DE102010006884A1 - Preparing drospirenone, comprises reacting methyleneprasterone with 1-halopropan-3-acetal compounds, oxidatively converting methylene-hydroxy-(dialkoxypropyl)-prasterone, enolizing methylen-spirolacton-androsten-one, and oxidizing - Google Patents

Abstract

Preparing drospirenone, comprises (a) reacting 15,16-methyleneprasterone (MEP) with 1-halopropan-3-acetal compounds (I) to obtain 15,16-methylene-hydroxy-(3,3-dialkoxypropyl)-prasterone (MAP), (b) oxidatively converting (MAP) to 15,16-methyleneprasteronespirol (MPSP) and further reacting (MPSP) to 15,16-methylen-17(S)-spirolacton-androst-4-en-3-one (MADO-lactone), (c) enolizing (MADO-lactone) to 3-methoxy-15,16-methyleneandrost-4,6-dien-3-on-spirolactone (MAGMA-lactone) and oxidizing to 15,16-methyleneandrost-4,6-dien-3-on-spirolactone (MDD-lactone), and (d) adding methylene to drospirenone. Preparing drospirenone, comprises: either (a) reacting 15,16-methyleneprasterone (MEP) with 1-halopropan-3-acetal compounds of formula (X-(CH 2) 3-(OR) 2) (I) to obtain 15,16-methylene-17beta -hydroxy-17alpha -(3,3-dialkoxypropyl)-prasterone (MAP), (b) oxidatively converting the MAP to 15,16-methyleneprasteronespirol (MPSP) and further reacting the MPSP under oxidative condition to 15,16-methylen-17(S)-spirolacton-androst-4-en-3-one (MADO-lactone), (c) enolizing (MADO-lactone) to 3-methoxy-15,16-methyleneandrost-4,6-dien-3-on-17(S)-spirolactone (MAGMA-lactone), subsequently oxidizing to 15,16-methyleneandrost-4,6-dien-3-on-17(S)-spirolactone (MDD-lactone), and (d) subsequently adding methylene to drospirenone; or (a1) reacting 15,16-methyleneprasterone (MEP) with 1-halopropan-3-ortho ester compounds of formula (X-(CH 2) 3-(OR1) 2) (II) to obtain 15,16-methylene-17beta -hydroxy-17alpha -(3,3,3-trialkoxypropyl)-prasterone (MOEP), (b1) converting the MOEP to MADO-lactone, and performing the steps (c) and (d) as above per se. X : halo, preferably bromo; R1 : alkyl, preferably methyl or ethyl; and R : alkyl, preferably methyl, ethyl, 1,2-ethyl or 1,3-propyl. An independent claim is included for intermediates for preparing drospirenone, comprising 15alpha ,16beta -methylen-17beta -hydroxy-17alpha -(3,3-dimethoxypropyl)-prasterone, 15alpha ,16beta -methylen-17beta -hydroxy-17alpha -(3,3-diethoxypropyl)-prasterone, 15alpha ,16beta -methylen-17beta -hydroxy-17alpha -(3,3-(1,2-ethyloxy)-propyl)-prasterone, 15alpha ,16beta -methylen-17beta -hydroxy-17alpha -(3,3-(1,3-propyloxy)-propyl)-prasterone, 15alpha ,16beta -methylen-17beta -hydroxy-17alpha -(3,3,3-trimethoxypropyl)-prasterone and 15alpha ,16beta -methylen-17beta -hydroxy-17alpha -(3,3,3-triethoxypropyl)-prasterone. ACTIVITY : Contraceptive; Antiandrogenic. MECHANISM OF ACTION : None given.

Description

The present invention relates to the synthesis of drospirenone from 15β, 16β-methylene dehydroepiandrosterone (Prasteron).

drospirenone

Drospirenone is a synthetic gestagen with antiandrogenic effects. It is used as part of hormonal contraceptives.

Numerous synthetic routes for the preparation of drospirenone are known in the art. These differ by the starting materials, the order of the functionalizations at the B and D ring as well as the structure of the Spirolactongerüstes at position 17 of the steroid.

