DD296494A5 - METHOD FOR THE PRODUCTION OF BETA-HYDROXY-NITRIL-STEROID DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of b-hydroxynitrile steroid derivatives. The title compounds are pharmacologically interesting steroid compounds or intermediates for the synthesis of pharmacologically highly potent steroid products. The process is characterized in that the 17-ketosteroids of the general formula I in which the rings A, B and C of the basic steroid skeleton which have the abovementioned meaning in the substructures a to h and the radicals in a one-pot process in inert organic solvents low temperatures with LiCH2CN, which is prepared in situ from CH3CN by reaction with lithium alkyls or Lithiumdialkylamiden (alkyl C1 to C6) reacted, the reaction products worked up vigorously, the compounds of general formula II, in which the rings A, B and C of Steroidgrundgeruestes the in the substructures a to h and the radicals have the abovementioned meaning isolated or by direct Saeurehydrolyse in abovementioned b-hydroxynitrile steroid derivatives of the general formula II, in which the rings A, B and C in the substructures i to s and the radicals have the abovementioned meaning, be transferred and isolated. {* * alkali metal salts; alkaline earth metal; Ammonium salts; alkylammonium; Production method; Cancer therapy; Protection of human cells; Protection of animal cells}

Description

represent, in a one-pot process in inert organic solvents at low temperatures with LiCH ₂ CN, which is prepared in situ from CH ₃ CN by reaction with lithium alkyls or Lithiumdialkylamiden (alkyl = C ₁ to C ₆ ), the reaction products were worked up aqueous, the Compounds of the general formula II in which the rings A, B and C of the steroid skeleton in the substructures a to h and the radicals have the abovementioned meaning isolated or by direct acid hydrolysis in the above ß-hydroxynitrile steroid derivatives of the general formula II, in the the rings A, B and C of the steroid skeleton which in the substructures i to s and the radicals have the abovementioned meaning, are transferred and isolated.

2. The method according to claim 1, characterized in that as inert organic solvents aliphatic or aromatic hydrocarbons, preferably pentane, hexane, heptane, benzene, toluene et al., Ethers, preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, anisole, dimethoxyethane, diethoxyethane, etc., or tertiary amines such. Triethylamine, diisopropylethylamine, pyridine and the like. are used, or these solvents are used as mixtures.

3. The method according to claim 1 and 2, characterized in that per mole of 17-ketosteroid 1 to 5 moles of acetonitrile and 1 to 5 moles Lithiumalkyl- or lithium dialkylamide used and the acetonitrile is reacted in situ at low temperatures to LiCH ₂ CN.

4. The method according to claim 1 to 3, characterized in that the reaction at temperatures <± 0 ° C, preferably in the temperature range from -2O ⁰ C to -90 ⁰ C is performed.

5. The method according to claim 1 to 4, characterized in that the aqueous workup preferably in the pH range S: pH 6 and temperatures <10 ⁰ C is performed.

6. The method according to claim 1 to 5, characterized in that the acid hydrolysis in the pH range <pH 6 is performed.

7. The method according to claim 1 to 6, characterized in that the pH range adjustment by the addition of salts such as NH ₄ Cl, NH ₄ OAc, NaH ₂ PO _4, etc. or addition of inorganic acids such. As HCl, H ₃ PO ₄ , H ₂ SO ₄ and others or organic acids such. As acetic acid, oxalic acid, p-toluenesulfonic acid, inter alia, to the workup mixture.

Field of application of the invention

The invention relates to a novel process for the preparation of β-hydroxynitrile steroid derivatives from 17-ketosteroids in a one-pot process.

β-hydroxynitrile steroid derivatives are pharmacologically interesting steroid compounds or also intermediates for the synthesis of pharmacologically highly potent steroid products, e.g. iTa-cyanomethyl-β-hydroxy-IS-methyl-gonyl-S-dien-3-one or else 17a-cyanomethyl-17β-hydroxy-13-ethyl-gona-4,9-dien-3-one and the 17a-cyanomethyl- 17β-hydroxy-13-alkylgona-4,9,11-triene-3-one derivatives which, owing to their specific hormonal or else antihormonal effects, can be used advantageously for the treatment of endocrinopathies and for the control of reproduction in human and veterinary medicine. Compounds of the 17a-cyanomethyl-17β-hydroxy-13-alkaline-gona-4,9-dien-3-one type, e.g. "Dienogest" are particularly suitable for the treatment of endometriosis.

Characteristic of the known state of the art c.

