BE569621A - - Google Patents

Description

       

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  The present invention relates to a process for preparing a
 EMI1.1
 - .. group-- of new alkyl-steroids, It relates more particularly to the process for the preparation of 16'alkyl ,,, 1 4-pregnadienes and their halogenated derivatives as well as certain new 16alky4¯pregnenes.
The preparation of pregnens is already well known, like that of cortisone and hydrocortisone, as well as that of pregnadienes, like prednisone and prednisolone, and 21-ester and 9-halo derivatives of these compounds.



  It was, however, found that alkylation at position 16 of steroids possessing anti-inflammatory properties conferred on the original steroids marked properties of na $ uresis and diuresis. Due to this exceptional and unexpected property the alkylation at position 16 of steroid compounds possessing anti-inflammatory properties but of limited therapeutic value due to their inherent sodium-retaining effects has widened their field of application.



   , The new compounds according to the invention are represented by the following structural formulas:
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 in which R is hydrogen or an acyl orarboxylic radical and preferably containing 1 to 8 carbon atoms, such as for example an al- radical
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 lower icanoyl such as acetate, propionic, cyclopentylpropionic, phenzoque phthalic, dimethyl-acetic, trimetII-acetic, butyl-acetic ter- <3Eire, phenoxy-acetic, thiophene-carboxylic, nicotinic, etc., R 'is an aicoi-41pha-ethyl, beta-ethyl;

  , alphapropyl, beta-propyl, alpha-isopropyl, beta-isopropyl, alpha-butyl, beta butyl9 tertiary alphabutyl, beta-tertiary butyl, X is 0. radical, (HoalphaoOH) or (H.bgta.ÔH) and Y is hydrogen or a halogen having an atomic weight, less than 81 such as bromine, chlorine or fluorine and, when X is (Ho, alpha.OH), Y is necessarily hydrogen. Compounds of this type in
 EMI1.4
 which X represents (H.alpha.OH), although they do not in themselves possess any therapeutic activity, are convertible by known methods of oxidation into
 EMI1.5
 ketone compounds having physiological activity. In addition, as stated, the dienes represented by formula B above show significantly greater therapeutic activity than the el-monoenes of formula A.



  The A4-monoene however constitute useful intermediates in the preparation of the dienes of formula B above. It should be noted that the replacement by an alpha-halogen atom of hydrogen in position 9 in the 16-al-
 EMI1.6
 coyl-glucocorticoldes according to the invention, just like in the ais of the known steroids (like, prednisone, prednisolone, etc.) improves their anti-inflammatory properties. Unfortunately the addition of these 90alpha-halogens has so far caused a marked increase in the salt retention properties of known anti-inflammatory steroids, which very often prevents their administration by mouth or by injection and makes their application topical. ex-

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 EMI2.1
 very hazardous.

   It was unexpectedly found, however, that the addition of a 16-lower alkyl group and in particular of the methyl radical, while inhibiting the increase in salt retention caused by the introduction
 EMI2.2
 The use of 9, alpha-halogen did not affect the improvement in the therapeutic properties of these halogenated derivatives. Thus, these compounds can now be administered safely. Likewise the salt retention properties of
 EMI2.3
 Non-halogenated steroids like cortisone and hydxocortisone are markedly reduced.

   The fact is particularly astonishing if one notes that the substitution of an alpha-methyl group in position 2 or 6 of steroids known as the
 EMI2.4
 9.alpha fluorohydrocortisone or g.alpha-fluoro-prednisolone does not attenuate the characteristic salt retention, which precludes their therapeutic application.
 EMI2.5
 



  It should also be noted that although the in.fd-3: rieur alkyl substituent may be introduced at position 16 by a number of methods - resulting in the 160 alpha formation of 16eb8ta-eortiaoides before or after introduction: of the group 9.alpha-halo, the following will be found below; preferred reaction leading to the formation of the compounds according to the invention.

   Thus the series of reactions A, B and 0 illustrate interesting methods of preparation.
 EMI2.6
 tion of the alaoylated l6obgta-corticades in accordance with the invention, sequence D is a process applicable to obtaining the 16alpha-alkyl-aortiootàes according to the invention and the following 3 a more convenient process for preparing the 9 alphahalo derivatives of the 16 .alpha-alkyl- et'16, beta-aiaoyl-sterotàes described in the suites A, B, C and 13n By way of illustration the preferred methyl and acetic groups are used in these suites as well as in the following description as radioal 16.alkyl and as 21-aoyl substituent and, as 9.alpha-halo radicals, the
 EMI2.7
 hubs% 1% uants 9.alpha- "bromo and 9aalhawfluoroo CE3 to UII3I t il, Q 3-aoetate of 16-pregnne-3.aipha- 01-11.20 dione CH3 ¯ ..

   N = N cil t '"2' PiÎ. # É / 0µµ ####.
 EMI2.8
 



  3-aoetate. l6-methyl'-l6-pre-3-acetate l6t'be1: a-methylprene-3.aipha-oi-11.20 dione gnanc-3.alpha-ol-11.20-dione ## 16.b8ta-methylpregnane -3.lpha. 16b'ta-methyl-17-alpha-cliol-11-20 dione 21'-acetate '.. ## prégnane-3.alpha..alphao21trïol-11.20 dione' 16.b8ta-methtl-pregnane-17.al- 4-Bromo-16.b'ta 21-acetate pha.21-diol-3-.11.20 trione #### methyl-pregnane-1 ?, alphao21diol-3.11.20-trione 16.bÔ '21-aoetate ta-methyl 16ota-methyloortisone ôor-tiëbne ¯¯¯¯ ¯¯¯ 16.b8ta-methylprednisone Ù '

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 EMI3.1
 
 <tb>
 <tb> CONTINUED <SEP> B
 <tb>
 
 EMI3.2
 16-bgta-methyl-21-acetate 204-ibromo-160 regnan-17oalphaa2ld.o1 beta-methyl-pregnane-170alphao 3,

  1à20-trione 21-âiol-3o11a20-t 3one #### 16o'btamthylm 21-aoetate
 EMI3.3
 
 <tb>
 <tb> prednisone
 <tb>
 
 EMI3.4
 CONTINUED C 21-aoetate 3.6 beta-methyl 21-acetate l6abta-me'hyl cortisone aoj, @ isone-3020-bis-semioa bazone
 EMI3.5
 
 <tb>
 <tb>
 <tb>
 
 EMI3.6
 164'bta-methyl = hydoco ^ tisone-16 obeta-methylhydrocortisone 3o20-b3.s-semioabaone. ¯¯¯¯ l6obta-methylpredn¯- -.s:

  ne 16.bdta-methylprednisolone 21-acetate
 EMI3.7
 
 <tb>
 <tb> CONTINUED <SEP> D <SEP>
 <tb>
 
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 3oalpha-hydroxy-16-pregnene-3oalpha-hydroxy-16oalha-methyl- 11. 20-dione pegn, na11 to 20-d.one
 EMI3.9
 
 <tb>
 <tb>
 <tb>
 
 EMI3.10
 3oalphao17oa7.phaodihydo, yo.6 21-acetate 3.alpha.17.alpha.

   alpha-methyllpregnane-llo20 21 -'trihydroxy-16 o alpha-methyldione 1., pregnane-llo20-àione ###
 EMI3.11
 
 <tb>
 <tb> 21-acetate <SEP> of <SEP> 17.alpha.21- <SEP> 21-acetate <SEP> of <SEP> 160alpha-methyl =
 <tb>
 
 EMI3.12
 dihyayl6oalpharmthylpe, prednisone '(l) nane-3.11.20-trione' 'acetate 160alpha-methyloornane-301l020-trione acetate 16oalpha-methylcor =
 EMI3.13
 
 <tb>
 <tb> tisone <SEP> (he)
 <tb>
 
 EMI3.14
 I, l6aalpha athylprecisone II ---> 16.alpha-methyloortisQne ¯¯p 16oalpha = methylprednis? Ne 16oa1pha-méthy.hydocortiscne) 160alpha-meihy) -preànisolone l6oalpha-methyl acetate
 EMI3.15
 
 <tb>
 <tb> prednisolone
 <tb> CONTINUED <SEP> E
 <tb>
 
 EMI3.16
 (a) 16-methylpred-21-acetate l6r-Biethyl-lo409 nisoldne (11)

   Pregnatriene-17balphao21acetate diol-3o20-dione 90alpha-bromo-16-methyl-prednisolone 21-acetate 9oalphaollabetao: eydo-16-methyl-l o4'-pregnadiene-17 oâlpha 21-diol-3.20-dione --Ô 21 -90alpha-fluoro- 16-methyrednisolone 21-acetate 9oalph.a'.aoo169oaiphalnoo15methyl-
 EMI3.17
 
 <tb>
 <tb> methyl-prednisone <SEP> prednisolone
 <tb>
 

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 ## \ ¯¯¯aa3.pha-fluoro-16-methyl-
 EMI4.2
 
 <tb>
 <tb> prednisone
 <tb> (b) <SEP> acetate <SEP> of <SEP> 16-methylhydro- <SEP> 21-acetate <SEP> of <SEP> 16-methyl-409
 <tb>
 
 EMI4.3
 cortisone (lljprgnadiene - 17oalphao 21-diol-3.20-dione - 9oalpha bromo-16-21-acetate 21-acetate from g.alpha-11.

   methylhydrqort3.sone #### beta-oxyào-16-methyl-4-
 EMI4.4
 
 <tb>
 <tb> pregnene-17.alpha.21-diol
 <tb>
 
 EMI4.5
 90alpha 21-acetate (fluoto-16- 9nalpha-fluoro-16-methyl-methylhydrooortisone hydrocortisone
 EMI4.6
 As a further illustration, the lower 16-aleoyl compounds (for example methyl) can be obtained according to the invention described in the reaction series A from the easily obtainable compound, a 3-acylate
 EMI4.7
 (for example acetate) of 16-pregnen-34alpha-oi-11.20-d3.ones Reaction of this ester with diazomethane gives in excellent yields 1-intermediate pyrazolin which, on pyrolysis at its melting point or at Above is converted to l6-? ethyl-l6-pregnene-3-acetate-3.alpha-ol-11.20-dione.

   When it is desired to obtain the 16.beta-ethyl, 16.dta-peppyl or 16beta-butyl derivative, for example, diazoethane, diazopropane or diazobutane, etc. is used. corresponding,. to obtain the corresponding compounds. Although it is preferable to pyrolyze pyrazoline by heating above its melting point, this pyrolysis can also be carried out by heating the substance in 1 .: an inert high boiling solvent such as p-cymene, tetrahydronaphthalene, etc. The unsaturation present in the D ring is conveniently removed by reductive hydrogenation in the presence of a catalyst such as
 EMI4.8
 palladium, to give lbbta-methylpregnane 3-aoetate = 3oalphaôl-11.20-dione.



   To introduce a hydroxide group to the O 17 atom, it was found that the C 20 ketone group of 3-acetate could easily be converted.
 EMI4.9
 16o'bta-methylpregnane-3aalpha-ol-11,20-dione to enol-acetate by heating under reflux with acetic anhydride and a strong acid such as p-toluenesu1fon * acid as for example. It is preferable not to isolate the enol-aaetate but rather to react this substance in situ with a peroxy-acid such as peracetic acid to give a second non-isolated intermediate, namely 17.20-epoxide.

   Treatment of the reaction mixture with a hy-
 EMI4.10
 drolysis of the epoxide in situ, forming 16o'beta-methylpregnene-3.alphaol7.al.phadiol-llo20-dioneo In this operation, which introduces the hydroxyl group to 0 17, it is possible to use instead of acetic anhydride of 'other acetylating agents such as lipopropenyl acetate'. D%. The strong acid catalyst is not necessarily limited to 1 <f p-tcSLuene-sulfonic acid due to that other strong acids such as perchloric acid are also effective in the production of
 EMI4.11
 the enol acetate intermediate. As has been said enol-aoetate is like peracetic acid, perbenzolque acid, monoperphthalic acid, per-tri-fluoro-acetic acid, etc.



   The introduction of the 21-acetoxy group or other ester of said is carried out
 EMI4.12
 in the usual manner such as booùunation of the C-21 methyl group followed by reaction of the brominated compound thus obtained with, for example, sodium or potassium acetate, which gives 16 * beta-methylpiegnand-3aalphao170 alphao21-acetate -triol-llo20-dione. Although acetoxylation has been chosen as an illustration, it is clear that other acyloxylations such as the introduction of a propionoxy group can be effected analogously.
 EMI4.13
 



  To obtain the 3-keto-4- or 4-keto G ... 1'4- system, the 21-acetate of 16, beta-methyl-pregnane-3oalphaol'.alpha21-triol-11.20-dione of the o The hydroxyl group is converted to C-3

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 EMI5.1
 in a keto group, preferably by means of N brooaceous amideg which gives the 21-acetate of l6obta-methylmpxêgnan, Zaalpha21dïo13o11.o20Qtrïoneo It appears that other equivalent oxidizing agents can be used in this operation, such as N-bromosuccinimideg l ' chromic anhydride-pyridine'41anhY = chromic acid-acetone-sulfuric acid, etc.

   The double bond in # is then conveniently introduced into ring A by bromination of 21-acetate 160
 EMI5.2
 bta mel; hyl-prégne, ne-.7 oalpha o 21 d.ol-3 1. 0 20trione in the usual manner, which forms the intermediate brominated compound, which may or may not be isolated.
 EMI5.3
 or preferable to halogenate by means of bromine other halogenating agents such as chlorine are also effective.

   Dehydrohalogenation of this 4-brominated intermediate in a customary manner such as reaction with semicp ,, rbaziae-4, resulting in hydrolysis of the resulting 3-monosewicarbazdne or heating to ref 1 with dimethylformamide, optionally in the presence of sodium chloride. lithium, or heating under reflux with organic bases such as collidine, causes the elimination of hydrogen halide with introduction of a / \ 4 double bond,
 EMI5.4
 which gives l6obtamethylesortisone 21-acetate This compound can then be saponified to produce diol-trione 16abeta-methyicortisone, by reacting 160beta-nethyl-contisone acetate with hydrolyzing agents such as potassium bicarbonate hydromethanolic, or reagents such as sdi carbonate.:.;

   sodium hydroxide, sodium alkoxides (such as sodium ethoxide) and acids such as p-toluene-sulfonic acid La 16d. bgta-methyloortisone can then be esterified at C 21 by introducing any desired acid residue. It has been found that, as is generally known, esterification further improves the duration of steroid alcohol activity and provides a compound which can be effectively administered parenterally o It has been found that acid residues such as those obtained from acetic acids,
 EMI5.5
 Ionic9 trimethylaoetic, t-butylacetic, ayclopentyl-propionic, furoic, phenoxyacetic, etc., provide useful esters.

