DK157005B - ANALOGY PROCEDURE FOR THE PREPARATION OF 2- (4-BENZYL-PHENOXY) ALKANIC ACID DERIVATIVES - Google Patents

Description

DK 157005 B

The present invention relates to an analogous process for the preparation of 2- (4-benzylphenoxy) alkanoic acid derivatives of the general formula 5

D _ _ A

Wherein X means hydrogen or halogen, especially chlorine, R means hydrogen, alkyl of 1-6 carbon atoms optionally substituted with or contained in a piperidyl, pyridyl or theophylline group, or pivaloyloxymethyl, and A1 and A2 are the same or different and represent hydrogen or alkyl of 1-6 carbon atoms, while A1 and A2 are not both methyl when X is hydrogen or chloro and R is hydrogen; methyl or ethyl, or pharmaceutically acceptable salts thereof, characterized in that a) a phenol of the general formula X - (= VCH 2 - O 0 (II) 25 'where X is as defined above); or a corresponding alkali metal or alkaline earth metal phenolate is reacted with a haloalkanoic acid alkyl ester of the general formula A1 Hal - C - COOR-1 (III) A2

DK 157005 B

2 wherein Hal represents chlorine or bromine, R1 represents an alkyl group of 1-6 carbon atoms, and A1 and A2 have the meanings given above, or b) a phenol of formula II is reacted in the presence of at least one trihalogenated methane derivative, especially chloroform, acetone chloroform , chloral hydrate or carbon tetrachloride, and in the presence of a strong base, especially potassium or sodium hydroxide having a ketone of the formula A - ^ - CO-A2, then one present in the compound 10 by a) or b) or by alkaline the desired esterified hydrolysis carboxyl group is esterified, either directly or upon introduction of a reactive group, preferably after conversion to an acid chloride, with an alcohol of the formula ROH or, if desired, one ester group present in the produced compound is converted by transesterification ( ester exchange) with another ester group -OR wherein R has the same meaning as above or an acid compound formed is converted into a site.

The implementation of the method can e.g. occurs in the manner that 4- (4 1-chlorobenzyl) phenol is condensed in a manner known per se with the ethyl ester of 2-bromo-2-methyl-butyric acid, the condensation product being transferred by hydrolytic decomposition of the ethyl group in 2- [4- (4'-Chlorobenzyl) phenoxy] -2-methyl-butyric acid which is transferred to the acid chloride by means of thionyl chloride. This can then be accomplished by reacting with an alcohol of the formula E-OH, where E means the group which one wishes to introduce into the molecule. This group E can e.g. also be a haloalkyl group, e.g. a chloroethyl group. In this case, it is possible with a subsequent condensation reaction, e.g. with a secondary amine, later to introduce a basic group.

It is known from GB patent 860,303 that aryl-oxycarboxylic acid esters can be used to treat elevated blood cholesterol and triglyceride levels. One of the compounds known from 35 GB patent 860,303, 2- (4'-chloro-phenoxy) -isosmoric acid methyl ester, also called

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3 brat "has gained a great deal of importance in human medicine. Furthermore, from DE publication 2 356 655, published on May 22, 1974, compounds of formula I are known in which X means chlorine, A1 and A2 mean methyl, and R 5 means hydrogen, methyl or ethyl which exhibits cholesterol lowering effect.

However, it has surprisingly been found that the compounds prepared by the process of the invention have a significantly better cholesterol lowering effect than 10 "Clofibrate" and a significantly better therapeutic index (i.e. toxicity to therapeutic effect ratio) than those of DE Publication No. 2,356,655 known compounds.

The following table lists the results of animal tests conducted with a representative selection of the compounds of this invention and with known compounds of the above types. Column (1) in the first part of this table indicates the identification number of the test connection in question. Columns (2) and (3) indicate the structure of the test compound of general formula I

A1 A1 25 Χ ~ (· -ζ - 0 - C - C00R (Ia) I2 3 0 where column (2) indicates a symbol for the part of the molecule that is in the formula (la) on the left side The symbols used have the following meaning: b = p-benzylphenyl 35 c = p- (p'-chlorobenzyl) -phenyl Column (3) indicates the substructure which is in the formula (la) on the right side of the dotted vertical line. The abbreviations "Met" and "One" respectively

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4 methyl and ethyl. The numbers in columns (4) and (5) indicate the amount of oral compound administered to the test animal in mg / kg body weight. Column (4) indicates the acute toxicity LD50 for mice. Column (5) indicates the daily dose 5 in rats lowering serum cholesterol levels by 25% (ED 25). In column (6) the therapeutic index is calculated from the numerical values in the two preceding columns, ie. the quotient LD50 / ED25.

