HU216630B - New androsta-1,4-diene or-1,3,5-triene derivatives as intermediates for 6-alpha,9-alpha-difluorized-steroides - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to novel androstane-1,4-diene or -1,3,5-triene derivatives of the general formula (VI), wherein R is a hydrogens or ester residue, X is a hydrogen gene or a fatty acid, and Y is a 3-coat with anthelmintic. -D4-system, or X-Hydrogen, and Y, together with the burned-on bullets, means a 3-OR1-D-3,5-system from which R1 is an ether or a residual ester thereof. They can be used to prepare known anti-rabies (I) general 6a, 9a-difluoroacetate times based on the compound of formula (II), by oxidation, 6-position flurrying, and ultimately flocculation of the epoxide. ŕ

Description

The present invention relates to novel androst-1,4-diene or -1,3,5-triene derivatives which are useful as intermediates in the preparation of 6a, 9a-difluorinated steroids.

It has now been found that the new androst-1,4-diene or -1,3,5-triene derivatives of formula VI wherein R is hydrogen or ester residue, X is hydrogen or fluorine and Y together with dotted lines are represents an oxo-A4 system or X represents a hydrogen atom and Y together with the dotted lines represents a 3-OR _r A3.5 system and in the latter formula R 1 represents an enol ether or ester residue - difluorinated steroid derivatives of formula I can be used - wherein R is as defined above in our new production process. The latter consists in treating the compound of formula II with an oxidative degrading agent, protecting the 3-position ketone function (oxo) of the compound of formula III thus obtained in the form of an enol ether or ester and optionally protecting the 17P-carboxylic acid in the form of an ester. reacting a compound of formula IV thus obtained wherein R and R 1 are as defined above with an electrophilic fluorinating agent; and finally treating a compound of formula V wherein R is as defined above with a nucleophilic fluorinating agent and optionally if R is an ester residue - the product of formula I thus obtained is saponified to give the corresponding free acid.

Thus, the compounds of formula IV and V together form the novel compounds of formula VI of the present invention.

The term "ester group" refers to any ester group well known to those skilled in the art of organic chemistry, especially C 1-6 alkyl, C 6-10 aryl or C 7-12 aralkyl.

When R is alkyl, it may be, for example, methyl, ethyl, propyl, isopropyl, η-butyl, sec-butyl, tert-butyl, pentyl or hexyl.

When R is aryl, it may be, for example, phenyl, phenyl substituted by one or more of the above-mentioned alkyl groups.

When R is aralkyl, it may be, for example, benzyl or phenethyl. The term "ester residue" also includes silylated ester residues such as trialkylsilyl residues such as trimethylsilyl or tert-butyldimethylsilyl or triarylsilyl residues such as triphenylsilyl or diarylsilyl. alkylsilyl residues such as diphenyl-tert-butylsilyl.

The 3-enol ether residue refers to groups which are capable of protecting the 3-oxo group of steroids in a manner well known in the art of organic chemistry. Examples of such groups include alkyl groups having 1 to 6 carbon atoms (such as methyl, ethyl or propyl), benzyl, tetrahydropyranyl or one of the silylated groups mentioned in the preceding paragraph.

The enol ester residue at the 3-position is understood as meaning -COR, wherein R is alkyl, aryl or aralkyl as defined above and these groups may be optionally substituted with one or more halogen atoms, in particular chlorine or nitro or aryl. With alkyl having 1 to 4 carbon atoms.

In a preferred embodiment of the aforesaid process, the carboxyl group of the compound of formula III is first protected, and the resulting 3-oxo group of the compound of formula III ', wherein R' is an ester or enol ester, is protected as above. to form a compound of formula IV, as defined above, wherein R is R 'as defined above. Subsequently, the synthesis may be continued as described above.

The protection of the 17-carboxyl group may be accomplished by the ester moieties mentioned above or by alkyl moieties, especially methyl and ethyl groups.

The protecting of the 3-oxo group can be accomplished with the aforementioned ether or ester moieties, the ester moieties being particularly preferred. To this end, mention may be made, in particular, of benzoyl groups optionally substituted by one or more chlorine atoms or nitro or methyl groups, and acetyl, propionyl, butyryl or valeryl groups.

