CH406208A - Process for the preparation of 3-amino steroids - Google Patents

Description

  

  Process for the preparation of 3-amino steroids In the series of mono-amino asteroids having an amino group in the 3-position and the oxygen in the side chain attached at the 17-position, so far only known , few compounds;

   note, in particular, that which comprises a primary amino group in position 3, in this case funtumine isolated from the Apocynacea Funtumia latifolia by Janot and his collaborators (C.R., 1958, 246, 3076);

   funtumine corresponds to the formula
EMI0001.0032
    Tertio-3-amino steroids carrying a tertiary amino group in position 3 in an undefined steric orientation have also been described, as well as their preparation from intermediate enamines.



  The present invention has been designed, in particular, with a view to enriching the class of 3-amino steroids, more especially in representatives having, in position. 3, their amino group in the beta orientation.

       It also aims to enrich the therapeutic arsenal with low-toxic compounds with a neuroleptic effect, more especially with compounds from the class of sedatives, in particular aggressiveness inhibitors. She    :

  was also designed on purpose. to provide a process for preparing many novel 3-amino steroids, some of them known, especially beta-oriented for the amino group in position 3, and to easily separate the stereoisomers produced.



  The licensee found, first, that by treatment with ammonia or primary or secondary amines and hydrogen, in the presence of hydrogenation catalysts, it was possible to produce,

  readily mixtures of isomeric 3-amino-steroids, in particular rich mixtures of compounds in the bata configuration for the amino group in position 3, from a wide variety of keto-steroids which, if desired, may include one or more substitutes insensitive to the action of:

  hydrogen under the hydrogenation conditions.



       Among the keto 3 steroids that can be used as raw materials, mention will be made, in particular, of those which have an OH, CO-CH ,,, CO-CH20H, CHOH-CH20H or CO-CH20-COCH3 group in the 17 -and position, optionally, an oxygen atom or an OH group in position 11,

   more particularly those which correspond to the general formula (I)
EMI0001.0144
  
    R
<tb> 311
<tb> CHsI
<tb> O <SEP> H <SEP> (I)
<tb> (or <SEP> A4.5) in which the symbols have the following meanings
EMI0002.0001
  
    Compound <SEP> N <SEP> R <SEP> R '<SEP> Configuration <SEP> Current <SEP> name <SEP> of the <SEP> compound
<tb> in <SEP> 4.5
<tb> the <SEP> -CO-CH3p, <SEP> ... <SEP> Ha <SEP> H2 <SEP> A4.5 <SEP> Progesterone
<tb> <B> lb </B> <SEP> -CO-CH3p, <SEP> ... <SEP> Ha <SEP> H2 <SEP> ....

   <SEP> H5 <SEP> Allo-pregnane-dione
<tb> <B> the <SEP> -CO </B> <SEP> -CH3 (3, <SEP> ... <SEP> Ha <SEP> H2 <SEP> -H5 (3 <SEP> Pregnane; dione
<tb> Id <SEP> -0H (3, <SEP> ... <SEP> Ha <SEP> H2 <SEP> .... <SEP> H5a <SEP> Androstanolone
<tb> le, <SEP> -OH <SEP> P, <SEP> ... <SEP> H <SEP> a <SEP> H2 <SEP> A4,5 <SEP> Testosterone
<tb> <B> if </B> <SEP> -CO-CH20HP, <SEP> ... <SEP> H <SEP> a <SEP> H2 <SEP> A4.5 <SEP> Deoxycorticosterone <SEP> (DOC)
<tb> Ig <SEP> -CO-CH20HP, <SEP> ... <SEP> Ha <SEP> H2 <SEP> - <SEP> H5 (3 <SEP> Hydro-Doc
<tb> Ih <SEP> -CHOH-CH20H <SEP> H2 <SEP> - <SEP> H5 (3
<tb> (OH <SEP> 20 (3) <SEP> ... <SEP> Ha
<tb> Ii <SEP> -CO-CH20COCH35, <SEP> H2 <SEP> A4.5 <SEP> Acetate <SEP> of <SEP> DOC <SEP> (DOCA)
<tb> ... <SEP> Ha
<tb> Ii <SEP> -CO-CH20COCH3 (3, <SEP> H, <SEP> -H5 (3 <SEP> Hydro-DOCA
<tb> ... <SEP> Ha
<tb> Ik <SEP> -CO-CH20HP, <SEP> ...

   <SEP> = <SEP> O <SEP> A4.5 <SEP> Cortisone
<tb> OHa
<tb> It <SEP> -CO-CH @ OCOCH3n, <SEP> -0H5 <SEP> A4.,; Hydrocortisone <SEP> Acetate <SEP>
<tb> ... <SEP> OHa A wide variety of amines can be used, in particular ammonia,:

  primary or secondary lower aliphatic amines, saturated cyclamines such as pyrrolidine, porpholine, piperidine, N-alkyl piperazines or araliphatic amines such as benzylamine.



  In general, the -amino compound (ammonia also being considered as an amino compound) is used in excess relative to the 3-keto-sterdide to be transformed. In the case of non-volatile amines, a slight excess,

          up to 10%, is sufficient. In the case of volatile amines (including ammonia), the excess may be a little larger.



       As catalysts, it is possible, in the first place, to use palladium, preferably mounted on a support, in particular on carbon black; for example, carbon black with 5% palladium is suitable.

   Platinum can also be used, in particular in oxide form, which can also be mounted on a support, for example on carbon black. Raney ide nickel can also be used.



  The 3-keto-steroid, amine and the catalyst are preferably distributed in an inert diluent under the conditions of execution of the hydrogenation.

       In this regard, the usual diluents for catalytic hydrogenation can be used. The lower aliphatic alcohols, which do not need to be strictly anhydrous, are particularly recommended.

   However, other organic solvents can be used, for example ethyl acetate, ether or dioxane. The amount of diluent used is not a decisive factor for success: and its choice is dictated above all by considerations of operational convenience.

   In general, from 5 to 50 parts by weight of diluent to one part by weight of 3-keto steroid can be used without these limits being overriding.



  It is generally sufficient, and convenient, to carry out the hydrogenation without pressure; however, it can also be carried out in apparatuses designed to maintain a certain hydrogen pressure, preferably below 10 kg / cm2. In general, the operation is carried out at temperatures below the boiling point of the diluent, preferably from 0 to 650,

   most often at laboratory temperature; in some cases it may be advantageous to cool to work below room temperature, in other cases to heat.

   As a general rule, the hydrogenation can be continued until the absorption of hydrogen has ceased or until the absorption of the calculated quantity, taking into account, if necessary, what is necessary to saturate any double bonds and to produce or, if desired, to avoid hydrogenolysis (for example,

      in the case of benzylamine, for the splitting of the benzyl group). Under these conditions, the reaction time can vary from a few hours to a few days.

      A marked advantage of the process forming the object and of the invention is that it makes it possible to produce, in not insignificant and often predominant quantity, compounds with a 3-amino group in 0-orientation, while, for example,

       the application of the Leuckart method only leads to equatorial oriented compounds and is practically applicable only to sterolic monocetones. Compared to the formic reduction of enamines,

      the -new .procédé offers the advantage of being operative with amines .other than pyrrolidine.



  By virtue of the mild hydrogenation conditions defined above, the reduction, which might have been feared, of carbonyl groups other than the group situated in the 3-position and which can be avoided completely or to a large extent, is possible. be included in the starter 3-keto steroid.



  In many cases an isomer can be isolated from the hydrogenation product, in this case the 3 (3) isomer, to the exclusion of another, by simple crystallization.



  When the amine used is benzylamine, it is found that, if the hydrogenation is not stopped after absorption of the theoretical quantity of hydrogen to produce the b @ enzylamine derivative in 3, the absorption con tinue, especially if one operates at a temperature above ambient temperature.

   Hydrogenalysis then takes place with cleavage of the benzylamine radical and formation of the corresponding primary amine.



  The invention comprises, in particular, .the corresponding embodiment, that is to say, in the case of b.enzylamine, the hydrogenation extended to the stage of hydrogenolysis, which makes it possible to produce very:

  easily, the corresponding primary amines, especially those which. have a configuration (3 for the group N112- Some of these primary amines, offer difficulties of isolation because of their instability in the base state, can be as a result of a condensation of the NH group with a CO group when there is another in the molecule.

    



  However, the licensee has found it particularly convenient, to isolate the primary amine in the pure state and with a good yield, to react with an appropriate aldehyde to -transform it into a Schiff base, to provided that it is then easy, from this base, to regenerate the primary amine.

   In this connection, benzoic aldehyde has been found to be suitable; the return to the primary purified amine can be carried out either by hydrogenation of the Schiff base,

      or by hydrolysis using a mineral acid. This mode of production and purification of the primary amine is, in fact, an interesting means of preparing the latter, although one can also,

  prepamer by direct reaction with ammonia and hydrogen but with greater difficulties of isolation and purification. These difficulties turn out to be less when, in the case of unsaturated 3-keto steroids, such as progesterone, one starts from the corresponding reduced compounds, for example pregnane-dione.



