DE1418857C - Process for the production of 3beta-hydroxy- (or-acyloxy) -9alpha, llbeta-dichloro-lobeta-methyl-salphasteroids of the pregnane series - Google Patents

Description

OAcyl -CH 3 or .— C- O H -CH 3 or ; C-
Il Il
O OH -CH oOAcyl, , - C-
il Il
O OH

and R is a hydrogen atom or an acyl group, characterized in that that a compound of the general formula II,

CH ₃

in which X and R have the meaning given, in the presence of an inorganic base or below Use of a water-immiscible organic solvent with the addition of Water selectively dichlorinated in the 9,11-position.

The invention relates to a process for the production of 3 /? - hydroxy (or -acyloxy ^ ix.ll / i-dichloro-16 /? - methyl-5a-steroids, used in the synthesis of steroids of the Pregnan range, the anti-inflammatory, and / or have adrenocortical activity, are particularly valuable.

It is known that various steroids with a 16-position methyl group with α- or / 9-configuration have valuable pharmacological properties and are generally more pronounced anti-inflammatory Properties and have fewer undesirable side effects than their counterparts Steroids without the 16 methyl group. Hence the preparation of such compounds important.

The manufacture of 16-methylsteroids from 11-ketosteroids the 5/9 Pregnan series has already been described. Some readily available and so far as starting compounds however, substances used to make adrenocortical hormones include the 5a series, such as B. Hecogenin.

An older proposal becomes a cheap one

ao process for the production of 16-methyl steroids developed, using a Z) ⁹ < ⁿ > -16-diene steroid of the Sa series, which can be easily obtained by breaking down hecogenin and other naturally occurring 5a steroids.

It is known that hecogenin acetate is converted into 3 / J-acyloxy-5 "-pregna-9 (II), 16-dien-20-one in several stages can be converted (Djerassi and employees, Journal of Org. Chem., 16 [1951], p. 1278, and Callow and James, Journal Chem. Soc.

[1956], p. 4739).

In the proposed process, 3/3-acyloxy-5 »-pregna-9 (II), 16-dien-20-ones are used as starting compounds for a multistage process which leads to further intermediate compounds which have a 16- (α- or / ?) - contain methyl group and in turn through a few more steps into the desired 16-methyl steroids, such as. B. 9 <% - Fluoro-16- («- or ß) -me thylprednisolonacetat can be converted.

If, however, intermediate products of the aforementioned kind are used, the difficulty arises that the 9 (11) positions are attacked by various reagents used in the synthesis be able. At one stage it can e.g. B. be required, an enol acylate with an unsaturated bond in 17 (20) position, and that would also epoxidize the 9 (11) double bond and thus lead to an undesired 9a, ll «-oxide grouping. The 9 (11) double bond must therefore protected so that it can be used in a further stage of the synthesis. It was found, that a very favorable method for such protection is the formation of a 9 ", 11/9 dichloro derivative is. This can easily be effected by direct chlorination of the /! »(!!» compound. The resulting di-chlorine compound is stable to many reagents, and the chlorine atoms can after implementation the desired reactions are removed and the 9 (II) -unsaturated bond can be reintroduced. The chlorine atoms can easily be reduced by such as

z. B. by catalytic hydrogenation or by "chemical" reduction, such as. B. by means of zinc / acetic acid or chromium (II) chloride can be removed. One can use the dichloro compounds better than other halogen compounds.

The production of 9 <x, ll /? - dihaogen steroids of the The pregnane or androstane series has already been proposed for compounds containing a 3-keto group and preferably one or more double

bonds contained in ring A. In contrast, however, the compounds according to the invention saturation in ring A and a hydroxy or acyloxy group in position 3.

The selective introduction of halogen in the 9- and 11-position is incomparably more difficult with these products and the stability of the 9,11-dihalogen compounds obtained is much lower than with the Δ ^u * compounds already described, which also applies to the process for isomerizing the Products matter.

