CA1144538A - Steroids of the pregnane series substituted in the 17-position, and their manufacture and use - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel corticoids of the general formula I

wherein each bond is a single or double carbon-to-car-bon bond, X represents H, F, Cl or CH3, Y represents H and Z
represents H, F or Cl or Y and Z together represent a carbon-to- carbon bond, V represents .beta.-hydroxymethylene, .beta.-chloro-methylene or carbonyl, W represents methylene, ethylidene or vinylidene, Q represents O or S, R1 represents C1-C8-alkyl optionally interrupted by O or represents benzyl and R2 repre-sents H or C1-C6-alkyl or R1 and R2 together represent tri-methylene or tetramethylene, and R3 represents H, F, Cl or free or esterified OH and processes for their manufacture. The novel corticoids of the formula I have an anti-inflammatory action and accordingly may be used as anti-inflammatory agents and may be made up with suitable carriers into pharmaceutical preparations. The Specification includes a microbiological process for the manufacture of 11.beta.-hydroxy-steroids of the pregnane series substituted in the 17.alpha.-position by an acetal group of the formula

Description

11'~4538 The present invention is concerned with new corti-coids, processes for their manufacture, their use and phar-maceutical preparations containing these corticoids.

It has been known for a long time that the topical activity of anti-inflammatorally active 17~-hydroxy-corticoids can be increased by esterifying their 17-hydroxyl group.
[In this connection see the general report of Thomas L. Popper and Arthur S. Watnick, "Anti-inflammatory Steroids in Anti-inflammatory Agents" Volume 1, Academic Press, New York, San Francisco, London (1974), pages 268-271].

It has now been found that the topical activity and/or the dissociation between the desired topical anti-inflammatory activity and the undesired systemic activity can be further increased by replacing the hydrogen atom of the 17~-hydroxy-groups of these corticoids, not by an ester group,but by an acetal group or a thioacetal group.

The present invention accordingly provides compounds of the general formula I

fH2R3 C=O R2 ~ OCH~Rl (I) V W

~ ~ Y j 0/~

X
~t

- 2 -11~4S38 in which each of the bonds in the 1,2- and 6,7-positions represents a single carbon-to-carbon bond or a double carbon-to-carbon bond, X represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, Y represents a hydrogen atom and Z represents a hydrogen atom, a fluorine atom or a chlorine atom or 10 Y and Z together represent a carbon-to-carbon bond, V represents a ~-hydroxymethylene group, a ~-chloromethy-lene group or a carbonyl group, W represents a methylene group, an ethylidene group or a vinylidene group t Q represents an oxygen atom or a sulphur atom, Rl represents an alkyl group containing 1 to 8 carbon atoms which may be interrupted by an oxygen atom, or repre-sents a benzyl group and R2 represents a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms or Rl and R2 together represent a trimethylene group or a tetramethylene group, and R3 represents a hydrogen atom, a fluorine atom, a chlorine atom or a free or esterified hydroxyl group. 5 mhe esterified hydroxyl group represented by R3 is understood herein to include a group derive~ not only from an orsanic acid but also from an inorganic acid.

As compounds of the present invention there may be mentioned, for example, compounds of the general formula Ia ~ - 3 -11~4S38 fH2R3 H ~ - ~ ~ ~ OCHQR
~V
l Z~ ¦ (Ia) 1~ 0~\~

X' in which W, Q, Rl, R2 and R3 have the meanings given above, X' represents a hydrogen atom, a fluorine atom or a methyl group and Z' represents a hydrogen atom, a fluorine atom or a chlorine atom, compounds of the general formula Ib C = O R
HO ~ ~ OCHQR
~ 1, O ~ (Ib) X' in which X', Z', W, ~, Rl, R2 and R3 have the meanings given above and compounds of the general formula Ic ~ - 4 -C = lR2 HO ~ ~ OCHQR

O ~ (Ic) X' in which X', W, Q, Rl, R2 and R3 have the meanings given above.

The new corticoids of the general formula I may contain as the substituent represented by Rl a straight chained or branched chain alkyl group containing 1 to 8, preferably 1 to 6, carbon atoms. Such alkyl groups are, for example, the methyl group, the ethyl group, the propyl group, the isopropyl group, the butyl group, the isobutyl group, the tert.-butyl group, the pentyl group, the isopentyl group, the hexyl group, the heptyl group or the octyl group.
However, the alkyl group represented by Rl may also be inter-rupted by an oxygen atom. Such groups are, for example, the 2-methoxyethyl group, the 3-methoxypropyl group or the 2-ethoxyethyl group.
The symbol R2 in the corticoids of the general formula I may represent an alkyl group containing 1 to 6, preferably 1 to 4, carbon atoms and may represent, for example, the methyl group, the ethyl group, the propyl group or the butyl group. Noteworthy are those corticoids of the general formula I in which R2 represents a hydrogen atom, as 1~4538 they are unable to form diastereoisomeric mixtures.

The inception of action and the duration of action of the new corticoidsand also their solubility in physio-logically tolerable solvents depend, as is the case with theknown corticoids, especially on whether any hydroxyl group in the 21-position is esterified and, if so, by what acid.

As esterified 21-hydroxy-groups represented by R3 there come into consideration preferably acyloxy groups containing 1 to 16 carbon atoms in the acyl group, more preferably 1 to 8 carbon atoms in the acyl group, sulphate groups or phosphate groups. Suitable acyloxy groups are, for example, those derived from straight chained or branched chained, saturated or unsaturated aliphatic mono- or di-carboxylic acids, which may be substituted in the usual manner, for example by hydroxyl groups or amino groups or halogen atoms.

There are also suitable as acyloxy groups those derived from cycloaliphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids, which may also be sub-stituted in the usual manner. As suitable acyloxy groups there may be mentioned, for example, formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, octanoy-loxy, undecanoyloxy, dimethylacetoxy, trimethylacetoxy, diethylacetoxy, tert.-butylacetoxy, benzoyloxy, phenacety-loxy, cyclopentyl-propionyloxy, hydroxyacetoxy, monochlorace-toxy, dichloracetoxy and trichlorac~toxy groups and also dimethylaminoacetoxy, trimethylaminoacetoxy, diethylamino-acetoxy, piperidinoacetoxy, nicotinoyloxy, ~-carboxypro-pionyloxy and ~-carboxypentanoyloxy groups.

For the production of water-soluble active sub-stances the 21-acyloxy-compounds containing a basic nitrogen group in the acyl group may be converted into the corresponding 11~4538 acid addition salts, for example the hydrochlorides, hydrobromides, sulphates, phosphates, oxalates, tartrates or maleates. Furthermore, the 21-dicarboxylic acid mono-esters, and also the sulphuric acid esters and phosphoric acid esters may be converted into their alkali salts, for example the sodium or potassium salts, in order to increase their solubility in water.

The new corticoids of the general formula I may be prepared according to one of the processes of the present invention, as defined below.

The present invention also provides a process for the manufacture of a compound of the general formula I, wherein a 17~-hydroxy-steroid of the general formula II

I

C = O
~ ~ - - OH
V ' - W

0~
X (II) in which the bonds , X, Y, Z, V and W have the meanings given above and R'3 represents a hydrogen atom, a fluorine atom, a chlorine atom or an esterified hydroxyl group, is reacted, if desired after intermediate protection of any ~ hydroxyl group, (a~ when Q represents an oxygen atom, with an acetal of the general formula III

~';

13 ~4538 R2HC(ORl)2 (III) in which Rl and R2 have the meanings given above, or (b) when Q represents an oxygen atom, with an ~halogen-ether of the general formula IV

2 ORl (IV) in which Rl and R2 have the meanings given above and Hal represents a chlorine atom, a bromine atom or an iodine atom, or (c) when Q represents an oxygen atom and R2 represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms, with a vinyl ether of the general formula V
R'2CH = CH-ORl (V) in which Rl has the meaning given above and R'2 represents a hydrogen atom or an alkyl group containing 1 to 3 carbon 2~ atoms, or (d) when Q represents a sulphur atom, with a sulphoxide of the general formula VI

~ R2CH2SORl (VI) in which Rl and R2 have the meanings given above, and, if desired, in any resulting steroid saturated in the 1,2-position obtained by any one of the variants (a) to (d) dehydrogenation is carried out in the 1,2-position, and/or in any resulting steroid any ll~-hydroxy group is oxidized to form an oxo group, and/or any 21-ester yroup is hydrolysed and/or any 21-hydroxyl group is esterified or exchanged for a fluorine atom or a chlorine atom.

This process of the present invention may be carried out under conditions that are known [Synthesis 1975, 2786, J.Chem.Soc. (66~, 1974, 431, J.Amer. Chem. Soc. 74, (1952), 1239, United States Patent No. 3,383,394 and Angew. Chemie, 90, (1978~, 289].

Thus, for example, the steroids of the general formula II may be reacted with an acetal of the general formula III
in the presence of acid catalysts, for example perchloric acid or para-toluenesulphonic acid, or advantageously phos-phorus pentoxide. This reaction may be carrie~ out in the absence of further sol~ents or in the presen~ of inert solvents (for exam~le chloro-form, meth~lene chloride, tetrachlorethane, tetrachlorcmethane, bDluene, ~iethyl ether, tetrahydr~furan or dioxan). miS reacti~n is usually carried out at a reaction tenperature between -20& to +~DC, and is suitable especially for the preparation of those steroids of the general formula I in which R2 represents a hydrogen atom.

On the other hand, the steroids of the general formula II may also be reacted with a vinyl ether of the general formula V. This reaction is preferably carried out in one of the above-mentioned inert solvents with the addition of acid catalysts (for example perchloric acid, para-toluene-sulphonic acid or methanesulphonic acid). The reaction is preferably carried out at a reaction temperature of -20 C
to 100C.

Furtherrnore, the steroids of the general formula II may also be reacted with an ~-halogen-ether of the general formula IV. This reaction may be carried out, for example, in an inert polar solvent, for example acetonitrile, dimethylforma-mide, N-methyl-pyrrolidone, hexamethyl-phosphoric acid tri-amide or hexamethylphosphoric acid triamide, with the addi-tion of basic catalysts, for example silver oxide, triethyl-amine or diisopropylethylamine. The reaction is preferably carried out at a reaction temperature of -20C to +100C.

_ 9 _ In the above-mentioned reactions there are formed cor-ticoids of the general formula I in which ~ represents an oxy-gen atom. For the preparationofcorticoids in which Q repre-sents a sulphur atom the corticoids of the general formula II
may be reacted with sulphoxides of the general formula VI.
This reaction may be carried out, for example, by reacting the sulphoxide and the steroid, if desired in an inert sol-vent (for example methylene chloride, tetraclorethane or tetra-hydrofuran), at approximately -20C to 100C with the addition of anhydrides (preferably acetic anhydride) and acid catalysts (for example acetic acid or boron trifluoride).

If for this process of the present invention there are used as starting compounds ll~-hydroxy-corticoids of the general formula II it is advantageous to protect the ll~-hy-droxy group intermediately, in order to avoid its partial acetalisation. This can be achieved, for example, by convert-ing the ll~-hydroxy group before the acetalisation into the corresponding nitrate, formate, or trihalogeno-acetate (es-pecially trifluoroacetate) and then splitting this ester after carrying out the process).

The esterification of the ll~-hydroxy-corticoids of the general formula II with nitric acid may be brought about, for example, with acetyl nitrate, prepared by mixing fuming nitric acid with acetic anhydride. After the 17~-acetalisa-tion the nitrates can be re-converted into the ll~-hydroxy corticoids, for example, by reaction with zinc dust in acetic acid.
The esterification of the ll~-hydroxy-corticoids of the general formula II with formic acid can be be brought for example, by means of formic acid-acetic acid anhydride with the use of 4-dimethylaminopyridine as catalyst. After the 17~-acetalisation, the resulting ll~-formyloxy-corticoids can then be converted into the corresponding ll~-hydroxy-11~4538 steroids by basic hydrolysis (for example by means of a solution of sodium methylate~ or by enzymatic hydrolysis.

The esterification of the ll~-hydroxy-corticoids of the general formula II with a trihalogeno-acetic acid, especially trifluoracetic acid, may be brought about, for example, by reacting the ll~-hydroxy-corticoids with a trihalogeno-acetic anhydride in pyridine. After the 17~-acetalisation, the trihalogeno-acyl group can be split off by hydrolysis (for example in a lower alcohol with the addition of weekly basic catalysts, for example sodium acetate or triethylamine).

The present invention further provides a process for the mah~facture of a compound of the general formula I, wherein (a) a 9,11-dehydro-steroid of the general formula VII

C=O lR2 ~ ---~ OCHQRl ~ (VII) , X
in which the bond . , X, W, Q, Rl, R2 and R3 have the meanings given above, is additively combined with chlorine or hypochlorous acid, or (b) the epoxy-ring of a 9,11-epoxy-steroid of the general formula VIII fH2R3 C= O 12 - - - OcHQRl O~ ~ (VIII) , X ~ 11 --in which the bonds , X, W, Q, Rl, R2 and R3 have the meanings given above, is opened up with hydrogen fluoride or hydrogen chloride, or (c) Z" or HZ" is split off from a 9-halogeno-steroid of the general formula IX

I

C=O 12 I

HO ~ -- - - OcHQRl ~ (IX) , o J
X
in which the bonds ..... , X, W, Q, R , R2 and R3 have the meanings given above and Z" represents a chlorine atom or a.
bromine atom, and, if desired, in any resulting steroid satur-ated in the 1,2-position obtained by any one of the variants (a) to (c) dehydrogenation is carried out in the 1,2-posi-tion, and/or in any resulting steroid any ll~-hydroxyl group is oxidized to form an oxo group, and/or any 21-ester group is hydrolysed and/or any 21-hydroxyl group is esterified or exhanged for a fluorine atom or a chlorine atom.
This process of the present invention may also be carried out under conditions known per se (United States Patents Nos. 3,678,034, 3,718,671, 3,845,085 and 3,894,063).

Thus, for example, the 9,11-dehydro-steroids of the gen-eral formula VII may be reacted in an inert solvent (for example acetic acid, tetrahydrofuran, dioxan or acetonitrile~
with reagents which in the presence of water and acids (for example sulphuric acid, phosphoric acid or perchloric acid) liberate hypoch.lorous acid during the reaction, thus es~ecial-ly reagents forming halo~en cations, for example N-chloracyl-amides (especially N-chloracetamide~ or N-chloracylimides ~1~4538 (especially N-chlorosuccinimide). In this reaction there are o~tained as the main products 9~-chloro~ hydroxy-corticoids of the general formula I, and also frequently as by-products the corresponding 9~ dichloro-corticoids of the general formula I. The latter are obtained as main products if the reaction is carried out with the exclucion of water in the presence of hydrogen chloride as acid.

On the other hand, the epoxy-ring of 9,11-epoxy-steroids Of the general formula VIII can be opened up, for example, with hydrogen chIoride or hydrogen fluoride, by dissolving the compounds of the general formula VIII in an inert solvent saturated with hydrogen chloride or hydrogen fluoride and, if desired, introducing into this solution additional hydrogen chloride gas. Suitable inert solvents are, for example, ethers (for example diethyl ether, diisopropyl ether, dioxan or tetrahydrofuran) or chlorinated hydrocarbons (for example methylene chloride, chloroform, carbon tetrachloride or tetra-chlorethane). In this reaction there are formed the 9~-fluoro-or 9~-chloro-11~-hydroxy-corticoids of the general formula I.

For splitting off a halogen from the 9-halogeno-steroids of the general formula IX the latter may be reacted, for example, in an inert solvent in the presence of radical formers (for example azodiisobutyronitrile, di-tert.-butyl peroxide or ultraviolet light) with trialkyl tin hydrides (for example triethyl tin hydride or tributyl tin hydride). Suitable inert solvents are, for example, ethers (for example diethyl ether, glycol dimethyl ether, dioxan or tetrahyarofuran), hydrocarbons (for example cyclohexane, benzene or toluene), alcohols (for example methanol, ethanol or isopropanol) or nitriles (for example acetonitrile). In this reaction there are formed the ll~-hydroxy-corticoids of the general formula I unsu~stituted in the 9~-position.
The splitting off of a hydrogen halide from the 9-halo-11~4S38 geno-steroids of the general formula IX may be carried out under the conditions which are customarily used in steroid chemistry for splitting off a hydrogen halide from halohydrins.

Thus, for example, the compounds of the general formula IX may be heated under reflux in a tertiary amine, for example pyridine, lutidine or especially collidine. A further suitable method for splitting off hydrogen bromide is, for example, the reaction of these compounds with lithium salts (for example lithium chloride~ and/or calcium carbonate in dimethylformamide or dimethylacetamide. In these reactions there are formed the ~ -corticoids of the yeneral formula I.

The starting substances of the general formulae VII to IX required for this process of the present invention can be prepared by acetalising the corresponding 17~-hydroxy-steroids under the conditions given above for the process of the present invention starting from compounds of the general formula II, or from the 17-acetalised corticoids unsubstitut-ed in the 9-position by dehydrating the latter to form the 9,11-dehydro-steroids of the general formula VII, additively combining HBr at the 9,11-double bond, and converting the re-sulting 9-bromo-steroids of the general formula IX by means of bases into the epoxides of the general formula VIII.
The products obtained by each of the variants of the processes of the present invention, as defined above, may, if desired, be further converted by dehydrogenating in the 1,2-position corticoids that are saturated in the 1,2-position, and/or oxidizing any ll~-hydroxyl group in these compounds to the ll-oxo group, and/or hydrolysing any 21-ester group and/or esterifying any 21-hydroxyl group or exchanging it for a fluorine atom or a chlorine atom.

The conditions under which corticoids saturated in the 1,2-position can be dehydrogenated in the 1,2-position are described later on.

A preferred method of exchanging a 21-hydroxyl group for a fluorine or chlorine atom consists of esterifying the 21-hydroxyl group with a sulphonic acid, preferably with methane-sulphonic acid or para-toluene-sulphonic acid, and then exchanging the sulphonic acid group for a halogen atom. The esterification of the 21-hydroxyl group is carried out, for example, by allowing a sulphonic acid chloride to act upon the 21-hydroxy~steroids in the presence of an organic base, for example pyridine, or in the presence of aqueous alkalis.
The exchange of the sulphonic acid group for a halogen atom is preferably carried out by reacting the 21-sulphonic acid esters with an alkali halide, for example lithium chloride or potassium hydrogen fluoride, in the presence of a polar solvent, for example dimethylformamide, at a reaction tempera-ture of 50C to 180C.

