g (96% from the theories of 4- (amio-o-methyl) -phenoxyacetic acid ethyl ester hydrochloride, mp 189-190 ° C. To a solution of 24.57 g (0.10 mol) of 4- (amnomethyl) ethyl ester hydrochloride .- phenoxy-acetic acid in 250 ml ayb. pyridine with stir-. 35.32 g (0.2 mol) of benzyl sulfonyl chloride is added dropwise to the temperature and then stirred for 2 hours at room temperature and poured into ice-water. The aqueous solution is acidified with concentrated hydrochloric acid, then extracted with ether and chloroform. The combined extracts are washed with dilute hydrochloric acid, dried and evaporated in vacuo. After recrystallization from isopropanol of the residue obtained by evaporation, 30.0 g (86% of theory) of 4- (benzenesulfonylaminomethyl) -phenoxy-acetic acid ethyl ester are obtained. C. Mix 20.96 g (60 mmol) of 4- (benzenesulfonylaminomethyl) phenoxyacetic acid ethyl ester with 250 MP of methanol and 180 ml (0.18 mol) II n. potassium hydroxide solution. The dark red solution is stirred for 2 hours at room temperature, then acidified with hydrochloric acid. Then methanol is distilled off in vacuum and cooled. The precipitated crystals are sucked off, shed with water, dried and recrystallized from isopropanol. Output 13,84 g (72% of theory) 4- (benzenesulfonylaminoethyl) -phenoxyacetic acid, so pl. 142-143 ° C. In a similar way, the following substances are obtained by the reaction of 4-aminophenoxyacetic acid ethyl ester with the corresponding sulfonyl chlorides in the presence of pyridine: 4- (benzenesulfonylamino) phenoxyacetic acid ethyl ester, mp. 127-128 with (ethyl acetate), yield 74% (from theory), and. from this substance by hydrolysis get 4- (benzenesulfonylamino) -phenoxyacetic acid, so pl. 157-158 ° C (acetone + water), yield 92% (from theory). Example 5: 2- {4-C2- (4-chlorobenzenesulfonylamino) -ethyl J-phenoxy -2-methyl-propionic acid. A mixture of 44.8 g (0.25 mol) of N-acetylthiramine, 69.5 g, (0.5 mol) of anhydrous powdered potassium carbonate and 750 ml of abs. 2-Butanol is heated under reflux for 2 hours to boiling point, then 73.2 g (0.375 mol) of 2-bromo-2-methyl-propionic acid ethyl ester and 1 g of potassium iodide are added and the mixture is heated to reflux temperature. After 40 and 70 hours of boiling, respectively, 35 g of yalium carbonate and 36.6 g of ethyl 2-bromo-2-methyl propionic acid are added. After 130 hours, the total reaction time is concentrated in vacuo, poured into ice-water and now extracted with ether. The ether extract is washed three times with 0.5N. sodium hydroxide solution, and then with water, dried over calcium chloride and evaporated. 83.8 g of an oily residue remain, which still contains 2g-bromo-2-methyl-propionic acid ethyl ester. This oil is incubated for 5 hours in a vacuum of 0.1 Torr at, then cooled. The resulting combination of crystals and mother liquor is washed with ligroin and dried. The output of 69.8 g (95% of theory). M.p. not completely pure ethyl ester 2-C4- (2-acetaminoethyl) -phenomenon of J-2-methyl-propionic acid 51-52c.
    jJacTBop 119.1 g (0.407 mol) of 2-C4- (2-acetaminoethyl) phenoxyJ-2-methyl-propionic acid ethyl ester in 750 ml of alcohol is mixed with a solution of 224.4 g (4; 0 mol) of potassium hydroxide in 800 ml of water and heated to boiling point for 8 hours. While cooling, 4.0 Cmol) of hydrogen chloride (for example, in the form of 2N hydrochloric acid) is added, it is cooled more strongly, and after some time the precipitated crystals are sucked off. The latter are washed with water and pro; dried. Output 48.4 g (53% of theo)
    | Rii), m.p. 274c (decomposed).
    j From the mother liquor after distillation of the alcohol and cooling get:
    32.5 g (36% of theory) from m. 263270 C. Untreated 2- {4- (2-amino ethyl) -phenoxy D-2-methyl-propionic acid is recrystallized from alcohol and water (4: 1 vol.), So pl. . The hydrochloride melts at 187-189s. :.
