DE1237566B - Process for the manufacture of delta 5-3 oxosteroids - Google Patents

Description

^ FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

CO 7 J 4l & t / ? FöQ v:

German KL: 12 ο - 25 / () | f

Number: I 237 566

File number: C 30386IV b / 12 ο

Filing date: June 6, 1963

Open date: March 30, 1967

Steroids substituted in the 6-position by a halogen atom, such as a fluorine or chlorine atom, in particular derivatives of progesterone and 6'-fluorocorticoids, e.g. B. δ-fluoro-prednisone, 6 <x-fluoro-prednisolone, 6 <x-fluoro-16 "-methyl-prednisolone, are of great importance because of their special phartnacological properties. The introduction of a fluorine atom in the 6 <x position is particularly easy starting from 5 (6) -unsaturated steroids, ζ. Β. by epoxidation to 5,6-epoxide and cleavage with hydrofluoric acid or boron trifluoride, or by addition of bromofluorine (from bromoacetamide and hydrofluoric acid) to the 5 (6) double bond. Therefore, J ⁵ steroids have acquired a very special importance today, and new processes for their production, which have advantages over the known methods, are of great interest. The present invention relates to a process for the preparation of A ⁶ -3-oxosteroids, starting from J ⁴ ** -3-oxosteroids. Since these starting materials for their part ^{are easily accessible from .d 4} -3-oxosteroids or 5-saturated 3-ketones, the present process is particularly valuable where it is necessary to introduce the 5 (6) double bond into saturated compounds or from a 4-position double bond to form. It is possible to introduce a 4 (5) double bond into a 3-ketone of the allore series, and on the other hand it is also known that Δ ⁴ -3-ketones are converted into Λ ⁶ -3- by enol acetylation and subsequent reduction with sodium borohydride. Hydroxysteroids can be transferred. However, the enol acylation is carried out under strongly acidic conditions, with high temperatures being common. As a side reaction, all other keto groups present in the starting material are also enolized and must be released again afterwards. In the case of sensitive substances, e.g. B. those with a dihydroxyacetone side chain, undesirable side reactions easily occur, so that the yields are sometimes poor. The present process avoids strongly acidic reaction conditions and can therefore also be used successfully with acid-sensitive substances.

The process according to the invention consists in treating a zI ^{4> e} -3-oxosteroid with zinc under nearly neutral conditions.

Although it is already known that J ⁴ - ⁶ -3-ketones of the steroid series ⁶ -3-ketone may be reduced with molar amounts of an alkali metal in liquid ammonia to the / J. However, this process is technically not easy to carry out, since working in liquid ammonia requires a large amount of equipment for the production of processes
/ J ⁵ -3-oxosteroids

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative:

Dr.-lng. Dr. jur. F- Redies, Dr. rer. nat. B. Redies and Dr. rer. nat. D. Türk, patent attorneys,

Opladen, Rennbaumstr. 27

Named as inventor:

Dr. Albert Wettstein, Riehen;

Dr. Georg Anner,

Dr. Karl Heusler,

Dr. Peter Wieland, Basel (Switzerland)

Claimed priority:

Switzerland of July 11, 1962 (8332, 8333)

conditional and - due to the explosive lithium-aluminum mixture - is not harmless. In addition, considerable amounts of saturated ketone are obtained as by-products. In addition, other reducible groups, in particular oxo groups, are reduced at the same time, which in turn reduces the yields and also makes it more difficult to isolate the desired end products. In contrast, the process according to the invention is technically particularly easy to carry out and can mainly also be used when sensitive substituents, eg. B. keto groups and acid-sensitive groups are present. It is Z. B. readily possible, ZJ ^{4 'a} -3,20-dioxo-pregnadiene or ^ I ^4' to reduce ^e -3,17-Dioxoandrostadien without the 20- or 17-oxo group must be protected. This is particularly important in the case of corticoids with a 17 ", 21-dihydroxy-20-oxo side chain. The existence of two different, albeit inadequate, processes already shows that the conversion of the -d * -ketone into a ^ '- compound is a problem for the steroid chemist. Since the method according to the invention brings about a significant improvement in the existing possibilities - it is extremely easy to carry out in terms of apparatus; it can also be used for substances that are sensitive to heat and acids

709 547/437

will; it can also be carried out for connections who carry free oxo and / or hydroxyl groups without damaging them - is that technical progress.

According to the present process, the zl ^ '- S-oxosteroids are reduced with zinc under almost neutral conditions, so that the / J ⁵ -3-oxosteroids formed are not ^{rearranged into the more stable I 4} -3-oxosteroids. Zinc is used for the reduction, e.g. B. in the form of zinc dust, which by brief treatment with an acid, e.g. B. with acetic acid, propionic acid or sulfuric acid, can be activated, or zinc alloys, such as zinc-copper alloys, or amalgamated zinc. The reduction is usually carried out in alcoholic media, advantageously in _{alcohols containing 1 to 5 ° / 9} water, such as methanol, ethanol, propanol or ethereal glycine. The activation of the zinc can also take place in the reaction medium itself by z. B. the alcohol small amounts of a carboxylic acid, e.g. B. 2 to 10% added. In this concentration capable weak acids such as acetic acid, propionic acid, butyric u. Ä., Not relocate the / 1 ⁵ ketones in the isomeric Δ '-3-ketones. The reduction according to the method is advantageously carried out at a somewhat elevated temperature, e.g. B. between 45 and 100 ° C carried out.