To determine the values in column (5), 10 groups of 8-10 normally fed male rats are administered daily once every 10 days for the test compound suspended in gum arabic. The determination of the total cholesterol content is made by Richterich (Klinische Chemie, S. Karger Basel / New York 1965, page 232). Based on the percentage changes in the group average values compared to control groups administered only gum arabic, are recorded on semi-logarithmic paper in dose-effect curve, where the ED25 value is read.

5

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Table, Part 1 (1) (2) (3) (4) (5) (6)

No. LD 50 ED25 Index 6274 c 0CH2C00H 2700 50 54 13.74 c 0CH2C00Et 3000 25 120 1700 29 59

22974 c AND (Met) COOH

,. 2500 33 76 2774 c 0CH (Met) C00Et,, »3000 54> 56 17474 c 0CH (Bfc) C00Et 24874 c 0CH (Met) C00 - Met 2700 28 96 26074 c 0C (Met) 2C00CH2 - ^^> · I1C1> 3000 14> 214 0 23174 c 0C (Met) 2C00 (CH2) 2 ~ N—- Met »3000 20> 150 1 In the second part of the table, the identification number of the seal compound is given, the meaning of the symbols in formula I, LD50 / ED50 and LD50 / ED50.

Met 15174 c OCH2COOCH2OCO-C (Met) »3000 25> 120 28274 c 0C (Met) (Et) C00CH20C0-C (Met) 3» 3000 21> 143 27874 c 0CH2C0NH2 ^ 3000 i 25 »120 27774 c 0C (Met) 2C0NH2 »3000 19> 158 6

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In addition to the potent cholesterol-lowering effect shown in the above table, the compounds of the general formula I herein have a markedly lowering effect on the triglyceride content of the blood and in this respect outperforms several times the effect of clofibrate. Thus, e.g. clofibrate a hypertriglyceridemia induced in rats by fructose addition to the drinking water at a dosage of 85 mg / kg per oz by 25%, while the same effect is obtained with the following compounds of formula I at the dosages indicated in mg / kg per oz in 10 brackets : No. 8674 (15) (known from DE Publication 2,356,655), no. 26074 (13) and no. 24074 (5.6).

For pharmaceutical purposes, the compounds of formula I can be used either as such or in the form of salts. When the compounds contain a free carboxyl group, salt formation can be made with physiologically harmless bases such as sodium, potassium, aluminum, ammonia or amines such as ethanolamine, dimethylamine, morpholine and the like. When the compounds contain a basic group, salt formation can be made with inorganic or organic acids such as hydrochloric, tartaric, malic and similar acids. The transfer of the compounds or their salts into drugs can be carried out in a manner known per se and using the usual adjuvants. The compounds may be used in the form of preparations, in particular capsules, tablets or drags, containing an active substance content of approx. 5-300 mg and in the form of emulsions, solutions and the like. For therapeutic purposes, dosages of between ca. 0.02 and 1.5 g per day.

Example Example 41-Chloro-4-ethoxycarbonylmethoxy-diphenylmethane ("Sad 20673") 9.0 g (0.18 mol) of sodium hydride in the form of a 55-60% emulsion in mineral oil is added to 40 ml of dimethylformamide 35 (DMF The mixture is slowly added to a solution of 39.3 g (0.18 mol) of 41-chloro-4-hydroxy-diphenylmethane in 90 ml of DMF.

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p

The resulting mixture is stirred for 15 minutes at 70 ° C, then a solution of 30.0 g (0.18 mol) of ethyl bromoacetate in 90 ml of DMF is added and stirred for 7 hours at 130 ° C.

Then the solvent is removed in a Büchi rotary evaporator.

The residue is treated with water and then extracted thoroughly with dichloromethane. The extract is dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on 20 g of Al2 O3, eluted with 200 ml of benzene and then distilled. 23.0 g of pure product is obtained with kp.

156-160 ° C (0.03 mm).