When chlorinating 16β-methyl-zl ⁹ < ^u > compounds, there is a risk of two side reactions, namely the isomerization of the side chain from the β to the configuration and, second, the chlorination in one of the two positions to the 20th Keto group. Both side reactions are favored by hydrogen chloride, which is released in the reaction mixture. According to the process according to the present invention, the hydrogen chloride is therefore removed by neutralization or extraction.

The use according to the invention of an inorganic base for neutralization, such as solid alkali bicarbonates, is new. It has over the already proposed use of a tert. organic Base, such as pyridine, has the advantage that it completely suppresses the two side reactions mentioned and leads to far higher yields of the desired 9a, ll / 9-dihalo compound than in its absence a base or in the presence of a tert. organic base. It has been found that using a tert. organic base the hydrochloride of this base the isomerization of the side chain and / or undesirable Chlorination is just as favored as free hydrogen chloride. The extraction according to the invention of the formed hydrogen chloride in the two-phase chlorination system consisting of water / organic solvent can also be used successfully in place of an inorganic base.

The process according to the invention for the preparation of 3/3-hydroxy (or acyloxy) -9 ", 11/3-dichloro-16j3-methyl-5a-steroids the pregnancy series of the general formula I.

-C-CH ₃ or
O

CH ₃

wherein X is one of the following groups
= C - CH ₃ or

OAcyl
- C - CH ₃ or

Il ο

OH

OH

■ C - CH ₂ O acyl
O

and R represents a hydrogen atom or an acyl group is that you have a compound of the general formula II,

^15th X

CH ₃

RO

in which X and R have the meaning given, in the presence of an inorganic base or with use a water-immiscible organic solvent with the addition of water selectively dichlorinated in the 9.11 position.

Important compounds of general formula I are, for. B. S ^ O-diacetoxy-QÄ.III-dichloro-lojS-methyl-5 "-pregn-17 (20) -en, 3/3-acetoxy-9", ll | 9-dichloro-16/5-methyl -5 "-pregnan-20-one, 9A ₁ IIiS-DiChIOr- 3ß, 17" -dihydroxy-16 ^ -methyl-5a-pregnan-20-one and 21-acetoxy-9a, ll / S-dichloro-3ß, 17a-dihydroxy-16 / S-methyl-5a-pregnan-20-one.

The chlorination is preferably carried out in that the starting compound in a suitable Solvents such as B. methylene chloride, carbon tetrachloride or chloroform and then dissolved the chlorinating agent, such as. B. molecular chlorine in gaseous or dissolved form is added. Molecular chlorine is the preferred chlorinating agent. Other chlorinating agents useful for this purpose are described in U.S. Patent 2894963, e.g. B. N-chlorosuccinimide or N-chloroacetamide, with e.g. B. lithium chloride and / or hydrogen chloride.

Difficulties can arise in the practical implementation that at the same time Substitution by chlorine takes place elsewhere on the steroid molecule, and since these substitution reactions form hydrogen chloride as a by-product, The latter can in turn have difficulties due to isomerization at another point in the steroid molecule cause.

The isomerization can, however, be inhibited by removing hydrogen chloride as soon as it is has formed, such as B. by extraction or neutralization. When the solvent with water is immiscible, this can be done by adding water to the solvent and simply extracting Hydrogen chloride to the extent of its formation, in the

aqueous layer are carried out. You can also use a base, such as. B. a solid alkali metal bicarbonate add to the solvent to neutralize hydrogen chloride in situ. Aqueous alkali metal bicar-

5 6

bonat is not very satisfactory as it has been made by chlorine (2.5 kg) in methylene chloride (16 liters) reacts to form alkali metal hypochlorites. Filtration cleared through kieselguhr and put into a But you can add a substance that is used as a buffer to bring a 50-liter, 4-Ha! S round-bottomed flask made of glass acts and so an inexpedient reduction of the pH immersed in a methanol bath. The steroid solution was made Value prevented. Suitable compounds are stirred with a stainless steel stirrer and Alkali metal salts of weak acids such as Na- to about + 15 ° C by adding dry ice to the trium acetate. The buffers can be in solid form or cooled in a cooling bath. The nitrosomethylurea and aqueous solution can be used. Potash solutions were over in separate places

Chlorine tends to react with methylene chloride at a rapid rate when exposed to light on the surface of the diene solution, and when adding the reaction proportional to the volume being exposed to light, it is preferable to control the total rate of addition of chlorine as a standard solution in carbon tetrachloride was added that the temperature of the reaction mixture was added. If such difficulties do not exist, the ^{temperature was kept at 15 to 17 °} C., but the external solution could be gaseous chlorine. Coolant had a temperature of about -5 ⁰ C.

