DE1468228C - Substituted? Naphthyloxyacetic acids, processes for their preparation and pharmaceuticals containing these compounds - Google Patents

Description

The present invention relates to new substituted naphthyloxyacetic acids of the general formula

O-CH ₇ -COOH

C = O

C = CH ₂

where R is methyl or ethyl or in which, when R is ethyl, in the 2-, 3- or 5-position in the naphthalene nucleus one hydrogen atom has been replaced by methyl or in the 2- or 5-position by chlorine, a process for their preparation and medicinal products containing these compounds.

The new compounds can be prepared by making a compound in a manner known per se the general formula

0-CH ₂ -COOH

C = O
CH,

where R is methyl or ethyl or in which, when R is ethyl, in the 2-, 3- or 5-position in the naphthalene nucleus a hydrogen atom is replaced by methyl or in the 2- or 5-position by chlorine, with one Salt of a secondary amine and formaldehyde or paraformaldehyde converts the salt formed Mannich amine compound treated with a weak base and optionally the salt obtained substituted naphthyloxyacetic acid converted into the free acid in the usual way.

The new compounds according to the invention have diuretic, natriuretic and chloruretic Effect on by increasing the amount of water, sodium and chloride excreted in the urine will. The increase in excretion for water, sodium and chlorine occurs to the same extent.

They are therefore suitable for the treatment of many diseases that are due to excessive retention of electrolytes, especially sodium or chlorine ions or sodium and chlorine ions, e.g. For the treatment of hypertension, edema, and other conditions associated with electrolyte and fluid retention. The compounds can also be used to increase urine output.
The effectiveness of the new compounds was tested against the product »Mersalyl«, which is known to be very active. The experimental procedure and the results are described below: Trained, non-purebred female dogs that have not eaten for about 12 hours are given orally 500 ml of water and 3.0 g of creatinine subcutaneously. An infusion of isotonic phosphate buffer containing mannitol is then given at a rate of 3.0 ml per minute. After 20 minutes, the urinary bladder is emptied for the first time using a catheter, then the emptying is repeated at intervals of 10 minutes. In the middle between two urinations, venous blood is drawn.

After this control phase, the dogs are injected intravenously with the compound to be tested in a Starting dose of 2.5 mg / kg. The dogs then receive the compound to be tested as an infusion in an amount of 3.0 mg / kg / hour. Urine and urine are taken 20 minutes after the initial dose is given then repeat the urine sampling every 10 minutes. In the middle between two Venous blood is taken from urine. The increase in the excretion of sodium caused by the connections to be tested is shown in the table below.

Comparison table of diuretic effectiveness Na ⁺ -
ouch
C) Show
the Ha
DC young
rn
Back
absorption
(%) K ⁺ - /
shit
from derr
C. ^ US
ung
ι urine
DC Cr-Aussc
from the
C. 6th heathen
urine
DC Excluded
Fluid
men
C ₁ ³ ) songs
ability-.
ge
D ₁ -C ₁ Connection,
manufactured
after
example Name of the connection to be tested D ² ) 732 99.8 D. 87 D. 885
10 879 6.0 i [2-chloro-4- (a-methylene 7th 942 88.8
99.2 14th 62 1134
10 1124 1.4 7.7 2 butyryl) -naphthyl- (l)] -
oxyacetic acid
[2-methyl-4- (a-methylene 739
71 1101 90.6
99.3 101
39 107 1330 1320 7.4
1.7 9.4 3 butyryl) -naphthyl- (l)] -
¹ oxyacetic acid
[4-methacryloyl- 1013
83 89.3 101
56 9.4
3.3 naphthyl- (l)] -
oxyacetic acid 1184 163 12.7

) Increase in excretion caused by administration of the control compound (microequivalents / min.). ) Increase in excretion caused by administration of the compound to be investigated (microequivalents / min.). ) Increase in excretion caused by administration of the control compound (ml / min.). *) Increase in excretion caused by administration of the compound to be examined (ml / min.).

continuation

Connection,
manufactured

after
example

Name of the connection to be tested

Na ⁺ excretion from the urine

Reabsorption
%

K ⁺ excretion
from the urine

C.
D.

D-C

Ci elimination
from the urine

C.
D.

D-C

Retired
Amount of liquid

C, ³ )

O ₁ - C ₁

[4- (a-Methylenebutyryl) -naphthyl- (1)] -oxyacetic acid

[5-chloro-4- (a-methylene

butyryl) -naphthy l- (1)] -

oxyacetic acid
[3-methyl-4- (a-methyleri-

butyryl) -naphthyl- (l)] -

oxyacetic acid

[5-Methyl-4- (a-methylenebutyryl) -naphthyl- (I)] -oxyacetic acid , ..!

OCH ₂ CO ₂ H
CNHCH ₂ CHCH ₂ HgOH O OCH ₃

13 1019

15 1124

34 1075

34 1327

67 645

1006 1109 1041 1293 '

99.6
83.7

99.1
93.1

13th
89

15th
~ 9Ö "

54
97

79
194

31

72

76

75

43

115

41

1131

H_

1319

5
1133

y_

1520

755

1127
1308
1128
1509

0.8

9.6

1.6

709

12.6

1.9

8.9
11.0

"Mersalyl"

¹ ) Increase in excretion caused by administration of the control compound (microequivalents / min.).