The synthetic strategies of the prior art suffer from unsatisfactory yields or the difficulty of accessing the starting materials used. Against this background, the object of the present invention is to provide means and methods which enable the economical synthesis of drospirenone while avoiding the disadvantages of the prior art.

This object is solved by the subject matter of the independent claims.

According to the invention, a process is provided according to which drospirenone is obtained starting from 15,16-methylenprasterone (MEP), the D-ring-methylated dehydroepiandrosterone.

In a first step, the position 17 is alkylated with a 3-C building block which has a protected aldehyde or acid function in the 3'-position.

According to one aspect of the invention, in a first step, by reacting the 15,16-methylene-prasterone with 1-halopropane-3-acetals of the general formula X- (CH ₂ ) ₃ - (OR) ₂ where X is halogen, preferably bromine, and R is alkyl, preferably methyl, ethyl or 1,2-ethyl or 1,3-propyl, in the presence of butyllithium to 15,16-methylene-17β-hydroxy-17α- (3,3 -dialkoxypropyl) -prasterone (MAP).

sowie weiter zum 15,16-Methylenprasteron-17(S)-spirolacton (MPL) oxidiert.This intermediate is then converted to the 15,16-methylene-prasterone-spirol (MPSP).

and further oxidized to 15,16-methylenprasterone-17 (S) -spirolactone (MPL).

According to an alternative aspect of the invention, in a first step, by reacting the 15,16-methylene-prasterone with 1-halopropane-3-ortho-esters of the general formula X- (CH ₂ ) ₃ - (OR ') ₃ wherein X is halogen, preferably bromine, and R is alkyl, preferably methyl or ethyl, in the presence of butyllithium to 15,16-methylene-17β-hydroxy-17α- (3,3,3-trialkoxypropyl) -prasterone (MOEP).

This intermediate reacts under mild conditions to 15,16-methylene-prasterone-17 (S) -spirolactone (MPL).

According to one embodiment of this aspect of the invention, the reaction to the MOEP may be by reaction with tert-butyllithium and ortho (3-bromopropionic acid) trimethyl ester BrCH ₂ Ch ₂ (OMe) ₃ in the presence of LDA at low temperatures. The reaction product is the methyl orthoester.

According to another embodiment of this aspect of the invention, the reaction from the MOEP to drospirenone may be by reaction with an organic acid, preferably p-toluenesulfonic acid.

umgesetzt. Bevorzugt ist die Reaktion mit Pyridiniumchlorchromat. Nachfolgend wird zu 3-Methoxy-15,16-methylenandrost-4,6-dien-3-on-17(S)-spirolacton (MOMA-Lacton) enolisiert,

zum 15,16-Methylenandrost-4,6-dien-3-on-17(S)-spirolacton (MDD-Lacton) oxidiert und

durch anschließende Methylenaddition zu Drospirenon umgesetzt.In a further step, which is common to both aspects of the invention, the 15,16-methylenprasterone-17-carbolactone MPL is oxidized to 15,16-methylene-17 (S) -spirolactone-androst-4-en-3-methyl on (MADO lactone);

implemented. The reaction with pyridinium chlorochromate is preferred. Subsequently, 3-methoxy-15,16-methylenandrost-4,6-dien-3-one-17 (S) -spirolactone (MOMA-lactone) is enolized,

oxidized to 15,16-methylenandrost-4,6-dien-3-one-17 (S) -spirolactone (MDD-lactone) and

implemented by subsequent methylene addition to drospirenone.

According to a preferred embodiment of the invention, the diastereomer 15β, 16β-methyleneprasterone is used as the 15,16-methylenepasterone (MEP), in particular in a purity based on the total content of MEP of more than 95%.

mit einer Base und Phenylmethylsulfinat zum Prasteronsulfoxid (PSO),

Abspaltung des Sulfoxids zum Prasteron-15-en (PREN)

und anschließende Umsetzung mit Trimethylsulfoxoniumiodid erhalten werden.According to another preferred embodiment of the invention, the 15,16-methylene-prasterone (MEP) can be prepared by reacting dehydroepiandrosterone (Prasteron).

with a base and phenylmethylsulfinate to the Prasteronsulfoxid (PSO),

Cleavage of Sulfoxide to Prasterone-15-ene (PREN)

and subsequent reaction with trimethylsulfoxonium iodide.