The starting compounds, for their preparation 15 (30 to 40 minutes). The reaction mixture was In the context of the present invention, no protection was heated to 23 ° C and 30 minutes at this temperature is requested can be produced as follows. Then 20 liters of water were added. The temperatures are given in degrees Celsius and the mixture is stirred vigorously during a ben. Nitrogen flow was bubbled through for 30 minutes,

ao to drive off excess diazomethane. The A. 3 /? - Acetoxy-16/3-methyl-5a-pregn-9 (II) -en-20-one methylene chloride phase was separated off and the

aqueous phase with the solvent (7 liters) again- -. around. extracted. The main extract was mixed with water ( Ί

3/3-acetoxy-l'-pyrazolino- (3 ', 4'-17,16a) - (2 x 20 liters), 0.25N hydrochloric acid (20 liters) and finally

5a-pregn-9 (ll) -en-20-one 25 borrowed again with water (20 liters) until neutral

washed. The second extract was used to extract _{the aqueous} washing liquids in turn.

a) Nitrosomethylurea (80 g) became one here. The extracts were combined and the main solution of 3/3-acetoxy-5a-pregn-9 (II), 16-dien-20-one amount of the solvent was distilled off. Then, (104 g) in methylene chloride (1.0 liters) and 30 4 liters of methanol was added and the distillation mixture continued with stirring at -5 ⁰ C in a methanol / under reduced pressure until no dry ice cooled. The suspension was left under methylene chloride. The residual stirring over the course of about ¹ Z ₂ hours .with a slurry was filtered off, the crystals of the 16,17-pyrazoline 50 ° / ₀ aqueous solution of potassium hydroxide compound washed with cold methanol and mixed at (160 ml) and the temperature at about -5 ° C 35 6O ⁰ C in an air oven dried (2.63 kg, 93.8%) maintained. After the addition was complete, the cooling bath F. = 158 ° C (with decomposition) [»] d = + 71 ° (c = 1.0 removed, and the temperature of the solution in chloroform, λ% ϊ °" ° ' 225 ηιμ (Ei * "= 40.5).
Rise room temperature in about 2 hours. then

1.5 liters of water were slowly added and stage 2

Mixture vigorously stirred for 15 minutes, the yellow 40 o / hm /: a ■ ™

Color essentially blurred. The methylene-3 /? - acetoxy-16-methyl-5 <x-pregna-9 (II), 16-dien-20-one

Chloride layer was separated and the upper _{aqueous} Using fl} u _ss i _gem paraffin

Phase extracted with methylene chloride (1 x 300 ml) and ' ^ö

this extract used for backwashing. The 5 g of the pyrazoline derivative described above were / ι

organic phase was the liquid in portions with stirring paraffin * · with water (3 x 350 ml) Sex 45 - · wash combined with the backwash liquid, and (20 ml), which was maintained at 160 ⁰ C, was added. |

