DE1248038B - Process for the preparation of Glycyrrhetinsaeure- and Oleanolsaeureamid and derivatives thereof - Google Patents

Description

GERMAN

E ₁ UT ₁ SCHLAND PATENT OFFICE Int. Cl .:

C07c

fit /

t / 3

EDITORIAL

German KL:

Number:
File number:
Registration date:
Display day:

B85538 IVb / 12ο
January 25, 1966
August 24, 1967

The invention relates to a process for the preparation of glycyrrhetinic acid and oleanolic acid amide as well as derivatives thereof of the general formula

wherein the radicals R are hydrogen atoms, Ci- to Ce-alkyl-, Ca- to Cs-cycloalkyl-, arylated Ci- bis Ca-alkyl or optionally by carboxylic acid, esterified carboxylic acid groups, halogen atoms, alkyl or haloalkyl radicals, substituted aryl radicals or together with the nitrogen atom form a heterocyclic ring which has 4 to 8 carbon atoms and optionally additionally sulfur, oxygen, nitrogen or an alkyl-substituted one Contains nitrogen, and X represents the glycyrrhetinyl or oleanolyl radical, the 3-hydroxy group can be esterified with an aliphatic Ci- to Cäo-monocarboxylic acid, or X denotes the 3-ketoglycyrrhetinyl or 3-Ketooleanolylrest, whereby one so works that in a known manner the acid chloride of 3-O-acylglycyrrhetinic acid or 3-O-acyloleanolic acid, 3-ketoglycyrrhetinic acid or 3-ketooleanolic acid with an amine of the general types Formula (R> 2NH converts and if desired the acyl group is hydrolyzed to release the hydroxy group.

COOH

HO

Process for the preparation of glycyrrhetinic acid and oleanolic acid amide and derivatives thereof

Applicant:

Biorex Laboratories Limited, London

Representative:

Dr. D. Thomsen and Dipl.-Ing. H. Tiedtke,

Patent Attorneys, Munich 2, Tal 33

Named as inventor:

John Cameron Turner, West Wickham, Kent;

William Alan McFarlane Davies,

Ilford, Essex (UK)

Claimed priority:

Great Britain 11 February 1965 (5891),
dated May 6, 1965 (19 063),
of October 7, 1965 (42 551)

The two parent acids on which the new compounds are based have the following structural formulas :

COOH

Glycyrrhetinic acid

Oleanolic acid

The new compounds prepared by the process according to the invention have interesting ones pharmaceutical properties such as excellent anti-inflammatory efficacy and low toxicity compared to comparable derivatives.

In the new compounds, R can mean methyl, ethyl, propyl, isopropyl, butyl or have hexyl. R can also represent, for example, cyclobutyl, cyclohexyl, cyclooctyl or have the meaning of butyl or ethylbenzene radicals, also phenyl radicals or in the specified Wise substituted phenyl radicals mean. If with the participation of the two radicals R together a heterocyclic ring is formed with the nitrogen atom, one may additionally be contained therein

709 638/574

Nitrogen atom can also be substituted by alkyl, so come the heptamethylene, piperazine, N-methylpiperazine or morpholining in question

Acids with which the 3-hydroxyl group is esterified can be, for example, acetic acid, Propionic acid, butyric acid, alkaline acid or stearic acid

The hydroxyl group of the parent acid is first protected by acylation for preparing the novel compounds according to the invention, _{beispiels-] 0,} by reaction with a Saureanhydnd Odei Sa, urehalogenid, then the carboxyl group is dei acyl compound thus obtained by reaction, for example with thionyl chloride, m a Acid chloride converted The acid halide obtained in this way is then reacted with the amine and then, if desired, the acyl group is hydrolyzed to liberate the hydroxyl group

