DEC0010467MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration date: December 22, 1954 Announcement night on August 23, 1θ56

GERMAN PATENT OFFICE

PA TENTAN REGISTRATION UNG

CLASS 12q GROUP 29oi INTERNAT. CLASS C07c

C 10467 IVb / 12 q

Dr. Jean Druey, Riehen, and Dr. Hans Isler, Bottmingen (Switzerland)

have been named as inventors

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl. -Ing. E. Splanemann, patent attorney, Hamburg 36

Process for the preparation of r-acyl butyric acids

The priority of the application in Switzerland from December 29, 1953 and November 19, 1954

is used

The invention relates to the preparation of γ-acyl butyric acids of the general formula

CH ₃ O- / 'S-CO-CH ₂ -CH-CH ₂ -COOH OCH ₃

as well as their salts. In this formula, R denotes a lower alkyl or lower alkoxy radical or a Halogen atom, but preferably a hydrogen atom. The invention particularly relates to manufacture der /? - phenyl-y- (2,4-dimethoxy-benzoyl) -butyric acid 15 the formula

CH ₃ O—

^ -CO-CH ₂ - CH-CH ₂ -COOH

OCH,

and their salts, such as metal, especially alkali and 25 Alkaline earth metal salts, or ammonium salts.

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C 10467 IVbI 12 q

The new y-acyl butyric acids and their salts possess pharmacological properties which are valuable compared to known compounds. So they show one strong choleretic effect. They are said to be used as a remedy.

The sodium salt of / 5-phenyl- γ- ( 2,4-dimethoxy-benzoyl) -butyric acid z. B. p-tolylmethylcarbinol-camphorTestersaurenDiethanolamin (TCD), a synthetic ester of p-tolylmethylcarbinol found in the essential oil of Curcuma domestica (advances in therapy, 17, 301 [1941]), superior. As a basis of comparison, the 20 ° / _O strength increase in the bile is selected (ED _20).

Animal species / S-phenyl-y- (2, 4-d.imetb.0xy-
benzoyl) butyric acid Na salt
ED ₂₀ (mg / kg) TCD
ED ₂₀ (mg / kg) Intravenous administration:
Dog.......
Guinea pig .."......
Rabbits
rat
Oral administration:
Guinea pig 0.6. ; ■ ..
., ... ■ O ₇ O - - ■
20.0
13.0
100.0 1.2
• 30.0 -
inhibition
no effect until
30.0
600.0

The sodium salt of /? - Phenyl-y- (2,4-dimethoxybenzoyl) -butyric acid proves to be superior to TCD not only in its quantitative superiority, but also in that, in contrast to the latter, it is not selectively effective only in individual animal species. In addition, is at oral administration, the effect is particularly pronounced.

One embodiment of the process consists in converting into a compound of the general formula

in which R ₁ and R _{2 are} methoxy groups or substituents which can be converted into these, a radical of the general formula by reaction with / 3-phenylglutaric acids or their functional derivatives

. -CO-CH ₉ -CH-CH ₉ -Z

where 'Z stands for the carboxyl group or a radical that can be converted into it and R has the meaning given above, and, in whatever order, any radicals R ₁ and R ₂ or Z convertible into methoxy groups or convertible into the carboxyl group are converted into such groups .

In methoxy groups convertible residues are z. B. Free Oxygruppeni: starting materials that have the above radical with a free carboxyl group or with one in a able to introduce such a transferable group are, for. B; apart from the / S-phenylglucaric acids, their functional ones Derivatives; such as esters, nitriles, acid halides and anhydrides. The conversion happens after an known methods directly or in stages. So the etherification of free oxy groups z. B. with Dialkyl sulfates or alkyl halides carried out. Esters, nitriles or acid halides are saponified converted into the free acids.

Another embodiment of the method consists in that compounds of the general formula

CH,

R,

to the ethylene double bond of compounds of the general formula

-CH = CH-Z

adds, where R, R ₁ , R ₂ and Z have the meaning given above, and optionally _{converts the radicals R 1} , R ₂ and Z in the compounds obtained, as set out above. For example, 2,4-D1-methoxyacetophenone can be condensed with an alkyl cinnamate in the presence of condensing agents or in the form of its metal salts and the esterified carboxyl group can be converted into the carboxyl group by saponification.

