WO1991014700A2

WO1991014700A2 - PROCESS FOR 9α-HYDROXY STEROID DEHYDRATION

Info

Publication number: WO1991014700A2
Application number: PCT/US1991/001863
Authority: WO
Inventors: Nicholas Carruthers; Sohaila Garshasb
Original assignee: Schering Corporation
Priority date: 1990-03-27
Filing date: 1991-03-25
Publication date: 1991-10-03
Also published as: AU7556291A; WO1991014700A3; JPH05501115A; EP0523132A1

Abstract

A process for preparing novel corticosteroid intermediates of formula (XXX) are disclosed. The process entails contacting a 9α-hydroxysteroid of formula (XX) with (A) in step (a) an anhydride, an organic acid and an acid reagent having a pKa of about 3 or less, followed by step (b) treatment with water, aqueous alkali or aqueous acid; or alternatively, with (B) either an anhydride and a proton acceptor or with an acyl halide and a proton acceptor, to give the steroid of formula (XXX). By using step (a) in Proces (A), novel steroid intermediates of formula (XXV) are also obtained.

Description

PROCESS FOR 9α-HYDROXY STEROID DEHYDRATION

BACKGROUND

The 9α-hydroxy (OH) steroids are useful intermediates for preparing corticosteroids. Such corticosteroids are useful for treatment of psoriasis, dermatological diseases and inflammation. U.S. Patent 4,127,596 describes a process for dehydrating 9α-hydroxysteroid type compounds with a strong acid (pKa less than 1) to give Δ9.II steroids. A Δ9.II steroid is one which possesses a double bond between positions 9 and 11 in the steroid ring. U.S. Patent 4,102,907 and European Patent Application number 87201933.6 teach dehydration of steroid intermediates. John Fried and John A. Edwards, Organic Reactions in Steroid Chemistry, Vol. II, Van Nostrand Reinhold Company, New York, New York (1972) pp. 382-385, L F. Fieser and M. Fieser, Steroids, Reinhold Publishing Corporation, New York, (1959) Chapter 18. Homo and Nor Steroids, pp. 577-599 and R.W. Draper and M.S. Puar Carbon- 13 Nuclear Magnetic Resonance Spectra of D-homoannulated 17- hydroxypregnan-20-ones, Steroids 54/1 , July 1989 pp. 1-10 disclose undesirable D-ring homologation via the 17-position by utilizing conventional acidic or alkaline reagents. However, none of these references teaches the concommittant dehydration of 9α-OH to Δ9.II and the formation of a 17-ester from a 9α-hydroxysteroid. It would be desirable to provide a process for preparing Δ9.II steroids possessing the requisite 17-ester moiety from 9α-hydroxysteroid starting materials. The Δ9.II steroids are useful intermediates for the preparation of pharmaceutically active corticosteroids as taught in L. F. Fieser and M. Fieser, Steroids, Chapter 19. Adrenocortical Hormones, pp. 600-726, supra., I. Nitta. and H. Ueno: New Synthesis of Corticoids. Yuki Gosei Kagaku, Vol. 45, No. 5, (1987) pp. 445-461, and in J. Redpath and F.J. Zeelen, in Chem. Soc. Rev., Stereoselective Synthesis of Steroid Side- chains, Vol. 12, (1983), pp. 75-98. Thus, it would be desirable to provide a process for preparing Δ9,ll steroids possessing the requisite 17-ester moiety which avoids D-ring homo-rearrangement and which can also reduce the steps required for their preparation.

SUMMARY

The present invention is directed towards a process for preparing steroid intermediates of formula (XXX):

wherein R1 represents -C≡CR⁷⁰ wherein R⁷⁰ is hydrogen or Si(CH₃)₃, or R¹ is Ioweralkyi, haloalkyl, phenyl or phenylalkyl, -COR¹¹, -COOR ¹ wherein R¹¹ represents hydrogen or Ioweralkyi; or R¹ is -COCH2R¹² wherein R¹² represents hydroxy, halo or alkanoyloxy; R⁴ represents H or Ioweralkyi, preferably methyl having either the α or β stereochemistry; R9 represents hydrogen, fluoro. chloro or Ioweralkyi and R¹⁰ represents hydrogen, phenyl, phenyl substituted with alkyl, halogen, alkoxy, nitro; or R¹⁰ is heteroaryl, alkyl or alkyl substituted with phenyl or halogen. Preferably -OCOR¹⁰ at position 17 has the α-stereochemistry. The present process comprises contacting a 9α-hydroxysteroid of the formula (XX):

wherein R¹ and R⁴ are as defined hereinbefore; Z is a group which can be substituted with the -COR¹⁰ moiety, and

represents

an enol ether of the formula:

wherein R⁵ represents Ioweralkyi or R^{1 a} R R³Si- wherein R^{1 a}, R² and R³ independently represent Ioweralkyi, phenyl or phenylalkyi; and R⁹ is as defined hereinbefore;