       The process described above has made it possible to prepare a certain number of new 3-amino-steroids and derivatives of 3-amino-steroids, with saturated A, B, C and D rings, in this case the compounds corresponding to the general formula II
EMI0003.0127
         in which the symbols R1, R2, R3, R4, R ,;

      and Am have the following meanings Rl = OH, CO-CH3, CHOH-CH3, CO-CH20H, CHOH-CH20H. CO-M -O-CO-CH3 R2 = H or OH, Ri and R2 cannot simultaneously mean OH,
EMI0003.0148
    Am representative according to case a)

       an NH 2 radical or the -N = CH -Ar type imine derived therefrom, Ar being an optionally -substituted benzene nucleus;

    b) a lower aliphatic, araliphatic or cyclanic amine residue, saturated, without substituents or with various substituents, which may optionally constitute a heterocycle with the nitrogen atom;

    c) a lower aliphatic acid -amide function, derived from the primary and secondary amines found defined in paragraphs a) and b) above;

    d) an amine group of a type defined above in paragraphs a) and b), salified or optionally transformed into an ammonium compound. quaternary;

    and, inter alia, the compounds for which the above symbols have the meanings indicated in the following Table I;

   in this table and in the rest of the description, (tube) indicates that the melting point, uncorrected, was measured with the capillary tube,. (K) that it was. on the Kofler bench and ( micr.), under a microscope.
EMI0004.0001
  
    <I> Table <SEP> 1 </I>
<tb> Position <SEP> 17 <SEP> Posi- <SEP> Position <SEP> 3 <SEP> Posi Compounds <SEP> tion <SEP> 1;

  1 <SEP> tion <SEP> 5 <SEP> Point
<tb> N <SEP> of <SEP> merge
<tb> R1 <SEP> R @ <SEP> R3 <SEP> Am <SEP> H <SEP> H
<tb> <B> \ j </B> <SEP> (3 <SEP>.,., <SEP> a <SEP> - @ <SEP> 132-133e
<tb> Ha <SEP> -COCH3 <SEP> .... Ha <SEP> H2 <SEP> -N <SEP> I
<tb> (tube)
<tb> IIb <SEP> -COCH3 (3 <SEP> .... Ha <SEP> H2 <SEP> -N (CH3) 2 <SEP> (3 <SEP> .... <SEP> a <SEP > - (3 <SEP> 96- <SEP> 971,
<tb> (tube)
<tb> IIc <SEP> -COCH3 (3 <SEP> .... Ha <SEP> H2 <SEP> -N <SEP> ",. <SEP> a <SEP> -P <SEP> 121-122
<tb> (tube)
<tb> IId <SEP> -COCH35 <SEP> .... Ha <SEP> H2 <SEP> -N <SEP> @O <SEP> (3 <SEP> .... <SEP> a <SEP> -P <SEP> 144-145
<tb> (tube)
<tb> IIe <SEP> -COCH3 (3 <SEP> .... Ha <SEP> H2 <SEP> <B> .... </B> <SEP> N @ Oa <SEP> -p <SEP > -p <SEP> 136-137
<tb> (tube)
<tb> 162-164o
<tb> IIf <SEP> <B> -COCH3p </B> <SEP> .... Ha <SEP> H2 <SEP> -N <SEP> N-CH3 <SEP> (3 <SEP> ... .

   <SEP> a <SEP> ._ <SEP> (3 <SEP> (pipe)
<tb> and
<tb> 168-169
<tb> IIg <SEP> -COCH3 (3 <SEP> .... Ha <SEP> H2 <SEP> .... N / <SEP> N-CH3a <SEP> - @ <SEP> -P <SEP > 147-149
<tb> (tube)
<tb> IIh <SEP> -COCH3 (3 <SEP> .... Ha <SEP> H2 <SEP> -NHCH3 <SEP> (3 <SEP> .... <SEP> a <SEP> - [3 <SEP> 81- <SEP> 820
<tb> (tube)
<tb> IIi <SEP> -COCH3 (3 <SEP> .... Ha <SEP> H2 <SEP> -NHCH2- <SEP> @@ <SEP> (3 <SEP> .... <SEP> a <SEP> - (3 <SEP> 138-140
<tb> (tube)
<tb> IIj <SEP> <B> -COCH3p </B> <SEP> .... Ha <SEP> H2 <SEP> <B> .... </B> <SEP> NHCH2- @ a < SEP> - (1 <SEP> - (;

   <SEP> (2 <SEP> j5
<tb> K
<tb> IIk <SEP> -COCH3p <SEP> .... Ha <SEP> H2 <SEP> -NH2 <SEP> (3 <SEP> .... <SEP> a <SEP> - (3 <SEP > 120-.122o
<tb> (tube)
<tb> IIl <SEP> -COCH3 (3 <SEP> .... Ha <SEP> H2 <SEP> <B> .... </B> <SEP> NH2a <SEP> - (3 <SEP> - [3 <SEP> 123-125o
<tb> (tube)
<tb> IIm <SEP> -COCH3 (3 <SEP> .... Ha <SEP> H2 <SEP> -NH2 <SEP> (3 <SEP> .... <SEP> a <SEP> ... . <SEP> a <SEP> 157-158
<tb> (tube)
<tb> lin <SEP> -COCH3 (3 <SEP> .... Ha <SEP> H2 <SEP> -N <SEP> = <SEP> CH- <SEP> (3 <SEP> .... < SEP> a <SEP> - (3 <SEP> 197-198
<tb> (tube)
<tb> lIa <SEP> <B> -COCH3p </B> <SEP> .... Ha <SEP> H2 <SEP> -N <SEP> = <SEP> CH <SEP> - @ <SEP> ( 3 <SEP> .... <SEP> a <SEP> ....

   <SEP> a <SEP> 202-204o
<tb> (tube)
<tb> IIp <SEP> -COCH3 (3 <SEP> .... Ha <SEP> H2 <SEP> <B> .... </B> <SEP> N = CH- @ a <SEP> - (3 <SEP> .... a <SEP> 200-202o
<tb> (tube)
<tb> Ilq <SEP> -COCH3 (3 <SEP> .... Ha <SEP> H2 <SEP> -N <SEP> = <SEP> CH- <B> \ - </B> OCH3 <SEP> (3 <SEP> .... <SEP> a <SEP> <B> -P <SEP> 1 </B> (tube)
<tb> IIr <SEP> -COCHSP <SEP> .... Ha <SEP> H2 <SEP> -N <SEP> = <SEP> CH- @ <SEP> OCH3 <SEP> (3 <SEP> .. .. <SEP> a <SEP> .... <SEP> a <SEP> 193-194
<tb> (tube)
<tb> IIs <SEP> <B> -COCH3p </B> <SEP> .... Ha <SEP> H2 <SEP> -NH-CH2- <B> / # - </B> OCH3 <SEP> [3 <SEP> ....

   <SEP> a <SEP> - (i <SEP> 124-125
<tb> (tube)
EMI0005.0001
  
    Position <SEP> 117 <SEP> Posi- <SEP> Position <SEP> 3 <SEP> Posi Compounds <SEP> tion <SEP> I1 <SEP> tion <SEP> 5 <SEP> Point
<tb> N <SEP> of <SEP> merge
<tb> Ri <SEP> R2 <SEP> R3 <SEP> Am <SEP> H <SEP> H
<tb> <B> \ _l </B> <SEP> I <SEP> [3 <SEP> (?) <SEP> .... <SEP> a <SEP>, ... <SEP> a < SEP> 179-180
<tb> IIt <SEP> -OH <SEP> (3 <SEP> .... Ha <SEP> H2 <SEP> -N
<tb> (tube)
<tb> 0
<tb> IIu <SEP> -OH <SEP> (3 <SEP> .... Ha <SEP> H2 <SEP> -N <SEP> [3 <SEP> (?) <SEP> .... < SEP> a <SEP> - @ <SEP> (?) <SEP> 2,34-23 <SEP> 6
<tb> IIv <SEP> -OH <SEP> (3 <SEP> .... Ha <SEP> H2 <SEP> -N (# 3) 2 <SEP> P <SEP> (?) <SEP>. ... <SEP> a <SEP> .... <SEP> a <SEP> 172-1740
<tb> (tube)
<tb> IIw <SEP> -COCH20H <SEP> (3 <SEP> .... Ha <SEP> H2 <SEP> -N <SEP> I <SEP> (3 <SEP> _...

   <SEP> a <SEP> -P <SEP> 152-154
<tb> <B> j </B>
<tb> (tube)
<tb> IIx <SEP> -CHOH-CH20H <SEP> (3 <SEP> .... Ha <SEP> H2 <SEP> -NH2 <SEP> (3 <SEP> .... <SEP> a < SEP> - (3 <SEP> 132-136o
<tb>, (20 <SEP> [3 <SEP> for <SEP> OH) <SEP> l (K)
<tb> IIy <SEP> -CHOH-CH20H <SEP> (3 <SEP> .... Ha <SEP> H2 <SEP> -N <SEP> = <SEP> <B> CH - // </ B > <SEP> (3 <SEP> .... <SEP> a <SEP> - (3 <SEP> 156K58o
<tb> (20 <SEP> (3 <SEP> for <SEP> OH) <SEP> (K)
<tb> IIz <SEP> -COCH2-O <SEP> .... Ha <SEP> H2 <SEP> -NH2 <SEP> (i <SEP> .... <SEP> a <SEP> - (3 <SEP> 176-178
<tb> -COCH3 <SEP> (3 <SEP> (pipe)
<tb> IIaa <SEP> -COCH2-O <SEP> .... Ha <SEP> H2 <SEP> -N <SEP> = <SEP> CH- <SEP> - [3 <SEP> .... <SEP> a <SEP> - (3 <SEP> 132-134o
<tb> -COCH3 <SEP> (3 <SEP> (pipe)
<tb> Ilab <SEP> -COCH20H <SEP> (3 <SEP> <B> .... </B> <SEP> OH <SEP> = <SEP> O <SEP> ....

   <SEP> N (CHs) 2 (HCl) <SEP> g <SEP> ^^ "<SEP> ^" "<SEP> g <SEP> 2'6'5
<tb> (K)
<tb> IIac <SEP> -COCH20H <SEP> (3 <SEP> .... OHa <SEP> = <SEP> O <SEP> - <SEP> <B> <I> N </I> </ B> <SEP> I <SEP> (HCl) <SEP> 265
<tb> <I> Mv <SEP> @v </I>
<tb> Ilad <SEP> -COCH20H <SEP> (3 <SEP> .... OHa <SEP> = <SEP> O <SEP> ....

