DE1230024B - Process for the preparation of fluorine-substituted steroids - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

German KL: 12 ο -25/02

Number: 1 230 024

File number: P32814IVb / 12o

Filing date: October 21, 1963

Opening day: December 8, 1966

The invention relates to a method of introducing fluorine into the steroid nucleus, in particular a new process for the preparation of α-fluoroketo steroids. It also includes a process for making new and valuable steroids, the Contain fluorine and nitrimino substituents on adjacent steroid carbon atoms.

Since then Fried and S a b ο [J. At the. Chem. Soc, 75: 2273 (1953); 76, 1455 (1954)] discovered that the introduction of a fluorine atom in the 9-position of cortisol led to increased biological activity, the research was in ever increasing numbers Measures aimed at finding new methods of introducing fluorine into the steroid core [s. for example, Bowers et al., J. Am. Chem. Soc, 84, 1050 (1962); as well as Fieser and Nasty; "Steroids", Reinhold Publishing Corp., 1959, especially pp. 682, 699 with regard to fluorocorticoids and pp. 592 to 597 with regard to fluorosteroids, which have anabolic properties (promotion of tissue structure, protein utilization)]. This increasing activity in the field of fluorosteroids is due to the benefits that are found often resulting from the presence of fluorine in steroidal drugs, e.g. B. increased effectiveness, decreased toxicity and stronger effects (e.g. strong anti-inflammatory effects).

The replacement of a hydrogen atom adjacent to a keto or hydroxyl group with fluorine leads to quite amazing modifications of the steroids. The known methods of implementation however, these replacements are indirect and complicated and require action, for example a fluorinating agent such as hydrogen fluoride or boron trifluoride, to steroid epoxides, the must be synthesized first. Other known fluorination methods are not suitable as a substitute of a hydrogen atom adjacent to a keto group. A process that does the conversion of steroids to a-fluoroketosteroids in good yield and in a direct and easy way, represents a considerable technical for these reasons The method according to the invention is straightforward and simple and impaired also does not affect the functional groups that may be present in the steroid molecule them only to a limited extent if they are sensitive.

The invention is a. Process for the preparation of fluorine-substituted steroids, which thereby is characterized in that a steroid which contains at least one endocyclic double bond, Process for the preparation of fluorine-substituted steroids

Applicant:

E. I. du Pont de Nemours and Company,

Wilmington, Del. (V. St. A.)

Representative:

Dr.-Ing. A. v. Kreisler, Dr.-Ing. K. Schönwald,

Dr.-Ing. Th. Meyer

and Dipl.-Chem. Dr. rer. nat. J. F. Fues,

Patent attorneys, Cologne 1, Deichmannhaus

Named as inventor:
Sam Andreades, Wilmington, Del .;
George Albert Boswell Jr.,
Newark, Del. (V. St. A.)

Claimed priority:

V. St. v. America October 23, 1962 (233 191)

in which the carbon atoms of this double bond are bonded to 1 or 2 hydrogen atoms, and each of these two carbon atoms is still bonded to 1 or 2 carbon atoms, which in turn are free of an unsaturated C - C bond, under practically anhydrous conditions and at temperatures below about 50 ⁰ C, optionally in the presence of an activator, in particular of hydrogen fluoride, is reacted with nitrosyl fluoride and the α-fluoronitriminosteroid obtained is optionally hydrolyzed.

The first stage of the process according to the invention leads to a new class of products, namely to a-Fluoronitriminosteroiden, which as part of the cyclic structural group the group

FN - NO ₂

where each carbon atom is bonded to a carbon atom that is not to C = C double bonds is involved, and the fourth valence of the fluorine-bearing carbon atom by water

609 730/434

substance or a carbon atom that is not involved in a C = double bond is saturated. The second stage of the process according to the invention leads to certain new α-fluoroketosteroids, the formed by hydrolysis of the new a-fluoronitriminosteroids.

The reaction of nitrosyl fluoride with unsaturated steroids described above is general applicable to all steroids which have at least one endocyclic double bond of the one described above Type included. The term "steroid" denotes all members of the class of substances which contain the cyclopentane [a] -hydrophenanthrene structure and in »International Union of Pure and Applied Chemistry Rules «are defined.

The main unsaturated steroids, therefore, of greatest interest for the purposes of the invention therefore belong to the following classes: Oestrene, Androstene, Pregnene, Cholene, Cholestene, Ergostene and stigmasters. As another less important classes of steroids to which the procedure is based the invention is also applicable, the intracyclic unsaturated cardanolides, bufanolides, Spirostans and furostans in question.

The reaction sequence described above can be represented by the following equations:

a)

+ 2NOF

b)

H-H ₂ O

N-NO ₂

+ H ₂ N-NO ₂

(Nitramine or decomposition products;
not isolated)

For the sake of simplicity, only the part of the steroid molecule involved in the reaction is in the above Equation shown. The location of the double bond in these equations was only for the purpose of Explanation chosen and is not to be construed as a limitation of the invention. As mentioned earlier, is the reaction is generally applicable to intracyclically unsaturated steroids of the type mentioned above and not limited to steroids in which the double bond has a very specific position.

In the equations explained above, those are linked via double bonds Carbon atoms of the steroidal olefin "trisubstituted"; i.e., just one of the double-bound Ring carbon atoms carries a hydrogen atom. However, the invention is not based on this "Trisubstituted" steroidal olefins, because a similar reaction takes place with a "disubstituted" steroidal olefin instead, d. H. in the case of a steroidal olefin in which each of the above Double bonds bonded ring carbon atoms carries a hydrogen atom. The only difference between a "trisubstituted" and a "disubstituted" reactant is that the fluorine-bearing carbon atom in the product of a "disubstituted" reaction component also carries a hydrogen atom. The reactive double bond can be anywhere in the steroid structure provided that it is in such a place that at least one of the double bonded carbon atoms carries a hydrogen atom.

