DE1643646A1 - Oleanolic acid derivatives and processes for their preparation - Google Patents

Description

FATE N ADVOCATE DR. DIETER THOMSEN - DIPL INQ. HARRO TIEDTKE

case F. 1838 / P.

Munich ι August 18, 1967

Valley"

TfNfani β · «/ ft ··» 4 TtfeframmrirciMi Thopilcnt

Biorex Laboratories Limited London, England

Oleanolic acid derivatives and processes for their preparation

The present invention relates to new and therapeutically useful derivatives of oleariolic acid and relates to the manufacture of these derivatives.

The novel olcanolic acid derivatives according to the invention are compounds the general formula

COOR-

(D

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SAOORfQtNAl.

where R stands for an alkylene chain with 1 to 6 carbon atoms and R- and Rp, which can be the same or different, Mean hydrogen atoms or alkyl radicals with up to 6 carbon atoms. Derivatives also fall within the scope of the invention of these compounds having an 11-oxo group or an additional Double bond Contained in the 9 »11 position as well as the Alkali and alkaline earth salts of those compounds which have one or two free carboxylic acid groups.

The new compounds of the general formula I can be prepared by reacting the anhydride of the general formula HOOC-R-COOH, in which R has the meaning given above, with oleanolic acid to give compounds of the formula I in which R, and Rp each represent hydrogen atoms or with an alkyl oleanolate for the preparation of compounds of the formula I in which R _{1 represents} a hydrogen atom and Rp represents an alkyl group.

If compounds of the formula I are to be prepared in which R, denotes an alkyl radical, then is preferred Oleanolic acid or an oleanolic acid alkyl ester with an acid halide of the general formula, R ^ OOC-R-COHaI, where R and R, which have the meanings given above and Hai stands for a halogen atom, brought to implementation.

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For the preparation of such Veroindungen of the formula I which contain a 11-oxo group or a 9 * H double bond, it is possible to start from 6s corresponding Oleanolsäurederivaten, ie, from the LL-0XO-LŠSS-olean-12-en-28- acid or the ISβ-01eana-0 (II), 12-dicn-2S-acid or an ester of such. ¹ pc. Optionally, oleanolic acid or an oleanolpäurepo'-or with an acid anhydride or acid halide in cer vorr, teho ;; ri oenchrie oeneu V / eise be converted, whereupon an 11-oxo group or a 0.11 double bond is introduced in known catfish .

The following examples illustrate the invention, without sio to restrict:

example 1

Succinic anhydride is purified by dissolving it in acetyl chloride and refluxing for a period of ten minutes. The solution is cooled, whereupon the kri.- '. line product is filtered off, washed copiously with ^ ether and dried in vacuo. Succinic Anhydride is used in Forr? * obtain white needles of P. 119.3 ois 119.6 ⁰ C. A solution of ^ g of methyl oleanolate in 50 ml of purified fyrldine is mixed with 1.3 g of the purified succinic anhydride

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mixed and refluxed for 8 hours. The solution is left to stand overnight, after which 200 ml of chloroform are added and the solution is poured into a mixture of ice and dilute hydrochloric acid . The chloroform layer is washed three times with 50 ml portions of a dilute hydrochloric acid saturated with sodium chloride and then three times with 50 ml portions of water, and then dried over anhydrous magnesium sulfate. When the chloroform solution evaporates, approximately 3 g of a brown, rubbery mass are obtained (yield 7 * 5 $). During the crystallization from methanol, white needles with a temperature of 185 to 193 ° C are obtained. Examination of the product by means of thin-layer chromatography together with methyloleanol and a mixed spot shows that only a partial conversion has taken place: the Rp value for Methyloleano.1 ί is 0.65, while the Rp-V / ert for methyl- ~ 5S -0-car'ooxypropioriyloleanolat is found to be 0.67.

If the above reaction is repeated with the product, an improved yield of the hemisuccir.a of methyl oleanolate is achieved. In the case of fractional crystallization from aqueous methanol, panels with a P. of 140 to 145 ^e C ([et] _D + 61.7 ° (c. * L, 01)) * are obtained.

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Analysis: C ,, Hj-qO, (molecular weight 470) ^: calculated: C 78.9 # H 10.6 # ^C 35 ^H 54 ° 6 (molecular weight 570) calculated: C 73.7 # H 9 found: Jk, 6 % 9

In the case of fractional recrystallization, the melting points are of the analysis samples not changed.