a ketal of the formula

wherein R^δ and R⁷ independently represent Ioweralkyi or -(CR²⁰R²¹) - and -(CR30R31)_W., respectively, wherein R²⁰, R² , R30 and R³¹ independently represent H, Ioweralkyi, or aryl and w and v independently represent an integer from 0 to 6 and v + w is an integer from 2 to 12, preferably 2, and wherein -(CR²⁰R²¹)_V- or -(CR³⁰R³¹)_W- are connected together in a ring or through an oxygen or nitrogen atom; and R⁹ is as defined hereinbefore;

an enamine of the formula

wherein R⁶ and R⁷ are as defined hereinbefore; or

a ketone of the formula

wherein R⁹ is as defined hereinbefore; with

(A) in step (a) an anhydride of the formula (R¹⁰CO)2θ wherein R¹⁰ is as defined hereinbefore, an organic acid and an acid reagent having a pKa of about 3 or less, preferably about 1 or less, followed by step (b) treatment with water, aqueous alkali or aqueous acid; or alternatively, with

(B) either an anhydride of the formula (R¹⁰Cθ2)O wherein R¹⁰ is defined hereinbefore and a proton acceptor or with an acyl halide of the formula R¹⁰COX wherein R¹⁰ is as defined hereinbefore and X is halogen, preferably chloro and a proton acceptor, to give the steroid (XXX).

In another embodiment, the present invention is directed toward a process for preparing novel compounds of the formula:

wherein R¹ represents -C≡CR⁷⁰ wherein R⁷⁰ is hydrogen or -Si(CH₃)₃, or R¹ is Ioweralkyi, haloalkyi, phenyl or phenylalkyi, -COR¹¹ or -COOR ¹ wherein R¹¹ represents Ioweralkyi, hydroxyaikyi or acyloxy, preferably where Ioweralkyi is methyl, hydroxyaikyi is hydroxymethyl and acyloxy is acetoxy; or -COCH2R¹² wherein R¹² represents hydroxy, halo or alkanoyloxy; R⁴ represents H or Ioweralkyi, preferably methyl having either the α or β stereochemistry; R⁴ represents H or Ioweralkyi, preferably methyl having either the α or β stereochemistry; R⁹ represents hydrogen, fiuoro, chloro or Ioweralkyi and R¹⁰ represents hydrogen, phenyl, phenyl substituted with alkyl, halogen, alkoxy or nitro or R¹⁰ is Ioweralkyi or alkyl substituted with phenyl or halogen; comprising contacting a compound of the formula (XX):

wherein R and R⁴ are as defined hereinbefore; Z is a group which can be substituted with the -COR¹⁰ moiety, and

represents

an enol ether of the formula:

wherein R⁵ represents^" Ioweralkyi or R^1a R²R³Si- wherein R^{1 a}, R² and R³ independently represent Ioweralkyi, phenyl or phenylalkyi; and R⁹ is as defined hereinbefore;

a ketal of the formula

wherein R⁶ and R⁷ independently represent Ioweralkyi or -(CR²⁰R²¹) - and -(CR3°R3¹)_W-, respectively, wherein R²⁰, R²¹ , R3° and R3¹ independently represent H, Ioweralkyi, or aryl and w and v independently represent an integer from 0 to 6 and v + w is an integer from 2 to 12, preferably 2, and wherein -(CR ⁰R²¹)_V- or -(CR³°R31)_W- are connected together in a ring or through an oxygen or nitrogen atom; and R⁹ is as defined hereinbefore;

an enamine of the formula

wherein R⁶ and R⁷ are as defined hereinbefore; or

a ketone of the formula

wherein R⁹ is as defined hereinbefore; with an anhydride of the formula (R ⁰COJ₂θ wherein R¹⁰ is as defined hereinbefore, an organic acid and an acid reagent having a pKa of about 3 or less, preferably about 1 or less. This process is the same as step (a) in Process A. The present invention is also directed to novel compound of formula (XXV) useful as intermediates for preparing the compounds of formula (XXX). The present invention is also directed to novel compounds of formula (XXX) as defined hereinbefore.

In another embodiment, the present process gives preferred compounds of formula (XXXi).

wherein R⁹, R¹⁰ and R¹² are as defined hereinbefore, the dotted line represents an optional double bond and the numbering system is illustrated for those preferred compounds.

The present process has the unexpected and surprising advantage of regio-specifically dehydrating the 9α-OH to form a Δ9,ll steroid possessing the desired R¹⁰ moiety for the production of such steroids in a single step or reaction vessel. The present process also has the advantage of effecting the desired transformation without D-ring rearrangement as described hereinbefore. It is believed that the presence of the 17-ester prevents D-ring homologation (ie. via rearrangement) during the present process. As such, the esterification at position 17 is desirable. The compounds of formulas (XXV) and (XXX) are useful intermediates for the production of corticosteroids from the steroid derived compound 9α-hydroxyandrost-4-ene-3,17-dione as described hereinbefore. The present process also has the advantage of providing a one-step process or a simplified two-step process for preparing the compounds of formula (XXX), whose compounds permit convenient substitution of functional groups at positions 9 and 11.

