DE2255108C3 - Process for the preparation of 3 α-hydroxy-5 α-steroids and 3 α-hydroxy-19-nor-5 α-pregnan-20-one - Google Patents

Description

ÄSÄS:

tion components is carried out

4. The method according to claim 3, characterized in that the alcohol is isopropanol.

5. The method according to any one of the preceding claims, characterized in that as Iridium compound chloroiridium (IV) acid ver - "^ process according to one of the preceding claims, characterized in that the trivalent phosphorus compound is Trimethy.phosgroße ^ ϊϊί! ί luch wenifier than to be satisfactory Product can also be less a,

d ^

example swe.se

17-position of
» ₅ for the formation of,
Soc. WHERE ^ S.

Sodium hydroxide
System too

_{in the presence of}

^ ^ 3SS according to one of the preceding Claims, characterized in that as organic base triethylamine is used.

8. The method according to any one of the preceding claims, characterized in that there is sufficient Base used to get a pH from 0 to 8 5

⁶ l ^bl procedural "en ^he ge ^a S one of the preceding claims, characterized in that one uses an asteroid as the starting steroid.

10 The method according to any one of the preceding claims, characterized in that the Catalyst system in the absence of the steroid and the base by refluxing during 16 to 72 h is preformed, one as a trivalent phosphorus compound is an ester of phosphorous Acid is used and that the amount of water present is sufficient to hydrolyze the phosphite ester plus a further 0.2 to 4.0 percent by volume, based on the total reaction mixture.

11 Method according to one of the preceding Claims, characterized in that the catalyst system in the absence of the steroid and odef of

$ uÄ.ß one that

Over
be. Using a

from a trivalent ^ g ^^^ Iridmmverb.ndung «^ water produced Yield of the desired 3a-hydroxysteroia essential

lent improve ^^ ** ^ Χ ^ £ Γ £ 4 <> he.t of sufficient ^
is carried out around the pH value

corresponding to ^Νε " ^ίΓΕ ! ^"' ^ηΖ ^ ^ε " ^ε ^ lS

Improvement m intended
hung the 'Stereospecificito ^^^
We.terh.n is the reaction rate
my improved, one ^Ve ~ ^chan g
wish. · Side effects, such as isomerization

17 hours with su: h brings is _advantageous

In addition, I have been found to be beneficial

5 'to prepare the catalyst system' d. J- ^ Ch «latw

prolonged heating ^ before man ds 3 ^ ₀ 5α steroid

inflicts. This is especially desirable when one

other inert phosphorus compounds than tri-esters the phosphoric acid used.

^to5 · ^0Mo '

The invention relates to a process for the production of η 5a-steroids, which contain a 3a-hydroxy group, by reducing the corresponding 3-oxo three-valued products Phosphorus compound, an iridium compound and water, in the presence or absence of the steroid, reduced.

The iridium compound can be, for example

Iridium salt or an acid such as iridium tn- and

tetrahalides, for example iridium tetrachtoride

and Iridiumtrichlor.d, or Chloroind.um- (IV) -acid

and their salts, for example ammonium or

oo iuö

use chloroiridate. It is preferred dVVsaure as an iridium compound

_ύ Phosphorus compound can, for example, be an ester of phosphoric acid

γ ^ - »* - 'p _s ter example, a di- or tri- or unsaturated aliphatic WWL · (^ beispielsiP low-alkyl of 1 to 6 carbon atoms), PP ^ tisehes (eg monocyclic having 1 to 6 coal. ? Ü ^ ifffliomen in d

“M or an alkoxy (for example nie- ^C M tv” with 1 to 6 carbon atoms) group. drigÄ ^xy _'fiir aeeijmete phosphites are trialkyl #'? ·, and in particular readily hydrolyzable 's such as trimethyl phosphite. Phosphites, which can be hydrolyzed with value, can also

^{Iger smiles} * Jet · become · Examples are triethyl, tris _if ρ ζ are used. ^

! ^Ora hhit An example of a Dialkyl-Ät Umseig can be used

T _R SuEÄ ^^^ usually a

^ThatS · t «Snomittel, preferably an Aikoorganisches Loswipm . To solve constituents

^h0l J ^U l create a häSktin system m

create.

wise isopropanol conveniently used in the form of isopropanol, which is of the order of '? ^{Contains up to} 15% volume / volume ^water , although the amount of water can vary considerably. Man

assumes that there must be at least sufficient water to hydrolyze the phosphite ester, but another amount is required, possibly as a source of hydrogen. In general it was found that this further amount 0.2 to 4.0 vol-

lum percent of the total reaction medium. The amount of water required to make the Hydrolyzing phosphite will vary with the ester in question, but it will be on the order of magnitude of 45 volume percent of the volume of ester if

trimethyl phosphite is used. .

Another advantage of using a base in the present invention is that when using low water concentrations,

the formation of 3a-ethers substantially avoids ao It has been found that when the amount of water is medng in the catalyst system, it also _reduce the amount of ^ orzjgt Kt dre.wert.ger ^hos P P £ ^{orv "b 'n} ^ _{.Although you get} good results

can be obtained if, for example, 10 to 15 A « Was ^ and no less ft ^ gj-gj, £

used, you got similar yields mKL Rem Achieve heal if you are less than 1 MJ or even as little as 0.1 mole is used m Wa «

Sol and cyclohexanol are like that in some cases As effective as isopropanol. The latter two Alke-S may require increased reaction times and and

y pre-react, pre-react together

Organic solvents can be used.

the reduc-

system also soluble. The use of this base is particularly effective in reducing the reaction time and thereby reducing the degree of isomerization that occurs at the I7 position of a 20-ketopregnane can occur. This increases the yield of the desired product.

Other bases can of course be used and examples of these are piperidine, N-ethylpiperidine and pyridine. The latter base gives results comparable to those obtained with triethylamine receives.

In general, sufficient base should be added to neutralize the reaction system, and it is preferred to conduct the reaction at a pH of about 7. Increasing the pH (for example to 8.5 in the case of triethylamine) has no adverse effect on the reaction time, but an increase in the degree of 17 isomerization occurs in cases where this is possible. It is therefore generally preferred that sufficient base be used to give a substantially neutral pH, ie, from 6 to 8.5, preferably from 7.0 to 8.0 or more preferably from 7.2 to 7.8.

If the steroid is reacted with a catalyst system that has not been preformed, the added Base initially give a pH above 8.5, for example about 9.5. However, the pH becomes too Beginning of implementation will fall in the 6 to 8.5 range.

The reaction of the steroid with the reducing system and the base is generally under reflux performed to solubilize the steroid in high concentrations. The response time can vary considerably, according to the particular conditions, depending, among other things, on the Amount of iridium compound that is present, the alcohol used, and the type and amount of added base. Reaction times of 16 to 26 hours are generally required when the ingredients all mixed at the same time or if relatively short catalyst preform times, for example up to 24 hours.