    Solution 58. g (0.26 mol) of the said carboxylic acid in 600 ml of abs. ethanol with stirring and cooling with ice is treated from the surface with dry chlorine with ammonia with hydrogen to saturation. Then, the initial mixture is closed and allowed to stand for 12 hours. The alcohol and hydrogen chloride are then removed in vacuo. Water is added to the residue, it is extracted three times with ether, the aqueous paiCTBop is made alkaline and extracted with chloroform. The extract in chloroform is washed in a small amount of water, dried over potassium carbonate and up-; ryvaet. Distillation of the residue prc 125-128 ° C and a pressure of 0.1 Torr PolU4aipT 53.2 (82% of theory) of colorless ethyl (2-aminoethyl) -phenoxy-2-methyl-propionic acid ethyl ester. The pure product obtained by gas chromatography has a refractive index of Tg.
     1.5075. :; .
    The reaction of (2-aminoethyl) phenoxy -2-methyl-propionic acid ethyl ester with 4-chlorobenzenesulfonyl chloride analogously to Example 2 gives the colorless 2- {4- 2- (4-chlorobenzenesulfonyl-amino) -ethyl-jf-ethyl amino-ethyl-jl-ethyl-jf-4- (4-chlorobenzenesulfonyl-amino) -ethyl-jf-ethyl-2-methyl (4-chlorobenzenesulfonyl amino) -ethyl-jf-amino-ester 2-{4- 2- (4-chlorobenzenesulfonyl-amino) -ethyl-jf-amino-ester 2- {4- 2- (4-chlorobenzenesulfonyl amino) -ethyl jf-aminomethyl ester jf ethyl 2-{4- 2- (4-chlorobenzenesulfonyl) amino-ethyl-jf-2-4 methyl propionic acid, 69% yield (from theory), and from this substance by hydrolysis, 2- {4- 2- (4-chlorobenzenesulf6nylamino) ethyl-phenoxy -2-methylpropionic acid. Output .67% (from theory), so pl. (Aceto Similarly receive ethyl ether
    2,4-2-benzolcyJ phosphonamino-ethyl phenoxy-j -2-methylpropionic acid from ethyl ether (2-aminoethylphenoxyJ-2-methyl-propionic acid and benzenesulfonyl chloride, mp. 66-67s (iopropanol) and benzenesulfonyl chloride, mp. 71% (from theory), and from this substance by hydrolysis - 2- {4- 2- (benzenesulfonylamino) -ethyl} -phenoxy -2-methylpropionic acid, mp 128129 s (ethyl acetate + naphtha), yield 85% of theory.
    PRI me R b. (Benzenesulfonylamino) -ethyl 3-phenoxyacetamide.
    A mixture of 67 g (0.2 mol) (ben eolsulfonyl-1mino) ethyl-phenoxyacetic acid, .400 ml of benzene and 71.5 g (0.6 mol) of 4H thionic chloride is heated to the boiling point. Then the benzene and excess thionyl chloride are distilled off in vacuum . The yield of crude product is quantitative. After recrystallization from methylene chloride, 61 g (86% of theory) of 4-C2- (benzenesulfonylmio) gethyl-phenoxy-acetyl chloride with mp. 78, In this case, it is possible to work without the addition of benzene, i.e. with pure thionyl chloride.