The present invention further provides a process for themanufacture of an ll~-hydroxy-steroid of the pregnane series substituted in the 17~-position by an acetal group of the general formula X

(X) , -OCH-ORl in which Rl and R2 have the meanings given above, wherein a corresponding ll-desoxy-steroid of the pregnane series or, when applicable, a 21-ester thereof is fermented with a culture of an ll~-hydroxylating microorganism. The fermenta-tion is preferably carried out with a fungal culture of a strain of the genus Curvularia, for example a fungal culture of a strain of the species Curvularia lunata.

A preferred embodiment of this microbiological process of the present invention is a process for the manufacture of an 11~-hydroxy-steroid of the general formula Id -` 114~538 C=O R2 HO ~ ---OCHQR
S l ~ J (Id~

in which , X, W, Q, Rl and R2 have the meanings given above and R4 represents a hydrogen atom or a hyaroxyl group, wherein an ll-desoxy-steroid of the general formula XI

CH2OR'4 C=O lR2 - - OCH

20~' ~ ~

o ~ (XI) X
in which X, W, Q, Rl and R2 have the meanings given above and R4 represents a hydrogen atom, a hydroxyl group or an alkanoy-loxy group containing 1 to 6 carbon atoms, is fermented with a fungal culture of a strain of the genus Curvularia, and, if desired, the resulting compound of the general formula Id saturated in the 1,2-position is dehydrogenated in the 1,2-position.

The present invention further provides the use of the~ hydroxy-steroids of the ~eneral formula Id as intermedi-ates for the production of steroids of the general formula XII

.....

fH2R4 C=O
HO ~ ~ - OH
~ _ O ~ (XII) in which the bond , X, W and R4 have the meanings given above.

It has been known to prepare anti-inflammatorially active ll~-hydroxy-steroids (for example the corticoids hydrocorti-sone, Prednisolone, Dexamethasone, Betamethasone, Prednyli-denes, Triamcinolone, Fluocinolone and Flurandrenolone) by means of a very expensive multi-stage partial synthesis from naturally occurring steroids (for example diosgenine), which have become more difficult to obtain in sufficient quantities.
Within the multi-stage synthesis of these compounds the micro-biological introduction of the ll~-hydroxyl group into the steroid structure is generally the most expensive and most wasteful step of the synthesis.
2~
In the year 1966 a process was developed by means of which the yield in the ll~-hydroxylation of ll-desoxy-17~-hydroxy-steroids of the pregnane series can be considerably increased by esterifying the 17~-hydroxyl group, then hydroxy-lating by means of fungi of the genus Curvularia and hydro-lysing the resulting ll~-hydroxy-17~-acyloxy-steroids (German Patent Specification No. 1,618,599~.

However, the acylation of the 17-hydroxyl group is quite expensive and the yields obtained in this manner are often unsatisfactor~.

The hydrolysis of the ll~-hydroxy-17a-acyloxy-steroids is also difficult as by-products mostly form so that an ex-pensive and wasteful purification of the resulting products is necessary to make them fulfill the criteria of purity necessary for medicinally active substances.

In the microbiological process of the present invention there are used, on the other hand, starting steroids which can be obtained in good yields from the corresponding 17-hydroxy-steroids, and the resulting products of the process can be hydrolysed rapidly and quantitatively to the corres-ponding 11~,17a-dihydroxy-steroids.

The steroids used in accordance with this process may be substituted in the usual manner and/or contain double bonds.

The presence of hydroxyl groups or acyloxy groups, for example in the 21-position, the presence of halogen atoms, preferably fluorine atoms, methyl groups or methylene groups, for example in the 6- and/or 16-position(s) have no effect in the carrying out of this process of the present invention.
For this process of the present invention there are preferably used as starting compounds those steroids which contain an oxo group in the 3-position and a double bond in the 4,5-position.

Apart from the use of different starting compounds, the microbiological process of the present invention is carried out under the conditions customarily used for the 11~-hydroxylation of steroids with fungi of the genus Curvularia.

Fungi of the genus Curvularia suitable for the hydroxy-lation are, for example, Curvularia falcuta QM-102 H, Curvularia genticulata IFO (6284), Curvularia lunata NRRL
2380, NRRL 2434, ATCC 12017 or IFO (6286~ or Curvularia maculans IFO (6292).

11~4S38 It may be metnioned that ll~-hydroxylating m~croorgan-isms other than those of the genus Curvularia are also suit-able for carrying out the microbiological process, but usually these microorganisms have no advantages over those of the genus Curvularia.

Under the cultivation conditions customarily used for these microorganisms submerged cultures are grown in a suitable nutrient medium with aeration. There is then added to the cultures the substrate (dissolved in a suitable solvent or preferably in an emulsified form~ and the fermentation is carried out until a maximum conversion of substrate is achieved.

Suitable substrate solvents are, for example, methanol, ethanol, glycol monomethyl ether, dimethylformamide and di-methyl sulphoxide. The emulsification of the substrate may be carried out, for example, by injecting it in micronized form or dissolved in a solvent miscible with water (for example methanol, ethanol, acetone, glycol monomethyl ether, dimethyl-formamide or dimethyl sulphoxide) under strong turbulence into (preferably decalcified) water which contains the usual emulsification assistants. Suitable emulsification assistants are non-ionic emulsifiers, for example ethylene oxide adducts or fatty acid esters of polyglycols. As suitable emulsifiers there may be mentioned by way of example the usual commercial wetting agents Tegin(R), TagattR), Tween(R) and Span(R).

The emulsification of the substrate frequently enables the throughput of substrate to be increased and thus the concentration of substrate to be increased. However, it is obviously also possible in carrying out the microbiological process of the present invention to use such other methods for increasing the throughput of substrate that are well known to the fermentation expert.

.~

The optimum concentration of substrate, the time of addition of the substrate and the duration of the fermentation depends on the structure of the substrate used and the nature of the microorganisms used. These factors must, as is gen-erally necessary in microbiological steroid conversions, bedetermined in each particular case by preliminary tests of the type that are familiar to the expert.

Aæ a subsequent optional step the dehydrogenation of ~4-steroids of the general formula I saturated in the l-position may be carried out both by microbiological methods and also purely chemical methods. Thus, for example, the a4-steroids can be dehydrogenated in the l-position under the usual condi-tions with bacterial cultures of the genus Bacillus (for example Bacillus lentus or Bacillus sphaericus) or Anthrobacter (for example Anthrobacter simplex). On the other hand, it is also possible to carry out the ~l-dehydrogenation by heat-ing the Q4-steroids with the oxidizing agents normally used for this reaction, for example selenium dioxide or 2,3-di-chloro-5,6-dicyanobenzoquinone in inert solvents.

The resulting products of the microbiological process can be split up in a simple manner to form the corresponding 11~,17~-dihydroxy-steroids.
This splitting is carried out under the conditions which are conventionally used for the hydrolysis or alcoholysis of acetals. Thus, for example, the compounds may be split up by reacting them in a lower alcohol, for example methanol or ethanol, or in an aqueous organic solvent, for example glycol monomethyl ether, tetrahydrofuran, dioxan, dimethyl-formamide, dimethyl sulphoxide, hexamethyl-phosphoric acid triamide or acetone, with a mineral acid, for example hydro-chloric acid, sulphuric acid, phosphoric acid or perchloric acid, a sulphonic acid, for example para-toluene sulphonic acid, a strongly acidic carboxylic acid, for example formic ~1~4538 acid, acetic acid or trifluoracetic acid, acid ion-exchangers or with a Lewis acid, for example boron trifluoride, zinc chloride, zinc bromide or titanium tetrachloride.

The new corticoids of the present invention of the gen-eral formula I are distinguished, as already mentioned, in topical application by a very good anti-inflammatory activity and they possess a very favourable dissociation between the desired topical activity and the undesired systemi side effect.

The topical activity can be determined by means of the vasoconstriction test as follows.

The test is carried out on healthy test persons of both sexes 8 at a time, who have had no local cortico-steroid treatment in the previous two weeks. After removal of the Stratum corneum up to the Stratum lucidum on the backs of the test persons (20-40 Tesa film tears), there is applied in each case 0.1 gm of the preparations on areas of 4 souare cms without an ~usive dress-ings. In order to avoid the same preparati~s being ap~lied at any time to identical skin areas, the aDplications are made in rotational succession.

The vasoconstriction is evaluated visually after 4 and 8 hours by the examiner in accordance with the following degrees of action: 1=aboslute paling. 2= little residual erythema. 3=medium degree of erythema, reddening intensity in the central region of the stripped, untreated and undamaged skin. 4=erythema with little clearing. 5=no paling or in-tensification of the erythema.

The individual evaluations are averaged.

In each of the series of tests there is used as reference substance diflucortolone-21-valerate (=6~,9~-difluoro~
hydroxy-16~-methyl-21-valeryloxy-~1'4-pregnadiene-3,20-dione=
DFV~.

.'.~

4~38 In each case the difference ~ between the average degree of action of D~V and the test substances in the individual series of investigations is determined. Positive deviations a indicate a more favourable, and negative deviations a less favourable, valuation of the test substance as compared with DFV.

In the following Tables are given the observed test re-sult8, which are produced in the treatment of the test persons with a preparation containing 0.1 ppm of the active substance.
-The systemic activity of the compounds can be determinedby the adjuvant-oedema test as follows.

For the production of a focus of inflammation SPF-rats weiyhing 130 to 150 gms are injected in the right rear paw with 0.1 ml of a suspension of 0.5% strength of Mycobacterium butyricum (obtained from the American firm Difko). Before the injection the volumes of the paws of the rats are measur-ed. 24 hours after the injection the volume of the paws are again measured to determine the extent of the oedema. There are then administered to the rats orally or subcutaneously different quantities of the test substance dissolved in a mixture of 29~ of benzyl benzoate and 71% of castor oil.
After a further 24 hours the paw volumes are again measured.

The control animals are treated in the same way but with the difference that they are injected with a benzyl benzoate-castor oil mixture free from test substance.
From the paw volumes obtained there is determined in the usual manner the ~uantity of test substance which is necessaxy to produce a reduction in the experimentall~ pro-duced paw oedema of about 50% by volume.

In the following Tables are given the test results ob-tained, the compounds of the present invention being compared in each case with the most structurally analogous known corticoids present in commercial preparations.

U U~ o~
u~ . ~ ~r _ o o ~i ~ ,~ o o Q .
O ~: Cl d 0 ~1 ~1 0 ~ ~ ~ ~r t~
~ ~D
V~ 0 11 ~ 1_ 1~ ~r In ~ D
~:5 ~ ~o +o +o +o +o +o o+
1n ,U~
O ~ ~r U O
O U h 'C1 u~ ~ ~ ~ o ~r a~ a~ co ~ ~ ~ o o o o o o o ~ ~ ~ l + + + + +
O c~ l X h a) ~ a) :~
S~ O I I ~~ I ~0 O ~ ~ ~ ~
S~ O ~ O IO ~ ,1 ~ O ~ ~ O
S`~ X ~1 ~1 X ~ O ~1 ~ a~
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Z (~1 N t~x~ ~1 11~4S38 The new compounds of the present invention are suitable in combination with the carriers customarily used in, for example, galenical pharmacy for the local treatment of con-tact dermatitis, eczemas of a very wide variety of types, neurodermatoses, erythrodermia, burns, Pruritis vulvae et ani, Rosacea, Erythematodes cutaneus, psoriasis, Lichen ruber planus et verrucosus and similar skin diseases.

The present invention accordingly further provides the use of a compound of the general formula I as an anti-inflam-matory agent.

The present invention further provides a pharmaceutical preparation which comprises a compound of the general formula I, in admixture or conjunction with a pharmaceutically suit-able carrier. The preparation may, if desired, contain one, two or three compounds of the general formula I.

The pharmaceutical preparation may be in a form suitable, for example, for local treatment.

The manufacture of the pharmaceutical preparations may be carried out in the usual manner by converting the active substances with suitable additives into the desired form of application, for example solutions, lotions, salves, creams or plasters. In the pharmaceutical preparations so formulat-ed the concentration of active substance depends on the form of application. In the case of lotions and salves there is preferably used a concentration of active substance within the range of from Q.001~ to 1~ by weight.

Furthermore, the new compounds of the general formula I, if desired ln combination with the usual carrier sub-stances and auxiliary substances, are also well suited for the production of inhalant prepaxations, which can be used for the therapy of allergic diseases of the respiratory system ~., for example bronchial asthma or rhinitis.

Furthermore, the new compounds of the general formula Iare also suitable for the production of capsules, tablet-g or dragees, which preferably contain 10 to 200 mg of active substance and are applied orally, or for the productlon of suspensions which may be in unit dosage form preferably con-taining 100 to 500 mg of active substance per dosage unit and are applied rectally, and also for the treatment of allergic diseases of the intestinal tractr for example Colitis ulcerosa and Colitis granulomatosa.

The following Examples illustrate the invention:

Example 1 a~ 21.63 gms of 3~,21-diacetoxy-17~-hydroxy-~-pregnen-20-one were dissolved in 150 ml of anhydrous methylene chloride and 100 ml of anhydrous formaldehyde-dimethyl-acetal. The solution was then cooled with water and a mixture of 21.6 gms of phosphorus pentoxide and 43 gms of kieselguhr was poured into the solution, and the whole was stirred for one hour at room temperature. The reaction mixture was then filtered and the residue was washed with methylene chloride, triethylamine was added to the filtrate until the pH-value was 9 and the mixture was concentrated in vacuo. The residue was recrystal-lized from methanol-methylene chloride and 22.68 gms of 3~,21-diacetoxy-17~-methoxymethoxy-~5-pregnen-20-one melting at 182-184C were obtained.
b) An Erlenmeyer flask of 2 litres capacity containing 1 litre of a sterile nutrient solution containing 0.3~ of yeast extract, 0.2% of corn steep liquor and 0.2% of glucose, ad-justed to a pH-value of 7.0, was inoculated with a dry culture of Flavobacterium dehydrogenans ATCC 13,930 and the whole was agitated at 30C for two da~s at 175 revolutions per minute.
An Erlenmeyer flask of 500 ml capacity containing 85 ml ~":
.,, ~

~144538 of the same nutrient medium was inoculated with 10 ml of the Flavobacterium dehydrogenans grown cul~ure and the whole was agitated at 3QC for 7 hours at 175 revolutions per minute.
There were then added to the culture 5 ml of a sterile solu-tion of 0.5 gm of 3~,21-diacetoxy-17~-methoxymethoxy-~5-pregnen-20-one in dimethylformamide and the whole was agitated at 30C for a further 65 hours at 175 revolutions per minute.
After the resulting fermentation the culture was extracted twice with 100 ml of ethylene chloride, the extract was con-centrated _ vacuo, the residue was purified by chromatography over aluminium oxide and 402 mg of 21-hydroxy-17~-methoxy-methoxy-44-pregnene-3,20-dione melting at 152-153C were ob-tained.
c) An Erlenmeyer flask of 2 litres capacity containing 1 litre of a sterile nutrient solution containing 2% of glucose and 2~ of corn steep liquor, adjusted to a pH-vlaue of 6.5, was inoculated with a washing of a dry culture of Curvularia lunata NRRL 2380 and the whole was agitated at 30C for 60 hours at 175 revolutions per minute.
An Erlenmeyer flask of ~00 ml capacity containing 90 ml of a sterile nutrient solution containing 1.0% of corn steep liquor and 1.25% of soya powder, adjusted to a pH-value of 6.2, was inoculated with 10 ml of the Curvularia lunata grown culture and the whole was agitated at 30C for 7 hours at 175 revolutions per minute. There was then added to the cul-ture 0.6 ml of a sterile solution of 30 mg of 21-hydroxy-17~-methoxymethoxy-a -pregnene-3,20-dione in dimethylformamide and the whole was fermented for a further 65 hours under the conditions given.

The fermentation culture was worked up as described in Example 1 ~ and 27 mg of 11~,21-dihydroxy-17~-methoxymethoxy-~ -pre~ene-3,20-dione melting at 18Q-182C were o~tained.
d) 2.5 ~ms of 11~,21-dihydroxy-17~-methoxymethoxy-~ -pregnene-

3,20-dione were dissolved in 40 ml of anhydrous methylene chloride, the solution was cooled to 0C and in the course of 11~4S38 15 minutes under argon there was added a solution of 2.25 ml of titanium tetrachloride in 10 ml of methylene chloride.
The reaction mixture was stirred for 90 minutes at room tem-perature, there were then added 150 ml of methylene chloride and 100 ml of a saturated aqueous solution of sodium bicar-bonate, and the mixture was stirred for 15 minutes, and the organic phase was separated off, washed until neutral, dried over sodium sulphate and concentrated in vacuo. The residue was recrystallized from chloroform and 2.19 gms of 11~,17~,21-1~ trihydroxy-a4-pregnene-3,20-dione decomposing at 215C were obtained.

Example 2 r a) To 50 gms of 3~,21-diacetoxy-17~-hydroxy~ pregnen-20-one were added 50 mg of anhydrous para-toluene-sulphonic acid and 350 ml of anhydrous methylene chloride, the mixture was cooled to 0C and, after the addition of 10 gms of methyl vinyl ether, the mixture was stirred for 4 hours at 0C. Triethyl-amine was then added to the reaction mixture until the pH-value was 9 and the mixture was concentrated in vacuo. There were obtained 58 gms of 3~,21-diacetoxy-17-(1'-methoxyethoxy)-Q5-pregnen-20-one in the form of a diastereoisomeric mixture melting at 80-118C. (A test sample recrystallized from methanol melting at 132-134C).
b) Under the conditions given in Example l(b) a solution of 600 mg of a 3~,21-diacetoxy-17~-(1'-methoxyethoxy)-~5-pregnen-20-one diastereoisomeric mixture in 5 ml of diemthylformamide was reacted with a culture of Flavobacterium dehydrogenans ATCC 13,930, the mixture was worked up and there were obtained 394 mg of 21-hydroxy-17~-(1'-methoxyethoxy~-~4-pregnene-3,20-dione in the form of a diastereoisomeric mixture melting at 166-178C.
cl ~ s~lutian of lOQ mg of a 21-hydroxy-17~ methoxyethoxy)-~ -pregnene-3,20-dione diastereoisomeric mixture in 2 ml of dimethylfor~a~mide was fermented unaer the conditions described in Example ltc~ ~ith a culture of Curvularia lunata NRRL 2380, 11~4S38 the mixture was ~orked up and there were obtained 105 mg of11~,21-dihydroxy-17~-(1'-methoxyethoxy) -a -pregnene-3,20-dione in the form of an oily diastereoisomeric mixture.

