CH704740B1 - Preparation of 17 beta-substituted 4-aza-androst-1-en-3-one compounds, e.g. finasteride, by 3-stage dehydrogenation of corresponding 1,2-saturated compound - Google Patents

Abstract

Production of 17beta -substituted 4-aza-androst-1-en-3-one compounds (I) involves: (1) protecting 3-keto-4-aza (lactam) group of 4-aza-androstan-3-one (II); (2) contacting product with dehydrogenation catalyst in presence of optionally substituted benzoquinone, allyl methyl carbonate, allyl ethyl carbonate and/or allyl propyl carbonate, to introduce 1(2)-double bond; and (3) removing protecting(s) groups. Production of 17beta -substituted 4-aza-androst-1-en-3-one compounds of formula (I) (or their salts if R = OH) involves: (1) introducing protecting groups into the 3-keto-4-aza (lactam) group of a corresponding 4-aza-androstan-3-one compound of formula (II) to give a product of formula (III) (and optionally also protecting R if R = OH); (2) contacting the product with a dehydrogenation catalyst in presence of optionally substituted benzoquinone, allyl methyl carbonate, allyl ethyl carbonate and/or allyl propyl carbonate, to introduce a 1(2)-double bond; and (3) removing the protection introduced in step (1). [Image] R : OH; 1-12C alkyl or 2-12C alkenyl (both optionally substituted); or phenyl, benzyl, OR 1, NHR 1or NR 1R 2; R 1H; or 1-12C alkyl, 2-12C alkenyl or phenyl (all optionally substituted); R 2H, Me, Et or propyl; or NR 1R 25- or 6-membered heterocycle; R 3trialkylsilyl; R 4alkoxycarbonyl (preferably tert. butoxycarbonyl (Boc)), phenoxycarbonyl or trialkylsilyl; or R 3+ R 4-CO-CO- or -CO-Y-CO-; Y : (CR 5R 6) n, C(R 5)=C(R 6) or o-phenylene; R 5, R 6H, 1-8C alkyl or alkenyl, optionally substituted phenyl or benzyl; n : 1-4. ACTIVITY : Cytostatic; Antialopecia. MECHANISM OF ACTION : 5alpha -Reductase Inhibitor.

Description

The present invention relates to a method for introducing a 1,2-double bond in 3-oxo-4-azasteroids by dehydration of 3-oxo-4-azasteroids saturated in the 1,2-position, in particular by dehydrogenation of 17β-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 17β-substituted 4-aza-5-alfa-androstanes with a 1,2-double bond by oxidizing the corresponding 1,2-dihydro compound using benzene-selenic anhydride. Further processes for introducing a 1,2 double bond in 17β-substituted 4-aza-5-alfa-androstanes are also described in EP 0 298 652, EP 0 428 366 and EP 0 473 225, for example. 17β-substituted 4-aza-5-alfa-androstanes with 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 beginning prostate hyperplasia or used by alopecia androgenetica. The known processes for the preparation of these compounds have specific disadvantages, so that there is a need for improved alternative processes. The present invention relates to such an alternative method of manufacture.

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):

wherein R is hydroxyl, linear or branched (C1-C12) -alkyl or (C1-C12) -alkenyl; Phenyl or benzyl; a radical -OR1, or a radical -NHR1, or a radical -NR1R2; R1 linear or branched (C1-C12) -alkyl or (C1-C12) -alkenyl, or phenyl; R2 methyl, ethyl or propyl; or -NR1R2 a 5- or 6-membered heterocyclic ring, and for R = hydroxyl also a pharmaceutically approved salt thereof, mean, characterized in that one (A) into the 3-keto-4-aza grouping (lactam grouping) of a compound of the general formula (II):

Introduces protective groups, so that a compound of the general formula (III) is formed:

wherein R3 trialkylsilyl, or together with R4 the radical -C (O) -C (O) -and R4 alkyloxycarbonyl or phenyloxycarbonyl, preferably Boc (= tert-butyloxycarbonyl); or trialkylsilyl, or together with R3 the radical -C (O) -C (O) -, and in which, if R is hydroxyl, this has optionally reacted with a protective group; (B) the compound obtained [according to step (A)] reacts in the presence of (i) a dehydrogenation catalyst and in the presence of (ii) optionally substituted benzoquinone, allyl methyl carbonate, allyl ethyl carbonate and / or allyl propyl carbonate, the Δ <1> double bond in 1 - / 2 position is introduced, and (C) the protective groups R3 and R4 are removed and, for R = hydroxyl, the compound obtained is optionally converted into a salt.