Examples

Example 1: Prasterone sulfoxide (PSO)

To a solution of potassium t-butoxide (12.4 g, 110 mmol) in DMSO (75 mL) is slowly added dropwise at room temperature to prasterone (15 g, 52 mmol) dissolved in DMSO (50 mL). The resulting solution is stirred for 30 minutes. Then phenylmethylsulfinate (12.5 g, 80 mmol) is added dropwise at 20.degree. The batch is stirred for 60 minutes and then poured onto ice-water (500 ml). The pH of the suspension obtained is brought to neutral with 1 N acetic acid and the precipitated white solid is filtered off, washed thoroughly with water (250 ml) and dried in vacuo.
Yield: 19.4 g, 90% of theory
Salary: 90% Fl.%

Example 2: En-Prasterone (PREN)

• a) A suspension of Prasteronsulfoxid (Example 1, 10.0 g, 24 mmol) in decalin (200 ml) is heated to 130 ° C with stirring. After complete conversion (control by thin-layer chromatography (TLC), about 5-6 h hours), the mixture is cooled to room temperature. The precipitated solid is filtered off, washed thoroughly with hexane (100 ml) and dried in vacuo. Yield: 5.5 g, 80% of theory

Example 3: Methylene Prasterone (MEP)

A suspension of potassium hydroxide (1.96 g, 35 mmol) and trimethylsulfoxonium iodide (7.7 g, 35 mmol) in DMSO (100 mL) is stirred at room temperature for 60 minutes. En-Prasterone (Example 2, 5.0 g, 17.5 mmol) is then added. The batch is stirred for 90 minutes at room temperature and then poured into ice-water (500 ml). The suspension obtained is neutralized with 1 N acetic acid. The resulting solid is filtered off, washed with water (250 ml) and dried in vacuo.
Yield: 4.8 g, 90% d. theory

Example 4:

15,16-Methylene-17β-hydroxy-17α- (3,3-dimethoxypropyl) -prasterone (MAP)

To diethyl ether (100 ml) is added at -50 ° C tert-butyllithium in n-pentane (1.5 mol / l, 66 ml, 100 mmol). The resulting solution is slowly added dropwise at the temperature 3-Brompropionaldehyddimethylacetal (8.8 g, 48 mmol) and stirred for 30 minutes.

A solution of MEP (Example 3, 4.0 g, 12.8 mmol) in THF (100 ml) at -50 ° C with LDA in hexane (2 mol / l, 8 ml, 16 mmol) was added. To this solution, the prepared reaction solution tert-butyllithium / 3-Brompropionaldehyddimethylacetal is slowly added and the resulting solution stirred at -50 ° C for 60 minutes. The mixture is then warmed to room temperature and the reaction is terminated by adding water (50 ml). The batch is extracted with methylene chloride (3 × 100 ml), the combined organic phases are dried over sodium sulfate and then the solvent is removed in vacuo. The resulting solid is crystallized from methanol.
Yield: 5.3 g, 80% of theory
Salary: 90%

Example 5: Methylene Prasterone Spirol (MPSP)

15,16-Methylene-17β-hydroxy-17α- (3,3-dimethoxypropyl) -prasterone (MAP, Example 4, 5.3 g, 10.2 mmol) is dissolved in acetone / water (9/1, 100 ml) and extracted with para Toluenesulfonic added. The mixture is stirred at room temperature for 3 hours and the conversion is monitored by thin layer chromatography (TLC). At complete conversion, reduce the volume of the reaction to 1/3 in vacuo and add water (100 ml). The resulting solid is filtered off, washed with water (200 ml) and dried in vacuo.
Yield: 4.7 g, 95% of theory
Salary: 90%