However, if the catalyst system has been preformed by refluxing for 16 to 72 hours heated and common concentrations of water relative to the trivalent phosphorus compound, such as calculated above, when used, the reduction is often in as short a time as 2 to 3 hours at reflux temperatures or terminated in about 16 hours at room temperature. Such mild reaction conditions bring it with them ensures that side reactions such as isomerization are kept to a minimum.

The activity of the reduction system can often be increased by having the reaction in a Carries out a hydrogen atmosphere.

The method according to the invention is generally applicable to 5 "steroids which have a 3-oxo group contain. It is particularly useful in the manufacture of 3 u-hydroxy-5 «steroids of the pregnan or 19-nor-pregnan series. Since the reduction is particularly selective with regard to the 3-oxo group, emphasizing that other functional groups may be present in the molecule (for example oxo groups at other positions in the molecule or carbon-carbon double bonds).

Examples of groupings which can be present in the stroid nucleus are: in the 2a-position an alkyl group (for example with 1 to 9 carbon atoms, preferably methyl) or a halogen atom, for example a bromine atom; in the ΙΟ-position a hydrogen atom or a methyl group; in the II-position an oxo or hydroxyl group; a double bond in the Δ ^1β or A ^{0 (1} "position; in the I6 position one or more alkyl groups (for example those with 1 to 6 carbon atoms, such as methyl); in the I7 / J position an acetyl group which

ίο may be substituted, for example a group of the formula OR ⁴ , in which R ^{4 is} hydrogen or a substituted or unsubstituted (for example by amino or carboxy groups) alkyl (for example lower-alkyl with 1 to 6 carbon atoms), cyclo

J5 alkyl, aryl (e.g. phenyl) or aralkyl (e.g. Benzyl) group or an aliphatic, araliphatic or aromatic acrylic group, an esterified one Carboxyl group, an N-mono- or disubstituted carbamoyl group or a cyano group means.

The androstane can, for example, contain a 17 /? - substituent of the formula -COR ¹ , in which R ¹ is:

i) an alkoxy group having 1 to 6 carbon atoms, which may be unsubstituted or substituted by a hydroxy, acyloxy or N-morpholino group, or

ii) a group of the formula -NR ² R ³ , in which R ^{2 is} an alkyl group having 1 to 4 carbon atoms and R ³

denote an alkyl group having 1 to 4 carbon atoms or a hydrogen atom or in which R ² and R ³ together with the nitrogen atom to which they are bonded represent a heterocyclic ring which is another nitrogen or

May contain oxygen atom.

A hydroxymethylene group can also be in the 2-position to be available. This generally becomes a 2'-methyl group during the reduction the 3-oxo group reduced.

An important member of the Pregnan series, which is used with advantage in the method according to the invention is 5a-pregnan-3, l 1,20-trione, which is reduced to 3 a-hydroxy-5 «-pregnan-11,20-dione

which has valuable anesthetic properties. This reduction can according to the invention Process can be carried out whereby there is an increased yield of the desired 3 ″ -hydroxy compound compared to the best previously known methods (about 86% compared to 63%). The reduction is considerably faster so that less 17-epimerization takes place. This result was particularly noteworthy when the reduction system was preformed (from Chloroirdium- (IV) - acid, trimethyl phosphite and aqueous isopropanol) and when triethylamine was used as the base.

Similar improvements can be made with other reductions in the pregnancies and with others Iridium catalyst reduction systems and bases

^{r> 0} can be found.

For example, again in the reduction of 5µ-pregnane-3,11,20-trione using the technique just mentioned, the ratio of 3a: 3ß- alcohols that are made can vary with the phosphite used. If one tris (2-chloroethyl) phosphite and diisopropyl phosphite used in place of trimethyl phosphite were ": ß ratios of 20: I and 14: I achieved, compared with a

14: 1 ratio with trimethyl phosphite. Under comparable conditions, using trimethyl phosphite, however, in the absence of an added base, the ratio was 3a: 3 / i-alcohol get 7: 1.

The process of the invention can result in a decrease in the degree of isomerization that occurs at the 17-position of a 20-oxopregnane, but in some cases it is desirable to eliminate the possibility entirely. This can be done by using an A ^ie steroid as the starting material (for example 5a-Pregn-16-ene-3,11,20-trione in the production of 3o-hydroxy-5a-pregr.an-1 1,20 -dion).

It has been found that 3o-hydroxy-5a-pregnan- »5 11,20-dione can be produced in high yield and in a high state of purity if 5a-pregn-16-en-3, l 1,20-trione is first prepared reduced using the process according to the invention and then the resulting 3'-hydroxy-5fi-pregn- * ° 16-en-l 1,20-dione hydrogenated (for example catalytically hydrogenated).

If the reduction process according to the invention is used for 5 r / -Pregn-16-en-3, 1 1,20-trione, it is surprising that the resulting mixture of 5 3h and 3 / -hydroxy ^{-A ie steroids} can be separated according to a simple crystallization process (in some cases by the mere addition of hot water to the reduction products), whereas the mixture of 3 h- and 3 / I-hydroxystroids obtained by 3 <> reduction of a 5H-prangan-3, 11,20-trione was obtained, is much more difficult to separate.

The method according to the invention can also be expediently used to obtain from the corresponding 3-Ketones make a wide variety of steroids that exhibit anesthetic activity, such as:

1. Su-Hydroxy-SH-prcgnnn ^ O-one,

2. 3H-Hydroxy-l9-nor-5a-prcgnan-l 1,20-dione,

3. Sn-Hydroxy - ^ - nor-Sn-prcgnan ^ O-on and

4. 2 (i-methyl-3ri-hydroxy-5a-preggnun-l 1,20-dione.

The compound 3 is a new compound and is also the subject of the present invention.

When the above compounds are to be used as anesthetics for intravenous administration, they can be brought into aqueous solution by using the method described in Belgian patent 7 52 165. For example, the compounds can be brought into solution with the aid of a physiologically compatible non-ionic obcrflttchcnuktiv agent, which has, for example, an HLB value of over 9 and preferably 9 to 18, and the solutions thus prepared can generally have the same composition in relation to ( In the steroid and the surfactant SS described in the above Belgian patent, the compounds can be used according to the procedures and in the dosages as described in Belgian patent 7 52 165 with respect to the 3M "hydroxy" 5H-pregnane -ll, 20'dlon described ^βο are administered.

The principle thin-layer chromatography (preparation I ve TLC) was carried out with silica gel. The term "petrol" as used in the present context means Potrolther (boiling point 60 to 80 ¹¹ C). «S.

