DE2261832A1 - 5-DIHYDROCORIOLIN C AND METHOD FOR MANUFACTURING THE SAME - Google Patents

Description

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8l-l-9 -.- 93.7P. 1 "8 -, - 12. 1972

ZAIDAN HOJIN BISEIBUTSU KAGAKU KENKYU ΚΑΙ, To k y ο (Japan)

5-Dihydrocoriolin G and method of preparation same

The invention relates to 5-dihydrocorioline. 0 as well as a process for the production of the same, in particular by breeding microorganisms belonging to the Basidiomycetes, which are capable of producing 5-dihydrocoriolinG in one suitable medium under aerobic conditions 5-dihydrocoriolin C too. form and obtain the 5-dihydro-coriolin C from the resulting culture medium.

The 5-Dlhydrocoriolin C according to the invention is a new substance which is capable of Coriolin C by oxidation
and to form 2'-dehydrocorloline G having antibacterial and anti-tumor effects.

81- (POS 29 558) UoHe

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2261332

The IR absorption spectrum of the 5-dihydrocoriolin according to the invention C (determined on a tablet made from 5-bihydrocoriolin G and potassium bromide) is the attached drawing refer to.

The 5-dihydrocoriolin C obtained according to the invention is obtained in the crude and crystalline state and has no antibacterial or anti-tumor effect by itself, however, coriolin C and 2'-dehydrocoriolin C, which are obtained by oxidizing 5-dihydrocoriolin G with an oxidizing agent, show a antibacterial effect against Staphylococcus aureus, Bacillus subtilis, etc. and a life-prolonging effect in Bhrlich's ascites tumor in house and mouse leukemia L-1210, as can be seen from the following test results (for Coriolin C, see Umezawa et al. Tetrahedron letters, No. 19 , (1970) pp. 1637-1639; 2'-Uehydrocoriolin G is a new compound).

The results of a study of the antibacterial effects of coriolin C and 2'-dehydrocoriolin (J after the Agar-agar dilution methods are given in Table 1 below.

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Table 1

Antibacterial effects of Coriolin C and 2'-Dehydrocoriolin 0

Test organisms Coriolin 0 2'-dehydro
coriolin C St. aureus PDA 209-P 1.56 *
1.56
1.56
<0.78
<0.78
<0.78
25.0
;> 100.0
12.5
•> 100.0 1.56 *
1.56
1.56
1.56
<0.78
1.56
100.0
;> 1oo, ο
12.5
'100.0 Terajima
Smith
M. flavus EDA-16 B. anthracis B. subtilis NRR B-558 £ L ^{co11 NIHJ}
S. t, yphi-T63 enteritis Ps. Aeruginosa AS

* Minimum inhibiting concentration (jug / ml)

Both of these compounds have an effect of inhibiting the growth of gram-positive microorganisms and almost the same effects can be achieved with both substances.

The effects of Ooriolin G and 2'-Dehydrocoriolin G on Ehrlich's ascites tumor in mice, mouse leukemia L-1210 and the growth of Yoshida sarcoma cells in tissue cultures were examined and the following results were obtained:

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Treatment of Ehrlich ascites tumors in mice was carried out with a daily administration of 0.19 to 12.5 mg / kg of each of the two compounds for 10 days. While all control animals were dead within 23 days after inoculation of the tumor cells, those with 12.5; 6.25; 3.12; 1.56 and 0.678 mg / kg Coriolin G or 2'-dehydrocoriolin G had been treated with administration in the abdominal cavity, at 90 yö, 80 <ß>, 65 ^, 63 ί ° and 60 io (when goriolin G was administered) more than 50 days and to 80 #, 75 "At 60 y", 60 y £ and 50 yi (when 2'-dehydrocoriolin C was administered) more than 50 days and no ascites retention was observed.

Treatment of mouse leukemia L-1210 by daily administration of 6 to 100 mg / kg Coriolin C or 2 * -dehydrocoriolin G for 10 days resulted in mice to which 6; 12.5; 25; 50 or 100 mg / kg Coriolin C or 2'-dehydrocoriolin C had been administered, a life-prolonging effect of 119 ^l / i>, 131 #, HO yo, 150> or 175> for Goriolin C and of 115>, 120 %, 125 '/ <>, 135 ^ or 160 yb for 2'-dehydrocoriolin G (based on the survival time of the control animals (100, i)).