² ) Increase in excretion caused by administration of the compound to be examined (microequivalents / min.).

³ ) Increase in excretion caused by administration of the control compound (ml / min.).

⁴ ) Increase in excretion caused by administration of the compound to be tested (ml / min.).

example 1

[2-chloro-4- (a-methylenebutyryl) -1-naphthyloxy] acetic acid

(Levels A and B describe the preparation of the starting compound)

Level a
3-chloro-4-hydroxy-l-butyronaphthone

26.6 g of aluminum chloride are added to a mixture of 17.8 g (0.1 mol) of 2-chloro-1-naphthol, 10.6 g (0.1 mol) butyryl chloride and 200 ml nitrobenzene added. The black solution will last for 20 hours Stirred at room temperature and the reaction mixture then poured into a mixture of 100 g of ice, 100 g of water and poured 100 g of concentrated hydrochloric acid. The organic layer is diluted with 200 ml of ether, separated from the aqueous layer and extracted with 20% aqueous sodium hydroxide solution. When acidifying the alkaline extract creates a black solid substance from which αμκΐι recrystallize from a Mixture of benzene and hexane 5.5 g of 3-chloro-4-hydroxy-1-butyronaphthone be won; F. = 111 to 113 ° C.

Analysis for C ₁₄ H ₁₃ ClO ₂ :

Calculated ... C 67.61, H 5.27%; found .... C 67.79, H 5.38%.

Level B.
(2-chloro-4-butyryl-1-naphthyloxy) acetic acid

A solution of 5 grams (0.02 moles) of 3-chloro-4-hydroxy-1-butyronaphthone in. 100 ml of absolute ethanol is mixed with 0.22 mol of sodium hydride. After 10 minutes 3.33 g (0.022 mol) of ethyl bromoacetate are added to the clear solution while stirring. the The solution is heated to reflux temperature for 3 hours and then 115 ml of sodium hydroxide solution are added. The mixture is boiled for another 20 minutes on the condenser and the ethyl alcohol is then distilled in vacuo away. The remaining aqueous solution is treated with decolorizing charcoal. The filtrate is with Acidified in hydrochloric acid, whereupon the product precipitates. After recrystallization from benzene, 3 g of (2 - chloro - 4 - butyryl -1 - naphthyloxy) acetic acid are obtained; M.p. = 124 to 125 ° C.

Analysis for C ₁₆ H ₁₅ ClO ₄ :

. Calculated ... C 62.65, H 4.93%;
found .... C 62.77, H 5.02%.

Level C

[2-chloro-4- (a-methylenebutyryl) -l-naphthyloxy] acetic acid

A mixture of 3.3 g (0.11 mol) (2-chloro-4-butyryl-1-naphthyloxy) acetic acid, 0.45 g (0.015 mol) paraformaldehyde, 1.2 g (0.015 mol) dimethylamine hydro-

chloride and 7 drops of 6Normal ethanolic hydrochloric acid are placed in a flask, and this is used in an oil bath of 115 ° C and the mixture temporarily stirred. After 10 minutes the mixture becomes soft and sticky. Then the plunger is 15 seconds attached to a moderate vacuum, heating continued, and vacuum treatment all Repeated for 5 minutes. After 45 minutes of heating, the reaction is complete and the heating is complete

will be interrupted. After cooling, the mixture is leached with 25 ml of acetone and filtered. 4.2 g of crude [2-chloro-4- (a-dimethylaminomethylbutyryl) -1-naphthyloxy] -acetic acid hydrochloride are obtained. A solution of 5.6 g of this crude salt of Mannich's base in 150 ml of water is with Made sodium bicarbonate alkaline and heated to 80 ° C for 20 minutes. The solution is brought to 20 ° C cooled and freed from a small amount of insoluble resinous substances by filtering. The filtrate will acidified and the crystals are collected.

After recrystallization from a mixture of benzene and hexane, 1.75 g of [2-chloro-4 - (α-methylenebutyryl) -1-naphthyloxy] -acetic acid; M.p. = 100 to 101.5 ° C. The yield is 37.8%.

Analysis for C ₁₇ H ₁₅ ClO ₄ :

Calculated ... C 64.05, H 4.74%;
found .... C 63.94, H 4.69%.

Example 2

[2-methyl-4- (a-methylenebutyryl) -l-naphthyloxy] acetic acid

(Levels A and B describe the preparation of the starting compound)

Level a
(2-methyl-1-naphthyloxy) acetic acid

10.0 g (0.063 mol) of 2-methyl-1-naphthol are dissolved in a solution of 0.0788 mol of sodium ethylate in 200 ml of absolute ethyl alcohol. The solution is heated to reflux temperature for 3 hours and then 115 ml of 1 η sodium hydroxide solution are added. The mixture is boiled for a further 20 minutes on the reflux condenser and the ethyl alcohol is then distilled off in vacuo. The remaining aqueous solution is treated with decolorizing charcoal. The filtrate is acidified with 1N hydrochloric acid. The brown oil which separates out soon solidifies and, after recrystallization from 100 ml of benzene, yields 10.0 g of (2-methyl-1-naphthyloxy) acetic acid; F. = 141 to 143 ⁰ C..

a light pink solid; Mp = 114 to 117 ⁰ C. By recrystallization from benzene is recovered (2 - methyl - 4 - butyryl -1 - naphthyloxy) - acetic acid; F. = 116 to 119 ⁰ C.