The synthesis of β-hydroxynitrile steroid derivatives such as ITa-cyanomethyl-IVβ-hydroxysteroids has been described in a number of patents. Thereafter, 17-ketosteroids are converted in a multistep synthesis into the steroid ^ -spiro-V ^ '- oxiranes.' * ^, Which are then reacted with alkali cyanide to give the ^ a-cyanomethyl-ß-hydroxysteroid derivatives. After K.Ponsold u.a. (DD-WP 132497) is 3-methoxy-13-alkylgona-2,5 (10) -diene-17ß-spiro-1 ', 2'-oxirane (prepared according to DD-WP 80023) by reaction with alkali metal cyanide and subsequent enol ether hydrolysis into the ^ a-cyanomethyl ^ ß-hydroxy-IS-alkylgon-5 (10) -en-3-one converted. The disadvantage of this synthesis is the use of the very unstable 3-methoxy-13-

Alkylgana ^ 2,5 (10) -diene derivatives, which are extremely acid-sensitive and can also be oxidized very easily, where arise in products with aromatic Α-ring. This requires, in all reactions with these compounds, as well as in their storage special precautions to take into account in order to minimize the formation of undesirable hydrolysis and oxidation products or minimize by-products by additional purification operations. An improvement to this method has been made by K. Ponsold et al. a. in DD-WP 160418, according to the 3,3-dimethoxy-13-alkylgona-5 (lO) -en-17-one derivatives with trimethylsulfonium iodide in the steroid-i7ß-spiro-1 ', 2'-oxiranes and followed by Reaction with alkali metal cyanide in the 17a-cyanomethyl-17ß-hydroxysteroids are converted, which after cleavage of 17a-cyanomethyl-17ß-hydroxy-i3-alkylgon-5 (10) -en-3-one derivatives.

Although the individual stages of this synthesis proceed in high yields, the overall economy is burdened by the use of expensive reagents and the high workload caused by the complex intermediate insulations. This process is characterized by the following stages of work.

Synthesis of trimethylsulfonium iodide from dimethyl sulfide and methyl iodide

Reaction of the steroid C17 ketone with trimethylsulfonium iodide in the presence of potassium tert-butoxide and isolation of the oxirane as a resinous distillation residue

Reaction of the oxirane with alkali cyanide and isolation of the cyanomethyl compound as a resinous distillation residue

- Ketalspaltung and isolation of the 3-keto-A ^{5 (10)} steroid as a crystalline product.

The main disadvantage of this procedure, however, is the high environmental impact associated with this synthesis, which is caused by the use of

- Trimethylsulfoniumjodid, which requires the disposal of the exhaust air and wastewater

- Alkali cyanide, a poison of the Dept.1 of the law of poison, which places special demands on the processing on an industrial scale and requires a special disposal of the exhaust air and waste water.

The use of the alkali metal cyanides in this synthesis results in a further drawback consisting in a residual cyanide content of the final product, the removal of which requires additional purification operations and also the use of additional testing methods for intermediate and final synthesis products.

E.Nittau.a. described in EP 231671 of 19.06.86 the synthesis of ^ a-cyanomethyl ^ ß-hydroxy-IS-alkylgona ^^ iitrien-3-one derivatives from the corresponding 17-ketosteroids using the K. Ponsold u.a. (DD-WP 160418)

reaction sequence described 17-ketosteroid> 17ß-spiro-1 ', 2'-oxirane> ^ a-cyanomethyl ^ ßhydroxy-steroidderivate.

Although this patent described novel compounds of the 17a-cyanomethyl-17β-hydroxysteroid type, no improvements to the original synthetic route could be disclosed; h., The above-mentioned lack of high workload and the strong environmental impact also exist in this process. In addition to the high costs already mentioned for the implementation of this synthesis, the continuous additional high expenditures for the disposal of the waste products, the wastewater arising as well as exhaust air with sulfur compounds and cyanides occur in the technical implementation, whereby the economy of the overall process undergoes substantial additional burdens.

Object of the invention

The aim of the invention is a new, generally applicable method for the synthesis of .beta.-hydroxynitrile steroid compounds, according to which the target products are accessible in a technologically and economically favorable manner and thus, in particular, the additional burden of secondary processes and disposal of effluents and exhaust air can be substantially minimized.