Analysis for C 17 H 17 ClO 3 (304.8):

Calculated C% = 66.98 H% = 5.62 Cl% = 11.64

Found C% 66.61 H% = 5.80 Cl% = 11.85 Example 2 p- (p1-Chlorobenzyl) -phenoxyacetic acid (N-methyl-4-piperidinyl) ester hydrochloride

A solution of 6.0 g (0.02 mole) of p- (p'-chlorobenzyl) phenoxyacetyl chloride in 40 ml of anhydrous xylene is added analogously to the process described in Example 1, a solution of 2.30 g (0.02 mole) 4-hydroxy-N-methylpiperidine in 20 ml of anhydrous pyridine, and the mixture is stirred at reflux for 24 hours. The mixture is worked up as described in Example 1 and by filtration of the benzene solution through 10 g of Al 2 O 3 there is obtained 8.5 g of brown resin which, after dissolving in ether and adding ethereal hydrochloric acid, is solidified by rubbing. The crude hydrochloride (5.8 g) is dissolved in acetone and boiled for 3 minutes with activated charcoal. After recrystallization from a mixture of acetone and ether, 3.5 g of hydrochloride 30, m.p. 170-171 ° C.

Analysis for C 21 H 24 ClNO 3 · HCl (410.3):

Calculated C% »61.47 H% = 6.14 N% - 3.41 Cl% = 17.28

Found C% = 61.36 H% = 6.14 N% = 3.43 Cl% = 17.54 35

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Example 3 3--p- (p1-Chlorobenzyl) -phenoxy-acetoxymethyl-1-pyridine A solution of 6.0 g (0.02 mol) of p- (p'-chlorobenzyl) -phenoxy-acetyl chloride in 50 ml of anhydrous benzene is added. a solution of 2.18 g (0.02 mol) of 3-hydroxymethylpyridine in 20 ml of anhydrous pyridine. The mixture is pressed for 45 minutes at room temperature and then for 6.5 hours under reflux. The mixture is worked up as described in the above examples, and the resulting residue is recrystallized from a mixture of ether and petroleum ether to give 4.0 g of product in the form of white shiny crystals, m.p. 77-78 ° C.

Analysis for C 21 H 18 ClNO 3 (367.5):

Calculated C% = 68.57 H% = 4.90 N% = 3.81 Cl%, 9.66 Found C% = 68.31 H% = 4.52 N% = 3.41 Cl% = 10, 24

Example 4 7 - Γβ- (p'-Chlorobenzyl) -phenoxy-acetoxyethyl-1-theophylline 20 A solution of 6.0 g (0.02 mol) of p- (p1-chlorobenzyl) phenoxyacetyl chloride in 50 ml of anhydrous xylene is added. a solution of 4.48 g (0.02 mol) of 7- (3-hydroxyethyl) theophylline in 25 ml of anhydrous pyridine. The mixture is heated for 20 hours under stirring and reflux and the residue is worked up as described in the above examples. Crystallization of a mixture of dichloromethane and methanol gives 6.5 g of product in the form of shiny white needles, m.p. 134-135eC.

Analysis for C24H23CIN4O5 (482.9):

Calculated C% = 59.69 H% = 4.80 N% = 11.60 Cl% = 7.34 Found C% = 59.35 H% = 4.97 N% = 11.51 Cl% = 7, 84

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Example 5 2-Methyl-2- [4- (4-chloro-benzyl) -phenoxy] -I-simaric acid ethyl ester ("Scrd 24774") C1-6000 C2% * - · CUH.- * 5 87, 0 g (0.4 mole) of 4-chloro-41-hydroxy-diphenylmethane 10 is heated together with 27.0 g (0.2 mole) of anhydrous potassium carbonate in 350 ml of anhydrous xylene for 30 minutes to reflux, then a solution of 83.5 g (0.4 mol) of 2-bromo-2-ethyl-2-methylacetic acid ethyl ester in 50 ml of anhydrous xylene The mixture is kept for 24 hours under vigorous stirring at reflux temperature, after filtration of separated potassium bromide and evaporation. of the solvent in a Büchi rotary evaporator, the residue is taken up in ether and extracted with 1N sodium hydroxide solution, The ether extract is washed with water, dried over HgSO 4 and evaporated to give Column of 200 g of basic Al 2 O 3 After evaporation of the solvent and destination under reduced pressure, 34.7 g of pure product are obtained with bp 200-204 ° C / 0.02-0.1 mm Hg .