The invention is explained below with reference to some Examples illustrated in more detail

example 1

30 g of S-O-acetyl-lSß-glycyrrhetinic acid chloride and 60 g of cyclohexylamine are heated to 80 ° C. for 1 hour, the reaction mixture is then cooled and poured into 50 ecm petroleum ether. The solid product obtained is filtered off and recrystallized, first from methanol and then from aqueous dimethylformamide. 10 g 3 - O - acetyl -18 / i - glycyrrhetinic acid - 30 - (cyclohexylamide) obtained in the form of a white, odorless powder with a melting point of 264 to 265 C, [a] f = + 133 + 1 ° (c = 1% in chloroform)

3-O-acetyl-18 / i-glycyrrhetinsaure-30-N-piperazid can also be used in an analogous manner can be prepared, m.p. 273-274 C.

Example 2

20 g of 3-O-acetyl-18ß-glycyrrhetinic acid chloride and 50 g of heptamethyleneimide are heated for 1 hour at 100 ° C., the reaction mixture is cooled and 300 ecm of petroleum ether are added there.The product obtained is filtered off and recrystallized several times from aqueous ethanol about 6 g of 3-O-acetyl-18 / i-glycyrrhetic acid-30- (heptameth> lenimide) were obtained in the form of white odorless needles with a melting point of 249.5 to 250 ° C., [a] ² _D ⁵ f-122 ± l ° (c-1% in chloroform)

B e 1 s ρ 1 e 1 3

35 g of 3-O-acetyl-18ß-glycyrrhetinsaurechlorid are dissolved in 200 ecm diethylamine, the solution is left for 1 hour at room temperature then from methanol-ethyl acetate (4 1) 15 g of 3-0-acetyl-18 / i-glycyrrhetinic acid diethylamide are obtained in the form of white, odorless needles with a melting point of 228 to 229 ° C., [a] f = 4 117.5 + 1 ° (c-1% in chloroform)

B e 1 s ρ 1 e 1 4

3-O-Lauroyl-18a-glycyrrhetinic acid is used in the Corresponding acid chloride is converted by adding it to benzene with a large excess of thionyl chloride is heated, the benzene and excess Thionyl chloride are distilled off in vacuo, the The last traces of thionyl chloride are obtained by redissolving the product in dry benzene and again evaporation removed. The acid chloride obtained is used as such without further purification used

2.5 equivalents of N-methylpiperazine are added to a benzene solution of this acid chloride, and the solution is boiled for 20 minutes.After cooling, N-methylpiperazine hydrochloride, which has been formed as a by-product, is filtered off, the filtrate is concentrated to a small volume, and the residue is allowed to crystallize. For purification, the product is recrystallized from methanol, a 30-40% yield of 3-O-lauroyl-18 «-glycyrrhetinic acid-30- (N-methylpiperazide) in the form of a white, odorless Powder with a melting point of 159 to 160 C gives [a] ²⁰ = + 47.5 + 1 (c - 1% in chloroform)

In an analogous manner, 3-O-Lauroyl-18 / i-glycyrrhetinsaure-30- (N-methylpiperazid) obtained, which can be purified by recrystallization from petroleum ether and then from hexane, mp 105-105 ° C ["]" = H105 + 1 ° (c = 1% in chloroform)

Starting from 3-Ketoglycyrrhetinsaurechlorid and N-methylpiperazine using the procedure described in example 1 is 3-ketoglycyrrhetinsaure-30- (N-methylpiperazide) manufactured

Example 5

3-O-acetyl -1 S- glycyrrhetinic acid chloride (prepared by boiling a mixture of acetylglycyrrhetinic acid and thionyl chloride for at least 30 minutes and then removing the excess thionyl chloride) is heated for 1 hour at 80 ° C with a four-fold excess of N-methylpiperazine. The reaction mixture is heated then poured into cold water, the reaction product, which separates out, is filtered off, washed with cold water and dried. (N-methylpiperazide) obtained in a yield of about 50% of the theoretical yield, melting point 243 to 245 C, [a] ² _D ° = + 120 + 1 ° (c - 1% in chloroform)