    With stirring to a solution of 10.6 g (30 mmol) of (benzenesulfonylamino) ethyl 3-phenoxyacetyl chloride in 100.ML abs. At a room temperature, dioxane drilled 3.3 ml of a concentrated ammonia solution, was quickly heated to 40 ° C and cooled. Then the contents of the flask are poured into ice water. The mixture is filtered off with suction and washed with water and treated with sodium bicarbonate solution. After suction and washing with water, recrystallization from acetone is carried out. The output of 7.2 g (72% of theory) 4-C2- (benzenesulfonylamino) -ethyl-phenoxyacetamide, so pl. 118-119C, the following amides are obtained by the reaction of (benzenesulfonylamino) -ethyl-phenoxyacetylchloride with the corresponding amkyam:. .
    A. (BenzeneSulphR-Ilamino) -ethylZ-Phenoxyacetansna To a solution of 7.08 g (20 mmol) of acid chloride in 35 ml abs. 3.73 g (40 mmol) of aniline was added dropwise while stirring the benzene, heated quickly and then benzene was distilled off. Methylene chloride and dilute hydrochloric acid are added to the residue, strongly agitated and the solutions are separated. The solution in methylene chloride is washed with 2N. hydrochloric acid and water, dried and evaporated. After recrystallization from ethyl acetate, 5.58 g (68% of theory) of the product with a m.p. 123 C.
    B. 2-Ethoxycarbonyl-ethylamide (benzenesulfonylamino) -e il-phenoxyacetic acid. A mixture of 4, God
    (30 mmol) ethyl ester / S-aminopropionic acid hydrochloride, 4.1 g (30 mmol) of powdered carbonate .calibrated in 100 ml of abs. After 20 min stirring under ice cooling, g (30 mmol) of acid chloride is added dropwise. Heat up to, and then within 30 minutes to 50 ° C, cool and pour about 500 MP of water with ice. The pH is adjusted to 5.5 by addition of hydrochloric acid, then extracted with methylene chloride. The solution in methylene chloride is washed several times with dilute hydrochloric acid, then with sodium bicarbonate solution and water, dried with sodium sulfate and evaporated. 10.5 g (81% of theory) of oily 2-ethoxycarbonyl-ethylamide (benzenesulfonylamino) ethyl-phenoxyacetic acid with a refractive index of 1.5490 remain.
    Analogously to Example 2, by hydrolysis, 2-carboxyethylamide (benzenesulfonylamino) ethyl-phenoxyacetic acid is obtained from this product, m.p. 64-b5 S. (acetone + water), yield 86% (from theory).
    In 4-ethoxycarbonyl-anilide (benzenesulfonylamino) -ethyl-phenyloxyacetic acid is prepared in a similar way (2 / from acid chloride, and 4-aminobenzoic acid ethyl ester hydrochloride, mp. 157-158 ° С (ethyl acetate), 72% of theories, and from this product the hydrolide of 1 - 4-carboxyanilide of 4-C2- (benzenesulfonylamino) -ethylZ-phenoxyacetic acid, mp, 186-185 s (acetone + water). 65% of the theory: -,
    G. 4- (Ethoxycarbonylmethylenoxy) -phenethylamide (benzenesulfonylamino) -ethyl-phenoxyacetic acid is prepared, analogously to (2), from acid chloride and 3- tyl ester of 4- (2-aminoethyl) -phenoxyacetic acid, mp. 97-98 C (acetic ester), yield 68% of theory, and from this product by hydrolysis - 4- (carboxymethylenoxy) -phenethylaide (benzenesulfonylamino) -ethylJ-phenoxyacetic acid,. 148-149 ° С (water - f acetone /.
    yield 60% of theory.
    Example p 7. (n-Octanesulfonylamino) -ethylJ-phenoxyacetic
    acid.
    26.1 g (0.1 mol) of 4- (2-amino-ethyl) -phenoxyacetic acid ethyl ester hydrochloride and 21.3 g (0.1 mol) of N-octanesulfonyl chloride are suspended in 400 ml of benole, with very strong stirring, dropwise. a solution of 27.6 g (0.2 mol) of potassium carbonate and 400 ml of water is added, stirred for 10 minutes and then the solutions are separated. The solution in benzene is washed with water, dried with sodium sulfate and evaporated in vacuo.