Analysis for C 20 H 23 CLO 3 (346.8): Calculated C% = 69.25 H% = 6.68 0% = 13.84 Cl% = 10.22

Found C% = 69.16 H% = 6.66 0% = 13.84 Cl% = 10.27

The analogue product without chlorine substituent has a boiling point of 154-162 ° C / 0.03 mm Hg ("Sgd 32574").

Example 6 2-Methyl-2- [4- (41-chlorobenzyl) -nhenoxyl-valeric acid-ethyl ester ("Sgd 33 474") Cl - / - - CH2 - / - - - - - C00 - 02H5 - · '\ - 7 CjErj

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11.7 g (0.04 mole) of 4-chloro-41-hydroxy-diphenylmethane and 2.76 g (0.02 mole) of K2CC> 3 are heated to reflux for 30 minutes in 40 ml of anhydrous mesitylene (1.3, 5-trimethylbenzene), then a solution of 8.9 g (0.04 mole) of 2-5 bromo-2-methyl-2-propylacetic acid ethyl ester in 10 ml of anhydrous mesitylene is added and heated under reflux for a further 24 hours. By working up as described in the above examples, 4.0 g of product is obtained in the form of an oil with b.p. 177-179 ° C / 0.01 mm Hg.

Analysis for C 21 H 25 ClO 3 (360.8):

Calculated C% = 69.89 H% = 6.98 Cl% = 9.83

Found C% = 70.00 H% = 7.23 Cl% = 9.37

Example 7 2-Methyl-2-Γ 4- (41-chlorobenzyl) phenoxy1-butyric acid (3-pyridylmethyl) ester hydrochloride ("Sqd 33374") / = \ S = \ CH3 / * - = zr \ »C'-0'c% - <_> ·” - · <_> “

à- D

Dissolve 78 g (0.232 mol) of 2-methyl-2- [4- (4'-chlorobenzyl) -phenoxy-butoxy] chloride in 300 ml of anhydrous benzene and 200 ml of anhydrous pyridine, and a solution of 27 g ( 0.247 mol) of 3-hydroxy-methylpyridine in 20 ml of anhydrous benzene. The mixture is heated for 5 hours with stirring to reflux, after which the mixture is evaporated in a Büchi rotary evaporator. The brown residue is taken up in ether, the solution is extracted with water, compressed over MgSO 4 and evaporated again under reduced pressure. The residue is dissolved in cyclohexane and filtered through a syringe of 250 g of basic Al 2 O 3. The light brown oil obtained by distillation of the cyclohexane is dissolved in ether and ethereal hydrochloric acid is added. After recrystallization of the crystalline precipitate of a mixture

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12 of dichloromethane and ether were obtained 40.0 g of hydrochloride in the form of white shiny crystals, m.p. 111-114eC.

Analysis for C24H24CINO3 · HCl (446.3):

Calculated C% = 64.58 H% = 5.65 N% = 3.14 0% = 10.75 Cl% = 15.89 Found C% = 64.95 H% = 5.65 N% = 2, 98% = 10.46 Cl% = 16.00

The 2-methyl-2- [4- (4'-chlorobenzyl) -phenoxy] -butyryl chloride used as the starting material can be prepared by saponifying the 10 ethyl ether of alcoholic potassium hydroxide solution prepared as product, and then transferring the resulting free acid to the acid chloride with thionyl chloride.

Example 8 2-Methyl-2- (~ 4- (41-chlorobenzyl) -ohenoxyl-butyric acid-7-theophylline-ethyl-ester) ester Sqd 33274 ").

CH O

29 g (0.086 mole) of 2-methyl- [4- (4'-chlorobenzyl) phenoxy] butyryl chloride is dissolved in 200 ml of anhydrous xylene and 50 ml of anhydrous pyridine are added and a solution of 19.35 g (0.086 mol) of 7- (2-hydroxyethyl) theophylline in 50 ml of anhydrous xylene and 50 ml of anhydrous pyridine is added. The mixture is heated for 24 hours. The mixture is evaporated to reflux and the mixture is evaporated in a Büchi rotary evaporator. The residue is extracted with dichloromethane and the organic phase is washed with water, dried over MgSO 4 and evaporated under reduced pressure.

Recrystallization of the resulting solid residue from methanol afforded 28.5 g of product, m.p. 105-106 ° C.