Example 2

A solution of 5 g of succinic anhydride in 50 ml of pure l; ^r , tf pyridine is treated with 5 g of oleanolic acid. The mixture was heated under reflux for 3 hours. The pyridine is removed by evaporation, leaving a dark solid. This solid is dissolved in chloroform and ligroin is added. The precipitate formed is filtered off rd w ^, where it turns out that it consists of succinic anhydride having a melting point of 110 to LL8 ^e C. The solution is evaporated to give a white solid. The investigation of the product by Dünnschichtchromato ^ ra phy shows together with oleanolic acid for comparison that the mixture contains 4 components whose values Rp 0.64, 0, ^l y '., Amount to 0.37 and 0.21. The bp value for oleanolaic acid was 0.58. In the case of fractional recrystallization from methanol, there is no separation of the components. The adsorption

BATH

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16436 Fig

this product on silica gel (35 χ 3 cm) and an elution with a mixture of ligroin and benzene consisting of equal parts by volume yield fractions that only contain oleanolic acid contains. A further elution with benzene gives mixtures of oleanolic acid with ^ ß-O-carboxypropionyl-oleenolic acid. Each fraction collected is analyzed by thin layer chromatography using oleanolic acid as the reference substance.

Example 3

The product · the reactions described in Examples 1 and 2 are combined, wherein the amount ungefa'hr 5 Z. This mixture contains oleanolic acid, its methyl ester and the hemisuccinate of the acid and the ester. A solution of this mixture in 100 ml of chloroform is treated with an excess of diazomethane in ether and left to stand overnight. The solvents are then evaporated and the residue is dissolved in 50 ml of chloroform / benzene. The solution is treated with a solution of 5 ml of β-carbomethoxypropionyl chloride in 7 ml of benzene, the solution being cooled during the addition. A drop of concentrated sulfuric acid is then added and the mixture is shaken for 1 hour. The mixture is poured into 50 ml of a dilute nitrium carbonate and extracted with three 100 wl portions united and three times it 50 m portions

IOtUI / 1717 * θαο original

Water washed. The solution is examined by means of thin-layer chromatography ie together with methyl oleanolate. It will only one pleoken with an Hp value of 0.74 was determined. Of the

R value for methyl oleanolate is 0.65. The ethyl acetate F

solution is dried over anhydrous magnesium sulfate and the solvent is evaporated . A yellow solid with a melting point of 147 to 159 ° C. (5.6 g, yield 90/6) is obtained. This is adsorbed on deactivated aluminum oxide and eluted with ligroin-benzene-ether. The fractions eluted with benzene contain only one component, while the later fractions contain traces of methyl oleanolate. The benzene fractions are combined and evaporated. Recrystallization from methanol / ethyl acetate provides methyl-3P-0-carbomethoxypropionyl-oleanolat in the form of needles having a melting point 164-167 ⁰ C. After recrystallization from methanol, the compound has an I66 of F. to 167 ⁰ C (UJ _D + 57.3 ° (c = 1.04)).

Analysis: ^c * 6 ^H r6 ° 6 (molecular weight 584) calculated: C 74.0 # H 9 found: 73.7 # 9

Example 4 »

A solution of 2.5 g of chromium trioxide in 35 ml 90jC-acetic acid is in the course laugsam -from JO minutes dropwise

«■

a solution of 2.6 g of methyl- ^ ß-O-methoxycarbonylpropionyl-

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1 [

180 oleanolate was added in 23 ml of glacial acetic acid. The mix will

S then refluxed for 90 minutes. Then 10 ml of water is added and the solution is allowed to cool. The white precipitate formed is filtered off, washed with water and dried to yield 2.1 g of a material. This material is adsorbed on 150 g of deactivated aluminum oxide and eluted with petroleum ether-benzene-ether. The fractions eluted with benzene and ether give in thin-layer chromatography only one spot with an R _p value of 0.63 (the R _p value for methyl 3β-0-carbomethoxypropionyl oleanolate is 0.7 ^ ·) · The Umkristalllsation three times from methanol / water yields 3.beta.-methyl-0-carbomethoxypropionyl-ll-oxo-l3ß-oleanolat in the form of needles having a melting point from 193 to 195.5 ⁰ C ([aJ _D * 66 + 2 ° (c = 0.87 in chloroform)).

