CA1105003A - Process for the preparation of 9,11-halogenated steroids - Google Patents
Process for the preparation of 9,11-halogenated steroidsInfo
- Publication number
- CA1105003A CA1105003A CA286,727A CA286727A CA1105003A CA 1105003 A CA1105003 A CA 1105003A CA 286727 A CA286727 A CA 286727A CA 1105003 A CA1105003 A CA 1105003A
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- Prior art keywords
- alpha
- radical
- hydrogen atom
- beta
- hydroxyl group
- Prior art date
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-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- C07J7/0015—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 not substituted in position 17 alfa
- C07J7/002—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 not substituted in position 17 alfa not substituted in position 16
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
9.alpha.-Chloro-11.beta.-fluoro-steroids are prepared according to a novel process by reacting a corresponding 9.alpha.-chloro-11.beta.-hydroxy-steroid with an aminosulphur trifluoride of the formula F3SX, in which X is an amino group derived from a secondary amine, especially diethylamine or piperidine.
Any hydroxyl groups and carboxyl groups which may be present are preferably temporarily protected during the reaction.
9.alpha.-Chloro-11.beta.-fluoro-steroids are prepared according to a novel process by reacting a corresponding 9.alpha.-chloro-11.beta.-hydroxy-steroid with an aminosulphur trifluoride of the formula F3SX, in which X is an amino group derived from a secondary amine, especially diethylamine or piperidine.
Any hydroxyl groups and carboxyl groups which may be present are preferably temporarily protected during the reaction.
Description
The subject of the presen-t invention is a novel pro-cess for the prepara-tion of 9~-chloro~ fluoro- compounds of the general formula I
F
~ x i b R (I) S
in which St is the remaining part~ which can be substituted or unsubstituted and/or modi~ied in some other way, of the steroid skeleton, Rx is a free or ketalised oxo group, a substituted or unsubstituted lower alkylidene radical, a ~ree, etherified or esterified hydroxyl group -together wi-th a hydrogen a-tom or a subs-tituted or unsubstituted lower ali-phatic hydrocarbon radical, or a hydrogen a-tom together with a substituted or unsubstituted lower alkyl radical, and Ry is a lower alkylidene radical, a free, etherified or esterified hydroxyl group together with a hydrogen atom, a lower alkyl , radical together with a:h~drogen atom~ or two hydrogen atoms, it being possible for a 16~17-double bond to be present in place of one of the said hydrogen atoms in radical Rx and one of the said hydrogen atoms in radical R~
The term "lower" used -to qualify an organic radical:
signifies an organio radical having at most 7, but preferabl~
having 1 to L~, carbon atoms.
:The radical St oomprises the ring ~ (carbon atoms C-l to C-5 and C~10) and the remaining carbon atoms of ring B
:
: . :
: 2 ': ' '' , ' ' ' : ~. ' ., ' ,':' '., ' ' ' " '' ' , . ' .: ' ' ~ 3 (C-6 and C-7) and carries -the angular methyl group (C-l9) in -the 10 position. I-t can also be modified in some o-ther way, for example it can have a structure with expanded or contracted rings, such as the A-nor or A-nor-B-homo structure and/or ring bridging, for example the 3a,5-cyclo linkage.
The rings A and B can, with respect to one another, assume the 5a- or 5~-con~iguration. The radical St can contain one, -two or several double bonds, such as in the 1,2-, 2,3-, 3,4-or 6,7-positions, but in particular in -the 4,5- or 5l6~
positions. The radical St can also be substituted by free, etherified and, especially, esterified hydroxyl groups, for example in the 3- and/or 19-positions and in particular in the 3~-position, by free or ketalised oxo groups, especially in the 3-position, by lower alkyl radicals, for example in the 7a-position or especially the 6a-posi-tion, or by halogen atoms, such as bromine atoms or, especially, chlorine or fluorine atoms, especially in the 2-position and/or, in particular, in the 6a-position.
A lower alkyl radical is, for example,an n-propyl, 1-propyl, n-bu-tyl, i-bu-tyl, sec.-butyl or tert~-butyl radical or a branched or preferably straight~chain pen-tyl, hexyl or heptyl radical1 bu-t in particular an ethyl or methyl radical, A lower allphatic~hydrocarbon radical is a lower alkyl radi-cal, for example one of those already mentioned, or a corres-ponding radical which also contains one or two multiple bonds, i e. double bonds or triple bonds, for example a lower alkenyl, lower alkynyl and allenyl radical, for example a -- ~
.
.
~ - , . .
vinyl, allyl, methallyl, propargyl or hexadi~nyl radical and in particular an ethynyl radical. A lower alkylidene radical is a radical which corresponds to the abovementioned lower alkyl radicals or lower alkenyl radicals and is divalent on one carbon a-tom, such as an ethylidene or isopropylidene radical and in particular a methylene radical, or, alter-natively, a vinylidene radical.
The lower aliphatic hydrocarbon radical already dis-cussed and~ if desired, also the lower alkylidene radical can be substituted by one or more identical or different sub-stituents which, in par-ticular, are in the a--position and/or ~-position (corresponding to the 20-position and 21-position respectively in steroid numbering) Possible substituen-ts are halogen atoms, for example chlorine and fluorine, free, etherified and, especially, esterified hydroxyl groups, ~ree or ketalised oxo groups and ~ree or esterified carboxyl groups, and the carboxyl groups can also be in the form of their salts, especially alkali metal salts. An esterified car-boxyl group is, in particwlar, to be understood as meaning a oarboxyl group which .is in -the form of its ester, especially one of its esters wi-th lower alkanols, but also that carboxyl group which, together with a suitably dis-tant hydroxyl group, whlch is present as a substituent, closes a 6-membered or, especially 7 5-membered lactone ring.
A ketalised oxo group isde~ved,especially, from lower a].k.anols, for example from me-thanol or ethanol, or preferably from a- or ~-lower alkanediols, for example 1,2- or 1,3-_ 4 _:
. ' `
`;, , ,, ' '' :
` ' -propanediol, or, in particular~ e-thylene glycol; however, i-t can also be derived from the corresponding sulphur analogues of the said alcohols and con-tain sulphur atoms in place of one or both of the oxygen atoms.
An etherified hydroxyl group is derived, especially, from a lower alkanol, preferably a straight-chain lower alkanol, for example methanol, ethanol, propanol or butanol, from an aryl-lower alkanol, preferably a phenyl-lower alkanol, ~or example benzyl alcohol or triphenylmethylcarbinol, or from an oxygen-con-tainirlg heterocyclic alcohol, for example 2-tetrahydropyranol or 2-te-trahydrofuranol Formally, however, it can also be derived from a l-lower alkoxy lower alkanol, for example l-~utoxyethanol; the l-butoxye-thoxy group may be mentioned as an example of a hydroxyl group etherified in this way In respect of the general sense, a hydroxyl group of the t~pe present in an acetalised or ketalised vicinal steroid-diol, for example 16a,17a-diol, is also to be regarded as an e-therified hydroxyl group. The non-steroid structural component, which -then always links two such vicinal etherified hydroxyl groups, .is preferably a lower alipha-tic, cycloalipha-tic or arylaliphatic ketone, for example acetone, cyclopentanone, cyclohexanone, acetophenone or benzophenone, or an aldehyde, for example formaldehyde. The 17a,20;20,21~
bis-methylenedioxy grouping may also be mentioned as a special case of etherified hydroxyl groups.
An esteri.fied hydroxyl group is derived, especially, . from an inorganic oxygen containing acid, for example from one : ; - 5 ~
~ . .
of the sulphuric or phosphoric acids, or, preferably, from an organic acid, for example from a sulphonic acid,forexample,~xman aromatic sulphonic acid, such as benzenesulphonic acid, toluenesulphonic àcid or p-bromobenzenesulphonic aeid, or ~rom an alkanesulphonic acid, such as methanesulphonic acid, or, especially from a carboxylic acid. A lactonised hydroxyl group is also to be regarded as an esterified hydroxyl group.
From its mode of formation and cer-tain substitution reactions, a halogen atom, for example an iodine or bromin~ atom and~
especially a chlorine or fluorine a-tom, is also to be regarded, especially when it is in the 21-posi-tion, as a special case, which nevertheless ~alls in-to this category, of a hydroxyl group esterified by a strong acid; i~e. a hydroxyl group esterified by hydriodic acid, hydrobromic acid, hydrochloric aeid or hydrofluorie acid.
Aeids which are possible as the earboxylie acid eom-ponent o~ àn esterified hydroxyl group are, in particular, the earboxylic acids eustomary in s-teroid chemistry, including those in the form o~ the corresponding orthocarboxylic acids, for example monoearboxylic acids hàving at most 18 carbon atoms, such as aliphatic carboxylic aeids or orthoearboxylic aeids, espeeially formie aeid, or-thoformie aeid or a lower alkaneearboxylie acid or lower alkane-orthoearboxylie acid in whieh the lower alkyl radieal is one of those mentioned above~
in partieular propionic acid, butyrîe aeid, isobutyrie aeid, valerie aeid, isovalerie acid, oenanthie acid and diethylaeetie aeid and espeeially caproic aeld, trimethylacetic acid and .
-:
.
., .
.
~. . .
.'-' " ' ' ' ~ ; ~ . . ' .'.. ~' .
- , .: . .
~ 3 ace-tic acid, bu-t also corresponding halogenated lower alkane-carboxylic acids, such as chloroace-tic acid, trichloroacetic acid or trifl.uoroacetic acid, and also caprylic acid, pelargonic acid, capric acid, lauric acid, myris-tic acid, palmitic acid and stearic acid~ undecylic and undecylenic acids, elaidic acid and oleic acid; cycloaliphatic or cyclo-aliphatic-aliphatic monocarboxylic acids, for example cyclo-propanecarboxylic acid~ cyclobutanecarboxylic acid, cyclo-pen-tanecarboxylic acid and cyclohexanecarboxylic acid and cyclopropyl-methanecarboxylic acid or cyclobutyl-methane-carboxylic acid and a cyclopentyl-ethanecarboxylic acid or cyclohexyl-ethanecarboxylic acid; aromatic carboxylic acids, for example benzoic acids or orthobenzoic acids which are unsubstituted or substi-tuted by fluorine, chlorine9 bromine, hydroxyl, lower alkoxy, lower alkyl or nitro groups; aryl- or aryloxy-lower alkanecarboxylic acids and their analogues which are unsaturated in the chain, for example phenylacetic and phenoxyacetic acids, phenylpropionic acids and cinnamic acids which are unsubstituted or substituted as indicated above for benzoic acid; and heterocyclic acids, for example furane-2-carboxylic acid, 5-tert.-butyl~urane-2 carboxylic acid, 5-bromofurane~2-carboxylic acid, thiophene~2-carboxylic acid, nicotinic acid or isonicotinic acid or 3-~4-pyridyl)-propionic ac.id, and pyrrole-2- or -3-carboxylic acids which are unsub-stituted or substituted by lower alkyl radicals, but also .
corresponding dicarbo~lic acids having at most 12 carbon atoms~ for example succinic acid, glutaric acid, adipic acid .
.
- . -'.- ,~ .
5~`~3 and phthalic acid and also corresponding ~-aminoacids, especially ~-amino-lower alkanecarboxylic acids, preferably those in -the naturally occurring configura-tion, for example glycine, proline, leucine, valine, -tyrosine, histidine and asparagine, and also glutamic acid and aspartic acid.