Analysis for C27H29CIN4O5 (525.0):

Calculated C% = 61.77 H% = 5.57 N% = 10.67 0% = 15.24 Cl% = 6.75

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Found C% = 61.83 H% = 5.59 N% = 10.57 0% = 15.15 Cl% = 6.94

Example 9 4- (41-Chlorobenzyl) -phenoxyacetic acid (pivalovloxy-5-yl) -ester cl - <^> - ch2 '<^^ -0- (¾-coo-ch2-ooû-c (ch3))

A solution of 9.3 g (0.03 mole) of 4- (4'-chlorobenzyl) phenoxyacetic acid in 50 ml of dimethylformamide is added 6.0 g (0.06 mole) of triethylamine, then the mixture is stirred for 30 minutes at room temperature and after addition of 9.0 g (0.06 mol) of chloromethyl pivalate is heated in an oil bath for 6 hours to 85-90 ° C. The residue obtained by evaporation at reduced pressure in a Büchi rotary evaporator is washed with 20 water and extracted with ether. The ether solution is washed again with water, dried over anhydrous magnesium sulfate and evaporated in a Büchi rotary evaporator to give an oil which immediately sprays. Upon recrystallization of a mixture of ether and n-hexane, 9.5 g of product in the form of white crystals 25, m.p. 54-55 ° C.

Analysis for C 21 H 23 ClO 5 (390.8):

Calculated C% = 64.53 H% = 5.93 Cl% = 9.07

Found C% = 64.57 H% = 5.88 Cl% = 9.67 Example 10 α- [4- (4 L-ChlorobenzylH-phenoxy) -propionic acid-pivaloyl-oxylmethyl) ester 35 - / \ -O-CH-C00-CHo-OCCO-C (CH), \ _ / 2 œ3 33

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A solution of 43.5 g (0.15 mol) of α- [p- (p'-chlorobenzyl) phenoxy] propionic acid in 250 ml of dimethylformamide is added to 30 g (0.3 mol) of triethylamine and after 1/2 hourly stirring at room temperature 45.0 g (0.3 mol) of chloromethyl pivalate. The reaction mixture is heated for 6 hours to 90 ° C, after which it is worked up analogously to the procedure described in Example 1, whereby 50.0 g of white needles are obtained, which upon recrystallization of n-hexane gives white needles with m.p. 65eC.

Analysis for C 22 H 25 ClO 5 (404.8): Calculated C% = 65.26 H% = 6.22 Cl% = 8.76

Found C% = 65.27 H% = 6.23 Cl% = 8.29

Example 11 α- [4- (41-Chlorobenzyl] -phenoxyl-iso-butyric acid-pivalovyl-15-oxymethyl) ester

Cl- /]> -0S2- / \ -O- ^ COO-CHg-OCO-CtCH,), \ _ / Λ_y ch ^ 20

To a solution of 27.4 g (0.09 mol) of p-fp'-chlorobenzyl) -phenoxy-isosmoric acid in 150 ml of dimethylformamide is added 18.0 g (0.18 mol) of triethylamine and after 1/2 hour stirring 25 at at room temperature, 27.0 g (0.18 mol) of chloromethyl pivalate are added. After heating for 6 hours to 90 ° C and working up analogous to the procedure described in the above examples, a liquid which, by destination, gives 26.0 g of pale yellow liquid product, b.p. 204-209 ° C / 0.02 mm Hg.

Analysis for C 23 H 27 ClO 5 (418.9):

Calculated C%, 65.94 H% = 6.50 Cl% = 8.46

Found C% = 66.34 H% = 6.56 Cl% = 8.42

Analogously and using α- [p- (p'-chloro-benzyl) -phenoxy] -α-methyl-butyric acid, α- [4- (4'-chlorobenzyl) -3-phenoxy] -α-methyl butyric acid (pivaloyloxymethyl) ester with b.p. 213-214 ° C / 0.01 mm Hg.

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Example 12 2-Methyl-2- [4- (41-chlorobenzyl) -phenoxyl-butyric acid

A \ A \ î1 * 3 K0H

5 01 \ / Œ2 \ / ° H + C = 0 + CHC13 --- ► ~ “έ2Η5 -► ci-Q-ch2- (Vo-c-cooh

~ CH

In a 1.5-liter flask equipped with a cooler, stirrer, thermometer and drip funnel, dissolve 20.8 g (0.095 mol) of 4'-chloro-4-hydroxy-diphenylmethane in 400 g (5.55 mol) of ethyl -15 methyl ketone. To the clear, colorless solution is added 61.5 g (1.1 moles) of potassium hydroxide and stirred for 10 minutes. To the suspension, which has become red, is added dropwise 35.0 g (0.29 mol) of chloroform dropwise.