In the investigation of growth inhibition on tissue cultures of Yoshida sarcoma cells in rats, a 60 y ^ ige Reproductive inhibition with 0.75 µg / mg with Coriolin C resp. 2'-hydrocoriolin C obtained.

Studies of the acute toxicity of goriolin G and 2'-Oehydrocoriolin C in mice showed that the ÜLcq in Abdominal administration above 50 mg / kg and subcutaneous administration above 90 mg / kg also survived

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in the case of continuous abdominal cavity administration for 10 days, all mice tested for more than 50 days even when the total dose reached TOO mg / kg and the toxicity was found to be low.

From the above it follows that coriolin G and 2'-dehydrocoriolin C have excellent antibacterial and anti-tumor effects.

Coriolin G can also be produced directly through a fermentation or fermentation process are generated, but the yield is so low that a process for its production by fermentation can hardly be carried out industrially because of too low productivity. On the other hand, 5-dihydrocoriolin C according to the invention can be obtained in high yield, and the 5-dihydroeoriolin G thus obtained can pass through smoothly Oxidizing agents can be converted into Coriolin G. The production of Goriolin G is therefore more economical via the oxidation of 5-dihydrocoriolin G than by a direct fermentative route. The 5-dihydrocoriolin obtained according to the invention G is therefore used as the starting material for the production of this goriolin G and the related 2'-dehydrocoriolin G very helpful.

The 5-dihydrocoriolin G obtained according to the invention has the following properties:

5-Dihydrocoriolin C comes in the form of colorless crystals obtained that melt at 183 ° C and soluble in methanol, ethanol, ethyl acetate, acetone, chloroform and benzene, but in Water and petroleum ether are slightly or not at all soluble. 5-dihydrocoriolin C shows no other ultraviolet absorption as end absorption. The IR absorption spectrum

3 0.9 8-2 6/1 1SA

of 5-bihydrocoriolin C, which was determined on 5-Mhydrocoriolin C potassium bromide tablets, is shown in the attached drawing. As can be seen, the main absorption occurs at wave numbers (cnf ¹ ) of 3490; 3360; 2950; 1741; 1649; 1460; 1419; 1389} 1370; 1340; 1315; 1270; 1184; 1139t 1109} 1081; 1032; 1003; 983; 965; 949; 921; 891; 868; 841; 809; 788; 781; 751; 716 and 672.

5-Dihydrocoriolin G has (determined by mass spectrometry) has a molecular weight of 424, and showing at the elemental analysis the following values: Cj 65.07 & Hi and 8.55 ° i \ it contains no nitrogen.

Based on the above values of the elemental analysis and the Molecular weights determined by mass spectrometry found as empirical formula C? 3 ** 36 ^ 7 (molecular weight: 424).

As a result of the analysis of the nuclear magnetic resonance spectrum of 5-dihydrocoriolin C and its behavior towards it Reagents, it was found that 5-dihydrocoriolin 0 has the following structural formula:

The 5-dihydrocoriolin C is also produced by Basidiomycetes formed, but differs in terms of physical

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chemical and chemical properties, molecular formula and structural formula from the already known products goriolin, coriolin B, coriolin G, 5 ~ ketocoriolin B or hirustic acid C and is to be regarded as a new substance, its existence and its Ghemismus were previously unknown.

The microorganism used in the context of the present invention which is capable of producing 5-dihydroeoriolin G is Coriolus consors (Berk) Imaz ATCC Hr. 20305, widely used from Honshu to Kyushu (Japan) and detailed in "Zoku Genshoku Hippon Kinrui Zukan" (colored Japanese "panic" bacterial picture book ", Ports.) By Rokuya Imazeki and Jiro Hongo, pages 141-142, Hoikusha Publishing Go., Japan, 1968 edition.

microorganisms capable of producing 5-dihydrocoriolin G are inoculated into a suitable medium and cultured under aerobic conditions, a culture liquor containing 5-dihydrocoriolin C can be obtained. Although it is possible to use a particulate culture method for cultivation, a liquid culture method is preferred for mass production. Regarding the culture temperature is not limited as long as the temperatures allow a growth of capable of forming 5-Dihydrocoriolin C microorganisms, however, are typically 15 to 30 ⁰ C and in particular 25 to 28 preferably ⁰ O for breeding.