Analysis for C ₁₇ H ₁₈ O ₄ :

Calculated ... C 71.31, H 6.34%;
found .... C 71.34, H 6.25%.

Level C

[2-Methyl-4- (a-dimethylaminomethylbutyryl) -1 -naphthy 1] -acetic acid hydrochloride

5.0 g (0.0175 mol) (2 - methyl - 4 - butyryl -1 - naphthyloxy) acetic acid, 0.75 g (0.025 mol) paraformaldehyde, 1.55 g (0.0193 mol) dimethylamine hydrochloride and 6 drops 6normaler alcoholic hydrogen chloride are mixed together and heated for 20 minutes 8O ⁰ C. The solution is cooled to 20 ° C. and a small amount of insoluble resinous substances is removed by filtration. The filtrate is acidified. The amount of the precipitated solid product after filtering off is 3.75 g; F. = 165 to 169 ° C. After recrystallization from isopropyl alcohol, [2-methyl-4- (a-dimethylaminomethylbutyryl) -1-naphthyloxy] -acetic acid hydrochloride is obtained; F. = 171 to 173 ⁰ C.

45 Analysis for C ₁₃ H ₁₂ O ₃ :

Calculated ... C 72.21, H 5.59%;
found .... C 72.29, H 5.60%.

Level B.

(2-methyl-4-butyryl-1-naphthyloxy) acetic acid

6.5 g (0.03 mol) of (2-methyl-1-naphthyloxy) acetic acid are dissolved in 60 ml of carbon disulfide. First 12.0 g (0.09 mol) of aluminum chloride and then 3.5 g (0.033 mol) of butyryl chloride are added to the solution with stirring. The mixture is stirred for 1 hour at room temperature and then for 3 hours at reflux temperature. After cooling to room temperature, 50 ml of a mixture of ice and water are added and the mixture is acidified with 2.5 η hydrochloric acid. The oily product is extracted with ether. The ether solution is dried over sodium sulfate, filtered through a filter aid and adsorption charcoal and concentrated. 8.7 g of a red oil are obtained. The oil is dissolved in 30 ml of a mixture of equal parts by volume of benzene and cyclohexane and the solution is cooled. 5.1 g of analysis for C ₂₀ H ₂₅ NO ₄ ■ HCl are obtained:

Calculated ... C 63.23, H 6.90, N 3.69%;
found .... C 63.40, H 7.05, N 3.48%.

Level D

[2-methyl-4- (a-methylenebutyryl) -l-naphthyloxy] acetic acid

A suspension of 2.7 g (0.0087 mol) of [2-methyl-4 - (α - dimethylaminomethylbutyryl) -1 - naphthyloxy] acetic acid hydrochloride in 75 ml of water is mixed with saturated sodium bicarbonate solution until the pH is 8 by weight and heated for 20 minutes 8O ⁰ C. The solution is cooled to 20 ° C. and a small amount of insoluble resinous substances is removed by filtration. The filtrate is acidified and the crystals treated. 1.95 g of [2-methyl-4 - (α-methylenebutyryl) -1-naphthyloxy] -acetic acid are obtained; F. = 65 to 69 ° C. Recrystallization from a mixture of benzene and hexane increases the melting point to 72 to 74.5 ° C.

Analysis for C ₁₈ H ₁₈ O ₄ :

Calculated ... C 72.46, H 6.08%;
found .... C 72.53, H 6.22%.

Example 3
(4-methacryloyl-1-naphthyloxy) acetic acid

(Step A describes the preparation of the starting compound)

Level a
(4-propionyl-1-naphthyloxy) acetic acid

300 ml of isopropyl alcohol are 0.11 mol Sodium hydride and then with 20.0 g (0.1 mole) 4-hydroxy-1-propionaphthone offset. One forms

homogeneous solution to which 18.37 g (0.11 mol) of ethyl bromoacetate are added. The solution is heated to reflux temperature for 3 hours and then 115 ml of 1 η sodium hydroxide solution are added. The mixture is boiled for a further 20 minutes on the reflux condenser and the ethyl alcohol is then distilled off in vacuo. The remaining aqueous solution is treated with decolorizing charcoal. The filtrate is acidified with 1N hydrochloric acid. 7.6 g of (4-propionyl-1-naphthyloxy) acetic acid are obtained; F. = 189 to 191 ^° C. Recrystallization from isopropyl alcohol increases the melting point to 190 to 193 ^° C.

Analysis for C ₁₅ H ₁₄ O ₄ :

Calculated ... C 69.75, H 5.46%;
found .... C 69.32, H 5.69%.

Level B.

