DE2916980C2 - Process for the preparation of thenoyl-phenoxyacetic acid esters - Google Patents

Description

U-

COOH

OH

(VI)

in which R ¹ and R ^{2 are} halogen, alkyl or alkoxy, and R ^{3 is} hydrogen straight-chain or branched alkyl, hydroxyalkyl or alkoxyalkylene, characterized in that one

a) a salicylic acid ester of the general formula

II: _Λ

COOR ⁴

(Π)

OH

in which the substituents R ¹ and R ² have the meanings given, and R ⁴ is lower alkyl, under conditions of a so Schotten-Baumann reaction with a Thiophencarbonsäurehalogenid of the general formula III:

(ΠΙ) in which the substituents R ¹ , R ² and R ^{4 have} the meanings given, saponified, d) the salicylic acid derivative VI with a haloacetic acid ester of the general formula VII:

X-CH ₂ -COOCH ₃ R ³

in which X and R ^{3 have} the meanings given, in the presence of alkalis to the corresponding 6-carboxylic acid phenoxyacetic acid ester VIII:

U-c

COOH

(VID)

R ¹ I 0-CH ₂ -COOCH ₂ R ³ R ²

in which the substituents R 'to R ^{3 have} the meanings given above, and e) decarboxylates the 6-carboxylic acid phenoxyacetic acid ester obtained.

C-X

in which X stands for halogen, to the corresponding phenol ester IV:

CO ₂ R ⁴

in which the substituents R ¹ , R ² and R ^{4 have} the meanings given, converts the pheno ester obtained with a Friedel-Crafts reagent under the conditions of a Fries shift to the corresponding alkyl salicylate of the general formula V:

COOR ⁴

(V)

in which the substituents R ¹ , R ² and R * have the meanings given, rearranged.

The invention relates to a method of manufacture

45 of thenoyl-phenoxyacetic acid esters. (IV) It has been shown that certain theiioyl-phenoxy-

acetic acid esters are effective as diuretics and have an improved therapeutic effectiveness compared to known, diuretically active compounds distinguish. These compounds exhibit improved diuretic activity while being affected by unwanted side effects are free, are well tolerated and have low toxicity. Compared to the described in DE-PS 20 48 372- NEN 4- (2'Thenoyl) -2 _r 3 dichlorphenoxysäure these esters are free from influence of a gastrointestinal at peroral administration. Furthermore, the toxicity of these esters is lower than that of 4- (2 * thenoyl) -2,3-dichlorophenoxy acid.

μ According to DE-PS 20 48 372, the production takes place the 3,4-DiGhlor-5- (2'thenoyl) -phenoxyacetic acid in the Way that one first reacts thiophene-2-carboxylic acid chloride with 23-dichloroanisole, the compound obtained with a haloacetic acid ester for reaction

h ^r > brings and saponified the ester obtained.

However, this reaction path has the following disadvantages: The starting material 2,3-dichloroanisole must be from the

relatively expensive and toxic 2,3-dichlorophenol can be produced. The following Friedel-Crafts reaction only runs in the highly flammable carbon disulfide as a solvent with useful yields. Then the ether has to be split again under Friedel-Crafts conditions.

The invention is based on the object of an improved production process for thenoyl-phenoxyacetic acid esters of the type mentioned above To make available. This improved method is primarily therefore known over others more advantageous, since the 3,4-dichlorosalicylic acid ester used as the starting compound is technically very simple and can be manufactured inexpensively.

The invention therefore relates to a process for the preparation of thenoyl-phenoxyacetic acid esters general formula I.

Ov-O-CH ₂ -CO-CH ₂ -R ³

R ¹

(D

that is characterized in that a) a salicylic acid ester of the general formula II:

COOR ⁴

(Π)

OH

(ΠΙ)

C-X

COOR ⁴

(IV)

IO

20th

25th

30th

35

in which the substituents R ¹ and R ^{2 have} the meanings given, and R ^{4 is} lower alkyl, preferably methyl or ethyl, under the conditions of a Schotten-Baumann reaction with a thiophenecarboxylic acid halide of the general formula III:

45

50

in which X is halogen, preferably chlorine or bromine, to the corresponding phenol ester IV:

55

60

in which the substituents R ¹ , R ² and R ⁴ have it. have given meanings, converts, b) the phenol ester obtained with a Friedel-Crafts reagent under the conditions of a Fries shift to the corresponding alkyl salicylate of the general formula V:

COOR ⁴

'• Μ

R ¹ T OH R ²

(V)

in which the substituents R ¹ , R ² and R ^{4 have} the meanings given, rearranges, c) the alkyl salicylate with alkalis to give the corresponding salicylic acid derivative of the general formula VI:

COOH

OH

(IV)

in which the substituents R ¹ , R ² and R ^{4 have} the meanings given, saponified, d) the salicylic acid derivative VI with a haloacetic acid ester of the general form! VII:

X-CH ₂ -COOCH ₂ R ³

(vn)

in which X and R ^{3 have} the meanings given, in the presence of alkalis to the corresponding 6-carboxylic acid phenoxyacetic acid ester VIII:

COOH

0 [Ol (VDD

O-CH ₂ -COOCH ₂ R ³

in which the substituents R ¹ to R ^{3 have} the meanings given, is reacted, and e) the 6-carboxylic acid phenoxyacetic acid ester obtained is decarboxylated

The radicals R ¹ and R ^{2 are} independently halogen, e.g. B. chlorine, bromine, iodine or fluorine, alkyl, especially straight-chain or branched Ci-C ₆ -alkyl, preferably d-C ₃ -alkyl, for example methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, pentyl, Hexyl or alkoxy, where the alkyte part of the alkoxy group preferably has 1 to 6 carbon atoms, in particular 1 to 3 carbon atoms, compounds in which the radical R ¹ and / or R ^{2 is} chlorine are preferred

The radical R ³ represents hydrogen, straight-chain or branched alkyl, in particular having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, e.g. B. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. Pentyl or hexyl, hydroxyalkyl with 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms in the alkyl chain, or alkoxyalkylene with 1 to 6 carbon atoms, in particular 1 to 4 carbon atoms

atoms in the alkyl chain, compounds in which R ^{3 is} hydrogen, methyl, hydroxymethylene or methoxymethylene, are very particularly preferred.

The method according to the invention has the following compared to the method according to DE-PS 20 48 372 Advantages:

The starting compounds H can be produced very easily and inexpensively. The following Schotten-Baumann reaction runs practically with quantitative yield. A direct Friedel-Crafts reaction in Carbon disulfide is not necessary. The Fries shift can easily be carried out in nitrobenzene. The subsequent etherification and decarboxylation are also good on a larger scale dominate.

The method according to the invention comprises five stages.

In the first stage z. B. a salicylic acid ester of general formula II

COOR ⁴

S '

(ΠΙ)

C-X

COOR ⁴

(IV)

ίο

(II)

in which R ^{4 is} lower alkyl, preferably methyl or ethyl, under the conditions of a Schotten-Baumann reaction with a thiophenecarboxylic acid halide of the general formula III

JO

35

in which X is halogen, preferably chlorine or bromine, to the phenol ester IV

40

45

50

converts The reaction takes place in an anhydrous solvent, e.g. B. anhydrous pyridine.

Anhydrous pyridine is preferred as the solvent. The reaction takes place at a temperature of 60 to 10O ⁰ C, preferably 8O ⁰ C. The MoIverhältnis salicylic acid to Thiophencarbonsäurehalogenid is 1: 1 to 1: 3, but preferably 1: 2. The reaction time is 1/2 hour to 2 hours, preferably 1 hour.

The preferred procedure is to dissolve the alkyl salicylic acid starting compound in the anhydrous solvent and to add the thiophenecarboxylic acid halide ^{while cooling to 0 ° C.} After b ^r> completion of the reaction the mixture is poured the reaction mixture into a mixture of FCI and hydrochloric acid, extracted with an organic solvent, preferably ether, washed with water until neutral and dried over a desiccant such as anhydrous sodium sulfate. After the solvent has been stripped off, the crude product obtained can be purified by recrystallization from a polar solvent, preferably from methanol.

In the second stage, the phenol ester obtained in this way is converted into the corresponding alkyl salicylate of the general formula V

U-

COOR ⁴

OH

(V)

rearranged The rearrangement takes place in an anhydrous, polar, organic solvent, preferably nitrobenzene.