R preferably denotes linear or branched (C1-C6) -alkyl, preferably methyl, ethyl, propyl or n-butyl, sec-butyl or tert-butyl, preferably tert-butyl; or a radical -OR1, or a radical -NHR1, or a radical -NR1R2. The radical -NHR1 is preferred.

If R is hydroxyl (or the radical -C (O) R is carboxyl), a pharmaceutically approved salt of the compound of formula (I) can also be prepared according to the invention, preferably an alkali metal salt, an alkaline earth metal salt or an ammonium salt, preferably a salt of sodium, potassium or ammonium, preferably a salt of sodium or potassium.

R1 preferably means linear or branched (C1-C6) -alkyl, preferably methyl, ethyl, propyl, n-butyl, sec-butyl or tert-butyl, preferably tert-butyl.

In the radical -NR1R2, R2 is preferably methyl.

The substituent -NR1R2 as a 5- or 6-membered heterocyclic ring preferably denotes a radical of piperidine or pyrrolidine.

The substitute -NHR1, in which R1 is tert-butyl, is preferred.

R3 preferably means trimethylsilyl, or together with R4 the radical -C (O) -C (O) -.

R4 preferably means Boc, trimethylsilyl, or together with R3 the radical -C (O) -C (O) -. R4 preferably denotes Boc or together with R3 the radical -C (O) -C (O) -.

R4 as alkyloxycarbonyl preferably means isobutyloxycarbonyl, tert-butyloxycarbonyl, tert-amyloxycarbonyl, cyclobutyloxycarbonyl, 1-methylcylobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, 1-methylcyclohexyl, preferably tert-butyloxycarbonyl.

To introduce the protective group trialkylsilyl, d.i. for the silylation of the NH group and / or the oxygen atom or the OH group [according to step (A)], an (alkyl) 3Si (halogen), e.g. (CH3) 3SiCl, or bis-trimethylsilyltrihaloacetamide, bis-trimethylsilylacetamide, hexamethyldisilazane and / or bis-trimethylurea, preferably bis-trimethylsilyltrifluoroacetamide, or a trialkylsilyl-trifluoromethanesulfonate, preferably trimethylsiluorosilyl-tri-tri-methylsilane. The reaction conditions for the silylation are known from EP 0 473 226.

For the introduction of a protective group in which R3 together with R4 denote the radical -C (O) -C (O) -, the compound of the general formula (II) or the lactam grouping [according to step (A)] with oxalyl chloride (oxalic acid chloride) or malonyl chloride (malonic acid chloride), with oxalyl chloride being preferred. The reaction conditions for the reaction with oxalyl chloride are known from EP 0 428 366 and can be used in an analogous manner for the reaction with malonyl chloride or compounds reacting similarly.

For the introduction of a protecting group in which R4 is alkyloxycarbonyl, e.g. tert-Butyloxycarbonyl (Boc), one proceeds in a manner known per se by adding the compound of the general formula (II) e.g. with Boc-anhydride (Boc-O-Boc) {[(CH3) 3C-OC (O)] 2-O} or with Boc-carbamate [(CH3) 3C-OC (O) -N (C1-4-alkyl ) 2]. Here, Boc stands for the other identically reacting compounds, that is to say compounds in which the tert-butyl radical has been replaced by another identically reacting radical such as, for example, the radicals mentioned tert-amyl, cyclobutyl, cyclopentyl or cyclohexyl. Such analogous reactions are described in large numbers in the specialist literature. If R3 signifies trialklylsilyl and R4Boc, the protective group Boc is first introduced and then silylated.