Explanation of the essence of the invention

The invention has for its object to provide a method for the synthesis of ß-hydroxynitrile steroid compounds from 17-Ketosteroidderivaten, made accessible in a technically simple and economically favorable way, the target products and the cost of ancillary processes, especially the removal of waste products / disposal of wastewater and exhaust air can be minimized as much as possible. According to the invention the object is achieved in that 17-ketosteroids of the general formula I, in which the rings A, 8 and C of the steroid skeleton have the meaning given in the substructures a to h and the radicals

R, = Me, Eth

R ₂ = alkyl (C ₁ to C ₄ )

R ₃ = acyl or H

R ₄ , R ₅ = Me, Eth or

R ₄ and R ₅ together are -CH ₂ CHj-,

Me _> Ιθ, -, -CIU-C-CII ₉ -,

for

represent in a one-pot process in inert organic solvents at low temperatures with LiCH ₂ CN prepared in situ from CH ₃ CN by reaction with lithium alkyls or lithium dialkylamides (alkyl = C ₁ to Ce) to form β-hydroxynitrile steroid derivatives of the general formula II are reacted with the abovementioned meaning of the rings A, B and C of the steroid skeleton and the radicals R ₁ to R ₆ , these isolated after aqueous workup or without intermediate isolation after acid hydrolysis in ß-hydroxynitrile steroid derivatives of the general formula II, in which the rings A, B and C of the steroid skeleton and the radicals have the meaning given in the substructures i to s, transferred and these are isolated.

This in situ metallation of the acetonitrile with lithium alkyl or lithium dialkylamides to LiCH ₂ CN and its subsequent reaction in a one-pot process with 17-ketosteroids to the ß-Hydroxynitrilsteroidderivten carried out in inert organic solvents such as aliphatic or aromatic hydrocarbons, preferably pentane, hexane, heptane, Benzene, toluene; Ether preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, anisole, dimethoxyethane, oiethoxyethane, etc. or in tertiary amines such as triethylamine, diisopropylethylamine, pyridine, among others, these solvents can also be used as mixtures. According to the inventive method per mole

17-Ketosteroid 1 to 5 moles of acetonitrile and 1 to 5 moles of lithium alkyl or lithium dialkylamide used, wi.td method,

that the acetonitrile is reacted in situ at low temperatures with the lithium derivatives used in the LiCHjCN äerfiffirfünd this with the 17-ketosteroid to ß-hydroxynitrile steroid derivative. This procedure also implies that the in situ preparation of LiCH ₂ CN occurs in the presence of the 17-ketosteroid and the follow-up reaction with the 17-ketosteroid to the β-hydroxynitrile steroid derivative can proceed almost simultaneously.

Advantageously, these reactions are carried out at low temperatures, ie in temperature ranges s ± 0 ° C, in which the reaction of LiCH ₂ CN with acetonitrile to

CH ₃ -C-CH ₂ CN -7 CH ₃ -C-CH ₂ -CN

as far as possible or completely suppressed. These are preferably the temperature ranges from -20 ° C. to -90 ° C. The reaction mixtures can be worked up by adding water, the reaction products being able to be isolated to give protective groups such as ketals or enol ethers, etc. These aqueous work-ups are advantageously carried out at temperatures <10 ° C in pH ranges> pH 6, whereby the pH adjustment also by additions of salts like

NH ₄ Cl, NH ₄ OAc, NaH ₂ PO _4, etc. or acids can be carried out.

However, the work-up can also be carried out so that the decomposition of the reaction mixtures, ie the destruction of the excess lithium organyl with the addition of water and acids or dilute acids and is carried out at pH ranges <6 and this case optionally present in the molecule protective groups such as ketals , Enol ethers, etc. are cleaved. As acids here inorganic acids such as HCI, H ₃ PO ₄ , H ₂ SO _4, etc., or organic acids such as acetic acid, oxalic acid, p-toluenesulfonic acid, etc. may be used.

In the workup, it is generally possible to proceed in such a way that the decomposition of the excess Li organyl is started at low temperatures and the acid hydrolysis is then continued at temperatures of up to 50.degree. The isolation of the reaction products can be carried out by extraction or precipitation, it is advantageous, however, to distill as far as possible from the reaction mixture under vacuum, the solvent mixture and to isolate the resulting crystals in high purity.

With the procedure according to the invention, the deficiencies identified in the known state of the art are eliminated, an easy-to-implement method is disclosed which substantially minimizes the previously required high material and time expenditure. With this new procedure, the known environmental pollution is avoided, since the solvents are largely recovered. The Li-SaIz, which folds during the work-up, is readily separable and the residual amounts of acetonitrile contained in the wastewater in dilute solutions are biodegradable (Martinez "Immobilization, Detoxification and Destruction of Chemicals", I.Auflage, Verlag Harri Deutsch, Thum Frankfurt (M. ), P.211) ..