    After recrystallization from ethyl acetate, 32.6 g (82% of theory) of ethyl ether (n-octanesulfonylamino-5-eyl-phenoxyacetic acid with mp 65-66 C (ethyl acetate) are obtained.
    A mixture of 15.4 g (38 mmol) of ethyl ether, 38 MP 2 N. solution of potassium hydroxide and 38 ml of ethanol is kept for 3 hours at. Then, in vacuum, ethanol is distilled off, acidified with hydrochloric acid, sucked off, and recrystallized from a mixture of water and dioxane. As a result, 12.4 g of 8B% of theory) (n-octanesulfonylamino) -ethyl 3-phenoxyacetic acid are obtained, m.p. .
    PRI me R 8. 4-12- (n-hexadequanesulfonylamino) ethyl 3-phenoxyacetic acid.
    To a mixture of 4.4 g (16.9 mol) of hydrochloride and ethyl ester of 4- (2-aminoethyl) -phenoxyacetic acid, 50 ml of benzene and 6.8 g (68 mmol) of triethylamine are added with stirring and temperature dropwise. , 5 g (16.9 mmol;) n-hexadecanesulfonyl chloride, stirred for 2 hours in an ice bath and left overnight at 20 ° C. It is then poured into ice water and acidified with hydrochloric acid and extracted with ether. The ether solution is washed with water, dried with sodium sulfate, evaporated and the residue is recrystallized from ethanol. 5.8 g (67% of theory) of 4-C2- (n-hexadecanesulfonylamino) -ethyl-phenoxyacetic acid ethyl ester are obtained with m.p. 91-92 S.
    The hydrolysis of the ester is carried out analogously to example 7 with an aqueous solution of caustic potash in methanol. The output of 68% (from theory) (n-hexadecanesulfonyl) -ethyl-phenoxyacetic acid with so pl. 137.5138 s (ethanol).
    Example 9. The method described in Example 3 by the reaction of ethyl ester hydrochloride (Bi4It & Ti) -3-phenrxyacetic acid with the corresponding sulfonyl chlorides in the presence of pyridine and potassium carbonate is obtained:
    A. 4-C2- (2-phenyl-ethanesulfonyl-Alamino) -ethyl-phenoxy-acetic acid ethyl ester in the form of a high-yielding oil product yield 76% (from theory), and from this product 4-C2- (2-phenyl-ethanesulfonylamino) is obtained by hydrolysis -ethyl phenoxyacetic acid with so pl. 124-125 s (ethanol + + 10% water), yield 74% (from theory).
    B. 4-2t-H2- (4-chlorophenyl) ethylsulfonylamino} -ethyl J-4-phenoxyacetic acid ethyl ester as a viscous oil (unprocessed product) yield 57% (from theory), and this product by 4- hydrolysis 2-t2- (4-chlorophenyl) -ethanesulfonyl mino-ethyl-phenoxyacetic acid, m.p. 128-130 s (ethyl acetate + naphtha), yield 73% (from theory). B. Ethyl ester of 4-C2- (4-acetylbe zolsulfonylamino) ethyl 3-phenoxy acetic acid, so pl. 113.5-114 C (acetic, ether + ligroin), yield 52 (from-theory), and from this product: by hydrolysis of 4-C2- (and-acetylbenzenesul: fonylamino) -tils-phenoxyacetic acid with so pl. (acetone), 63% yield (from theory). PRI me R 10. (1-Hydroxy-2-propyl amide) - 4-C2- (benzenesulfonylamino) -ethyl} -phenoxyacetic acid. To a mixture of 5.4 g (72 mmol) of 1-oxy-2-amino-propane and 35 ml of water over 2 hours at 0-5 ° C, a solution of 6.4 g (18 mmol) of 4- f2-, (benzenesulfonylamino) -ethyl} -phene-acetyl chloride in 25 ml of abs. benzene, a precipitate slowly forms: After just overnight with suction, the filter cake is washed with a dilute solution of sodium hydroxide, then with water and dried. After recrystallization from ethyl acetate, 5.2 g (74% of the theory) of the product are obtained with m.p. 9O-91 C. When m er 11. 