CH695422A5 - A process for introducing a 1,2 double bond at 3-oxo-4-azasteroidverbindungen. - Google Patents

Description

CH 695 422 A5

description

The present invention relates to a process for introducing a 1,2-double bond in 3-oxo-4-azasteroid by dehydrogenation of saturated in the 1,2-position 3-oxo-4-azasteroid, in particular by dehydrogenation of 17ß-substituted 3-Oxo-4-azasteroids, for the preparation of the corresponding 17β-substituted 3-oxo-4-azasteroids, which have a double bond in the 1,2-position.

From EP 0 155 096 it is known to prepare 17ß-substituted 4-aza-5-alpha-androsterones with a 1,2-double bond by oxidizing the corresponding 1,2-dihydro compound by means of benzene-selenic anhydride. Other methods of introducing a 1,2-double bond in 17β-substituted 4-aza-5-alfa-androstanes are also described, for example, in EP 0 298 652, EP 0 428 366 and EP 0 473 225. 17β-Substituted 4-aza-5-alpha-androstanes having a 1,2-double bond are widely used pharmaceutically active compounds. Of particular importance is 17β- (N-tert-butylcarbamoyl) -4-aza-androst-1-en-3-one (finasteride), which is used, for example, as a 5-alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia or is used by Alopia androgenetica. The known processes for preparing these compounds have specific disadvantages, so that there is a need for improved alternative processes. The present invention relates to such an alternative manufacturing method.

The present invention is defined in the claims. The present invention relates to a process for the preparation of 17β-substituted 4-aza-androst-1-en-3-one compounds of the general formula (I):

O

R

(I)

H

wherein

R optionally substituted, linear or branched (C -C) alkyl or (C -C) alkenyl; Phenyl or benzyl; a radical -OR1 or a radical -NHR ^ or a radical -NR ^;

R is optionally substituted, linear or branched (C -C) alkyl or (C -C) alkenyl, or phenyl;

Rg is methyl, ethyl or propyl; or -NR-R is a 5- or 6-membered heterocyclic ring, characterized in that

(a) a compound of general formula (II):

O

R

(II)

in which R has the abovementioned meanings, with a suitable alkylating agent, preferably with a dialkyl sulfate, a diazoalkane or a trialkyloxonium fluoroborate, on the oxygen atom of the lactam moiety to form the compound of the general formula (III):

Alkyl O N

H

(III)

in which R has the meanings given above, alkylated,

(b) subsequently the compound of the general formula (III) with a suitable hydroxylating agent, preferably with osmium tetraoxide (OsO) or with osmium tetraoxide in combination with a suitable oxidizing agent.

CH 695 422 A5

tel, oxidized, and

(c) converting the resulting hydroxylated compound into the compound of formula (I).

R is preferably linear or branched (C -C) alkyl, preferably methyl, ethyl, propyl or n-butyl, sec-butyl or tert-butyl, preferably tert-butyl; or a radical -OR ^ or a radical -NHR ^ or a radical -NR1R2. Preferably, the radical -NHR ^

R is preferably linear or branched (C ^ Cg) alkyl, preferably methyl, ethyl, propyl, n-butyl, sec-butyl or tert-butyl, preferably tert-butyl.

In the radical -NR1R2, Rg is preferably methyl.

The substituent -NR ^ as a 5- or 6-membered heterocyclic ring is preferably a radical of pi-peridine or pyrrolidine.

Preferably, the substituent -NHR ^ wherein R1 is tert-butyl.

Preferred Trialkyloxoniumfluoroborate are trimethyl and triethyloxonium fluoroborate.

In the hydroxylation according to step (b) it is assumed that a compound of general formula (IV) is formed:

In the compound of the formula (III), alkyloxy (alkyl-O-) is preferably methoxy or ethoxy. As the alkylating agent, dimethyl sulfate or diethyl sulfate is preferably used. Further suitable alkylating agents are, for example, diazoalkanes, such as diazomethane or diazoethane, furthermore trialkyloxonium fluoroborates, such as trimethyl- or triethyloxonium fluoroborate.

As the preferred hydroxylating agent, osmium tetraoxide (0s04) or osmium tetraoxide is used in combination with a suitable oxidizing agent. In this case, the osmium tetraoxide is used in the forms known per se. Preferably, microencapsulated osmium tetraoxide is used. The production of microencapsulated osmium tetraoxide is described, for example, in S. Nagayama et al., J. Org. Chem. 1998, 63, 6094/5. If osmium tetraoxide is used in combination with a suitable oxidizing agent, osmium tetraoxide is preferably used in catalytic amounts. The oxidizing agents suitable for this case are, for example, hydrogen peroxide, metal chlorates, preferably alkali metal chlorates, e.g. Sodium chlorate or potassium chlorate, but e.g. also silver chlorate (AgCIO), tert-butyl hydroperoxide, N-methyl-morpholine N-oxide, alkali metal periodates, e.g. Sodium periodate or potassium periodate, alkali metal permanganates, e.g. Sodium permanganate or potassium permanganate, oxygen, or alkali metal hypochlorites, preferably sodium hypochlorite or potassium hypochlorite.

The conversion of the hydroxylated compound into a compound of formula (I) or the preparation of the de-hydrolactam from the hydroxylated compound of general formula (IV) [step (c)] is done for example by reacting the hydroxylated compound with piperidino sulfur trifluoride and subsequent neutralization, for example with sodium bicarbonate. Further possibilities for the conversion of the hydroxylated compound of the formula (IV) into a compound of the formula (I) [step (c)] are, for example, the reaction with thionyl chloride or phosgene and subsequent neutralization, for example with sodium bicarbonate.

As the solvent, numerous organic anhydrous compounds can be used, such as tert-butyl alcohol, diethyl ether, acetone, benzene, dioxane, tetrahydrofuran, chloroform, dimethylformamide or pyridine.

The dehydration of the compound of formula (IV) may also be carried out under basic conditions, e.g. by heating with lithium carbonate, if appropriate in the presence of lithium bromide, in dimethylformamide or dimethylacetamide, or by heating in pyridine or collidine.

The following examples illustrate the invention.

O

(IV)

3

CH 695 422 A5

Example 1 [0017]

To a solution of 3.33 g (10 mM) of 3-oxo-4-aza-5-alfa-androstane-17-beta-carboxylic acid methyl ester (1) in 25 ml of CH 2 Cl 2, 2.0 g (= 10.6 mM) of triethyloxonium fluoroborate are added. The reaction mixture is then stirred for 5 hours at room temperature, then cooled to about 5 ° C and treated with a 50% K2CO3 solution until a pH of about 8 is reached. The precipitated KBF4 is filtered off and washed with CH 2 Cl 2. The aqueous phase is separated and extracted with CH 2 Cl 2. The organic layer is washed with water, dried with Na 2 SO 4 and evaporated in a water jet vacuum. The resulting residue is dissolved in ethanol to 40 ° C and the solution stirred for 16 hours at a constant temperature. Concentration of the solvent yields a mixture of the two isomeric compounds (2) and (3) which can be characterized spectroscopically and, if desired, separated into the two components by chromatography on silica gel. However, it may be further processed directly in accordance with process steps (b) and (c) of the present invention.

Example 2 [0019]

MeOH j✓rf 'yesNjO-,

Mol. WL: ÎS8.59

A mixture of 3.74 g (10 mM) of 3-oxo-4-aza-5-alfa-androstane-17-beta-carboxylic acid t-butylamide (4) and 0.22 ml (2.3 mM) of dimethyl sulfate in 20 ml of toluene is heated with stirring to 80 ° C. Subsequently, at a constant temperature within 30 minutes, additional 0.73 ml (7.7 mM) dissolved in 10 ml of toluene are added dropwise. After completion of the addition, stirring is continued for 5 hours at 80.degree. The reaction mixture, cooled to room temperature (RT), is treated with vigorous stirring with a solution of 415 mg of NaOH in 0.7 ml of water and 20 ml of methanol and stirring is continued at about 50 ° C. for 20 minutes. The cooled to RT reaction mixture is mixed with 100 ml of toluene and 100 ml of water. The aqueous phase is separated off and the organic layer is washed again with water, dried and evaporated in a water jet vacuum. The mixture thus obtained, consisting of the two isomeric compounds (5) and (6), can be processed further directly according to the invention.

4

CH 695 422 A5

Example 3 [0021]

To a solution of 0.5 g (2 mM) OsO and 5.0 g of N-methyl-morpholine-N-oxide (19 mM) in 30 ml of THF and 100 ml of tBuOH are added in portions 6.8 / g (19 mM) -Ethoxy-4-aza-androst-2-en-17-carboxylic acid methyl ester (3) a mixture of the two isomeric azasteroids (2) and (3)] is added. The reaction mixture is further stirred for 48 hours, then discharged on ice-water and extracted three times with 250 ml of ether. The organic phases are washed successively with 150 ml of dilute aqueous HCl, then with water, then with dilute aqueous NaHCO 3 solution and again with water, dried with Na 2 SO 4 and evaporated in vacuo. The residue is dissolved in CH 2 Cl, filtered through 10 times the amount of alumina and then chromatographed in toluene / ethyl acetate (4: 1) on 30 times the weight of silica gel. Evaporation of the eluates and optionally by additional purification, the pure hydroxylactam (7) is recovered.

Example 4 [0023]

(6) (8)

To a suspension of encapsulated osmium tetroxide [EC OsOJ, prepared according to S. Nagayama et al., J. Org. Chem. 1998, 63, 6094, containing about 0.12 g (5 mol%) of osmium tetroxide, in 100 ml of a 1: 1: 1 mixture of water / acetone / acetonitrile, 3.88 g (= 10 mM) of imino ether of the formula (6 ) (see Example 2) and 1.17 g (10 mM) of N-methyl-morpholine-N-oxide. The reaction mixture is stirred for 12 hours at room temperature and then separated by filtration from MC 0s04. The filtrate is mixed with water and methylene chloride and worked up as usual. By distilling off the organic solvent, the corresponding Hydroxylactam (8) is recovered. It can be used directly, without further purification as the starting material for the subsequent reaction stage.