   <SEP> N <SEP> I <SEP> 1 / 2H <I> 2 </I> O <SEP> 228-230
<tb> (twbe <SEP>)
<tb> <B> \ -l </B>
<tb> Ilae <SEP> -COCH, -O <SEP> .... OHa <SEP> -OHP <SEP> - <SEP> NH2 @@ <SEP> no <SEP> idét.
<tb> <B> -COCHs </B> <SEP> (3
<tb> IIaî <SEP> -COCH2-O <SEP> .... OHa <SEP> -OHP <SEP> --N = CH-ü @ <SEP>. @ ... @ <SEP>. @. .- @ <SEP> 204-2050
<tb> -Ci <SEP> (pipe)
<tb> 102-104o
<tb> (tube)
<tb> IIag <SEP> -COCH3 (3 <SEP> .... Ha <SEP> H2 <SEP> <B> .... </B> <SEP> N_ <SEP>} <SEP> a < SEP> - (I <SEP> .... a <SEP> 106-108
<tb> (K)
<tb> IIah <SEP> -COCH3 <SEP> (3 <SEP> .... Ha <SEP> H2 <SEP> -NH-COCH3 <SEP> (3 <SEP> .... <SEP> a. <SEP> - (3 <SEP> 1;

  27-1280
<tb> (tube)
<tb> 188-190
<tb> II @ ai <SEP> -CHOH-CH2OH <SEP> (3 <SEP> .... Ha <SEP> H2 <SEP> <B> <I> _N \ <SEP> j </I> < / B> <SEP> (3 <SEP> .... <SEP> a <SEP> - (3 <SEP> (pipe)
<tb> (20P <SEP> for <SEP> OH)
<tb> IIaj <SEP> -CO-CH20 <SEP> .... Ha <SEP> H2 <SEP> -NH-COCH3 <SEP> (3 <SEP> .... <SEP> a <SEP> - (3 <SEP> 129-131
<tb> -COCHs <SEP> (3 <SEP> (pipe)
<tb> 116-118o
<tb> Ilak <SEP> -COCH3 <SEP> (3 <SEP> .... Ha <SEP> H2 <SEP> ....

   <SEP> @ # <SEP> a <SEP> - (3 <SEP> - (3 <SEP> {.tube <SEP> and <SEP> K) Also taken into account are the salts that the compounds described below. above form possibly with mineral and organic acids which are acceptable from a pharmaceutical point of view, in particular with hydrochloric, fumaric, maleic and ascorbic acids,

   as well as - for tertiary amines
EMI0006.0009
  
    <I> Table <SEP> 2 </I>
<tb> Position <SEP> 17 <SEP> Position <SEP> 11 <SEP> Position <SEP> 3 <SEP> Position <SEP> 5
<tb> Compound <SEP> Point
<tb> Ri <SEP> Rs <SEP> R3 <SEP> Am <SEP> H <SEP> H <SEP> from <SEP> merge
<tb> 127-129
<tb> (tube)
<tb> IIA <SEP> COCH3 <SEP> (3 <SEP> .... H <SEP> a <SEP> H @ <SEP> - <SEP> <B> <I> N </I> </ B> <SEP> (3 <SEP> .... <SEP> a <SEP> .... <SEP> a <SEP> 128-130o
<tb> (K)
<tb> IIB <SEP> COCH3 <SEP> (3 <SEP> .... H <SEP> a <SEP> H., <SEP> -N (CH ;;) @ <SEP> r3 <SEP>. ... <SEP> a <SEP> .... <SEP> a <SEP> 56- <SEP> (pipe)
<tb> <B> HIC </B> <SEP> COCH3 <SEP> (3 <SEP> <B> .... </B> <SEP> H <SEP> a <SEP> H. <SEP> .... NH;

  ,) <SEP> a <SEP> - <SEP> [3 <SEP> .... <SEP> a <SEP> 120-l24
<tb> (tube)
<tb> 157-159
<tb> IID <SEP> COCH3 (3 <SEP> .... Ha <SEP> H. <SEP> .... N <SEP> <B> \ J </B> <SEP> a <SEP> - (3 <SEP> - (3 <SEP> (K) The study .des IR spectra of the amino-steroids prepared according to the present invention made it possible to highlight a certain number of characteristic bands for each type of steric isometry in positions 3 and 5.

   Most of these bands differ depending on the nature of the amino residue, and are no longer recognizable if the ateroid is studied in the form of a salt or if the amino residue is strongly chelated. Nevertheless, valuable information has been gained in the course of this work from the study of the IR spectra of isolated amino steroids.



  In particular for the primary amines, one observes, in the region of 6.25-6.30 It (deformation of NH) a slightly intense band, but clear, in only the laminated steroids in 3 a,. 3-amino steroids (3s have no or very little absorption in this region.

   In addition, in the region of 14.70 µ, a band characteristic of only compounds with an axial NH 4 group is observed, totally absent in the equatorial derivatives.



  For tertiary amines I) In the region of 7.0-7.6 <B> [t </B> (absorption probably due to vibrations
EMI0006.0043
  
    \ <SEP> \ <SEP> I
<tb> <B> -C- <SEP> H </B> <SEP> du <SEP> .reste <SEP> j <SEP>% <SEP> - <SEP> H) we observe in -all cases a doublet for compounds having the amino group in an equatorial position (hence -H axial), while, if the amino group is in an axial position (therefore -H equatorial),

          there is a triplet. It is obvious that the spectra determined in suspension in the n: ujol cannot give any valid indication in this region. only - quaternary ammonium compounds of said bases, in particular iodomethylates.



  In addition, the method which is the subject of the invention provides a new route of access to the compounds listed in Table 2 and corresponding to the same formula (II) with the following meanings for the symbols. II) In the region between 8.80 and 9.20 it, there are only indications for steroids with a pyrrolidinated residue: in 3: a strong absorption band is observed at 9.20 it when the pyrrolidinated residue is axial.

   In addition, there is a strong absorption at 8.92u in the compounds with pyrrolidi residue: born oriented in 3 (3, slums that equatorial pyrrolidino-3a-steroids (H-5 (3) absorb intensely around 8.85 8) , 80 u.



  III) In the region of 11.35-11.38 u, most tertiary amino group steroids absorb, but equatorial amines have a band at 11.36-11.38 u, while the band of amines axial values is between 11.50 and 11,

  60 u. This is valid regardless of the spectrum recording mode (solution in CS. Or CHCl3 or even suspended in nujol).



  In addition, the study of IR spectra often gives very precise indications on the configuration in 5 (a or (3) of keto-20-stero: ides,: because the presence of the Andean function ien 3 does not prevent see the characteristics of normal or viola ketones in the region between 1300 cm-1:

  and 900 cm-1 at least when there are: not too many interactions due to other groups (case of .amino-steroids derived from cortisone) or to the solvent (chloroform ).



  The compounds listed in Tables 1 and 2 were subjected to numerous tests aimed at demonstrating their pharmacodynamic properties and in particular their activity on the central nervous system.

   Among the tests used are toxicity in mice, changes in the behavior of mice, rats and cats, disorders of equilibration functions, the onset of catatonia, anorectic power, changes in blood pressure. aggressive behavior (rat vis-à-vis the rat, cat vis-à-vis the mouse),

      action on spontaneous motricity or motricity caused by benzeldrin, antagonism vis-à-vis the catatonizing action of prochlorperazine, action on behavior, of conditioned animals.



       These bodies have been administered as a base or as salts, parenterally or orally.



  In general, compounds IIk, IIl, IIm, IIz and IIC, comprising an NH @ group in position <B> 3, </B> have been shown to be sedative. The compound IIk shows exceptional properties.

   It has moderate toxicity (1P LD50 175 mg / kg, oral LD50 1 g / kg). By the intraperitoneal route it calms the aggressiveness of rats at a dose of 15 mg / kg and that of cats at 2.5 mg. kg and this action persists for 24 hours. At doses of 10 and 20 mg / kg in cats, the sedative action lasts several days. At these doses, the product does not modify the arterial pressure or the heart rate.

   To alter motor skills and balance, doses of 50 mg / kg should be achieved. At high doses, 100 mg / kg, there is no catatonia.



  This product IIk potentiates, on the other hand, the action of various sedative or tranquilizing substances. In fact, when an inactive dose (1 mg / kg) of this compound is administered to the rat simultaneously with an equally inactive dose of acepromazine (1 mg / kg) or of chlorpromazine,

      a powerful sedating effect is produced.



  Other interesting compounds are compound IIaa (benzylidene-amino derivative of hydro-DOCA Ij) which has been shown to be sedative and compound IIai (pyrrodidine derivative 3 (3 of preb ane-5 G-1.ial-20 (321) which was shown to be clearly sedative.



  The following examples illustrate the invention. The IR spectra were recorded on a BAIRD double beam spectograph, with C1Na prisms, in compensated solutions (CHC13, CS,) or in suspension in nujol, except for certain steroids melting below 135 which were sometimes examined. in a thin layer, after melting and resolidification on the rock salt slide (micro-cell).



  References such as Ia, IIa refer to the formulas and tables presented above.



  <I> Example 1 </I> Pyrrolidino-3 [3 and -3a pregnane-5a ones-20 (IIA and IIag) In an apparatus for hydrogenation under ordinary pressure, provided with an electromagnetic stirrer, 3, 15 g (0.01 mole) of pregaane-5a dione- 3.20 (lb) (melting point = 117-119), 0.9 ml of pyrrolidine (0.011 mole), 105 ml of absolute alcohol and 0,

  3 g of palladium deposited on charcoal, at 5% Pd. The hydrogenation of the mixture is carried out at laboratory temperature. The theoretical amount of hydrogen (224 ml) is absorbed in about an hour.

    The catalyst is then filtered off, the filtrate is evaporated to dryness, the residue is taken up in petroleum ether and allowed to crystallize. 1.5 g of a white product are obtained, melting at 120-1250 (tube) and which is recrystallized from petroleum ether.

   It is pyrrolidino-3P pregnane-5a one-20 (IIA); melting point l27-129 (tube) optical rotation:

       [a] D, 5 = + 83.50 (concentration = 1% in chloroform,

          which -does not give depression by mixed fusion -with the base prepared by formic reduction of the pyrrolidinated enamine of pregnane-5a-dione-3,20 (Ib) and has an identical IR spectrum (determined in;

  solution in CSZ). This blase, added to an aqueous solution of fumaric acid, gives rise to an acid fumarate which is recrystallized from water; white crystals, melting point = 72-750 (tube).



  The ethero-petroleum mother liquors after isolation of the amine-3a are evaporated to dryness. The residue is dissolved in alcohol.

   1 g of fumaric acid is added to the solution. The fumarate which arises is precipitated by addition of ether and petroleum ether. It is filtered and @on recrystallized from isopropanol and then from water.

   0.3 g of C.sub.2SH410N, C4H404 acid fum.arate, melting point (tube): 209-2120 is thus isolated.



