Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton

Definitions

• This invention relates to the preparation of steroid enolates and of esters derived therefrom.
• Steroid 1,4diene-3,11-diones are frequently encountered among the physiologically active steroids, especially the corticosteroids, and it is oten found that the derivatives carrying substituents at the 6- or 9-position possess enhanced activity.
• 9e-fiuoro-16/3-methylprednisone (betamethasone) possesses greater anti-inflamrnatory activity than 16 8-methyl prednisone and 6- methyl prednisone also exhibits greater activity than prednisone.
• the 6- or 9- substituent is usually introduced at a relative early stage, before the 1,4-diene-3,l1-dione system is formed but considerable difiiculty has been experienced in substituting at the sterically hindered 9-position.
• the rearrangement appears to be bimolecular, one molecule of 3-enolate reacting with one molecule of -3,l1-dione to yield one molecule of regenerated -3,1l-di0ne and one molecule of 9(ll)enolate.
• unreacted -3,11-di0ne need only be present in a catalytic quantity since it is constantly regenerated.
• the bimolecular rearrangement is considerably slower than the enolisation and if an excess of base is added, the -3 enolate will be formed quantitatively before rearrangement can take place to a significant extent.
• the bimolecular rearrangement is so slow as to be negligible and at such temperatures substantially only 3-enolate is apparently present (as demonstrated by forming an enol ester). It can thus be seen that if the reaction conditions are selected so that the initially formed 3-enolate cannot come in contact with the unreacted dione, or can only contact the dione under conditions in which rearrangement will not occur, the 3-enolate is obtained as reaction product, whereas if the reaction conditions are selected so that the initially formed 3-enolate can contact unreacted dione under conditions in which rearrangement can occur, the 9(ll)enolate is obtained.
• the present invention therefore we provide a process for the selective 3- or 9( l1)-enolisation of a steriod 1,4-diene-3,11-dione in which the 1,4-dione-3,l1- dione is treated under substantially oxygen-free and anhydrous conditions in a non-hydroxylic solvent with an alkali metal base other than a lithium base soluble in the solvent to form the 3-enolate; when the 9(ll)enolate is required, the dione in non-enolised form being allowed or caused either subsequently or simultaneously to react with the 3-enolate initially formed; when the 3-enolate is required the reaction being carried out at a temperature below 50 C. or the reaction being carried out in a manner whereby contact between the 3-enolate and unreacted dione is reduced or avoided.
• alkali metal base that is a sodium, potassium, rubidium or caesium base, acting as a strong nucleophile under anhydrous non-hydroxylic conditions is required to abstract the desired proton from the 6- and 9-position.
• the enolates formed are advantageously, as indicated above, converted directly into enol esters.
• the reaction with the alkali metal base may be conveniently quenched and the corresponding ester pro,- symbolized, by treating the reaction mixture in situ with an acylating agent, e.g. a reactive ester, for example, the acid halide, or more particularly, the anhydride, of an organic acid such as an aliphatic, araliphatic or aromatic carboxylic or sulphonic acid.
• an acylating agent e.g. a reactive ester, for example, the acid halide, or more particularly, the anhydride, of an organic acid such as an aliphatic, araliphatic or aromatic carboxylic or sulphonic acid.
• an acylating agent e.g. a reactive ester, for example, the acid halide, or more particularly, the anhydride, of an organic acid such as an aliphatic, araliphatic or aromatic carboxylic or
• Any steroid l,4-diene-3,ll-dioue can be enolised by the process according to the present invention, especially corticosteroids of the prednisone type and suitably substituted progesterone and androstane derivatives.