To this mixture were added 3 ml of methanol and 0.5 ml of 2N-aqueous hydrochloric acid and the whole was agitated for 5 hours at room temperature. 4 ml of water were then added to the mixture, the mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, and extract-ed twice with 8 ml of ethylene chloride each time, the or-ganic phase was evaporated in vacuo, the residue was purified by chromatography over a column of aluminium oxide and 69 mg of 11~,17a,21-trihydroxy-~4-pregnene-3,20-dione melting at 217-219C were obtained.
Example 3 a) To 10.0 gms of 21-acetoxy-17~-hydroxy-Q4-pregnene-3,20-dione were added 13 mg of anhydrous para-toluene-sulphonic acid and 130 ml of anhydrous methylene chloride, the mixture was cooled to 0C and, after the addition of 2.3 gms of methyl vinyl ether, the mixture was stirred for 7 hours at 0C. The reaction mixture was worked up as described in Example 2(a) and there were obtained 11.6 gms of 21-acetoxy-17~-(1'-methoxy-ethoxy)-~4-pregnene-3,20-dione melting at 135-150C.
b) A solution of 0.1 gm of a 21-acetoxy-17~-(1'-methoxy-ethoxy)-~4-pregnene-3,20-dione diastereoisomeric mixture in 2 ml of dimethylformamide was fermented under the conditions described in Example l(c~ with a culture of Curvularia lunata NRRL 2380 and wor~ed up. The 11~,21-dihydroxy-17~-(1'-methoxyethoxy)-~4-pregnene-3,20-dione so obtained was then hydrolysed under the conditions described in Example 2(c) and 78 m~ of 11~,17~,21-trihydroxy-~4-pregnene-3,20-dione melt~ng at 217-219C were obtained.

Example 4 a~ 10.0 gm~ o~ 21-acetox~-17~-~ydroxy-~ -pregnene-3,20-dione ~,:

~14~538 were reacted under the conditions described in Example 3(a~with 2.50 gms of ethyl vinyl ether and worked up, and 12.5 gms of 21-acetoxy-17a-(1'-ethoxyethoxy~-~4-pregnene-3,20-dione were obtained in the form of an oily diasteroisomeric mixture.
b) A solution of 0.1 gm of the 21-acetoxy-17a-(1'-ethoxy-ethoxy~-~4-pregnene-3,20-dione mixture in 2 ml of dimethyl-formamide was hydroxylated under the conditions described in Example l(c~ with Curvularia lunata NRRL 2380 and worked up, and there was obtained 17~-(1'-ethoxyethoxy)-11~,21-dihydroxy-~4-pre~nene-3,20-dione, which was hydrolysed under the conditions described in Example 2(c) to form 63 mg of 11~,17~,21-trihydroxy-~4-pregnene-3,20-dione melting at 216-217.5C.

Example 5 a) Under the conditions described in Example 3(a) 10.0 gms of 21-acetoxy-17~-hydroxy-a4-pregnene-3,20-dione were reacted with 4.Q gms of isobutyl vinyl ether and worked up, and there were obtained 13.5 gms of 21-acetoxy-17~-(1'-isobutoxyethoxy)-a -pregnene-3,20-dione in the form of an oily diastereoiso-meric mixture.
b) Under the conditions described in Example l(c) a solution of 0.1 gm of the 21-acetoxy-17~-(1'-isobutoxyethoxy)-~4-pregnene-3,20-dione mixture in 2 ml of dimethylformarnide was hydroxylated with Curvularia lunata NRRL 2380 and worked up, and the resulting 11~,21-dihydroxy-17~-(1'-isobutoxyethoxy)-Q -pregnene-3,20-dione was hydrolysed under the conditions described in Example 2(c~ to form 68 mg of 11~,17~,21-tri-hydroxy-L4-pregnene-3,20-dione melting at 214-216C (with decomposition~.

Example 6 a) To 1.95 gms of 21-acetoxy-17~-hydroxy-~4-pregnene-3,20-dione were added 5 mg of anhydrous para-toluene-sulphonic acid, 25 ml of anhydrous methylene chloride and 3.5 ml of dihydropyran and the whole was stirred for 13 hours at room ~ 34 -~k 11~4S38 temperature. The reaction mixture was worked up as describedin Example 3(a~ and there were obtained 2.0 gms of 21-acetoxy-17~-(2'-tetrahydropyranyloxy~-~4-pregnene-3,20-dione in the form of a diastereoisomeric mixture melting at 185-200C.
b~ Under the condtions described in Example l(c) a solution of 0.1 gm of the 21-acetoxy-17a-(2'-tetrahydropyranyloxy)-~4-pregnene-3,20-dione mixture in 2 ml of dimethylformamide was hydroxylated with Curvularia lunata NRRL 2380 and worked up, and there was obtained 11~,21-dihydroxy-17~-(2'-tetrahydro-pyranyloxy) -a -pregnene-3,20-dione, which was hydrolysed under the conditions described in Example 2(c) to form 72 mg of 11~,17~;21-trihydroxy-a4-pregnene-3,20-dione melting at 215C (with decompositionl.
Exampl _ a) Under the conditions described in Example 3(a) 50 gms of 21-acetoxy-17~-hydroxy-6~-methyl-a4-presnene-3,20-dione were reacted with 13.9 gms of methyl vinyl ether and worked up, and 59 gms of 21-acetoxy-17~-(1'-methoxyethoxy)-6~-methyl-~4-pregnene-3,20-dione were obtained in the form of an amorphous mass.
b) Under the conditions described in Example l(c) a solution of 200 mg of 21-acetoxy-17~-(1'-metnoxyethoxy)-6~-methyl-~4-pregnene-3,20-dione in 0.4 ml of dimethylformamide was hydroxy-lated with Curvularia lunata NRRL 2380 and worked up, and the resulting 11~,21-dihydroxy-17~-(1'-methoxyethoxy)-6~-methyl-Q4-pregnene-3,20-dione was hydrolysed under the conditions described in Example 2(c~ to form 15 mg of 11~,17a-21-tri-hydroxy-6~-methyl-~ -pregnene-3,20-dione melting at 139-192C.

Example ~ -a~ To 2.0 gms of 21-acetoxy-17~-hydroxy-16~-methyl-~ -preg-nene-3,2Q-di;one were added 5 rng of para-toluene-sulphonic acid (anhydrous~ and 25 ml of anhydrous methylene chloride and the mixture was cooled to 0C. There was then added to the mixture while stirring 0.5 gm of methyl vinyl ether, the mixture was stirred for 5 hours at 0C and for a further 12 hours at room temperature and then worked up as described in Example 3(a) and 2.1 gms of 21-acetoxy-17~-(1'-methoxyethoxy)-16~-methyl-~4-pregnene-3,20-dione were obtained in the form of an oily diastereoisomeric mixture.
b) Under the conditions described in Example l(c) a solution of 50 mg of the 21-acetoxy-17~-~1'-methoxyethoxy)-16~-methyl-a -pregnene-3,20-dione mixture in 1 ml of dimethylformamide was hydroxylated with Curvularia lunata NRRL 2380 and worked up and the resulting 11~,21-dihydroxy-17~-(1'-methoxyethoxy)-16~-methyl-~4-pregnene-3,20-dione was hydrolysed under the conditions described in Example 2(c) to form 32 mg of 11~,17~, 21-trihydroxy-16~-methyl-~4-pregnene-3,20-dione melting at 204-207C.

Example 9 a) Under the conditions described in Example 3(a) 50 gms of 17~-hydroxy-~ -pregnene-3,20-dione were reacted with 15 gms of methyl vinyl ether and worked up, and there were obtained 51.2 gms of 17~-(1'-methoxyethoxy)-~4-pregnene-3,20-dione melting at 115-152C.
b) Under the conditions described in Example l~c) a solution of 0.1 gm of 17~-(1'-methoxyethoxy)-~4-pregnene-3,20-dione in 1 ml of dimethylformamide was fermented with a culture of Curvularia lunata NRRL 2380 and worked up. The resulting hydroxy-17~-(1'-methoxyethoxy)-a4-pregnene-3,20-dione (melting at 85-103C) was hydrolysed under the conditions described in Example 2(c~ and there were obtained 63 mg of 11~,17~-dihydroxy-~ -pregnene-3,20-dione melting at 222-223.5&.

Example 10 al Under the conditions described in Example l~a) 50 gm of 3~,21-diacetoxy-17~-hydroxy-~5-pregnen-20-one in 150 ml of methylene chloride were reacted with 380 gm of formaldehyde bis-glycol monomethyl ether acetal, 50 gms of phosphorus ,, .

11~4538 pentoxide and lOQ gm of kieselguhr and worked up, and there were obtained 45.8 gms of 3~,21-diacetoxy-17~-(2'-methoxy-ethoxy-methoxy~-~5-pregnen-20-one melting at 160-161 C.
b~ Under the conditions described in Example l(b) 0.5 gm of 3~,21-diacetoxy-17a-(2'-methoxyethoxy-methoxy)-~ -pregnen-20-one was reacted with a culture of Flavobacterium dehydro-qenans ATCC 13,930 and worked up, and there were obtained 390 mg of 21-hydroxy-17~-(2'-methoxyethoxy-methoxy)-~4-preg-nene-3,20-dione in the form of vitreous mass.
c) Under the conditions described in Example l(c) 30 mg of 21-hydroxy-17~-(2'-methoxyethoxy-methoxy)-~ -pregnene-3,20-dione were reacted with a culture of Curvularia lunata NRRI
2380 and worked up, and there were obtained 24 mg of 11~,21-dihydroxy-17~-(2'-methoxyethoxy-methoxy)-G4-pregnene-3,20-dione melting at 143-147C.
d) Under the conditions described in Example l(d) 10 mg of 11~,21-dihydroxy-17~-(2'-methoxyethoxy-methoxy)-~ -pregnene-3,20-dione in 2 ml of methylene chloride and 0.01 ml of titanium tetrachloride were reacted and worked up, and there were obtained 8 mg of 11~,17~,21-trihydroxy-~ -pregnene-3,20-dione decomposing at 213C.

Example 11 An Erlenmeyer flask of 2 litres capacity containing 500 ml of a sterile nutrient solution containing 0.1~ of yeast extract, 0~5~ of corn steep liquor, 0.1~ of glucose, adjusted to a pH value of 7.0 was inoculated with a washing of a dry culture of _ throbacter simplex ATCC 6~46 and the mixture was agitated at 30C for 48 hours at 190 revolutions per minute.
An Erlenmeyer flask of 500 ml capacity containing 90 ml of the above described nutrient medium was inoculated with 10 ml of the Arthrobacter simplex grown culture and the whole was a~itated at 30 C for 6 hours at 165 revolutions per minute.
There was then added to the culture 1 ml of a sterile solution of 50 mg of 11~,21-dihydroxy-17a-methoxymethoxy-~ -pregnene-3,20-dione in dimethylformamide and the mixture was fermented ~, 11~4538 for a further 42 hours.

The fermentation culture was worked up as described in Example l(b) and there w~re obtained 44.5 mg of 11~,21-di-hydroxy-17~-methoxymethoxy-~1'4-pregnadiene-3,20-dione melting at 229/230-231C.

Example 12 An Erlenmeyer flask of 2 litre capacity containing 500 ml of a sterile nutrient solution containing 1% of yeast extract (Difco), 0.45% of disodium hydrogen phosphate, 0.34~ of potassium hydrogen phosphate, 0.2% of Tween 80 adjusted to a pH value of 6.7 was inoculated with a washing of a dry culture of Nocardia globerula ATCC 9356 and the mixture was agitated at 30C for 72 hours at 190 revolutions per minute.

An Erlenmeyer flask of 2 litres capacity containing 950 ml of a sterile nutrient solution containing 2.0% of corn steep liquor, 0.3~ of diammonium hydrogen phosphate, 0.25~ o Tween 80 adjusted to a pH value of 6.5 was inoculated with 50 ml of the Nocardia globerula grown culture and the mixture was agitated at 30C for 24 hours at 190 revolutions per minute.
There were then added to the culture 5 ml of a sterile solu-tion of 0.25 gm of 11~,21-dihydroxy-17a-(1'-methoxyethoxy)-6a-methyl-Q4-pregnene-3,20-dione in dimethylformamide and the mixture was fermented for a further 72 hours. The fer-mentation culture was worked up as described in Example l(b) and there was obtained 0.21 gm of 11~,21-dihydroxy-17a-(1'-methoxyethoxy)-6a-methyl-4 '4-pregnadiene-3,20-dione melting at 173C.

Example 13 a) 50 yms of 21-acetoxy-17~-hydroxy-~ -pregnene-3,20-dione were suspended with 600 ml of formaldehydediethylacetal and 6Q0 ml of methylene chloride and the mixture was cooled to -30 to -40C. There was then introduced while stirring a mixture of 75 gms of phosphorus pentoxide and 150 gms of 11~4S38 kieselguhr and the mixture was stirred for 30 hours at -30 C.
The solution was filtered and neutralized with triethylamine.
After distilling off the solvent the mixture was again dis-tilled with methanol and the residue was recrystallized from methanol. There were obtained 34.9 gms of 21-acetoxy-17~-ethoxymethoxy-~4-pregnene-3,20-dione which, after repeated recrystallization, melted at 137-139C.
b) An Erlenmeyer flask of 2 litres capacity containing 1 litre of a sterile nutrient solution containing 1% of corn steep liquor, 1.25% of soya powder adjusted to a pH value of 6.2 was inoculated with a washing of a dry culture of Curvularia lunata NRRL 2380 and agitated at 30 C for 72 hours at 175 revolutions per minute.

A fermenter of 50 litres capacity containing 29 litres of a sterile nutrient medium as described above was inoculated with 1 litre of the Curvularia lunata grown culture and cultivation was carried out for 24 hours at 30C with aeration at the rate of 2 cubic metres per hour.
A fermenter of 50 litres capacity containing 36 litres of a sterile nutrient solution as described above was inocu-lated with 4 litres of the Curvularia lunata pre-fermenter culture and cultivated for 10 hours at 30C with aeration at the rate of 2 cubic metres per hour and stirring at 220 revo-lutions per minute. There were then added to the culture 10 gms of 21- acetoxy-17~ ethoxymethoxy-4 -pregnene-3,20-dione in 2Q0 ml of ethylene glycol monomethyl ether. From the 10th hour the pH value was maintained between 6.5 and 7Ø After a further 4 hours there were added a further 10 gms of 21-acetoxy-17~-ethoxymethoxy-a -pregnene-3,20-dione in 200 ml of ethylene glycol monoethyl ether and the fermentation was continued for a further 23 hours under the conditions given.

The fermentation culture was extracted three times with 10 litres of ethylene chloride and was then further worked ~ 39 -1~4S38 up as described in Example l(b~. There were obtained 13.8 gms of 11~,21-dihydroxy-17~-ethoxymethoxy-~4-pregnene-3,20-dione melting at 153-154C.

Example 14 a) 25 gms of 2l-acetoxy-l7a-hydroxy-~ -pregnene-3,20-dione were suspended with 200 ml of formaldehyde-dipropylacetal and 320 ml of methylene chloride and cooled to -20C. A
mixture of 49.3 gms of phosphorus pentoxide and 97 gms of kieselguhr was introduced while stirring and stirring was con-tinued for 22 hours at -20C. The solution was filtered and neutralized with triethylamine. The methylene chloride was distilled off ln vacuo and the formaldehyde-dipropylacetal phase was decanted from oil that had separated. After dis-tilling off further solvent in vacuo 19 gms of 21-acetoxy-1'~-propoxymethoxy-~4-pregnene-3,20-dione melting at 145-147 C
crystallized.
b) 10 gms of 21-acetoxy-17~-propoxymethoxy-~4-pregnene-3,20-dione were ground with 1 gm of Tween 80 and three times the quantity of water in a Dyno-mill type XDL (Firm Bachofen, Basle). This ground material was sterilized with hydrogen peroxide of 1% strength for at least 4 hours.

Curvularia lunata NRRL 2380 was cultivated, as described in Example 13(b), in a shaking flask and prefermenter and the main fermenter was inoculated therewith. This fermenter was also prepared as described in Example 13(b) and cultivated for 10 hours also in accordance with the conditions described in Example 13(b). There was then added to the culture the ground material containing the 21-acetoxy-17~-propoxymethoxy--pregnene-3,20-dione and fermentation was carried out for a further 44 hours, the pH value being maintained between 6.4 and 6.7. The fermentation culture was worked up as described in Example 13(b) and there were obtained 6.5 gms of 11~,21-dihydroxy-17~-propoxymethoxy-~4-pregnene-3,20-dione melting at 134~135-136C.

Example 15 a~ 50 gms of 21-acetoxy-17a-hydroxy-~4-pregnene-3,20-dione were suspended in 50Q ml of formaldehyde-dibutylacetal and 500 ml of methylene chloride and the whole was cooled to -35C. A mixture of 74 gms of phosphorus pentoxide and 150 gms of kieselguhr was introduced while stirring and the whole was stirred for 30 hours at -35C. The solution was filtered and neutralized with triethylamine. The methylene chloride was distilled off ln vacuo and the formaldehyde-dibutyl-acetal phase was decanted from oil that had separated. After distilling off further solvent in vacuo 38.7 gms of 21-acetoxy-17a-butoxymethoxy-a4-pregnene-3,20-dione melting at 123.5-124.5C crystallized.
b) 8 gms of 21-acetoxy-17~-butoxymethoxy-a4-pregnene-3,20-dione were ground with 0.8 gm of Tween 80 as described in Example 14(b).

Curvularia lunata NRRL 2380 was cultivated and fermented in a shaking flask, pre-fermenter and main fermenter as described in Example 13(b). At the 10th hour of the main fermenter the steroid substrate prepared as described above was added and fermentation was continued for a further 50 hours.

The fermentation culture was worked up as described in Example 13(b) and 3.7 gms of 11~,21-dihydroxy-17a-butoxy-methoxy-a -pregnene-3,20-dione melting at 79-81 C were ob-tained.

Example 16 a) 10.60 gms of 21-acetoxy-6a-fluoro-17a-hydroxy-a -pregnene-3,20-dione were dissolved in 265 ml of methylene chloride and 47.7 ml of formaldehyde-dimethylacetal. A mixture of 7.95 gms of phosphorus pentoxide and 15.9 gms of kieselguhr was added in portions and the mixture was stirred for 90 minutes under nitrogen at room temperature. The solution was ,.~

11~4538 filtered and 2.1 ml of triethylamine were added. The solvents were distilled off and the residue was recrystallized from methanol. There were obtained 7.6 gms of 21-acetoxy-6-fluoro-17~-methoxymethoxy-~4-pregnene-3,20-dione melting at 161-167C.
. b) Curvularia lunata NRRL 2380 was cultivated in a shaking flask, pre-fermenter and main fermenter as described in Example 13(b). At the 10th hour of the main fermenter 5 gms of 21-acetoxy-6~-fluoro-17~-methoxymethoxy-~ -pregnene-3,20-dione in 100 ml of ethylene glycol monomethyl ether were added.
From this moment the pH value was maintained between 6.5 and 7Ø At the 14th hour a further 5 gms of 21-acetoxy-6a-fluoro-17~-methoxymethoxy-~4-pregnene-3,20-dione in 100 ml of ethylene glycol monomethyl ether were added and the mixture was fermented for a further 26 hours.