evaporated to dryness under reduced pressure. The solution was stirred at this temperature until the residue (about 99 ° / ₀ yield, mp 153 ° C) nitrogen evolution ceased (about 10 minutes), was of boiling petroleum ether (. 100 to 120 ⁰ C and then to room temperature cooled and treated with 750 mL) and then added again to about 500 ml einge- petroleum ether (bp. 100 to 120 ⁰ C) (50 ml). The evaporated to remove all traces of methylene chloride. The solution was removed in the refrigerator for several hours. The solution was kept to room temperature and filtered off the solid substance obtained, j cooled and the solid substance was filtered off with a little with a little petroleum ether (bp. 100 to 12O ⁰ C.) petroleum ether (bp. 100 to 120 ° C) and dried in and at 8O ⁰ C for 1 hour dried. The vacuum obtained is dried at 100 ° C, the pyrazoline 55 3 / S-acetoxy-16-methyl-5 "-pregna-9 (II), 16-dien-20-one of 3/3-acetoxy-5a-pregna- 9 (ll), 16-dien-20-one back- (1.81g) had a temperature of 135 to 138 ° C, [<x] _D = + 49.5 ° remained (106.5 g, 92 ° / ₀ Yield), m.p. = 158 ° C under Zer- (c = 1 in chloroform) and l _max = 249.5 ηιμ, E !? "sctzung, [<x] d + 72 ° (c = 1 in chloroform), X _max = 228. The compound was made from ethanol (4 ml) = 229 ΐημ and EIS ,, = 29.3. recrystallized, stored in the refrigerator and the

b) A solution of nitrosomethylurea (1.33 kg) 60 solid substance was filtered off, washed with cold ethanol (1 x 1 ml) in dimethylformamide (4.2 liters) was washed at 20 ⁰ C and dried in vacuo at 60 ° C,
clarified by filtering through kieselguhr to remove ... _{or ,, r} , ._, _o traces of inorganic salts and other solid sub-, U5g from F 139 to 142 C and Wz> == +49 5 ° punch. A solution of potassium hydroxide ifi = 1 m CHCl ₃ ) and X _max = 249.5 ιημ, E ... «235. (1.2 kg) in distilled water (2 liters) was just 65 ..

if prepared, cooled to about 15 "C and ^{removed from b} ) ^Using ethylene glycol,

insoluble particles carefully decanted. A solution of 48 g of the pyrazoline derivative described above of 3 // - Acetoxy-5 <x-pregna-9 (II), 16-dien-20-one the partly with stirring in ethylene glycol

7 8

(200 ml) and heated ^{at 160 to 165 0 C.} Select level 3

During the addition, which lasted about 5 minutes, found 3 /? - acetoxy-16 / S-methyl-5 "-pregna-9 (II) -en-20-one vigorous decomposition takes place. The mix was

A further 10 minutes after the addition was complete, the ^{temperature was kept at about L Without} prior reduction of the catalyst, 165 ^° C. and then cooled. The oily droplets suspended in the 5 3 ^ -acetoxy-16/3-methyl-5 "-pregn-9,16-dien-20-one ethylene glycol began (2 kg) were in tetrahydrofuran (12 liters) with about 100 ° C to solidify, and then became water. Triethylamine (2 liters) dissolved as base and added at (600 ml). The mixture was cooled to room temperature and atmospheric pressure below the temperature and the precipitated solid sub-turn of 10% palladium oxide on charcoal punched with methylene chloride (1-200ml; 3-5OmI) 10 (170 g) was hydrogenated as a catalyst. The hydrogen extracted. The first three extracts with water uptake amounted to 139.8 liters in 150 minutes. (2 x 200 ml) and the combined aqueous. The catalyst was filtered off through kieselguhr, phases backwashed with the fourth extract. The organic extracts and the reduced pressure solvent were combined, removed to dryness. The residue was evaporated with methanol (2 liters) and the solid residue treated in methanol 15 and methanol also dissolved under reduced pressure (about 60 ml) and a sample removed in vacuo to pressure. The residue was distilled overnight to remove residual methylene chloride. Vacuum at 40 ° C with formation of crude 3/3-Acet-The solution was cooled overnight and the solid oxy-16 /? - methyl-5 <x-pregn-9 (II) -en-20-one (1999 g; substance filtered off and dried in vacuo at 100 ° C 99.4%) from mp 106 to 110 ° C and [<x] _D + 30.2 °. . 20 (c = 1 ° / ₀ in chloroform) dried.