  From this fumarate, the corresponding base is liberated by ammonia. After extraction with ether, washing the ethereal solutions with water, drying over SO4Naz, filtration and evaporation of the solvent, the regenerated amine is recrystallized from methanol.

         It is pyrrolidino-3a pregnane-5a one-20 (I1ag). Melting point (tube): 102-1040. Rotary power [a] D _ -h 82.60 (concentration: 0.5% in chloroform).

   This product does not give a melting depression mixed with the base prepared by pyrroldnea aminolysis of tosylate.
EMI0007.0234
    The IR spectra, determined as they are after fusion, are also superimposable.



  <I> Example 2 </I> Pyrrolidino-3p and -3a pregnane-5 (3 ones-20 (II, a and Hak) a) from pregnane-5e dione-3,20 (Ic) The operation is carried out exactly as in the case of the H5a derivative, from 3.15 g (0.011 mole) of pregnane-5 (3-dione-3.20 (Ic)

          but instead of evaporating to dryness after filtration of the catalyst, the mixture is concentrated to 25 cm3 and the mixture is allowed to crystallize. Thus, by cooling, a first jet of pyrrolidino-3 (3 pregnan-53 one, 20 (IIa) (white crystals, melting point (tube): 132-1330) is obtained; weight:

   1.35 g) then, by concentration of mother liquors after filtration, 0.15 g of the same product, melting point (tube): 131 132a; optical rotation: [a] D, 5 = -I- 98.10 (concentration: 1% in CHC13).



       This base, in solution in anhydrous acetone, gives rise, by addition of fumaric acid, to an acid fumarate. The latter is recrystallized from anhydrous acetone <B>; </B> melting point (tube) 198-201.



  The alcoholic mother liquors, after isolation of the pyrrodidino-33 pregnane-5p one-20, are salted with fumaric acid. The fumarate is precipitated with a mixture of ether and petroleum ether. The crystals obtained are filtered off and recrystallized from acetone, then from water. 0.7 g of a fumarate is thus isolated (melting point (tube) 172-174).

   The base is liberated from the latter with ammonia as was stated in Example 1 and the regenerated amine is recrystallized from petroleum ether. 0.3 g of a compound (melting point 116-1180 (tube)) is thus isolated which does not give rise to depression by melting mixed with pyrrolidino-3a pregnane-53 dione-3.20, ILak. IR spectra,

   determined in carbon sulphide, are moreover superimposable.



  from progesterone (la) 5.2 g of progesterone (la), <B> 175 </B> ml of alcohol, absolute, are introduced into an apparatus for hydrogenation under ordinary pressure, fitted with an electromagnetic stirrer and 0.5 g of 5% palladium on charcoal. In 20 minutes, at room temperature, the theoretical amount of hydrogen is absorbed.



  It is filtered, the filtrate is evaporated to dryness and then the residue is taken up in 20 ml. of ethanol and left to slow crystallization.

   2.65 g of a white product are isolated in this way (melting point: 128-1330 (tube) which, recrystallized from ethanol, melts at 132-1330 (tube) and does not give any depression by melting. mixed with pyrrolidino-3p pregnane-5p one-20 prepared by method a.

   The IR spectra, determined in CS. ,, are moreover superimposable. <I> Example 3 </I> Dimethylamino-33 pregnane-5p one-20 (Ilb) The starting point is a mixture of 0.0033 mol, or 1.05 g, of pregnane-5p dione-3.20 (1c ). with 30 ml of absolute alcohol,

   5 ml of alcoholic solution of dimethylamine at 20% and 0,

  1 g of 5% palladium on charcoal. Hydrogenation is carried out at ordinary pressure and at 40-45, using a heating electromagnetic stirrer. The reaction is very slow (5 to 6 hours).

   As soon as it is finished (after fixing of 74 cm3 of hydrogen), filtered to remove the catalyst, the filtrate is evaporated to dryness, taken up in absolute alcohol and 0.4 g of fumaric acid is added. The fumarate which arises is filtered and recrystallized from alcohol; weight 0.6 g.

   It is <B> </B> dimethylamino-33 pregnan-53 one-20 acid fumarate; its melting point (tube) is 212-, 2140, its optical rotation [a] 24> 5 = -i- 72.10 (concentration: 1% in CH30H).



  The base released from the acid fumarate according to the usual technique melts at 96-97 (tube). Examination of the IR spectrum of this amine, determined in solution in CS. ,,. Reveals the presence of the characteristic bands of ketones at 20, with normal configuration at C5 (R.

   Nor man Jones and codl. ; J. bitter. chem. Soc., 1955, 77, 651) with a tertiary amino group in 3 axial configuration (therefore 3) (triplet in the region of 7.2-7, -6 R, and absorption at <B> 11, 60 </B> ti with a minimum of 11.40 <I> Example 4 </I> Morpholino-33 and -3a pregnane-53 one-20 We start with a mixture of pregnane-53 dione-3.20 (1c ) (0.02 mode)

   dry piperidine (2.4m], 0.022 mol), 5% palladium on charcoal (0.1 g) and absolute alcohol (50 ml) which is hydrogenated at ordinary pressure, at 500, with the help of a heating electromagnetic stirrer. The reaction is very slow. It takes more than 24 hours to be complete.

   After filtration and concentration, the piperidino-33 pregnane-53 one-20 (IIc) crystallizes. Weight: 3.60 g; melting point (tube) 116-119. It melts at 121-122 (tube) after recrystallization from absolute alcohol.

   Optical rotation [a] D = -I- 94.2 () (concentration: 1% in chloroform). <I> Example 5 </I> Morpholino-33 and 3a pregnane-53 one-20 (Ild and IIe) The hydrogenation is carried out exactly as in Example 4, replacing the piperidine with 1.9 g (0.022 mole) from:

  dry morpholine. Absorption is even slower. In 34 hours, only 328 cc of hydrogen was fixed out of the 448 cc predicted by theory. Also, after filtration and evaporation of the treated wire to dryness under vacuum, the residual oil is dissolved in 5 ml of acetic acid. Diluted with 250 ml of water. The amines remain in solution in the form of salts and the non-basic products (2.4 g) can be extracted with ether. The aqueous solution of amine acetates is then basified and the liberated bases are extracted with ether.

   The extraction ether is washed with water and dried over SO4Na 3. After filtration and evaporation to dryness, the colorless oil obtained (weight 5.2 g), taken up in petroleum ether, gives up, by slow crystallization, 3.4 g of a white product, melting point: 142-1440 (K), which is recrystallized from petroleum ether.

   It is morpholino-33 pregnan-53 one 20 (Ild); melting point (tube): 144-145;

    optical rotation: [a] D = -f- 89.70 (concentration 1% in chloroform). Ethereal mother liquors:

  Petroleum products are concentrated to dryness and the residue obtained (p = 1.6 g) is salified with a solution of 0.5 g of fumaric acid in 4.5 cm 3 of isopropyl alcohol. A gelatinous fumarate is thus obtained, which is crystallized several times from acetone.

   Finally, 1.0 g of white crystals are obtained; , melting point (tube) 164-166o (dec.). This fu.marate is decomposed .with ammonia and the liberated base, isolated according to the usual technique, is recrystallized from light petroleum ether.

   It is morpholino-3a pregnane-5p one-20 (11e); melting point (tube) 136-1370; rotating power    :

   [a] 27 = -I-1030 (concentration: 1% in chloroform). <I> Example 6 </I> (4-methyl pipenazinyl-1) -3 (3 and -3a pregnane-5p ones-20 (IIf and IIg) These amines are prepared like the corresponding morpholine derivatives, but from of <B> 2,

  2g </B> of N-methylpiperazine in .place and place .of moapholine. The absorption is also very slow there: in 54 hours the theoretical quantity of hydrogen is not yet completely fixed.

   From the basic fraction, 3.1 g of white crystals, double: melting point: 159-160 and 166-167 (tube), are isolated in petroleum ether. It is (4-methyl piperazinyi-1) -3r pregnane-5r one-20 (IIf). The constant melting point sample is recrystallized from petroleum ether: double melting point (tube): 162-164 and 168-169;

       rotary power: [] 25 = -I- 90.6 (concentration: 1% in chloroform).



  The mother liquors are evaporated to dryness and the residue,: taken up in <B> of </B> acetone,: is salified with a concentrated methanolic solution of fumaric acid. The precipitated fumarate is recrystallized from 95% alcohol. From this fumarate (weight:

       1.70 g, melting point (K)> 270) the base is liberated with ammonia and the (4-methylpiperazinyl-1) -3a pregnane-5p one is isolated according to the usual technique -20 (II @ g);

    melting point (tube): 147-149 (in petroleum ether: light); optical rotation: [a] D = -I- 83.5o (concentration: 1% in chloroform). <I> Example 7 </I> Methylamino-3r pregnane-5p one-20 (IIh) 6.3 g, or 0.02 mole of pregnane-5p-dione-3.20 (Ic), are dissolved,

          in 120 ml of absolute alcohol. 30 ml of a 20% by weight solution of methylamine in ethanol, absolute and 0.1 g of 5% palladium on carbon are added.

   At the end of 8 and a half hours, the theoretical quantity of hydrogen is absorbed (we worked at 50o using a heating electromagnetic stirrer). It is filtered, the filtrate is evaporated to dryness, then it is recrystallized from isopropyl ether and: then: in methanol.

   The crystals obtained, of not very clear melting point, are then distilled in an oil bath at <B>: </B> boiling point at 0.05 mm Hg: 2150 (bath temperature). It is methyl-amino-3 (3 pregnane-5p: one-20 (IIh); melting point (tube):

   81-820 <I> Example 8 </I> Benzylamino-3p pregnane-5 @ one-20 (IIi) a) with palladium as catalyst- in an apparatus to be hydrogenated under ordinary pressure with electromagnetic stirring, 25.2 g are introduced progesterone (0.08 mole), 9.6 g of benzylamine (0.088 mole), 200 ml of absolute alcohol, and 2,

  4 g of 5 0/0 palladium on charcoal. At laboratory temperature, in 9 hours, 3900 cana of hydrogen are fixed (theoretical quantity 600 cm3). A white product crystallizes and is deposited on the catalyst. On, filter and on:

  extract the catalyst cake with chloroform or hot benzene. On evaporation of the solvent, benzylamino-3r pregnane-5r one- @ 20 crystallizes (weight: 21 g) (yield = 64.3%).