   Likewise semi-esters of diacids such as those obtained from phthalic, succiaic, tertric, citric, etoo acids provide esters which can be solubilized by formation of a salt of the free carboxylic group with an alkali metal such as sodium. Instead of organic diacids, mineral acids such as phosphates and the like can be used, resulting in a phosphate with two acidic hydrogen atoms which can itself be solubilized by formation of a salt.
 EMI5.6
 The introduction of a double linkonk 1 is preferably carried out by subjecting the 21-acetate of 16, 'beta-methyloortisone or 16o'bta-methylocrt3.som ne to the microbiological action of a dehydrogenating microorganism.

   It is preferable to use Baoillus sphaericus (American Type Culture Collection 7055) or Corynebaoterium simplex AoToCoCo 6946 according to the analogous p: F6oédés described in Belgian patent N 5400748. It is however essential that the compound subjected to dehydrogenation by fermentation contain a 3cetr system. g- and thus the first convenient time to insert the / \ "bond is after the formation of 16obeta-methyl-cortisone or its 21-ester.

   We thus obtain the 16, beta = methyllo4pregnadieneml'oalphao2ldiol 3o.1o20 trione
The dehydrogenation of ring A allowing the insertion of bond # 1 can also be carried out by other known methods, for example by re-
 EMI5.7
 Pregnane ester pion, l6abtamethylcort.sones 21-acetate or saturated pregnan9 16o'beta methylmprégnans 21-acetate.7aalphao2ldio1m3o11:

  , 20-trione with selenium dioxide for example or with chloranil at high temperatures or by the well known methods of halogenation and dehydrohalogenationo
 EMI5.8
 An example of this latter dehydrogenation process is sequence B. whereby 16ob6ta'-methyl 21-acetate = 'pFégnane-17Dalphao21-diol-301020-trione is preferably dehalogenated by means of bromine to form the intermediate 21-acetate of 204 dibroaol6obeta methy, pregnan-lQal. "'ldiol 3oilo20 trione.

   Di-dehydrobromgration using basic agents, preferably dimethylformamide, produces 160 "b% ta-methyl-pTed 21-acetate, isone.

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 EMI6.1
 which can be saponified using bydrolyn-.ts agents such as liér'ri tlJ above, such as potassium bicarbonate, with corresponding C 21 alcohol formulation It is evident that in the final state From l6beta-methyl-prednisone-, various este-ro groups can be introduced at i. lu The reactions and previous discussions have been applied
 EMI6.2
 that in the preparation of compounds contains a 0 110 ketone function It is obvious that if any of the raw materials contains a hy-
 EMI6.3
 drç: 41st .t C 11.alpha, this group is obtained by the series of reactions.

   However, in view of the easy availability of the original raw material, 16-prepregnene-3oalpha-o11.20.ione 3-acetate, it is preferable to carry out the reactions initially so as to produce II-ketone substances and, when necessary, reduce the 11-ketone group to the 11-hycroy group preferably having the beta configuration. This transformation is shown schematically in the series of reactions c giving rise to 3.20-bie-semicarbazone of 160beta-methyl-oortisone acetate by reaction of the latter compound with semicarbazide.

   After protecting the sensitive 3o20-diketone groups, the 11-ketone function is reduced by means of sodium borohydride within
 EMI6.4
 aqueous tetrahydrofuran, which gives the bis-smicarbazone of 16-beta-methylhydrocortisone. The C 3 and C 20 constituents are removed in a customary manner, for example by means of pyruvic acid, or by means of hydrolysis processes, for example using extended hydrochloric acid or nitrous acid, which gives
 EMI6.5
 16.beta-methylhydrocortisone.



   Other methods of protecting the 3020 diketone groups can be applied such as forming a 3020-bis-ethylene-ketal, followed by reduction of the 11-ketone group using sodium borohydride, litium borohydride, or sodium borohydride. lithium aluminum hydride, etc. The acid hydrolysis of 11-hy- '
 EMI6.6
 drc5rb, sceta, thus formed gives 160b3ta-methyl-hydrocortisoneo. 160beta-methyl-hydrooor% isone can be converted to l6ob3ta-methyl-prednisolone by micro-biological fermentation or by chemical methods described above for the conversion of 16.bgta-methyl-cortisone in 160 beta-methyl-prednisone.

   Likewise, 16bosta-methyl-prednisolone can be esterified according to any of the well-known techniques so as to produce the corresponding 21-acylate, for example 16abé% a-methyl-prednisoloneo 21-acetate. 6bota-methylprednisone itself can be converted to 16b8ta-methylprednisolone 21-acetate by first protecting the 3020 diketo groups as described for mono-enes followed by selective reduction of the 11-keto function .



   The 160alpha-lower alkyl compounds according to the invention are suitably prepared by the process illustrated in sequence D above in
 EMI6.7
 which is added a 3.alpha-hydroxy-16.alpha-pregnene-11.20-dione to a standard Grignard reagent such as for example methyl-magnesium iodide9 prepared from methyl iodide and magnesium, then we reflux heats up
 EMI6.8
 re to carry out the production of the corresponding saturated 160alpha-methyl derivative, 3aalpha-hydroxy-l6oalpha-methyl-prégnane-llo20-dioneo The derivative, methyl iodide is used by way of illustration but it is obvious that when it is desired to prepare other l6-alpha-lower alkyl compounds such as 16-alpha-ethyl,

   16.alpha-isopropyl or 16.alpha-tertiary butyl homologs, for example used as Grignard reagent those corresponding to ethyl-magnesium iodide, isopropyl-magnesium iodide or tertiary butyl-magnesium iodide , or their brominated or chlorinated equivalents
 EMI6.9
 The product of the Grignard reaction, 30alpha-hyàroxy-160alphamé% hyl-prégnne-llo2O-àioney is then hydrated by standard C 17 methods, for example by reaction with acetic anhydride and p-toluene acid. -sulfonic acid, then peracetic acid,

     then by alkaline hydrolysis which gives the

  <Desc / Clms Page number 7>

 
 EMI7.1
 3 .alphao170alpha-dihydroxy-160alpha-methylpregnane-llo20-dioneo The introduction of the C 21 acetoxy group or other ester is carried out by known methods, by
 EMI7.2
 example by "oroaation of the C 21 methyl group in an inert solvent such as chloroform followed by reaction of this product with sodium or potassium acetate in acetone or dimethyl7.

   ormam3deo The product thus formed is 30alphao170alphao21-trihyàroxy-160alpha-methylpregnane-llo 20-dione 21-acetate. The hydroxyl group at position 3 in the last compound is then
 EMI7.3
 transformed into a ketone group, preferably by means of N'bromoaeetamide, so as to effect the production of 21-acetate from 17a alphs, 0 2ldihyâ.rxyl6 alpha-methylpregnane-3 011 020-trione
Other known equivalent oxidizing agents such as those described above can also be used for the preparation of the 3-ketone derivative of compounds.
 EMI7.4
 posed 16.bgta-methyl.

   The double lia.sonal4 are then introduced into ring A by dihalogenation, for example, exsmp3.e-i9..b omurat3, ox of this 3-ketone derivative, by rapid introduction of brgme into an appropriate non-reactive organic solvent which is not reactive. dioxane, followed by dexhyàoeohalogenation in the usual manner, for example by refluxing the bromo-steroid with dimethyl-formamide in the presence of calcium carbonate and lithium chloride, or of collidine to the analogue, or by other standard methods such as as described above in relation to the preparation
 EMI7.5
 tion of l6obtamétn .iéneso The resulting product is 16-21-acetate.

   alpha-methyl-prednisoneo 17.alphL 21-acetate, 21-dîhydroxy-16o.1phamethylpregnane3o11o0trione can also be modified by introducing only the double bond, 4 so as to form 16.alpha-methyloortisone acetate. This is normally done by halogenation of the first compound (preferably by means of bromine
 EMI7.6
 'in medium such as tertiary butyl alcohol) there about 30 to 35C aveo subsequent dehydrohalorenation by a usual reaction for example with semicarbazide followed by hydrolysis of the 3-mono-semicarbazone thus obtained with pyruvic acid or the like.

   The 16oalpha = methylcortisone acetate thus formed or the corresponding diene, for example 160alpha-nethylpTedniscne 21-acetate, can then be saponified by reaction with usual hydrolysing reagents such as sodium or potassium bicarbonate, as described above in relation-
 EMI7.7
 ment to the 16 obtamethylstero.des correspondents of. so as to remove the acyl radical in C 21 and form the alcohol 16oalpha-methyloortisone or 16.alpha-methylprednisoneo These compounds can be re-esterified if desired to further improve the duration of action as it was said previously for which
 EMI7.8
 concerns the corresponding l6o-beta & thylcorco.

   Cortisone acyls substituted with a 16alpha-lower alkyl group such as 16oalpha-methyl-cortisone acetate can also be converted to 16alphamethyhhydrom cortisone by first reacting with semioarbazide to produce, for example, 16aalpha-acetate. methylco tison.eo20Ubissea: icaa'be, exs which is reacted with a metal borohydride as reducing agent ;, such as sodium or potassium borohydride, so as to reduce the C 11 ketone group to llobeta group -hydroxy while saponifying the position at the same time
 EMI7.9
 C 21 forming the alpha-methyl hydrocortisoneo 20'bissemicar'baone. The latter produced is then hydrolyzed by the usual methods;

  , for example by means of extended aqueous hydrochloric acid, so as to form 16.alpha-me-
 EMI7.10
 thy-3.lardrocert.sonso This intermediate can then be microbiologically transformed by processes analogous to those described in Belgian patent No. 540,748 which has been mentioned using a dehydrogenating microorganism such as Corynebaote-
 EMI7.11
 rium simplex (ATCC 6946), Bacillus sphaericus (ATCC 7055) so as to form 16oalpha-methylpredniselone which constitutes an interesting anti-inflammatory steroid This compound can then be esterified so as to form, for example, an acylate such as 21-acetate of l6oalphab2thyZpvednisolone by reaction with acetic anhydride in a suitable inert solvent such as pyridine or lutidine followed by crystallization.



   'According to a preferred method as described below E atc-

  <Desc / Clms Page number 8>

 me 9'alpha-halogen, preferably the 90alpha-fluoro atom, is introduced into the
 EMI8.1
 mono-enes and 19-ester 19-ester 16bgta-methyl dienes, for example represented by 160alpha-methyl- and 160beta-methyl-p acetate;

  ednisolone or the corresponding monoenes, 16 alpha-methyl- or 1-beta-methyl-hydrocortisone, by dehydration of 16-alpha-methyl-or 16-beta-methyl-preclnisolone acetate, for example by means of a chloride of 16. alkyl- or aryl-sulfonyl such as methanesulfonyl chloride in organic.alkaline media, for example pyridine, to produce the corresponding derivative9 II), for example
 EMI8.2
 16-alpha-methyl- or 16-beta-methylm- or 16-beta-methylm - - 91) mpregnatiènel7oa1phao2l-diol-3020-dione and 160alpha-methyl- or l60beta-methyl- or l60beta-methyl- 21-acetate, "4 (11- piégnadiene -170alphaa21-diol-3020-dioneo For convenience, in the subsequent description of this reaction sequence, the alpha or beta isomerism of stzb constitutes:

  .6-methyl will be understood explicitly as in the following I above, this character not affecting the succession of reactions nor do these reaction stages affect the particular 16 alpha or 16 beta isomerism of the reacting alkyl steroid. .

   The introduction of a halogen, and preferably bromine, at this point in the process, to the alpha carbon atom is effected by ordinary means, for example by reacting the steroid # 911 with the acid. of hypobromous which can be prepared in situ and preferably for example by
 EMI8.3
 of N-bromoacetami.

   and perchloric acid which directly give 90alpha-bromo-16-me% hyl-prednisolone 21-acetate and a5.pha bxomoi6-methyi-hydrooortisoneu 21-acetate. Esters of this type are useful anti-inflammatory compounds. and are at the same time easily converted by oxidation to the corresponding 11-ketones by known techniques such as, for example, by means of chromic anhydride in pyridine and hydrolyzed at the C 21 position by standard hydrolysing agents such as methanol potassium bicarbonate. that, sodium carbonate, hydrochloric acid concentrated in methanolchloroform or similar substances as described above, so as to prepare the corresponding 21-alcohols.



   The 90 alpha-hydrobromide can be further heated to reflux with a moderate base, for example with the aid of methanolic sodium acetate in such a way
 EMI8.4
 'to form the derivatives 9 beta-oydoy the 21-acetate of 90betaailabeta-oxydo-16-methyl-1 4-pregnad.ene 1 alpha 21-diol-3 20-dione and the 21-acetate of 9.beta-11 beta -ordo-16 - methyl -pregnene-17 alpha, 2lmdiolo These latter compounds are then reacted with hydrofluoric acid in chloroform, in the presence or absence of ethanol and (or) of tetrahydrofuran, of way to provo-
 EMI8.5
 The formation of 9oalpha-fluoro-16-methyl-prednisolone acetate and 11-alpha-fluoro-16-methyl-hydrocortisone acetate.



   Likewise, the replacement of hydrofluoric acid by anhydrous hydrochloric acid in this reaction results in the production of the corresponding 9 alphachloro derivatives. Here again these compounds can be oxidized to the corresponding 11-ketones by standard agents such as chromic anhydride or N-
 EMI8.6
 halosuccinimides or hydrolyzed to the corresponding 21-alcohols by normal saponification methods (for example by means of hydromethanolic potassium bicarbonate or concentrated methanolic hydrochloric acid).

   Thus the compounds
 EMI8.7
 Preferred halogens according to the invention, 9calpha-fluoro-16-alaoyl (info) prednisolones and 9 alpha-fluoro-16-alkyl (inf.) prednisones, and in particular 9-alpha-fluoro-16-alpha-methyl-prednisolone , 9.alpha-fluoro-16.alpha-methyl-prednisone, 90alpha-fluoro-160beta-methyl-prednisolone and 9 alpha-fluoro-16bm ta-methyl-prednisone are prepared by these methods.



   As noted previously the compounds according to the invention can be prepared by a number of methods. One of them, as he-
 EMI8.8
 illustration, results in the production of the 15oalpha-methyl and 160beta-me% hyl-steroids described herein, the halogen atom in 90alpha possibly being present in the starting steroid or being able to be introduced in the following by the methods. that we have just described. By way of illustration of these materials, mention may be made of 4.16.
 EMI8.9
 Pregnad.ene-2I-ol-5 III 20-trione9 la q. 16-prégnaaiénellobétaa2ldiol320-dion.e

  <Desc / Clms Page number 9>

 
 EMI9.1
 and 90alpha-halogenated derivatives, for example bromé2, chlorinated or fl'1,)! compounds.

   These 9 ohalo pgne, d.: Born like the 90alpha = fluoro-prégnadiè. may for example be prepared from 90alpha-fllioohydrocotia 9oalphaâluoocotisone by reaction with semicai-bazide in the mée preferably in a molar ratio of about 1/2 of the steroid to the sqdmi, zide so as to form the 3o20 -bis-semioa, rbaside which is itself put e. action with acetic anhydride, for example, and heated to effect the hydration of the C 17 hydroxyl group.