DETAILED DESCRIPTION OF THE EMBODIMENTS

When utilized in the present specification and in the appended claims the terms listed hereinbelow, unless otherwise indicated are defined as follows:

The wavy line bond, ie. "«~~~-" indicates the substituent possesses either the alpha (α) or beta (β) stereochemistry. A substituent possessing the α stereochemistry lies below the plane of the paper, whereas a substituent possessing the β"^*stereochemistry lies above the plane of the paper, as defined in Leland J. Chinn, Paul D. Klimstra, John S. Baran and Raphael Pappo, The Chemistry and Biochemistry of Steroids, Intra-Science Chemistry Reports, Vol. 3 No. 1 , Intra-Science Research Foundation, Santa Monica, California 1969, pp. 1-82. The " ^" symbol indicates a methyl substituent possessing the β stereochemistry.

The dashed line in conjunction with a solid line , ie. " " indicates an optional single or double bond. The term "alkyl" or "loweralkyl"(including the alkyl portion of alkanoyloxy) refers to a straight chain saturated hydrocarbon moiety containing from 1 to 10 carbon atoms, or a branched saturated hydrocarbon moiety of 3 to 10 carbon atoms, such as for example, methyl (ie. -CH3), ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.

The term "phenylalkyi" refers to a phenyl moiety convaiently bonded to an alkyl moiety of one to six carbon atoms such as, for example, phenylmethyl, 2-phenylethyl and the like. The term "heteroaryl" refers to a cyclic group having at least one O, S and/or N interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the heteroaryl group having from 2 to 14, preferably from 2 to 14 carbon atoms, e.g., 2-, 3- or 4-pyridyl, 2- or 3- furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-imidazolyl, 2-, 4- or 5- pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6-[1 ,2,4-triazinyl], 3- or 5-[1 ,2,4-thiadizolyl], 2-, 3-„ 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, etc. Preferred heteroaryl groups are 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-imidazolyl or 7-indolyl;

The term for "Z" can represent hydrogen or any protecting group which is sufficiently labile to permit substitution of the -Z moiety with the -COR¹⁰ moiety under the process conditions. Such groups include but are not limited to tetrahydropyranyl, alkoxyalkyl, alkoxyalkyl substituted with halogen, oxygen or silicon ie. 2-(trimethylsilyl)ethoxy- methyl and trisubstituted silyl of the formula -SiR^{1 a}R²R³ wherein R^{1 a}, R² and R³ independently represents Ioweralkyi, phenyl or phenylalkyi, preferably -Si(CH3)3. Other suitable protecting groups are described in Theodora W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, New York, (1981) 349 pp.

The processes of the present invention may be schematically illustrated as follows:

proton acceptor

wherein ring A, R¹, R⁴, R⁹, R¹⁰ and Z are as defined hereinbefore. in Step (a) of Process (A), the steroid of formula (XXV) is prepared by contacting the compound of formula (XX) with an anhydride, an organic acid, and an acid reagent having a pKa of about 3 or less, preferably 1 or less. Suitable anhydrides are of the formula: (R¹⁰CO)2θ wherein R¹⁰ represents hydrogen; phenyl; phenyl substituted with alkyl, halogen, alkoxy or nitro; Ioweralkyi; or Ioweralkyi substituted with phenyl or halogen such as perfluoroalkyl of one to 10 carbon atoms. Preferably R¹⁰ is methyl or trifluoromethyl (-CF₃). Preferably the anhydride is acetic anhydride or trifluoroacetic anhydride ((CF3CO)2θ). Also contemplated are unsymmetrical anhydrides having differing values for R¹⁰. The anhydride can be contacted with the compound of formula (XX) in a ratio ranging from excess to about equimolaπl (moles of anhydride: mole compound of formula (XX)), more preferably from about 20 to 5:1 , most preferably about 10 to 1 :1.

Suitable organic acids include acids containing from one to 10 carbon atoms. Such acids can be of the formula R³⁰COOH (X) wherein R³⁰ represents Ioweralkyi, preferably ethyl or Ioweralkyi substituted with halogen, preferably fluoro. Representative organic acids include the C-1 to C-10 alkanoic acids such as formic, acetic, propanoic acid, and the like or mixtures thereof, preferably acetic or propanoic. For purposes of this invention, the term "organic acid" does not include the same compounds as does the term "acid reagent". The organic acid can be contacted with the compound of formula (XX) in a ratio ranging from excess to about equimolaπl (moles of organic acid: mole compound of formula (XX)), more preferably from about 100 to 1 , most preferably from about 35 to 1 :1.