• Particularly desirable enolates are formed from prednisone BMD ,(17,20:20,21-bismethylenedioxyprednisone) and its 160: and l6fi-meth'yl analogues, n -ll-ketoprogesterone ethylene ketal and androstane-l,4-diene-3,l1,17-trione-l7- monoethylene ketal.
• the 3- and 9(ll)-enol esters or the parent 3- and 9(l1)- enolates are, as indicated previously, particularly useful as starting compounds for electrophilic substitution reactions at 6- or 9-positions.
• reaction with sources of positive halogen such as molecular chlorine or bromine, introduces a halogen atom at the 6- or 9'position.
• fluorine especially at the 9a-position, by reacting an enolate or enol ester with an electrophilic fluorinating agent, such as perchloryl fluoride, or a hypofiuorite reagent such as trifluoromethyl hypofiuorite.
• the method according to the invention thus allows 9cz-fill0l0 prednisone or a 16mmethyl or l6fl-methyl derivative to be prepared directly from prednisone or its l-methyl derivatives.
• Example 2 Slow addition of steroid to base Prednisone BMD (200 mg., 0.5 mmole) in dry TI-IF (10 ml.) was added dropwise over 30 minutes with vigorous stirring to sodium bistrimethylsilylamide (120.3 mg., 0.55 mmole) in THF (5 ml.) under argon, the mixture remaining at room temperature throughout the addition. The mixture was then stirred a further 2 minutes and benzoic anhydride (452 mg., 2.0 mmoles) added. The mixture was then worked up as before to yield the 3-enol benzoate (207 mg., 0.405 mmole; 82%). Use of triphenylmethylsodium (3 mol.
• the 9(l1)-enol benzoates of l6u-methyl prednisone BMD, IGB-methyl prednisone BMD, A -1l-keto-progesterone-ZO- ethylene ketal and androstrane-1,4-diene-3,l1,17-monoethylene ketal may be prepared.
• Use of triphenylmethylsodium (2 mol. equiv.) or sodium acetylide (2 mol. equiv. dispersed in xylene/tetrahydrofuran) yields the identical 9(11)-eno1 benzoate.
• Example 5 Reaction of prednisone BMD 9(11)-enol benzoate with trifluoromethyl hypofluorite (CF OF)
• Prednisone BMD 9(11)-eno1 benzoate 500 mg. was dissolved in a mixture of Freon (100 ml.) and methylene chloride (50 ml.) and reacted with CF OF in the presence of CaO (200 mg.) under nitrogen at about 78 C.
• the crude product (572 mg.) was chromatographed over alumina (grade 3, 40 g.). Elution with benzene, followed by ether/benzene mixtures up to 10% ether, produced small amounts of several non polar products (total weight 103 mg.) which were not studied further.
• a process for the selective 9(11)-enolisation of a 1,4- diene-3,l1-dione steroid of the androstane or pregnane series in which the 1,4-diene-3,l1-dione is treated under substantially oxygen-free and anhydrous conditions in a non-hydroxylic solvent with an alkali metal base other than a lithium base soluble in the solvent, to form the 3- enolate; the dione in non-enolised form being allowed or caused either subsequently or simultaneously to react with the 3-enolate initially formed.

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

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Country Status (11)

• 1970
  • 1970-10-23 BE BE70@@@@@@@@A patent/BE759289A/xx unknown
  • 1970-11-23 IL IL35706A patent/IL35706A/en unknown
  • 1970-11-23 CH CH1731370A patent/CH571540A5/xx not_active IP Right Cessation
  • 1970-11-23 JP JP45102645A patent/JPS5111112B1/ja active Pending
  • 1970-11-23 US US92216A patent/US3705893A/en not_active Expired - Lifetime
  • 1970-11-23 FR FR7041982A patent/FR2072246A5/fr not_active Expired
  • 1970-11-23 ZA ZA707908A patent/ZA707908B/xx unknown
  • 1970-11-23 DK DK594370AA patent/DK134071B/da unknown
  • 1970-11-23 DE DE19702057541 patent/DE2057541A1/de active Pending
  • 1970-11-23 NL NL7017087A patent/NL7017087A/xx unknown
  • 1970-11-24 GB GB5742569A patent/GB1325004A/en not_active Expired

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