As a culture medium for the formation of 5-dihydrocoriolin C can be a carbon source, nitrogen source, inorganic Medium containing salts, production promoters, etc. can be used.

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Commercially available sugars, oils and fats, etc., such as, for example, can be used as the carbon source Glucose, glycerine, starch, dextrin, maltose, lactose, sucrose, oil and fat, molasses etc. in pure or raw State.

Soybean powder, meat extract, peptone, dried brewer's yeast, yeast extract, cereal softener, Casein, cottonseed oil, (coarse) fish meal, nitrates, ammonium salts, urea, amino acids such as glutamic acid etc. can be used.

Inorganic salts are sodium chloride, potassium chloride, Magnesium sulfate, calcium carbonate, phosphates etc. or very small amounts of salts of heavy metals such as Copper, manganese, iron, zinc, etc., into consideration. Furthermore, increases the addition, in particular the addition of acetic acid or Malonic acid or mevalonic acid, the formation of 5-dihydrocoriolin C during cultivation.

An example of a suitable culture medium for the production of 5-dihydrocoriolin G is given below:

Composition I (inoculation medium)

Glucose 5.0 i>

Peptone 0.2 f °

dried brewer's yeast 0.3%

Kai iumdihyd hydrogen phosphate 0.3 ° i

Magnesium Sulphate $ 0.1

polyoxyathylenisch.es above _{n ni c} . · surface-active agent ^{υ> υι Α}

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Composition II (production medium)

Glucose 5.0 ^c / o

Pe pt on 0.2 "/ ο

dried brewer's yeast. 0.3 %

Potassium dihydrogen phosphate 0.3 i »

Magnesium sulfate, 0.1 ° / o

polyoxyethylene surface _{n ni uf}

active mean υ, υι _{/ 0}

Calcium carbonate 1.6 fo

Sterilized separately and added to the medium at the start of the culture.

In the iJurchführung the invention, a vaccine capable of forming 5-Dihydrocoriolin G microorganisms with shaking will liquor cultured in the area designated as Composition I Mediun cultured first in your designated as Composition H medium for several days at 15 to 3O ⁰ G. In the case of large-scale cultivation using a fermentation tank, inoculation cultivation is carried out in two stages. According to the usual procedure, the first inoculating liquor obtained by cultivation in an inoculation medium in a shake flask is first transferred to a fermentation tank previously provided with inoculation medium and subjected to cultivation. Finally, the second inoculated liquor is inoculated into the production medium contained in another fermentation tank and subjected to cultivation. However, it is also possible to omit the second inoculation cultivation.

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Through these cultivations Coriolin _t Coriolin B, 5-Ketocoriolin B and 5-Dihydrocoriolin G are formed, and since the Coriolin is mainly present in the liquid part, while Goriolin B, 5-Ketocoriolin 3 and 5-Dihydrocoriolin G are mainly present in the mycelium, the mycelium portion of the culture fluid containing Coriolin B, 5-Ketocoriolin B and 5-Dihydrocoriolin G is separated by generally known methods such as filtration, centrifugal separation, etc. If this mycelium portion is subjected to extraction with organic solvents such as methanol, acetone, ethyl acetate, butyl acetate, methyl isobutyl ketone, etc., the 5-dihydrocorioline C. is transferred to the layer formed by the organic solvent.

If a water-miscible organic solvent such as acetone, methanol, Ethanol, etc. is used as an extractant, so will the extract liquid was concentrated under reduced pressure and then re-extracting the concentrated liquid with a non-hydrophilic organic solvent such as for example, ethyl acetate, methyl isobutyl ketone, etc. subjected, thereby removing water-soluble impurities can be.

In addition to the desired 5-dihydrocoriolin C, there are also coriolin B and 5-ketocoriolin B in the extract liquid etc included; but since goriolin B is the least soluble of these byproducts in ethyl acetate, it is made by Ein ^ Narrow of the liquid extract is excreted first and can be removed by filtration.

5-Dihydrocoriolin G is easier to crystallize from the mother liquor (obtained in the process) than 5-ketocoriolin B, see above

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that the concentration of the Coriolin B freed mother liquor and letting the concentrated liquid stand to excrete 5-dihydrocoriolin 0 in the form of needle-like crystals that can be won.

