CH618696A5 - Process for the preparation of phenoxyacetic acid derivatives - Google Patents

Abstract

The compounds correspond to the general formula: <IMAGE> in which A represents oxygen or sulphur, X1 and X2 represent hydrogen, a methyl or a halogen but not two halogens ortho with respect to each other, and Z1/Z2 represent oxygen,, H/OH or NOH. They are prepared by reaction of a 2-furyl or 2-thienyl 4-hydroxyphenyl ketone in alkaline medium with a 2-haloacetic acid or an alkyl ester of this acid and, in the latter case, saponification of the ester thus formed. Before saponification, the ketone functional group can be reduced to the hydroxyl group with aluminium isopropoxide; a corresponding reduction can be carried out on the acids themselves (I), for example using sodium borohydride. It is also possible to convert the ketone functional group to an oxime, by reaction with hydroxylamine. The compounds I and their salts have specific uricosuric properties and can be used especially in the treatment of gout.

Description

The present invention relates to processes for the preparation of 4-keto-phenoxyacetic acids, their reduced derivatives and their oximes.

These compounds correspond to the following general formula:

och2-cooh

(I)

3

618,696

in which A represents O or S,

Zi and Z2 represent either one H and the other OH, or considered together the oxygen atom or the NOH group, and Xi and X2 which are identical or different each represent H, a methyl group or a halogen atom with provided that the benzene nucleus is never substituted by 2 halogens in ortho, one compared to the other.

Certain dihalogenated compounds of this type have been described in Swiss Patent No. 530,976; they are uricosuric agents, but above all powerful diuretic agents. However, in the treatment of certain diseases, including gout, it is necessary to administer exclusively uricosuric drugs, an associated diuretic effect being on the contrary troublesome. In addition, it is known that many commonly used diuretics have a hyperuricemic effect, which requires the simultaneous administration of uricosurics in the treatment of certain cardiovascular diseases and the compounds of formula I are of definite interest in this therapeutic field.

The ketonic acids of formula I are prepared by condensation in an alkaline medium of a phenol of formula:

x2

in which A, Xi and X2 have the same meanings as above,

with a compound of formula XCH2COOR (III), in which X represents a halogen atom and R represents a hydrogen atom or an alkyl group. The compound thus obtained is saponified in the case of an ester (R = alkyl) and, where appropriate, a chemical reduction of the ketone function is carried out in order to obtain the corresponding alcohol, or the reaction is carried out with hydroxylamine to obtain oxime.

The alcohols of formula I (Zi = H and Z2 = OH) are prepared, according to the invention, by chemical reduction of the ketones of formula I in the form of their alkaline salts, for example in alcoholic solution by the action of sodium borohydride, or alternatively in the form of their esters in solution in isopro-panol with aluminum isopropylate. The reduction provides the two optical isomers in equal amounts.

The oximes of formula I (ZjZ2 = NOH) are advantageously prepared by the action of hydroxylamine hydrochloride on the ketones in solution in pyridine. They are generally obtained in the form of a mixture of their two stereoisomers. The relative proportions of these two isomers of the carbimino group can be determined, for example, on the nuclear magnetic resonance spectra.

The salts of the acids of formula I are prepared by action on the acid in solution, for example in an alcohol, or a ketone, of an alkaline hydroxyl or of a pharmaceutically acceptable amine.

The following examples illustrate the invention. The mentioned compounds were the subject of an analytical study (elementary analysis, potentiographic assays, I.R. and R.M.N. spectra) and they are characterized by their melting points, determined on a Köfler bench.

Example 1

2,6-dimethyl (2-thoyl) -4 phenoxyacetic acid A) (2-thienyl) (3,5-dimethyl-4-methoxy phenyl) ketone

In a solution of 60 g of 2,6-dimethyl anisole and 62.7 g of 2-thiophene carboxylic acid chloride in 250 ml of anhydrous methylene chloride, 58.5 g of chloride are introduced in 30 minutes maintaining the temperature around 10 ° C. The reaction medium is then brought 2 h 30 to the reflux temperature of the solvent, then poured onto 1 kg of crushed ice and 150 ml of concentrated hydrochloric acid. The organic phase is decanted, the aqueous phase is extracted with methylene chloride and the organic phases are washed with an aqueous solution of sodium hydroxide, then with water. After drying and evaporation of the solvent, 110 g of oil are isolated, which is distilled under reduced pressure to give 89 g of ketone E14 mm = 225 ° C.