In accordance with the process, it is also possible to proceed in such a way that compounds of the general formulas

CO-CH = CH

\ ■

M- * R

; ■ -

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C 10467 IVb / 12 q

and

CH,

in which R, R ₁ , R ₂ and Z have the meaning given above and Z _{1 is} a radical which can be replaced by hydrogen and in which Z and Z ₁ are selected in this way

ίο are that the methylene group is activated, condensed with one another, the radical Z _{1 is} replaced by hydrogen and optionally the radicals R ₁ , R ₂ and Z are converted.

The remainder of Z ₁ is z. B. an esterified carboxyl group, an acyl or nitrile group. These groups can be formed by methods known per se, e.g. B. by acid cleavage of a / J-ketocarboxylic acid ester or saponification of an ester or nitrile and subsequent decarboxylation, can be replaced by hydrogen. B. a malonic acid diester, an acyl acetic ester, a cyanoacetic acid ester or cyanoacetic acid amide in the presence of basic condensing agents or in the form of its metal compounds, e.g. B. alkali metal compounds, condense with a chalcone of the formula given, whereupon the radical Z ₁ and optionally the radicals R ₁ , R ₂ and Z are converted in the manner described in the compounds obtained.

The reactions are carried out in the presence or absence of diluents and / or condensation agents, at ordinary or elevated temperature and carried out in an open or closed vessel. Depending on the reaction conditions, the new compounds are in the form of the free acids or their salts, such as metal, e.g. B. alkali or alkaline earth metal salts, or ammonium salts obtained. From the Salts can be made free of acids in the usual way; from the acids can also prepare the salts by reaction with bases according to known methods.

The starting materials are known or can be prepared by processes known per se. Acids can also be used in the form of their salts. Preferably one uses such starting materials, that in the implementation of the end products described as particularly valuable arise.

As a remedy, the new compounds are used in the form of pharmaceutical preparations, which the new acids or their salts in admixture with a therapeutic, e.g. B. for enteral or Contain organic or inorganic carrier material which can be used for parenteral administration.

The invention is described in more detail in the following examples.

Example ι

In a well-stirred solution of 1 part by weight of resorcinol dimethyl ether and 1.4 parts by weight of phenylglutaric anhydride in 8.6 parts by volume of nitro) benzene, 1.9 parts by weight of aluminum chloride are introduced in small portions at a low temperature. After the entries have ended, stirring is continued for a few hours with ice cooling, left to stand overnight, then poured onto ice and the nitrobenzene is then blown over with steam. The steam distillation residue is cooled well, suction filtered and the residue on the suction filter is taken up in excess 2 percent sodium hydroxide solution. The solution is clarified with animal charcoal and acidified with 2N hydrochloric acid. Then, after good cooling, it is suction filtered and the residue is recrystallized first from dilute acetic acid (1: 1) and then from ethyl acetate. This gives /? - Phenyl-y- (2,4-dimethoxy-benzoyl) -butyric acid of the formula

. ■■■■■■. · ■ ... κ ./ · '. · ... '■'

CH ₃ O - <

CH ₉ - CH-CHo-COOH;

OCH.

from F. 113 to 115 ⁰ . Yield: 1.9 parts by weight.

Example 2 "

In a well-stirred solution of 5.5 parts by weight of resorcinol dimethyl ether and 8.8 parts by weight of β- (p -methoxyphenyl) -glutaric anhydride in 50 parts by volume of dry nitrobenzene, 10.7 parts by weight of aluminum chloride are introduced in small portions between 0 and 5 ° . The mixture is then stirred for a further 3 hours with ice cooling and left to stand overnight. This is followed by pouring onto 110 parts by weight of ice and distilling with steam until all the nitrobenzene has been blown over The aqueous solution, clarified with animal charcoal, is acidified with concentrated hydrochloric acid and exhausted with ether. The ethereal solution, dried over sodium sulfate, is evaporated to dryness. 2,4-dimethoxy-benzoyl) butyric acid of the formula

CH, 0

VcO-CH ₂ -CH-CH "-COOH OCH,

OCH ₃ ;;

which melts at 122 to 124 ^{0 after recrystallization from methanol.} Yield: 10.4 parts by weight. ^:

The / used as starting material - (p-methoxyphenyl) -glutarsäureanhydrid mp 165-157 ⁰ can by boiling ß (p-methoxyphenyl) glutaric acid are obtained with acetic anhydride.