   The product thus formed is reacted with pyruvic acid and p-toluene-sulfonic acid to give 16-desny-
 EMI9.2
 corresponding dro-20-keto-2't-dihydroxy-9oalpha-fluoi'o-steroids such as for example 9oalpha ± luoo.

   016p ^ egnad.ene21oh3 0., 0 20 .one or 9oa1pha9fluoro- 4016-pregnadiene-llob @ tao21-diol = 3020 = dione of which we have spoken The sequence of reactions for the preparation of 16-alpha-methyl- and l6obeta-methyl-steroids according to the invention from these 9 <> alpha-halo- and non-halo-4016 dienes is carried out in a similar way by initial reaction with nitroaloanes (such as nitromethane) in an organic base such as piperidine with formation of
 EMI9.3
 corresponding 160alpha-nitromethyl derivative which can be reduced, for example by means of tin and hydrochloric acid, to l6oaphaaainomëthyï, mst oâ. which can be subjected to quaternization by means of methyl iodide and then pyrolyzed with formation @ Aivé 16-methylene corresponding,

   which one can be at
 EMI9.4
 in turn converted into compound 16-methyl-20-keto-16 (17) -àéxhydroa This latter compound can also be derived as indicated above, for example in 3acetate 16 methyl = 16 pregnene-3alpha-ol-llp20-dioneo The peroxidation of this last compound by means of hydrogen peroxide causes the formation of 16.alpha.

   joalpha-oxydol6abtamthyl-20mcétosteo, from which, reacted with hydrobromic acid, for example, forms the corresponding bromhydrin, the debrodination of which gives a mixture (separable by chromatography) of 16.alpha-me- derivatives.
 EMI9.5
 ethyl and 16,, bata-methyl for example .pégn.êneml7 o alp'ha o 2 d.ol3 11.20-trione, qp ^ égn.ênemll ebta o 1 oapha o 21 ta2o1-3 0 20d "ione and their 9.alpha-halo derivatives (for example fluoro) o These mono-enes can be converted into the corresponding 1.4-dienes miorobiologically using for example 1 Bacillus phaexcus (A1'CC 7055) or Corynebaoterium simplex (ACCO 6Q.6 j These operating steps are carried out by methods well known to steropid chemists.

   It is thus evident that, if higher homologs of nitromethane (eg nitroethane, 2-nitropropane,
 EMI9.6
 etc.) with a 16-dehydrosteroid such as alghamacetoxyl6p. egene11o20-dio - ne, the corresponding alkyl homologues are obtained in the 16-position, for example .6-ethyll6dehyd.ad20mcëtos erodes 16.sopcpy â "16 == riéshydo 20-keto-steroldesq etco) a The 16-alcoyi- 16-aeshydxo-20-keto-steroids resulting from the pyrolysis of quaternized aterolates can be converted to corticosteroids - as already described;

  , i.e. hydrogenation-of the double J, 1>, ls> Jn by means of palladium on carbon or Raney nickel, introduction of the 17- group
 EMI9.7
 hydroxy- by acetyl, enolic tion and peroxidation (for example by means of acetic anhydride and p-toluene = sulfonic acid with subsequent treatment by means of peracetic acid} v introduction of 21-aceta% e by bromination and acetoxylation ( sodium acetate in dimethyl-foimamide) and elaboration of ring A. in the usual manner with introduction of double bonds # 4 or # 14 and of a 3-ketone group.

   They can also be epoxidized using hy-
 EMI9.8
 drogen allif. which gives the l6oalpha, oloe, lphaoepoql6obétaalcoy.20cétosteroideso "thus, these are then treated by means of a ha3.ohydiq.e acid such as hydrobromic acid and del ,,, roniureas9 for example by means of powder of zinc or nickel of Baneyp or palladium and hydrogen The operation gives both the 16aalpha-àlcoyl-170alpha-hydroxy-20-keto-steroids and the 16a "beta-àlaoyll'o, lph.ahydoy-20cétosté odeso After separation, for example by chromatography, they are then treated in the usual manner;

   for example, the 21-acetate group is introduced by bromination and acetoxylation and the ring is formed
 EMI9.9
 A by oxidation of the 3-hydroxyl group (if present) followed by bxoauationmdë- bromurationo

  <Desc / Clms Page number 10>

 
 EMI10.1
 The higher diazoalkanes being quite difficult to prepare, it is
 EMI10.2
 preferable to convert the 16 alpha-alkyl-20-ketosterodes to 160beta-alaoyl-20-keto-steroids by a relatively simple process The 16 alphaa.coyl-steroi
 EMI10.3
 are brominated in position 17, for example using 'bromine in a solvent
 EMI10.4
 inert (such as pyridine) or N-bromo-succinimide and the resulting compound is
 EMI10.5
 dehydrobromide, for example by means of collidine or ma- dimethylformamide
 EMI10.6
 negate to give the 16-alkyl-16-dehydro-20-keto-steroids.

   The hydrogenation of these compounds gives the 16 alpha-alooyl20, = ketomsterodes.
 EMI10.7
 here as raw materials only compounds removed from bile acids There are, however, several other classes of extremely interesting raw materials, such as diosgen and smilagenino Thus diosgenin is, easily converted into 16-dehydropregnenolone, which can be easily con -
 EMI10.8
 vertiaen 16 alpha-methylprpgnenolone by Grignard reaction and in 16-methyl-16-dehypropregnênolone by the diazomethane prooédéo The first compound is hydrogenated, for example by means of -catalyst with palladium,

   in 160a1pha-methyl-al-10-pregnan-30beta-ol-20-one 'and the elaborate cortical side chain of the' ma-
 EMI10.9
 usual nière (enolic acetylation in 0 17 and epoxidation with formation of the
 EMI10.10
 17.alpha-hydroxy-20-oµtone followed by bromination and dtacetoxylation in 0 21).
 EMI10.11
 The hydroxyl at O 3 is oxidized to ketone, a 204 dibromide prepared using bro-
 EMI10.12
 me and dioxane or #;., jre inert solvent and the dehydrobromination carried out by means of collidine or de4dmethYl-formamide so as to provide the 21-acetate of 160alpha-methyl-10-prregnadiene -l alphaa21mdiol-3 20 dione.

   This can be hydrolyzed in the C 11 position with the formation of l6tralph, -méthy.pred.nisolone or 160alpha-me% hyi-11-épipieàniso% oneo This last compound can be acety-
 EMI10.13
 selectively at C 21 with formation of a mono'-acetate then oxidized at C II with
 EMI10.14
 formation of 16oalpha-methylprednisoneo 21-acetate 16.alpha- 21-acetate
 EMI10.15
 methyl-ll-epiprednisolone can be dehydrated at C 11 by tosylation of the group
 EMI10.16
 0-1l.alpha-hydroxyl followed by treatment with 1 sodium myµtiiacetate so as to give the 21-acetate of 16 alpha-methyl 4? \.

   -pregnatriene-17.al-pha.21-
 EMI10.17
 diol-3.20-dione, compound previously described as an intermediate in the preparation
 EMI10.18
 tion, des 9 alpha-ha.o-16 aZphammethyl-carticoâdes La 16.alpha- ou, 6nbta, alkyl-alloprêgn, ne-17, lpha 21dio13 20 dione or. its 21 acetate can be hydroxylated in position 119, for example by means of Rhi2opüs nigrioans (ATCC 6227 B) or Curvularia lunata (NBRL 2380), the aoetylated 21-hydroxyl group and the 3-keto-4- or 3-oeto system, l 4 introduced in the usual way.

   The 16-methyl-16-dehyàropregnenolone described above is hydrogenated to 16 beta-methylalioprene3 betaol20mone This is treated in exactly the same way which gives the 21-aoetate of 16obeta-methyl-A 4-pregnadiene-17.alpha-21 -diol-3,20-dione, 160beta-methyl-preanisolone 21-acetate, 160beta-me% hyl-11-epipreànisolone 21-acetate and 16o'bota-'methyl-499 acetate ( 11) Pregnatriene-17 alpha21-diol-3 20-dione (compound previously described as an intermediate in the preparation of 9 alpha-halo-16 'bLta-methylm
 EMI10.19
 corticosteroids).



  Other important raw materials are 12-oxygen-sapogenins such as hecogenin, rookogenin and gentrogenin. For example, we have found
 EMI10.20
 verti llheoogenin in 11-oeto-16-dehyclro-allo-pregnan-3.bgta-ol-20-one. A 16,, alpha-methyl substituent can be introduced by the Grignard reaction and form
 EMI10.21
 mer the side chain and the nucleus A in the usual way to obtain the
 EMI10.22
 Ô4 and - 4- double bonds, 3-ketone group and 21-alkyloxy groups
 EMI10.23
 or hydroxyl or introducing the 16-methyl substituent by reaction with diazomethane and developing the side chain and ring A by these same methods.
 EMI10.24
 



  The ooosés.nouveaux prepared according to the invention, that is to say the 16.alpha- and 160bé% a-alooyl derivatives of cortisone, of hydtocortisone,
 EMI10.25
 'prednisone and prednisolone, non-halogenated or halogenated in position
 EMI10.26
 9 alpha, as well as their C 21-esters (except explicitly the lloalpha-h; N-iiraxy-16alkyl-corticosteroids which, however, constitute inter-esf rite intermediates in the formation of the '1.l' ': oeto-s tero! correspondents, for example the oortJ.Ijt..I; t18 the

  <Desc / Clms Page number 11>

 prednisone) have, as has been said, interesting anti-inflammatory and diuretic properties (ie excretion of sodium and water).

   The
 EMI11.1
 Alkylated dienes (especially 16.alpha-methyl- and 16.beta-methyl-dienes), with or without '.alpha-halo substituent, constitute particularly interesting therapeutic agents possessing similar therapeutic effects in the treatment of inflammatory diseases such as for example arthritis, dermatitis,
 EMI11.2
 asthma, etc., and are normally administered in daily maintenance doses of the order of 0.5 to 10 n; g; The preferred dose g, a, o, id.enna of the non-hfilo- geneated dienes is about 2 to 10 mg and saddle of the halogenated and of the preferred 9 alpha-fluorinated dienes of the order about 0.5 to 5 mg.



  The 16-alpha-alkyl- and 160-beta-alkyl-mono-enes according to the invention are also useful intermediates in the manufacture of the corresponding dienes, which are also anti-inflammatory agents and inhibitors of renal tubular reabsorption of sodium. A daily dose of 25 to 100 mg is recommended for oral administration of these monomers to induce sodium and aqueous diuresis, for example in the treatment of asia, congestive heart attacks and cyclic edema.
 EMI11.3
 



  Likewise, the 9 halo-16.alpha- and 90halo-160béta-alkyl-monoénes according to the invention are interesting because they show a greater activity in the treatment of inflammatory diseases such as arthritis. , dermatitis, asthma, etc. Administered by mouth, the daily dose is of the order of 4 to 15 mg.
 EMI11.4
 



  When such treatment is indicated, these 16.alpha-alkyl- or 16.beta-aloq, γ4-dienes and mono-enes can be administered parenterally in therapeutically acceptable solutions and suspensions, for example in media. aqueous, or when oral administration is indicated, can be incorporated into tablets (normally 0.5 to 5 mg per tablet), elixirs and other pharmaceutical forms known by usual methods.

   They can also be administered as topicals in the form of ointments or creams or as
 EMI11.5
 forms of solutions, for example in the. dimethyl azetamide or diethyl acetamide, or in the form of suppositories dissolved or suspended in a fatty or waxy vehicle melting at substantially body temperature or in the form of an aerosol, in admixture with suitable materials such as myristate d isopropyl and dichloro-difluoromethane ("Freon").



   The following examples illustrate the present invention.
 EMI11.6
 



  Example 1 - 16abé% a-methyicor% isoneo 21-acetate A. Reaction product of 16-pregnene-3aalpha-oi-ilo20-dione 3-acetate with diazomethane
 EMI11.7
 A solution of 3.72 g of l6regnene3oalpham ol-11.20-dione acetate in 5 ml of methylene chloride is added to a solution of about 1 g of diazomethane in 70 ml of ether cooled to -10 C. The mixture is maintained. mixture at 0 ° C. for four hours then allowed to warm to room temperature.



  The pyrazoline thus obtained crystallizes directly within the reaction mixture.
 EMI11.8
 nel by giving 332 g of product melting at $ 19 - 200 0. by decomposing (0) + 149 6 (dioxane) o
 EMI11.9
 -,Analysis. Calculated for 0 n 10 N 0 m 69.23; H 8.27; N = 6.76% "Found z 0 m 69.51; II - 7.98;

   NOT . 6.69% 3.2-acetate 16-methyl-16-pregnene-30alpha-ol-lio20-dione
3 g of the pyrazoline of Example 1 A are heated under reduced pressure at about 2100 C. until the evolution of nitrogen ceases. The oil thus formed is cooled to room temperature and then crystallized by the addition of ether. The precipitate is separated by filtration and dried: it is
 EMI11.10
 obtains 2.12 g of 16-methyl-16-pregnene-30aipha-oi-iio20-dione 3-acetate, melting at 163-16,600. ([alpha]) D = + 69 9 (dioxane).

  <Desc / Clms Page number 12>

 
 EMI12.1
 



  At max 248 ma. (10,0800 Analysis. Calculated for C24g34fl4 '0 74.57; II - 8987%.



  Found: 0 = 74.85; H = 8.55% Co 3-acetate of 16.bgta-methylpregnan-3.alpha-ol-11.20-dione
12 g of 16-pregnene of Example 1B in 250 ml of glacial acetic acid in the presence of 3 g of 10% palladium on carbon catalyst are subjected to hydrogenation at room temperature and under atmospheric pressure. When the reduction is complete (approximately one and a half hours), the catalyst is removed by filtration and the filtrate is concentrated under reduced pressure to approximately 100 ml.

   The residue is poured into water and the precipitated solid is filtered off, washed and dried to give 11.4 g of 16-beta-3-acetate.
 EMI12.2
 Methyl-pregnan-3oalpha-ol-llo20 dione impure melting at 148 - 155 00 After reoristallization in acetone-hexane, 8.40 g of the product of this example 1 C melting at 160 - 163 0 is obtained, no absorption UV at 220 - 300 mu, (o () D = + 93 6 (dioxane).
 EMI12.3
 



  Analysis. Calculated for 0 24 Il 38 0 4 0 = 'J4.193 9.34%. found: 0 = 74.37; S 9.06% 0 D. 16 o'éta-me'hylpr & gnane-3 o alpha l 'o alpha-do-.1, a 20-dione A solution of 6.77 g of 16, beta-methyipregnane-30aipha-oi-iio20-dione 3-acetate in 156 ml of acetic anhydride containing 3.89 g of p-toluene-sulfunic acid, during which approximately 16 ml of distillate is distilled every half. hours per vacuum application.

   The oily residue thus obtained is dissolved in 80 ml of benzene and washed three times with water, then with a solution of 1.55 g of acetate.
 EMI12.4
 of sodium in 20 ml of water The benzenic layer is dried over magnesium sulfate and then stirred for eighteen hours at 25 ° C. with a mixture of 0.52 g of sodium acetate in 12 ml of sodium acetate. 40% commercial peracetic acid.