In addition to the necessary reactive double bonds of the type described above, can the steroids suitable as starting materials for the process according to the invention are additional intracyclic ones Contain double bonds that may be of the same reactive type or unable to work with to react with the nitrosyl fluoride (i.e. those which have no Contain hydrogen atom). When two or more reactive, non-conjugated C = C double bonds are present, each is capable of reacting with nitrosyl fluoride to form a product containing two or contains more α-fluoronitrimino groups. However, if worked under the mildest possible conditions and an excess of nitrosyl fluoride is avoided, it is possible to stop the reaction at least partially to be restricted to a reactive double bond. Intracyclic double bonds, in those with only one of the doubly bonded carbon atoms carrying a hydrogen atom are more reactive than those in which both double-bonded carbon atoms carry a hydrogen atom, and are preferentially attacked by nitrosyl fluoride. A multiple bond (ethylenic or acetylenic) can also be present in the side chain in position 17. If she is reactive enough (trisubstituted double bond), this double bond can also react with nitrosyl fluoride.

Substituents that are either completely inert or not sufficiently reactive with nitrosyl fluoride to achieve the Formation of a-fluoronitrimine to a useful extent to prevent can on a ring carbon atom and / or carbon atom of the side chain be present in the 17 position. Possible substituents of this type are: hydrocarbon radicals (preferably lower alkyl radicals) and functional groups, e.g. B. the hydroxyl group, further the ether group, the oxo, acyloxy or a free one

or esterified carboxyl group, furthermore oxirane oxygen, the Ν, Ν-dialkylamino or halogen group. These substituents are usually found in the 3- and / or 17-position of the steroid nucleus.

As starting materials for the process according to the invention are preferably unsaturated Steroids are used that contain a total of 18 to 36 carbon atoms, including all substituents. Better results are obtained with steroids that have only one reactive intracyclic double bond of the type mentioned, and these steroids are another preferred class. Because the reaction takes place more easily with steroids in which only one of the double bonds is bound Ring carbon atoms carries a hydrogen atom, these steroids are used as starting materials particularly advantageous. The unsaturated / | 5 (6) _steroids, especially those of the androstene and Pregnengruppe, are the most readily available and are therefore preferred.

In the first stage of the process according to the invention, nitrosyl fluoride is unsaturated with Steroid of the type mentioned implemented, an α-fluoronitriminosteroid obtained according to equation (a) will. This result is very surprising in view of the fact that the known reaction of nitrosyl chloride with olefins rather to α-chloronitroso adducts or the isomeric α-chlorooximes and that the latter is dehydrohalogenated by hydrolysis will. It was therefore completely surprising to find that the reaction of nitrosyl fluoride with unsaturated steroids to a-fluoronitrimine and not to a-fluoro-oxime and that the a-fluoro-nitrimine has no tendency to dehydrohalogenation shows.

This reaction is carried out by mixing nitrosyl fluoride with the unsaturated steroid that is is at least partially dissolved in an anhydrous organic solvent, which under the reaction conditions is essentially inert to nitrosyl fluoride. Suitable solvents are for example the saturated hydrocarbons, e.g. B. the hexanes or octanes, and saturated halogenated hydrocarbons, e.g. B. carbon tetrachloride, trichlorofluoromethane, symmetrical Tetrachlorodifluoroethane, perfluorooctane or perfluorodimethylcyclohexane. In the trials that are described in the examples, the nitrosyl fluoride was fed from the outside of the reaction vessel, however, it can also be done in situ by the reaction of hydrogen fluoride with sodium nitrite or an alkyl nitrite.

The quantitative ratio of the two reaction components is not critical; around however to ensure full implementation and to facilitate the isolation of the product used the nitrosyl fluoride is preferably used in an amount of at least 2 moles per mole of unsaturated Steroids. However, this is not essential. Also a lower molar ratio, e.g. B. 1: 1, can be used if, for example, selective reaction at one or more reactive double bonds it is asked for. An excess of the nitrosyl fluoride up to, for example, 10 moles per Mol is not a disadvantage if the substituents present are not overly reactive; he is often desired to ensure that the reaction proceeds to completion. With something sensitive substituents, e.g. B. hydroxyl groups, a large excess of the nitrosyl fluoride is undesirable.

The reaction is exothermic and can occur at very low temperatures, e.g. B. down to -8O ⁰ C take place. Temperatures above about 50 ° C lead to undesirable side reactions, e.g. B. Nitration, and are not recommended. In trisubstituted steroidal olefins, the preferred temperature range between -20 and +5 ⁰ C. In disubstituted steroidal olefins is responsive carrier, or are difficult to access double bonds outside temperatures in the range of 20 to 50 ⁰ C is desirable when no activator z. B. hydrogen fluoride (which forms a complex with the nitrosyl fluoride and increases its activity) is used.

The method according to the invention is to be carried out largely with the exclusion of moisture, because nitrosyl fluoride reacts quickly with water. However, small amounts of moisture can in Purchase provided that there is enough nitrosyl fluoride for the desired reaction remains. The exclusion of atmospheric oxygen is also desirable, since oxygen is disadvantageous affects nitrosyl fluoride and would cause a loss of some of this reactant. The reaction is carried out in apparatus made of materials which are essentially inert to them Nitrosyl fluoride are, are manufactured or are lined with these materials. Suitable materials are for example polytetrafluoroethylene, polyethylene, nickel and nickel-rich alloys, e.g. B. Monel metal and the alloys known under the name "Hastelloy".

The reaction is most conveniently carried out at normal pressure, but it can also be carried out under overprinting to be worked. For the less reactive steroids, e.g. B. in the above-mentioned or those, the intracyclic double bond of which one electron is withdrawn, the one in the α-position an electron-accepting one Group, e.g. B. a keto group is present, it is often appropriate or even necessary, in a closed vessel under the intrinsic pressure or additional inert gas pressure to work. Sluggishly reacting double bonds of this type can, however, remain uninvolved if is carried out at normal pressure and / or low temperature, so that optionally a selective Attack of the nitrosyl fluoride on only one reactive double bond is possible.