When they are in a favourable position, for example when they are separated from one another by two or three carbon atoms, two hydroxyl groups can, together with one ~ole-cule of an orthocarboxylic acid, form cyclic esters, such as, especlally, in the case of ortho-esters of lower aliphatic ortho-acidswith 17~,21-dihydroxypregnane compounds. The third oxygen atom of the ortho acid functional group is then usually occupied by the radical of a lower alkanol, in particular by me-thyl or ethyl. Ortho-es-ters of ortho-carbonic acid with 17a,21-dihydroxypregnane compounds are also formed in an analogous manner~; in -this case, the central carbon atom also carries two lower alkoxy groups.
m e 9~-chloro~ fluoro-steroids prepared according to the invention are known as a category of compounds and can be used as intermediates ~or the synthesis o~ valuable pharma-ceutical active compounds, especially for the therapy of in~lamma-tory conditions and also for fertility control, or the compounds themselves show a biological activi-ty and, accord-ing].y, can be used direct as active compounds in the above-mentioned fields o~ applicationO
Hitherto, 9a-chloro-11~-fluoro~steroids were accessible from corresponcling 9(11)-unsa-turated star-ting materials by the : : ~ : . . .: . . . : :
.:. :. . . ~ -, . : . - , . .
- : : : :: ~ . :
simultaneous addi-tion of fluorine and chlorine, c.f., for example, U.S. Paten-t No. 2,894,963 and German Offenlegungs-schrift No. 2,053,14~. The addi-tion can be effected by reaction with fluorine monochloride; usually, however~ a N~
chloro-acylamide or -acylimide~ such as, especially, N-chloroacetamide or N-chlorosuccinimide, and anhydrous hydrogen ~luoride are allowed to act on -the s-tarting material at the same time The known aggressi~eness of the last~mentioned agent, both towards the starting materials to be reacted and towards the reaction vessels, already constitutes a grea-t dis-advantage, especially for the indust~1 opera-tion of the process;
moreoverS the course of the reac-tion is complicated by competing reactions, c~f., for example, J. Am. Chem. Soc. 82~
2308-2311 (1960), and the yields which can be achieved are low.
The process according to -the invention is not subject to such disadvantages: the halogenating agen-t of -the formula F3SX, which is characterised further belowg acts speci~ically under very mild conditions and within a short reaction time, which makes high yields possible, and, moreover, it does not ..
attack glass, so that conventional glass apparatus can be used without any di~ficulty.
The process according to the invention comprises the reaction o~ a 9a chloro~ h~dro~y-steroid, in which any carboxyl groups and hydroxyl groups which may be present are preferably -temporarily protected, with a compound o~ the formula F3SXt in which X is an amino group derived from a secondary amine.
_ g _ .
.
-:: . .
- - . ~ : . : . : ,,-: . : :
, Compounds.of the general fo-rmula ~ X
~ (II) ..
in which St, Rx and Ry are as defined above and any other hydroxyl groups and carboxyl groups which may be present are preferably in an esterified form, are preferred as starting materials~
Within the scope of the end products of the formula I, the resul-ting products are, if desired, converted into one another in a manner which is known per se, for example by setting ~ree protected functional groups~ such as, in particular, esterified carboxyl groups and esterified hydro~l groups, or by setting free the dihydroxyacetone side chain from the 17a,20;20,21 bis-methylenedioxy groupingO ~urther con-: versions customar~ in steroid chemistry can also be carried , out; 1n particular, ~hydroxyl groups can be esterified, ahydrox~l group in the 21~position esteriPied by an organic sulphonic acid can be replaced b~ a chlorine or bromine atom and/or ~urther double bonds can be introduced. ~hese sub-~equent conversi.ons can each be carried out independently or can be carried out in:appropriate combinations.
The course o~ the process according to the invention is very surprising because the reactant of the ~ormula F3SX
~hich is used reacts with the analogous 9a-fluoro~ hydroxy-- . :
- 10 - "
:':
':''' ' ", ', ' ~' ''.', .'' ' '' ' ' '. ' ' ' '~ ',' ' ' ''' '" ` ., . . ' ' "
, . . .. , ' , ' .'. , ~
. ' . ~ ~ . . . ' . . ~, . , , .
' ' ' ' ' ' ' ' " .' " " . . . '. '' . . .
' ' ' ~ ' ~ .
steroids with the formation of the 11,12-double bond exclusive~
ly, by detaching the hydroxyl group in the ll-position, c.f.
our United S-tates Patent 4,172,075.
The process according to the invention proceeds readily even under very mild reaction conditions, so that other functional groups usually remain unaffected. ~Iowever, it is recomm~nded that any car~oxyl groups which may be present in the starting materials of the formula II should be in an esterified form to protect them against convers.ion into an acid fluoride.
In the starting materials of the for.mula II, any hydnoxyl groups which may be present, with the e~ception of the ll~-h~droxyl group, which is to be reacted, should also be in a protected form such as an etherified or, preferably, esterified form during the reaction. Readily hydrolysable etherified hydroxyl groups, for example -tetrahydropyrany].oxy groups, and also ketalised oxo groups c~n be split hydrolytically, in the course of the fluorination reaction or durin~ processing of the reaction mixture, to give free hydroxyl groups and o.xo groups respectively. ~Iowever, ~or adeguate protection of the dihydroxyacetone side chain it suffices when one of the two hydroxyl groups is esterified by a carboxylic acid h~ving at least three carbon atcms, such as one of those mentioned above in particular pr~pianic acid, ~utyric acid or trimethyl-acetic acid. A protective group of such a siæe already sufices to keep the reagent away from both the hydrDxyl g~oups, i.e. both tL~ e~terified hy~roxyl group and :
.. . ,i ,~
. ~ . ~ ~ ' . ! . .
" . .' ' , .'~ ' - '- ' ' ~ ' ' ' ~ ' ' . , " ' ~ ,' ' . ' ~ '' .' , ' . ' . ' . ~ ' ,.
' ,' ~ . ' '. '. ~ I , .
~' . . ~ .' ' . ' ' , .
. ' , , . ~' ; ' ' ' ' ' . ' ' ~ ' ' ' the free hydroxyl group. Of course, the dihydroxyacetone side chain can be in the ~orm of a 17~,20;20,21-bis-methylene dioxy grouping. (The term "dihydroxyacetone side chain" is understood as ~eaning the 17~,21-dihydroxy-20 oxo-pregnane grouping.) m e groupings mentioned can subsequently be converted into the desired free groups in a known manner, for example by hydrolysis.
m e reactant (fluorinating agent) of the formula F3SX
is a disubstituted amino-sulphur trifluoride, i.é. an amino-sulphur trifluoride in which the nitrogen atom is bonded to -the sulphur atom and to two carbon atoms. Accordingly, the substi-tuents o~ the amino group are two identical or di~ferent open-chain or carbocyclic hydrocarbon radicals, which can be aromatic, and in particular are lower alkyl radicals, for example those mentioned above, or phenyl radicals, and the two radicals can be linked -to one another by a single C-C ~ond, by an oxygen bridge or by a lower alkylated nitrogen atom.
m e amino group designated by X is preferably a di-lower alkyl-amino group or lower alkyl~phenyl-amino group, such as the dimethylamino~ methylethylamino, methylpropylamino, me-thyl-phenylamino, ethylpropylamino, ethylphenylamino~ dipropylamino, diisopropylamino or dibutylamino group, or a pyrrolidino, piperidino, morpho].ino or N'-lower alkylpiperazino group~
which is unsubstituted or C~lower alkylated, such as an N'-me-thylpiperazino group, and symmetrical amino groups are particularly preferred~ In particular, this amino group is the piperidino, morpholino or diethylamino group,and the .
. . . ., ,,,. .; ,,. . ,".. ,,,.,~,," ,,,. ~, , - . ~ .. , , , . .
, . : ~ - - :
. , ~ .
' :'- ' :
.
corresponding fluorinating agent is piperidinosulphur tri-fluoride, morpholinos~lphur trifluoride or die-thylamino- -sulphur trifluoride respec-tively.
The reaction according -to the invention can be carried out in the presence of inert solvents or mixtures thereof.
The reaction temperature depends on -the specific properties of each reaction mixture and generally varies between about -8Q and about ~80 and preferably between about -15 and about +30; the reaction is advantageously carried out at between 0 and room temperature.
The inert solvents used are those which, under the reaction conditions employed 9 do not react irreversibly either with the reactants or wi-th the products. In particular, the following solvents can be used: carbocyclic hydrocarbons, for example saturated carbocyclic hydrocarbons, such as cyclo-pentane9 cyclohexane, cycloheptane and decahydronaphthalene, or aromatic carbocyclic hydrocarbons, such as benzene, toluene or xylenes, which can also be halogena-ted in the nucleus, such as chlorobenzene, dichlorobenzenes, bromobenzene or fluorobenzene, and especially aliphatic saturated hydrocarbons, preferably those whlch are liquid under atmospheric pressure and at room temperature, such as pentanes, hexanes, hep-tanes and octanes, or those which are halogena-ted, especially chlorinated, such as chloroform, 1,1- or 1,2-dichloroethane, 1,1-, 1~2- or 1,3-dichloropropane and, in particular, methylene chloride. Furthermore, aliphatic and especially cyclic ethers, such as diethyl ether, diisopropyl ether, ethylene , ., .
.
.. . . , . . . .. . , . .. . ,. . ,.. : .... ,.. ~., .~ . ,,:
..
:. . . . . ..
: . . :
. . . ~ .
, . .. . . : .
: , ~S~ 3 glycol dimethyl ether, tetrahydrofurane and~ in par-ticular, dioxane, and also nitrogen-containing aromatic heterocyclic compounds, such as pyridine and its homologues or quinoline, can also be used~ If desired, an excess of the fluorinating agent can be used as the solvent, and/or several of the sol-vents mentioned can be combined with one another.
The protected oxygen-containing functional groups in the resulting process products are subsequently set free in a manner which is known per se, preferably by hydrolysis.
Etherified hydroxyl groups are preferably hydrolysed under the conditions of acid catalysis in the presence of an inorganic acid, for example sulphuric acid or a hydrogen halide acid7 such as hydrochloric acid, hydrobromic acid or hydriodic acid, or of an organic acid, ~or example a sulphonic acid, such as p-toluenesulphonic acid or sulphosalicylic acid, or of a relatlvely s-trong carboxylic acid, such as oxalic acid or formic acid. Enol--ethers and ketals or acetals are also hydrolysed analogously to the corresponding oxo derivatives.
Carbonyl-containing ester groups of various types, whéther these be esterified hydroxyl groups, esterified carboxyl groups, enol-acyla-ted oxo groups or lactone groups, can be hydrolysed under acld conditions 7 preferably, however, they are hydrolysed by means of base catalysis. m e basic cata-lysts used are~ preferably, hydroxides, carbonates or bicar-bonates of the alkali metals9 especially o~ sodium or potassium.
As is known, it is also possible, by suitable choice of the reactants and conditi~ns, selectively to set ~ree individual :
, , ;, , ;. . . ~ , . :~
,'' '. ' ,, ' ~
;;
~s~
hydroxyl groups, for example of the two esterified hydroxyl groups .in a 17~,21-ortho-ester to set free only tha-t in the 21-position, -the hydroxyl group in the 17~-position remaining as a normal esterified hydroxyl group.