Instead of methanol (2 liters) to the residue

31.7 g (71 ° / ₀ yield) with a melting point of 138 to 140 ° C after the tetrahydrofuran has been removed,

and [<x] d + 50 ° (c = 1 in chloroform), / W ^ = 249.5 ΐημ., the residue can be dissolved in acetone (1600 ml per kg

EU = 224th steroid) and water (3200 ml) slowly

25 can be added with vigorous stirring. The critical

c) Using diethylene glycol stalline solid substance can be filtered off and up to

Constant weight can be dried. With this

The pyrazoline derivative (222 g), which, as described above, does not cause any significant loss of material. Written, was obtained, was partially (in about "., · *, ■« j ί · j. ^. ■ 25 minutes) with stirring in diethylene glycol (880 ml) 30 ^{2 Mlt} prior reduction of the catalyst at 165 ° C . The solution was stirred an additional 15Mi- 10% palladium oxide on charcoal (0.85 g) in minutes at this temperature until the nitrogen tetrahydrofuran (20 ml) had been terminated with evolution of hydrogen, and the mixture was then shaking at room temperature and atmospheres cooled to about 100 ° C; then the pressure started to reduce (about 10 minutes) before the reaction. Crystallization. Then 3.0 liters of water were added slowly with vigorous stirring, the amine and Sβ-acetoxy-lo / S-methyl-Sa-pregnal, dissolved from 9 (II), 16-dien-20-one (10 g) The solid substance precipitated in tetrahydro was filtered off, ge furan (40 ml) was added with water and the mixture was washed and dried at 100.degree. C. in vacuo. The same conditions as in the pre-reduction process compound was crystallized from ethanol (210 ml), hydrogenated ren. After completion of hydrogen overnight at room temperature, allowed to stand for 40 uptake, the catalyst was filtered off through a layer of /, filtered (20 mL), diatomaceous earth with 20% aqueous ethanol and the diatomaceous earth with chloroform and then with 50 ° / ₀ aqueous ethanol (100 ml) (100 ml). The solution was washed under vermine and dried at 100 ° C. in vacuo, the pressure being evaporated to dryness. The solid whereby 3/3-acetoxy-16-methyl-5 "-pregn-9 (II), 16-diene residue was dissolved in methanol (14 ml) and 20-one (146 g, 71% yield), dated F. = 139 to 45 the solvent again under reduced 142 ° C and [k] d = + 53 ° (c = 1 in chloroform), pressure removed. The solid residue was formed from X _max == 249 ΐημ, EU = 235. Methanol (14 ml) crystallized out at 0 ° C. overnight.

The crystals were filtered off, washed with methanol

d) Using dimethylformamide wash, and dried in vacuo at 6O ⁰ C.

A suspension of the above-described 16,17-pyr- a) triethylamine (10 ml) was used as the base

azoline derivative (2.5 kg) in dimethylformamide (8 liters) hydrogen uptake was 660 ml in 23 minutes,

was stirred and carefully brought to reflux temperature and this gave Sß-acetoxy-lo / S-methyl-Sa-pregn-

(152 ° C) heated. At 130 to 140 ° C strong stick-9 (II) -en-20-one (8.94 g; 88.9 ° / ₀ ) appeared as needles from

Substance development a. The solution was for 1 hour at 55 F. 109 to 111 ° C and [<%] _B + 31.7 ° (c = 1 ° / ₀ in

Heated to reflux temperature; then was the chloroform).

Nitrogen evolution ended. Dimethylformamide b) piperidine (5 ml) was used as the base, the

(5 liters) were distilled off under reduced pressure- hydrogen uptake was 860 ml in 120 minutes,

liert and water (11 liters) at first very slowly and and that resulted in S / J-Acetoxy-lojfJ-methyl-Soc-pregn-

added with vigorous stirring. The crude aus- 60 9 (II) -en-20-one (8.07 g; 80.2%) as needles from

accrued 16-methyl diene was filtered off strength with water F. 110-111 ° C and [<x] _D + 30.5 ° (L ° / _o solution in

washed and dried at 70 ° C. The recrystalline chloroform).