4- 2- (N-Methyl-benzene sulphonylamino) ethyl-phenoxyacetic acid. To a mixture of 9.1 g (25 mmol) of ethyl 4-C2-ester (benzole-naphthanol) -ethyl-phenoxyacetic acid, 50 ml of triamide hexamethylphosphoric acid and 50 ml of abs. toluene was added 0.6 g (25 mmol) of sodium hydride as a suspension of mineral oil and then stirred for 2 hours at. Then it is cooled, a mixture of 10, b (75 mmol) of methyl iodide and 10 ml of hexamethylphosphoric acid triamide is added, stirring for 15 minutes at, and then kept at 3 hours. After cooling, the hydrochloric acid is poured into ice water and the pH is adjusted. to 3 and extracted several times with on: the power of toluene. The solution, in toluene, is evaporated, the residue obtained by evaporation is subjected to chromatography with silica gel / toluene. Obtain 3.9 g (41% of theory) of ethyl 4-C2- (M-methyl-benaene-sulfonylamino) ethyl-phenoxyacetic acid, pure in the form of a colorless oil. Coefficient coefficient is t, 1.5440. In a similar manner, benzenesulfonic acid amide and ethyl are obtained from the amide. iBoro 4- (2-broth 1-methyl) -phenoxy-acetic acid ethyl 4-C 2- (benzenesulfonylamino) -ethyl 3-phenoxy-acetic acid with m.p. 6B-70 ° C. Example 12. (Benzenesulfonylamino) propyl-phenoxyacetic acid. A mixture of 14.5 g (75 mmol) of 4- (3-acetamino-propyl) -phenol, 16.8 g (122.5 mmol) of powdered potassium carbonate and 150 ml of butanone-2 is kept at boiling point for 2 hours, then 20.6 g (122.5 mmol) of bromoacetic acid ethyl ester are added to the tip of potassium iodide and kept for 6 hours at. Then it is filtered off with suction and the filtrate is evaporated in a vacuum, and in order to separate the excess bromoacetic ether, it is sprayed into a vacuum created by an oil pump. The residue obtained by evaporation is dissolved in methylene chloride and extracted with cold 0.5N sodium hydroxide solution, then with water. After drying with sodium sulfate, it is evaporated and recrystallization is carried out by cooling with the addition of ether. After recrystallization from ether, 14.9 g (71% of theory) of 4- (3-acetamino-propyl) phenoxyacetic acid ethyl ester with mp. 57-58C. . A mixture of 16.2 g (58 mmol) of ethyl ester of 4- (3-acetamine-propyl) -phenoxyacetic acid, 100 ml of ethanol and 100 ml of water, and also 32.5 g (0.58 mol) of potassium hydroxide for 16 h maintained at boiling point. Then cooled, using 6 n. hydrochloric acid is adjusted to pH 6.5 and the sand-colored precipitate is filtered off with suction. After prok-. Vani water and drying will receive 12.0 g (quantitative yield) of 4- (3-aminopropyl) -phenoxyacetic acid with so pl. , A mixture of 9.7 g (46.5 mmol) of 4- (3-aminopropyl) -phenoacetic acid, 6.9 g (50 mmol) of potassium carbonate and 100 ml of water is heated to 80 ° C and added dropwise at this temperature 8.5 g (48 mmol) of benol sulfonyl chloride. Then, at 80 ° C., it is kept for another 2 hours, after which it is cooled and using 2 n. hydrochloric acid The pH is adjusted to 2. The precipitated precipitate is sucked off, dried and recrystallized; ayYTis of acetic ester, and then ethyl ice acetic acid. Obtain 8.26 g (51% of theory) (benzenesulfonylamino) -propyl J-phenoxyacetic acid with so pl. 14b-147 with. EXAMPLE 13 2-C4- (4-Chlorobenzenesulfonylamino) -phenoxy} -2-methylpropionic acid. A mixture of 139.1 g (1 mol) of 4-nitrophenol, 1 l of butanone-2 and 2P7.3 g (1.5 mol) of powdered anhydrous potassium carbonate with stirring for 2 hours is maintained at boiling point, then