AT230878B - Process for the preparation of new aliphatic α-hydroxycarboxylic acids substituted by an aromatic radical and derivatives thereof - Google Patents

Description

  

   <Desc / Clms Page number 1>
 



  Process for the preparation of new aliphatic (1-hydroxycarboxylic acids and derivatives thereof substituted by an aromatic radical)
The invention relates to a process for the preparation of compounds suitable for use in antihypertensive agents, u. between the production of aryl-substituted aliphatic a-hydroxycarboxylic acids, which act as inhibitors for mammalian decarboxylase. This property is valuable for the formation of antihypertensive agents. Some of these compounds act as antihypertensive agents by themselves.



   The compounds prepared according to the invention have the general formula
 EMI1.1
 in rut means a straight-chain lower alkyl radical, and also include the alkali and ammonium salts and the esters.



   According to the invention, the compounds can be prepared from a ketone of the general formula
 EMI1.2
 are shown, in which Rl has the above meaning.



   The preparation according to the invention of the compounds can be illustrated by the preparation of 2- (3 ', 4 * -dihydroxybenzyl) lactic acid (V) from 1- (3', 4'-dimethoxyphenyl) -2-propanone (I) by the following reaction scheme will :

 <Desc / Clms Page number 2>

 
 EMI2.1
 
 EMI2.2
 

 <Desc / Clms Page number 3>

 



    The compounds prepared according to the invention inhibit mammalian decarboxylase when they are administered orally in daily doses of about 0.25 to about 10 g, preferably divided over the day. The preferred dose is in the range of about 0.5 to 5 g per day. These compounds can be found in gelatin capsules. are served, which contain about 0.1-0.5 g of active ingredient, as well as tablets that contain about
 EMI3.1
 aqueous suspensions can be administered orally. On the other hand, the connections can also be in the form of their
Alkali salts in sterile solutions in suitable solvents, such as water, are administered parenterally in daily amounts of about 0.1 to 2 g, which are preferably distributed over the day.

   If the compounds are used in combination or in a mixture with agents that cause a strong withdrawal of
Catecholamines from the heart and brain tissue have an antihypertensive effect.



   Some of these compounds are antihypertensive on their own, possibly because they have both of these properties.



     Example: a) 2- (3 ', 4'-Dimethoxybenzyl) -lactonitrile: A solution of 63 g (0.967 mol) potassium cyanide and 126 g (0.649 mol) 1- (3', 4'-dimethoxyphenyl) - - 2-propanone (I) in 145 cm3 157.5 cm3 of 400% sulfuric acid are added dropwise to water and 363 cm3 of methanol over the course of 6 h. During the addition of the sulfuric acid, the mixture becomes
 EMI3.2
    (3 ', 4'-Dimethoxybenzyl) -lactonitrile47.7 g (0.215 mol) 2- (3', 4'-dimethoxybenzyl) -lactonitrile (II), prepared according to section a), are 36% strength with 108 cm3 Hydrochloric acid added. The mixture is refluxed for 5 h, then cooled to room temperature and extracted with ethyl acetate.

   The ethyl acetate extract is washed with water, treated with 1 g of decolorizing charcoal ("Nuchar C"), filtered and concentrated in vacuo to a small volume of liquid which contains crystals. When adding 100 cm3 of ether, the product crystallizes out completely. The mixture is left to stand for 16 hours, filtered and washed and the crude 2- (3 ', 4'-dimethoxybenzyl) lactic acid is dried. Bulge 24, 84 g; M.p. 118-121 C; # CH3OH m (E% 339), max 278 mil (E% 112), 283 mg (shoulder) (E% 102).



    - c) 2-Acetoxy-2- (3 ', 4'-diacetoxybenzyl) propionic acid: 13.85 g (0.0627 mol) of the 2- (3', 4'-dimethoxybenzyl) lactic acid prepared according to section b) (III) 78.5 cm3 of 58% hydrobromic acid are added. The mixture is blown out with nitrogen, heated on the reflux condenser for 2 h and concentrated in vacuo. The residue is dissolved in tert-butanol and evaporated to dryness in vacuo. This procedure is repeated.



   The residue of crude 2- (3 ', 4'-dihydroxybenzyl) lactic acid finally obtained is dissolved in 65 cm3 of pyridine and the solution, with cooling of the reaction flask from the outside to an internal temperature in the range of 10 to 20 ° C., is 65 cm3 Acetic anhydride added. The reaction mixture is left at room temperature for 16 hours and then evaporated to a resin in vacuo. The resin is dissolved in ethyl acetate and the solution is extracted successively with dilute hydrochloric acid, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue is recrystallized from a solution of 5010 benzene and 50% hexane.

   2-acetoxy-
 EMI3.3
 Band), 5, 7 p-5, 75 u, 5.85 p, 6.25 p and 6.61 u.
 EMI3.4
 
<tb>
<tb>



  Analysis <SEP>: <SEP>
<tb> Calculates <SEP> for <SEP> C <SEP> H <SEP> 0 <SEP>: <SEP> C <SEP> = <SEP> 56, <SEP> 80lu <SEP>; <SEP> H <SEP> = <SEP> 5, <SEP> 36lu <SEP>; <SEP>
<tb> found <SEP>: <SEP> C <SEP> = <SEP> 56, <SEP> 72% <SEP>; <SEP> H <SEP> = <SEP> 5, <SEP> 66%. <SEP>
<tb>
 

 <Desc / Clms Page number 4>

 
 EMI4.1
 according to section c), 86.3 cm3 of 2, 5N hydrochloric acid and 30 cm3 of water are flushed with nitrogen and heated to reflux temperature for 2 h under a nitrogen atmosphere. The reaction mixture is in vacuo
 EMI4.2
 
 EMI4.3
 
<tb>
<tb> 4'-Dianalysis <SEP>:
<tb> Calculated <SEP> for <SEP> C18H12O5 <SEP>: <SEP> C = 56.60%; <SEP> H = 5.7%;
<tb> found: <SEP> C = 56.64% <SEP>; <SEP> H = 5.97%.
<tb>
 



   This product is purified by dissolving it in ether and slowly evaporating the solvent, producing long, transparent needles; M.p. 95-1010C (dec.).

 

Claims (1)

PATENT CLAIM: Process for the preparation of new aliphatic α-hydroxycarboxylic acids of the general formula which are substituted by an aromatic radical EMI4.4 in which R is a straight-chain lower alkyl radical, and derivatives thereof, characterized in that a ketone of the formula EMI4.5 with an alkali metal cyanide and a strong mineral acid, the resulting nitrile is hydrolyzed with an aqueous solution of a mineral acid, in the resulting α-hydroxycarboxylic acid by heating with about 35 to 55% hydrobromic acid to a temperature in the range from 90 ° C. to the reflux temperature Methyl ether groups are demethylated, and optionally in the thus obtained? -Hydroxy-ß-hydroxyphenylalkanoic acid acylates the free hydroxyl groups by reaction with a lower aliphatic carboxylic acid anhydride in the presence of a free base and the acyl derivative is rehydrolyzed to α-hydroxy-ß-hydroxyphenylalkanoic acid or the carboxyl group is esterified with a lower alkanol or an alkanol or subjected to ammonium salt formation.