Suitable acid reagents having a pKa of about 3 or less, preferably about 1 or less include trifluoroacetic acid, para-toluene sulfonic acid, sulfuric acid, perchloric acid, hydrochloric acid, or strong cationic exchange resins possessing sulfonic acid type functionalities, such as described in A.J. Gordon and Richard A. Ford, The Chemist's Companion, A Handbook of Practical Data, Techniques, and References, John Wiley & Sons, New York, New York (1972). The acid reagent can be contacted with the compound of formula (XX) in a ratio ranging from 10 to about 0.1 :1 (moles of acid reagent: mole compound of formula (XX)), more preferably from about 10 to 1 :1.

Optionally and preferably, step (a) in process A is carried out in a solvent. Suitable solvents include the chlorinated hydrocarbons such as chloroform, dichloromethane, and carbon tetrachloride; and alkane solvents such as hexane or heptane. The amount of solvent can range from an excess amount to an amount sufficient to dissolve the reactants, generally about 10 percent volume basis per reaction mixture. In step (a) of Process (A) the order of addition of the starting materials ie. reactants, in the present process is not critical. As such, the reactants can be added in any convenient order or together at about the same time. Step (a) can be conducted at ambient pressures and at temperatures ranging from about 0 degrees Celsius (°C) to about 55°C, more preferable from about 0 °C to about 25 °C. The reaction mixture is stirred for a time sufficient to effect the desired completion of the reaction, generally from about 30 minutes to about 24 hours or more. The desired steroids of formula (XXV) thus prepared can be recovered by adding water to the reaction mixture, adjusting the pH to neutrality, ie. about 7, with a suitable base such as sodium or potasssium hydroxide, separating the organic layer containing the desired compound (XXV) from the aqueous layer, drying the organic layer over a drying agent such as anhydrous magnesium sulfate (MgSO.4) or sodium sulfate (Na₂S0₄). The desired steroid (XXV) can be recovered by conventional procedures, such as evaporation of any solvents present, filtration, crystallization, chromatography, distillation and the like.

In Step (b) of Process (A) the desired steroids of formula (XXX) can be prepared by contacting the reaction media from step (a) containing the steroid of formula (XXV) with water, aqueous alkali or aqueous acid under conditions effective to give the desired steroid of formula (XXX). Alternatively, the steroid (XXV) can be separated from the reaction mixture before contacting with^" the aqueous media. Suitable alkali sources include bases of alkali and alkaline earth metals including carbonates such as sodium, potassium and cesium carbonates; and hydroxides such as sodium or potassium hydroxides. The aqueous alkali should be sufficient to adjust the pH of the reaction mixture to between about 9-14. Aqueous acid sources include the mineral acids such as hydrochloric, sulfuric, phosphoric and the like. The amount of the aqueous acid should be sufficient to adjust the pH of the reaction mixture to between about about 1-4, preferably less than 2. Where water is employed, an amount of water about equivalent to or greater than the amount of solvent employed can be used. The steroids of formula (XXX) thus prepared can be recovered by separating the organic layer containing the desired compound (XXX) from the aqueous layer, drying the organic layer over a drying agent such as anhydrous magnesium sulfate (MgS04) or sodium sulfate (Na2S0₄) using conventional procedures as described hereinbefore to give the desired steroid (XXX).

In alternative Process (B), the steroid of formula (XXX) can be prepared by contacting the compound of formula (XX) with an anhydride and a proton acceptor or an acyl halide and a proton acceptor under conditions effective to yield (XXX). Suitable anhydrides are of the formula: (R¹⁰CO)2θ wherein R¹⁰ is as defined hereinbefore. Preferably R¹⁰ is methyl. Also contemplated are unsymmetrical anhydrides having differing values for R¹⁰. The anhydride can be contacted with the compound of formula (XX) in a ratio ranging from excess to about equimolaπl (moles of anhydride: mole compound of formula (XX)), more preferably from about 50 to 5:1 , most preferably about 40 to 1 :1.

Suitable acyl halides are of the formula R¹⁰CO-X wherein R¹⁰ is as defined hereinbefore and X is halo, preferably chloro. The acyl halide can be contacted with the compound of formula (XX) in a ratio ranging from about excess to about equimolaπl (moles of acyl halide: mole compound of formula (XX)), more preferably from about 40 to 1 :1. Suitable acyl halides include but are not limited to acetyl chloride, propanoyi chloride, trifluoroacetyl chloride, benzoyi chloride, 2-furyl chloride and the like.

Suitable proton acceptors are represented by amine bases which include the tertiary amines such as 1 ,5-diazabicyclo[4.3.0]non-5- ene (DBN), 4-N,N-dimethylaminopyridine (DMAP), 1,8- diazobicyclo[5.4.0] undec-7-ene (DBU), 1 ,4-diazabicyclo[2.2.2]octane otherwise known as Dabco or triethylenediamine, dimethylaniline, N,N- dimethyl-n-propylamine, N,N-diethylisopropylamine, N- methylpiperidine, N,N-diethylbutylamine; and heterocyclic nitrogen containing compounds such as morpholine, pyridine, imidazole or mixtures of any of the above. The proton acceptor is employed in amounts effective to neutralize acid formed during the reaction. The amine base can be contacted with the compound of formula (XX) in a ratio ranging from about 5 to about equimolaπl (moles of acylating catalyst: mole compound of formula (XX)), more preferably from about 2 to 1.