The following examples (some are 'comparison endings) explain the (invention without, however, limiting it, the temperatures are given in "C. and the percentages are by weight unless otherwise specified. All rotation values were Determined in about 1% (weight / volume) chloroform, unless otherwise stated. "Floor"- Chloroiridic acid solution was prepared by adding a mixture of chloroiridic (IV) acid (0.09 g), isopropanol (200 ml) containing 10% water), and trimethyl phosphite (16 ml) over 16 hours refluxed. The solution was neutralized with triethylamine immediately before use.

example 1
3 a-Hydroxy-Sa-pregn-16-en-1 1 20-dione

Chloroiridic (IV) acid (0.6 g) was added to a mixture of isopropanol (1410 ml), water (225 ml) and trimethyl phosphite (195 ml). After refluxing for 4.5 h, the colorless solution was cooled to about 60 ° C. and triethylamine (247 ml) and then 5a-pregn-16-ene-3,11,20-trione (150 g) were added admitted. The mixture was heated to reflux and after a further 25 h, water (1750 ml) was added to the stirred solution at 65 ° C. After cooling and storage at + 5 ^° C. for 16 h, the white crystalline solid was filtered off, washed with water (1000 ml) and dried to constant weight ^{at 40 ° C. in vacuo.} 116.7 g (77.8% weight / weight 77.3% of theory), melting point = 231 to 237 ° C., were obtained. GLC (gas-liquid chromatography) analysis: 97.7% title compound, 1% 3 /? Isomer.

Example 2

Isopropyl alcohol (56.5 ml), distilled water (9 ml), trimethyl phosphite (7.5 ml) and chloroiridium (IV) acid c (12 mg) was heated to reflux for 12 hours and then the reaction mixture was left cooling down. Five 12 ml aliquots were removed and to each solution one added:

Flask l: 5n-Pregn-l6-cn-3, l 1,20-trione (I g) (»Trion A «):

Flask 2: triethylamine (1.1 ml; 0.75 mol / mol trimethyl phosphite) imd Trion A (I g);

Plunger 3:; triethylamine (1:45 ml; ₁ O mol / mol Trimcthylphosphit I) and Trion A (I g)

Flask 4: triethylamine (2.1 ml; 1.5 mol / mol trimethyl phosphite) and trione A (1 g);

Flask 5: pyridine (0.8 ml; 1.0 mol / mol trimethyl phosphite) and Trion A (I g).

Each mixture was refluxed for 5 hours and then subjected to TLC study (Merck Kicsclgcl F 254; benzene / ethyl acetate [1: 1]; Visualization by means of ultraviolet light. The settlement mechanism had a λ / value of 0.75 and was converted into the 3-hydroxy compounds, λ / value 0.5). Samples I, 2 and 5 were each to the extent of 5%, Sample 3 to the extent of about 40% and sample 4 reugged to the extent of about 50%.

Example 3

The reaction solution was prepared as in Example 2, five 12 ml aliqiioto parts were removed, and /. to each one added:

Sample 1: 5fi-Pregn-16-cn-3, ll, 20-trion (I g) (»Trion Bi

Sample 2: triethylamine (1.45 ml; I mol / mol trimethylphosphate) and trione B (I g);

700 630/221

Sample 3: triethylamine (2.18 ml; 1.5 mol / mol trimethyl phosphite) and trion B (I g);

Sample 4: triethylamine (2.9 ml; 2.0 mol / mol trimethyl phosphite) and trion B (1 g);

Sample 5: pyridine (1.67 ml; 2 mol / mol trimethyl phosphite) and Trion B (I g).

The mixtures were heated to reflux for 5.25 h and then, as described in Example 2, examined by thin layer chromatography. Sample 1 had to an extent of about 10% that Samples 2 and 5 to an extent of about 50% each and Samples 3 and 4 to an extent of about 60% reacts.

Example 4 * 5

Isopropyl alcohol (56.5 ml), distilled water (9 ml), trimethyl phosphite (7.5 ml) and chloroiridic (IV) acid (20 mg) were refluxed for 15 h, cooled, and then six 12 ml - _ao aliquots taken. To each one added:

Sample 1: triethylamine (1.56 ml; 1.08 mol / mol trimethyl phosphite) and Trion B (1 g);

Sample 2: N-ethylpiperidine (1.24 ml; 0.87 mol / mol

Trimethyl phosphite) and Trion B (1 g); as

Sample 3: N-ethylpiperidine (1.57 ml; 1.09 mol / mol trimethyl phosphite) and Trion B (1 g);

Sample 4: piperidine (0.92 ml; 0.9 mol / mol trimethyl phosphite) and Trion B (1 g);

Sample 5: piperidine (1.12 ml; 1.09 mol / mol trimethyl phosphite) and Trion B (1 g);

Sample 6: Trion B only (I g).

After refluxing each flask for 7 hours, the samples were subjected to thin layer chromatography (as in Example 2) investigated. It was found:

Sample 1 had about
Sample 2 had about
Sample 3 had about
Sample 4 had about
Sample 5 has.'c to about

60% reacts
70% reacts
80% responds
70% reacts
95% responds
Sample 6 reacted about 30%.

10

if diisopropyl phosphite was used, the product had an a //? ratio of 14: 1.

Example ό
Sa-Hvdroxy-Sa-pregn-lo-en-l 1,20-dione

Chloroiridium- (IV) acid (176 mg) was added to a mixture of isopropanol (112.5 ml), water (18 ml) _{un (i} trimethyl phosphite (15 ml). After 6 h _m was heated to reflux, was the colorless solution is cooled to about 60 ° C, and triethylamine (17.5 _m l) was added, and then 5a-pregn-16-en-3 added, l 1,20-trione (12 g). the mixture was 18 h, heated to reflux, and water (130 ml) ^{mii emer} T ^em P ^he ature of 8O ⁰ C was added slowly. After cooling and store at +5 ⁰ G for 16 h the white crystalline solid was filtered, washed with water (100 ml) and dried in vacuo at 40 ⁰ C to a constant weight of 9.57 g dried (79.8% w / w; 79.1% of theory), F = 230 to 235 ° C under weak decomposition.

GLC analysis: 96.7 / ₀ title compound
AU /, j / i isomer.

4 »

Example 5
3 tt-1-hydroxy-5 "-pregnane-11,20-dione

Chloroiridium (IV) silurc (17.3 mg) and trimethyl phosphite (2 ml) and 10% strength aqueous isopropanol (25 ml) were refluxed for 16 hours. The pH of the solution was increased to 7 by addition of methylamine set, and 3 a-Pregnan-3,11,20-

^ ¹⁰ »]; ¹ ,?! ^only ft ™ * ™ ^{ ? ^{\ P ^{ic Le "u"} e was 18 h heated to reflux (ml 200) poured into water and cxtruhicrt with Mcthylenehlorid. The extracts were washed with a 2% Nntriumbicurbonatlösung and then with water. The solution was dried (Nu ₁ SO ₄ ) and evaporated to a foam (0.97 g). Gas chromatography showed three main pcuks:

3α-Hydroxy-5a-pregnun-l 1,20-dione ... 86.0% Example 7
3u-hydroxy-19-nor-5a-pregnan-l 1,20-dione

Chloroiridic (IV) acid (0.09 g), 10% aqueous isopropyl alcohol (200 ml) and trimethyl phosphite (16 ml) were refluxed for 16 hours. The solution * "*? F ^{h & c} ^ f ^and neutralized with. Triethylamine . P ₁ ^{fj eser} V?" ¹ * ^{w "earthing" "9} Jr ⁵
Solution was cooled between water and
and the organic layer was washed well with water, dried (Na ₂ SO ₄ ) and evaporated. The residue was subjected to preparative thin-layer chromatography (ethanol) and recrystallized from acetone to give the title compound (0.6 g, 67%) in the form of white needles. F ~ 154 ° C, [r «] / H-200 °.