Ausführungseispiele example 1

A.S-dimethoxy-a-cyanomethyl ^ ^ ß-hydroxy-SdOKestren

42 ml of butyllithium solution (68 mmol of butyllithium) are introduced into a reaction vessel which has been purged with inert gas and diluted with 25 ml of purified dry tetrahydrofuran at a temperature of <-60.degree. Then, to the almost clear solution with stirring and cooling at temperatures <-60 ° C, 3.5 ml of acetonitrile (68 mmol). After the acetonitrile has been added, a solution of 5 g of 3,3-dimethoxy-5 (, 10) -estren-17-one (23 mmol) in 25 ml of tetrahydrofuran is added to the resulting suspension. The addition must be carried out so that the reaction temperature of <-6O ⁰ C. After a post-reaction time of 30 min, the reaction solution is heated and the mixture is added dropwise at 20 ° C. to water at a temperature of 0 ° C. to 10 ° C. The resulting two-phase system is separated and the organic phase is concentrated in vacuo. Then the crude product is dissolved in 40 ml of chloroform and the organic phase is washed 3 times with 20 ml of water. After renewed concentration, 5.4 g of yellow oil (95% of theory) are obtained. DC studies showed a uniform product.

Example 2

17a-cyanomethyl-17-hydroxy-5 (10) -estrene-3-one

5 g of 3,3-ethylenedioxy-5 (10) -estren-17-one are reacted according to the experimental procedure listed in Example 1 to give 17a-cyanomethyl-3,3-ethylenedioxy-17β-hydroxy-5 (10) -esterone. After the postreaction time, dilute with HjSO ₄ and stir vigorously for 30 minutes at room temperature. After phase separation, the organic phase is concentrated and the resulting oil is crystallized using acetone.

There are obtained 4.55 g (^ 92% of theory) of 17a-cyanomethyl-17β-hydroxy-5 (10) -estren-3-one.

Fp: 17S, 7Xbis177,4X

¹ HN MR spectrum (80 MHz, CDCl ₃ , δ vs. TMS as internal standard) 0.98 ppm (see 3 H, 18 -CH ₃ ); 2.46 ppm (m, 4 H, 1-CH ₂ , 2-CH ₂ );

2.63 ppm (m, 2H, 17a-CH ₂ CN); 2,76ppm (m 2H, 4-CH ₂ )

Example 3

17a-cyanomethyl-17.beta.-hydroxy-4-androstene-3-one

10 ml of butyllithium solution (13 mmol of butyllithium) are placed under an inert gas stream in the reaction vessel and cooled. At temperatures <-6OX, the solution is mixed with 10 ml of tetrahydrofuran and then with 0.75 ml of acetonitrile (14 mmol). To the resulting suspension, a solution of 1.9 g of 3-methoxy-3,5-androstadien-17-one (6.3 mmol) in 10 ml of tetrahydrofuran is added so that the reaction temperature -60 ⁰ C is not exceeded. The further work-up is carried out as in Example 1. The product is then reacted in methanol with addition of acid to 17a-cyanomethyl-17ß-hydroxy-4-androsten-3-one. 1.85 g (0.85% of theory) of crystals are obtained

 Mp: 278.8X to 281, rc

^ H-NMfl spectra (SOMHz, CDCI _3. Δ vs. TMS as internal standard) 0.98 ppm (s, 3H, 18-CH ₃ ); 1.23 ppm (s, 3H, 19-CH ₃ ); 2.52ppm u. 2.63ppm (d, 24,17a-CH ₂ CN); 5.76ppm (s, 1H, 4-CH).

Example 4

17a-cyanomethyl-3,17ß-dihydroxy-5-androstene

Under inert gas, 20 ml of butyllithium in a reaction vessel, cooled to about -70X and then treated with 20 ml of tetrahydrofuran. With stirring and cooling, 1.5 ml of acetonitrile in 10 mM tetrahydrofuran are added to this solution. Subsequently, a solution of 3.6 g of androstenolane in 30 ml of tetrahydrofuran is added so that the reaction temperature of -6OX is not exceeded. After addition of the steroid solution is allowed to react for up to 1 hour, therefore allowed to warm to about 10X and then the mixture with stirring in water. The reaction product is extracted by extraction with chloroform, the CHCfo phases are washed several times with water and then concentrated as far as possible under vacuum. The residue is then crystallized from CHCl ₃ .

Yield: 78% d. Th.

Mp 214,7Xbis214,9X

¹ H-NMR spectrum (80 MHz, CDCl ₃ , δ vs. TMS as internal standard) 0.81 ppm (s, 3H, 18-CH ₃ ); 0,99ppm (s, 3H, 19-CH _3); 2-, 63ppm (s, 2H, 17a-CH ₂ CN).