The subsequent esterification of hydroxyl groups in the resulting compounds is also ef~ected in a manner which is known per se. ThusJ for example, the compound -to be esteri-fied is treated with an excess o~ the acid itself, such as with formic acid, or with a reac-tive derivative -thereof, f`or example with a derivative of` one of the abovementioned acids, especially with an anhydride or acid halide J advantageously in the presence of a tertiary base, such as pyridine, qui.noline or N-ethyl-piperidine. Hydroxyl groups which are difficul-t to esterify, for example a -tertiary 17~-hydroxyl groupt can advantageously be esteri~ied with an acid anhydride under the catalytic action of organic sulphonic acids, for example benzenesulphonic acid, p~toluenesulphonic acid, salicyl-sulphonic acld or camphorsulphonic acid. In order to f`orm ortho-esters, ~especially those derived from 17a,21-dihydroxy compounds, the reaction is carried out in a known manner under the conditions of -transesterification, for example by treating a suitable compolmd having a free dihydroxyacetone side chain wi.th an excess of the desired orthocarboxylic acid ester, f`or exampIe trlethyl orthopropionate, in the presence of a s-trong acid. Advantageously, provision is made for the removal of`
the volatile lower alkanol which is set free.
The replacement of the sulphonyloxy group in the 21-::
.. , ~ ~ .. . .
'. , ' , .
. . .
-.
~ 3 position by a bromine atom or chlorine atom is also ef~ected in a manner which is known per se. The organi.c sulphonic acid by means of which the hydroxyl group is esterified is an aliphatic or carbocyclic sulphonic acid and can be saturated or unsaturated oris an aromatic sulphonic acid, such as an unsubstitu-ted or substi-tuted, for example halogenated, lower alkanesulphonic-acidg a cycloalkanesulphonic acid or camphor-sulphonic acid, or a benzenesulphonic acid which is unsub-stituted or substituted, for example by lower alkyl, lower alkoxy, halogen and/or nitro. Typical examples which may be men-tioned of these acids are -tri~luoromethanesulphonic acid, (~)-camphor-10-sulphonic acid-(~), p-bromobenzenesulphonic acid and~ especially, p-toluenesulphonic acid and in par-ticular methanesulphonic acidO The replacemen-t reaction is usually carried ou-t, ~or example, by treating the corresponding 21-sulphonic acid ester9 characterised above, at elevated tem- :
perature with an alkali metal bromide or. alkali metal chloride in the presence of an aprotic organic solvent which has a dielectric constant of 29 or above. Lithium is preferred as the alkali metal in this halide~ Solven-ts which can be used as an aprotic organic solvent which has a dielec-tric con-stant of 29 or above are, especially, dlalkylsulphoxides, such as dlmethylsulphoxide, N,N-dialkylamides of lower aliphatic carboxylic acids, such as N,N-dimethyl.formamide and N,N-dimethylacètamide, alkane~ni-triles and alk-2-ene-nitriles, such as acetoni-trile and propene nitrile re~ectively, and hexaalk~l~hos-pho~c acid al~ es,such ashexamethylphosphoric acid amide.
-:16 -.
... ...
.
Preferably, the reaction is carried ou-t in the presence of at least one molar equi~alent of this solvent, N,N-dime-thylform amide being par-ticularly preferred. The reaction is approp- -riately carried out at be~een 50 and the boiling poin-t of the reaction mix-ture and is effected with at least o~e molar equivalent o~ the alkali metal halide. It i~ a]so possible to dilute the reac-tion mixture with a fur-ther solvent; organic ketones, especially those of the aliphatic or carbocyclic series having 3 to 10 carbon atoms~ for example acetone,-2-butanone, 2- or 3-pentanone, 2-hexanone, 4-decanone, cyclo-pen-tanone or cyclohexanone, are advantageously used for this purpose. In the latter case, and especially when acetone is usedz the reaction can be carried out in this solvent,on its own and can even be carried out at room temperature.
It is also possible -to introduce double bonds into the resulting end products in a manner which is known per se.
For example, ~4-3-oxo compounds, which can be in the form of ~heir 3-enol-acylates or ~-enol-e-thers, can be reacted with dehydrogenating quinones, such as chlor~nil or, especially,
F
~ x i b R (I) S
in which St is the remaining part~ which can be substituted or unsubstituted and/or modi~ied in some other way, of the steroid skeleton, Rx is a free or ketalised oxo group, a substituted or unsubstituted lower alkylidene radical, a ~ree, etherified or esterified hydroxyl group -together wi-th a hydrogen a-tom or a subs-tituted or unsubstituted lower ali-phatic hydrocarbon radical, or a hydrogen a-tom together with a substituted or unsubstituted lower alkyl radical, and Ry is a lower alkylidene radical, a free, etherified or esterified hydroxyl group together with a hydrogen atom, a lower alkyl , radical together with a:h~drogen atom~ or two hydrogen atoms, it being possible for a 16~17-double bond to be present in place of one of the said hydrogen atoms in radical Rx and one of the said hydrogen atoms in radical R~
The term "lower" used -to qualify an organic radical:
signifies an organio radical having at most 7, but preferabl~
having 1 to L~, carbon atoms.
:The radical St oomprises the ring ~ (carbon atoms C-l to C-5 and C~10) and the remaining carbon atoms of ring B
:
: . :
: 2 ': ' '' , ' ' ' : ~. ' ., ' ,':' '., ' ' ' " '' ' , . ' .: ' ' ~ 3 (C-6 and C-7) and carries -the angular methyl group (C-l9) in -the 10 position. I-t can also be modified in some o-ther way, for example it can have a structure with expanded or contracted rings, such as the A-nor or A-nor-B-homo structure and/or ring bridging, for example the 3a,5-cyclo linkage.
The rings A and B can, with respect to one another, assume the 5a- or 5~-con~iguration. The radical St can contain one, -two or several double bonds, such as in the 1,2-, 2,3-, 3,4-or 6,7-positions, but in particular in -the 4,5- or 5l6~
positions. The radical St can also be substituted by free, etherified and, especially, esterified hydroxyl groups, for example in the 3- and/or 19-positions and in particular in the 3~-position, by free or ketalised oxo groups, especially in the 3-position, by lower alkyl radicals, for example in the 7a-position or especially the 6a-posi-tion, or by halogen atoms, such as bromine atoms or, especially, chlorine or fluorine atoms, especially in the 2-position and/or, in particular, in the 6a-position.
A lower alkyl radical is, for example,an n-propyl, 1-propyl, n-bu-tyl, i-bu-tyl, sec.-butyl or tert~-butyl radical or a branched or preferably straight~chain pen-tyl, hexyl or heptyl radical1 bu-t in particular an ethyl or methyl radical, A lower allphatic~hydrocarbon radical is a lower alkyl radi-cal, for example one of those already mentioned, or a corres-ponding radical which also contains one or two multiple bonds, i e. double bonds or triple bonds, for example a lower alkenyl, lower alkynyl and allenyl radical, for example a -- ~
.
.
~ - , . .
vinyl, allyl, methallyl, propargyl or hexadi~nyl radical and in particular an ethynyl radical. A lower alkylidene radical is a radical which corresponds to the abovementioned lower alkyl radicals or lower alkenyl radicals and is divalent on one carbon a-tom, such as an ethylidene or isopropylidene radical and in particular a methylene radical, or, alter-natively, a vinylidene radical.
The lower aliphatic hydrocarbon radical already dis-cussed and~ if desired, also the lower alkylidene radical can be substituted by one or more identical or different sub-stituents which, in par-ticular, are in the a--position and/or ~-position (corresponding to the 20-position and 21-position respectively in steroid numbering) Possible substituen-ts are halogen atoms, for example chlorine and fluorine, free, etherified and, especially, esterified hydroxyl groups, ~ree or ketalised oxo groups and ~ree or esterified carboxyl groups, and the carboxyl groups can also be in the form of their salts, especially alkali metal salts. An esterified car-boxyl group is, in particwlar, to be understood as meaning a oarboxyl group which .is in -the form of its ester, especially one of its esters wi-th lower alkanols, but also that carboxyl group which, together with a suitably dis-tant hydroxyl group, whlch is present as a substituent, closes a 6-membered or, especially 7 5-membered lactone ring.
A ketalised oxo group isde~ved,especially, from lower a].k.anols, for example from me-thanol or ethanol, or preferably from a- or ~-lower alkanediols, for example 1,2- or 1,3-_ 4 _:
. ' `
`;, , ,, ' '' :
` ' -propanediol, or, in particular~ e-thylene glycol; however, i-t can also be derived from the corresponding sulphur analogues of the said alcohols and con-tain sulphur atoms in place of one or both of the oxygen atoms.
An etherified hydroxyl group is derived, especially, from a lower alkanol, preferably a straight-chain lower alkanol, for example methanol, ethanol, propanol or butanol, from an aryl-lower alkanol, preferably a phenyl-lower alkanol, ~or example benzyl alcohol or triphenylmethylcarbinol, or from an oxygen-con-tainirlg heterocyclic alcohol, for example 2-tetrahydropyranol or 2-te-trahydrofuranol Formally, however, it can also be derived from a l-lower alkoxy lower alkanol, for example l-~utoxyethanol; the l-butoxye-thoxy group may be mentioned as an example of a hydroxyl group etherified in this way In respect of the general sense, a hydroxyl group of the t~pe present in an acetalised or ketalised vicinal steroid-diol, for example 16a,17a-diol, is also to be regarded as an e-therified hydroxyl group. The non-steroid structural component, which -then always links two such vicinal etherified hydroxyl groups, .is preferably a lower alipha-tic, cycloalipha-tic or arylaliphatic ketone, for example acetone, cyclopentanone, cyclohexanone, acetophenone or benzophenone, or an aldehyde, for example formaldehyde. The 17a,20;20,21~
bis-methylenedioxy grouping may also be mentioned as a special case of etherified hydroxyl groups.
An esteri.fied hydroxyl group is derived, especially, . from an inorganic oxygen containing acid, for example from one : ; - 5 ~
~ . .
of the sulphuric or phosphoric acids, or, preferably, from an organic acid, for example from a sulphonic acid,forexample,~xman aromatic sulphonic acid, such as benzenesulphonic acid, toluenesulphonic àcid or p-bromobenzenesulphonic aeid, or ~rom an alkanesulphonic acid, such as methanesulphonic acid, or, especially from a carboxylic acid. A lactonised hydroxyl group is also to be regarded as an esterified hydroxyl group.
From its mode of formation and cer-tain substitution reactions, a halogen atom, for example an iodine or bromin~ atom and~
especially a chlorine or fluorine a-tom, is also to be regarded, especially when it is in the 21-posi-tion, as a special case, which nevertheless ~alls in-to this category, of a hydroxyl group esterified by a strong acid; i~e. a hydroxyl group esterified by hydriodic acid, hydrobromic acid, hydrochloric aeid or hydrofluorie acid.
Aeids which are possible as the earboxylie acid eom-ponent o~ àn esterified hydroxyl group are, in particular, the earboxylic acids eustomary in s-teroid chemistry, including those in the form o~ the corresponding orthocarboxylic acids, for example monoearboxylic acids hàving at most 18 carbon atoms, such as aliphatic carboxylic aeids or orthoearboxylic aeids, espeeially formie aeid, or-thoformie aeid or a lower alkaneearboxylie acid or lower alkane-orthoearboxylie acid in whieh the lower alkyl radieal is one of those mentioned above~
in partieular propionic acid, butyrîe aeid, isobutyrie aeid, valerie aeid, isovalerie acid, oenanthie acid and diethylaeetie aeid and espeeially caproic aeld, trimethylacetic acid and .