B) (2-Thienyl) (3,5-dimethyl-4-hydroxyphenyl) ketone A mixture of 20 g of the ketone obtained according to (A) and 46 g of pyridine hydrochloride is brought to 180 ° C. for 6 hours, then poured on ice water. The mixture is then extracted into ethyl ether and then into an aqueous solution of sodium hydroxide. After acidification of this solution, the phenol is extracted into ethyl ether, the solvent evaporated and the residual oil distilled to give 17 g of pure phenol. Eo.is mm = 185 ° C - F = 50 ° C.

C) 2,6-Dimethyl (2-thienyl) -4 ethyl phenoxyacetate A solution is kept at 60 ° C. for 3 hours in 150 ml of dimethylformamide of 10 g of the phenol obtained according to (B), 3 g of hydroxide potassium and 9 g ethyl bromoacetate. Filtered, the solvent evaporated, the residue dissolved for example in ethyl ether, from which the impurities are extracted in a basic aqueous solution. After concentration of the solvent, 11.2 g of ester are obtained, which melts at 89 ° C.

D) 2,6-Dimethyl (2-thenoyl) -4 phenoxyacetic acid 11 g of the ester obtained according to (C) are dissolved in 150 ml of aqueous ethanol (50/50) containing 2.7 g of hydroxide sodium; the solution is kept for 3 hours at 95 ° C., the ethanol evaporated under reduced pressure and the aqueous phase acidified; 9.4 g of acid precipitate - F = 115 ° C.

Example 2

2,3-dimethyl (2-thenoyl) -4 phenoxyacetic acid

A) (2-Thienyl) (2,3-dimethyl-4-methoxyphenyl) ketone This compound is prepared with 86% yield by applying the procedure described in Example 1 (A) with 2-thiophene acid chloride carboxylic acid and 2,3 dimethyl anisole.

B) (2-Thienyl) (2,3-dimethyl-4-hydroxyphenyl) ketone 123 g of the above ether are dissolved in 1300 ml of benzene and introduced into the medium in 1 hour 30 minutes, 133 g of aluminum chloride; the mixture is then kept for 5 hours at its reflux temperature and then poured onto ice / hydrochloric acid. The phenol is extracted into ether and purified by dissolution in an aqueous solution of sodium hydroxide from which it precipitates by acidification. 67 g of the product melting at 144 ° C. are then obtained.

C) 2,3-Dimethyl (2-thenoyl) -4 ethyl phenoxyacetate 23.2 g are introduced into a solution of sodium ethylate, prepared by the action of 2.3 g of sodium on 200 ml of ethanol of phenol, 14.9 g of sodium iodide and 13.5 g of ethyl chloroacetate. Bring to reflux temperature 8 hours, filter the hot solution and evaporate the solvent, the unreacted phenol is removed from the residue by extraction in an aqueous solution of sodium hydroxide; 22.15 g of pure ester are thus isolated, after drying, in the form of an oil.

D) 2,3-dimethyl (2-thenoyl) -4 phenoxyacetic acid This compound is obtained by hydrolysis of its ethyl ester s

10

15

20

25

30

35

40

45

50

55

60

65

618,696

4

in aqueous ethanol, in the presence of potassium hydroxide. - After recrystallization from benzene or 1,2-dichloroethane, the pure acid melts at 134 ° C.

EXAMPLE 3 2,3-Dimethyl-2-thienyl-4-hydroxy-methyl-4-phenoxyacetic acid A solution is poured into 5 ml of a 0.2N solution of sodium hydroxide containing 0.8 g of sodium borohydride 8.15 g of 2,3-dimethyl (2-thenoyl) -4 phenoxyacetic acid and 2.1 g of sodium hydroxide in 75 ml of water. After 12 hours of stirring at room temperature, the solution is acidified by addition of acetic acid, then hydrochloric acid. The precipitate is isolated, then recrystallized from an acetone / water mixture (50/50). 7 g of acid are thus obtained which melts at 154 ° C.