Another preferred embodiment of said process is that the 3-oxo group and the 173-carboxyl group are protected in the same operation in the form of an enol ether or an enol ester and then with the compound of formula IV, where where R and R 1 are the same protecting group, the synthesis is carried out as described above.

In such cases, protection of the 3- and 17-positions is preferably carried out in the form of the silylated ethers and esters as defined above.

In yet another preferred embodiment of said process, only the 3-oxo group is protected in the form of an enol ether or an enol ester, followed by the synthesis of the compound of formula IV, wherein R is hydrogen, as described above. to be continued.

The protection of the 3-position is preferably carried out in the form of an enol ester, in particular in the form of the enol esters mentioned above.

Said oxidative degrading agent can be, for example, periodic acid, lead tetraacetate, potassium permanganate, hydrogen peroxide, catalytic amounts used in the presence of hydrogen peroxide, alkaline persulphates such as oxone (2KHSO5-KHSO4-kS0 . The use of pionic acid is particularly preferred.

The choice of the various protecting groups for the above-mentioned 3- and 17-positions and the

The choice of different reagents for the formation of protecting groups is not a problem for one skilled in the art according to the literature. The ester group of the 17-position may be protected, for example, by reaction with an appropriate alcohol in an acidic medium, by reaction with dicyclohexylcarbodiimide and dimethylaminopyridine or, in the case of a methyl ester, with diazomethane, methyl sulfate or methyl carbonate.

It may be advantageous to carry out the above mentioned reactions in a heterogeneous phase in the presence of a phase transfer catalyst such as a quaternary ammonium salt such as tetrabutylammonium bromide, triethylbenzylammonium chloride or tricaprylmethylammonium chloride or a phosphonium salt. The organic solvent used for the reaction is a chlorinated solvent such as chloroform, methylene chloride or dichloromethane; an aromatic solvent such as toluene, xylene or benzene; or an aliphatic or cycloaliphatic solvent such as hexane or cyclohexane.

The enol ester protecting group at the 3-position may be formed by reaction with an appropriate acid chloride in the presence of a nitrogen-containing base or by an enol ester such as acetate or transesterification. The enol ether protecting group may be formed, for example, by reaction with an alkyl halide in an alkaline medium, or by reaction with dihydropyran, an alkyl ortho-formate or an alcohol in an acidic medium.

The formation of the ester group at the 17-position and the enol ether form at the 3-position can be carried out in the same operation, more particularly when the protecting group is a silylated ester or ether group. A suitable halide is used for this purpose. It is noted that in these cases, due to the particularly labile nature of the silylated ester group, the acid form will be recovered during hydrolysis after 6-fluorination.

As mentioned above, said fluorescent grains must be electrophilic, for example.

Examples of such an electrophilic fluorinating agent include perchloryl fluoride, trifluoromethanesulfonyl fluoride and its derivatives, N-fluoropyridinium pyridine heptafluorodiborate, acetyl or trifluoroacetyl hypofluoride, N-fluoropyridinium, N-fluoropyridinium, N -fluorosulfonimides such as N-fluorobenzenesulfonimides or, preferably, the trade name Selectfluor or N-fluoro, N-chloromethyl triethylene diamine bis-tetrafluoroborate. The reaction is carried out in a solvent medium such as tetrahydrofuran, acetone, methylene chloride, toluene and, in particular, in the case of fluorination using Selectfluor, in a protic or aprotic polar solvent such as dimethylformamide, methanol or, preferably, acetonitrile. may be carried out in the presence of water. The reaction temperature is room temperature or lower. The reaction is carried out in the presence of a phase transfer catalyst, in particular one of the aforementioned catalysts and optionally a cosolvent, in particular a chlorinated solvent, for example one of the chlorinated solvents mentioned above.

Following the 6-position electrophilic fluorination, the hydrolysis is performed and the 3-position oxo is deprotected to form a 1,4-double bond system.