[4- (α-Methyl - /? - dimethylaminopropionyl) -1-naphthyloxy] acetic acid hydrochloride

P A mixture of 4.0 g (4-propionyl-1-naphthyloxy) acetic acid, 0.48 g paraformaldehyde, 1.26 g dimethylamine hydrochloride, 12 drops of glacial acetic acid is placed in a flask and this is placed in an oil bath of 115 ° C was used and the mixture was temporarily stirred. After 10 minutes the mixture becomes soft and sticky. The flask is then placed in a moderate vacuum for 15 seconds, heating continued and the vacuum treatment repeated every 5 minutes. After 45 minutes of heating, the reaction is complete and the heating is discontinued. After cooling, the mixture is leached with 25 ml of acetone and filtered. 4.7 g of [4 - (α - methyl - β - dimethylaminopropionyl) -1 - naphthyloxy] acetic acid hydrochloride, which melts at 177 to 179 ° C. after recrystallization from alcohol, are obtained.

Analysis for C ₁₈ H ₂₁ NO ₄ HCl:

Calculated ... C 61.44, H 6.30, N 3.98%;
found .... C 61.47, H 6.42, N 3.90%.

Level C
(4-methacryloyl-1-naphthyloxy) acetic acid

8 g of [4 - (α - methyl - β - dimethylaminopropionyl) -1-naphthyloxy] acetic acid hydrochloride are dissolved in 400 ml of water. The solution is made alkaline with sodium bicarbonate and heated to 80 ° C for 20 minutes. The solution is cooled to 2O ⁰ C and removed by filtration of a small amount of insoluble resinous substances. The filtrate is acidified. A resinous product separates out. The supernatant liquid is poured off and the product is dissolved in 10 ml of hot benzene. On cooling to ⁰ ° C., a crystalline product separates out in an amount of 2.3 g; F. = 117 to 119 ^° C. Recrystallization from hot n-butyl chloride gives 2.0 g of (4-methacryloyl-1-naphthyloxy) acetic acid; F. = 117 to 12O ⁰ C and 133 to 135 ⁰ C. The yield is 32%.

Analysis for C ₁₆ H ₁₄ O ₄ :

Calculated ... C 71.10, H 5.22%;
found .... C 70.90, H 5.38%.

Example 4
[4 - («- methylenebutyryl) -l-naphthyloxy] acetic acid

(Step A describes the preparation of the starting compound)

Level a
(4-Butyryl-1-naphthyloxy) acetic acid

A solution of 27.2 g (0.134 mol) of (1-naphthyloxy) acetic acid in 200 ml of carbon disulfide is mixed with 15.8 g (0.148 mol) of n-butyryl chloride. After cooling the solution to 0 ° C., 50.8 g (0.38 mol) of anhydrous aluminum chloride are added over the course of 15 minutes, whereupon the reaction according to Example 2, stage B, is carried out. The solid precipitate is filtered off and washed well with water. The solid (4-butyryl-1-naphthyloxy) acetic acid is dissolved in 300 ml of benzene, the solution is filtered through a filter aid and adsorption charcoal and cooled. 37 g of a yellow solid are obtained; Mp = 125-132 ⁰ C. After recrystallization from 75% alcohol melts (4-Butyryll-naphthyloxy) acetic acid at 137 to 139 ° C.

Analysis for C ₁₆ H ₁₆ O ₄ :

Calculated ... C 70.57, H 5.92%;
found .... C 70.41, H 6.03%.

Level B '

[4- (α-Dimethylaminomethylbutyryl) -l-naphthyloxy] acetic acid hydrochloride

0.31 g (0.0103 mol) of paraformaldehyde, 0.84 g (0.0103 mol) of dimethylamine hydrochloride and 2.0 g (0.00735 mol) of (4-butyryl-1-naphthyloxy) acetic acid are combined in one 50 ml round bottom flasks mixed well and mixed with 5 drops of 6 normal ethanolic hydrogen chloride solution. The mixture is heated to about 115 ° C. and a moderate vacuum is temporarily applied. The reaction is complete after 45 minutes. After cooling, it is leached with 25 ml of acetone, 2.0 g of a white, solid substance being obtained; F. = 172 to 177 ^° C. A single recrystallization from ethyl alcohol gives pure [4- (a-dimethylaminomethylbutyryl) -1 - naphthyloxy] acetic acid hydrochloride; F. = 176 to 178 ° C.

Analysis for C ₁₉ H ₂₃ NO ₄ HCl:

Calculated ... C 62.37, H 6.61, N 3.85%;
found .... C 62.34, H 6.65, N 3.78%.

Level C
[4- (n-Methylenebutyryl) -l-naphthyloxy] acetic acid

Dissolve 1.0 g (0.003 mol) of [4- (a-dimethylaminomethylbutyryl) -1-naphthyloxy] acetic acid hydrochloride in 25 ml of warm water, whereupon saturated sodium bicarbonate solution (approx. 2 ml) is added until the pH value is 8 amounts to. The clear solution is heated for 20 minutes 8O ⁰ C. The solution is cooled to 20 ° C. and a small amount of insoluble resinous substances is removed by filtration. The filtrate is acidified and [4 - («- methylenebutyryl) -l-naphthyloxy] acetic acid is obtained in an amount of 0.15 g; F. = 103 to 107 ^° C. Recrystallization from n-butyl chloride increases the melting point

109553/437

35

40

45

to 106 to 109 ^° C. The yield is 0.15 g, that is to say 17.6%.