-:
.
., .
.
~. . .
.'-' " ' ' ' ~ ; ~ . . ' .'.. ~' .
- , .: . .
~ 3 ace-tic acid, bu-t also corresponding halogenated lower alkane-carboxylic acids, such as chloroace-tic acid, trichloroacetic acid or trifl.uoroacetic acid, and also caprylic acid, pelargonic acid, capric acid, lauric acid, myris-tic acid, palmitic acid and stearic acid~ undecylic and undecylenic acids, elaidic acid and oleic acid; cycloaliphatic or cyclo-aliphatic-aliphatic monocarboxylic acids, for example cyclo-propanecarboxylic acid~ cyclobutanecarboxylic acid, cyclo-pen-tanecarboxylic acid and cyclohexanecarboxylic acid and cyclopropyl-methanecarboxylic acid or cyclobutyl-methane-carboxylic acid and a cyclopentyl-ethanecarboxylic acid or cyclohexyl-ethanecarboxylic acid; aromatic carboxylic acids, for example benzoic acids or orthobenzoic acids which are unsubstituted or substi-tuted by fluorine, chlorine9 bromine, hydroxyl, lower alkoxy, lower alkyl or nitro groups; aryl- or aryloxy-lower alkanecarboxylic acids and their analogues which are unsaturated in the chain, for example phenylacetic and phenoxyacetic acids, phenylpropionic acids and cinnamic acids which are unsubstituted or substituted as indicated above for benzoic acid; and heterocyclic acids, for example furane-2-carboxylic acid, 5-tert.-butyl~urane-2 carboxylic acid, 5-bromofurane~2-carboxylic acid, thiophene~2-carboxylic acid, nicotinic acid or isonicotinic acid or 3-~4-pyridyl)-propionic ac.id, and pyrrole-2- or -3-carboxylic acids which are unsub-stituted or substituted by lower alkyl radicals, but also .
corresponding dicarbo~lic acids having at most 12 carbon atoms~ for example succinic acid, glutaric acid, adipic acid .
.
- . -'.- ,~ .
5~`~3 and phthalic acid and also corresponding ~-aminoacids, especially ~-amino-lower alkanecarboxylic acids, preferably those in -the naturally occurring configura-tion, for example glycine, proline, leucine, valine, -tyrosine, histidine and asparagine, and also glutamic acid and aspartic acid.
When they are in a favourable position, for example when they are separated from one another by two or three carbon atoms, two hydroxyl groups can, together with one ~ole-cule of an orthocarboxylic acid, form cyclic esters, such as, especlally, in the case of ortho-esters of lower aliphatic ortho-acidswith 17~,21-dihydroxypregnane compounds. The third oxygen atom of the ortho acid functional group is then usually occupied by the radical of a lower alkanol, in particular by me-thyl or ethyl. Ortho-es-ters of ortho-carbonic acid with 17a,21-dihydroxypregnane compounds are also formed in an analogous manner~; in -this case, the central carbon atom also carries two lower alkoxy groups.
m e 9~-chloro~ fluoro-steroids prepared according to the invention are known as a category of compounds and can be used as intermediates ~or the synthesis o~ valuable pharma-ceutical active compounds, especially for the therapy of in~lamma-tory conditions and also for fertility control, or the compounds themselves show a biological activi-ty and, accord-ing].y, can be used direct as active compounds in the above-mentioned fields o~ applicationO
Hitherto, 9a-chloro-11~-fluoro~steroids were accessible from corresponcling 9(11)-unsa-turated star-ting materials by the : : ~ : . . .: . . . : :
.:. :. . . ~ -, . : . - , . .
- : : : :: ~ . :
simultaneous addi-tion of fluorine and chlorine, c.f., for example, U.S. Paten-t No. 2,894,963 and German Offenlegungs-schrift No. 2,053,14~. The addi-tion can be effected by reaction with fluorine monochloride; usually, however~ a N~
chloro-acylamide or -acylimide~ such as, especially, N-chloroacetamide or N-chlorosuccinimide, and anhydrous hydrogen ~luoride are allowed to act on -the s-tarting material at the same time The known aggressi~eness of the last~mentioned agent, both towards the starting materials to be reacted and towards the reaction vessels, already constitutes a grea-t dis-advantage, especially for the indust~1 opera-tion of the process;
moreoverS the course of the reac-tion is complicated by competing reactions, c~f., for example, J. Am. Chem. Soc. 82~
2308-2311 (1960), and the yields which can be achieved are low.
The process according to -the invention is not subject to such disadvantages: the halogenating agen-t of -the formula F3SX, which is characterised further belowg acts speci~ically under very mild conditions and within a short reaction time, which makes high yields possible, and, moreover, it does not ..
attack glass, so that conventional glass apparatus can be used without any di~ficulty.
The process according to the invention comprises the reaction o~ a 9a chloro~ h~dro~y-steroid, in which any carboxyl groups and hydroxyl groups which may be present are preferably -temporarily protected, with a compound o~ the formula F3SXt in which X is an amino group derived from a secondary amine.
_ g _ .
.
-:: . .
- - . ~ : . : . : ,,-: . : :
, Compounds.of the general fo-rmula ~ X
~ (II) ..
in which St, Rx and Ry are as defined above and any other hydroxyl groups and carboxyl groups which may be present are preferably in an esterified form, are preferred as starting materials~
Within the scope of the end products of the formula I, the resul-ting products are, if desired, converted into one another in a manner which is known per se, for example by setting ~ree protected functional groups~ such as, in particular, esterified carboxyl groups and esterified hydro~l groups, or by setting free the dihydroxyacetone side chain from the 17a,20;20,21 bis-methylenedioxy groupingO ~urther con-: versions customar~ in steroid chemistry can also be carried , out; 1n particular, ~hydroxyl groups can be esterified, ahydrox~l group in the 21~position esteriPied by an organic sulphonic acid can be replaced b~ a chlorine or bromine atom and/or ~urther double bonds can be introduced. ~hese sub-~equent conversi.ons can each be carried out independently or can be carried out in:appropriate combinations.
The course o~ the process according to the invention is very surprising because the reactant of the ~ormula F3SX
~hich is used reacts with the analogous 9a-fluoro~ hydroxy-- . :
- 10 - "
:':
':''' ' ", ', ' ~' ''.', .'' ' '' ' ' '. ' ' ' '~ ',' ' ' ''' '" ` ., . . ' ' "
, . . .. , ' , ' .'. , ~
. ' . ~ ~ . . . ' . . ~, . , , .
' ' ' ' ' ' ' ' " .' " " . . . '. '' . . .
' ' ' ~ ' ~ .
steroids with the formation of the 11,12-double bond exclusive~
ly, by detaching the hydroxyl group in the ll-position, c.f.
our United S-tates Patent 4,172,075.
The process according to the invention proceeds readily even under very mild reaction conditions, so that other functional groups usually remain unaffected. ~Iowever, it is recomm~nded that any car~oxyl groups which may be present in the starting materials of the formula II should be in an esterified form to protect them against convers.ion into an acid fluoride.
In the starting materials of the for.mula II, any hydnoxyl groups which may be present, with the e~ception of the ll~-h~droxyl group, which is to be reacted, should also be in a protected form such as an etherified or, preferably, esterified form during the reaction. Readily hydrolysable etherified hydroxyl groups, for example -tetrahydropyrany].oxy groups, and also ketalised oxo groups c~n be split hydrolytically, in the course of the fluorination reaction or durin~ processing of the reaction mixture, to give free hydroxyl groups and o.xo groups respectively. ~Iowever, ~or adeguate protection of the dihydroxyacetone side chain it suffices when one of the two hydroxyl groups is esterified by a carboxylic acid h~ving at least three carbon atcms, such as one of those mentioned above in particular pr~pianic acid, ~utyric acid or trimethyl-acetic acid. A protective group of such a siæe already sufices to keep the reagent away from both the hydrDxyl g~oups, i.e. both tL~ e~terified hy~roxyl group and :
.. . ,i ,~
. ~ . ~ ~ ' . ! . .
" . .' ' , .'~ ' - '- ' ' ~ ' ' ' ~ ' ' . , " ' ~ ,' ' . ' ~ '' .' , ' . ' . ' . ~ ' ,.
' ,' ~ . ' '. '. ~ I , .
~' . . ~ .' ' . ' ' , .
. ' , , . ~' ; ' ' ' ' ' . ' ' ~ ' ' ' the free hydroxyl group. Of course, the dihydroxyacetone side chain can be in the ~orm of a 17~,20;20,21-bis-methylene dioxy grouping. (The term "dihydroxyacetone side chain" is understood as ~eaning the 17~,21-dihydroxy-20 oxo-pregnane grouping.) m e groupings mentioned can subsequently be converted into the desired free groups in a known manner, for example by hydrolysis.
m e reactant (fluorinating agent) of the formula F3SX
is a disubstituted amino-sulphur trifluoride, i.é. an amino-sulphur trifluoride in which the nitrogen atom is bonded to -the sulphur atom and to two carbon atoms. Accordingly, the substi-tuents o~ the amino group are two identical or di~ferent open-chain or carbocyclic hydrocarbon radicals, which can be aromatic, and in particular are lower alkyl radicals, for example those mentioned above, or phenyl radicals, and the two radicals can be linked -to one another by a single C-C ~ond, by an oxygen bridge or by a lower alkylated nitrogen atom.
m e amino group designated by X is preferably a di-lower alkyl-amino group or lower alkyl~phenyl-amino group, such as the dimethylamino~ methylethylamino, methylpropylamino, me-thyl-phenylamino, ethylpropylamino, ethylphenylamino~ dipropylamino, diisopropylamino or dibutylamino group, or a pyrrolidino, piperidino, morpho].ino or N'-lower alkylpiperazino group~
which is unsubstituted or C~lower alkylated, such as an N'-me-thylpiperazino group, and symmetrical amino groups are particularly preferred~ In particular, this amino group is the piperidino, morpholino or diethylamino group,and the .
. . . ., ,,,. .; ,,. . ,".. ,,,.,~,," ,,,. ~, , - . ~ .. , , , . .
, . : ~ - - :
. , ~ .
' :'- ' :
.
corresponding fluorinating agent is piperidinosulphur tri-fluoride, morpholinos~lphur trifluoride or die-thylamino- -sulphur trifluoride respec-tively.
The reaction according -to the invention can be carried out in the presence of inert solvents or mixtures thereof.
The reaction temperature depends on -the specific properties of each reaction mixture and generally varies between about -8Q and about ~80 and preferably between about -15 and about +30; the reaction is advantageously carried out at between 0 and room temperature.