Aluminum chloride, Iron (IH) chloride or boron trichloride can be used, the rearrangement preferably using Aluminum chloride is carried out. The rearrangement catalyst is, based on the used Starting product, used in excess, preferably 3-fold. The rearrangement takes place at a temperature of 80 to 100 ° C., preferably 100 ° C. The The reaction time is 2 to 4 hours, preferably 3 hours. Working up the reaction mixture takes place e.g. by decomposition with ice / hydrochloric acid, extraction with a solvent, e.g. B. ethyl acetate, Washing with an alkaline solution, for example a sodium hydrogen carbonate solution, and water. It is then dried in the usual way and the solvent mixture, for example, in vacuo removed The residue obtained can be recrystallized from a solvent, for example methanol will.

In the third stage, the alkyl salicylate obtained in this way is used to the corresponding salicylic acid derivative of the general formula VI

COOH

R ¹ I OH R ²

(VI)

saponified The saponification is carried out with alkalis, such as dilute sodium hydroxide solution.

For the saponification, it is expedient to proceed in such a way that the ester is in a solvent such as ethanol, Methanol or isopropanol, with ethanol being preferred, dissolves, mixed with the saponifying agent and preferably boils under reflux. The saponification agent used is used in excess, preferably 30x. After the saponification is complete, the salt obtained is not by adding a water Miscible solvent, for example ether, dichloromethane or ethyl acetate, ether being preferred is, precipitated, and sucked off the deposited salt. The conversion into the acid can be achieved by dissolving in hot water and acid precipitation, for example

concentrated hydrochloric acid. The verse fiingszeit is' /; up to 2 hours, but preferably I hour.

In the fourth stage, the salicylic acid derivative obtained is used with a haloacetic acid ester of the general formula VII

X - Cl I, - COOC II, K '

(V!

to the corresponding 6-carboxylic acid phenoxyacetic acid ester VIII

> - C

Il \ / \.

ο Y ₀ ;

R ^;

COOH

(MII)
Y) C'll · COOCH-U ¹

implemented. The reaction is expediently carried out in a solvent, e.g. B. anhydrous dimethylformamide or dimethyl sulfoxide, with anhydrous dimethylformamide being preferred. Before adding the haloacetic acid ester, it is advisable to add a basic agent, e.g. B. potassium carbonate, zn iintl waits for the COj development caused by this. The haloacetic acid ester is then added. The reaction temperature is 40 to 80 ^° C., preferably 60 ^° C. The reaction time is 2 to 4 hours, preferably 3 hours. The molar ratio of the compound of the formula VI to the haloacetic acid ester is 1: 1 to 1: 3. preferably 1: 1.6. Working up is carried out in the customary manner, for example by stirring into a mixture of ice and hydrochloric acid. After suctioning off, it is washed neutral and recrystallized from a solvent such as methanol.

In the last stage of the process according to the invention, the δ-carboxylic acid phenoxyacetic acid ester obtained is decarboxylated to give the thenoyl-phenoxyacetic acid ester according to the invention. The decarboxylation is preferably carried out in an inert solvent, such as quinoline, decalin or diphenyl ether, with cninoiin being preferred, and using '/ jsiund. to isiund. Heating to a temperature of 200 to 300 ⁰ C, preferably 250 ° C. The reaction product may, for example, by stirring the reaction mixture into ice / hydrochloric acid and extraction with a water immiscible solvent such as ether, and washing until neutral, drying over a desiccant, such as anhydrous sodium sulfate. Stripping off the solvent and optionally recrystallization can be obtained.

The new thenoyl-phenoxyacetic acid esters of the formula I prepared in this way crystallize well Compounds identified by elemental analysis as well as IR and NMR spectral analysis.

The invention is illustrated in the examples.

example 1

Production of 23-dichloro-4- (2-thenoyl) -phenoxyacetic acid methyl ester

a) Thiophene-2-carboxylic acid (23-dichloro-6-carboxylic acid methyl ester) phenyl ester

1! g (0.05 Mo!) 3,4-dich! ors2 !! cy! säuremethy! ester are dissolved in 90 ml of anhydrous pyridine and 15 g (0.1 mol) of thiophene-2carboxylic acid chloride with stirring at O "C / ugropfi. The mixture is then heated for 1 hour to 80 "C. a clear solution is formed. After cooling to room temperature, the mixture is stirred into a mixture of ice and hydrochloric acid. extracted with ether, washed neutral with water and dry! over sodium sulfate. After the solvent has been removed, it is crystallized from methanol. Colorless needles from F. 98 "C.

