WO1996031524A1

WO1996031524A1 - Process for the preparation of (20r)-16 alpha,17 alpha -butylidenedioxy-6 alpha,9 alpha-difluoro-11 beta-hydroxy 17 beta-(methylthio) androst-4-3-one

Info

Publication number: WO1996031524A1
Application number: PCT/GB1996/000830
Authority: WO
Inventors: Andrew William Bridge; Ian Michael Mcfarlane; Nigel Christopher Parkinson
Original assignee: Rhone-Poulenc Rorer Limited
Priority date: 1995-04-06
Filing date: 1996-04-03
Publication date: 1996-10-10
Also published as: IL117834A0; GB9507135D0; ZA962770B; AU5281096A

Abstract

A process is described for the preparation of (20R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11β-hydroxy-17β-(methylthio)androst-4-en-3-one comprising a six step synthesis from a compound of formula (I). (20R)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11β-hydroxy-17β-(methylthio) androst-4-en-3-one is a pharmacologically active steroid which possesses anti-inflammatory, immunosuppressive and anti-allergic activity.

Description

PROCESS FOR THE PREPARATION OF (20R)-16. alpha, 17. alpha. -BUTYLIDENEDIOXY-

6.alpha,9.alpha-DIFLU0R0-ll.beta-HYDR0XY 17.beta-(METHYLTHIO) ANDROS-4-3- ONE.

This invention relates to a process for the preparation of (20R) -16α, 17α-butylidenedioxy-6α, 9α- dif luoro-llβ-hydroxy-17β- (methylthio) androst-4-en-3- one (hereinafter referred to as 'Compound A'), a steroid which possesses excellent ant i- inflammatory, immunosuppressive and anti-allergic activity.

Compound A and its preparation are described in International Patent Application Publication No. WO 94/14834. The synthetic route therein is convenient for preparing laboratory scale quantities of Compound A, but provides only a slow conversion of the 17β-carboxyl group to the product 17β-thiomethyl group via the corresponding 'Barton ester'. A potential adverse consequence of the slow reaction time for this step is the possibility of premature decomposition of the 'Barton ester' with attendant increased formation of impurities.

We now describe herein an improved multi-stage process for the preparation of Compound A. We have surprisingly found that protection of the llβ-hydroxyl group prior to conversion of the 17β-carboxyl group to the product 17β-thiomethyl group via the corresponding 'Barton ester' increases the reaction rate for the formation of the 'Barton ester' . This, in turn, improves the cycle-time of the reaction and also enables the timing of the reaction sequence to be modified to minimise the length of time between formation of the 'Barton ester' and its subsequent use for controlled radical generation. Consequently, the present process is particularly suitable for the large scale synthesis of Compound A,

According to a first aspect, the present invention provides a multi-stage synthesis for the preparation of Compound A comprising:

Staσe 1 acylating a compound of formula (I)

(I)

to provide a compound of formula (II)

(ID

in which R¹ represents an acyl group; Staσe 2 : hydrolysing said compound of formula (II) to provide a compound of formula (III)

(III)

in which R¹ is as defined above;

Staσe 3 : oxidising said compound of formula (III) to provide a compound of formula (IV)

(IV)

in which R^- is as defined above; Staσe 4 : hydrogenating said compound of formula (IV) to provide a compound of formula (V)

(V)

in which R¹ is as defined above;

Staσe 5 : converting said compound of formula (V) to the corresponding N-hydroxy-2-thiopyridone O-ester (i.e. 'Barton ester') followed by thermochemical initiation and reaction with methyl disulphide to provide a compound of formula (VI)

(VI)

in which R¹ is as defined above; Staσe 6 : hydrolysing said compound of formula (VI) to provide Compound A

Compound A

As used herein, the term "acyl" includes a group with 1-10 carbon atoms arranged in a straight or branched chain and is preferably a C2-6alkanoyl group, especially acetyl.

Convenient process conditions for effecting Stages 1 to 6 referred to hereinabove are described below.