Example 6

9 g of the 3-O-acetyl-18 / ^ - glycyrrhetinsaure-30- (N-methylpiperazid) according to Example 5 are heated for 2 hours at 60 ° C. in 200 ml of 50% alcohol with a content of 10 g of potassium hydroxide. The reaction mixture is then poured into cold water, the precipitated reaction product is filtered off, washed with water and dried. After recrystallization from aqueous dimethylformamide, 5 g of ISβ - glycyrrhetinic acid-30- (N-methylpiperazide) are obtained, melting point 252 to 253 ° C. [a \ ² S = + 140 + 1 (c = 1% in chloroform)

B e 1 s ρ 1 e 1 7

3-O-Acetyl-18 / ^ - glycyrrhetinsaurechlond is used in about 80 C for 30 minutes with a quadruple

Excess m-fluoromethylanilm is heated. The reaction mixture is then poured into dilute hydrochloric acid, the precipitated reaction product is filtered off, washed first with dilute hydrochloric acid and then with water and dried. After recrystallization from aqueous ethanol, pure 3-O-acetyl-18/3-glycyrrhetinic acid is obtained -30- (m-fluoromethylanilide) obtained in a yield of about 70% of the theoretical yield, mp 262 to 263 ° C, [a] i ° = +166 ± 1 ° (c = 1% in chloroform)

Example 8

15 g of 3-O-acetylenic acid chloride and 25 g of Me- i <; thylanthranilat are mixed together well and heated for 40 minutes at 170 to 180 ° C. After cooling, the reaction mixture is dissolved in ether and extracted several times with dilute hydrochloric acid and then with water Ethanol is purified. In this way 15 g of 3-O-acetyloleanolic acid-28- (o-carbomethoxyanihd) are obtained, melting point 216 to 217 ° C., [a] f = 32 ± 1 ° (c = 1% in chloroform)

Example 9

13 g 3-O-Acetyloleanolsaure-28- (o-carbomethoxyanihd) and 7 g of potassium hydroxide are dissolved in 170 ml of 80% warm aqueous ethanol and heated for 2 hours at 50 to 6O ⁰ C The solution is then acidified with dilute hydrochloric acid, the precipitated product is filtered off, washed with water and dried. The product is purified by recrystallization from aqueous ethanol. 8 g of oleanolic acid-28- (o-carboxyamlide) are obtained, mp 232-234 ° C., [a] i ° = - ^ 35 ± 4 ^Ü (c - 0.2% in chloroform)

Example 10

15 g of acetyl-18 / f-glycyrrhetinic acid chloride (manufactured by boiling a mixture of acetyl-18 / i-glycyrihetic acid and thionyl chloride for at least 30 minutes and then removing the excess Thionyl chloride) are mixed with 75 ml of pyndine and 15 g of anthranilic acid at 100 ° C. for 1 hour The reaction mixture is cooled to room temperature and acidified, the solid product is filtered off and from aqueous acetic acid recrystallized, 10.3 g of 3-O-acetyl-30-anthranihd of 18/3 glycyrrhetinic acid result in this Product has a melting point above 350 ° C

55 Example 11

10.3 g of the 3-O-acetyl-30-anthranihd of 18 / ^ - glycyrrhetinic acid according to Example 10 are dissolved in 50% aqueous methanol containing 6 g of sodium hydroxide, and the reaction mixture is kept at 50 ° C. for 3 hours acidification of the reaction mixture led to the precipitation of the 30-anthranilide of 18 / i-glycyrrhetinic acid, this product is isolated and purified by recrystallization from aqueous dimethylformamide. The yield is 8 g, the compound has a melting point of about 355 ° C, EJ ^ _n , = 439 ± 5 at 253 ηΐμ in methanol with a content of 4% 1 n-sodium hydroxide solution