The inert solvents used are those which, under the reaction conditions employed 9 do not react irreversibly either with the reactants or wi-th the products. In particular, the following solvents can be used: carbocyclic hydrocarbons, for example saturated carbocyclic hydrocarbons, such as cyclo-pentane9 cyclohexane, cycloheptane and decahydronaphthalene, or aromatic carbocyclic hydrocarbons, such as benzene, toluene or xylenes, which can also be halogena-ted in the nucleus, such as chlorobenzene, dichlorobenzenes, bromobenzene or fluorobenzene, and especially aliphatic saturated hydrocarbons, preferably those whlch are liquid under atmospheric pressure and at room temperature, such as pentanes, hexanes, hep-tanes and octanes, or those which are halogena-ted, especially chlorinated, such as chloroform, 1,1- or 1,2-dichloroethane, 1,1-, 1~2- or 1,3-dichloropropane and, in particular, methylene chloride. Furthermore, aliphatic and especially cyclic ethers, such as diethyl ether, diisopropyl ether, ethylene , ., .
.
.. . . , . . . .. . , . .. . ,. . ,.. : .... ,.. ~., .~ . ,,:
..
:. . . . . ..
: . . :
. . . ~ .
, . .. . . : .
: , ~S~ 3 glycol dimethyl ether, tetrahydrofurane and~ in par-ticular, dioxane, and also nitrogen-containing aromatic heterocyclic compounds, such as pyridine and its homologues or quinoline, can also be used~ If desired, an excess of the fluorinating agent can be used as the solvent, and/or several of the sol-vents mentioned can be combined with one another.
The protected oxygen-containing functional groups in the resulting process products are subsequently set free in a manner which is known per se, preferably by hydrolysis.
Etherified hydroxyl groups are preferably hydrolysed under the conditions of acid catalysis in the presence of an inorganic acid, for example sulphuric acid or a hydrogen halide acid7 such as hydrochloric acid, hydrobromic acid or hydriodic acid, or of an organic acid, ~or example a sulphonic acid, such as p-toluenesulphonic acid or sulphosalicylic acid, or of a relatlvely s-trong carboxylic acid, such as oxalic acid or formic acid. Enol--ethers and ketals or acetals are also hydrolysed analogously to the corresponding oxo derivatives.
Carbonyl-containing ester groups of various types, whéther these be esterified hydroxyl groups, esterified carboxyl groups, enol-acyla-ted oxo groups or lactone groups, can be hydrolysed under acld conditions 7 preferably, however, they are hydrolysed by means of base catalysis. m e basic cata-lysts used are~ preferably, hydroxides, carbonates or bicar-bonates of the alkali metals9 especially o~ sodium or potassium.
As is known, it is also possible, by suitable choice of the reactants and conditi~ns, selectively to set ~ree individual :
, , ;, , ;. . . ~ , . :~
,'' '. ' ,, ' ~
;;
~s~
hydroxyl groups, for example of the two esterified hydroxyl groups .in a 17~,21-ortho-ester to set free only tha-t in the 21-position, -the hydroxyl group in the 17~-position remaining as a normal esterified hydroxyl group.
The subsequent esterification of hydroxyl groups in the resulting compounds is also ef~ected in a manner which is known per se. ThusJ for example, the compound -to be esteri-fied is treated with an excess o~ the acid itself, such as with formic acid, or with a reac-tive derivative -thereof, f`or example with a derivative of` one of the abovementioned acids, especially with an anhydride or acid halide J advantageously in the presence of a tertiary base, such as pyridine, qui.noline or N-ethyl-piperidine. Hydroxyl groups which are difficul-t to esterify, for example a -tertiary 17~-hydroxyl groupt can advantageously be esteri~ied with an acid anhydride under the catalytic action of organic sulphonic acids, for example benzenesulphonic acid, p~toluenesulphonic acid, salicyl-sulphonic acld or camphorsulphonic acid. In order to f`orm ortho-esters, ~especially those derived from 17a,21-dihydroxy compounds, the reaction is carried out in a known manner under the conditions of -transesterification, for example by treating a suitable compolmd having a free dihydroxyacetone side chain wi.th an excess of the desired orthocarboxylic acid ester, f`or exampIe trlethyl orthopropionate, in the presence of a s-trong acid. Advantageously, provision is made for the removal of`
the volatile lower alkanol which is set free.
The replacement of the sulphonyloxy group in the 21-::
.. , ~ ~ .. . .
'. , ' , .
. . .
-.
~ 3 position by a bromine atom or chlorine atom is also ef~ected in a manner which is known per se. The organi.c sulphonic acid by means of which the hydroxyl group is esterified is an aliphatic or carbocyclic sulphonic acid and can be saturated or unsaturated oris an aromatic sulphonic acid, such as an unsubstitu-ted or substi-tuted, for example halogenated, lower alkanesulphonic-acidg a cycloalkanesulphonic acid or camphor-sulphonic acid, or a benzenesulphonic acid which is unsub-stituted or substituted, for example by lower alkyl, lower alkoxy, halogen and/or nitro. Typical examples which may be men-tioned of these acids are -tri~luoromethanesulphonic acid, (~)-camphor-10-sulphonic acid-(~), p-bromobenzenesulphonic acid and~ especially, p-toluenesulphonic acid and in par-ticular methanesulphonic acidO The replacemen-t reaction is usually carried ou-t, ~or example, by treating the corresponding 21-sulphonic acid ester9 characterised above, at elevated tem- :
perature with an alkali metal bromide or. alkali metal chloride in the presence of an aprotic organic solvent which has a dielectric constant of 29 or above. Lithium is preferred as the alkali metal in this halide~ Solven-ts which can be used as an aprotic organic solvent which has a dielec-tric con-stant of 29 or above are, especially, dlalkylsulphoxides, such as dlmethylsulphoxide, N,N-dialkylamides of lower aliphatic carboxylic acids, such as N,N-dimethyl.formamide and N,N-dimethylacètamide, alkane~ni-triles and alk-2-ene-nitriles, such as acetoni-trile and propene nitrile re~ectively, and hexaalk~l~hos-pho~c acid al~ es,such ashexamethylphosphoric acid amide.
-:16 -.
... ...
.
Preferably, the reaction is carried ou-t in the presence of at least one molar equi~alent of this solvent, N,N-dime-thylform amide being par-ticularly preferred. The reaction is approp- -riately carried out at be~een 50 and the boiling poin-t of the reaction mix-ture and is effected with at least o~e molar equivalent o~ the alkali metal halide. It i~ a]so possible to dilute the reac-tion mixture with a fur-ther solvent; organic ketones, especially those of the aliphatic or carbocyclic series having 3 to 10 carbon atoms~ for example acetone,-2-butanone, 2- or 3-pentanone, 2-hexanone, 4-decanone, cyclo-pen-tanone or cyclohexanone, are advantageously used for this purpose. In the latter case, and especially when acetone is usedz the reaction can be carried out in this solvent,on its own and can even be carried out at room temperature.
It is also possible -to introduce double bonds into the resulting end products in a manner which is known per se.
For example, ~4-3-oxo compounds, which can be in the form of ~heir 3-enol-acylates or ~-enol-e-thers, can be reacted with dehydrogenating quinones, such as chlor~nil or, especially,
2,3-dlchloro-5,6-dicyano-1,4 benzoquinone, and, depending on the choice of the reaction conditions, which are known per se, this results in the ~ormation of a 6,7- and/or 1,2-double bond.
The 1,2-dehydrogenation o~ ~4-3-ketones can also be achieved in a man~er which is known per se, by treatment with selenium dioxide, or microbiologically, for example b~ means of the micro-organisms Corynebacterium simplex or Septomyxa affinis; 697-dehydrogenation is also achieved by reacting an ' - ~7 -.
,, . -- , ~ . . .
.. - . ~. . . . . .
- . ..
enol-e-ther of ~ ~4-3-ke-tone wi.th manganese dioxide.
Compounds of par-ticular in-terest amongst the 9a-chloro-fluoro-steroids ob-tainable according -to the invention are those of the general formula IA
fH~Rl~
R5 ~ ~ 9 (I~) . 7 in which R5 is a hydrogen atom, an a-oriented me-thyl radical or5 if a 1,2-double bond is presen-t, a chlorine atom, R6 is an oxo group or a hydrogen atom toge-ther with a free or esteri~ied hydroxyl group~ R7 is a hydrogen atom, a methyl radical or a halogen atom, R8 is two hydrogen atoms, a methylene radical or a hydrogen atom together with an a- or ~-oriented methyl radi--. cal or an à~oriented free hydroxyl group, Rg is a hydrogen atom or a ~ree or esterified hydroxyl group and R1o is two hydrogen ~.
atoms, a free, hydrated or acetalised oxo group or a hydrogen atom toge-ther with a free, esterified or etherified hydroxyl group7 and in which~one double bond can be present in the 1~2-position and/or the 697-position, and in which the 16a~17a-diol grouping, which may be present, can be ke-talised or acetalised by an oxo compound of the formula R11-CO-R12, in which Rll and R12 .independently of one another are a hydrogen : .
- . . ~
- : . . , ... ~. :
I . .
' ': ' ' ; ~ .
.
~ 3 a-tom or a lower alkyl, phenyl or benzyl radical, or together form the tetramethylene or pentamethylene radical. 1`hese compounds are dis-tinguished by valuable hormone-like properties and can -therefore be used in place of natural hormones, or their known analo~ues, in corresponding specific indica-tions.
m ose compounds of the general formula IA in which R5 is a hydrogen atom or9 if a 1,2-double bond is present, a chiorine atom, R6 is an oxo group~ R7 is a hydrogen atom or a fluorine atom, R8 is two hydrogen atoms or a ~ydrogen atom together with a hydroxyl group in the ~-position or a me-thyl radical in the ~- or a-position9 Rg and Rlo independently are each a free hydroxyl group or an asterified hydro~yl group, especially a hydroxyl group esteri~ied by a lower alkane-carboxylic acid, and in which -the l,Z-double bond is preferably present, are particularly valuable as analogues of -the adreno-corticotrophic hormones. The 16,17-ketals, especially acetonides, cyclopentanonides, cyclohexanonides and aceto-phenides of those compounds which have already been mentioned as preferred and which have a hydroxyl group in the 16~-.
posi-tion and in the 17a-position, are also preferred.
Furthermore, the compounds of the formula IA in which R5, R6, R7 and R1o have the preferred meanings already indicated, R8 is hydrogen together with a methyl group and Rg is hydrogen are also preferred. Because o~ their anti-inflammatory activity? in particular, these compounds are especially valu-able. Some typical representatives of these preferred com-pounds are indicated in the examples; where they are novel, : : .
- 19 _ -- . - . . . . - .. .: : . .
: . . . : .
. . : .. - . , ~ , . : . :
..
: ~ . : . ~ , . . . ..
- . , . .. , -, , , ~ :
.: - - . . .
these compounds are also a subject of the invention. The compounds of the formula IA9 characterised above, are in general obtainable direct from the corresponding ll~-hydroxy-9a-chloro compounds by the fluorination process according to the invention, with the proviso that the other free hydroxyl groups are protected in a suitable manner, for example by esterification. It is to be noted that, for adequate pro-tection of ~he two hydroxyl groups in the 17~-position and the 21-position3 it suffices when only one o~ the t~o hydroxyl groups, it being irrespective which group) is esterified by a carboxylic acid having at least 3 carbon a-toms, such as propionic acid? bu-tyric acid, valeric acid or trime-thylacetic acid~ If compounds oX the formula IA which contain free hydroxyl groups are desired, they are obtained ~rom the corres-ponding esters or ethers by hydrolysis, pre~erably in the manner described initially. Conversely, in compounds which contain free hydroxyl groups, these groups can be esterified in a known manner, or the 16a,17~-diol grouping can be ketalised or acetalised. If desired, the 1,2-double bond can also be introduced into a resulting compound which is satura-ted in the corresponding positions; advantageously, the dehydrogena-tion methods mentioned initially are used for this purpose.