Staσe 1 may conveniently be effected using conventional methodology. Thus, for example, the acylation may be carried out by treating a compound of formula (I) with an acylating agent such as acetic anhydride, preferably in the presence of a suitable base such as an amine (e.g. 4-dimethylaminopyridine or a mixture of 4-dimethylaminopyridine and triethylamine) and a solvent such as a halogenated hydrocarbon (e.g. dichloromethane) . The reaction may conveniently be carried out at an elevated temperature (e.g. under reflux).

Staσe 2 may conveniently be effected using conventional methodology. Thus, for example, the selective deacylation may be carried out by acid hydrolysis using, for example, an inorganic acid such as sulphuric acid. The reaction may conveniently be carried out in a suitable solvent such as an alcohol (e.g. ethanol or industrial methylated spirit) at an elevated temperature (e.g. under reflux).

Staσe 3 may conveniently be effected using an oxidising agent such as periodic acid (e.g. aqueous periodic acid) , and in a suitable solvent such as an alcohol (e.g. ethanol or industrial methylated spirit) at about ambient temperature.

Staσe 4 may conveniently be effected by hydrogenating a compound of formula (IV) in the presence of a suitable catalyst such as a rhodium compound [e.g. tris(triphenylphosphine)rhodium chloride]. The hydrogenation may conveniently be carried out under elevated pressure (e.g. about 50-55 psi) at an elevated temperature (e.g about 40° to 80°C) and in a suitable solvent such as an aromatic hydrocarbon (e.g. toluene), or an alcohol (e.g. ethanol or industrial methylated spirit), or an ether (e.g. tetrahydrofuran) , or a mixture thereof.

Staσe 5 may be effected by treating a compound of formula (V) under conventional conditions to form the 'Barton ester', a compound of formula (VII)

(VII)

in which R¹ is as defined above, which may conveniently be reacted in situ with methyl disulphide in the presence of a radical initiator such as α, α ' -azobisisobutyronitrile and at an elevated temperature (e.g. about 70°-110°C) in a suitable solvent such as an aromatic hydrocarbon (e.g. toluene) .

The formation of the 'Barton ester' may conveniently be effected by treating a compound of formula (V) with a halophosphate (R³0) 2P(O)Hal (where R³ is a Ci- 6 alkyl group such as ethyl and Hal is a halogen atom such as chlorine) in a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or an ether (e.g. tetrahydrofuran) , preferably in the presence of a suitable base such as an amine (e.g. triethyla ine) , followed by the addition of N-hydroxy-2-thiopyridone and reaction with the exclusion of light. The reaction may conveniently be carried out at about ambient temperature. Staσe 6 may conveniently be effected by base hydrolysis using, for example, an alkali metal hydroxide (e.g. lithium hydroxide, potassium hydroxide or sodium hydroxide) or an alkali metal carbonate (e.g. potassium carbonate) . The reaction may be carried out in a suitable solvent such as an alcohol (e.g. methanol, ethanol or industrial methylated spirit), conveniently at a temperature of about 20° to 60°C.

It is to be understood that each of Stages 1 to 6 and sequential combinations of two or more of such Stages represent further aspects of the present invention. Stages 5 and 6 represent particular embodiments of the present invention.

It is to be further understood that Stage 1 may comprise a stepwise acylation utilising different acylating agents to provide a compound of formula

(II) in which the R-Lo groups occupying the 11 and 21 positions are different acyloxy substituents. Where it is necessary to protect any labile groups during the stepwise acylation procedure suitable protecting groups will be readily comprehended by the skilled worker.

As depicted, compounds of formulae (I) to (VII) are specific diastereoisomerε, namely the 20R androstane and 22R pregnane derivatives. It is to be further understood that the multi-stage process of the present invention may also be applied to the corresponding 20S androstane and 20S pregnane derivatives and mixtures of R and S isomers. Compounds of formulae (II) to (VII) and mixtures of such compounds with their corresponding 20S-isomers are novel intermediates and represent further individual aspects of the present invention.

The compound of formula (I) is a known compound described by Bofors in West German Patents Nos. 2323215 and 2323216.

The following Examples illustrate the invention, but are not intended to limit the invention in any way.