However, if there is a lot of impurities in the extract, then there is the excretion of 5-dihydroeoriolin C crystals difficult and the 5-dihydrocoriolin C is therefore usually converted from 5-ketocoriolin B by chromatographic methods using silica gel as a carrier medium and a mixed solution of methanol-chloroform, chloroform, benzene etc. separated as eluents. During the elution, 5-ketocoriolin B is eluted first and then the 5-dihydrocoriolin C. Their separation is satisfactory, since the number of hydroxyl groups in the molecule is around in both compounds two differ from each other.

The elution fraction obtained by concentrating the 5-dihydrocoriolin C raw powders obtained to dryness are in a low Dissolved amount of an organic solvent, and the 5-dihydrocoriolin C can be obtained from it in the form of needle-like Crystals by adding solvents in which 5-dihydrocoriolin C is sparingly soluble, such as n-hexane, V / ater etc. are excreted.

For the production of Coriolin C and 2'-Dehydrocoriolin C. from 5-dihydrocoriolin C by oxidation, different methods are available, such as (1) the oxidation with Chromic acid in pyridine, (2) the oxidation with manganese dioxide in neutral solution, (3) the oxidation with a dicyclohexylcarbodiimide solution in dimethyl sulfoxide, etc .; for achieving of the two compounds, however, procedures (1) and (2) are particularly useful.

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The invention is explained in more detail below with the aid of examples.

Example 1

25 g of wood chips (corresponding to about 0.3 to 0.85 mm clear mesh width) of Magnolia hypoleuca 1 capacity were placed in a conical flask of 1 and 170 ml of a 2 $> glucose and 0.5 $ dried brewer's yeast-containing liquid culture medium (hereinafter kedium ^GY-11 denoted by ") was added. spell was sterilized bottle in an autoclave at 120 G ⁰ for 20 minutes and then with capable of forming 5-Dihydrocoriolin C microorganisms (ATCO no. 20,305) by an agar the resulting culture were cultured Schrägkultür (agar slant) vaccinated, the 10 to 14 days "nter stationary condition at 25 to 27 ⁰ G. was used as the wood chips Impfvorrat.

This was then added to 500 ml of sterilized GY medium to produce a microorganism suspension and 100 ml of the microorganism suspension were placed in 5 conical 5 1 bottles with 1 1 medium of the following composition I and inoculated for 72 hours cultivated a rotatable shaking cultivator with 190 rpm at 27 ^{0 O.}

Composition I (inoculation medium)

glucose

Peptone

dried brewer's yeast potassium dihydrogen phosphate Magnesium sulfate

polyoxyethylene surfactant

5.0 * 0.2 0.3 0.3 0.1 0.01

3 0 9 8 2 6/1 1 5 A

The total amount of this first inoculating liquor was introduced or inoculated into a 200 1 stainless steel fermentation tank with 120 1 of a medium having the same composition as above and inoculated for 72 hours with stirring (200 TJpm) and at an aeration rate of 120 l / min cultivated at 27 ^{0 G.}

Thereafter, 12 liters of the resulting second inoculum liquor were used in a 200 liter stainless steel fermentation tank 120 1 medium of the following composition II brought or inoculated and 168 hours under the same culture

S.

conditions cultivated as above.

Composition II (production medium)

Glucose '' $ 5.0 peptone. 0.2 fo

dried brewer's yeast 0.3 'p'

Potassium dihydrogen phosphate 0.3 ^

Magnesium Sulphate $ 0.1

polyoxyethylene surfactant Medium $ 0.01

Gallium carbonate 1.6 ^

Sterilized separately and added to the medium when starting the Cultivation added.

After the cultivation was finished, the resulting Culture fluid filtered off, leaving 5.5 kg of moist mycelium were obtained. This was transferred to a container, 9 l of acetone were added, and the solution was stirred afterwards filtered off and the mycelium washed further with 3 l acetone and the washing liquid and the filtrate are combined and concentrated,

The resulting concentrated liquor was mixed with 5 liters of ethyl acetate, stirred and extracted.

The solvent layer was separated and concentrated to 350 ml under reduced pressure and allowed to stand. whereby crystals of the by-product Coriolin 3 are deposited. The crystals were filtered off and with a small amount Washed benzene. The wash liquid and the filtrate were combined and further concentrated to 150 ml, leaving a 5-dihydrocorioline C precipitate was deposited. This was filtered off, washed with benzene and dried, whereby 8.59 g of crude crystals were obtained.