The α-fluoronitriminosteroid formed can be isolated in a simple manner by evaporating the solvent under normal pressure or reduced pressure. Another way of removing the hydrogen fluoride formed as a by-product is to treat the reaction mixture with water and then extract the organic material with a suitable solvent, e.g. B. Carbon tetrachloride. In this context, is remarkable for 'in spite of the fact that the Nitriminogruppe to the keto group can be hydrolyzed (this is the 2nd stage of the process), no significant hydrolysis in the treatment with water alone at temperatures of no more than about 50 ⁰ C takes place, especially if it does not last excessively long. By washing the reaction product with water at ordinary temperature

7 8

temperature and subsequent extraction, the nitrimino group is at least stoichiometrically equi-

Yield not significantly reduced. is valentine, d. H. in a molar ratio of little

A purification of the a-fluoronitriminosteroid is at least 1: 1, based on the nitrimino compound. not required if it is in the a-fluoroketone- aluminum steroid used for chromatography should be converted. If its isolating oxide is known in the trade in various tion is desired as such, the α-fluorine varieties can be obtained whose "activities" mainly nitrimino compound according to customary methods depending on the water content [s. for example be cleaned, e.g. by crystallization, frak-Brockmann and Schrodder; Ber., 74, 73 ionized crystallization or chromatography. Die (1941)]. Aluminum oxides of activity II to V, α-Fluoronitriminosteroids are solid, crystalline males containing 3, 6, 10 or 15 percent by weight of water, those in most ordinary organisms are suitable for the hydrolysis of the ct-fluorine species Solvents are soluble. nitriminosteroids. Also more hydrated AIu-

The structure of these compounds is due to the miniumoxide which can be used, provided

the following facts proved: that it is in the state of a free-flowing solid

1. Since an α-fluoroketone of 15 remains during hydrolysis. The most suitable material is aluminum oxide of proven structure (see below) is obtained is activity III, which contains 6% water,
undoubtedly an α-fluoroketimino group present. In the event of contact with the water-containing aluminum

2. The infrared spectrum shows bands that for oxide finds hydrolysis of the a-fluoronitriministeroid C = N (6.15 μ) and for - NO2 (6.4 and 7.6 μ) to the corresponding a-fluoroketosteroid practical are characteristic. 20 instantly at room temperature. (Even

3. The ultraviolet spectrum shows maximum absorption - higher or lower temperatures can be absorbed in ethanol at 267 πΐμ (f = about 500), which are turned, but this is not an advantage is typical of a nitro group. connected.) The obtained a-fluoroketosteroid is

4. The elementary then carried out if necessary from the column of the absorbent by analyzing agree with the assigned structure ² 5 elution with a suitable solvent, eg. B. match. Another proof is the fact that diethyl ether, petroleum ether, benzene, etc., or one that removes the nitrimines against irradiation with an ultraviolet solvent mixture. When contaminant light is stable under conditions known to cause photolysis, by-products, or unchanged nitrite removal. material are present, this measure serves

The hydrolysis of the a-fluoronitrimino steroid to 3 ° would take place at the same time as a chromatographic separation,

a-fluoroketosteroid, d. H. the by equation (b) because the products present with different

reaction shown, can be carried out, speeds can be eluted. When on this

by exposing the nitrimino compound to multiple fractions, it can be obtained

of water or acidified water, which can preferably be determined by infrared analysis

wisely contains the desired products in a mixture with a water-miscible fraction,

organic liquid (e.g. dioxane, methanol, the a-fluoroketosteroid obtained in this way

Ethanol, acetone, etc.) which is a solvent for which is then made in any convenient way from its

represents compound to be hydrolyzed, subjects. Solution in organic solvent isolated. These

As already mentioned, this reaction is common in products (some of which are already in the literature

Licher temperature sluggish, so that were preferably described at 4 °) are crystalline solids that

elevated temperatures in the range from 50 to 100 ⁰ C in most common organic solutions

at normal pressure or up to approx. 150 ⁰ C are in average soluble.

closed vessels is operated at overpressure. Evidence of the structure of these products The progress of the hydrolytic reaction can be based on elemental analysis, infrared and easily followed by means of the infrared spectrum of the ultraviolet spectrum, nuclear magnetic resonance duct. The reaction is considered to be essential in the spectra for protons and F ^19, a comparison loan completed when the intensity of the physical constants remains constant with the (μ 5.8) in the ketone absorption band. The literature reported (if possible) and the a-fluoroketosteroid received can then be used as an example of the chemistry of the a-fluoroketones.
wise by diluting the reaction mixture with 50. The water prepared by the process according to the invention and extraction with an organic soluble α-fluoronitriminosteroids are valuable solvents which can be isolated. It does not require intermediates. You can e.g. B., as mentioned, to isolate the α-fluoronitriminosteroid prior to this treatment by simple hydrolysis into the α-fluoroketosteroids, since this treatment is immediately converted. The latter are already well established in which the product of the reaction between nitrosyl fluoride 55 biology and attain increasing and the unsaturated steroid after removal of the meaning can be used either as such or as a starting solvent. material for other fluorinated steroids in which the

Quite surprisingly, another hydro-keto group was made according to known methods by others

lyrical procedure found. This method is functional groups, e.g. B. the hydroxyl group,

preferred because it replaces rapid hydrolysis of the ^6o.

a-Fluoronitriminosteroids at room temperature- The melting mentioned in the following examples is possible. In this method, the graphical treatment can be viewed as chromatographic points using a Fischer-Johns instrument, unless otherwise stated. It is a solution of the a-fluoronitrimino steroid in itself with uncorrected values. All determinations are made in an inert organic solvent, e.g. B. Di- ⁶ 5 gene of optical rotation were made in chloroform ethyl ether, petroleum ether, benzene, etc., on a column solution. The values are followed by the value absorbed by neutral aluminum oxide, the letter c and a number that contains the concentration of water in an amount that indicates the amount present (grams of substance per 100 cm ^{8 of} solvent).

example 1 A. Sß-Chlor-Sa-fluoro-o-nitriminocholestane

2NOF

10

HF

^{Cholesteryl chloride (5.0 g, 12 ^ 3 mmol) and carbon tetrachloride (25 cm 3} ) were added to a dry 100 cm ³ reactor made of polyethylene, which was equipped with a magnetic stirrer and gas inlet and outlet pipes. Nitrogen was slowly bubbled through the system to remove moisture and air. The reactor was cooled in an ice bath while nitrosyl fluoride (3 g, 61.3 mmol) was bubbled into the solution for 2 hours with stirring. The resulting green reaction mixture was poured into water and the phases were separated. The aqueous phase was extracted with additional carbon tetrachloride. The carbon tetrachloride extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue NO ₂

(1.12 g) crystallized spontaneously. A portion of the crude -fluoronitrimine was triturated with petroleum ether and recovered by filtration (2.59 g). Recrystallization of this material from petroleum ether gave analytically pure S / I-chloro-Sa-fluoro-δ-nitriminocholestane (1.93 g, first connection) in the form of thick, colorless prisms with a melting point of 123 ° C; [a]% = -59 ° (c = 2.05). The infrared spectrum showed AS = 6.12 μ (C = N), 6.35 and 7.65 μ (- NO ₂ ) and 8.67 μ (C - F).
Ultraviolet spectrum: λ ™ * ^ηο] = 267 μ (ρ = 522).