   We destroy
 EMI12.5
 then the excess of peracetic acid by adding a solution of 155 g of sodium sulphite in 52 ml of water while maintaining the temperature between 10 and 20Co. 1.57 g of more sodium sulphite are then added and The mixture is stirred for about sixteen hours until the iodine-starch test is negative. The benzene layer is separated, washed three times with water and evaporated. To the residue obtained dissolved in 345 ml of methanol is added a solution of 3.62 g of sodium hydroxide in 39.5 ml of water and the mixture is heated under reflux for fifteen minutes. After neutralization with 4 ml of Glacial acetic acid is concentrated under reduced pressure to a volume of about 50 ml.

   This concentrate is poured into a mixture of ice and water and the solid which precipitates is filtered and dried. 6.69 g of beta-methyl-
 EMI12.6
 prgne, ne-3.s, lfha..7aalpha-diol-11020 dione melting at 105-14000. It is subjected to chromatography. on Florisil and the fractions of eluate ether-hexane 33-50% are combined and crystallized from acetone-hexane, which gives 2.09 g
 EMI12.7
 of 16, bta-methyl-pregnan-3oalphaal'os, lphadiol-11a2O dione mp 181 * 5-18,500. (0 (D = 83.6 (dioxane). Analysis. Calculated for 0.22 µl 34040 - 72.89; H, 9.45%.
Find . C, 72.82; H, 9.25%.
 EMI12.8
 



  16nbeta-me% hylp-30alphaa170alphadiol-11e20-dione 3-acetate is prepared by adding to 1 g of the corresponding 16nbeta-methyl-pregnanediol a solution of 0.5 ml of acetic anhydride in 2,3 ml of pyridine After standing for one hour at room temperature, the reaction mixture is poured into ice and hydrochloric acid. The resulting solid is separated by filtration, dried and recrystallized from acetone-hexa-
 EMI12.9
 ne, which gives the 3-acetate of 16.bgta-methylpregnane-3.alpha.17.alpha-diol- 11.20-diane melting at 169 - 172 C The infra-red spectrum indicates the pre-

  <Desc / Clms Page number 13>

 sence of an acetate, a hydroxyl and two oetonic groups. -
 EMI13.1
 Analysis.

   Calculated for 24H3605: 0 71.25; H = 7597 bzz Found s 0 - 71.29; E - 'j992 o Ee 21-acetate of 16o'bta-methylpregnane-3oalphaol'oalpha-27-trial-1.1o20-dionq "One proceeds to the bromination at -2500 of a solution of 362 mg of 160 bta-methylpregnane -3oalphaol7oalpha dïol.1020dione in 18 ml of chemically pure chloroform (containing a few drops of an ohloroform solution saturated with hydrobromic acid) by adding, over three hours, 165 mg of bromine in 10 ml of chloroform. solvent removal under pressure
 EMI13.2
 reduced, 10 ml of dimethylformamide and J g of podium acetate are added. The mixture was stirred at 60 ° C. for two hours, allowed to stand overnight at room temperature and then heated for a further two hours at 60 ° C.

   The mixture is poured into water and the precipitated solid is filtered off and dried.
 EMI13.3
 which gives 370 mg of impure l6obeta-methylpregnane-3ealphao.7oalphao2ltriol-11o20-dione 21-acetate, melting at 192 - 203 Co Recrystallization from aoetone-hexa. gives 280 mg of the product of this example melting at 199 - 205Ce The analytical sample, after further recrystallization, melts at 200 - 2t5Co Analysis. Calculated for C24H3605; 0 68.54; H 8963%, Found: C '= 68.79; H 8.39% 0 F. 21-aoetate of 16 o'b ta-me-hrlprcgnane1 j 'o alpha-0 21 mdiol-3 e 17. a 20-trione A solution of 21-acetate of 16 is cooled to 1000. .bgta-methylpregnane-3oalphao :, oâlphao2l-trio.-11020 dione in 30 ml of 80% acetone-water.



  A drop of concentrated hydrochloric acid is added together with 150 mg of N-bromosuocinimide and the mixture is allowed to react for twenty-two hours at 10 ° C. in the dark. An excess of sodium sulfite solution is then added and the mixture is concentrated under reduced pressure to a small volume, which precipitates.
 EMI13.4
 120 mg of .6o'beta-methylpregnane 21-aoetate -. 'Alpha.2'1-dioï-3o1io20-trione, melting at 190-195 C and decomposing. The purification is carried out by means of powdered zinc in aqueous acetone containing 2 drops of acetic acid.



  The zinc is removed by filtration, the filtrate is concentrated and 1 water is added so as to obtain the crystallization of 100 mg of the product of this example, melting at 198-202 C.
 EMI13.5
 



  Go 21-acetate of 4obtambxoxao-l6obta-methy.pxégnaneml "jalphao21-d.ol-3011020- trione,
A solution of 84 mg of 21-acetate of
 EMI13.6
 l6obetamëthylprëgnanel'aalphao2s-diol-3o11o20-trione in 3 ml of tertiary butyl alcohol and 3 ml of methylene chloride, at 30 - 35 ° C., quickly adding the solution to a solution of 32 mg of bromine in 3 ml tertiary butyl alcohol. When the bromination is complete (one and three quarters of an hour), the solution is evaporated to dryness under reduced pressure.

   The residue is diluted in water, it is filtered
 EMI13.7
 tre and dried, which gives 90 mg of 4obta-braao-l6qbêtamethylpregnane-17, alphao21-diol-3w11,20-trione 21-acetate, melting at 115 - 130 C while decomposing, which represents a purity sufficient for the conversion described in the following process.
 EMI13.8
 



  16-bgta-methyloortisone 21-acetate The q.o'eta'bromoml6obta-methylmprëgnane-17o alphao21-diol-3011020-trione 21-acetate of example G above is dissolved in a mixture of 30 mg.
 EMI13.9
 of semica baaide9 '4 ml of tertiary butyl alcohol and 2 ml of methylene chloride, and stirred under a nitrogen atmosphere for two hours at 25-30 C.



  After removing the solvent under reduced pressure, the residue is dissolved in 5 ml of 80% aqueous acetic diacid with an excess of 70% pyruvic acid and the reaction mixture is allowed to stand at room temperature for twenty hours. The solution is brought to a pH of approximately 7 by means of sodium hydroxide

  <Desc / Clms Page number 14>

 extended to 5% and then exhausted with methylene chloride. The organic extracts are evaporated and the residue is subjected to chromatography on "Florisil".



  The 25 mg of crystallized material obtained from the 50% ether-hexane eluates and the 100% ether eluates recrystallized from acetone-hexane give 20
 EMI14.1
 mg of 16, beta-methyi-aontisone 21-acetate, melting at 198 - 20800.



  XEOH 238 m f (12. 800 max Example 2.- 16.beta-methyl-oortisone
1 g of 160beta-methylcortisone 21-acetate (prepared as in Example 1) is dissolved in 25 ml of methanol and 5 ml of water containing 0.2 g of potassium bioarbonate. This solution is heated under reflux for half an hour and then it is concentrated under reduced pressure. Water is added to the residue and the precipitate formed is filtered and dried. Crystallization from acetone6
 EMI14.2
 hexane gives 16.beta-methyl-oortisoneo Example 3-16ob3ta-methylhydrooortisone A. 16.bta-methy, cortisone-.20-bis-semi.carbaone A mixture of 5 g of 16 is refluxed for sixteen hours. bê-
 EMI14.3
 ta-methyloortisone, 8.3 g of semicarbazide hydrochloride, 6 g of pyridine, 50 ml of water and 200 ml of methanol.

   The solution is concentrated to about 60 ml and then poured into water so as to precipitate 3.20-bis-semicarbazone from 16.bAta-methyloortisone.



  ,!. 3.20-bis # somioarbazono of 16.bAta-methylhydrocortisone A solution of 6 g of the bissemicarbazone from Example 3 A above and 4 g of potassium borohydride in 6 hours is refluxed for six hours.
 EMI14.4
 200 ml of tetrahydrofuran and 100 ml of water. The solution is cooled and acetic acid is added to pH 5.5.

   The organic solvent is distilled off and the solids present in the residue are filtered off so
 EMI14.5
 to obtain the .0-b.sisemicirbaone of 1 & nbte, -méthy, hydrocortisoneo C. 16, b8ta-methyl-hydroaortixonea Under a nitrogen atmosphere, 5 g of the bis-semioarbazone of 11 Example 3 B are dissolved in 250 ml of 2.4 No hydrochloric acid The solution is cooled to 5 ° C. then 2.5 g of sodium nitrite are added over the course of fifteen minutes
 EMI14.6
 in 25 ml of water at 5C.

   The reaction mixture is stirred for a further thirty minutes then cooled below 15 ° C., neutralized with 20% sodium hydroxide and exhausted several times with chloroform The solvent is removed under pressure reduced and a solid residue is obtained which has--
 EMI14.7
 near crystallization from acetone-hexane gives 16.bta-methyl-hydrocortisone. ixem.e 4.-21 160beta-methylhydrooortisone acetate To 1 g of 16.beta-methlhydrocortisone prepared as in Example 3, 0.5 ml of acetic anhydride in 2.3 ml of pyridine is added. After standing for one hour at room temperature, the mixture is poured into ice and hydrochloric acid.

   The precipitate thus formed is separated by filtration and it is crystallized from aqueous methanol so as to obtain the
 EMI14.8
 16'-acetate <beta-methylhydrooortisoneo Example 5.- 16-alpha-methyloortisone A., 6 "alp, e, -methylpré; nén, e- o alpha-ol-11 n 20-aione A mixture of 39 d2 is added. g of 16-pregnene-3.alpha-ol-11o20-dione in 20 ml of dry toluene to a Grignard reagent prepared by means of 7 g of methyl iodide and 1.2 g of magnesium in 40 ml of ether and containing 200 mg of cupric chloride The reaction mixture is distilled until a vapor temperature of 100 C. The distillation is then stopped and the temperature is maintained at 100 C. for five hours.

   We then cool the

  <Desc / Clms Page number 15>

 mixture by pouring it over ice and an aqueous solution of ammonium chloride and the layers of solvent are separated. The organic layer is distilled under vacuum until an oily residue (3.98 g) is obtained which is subjected to by chromatography on "Florisil".

   The eluates are mixed with 20% ether-hexane and evaporated to obtain 2.08 g of a residue which is crystallized from within
 EMI15.1
 acetone-hexane so as to obtain l6oalpha-methyZpregnane-3.alpha-l-11.20 dione melting at 149 - 154 C (c6) = + 100 5 (dioxane) o B. l6alpha-méthy.pégnane-3oalphaol7aalpha- diol-11o20-dione 7.44 g of 16.alpha-methylpregnan-3.alpha-ol-11.20 dione prepared as in Example 5 A are dissolved in 156 ml of acetic anhydride containing 3.89 g of p acid -toluene-sulfoniquea The reaction mixture is heated to 100 ° C. and approximately 10 ml of distillate is collected under vacuum every thirty minutes.

   After six hours, the oily residue remaining is dissolved in 80 ml of benzene and the solution is washed with water three times, then once with a solution of 1.55 g of sodium acetate in 20. ml of water. A mixture of 12 ml of peracetic acid containing 0.52 g of sodium acetate is added to the benzene solution and the mixture is stirred at room temperature over nineteen hours. A solution of 15.5 g of sodium sulphite in 80 ml of water at a temperature below 25 ° C. is added then 1.6 g of sqdum sulphite are added and the mixture is stirred for approximately sixteen hours. The layers of solvents are separated. The organic layer is washed three times with water, dried over calcium chloride, filtered and evaporated under reduced pressure so as to obtain an oily residue.

   The residual oil is dissolved in 345 ml of methanol and 39.5 ml of water containing 3.62 g of sodium hydroxide and the mixture is heated under reflux for a quarter of an hour. After neutralization of the excess base with 5 ml of acetic acid, the methanol is removed by vacuum distillation.



  Water is added to the residue thus obtained and a solid separates (5.25 g, melting at 173 - 179 C) which, filtered and crystallized from acetone, gives 2.36 g.
 EMI15.2
 of 16, alpha-methyl-pregnan-30alphao170alpha-diol-1120-dione melting at 181 5 - 1840C (o () n = + 74 4 (dioxane).



  C. 21-160alpha-methylpregnane-30alphao170alphao21-triol-11020-dione acetate
A solution of 362 mg of 16.alpha-methyl-pregnanediol of Example 5 B in 18 ml of chloroform, at -20 to -30 C, is subjected to bromination by the dropwise addition of 160 mg of bromine in 10 ml of chloroform over forty-five minutes Stirring is continued for a further twenty minutes then the solvent is removed under reduced pressure at 10 ° C. The residue is dissolved in 10 ml of dimethylformamide, 1g of sodium acetate is added and the reaction mixture is stirred at 60 ° C. for twelve hours. The reaction mixture is then poured into 10 ml of concentrated hydrochloric acid and ice-cold, the solid precipitate is filtered off, washed. with water and dried.

   Yield 250 mg, melting point.



  150-158 C. The filtrate is exhausted with methylene chloride and the extracts are evaporated to give an oily residue of 180 mg. The solid (250 mg) and the oil (180 mg) are mixed and chromatographed on "Florisil". The eluates in 40% ether-hexane, mixed and distilled, give 110 mg of a residue melting at 140-155 ° C. and consisting essentially of 16-alpha-21-acetate.
 EMI15.3
 L1 & thYlPrefinan-3 alpha-170aiphao21-triol-11020 dione. ' This product is used without further purification as a raw material in the following process.



  D. 16-alpha-methylpreg-nane-17.alpl 21-acetate, a.21-diol-3.11-20-trione To a solution of 110 mg of the product of the example above 5 C in 2.5 ml of 80% tertiary butyl alcohol, 1 ml of glacial acetic acid and a drop of concentrated hydrochloric acid are added 100 mg of N-bromoacetamide at 5 ° C. and the reaction mixture is maintained at -5 ° C. for twenty hours. An aqueous solution of sodium bisulfite is added and the mixture is exhausted with methylene chloride. The organic extracts are evaporated so as to obtain a residue which is subjected to debromurization by treatment with powdered zinc in half.

  <Desc / Clms Page number 16>

 instead acetone-acetic acid. After filtration of the zinc from the reaction mixture, water is added to the filtrate.

   The precipitate thus obtained is filtered off and dried so as to obtain 40 mg of 16-alpha-methyl-pregnan-17-alpha-21-acetate. 21-diol-3.11. .
 EMI16.1
 



  E. 4-Bromo-160alpha-methjlpregnan-17 alphao21-diol-3.llo20 trione 21-acetate 80 mg of 16.alpha-methylpregnan-17.alpha.21-diol-3.11.20-trione prepared as it is dissolved. is described in Example 5 D in 3 ml of tertiary butyl alcohol and 3 ml of methylene chloride and subjected to bromination at 30-35 C by rapid addition of a solution of 32 mg of bromine in 4 ml of d tertiary butyl alcohol. The bromination is completed in two hours and the solution evaporated to siocity under reduced pressure.