The fermentation culture was worked up as described in Example 13(b) and there were obtained 4.2 gms of 11~,21-dihydroxy-6~-fluoro-17~-methoxymethoxy-~ -pregnene-3,20-dione melting at 190-192C.

Example 17 a) 43 gms of 3~,21-diacetoxy-17~-hydroxy-16~-methyl-~5-pregnen-20-one were dissolved in 800 ml of formaldehyde-di-methylacetal and the mixture was cooled to -15 C. A mixture of 43 gms of phosphorus pentoxide and 86 gms of kieselguhr was introduced in portions and the mixture was stirred for 15 hours at about -15C. The solution was filtered, then neutralized with triethylamine and the solvents were dis-tilled off _ vacuo. The residue was recrystallized frommethanol and there were obtained 31.5 gms of 3~,21-diacetoxy-17~-methoxymethoxy-16~-methyl-~ -pregnen-20-one melting at 117-118C.
b) F vobacterium dehydrogenans ATCC 13,930 was cultivated and fermented as described in Example l(b). At the 7th hour there were added to the culture 4 ml of a sterile solution 11~4538 of 0.2 gm of 3~,21-diacetoxy-17a-methoxymethoxy-16~-methyl-~ -pregnen-20-one in dimethylformamide and the mixture was agitated for a further 65 hours.

After the fermentation the culture was worked up as des-cribed in Example l(b) and there were obtained 163 mg of 21-hydroxy-17~-methoxymethoxy-16~-methyl-~4-pregnene-3,20-dione melting at 126/128-129C.
c) Curvularia lunata NRRL 2380 was grown and fermented as described in Example l(c). At the 7th hour there were added to the culture 1 ml of a sterile solution of 50 mg of 21-hydroxy-17~-methoxymethoxy-16~-methyl- a -pregnene-3,20-dione in dimethylformamide and fermentation was continued for 65 hours. The fermentation culture was worked up as described in Example l(b) and there were obtained 34.5 mg of 11~,21-dihydroxy-17~-methoxymethoxy-16~-methyl-a4-pregnene-3,20-dione melting at 204/205-206C.

Example 18 To 3 oms of 11~,21-dihydroxy-17~-methoxymethoxy-~ -pregnene-3,20-dione in 20 ml of pyridine were added 5 ml of acetic anhydride and the mixture was stirred for 5 hours at room temperature. After precipitation in 200 ml of ice-water the mixture was filtered with suction and there were obtained 3.23 gms of 21-acetoxy-11~-hydroxy-17~-methoxymethoxy-~4-pregnene-3,20-dione which melted at 172-177C after recrystal-lization from acetone.

Example 19 To 4 gms of 11~,21-dihydroxy-17~-methoxymethoxy-~4-pregnene-3,20-dione in 25 ml of pyridine were added 8 ml of propionic anhydride and the mixture was stirred for 105 minutes at room temperature. After precipitation in 500 ml of ice-water stirring was carried out until the anhydride had been split, filtration with suction was then carried out and there were obtained 4.43 gms of 11~-hydroxy-17~-methoxy-methoxy-21-propionyloxy~ -pre~nene-3,2Q-dione which melted at 119-121C after recrystallization from methanol.

Example 20 To 4 gms of 11~,21-dihydroxy-17~-methoxymethoxy-~4-,pregnene-3,20-dione in 25 ml of pyridine were added 9 ml of butyric anhydride and the whole was stirred for 105 minutes at room temperature. After precipitation in 500 ml of ice-water the mixture was further stirred for 3 hours, then filtered with suction and there were obtained 4.55 gms of 21-butyryloxy-11~-hydroxy-17~-methoxymethoxy-~ -pregnene-3,20-dione which melted at 140-142C after recrystallization from methanol.

Example 21 To 4 gms of 11~,21-dihydroxy-17~-methoxymethoxy-~ -preg-nene-3,20-dione in 25 ml of pyridine were added 11 ml of trimethylacetic anhydride and 100 mg of 4-dimethyl-amino-pyridine. After six hours at room temperature ice-water was added, the mixture was extracted with methylene chloride, the extract was washed with aqueous acetic ac'id, a solution of sodium bicarbonate and water, then dried with sodium sulphate and the solvent was distilled off in vacuo. There were ob-tained 4.8 gms of 11~-hydroxy-17~-methoxymethoxy-21-tri-methylacetoxy-~,4-pregnene-3,20-dione which melted at 182-184C after recrystallization from methanol.

Example 22 To 5 gms of 11~,21-dihydroxy-17~-methoxymethoxy-~ '4-pregnadiene-3,20-dione in 30 ml of pyridine were added 8 ml of acetic anhydride and the mixture was stirred for 1.5 hours at room temperature. After precipitation in 300 ml of ice-water the mixture was filtexed with suction and there were obtained 5.08 gms of 21-acetoxy-1~-hydroxy-17-methoxymethoxy-~1~4-pre~na,diene-3,2~-dione ~hich melted at 214C after re-crystallization from methanol and some methylene chloride.

Example 23 To 1 gm of 11~,21-dihydroxy-1.-~-methoxymethoxy-~1'4-pregnadiene-3,20-dione in 6 ml of pyridine were added 2 ml of butyric anhydride and the mixture was stirred for 1.5 hours at room temperature. After precipitation in ice-water the mixture was stirred for 2 hours, then filtered with suction and there were obtained 1.11 gms of 21-butyryloxy-~ hydroxy-17~-methoxymethoxy-~1' pregnadiene-3,20-dione which melted at 182C after recrystallization from methanol with a small amount of methylene chloride.

Example 24 To 0.32 gm of pyridine chlorochromate were added 2 ml of anhydrous methylene chloride and there were then added while stirring a solution of 0.45 gm of 21-acetoxy-11~-hydroxy-17~-methoxymethoxy-~ -pregnene-3,20-dione in 7 ml of methylene chloride. After 4 hours at 20C the mixture was filtered with suction over kieselguhr, then washed with methylene chloride/diethyl ether 1:1, a few drops of methanol were added and the solvent was distilled off in vacuo. The residue was stirred with water and filtered off with suction.
Recrystallization from methanol yielded 0.28 gm of 21-acetoxy-17~-methoxymethoxy-~ -pregnene-3,11,20-trione melting at 160-161C.
Example 25 6 gms of cortisone acetate were dissolved in 120 ml of formaldehyde-dimethylacetal and 120 ml of methylene chloride and, while cooling with ice, a mixture of 12 gms of phos-phorus pentoxide and 24 gms of kieselguhr was added. Afterstirring the mixture for 4.5 hours it was filtered, then neutralized with triethylamine and the solvent was distilled off ~n vacuo. The residue was chromatographed over silica gel with toluene-ethyl acetate mixtures and there were obtain-ed 3.85 gms of 21-acetoxy-17~-methoxymethoxy-~4-pregnene-3,11,20-trione which melted at 160-161C after recrystalliza-tion from methanol.

~1~4538 Example 26 a) 2 gms of 21-acetoxy-11~-hydroxy-17~-methoxymethoxy-a4-pregnene-3,20-dione were dissolved in 20 ml of pyridine and 0.6 ml of thionyl chloride was added while cooling with ice.
After 30 minutes precipitation in ice-water and filtration with suction were carried out. There were obtained 1.76 gms of 21-acetoxy-17~-methoxymethoxy-Q '9( 1)-pregnadiene-3,20-dione which melted at 194-196C after recrystallization from methanol with some methylene chloride.
b) 5.0 gms of 21-acetoxy-17a-methoxymethoxy-~4'9(11)-pregna-diene-3,20-dione were suspended in 50 ml of tetrahydrofuran and at +20C 20.56 ml of lN-perchloric acid and 5.14 gms of N-bromosuccinimide were added. The mixture was then stirred for 15 minutes. The reaction mixture was precipitated in a solution of 5.14 gms of sodium sulphite and 350 ml of ice-water. The crystallizate was filtered off with suction, washed until neutral with water and the still moist crystalli-zalte was recrystallized from methanol/water. There were obtained 5.0 gms of 21-acetoxy-9~-bromo-11~-hydroxy-17-methoxymethoxy-~ -pregnene-3,20-dione melting at 130-131C.
c) 51.8 gms of 21-acetoxy-9~-bromo-11~-hydroxy-17~-methoxy-methoxy-~ -pregnene-3,20-dione were suspended in 518 ml of ethanol and 45.3 gms of anhydrous potassium acetate were added. The mixture was refluxed for one hour and, after cool ing to +20C, it was precipitated in 5180 ml of ice-water.
The crystallizate was filtered off with suction, washed with water and dried at +20C. There were obtained 41.75 gms of 21-acetoxy-9~ -epoxy-17~-methoxymethoxy-~4-pregnene-3,20-dione which melted at 138-139.5C after recrystallization from methanol.
d~ 1.0 gm of 21-acetoxy-9~ epoxy-17~-methoxymethoxy-a -pregnene-3,20-dione was dissolved in 10 ml of methylene chloride and cooled with ice-water. Hydrogen chloride gas dried over sulphuric acid was introduced in a slow stream until no starting material was present in the thin-layer chromato~ram. The reaction mixt~lre was precipitated in 20 ml _ 46 -. ~ . ~, of a solution of 1% strength of sodium bicarbonate. The methylene chloride phase was separated, washed until neutral with water, dried and concentrated to dryness. There were obtained 1.1 gms of 21-acetoxy-9~-chloro~ -hydroxy-17~-methoxymethoxy-~4-pregnene-3,20-dione which has a melting point of 194.5C after recrystallization.

Example 27 5.0 gms of 21-acetoxy-17~-methoxymethoxy-~4'9(11~-pregnadiene-3,20-dione were suspended in 50 ml of tetrahydro-furan and at ~20C 20.56 ml of lN-perchloric acid and 2.78 gms of N-chlorosuccinimide were added. The mixture was then stirred for 24 hours and a further 3.52 ml of perchloric acid of 70% strength were added. The reaction mixture was lS precipitated in a solution of 5.14 gms of sodium sulphite and 350 ml of ice-water. The crystallizate was filtered off with suction, washed until neutral with water, and the moist crystallizate was recrystallized from methanol/water. There were obtained 1.5 gms of 21-acetoxy-9~-chloro-11~-hydroxy-17~-methoxymethoxy-~ -pregnene-3,20-dione which melted at 189-192C after crystallization from ethyl acetate and acetone.

Example 28 10 gms of 9~-fluoro-hydrocortisone acetate were dissolv-ed in 67.4 ml of methylene chloride and 134.8 ml of methylal and the solution was cooled with an ice-methanol bath. Into this solution were introduced 10 gms of phosphorus pentoxide mixed with 20 gms of kieselguhr and the mixture was then stirred at -15C for 5 hours. The solution was filtered and neutralized with triethylamine. After distilling off the solvent the mixture was further distilled with methanol and the residue was crystallized from methanol. By chromatography o~er silica gel w~th methylene chloride and 5% of methanol the product was separated, and there were obtained 3.28 gms of 21-acetoxy-~-fluoro-11~,17~-dimethoxymethoxy-a4-pregnene-3,20-dione melting at 132-134C, 0.56 gm of 21-acetoxy-9a-11~4538 fluoro~ hydroxy-17~-methoxymethoxy-~ -pregnene-3,20-dione melting at 211-214C and 0.79 gm of 21-acetoxy-9~-fluoro-17~-hydroxy-ll~-methoxymethox~-~ -pregnene-3,20-dione melting at 1g6-lggc .

Example 29 5.0 gms of 21-acetoxy-9~-chloro-11~-hydroxy-17~-methoxy-methoxy-~ -pregnene-3,20-dione were suspended in 10 ml of methylene chloride and 20 ml of methanol and the mixture was cooled to +3C. During the course of 5 minutes a solution of 0.31 gm of potassium hydroxide in 11 ml of methanol was added dropwise and the mixture was then stirred for 80 minutes. The reaction mixture was neutralized with 0.34 ml of glacial acetic acid and precipitated in 350 ml of water.
The crystallizate was filtered off with suction and dried.
There were obtained 2.32 gms of 9a-chloro-11~,21-dihydroxy-17-methoxymethoxy-a -pregnene-3,20-dione which had a melting point of 188-189C after recrystallization from methanol/
methylene chloride.
Example 30 a) To a solution of 5.0 gms of prednisolone 21-acetate in 25 ml of pyridine were added dropwise at -15 C 3 ml of tri-fluoracetic anhydride and the mixture was stirred for 10 minutes at -10C. The mixture was introduced into a solution of ice-water and sodium chloride and the precipitate was filtered off. The residue was taken up in methylene chloride, washed until neutral and concentrated in vacuo after drying over sodium sulphate. The yield was 6.3 gms of 21-acetoxy-17a-hydroxy-11~-trifluoracetoxy-~ ~4-pregnadiene-3,20-dione.
b) 3.0 gms of the above crude product were stirred overnight in a mixture of 25 ml of dimethyl sulphoxide, 15 ml of acetic anhydride and 4.8 ml of glacial acetic acid at room tempera-ture. The reaction sol~tion was added to a solution of 10%
strength of sodium carbonate and the precipitate was filtered off. The residue was dissolved in methylene chloride and worked up in the usual manner after being washed until neutral.

11~4~38 After chromatography over 350 mg of silica gel with a methy-lene chloride-acetone gradient ~0-8% of acetone) there were isolated 2.83 gms of 21-acetoxy-17a-methylthiomethoxy-11~-trifluoracetoxy-~l'4-pregnadiene-3,20-dione.
c) 1.5 gms of 21-acetoxy-17~-methylthiomethoxy-11~-tri-fluora~etoxy-al'4-pregnadiene-3,20-dione in 38 ml of methanol and 1.9 ml of triethylamine were stirred for 4 hours at room temperature. The crude product was purified over 300 gms of silica gel with a methylene chloride-acetone gradient (0-8~ of acetone) and there were isolated 1.2 gms of 21-ace-toxy-ll~-hydroxy-17~-methylthiomethoxy-~1'4-pregnadiene-3,20-dione melting at 155C.

Example 31 a) 20.0 gms of 21-acetoxy-9~-fluoro-11~,17~-dihydroxy-a -pregnene-3,20-dione were reacted in a manner analogous to that described in Example 30(a) with trifluoracetic anhydride to form 23.6 gms of 21-acetoxy-9~-fluoro-17~-hydroxy-11~-tri-fluoracetoxy-~4-pregnene-3,20-dione.
b) 3.0 gms of the above crude product were treated in a manner analogous to that described in Example 30(b) with di-methyl sulphoxide, acetic anhydride and glacial acetic acid.
The crude product was purified over 300 gms of silica gel with a methylene chloride-acetone gradient (0-8~ of acetone).
The yield of 2.58 gms of 21-acetoxy-9~-fluoro-17~-methylthio-methoxy-ll~-trifluoracetoxy-44-pregnene-3,20-dione in 28 ml of methanol was reacted with 1.4 ml of triethylamine in a manner analogous to that described in Example 30(C) and the crude product was purified over 100 gms of silica gel with a methyl chloride-acetone gradient (0-12% of acetone). The yield was 914 mg of 2]-acetoxy-9~-fluoro-11~-hydroxy-17-methylthiomethoxy-a4-pregnene-3,20-dione melting at 193 C.

Example 32 a~ To a suspension of 6,0 gms of 21-acetoxy-17~-hydroxy-a ~ ~ 9-pregnatriene-3,20-dione in 46 ml of anhydrous acetoni-trile were added 11.5 ml of methoxyethoxymethyl chloride and ~3~ ~;
-11~4S38 11.5 ml of diisopropylethylamine and the mixture was stirred for 7.5 hours at 30C. After precipitation in ice-water the precipitate filtered off with suction was dissolved in methy-lene chloride, washed until neutral and concentrated after S being dried. The reaction product was purified over 800 gms of silica gel with a hexane-ethyl acetate gradient (0-30%
of ethyl acetate). The yield was 4.9 gms of 21-acetoxy-17~-(1,3,6-trioxaheptyl)-al'4'9-pregr.atriene-3,20-dione melting at 140C.
b) To a solution of 1.0 gm of 21-acetoxy-17~-(1,3,6-trioxa-heptyl)-~ ' '9-pregnatriene-3,20-dione in 10 ml of dioxan were added 900 mg of N-chlorosuccinimide and 5 ml of perchloric acid of 10% strength. The mixture was stirred for 3.5 hours at room temperature and introduced into an ice-water-sodium chloride-sodium hydrogen sulphate solution. The mixture was filtered and the residue was taken up in methylene chloride, washed until neutral and concentrated after being dried over sodium sulphate. The crude product was purified over 100 gms of silica gel with amethylene chloride-acetone gradient (0-15% of acetone). The yield was 760 mg of 21-acetoxy-9~-chloro-11~-hydroxy-17~-(1,3,6-trioxaheptyl)_~l'4-pregnadiene-3,20-dione (melting point 204 C~, and also 180 mg of 21-acetoxy-9~ -dichloro-17~-(1,3,6-trioxaheptyl)-~1'4-pregna-diene-3,20-dione (melting point 148C).
Example 33 a) 4.0 gms of 21-acetoxy-17~-hydroxy-~ '4'9-pregnatriene-3,20-dione were dissolved in 28 ml of anhydrous methylene chloride and 18 ml of formaldehyde-dimethyl-acetal and there was added in portions a mixture of 6.0 gms of dieselguhr W
20 and 3.0 gms of phosphorus pentoxide. The mixture was stirred for 45 minutes at room temperature, then filtered with suction and the residue was eluted again with methylene chloride which contained 3-5% of triethylamine. The crude product was purified over 75Q gms of silica gel with a methylene chloride-acetone gradient (0-12% of acetone). The - 50 ~