Analysis for C ₁₇ H ₁₆ O ₄ :

Calculated ... C 71.82, H 5.67%;
found .... C 71.80, H 5.81%.

Example 5

[5-chloro-4- (o-methylenebutyryl) -1-naphthyloxy] -acetic acid

(Levels A and B describe the preparation of the starting compound)

Level a
(5-chloro-1-naphthyloxy) acetic acid

A solution of 16 g (0.09 mol) of 5-chloro-1-naphthol in a solution of 0.11 mol of sodium ethylate in 200 ml of absolute ethanol is stirred for 5 minutes and then mixed with 18.3 g (0.11 mol) of ethyl bromoacetate. The solution is refluxed for 3 hours heated and then mixed with 115 ml of sodium hydroxide solution. The mixture is refluxed for a further 20 minutes and then distilled off the ethyl alcohol in vacuo. The remaining aqueous solution is treated with decolorizing charcoal. The filtrate is acidified with 1N hydrochloric acid. You get (5-chloro-1-naphthyloxy) acetic acid, which according to the Recrystallization from a mixture of benzene and methanol gives 14.7 g of product; F. = 179 to 181 ° C.

Analysis for C ₁₂ H ₉ ClO ₃ :

Calculated ... C 60.90, H 3.83%;
found .... C 61.16, H 4.02%.

Level B.
(5-chloro-4-butyryl-1-naphthyloxy) acetic acid

24.6 g (0.18 mol) of aluminum chloride are slowly added to a mixture of 12.3 g with thorough stirring (0.05 mol) (5-chloro-1-naphthyloxy) acetic acid, 6.3 g (0.06 mol) butyryl chloride and 300 ml carbon disulfide added and the mixture for 60 minutes at room temperature and 3 hours at reflux temperature touched. After adding ice water and acidifying with 2.5N HCl, a solid one is obtained Body that is recrystallized from a mixture of benzene and methanol. 12.4 g are obtained (5 - chloro - 4 - butyryl - 1 - naphthyloxy) acetic acid; F. = 164 to 165.5 ° C.

Analysis for C ₁₆ H ₁₅ ClO ₄ :

Calculated ... C 62.65, H 4.93%;
found .... C 62.75, H 4.93%.

Level C

[5-chloro-4- (a-methylenebutyryl) -l-naphthyloxy] acetic acid

A mixture of 2.4 g (0.008 mol) (5-chloro-4-butyryl-1-naphthyloxy) acetic acid, 0.36 g (0.012 mol) paraformaldehyde, 0.96 g (0.012 mol) dimethylamine hydrochloride and 7 Drops of normal ethanolic solution of hydrogen chloride are placed in a flask and this is placed in an oil bath at 115 ° C. and the mixture is temporarily stirred. After 10 minutes the mixture becomes soft and sticky. The flask is then placed in a moderate vacuum for 15 seconds, heating continued and the vacuum treatment repeated every 5 minutes. After 45 minutes of heating, the reaction is complete and the heating is discontinued. After cooling, the mixture is leached with 25 ml of acetone and filtered. A crude product is obtained which is stirred with ether and dissolved in 100 ml of water, whereupon the solution is made alkaline with aqueous sodium bicarbonate solution and heated to 80 ° C. for 20 minutes. The solution is cooled to 2O ⁰ C and removed by filtration of a small amount of insoluble resinous substances. The filtrate is acidified. The resin which separates out is recrystallized from benzene. 1 g of [5 - chloro - 4 - (α - methylenebutyryl) -1 - naphthyloxy] acetic acid is obtained; F. = 178 to 179 ° C. The yield is 39%.

Analysis for C ₁₇ H ₁₅ ClO ₄ :

Calculated
found .

C 64.05, H 4.79%; C 63.80, H 4.70%.

Example 6

[3-methyl-4- (a-methylenebutyryl) -l-naphthyloxy] acetic acid

(Levels A to E describe the preparation of the starting compound)

Level a
4-bromo-3-methyl-1-methoxynaphthalene

A solution of 34.4 g (0.20 mol) of 1-methoxy-3-methylnaphthalene is heated in 400 ml of glacial acetic acid at 8O ⁰ C. Then a solution of 33.6 g (0.21 mol) of bromine in 100 ml of glacial acetic acid in approximately 2 hours with stirring is added dropwise, the temperature being maintained at 8O ⁰ C. The reaction mixture is then stirred for a further 15 minutes, then poured onto 2 l of ice water and the product is extracted with ether. The ether extract is washed with water, sodium hydroxide solution and finally with water. The ether solution is dried and evaporated under reduced pressure. The crude product is obtained as a solid in a yield of 90%. Recrystallization from methanol-water or acetic acid _t is obtained 4-bromo-3-methyl-l-methoxynaphthalene with a melting point 62 to 63.5 ° C.

Analysis for C ₁₂ H ₁₁ BrO:

Calculated ... C 57.39, H 4.42%; found .... C 57.22, H 4.44%. 55

Level B.