   The residue obtained is stirred with water, filtered and dried to give 92 mg of a 4-bromo-16 21-acetate. alpha-methyl-pregnan-17.alpha.21-diol-3.11.20-trione which is used without further purification in the process which follows immediately
 EMI16.2
 F. 16.alpha-methyloortisone 21-acetate 92 mg of 4-bromo-16.alpha-methylpregnanel7.alpha-diol-3.11.20-trione 21-acetate of the above example are dissolved in 5 E in a mixture of 30 mg of semicarbazide, 4 ml of tertiary butyl alcohol and 2 ml of methylene chloride and stirred under nitrogen atmosphere for two hours at 25 - 30 C.

   The solvent is removed in vacuo and the residue thus obtained is dissolved in 5 ml of acetic acid and 80% water with an eight-fold molar excess of 70% pyruvic acid having regard to the molar quality of 4-bromo. -16.alpha-methylpregnane starting.



  The reaction mixture is allowed to stand at room temperature for twenty hours. Extended 5% aqueous sodium hydroxide is added until the pH of the reaction mixture is about 7 and the solution is then depleted with methylene chloride. The organic extracts are evaporated and the residue obtained is subjected to chromatography on "Florisil".

   The 50% ether-hexane eluates and the 100% ether eluates are mixed and evaporated to give a crystallized residue (25 mg) which is crystallized in acetone-hexane.
 EMI16.3
 so as to obtain 20 mg of 16-alpha-methyloortisone 21-acetate. 1% GeOH 238 mu (É 14e800) e max Example 6- l6.alpha-methylcortisone
 EMI16.4
 0.5 g of 1.6.alpha-methylcortisvne 21-acetate prepared as in Example 5 is dissolved in 20 ml of methanol and 2 ml of water containing 0.1 g of potassium bicarbonate. The solution is heated under reflux for half an hour then it is concentrated to half of its volume under vacuum and water is added.



  The precipitated solid is separated by filtration, dried and crystallized from methanol to give 16.alpha-methyl-oortisoneo.
 EMI16.5
 'j e0H 238 (15.200) 0 max II1f Example 70- 16.alpha-methylhydrocortisone
 EMI16.6
 A. 3.20-bis-semicarbazone of 16oalpha-methylortisone 21-acetate.



  A mixture of 2.5 g of 16-alpha-methyloortisone acetate prepared as in Example 5, 2 g of semicarbazide hydrochloride, 3 g of pyridine, 25 ml of water and reflux is refluxed for sixteen hours. 100 ml of methanol. The solution is concentrated to about 30 ml and then poured into water to
 EMI16.7
 precipitate with almost quantitative yield the 3e20-bis-semi-aarbAzone 16-alpha-methyl-cortisone 21-acetate, which is filtered and dried and used without further purification in the process which immediately follows .
 EMI16.8
 B. 3'20-bis-semioarbazone from 16.alpha-methylhydrooortisone
A solution of 3 g of the bis-semicarbazone from Example 7 A and 2 g of potassium borohydride in 100 ml of tetrahydrofuran and 50 ml of water is refluxed for three hours.

   The solution is cooled and

  <Desc / Clms Page number 17>

 acetic acid up to pH 5.5. The organic solvent is removed by distillation.
 EMI17.1
 The solids were collected by filtration to give the 3.20-bis-semicarbazone of 16-alpha-methylhydrocortisone which was used without further purification in the immediately following process.
 EMI17.2
 C. 160alpha-methylhydrocortisone
Under a nitrogen atmosphere, 5 g of the bis-semicarbazone of Example 7 B are dissolved in 250 ml of 2.4 N hydrochloric acid. The solution is cooled to 5 Ce and a solution of 2.5 g of sodium nitrite clans, 25 ml of water at 5 Ce over fifteen minutes.

   The reaction mixture is stirred for a further thirty minutes and then neutralized with 20% sodium hydroxide at a temperature below 15 ° C. The reaction mixture is exhausted several times.
 EMI17.3
 darned with chloroform. The chloroormic extracts are mixed and distilled under vacuum so as to obtain a solid residue which, crystallized from acetone, gives 160alpha-methjlhydnoeortisonea \ MeOH 240 mu (1 ° to 700) max Example 8 - 21-acetate of 16oalpha-methylhydrocortisone 100 mg of 16-alpha-methylhydrocortisone prepared as in Example 7 dissolved in 2 ml of pyridine containing 100 mg of acetic anhydride are left to stand at room temperature for one hour and left to stand at room temperature for one hour. room temperature for one hour.

   The reaction mixture is poured onto ice and hydrochloric acid and the precipitated solid is separated by filtration and crystallized from aqueous methanol to give 16-alpha-methylhydrocortisoneo 21-acetate.
 EMI17.4
 , IGIeOH 240 mf, <f 15 * 000) v max Example 9-16-alpha-n-butyloortisone A. 16-alpha-n-butylpregnan-3aalpha-ol-11o20-dione 16opregnene-3oalpha-ol-11 is reacted. 20-dione with butyl iodide and magnesium as described in Example 5 Ag to give 16.alpha-n-butylpregnan-3.alpha-ol-11o20-dione, which is crystallized in acetone-hexane breast.



  B. 16aalpha-n-butylpregnane-30alpha17 alpha-diol-llo20-dione The first step is to react the 16.alpha-n-butylpregnane-3oalpha-ol-11.20 dione prepared as in Example 9 A with the acid p- toluenesulphonic in acetic anhydride, then with 40% peracetic acid and sodium acetate, finally with an aqueous solution of sodium hydroxide as described in Example 5 Bo A solid product which, crystal-
 EMI17.5
 read within acetone, gives 16.alpha-n-butylpregnane-3.alpha.17.alpha-diol-11. 20-dtione.



  C. 16.alpha-n-butylpregnane-3oalphaol7oalpha.21-triol-11.20-dione 21-acetate
The bromination of 16.alpha-n-butylpregnane-3.alpha is carried out.



  17.alpha-11.20-dione, prepared as in Example 9B, then the product is treated with sodium acetate in dimethylformamide as described in Example 5 C. The product is isolated from reaction and purified as described to give 16-alpha-n-butylpregnane-3.alpha.17.alpha.21-triol-11.20-dione 21-acetate
 EMI17.6
 D. 160alpha-n-batylpregnan-17-alphaa21-diol-3.Il.20-trione 21-acetate 16.alpha-n-butyl-pregnan-3.alpha 21-acetate is reacted.



  17.alpha.21-triol-11o20-dione prepared as in Example 9 C with N-bromoacetamide and the product formed is isolated which is purified as described in Example 5 to give 21- 16 * alpha-n-butyÀp acetate> agan-17aalphaa 21-diol-3.11-20-trione.

  <Desc / Clms Page number 18>

 
 EMI18.1
 E. 4 - bromo-16 21-acetate. alpha-n-butylpregnan-17. alpha. 21 -diol-3.11.20-tri- one
The bromination of 16-alpha-n-butylpregnane 21-acetate is carried out.
 EMI18.2
 17.alpha.21'-diol-3.11.20-trione prepared as in Example 9 D and the product is isolated as described in Example 5 E to give ° -bromo- 21-acetate. 16.alpha-n-butylpregnan-17.alpha-21-diol-3e11.20-trione which is used without further purification in the next reaction.



  F. 16-alpha-n-butyloortisone 21-acetate
The 4-bromo-pregnan prepared in Example 9 E is reacted with semicarbazide, then with acetic acid and pyruvic acid as described in Example 5 F. The product is isolated and it was purified as described to give 16.alpha-n-butylcortisone 21-acetate.
 EMI18.3
 



  MEOH 238 (E14.800) o max Gas "''" i 'VOV, Example 10.- 16.alpha-n-butylcortisone
The 16-alpha-n-butylcortisone 21-acetate prepared as in Example 9 is hydrolyzed by means of potassium bicarbonate in methanol and
 EMI18.4
 of water as described in Example 6 to give 16.al.pha-n-butylcortisone.



  ... lYLeOH 238 mF (E 15,000 max Example 11.- 16.alpha-n-butylcortisone 21-n-butyrate
 EMI18.5
 100 mg of 16-alpha-n-butyloortisone prepared as in Example 10 are dissolved in 2 ml of pyridine containing 100 mg of butyric anhydride and left at room temperature for one hour. The reaction mixture is then poured into a mixture of ice and hydrochloric acid. A precipitate forms which is filtered and crystallized from aqueous methanol, this
 EMI18.6
 which gives .6.alpha-n-butylcortisone 21-n-butyrate.



  MeOH 238 (SI 1 ° o oo, Example 12- 9oalpha-bromo-16-21-acetate. 16-beta-methylhydrocortisone A. 16-ebeta-methyl-ó9 acetate, -pregnadien.e-17ealpha.21-diol-3.20 -dione
To a solution of 0.3 g of 16-beta-methyl-hydrocortisone 21-aoetate prepared as in Example 4 in 5 ml of pyridine is added 0.2 ml of benzene-sulfonyl chloride in 3. ml of pyridine. The solution is left to stand for four hours and then poured into a mixture of ice and hydrochloric acid.

   It precipitates a solid which is filtered and crystallized from acetone-hexane so as to obtain 16-beta-methyl-acetate.
 EMI18.7
 49-Pregnadien-17.alpha-diol-3e20-dione. max 239 m, (16.020), max B. 21-acetate of 9.alpha-'bromo-16.beta-methylhydrocortisone A suspension of 02 g of 16.beta-methyl- ° .9-pregna is stirred gently for two hours. .iene- of Example 1 A above in 20 ml of purified dioxane, 2 ml of water containing 0.1 g of N-bromo-acetamide and 1 ml of 1.5 N perchloric acid. this time the mixture becomes homogeneous.

   We then add
 EMI18.8
 an olifbion of 0.2 g of sodium sulphite in 2 ml of water and the solution is depleted with methylene chloride o The organic extracts are washed with water, dried and evaporated in such a way in obtaining a solid residue which is crystallized from acetone, which gives 9-alpha-bromo-16 21-acetate. beta-methylhydrocortisoneo
 EMI18.9
 At MeOR 243 mu (16 0100, / 1 max Example 13. - 9oalPha-bromo-160beta-methylhydrocontisone

  <Desc / Clms Page number 19>

 It is left to stand for forty-eight hours at room temperature.
 EMI19.1
 biante a mixture of 0.5 g of 9oalpha-bromo-16-beta-methylhydrocortisone 21-acetate prepared as in Example 12 in 100 ml of methanol, 20 ml of chloroform, 5 ml of water and 5 ml concentrated hydrochloric acid.

   Water is then added and the mixture is exhausted with methylene chloride. The organic extracts are washed with water, dried and concentrated to obtain a residue. The crystallization of this residue in acetone gives the 9.alpha-
 EMI19.2
 iromo-16.bgta-methylhydrocortisone.



  Example 14.- 21-g.alpha-fluoro-16-beta-methylhydrocortisone A acetate 9abétaalabeta-oxydo-16.béta-methyl- ° -pregnen7.alphaa21diol-3.20 dione A 0.3 g of 21 -9alpha bromo-16beta-acetate-methyl-hydrocortisone prepared as in Example 12 in 20 ml of methanol 0.3 g of potassium acetate is added a The mixture is heated under reflux for two hours, then concentrated under empty so as to obtain a residue.

   Water is added to the residue and a solid separates which is filtered and crystallized from methanol-ether so as to obtain 0.1 g of 9-beta-11-beta 21-acetate. -oxydo- 16.beta-methyl-4-pregnene-17.alpha.21-diol-3.20 dione.
 EMI19.3
 9aalpha-fluoro-16abeta-methylhydrocortisone 21-acetate A solution of 0.2 g of the 9 alpha.ll.beta-oxido-4 "pregnene of Example 14 A in 10 ml of chloroform free from is saturated. alcohol using anhydrous hydrofluoric acid at 0 C. The mixture is left to stand for four hours at 0 C., then the mixture is concentrated in vacuo until a residue is obtained. Crystallization of the residue from acetone-hexane gives 0.1 g of 9.alpha-flu- 21-acetate
 EMI19.4
 oro-16.beta-methyl-hydrocortisone.



  Example 15-21-Acetate 9.alpha-choro-16.beta-methylhydrocortisone A solution of 0.2 g of 9abeta.llabeta-oxydo-prean of Example 14 A in 30 ml of chloroform free of alcohol at 0 ° C. with anhydrous hydrochloric acid and the mixture is left to stand at 0 ° C. for six hours.

   The solvent is distilled off the reaction mixture under vacuum, which leaves a residue which, crystallized from acetone and water, gives 0.2 g of 9.alpha-
 EMI19.5
 16-ohloro-obeta-methylhydrocortisone '\ MeOH 241 (C 16 0 600) max mr v Example 16, - 9'alpha "fluoro-16.beta-methylhydrooortisone As described in Example 13, the 21-acetate is converted from balpha-fluoro-l6abêtamethylhydrooortisone prepared as in Example 14 in 9oalpha-fluoro-l6abêta-methylhydrocortisone by means of hydrochloric acid in a: methanol-chloroform-water mixture.



  Example 17¯.- 21-alpha-bromo-l6aalphamethylhydrooortisone A. 21-acetate .6alpha-methyl-á9-prégnadzcne-aalpha21-dîoZ-3a20 dione 0.2 g of 16-alpha-21-acetate is added. methyl-hydrocortisone prepared as in Example 7 in 3 ml of pyridine and 0.1 ml of benzene-sulfonyl chloride in 2 ml of pyridine is added. The solution is left to stand for four hours and then poured into a mixture of ice and hydrochloric acid.

   It precipitates a solid which is separated by filtration and which is crystallized in acetone so as to obtain 16-alpha-methyl-4- 21-acetate.
 EMI19.6
 9-prégnadiênel7aalpb.aa21-dzol-3a20 dione M60H 238 m, (E 16a300) a // P "ma G vx B. 21-oalpha-'bramol6oalpha-methylhydrocortisone acetate A 0.2 g suspension of 16 .alpha-methylpreea-diene of Example 17 A in 20 ml of purified dioxane, 2 ml of water and contained

  <Desc / Clms Page number 20>

 0.08 g of N-bromoacetamide and 0.8 ml of 1.5 N perchloric acid for two hours. During this time the mixture becomes homogeneous. A section of 0.2 g of sodium sulphite in 4 ml of water is added and the solution is then depleted with methylene chloride.

   The organic extracts are washed with water, dried, filtered and evaporated to give a residue of 0.1 g of 21.-
 EMI20.1
 9.alpha-'bromo-16alpha-methylhydrocortisone acetate.



  At MeOR 242 rof (± 16,400). max / a (Example 18.- 9.alpha-fluoro-16.alpha-methylhydrocortisene A. 21-acetate of g.beta.1l.bgta-oxydo-16.alpha-methyl-4-pregnene-17.alpha.21 - diol-3.20 dione
A mixture of 0.3 g of 21- is refluxed for two hours.
 EMI20.2
 9.alpha-bromo-16, alpha-methylhydrocoitisone acetate prepared as in Example 17 in 20 ml of methanol and 0.3 g of potassium acetate, then concentrated to obtain a residue.