If desired, compounds of the ~ormula IA in which Rlo is a hydrogen atom together with a hydroxyl group esterified by an organic sulphonic acid can be converted in a manner which is known per se, preferably as described initially, into corres-ponding 21-chloro- or 21-bromo-compounds of the formula IA in :.
,, ,: . , ~3 which Rlo is a chlorine atom or bromine a-tom -together with a hydrogen atom. The compounds of the general formula IA
are also obtained when corresponding compounds, in which one or more oxo groups are presen-t in the form of a ketal, enol-ether or enol-acylate, are hydrolysed in a manner which is knowm per se, especially as described above. The compounds of the formula IA in which Rg is a ~ree hydroxyl group and Rlo is a hydrogen atom together with a ~ree hydroxyl group are also obtained when a corresponding 17~,20;20921-bis-meth~lene-dioxy-pregnane compound is saponified. Preferred conditions for this reaction are -those o~ acid-catalysed hydrolysis, for example by means o~ a dilute lower aliphatic carboxylic acid, such as formic acid or acetic acid, or by means o~ hydrofluoric acid9 if appropria-te in the presence of urea.
The invention also relates to those embodiments of the above process in which a compound obtainàble as an intermediate a-t any s-tage is used as the starting material and the missing steps are carried out, or in which a star-ting material is formed under the reaotion conditlons.
The starting ma-terials ~or the processes of -the present invention are known or can be prepared in a manner which is known per se. Appropriately, those startln~ materials which contain the substituents mentioned in particular above, and especially those which result in the end products described specifically or singled out by formulae, are used.
I~e present invention also relates to the preparation of pharmaceutical formulations which contain the novel :
~ 21 -. : . :.. . - ~ . . ..
.:
. . . . .. . .
:, , , , , , , : - :
. . - - , ; - . . .
f~5~P3 pharmacologically active compounds, d-escribed above, of the present invention as active substances~ toge-ther with a pharmaceu-tical excipient. The excipients used are organic or inorganic subs-tances which are suitable for enteral, for example oral, or paren-teral administration or ~or topical application. Substances which can be used as the excipients are those substances which do not react with the novel com pounds, for example water, gela-tineg lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols9 gum, poly-alkylene glycols, whi-te petroleum jelly, cholesterol and other known medicinal excipients. The pharmaceutical ~or~ulations can be in a solid form, for example in the form of tablets, dragees or capsules, or in a liquid or semi-liquid form, as solutionsg suspensions, emulsions, ointments or creams.
I~ desired7 these pharmaceu-tlcal ~ormulations are sterilised and/or contain auxiliaries, such as preservatives, s-tabilisers, wetting agents or emulsifiers~ salts for regulating the osmo-tic pressure or bu~fers. ~ley can also contain yet further therapeutically valuable or biologically active compounds.
The invention is described in more detail in the examples which ~ollow7 without its scope being restricted as a result. m e temperatures are given in degrees centigrade.
~a~ .
A solution o~ 115 mg of 9~-chloro~ hydroxy-1,4-pregnadiene-3,20-dione in 5 ml o~ methylene chloride is cooled to -60, while passing dry nitrogen over the solution, and trea-ted with 0.1 ml o~ piperidinosulphur trifluoride. The .
, .. .. ' '. ~ ', ', , ' ;
- . , , - - . ...... . . . . .
. .
S~3 reaction mix-ture is stirred for 5 hours a-t cons-tant tempera-ture and then -treated wi-th wa-ter and a saturated solution o~
sodium bicarbona-te. The product is taken up in methylene chloride and the aqueous phase is then extracted with methylene chloride. The organic phases are washed with water, dried and evaporated under a waterpump vacuum~ m e yellowish crude product which is obtained is purified by chromatography on silica gel using toluene/e-thyl acetate (93:7) as the solvent and by -this means it gives 9a-chloro-11~-fluoro-1,4~
pregnadiene-3,20~dione, which a~-ter recrystallising twice from methylene chloride/petroleum ether 9 melts at 218-220.
Exam~
A solutions which has been cooled to 4, of 2.0 g o~
9a-chloro-6a-fluoro~ ,17,21-trihyclroxy-16a-methyl-1,4-pregna-diene-3,20-dione 17,21-diacetate in 30 ml o~ dioxane is treated, under a nitrogen a-tmosphere? wi-th 1.6 ~1 of diethyl-aminosulphur trifluoride and the mixture is stirred for 2 hours at 4. The reaction mixture is poured into ice-cold sodium bicarbonate solution,and -the produc-t is taken up in ethyl ~cetate, the organic phase is washed until neutral, the aqueous phase is further extracted and the organic phase is dried and evaporated under a waterpump vacuum. The residue is dis-solved in a small amount of methylene chloride and chromato-graphed on 50 times the amount by weight of silica gel.
Elution with a mixture of hexane/ethyl ace-tate (2:1) gives 9a-chloro-6a~ difluoro-17~21 dihydroxy~l6a methyl-1,4-pregna-diene-3,20-d1one diacetate, which a~ter rec-rystal]isation from :
.
- . . . ~ ~ .
,......... , .. ~ ... . . . .. . . ..
.
- ~ .
.. . , ,, . :,:
~ 3 methylene chloride/ether melts at 252-254.
A solu-tion of 1.5 g of 9a-chloro-6a ~luoro~ ,17,21-trihydroxy-16~~methyl-1,4-pregnadiene-3,20 dione 21-valerate in 15 ml of absolute dioxane is treated, at 4-6 under an argon atmosphere, with 1.3 ml o~ piperidinosulphur tri~luoride and the mixture is stirred for 2 hours. The reaction mixture is poured into ice-cold sodium bicarbonate solution, the produc-t is taken up in methylene chloride and the organic phase is washed until neutral. The dried organic phase is evaporated under a waterpump vacuum and -the crystalline resldue is taken up in a little methylene chloride and chromatographed on 50 times the amount by weight of silica gel. 9~-Chloro 6a,11~-difluoro-17,21-dihydroxy~16~-methyl-1,4~pregnadiene-3,20-dione 21-valerate, which is eluted with hexane/ethyl acetate (3~
melts, after recrystallisation from methylene chloride/acetone, at 170 173.
~ . ' ' A solution of 570 mg of 2,9~-dichloro-6u-fluoro-11~, 17,21-trihydroxy-16~-methyl-1~4-pregnadiene-3,20-dione 17,21-dipropiona-te in a mixture o~ 5 ml of dioxane and 10 ml o~
methylene chloride is cooled to about 4 and treated with 0.4 ml of piperidinosulphur trifluoride and the mixture is stirred for 2 hours at constant temperature. I'he reaction mixture is then poured into ice-water and extracted twice with .ethyl acetate,and the organic phases are washed with a satura-ted solutlon o~ sodium chloride, dried and evaporated under a .:
~ - 2~ -, .' '- ' ,',: :' - , , ~. .
~ 3 waterpump vacuum. After purifica-tion by chroma-tography and subsequent recrys-tallisation from methylene chlorlde/ether, the resulting 2,9a-dichloro-6a,11~~di:Eluoro-17,21-dihydroxy-16~-me-thyl-1,4-pregnadiene-3,20-dione dipropionate melts at 164-165.
Example~5 A solution, which has been cooled -to -40, o~ 500 mg vf 2,9u-dichloro-6a-~luoro~ ,1;7,21-trihydroxy-16u-me-thyl-1,4-pregnadiene-3,20-dione 21~trimethylaceta-te in 25 ml of methylene chloride is -treated with 0.4 ml of p~peridinosulphur trifluoride and the mixture is stirred for 2~ hours at -40 -to 30. m e reaction mixture is then poured in-to an ice-cold solution of sodium bicarbonate and ex-tracted with methyl-ene chloride,and the organic extracts are dried and evaporated under a waterpump vacuum. Chromatography on ~0 times the amount by weight o~ silica gel using -toluene/ethyl acetate (95:5) as -the solventt and subsequen-t crystallisation from ethyl acetate/hexane, gi~es 2,9a dichloro-6a,11~-difluoro-17~21-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione 21-trimethylacetate which melts at 226-228~
In a manner analogous to that described in Example ~
or 5, 2,9a-dichloro~6a-~luoro-11~917,21-trihydroxy-16a-methyl-1,4 pregnadiene-3,20-dione 17,21-ethylorthopropionate is con-.
verted into 2~9a-dichloro~6a,11~-di~luoro-17,21-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione 17,21-ethylorthopropionate, which has a melting point o~ 200~202.
.
:
' '.' :.,~.'''.
' , ' " , ~ 3 xam~ 7 In a manner analogous to that described in Example 5, 9~-chloro~11~,17,21--trihydroxy-16~-methyl-1,4-pregnadiene~
The 1,2-dehydrogenation o~ ~4-3-ketones can also be achieved in a man~er which is known per se, by treatment with selenium dioxide, or microbiologically, for example b~ means of the micro-organisms Corynebacterium simplex or Septomyxa affinis; 697-dehydrogenation is also achieved by reacting an ' - ~7 -.
,, . -- , ~ . . .
.. - . ~. . . . . .
- . ..
enol-e-ther of ~ ~4-3-ke-tone wi.th manganese dioxide.
Compounds of par-ticular in-terest amongst the 9a-chloro-fluoro-steroids ob-tainable according -to the invention are those of the general formula IA
fH~Rl~
R5 ~ ~ 9 (I~) . 7 in which R5 is a hydrogen atom, an a-oriented me-thyl radical or5 if a 1,2-double bond is presen-t, a chlorine atom, R6 is an oxo group or a hydrogen atom toge-ther with a free or esteri~ied hydroxyl group~ R7 is a hydrogen atom, a methyl radical or a halogen atom, R8 is two hydrogen atoms, a methylene radical or a hydrogen atom together with an a- or ~-oriented methyl radi--. cal or an à~oriented free hydroxyl group, Rg is a hydrogen atom or a ~ree or esterified hydroxyl group and R1o is two hydrogen ~.
atoms, a free, hydrated or acetalised oxo group or a hydrogen atom toge-ther with a free, esterified or etherified hydroxyl group7 and in which~one double bond can be present in the 1~2-position and/or the 697-position, and in which the 16a~17a-diol grouping, which may be present, can be ke-talised or acetalised by an oxo compound of the formula R11-CO-R12, in which Rll and R12 .independently of one another are a hydrogen : .
- . . ~
- : . . , ... ~. :
I . .
' ': ' ' ; ~ .
.
~ 3 a-tom or a lower alkyl, phenyl or benzyl radical, or together form the tetramethylene or pentamethylene radical. 1`hese compounds are dis-tinguished by valuable hormone-like properties and can -therefore be used in place of natural hormones, or their known analo~ues, in corresponding specific indica-tions.
m ose compounds of the general formula IA in which R5 is a hydrogen atom or9 if a 1,2-double bond is present, a chiorine atom, R6 is an oxo group~ R7 is a hydrogen atom or a fluorine atom, R8 is two hydrogen atoms or a ~ydrogen atom together with a hydroxyl group in the ~-position or a me-thyl radical in the ~- or a-position9 Rg and Rlo independently are each a free hydroxyl group or an asterified hydro~yl group, especially a hydroxyl group esteri~ied by a lower alkane-carboxylic acid, and in which -the l,Z-double bond is preferably present, are particularly valuable as analogues of -the adreno-corticotrophic hormones. The 16,17-ketals, especially acetonides, cyclopentanonides, cyclohexanonides and aceto-phenides of those compounds which have already been mentioned as preferred and which have a hydroxyl group in the 16~-.
posi-tion and in the 17a-position, are also preferred.