Process (B) can be carried out neat. When carried out neat, excess amounts of any of the reactants ie. the proton acceptor, acyl halide or anhydride, can be used to solubilize the reaction mixture. Where a solvent is employed, suitable solvents include the aromatic hydrocarbons such as benzene, xylenes and toluenes.

Process (B) can be conducted at ambient pressures and at temperatures ranging from about ambient to about 150 °C, more preferably from about 80°C to about 105°C. The reaction mixture can be stirred for a time sufficient to effect the desired completion of the reaction, generally from about 30 minutes to about 24 hours or more. The desired steroids of formula (XXX) thus prepared can be recovered by aqueous washings of the organic reaction mixture, followed by washings with brine. The organic layer can be dried over a drying agent such as anhydrous magnesium sulfate (MgSθ4) or sodium sulfate (Na2S04). The desired steroid (XXX) can be recovered by conventional procedures as described in Process A.

The following examples illustrate various embodiments by which the present invention can be practised, but as such, should not be limited to the overall scope of the same. All temperatures are in degrees Celsius (°C) EXAMPLE 1 Process A: 17α-(AcetvloxvV16β-methvlpregna-4.9π 1 Vdiene-3.20- dione

t

9α, 17α-Dihydroxy-16β-methylpregn-4-ene-3,20-dione (0.54 grams (g) in dichloromethane (5 milliliters) (ml) is added to a cold (ice bath temperature) mixture of para-toluenesulfonic acid monohydrate (0.285 g), acetic acid (2.92 ml) and trifluoroacetic anhydride (2.33 ml) in dichloromethane (5 ml). Upon completion of reaction, as determined by thin layer chromatography (tic), the reaction mixture is treated with water (10 ml), cooled (ice bath temperature) and 20 percent (%)(g/ml basis) sodium hydroxide solution is added until the pH of the solution is 9 to 10. The organic layer is separated, washed with water until the washings are neutral (pH 7), dried over magnesium sulfate and evaporated to give crude product. The title compound is obtained after filtration through a short column of silica gel by eluting with a mixture of ethylacetate and hexane (0.166 g). Nuclear Magnetic Resonance (NMR) (CDCI3), δ ppm 0.59, 1.28, 1.33, 1.92, 2.08, 5.49 and 5.68. EXAMPLE 2 Process A: 17α-21 -BistecetvloxvH 6β-methvlpregna-4.9n 1 diene-

3.20-dione

21 -(Acetyloxy)-9α,17α-dihydroxy-16β-methylpregn-4-ene- 3,20-dione (0.30 g) in dichloromethane (6 ml) is added to a cold (ice bath temperature) mixture of para-toluenesulfonic acid monohydrate (0.137 g), acetic acid (1.4 ml) and trifluoroacetic anydride (1.12 ml) in dichloromethane (9 ml). The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction mixture is diluted with water (10 ml) and the pH adjusted to 9-10 by addition of 20% sodium hydroxide. The organic layer is separated, washed with water until the washings are neutral (pH 7), dried over magnesium sulfate and evaporated to give the title compound (0.239 g). NMR (CDCI3) δ 0.78, 1.30, 1.38, 2.11 , 2.18, 4.35, 4.81 , 5.52 and 5.73.

EXAMPLE 3 Process A: 17α-(Acetyloxy^-pregna-4.9.11 diene-3.20-dione

A solution of 9α,17α-dihydroxypregn-4-ene-3,20-dione (0.5 g) in dichloromethane is added to a stirred solution of para- toluenesulfonic acid monohydrate (0.266 g), acetic acid (2.7 ml) and trifluoroacetic anhydride (2.2 ml) at 0°. After stirring for 10 minutes the reaction mixture is diluted with dichloromethane (20 ml) and washed with 5% aqueous sodium bicarbonate solution then water. The organic portion is separated, dried over magnesium sulfate and evaporated to give a crude product. The crude material is slurried with diethyl ether and filtered to give the title compound (0.23 g). NMR (CDCI3), δ ppm; 0.627, 1.349, 2.07, 2.10, 5.56 and 5.77 containing about 15% of 17α- acetoxy-9α-hydroxypregn-4-ene-3,20-dione.

EXAMPLE 4 Process A: 17a-21-Bisfacetvloxv prsgna-4. 9M 1 .-diene-3.20-dione

21 -(Acetyloxy)-9α-17α-dihydroxypregn-4-ene-3,20-dione (0.29 g) is added to a stirred solution of βa -toluenesulfonic acid monohydrate (0.133 g), acetic acid (1.35 ml) and acetic anhydride (0.8 ml) at 0°. The reaction mixture is stirred for 1 hour at room temperature, treated with trifluoroacetic anhydride (0.198 ml), stirred for 1 hour and poured into water. The precipitated solid is washed with water and dried in vacuo at 50° to afford the title compound (0.28 α). NMR (CDCI3), δ ppm; 0.709, 1.342, 2.09, 2.17, 4.66, 4.90, 5.56 and 5.76.