cation from technical denatured alcohol (2.7 liters) gave c) N-ethylpiperidine (5 ml) was used as the base

the pure compound, which with diluted, technical det, the hydrogen uptake was 750 ml in

Washed denatured alcohol and dried at 70 ° C 65 22 minutes, and that gave 3 / J-AcCtOXy-16 / f-metliyl-

would. (1.63 kg, 70.3%), melting at 139 to 142 C and 5 ^Ü "pregn-9 (ll) -en-20-one (8.05 g; 80.0%) as needles

[«] /> -1-47.7 ° (<· = - 1.0 in chloroform), λ; ^ Γ" from F. UI to 112 "C and [λ] ,, - = 31.0" (ί · - ■ I% iu

= - = 251 πψ. (Ki ?. - 230). Chloroform).

9 10

d) Pyridine (5 ml) was used as the base, the hydrogen uptake with a solution of chlorine in carbon tetrachloride was 890 ml in 120 minutes, (1.86N; 34.6 ml; 20% excess) for 5 minutes and this gave S. / J-acetoxy-lo / J-methyl-Sa-pregn- treated. The mixture was stirred for a further 5 minutes of 9 (II) -en-20-one (10.3 g; 102.5%) in crude, not kri- long and then filtered. The filtrate was evaporated to the crystallized state from - mp 110 to 112 ° C and 5 dryness and the residue from acetone - [oc] d = + 31.2 ° (c = 1% in chloroform). Water (4: 1) crystallizes, with 8.97 g of 3/9-acetoxy-

e) Aniline (5 ml) was used as the base, the 9%, II / 9-dichloro-16/9-methyl-5 "-pregnan-20-one of the F. Hydrogen uptake was 770 ml in 115 minutes, 164 to 166 ° C and [<x] _D + 48 ° (c - 0.5% in chloro- and this resulted in 3/9-acetoxy-16/9-methyl-5 "-pregn- form).

9 (II) -en-20-one (5.63 g; 56%) as needles from F. 108 io d) The starting steroid (300 g) in methylene chloride

up to 110 ⁰ C and [a] p + 29.9 ° (c = 1% in chloroform). (3 liters) which is a suspension of sodium bicarbonate

f) 2% palladium oxide on calcium carbonate (4.25 g) (150 g), was stirred at 4 ° C (cooling bath), was used as a catalyst and triethylamine with chlorine (about 23 liters) in the course of 10 minutes (10 ml ) used as a base. The hydrogen uptake was bubbled through. The temperature of the Reakbetrug 630 ml in 30 minutes and the returned 3/9-acetaldehyde 15 tion mixture rose at the end of this period at 12 ⁰ C. oxy-16 /? - methyl-5.x-pregn-9 (ll) - en-20-one (8.5 g; the excess chlorine was removed in a nitrogen-84.5%) as needles from the mp 107 to 110 ⁰ C and stream, the suspension filtered and the filtrate [ix] d +29 , 3 ° (c = 1% in chloroform). evaporated under reduced pressure. The residue was made from acetone (1.8 liters) and water

B. 3 / 9,20-diacetoxy-16 /? - methyl- ² ° (450 ml) crystallized, whereby 273.4 g of 3/9-acetoxy-

5 "-pregna-9 (ll) 17 (20) -diene 9", ll / 9-dichloro-16/9-methyl-5 "-pregnan-20-one from F.

167 to 169 ° C and [<x] _D + 47.8 ° (c = 0.5% in chloro-

3 /? - acetoxy-16 /? - methyl-5a-pregn-9 (II), 16-diene form) was obtained.