In particular, the nucleophilic fluorinating agent reacted with the compounds of formula V may be hydrogen fluoride, especially aqueous hydrofluoric acid, or a complex of hydrogen fluoride with tetrahydrofuran or, preferably, dimethylformamide. The reaction is carried out at temperatures between -10 ° C and 25 ° C, preferably in the presence of a cosolvent.

Optionally, the final step of saponification may be carried out by methods well known in the art. For example, hydrolysis or alcoholysis may be carried out in the presence of a base, in particular an alkali metal or alkaline earth metal hydroxide or a suitable nitrogenous base.

The compound of formula II is known from U.S. Patent No. 3,947,409.

Compounds of formula I are known, for example, from French Patent 2026919. These esters are anti-inflammatory.

The following example and reference examples are intended to illustrate the invention in greater detail.

Example

6d.-Fluoro-9.11 (h-epoxy-1 H -Methyl-17? -Hydroxy-17? - (methoxycarbonyl) -androst-1,4-dien-3-one

The step

$ 9.11 -Epoxy-16α-methyl-17α, -hydroxy-17α (i-carboxyandrosta-1,4-dien-3-one

200 g of 9.1 iP-epoxy-16α-methyl-17α, 21-dihydroxy-20-keto-pregna-1,4-dien-3-one are mixed with 800 ml of methanol and the resulting mixture is stirred at a temperature of up to 40 ° C for 20 minutes. 128.5 g of ortho-periodic acid are added during the course of the reaction. The resulting slurry was maintained under an inert gas atmosphere at 23-25 ° C for 1 hour with stirring and then poured into a mixture of 1000 ml of water, 2000 g of ice and 200 g of sodium metabisulphite over 5 minutes. The resulting mixture was then stirred at 0-10 ° C for 30 minutes, then filtered and the filtrate rinsed with water. After drying, 192 g of the title compound are obtained, which product is used directly in the next step.

IR (CHC1 ₃₎ t = absorption peaks at 3600 cm-OH; 1706 cm @ ^-1 : savC = O; 1662, 1623, 1607 cm ^-1 : oxo-3-delta, 4.

NMR (CDC1 ₃ MHz, ppm): 0.97 (d): 16CH _3; 1.09 (s): 18-CH ₃ ; 1.45 (s); 19-CH ₃ ; 3.21 (s): H _n ; 3.94: OH; 6.19 (s): H ₄ ; 6.23 (dd): H ₂ ; 6.64 (d): H,.

Step B.

9,11 $ -Epoxy-16tt-methyl-17α, -hydroxy-17β- (methoxycarbonyl) -androsta-1,4-dien-3-one

193 g of the product obtained in Step A above are mixed with 800 ml of methylene chloride and 4 g of tetrabutylammonium bromide, and the resulting mixture is stirred under an inert gas atmosphere for 5 minutes,

HU 216 630 Β

400 ml of 2N aqueous sodium carbonate solution are added at 18-22 ° C followed by 45.8 ml of dimethyl sulfate. The reaction mixture was stirred for 1.5 hours, then decanted and the aqueous phase re-extracted with methylene chloride. The combined organic layers were washed with water and concentrated to about 400 mL. Subsequently, by distillation, methylene chloride is replaced by isopropyl ether. The resulting solution was then cooled to room temperature over 1 hour with stirring and then allowed to stand at room temperature for 1 hour. The precipitated crystals were then collected, rinsed with isopropyl ether and dried. 185.4 g of the title compound are obtained.

IR (CHC1 ₃₎ = 3600 and the absorption peaks at 3540 cm-OH; 1743, 1713 and 1438 cm @ -1: CO ₂ Me; 1662, 1624 and 1608 cm oxo-3-1.4.

Nuclear Magnetic Resonance Spectrum (CDC13, 300 MHz, ppm): 0.93 (d): 16-CH3; 0.98 (s): 18-CH ₃ ; 1.44 (s): 19-CH ₃ ; 2.97 (s): OH; 3.21 (t): H 1; 3.77 (s): CO ₂ CH ₃ ; 6.15 (s): H ₄ ; 6.19 (dd): H ₂ ; 6.61 (d): H,.

Analytical results based on the formula C ₂₂ H _{2 S} O ₅ (MW 372.5):

Calculated: C, 70.9; H, 7.6; Found: C, 71.0; H, 7.8.