EXAMPLE 5 Process A: 17α-21 -Bisfacetvloxv pregna-4. 9(11 Vdiene-3.20-dione

21 -(Acetyloxy)-9α-17α-dihydroxypregn-4-ene-3,20-dιone (0.52 g) is added to a stirred solution of jara-toluenesulfonic acid . monohydrate (0.266 g), acetic acid (2.7 ml) and acetic anhydride (1.6 ml) at 0°. The reaction mixture is stirred at room temperature for 6 hours and then treated with a few drops of concentrated hydrochloric acid to hydrolyze any 3,17α,21-tris (acetyloxy)pregna-3,5,9(11 )-triene-20-one that forms. After stirring for a further 30 minutes the reaction mixture is poured into water. The precipitated solid is washed with water and dried in vacuo at 50° to afford the title compound (0.32 g).

EXAMPLE 6 Process B: 17α-(AcetvloxvV16β-methylpregna-4.9M 1 Vdiene-3.20- dione

9α,17α-Dihydroxy-16β-methylpregn-4-ene-3,20-dione (0.1 g) in acetic anhydride (1 ml) is treated with 4-N,N-dimethylaminopyridine (0.041 g) and heated at 100°. After 12 hours formation of 17α- (acetyloxy)-9α-hydroxy-16β-methylpregn-4-ene-3,20-dione is observed, by thin layer chromatography. The reaction mixture is treated with pyridine (0.5 ml) and 4-N,N-dimethylaminopyridine (0.04 g) and maintained at 100° until complete formation of the title compound is observed. The reaction mixture is treated with a few drops of water then poured into water (10 ml) and ethylacetate (10 ml). The organic portion is separated, washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give the title compound.

Preparation of Starting Materials

The steroids of formula (XX) are known or can be prepared according to known methods such as described in European Patent Application 87201933.6, Patent Publication 0263569 whose preparative teachings are incorporated herein by reference.

The steroids of formula (XXi) wherein R1 is -C≡CR⁷⁰ are known or can be prepared by contacting a compound of formula (I) with a suitable lithium acetylide compound of the formula LiC≡CR⁷⁰, followed by aqueous or acid hydroloysis to give compound (XXi) as schematically illustrated below:

(I) (XXi)

wherein R⁴ and R⁷⁰ are as defined hereinbefore.

The compound of formula (XXii) wherein R¹ is Ioweralkyi, haloalkyl, phenyl or phenylalkyi can be prepared by contacting the compound of formula (I) with the corresponding organometallic reagent ie. Grignard Reagent or organolithium as taught in J. March, Advanced Organic Chemistry, Reactions, Mechanisms and Structure, Third Edition, John Wiley and Sons, New York, 1985, 1346 pp. as illustrated below:

wherein R^1b and R⁴ are as defined hereinbefore and M is the metal which can be lithium, magnesium and the like.

The carboxy compound (XXiiϊ) wherein R¹ is -COOH and Z is H:

(XXiii)

can be prepared by hydrolyzing the compound of formula (XXiii) wherein Z is H or any other labile group under acidic conditions to give the desired carbonyl compound. PREPARATIVE EXAMPLE 1 9α.17α-Dihvdroxv-16β-methvl-3-(1 -pvrrolidinvnpregna-3.5-diene-20-

9α,17α-Dihydroxy-16β-methylpregn-4-ene-3,20-dione (3.04 g) in methanol (12 ml) is treated with pyrroiidine (0.987 ml) and heated to reflux temperature. The solution momentarily becomes homogeneous, then a precipitate forms. Heating is stopped, the reaction mixture cooled (ice bath temperature) and the precipitate is isolated by filtration and washed with cold methanol. After drying jjn vacuo the title compound (2.86 g) is obtained. NMR (CDCI3), δ ppm; 0.89 1.07, 1.11 , 2.21 , 3.15, 4.78 and 5.09.

PREPARATIVE EXAMPLE 2 1 -(21 -bromo-9α.17α-dihvdroxv-16β-methvl-20-oxopregn-4-en-3- . ylidene^pyrrolidinium bromide

9α,17α-Dihydroxy-16β-methyl-3-(1-pyrrolidinyl)pregna- 3,5-diene-20-one (2.86 g) is added to a stirred solution of HCI (5.0 equivalents) in ethanol. This solution is cooled to -60° and treated with a solution of bromine (1.5 equivalents) in ethanol. Once the addition is complete the reaction mixture is warmed to room temperature and stirred until the bromine color has discharged whereupon the reaction mixture is evaporated to an oil. The oil is redissolved in ethanol and triturated with diethylether to precipitate the title compound (3.28 g) which is isolated by filtration. NMR (CDCI3), δ ppm; 0.73, 1 02, 1.10, 3.89, 4.56 and 6.50.