Furthermore, the compounds of the formula IA in which R5, R6, R7 and R1o have the preferred meanings already indicated, R8 is hydrogen together with a methyl group and Rg is hydrogen are also preferred. Because o~ their anti-inflammatory activity? in particular, these compounds are especially valu-able. Some typical representatives of these preferred com-pounds are indicated in the examples; where they are novel, : : .
- 19 _ -- . - . . . . - .. .: : . .
: . . . : .
. . : .. - . , ~ , . : . :
..
: ~ . : . ~ , . . . ..
- . , . .. , -, , , ~ :
.: - - . . .
these compounds are also a subject of the invention. The compounds of the formula IA9 characterised above, are in general obtainable direct from the corresponding ll~-hydroxy-9a-chloro compounds by the fluorination process according to the invention, with the proviso that the other free hydroxyl groups are protected in a suitable manner, for example by esterification. It is to be noted that, for adequate pro-tection of ~he two hydroxyl groups in the 17~-position and the 21-position3 it suffices when only one o~ the t~o hydroxyl groups, it being irrespective which group) is esterified by a carboxylic acid having at least 3 carbon a-toms, such as propionic acid? bu-tyric acid, valeric acid or trime-thylacetic acid~ If compounds oX the formula IA which contain free hydroxyl groups are desired, they are obtained ~rom the corres-ponding esters or ethers by hydrolysis, pre~erably in the manner described initially. Conversely, in compounds which contain free hydroxyl groups, these groups can be esterified in a known manner, or the 16a,17~-diol grouping can be ketalised or acetalised. If desired, the 1,2-double bond can also be introduced into a resulting compound which is satura-ted in the corresponding positions; advantageously, the dehydrogena-tion methods mentioned initially are used for this purpose.
If desired, compounds of the ~ormula IA in which Rlo is a hydrogen atom together with a hydroxyl group esterified by an organic sulphonic acid can be converted in a manner which is known per se, preferably as described initially, into corres-ponding 21-chloro- or 21-bromo-compounds of the formula IA in :.
,, ,: . , ~3 which Rlo is a chlorine atom or bromine a-tom -together with a hydrogen atom. The compounds of the general formula IA
are also obtained when corresponding compounds, in which one or more oxo groups are presen-t in the form of a ketal, enol-ether or enol-acylate, are hydrolysed in a manner which is knowm per se, especially as described above. The compounds of the formula IA in which Rg is a ~ree hydroxyl group and Rlo is a hydrogen atom together with a ~ree hydroxyl group are also obtained when a corresponding 17~,20;20921-bis-meth~lene-dioxy-pregnane compound is saponified. Preferred conditions for this reaction are -those o~ acid-catalysed hydrolysis, for example by means o~ a dilute lower aliphatic carboxylic acid, such as formic acid or acetic acid, or by means o~ hydrofluoric acid9 if appropria-te in the presence of urea.
The invention also relates to those embodiments of the above process in which a compound obtainàble as an intermediate a-t any s-tage is used as the starting material and the missing steps are carried out, or in which a star-ting material is formed under the reaotion conditlons.
The starting ma-terials ~or the processes of -the present invention are known or can be prepared in a manner which is known per se. Appropriately, those startln~ materials which contain the substituents mentioned in particular above, and especially those which result in the end products described specifically or singled out by formulae, are used.
I~e present invention also relates to the preparation of pharmaceutical formulations which contain the novel :
~ 21 -. : . :.. . - ~ . . ..
.:
. . . . .. . .
:, , , , , , , : - :
. . - - , ; - . . .
f~5~P3 pharmacologically active compounds, d-escribed above, of the present invention as active substances~ toge-ther with a pharmaceu-tical excipient. The excipients used are organic or inorganic subs-tances which are suitable for enteral, for example oral, or paren-teral administration or ~or topical application. Substances which can be used as the excipients are those substances which do not react with the novel com pounds, for example water, gela-tineg lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols9 gum, poly-alkylene glycols, whi-te petroleum jelly, cholesterol and other known medicinal excipients. The pharmaceutical ~or~ulations can be in a solid form, for example in the form of tablets, dragees or capsules, or in a liquid or semi-liquid form, as solutionsg suspensions, emulsions, ointments or creams.
I~ desired7 these pharmaceu-tlcal ~ormulations are sterilised and/or contain auxiliaries, such as preservatives, s-tabilisers, wetting agents or emulsifiers~ salts for regulating the osmo-tic pressure or bu~fers. ~ley can also contain yet further therapeutically valuable or biologically active compounds.
The invention is described in more detail in the examples which ~ollow7 without its scope being restricted as a result. m e temperatures are given in degrees centigrade.
~a~ .
A solution o~ 115 mg of 9~-chloro~ hydroxy-1,4-pregnadiene-3,20-dione in 5 ml o~ methylene chloride is cooled to -60, while passing dry nitrogen over the solution, and trea-ted with 0.1 ml o~ piperidinosulphur trifluoride. The .
, .. .. ' '. ~ ', ', , ' ;
- . , , - - . ...... . . . . .
. .
S~3 reaction mix-ture is stirred for 5 hours a-t cons-tant tempera-ture and then -treated wi-th wa-ter and a saturated solution o~
sodium bicarbona-te. The product is taken up in methylene chloride and the aqueous phase is then extracted with methylene chloride. The organic phases are washed with water, dried and evaporated under a waterpump vacuum~ m e yellowish crude product which is obtained is purified by chromatography on silica gel using toluene/e-thyl acetate (93:7) as the solvent and by -this means it gives 9a-chloro-11~-fluoro-1,4~
pregnadiene-3,20~dione, which a~-ter recrystallising twice from methylene chloride/petroleum ether 9 melts at 218-220.
Exam~
A solutions which has been cooled to 4, of 2.0 g o~
9a-chloro-6a-fluoro~ ,17,21-trihyclroxy-16a-methyl-1,4-pregna-diene-3,20-dione 17,21-diacetate in 30 ml o~ dioxane is treated, under a nitrogen a-tmosphere? wi-th 1.6 ~1 of diethyl-aminosulphur trifluoride and the mixture is stirred for 2 hours at 4. The reaction mixture is poured into ice-cold sodium bicarbonate solution,and -the produc-t is taken up in ethyl ~cetate, the organic phase is washed until neutral, the aqueous phase is further extracted and the organic phase is dried and evaporated under a waterpump vacuum. The residue is dis-solved in a small amount of methylene chloride and chromato-graphed on 50 times the amount by weight of silica gel.
Elution with a mixture of hexane/ethyl ace-tate (2:1) gives 9a-chloro-6a~ difluoro-17~21 dihydroxy~l6a methyl-1,4-pregna-diene-3,20-d1one diacetate, which a~ter rec-rystal]isation from :
.
- . . . ~ ~ .
,......... , .. ~ ... . . . .. . . ..
.
- ~ .
.. . , ,, . :,:
~ 3 methylene chloride/ether melts at 252-254.
A solu-tion of 1.5 g of 9a-chloro-6a ~luoro~ ,17,21-trihydroxy-16~~methyl-1,4-pregnadiene-3,20 dione 21-valerate in 15 ml of absolute dioxane is treated, at 4-6 under an argon atmosphere, with 1.3 ml o~ piperidinosulphur tri~luoride and the mixture is stirred for 2 hours. The reaction mixture is poured into ice-cold sodium bicarbonate solution, the produc-t is taken up in methylene chloride and the organic phase is washed until neutral. The dried organic phase is evaporated under a waterpump vacuum and -the crystalline resldue is taken up in a little methylene chloride and chromatographed on 50 times the amount by weight of silica gel. 9~-Chloro 6a,11~-difluoro-17,21-dihydroxy~16~-methyl-1,4~pregnadiene-3,20-dione 21-valerate, which is eluted with hexane/ethyl acetate (3~
melts, after recrystallisation from methylene chloride/acetone, at 170 173.
~ . ' ' A solution of 570 mg of 2,9~-dichloro-6u-fluoro-11~, 17,21-trihydroxy-16~-methyl-1~4-pregnadiene-3,20-dione 17,21-dipropiona-te in a mixture o~ 5 ml of dioxane and 10 ml o~
methylene chloride is cooled to about 4 and treated with 0.4 ml of piperidinosulphur trifluoride and the mixture is stirred for 2 hours at constant temperature. I'he reaction mixture is then poured into ice-water and extracted twice with .ethyl acetate,and the organic phases are washed with a satura-ted solutlon o~ sodium chloride, dried and evaporated under a .:
~ - 2~ -, .' '- ' ,',: :' - , , ~. .
~ 3 waterpump vacuum. After purifica-tion by chroma-tography and subsequent recrys-tallisation from methylene chlorlde/ether, the resulting 2,9a-dichloro-6a,11~~di:Eluoro-17,21-dihydroxy-16~-me-thyl-1,4-pregnadiene-3,20-dione dipropionate melts at 164-165.
Example~5 A solution, which has been cooled -to -40, o~ 500 mg vf 2,9u-dichloro-6a-~luoro~ ,1;7,21-trihydroxy-16u-me-thyl-1,4-pregnadiene-3,20-dione 21~trimethylaceta-te in 25 ml of methylene chloride is -treated with 0.4 ml of p~peridinosulphur trifluoride and the mixture is stirred for 2~ hours at -40 -to 30. m e reaction mixture is then poured in-to an ice-cold solution of sodium bicarbonate and ex-tracted with methyl-ene chloride,and the organic extracts are dried and evaporated under a waterpump vacuum. Chromatography on ~0 times the amount by weight o~ silica gel using -toluene/ethyl acetate (95:5) as -the solventt and subsequen-t crystallisation from ethyl acetate/hexane, gi~es 2,9a dichloro-6a,11~-difluoro-17~21-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione 21-trimethylacetate which melts at 226-228~
In a manner analogous to that described in Example ~
or 5, 2,9a-dichloro~6a-~luoro-11~917,21-trihydroxy-16a-methyl-1,4 pregnadiene-3,20-dione 17,21-ethylorthopropionate is con-.
verted into 2~9a-dichloro~6a,11~-di~luoro-17,21-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione 17,21-ethylorthopropionate, which has a melting point o~ 200~202.
.
:
' '.' :.,~.'''.
' , ' " , ~ 3 xam~ 7 In a manner analogous to that described in Example 5, 9~-chloro~11~,17,21--trihydroxy-16~-methyl-1,4-pregnadiene~
3,20-dione 17,21-dipropionate is converted in-to 9~chloro~
fluoro-17,21-dihydroxy-16~-methyl-1,4-pregnadiene-3,20-dione dipropionate, which has a mel-ting point of 160-162.
,, ~ - 26 -:: :
-., .. -. . . .
.
fluoro-17,21-dihydroxy-16~-methyl-1,4-pregnadiene-3,20-dione dipropionate, which has a mel-ting point of 160-162.