«Example 8

3 "-Hydroxy-19-nor-5" -prgnan-20-one
A solution of 19-nor-5H-pregnnn-3,20-dione (0.25 g) in chloroiridium (IV) -suurc solution was

"O _{w n} j io Example 7. (30 ml) and 24 h heated to reflux. The resulting solution was poured into water. The precipitated solid was collected by filtration; washed with water and dissolved in chloroform. The resulting solution

was dried (Na ₄ SO ₄ ) and evaporated. The residue was recrystallized from acetone / Pctroluther to give the title compound (0.17 f, 68%) in the form of white platelets. F 1 170 to 172 ⁰ C [a] ß-H ^{2 O e} (c 1.4).

Example 9

". ....... u. . ,,. . 5 "-pregnan-3.20.dlon (7.0 g, 22 moles) was added zi

A similar experiment was made using Chloroiridium (IV) acid reagent, Indon Tris. (2-chlorothyn-phosphl carried out, a mixture of Chlorairldium (IV) -8Üun was obtained

a material, and the aaiehromatographic indicated. (116 mg), 10% aqueous liopropyl alcohol (231

that it had a "///" ratio of 20: 1. Used ml) and trimethyl phosphite (19 ml) on overnight

Refluxed and then neutralized with triethylamine] and the mixture was refluxed for 24 hours. The reaction mixture was poured into water and the product was extracted with chloroform. The combined extracts were washed with water, dried (Na ₂ SO ₄ ) and evaporated in vacuo. Crystallization of the residue (6.7 g) from ethyl acetate gave the title compound (4.5 g, 64%). F = 170 to 172 ⁰ C ₁ [a] _D + 99.3 ° (c 0.8). ίο

In a similar experiment in which triethylamine was not used and in which the reduction system was not preformed, the yield was 35%.

Example 10
3 α-Hydroxy-2 α-methyl-5 α-pregnane-11,20-dione

A solution of chloroiridic (IV) acid (40 mg) and trimethyl phosphite (6 ml) in 10% aqueous ao Isopropanol (75 ml) was heated to reflux for 17 hours. It was cooled and neutralized with triethylamine.

A portion of this reaction mixture (2 ml) and 2a-methyl-5a-pregnane-3, l 1,20-trione (45 mg) were refluxed together for 48 hours. The reaction mixture was then partitioned between water and methylene chloride. The organic layer was dried (MgSO ₄ ) and evaporated to give the title compound (20 mg) which, in its nuclear magnetic resonance spectrum (in CDCl ₃ ), had a doublet at τ 9.06 (d, J = 7 Hz) for the 2nd <x methyl protons showed. The yield was 44%.

In a similar experiment in which the triethylamine was not used and in which the reduction system was not preformed, the yield was 30%.

Example U
2 l-benzyloxy-3 a-hydroxy-5 "-pregnane-11,20-dione

A solution of 20 / J.21-epoxy-3 a-hydroxy-5 apregnnn-11-one (0.75 g) in benzyl alcohol (20 ml) was treated with boron trifluoride / ethyl ether (0.3 ml) at room temperature for 24 hours. The solution was then partitioned between water and ether and the organic layer was washed with water, dried (Na ₄ SO ₄ ) and evaporated.

A solution of the residue, crude »21-benzyloxy-3,20 // -dihydroxy-5α-pregnan · 11-one in acetone (20 ml), was mixed with an excess of Joncii reagent (approximately 5» 1.7 ml ) treated. The mixture was then partitioned between water and ether and the organic layer was washed with water, dried (Na ₁ SO ₄ ) and pumped down. The residue was purified by prupurulative thin-layer chromatography (EtOAc / Pctrolülhcr l / l), the 21-uenzyloxy-5u-preggnan-3,11,20-trione being obtained as a white foam.

The 2l-benzoyloxy-5 "" pregnane-3,11,20-trione obtained was treated with "Stouk"-chloroiridivim> (IV) -silurelö-Hung (30 ml). The resulting solution was refluxed for 16 hours, cooled and partitioned between water and ether. The organic layer was washed with water, dried (Na ₉ SO ₄ ) and evaporated. The residue was subjected to the preliminary thin-layer chromatography (CHCI _n ), whereby the titanium compound (0.2 g, 45% ocsamt yield) was obtained. [a] tH-70 ° (c 1.4), A
230 mn (β 900).

Example 12
21 -Cyclopentyloxy-3α-hydroxy-5α-pregnane-11,20-dione

A solution of 20 / ?, 21-epoxy-3u-hydroxy-5apregnan-11-one (0.75 g) in cyclopentanol (20 ml) was treated with boron trifluoride diethyl etherate (0.3 ml) at room temperature for 24 hours. The solution was then partitioned between water and ether and the organic layer was washed with water, dried (Na ₂ SO ₄ ) and evaporated.

A solution of the residue, crude 2l-cyclopentyloxy-3a, 20/5-dihydroxy-5a-pregnan-II-one, in acetone (20 ml was treated with a slight excess of Jones reagent (about 1.8 ml) The mixture was then partitioned between water and ether and the organic layer was washed with water, dried (Na ₂ SO ₄ ) and evaporated The residue was purified by preparative thin layer chromatography (EtOAc / petroleum ether 1: 1) to give the 21-cyclopentyloxy -Sa-pregnan-Sl 1,20-trione in the form of a white foam.

The 21-cyclopentyloxy-5α-pregnane-3, ll, 20-trione obtained was treated with "stick" chloroiridium (IV) acid solution (30 ml). The resulting solution was refluxed for 16 hours, cooled and partitioned between water and ether. The organic layer was washed with water, dried (Na ₂ SO ₄ ) and evaporated. The residue was subjected to preparative thin layer chromatography (CHCl ₃ ) to give the title compound (0.3 g), [α] + 80 ° (c 1.1).