Analysis: Calculated C- ^ H ^ O «(molecular weight 598); C 72.0 # H 9.0 $ found: 71 > 3% 8.9 #

Example 5

A solution of 212 mg of methyl 3β-0-carbomethoxypropionyl-iloxo-18β-oleanolate in 10 ml of dimethylformamide is mixed with about 1 g of dried lithium iodide and placed in a flask given, which is provided with a reflux condenser. The solution is after saturating the apparatus with nitrogen for 22 hours

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ORHSiNM.

heated under reflux for a long time. Strict attention is paid to the exclusion of air and water. The reaction mixture is poured into 100 ml of ice and water, whereupon the precipitate formed is filtered off. The precipitate is washed with water and dried to give 176 mg of material (84 # yield). Recrystallization from acetic acid falls 3.beta. ~ 0-carboxypropionyl-ll-oxo-l8ß-oleanolic acid in the form of bars with a F. 257-278 ⁰ C. ^

Example 6

A solution of 220 mg of methyl- ^ ß-O-carbomethoxypropionyl oleanolate in 10 ml of dimethylformamide is mixed with approximately 1 c dry lithium iodide. The solution is saturated with dry nitrogen and refluxed for 20 hours. The nitrogen is bubbled through a solution of silver nitrate ¹ in alcohol. It forms a white precipitate that darkens the light and is insoluble with the addition of nitric acid the like. The reaction mixture is cooled and poured into 100 ml of water. The precipitate formed is filtered off, washed with water and dried. In this case, 200 mg of a material (yield - "$ 82) get; Recrystallization from acetic acid falls 3.beta.-0-carboxypropionyl-oleanolic acid in the form of bars having a melting point 260-265 ⁰ C. The product is purified by Dünnschichtchromgraphie.. A spot with an R ^ value is examined

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discovered by 0.2. The R _p value for the original carbomethoxypropionate is 0.7 ^

Example 7

A solution of 1.7 g of 3.beta.-0-Carooxypropionyl-oleanolic acid in 50 ml of carbon tetrachloride and 3 * 6 ml of petroleum ether (Kp.6 ') to 80 ⁰ C) is treated with 0.34 g N-bromosuccinimide. The reaction mixture is irradiated for 7 minutes with a 250 watt lamj *, during which time the mixture is under

Reflux is maintained. The reaction mixture is cooled rapidly and the succinimide formed is filtered off. 30 ml of xylene and 10 ml of pyridine are added to the filtrate, whereupon the solution is evaporated at ⁰ ° C. to remove low-boiling solvents. After the addition of 5 '"1 pyridine, the solution is refluxed for 20 minutes and then filtered. A yellow solid is obtained on evaporation of the solvent under reduced pressure. Recrystallization from aqueous ethanol and then from aqueous acetic acid yields 3ß-0-carboxypropionyl-l8 ^ - oleana-9 (ll), 12-dien-28-acid in the form of needles with a melting point of 256 to 257 ^° C.

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Claims (1)

- 14 -patent claims 1. Oleanolic acid derivatives of the general formula COOR ₂ R ₁ OOC-R-COO where R stands for an alkylene chain with 1 to 6 carbon atoms and R, and R ^, which may be the same or different k ^: h ;, o _w , represent hydrogen atoms or alkyl radicals with up to 6 carbon atoms, derivatives of these Veroindungen, which have a 11 -Oxo group or an additional double bond in the 9, ll-3tellu !. _; contain as well as the alkali and alkaline earth salts $ of those compounds which have one or two free carboxylic acid groups, Ä 2, methyl- ^ ß-O-carboxypropionyl-oleanoxate, 5. ^ ß-Q ^ carboxypropionyl-oleanolic acid. k, methyl- ^ ß-O-carbomethpxypropionyl-oleanolat. 5. Methyl- ^ ß-O-carbomethoxypropionyl-ll-oxo-lSß-oleanolate. 109838/1717 - 12 - - i • r. ■ Γ 6. 3fl-O-Carboxypropionyl-11 -oxo-18ö-oleftnolsäure · 7. 3S-0-carboxypropionyl-18β-olean-9 (II), 12-diene-28-acid. 8. Process for the preparation of oleanolic acid derivatives according to Claim 1, characterized in that a compound of the general formula wherein JU has the meaning given above, or a corresponding compound which has an 11-oxo group or a contains additional double bond in the 9, ll-3 position, either with an anhydride of an acid of the general formula HOOC-R-COOH, where R is as defined above possesses, for the manufacture of a product in which Rg for represents a hydrogen atom, or is reacted with an acid halide of the general formula R ^ OOC-R-COHal, in which R has the meaning given above. Shark for one Halogen atom and Rj is an alkyl radical with up to 6 carbon 109938/1717 Λ ': ^: represents material atoms, to obtain a product in which Rp denotes an alkyl radical * is reacted, whereupon, if R- and / or R «stand for Vfassstoff, the product obtained is optionally converted in a known manner into the corresponding alkyl ester or in a known manner Manner is converted into a corresponding alkali or alkaline earth salt, if the product obtained has no 11-oxo group or double bond in the 9, H position, such a group or double bond is optionally then: - Λ send is introduced in a known manner. 109838/1717