3 1~4538 yield was 3.3 gms of 21-acetoxy-17~-methoxymethoxy-al'4'9-pregnatriene-3,20-dione melting at 160C.
b) 1.6 gms of 21-acetoxy-17~-methoxymethoxy-~1'4'9-pregna-triene-3,20-dione were dissolved in 16 ml of dioxan and 1.5 gms of N-chlorosuccinimide were added. After the dropwise addition of 8 ml of aqueous perchloric acid of 10~ strength, the mixture was then stirred for 3 hours at room temperature and introduced into an ice-water-sodium chloride-sodium hydrogen sulphite solution. The product was filtered off and worked up in a manner analogous to that described in Example 32(b). The crude product was purified over 175 gms of silica gel with a methylene chloride-acetone gradient (0-12% of acetone). The yield was 1.1 gms of 21-acetoxy-9a-chloro-11~-hydroxy-17~-methoxymethoxy-~1'4-pregnadiene-3,20-dione (melt-ing point 224 C), and 250 mg of 21-acetoxy-9a,11~-dichloro-17a-methoxymethoxy-~ '4-pregnadiene-3,20-dione (melting point 162C) Example 34 a) 1.8 gms of 21-acetoxy-17~-(1,3,6-trioxaheptyl)_~l'4'9-pregnatriene-3,20-dione were dissolved in 18 ml of dioxan and 1.6 gms of N-bromosuccinimide were added. After the drop-wise addition of 8.5 ml of aqueous perchloric acid of 10%
strength the mixture was then stirred for 30 minutes at room temperature and introduced into an ice-water-sodium chloride-sodium hydrogen sulphite solution. Working up was carried out in a manner analogous to that described in Example 32(b).
There were obtained 2.3 gms of crude 21-acetoxy-9~-bromo~
hydroxy-17~-(1,3,6-trioxaheptyl~-~ ' -pregnadiene-3,20-dione.
b) 2.Q gms of the above crude product were dissolved in 20 ml of hexamethyl-phosphoric acid triamide and stirred with 2.4 gms of lithium chloride for Q.5 hour at a bath temperature of 80 C. ~fter precipitation in ice~water-sodium chloride the product was filtered off and worXed up in the usual manner.
~35 The crude product was purified over 350 gms of silica gel with a methylene chloride-acetone gradient (0-15% of acetone).
The yield was 570 mg of 21-acetoxy-11~-hydroxy-17a-(1,3,6-trioxaheptyl)_~l'4'8-pregnatriene-3,20-dione melting at 170&.
,~

ll~DtS38 Example 35 a) 3.2 gms of tristriphenyl-posphine rhodium (I) chloride were dissolved in a mixture of 100 ml of methanol and 300 ml of benzene and prehydrogenation was carried out for 1.5 hours.
After the additior. of 4.0 gms of 21-acetoxy-17~-methoxymethoxy-pregnatriene-3,20-dione hydrogenation was continued for 6.5 hours under atmospheric pressure. The solution was con-centrated in a rotary evaporator and the residue was purified over 400 gms of silica gel with a methylene chloride-acetone gradient (0-12~ of acetone). The yield was 2.1 gms of 21-acetoxy-17~-methoxymethoxy-~ '9-pregnadiene-3,20-dione.
b) In a manner analogous to that describedin Example 33(b), 1.1 gms of 21-acetoxy-17~-methoxymethoxy-~ '9-pregnadiene-3,20-dione were treated with N-chlorosuccinimide and perchloric acid. After purification 430 mg of 21-acetoxy-9~-chloro-ll~-hydroxy-17~-methoxymethoxy-A4-pregnene-3,20-dione melting at 195C were isolated.

Example 36 a) 17.5 gms of 21-chloro-17a-hydroxy-Q4'9-pregnadiene-3,20-dione were reacted and worked up in a manner analogous to that described in Example 33(a) with 236 ml of formaldehyde-dimethylacetal. The crude product was purified over 2.25 kg of silica gel with a methylene chloride-acetone gradient (0-4%
of acetone). The yield was 7.6 gms of 21-chloro-17~-methoxy-methoxy-~ '9-pregnadiene-3,20-dione melting at 152C.
b) 1.8 gms of 21-chloro-17~-methoxymethoxy-~4'9-pregnadiene-3,20-dione were treated in a manner analogous to that des-cribed in Example 33(b) with N-chlorosuccinimide and perchlor-ic acid. The crude product was purified over 100 gms of silica gel with a methylene chlorride-acetone gradient (0-10% of acetone). There were isolated 126 mg of 9~,21-di-chloro-ll~-hydroxy-17~-methoxymethoxy-~ -pregnene-3,20-dione melting at 197C (with decomposition).

.~. ,. ~

11~4S38 Example 37 a) 3.0 gms of 21-fluoro-17~-hydroxy-~ ' '9-pregnatriene-3,20-dione were reacted in a manner analogous to that described in Example 33(a) with 14 ml of formaldehyde-dimethylacetal.
Working up was carriedoutunder the conditions described in Example 4. The crude product was purified over 450 gms of silica gel with a methylene chloride-acetone gradient tO-8%
of acetone). The yield was 1.5 gms of 21-fluoro-17~-methoxy-methoxy-~1'4'9- pregnatriene-3,20-dione.
b) Under the conditions given in Example 33tb) 500 mg of 21-fluoro-17~-methoxymethoxy-~ '4'9-pregnatriene-3,20-dione were reacted with N-chlorosuccinimide and perchloric acid.
After the working up procedure already described and purifi-cation over silica gel there were isolated 420 mg of 9~-chloro-21-fluoro-11~-hydroxy-17~-methoxymethoxy-~ '4-pregnadiene-3,20-dione melting at 245~C.

Example 38 ~) 1.0 gm of 17~-hydroxy-~ ' '9-pregnatriene-3,20-dione was reacted under the conditions described in Example 33(a) with formaldehyde-dimethylacetal. There were isoiated 823 mg of 17~-methoxymethoxy-~1'4'9-pregnatriene-3,20-dione as a crude product.
b) 823 mg of the above crude product were treated in a manner analogous to that described in Example 33(b) with N-chloro-succinimide and perchloric acid and working up and purification were carried out under the conditions described therein. The yield was 410 mg of 9~ chloro-11~-hydroxy-17~-methoxymethoxy-~ '4-pregnadiene-3,20-dione melting at 227C.
Example 39 a) In a manner analogous to that described in Example 34(a) 1.0 gm of 21-fluoro-17~-methoxymethoxy-~ '4'9-pregnatriene-3,20-dione was treated with 900 mg of N-bromosuccinimide and 5 ml of aqueous perchloric acid of 10% strength. There were isolated 1.1 g~s of 9~-bromo-21-fluoro-11~-hydroxy-17~-methoxy-methoxy-~ '4-pregnadiene-3,20-dione.

-~i b) 1.1 gms of the crude 9~-bromo-21-fluoro-11~-hydroxy-17~-methoxymethoxy-~1'4-pregnadiene-3,20-dione were reacted with 1.4 gms of lithium chloride in a manner analogous to that described in Example 34(b) to form 21-fluoro-11~-hydroxy 17~-methoxymethoxy-a~'4' -pregnatriene-3,20-dione. The yield was 490 mg melting at 218C.

Exarnple 40 a) 3.3 gms of 21-chloro-17~-hydroxy-~1'4'9-pregnatriene-3,20-dione were reacted under the conditions given in Example 33(a) with formaldehyde-dimethylacetal. There were isolated 2.4 gms of 21-chloro-17~-methoxymethoxy-~1'4'9-pregnatriene-3,20-dione.
b) 1.4 gms of 21-chloro-17a-methoxymethoxy-~ -pregnatriene-3,20-dione were treated with N-bromosuccinimide in a manner analogous to that described in Example 34(a) and there were isolated 1.7 gms of 9~-bromo-21-chloro-11~-hydroxy-17~-me-thoxymethoxy-~l'4-pregnadiene-3,20-dione in the form of a crude product.
c) Under the conditions given in Example 34(b) 1.7 gms of 9~-bromo-21-chloro-11~-hydroxy-17~-methoxymethoxy-~ '4-preg-nadiene-3,20-dione were reacted with 2.1 gms of lithium chlo-ride. The crude product was purified over 300 gms of silica gel with a methylene chloride-acetone gradient (0-8~ of ace-tone). The yield was 530 mg of 21-chloro~ -hydroxy-17~-methoxymethoxy-Q-'4'3-pregnatriene-3,20-dione melting at 166C.

Example 41 a) 3.4 gms of 21-fluoro-17~methoxymethoxy-~ '9-pregnadiene-3,20-dione were prepared in a manner analogous to that des-cribed in Example 33(a) from 7.6 gms of 21-fluoro-17~-hydroxy-~ '9-pregnadiene-3,20-dione and 68 ml of formaldehyde-dimethyl-acetal.
b) Under the conditions described in Example 33(b) 1.4 gms of 21-fluoro-17~-methoxymethoxy-A '9-pregnadiene-3,20-dione were treated with N-chlorosuccinimide and perchloric acid. The crude product was purified over 100 gms of silica gel with a ~ 4538 methylene chloride-acetone gradient (0-10% of acetone). The vield was 380 mg of ~-chloro-21-fluoro~ -hydroxy-17~-methoxy-methoxy-G -pregnene-3,20-dione melting at 214C ~with decompo-sition).

Example 42 a) Into a mixture of 100 ml of pyridine and 12 ml of tri-fluoroacetic anhydride were introduced at -10C 20.0 gms of 9~-fluoro~ ,17~-dihydroxy-21-propionyloxy~ pregnadiene-3,20-dione and the mixture was then stirred for 10 minutes at - 0C. After precipitation in ice-water the mixture was fil-tered and the residue was taken up in methylene chloride.
After being washed and dried, the organic solution was con-centrated ln vacuo~ whereby 22.0 gms of 9~-fluoro-17~-hydroxy-21-propionyloxy-11~-trifluoroacetoxy-~1'4-pregnadiene-3,20-dione were isolated.
b) 22.0 gms of the above crude product were reacted under the conditions given in Example 33(a) with 90 ml of formaldehyde-dimethylacetal, and 9~-fluoro-17~-methoxymethoxy-21-propiony-loxy-ll~-trifluoroacetoxy-a ' -3,20-dione was isolated as a crude product.
c) The crude 9~-fluoro-17~-methoxymethoxy-21-propionyloxy-ll~-trifluoroacetoxy-~ '4-pregnadiene-3,20-dione was dissolved in 500 ml of methanol and, after the addition of 25 ml of triethylamine, was then stirred for 30 minutes at room tem-perature. The reaction solution was concentrated to dryness in vacuo and the residue was chromatographed over 2.25 kg of silica gel with a methylene chloride-acetone gradient (0-12% of acetone). The yield was 12.3 gms of 9~-fluoro-11~-hydroxy-17~-methoxymethoxy-21-propionyloxy-~ ' -pregnadiene -3,20-dione melting at 241C.

Example 43 a) Under the conditions given in Example 42(a) 1.0 gram of 21-butyryloxy-9~-fluoro-11~,17-dihydroxy-~ ' -pregnadiene-3,20-dione was reacted with trifluoroacetic anhydride and worked up.

~, j .

11~4538 There was isolated 0.9 gm of 21-butyryloxy-9~-fluoro-17~-hydroxy-ll~-trifluoroacetoxy-~l'4-pregnadiene-3,20-dione.
b) 800 mg of the above crude product were treated with 3.6 ml of formladehyde-dimethylacetal in a manner analogous to that described in Example 33(a). After working up there were ob-tained 1.1 gms of crude 21-butyryloxy-9~-fluoro-17~-methoxy-methoxy-ll~-trifluoroacetoxy-~ ' -pregnadiene-3,20-dione.
c) 1.1 gms of crude 21-butyryloxy-9~-fluoro-17~-methoxymethoxy-ll~-trifluoroacetoxy-al'4-pregnadiene-3,20-dione were reacted with triethlyamine in a manner analogous to that described in Example 42(c) The crude product was chromatographed over 75 gms of silica gel with a methylene chloride-acetone gradient (0-15% of acetone). The yield was 540 mg of 21-butyryloxy-9-fluoro-11~-hydroxy-17~-methoxymethoxy-al'4-pregnadiene-3,20-dione melting at 247C.

Example 44 2.0 gms of 21-butyryloxy-9~-fluoro-17~-hydroxy-~1'4-pregnadiene-3,11,20-trione were reacted with 9 ml of formal-dehyde-dimethylacetal and worked up in a manner analogous to that described in Example 33(a). The crude product was puri-fied over 300 gms of silica gel with a methylene chloride-acetone gradient (0-10% of acetone). The yield was 2.07 gms of 21-butyryloxy-9~-fluoro-17~-methoxymethoxy-Ql'4-pregnadiene-3,11, 20-trione melting at 192C.

Example 45 . _ In a manner analogous to that described in Example 32(a) 700 mg of 21-butyryloxy-9~-fluoro-17~-hydroxy-~1'4-pregnadiene-3,11,20-trione were reacted with 1.54 ml of me-thoxymethoxymethyl chloride. The crude product was purified over 135 gms of silica gel with a methylene chloride-acetone gradient (0-5~ of acetone). The yield was 430 mg of 21-buty-ryloxy-9~-fluoro-17~-(1,3,6-trioxaheptyl)-A '4-pregnadiene-3,11,20-trione melting at 126C.

~4538 Example 46 a) 15.2 gms of 9~-fluoro~ ,17~-dihydroxy-16~-methyl-21-propionyloxy-~l'4-pregnadiene-3,20-dione, prepared from 9~-fluoro-11~,17~,21-trihydroxy-16~-methyl-~1'4-pregnadiene-3,20-dione and propionic anhydride, were treated with 9.1 ml of trifluoroacetic anhydride in a manner analogous to that des-cribed in Example 42(a) There were obtained 15.4 gms of 9a-fluoro-17~-hydroxy-16~-methyl-21-propionyloxy-11~-trifluoro-acetoxy-~l'4-pregnadiene-3,20-dione.
b) 15.4 gms of the above crude product were reacted under the conditions given in Example 33(a) with formaldehyde-dimethylacetal to form 9~-fluoro-17~-methoxymethoxy-16~-methyl-21-propionyloxy-11~-trifluoroacetoxy-al'4-pregnadiene-3,20-dione. The yield was 16.9 gms of the crude product.
c) A solution of the crude 9~-fluoro-17~-methoxymethoxy-16~-methyl-21-propionyloxy-11~-trifluoroacetoxy-Ql'4-pregnadiene-3,20-di,one in 250 ml of methanol was treated with 30 ml of triethylamine in a manner analogous to that described in Example 42(c). After working up, the crude product was puri-fied over 1.5 kg of silica gel with a methylene chloride-acetone gradient (0 - 10% of acetone). The yield was 9.6 gms of 9~-fluoro-llB-hydroxy-17~-methyxymethoxy-16~-methyl-21-propionyloxy-Al' -pregnadiene-3,20-dione melting at 169C.

Example 47 Under the conditiQns given in Example 35(a) 600 mg of 9~-fluoro-11~-hydroxy-17~-methoxymethoxy-16~-methyl-21-propionyloxy-Q '4-pregnadiene-3,20-dione were hydrogenated with 500 mg of tristriphenyl-phosphine rhodium-(I) chloride and worked up. After chromatography of the crude product over 65 gms of silica gel with a methylene chloride-acetone gradient (0-10% of acetone) there were isolated 347 mg of 9~-fluoro-ll~-hydroxy-17~-methoxymethoxy-16B-methyl-21-propionyloxy-~ -pregnene-3,20-dione melting at 165C.

11~4538 Example 48 A suspension of 6.9 gms of 9-fluoro~ hydroxy-17-methoxymethoxy-16~-methyl-21-propionyloxy-~1'4-pregnadiene-3,20-dione in 80 ml of a 0.2N-methanolic solution of potassium hydroxy was stirred for 45 minutes at 0C. Neutralization was carried out with acetic acid of 10~ strength and, after precipitation in ice-water and working up, there was obtained a crude product which was purified over 450 gms of silica gel with a methylene chloride-acetone gradient (0-20% of acetone).
The yield was 4.1 gms of 9~-fluoro-11~,21-dihydroxy-17~-methoxy-methoxy-16~-methyl-Q~'4-pregnadiene-3,20-dione melting at 200C.

Example 49 a) A solution of 1.7 gms of 9~-fluoro-11~,21-dihydroxy-17~-methoxymethoxy-16~-methyl-~1'4-pregnadiene-3,20-dione in 17 ml of pyridine was stirred with 2.04 gms of tosyl chloride for 1 hour at room temperature. After precipication in ice-water, the precipitate was taken up in methylene chloride and worked up in the usual manner. The crude product was puri-fied over 135 gms of silica gel with a methylene chloride-acetone gradient (0-10% of acetone). The yield was 876 mg of 9~-fluoro-11~-hydroxy-17-methoxymethoxy-16~-methyl-21-tosyloxy- ~ ' -pregnadiene-3,20-dione.
b) 876 mg of the above product in 17 ml of hexamethylphos-phoric acid triamide were stirred with 880 mg of lithium chloride for 1 hour at 80C. The mixture was poured into ice-water and the precipitate was filtered off. After the usual working up, the crude product was recrystallized from hexane/
acetone. The yield was 485 mg of 21-chloro-9~-fluoro-11~-hy-droxy-17-methoxymethoxy-16~-methyl-~1'4-pregnadiene-3,20-dione melting at 204C.

Example 50 a) A suspension of 11.2 gms of 9~-fluoro-11~-hydroxy-17-methoxymethoxy-21-propionyloxy-~ ' -pregnadiene-3,20-dione in 129 ml of a 0.2N-methanolic solution of potassium hydroxide ~ ~4538 was prepared. The suspension was stirred for 1 hour at room temperature and worked up as described in Example 48. ~fter chromatography over 1.5 kg of silica gel with a methylene chloride-acetone sradient (0-35% of acetone) there were iso-lated 7.5 gms of 9~-fluoro~ ,21-dihydroxy-17~-methoxymethoxy-a ' -pregnadiene-3,20-dione.
b) In a manner analogous to that described in Example 49(a) 1.0 gm of the above crude product was reacted with 2.0 gms of tosyl chloride. The crude product was purified over 200 gm~ of silica gel with a methylene chloride-acetone gradient (0-10% of acetone). The yield was 886 mg of 9~-fluoro-11~-hydroxy-17~-methoxymethoxy-21-tosyloxy~a ' -pregnadiene-3,20-dione.
c) 886 mg of 9~-fluoro-11~-hydroxy-17~-methoxymethoxy-21-tosyloxy-a ' -pregnadiene-3,20-dione were treated under the conditions given in Example 49(b) with lithium chloride and worked up. Purification was carried out by recrystallisation from acetone/hexane. The yield was 392 mg of 21-chloro-9~-fluoro-11~-hydroxy-17a-methoxymethoxy-a '4-pregnadiene-3,20-dione melting at 225C.

