DD217806A1 - PROCESS FOR THE PREPARATION OF 14BETA, 17BETA-STEROID-14,20-DIOLENE - Google Patents

Abstract

Process for the preparation of 14b, 17b-steroid-14,20-diols, which serve as starting material for the synthesis of steroids possessing the structural features of cardiac active compounds. The aim and object of the invention is the economically favorable and technically simple conversion of D8 (14) -17-ketosteroids into the title compounds. For this purpose, the former were alkylated with a Wittig reagent and the resulting D8 (14), 17 (20) steroids hydroborated in two stages and worked up oxidatively.

Description

Title of the invention

Process for the preparation of 14β, 17β-steroid-14,20-diols

Field of application of the invention

The invention relates to a process for the preparation of 14β, -17β-steroid-14,20-diols of general formula 3

wherein R is a Η-atom or an acyl radical and R is a Η-atom or an alkyl radical having 1 to 4 carbon atoms · These

14,20-Diols are of particular interest because of their ability to access compounds having important structural features of cardiac active steroids, such as those disclosed in US Pat. £ 14ß-Hydroxy-steroid-17ß-carbaldehyde and 14ß-Hydroxy-steroid-17ß-E-acrylic-acid-alkylester ·

Characteristic of the known technical solutions

Processes for the preparation of the compounds of the formula Λ with R ² s H have been proposed in the patent application WP 0 07 J / 231 59V4, with R ² alkyl they are new and have not hitherto been described in the chemical literature and in patents.

For the preparation of compounds of formula ^, R »H, the introduction of a 14ß-hydroxy group was first carried out so far

by hydroboration of a Δ 8 (14), 17J ^ -hydroxy-steroid., (WF 128 564, Langbein, et al., Mitteilungsblatt Chemische Gesellschaft der DDR, Supplement 68, p. 163), and then the synthesis of 17β-H 3 droxy-methyl Grouping by Oxidation, Methylation and Hydroboration (Patent Application WP 0 07 J / 231 59V ² O) The yields of the A8 (14) -hydroboration stage are only 30 to 40 % ₉ since, in addition to the hydroboration products in the 14-position, there are always certain amounts of ^.:. ^ $ - 15 ßteilung arise \ VIDD hydrobprierten products with a with the Δ 17 (20) -Hydroborierungsstufe obtained yields of 40 to 50% without, and 60 to 70% with preceding silylation of 14 £ - hydroxy "In this stage always produces the 17 * isomer as a byproduct. "Their overall yield over both hydroboration stages is therefore only 12 to 20 or 18 to 28 %, depending on the procedure.

Object of the invention

The aim of the invention is the economically favorable preparation of new and already known 14ß, 17ß-steroid-14,20-diols of the general formula 4, in which the abovementioned disadvantages are largely avoided.

Explanation of the essence of the invention

The invention has for its object to provide a technically simple method that starting from 4Ä8 (14), 17-ketosteroids both the preparation of the known 14 pounds, 17B-steroid-14,20-diols of the general formula jl, R ² . H in higher yields than previously permitted, as well as the synthesis of previously unknown compounds of general formula 4, R ² s alkyl allows

According to the invention, the object is achieved by reacting Δ 8 (14), 17-ketosteroids (2) (WP 200 227/0) with a Wittig reagent, preferably a triphenylalkylenephosphorane, in an aprotic dipolar solvent, preferably tetrahydrofuran Temperature between 50 and 100 ⁰ O reacted, taking the corresponding A8 (i4) _f 17 (20) steroids

· receives These were prepared with diborane, ζ · · Β from Watriumborhydrid and boron trifluoride etherate, or thexylborane prepared from diborane and 2,3-dimethylbut-2-en in tetrahydrofuran, at a temperature between -10 and +30 ⁰ By oxidative work-up with hydrogen peroxide in the presence of an alkali metal hydroxide or alkali carbonate, Δ 8 (14), 20-hydroxy-17β-steroids (£) are obtained. These have been preferably subjected without purification to a second hydroboration with diborane in tetrahydrofuran, at a temperature between 40 and 80 ⁰ O and oxidatively worked up as above, is obtained under regio- and stereo-selective hydroxylation of the 8 (14) double bond in 14ss Position 14B, 17β-steroid 14J20-diols Q) in 65 to 73 pounds yield;

This result is quite surprising, since it is known that in the hydroboration of the 8 (14) "double bond of steroids the boron is completely (£> Mincione, F. Feliziani, Chem. Commun. 1973. 942) or in the case of 17ß-hydroxy-4 8 (14) steroids migrates partially in the 15- or 7-position and thereby only or partially 15- or 7-hydroxysteroids are obtained. An additional advantage of the process is that the high yields were achieved without auxiliary stages, such as, for example, the intermediacy of silylation in the above-mentioned process (WP 0 07 J / 231 59Ί- / 4) »

The process is illustrated by the following scheme:

R \ high

embodiments

1 · 3β-acetoxy-17-anethylene-5β-est-8 (14) -en, Q, R ¹ a 0ΗΛ30, IT .a H)

1 »37 g of 3β-hydroxy-5β-est-8 (14) -en-17-one (5 mmol) are added under stirring and under argon in 20 ml of tetrahydrofuran with 4 g of triphenylmethylphosphonium iodide (10 mmol) and 1.2 g of potassium tert.-butanolate (10.7 mmol) heated under reflux for 30 minutes. »For working-up, dilute sodium sulphate solution, extract with methylene chloride and evaporate in vacuo. The residue is left to stand overnight with 15 ml of 1: 1 acetic anhydride mixed with sodium bicarbonate solution, extracted with methylene chloride and evaporated in vacuo. The residue is filtered through silica gel with toluene and eluted with toluene. This gives 1.53 g of 2t R ¹ * OH ^ OO, H ² = H (97%), after crystallization from ßbanol-water 1 # 4 · 3 S (91%) of from: 87 to 89 ⁰ O and gcCj ² ^ * + 108 °, (ca 1, ^B

17-hydroxymethyl-5ß "14ss-8stran-3.beta.» 1 ^/ ^ iiol, QI, R ¹ a R ² = H) A variant

From 350 mg of sodium borohydride (9 _f 0 mmol) in 4 ml of tetrahydrofuran and 0.25 ml of boron trifluoride etherate (2.0 mmol), a diborane solution is prepared by stirring for 20 minutes under argon. In this 315 mg 2 $ R = OH-OO ₁ R ² β H, (1.0 mmol) dissolved in 4 ml of tetrahydrofuran were added dropwise After stirring for 15 minutes at 20 ⁰ G while cooling 3 ml of water, 20 ml of methanolic 1N NaOH and 4 ml 3Q06iges hydrogen peroxide added dropwise. After a further 15 minutes, sodium sulfate solution is added, the mixture is extracted with methylene chloride and evaporated in vacuo. 370 mg of crude 3β-acetoxy-17β-hydroxymethyl-5β-estr-8 (14) -ene are obtained This is added, dissolved in 4 ml of tetrahydrofuran, to a diborane solution prepared as described above and refluxed under argon for 30 minutes. After cooling, the mixture is worked up by oxidation as described above.

.The steroid obtained is heated to complete saponification of the 3ß-acetate with 25 ml of methanolic 1N NaOH for 15 minutes to boiling under reflux, treated with sodium sulfate solution, extracted with methylene chloride and evaporated in vacuo. The residue (350 mg) is subjected to a gradient chromatography on silica gel with toluene-acetone 9 "1 to 1 t 1" 230 mg (74 36) is obtained as the main product. , 1, R ¹ β R ² = H.

For characterization, the diacetate is prepared with acetic anhydride-pyridine and recrystallized from heptane to give 255 mg (65 SS) of the F ·: 163-164 ⁰ O and ^I * J ^{+ + 24} ° (C = 1, OHOl ₃ ). ^D

Variant B

From 350 mg of sodium borohydride (9.0 mmol) in 4 ml of tetrahydrofuran and 0.25 ml of boron trifluoride etherate (2.0 mmol) is prepared by stirring for 20 minutes under argon a diborane solution; in this 1.0 ml of 2,3-dimethylbut-2-ene (8.4 mmol) was dropped in 2 ml of tetrahydrofuran at -10 to 0 ⁰ C and after 1 hour at 0 ⁰ O 315 mg 2, R _'3 OH GO, R β H (1 mmol) dissolved in 2 ml of tetrahydrofuran, given * After 20 hours of reaction time at 20 ⁰ O is oxidatively worked up as described in Variant A "350 mg of crude 3ß-acetoxy-17ß-hydroxymethyl-5ß get - östr-8 (i4) -en · This is subjected to a second hydroboration as described in variant A and then saponified the 3ß acetate as described · After gradient chromatography, 215 mg (70 %) Λ, R ¹ s R ² = H · For the characterization, the diacetate is prepared with acetic anhydride-fyridine and recrystallized from heptane to give 235 mg (60%). From F * t 161 to 164 ° C.

2. 3β-acetoxy-19-nor-5β- ^i- pregna-8C14), 17 (20) -diene Q, R ¹ a CH ₃ CO, R ² s CH ₃ )

37 g of 3β-hydroxy-5β-est-8 (14) -en-17-one (5 mmol) are added under stirring and under argon in 20 ml of tetrahydrofuran with 4.2 g of triphenylethylphosphonium iodide (10 mmol) and 1.2 G

Potassium tert-butoxide (10.7 mmol) heated for 1 hour under reflux. Bs is worked up as described in Example 1 and acetylated. The separation of the phosphine oxide and phosphonium salt is carried out by filtration through silica gel with hexane-Sther 95 t% to give 1.4 g (85 %) of J, R ¹ »OH ₃ OO, E 3 OH« as Ε, Ζ-isomer mixture, after recrystallization from heptane gives 1.29 g (75 %) of Z-isomers of the F .: 121 to 126 ⁰ O and / 7'L 7 ²⁵ J + 157 ° (c = I ₉ 0H01.,) ·

19-nor-5β, 14β-pregnan-ββ _f 14,20-triol Q, R ¹ = H, E ² α)

Ss the same amount as described in Example 1 diborane solution is prepared. In this 330 mg of J, R s OH ₃ OO, R ² = OH ₃ , (1 mmol) dissolved in 4 ml of tetrahydrofuran are added dropwise. After stirring for 25 minutes at 20 ⁰ O is worked up as described in Example 1 oxidatively. 380 mg of crude 3β-acetoxy-19-nor-5β-pregn-8 (14) -ene-20-ol are obtained, which is refluxed for 1 hour with dibrorane as described in Example 1. The reaction is carried out as in Example 1 The product (360 mg) is subjected to a gradient chromatography on silica gel with toluene-lther 95: 5 to 4: 1 and with toluene-acetone 95: 5 to 1 ί 1 receives as the main product 250 mg (77 _f 5 %) , 1, R ¹ H, R ² s OH _3. For characterization, the diacetate is prepared by heating for 1 hour with acetic anhydride-pyridine 1: 1 to 100 ⁰ O and recrystallized from heptane to give 265 mg (65 %) from Fs 186 to 189 ⁰ O and C ⁰⁰ J ^ ^{1 + 24} ° ^ ⁰ = ¹ »OHOl ₃ ).

Claims (1)

ου * -7- Brfindungsanspruch Process for the preparation of 14e, 17B-steroid-14,20-diols of general formula Λ, in which R ^{1 is} an Η-atom or an acyl radical, preferably an acetyl radical and R is an Η-atom or an alkyl radical having 1 to 4 carbon atoms, characterized in that 8 8 (14), 17-ketosteroids of the general formula 2, in which R has the abovementioned meaning, with a Wittig reagent, preferably a triphenylalkylenephosphorane, in an aprotic dipoiaren solvent, preferably tetrahydrofuran, at a temperature between 50 and 100 ⁰ O, the obtained Δ 8 (14), 17 (2O) - Steroids with diborane, prepared for example from sodium borohydride and boron trifluoride etherate, or with thexylborane, prepared from diborane and 2,3-dimethylbut-2-ene, in tetrahydrofuran, at a temperature between -10 and +30 ⁰ O, the products are worked up oxidatively with hydrogen peroxide in the presence of an alkali hydroxide or alkali carbonate, the resulting ^ 8 (14), 20-hydroxy-17ß-8teroide, preferably without prior purification, a second hydroboration with diborane in tetrahydrofuran, at a temperature between 40 and 80 ⁰ O, the products oxidatively worked up as above and the desired 14ß, 17ß-steroid-14,20-diol in 65 to 7556iger yield receives.