20-one made according to Step 2 above, e) The starting steroid (2 g) was in glacial acetic acid

was dissolved and dissolved in 385 ml of carbon tetrachloride (20 ml) and a solution of chlorine (0.38 g) cooled to ^{0 ° C.} 65 ml of a solution of perchloric acid in carbon tetrachloride (12.2 ml) as soon as mögsäure (0.4 ml) in acetic anhydride (84 ml) of 0 ⁰ C, borrowed under stirring. A saturated solution was added over 5 minutes with cooling and sodium metabisulfite (20 ml) was added immediately with stirring. The mixture was poured overnight and the stirring was ^{kept at 0} ° C. for about 1 minute and diluted with water (11 ml). 30 set. After the phases had separated, the temperature was then allowed to rise to the organic layer with sodium bicarbonate solution and room temperature while stirring. The solution was then washed with water. The organic solution of water, sodium bicarbonate solution and again with was dried and washed with water under reduced pressure. After drying over sodium, evaporating to give a gummy product back sulfate, the organic layer was left which was crystallized from aqueous acetone containing the desired compound. whereby 1.44 g of dichloro compound with a melting point of 166 to 169 ^° C.

The following examples illustrate the invention. and [«] d + 49.3 ° (c = 0.5% in chloroform)

stayed.

B e i s ρ i e 1 1 0 The starting steroid (19.8 g) was dissolved in methylene

40 chloride (200 ml) dissolved and quickly with sodium

/ 3 - acetoxy-9 ", 9 _{ll-Dichloro-16/9-methyl-aceta} t (2.8 g) were stirred / dissolved in water (20 ml) at 5 ⁰ C.

5 "-pregnan-20-one chlorine gas was introduced into the solution, and after

Optional procedure 10 minutes the color of the solution turned yellow. the

After a further minute, the chlorine stream was

a) The starting steroid 3β-acetoxy-16/3-methyl- 45 was broken and a suspension = of sodium bicarbonate 5 "-pregn-9 (II) -en-20-one (10.0 g) was dissolved in methylene (5 g ) in water (50 ml) was added and the stirring dissolved chloride (100 ml) and water (10 ml) added - continued for 5 minutes. The organic layer joined. The mixture was stirred at 16 ⁰ C and was separated and washed with 8% aqueous sodium To a solution of chlorine in carbon tetrachloride bicarbonate solution (65 ml) and water (50 ml) Ge- (1.56 N; 41.4 ml; 20% excess Wash 50 for 5 minutes and methylene treat the washes. After a further 5 minutes, sodium chloride (40 ml) was back extracted. The extracts were added to bicarbonate solution (8%; 50 ml). The yellow combined and concentrated in vacuo and the reverse color rapidly faded. The organic layer was dissolved in warm acetone (20 ml) which was separated, washed with water and evaporated, evaporating a crystalline solid sub-dryness. The residue was left behind from punch. The product was crystallized from acetone acetone (65 ml) and water (15 ml), whereby (100 ml), which water (30 ml) and sodium acetate S / J-Acetoxy-Qa.ll / J-dichloro-lo / S- methyl-Sa-pregnan- (0.8 g) contained, recrystallized, with 9 #, II /? - dichloro-20-one (9.18 g) from 164 to 165 ° C and [<x] _D + 48 ° lo / S-methyl-Sa-pregnan ^ O-one (21.2 g) of m.p. 164.5 (CHCl ₃ ). up to 165.5 ° C (capillary) and [<x] _D + 48 ° (c = 2 in

b) The above procedure was exactly repeated- 60 chloroform) was obtained,
picks up, but was only a 5% excess

Chlorine solution used (2.015 η; 28.0ml). The example 2

The booty was 8.99g of 3/9-acetoxy-9.x, ll /? - dichloro-, "» «". ~ .. ".. ... ^,

HP-methyl-5.x-pregnan-20.on vom F. 163 "C and S / ^ O-Diacetoxy - ^. U ^ dichlor-lo / J-methyl-

[«Xjfl f-49.5" (c = 0.5% in chloroform). 6 ₅ 5x-pregn-17 (20) -en

c) The starting steroid (10.0 g) in methylene chloride A solution of the compound 3 / J.2O - diacetoxy- (100 ml), which is a suspension of sodium bicarbonate 16 /? - methyl - 5 * -pregna-9 (11), 17 (7.0) -diene (85.7 g) in c: irbon: it (5.0 g) was stirred at 16 "C and carbon tetrachloride (about 720 ml) was stirred