Step C.

3- (Benzoyloxy) -9,11 (i-epoxy-6α, methyl-17α-hydroxy] -7β-methoxycarbonyl-androsta-1,3,5-triene

Under an inert gas atmosphere at 20-22 ° C, 30 g of the product obtained in Step B above are mixed with 75 mg of hydroquinone and 42 ml of pyridine, and the resulting mixture is heated to 70 ° C and 13 ml of benzyl chloride is added. The reaction mixture was then heated at 70 ° C for 6 hours and then allowed to cool to 40 ° C. Methanol (30 mL) was added and the mixture was stirred at 40 ° C for 30 minutes and then allowed to cool to room temperature. The resulting solution was added to a mixture of 300 mL of water and 44 mL of 22 ° C hydrochloric acid. Methanol (270 ml) was added and stirring was continued for 1 hour. The precipitated crystals were collected, washed with water and dried. This gave 36.95 g of the title compound, which was purified by dissolving it in two volumes of methylene chloride, adding 5 volumes of methanol and distilling off the methylene chloride. The residue was allowed to cool to room temperature with stirring and then kept at 0 ° C for one hour. 24.97 g of the title compound is isolated in dry form.

IR (CHC1 ₃₎ = absorption peaks at 3600 and 3540 cm> than OH; 1730 cm < 1 >: C =; 1438 cm < ₁ >: OCH3; 1657, 1620, 1603 and 1585 cm @ ^-1 : aromatic C = C's.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz, ppm): 0.94 (d, J = 7): 16-CH ₃ ; 0.98 (s): 18-CH ₃ ; 1.28 (s): 19-CH ₃ ; 3.11 (s): H at position 11; 3.78 (s): CO ₂ CH ₃ ; 5.49 (d, J = 10): H at the 1-position; 5.80 (dd): H at 2-position; 5.8: H at 6; 5.93 (s): H at the 4-position; 7.48: Meta-H; 7.61 (tt): para-H; 8.08: ortho-H.

Analysis for C ₂₉ H ₃₂ O ₆ (MW 476.6):

Calculated: C, 73.1; H, 6.8;

Found: C, 72.9; H, 6.9.

Step D.

6α-Fluoro-9,11H-epoxy-16α-methyl-17α-hydroxy-17β-methoxycarbonyl-androsta-1,4-dien-3-one

Under an inert gas atmosphere, 20 g of the product obtained in Step C above are mixed with 100 ml of acetonitrile and 2 ml of water are added. The resulting suspension is cooled to -1 ° C to +1 ° C and 17.4 g of N-fluoro-N-chloromethyltriethylenediamine are added slowly. After the addition was complete, the suspension was stirred at -1 ° C to +1 ° C for 1 hour and then poured into 400 ml of water and 10 ml of 20% aqueous ammonium hydroxide solution. Sodium metabisulfite (0.4 g) was then added with stirring, followed by stirring at room temperature for 30 minutes. A sufficient amount of 20% aqueous ammonium hydroxide solution was then added to adjust the pH to 8, and the precipitated crystals were collected, washed with water and dried. 16.34 g of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz, ppm): 0.93 (d): CH ₃ -CH; 0.99 (s): 18-CH ₃ ; 1.41 (s): 19-CH ₃ ; 3.33 (d): epoxide-H; 3.78 (s): -CO ₂ CH _3; 5.43 (dddd, J HF = 49): όβ at H; 6.25 (dd): H at 2-position; 6.44 (t): H at the 4-position; 6.52 (dd): 1 H.

Analysis results for C ₂₂ H ₂₇ FO ₅ (molecular weight: 390.45):

Found: C, 67.67; H, 6.97; F, 4.87;

Found: C, 67.9; H, 6.9; F, 4.7.

t. PREPARATION

6cf., 9ct-Difluoro-17β-7β- (β-dihydroxy-16α-methyl-17β-methoxycarbonyl-androsta-1,4-dien-3-one In an inert gas atmosphere as described in Step D above, 18 g of the product thus obtained are mixed with 180 ml of hydrogen fluoride dimethylformamide complex and the resulting mixture is stirred at 22 ± 3 ° C for 3 hours and then with 1.8 L of water and 9 ml of 22 ° BE. Ammonium hydroxide solution is poured into a mixture of 0 to 2 ° C. While maintaining the temperature below 10 ° C, an additional 290 ml of 0.867 g / cm ³ (22 ° BE) of ammonium hydroxide is added in sufficient quantity. to maintain the pH at 4.5 ± 0.5.