Analysis for C ₂₇ H ₄₄ O ₂ N ₂ FCl:

Calculated ... C 67.4, H 9.08, N 5.8, F 3.93%; Found ... C 67.46, H 9.23, N 5.72, F 3.73 ° / ₀ .

B. 3/3-chloro-5a-fluoro-6-ketocholestane

H ₂ O

(Aluminum oxide)

NO ₂

The remaining, crude crystalline u-fluoronitrimine (2.50 g) was dissolved in petroleum ether and adsorbed on a column of neutral aluminum oxide (120 g, activity III). Elution with petroleum ether gave chromatographically pure 3 /? - chloro-5u-fluoro-6-ketocholestane (1.94 g, yield 85%) in the form of white flakes with a melting point of 109 to 111 ^° C. Recrystallization of these leaflets (1.94 g) from petroleum ether gave analytically pure material (1.4 g, 62% yield) in the form of colorless tufts of needles with a melting point of 113 ° to 115 ° C .; [a] ² _D ⁴ ° = -5 ° (c = 2.05). The infrared spectrum gave λ ^ α = 5.79 μ (C = O) and 8.65 μ (C - F). The nuclear magnetic resonance spectrum for F ¹⁹ at 56.4 megahertz / sec. showed two broad peaks at 5220 and 5270 Hertz / sec., related to Freon 112 (international reference substance) of the same intensity. The nuclear magnetic resonance spectrum for protons showed no vinyl hydrogen atoms.

Analysis for C ₂₇ H ₄₆ OClF:

Calculated ... C 73.9, H 10.4, F 4.33%;
found ... C 73.07, H 9.91, F 4.26%.

+ [H ₂ N-NO ₂ ]

The hydrolysis was also carried out by treating the nitrimino derivative with water as follows:

A solution of 1.26 g of 3β-chloro-5a-fluoro-6-nitriminocholestane in a mixture of 50 cm ^{3 of} dioxane and 10 cm ^{3 of} water, which also contained 0.2 g of urea (for faster decomposition of the nitramine), was 30 Heated for hours on the reflux condenser. The colorless solution was diluted with water and extracted with ether. The ether extracts were washed with water and saturated with brine, evaporated, dried over magnesium sulfate and concentrated under reduced pressure to dryness to give a crystalline residue was obtained (1.09 g, 95% yield), mp 102 to 105 ⁰ C, the infrared spectrum, the Disappearance of the nitrimine function and a strong ketone band at 5.80 μ showed and was identical in every respect with the spectrum of 3ß-chloro-5a-fluoro-6-ketocholestane already marked.

In a further identical experiment, the work-up was about 50% after 9 hours Resulting in hydrolysis, estimated from the infrared spectrum.

609 730/434

Example 2 A. SjS-Acetoxy-Sa-fluoro-o-nitriminocholestane

H ₃ CCOO

+ NOF

H ₃ COCO

+ HF

A solution of cholesteryl acetate (19.11 g, 44.6 mmol) in carbon tetrachloride (60 cm ³ ) was treated for 10 hours in the manner described in Example 1 with slowly flowing nitrosyl fluoride (10 g, 204 mmol). The product was isolated as in Example 1. Evaporation of the solvent under reduced pressure gave a blue-green residue which solidified on trituration with a little petroleum ether. A portion of this solid (9.19 g) was collected by filtration. The product consisted of substantially pure SSS-acetoxy-Sa-fluoro-o-nitriminocholestan having a melting point 160-162 ⁰ C (after two recrystallizations from petroleum ether-chloroform 163-165 ° C).

Analysis for C ₂₉ H ₄₇ O ₄ N ₂ F:

Calculated ... C 68.9, H 9.25, N 5.53, F 3.76%; Found ... C 68.74, H 9.58, N 5.41, F 3.39%.

Molecular weight 506.64.

Molecular weight in boiling ethylene dichloride 510.

Infrared analysis: / IS = 5.80 and 8.10 μ (acetate), 6.13 μ (C = N), 6.40 and 7.65 μ (-NO ₂ ) and 8.65 μ (C - F) .

^{Ultraviolet spectrum} : A * £ ano1 = 267 μ (e = 480). Optical rotation: [a] V ° = -66 ⁰ C (c = 2.28).

The material remaining after the above sample was taken (10.65 g) was a light green oil, that froze when left standing. The infrared spectrum was essentially identical to that of des isolated solid as well as with that of the entire crude product.

H3COCO

B. S / S-acetoxy-Sa-fluoro-o-ketocholestane

H ₂ O

(Aluminum oxide) H ₃ COCO

6.54 g raw S.
stan. (obtained from another preparation) were dissolved in benzene without prior purification. The solution was adsorbed on a column of neutral aluminum oxide (200 g, activity III). First 0.91 g of unreacted cholesteryl acetate was obtained by elution with petroleum ether. Further elution with petroleum ether-benzene (1: 1) gave a white, crystalline material (3.76 g) which was recrystallized from ethanol to give S / J-acetoxy-Sa-fluoro-6-ketocholestane (2.79 g, Yield 62.8%, based on converted cholesteryl acetate) was obtained in the form of long, white flakes with a melting point of 123 to 124 ° C; [a] ² _B ⁴ ° = -6 ° (c = 2.09). Infrared spectrum: A ^ = 5.76 μ (double intensity due to C = O and acetate), 8.15 μ (acetate) and 8.65 μ (C - F).

The nuclear magnetic resonance spectrum for F ¹⁹ at 56.4 megahertz / sec. showed two broad peaks of equal intensity at 5145 and 5180 Hertz / sec., based on Freon 112 (outside). These values agree with the values given by H e η best and W rig 1 ey in »J. Chem. Soc, 1957, 4765 «.

Analysis for C ₂ 9H ₄ 7O ₃ F:

Calculated ... C 75.4, H 10.1, F 4.12%;
Found ... C 75.59, H 10.13, F 4.13%.