Example 5

-3--estrarien 17a-methoxy-17-hydroxy-cyanomethyl-1,3,5 (10)

13 ml of butyllithium solution (20 mmol) are cooled under inert gas and stirring to <-60X and mixed with 15 ml of tetrahydrofuran. After addition of 1.1 ml of acetonitrile (20 mmol) at a reaction temperature <-60X, a white suspension is obtained. 2.5 g of estrone-3-methyl ether are suspended in 20 ml of tetrahydrofuran or partially dissolved and the reaction solution is added so that a temperature of -60X is not exceeded. After stirring for 30 minutes at <-60X, it is decomposed with 20 ml of water. The phases are separated and the organic phase is concentrated under vacuum. The 17a-cyanomethyl-17ß-hydroxy-1,3,5-estratriene-3-methyl ether crystallized from a mixture of acetone / water in a yield of 78% d. Th. Off.

Mp 149,2Xbis149,9X

¹ H-NMR spectrum: (80MHz, CDCl ₃ , δ vs. TMS as internal standard) 0.95ppm (s, 3H, 18-CH ₃ ), 2.59ppm (d, 1 H, J = 16Hz, 17a-CH ₂ CN), 2,69ppm (d, 1 H, J = 16 Hz, 17a-CH ₂ CN), 3,80ppm (s, 3H, _3-OCH3), 6,68ppm (m, 1H, 4-CH) , 6.72ppm (dd, 1H, J = 2 9Hz), 7.22ppm (d, 1H, J - 9Hz, 1-CH).

Example 6

3-methoxy-13-ethyl-17a-cyanomethyl-17-hydroxy-3,5-gonadien

Under inert gas, 10 ml of butyllithium solution (0.22 mol of butyl lithium) in a reaction vessel, cooled to temperatures <-35X and then mixed with 30ml of purified, dry tetrahydrofuran. 1.15 ml of acetonitrile (0.022 mol) are added to this solution with stirring and cooling. Subsequently, a solution of 3.0 g of 3-methoxy-13-ethyl-3,5-gonadien-17-one (0.01 mol) in 25 ml of tetrahydrofuran is added so that the reaction temperature of -30X is not exceeded. After addition of the steroid solution is allowed for 30 min. react, then allowed the reaction mixture to warm to about -10X and added dropwise at this temperature with 50 ml of water, the reaction temperature can rise to + 1OX.

The resulting two-phase mixture is separated and the organic phase concentrated under vacuum as far as possible. The residue obtained is taken up in chloroform, the CHCl ₃ solution is washed neutral with water, dried over Na ₂ SO ₄ and then concentrated under vacuum as far as possible.

Yield: 69%

'H-NMR spectrum (80 MHz, CDCl _3. Δ vs. TMS as internal standard) 1.04 ppm (tr, 3H, J = Hz, 18-CH ₂ -CH ₃ ); 2.53 ppm (d, 1H, J = 16Hz, 17Ci-CH ₂ CN); 2,68ppm (d, 1 H, J = 16 Hz, 17a-CH ₂ CN); 3.60 ppm (s, 1H, J = 16Hz, 170.-CH ₂ CN); 3,60ppm (s, 2H, 3-OCH _3), 5.25 ppm (s, 1 H, 4-CH); 5.28ppm (m, 1H.6-CH).

Example 7

13-Meihyl-17a-cyanomethyl-17-hydroxy-4-Gonen-3-one

In analogy to Example 6, 3.0 g of 3-methoxy-13-methyl-3,5-gonadien-17-one are reacted. Yield: 74% d. th

 Mp 243Xbis246X

H-NMR spectrum: (80 MHz, CDCl _3. Δ vs. TMS as internal standard) 0.84 ppm (s, 3H, 18-CH ₃ ); 263 ppm (2 d, 2 H, 17a-CH ₂ CN); 5.75ppTi (s, 1H, 4-CH).

Claims (1)

-'- 296 491 Claims: 1. A process for the preparation of ß-hydroxynitrile steroid derivatives from 17-ketosteroids, characterized in that 17-ketosteroids of the general formula I, in which the rings A, B and C of the steroid skeleton have the meaning given in the substructures a to h meaning and the radicals R ₁ = Me, Eth R ₂ = alkyl (C ₁ to C ₄ ) R ₃ = acyl or H - - - " R ₄ , R ₅ = Me, Eth or
R ₄ and R ₅ together Me Me -CH ₂ -CU ₂ -; -CH ₂ -C-CH ₂ -; CH ₃ -CH-CH ₂ -CH-CH ₃