: Example 3

In a well-stirred solution of 6.3 parts by weight and 10 parts by weight Resorcindimethyläther .beta. (p- chlorophenyl) -glutarsäureanhydrid dry in 50 parts by volume of nitrobenzene to wear between 0 and 5 ⁰ 12.2 weight parts of aluminum chloride in small por-

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options a. After the end of the entry, stirring is continued for a further 3 hours with ice cooling and over Left for the night. Then it is poured to 120 parts by weight Ice and distilled with steam until all the nitrobenzene is overdone. From the The distillation residue is poured off, the resin is taken up in 120 parts by volume of 1 η sodium hydroxide solution and etherified. The aqueous solution clarified with animal charcoal is acidified with concentrated hydrochloric acid and exhaustively etherified. The ethereal solution, dried over sodium sulphate, is evaporated to dryness. The remaining glassy mass is / S- (p-chloro-phenyl) -y- (2,4-dimethoxy-benzoyl) -butyric acid the formula

CHoO

- CHo - CH - CHo - COOH

OCH,

. Recrystallized from methanol, it melts at 104 to 10 6 °. Yield: 13.8 parts by weight.

The used as starting material /? - (p-chloro-phenyl) -glutaric anhydride from F. 131 to 133 ⁰ can by condensation of p-chloro-benzaldehyde with

Acetoacetic ester in piperidine and ethanol, hydrolysis of the p-chloro-benzylidene-bis-acetic acid ester obtained in this way with an aqueous solution of potassium hydroxide and boiling of the free ß- (p-chloro-phenyl) -glutaric acid with acetic anhydride.

From the / S-phenyl-y- (2,4-dimethoxy-benzoyl) -butyric acids described above their salts can be obtained in the usual way with bases. So you get z. B. their sodium salts by reacting the acids with the calculated amount of sodium hydroxide solution, evaporation of the solution and recrystallization of the residue an alcohol, e.g. B. from isopropanol.

The sodium salt of / 3-phenyl- γ- ( 2,4-dimethoxy-benzoyl) -butyric acid can advantageously be obtained in the following way:

24.15 parts by weight are carried in 3200 parts by volume of isopropanol Sodium Schnitzel a. When all the sodium has been dissolved, 328 parts by weight of? - phenyl-γ- (2,4-dimethoxy-benzoyl) -butyric acid are added added. 128 parts by volume of water are added dropwise to the boiling solution.

After adding a little animal charcoal, the mixture is kept ^{at the boil for a further x} / ₄ hours with stirring. Now it is sucked off while still hot and the filtrate is cooled while stirring. After standing overnight it is sucked off and. the suction filter residue was dried at 12 mm and 75 to 80 °. Yield: 338 parts by weight.

Example 4

176 parts by weight of ethyl cinnamate and 152 parts by weight 2,4-Dimethoxy-acetophenone are dissolved in 2000 parts by volume of absolute ether. To do this there 68 parts by weight of sodium ethylate and left to stand for several days. Then you shake it several times with a little water. Distilled unchanged from the dried ether residue Cinnamic acid ester and 2, 4-dimethoxy-acetophenone. The residue is obtained by heating for several hours saponified with 2N sodium hydroxide solution. After removing undissolved neutral bodies by extracting with The clear, aqueous-alkaline solution is acidified with ether and extracted exhaustively with chloroform. The dried chloroform residue is recrystallized first from dilute acetic acid and then from ethyl acetate. The / S-phenyl-y- (2,4-dimethoxy-benzoyl) butyric acid described in Example 1 is thus obtained from same melting point. Yield: 46 parts by weight.