   Water is added to the residue and the precipitated solid is separated by filtration, which is crystallized from ma- methanol.
 EMI20.3
 nière to obtain 0.1 g of 21-acetate of 9.beta.ll.beta-oxydo-16.alpha-methyl-4-pregnene-17.alpha.21-d16Ç-3020 dione B. 21-acetate of 90alxha- fluoio-160alpha-methylhydiocoitisone A solution of 0.2 g of 9ebeta.3.l.leta-bcydo.alpha-methyl-4-pregnene of the above example 18 A in 10 ml of chloroform free of alcohol using anhydrous hydrofluoric acid at 0 ° C. The mixture is left to stand for five hours at 0 ° C. then the mixture is concentrated under reduced pressure until a residue is obtained. Crystallization of the residue from acetone-hexane gives
 EMI20.4
 ne 0.1 g of 9.alpha-fluoro-16.alpha-methylhydrocortisone 21-acetate.



  , 3 of 0H 238 mu (1116,200). max C. 9 alpha-flupro-16.alpha-methylhydrooortisone As described in Example 13, the 21-acetic ester prepared in Example 18 B is converted into the free alcohol, 9ealpha-fluoro-l6ealphamethylhydrocortisone by means of hydrochloric acid within methariol-chloroform-water.



  Example 19.- 16-beta-n-butyl-oortisone 21-acetate
 EMI20.5
 A. 17-bromo-16.alpha-n-butylpregnan-3.alpha-ol-11.20-dion 1 g of 16.alpha-n-butylpregnan-3.alpha-ol-11.20-dione prepared as in Example 9 A in 10 ml of acetic acid and then the bromination is carried out using 1.1 equivalents of bromine in acetic acid. When the color of the bromine has disappeared, the solution is poured into the water which causes the pre-
 EMI20.6
 capitation of a solid formed essentially of 17-bromo-16.alpha-n-butyl-pregnan-3.alpha-ol-11.20-dione.

   This 17-brominated compound is filtered off which is used in the operation which follows without further purification.
 EMI20.7
 B. 16-n-butyl-16-pregnene-3.alpha-ol-11.20-dione To 17-bromo-16.alpha-n-butylpregnane prepared in the example above
 EMI20.8
 To this is added 10 ml of dimethylformamide and the reaction mixture is heated under reflux for two hours. The solution is poured into extended hydrochloric acid and then exhausted with methylene chloride. The organic extracts are washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo until a residue formed essentially of 16-n-butyl- is obtained.
 EMI20.9
 16-Pregnene-3.alpha-ol-11.20-dione which is used without further purification in the process which follows.



  C. 16.beta-n-butylpregnan-3.alpha-ol-11.20-dione
 EMI20.10
 The 16-n-butyl-16-pregnene-3ealpha-ol-11.20-dione prepared in the above example 19 B is dissolved in 10 ml of acetic acid and subjected to hydrogenation with the aid of a palladium-on-charcoal catalyst. When a

  <Desc / Clms Page number 21>

 hydrogen molecule has been absorbed, the reaction is stopped, the catalyst is removed by filtration and the filtrate is poured into water ... 11 precipitates a solid which is filtered and crystallized in acetone-hexane and who is there
 EMI21.1
 16.bgta-n-butylpregnan-3, alpha-ol-11.20-dione.



  D. 16, beta-n-butylpregnan-30alpha.170alpha-diol-llo20-dione As described in Example 1 D is first reacted there 16.beta-n-butylpregnan-3.alpha-ol -11.20-dione prepared as in Example 19 C with p-toluenesulfonic acid in acetic anhydride, then with sodium acetate in 40% peracetic acid, finally with aqueous sodium hydroxide.

   The product thus obtained is isolated and it is purified in the manner
 EMI21.2
 re described in Example 1D which gives 16.bgta-n-butylpregnane-3.alpha.17. alpha-diol-llo20-dioneo E. 21-acetate of 16obeta-n-butylpregnane-3oalpha.17.alpha-21-triol-11.20-dione The 160beta-n-butylpregnane of Example 19 D is reacted first with bromine in chloroform, then with sodium acetate and dimethylformamide and the product is isolated and purified as described.
 EMI21.3
 in Example 1 E, which gives 16beta-nbutylpregnane-3.a1pha.17.alpla.21-triol-11.20-dione 21-acetate.



  F. 16ebeta-n-butylpnegan-170alphao21-diol-3011020-trione 21-acetate As described in Example 1 F, the bromination of 16-beta-n-butylpregnane-3.alpha 21-acetate is carried out .17.alpha.21-triol-11.20-dione and the product formed is isolated, which is purified so as to obtain .beta-n-butyl-pregnanel7oalphao2ldiol-3o11o20-trione 21-acetate.



  G. 21-acetate de 4-bnomo-160béta-n-butylpégnane-170alpha.21-àiol-3011.20-trione The 21-acetate of 16.beta-n-butylpregnanel7.alphao21-diol-3.11ô20- is bromined. trione as described in Example 1G to give 4-bromo-16.beta-n-butylpregnan-17.alpha.21diol-3o11.20-trione 21-acetate.



  H. 21-beta-n-butylcortisone acetate
The 4-bromo derivative of the above example 19 C is dehydrobrominated by means of semicarbazide and 80% aqueous acetic acid and 70% pyruvic acid in the manner described in Example 1H, which gives the
 EMI21.4
 16-beta-n-butylcortisoneo 21-acetate MEOH 238 ml'- (t 14,500).



  / 1 max Example 20- 16.beta-n-butylcortisone The 21-acetate of 16obeta-n-butylcortisone is hydrolyzed with a hydroalcoholic solution of potassium bicarbonate as described in Example 2 to give 16.beta-n-butylcortisone.
 EMI21.5
 



  MeOH 238 mu (t 15,000).



  Max 1 Example 21.- 16-beta-methylprednisone A-21-acetate 204-dibromo-16 21-acetate <beta-methylpregnan-17, alpha.21-diol-3, Il * 20- trione
A solution of 167 is subjected to dibromuration in position 2 and 4
 EMI21.6
 mg of 16.beta-methylpregnan-17.alphao21-diol-3.llo20-trione 21-acetate, the compound of Example 1 F, in 3 ml of dioxane by the rapid addition of 130 mg of bromine in 1 ml of dioxane at room temperature. The solution is poured into water and the precipitated solid is filtered off to give 180 mg of
 EMI21.7
 2o-dzbromo-16a'beta-methyl-px agan-17oa11haa21-diol-3.3.1.20-trione 21-acetate of sufficient purity to be used in the conversion described in the following process.

  <Desc / Clms Page number 22>

 



  B. 16-beta-methylprednisone 21-acetate
180 mg of 2.4-dibromide prepared in Example 21 A above are dehydrated by reflux for two hours with 4 ml of dimethylformamide containing 30 mg of calcium aarbonate. The mixture is poured into extended hydrochloric acid and exhausted with methylene chloride.



  The organic extract is evaporated so as to obtain a residue of 150 mg which is subjected to chromatography on "Florisil". The fractions obtained by elution with 20% ether-hexane are crystallized from acetone-hexane, which gives 40 mg of 16-beta-methylprednisone 21-acetate, melting at 210-216 ° C.



  Further crystallization gives a melting point of 215 - 218 C.



  #MeOH max 237 m (# 13.500).



  Example 22-16 beta-methylprednisone
16.beta-methylprednisone 21-acetate (0.5 g), compound of Example 21, hydrolyzed with hydroalcoholic potassium bicarbonate as described in Example 2 gives 16.beta-methylprednisone.



   Another method of preparing the compound of this example is as follows.



   Bacillus sphaericus var.fusiformis (ATCC 7055) is incubated in nutrient agar (composed of "Bacto" beef extract 3 g, "Bacto" peptone 5 g, sodium chloride 8 g, agar 15 g, water. ordinary 1 liter) for twenty-four hours at 28 C.



   To 100 ml of a sterile nutritive broth (composed of "Bacto" beef extract 3 g, "Bacto" peptone 5 g per liter of ordinary water) in a 300 ml flask is added a loop of the culture subjected to the test. incubation and then the mixture is incubated for twenty-four hours at 28 ° C. on a shaking machine.



  The culture broth thus obtained is used as an inoculum (1%).



   In ten flasks each containing 100 ml of sterile nutrient broth, 1 ml of inoculum is added. The fables are stirred on a rotary shaker for eight hours at 240 passes per minute. After this development period a solution of 25 mg of 16-beta-methylcortisone, compound of Example 2, in 0.5 ml of methanol, is aseptically added to each vial which is shaken again for a further twenty-four hours. The final pH is 7.8.



   The contents of the vials are mixed and exhausted three times with 2 liters of chloroform per exhaustion. The mixture of chloroform extracts is evaporated to dryness to give 310 mg of crude product. The crude steroid is purified by chromatography on the chromatographic system described by G.M. Shull, Abstracts of Papers of the 16th Merting of the American Chemieal Society, December 12-17, 1954, p. 9a, N 24. Chromatographic evaluation shows a quantitative conversion of starting material to diene when a chemically pure sample of 16-beta-methylprednisone is used as a control.



   The crude product can be recrystallized from acetone, which gives 225 mg of l6.bêta-methylprednisone.



    Exempt 23 o- 16.beta-methylprednisolone
The compound of Example 3, 16-beta-methylhydro-cortisone, is fermented with Bacillus sphaerious, var. fusiformis, (ATCC 7055) as described in the alternate method of Example 22 to produce 16.beta-methyl-predniseloneo Example 24 - 16-beta-methylprodnisolone 21-acetate
The 16-beta-methylprednisolone of Example 23 was treated with acetic acid and pyridine as described in Example 4 to give 16-beta-methylprednisolone 21-acetate.

  <Desc / Clms Page number 23>

 



  Example 25 16-alpha-methylprednisone 21-acetate
Debromination of a solution of 40 mg of 21-acetate is carried out
 EMI23.1
 of l7.alpha-.21-dihydroxy-l6.alpha-methylpregnane-3a11.20-trione, the compound of Example 5 D, in 2 ml of dioxane, by rapid addition of 32 mg of bromine in 1 ml of dioxaneo Water is added and the mixture is exhausted with methylene chloride. The solvent is dried over magnesium sulfate, filtered and distilled under reduced pressure. The residue thus obtained (55 mg) is heated to reflux with 2 ml of dimethylformamide and 10 mg of calcium carbonate for two hours, then poured into ice-water containing 2 ml of concentrated hydrochloric acid.

   The mixture is exhausted with methylene chloride, the organic extracts are washed with an extensive solution of sodium bicarbonate and with water and then evaporated until a residue is obtained, which is subjected to washing. chromatography on "Florisil" to give 15 mg of 16-alpha-methyl prednisone 21-acetate. max 238 m (# 14.000).
 EMI23.2
 



  Example 26.- 16oalpha-methylprednisone
As described in Example 6, the hydrolysis of 0.3 g of 16.alpha-methylprednisone 21-acetate using a hydroalcoholic solution of bi-
 EMI23.3
 potassium carbonate gives 16 alpna-methylprednisone.



  Example 27 16-alpha-methylprednisone 21-propionate
The compound of Example 26, 16.alpha-methylprednisone, was reacted with the propionic anhydride according to Example 4 to give 16.alpha-methylprednisone 21-propionate. Example 28-16. alpha-methylprednisolone
Bacillus sphaericus var. fusiformis (ATCC 7055) on nutrient agar (with "Bacto" - beef extract 3 g, "Bacto" peptone 5 g, sodium chloride 8 g, agar 15 g and plain water 1 liter) for twenty-four hours at 28 C .



   To 100 ml of sterile nutrient broth (composed of "Bacto" beef extract 3 g, "Bacto" peptone 5 g per liter of ordinary water) in a 300 ml flask is added a loop of the incubated culture and incubated. mixing for a further twenty-four hours at 28 ° C on a shaking machine. The broth thus obtained is used as an inoculum (1%).



   In ten vials each containing 100 ml of sterile nutrient broth, 1 ml of the inoculum is added. The vials are shaken on a rotary shaking machine at 28 ° C. and 240 passes per minute. After this development period, a solution of 25 mg of 16 alpha-meta is aseptically added to each vial.
 EMI23.4
 thyl-hydrooortisone, the compound of Example 8, in 0.5 ml of methanol, and again shaken for twenty-four hours. The final pH is 7.80
The contents of the flasks are mixed and exhausted three times with 2 liters of chloroform by extraction. The mixture of chloroform extracts is evaporated to dryness, which gives 310 mg of a residue which is crystallized from within. acetone-hexane, which gives 16.alpha-methylprednisolone.



    Example 29 - 16-alpha-methylprednisolone 21-acetate
A solution of 100 mg of 16.al- is left to stand for one hour.
 EMI23.5
 pha-methylprednisolone in 2 ml of pyridine containing 100 mg of acetic anhydride. The mixture is poured into a mixture of ice and hydrochloric acid and the mixture is poured. a precipitate is obtained which is removed by filtration.

   Crystallization of the precipitate from aqueous methanol gives 16.alpha-methyl-prednisolone 21-acetate.
 EMI23.6
 example 300- 21-acetate de.9alpha-bromo-16o'beta-methylprednisolone A. 21-acetate of 16.bgta-methyl-1-.4.9 (II) -pregnatriene-17.alpha.21-diol-3.20-dione

  <Desc / Clms Page number 24>

 
A solution of 0.5 g of 16-beta-methylprednisolone 21-acetate, the compound of Example 24, in 3 ml of pyridine is reacted with 0.3 ml of methanesulfonyl chloride in 4 ml of pyridine. . The solution is left to stand for six hours and then poured into a mixture of ice and hydrochloric acid.

   A solid precipitate is obtained which is removed by filtration and which is crystallized from acetone-hexane, which gives 21-acetate.
 EMI24.1
 16.beta-methyl-1.4.9 (11) -pregnatriene-17.alpha.21-diol-3.20-dione, \ MeOH 238 1I1J, l (E 14e750) a max B. 9-alpha-bromo 21-acetate -16.bgta-methylprednisolone
A suspension of 0.5 g of the 16-beta-methyl-pregnatriene of Example 30 A above in 50 ml of purified dioxane in 5 ml of water is gently stirred.
 EMI24.2
 containing 0.2 g of N-bromoacetamide and 2 ml of 1.5 'N perchloric acid for a period of two hours during which the mixture becomes homogeneous.



  A solution of 0.5 g of sodium sulfite in 5 ml of water is added and the reaction mixture is exhausted with methylene chloride. The organic extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. The solid thus obtained is crystallized from acetone so
 EMI24.3
 to obtain 0.3 g of 9.alpha-bromo-16-beta-methyl-preclnisoline 21-acetate. # MeOH max 242 m (# 14.950).
 EMI24.4
 



  Example 31 9α.lpha-fluoro-16.beta-methylprednisolone 21-acetate A. 90betaollobeta-oxyano-16-beta-acetate, beta-methyl-lo4-pregdaien-170alpha.