adding T2 292.5 g (1.5 mol) of 2-bromo-2-m-propyl acid ethyl ester and 92 hours are maintained at boiling point. After the addition of the following 69/1 g (0.5 mol) of potassium carbonate and 97.5 g (0.5 mol) of 2-bromo-2-methylpropionic acid ethyl ester for 2 hours, the mixture is stirred at the boiling point. Then sucked off. The filtrate is evaporated in vacuo (to eliminate excess bromine, ether is connected to a high vacuum); the product obtained by evaporation is placed in ether, filtered and the ether phase is extracted several times with 1N. sodium hydroxide solution. After neutral washing and drying it is evaporated, 153 g (60% of theory) of an oily crude Product are obtained. After distillation at 155.5-156 ° C (0.05), pure ethyl ester is obtained as a yellow oil. 2- (-nitrophenoxy) -propionic acid with a yield of 46%. The refractive index nj, 1.5288, a mixture of 50.6 g (0.2 mol G of 2-methyl-2- (4-nitrophenoxy) propionic acid ethyl ester, 500 ml of ethanol and approximately 20 g of 5% palladium carbon is hydrogenated to shaking flask at room temperature and normal pressure until the required amount of hydrogen is available. Then the liquid phase is evaporated off and the quantitative yield of the crude ethyl ester 2-4-aminophenoxy -2-methylpropanol is obtained in quantitative yield. acids, t, bp 134-135C at 0.05, the ratio of the Aleni ratio is 1.5034. Pl. By diluting the crude ester with 1 g of a solution of caustic potassium in ethanol as in Example 2, crystalline 2-C4- (4-chlorobenzenesulfo-nylamino) phenoxy -2-methylpropionic acid is obtained with a mp of 146.5-147 C ( acetic ester + ligroin), 91% yield (from theory). In a similar way, the following is obtained: A. Ethyl ester (4-chlorosti roolsulfonylamino) phenoxyJ-2-methylpropionic acid from p-chloroethyryl sulfonyl chloride and 2- (4-aminophenoxy ethyl ester ) -2-methylpropionic acid, mp, (ethyl acetate), yield 87% (from theory), is obtained by hydrolysis (4-chloro but stirolsulFonilami) phenoxy-2 J-kis metilpropioyovuyu lot, m.p. 172-173s (ethyl acetate). Output 73% (from theory). B. Ethyl ester of 2- {4- 2 (1'-chlorstyrstylesulfonylamino) -ethyl j-phenoxy-2-methylpropionic acid from p-chlorostyrryl-sulfonyl chloride and (2-amino-ethyl-ethyl-phenyl) ethyl ester of J-2-methylpropionic acid, oil, 1.5625, and from this product by hydrolysis of 2- {4-C2- (1-chlorostyrene-sulfonylamino) -ethyl II-phenoxy -2-methylpropionic acid, m.p. 148-149 with (benzene), yield, 76% (from theory). AT; 2- {4- {2- 2 - (- chlorophenyl) ethanesulfonyl-amino-jr-ethyl} -phenoxy-2-methylpropionic acid ethyl ester from 2- (i-chlorophenyl) -ethane | Sulfonyl chloride and ethyl, 2-L 4- ( 2-aminoethyl) -phenoxy J-2-methylpropionic acid, a colorless oil, 77% yield (from theory), and from this product by hydrolysis of 2-4- {2-C2- (4-chlorophenyl) -ethanesulfonylamino ethyl-phenoxy-2 -methylpropionic acid, So pl. 138-139s (ethyl acetate + naphtha), yield 53% (from theory). EXAMPLE 14 A mixture of 17.92 g (0.1 mol) of 4- (2-acetaminoethyl) phenol, 17/3 g (0.125 mol) of potassium carbonate powder and 150 ml of 1gbutanol-2 is stirred in 27.9 g (0.125 mol) of 2-bromohexanoic acid ethyl ester are added at the tip of potassium iodide and kept for another 28 hours at boiling temperature. Then it is filtered off with suction and the filtrate is evaporated under vacuum. The solution is dissolved in ether; the ethereal solution is extracted with 2N hydrochloric acid, WATER, 