Example 5

23 parts by weight of sodium are dissolved in 1000 parts by volume of absolute ethanol. 160 parts by weight of malonic acid diethyl ester and after a short time 268 parts by weight of eo-benzylidene-2,4-dimethoxy-acetophenone are added to the solution. The mixture is left to stand for several days at room temperature, then 224 parts by weight of caustic potash and 300 parts by weight of water are added and the mixture is refluxed for several hours. The ethanol is then distilled off at 12 mm, 1000 parts by volume of water are added and the mixture is extracted with ether. The clear, aqueous alkaline solution is extracted with hydrochloric acid 1: 1 acidified, extracted exhaustively with chloroform and the dried chloroform heated residue decarboxylation in order for several hours at 150 ^0th The residue is recrystallized first from dilute acetic acid and then several times from ethyl acetate. The acid described in Example 1 with a melting point of 113 ° to 115 ° is obtained in this way. Yield: 63 parts by weight.

Example 6

Dry in a well-stirred solution of 550 parts by weight of resorcinol and 950 parts by weight of / 3-phenylglutaric in 6000 parts by volume, nitrobenzene one carries an anhydrous zinc chloride in small portions at 95 to 98 ⁰ 1360 parts by weight. After the end of the entry, stirring is continued for a few hours at the above temperature and then left to stand overnight. It is poured onto 14,000 parts by weight of ice and the nitrobenzene is driven off by steam distillation. After cooling, the distillation residue is exhaustively extracted with ether and this ether extract is shaken out with saturated sodium bicarbonate solution until nothing is absorbed by the latter. The sodium bicarbonate solution clarified with animal charcoal is acidified with concentrated hydrochloric acid, extracted again with ether and the ether extract is dried over sodium sulfate. First /? - phenylglutaric acid and then crude / 3-phenyl-y- (2,4-dioxybenzoyl) -butyric acid can be obtained from the ether residue by dissolving it in ethyl acetate and fractional precipitation with petroleum ether. The latter is obtained in pure form by repeated recrystallization from ethyl acetate; F. 178 to 180 °. Yield: 60 to 80 parts by weight.

300 parts by weight / S-phenyl-y- (2, 4-dioxy-benzoyl) -butyric acid and 1000 parts by volume of 1 N sodium hydroxide are heated with stirring to 65 to 70 ^0th Now one drips at the same time 2300 parts by volume in soda

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alkali and 277 parts by weight of dimethyl sulfate in such a way that an alkaline reaction always prevails and the temperature is maintained at 65 to 70 °. When the dropwise addition is complete, the temperature is maintained at the above temperature for a further ¹ Z ₂ hours. The mixture is then cooled, concentrated hydrochloric acid is carefully added until the Congo acidic reaction has occurred, then extracted exhaustively with chloroform and this extract is dried over sodium sulfate. Recrystallization of the chloroform residue from ethyl acetate gives the /? - Phenyl-y- (2,4-dimethoxy-benzoyl) butyric acid with the same melting point as in Example i. Yield: 197 parts by weight.

Claims (1)

Patent claim: Process for the preparation of γ-acyl butyric acids the general formula CH, O CO-CH, -CH-CH ₉ -COOH OCH, - R in which R denotes a hydrogen atom, a lower alkyl radical, lower alkoxy radical or a halogen atom, as well as their salts, characterized in that one
a) into a compound of the general formula by reaction with /? - phenylglutaric acids or their functional derivatives are a radical of the general formula - CO - CH ₉ - CH - CH, - Z —R introduces or b) compounds of the general formula R ₁ - / V- CO - CH, to the ethylene double bond of compounds 55 of the general formula Y-CH = CH-Z attaches or c) compounds of the general formulas -CO-CH = CH CH ₉ condensed with each other, wherein R ₁ and R groups ₂ methoxy ⁸ ° or these convertible substituent, Z is the carboxyl group or a convertible therein radical and Z ₁ represents a replaceable by hydrogen radical, an optionally present group Z ₁ is replaced with hydrogen and 85 optionally _{Any radicals R 1} and R ₂ or Z which are present and which can be converted into methoxy groups or into the carboxyl group are converted into such groups and, if appropriate, the γ-acylbutyric acids obtained are converted into their salts with bases. 90 Considered publications: German Patent Specifications No. 881 944, 521 458.