,, ~ - 26 -:: :
-., .. -. . . .
.
Claims (14)
1. A process for the preparation of 9.alpha.-chloro-11.beta.-fluoro-steroids, wherein a 9.alpha.-chloro-11.beta.-hydroxy-steroid is reacted with a compound of the formula F3SX, in which X is an amino group derived from a secondary amine.
2. A process according to claim 1 for the preparation of a compound of the general formula I
(I) in which St is the remaining part, which can be substituted or unsubstituted and/or modified in some other way, of the steroid skeleton, Rx is a free or ketalised oxo group, a substituted or unsubstituted lower alkylidene radical, a free, etherified or esterified hydroxyl group together with a hydrogen atom or a substituted or unsubstituted lower ali-phatic hydrocarbon radical, or a hydrogen atom together with a substituted or unsubstituted lower alkyl radical, and Ry is a lower alkylidene radical, a free, etherified or esterified hydroxyl group together with a hydrogen atom, a lower alkyl radical together with a hydrogen atom, or two hydrogen atoms, it being possible for a 16,17-double bond to be present in place of one of the said hydrogen atoms in radical Rx and one of the said hydrogen atoms in radical Ry, wherein a compound of the general formula II
(II) in which St, Rx and Ry are as defined above is employed as the starting material.
(I) in which St is the remaining part, which can be substituted or unsubstituted and/or modified in some other way, of the steroid skeleton, Rx is a free or ketalised oxo group, a substituted or unsubstituted lower alkylidene radical, a free, etherified or esterified hydroxyl group together with a hydrogen atom or a substituted or unsubstituted lower ali-phatic hydrocarbon radical, or a hydrogen atom together with a substituted or unsubstituted lower alkyl radical, and Ry is a lower alkylidene radical, a free, etherified or esterified hydroxyl group together with a hydrogen atom, a lower alkyl radical together with a hydrogen atom, or two hydrogen atoms, it being possible for a 16,17-double bond to be present in place of one of the said hydrogen atoms in radical Rx and one of the said hydrogen atoms in radical Ry, wherein a compound of the general formula II
(II) in which St, Rx and Ry are as defined above is employed as the starting material.
3. A prccess according to claim 1, wherein the reaction is carried out with an amunosulphur trifluoride in which the amino group is a di-lower alkylamino group or an unsubstituted or C-lower alkylated pyrrolidino, piperidino, morpholino or N'-lower alkyl-piperazino group.
4. A process according to claim 1, wherein the reaction is carried out with a symmetrically substituted aminosulpur trifluoride.
5. A process according to claim 4, wherein the aminosulphur trifluoride is diethylaminosulphur trifluoride, morpholinosulphur trifluoride or piperidinosulphur tri-fluoride.
6. A process according to claim 1, 3 or 4, wherein a starting material is reacted in which any free carboxyl and/or hydroxyl groups which may be present are temporari-ly protected.
7. A process according to claim 1, 3 or 4, wherein a 17.alpha.,21-dihydroxy-20-oxo-pregnane derivative in which at least one of the two hydroxyl groups is esterified by a carboxylic acid containing at least 3 carbon atoms is used as the starting material.
8. A process according to claim 1, 3 or 4, wherein in a resulting product, esterified hydroxyl groups are set free by hydrolysis.
9. A process according to claim 1, 3 or 4. wherein, in a resulting product, etherified hydroxyl groups are set free by hydrolysis or the 17.alpha.,20;20,21-bis-methylene-dioxy grouping is hydrolysed to the 17.alpha.,21-dihydroxy-20-oxo grouping.
10. A process according to claim 2, wherein a 9.alpha.-chloro-11.beta.-fluoro-steroid of the general fonmula IA
(IA) is prepared in which R5 is a hydrogen atom, an .alpha.-oriented methyl radical or, if a 1,2-double bond is present, a chlorine atom, R6 is an oxo group or a hydrogen atom together with a free or esterified hydroxyl group, R7 is a hydrogen atom, a methyl radical or a halogen atom, R8 is two hydrogen atoms, a methylene radical or a hydrogen atom together with an .alpha.-or .beta.-oriented methyl radical or an .alpha.-oriented free hydroxyl group, R9 is a hydrogen atom or a free or esterified hydroxyl group and R10 is two hydrogen atoms, a free, hydrated or acetalised oxo group, or a hydrogen atom together with a free, esterified or etherified hydroxyl group, and in which one double bond can be present in the 1,2-position and/or the 6,7-position, and in which the 16.alpha.,17.alpha.-diol grouping, which may be present, can be ketalised or acetalised by an oxo compound of the formula R11-CO-R12, in which R1 and R12 independently of one another are a hydrogen atom or a lower alkyl, phenyl or benzyl radical or together form the tetramethylene or pentamethylene radical.
(IA) is prepared in which R5 is a hydrogen atom, an .alpha.-oriented methyl radical or, if a 1,2-double bond is present, a chlorine atom, R6 is an oxo group or a hydrogen atom together with a free or esterified hydroxyl group, R7 is a hydrogen atom, a methyl radical or a halogen atom, R8 is two hydrogen atoms, a methylene radical or a hydrogen atom together with an .alpha.-or .beta.-oriented methyl radical or an .alpha.-oriented free hydroxyl group, R9 is a hydrogen atom or a free or esterified hydroxyl group and R10 is two hydrogen atoms, a free, hydrated or acetalised oxo group, or a hydrogen atom together with a free, esterified or etherified hydroxyl group, and in which one double bond can be present in the 1,2-position and/or the 6,7-position, and in which the 16.alpha.,17.alpha.-diol grouping, which may be present, can be ketalised or acetalised by an oxo compound of the formula R11-CO-R12, in which R1 and R12 independently of one another are a hydrogen atom or a lower alkyl, phenyl or benzyl radical or together form the tetramethylene or pentamethylene radical.
11. A process according to claim 10 wherein a 9.alpha.-chloro-11.beta.-fluoro-steroid of the formula IA indicated in claim 10 is prepared in which R5 is a hydrogen atom or, if a 1,2-double bond is present, a chlorine atom, R6 is an oxo group, R7 is a hydrogen atom, a methyl radical or an .alpha.-oriented fluorine atom, R8 is two hydrogen atoms or a hydrogen atom together with a hydroxyl group in the .alpha.-position or a methyl radical in the .beta.- or .alpha.-position, and R9 and R10 independently are each a free or esterified hydroxyl group, and in which a 1,2-double bond is preferably present.
12. A process according to claim 2, wherein a 9.alpha.-chloro-11.beta.-fluoro-steroid of the formula IA indicated in claim 10, in which R5, R6, R7 and R10 are as defined in claim 11, R8 is a hydrogen atom together with a hydroxyl group in the .alpha.-position and R9 is a hydroxyl group, and in which a 1,2-double bond is present, is prepared in the form of the corresponding 16,17-ketal.
13. A process according to claim 2, wherein a 9.alpha.-chloro-11.beta.-fluoro-steroid of the formula IA indicated in claim 10, in which R5, R6, R7 and R10 are as defined in claim 11, R8 is a hydrogen atom together with a hydroxyl group in the .alpha.-position and R9 is a hydroxyl group, and in which a 1,2-double bond is present, is prepared in the form of the corresponding acetal, cyclopentanal, cyclo-hexanal or acetophenal.
14. A process according to claim 2, wherein 2,9.alpha.-dichloro-6.alpha.,11.beta.-difluoro-17,21-dihydroxy-16.alpha.-methyl-1,4-pregnadiene-3,20-dione dipropionate, 2,9.alpha.-dichloro-6.alpha.,11.beta.-difluoro-17,21-di-hydroxy-16.alpha.-methyl-1,4-pregnadiene-3,20-dione 21-trimethyl-acetate or 2,9.alpha.-dichloro-6.alpha.,11.beta.-difluoro-17,21-dihydroxy-l6.alpha.-methyl-1,4-pregnadiene-3,20-dione, 17,21-ethylorthopropionate or 9.alpha.-chloro-11.beta.-fluoro-17,21-dihydroxy-16.beta.-methyl-1,4-pregna-diene-3,20-dione dipropionate is prepared.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU75809A LU75809A1 (en) | 1976-09-16 | 1976-09-16 | |
| LU75809 | 1976-09-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1105003A true CA1105003A (en) | 1981-07-14 |
Family
ID=19728351
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA286,727A Expired CA1105003A (en) | 1976-09-16 | 1977-09-14 | Process for the preparation of 9,11-halogenated steroids |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5337652A (en) |
| AT (1) | AT356303B (en) |
| AU (1) | AU514425B2 (en) |
| BE (1) | BE858709A (en) |
| CA (1) | CA1105003A (en) |
| DE (1) | DE2741067A1 (en) |
| DK (1) | DK410077A (en) |
| FR (1) | FR2364928A1 (en) |
| GB (1) | GB1584826A (en) |
| LU (1) | LU75809A1 (en) |
| NL (1) | NL7710086A (en) |
| SE (1) | SE7710337L (en) |
| ZA (1) | ZA775537B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1209140B (en) * | 1979-11-16 | 1989-07-10 | Prochem Ets | 6 ALFA-FLUORO-PREDNISOLONE 17,21-DIESTERI. |
| EP0029924B1 (en) | 1979-11-16 | 1984-08-15 | STEROSYNT Ltd. | 6-alpha-fluoro-16-methyl-prednisolone-17,21 diesters and pharmaceutical compositions containing them |
-
1976
- 1976-09-16 LU LU75809A patent/LU75809A1/xx unknown
-
1977
- 1977-09-13 DE DE19772741067 patent/DE2741067A1/en not_active Withdrawn
- 1977-09-14 CA CA286,727A patent/CA1105003A/en not_active Expired
- 1977-09-14 FR FR7727739A patent/FR2364928A1/en active Granted
- 1977-09-14 GB GB38343/77A patent/GB1584826A/en not_active Expired
- 1977-09-14 NL NL7710086A patent/NL7710086A/en not_active Application Discontinuation
- 1977-09-15 SE SE7710337A patent/SE7710337L/en not_active Application Discontinuation
- 1977-09-15 DK DK410077A patent/DK410077A/en unknown
- 1977-09-15 ZA ZA00775537A patent/ZA775537B/en unknown
- 1977-09-15 AT AT663077A patent/AT356303B/en not_active IP Right Cessation
- 1977-09-15 BE BE180914A patent/BE858709A/en unknown
- 1977-09-15 AU AU28848/77A patent/AU514425B2/en not_active Expired
- 1977-09-16 JP JP11060977A patent/JPS5337652A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ATA663077A (en) | 1979-09-15 |
| FR2364928A1 (en) | 1978-04-14 |
| DK410077A (en) | 1978-03-17 |
| NL7710086A (en) | 1978-03-20 |
| AU514425B2 (en) | 1981-02-12 |
| AT356303B (en) | 1980-04-25 |
| GB1584826A (en) | 1981-02-18 |
| AU2884877A (en) | 1979-03-22 |
| SE7710337L (en) | 1978-03-17 |
| ZA775537B (en) | 1978-07-26 |
| LU75809A1 (en) | 1978-05-12 |
| JPS5337652A (en) | 1978-04-06 |
| DE2741067A1 (en) | 1978-03-23 |
| FR2364928B1 (en) | 1981-03-06 |
| BE858709A (en) | 1978-03-15 |
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| MKEX | Expiry |