  21-diol-3.20 dione 1 g of 9, alpha-bromo-16, beta-methyl-piednisolone 21-acetate, the compound of Example 30, is added to 65 ml of methanol and 1 g of acetate. of potassium and the mixture is heated under reflux for two hours, then concentrated to a residue. Water is added to the residue and the sol is removed.
 EMI24.5
 lide formed by filtration. It is crystallized in seim-methanol-water and 0.6 g of g.beta.1l.bgta-oxido-16.beta-methyl-1.4-pregnadien-17.alpha.21- 21-acetate is obtained. diol-3.20-dione.
 EMI24.6
 



  'maOxH 242 mu (L 13.850).



  B. 21-acetate 9.alpha-fluoro-16.beta-methylprenisQlcane A solution of 0.4 g of the 9abetaollobeta-oxido-1. ° -pregnadiene of Example 31 A in 20 ml of free chloroform is saturated. alcohol by means of anhydrous hydrofluoric acid at 0 ° C. The mixture is left to stand for four hours at 0 ° C. then the mixture is concentrated under reduced pressure so as to obtain a residue.



  Crystallization of the residue from acetone-hexane gives 0.2 g of 21-acetate
 EMI24.7
 of 90alpha-fluoro-160beta-methylpieanisoloneo j MeOH 238 mu (15,100). max Example 32. 9.alpha-fluoro-16.beta-methylprednisolone The 90alpha-fluoro-160beta-methyl-prednisolone 21-acetate of Example 31 is converted to 9.alpha-fluoro-16obLta, methyl-pred. niso7, ihe using hydrochloric acid in methanol-chloroform-water medium as described in Example 13.
 EMI24.8
 



  Example 330- 9'alpha-bromo-16 obeta-methylprednis olone The 9oalpha-bromo-16, beta-methyl-prednisolone 21-aoetate of Example 30 from Example 30 is converted to 9oalpha-bromo-16.beta-methylprednisolone according to Example 13 using ohlorhydriqe acid in methanol-chloroform-water medium. example 3a- 21-acetate of 90alpha-chloro-16 beta-methylprednisolone A solution of 0.3 g of 90betaollabeta-oxy- 21-acetate is saturated.

  <Desc / Clms Page number 25>

 
 EMI25.1
 do-16obeta-methyl-1.4-pregazadiene-17oa1phao27-diol-3.20-dione of Example 31 A in 40 ml of alcohol-free chloroform, at 0 C, by means of anhydrous hydrochloric acid, and the mixture is left stand at 0 C for six hours.

   The mixture is concentrated under reduced pressure so as to obtain a residue which is crystallized from acetone and water, which gives 0.2 g of 9.alpha- 21-acetate.
 EMI25.2
 chloroLl6obéfla-methylprednis'ôlonee MeOH '240 mp (150000>, max 15-000) - Example 35.- g.alpha-chloro-16.bgta-methylprednisolone According to example 13, the 21-acetate of g, alpha is converted -chloro-16. beta-methylprednisolone to 9aalpha-chloro-160beta-methylprednisolone.



  Example 360- 9oalpha-fluoro-16obeta-methyl-prednisone 21-acetate To a solution of 0.3 g of 9.alpha-fluoro-16-beta-methylprednisolone 21-acetate from Example 31 in 15 ml of acetic acid is added dropwise a solution of 60 mg of chromic anhydride in 1 ml of water and 3 ml of acetic acid. The mixture thus obtained is left to stand for five hours then it is spread with water and exhausted with methylene chloride. The organic extracts are washed with water, dried over magnesium sulphate, filtered and evaporated, which gives a residue which is crystallized within m-,
 EMI25.3
 thanol which gives 0.1 g of 90alpha-fluono-160beta-methyl-piednisone 21-acetate.



  Example 37 - 9 o alpha-fluoro-16obeta-methylprednisone 'As described in example 13, the 21-acetate of 90alpha-fluoio-16abeta-methylpnednisone is hydrolyzed to 9oalpha-fluoro-160beta-methylprednisone by means of chlorh acid drric in methanol-chloroform-water medium.



  Example 38 - 9oalpha-chloro-16obeta-methylprednisone.A. 9oalpha-ohloro-l6obeta-methylprednisone 21-aoetate 90alpha-chloio-1 $ obeta-methylpiednisole 21-acetate from Example 34 is reacted with chromic anhydride in aqueous acetic acid according to Example 36 and 90alpha-chloio-160betamethylprednisone 21-acetate is obtained.



  B. 9oalphabromo-l6obeta-methylprednione
As described in Example 13, the 21-acetate of Example 38 A is reacted with hydrochloric acid in methanol-chloroform-water.
 EMI25.4
 which gives g.alpha-chloro-16.beta-methylprednisone., Example 39.- g.alpha-bromo-16.beta-methylprednisone A. 9.alpha-bromo-16.beta-methylprednisone 21-acetate. reacting the 90alpha-biomo-160beta-methylpranisolone 21-acetate of Example 30 with chromic anhydride in aqueous acetic medium according to Example 36, which gives 9pâlpha-'bromo-l6obeta-methylprednisone 21-acetate .



  B. 9oalpha-bromo-16.beta-methylprednisone
In the manner of Example 13, the 21-acetate of Example 39 A is reacted with hydrochloric acid in methanol-chloroform-water medium, this
 EMI25.5
 which gives 90alpha-boeomo-160beta-prednisoneo Example 400- 9.alpha-bromo-16oalpha-methylprednisolone A. 16oa.phammethyl-1a4o9 acetate (11-prégnatriene-l7oalpha-21diol-3o20 dione
 EMI25.6
 A solution of 0.3 g of 160a1pha-methyl-prednisolone 21-acetate from Example 29 in 2 ml of pyridine is reacted with 0.1 ml of methyl chloride.

  <Desc / Clms Page number 26>

 thane-sulfonyl in 2 ml of pyridine. The solution is left to stand for five hours and then poured into a mixture of ice and hydrochloric acid.



  A solid precipitate forms which is separated by filtration and which is crystallized from acetone so as to obtain 16-alpha-methyl-21-acetate.
 EMI26.1
 1.4-9. (Il) -pregnatriene-17.alpha.2l'-diol-3.20-dione. eoH 238 m (15.200). max B. 21-alpha-bromo-16.alpha-methylprednisolone acetate A 0.3 g suspension of the 16.alpha-methyl-1.4,9 (II) -prregnatriene of Example 40 A is gently stirred in 30 ml of purified dioxane, 3 ml of water,
 EMI26.2
 containing 0.1 g of N-bromoacetamide and 1 ml of 1.5 N perchloric acid for a period of two hours during which the mixture becomes homogeneous. A solution of 0.3 g of sodium sulphite in 5 ml of water is added, then the solution is exhausted with methylene chloride.

   The organic extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. The solid thus obtained is crystallized from methanol, which gives 0.2 g of
 EMI26.3
 .Alpha-bromo-16.alpha-methylprednisolone 21-acetate.



  At MeOH 243 mu (14,800). max Go 9.alpha-bromo-1 & oa, lpha-methylprednisolone As described in Example 13, 9 * alpha-bromo-l6oalpha-methylprednisolone 21-acetate is reacted with hydrochloric acid in methanol-chloroform -water, which gives 9.alpha bromo-16.alpha-methyl-prednisolone.



  Example 410- g.alpha-fluoro-16.alpha-methylprednisolone / A. 21-acetate of 9bi; a.ll, beta-oxydo-16.alpha-methyl-1.4-pregnadiene-l'j.alpha.



    21-diol-3o20-dione
A mixture of 0.5 g of 21- is refluxed for two hours.
 EMI26.4
 9aalpha-bromo-16.alpha-methylprednisolone acetate from Example 40 B, 30 ml of methanol and 0.5 g of potassium acetate then the mixture is concentrated so as to obtain a residue. Water is added to the residue , the precipitated solid is filtered off and crystallized from methanol, which gives 0.3 g of 9.bê- 21-acetate.
 EMI26.5
 ta, II, beta-oxido-16, alpha-methyl-lo4-piégnadien-17aaiphao21-aliol-3 * 20-dione.



  \ MeOH 243 T (t. 140050) A1 max B. 9.aipha-fluoro-16oalpha-methylprednisolone 21-acetate A solution of 0.2 g is saturated with 9ebtaell.beta-oxydo-16.alpha-methylpregnadiene. Example 41 A in 10 ml of chloroform free from alcohol using anhydrous hydrofluoric acid at 0 C. The mixture is left to stand for five hours at 0 C. then the mixture is concentrated so as to obtain a residue, under reduced pressure. Crystallization of the residue from acetone-hexane gives
 EMI26.6
 0.15 g of 9.alpha-fluoro-l6aalpha-methyl-prednisolone 21-acetate.



  \ MeOH 238 (5.200).



  1 \ max C. 9oalPha-fluoio-16, alpha-methylpiednisolone
According to the process of Example 13, using hydrochloric acid in chloroform-methanol-water, the 21-acetate is converted to 9.alpha-fluoro--
 EMI26.7
 16.alpha-methylprednisolone to 9.alpha-fluoro-l6oalpha-methylprednisolone.



  Example 42o- 9.alpha-chloro-16.alpha-methylprednisolone .A .. 9-alpha-chloro-16oalpha-methylprednisolone 21-acetate A solution of 0.2 g of 90betaolibeta-oxydo-piégnadiene is saturated with. example 41 A in 30 ml of chloroform free of alcohol at 0 C using anhydrous hydrochloric acid and the mixture is left to stand at this temperature for a while

  <Desc / Clms Page number 27>

 for six hours.

   The mixture is concentrated under reduced pressure so as to obtain a residue which is crystallized from acetone-hexane, which gives
 EMI27.1
 0.15 g of 9oalpha-chloro-l6aalpha-methylprednisoloneo 21-acetate or 241 (15 0 250) max B. 9aalpha-chlono-160alpha-methylpnednisolone According to the process of Example 13 using hydrochloric acid in 'chloroform-methanol-water medium, the 21-acetate of Example 42 A is converted into
 EMI27.2
 9.alpha-chloro-16.alpha-methylprednisolone.



  Example 43 '"9" a-1pha-fluoro-lë o alpha-methylprednisone Ao 90alpha-fluoro-160alpha-methylprednisone 21-acetate To a solution of z2 g of 90alpha-fluoro-160alpha-methylprednisolone 21-acetate from Example 41 B 10 ml of acetic acid are added dropwise to a solution of 40 ming of chromic anhydride in 1 ml of water and 2 ml of acetic acid. The mixture thus obtained is left to stand for six hours, then it is spread with water and exhausted with methylene chloride. The organic extracts are washed with water, dried over magnesium sulfate, filtered and evaporated to dryness, then the residue is crystallized from methanol,
 EMI27.3
 which gives 0.1 g of 21-acetate of g.alpha-fluoro-16,> alpha-methylpredhisonP.



  MEOH 237 my (t, 140000) 0 max B. 90alpha-flupro-160alpha-methylpnednisone The 21-acetate of Example 43 is hydrolyzed to 9oalpha-fluoro-16.alpha-methylprednisone according to Example 130 Example 440-9. al) ha-chloro-16.alpha-methylprednisone As described in Example 43 A, the 9aalpha-chloro-16oalphamethylprednisolone 21-acetate of Example 42 is reacted with chromic anhydride to give 21 -9aalphachloro-l6.alpha-methylprednisoneo acetate
As described in Example 13, the 21-acetate of this example is reacted with hydrochloric acid, in chloroform-methanol-water medium,
 EMI27.4
 which gives 1 alphachlorol6os,

  lphammethylprednisoneo Example 45 - g.alpha-bromo-16 .alpha-methylprednisone As described in Example 43, the 9-alpha-bromo-16oalpha-methylprednisolone 21-acetate of Example 40 B is reacted with Example 40B. chromic anhydride which gives 9oalphabromol6oalpha-methylpreânisoneo 21-acetate
This 21-acetate, treated with hydrochloric acid in a chlorofor- medium. me-methanol-water according to the method of Example 13, gives the free alcohol 90alpha-bromo-16.alpha-methylprednisone.
 EMI27.5
 



  Example 46 - 9oalpha-chloro-16oalpha-methylhydrocortisone As described in example 42, the 9-beta-lobeta-oxydo-16oa7phamethyl-° pregnene-17oa1pha.21-diol 21-acetate of Example 18 A is reacted. with hydrochloric acid in chloroform medium, which gives 9, alpha-chloio-16aalpha-methylhyàrocoitisoneo A lYleOH 252 oey 21-acetate (t. 16,400)
The 21-acetate above hydrolyzed with hydrochloric acid in chloroform-methanol-water medium according to the process of Example 13 gives the 90alpha-
 EMI27.6
 methyhydrocortisone.



  Example 7 9oalphaciloro-16oalphamethylcort.sone As described in Example 36, 9.alpha-chloro-16-alpha-methylhydrocortisone 21-acetate is reacted with chromic anhydride in the breast.

  <Desc / Clms Page number 28>

 
 EMI28.1
 water and acetic acid to give g.alpha-chloro-16.alpha-methylcortisone 21-acetate.
 EMI28.2
 MEOH 239 flp (É15 o100) o max
The 21-acetate above hydrolyzed with hydrochloric acid in chloroform-methanol-water medium according to the process of Example 13 gives the 9.alpha-
 EMI28.3
 Chloro-16.alpha-methyloortisone.



  Example 48. - 9.alpha-fluoro-16.alpha-methylcortisone
As described in Example 36, the 21-acetate is reacted
 EMI28.4
 of 9.alpha-fluoro-16.alpha-methylhyd, rocortisone of Example 18B with chromic anhydride in water and acetic acid, to give the 21-acetate of g.alpha-fluoro- 16.alpha-methyloortisone. max P37 lùf (15 e000) max
According to Example 13, the above 21-acetate is hydrolyzed by means of hydrochloric acid in chloroform-methanol-water, which gives 9.alpha-fluoro-16.alpha-methylcortisone.
 EMI28.5
 



  Example 49.- 9'a-lp -'bromo-16. alpha-methylcortisone As described in Example 36, the 9-alpha-bromo-16-alpha-methylhydrocortisone 21-acetate of Example 17 B is reacted with chromic anhydride in acetic medium, to give the 9.a.lpha-bromo-16 21-acetate. alpha-methylcortisone.



  MEOH 241 (14 e'ï0o) #max
The 21-acetate above hydrolyzed with hydrochloric acid in methanol-water-chloroform medium in the manner described in Example 13 gives
 EMI28.6
 the 9, alpha-biomo-16, alpha-methylcoitisonea Example 50.- 21-acetate of 16oalpha-ethylcortisone By carrying out the series of reactions described in example 9 (A to F), the 16-pregnene is first reacted -3alpha-olelle2Q-dione with ethyl-magnesium iodide which gives the desired intermediate, 16.alpha-ethylpregnan-3.alpha-ol-11.20-dione which is itself finally converted into 21-acetate of 16.alpha-ethyloortisone which is isolated and purified as described in Example 9 F.