Example 13
21 -Chlorethoxy-3 "-hydroxy-5α-pregnane-11,20-dione

A solution of 20 [beta], 21-epoxy-3a-hydroxy-5apregnan-11-one (1.0 g) in ethyl chlorohydrin (25 ml) was treated with boron trifluoride diethyl titrate (3 drops) at room temperature for 1.5 hours. The solution was then partitioned between water and ether and the organic layer was washed with water, dried (Na ₂ SO ₄ ) and evaporated. The more polar product, crude 2l-ChloriUhoxy-3a, 20 /? -Dihydroxy-5'iprcgnan-11-one, (1.3 g) was dissolved in acetone (98 ml) and treated with Jones-Rcugcns (1.8 ml) Treated at O ⁰ C for 5 min. The resulting mixture was partitioned between water and ether and the organic layer was washed, dried (Να _β 8Ο ₄ ) and evaporated. The less polar product, crude 21-chloroethoxy-5u-pregnane-3, l 1,20-trione (1.2 g) was treated with Stockw-Chloroiridium-dVJ-stturclösung (36 ml). The resulting solution was refluxed for 24 hours, cooled and partitioned between water and ether. The organic layer was washed with saturated aqueous sodium bicarbonate solution and water, dried (Na ₁ ISO ₄ ) and evaporated. The residue was subjected to preparatory thin-layer chromatography (EtOAc / petroleum ether 1: 1), the title compound (0.674 g, 55% yield) being obtained in the form of a white foam. [φ- | -62 ^ο (c 0.9),

Example 14
21-Chloropropoxy-3 α-hydroxy-5 α-prgnane-11,20-dione

A solution of 20 / 9.21 -Epoxy-3 a-hydroxy-5 apregnan-U-one (1.0 g) in 3.ChloMVpropanol (5 ml)

was treated with boron trifluoride diethyl etherate (6 drops) at room temperature for 5 hours. Another amount of boron trifluoride diethyl etherate (6 drops) was added and the mixture was kept at room temperature for an additional 1.5 hours. The mixture was then poured into water and the gummy precipitate was separated by filtration and washed with water. A solution of the precipitate in chloroform was dried (Na ₂ SO ₄ ) and evaporated.

The more polar product, crude 21-chloropropoxy-3 ", 20 / J-dihydroxy-5a-pregnan-II-one, (1.25 g) was dissolved in acetone (63 ml) and treated with Jones reagent (1.4 ml ) treated at room temperature for 5 min. The mixture was partitioned between water and ether and the organic layer was washed with water, dried (Na ₈ SO ₄ ) and evaporated.

The less polar residue, crude 21-chloropropoxy-5u-pregnane-3, l 1,20-trione (1.1 g) was treated with "stick" chloroiridium (IV) acid solution, ao. The mixture was then left for 24 h heated to reflux, cooled and partitioned between water and ether. The organic layer was washed with water, dried (Na _a SO ₄ ) and evaporated. The residue was subjected to preparative thin layer chromatography (EtOAc / petroleum ether 1: 1) to give the title compound (0.54 g, 45%) as a white foam. ([α] »- | 73 ° (c 1.3).

Example 15

3 "-Hydroxy-21-methoxy-16" -mcthy 1-5 "-pregnan-11,20-dione

3 Hydroxy-16 "-methyl-5" -pregnane-11,20-dione (5 g) was dissolved in dry methanol (350 ml) and at ⁰ ° C. with a solution of bromine (1 ml) in dry methanol ( 24 ml) at such a rate that the yellow color disappeared before further addition. After the addition was complete, the mixture was poured into water. The precipitated product was dried and dissolved in chloroform (20 ml) and poured onto a silica gel with silica gel (700 g) , 6 g) in the form of a foam. [U] ir \ 112.4 ".

The bromine compound (3 g) in methanol (70 ml) and dry tetrahydrofuran (15 ml) was stirred with nutrium borohydride (300 mg) and water (H) ml) for 30 min. Glacial acetic acid (0.3 ml) was then added , and the mixture was stirred with 2N nutrium hydroxide (18 ml) for 1 hour. The mixture was poured into water, stirred, and the precipitate was collected by filtration and dried on a pump, taking 20 / J-2l- Epoxy-3H-hydroxy-5fi-pregnnn-1 I-one (2.7 g), which was then treated with dry ncm methanol (125 ml) and boron trifluoride diutyl-Itthcrut (2 ml) with stirring for 4 hours was neutralized with saturated wuUrigcn Nutriumbicurbonut and evaporated. The residue was dissolved in chloroform (250 ml), washed with water ^e <>, dried (Na ₁ SO ₄₎ and evaporated to give mun dus in ^ O / MDihydroxy ^ l-mcthoxy- ICiH-mcthyU5ri-prcgnan-l l-one (2.4 g), which was dissolved in acetone (175 ml) and treated with a slight excess of Joncs-Reugcns until it was completely oxygenated xydation treated. The Reuktlonsmlsclumg was distributed between water and ether, the ether layer was washed with water, dried (Na ,, SO ₄ ) and evaporated. The entire crude product was refluxed for 18 hours in a "stick" chloroiridium (! V) catalyst solution (75 ml). The reaction mixture was partitioned between water and ether, the ether layer was washed with water, dried (Na ₂ SO ₄ ) and evaporated. The product was purified by preparative thin layer chromatography [ethyl acetate / chloroform (1/1)] to give the title compound (0.95 g). [«]» 4-84.9 "(c 1.09).

Example 16
3α-Hydroxy-21-methoxy-5α-pregnan-20-one

A stirred solution of 3u-hydroxy-5u-pregnan-20-one (5 g) in AR-Mcthanol (350 ml) was mixed at ⁰ ° C. with a solution of bromine (1 ml) in methanol (23 ml) with such Treated speed so that the yellow color disappeared before further addition. The resulting suspension was poured into water and stirred for 30 minutes. The precipitate was collected by filtration and dried in vacuo. The product was purified by column chromatography. Elution with benzene / ethyl acetate (1/1) gave the 21-bromo-3a-hydroxy-5 (i-prgnan-20-one (5.2 g), Mw-I-105.5 ".

The total product (5.2 g) in methanol (200 ml) and dry tetrahydrofuran (50 ml) was stirred with sodium borohydride (440 mg) and water (20 ml). After 1 hour, glacial acetic acid (0.4 ml) was added, followed by the addition of 2N sodium hydroxide (25 ml) and stirring for a further 2 hours. The solution was then poured into water (11) and stirred for 30 minutes. The precipitated 20 / ?, 2l-epoxy-3 <i-hydroxy-5 <iprcgnan (4.9 g) was collected by filtration and dried in vacuo (4.9 g). It was treated with AR-methanol (225 ml) and boron trifluoride diethyl etherate (2 ml) with stirring for 15 hours. The solution was then neutralized with saturated sodium bicarbinate solution and evaporated. The residue was dissolved in chloroform (500 ml), washed with water, dried (N _a SO ₄₎ and evaporated to give the 3, '20 / f-Dihydroxy-2l-methoxy-5' pregnan (3.7 g ) received. This was dissolved in acetone (250 ml) and treated with a slight excess of Jones reagent until completely oxidized. The reaction mixture was partitioned between water and ether, and the ether layer was washed with water, dried (Nn ₁₁ SO ₄ ) and dumped. The product was recrystallized from Accton / Pctrolllthcr, whereby the 2l-methoxy-5u-pregnane-2,30-dione was obtained in the form of white noodles (1.85g), F «156 ⁰ C, Μ« + Ι4Γ (c 0, 16).