Example 4

Dibromo-2,6 (furoyl-2) -4 phenoxyacetic acid A) (Furyl-2) (3,5-dibromo-4-hydroxyphenyl) ketone Is introduced into a solution of 28 g of sodium acetate and 60 ml methanol, 19 g of (furyl-2) (4-hydroxyphenyl) ketone (F = 164 ° C) prepared according to the procedure described in Example 1 (A) and (B), then drop by drop , 11 ml of bromine dissolved in 14 ml of acetic acid; after 2 hours of stirring at room temperature, the mixture is poured into 3 volumes of water and the precipitate which has appeared is isolated. After recrystallization from dichloroethane, 22 g of dibrominated phenol, melting at 164 ° C., are obtained.

B) 2,6-Dibromo (2-furoyl) -4 ethyl phenoxyacetate 300 ml of methyl ethyl-

ketone containing 21 g of the phenol previously obtained, 15 g of potassium carbonate and 18 g of ethyl bromoacetate. After hot filtration, the solvent is evaporated and the solid is recrystallized from ethanol. 21 g of ester are thus obtained, which melts at 114 ° C.

C) Dibromo-2,6 (furoyl-2) -4 phenoxyacetic acid This compound is obtained by hydrolysis of its ester in aqueous ethanol (50/50) in the presence of potassium carbonate with 90% yield. It melts at 167 ° C.

EXAMPLE 5 2,6-Dibromo-2-furyl-4-hydroxy-methyl-4-phenoxy-acetic acid

A) Dibromo-2,6 (furyl-2-hydroxymethyl-

4 isopropyl phenoxyacetate 10 g of 2,6-dibromo (2-furoyl) -4 ethyl phenoxyacetate and 9.8 g of aluminum isopropylate are dissolved in 300 ml of isopropanol and the mixture is heated for 20 hours. 82 ° C by distilling acetone as it is formed. The solvent is then evaporated and poured into ice water. The precipitate formed is removed, and the final product is extracted into ethyl ether. After drying, the solvent is removed and the precipitate appeared recrystallized from isopropyl ether. 5.5 g of ester are thus obtained, which melts at 119 ° C.

B) Dibromo-2,6 (furyl-2) -hydroxy- acid

4-methylphenoxyacetic acid This acid is obtained by hydrolysis of the isopropyl ester with potassium carbonate in aqueous ethanol. H bottom at 136 ° C.

Example 6 2,6-Dimethyl (2-thienyl) -hydroxy-iminomethyl-4 phenoxyacetic acid 4 g of 2,6-dimethyl (2-thoyl-2) phenoxyacetic acid and 4 g of hydroxylamine hydrochloride are dissolved in 30 g. ml of pyridine and brought to reflux for 3 hours. The mixture is then poured into an aqueous solution N of hydrochloric acid and the oxime is extracted into ethyl ether. The solid remaining, after evaporation of the solvent, is a mixture of the 2 isomers of the oxime which melts at 152 ° C.

Example 7

2,6-Diiodo acid (2-thenoyl) -4 phenoxyacetic acid

A) (3,5-Diiodo-4-hydroxyphenyl) (2-thienyl) ketone and (3-iodo-4-hydroxyphenyl) (2-thienyl) ketone. 76.2 g of iodine and 104 g are slowly introduced into a solution of 50 g of (4-hydroxyphenyl) (2-thienyl) ketone, in 400 ml of 3% aqueous sodium hydroxide solution 'potassium iodide in solution in 400 ml of water. After 12 hours of stirring, the precipitate is removed, then a 5% aqueous solution of sodium bisulfite is introduced until acid pH. The precipitate which appears is isolated. It contains mono and diiodinated phenols which are separated thanks to their differences in solubility in chloroform. There is thus obtained, after recrystallization from ethanol, 14 g of (3,5-diiodo-4-hydroxy-phenyl) (2-thienyl) ketone which melts at 158 ° C. and 40.2 g of (3-hydroxy-4-iodo) phenyl) (2-thienyl) ketone: F == 190 ° C [recrystallization from aqueous dioxane (50/50)].