EXAMPLE 1

(20R) -16α.17α-BUTYLIDENEDIOXY-6α.9α-DIFLUORO-llβ- HYDROXY-17β- (METHYLTHIO)ANDROST-4-EN-3-ONE

(A) (22R)-llβ.21-DIACETOXY-16α.17α-BϋTYLIDENEDIOXY-

60C, 9α-DIFLUOROPREGNA-1.4-DIENE-3.20-DIONE A solution of a mixture of predominantly (22R)- with some (22S)- 16α, 17α-butylidenedioxy-6α, 9α-difluoro- llβ, 21-dihydroxypregna-l,4-diene-3, 20-dione (lOOg) in dichloromethane (0.6L) was heated to reflux under nitrogen. The solution was allowed to come off the boil and 4-dimethylaminopyridine (1.62g) and triethylamine (92.3ml) were added. The solution was heated back to reflux and acetic anhydride (83.6ml) was added dropwise over 20 minutes. After approximately one third of the acetic anhydride had been added a thick precipitate had formed. After all of the acetic anhydride had been added the mixture thinned out. The mixture was then refluxed until the reaction was complete. The mixture was cooled to 20-25°C and a solution of ethanol (32ml) in dichloromethane (68ml) was added over 15 minutes, keeping the temperature below 30°C. The solution was stirred for 15 minutes then washed with 2N hydrochloric acid (200ml) followed by saturated aqueous sodium bicarbonate (300ml) . The organic fraction was diluted with ethanol (700ml) then solvent was removed by distillation until the vapour temperature reached approximately 78°C. The solution of a mixture of predominantly (22R)- with some

(22S) -llβ, 21-diacetoxy-16α, 17α-butylidenedioxy-6α, 9α- difluoropregna-1, 4-diene-3, 20-dione was cooled and used for the next step without further manipulation.

(B) (22R) -llβ-ACETOXY-16α.17α-BUTYLIDENEDIOXY-6α.9(X-

DIFLϋORO-21-HYDROXYPREGNA-1.4-D ENE-3.20-DIONE The solution of a mixture of predominantly (22R)- with some (22S)- llβ, 21-diacetoxy-16α, 17α-butylidene- dioxy-6α, 9α-difluoropregna-1, 4-diene-3, 20-dione prepared above was diluted over 5 minutes with stirring under nitrogen with demineralised water (280ml) . 2N Sulphuric acid (220ml) was added and the mixture was heated at reflux until the reaction was complete. The mixture was cooled to ambient to give a solution of a mixture of predominantly (22R)- with some (22S) -llβ-acetoxy-16α, 17α-butylidenedioxy-6α, 9α- difluoro-21-hydroxypregna-l, 4-diene-3, 20-dione in aqueous ethanol which was used for the next step without further manipulation. (C) (20R)-llβ-ACETOXY-16α.17α-BϋTYLIDENEDIOXY-6tt.9α-

DIFLϋORO-3-OXOANDROSTA-1.4-DIENE-17β-CARBOXYLIC ACID The solution of a mixture of predominantly (22R)- with some (22S)-llβ-acetoxy-16α, 17α-butylidenedioxy- 6α, 9α-difluoro-21-hydroxypregna-l, 4-diene-3, 20-dione in aqueous ethanol which was prepared above was stirred under nitrogen at 20-25°C and a solution of periodic acid dihydrate (60.47g) in demineralised water (141ml) was added over 5 minutes. The mixture was stirred at 20-25°C until the reaction was complete. Water (600ml) was added dropwise over 15 minutes. The precipitated solid was filtered, washed four times with demineralised water (500ml) and dried in a vacuum oven at 55-60°C/100torr overnight to give a mixture of predominantly (20R)- with some (20S)- llβ-acetoxy-16α, 17α-butylidenedioxy-6α, 9α-difluoro-3- oxoandrosta-1,4-diene-17β-carboxylic acid (88.88g).

If required (20R) -llβ-acetoxy-16α, 17α-butylidene- dioxy-6α, 9α-difluoro-3-oxoandrost -l,4-diene-17β- carboxylic acid (l.Og) can be recrystallised from a mixture of acetone (5ml) and water (5ml) in 63% return.