All of the crude product was dissolved in stick chloroiridium (IV) acid solution (90 ml) and the resulting solution was refluxed for 16 hours. The solution was allowed to cool and partitioned between water and ether. The ether layer was washed with water, dried (Nu ₁₁ SO ₄ ) and evaporated. The crystalline residue was dried in vacuo and recrystallized from acctone / pctrolate, whereby the titanium compound (0.84 g) was substantially equal to. 163 to 164 ¹¹ C ₁ [u] " | -85.4" (c 0.96).

Example 17 3 H-hydroxy-5 "'pregnan- II, 20-dione

u) Chloroirldium- (IV) -suurc (50 mg) was found in Prc pnn-2-ol (94 ml) and water (6 ml) «clus

Trimethyl phosphite (8 ml) was added and the solution was refluxed for 24 hours. 5 M-Pregnan-3,11,20-trione Ί g) was in the ChIoroiridic (IV) acid reagent (25 ml) dissolved, buffered with triethylamine to a pH value of 6.9, and the solution was refluxed for 2.5 hours then poured into water and the steroid extracted with chloroform. The G.L.C. analysis of the product showed approximately the following composition: Title compound (88%), 3 / Msomeres (7%), starting material (2%) and 17u-isome-

Crystallization from aqueous methanol gave the title compound (630 mg), mp = 163 to 166 ^° C.

Moisture content of chloroiridic (IV) acid reagent: 3.2% (w / v) (Karl Fischer).

b) The chloridic (IV) acid reagent (15 ml), prepared as above under a), was with triethyl- »o amine buffered to a pH of about 7.

5 a-Pregnan-3,11,20-trione (30 mg) was used in the The reagent was dissolved and the reaction mixture was stored at room temperature for 24 hours. The Steroid was isolated by pouring the reaction mixture into water and adding chloroform extracted. G.L.C. analysis of the product showed approximately the following composition: Title compound (89%), 3 / Msomeres (5%) and starting material (6%).

c) Chloroiridium (IV) acid (50 mg) was dissolved in propan-2-ol (97 ml) and water (3 ml) was added. Ti imethylphosphite (4 ml) was added, and the solution was refluxed for 24 hours. Chloroiridic (IV) acid reagent (25 ml), buffered with triethylamine to a pH value of 6.9, became 5 a-pregnane-3,11,20-trione (1 g) was added and the solution was refluxed for 2 hours. She was then poured into water and the steroid (1.01 g) was extracted with chloroform. G.L.C. analysis showed something like the following Composition: title compound (90%), 3 / Msomeres (7%), 17a-Isomeres (2%) and starting material (2%).

Moisture content of chloroiridic (IV) acid reagent: 2.2% (weight / volume) (Karl Fischer).

d) Chloroiridic (IV) acid (50 mg) was dissolved in propan-2-ol (99 ml) dissolved, and water (I ml) and trimethyl phosphite (I ml) were added, and the solution was refluxed for 3 days.

5 α-pregnane-3,11,20-trione (1 g) was dissolved in the chloroiridic (IV) acid reagent (12.5 ml), buffered to pH 7 with triethylamine and then propan-2-ol was added (12.5 ml). The reaction mixture was refluxed for 3 h, poured into water, and the Steroid was extracted with chloroform. The G.L.C. analysis showed roughly the following composition: Title compound (89%), 3 / Msomeres (5%) and starting material (6%).

Moisture content of chloroiridic (IV) acid reagent: 0.8% (Karl Fischer).

buffered at pH 7. 5u-Pregn-16-en-3, 11, 20-irion (2 g) was added and the solution was refluxed for 2.5 h. At this point the steroid began to crystallize. Water (30 ml) was added and the reaction mixture was ^{stored at 5 °} C. for 17 h. The crystalline solid was filtered off to give (g 1.516, 76% w / w), the title compound, m.p. = 230-233 ⁰ C. The GLC analysis showed that the product contained about 2% 3 / Msomeres and 3% starting material .

Example 19
21-acetoxy-3a-hydroxy-5a-pregnane-1 1,20-dione

Chloroiridic (IV) acid (50 mg), propan-2-ol (94 ml), water (6 ml) and trimethylphosphile (8 ml) were refluxed for 24 hours . The solution was cooled to room temperature, buffered to pH 6.9 with triethylamine, and 21-acetoxy-5apregnane-3,11,20-trione (400 mg) was added. The reaction mixture was stored at room temperature for 17 hours, poured into water, and the steroid was extracted with chloroform. Crystallization from acetone / petroleum ether (b.p. 40 to 6O ⁰ C) gave 21-acetoxy-3a-hydroxy-5a-pregnan-l 1,20-dione (230 mg), F = 180 to 184 ° C.

Example 20

3a-Hydroxy-17 /? - (3'-morpholinopropoxycarbonyl) -5a-androstan-II-one

A solution of 17 / J- (3'-morpholinopropoxycarbonyl) -5a-androstane-3, l 1-dione (140 mg) in isopropanol (1 ml) became a "stick" solution of the Chloroiridic (IV) acid reagent (7 ml) mixed with triethylamine immediately before adding to a pH of about 6 had been neutralized, was added. After refluxing for 7 h, isolation of the product gave a gum (150 mg), after purification by preparative thin layer chromatography, the title compound in the form of a white foam gave (112 mg), [«] ο + 5Γ (c 0.6).

Example 21

Chloroiridic (IV) acid (50 mg) was dissolved in propan-2-ol (94 ml) and water (6 ml). Trimethyl phosphite (8 ml) was added and the solution was refluxed for 24 hours. 10 ml aliquots were made removed, and added to each solution:

Example 18
3 "-Hydroxy-5" -prcgn-16-en-1 1,20-dione

Chloroiridic (IV) acid reagent (20 ml) as in Example I7d), with triethylamine on sample 1: 5 a-pregnane-3,11,20-trione (20 mg)

("Trion C"); pH 1.6
Sample 2: triethylamine (0.5 ml) and Trion C (20 mg);

pH 3.3
Sample 3: Triethylamine (0.7 ml) and Trion C (20 mg);

pH 4.4
Sample 4: Triethylamine (0.77 ml) and Trion C (20 mg);

pH 4.9
Sample 5: triethylamine (0.8 ml) and Trion C (20 mg);

pH 6.5
Sample 6: triethylamine (0.85 ml) and Trion C (20 mg);

pH 7.2
Sample 7: Triethylamine (1.0 ml) and Trion C (20 mg);

pH 7.8
Sample 8: Triethylamine (1.2 ml) and Trion C (20 mg); pH 8.0

Sample 9: triethylamine (1.4 ml) and Trion C (20 mg); Example 26

P ^{H 8> 1} To a mixture of chloroiridium (IV) acid

Each mixture was made 5 r at room temperature ^{to- (4 mg), l} ^^^^ £ _T ^ _ü SZ ml '