C,, HtCIjO ₄ S (331.2)

Ber. C = 47.15. H = 2.43. Cl = 21.41. O = 19.32,

S = 9.68%.

found C = 47.I4. H = 2.4 3rd (1 = 21.34. O = 19.27.
S = 9.65%.

b) 3,4-dichloro-5- (2-thenoyl) -saiicvlsauremethyliester

11 g of aluminum chloride are in 60 ml of anhydrous nitrobenzene suspended. 11 g (0.03 Mol) thiophene-2-carboxylic acid (2.3-dichloro-6-carboxylic acid methyl ester) -pher, yl ester (product A) was added and the mixture is heated to 100 ° C. for 4 hours. After cooling, it is decomposed with ice / hydrochloric acid and extracted with Ethyl acetate, washes with sodium hydrogen carbonate solution and water neutral, dries and removes the solvent mixture in vacuo at 100 ° C. The solid The residue is crystallized from methanol. Colorless flakes. F. I 79 "C.

CmHhCjjO, S (331.I77)

Ber. C = 47.I5. 11 = 2.45, Cl = 21.41. O = 19.32.

S = 9.68%,

found C = 47.09. H = 2.54, Cl -. '1.20, O = 19.39.
S = 9.52%.

c) 3,4-dichloro-4- (2-thenoylj-salicylic acid

Then 12 g (0.036 mol) of methyl 3,4-dichloro-5- (2-thenoyl) salicyate are obtained dissolved in 120 ml of ethanol, treated with 7.2 ml of 40% sodium hydroxide solution and 1 hour refluxed. After cooling, the solution is mixed with 500 ml of ether and the precipitated product is sucked off Salt off. The conversion to the desired acid is carried out by dissolving in 500 ml of fresh water and precipitating it achieved with concentrated hydrochloric acid. After neutralization with water and drying, the 3,4-dichloro-5- (2-thenoyl) salicylic acid melts at 230 ° C with decarboxylation.

d) 2,3-dichloro-4- (2-thenoyl) -6-carboxylic acid phenoxyacetic acid methyl ester

To a solution of 0.1 Moi 3,4-dichloro-5- (2-thenoyl) salicylic acid in 75 ml of anhydrous dimethylformamide is 034 mol of potassium carbonate and heated with stirring at 6O ⁰ C. After completion of the evolution of CO ₂ is added 0, 16 mol of methyl chloroacetate are added and the mixture is stirred for 4 hours at 60 ° C. It is then allowed to cool and poured into a mixture of ice and hydrochloric acid. It is filtered off with suction, washed neutral and crystallized from methanol.

e) methyl 23-dichloro-4- (2-thenoyl) phenoxyacetate

0.03 mol of 23-dichloro-4- (2-thenoyI) -6-carboxylic acid phenoxyacetic acid methyl ester are in! 0Q m! Quinoline dissolved and heated to 250 ° C for 1 hour (CO2 development

lung). After cooling, stir in EisSal / saurc and extract the product with ether. It is washed neutral, dried over sodium sulfate, the solvent is drawn off and recrystallizes. The methyl 2.3-dichloro-4 (2-thenoyl) phenoxyacetate is obtained with a melting point of 88 ° C. It is recrystallized from methanol.

IO

CH _1n U ₁ -O ₄ S (J45.2)

Her. C = 48.71. H = 2.42. Cl = 20.54. O = 18.54.

S = 9.29%,
found C = 48.86, H = 3.08. Cl = 20.49. O = 18.56.

S = 9.13%.

Analogously to Example I, the following were produced:

example

2.3-The Ii Io r-4- (2-1 he noy I (-phenoxy acetic acid ether

2.3-1) khlor-H2-thenoy I (-phenoxyacetic acid glycol ester

2.3-dichloro-4- (2-thenoyl (-phenoxyacetic acid- / f-nu ■! ho χ viii hy I ester

I. analysis Her Ciet. 55 ( C. 50.18 50.3 « (Ethanol) M. 3.37 3.42 Cl I 9.69 19.60 C) 17.X3 17.90 S. 8.93 8.77 85 ( C. 48.02 48.00 (Ether) Il 3.22 3.12 80 ( C. 49.37 49.50 (Ether) Il 3.63 3.67

Claims (1)

Claim: Process for the preparation of thenoyl-phenoxyacetic acid esters of the general formula I: 0-CH ₂ -CO-CH ₂ -R ³ (D. c) the alkyl salicylate with alkalis to form the corresponding salicylic acid derivative of the general formula VI: