DD296495A5 - PROCESS FOR PREPARING 17ALPHA-CYANOMETHYL-17BETA-HYDROXYSTEROID DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of 17a-cyanomethyl-17b-hydroxysteroidderivaten. 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 17b-ketosteroids of the general formula I in which the rings A, B and C of the basic steroid moiety have the abovementioned meaning in substructures a to c and the residues in a one-pot process in inert organic solvents 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 in the substructures a to c and the radicals have the abovementioned meaning isolated or by direct Saeurehydrolyse in above-mentioned 17a-cyanomethyl-17b-hydroxysteroidderivatives of the general formula II, in which the rings A, B and C in the substructures d to f and the Residues have the meaning given, are transferred and isolated. {17a-cyanomethyl-17b-hydroxysteroidderivate; 17-ketosteroids; One-pot acetonitrile; lithium alkyl; lithium dialkylamide; Work-up, water-based; acid hydrolysis; Solvent, organic, inert}

Description

For this 1 page drawing

Field of application of the invention

The invention relates to an improved process for the preparation of lya-cyanomethyl-i? β-hydroxysteroid derivatives of 17-ketosteroids in a one-pot procedure.

17a-cyanomethyl-17β-hydroxysteroidderivate are pharmacologically interesting steroid compounds or intermediates for the synthesis of pharmacologically highly potent steroid products such. 17a-cyanomethyl-17β-hydroxvestra-4,9-dien-3-one, "dienogest", or 17a-cyanomethyl 1-17β-hydroxy-13-alkyl-4,9-gonadien-3-one or else ^ a-cyanomethyl-lTß-hydroxy-IS-alkyM.SH-gonatrien-S-onderivaten, which can be used advantageously for the treatment of endocrinopathies and for reproductive control in human and veterinary medicine because of their specific hormonal or antihormonal effects, for the treatment In particular endometriosis compounds of the type 17a-CyanomethyM7ß-hydroxy-13-alkyl-4,9-gonadien-3-one are suitable.

Characteristic of the known state of the art

The synthesis of ITa-cyanomethylMTβ-hydroxysteroids such as ^ a-cyanomethylmyβ-hydroxy-IS-alkyl-gonyl-S-diene-S-on and 17a-cyanomethyl-17β-hydroxy-13-alkylgona-4,9,11-triene-3-one have been described in a number of patents. Thereafter, 17-ketosteroids are converted in multistage syntheses into the steroid 17ß-spiro-1 ', 2'-oxiranes, which are then reacted with alkali cyanides

be converted to the 17 a-cyanomethyl-17 ß-hydroxysteroidderivaten. After the introduction of this steroid 17 a-

Side chain structure is then the further transformation of the steroid backbone for the introduction of double bonds in the Positions 4,9 and 4,9,11 required. After K.Ponsold u.a. (DD-WP 160418) are 3,3-dimethoxy-13-alkyl-gona-5 (10) -en-17-one derivatives with Trimethylsulfoniumjodid in the steroid-17 ß-spiro-1 ', 2'-oxiranes and subsequently by reaction with alkali metal cyanide in the

17a-cyanomethyl-17β-hydroxy derivatives which, upon ketal cleavage, give 13-alkyl-5 (10) -gone-3-one derivatives.

The interesting, pharmacologically active compounds are characterized by the introduction of the double bonds in

get the positions 4,9 and 4,9,11 what z. B. by bromination of the A ^ '- double bond and subsequent

Dehydrobromierung or by dehydrogenation with dichlorodicyanobenzoquinone (ODQ) can take place. Although the individual stages of Synthes for the introduction of 17a-cyanomethyl-17 ß-hydroxygruppeng in high yields

The overall economy of the process is burdened by the use of expensive reagents and the high costs

Labor, caused by the complex intermediate insulation. This sub-process of the overall synthesis is characterized by the following stated work stages:

Synthesis of trimethylsulfonium iodide from dimethylsulfide and methyl iodide.

Reaction of the steroid C17-ketone with trimethylsulfonium iodide in the presence of bases such as e.g. Potassium t-butylate, sodium hydroxide, and the like. 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 S-keto-A ^ '- steroid as a crystalline product.

However, the main disadvantage of this complex procedure is the environmental pollution associated with this synthesis which is caused by the use of

- Dimethylsulfide, trimethylsulfonium iodide, which requires the disposal of the exhaust air and the 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 alkali metal cyanide in this synthesis results in a further drawback, which is the residual cyanide content of the final product, the complete removal of which requires additional purification operations and the use of additional, elaborate testing methods for intermediate and final synthesis products. The second section of the synthesis concerns the introduction of double bonds into the product Steroid backbone at positions 4 and 9. K. Ponsold et al. Describe this procedure of bromination and dehydrobromination in DD-WP 160418. B. Menzenbach, M.Hübner and K. Ponsold (Journal of Practical Chemistry, Vol.326, No. 6,1984 , Pp. 893 to 898) have carried out in-depth studies on this problem. The main problem after this is the avoidance of byproduct formation, which is often the result of slight changes in the reaction conditions. Another problem is the exact dosage of the brominating agent, since at the ^{top of} the formation of 4-bromo-A ^4l9 -diene derivatives, inter alia, on the other hand, under dosage leads to the whereabouts of incompletely converted starting material. The 4-bromo-A ^4-9 -diene derivatives are particularly stressful because they are difficult to remove by conventional purification methods. This situation places a heavy burden on the overall synthesis, since by-product formation in the final stage of the synthesis can reduce the overall synthesis results.

By E. Nitta u. a. EP 231 671 is used for the synthesis of the 17a-cyanomethyl-17β-hydroxy-13-alkyl-4,9,11 -gospatrien-3-one derivatives of K.Ponsold et al. used in DD-WP 160418 reaction sequence 17-ketosteroid - * 17ß-spiro-1 ', 2'-oxirane - »17a-cyanomethyl-17 ß-hydroxysteroidderivate used. Although new compounds of the 17a-cyanomethyl-17β-hydroxysteroid type have been described in this patent by E. Nitta, no improvements of the original synthetic route have been 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 technical implementation of the additional additional high expenditures for the disposal of the waste products-the wastewater and exhaust air with sulfur compounds and cyanides-causes the economy of the overall process to suffer substantial additional burdens.

Object of the invention

The aim of the invention is a new, generally applicable process for the synthesis of 17a-cyanomethyl-17ßhydroxysteroidderivaten, according to the technologically and economically favorable way the target products are accessible and thus in particular the additional burden of secondary processes and the disposal of wastewater and exhaust air can be substantially minimized.

Explanation of the essence of the invention The invention has for its object to provide a process for the synthesis of 17a-cyanomethyl-17ß-hydroxysteroidderivaten

To provide 17-ketosteroids, made accessible to the target products in a technically simple and economically favorable manner and the cost of ancillary processes, in particular the removal of exhaust air / disposal of waste water and exhaust air are minimized as far as possible.

According to the invention the object is achieved in that 17-ketosteroids of the general formula I, in which the rings A, B and C

of the steroid backbone have the meaning given in the substructures a to c and the radicals R, = Me, Eth

R ₃ , R ₃ = Μ ©, Eth or also

R ₂ and R ₃ together are -CH ₂ -CH ₂ -, -CH ₂ -C-CII ₂ -,

-3- 296 4 «

in a one-pot process in inert organic solvents at low temperatures with UCH ₂ CN, which is prepared in situ I from CH ₃ CN by reaction with lithium alkyls or Lithiumdialkylamiden (alkyl - C ₁ to C ₆ ), reacted, the reaction products were worked up aqueous, the compounds of general formula II in which the rings A, B and C of the «φ.

Steroid skeleton in the substructures a to c and the radicals have the stated meaning, isolated or by indirect acid hydrolysis in the above 17a-cyanomethyl-17 ß-hydroxysteroidderivative of the general formula II in which the rings A, B and C and the radicals in the Substructures d to f have the meaning, are transferred and isolated, .i As inert organic solvents are aliphatic or aromatic hydrocarbons, preferably pentane, hexane, Jv heptane, benzene, toluene, among others. Ethers, preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, anisole,

Dimethoxyethane, diethoxyethane, and the like. or tertiary amines such. Triethylamine, diisopropylethylamine, pyridine and the like. a. ;

used or these solvents are also used as mixtures. - _ · · - ^

According to the procedure of the invention, 1 to 5 moles of acetonitrile and 1 to 5 moles of lithium alkyT or lithium dialkylamide are used per mole of 17-ketosteroids, and the acetonitrile is reacted in situ at low temperatures to form LiCH ₂ CN. Advantageously, these reactions are carried out at low temperatures, ie in temperature ranges below ± OX, in which the reaction of LiCHiCN with acetonitrile for