   The melting point is constant after recrystallization from ethanol: weight 1.6.1 g; melting point (tube): 138-1400 (yield very close to 50%); [a] D = -I- 85.10;

       concentration 1% in: chloroform. The IR spectrum reveals the presence of a ketone in 20 of the normal series and of a monosubstituted aromatic nucleus (determination in solution in carbon disulphide).



  b) - with platinum oxide as catalyst: 6.3 g (0.02 mole) of progesterone, 0.63 g of platinum oxide (Il aker Ltd), 1.2 g of purified animal black, 2,

  45 ml of benzylamine and 50 ml of absolute alcohol are hydrogenated at room temperature with electromagnetic stirring. When two equivalents of hydrogen are:

  absorbed (over 4 and a half hours), a product crystallizes in the reaction mixture, but the absorption continues at a not insignificant speed. After 22 hours, the reaction is stopped:

  and we filter. The steroid retained by the filter is then extracted with chloroform with the catalyst, after addition of ammonia to prevent colloidal platinum from passing into the filtrate. The chloroform solutions are then evaporated under vacuum to dryness (weight = 4.83 g).

    The dried residue is recrystallized from absolute alcohol. It melts at 136-1390 (K)

      and do not give depression with benzylamino-3r pregnane-5P one-20 obtained as it. has been indicated above in a. The IR spectra are in addition: almost superimposable,:

  although some differences in the region of 8 to 9 suggest the presence of isomers of H5a configuration in significant amounts.



  c) with Raney nickel as catalyst: 6.3 g of: progesterone (0.02 mole), 3 g of freshly prepared Raney Ni, 2.45: ml of benzylamine and 50 ml of absolute alcohol are hydrogenated at room temperature in a shaker. The absorption of gas is quite slow.

   It takes about 15 hours for two hydrogen equivalents to be attached to the sterdide. The latter crystallizes in 1 ;. middle. We filter. The steroid precipitated with the catalyst is extracted with chloroform. Evaporated in vacuo to dryness and dried. The residue weighs 5.1 g. It is recrystallized from absolute alcohol.

   Melting point (K): 136-138; no depression by melting mixed with the product prepared according to a.



  From the rearistallization mother liquors, 0.28 g of a product with a melting point (K)> 250G is removed. <I> Example 9 </I> Amino-3 (3 pregnane-5p one-20 (IIk) and derivatives a) via the derivative IIn with a benzylidene residue In a hydrogenation apparatus at ordinary pressure, equipped with a heating electromagnetic stirrer,

   6.3 g of pregnane-5p di-one-3.20 (0.02 mole) (le), 80 ml of absolute alcohol, 2.4 g of redistilled benzylamine (0.022 mole) and 0.6 g are introduced 5% palladium on carbon. We heat at 50G for the duration of the operation (5 hours in total)

       during which a little more than two equivalents of hydrogen (1020 cm3 for a theoretical quantity of 896 cm3) are absorbed. It is filtered and 0.022 mol, ie 2.4 g of benzaldehyde, is added to the filtrate. It is concentrated until the start of hot crystallization.

   5.4 g of derivative with a .benzylidene IIn residue are thus isolated; melting point (tube) 188-190G. A sample of compound IIn, benzylidene-amino-3 (3 preb nane-5p one-20, is recrystallized from ethyl acetate; melting point (tube) 197-198G.



  The crude derivative, containing a benzylidene IIn residue, is subjected to catalytic hydrogenation under conditions identical to those described above, in the presence of 5% carbonaceous carbon (0.5 g) and 150 ml of ethanol absolute.

   After 2.5 hours, an. Has substantially absorbed the amount of hydrogen necessary to split the regenerated benzylamine derivative. It is filtered, eva pore under vacuum to dryness, the residue is taken up in boiling petroleum ether and left to crystallize slowly.

   2.0 g of large colorless crystals are thus isolated, melting point (tube) 120-122G, while, from the mother liquors, another 1.2 g of a product having a melting point (tube) is removed. of 95-105G, but .s' altering when it is desired to purify it by recrystallization. Rotating power of the melting product at 120-122G:

       [] D = -1-- 98.40 (concentration: 1% in chloroform). The IR spectrum, determined in nujol, shows zero or very low absorption in the 6.25-6.30 u region, unlike 3a-amino steroids. And a very clear absorption in the 14.70u region. .



  The N-acetyl derivative of this amine is prepared in quantitative yield by action of acetic anhydride on the free base.

   White crystals, IIah, are thus obtained after recrystallization from isopropyl ether; melting point (tube): 127-128G; optical rotation: [a] D @ = - 90.70 {concentration: 1% in ethanol).



  b) via acid fumarate 5.15 g of pregnane diane <B> le </B> are added 165 ml of absolute alcohol, 3 g of benzylamine and 0.5 g of 5% palladium on charcoal . Hydrogenate at ordinary pressure and heat at 40-43 until we,

  has fixed the sufficient quantity of gas to promote the e-hydrogenolys of the intermediate benzylamine derivative IIi. The primary amine is filtered off and separated in the form of acid fumarate; weight: 2.4 g; Fusion point :

   176-178 (tube), very difficult to purify. The base is liberated from this fumarate by ammonia and extracted with cyclohexane. Washed with water and <I> dried </I> over SO4Na2 cyclohexane solutions. By evaporation the amino steroid is obtained which is recrystallized several times from petroleum ether.

   This purification is accompanied by resinifications and very abundant losses; the melting point of 3-amino-pregnane-5p one-20 (IIk) could not be raised above 112-114 (1 (tube).



  c) by hydrogenolysis of the purified benzylamine derivative IIi, itself prepared from .progesterone (see above).



  16.1 g of benzylam.ino-3p pregnane-5 (1 one-purified (IIi), melting point: 138-140 (tube) prepared by catalytic reductive amination (in the presence of Pd) of 25.2 g of progesterone (see above), are suspended in 200 ml of absolute alcohol and stirred electromagnetically at <B> 500 </B> in a hydrogen atmosphere at ordinary pressure and in the presence of 1,

  6 g of 5% palladium-carbon. Within 4 hours, the hydrogenolysis is virtually complete, the theoretical amount of hydrogen (900 ml) having been absorbed.

   It is filtered to remove the catalyst and the alcohol is evaporated off under vacuum at <B> 500. </B> The residue is taken up in 40 ml of boiling petroleum ether. The mixture is left to slow crystallization and 11.0 g of 3-amino (3 pr .egnane-50 one-20, IIk, melting point: 118-120G (tube) are thus isolated, after drying, not giving depression by melting mixed with the product obtained by process a).

   The yield of the reaction is 74% (or a total of 37% from progesterone).



       In a similar experiment, the amine was isolated as an acid maleate by adding a concentrated ethanolic solution of cornic acid to the crude filtered hydrogenolysis product. By recrystallization from water, the salt was obtained pure for analysis.

   Melting point (tube): 184-186G; [a] 25 = -f- 71.9G; (1% concentration in 96% alcohol).



  d) preparation of the ascorbate of 3p-amino-preganan-5 [3 one-20 (IIk) by hydrogenolysis of the purified benzylamino derivative IIi, itself prepared from progesterone (see above) .



  20.0 g of purified benzylamin.o-3 (3 pregnane-5F one-20 (IIi),: melting point: 138-1400 (tube), are suspended in 200 ml of isopropanol and stirred electromagnetically at 50 at ordinary pressure in the presence of 2 g of 5% palladium on carbon After 5 hours the hydrogenolysis is almost complete (1120 ml of hydrogen absorbed) Filter to remove the catalyst.

   To the resulting solution brought to the boil, a boiling methanol solution: ascorbic acid, prepared from 10 g of ascorbic acid and 75 ml of methanol, is added under a nitrogen atmosphere.



  The methanol evaporates and the ascorbate crystallizes. After cooling, the white cris rates are filtered off. We: dry under high vacuum. Weight obtained: 20.8 g,

          or a yield of 86% from the benzylamine derivative IIi and of 43% from the progesterone.

   Melting point (tube) 179-181 Optical rotation: [u] 25 '= @ - 106.70 (concentration: 0.5% in water).



  This ascorbate is one of the rare salts of base IIk which is easily soluble in water.



  e) by hydrogenolysis test of the derivative containing anisylidene residue (11q). Isolation of (4-methoxyphenyl-methyl-amino) -3 [3 pregnane-5p one-20 (Hs).



  Is hydrogenated as indicated above under a, a mixture of @ pregnan - 5 (3-dione-3,20 (Ic) (6.3 g) and, b.enzylamine (2.4 g) .

       The crude primary amine formed by hydrogenolysis is condensed with anisaldehyde (4.4 g) in an alcoholic medium, for one hour at reflux. The mixture is concentrated to 150 ml and 6.3 g of Schiff's base with anisylidene residue (11q), melting point (tube) are isolated by crystallization:

   175-177. The pure imine for analysis is obtained by recris: tallisiation in ethyl acetate <B>: </B> melting point: 179-180 (tube).



  2.2 g of this derivative (11q) are treated with hydrogen at ordinary pressure in the presence of 5% palladium on carbon (0.2 g). The operation is carried out at 50-52. In absolute alcohol. In fact, only one equivalent of hydrogen ballast is absorbed (135 ml, whereas 226 ml would be needed for hydrogenolysis). Moreover, after filtration of the catalyst, evaporation to dryness under vacuum and:

  crystallization from boiling petroleum ether, secondary amine (IIs), melting point (tube): 124-1250; optical rotation: [a] D, 5 -f- 81.7 (l (concentration = 1% in ethanol).



  <I> Example 10 </I> A.mino-3 (3. And -3ca pregnane-5a one-20 {IIm and IIc) and derivatives Isolation of funtumine a) with benzylamine as nitrogen source In an apparatus to be hydrogenated at normal pressure equipped with a heating electromagnetic stirrer, 6.3 g of pregnane-5a-di-one-3.20 (Ib) (0.02 mol), 80 ml of absolute alcohol, 2, are introduced.