The crude crystals were recrystallized from an aqueous 80 ^c / o methanol solution to obtain 5.19 g of pure 5-Bihydrocoriolin C (melting point: 183 ⁰ G) were obtained.

Example 2

10 ml of similarly obtained as in Example 1 second Impfliquors were dissolved in 150 shake flasks (with a capacity of 500 ml) with 125 ml of medium of composition II given and 7 days at 27 ⁰ C on a reciprocating 3chüttelmaschine cultivated with 130 reciprocations per minute. 15.5 liters of the resulting culture liquid was filtered, whereby 550 g of wet mycelium was obtained.

This moist mycelium was mixed with 2 l of acetone, stirred, extracted, filtered and washed with 1 l of acetone. The washing liquid and the filtrate were combined and concentrated under reduced pressure. 600 ml of the concentrated liquor were mixed with 1.2 l of ethyl acetate and extracted.

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The resulting solvent layer was separated, concentrated under reduced pressure to about 50 ml and allowed to stand, whereby crystals of the by-product goriolin B were excreted. The crystals were filtered off and washed with benzene.

The filtrate and the ash liquor were combined and concentrated to dryness under reduced pressure to give 5.6 g of a containing the desired 5-dihydrocoriolin O. oily "material was obtained.

This oily material was dissolved in a small amount of chloroform and passed through a column packed with 250 ml of silica gel (suspended in chloroform) for adsorption. Thereafter, a 1 ^o ß> methanol-chloroform solvent mixture in an approximately equal volume of the column was passed through the column, whereby 5-ketocoriolin B was eluted first, followed by further passage of the solvent mixture in an amount approximately twice the column volume through the column the desired 5-bihydrocoriolin C was eluted. The 5-dihydrocoriolin C fraction was collected, concentrated to dryness under reduced pressure and recrystallized from an aqueous 80% methanol solution, whereby 2.54 g of pure 5-dihydrocoriolin C (melting point: 183 ^° C.) were obtained.

Reference example 1

3 g of 5-dihydrocoriolin C were dissolved in 30 ml of pyridine and with a suspension of a chromic acid-pyridine complex in pyridine, which by adding 2.5 g of chromic acid to 40 ml pyridine was obtained, mixed with stirring and subjected to reaction at 3 to 5 ° C for 6 days.

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After the reaction, 350 ml of ethyl acetate were added and the deposited impurities were filtered off The filtrate was washed in portions with a total of 500 ml of water and an upper layer separated and concentrated to dryness under reduced pressure to give 2.53 g of a crude product became.

The crude product was dissolved in 10 ml of ethanol and adsorbed in a column filled with 100 ml of Sephadex LH 20 (trademark for a dextran derivative used for gel filtration in organic solvents or liquids and manufactured by Pharmacia Pine Chemieale, Inc.). The column was eluted with a total of 85 ml of ethanol. The last 25 ml of the eluted liquid was collected and concentrated to dryness under reduced pressure. The concentrated residue was dissolved in 5 ml of chloroform and adsorbed in a column filled with 50 ml of silica gel. The column was eluted with 100 ml of a 1 % methanol-chloroform mixed solvent, whereby an eluted fraction of 2'-dehydrocoriolin C was obtained.

The column was then eluted with 100 ml of a 2 $> methanol-chloroform solution medium, whereby an eluted Coriolin C -precision was obtained.

Both fractions (individually) were concentrated to dryness under reduced pressure, whereby 267 mg of powdery 2 ^I -dehydrocoriolin C (melting point t 51 to 55 ° C) and 851 mg of crude crystals of Coriolin C were obtained.

The crude crystals were recrystallized from coriolin C from n-hexane to give 722 mg coriolin C (melting point *, 73 to 75 ⁰ C) was obtained.

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The Coriolin C obtained in the present example is a known substance with the following structural formula?