4- (1-hydroxybutyl) -3-methyl-1-methoxynaphthalene

A Grignard reagent is prepared from 1.34 g (0.055 mol) of magnesium and 12.56 g (0.05 mol) of 4-bromo-3-methyl-1-methoxynaphthalene in 60 ml of tetrahydrofuran; the reaction is initiated with a few drops of ethylene dibromide. The Grignard reagent is cooled to -3O ⁰ C and treated with a solution of 3.97 g (0.055 mol) of butyraldehyde in 40 ml tetrahydrofuran was added dropwise under run for 25 minutes. The mixture is then placed in an ice bath and stirred for 20 minutes, the temperature

slowly rises to 25 ^{° C.} Tetrahydrofuran is then removed under reduced pressure and 100 ml of ether are added; the mixture is cooled in ice and decomposed by adding a solution of 5.35 g (0.1 mol) of ammonium chloride in 50 ml of water. The ether layer is separated off, washed with water, dried and concentrated under reduced pressure. 4 - (1 - Hydroxybutyl) - 3 - methyl -1 - methoxynaphthalene is obtained as a viscous yellow oil in a yield of 11.8 g.

Level C

4-butyryl-3-methyl-1-methoxynaphthalene

A pyridine-chromium complex is prepared by cooling 500 ml of pyridine to 15 ° C. and adding 50.0 g (0.5 mol) of chromium trioxide in small portions with stirring in about ¹ _1/2 hours. The reaction mixture is stirred for a further ¹ Z ₂ hours, the temperature rising ^{to 25 ° C.} The suspension is cooled to 5 ° C. and a solution of 43.0 g of 4 - (1 - hydroxybutyl) - 3 - methyl - 1 - methoxynaphthalene in 500 ml of pyridine is added. The mixture is stirred IV2 hours at 5 ⁰ C and at room temperature overnight. The dark mixture obtained in this way is poured into 5 l of water and then extracted with ether. The ether extract is washed with water, in-hydrochloric acid, in sodium hydroxide solution and finally with water, dried and concentrated under reduced pressure to give a yellow liquid in an amount of 36.2 g. During distillation distilled 4-butyryl-3-methyl-l-methoxynaphthalene at 145 to 15O ⁰ C at 0.5 mm pressure, n% ⁵ = 1.5875.

Analysis for C ₁₆ H ₁₈ O ₂ :

Calculated ... C 79.31, H 7.49%;
found .... C 78.94, H 7.34%.

Level D
4-butyryl-3-methyl-1-naphthol

A mixture of 3.22 g (0.14 mol) of sodium and 25 ml of pyridine is ^{heated for 15 minutes under nitrogen to 160 to 180 °} C. with vigorous stirring. 4.85 g (0.02 mol) of 4-butyryl-3-methyl-1-methoxynaphthalene are then added to 20 ml of pyridine; excess pyridine is distilled out a side tube, while the bath temperature is increased to 200 ⁰ C. The mixture is heated to 200 ° C. for 5 hours. After cooling, a few milliliters of pyridine and then carefully added 50 ml of water. The aqueous solution is washed with ether, the ether solution is washed with 1N hydrochloric acid and then extracted with 1N sodium hydroxide solution. The alkaline extract and the aqueous solution are combined and acidified with excess hydrochloric acid. The solid which separates out is extracted with ether; the ether extract is washed with water, dried and concentrated under reduced pressure. A yellow solid with a melting point of 144 to 147.5 ° C. is obtained in a yield of 71%. Recrystallization from ethanol-water gives pure 4-butyryl-3-methyl-1-naphthol as a yellow solid. F. = 148.5 to 149.5 ° C.

Analysis for C ₁₅ H ₁₆ O ₂ :

Calculated ... C 78.92, H 7.06%;
found .... C 78.78, H 7.35%.

Level E.

(4-Butyryl-3-methyl-1-naphthyloxy) acetic acid

4-Butyryl-3-methyl-1-naphthol (0.78 g, 0.0034 mol) is added to a solution of 25 ml of absolute ethanol, which contains 0.0034 mol of sodium ethoxide, and then with 0.68 g (0.004 Mol) ethyl bromoacetate added. The solution is heated to reflux temperature for 3 hours and then 115 ml of 1N sodium hydroxide solution are added. The mixture is boiled for a further 20 minutes on the reflux condenser and the ethyl alcohol is then distilled off in vacuo. The remaining aqueous solution is treated with decolorizing charcoal. The filtrate is acidified with 1η hydrochloric acid. (4-Butyryl-3-methyl-1-naphthyloxy) -acetic acid is obtained in 84% yield as an oily mass which changes to a pale yellow solid with a melting point of 126 to 129 ° C. Recrystallization from n-butyl chloride, a white solid is obtained of melting point 131 to 132.5 ⁰ C.

Analysis for C ₁₇ Hj ₈ O ₄ :

Calculated ... C 71.31, H 6.34%; found .... C 71.15, H 6.56%.