(D) (20R) -llβ-ACETOXY-16α.17 -BUTYLIDENEDIOXY-6α.9α- DIFLϋORO-3-OXOANDROST-4-ENE-17β-CARBOXYLIC ACID Method A: A stirred solution of (20R)-llβ-acetoxy- 16α, 17α-butylidenedioxy-6α, 9α-difluoro-3-oxoandrosta- 1, 4-diene-17β-carboxylic acid (60.Og) in toluene (420ml) and ethanol (180ml) was degassed by reducing the pressure to about lOOtorr for 2 minutes, then refilling the flask with nitrogen. This procedure was repeated twice more then tris (triphenyl- phosphine)rhodium chloride (2.24g) was added. The mixture was degassed by reducing the pressure to about lOOtorr for 2 minutes, then refilling the flask with nitrogen. This procedure was repeated then the reaction flask was pressurised to 50-55psi with hydrogen. The mixture was heated at 60-65°C under an atmosphere of hydrogen until the reaction was complete. The mixture was cooled to room temperature and extracted three times with 4%w/v aqueous sodium bicarbonate solution (254ml; 127ml; 127ml) . The combined extracts were washed twice with t-butyl methyl ether (150ml) then the aqueous layer was stirred under reduced pressure for 30 minutes. The aqueous layer was stirred and 2N sulphuric acid (approximately 135ml) was added dropwise over 30 minutes until the mixture reached pH 1-2. The mixture was stirred for one hour, then filtered and the filter cake was washed three times with water (150ml) . The solid was dried in a vacuum oven at about 50-60°C/100torr to leave (20R) -llβ-acetoxy- 16α, 17α-butylidenedioxy-6α, 9α-difluoro-3-oxoandrost- 4-ene-17β-carboxylic acid (50.86g) .

Method B: A stirred solution of (20R) -llβ-acetoxy- 16α, 17 -butylidenedioxy-6α, 9α-difluoro-3-oxoandrosta- 1, 4-diene-17β-carboxylic acid (50. Og) in toluene

(350ml) and tetrahydrofuran (200ml) was degassed by reducing the pressure to about lOOtorr for 2 minutes, then refilling the flask with nitrogen. This procedure was repeated twice more then tris (triphenylphosphine) rhodium chloride (1.86g) was added. The reactor was evacuated to about lOtorr for two minutes then hydrogen was introduced to atmospheric pressure. This procedure was repeated then the reactor was pressurised to 50-55psi with hydrogen. The mixture was hydrogenated at about 63- 67°C until the reaction was complete. The mixture was cooled to ambient temperature, then extracted with aqueous sodium bicarbonate solution (282ml;

141ml; 141ml; 141ml; 141ml) . The combined extracts were washed with t-butyl methyl ether (125ml) . The aqueous layer was stirred under reduced pressure for 30 minutes then 2N sulphuric acid (160ml) was added dropwise over 30 minutes until the mixture reached pH 1-2 and stirring was continued for one hour. The resulting solid was filtered, then washed three times with demineralised water (150ml) and then dried at about 50-60°C/100torr to give (20R) -llβ-acetoxy- 16α, 17α-butylidenedioxy-6α, 9α-difluoro-3-oxoandrost- 4-ene-17β-carboxylic acid (40.88g, 81.4%).

A suspension of (20R) -llβ-acetoxy-16α, 17α-butylidene- dioxy-6α, 9α-difluoro-3-oxoandrost-4-ene-17β- carboxylic acid (50.Og) in methanol (250ml) was heated to reflux, giving a solution. Demineralised water (200ml) was added to the refluxing solution over 40-45 minutes, then the mixture was refluxed for 15 minutes. The mixture was cooled to 20-25°C over about 1 hour, then to 10-12°C and stirred for 1 hour. The resulting solid was filtered, then washed with a mixture of methanol and water (90ml; 5:4; v/v) , then dried at 55-60°C to give (20R)-llβ- acetoxy-16α, 17α-butylidenedioxy-6α, 9α-difluoro-3- oxoandrost-4-ene-17β-carboxylic acid (41.97g; 83.9%), m.p.215-217°C.