Further elution of the aluminum oxide column with diethyl ether gave an oil (0.42 g), which by the Infrared spectrum as the hydrolysis product of the above compound, i.e. H. as 5a-fluoro-6-ketocholestan-3/3-ol

(see following example) was identified.

Example 5a-Fluoro-6-ketocholestan-3 ^ -ol

HO

+ 2NOF

HO

H ₂ O

(Aluminum oxide) HO

This example illustrates the reaction of cholesterol with nitrosyl fluoride and the subsequent one Hydrolysis of the intermediate α-fluoronitrimino derivative. As can be seen from the above equations, side reactions take place in this case. In the first stage takes place apparently partial oxidation of the cholesterol with the nitrosyl fluoride with the formation of a keto group in 3 position instead. Upon hydrolysis, the nitrimino group in this intermediate compound hydrolyzed as usual, while at the same time hydrogen fluoride in the keto group formed in the meantime split off with formation of a double bond between the carbon atoms in the 4- and 5-positions will. The end product is thus a mixture of 5a-fluoro-6-ketocholestan-3 ^ -ol and 4-cholestan-3,6-dione. However, these products can be separated in pure form.

A solution of recrystallized and dried cholesterol (6.0 g, 15.5 mmol) in carbon tetrachloride (25 cm ³ ) was treated with slow flowing nitrosyl fluoride (2.4 g, 49 mmol) in the manner described above for 45 minutes. The usual work-up gave a red oil whose infrared spectrum showed that it was an α-fluoronitrimino derivative and that partial oxidation of the hydroxyl group to a keto group had taken place: S = 2.95 μ (- OH), 5.80 μ (C = O, weak), 6.0 μ (—ONO), 6.15 μ (C = N), 6.4 and 7.65 μ (- NO ₂ ) and 8.6 μ (doublet, C - F). The presence of a nitrite band indicates that partial esterification of the hydroxyl group had taken place. However, the obtained nitrite was hydrolyzed in the subsequent treatment.

The crude product was dissolved in benzene and adsorbed on neutral aluminum oxide (180 g, activity III). Elution with benzene-diethyl ether (1: 1) gave a partially crystalline fraction (1.03) consisting of a mixture of 5a-fluoro-6-ketocholestan-3 / S-ol and 4-cholestene-3,6-dione (see below) existed. Further elution with the same pair of solvents gave a crystalline material (1.108 g, 17%), from which, by recrystallization from methanol, analytically pure 5a-fluoro-6-ketocholestan-3/3-ol with a melting point of 75 to 78 and 121 to 122 ° C (double melting point) was obtained; [α]? ° = +9 "(c = 2.1), infrared analysis: AS = 2.78 μ (OH), 5.77 μ (C = O) and 8.65 μ (CF). The nuclear magnetic resonance spectrum for F ¹⁹ at 56.4 megahertz / sec. showed two broad peaks of approximately the same intensity at 5145 and 5180 Hertz / sec., based on Freon 112 (external reference substance).

Analysis for C ₂₇ H ₄₅ O ₂ F:

Calculated ... C 77.2, H 10.65, F 4.52%;
found ... C 76.78, H 10.70, F 4.28%.

In a comparative experiment, a solution of cholesterol (10.0 g, 25.8 mmol) in carbon tetrachloride (40 cm ³ ) was treated for 3 hours in the manner already described with slowly flowing nitrosyl fluoride (5.5 g, 112 mmol). The entire

Crude product was taken up in benzene and adsorbed on aluminum oxide (300 g, activity III). Elution with the same solvent (benzene) gave a yellow crystalline solid (0.54 g).

Infrared analysis: AS = 5.90 µ (conjugated C = O bond).

Several recrystallizations from methanol gave 4-cholestene-3,6-dione (0.196 g) in the form of yellow flakes with a melting point of 122 to 124 ° C .; [ _a ] l ⁴ ° = -67 ° (c = 2.23). Ultraviolet adsorption: A ^ _x ² " ⁰ ' = 250 μ (ε = 10 100)

and 325 µ (ε = 155). These metrics agree well with the values reported by Fieser (J. Am. Chem. Soc, 75, 4386 [1953]) for this compound.

By further elution with benzene ether (2: 1) a crystalline material was obtained (0.834 g, melting point 77 and 122 ° C). Recrystallization from methanol gave pure Sa-fluoro-o-ketocholestan-3 ^ -ol (0.69 g) with a melting point of 77 ° C (122 to 124 ° C). Most of the reaction mixture remained on the alumina column.

example

3) S-acetoxy-5a-fluoro-6-keto-22-stigmasten

H ₃ COCO

+ NOF

H ₃ COCO

H ₃ COCO - \ y

H ₂ O

(Aluminum oxide)

In the manner described in Example 1 and using the apparatus described there, nitrosyl fluoride (1.5 g, 31 mmol) was slowly stirred in a solution of stigmastyl acetate (4.0 g, 8.8 mmol) in Carbon tetrachloride (20 cm ³ ) passed. The reaction product was isolated in the manner described in Example 1 using carbon tetrachloride. The infrared spectrum of this product indicated that it contained 3/3-acetoxy-5a-fluoro-6-nitrimino-22-stigmasten, but the relative intensities of the bands indicated that some unreacted starting material was present.

Infrared analysis: / «J = 5.80 and 8.15 µ (acetate), 6.15 µ (C = N), 6.40 and 7.65 µ (-NO ₂ ), 8.65 µ (C - F ) and 10.3 μ

Hn

> C = C <

Ή,

The entire crude product was dissolved in a small amount of benzene and adsorbed on an alumina column (150 ⁰ C, type III) to hydrolyze the Nitrimin to the corresponding ketone. Elution with petroleum ether-benzene (1: 1) gave 2.84 g of unreacted stigmastyl acetate. Further elution with the same pair of solvents gave a semi-crystalline mixture (0.382 g) which was discarded. Further elution crystalline (21.2% yield 0.91 g,) was added 3/9-acetoxy-5-fluoro-6-keto-22-stigmastene obtained with a melting point of 152 ⁰ C.

Infrared analysis: AS = 5.80 μ (C = O and acetate), 8.15 µ (acetate), 8.65 µ (C-F) and 10.3 µ

6ο Ι ^{Χ Χ} Η /

Recrystallization from ethanol gave colorless needles (0.61 g, melting point 163 to 164 ° C; [a \ r = ± 0 ° (c = 1.52).