The starting materials used for the process ^{according to the invention are J 4} '* -3-ketosteroids, e.g. B. those of the Cholestan, Stigmastan, Pregnan or Androstan series, which in the positions 9, 11, 12, 14, 15, 16, 17, 20 and 21 have further substituents such as free or esterified hydroxyl groups, oxo groups, alkyl such as lower alkyl, e.g. B. methyl groups, and / or halogen atoms, such as fluorine or chlorine atoms, may have. Particular compounds that may be mentioned are ^ * · ^e -3,20-dioxo-pregnadienes, such as Δ * ■ '-3,20-dioxo-17a, 21-dihydroxy-pregnadienes, which z. B. in the 11-position an oxo or: may have a free or esterified hydroxyl group or are unsaturated in the 9, 11-position. These compounds can also have a methyl group in the 16-position.

Particularly important. Starting materials are those Δ ⁴ · ^e -3 "20-dioxo-17i% -hydroxy-21-acetoxy-pregnadienes which have a formyloxy group in the ΙΐΛ-position. ^{The zJ 4> e} -3-oxosteroids used as starting materials can be prepared by known methods.

The following examples explain the process according to the invention. The temperatures are in CelsiuSr degrees indicated.

example 1

463 mg of 6-dehydro-testosterone propionate are dissolved in 45 ml of absolute alcohol and, after adding 4.5 ml of water and about 5 g of activated zinc dust, heated to boiling for 30 minutes while stirring. (To activate it, the zinc dust is first treated briefly with 2N sulfuric acid, then washed neutral with water and washed first with acetone, then with alcohol). After the reaction time has elapsed, the solution no longer shows any absorption in UV light and contains the amorphous zl ⁵ -3-oxo-17 /? - propionyloxyandrostene; IR bands (in methylene chloride) at 5.77, 5.82, 8.37, 9.24 and 9.71 µ.

The 6-dehydro-testosterone propionate used as the starting compound is produced as described below:

2.0 g of a by bromination of Ι-Οχο-Πβ-ρτο- Piony) oxy-5oC-androstan obtained crude dibromide are dissolved in 40 ml of a 10 ° / ₀ solution of lithium chloride in dimethylformamide for 24 hours at 60 ° heated. The reaction mixture is then poured into 400 ml of water and extracted several times with benzene. The extracts, washed with water and dried, are evaporated in a water jet vacuum. From the crude product, which is in the UV spectrum

ίο has a maximum at 282 ΐημ (e = 13100), 0.72 g of 6-dehydro-testosterone propionate is isolated after chromatography on 60 g of aluminum oxide, which melts at 135 to 136 ° after crystallization from methanol; [«] /> = + 29 ° (in chloroform); UV maximum at 283 τημ (ε = 26600).

Example 2

500 mg ^ ⁴ - * - 3,20-Dioxo-17Ä-hydroxy-21-acetoxypregnadiene are dissolved in 100 ml fine liquor and, after adding 5 ml water, 10 g zinc dust and 2 ml glacial acetic acid, stirred for 30 minutes at 60 °. After this time the UV absorption has disappeared. The zinc is filtered off with suction, washed with 20 ml of alcohol,

The filtrate is thinned with 300 ml of water and the alcohol is distilled off at 35 ° in a water jet vacuum. Filtration gives 508 mg of crude zl ⁶ -3,20-dioxo-17 "-hydroxy-21-acetoxy-pregnene, which, after being dissolved from benzene and acetone-ether, melts at 174 to 176"; [«]? = +84 , 5 ° (in chloroform); TR bands among others at 2.79, 5.70, 5.78 and 8.15 μ; no UV absorption; after adding sodium hydroxide to the alcoholic solution of a sample, strong maximum at 242 τημ (ε ~ 15000).

To prepare the starting material, 5.0 g of anhydrous lithium bromide in 50 ml of anhydrous Dissolved dimethylformamide; 2.5 g of 2,4-dibromo-3,20-dioxo-17oc-hydroxy-21-acetoxy-allopregnane are added to the cooled solution and the reaction mixture is stirred for 16 hours at 65 °. Then you pour in 500 ml of saturated sodium chloride solution and the precipitated product is filtered off. The residue is dissolved in Benzene, dry the solution, filter through 25 g of aluminum oxide and wash with 1000 ml of benzene.

+5 The benzene solution is evaporated, and by trituration with a mixture of ether and ethyl acetate, 1.1 g of Δ ⁴ · ^e -3,20-dioxo-17Ä-hydroxy-21-acetoxy-pregnadiene, which after repeated recrystallization at 220 to Melts 221 °.