  Example 51 - 16.alpha-ethyloortisone
 EMI28.7
 The above 16-alpha-ethylcortisone 21-acetate, hydrolyzed with aqueous potassium bicarbonate as described in Example 2, gives 16.alpha-ethyl-cortisone.



  Example 52.- 16ea1pha-ethylpranisone
The 160alpha-ethylcortisone of Example 51 is subjected to the action of Bacillus sphaericus var. fusiformis and the 16.alpha-ethylprednisone thus obtained is isolated and purified according to Example 22.



  Example 53 - 16.alpha-ethylhydrocortisone
160alpha-ethylcortisone 21-acetate is converted to bis-semicar-
 EMI28.8
 bazone which supplies L6.alpha-ethylhydrooortison. as described in Example 7.



    CLAIMS.

** ATTENTION ** end of DESC field can contain start of CLMS **.


    

Claims (1)

"Having thus described our invention and reserving the right to make any improvements or modifications that we consider necessary, we claim as our exclusive and provative property". <Desc / Clms Page number 29> 1) Process for the synthesis of derivatives of cortisone, hydrocortisone, prednisone, prednisolone and their 90alpha-halides and 21-esters from steroids having the carbon skeleton of pregnane and a 16-17 double bond conjugated with a group 20 ketone, consisting in reacting the starting 16-dehydro compounds with one or more reagents capable of introducing a lower alkyl group in position 16 of the steroid compound ', then in EMI29.1 troduct a 170alpha-hydroxy group in said 16-alkyl-steroid, which gives a 16-alkyl (ini) -170alpha-hydroxy-steroid consisting of or convertible to an alkyl derivative at position 16 of cortisone, hydrocortisone, prednisone , prednisolone and their 9 ′ alpha-halides or 21-esters. 2) Methods of carrying out the above process characterized by the following points separately or in combinations: EMI29.2 a) the lower alkyl group is introduced in posit -'i'cà-16.alpha; b) the lower alkyl group is introduced in position 16.beta; c) said alkyl group is a methyl group; @ d) said alkyl group is an ethyl group; e) the reagent is a lower diazoaloane and the intermediate pyrazolin derivative formed is heated so as to form 16-alooyl-16-pregnene; f) the reagent is a lower alkyl type compound and provides a 16-lower alkyl derivative; g) the reagent is an alkyl (info) -magnesium halide; h) the reagent is a lower diazoalkane; i) the reagent is diazomethane; j) the reagent is a lower nitroalkane; k) the reagent is nitromethane; 1) the starting compound is a 16-pregnene-3-ol-20-one or its allo epimer or its esters; EMI29.3 m) the starting compound is 16-pregnene-3-ol-lio20-aione or its allo epimer or its esters; n) the starting compound is 5o -16-pregnadiene-3-ol-20-.one. or its esters; o) application to a process for preparing a compound of formula EMI29.4 in which R is hydrogen or an acyl group, R 'is an alkyl radical EMI29.5 lower, X represents 0, HaalphaOH9 or Eobeta-0E and Y is halogen with an atomic weight less than 81 or hydrogen but is hydrogen when - X is Eealpha-0 ($) and its deshy & ro9 analogs comprising the reaction of a 3-oxygeno-16-pregnene-20-one having one of the formulas: <Desc / Clms Page number 30> EMI30.1 where X 'is hydrogen, oxygen, H.alpha-OH or H.beta-OH and Y is halogen with an atomic weight less than 81 or hydrogen but is hydrogen when X 'is hydrogen or H.alpha-OH, R "is hydrogen or a lower alkanoyl group and R"' is hydrogen, a hydroxy or acyloxy group, with a diazo lower alkane of so as to cause the formation of the pyrazoline derivative corresponding to C-16 / C-17 and to heat the pyrazolin derivative thus formed at an elevated temperature so as to produce 3-oxygen-16. alpha-16-pregnene corresponding, then introducing a 17-alpha-hydroxy group in said 3-oxygen-16-alkyl-16-pregnene; p) the 3-oxygen-16-alkyl-16-pregnene obtained by heating the pyrazolinic compound is subjected to epoxidation so as to obtain 16.alpha-17-alpha-epoxy-16-alkyl-prégnane, one reacts said derivative will oxidize: with a hydrohalic acid then the reduction is carried out so as to obtain the 16-alkyl-17.alpha-hydroxy-16.17-dihydro derivative of said 16-pregnene, or the corresponding 1-dehydro analog; g) a 3.20-dikety-16-pregnene of formula is reacted EMI30.2 wherein X ', Y and R "' have the meanings given above with a 'diazoalkane so as to obtain the corresponding pyrazonilic derivative and the reaction mixture is heated to an elevated temperature so as to produce the corresponding 16-alkyl-16-pregnene , then a 17.alphahydroxy group is introduced into said 16-alkyl-16-pregnene; r) a 3-oxygen-20-keto-16 pregnene is reacted EMI30.3 <Desc / Clms Page number 31> with a lower diazoalkane and the pyrazolin derivative thus obtained is heated to an elevated temperature so as to produce 16-alkyl-16-pregnene, then EMI31.1 introduces a 17oalpha-hydroxy group into said 16-alkyl-16-pregnene; s) after alkylation at position 16 and after saturation of the 16-17 double bond possibly still present, a 16-17 (saturated) -16alkyl (inf.) - 20-keto-pregnane or its allo epimer not containing d is converted. Another substituent at the 17 carbon atom to the enol ester, the product is reacted with a peracid to form 17020-epoxide and the latter is hydrolyzed. EMI31.2 re forming a 16-alkyl (info) -pregnan-17oalpha-, 1-20-one or its allo epimer; t) a 16.beta-methylpregnan-3-ol-20-one or its epimer allo is heated to reflux with acetic anhydride and a strong acid, the product is reacted with a peracid and the 17.20-epoxide is hydrolyzed thus formed with a 16. beta-methylpregnan-3.17-alpha-diol-20-one or its allo epimer; EMI31.3 u) reacting a 16.alpha-methylpregnan-3-ol-20-one or its epimer, re allo, at reflux, with acetic anhydride and a strong acid, the product is reacted with a peracid and the 17.20-epoxide thus formed is hydrolyzed from EMI31.4 so as to respectively obtain 16oalpha-methyl-pregnan-3.17.alpha-diol-20-one or its allo epimer; v) the pyrazolin derivative is treated at a temperature of the order of 150 to 250 ° C. so as to produce the 16-alkyl-16 pregnene; EMI31.5 w) the starting compound is 16-pregnene-3.alpha.21-diol-11.20-dione or its 3-esters; x) the starting material is 9oalpha-fluoro- °, 16-pregnadiena-11.beto.21-diol-3.20-dione or its 21-acetate; y) the raw material is g.alpha-fluoro-1-4.16-pregnatriene-11. beta.21-diol-3.20-dione. or its 21-acetate; z) the raw material is g.alpha-fluoro-4.16-pregnadiene-21-ol-3.11.20 trione or its 21-acetate; aa) the "starting material is g.alpha-fluoro-1.4-16-pregnatriene-21-01-3.11.20-trione or its 21-acetate; ab) process for manufacturing a compound of formula EMI31.6 or its 5-dehydro analogs consisting in reacting a 16-pregnene of formula EMI31.7 <Desc / Clms Page number 32> in which the various symbols have the meanings previously indicated. with a Grignard-type reagent so as to form the derivative 16.alpha-al- EMI32.1 coyl-16.17-dihydra, then introducing a 17-alpha-hydroxy group so as to form the 160-alpha-alkyl-17-alpha-hydroxy-16011-dhydro derivative of said starting 16-pregnenes; ac) the Grignard reagent is an alkylmagnesium halide; ad) the operation is carried out in the presence in the reaction mixture of a cupric halide or a cuprous halide as catalyst; ae) the alkyl-magnesium halide is a methyl-magnesium halide; af) the catalyst is cupric chloride; ag) the catalyst is cuprous chloride; EMI32.2 ah) the starting compound is 16-pregnene-3oalpha-21-diol-11.20-dione 3-acetate; ai) the starting compound is "-16-Pregnene-3.alpha.ll. beta.21-triol-20 one; aj) process for the preparation of a compound of formula I comprising reacting a compound of formula 2, 3, 4 or 5, in which formulas the various symbols have the meanings previously indicated, (but here R "is a member of the group consisting of hydrogen and lower alkanoyl and R "'is a member of the group consisting of hydrogen, hydroxy and lower alkanoyl-oxy), EMI32.3 with a nitroalkane, which gives the corresponding 16oalpha-nitro-alkyl derivative, reducing said derivative to form the 16-alpha-aminoalkyl derivative, reacting this compound with an alkyl halide to form the quaternary salt thereof. curing and heating said salt to an elevated temperature so as to produce the corresponding 16-alkyl-20-keto-16 (17) -dehydro compound, epoxidizing the latter compound to form derivative 16 (17-oxydo, reacting the latter with an a- EMI32.4 hydrohalic cide, then reducing so as to obtain the corresponding 16-alkyl-17.alpha-hydro, y-16.17-dihydro derivative of said 16-pregnene; ak) the nitroalkane is nitromethane; a1) the starting 16-pregnene is: EMI32.5 1) 16-pregnene-3oalpha.21-diol-1I.20.dione or its 3-acetate; 2) 9.alpla.-fluoro-ó16-pregnadiene-11.beta.21-diol-3.2b-dione or its 21-aoetate; 3) 9.alpha-fluoro- ° .16-pregnadien-21-ol-3.11.20-trione or its 21-acetate; 4) 9, alpha-fluoro-1.4016-pregnatriene-llobetaa21-diol-3020-dione or its 21-acetate; 5) 90alpha-fluoro-lo4016-pregnatriene-21-ol-3.Il.20-trione or its 21-acetate. 3) Steroid compounds obtained by the above processes such as: a) saturated pregnane or allopregnan with a lower alkyl substituent in position 16.alpha or -16beta, - having an oxygen function in position 3; b) compound as above having at least one oxygen function in position 11, 17 and (or) 21; EMI32.6 c) compound 16.alpha- or 16.bêtaalcoy7, (inf.) - 3-oxygen-5-pregnane having an additional oxygen function at least in one of positions 11, 17 and (or) 21; <Desc / Clms Page number 33> EMI33.1 d) 16.alpha- or l6abeta-alooyl (info) -3-keto-4-pregnene having an oxygen function at least in one of the 'positions 11 17 and (or) 21; e) 16.alpha- or 160beta-alkyl (info) -3-keto-1 * 4-P> egnadiene; f) compound according to d or e having a halogen atom in position EMI33.2 9. alpha and an 11-keto or 11-beta-hydroxy group; g) 16-alkyl (inf.) - pregnan-3.17.alpha-diol-11.20-diones-and their allo epimers; EMI33.3 li) compound of formula CH2OR 0 = 0 CH 3 - - - - OH in which the various symbols have the meanings indicated above, and their 1-dehydro analogues; i) compound according to h in which R 'is in the 16 alpha position; j) compound according to h in whichR 'is in position 16.'beta; EMI33.4 k) li-oxygen-16-alkyl (inf.) - 4-Pregnene-170alpha a21-diol-3020-diones and their 1-dehydro analogues and their 21-esters; 1) 11beta-hydroxy-16-alkyl (infa) - ° -pregnene-17.alphao2l-dzol-3o20diones and their 1-dehydro analogues and their 21-esters; m) lloalpha-hydnoxy-16-alkyl (info) -4-Pregnene-170alpha.21-diol-3.20-diones and their 1-dehydro analogues and their 21-esters; n) 11-keto-16-alkyl (info) -4-Pégnene-17.alphao21 -diol-3020-diones and their 1-dehydro analogues and their 21-esters; o) llobeta-hydroxy compound according to 1) having a halogen atom with an atomic weight of less than 81 in the 9'alpha position; p) 11-ketone compound according to n) having a halogen atom with an atomic weight of less than 81 in position 9.alpha; EMI33.5 q) 16.alpha-methyl-g.alpha-fluoro-prednisone and its 21-esters; r) 16.alpha-methyl-prednisone and its 21-esters; s) 16.beta-methyl-g.alpha-fluoro-prednisone and its 21-esters; t) beta-methyl-prednisone and its 21-esters; u) 16.alpha-methyl-9.alpha-fluoro-prednisolone and its 21-esters; v) 160alpha-methyl-preanisolone and its 21-esters; w) l6obeta-me-hyl-9oalphafluoro-prednisolone and its 21-esters; x) 16.beta-methyl-prednisolone and its 21-esters; y) compounds according to q) to x) in which the 21-ester is 21-acetate; z) a therapeutic composition comprising a non-toxic vehicle and a compound of formula according to h); <Desc / Clms Page number 34> EMI34.1 aa) 16.alpha- or 16.beta-alkyl (inf.) - pregnan-3-OR (alpha or beta) - 17.Z-11.20-dione in which R is hydrogen or a lower alkanoyl group and Z is hydrogen or a hydroxyl group; ab) 16.alpha or 16.beta-alkyl (inf.) - pregnan-3-W-17.alpha.21-diol- 11.20-dione where W is alpha-OR, beta-OR or 0 and R is hydrogen or a lower alkanoyl group, and, 21-lower alkanoyl esters thereof; ac) 16.alpha or 16.beta-alkyl (inf.) - 16-pregnene-3-01 (alpha or beta) - 11.20-dione and its lower alkanoyl esters; ad) 4-bromo-16-alkyl (info) alpha or beta) pregnan-17.alpha.21-diol-3.11.20-trione and its lower 21-alkanoyl esters; ae) 3. 16-alpha-methyloortisone 20-bis-semicarbazones, 16. EMI34.2 beta-methyl-cortisone, 16.alpha-methylhydro-cortisone, 16.beta-methylhydro- "cortisone and their lower 21-alkanoyl esters; af) 21-lower alkanoates of 16-methyl (alpha u beta) -4.9 ( 11) - EMI34.3 Pregnadiene-17.alpha.21-diol-3'.20-dione and their A -dehydro analogs; ag) 21-lower alkanoates of g.beta.li.beta-oxydo-16-methyl- (alpha or beta) -4-Pregnene-17.alpha.21-diol-3.20-dione and their -de- hydra analogs; ah) 21-lower alkanoates of 2.4-dibromo-16-methyl- (alpha or EMI34.4 beta-prregnene-17.aipha.21-dioi-3.11Q2ü-trione. 4) Process for the synthesis of derivatives of cortisone, hydrocortisone, prednisone, prednisolone and 9.alpha-halides and 21-esters of these compounds having the carbon skeleton of pregnane and a double bond 16, 17 conjugated with a group Ketone and analogs # 4 and # 1,4 thereof consisting in reacting the starting compound 16-dehydro with a reagent or reagents capable of introducing a lower alkyl group at the 16 position of the steroid compound thereby gives a 16-lower alkyl derivative which is, or is convertible to 16-alkyl derivatives of cortisone, hydrocortisone, prednisone, prednisolone and their 9.alpha halides and 21-esters.