EP0523132A1 - PROCEDE DE DESHYDRATATION DE 9$g(a)-HYDROXY STEROIDES - Google Patents

PROCEDE DE DESHYDRATATION DE 9$g(a)-HYDROXY STEROIDES

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Publication number
EP0523132A1
EP0523132A1 EP19910907307 EP91907307A EP0523132A1 EP 0523132 A1 EP0523132 A1 EP 0523132A1 EP 19910907307 EP19910907307 EP 19910907307 EP 91907307 A EP91907307 A EP 91907307A EP 0523132 A1 EP0523132 A1 EP 0523132A1
Authority
EP
European Patent Office
Prior art keywords
formula
ioweralkyi
phenyl
defined hereinbefore
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19910907307
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German (de)
English (en)
Inventor
Nicholas Carruthers
Sohaila Garshasb
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme Corp
Original Assignee
Schering Corp
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Filing date
Publication date
Application filed by Schering Corp filed Critical Schering Corp
Publication of EP0523132A1 publication Critical patent/EP0523132A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
    • C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
    • C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
    • C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
    • C07J7/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16
    • C07J7/0055—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
    • C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom

Definitions

  • the 9 ⁇ -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 9 ⁇ -hydroxysteroid type compounds with a strong acid (pKa less than 1) to give ⁇ 9.II steroids.
  • a ⁇ 9.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.
  • the present invention is directed towards a process for preparing steroid intermediates of formula (XXX):
  • R1 represents -C ⁇ CR 70 wherein R 70 is hydrogen or Si(CH 3 ) 3 , or R 1 is Ioweralkyi, haloalkyl, phenyl or phenylalkyl, -COR 11 , -COOR 1 wherein R 11 represents hydrogen or Ioweralkyi; or R 1 is -COCH2R 12 wherein R 12 represents hydroxy, halo or alkanoyloxy; R 4 represents H or Ioweralkyi, preferably methyl having either the ⁇ or ⁇ stereochemistry; R9 represents hydrogen, fluoro.
  • R 10 represents hydrogen, phenyl, phenyl substituted with alkyl, halogen, alkoxy, nitro; or R 10 is heteroaryl, alkyl or alkyl substituted with phenyl or halogen.
  • -OCOR 10 at position 17 has the ⁇ -stereochemistry.
  • the present process comprises contacting a 9 ⁇ -hydroxysteroid of the formula (XX):
  • R 1 and R 4 are as defined hereinbefore;
  • Z is a group which can be substituted with the -COR 10 moiety, and
  • R 5 represents Ioweralkyi or R 1 a R R 3 Si- wherein R 1 a , R 2 and R 3 independently represent Ioweralkyi, phenyl or phenylalkyi; and R 9 is as defined hereinbefore;
  • R ⁇ and R 7 independently represent Ioweralkyi or -(CR 20 R 21 ) - and -(CR30R31) W ., respectively, wherein R 20 , R 2 , R30 and R 31 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 20 R 21 ) V - or -(CR 30 R 31 ) W - are connected together in a ring or through an oxygen or nitrogen atom; and R 9 is as defined hereinbefore;
  • R 6 and R 7 are as defined hereinbefore;
  • R 9 is as defined hereinbefore;
  • the present invention is directed toward a process for preparing novel compounds of the formula:
  • R 1 represents -C ⁇ CR 70 wherein R 70 is hydrogen or -Si(CH 3 ) 3 , or R 1 is Ioweralkyi, haloalkyi, phenyl or phenylalkyi, -COR 11 or -COOR 1 wherein R 11 represents Ioweralkyi, hydroxyaikyi or acyloxy, preferably where Ioweralkyi is methyl, hydroxyaikyi is hydroxymethyl and acyloxy is acetoxy; or -COCH2R 12 wherein R 12 represents hydroxy, halo or alkanoyloxy; R 4 represents H or Ioweralkyi, preferably methyl having either the ⁇ or ⁇ stereochemistry; R 4 represents H or Ioweralkyi, preferably methyl having either the ⁇ or ⁇ stereochemistry; R 9 represents hydrogen, fiuoro, chloro or Ioweralkyi and R 10 represents hydrogen, phenyl, phenyl substituted with alkyl, halogen
  • R and R 4 are as defined hereinbefore;
  • Z is a group which can be substituted with the -COR 10 moiety, and
  • R 5 represents " Ioweralkyi or R 1a R 2 R 3 Si- wherein R 1 a , R 2 and R 3 independently represent Ioweralkyi, phenyl or phenylalkyi; and R 9 is as defined hereinbefore;
  • R 6 and R 7 independently represent Ioweralkyi or -(CR 20 R 21 ) - and -(CR3°R3 1 ) W -, respectively, wherein R 20 , R 21 , R3° and R3 1 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 0 R 21 ) V - or -(CR 3 °R31) W - are connected together in a ring or through an oxygen or nitrogen atom; and R 9 is as defined hereinbefore;
  • R 6 and R 7 are as defined hereinbefore;
  • R 9 , R 10 and R 12 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 9 ⁇ -OH to form a ⁇ 9,ll steroid possessing the desired R 10 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 9 ⁇ -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.
  • the wavy line bond ie. " « ⁇ -" indicates the substituent possesses either the alpha ( ⁇ ) or beta ( ⁇ ) stereochemistry.
  • a substituent possessing the ⁇ stereochemistry lies below the plane of the paper, whereas a substituent possessing the ⁇ " * 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 ⁇ stereochemistry.
  • 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.