  4 g of benzylamine (0.022 mol) and 0.6 g of 5% palladium on charcoal. Stirred 5 hours at 500; 960 ml of hydrogen are thus absorbed (theory 896 ml to carry out the reduction and the hydrogenolysis). The catalyst is removed by filtration; 2.4 g (ie 0.022 mol) of benzaldehyde are added to the filtrate, concentrated to: half and left to crystallize.

   3.5 g of benzylidene-amino, 3 (3 pregnane-5a one-20 (IIo), melting point (tube): 195-197 are thus isolated. The latter recrystallized from ethyl acetate,, weighs 2.5g and melts at 202-204 (tube).



  The derivative with a benzylidene residue (IIo) thus purified is hydrogenated at 500 (ordinary pressure) in 80 ml of alcohol in the presence of 0.2 g of 5% palladium black. In two hours, the theoretical quantity of hydrogen necessary to: create the free -NH2 'group is absorbed.

   After filtration of the catalytic converter, the alcohol is evaporated off under vacuum. The residue crystallizes. After dissolving in boiling cyclohexane and slowly evaporating, there is obtained 3-amino-3 (3 pregnane-5a ane-20 pure (Hm), melting point (tube): 157-158; weight: 1.45 g ;

   optical rotation: [a] D = -I- 96.30 (concentration: 1% in chloroform). The IR spectrum, determined in nujol, shows the presence of the characteristic bands of equatorial compounds.



  From this base, an acid fumarate, of melting point (tube) = 232-2340, recrystallized from methanol, and a canine (IIr) were prepared:

  with anisaldehyde (obtained in alcohol, recrystallized from ethyl acetate); melting point (tube): 193-1940.



  The various mother liquors obtained after separation of the derivative with a benzyhdene residue (IIo), melting point 202-204 (1, belonging to the 3-amino series (3, are evaporated in vacuo to dryness. The residue obtained is treated a overnight with dilute CIH after dissolution in isopropyl ether or in ethyl ether In this way, the imine is hydrolyzed and an amine hydrochloride, very poorly soluble, precipitates.

   It is purified by recrystallization from a chloroform-acetone mixture. It is funtumine hydrochloride, or pre-gnane-5a amino-3a hydrochloride RTI ID = "0011.0229" WI = "11" HE = "4" LX = "1529" LY = "2076"> one- 20; melting point (micr.): 260-2650; weight: 1.4g.



  This hydrate, treated with ammonia, liberates the funtumme base (IIC) which passes into the ether. We decant. The separated ether extracts are washed with water and dried over SO4N.a2. The ether is then driven off under vacuum and the residual oil is obtained crystallized at,

  Starting from a mixture of ether and light petroleum ether (boiling 35,450. 1.1 g of base are thus isolated, melting point (tube): 113-117.



  The pure sample for analysis of funtumm.e, the constants of which are practically identical to those of the product isolated from, from Funtumia latifolia (Apocynaceae) by Janot et al., Is obtained by a further crystallization in the mixture of ether and ether,

  of light petroleum. It is amino-3a pregnane-5a one-20 (funtumin, IIC); melting point (tube): 120-124; rotational power: [a] D S @ = -i- 103.1 (1 (concentration: 1% in chloroform).

   The IR spectrum, determined in suspension in nujol confirms this configuration.



  The funtumme, in alcoholic solution, gives rise by addition of benzoic ald6hyde <B> (30 </B> minutes at reflux) to an imine with a henzylidene residue which is crystallized in petroleum ether, then methanol. It is benzylidene-amino-3a. pre- gnane-5a one-20 (I: Ip), optical rotation:

   [a] D = \ -, 96.90 (concentration: 1% in CHCl3); melting point: 200-202 (tube), giving a melting depression mixed <I>. </I> with the benzylidene-amino-3a (IIo) isomer obtained above.



  b) with ammonia NH3 as the source of nitrogen In an apparatus with hydrogenation under ordinary pressure, equipped with a heating electromagnetic stirrer, 6.3 g of pregnane-5cr dionc-3.20 (Ib) are introduced , or 0.02 mole, dissolved in 100 ml of absolute alcohol.

   20 ml of a 7% gaseous ammonia solution in absolute alcohol and 0.6 g of 5% palladium on carbon are added. The hydrogen absorption is slow:

       it takes 11 hours to fix 480 ml of gas, which is a little more than the theoretical quantity (448 ml). It is filtered to remove the catalyst. This retains crystals of an organic product which is extracted with chloroform, but there are no amino compounds in the residue obtained after evaporation of the chloroform.

   The bases which originated in the reaction therefore remained in alcoholic solution. This solution, evaporated under vacuum to dryness, gives up a residue weighing 5.3 g which is dissolved in the minimum amount of alcohol and which is converted into Schiff's base by adding .benzaldehyde. The derivative with a benzylidene residue, which: originates by friction with the walls, is isolated.

   It weighs 1.9 g. Its melting point (K) is 190-192 ". It is recrystallized from ethyl acetate. Benzylidene-: amino-3 [3 pregnane-5a one-20, thus prepared ( Ho), melting point (tube): 198-201, does not give a depression by melting mixed with the melting product:

       202-204c, (tube), obtained as it. Has been edited here; des: sus. Under a).



  <I> Example 11 </I> Pyrrolidino-3 (3 androstane-5a o # l-17f) (IIt) 5.8 g of androstanolone (Id) (0.020 mole) and 1.8 ml of pyrrolidine (0.022 mole ),: in solution in 210 ml of absolute ethanol, are hydrogenated at ordinary pressure and temperature in the presence of 0.6 g of 5% palladium on carbon. The absorption of the theoretical quantity of hydrogen (450 ml) is not very rapid.

   After filtration of the catalyst at concentration to 75 ml, the mixture is allowed to cool slowly. Pyrrohdino-3p .androstane-5a 01-17 (3 (IIt) crystallizes. Weight: 4.3 g. Melting point: 182-1840 (tube).

   It is obtained pure for analysis after recrystallization from ethyl acetate. Melting point (tube): 179-182. Rotary view: [a] D = -t- 8.81, (1% concentration in chloroform). The steric structure is determined by analogy.



  <I> Example 12 </I> Dimethylamino-3p androstane-5a o1-17 (3 (11v) It is prepared like the previous derivative (IR), replacing the pynrolidine with an alcoholic solution (30 ml) of dimethyl.amin .e at 20 0/0.



  The product (at constant melting point; weight 2.2 g) is obtained after two recrystallizations from ethyl acetate.



  Melting point (tube): 172-174.



  Optical rotation: [] D = -I- 8.8 (concentration 1% in CHCl3).



       The iodomethylate of compound IIv is prepared by dissolving the base (1.5 g) in absolute alcohol <B> (</B> 15 ml), then adding an excess of methyl iodide.

   The quaternary salt crystallizes spontaneously. The white crystals, which turn yellow in air, are drained and recrystallized from absolute ethanol;

   melting point (K)> 265 (l. <I> Example 13 </I> Pyrrolidino-3F androstane-5 (3 o1-175 (IIu) 2.9 g of testosterone (0.01 mole) and 0.9 ml of pyrrolidine <B> (0.011 </B> mole), dissolved in 50 ml of absolute alcohol, are hydrogenated at ordinary pressure and temperature in the presence of 0.15 g of good palladium charcoal at 5 0/0.



  After absorption of the theoretical amount of hydrogen (448 ml), filtered and concentrated. The pyrrolidino-3 @: androstane-5 (3 01-17 (3 (Hu) which arises is recrystallized from ethyl acetate. Weight: 0.5 g.



  Melting point (Kofler): 234-236o.



  Rotary power: [a] 24.5 '_ 23.5o (1% cancer in CHC13).



  <I> Example 14 </I> Hydroxy-21 pyrrolidino-3 (3 pregnane-5 (3 one-20 (IIw)) In a flask to be hydrogenated, 5.5 g of hydro-DOC (Ig) are introduced, 150 ml of absolute alcohol, 1.5 ml of pyrrodidine and 0.3 g of 5% palladium on charcoal.

   Stirred electromagnetically at ordinary pressure and temperature. After absorption of the theoretical quantity of hydrogen (373 ml), the catalyst is filtered off and the filtrate is evaporated in vacuo to dryness.



       Crude 21-hydroxy-pyrrolidino-3 (3 pregnane-5 [3 ane-20 (Ilw) (weight: 3.5 g) recrystallized from isopropyl ether in the form of white needles.
EMI0013.0001
  
    Melting point <SEP> <SEP> (tube) <SEP>: <SEP> 149-151 <SEP> (weight <SEP> 2.2 <SEP> g).
<tb> Sample <SEP> pure <SEP> for <SEP> analysis <SEP> background <SEP> to <SEP> 152-154
<tb> (tube).
<tb>



  Rotary <SEP>: <SEP> [a] 24> 5 <SEP> = <SEP> -I- <SEP> 86.20 <SEP> (concentration <SEP> 1 <SEP>% <SEP> in < SEP> CHCl3).
<tb>



  It <SEP> gives <SEP> a <SEP> depression <SEP> by <SEP> fusion <SEP> mixed <SEP> .with
<tb> isomer <SEP> to <SEP> configuration <SEP> 3a <SEP> - <SEP> Fusion <SEP> (K) <SEP>: <SEP> 157-1590
<tb> (IID) <SEP> obtained <SEP> by <SEP> reduction <SEP> formic <SEP> of <SEP> enamine
<tb> pyrrolidinated <SEP> from <SEP> hydro, DOC.
<tb>



  <I> Example <SEP> 15 </I>
<tb> Pyrrolidino-3 (3 <SEP> pregnane-5 (3 <SEP> diol-20 (3, <SEP> 21 <SEP> (IIai)
<tb> On <SEP> proceed <SEP> like <SEP> in <SEP> the example <SEP> 14 <SEP> -en <SEP> replacing <SEP> the hydro-DOC <SEP> by <SEP > <SEP> dihydroxy-205, <SEP> 21 <SEP> pregnane 5p <SEP> one-3 <SEP> (1h).
<tb>



  After <SEP> recrystallization <SEP> in <SEP> of <SEP> the ether <SEP> isopropyh que, <SEP> on <SEP> isolates <SEP> 1.8 <SEP> g <SEP> of <SEP> pyrrolidino-3 @ <SEP> pregnane-5 (3
<tb> diol-20 (3, <SEP> 21 <SEP> (Ilai) <SEP>; <SEP> point <SEP> of <SEP> fusion <SEP> (K) <SEP>: <SEP> 188- 1900.
<tb> The <SEP> compound <SEP> does <SEP> give <SEP> not <SEP> from <SEP> depression <SEP> by <SEP> merge
<tb> mixed <SEP> with <SEP> a <SEP> sample <SEP> <I> .prepared </I> <SEP> by <SEP> aminolysis
<tb> pyrrolidinated <SEP> of the corresponding <SEP> tosylate <SEP> 3a <SEP>, <SEP> therefore <SEP> of
<tb> steric <SEP> structure <SEP> well established <SEP>, <SEP> and <SEP> melting <SEP> to <SEP> 187-188 ()
<tb> (K). <SEP> The <SEP> spectra <SEP> IR, <SEP> determined <SEP>. In <SEP> solution <SEP> ch # loTo formic, <SEP> are <SEP> superimposable.