Analysis for C _3x H ₄₉ O ₃ F:

Calculated ... C 76.2, H 10.0, F 3.99%;

Found ... C 76.65, H 10.17, F 3.55%.

Example 5 S / J-Acetoxy-Sa-fluorandrostane-o ^ V-dione

H ₃ COCO

+ 2N0F

H ₃ COCO

+ HF

(Aluminum oxide)

H ₃ COCO -Ky

+ [H ₂ N-NO ₂ ]

Nitrosyl fluoride (7 g, 143 mmol) was added dropwise over 6 hours at O slow / i-acetoxy-5 (6) -androsten-17-one (10.0 g ⁰ C in the manner described with stirring in a solution of 3, 30 mmol) in carbon tetrachloride (60 cm ³ ). Isolation of the product after the usual work-up gave SjS-acetoxy-Sa-fluoro-o-nitriminoandrostan-IV-one in the form of an almost colorless, glass-like material.

Infrared analysis: ΛS = 5.78 μ (C = O and acetate), 6.0 μ (C = CNO ₂ or C = N) (weak), 6.12 μ (C = N), 6.40 and 7, 65 µ (-NO ₂ ), 8.15 µ (acetate) and 8.65 µ (C - F).

The entire crude product was ^{dissolved in benzene (20 cm 3} ) without further purification and adsorbed on a column of neutral aluminum oxide (300 g, activity III), prepared with petroleum ether. Elution with petroleum ether (12 fractions of 100 cm ³ each) gave a gummy material (0.387 g) which was discarded. Further elution with petroleum ether-benzene (1: 1, 29 fractions of 100 cm ³ ) gave 3β -acetoxy-5α-fluoroandrostane-6.17-dione (7.74 g, 70.8% yield) as a white , crystalline solid with a. Melting point of 184 to 187 ° C obtained.

Dion, the fluorine in the form of long white flakes (6.7 g) was obtained with a melting point 187-189 ⁰ C by recrystallization from petroleum ether-methylene chloride. An analytical sample was recrystallized twice from a petroleum ether-acetone mixture, thick, colorless hexagons with a melting point of 189 to 189.5 ° C. (capillary tubes) being obtained; [a]% ⁴ ° = + 55 ° (c = 2.07).

Infrared analysis: Ag ^ = 5.78 µ (C = O and acetate), 8.15 µ (acetate) and 8.65 µ (CF).

Analysis for C21H29O4F:

Calculated ... C 69.2, H 7.96, F 5.22%;
Found ... C 69.58, H 8.04, F 5.15%.

The higher polarity fractions (0.971 g) eluted with ether and methanol were partial crystalline and, due to their infrared spectrum, consisted of stanol, which was produced by hydrolysis of the Acetate group had been formed on the column.

Examples 3β-acetoxy-5a-fluoropregnane-6,20-dione

H ₃ COCO

+ 2NOF

H ₃ COCO

+ HF

(Aluminum oxide)

609 730/434

l 230

Nitrosyl fluoride (6 g, 122 mmol) was dissolved in 3 / S-acetoxy-5 (6) -pregnen-20-one (6.5 g, 18.5 mmol) in carbon tetrachloride (100 cm ³ ) directed. The reaction mixture was poured into water and extracted repeatedly with carbon tetrachloride. The extracts were washed with water, saturated with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, whereby S ^ -acetoxy-Sa-fluoT-o-nitriminopregnan-20-one was obtained in the form of a thick yellow syrup.

Infrared analysis: AS = 5.80 μ (acetate, 5.88 μ (C = O), 6.15 μ (C = N), 6.40 and 7.65 μ (- NO ₂ ), 8.15 μ ( Acetate) and 8.65 µ (C - F).

The entire crude reaction product was dissolved in benzene (about 20 cm ³ ) without further purification and adsorbed on a column of neutral aluminum oxide (180 g, activity III) prepared with petroleum ether. Elution with petroleum ether (50 fractions of 80 cm ³ ) gave a gummy material (0.048 g) which was discarded. Further elution with petroleum ether-benzene (1: 1) (19 fractions of 80 cm ³ ) gave 3 ^ -acetoxy-5a-fluoropregnane-6,20-dione (5.04 g, yield 71%) in the form of a white, crystalline solid with a melting point of 150 ⁰ C obtained.

Infrared analysis: 'Ajüä' = 5.75 μ (partially resolved Doublet, attributed to C-6 C = O and acetate), 5.85 μ (C-20 C = O), 8.15 μ (acetate) and 8.65 µ (C-F).

This product was recrystallized from methanol to give long white needles with a melting point of 150 to 153 ° C. An analysis sample was recrystallized twice from methanol. Melting point 159 to 161 ⁰ C; [a] T = + 42 ° (c = 1.65); A °° f = 5.78 μ (C-6 C = O and acetate), 5.90 μ (C-20 C = O), 8.10 μ (acetate) and 8.65 μ (C - F) .

H ₃ COCO

IO analysis for C23H33O4F:

Calculated ... C 70.3, H 8.42, F 4.85%;
Found ... C 70.13, H 8.65, F 5.42%.

The next two examples illustrate the application of the procedure to 2-cholesterol, a disubstituted olefinic steroid, d. H. a steroid in which each of the doubly bonded carbon atoms carries a hydrogen atom. In the case of reaction components of this type, it was found:

a) The reaction is slower at low temperatures (not significantly above 0 ° C) than with trisubstituted olefinic steroids in which only one of the carbon atoms bonded via double bonds carries a hydrogen atom. However, it has been found that by using hydrogen fluoride in conjunction with nitrosyl fluoride, the reaction rate of the latter at low Temperatures is increased.

b) At higher temperatures, e.g. B. in the order of 20 to 30 ° C, the reaction also proceeds in the absence of an activator such as hydrogen fluoride, at a good rate. Under these conditions however, a competitive reaction begins to take place to an extent that is mainly seems to be temperature dependent. In this reaction a nitroolefin is formed, in which the nitro group is bonded to one of the double bonded carbon atoms.

c) In the first stage of the reaction, in addition to the a-fluoronitrimine, a certain amount of Amount of the a-fluoroketone formed in the Hydrolysis of the fluoronitrimine occurs. The two connections can be separated, e.g. B. by chromatographic methods, but this separation is unnecessary if the α-fluoroketone is desired as the product will.