(E) (20R) -llβ-ACETOXY-16(X.17α-BUTYLIDENEDIOXY-6α.9α- DIFLUORO-17β- (METHYLTHIO)ANDROST-4-EN-3-ONE (20R) -llβ-Acetoxy-16α, 17α-butylidenedioxy-6α, 9α- difluoro-3-oxoandrost-4-ene-17β-carboxylic acid

(49.25g) was stirred at room temperature in dichloromethane (492ml) under nitrogen.

Triethylamine (33.16ml) was added over about 5 minutes and the mixture was stirred until all the suspended solid had dissolved. Diethyl chlorophosphate (15.8ml) was then added over about 5 minutes and the solution was stirred overnight. The reaction flask was wrapped in aluminium foil. Freshly dried N-hydroxy-2-thiopyridone (14.5g) was added and the mixture was stirred in the dark for 3.5 hours. Methyl disulphide (20ml) and α,α'-azobis- isobutyronitrile (1.65g) were added and the resultant solution was then added dropwise over 2.5 hours, under a gentle flow of nitrogen and shielded from light, to a hot (about 90°C) , degassed solution of methyl disulphide (179ml) and α, α ' -azobisisobutyro- nitrile (0.4g) in toluene (483ml) . During the addition dichloromethane was removed via distillation to maintain an internal temperature of about 85-95°C .

After the addition was complete the solution was heated for 15 minutes and then cooled to ambient temperature. The solution was washed with 2M hydrochloric acid (500ml), then with 1M sodium hydroxide (500ml), then with water (50.0ml) and then three times with aqueous sodium chloride (500ml; 5%w/v; ) . The organic layer was then dried with magnesium sulphate and filtered: the filtrate was stirred with chromatography grade silica (15g) for 15 minutes, filtered, the silica washed twice with toluene (30ml) and the combined filtrate and washings were evaporated under reduced pressure. The residue was mixed with toluene (400ml) and evaporated under reduced pressure. The residue was then stirred with warm methanol (159ml) until crystallisation was complete then water (34ml) was added. The mixture was cooled to about 10°C, the product was collected, washed with a mixture of water and ethanol (60ml; 1:5; v/v) and dried under reduced pressure at about

50°C to give (20R)-llβ-acetoxy-16α,17α-butylidene- dioxy-6α, 9α-difluoro-17β-(methylthio)androst-4-en-3- one (21.89g), m.p.l41-143°C.

(F) (20R) -16CC, 17α-BUTYLIDENEDIOXY-6α.9(X-DIFLU0R0-llβ- HYDROXY-17β- (METHYLTHIO1ANDROST-4-EN-3-ONE Method A: (20R)-llβ-Acetoxy-16cc, 17α-butylidenedioxy-

6α, 9α-difluoro-17β- (methylthio) androst-4-en-3-one

(lO.Og) was suspended in ethanol (100ml) under an atmosphere of nitrogen. The mixture was heated at reflux for 30 minutes and then cooled to room temperature. Ascorbic acid (0.71g) was added, the mixture was stirred for 5 minutes and then 1M aqueous lithium hydroxide (40.2ml) was added over 10 minutes. The mixture was stirred at about 35-40°C until hydrolysis was complete (about 6 hours). Aqueous ammonium chloride (100ml; 5% w/v) was added over 15 minutes, the mixture was stirred for 15 minutes and was then cooled to room temperature. The solid was collected, washed with a mixture of ethanol and water

(40ml; 1:1) and dried at about 60°C to leave (20R) -16α, 17α-butylidenedioxy-6α, 9α-difluoro-llβ- hydroxy-17β- (methylthio)androst-4-en-3-one (8.6g) . A sample of the product (7.5g) was heated in methanol (37.5ml) to give a solution. Charcoal (0.375g) was added and the mixture was heated at reflux for 15 minutes. The hot suspension was filtered through a pad of celite and the pad was washed with hot methanol (7.5ml). The combined filtrate and washings were returned to the boil, water (5.2ml) and methanol (7.5ml) were added and the mixture was heated to give a solution. The solution was cooled to room temperature, the product was collected and washed with a mixture of methanol (20ml) and water (2ml) and was then dried to give (20R) -16α, 17α-butylidenedioxy- 6α, 9α-difluoro-llβ-hydroxy-17β- (methylthio) androst-4- en-3-one (5.94g), having physical characteristics corresponding to those of an authentic sample of the desired compound.