After further stirring for a few minutes, the reaction mixture is heated to 50 ° C and this temperature is kept under continued stirring for 4 hours.

The resulting yellow suspension is evaporated in a Büchi rotary evaporator under reduced pressure (water jet pump) to dryness. The solution obtained after dissolving the 25 yellow residue in 250 ml of water is stirred for 10 minutes after the addition of 1 g of activated charcoal, filtered through diatomaceous earth (Deca-lit), acidified with 2N hydrochloric acid and extracted twice with 250 ml each time. ml of ether. The ether solution is extracted twice with 200 ml of sodium carbonate solution (10% 1 s) each time. The 30 combined basic extracts are acidified with 2N hydrochloric acid and extracted with 250 ml of ether twice. The ether extract is dried over magnesium sulfate, filtered and completely evaporated in a Büchi rotary evaporator (bath temperature 40 ° C) to give 25 g of crude product in the form of a dark brown viscous oil.

By dissolving the whole crude product in 10 ml of n-hexane and

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16 chromatographic purification on 75 g of silica gel (WOELM, activity III / 30 mm; column diameter 20 mm) eluting with 4 times 250 ml of n-hexane, 14 g of pure product was obtained as a crude oil (yield: 46.6%).

Analysis for C18H19C103 (M = 318.8)

Calculated C% = 67.82 H% = 6.00 0% = 15.06 Cl% = 11.12

Found C% = 67.80 H% = 5.99 0% = 15.17 Cl% = 11.41

The structure of the product produced is confirmed by 10 similar assays.

Example 13 dl-2-Methyl-2- [4- (41-chlorobenzyl) -phenoxy] -butyric acid ethyl ester

CH CH

c1-Q-ch2- (^ -o-c-cooh 2 ^ Cl - (^) - CH2- (^ -O-C-COCl - C2H5 ~ C2H5

20 CH

C ~ H, OH Y 3 ClO f -CHCH2- ^ Vo-C-COOC2H5 ~ C2H5 50 g (0.159 mol) of the Example 2 prepared 2-methyl-2- [4- ( Dissolve 4'-chlorobenzylphenoxy] -butyric acid in 140 ml of anhydrous benzene, add 15 drops of pyridine to the solution, and dropwise 22.8 ml (0.319 mol) of thionyl chloride to the yellow solution over 5 minutes.

It is then stirred for 30 minutes at 40 ° C and then further 90 minutes at 60 ° C, after which the reaction mixture is completely evaporated under reduced pressure.

To the oily residue is added dropwise 100 ml of absolute ethanol, and the resulting solution is boiled for 2 hours and then evaporated under reduced pressure to dryness.

35 In this way, 53 g of a black oil is obtained. This is read in 15 ml of n-hexane and filtered through a column with 120 g of basic

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17 alumina. Elution with n-hexane and evaporation afforded 48.6 g of gui oil, of which 43.1 g of product was obtained in the form of a light gui oil with a purity of 96-97% and a boiling point of 170-173 ° C. at 0.001 mbar. Yield: 78.9% 5 of theory.

The structure of the product produced is confirmed by similar analyzes.

EXAMPLE 14 dl-2-Methyl-f 4- (41-chlorobenzyl-phenoxy] -butyric acid 3--pyridylmethyl) ester hydrochloride O - ch3 ho-ch2-Q ch3 -CHO- \ YOC-C00CoHc -► Cl · ^ Vo-C-COO-CH ,, 2W è * 2 5 ^ ^ έ2Η5Λ2

+ C2H5OH

2040 g (3 moles) of the ethyl ester prepared in Example 20 are heated together with 327 g (3 moles) of 3-hydroxymethylpyridine in 2.7 liters of anhydrous toluene with stirring until 0.3 liters of toluene is distilled off. After cooling to room temperature, a warm solution of 1.2 g of sodium in 32.7 g (0.3 mole) of 3-hydroxymethylpyridine is added to the mixture and the reaction mixture is allowed to stand for 1/2 hour. Then heat slowly for approx. 3 hours to approx. 127 ° C, thereby distilling off toluene and forming ethanol. To the cooled reaction mixture is added 750 ml of ether and extracted with 7x 500 ml of water. The ether phase is dried over sodium sulfate and completely evaporated in a rotary evaporator to give 1201 g of a red oil. This is dissolved in 650 ml of cyclohexane and treated with 2x 500 g of basic alumina, Activity I, and 20 g of activated carbon "Norit", filtered and evaporated again. The 1044 g of oil thus obtained was obtained

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Dissolve 18 orange in 4 liters of ether and, under intense stirring, slowly add 550 ml of a saturated ethereal hydrogen chloride solution and stir for an additional hour.