B) Diiodo-2,6 (thénoyl-2) -4 ethyl phenoxyacetate The sodium salt of 13.65 g of phenol is prepared by the action of 2 g of sodium methylate in methanol; the solution is poured into 100 ml of dimethylformamide, the methanol eliminated and 6.2 g of ethyl bromoacetate are introduced. After 12 hours at room temperature, 3 volumes of water are introduced into the medium and extracted into ethyl ether. The ethereal phase, washed with an aqueous solution of sodium hydroxide and then with water, is then dried and the solvent removed. The ester is recrystallized from 95% aqueous ethanol.

We obtain 9 g which melts at 93 ° C.

C) 2,6-Diiodo acid (2-thenoyl) -4 phenoxyacetic acid Prepared from its ester with 90% yield by hydrolysis in aqueous ethanol, in the presence of K2CO3, It melts at 160 ° C.

Example 8

Iodo-2 (thenoyl-2) -4 phenoxyacetic acid

A) Iodo-2 (thénoyl-2) -4 ethyl phenoxyacetate

This compound is prepared by applying the procedure described in Example 7 (B). It melts at 123 ° C. after recrystallization from ethanol.

B) Iodo-2 (2-thenoyl-2) -4-phenoxyacetic acid Prepared by hydrolysis with its ethyl ester with 97% yield, it melts at 164 ° C.

Example 9

2-bromo-2-thenoyl-4 phenoxyacetic acid

A) Bromo-2 (2-thenoyl) -4 ethyl phenoxyacetate This ester is prepared with 95% yield per action,

for example, ethyl bromoacetate on (3-bromo-4-hydroxyphenyl) (2-thienyl) ketone. It is an oil.

B) Bromo-2 (thenoyl-2) -4 phenoxyacetic acid

This acid is obtained by hydrolysis in basic medium of its ethyl ester. It melts at 180 ° C.

5

10

15

20

25

30

35

40

45

50

55

60

65

Table I

Example Structural formula

F (° C)

OR

s H

o

-ch2-cooh

115

ch-

-ch -cooh 2

134

ch3 ch3

lMl_è_> C_0-CH2-COOH

Oh

154

U> -

"

-ch2-cooh 167

P-

Ì

!

oh o-ch2-cooh

136

0-ch2-c00h 152

0-ch2-c00h 160

6

Table I (continued)

Example Structural formula

F (° C)

-CH2-COOH 164

i i

Br

V \ o-ch2-cooh

180

10

THIS

120

11

12

"IF

noh

-ch2-cooh 144

13

Br

0-ch2-c00h 180

14

Br noh

Br

-ch2-cooh 190

15

he I

VS

NOH

0-ch2-c00h

16

/ - 0-CH2-C00H 164

NOH

7

Table I (continued)

618,696

Example Structural formula

F (° C)

17

o-ch2-cooh 193

18

NOH

19

H

& O-CH -COOH Sei de Na 192

2 (1/2 C2H5OH)

20

-CH2-COOH 100

21

-CH2-COOH

166

22

207

23

0-CH2-C00H

110

The compounds prepared according to the invention were subjected to various pharmacological tests which revealed, in particular, their interest in the field of uricosuric agents; the following results illustrate this property.

The uricosuric activity was studied on batches of 5 rats, weighing 250 to 280 g; the products of formula I were administered, to animals, orally, doses ranging from 5 to 200 mg / kg. One hour after this administration, after anes-

thesis with ether, the animals receive an intravenous injection of 1 cm 3 of 1% aqueous solution of phenol red. The blood samples are taken 15,30,45 and 60 minutes after this injection, and the amount of phenol red in the blood is measured 6s. This method is described by H.C. Scarborough and G.R. Me Kinney in (J. Med. Pharm. Chem. 5 175 [1962]) and E. Kreppel in (Med. Exptl. 1 285 [1959].)