Example 51 a) 2C.0 gms of 21-acetoxy-9~-fluoro-11~,17~-dihydroxy-a4-pregnene-3,20-dione were reacted in a manner analogous to that described in Example 42(a) with 12 ml of trifluoroacetic an-hydride to for~ 21-acetoxy-9~-fluoro-17~-hydroxy~ -tri-fluoroacetoxy-a -pregnene-3,20-dione.
b) 5.0 gms of the above crude product were converted in a manner analogous to that described in Example 33(a) with 22.5 ml of formaldehyde-dimethylacetal into 21-acetoxy-9~ fluoro-17~-methoxymethoxy-11~-trifluoroacetoxy-a -pregnene-3,20-dione. The yield was 5.3 gms.
c) 5.3 gms of 21-acetoxy-9~-fluoro-17~-methoxymethoxy-11~-trifluoroacetoxy-a -pregnene-3,20-dione were treated with tri-ethylamine in a manner analogous to that described in Example 42(c). The crude product was purified over 500 gms of silica 1~44538 gel with a methylene chloride-acetone gradient (0-8% of acetone). The yield was 560 mg of 21-acetoxy-9~-fluoro~
hydroxy-17~-methoxymethoxy-Q -pregnene-3,20-dione melting at 213C.

Example 52 Under the conditions given in Example 35(a) 1.0 gm of 21-butyryloxy-9~-fluoro-11~-hydroxy-17~-methoxymethoxy-~ ' -pregnadiene-3,20-dione was hydrogenated with 800 mg of tristriphenyl-phosphine rhodium-(I) chloride and worked up.
After chromatography of the crude product over 100 gm of silica gel with a methylene chloride-acetone gradient (0-10%
of acetone) there were isolated 620 mg of 21-butyryloxy-9~-fluoro-ll~-hydroxy-17~-methoxymethoxy-Q -pregnene-3,20-dione melting at 183~C.

Example 53 a) In a manner analogous to that described in Example 48, 28.0 gms of 21-acetoxy-9~-fluoro-11~-hydroxy-17~-methoxy-methoxy-Q -pregnene-3,20-dione were hydrolysed with a 0.2N-methanolic solution of potassium hydroxide to form 9~-fluoro-11~,21-dihydroxy-17~-methoxymethoxy-Q -pregnene-3,20-dione.
b) A solution of 500 mg of 9~-fluoro-11~,21-dihydroxy-17~-methoxymethoxy-A -pregnene-3,20-dione in a 5 ml of pyridine was stirred with 7.5 ml of n-valeric anhydride for 1 hour at room temperature. After precipitation in ice-water, the pre-cipitate was filtered off and worked up in the usual manner.
The crude product was purified over 400 gms of silica gel with a hexane-ethyl acetate gradient (0-30% of ethyl acetate) The yield was 235 mg of 9~-fluoro-11~-hydroxy-17~-methoxyme-thoxy-21-valeryloxy-~ -pregnene-3,20-dione melting at 181C.

Example 54 a) 29.1 gms of 21-acetoxy-6-chloro-17~-hydroxy-Q '5-preg-nadiene-3,20-dione were dissolved in 730 ml of methylene ch]oride and 131.0 ml of formaldehyde-dimethylacetal. A

mixture of 22.12 gms of phosphorus pentoxide and 44 gms of kieselguhr was added in portions and the mixture was stirred for 2.5 hours under nitrogen at room temperature. The solu-tion was filtered and 5.8 ml of triethylamine were added.
The solvents were distilled off and the residue was recrystal-lized from methanol with the addition of active carbon and 1%
of triethylamine. There were obtained 15.6 gms of 21-acetoxy-6-chloro-17~-methoxymethoxy-~4'6-pregnadiene-3,20-dione melting at 183-186C.
b) Curvularia lunata NRRL 2380 was grown, as described in Example 13(b), in a shaking flask and pre- and main-fermenter.
at the 10th hour of the main fermenter there were added 3 gms of 21-acetoxy-6-chloro-17~-methoxymethoxy-~4'6-pregnadiene-3,20-dione in 60 ml of ethylene glycol monomethyl ether.
From this moment at the pH-value was maintained between 6.4 and 6.7 and fermentation was continued for a further 20 hours.
The fermentation culture was worked up as described in Example 13(b) and there were obtained 1.8 gms of 11~,21-dihydroxy-6-chloro-l~-methoxymethoxy-a '6-pregnadiene-3,20-dione melting at 234/235-236.C

Example 55 a) 38.85 gms of 21-acetoxy-17a-hydroxy-a -pregnene-3,20-dione were stirred with 235 ml of formaldehyde-diisopropyl-acetal and 500 ml of methylene chloride and cooled to -20C.
A mixture of 75 gms of phosphorus pentoxide and 150 gms of kieselguhr was introduced while stirring and the mixture was stirred for 20 hours at -20C. The mixture was filtered, washed with methylene chloride and adjusted to a pH-value of 9 with triethylamine. The solvents were distilled off ln vacuo and the residue was taken up in methylene chloride.
. _ The resulting solution was washed with a semi-saturated solution of sodium chloride, dried with sodium sulphate, treated with active carbon, passed over kieselguhr with suction and concen-trated in vacuo. The residue was chromatographed over silica gel with mixtures of toluene and ethyl acetate. There were .

~ 61 ~
r ~ ~

5;38 obtained 35.8 gms of 21-acetoxy-17~-isopropoxy-methoxy-~4-pregnene-3,20-dione which, after crystallization with pentane, melted at 111-117C.
b) Curvularia lunata NRRL 2380 was grown, as described in Exmaple 13(b), in a shaking flask and pre- and main-fermenter.
At the 10th hour of the main fermenter 12 gms of 21-acetoxy-17~-isopropoxymethoxy-~ -pregnene-3,20-dione in 240 ml of ethy-lene glycol monomethyl ether were added. From this moment the Ph-value was maintained between 6.5 and 7.0 and the fer-mentation was continued for a further 15 hours. The fermen-tation culture was worked up as described in Example 13(b) and there were obtained 8.4 gms of 11~,21-dihydroxy-17~-iso-propoxymethoxy-Q -pregnene-3,20-dione melting at 71/73-78C.
c) Arthrobacter simplex ATCC 6946 was grown as described in Example 11 in a growth flask and a fermantation flask. At the 6th hour there was added to the fermantation flast 1 ml of a sterile solution of 50 mg of 11~,21-dihydroxy-17~-iso-propoxymethoxy-~4-pregnene-3,20-dione in ethylene glycol mono-ethyl ether and the fermantation was continued for a further 42 hours.

The fermentation culture was worked up as described in Example l(b) and there were obtained 32 mg of 11~,21-dihydroxy-17~-isopropoxymethoxy -a ~ 4-pregnediene-3,20-dione melting at 58/63-6iC.

Example 56 a) 10.0 gms of prednisolone 21-acetate were dissolved with 40 gms of 4-dimethylaminopyridine and S00 ml of ethylene chloride, and the mixture was cooled to -15C and 25 ml of acetic anhydride were added. In the course of 10 minutes 10 ml of formic acid were added dropwise and the mixture was stirred for a further 135 minutes at -10 to -15C. The solution was extracted with water, hydrochloric acid of 4~
strength and a solution of sodium bicarbonate, and the or~anic phase was dried with sodium sulphate and concentrated in vacuo.

The residue was recrystallized from methanol with the addi-tion of some methylene chloride and there were obtained 9.34 gms of 21-acetoxy~ formyloxy-17a-hydroxy-Q '4-pregnadiene-3,20-dione melting at 221-223C.
b) 5.0 gms of 21-acetoxy-11~-formyloxy-17a-hydroxy-~ '4-pregnadiene-3,20-dione were dissolved in 150 ml of methylene chloride and 30 ml of formaldehyde-diethylacetal and the whole was cooled to 0C. A mixture of 5 gms of phosphorus pentoxide and 10 gms of kieselguhr was introduced while stir-ring and the mixture was stirred for 2.5 hours in an ice-bath. The mixture was filtered, washed with methylene chloride and adjusted to a pH-value of 9 with triethylamine. After distilling off the solvents there were obtained 10.5 gms of crude 21-acetoxy-17a-ethoxymethoxy~ formyloxy-~1'4-pregnadiene-3,20-dione in the form of a semi-solid mass.
c) 0.34 gms of crude 21-acetoxy-17a-ethoxymethoxy-11~-formyloxy-~l'4-pregnadiene-3,20-dione was dissolved in 13 ml of methanol and under argon the solution was added to a solu-tion of 0.126 gm of sodium bicarbonaté in 1.32 ml of water at 60C. The mixture was heated under reflux for 10 minutes then cooled down, water was added and the mixture was extracted with methylene chloride. The methylene chloride solution was dried with sodium sulphate, then concentrated and the re-sidue was chromatographed over silica gel with mixtures of toluene and ethyl acetate. There was obtained 0.1 gm of 17a-ethoxymethoxy-11~,21-dihydroxy-~1'4-pregnadiene-3,20-dione melting at 149.5-152C.

Example 57 a) 20.0 gms of 11~,21-dihydroxy-17a-methoxymethoxy-~ -preg-nene-3,20-dione were dissolved in 200 ml of pyridine and 20 ml of methanesulphonic acid chloride were added dropwise while cooling. The mixture was stirred for 30 minutes at room temperature and precipitated in 2000 ml of ice-water.
After filtering with suction, washing and drying there were obtained 23.85 gms of 11~-hydroxy-21-methanesulphonyloxy-17a-,~ .

~1~4538 methoxymethoxy-~ -pregnene-3,20-dione decomposing at 154-155C.
b) To 20 gms of 11~-hydroxy-21-methanesulphonyloxy-17~-me-thoxymethoxy-~ -pregnene-3,20-dione were added 600 ml of acetone, a solution of 20 gms of sodium iodide in 520 ml of acetone was added and the mixture was heated under reflux for 11 hours. After cooling the mixture, the insoluble matter was filteredoff, the acetone solution was concentrated in vacuo and there was added to the residue water and a small amount of a solution of sodium thiosulphate. The crude product was filtered off with suction, washed with water and recrystallized from acetone. There were obtained 16.6 gms of ll~-hydroxy-21-iodo-17~-methoxymethoxy-~ -pregnene-3,20-dione decomposing at 123-126C.
c) 1 gm of 11~-hydroxy-21-iodo-17~-methoxymethoxy-~ -pregnene-3,20-dione was heated under argon for 30 minutes at 55C
with 20 ml of toluene and 1.3 ml of tributyl tin hydride. The toluene was then distilled off in vacuo and the residue was treated with pentane. There was obtained as a crystallizate 0.64 gm of 11~-hydroxy-17~-methoxymethoxy-~4-pregnene-3,20-dione melting at 191-194C.
Example 58 a) 9.0 gms of 21-acetoxy-17~-hydroxy-~4~9(11)-pregnadiene-3,20-dione were dissolved with 72 ml of formaldehydediethyl-acetal and 280 ml of methylene chloride and the solution was cooled to 0C. A mixture of 9.0 gms of phosphorus pentoxide and 18 gms of kieselguhr was introduced while stirring and the whole was stirred for 2.5 hours in an ice bath. The mix-ture was filtered and washed with methylene chloride. The solution was adjusted to a pH-value of 9 with triethylamine, then concentrated and the residue was chromatographed over silica gel with mixtures of toluene and ethyl acetate. There were obtained 5.93 gms of 21-acetoxy-17~-ethoxymethoxy-~4'9(11)-pregnadiene-3,20-dione melting at 167 - 169C.

~4~538 b) 5.8 gms of 21-acetoxy-17a-ethoxymethoxy-~ '9(11)-pregna-diene-3,20-dione were reacted under the conditions given in Example 26(b), but without recrystallization, and there were obtained 7.6 gms of crude 21-acetoxy-17a-ethoxymethoxv-9a-bromo-11~-hydroxy-~4-pregnene-3,20-dione in the form of a vitreous substance.
c) 7.6 gms of crude 21-acetoxy-17a-ethoxymethoxy-9a bromo-ll~-hydroxy-~ -pregnene-3,20-dione were reacted under the con-ditions described in Example 26(c) and the methanolic solution of the crude product was filtered over silica gel. There were obtained 5.49 gms of crude 21-acetoxy-17~-ethoxymethoxy-9~, ll~-epoxy-~ -pregnene-3,20-dione as an amorphous substance.
d) 5.4 gms of crude 21-acetoxy-17a-ethoxymethoxy-9~,11~-epoxy-~ -pregnene-3,20-dione were reacted under the conditions described in Example 26(d). The crude product was chromato-graphed over silica gel with mixtures of toluene and ethy~
acetate and there were obtained 1.78 gms of 21-acetoxy-17a-ethoxymethoxy-9~-chloro-11~-hydroxy-Q -pregnene-3,20-dione melting at 148 - 151C.
Example 59 a) 6.0 gms of hydrocortisone 21-acetate-11-formate were dis-solved in 150 ml of methylene chloride and 63 gms of formla-dehyde-dihexylacetal and the solution was cooled to 10C.
A mixture of 6 ~ms of phosphorus pentoxide and 12 gms of kieselguhr was added in portions under argon and the mixture was stirred for one hour at 10C and one hour at 15C. The mixture was filtered, washed with methylene chloride and ad-justed to a pH-value of 8 with triethylamine. The methylene chloride was evaporated in vacuo and the residue was cooled in an ice-bath. The solution was decanted from the oil that had precipitated and chromatographed over silica gel with mixtures of toluene and ethyl acetate. There were obtained

4.2 gms of 21-acetoxy-11~-formyloxy-17a-hexyloxymethoxy-~ -pregnene-3,20-dione which melted at 110C after crystallization with pentane.

11~4S38 b) 0.38 gm of 21-acetoxy-11~-formyloxy-17a-hexyloxy-methoxy-4 -pregnene-3,20-dione was reacted under the condi-tions described in Example 56~c) and 0.1 gm of 11~,21-dihy-droxy-17~-hexyloxymethoxy-~4-pregnene-3,20-dione was obtained.

Example 60 a) 6.0 gms of hydrocortisone 21-acetate-11-formate were dis-solved in 150 ml of methylene chloride and 65 gms of formalde-hyde-dibenzylacetal and in a water bath at room temperature there was added in portions while stirring under argon a mixture of 6 gms of phosphorus pentoxide and 12 gms of kieselguhr. After 4 hours the mixture as filtered, washed with methylene chloride and adjusted to a pH value of 8 with triethylamine. The methylene chloride was evaporated in vacuo and the residue was chromatographed over silica gel with mixtures of toluene and ethyl acetate. There were ob-tained 3.0 gms of 21-acetoxy-17~-benzyloxymethoxy-11~-formyl-oxy-~4-pregnene-3,20-dione.
b) 0.38 gm of 21-acetoxy-17~-benzyloxymethoxy-11~-formyloxy-~ -pregnene-3,20-dione was reacted under the conditions described in Example 56(c) and there was obtained 0.11 gm of 17a-benzyloxymethoxy-11~,21-dihydroxy-~4-pregnene-3,20-dione.

Example 61 a) Flavobacterium dehydrogenans ATCC 13,930 was cultivated and fermented as described in Example l(b). At the 24th hour of the main fermenter 19.5 gms of 16~-methylene-3~,21-diacetoxy-17~-methoxymethoxy-~ -pregnen-20-one in 500 ml of dimethylformamide were added and the fermentation was contin--ued for a further 28 hours.

The fermentation culture was worked up as described in Example l(b) and there were obtained 15.5 gms of 16-methylene-21~hydroxy-17~-methoxymethoxy-4 -pregnene-3,20-dione melting at 147/150-151C.

11~4538 b) Curvularia lunata NRRL 2380 was grown, as described in Example 13(b~, in a shaking flask and a pre- and main fermenter. At the 10th hour of the main fermenter there were added 20 gms of 16-methylene-21-hydroxy-17~-methoxymethoxy-~ -pregnene-3,20-dione in 400 ml of ethylene glycol mono-methyl ether. From this moment the pH value was maintained between 6.4 and 6.7 and the fermentation was continued for a further 8 hours.

The fermentation culture was worked up as described in Example 13(b) and there were obtained 11 gms of 16-methylene-11~,21-dihydroxy-17~-methoxymethoxy-a4-pregnene-3,20-dione melting at 205/206-208C.

lS Example 62 Arthrobacter simplex ATCC 6946 was grown as described in Example 11 in a growth flask and a fermentation flask. At the 6th hour there was added to the fermentation flask 1 ml of a sterile solution of 50 mg of 11~,21-dihydroxy-17-propoxymeth~xy-~4-pregnene-3,20-dione in ethylene glycol monomethyl ether and fermentation was continued for a further 42 hours. The fermentation culture was worked up as des-cribed in Example l(b) and there were obtained 41 mg of 11~, 21-dihydroxy-17~-propoxymethoxy-~1'4-pregnadiene-3,20-dione melting at 121/125-127C.

Example 63 3.0 gms of 11~,21-dihydroxy-17~-methoxymethoxy-16-methylene-~4-pregnene-3,20-dione were dissolved in 12 ml of pyridine at +20 C and 2.37 ml of acetic anhydride were added.
The reaction mixture was then stirred for 2 hours at +20 C
and was then precipitated in 144 ~1 of ice-water. The whole was then stirred for one hour. The crystallizate was filtered off with suction, washed with water and dried. After recry-stallization from ethyl acetate there were obtained 2.74 gms of 21-acetoxy-11~-hydroxy-17~-methoxymethoxy-16-methylene-~4-pregnene-3,20-dione melting at 166-167 C.

