CH695338A5 - A process for introducing a 1,2 double bond at 3-oxo-4-azasteroidverbindungen. - Google Patents

Description

CH 695 338 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-androstanes 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 5-alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia or is used by alopecia 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):

[0004]

wherein

R is optionally substituted, linear or branched (C 1 -C 2) -alkyl or (C 3 -C 6) -alkenyl; Phenyl or benzyl; a radical -OR1 or a radical -NHR1, or a radical -NR ^;

R 1 is optionally substituted, linear or branched (C 1 -C 4 alkyl or (C 1 -C 6) alkenyl, or optionally substituted phenyl;

R 2 is methyl, ethyl or propyl; or -NR ^ is a 5- or 6-membered heterocyclic ring,

mean, characterized in that (A1) in a compound of general formula (II)

wherein R has the meaning given above, the 3-keto-4-aza group (Lactamgruppierung) is reacted with a silylating agent, or

(A2) in a compound of the above general formula (II), wherein R has the meaning given above, which reacts 3-keto-4-aza group with oxalyl chloride or malonyl chloride,

(B) then the resulting compound with a suitable hydroxylating agent, preferably with osmium tetraoxide (0s04) or with osmium tetraoxide in combination with a suitable oxidizing agent, oxidized, and

(C) converting the compound [obtained in step (B)] into the compound of formula (I) by removing, in any order, the substituents introduced by silylation or reaction with oxalyl chloride or malonyl chloride [step (C1) ] and introduce the A1 double bond into the 1/2-position [step (C2)]. Preferably, by removing the substituents introduced by the silylation or the reaction with oxalyl chloride or malonyl chloride [step (C1)] and then introducing the A1 double bond into the 1/2-position [step (C2)].

R is preferably linear or branched (C 1 -C 4) -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 residue NHRr is 1 1

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

In the radical -NR R, R 2 is preferably methyl.

The substituent -NR 1 R 2 as a 5- or 6-membered heterocyclic ring is preferably a radical of pi-peridine or pyrrolidine.

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

As the silylating agent for silylating the NH group [in the step (A1)], it is preferable to use an (alkyl) 3 Si (halogen), e.g. (CH) SiCl, or bistrimethylsilyltrihaloacetamide, bistrimethylsilylacetamide, hexamethyldi-

2

CH 695 338 A5

silazane and / or bistrimethylurea, preferably bistrimethylsilyltrifluoroacetamide, or a trialkylsilyl, preferably trimethylsilyltrifluoromethanesulfonate. The reaction conditions for the silylation are known from EP 0 473 226.

For the reaction of the compound of general formula (II) or the Laktamgruppierung [according to step (A2)] with oxalyl chloride (oxalic chloride) or malonyl chloride (malonic chloride) oxalyl chloride is preferred. The reaction conditions for the reaction with oxalyl chloride are known from EP 0 428 366 and are to be used in an analogous manner for the reaction with malonyl chloride or analogously reacting compound.

Suitable hydroxylating agents are, for example, osmium tetraoxide (0s04), hydrogen peroxide, metal chloro-te, preferably alkali metal chlorates, e.g. Sodium chlorate or potassium chlorate, but e.g. also silver chlorate (AgClO 3), 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 or osmium tetraoxide in combination with a suitable oxidizing agent.

As the preferred hydroxylating agent, osmium tetraoxide (0sO 4) or osmium tetraoxide is used in combination with one of the above-mentioned suitable oxidizing agents. In this case, the osmium tetraoxide is used in the forms known per se. Preferably, microencapsulated osmium tetraoxide is used. The preparation 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. Such combinations are known per se and described in the literature. The reaction conditions specified there are also applicable here.

In step (C), the compound obtained according to step (B) is converted into the compound of formula (I). It is important to remove both the introduced with the silylation and / or the reaction with oxalyl chloride or malonyl substituent [step (C1)] and the a1 double bond in the 1/2-position to introduce [step

Substituting in a compound of the above general formula (II), the 3-keto-4-aza grouping (Laktamgruppierung) with a silylating agent to [route (A1)], it proceeds so that then the si -lylated compound according to step (B) oxidized. In step (C), the compound obtained is then converted into the compound of formula (I) by removing the substituents introduced with the silylation [step (C1)] and into the compound thus obtained the a1 double bond in the 1- / 2-position [step (C2)]. The substituents introduced with the silylation are removed, for example, by treating the resulting compound with a suitable acid, preferably with trifluoroacetic acid.

Substituting in a compound of the above general formula (II), the 3-keto-4-aza grouping (Laktamgruppierung) with oxalyl chloride or malonyl chloride to [route (A2)], it proceeds so that one with Oxalyl chloride or malonyl chloride reacted compound according to step (B) oxidized. In step (C), the compound obtained is then converted into the compound of formula (I). In this case, it is only necessary in step (C) to introduce the A1 double bond into the 1/2-position [step (C2)]. Surprisingly, in fact, in the oxidation according to step (B), the bivalent substituent introduced in the reaction with oxalyl chloride or malonyl chloride is also removed; with the oxidation according to step (B), step (C1) is also carried out simultaneously. As a precaution, it is possible to remove any remaining divalent radicals, for example with 2-methylamino) ethanol, and analogous compounds.

It is assumed according to the present invention that after the oxidation step [step (B)] and after the removal of the substituents [step (C1)], the compound of formula (III) is present:

in which then the A'-double bond is introduced. However, the present invention is not bound by this explanation.

The introduction of the A1 double bond in the 1- / 2-position [step (C2)] is done for example by reacting the resulting compound with piperidino sulfur trifluoride and subsequent treatment with sodium bicarbonate. Further possibilities for the introduction of the A1 double bond in the 1/2-position [step (C2)] for obtaining the compound of the formula (I) are, for example, the reaction with thionyl chloride or phosgene and subsequent treatment with sodium bicarbonate.

The introduction of the A1 double bond in the 1/2-position [step (C2)] can also be carried out under basic conditions, e.g. by heating with lithium carbonate, if appropriate in the presence of lithium bromide, in dimethylformamide.

(C2)].

O

(Iii)

3

CH 695 338 A5

or dimethylacetamide, or by heating in pyridine or collidine.

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 following examples illustrate the invention.

example 1

A) A solution of 10 g (26.7 mmol) of 3-oxo-4-aza-5-alfa-androstane-17-beta-carboxylic acid-t-butylamide in 300 ml of methylene chloride and 26.7 ml of pyridine by distilling off 100 concentrated by evaporation of methylene chloride. The cooled to -70 ° C solution is then added dropwise within 10 minutes with 2.56 ml (29.4 mmol) of oxalic acid dichloride according to EP 0 428 366, then slowly heated to 0 ° C and stirred for 150 minutes under nitrogen. By adding 200 mg of caprolactam, the small excess of oxalyl chloride present is bound and the solution is evaporated to dryness in a water-jet vacuum on a rotary evaporator. The resulting crude vinylidene-oxazolidinedione-derivatvate can be used directly in the next step without further purification.

B) to a solution of 0.5 g (2 mmol) 0s04 and 5.0 g of N-methylmorpholine-N-oxide (19 mmol) in 30 ml of tetrahydrofuran (THF) and 100 ml of tert-butanol with stirring in portions total 8.15 g (19 mmol) of the crude product prepared according to section a) were added. The reaction mixture is further stirred for 5 hours, then discharged on ice water and extracted three times with 250 ml of ether. The organic phases are washed successively with 150 ml each of dilute aqueous hydrochloric acid (HCl), water, dilute aqueous NaHCO 3 solution and again with water, dried over Na 2 SO 4 and evaporated in vacuo.

C) A solution of the crude product obtained in the preceding stage b) in 100 ml of methylene chloride is cooled to -60 ° C and reacted at a temperature maintained below -50 ° C with 2- (methylamino) ethanol (10.0 g). The course of the reaction is monitored by means of thin-layer chromatography or HPLC. If necessary, add smaller amounts of the aminoalcohol in portions and slowly raise the temperature to 20 ° C. The reaction solution is filtered from any solid fractions present and washed successively with water, dilute aqueous HCl, water, dilute aqueous NaHCOg solution and with water, dried and evaporated in a water-jet vacuum.

A cooled to -60 ° C solution of 810 mg of the crude product thus obtained is stirred in 15 ml of CH Ci with 0.5 ml of piperidino sulfur trifluoride (prepared by reaction of SF4 with trimethylsilylpiperidine) and stirred for 125 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 CH Cl2. 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, pure dehydrolactam (finasteride).

Example 2

A) A solution of 5.6 g (15.0 mmol) of 3-oxo-4-aza-5-alfa-androstane-17-beta-carboxylic acid-t-butylamide and diisopropylethylamine (22 ml, 230 mmol) in 300 ml of methylene chloride is cooled according to EP 0 473 226 to -78 ° C and treated dropwise with Trimethylsilyltrifluoromethansulfonat (TMSOTf, 22 ml, 114 mmol). The temperature is slowly raised to -20 ° C and the reaction mixture is stirred for two hours, then allowed to stand at room temperature overnight and evaporated carefully in vacuo.

B) To a solution of 0.5 g (2 mmol) 0s04 and 3.6 g of N-methylmorpholine-N-oxide (15 mmol) in 30 ml of THF and 100 ml of tert-butanol are added in portions 7.78 g (15 mmol ) of the crude product prepared according to section a). The reaction mixture is further stirred for 5 hours, then discharged to ice-water and extracted three times with 250 ml of ether. The organic phases are washed successively with 150 ml of dilute aqueous HCl, water, dilute aqueous NaHCO 3 solution and again with water, dried over Na S 4 and evaporated in vacuo. The crude product thus obtained is dissolved in trifluoroacetic acid (50 ml) and stirred at 50 ° C for 5 hours. The solution is evaporated in a water jet vacuum, the residue is combined with water (200 ml) in 200 ml of methylene chloride, the organic solution with dilute aqueous sodium bicarbonate solution and then washed with water, dried and evaporated in vacuo. The crude finasteride thus obtained is purified by chromatography and then crystallized.

Claims (12)

claims 1. Process for the preparation of 17β-substituted 4-aza-androst-1-en-3-one compounds of the general formula (I): wherein R is optionally substituted, linear or branched (C 1 -C 4) -alkyl or (C 1 -C 12) -alkenyl; Phenyl or benzyl 4 CH 695 338 A5 cyl; a radical -OR ^ or a radical -NHR ^ or a radical -NR ^; R is optionally substituted, linear or branched (C 1 -C 2) -alkyl or (C 1 -C 3) -alkenyl, or optionally substituted phenyl; Rg is methyl, ethyl or propyl; or -NR ^ is a 5- or 6-membered heterocyclic ring, characterized in that (A1) in a compound of the general formula (II): wherein R has the meaning given above, the 3-keto-4-aza group (Laktamgruppierung) reacting with a silylating agent, or (A2) in a compound of the above general formula (II) wherein R is as defined above, reacting the 3-keto-4-aza group with oxalyl chloride or malonyl chloride, (B) then the resulting compound with a suitable hydroxylating agent, preferably with osmium tetraoxide (0s04) or with osmium tetraoxide in combination with a suitable oxidizing agent, oxidized, and (C) converting the compound [obtained in step (B)] to the compound of formula (I) by removing in any order the substituent introduced by the silylation or the reaction with oxalyl chloride or malonyl chloride [step (C1)] and A1 double bond in the 1/2-position introduces [step (C2)]. 2. The method according to claim 1, characterized in that the introduced with the silylation or the reaction with oxalyl chloride or malonyl chloride substituents removed [step (C1)] and then the a1 double bond in the 1- / 2-position [step ( C2)]. 3. The method according to claim 1 or 2, characterized in that R is linear or branched (C 1 -C 4) -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 a radical -NHR ^ means. 4. The method according to any one of claims 1 to 3, characterized in that R is linear or branched (C -C) alkyl, preferably methyl, ethyl, propyl, n-butyl, sec-butyl or tert-butyl, preferably tert Butyl, means. 5. The method according to claim 1, characterized in that in the radical -NR1R2, the substituent R2 is methyl. 6. The method according to claim 1, characterized in that -NR1R2 as a 5- or 6-membered heterocyclic ring is a residue of piperidine or pyrrolidine. 7. The method according to claim 1, characterized in that in the radical -NHR1, the substituent R1 is tert-butyl. 8. The method according to any one of claims 1 to 7, characterized in that as the silylating agent for silylation of the NH group is an (alkyl) 3Si (halogen), preferably (CH) SiCl, or Bistrimethylsilyltrihalogenacetamid, Bistrimethylsilylacetamid, hexamethyldisilazane and / or Bistrimethylharnstoff, Preferably bistrimethylsilyl trifluoro-roacetamide, or a trialkylsilyl trifluoromethanesulfonat, preferably trimethylsilyl trifluoromethansulfonat used. 9. The method according to any one of claims 1 to 8, characterized gekennnzeichnet that as the hydroxylating agent osmium tetraoxide, hydrogen peroxide, a metal chlorate, preferably alkali metal chlorates, preferably sodium chlorate or potassium chlorate, silver chlorate (AgClO3), tert-butyl hydroperoxide, N-methyl-morpholine -N-oxide, an alkali metal peri-odate, preferably sodium periodate or potassium periodate, an alkali metal permanganate, preferably sodium permanganate or potassium permanganate, oxygen, or an alkali metal hypochlorite, preferably sodium hypochlorite or potassium hypochlorite, or osmium tetraoxide in combination with one of said oxidants. 10. The method according to any one of claims 1 to 9, characterized in that one removes the introduced with the silylating substituents by treatment with trifluoroacetic acid. 11. The method according to any one of claims 1 to 10, characterized in that one carries out the introduction of the A1 double bond in the 1- / 2-position by reaction with piperidino sulfur trifluoride or by reaction with thionyl chloride or phosgene. 12. The method according to any one of claims 1 to 10, characterized in that one carries out the introduction of the A1 double bond in the 1- / 2-position 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. 5