N-Li Ο

* / it ^ / γ

CH ₃ CN + LiCH ₂ CN - ^ _CH3 -C-CH ₂ CN -o f CII ₃ -C-CH ₂ CN

as far as possible or completely suppressed. Preferably, these are the temperature ranges from -2OX to -9OX. The workup of the reaction mixtures can be carried out by addition of water, wherein the reaction products can be isolated to obtain protective groups such as ketals or enol ethers, inter alia. These aqueous work-ups are advantageously carried out at temperatures s 10X in pH ranges pH pH 6, wherein the pH adjustment can also be effected by additions of salts such as NH ₄ Cl, NH ₄ Ac, NaH ₂ PO ₄ , inter alia or acids.

However, the work-up can also be carried out in such a way that the decomposition of the reaction mixtures, ie the destruction of the excess lithium organyl, is carried out with addition of water and acids or dilute acids and is carried out at pH ranges £ 6 and protective groups which are optionally present in the molecule, such as ketals, Enol ethers are split, inter alia. 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-ToluensuHonsäure be used inter alia. 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 carried out at temperatures of up to 5 OX or up to the boiling point of the reaction mixture. The isolation of the reaction products can be carried out by extraction or precipitation, but it is advantageous to distill the solvent mixture from the reaction mixture under vacuum as far as possible and optionally by addition of further solvents to create favorable crystallization conditions, which allow this in high purity resulting crystals in high yield isolate.

The procedure according to the invention eliminates the deficiency noted in the known prior art for the stepwise introduction of the 17a-cyanomethyl-17β-hydroxy group. The use of the 5 (10), 9 (11) -diene steroid derivatives for this reaction also precludes the formation of by-products in the bromination-dehydrobromination reaction possible in the conventional manner, thus ensuring the recovery of the target products in high purity. With this new procedure, an easy to be performed method is disclosed, which substantially minimizes the previously required high material and time. With this new procedure, the known environmental pollution is avoided, since the solvents can be largely recovered, separated during workup resulting Li salts and contained in wastewater residual amounts of acetonitrile in dilute solutions are biodegradable (Martinez «immobilization, detoxification and destruction and Destruction of Chemicals, "I. edition, published by Harri Deutsch, Thun-Frankfurt (Main), page 211).

embodiments example 1

17a-cyanomethyl-17.beta.-hydroxy-i3-methyl-5 (10), 9 (11) -gonadien-3-one

In a reaction vessel flushed with inert gas, 36 ml of butyl-lithium solution (1.3 mol / l) are initially charged and stirred at -60X

Diluted 10ml THF. With stirring and cooling, 3 ml of acetonitrile are added to this solution so that the temperature does not exceed 6OX. To this reaction mixture is then added dropwise a solution of 2.5 g of 13-methyl-3,3-dimethoxy-5 (10), 9 (11) -gonadien-17-one in 20 ml of tetrahydrofuran so that the predetermined temperature range is not exceeded , After addition of the substance, the reaction mixture is stirred for a further 30 min, then allowed to warm to ± OX, the mixture is added

Reaction mixture dropwise with dilute sulfuric acid and stirred for a further 30 min. At room temperature. Subsequently

the aqueous phase is separated, after-extracted twice with methylene chloride, the combined org. Phase washed free of acid and then concentrated under vacuum. The distillation residue is treated with acetone for crystallization and the crystalline ^

Product vacuumed after standing overnight. · "~~~ Yield: 82% d. Th.

'H-NMR spectrum; (80MHz, COCI ₃ , δ vs TMS as internal standard)

0.93ppm (s, 3H, 18 CH3); 2.56 ppm (m, 6H, 1-CH ,, 2-CH ₂ , 170.-CH ₂ CN); 2.90ppm (m, 2H, 4-CH ₂ ); 5.65ppm (m, 1H, 11-CH)

Example 2

l3-ethyl-17a-cyanomethyl-17beta-hydroxy-4,9-gonadien-3-one

According to the method described in Example 1, 16.5 ml of butyl lithium solution, 30 ml of THF, 1.8 ml of acetonitrile with 13-ethyl

3,3-ethylenedioxy-5 (10), 9 (11) -gonadien-3-one at temperatures £. -30X and subsequent decomposition with 30 ml of water to give the 13-ethyl-3,3-ethylenedioxy-17a-cyanomethyl-17β-hydroxy-5 (10), 9 (11) -gonadiene.

Isolation of the product and reaction with conc. Hydrochloric acid in ethanol leads to CHCI ₃ extraction, concentration and crystallization

from ethanol / WasserzumiS-ethyl ^ a-cyanomethyl ^ ß-hydroxyAS-gonadien-S-one.

Yield: 56% d. Th.

Mp: 214 »Cbis215'C

¹ H-NMR spectrum: (80 MHz, CDCl ₃ , δ against TMS as internal standard)

1.16ppm (tr, 3H, J = 7Hz, 18-CH ₂ -CH ₃ ); 2,53ppm (d, 1 H, J = 16Hz, 17aCH ₂ CN); 2,68ppm (d, 1H, J = 16 Hz, 17a-CH ₂ CN), 5.78 ppm (s, IH, 4-CH)

Example 3

13-methyl-17a-cyanomethyl-17.pihydrp> cy-4,9-gonadien-3-one *

Under inert gas, 16.5 ml of butyl-lithium solution in a reaction vessel, cooled to temperatures ^ - 35 ° C and mixed with

15ml tetrahydrofuran. 1.8 ml of acetonitrile / 10 ml of tetrahydrofuran are added to this solution. Then a solution of 5 g of 3,3- (1,3-propylenedioxy) -13-methyl-5 (10), 9 (11) -gonadien-17-one in 30 ml of THF is added and the reaction mixture is kept at temperatures <-25 'C held, then decomposed with the addition of 40ml of water, the reaction mixture and the org.

Phase isolated. The org. Phase is concentrated, taken up in ethanol, with 1 ml of conc. HCI is added and 2 hours Stirred room temperature, the solution was concentrated and the resulting crystals were isolated.

Yield: 4.0g

Mp 208 ⁰ C to 211.5 ° C

'H-NMR spectrum: (80MHz, COCI ₃ , vs. TMS as internal standard)

I.OSppmte.SHje-CH ^^ ppmlMH.I-CHZU ^ ^ -CHjh ppmtsjaJ = 16.4 Hz, 17a-CH ₂ CN); 2,63ppm (s, 1 H, J = 16.4 Hz,

17a-CH ₂ CN); 5.71 ppm (s, 1H, 4-CH).

196

Claims (7)

1. A process for preparing α-cyanomethyl-β-hydroxysteroid 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 in the substructures a to c have the meaning given and the radicals Ri = Me, Eth R2 # R3 = Me, Eth or even ... - Me vMo - ~ R ₂ and R ₃ together are -CH ₂ -CH ₂ -, -CH ₂ C-CH, -, -CH ₃ -CH-ClI ₂ -CH-CH ₃ 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 ), reacted, the reaction products worked up aqueous, the compounds of general formula II in which rings A, B and C of the steroid skeleton have the abovementioned meaning in substructures a to c and the radicals have the abovementioned meaning or by direct acid hydrolysis in the abovementioned 17a-cyanomethyl-17β-hydroxysteroid derivatives of general formula II, in the rings A, B and C, which in the substructures d to f and the radicals have the abovementioned meaning, transferred and isolated. 2. The method according to claim 1, characterized in that as the inert organic solvent! aliphatic or aromatic hydrocarbons, preferably pentane, hexane, heptane, benzene, toluene and the like, ethers, preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, anisole, dimethoxyethane, diethoxyethane and the like, or tertiary amines, such as. Triethylamine, diisopropylethylamine, pyridine and the like. be used or these solvents are also used as a mixture. 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 of lithium alkyl or lithium dialkylamide are 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 reactions at temperatures: £ ± ^{0 0} C, preferably in the temperature range from -20 ⁰ C to -90X is performed. 5. The method according to claim 1 to 4, characterized in that the aqueous work-up in the pH range S pH 6 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 addition of salts such as NH ₄ Cl, NH ₄ OAc, NaH ₂ PO _4, etc. or addition of inorganic acids such as ζ. B. HCI, H ₃ PO ^ H ₂ SO ₄ , HCIO ₄ inter alia, or organic acids such as acetic acid, oxalic acid, p-toluenesulfonic acid, inter alia, to the work-up.