Example 12

20 g of SO-acetyl-lS-glycyrrhetinic acid chloride, 30 g of methyl p-aminobenzoate and 25 ml of pindine are heated for 2 hours at a bath temperature of 130 ° C., the cooled reaction mixture is then added to 300 ml of ether and 100 ml of chloroform is washed with dilute hydrochloric acid and then with water. The organic layer is separated and dried over anhydrous sodium sulfate, the solution is evaporated to dryness and the residue is recrystallized first from aqueous alcohol and then from acetone-ether, with 17 g of 3-O -Acetyl-30- (p-carbomethoxyanihd) der 18 / i-Glycyrrhetinsaure result, this product has a melting point of 282 to 283 ⁰ C, [«]" - 200i 1 ° (c = 1% in chloroform)

Example Π

15 g of the 3-O-acetyl-30- (p-carbomethoxyanihd) of 18 / i-Glycyrrhetinsdure according to Example 12 are finely ground and heated for 2 hours at 50 C with 300 ml of ethanol and 50 ml of 20% potassium hydroxide solution Allowing to cool to room temperature and further standing for a certain time, the reaction mixture is acidified and diluted with water, resulting in a solid product which is isolated and recrystallized from aqueous acetic acid, 11 g of 30- (p-carboxyanide) of 18 / i -Glycyrrhetinic acid with a melting point of about 355 C, [a] _D - + 215 ± 4 ° (c - 0.2% in chloroform)

Example 14

A mixture of 20 g of 3-O-acetyl-18 / i-glycyrrhetinsaurechlond and 25 ml of morphoene is heated for 1 hour at a bath temperature of 100 C. The reaction mixture is then cooled and diluted with water, the precipitated solid is filtered off and recrystallized Aqueous ethanol isolated, giving 19 g of 3-O-acetyl-30-morpholide of 18 / y-glycyrrhetinic acid with a melting point of 252 to 254 C, [«] ₀ - -h129 ± 1 (c-1 ° / o in Chloroform) Further recrystallization did not change the melting point

Example 15

17 g of 3-O-acetyl-30-morphohd of 18 / i-glycyrrhetinic acid according to Example 14 are mixed with 300 ml of ethanol and 12 g of sodium hydroxide in 15 ml of water and heated to 50 ° C. for a few minutes, resulting in a clear solution, the temperature is then kept at 30 to 40 ° C. for 2 hours. A crystalline precipitate begins to separate out after about 30 minutes 13.5 g of pure 30-morpholide of 18 / i-glycyrrhetic acid result, this product has a melting point of 243 to 245 C, [u] _D = + 141 ± 1 ° (c = 1% in chloroform)

Claims (1)

Claim: Process for the preparation of glycyrrhetinic acid and oleanolic acid amide and derivatives same of the general formula / ^R in which the radicals R are hydrogen atoms, Ci- to Ce-alkyl, C ₄ - to Cs-cycloalkyl, arylated Cibis Ca-alkyl or aryl radicals optionally substituted by carboxylic acid, esterified carboxylic acid groups, halogen atoms, alkyl or haloalkyl radicals or together with form a heterocyclic ring with the nitrogen atom, which contains 4 to 8 carbon atoms and optionally also sulfur, oxygen, nitrogen or an alkyl-substituted nitrogen, and X represents the glycyrrhetinyl or oleanolyl radical, where the 3-hydroxy group can be esterified with an aliphatic Ci- to Gzo-monocarboxylic acid, or X the 3 -Ketoglycyrrhetinyl or 3-ketooleanolyl radical, characterized in that the acid chloride of 3-O-acylglycyrrhetinic acid or 3-O-acyloleanolic acid, 3-ketoglycyrrhetinic acid or 3-ketooleanolic acid with an amine of the general formula (R ) ₂ NH converts and, if desired, hydrolyzes the acyl group with liberation of the hydroxyl group. A test report was displayed when the registration was announced. 709 638/574 8 67