11 12

and with a solution of chlorine in carbon tetrachloride- B e i s ρ i e 1 4

substance (1.46 n; 283 ml) in the course of one minute be _ ga.ll / S-DichlorO / S.nadihydrox

acts. The reaction mixture was stirred and lo / I-methyl-Sa-pregnan ^ O-one

in a vacuum to a volume of about 250 ml. _, _ ,. . . ,,, _ ,,,

daniDft 5 ³ ^ By chlorination with molecular chlorine

750 mg 3 / S, 17 «-dihydroxy-16je-methyl-5a-pregn-

_R ·, ^ 9 (ll) -en-20-one prepared according to Belgian Patentee '^ P * ^{e »J} writing 593,215, in chloroform (110 ml) were mixed with 21-Acetoxy-9" llö-dichloro- Chlorine (1.1 mole equivalents) in carbon tetrachloride

3 / 3.17 "-dihydroxy-16/3-methyl-5" -pregnan-20-one ¹⁰ (6.25 ml) treated for 3 minutes at room temperature.

The chloroform solution was successively mixed with

A solution of sodium acetate (4.2 g) in water, dilute sodium thiosulphate solution and water (30 ml) was washed to 21-acetoxy-3 / ?, 17 "-dihydroxy-, dried over magnesium sulphate and in 16jS-methyl-5" -pregn-9 (II) -en-20-one (10 g), which is evaporated in vacuo. Treatment of the reverse methylene chloride (360 ml) was dissolved, added 15 stand with cold acetone gave a white solid sub- and the mixture cooled ^{to 0 ° C.} Chlorine was punched out, which when recrystallized from chloroform at constant speed under vigorous rest- 9a, 11/9-dichloro-3 / 3,17a-dihydroxy-16 /? - methyl-5i% -preren, until the yellow color persisted, initiated. A gnan-20-one (335 mg) with a temperature of 201 to 204 ° C and saturated sodium bicarbonate solution (34 ml) was [<x] d + 75 ° (c = 0.52 in dioxane),
added and the mixture stirred for 5 minutes, ao. . . . .
The organic phase was separated off and treated with b) chlorination with N-chlorosuccimmide
Water (200 ml) and then ^m verminder- acetic acid, which contained Lithiumchlond
evaporated tem pressure at about 30 ° C. Methyl cyanide To a suspension of 3 / ?, 17a-dihydroxy-16 /? - me- (80 ml) was added to the foam obtained, thyl-5 «-pregn-9 (II) -en-20-one (400 mg ) and lithium to dissolve, and the mixture was kept overnight at 35 chloride (2.7 g) in glacial acetic acid (40 ml) with stirring at ⁰ ° C. The crystalline product was filtered off, washed with methyl cyanide (10 ml) in the dark and under a nitrogen atmosphere, and chlorosuccinimide (200 mg, 94%) and then dried at 60 ° C. in vacuo for 2 hours. 4.87 g immediately became a solution of hydrogen chloride (47 mg) in 21-acetoxy-9a, ll / 3-dichloro-3 / 9.17a-dihydroxy-16 /? - me-tetrahydrofuran (0.77 ml peroxide-free) given. According to thyl-5 «-pregnan-20-one from mp 164 to 166 ° C (less than 30 1 hour, the reaction mixture was in dilute decomposition) and [λ] ο + 92.9 ° (c = 0.5 in dioxane) poured · sodium acetate solution. Keep the precipitate. was filtered off, washed with water, in vacuo

dried and treated with ether (25 ml). It was

Analysis C ₂₄ H _3e O _B Cl _a : 9 ", 11/3-dichloro-3 _j S, 17" -dihydroxy-16iS-methyl-5 "-pre-

Calculated ... Cl 14.9; 35 gnan-20-on obtained, its IR spectrum with a

found ... Cl 15.0. matched authentic sample.

Claims (1)

Claim: Process for the production of 3/9 hydroxy (or acyloxy) - 9a, ll / 9 - dichloro - 16 /? - methyl-5a steroids the pregnancy series of the general formula I, CH ₃ wherein X is one of the following groups
= C - CH ₃ or