Then the steroid was isolated by adding 5 ^^ K * 3Sffiu £% i Mii &

-products showed that the sample i not 3-hydroxy- (I g) to ^"nd f ^{erh d 6} ^" ^g _FOR g _e a _e b _{eri U} n5 di;

samples 6 and 7 received about 45% and samples 8 and 9 with a 3 «: 3 / i ratio of 100. I,

about 40% 3a-hydroxy-Sa-pregnan-1 1,20-dione ent- Example 27

held. The conversions were not carried out until the BeruumiriHnim uv) MMr ^ s _n \

completion carried out and the specified yield. A mixture of Ch ° £ '^ J ₂ " _m u>X" hl ⁸⁾ '

th serve only to the effect of the changes> _s Dimethylacetam.d (10ml), water (2 ml) Ph <»Phoriger

huh. i-i. Acid f 1 74 e) and 5 a-Pregn-1 o-en-3.11, ΛΗποη (2.0g)

.m pH compared to. Si has heated to 98'C. Hot water (3 ml) _wu ?

de added, and the 3a-hydroxy-5a-pregnan-l 1.20-

Example 22 Ji _0n was produced in a rather 73% yield with a

A mixture of isopropyl alcohol (50 ml), 3α: 3 / Msomer ratio of 100: 0.9 separated. Water (1.83 ml), trimethyl phosphite (4 ml), chloro-

iridic (IV) acid (18.5 mg) and triethylamine (4 ml) preparation for the preceding examples were refluxed for 16 h. The 5a-Pregnan- used starting materials
3 11,20-trione (2 g) was added, and after \ \ _{[a-hydroxy-i9-nor-pregna-4,16-diene-3,20-dione} 18 further urinary reflux had heated showed the thin - »5"., "■■.,., -, ^. Layer chromatographic investigation that the A solution of a mixture of Π α, 17a-di-conversion was complete. The crude product (1.95 g) hydroxy-19 -nor-pregn-4-en-3 20-d.on (4 g) and ISemi was isolated by precipitation with water and analyzed by chromatography on gas carbazide hydrochloride (4 g) in methanol (200 ml) which was found to be 2 h The methanol was de-isolated from 85.5% Sci-Hydroxy-Sa-pregnan-11 ^ O -3 ° then dione with 5% 3 /? -Hydroxy-5a-pregnan-1 by distillation under reduced pressure 1,20-dione was removed, and water was added to the residue, and the precipitated solid was purified by filtration

collected, washed with water and dried over P ₂ O ₅ im

Example 23 vacuum dried. A solution of this solid in

A mixture of isopropyl alcohol (9.4 ml), a mixture of glacial acetic acid (80 ml), water (28 ml)

Water (1.5 ml), trimethyl phosphite (1.25 ml), chloro- and pyruvic acid (4 ml) was added to a

iridic (IV) acid (5 mg), triethylamine (1.45 ml) and steam bath heated for 1 h. The resulting solution was

5a-Pregn-16-en-3.il, 20-trione (1 g) was concentrated at the back under reduced pressure and between

river heated. The reaction was thin-layer saturated aqueous sodium bicarbonate and ethyl

followed by chromatography and it was slowly and acetate distributed. The organic layer was washed with water

95% complete only after 42 h. Washed water with hot water, dried (Na ₂ SO ₄ ) and to dryness

(11 ml) was added and then allowed to evaporate. The residue became the preparative one

Crystallize product (70.23%). Gas-liquid thin-layer chromatography [CHCy (CHj) ₂ CO (15 /

keits chromatography (G.L.C.) showed that it was subjected to I)] and converted from acetone / petroleum ether

Was 96.5% pure and contained 2% 30 isomer. 45 crystallizes, the title compound (1.6 g) in

Received form of white needles from F = 149 ° C.

Example 24 2. 19-Nor-5a-piegna-3, l 1,20-trion over 3 f, lla, 20f-

A mixture of isopropyl alcohol (56.5 ml), trihydroxy-19-nor-5 "-pregnane

Water (9.0 ml), trimethyl phosphite (7.5 ml) and 5 <> A solution of 11 a-hydroxy-19-nor-pregna-4,16-

Iridium tetrachloride (25 mg) was refluxed for 18 hours with diene-21,20-dione (2.5 g) in dry tetrahydrofuran

heated. To a 12 ml aliquot (200 ml) was added to a solution over 5 minutes

Triethylamine (1.58 ml) and 5a-Pregn-16-en-3, ll, 20- of lithium (5 g) in liquid ammonia (2.5 I)

trione (1 g) and refluxed for an additional 24.5 h. added. The solution was then held for 30 minutes.

Thin layer chromatography showed this to 55 Then ethanol (about 100 ml) was added until the

/ xitpunkt that the conversion was complete. blue color disappeared, and then that left that

Vaporize ammonia. The residue was between

. . see water and ether distributed. The organic

Example 25 Layer was washed, dried (Na ₁ SO ₄ ) and

Evaporated to a mixture of chloroiridium (IV) acid ^6o , crude 3 ξ, 11 α, 20 f-tri-

(4 mg), isopropyl alcohol (9.4 ml), water (0.94 ml), hydroxy-19-nor-5a-pregnane (1.5 g).

Methanol (1.28 ml), phosphorous acid (O _v 87 ml) and a solution of crude 3 ξ, 1 1 α, 20 f-trihydroxy-19-

Triethylamine (1.45 ml) was added to Sa-Pregn-lo-en-nor-5a-pregnan (4 g) in acetone (280 ml) was added

3,11,20-trione (1.0 g) and heated the solution for 21 h on a solution of potassium dichromate (8.0 g) in 2N-

Reflux. Hot water (II ml) was added, ⁶ 5 sulfuric acid (38 ml) treated for 1 hour at room temperature

and the crystalline product was delt in yield. Another amount of potassium dichromate (8 g) in

of 67.8% with a 3a: 3 / J isomer ratio of 2N sulfuric acid (38 ml) was then added, and

100: 1.1 separated. then the reaction mixture was 15 min at room

before Til

temperature kept. The solution, then methyl acetate / petroleum ether, gave the title compound

distributed between water and ether, and the organic (0.21 g), F = 176 ° C, [a] _D + 136 °.

Layer was washed with water, dried, "," ... "-, _nJ .