In step (B) the compound obtained in step (A) is reacted in the presence of (i) a dehydrogenation catalyst and in the presence of (ii) optionally substituted benzoquinone, allyl methyl carbonate, allyl ethyl carbonate and / or allyl propyl carbonate, the Δ <1 > -Double bond is introduced in the 1/2 position. The dehydrogenation catalyst is preferably selected from compounds (salts and complexes) of the group of transition metals of the Periodic Table of the Elements, in particular selected from compounds of the metals of Group VIII of the Periodic Table, in particular of iron (Fe), ruthenium (Ru) and osmium (Os) ; Cobalt (Co), rhodium (Rh) and iridium (Ir); Nickel (Ni), palladium (Pd) and platinum (Pt) as well as group IB, i.e. of copper (Cu), silver (Ag) and gold (Au). Compounds of metals of group VIII of the periodic table are preferred. Compounds or dehydrogenation catalysts based on rhodium (Rh), palladium (Pd) and platinum (Pt) are particularly preferred. Palladium compounds are preferred. Examples of such palladium compounds are: Pd (0) compounds such as tris (dibenzylidene acetone) di-palladium-chloroform complex and Pd (II) compounds such as PdCl2, Pd (dppe) 2, [dppe = bis- (1,2-biphenylphosphino) ethane] , Pd (dppe) Cl2, Pd (OAc) 2, Pd (dppe) (OAc) 2, π-allyl-Pd complexes, preferably π-allyl-Pd-chloride dimer. Pd (0) compounds are preferred, in particular tris (dibenzylideneacetone) di-palladium chloroform complex. These compounds or salts and complexes are known per se and have been described in the literature.

For thermal stabilization of the palladium complex, an additional complexing agent such as 2,2'-bipyridyl or 1,10-phenanthroline can be used, preferably 2,2'-bipyridyl.

For the sake of explanation, the mechanism of catalysis can be stated that a Pd species on the C atom in the 2-position with cleavage of the oxygen protecting group [e.g. the -Si (CH3) 3 group] is added. A subsequent beta-hydrogen splitting off at the carbon atom in the 1-position leads to the desired Δ <1> double bond in the 1- / 2-position and releases another palladium species, which is returned to the catalytic cycle. Instructions for this reaction mechanism can be found in Tetrahydron Letters, page 4783, (1984). However, the present invention is not limited to this explanation.

A substituted quinone can also be used as the quinone, for example a quinone substituted by C1-4-alkyl, halogen, cyano or nitro. Such quinones are known per se.

In step (C) the compound obtained is then converted into the compound of the formula (I) by removing the protective groups introduced. The easiest way to do this is by treatment with a suitable acid, for example with formic acid, acetic acid and / or trifluoroacetic acid, preferably with formic acid. The compound obtained can then, if appropriate, be converted into a pharmaceutically acceptable salt in a manner known per se (for R = hydroxyl).

Preferably, the compound obtained is recrystallized. This recrystallization can be carried out in non-polar solvents such as gasoline, heptane, hexane and toluene, preferably toluene. The compound of the formula (I) is in particular the compound 17β- (N-tert-butylcarbamoyl) -4-aza-androst-1-en-3-one (finasteride) mentioned at the outset, which comes in two polymorphic forms , namely polymorphic form I and polymorphic form II, occurs, with form I being preferred. Form I is formed, for example, in the recrystallization of crude finasteride obtained according to the invention from a saturated solution of toluene (about one part of crude finasteride in about six parts of toluene) on cooling to about 25 ° C. The polymorphic form II arises, for example, in the recrystallization of crude finasteride obtained according to the invention from a solution of toluene (about one part of crude finasteride in about six parts of toluene) on cooling to about 0 ° C.

For the method described with steps (A) - (C) numerous organic anhydrous compounds can be used as solvents, such as toluene, gasoline, hexane, heptane, tert-butyl alcohol, diethyl ether, acetone, benzene, dioxane, tetrahydrofuran , Chloroform, dimethylformamide or pyridine. The following examples illustrate the invention.

Example 1 (substitution of dihydrofinasteride with Boc on the nitrogen atom of the 3-keto-4-aza group)

10 g (26.7 mmol) of dihydrofinasteride are placed in tetrahydrofuran (THF) and cooled to -78 ° C. 15 ml (30 mmol) of lithium diisopropylamide solution (LDA solution) are metered into the suspension obtained and the clear solution is stirred for about 30 minutes. Then a solution of 6.7 g (30 mmol) of Boc anhydride in THF is metered in. The solution is now allowed to warm to room temperature (RT). After the usual work-up, a moist yellow powder is obtained which is stored in a drying cabinet overnight and used directly in Example 2.

Example 2 (silylation of the compound prepared in example 1)

1 g (2.1 mmol) of N-Boc-dihydrofinasteride are dissolved in THF. 2.3 ml (4.6 mmol) of LDA solution are added to the clear yellow solution while cooling with methanol and ice. The suspension is stirred for about 45 minutes, after which 0.46 g (4.2 mmol) of trimethylchlorosilane (TMSCl) is added dropwise at 18-20 ° C. The clear solution is concentrated and the residue is taken up in heptane. After filtration, the filtrate is concentrated as far as possible and the honey-brown oil obtained is used in the following stage (Example 3).

Example 3 (introduction of the Δ <1> double bond)

0.145 g (0.65 mmol) of palladium acetate are dissolved in acetonitrile with 0.07 g (0.65 mmol) of benzoquinone and presented. 0.8 g (1.5 mmol) of the silyl compound, prepared according to Example 3, are taken up in acetonitrile and added dropwise at an internal temperature (IT) of 20-25 ° C. The reaction mixture is stirred for 8 hours and purified over silica gel. The slightly colored clear solution is concentrated at AT 55-60 ° C. The resulting solid substance is used in Example 4.

Example 4 (removal of protective groups and crystallization)

A) 0.5 g of the solid substance from Example 3 are mixed with 20 g (0.175 mol) of trifluoroacetic acid and refluxed for about 15 hours. The trifluoroacetic acid is used as a reagent and as a solvent. After cooling, the reaction mixture is poured onto a mixture of 300 g of saturated sodium bicarbonate solution and 50 g of ice and extracted with 20 g of ethyl acetate.

B) The brown crude product obtained in the previous section a) is dissolved in toluene at 90 ° C (mass ratio toluene: raw material = 6: 1) and cooled to 20-25 ° C. The precipitated, gray-white mass is filtered off at 20-25 ° C and dried. Finasteride Polymorph I is obtained.

Example 5 (introduction of the Δ <1> double bond)

2.0 g (3.7 mmol) of silyl enol ether from Example 2 are mixed with 1.29 g (11.1 mmol) of allyl methyl carbonate in acetonitrile. The mixture is added dropwise to a solution of 166 mg (0.74 mmol) palladium (II) acetate in acetonitrile at 60-70 ° C. After 1-2 hours at reflux, work-up is carried out as described in Example 3. 3 g of solid substance are obtained.

Example 6 (introduction of the Δ <1> double bond)

A) 60 g of the oxalyl enol ether (R3 and R4 of the enol ether with -C (O) -C (O) - connected, 0.134 mol) are combined with 29 g of allyl methyl carbonate (0.250 mol) and 11.1 g of tris (dibenzylideneacetone) diPalladium Chloroform complex (8 mol%, 10.7 mmol) and 5 g of 2,2'-bipyridyl (32 mmol, 3eq or catalyst) heated to reflux temperature for about 4-6 hours. Any Pd which has precipitated is removed by filtration and the residue is taken up in methanol. Any precipitated complex is filtered off and the clear, almost colorless solution is concentrated as far as possible.

B) The brown crude product obtained in section a) above is dissolved in toluene at 90 ° C (mass ratio toluene: raw material = 6: 1) and cooled to 20-25 ° C. The precipitated, gray-white mass is filtered off at 20-25 ° C and dried. Finasteride Polymorph I is obtained.

Claims (19)

1. Process for the preparation of 17β-substituted 4-aza-androst-1-en-3-one compounds of the general formula (I): wherein R is hydroxyl, linear or branched (C1-C12) -alkyl or (C1-C12) -alkenyl; Phenyl or benzyl; a radical -OR1, or a radical -NHR1, or a radical -NR1R2; R1 linear or branched (C1-C12) -alkyl or (C1-C12) -alkenyl, or phenyl; R2 methyl, ethyl or propyl; or -NR1R2 a 5- or 6-membered heterocyclic ring, and for R = hydroxyl also a pharmaceutically approved salt thereof, mean, characterized in that one (A) into the 3-keto-4-aza grouping of a compound of the general formula (II): Introduces protective groups, so that a compound of the general formula (III) is formed: wherein R3 trialkylsilyl, or together with R4 the radical -C (O) -C (O) - and R4 alkyloxycarbonyl or phenyloxycarbonyl, preferably tert-butyloxycarbonyl (Boc); or trialkylsilyl, or together with R3 the radical -C (O) -C (O) -, and in which, if R is hydroxyl, this has optionally reacted with a protective group; (B) the compound obtained is reacted in the presence of (i) a dehydrogenation catalyst and in the presence of (ii) optionally substituted benzoquinone, allyl methyl carbonate, allyl ethyl carbonate and / or allyl propyl carbonate, the Δ <1> double bond being introduced in the 1/2 position will, and (C) the protective groups R3 and R4 are removed and, for R = hydroxyl, the compound obtained is optionally converted into a salt. 2. The method according to claim 1, characterized in that R is linear or branched (C1-C6) -alkyl, preferably methyl, ethyl, propyl or n-butyl, sec-butyl or tert-butyl, preferably tert-butyl; or a radical -OR1, or a radical -NHR1, or a radical -NR1R2, preferably a radical -NHR1, preferably -NH-tert-butyl. 3. The method according to claim 1 or 2, characterized in that R1 is linear or branched (C1-C6) -alkyl, preferably methyl, ethyl, propyl, n-butyl, sec.-butyl or tert.-butyl, preferably tert.- Butyl, means. 4. The method according to claim 1 or 2, characterized in that in the radical -NR1R2 the substituent R2 is methyl. 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 any one of claims 1 to 5, characterized in that R3 is trimethylsilyl, or together with R4 is the radical -C (O) -C (O) -. 7. The method according to any one of claims 1 to 5, characterized in that R4 alkyloxycarbonyl, preferably isobutyloxycarbonyl, tert-butyloxycarbonyl, tert-amyloxycarbonyl, cyclobutyloxycarbonyl, 1-methylcylobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, preferably 1-methylcyloxycarbonyl, tertiary. -Butyloxycarbonyl, means. 8. The method according to any one of claims 1 to 7, characterized in that R4 is Boc, trimethylsilyl, or together with R3 the radical -C (O) -C (O) -, preferably Boc or together with R3 the radical -C (O) ) -C (O) -, means. 9. The method according to any one of claims 1 to 7, characterized in that Boc anhydride or Boc carbamate or an analogous compound in which the tert-butyl radical is used to introduce the protective group into the compound of the general formula (II) is through tert-amyl, cyclobutyl, cyclopentyl or cyclohexyl. 10. The method according to any one of claims 1 to 9, characterized in that the dehydrogenation catalyst is selected from compounds of the metals of group VIII of the Periodic Table of the Elements, preferably from compounds of iron, ruthenium and osmium; Cobalt, rhodium and iridium; Nickel, palladium and platinum; preferably from compounds based on rhodium, palladium and platinum. 11. The method according to claim 10, characterized in that the dehydrogenation catalyst is selected from Pd (0) compounds, and is preferably the tris (dibenzylideneacetone) di-palladium-chloroform complex. 12. The method according to claim 10, characterized in that the dehydrogenation catalyst is selected from Pd (II) compounds, preferably from PdCl2, Pd (dppe) 2, Pd (dppe) Cl2, Pd (OAc) 2, Pd (dppe) ( OAc) 2 and / or from π-allyl-Pd complexes, preferably π-allyl-Pd-chloride dimer. 13. The method according to any one of claims 1 to 12, characterized in that for thermal stabilization of the dehydrogenation catalyst, preferably the palladium salt or the palladium complex, an additional complexing agent, preferably 2,2'-bipyridyl or 1,10-phenanthroline, preferably 2,2' -Bipyridyl, is present. 14. The method according to any one of claims 1 to 13, characterized in that a substituted benzoquinone is used as benzoquinone, preferably a benzoquinone substituted by C1-4-alkyl, halogen, cyano or nitro. 15. The method according to any one of claims 1 to 14, characterized in that the introduced protective groups are removed by treatment with a suitable acid, preferably by treatment with formic acid, acetic acid and / or trifluoroacetic acid, preferably with formic acid. 16. The method according to any one of claims 1 to 15, characterized in that the compound obtained, wherein R is hydroxyl, in an alkali metal salt, an alkaline earth metal salt or an ammonium salt, preferably in a salt of sodium, potassium or ammonium, preferably in a salt of sodium or potassium. 17. The method according to any one of claims 1 to 15, characterized in that the compound of formula (I) obtained is crystallized from an apolar solvent, preferably from gasoline, heptane, hexane and / or toluene, preferably from toluene. 18. The method according to claim 17, characterized in that the compound of formula (I) obtained, which is 17β- (N-tert-butylcarbamoyl) -4-aza-androst-1-en-3-one, from a saturated solution of toluene at a temperature of about 25 ° C in the polymorphic form I crystallized. 19. The method according to claim 17, characterized in that the compound of formula (I) obtained, which is 17β- (N-tert-butylcarbamoyl) -4-aza-androst-1-en-3-one, from a saturated solution of toluene at a temperature of about 0 ° C in the polymorphic form II crystallized.