Level F

[3-methyl-4- (a-methylenebutyryl) -l-naphthyloxy] acetic acid

A mixture of 1.0 g (0.0035 mol) of (4-butyryl-3-methyl-1-naphthyloxy) acetic acid, 0.12 g (0.004 mole) paraformaldehyde, 0.30 g (0.0036 mole) dimethylamine hydrochloride and 10 drops of glacial acetic acid is on the steam bath for 3 hours with occasional partial evacuation heated. The Mannich base, which is obtained as an intermediate product, namely [3-methyl-4- (a-methylenebutyryl) -l-naphthyloxy] -acetic acid, does not need to be isolated; it is dissolved in a mixture of 25 ml of ether and 25 ml of water. The ether layer is separated off, washed with dilute hydrochloric acid and water, dried and reduced under reduced pressure Pressure restricted. [3-Methyl-4- (a-methylenebutyryl) -l-naphthyloxy] -acetic acid is obtained as a yellow dye in an amount of 0.86 g (83%) and a melting point of 152 to 154 ° C. When recrystallizing from isopropanol-water the melting point rises to 154-155.5 ° C. The yield is 0.86 g, that is 83%.

Analysis for C ₁₈ H ₁₈ O ₄ :

Calculated ... C 72.46, H 6.08%; found .... C 72.58, H 6.20%.

Example 7

[5-methyl-4- (a-methylenebutyryl) -l-naphthyloxy] acetic acid

(Levels A to I describe the preparation of the starting compound)

Level a
1-Hydroxy-1-methyl-1,2,3,4-tetrahydro-5-naphthol

A Grignard reagent is made by treating 43.8 g (1.8 moles) of magnesium with 256 g (1.8 moles) Methyl iodide shown in 900 ml of ether under nitrogen. Then 74.0 g (0.36 mol) of 5-acetoxy-3,4-dihydro-1 (2H) -naphthalenone are obtained in 750ml tetra

hydrofuran was added and the mixture was stirred under nitrogen for 48 hours. After removing the Ether and tetrahydrofuran under reduced pressure are added to 500 ml of ether and the mixture decomposed by aqueous ammonium chloride solution added in excess. The ether layer becomes separated, washed with a mixture of water and dilute hydrochloric acid, dried and under concentrated under reduced pressure. 63 g of 1-hydroxy-1-methyl-1,2,3,4-tetrahydro-5-naphthol are obtained as a yellow solid.

"Level B

Ethyl (5-hydroxy-5-methyl-5,6,7,8-tetrahydrol-naphthyloxy) acetate

63 g (0.35 mol) of crude 1-hydroxy -1-methyl -1.2, 3,4-tetrahydro-5-naphthol are mixed with 65.1 g (0.39 mol) of ethyl bromoacetate and 16.7 g (0.37 mol) of sodium ethoxide reacted; one obtains crude ethyl (5-hydroxy-5 - methyl - 5,6,7,8 - tetrahydro -1 - naphthyloxy) acetate in almost quantitative yield as a dark yellow oil.

Level C
Ethyl (7,8-dihydro-5-methyl-1-naphthyloxy) acetate

The crude product obtained after stage B is by dissolving 32.4 g (0.123 mol) in 40 ml of benzene and 75 ml of pyridine and the addition of 20 g (0.13 mol) of phosphorus oxychloride are dehydrated. The mixture will Stirred on the steam bath for 2 hours; the solvents are under reduced pressure removed. The residue mixture of oil and solids is dissolved in 250 ml of ether and 100 ml of water recorded; the ether layer is separated, washed with dilute hydrochloric acid and water, dried and under reduced pressure to a dark yellow oil in a yield of 26.1 g (87%) constricted. The product obtained is ethyl- (7,8-dihydro-5-methyl-1 -naphthyloxy) acetate.

Level D

Ethyl (5-methyl-5,6,7,8-tetrahydro-1-naphthyloxy) acetate

Level E.

(5-methyl-5,6,7,8-tetrahydro-1-naphthyloxy) acetic acid

11.8 g (0.0476 mol) of the product from stage D are dissolved in 100 ml of ethanol, and 5.61 g (0.10 mol) of potassium hydroxide in 25 ml of water are added. The solution is heated on the reflux condenser V for ₂ hours, the ethanol is removed under reduced pressure and the salt is dissolved in 150 ml of water. The wass

20 membered solution is washed with ether and acidified with excess hydrochloric acid and nitrided. 8.1 g of a yellow-brown solid with a melting point of 152 to 155 ° C. are obtained. Recrystallization from ethanol-water gives (5-methyl-5,6,7,8-tetrahydro-1-naphthyloxy) -acetic acid with a melting point of 156.5 bis 158.5 ° C.

Analysis for C ₁₃ H ₁₆ O ₃ :

Calculated ... C 70.89, H 7.32%; found .... C 70.81, H 7.17%.

Level F

(4-Butyryl-5-methyl-5,6,7,8-tetrahydrol-naphthyloxy) -acetic acid

If (2-methyl-1-naphthyloxy) acetic acid and carbon disulfide in Example 2, stage B, against equimolar amounts of the product according to stage E and Exchanging methylene chloride and extending the reflux condenser treatment to 16 hours is obtained (4 - butyryl - 5 - methyl - 5,6,7,8 - tetrahydro -1 - naphthyloxy) acetic acid as a yellow oil in a yield of 94%.