Example 6: Methylenprasterone lactone MPL from MPSP

A solution of methylenprasterone spirol (MPSP, Example 5, 4.0g, 10mmol) and TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl: 0.07mmol) in methylene chloride (25ml) is added with an aqueous solution while stirring Solution of KBr (0.12 g, 1 mmol in 10 mL) and cooled to -15 ° C. To the reaction mixture is slowly added dropwise a 1 M NaOCl solution in water (8 mmol) within 5 minutes. The internal temperature must not rise above 10 ° C. After a further 5 minutes the organic phase is separated and the aqueous phase extracted with methylene chloride (2 × 25 ml). The combined organic extracts are washed with 10% hydrochloric acid (20 ml) and then with sodium bicarbonate, dried over sodium sulfate. The solvent is concentrated in vacuo and the product crystallized from ethyl acetate.
Yield: 2.9 g, 72% of theory
Salary: 85%

Example 7:

15,16-Methylene-17β-hydroxy-17α- (3,3,3-trimethoxypropyl) -prasterone (MOEP)

To diethyl ether (100 ml) is added at -50 ° C tert-butyllithium in n-pentane (1.5 mol / l, 66 ml, 100 mmol). To the resulting solution is slowly added dropwise at constant temperature ortho- (3-bromopropionic acid) trimethyl ester (10.2 g, 48 mmol) and stirred for 30 minutes.

A solution of dimethylendione MEP (Example 3, 4.0 g, 12.8 mmol) in THF (100 ml) is added at -50 ° C with LDA (lithium diisopropylamide) in hexane (2 mol / l, 8 ml, 16 mmol). To this solution, the prepared reaction solution tert-butyllithium / 3-ortho- (3-bromopropionic acid) trimethyl ester is slowly added and the resulting solution stirred at -50 ° C for 60 minutes. The mixture is then warmed to room temperature and the reaction is terminated by adding water (50 ml). The batch is extracted with methylene chloride (3 × 100 ml), the combined organic phases are dried over sodium sulfate and then the solvent is removed in vacuo.
Yield: 5.2 g, 75% of theory
Salary: 85%

Example 8: Methylene prasterone lactone MPL from MOEP

15,16-Methylene-17β-hydroxy-17α- (3,3,3-trimethoxypropyl) -prasterone (MOEP, Example 7, 5.0 g, 11.3 mmol) is dissolved in acetone / water (9/1, 100 ml) and with para-toluenesulfonic acid (0.2 mmol). The mixture is stirred at room temperature for 3 hours and the reaction is monitored by TLC. At complete conversion, reduce the volume of the reaction to 1/3 in vacuo and add water (100 ml). The resulting solid is filtered off, washed with water (200 ml) and dried in vacuo.
Yield: 4.5 g, 90% of theory
Salary: 80%

Example 9: 15,16-Methylene-17 (S) -spirolactone-androst-4-en-3-one (MADO-lactone)

To a solution of 15,16-methylene-prasterone-17 (S) -spirolactone (MPL; Examples 6, 8, 2.5 g, 7.0 mmol) in DMF (100 mL) is added pyridinium chlorochromate (4.5 g, 21 mmol). The batch is stirred for 24 h at room temperature. Then 50 ml of saturated sodium bisulfite solution are added, stirred for 15 minutes and the mixture extracted with methylene chloride. The organic extracts are washed with water and dried over sodium sulfate.

The solvent is removed in vacuo. The resulting solid is recrystallized from methanol.
Yield: 2.0 g (80% of theory)

Example 10: 15,16-Methylenandrost-4,6-dien-3-one-17 (S) -spirolactone (MOMA-lactone)

To a solution of MADO-lactone (Example 9, 2.0 g, 5.6 mmol) in THF (20 mL) is added trimethyl orthoformate (1 g, 9 mmol) and para-toluenesulfonic acid (30 mg, 0.2 mmol) and stirred at room temperature. Sales are controlled by DC. After complete conversion (about 2-3 h), the mixture is poured onto ice-water (100 ml) and stirred for 30 minutes. The solid is filtered off, washed with water (200 ml) and dried in vacuo.
Yield: 1.9 g, 90% d. theory

Example 11: MDD lactone

A solution of MOMA lactone (Example 10, 1.5 g, 4 mmol) in acetone / water (9/1, 50 ml) is added with chloranil (1.0 g, 4.5 mmol) and stirred at room temperature for 5 hours. Then, water (100 ml) is added to the batch and the acetone is distilled off. The batch is extracted with methylene chloride. The combined organic extracts are washed with 1 M sodium hydroxide solution (3 × 50 ml) and dried over sodium sulfate. The solvent is removed in vacuo and the residual solid is recrystallized from acetone.
Yield 1.2 g, 75% of theory