Claims (163)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN
EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS
FOLLOWS:

1. A process for the manufacture of a compound of the general formula I

(I) in which each of the bonds in the 1,2- and 6,7-positions repre-sents a single carbon-to-carbon bond or a double carbon-to-carbon bond, X represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, Y represents a hydrogen atom and Z represents a hydrogen atom, a fluorine atom or a chlorine atom or Y and Z together represent a carbon-to-carbon bond, V represents a .beta.-hydroxymethylene group, a .beta.-chloro-methylene group or a carbonyl group, W represents a methylene group, an ethylidene group or a vinylidene group, Q represents an oxygen atom or a sulphur atom, R1 represents an alkyl group containing 1 to 8 carbon atoms which may be interrupted by an oxygen atom, or represents a benzyl group and R2 represents a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms or R1 and R2 together represent a trimethylene group or a tetra-methylene group, and R3 represents a hydrogen atom, a fluorine atom, a chlorine atom or a free or esterified hydroxyl group which comprises, (a) reacting a 17.alpha.-hydroxy-steroid of the general formula II

(II) in which the bonds , X, Y, Z, V and W have the meanings given above and R'3 represents a hydrogen atom, a fluorine atom, a chlorine atom or an esterified hydroxyl group, when required after intermediate protection of any 11.beta.-hydroxyl group, (i) when Q is required to represent an oxygen atom, with an acetal of the general formula III

R2HC(OR1)2 (III), in which R1 and R2 have the meanings given above or, (ii) when Q is required to represent an oxygen atom, with an .alpha.-halogen-ether of the general formula IV

Hal-R2-CH-OR1 (IV), in which R1 and R2 have the meanings given above and Hal represents a chlorine atom, a bromine atom or an iodine atom, or (iii) when Q is required to represent an oxygen atom and R2 a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms, with a vinyl ether of the general formula V

R'2CH = CH-OR1 (V), in which R1 has the meaning given above and R'2 represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms, or (iv) when Q is required to represent a sulphur atom, with a sulphoxide of the general formula VI

R2CH2DOR1 (VI), in which R1 and R2 have the meanings given above.
(b) additively combining a 9,11-dehydro-steroid of the general formula VII

(VII) , in which the bond , X, W, Q, R1, R2 and R3 have the meanings given above with chlorine or hypoclorous acid, or (c) opening up the epoxy-ring of a 9,11-epoxy-steroid of the general formula VIII

(VIII) in which the bonds , X, W, Q, R1, R2 and R3 have the meanings given above with hydrogen fluoride or hydrogen chloride, or (d) splitting off Z'' or HZ'' from a 9-halo-steroid of the general formula IX
(IX), in which the bonds , X, W, Q, R1, R2 and R3 have the meanings given above and Z" represents a chlorine atom or a bromine atom, and when required in any steroid obtained saturated in the 1,2-position dehydrogenation is carried out in the 1,2-position, and/or in any steroid obtained any 11.beta.-hydroxyl group is oxidized to form an oxo group, and/or any 21-ester group is hydrolysed and/or any 21-hydroxyl group is esterified or exchanged for a fluorine atom or a chlorine atom, or (e) fermenting an 11-desoxy-steroid of the general formula XI

(XI), in which X, W, Q, R1 and R2 have the meanings given above and R'4 represents a hydrogen atom, a hydroxyl group or an alkanoy-loxy group containing 1 to 6 carbon atoms, with a fungal culture of a straim of the genus Curvularia, and, when required the compound obtained saturated in the 1,2-position is dehydrogenated in the 1,2-position.

2. A process as claimed in claim 1, wherein the fermentation is carried out with a fungal culture of a strain of the species Curvularia lunata.

3. A compound of the general formula I

(I) in which each of the bonds , in the 1,2- and 6,7-positions represents a single carbon-to-carbon bond or a double carbon-to-carbon bond, X represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, Y represents a hydrogen atom and Z represents a hydrogen atom, a fluorine atom or a chlorine atom or Y and Z together represent a carbon-to-carbon bond, V represents a .beta.-hydroxymethylene group, a .beta.-chloro-methylene group or a carbonyl group, W represents a methylene group, an ethylidene group or a vinylidene group, Q represents an oxygen atom or a sulphur atom, R1 represents an alkyl group containing 1 to 8 carbon atoms which may be interrupted by an oxygen atom, or repre-sents a benzyl group and R2 represents a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms or R1 and R2 together represent a trimethylene group or a tetra-methylene group, and R3 represents a hydrogen atom, a fluorine atom, a chlorine atom or a free or esterified hydroxyl group whenever prepared or produced by the process as claimed in claim 1 or 2 or an obvious chemical equivalent thereof.

4. A process as claimed in claim 1, in which Y

is hydrogen; V is a .beta.-hydroxy methylene group; the bonds are single carbon-to-carbon bonds; X is hydrogen a fluorine atom or a methyl group and Z is a hydrogen atom a fluorine atom or a chlorine atom.

5. A compound of the general formula Ia (Ia) in which W represents a methylene group, an ethylidene group or a vinylidene group, Q represents an oxygen atom or a sulphur atom, R1 represents an alkyl group containing 1 to 8 carbon atoms which may be interrupted by an oxygen atom, or represents a benzyl group and R2 represents a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms or R1 and R2 together represent a trimethylene group or a tetra-methylene group, and R3 represents a hydrogen atom, a fluorine atom, a chlorine atom or a free or esterified hydroxyl group X' represents a hydrogen atom, a fluorine atom or a methyl group and Z' represents a hydrogen atom, a fluorine atom or a chlorine atom whenever prepared or produced by the process as claimed in claim 4 or an obvious chemical equivalent thereof.

6. A process as claimed in claim 1, in which Y is hydrogen; V is a .beta.-hydroxy methylene group; the bonds are double carbon carbon bonds; X is hydrogen, a fluorine atom or a methyl group and Z is a hydrogen atom a fluorine atom or a chlorine atom.

7. A compound of the general formula Ib (lb) in which X' represents a hydrogen atom, a fluorine atom or a methyl group Z' represents a hydrogen atom, a fluorine atom or a chlorine atom W represents a methylene group, an ethylidene group or a vinylidene group, Q represents an oxygen atom or a sulphur atom, R1 represents an alkyl group containing 1 to 8 atoms which may be interrupted by an oxygen atom, or represents a benzyl group and R2 represents a hydrogen atom or an alkyl group contain-ing 1 to 6 carbon atoms or R1 and R2 together represent a trimethylene group or a tetra-methylene group, and R3 represents a hydrogen atom, a fluorine atom, a chlorine atom or a free or esterified hydroxyl group whenever prepared or produced by the process as claimed in claim 6 or an obvious chemical equivalent thereof.

8. A process as claimed in claim 1, in which Y

and Z together represent a carbon carbon bond, the bond in the 1,2-position is a carbon carbon double bond and in the 6,7-position a carbon carbon single bond, V is a .beta.-hydroxy methylene group and X is hydrogen, a fluorine atom or a methyl group.

9. A compound of the general formula Ic (Ic) in which X' represents a hydrogen atom, a fluorine atom or a methyl group W represents a methylene group, an ethylidene group or a vinylidene group, Q represents an oxygen atom or a sulphur atom, R1 represents an alkyl group containing 1 to 8 carbon atoms which may be interrupted by an oxygen atom, or represents a benzyl group and R2 represents a hydrogen atom or an alkyl group contain-ing 1 to 6 carbon atoms or R1 and R2 together represent a trimethylene group or a tetra-methylene group, ann R3 represents a hydrogen atom, a fluorine atom, a chlorine atom or a free or esterified hydroxyl group whenever prepared or produced by the process as claimed in claim 8 or an obvious chemical equivalent thereof.

10. A process as claimed in claim 4, in which X' is a hydrogen atom.

11. A compound of formula la as given in claim 5, where W, Q, R1, R2, R3 and Z' are as in claim 5 and X' is hydrogen whenever prepared or produced by the process as claimed in claim 10 or an obvious chemical equivalent thereof.

12. A process as claimed in claim 6, in which X' is a hydrogen atom.

13. A compound of formula Ib given in claim 7, where W, Q, R1, R2, R3 and Z' are as in claim 7 and X' is hydrogen whenever prepared or produced by the process as claimed in claim 12 or an obvious chemical equivalent thereof.

14. A process as claimed in claim 8, in which X' is a hydrogen atom.

15. A compound of formula Ic given in claim 9, where W, Q, R1, R2 and R3 are as in claim 9 and X' is hydrogen whenever prepared or produced by the process as claimed in claim 14 or an obvious chemical equivalent thereof.

16. A process as claimed in claim 10, in which Z' is hydrogen.

17. A compound of formula I as given in claim 5, where W, Q, R1, R2, and R3 are as in claim 5 and X' and Z' are hydrogen whenever prepared or produced by the process as claimed in claim 16 or an obvious chemical equivalent thereof.

18. A process as claimed in claim 12, in which Z' is hydrogen.

19. A compound of formula Ib given in claim 7, where W, Q, R1, R2, and R3 are as claim 7, and X' and Z' are hydrogen whenever prepared or produced as claimed in claim 18 or an obvious chemical equivalent thereof.

20. A process as claimed in claim 10, in which Z' is fluorine or chlorine.

21. A compound of formula I given in claim 5, where W, Q, R1, R2, and R3 are as in claim 5, X' is hydro-gen and Z' is fluorine or chlorine whenever prepared or produced by the process as claimed in claim 20 or an obvious chemical equivalent thereof.

22. A process as claimed in claim 12, in which Z' is fluorine or chlorine.

23. A compound of formula Ib given in claim 7, where W, Q, R1, R2 and R3 are as in claim 7, X' is hydrogen and Z' is chlorine or fluorine whenever prepared or produced by the process as claimed in claim 22 or an obvious chemical equivalent thereof.

24. A process as claimed in claim 1, wherein W
represents a methylene group.

25. A compound of formula I given in claim 1, in which Q, R1, R , R3, X and Z are as in claim 1 and W is methylene whenever prepared or produced by the process as claimed in claim 24 or an obvious chemical equivalent thereof.

26. A process as claimed in claim 24, wherein Q represents an oxygen atom.

27. A compound of formula I given in claim 1, in which R1, R2, R3, X and Z are as in claim 1, W is methylene and Q is oxygen whenever prepared or produced by the process as claimed in claim 26 or an obvious chemical equivalent thereof.

28. A process as claimed in claim 24, wherein Q

represents a sulphur atom.

29. A compound of formula I given in claim 1, in which R1, R2, R3, X and Z are as in claim 1, W is methylene and Q is sulphur whenever prepared or produced by the process as claimed in claim 28 or an obvious chemical equivalent thereof.

30. A process as claimed in claim 26, wherein R2 represents a hydrogen atom.

31. A compound of formula I given in claim 1, in which R1, R2, X and Z are as in claim 1, W is methylene, Q is oxygen and R2 is hydrogen whenever prepared or produced by the process as claimed in claim 30 or an obvious chemical equivalent thereof.

32. A process as claimed in claim 26, wherein R2 represents an alkyl group containing 1 to 6 carbon atoms.

33. A compound of formula I given in claim 1, in which R1, R3, X and Z are as in claim 1, W is methylene, Q is oxygen and R2 is C1-C6 alkyl whenever prepared or produced by the process as claimed in claim 32 or an obvious chemical equivalent thereof.

34. A process as claimed in claim 30, wherein R3 represents a hydroxyl group or an acyloxy group containing 1 to 8 carbon atoms.

35. A compound of formula I given in claim 1, in which R1, X and Z are as in claim 1, W is methylene, Q is oxygen, R2 is hydrogen and R3 is as in claim 34 whenever prepared or produced by the process as claimed in claim 34 or an obvious chemical equivalent thereof.

36. A process as claimed in claim 32, wherein R3 represents a hydroxyl group or an acyloxy group containing 1 to 8 carbon atoms.

37. A compound of formula I given in claim 1, in which R1, X and Z are as in claim 1, W is methylene, Q is oxygen, R2 is C1-C6 alkyl and R3 is as in claim 36 whenever prepared or produced by the process as claimed in claim 36 or an obvious chemical equivalent thereof.

38. A process as claimed in claim 30, wherein R3 represents a fluorine atom or a chlorine atom.

39. A compound of formula I given in claim 1, in which R1, X and Z are as in claim 1, W is methylene, Q is oxygen, R2 is hydrogen and R3 is as in claim 38 whenever prepared or produced by the process as claimed in claim 38 or an obvious chemical equivalent thereof.

40. A process as claimed in claim 32, wherein R3 represents a fluorine atom or a chlorine atom.

41. A compound of formula I given in claim 1, in which R1, X and Z are as in claim 1, W is methylene, Q is oxygen, R2 is C1-C6 alkyl and R3 is as in claim 40 whenever prepared or produced by the process as claimed in claim 40 or an obvious chemical equivalent thereof.

42. A process as claimed in claim 1, which compris-es fermenting 21-hydroxy-17.beta.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione in dimethylformamide with a Curvularia lunata grown culture.

43. 11.beta.,21-Dihydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 42 or an obvious chemical equivalent thereof.

44. A process as claimed in claim 1, which compris-es fermenting 21-hydroxy-17.alpha.-(1'-methoxyethoxy)-.DELTA.4-pregnene-3,20-dione in dimethyl formamide with a Curvularia lunata grown culture.

45. A process as claimed in claim 1, which compris-es fermenting 21-acetoxy-17 .alpha.-(1'-methoxyethoxy)-.DELTA.4-pregnene-3,20-dione in dimethylformamide with a Curvularia lunata grown culture.

46. 11 .beta.,21-dihydroxy-17 .alpha.-(1'-methoxyethoxy)-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 44 or 45 or an obvious chemical equiva-lent thereof.

47. A process as claimed in claim 1, which compris-es fermenting 21-acetoxy-17.alpha.-(1'-ethoxyethoxy)-.DELTA.4-pregnene-3,20-dione in dimethylformamide with a Curvularia lunata grown culture.

48. 17 .alpha.-(1'-ethoxyethoxy)-11.beta.,21-dihydroxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 47 or an obvious chemical equiva-lent thereof.

49. A process as claimed in claim 1, which compris-es fermenting 21-acetoxy-17.alpha.-(1'-isobutoxy-ethoxy)-.DELTA.4-pregnene-3,20-dione in dimethylformamide with a Curvularia lunata grown culture.

50. 11.beta.,21-dihydroxy-17 .alpha.-(1'-isobutoxyethoxy)-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 49 or an obvious chemical equiva-lent thereof.

51. A process as claimed in claim 1, which comprises fermenting 21-acetoxy-17 .alpha.-(2'-tetrahydropyranyloxy)-.DELTA.4-pregnene-3,20-dione in dimethylformamide with a Culvularia lunata grown culture.

52. 11.beta.,21-dihydroxy-17 .alpha.-(2'-tetrahydropyranyloxy)-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 51 or an obvious chemical equiva-lent thereof.

53. A process as claimed in claim 1, which compris-es fermenting 21-acetoxy-17.alpha.-(1'-methoxyethoxy)-6 .alpha.-methyl-.DELTA.4-pregnene-3,20-dione in dimethylformamide with a Culvularia lunata grown culture.

54. 11.beta.,21-dihydroxy-17.alpha.-(1'-methoxyethoxy)-6.alpha.-methyl-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 53 or are obvious chemical equivalent thereof.

55. A process as claimed in claim 1, which compris-es fermenting 21-acetoxy-17 .alpha.-(1'-methoxyethoxy)-16.alpha.-methyl-.DELTA.4-pregnene-3,20-dione in dimethylformamide with a Culvularia lunata grown culture.

56. 11.beta.,21-dihydroxy-17.alpha.-(1'-methoxyethoxy)-16.alpha.-methyl-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 55 or an obvious chemical equivalent thereof.

57. A process as claimed in claim 1, which compris-es fermenting 17 .alpha.-(1'-methoxyethoxy)-.DELTA.4-pregnene-3,20-dione in dimethylformamide with a Culvularia lunata grown culture.

58. 11.beta.-hydroxy-17 .alpha.-(1'-methoxyethoxy)-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 57 or an obvious chemical equivalent thereof.

59. A process as claimed in claim 1, which compris-es fermenting 21-hydroxy-17.alpha.-(2'-methoxyethoxy-methoxy)-.DELTA.4-pregnene-3,20-dione in dimethylformamide with a Culvularia lunata grown culture.

60. 11.beta.,21-dihydroxy-17.alpha.-(2'-methoxyethoxy-methoxy) -.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 59 or an obvious chemical equiva-lent thereof.

61. A process as claimed in claim 42, in which the 11.beta. 21-dihydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione obtained in dimethylformamide is fermented with Arthrobacter simplex grown culture.

62. 11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 61 or an obvious chemical equiva-lent thereof.

63. A process as claimed in claim 53, in which the 11.delta.,21-dihydroxy-17.alpha.-(1'-methoxyethoxy)-6.alpha.-methyl-.DELTA.4-pregnene -3,20-dione so obtained in dimethylformamide is fermented with Nocardia globerula grown culture.

64. 11.beta.,21-dihydroxy-17.alpha.-(1'-methoxyethoxy)-6.alpha.-methyl-.DELTA.4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 63 or an obvious chemical equivalent thereof.

65. A process as claimed in claim 1, which compris-es fermenting 21-acetoxy-17.alpha.-ethoxymethoxy-.DELTA.4-pregnene-3,20-dione in ethylene glycol monomethyl ether with Curvularia lunata grown culture.

66. 11.beta.,21-dihydroxy-17.alpha.-etnoxymethoxy-.alpha.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 65 or an obvious chemical equivalent thereof.

67. A process as claimed in claim 1, which compris-es fermenting 21-acetoxy-17 .alpha.-propoxymethoxy-.DELTA.4-pregnene-3,20-dione in ethylene glycol monomethyl ether with Curvul-arla lunata grown culture.

68. 11.beta.,21-dihydroxy-17.alpha.-propoxymethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 67 or an obvious chemical equivalent thereof.

69. A process as claimed in claim 1, which compris-es fermenting 21-acetoxy-17 .alpha.-butoxymethoxy-.DELTA.4-pregnen-3,20-dione in ethylene glycol monomethyl ether with Curvularia lunata grown culture.

70. 11.beta.,21-dihydroxy-17.alpha.-butoxymethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 69 or an obvious chemical equivalent thereof.

71. A process as claimed in claim 1, which compris-es fermenting 21-acetoxy-6 .alpha.-fluoro-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione in ethylene glycol monomethyl ether with Curvularia lunata grown culture.

72. 11.beta.,21-dihydroxy-6.alpha.-fluoro-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 71 or an obvious chemical equiva-lent thereof.

73. A process as claimed in claim 1, which compris-es fermenting 21-hydroxy-17.alpha.-methoxymethoxy-16.beta.-methyl-.DELTA.4-pregnene-3,20-dione in dimethylformamide with a Curvularia lunata grown culture.

74. 11.beta.,21-dihydroxy-17.beta.-methoxymethoxy-16.beta.-methyl-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 73 or an obvious chemical equiva-lent thereof.

75. A process as claimed in claim 42, in which the 11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione so obtained is reacted with acetic anhydride in pyridine.

76. 21-Acetoxy-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 75 or an obvious chemical equiva-lent thereof.

77. A process as claimed in claim 42, in which the 11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione so obtained is reacted with propionic anhydride-pyridine.

78. 11.beta.-hydroxy-17 .alpha.-methoxymethoxy-21-propionyloxy -.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 77 or an obvious chemical equivalent thereof.

79. A process as claimed in claim 42, in which the 11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione so obtained is reacted with butyric anhydride-pyridine.

80. 21-butyryloxy-11.beta.-hydroxy-17 .alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 79 or an obvious chemical equiva-lent thereof.

81. A process as claimed in claim 42, in which the 11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione so obtained is reacted with trimethylacetic anhydride in 4-dimethyl-amino-pyridine.

82. 11.beta.-hydroxy-17.alpha.-methoxymethoxy-21-trimethyl-acetoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 81 or an obvious chemical equivalent thereof.

83. A process as claimed in claim 61, in which the 11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is reacted with acetic anhydride in pyri-dine.

84. 21-acetoxy-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.1,4 -pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 83 or an obvious chemical equiva-lent thereof.