   <SEP> Rotary <SEP>
<tb> [a] 24 <SEP> = <SEP> -I- <SEP> 17.50 <SEP> (concentration: <SEP> 0.7 <SEP>% <SEP> in <SEP> CHC13).
<tb> <I> Example <SEP> 16 </I>
<tb> Acetoxy-21 <SEP>, amino-3 @ <SEP> pregnane-5 (3 <SEP> one-20 <SEP> (LLz)
<tb> and <SEP> derived
<tb> a) <SEP> to <SEP> from <SEP> from <SEP> acetate <SEP> d <SEP> .e <SEP> deoxycorticosterone <SEP> (Ii)
<tb> On <SEP> hydrogen <SEP> to cold <SEP> <SEP> and <SEP> to <SEP> the <SEP> pressure <SEP> ordinary
<tb> a <SEP> mixture <SEP> of <SEP> 22.2 <SEP> g <SEP> of <SEP> DOCA <SEP> (Ii) <SEP> (0.06 <SEP> mole),
<tb> 320 <SEP> ml <SEP> of absolute <SEP> alcohol, <SEP> 7.2 <SEP> g <SEP> of <SEP> benzylamine
<tb> (0.066 <SEP> mode) <SEP> and <SEP> 2.2 <SEP> g <SEP> of <SEP> charcoal <SEP> paldadié <SEP> to <SEP> 5 <SEP> 0/0 .
<tb>



  In <SEP> 7 <SEP> hours <SEP> approximately, <SEP> 0.12 <SEP> mole <SEP> of hydrogen
<tb> are <SEP> .absorbed <SEP> (2830 <SEP> ml) <SEP> for <SEP> the <SEP> .reduction <SEP> .of <SEP> the
<tb> double <SEP> bond <SEP> and <SEP> the reductive <SEP> amination. <SEP> On
<tb> heats up <SEP> then <SEP> to <SEP> 50-55. <SEP> The <SEP> absorption that <SEP> had
<tb> very <SEP> strongly <SEP> slowed down <SEP> resumes <SEP> (hydrogenolysis <SEP> of
<tb> derivative <SEP>, benzylamine <SEP> intermediate) <SEP>. and <SEP> on <SEP> note <SEP> the
<tb> consumption <SEP> of <SEP> 0.06 <SEP> mode <SEP> of hydrogen <SEP> in <SEP> five
<tb> hours.

   <SEP> On <SEP> filter <SEP> to <SEP> remove <SEP> the <SEP> catalyst, <SEP> on
<tb> add <SEP> to <SEP> filtrate <SEP> 8 <SEP> g <SEP> of <SEP> @ benzaldehyde, <SEP> then <SEP> on <SEP> con center <SEP> to <SEP> mid-volume <SEP> and <SEP> on <SEP> let <SEP> crystallize <SEP> imitate it
<tb> (Haa) <SEP> which <SEP> has <SEP> taken <SEP> birth. <SEP> This <SEP> is <SEP> filtered <SEP> and
<tb> recrystallized <SEP> in <SEP> of <SEP> alcohol <SEP> absolute <SEP> (weight
<tb> 15.0 <SEP> g) <SEP>; <SEP> <SEP> point <SEP> merge <SEP> (pipe) <SEP>: <SEP> 128-131.
<tb>



  Acetoxy-21 <SEP> benzylidene, ammo-3 (3 <SEP> pregnane 5 (3 <SEP> ane-20 <SEP> (Ilaa), <SEP> at <SEP> point <SEP> of <SEP> merge <SEP> constant, <SEP> is
<tb> obtained <SEP> after <SEP> a new <SEP> <SEP> crystallization.
<tb>



  Melting point <SEP> <SEP> (tube) <SEP>: <SEP> 132-134.
<tb>



  Rotary <SEP>: <SEP> [a] 24 <SEP> <SEP> = <SEP> -i- <SEP> 100o <SEP> (concentration <SEP> 1 <SEP>% <SEP> in <SEP > CHC13).
<tb>



  4.6 <SEP> g <SEP> of the <SEP> derivative <SEP> to <SEP> remains <SEP> benzylidene <SEP> (IIaa)
<tb> (<SEP> point of <SEP> fusion <SEP> (tube) <SEP>: <SEP> 128-1310) <SEP> are <SEP> hydrogenated <SEP> to <SEP> the <SEP> pressure <SEP> ordinary <SEP> and <SEP> to <SEP> 500 <SEP> in <SEP> presence <SEP> of
<tb> 80 <SEP> ml <SEP> of alcohol <SEP>: absolute <SEP> and <SEP> of <SEP> 0.5 <SEP> g <SEP> of <SEP> charcoal <SEP> linked <SEP> to <SEP> 5 <SEP> 0/0.

       
EMI0013.0002
  
    After <SEP> fixing <SEP> of <SEP> 1a <SEP> theoretical <SEP> quantity <SEP> of hydrogen <SEP> (448 <SEP> ml), in <SEP> 2 <SEP> hours, < SEP> on <SEP> filter <SEP> for <SEP> to remove the <SEP> the <SEP> catalyst, <SEP> on <SEP> evaporates <SEP>: the alcohol <SEP> and <SEP> on <SEP > re takes <SEP> the <SEP> residue <SEP> by <SEP> of <SEP> ether. <SEP> After <SEP> evaporation
<tb> partial <SEP> of the <SEP> solvent, <SEP> on <SEP> isolates <SEP> 0.9 <SEP> g <SEP> of acetoxy-21
<tb> amino-3 (3 <SEP> pregnane-5 (3 <SEP> one-20 <SEP> (IIz) <SEP>; <SEP> point <SEP> of <SEP> fusion <SEP> (tube ) <SEP>: <SEP> 163-1670.
<tb>



  The <SEP> purification <SEP> by <SEP> recrystallization <SEP> in <SEP> of
<tb> ether <SEP> or <SEP> of <SEP> ethyl acetate <SEP> <SEP> is <SEP> delicate <SEP> because <SEP> the
<tb> product <SEP> is corrupted. <SEP> Melting point <SEP> <SEP> (tube) <SEP> 176-1780
<tb> - <SEP> Rotary <SEP> <B>: </B> <SEP> [a] <SEP> D <SEP> <SEP> _ <SEP> -I- <SEP> 100.4 < SEP> (concentration <SEP> 1 <SEP>% <SEP> in <SEP> CHCd3).
<tb>



  The <SEP> derivative <SEP> N @ acetylated <SEP> of <SEP>, this <SEP> amine <SEP> is <SEP> prepared <SEP> with <SEP> a <SEP> yield <SEP> quantitative < SEP> by <SEP>, action <SEP> of
<tb> <SEP> acetic anhydride <SEP> on <SEP> la. <SEP> free <SEP> base. <SEP> On <SEP> gets
<tb> - thus <SEP> white <SEP> crystals <SEP>, <SEP> IIaj, <SEP> after <SEP> recrystallization <SEP> in <SEP> of <SEP> isopropyl ether <SEP> . <SEP> <SEP> point of <SEP> merge
<tb> (, tube): <SEP> 129-13.1o. <SEP> Rotary <SEP> <SEP>: <SEP> [a] 24 <SEP>, 5 '<SEP> _
<tb> -f- <SEP> 84,9,1 <SEP> (concentration: <SEP> 1 <SEP>% <SEP> in <SEP> the <SEP> chloro form).
<tb>



  On <SEP> a <SEP> of <SEP> best <SEP> yields <SEP> in <SEP> precipitating
<tb> the <SEP> base <SEP> after <SEP> filtration <SEP> of the <SEP> catalyst, <SEP> in <SEP> form
<tb> of <SEP> maleate <SEP> acid, <SEP> by <SEP> addition <SEP> of a <SEP> solution
<tb> maleic acid <SEP> <SEP> in ethyl <SEP> acetate <SEP>. <SEP> On <SEP> isolates
<tb> thus <SEP> 2.7 <SEP> g <SEP> of <SEP> maleate <SEP> crystallized <SEP> (point <SEP> of <SEP> fusion
<tb> (tube) <SEP> 171-1730) <SEP> that <SEP> purify <SEP> by <SEP> TeacnistaUisa tion <SEP> in <SEP> of <SEP> cold <SEP> water <B>; </B> <SEP> point <SEP> of <SEP> .fusion <SEP> (pipe)
<tb> 178-1800 <SEP>; <SEP> rotary <SEP> power: <SEP> [a] 21.5 '<SEP> = <SEP> -I- <SEP> 80.20
<tb> (concentration <SEP> 1 <SEP>% <SEP> in <SEP> CHC13).
<tb>



  b) <SEP> to <SEP> from <SEP> d <SEP> e <SEP> hydro-DOCA <SEP> (Ij)
<tb> On <SEP> adopts <SEP> the same <SEP> technique <SEP> as <SEP> above,
<tb> but <SEP> in <SEP> using <SEP> 3.75 <SEP> g <SEP> d <SEP> e <SEP> (Ij) <SEP> (0.01 <SEP> mole), < SEP> say under <SEP> at <SEP> hot <SEP> in <SEP> 80 <SEP> ml <SEP> of-alcohol <SEP> absolute, <SEP> 1,2 <SEP> g <SEP> of
<tb> benzylarnne <SEP> and <SEP> 0.4 <SEP> g <SEP> of <SEP> coal <SEP> .palladie <SEP> to <SEP> 5 <SEP> 0/0 <SEP>;
<tb> after <SEP> .absorption <SEP> of <SEP> 0.02 <SEP> mole <SEP> of hydrogen, <SEP> elimination <SEP> of the <SEP> catalyst <SEP> by <SEP> filtration <SEP> and <SEP> addition <SEP> of
<tb> 1,5 <SEP>; g <SEP> of <SEP> benzaldehyde, <SEP> on <SEP> isolates <SEP> 3.8 <SEP> g <SEP> idederivative <SEP> at
<tb> rest <SEP> benzylidene <SEP> (Haa) <SEP>:

   <SEP>: its <SEP> point <SEP> of <SEP> merge
<tb> (tube) <SEP> is <SEP> from <SEP> 125-127o <SEP> and <SEP> it <SEP> is <SEP> identical <SEP> to @ u <SEP> pro luit <SEP> prepared <SEP> according to <SEP> a).
<tb>



  <I> Example <SEP> 17 </I>
<tb> Amination <SEP> reducing <SEP> by <SEP> the <SEP> benzylamine
<tb> of <SEP> the <SEP> dihydroxy-200, <SEP> 21 <SEP>, pregnano-5S <SEP> one-30
<tb> (1h)
<tb> 1.5g <SEP> of the <SEP> compound <SEP> lh <SEP> (point <SEP> of <SEP> fusion <SEP> (Kofler)
<tb> 160-1620) <SEP> are <SEP> dissolved <SEP> in <SEP> 25 <SEP> ml <SEP> of alcohol <SEP>:

  absolute.
<tb> On <SEP>. add <SEP> 0.55 <SEP> ml <SEP> of <SEP> benzylamme <SEP> and <SEP> 0.15 <SEP> ml <SEP> of
<tb> charcoal <SEP> palladium <SEP> to <SEP> 5 <SEP> 0/0. <SEP> On <SEP> hydrogen <SEP> to <SEP> 500 <SEP> to <SEP> the
<tb> ordinary <SEP> pressure, <SEP> in <SEP> using <SEP> a heated <SEP> electromagnetic <SEP> <SEP> stirrer. <SEP> The <SEP> absorption of <SEP> H2 <SEP> is <SEP> very
<tb> slow. <SEP> After <SEP> 30 <SEP> hours, <SEP> 115 <SEP> ml <SEP> of hydrogen <SEP> only <SEP> have <SEP> been <SEP> fixed.

   <SEP> For <SEP> capture <SEP> the <SEP> theoretical <SEP> quantity
<tb> for <SEP> reductive <SEP> amination <SEP> and <SEP>, subsequent hydrogenolysis <SEP> <SEP> (200 <SEP> ml), <SEP> <SEP> must be < SEP> add <SEP> of fresh <SEP> catalyst <SEP>
<tb> (0.15 <SEP> g) <SEP> and <SEP> shake <SEP> at <SEP> 500 <SEP> for <SEP>. one <SEP> ten <SEP> of hours
additional <tb>. <SEP> On <SEP> filter, <SEP> on <SEP> rinses <SEP> with <SEP> boiling alcohol <SEP> <SEP> and <SEP> on <SEP> evaporates <SEP> the <SEP > filtrate <SEP> under empty <SEP>. The residual oil crystallizes from ether; wt 0.67 g; melting point (Kofler): 132-136; the recrystallization tests failed, the product being very deteriorable.

   This 3p-amino pregnan-5p diol-20 (3, 21 crude, (11x) is dissolved in alcohol and treated for one hour in a boiling water bath with a slight excess of benzaldehyde, the solution obtained is concentrated.

   On friction, the imine with a benzylidene residue (IIy) crystallizes; it is purified by hot dissolution in absolute alcohol <B>; </B> melting point (Kofler): 156-158.



  The analytical purity of the product thus isolated is not yet perfect.



  <I> Example 18 </I> Pyrrolidmo-3 @ dihydroxy-17a, 21 pregnane-5 @ dione-11.20 (IIac and IIad) 4.8 g of cortisone (Ik) or 0.0132 mole, are given under in 140 ml of absolute alcohol. 1.2 ml of pyrrolidine and 0.30 g of 5% palladium-on carbon are added.

    It is treated with hydrogen at ordinary pressure and temperature. 630 ml: of hydrogen are thus absorbed (theory 584 ml). The mixture is filtered off and concentrated under vacuum at 350 with a capillary tube connected to a dry nitrogen generator. The residue is taken up, under nitrogen, in anhydrous ether.

   Is isolated .ainsi 1.65 g of a crystalline product, pou .stable; melting point (Kofler): 208; it is recrystallized with difficulty from absolute ethanol.

   It is pyrrolidino-35 dihydroxy-17a, 21 pregnane-5 @ dione-11,20 (! Lad) as the hemihydrate; melting point (tube): 228-2.301,;

    optical rotation: [#] 241 _; 74.70 (1% concentration in CHCl3); it is assumed that the two orientations 5 are amno-3a and H5a orientations.



  * The ethereal mother liquors, separated after isolation of the hemihydrate, above, are evaporated under vacuum to dryness, and the residue is taken up in absolute alcohol.

   By the action of concentrated CJH, its amines present in the form of hydrochlorides are precipitated. The crude hydrochloride is filtered off and triturated in absolute alcohol. Thus, 3 g of a salt which is slightly soluble in ethanol is obtained, which salt is recrystallized from methyl alcohol. IIac - weight: 1.35 g.



  Melting point (Kofler):> 2650.



  Optical rotation: [a] D'5 = 65.80 (1% concentration in 95% alcohol).



  <I> Example 19 </I> Dimethylamino-3 @ dihydroxy-17a, 21 preb nane-5 @ dione-11,20 (IIab) It was prepared as indicated in the previous example,

      replacing the pyrrolidine with an alcoholic solution of dimethylamine. No basic product crystallizes directly - and the chlor hydrate is simply precipitated from an alcoholic solution of crude amine which is recrystallized to a constant melting point (Kofler) = 265. <I> Example 20 </I> Acetoxy,

  21 amino-3 @, dihydroxy-Il (3, 17a pregnanc-5 @ one-20 (IIae) and derivatives In an apparatus to be hydrogenated at ordinary pressure, provided with a heated electromagnetic stirrer, is introduced 4 g of hydrocortisone acetate, ie approximately 0.01 mol;

  ,, 80 ml of absolute alcohol, 1.2 g of benzylamine and 0.4 g of 5% pall. Heat to 50 and allow hydrogenation to continue until 0.03 mole of H is absorbed, which takes about 8 hours.

   The mixture is filtered off, rinsed with alcohol, 1.5 g of bnzaldehyde are added to the filtrate and the mixture is heated for 10 minutes at reflux. The alcohol is evaporated off in vacuo, the residue taken up in boiling cyclohexane to remove the excess aldehyde. The residue, washed with ether, is recrystallized from methanol (weight: 1 g); melting point (tube): 204 205.

   It is acetoxy-21 benzylidene-amino-3 @ di-hydroxy-11 (3, 17a pregnane-5 @ one-20 (IIaf): optical rotation [a] D, 5 = -f- 790 (concentration 1 % in CHC13).



  By hydrogenation of the Haf derivative, the free amine Hae is obtained, which is quite alterable and which crystallizes with difficulty.



  By treating 6.3 g of pregnanc-5r-dione-3,20 (le) with ammonia and hydrogen, under conditions exactly identical to those described for dione lb (Example 10 , paragraph b), after recrystallization from ethyl acetate, 0,

  5g of benzylidene-amino-3a prcgnan-5 (3 one-20 (IIn) melting point (tube): 189-193; it gives no depression. By fusion mixed. With an authentic sample prepared as indicated in the paragraph a) of example 9.



  Similarly, dîmethylam: ino-3 (3 -pregnane-5p one-20, or methyl-dihydroholaphylhne, IIB (Janot et al., Bull. Sue. Chim. France, 1959, 896), melting point:

       56.1 (tube) was prepared by catalytic reductive amination of pregnanie-5a-dione-3,20 (1b) with RTI ID = "0014.0236" WI = "23" HE = "4" LX = "1217" LY = "1841"> dimethylamine. The fumarate of this base, recrystallized from acetone, melts at 159-161 (tube);

    its optical rotation: [a] D> 5 _ -f- 65.9o (concentration: 0.8% in methanol).

 

Claims (1)

CLAIM Process for preparing 3-diamino steroids, ca ractérisé in that -treatment both with ammonia, primary amines or amines: secondary and hydrogen, in the presence of hydrogenation catalysts, 3-keto steroids which, where appropriate, may contain one or more substituents insensitive to the action of hydrogen under the conditions: d 'hydro genation. SUB-CLAIMS 1. Method according to claim, characterized in that the starting 3-keto steroid is progesterone, allo-pregnane-dionc, pregnane dione, androstanolone, testosterone, deoxycorticosteron, l 'hydro-deoxycorticosterone, deoxy-corticosterone acetate, deoxycorticosterone hydroacetate, cortisone, hydrocortisone acetate or 20-dihydroxy (3, 21 pregnane-5 (3 one-3. 2. Process according to claim, characterized in that the amines are lower aliphatic amines, saturated cyclams such as pyrrohdine, piperidine, morphaline and N-alkyl piperazines or arahphatic amines such as b.enzylamine. 3. Process according to the claim, characterized in that the reductive amination is carried out in a diluent, in particular: a lower aliphatic alcohol. 4. Method according to claim, characterized in that the operation is carried out at a pressure equal to or greater than atmospheric pressure. 5. The Bedon la sous process, claim 3, characterized in that the operation is carried out at a temperature below the boiling point of the diluent, in particular from 0 to 65o C. 6. Method according to claim, characterized in that the hydrogenation is continued until the end of the absorption of hydrogen. 7. Process according to claim, in which benzylamine is used as the amine, characterized in that the hydrogenation is continued until the initial benzylamine group has been cut off. 8. Process according to sub-claim 7, character ized .in that: the primary amine obtained is roransformed by Schiff in order to purify it, in particular by reacting it with benzoic aldehyde ode, then regenerating the famine .