Example 12: Drospirenone, crude

A suspension of potassium hydroxide (1.4 g, 25 mmol) and trimethylsulfoxonium iodide (5.5 g, 25 mmol) in DMSO (50 ml) is stirred at room temperature for 60 minutes. Subsequently, MDD-lactone (Example 11, 1.5 g, 4.3 mmol) is added. The batch is stirred for 48 hours at room temperature and then poured into ice-water (100 ml). The suspension obtained is neutralized with 1 N acetic acid. The resulting solid is filtered off, washed with water (50 ml) and dried in vacuo.
Yield: 1.0 g (60% of theory)

Claims (5)

Process for the preparation of drospirenone starting from 15,16-methylenprasterone (MEP) a) Reaction with 1-halopropane-3-acetals of the general formula X- (CH ₂ ) ₃ - (OR) 2 where X is halogen, preferably bromine, and R is alkyl, preferably methyl, ethyl or 1,2-ethyl or 1,3-propyl, to give 15,16-methylene-17β-hydroxy-17α- (3,3-dialkoxypropyl) - prasterone (MAP); b) oxidative conversion of MAP to 15,16-methylenprasterone spiro (MPSP) and further reaction of MPSP under oxidative conditions to give 15,16-methylene-17 (S) -spirolactone-androst-4-en-3-one (MADO-lactone ); c) Enolization to 3-methoxy-15,16-methylenandrost-4,6-dien-3-one-17 (S) -spirolactone (MAGMA-lactone), subsequent oxidation to 15,16-methylenandrost-4,6-diene -3-on-17 (S) -spirolactone (MDD-lactone) and d) subsequent methylene addition to drospirenone. A process for the preparation of drospirenone starting from 15,16-methylenprasterone (MEP) by a) reaction with 1-halopropane-3-ortho esters of the general formula X- (OH ₂ ) ₃ (OR) 3 wherein X is halogen, preferably bromine, and R is alkyl, preferably methyl or ethyl, to 15,16-methylene-17β-hydroxy-17α- (3,3,3-trialkoxypropyl) -prasterone (MOEP) b) reaction of MOEP to 15,16-methylene-17 (S) -spirolactone-androst-4-en-3-one (MADO-lactone); c) Enolization to 3-methoxy-15,16-methylenandrost-4,6-dien-3-one-17 (S) -spirolactone (MAGMA-lactone), subsequent oxidation to 15,16-methylenandrost-4,6-diene -3-on-17 (S) -spirolactone (MDD-lactone) and d) subsequent methylene addition to drospirenone. Process for the preparation of drospirenone according to one of the preceding claims, wherein the diastereomer 15β, 16β-methylene-prasterone is used as 15,16-methylene-prasterone (MEP). A process for the preparation of drospirenone according to any one of the preceding claims wherein the 15,16-methylene-prasterone (MEP) is converted by reaction of dehydroepiandrosterone with a base and phenylmethylsulfinate to the prasterone sulfoxide (PSO), splitting the sulfoxide to the prasterone-15-ene (PREN) and subsequent Reaction with trimethylsulfoxonium iodide is obtained. Intermediates for the synthesis of drospirenone: a) 15β, 16β-methylene-17β-hydroxy-17α- (3,3-dimethoxypropyl) -prasterone; b) 15β, 16β-methylene-17β-hydroxy-17α- (3,3-diethoxypropyl) -prasterone; c) 15β, 16β-methylene-17β-hydroxy-17α- (3,3- (1,2-ethyloxy) -propyl) -prasterone; d) 15β, 16β-methylene-17β-hydroxy-17α- (3,3- (1,3-propyloxy) -propyl) -prasterone; e) 15β, 16β-methylene-17β-hydroxy-17α- (3,3,3-trimethoxypropyl) -prasterone; f) 15β, 16β-methylene-17β-hydroxy-17α- (3,3,3-triethoxypropyl) -prasterone.