PREPARATIVE EXAMPLE 3 21 -Bromo-9α.17α-dihvdroxv-16β-methvlpregn-4-ene-3.20-dione

1-(21 -Bromo-9α,17α-dihydroxy-16β-methyl-20-oxopregn- 4-en-3-ylidene)pyrrolidinium bromide (3.2 g) in ethanol (48 ml) is treated with a solution of potassium bicarbonate (2.33 g) in water (48 ml). After stirring at room temperature for 3 hours the reaction mixture is poured into water (80 ml), stirred for 90 minutes and a precipitate is isolated by filtration. The solid is washed with water (100 ml) and dried in vacuo to afford the title compound (1.8 g). NMR (CDCI3), δ ppm; 0.77, 1.06, 1.25, 4.48, 4.62 and 5.69.

PREPARATIVE EXAMPLE 4 21 -f Acetyloxy V9α.17 -dihvdroxy-16β-methvlpregn-4-ene-3.20-dione

21 -Bromo-9α,17α-dihydroxy-16β-methylpregn-4-ene-3,20- dione (0.7 g) in acetone (70 ml) is treated with potassium acetate (3.0 g) and heated at reflux for 5 hours. Evaporation of the solvent gives a solid which is slurried in acetone/water and filtered to give the title compound (0.554 g). NMR (CDCI₃), δ ppm; 0.82, 1.12, 1.30, 2.20, 4.95 and 5.88.

Claims

In the Claims;

A process for preparing steroid intermediates of formula

(XXX):

wherein R¹ represents -C≡CR⁷⁰ wherein R⁷⁰ is hydrogen or Si(CH3)3, or R¹ is Ioweralkyi, haloalkyl, phenyl or phenylalkyi, -COR¹¹, -COOR¹¹ wherein R¹¹ represents hydrogen or Ioweralkyi; or R¹ is -COCH2R¹² wherein R¹² represents hydroxy, halo or alkanoyloxy; R⁴ represents H or Ioweralkyi, preferably methyl having either the α or β stereochemistry; R⁹ represents hydrogen, fluoro, chloro or Ioweralkyi and R¹⁰ represents hydrogen, phenyl, phenyl substituted with alkyl, halogen, alkoxy, nitro; or R¹⁰ is heteroaryl, alkyl or alkyl substituted with phenyl or halogen; comprising contacting a 9α-hydroxysteroid of the formula (XX):

wherein R¹ and R⁴ are as defined hereinbefore; Z is a group which can be substituted with the -COR¹⁰ moiety, and represents

an enol ether of the formula:

wherein R⁵ represents Ioweralkyi or R^1a R²R³Si- wherein R^{1 a}, R² and R³ independently represent ioweralkyi, phenyl or phenylalkyi; and R⁹ is as defined hereinbefore;

a ketal of the formula

wherein R⁶ and R⁷ independently represent Ioweralkyi or -(CR²⁰R²¹)_V- and -(CR³°R³¹)w-, respectively, wherein R²⁰, R²¹, R³⁰ and R³¹ independently represent H, Ioweralkyi, or aryl and w and v independently represent an integer from 0 to 6 and v + w is an integer from 2 to 12, preferably 2, and wherein -(CR²⁰R²¹)_V- or -(CR³⁰R³ )_W- are connected together in a ring or through an oxygen or nitrogen atom; and R⁹ is as defined hereinbefore;

an enamine of the formula

wherein R⁶ and R⁷ are as defined hereinbefore; or

a ketone of the formula

wherein R⁹ is as defined hereinbefore; with (A) in step (a) an anhydride of the formula (R¹⁰CO)₂θ wherein R¹⁰ is as defined hereinbefore, an organic acid and an acid reagent having a pKa of about 3 or less, preferably about 1 or less, followed by step (b) treatment with an water, aqueous alkali or aqueous acid; or alternatively, with

(B) either an anhydride of the formula (R¹⁰CO2)O wherein R¹⁰ is defined hereinbefore and a proton acceptor or with an acyl halide of the formula R¹⁰COX wherein R¹⁰ is as defined hereinbefore and X is halogen and a proton acceptor, to give the steroid (XXX).

2. The process of claim 1 , wherein the compound of formula ^'

(XX) is of the formula:

wherein R¹ is -COR ¹ or -COCH2R¹² wherein R¹ and R¹² are as defined hereinbefore.

3. The process of claim 1 , wherein the compound of formula

(XXV) is of the formula:

wherein R¹ is -COR¹¹ or -COCH₂R¹² wherein R¹¹ and R¹² are as defined hereinbefore.

4. The process of claim 1 wherein in process (A), the anhydride is of the formula (R¹⁰CO)2θ wherein R¹⁰ is Ioweralkyi or perfluoroalkyl of one to 10 carbon atoms and the organic acid is of the formula R³°COOH (X) wherein R³⁰ represents Ioweralkyi.

5. The process of claim 1 wherein in Process (A) the anhydride is acetic anhydride or (CF3CO)2θ, the organic acid is acetic acid or propanoic acid and the acid reagent is para-toluene sulfonic acid.