OGO-GH (CH ₂₎ OH

The 2'-dehydrocoriolin C, on the other hand, is a new compound with the following properties: colorless powder; Melting point: 51 to 55 ° G; [of] ψ : -19.0 ° (C = 1 '#;chloroform); Soluble in methanol, ethanol, ethyl acetate, acetone, chloroform, benzene and carbon tetrachloride, but little or not at all soluble in water, η-hexane and petroleum ether. The elemental analysis of 2'-dehydrocoriolin C gives 65 »69 ° ß> carbon and 7.67 $ hydrogen, from which, taking into account the molecular weight determined by mass spectrometry, a sum formula of ^G 23 ^H 32 ° 7 ^er S ^ib t. As a result of an analysis of the nuclear magnetic resonance spectrum, it was found that the 2'-dehydrocoriolin G has the following structural formula:

ti 0

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Reference example 2

1 g of 5-dihydrocoriolin G was dissolved in 100 ml of anhydrous Benzene dissolved and mixed with 8 g of manganese dioxide with stirring and subjected to the reaction at room temperature for 32 hours. The reaction mixture was filtered and the precipitate washed with anhydrous benzene. The filtrate and the washings were combined and concentrated to dryness under reduced pressure, yielding 610 mg of solid material were obtained.

This solid material was dissolved in 3 ml of ethanol and adsorbed in a column filled with 25 ml of Sephadex®LH 20. The column was eluted with a total of 25 ml of ethanol. The last 9 ml of the eluted liquid fractions were collected and concentrated to dryness under reduced pressure.

The concentrated residue was dissolved in 1.2 ml of chloroform and adsorbed in a column filled with 15 ml of silica gel. The column was eluted with 30 ml of a 10 % methanol-chloroform mixed solvent, whereby an eluted fraction of 2'-dehydrocoriolin C was obtained. Thereafter, an eluted fraction of Coriolin C was obtained by eluting the columns with 30 ml of a 2 > methanol-chloroform solvent mixture. Both fractions were concentrated to dryness under reduced pressure, whereby 62 mg of powdery 2'-dehydrocoriolin G (melting point: 51 up to 55 ° C) and 180 mg of crude crystals of Coriolin C were obtained.

The latter were recrystallized from η-hexane to give 132 mg coriolin G crystals having a melting point of 73-75 ⁰ G were obtained.

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Reference example 3

200 mg of 5-dihydrocorioline were ο in a solution mixture of 1.2 ml of anhydrous dirnethyisulfoxide, 0.7 ml of benzene, 0.0-7 ml of pyridine and 0.038. ml of trifluoroacetic acid dissolved and mixed with 300 mg of dicyclohexyl.carbodiimide with stirring. The solution was allowed to stand at normal temperature for 1 hour and then who
Subject to reaction.

left and then continued for 15 hours at 3 to 4 G der

After completion of the reaction, 12 ml of ether and 130 mg of oxalic acid (as a 10 consecutive solution in methanol) were added and, after 30 minutes, 12 ml of water were added. The resulting precipitates were filtered off and washed with ether.

An ethereal layer was separated from the filtrate and washed with a 5% aqueous sodium bicarbonate solution and then with water and concentrated under reduced pressure. The concentrate was separated by chromatography on silica gel in the same way as in Reference Example 1, whereby 42 mg of Coriolin G crystals (melting point; 73 Ws 75 ⁰ O) and 13 mg of powdery 2'-dehydrocoriolin G (melting point; 51 to 55 ⁰ C) were obtained.

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Claims (7)

Claims 1. 5-Dihydrocoriolin C of the formula: OCO-CH- (GH ₂ OH 2. Process for the preparation of 5-dihydrocoriolin C, characterized in that one to microorganisms belonging to the Baaidiomycetes, which are capable of forming 5-dihydrocoriolin C, in a suitable Medium for the formation of 5-dihydrocoriolin C cultivated under aerobic conditions and the 5-dihydrocoriolin C formed wins from the resulting culture. 3. The method according to claim 2, characterized in that the cultivation at 15 to 30 ⁰ C is carried out. 4. The method according to claim 2, characterized in that the recovery of the 5-dihydrocoriolin C from the resulting Culture using an organic solvent8, which is capable of dissolving 5-dihydrocoriolin C is made. 309826/1 1 54 5. The method according to claim 2, characterized in that Goriolus consors is used as the microorganism which is capable of forming 5-bihydrocoriolin C 6. The method according to claim 2, characterized in that Coriolus consors ATGG 20 305 is used as the microorganism which is capable of forming 5-dihydrocoriolin C. 7. Use of 5-dihydrocoriolin G for the production of goriolin C and 2'-dehydrocorxoline C by oxidation. 309826/1 154 Blank page