The reaction mixture was allowed to warm to room temperature over 1 hour with stirring and then allowed to stand for 1 hour. The precipitated crystals were collected, washed with water to a neutral pH and dried. 18.86 g of the desired product are obtained in crude form. This was taken up in 7 volumes of chloroform, and the solution was heated to reflux, nearly _^2/3 of the chloroform was distilled off and the residue was slowly cooled to 0-5 ° C and maintained at this temperature for 1 hour. The precipitated crystals were collected and dried. This gives 18.3 g of the desired product, which still needs to be desolvated. For this purpose the crystals

Add 216,630 Β of water and stir at 90-95 ° C for 30 minutes while chloroform was distilled off. After cooling, the precipitated crystals were collected, washed with water and dried. 15.8 g of the title compound of this step are obtained, m.p. 227 ° C. Specific rotation [α] j = 60 ° ± 1 ° (c = 1%, DMF). Calculated Fluor: 9.25, Found Fluor: 9-9.2%.

The hydrogen fluoride dimethylformamide complex used in this step was prepared as follows.

Under an inert gas atmosphere, 210 ml of dimethylformamide are stirred at 19-20 ° C for 10 minutes and then condensed hydrogen fluoride cooled to (-15) - (- 20) ° C is added slowly. The temperature was then allowed to warm to about 45 ° C and the rise was stopped at 50-60 ° C with an external bath at (-15) to (-20) ° C. In this way, a total of 250 g of hydrogen fluoride was added over 1 hour and 15 minutes. The resulting solution was stirred for a few minutes under an inert gas atmosphere before the addition of the steroid under the conditions described above.

Reference Example 2

6α, 9α-Difluoro-1β, 7β-dihydroxy-16α-methyl-17β-carboxy-androsta-1,4-dien-3-one

7.9 g of the product of Reference Example 1 are mixed with 75 ml of methanol and 4 ml of water under an inert gas and the resulting mixture is stirred for 10 minutes at room temperature. A solution of potassium carbonate (2.5 g) in water (20 ml) was added over 5 minutes and the reaction mixture was refluxed slowly. After refluxing for 3.5 hours, the reaction mixture was cooled to 50 ° C, and then acetic acid (about 3 ml) was added to adjust the pH to about 6. The reaction mixture was concentrated to about 40 mL, cooled to 20 ° C, and water was added. The precipitated crystals were separated with a mixture of methanol and water, washed with water and finally dried.

The product (7.3 g) was purified by slurrying in hot methanol and recrystallizing from acetone after treatment with charcoal.

Specific rotation [α] 20 D = + 65.5 ° (c = 1%, DMF).

Analysis calculated for C21 H26 F2 O5: C, 63.79; H, 6.63; F, 9.61; Found: C, 63.7; H, 6.6; F, 9.3.

Nuclear Magnetic Resonance Spectrum (CHCl ₃ , 300 MHz, ppm):

1.02 (d): CH ₃ ; 1.26 (s): 18-CH ₃ ; 1.58 (s): 19-CH ₃ ;

4.40 (d, m): H at the 11-position; 5.40 (d, m): H at the 6-position; 6.33 (d): H at 2-position; 7.18 (d): H at the 1-position; 7.43 (s): 4-position H.

IR spectrum (nujol) = absorption peaks at 3559-3541 cm t: OH; 1698-1661 cm; C = O and conjugated C = O; 1615-1603 cm Η C = O.

Claims (1)

A compound of formula VI wherein R is hydrogen or ester residue, X is hydrogen or fluorine and Y is a 3-oxo-A4 system with dotted lines, or X is hydrogen and Y with dotted lines 3OR _r A-3,5 represents the system where R 1 represents an enol ether or an enol ester residue.