All the compounds of formula i decrease the elimination speed

618,696

8

nation of phenol red in rats, at the doses mentioned, and can therefore be considered as specifically uricosuric agents. In Table II below are reported the results obtained during the administration of a number of them, as well as benziodarone, uricosuric commonly used in human therapy.

As, moreover, the lethal dose 50 of all the compounds of formula I, determined by the method of C.I. Bliss (Quart.

J. Pharm. Pharmacol. 2 192-216 [1938]) is, orally, greater than 1000 mg / kg; it can be seen that the therapeutic index of the compounds of formula I and their salts makes it possible to envisage their use in human therapy, at daily doses ranging from 10 mg to 1 g; the compounds may be administered orally or parenterally, in combination or not with known excipients, in the form of capsules, tablets or solutions.

Table II

Example No. Dose mg / kg Uricosuric activity (% retention of phenol red compared to control animals)

after after after after

15 mins

30 mins

45 mins

60 mins

2

50

+

61 -

+ 88

+ 86

+ 160

3

100

+

83

+ 84

+ 66 *

+ 21 *

5

100

+

37

+ 41

+ 19 *

+ 21 *

7

50

+

113

+ 100

+ 93

+ 79

25

+

78

+ 66

+ 50

+ 71

8

50

+

59

+ 88

+ 84

+ 35

25

+

88

+ 111

+ 92

+ 52

11

100

+

69

+ 75

+ 100

+ 75

50

+

52

+ 59

+ 80

+ 65

13

50

+

55

+ 43

+ 65

+ 40

21

100

+

68

+ 123

+ 105

+ 58

50

+

48

+ 23 *

+ 36 *

+ 38 *

benzio

Darone

100

+

37

+ 50

+ 53

+ 18

* insignificant results

B

Claims (5)

618,696 2 CLAIM 1. Process for the preparation of compounds corresponding to the general formula: x, 0-ch2-c00h (i) x, in which A represents O or S, and Xi and X2, identical or different, each represent H, the methyl group or a halogen atom, provided that the benzene nucleus is never substituted by 2 halogens in position ortho to each other, as well as the alkaline salts or the addition salts of these acids with physiologically acceptable amines, characterized in that a phenol of formula: with a compound of formula XCH2COOR, in which X is a halogen atom and R represents an alkyl group, the ketone function of the ester thus formed is reduced, of formula: 20 25 0-ch2-c00r using aluminum isopropylate in solution in isopro-panol and the ester thus obtained is saponified. (ii) 5. Process for the preparation of compounds corresponding to the general formula: in which A, Xi and X2 have the same meanings as above, with a compound of formula XCH2COOR (HI) in which X represents a halogen atom and R represents H or an alkyl group, and the compound thus obtained is saponified in the case where it is an ester. 2. Process for the preparation of the compounds corresponding to the general formula: o-ch2-cooh 40 x „ choh o-ch2-cooh in which A, Xi and Xi have the meanings indicated in claim 1, as well as alkaline salts or addition salts of these acids with physiologically acceptable amines, characterized in that one prepares by the process according to claim 1 of the compounds of formula I above and that said compounds are subjected to a chemical reduction of the ketone function. 3. Method according to claim 2, characterized in that the reduction is carried out siïrles alkaline salts of the compounds of formula I, by the action of sodium borohydride in alcoholic solution. 4. Process for the preparation of compounds corresponding to the general formula given in claim 2, as well as alkaline salts or addition salts of these acids with physiologically acceptable amines, characterized in that one reacts in an alkaline medium phenol of formula II above in which A, Xi and X2 have the meanings indicated in claim 1, as well as alkali salts or addition salts of these acids with physiologically acceptable amines, characterized in that 'Compounds of formula I above are prepared by the process according to claim 1 and hydroxylamine is reacted with the ketone function of said compounds. 6. Method according to claim 5, characterized in that the hydroxylamine is used in the form of its hydrochloride and that the reaction is carried out in pyridine. 50