85. A process as claimed in claim 61, in which the 11.alpha.,21-dihydroxy-17.alpha.-methoxymethoxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is reacted with butyric anhydride-pyridine.

86. 21-butyryloxy-11.beta.-hydroxy-17 .alpha.-methoxymethoxy-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 85 or an obvious chemical equivalent thereof.

87. A process as claimed in claim 75, in which the 21-acetoxy-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione so obtained in methylene cnloride is treated with pyridine chlorochromate in anhydrous methylene chloride.

88. A process as claimed in claim 1, which compris-es treating cortisone acetate in formaldehyde-dimethylacetal and methylene chloride with phosphorus pentoxide and kieselguhr.

89. 21-acetoxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,11,20-trione whenever prepared or produced by the process as claimed in claim 87 or 88 or an obvious chemical eqivalent thereof.

90. A process as claimed in claim 1, which compris-es treating 21-acetoxy-9.beta.,11.beta.-epoxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione in methylene chloride with cooling with dry hydrogen chloride gas.

91. A process as claimed in claim 1, which compris-es treating a suspension of 21-acetoxy-17.alpha.-methoxymethoxy-.DELTA.4,9(11)-pregnadiene-3,20-dione in tetrahydrofuran with perchloric acid and N-chlorosuccinimide.

92. A process as claimed in claim 1, which compris-es treating 21-acetoxy-17 .alpha.-methoxymethoxy-.DELTA.4,9-pregnadiene-3,20-dione dioxan with N-chlorosuccinimide and aqueous perchloric acid.

93. 21-acetoxy-9.alpha.-chloro-11.beta.-hydroxy-17.alpha.-methoxy-methoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 90, 91 or 92 or an obvious chemical equivalent thereof.

94. A process as claimed in claim 1, which compris-es treating 9.alpha.-fluoro-hydrocortisone acetate in methylene chloride and methylal with phosphorus pentoxide and kiesel-guhr at low temperature.

95. 21-acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxy-methoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 94 or an obvious chemical equivalent thereof.

96. A process as claimed in claim 90, in which the 21-acetoxy-9.alpha.-chloro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione so obtained suspended in methylene chloride and methanol with cooling is treated with potassium hydroxide.

97. 9.alpha.-chloro-11.beta.,21-dihydroxy-17 .alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 96 or an obvious chemical equiva-lent thereof.

98. A process as claimed in claim 1, which compris-es treating 21-acetoxy-17.alpha.-hydroxy-11.beta.-trifluoracetoxy-.DELTA.1,4-pregnadiene-3,20-dione in dimethyl sulphoxide with acetic anhydride and glacial acetic acid and treating the 21-acetoxy-17.alpha.-methylthiomethoxy-11.beta.-trifluoracetoxy-.DELTA.1,4-pregnadiene-3,20-dione obtained in methanol with triethylamine.

99. 21-acetoxy-11.beta.-hydroxy-17 .alpha.-methylthiomethoxy-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 98 or an obvious chemical equivalent thereof.

100. A process as claimed in claim 1, which compris-es treating 21-acetoxy-9.alpha.-fluoro-17.alpha.-hydroxy-11 -trifluor-acetoxy-.DELTA.4-pregnene-3,20-dione in dimethyl sulphoxide with acetic anhydride and glacial acetic acid and treating the 21-acetoxy-9.alpha.-fluoro-17.alpha.-methylthiomethoxy-11.beta.-trifluor-acetoxy-.DELTA.4-pregnene-3,20-dione obtained in methanol with triethylamine.

101. 21-acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methyl-thiomethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 100 or an obvious chemical equivalent thereof.

102. A process as claimed in claim 1, which compris-es treating 21-acetoxy-17.alpha.-methoxymethoxy-.DELTA.1,4,9-pregnatriene -3,20-dione in dioxan with N-chlorosuccinimide and aqueous perchloric acid and separating the 21-acetoxy-9.alpha.-chloro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.1,4-pregnadiene-3,20-dione from the product obtained.

103. 21-acetoxy-9.alpha.-chloro-11.beta.-hydroxy-17.alpha.-methoxy-methoxy-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 102 or an obvious chemical equivalent thereof.

104. A process as claimed in claim 102, in which 21-acetoxy-9.alpha.,11.beta.-dichloro-17.alpha.-methoxymethoxy-.DELTA.1,4-pregna-diene-3,20-dione is separated from the product obtained.

105. 21-acetoxy-9.alpha.,11.beta.-dichloro-17.alpha.-methoxymethoxy-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 104 or an obvious chemical equivalent thereof.

106. A process as claimed in claim 1, which compris-es treating 21-chloro-17.alpha.-methoxymethoxy-.DELTA.4'9-pregnadiene-3,20-dione in dioxan with N-chlorosuccinimide and aqueous perchloric acid.

107. 9.alpha.,21-dichloro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 106 or an obvious chemical equiva-lent thereof.

108. A process as claimed in claim 1, which compris-es treating 21-fluoro-17.alpha.-methoxymethoxy-.DELTA.1,4,9-pregnatriene-3,20-dione in dioxan with N-chlorosuccinimide and aqueous perchloric acid.

109. 9.alpha.-chloro-21-fluoro-11.beta.-hydroxy-17.alpha.-methoxy-methoxy-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 108 or an obvious chemical equivalent thereof.

110. A process as claimed in claim 1, which compris-es treating 17.alpha.-methoxymethoxy-.DELTA.1,4,9-pregnadriene-3,20 -dione in dioxan with N-chlorosuccinimide and aqueous per-chloric acid.

111. 9.alpha.-chloro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.1,4, -pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 110 or an obvious chemical equivalent thereof.

112. A process as claimed in claim 1, which compris-es treating 21-chloro-17.alpha.-methoxymethoxy-.DELTA.1,4,9-pregnadiene-3,20-dione in dioxam with N-bromosuccinimide and aqueous perchoric acid and reacting the 9.alpha.-bromo-21-chloro-11.beta.-hydroxy-17 methoxymethoxy-.DELTA.1,4-pregnadiene-3,20-dione obtained in hexamethyl-phosphoric acid triamide with lithium chloride.

113. 21-chloro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.1,4,8 -pregnadriene-3,20-dione whenever prepared or produced by the process as claimed in claim 112 or an obvious chemical equivalent thereof.

114. A process as claimed in claim 1, which compris-es treating 21-fluoro-17.alpha.-methoxymethoxy-.DELTA.1,4,9-pregnadiene-3,20-dione in dioxan with N-bromosuccinimide and aqueous perchloric acid and reacting the 9.alpha.-bromo-21-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.1,4-pregnadiene-3,20-dione obtained in hexamethyl-phosphoric acid triamide with lithium chloride.

115. 21-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.1,4,8 -pregnadriene-3,20-dione whenever prepared or produced by the process as claimed in claim 114 or an obvious chemical equivalent thereof.

116. A process as claimed in claim 1, which compris-es treating 21-fluoro-17.alpha.-methoxymethoxy-.DELTA.4,9-pregnadiene-3,20-dione in dioxan with N-chlorosuccinimide and aqueous perchloric acid.

117. 9 .alpha.-hloro-21-fluoro-11.beta.-hydroxy-17.alpha.-methoxy-methoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 116 or an obvious chemical equivalent thereof.

118. A process as claimed in claim 1, which compris-es reacting 9.alpha.-fluoro-17.alpha.-hydroxy-21-propionyloxy-11.beta.-trifluoracetoxy-.DELTA.1,4-pregnadiene-3,20-dione in anhydrous methylene chloride with formaldehyde-dimethylacetal in the presence of kieselguhr and phosphorus pentoxide and treating the 9.alpha.-fluoro-17.alpha.-methoxymethoxy-21-propionyloxy-11.beta.-tri-fluoracetoxy-.DELTA.1,4-pregnadiene-3,20-dione obtained in methanol with triethylamine.

119. 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-21-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 118 or an obvious chemical equivalent thereof.

120. A process as claimed in claim 1, which compris-es reacting 21-butyryloxy-9.alpha.-fluoro-17.alpha.-hydroxy-11.beta.-trifluor-acetoxy-.DELTA.1,4-pregnadiene-3,20-dione in anhydrous methylene chloride with formaldehyde-dimethylacetal in the presence of kieselguhr and phosphorus pentoxide and treating the 21-butyryloxy-9.alpha.-fluoro-17.alpha.-methoxymethoxy-11.beta.-trifluoracetoxy -.DELTA.1,4-pregnadiene-3,20-dione obtained in methanol with triethylamine.

121. 21-butyryloxy-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxy-methoxy-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 120 or an obvious chemcial equivalent thereof.

122. A process as claimed in claim 1, which compris-es reacting 21-butyryloxy-9.alpha.-fluoro-17.alpha.-hydroxy-.DELTA.1,4-pregnadiene-3,11,20-trione in anhydrous methylene chloride with formaldehyde-dimethylacetal in the presence of kieselguhr and phosphorus pentoxide.

123. 21-butyryloxy-9.alpha.-fluoro-17.alpha.-methoxymethoxy-.DELTA.1,4-pregnadiene-3,11,20-trione whenever prepared or produced by the process as claimed in claim 122 or an obvious chemical equivalent thereof.

124. A process as claimed in claim 1, which compris-es reacting 9.alpha.-fluoro-17.alpha.-hydroxy-16.beta.-methyl-21-propionyloxy-11.beta.-trifluoracetoxy-.DELTA.1,4-pregnadiene-3,20-dione in anhydrous methylene chloride with formaldehyde-dimethylacetal in the presence of kieselguhr and phosphorus pentoxide and treating the 9.alpha.-fluoro-17.alpha.-methoxymethoxy-16.beta.-methyl-21-propionyloxy-11.beta.-trifluoracetoxy-.DELTA.1,4-pregnadiene-3,20-dione obtained in methanol with triethylamine.

125. 9.alpha.-fluoro-11.beta.-hydroxy-17.beta.-methoxymethoxy-16.beta.-methyl-21-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 124 or an obvious chemical equivalent thereof.

126. A process as claimed in claim 124, in which the 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-16.beta.-methyl-21-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is hydrogenated with tristriphenyl-phosphine rhodium-(I) chlor-ide.

127. 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-16.beta.-methyl-21-propionyloxy-.DELTA.4-pregnene-3,20-dione whenever pre-pared or produced by the process as claimed in claim 126 or an obviaus chemical equivalent thereof.

128. A process as claimed in claim 124, in which the 9.alpha.-luoro-11.beta.hydroxy-17.alpha.-methoxymethoxy-16.beta.-methyl-21-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione obtained is treated with methanolic potassium hydroxide.

129. 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-16.beta.-methyl-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 128 or an obvious chemical equivalent thereof.

130. A process as claimed in claim 124, in which the 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-16.beta.-methyl-.DELTA.1,4-pregnadiene-3,20-dione obtained is reacted with tosyl chloride in pyridine and the 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-16.alpha.-methyl-21-tosyloxy-.DELTA.1,4-pregnadiene-3,20-dione obtained reacted with lithium chloride in hexa-methyl-phosphoric acid triamide.

131. 21-chloro-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxy-methoxy-16.alpha.-methyl-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 130 or an obvious chemical equivalent thereof.

132. A process as claimed in claim 118, in which the 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-21-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione obtained is treated with methan-olic potassium hydroxide, the 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.
-methoxymethoxy-.DELTA.1,4-pregnadiene-3,20-dione obtained reacted with tosyl chloride in pyridine and the 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-21-tosyloxy-.DELTA.1,4-pregnadiene-3,20-dione obtained reacted with lithium chloride in hexa-methyl-phosphoric acid triamide.

133. 21-chloro-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxy-methoxy-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 132 or an obvious chemical equivalent thereof.

134. A process as claimed in claim 120, in which the 21-butyryloxy-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.1,4-pregnadiene-3,20-dione obtained is hydrogenated in tristriphenyl-phosphine rhodium-(I) chloride.

135. 21-butyryloxy-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 134 or an obvious chemical equivalent thereof.

136. A process as claimed in claim 94, in which the 21-acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione obtained is hydrolysed with methan-olic potassium hydroxide.

137. 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 136 or an obvious chemical equivalent thereof.

138. A process as claimed in claim 136, in which the 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene -3,20-dione obtained is reacted with n-valeric anhydride in pyridine.

139. 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-21-valeryloxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 138 or an obvious chemical equivalent thereof.

140. A process as claimed in claim 1, which compris-es fermenting 21-acetoxy-6-chloro-17.alpha.-methoxymethoxy-.DELTA.4,6-pregnadiene-3,20-dione in ethylene glycol monomethyl ether with Curvularia lunata grown culture.

141. 11.beta.,21-dihydroxy-6-chloro-17.alpha.-methoxymethoxy-.DELTA.4'6-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 140 or an obvious chemical equivalent thereof.

142. A process as claimed in claim 1, which compris-es fermenting 21-acetoxy-17.alpha.-isopropoxymethoxy-.DELTA.4-pregnene-3,20-dione in ethylene glycol monomethyl ether with Curvularia lunata grown culture.

143. 11.beta.,21-dihydroxy-17.alpha.-isopropoxymethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 142 or an obvious chemical equiva-lent thereof.

144. A process as claimed in claim 142, in which the 11.beta.,21-dihydroxy-17.alpha.-isopropoxymethoxy-.DELTA.4-pregnene-3,20-dione obtained is fermented in ethylene glycol monomethyl ether with Arthrobacter simplex grown culture.

145. 11.beta.,21-dihydroxy-17.alpha.-isopropoxymethoxy-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 144 or an obvious chemical equiva-lent thereof.

146. A process as claimed in claim 1, which compris-es reacting 21-acetoxy-11.beta.-formyloxy-17.alpha.-hydroxy-.DELTA.1,4-pregna-diene-3,20-dione in methylene chloride with formaldehyde-diethylacetal in the presence of phosphorus pentoxide and kieselguhr and refluxing the 21-acetoxy-17.alpha.-ethoxymethoxy-11.beta.-formyloxy-.DELTA.1,4-pregnadiene-3,20-dione obtained in methanol aqueous sodium bicarbonate under argon.

147. 17.alpha.-ethoxymethoxy-11.beta.,21-dihydroxy-.DELTA.1,4-pregna-diene-3,20-dione whenever prepared or produced by the process as claimed in claim 146 or an obvious chemical equivalent thereof.

148. A process as claimed in claim 42, in which the 11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pxegnene-3,20-dione obtained is reacted in pyridine with methanesulphonic acid chloride, the 11.beta.-hydroxy-21-methanesulphonyloxy-17.alpha.-methoxy-methoxy-.DELTA.4-pregnene-3,20-dione obtained is reacted in acetone with sodium iodide and the 11.beta.-hydroxy-21-iodo-17.alpha.-methoxy-methoxy-.DELTA.4-pregnene-3,20-dione obtained is heated under argon in toluene with tributyl tin hydride.

149. 11.beta.-hydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 148 or an obvious chemical equivalent thereof.

150. A process as claimed in claim 1, which compris-es reacting 21-acetoxy-17.alpha.-methoxymethoxy-9.beta.,11-epoxy-.DELTA.4-pregnene-3,20-dione in methylene chloride and cooling with dried hydrogen chloride.

151. 21-acetoxy-17.alpha.-ethoxymethoxy-9.alpha.-chloro-11.beta.-hydroxy-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 150 or an obvious chemical equivalent thereof.

152. A process as claimed in claim 1, which compris-es reacting hydrocortisone 21-acetate-11-formate in methylene chloride with formaldehyde-dihexylacetal in the presence of phosphorus pentoxide and kieselguhr under argon and the 21-acetoxy-11.beta.-formyloxy-17.alpha.-hexyloxymethoxy-.DELTA.4-pregnene-3,20-dione obtained is refluxed in methanol under argon with aqueous sodium bicarbonate.

153. 11.beta.,21-dihydroxy-17.alpha.-hexyloxymethoxy-.DELTA.4-preg-nene-3,20-dione whenever prepared or produced by the process as claimed in claim 152 or an obvious chemical equivalent thereof.

154 A process as claimed in claim 1, which comprises reacting hydrocortisone 21-acetate-11-formate in methylene chloride with formaldehyde-dihexylacetal in the presence of phosphorus pentoxide and kieselguhr under argon and the 21-acetoxy-17.alpha.-benzyloxymethoxy-11.beta.-formyloxy-.DELTA.4-pregnene-3,20-dione obtain-ed refluxed in methanol under argon with aqueous sodium bicarbonate.

155. 17.alpha.-benzyloxymethoxy-11.beta.,21-dihydroxy-.DELTA.4-preg-nene-3,20-dione whenever prepared or produced by the process as claimed in claim 154 or an obvious chemical equivalent thereof.

156. A process as claimed in claim 1, which comprises fermenting 16-methylene-21-hydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione in ehtylene glycol monomethyl ether with Curvularia lunata grown culture.

157. 11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-16-methyl-ene-.DELTA.4-pregnene-3,20-dione whenever prepared or produced by the process as claimed in claim 156 or an obvious chemical equivalent thereof.

158. A process as claimed in claim 67, in which the 11.beta.,21-dihydroxy-17.alpha.-propoxymethoxy-.DELTA.4-pregnene-3,20-dione obtained in dimethylformamide is fermented with Arthrobacter simplex grown culture.

159. 11.beta.,21-dihydroxy-17.alpha.-propoxymethoxy-.DELTA.1,4-preg-nadiene-3,20-dione whenever prepared or produced by the pro-cess as claimed in claim 158 or an obvious chemical equivalent thereof.

160. A process as claimed in claim 156, in which the 11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-16-methylene-.DELTA.4-pregnene-3,20-dione obtained is reacted with acetic anhydride in pyridine.

161. 21-acetoxy-11.beta.-hydroxy-17.alpha.-methoxymethoxy-16-methylene-.DELTA.4-pregnene-3,20-dione whenever prepared or produc-ed by the process as claimed in claim 160 or an obvious chemical equivalent thereof.

162. A process as claimed in claim 1, which comprises reacting 21-acetoxy-9.alpha.-fluoro-17.alpha.-hydroxy-11.beta.-trifluoracetoxy -.DELTA.4-pregnene-3,20-dione in anhydrous methylene chloride with formaldehyde-dimethylacetal in the presence of phosphorus pentoxide and kieselguhr and treating the 21-acetoxy-9.alpha.-fluoro-17.alpha.-methoxymethoxy-11.beta.-trifluoracetoxy-.DELTA.4-pregnene-3,20-dione with triethylamine in methanol.

163. 11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-.DELTA.4-pregnene-3,20-dione so obtained is reacted with butyric anhydride-pyridine whenever prepared or produced by the process as claim-ed in claim 162 or an obvious chemical equivalent thereof.