0.5N. sodium hydroxide solution and again with water, dried over sodium sulfate and evaporated. As a result, 32.1 g (quantitative yield) of (2-acetaminoethyl) phenoxyJ-and-hexanoic acid ethyl ester are obtained in the form of a colorless oil, the refractive index is nj 1,5010. A mixture of 25.7 g (80 mmol) of ethyl ester (2-acetaminoethyl} -phenoxy-H-hexanoic acid, 150 ml of water, 150 ml of ethanol and 44.9 g (0.8 mol) of potassium hydroxide was held for 16 hours at the boiling point and then the alcohol is distilled off in vacuo. After adding 150 ml of water, the acid is acidified with hydrochloric acid to pH 4 and the precipitate formed is filtered off with suction, washed with water and dried, 12.5 g are obtained (62% of theory) 2-G4-2 -aminoethyl) -phenoxy-H-pentanecarboxylic acid with m.p. 274-276 s. I. The reaction of 2-C4- (2-aminoethyl) -phenoxy J-n-pentanecarboxylic acid with 4-chlorobenzenesulfonyl chloride in the presence of an aqueous solution of potassium carbonate as in example 1 gives 2- {4- 2- (U-chlorobenzenesulfonylamino) -ethyl - phenoxy J-m-pentanecarboxylic acid with t, mp, 138-139 (ethyl acetate, cyclohexane), yield 32%.
    权利要求:
    Claims (1)
    [1]
    The method of obtaining derivatives of .phenoxyalkylcarboxylic acid of the General formula 7 7- Щ '·' '__' 'Κι <
    } k, # k- "ED„ chO / - 0 - - e ° he 'c. c "0) where R is hydrogen or a lower alkyl radical;
    Rj - alkyl radical with 1-16 'carbon atoms, naphthyl radical, unsubstituted phenyl radical or substituted by fluorine, chlorine,. a lower alkyl, alkoxy, acetoxy group, lower alkenyl radical or lower alkenyl or alkyl radical and chlorine, in the para position a phenyl radical;
    R 3 ~ are the same or different and mean hydrogen or a lower alkyl radical, PGO-3, as well as their salts, esters and amides of acid, with the exception that the amine of the general formula where R is hydrogen or a lower alkyl radical in which the amino or oxy group is protected, * P has the indicated meanings, is reacted in any sequence with a sulfonyl chloride of the general formula
    R 4 S0 2 CI,; (ill) where I 1 has the indicated meanings; ' and with a compound of the general formula `` x-e-γ fw). · '* Where R2 and Rj have the indicated values.
    . niya; 'X - chlorine or bromine |
    Y is a group of 'COOR 4 -, in which Hydrogen or lower alkyl; a radical or an amide group in the presence of an acceptor of hydrohalic acid and, if necessary, a compound of general formula 1, in which R is hydrogen, is subjected to alkylation with lower haloalkyl in -. in the absence of sodium hydride, and the desired product is isolated in the free form either as an ester or as an acid amide.
    SIL, 1052152
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    ATA161979A|1981-12-15|
    IL56734D0|1979-05-31|
    YU42300B|1988-08-31|
    DK164545B|1992-07-13|
    HU183085B|1984-04-28|
    JPS5735910B2|1982-07-31|
    YU98186A|1986-10-31|
    DE2960222D1|1981-04-23|
    EP0004011B1|1981-04-01|
    DK164545C|1992-11-30|
    SU1097194A3|1984-06-07|
    FI790727A|1979-09-05|
    AU508419B2|1980-03-20|
    DD142334A5|1980-06-18|
    US4258058A|1981-03-24|
    PL223895A1|1981-05-22|
    CA1136158A|1982-11-23|
    FI71305B|1986-09-09|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19782809377|DE2809377A1|1978-03-04|1978-03-04|PHENOXYALKYL CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
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