Level G

Ethyl (and methyl) - (4-butyryl-5-methyl-5,6,7,8-tetrahydro-1-naphthyloxy) acetate

The ethyl ester is prepared from 5.4 g (0.0185 mol) of the product after stage F by heating under reflux with 75 ml of absolute ethanol and a few drops of concentrated sulfuric acid for I ¹ Z ₂ hours while slowly distilling off the ethanol. The ethanol is removed under reduced pressure and the residual oil is taken up in ether.

The ether extract is washed with water and cold sodium carbonate solution, dried, filtered and concentrated. By means of short-path distillation, 4.4 g of ethyl (4-butyryl-5-methyl-5,6,7,8-tetrahydro-1-naphthyloxy) acetate at 208 to 212 are obtained under a pressure of 0.5 mm ° C; nS ⁵ = 1.5364.

The crude product obtained after stage C is absolute by dissolving 53.0 g (0.215 mol) in 200 ml Ethanol and shaking with activated carbon containing 5% palladium under a pressure of 2.04 at of hydrogen shaken until hydrogen is absorbed in approximately the theoretical amount and the hydrogenation has ended. The mixture is filtered under nitrogen and the filtrate under reduced pressure Pressure restricted. Ethyl (5-methyl-5,6,7,8-tetrahydro-1-naphthyloxy) acetate is obtained in almost quantitative yield.

Analysis for C ₁₉ H ₂₆ O ₄ : ·.

Calculated ... C 71.67, H 8.23%; *

found .... C 71.60, H 7.98%.

The methyl ester is obtained if the above procedure is followed and methanol is used instead of ethanol begins.

Level H
Methyl (4-butyryl-5-methyl-1-naphthyloxy) acetate

9.11 g (0.03 mol) of methyl (4-butyryl-5-methyl-5,6,7,8-tetrahydro-1-naphthyloxy) acetate are in 100 ml of anhydrous benzene dissolved. Then 8.52 g (0.0375MoI) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are obtained added and the mixture stirred under reflux and nitrogen for 3 hours. Another 8.52 g portion (0.0375 mol) of quinone is added and the reflux treatment is continued for 16 hours.

The cooled reaction mixture is filtered and the filtrate under reduced pressure to a dark

IO

20th

len oil concentrated. This is taken up in 100 ml of ether, the ether solution thoroughly with water, cold sodium bicarbonate solution and again with Washed with water, dried and concentrated under reduced pressure. 5.90 g of methyl (4-butyryl-5-methyl-1-naphthyloxy) acetate are obtained as a yellow-brown solid. When recrystallizing from isopropanol-water a pure product with a melting point of 89 to 94 ° C is obtained.

Level I.
(4-Butyryl-5-methyl-1-naphthyloxy) acetic acid

By hydrolysing the product after stage H, the free acid is obtained in a yield of 82%. The white solid is recrystallized from isopropanol-water. This gives pure (4-butyryl-5-methyll-naphthyloxy) acetic acid of melting point 138.5 to 14O ⁰ C.

Analysis for C ₁₇ H ₁₈ O ₄ :

Calculated ... C 71.31, H 6.34%;
found .... C 71.11, H 6.42%.

Level J

[5-methyl-4- (a-methylenebutyryl) -l-naphthyloxy] acetic acid

A mixture of 0.65 g (0.00227 mol) of the product from stage I, 0.19 g (0.00233 mol) of dimethylamine hydrochloride, 0.07 g (0.00233 mol) of paraformaldehyde and 6 drops of glacial acetic acid is added the details of Example 6, level F, treated. To obtain a white solid in an amount of 0.35 g, melting at 137-141 ⁰ C from the ether layer. The aqueous layer is made alkaline with sodium bicarbonate solution and heated to 80 ° C. for 20 minutes. The solution is cooled to 20 ° C. and a small amount of insoluble resinous substances is removed by filtration. The filtrate is acidified. This gives a further amount of 0.23 g of the process product of melting point 136 to 139.5 ⁰ C. By recrystallization from n-butyl chloride obtained [5 - Methyl - 4 - (α - methylenebutyryl) -1 - naphthyloxy] acetic acid from melting point 144 g 0.53 to 145.5 ⁰ C. the yield, ie 78%.

Analysis for C ₁₆ H ₁₈ O ₄ :

Calculated ... C 72.46, H 6.08%;

found .... C 72.24, H 6.00%.

Claims (3)

Patent claims: 1. Substituted naphthyloxyacetic acids of the general formula CH, - COOH C = O
C ⁼⁼ CH ₂ wherein R is methyl or ethyl or in which, when R is ethyl, in the 2-, 3- or 5-position im Naphthalene nucleus has one hydrogen atom replaced by methyl or in the 2- or 5-position by chlorine is. 2. Process for the preparation of compounds according to claim. 1, characterized in that a compound of the general formula is used in a manner known per se O-CH, -COOH C = O CH ₂ where R is methyl or ethyl or in which, when R is ethyl, a hydrogen atom in the 2-, 3- or 5-position in the naphthalene nucleus has been replaced by methyl or in the 2- or 5-position by chlorine , with a salt of a secondary amine and converting formaldehyde or paraformaldehyde , treating the salt of the Mannich amine compound formed with a weak base and optionally converting the salt of the substituted naphthyloxyacetic acid obtained into the free acid in the customary manner. 3. Medicament, characterized by a content of a compound according to claim 1. 109553/437