Example 7 2a-fluorocholestan-3-one and 3 <z-fluorocholestan-2-one

+ 2NOF ₁
(0 ⁰ C)

O ₂ N - N

O ₂ NN

H ₂ O

(Aluminum oxide)

A solution of 2-cholesterol (2.0 g, 5.4 mmol) in carbon tetrachloride (25 cm ³ ), which was cooled in an ice bath, was simultaneously stirred with slowly flowing nitrosyl fluoride (2 g, 41 mmol) and for 3 hours treated with slowly flowing hydrogen fluoride (about 4 g). The reaction mixture, the color of which changed from red to blue within this time, was poured into water and extracted with carbon tetrachloride. The extracts were washed with water, saturated with brine, dried and evaporated under reduced pressure. The infrared spectrum of the residue (2.44 g) indicated that it was 2- (and 3-) fluoro-3- (and -2) -nitriminocholestane (both isomers were present as subsequent hydrolysis showed) and that some fluoroketocholestane was also present.

Infrared analysis: λ S = 5.75 μ (C = O, weak), 6.0 μ (C = C, weak), 6.1 μ (C = N) and 6.4 μ (-NO ₂ ).

The entire crude product was taken up in petroleum ether and adsorbed on a column of neutral aluminum oxide (60 g, activity III). Elution with petroleum ether first gave a partially crystalline mixture (0.80 g), the infrared spectrum of which showed that it contained a certain amount of unreacted nitrimine. Further elution with hexane-benzene (1: 1) gave a partially crystalline material (0.43 g), the infrared spectrum of which showed that it was obtained from the previously unknown 3-fluorocholestan-2-one [λ% £ = 5.82 μ (C = O) and 8.2 μ (C - F)]. This material was not easy to clean.

Further elution with the same pair of solvents gave a crystalline substance (0.246 g) which showed the following infrared absorptions: i ^ = 5.75 μ (C = O) and 9.2 μ (C - F). This substance was recrystallized from petroleum ether to give substantially pure 2-fluorocholestane-3-one (0.23 g in two Anschüssen, m.p. 165-168 ⁰ C) was obtained. The first first shot was recrystallized from hexane to give colorless, glittering platelets were obtained with a melting point of 173-174 ⁰ C.

Analysis for C ?? H45OF:

Calculated ... C 80.15, H 11.21, F 4.70%;
Found ... C 79.59, H 11.20, F 4.98%.

The melting point and the spectral values agree with those of Jensen and Gabbard, J. Org. Chem., 23, 1406 (1958), the information given for this compound.

Example 8
2-fluorocholestan-3-one

An ice-cooled solution of 2-cholesterol (2.0 g, 5.4 mmol) in carbon tetrachloride (20 cm ³ ) was treated with slowly flowing nitrosyl fluoride (2 g, 41 mmol). The product was isolated in the manner described in Example 7 using carbon tetrachloride. It contained mostly unreacted 2-cholesterol, an indication of a slow reaction rate.

The recovered material was then redissolved in carbon tetrachloride (20 cm ³⁾ and again (2 g, 4ImMoI) with slowly pouring nitrosyl fluoride at about 25 ⁰ C treated. The blue reaction mixture was poured into water and the product extracted with carbon tetrachloride. Evaporation of the extract under reduced pressure gave a green syrup, the infrared spectrum of which indicated the presence of a nitroolefin [λ co, = 5.77 _μ (C = O, weak), 6.0 μ

-NO ₂

strong

6.35, 6.40 and 6.45 µ (- NO ₂ , strong, partially resolved triplet), 6.58 µ (- NO ₂ ) and 7.65 µ (-NO ₂ , medium intensity)].

The entire crude product was taken up in a small amount of benzene and adsorbed on a column of neutral aluminum oxide (activity III). Elution with petroleum ether gave a colorless, glass-like substance as the first fraction (fraction A, 0.845 g). Further elutions with petroleum ether (four portions of 100 cm ³ ) gave a crystalline material (fraction B, 0.462 g).

To complete the hydrolysis, fraction A was dissolved in methanol (50 cm ³ ) containing 5 cm ^{3 of} concentrated hydrochloric acid. This solution was refluxed for 1 hour (further experiments showed, however, that this additional step was unnecessary). The reaction mixture was poured into water and the product extracted with ether. The extract was washed with water, dried and evaporated to give an oil which was chromatographed on neutral alumina (30 g, activity III). The first elution with petroleum ether (60 cm ³ ) gave a clear oil (0.445 g) which was found to be a mixture on infrared analysis and could not be crystallized. Further elutions with petroleum ether (three portions of 60 cm ³ ) gave a crystalline material whose

Infrared spectrum was identical to that of fraction B mentioned above. This product was combined with fraction B for further analysis (see below). Further elution with benzene then gave a crystalline material (0.074 g) which, according to the infrared spectrum and melting point, consisted of 2a-fluorocholestan-3-one, which was identical to the product isolated and identified according to Example 7. The B fraction was recrystallized from an ethanol-ether mixture to give pale yellow microcrystals were obtained with a melting point of from 88 to 9O ⁰ C. According to elemental analysis and spectral data, this product was 2-nitro-2-cholesterol (and / or its isomer, 3-nitro-2-cholesterol).

Analysis for C27H45NO2:
Calculated ... C 78.1, H 10.75%;
found ... C 77.94, H 10.83%.

Ultraviolet spectrum:
and 220 ηΐμ (ε = 4100).
Infrared spectrum: λ ^

= 257 m ^ _£ = 5670)

= 5.97 µ
/ NO ₂ ¹ yr

6.60 and 7.45 µ, (- NO ₂ ).
Optical rotation: [a \ g ° = + 104 ° (c = 1.04).