6. The process of claim 1 wherein in Process (B) the anhydride is acetic anhydride and the proton acceptor is 4-N.N- dimethylaminopyridine.

7, A process for preparing novel compounds of the formula:

wherein R1 represents -C≡CR⁷⁰ wherein R⁷⁰ is hydrogen or -Si(CH3)₃, or R¹ is Ioweralkyi, haloalkyi, phenyl or phenylalkyi, -COR¹¹ or -COOR¹¹ wherein R¹¹ represents Ioweralkyi, hydroxyaikyi or acyloxy, preferably where Ioweralkyi is methyl, hydroxyaikyi is hydroxymethyl and acyloxy is acetoxy; or R¹ is -COCH2R¹² wherein R¹² represents hydroxy, halo or alkanoyloxy; R⁴ represents H or Ioweralkyi, preferably methyl having either the ά or β stereochemistry; R⁴ represents H or Ioweralkyi, preferably methyl having either the α or β stereochemistry; R⁹ represents hydrogen, fluoro, chloro or Ioweralkyi and R¹⁰ represents hydrogen, phenyl, phenyl substituted with alkyl, halogen, alkoxy or nitro or R¹⁰ is Ioweralkyi or alkyl substituted with phenyl or halogen; comprising contacting a compound of the formula (XX):

represents

an enol ether of the formula:

wherein R⁵ represents Ioweralkyi or R^1a R R³Si- wherein R^{1 a}, R² and R³ independently represent Ioweralkyi, phenyl or phenylalkyi; and R⁹ is as defined hereinbefore;

a ketal of the formula

wherein R⁶ and R⁷ independently represent Ioweralkyi or -(CR²⁰R²¹)_V- and -(CR³⁰R³¹)w-, respectively, wherein R²⁰, R²¹, R³⁰ and R³¹ independently represent H, Ioweralkyi, or aryl and w and v independently represent an integer from 0 to 6 and v + w is an integer from 2 to 12, preferably 2, and wherein -(CR²⁰R ¹)_V- or -(CR³⁰R³¹)_W- are connected together in a ring or through an oxygen or nitrogen atom; and R⁹ is as defined hereinbefore;

an enamine of the formula

wherein R⁶ and R⁷ are as defined hereinbefore; or

a ketone of the formula

wherein R⁹ is as defined hereinbefore; with an anhydride of the formula (R¹⁰CO)₂θ wherein R¹⁰ is as defined hereinbefore,^' an organic acid and an acid reagent having a pKa of about 3 or less.

8. The process of claim 7, wherein the compound of formula

(XXX) is of the formula:

wherein R¹ is -COR^{1 1} or -COCH2R¹² wherein R¹ and R¹² are as defined hereinbefore.

9. The process of claim 7 wherein in Process (A) the anhydride is (CF3CO)2θ, the organic acid is acetic acid or propanoic acid, and the acid reagent is para-toluene sulfonic acid.

10. A compound of the formula:

wherein R¹ represents -C≡CR⁷⁰ wherein R⁷⁰ is hydrogen or -Si(CH3)3, or R¹ is Ioweralkyi, haloalkyi, phenyl or phenylalkyi, -COR^{1 1} or -COOR^{1 1} wherein R^{1 1} represents Ioweralkyi, hydroxyaikyi or acyloxy, preferably where Ioweralkyi is methyl, hydroxyaikyi is hydroxymethyl and acyloxy is acetoxy; or -COCH2R¹² wherein R¹² represents hydroxy, halo or alkanoyloxy; R⁴ represents H or Ioweralkyi, preferably methyl having either the α or β stereochemistry; R⁴ represents H or Ioweralkyi, preferably methyl- having either the α or β stereochemistry; R⁹ represents hydrogen, fluoro, chloro or Ioweralkyi and R¹⁰ represents hydrogen, phenyl, phenyl substituted with alkyl, halogen, alkoxy or nitro or R¹⁰ is Ioweralkyi or alkyl substituted with phenyl or halogen.

11. The compound of claim 10 of the formula:

12. A compound of the formula:

wherein R1 represents -C≡CR⁷⁰ wherein R⁷⁰ is hydrogen or -Si(CH3)₃, or R¹ is Ioweralkyi, haloalkyi, phenyl or phenylalkyi, -COR¹¹, -COOR¹¹ wherein R¹¹ represents hydrogen or Ioweralkyi; or R¹ is -COCH₂R¹² wherein R¹² represents hydroxy, halo or alkanoyloxy; R⁴ represents H or Ioweralkyi, preferably methyl having either the α or β stereochemistry; R⁹ represents hydrogen, fluoro, chloro or Ioweralkyi and R¹⁰ represents hydrogen, phenyl, phenyl substituted with alkyl, halogen, alkoxy, nitro; or R¹⁰ is heteroaryl, alkyl or alkyl substituted with phenyl or halogen.

13. The compound of claim 12 of the formula: