BE627015A - - Google Patents

Description

       

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 EMI1.1
 



  , tI1tuCHDH DE i'ïi.'AkA'r7: U 1M 1, (JlfV ".bAUlC tdGt - '. t', ItOITIkS
The present invention relates to a process for the preparation of trans-fused ring derivatives of oyolobutane by means of ring constraint of the corresponding fused ring derivatives of cyclopentane, and to the new class of fused ring derivatives thereby available. in the trance position of cyclobutane themselves, as such compounds are not intended for direct use in medicine / human.



   -In particular, the invention relates to the new
 EMI1.2
 class of D-nor-ot6rolden which are accessible by a method 1 which consists in photolyzing a steroid substituted in the ring D, preferably at one of positions 15 and 17, by a group
 EMI1.3
 keto, and uar an üiazo group in position relative to this keto group, alocoue in an inert organic solvent

  <Desc / Clms Page number 2>

 
 EMI2.1
 containing a cortu'one which; had to be added, the C-0 double bond do at t.zzewg ct 2 .. inolate the D-nor-'ctdroYdea thus formed and, if read t! between, transform them by reactions conniicu a'apruu the chemistry ues nteroïdoo, in analogies of the type Ji-iior d 3. "Uc7A: known).



  01 '.. t finds, however, that the preparation of derivatives of oyolohut'1Jl (h nuclei t, axldfwllf3w in position tra.na from the corrG!.' "Derivatives iond8.ntn nuclei oondonneo in position trans of cyc1optmtvno is pac .l1l! lit with compounds cyaiit a 0 ruotvro 1t'ro! des, but it is capable of Zér-6rnlo application; the invention also includes the use of ... ac: finite photolysis rooéd6 for the transformation of o: -d1azo -., yclopentnnonoo k condensed nuclei in the trans position, in a tro central way, into oyolo-butl acids. '\ no -o9rboxrlit1ueH l corroopondR.1 cond onuéa corroopondR.1 \ ta and derivative functi01Hleln clo can c, razs. tan studied in detail below first of all the part of the invention which relates to the use of the starting compounds having a ntracture from ct: raxas.



  1-4,, 1 rc ': n.sr place, we will aar3.re in a few motorcycles the ntl.'lJc1m.rrs of JJ-nOr-f.itt1rOr10t1 oufcofitibloti to be obtained coni'Ort: 1émlmt to the invention, and the. nomenclature used ioit These D-nor-atéi'oïdes; ra: ric.x a nystbine of h rings carbon skeleton designed indicated ai-aeceoiim s
 EMI2.2
 
 EMI2.3
 The cycluo are denied ;; born! 1 cO '' '' '' ': 1e customary for steroids by the lettered A, by C and L.

   Likewise, the carbon atoms of the rings A, B and 0 are fl1L: .éroteo of the nr-jiièro clansique ,, J) Ul6 the ajt there. position. 17 has been deleted, so that carbon atoms 1 b and z are read directly! however, the constituent element f'.l1.'U1Aircs which should be fixed

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 at carbon atoms 13 and 10 (in the above formula, for simplicity, methyl groups have been represented, although this is not mandatory for the products of the invention), retain the numbers 18 and 19, respectively, as is usual for steroids, so position 17 does not exist at all. Exactly as in conventional steroids in which the D ring is pentagonal, the cyclobutane ring of the D-nor-steroids according to the invention is condensed in the trans position with the C ring.

   This configuration, i.e. the transformation of the derivatives of cyclopentans in which the ring of cyclopentane is condensed in the trans position with a hexagonal ring, into corresponding derivatives of oyolobutane with condensed rings in the trans position, must be considered as surprising, because, on account of the constraints created by the contraction of such pentagonal nuclei joined to another nucleus, it had so far appeared improbable that derivatives of cyclobutans in which * the oyolobutane nucleus is attached to a hexagonal nucleus are relatively stable compounds.



   In the formulas described below, the dotted bonds, as usual, indicate that the substituents of interest are attached at the [alpha] position; dashed bonds indicate the ss configuration if more than one configuration is possible; wavy bonds include both isomers and ss. Likewise, removing the configuration symbol ([alpha] or ss) in the names of substances will mean that both configurations are included. Correspondingly, terms such as "androstane series compounds" include both type 5 [alpha] - and 5ss-androstane derivatives.



   When it is a question here of pregnans, androetans, oestranes (or corresponding analogues of the nor- type) in general, or compounds (derivatives) of the pregnan, androstane or oestrane series (or drifts

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 In general, unlike the case in which particular compounds are mentioned, it should be understood that these expressions include unsaturated compounds.
 EMI4.1
 res such as miscellaneous, pre, nnee, androstenes, oestrenes, -dienes, -trienes, etc., and unsaturated compounds of the nor- type, respectively.



   As the starting compounds necessary for the process of the invention as defined above, that is to say
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 K-diazo'-oéto-'stero'Edes (with the functions specified in cycle D), are also new compounds, a possible preparation process for these starting compounds is first
 EMI4.3
 described using 15-diaza as an example. 1'7-deta-al; xade which are preferred as starting compounds It is understood that other K-diaao-oeto-Bteroidea can be obtained in an analogous manner.

   Further, it is of course important in the process of the invention for the preparation of the D-nor-steroids that the starting compounds are obtained as indicated or otherwise.
 EMI4.4
 In the oven to prepare the 16-dlazo-17¯oeto-steroids, the corresponding oeteterodea unsubstituted at the 16-position can first be oximated by treatment with a nitrous ester of an inner aliphatic alcohol ("nitrite
 EMI4.5
 alooyl ") in particular by means of isoamyl nitrite, for example in the presence of a base, such as an alooolate.



  (Instead of this base, an acid can also catalyze this
 EMI4.6
 oximation). The 't6-oximino -'! 7-oeto'-steroXdes obtainable in this way - generally solids O? J, ste.1l1ne melting at high temperature which can be easily purified by recrystallization from polar solvents such as alcohols, nitriles or similar solvents - can then be processed to give the
 EMI4.7
 16-.cia2a. 17-a & 'o-.steroidea desired by known methods, such as by treatment with ohloramine, preferably in ether solution. (The necessary chloramine can be prepared either

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 EMI5.1
 independently or in situ).

   The 16-d1azo-17woeto-stero! Dee obtainable in this way are yellow crystalline compounds melting at high temperature, which are advantageous.
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 ment purified by reoriatal11sation from alcohol.



   The process whose principle has just been explained allows the preparation of any steroid containing a keto group in the D ring and a diazo group in the [alpha] position with respect to this keto group, whatever the substitutions. in cycles A, B and 0 and at the residual position of cycle D.

   The only limitation on the structure of the generator compound into which the diazo moiety is to be introduced is that the 16-unsubstituted generator compound should not contain substituents which are attacked by the reagents used, if so and whether such sensitive substituents are to be present
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 in ùiazo-oeto-ot6roIdo and in D-nor-atero! de prepared from it according to the invention, their temporary protection becomes necessary. This particularly applied
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 to Itoxlmatïon generating compounds such as 17'-oeto-steroids which, in addition to that at position 16 which is activated by the keto / group,

   contain at least one other reactive methylene group, as in the oximation of derivatives
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 of the type ,, 17-d.ioto-androetn .. In this camp the group or methylene groups activated by the 3-keto group
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 can be protected for example by temporary selective o4taliuation or transformation into an enamine of the 3-keto group. It is the same, by making the necessary changes, for the other sensitive places of the molecule.



  (If a keto group is present at the 11 position, no such protection is necessary due to the steric hindrance evident in the 0 ring).



   The essential phase of the process according to the invention consists in the photolytic conversion of the starting compounds. This transposition is carried out by submitting the

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 EMI6.1
 Composed from the start, difuo in an inert organic solvent, at a suitable irradiation, probably with ultraviolet radiation, preferably having a range of wavelengths close to the visible spectrum.



   The solvent used is decisive for the structure of the immediate products of photolysis * To understand this, one must realize the probable Mechanism of the reaction
 EMI6.2
 of photolysis! it is believed that the starting za-oyc7.oentanone, when irradiated, by (obvious) elimination of nitrogen, is first converted into oyolobutane-oetane oaxraapandcnt, which then stabilizes d ' known by adding an available molecule containing active hydrogen to the 0-0 double bond of the grotipenent ketenes. The product of this stabilization will naturally depend on the nature of the compound susoep- 'tibit d 'be adding' it. the f3.tJ double bond of the internal odtbne ... hypothetical diapre, which is binding during photolysis.



  Normally, aqueous solutions will be used, and in this case, oyolobutane-oarboxylic acids or produced im-edlates of photolyoo, such as orboxy-V-nol-t6ro! De8. when using 6-diazo'-17-meto-atéroldne as a starting compote. Correspondingly, if the eolvrrnt contains alooole, ammonia or a primary or secondary araino, the 16 tsp. xba3, ooxy.D r, arstdradRr or lea 16 | 3-carbamyl *]) - nor- flteroïd o ut) betltj4m or not on the corresponding nitrogen Known true solvent of the reaction mixture subjected to photolysis, it is possible in principle to use Any inert, practically transparent to radiation solvent used Organic solvents such as tetrahydrofuran and dioxane are generally preferred.

   



   The light source for the photolysis reaction is usually a usu = 1 emitter of ultraviolet rays As, as specified above, the upper regions of the ultraviolet, bordering the plago visible from r

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 spectrum, appear to be more efficient than ultraviolet at shorter wavelengths, ordinary glass apparatus can be used for the photolysis reaction.



   As mentioned above, elemental nitrogen is evolved during the reaction. This can be used to determine the end of the reaction by measuring the nitrogen evolved.



   Photolysis may be exothermic, and thus be accompanied by an increase in the temperature of the resetion medium.



  In general, the temperature can be allowed to rise slightly above room temperature; sometimes, however, cooling of the reaction mixture is advantageous to minimize the formation of by-products. In principle, photolysis can be carried out at any desired temperature, the most suitable temperature range to be fixed in each. special case depending on the physical and chemical properties of the starting compound and the desired photolysis product,
If the starting compound and / or the desired photolysis product is sensitive to oxidation, it may be advantageous to conduct the photolysis in an atmosphere consisting of an inert gas, such as nitrogen or anhydride. carbonic.



   The products of photolysis can be isolated by known techniques. Thus, for example, if the photolysis is carried out in an aqueous organic solvent, and thus a free oarboxylic acid can be expected as a product, this acid can be isolated by means of alkali reagents and by usual extraction techniques. . In the case of ester and amide type products, the reaction mixture is preferably poured into a large volume of water and then extracted with a suitable solvent.



   The preferred starting compounds for the photolysis process according to the invention are the compounds of the 16-diazo-17-keto type of the androstane and estrane series.

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 containing one or more of the following substituents in rings A, B and / or C t keto groups at positions 3 and 11, hydroxyl groups or esterified hydroxyl groups ([alpha] - or at positions 3 and 11, alkyl groups at positions 2 and 6, halogen atoms at positions 2, 4, 6, 9 and 11; in addition, rings A, B and 0 may contain one or more double bonds, isolated or conjugated.

   Particularly preferred groups in the starting compounds are the 3-keto-# 4-, 3-keto-# 1,4- and 3-hydroxy- (or acyloxy) # 5- systems. Of course, however, , that the above substituents and double bonds are exemplary and in no way limit the invention.



   If the photolysis process according to the invention is applied to the preferred starting compounds of the 16-diazo- types
17-keto-androstane and -oestrane, the intermediates consist of compounds of the D-nor-androstane and -oeetrane types, respectively, substituted at position 16ss by a group -CO-X. wherein X represents the residue remaining after removal of the active hydrogen atom of the compound capable of adding the C-O double bond of ketoins which has been added to the solvent; thus, depending on the compound added to the solvent in the particular case, X preferably represents a group. hydroxy, alkoxy, amino or ALCOYL6AMINO.

   Consequently, the intermediates of the photolysis process according to the invention are essentially 16ss-carboxy-D-nor-steroids and functional derivatives of these carboxylic acids.



   The invention comprises the optional further conversion of the immediate products of photolysis defined above, by reactions known in steroid chemistry, into D-nor-type analogs of known steroids.



   Among these optional subsequent reactions, from a systematic point of view, two types of reactions must be distinguished:
On the one hand, the reactions effecting the transformation of

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 substituents 16ss-CO-X in substituents at position 16 corresponding to the substituents at position 17 which are decisive for the classification of a steroid as belonging to the pregnan, androstane or oeatran series, these reactions tions being necessarily carried out after the photolysis oon- form to the invention;

     and on the other hand the reactions which relate to the substituents and the degree of saturation in rings A, B and 0, the introduction or modification of any substituent in position 15 of the tetragonal ring D, and optionally the angular substituents, these reactions being able in principle all well, and sometimes even advantageously, to be carried out before the photolytic oontraotion of the cycle, although their realization after this contraction is also included in the invention.



   The optional further transformation of the immediate products of photolysis to D-nor-type analogs of known steroids can be accomplished by any known method of steroid chemistry, in particular, the 16ss-carboxy group appearing in the immediate products. - diates of photolysis either in the free form or in the form of a functional derivative, can be transformed into a 16-keto function,

       16-hydroxy-16-acetyl or another function at position 16 by the same methods as those used for the transformation of 17-carboxylic acids from the air of androstane and oestrane to 17- derivative keto and 17-hydroxy of the androstano and ocatrane series, respectively, in compounds of the pregnan or 19-nor-pregnan series, respectively, or other steroids with substituents in position 17.



   Thus, for example, to obtain from the immediate products of photolysis compounds of the D-nor-prégnane series, that is to say D-nor- analogs of the progesterone type or analogs in D-nor- corticosteroids, methods similar to those can be used

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 known for the preparation of progesterone and oortioo- '
 EMI10.1
 etero3: des, CO "l! 1lû cortisone, 1.hydroaaxtiaone, prednieone, prednisolone, etc., from t3, aaha.aniqu (etianiquo) acid and etiooholenic acid.



  The -nor-androstane and D-nor-estrane 'series are accessible, for example, by converting the immediate products of photolysis first into one. composa from the series of (or, if the starting compound for photolysis is from the series of estrane, into a compound of the
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 series of 19-nor-D-nor ... prHne), and then, by oxidative degradation, into derivatives of D-nor-androatane and D-nor-oestrane, reepect''vanent. The u-nox oeatran derivatives of which also accessible by elimination of the 19-methyl group of suitable compounds of the D-nor-azzdrostano series by known methods, for example by pyrolysis.



  1 further processing, in particular the introduction (or modification) of a substituent in
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 the 15 position of the tetracomrtl D ring - according to confluence methods :! of In chemistry don eteroido for the introduction of substituents in position 16 - and the notification of the angular substituent in position 13 by methods known in chemistry
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 3teroÏdcB, as well as however the introduction, elimination or modification of aubstituents or of double bonds in the rings A, and / or zip may follow the construction or characteristic characteristic of the derivatives of, -nor pregnans, androstane and (oectrane,

   or can be carried out before this construction or between its elementary operations. Examples of all these additional transformations, which can be carried out after the pnotolysis according to the invention, will be given below. It is understood that these examples, although they are numerous, do not limit any
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 way the existing poaelabilitéo.

   Starting from 3c3-.hyd-axy-16..ce.xboy.-T - nor.5- androstane, after having protected the hydroxyl group in

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 C-3 by formation of an ester, for example an acetate, this compound can first be converted into the corresponding 16ss acid chloride by treatment with a reagent such as thionyl chloride, trichloride phosphorus,
 EMI11.1
 ito :: hore pentachloride, and preferably oxttlyl chloride.

   The acid chloride thus formed, for example j.-aadtoxy-16, -chJ.oraanrbonyl-D-nor-5-andxostene, can in turn be treated: with an alkylating agent con.110 dir. 1ethyl-cdr; iurn, aOl1uant giving rise to the formation of 3-acetate of u nor.-5-aré; p.ne-: 5i-al-20-one au, after hydrolysis of the ester in 0-3, do l) -tior-5-preabne-3-ol-20-onou Degradation of such l..nor-pregnan can be effected by oxidation of .daeyer-Villiger using a peraolde such as perbenzoque acid or m-chloroperbonzolque acid, and 1'-nor..5. a, nàrostne-33,163..diol. resulting, (aurbe hydrolysis of the above 3,16-diacetate) or D-nor-5-andxostne..j3-.al-20-anQ-16-acetate, respectively, when subjected to d-oxidation. 'Oppenauer of the group 3-0H, oondui th In.

   formation of D-nor-testosterone or its 16-acetate, respectively, the latter compound which can be hydrolyzed with potassium carbonate to give
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 also D-nor-teatosterone. In this series of reactions, it is necessary to protect bond # 5 against oxidation.
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  Suitable protection can be provided by a halogenatlor. binding (preferably by means of chlorine), followed by dehalogenation with zinc, for example, after the Baeyer-Vllliger oxygenation procedure.
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  The .ü.-nar ..- nrdrostene-ji, 16t.-diol appearing as an intermediate in the procedure described above, by an oxidation of the Jones type using a chromic acid / sulfuric acid reagent, can be transformed into
 EMI11.5
 D¯nor-4¯androstènē3 1 6-dione.



  In a similar fashion to that described above, D.-nor-rndroatane-33.07 .-. 16 ... acrboxylic acid 3-aoetate

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 can be transformed into acid chloride in position 16 oor
 EMI12.1
 respondent which, on reaction with dimethyloadmium, gives D-.nor-5oc-prégzrngne-ii o, 0-ons acetate. Oxidation with perbenzoic acid followed by hydrolysis of 316-dlacetate gives p nor5a-androetana-3,15N-di, o7., which can be oxidized by chronic acid in the presence of pyridine to give D-nor-5ot-androstane-, 16..ù3, ons, The treatment of the latter compound by bromine, followed by debromination by dimethylacetamide using known techniques, gives the corresponding 1,4-bisdehydro analog,

     that is to say
 EMI12.2
 D-nor-1,4-andrastadien-, 16-aione, which on reduction with lithium in ammonia gives D-nor-testontone.



  D-nor-1,3,5 (iO) -oestratrlfenes can be obtained from D-iior-androt3taneo ,, For example, the pyrolysis of D..nor.-1, .- androstadins-3 , 16-d.ione at approximately 55U'0 gives D-nor-estrone (= D-nor-1,, 5 (1U) -oaatrtribne-3-ol-16-ana) which is convertible into 3-methyl ether by reaction with methyl sulfate, or which is convertible into D-nor-
 EMI12.3
 estradiol (-nor-1,, 510) -asotzatr.ëne., 16G3 d.ol.) by reduction using a reducing agent: t1oomrnc sodium boy'hydride. Alternatively, the h..nax.i, 3 r 5 (1 U) ceotratribes can be prepared by the 1,2-dehydrogenation of a -.adto-Q '- D-nor-19-nor-androstane.

   Thus, for example, D nor-1 y-nor-testosterone (which can be obtained as described below in Examples 18 and 52), when it is subjected to the action of a
 EMI12.4
 1, 2 dehydrogenating microorganism such as 9.ebanterium Simplex (Aoll 0 * 0 * 6946), gives D-nor-oeetradiol (-aD-nor- 1, 3, 5 (1 O.aefltxatrins', 153- diol).



   D-nor-estranes as defined by Formula III below, wherein R1 is hydrogen (i.e. D-nor-19-nor-androstanee) can be prepared from
 EMI12.5
 D-nor-estratrienes of formula IV below. Thus, for example, D-nor-estrone methyl ether (i.e., D-nor-1, 3,5 (10) -oestratriene-3-ol-i6 3-methyl ether -

  <Desc / Clms Page number 13>

 
 EMI13.1
 therefore), by reduction using lithium in aninonia, donno ether 3-methyllqua do -nar-2.5 (1 p) .- oertxatxino-.3,16'N-. diol which, by the action of mothanoliquo hydrochloric acid, had convertible into D-nor-19-nor-tootosterone (i.e.-nor --- ocetrs: ncr-16.3-al-3- one or D-nox 19-nor-4-andxoatene.



  16-ol-3-one), night not turn can be oxidized by chronic acid by doo methods known in It..nor-4 aestxêno- 3,16-dione (= u..nax-13-nor-- -a.naraat; ne-3,1.-dione). Similarly, dcr D-nox-2, (10) -aQntxac.éns 3-methyl ether 3,16p-d.al. may be oxidized by chromic acid to give the 16-keto oorronpondsnt derivative.



  A Tr-rror-oeatrono (obtainable as described above) can be transformed, by reaction with 8odj'n acetylide, into 1 a. thyny.-1-.nar 1,; r5 (1C?) ^ oeetratxiane-3,16-diol. In a similar manner, the 3rnethylinuo ether of ..nor-2, (10) .. ae7 tradi: ne-3-ol-16-one (obtainable as ûerlt uana the previous paragraph), D-nor -4- ogrtràrie-, 16 ciana and L-nor-4¯androBt9ne-2, i6-dione have tr'l1J; i'orl: llJ t> the Either '-methyl of 16-ethynyl ..



  I-nor, (10) ae; itrFZdiirne-, 5,16E3-d.a., En 16ccthynyl-D- nnr.w4-aoatrno-1 41J-0.1. , -arl.0 and 16-ethyl-D-nor-4-. androntfme-1 6i5-ol-3-one, respectively In the case of soft dorniHrf1 composas, it is preferable to protect the
 EMI13.2
 3-keto function for example by preparing 3-pyrrolidyl-
 EMI13.3
 en1in follows the reaction of sodium aoetylide. When we want the l6cc- (ohl.oroethynyl) derivative, we can make a l6-keto-D-nor <-aterodo with lithium chloroaoetylide (prepared from cia-dichlaxo-ttryhene and methyl-lithium by known techniques) so as to form the corresponding 16tx -. (airloraEthynyl) -16; -hydror.yD-nor strocïe corresponding - whose.

   For example, the 3 "-pyï'rolidyl-enanine of 1> -nor-4-anurootene-3,16-dione can be reacted with litniwn chloroacetyluro, after which the enaalne is split by treatment with l '. aaàiwn acetate and Lr acetic acid in a mixture

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 EMI14.1
 methmiol-eaii, to obtain 1 tcr- (airloroétlzyny.) .. u-nar.
 EMI14.2
 testosterone, which can be used as a contraceptive. Of a
 EMI14.3
 Similarly, when we define a 16a-Irahmyl (0 'is - $ .- ary a 1 âcx-: ntl:, y3 .-. ethynyJ.) .- 1? -. nor-steroav, we can' *; reacting a 16-06to-1I-nor-atóro! de with sodium r-iethyl-ao6tyliter, and, for example, D-nor-4-androat & ne-3, i6-dione by retiotioii uvoc the methyl-acetylide of sodium gives In 16a..pranynyl. , .- noz.-4-x3n.iraatna-16.-0l---.one.



  Doa l) -nor-b (10) -ooatr <! înec whose exesiploc are 1) -. nor ^ rrt6raïùec3 an i'onmie V oi-aprt; e can also be obtained: 1 from ï -nor-1, 3, (1) .ovatr. tx ine ci-doeuup by treatment of a D "nor-2 ,, (10) -oeatradiono (obtainable by reduction of a u.-uox ^ 1,3,5 (10) -o: ac xtxtri? ; xle as described in vvar: t-derrrxr: r: r; t-ra, im) with oxalic acid For example, S-nuthliouEr ether du.-nar ^ 2, (1U) -acrcrtradi6ncr ^ j, 1tih3-à.ol, on reaction with oxjJ..quc acid, gives -.nar- (10) -oeatrm-lt ^ OL ^, - OriP. J'azm similarly, ether 3 -nttiyüque to 16cA: -vth; vnyl-D-nor-2 "(1 Ù) -oeotjrH- d, nvw, l5iio. (may title obtained CO ,, 11:10 described t précédentl.ù1t.J the previous paragraph), onr truitenant an average of oxalic uoid, gives the 16u-wta: yny. ^ ß ^ nar- (1 U) -nsctrbtm -.16io.



  2-one which is lut6retH.1Hnte COr: l;: 1st contraceptive agent, The reaction of a D-nor-oeBtrO! 1f! with a reagent i3f> (îrignard such as iouuro ue wthy1-r.î'1.I;: ÓHiu! ll or bromide cl té '.; hyl-! llngnciu:}, conform:' 1é:; wnt ax tuchniquP13 conllU60 doluie le 1 ^ mthyl-ï-nar-i,, (1 Oiocotra trina-i, i 6s-.d, ial. and l6cx..dthyl-I) -nar-l, â, (10j- ocstrr, ariîna-3, i6 ^ dio ,, roopeoti- vely. From 1.10mo, the Tr: or .-- ac: ut, rzzv-3,1G-diorw and the D-no1 "- 4-a, ndrosténe ^ 3,1n-ùione cslr4s trf: r: c: far: zrztion in 3-'pyrx'olidyl- l'la.r .: ines corrvrondr, xzte; s and reaction with Gland's reagent zone jams the iodide of ItHflyl - ;: at: 1HL> iuUl give 16a :: - roethyl- J3-nor-4-oeetrlno-165-ol-3-one 6i la ltoc ^: r, r: tt: rl.-r.or. 4.-Indrastene - '! 66-ol-3-one (1 Ó -methyl-1J-nor-teLi tOlJterone), renI'octi ver: wnt.



  Des 1J-nor "'' pre;: '. J.lnef, y cO:' fritJ those defined by the

  <Desc / Clms Page number 15>

 
 EMI15.1
 forrnie Here e-fir ::, can au -ai be prepared from ua products; 't0oiy:' j ac Acid u-.nor .-; tëro: ua 15o..caroox; r- lic. The D-: lo; r. '": Jro,:; is' :: 1'OIW (#.-Nar-.A.-rë :: na-, 2U-GotaE :,
 EMI15.2
 
 EMI15.3
 can easily be obtained from D-nor-5'-preene'-3J # j ol-20-one (obtainable as described above) by oxidation using of a chromic acid / acid reagent orl t \ 1l'1qu..cn variant, aciae ïi-nor-4-anaro8t6nc -3-oaōiÔ!> jo # boxyliquo (which can be obtained by photolysis of 111 16- i à.cr.ao-.A czzzax o: .x: m¯ j, 1 Ia. one, which has its heart! JOUi: to be obtained at yrirtir ac la 16- (jiao-5-'I.! l \ J.rostlm '.'- jp-ol-1' {- Olle par action do i1flVobtlct, n'ium a tihty> trupnnn e), lî.t \ r (;:

   tr'1! lB: tol ".., 1- '\; ion err oh1orurt: <1 '\\ Jl (1 anrrweauond.:W par:; 1.C1.iJ.on au on, c.7xc, zrc a'oxalyic, followed by a reaction with dianométnaixo and u'LUxc reaction ulborieuro at the 21..t.Ei :: ol-rrax ^ r, * r: na-; 3U. D.oxxc? Ailwi lori'u'o (, 'aborl.4' \ Vt! C i'noid <3 1, .lro: allyul'1rut>, then uu oax4 .; .,.:

   j
 EMI15.4
 
 EMI15.5
 21-bromw rë ^ ult.uzt with odium iodide, followed by acid Israel, gives the. nar zxo ;;; aatëxolra DNJ; rou11omcHt1 1 t;> 4, (, .. and 1. iryuxoayl, o can 6trt? '
 EMI15.6
 
 EMI15.7
 in trodui tt1 from a mole hearing of D-nor-prégnrme by teohni ... quon tollou quo cellen ddari4ds in the J: J:>: t! l: 11) the 40 oi-apruf of .4Eçair ht: t ': HUliol'111or lit 1-czirco-J-nor-AwpxëZtana - ;, "3- diono in D-nor-4-prtJruùne-1t) afii1-diol-3, iiO <-dione La tr'ina- formation de co duxualer 00: 111 '::: 6' eu 161 (... hyi.lx'o :: -. y ... J) .... nOl, .. .proger, l ... terone p ut e'eff octuor i'nc:!. loJWl1.t in efctc; ri.: The ion in z-21 by means of methaneaulfonylet chloride after which the 21 is reduced -enter o.in:

  11 formed by means of sodium iodide in acetone, then treated with acetic acid. The esterification of the 16α-hydroxy group in the 16α-hydroxy-D-
 EMI15.8
 nor-progesterone can conveniently be effected by reaction with an acid such as acetic or caproic acid in the presence
 EMI15.9
 trifluoroaoetic anhydride so as to. form 16-acetate and 16-cararoato, re7lect.i.vemerzt, from 16cc-hydroxy-D-nor¯ pl'oe; olJt6rone.



  An 11-hydroxyl function can be introduced into the molecule by cis.3sai, uea methods; micro techniques

  <Desc / Clms Page number 16>

 
 EMI16.1
 biological hundred co.oe ::, le;:; 1 oro-or ,: '1Ji b' '-, t ;, " <, 1: "..;" J ..:.!. N :: 2 :.



  (; iR1t.L. 23 & 0) being used 1.rt'i.ré! '(.:. c':. unr i: tror1; Ü! 'un groupeuent 11, -hydroxylij, t' - 'ndie that "3.ç: -r, lly c: 1 ', .'-,:, 1l.a ta! ZO 10 59-10 D34) () fit.) R..f: r" d., Ll1 mr l introduction of a roupenent 11 et-hydroxyl. Thus, the r-.nox-.4 ..> rcn, ne .. 111j 16ct, 1-.ti.a2-3,2U - âiore, quar: d it is voumizo in Curry luna.ta is trt.or : no er.

   L-'nor-hydrocortisoi'n? ('= D-nor-4- prnn :. 113,1ctt, 21-triol, -3,2U-diane), i.'aatrilo! Xtion of the hydroxyl group in C-21 pure anhydride ncétiq UQ 3s: zur pyridine, followed by oxymtion to ,, 10Y01'1 of chroiniquo / sulfuric acid from rou; yeraent 11-.rlydro.xy J. <1 <irz: 3 the 21-ucetate of 1J-nor-hydrocortioone xéou.tf.n gave the 21-u.odtntte of D-nor-cortisone (elect-i4-dïre the 21-acetate ao lJ-nor-4-prec ., rn. (. ne- 1 Grâce, 1-.d, o 311, Qr3.one) 1 The introauction of a double 114aition A '1 dnJ1B those of the new D-nor ..., preB'üé \. ZlQ fJ,, -nox-uùxcinl; cma and D-nor'- estranes which contain a fJyate! 110 3-keto-to4 pou1 ({1 \ !:

  t'fQot \\ er
 EMI16.2
 by known chemical methods, for example by means of
 EMI16.3
 selenium dioxide or by using d.ail.orodiayr.zio benzoquinone, or alternatively a rniorobiologic method using mi or o-or {;:, nni amo a ootfcne COrY11, e bn., q, tol'i 'tun slmplex (ATOtO. 6946). far cxdm.e, 1J-nor ... tootoaterone (m -nor.44s.ndroattne.1 GE3.-o.3-ons), 1 âbt-hydraxyD nor progesterone, D-nor-oortiMone acetate and D-nor-hydro. cortisone (which may be 01.1 held OO: 'f! 1e described here), when subjected to. the action of C.or.vnebact, eri'Ult1. a oimplex conform-
 EMI16.4
 ment to the procedures described in the US patent
 EMI16.5
 United h 2,637,464 du, gives D-nor-1-dehydrotestosterone (s -nor..i, 4-andxostadiena-16-0l -.- one), 16a-hydroxy-1-dehydro-D- nor-prot;

  asterone (a D-nor-1,4- prégnaredi, ne-16oc. ol ..-, 20..d.one), D-nor-prednisone acetate
 EMI16.6
 and D-nor-prednisolone, respectively.



  In general, unsaturation can be introduced into a saturated A ring by first transforming a group

  <Desc / Clms Page number 17>

 
 EMI17.1
 3-hydroxyl preAt .: t1't to a 3-ketonQ (by oxidation with chromic oxide, for example) after which we treat with n61enin dioxide :,}, or by bromination and <1abrOflluration ue the r: t''inir'3 unuelle.



  ]) 0: 1 'mllo' ', WI3 in D-nor de,, 41¯A.; Sd.hydxo ttndroft \ JnO (1 and -: 7rén; nrfs oo-rne for example those represented by len formula II and 311 oi-aprbo can be obtained by murtir don j5-kéto- i'-nor-4'-androatbno0 ot -P't "l, èno (3 Oa''6; 3 .. ponduj'itrit Pur oomulo, In D- nor- * 4-andro3tënG-3tl6-dione and the JJ-no: r-nro: r.t6rOH (, 01.ttU1'J (Ù1QO are J30UrniBen has the concept of 1. 'h: <the "o6mû on t.xriESrnar of a catalyst such as palladium (dnnn 'ln nolv'nt corne ilirinole ethyl acetate or betrahydrofuran) uonnent 1'1.. rior.fr.droota, nP -, 16-d, ons and D-nox¯ct-rrfr, rm.nc¯3, U-di, ane, respectively The reaction of 003 produced 'hy'ronation with an equivalent of a heJ O, '; Gr..c cor.uno the bromine oonnc the analog 2 "tromé correlates yes not to be df.H: hrtlogèl1hyr1raté to the nucleon of a rrla.ci;

  .i 'oo'TM the cúl11.oinc or dlnethylformamlde in!) reel1ence of c' - \: rb ') J:' 1tQ of c.alr: Lz., r, giving the I -nor-1¯androstwne- 3> 16¯dlone and let -rtor¯cc-1-s, x; r; rW nc: -, U-cion, 1'0 (3 Í, aoti v.



  J,) r (! Zzlcnatr; en 6-r.léh, y'iro des délvéo of D-nor- or, r; 1ror; t; m '-t nn .IJ-l1or-; I: r (! I : '! 1f: nn can be prepared directly mont h, o'7.'tj r a. ::; tu-rivén correHDondnnts du; .. keto .... iJ-nor-4- 1: 1.hdro: : t (ne, dt -cto D-nox ^ -4-.xé;: n, du 3 ato..D.nox1, 4- FJ.) drîJcto. \ Üimf1 oj c3z, ^^ cna.-zr Tlar 1 , A ... ax; nf.nad.ne (for example xs .a, .rt.ir 9 j-ei .u-1oz .- 'r - :, t:,: ra, rtnā3, iâ di , ona or 21-acetate of Sa-fl '> oro-I * nor-preàni9olon <î) by dr381t; dxa ;; f3, TIi3t.on by means of an n.rr: n such that. chJ.orJl1ilo in heated xylene without reflux;

   OJ,! ',' 1: r hwllo - '.' 'Allyllque nation' lU agent means ca:.: .. r le.-Bro ': 1o!: "CJinLJ.je turn forcing the in.tex troduct : nd.a3 .--
 EMI17.2
 
 EMI17.3
 re 6.ixa: n corre2roeiiarit (for example 6-broao-D-nor-4-andros-! t'nc: ,, 16-rz.au: or 6-oromo-9û ± -fluoro 21-acetate -D¯nor-, xfoâriralo: e, xc: ..; ect.v; wwt) and <1echalo, ùnhydre.to.to.tion later in chn'df.'8r..1;

   at reflux of collidine or lutidine nO'.l :: r; iCr :: lf ": X 'Le. co' 0 :: 6 6-d corresponding hydro, 'Car exemole

  <Desc / Clms Page number 18>

 
 EMI18.1
 D, nor-. °, fr.-rxzlcïroctt; diuzio3, i6 alan or 21 -acetate of 9o: -fluoro-1) -nor-b-dt511; vdro-p1'oclnil101one, respectively, Des --ec. 5tcü.-ïlfllct, no-J-.zzar-.i, 4-irtnrtai: amc (could be obtained cc,:. A: .ra describes anjif. The p! '1.rn {.': L ' l '\. phc nréaédout) ocuvont' () 1'vir, 3.ntc: r:., r <tii ri.x'en for nrémiror los,) - nor-1 "... p: d {; na.dièll ('! f1 (for example lao Hll'J.lO''llf1l3 en A' dort JJ- 110: r- Btôroïcsoo du oriiulf 11 r.:i.;x3) by r6nd.ion <iveo the sine in th! 1no1. a user. de niodoj ascx'attaJ.rfrr o.nr1l0lHw fi those ddcritf d'.no .The patent r'nEi2'i oru.n, JI) .üEa.6c du t A..i.zlrzi, 1s l1r (':: 1H1.'nt your fillylique du 1 "'n.cétL1. Te da .ù-nor-r1'l'ÚnÜ101onf! Nu!.:

  al'f121 of H "'!) 1'O! 110S \ lCC nimidc, followed by a reaction of the 21-acetate head of 6.bror: 10 -J) -nOl" -prcdni! Jolone thus 10 # i4 with the sine dnnu lt <3t: 1: u \ ol donnorn lo 21¯acetate from ü no '1, -w ^ E? Ar.dinc! -11,, 1Eic, 1tz.io .-; â, c: -d3alla, interesting cott'ne n; unt cortioni, r: lxti..illlFUr,: ùatoï.xa, with secondary effects. '.; cortienux: rl (m 1. t :.



  The introduction u'un0. io ;; l: la ljrÙ ± J01l 9 (11) in the new D-tior-cteronc :. and ta l ..: rrln: fln "; j,.: r1, ::. on \ Ütf: rL (! \ 1: ra des colnaotz; in fj9 (11) aiiu oi1tl..1nUf1 on, 11.-i : s, oolayir.ino: Rfc in derivatives, ili "'(i} a4l.Ld /" E'lt = t' 1 '.,. \' l'llt 'l'1'4'hût <3J '' ttl.i: i.Î, pure of! ' t '. t ', lat3 (; "(IUlrÙOf'1ç'f'I;, (: 11.t:' ati1.i: JtJH vlL; tlCfi 11 \ chimie dos ttrodea..in. ^ ,, en: mu:.: ctt..1W! # .tr.lîc5 ':. "- é ^ t = t. ;; tl'lif3" Gtt, 1-. diol ..., 20-dione 1 the action of.: 1icro-or <..n Ü '.: \ l1 P.lo: oz: s1J.1.!. i.as ^ tzlatf :, enivif (1 '.'; ': 11 "' c> v: 'i yaro,: i5ivit.icn ai 1 \; 1'1 \' 1 '11O: -LY, O ; .y 1'00 \ 1.1 tmt un ";"> :: 011 ml.,. 1l'O - (,) 1 ';.:'. n L: .., ') Ur'.b') 0 ¯t <'r¯iu.; t; ï.ta l.fr, on 11.:mt get the .- .: aor-1, 4-i rf.; f; .zui?: raEa-t icK, i rxc , 1 -trio -, dione, Ine 'lta G; ,,.'. Li11J.0; i:

   r # .l.f ';: .. Î l'C, d, "l" O, l.Q..10Ut G-1 -!. :: dro;, yle of the latter cospooé, followed by' u: l <10: tcÍ1'll'jorltion Las 11-iiydrûA, -.- le by the chloride o; E3:: {: .111C:; li'aTl; ... E 'd'ihH 1 l'yriù1no, gave l 'ester uixte 1 -.;:. ESt: ¯': lccr; llt'c: îßt..élr: rE, te (1 ..r, or-1,4- t1T'tlad, xlE! litC, ib4C, lvr..01.-rGlJ, axl J 'reaction -tv c sodium aocrtateaae QtU1 ::> ricetic acid tr-nr-fome this outf; 1' mixed in CIJi.% t? .r, l ± ' '9 (11) -déiiyaro 4ü1 "x'C; ¯'yL: .1'1 :, c'e.'jt -'.- <! iru 1 'c,' 1 cit: head of D-: 1o: r-1,4, Si {11 i) .¯ ',: "l: .tx'i L: ât' 1x ':

  C, lriio .-. 5, ü- <.Ctxrs

  <Desc / Clms Page number 19>

 
 EMI19.1
 J. ! v7.,% C1 ga variant, of the 9 if 1) dehydro., nor-eteroldea such as those mentioned above can be conveniently prepared from a 119-hydroxy-eteroid by the action of methanoeultonyl chloride in 3, ethyltorraamide The D-nor-predniaolone 21-acetate can be converted in one step to 11-nor-14,9iij-prgnatrieneioa 2t-acetate, 21-diol-3,1w dione by reaction with methaneaulfoayl chloride.



  D-nar-9tf 1 j..dehyrdroprep, nanee -androstanes and fflotrande can serve as intermediates to prepare the 9tH "halphydrinee and the 9911-cUhaogenated oorreapond derivative 11 ^ 4r example, the treatment of the 21-acetate of D -noe. by N-broac- aodtamide and perchloric acid in aqueous dioxane gives
 EMI19.2
 the corresponding bromhydrin, i.e. 21-acetate '
 EMI19.3
 by 9abx.paa.I.narpredrri.ealarre.

   The treatment of the latter ompoui with potassium acetate in ltaod-.oue leads to the derivative 9, corresponding ti-axyda # atout-h-dîre le i. 9 acetate <xydo-D- <i <! r-t, 4-pr <! nadione '-) 6o:, 2 <-iol- 3,20-dione, By the action of hydrofluoric acid or hydrochloric acid on this compound, we can prepare * the corresponding derivative of the types hydrochloride and fluorhydi-lueb Ainei,
 EMI19.4
 when hydrofluoric acid is added to 21-acetate
 EMI19.5
 9t 1 -oxjrdo-Û-nor-t, 4-prégnadiene-t 6ct, 2 <-diol-3,20-dj.one, 9at-i'luatoIar 21-acetate is obtained. p redn, iaotone, while Inaction of hydrochloric acid on the 9) t '* oa <yd Daoratéroida mentioned above will give the 21-acetate of 9) t-chloro-J) -aor "prednieolone, the 9 (l1) -dehydrc-DHaor-steroid can also serve as intermediates for the preparation of 9ot, fi3-dihalagiuo) ..

   nor-eteroïdea using techniques similar to those described in US Patents Nt 2 * 8949963 du and 3,009,928 to 5,009,933 du. for example, D-nor-1,4,9 (tl) -pregna.triene-16a, 2.i- dà.o33,20-diotite 21-noetate by reaction with chlorine in ohloroform gives 9K 21-acetate, n-diohloro-J) - & or <-4-pregnadlea

  <Desc / Clms Page number 20>

 
 EMI20.1
 16a, 21-diol-3,2O-dione, but the reaction with H-brmoacetmide and hydrochloric acid in acetic acid will give 9rt-bromo.11 2 t -acetate -ohlQxo..D- 1,4-nor-pr6, gnedinel6oc, 21-diol, 20-dione, When a 9, .t11hal08éno-n-nor-proge8t'ronl is removed, the desired 9,11-dehydro intermediate may not be prepared in introducing a tt f3-hydroxy group;

  yl. in D-nor-progeatone, such as <6 <! <ioetoïy <-]) - nor-progeaterone, by the action of micro- oru1m. Ourynlara 1mato't after which the 16-acetate of 11;, t6 -dJ.hydroxy-J) .. n0r-prol.t'rone thus formed by aethaneaulfonyl chloride in dimdthyltormamldeo is treated to give 16oc-aaitoxy. ..nor (11 Ldehydrapro, eateronet 1m reaction with chlorine in acetic acid according to known techniques gives 9a, 11 .d3ahiaraf 6oc..roitaxy¯ J) .. ftOr-P1'OPlt'rone which, in addition to oe that it has progestational activity, is interesting as a topical auti- iaatllJllllS8 agent The immediate product of photolysis acid 6a:

  - ', ethyl- <D-ttorw4 -androBtene-3 $ \ iwüone16j3.oarboxylic, by undergoing transformation * similar to oail, ea described 01- above and in the Examples ol-aprbou will make available the k .... 'thy1-kor-hydrooOI' t1lont, 6cIC-mithfl- -nor-oorU.one and their 1d analogues, dhydro, which are all valuable anti-inflammatory drugs. For example, using techniques. analogues to Oellea of Example 34 below, 6oc-ethyl-D-nor-4 ndroatène-3 1 1 -dioruM 6p-oarboxyli-
 EMI20.2
 which can be transformed into the corresponding aldehyde chloride, and
 EMI20.3
 then to 2î-diazio-6ce-ethyl-1Mior-4-pregnene-3,11> ïtO-trione.

   Using operating methods * similar to those of the example
 EMI20.4
 ple 40 below, the aforementioned compound can be converted into
 EMI20.5
 21,21di.brono.fnadtb, yl.D.aar-4-prégnrne-3, t1,2. tr.ane which, when subjected to the transposition of layorsk1i in ut11iij: J.nt sodium methoxide, gives 6a-methyl-D-nor- 4,1fi (10) -prtÎÊnaclifcne-3, ii-dona Methyl 21-oate, which has

  <Desc / Clms Page number 21>

 
 EMI21.1
 my tourf apx $ transformation a 3-ethylene-odWe derivative can be very reduced by lithium aluminum hydride, ready what a hydrolysis of the odtal group gives the 6 - aetoyl-D-no) 4, t6 (& 0) - pregnadienet <, 2tdiol-3-one.

   The introduction of the t & ochydrocyooito system can be effected by oxidation of 21-acetate lieuter of the aforementioned compound with hydrogen peroxide in 4-butanol to produce osnttua tetroxide and pyridinau giving 6oc 21-aoftate. - thyl "ï)! 'noy''drooortieentt The oxidation of the latter by ohromic oxide domo aolda autueque will give ooaponé 11-odto corr4apmdant # oeat-h-dire the 21-aoétata of 6 -' mithylD = norwoortidane, The hydrolysis of these entera 21-aoitata can be ettactiid by means of the carbonate of potaaalun9 giving the M-methyl4) -nor-hydrocorti are and the 6 <n <thyl-Dor- oortiaone, respectively # subsequent blintro4uotion of a double bond A by means of the micro.organism Oynbt'i Bimolax ponformiaaant in the optfratoira mode of louxempie 97 oi,

   aprlta gives 6 -mdthyl-14nor-prodaisolbat and 6 -methyl-D-cor-prednisont respectively @ When prepared daa B-nor-ateroIdea which aoat alb '; 4uand on. prepare D-noy- * t <yoTdww which have tuba- altuated to one or more of the carbon atoms 2f 4 6, 9 "t1 and t 5, for example oo! Na <shown in formulas H and V oi * apr & 0f it is in general preferable to have any leu aubatituanta present before the building up of the 6-6-pygMnt side chain, and to subsequent degradation (when preparing D anologuee -nor derivative * of leandroutoue and loéettone), or its subsequent transformation into the corresponding D-nor analogs of t6a :, 2I'ydroxy <-oorticoïd "prëgnanM.



  However # of subatituants can be introduced i, a stage
 EMI21.2
 any of the synthesis *
 EMI21.3
 Thus, for example, a D-nor-androatane such as D-nor-'testoaterone can be treated with ethylene glycol by known techniques to form the 3-ethylene-ketai derivative which, in turn, can be treated with ethylene glycol. epoxidized by tra3.
 EMI21.4
 by means of a peraoid such as peracetic acid or

  <Desc / Clms Page number 22>

 
 EMI22.1
 preferably mOl1oper acid, P1 \ tal1qu. to give the 3-ethyleno-oetal of 5ac, 6ac-fpoxy :, nor-undrostane14-0l3ort1 "The checkerboard compound can survive as an intermediate to introduce a 6-m substituent <! tinyl or 6-halo (eg 6-fluoro, 6-ohloro and 6-bromo) in the kor-an4ro.ian ring.



  Ainal, the action of alum aid hal6ùnb, driqu., For example hydrofluoric acid, on this intermediate hydrolyzes the ethylene-adtal group and ati-m4mo time outires the epoxy ring, giving 6 | d-fluoro -D-> nor-androetune> 90C | 16 | 3 <-dlol 9 * -OMt 1iandil.f that the addition of a reaction of drîgnard coma 3.l.odura of J: .1Chhyl-ma ncfu1wu .1; .. 1.'11141'01) '.. later gives 63-md thyl-noandroatana; ac, 16 d-di.ol-3 ona.

   A reagent such as oblorhl4r1qu, ethanolic acid or one of the two preceding 5'-mbydroxy-613-subatitude dehydrates the 5 -hydroxy- and 'piIll41'18' group to 111'111 'teupa subotitating it by 6p for dOlu1.r. Respectively # 6GrtluoroIl..nor4 androatènal6Ei-al - ona and 6a-radthyl¯D-uor¯4-androBtene-i6 ± ¯ ol 3¯on Par 1 & 111 ...

   when 5a-hydroxy-6 | i- substituted acupoudi are treated, for example # with about 90 SI aoetic acid or with thioethyl chloride in seen
 EMI22.2
 cold basic medium as in pyridine, we obtain
 EMI22.3
 oomponde substituted in 6j9 coma * la 6) -fluoro-nor-4-MdycathM- '6ol - "' ObO and d..rcityl.,. nor-4-udrastdnew163..o1-âwons, Mspeotivectentt Les produced substituted in 6ac can thus and prepare from two corresponding 60 substituted isomers by means of alcoholic solutions of alides or COI bases:!. l! 18 ethanolic hydrochloric acid and potassa dtiiano-
 EMI22.4
 lique.



  Similar transformations can be carried out on the derivatives of D-nor-prégnane as illustrated by the
 EMI22.5
 following process for preparing Ó # -mdthyl-D-nor-hyJrooor- tiocnoe D-nor-hydroeort1oone can be converted to its 3 2O-biB # ethylene-ketal, after which epoxidation of the 5-double bond is carried out , 6 by means of a poraoid such as perbenzolque lakes * The reaction of ', 2o-bie-ethyl ne-oetal with

  <Desc / Clms Page number 23>

 
 EMI23.1
 c, 6a-oxyâo---nor-} ivyàrooortiaone thus known with a Grijnard reagent CO ':, 1e ethyl-Nanenimrt uour bromide. the derivative 5-h, vdroxy-63 - :: léthylé corresponding * The cotai group can be removed with the nucleon of dilute sulfuric acid which dehydrates in a6: ne tO: 'J1JS the 5 -hydroxy and el) i!, iE- rit3ia the 6 (-n) uthyle group in 6ct:

  -methyl, giving 6āniéthyī D ... nor-hydrocortil3ona which, when subjected to the action of Qqrynebaotoriura iiri2.lex, gives 6cc-methyl-D-nor-predn: tt1o- lono, puianant fvent nntj-in: t'1a: 'Cortical xnatory. 4î we c '' do hydrofluoric acid r .u '5, iîO -blïi ethylbnecetal and 3t <., L: f o: ty .o ...: U ... nor-hydroco: rt;!. OonlJ, we get lu ' <J, KO <-biR-ethylèu'3 "oet! tl of 5o: -11:, droxy-6.; ... flnoro-D" '110r-hydroeort: 1.EJono, qii-lt <mand il y'it nvBO hydric acid '' thanollque, fornsy la qui pont Ctro ty'T'tofoyMdo iloyon du Po: rma, l>, rtg, to,: r1, u, I! I,.!? p; \ ', j {en non nn-ïlo / u' 'i-dôro, the other powerful ncynb them ni ¯ infiM'Mtoira coytioTl. t, ubcitittiant.9 tala that the following z ... hydroxy, oc- and | 5¯filooylo8 Lower, and K- and | 3 -halogdno can 6tyt} introduced <1 year: J 1 (\ nucleus of D-nor-ntÓ: t'o5:

  do in 0-15 using doc teohniqueo olmila: 1.rlH1 by known methods for the introduction of the corresponding substituents at 0-16 in a 5-membered D-ring etol.



  For example, to introduce a 1 $ ot methyl group in the JJ "nor" I ': r'ÓcrnGnolonc [t1 :: D-.nor'-5-l'rinene'-3-' ol-20-one), which can be obtained as described above and in Example 32 ol-aprbs7, the required 15-dehydro: intermediate can first be prepared by bromination of D-nor-preneolone in chloroform using bromine, after which is treated the derivative 5,6,16-tri bro'n6 thus formed by sodium iodide in Itacetone to obtain l6-brono-.D-nor-5-prenene-3, -
 EMI23.2
 ol-20-one which can be heated with collidine to
 EMI23.3
 give the desired D-nor-5; 15-I) recnadiene-33-01-20-one.

   Similarly, when D-nor-prGgnana-3p..ol-20-one is

  <Desc / Clms Page number 24>

 
 EMI24.1
 bromide and then deroiihydrate co'r; ll't described here-docatieg we get D-nor1 -pxnne..3; 3-al-20-ane..L'radd.t.an of a normal Grignard reagent , cornai iodide of:; tthy. raan3- siuiag to a 1 5-dehyâro-D-nor-steroid using known techniques results in the production of the corresponding 15 -methyl derivative, for example 1 a-mthy.-7-nor prégnnQ.- .. a.-20-ass.

   When other 1 r '"c substituted derivatives are desired
 EMI24.2
 with a lower alkyl, one must use other Grignard reagents comprising the corresponding lower alkyl, for example
 EMI24.3
 example isopropyl methyl bromide, wn, iodux. magnesium or 1-butyl-ina & metjiwa # iodide and thus obtain the derivative 150: -úthyle, 15 -Îoopropyle or 1 x-.buty.e of D-nor -, - pr6gnene-'p.ol-20 ... corresponding ono.



  One method of introducing a 1) -nor-ot6ro! Tdo 0 ooruno 15-lower alkyl yadiofti to D-nor -5 1 .prgrnv! 'A.'ü..axW is to react the bond 15 dehydro with d1a.omthtme, so as to obtain 15.16-. pyraaolin-D-nor-5a-pr6gnano-3 [3-ol-20 -one which, after pyrolysis at the melting point of intormodiairo pyrazolino or below, gives 9 5.metxay.9 a-.rdhydra.- ..nax -atdrada corresponding, for example 15¯methyl-D-nor-5 -15-preenbne 3 (α-ol -20-ono.



  (Although it is preferable to pyrolysis by heating the pyra-
 EMI24.4
 zoline above its fuaion point, this pyrolysis can
 EMI24.5
 be carried out by heating the substance "in an inert solvent boiling at high temperature, such as 27cymene, tetralin or a similar solvent). The 0-15 unsaturation in
 EMI24.6
 the D-nor ring can conveniently be removed by reductive hydrogenation, preferably in the presence of a catalyst,
 EMI24.7
 such as palladium, so as to obtain z-methy.-I-nor-.5at-prgnane-3f3-o.-2G-one. Similarly, a-.nar.-5,15..pregnad.ene-i.-o.-2t7-ane, by reaction with diazomethane followed by pyrolysis and subsequent partial hydrogenation, gives 15 (3.-methy..3-.nor-5-.pr (rzene-3j3¯ol-20¯one.

   When you want the 153-ethyl derivative. 159-

  <Desc / Clms Page number 25>

 
 EMI25.1
 propyl or 15-butyl, is used in the procedure
 EMI25.2
 described above diazoethane, diazopropane, diazobutano,
 EMI25.3
 etc., correspondent.
 EMI25.4
 Intermediate 1 5¯alooyl-1 5-dehydro- prepared as
 EMI25.5
 described oi-deosus can also serve as an intermediate for
 EMI25.6
 the preparation of 15-Methylbne-D-nor-stéro'EdeSt Thus, using known techniques, 15-mdthyl-D-nor-5 # 15- pre, mad.no-3-0.-2J-ona, by treatment with alkaline hydrogen peroxide gives the corresponding 15c, 16x-dpoxyds, ie 1 ac, 16a-.oxyda-1 -msthy.-.- nor.5-pxdgnàne - ol-20. . orza.

   Treatment of 15a, 16a-.orydo.-nor-atéraxda with ha7.ogtnhydricucz acid, for example hydrobromic acid, produces the 15-tnethyl.ne..l6cK-hydroxyorroopondant derivative, for example 1! -Mdtkzyl. ne-I7-nor.5-prfm.tsna..3,16at-.dio.-20-one. The action of the microorganism Pliivobacte à c1ohYdro (1, en.an, I !, using conventional techniques, transforms 15-methylene-D-nor-5-prd, n tna-3y 16a..ci.o. -2U..ono in 1 5-methylene-1 6a-hydroxy-D-nor-progesterone (1 -r.zethylen-D-nor - prégnbne-16ac.ol .-. 5.20-.
 EMI25.7
 diane) which can be acetylated using acetic anhydride
 EMI25.8
 and ptol.une..su7.on.cuo acid to give 15-methylene-16o-acdtaxy-U-nox-proeatons, which is a progestogenic agont
 EMI25.9
 potent by mouth.

   
 EMI25.10
 From 15-nzCthylèna-.l6oc..hydxoxy-1? -Nor-pxoges-
 EMI25.11
 terone produced as described above, it is possible to obtain
 EMI25.12
 interesting 21-oxygenated derivatives of 15-methylene pregnane
 EMI25.13
 possessing cortical activities. So, for example, the
 EMI25.14
 ') 5-Nethylbne-16 <x * -hydroxy'-D-nor-prosesterone can be converted by oxidation using Ith.zo nifmicans to the corresponding 11-hydror.y derivative, which in turn can be trans-
 EMI25.15
 formed by the action of an iodine / calcium oxide derivative mixture
 EMI25.16
 Corresponding 21-iodine, transformed by aceta, yse to 21-aoetoxy derivative, 21-ethylene-D-nor-4-pregnene-Ot, 1E'xc, 1-triol-3,0-dione "La transformation of the 11-hydroxy system into a system

  <Desc / Clms Page number 26>

 
 EMI26.1
 9oc- ',

  corresponding uoro.11t3.hydroxy can be carried out by
 EMI26.2
 methods similar to those well known to those skilled in the art as described above, and one can thus obtain 21 -acetate
 EMI26.3
 of ac - .. uoxo-15-.:nEthy.ne -nar-hydracortiaone, which by incubation with Corviiebacteriun simplex gives 9oc-f 1 "\ oro-1 5-methylene-D-nor-predniaolono, corticosteroid powerful, interesting horn agent ru.t, -3.nf.funnrxto.xs.

   Alternatively, treatment of 15-rndtlzy.bna..l6s-txydxoxy-D nor-.prassot: xono with mioro-orglUlome aliivulriria lunata gives the 11j3-hydroxy derivative corroaondant, 1 -mc3tlfy.dma-u -nox.-prrzna-11 3,15c-dio.- 3,20-diono, which, after treatment with an inelaneo iodine / oxyda of arsl, oxrm (giving the derivative 21 .-, odE) miivl of a given ao6tolyeop le -o.cÓtato de 1 h-rnëthy.2ne..D-nox-hydxooort, ezono the latter can atra trnnC3! 'orm / o on 15-raethylëno U-nor¯prGdni0Olono by 10 O, or: ± .n, oba.cta, 1'iU!: \ pir.1TJ, lex, Les 15-: nô'hy.bno. D..nar atéroxdoa capable of being obtained as described above, which in turn can be transformed by reduction to give the corresponding 15a.- and 15-methyl analogue.

   Thus, for example, 15-methylene-D-nor-prednisolone and 9a-fluoro-1 5-methylene-D-nor-pxc: dn, salone, by reduction with one equivalent of hydrogen in presence of palladium on charcoal ooiarao catalyst, gives a mixture of the isomers 15'x-aëthyle and 1-i-nâthy. Q of 15-: aethyl-D-nor-prednicolono ot of C.'luoxo 15- : nthyl-3-nor.-nroduiealane, renoeotively, which can be separated by chronatographic techniques so as to obtain 15cx.:a6thylv-nox.pradnïso.one and 15ethyl-D.-nor-predn.ioo. one, or 9K-'fluoro-'t5cc'- <nethyl- 'D-nor-prednisolone and xr-fluora-15 ..: anthyl-.i} -nor prodni-
 EMI26.4
 colone, respectively.
 EMI26.5
 



  Alternatively, the 15 meti: yL-13. nor-coxticodaa which can be prepared from 15-methyl-l-norprr, no.anea, such as 15a-.méthy. b-.norm5 prenene j, -al-20..ono and the 15, ... mâthy.-. , iJ - nor-5 pxgnne; -. 01.-20-.one by transformation into t 5 met: .yZ.



  D-nor-progesteroneo corresponding bone by oxidation of üpp (mp.or,

  <Desc / Clms Page number 27>

 
 EMI27.1
 by hydroxylation with Glonerella ainnulgtq or Rhlapmia nirriemii3 according to known techniques to give the 15 <x-methyl-1K-hydroxy-D-nor'-progesterone and 15, bthyl-i loc-hydroxy.-D-nox-pxogestcrone, respectively, by
 EMI27.2
 oxidation giving the 11-ketones by means of chromic acid, and then carrying out the series of elaboration reactions
 EMI27.3
 den structures. nox-coxt, co: des by proceeding in a manner analogous to that described in the review "J. Ara, Ohom. Soc." 11.



  4436 (1955), to obtain the 15c <-methyl-D-nor-predniBOlone and 15p-methyl-D-nor-rredniaolone, respectively * Y Alternatively ('I11C01'0, 1 "' -J \ ethyl ... 9; t ... nuoro -D..nor ... predninolonc can prepare this from 1: .rauthyl- D-nor-'5-probnen <? '- 3'3'-ol'-20-one by operating in a manner analogous to that described in the review "J. Am. Ohea. Soo." 809 4431 (195) for the preparation of 16K-methyl-9 <x-fluoro-
 EMI27.4
 prednisolone.
 EMI27.5
 



  The introduction of a 15x.-hydroxyl group into unsubstituted D-nor-steroXdoa can conveniently be accomplished using microorganisms such as the following! s liormo (iondnim olivageiun (A..CC 13e 596) e ge! Le-t-2- tri oli antirrliea # .i: ani n2ttila, (] ¯nloneotrla from 09r. ± \ (by methodoEl deorites in the German patent N 1,067,020 (by Methodep described in German patent? 1,067,020 du),, G, ib, be.el; LE \ bac ou i bberellà sQubin1ïh, A preferred method consists in Introducing the group 15 - hydroxy through 1 'Hprmodandru!' !! olivagoum (A..CCC 13, 596) according to z, techniques similar to those described for D-ring sterols
 EMI27.6
 pentagonal by S. Bernstein et al in the review "J, Am.
 EMI27.7
 



  Chea. Soc. "82, 3685 (1960). Thus, using these known techniques, la -nor 4 pxé, mtne-16ac, 21-d3.o1-3, a-dione (can
 EMI27.8
 be obtained as described in Example 43 below), when it
 EMI27.9
 is subjected to the aotion of Hornodendrum plivaoeum, is transformed into derivative 1i? (Corresponding X-hydroxy, o est-a-'dire D-nor-4-pxénnc-15ce, 16uc, 21-txiol-3 , 20-dione. The introduction

  <Desc / Clms Page number 28>

 
 EMI28.1
 of an 11 s-hydxaxyl group by means of uurvularin luna.ta followed by ti.arob, o.oric dehydrogenation to 0.-y and cl.2 by means of CorYrJ, ebacteriu.! 11 flir.plcx, dor .ne D..nor-1, 4-pregnadiene-1 1 3 1 5a, 1 6a, 21 -tetrol¯2, 20-di ono.



  Similarly, 6ac.-methyl-D-nor-oortisone, 6a-methy, -D.-hydracart.eanc, 6a-aidhyhw..nar-prcdn.sone, 6aCtndthy.-Ii-nar. reun.eo.arts (which can be obtained as described above) can be transformed into the corresponding 1 att .. hydroxyl derivatives by the action of lior: nod, cndrwn oliva.- een giving 5ot-.mdttxy, -15a. udxoxy-u-nar-cortieane, 6oc. mdthy. 15oc-.hydxoxy-nax-hyâ ^ oaorticana, 6o: -roethyl-150: - hydraxr.A-nor-predn.aone and 6ce-:

  aCthyl-1> ct.hydxoxy - nar .. prednisolone, respectively, The esterifJ, oation of the corresponding ,,. 1 & x-21-triols by means of acetic anhydride in the pyridine gives the corresponding 15,21-diacetate esters.
 EMI28.2
 To introduce a halogen, for example fluorine,
 EMI28.3
 in 0-15 in a 13-nor-otdraide, we had to use techniques
 EMI28.4
 similar to those used to introduce a 16-halogen
 EMI28.5
 in a steroid 0. cycle D pentagonal xar example, to prepare the corticosteroid, the 21-acetate of 15K-fluoro-D-nor-pred-nisolone, one can use co: .Tme intermediate starting the A.-nor -4,16 (20) -pxdgnadiëne-21-ol-3,0-d, one (which can also be obtained from 21-diazo-D-nor-progesterone as indicated in Example 40 below ).

   A 1 1 ji-hydroxyl function can be introduced by the action of the microorganism Curvu7.e, xa lunata, then subjecting D-raor-1., 16 (20) -irdgnatriéns-11,21-diol-3 -one resulting from the action of Corynebaoterium simplex so that the analog 1 is formed, a'cet D - nox-1,9,16 (20) .. pregnatxin-11 3, 21-dio7.-3-one, After esterification of the 21-hydroxy function with aoetic anhydride in pyridine, the introduction of a 15x-hydroxy function (carried out by m3erob.ologiquee techniques such as
 EMI28.6
 described above) gives triol-triene, 21-acetate
 EMI28.7
 A.-nar1 t4.16 (20) -pre, rnatr3no-11i, 1, 2l..triol-3-one.

   The

  <Desc / Clms Page number 29>

 
 EMI29.1
 reaction with thionyl chloride in tributylam1ne results in the. formation of 21 -acetate of 20-ohloro-1) .- nor-1 p4- 1-pre-xatr,: rze-113, Z1-d.o1 - one which, after titration by means of hydroxide of God11 ù6oino1 , dpnno 20,21-oxydo-D-nor- 1,, 15-px,; nr> l; x .: u: .. 11: -01.-3-ona. Lia treatment do co last coml'Of1l! P '\!' hydrofluoric acid followed by acetylation of 1 ct .- '. uoxa - nox-1, 4,1 a (2U) -pxu ,, fntri: na-11, 1 - diol-3 .. one 1) .1n (: 1 produced gives the enter 21-acdtate oorreapondfuit which,: UfJ.J1J. It ert OYY1 by the H-: 16thylm.orj) holine ... oxide-poroxydlJ on ty'c: fC: lG3 of ofmium tetroxide, gives the 21-ao-state of 15a-i'lworo-i> -nor-predni3olonf which possesses anti-inflammatory activity.



  Another method of izitroducing a 15-halogen (and one in particular a 15.:3-halogen) in a D-norprégnane uses 00 $: 10 inter :: 16d.ie..ire the D compound -nor -5a - 16 (20) -> d, .no 3-0.-l..aal; a of methyl which can oc prepare using aon toonniquos imilres oelleo described in) 7. (JIt \ rJlec 34 and 40 oi.-a.pxÉe.

   Thus, the aid ori.oxux4 of the 3 <- 'aoûlaby do 1 op-oarbozy-D nor-andrQstan0 "3 | 3¯ol can E3tra trano formt? on 3-acôtate do 1 .d, caMow, U.norJacxzrGcr, nd.2U one by tr'iito'Mnt an diuo '! lthanê' the reaction of die.zooétone r: .vac le bro.on IJO.1r clouner the 1,21-dibromu; c, followed by a 'tl.'; irliJsO:>. t.Ol1 dG, 'c'l.vG7x'i71:, .. hl' ido of sodium r.l4thylata, daizn the:

   product interr.it diairw, the i> nor-5 1 6 (20) -vvôgnbn - '$ p- ol-21-oute ao, .1étnyleJ the esterification of checkerboard bone 00!: 1! .oB4 f311 3-actte , frivio of a bro: auration by means of 1T. bxamo- oucclniulde in 001. gives the 3-acetate of 15oc-broiao-D n.or-x-.16 (20r; r; in: nQ-3.-a ... 1 oato dra methyl displaces it-
 EMI29.2
 mount of the orome atom by silver fluoride in
 EMI29.3
 Aceton, '- trile results in the formation of 3-acetate dU15j-fluoro.-Drnor-.oc-.16 (2) -. D; xxena-3; .01-21 methyl oate.



  Li colvolyn: du :: ro11J; c:; i'3nt 3-acetate in methanol in the presence of Ii'Ôth {.r: lt ne trifluoru1 "6 boron, followed by oxy-
 EMI29.4
 dation of the 3-hydroxy function by chromic acid, gives

  <Desc / Clms Page number 30>

 
 EMI30.1
 the 1µ (3-flworo-D-nor¯5a-16 (20) -pri <methyl genenē3-one-2t-of \ n. the trF..llf1i'ormo.tion ae this last corner) ocd 1 '3- thylëno-oétf.LL 111'11' l '(' thyJ.ène-glyool in the bonz! l13 in the presence of a catalyst acid, followed by a redu.ctj '11 by means of lithium aluminum hydride in 0 0 tttrt ydrofuran, the acutylntion of the resulting product by ii anhydride of o.oétiquo, hilU1 pyridine and release the aqueous acetic acid by tripping tritoment; hot produces a very effective interim product: l1t, the 21-nodtat! i of 15t3-fluoro-D-nor - 16 (20 ) -preten-21-ol -'-one.

   The latter compound is oxidized by N-methyltorpholinQ-veroxydo. roonco do osmium tetroxide gives' ..i 21-actatQ of 15f3-Íluoro-D-nor-50: -prl1 [nene ... 16tt, 21-to101-3, () - dione which can be converted into l 'analogue' by bruouration in dioxane using two molar equivalents no bromine to give the 2,4-dibromo derivative and subsequent dehydration in dimdtlivlformamide in weconco of lithium uromide and oaloiuln carbonate to give 21 -acetate do 15o'-fluoro "D '-. nor-1,4''prdo.dibns''16ût, 21-Qiol-'3,20'-dione, The uoycn hydroxylation of P, u; r. \' u,; Vr1Tn.) .un: jtl: 1, at position 11p gives Ilacetato de 15-fluoro-D-uor-prodni olone.



  0 We're going to df-'crlrc again! oi-.1.prùr. a'other typical eraoe trimaforma'- tions which have been obtained donation of D'-nor'- steroids which pocnhdcnt a therapeutic activity or which are of interest CO: .1: .Hf produced iiit ee-iédiary 13 2ar example, D-or ... l1ldor3trone can be obtained from JD¯nor-4-prt! gnènē2 1-01-3 20-dione which, in turn, can be obtained by hydrolysis of con ester 21- acetate
 EMI30.2
 (the compound of Example 39 below) by means of carbonate
 EMI30.3
 of potassium in accordance with: Operational day of 101..xeriple 40Hé To obtain D-nor-aldNJterone, an 11-hydroxylo group can first be introduced into D-nor-4-pre & nene-21-ol¯ 3.20 #dione by means of: nicI'o-orgrmiume Curvularin. ;

  tw1a.ta, after which the D-nor-4-prlene-11j, 21-diol - '. 2v- is processed
 EMI30.4
 

  <Desc / Clms Page number 31>

 
 EMI31.1
 resulting dione (D-nor-cortioo-stërone) by ethylene glycol and p-tolubnesulfoniqite acid in benzene, so as to form the 3,20-bie-ethylene-ketal derivative which can first stem acetylated in 0-21 by means of acetic anhydride in 3.pay.d ..,
 EMI31.2
 then esterified in 0-11 by means of nitrosyl chloride dama
 EMI31.3
 pyridine to form a product im: e: rmed1a1re very Yànpt "3,20-be-ethy.àne.otal. of 11-nitrite-21-ao'ta-te of 1) ... nor-4-prene -11, 1-â.al -,.,. D.an. The. Photol7 of the last compound dissolved in toluene by 1; .1-, ultraviolet light oonformúent to 1 toalfo.

     & '- orites by Barton and .8oa ton in the = view mJ * Am *' Sh * ôuî1 µ2, 750 (1961) given 30-bl8-M) ylen <t t1 * oiiMi of 1 -o.mina .-. norrrsnl1 t'd .., c. sCd. when treated with aoidt nitr9uaty dom * le '' 0 ,, ethylbneoetal of 9-, atat "a'à, .. '4i ,,'. 1!) t diol ... 20 ... dione which, by i: r. "l.1b: ttnt 1. '" Mùgum. 41% ffl 9M3t & .tt aqueu81 90 ± dt 1 \ 01de ..o' '' 1q .. Confessed 1 '..¯. t. l> * iiiN * â: àii3Jfe <| tarons all its forma h.4mi40''MJ .. <c * t> at 4 4iï% X% & tl * w & * 8 * # <i) 1 11 (, "I .ada.Y-norr # a'è11r9.za., 3a aaa L '.



  'box Ut I3 -noï <-aldostdron peweMe 4 ïi4 '' < <îft * OrU tè mineral and goal thus \ 1.ti11.8.'bl. d.8.1 \ 8 the u..t ..-.- t. 'bl- such as disease d t Add1ltuh Des D-nor-1 6 ... l \ Ipi: t "Olaototteli 1séï'0Î <àl2. ' % !. 11; useful anti ... '1ldoe1irone tt -d.1 \ U:' tU '' '' '' 'èfJ n3' "prepare essentially oonïfoxt3ié'a nt at 4) Kt <fMe known to Etereid Chemistry. AJLnait the 1 $ 8MSiï2R * yiL * 'D.nar. tatot6rana can ttrt tran.fCrm '. e & * îMn'14 Jf 4Lfca * * metal- A5 in the manner h..1'u ,, CG 4 null ±> .... 1. "" .1t transforms into reagent of ij: tigfie.rd "t) -et: 1: tM \ i't. êftftaa <6 with tutithyl4ê1um bromide. ze \ r-a1t ... ll. "'" of carbonic of the compound do * r4>, thus' té-. 4w WIItiiiJ ae with 'tzyln acid, d. : cXt3 '"s j 6ar.-prapynüu.

   A 1'Oc'n ': U.0I \ 8 $ 1. (:' \ 1 ".. lA tr4> 1 * bond by an equivalent 4. thydro.gn., Ei4.t" 3 ..., .. . ment of the crude product not an a01de mineral .. 4: bI.: 'ab1t:

  <Desc / Clms Page number 32>

 
 EMI32.1
 acid - (3-oeto-16-hydroxy-D-c.or-4-androateno-. 16 K-. y1) -propenaq, us. Selective hydrogenation of the double
 EMI32.2
 bond of the side chain by one equivalent of hydrogen
 EMI32.3
 gives the lactone of the acid - (âceto-16E3-hydraxyU-nox 4- androetênel5ot-yl) -propio:. which the latter compound can
 EMI32.4
 be dehydrogenated to the 6-dehydro analog using ohloranil, and then thio acid can be added
 EMI32.5
 acetic to the 3..aetow4, -dihe system to obtain the laotone of -. (7r-thioaaetoxy-3 keto-i 6E3.-hydroxy-D-nor-4. androstene-16 -yl) -propionic acid.



  15a (16a) -otal and aoetal derivatives of D-nor- 15oc-hydroxyaoxti.aodas, which are anti-inflammatory agents
 EMI32.6
 very powerful roofs, can be prepared from them by conventional methods. Thus, the treatment
 EMI32.7
 D.nar.-1,4-pxégnadien-11,15a, 16a, 21.ttrol.-3,20-.d.one by acetone in the presence of tolunesu7.onic acid gives 15a (16a ) -aoetonide corresponding.



  The 16 (2l) -odtal and acetal derivatives of D-nor-
 EMI32.8
 oortiooldes can also be prepared in the usual way.



  These compounds are useful as anti-inflammatory agents by themselves, and they are also useful intermediates for the preparation of other useful corticosteroids such as
 EMI32.9
 D-nor-cortîooldes substituted at 21 by lower alkyl.
 EMI32.10
 For example, D-nor-prednisolone, when treated with
 EMI32.11
 dimethoxy-propane in dimethylformamide in the presence of a strong acid such as p-toluenesulfonic acid, gives the 16a (21) -aoetoniàe of D-nor-prednisolone. The latter compound
 EMI32.12
 can be alkylated and the aoetonide function hydrolyzed to
 EMI32.13
 give a 21.-al.ooyl-D..nor-predz.eo.ane.

   Thus, the 16th (21) - '
 EMI32.14
 D-nor-prednisolone aoetonide, by treatment with butylate on
 EMI32.15
 potassium, followed by methyl iodide, gives 16cc (81) - 21.mthy.-D.ar.predn.so.one acetonide, which can be
 EMI32.16
 hydrolysis with hot aqueous acetic acid to give the
 EMI32.17
 21-methyl-D-nor-prodnii3oloneâ

  <Desc / Clms Page number 33>

 
 EMI33.1
 16oc (20j, 2 (21j-'bis-3ndthy.énad, oy derivatives of D-nor-atèroldeu having a 16a, 21¯hydroxy-20-keto system can also be prepared by techniques similar to those known in the art. Steroid chemistry These derivatives are useful intermediates for effecting subsequent transformations of the molecule with complete protection of the sensitive dihydroxy-keto side chain.

   The group
 EMI33.2
 bis-methylene-dioxy can then be hydrolyzed with regeneration of the corticosteroid side chain. For example, D-nor-hydrooortisone can be transformed into its derivative
 EMI33.3
 16a (20), 20 (21) -bis-methylene-dloxy by treatment with formaldehydo and hydrochloric acid in the chloroformate The derivative can then be condensed with dimethyl oxalate
 EMI33.4
 the in the presence of alum base to give the derivative 2-methoxaly, e.



  Treatment of the latter with methyl iodide and a base gives the bis-methylene-dioxy derivative of 2oc.mthy.



  D-nor-'hydrooortiûone * The bis-methylbne-oioxy group can then be hydrolyzed by heating with formic acid to give 2a-methyl-D-nor-hydrooortlaone Des 21-halo-20-oeto-D-nor- eteroldon can easily be prepared from 21-hydroxy-20-oeto-JD -noï> steroids. The 21-hydroxy group can be transformed into
 EMI33.5
 a suitable ester of the sulphonate type, such as methaneaultonate, and the latter can be replaced by a halogen atom by treatment with an alkali metal halide such as lithium chloride, lithium bromide or iodide sodium.

   For the synthesis of 21-fluorinated compounds, it is preferable to prepare the 21-iodine compound from the sulfonate and then replace the iodine with fluorine by treatment with
 EMI33.6
 silver fluoride in wet acetonitrile. For example, D-nor-.deocyaartiooetrono (= D-nor¯4-prégnene-21¯ol-3,2Q-dione) can be converted to its 21-methanesul.f orate using methanesulfonyl chloride in pyridine. The treatment of the latter compound with sodium iodide in

  <Desc / Clms Page number 34>

 
 EMI34.1
 acetone gives 21-iodo-D-nor-progeetone which, on treatment with silver fluoride in wet aetan.trile, gives 21. '. u.aro - 17-.nox-. , pxogeetdrane.

   Similarly, D-nor-prednieolone can be converted to D-nor-prednisolone 21-muthanesulfonate; thence to 21-iodo-D-nor-1 # 4 ...: irégna-d3, ne-t 1 3.1 ôaxd.ol-3,2d-dione; and finally to 21-fluoro- D.nor-.1,4-; xnadiene-11,16oc-d3.ol.-3,24-diane.



  P-nor-3-oeto-4.9 (10) -diene-eteroid8 can
 EMI34.2
 also prepare by deo procedures similar to those
 EMI34.3
 known in the steroid art. Thus, the 16 <Xr thyx, y.-D-snox-5 ('10) -oesbrne-l6-ol - one, per treatment
 EMI34.4
 by means of pyridinium bromide-hydrobromide in pyri-
 EMI34.5
 dine, gives 1 & ct.-ethyny, -D-nor-., 9 (10) -oe, eErad.ne-16- ol-3-onot Similarly, 16a-uhloro-thynyJ.- 1 -nox-.â (1C7) .oestrne. 163-0. .-ane, (which can be obtained from 3.-mdthaxr.D-.nox-r, 5 (10) o etracl.ene-1? -one by treatment with lithium ohloro-aoetylide followed by
 EMI34.6
 hydrolysis with oxalic acid), by bromination in pyridine
 EMI34.7
 gives 16ot-oh.oxoétüynyi - D-narw4,9 (10) -oestxadine.16j3 ol-3'-one. These compounds are highly effective contraceptive agents
 EMI34.8
 active.



  D-nor analogs of known anabolic agents can also be readily obtained. Thus, the processing of
 EMI34.9
 D-nor-testosterone acetate with alkaline hydrogen peroxide, followed by re-acetylation, gives 4,5-epoxide oorreopon-
 EMI34.10
 dant; The latter, by treatment with hydrochloric acid in acetic acid, gives 4-chloro-D-nor-testosterone acetate. Similarly, 19-nor-D-nor- acetate
 EMI34.11
 testosterone and l6 <x-methyl'-D-nor-testosterone can
 EMI34.12
 be transformed into their 4-chlorine analogues, acetate
 EMI34.13
 4-ohloro-19-nor-D-nor-testosterone and 4-ahloxo-16a.-rnthy.- D-'nor-testosterone, respectively.

   In a similar way,
 EMI34.14
 but by using a small amount of sulfuric acid in acetic acid instead of hydrochloric acid, one can

  <Desc / Clms Page number 35>

 
 EMI35.1
 obtain the corresponding 4-hydroxy compounds, 4¯hydroxy¯1 y¯ nor-D-nor-testosterone acetate acetate and 4-hydroxy.16 -m-tliyl.D-nor-
 EMI35.2
 testosterone.
 EMI35.3
 



  Def3 dihydro-D-nor-testosterone analogues can be prepared known as: D-nor - pregnan-3ol-20-one
 EMI35.4
 can be oxidized by m-chloro-perbenzoic acid to
 EMI35.5
 give 16¯ D-nor-androstane-3,1Óp-diol acetate. This last ec -,> 0Bé, when it is oxidized by the acid chrO :: 'irp'o. gives the compound 3-keto, Itao6tate of D ... nor-dih.Ù: rc-testost6- rone * Its condensation with the etiole formate in the presence of a low gives 2-hydroxyraethylbne-D-nor-àihydro -testo-
 EMI35.6
 sterone which, by hydrogenation in the presence of a catalyst
 EMI35.7
 palladium or charcoal, gives 2 (X-met: hyl-D-uor-dihydro- 'teatoaterone.



  From 6-methylene derivative of D-nor-stëroldea can 6-methyl-li-nor-4-aidrontbne-3-onep 6-methyl-D-> nor-4-iJréciriëno -3-onec, Thus, a Dn or-6-met! Yl-:! '- oto-4-dbhydro-'Htdroid can be converted into its 3-alkyl ether of 6nol, for example by means of an orthoformate
 EMI35.8
 1.11 alkyl and the corresponding alcohol in the presence of an oata-
 EMI35.9
 acid lysour, and this enol ether can be reacted with
 EMI35.10
 bioxydo de active, freshly prepared in accordance with
 EMI35.11
 according to the procedure of American Patent HO 2,980,711 du, resulting in the formation of the desired D-nor-6-methylene -) - oeto-4-dehydro-ato!

   (The checkerboard can be converted to the corresponding 1-dehydro analogy in the usual manner, for example by treatment with diohio-! Ro-dio3rano-bonzoquinonet Thus, 6-methyl-D. Nox-hydrocortisone 21-acetate , by treatment with ethyl orthoformate, ethanol and pj-toluene-sulphide acid in the
 EMI35.12
 dioxane, gives 3-ethyl ether enol, 21-acetate 3-
 EMI35.13
 ethoY-6-methyl-D-nor - ,, 5-pr6Gnadione-11.1 & x, 1-triol-2O-one.
 EMI35.14
 



  The reaction of the latter compound with manganese dioxide

  <Desc / Clms Page number 36>

 
 EMI36.1
 active dani3 the bonzbtie aoutit 1 gold: atla: â eu 21-Doéiate de 6..réthylne-a3-nor.-hdrocoat:, oono. La cier, .. ro: itizitioi, rir an equivalent of dichloro-ciicyano-benaonuinoiic armed dioxano gave 21-acetate do 6-RethyU'no-D-nor-r "dnif <olone.



  Dos oters of D-iior-etdroldeu can 5tro prepared according to olancic techniques. Ai.,. Iii # lower alkanoyl esters can be prepared by reacting the corresponding hydroxy compound with pyridine and an acid hydrochloride. By oxenpic, D-nor-.teatostrone, D-nor-oestrono and D-nor-predniriolone, by reaction with anhydri-
 EMI36.2
 of acetic in pyridino, give ion correopon acetates.
 EMI36.3
 dants, oest-h-diro the 1 fi-n.aûtata of D-nor-4v-etito,% tt.4ronc, D-nor-estrone acetate and D-nor-prednioolo- 21-acetate ne, respectively ,, By substituting other lower aloanoic acid anhydrides such as propionic anhydride or 7.anlty .. caproic drido, the proplonatoo or oaproates cor-
 EMI36.4
 respondents,
 EMI36.5
 To verify a group 11.

   and / or a 16-hydroxy duno dec oMpocoo group such as 16-hydroxy.



  D-nor-proCest6rono ot ü.-narpradnisa.ona 21-acetate, ootérlfiant acid can be used in the presence of anhydri-. trifluoro-a-oetic acid, or acid anhydride
 EMI36.6
 esterifying in the presence of a strong acid catalyst such as
 EMI36.7
 g-tolubneaultoniqueo For example, 16o..b.ydracy 3) nor -pro008térônô and Si-acetate of D-nor-predneolone,
 EMI36.8
 by treatment with acetic acid in the presence of anhydride
 EMI36.9
 of trifluoro-aoetic void, give, respectively, the 16a <-aoetoxy-D-nor-progestdrone and D-nor- prednisolon or trlaoetatg Other 21-esters of 21-hydroxy-D-nor-presnanoa
 EMI36.10
 can be prepared by known methods.

   Thus, D-
 EMI36.11
 # nor-pregnans like D-nor-predniaolone and D..nar-predn.son
 EMI36.12
 by reaction in pyridine with a di- acid anhydride
 EMI36.13
 carboxylic acid such as suokinic or phthaliquo anhydride, or with halides of aryl carboxylic acids such as chloride

  <Desc / Clms Page number 37>

 
 EMI37.1
 of bonzoyl, will give the corresponding 21-ostera, 0 'eot-? l- say 21-nuccinate, 21- ±> htalate or 21-benzoate, respectively, f) -nor-lirednit3olone or .

   D-nor-prednioQ1t), One can auani prepare 21-osterc of 21¯hydroxy¯D-nor-prdimaneo mineral acids by using ooitniieris toonniques 2ur OXOI: 1plo, one can transform the D-nor -I) redni- noloiie or non 21-loduro on passing through 21-mdthaneaulfonate or 21-E-toluèneaultonto, then treating with a nono'baoique phosphate of urBent, as described in Ohemiatry and Industry ", page 1260 (195fj). Other known techniques which can also be used. An alkali metal salt of 21-phoonhate, OO :: Uil (; the dinodiquo, can then be formed smoothly, for example by reaction of the phosphoric ester. with black soda give the disodium 21-phosphate of D-no: r-prlJdn1! 3ono.



  $ n v-tri, -intai lo trrj fall from a '21 -hydroxy-D-nor- Ijr6gnnno, [Jar example D-nor-prsdnisolone, in pyridine, by a pyridins-sulfuric anhydrida coviplox, followed by ' a trld tc'nont H. the aotuase (according to the known methods of (JTJlicirlliotOf1, gives Io corresponding potaooium salt of enter {nitric, by oxeraple the 21-potassium sulphate of V-nor-, rn.lnl E : 01 o rH '), which, after neutralization with a Reido oo #:.: / = Hydrochloric steel, gives the sulfuric ester, by e: r.o'lil.le the 21-fialfate of D-nor -produisolonet Len pliin luportants to nor-steroids obtained by the trnm: i'or ::. '3.tior.o 1J1J.,): Üé :: entairea described above from the produced iL1'J'i6diate of the photolysis of the invention Including enrcntiellecnt characterized by the following structure in the D nucleus:

   
 EMI37.2
 13 D 16z 14 15
 EMI37.3
 or A r011Z'úDcnto soft hydrogen atoms, a lower alkylene residue, an a # a: e of hydrogen and a lower alkyl radical (ce- or wi--), an atom-38 el 'hydrodme and an atone d 'halogen (at.

  <Desc / Clms Page number 38>

 
 EMI38.1
 or -), or a hydrodm atom and a hydroxy group (preferably 0 :-) which can ± be esterified, and Z represents one of the following erotilieritiltE3: Il 1 - C c 0, - 0 ....

   R, 0 0! I #a .... s in which B is a hydrogen atom or the group OV 2
 EMI38.2
 R is a hydrogen atom or a hydrocarbon radical which
 EMI38.3
 may be non-natural and / or substituted - particularly lower alkyl, lower alonyl, dthynyl, (3ahloo ethynyl or propynyl -, and W is a methyl group which in turn may be v = zzba CiLud pure a .tol.1A of halogen, or by the group 0'V, or by the group OV3 plus a lower alkyl rudioal, V., Y and v 3 ro!} rl5ncllt ... nt each a hydro- atom gene or an acyl group, the novle group is preferably derived from a c :: r = a :: ylic acid having, i \ 1L'IH \ '? \ utainan of carbon or - a: ll'ticu.lio1 " of a '1 01 \ 1 "of V 3' 'one mineral acid CO: .1:

  '1Q l'ncida t1ulf "r.1.quH or acid!' Hoophoriquet including leo r.pirol'lctonpr in lonquolinn lv rldic, l of hydrocarbon R eot identical to partio H :,, ll ' Oc'l1 "oon1o of V '; and y co-.prio the 2C (2o) ¯ulcoylidt derivatives <neûiox% v do oao)) - nor- At6rodeo, the derivative c 1 x (1 tia) -nl, caylidnGi.axy of those of those i? Mnox-straide4 in which A (ü, a..c; .i ) and he OR, and the derivatives lcSa (21) -r3, lGO;, rLI.tlediaXy and lEc (eU), 2c3 (21) -. bà .: a.cay.ènedit: c5âc: those of these i) - nor¯atdroid3 dima lenq \ 101H B - OH and w ... Ch2úH.



  The expression "acyl groups" when allQ60t used above and below ('3c must be CO: .J riaf OO: -'; lle encompassing any radical of a m1ntfrlll or organic acid. mineral acids, as noted above, uric acid and acid are preferred; nos ['horill \ lC, and iar3. len ucideo arr ;; zxzi-. i ... b .to:.: ec ae cc-rbone, that is to say the acids alkanoicuea infuriours CO;: I lein fi cils fornic, acetic, propionic and butyric, as well as doc acids rxro-
 EMI38.4
 

  <Desc / Clms Page number 39>

 matics such as benzoic and toluic acids; are included
 EMI39.1
 also dice.rbox7..ques acids such as maleic, aukkinic and phthalic acids.

   In addition, the term "acyl" should t, 4, rt understood to include radicals of polyvalent acids i
 EMI39.2
 which on the one hand are attached to the nucleus of D-nor-sterolde by an ester bond, and on the other hand are neutralized by formation of a salt, for example a salt of an alkali or alkaline metal-
 EMI39.3
 earthy. Examples of such radicals are those of sodium hemoacoinate, codium acid phosphate or diaodium phosphate, and sodium sulfate.



   The term "lower hydrocarbon radicals
 EMI39.4
 (alkyl groups, aloylenes, a "oeny.ea) when used herein, refers to radicals or groups, respectively, having up to four carbon atoms.



   Among the D-nor-prégnans having structure 1, those of general formula II are preferred.
 EMI39.5
 
 EMI39.6
 where A and Ap each represent one of the following groups two atoms of hydrogen, a lower alkylene radical, a
 EMI39.7
 hydrogen atom and a lower alkyl group (0: - or 3-.), a hydrogen atom and a halogen atom ([alpha] - or ss-). or a hydrogen atom plus a hydroxy group which may be
 EMI39.8
 esterified; L represents a double bond A t 1) 'a 9,11-spoxy group, or one of the groups 9ocF, 11- (H, H), oc Hr 11-CH, ox) 9a-H, 11-0, 9oc-haxogen, 11 r.0,9K-halogenTH- (i3 -.- OH) 'x .halogen, 11-tH, ha7, ogen);

   R 'is a hydrogen atom or a methyl group; Y is a keto group or the group

  <Desc / Clms Page number 40>

 
 EMI40.1
 (HOOV4); B and V have the meaning indicated above and V4 has the. meaning indicated above for V ,, V and V 3 including the analogs A4 ,, A1 A ry6 Lj14,6 e, A '# 5 of those of those compounds in which Y represents the keto group,
 EMI40.2
 and analogs A 5 of those of these compounds in which Y represents the group (H, OV 4); and including 15oe derivatives (16 <x) -alkylidenedioxy of those of these compounds in which A2 m (H, oc-OH) and B - OH, and the ex (21) - aloaylidêned3.oy derivatives of those of these compounds in which 8 r OH and W = CH2OH.



   Important examples of those derives from D-nor-prégnane according to general formula II which do not contain an oxygen function in position 21 ("21-deoxy-
 EMI40.3
 D-nor-prégnanes ") are the following D-nor-progeatéron (m t-nax..4wpxgtnn-, CO..dione j, 15x.hydraxy-ü-norprogesteroria and its 16 esters with lower alkanotic acids, 1p- methylene-t oK-hydroxy-D-nor-progeatérono, 15-methylene-16oc. aataxy.D-.nox-pragestéa. ane r 9oc, i 1 3-.diohi.oro-A-nor progesterone, 9çt, 11 - .diahloro.1 6a-aaetoxy-D - nor. pro, 9oc- esteron, uaxa.-11 1 p-hydroxy-D-nor-progesterone 6x-methyl-1 6oC.

   acetoxy-D-nor-progesterone and 21.l.uoxa-A-nar-progegtexoner
Important examples of those of the D-nor-prégnane derivatives according to general formula II which do not contain an oxygen function in position 21 ("21-deoxy-D-nor-prégnanes") are as follows: D- nor-progesterone
 EMI40.4
 (TJ..nor-4-Pregnne .3,0-d.one), 1 Soc-hydroxy -D-nor-progesterone and its 16-esters with lower aloanoic acids, 15-aôthy3, ne.i 6aC-hydxoxy A.nor-progeetone, 1 5¯methylene-16cc-acetoxy-D-nor-progeetonep 5oc, 11 -.d, ichloxo-.D-nor-.progesw terone, 9oc, 11 3 diah7.ora-16-aaetoxy- D-nor-pxogestéxone, 9k-, uoro-11 -hydraxay D-nor-.progestrone, 6a-methyl..16a-aotoxy.



  D-nor-progesterone and 21-fluoro-D-nor-progesterone.



   Important examples of those of derivatives of
 EMI40.5
 D-nor-prégnane conforming to general formula II which posi-

  <Desc / Clms Page number 41>

 
 EMI41.1
 your 21 contain a hydroxy group which can be esterified
 EMI41.2
 ("D..nor-p1'éana." Oxygenated loa in 21 ") are the following s D-nor-corticoet6rone (m D-nor-4-presnènē11p, 21-diol-3 20-dlone), D -nor-dBoxy-oortioosterone (m D-nor-4-pregnene-21-o1 - ', 2o- dione), D-nor-prednisone, D "nor- * predii80lone, and analogues 6 (a- and 9- > methyl, 6 (oc- and F3 -) - tluoro, 1S-methylene and 15 (a- and µ -) - methyl of these compounds as well as the 9 -haloene derivatives of all these compounds, as the 90> fluoro- D.

   nor-predniaone, la'15-methylen & "D-nor-prednico1one, 9 #, 11diohloro-D-nor ... 1,4-prenadien-16M, 21 -diol-3 20-dione, 1 ita- mdthyl-D-mor- prednîsonep 9Ix-fluoro-15 -methyl-D-nor-prednieone, 6ct- methyl-D-nor-prednisolono, & xT15 -dimethyl-D-nor-prednisone, 6 - ± luoro-D-nor-predniaolone and D-nor-1,5-pregnadine-11 pf21-diol-3,2O-.dione.
 EMI41.3
 the preferred derivatives of D-nor-androstane and D-
 EMI41.4
 nor-oastran having structure 1 are those of general formula III
 EMI41.5
 
 EMI41.6
 where l1, A 1, Rt and Y have the meaning, indicated above and ZI represents one of the groups -.0! m 0 and OV1 1 # 0 * * # A
 EMI41.7
 
 EMI41.8
 or R and Y1 have the meanings given above;

   including the analogs A4, 1 o4 4 # 6 and Bzz'6 of those of those compounds in which Y represents the oeto group, and y
 EMI41.9
 including analogues A of those of these compounds in the
 EMI41.10
 which Y represents the group (H, OV4).

  <Desc / Clms Page number 42>

 
 EMI42.1
 



  Other preferred derivatives of D-nor-estrane ay-wi-, structura 1 are those which correspond to one of! 01IlU-
 EMI42.2
 general IV and V
 EMI42.3
 
 EMI42.4
 in which Al # Ap, L and Z 'have la. indicated meaning oi'-do8SU6 and Tala m6) means only V4 or is a lower alkyl group; This includes the ethers which are derived from the 5-enol tautomeric form of compounds conforming to the general formula V (derived from 3¯alooxy-2,5 (10) -oestradiene).



  Important examples of the D-nor-andron-tane derivatives represented by the general formula III are the following s D-nor-testosterone ("JD-nor-4¯androQtene-i6p-ol-3-one) and its 16 -acetate, D-nor-5 <x-androata.ne - '! 3,163-diol. D-nor-5c <** andro8tan9 '? ce-'ol-16-one, D-no1 "- idrostan - ,, 16-dione and its analogues A and Ut 16 -eth: {1 <yl-D-nor-tclJtoDt1 "one, 16o: -ethynyl-D- nor" '! , 4-androstadien-6-ol-3-oe. 16c !:

  -mthyl-D-nor-4-andro "ntene-16a-ol -'- ono, 1 & x- (c} oro-ethynyl) -D-nor-toato6té1" Qne and 4-c3aloro-i> -nor-tes toatérono Dos examples irapo1 "h.nta of the derivatives of D-nor-oeatran represented by the general formula 111 and coni'orea to the general formulas IV and V are the ouivrnt. 9 D-nor-oestrone Jjt B-nor-1, 3f5 (10) -oostratril> ne 3-ol-.i6-one7, D-nor-estrone 3-tiethyl ether, D-nor-oi'.radiol Z * m D-nor-1.3,5 (10) - oe8tratr! ene-3,16 ± -dlo2,7, 16o!: - é '!: hynyl-D-! tor-oestradiol,

  <Desc / Clms Page number 43>

 
 EMI43.1
 D-nor-5 (10) estx; ne-163-0 ..- 3-.one, D-nor.-4-estrne..163.-al-3-one (a T-nax'-16. ox -.... androetàne..163-0l-3-one), D-nor-4- aeatri:

  na-3,16-diane, 16ce-methyl-D-nor-4-estrene-16p-ol-3- one, 16cx-ëthyny.-7-nar-.4-estrene-16.-01-3-one , l6at- (ohloroethynyl) -D-nor-4 - oostrene-16-0 -. ass and 1 6cc-ethynyl <iD - nor # 5 (1 ajwoaatrne-163.-a.-3-ane.



   The immediate products of photolysis according to the invention are useful mainly as intermediates in the preparation of D-nor analogs of steroida.
 EMI43.2
 known and other desired D-nor-et4roldons. - In addition, however, it has been found that some of these immediate products of photolysis also have an interesting physiological activity.
 EMI43.3
 health, Thus, for example, it was found that.-hy'dxaey163. carboxy-D-nor-androatano exhibits both oeotrogenic and androcene manifestations in small animals.



  The D-nor analogs of known eteroidea which, according to the present invention, can be prepared by transport.
 EMI43.4
 Further formation of the iramedlata products of photolysis, in general exhibit a physiological activity which qualitatively corresponds to that of the corresponding compound with a pentagonal D ring.
 EMI43.5
 



  In particular, for example, the 21-desaxy-D-nox .. pregnans represented by the general formula II possess progestational activity and, as such, can be used in the same way and to remedy the same problems as progestins known as progesterone,
 EMI43.6
 ethisterone (- 17a-ethynyl-testosterone) and similar compounds. In addition, certain compounds of this class, such as 9oc, 11 E3-diha7.ogdzo-21-i luoro-16a..hydxoxy -D-.nox-pragestéxanc, possess anti-inflammatory activity.



   The 20-oeto-D-nor-pregnans represented by the general formula II having an oxygen function in position
 EMI43.7
 11 (except derivatives of 11ctf-hydroxy-pregnan which are interesting mainly as intermediates) which also have at least one hydroxyl group at positions 16 [alpha] and 21 and

  <Desc / Clms Page number 44>

 
 EMI44.1
 the corresponding 9ac, t t -diha.ogno compounds exhibit cortical activity * In addition, some of these compounds, for example 16a derivatives:

  , 21'-dihydroxy-D-nor-pregnano and compounds such as 1 (2) -d.hydro-6cc-methyl-9cc-tluoroti, 16c.-dihydroxy-.D-nor.-prcgesterane have a anti-inflammatory activity and can be used qualitatively in the same way that corticosteroXdes known as takes it. nisone and prednisolone.



   D-nor-estranes according to general formula IV have properties of lowering the level of oholesterol.
 EMI44.2
 



  D-nor-androstane derivatives according to general formula III are in general anabolic agentsa having a high ratio of anabolic activity to androgenic activity * of high ratio makes these derivatives of
 EMI44.3
 D-nor-androetane, such as for example ri-nar-lraatoatdrona and 1 xwmth.lrlno testotdxana o.in.1 as their 1 ... dehydro analogues, useful for the treatment of disorders of old age, metabolic imbalance in gave birth to them, states of debility as well as for bridge therapy. operative. Ile can be used advantageously in
 EMI44.4
 pharmaceutical preparations in place of known annbolic-androgen agonies.



  In addition, 16at-ethynyl-D-nor-testoaterone has progestational and contraceptive properties. 16oc ethynyl-19-nor-D-nor-teatoaterone and 16K-ethynyl-D <-nor- 5 (') 0)' - estrene-16p-ol-'3-one are contraceptive agents, too; while D-nor-androsterone (= D-nor-androetan-3cc-ol-16-one) has cholesterol lowering properties and can be used in the treatment of degenerative disorders such as atherosclerosis.



    Other A-ring saturated 3-hydroxy derivatives of D-nor-andro-stane and the aforementioned enol ethers of compounds according to general formula V are particularly useful as intermediates.

  <Desc / Clms Page number 45>

 



   Those of the compounds according to the invention in which the hydroxy group (s) are esterified are important, on the one hand, because these ester groups protect the hydroxy groups concerned in a possible further reaction of the compound concerned, on the other hand, the esters of those of the compounds according to the invention which have therapeutic activity are useful in that their therapeutic activity is generally longer lasting than that of the corresponding D-nor-steroid having a free hydroxyl group.

   In addition, the alkali metal and aloalino-earth metal salts of those esters the acyl radical of which is derived from polyvalent acids such as dioarboxylic acids, sulfuric acid or phosphoric acid, generally exhibit the the additional advantage of being water-soluble, as specified above, the photolysis process according to the invention is not limited to the starting compounds having a steroid structure, but it is can be used for the contraction of any [alpha] -diazo-cyclopentanone with condensed nuclei in the trans position, whatever the structure of the rest of its molecule,

   to form the corresponding condensed ring cyclobutanecarboxylic acid or its functional derivatives. In the starting compounds, the pentagonal ring containing the [alpha] -diazo-keto group can be attached to an isoarbooyclic ring or to a hetero-ring, and the ring to which it is attached may in turn be attached to d 'other cycles.

   If the ring attached to the pentagonal ring is a hetero-ring, the hetero atoms may be atoms of oxygen, sulfur, nitrogen and other atoms. In addition, the ring attached to the pentagonal ring and any which cycle attached to it can be substituted in any arbitrary manner, with the sole condition that the cycle which is attached to the pentagonal cycle, to the monk, must not be destroyed by the radiation used for the contraction of the cycle.



   The starting compounds of the type [alpha] -diazo-cyclopentanone

  <Desc / Clms Page number 46>

 condensed nuclei in the trans position are accessible as in-
 EMI46.1
 diqud oi-deeaun for 16-diazo-17'odto-steroids in particular by the general method set forth in Example 1 and, where possible, in Example 2 below. Photolysis of these starting compounds gives the corresponding cyolobutane-oarboxylic acids h cores condensed in the trans position or their functional derivatives such as esters and amiden. Thus, by
 EMI46.2
 example, by photolysis of a -diazo-tran6-hexahydroindan-1-one in an aqueous organic medium, trans-bexanydro-2,3-benz¯cyolobutane-oarboxylic acid is obtained.



  Certain known derivatives of oyolobutane are physio-
 EMI46.3
 logîquemant active, for example certain derivatives of 3-ayolobutyl-propioniquQ acid which are antibaoterione. The process according to the invention makes it possible to obtain core analogs
 EMI46.4
 condensed in the trana position of these therapeutically relevant compounds, after photolysis, a suitable side chain is attached to the oyolobutane ring. This construction can be carried out by known methods.



   The following non-limiting examples further illustrate preferred methods for the preparation of representative.
 EMI46.5
 important to the olacae of compounds according to the invention.



   EXAMPLE
 EMI46.6
 léthod $ & ernle dG preparation of-diazopyc19pantpne noya-tix, condenadi3 in ionitioti, tana 1 mole of potassium is dissolved in about 1 liter
 EMI46.7
 '. of anhydrous t¯-butanol. Stirred and a solution of 1 mole of the envisaged cyclopentanone with condensed cores in the trance position added. Stirring is continued and mole of isoanyl nitrite is added dropwise. The reaction mixture is stirred for several hours, then poured into water. The mixture is extracted with methylene chloride and the extract is cut off. The sowing phase is acidified and
 EMI46.8
 '* # it is subjected to an ether extraction.

   One cools and the extracts are dried, then they are evaporated so as to obtain

  <Desc / Clms Page number 47>

 a residue consisting of the -oximino derivative of the condensed ring cyclopentanone used.



   The above α-oximino-ketone is dissolved in an excess of an aqueous solution of potassium hydroxide.
 EMI47.1
 



  It is cooled to 500 and an excess of chlorarumin in ether is added. The mixture is stirred for several heifers, then the yellow layer of ethor is separated. The treatment of the aqueous phase with the solution of chloramine in ether was repeated. The ethereal solutions were combined, washed with water and dried over.
 EMI47.2
 sulphate of anhydrous magnéniura and evaporated to obtain a residue constituted by the crude cc-diaao derivative of cyolopentan? - only 4 condensed cores used,
EXAMPLE 2
 EMI47.3
 Nothode aénéX:

  l1J, e de prpteotiori des-4ràLou me. fs in the preparation of compounds ae dprt en.re '& nt¯ rour examines a starting compound a) l.L1d - .. Jne a, t1 "' ioture, 1! J! ..... 4:., rmdrp5 ', 11.17-tdone) For 5 and a half hours, we ohal.t1': te uno ü (llu'tlion of 1 g of 4-androotbne-3,11,17-tronn and iii Mo aegoid y-tolueneaulfoniqut in 16 em3 of pure 2-methyl-2 "ethyl.3'ioxolano, so that a cU.stil: 1.ab drinks the separate intoititsrat from a column of fraotionrament connected @ 4U reaction vessel * We get rid of the tobal diatillab of approximately 10 m 30 The remaining reaction mixture is cooled, diluted with benzine, washed first with a solution! illutÙS (I 4 ':

  j% sodium bicarbonate, then with water, it is dried over magnesium sulfate, then it is concentrated under reduced pressure to obtain a residue. The residue is crystallized from methanol containing a drop of pyridine, or which
 EMI47.4
 gives 4-androsttjne- 3-ethylenecetal, 17-irione. Similarly, other reactive aethylenecetal can be protected by selective ketalization of the
 EMI47.5
 keto activating group, for example the ntetliylbue group reactive by reaction with 2-m4tb.yl-2 ,,. 6thyl-1,3-JioxQlun.o in the eJ.-deucjut3 manner.

   

  <Desc / Clms Page number 48>

 
 EMI48.1
 and thus obtained the 3-ethylîmeoetal of 4-attdrostena- 11 --ol-, 1? -dione, EJffiKKLB General method for the preparation of o a2obnttane..vro lic acids with condensed rings from u: -diazo -'oyclopetitanonej3 with condensed nuclei in the trans position
 EMI48.2
 To prepare a cyolobutane carboxylic acid with
 EMI48.3
 nuclei condensed in the trunn position, a 5 16 solution of 10 cc-diazo-cy cl opent anone in a dioxane-water mixture (4 t "! j) is irradiated by means of a source of ultra-violet rays 4 low Energy * When the evolution of nitrogen is increased, the solution is concentrated to about 1/3 of a volume.



  Dilute the chloride with water, add an alkali exoea and extract with methylene chloride. Extracts are not provided. The aqueous phase is acidified and extracted with ether. The nolg is dried.
 EMI48.4
 tion b the other and evaporated to obtain a residue consisting
 EMI48.5
 by the crude oyolobutane-carboxyliquo acid 4 cores condensed a trance position To remove the corroopondant entera of the aoideo oyalobutane-ourboxyliquee h cores led-on position traM),
 EMI48.6
 the photolyue can be carried out in alcoholic solution rather than in solution in aqueous dioxane, the alcohol being chosen
 EMI48.7
 depending on the ester desired ooinme for example methanol, etimnol or autrou a.noola rali.yheti.q, ua ai we want the
 EMI48.8
 methyl esters,

   ethyl or other aliphatic esters,
 EMI48.9
 xrrupeativusncxat. Cyclobutane-darboxylic acid aster a
 EMI48.10
 Nuclei condensed to a trana position are then isolated by diluting the reaction mixture and extracting. *
 EMI48.11
 One can auboi obtain oyolobutaneeu4DDXZ diacid esters (Iiquub 4 nucleusjt aondenEoa'en trans poition by preparing d'bûrd the cyclooutunu-yes-boxylic ticima 4 nuclei conducted free uorreHjondtn. acuWarwdumst uur classical tools, aui.uào I) ar ex.c uuc with diazomethane nucleus, lilu.> iu wuiiiùi'u shell specifies oi-deasus

  <Desc / Clms Page number 49>

 
 EMI49.1
 for the ctireote preparation of aoidaa ttseet'a o?, clobuta.'1.eotU'b01tYiqu8a k oondenf nuclei; l6:

  ., other functional derivatives of 4-ring OY01tano-carboXYliqUa acids can be obtained directly by photolysis in an solvent containing, for example, ammonia, a primary alipliatic amine or. ea / ondaire, pipidino, pyridine, pyrrolidine or
 EMI49.2
 morpholino.
 EMI49.3
 L-iXTIMPLË l6-dia; zû-androatMie-3t! 3L-t '-. pna 28.4 µg of potasolum is dissolved in 1 liter of 1-butanol anbydroi, Cn adds 28 g of andro8tane 33-ol-17-on0 and The mixture is vigorously roosted for one hour. One adds 0 ocr of di-amyl nitrite and stirring is continued for eight hours. We. Q.j (another 20 cun 3 of isoamyl nitrite and stirred Juûqatttu the next day.

   An equal volume of water was added and, one acidified tm moyon of 3N hydrochloric acid, One proceeded to a BoïLmourja nxtraotion with ether, The ethereal solution was washed with a solution of oa-rbonato de potacniumi then the aouaet h an extraction oo..lplbte l ,. using an O.51l solution of 1> o'l; aooa.

   Or heat the alkaline extract to drive off the ethor, then cool and filter. The filtrate is acidified with 3Mt hydrochloric acid. The precipitate is collected 16-oximino-androi3tano-3-ol-17-onc , for a filter and we dry 1 yield m z4, 9 go point de fuaien l'ÍII We dissolve 2.5 g of elbow in 400 ounces of water contained in a 3 liter flask Cool in ice and, while while stirring, one adds go> g of 16-oxiuino-androutane- ':) - ol17 ... onl3. One then adds 50 su- of a distilled / prepared dtber 'ulutioa chloraaln dddrit in "Orgtmio Synthe1! 1a", Volume 1 # page 59 (195917 and 600 diether, On
 EMI49.4
 stirred for 12 hours and the layer is separated by decantation
 EMI49.5
 yellow-ether.

   VA repeats the treatment with shioramine and ethev, allowing the reaction mixture to reach
 EMI49.6
 Room temperature. One separates again by decantation.

  <Desc / Clms Page number 50>

 
 EMI50.1
 la ouoht) dldtlior and or combines it with the coucha of other already -tnij.arée pure d6a, iitatiot%, Un Idvu several times by means of 1) \) 1 'tlOUIJ of t 00 CI} of euu lu etharee solution combined, then either dumtcl.a and dvul) ol, e, - to obtain a residue constituting 7.5 K of 16-di! l2o-undrootl10-j-ol-17-on8, melting point 110- 1 '(jOC Ul'X'tJlJ purification .by ooritltallation from, iaetiumol, uulon point:. 171J-17 ", 50 (ùÓcompQai tion).



  (u) Js- 11., o (o. 0, h9o). i'r!.: tr "Li () n, jfu.lotM datrot '1', 0-17 -oeto-stQrO9aa.



  By suu.logie with 1 a -mode., Operative described h 1 # Lxoini, lu 4, further 1Ó-u! ± :: o.,. 1 '.. oéto-oiiérotdes coiivae the Qû; npoaa gLiitiratourn whose lista aut given in Table 1 oi-daatjoua will give itto diriviia 16-dia ::. o OOrref: JI) ondants passing IiÀr the i1.ùr..dillirc. ctlitl IJUd.VUb.J1; I 16-ù.x.J.lJ.dt '$, the derivative 16-uiazo titllnt utilue Moi, lille cofnpoaéu of departure for the process of Ilhotolyuo conforma to the invuntion.



  11 oot bieii outandu que danu let) case where the 3-neto group of the corilioue,; clI \ 5ra.teur not oubutitué in 16, before lioxi- iuution, was cEit11 (1é, the pn.rtio a tal must be removed by hydrolyae eî we want to arrive at the 16-oxïmée compounds lJrélim1- nairee indicated in Tublaau I, pela can be carried out by the general method 1.11.1.1 VI: I!; te i To g '-âthyl nlto4thl of the 16- oxitain-etdroldu obtained first, about 20,0111% dl \ 1/10 1301u t10n atjueuiie 4,80.4 ncJt1que acid are added and the resulting U1elan /. is heated in boiling bath for one hour. .



  .1:; HUU1t11 we cool, or dilute the eúL.1 and we filter the 11'001- pifcô resulting in the 16-oximino-utu'roldo orroopon- 'dant having a rou! 0 3-cto read. x'AblJbAU, 1
 EMI50.2
 Compound eêuJ: rl.1ttJ \ lr COf, I!, CfJé irélimin! Lir6 frodait 16-diazo not orbstituted in 16 oximé el '1 ci.

   (starting point
 EMI50.3
 
 <tb> for <SEP> the <SEP> photolysis
 <tb>
 
 EMI50.4
 according to the invention
 EMI50.5
 
 <tb> tion)
 <tb>
 
 EMI50.6
 , & tandrântane-3cx-ol- 16-orimino-androntane 16-dinzo-androat * "17¯one 3a-ol-17- one 3cc-ol-17rone iât 3-d tliyi L-lie cé t ai 16-oximiro-androutane - 16-dinzo- anarofrtav * '* unctroutanc-3,7- 3 17-dione 16oo <.1inzo- 771
 EMI50.7
 
 <tb> dione
 <tb>
 

  <Desc / Clms Page number 51>

 
 EMI51.1
 Compound generator Oompo!: Preliminary product 16-diazo unsubstituted or 16 oximated in 16 (starting com, 006 for photolysis. Conforms b, the iaven # tion) Çts-Ckyibnacëta.l. of tion) i6-cüazo -. 1 - nxâao.



  4-aadroatêoe-, 1? - at2sn-, 17-soul atnc -, 1t - do ::: 9-androstboe-; 5f3-.al 1 ti-oxin: .na - s.ndro i 6-ciir : rr, xctx'c n 17¯one st bne-3; -0.-1 l - ona 3 p¯ol- .1> "1É * -Jcai. (At k '' .- E 3-ethylt> 6-oxiiaitio-4 -andro- 16-d -andru neoetal: tbnr-3,11, F3t: IlOj, 11, 1 lr.icna ne -., 11; i '' -. titz.a 17-trioue 16 -oxilfiilo-4-anùr9 '"16-diazo-4-o.rùi'f) tè- Pi4-androatàne-11- 1 6-o> dmiiio-4 - aiidrO' 1 f.diuzo 4- & rswr oj, 1 (-i.ane oteno-11-oiL-3,17- <ilouo 11; .oa-, 1't-dic # s 1:: 1,4-adrootadi! ne- 16-oxitnino-l, 4-: mdrct-1 '.- diaHO-1 4-.ndro-, 11, t'l - tx.ane, st.dibrs., 1 ', 1'1. r3xditne. ; b i 1, 1? .-
 EMI51.2
 
 <tb> let's sort <SEP> let's sort
 <tb>
 
 EMI51.3
 H = 1 4-andraetadi3ne- i 6.ox.u.na..1,4wcandrcr 1 -c.a.zr.i, 4-mdro.



  1'Î 0. 3, l7wd.asle eliada.ènc..l1 wo .., 17- is.v.ipn ..11,3wa, -, 1'1w dion13 d: .one IsMethylether 4 o 8¯ Nethyl ether de 16- Mllthylether do 16- crene oxiraino-oestrono d; .a3û-o8trot \ o, s1,4,9 (11) -cindra 16.oac.iina-1,, 9 (ii) -lW.c.zza-i , it, 11) .- atatrisna..j, i1 andraatntr., r1.3, i '! e, n, 3. "ancatx.Ll.u. dione dione;, 1 -c.iuxs K s çbc.Zuoro 1, 4 1 6-oxiuitno-e - eluoro- 1 o-dia? oi) -f luoro - androutadibne- 1 .aidxos; ti t: na, 4-nncvantal:. & no.



  3,11,1'l7-triona ", i 1 1? -T: .. have, J, 11 l 'f, -tritme, xJs9cr'" nlr.ora-i, 4 16oiwi.no-.9cc .. 01.1orow 169zo 9a rh.ux'o. Midrost & di! Iue- t, 4wrndroaaaJ.h: the 1,4-ux.droctr..t, raa.,.



  , 11 17-'tx: onc, 11 1'Ï-tr.au, 6 ', 11, l'l-trJ.ontt, sdoc..uytyr.t, -1, 4- 16-oc.tn.nowtmuthy - i 6-û.oo - & - aci: y .. t-1llùroatudiàne ... 1.4-al1d: rostaJ.ièna .. 1 r4-urdaratc, dia- 3,11,1'I-tri.one; , 11, i'ttrian. yi, 11 p 1 '.tr3ona T s 6ac-laoro-1, 4 16rox.mino Cxr.wilLraro 1 ti-z = no-a-, noro. nndrpatadibne- 1,4-andruat: d.bne. 1, 4-androstudiene, 11; 17 t; ci ane, 11,1'I-txlou 5,11,17-trione Ê 1 9¯n6r-5-andro- 1 6-oxindno-t 9-nor-5- 16-diazo-t9 * -Roy-5- a'bne-i-o1-1'-ana mdroatèno -. 0 ..- 1'w Elad'ot.ltèr.a .., j3-o1- have 17 * -one
 EMI51.4
 J19difioat: j.on des derivatives 6-d ..nvt-tu lC, 1I, r iVli.flft.i'Pft '"m ccmpoa6a to d.6ulirt, dU.l} o., K -l00 (idd of tllotaliflke '0' 'the invention> .i (i #Am s wf,' f # '.lf reoaration of 3-oeters of coinr) oflet Las 3-acdtates de la 16-4iHo-àit | i | î * || Miâ iVA- <? J'ifâ (being able Otrü obtained confoi-ui: ,, j4it h l'û>; iiij) ï.o;

   4) ov two - \ products of the Example which contain a (rÙlll '(. Hydroxy C:' 1-

  <Desc / Clms Page number 52>

 
 EMI52.1
 punishment jat or 3, coMae la 15 - dikzo.ndraaiane-ac-a1..1 '/ - one, la 1 -digzo-5rcndracr wtng - 0l-1'l-ana and 6-dias.om-nor - '
 EMI52.2
 are obtained by allowing to ropout overnight at room temperature a solution of
 EMI52.3
 1 g of the corresponding 3-hydroxy compound in 10 oma of pyridine where 1 oma a-acetic anhydride is added;

   the solution is then poured into 100 oma of water, filtering the resulting precipitate and recreating from diethyl acetate to obtain, reupec-tlvetariitt, 3r-uatR, y-16. diaxo-mdrastettl 17-one, la -acetoxy-16-diazo-androatan-17-one la 3-. aoi5toïy-16-diazo-5-andi * oBtkio-l7 ono and 3-nataxy-16. d.azo-19-: or'-5..trndroatrrewl7-ono ", n By constituting an anhydride of another acid, such as propionic or vaidric acid, to .1 * anhydride of acetic acid, one can obtain from the same the 3-cstsrs oorreapondanta, ccmie the 3-rrojilonatti or the 3-valératt) corresponding reapooti- Vetaent.



  13, l6din, aadroatbnn. ', li-diondwh.pxt, x ēl! ! 6: du.! O: 5: ndrwa t & rmrro1.w17-one- According to Example 5 0 above, 16-diazo- 4> androutnû-'j, 17 * dione can be * obtained from selective keta.liaut1on of group owo3tot oxîiùation, ru-liberation of group 34-keto # and reaction of 16-oxi, rl.no-4-sr:

  drogtène.-ât7diona thus obtained with the oh1.orQ.Ulin. however, 16-diazo-5-lUldros'tene-'l3-o1-17-one
 EMI52.4
 can also be prepared first by oximatibn from 5-andro -
 EMI52.5
 etna. i-ol-1? -Qrie and treatment of the 16-oximino-5-euadro- atn-'ol-17-one thus fortified by ahx.orrurrina, and it can be further adorned by operating in a similar manner to the known preparation of 4 ... androatene- '..17 -diQne from 5-.narutene.33-0.-17-one, to give * t6¯diaao-4- by a method such that the following jt We first prepare a ') 1.1.1 tl.U'B of. &' lavobacteriW1l ddlJ'1r (J (l} 1I'JlH:

   Colleation of rutger xdo 130) -by propagating

  <Desc / Clms Page number 53>

 
 EMI53.1
 oe mior.o..organ.isl.lC3 in a nutrient medium on agar at ;; 0 0 for a period of 24 72 hoursea 2o.-idartt oette incubation, the tube dW1, O 1 (; 1 ("101 we perform the 1hoou.lt t: J, we oiet expoo6 to the lutaibre, resulting in the neveloplientent of a yellow pi6 '"ment which is oo.rlilo't6rietiquf.I de ilosi, bae.

   The evoj> culture is annuity separated by rinsing the gdiotie in etérilon oondi tionu and mine in a sterile medium of pH 6, at OOMÉO06 like night!
 EMI53.2
 Yeast extract ("Dïtcon) d tu Il Phosphate 'de potaueium aonobaaiquo 4, 4 / jg Sodium ptipephate d1 biLs1que 4t6b g au. Ord1rJ.WJ.rl aCIl1l111m''1t h 1 liter and which has been previously maintained for minutes in
 EMI53.3
 an autodiave bous a prll3l²1on 14i (, rulllnt "tJ.! J4rburM to an atmosphere so as to achieve this aeoptic oond1tion6, then cooled, A cultivates the m1Qro ... orl ± fmi6! nAnd in this medium we Conotant illumination # using the [Visible in the spectrum, the temperature of inQ1.I.b'Ç1on Ît '.. ot maintained at about 3390, and dao condJ. T:

  1.onD arebieH, aeration is achieved by agitation and / or blowing air through the culture medium.



   Uno tolu quo quo the organism develops' For a period of 12 to 24 hours (or longer if desired) 100 cc portions of the developing culture are introduced into ten flasks, and into each flask are
 EMI53.4
 adds 100 mg of 16-diazo -, - androatènc-'ol-17-one, dissolved in a minimum volume of ethanol. The reaction mixtures are then shaken at 30 ° C. for 12 to 72 hours. The reaction is stopped when paper chromatography indicates that there is no more starting material present. The contents of the flasks are then combined and subjected to an extraction with chloride, methylene.

   The extracts are concentrated and the
 EMI53.5
 residue is crystalline from an ao6tone-hexanes mixture giving 16-diazo-4-a.ndroBtèno - :: S, 17 ... dione,
Example 6B above shows that some com-

  <Desc / Clms Page number 54>

 
 EMI54.1
 starting pond 16.-czia :: o, to the liou to be prepared from the pupottd iioti aubutltué in 16 corresponding, can ut4ouï Otrt) obtained in trrrrt3'az.nt another 17-oéto stdroydo had tjon a:

  r.v6 1 fi - aiazo and we transform the latter by 1 # G'ilt.ßt, ld.t oonnucu lour obturilr the t6-diazo-17''ooto-atëro'Ede 5trvJ.etul, icr, ddrtird. liaturfilluititint, cos muvo transforiiations, * nnuui take place at study 1à-.ax.rn.taa. feivrn, t the conditions oi) daialeii da cii.tltia aras ertiav'iliur, one or the other method ouru pr '! f6rabl.o 1) ottr the rrephrutiou of the 16 "diaso-t7-odto- utth'oïda j .riiûl'Ut3tit.



  Xdtj: U, Aa) <Ioru; dt'tn- au, 1 Gaaul'LUx; li Un diwuout 4 <î do 1û-diuviû-undrowtuno-'J! i (3p.ol- 17-or dunu <: t0 otn3 Liltui iiit'laiiio JJ.oxa4ie-eau (5 & k) o We irradiate the talutiort tan hub of tt4beu .Cluorattoanta "l, wrGittre noire * èiylvunja uurtte CM tuo la difCiti, (ir4utit j'nzote elarillète, 4u lumruti uu'viron) t Un oonoùntpa unuuite a rotutive evanoratour h couolio luilicet We say all the rémidu dana lldtliur and we itt eaawsust It a ui, .truottoii j'nr a solution of uouda. Ut) read the ftxtrftita M 7! .eis dttmr and cry the filters. rr Holdifiw lu filtrate with oil Olftoidti alilorliydriiluo 314 ,, dr filter read vrécll, ltt (recirculating, washing it at Iteau and aocdùol4c or empty.

   The residue is triturated with hot acetone and recriutated from aqueous acetone to afford D-nor- & ndrostyl-3-ol-1,6ii.-oEtrboxylJ as the melting point ax 21i. , (-: lk.e5Q0, (tx) 2i- 44.3 "(0. 2.34).



  , ii variant, instead of the source of rayornietaent eti- detieuet, leu rayotiii altru-violttfj convent Btru supplied by WIO xiispe L vc, Fc: ur de, iûreure iitmovia do 2Uu or 4ou 'watts twaa a 2yrùx or tri Oorux filter . when we used lu Ituape litttiovia of 2uu wat-ta avue a Corax filter, the photolysis reaction t: st turuindu in i to 4 .Ueurefi.



  In the blur of the iîurvelller Its uC ,, u, eiient d'azotu, we PU% 4t aatc: 3, enivra iM devolor-1) 0.lént da lu photylie reaction in ûo ... j,) ariuit 1. .: "a.cc; t, rrr a1 ultraviolet absolution,

  <Desc / Clms Page number 55>

 
 EMI55.1
 d1 samples o1hl "ot ... lu; '1, J.,. 10 reaction: the reaction is c01Jp16ta when the characteristic duucaxp3on band in the ultra-violot of 16-diazo-17-ketone (approximately 250 and ll .ultr! '- Violot de la 16-diazo-17-kétone (approximately é! 50 r JrJjÇc.1 M \ & B irtffayfttiou .Ulalo>' \ 1ù other ac; J.;,. n .J-nor -Iftéru \ "dp-16.jo .: curt, olli l lle! 1 By tinulojis uvoc on 1): ocJJ4 of 11'xÍ1:

   11Jlo 7, or little * prepare uutrea .1cidtJO n-nor ... 6teroIJ, e-16ç.aroo "Yli'l \ l.e3 had lJhetolymmt the 16-diazo-17-keto-otérodi3a corxarspar: d ;. a.nta., such as ores listed in Table II below 3enf3cn.is. | TABLE 11 '"' '" "" #' ** '
 EMI55.2
 
 <tb> Composed <SEP> of <SEP> departure <SEP> Product <SEP> of <SEP> the <SEP> photolysis
 <tb>
 
 EMI55.3
 Ai Product of the example tSA. acid 1> -n () 1 '.. a.l'ldroHta.ne ",": c-ol- - 1t5ji-carboxyLiq, uo Jj LixEraw1e 511 acid! J-nor-: ll \ (lroHt ± 1 .ne- "cno- 1 ây:

    cua u.cy ligua 01 Product of Example 50 or D -ncir-4-and3. * OBtnG * 5-orict - 6R 161> QrboiCyU.'1ue !! a Product! from example 5 :) Fc.i.dcr D-: ur - H..dvc'ai:! in8-p - '') '-' 161: '- CIlr () ox', 1, U Ht Product of the example Ci l'widf 'J) -noïī4->' 4roytàn9-2 | 11¯ ili ono-t b,? - O: U'bOx: yJ ... 11UO J: 'Product do J .IOXtllJ1plo 5 Mido: P "'uO: r.' '' '4-41, .rd'LIbh (; ... 11': -0: 1.



  -ori <. ") 6'-o < <r! joj <: yj.iue ga Product of 5G oxaftipio "", 1dO r-nraz. 1, .- tmdxotudi.bne-, 1 '' .GIllI "'^ C = k12'7f),,' l.rt'j'L147 <ïr, smelled dM uAMtl <t 5! I uoidû D-nui'-i i4-Widroataaionù-.



  1 ws, -o,.: - ocaa..ap..xaoxy ,, qtxo 11 Product do 18 UXOlul, lo 51 3-, a'tlstaa âscr.do .1-rr! x. p (1 0) -oootrutriîiin9-'jS "Ol-1 op- o.IX'IJoxyli,! lll.1 J, i product of example jj l.1u1iu u.-n 1 i11 ivltuxc: WÜ., tri c im Mt3tl, ts, -Ct: 7'C'rcy.,. CuKt &. Oxoiûple product%>, ca. l, -fJL't (? rë-D-: tor '-, 4dro'- M6 ç .Gt tne # ,, i-1 .c, .o., A ',,', * ..., oixwc. Rlbu ,, ''.; ;;, i; # '#' ##, # '# * # ... (., #> xi Product of example L noian -tr.P4 .'- M: dr & -. lItüùirH'; '' ''; - '';: / 4 :. A '1).,. 1,, t, a; cxr: r: l ,, cy,' ';.,': '' 3 '', ', l' .. "'.) I bzz' # 1 ÎJi Prod'ait of example 5M UCid'fJ 6ù '-) / t,' uyl-D * .Mo-t, 4-'i'.iro- IJ t.t'.ii; Jl (-j , 11-uionQ-1 úr: - c: lT'uoy.yl.L! LUO

  <Desc / Clms Page number 56>

 
 EMI56.1
 oc, .. I) oi3d of d3;

   crt Product of photol1, ao Ht vrod-iit use example 5M acid üuuc-tl.ucro-L..nor-1, - cndro utadiao # 3 1-djone-1b | i-cart) ûxy-
 EMI56.2
 
 <tb> liquo
 <tb>
 
 EMI56.3
 0: Product of exemylo "i) 0 acido-nor-13-nax-5wf.ndroattno 3-ol-1 bj.-crboxyliqutt P 3-ucëtoxy- <6-sun: o <- '3p-aotoxy-D-nor acid <-audyoat & no- "" ainix'oat6ne-17-ono z 16ji-curboxyliquo gs 3et-aceßi; oxy-16-dino-acid 3 -aoetoxy-1> '- noï'-a uxto8tane- atitirotitaiie- 1'l-one * 16p-carboxyliq) iu ..its 3-ti (, -ê toxy-1 6-diazc) -5- acid 3p'bc <! toxy-D-nor-5- {tdr08t {) - rzdraatt; tzo-5! -o .e ne-1 6p-carboxyliquo 0:

   s j¯eatoxy..1 b.-dlzo-.19. 3f-aQtoxy - nor - noï.5- acid. nor-.5-rz.nuroztna-1? -ane anuroatbno-16 (i-carboxylic
 EMI56.4
 * obtainable contorraémont to Lxumple 6A * .u 8 uua manner (similar to that described o1-dtUJwa for the preparation of acidor 16-oI1rooxylil: tU (f8 librun, we can prepare lou derivas tonot.:1.onnalo co ,, -, rei3l) o., - idante of these i6p-curboxylic acidsD we replaced the water by another aoivant
 EMI56.5
 suitable,
 EMI56.6
 JjXhiu.'UJ.ff Léryt ': onoti9! L:! Lt; llb de 161 "cnrboy..Y-lI; -noX'-l3tero,! Dafl obtemis IJ1''r 1.,' j, l. WrC1 <.lOB I.tO; I.iJfJÌ, 16; "l'Jnr, boxtvliguOB libren rr1l1ll, rmdrdl11 (n .fi <fn r | t txiieile 12 ..

   D nor, -ftnUvoutftne ol: -t61?:. S! Flu au, m! TJ.! .. Y1 ± l Instead of preparing, d.LrC1otell1ent 46fJ derivative h fana- tiounolu ttaa l6-Ha.rboxy-D- nor-9t < <t'oïdaH, in an addition oonvuuub, 1'1 to the colvapt of {) hotclyB <t we also need to obtain coo functional drifts by prôvarnllt of & edge (by photolysis dulie deu fiolvanta aqlAuux) aoidea 160-carboxylt laws 'read J-lbres COl': roB,! Jondalltl3 ot by transforming (case d.rn1C1 into their derivatives functional oonfoi-even k don known technique, Ainai, we mrrive to duo outera of 16ourboxy acido- leagues, athidua of 16 (3-oarboxylic acids (with the atom of asoto not aUÏ) st.1:

  cuÓ, or monu- or diQ.1CloytS), don huloSÁnlU'8a diaciuon I6 |> -carboxyliquoe and composta of the same kind, Thus, jttr example, we obtain Io D-nor-androstane- 3-ol-1 boarboxylato said mdthyle (m 163-oe.rbomethOxY-D-nor

  <Desc / Clms Page number 57>

 
 EMI57.1
 when the acid <D-npr -RndroÊ) tana-5 | 3-ol <6p-.oayboxyJ.iqu9 free is treated with diuzometban, This methyl ester, after crystallization from a m61Rnd8 ëthor-Kxane, melting point 133 5 ¯ 134 0 * BXBMgtfi 10 Bor-5oc'-ranel-20-e .



  , JZ .m \ f?, Faf \ Afô? I? JtfàPF "µ & iïF? Yfàïi! Br? / 9? I-) l A. Acid, ffiVacé'toxD-nora A (solution of 40U lJJ to.'uo. 1do 3J-nor -an (irioteJi0- 'ol ...' pp..oarbox: tliqu (; 1 in 5 om3 of j) yridino, on I3.jov.te '0 "Ota 3 of acdticlue anhydride and on laluso Roponer the mixture 'do: r6aation overnight with temrakaro w.iJiaatf.h 01 ;. diluted completely with ether and the ethereal solution is subjected to extraction with an aqueous solution of normal Gouda, neutralized with cold hydrochloric acid, the resulting precipitate is filtered off, washed with water, and then reoristallized to leave = noetol-water mixture.

   A ructoll precipitated him,
 EMI57.2
 on a
 EMI57.3
 filter 'and we deaubohao Be Ohl2nro de 1 o1d! L Jj9dto, xy-D-no-lfI.udt'oasq1! ,,' 6 iffiairibr9ixfYilj.i (| [| -ua
 EMI57.4
 A mixture is heated under reflux for one hour.
 EMI57.5
 of 2 # 63, s of 'fj-aoetoxy- "nor ... o.nèx'o8tan $" 16oarboxylic acid and 2.5 "of oxalyl chloride in 0 ohm of anhydrous benzine,
 EMI57.6
 then the oxalyl chloride is removed by vacuum distillation
 EMI57.7
 and excess benzene.

   The oonut residue essentially consists of 3- otoxy - nor-andro8tBLne- * 16-oarboxylic acid chloride is used without IJUHlé purification: ue: ntaire in the reaction described above imnedlatumunt, 00 acetoxy-Dnor-5K -prëano-2Q-ona .3-aoetoxy-1,61j, -a.cet: y'1-1J-nor..a! ldrot3tEJne)
 EMI57.8
 One prepares a solution of those equivalent to
 EMI57.9
 dimethyl-cudmiuja in benzine according to the technique described in "Organio ReaQtions". Volume VIII (t954) * Add a slow solution (goutta drop) to .., no solution

  <Desc / Clms Page number 58>

 
 EMI58.1
 tioa. stirred chloride) diuoide obtained "h lf:) xerap1.cJ ON in 5U air of bouzùne ajùjydi-ui We stir the réaultuat mixture PqU- dld} j 1liuttru, then read ol" :). 1.t'.re au reflux for 15 minutes.



  The reaction mixture is cooled, then blurred with a theatric acid extract. The extracts are combined. l ',. 1tiltl1'. we firstly wash the iioido uitiorhydriqua JNO puid to the utlU, and: finu.lalul1t it the aid of an insulation of bicarbonate of the aodiu, and we nec) io faur of the LUli'.te of the ut1fl ' llSni \ .1! i1e We evaporate liétt, ur ut on ulu "Oiuutot, ruphio the residue recedes tlU1t on de .111.d, u: ÜulJ 'ÜulJ' otre du Woolui, ul1d.

   Ul0 quality activity 11 1, uvu lutio mt) h0yu d''un Ilélntl) 't3 haxano-benzne (7l) # Un combina leu tiuatu et on ISvullo; rt) pom' get a J'éu1du do 't, Lw .ut (, .y-.J..I "'UOl' - :: Î '(- pr': I1nwle ... O" ono. vit purifies by recris tulllwiitiou jartir dhujtwiat Un CtlU \ 1.Ú '\: t tIti l'ù1'l \ .i, Gd..tut. 2 lieuruB a solution dw SCI1 tg Jo 3, Vaûétyl * D-nor-î) * iC iTétianB "20 ûHe and 100 garlic, from ourbotiutu du l, C ,, I'tLlJlJ1I.1JJl duiiv 40 cal of a tI, ûlo.nc: e methanol- Heu (311) 0 Indu cil dilute the water we filter the prdail1it do l / -w :)): '' '' '' '- {itl \ lUit1 ...; S) -ol-2 \ J ... OIIG.



  1 D-MJK-nrotttanu & M-dio 4 Diactute ... D: n2r :: R! 1d!: O! T !! n! .. t, 13 :: d! O! Or prepare a (solution of 280 Mg of a 3 (at-> aoetoxy- (the tie l'RjtutQple 10 0) and z2 fllL: al t.L01dlt orbenzottltie dunn 2 ex de cl.J.oroto1'l.1o and we llitieu rti> oc0Y the solution of a darkness lays 6 jO \ .U'1I b. 1,11 tOI, 1 é: r'u.turtl u.biH.t9. 0.% dilute if iiglancl, e of reaction the ether wing ut we read the organic boiutiun from subord to the U ', oyt .: 1i.

   COIIIIL Loiutiou (! Et 0-trti (liatu de (Joa1u .. 'J:., Litllîl 4 water Ln ùeaiihauu the solution on aulfute of IIIllt, '11 ÓsiuJl1, Oh filter and garlic evapora, or cJj: oii.atcrTaiiiiie 1 sniffed the uur result of the neutral oil of WOtJ1Jn, having an activity of the quality Ille dr..11U huxano, and we elected nu 1J., 0yen of a uela.I1t: c hexaue'- bt: n :: f1ne (111) We combine the iltiata and the Lélu.ntt

  <Desc / Clms Page number 59>

 
 EMI59.1
 #hexane -benzene by distillation BOUS emptied to obtain a reîdu-consisting essentially of -l1o..a.nd! 'o' -j ': .aue-,), 16iol.

   Purification is carried out by sublimating the residue and recrystallizing the sublimated product from aqueous etlianol, D-nor * .MtdroGtùne33, t6 & -diol A mixture of 20 µ-mg of D-nor-androstane dlaoetate is refluxed for 2 hours. -33.16g-dïol and, 2UO mede potassium carbonate in 40 in # 5 of a methanol-water mixture (311) * The reaction melon is diluted with water koyeji and filtered to obtain a 4th iz residue -nor-atidrootane- ,, 16iol.

   A purifies the residue by etirotuatobrapliîo nùr neutral Woelra alumina, having qulit rI activity, in ether, glutinous uu hub Ù 'nCfitona b. 6 14 of an ether, after which we reodstal.l1ae by means of #thoacl
 EMI59.2
 aqueous*
 EMI59.3
 .A variety, the oouiiioaéa 4.0 this J5; celnj, ll $ pau r nt 00 prepoxer coimue cooked We prepare a diatilde solution tï ':. Fluwoperaoi5 tique we add 2,7ti cira uniijdvidti tdt'luor (\ o, nrtt1qu. h 0 ".4a am 'of water, oxygena. ko in 15 µm 1 of rc6thyJ ulllorr61, oru't.

   We. add 10 om of this solution of a.o.1.da trifJuoropeyaQHcjiue to a Mixture of 1 # 2 g of 3-a <: <'itJxy * U'-nc'r''M.' 'prRn & n <'' - 2CLoe and 302 g of dinodium phosphate dann 2 ora of Ql: ru8 of mitllylkne, One heats the mixture under reflux until 1p4eMin. 'then we. add another 3-2 g of sodium phosphate and the remainder. of the trifluoroperaoëtiquet acid solution. Heat the mixture under reflux for a further 6 hours, put. we cool1,
 EMI59.4
 the reaction mixture is washed three times with water and deasbohe
 EMI59.5
 the solution in the solution in ll1 "tllylime over magnesium sulphate, filtered and evaporated to obtain a residue consisting essentially of A) -nor-andraatane dinotitate. , î6f3-. diol, which is used without pt: .ri1'1C! itiuU au!) p1Jluenta.e of a described operation Immtediateinatit oi-ap:

  r6fJ, Dune of the cooled ether bound to the gl'oe, we place 1.1 g

  <Desc / Clms Page number 60>

 
 EMI60.1
 of the prepared diacetate oi-deasau and a molar excess of hydride
 EMI60.2
 lithium and aluminum. A stir the reaction mixture
 EMI60.3
 for 2 and a half hours, then the hydride is decomposed into exobo by adding water and the precipitated salts of
 EMI60.4
 solution in ether, Wash the ether solution first
 EMI60.5
 h hydrochloric acid} tit "then with water, and finally with the aid of a solution of sodium bicarbonate, it is diluted with ial-eidolum uulfate, filtered and evaporated to obtain get a residue of D'-nor-auctrotitaM-3i3,6 (-diolt L Lt 'LI ::

   12 nor-androatare - ,, 16-diQn! Da, to an ice-cooled solution of 0.36 g of in 10 ON "of pyridino is added 405 d of chromium trioxide in Si cm 3 of ice-cooled pyridine. The reaction mixture is allowed to re-solidify.
 EMI60.6
 warm to room temperature and stir for 36 hours, add water and submit the reaction mixture
 EMI60.7
 k an extraction with the 6thttr. The ethereal solution is washed first with ohlorhy4r acid: LufI 3H, then with water, and finally with sodium bicarbonate solution, then n la. danebolle
 EMI60.8
 over anhydrous magnesium sulfate and evaporated to obtain
 EMI60.9
 nir a group consisting eatientlollemeut of D-Mr-androctune- 't16-dion ..

   Woaint noutro alumina, with grade III activity, is purified into dlwl4, nt by means of a nexane-benzene mixture (1 '1) by ohr'lUlatoarnph1e but. Combine the eluate and evaporate it to obtain a residue, and the residue is recrystullinated from ether.



  ²XJ: iI 1.L 'U-nor- t -M tdroBtdibnH'-, 16-dione A 2 t4i-> dibiro [i> 0 "D-black¯uiniîiro tai:> e 3fl 1 6-dlone A a solution of g of D-norwkdroàtane-3 # 16-diont ..d1a 10 or of aodtic acid at room temperature, we first add 0.2 cm of a 4N eolut1Qu 4N of hydrobromic acid dimo acetic acid, then 1b , 3 cm of a solution of z, 6 g at 25 picks or acetic dlitoidii. After d.1 ion of

  <Desc / Clms Page number 61>

 
 EMI61.1
 the color of the bromine, f4 heated the solution l 5000 and in the laieBt.-rest at room temperature, laying 4 hrs <Dilute IJ01e; neUS8'I1 "nt the solution with water and filter the prî- 01p1t (: reultunt, wash well b. The water and unpick to obtain the X, 4-dibroao-norandrotaM ) ''. t6-dion <t.

   Purification is carried out by crystallization from an indlàtige D.o & tone-hexo.no, ±> # p-nor-1 "jdrçBtadnef 1 -dlpno Heating at a tl4p'to of reflux an ouopon- I: l.on oarbon. ate oaJ.aiu.m nnhy (! n cinna 0lA 'Bien de' ci anhydrous calcium carbonate dune Io = 3 ci- $ 4: 1.m'tniiao'tand4 .. then add 1 g of a, 4Mà1bromQ-P -no- andr08QJ1e - ', 1 -c1ion, and the mixture was heated to reflux. The mixture was then cooled and the reaction mixture poured into cold hydrochloric acid.

   The precipitate is filtered, 'reducing # we wash 4 the water and deenbol it to obtain D-nGi'-1, 4 ... anùrostad1àne-' Il 16 ... (110n8, Qn purified by reprocessing 4 from an ac6tone-hexanes mixture '¯ &% M'éï &: 14 D-no: r-Óe b tl'on, c:' D-nor-l.1.5 (, 1 0) "" oe jJ ti 'atrihne-jî-ol-i t6: .. on, Q7 et un dit, cr 3-4rt' tliyl¯iuuo We pass a suapenoion of 5 g of D-nor-1,4- in 250 because no oil wineral in a Vyoor glass column filled with helioea in pyrex glass heated to 55,000 exivîron at a rate of about 10 car / minute in an azreteo atmosphere vn collects the effluent in a receiver cooled 4 ice, it is diluted with hexane and extracted with a 5% aqueous solution of sodium hydroxide.

   The extracts are acidified with acid. :) l1J, dilute or'lydr1qu \ 3
 EMI61.2
 and the resulting precipitate is filtered, washed with water and
 EMI61.3
 deaaeohe to obtain D-noz, -oestronae It is purified by crystallization 4 from ethyl acetate after treating the solution in acetate α # ethylo3 with charcoal
 EMI61.4
 bleaching
 EMI61.5
 B, Ether mehlquede! A): n2r: O! B! R2n2 ,.



   <-2-.3Éy-2 OLēla no-1 ', 2 (! Ol-2 2t! A] r! Ene =
 EMI61.6
 â-oi-1'l-an

  <Desc / Clms Page number 62>

 
 EMI62.1
 t'Li Ijuutf! 3 o'.r of tulfto do ditftthyl <s to a Holu- tiun ujltititf du au D-Mo.t'-ou'ctrono and 18 6 of pottiode garlic (10 1 *> U ain da; 1I6tl1 (1n01 and 30 onr d '00.1.1.,' ' ".J1 f): Intuiw.dl.uu of 30 <iinu): tn, oit tijuate troit) portions eup- .u'L.U'un from o..r of IJÙJ..t'4 \ U to ciluidtiiylco 'p1,:!. U shake' # '' Wil i, '' 1, QUd: ill'li l ', uilou2, u uni). hulU, "J8 Un 41imino lu majouri ilïtlltu du IJCI.1'VuUt lioiki vitiu, ifuia we added water and we ± 1 u 1) ioîl) ltë) .m.LtHnt. '' Lu prciit and well washed h 00 ut t: hHtI (jhÓ ll,) l 'd01ULU1' J.'t, \ UHil ': Ht.lyli'qU9 de la D-aor *' oentrouOt a llUl'Ha by here tulliuution h of tnthanol mluoux.



  R.X..M'1 '! LB-Mtup At an aolutioji at 1 ± j do 1J-nol'-OOl3t: wheel in 30 oa 3 ae lIIéthhl1C11 cooled diiiiti Him wun de.glace, 250 mg of t) 0rohydi * 'u'u of tiodjwuo Aprua uchêvoment where the addition is maintained in tOlll, 4llltlU'u tunbialite laying 2 hours, thick with the dilliclt .1 .. 'in and or the hydrochloric aciao attcidifiu) i7Àeiit t hydrochloric aciao. a filter remul.tiint the liquid, it is washed in Iloitu and detiul-che to obtain the D-nor-ouutra-uiol. on 1M purifies the oritul'iiunticn from wdthunol
 EMI62.2
 aqueous..
 EMI62.3
 



  ; 6 -ú, tl ', <n.x1-1J-l1or-.ocJ3 tr) diol / â. JJ'y '' '' * ',? F t' -'i P) - 'oe strn.tribnu-3 6iâ-diol7 ..A ine solution of!? OR mg of D-nor-oaatron'.! (Combination 14A, ICY is dimethylsulfon.) do. sodium aodtylide obtained by ccutdtuc; use of 195 that d, "1c {: tyluru da B0d4.ua at 1u,: in xylene. ûh stir the 146lan- 4 20 0 for 15 minutes then pour in the water ice-cold and acidified with dilute hydrochloric acid. Mostly filtered, washed with water and dried to obtain,. it't 161x-ethynyl-11-nor -oeBtrf1dial Purify by crystallizing.
 EMI62.4
 tion at the urt1r of a ..... f3.t1jI8 aoét0nt> ¯hexiaio.

  <Desc / Clms Page number 63>

 
 EMI63.1
 



  17 327015 D-nor-5 (1 ÇQ-oentrbne-t 6 3-ol-3-pno A. Ether 3-métliyIlqUe du '"2' '' ll''2â2 * 3 '*' '-' oL A a aCit6d solution of 1 g of D-nor-oec ethyl acetate (the compound of Example 14 ii) in 100 cc of ether and 100 cc of liquid ammonia is approximately -6000.
 EMI63.2
 add 1 g of metallic lithium in small Pieces. To the care-;
 EMI63.3
 The resulting blue residue, 32 est of ethnol is added dropwise over a period of about 50 minutes. The decolorized solution is allowed to evaporate, water is added to the residue and extracted with ether. One combines the., extracted with the other, or washed with water, dried over aa. {ié33um pulfate and concentrated to obtain a residue of.-nor-2 ether -.mth3rlious. , 5 (1 (1) -oestradina-3,163.-do. Purification is carried out by crystallization from an acetone-liexane mixture.



  B. 7-nor-5 (10. estrneM16a1-3-one
 EMI63.4
 Maintained at room temperature for 40
 EMI63.5
 minutes a solution of 200; ng of 3-methyl ether of D-nor¯ 2, 5 (10 j-oestxs.d.6na..3, i 6; 3-d.ol in 16 car of methanol and 3 cnr 3 of water containing 250 rats; of oxalic acid.
 EMI63.6
 Put the reaction mixture into water placed, the resulting precipitate is filtered, washed with water and dried to
 EMI63.7
 obtain D-nox5 (10) -aestxane. 163-0l -. Ass. Purification is carried out by oristallization from an ether-hexane * Em'M 18 7-.noz.-.- estrn.-16 ..01 mixture. "."we have
 EMI63.8
 A solution is heated under reflux for 20 minutes.
 EMI63.9
 tion of 200 tng of D¯nor-2 5C10) -O9stra-dieno-, 3-methyl ether, 16 (3-d.o.

   (the compound of Example 17A) in 50% of 90% aqueous methanol containing 0.5 µm3 of concentrated hydrochloric acid. The reaction mixture is cooled and
 EMI63.10
 concentrates under vacuum. Cold water is added to the residue, the resulting precipitate is filtered off, washed with water and carried out.
 EMI63.11
 dries up to get 11-nor4-oestxcnc.163..01 --- one. We
 EMI63.12
 . purified by crystallization from an acetone-mixture

  <Desc / Clms Page number 64>

 hexane.
 EMI64.1
 



  J :: 1 '.: H} LE 19 D-nar-A.-aeatx & n, 16 - dionc A a solution of 50 cm of D-nox-4-aastrënewl6i-ol-3-one in 5 cm3 of acetone , cooled to 5 ° C., a chromic acid-sulfuric acid reagent (266 mg of CrO3 / cm3) is added dropwise until a permanent orange color is obtained. The solution is kept at room temperature for 5 minutes, then a small amount of methanol is added to destroy any excess reagent. The solution is poured into ice water and extracted with ether.



  The extracts are combined with ether, washed and dried over
 EMI64.2
 ms.gnéeium sulfate and evaporated in vacuo to obtain a residue of D-nor <-4-estrene-3,16¯dione. Purification is carried out by crystallization from an acetone-hexane mixture.
 EMI64.3
 }; XB: \ ll.1LE 20 16a-m6thy..D.-nor-4-oestrin..l6p-ol .. -one Au 3-pyrroldlénainode àDnoroosrne-.3,6; one We heat with boil a solution of 1 g of
 EMI64.4
 D-nor-4-oeatreno-3,16-dione in 10% of methanol, then 0.75 cm3 of pyrrolidine is added. The mixture is boiled for 10 minutes, then cooled.

   The resulting precipitate is filtered off, washed with cold methanol and dried.
 EMI64.5
 to obtain 3-pyrralidy. namine of D-nor-4-oeatrene-2,16-dione which is used without further purification in the operation which immediately follows.



  . 16oc-ethl. h.-nor.-oc strene-16, -0 .-. 3-one
To 1.5 g of magnesium turn in 50 cm3 of anhydrous ether is added dropwise, under conditions
 EMI64.6
 anhydrous, z0 = 3 iodomethane at a rate sufficient to maintain a slight reflux. Then 50 cm3 of tetra-
 EMI64.7
 purified hydrofuran and distilled until the temperature of the mixture is 60C7.

   Then 50 cm 3 of ether are added, then a solution of 1.4 g of 3-pyrrolidyl-enamel from D-nor-4 oetrene-3, t6-dion3 in 50 or more is added dropwise.

  <Desc / Clms Page number 65>

 
 EMI65.1
 té-crahyarofuran The reaction mixture is distilled to a boiling point of 60 <'0, then we continue upwards';

  , gold at reflux for 3 hours, and stirred overnight at room temperature until the next day. Cooled over an ice bath and added dropwise 28 ounces of water, then a solution. of 8 OM3 of aoidoacetic acid to 50% of methanol * The reaction mixture is boiled for 30 minutes then cooled * and 28 aar of a 10% sodium hydroxide solution is added. Reaction for 30 minutes, cooled to room temperature, acidified with acetic acid and concentrated to a vacuum of about 75 ohms.

   To this residue is added a mixture of 5 µm 3 of concentrated hydrochloric acid and 5 g of ice. a somaot the reaction solution L a
 EMI65.2
 extraction with methylene chloride and the combined extracts are washed first with water, then with dilute sodium hydroxide solution, and then again with water, dried over magnesium sulfate and we concentrate them to obtain a
 EMI65.3
 residue consisting essentially of 16a: -mëthyl-D-nor-4- * oeotrene-16p.ol -'-one. Purification is carried out by chromatography on Florisil, in elumit by means of ether-hexane mixtures,
 EMI65.4
 In a similar way, one can prepare other
 EMI65.5
 drifts dos 1 & x-alkyl-D-nor-4-esterenoc, and for example neither ethyl bromide is used in the above operation 4 instead of methyl iodide, one obtains the 16 <x-Ethyl-D-nor-4-estrene-16ol -'-one.



  * BjÇgii-IfLti 21 1.6a: -ethynYl-D.-nor-4-oastrene-16B: -ol-3-one A solution of 500 ag of 3-pyrrolidyl-ena-mine of D-nor-4 is treated -oestrèna- ', 16-dionc in 10 cm of dimethylcuifoxide with sodium acetylide according to the method
 EMI65.6
 procedure of Example 16. The resulting product is essential.
 EMI65.7
 also the 3-pyrrolidyl-enanine of the 1 6ct¯é fchynyl-D¯nor¯4¯ oCfJtrene-16j-ol -'- ono "We breed the enaiaino prepared above in a mixture,

  <Desc / Clms Page number 66>

 
 EMI66.1
 .n go of 1, G (ç ù'aacbuèo do soaiuni, because of water, one * of ancient alôa and 20 0.'11 'of methanol ..

   It is heated under refx for 3 hours, then the solvent is ohncae in vacuo and the resulting residue is dissolved in methylene chloride O1, the organic solution washed first with water, then dilute hydrochloric acid, followed by the aid of a dilute colution of sodium bicarbonate, and finally this again with water, then add 1lncnc1um sulfate and concentrate in vacuo to obtain a residue consisting of 16a-ï5thynyl-l '- nor-. 4-09otr6ne-163-ol¯? -One It is purified by chromatography on Floriail, glutinating with a mixture of ... these ethor-hoxanes. LiXha-iPLB, 22 .t.hc.r.; -Lt <th: y; 19U03 ..of D-: 11, o ,;

  r-2. 5 (10) ... ooetrpdiene, -, - o. ", 1 G-O9 To a solution of 1.5 g of 3-metl, .YlJ. ether that of D'.nor'-2,5 ( 0) -oestradihna-3,16H-diol (the oOlllpoe6 of Example 17 A) drnl3 15 cm of nyridine, a reaction prepared by adding 115 g of chloro trioxide 1.13 to 15 cm of PY1-i- is added. Linen maintains the mixture at room temperature until the water is poured into the water. The resulting precipitate is filtered off, washed well with water and stripped, to obtain essentially 114. -D¯nor-2,5 (10) ¯oeotradièno-2-ol¯16-one 3-methyl ether.

   Purification is carried out by crystallization from inopropyl ether ËXl.! 1H, -, 'ther â-7.t) iZIque of 1ifi6geith; yiylr-npr¯2 | tii (10) ¯ocsTradiieineii - 3.16o-niol. a solution of 300 mg of 3-odthyl ether in 6 ounces of dL-a6thylmtlf oxidized with sodium acetylide in accordance with
 EMI66.2
 to the procedure of Example 16p except that the aqueous suspension obtained by pouring the reaction mixture into
 EMI66.3
 the water is not acidified * The precipitate formed after the reaction mixture has been removed from ice-cold water is filtered, washed with water and desiccated # giving escentially

  <Desc / Clms Page number 67>

 
 EMI67.1
 16a-ethynyl-D-nor-2,5 (10) -oestradiene- 3-methyl ether, 16p..diol. Purification is carried out by crystallization from ether.



  }; XJ: 1i: .I?!. E 24 1 & x-ethynY1 "D-nor-5 (10) 2EAtren-16S-ol - one
A solution of 150 mg of 3-methyl ether is allowed to react according to the procedure of Example 17 B.
 EMI67.2
 l6c <: - ethynyl-D-nor-2,5 (10) -oe8tradien-3, l6t3-diol with oxalic acid. The resulting product, 1 f-Xx-ethyny1-D-nor-5 (10) -oootran-16-ol-3-one, was purified by crystallization from ûthor isopropyliqua.



  ± Xa: fKUb '25 6oe-dthyTriyl-D-norj.and
In accordance with the procedure of Example 16, sodium acetylide is allowed to react with a solution of
 EMI67.3
 500 mg of D-nor-1,4-o.udrostadiene-3,16-dione (in the compound of Example 13 B) added to 10 01113 from dJindt1iyls.ilfo> Vde. A:;: r'fJ0 having poured the reaction mixture into ice water and
 EMI67.4
 acidid with ohlorhydriquo acid, stirred at room temperature for 1 hour, then the further precipitate is filtered, washed with water and dried, to obtain eosontielleroent 1ethlyl "D-nor-. 1,4-androDtaaiàno-1Gol-- one.

   Purification is carried out by crystallization from an acetone-hexane mixture,
 EMI67.5
 ftm'IPLB.26 fioytotpa.érpne
Has a stirred solution of 1 g of metallic lithium in 200 cm3 of liquid ammonia at a temperature of -60 h
 EMI67.6
 '-7000, a solution of 2 9 of D..nor-1, 4-a.ncll'olJtr.di? Me-3, 16 ... dione (the oompouÓ of HxenpIe 13 B) in loü on% 3 of purified tetrahydrofuran.

   The mixture is stirred under anhydrous conditions for 1 minute, then
 EMI67.7
 solid ammonium chloride is added with vigorous stirring until the blue color disappears. The ammonia is allowed to evaporate, then water is added to the residue. We

  <Desc / Clms Page number 68>

 The resulting solid is filtered off, washed well with water, then dissolved in acetone and trouted with charcoal, decolorizing wood. Crystallization is produced by addition of hexagonal and concentration of the solution. The resulting precipitate
 EMI68.1
 is filtered and desecrated, essentially yielding D-nor-teK-tosterone.

   Purification is carried out by recrystallization from isopropyl ether.
 EMI68.2
 hXÀl-ïkLE 27? ronio, n3.te of D-ppr-tostopt6r.one (roj:) ionatjD-nor- <0.5 cc of propionic anhydride was added to a solution of D-nor-tuutosterone in 5 µm of pyridin. The mixture is maintained at the. room temperature for 24 hours, then the reverse side is placed in water and stirred for 30 minutes.

   The precipitate resulting from propio-
 EMI68.3
 nate of D-nor-t>. :: stoot6rone and purified by crystallization from an acetono-hoxne mixture, .bXl.;.,!. t: Lr; 2b p '.... nor-4 -rmd, ro ot, èno-'. 1 6-.d; Lona 'OonfoméMont in the procedure of Example 19, the D¯nor 4¯androstene 16 | â-ol-5 on9 in acetone is oxidized by means of an ohromic acid reagent. sulfuric oic1e. The resulting product, D-nor-4..and: roetene - ', 16-dione, is purified by crystallization from an acetone-hesane mixture.



   EXEMPEL 29 16 [alpha] -methyl-D-nor-4-androstene-16
 EMI68.4
 A * 2-Uyrrolidyl-dnuiine do āD-nor4androton.e-'16'-dit) na We tr-ncformo la to obtain 2-pyrrolldyl enamine oorreapondanto by treatment with pyrrolidino dtaio jldtlianol according to the procedure of Iixouplo 20 A. The resulting product is filtered, washed with metho-lOl and clennbolio is read to obtain 3-pyr: rolidyl-dnamine of D-nol "-4 ... androlJtono- ', 16- <iiOIlG which is used for further purification in the following operation.

  <Desc / Clms Page number 69>

 
 EMI69.1
 



  '"V,., 0 v & ti B. l''Ë'3'lDor4androtno-j, 6-.ol3one Oonfornémont in the operating mode, from the: B: r.ol: vle 20 Goal We lo.1nnet react a solution of iodide of Mthyl'-masnuaium donu a faulanso dthor-tdtrttliydrofurane uvoo uno aolution of 1 day do "p; 1'rolidyl ... dna.m1nt) of i -aor 4-androatëne 2 i6¯dlono danu le tútrahydrofurrJ.I'u). It was produced in the Doritic manner with NxORipla 20 d to obtain 16cc-methyl-D-nor-4-iMidrootbno-16p'-ol'-3-.on.c.



  From a number r.d1ailo.1ro, we replaced the iodide do by the bromide in the opdeatoixe mode oi-dorWUfJ, we obtained the 1 6a- <4-'androfj 'ethyl-D-nor: bno-16-ol-3-one.



  ËJ = ëËL2S D-nor-ëthintdrone (m 1 i6 īéithynyil¯Dīinoiri-4-anàirpjBt / mO "'1 6 $ ¯ol-p-one) Ooilforn6., Not in the procedure of example 16, on the first line: HJo ra, write the sodium aoetylide with a solution of 250 mG of 3-pyrrolidyl-dnajnine of D-nor-4-androotene - ', 16-dione (1 (; compound of Example 29 A) in 5 ocr of d1: 1ethyl ... tallow oxide The resulting product is isolated according to the procedure of ixomplo 21. One purifies by oristallization b from a radiant acetone-hoxono to obtain D -nor- <! thintdrone.



  RiLH Acid, 3; .6-acoto.r.yi -X) īinor¯¯p.ndronteneī1 6 icarbojxylic The repair of this compound was described in the example-
 EMI69.2
 ple 8 R with reference to general techniques
 EMI69.3
 expondon in Uxem; on 7. In these techniques, the separation of the product can be modified as follows: the residue obtained by conceiitration of the reaction mixture is dissolved in ether on the rotary thin-film evaporator, and the thJrated notation was washed with water, then concentrated in vacuo to obtain an r-a.c6toX'JD-nor-5-o.ndroetono ... 163-ca. rboxy- 1iquc. Purified by crystallization from acetone flG, ur :: UCJe.

  <Desc / Clms Page number 70>

 
 EMI70.1
 



  .. ;; (;:,: 1..1: Ll't) 2 P-n.9.r: ... 2 = pr6 fn "j n :: '- ol-2o-9no
 EMI70.2
 AT. Ohloruro do 1. ':: oicla' ... aof toxy-D ... nor-5 ... o.ndrOfJtbne ... 166- \ - - - M - - "" - - - - - M - - - - - - 2a :: b2x1q- Au C d'ncido 33..nataxy.l-.nar5-randraa Lânawi 5., enrboxyliquo dana 25 01 \ "do anhydrous banana, we added 2, ', am 3 in chloride The mixture was heated under reflux for one hour. On OhU8IJO the benzine by dictillatiomeio empty diiir, doc conditiono anhydrous. The rdaidu rdoultunt; t'ot ".n4 cr; tczzlt.o.'t:;. N: nt; aliloruro of lt 0.01do 5 (i aodtoxy¯D-nor-5- 'Rndrocttno" 1G (3 -OHrboxyliqu8 eot used oan purification (lu I) PI6: is area dzuici the following operation, r, v: n6d.atcman.



  13. EI: a:; 6! Or: .y :: 21-è.12: z2 - t! O;: - 2-.Ers.àne = 2Q-2n A solution of 1 g in ohloruro of l 'acid zij3. ^ .atax.y.-D.-rax-.5-nndxaatÊrze-16t', apxboxyy .qua (prepared as described in. [; xt:; 1 ', ple 32 A) in 25 char of 'benzine, a solution of di, a rudth.r7.o in ether is added until a persistent yellow color is obtained. A laie GO propose the mixture h la. room temperature laying 30 minutes, then we concentrated it coite! prooolon reduced to obtain a residue do 3ô-acii: oxy-21¯diaiO-B¯î-ior¯5 - pr (5/2) ifene- ±: 0-one A purifies by criatü.lli, catio1'l \ from a 1.1elfl.ll .; Q ether¯hexane â, e.ç'tox; rI3naxrf-nna-20-anr, A a solution of OO ma 3o-acetoxy'-2t * -diazo- ',. ; ox., 'rCfune-2U.ari in 50 μl of ether, an additional amount of approximately 500 kg of crouhjdriquc acid in 15 cc of ether is added.



  VS . Celts the .r.Claïu: e: t the temperature aablonte for 30 mlnuteo, then it is washed first with cold water, then with cold sodium bicarbonate and finally at again at 1 f elected, on 1.118 it is dried over sulphate of: .rrW u :. and concentrated under reduced pressure. At xr¯i3.z it resulted containing the. 3 * 'actoxy-21-broo-D-'nor'-5- I''l'égnh.c-2Q-on.c, 15 sets of acetone and a solution of 1 5 g of iodide are added. sodium doris 15 = 3 acetone.

   Crn heat the reaction .i.1lanee 3. the reflux ter-prature for one hour, then add 1 al of acetic acid and heat with

  <Desc / Clms Page number 71>

 reflux for a further 30 minutes. The resulting brown solution is decolorized by the addition of an aqueous solution of sodium bisulphite, followed by pouring into ice water. The resulting precipitate is filtered, washed with water and soldered. the dry-
 EMI71.1
 che to obtain 3p-! tketoxy-D-nor-5-pregnene-20-one. It was purified by crystallization from hexane.



   Alternatively, the compound of this example can be pre-
 EMI71.2
 parry by reacting the chloride of the acid 3P -'ao6toxy- D-nor "? - amt: t'orJt (.no-16oC \ rboxyliqua (the compound of ex (3.Jple> 2 A) with Io dim6ethyl-cad, .alum as described in Example 100.



  D. B¯nor¯5¯nrégnenē3i3¯ol¯2Q -one 300 mg of 3ô-aoëtoxy-L-n are dissolved <: 'r-5-prbm'- 20-ono in a nelango of 10 cc of acetone and 20 cc of a 5% solution of hydrochloric acid in 90% / v aqueous meth! The solution is left to stand under ambiguous temperature for 24 hours, then approximately half of the solvent is removed under reduced pressure, the residual solution is poured into gloc water, the resulting precipitate is filtered off.
 EMI71.3
 of D-nor-5-precnene-3p-ol-20-one and purified by crystallization from an aoetono-hexole mixture. l: tr ... Br, # Li 33 "o, id, a .... D ..": 'tl0r-4, -aud;: op, èno -'- tle "'. 16 p-ca. : r:, bo, x: y: l i9.'q.



   The preparation of this compound has been described in Example 80 above with reference to the general techniques set forth in Example 7. These techniques can be modified as Eight!
A solution of 5 g of 16-diazo-4-andro-
 EMI71.4
 3-stene 17¯dlone (prepared in Example 6 B) in 5 cc of aqueous dioxane for 4 hours using a 200 watt mercury vapor lamp fitted with a Corax sleeve. The solvent is then fortified under reduced pressure,

   the resulting residue is triturated with water and dried to obtain the acid
 EMI71.5
 D-nor-4¯androBtene-3-onōi63¯carboxylic. Purification is carried out by crystallization from acetone.

  <Desc / Clms Page number 72>

 



  EXAMPLE 34
 EMI72.1
 D-nor-4-M '\ bne-32P
 EMI72.2
 (= I) - nor-r'routërone) A. Acid 5¯S ± "l¯èriâr2f'i? 3Her2¯0S0" ê: carboxylic acid
A solution of
 EMI72.3
 500 ml of U-nor-4¯androotlnē3-one-16jJ-carboxylic acid in 20 cm3 of anhydrous benzine containing 5 drops of pyridine, then 2 cm3 of oxalyl chloride is added. The mixture was stirred at room temperature for 1 hour under anhydrous condition, then the solvent was removed under reduced pressure.



  To the resulting residue was added 20 cm3 of dry benzene, then the solution was filtered and insoluble matter was discarded. The filtrate is concentrated to obtain a residue consisting essentially of D-nor-4- acid chloride which is used without further purification in part B of this example.
 EMI72.4
 



  B <21 '-diazo-D-nor'-4prun-3 ZOdiono A a chloride solution of D-nor-4-andro-oteno-3-one-16i' -'-oarboxylic acid obtained as in Example A solution of diazomethane in ether is added to 20 CM3 of bfnnbae until a persistent yellow color is obtained. The mixture is maintained at room temperature for 30 minutes and then concentrated under vacuum to obtain
 EMI72.5
 one residue consisted essentially of 21'-dia.zo-D-nor-4-pregne-ne-3,20-dione. Purification is carried out by crystallization from an acetone-hexenc mixture.
 EMI72.6
 



  This ë '* S E' '* SS: E 30'-dine Of the first described in Example 32 o, the 21-diazo-D-nor-4-prégnèna -', 20-dione is treated with hydrobromic acid, then the resulting 21-bromo-D "nor-4-pr6gnan ... ,, 20dione is allowed to react with the codium iodide in acetone, and then with the acetic acid. resulting product
 EMI72.7
 as described and D-nor-4-prdgnèno-3v2O is obtained. dione. Purification is carried out by crystallization from an acetone-hexane mixture.

  <Desc / Clms Page number 73>

 



  A variant, the composa of this example can be pre-
 EMI73.1
 parer OQr "rlO m, it: At a solution of 250 rag of & ¯nor¯5 - *> regnfcne- 3f3-ol-ïÒ-ona in 10 oin3 of acetone cooled to 500 # we add an ohroMic acid reagent'- Cultural aid according to the procedure of Example 19. The residue is dissolved (i-
 EMI73.2
 ± 1016 of the number described in Example 19) in acetone where approximately 2 cm3 of 3N hydrochloric acid has been added. The colution is left to stand at room temperature for
 EMI73.3
 1 hour ?, then we drop it in the water.

   The precipitate is filtered continuously consisting of I / nr-4-precene 2fE0 dione, washed with water, deo8bohe and purified by oristDlliootion from an ammonium-hexane mixture.



  D-norrdgnne-3,20-dione is subjected to the action of a culture of gort; \ e, bq..o, t.eri; a Mlmelex (A.'r.O.O.O. NO 6946) of the. following way t
A solution of 1 g of yeast extract ("Difec") in 1 liter of tap water, the pH of which has been adjusted to 6.9,
 EMI73.4
 is divided between ten flasks of Erlenmoyer of 300 = 3p and one adds in each flask 2 this approximately 5 of a culture of Oorynobaoteyium aimplox. The resulting Huapensione are incubated at 3000 on a shaking machine for 18 hours. 0.5 e of D-nor-4-pregnene-3,20-dione in 25 cm3 of acetone and the resulting solution is also distributed between the ten vials containing the culture of Corvne-
 EMI73.5
 b.oterUtn pimnlax developed for 18 hours.

   The culture containing D-nor-4-pre, gnr! Ne -), 20-dione is then incubated at 30 ° for a further 24 hours. The contents of the vials are then combined and extracted with a total of 3 liters of chloroform. The crude chloroform extract from processing is concentrated to give a residue which is crystallized from a chloride mixture.
 EMI73.6
 of methylene-hexanep giving D-nor-1,4-pregnadiene - ', 20-dione.

  <Desc / Clms Page number 74>

 
 EMI74.1
 



  . ,, .., 3 .. '6 P. =. 1l2}' ..:. 1 =.: =: IL0., :: J: .b.1 ±: "1 61", o.-. 9.n ± (l.yar..t "": ", to:; t: swxostcs e (Jon 6a, t! 1r eoti2ue) A. 5 ç. C.'l7 LOI'awIr02't1" cnk2, ilaa , .allQ A utio solution do 1; de D ... no: r-5-prér, ntno-, s ... ol- 20-ortiî (the Co) \ poné dos 1 t ± x (;! 11plo 32 D) in a mixture of 5 in n of carbon tetrachloride, 5 orz of fluoride of fi> - t! 1yleno and 0.75 of pyridino, one adds h, -20 0 a sd u- tien of; 240 me: ..the chlorine dlU1fJ 2.7 cm 'of tcftxcai, axuxe do carbon <2. Cn the tulatii * e at "200 for 30 minutes, pv.4a on If the room temperature is warmed in a time period. Dilute lo! R. <51ane î of ydac-tion at 01: .oride Av .., t.bxza and on .tzvc3 the organic folution first of all in water, p'Jif1 h the iddo ù '' U11O solution of sodium thiosulfate , tt: lina "lencnt do to.zvcru cs the anu.

   We daouboho the solution in the chicvurc do; ctlsy.Czzo and the result of ml. \ Gn6oi \ 1n1, p1.Ù.a we concentrate it red to obtain the residue of the oonuti killed .tJl '; ontiol1e- aent de i} 6¯QlchiorōD¯nor¯pr <St? Iajiē3 $ -ol 20¯Qne. Purified by crystallization from a mixture of methylene chloride * POl'ltLUHh E. 16 = a ± éaēd 2'2-2i9h! Or2 "o1rg3aue = 'Èt16ê-2i21- A w1 solution do 300 s do 5, 6-diohloroh Ai1 trnne - ,.) - ol-20-onc in 5 oa. Of chloroform, 140 'JI1 :: of rnar.a ^ a.-u ° r * tcsa:, axgues We laiHU stand the ja-'i.ir-o il, la ', rr = fr, ï.n. vli: 3 rb.t.:tcs for 72 hours, then it is diiuc nu wûthylene chloride and it is washed first using c3at; ssoJ..zv3c: rs of bisulfite codions, then using a cis bicarbonr-te do fsodixua solution, and finaloaont h l.te \ 1.

   We dcc.v> cïm la. t'o.1.'lticn or- jvique nur sulphate of: n. '. lt, "n6e1' \ lm, then concentrate it to obtain 'in rÓidu. constitutes 8IH.on- tiellonent of 16-fictatc ae, (y-c33ch1aroI3-nox-.azdroete, n, = sl6:; -. ci.o .. un, orified by cree n from ather.



  0. '! 6-3.c6t "te this D-nor-5-ol1drotne-3j, 16d-diol To a zoo solution: 3 of 9 6 satrte de, 6-ci3ctû.st x? Itaxf'.ri. itQ t'tvrGx 1 ..; ï.Crl, d;: 21: 5 0. "a3 (1'ucètonu, we added

  <Desc / Clms Page number 75>

   a solution of 500 mg of sodium iodide in 5 cm3 of acetone. Stir the mixture at room temperature for 5 hours, then add sodium bisulfite solution until the brown solution is discolored.

   The reaction mixture is poured into ice water, the resulting precipitate, consisting essentially of 16-acetate, is filtered.
 EMI75.1
 D-nor-5-androstenc-3,16diol, washed with water and dried, Purified by crystallization from an acetone-hexanes mixture
 EMI75.2
 D * 16: a6! Il! Ēd E-no! -1-rE8! Ene = 1o-2-2n! De la nantira described in the operating variant of the jdxaaple 34 Co is oxidized the 16-llctte of 1) ¯nor¯5 "-androotene 3Pr1o? ¯ûiol using a chro acid reagent:

  aique '- "sulfuric acid, after which the treatment is treated with dilute hydrochloric acid,! The resulting product is isolated, consisting essentially of 16-
 EMI75.3
 D-nor-4-androBthno-l 6p-ol '"3-one acetate as described and purified by crystallization from a
 EMI75.4
 Ac6tone-hoxanoo mixture Be D-nor-4-androotone-> 16 (5-ol-3¯one On hydrolyzed lo 16-acetate of D-nor-4 ... a.ndroatene ...



  16} 3-ol-3'-ona with jnoyen do potassium carbonate in a methanol-water mixture as described in Example II J :: I.



  The resulting product, D-llor-4-androstenc-163-01 -'-one, is isolated and purified as described.



   EXAMPLE 37
 EMI75.5
 D-nor-1 4-f indroo tadine. 1 6I3-o1 ::. 2 ...! We add the D-iior-4-androbtbne-1 6-01-3-one to the action of a Pror culture.} 'Y101' '' c:!:. 2.r! \: Ln.! 1.ax of the inanibre described in Example 35. The resulting product is isolated as described to afford D-nor-1,4 ... androetene-16-ol-3-one.

  <Desc / Clms Page number 76>

 



  EXAMPLE 38
 EMI76.1
 6a: -chl o: ro-D-nor-4-pr, s!: 1! enn- '., 2O-di one 1 # 5, 6-dichoroD-norprenan-3,20dione 5,6-dichloro-D-nor-pr snane-'p..ol-20-one (the compound of example 36 A) with a chro acid reagent, alic-acid 3u.l! 'uriq1J, o according to the procedure of Example 19. The resulting product is isolated as described and the 5,6'- is obtained. diohlor <? - I) -nor-prûgn.ano-3,20- 'dione.



  B.: c1 ± r ± -E-oE-i- ± ri e = L2Q-i2n! Is made pa.SCC1 'a current of hydrochloric acid through a solution of 150 me of 5,6-diohloro-D-nor-prégnan' 3,20-dione in 20 cm3 of acetone cooled to 0 C for hours The reaction mixture is kept at 0 ° C. for 2 hours, then concentrated in vacuo to a residue of about 5 cm 3. The residue is poured into water and the resulting precipitate is filtered off, washed with water and dried,
 EMI76.2
 to obtain essentially 6o: -chloro-D-nor-4-prÓgnene- '3,20-dione. Purification is carried out by crystallization from an aoetone-hexane mixture.



   EXAMPLE 39
 EMI76.3
 D-nor-¯ A26-acetate D-nor-ddsoxycorticoctérou) 180 mg of 21-diazo-D-nor'-4-prdgnene-3 # 20-Uone (the compound of Example 34 B) to 10 horns of boiling acetic acid. The resulting solution was refluxed for 5 minutes, then the solvent was removed under reduced pressure. The resulting residue is purified by crystal. lization from an ethor-acetone mixture to obtain the
 EMI76.4
 D-nor-4-pr0) 21-acetate, genene-21-ol-3,20-dione U-YJ, 11ii ™ M 40 D-nor-pre / ne6.21 .2.o-dion.



  A 1212r ± m ± -Eo-1- ± r & ào = '22 -2i2n To a stirred solution of 5 g of 21-diazo-D-nor-4- prégnfenē3 20-dlone in 100 om of chloroform, is added dropwise by drop a solution of 2.5 g of bromine in 15 cm3

  <Desc / Clms Page number 77>

 
 EMI77.1
 by chltceof orrne. Stirring is continued until the oon11 ... lation stops and the color of the bromine disappears. The solvent is brought to room temperature under pressure.
 EMI77.2
 reduced to obtain a remix consisting of 21,21-dib: romo-D-nor-4-prone - ,, 20-diono, which was used for further purification in the next step.
 EMI77.3
 



  Bo B-aoN, 16i2Q): 1) é (511 !! d.è! L: ': on-g1: 2-'Ù2- of Nhyl To a solution of 2 g of 21,21-dibromo-nor-4 - '[) rÓe; nJme - ,, 20 ... diono (obtained as in Example 40 A) in 40 cm 3 of methanol) where 15 cm 3 of an 8% solution of meth: y1 are added. The mixture is stirred in a nitrogen atmosphere at room temperature for 16 hours, then poured into cold water and the mixture is extracted with chloroform.

   The combined chloroform extracts were washed with water, then concentrated under reduced pressure to obtain essentially D-nor-.
 EMI77.4
 Methyl 4,16 (20) -prégndiono -'- on-21-oate The residue is purified by chromatography on Florisil, eluting by means of liexane-6tlier-aodtonee melanecti The fractions having the same ultra-violet spectra are combined and infra-red, retaining that of those fractions in which the infra-red spectrum indicates the presence of an ester group and the ultra-violet spectrum the presence of two conjugated systems.

   The selected combined fractions were concentrated to obtain a residue, which was crystallized from acetone-hexane.
 EMI77.5
 



  Ce -2thyàc2éa. * QūD: n2r = 512 (methyl gOl-Er2e.1in-n: 21-ga.e-
Has a solution of 1.5 g of D-nor-4,16 (20) -prégna-
 EMI77.6
 Methyl dibne-3-on-21-oate in 150 ml of benzene, 7.5 cm of ethylCme-glyool and 0.15 g of p-toluene-culfoniquo acid are added. It is stirred at reflux temperature for 6 hours, then cooled and washed with 100 cc of a 1% aqueous sodium bicarbonate solution. The washed benzene solution is placed on a column of

  <Desc / Clms Page number 78>

 
 EMI78.1
 Floriail was read and helped with ether. We combine factions! elu4on and one lou evaporates to obtain an aont residue! Il111t
 EMI78.2
 
 EMI78.3
 onr-ontiollenont lo 3-tÎtllylûllooetal du D-nor-i ?, 16 (20).]
 EMI78.4
 
 EMI78.5
 dH'no-'3-'on-21-'opte (methyl.

   It is purified by oriata .. iaation from an aotorl mixture ... hxan ..



  ... thyèo2J! J.! of R '*' BC'E''Ë'ii2PESSË?. '' one Or added drop by drop, stirring, a solution to g of 3-uthylneotal of D-nor-5,16 (20) prégna4i'ua -3 - lIuSthyl ort-21-oate in 50 am3 of tetrahydrofurant- frai- chcaont (1î .-- tîllt # at a suoponsion of 50U niS of hydru. ') Of lithium ot aluninium in a 25 om of tetrnhyd: t.'ofura: e. We ciuiufi> the mixture at the reflux temperature for 1 hour,,> ai ± j we cool and we added dropwise H 'om' of 0.06- tato ci 'ethyl r'uio 5 OM3 of a solution watery sauras from anifato do odimn. Fino.letMnt, a little solid 1'c.'U: n mlfate is added and the mixture is filtered. A separates the solvent from the filtrate: ouu 1.1'00 (11011 reduced to obtain a residue constituting a 3-ethyleneoetal compound of D-nor-5.16 (20) - prÓgl1adiènc-21 .... ol -3-one.

   It is purified by oriota.111oa.tion to. help <> ther il S "SE" i 'lië PELt3i.El' * 23onē To a solution of 5w crQ3 of 3-6thylenoketal of Î3¯nor-5 16 (20) -pregnadienē21-ol-3-one in 40 om3 of a colu- tion. anu-uce at 60 fv of acetone, 0.5 cm of aid is added.



  ; :: ': t: riquc .. The mixture is maintained at room temperature pcndar.t 1b 1., then an aqueous solution of sodium bicarbonate is added until the reaction mixture is baeiquc. We concentrate the basic colution to remove
 EMI78.6
 the. most of the acetone, then water is added.
 EMI78.7
 



  The resulting precipitate is filtered, washed with water and dried, yielding eSBcntielle.1 (mt la D-no1 "-4,16 (20) -prélJ! '1a.di na-21-01- 3-one . We purify by cr.:ntc.J.1iC"ltion from a mixture acDtonēhoxrjTie 2 * 21 - ic'tate of l-D2A'Él''Ë ': i: *' '* 22 if. a 2 s solution of D-nor-4, i6 (2O) ¯pregnadlone
 EMI78.8
 

  <Desc / Clms Page number 79>

 
 EMI79.1
 21-o1-3-on ± 'in 10 cm-3 of pyridine, add 2 m 3 of acetic dride and keep the mixture at room temperature overnight, then pour the mixture into ice water and stirred for 30 minutes. The resulting precipitate formed essentially of 21-acetate is filtered, then washed with water and dried. It is purified by crystallization from an aoetone-hexane mixture.
 EMI79.2
 



  G, g1: asé! N! Ōd2 la A a solution of 500 1118 of 21-aoetate of D-nor-4,16 (20) -prregnadiene-21-o1 -'- one in 50 om of anhydrous -butanol Ot3 onr of pyridine and 1.2 m of t¯butanol containing 11 mg of osmium tetroxydo are added. To this mixture is added dropwise, with stirring, 4.8 cm3 of a 0.82N solution of hydrogen peroxide in anhydrous t-butanol.

   The reaction mixture is kept at. room temperature for 5 hours, then nitrogen is bubbled through the solution for 15 minutes, after which 600 mg of sodium sulfite in 30 cm3 of water are added. After 5 minutes, the mixture is neutralized with medium 10% acetic acid and diluted with 200 cm3 of water, then extracted with chloroform. The combined extracts were washed with water and then concentrated at reduced pressure to give a residue. The residue is dissolved in a mixture of 5 cm3 of pyridine and 1 cm3 of acetic anhydride and left to stand overnight.

   The mixture is poured into ice-water and the resulting precipitate is filtered.
 EMI79.3
 both composed essentially of 21-acetate of D-nor-4-prégnene-16oc, 21-diol-3,20-dionet It is purified by crystallization from an acetone-hexane mixture, H. -oi-Er ± èe: 12! -I2l: 'L2Q-si ± n ± A a solution of 250 ml of 81-acetate of D-nor-4- preen (ne-l (, 21-diol-3,20-dione in 25 cl 3 of methanol, 1.5 cm3 of a 10% aqueous solution of potassium carbonate are added and the mixture is stirred under a nitrogen atmosphere

  <Desc / Clms Page number 80>

 for 1 hour. The mixture is then neutralized here
 EMI80.1
 10% acetic acid, diluted with water, and the melia is removed. nol Doue reduced pressure.

   The resulting precipitate is filtered off. m e !! 2IJnticllecent of U-nor-4¯pregnfene-i6 f21 diol <-> 3.20 "-dine, Purified by crystallization from an acetone-hexane mixture
EXAMPLE 41
 EMI80.2
 D-nor-prën; e6 <tl and its 16-holes A. g1 :: l ': t21Eè !! et'2n!: t ± !! e - D: n. ± r: 4 :: p :: é01n! "' l, g1: d! c;, '"';}, 20- <') ione To a solution of 1 g of D-noïI 4 prolgnènē1 60, 21 ## diol -}, 20-dione in 20 oz of pyridine cooled to -2 (' '0, a solution of 1 is added g of Jl-tolu.ènosul: onl chloride in 5 cm3 of methylene chloride. The mixture is stirred '') at -20 C overnight, then a few pieces of ice are added and diluted with methylene chloride .

   The organic solution is washed first with water, then with dilute ohlorhydriquo acid,
 EMI80.3
 then it is used with sodium bicarbonate solution and finally with water again, then it is added. dries over sulfate
 EMI80.4
 '. \ 0 sJ1acnea:!. Urn and it is concentrated under reduced pressure to obtain a residue consisting essentially of 21 * -p-toluëne'- Tï'j.foAate do JJ-nor-4-prû {ene ... 16c (, 21- <1101- ', 20-diona. It is obtained by criatallisr.tt1on from an acetone mixture. We choose a 300 cm solution of 21-p-toluëne-: lfonRt <: of D-nor-4¯ïnî ± 3ibne-16 t21-diol-3 | 20-0lone fana 10 in 3 of acetone, pif: add a hot solution of 1 g ioduru do codium in 5 cm d 'acetone.

   The mixture is heated, uh.tllt-g, tt: t'i (Playing for 15 minutes, then 1.3 of acetic acid is added and the mixture is heated for a further 15 minutes. A bisulfite solution is added. of sodium until the color of the reaction mixture disappears, diluted with water, filtering the resulting precipitate formed

  <Desc / Clms Page number 81>

 
 EMI81.1
 mostly h-nor.-4. pxéçrzbne-16c-o.-3,20-d.ana, washed with water, dried and purified by crystallization from an aoetone-hexane mixture.
 EMI81.2
 



  0. 16: aEÓnōd D. nor-4. prnbne-16 -o ..- S, Câ..ane A solution of 2 g of T? .- nox-.4.-xn & ne 16atwol 3, t3-d.ans in a mixture of 20 cl of acid is heated. acetic and 4 cm3 of trifluoroaoetic acid anhydride, in a water bath boiling under anhydrous conditions for 1 hour. The reaction mixture is poured into ice water and the resulting precipitate, consisting essentially of D- 16-acetate, is filtered.
 EMI81.3
 , ox. ° prcrzèna l5uc.-ol., 0..d, ana. It is purified by crystallization from aoetone-hexane mixture.



  D, 16-oaproate aa bnorr4p6, mbne 5ct - a. 3, nd.onp A solution of 500 mg of .nox-Apx6genez l6ac-al-3, d-dione is heated in a mixture of 5% capro% acid and 1 osr of trifluoroacetic anhydride at 80 ° C. for 45 minutes. minutes. The mixture is poured into ice water and neutralized with sodium carbonate. The mixture is extracted with methylene chloride. The combined extracts were washed with water, dried over magnesium sulfate, then concentrated to give a residue consisting essentially of 16-oaproate.
 EMI81.4
 T1-nox-.4 .-. Pxdn.bne-l6cC-o1.3,2Q-dior: Q. It is purified by crystallization from ether.



   EXAMPLE 42
 EMI81.5
 37-nax-1 .areibns-16a-o1- 20-.dione and its 16-acetate A. n.-nor-.1,4.j; xgnad.dna-16oc-o1-3,20 d.one On subjects the -nor -.- prégnAne..l6-07 .-, 20-d.years (the compound of Example 41 B) to the action of an Oormbacteriim nielpz culture as described in Example 35.



  The resulting product is isolated as described and purified.
 EMI81.6
 by crystallization from an aaeton-he5ca mixture, na, giving Jâ. nar 1, 4- prE, r, nsditne t ec a.-3,2G-.d.one.



  Bu 16-r G -taa ds aDnor '! 4prëgnadene ;; 1 & Xo-3 t20donē The -nor-1 is acetylated. pre.diôn.a-16oC. o.-i, 2U.

  <Desc / Clms Page number 82>

 
 EMI82.1
 ù..t0110 iu .oc: xx c1'4: c3.3Q acetic and trifluoride anhydrdda of the ùûorite mniuru in Example 110. We lac '. Q the product rucultitut UfJ la z: .z3.itxQ darite and it is purified) by c1'1uta.ll.1.t '::. Ti.on from an acetone-hexaue uelane, fiur obtctiiy the iû- , 4'tai: câo D..nor-1, 4-IJrégnt \ ùi? LlH: oI-1 & :, "'01-; 20-
 EMI82.2
 dione. EXAMPLE 4 ?.
 EMI82.3
 



  D-t10r, -4 = .J.! Fér: ni'mú-11, 1, | 3.f 1tKx 21 tr3, a '2 (J d. Ne (Ir Da, o, r, -lu: .: ..! rocol'tipono) and (Jon, 21-o, cÓt, 'tto A .. -llor-i-; l't.; \'!.: y: 110J.1 Q J.21- .! lro-, gO: d! la- un aoumc-t la nar -.- pri, âna - 1 x, 2l..do.w2C7.diwn (the Qoupood of the 1 <; -: 1: 1.11: 1e 40) h the action of a barley obtura.



  11, 'wl, t3 vt; rlc. ''. ",, rv" ,,; ll1pt. {(N.R.R.L. 2380) of the. following way.



  A living culture of the organism iOii1ryulariift unfea (1lrt.kt. 2 $ bQ) ost riaoéo K from an inclined opening tiar.B the 51a ^ c, dano of otërilec conditions, in a rzt medium:., C3 COX ' \ Ul1: J.llt; in water <11 otilléo, auctdc3 a pH of 7.0 by means of} Jotnccc, constituanto cxiiVLntc
 EMI82.4
 malt extract 5th Sucrose 1 Codiun nitrate 0.2 Po-tE chloride:; im 0.05 spleen of G'JLLfate of ma'11éDi'U; n 0.0ii 1: cpta.h: ldratc of ferrous sulfate opo5% 1'llac, tato acidu dipot3sique ûf1 $ &
 EMI82.5
 We {la.os I. "1 crtic.z: from 100 to of this medium in several l> w.2.,. N13 of 500 c'13. DWH1 each flask, 50 mg of 7 - .. xrr are added -4-r:. ^ I;,. ¯t ficx, i..â.ct ..- ', 2t. DivnY 61 ± lOOUS in a small volu ... <:? acetone.

   We shake the l16l (.L'1.go for a period of 7 days at a te.; Yi4xs: ambient temperature of about 2B Q * The contents aen 1J!:. Llom go oncuitc corbirzrs and extracted by means of ùo t 'iusicun portion *! of dici1l0l "'. tl" O :) of ethyH'ne using oa-ne liver '; .n C.:.rt;it: 1 "Gr.i:.". cie la .hase & Lit'.x.t0 "The OrL; '1.iuee ccbinn extracts are deeé68 tur sodium sulfate, filtered and cG: zan: rûu gous empty to give a residue

  <Desc / Clms Page number 83>

 
 EMI83.1
 aynnt a volume of 1 2 c: a, which is then placed on a chro, nato; r2.phique column consisting of silica gel, mixed with a small volume of methylene chloride.

   The column is washed with methylene chloride, and the eluates are cleaned and concentrated in a vacuum to give a r6: ridu which is crystallized from a mixture of 1 "; o ketono- hexr.t.:le to give the.-npr-4 - px,: a: na-11 3,16t, 1.-tx3.o1 -.;, ... dione. B. g1: a ± úlao ¯d ± i) -nor-4-x;, nneTl131 tix21.tr.ol.3,24.-dw azze On! 1inti () nt la tet1r? Ra tUl'B a. ': 1biu. "1.to until .ez2dett.n a solution of 1 d of Ii-.laot -.-- in'o.;. xGttG-.11; 3.1% h, 21-triol-3,20-dione dino 10 oni do pyridine and 1 in? un- hydrido n c t.7ue On, voroc the reaction mixture in the enu '' '
 EMI83.2
 
 EMI83.3
 ice-cold and the resulting precipitate is filtered off to form L-nox-4-pxrzénQ.11,3r1t 21-acetate, 21-.tr.a..x.0. diane we wash it ut the eu ot we purify it by c: r.'il3tD.lliAtion Î, 1): 1rUr of a mixture of acetO! 1.f1-beJw: w.



  1X! '; lPLb 9-.4, or ",, 1 xl" nçlna-11 6çdltxial -.... x .. 'dane (: "D-hOl'-pl: ±! lQl ... <mçl: .t..t'o1L2, -aoto.te, A. E "':: o ::"' ld: -Er!; ni ± n ± "" 11 ê, 16s, g1: t :: i21 =, .r.2Q "'f:! 12n! From dticrite h.; am, lv 35, we submit D-.na:r4-pxAnne11, 16ot,? 1. tx, al., 20.3 .one, the aotion of an ulturo do .p.ort) 21obE :: \ ctC!, ri.i1J, ra, nlvx The resulting ioolo 10 was produced as described and was tripled by orist. 1-
 EMI83.4
 
 EMI83.5
 libation from a naélango l.1o & ono-hoxM (I to obtain the. D-nor-1 4 px, ¯nad, ina.11 r, 1 dā, 1-.tx, a .3, O.d.one.



  S '! 1: agÓa] ēd2 o.¯D: ngr: 1.r.4: PEwn2dac: 11.r.1.r.21-r! O *, 2lwdiona, De la In "niore described Px 1 'exempta 43 B, the -nox. 9, 4.xCnrv, dt: xa.11 a, 16t, 1 rl; xa 3, O.diazo by means of acetic anhydride in prér.ofioo of ï.rl. The product is isolated in the manner described and crystallized b. from an acetono-hexnno mixture to give 10 1 a, airtc of D-nor-1,4-pregnadiene-11.1 & xt21-triol- ,, 20..d1one.

  <Desc / Clms Page number 84>

 



  EXAMPLE 45
 EMI84.1
 1-acete of D-nor-4-pr (ene-16oc, 21-diO-f11,20-trpn Ac4, D-nor-corticone tate) and not: r..n'.11o ;; ue, '-deh; zdro .., c: Aç & t' ': te, de one A solution of 200 mg of 21-acetate of D-nor-4-pref, nene-11.1 & x, 21-triol-3, is oxidized. 20-dione (the compound of Example 43B) in acetone using a chroaic acid-sulfuric acid reagent of 1a. manner described in Example 19. The resulting product is isolated in the manner
 EMI84.2
 described and purified by crystallization h. starting from an acetone-hexane mixture to obtain 21-D-nor-4-pregnene-1 & x, 21-diOl-t11,20-trione acetate.



  In a similar fashion, D-nor-1,4-prenadiene-11.1 21-acetate is oxidized xt21-tr1ol-3,11-dione (the compound of Example 44 B) by means of an acid reagent. chromic - sulfuric acid, then isolate and purify the product
 EMI84.3
 resulting to obtain D-nor-lg4-prdgaadiene 21-acetate.



  16x, 21-d101-3.11.20 "trione.



  SXHtË46,; p'-nor. "', 4-: p: d, \; I'l <Jnè-11tt. 16 <x, 21: -triol "2Q .... diono son 21-aoétàte e, their, .analoC8-d¯ La D-nor-4-prégnone-1 & x, 21-d101 - ,, 20-diona (the oompooé of Example 40) subjected to the action of a culture of the microorganism Llomnrella oi-nml2 a (Ae2.0-0. 10!? 34) as follows:

   
 EMI84.4
 Solidified culture media obl: 1.quer.: In agar containing the oonstituanta ouivante
 EMI84.5
 
 <tb> Asparagine <SEP> 10 <SEP> g
 <tb>
 <tb>
 <tb>
 <tb> Glucose <SEP> 25 <SEP> g
 <tb>
 <tb>
 <tb>
 <tb>
 <tb>
 <tb> KH2PO4 <SEP> 0.5 <SEP> g
 <tb>
 <tb>
 <tb>
 <tb>
 <tb> MgSO4, <SEP> 7:20 a.m. <SEP> 0.25 <SEP> g <SEP>
 <tb>
 <tb>
 <tb>
 <tb>
 <tb> Water. Ordinary <SEP> <SEP> Complement <SEP> to <SEP> 1 <SEP> liter
 <tb>
 and 1.5% by weight of the agar are sterilized for 15 minutes
 EMI84.6
 at 121 0 sets a pressure slightly greater than 1 atmosphere aou, uxe pre, nn .6gàxem.t eupxiauxe 1

  <Desc / Clms Page number 85>

 
 EMI85.1
 puin cooled to about 2toto, tilt, inoculas of a culture! vegetative development of Gloyerella ì¯:.? ±:

  l. , A.fi..C. 1054) 'J then Mis an înoiibation It uno temperature of 26Qû until i. 00 that an intense oporulation occurs A 2 liter vial of kxl.ennayar containing 500 am of an antoriliud broth ot cooled in a uira11 '.tl "way: from the medium ... dclJ: ..) 1v: nut 1.O \ lH11rJO il an inoculation rirez ::; - 'O!' \ ;! J from one of a culture in the, Mfl, n.:, T T colidifidû
 EMI85.2
 
 EMI85.3
 obllq, uor.i9nt having undergone wo uporulation ina..î3e, and we added 10 ci of a t, -, crit o.nti "'10 \) ,. HJ!), the rftxt'î (1 5 *, 'i' c (: bd.v ,, 0 'of tna the oil of 1!) id) naked medium 110 culture s.in..l obi a, <# -, is enuuito win in lncubfition during no; ',: cHU, 1:}: the 2 I 36 hour ±! at 2fa 0 on a rotary cutter .HHI.; w, :: ü, .t; l; r6GlrfI at 3ü revolutions / minute.

   At the end of this period, we add a solution of 500 ag of D-nor 4-preanî> n <3-16a, i.1- <llol 3i, 20¯
 EMI85.4
 
 EMI85.5
 dione dune 5 or 6th'mol. We. again place the: 'wo,:. o ouy the rotary socoueuM and on. continues the inçr..H) 3.tion laying down 1,, 11. , another period of 24 to zou hours During this last period
 EMI85.6
 of, samples of 10 cm 'are taken from time to time,
 EMI85.7
 j courset with deo extraction with chloroform and chromate-;
 EMI85.8
 spelling on paper (according to 4 the modified Bush method '
 EMI85.9
 by ahull) using a tohuna / a solvent system, aéts4e
 EMI85.10
 ethyl alcohol, the paper was impregnated with water and acetone (this
 EMI85.11
 demibro being px6rar, your SOU: 3 forms a dll3! "': L', ant qui Q 'V! I'O'! Ro quickly).

   On: ou.rl; ui t incubation ju.fJ'j1.1. ' h what the. ohro * 1 ma.to {raph10 on paper indicates a transformation aoao, 2: ta de la The mixture of broth not found in the vial of:.) rllJn! ïl) yor is then AOUJnifJ 9. an extraction with ohlorofonso and the Chloroform kept evaporated in the vacuum to give a residue of D-nor-4-p: rÓanOllO-11a, 1oc. txia .-, Q.diana which is reorïot - lliFj6 from a r, r;., nr.; o acetona-ether.



  B. D-nor-, 4ar ^ radin2-1 tt, 1 ôac, 21trialr'0.-d3.çne We submit the Aprd, n8ne.1la, ifia, i.txi.o, .3r0-âi.ona

  <Desc / Clms Page number 86>

 
 EMI86.1
 h. the action of a culture of the m1cro-o: rCf. \ xú.mao Co; ryneboter; L; wu r.i! wlcx, as described in Example '5. The product is isolated as described and crystallized from an acetone-ether mixture to afford D-nor-1,4-pr-6Vladinp-11,1 & xt21-triol - ,, 20-dione. vs. g1:! \, ge.o ... d ± Ë-nor'.4-nrudne-K, 6o :, 21: triol 3,20 ;; <UoM A solution of 2 of D-nor 1, 4-prc'i.mo is cooled to z -.15 0 <Slèno-11o :, 1âa :, 21-triol¯3 20-aionc dune 10 because of pyridinc, then we add at g-outto 3 cm 'of a mixture (3: 1) of acetic acid and aeotyla chloride. An additional liver, ioii plots, we read m61 :: m {; Q during 1 hour at mid-tun, 1.6rctture of -10 h -! 5 "0 in anhydrous conditions.



  Pour the i, '1,% nUo dono claoated water, the resulting precipitate is filtered from 21-D-nor-1, 4-pre acetate (.' Nadiene-11ct; 1 & x, 21 ... 1 triol¯3i20¯oione, wash well with water and dry <It is purified by crystallization from an acetone mixture
 EMI86.2
 hexane.
 EMI86.3
 



  In a similar manner, D..nor-4-preenne-11, 16a :, 21-'triol-3,20-dione, by reaction with acetic acid and dlaodtyl chloride in pyridine oon: fortlél11ent au procedure described above, gives D-nor-4-prOt: n ne-11 #, 16a :, 21-triol - ', 20-dione 21-acetate.



  EXUlîPlft 47, 21-2c6tate tle 1 ... (1.in1- '.29,' "
 EMI86.4
 dione
 EMI86.5
 A. 11 mthanpu3; fongto-21 ceJbedo Dnorl .4prgndene 1J ec, 1.6ac, 21 = 1 IS'- 2ne To a solution of 1 g of Xi-acetate of D-nor- 1 | 4- prégne.dino-11.1 & x , 21..tr101 - '. 20-diono To 10 µl of cooled pyridine to 0 0, 1 cc of methaneculfonyl chloride is added. The mixture is maintained b. the. room temperature for 18 hours, then poured into eluted water containing OC4i bicarbonate = * The mixture is stirred for 10 minutes, then the precipitate is filtered off from

  <Desc / Clms Page number 87>

 
 EMI87.1
 D-nor-1,4-prÓgnajiene-11-methane2ulfonate-21-acetate- 11, 16 <x, 21-triol-3,20-dione, washed well with water and dried.

   It was purified by crystallization from
 EMI87.2
 of an acetone-hcxro1e mixture. 21-ac4tate-de $ '' 5 E''l'd'S (lU "SSs.l''2:
3,20-dione
A solution of 2 g of anhydrous sodium acetate in 20 cm3 of acetic acid is heated to about 100 ° C., then 1.5 g of D-nor- 11-methanesulfonate-21-acetate are added.
 EMI87.3
 1, 4-p: t'6nadHm.o-11cr., 16a :, 21-triol - ,, 20-dionc. One heats the radiant under reflux for 1 hour and dC 4, 0, then it is cooled and diluted with water. The r6ru.l- high F "'is filtered off and crystallized from an acetone-ether mixture, to give D-nor-1.4 9O 1) -pr 21-acetate. <? gnatri6no- 16 #, 21-diol- ', 20-tlione.



  Alternatively, the compound of this example may be
 EMI87.4
 parer as follows: 1 g of D-nor-lo4- 21-acetate (the compound of
 EMI87.5
 Example 44 B) in a 5 om3 rnclanao of dimethylformamido. distilled and 5 cm3 of anhydrous pyridine, pill is added
 EMI87.6
 0.5 om3 of mcthanoaulfonyl ohloruro. The radiant heat is heated to about 80 ° C. for 1 hour, then it is poured into ice water while stirring. After 10 minutes, the preci-
 EMI87.7
 resulting pite # we wash it well hl 'l1.rl. and Io dissolved in acetone. The acetonic solution is dOClo (! Ch \) and then concentrated to obtain a residue containing the 21 * ac <5 D-nor- '), 4.9 (11) -prcatricne-16cc, 21-diol-3, SO-dicne.

   The iorinil is purified by chroria-borriuhy, first diluting with a mixture of 6thor-hex: '\ no (1: 1), then ether. The elutes are concentrated, then the fractiono crystallines are combined and recrystallized from an acetone-ether mixture.

  <Desc / Clms Page number 88>

 



  EXAMPLE 48
 EMI88.1
 21-acetate dei gocbrpMO-Bnpr-iyréQdine-ii 8,1 foc, 21 - triol-3,20-dione A solution of 500 mg of 21-actate of D-nor-1, 4, is cooled in an ice bath. 9 (11) -Pregnatrlene-16a, 21-diol-3t20-dicne in a mixture of 40 am3 of purified tetrahydrofuran and 8 cm 3 of water, then 250 mg of
 EMI88.2
 N-bromo-acetamide, and then 2.5 cases of 1.5N perchloric acid. The mixture is stirred in the dark at room temperature for 3 hours.

   A solution of 500 mg of sodium sulphite of 5 cm3 of water is added with stirring, then the mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed. first using an aqueous solution of sodium bicarbonate, then with water, they are dried over magnesium sulphate and they are concentrated empty to
 EMI88.3
 obtain a renidu formed essentially of 9oc-brorao-D¯nor-1, 4- pr 21-aoÓtate <5gna.dlonē1 1 p, 1 6a, 21 trlol 3,20-dione It is purified by crystallization from an acetone-hexanes mixture
 EMI88.4
 KXKl'li'ElJ 49, -fluoro-Dnor-4, prodia 16 (. (,, 2 '... tr; l.o9-doq gsefluorpDnprpredniaplone), 21-acetate-de µj.U xyâ. Jt.PEEE; : s' * jtl ''! 1i2l:

  'LêQ-ÈiS! N! To a solution of 300 mg of 21-acetate 9'x "bromo-'Dnor-1,4-premadina-11.1 & x, 21-triol-'t20-d1one in 20 cm' of acetone is added 500 mg. The mixture was heated under reflux for 16 hours, then concentrated to a volume of about 10 cm 3 under reduced pressure and the residual solution poured into the ice-water. The resulting precipitate was filtered off and melted. crystallizes it from an acetone-hexano mixture to obtain 9ss, 11ss-oxydo-D- 21-acetate
 EMI88.5
 nor-1,4-pregnad1eno ... 16, 21- .iol-3,20-dione.

  <Desc / Clms Page number 89>

 
 EMI89.1
 



  '. B. 1: agéaōd r'2 "ë" 2E "lB''l'l '- - - - - - - - - - - ... 1ro! -2, O: dolia- On uluoe USJ16 a container in polyethylene a '. - ... r solution do 500: u; 21-acetate of 9,3,11 3-ox; do-D-nor-1, 4- preL:,' nadit, nfj-16 <.c, 1 ... diol "'3, .2U-àionl3 ùlJJ1a 20 cm.1 of s chloride> .:'. txiy.:no t uit 1-citroidit the Olwr'la1Jlo a {JH a bath dc jlaoe * We add, in e.git! ... nt, 2 eli3 of a solution a.qucuse 4b; 1 of :, cidé: tluol'hYClriqllQ,, J1ÜfJ we have ;; i.tE the mixture age dun; 4, cold for 3 hours We pour 10. <51a.nge of reaction in a cold aqueous solution of sodium bicarbonate, except for the couohoo. The organic layer is washed with water and concentrated under reduced pressure to give a residue consisting essentially of 9a-f.uoxu-D-Mor-1,4-prgnadinc-1, 6o 21-acetate: , 21-triol-3,20-dione.

   It is purified by crirJtrz2.isrztian from an acetone-mixture.
 EMI89.2
 hoxane.
 EMI89.3
 Go 2OC: ftu2r2 - oE-l, 1-r ± lain-11g,!, G1 = ti ± 1 = 'L: d! Oe- 50 mte of ac-luoxo-D- nor- 21-acetate are hydrolyzed '!, 4-prtn.dim-H; 3, l6c <:, 2 '] - triol-3,20-dione by stirring d, .zit3 5 oa 3 do a: .ét.1.anol containing 0.12 o: n. 3 of perchloric aciue 70.-To 1. LeRcrtur, endliit 16 hours. We neutralize the solution. au ::: ';): ïcnl of a solution. 5 of bicarbonate of 1J0: liu.1.1, or the i3..x: xs .ireu and on ltc; tr ::.:. It ") .1). Chloride
 EMI89.4
 
 EMI89.5
 do On>} ombin ies organic extracts, we wash at 2'e:, ..: ut on lec cor¯c.:. be under pref3s10n. reduced to get! ij 'HG.p ^ T y, fy + .. i L': "t? iS ii: ^ i, Fqt 1; Û, E; .C, ¯.LluJra ^ t .-. ilai .'- f . & j yxc, .mrî. = nc-11, 's, l6, c1-iri.al-3,0.-ct.one. ün purified by criDtllf "Ttior ..

   Z start with an acetone-hexane stimulus.
 EMI89.6
 
 EMI89.7
 t.:.t...Ü J 5P i-tc xtc cïe ax-c: lora-rior-1 pr: zad.ène-'i 1 r, 16a2i -, t} 'iol, -J..L. ; Wd ion / "AU: lG .noll.ltjol1 of 100 ine of 9p Si-acetate, 113-
 EMI89.8
 (composed it
 EMI89.9
 do x '::; c.:rp.e .9.) dU11U 20 ca)' do chloroform 0 <'C, we add 2 3 of a solution f: j :: .. tl.1rt; O dtacido ch1.orhydrirue

  <Desc / Clms Page number 90>

 
 EMI90.1
 tu u, '..' # ci :: 1. ')',): '01 '. :. t, r:, .rr: i.rt: Lc; W fiolution h. 0 ',: crttd.t'b ...: .1,: l'tH t 5vJ.f1 en lu 1-ivu u' ,, 1) 01'd r .. using a, olut101f t : - ..,:; .. t ': I; (..!: .c.; ¯.:; t't,: c ':.,> ;: i, t: l, .'a: read, then we 11. concentrate rc,,.' '' , ¯:.): 1 ,, "'., R¯.4.' , * because get an r <5cidu form 9ac.um ..



  O + ,: l, 11. en :,. "21 r; t '". e Oo 0 5 ^ oit.l.oro-i3.-naxw1, wp i, ^ lzdizxr 1 ': x 1 ttM, 1. ; z o;.;,; t. iaue. Un ivurifies x axa.ntr.r.7..aa. \; 1 cn?,;. \\ 1 't. ". 1 t a ?, IZ; d acto: lc ^ hoxane.



  ....:: uiv ut Il.: od ('operative f.> iIJ1ilr.ù.ro à. oel \ t1 rfc'j * r'! '-> # - v.!. <49 C, the set corner of this Example may be} the ..1.'0J. ",: '6' # 0 <r, .c'n, tx. the corresponding free 21-alcohol, that is, N #. w; ' the c '.,. orawli.nor ^ 1 =; c, rc: y; ùièrxc. 11 p, 1 Cxt, 21 .i: r.al \, '; 1 -0. J P! L (?.



  KA ,,.:. ILIv p1 pQ}:.: Q! T: ') - ol-16ono -IIO'; 7all'Ult i'hOriE 'D-no1'-50: - rc .-'; n-. 3o: -ol-20-oc Un rnt6t'it.'ie D-nor-Midrontune-3āol-16 | iJ- cnr!.: O = :: tlirl'.h1 (lo ca ..: > o ;: ae l ';. er7u.eb A) au noyen d' c.nl1y- f.1'id "dt: \ ci" 3 î -io't "'" uo dene I li pyridine according to the mode oî> c2 \ toire of '...:,'. e 10 As i-uia on fl ', it reddish the 2¯act? tate r' .'- i.'t .ut. "¯t '': C le C: 'i.3.C.il2c: ti'fl "::.,'. P COIL'al'i. ^. F; P '!: Tl' 'cl the method of E ;; '. ".!' lo 10 B po'ir c: t! .. 'nil' the chloride that coincides 3oc- t, ":; ") 1: '- 1J-n0r-! Èro.t, !! t; -16 (-c ...' rboxylic.

   Ln lines ce ':.'. '): J,. (' :: "cO ':' .. ':(,: 1r xo dl: .J t;,: d-cuè. :: Ü \ t: .1l of the!: 1'nirc described {':; ";":.,' ;;:;.; '1.' \ 10 Ct 0: 1 hydrolyzes the 3 <x¯acfctoxy-û-nor-5oc¯ "irr? '"' E '-! - C112' f'r: t. ";: vÇ 'au:'. O'C'Yl of C'lTtanr, ryc de potasslua 1: ':': n., 1: -> \. \ '' ..l: 1.h '! ol - (; h Cl7Ilï01'ti.'. '. ". t3lS.'Z' lU; l3CE 'operative de l'cK'-rle 10 D, rour çottntr la I: or-.ja ^ r; r.znr ^ 3tt-o.- f .. v ^ "Â7if3 .il .. 3 ((( -t't 't "r :: 1J'QrOrVl" U1 \' lo:; yD-nor-; r (-; ') rj;' r; 1 ne-20-onc À vum> r 01 tio ûe 2 , 0 g of D-'nor'-5 <X-'pr <? 'mne-3 <X'- tjl-; 0-cH '":. ::; 20 C} do tetrahydrofurano and 5 of 2,3- c3.l.yâzo.yz; .4e, add 13, c. W ô' oxychlo: rurc of phoaphoro <We leave it <; elll: 1,.,. ': at room temperature for 3 hours,

  <Desc / Clms Page number 91>

 
 EMI91.1
 then we varnish it '> d "\ (1: 1 1 t ertq iced.

   The reducing precipitate is filtered off and purified by crystallization from an a.cetono-hoxane mixture to obtain the 3. <-Tetrahydro-pyranyloxy-D-nor-5a-pr dcnan-20-one.



  C 16: a ± 6 !! ēd2: t ± tayr2Prn12xl-E-o-r2s! Ae =
 EMI91.2
 163-01
 EMI91.3
 . t-, # M
 EMI91.4
 In a similar manner 4 that described in Example
 EMI91.5
 36 B, 3 ¯tetrahydropyranyloxy-D¯nor-5āprégtian- '20-one is oxidized with m-chloro-parbenzoic acid and isolated
 EMI91.6
 
 EMI91.7
 the product; réaultant, the 16-acdtpta da 3a-tetrahroyyrvtnylo.a:, - ij D-nor-androatllne ... 16?> - ol. It is purified by orintallisaticn z. from a ", 61ang. acetone-Mx" "..



  D. 3a-tetrahydropjrranjrlox-D¯nor-androstan-1 63-ol The mixture is refluxed for 15 minutes at bo mg of 3 -tdtrahydropyranylosor iiadrOBta e 1 6¯; v,;, .03, dissolved in 15 CM "(t1uns 'o oluton,.,:, r) fti: 9 - ,: lJt -'. a methane:!. aqueous has 90 es On ûoaoentï '$'; <ja) ' <M do jcdaetlon at around, la. The residue is poured into water. The residue is filtered off, washed with water and doneboho to give the -tetrnhydropyroolyloxy half 'd $ LHm' (yOf ,, 61i1d: r, .2). -D-nor-tmdrostanc-16ol.

   It was purified by orietnllieation from aqueous methanol oontonant a
 EMI91.8
 drop of pyridine,
 EMI91.9
 3o: ttraydropyrnyloxy-D-nor-ndron3.ne1 "on is oxidized a solution of 500 mg of 3cc-tetrahydl" o-pyranyloxy-D -nor-androotane-1 6j3-ol in, c13 of pyridine with
 EMI91.10
 using a chromic acid-pyridine reagent (from
 EMI91.11
 0.5 g of cr03) in accordance with ",, 1.1. Gold mode.> (3ratory of the J :: x <3J! 11:> the
 EMI91.12
 22. The isolated product is purified by crystallization from
 EMI91.13
 of an acetone-hexane mixture to obtain 3 -té4w-rahydro-pyranyloxy-D-nor-androstane-16-onc.



  F. D-nor-androsterone-
 EMI91.14
 A solution is heated under reflux for 30 minutes
 EMI91.15
 500 ms of 3-tetrahydropyrnyloxy-D-nor-androstane-16-

  <Desc / Clms Page number 92>

 
 EMI92.1
 one in 10 cm of alcohol containing 100 ag ± -toluenesulfonic acid. The reaction mixture is cooled and poured into ice water. The resulting precipitate is filtered, washed well with water and then dried to obtain essential-
 EMI92.2
 lement D-nar - androatane - :, iot.al.-16-ons. It is purified by crystallization from an ether-pentane mixture.



   EXAMPLE 52
 EMI92.3
 D-nor-1-nor-teatoate acetate A. Dwnar-1 -nor-5-.remna-3..0 ... 0-one acetate
In a manner similar to that described in Examples 32 A, 32 0 (operating variant) and 32 D, (1) the acid is treated
 EMI92.4
 3i3-acetoxy¯D-nor 1 9-îiûr¯5¯aïidrostfen - "1 6 | -oarboxyllque (the compound of Example 8 S) with oxalyl chloride, (2)
 EMI92.5
 the resulting chloride of 3-aaetoxy.ï üc19no'dc'atene16 oarboxy, 3 u acid is treated with d, mhyw,; v '' cadmium, and (3) the 3aotoxy-Koy * l9-'nor- '# pr4galne 20 * onô ainei formed medium is hydrolyzed. It t 1. \ 01110 crxtys, ua - ..' m4tha.nO :! .; LQUI, to obtain D * nôr-i9 -nor-5 prégnen0-3jft-. '0.0-ozae' "'' '' ', r, B.

   Acetate G¯D: n2r: 1-uo! 0! T2B! ErOEe- In a manner similar to the glue described in parts A to D of Example 36o (1) Ewnor is chlorinated. 19-nox ... pr6nne â-al2t7-an, (2) the resulting 5, 6-dichloro-D-nor-19-nor- px.canne-i.-o1w20-aze is oxidized by the acid -chloro - perbenzolquer z) the 16-acetate of 5,6-diohloro- thus formed is treated by means of sodium iodide in acetone, and (4) the 16-aotate of
 EMI92.6
 I3-.nor-19wnox-5. andro; tna-3 (3,16E-.diaJ. resulting by a sulfuric acid / chromic acid reagent to obtain D -nor¯19-nor¯teatoeterone aoetate, ::

  ruiik'.Gr 53 J3 nor¯qRiBtrfiidioili h from D-nor-1-nor testosterone acetate In a manner similar to that described in Example
 EMI92.7
 35s D-nor-19-nor-testoeterone acetate (prepared

  <Desc / Clms Page number 93>

 
 EMI93.1
 oommc rewrites. Example 52) to the action of a culture of .Q.Qr: vn} lb! lcte1 "I.; UfIJ tvex. The product resulting from the uit3.11ittx'fT ddorito is isolated to obtain the D-nor -oestradiol / JD-nor- 1 rrl) oarar.in-.r163-. ' o%


    

Claims (1)

EMI94.1 i & y & aiiCA'Jioss Having ainni described our invention and nus reserving to bring any improvements or. modifications which knot n6ocriz; tiirocp we claim 'as our EMI94.2 exclusive and private property EMI94.3 10 / A preparatory process for D-nor..Jtero1: des, craot6ria <! we can see that an etdrolde ruootitud dano lo cycle D, do it one of the positions 1 !? and '7, by a groupa ketot and pnr an el'Ol1}) (') di # where position IX with respect to oe (îroupa cdtot diHaou.8 in it foivrmt inorto organic having a coiapoa6 which can be added l . the double bond V-0 '? .c? 06tbnocl, have photolyod, and that the ION D-nor steroids funi4c make ïriol6L ot, if one wishes lo: U1.cfo: t'lnâa still by two reactions oonnuos do la ohimlo dos ottfroïdas en, .2ialoi ,, iico D-nor de pt (<known roldoc. 20 / D06! 4odeo do iaiso in cover of 00 process presenting the purticularities of Du.1vlnteo, priceo 06pardment EMI94.4 or colon the various pooeibloB combinations EMI94.5 a) one uses comae composa starting a 16-diao-17-keto compound of the cree of androetane or oeetrane, the no. before contains water, ammonia, an alcohol or a pTii ? prltaaire or cccond, 1i: rc, and, from the reaction mixture obtained by photolysis, len D-nor-16p-carboxylic acids, Hviîrc aliaiûor, esters or tuaidea substituted for the szote, ccrif of 1. 'nncroctHne or centering? , rQfJpoctivernttnt, coiit itol ':' and if we undo it, we still make them react co.il * .i indicates; b) the solvent contains water, the imit al product obtained, a D-nor-1 63-carboxylic acid from the endro3tane or oeetran series, is first converted into EMI94.6 corresponding acid chloride, and this acid chloride, if EMI94.7 it was used cc: nmC intcméd1aire for the preparation of other an.Ù t.wuea in JD-nwf of steroids coimue c) for the preparation of D-nor ancestors of known vteroIdce ceria of pregnan, Androstane or <Desc / Clms Page number 95> EMI95.1 -. w \ -. estrane, we use as a starting compound a compound EMI95.2 16-diazo-17-edto of the ceria of androstane, the intermediate D-nor-16-carboxylic acid chloride of the androstane series, by reaction with an organo-metallic compound such as dimethyl-cadrii = or with diazomethane, is converted into a derivative of D-nor-prdgnane, this derivative of D-nor-. Pregnan is then converted either by known reactions in steroid chemistry into other D-nor analogs * of known derivatives of pregnane, or by degradation by oxidation EMI95.3 - of the side chain in position 16, followed 'evontuell'c "".' 'T. and other trMs: t'orr.lD. tiol1t commuted from the chiule due to teroidea, into D-nor analogues of known derivatives of ndl "osta.ne, ot ooo derived from D-nor-andro8tane, if desired and tmnnnforidc by pyrolysis, possibly followed by autroa known foras'ilîionf of the chemistry of ateroids, one an: ÙoG '"\ lf1C D-nor da known derivative of estran; d) for the preparation of D-nor analogs of cte- EMI95.4 known roldeo from the 1 9-iior¯prrfgnane or MetraM series, a 16-diazo-17-keto compood from the Iloontrano series # the acid oliloride D-nor-1 63 is used as the starting compound. - oarboxyliquc inter-addinire of the holiday of 1t oeetrrolt is treaie- forîa6t by reaction with an oompooé orço.l1o ... m6tcù.liqut OtMMc the dimÓthyl-ct: \ dmiwJ1 or with diazomethane, into a derivative of D-nor-nor-preînano, and this derivative of D-nor19''nor-'procn.! MM aat must be transformed by no known reactions of the iro10 dcc eteroids into others tl! llo ... 'Uea D-nor of 19-nor drifts oonn> o. pregnane, or converted by oxidative degradation of the side chain in position 16, possibly followed by other EMI95.5 known changes in chemistry don otaroïdea, in D-nor analog of known derivatives of estrane: e) for the photolysis of the starting compound, ultraviolet rays are used, preferably of a wavelength range close to the visible spectrum, and a liquid transparent to these rays is used as solvent, preferably dioxane or tetrahydrofuran; <Desc / Clms Page number 96> 30 / The application of the above photolysis process EMI96.1 to the transformation of K-diazo-cyclopentanones in condensed rings, in a very general way, into cyclobutane-carboxylic acids with corresponding royal condensates and into functional derivatives of the latter. 4 / A process for the preparation of the [alpha] -diazo-keto-steroids necessary as starting compounds for the process specifies Doua 1 / and 2 /, characterized in that the EMI96.2 The corresponding oe-oximino-keto-steroSdec are reactivated with chloranin, 50 / Un p: cc6dÓ of 16-diazo component release. 17-oeto of the variety of ltandroetane in accordance with paragraph 4 | characterized in that a corresponding derivative of 16-oximino. 1 7-keto-androstane is reacted with ohlorin. 6 / The compounds obtained by the aforementioned processes. 7 / The following varieties of these compounds! a) derivatives of cyclobutane with condensed rings! EMI96.3 b) condensed ring oyolobutane carboxylic acids and their functional derivatives; EMI96.4 0) D-nor-atero! Dea d) D¯nor-oti5roïdeo having the following structure in the D ring: EMI96.5 (I) 14 A EMI96.6 or z, represents two hydro6one atoms, one. radioal lower alooylene, a hydrogen atom and a lower aloyl group ([alpha] - or ss-), a hydrogen atom ot a halogen atom ([alpha] - or ss -), or an atom of hydrogen and a hydroxy group (preferably [alpha] -) which can be esterified, and Z represents one of the following groups: W EMI96.7 OY OV1, 0 = 0 1 #, #, #, <Desc / Clms Page number 97> EMI97.1 inf3 which xi aut an atone of hyurojùno or 1 '.' r6: .. idu 'oV2' R. has an atom cïrkayc; ro; , na 0 '), a hydrocarbon radical which may be non-natural and / or substituted in particular H11 alkyl radical iuW'.rieur, alkenylo i! l: r, ri'J1i :::,:,' wh, ;:, v:, cr -ahloro-6tnynylrj or uropynyle-, and W this one, the OUW) .n6 "v'r.ylc qu1n h uon turn, oeut fître nu1Jcti t.1). by a; 'i ; u:; <,. ' t "t, lv,) H1e or by 1g croup OV3 or by the L: rcm 110 UV'j p11w a radiate /.'- lower alkyl, Vit r V 2 ot v 3 rer> rEÍpcnta.'1t chaouu an 11- : "" ..: from hyàrog no or an acyl group, the group f1.ci!. () stunt 1; pr-: # -] reference derived from a carboxylic acid having jubou *% # '.. "' ,; 0" '1 "" of carbon or - in particular in the case of V 3 - of an 8. r; ... da inorganic such as sulfuric acid or aci1e phOBpho: r1 including opirolactones in which.: radical cï Â: "'' w ;. carbide R is identical U the hydroor.n'bon1e cta part 7 .; and including derivatives 2U (20) - ': lcay..d.'n.at ..: r co co-j f1té: r,.,;! ijl :: - t 100 derivatives 1! fa (16a) ¯alcoylidynodioxy from those of 00 .: D-1.or- Ntxdf3t1 d! 3rri .... f: '; UU.l.t3 A .-- (ii, a-0Ii) and S # - Cl, ot 1, ',', derivative (21) -rJ.ao;, '1.! :: iltï'Sry and 16a (20), 2u (21) -> j1 ¯ alcoylid "no, U 0 XJ' <îo those of these 1-nar - a ûc: ro'ü + s :; dn'j 1 e "'," ü "" .û Where ot W a C.011; o) co. o.,:. ^, du; - ntrr-unlro ;; I1f; and wc, c: .tx¯ "<. .t1.: \ tl tw5t .: 11.1 ,,;) :; 1 t, iO; l 16 | 3 pur un; .r "OR.:, 0; l (Jt -01 ..: - 1, o ' I X rot-rt5 (i - ntf le 2 '..', ±: ti ''; 'i;,! 2t n:> r'ni deduction da l' (1.tofl1fj of hy- t2'C3 ; "{: 71C; actii" 'i a <': o .-: f'o: é qui tiout 6tre ',,' Z'l: G: 1 the double 11ttioon aa do c ': tiJI10H, one particular a r;: r: '. H. "r \ lt.rctZ'o! ;; alooxy or IJ.I: 1ino. co uernicr group which can be rO: Jrlc6 by ujx m.c3.c :, alkyl f) D -nor-oterodos de la urio de 3.'drc'rto.r. 'G)? ci.do .no;: - c: .J.xortz: n-.a Ol. "t, 3-aarw4> J lique and egg ratura 1 FF, ..? coyli, aat cou p7 le D-nor-a..ndro! 3't ':' rJ.f) -, 0.1 â, rzrbox;, r.ate a: at: .ylo; EMI97.2 EMI97.3 h).-nor nxraûtrznA acid. .5-11.-Caxbrxri qS, z + fl i) acid -.ncr.zzdror: L: an + .... one-.1 ;. caxhox;, r..āxc,;, EMI97.4 EMI97.5 j) -nor-.wndroat? acid: ē3-one 1 ± ï, -ac.rl, a :. lique ot its esters 1; :: - :. ùcQyliquCG. ^, or: j: the D¯nor-4- wtdroPtnt. <Desc / Clms Page number 98> EMI98.1 wn.e.16iworzxoxy.ato do radthyle EMI98.2 k) D-110r acid "5-13.1Id.rostèJ1o" '-) ... ol-163 ... EMI98.3 carboxylic; EMI98.4 1) D ... nOl '.. 4 ... o.nàrorrtôno-', 11..diuno ... 1! 3-carboxylic acid; m) D¯nor-4¯androatènē1 1 (α-ol-3 one <- 1 gp-carboxylic 11) acid D-nor-1,4-audrostllù1 ne - ', 11 ... dione- 1 60 -oarboxyliquo jc) acid D -!]. or-1,4,9 (H) '* androata'tyiëne-'3-o: ie'- 16carboYlic p) acid 9cc-fluoro-D-nor-1,4- androstadine- * 11-ol -'-ono-16carboxyliqua; q) & x-methyl-D-nor-1,4-androetadiene- ', 11-dione-166-carboxylic acid G r) 6āfluoro-D-nor - 1, 4-ondrootadlàrve- ,, 11-dione- acid 16-carboy.yliqup. a) D-nor-teetostdrone t) 160: -: lethyl "D..nor-1; ttBto ({terone u) 16 <x-mthyl-'D-nor-1,4-anQroct & diMn6- ') ëp- 01 -, - 0n, ev) 16a-ethynyl-D-nor-tor'tosterone jw), U-nor-5a-androatano-3o ± -ol-16-oni0; x) 3-acid acetate I) ¯ nor ïtēandroatajri9¯3j⯠ol-16oarboxylic y) D-ncr-èa-androatane- 3 -oi-1 66-oarboxylquo jz) 3-acetate D-nor-5- acid androatôno- '0l-16oarboxy11que and its 16-entera ooaaô D-nor-'3-anetoxy- 5 androetene 16 | â-ocrboxylato de aôthyle j au) D-nor-ctéro% de of the otstrane series EMI98.5 ab) D-nor-estrono; EMI98.6 ac) D-nor-oQntrd101; ad) 16α-ethynyl "î) -nor-ooatraiiiaX <Desc / Clms Page number 99> EMI99.1 1 1 oā .: - thyiyl-D-nor-5 1 0) -owrtrbne-1 6i3-ol-3-o'X'.1; ī '') J-: ior-1V-noi'-t ï: to "tironc;? 1J: - <'t: iyuyl-Dn.or-.1 # ncr-tctotëro!' iG; #jb), i "'... ¯,. - 4 :: uc acid D-nc'r'-19-Kor-5- un-tro--: tone-5 .-- ol-1 ô-j-cro j-yliquc #i) <. ' L, "..: r? - '.' 'Thyliq'f de:,; .idf3 D-nor-2 (lC) - 0 <'! '!; r'rti -:"' '- 3-nl <-1 # -. '## irboxylLnup; i \ i) '' - ''. 'r 3--.:s' t: p.i;: c do 1 #: #; # ào l / ¯ncr-1 # ?,. - (1U) -oc: -tr't.ri .. '?:'? - 3 .-- ol16i'-c-trM: y.!.:. U .. '; : t ,: '!' -'- t: '.- -or-.3. "-' t. ': oxy-1,3, (') 0) -or; 'tr': r !. ' -l3-c '; rbo \', 'bzz to do: <? thyle; t \ .z) T, -: cw-.staz ,, ïe :: de l'i {####' r. U3 -lu ¯'yr: - '<' fil) li - 11U + '- il i) .;.>' ;: YJ2: f an) 16u: -:!. Lc.'moyle inf-riour-oxy- D-no11 -;: I "G, '. T: tt; x'a110 j an) 9o: -i'loro-'15-Mt.hyl-D-.nor - !! radniGolono; ao) tio-; at? GOyl-; J-n.ar.nrtan.wol.ont3; an) .10z "-;) xt: ctzl.L: '3of14; aq) D-uor -'. u''c: dtiioolono nr) 1J> -: 3t''thyl-B¯nor-.proanicoiono j ao ) j5-acet ': to da D-nor-5o -' ï ';! c'-3j3-ol'- 0-ot-m; at) 3-ucetate of D nor-! J: -!) r (igiiiRne 3a-ol- EMI99.2 20-ono; EMI99.3 au) 2-riodtato de U'-nor-'5-'r <* '' 3 - '' ol '' '- o "to; av) 3-: xc: ^, c de J-nar-1 - r.arw.jp "rmr.e ... EMI99.4 Ol-20-ono; EMI99.5 aw) 21-diaso-D-iaor 3-acetate 5> -préfitibno- 3d-ol-20-one aux) 21¯dla: jo-D-nor-4¯pr <Wi \ bnē3,20-àionG j ay) 21-D-nor4- prdc7 \ cnQ-21-ol 2 2O- acetate EMI99.6 dione; <Desc / Clms Page number 100> EMI100.1 as) St'oT'f ::, ub! 1tl tu, ';: dnr: 11: ,,:. f, ll' D, a particular d (a. ,, Il .. & nHio: m 15 and 1 ' l,; -i? -n -zou,> c keto and by a (rou.,; t 'cli'tjo en;: 0 :::' "..10n ce r't2 'ru ;,' Ot at this keto group ba) Comice '': '1 â.-âi. :: o. 1? -or'4o do: 1 nériu :! do andrcatane and 3.'or:, trane; bb) 16-.lirs o - v.irontnF '-. a-.n. 17.-oz; tic) 16 ... di: \. o - ': .. rI: .. IrolJtfull ...) a "' ol-17-onG; bd) 1 br; irlf: on.: rir,) d" n , '- 3, 1'! - 'Jionc; be) 16-cr.r: yo - zr.! rocttziN-, 1'l-ü.o> y; bf) 1 hwdi, r.z. ^. ow5-androct.ncz-3: s.Mo1-1't.onc; bfr) 9 H¯, W ".xs: U-1-r; .rtdx'o ;: ti; rit: - '3,1 i, 1'T.-tr .Ono bn) 16-d, aho- '-xtrrdroa tvno.-11 .-- 0l-3,1'I - üi onc; bi) 16-oio.,: 0-1, 4 - &. ndronta <1ii'nl'-3,11, 17 -trione; bj) 16-d ia.:o-4-U:ldr(,Htm(j-11C(-ol-'3, 17 -diono; bk) 16.-dir :: a-1, z1, 9 (11 i .. 'n: ra: rt, rstri: no.-3,1i d, pne; bl) 1 -.dir. ^. O-nxc-Pluaro-11, -txc3xor.-1, - androatadi ?; na -., 1'l - ci.orm; 1) [: 1) 16-difizo-6t (-raethyl-1, -andro: tarl.tno-3,11, 17 EMI100.2 trione. EMI100.3 Q / Un j, roc: ùf de}) rei> aration of therapeutic compOfJitionf3 preej.tunt an activity of hormone IJ t6ro! Do, 00. l '/' !, tered in oc that at least one xn..otuo D-nor of an oteroid phyoio- logically motif is me uouu a convon-'it'io form for uno therapeutic gas administration / Un! JIotla de mica on this i, rrocédé characterized in that the D -nor-l3t6: ro5: do is mixed with au EMI100.4 minus a single pharmaceutical vehicle. EMI100.5 10 / The hor.nonen copoBit1ono obtained by the process specified under Q0 / and 9 /. <Desc / Clms Page number 101> EMI101.1 11 / A hormone composition containing iu 'aoi-, e an analog.': TtCt D-nor of an active at <3roïdo phyoiologic1J.0! 11E; nt and at least a usual pharmaceutical vihieulo. 1 / A eO /: 1rJolJi t.ion of horroone confortas au pan- l .., '' X't.lphtJ 11, cnxrC'L: J.cl3fi in this' .u'ol.Lo contains to the monk. One donation Co.:lnU.3éE3 rq'8c: .. f..iD .3oua 7, alinÓD.1J c) h ay).