After filtration, washing with one liter of ether and drying 5 at 40 ° C, 933 g of crude product is obtained. For purification, this is readily dissolved in 750 ml of methylene chloride which is filtered, one liter of ether is added and after initial crystallization another 4 liters of ether are added. After longer standing, filtering, washing with one liter of ether and drying at 35 ° C, 875 g of 10 crystals are obtained which are dissolved in 4.5 parts of boiling vinegar ester and treated with 10 g of activated charcoal. After recrystallization, 774 g of pure product were obtained, mp 113-115 ° C.

Analysis for C24H24CINO3 (M = 446.3)

Calculated C% = 64.58 H% = 5.64 N% = 3.14 0% = 10.75 Cl% = 15.89 Found C% = 63.68 H% - 5.56 N% = 3, 32% = 10.62 Cl% = 16.23

Example 15 2-Methyl-2- [4- (4-chloro-benzyl) -phenoxy] -butyric acid ethyl ester 20

O CH _ _ CH

-CH2 - / ^ - 0H + c = 0 + CBr4 ^ ÎL> .ci - <^) - ch2 - ^^ - o-c-cooh W έ2Η5 έ2Η5 _ CH, -CH2- / Vo-C-COOC2H5 ~ C2H5

A mixture of 38.6 g (0.17 mole) of 4'-chloro-4-hydroxy-diphenylmethane, 308 g (4.3 mole) of ethyl methyl ketone and 69 g (1.72 mole) of sodium hydroxide is heated for 45 minutes under intense pressure. to reflux, after cooling to 75 ° C over 35 minutes, 100 g (0.3 mole) of carbon tetrabromide are added portionwise. The reaction mixture 35 is thereby maintained on the basis of the reaction heat at the boiling point.

It is then heated for 5 hours to reflux. then

DK 157005 B

19, 500 ml of water is added, adjusted to acidic reaction by the addition of concentrated hydrochloric acid and extracted with chloroform. The organic phase is shaken with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 40 g of residue. This is taken up in 250 ml of 2N sodium carbonate solution and extracted with ether.

The aqueous-alkaline phase after acidification with concentrated hydrochloric acid gives 34 g of brownish product. This is dissolved in a mixture of 160 ml of ethanol and 100 ml of benzene and is kept after refluxing 4 ml of concentrated sulfuric acid at reflux temperature for 8 hours. In usual work-up, a brownish oil is filtered through a column of 50 g of basic alumina and, after destination, gives 15 g of 2-methyl-2- [4- (4-chloro-benzyl) -phenoxy] -butyric acid ethyl ester as a colorless solution oil with a boiling point of 203-204 ° C at 0.03 mbar. The thin-layer chromatogram is identical to the thin-layer chromatogram of the conventional manufactured product (condensation of phenol with halogenated carboxylic acid ester) and also the IR spectra coincide.

Analysis for C 20 H 23 ClO 3 (M = 346.8)

Calculated C% = 69.25 H% = 6.68 Cl% = 10.22

Found C% = 69.40 H% = 6.80 Cl% = 10.55

Claims (1)

35 In A2 where Hal means chlorine or bromine, r! means an alkyl group DK 157005 B having 1-6 carbon atoms and A1 and A2 having the meanings given above, or b) reacting a phenol of formula II in the presence of at least trihalogenated methane derivative, especially chloroform, acetone chloroform, chloral hydrate or carbon tetrachloride, and in the presence of a strong base, especially potassium or sodium hydroxide having a ketone of the formula A 1 -CO-A 2, after which one present in the compound prepared by a) or b) or by basic hydrolysis released carboxy group if desired is esterified, either directly or after entrapping a reactive group, preferably after conversion to an acid chloride, with an alcohol of the formula ROH, or, if desired, one ester group present in the compound obtained by conversion (ester exchange) with another ester group -OR, wherein R has the same meaning as above or an acid compound formed is converted into a site.