(Na ₈ SO ₁ ) and evaporated. The oil that remained was ⁶ · 3 α-hydroxy-16 α-methyl-5a-pregnane-1 1,20-dione
was the preparative thin layer chromatography 5 to a stirred slurry of copper (l) -

subjected (CHCl ₃ ) and from acetone / petroleum ether iodide (950 mg) in dry ether (75 ml) was added

recrystallized, the 19-nor-5a-pregnan- be 'O ⁰ C under dry nitrogen a solution of

3,11,20-trione (1.04 g, 25%) in the form of white prisms add methyllithium in ether (c 1.6 M, 6 ml) until

received, F = 151 ⁰ C, [a] ß + 240 °, the initially formed yellow precipitate just again

J ones reagent was dissolved and a clear solution was obtained. To the

A solution is referred to as “Jones reagent”. A solution of stirred solution was added at 0 ^° C.

of chromium trioxide (267 g) in a mixture of 3a-hydroxy-5a-pregn-! 6-en-ll, 20-dione (600 mg) in

concentrated sulfuric acid (230 ml) and water, dry tetrahydrofuran (50 ml). During the

(400 ml), made up to 1 l with water (8n W.R.T. addition, a light yellow precipitate formed

Oxygen). 15 mixture was stirred for 30 min at 0 ⁰ C and then in

a cold saturated ammonium chloride solution poured

3. 20,20-ethylenedioxy-2-hydroxymethylene-5ases. More ether was added, and the orgapregnan-3, ll-dione niche layer was separated with saturated

Xi _n .,:, «, 1,, j. · ^ _M “,. , ".., ammonium chloride solution and washed with water,

• nrtS1 « ^{Wl 8)} TÄÄ T 5 · rfY ^{U a} ° dried over Na ₁₁ SO ₄ and thinned by preparative

r JS Nn ^ nn? X? T ί Ϊ * I ^ t layer chromatography using ethyl

pregnan-3, ll-d.on (0.3 g) and Athy formate (0.3 ml) _{acetate g (; cleans)} ^B _W0 ^H _{when a} product was obtained that

in dry benzene (6 ml) was added under nitrogen. _by ^g _rä ⁸ _ti ' _ve thin layer chromatography under

The Reakt.onsm.schung at room temperature was _USAGE ^P _{dun of} ethyl acetate / chloroform (1/1) kept h further 24 and then to dryness under vacuum. ^ T * _w £ _{rd. to 'a white} solid ß _e n

evaporated. Aqueous Chlorwassentfoffsaure (2n) ₃₈₀ f _m |, _{erhie, t of from} ether / petroleum ether umkristalli-

was added to the residue, and after _{si w} * ;. _{dd the title compound (248 mg) in the form}

After 30 minutes of stirring, the solid ( _{0.33 g) became colorless platelets b F} J \ _iS ^ _14Q o _C

collected by filtration. Treatment with active _r ■,. o «» _ η q «

coal and crystallization from methyl acetate to petroleum ₃₀ ¹⁰ J ⁰ ^ ' ^cu · ^ ³ ·

ether gave the title compound (0.126 g, 39%), 7. 21-bromo-3a, 20/3-dihydroxy-5a-pregnan-II-one

5s ς ⁼ I ⁴ I ₈ S ¹⁵¹ ° ^C ' ^{[alö + 121} ° ^(c °' ⁵ ) ' ^Xmax raw unchromatographed 21 -Brom-3 a-hydroxy-

Z8D nm, (ε / 8UU). 5a-pregnan-l 1,20-dione (411 mg) in methanol (25 ml)

λ min x * u ι α- τ * u ι c -. , ι ^and water (5 ml) was at room temperature with

4. ^ O-Ethylenedioxy ^ a-methyl-Sa-pregnan ^ ll- _{35 sodium uni} borohydride (39 mg) stirred. After 90 min

ⁿ was added acetic acid (0.1 ml) was added and the solution

A solution of chloroiridic (IV) acid (30 mg) was evaporated to a small volume and placed between

and trimethyl phosphite (4.5 ml) in 10% isoprene see water and chloroform distributed. The organic

panol (60 ml) was refluxed for 17 h. Phase was dried (Na ₂ SO ₄ ) and under reduced

Then the solution was evaporated neutral- 4 ° with triethylamine pressure, giving a white

siert, and 20,20-ethylenedioxy-2-hydroxymethylene-5 a foam (438 mg) was obtained. This was the prepara-

pregnan-3, U-dione (2 g) was added. Subjected to medium thin layer chromatography (40 g),

The mixture was refluxed for 40 h, then the plates were eluted twice with chloroform.

cools and evaporates between water and methylene chloride. The main component came out as a white solid

Splits. The organic layer was dried 45 (200 mg) obtained which was encryped from ether,

(MgSO ₄ ) and evaporated in vacuo. The back - using colorless needles (86 mg) of the title compound

level (1.94 g) was obtained from the preparative thin-layer manure at temperatures from 195 to 197 ° C. Change of

Subjected to chromatography, two frac-crystalline form at 180 to 183 ° C, [α] β + 45.7 °

received. The less polar fraction (0.18 g) c 1.16.

was crystallized from methanol, the 5 <> -ilj _{c Mft}

Title compound (0.13 g) F = 179-180 ⁰ C, ⁸ "20 ^, _{21-epoxy-3a-hydroxy-5a-P} regnan-ll-one
[a] _D +77.5 ^o . A solution of 21 -Bromo-3 o-hydroxy-5 a-pregnan-

11,20-dione (1.18 g) in methanol (75 ml) was mixed with

, ~ _w . ,, · ,, ■ -, «· a solution of sodium borohydride (110 mg) in water

5. 2a-methyl-5a-pregnan-3, ll, 20-trione _{55 ser (lfi ml)} ^ j _room temperature stirred. After 1 h

A solution of 20,20-ethylenedioxy-2 α-methyl- was added glacial acetic acid (0.15 ml) and the resulting

5a-pregnan-3, ll-dione (0.39 g) and p-toluenesulfone - standing solution with 2N sodium hydroxide (6 ml)

acid (30 mg) in acetone (30 ml) was added under nitrogen for 1.5 h. After 1.5 h the solvent became

Stored at room temperature. evaporated and water was added. The Mi

The solution was then mixed to a low volume of 6 °, stirred for 1 hour and filtered. The residue

evaporated, and an aqueous solution of sodium was washed with water and dried, whereby

bicarbonate was added. The solid one gives the title compound (784 mg) in the form of very fine

was collected by filtration. Crystallization obtained from needles, F = 231-236 ° C.

Claims (2)

Compounds and the compound 3 «-Hydroxy-19- I. Vertaten for the production of 3 ,, - Hydroxy wool: Eipny * .tea beta one in the presence of an organic base and De production soicner ν more satisfactory of a catalyst system which, in the presence or in an adequately pure state and in a sufficient condition According to known methods, the absence of the steroid from a trivalent yield does not succeed Phosphorus compound, an iridium compound, and _{lightness has been} suggested 3- Water was produced, reduced. In the ^Ve . ^r p ^nge """· _Anza St. procedures 2. The method according to claim 1. thereby- Hydroxystero.de according to a number of verranren