Example 5

A solution of 1.95 g (5 mM) of hydroxylactam (8), prepared according to Example 4, in 30 ml of freshly distilled dimethylacetamide is added after addition of 2 g of finely powdered (dried in a high vacuum) calcium carbonate for 5 hrs ° C stirred. The cooled reaction mixture is separated from insoluble fractions and the filtrate evaporated in vacuo. The crude product thus obtained is dissolved in methylene chloride and washed with water. The organic phase is dried and evaporated in vacuo. Chromatography and recrystallization of the residue from ethyl acetate / water gives pure finasteride.

Example 6

A cooled to minus 60 ° C solution of 675 mg (= 1.93 mM) of the obtained in Example 3 hydroxylated compound (7) are dissolved in 15 ml CH CI with 0.5 ml piperidino-sulfur trifluoride (prepared by reaction of SF4 with tri-methylsilylpiperidine) mixed and stirred for 1.5 hours under nitrogen at -60 ° C. After careful addition of 1.5 ml of water, the mixture is warmed to 5 ° C and extracted with CHCl. The organic phase is washed neutral with dilute sodium bicarbonate solution and then with water, dried and evaporated. The solid residue is chromatographed on 30 g of silica gel. The fractions eluted with CH 2 Cl 2 / hexane / ethyl acetate mixtures (increasing polarity) give, after crystallization, the pure dehydrolactam.

5

CH 695 422 A5

Claims (1)

claims 1. Process for the preparation of 17β-substituted 4-aza-androst-1-en-3-one compounds of the general formula (I): O "r (I) wherein R is optionally substituted, linear or branched (C -C12) -alkyl or (C -C) -alkenyl; Phenyl or benzyl; a radical -OR, or a radical -NHR, or a radical -NR R; 1 1 1 12. R is optionally substituted, linear or branched (C -C -t) -alkyl or (C -C -alkenyl), or phenyl; Rg is methyl, ethyl or propyl; or ■ "!" '"' '' '' - • • • denotes that (a) a compound of the general formula (II): -NR 1 R 2 denote a 5- or 6-membered heterocyclic ring, (II) in which R has the abovementioned meanings, with a suitable alkylating agent, preferably with a dialkyl sulfate, a diazoalkane or a trialkyloxonium fluoroborate, on the oxygen atom of the lactam moiety to form the compound of the general formula (III): Alkyl n {IH) in which R has the meanings given above, alkylated, (b) subsequently oxidizing the compound of general formula (III) with a suitable hydroxylating agent, preferably with osmium tetraoxide (0s04) or with osmium tetraoxide in combination with a suitable oxidizing agent, and (c) converting the resulting hydroxylated compound into the compound of formula (I). 2. The method according to claim 1, characterized in that R is linear or branched (C1-C) -alkyl, preferably methyl, ethyl, propyl or n-butyl, sec-butyl or tert-butyl, preferably tert-butyl; or a rest -OR, or 4th a rest -NHR ,, or a rest NRiR2 ' preferably -NHR means. 3. The method according to claim 1 or 2, characterized in that R is linear or branched (C is - preferably methyl, ethyl, propyl, n-butyl, sec-butyl or tert-butyl, preferably tert-butyl. CJ-alkyl, pre-process according to claim 1, characterized in that Rg in the rest NRiRg methyl means. 5. The method according to claim 1 or 2, characterized in that the substituent -NR1R2 as a 5- or 6-membered heterocyclic ring is a radical of piperidine or pyrrolidine. 6. The method according to claim 1 or 2, characterized in that R is the substituent -NHR1 and R is tert-butyl. 7. The method according to any one of claims 1 to 6, characterized in that is used as the alkylating agent Dimethylsul- 6 CH 695 422 A5 fat, diethyl sulfate, diazomethane, diazoethane, trimethyl or triethyloxonium fluoroborate. 8. The method according to any one of claims 1 to 7, characterized in that microencapsulated Osmiumtetraoxid used as the hydroxylating agent. 9. The method according to claim 8, characterized in that Osmiumtetraoxid in kataiytischen amounts and in combination with at least one oxidizing agent selected from hydrogen peroxide, metal chlorates, tert-butyl hydroperoxide, N-methyl-morpholine-N-oxide, alkali metal periodates, alkali metal permanganates , Oxygen and alkali metal hypochlorites. A process according to claim 9, characterized in that osmium tetraoxide is used in catalytic amounts and in combination with at least one oxidizing agent selected from sodium chlorate, potassium chlorate, silver chlorate, sodium periodate, potassium periodate, sodium permanganate, potassium permanganate, sodium hypochlorite and potassium hypochlorite. 11. The method according to claim 1, characterized in that the reaction of the hydroxylated compound according to reaction step (c) with piperidinosulfur trifluoride, thionyl chloride or phosgene and subsequent neutralization is performed. 12. The method according to claim 1, characterized in that the reaction of the hydroxylated compound according to reaction step (c) is carried out under basic conditions, preferably by heating with lithium carbonate, optionally in the presence of lithium bromide, in dimethylformamide or dimethylacetamide, or by heating in pyridine or collidine , 7