HUT61030A - Process for producing corticosteroid intermediates - Google Patents

Abstract

A process for preparing oxazoline corticosteroid intermediates of formula (V) wherein R<1> represents hydrogene (H), loweralkyl, phenyl or phenylalkyl; R<4> represents H or loweralkyl, preferably methyl having either the alpha or beta stereochemistry; and R<9> represents hydrogen, fluoro, chloro or loweralkyl. The process comprises contacting a compound of formula (III) herein, with (A) Vilsmeier reagent, followed by acid hydrolysis to yield the compound of formula (V); or alternatively, (B) an acid having a pKa of less than 5, to yield the compound of formula (V).

Description

These corticosteroids are useful in the treatment of psoriasis, dermatological diseases and inflammation. U.S. Pat. No. 4,127,596 discloses a process for dehydrating 9? -Hydroxyandrostenedione ion compounds with chlorosulfonic acid to yield h 9,11-steroids. U.S. Patent No. 4,102,907 and European Patent Application No. 87201933.6 disclose dehydration of steroid intermediates. British Patent Application No. 2O869O7A (Barton et al.) Discloses the preparation of oxazoline steroid intermediates using peracid. U.S. Patent 4,585,590 discloses the preparation of a C 4 protected form of oxazoline from specific steroid intermediates. However, none of these references discloses the simultaneous dehydration and oxazoline formation from 9X-hydroxy steroids with an acid or Vilsmeier reagent having a pKa of about 5 or less. In the method of Barton et al., The oxazoline group appears to be a useful precursor to pregnanes and corticosteroids. It would be desirable to develop a process for the preparation of Δ 9,11-steroids having the required oxazoline moiety from your 9-hydroxy steroid starting materials. The δ9,11 double bond • · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 3 steroids are useful intermediates for the preparation of pharmaceutically active corticosteroids / Louis F.

Fieser and Mary Fieser, Steroids, Reinhold. Publishing Corporation, New York (195917). Thus, it would be desirable to develop a process for the preparation of A9,11-steroids having the requisite oxazoline moiety and which reduces the operations required for its preparation.

The present invention relates to a process for preparing oxazoline corticosteroid intermediates of formula (V): wherein: hydrogen, lower alkyl, phenyl or phenylalkyl,

R 4 is hydrogen or lower alkyl, preferably methyl, in the stereochemical form of O or O; and

R 4 is hydrogen, fluoro, chloro or lower alkyl.

According to the invention, the process is carried out by reacting a 9cZ-hydroxy steroid of formula (III), a tautomer thereof or mixtures thereof, wherein Z is a hydrogen atom, an alkoxyalkyl group, a trisubstituted compound of the formula -Si silyl 2 3 groups in which R ^x , R, and R · ⁵ are independently • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · «

- 4 lower alkyl, phenyl or phenylalkyl groups; the moiety (a) is an enol ether of formula (b) or (c) - wherein R 4 is lower alkyl, R 4 is as defined above and R 4 ^a , R ² and R 4 are as follows, a ketal of formula (d) - wherein R and R are each independently lower alkyl, or - (CR ²⁰ R 14 ' ^L ) v, or - (CR ²⁰ R ¹² ') wherein R, R, R ^2, and R ^{2 are} ; each independently is hydrogen, lower alkyl or aryl, v and w are each independently 0-6 and v + w is 2-12, preferably 2 and - (CR ^{2 O} R ²¹ ) V or - (CR 4 R) · ^ form ¹⁾ ^ ring, or an oxygen or nitrogen keQ coupled via, and R is as defined above -, an enamine of formula (e) wherein - R and R are as defined above - or a formula g (f)

ketone - where R is as defined above -

A) Reaction with Vilsmeier reagent followed by acid hydrolysis to give a compound of formula V; obsession

B) reacting with an acid having a pKa of about 5 or less to give a compound of formula V; the acid may be chlorosulfonic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, perchloric acid or trifluoroacetic acid, or mixtures thereof, most preferably ···· ···· · ······

- 5 in chlorosulfonic acid.

In another embodiment, the present invention relates to a process for the preparation of a compound of formula IV wherein: and r 4 is as defined above and the moiety (a ') is an enol ether of formula (b') or (c ') - wherein R 4 is lower alkyl, R ^{3 is} as defined above and R 4 ^a , R ² and R ³ the following, a ketal of formula (d '): wherein R and R are independently lower alkyl or a (CR ²⁰ R ²¹ ) or (CR ³ ° R ³¹ ) ν W

A group consisting of R 30, R 1, R ² and R 4 independently of one another hydrogen, lower alkyl or aryl, v and w independently of one another 0 to 6 and v + w are 2 to 12, preferably 2 and - ( CR ² ^ R ² ^) _v - and - (CR 2 ^ R ^J ) - form a ring or are bonded via an oxygen or nitrogen atom, and R is as defined above, an enamine of formula (e *) wherein R and R is as defined above - or a ketone of formula (f ') wherein R is as defined above. The process is carried out by reacting a compound of formula (III) with a Vilsmeier reagent under conditions to provide a compound of formula (IV).

In one embodiment of the process of the present invention, the preferred compounds of formula (IV ') are:

- 6, wherein the dashed line represents the optional double bond and the numbering system refers to the preferred compounds.

The process of the present invention has the unexpected and surprising advantage that the 9 '-OH steroid can be region-specific dehydrated by the simultaneous formation of the Δ 9,11-steroid containing the requisite oxazoline group in a single operation or reactor. This combination can be used to prepare corticosteroids from the steroid 9? -Hydroxyandrost-4-ene-3,17-dione. A further advantage of the process according to the invention is that it provides a one-step procedure which allows the simple addition of important functional groups to the C-21 position adjacent to the oxazoline group in the product of formula (V).

Unless otherwise indicated, the terms used in the specification and claims are defined below.

The term " ^r, alkyl or lower alkyl" refers to C 1-6 straight chain saturated hydrocarbons or C 3-6 branched saturated hydrocarbon groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.

The alkoxy term is a neighboring structural • · 4 4 ···· * * · · · · * 4 »* · 4 · · 4 · ··

4 · 4 444 * 4 4 * · ·· «

Refers to an alkyl group covalently bonded to 7 elements by oxygen atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexoxy and the like.

The term alkoxyalkyl refers to a C 1-6 alkoxy group covalently bonded to a C 1-6 alkyl group.

The term "phenylalkyl" refers to a phenyl group covalently bonded to a C 1-6 alkyl group such as phenylmethyl, 2-phenylethyl and the like.

Chlorosulfonic acid (chlorosulphuric acid) has the formula CISOgOH. Chlorosulfonic acid is a known compound formed when sulfuric trioxide or fuming sulfuric acid is treated with hydrochloric acid.

The Z symbol can be any group that is labile enough to allow the formation of the required oxazoline. Examples thereof include - without limitation - the hydrogen atom, an alkoxy group, a tri-substituted silyl SiR RR formula of which ^the R and are independently lower alkyl, phenyl or phenylalkyl, preferably -Si (CH) ^.

One of ordinary skill in the art will recognize that starting compounds of formula (III) are compounds of formula (III) and (III ').

V · · «··« · • · · · 4 4 · · · ·

They can exist in 8 tautomeric forms.

The invention also encompasses the use of any tautomer and mixtures thereof.

The process of the present invention is schematically illustrated in Scheme A7. Process (A) consists of operations (A1) and (A2). In step (Al), a Vilsmeier reagent or variants thereof may be used to convert the compound of formula (III) to the required oxazoline corticosteroid of formula (V). The Vilsmeier reagent is prepared by mixing a formamide of formula (VI), in which the alkyl or phenyl group is independently selected from sulfinyl chloride or phosphoryl chloride, preferably sulfinyl chloride. Preferred (VI) formamide of the formula wherein R41 and R ^ j_ _s methyl, dimethylformamide. The Vilsmeier reagent may be prepared by known methods, as described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, John Wiley and Sons, Inc., New York (1967); J. March (ed.) Advanced Organic Chemistry, 3rd Edition, John Wiley and Sons, New York (1985) p. 487-488; RS Kittila ”DMF Chemical Uses (1967) and RS Kittila Supplement to DI; Chemical Uses ”EI DuFont De Nemours and Co.Inc. (1973) ./.

The preparative experience of these references is incorporated herein by reference. A Vilsmeier · «· • · · 4« «*« 4 · ♦♦ · · · · · · · · · 4 _V «t« «

To prepare 9 reagents, excess or approximately equimolar amounts of formamide VI may be reacted with one mole of synynyl chloride or phosphoryl chloride to give the Vilsmeier reagent. It is preferred to use about 3 to about 2 moles of dimethylformamide of formula VI. The Vilsmeier reagent may be prepared on its own, but is preferably prepared in the presence of a solvent such as dimethylformamide or dichloromethane, preferably from about -25 ° C to about 25 ° C. At 0 ° C. When used in molar excess dimethylformamide, it can serve as both a reagent and a solvent.

The 9 t-hydroxy steroid (III) and the Vilsmeier reagent are reacted in the presence of a base to neutralize the acid formed during the reaction. The base may be pyridine, collidine, lutidine and mixtures thereof, preferably collidine. The base is used in an effective amount to neutralize the acid formed during the preparation of compounds of formula (IV) or (V) and formed by the Vilsmeier reagent itself. The base may be used in excess or in about equimolar amounts to 1 mole of sulfinyl chloride or phosphoryl chloride, preferably about 10 to 2 moles of base, more preferably about 2 moles of base.

The Vilsmeier reagent used in the method of the invention is used in sufficient amounts.

- 10 to form the £ 9,11 double bond on the steroid ring of the compound of formula (III) and simultaneously form the required oxazoline species. Such amounts of Vilsmeier reagent are excess reagent or about equimolar amount to 1 mole of compound of Formula III, preferably about 5 to 2 moles of Vilsmeier reagent.

The order in which the components are mixed in step (A1) is not critical, but preferably the base, if used, is mixed with the compound of formula (III) before the Vilsmeier reagent is added. Process (A1) is carried out at atmospheric pressure and at a temperature of about -50 ° C to about 50 ° C, preferably about -20 ° C to about 0 ° C. The reaction mixture is stirred for a sufficient period of time to complete the reaction, usually about 30 minutes to 2 hours or more.

The oxazoline corticosteroid target products of formula (IV) thus obtained can be recovered by adding water to the reaction mixture and diluting the aqueous mixture with an organic solvent such as dichloromethane or ethyl acetate. The dilute aqueous / organic mixture is washed with dilute aqueous alkali such as sodium bicarbonate followed by brine, such as a saturated sodium chloride solution, and dried with a drying agent such as anhydrous magnesium sulfate or sodium sulfate to give the desired compound (IV). oxazoline.

• · ·

In step (A2), the compound of formula (IV) is reacted with an organic or mineral acid in an amount sufficient to hydrolyze the compound of formula (IV) to the desired oxazoline of formula (V). The mineral acids which may be used are hydrochloric acid, sulfuric acid, phosphoric acid and the like, with hydrochloric acid being preferred. Useful organic acids include C 1-10 alkanoic acids such as formic acid, acetic acid, propionic acid and the like. The acid may be used in excess or in an amount of about 0.1 equivalents, preferably about 2 to about 0.1 equivalents. The reaction may be carried out at a temperature of -20 ° C to 50 ° C, preferably about 0 ° C. The oxazoline target product of formula (V) thus obtained can be prepared by conventional methods, such as evaporation of the solvent present, filtration, crystallization, chromatography. by distillation and the like.

In process B, the compound of formula (III) is reacted with an acid having a pKa of 5 or less, preferably less than 1, as noted above. If chlorosulfonic acid is used, the process may be carried out without a solvent, but the presence of a solvent is preferred. Suitable solvents include chlorinated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride, and alkylated hydrocarbons such as hexane or heptane. The amount of solvent used should be sufficient to dissolve the reagents. The solvent may be in excess or about 10% by volume in the reaction mixture.

The acid is reacted with the compound of formula (III) in an amount such that about 10 to 2 molar equivalents of acid, preferably about 5 to 2 molar equivalents, are added to 1 equivalent of 9-hydroxy steroid of formula (III). In Process B, the temperature, reaction time and yield procedures are similar to those described in Process A.

Various embodiments of the present invention are illustrated by the following examples, but are not to be construed as limiting.

lx_2elda_ (A12_müyelet

-spiro / androsta-4,9 (II)-diene-17,5 '(4 ^, H) -oxazole

A Vilsmeier reagent was prepared by treating a mixture of 0.56 dimethylformamide and 15 mL of dichloromethane with 0.5 mL of sulfinyl chloride at 0 ° C. After 10 minutes, this solution at 0 ° C was treated with 2.49 g of N- (3,3- [2,2-ethanediylbisoxy) -17o (- (1-ethoxyethoxy) -9o <-hydroxy-16 / Add methyl methyl pregn-5-ene-20-ylidene-7-acetamide, 25 mL methylene chloride and 1.6 mL collidine After 30 minutes at the same temperature, 10 mL water was added to the reaction mixture and stirred for 15 minutes. reaction • · ·

The mixture was diluted with methylene chloride (200 mL), the organic layer was separated, washed with brine (100 mL), dried over anhydrous sodium sulfate and evaporated to give 0.89 g of the title compound.

MMR (CDCl3) δ T ppm: 0.78, 1.09, 1.20, 2.0, 3.9,

4.3, 5.22 and 5.42.

2i_2 Le ^ £ ÍA? 2_5Byelet

2 ', 16/3 -Dimethyl-4'-methylene-spiro-ssdrosta-4,9 (II)-diene-17,5 * (4 ^, H) -oxazole, 7-3-one

0.025 g of 3,3-Z1,2-ethanediylbisoxyl-7 ', 16/3-dimethyl-4 * -methylene-spiro-zandrosta-4,9 (II)-diene-17,5' (4 ') - oxazole-7- Dissolve 1.5 ml of 10% aqueous methanol and treat with 0.088 ml of 2M hydrochloric acid. After 2 hours at room temperature, the solvent was evaporated to give 0.02 g of the title compound. MMR (CDCl 3) δ ppm: 0.8, 1.08, 1.3, 2.05, 4.33, 5.27, 5.5 and 5.71.

3._2 £ IOA

2 *, 16 &apos; -Dimethyl-4 ^, ~ methylene-spiro-zandrosta-4,9 (II) -diene-17,5? (4 ') on -oxazol7-3

0.52 g of N-Z3, 3- [2, 2-ethanediylbisoxy] -17c <- (1-ethoxyethoxy) -9c <-hydroxy-16 [beta] -methyl-pregn-5-ene-2O-

A mixture of -14-ylidene-7-acetamide and 8 ml of dichloromethane was cooled to -20 ° C and 0.2 ml of chlorosulfonic acid dissolved in 2 ml of dichloromethane was added dropwise. After 45 minutes, the reaction mixture was treated with 15 ml of water and 100 ml of dichloromethane. The organic layer was separated, washed with 100 mL of saturated sodium bicarbonate solution and 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate to give 0.3 g of the title compound.

4 .__ 2®lóa

2 * 16 ^{β-Dimethyl-4>} s'piroZandroszta-methylene-4,9 (11) -diene-17,5 '(4 ^H) -oxazol7-3-one

0.36 g of N-Z17a - (1-ethoxyethoxy) -9β-hydroxy-3-methoxy-16β-methylpregna-3,5-diene-20-ylidene-7-acetamide in 5 ml of methylene dichloromethane was cooled to -25 ° C and a mixture of 0.23 mL of chlorosulfonic acid and 1.27 mL of dichloromethane was added dropwise. The mixture was stirred at -25 ° C for 10 minutes and then at - (25-10 ° C) for 15 minutes. The reaction mixture was added dropwise to 30 ml of saturated sodium bicarbonate solution, stirred for 30 minutes, and the organic phase was separated. The aqueous layer was extracted with ethyl acetate (2 x 50 mL), and the combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated. 0.23 g of the title compound is obtained.

Preparation of starting materials

The steroids of formula (I) are known or can be prepared by known methods, such as those described in European Patent Application 0263569, which is described below.

A 17? -Hydroxy-17-cyano compound of formula (I) wherein the above meaning is generally treated with an etherifying reagent such as a lower alkyl vinyl ether such as ethyl vinyl ether, methyl vinyl ether and the like, in the presence of an acid catalyst such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate or pyridine hydrochloride, and thus a compound of formula II, wherein Z is, for example, -0Η (0Η ^ θ) 0Η. R 4 is a lower alkyl group. The process is carried out under the conditions described in U.S. Patent 4,585,590, whose preparatory instructions are incorporated herein by reference.

The ether of formula (II) is treated with methyl lithium (CH 2 Cl 2) followed by acetic anhydride in the presence of a solvent such as diethyl ether or cumene at C-40 ° C or at the reflux temperature of the solvent to give (III). starting material.

· · · · * ··· ····················································································· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··

- 16 3.3-ΖΪ.2-Ethanediyl-bigzox17-9 x x, 17 <-dihydroxy-16--methyl-androst-5-ene-17 -k -carbonitrile

3.69 g of 9? X, 17? -Dihydroxy-16? -Methyl-3-o-o-androst-4-ene-17? -Carbonitrile, 30 mL of ethylene glycol,

A mixture of 3.8 ml of trimethyl orthoformate and 18 ml of benzene is treated with 0.14 g of para-toluenesulfonic acid) and the mixture is stirred at room temperature. After 4 hours, diethyl ether (34 mL), water (34 mL) and pyridine (0.8 mL) were added to the reaction mixture. After 1 hour, the reaction mixture was filtered, the solid was washed with water (300 mL) and dried under reduced pressure to give 2.0 g of the title compound.

MMR (CDCl3) δ ppm; 0.92, 1.12, 1.28, 3.96 and

5.33.

3,3-Z1,2-Ethanediyl-bisoxyl-17 ^? - (1-ethoxy-ethoxy) -9 ^<: <-hydroxy-16H-methyl-androst-5-ene-17H-carbonitrile

15.16 g of 3, 3- [1,2-ethanediylbisoxy-7- [?, 17? -Dihydroxy-16? -Methyl-androst-5-ene-17? -Carbonitrile, 100 mL of methylene chloride, 50 mL of ethyl vinyl]. ether and 0.5 g of pyridine hydrochloride are heated in a sealed flask at 55 ° C for 18 hours. The reaction mixture is vented _; and evaporating the solvent. so we get oil that is short • ·

- Filter through 17 columns of silica gel. 17 g of the title compound are obtained.

MMR (CDCl3) δ ppm: 0.92, 1.12, 1.18, 1.25, 1.30, 3.54, 3.90, 5.01 and 5.36.

3r_E £ £ ®B & atiy_r> Eldan

N-3,3-Z1,2-Ethanediylbisoxy-17 * - (1-ethoxyethoxy) -9? -Hydroxy-16 (3-methyl-pregn-5-en-20-ylidene) acetamide

22.63 g of 3, 3- [1,2-ethanediylbisoxy] -17-? - (1-ethoxyethoxy) -9? -Hydroxy-16? -Methyl-androst-5-ene-17? -Carbonitrile and A mixture of 50 ml of diethyl ether was treated with lithium methylene in cumene (1.31M, 207 ml) at 0 ° C. When the addition was complete, the reaction mixture was heated to 40 ° C. The reaction mixture was allowed to stand at this temperature for 5 hours and then added to a pre-cooled solution of acetic anhydride (38 ml) in ice / acetone (100 ml). The combined solutions were washed with 3 x 250 mL of phosphate buffer (7pH), 2 x 250 mL of saturated sodium bicarbonate solution and 250 mL of phosphate buffer, dried over anhydrous magnesium sulfate and evaporated. 25 g of the title compound are obtained.

MMR (CDCl 3) δ ppm; 0.76, 1.12, 1.20, 1.90,

3.49, 3.92, 4.89 and 5.38.

· * · · ♦ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·

- 18 17 ^ - (l-ethoxy-etcxi) -9ex. -hydroxy-3-methoxy-16β-methyl-androst-3,5-diene-17β-carbonitrile

21.86 g of 9 <<, 17 <K. dihydroxy-3-methoxy-16 H -methyl-androsta-3,5-diene-17β-carbonitrile, 180 ml of toluene, 20 ml of methylene chloride, 200 ml of ethyl acetate. A mixture of vinyl ether and 2.0 g of pyridine hydrochloride was heated in a sealed flask at 80 ° C. After 24 hours, the reaction mixture was cooled, treated with 10 mL of triethylamine, washed with 3 x 200 mL of phosphate buffer (pH 7) and 200 mL of phosphate buffer (7pH), and 200 mL of saturated sodium chloride solution. dried over sulfate and evaporated. 19.25 g of the title compound are obtained. 1 H NMR (CDCl 3) δ ppm: 0.99, 1.09, 1.19, 1.23, 1.35, 3.58, 5.05, 5.15 and 5.28.

5χ_2 θ25Ξ & ϋΖ £ »^ 2 2®1

N-Z17c <- (1-Ethoxyethoxy) -9o ^< > -hydroxy-3-methoxy-16β-methyl-pregna-3,5-diene-20-ylidene-7-acetamide

A mixture of 1.5 g of 17c <- (1-ethoxyethoxy) -9 &apos; -hydroxy-3-methoxy-16 (R &apos; -methyl-androst-3,5-diene-17 &apos; -carbonitrile and 5 ml of diethyl ether. The reaction mixture was treated with methyl lithium in cumene (1.25 M, 15.4 mL) at 0 ° C. When the addition was complete, the reaction mixture was heated to 40 ° C.

After an hour, the reaction mixture was treated with 2.7 ml of acetic anhydride · ·········································································································································

- Add 19 ml and 7 ml of toluene pre-cooled in ice / acetone. The solution was warmed to room temperature overnight, treated with 25 ml of phosphate buffer (pH 7), stirred for 30 minutes and diluted with 150 ml of ethyl acetate. The organic portion was separated and the aqueous portion was re-extracted with 150 mL ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution (2 x 100 mL) and phosphate buffer (100 mL), dried over anhydrous magnesium sulfate and evaporated. 1.58 g of the title compound are obtained. 1 H NMR (CDCl 3) δ ppm: 0.72, 0.98, 1.12, 2.08, 3.45, 4.79, 5.08 and 5.21.

Claims (11)

Claims A process for the preparation of an oxazoline of formula V corticosteroid intermediates in the formula R ^{3 is} hydrogen, lower alkyl, phenyl or phenylalkyl, R 4 is hydrogen or lower alkyl, preferably methyl, -X or (in stereochemical form), and R is hydrogen, fluoro, chloro or lower alkyl - characterized in that a compound of formula III, a tautomer thereof or mixtures thereof - wherein Z is a hydrogen atom, an alkoxyalkyl group or a -SiR 3 la 2, RR formula trialkyl szilil1 _p QQ group of the formula wherein R ^x, IC and R ^J are each independently lower alkyl, phenyl or phenylalkyl; the moiety (a) is an enol ether of formula (b) or (c) - wherein R is a lower alkyl group, R is as defined above, and R ' ^a , R ² and R ^{3 are} as defined above by a ketal of formula (d) <* 7 nos - wherein R 0 and R are independently lower alkyl or a lower alkyl group or a lower alkyl group; · - (CR ^{2 O} R ²¹ ) v - or - (CR 3 ^O R ³¹ ) w - in which R ²³ , R ^{2 '} R ^{3 <3} and R ^3' are each independently hydrogen, lower alkyl or commodity group. , w and v are independently 0-6 integers Of) ΟΊ and v + v, '2 to 12 are integers, preferably 2, and - (CR R) 30 31 or - (Οΐν R) - rings, either oxygen or nitrogen, and R ^{3 is} as defined above, an enamine of the general formula (e) wherein R and R 'are as defined above or one Q is a ketone of formula (f) wherein R 4 is as defined above - A) Reaction with Vilsmeier reagent followed by acid hydrolysis to give a compound of formula V; obsession B) reacting with an acid having a pKa of about 5 or less to produce a compound of formula (V). 2. A process according to claim 1, wherein the Vilsmeier reagent is prepared by reacting a formamide of formula (VI), wherein R and R ³ are independently alkyl or phenyl, with sulfinyl chloride or phosphoryl chloride. Process according to claim 1 or 2, characterized in that the Vilsmeier reagent is prepared by mixing dimethylformamide of the formula (VI) with sulfinyl chloride. The process according to any one of claims 1 to 3, characterized in that the acid hydrolysis is carried out by reacting a compound of formula (IV) with a sufficient amount of an organic or mineral acid to produce a compound of formula (IV) ). 5. A process according to any one of claims 1 to 3, wherein the organic acid is formic acid, acetic acid or propionic acid. 6. Process according to any one of claims 1 to 3, characterized in that the mineral acid is hydrochloric acid, sulfuric acid or phosphoric acid. 7. Process according to any one of claims 1 to 3, characterized in that the 9c-hydroxy steroid of formula (III) and the Vilsmeier reagent are reacted in the presence of a base. 8. A process according to any one of claims 1 to 3, wherein the base is pyridine, collidine, lutidine or mixtures thereof. 9. A process according to claim 1 wherein in process B a compound of formula III is reacted with an acid having a pKa of 1 or less. Process according to claim 9, characterized in that the acid is chlorosulfonic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, perchloric acid, trifluoroacetic acid or mixtures thereof. 11. A process according to claim 1, 9 or 10 wherein the acid is chlorosulfonic acid.