  • phenylalkyi refers to a phenyl moiety convarriably bonded to an alkyl moiety of one to six carbon atoms such as, for example, phenylmethyl, 2-phenylethyl and the like.
  • 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- classroom 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
  • Z can represent hydrogen or any protecting group which is sufficiently labile to permit substitution of the -Z moiety with the -COR 10 moiety under the process conditions.
  • 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 R 2 R 3 wherein R 1 a , R 2 and R 3 independently represents Ioweralkyi, phenyl or phenylalkyi, preferably -Si(CH3)3.
  • R 1 a , R 2 and R 3 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, (19
  • 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: (R 10 CO)2 ⁇ wherein R 10 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.
  • R 10 is methyl or trifluoromethyl (-CF 3 ).
  • the anhydride is acetic anhydride or trifluoroacetic anhydride ((CF3CO)2 ⁇ ).
  • unsymmetrical anhydrides having differing values for R 10 .
  • the anhydride can be contacted with the compound of formula (XX) in a ratio ranging from excess to about equimola ⁇ l (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 R 30 COOH (X) wherein R 30 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.
  • 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 equimola ⁇ l (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.
  • 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.
  • 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.
  • 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 (Na 2 S0 4 ).
  • a drying agent such as anhydrous magnesium sulfate (MgSO.4) or sodium sulfate (Na 2 S0 4 ).
  • MgSO.4 anhydrous magnesium sulfate
  • Na 2 S0 4 sodium sulfate
  • the desired steroid (XXV) can be recovered by conventional procedures, such as evaporation of any solvents present, filtration, crystallization, chromatography, distillation and the like.
  • 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).
  • 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 (Na2S0 4 ) using conventional procedures as described hereinbefore to give the desired steroid (XXX).
  • MgS04 anhydrous magnesium sulfate
  • Na2S0 4 sodium sulfate
  • 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: (R 10 CO)2 ⁇ wherein R 10 is as defined hereinbefore.
  • R 10 is methyl.
  • unsymmetrical anhydrides having differing values for R 10 .
  • the anhydride can be contacted with the compound of formula (XX) in a ratio ranging from excess to about equimola ⁇ l (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 R 10 CO-X wherein R 10 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 equimola ⁇ l (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.
  • tertiary amines such as 1 ,5-diazabicyclo[4.3.0]non-5- ene (DBN), 4-N
  • 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 equimola ⁇ l (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 (MgS ⁇ 4) or sodium sulfate (Na2S04).
  • MgS ⁇ 4 anhydrous magnesium sulfate
  • Na2S04 sodium sulfate
  • the desired steroid (XXX) can be recovered by conventional procedures as described in Process A.
  • 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.
  • 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 ⁇ CR 70 are known or can be prepared by contacting a compound of formula (I) with a suitable lithium acetylide compound of the formula LiC ⁇ CR 70 , followed by aqueous or acid hydroloysis to give compound (XXi) as schematically illustrated below:
  • R 4 and R 70 are as defined hereinbefore.
  • the compound of formula (XXii) wherein R 1 is Ioweralkyi, haloalkyl, phenyl or phenylalkyi can be prepared by contacting the compound of formula (I) with the corresponding organometallic reagent ie.
  • 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:
  • R 1b and R 4 are as defined hereinbefore and M is the metal which can be lithium, magnesium and the like.
  • PREPARATIVE EXAMPLE 2 1 -(21 -bromo-9 ⁇ .17 ⁇ -dihvdroxv-16 ⁇ -methvl-20-oxopregn-4-en-3- . ylidene ⁇ pyrrolidinium bromide

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

Procédé de préparation de nouveaux intermédiaires de corticostéroïdes de la formule (XXX). Le procédé consiste à mettre en contact un 9alpha-hydroxystéroïde de la formule (XX) avec (A) dans l'étape (a) un anhydride, un acide organique et un réactif acide ayant un pKa d'environ 3 au moins, suivie par l'étape (b) de traitement à l'aide d'eau, d'alcali aqueux ou d'acide aqueux; ou selon un autre mode de réalisation, avec (B) soit un anhydride et un accepteur de protons, soit un halogénure d'acyle et un accepteur de protons, afin d'obtenir le stéroïde de la formule (XX). L'emploi de l'étape (a) dans le procédé (A) permet également d'obtenir de nouveaux intermédiaires de stéroïdes de la formule (XXV).
EP19910907307 1990-03-27 1991-03-25 PROCEDE DE DESHYDRATATION DE 9$g(a)-HYDROXY STEROIDES Withdrawn EP0523132A1 (fr)

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See references of WO9114700A2 *

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WO1991014700A3 (fr) 1991-11-14
JPH05501115A (ja) 1993-03-04
WO1991014700A2 (fr) 1991-10-03
AU7556291A (en) 1991-10-21

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