Method B: (20R) -llβ-Acetoxy-16α, 17α-butylidenedioxy- 6α, 9α-difluoro-17β- (methylthio) androst-4-en-3-one

(10.72g) was stirred and heated at reflux in methanol (150ml) under an atmosphere of nitrogen for 15 minutes . The mixture was cooled to room temperature and treated with L-ascorbic acid (1.52g) then with anhydrous potassium carbonate (5.05g) . After stirring at ambient temperature for 24 hours the reaction mixture was treated with a solution of ammonium chloride (150ml, 5%w/v) over 15 minutes, then cooled to 10°C. After 30 minutes the resulting solid was filtered, then washed with a mixture of cold methanol and water (24ml, 1:1), then dried by suction and then dried at 50°C to give (20R)-16α, 17α- butylidenedioxy-6α, 9α-difluoro-llβ-hydroxy-17β- (methylthio)androst-4-en-3-one, (9.24g, 94.2%).

A solution of (20R)-16α, 17α-butylidenedioxy-6α, 9α- difluoro-llβ-hydroxy-17β- (methylthio)androst-4-en-3- one (8.24g) in hot methanol (33 ml) was treated with charcoal (0.41g). The mixture was heated at reflux under nitrogen for 30 minutes then allowed to cool to 55°C and filtered through a bed of hyflo. The filter pad was washed with hot methanol (8ml) . The combined filtrate and washings were heated to reflux. Water (5.6ml) was added to the refluxing solution over 10 minutes then the mixture was cooled to 10°C. The resulting solid was filtered, then washed with a mixture of methanol and water (12 ml, 7:1), then dried by suction and then dried at 50°C. The solid

(6.77g) was recrystallised again following the above procedure to give (20R) -160C, 17α-butylidenedioxy-

6α, 9α-difluoro-llβ-hydroxy-17β- (methylthio)androst-4- en-3-one (5.74g).

Method C: (20R) -llβ-Acetoxy-16α, 17α-butylidenedioxy-

6α, 9α-difluoro-17β- (methylthio) ndrost-4-en-3-one

(5.0g) was stirred and heated at reflux in industrial methylated spirit (50ml) under an atmosphere of nitrogen for 15 minutes. The mixture was cooled to about 40°C and treated with L-ascorbic acid (0.71g) then with IN sodium hydroxide solution (22ml) over 20 minutes. The mixture was stirred at 40-45°C for about 6.5 hours then treated with a solution of ammonium chloride (50ml, 5% w/v) over 20 minutes. The mixture was cooled to 10°C. The resulting solid was filtered then washed with a cold mixture of methanol and water (12ml, 1:1) then dried by suction and then dried at

50°C to give (20R) -16α, 17α-butylidenedioxy-6α, 9α- difluoro-llβ-hydroxy-17β- (methylthio) androst-4-en-3- one, (4.22g, 92.5%) .

Method D: (20R) -llβ-Acetoxy-16α, 17α-butylidenedioxy-

6α, 9α-difluoro-17β- (methylthio) androst-4-en-3-one

(5.0g) was stirred and heated at reflux in industrial methylated spirit (50ml) under an atmosphere of nitrogen for 10 minutes. The mixture was cooled to about 40°C and treated with L-ascorbic acid (0.71g) then with IN potassium hydroxide solution (22ml) over 25 minutes. The mixture was stirred at 40-45°C for about 6 hours then treated with a solution of ammonium chloride (50ml, 5% w/v) over 30 minutes. The mixture was cooled to 10°C. The resulting solid was filtered then washed with a cold mixture of methanol and water (12ml, 1:1) then dried by suction and then dried at 50°C to give (20R) -16α, 17α-butylidenedioxy- 6α, 9α-difluoro-llβ-hydroxy-17β- (methylthio) androst-4- en-3-one, (4.34g, 95.2%) .

Claims

1. A process for the preparation of (20R) -16α, 17α- butylidenedioxy-6α, 9α-difluoro-llβ-hydroxy-17β- (methylthio)androst-4-en-3-one (Compound A) comprising the sequential steps (1) to (6) as follows:

(1) acylating a compound of formula (I)

(I)

to provide a compound of formula (II)

(ID

in which R¹ represents an acyl group; (2) hydrolysing said compound of formula (II) to provide a compound of formula (III)

(III)

in which R¹ is as defined above;

(3) oxidising said compound of formula (III) to provide a compound of formula (IV)

(IV)

in which R¹ is as defined above; (4) hydrogenating said compound of formula (IV) to provide a compound of formula (V)

(V)

in which R¹ is as defined above;

(5) converting said compound of formula (V) to the corresponding N-hydroxy-2-thiopyridone O-ester (i.e. 'Barton ester') followed by thermochemical initiation and reaction with methyl disulphide to provide a compound of formula (VI)

(VI)

in which R¹ is as defined above;

(6) hydrolysing said compound of formula (VI) to provide Compound A.

2. A process for the preparation of (20R)-16α, 17α- butylidenedioxy-6α, 9α-difluoro-llβ-hydroxy-17β-

(methylthio)androst-4-en-3-one (Compound A) comprising:

converting a compound of formula (V)

(V)

(in which R¹ represents an acyl group) to the corresponding N-hydroxy-2-thiopyridone O-ester (i.e. 'Barton ester¹) followed by thermochemical initiation and reaction with methyl disulphide to provide a compound of formula (VI)

(VI)

(in which R¹ is as defined above) , and thereafter hydrolysing said compound of formula (VI) to provide Compound A.

3. A process for the preparation of a compound of formula (VI)

(VI )

(in which R^ represents an acyl group) comprising converting a compound of formula (V)

(V)

(in which R¹ is as defined above) to the corresponding N-hydroxy-2-thiopyridone O-ester (i.e. 'Barton ester') followed by thermochemical initiation and reaction with methyl disulphide.

4. A process according to any one of claims 1,2 or 3 in which the 'Barton ester', a compound of formula (VII)

(VII)

(in which R¹ represents an acyl group), is prepared by treating a compound of formula (V) (as defined in claim 1) with a halophosphate (R³0)2-P(0)Hal (where R³ is a Cχ_g alkyl group and Hal is a halogen atom) followed by the addition of N-hydroxy-2-thiopyridone with the exclusion of light.

5. A process according to any one of claims 1, 2 or 3 where the reaction with methyl disulphide is carried out in the presence of a radical initiator at an elevated temperature.

6. A process according to any one of claims 1, 2 or 3 in which the N-hydroxy-2-thiopyridone O-ester (i.e.

'Barton ester') is reacted in situ with methyl disulphide in the presence of a radical initiator at an elevated temperature.

7. A process according to claim 5 or claim 6 where the reaction is effected at a temperature of about 7 0 ° - 1 1 0 ° C .

8. A process according to any one of claims 5-7 where the reaction is effected in an aromatic hydrocarbon solvent.

9. A process according to claim 1 or claim 2 in which Compound A is prepared by hydrolysing a compound of formula (VI)

(VI)

(in which R¹ represents an acyl group) under basic conditions.

10. A process according to claim 9 in which the hydrolysis is effected using an alkali metal hydroxide or an alkali metal carbonate.

11. A process according to claim 10 where the reaction is effected in an alcohol solvent.

12. A process according to any preceding claim in which R¹ represents acetyl.

13. Intermediate compounds of formulae (II), (III),

(IV), (V), (VI) and (VII) in which R¹ represents acyl and mixtures thereof with their corresponding 20S-isomers .

14. Compounds according to claim 13 in which R^ represents acetyl.

15. A new process for the preparation of a compound substantially as herein described.

16. A new compound substantially as herein described.