H3COCO

Example 9 A. S / ^ Of-Diacetoxy-Sa-Fluoro-o-Nitrimonipregnane

CH ₃
HC-OCOCH3

+ 2NOF

H3COCO

CH ₃
HCOCOCH ₃

+ HF

N -NO ₂

Nitrosyl fluoride (10 g, 0.21 mol) was stirred for 7 hours in an ice-cold solution of 3 / 3,20-diacetoxy-5-pregnen (mixture of 20/3 and 20a-epimers; 10.2 g, 26 mmol ) in carbon tetrachloride (50 cm ³ ). The reaction mixture was isolated in the manner already described as a pale green oil which crystallized when it was triturated with a petroleum ether-acetone mixture. The crude 3β, 20ξ - diacetoxy - 5a - fluoro - 6 - nitriminopregnane melted at 110 to 120 ⁰ C. Its infrared spectrum showed absorptions at 5.8 and 8.0 μ (acetate), 6.14 μ (C = N), 6.4 and 7.6 µ (-NO ₂ ) and 8.6 µ (C - F). 1.0 g of this product melted after recrystallization from petroleum ether-acetone at 165 to 168 ° C .; Softening point 130 ^° C .; optical rotation: [a] ¥ ° = -63 ° (c = 2.05); Infrared spectrum: ASJ = 5.76 μ (CO), 6.1 μ (C = N), 6.37 and 7.63 μ (- NO ₂ ), 8.15 μ (acetate) and 8.65 μ (C - F).

Analysis for C25H37N2O6F:

Calculated ... C 62.5, H 7.7, F 3.96, N 5.83%; Found ... C 62.73, H 7.53, F 3.72, N 5.86%.

H3COCO

B. 3,8,20f-diacetoxy-5a-fluoropregnane ^: 6-one CH ₃
HCOCOCH ₃

H ₂ O

(Aluminum oxide) H ₃ COCO

N -NO ₂

CH ₃
HCOCOCH ₃

The crude nitrimine (about 9 g) was dissolved in a small amount of benzene and adsorbed on a column of neutral alumina (300 g, activity III) prepared with petroleum ether. Elution with petroleum ether (17 80 cm ³ portions) gave a semi-crystalline material (0.87 g) which was not investigated further. Further elution with a petroleum ether-benzene mixture (2: 1) (18 portions of 80 cm ³ ) gave 5.96 g of crystalline 3ß, 20 £ -diacetoxy-5a-fluoropregnan-6-one with a melting point of 147 to 151 ⁰ C '' softening point 135 ° C).

Infrared analysis: λ ^ = 5.8 μ (C-6, C = O and C-20 acetate, strong, partially resolved doublet), 8.15 μ (acetate) and 8.65 μ (CF). Further elution with benzene (four fractions of 80 cm ³ ) gave a partially crystalline material (1.57 g) which was believed to be a mixture of the C-20 epimers and whose infrared spectrum was essentially identical to that of the earlier fractions . The combined fractions were recrystallized from methylene chloride-petroleum ether, and further recrystallization of an analytical sample from hexane gave fine, colorless needles as the product

with a melting point of 155 to 158 ° C; [a] ² _D ⁴ ° = 0 ° (c = 1.68). The nuclear magnetic resonance spectrum for F ¹⁹ at 56.4 megahertz / sec. showed a doublet at 5155 and 5200 Hertz / sec., based on Freon 112 as the external reference substance.

This product forms crystalline hydrates. The water is held on quite stubbornly, can

however, can be removed by prolonged drying under vacuum.

Analysis for C25H37O5F:

Calculated ... C 68.8, H 8.48, F 4.36%;
Found ... C 69.20, H 8.69, F 4.58%.

H3COCO

Example 10 3 / 3.1 7/3-Diacetoxy-5a-fluoroandrostan-6-one

H3COCO

N -NO ₂

H2O (aluminum oxide)

H3COCO

OCOCH3

Nitrosyl fluoride (7 g, 0.142 mol) was slowly passed into a solution of 3 / 9.17 /? - diacetoxy-5-androstene (14 g, 37.5 mmol) in carbon tetrachloride (50 cm ³ ) with stirring over a period of several hours that was chilled in an ice bath. The reaction product was isolated in the usual way with carbon tetrachloride as a greenish oil (16.82 g). The infrared spectrum showed that a good conversion to 3 / 9,17j3-diacetoxy-5a-fluor-6-nitriminandrostane had been achieved.

Infrared spectrum: / ££ ['= 5.8 and 8.15 μ (acetate), 6.15 μ (C = N), 6.4 and 7.65 μ (-NO ₂ ) and 8.65 μ (CF ).

Most of the crude nitrimine (12.8 g) was dissolved in benzene and the solution was adsorbed on a column of neutral alumina (300 g, activity III) which had been prepared with petroleum ether. Elution with petroleum ether (six fractions of 80 cm ³ ) gave a mixture of the starting material with α-fluoroketone (2.43 g). Further elution with a petroleum ether-benzene mixture (1: 1) (17 fractions of 80 cm ³ ) gave the crystalline α-fluoroketone (6.8 g). Continuing elution with benzene gave an additional 0.98 g of the same product. The eluates obtained with the petroleum ether-benzene mixture and benzene were combined and recrystallized from hexane and then from methanol, whereby 6.04 g of pure 3; 8,17jS-diacetoxy-5a-fluoroandrostan-6-one with a melting point of 160 to 162 ⁰ C were obtained; [a]% ° = -IT (c = 2.07). The nuclear magnetic resonance spectrum for F ¹⁹ at 56.4 megahertz / sec.

showed a doublet at 5155 and 5200 Hertz / sec., based on Freon 112 as the external reference substance.
Analysis for C23H33O5F:

Calculated ... C 67.64, H 8.09%;

Found ... C 67.13, H 8.25%.

Claims (3)

Patent claims: 1. A process for the preparation of fluorine-substituted steroids, characterized in that a steroid which contains at least one endocyclic double bond in which the carbon atoms of this double bond are bonded to 1 or 2 hydrogen atoms, and each of these two carbon atoms is further bonded to 1 or 2 carbon atoms which in turn are free of an unsaturated C - C bond, under practically anhydrous conditions and at temperatures below about 50 ^° C., optionally in the presence of an activator, in particular hydrogen fluoride, reacts with nitrosyl fluoride and optionally hydrolyzes the α-fluoronitriminosteroid obtained. 2. The method according to claim 1, characterized in that the hydrolysis stage by chromatographic treatment over hydrated alumina is carried out. 3. The method according to claim 1 and 2, characterized in that as a steroid output compound Cholesteryl chloride, stigmasteryl acetate, 3ß-acetoxy-5 (6) -androsten-17-one, 3 / S-acetoxy-5 (6) -pregnen-20-one or 3 / ?, 20-diacetoxy-5-pregnene can be used.