B e i s ρ i e 1 3

500 mg of Δ ⁴ ' ^e -3,20-dioxo-lla-formyloxy-16a-methyl-17 * -hydroxy-21-acetoxy-pregnadiene are dissolved in 50 ml of alcohol, 2.5 ml of water and 1 ml of glacial acetic acid, and the After adding 5.0 g of zinc dust, the mixture is stirred at 60 ° for 30 minutes. It is then filtered off with suction, washed with 15 ml of alcohol and the filtrate is poured into 200 ml of water. The alcohol is then distilled off in a water jet vacuum. The precipitated reaction product is filtered off with suction, the filter residue is dissolved in methylene chloride and the solution is dried and evaporated. Trituration of the crude product with benzene gives 362 mg / 4 ⁵ -3,20-dioxo-II: x-formyloxy-16 <x-methyl-17 & -hydroxy-21-acetoxy-pregnane,

which after redissolving from methylene chloride-acetone-ether melts at 188 to 190 °; [a] f = + 27 ° (in chloroform); IR band at 2.80, 5.70, 5.78, 8.13 and 8.55 μ, among others.

To produce the exhaust substance, 10.0 g of crystallized, crude 2,4-dibromo-3,20-dioxo-II (X-formyloxy-16 <x-methyl -17. The reaction mixture is stirred under nitrogen for 16 hours at 60 ° C. The mixture is then poured into 2000 ml of saturated sodium chloride solution, the precipitate is filtered off with suction, washed thoroughly with water and the moist residue is taken The solution is washed with water, dried and evaporated. 7.62 g of crude product are obtained, which has a maximum (£ = 13500) in the UV spectrum at 282 μm. The crude product is purified by chromatography on 15%. o water-containing silica gel with benzene-Essigester. 4: 1-mixture is first a non-absorbing in the UV spectrum compound (600 mg) removed, then 3.2 g of the z J ^{4 'e} -3,20-dioxo-LLA formyloxy-16a-methyl-17Ä-hydroxy-21-acetoxy-pregnadiens, which after dissolving from Acetone-ether melts at 183 to 184 °; [ _Λ ] «= +63.5 (in chloroform); UV maximum at 283 ηιμ (e = 22800); IR bands at 2.73, 5.70, 5.78, 6.00, 6.13, 6.28, 8.12, 8.47, 9.58 and 11.16 µ, among others.

Example 4

1.0 g. <! ⁴ '»'» < ^lx ) -3 _< 20-Dioxo-16 * -methyl-17, »- bydroxy-21-acetoxy-pregnatriene is dissolved in 150 ml of absolute alcohol and after adding 7.5 ml of water, 10 g Zinc dust and 3 ml of glacial acetic acid were stirred at 60 ° for 30 minutes. Then, as described in the previous example, work-up is carried out. 800 mg of the crude oily / ^{I 6} - ^e ( ^u > -3,20-dioxo-16 <x-methyl-17a-hydroxy-21-acetoxy-pregnadiene are obtained.

To prepare the starting material, 10 g of 2,4-dibromo-3,20-dioxoll * -tosyloxy-16 "-raethyl-17iic-hydroxy-21-acetoxy-allopregnan are added to a solution of 20 g of lithiurabromide in 200 ml of dimethylformamide. The reaction mixture is stirred for 40 hours at 60 ° under nitrogen. The reaction mixture is then worked up in the usual way and the crude product is then purified by chromatography on silica gel. With benzene-ethyl acetate-4; 1 mixture, 2.6 gA ^^ WS ^ O- Oxo-16 «-methyl-17 <x-hydroxy-21-acetoxy-pregnatriea are isolated which, after crystallization from methylene chloride-acetone-ether, melt at 187 to 188 ° ; d = -30 °; UV maximum at 284 ΐημ (β = 20400).

Claims (6)

Patent claims: 1. A process for the preparation of / J * -3-oxosteroids, characterized by treating a corresponding ⁴ .d ^'e -3-oxosteroid under almost neutral conditions with zinc. 2. The method according to claim 1, characterized in that zinc activated with acid used. 3. Process according to Claims 1 and 2, characterized in that the zinc activated by adding small amounts of a lower alkanecarboxylic acid to the reaction medium. 4. Process according to claims 1 to 3, characterized in that the reduction with zinc in a lower alkanol. 5. Process according to claims 1 to 4, characterized in that the reduction in In the presence of 1 to 5% water. 6. Process according to claims 1 to 5, characterized in that the starting material used is a Δ * - ^e -3-ketone of the androstane or pregnane series, in particular a .d ⁴ ' ^e -3,20-dioxo-17 «-hydroxy -21 - acetoxy - pregnadieu, Δ ⁴ · «- 3.20 - dioxo -11λ, 17a-dihydroxy-16 * -methyl-21-acyloxy-pregnadiene or an Ila ester thereof or a zj ⁴ pregnatrien used.